KIT inhibitors, compounds, pharmaceutical compositions, and methods of use thereof

Abstract

The present invention provides compounds and compositions useful for inhibiting receptor tyrosine kinase KIT. The compounds and compositions provided herein are useful for the prevention or treatment of one or more KIT-mediated diseases or disorders (e.g., cancer, autoimmune diseases, allergic diseases, inflammatory diseases, fibrosis, metabolic disorders, and neurodegenerative diseases).

Description

Technical Field

[0001] The present application relates to inhibitors of the receptor tyrosine kinase KIT (c-KIT) and methods of using the same, for example, to prevent or treat one or more KIT-mediated diseases or conditions. Background Art

[0002] Protein phosphorylation is an important cellular regulatory mechanism as many enzymes and receptors are activated / inactivated through phosphorylation and dephosphorylation events utilizing kinases and phosphatases. Receptor tyrosine kinases (RTKs) play important roles in a variety of cellular processes including growth, motility, differentiation, and metabolism. KIT (c-KIT) is a tyrosine kinase receptor that acts as a facultative oncoprotein and regulates the development and function of a variety of different cell lineages. These cell lineages include hematopoietic progenitors, melanocytes, germ cells, and mast cells (MCs), all of which are significantly affected by loss-of-function mutations in KIT or its cytokine ligand stem cell factor (SCF) (Valent et al., Theranostics 2020, 10(23), 10743).

[0003] Abnormalities in KIT expression and function are associated with several human diseases. KIT activation has been associated with various human cancers including mastocytosis, germ cell tumors, small cell lung cancer, gastrointestinal stromal tumors (GIST), acute myeloid leukemia, neuroblastoma, melanoma, ovarian cancer, and breast cancer (Turner et al., Blood 1992, 80: 374-381; Heinrich et al., J Clin Oncol 2002, 20: 1692-1703). KIT activation in these tumors is usually achieved through one or more of three mechanisms: autocrine and / or paracrine stimulation of SCF, cross-activation of other kinases, and / or acquisition of activating mutations (Hirota et al., Science (Wash DC) 1998, 279: 577-580; Heinrich et al., 2002). Pharmacological inhibition of KIT or SCF by small molecule inhibitors or specific antibodies can also affect the function of healthy and oncogenic cells expressing the KIT receptor (Valent et al., J Allergy Clin Immunol 2022, 149:1866-74). In fact, several kinase inhibitors have been approved for the treatment of GIST and other malignancies with KIT activation in humans and non-human mammals.

[0004] Clearly, KIT and its ligands are involved in the development and function of a variety of different cell lineages. These cell lineages include cells in parts of the central nervous system, interstitial cells of Cajal in the intestine, taste cells, and several hematopoietic cell lineages other than MCs, including dendritic cells, eosinophils, and ILC2s (Tsai M et al., J. Allergy Clin. Immunol. 2022, 149:1845-54). Although most lineages lose KIT upon differentiation, MCs are one of the few cell types that retain KIT expression even after differentiation into mature cells (Lennartsson J et al., Stem Cells 2005, 23:16-43).

[0005] KIT and its ligand SCF play a leading role in the development and maturation of tissue MCs. Compared with other myeloid cells, MCs have a longer lifespan. This is because it may take several months for a fully mature MC to develop from a stem cell through a multipotent and directed MC progenitor cell. In addition, some mature tissue MCs survive for months or possibly years when they reside in the local tissue microenvironment (Cerny-Reiterer S et al., Oncotarget 2015, 6:3071-84). When mature, MCs are located in local tissue sites that express SCF and other growth factors and cytokines, supporting long-term survival and effector cell functions.

[0006] As multifunctional cells of the innate immune system, MCs contribute to adaptive immune responses and also play a role in allergic and other inflammatory responses. MCs express high-affinity receptors for IgE and produce a large number of bioactive substances, some of which are stored in cytoplasmic granules for rapid release (Valent et al., 2020). MCs can be activated by many different stimuli (including allergens via IgE and IgE receptors), IgG immune complexes, complement and cytokines, toxins, venoms and bacterial byproducts, and certain drugs (Valent et al., 2020). MC activation occurs in many different disease states and pathologies. Clinical symptoms can be severe and pose challenges to daily life. In patients with allergic (atopic) disorders and mastocytosis, MC activation can be substantial and systemic, even leading to overt anaphylaxis.

[0007] Imatinib is a small molecule TKI that blocks KIT and other kinases, including ABL1, ABL2, PDGFR, and others. Imatinib was originally developed as a targeted cancer drug and is approved by both the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of systemic mastocytosis (SM), in which the number of MCs is excessively elevated. The rationale for the use of imatinib in SM comes from several studies. In one report, patients with chronic myeloid leukemia were treated with imatinib for several years. During this treatment, a decrease in the number of MCs in the bone marrow was found after 12 months; after 24 months, MCs were almost completely absent from bone marrow sections (Cerny-Reiterer S et al., 2015). At the same time, serum tryptase levels, a marker of MC activation, decreased to undetectable levels (Cerny-Reiterer S et al., 2015). In another study, 62 patients with poorly controlled or uncontrolled severe asthma who developed airway hyperresponsiveness despite maximal medical therapy were treated with imatinib (400 mg orally daily) for 24 weeks. Treatment with imatinib was found to be more effective in reducing airway hyperresponsiveness and bronchoalveolar lavage fluid tryptase levels in these patients compared with placebo control (Cahill KN et al., NEngl J Med 2017, 376:1911-20). Taken together, these data suggest that treatment with drugs targeting KIT may lead to partial or even complete eradication of the MC lineage in patients with various MC diseases. In addition, some of these TKIs can also inhibit IgE-dependent activation of MCs and basophils (Valent et al., 2022). Therefore, highly specific KIT inhibitors may provide a new and safer treatment option for patients with severe MC disease. Summary of the invention

[0008] Compounds useful for inhibiting KIT and compositions comprising such compounds are provided herein, inter alia. Specifically, disclosed herein are methods for inhibiting KIT activity by administering to a subject a therapeutically effective amount of one or more compounds or compositions provided herein, for preventing or treating KIT-mediated diseases or conditions associated with improper regulation of kinase signaling of MCs, such as cancer, autoimmune diseases, allergic diseases, inflammatory diseases, fibrosis, metabolic disorders, and neurodegenerative diseases.

[0009] In one embodiment, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof:

[0010] [Chemical formula 1]

[0011]

[0012] in:

[0013] R 1 It is hydrogen, C 1-3 -alkyl or C 1-3 -deuterated alkyl,

[0014] R 2 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group,

[0015] R 3 is hydrogen or C 1-4 -alkyl,

[0016] Ring A:

[0017] [Chemical formula 2]

[0018]

[0019] is a group of the formula:

[0020] [Chemical formula 3]

[0021]

[0022] The wavy line indicates the point of attachment to the rest of the molecule.

[0023] R 4 Yes-N(R A )(R B ),-OR A or optionally selected from halogen, C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl substituents substituted with 1-2 -alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino groups,

[0024] R 5 is hydrogen, halogen or C 1-4 -alkyl,

[0025] R 6 YesRA ,

[0026] X 1 and X 2 Each independently is N or CR 7 ,

[0027] R 7 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group,

[0028] X 3 is N or C (R 8 ) n ,

[0029] R 8 is hydrogen or a halogen,

[0030] n is an integer value of 1 or 2,

[0031] Y is O or S,

[0032] The dashed line is a single bond or a double bond, provided that when X 3 is N or C (R 8 ) n , where n is an integer value of 1, the dashed line is a double bond,

[0033] R A is optionally selected from halogen, C 3-6 -Cycloalkyl, aryl, heterocyclic and heteroaryl groups or more substituted C 1-4 -alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted with C 3-6 -cycloalkyl; optionally selected from halogen, cyano, hydroxyl, C1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted aryl, wherein the C 1-4 -Alkyl may further optionally have halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino is substituted with a heterocyclic group; optionally selected from halogen, cyano, hydroxy, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino) or one or more groups substituted heterocyclic group; or optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino) group or groups substituted with heteroaryl; and

[0034] R B It is hydrogen, C 1-4 -alkyl or C 3-6 - cycloalkyl, or

[0035] -N(R A )(R B ) at R A and R B Together with the nitrogen atom, it forms a radical optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted with a N-containing heterocyclic ring.

[0036] In another embodiment, provided herein is a compound represented by the following formula (Ia), or a pharmaceutically acceptable salt thereof:

[0037] [Chemical formula 4]

[0038]

[0039] in:

[0040] R 1 is hydrogen or C 1-3 -alkyl,

[0041] R 2 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group,

[0042] R 3 is hydrogen or C 1-4 -alkyl,

[0043] Ring A 1 :

[0044] [Chemical formula 5]

[0045]

[0046] is a group of the formula:

[0047] [Chemical formula 6]

[0048]

[0049] The wavy line indicates the point of attachment to the rest of the molecule.

[0050] R 4 Yes-N(R A )(R B ),-OR A or optionally selected from halogen, C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl substituents substituted with 1-2 -alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino groups,

[0051] R 4A Yes-N(R A )(R B) or is optionally selected from halogen, C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl substituents substituted with 1-2 -alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino groups,

[0052] R 5 is hydrogen, halogen or C 1-4 -alkyl,

[0053] R 6 YesR A ,

[0054] X 1 and X 2 Each independently is N or CR 7 ,

[0055] R 7 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group,

[0056] X 3 is N or C (R 8 ) n ,

[0057] R 8 is hydrogen or a halogen,

[0058] n is an integer value of 1 or 2,

[0059] Y is O or S,

[0060] The dashed line is a single bond or a double bond, provided that when X 3 is N or C (R 8 ) n , where n is an integer value of 1, the dashed line is a double bond,

[0061] R A is optionally selected from halogen, C 3-6 -Cycloalkyl, aryl, heterocyclic and heteroaryl groups or more substituted C 1-4-alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; optionally selected from halogen, cyano, hydroxy, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted with C 3-6 -cycloalkyl; optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted aryl, wherein the C 1-4 -Alkyl may further optionally have halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino is substituted with a heterocyclic group; optionally selected from halogen, cyano, hydroxy, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino) or one or more groups substituted heterocyclic group; or optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino) group or groups substituted with heteroaryl; and

[0062] R B It is hydrogen, C 1-4 -alkyl or C 3-6 - cycloalkyl, or

[0063] -N(R A )(R B ) at R A and R B Together with the nitrogen atom, it forms a radical optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted with N-containing heterocyclic ring,

[0064] Provided that the compound is not

[0065] [Chemical formula 7]

[0066] .

[0067] Another embodiment includes a method of preventing or treating a KIT-mediated disease or condition in a subject by administering to the subject a therapeutically effective amount of one or more of the disclosed compounds or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising the compounds.

[0068] Also provided herein is the use of one or more disclosed compounds, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for preventing or treating a KIT-mediated disease or condition.

[0069] In another embodiment, provided herein is one or more disclosed compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the disclosed compounds, for use in preventing or treating a KIT-mediated disease or condition. DETAILED DESCRIPTION

[0070] definition

[0071] The term "alkyl", used alone or as part of a larger moiety such as "haloalkyl", "cycloalkyl", "alkylamino", etc., means a saturated aliphatic straight or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 4 carbon atoms, i.e., C 1-4 -alkyl. As used herein, "C 1-4 "-Alkyl" means a group having 1 to 4 carbon atoms in a straight or branched chain arrangement and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0072] The term "deuterated alkyl" means an alkyl group having one or more deuterium atoms. 1-3 "-deuterated alkyl" means a group having 1 to 3 carbon atoms and includes monodeuterated, dideuterated and trideuterated methyl groups.

[0073] The term "alkylamino" means an amino group substituted with one or more alkyl groups. For example, "mono(C 1-4 -alkyl)amino or di(C 1-4 The term "-alkyl)amino" includes methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, (ethyl)(methyl)amino, (isopropyl)(methyl)amino and (tert-butyl)(methyl)amino.

[0074] The term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms. 1-4 "-haloalkyl" includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, bromomethyl, fluoroethyl, difluoroethyl, dichloroethyl and chloropropyl. In one aspect, C 1-4 Examples of -haloalkyl include difluoromethyl or trifluoromethyl, and in another aspect, C 1-4 Examples of the -haloalkyl group include a trifluoromethyl group.

[0075] The term "halogen" or "halo" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0076] The term "aryl" means a monocyclic or bicyclic aromatic hydrocarbon group, such as phenyl, naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl and indenyl. In one aspect, examples of aryl include phenyl or naphthyl, and in another aspect, examples of aryl include phenyl.

[0077] The term "cycloalkyl" means a 3-12 membered saturated aliphatic cyclic hydrocarbon group. It can be a monocyclic, bicyclic (e.g., bridged, spiro-fused or fused bicyclic) or tricyclic. For example, a monocyclic C 3-6 -Cycloalkyl means a group having 3 to 6 carbon atoms arranged in a single ring. For example, "C 3-6 "-Cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl and spiro[2.3]hexyl.

[0078] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring group having at least one (usually 1 to 4, more usually 1 or 2) heteroatom (e.g., oxygen, nitrogen or sulfur). Examples of such heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl and imidazopyridinyl.

[0079] The term "heterocyclic group" refers to a monocyclic or bicyclic non-aromatic ring group having at least one (usually 1 to 4, more usually 1 or 2) heteroatom (e.g., oxygen, nitrogen, or sulfur). Each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones). Some of the bonds constituting the heterocyclic group may be unsaturated bonds. A portion of the bicyclic heterocyclic group may have aromaticity. Examples thereof include a state in which a monocyclic heterocyclic group having a 5-membered and 6-membered ring is fused with a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, an oxazole ring, a thiazole ring, or a pyridine ring, and a state in which an at least partially unsaturated hydrocarbon ring group having a 5-membered and 6-membered ring is fused with a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, an oxazole ring, a thiazole ring, or a pyridine ring. Examples of such heterocyclic groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyridazinyl, tetrahydropyridazinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, dihydrothiopyranyl, piperidinyl, ]oxazinyl, morpholinyl, thiomorpholinyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, tetrahydrobenzoxazolyl, dihydrofuropyridinyl, dihydropyrazolomorpholinyl, pyridodioxinyl, dihydroazabenzofuranyl, dihydroazaisobenzofuranyl, dihydroazaindolyl, 2-oxaspiro[3.5]nonyl and 2-oxaspiro[3.3]heptyl.

[0080] By -N(R A )(R B ) at R A and R B Examples of the "N-containing heterocyclic ring" formed together with a nitrogen atom include azetidine, pyrrolidine, pyrazole, imidazole, triazole, tetrazole, piperidine, dihydropyridine, tetrahydropyridine, piperazine, morpholine and thiomorpholine.

[0081] If a group is described as "substituted", a non-hydrogen substituent is in the place of a hydrogen substituent on a carbon, sulfur or nitrogen of the substituent. Thus, for example, a substituted alkyl is an alkyl group in which at least one non-hydrogen substituent replaces a hydrogen substituent on an alkyl substituent. For illustration, a monofluoroalkyl group is an alkyl group substituted with a fluorine substituent and a difluoroalkyl group is an alkyl group substituted with two fluorine substituents. It should be recognized that if more than one substituent is present on a substituent, each non-hydrogen substituent may be the same or different (unless otherwise specified).

[0082] Compounds with one or more chiral centers may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric and epimeric forms as well as racemates and mixtures thereof. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration. The term "geometric isomer" refers to a compound having at least one double bond, wherein the double bond may exist in the cis (also known as syn or entgegen (E)) or trans (also known as anti or zusammen (Z)) form and mixtures thereof. When a disclosed compound is named or described by structure without indicating stereochemistry, it should be understood that the name or structure encompasses one or more possible stereoisomers or geometric isomers, or a mixture of the included stereoisomers or geometric isomers.

[0083] When geometric isomers are described by name or structure, it is understood that the named or described isomer is present in a greater degree than the other isomer, that is, the geometric purity of the named or described geometric isomer is greater than 50% by weight, such as at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. Geometric purity is determined by dividing the weight of the named or described geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.

[0084] A racemic mixture means 50% one enantiomer and 50% the corresponding enantiomer. When a compound having one chiral center is named or described without indicating the stereochemistry of the chiral center, it is understood that the name or structure includes both possible enantiomeric forms of the compound (e.g., enantiomerically pure, enantiomerically enriched, or racemic). When a compound having two or more chiral centers is named or described without indicating the stereochemistry of the chiral center, it is understood that the name or structure includes all possible diastereomeric forms of the compound (e.g., diastereomerically pure, diastereomerically enriched, and equimolar mixtures of one or more diastereomers, such as racemic mixtures).

[0085] Enantiomeric and diastereomeric mixtures can be separated into their component enantiomers or stereoisomers by known methods, such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallization of the compound as a chiral salt complex or crystallization of the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically or enantiomerically pure intermediates, reagents and catalysts by known asymmetric synthesis methods.

[0086] When a compound is designated by a name or structure that indicates a single enantiomer, the optical purity (also referred to as "enantiomeric purity") of the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9%, unless otherwise indicated. The optical purity is the weight of the named or described enantiomer in the mixture divided by the total weight of the two enantiomers in the mixture.

[0087] When the stereochemistry of a disclosed compound is named or described by a structure, and the named or described structure contains more than one stereoisomer (e.g., as a diastereomeric pair), it is understood that one of the included stereoisomers or any mixture of the included stereoisomers is included. It is further understood that the stereoisomeric purity of the named or described stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. In this case, the stereoisomeric purity is determined by dividing the total weight of the stereoisomers contained in the mixture by the total weight of all stereoisomers in the mixture.

[0088] It should be understood that when a compound is represented herein by a structural formula or by a chemical name herein, all other tautomeric forms that may exist for the compound are encompassed by the structural formula.

[0089] The term "pharmaceutically acceptable salt" as used herein refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation and allergic reaction, and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in J. Pharm. Sci., 1977, 66: 1-19.

[0090] Pharmaceutically acceptable salts of the compounds disclosed herein are included in the present disclosure. Compounds having a basic amino group can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and organic acids (e.g., acetic acid, trifluoroacetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). Compounds having an acidic group such as a carboxylic acid can form pharmaceutically acceptable salts with a pharmaceutically acceptable base. Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (e.g., sodium and potassium salts), and alkaline earth metal salts (e.g., magnesium and calcium salts).

[0091] In addition, the present invention also includes various hydrates or solvates of the compounds of formula (I) and pharmaceutically acceptable salts thereof and any crystalline polymorphs. In addition, the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

[0092] It should be noted that the compounds of formula (Ia) and (Ib) are included in the scope of the compound of formula (I), and thus suitable examples or embodiments of the compounds of formula (Ia) and (Ib) refer to those exemplified as the compounds of formula (I).

[0093] Compositions and compounds of the present invention

[0094] In a first embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof:

[0095] [Chemical formula 8]

[0096]

[0097] in:

[0098] R 1 It is hydrogen, C 1-3 -alkyl or C 1-3 -deuterated alkyl,

[0099] R 2 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group,

[0100] R 3 is hydrogen, aryl, carboxyl, -CO-O-(C 1-4 -alkyl) or C 1-4 -alkyl,

[0101] Ring A:

[0102] [Chemical formula 9]

[0103]

[0104] is a group of the formula:

[0105] [Chemical formula 10]

[0106]

[0107] The wavy line indicates the point of attachment to the rest of the molecule.

[0108] R 4 Yes-N(R A )(R B ),-OR A or optionally selected from halogen, C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl substituents substituted with 1-2 -alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino groups,

[0109] R 5 is hydrogen, halogen or C 1-4 -alkyl,

[0110] R 6 YesR A ,

[0111] X 1 and X 2 Each independently is N or CR 7 ,

[0112] R 7 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group,

[0113] X 3 is N or C (R 8 ) n ,

[0114] R 8 is hydrogen or a halogen,

[0115] n is an integer value of 1 or 2,

[0116] Y is O or S,

[0117] The dashed line is a single bond or a double bond, provided that when X 3 is N or C (R 8 )n , where n is an integer value of 1, the dashed line is a double bond,

[0118] R A is optionally selected from halogen, hydroxy, -O-(C 1-4 -alkyl), C 3-6 -Cycloalkyl, aryl, heterocyclic and heteroaryl groups or more substituted C 1-4 -alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted with C 3-6 -cycloalkyl; optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted aryl, wherein the C 1-4 -Alkyl may further optionally have halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino is substituted with a heterocyclic group; optionally selected from halogen, cyano, hydroxy, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C1-4 -alkyl)amino or di(C 1-4 -alkyl)amino) or one or more groups substituted heterocyclic group; or optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino) group or groups substituted with heteroaryl; and

[0119] R B It is hydrogen, C 1-4 -alkyl or C 3-6 - cycloalkyl, or

[0120] -N(R A )(R B ) at R A and R B Together with the nitrogen atom, it forms a radical optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted with a N-containing heterocyclic ring.

[0121] In a second embodiment, the present invention provides a pharmaceutical composition according to the first embodiment, which is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[0122] [Chemical formula 11]

[0123]

[0124] in:

[0125] R 1 is hydrogen or C 1-3 -alkyl,

[0126] R 2 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4-alkyl)amino group,

[0127] R 3 is hydrogen or C 1-4 -alkyl,

[0128] Ring A:

[0129] [Chemical formula 12]

[0130]

[0131] is a group of the formula:

[0132] [Chemical formula 13]

[0133]

[0134] The wavy line indicates the point of attachment to the rest of the molecule.

[0135] R 4 Yes-N(R A )(R B ),-OR A or optionally selected from halogen, C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl substituents substituted with 1-2 -alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino groups,

[0136] R 5 is hydrogen, halogen or C 1-4 -alkyl,

[0137] R 6 YesR A ,

[0138] X 1 and X 2 Each independently is N or CR 7 ,

[0139] R 7 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4-alkyl)amino group,

[0140] X 3 is N or C (R 8 ) n ,

[0141] R 8 is hydrogen or a halogen,

[0142] n is an integer value of 1 or 2,

[0143] Y is O or S,

[0144] The dashed line is a single bond or a double bond, provided that when X 3 is N or C (R 8 ) n , where n is an integer value of 1, the dashed line is a double bond,

[0145] R A is optionally selected from halogen, C 3-6 -Cycloalkyl, aryl, heterocyclic and heteroaryl groups or more substituted C 1-4 -alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted with C 3-6 -cycloalkyl; optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted aryl, wherein the C 1-4 -Alkyl may further optionally have halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino or mono(C 1-4-alkyl)amino or di(C 1-4 -alkyl)amino is substituted with a heterocyclic group; optionally selected from halogen, cyano, hydroxy, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino) or one or more groups substituted heterocyclic group; or optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino) group or groups substituted with heteroaryl; and

[0146] R B It is hydrogen, C 1-4 -alkyl or C 3-6 - cycloalkyl, or

[0147] -N(R A )(R B ) at R A and R B Together with the nitrogen atom, it forms a radical optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted with a N-containing heterocyclic ring.

[0148] In a third embodiment, the present invention provides a pharmaceutical composition according to the second embodiment, wherein R 1 is hydrogen, methyl, ethyl or isopropyl, and R 3 is hydrogen or methyl.

[0149] In a fourth embodiment, the present invention provides a pharmaceutical composition according to the third embodiment, wherein the ring A:

[0150] [Chemical formula 14]

[0151]

[0152] is a group of the formula:

[0153] [Chemical formula 15]

[0154] .

[0155] In a fifth embodiment, the present invention provides a pharmaceutical composition according to any one of the first to fourth embodiments, wherein R 4 Yes-N(R A )(R B ) or -OR A , and R 5 is hydrogen, where R A is optionally selected from halogen, C 3-6 -C substituted with one or more of: cycloalkyl, phenyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl and indazolyl. 1-4 -alkyl, wherein the C 3-6 -cycloalkyl, phenyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl and indazolyl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted with C 3-6 -cycloalkyl; optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted phenyl, wherein the C 1-4 -alkyl may be further substituted by tetrahydropyranyl, piperidinyl or piperazinyl, each of which may be further substituted by halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; tetrahydropyranyl, piperidinyl or piperazinyl, each of which may be selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4-haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group; or pyridyl, pyrimidinyl or indazolyl, each of which may be selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino groups; and R B It's methyl.

[0156] In a sixth embodiment, the present invention provides a pharmaceutical composition according to the fifth embodiment, wherein R A is isopropyl; is selected from halogen, cyano, C 1-4 -alkyl and C 1-4 -C substituted with one or more haloalkyl groups 3-6 -cycloalkyl; is selected from halogen, cyano, C 1-4 -alkyl and C 1-4 -phenyl substituted with one or more groups of haloalkyl; or substituted with one or more groups selected from halogen, cyano, C 1-4 -alkyl and C 1-4 -pyridyl substituted with one or more haloalkyl groups.

[0157] In a seventh embodiment, the present invention provides a pharmaceutical composition according to the first embodiment, wherein the compound is selected from

[0158] N-((6-(2-fluorophenoxy)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0159] N-((6-(4-fluorophenoxy)pyridin-3-yl)methyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0160] 6-Fluoro-N-((6-(2-fluorophenoxy)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0161] N-((6-(2,4-difluorophenoxy)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0162] N-((2-(4-fluorophenoxy)thiazol-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0163] N-(1-(6-(4-fluorophenoxy)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0164] (S)-N-(1-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0165] N-((6-((4-fluorophenyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0166] N-((6-((4-fluorophenyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0167] N-((6-((4,4-difluorocyclohexyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0168] N-((6-(isopropyl(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0169] 1-methyl-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0170] (S)-N-(1-(6-((4-fluorophenyl)(methyl)amino)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0171] (S)-1-methyl-N-((6-(2-methylpyrrolidin-1-yl)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0172] N-((6-(1-(4-fluorophenyl)ethyl)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0173] N-((6-(fluoro(4-fluorophenyl)methyl)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0174] N-((1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0175] N-((1-(4,4-difluorocyclohexyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0176] N-((1-(2-fluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0177] 1-methyl-2-oxo-N-((1-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0178] N-((3-(2,6-difluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0179] N-((6-(3-cyanophenoxy)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0180] N-((6-(cyclopropyl(4-fluorophenyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0181] 1-methyl-N-((6-(methyl(1-methylpiperidin-4-yl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0182] N-((2-((4,4-difluorocyclohexyl)amino)thiazol-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0183] 1-methyl-N-((6-(methyl(3-((4-methylpiperazin-1-yl)methyl)phenyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0184] N-(1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0185] N-((6-((4,4-difluorocyclohexyl)(methyl)amino)pyrazin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0186] 1-methyl-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyrazin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0187] 1-methyl-N-((6-(methyl(spiro[2.3]hexan-5-yl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0188] (S)-N-((6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0189] (R)-N-((6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0190] N-((6-((3-(difluoromethoxy)cyclobutyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide and its cis- and trans-isomers,

[0191] 1-(trideuterated methyl)-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0192] 6-fluoro-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0193] 1-methyl-N-((6-(methyl(3-(trifluoromethoxy)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide and its cis- and trans-isomers,

[0194] N-((6-(((1S,3R)-3-fluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0195] N-((6-(((1R,3S)-3-fluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0196] N-((6-((6,6-difluorobicyclo[3.1.0]hex-3-yl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, and

[0197] N-((6-((4,4-difluorocyclohexyl)(methyl)amino)pyridin-3-yl)methyl)-6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0198] or a pharmaceutically acceptable salt thereof.

[0199] In an eighth embodiment, the present invention provides a compound represented by the following formula (Ia), or a pharmaceutically acceptable salt thereof:

[0200] [Chemical formula 16]

[0201]

[0202] in:

[0203] R 1 It is hydrogen, C 1-3 -alkyl or C 1-3 -deuterated alkyl,

[0204] R 2 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group,

[0205] R 3 is hydrogen, aryl, carboxyl, -CO-O-(C 1-4-alkyl) or C 1-4 -alkyl,

[0206] Ring A 1 :

[0207] [Chemical formula 17]

[0208]

[0209] is a group of the formula:

[0210] [Chemical formula 18]

[0211]

[0212] The wavy line indicates the point of attachment to the rest of the molecule.

[0213] R 4 Yes-N(R A )(R B ),-OR A or optionally selected from halogen, C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl substituents substituted with 1-2 -alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino groups,

[0214] R 4A Yes-N(R A )(R B ) or is optionally selected from halogen, C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl substituents substituted with 1-2 -alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino groups,

[0215] R 5 is hydrogen, halogen or C 1-4 -alkyl,

[0216] R 6 YesR A ,

[0217] X 1 and X 2 Each independently is N or CR 7 ,

[0218] R 7 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group,

[0219] X 3 is N or C (R 8 ) n ,

[0220] R 8 is hydrogen or a halogen,

[0221] n is an integer value of 1 or 2,

[0222] Y is O or S,

[0223] The dashed line is a single bond or a double bond, provided that when X 3 is N or C (R 8 ) n , where n is an integer value of 1, the dashed line is a double bond,

[0224] R A is optionally selected from halogen, hydroxy, -O-(C 1-4 -alkyl), C 3-6 -Cycloalkyl, aryl, heterocyclic and heteroaryl groups or more substituted C 1-4 -alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; optionally selected from halogen, cyano, hydroxyl, C 1-4-alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted with C 3-6 -cycloalkyl; optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted aryl, wherein the C 1-4 -Alkyl may further optionally have halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino is substituted with a heterocyclic group; optionally selected from halogen, cyano, hydroxy, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino) or one or more groups substituted heterocyclic group; or optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino) group or groups substituted with heteroaryl; and

[0225] R B It is hydrogen, C 1-4 -alkyl or C 3-6 - cycloalkyl, or

[0226] -N(R A )(R B ) at R A and R BTogether with the nitrogen atom, it forms a radical optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted with N-containing heterocyclic ring,

[0227] Provided that the compound is not

[0228] [Chemical formula 19]

[0229] .

[0230] In a ninth embodiment, the present invention provides a compound according to the eighth embodiment, which is a compound represented by the following formula (Ia), or a pharmaceutically acceptable salt thereof:

[0231] [Chemical formula 20]

[0232]

[0233] in:

[0234] R 1 is hydrogen or C 1-3 -alkyl,

[0235] R 2 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group,

[0236] R 3 is hydrogen or C 1-4 -alkyl,

[0237] Ring A 1 :

[0238] [Chemical formula 21]

[0239]

[0240] is a group of the formula:

[0241] [Chemical formula 22]

[0242]

[0243] The wavy line indicates the point of attachment to the rest of the molecule.

[0244] R 4 Yes-N(R A )(R B ),-OR A or optionally selected from halogen, C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl substituents substituted with 1-2 -alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino groups,

[0245] R 4A Yes-N(R A )(R B ) or is optionally selected from halogen, C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl substituents substituted with 1-2 -alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino groups,

[0246] R 5 is hydrogen, halogen or C 1-4 -alkyl,

[0247] R 6 YesR A ,

[0248] X 1 and X 2 Each independently is N or CR 7 ,

[0249] R 7 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C1-4 -alkyl)amino group,

[0250] X 3 is N or C (R 8 ) n ,

[0251] R 8 is hydrogen or a halogen,

[0252] n is an integer value of 1 or 2,

[0253] Y is O or S,

[0254] The dashed line is a single bond or a double bond, provided that when X 3 is N or C (R 8 ) n , where n is an integer value of 1, the dashed line is a double bond,

[0255] R A is optionally selected from halogen, C 3-6 -Cycloalkyl, aryl, heterocyclic and heteroaryl groups or more substituted C 1-4 -alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted with C 3-6 -cycloalkyl; optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted aryl, wherein the C 1-4 -Alkyl may further optionally have halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino or mono(C1-4 -alkyl)amino or di(C 1-4 -alkyl)amino is substituted with a heterocyclic group; optionally selected from halogen, cyano, hydroxy, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino) or one or more groups substituted heterocyclic group; or optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino) group or groups substituted with heteroaryl; and

[0256] R B It is hydrogen, C 1-4 -alkyl or C 3-6 - cycloalkyl, or

[0257] -N(R A )(R B ) at R A and R B Together with the nitrogen atom, it forms a radical optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted with N-containing heterocyclic ring,

[0258] Provided that the compound is not

[0259] [Chemical formula 23]

[0260] .

[0261] In the tenth embodiment, the present invention provides a compound according to the ninth embodiment or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, methyl, ethyl or isopropyl, and R 3 is hydrogen or methyl.

[0262] In the eleventh embodiment, the present invention provides a compound according to the tenth embodiment or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Each is independently CR7 , where R 7 is hydrogen or a halogen.

[0263] In the twelfth embodiment, the present invention provides a compound according to the eleventh embodiment or a pharmaceutically acceptable salt thereof, wherein the ring A 1 :

[0264] [Chemical formula 24]

[0265]

[0266] is a group of the formula:

[0267] [Chemical formula 25]

[0268] .

[0269] In the thirteenth embodiment, the present invention provides a compound according to the eighth to twelfth embodiments or a pharmaceutically acceptable salt thereof, wherein R 4 and R 4A Each is -N(R A )(R B ), R 5 is hydrogen, and R 6 YesR A , where R A is optionally selected from halogen, C 3-6 -C substituted with one or more of: cycloalkyl, phenyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl and indazolyl. 1-4 -alkyl, wherein the C 3-6 -cycloalkyl, phenyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl and indazolyl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted with C 3-6 -cycloalkyl; optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted phenyl, wherein the C 1-4 -alkyl may be further substituted by tetrahydropyranyl, piperidinyl or piperazinyl, each of which may be further substituted by halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; tetrahydropyranyl, piperidinyl or piperazinyl, each of which may be selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group; or pyridyl, pyrimidinyl or indazolyl, each of which may be selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino groups; and R B It's methyl.

[0270] In the fourteenth embodiment, the present invention provides a compound according to the thirteenth embodiment or a pharmaceutically acceptable salt thereof, wherein R A is isopropyl; is selected from halogen, cyano, C 1-4 -alkyl and C 1-4 -C substituted with one or more haloalkyl groups 3-6 -cycloalkyl; is selected from halogen, cyano, C 1-4 -alkyl and C 1-4 -phenyl substituted with one or more groups of haloalkyl; or substituted with one or more groups selected from halogen, cyano, C 1-4 -alkyl and C 1-4 -pyridyl substituted with one or more haloalkyl groups.

[0271] In the fifteenth embodiment, the present invention provides a compound according to the eighth embodiment or a pharmaceutically acceptable salt thereof, wherein:

[0272] R 1 It is hydrogen, C 1-3 -alkyl or C1-3 -deuterated alkyl,

[0273] R 2 is hydrogen or a halogen,

[0274] R 3 is hydrogen or C 1-4 -alkyl,

[0275] Ring A 1 :

[0276] [Chemical formula 26]

[0277]

[0278] is a group of the formula:

[0279] [Chemical formula 27]

[0280]

[0281] The wavy line indicates the point of attachment to the rest of the molecule.

[0282] R 4A Yes-N(R A )(R B ),

[0283] R 5 is hydrogen or a halogen,

[0284] X 1 and X 2 Each independently is N or CR 7 ,

[0285] R 7 is hydrogen or a halogen,

[0286] R A is selected from halogen, C 1-4 -haloalkyl and -O-(C 1-4 -haloalkyl) substituted with one or more groups 3-6 -cycloalkyl, and

[0287] R B is hydrogen or C 1-4 -alkyl.

[0288] In the sixteenth embodiment, the present invention provides a compound according to the eighth embodiment, wherein the compound is selected from

[0289] N-((2-(4-fluorophenoxy)thiazol-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0290] N-((6-((4-fluorophenyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0291] N-((6-((4-fluorophenyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0292] N-((6-((4,4-difluorocyclohexyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0293] N-((6-(isopropyl(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0294] 1-methyl-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0295] (S)-N-(1-(6-((4-fluorophenyl)(methyl)amino)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0296] (S)-1-methyl-N-((6-(2-methylpyrrolidin-1-yl)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0297] N-((6-(1-(4-fluorophenyl)ethyl)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0298] N-((6-(fluoro(4-fluorophenyl)methyl)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0299] N-((1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0300] N-((1-(4,4-difluorocyclohexyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0301] N-((1-(2-fluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0302] 1-methyl-2-oxo-N-((1-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0303] N-((3-(2,6-difluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0304] N-((6-(cyclopropyl(4-fluorophenyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0305] 1-methyl-N-((6-(methyl(1-methylpiperidin-4-yl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0306] N-((2-((4,4-difluorocyclohexyl)amino)thiazol-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0307] 1-methyl-N-((6-(methyl(3-((4-methylpiperazin-1-yl)methyl)phenyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0308] N-((6-((4,4-difluorocyclohexyl)(methyl)amino)pyrazin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0309] 1-methyl-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyrazin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0310] 1-methyl-N-((6-(methyl(spiro[2.3]hexan-5-yl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0311] (S)-N-((6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0312] (R)-N-((6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0313] N-((6-((3-(difluoromethoxy)cyclobutyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide and its cis- and trans-isomers,

[0314] 1-(trideuterated methyl)-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0315] 6-fluoro-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0316] 1-methyl-N-((6-(methyl(3-(trifluoromethoxy)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide and its cis- and trans-isomers,

[0317] N-((6-(((1S,3R)-3-fluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0318] N-((6-(((1R,3S)-3-fluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0319] N-((6-((6,6-difluorobicyclo[3.1.0]hex-3-yl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, and

[0320] N-((6-((4,4-difluorocyclohexyl)(methyl)amino)pyridin-3-yl)methyl)-6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide,

[0321] or a pharmaceutically acceptable salt thereof.

[0322] In the 17th embodiment, the present invention provides a compound represented by the following formula (Ib), or a pharmaceutically acceptable salt thereof:

[0323] [Chemical formula 28]

[0324]

[0325] in:

[0326] R 1 It is hydrogen, C 1-3 -alkyl or C 1-3 -deuterated alkyl,

[0327] R 2 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group,

[0328] R 3 is hydrogen, aryl, carboxyl, -CO-O-(C 1-4 -alkyl) or C 1-4 -alkyl,

[0329] Ring A 2 :

[0330] [Chemical formula 29]

[0331]

[0332] Is a group of the formula:

[0333] [Chemical formula 30]

[0334]

[0335] The wavy line indicates the point of attachment to the rest of the molecule.

[0336] R 4B Yes-OR C ,

[0337] R 5 is hydrogen, halogen or C 1-4 -alkyl,

[0338] X 1 and X 2 Each independently is N or CR 7 ,

[0339] R 7 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group,

[0340] R C is optionally selected from halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group or groups substituted with C 3-6 -cycloalkyl.

[0341] In the eighteenth embodiment, the present invention provides a compound according to the seventeenth embodiment or a pharmaceutically acceptable salt thereof, wherein:

[0342] R 1 It is hydrogen, C 1-3 -alkyl or C 1-3 -deuterated alkyl,

[0343] R 2 is hydrogen or a halogen,

[0344] R 3 is hydrogen or C 1-4 -alkyl,

[0345] R 5 is hydrogen or a halogen,

[0346] R 7 is hydrogen or a halogen, and

[0347] R C is selected from halogen, C 1-4 -haloalkyl and -O-(C 1-4 -haloalkyl) substituted with one or more groups 3-6 -cycloalkyl.

[0348] In certain embodiments, the present invention is any one of the compounds described in the example section of the present application; and pharmaceutically acceptable salts and neutral forms of these compounds are also included in the present invention. Specifically, the present invention is any one of the compounds described in Examples 1-147; and pharmaceutically acceptable salts and neutral forms of these compounds are also included in the present invention. In a preferred embodiment, the present invention is any one of Compounds 1-147; and pharmaceutically acceptable salts and neutral forms of these compounds are also included in the present invention.

[0349] Process for preparing the compounds of the present invention

[0350] The present invention discloses a method for preparing a compound of formula (I). Generally speaking, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by reacting a compound of formula (II) or a salt thereof

[0351] [Chemical formula 31]

[0352]

[0353] and a compound of formula (III) or a salt thereof

[0354] [Chemical formula 32]

[0355]

[0356] Prepared by reaction.

[0357] Suitable salts of compounds (II) and (III) can be referred to the salts exemplified for compound (I).

[0358] The reaction is usually carried out in the presence of a conventional condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) or its hydrochloride, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) or propanephosphonic anhydride (T3P), in a conventional solvent such as dichloromethane, chloroform, pyridine, dioxane, tetrahydrofuran or N,N-dimethylformamide.

[0359] The reaction temperature is not critical, and the reaction can be carried out under cooling, at room temperature or under heating.

[0360] This reaction is preferably carried out in the presence of a conventional inorganic base or a conventional organic base.

[0361] The compound obtained by the above-mentioned method can be isolated and purified by conventional methods such as pulverization, recrystallization, chromatography and reprecipitation.

[0362] Detailed synthetic schemes for preparing exemplary compounds of formula (I) and intermediate compounds thereof can be referenced to the following examples and preparations or in analogous or conventional manners.

[0363] Pharmaceutical composition

[0364] The compounds of formula (I) disclosed herein are KIT inhibitors. The pharmaceutical compositions of the present invention comprise one or more KIT inhibitors or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or diluent.

[0365] "Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to substances that facilitate the formulation and / or administration of the active agent and / or absorption by the subject, and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects on the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, physiological saline solutions, lactated Ringer's solutions, physiological sucrose solutions, physiological glucose solutions, adhesives, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, salt solutions (e.g., Ringer's solutions), alcohols, oils, gelatin, carbohydrates such as lactose, straight-chain starch or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and pigments, etc. Such preparations can be sterilized and, if necessary, can be mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, and / or aromatic substances, etc., that do not react adversely with the compounds provided herein or interfere with their activity. Those of ordinary skill in the art will recognize that other pharmaceutical excipients are also suitable for use with the disclosed compounds.

[0366] The pharmaceutical composition of this teaching optionally includes one or more pharmaceutically acceptable carriers and / or diluents, such as lactose, starch, cellulose and glucose. Other excipients may also be included, such as flavoring agents, sweeteners and preservatives, such as methylparaben, ethylparaben, propylparaben and butylparaben. A more complete list of suitable excipients can be found in Handbook of Pharmaceutical Excipients (5th edition, Pharmaceutical Press (2005)). Those skilled in the art will know how to prepare preparations suitable for various types of routes of administration. Conventional procedures and ingredients for selecting and preparing suitable preparations are described in, for example, Remington's Pharmaceutical Sciences (2003-20th edition) and The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. The carrier, diluent and / or excipient is "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0367] Treatment

[0368] Disclosed herein are methods for preventing or treating KIT-mediated diseases or conditions in a subject, particularly KIT-mediated diseases or conditions associated with improper regulation of kinase signaling in mast cells. The method may include administering to the subject a therapeutically effective amount of one or more compounds or compositions of formula (I) provided herein.

[0369] A "subject" is a mammal, preferably a human, but may also be an animal requiring veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0370] In one embodiment, the KIT-mediated disease or condition is cancer. Examples of cancer include, but are not limited to, mastocytosis, mastocytoma, solid tumors, gastrointestinal stromal tumors ("GIST"), small cell lung cancer, non-small cell lung cancer, acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myeloid leukemia, colorectal cancer, gastric cancer, testicular cancer, glioblastoma, astrocytoma, melanoma, mast cell tumor, neuroblastoma, sarcoma, and seminoma.

[0371] In other embodiments, the KIT-mediated disease or condition is an autoimmune disease. Examples of autoimmune diseases include, but are not limited to, multiple sclerosis, psoriasis, inflammatory bowel diseases, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, localized and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjögren's syndrome, systemic arteritis nodosa, autoimmune enteropathy, and proliferative glomerulonephritis.

[0372] In some embodiments, the KIT-mediated disease or condition is an allergic disease. Examples of allergic diseases include, but are not limited to, asthma, severe asthma, allergic rhinitis, chronic rhinitis, allergic sinusitis, allergic syndrome, urticaria, food allergies, seasonal allergies, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, necrotizing venules of the skin, insect bite skin inflammation, and blood-sucking parasite infestation.

[0373] In other embodiments, the KIT-mediated disease or condition is an inflammatory disease. Examples of inflammatory diseases include, but are not limited to, rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and eosinophilic esophagitis.

[0374] In other embodiments, the KIT-mediated disease or condition is fibrosis. Examples of fibrosis include, but are not limited to, pulmonary fibrosis, liver fibrosis, cardiac fibrosis, and myelofibrosis.

[0375] In other embodiments, the KIT-mediated disease or condition is a metabolic disorder. Examples of metabolic disorders include, but are not limited to, diabetes and its chronic complications, obesity, type I diabetes or type II diabetes, hyperlipidemia and dyslipidemia, atherosclerosis, hypertension, and cardiovascular disease.

[0376] In other embodiments, the KIT-mediated disease or condition is a neurodegenerative disease. Examples of neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion disease, motor neuron disease (MND), and amyotrophic lateral sclerosis (ALS).

[0377] In other embodiments, the KIT-mediated disease or condition comprises bone loss, tumor angiogenesis, interstitial cystitis, pulmonary arterial hypertension (PAH), and primary pulmonary hypertension (PPH).

[0378] Method of administration and dosage form

[0379] The exact amount of compound administered to a subject to provide an "effective amount" will depend on the mode of administration, the type and severity of the disease or condition, and the characteristics of the subject, such as general health, age, sex, weight, and drug tolerance. A skilled person will be able to determine an appropriate dosage based on these and other factors. When administered in combination with other therapeutic agents, such as anticancer agents, the "effective amount" of any additional therapeutic agent will depend on the type of drug used. For approved therapeutic agents, suitable dosages are known and can be adjusted by a skilled person based on the subject's condition, the type of condition being treated, and the dosage of the compound of the invention, following, for example, dosages reported in the literature and recommended in the Physician's Desk Reference (57th edition, 2003).

[0380] The term "effective amount" means an amount that produces beneficial or desired results, including clinical results, when administered to a subject, such as an amount that inhibits, suppresses or alleviates the symptoms of the condition being treated in the subject as compared to a control. For example, a therapeutically effective amount can be administered in a unit dosage form (e.g., 0.1 mg to about 50 g per day, or 1 mg to about 5 grams per day; another option is 10 mg to 1 gram per day).

[0381] As used herein, the term "administering" refers to methods that can be used to deliver a composition to a desired biological site of action. These methods include, but are not limited to, intraarticular (in a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhaled, transdermal, rectal, and the like. For administration techniques that can be used for the agents and methods described herein, see, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics, latest edition, Pergamon; and Remington's Pharmaceutical Sciences (latest edition), Mack Publishing Co., Easton, Pa.

[0382] In addition, the compounds of formula (I) can be co-administered with other therapeutic agents. The terms "co-administration", "combined administration" and their grammatical equivalents used herein are intended to cover the administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times. In some embodiments, one or more compounds described herein will be co-administered with other agents. These terms cover the administration of two or more agents to a subject so that the two agents and / or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions, administration at different times in separate combinations, and / or administration in a composition in which two agents are present. Therefore, in some embodiments, the compounds described herein and other agents are administered in a single composition. In some embodiments, the compounds described herein and other agents are mixed in the composition. In some embodiments, the compounds of formula (I) can be used in combination with other agents for treating or preventing KIT-mediated diseases or conditions that are known to have beneficial activity with the compounds of formula (I). For example, compounds of formula (I) may be administered alone or in combination with one or more other anticancer, immunomodulatory, antiallergic, anti-inflammatory, antifibrotic, antimetabolite and anti-neurodegenerative agents for the treatment or prevention of KIT-mediated diseases or conditions.

[0383] The specific mode of administration and dosing regimen will be selected by the attending physician based on the specific circumstances of the case (e.g., subject, disease, disease state involved, specific treatment). Treatment may include daily or multiple daily or less than daily (e.g., weekly or monthly, etc.) dosing over a period of several days to several months or even several years. However, by looking to the dosage of approved compositions using compounds of formula (I) for the prevention or treatment of KIT-mediated diseases or conditions as a guide, one of ordinary skill in the art will immediately recognize appropriate and / or equivalent dosages.

[0384] As will be appreciated by those skilled in the art, the compounds or corresponding pharmaceutical compositions taught herein can be administered to the patient in various forms according to the selected route of administration. The compounds disclosed herein can be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and corresponding formulated pharmaceutical compositions. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical administration. Parenteral administration can be performed by continuous infusion over a selected period of time.

[0385] The pharmaceutical composition of the present invention is formulated to be compatible with its intended route of administration. In one embodiment, the composition is formulated according to conventional procedures to be suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans. In a preferred embodiment, the pharmaceutical composition is formulated for oral or intravenous administration.

[0386] Typically, for oral therapeutic administration, the compounds of the present teachings may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0387] Typically, for parenteral administration, solutions of the compounds of the present teachings can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in alcoholic or non-alcoholic glycerol, liquid polyethylene glycol, DMSO and mixtures thereof and in oils. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth.

[0388] Generally, for injectable use, sterile aqueous solutions or dispersions of the compounds described herein and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions are suitable.

[0389] [Example]

[0390] Synthesis and Preparation of Compound Embodiments

[0391] Abbreviations

[0392] [Table 1]

[0393] Boc tert-Butyloxycarbonyl bs Broad single peak CDI 1,1'-Carbonyldiimidazole d Twin Peaks DAST (Diethylamino)sulfur trifluoride DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane dd Double Twin Peaks DIPEA Diisopropylethylamine DMAP 4-(Dimethylamino)pyridine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DPPA Diphenylphosphoryl azide EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc Ethyl acetate EtOH Ethanol h Hour HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOAt 1-Hydroxy-7-azabenzotriazole HOB 1-Hydroxybenzotriazole HPLC High performance liquid chromatography KO Potassium tert-butoxide LC-MS Liquid chromatography-mass spectrometry m Multi-peak M Moore MeOH Methanol min minute MHz Megahertz N Equivalent acid or base NMR Nuclear Magnetic Resonance <![CDATA[Pd2(dba)3]]> Tris(dibenzylideneacetone)dipalladium(0) PTSA p-Toluenesulfonic acid PyBOP Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate RT Room temperature s Single Peak t Three Peaks t-BuOH Tert-Butanol <![CDATA[T3P]]> Propanephosphonic anhydride TFA Trifluoroacetic acid THF Tetrahydrofuran Xphos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0394] Example-1

[0395] [Chemical formula 33]

[0396]

[0397] Step-1: 6-(2-Fluorophenoxy)nicotinonitrile

[0398] To a stirred solution of 2-fluorophenol (9 g, 80.28 mmol) in DMF (90 mL) was added NaOH (3.53 g, 88.31 mmol) followed by 6-chloronicotinonitrile (11.12 g, 80.28 mmol) and stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and stirring was continued for 2 h. The separated solid was collected by filtration and dried to give the title compound (10 g, 58.1%). LC-MS: 215 [M+H] +

[0399] Step-2: tert-Butyl ((6-(2-fluorophenoxy)pyridin-3-yl)methyl)carbamate

[0400] To a solution of 6-(2-fluorophenoxy)nicotinonitrile (3 g, 14 mmol) in MeOH (40 mL) was added NiCl2·6H2O (1.66 g, 7 mmol) at 0°C, followed by the addition of di-tert-butyl dicarbonate (4.58 g, 21 mmol) dropwise and stirred for 5 min. Then, maintaining the same temperature, NaBH4 (1.06 g, 28.01 mmol) was added portionwise thereto. After stirring at RT for 2 h, the reaction mass was concentrated to remove the solvent, diluted with EtOAc and filtered on a celite bed. The filtrate was washed with water, dehydrated over anhydrous Na2SO4 and concentrated to give the title compound (3.5 g, 78.6%). LC-MS: 319 [M+H] +

[0401] Step-3: (6-(2-Fluorophenoxy)pyridin-3-yl)methanamine hydrochloride

[0402] To a solution of tert-butyl ((6-(2-fluorophenoxy)pyridin-3-yl)methyl)carbamate (3 g, 9.4 mmol) in 1,4-dioxane (5 mL) was added a solution of 4 N HCl in 1,4-dioxane (20 mL), and stirred at RT for 2 h. The reaction mixture was then concentrated, diethyl ether was added thereto, and the solid was collected by filtration to give the title compound (2.35 g, 97.9%). LC-MS: 219 [M+H] +

[0403] Step-4: N-((6-(2-fluorophenoxy)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 1)

[0404] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (2 g, 10.4 mmol) in DMF (30 mL) was added HATU (4.99 g, 13.11 mmol) and triethylamine (5.53 g, 54.64 mmol) and stirred at RT for 10 min. Then (6-(2-fluorophenoxy)pyridin-3-yl)methanamine hydrochloride (2.38 g, 9.34 mmol) was added thereto and the mixture was stirred at RT for 24 h. The reaction mixture was poured into ice-cold water and extracted with EtOAc. The separated organic layer was washed with brine, dehydrated over anhydrous Na2SO4 and concentrated to give the crude compound. The crude compound was purified by combined flash column chromatography using 10% MeOH in DCM as eluent to obtain the title compound (0.4 g, 10.9%). LC-MS: 393 [M+H] + ; 1 H-NMR (400 MHz, DMSO-D6) δ 11.11 (s, 1H), 8.95 (t, 1H), 8.07(s, 1H), 7.88(d, 1H), 7.63 (d, 1H), 7.53 (s, 1H), 7.4-7.2 (m, 4H), 7.2-7.1 (dd, 2H), 4.45-4.43 (d, 2H), 3.33 (s, 3H).

[0405] Example-2

[0406] [Chemical formula 34]

[0407]

[0408] Step-1: 4-(Isopropylamino)-3-nitrobenzoic acid

[0409] To a solution of 4-fluoro-3-nitrobenzoic acid (1 g, 5.4 mmol) in 1,4-dioxane (10 mL) was added DIPEA (2.09 g, 16.2 mmol) followed by propan-2-amine (0.32 g, 5.4 mmol) and stirred at 80 °C for 12 h. The reaction mixture was then cooled to RT, acidified with citric acid, and poured into ice-cold water. The separated solid was collected by filtration and dried to give the title compound (1 g, 10.9%). LC-MS: 223 [MH] -

[0410] Step-2: 3-Amino-4-(isopropylamino)benzoic acid

[0411] To a solution of 4-(isopropylamino)-3-nitrobenzoic acid (0.7 g, 3.12 mmol) in EtOH (5 mL) was added Pd / C (0.99 g, 9.3 mmol) under nitrogen atmosphere and RT, and the reaction mixture was stirred under hydrogen balloon pressure for 16 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.45 g, 74.2%). LC-MS: 195 [M+H] + ; 1 H-NMR (400 MHz, DMSO-D6) δ 12.7 (s, 1H), 7.18-7.13 (m, 2H), 6.42-6.40(d, 1H), 4.84-4.82 (d, 2H), 4.6 (s, 1H), 3.64-3.62 (m, 1H), 1.17-1.16 (d,6H).

[0412] Step-3: 1-Isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid

[0413] To a solution of 3-amino-4-(isopropylamino)benzoic acid (0.2 g, 1.03 mmol) in THF (8 mL) was added CDI (0.33 g, 2.06 mmol) and stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and acidified with 1 N HCl, which was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the title compound (0.2 g, 88.4%). LC-MS: 221 [M+H] +

[0414] Step-4: N-((6-(4-fluorophenoxy)pyridin-3-yl)methyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 2)

[0415] To a stirred solution of 1-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.1 g, 0.45 mmol) in DMF (5 mL) was added DIPEA (0.17 g, 1.36 mmol) followed by PyBOP (0.35 g, 0.68 mmol) and stirred at RT for 10 min. Then (6-(4-fluorophenoxy)pyridin-3-yl)methanamine (0.11 g, 0.49 mmol) was added thereto and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude compound. The crude compound was purified by preparative TLC using 5% MeOH in DCM as eluent to give the title compound (0.04 g, 21.1%). LC-MS: 421 [M+H] + ; 1 H-NMR(400 MHz, DMSO-D6) δ 11.07 (s, 1H), 8.95 (t, 1H), 8.08 (s, 1H), 7.8-7.78 (d,2H), 7.59-7.57 (d, 1H), 7.5 (s, 1H), 7.33-7.31 (d, 1H), 7.25-7.21 (m, 2H), 7.16-7.13 (m, 2H), 7.01-6.99 (d, 1H), 4.42-4.40 (d, 2H), 1.45 (d, 6H).

[0416] Example-3

[0417] [Chemical formula 35]

[0418]

[0419] Step-1: 4-Bromo-5-fluoro-N-methyl-2-nitroaniline

[0420] To a stirred solution of 1-bromo-2,4-difluoro-5-nitrobenzene (4 g, 16.80 mmol) in THF (40 mL) was added K2CO3 (5.8 g, 42.01 mmol) followed by methylamine hydrochloride (1.36 g, 20.16 mmol) and stirred at RT for 12 h. The reaction mixture was concentrated and poured into ice-cold water, which was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude compound. This was purified by combined flash column chromatography using 10% EtOAc in hexane as eluent to give the title compound (2.7 g, 64.6%). 1H-NMR (400 MHz, DMSO-D6) δ 8.35-8.31(m, 2H), 7.01-6.98 (d, 1H) 2.92-2.91 (d, 3H).

[0421] Step-2: 4-Bromo-5-fluoro-N 1 -Methylbenzene-1,2-diamine

[0422] To a stirred solution of 4-bromo-5-fluoro-N-methyl-2-nitroaniline (2 g, 8.03 mmol) in THF (20 mL) and EtOH (20 mL) was added ammonium chloride (2.14 g, 40.15 mmol) followed by iron powder (2.24 g, 40.15 mmol) and stirred at 80 °C for 8 h. The reaction mixture was filtered over a bed of celite and the filtrate was poured into ice-cold water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the title compound (1.5 g, 85.2%). LC-MS: 219 [M+H] +

[0423] Step-3: 5-Bromo-6-fluoro-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

[0424] To 4-bromo-5-fluoro-N 1 To a solution of -methylbenzene-1,2-diamine (0.04 g, 0.16 mmol) in n-butanol (5 mL) was added urea (1.31 g, 21.91 mmol) and stirred at 140 °C for 16 h. The reaction mixture was cooled to RT, acidified with 1 N HCl and concentrated. The crude material was stirred with diethyl ether and collected by filtration to give the title compound (0.02 g, 51%). LC-MS: 245 [M+H] +

[0425] Step-4: 6-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile

[0426] To a solution of 5-bromo-6-fluoro-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.25 g, 1.02 mmol) in DMF (5 mL) was added zinc cyanide (0.24 g, 2.04 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.2 mmol) and stirred at 100 °C for 12 h. The reaction mixture was poured into ice-cold water, extracted with 10% MeOH in DCM, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude compound. It was purified by combined flash column chromatography using 5% MeOH in DCM as eluent to give the title compound (0.15 g, 77.3%). LC-MS: 190 [MH] - ; 1 H-NMR (400 MHz, DMSO-D6) δ 11.36 (s, 1H), 7.42-7.40 (s, 1H), 7.38-7.36 (s, 1H), 3.3-3.5 (s, 3H).

[0427] Step-5: 6-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid

[0428] To a solution of 6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile (0.15 g, 0.78 mmol) in water (3 mL) and EtOH (3 mL) was added KOH (0.88 g, 15.7 mmol) and stirred at 90 °C for 24 h. The reaction mixture was then concentrated, diluted with water and acidified with 1 N HCl. The formed precipitate was collected by filtration and dried to give the title compound (0.12 g, 73%). LC-MS: 209 [MH] - ; 1 H-NMR (400 MHz, DMSO-D6) δ 12.87 (s,1H), 11.36 (s, 1H), 7.46-7.45 (d, 1H), 6.87-6.84 (d, 1H), 3.26-3.25 (s, 3H).

[0429] Step-6: 6-Fluoro-N-((6-(2-fluorophenoxy)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide trifluoroacetate (Compound 3)

[0430] To a solution of 6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.06 g, 0.29 mmol) in DMF (2 mL) was added EDC·HCl (0.066 g, 0.34 mmol) and HOBt (0.047 g, 0.34 mmol) and stirred at RT for 10 min. Then (6-(2-fluorophenoxy)pyridin-3-yl)methanamine (0.05 g, 0.23 mmol) and then triethylamine (0.087 g, 0.85 mmol) were added thereto and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give the crude compound. It was purified by preparative HPLC using method A to give the title compound (0.022 g, 23.4%) as a TFA salt. LC-MS: 411 [M+H] + ; 1 H-NMR (400 MHz, DMSO-D6) δ 11.04 (s, 1H), 8.67-8.66 (d, 1H), 8.04-8.03(d, 1H), 7.84-7.81 (dd, 1H), 7.3-7.0 (m, 7H), 4.42-4.40 (d, 2H), 3.3-3.28(s,3H).

[0431] Example-4

[0432] [Chemical formula 36]

[0433]

[0434] Step-1: 6-(2,4-difluorophenoxy)nicotinonitrile

[0435] To a stirred solution of 2,4-difluorophenol (0.93 g, 7.21 mmol) in DMF (3 mL) was added NaOH (0.43 g, 10.82 mmol) followed by 6-chloronicotinonitrile (1 g, 7.21 mmol) and stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and stirred for an additional 2 h, the separated solid was collected by filtration and dried. It was purified by combined flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the title compound (0.8 g, 48%). 1H-NMR (400 MHz, DMSO-D6) δ 8.65-8.65 (d, 1H), 8.39-8.36 (dd, 1H), 7.52-7.44(m, 2H), 7.4-7.38 (d, 1H), 7.2-7.15 (m, 1H).

[0436] Step-2: tert-Butyl ((6-(2,4-difluorophenoxy)pyridin-3-yl)methyl)carbamate

[0437] To a solution of 6-(2,4-difluorophenoxy)nicotinonitrile (0.4 g, 1.72 mmol) in MeOH (5 mL) was added NiCl2·6H2O (0.21 g, 0.86 mmol) at 0°C, followed by the addition of di-tert-butyl dicarbonate (0.75 g, 3.44 mmol) dropwise and stirred for 5 min. Then, maintaining the same temperature, NaBH4 (0.098 g, 2.58 mmol) was added portionwise thereto. After stirring at RT for 1 h, the reaction mass was concentrated to remove the solvent, diluted with EtOAc and filtered on a celite bed. The filtrate was washed with water, dehydrated over anhydrous Na2SO4 and concentrated to obtain the title compound (0.55 g, 95%). LC-MS: 337 [M+H] +

[0438] Step-3: (6-(2,4-difluorophenoxy)pyridin-3-yl)methanamine hydrochloride

[0439] To a solution of tert-butyl ((6-(2,4-difluorophenoxy)pyridin-3-yl)methyl)carbamate (3.4 g, 10.1 mmol) in 1,4-dioxane (10 mL) was added 4 N HCl in 1,4-dioxane (30 mL) and stirred at RT for 1 h. The reaction mixture was then concentrated, diethyl ether was added thereto and the solid was collected by filtration to give the title compound (2.7 g, 98.9%). LC-MS: 237 [M+H] +

[0440] Step-4: N-((6-(2,4-difluorophenoxy)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 4)

[0441] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (1.2 g, 6.2 mmol) in DMF (5 mL) was added HATU (2.84 g, 7.49 mmol) and triethylamine (1.89 g, 18.73 mmol) and stirred at RT for 10 min. Then (6-(2,4-difluorophenoxy)pyridin-3-yl)methanamine hydrochloride (1.03 g, 3.77 mmol) was added thereto and the mixture was stirred at RT for 2 h. The reaction mixture was added to ice-cold water and the precipitate formed was collected by filtration and dried. It was further purified by coupling flash column chromatography using 5% MeOH in DCM as eluent to give the title compound (0.87 g, 56%). LC-MS: 411 [M+H] + ; 1 H-NMR (400 MHz, DMSO-D6) δ 11.05 (s, 1H),8.92-8.89 (t, 1H), 8.01-8.0 (s, 1H), 7.80-7.78 (dd, 1H), 7.6-7.58 (d, 1H),7.47 (s, 1H), 7.3 (m, 2H), 7.13-7.06 (m, 3H), 4.38-4.37 (d, 2H) 3.29-3.27 (s, 3H).

[0442] Example-5

[0443] [Chemical formula 37]

[0444]

[0445] Step-1: (2-bromothiazol-5-yl)methanol

[0446] To a solution of 2-bromothiazole-5-carbaldehyde (2 g, 10.41 mmol) in MeOH (20 mL) was added NaBH4 (0.59 g 15.62 mmol) and stirred at RT for 1 h. The reaction mass was concentrated to remove the solvent and the residue was dissolved in EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated to give the title compound (2 g, 99%). LC-MS: 194 [M+H] +

[0447] Step-2: (2-(4-Fluorophenoxy)thiazol-5-yl)methanol

[0448] To a stirred solution of 4-fluorophenol (1.38 g, 12.36 mmol) in DMF (20 mL) was added K2CO3 (2.13 g, 15.46 mmol) and stirred at 130 °C for 30 min. The reaction mass was cooled to 80 °C and then (2-bromothiazol-5-yl)methanol (2.13 g, 15.46 mmol) was added thereto and stirred at 130 °C for 16 h. The reaction mixture was poured into ice-cold water, diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated. The crude residue was purified by combined flash column chromatography using 20% ​​EtOAc in hexane as eluent to obtain the title compound (1 g, 35.9%). LC-MS: 226 [M+H]+

[0449] Step-3: 5-(Azidomethyl)-2-(4-fluorophenoxy)thiazole

[0450] To a stirred solution of (2-(4-fluorophenoxy)thiazol-5-yl)methanol (0.1 g, 0.44 mmol) in DCM (3 mL) and toluene (3 mL) was added DPPA (0.24 g, 0.88 mmol) followed by DBU (0.13 g, 0.88 mmol) and stirred at 0 °C for 2 h and then at RT for 16 h. The reaction mixture was poured into ice-cold water, extracted with DCM, dried over anhydrous Na2SO4 and concentrated to give a residue. This was purified by combined flash column chromatography using 10% EtOAc in hexanes as eluent to give the title compound (0.08 g, 72.7%). LC-MS: 251 [M+H] + ; 1 H-NMR (400 MHz, DMSO-D6) δ 7.45-7.41 (m, 1H), 7.3-7.2 (m, 4H), 4.49 (s, 2H).

[0451] Step-4 (2-(4-Fluorophenoxy)thiazol-5-yl)methanamine hydrochloride

[0452] To a solution of 5-(azidomethyl)-2-(4-fluorophenoxy)thiazole (0.04 g, 0.16 mmol) in THF (1 mL) and water (1 mL) was added PPh3 (0.063 g, 0.24 mmol) and stirred at RT for 12 h. Then 4 N HCl in 1,4-dioxane (1 mL) was added to the reaction mixture at 0 °C and stirred for 1 h. The reaction mass was concentrated, diethyl ether was added thereto and the solid was collected by filtration to obtain the title compound (0.04 g, 96%). LC-MS: 225 [M+H] +

[0453] Step-5: N-((2-(4-fluorophenoxy)thiazol-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide trifluoroacetate (Compound 5)

[0454] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.25 g, 1.3 mmol) in DMF (10 mL) was added HATU (0.59 g, 1.56 mmol) and triethylamine (0.65 g, 6.5 mmol) and stirred at RT for 10 min. Then (2-(4-fluorophenoxy)thiazol-5-yl)methanamine hydrochloride (0.27 g, 1.04 mmol) was added thereto and the mixture was stirred at RT for 2 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude compound. It was purified by preparative HPLC using method A to give the title compound as a TFA salt (0.045 g, 63.3%). LC-MS: 399 [M+H] + ; 1 H-NMR (400 MHz, DMSO-D6)δ 11.1 (s, 1H), 9.05 (m, 1H), 7.60-7.58 (d, 1H), 7.41 (s, 1H), 7.41-7.36 (m,2H), 7.32-7.26 (m, 2H), 7.18-7.13 (m, 2H), 4.47-4.46 (d, 2H), 3.46 (s, 3H).

[0455] Example-6

[0456] [Chemical formula 38]

[0457]

[0458] Step-1: 1-(6-(4-Fluorophenoxy)pyridin-3-yl)ethan-1-one

[0459] To a stirred solution of 1-(6-bromopyridin-3-yl)ethan-1-one (2.67 g, 13.39 mmol) in DMF (30 mL) was added K2CO3 (5.54 g, 40.17 mmol) followed by 4-fluorophenol (1.5 g, 13.39 mmol) and stirred at 130 °C for 6 h. The reaction mixture was poured into ice-cold water and the separated solid was collected by filtration and dried to give the title compound (3.0 g, 86.5%). LC-MS: 232 [M+H] +

[0460] Step-2: 1-(6-(4-Fluorophenoxy)pyridin-3-yl)ethan-1-amine

[0461] To a stirred solution of 1-(6-(4-fluorophenoxy)pyridin-3-yl)ethan-1-one (1 g, 4.32 mmol) in MeOH (25 mL) was added ammonium acetate (3.33 g, 43.29 mmol) followed by sodium cyanoborohydride (0.82 g, 12.98 mmol) and stirred at RT for 16 h. The reaction mixture was concentrated to remove the solvent, the residue was diluted with water and basified with sodium hydroxide until pH ~12, and then it was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated to give the title compound (0.9 g, 89.64%). LC-MS: 233 [M+H] +

[0462] Step-3: N-(1-(6-(4-fluorophenoxy)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 6)

[0463] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.15 g, 0.78 mmol) in DMF (5 mL) was added T3P (0.745 g, 2.34 mmol) and stirred at RT for 10 min. Then 1-(6-(4-fluorophenoxy)pyridin-3-yl)ethan-1-amine (0.36 g, 1.56 mmol) and then DIPEA (0.30 g, 2.34 mmol) were added thereto and the mixture was stirred at RT for 16 h. The reaction mixture was added to ice-cold water, extracted with ethyl acetate, dried over anhydrous Na2SO4 and concentrated to give the crude product. It was purified by combined flash column chromatography using 4% MeOH in DCM as eluent to give the title compound (0.14 g, 24.6%). LC-MS: 407 [M+H] + .

[0464] Step-4: Optical isomers of N-(1-(6-(4-fluorophenoxy)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 6 Peak 1 and Peak 2)

[0465] The obtained compound 6 was further subjected to chiral separation to obtain two optical isomers of the compound as compound 6 peak 1 (0.025 g, 4.38%) and compound 6 peak 2 (0.025 g, 4.38%).

[0466] (Preparative HPLC method: Column- Chiralpak IA (250 x 20 x 5 µm); Eluent: A – 0.1% DEA in hexane, B- IPA:DCM (90:10)%; Isocratic: A:B (60:40); Flow rate: 15 mL / min)

[0467] Compound 6 peak 1: LC-MS: 407 [M+H]+; 1 H-NMR (400 MHz, DMSO-D6) δ 11.07 (s,1H), 8.8 (d, 1H), 8.1 (s, 1H), 7.85 (dd, 1H), 7.6 (dd, 1H), 7.5 (s, 1H),7.21-7.12 (m, 5H), 7.0 (d, 1H), 5.14 (t, 1H), 3.3 (s, 3H), 1.48 (d, 3H); Chiral HPLC RRT: 5.85.

[0468] Compound 6 peak 2: LC-MS: 407 [M+H]+; 1 H-NMR (400 MHz, DMSO-D6) δ 11.07 (s,1H), 8.8 (d, 1H), 8.1 (s, 1H), 7.85 (dd, 1H), 7.6 (dd, 1H), 7.5 (s, 1H),7.21-7.12 (m, 5H), 7.0 (d, 1H), 5.14 (t, 1H), 3.3 (s, 3H), 1.48 (d, 3H); Chiral HPLC RRT: 9.16.

[0469] Example-7

[0470] [Chemical formula 39]

[0471]

[0472] Step-1: 1-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethan-1-one

[0473] To a stirred solution of 3,4-difluorophenol (1.61 g, 12.49 mmol) in DMF (3 mL) was added Cs2CO3 (16.27 g, 49.99 mmol) followed by 1-(6-bromopyridin-3-yl)ethan-1-one (2.5 g, 12.49 mmol) and stirred at 130 °C for 6 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude compound. The compound was purified by combined flash column chromatography using 30% EtOAc in hexane as eluent to give the title compound (2 g, 64.3%). LC-MS: 250 [M+H] +

[0474] Step-2: (R)-N-((S)-1-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfenamide

[0475] To a solution of 1-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethan-1-one (1 g, 4.04 mmol) in THF (15 mL) was added tetraethoxytitanium (1.83 g, 8.02 mmol) and (R)-2-methylpropane-2-sulfenamide (0.48 g, 4.01 mmol) under inert atmosphere. The reaction mass was heated to reflux for 18 h. The reaction mass was cooled to -60 °C, NaBH4 (0.60 g, 16.05 mmol) was added thereto and stirred at the same temperature for 30 min and then at RT for 12 h. The reaction mass was poured into ice-cold water, extracted with EtOAc, dehydrated over anhydrous Na2SO4 and concentrated to obtain the title compound (1.4 g, 97%). LC-MS: 355 [M+H] +

[0476] Step-3: (S)-1-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethan-1-amine hydrochloride

[0477] To a solution of (R)-N-((S)-1-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfenamide (1.4 g, 3.95 mmol) in DCM (10 mL) was added 4 N HCl (8 mL) in 1,4-dioxane and stirred at RT for 3 h. The reaction mass was then concentrated, diethyl ether was added thereto and the precipitate was collected by filtration to give the title compound (0.95 g, 96%). LC-MS: 249 [MH] -

[0478] Step-4: (S)-N-(1-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 7)

[0479] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.15 g, 0.78 mmol) in DMF (8 mL) was added HATU (0.35 g, 0.93 mmol) and triethylamine (0.39 g, 3.9 mmol) and stirred at RT for 10 min. Then (S)-1-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethan-1-amine hydrochloride (0.22 g, 0.78 mmol) was added thereto and the mixture was stirred at RT for 12 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give the crude compound. It was purified by combining flash column chromatography using 100% EtOAc as eluent to give the title compound (0.05 g, 15%). LC-MS: 425 [M+H] + ; 1 H-NMR (400 MHz, DMSO-D6) δ 11.11 (s, 1H), 8.78-8.76 ( d, 1H), 8.19 (d, 1H), 7.95-7.92 (dd,1H), 7.68-7.66 (d, 1H), 7.55-7.46 (m, 1.53-1.51 (d, 2H).

[0480] Example-8

[0481] [Chemical formula 40]

[0482]

[0483] Step-1: 6-((4-Fluorophenyl)amino)nicotinonitrile

[0484] To a stirred solution of 6-chloronicotinonitrile (0.686 g, 4.95 mmol) in DMSO (5 mL) was added DIPEA (1.454 g, 11.25 mmol) followed by 4-fluoroaniline (0.5 g, 4.5 mmol) and stirred at 100 °C for 12 h. The reaction mixture was concentrated to remove DIPEA and then poured into ice-cold water, the resulting solid was collected by filtration and dried. The crude residue was purified by combined flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the pure title compound (0.5 g, 52.11%). LC-MS: 214.05 [M+H] +

[0485] Step-2: tert-Butyl ((6-((4-fluorophenyl)amino)pyridin-3-yl)methyl)carbamate

[0486] A solution of 6-((4-fluorophenyl)amino)nicotinonitrile (0.4 g, 1.88 mmol) in MeOH (8 mL) was cooled to 0°C, NiCl2·6H2O (0.22 g, 0.93 mmol) was added thereto, and then di-tert-butyl dicarbonate (0.61 g, 2.81 mmol) was added dropwise and stirred for 5 min. Then, maintaining the same temperature, NaBH4 (0.14 g, 3.75 mmol) was added thereto portionwise. After stirring at RT for 2 h, the reaction mass was concentrated to remove the solvent. The residue was diluted with EtOAc, washed with water, dehydrated over anhydrous Na2SO4 and concentrated to give the title compound (0.5 g crude). LC-MS: 318 [M+H] +

[0487] Step-3: 5-(Aminomethyl)-N-(4-fluorophenyl)pyridin-2-amine hydrochloride

[0488] To a solution of tert-butyl ((6-((4-fluorophenyl)amino)pyridin-3-yl)methyl)carbamate (0.4 g, 1.26 mmol) in 1,4-dioxane (2 mL) was added 4 N HCl in 1,4-dioxane (4 mL) and stirred at RT for 2 h. The reaction mass was concentrated, diethyl ether was added thereto and the solid was collected by filtration to give the title compound (0.4 g). LC-MS: 218 [M+H] +

[0489] Step-4: N-((6-((4-Fluorophenyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide trifluoroacetate (Compound 8)

[0490] To a solution of 2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.18 g, 1.01 mmol) in DMF (6 mL) was added EDC·HCl (0.23 g, 1.21 mmol) and HOBt (0.16 g, 1.21 mmol) and stirred at RT for 10 min. 5-(Aminomethyl)-N-(4-fluorophenyl)pyridin-2-amine hydrochloride (0.22 g, 0.86 mmol) was then added thereto, followed by triethylamine (0.51 g, 5.05 mmol), and the mixture was stirred at RT for 16 h. The reaction mixture was added to ice-cold water, and the precipitate formed was collected by filtration and dried. The crude residue was further purified by preparative HPLC using method A to give the title compound as a TFA salt (0.07 g, 16.5%). LC-MS: 378 [M+H] +

[0491] 1 H-NMR (400 MHz, DMSO-D6) δ 10.85 (d, 2H), 9.5 (bs, 1H), 8.85 (m, 1H), 8.0 (s, 1H), 7.7-7.55 (m, 3H), 7.1 (d, 1H), 7.4 (s, 1H), 7.1 (t, 2H), 6.9 (d,1H), 6.8 (d, 1H), 4.3 (d, 2H).

[0492] Example-9

[0493] [Chemical formula 41]

[0494]

[0495] Step-1: 6-((4-Fluorophenyl)amino)nicotinonitrile

[0496] To a stirred solution of 6-chloronicotinonitrile (13.7 g, 98.99 mmol) in DMSO (100 mL) was added DIPEA (29.08 g, 225.0 mmol) followed by 4-fluoroaniline (10 g, 89.99 mmol) and stirred at 100 °C for 12 h. The reaction mixture was concentrated to remove DIPEA and then poured into ice-cold water, the separated solid was collected by filtration and dried. It was purified by combined flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the title compound (9.0 g, 46.91%). LC-MS: 214 [M+H] +

[0497] Step-2: 6-((4-Fluorophenyl)(methyl)amino)nicotinonitrile

[0498] To a stirred solution of 6-((4-fluorophenyl)amino)nicotinonitrile (9 g, 42.21 mmol) in DMF (90 mL) was added NaH (60% dispersion in mineral oil) (1.07 g, 24.45 mmol) followed by dropwise addition of iodomethane (6.59 g, 46.4 mmol) at 0 °C and stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and the separated solid was collected by filtration and dried. It was purified by combined flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the title compound (8 g, 83.40%). LC-MS: 228 [M+H] +

[0499] Step-3: 5-(Aminomethyl)-N-(4-fluorophenyl)-N-methylpyridin-2-amine hydrochloride

[0500] A solution of 6-((4-fluorophenyl)(methyl)amino)nicotinonitrile (2.5 g, 11.00 mmol) in MeOH (25 mL) was cooled to 0°C, 7 N ammonia in MeOH (2.5 mL) was added thereto, and then Raney nickel (2.5 g, was added thereto, and stirred under hydrogen balloon pressure at RT for 1 h. The reaction mass was filtered through celite, and the filtrate was concentrated. The material was transferred into 1,4-dioxane (10 mL), 4 N HCl in 1,4-dioxane (10 mL) was added thereto at 0°C, and stirred at RT for 2 h. The reaction mass was concentrated, washed with diethyl ether and collected by filtration to obtain the title compound (2.3 g, 78.2%). LC-MS: 232 [M+H] +

[0501] Step-4: N-((6-((4-Fluorophenyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide trifluoroacetate (Compound 9)

[0502] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (1.12 g, 5.83 mmol) in DMF (12 mL) was added HATU (2.66 g, 6.99 mmol) and stirred at RT for 10 min. Then 5-(aminomethyl)-N-(4-fluorophenyl)-N-methylpyridin-2-amine hydrochloride (1.6 g, 5.94 mmol) was added thereto, followed by DIPEA (2.95 g, 22.82 mmol), and the mixture was stirred at RT for 16 h. The reaction mixture was added to ice-cold water, and the precipitate formed was collected by filtration and dried. It was further purified by preparative HPLC using method A to give the title compound as a TFA salt (0.35 g, 11.40%). LC-MS: 406 [M+H] + ; 1 H-NMR (400 MHz, DMSO-D6) δ 11.05 (s,1H), 8.9 (bs, 1H), 8 (s, 1H), 7.6 (d, 2H), 7.5 (s, 1H), 7.25-7.4 (m, 4H),7.15 (d, 1H), 6.65 (bs, 1H), 4.3 (d, 2H), 3.4 (s, 3H), 3.3 (s, 3H).

[0503] Example-10

[0504] [Chemical formula 42]

[0505]

[0506] Step-1: 6-((4,4-difluorocyclohexyl)amino)nicotinonitrile

[0507] To a stirred solution of 6-chloronicotinonitrile (4.5 g, 32.47 mmol) in DMSO (100 mL) was added DIPEA (20.98 g, 162.39 mmol) followed by 4,4-difluorocyclohexan-1-amine hydrochloride (5.57 g, 32.47 mmol) and stirred at 100 °C for 12 h. The reaction mixture was concentrated to remove DIPEA and then poured into ice-cold water, the separated solid was collected by filtration and dried. It was purified by combined flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the title compound (5.2 g, 67.48%). LC-MS: 236 [MH] - .

[0508] Step-2: 6-((4,4-difluorocyclohexyl)(methyl)amino)nicotinonitrile

[0509] To a stirred solution of 6-((4,4-difluorocyclohexyl)amino)nicotinonitrile (5.2 g, 21.9 mmol) in DMF (30 mL) was added NaH (60% dispersion in mineral oil) (0.876 g, 21.9 mmol) followed by dropwise addition of iodomethane (3.80 g, 26.74 mmol) at 0 °C and stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and the separated solid was collected by filtration and dried. It was purified by coupling flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the title compound (5 g, 90.9%). LC-MS: 252 [M+H] +

[0510] Step-3: 5-(Aminomethyl)-N-(4,4-difluorocyclohexyl)-N-methylpyridin-2-amine

[0511] To a solution of 6-((4,4-difluorocyclohexyl)(methyl)amino)nicotinonitrile (2 g, 7.95 mmol) in EtOH (40 mL) was added Raney nickel (2 g) and stirred under hydrogen balloon pressure at RT for 24 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (1.8 g, 88.6%). LC-MS: 256 [M+H] +

[0512] Step-4: N-((6-((4,4-difluorocyclohexyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 10)

[0513] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (1.5 g, 7.84 mmol) in DMF (15 mL) was added EDC·HCl (1.52 g, 7.92 mmol) and HOBt (0.80 g, 5.92 mmol) and stirred at RT for 10 min. Then 5-(aminomethyl)-N-(4,4-difluorocyclohexyl)-N-methylpyridin-2-amine (1.52 g, 5.96 mmol) and then triethylamine (3.57 g, 35.25 mmol) were added thereto and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water and the precipitate formed was collected by filtration and dried. It was purified by combining flash column chromatography using 5% MeOH in DCM as eluent to give the title compound (0.6 g, 23.78%). LC-MS: 430 [M+H] + ; 1 H-NMR (400 MHz, DMSO-D6) δ 11.0 (s, 1H), 8.8 (m, 1H), 8 (d, 1H), 7.6 (d,1H), 7.45 (m, 2H), 7.1 (d, 1H), 6.6 (d, 1H), 4.6 (m, 1H), 4.35 (d, 2H), 3.25 (s, 3H), 2.85 (s, 3H), 2.0-2.1 (m, 3H), 1.95 (m, 1H), 1.7 (m, 2H), 1.6 (d, 2H).

[0514] Example-11

[0515] [Chemical formula 43]

[0516]

[0517] Step-1: 6-(Isopropylamino)nicotinonitrile

[0518] To a stirred solution of 6-chloronicotinonitrile (3.5 g, 25.26 mmol) in DMSO (35 mL) was added DIPEA (16.3 g, 126.3 mmol) followed by propan-2-amine hydrochloride (4.83 g, 50.52 mmol) and stirred at 100 °C for 12 h. The reaction mixture was concentrated to remove DIPEA and then poured into ice-cold water, the separated solid was collected by filtration and dried. It was purified by combined flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the title compound (2.8 g, 68.8%). LC-MS: 162 [M+H] +

[0519] Step-2: 6-(isopropyl(methyl)amino)nicotinonitrile

[0520] To a stirred solution of 6-(isopropylamino)nicotinonitrile (2.8 g, 17.36 mmol) in DMF (28 mL) was added NaH (60% dispersion in mineral oil) (1.04 g, 26.04 mmol), followed by dropwise addition of iodomethane (2.95 g, 20.8 mmol) at 0 °C and stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and the separated solid was collected by filtration and dried. It was purified by combined flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the title compound (2.5 g, 68.8%). LC-MS: 176 [M+H] +

[0521] Step-3: tert-Butyl ((6-(isopropyl(methyl)amino)pyridin-3-yl)methyl)carbamate

[0522] A solution of 6-(isopropyl(methyl)amino)nicotinonitrile (2.5 g, 14.26 mmol) in MeOH (500 mL) was cooled to 0 °C, NiCl2·6H2O (0.51 g, 2.13 mmol) was added, followed by di-tert-butyl dicarbonate (6.22 g, 28.53 mmol) dropwise, and stirred for 5 min. Then, NaBH4 (0.81 g, 21.39 mmol) was added portionwise thereto while maintaining the same temperature. After stirring at RT for 1 h, the reaction mass was concentrated to remove MeOH. The residue was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by combined flash chromatography using 20% ​​EtOAc in hexane as eluent to obtain the title compound (1.6 g, 40.9%). LC-MS: 280 [M+H] +

[0523] Step-4: 5-(Aminomethyl)-N-isopropyl-N-methylpyridin-2-amine hydrochloride

[0524] To a solution of tert-butyl ((6-(isopropyl(methyl)amino)pyridin-3-yl)methyl)carbamate (1.6 g, 5.7 mmol) in 1,4-dioxane (10 mL) was added 4 N HCl in 1,4-dioxane (10 mL), and stirred at RT for 2 h. The reaction mixture was then concentrated, diethyl ether was added thereto, and the resulting residue was collected by filtration to give the crude title compound (1.6 g). LC-MS: 180 [M+H] +

[0525] Step-5: N-((6-(isopropyl(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide trifluoroacetate (Compound 11a)

[0526] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (1.78 g, 9.26 mmol) in DMF (25 mL) was added EDC·HCl (1.77 g, 9.26 mmol) and HOBt (0.63 g, 4.63 mmol) and stirred at RT for 10 min. 5-(Aminomethyl)-N-isopropyl-N-methylpyridin-2-amine hydrochloride (1.6 g, 7.41 mmol) was then added thereto, followed by triethylamine (5.61 g, 55.56 mmol), and the mixture was stirred at RT for 16 h. The reaction mixture was added to ice-cold water, and the precipitate formed was collected by filtration, washed with water and dried. It was further purified by preparative HPLC using method A to give the title compound as a TFA salt (0.7 g, 20.2%). LC-MS: 354 [M+H] +

[0527] Step-6: N-((6-(isopropyl(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide hydrochloride (Compound 11b)

[0528] N-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide trifluoroacetate was dissolved in a mixture of 0.1% aqueous HCl:acetonitrile (60:40) (700 mL) and concentrated completely at RT to give the title compound as an HCl salt (0.476 g, 81.8%). LC-MS: 354 [M+H] + ; 1 H-NMR (400 MHz, CD3OD) δ 8.06-8.03 (dd, 1H), 7.88 (m, 1H), 7.69-7.67 (dd, 1H), 7.61 (d, 1H), 7.38-7.35 (d, 1H), 7.21-7.19 (d, 1H), 4.49 (s, 2H), 4.42 (m,1H), 3.43 (S, 3H), 3.11 (s, 3H), 1.35 (d, 6H).

[0529] Example-12

[0530] [Chemical formula 44]

[0531]

[0532] Step-1: 6-((cis-3-(trifluoromethyl)cyclobutyl)amino)nicotinonitrile

[0533] To a stirred solution of 6-chloronicotinonitrile (1.42 g, 10.24 mmol) in DMSO (20 mL) was added DIPEA (7.95 g, 61.49 mmol) followed by cis-3-(trifluoromethyl)cyclobutan-1-amine hydrochloride (2.00 g, 11.40 mmol) and stirred at 100 °C for 12 h. The reaction mixture was concentrated to remove DIPEA and then poured into ice-cold water, the separated solid was collected by filtration and dried. It was purified by combined flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the title compound (2.32 g, 93.9%). LC-MS: 242 [M+H] + .

[0534] Step-2: 6-(Methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)nicotinonitrile

[0535] To a stirred solution of 6-((cis-3-(trifluoromethyl)cyclobutyl)amino)nicotinonitrile (2.32 g, 9.62 mmol) in DMF (25 mL) was added NaH (60% dispersion in mineral oil) (0.38 g, 9.6 mmol), followed by dropwise addition of iodomethane (1.64 g, 11.54 mmol) at 0 °C and stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and the separated solid was collected by filtration and dried to give the title compound (2.4 g, 97%). LC-MS: 256 [M+H] +

[0536] Step-3: 5-(Aminomethyl)-N-methyl-N-(cis-3-(trifluoromethyl)cyclobutyl)pyridin-2-amine

[0537] To a solution of 6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)nicotinonitrile (2.4 g, 9.40 mmol) in EtOH (25 mL) was added 7 N ammonia in MeOH (2.3 mL) followed by Raney nickel (2.4 g) and stirred under hydrogen balloon pressure at RT for 12 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (2.3 g, 94.6%). LC-MS: 260 [M+H] +

[0538] Step-4: 1-methyl-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 12)

[0539] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (1.45 g, 7.54 mmol) in DMF (25 mL) was added EDC·HCl (1.45 g, 7.54 mmol) and HOBt (0.54 g, 3.99 mmol), and stirred at RT for 10 min. 5-(aminomethyl)-N-methyl-N-(cis-3-(trifluoromethyl)cyclobutyl)pyridin-2-amine (2.3 g, 8.87 mmol) and then triethylamine (4.48 g, 44.35 mmol) were then added thereto, and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, and the precipitate formed was collected by filtration and dried. It was further washed with diethyl ether (3 x 25 mL) and then pentane (25 mL) to give the title compound (1.28 g, 39.26%). LC-MS: 434 [M+H] +

[0540] 1 H-NMR (400 MHz, DMSO-D6) δ 11.1 (s, 1H), 8.8 (t, 1H), 8.05 (s, 1H), 7.6 (d, 1H), 7.5 (m, 2H), 7.1 (d, 1H), 6.6 (d, 1H), 4.9 (t, 1H), 4.3 (d, 2H), 3.3 (s, 3H), 2.9 (m, 4H), 2.35 (m, 2H), 2.2 (m, 2H).

[0541] Example-13

[0542] [Chemical formula 45]

[0543]

[0544] Step-1: 6-((4-Fluorophenyl)amino)nicotinonitrile

[0545] To a stirred solution of 6-chloronicotinonitrile (6.85 g, 49.4 mmol) in DMSO (40 mL) was added DIPEA (14.54 g, 112.49 mmol) followed by 4-fluoroaniline (5 g, 44.99 mmol) and stirred at 100 °C for 12 h. The reaction mixture was concentrated to remove DIPEA and then poured into ice-cold water, the separated solid was collected by filtration and dried to give the title compound (9.5 g, 90.2%). LC-MS: 214.1 [M+H] +

[0546] Step-2: 6-((4-Fluorophenyl)(methyl)amino)nicotinonitrile

[0547] To a stirred solution of 6-((4-fluorophenyl)amino)nicotinonitrile (5 g, 23.449 mmol) in DMF (30 mL) was added NaH (60% dispersion in mineral oil) (0.916 g, 22.990 mmol) followed by dropwise addition of iodomethane (3.99 g, 28.14 mmol) at 0 °C and stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and the separated solid was collected by filtration and dried. The crude residue was purified by combined flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the pure title compound (2.5 g, 46.92%). LC-MS: 228.0 [M+H] +

[0548] Step-3: 6-((4-Fluorophenyl)(methyl)amino)nicotinic acid

[0549] To a stirred solution of 6-((4-fluorophenyl)(methyl)amino)nicotinonitrile (2 g, 8.80 mmol) in ethanol (10 mL) and water (10 mL) was added KOH (0.99 g, 17.60 mmol) and heated to reflux for 12 h. The reaction mixture was concentrated to remove EtOH, and then the pH of the reaction mixture was adjusted to 2 using 1 N HCl. The precipitated solid was collected by filtration and dried to give the title compound (1.7 g, 78.7%). LC-MS: 245 [MH] -

[0550] Step-4: 6-((4-Fluorophenyl)(methyl)amino)-N-methoxy-N-methylnicotinamide

[0551] To a solution of 6-((4-fluorophenyl)(methyl)amino)nicotinic acid (2 g, 8.12 mmol) in DMF (15 mL) was added HATU (4.63 g, 12.18 mmol) and stirred at RT for 10 min. N,O-dimethylhydroxylamine hydrochloride (0.95 g, 9.74 mmol) and then DIPEA (2.46 g, 19.03 mmol) were then added thereto and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give the title compound (2.7 g), which was used further without purification. LC-MS: 290 [M+H] +

[0552] Step-5: 1-(6-((4-Fluorophenyl)(methyl)amino)pyridin-3-yl)ethan-1-one

[0553] To a stirred solution of 6-((4-fluorophenyl)(methyl)amino)-N-methoxy-N-methylnicotinamide (2.7 g, 9.33 mmol) in THF (15 mL) at 0 °C was added methylmagnesium bromide (2.22 g, 18.66 mmol) and the mixture was stirred at RT for 12 h. The reaction mixture was quenched with saturated ammonium chloride, diluted with water and extracted with DCM. It was purified by coupled flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the title compound (1.85 g, 81.5%). LC-MS: 245 [M+H] +

[0554] Step-6: (R)-N-((S)-1-(6-((4-fluorophenyl)(methyl)amino)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfenamide

[0555] To a stirred solution of 1-(6-((4-fluorophenyl)(methyl)amino)pyridin-3-yl)ethan-1-one (1.0 g, 4.09 mmol) in THF (20 mL) was added tetraethoxytitanium (1.86 g, 8.18 mmol) followed by (R)-2-methylpropane-2-sulfenamide (0.50 g, 4.09 mmol) at 0°C and the mixture was refluxed for 36 h. The reaction mixture was cooled to -60°C, sodium borohydride (0.62 g, 16.37 mmol) was added and stirred at the same temperature for 0.5 h. The reaction mixture was further warmed to RT and stirred for 12 h. The reaction mixture was filtered, the filtrate was diluted with water and extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude residue. This was purified by coupling flash column chromatography using 30% EtOAc in hexane as eluent to give the title compound (1.1 g, 76.9%). LC-MS: 350 [M+H] +

[0556] Step-7: (S)-5-(1-aminoethyl)-N-(4-fluorophenyl)-N-methylpyridin-2-amine hydrochloride

[0557] To a solution of (R)-N-((S)-1-(6-((4-fluorophenyl)(methyl)amino)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfenamide (1.2 g, 3.43 mmol) in 1,4-dioxane (5 mL) was added 4 N HCl in 1,4-dioxane (10 mL) and stirred at RT for 2 h. The reaction mass was concentrated, diethyl ether was added and the solid was collected by filtration to give the title compound (1.1 g) which was used further as is. LC-MS: 246 [M+H] +

[0558] Step-8: (S)-N-(1-(6-((4-fluorophenyl)(methyl)amino)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 13)

[0559] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.25 g, 1.3 mmol) in DMF (7 mL) was added HATU (0.59 g, 1.56 mmol) and HOAt (0.21 g, 1.56 mmol) and stirred at RT for 10 min. Then (S)-5-(1-aminoethyl)-N-(4-fluorophenyl)-N-methylpyridin-2-amine hydrochloride (0.29 g, 1.04 mmol) followed by triethylamine (0.66 g, 6.5 mmol) was added thereto and the mixture was stirred at RT for 16 h. The reaction mixture was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give a crude residue. This was purified by coupling flash column chromatography using 10% MeOH in DCM as eluent to give the title compound (0.01 g, 1.83%). LC-MS: 420 [M+H] + ; 1 H-NMR (400 MHz, CD3OD) δ 8.15 (d, 1H), 7.65 (dd, 1H), 7.55 (d,1H), 7.5 (dd, 1H), 7.25 (m, 2H), 7.15 (m, 3H), 6.5 (d, 1H), 5.1-5.2 (q, 1H), 3.2-3.5 (m, 8H), 1.5 (d, 3H).

[0560] Example-14

[0561] [Chemical formula 46]

[0562]

[0563] Step-1: (S)-6-(2-methylpyrrolidin-1-yl)nicotinonitrile

[0564] To a stirred solution of 6-fluoronicotinonitrile (2.2 g, 18.02 mmol) in acetonitrile (10 mL) was added DIPEA (13.97 g, 108.1 mmol) followed by (S)-2-methylpyrrolidine (2.41 g, 28.3 mmol) and stirred at 100 °C for 12 h. The reaction mixture was concentrated to remove DIPEA and then poured into ice-cold water, the separated solid was collected by filtration and dried. It was purified by combined flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the title compound (3.3 g, 97.82%). LC-MS: 188 [M+H] +

[0565] Step-2: (S)-tert-butyl ((6-(2-methylpyrrolidin-1-yl)pyridin-3-yl)methyl)carbamate

[0566] A solution of (S)-6-(2-methylpyrrolidin-1-yl)nicotinonitrile (1.75 g, 9.35 mmol) in MeOH (350 mL) was cooled to 0 °C, NiCl2·6H2O (0.22 g, 0.93 mmol) was added thereto, followed by dropwise addition of di-tert-butyl dicarbonate (4.08 g, 18.69 mmol) and stirring for 5 min. Then, maintaining the same temperature, NaBH4 (2.48 g, 65.42 mmol) was added thereto portionwise. After stirring at RT for 1 h, the reaction mass was concentrated to remove the solvent. The residue was diluted with EtOAc, washed with water, dehydrated over anhydrous Na2SO4 and concentrated. The crude compound was purified by combined flash chromatography using 20% ​​EtOAc in hexane as eluent to obtain the title compound (2.2 g, 80.8%). LC-MS: 292 [M+H] +

[0567] Step-3: (S)-(6-(2-methylpyrrolidin-1-yl)pyridin-3-yl)methanamine hydrochloride

[0568] To a solution of (S)-tert-butyl((6-(2-methylpyrrolidin-1-yl)pyridin-3-yl)methyl)carbamate (1.9 g, 6.52 mmol) in 1,4-dioxane (15 mL) was added 4 N HCl in 1,4-dioxane (20 mL) and stirred at RT for 2 h. The reaction mixture was concentrated, diethyl ether was added, and the solid was collected by filtration to give the title compound (1.3 g, 87.8%). LC-MS: 192 [M+H] +

[0569] Step-4: (S)-1-methyl-N-((6-(2-methylpyrrolidin-1-yl)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 14)

[0570] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (1.09 g, 5.65 mmol) in DMF (15 mL) was added EDC·HCl (1.08 g, 5.64 mmol) and HOBt (0.51 g, 3.7 mmol), and stirred at RT for 10 min. Then (S)-(6-(2-methylpyrrolidin-1-yl)pyridin-3-yl)methanamine hydrochloride (1.2 g, 5.27 mmol) and then triethylamine (4.44 g, 43.91 mmol) were added thereto, and the mixture was stirred at RT for 16 h. The reaction mixture was diluted with water, extracted with 5% MeOH in DCM, and concentrated under reduced pressure. The crude residue was further washed with a 1:1 solution of DCM and diethyl ether (3x 25 mL) to give the title compound (0.71 g, 37.1%). LC-MS: 366 [M+H] + ; 1 H-NMR (400MHz, CD3OD) δ 11.05 (s, 1H), 8.8 (t, 1H), 8.0 (d, 1H), 7.6 (dd, 1H), 7.5 (d,1H), 7.45 (dd, 2H), 7.1 (d, 1H), 6.4 (d, 1H), 4.3 (d, 2H), 4.1 (m, 1H), 3.4(m, 2H), 3.3 (s, 3H), 3.2 (m, 2H), 1.8-2.1 (m, 3H), 1.1 (m, 1H).

[0571] Example-15

[0572] [Chemical formula 47]

[0573]

[0574] Step-1: 5-Bromo-N-methoxy-N-methylpicolinamide

[0575] To a solution of 5-bromopicolinic acid (4.0 g, 19.8 mmol) in DMF (20 mL) was added HATU (6.78 g, 17.82 mmol) and stirred at RT for 10 min. Then N,O-dimethylhydroxylamine hydrochloride (2.32 g, 23.76 mmol) was added thereto followed by triethylamine (7.51 g, 74.25 mmol) and the mixture was stirred at RT for 2 h. The reaction mixture was added to ice-cold water and extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give a residue. This was purified by combined flash column chromatography using 20% ​​EtOAc in hexane as eluent to give the title compound (3.8 g, 84.45%). LC-MS: 245 [M+H] +

[0576] Step-2: 1-(5-bromopyridin-2-yl)ethan-1-one

[0577] To a stirred solution of 5-bromo-N-methoxy-N-methylpicolinamide (3.8 g, 15.5 mmol) in THF (40 mL) at 0 °C was added methylmagnesium bromide (2.77 g, 23.25 mmol) and stirred at RT for 12 h. The reaction mixture was quenched by saturated ammonium chloride solution and extracted with DCM, dried over anhydrous Na2SO4 and concentrated to give the title compound (2.8 g, 90.3%). LC-MS: 200 [M+H] +

[0578] Step-3: 1-(5-Bromopyridin-2-yl)-1-(4-fluorophenyl)ethan-1-ol

[0579] To a stirred solution of 1-(5-bromopyridin-2-yl)ethan-1-one (2.8 g, 14.45 mmol) in THF (25 mL) at 0 °C was added (4-fluorophenyl)magnesium bromide (4.32 g, 21.67 mmol) and stirred at RT for 12 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with DCM, dried over anhydrous Na2SO4 and concentrated to give a residue. It was purified by combined flash column chromatography using 30% EtOAc in hexanes as eluent to give the title compound (1.5 g, 35.12%). LC-MS: 296 [M+H] +

[0580] Step-4: 5-Bromo-2-(1-(4-fluorophenyl)vinyl)pyridine

[0581] To a solution of 1-(5-bromopyridin-2-yl)-1-(4-fluorophenyl)ethan-1-ol (1.5 g, 5.07 mmol) in toluene (10 mL) was added PTSA (0.096 g, 0.50 mmol) at 0 °C and stirred at 100 °C for 16 h. The reaction mixture was quenched with water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give a residue. It was purified by combined flash column chromatography using 10% EtOAc in hexanes as eluent to give the title compound (0.9 g, 69.23%). LC-MS: 280 [M+H] +

[0582] Step-5: 6-(1-(4-fluorophenyl)vinyl)nicotinonitrile

[0583] To a solution of 5-bromo-2-(1-(4-fluorophenyl)vinyl)pyridine (0.7 g, 2.51 mmol) in DMF (5 mL) was added zinc cyanide (0.36 g, 3.02 mmol). The reaction mixture was degassed with argon for 15 min, tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.25 mmol) was added thereto, and heated at 120°C for 10 h. The reaction mixture was quenched with KMnO4 solution, and EtOAc was added thereto. The organic layer was separated, dehydrated over anhydrous Na2SO4 and concentrated to obtain a residue. It was purified by combined flash column chromatography using 30% EtOAc in hexane as eluent to obtain the title compound (0.45 g, 79.73%). LC-MS: 225 [M+H] +

[0584] Step-6: (6-(1-(4-fluorophenyl)ethyl)pyridin-3-yl)methanamine

[0585] To a stirred solution of 6-(1-(4-fluorophenyl)vinyl)nicotinonitrile (0.35 g, 1.56 mmol) in MeOH (8 mL) was added Raney nickel (0.092 g, 1.56 mmol) followed by a solution of ammonia in methanol (0.027 g, 1.56 mmol) and stirred at RT under hydrogen balloon pressure for 1 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.21 g, 58.4%). LC-MS: 231 [M+H] +

[0586] Step-7: N-((6-(1-(4-fluorophenyl)ethyl)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 15)

[0587] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.10 g, 0.52 mmol) in DMF (6 mL) was added HATU (0.24 g, 0.62 mmol) and stirred at RT for 10 min. Then (6-(1-(4-fluorophenyl)ethyl)pyridin-3-yl)methanamine (0.11 g, 0.47 mmol) and then triethylamine (0.26 g, 2.6 mmol) were added thereto and the mixture was stirred at RT for 2 h. The reaction mixture was added to ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give a residue. It was purified by preparative HPLC using method A to give the title compound (0.007 g, 3.33%). LC-MS: 405 [M+H] + ; 1 H-NMR (400 MHz, DMSO-D6) δ 11.08 (bs,1H), 8.93 (t, 1H), 8.45 (bs, 1H), 7.62- 7.60 (d, 2H), 7.49 (s, 1H), 7.33-7.30(t, 2H), 7.25-7.23 (d, 1H), 7.14- 7.12 (d, 1H), 7.09-7.05 (t, 2H), 4.42-4.40(d, 2H), 4.26-4.25 (q, 1H), 3.29 (s, 3H), 1.57-1.56 (d, 3H).

[0588] Example-16

[0589] [Chemical formula 48]

[0590]

[0591] Step-1: 5-Bromo-N-methoxy-N-methylpicolinamide

[0592] To a solution of 5-bromopicolinic acid (2.0 g, 9.9 mmol) in DMF (20 mL) was added HATU (4.52 g, 11.88 mmol) and stirred at RT for 10 min. Then N,O-dimethylhydroxylamine hydrochloride (1.16 g, 11.88 mmol) followed by triethylamine (3.00 g, 29.69 mmol) was added thereto and the mixture was stirred at RT for 16 h. The reaction mixture was added to ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give a residue. It was purified by combined flash column chromatography using 20% ​​EtOAc in hexane as eluent to give the title compound (0.75 g, 30.91%). LC-MS: 245 [M+H] +

[0593] Step-2: (5-bromopyridin-2-yl)(4-fluorophenyl)methanone

[0594] To a stirred solution of 5-bromo-N-methoxy-N-methylpicolinamide (0.75 g, 3.06 mmol) in THF (10 mL) was added (4-fluorophenyl)magnesium bromide (1.22 g, 6.12 mmol) and stirred at RT for 1 h. The reaction mixture was quenched with ammonium chloride, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give a residue. This was purified by combined flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the title compound (0.68 g, 79.34%). LC-MS: 280 [M+H] +

[0595] Step-3: (5-bromopyridin-2-yl)(4-fluorophenyl)methanol

[0596] To a stirred solution of (5-bromopyridin-2-yl)(4-fluorophenyl)methanone (0.68 g, 2.42 mmol) in MeOH (5 mL) was added NaBH4 (0.14 g, 3.65 mmol) at 0 °C and stirred at RT for 1 h. The reaction mass was concentrated and diluted with EtOAc and water. The organic layer was dried over anhydrous Na2SO4 and concentrated to get a residue. It was purified by coupled flash column chromatography using 30% EtOAc in hexane as eluent to get the title compound (0.5 g, 73.03%). LC-MS: 282 [M+H] +

[0597] Step-4: 5-Bromo-2-(fluoro(4-fluorophenyl)methyl)pyridine

[0598] To a solution of (5-bromopyridin-2-yl)(4-fluorophenyl)methanol (0.5 g, 1.772 mmol) in DCM (5 mL) was added DAST (0.43 g, 2.65 mmol) at 0 °C and stirred at RT for 1 h. The reaction mixture was quenched with sodium bicarbonate solution, extracted with DCM, dried over anhydrous Na2SO4 and concentrated to give a residue. It was purified by combined flash column chromatography using 1% EtOAc in hexanes as eluent to give the title compound (0.35 g, 69.52%). LC-MS: 286 [M+H] +

[0599] Step-5: 6-(Fluoro(4-fluorophenyl)methyl)nicotinonitrile

[0600] To a solution of 5-bromo-2-(fluoro(4-fluorophenyl)methyl)pyridine (0.35 g, 1.23 mmol) in DMF (5 mL) was added zinc cyanide (0.029 g, 0.24 mmol). The reaction mixture was degassed with argon for 15 min, then tetrakis(triphenylphosphine)palladium(0) (0.14 g, 0.12 mmol) was added and heated in a microwave oven at 100 °C for 1 h. The reaction mixture was quenched with KMnO4 solution and EtOAc was added thereto. The organic layer was separated, dehydrated over anhydrous Na2SO4 and concentrated to obtain a residue. It was purified by combined flash column chromatography using 10% EtOAc in hexane as eluent to obtain the title compound (0.22 g, 77.57%). LC-MS: 231 [M+H] +

[0601] Step-6: tert-Butyl ((6-(fluoro(4-fluorophenyl)methyl)pyridin-3-yl)methyl)carbamate

[0602] To a stirred solution of 6-(fluoro(4-fluorophenyl)methyl)nicotinonitrile (0.22 g, 0.96 mmol) in MeOH (5 mL) was added nickel(II) chloride hexahydrate (0.11 g, 0.47 mmol) followed by di-tert-butyl dicarbonate (0.42 g, 1.91 mmol). Then NaBH4 (0.054 g, 1.43 mmol) was added thereto portionwise at 9 °C and the reaction mixture was stirred at RT for 2 h. The reaction mass was concentrated and the residue was diluted with EtOAc and filtered through a pad of celite. The filtrate was concentrated and purified by combining flash column chromatography using 8% EtOAc in hexane as eluent to obtain the title compound (0.14 g, 42.23%). LC-MS: 335 [M+H] +

[0603] Step-7: (6-(Fluoro(4-fluorophenyl)methyl)pyridin-3-yl)methanamine hydrochloride

[0604] To a stirred solution of tert-butyl ((6-(fluoro(4-fluorophenyl)methyl)pyridin-3-yl)methyl)carbamate (0.14 g, 0.40 mmol) in 1,4-dioxane (1 mL) was added 4 N HCl in 1,4-dioxane (2 mL) at 0 °C and the reaction mixture was stirred at RT for 2 h. The reaction mass was concentrated and the solid was washed with diethyl ether to afford the title compound (0.11 g, 42.23%). LC-MS: 235 [M+H] +

[0605] Step-8: N-((6-(Fluoro(4-fluorophenyl)methyl)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 16)

[0606] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.09 g, 0.47 mmol) in DMF (2 mL) was added EDC·HCl (0.108 g, 0.56 mmol) and HOBt (0.076 g, 0.55 mmol), and stirred at RT for 10 min. Then (6-(fluoro(4-fluorophenyl)methyl)pyridin-3-yl)methanamine hydrochloride (0.11 g, 0.42 mmol) and then triethylamine (0.14 g, 1.4 mmol) were added thereto, and the mixture was stirred at RT for 2 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give a residue. It was purified by washing with diethyl ether (3 x 25 mL) to give the title compound (0.022 g, 11.51%). LC-MS: 409 [M+H] + ; 1 H-NMR(400 MHz, DMSO-D6) δ 11.08 (s, 1H), 8.98 (t, 1H), 8.50 (bs, 1H), 7.80 (d,1H), 7.63- 7.61 (d, 1H), 7.58- 7.56 (d, 1H), 7.5 (s, 1H), 7.4 (t, 2H), 7.23-7.19 (t, 2H), 7.16- 7.14 (d, 1H), 6.57 (s, 1H), 4.4 (s, 2H), 3.3 (s, 3H).

[0607] Example-17

[0608] [Chemical formula 49]

[0609]

[0610] Step-1: 5-Bromo-1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0611] To a stirred solution of 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (4.0 g, 20.09 mmol) in DMF (40 mL) was added sodium hydride (0.69 g, 30.14 mmol) at 0°C and stirred for 10 min. Then 2-iodopropane (4.44 g, 26.12 mmol) was added thereto at 0°C and the reaction mixture was stirred at 100°C for 16 hr. The reaction mixture was quenched with ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give a residue. It was purified by combined flash column chromatography using 20% ​​EtOAc in hexane as eluent to give the title compound (2.8 g, 57.79%). LC-MS: 241 [M+H] +

[0612] Step-2: 1-Isopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile

[0613] To a stirred solution of 5-bromo-1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (1.1 g, 4.56 mmol) in t-BuOH (10 mL) and water (10 mL) was added K4[Fe(CN)6]·3H2O (0.77 g, 1.82 mmol) and DBU (0.17 g, 1.14 mmol). The reaction mixture was degassed with argon for 15 min, then tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.22 mmol) was added and the reaction mixture was heated to 85 °C for 4 h. The reaction mixture was cooled to RT, diluted with 10% MeOH in DCM and filtered through celite. The filtrate was concentrated and purified by combined flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the title compound (0.5 g, 58.54%). LC-MS: 188 [M+H] +

[0614] Step-3: (1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine

[0615] To a stirred solution of 1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (0.3 g, 1.60 mmol) in EtOH (15 mL) was added Raney nickel (0.019 g, 0.32 mmol) followed by a solution of ammonia in methanol (1 mL) and stirred at RT under hydrogen balloon pressure for 1 h. The reaction mass was filtered through a pad of celite and the filtrate was concentrated to give the title compound (0.3 g, 98%). LC-MS: 192.15 [M+H] +

[0616] Step-4: N-((1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 17)

[0617] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (1.3 g, 6.76 mmol) in DMF (10 mL) was added HATU (3.087 g, 8.11 mmol) and stirred at RT for 10 min. Then (1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine (1.16 g, 6.09 mmol) followed by triethylamine (3.42 g, 33.82 mmol) was added thereto and stirred at RT for 16 h. The reaction mixture was added to ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give a residue. It was purified by preparative HPLC using method B to give the pure title compound (0.28 g, 11.33%). LC-MS: 366 [M+H] + ; 1 HNMR (400 MHz, DMSO-D6) δ11.01(s, 1H), 8.88 (t, 1H), 7.61 (dd, 1H), 7.54 (bs, 1H), 7.4 (d, 1H), 7.1(d, 1H), 4.2 (d, 2H), 4.1 (t, 1H), 3.77-3.73 (t, 2H), 3.2 (s, 3H), 3.1 - 3.06(t, 2H), 2.83 (m, 1H), 1.2 (d, 6H)

[0618] Example-18

[0619] [Chemical formula 50]

[0620]

[0621] Step-1: 5-Bromo-1-(4,4-difluorocyclohexyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0622] To a stirred solution of 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (2.7 g, 13.56 mmol) in MeOH (60 mL) was added 4,4-difluorocyclohexan-1-one (2.73 g, 20.34 mmol), acetic acid (2.04 g, 33.9 mmol) and 2-methylpyridine borane complex (3.525 g, 33.91 mmol) at 0 °C and stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give a residue. It was purified by combined flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the title compound (3.6 g, 83.68%). LC-MS: 319 [M+H] +

[0623] Step-2: 1-(4,4-difluorocyclohexyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile

[0624] To a stirred solution of 5-bromo-1-(4,4-difluorocyclohexyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (3.6 g, 11.35 mmol) in t-BuOH (50 mL) and water (50 mL) was added DBU (0.43 g, 2.83 mmol) followed by potassium ferrocyanide (1.92 g, 4.54 mmol). The reaction mass was degassed with argon for 15 min. Then tetrakis(triphenylphosphine)palladium(0) (0.66 g, 0.56 mmol) was added thereto and stirred at 100 °C for 4 h. The reaction mass was concentrated to remove t-BuOH and the residue was diluted with water, extracted with EtOAc, dehydrated over anhydrous Na2SO4 and concentrated. The crude residue was purified by combined flash column chromatography using 30% EtOAc in hexane as eluent to obtain the title compound (2.4 g, 80.32%). LC-MS: 264 [M+H] +

[0625] Step-3: (1-(4,4-difluorocyclohexyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine

[0626] To a stirred solution of 1-(4,4-difluorocyclohexyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (2.4 g, 9.11 mmol) in EtOH (40 mL) was added Raney nickel (2.4 g) followed by ammonia in methanol (2.4 mL) and stirred at RT under hydrogen balloon pressure for 30 min. The reaction mass was filtered through a pad of celite and the filtrate was concentrated to give the title compound (2.4 g, 98.49%). LC-MS: 268 [M+H] +

[0627] Step-4: N-((1-(4,4-difluorocyclohexyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 18)

[0628] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (2.32 g, 12.12 mmol) in DMF (2 mL) was added EDC·HCl (1.72 g, 8.97 mmol) and HOBt (1.09 g, 8.07 mmol), and stirred at RT for 10 min. Then (1-(4,4-difluorocyclohexyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine (2.4 g, 8.97 mmol) and then triethylamine (4.54 g, 44.85 mmol) were added thereto, and the mixture was stirred at RT for 16 h. The reaction mixture was added to ice-cold water, and the precipitate formed was collected by filtration and dried. The obtained crude compound was washed with diethyl ether (3 x 50 mL) to give the title compound (1.2 g). LC-MS: 442 [M+H] + ; 1 H-NMR (400MHz, DMSO-D6) δ 11.0 (bs, 1H), 8.7 (t, 1H), 7.7 (s, 1H), 7.6 (d, 1H), 7.5(bs, 1H), 7.2 (bs, 1H), 7.1 (d, 1H), 4.2 (d, 2H), 4.0 (s, 1H), 3.4 (t 2H), 3.29 (s, 3H), 2.9-2.8 (t, 2H), 2.06 (s, 3H), 1.95 (s, 1H), 1.7-1.6 (t, 4H).

[0629] Example-19

[0630] [Chemical formula 51]

[0631]

[0632] Step-1: 1-(2-Fluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile

[0633] To a stirred solution of 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (0.25 g, 1.72 mmol) in 1,4-dioxane (3 mL) was added 1-fluoro-2-iodobenzene (0.90 g, 5.17 mmol) followed by cesium carbonate (1.68 g, 50.52 mmol). The reaction mass was degassed with argon for 15 min. To it was added Xphos (0.082 g, 0.17 mmol) and Pd2(dba)3 (0.079 g, 0.08 mmol) and heated to 100 °C for 6 h. The reaction mass was filtered through a pad of celite and concentrated to get a residue. It was purified by combined flash chromatography using 40% EtOAc in hexane as eluent to get the title compound (0.26 g, 61.89%). LC-MS: 240 [M+H] +

[0634] Step-2: (1-(2-Fluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine

[0635] To a solution of 1-(2-fluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (0.13 g, 5.43 mmol) in EtOH (4 mL) was added Raney Nickel (0.13 g) and stirred at RT under hydrogen balloon pressure for 30 min. The reaction mass was filtered through a celite pad and the filtrate was concentrated to give the title compound (0.13 g, 100%). LC-MS: 244 [M+H] +

[0636] Step-3: N-((1-(2-Fluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 19)

[0637] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.15 g, 0.80 mmol) in DMF (2 mL) was added EDC·HCl (0.12 g, 0.64 mmol) and HOBt (0.098 g, 0.64 mmol) and stirred at RT for 10 min. Then (1-(2-fluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine (0.13 g, 0.53 mmol) and then triethylamine (0.22 g, 2.13 mmol) were added thereto and the mixture was stirred at RT for 16 h. The reaction mixture was added to ice-cold water and the precipitate formed was collected by filtration and dried to give a residue. It was further purified by preparative HPLC using method A to give the title compound (0.1 g, 44.86%). LC-MS: 418 [M+H] + ; 1 H-NMR (400 MHz, CD3OD) δ 7.89 (s, 1H), 7.68 (dd, 1H), 7.67-7.6 (t, 2H), 7.58-7.52 (m, 2H), 7.38-7.35 (m, 2H), 7.21-7.19 (d, 1H), 4.49 (s, 2H), 4.35 (t, 2H), 3.46 (t, 2H), 3.42 (s, 3H).

[0638] Example-20

[0639] [Chemical formula 52]

[0640]

[0641] Step-1: 1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile

[0642] To a stirred solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (0.65 g, 3.30 mmol) in DMF (10 mL) was added zinc cyanide (0.47 g, 3.95 mmol). The reaction mixture was degassed with argon for 15 min, then tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol) was added and the reaction mixture was heated in a microwave oven at 100 °C for 1 h. The reaction mixture was quenched with KMnO4 solution and an ice-cold water mixture was added, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give a residue. It was purified by combined flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the title compound (0.4 g, 84.7%). LC-MS: 144 [M+H] +

[0643] Step-2: 1-Phenyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile

[0644] To a stirred solution of 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (0.4 g, 2.79 mmol) in toluene (8 mL) was added iodobenzene (1.14 g, 5.59 mmol), copper iodide (0.053 g, 0.27 mmol), N,N'-dimethylethylenediamine (0.049 g, 0.55 mmol) and K3PO4 (0.38 g, 2.79 mmol) and degassed with argon for 15 min. The reaction mixture was then heated to 100 °C in a microwave oven for 6 h. The reaction mixture was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give a residue. This was purified by combined flash column chromatography using 20% ​​EtOAc in hexanes as eluent to give the title compound (0.38 g, 62.04%). LC-MS: 220 [M+H] +

[0645] Step-3: (1-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine

[0646] To a stirred solution of 1-phenyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (0.4 g, 1.82 mmol) in EtOH (15 mL) was added Raney nickel (0.4 g) followed by a solution of ammonia in methanol (0.5 mL) and stirred at RT under hydrogen balloon pressure for 30 min. The reaction mass was filtered through a pad of celite and concentrated to give the title compound (0.4 g, 99%). LC-MS: 224 [M+H] +

[0647] Step-4: 1-Methyl-2-oxo-N-((1-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 20)

[0648] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.22 g, 1.12 mmol) in DMF (4 mL) was added EDC·HCl (0.26 g, 1.34 mmol) and HOBt (0.18 g, 1.34 mmol), and stirred at RT for 10 min. Then (1-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine (0.2 g, 0.90 mmol) and then triethylamine (0.34 g, 3.35 mmol) were added thereto, and the mixture was stirred at RT for 16 h. The reaction mixture was diluted with ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give a residue. This was purified by coupled flash column chromatography using 60% EtOAc in hexanes as eluent to give the title compound (0.09 g, 20.24%). LC-MS: 398 [M+H] + ; 1 H-NMR (400 MHz, DMSO-D6) δ 11.0 (bs, 1H), 9.0-8.9 (t, 1H), 8.59(s, 1H), 8.31 (s, 1H), 8.0 (d, 1H), 7.94-7.93 (d, 1H), 7.90-7.88 (d, 1H), 7.6(d, 1H), 7.5 (t, 3H), 7.3 (t, 1H), 7.1 (d, 1H), 6.7 (d, 1H), 4.5 (s, 2H),3.29 (s, 3H).

[0649] Example-21

[0650] [Chemical formula 53]

[0651]

[0652] Step-1: 6-((2,6-difluorophenyl)amino)-5-nitronicotinonitrile

[0653] To a stirred solution of 6-chloro-5-nitronicotinonitrile (0.25 g, 1.36 mmol) in DMF (28 mL) was added NaH (60% dispersion in mineral oil) (0.082 g, 2.04 mmol) at 0 °C and stirred at RT for 1 h, further 2,6-difluoroaniline (0.22 g, 1.70 mmol) was added thereto and refluxed for 16 h. The reaction mixture was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated. The crude compound obtained was purified by combined flash chromatography using 20% ​​EtOAc in hexane as eluent to obtain the title compound (0.13 g, 34.56%). LC-MS: 275 [MH] -

[0654] Step-2: 5-amino-6-((2,6-difluorophenyl)amino)nicotinonitrile

[0655] To a solution of 6-((2,6-difluorophenyl)amino)-5-nitronicotinonitrile (0.13 g, 0.45 mmol) in ethanol (4 mL) was added Pd / C (0.025 g) under nitrogen atmosphere and stirred under hydrogen balloon pressure at RT for 1 h. The reaction mass was filtered through celite and concentrated to give the title compound (0.1 g, 90%). LC-MS: 247 [M+H] + .

[0656] Step-3: 3-(2,6-difluorophenyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile

[0657] To a stirred solution of 5-amino-6-((2,6-difluorophenyl)amino)nicotinonitrile (0.1 g, 0.41 mmol) in triethyl orthoformate (3 mL) was added HCl (0.028 g, 0.81 mmol) and refluxed at 85 °C for 3 h. The reaction mixture was concentrated and the residue was purified by column chromatography using 40% EtOAc in hexanes as eluent to give the title compound (0.09 g, 86.52%). LC-MS: 257 [M+H] + .

[0658] Step-4: (3-(2,6-difluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)methanamine

[0659] To a solution of 3-(2,6-difluorophenyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile (0.080 g, 0.31 mmol) in EtOH (4 mL) was added Raney nickel (0.080 g) and stirred under hydrogen balloon pressure at RT for 2 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.080 g, 98%). LC-MS: 261 [M+H] + .

[0660] Step-5: N-((3-(2,6-difluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide trifluoroacetate (Compound 21)

[0661] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.08 g, 0.42 mmol) in DMF (4 mL) was added EDC·HCl (0.084 g, 0.43 mmol) and HOBt (0.059 g, 0.43 mmol) and stirred at RT for 10 min. Then (3-(2,6-difluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)methanamine (0.065 g, 0.25 mmol) and then triethylamine (0.15 g, 1.45 mmol) were added thereto and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water and the precipitate formed was collected by filtration and dried. It was further purified by preparative HPLC using method A to give the title compound as a TFA salt (0.017 g, 12.4%). LC-MS: 435 [M+H] + ; 1 HNMR(400 MHz, CD3OD) δ 8.6 (s, 1H), 8.45 (d, 1H), 8.2 (s, 1H), 7.7-7.6 (m, 2H),7.6(d, 1H),7.3 (t, 2H), 7.15 (d, 1H), 5.0-4.7 (m, 2H), 3.5-3.2 (m, 3H).

[0662] Example-22

[0663] [Chemical formula 54]

[0664]

[0665] Step-1: 6-(3-iodophenoxy)nicotinonitrile

[0666] To a stirred solution of 3-iodophenol (2 g, 9.08 mmol) in DMF (15 mL) was added NaOH (0.55 g, 13.75 mmol) followed by 6-chloronicotinonitrile (1.25 g, 9.02 mmol) and stirred at RT for 12 h. The reaction mixture was poured into ice-cold water and stirring was continued for 2 h. The separated solid was collected by filtration and dried to give the title compound (2.2 g, 75.7%). LC-MS: 323 [M+H] +

[0667] Step-2: tert-Butyl ((6-(3-iodophenoxy)pyridin-3-yl)methyl)carbamate

[0668] To a solution of 6-(3-iodophenoxy)nicotinonitrile (2.2 g, 6.83 mmol) in MeOH (20 mL) was added NiCl2·6H2O (0.81 g, 3.42 mmol) followed by dropwise addition of di-tert-butyl dicarbonate (2.99 g, 13.70 mmol) at 0°C and stirred for 5 min. Then NaBH4 (0.39 g, 10.26 mmol) was added portionwise maintaining the same temperature. After stirring at RT for 3 h, the reaction mass was concentrated to remove the solvent, diluted with EtOAc and filtered on celite. The filtrate was washed with water, dehydrated over anhydrous Na2SO4 and concentrated to get the crude compound which was purified by combined flash column chromatography using 10% EtOAc in hexane as eluent to get the title compound (1.3 g, 44.8%). LC-MS: 427 [M+H] +

[0669] Step-3: tert-Butyl ((6-(3-cyanophenoxy)pyridin-3-yl)methyl)carbamate

[0670] To a solution of tert-butyl ((6-(3-iodophenoxy)pyridin-3-yl)methyl)carbamate (1.2 g, 2.81 mmol) in DMF (10 mL) was added zinc cyanide (0.07 g, 0.56 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (0.32 g, 0.28 mmol) and stirred at 80 °C for 12 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude compound. It was purified by combined flash column chromatography using 23% EtOAc in hexane as eluent to give the title compound (0.26 g, 28.5%). LC-MS: 326 [M+H] +

[0671] Step-4: 3-((5-(Aminomethyl)pyridin-2-yl)oxy)benzonitrile hydrochloride

[0672] To a solution of tert-butyl ((6-(3-cyanophenoxy)pyridin-3-yl)methyl)carbamate (0.26 g, 0.79 mmol) in 1,4-dioxane (2 mL) was added 4 N HCl in 1,4-dioxane (2.85 mL) and stirred at RT for 1 h. The reaction mixture was then concentrated, diethyl ether was added, and the solid was collected by filtration to give the crude title compound (0.25 g) which was used further without purification. LC-MS: 226 [M+H] +

[0673] Step-5: N-((6-(3-cyanophenoxy)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide trifluoroacetate (Compound 22)

[0674] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.23 g, 1.19 mmol) in DMF (10 mL) was added HATU (0.55 g, 1.43 mmol) and triethylamine (0.61 g, 5.98 mmol) and stirred at RT for 10 min. Then 3-((5-(aminomethyl)pyridin-2-yl)oxy)benzonitrile hydrochloride (0.25 g, 0.95 mmol) was added and the mixture was stirred at RT for 6 h. The reaction mixture was added to ice-cold water and the formed precipitate was collected by filtration and dried. The crude residue was further purified by preparative HPLC using method A to give the title compound as a TFA salt (0.03 g, 5%). LC-MS: 400 [M+H] + ; 1 H-NMR (400 MHz, DMSO-D6) δ 11.06 (s, 1H), 8.93 (t, 1H), 8.09 (s, 1H), 7.83-7.81 (dd, 1H), 7.65-7.64 (m, 2H), 7.60-7.57 (m, 2H), 7.47-7.46 (m, 2H), 7.13-7.11 (dd, 1H), 7.08-7.06 (dd, 1H), 4.40-4.39 (d,2H) 3.27 (s, 3H)

[0675] Example-23

[0676] [Chemical formula 55]

[0677]

[0678] Step-1: 6-(Cyclopropyl(4-fluorophenyl)amino)nicotinonitrile

[0679] To a solution of 6-((4-fluorophenyl)amino)nicotinonitrile (1 g, 4.68 mmol) in acetonitrile (10 mL) was added pyridine (1.29 g, 16.41 mmol), cyclopropylboronic acid (0.80 g, 9.30 mmol) and copper(II) acetate (0.17 g, 0.93 mmol), followed by stirring at 45 °C for 40 h. The reaction mixture was poured into water and extracted with EtOAc. The separated organic layer was washed with brine, dehydrated over anhydrous Na2SO4 and concentrated to give the crude compound. The crude compound was purified by combined flash column chromatography using 20% ​​EtOAc in hexane as eluent to give the title compound (0.45 g, 37.9%). LC-MS: 254 [M+H] + . 1 H-NMR (400 MHz, DMSO-D6) δ 8.45 (d, 1H), 7.97-7.95 (dd, 1H), 7.27-7.25 (m, 4H), 7.02-7.00 (d, 1H), 3.13-3.10 (m, 1H), 0.94-0.92 (m, 2H),0.53-0.51 (m, 2H).

[0680] Step-2: 5-(Aminomethyl)-N-cyclopropyl-N-(4-fluorophenyl)pyridin-2-amine

[0681] A solution of 6-(cyclopropyl(4-fluorophenyl)amino)nicotinonitrile (0.22 g, 0.86 mmol) in MeOH (2 mL) was cooled to 0 °C. To the solution was added 7 N ammonia in MeOH (0.3 mL) followed by Raney nickel (0.22 g) and stirred under hydrogen balloon pressure at RT for 2 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the crude title compound (0.22 g) which was used further without purification. LC-MS: 258 [M+H] + .

[0682] Step-3: N-((6-(cyclopropyl(4-fluorophenyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 23)

[0683] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.2 g, 1.04 mmol) in DMF (4 mL) was added EDC·HCl (0.23 g, 1.2 mmol) and HOBt (0.16 g, 1.2 mmol) and stirred at RT for 10 min. Then 5-(aminomethyl)-N-cyclopropyl-N-(4-fluorophenyl)pyridin-2-amine (0.21 g, 0.8 mmol) and then triethylamine (0.31 g, 3.12 mmol) were added thereto and the mixture was stirred at RT for 6 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give a crude compound. It was purified by combining flash column chromatography using 5% MeOH in DCM as eluent to give the title compound (0.01 g, 2.3%). LC-MS: 432 [M+H] + ; 1 H-NMR (400 MHz, DMSO-D6) δ 11.06 (s, 1H), 8.84 (m, 1H), 8.02(d, 1H), 7.62-7.6 (m, 2H), 7.49 (s, 1H), 7.23-7.14 (m, 4H), 6.98-6.96 (d,1H), 4.33-4.31 (d, 2H), 3.32-3.30 (m, 3H), 2.98 (m, 2H), 0.89 (m, 2H), 0.47-0.46 (m, 2H).

[0684] Example-24

[0685] [Chemical formula 56]

[0686]

[0687] Step-1: 6-(Methyl(1-methylpiperidin-4-yl)amino)nicotinonitrile

[0688] To a stirred solution of 6-chloronicotinonitrile (0.2 g, 1.44 mmol) in 1,4-dioxane (4 mL) was added N,1-dimethylpiperidin-4-amine (0.20 g, 1.59 mmol) followed by cesium carbonate (1.41 g, 4.33 mmol). The reaction mass was degassed with argon for 15 min. Xantphos (0.17 g, 0.28 mmol) and Pd2(dba)3 (0.07 g, 0.07 mmol) were added thereto and the mixture was heated to 100 °C in a microwave oven for 2 h. The reaction mass was filtered through celite and concentrated. The crude residue was dissolved in water and extracted with EtOAc. The separated organic layer was washed with brine, dehydrated over anhydrous Na2SO4 and concentrated to obtain the crude compound. The crude compound was purified by combined flash chromatography using 10% MeOH in DCM as eluent to give the title compound (0.33 g, 99.4%). LC-MS: 231 [M+H] +

[0689] Step-2: 5-(Aminomethyl)-N-methyl-N-(1-methylpiperidin-4-yl)pyridin-2-amine

[0690] A solution of 6-(methyl(1-methylpiperidin-4-yl)amino)nicotinonitrile (0.33 g, 1.43 mmol) in MeOH (4 mL) was cooled to 0 °C, to which was added Raney Nickel (0.33 g) followed by 7 N ammonia in MeOH (0.4 mL) and stirred under hydrogen balloon pressure at RT for 3 h. The reaction mass was filtered through celite and the filtrate was concentrated to get the crude compound. The crude compound was purified by washing with diethyl ether to get the title compound (0.3 g, 89.5%). LC-MS: 235 [M+H] +

[0691] Step-3: 1-methyl-N-((6-(methyl(1-methylpiperidin-4-yl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 24)

[0692] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.18 g, 0.93 mmol) in DMF (4 mL) was added EDC·HCl (0.18 g, 0.93 mmol), HOBt (0.13 g, 0.96 mmol), and stirred at RT for 10 min. Then 5-(aminomethyl)-N-methyl-N-(1-methylpiperidin-4-yl)pyridin-2-amine (0.15 g, 0.64 mmol) and then triethylamine (0.24 g, 2.34 mmol) were added thereto, and the mixture was stirred at RT for 12 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. It was purified by preparative HPLC using method B to give the title compound (0.03 g, 8.98%). LC-MS: 409 [M+H] + ; 1 H-NMR (400 MHz, DMSO-D6) δ 7.95-7.85 (m, 2H), 7.59-7.55 (d, 1H), 7.48 (s, 1H), 7.34-7.28 (d,2H), 7.16- 7.14 (d, 1H), 4.35 (s, 2H), 4.32-4.28 (bs, 1H), 3.55-3.45 (d, 2H),3.28 (s, 3H), 3.1-3.0 (t, 2H), 2.94 (s, 3H), 2.77 (s, 3H), 2.05-1.98 (m, 3H),1.92-1.85 (d, 2H).

[0693] Example-25

[0694] [Chemical formula 57]

[0695]

[0696] Step-1: 2-((4,4-difluorocyclohexyl)amino)thiazole-5-carbonitrile

[0697] To a stirred solution of 2-chlorothiazole-5-carbonitrile (0.50 g, 3.46 mmol) in DMSO (5 mL) was added DIPEA (1.34 g, 10.37 mmol) followed by 4,4-difluorocyclohexan-1-amine hydrochloride (0.59 g, 3.46 mmol) and stirred at 100 °C for 16 h. The reaction mixture was poured into ice-cold water and extracted with EtOAc. The separated organic layer was washed with brine, dehydrated over anhydrous Na2SO4 and concentrated to give the crude compound. The crude compound was purified by combined flash column chromatography using 20% ​​EtOAc in hexane as eluent to give the title compound (0.40 g, 47.56%). LC-MS: 242 [MH] - .

[0698] Step-2: tert-Butyl (5-cyanothiazol-2-yl)(4,4-difluorocyclohexyl)carbamate

[0699] To a solution of 2-((4,4-difluorocyclohexyl)amino)thiazole-5-carbonitrile (0.20 g, 0.82 mmol) in acetonitrile (5 mL) was added triethylamine (0.25 g, 2.47 mmol) and DMAP (0.01 g, 0.08 mmol), followed by the addition of di-tert-butyl dicarbonate (0.21 g, 0.98 mmol) dropwise at 0 °C. The reaction mixture was stirred at RT for 12 h, then poured into water and extracted with EtOAc. The separated organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude compound. The crude compound was purified by combined flash column chromatography using 30% EtOAc in hexane as eluent to give the title compound (0.16 g, 56.93%). LC-MS: 344 [M+H] + .

[0700] Step-3: tert-Butyl (5-(aminomethyl)thiazol-2-yl)(4,4-difluorocyclohexyl)carbamate

[0701] To a solution of tert-butyl (5-cyanothiazol-2-yl)(4,4-difluorocyclohexyl)carbamate (0.29 g, 0.84 mmol) in EtOH (5 mL) was added Raney nickel (0.29 g) and stirred under hydrogen balloon pressure at RT for 12 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.25 g, 85.61%). LC-MS: 349 [M+H] + .

[0702] Step-4: tert-Butyl (4,4-difluorocyclohexyl)(5-((1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamido)methyl)thiazol-2-yl)carbamate

[0703] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.21 g, 1.09 mmol) in DMF (5 mL) was added EDC·HCl (0.19 g, 0.99 mmol) and HOBt (0.13 g, 0.96 mmol), and stirred at RT for 10 min. Tert-butyl (5-(aminomethyl)thiazol-2-yl)(4,4-difluorocyclohexyl)carbamate (0.25 g, 0.72 mmol) and then triethylamine (0.33 g, 3.24 mmol) were added thereto, and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, and the formed precipitate was collected by filtration and dried to give the crude title compound (0.15 g, 39.94%). LC-MS: 522 [M+H] + .

[0704] Step-5: N-((2-((4,4-difluorocyclohexyl)amino)thiazol-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 25)

[0705] To a solution of tert-butyl (4,4-difluorocyclohexyl)(5-((1-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxamido)methyl)thiazol-2-yl)carbamate (0.15 g, 0.29 mmol) in 1,4-dioxane (2 mL) was added 4N HCl in 1,4-dioxane (4 mL) and stirred at RT for 2 h. The reaction mass was concentrated to get the crude compound. It was purified by preparative HPLC using method B to get the title compound (0.03 g, 22.0%). LC-MS: 422 [M+H] + ; 1 H-NMR (400 MHz, CD3OD) δ 7.67-7.65 (dd, 1H), 7.60-7.59 (d, 1H), 7.26 (s, 1H), 7.21-7.20 (d, 1H), 4.55 (s, 2H), 3.70-3.67 (m, 1H), 3.44 (s, 3H), 2.16-2.10 (m, 4H), 2.01-1.92 (m, 2H), 1.77-1.72 (m, 2H).

[0706] Example-26

[0707] [Chemical formula 58]

[0708]

[0709] Step-1: 1-Methyl-4-(3-nitrobenzyl)piperazine

[0710] To a stirred solution of 1-methylpiperazine (3.24 g, 32.40 mmol) in acetonitrile (80 mL) was added K2CO3 (8.96 g, 64.80 mmol) followed by 1-(bromomethyl)-3-nitrobenzene (7.0 g, 32.40 mmol) and stirred at 80 °C for 10 h. The reaction mixture was poured into ice-cold water and extracted with EtOAc. The separated organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give the title compound (5.6 g, 73.56%). LCMS: 236 [M+H] +

[0711] Step-2: 3-((4-methylpiperazin-1-yl)methyl)aniline

[0712] To a stirred solution of 1-methyl-4-(3-nitrobenzyl)piperazine (5.0 g, 21.25 mmol) in concentrated HCl (15 mL) at 0 °C was added tin powder (5.04 g, 42.50 mmol) and stirred at 100 °C for 12 h. The reaction mixture was poured into water, basified with sodium bicarbonate, and extracted with 15% MeOH in DCM. The extract was dried over anhydrous Na2SO4 and concentrated to give the title compound (2.7 g, 61.9%). LCMS: 206 [M+H] + .

[0713] Step-3: N-methyl-3-((4-methylpiperazin-1-yl)methyl)aniline

[0714] A solution of 3-((4-methylpiperazin-1-yl)methyl)aniline (0.8 g, 3.89 mmol) in formic acid (0.2 g, 4.86 mmol) was stirred at 110 °C for 16 h. The reaction mixture was concentrated, the residue was diluted with THF (10 mL), and a 2M solution of lithium aluminum hydride in THF (0.18 g, 4.74 mmol) was added thereto at 0 °C. The reaction mixture was stirred at RT for 2 h and then quenched with EtOAc. The reaction mass was filtered through celite and the filtrate was concentrated. The crude compound was purified by combining flash column chromatography using 10% MeOH in DCM as eluent to obtain the title compound (0.6 g, 70.22%). LCMS: 220 [M+H]+

[0715] Step-4: 6-(methyl(3-((4-methylpiperazin-1-yl)methyl)phenyl)amino)nicotinonitrile

[0716] To a solution of N-methyl-3-((4-methylpiperazin-1-yl)methyl)aniline (0.36 g, 1.64 mmol) in toluene (6 mL) was added 6-chloronicotinonitrile (0.6 g, 4.33 mmol) followed by KOtBu (0.37 g, 3.28 mmol). The reaction mixture was degassed with argon for 15 min. Pd2(dba)3 (0.08 g, 0.08 mmol) and 2-(dicyclohexylphosphino)biphenyl (0.03 g, 0.08 mmol) were added and stirred at 110 °C for 16 h. The reaction mixture was concentrated to give the crude compound. It was further purified by preparative HPLC using method B to give the title compound (0.21 g, 39.80%). LCMS: 322 [M+H] + .

[0717] Step-5: 5-(Aminomethyl)-N-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-2-amine

[0718] To a stirred solution of 6-(methyl(3-((4-methylpiperazin-1-yl)methyl)phenyl)amino)nicotinonitrile (0.07 g, 0.218 mmol) in MeOH (5 mL) was added Raney Nickel (0.07 g) followed by ammonia in methanol (1 mL) and stirred at RT under hydrogen balloon pressure for 1 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.07 g, 98.5%). LC-MS: 326 [M+H] + .

[0719] Step-6: 1-Methyl-N-((6-(methyl(3-((4-methylpiperazin-1-yl)methyl)phenyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide trifluoroacetate (Compound 26)

[0720] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.10 g, 0.54 mmol) in DMF (4 mL) was added EDC·HCl (0.07 g, 0.39 mmol) and HOBt (0.05 g, 0.35 mmol) and stirred at RT for 10 min. Then 5-(aminomethyl)-N-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-2-amine (0.13 g, 0.40 mmol) and then triethylamine (0.24 g, 2.39 mmol) were added thereto and the mixture was stirred at RT for 16 h. The reaction mixture was concentrated to give the crude compound. It was further purified by preparative HPLC using method A to give the title compound as a TFA salt (0.03 g, 10.2%). LC-MS: 500 [M+H] + ; 1 H-NMR (400 MHz, CD3OD) δ8.03-8.00 (dd, 1H), 7.91 (d, 1H), 7.65-7.61 (m, 3H), 7.57-7.53 (m, 2H), 7.47-7.44 (d, 1H), 7.16-7.14 (d, 1H), 7.04-7.01 (d, 1H), 4.47 (s, 2H), 4.14 (s,2H), 3.55 (s, 3H), 3.50 (bs, 4H), 3.39 (s, 3H), 3.30-3.28 (m, 4H), 2.91 (s,3H).

[0721] Example-27

[0722] [Chemical formula 59]

[0723]

[0724] Step-1: 1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethan-1-one

[0725] To a stirred solution of 1-(6-bromopyridin-3-yl)ethan-1-one (0.5 g, 2.5 mmol) in DMF (10 mL) was added Cs2CO3 (1.63 g, 5.0 mmol) followed by 2,4-difluorophenol (0.32 g, 2.5 mmol) and stirred at 130 °C for 6 h. The reaction mixture was poured into ice-cold water and the separated solid was collected by filtration and dried to give the title compound (0.62 g, 100%). LC-MS: 250 [M+H] + .

[0726] Step-2: (E)-1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethan-1-one oxime

[0727] To a stirred solution of 1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethan-1-one (0.8 g, 3.2 mmol) in water (10 mL) was added sodium acetate (0.79 g, 9.63 mmol) followed by hydroxylamine hydrochloride (0.45 g, 6.42 mmol) and stirred at RT for 7 h. The reaction mixture was concentrated to remove the solvent, water was added thereto, and then extracted with ethyl acetate, which was dehydrated over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude compound (0.55 g, 83.45%). LC-MS: 265 [M+H] + .

[0728] Step-3: tert-Butyl (1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethyl)carbamate

[0729] A solution of (E)-1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethan-1-one oxime (0.55 g, 1.88 mmol) in methanol (10 mL) was cooled to 0°C, NiCl2·6H2O (0.25 g, 1.04 mmol) was added thereto, and then di-tert-butyl dicarbonate (0.68 g, 3.12 mmol) was added dropwise, and stirred for 5 min. Then NaBH4 (0.12 g, 3.12 mmol) was added thereto portionwise by maintaining the same temperature. After stirring at RT for 1 h, the reaction mass was concentrated to remove methanol. The residue was diluted with ethyl acetate, washed with water, dehydrated over anhydrous Na2SO4 and concentrated to obtain the title compound (0.5 g, 68.59%). LC-MS: 351 [M+H] + .

[0730] Step-4: 1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethan-1-amine hydrochloride

[0731] To a solution of tert-butyl (1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethyl)carbamate (0.25 g, 0.71 mmol) in 1,4-dioxane (1 mL) was added 4 M HCl (2 mL) in 1,4-dioxane and stirred at RT for 2 h. The reaction mixture was then concentrated, diethyl ether was added thereto, and the solid was collected by filtration to give the title compound (0.16 g, 78.43%). LC-MS: 251.05 [M+H] + .

[0732] Step-5: N-(1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 27)

[0733] To a solution of 2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.10 g, 0.52 mmol) in DMF (3 mL) was added HATU (0.122 g, 0.57 mmol) and stirred at RT for 10 min. Then 1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethan-1-amine hydrochloride (0.15 g, 0.52 mmol) followed by triethylamine (0.21 g, 2.08 mmol) was added thereto and the mixture was stirred at RT for 16 h. The reaction mixture was added to ice-cold water and the precipitate formed was collected by filtration, washed with water and dried. It was purified by coupling flash column chromatography using 5% MeOH in DCM as eluent to give the title compound (0.02 g, 11.4%). LC-MS: 425 [M+H] + .

[0734] 1 HNMR (400 MHz, DMSO-D6) δ 11.07 (s, 1H), 8.73-8.71 (d, 1H), 8.09-8.08(d, 1H), 7.91-7.88 (dd, 1H), 7.64-7.62 (d, 1H), 7.51 (d, 1H), 7.42-7.36 (m,2H), 7.15-7.09 (m, 3H), 5.15 (t, 1H), 3.30 (s, 3H), 1.49-1.47 (d, 3H).

[0735] Preparation-1

[0736] [Chemical formula 60]

[0737]

[0738] Step-1: 6-((1,3-dihydroisobenzofuran-5-yl)amino)nicotinonitrile

[0739] To a stirred solution of 6-fluoronicotinonitrile (0.02 g, 0.18 mmol) in acetic acid (1 mL) was added 1,3-dihydroisobenzofuran-5-amine (0.02 g, 0.18 mmol) followed by sodium acetate (0.01 g, 0.18 mmol) and the mixture was stirred at 100 °C for 48 h. The reaction mass was concentrated and the residue was purified by column chromatography using 40% EtOAc in n-hexane as eluent to obtain the title compound (0.02 g, 37%). LC-MS: 238 [M+H] + .

[0740] Preparation-2

[0741] [Chemical formula 61]

[0742]

[0743] Step-1: 1,1-Difluorospiro[2.3]hexane-5-carbonitrile

[0744] To a stirred solution of 3-methylenecyclobutane-1-carbonitrile (1.0 g, 10.73 mmol) in THF (10 mL) was added trimethyl(trifluoromethyl)silane (5.87 g, 37.5 mmol) followed by sodium iodide (0.8 g, 5.36 mmol) and the mixture was stirred at 70 °C for 4 h. The residue was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by combined flash column chromatography using 20% ​​EtOAc in n-hexane as eluent to give the title compound (1.1 g, 74.3%). 1 H-NMR (400 MHz, CDCl3): δ 3.28-3.25 (m, 1H), 2.74-2.64 (m, 2H), 2.63-2.61 (m, 2H), 1.37-1.32 (m, 2H).

[0745] Step-2: 1,1-Difluorospiro[2.3]hexane-5-carboxylic acid

[0746] To a stirred solution of 1,1-difluorospiro[2.3]hexane-5-carbonitrile (0.5 g, 3.49 mmol) in EtOH (5 mL) and water (2.5 mL) was added KOH (0.98 g, 17.46 mmol), and the mixture was stirred at 90 °C for 24 h. The reaction mixture was concentrated, and the residue was acidified with 1 N HCl, extracted with DCM, dried over anhydrous Na2SO4 and concentrated to give the title compound (0.5 g, 88.0%). 1H-NMR (400 MHz, DMSO-d6): δ 12.35 (bs, 1H), 4.04-4.03 (s,1H), 3.32-3.16 (m, 4H), 2.31-1.99 (m, 2H).

[0747] Step-3: tert-Butyl (1,1-difluorospiro[2.3]hexan-5-yl)carbamate

[0748] To a stirred solution of 1,1-difluorospiro[2.3]hexane-5-carboxylic acid (0.5 g, 3.08 mmol) in toluene (10 mL) was added triethylamine (0.68 g, 6.78 mmol) followed by DPPA (1.27 g, 4.62 mmol) and the mixture was stirred at RT for 10 min. Then t-BuOH (1 mL) was added and stirred at 80 °C for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified by combined flash column chromatography using 20% ​​EtOAc in n-hexane as eluent to give the title compound (0.5 g, 69.5%). 1 H-NMR (400MHz, CDCl3): δ 7.03-7.01 (m, 1H), 4.37-4.33 (m, 1H), 2.66-2.60 (m, 2H), 2.29-2.28 (m, 2H), 1.47 (s, 9H), 1.25-1.20 (m, 2H).

[0749] Step-4: 1,1-Difluorospiro[2.3]hexane-5-amine hydrochloride

[0750] To a solution of tert-butyl (1,1-difluorospiro[2.3]hexan-5-yl)carbamate (0.5 g, 2.14 mmol) in 1,4-dioxane (5 mL) was added 4 N HCl in 1,4-dioxane (5 mL), and the mixture was stirred at RT for 4 h. The reaction mixture was concentrated to give the title compound (0.3 g, 82%). LC-MS: 134 [M+H] + .

[0751] Preparation-3

[0752] [Chemical formula 62]

[0753]

[0754] Step-1: (5-cyanopyridin-2-yl)alanine methyl ester

[0755] To a stirred solution of 6-fluoronicotinonitrile (0.5 g, 4.09 mmol) in DMSO (10 mL) was added DIPEA (2.64 g, 20.47 mmol) followed by alanine methyl ester hydrochloride (0.57 g, 4.09 mmol) and the mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated to remove DIPEA, poured into ice-cold water, and the separated solid was collected by filtration and dried to give the title compound (0.58 g, 69%). LC-MS: 204 [MH] - .

[0756] Step-2: N-(5-cyanopyridin-2-yl)-N-methylalanine methyl ester

[0757] To a stirred solution of (5-cyanopyridin-2-yl)alanine methyl ester (0.58 g, 2.82 mmol) in DMF (6 mL) at 0°C was added NaH (60% dispersion in mineral oil) (0.17 g, 4.23 mmol) followed by dropwise addition of iodomethane (0.48 g, 3.39 mmol) and the mixture was stirred at RT for 1 h. The reaction mixture was poured into ice-cold water and the separated solid was collected by filtration and dried to give the title compound (0.59 g, 95%). LC-MS: 220 [M+H] + .

[0758] Step-3: 6-((1-hydroxypropan-2-yl)(methyl)amino)nicotinonitrile

[0759] To a stirred solution of N-(5-cyanopyridin-2-yl)-N-methylalanine methyl ester (0.09 g, 0.41 mmol) in THF (2 mL) was added LiBH4 (0.03 g, 1.64 mmol) at 0°C, and the mixture was stirred at RT for 2 h. The reaction mixture was quenched with saturated sodium sulfate solution and extracted with EtOAc. The separated organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give the title compound (0.09 g, 114.6%). LC-MS: 192 [M+H] + .

[0760] Step-4: 2-((5-(Aminomethyl)pyridin-2-yl)(methyl)amino)propan-1-ol

[0761] To a stirred solution of 6-((1-hydroxypropan-2-yl)(methyl)amino)nicotinonitrile (0.09 g, 0.47 mmol) in EtOH (10 mL) was added 7 M ammonia in MeOH (2 mL) followed by Raney nickel (0.1 g) and stirred under hydrogen pressure at RT for 3 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.09 g, 97%). LC-MS: 196 [M+H] + .

[0762] Preparation-4

[0763] [Chemical formula 63]

[0764]

[0765] Step-1: 4,5-Diamino-2-fluorobenzonitrile

[0766] To a stirred solution of 4-amino-2-fluoro-5-nitrobenzonitrile (0.80 g, 4.41 mmol) in EtOH (4 mL) was added Pd / C (0.4 g) and stirred under hydrogen balloon pressure at RT for 1 h. The reaction mass was filtered through celite and the filtrate was concentrated to afford the title compound (0.65 g 97%). LC-MS: 152 [M+H] + .

[0767] Step-2: 6-Fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile

[0768] To a stirred solution of 4,5-diamino-2-fluorobenzonitrile (0.65 g, 4.30 mmol) in THF (15 mL) was added CDI (1.05 g, 6.45 mmol), and the mixture was stirred at 70 °C for 16 h. The reaction mixture was poured into ice-cold water, and the separated solid was collected by filtration and dried to give the title compound (0.7 g, 92%). LC-MS: 178 [M+H] + .

[0769] Step-3: 6-Fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid

[0770] To a stirred solution of 6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile (0.65 g, 3.7 mmol) in EtOH (12 mL) was added KOH (3.7 g, 66.6 mmol) in water (12 mL), and the mixture was stirred at 80 °C for 24 h. The reaction mixture was concentrated to remove EtOH, diluted with water and acidified with 1 N HCl. The formed precipitate was collected by filtration and dried to give the title compound (0.55 g, 76%). LC-MS: 197 [M+H] + .

[0771] Preparation-5

[0772] [Chemical formula 64]

[0773]

[0774] Step-1: Methyl 3,4-diamino-5-chlorobenzoate

[0775] To a stirred solution of methyl 4-amino-3-chloro-5-nitrobenzoate (0.75 g, 3.25 mmol) in THF (15 mL) and water (6 mL) was added ammonium chloride (1.04 g, 19.5 mmol) followed by zinc powder (0.64 g, 3.36 mmol) and the mixture was stirred at RT for 3 h. The reaction mass was diluted with EtOAc and filtered through a celite bed. The filtrate was washed with water, dried over anhydrous Na2SO4 and concentrated to give the title compound (0.63 g, 96%). LC-MS: 201 [M+H] + .

[0776] Step-2: 7-chloro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid methyl ester

[0777] To a stirred solution of methyl 3,4-diamino-5-chlorobenzoate (0.73 g, 3.64 mmol) in THF (15 mL) was added CDI (1.18 g, 7.28 mmol), and the mixture was stirred at 65 °C for 12 h. The reaction mixture was poured into ice-cold water, and the separated solid was collected by filtration and dried to give the title compound (0.7 g, 85%). LC-MS: 227 [M+H] + .

[0778] Step-3: 7-Chloro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid

[0779] To a stirred solution of methyl 7-chloro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate (0.7 g, 3.08 mmol) in THF (6 mL) and MeOH (6 mL) was added LiOH (0.39 g, 9.24 mmol) in water (3 mL) and stirred at RT for 12 h. The reaction mixture was concentrated to remove THF and MeOH, diluted with water and acidified with 1 N HCl. The formed precipitate was collected by filtration and dried to give the title compound (0.65 g, 99%). LC-MS: 213 [M+H] + 。

[0780] Preparation-6

[0781] [Chemical formula 65]

[0782]

[0783] Step-1: 4-Bromo-2,3-difluoro-6-nitroaniline

[0784] To a stirred solution of 2,3-difluoro-6-nitroaniline (1.0 g, 5.74 mmol) in DMF (20 mL) was added N-bromosuccinimide (1.02 g, 5.74 mmol) at 0 °C, and the mixture was stirred at RT for 12 h. After the reaction was complete, the reaction mixture was added to ice-cold water, and the precipitated solid was collected by filtration and dried to give the title compound (1.0 g, 68.82%). LC-MS: 253 [M+H] + .

[0785] Step-2: 5-Bromo-3,4-difluorobenzene-1,2-diamine

[0786] To a stirred solution of 4-bromo-2,3-difluoro-6-nitroaniline (1.0 g, 3.95 mmol) in THF (30 mL) was added ammonium chloride (1.26 g, 23.71 mmol) in water (10 mL) followed by zinc powder (0.77 g, 11.85 mmol) and the mixture was stirred at RT for 2 h. The reaction mixture was filtered through celite and the filtrate was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated to give the title compound (0.83 g, 94.1%). LC-MS: 221 [MH] - .

[0787] Step-3: 6-Bromo-4,5-difluoro-1,3-dihydro-2H-benzimidazol-2-one

[0788] To a stirred solution of 5-bromo-3,4-difluorobenzene-1,2-diamine (0.82 g, 3.67 mmol) in THF (20 mL) was added CDI (1.3 g, 8.06 mmol) and stirred at 70 °C for 3 h. The reaction mixture was concentrated to remove THF and then poured into ice-cold water, the precipitated solid was collected by filtration and dried to give the title compound (0.9 g, 98.30%). LC-MS: 247 [MH] - .

[0789] Step-4: 6,7-difluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid methyl ester

[0790] To a stirred solution of 6-bromo-4,5-difluoro-1,3-dihydro-2H-benzimidazol-2-one (0.5 g, 2.0 mmol) in MeOH (5 mL) was added triethylamine (1.46 g, 14.4 mmol). The reaction mass was degassed with argon for 15 min. Then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.35 g, 0.48 mmol) was added thereto and stirred at 80 psi of carbon monoxide and 80 °C for 12 h. The reaction mixture was filtered through celite and the filtrate was concentrated to obtain the title compound (0.4 g, 87%). LC-MS: 227 [MH] - .

[0791] Step-5: 6,7-Difluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid

[0792] To a stirred solution of methyl 6,7-difluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate (0.35 g, 1.53 mmol) in THF (1 mL) was added NaOH (0.24 g, 6.13 mmol) in water (2 mL) and stirred at 65 °C for 6 h. The reaction mixture was concentrated to remove THF and acidified with 1 N HCl. The formed precipitate was collected by filtration and dried to give the title compound (0.28 g, 85.24%). LC-MS: 213 [MH] - .

[0793] Preparation-7

[0794] [Chemical formula 66]

[0795]

[0796] Step-1: 3-Fluoro-N-methyl-2-nitroaniline

[0797] To a stirred solution of 1,3-difluoro-2-nitrobenzene (2.0 g, 12.57 mmol) in MeOH (40 mL) was added 2 M methylamine (0.39 g, 12.57 mmol) in THF at 0 °C and the mixture was stirred at RT for 16 h. The reaction mass was concentrated and diluted with ice-cold water. The mixture was extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give the title compound (1.5 g, 70.13%). LC-MS: 171 [M+H] + .

[0798] Step-2: 4-Bromo-3-fluoro-N-methyl-2-nitroaniline

[0799] To a stirred solution of 3-fluoro-N-methyl-2-nitroaniline (1.5 g, 8.81 mmol) in DMF (20 mL) was added N-bromosuccinimide (1.56 g, 8.81 mmol) at 0 °C and the mixture was stirred at RT for 3 h. After completion of the reaction, the reaction mass was added to ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography using 15% EtOAc in n-hexane as eluent to obtain the title compound (1.0 g, 45.55%). LC-MS: 249 [M+H] + .

[0800] Step-3: 4-Bromo-3-fluoro-N 1 -Methylbenzene-1,2-diamine

[0801] To a stirred solution of 4-bromo-3-fluoro-N-methyl-2-nitroaniline (1.0 g, 4.01 mmol) in THF (30 mL) was added ammonium chloride (1.29 g, 24.09 mmol) in water (5 mL) followed by zinc powder (0.78 g, 12.04 mmol) and the mixture was stirred at RT for 3 h. The reaction mixture was filtered through celite and the filtrate was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated to give the title compound (0.8 g, 90.95%). LC-MS: 219 [M+H] + .

[0802] Step-4: 5-Bromo-4-fluoro-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

[0803] To 4-bromo-3-fluoro-N 1To a stirred solution of 1-methylbenzene-1,2-diamine (0.8 g, 3.65 mmol) in acetonitrile (10 mL) was added CDI (1.18 g, 7.3 mmol) and stirred at 65 °C for 12 h. The reaction mixture was concentrated and poured into ice-cold water, and the precipitated solid was collected by filtration and dried to give the title compound (0.8 g, 89.39%). LC-MS: 245 [M+H] + .

[0804] Step-5: 4-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile

[0805] To a stirred solution of 5-bromo-4-fluoro-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.75 g, 3.06 mmol) in N,N-dimethylacetamide (40 mL) was added sodium carbonate (0.08 g, 0.81 mmol) followed by potassium ferrocyanide trihydrate (0.55 g, 1.3 mmol) and degassed with argon for 15 min. Palladium diacetate (0.07 g, 0.32 mmol) was added to the reaction mixture and stirred at 120 °C for 4 h. The reaction mass was filtered through celite, the filtrate was diluted with water and extracted with EtOAc, dehydrated over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography using 70% EtOAc in n-hexane as eluent to obtain the title compound (0.36 g, 57.68%). LC-MS: 190 [MH] - .

[0806] Step-6: 4-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid

[0807] To a stirred solution of 4-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile (0.33 g, 1.72 mmol) in EtOH (15 mL) was added KOH (0.29 g, 5.17 mmol) dissolved in water (3 mL) and stirred at 85 °C for 16 h. The reaction mixture was then concentrated and acidified with 1 N HCl. The precipitated solid was collected by filtration and dried to give the title compound (0.13 g, 35.83%). LC-MS: 211 [M+H] + .

[0808] Example-103

[0809] [Chemical formula 67]

[0810]

[0811] Step-1: 6-(3-(Trifluoromethyl)cyclobutyloxy)nicotinonitrile

[0812] To a stirred solution of 6-chloronicotinonitrile (0.18 g, 1.29 mmol) in THF (4 mL) was added 3-(trifluoromethyl)cyclobutan-1-ol (0.2 g, 1.42 mmol) followed by KOtBu (0.22 g, 1.95 mmol) and the mixture was stirred at RT for 12 h. The reaction mixture was quenched with ice-cold water and extracted with EtOAc. The separated organic layer was dried over anhydrous Na2SO4 and concentrated to give the title compound (0.3 g, 95%). LC-MS: 243 [M+H] + .

[0813] Step-2: (6-(3-(Trifluoromethyl)cyclobutyloxy)pyridin-3-yl)methanamine

[0814] To a stirred solution of 6-(3-(trifluoromethyl)cyclobutyloxy)nicotinonitrile (0.45 g, 1.85 mmol) in EtOH (30 mL) was added 7 M ammonia in MeOH (2 mL) followed by Raney nickel (0.5 g) and the mixture was stirred at RT under hydrogen balloon pressure for 3 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.42 g). LC-MS: 230 [M-NH2] + .

[0815] Step-3: 1-Methyl-2-oxo-N-((6-(3-(trifluoromethyl)cyclobutyloxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 103)

[0816] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.28 g, 1.46 mmol) in DMF (6 mL) was added EDC HCl (0.24 g, 1.29 mmol) followed by HOBt (0.08 g, 0.6 mmol) and the mixture was stirred at RT for 10 min. To the reaction mixture was added triethylamine (0.98 g, 9.7 mmol) followed by (6-(3-(trifluoromethyl)cyclobutyloxy)pyridin-3-yl)methanamine (0.4 g, 1.62 mmol) and stirred at RT for 12 h. The reaction mass was quenched with ice-cold water and extracted with EtOAc. The separated organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC using method C to give the title compound (0.08 g, 11%).

[0817] LC-MS: 421 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 8.89-8.86 (t, 1H), 8.05 (s, 1H), 7.65-7.57 (dd, 2H), 7.46 (s, 1H), 7.12-7.10 (d,1H), 6.76-6.74 (d, 1H), 5.11-5.04 (m, 1H), 4.35-4.33 (d, 2H), 3.29-3.09 (t,3H), 2.99-2.88 (m, 1H), 2.66-2.61 (m, 2H), 2.09-2.02 (m, 2H).

[0818] Example-104

[0819] [Chemical formula 68]

[0820]

[0821] Step-1: 3-((tert-Butyldimethylsilyl)oxy)cyclohexan-1-amine

[0822] To a stirred solution of 3-aminocyclohexan-1-ol (1.3 g, 11.3 mmol) in DCM (20 mL) was added imidazole (1.77 g, 26.04 mmol) followed by tert-butyldimethylsilyl chloride (1.96 g, 13.02 mmol) at 0 °C, and the mixture was stirred at RT for 4 h. The reaction mixture was quenched with ice-cold water and extracted with DCM. The separated organic layer was dried over anhydrous Na2SO4 and concentrated to give the title compound (2.5 g, 96%). LC-MS: 230 [M+H] + .

[0823] Step-2: 6-((3-((tert-butyldimethylsilyl)oxy)cyclohexyl)amino)nicotinonitrile

[0824] To a stirred solution of 6-chloronicotinonitrile (1.5 g, 10.8 mmol) in DMSO (20 mL) was added 3-((tert-butyldimethylsilyl)oxy)cyclohexan-1-amine (2.48 g, 10.8 mmol) followed by DIPEA (5.58 g, 43.3 mmol) and the mixture was stirred at 100 °C for 12 h. The reaction mixture was poured into ice-cold water and extracted with EtOAc. The separated organic layer was dehydrated over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography using 10% EtOAc in n-hexane as eluent to give the title compound (1.0 g, 27.86%). LC-MS: 332 [M+H] + .

[0825] Step-3: 6-((3-((tert-butyldimethylsilyl)oxy)cyclohexyl)(methyl)amino)nicotinonitrile

[0826] To a stirred solution of 6-((3-((tert-butyldimethylsilyl)oxy)cyclohexyl)amino)nicotinonitrile (1.0 g, 3.01 mmol) in DMF (10 mL) at 0°C was added NaH (60% dispersion in mineral oil) (0.18 g, 4.52 mmol) followed by dropwise addition of iodomethane (0.51 g, 3.61 mmol) and the mixture was stirred at RT for 1 h. The reaction mixture was poured into ice-cold water and extracted with EtOAc. The separated organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography using 10% EtOAc in n-hexane as eluent to give the title compound (0.8 g, 76.7%). LC-MS: 346 [M+H] + .

[0827] Step-4: 5-(Aminomethyl)-N-(3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-N-methylpyridin-2-amine

[0828] To a solution of 6-((3-((tert-butyldimethylsilyl)oxy)cyclohexyl)(methyl)amino)nicotinonitrile (0.8 g, 2.43 mmol) in EtOH (10 mL) was added 7 M ammonia in MeOH (3 mL) followed by Raney Nickel (0.8 g) and the mixture was stirred under hydrogen balloon pressure at RT for 4 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.8 g, 98%). LC-MS: 350 [M+H] + .

[0829] Step-5: N-((6-((3-((tert-butyldimethylsilyl)oxy)cyclohexyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide

[0830] To a solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.39 g, 2.05 mmol) in DMF (10 mL) were added EDC·HCl (0.39 g, 2.05 mmol) and HOBt (0.14 g, 1.03 mmol), and the mixture was stirred at RT for 10 min. To the mixture were added 5-(aminomethyl)-N-(3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-N-methylpyridin-2-amine (0.8 g, 2.29 mmol) and then triethylamine (1.15 g, 11.44 mmol), and the mixture was stirred at RT for 12 h. The reaction mixture was poured into ice-cold water and the precipitated solid was collected by filtration and dried to give the crude compound, which was purified by column chromatography using 90% EtOAc in n-hexane as eluent to give the title compound (0.23 g, 19.2%). LC-MS: 524 [M+H] + .

[0831] Step-6: N-((6-((3-Hydroxycyclohexyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 104)

[0832] To a solution of N-((6-((3-((tert-butyldimethylsilyl)oxy)cyclohexyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (0.23 g, 0.44 mmol) in MeOH (4 mL) was added 4 N HCl in 1,4-dioxane (2 mL), and the mixture was stirred at RT for 12 h. The reaction mixture was concentrated to remove the solvent. The residue was dissolved in water and the pH was adjusted to neutral. The precipitated solid was collected by filtration and dried to give the title compound (0.09 g, 50.0%).

[0833] LC-MS: 410 [M+H] + ; 1H-NMR (400 MHz, DMSO-d6): δ 11.3-11.2 (s, 1H),9.04-9.01 (t, 1H), 7.97-7.95 (d, 1H), 7.90 (s, 1H), 7.64-7.61 (dd, 1H), 7.50(s, 1H), 7.34-7.32 (s, 1H), 7.17-7.15 (s, 1H), 4.38-4.36 (dd, 2H), 4.09 (bs,1H), 3.59-3.51 (bs, 2H), 3.31 (s, 3H), 3.01 (s, 3H), 1.88-1.80 (m, 2H), 1.73-1.70 (d, 1H), 1.60-1.58 (d, 1H), 1.51-1.37 (m, 3H), 1.10-1.06 (q, 1H).

[0834] Example-105

[0835] [Chemical formula 69]

[0836]

[0837] Step-1: (S)-6-((3,3-difluorocyclopentyl)amino)nicotinonitrile

[0838] To a stirred solution of 6-fluoronicotinonitrile (0.1 g, 0.82 mmol) in DMSO (5 mL) was added DIPEA (0.27 g, 1.6 mmol) followed by (S)-3,3-difluorocyclopentan-1-amine hydrochloride (0.13 g, 0.82 mmol) and the mixture was stirred at 110 °C for 12 h. The reaction mixture was concentrated to remove DIPEA and then poured into ice-cold water. The separated solid was collected by filtration and dried to give the title compound (0.18 g, 99%). LC-MS: 224 [M+H] +

[0839] Step-2: (S)-6-((3,3-difluorocyclopentyl)(methyl)amino)nicotinonitrile

[0840] To a stirred solution of (S)-6-((3,3-difluorocyclopentyl)amino)nicotinonitrile (0.2 g, 0.89 mmol) in DMF (8 mL) at 0°C was added NaH (60% dispersion in mineral oil) (0.05 g, 1.34 mmol) followed by dropwise addition of iodomethane (0.15 g, 1.07 mmol) and the mixture was stirred at RT for 3 h. The reaction mixture was poured into ice-cold water and the separated solid was collected by filtration and dried to give the title compound (0.2 g, 95%). LC-MS: 238 [M+H] +

[0841] Step-3: (S)-tert-butyl((6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)carbamate

[0842] To a solution of (S)-6-((3,3-difluorocyclopentyl)(methyl)amino)nicotinonitrile (0.2 g, 0.84 mmol) in MeOH (40 mL) was added NiCl2·6H2O (0.03 g, 1.27 mmol) at 0°C followed by dropwise addition of di-tert-butyl dicarbonate (0.27 g, 1.26 mmol) and the mixture was stirred for 5 min. NaBH4 (0.22 g, 5.82 mmol) was added portionwise to the reaction mixture by maintaining the same temperature. After stirring at RT for 2 h, the reaction mass was concentrated to remove the solvent, diluted with EtOAc and filtered on a celite bed. The filtrate was washed with water, dehydrated over anhydrous Na2SO4 and concentrated. The residue was purified by combined flash column chromatography using 20% ​​EtOAc in n-hexane as eluent to obtain the title compound (0.17 g, 59%). LC-MS: 342 [M+H] +

[0843] Step-4: (S)-5-(Aminomethyl)-N-(3,3-difluorocyclopentyl)-N-methylpyridin-2-amine hydrochloride

[0844] To a stirred solution of (S)-tert-butyl((6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)carbamate (0.15 g, 0.44 mmol) in 1,4-dioxane (5 mL) was added 4 N HCl in 1,4-dioxane (5 mL), and the mixture was stirred at RT for 1 h. The reaction mixture was concentrated to give the title compound (0.1 g, 95%). LC-MS: 242 [M+H] +

[0845] Step-5: (S)-N-((6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 105)

[0846] To a stirred solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.09 g, 0.46 mmol) in DMF (4 mL) was added EDC·HCl (0.09 g, 0.46 mmol) followed by HOBt (0.03 g, 0.22 mmol), and the mixture was stirred at RT for 10 min. Then (S)-5-(aminomethyl)-N-(3,3-difluorocyclopentyl)-N-methylpyridin-2-amine hydrochloride (0.11 g, 0.46 mmol) followed by triethylamine (0.28 g, 2.7 mmol) was added thereto, and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC using method C to give the title compound (0.03 g, 18.0%). LC-MS: 416 [M+H] + ; 1 H-NMR (400 MHz, CD3OD): δ 8.10 (d, 1H), 7.66-7.64 (dd, 1H), 7.62-7.58 (dd, 2H), 7.18-7.16 (d, 1H), 6.71-6.69 (d, 1H), 5.27-5.23 (m, 1H), 4.45 (s, 2H), 3.43 (s, 3H), 2.91 (s, 3H), 2.36-1.96 (m, 6H).

[0847] Example-106

[0848] [Chemical formula 70]

[0849]

[0850] Step-1: tert-Butyl (3-oxocyclobutyl)carbamate

[0851] To a stirred solution of 3-aminocyclobutan-1-one hydrochloride (1.5 g, 12.33 mmol) in DMF (20 mL) was added triethylamine (1.88 g, 18.5 mmol) followed by di-tert-butyl dicarbonate (3.2 g, 14.80 mmol) at 0 °C and the mixture was stirred at RT for 12 h. The reaction mixture was concentrated to remove the solvent. The residue was purified by combined flash column chromatography using 5% MeOH in DCM as eluent to give the title compound (1.7 g, 74.3%). 1 H-NMR (400MHz, DMSO-d6): δ 7.43-7.40 (bs, 1H), 4.13-4.11 (m, 1H), 3.32-3.22 (m, 2H), 3.02-3.00 (m, 2H), 1.40 (d, 9H).

[0852] Step-2: tert-Butyl (3-hydroxycyclobutyl)carbamate

[0853] To a stirred solution of tert-butyl (3-oxocyclobutyl)carbamate (0.7 g, 3.77 mmol) in EtOH (20 mL) was added NaBH4 (0.07 g, 1.78 mmol) at 0°C and the mixture was stirred at RT for 1 h. The reaction mass was concentrated to remove EtOH. The residue was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated to give the title compound (0.6 g, 59%). 1 H-NMR (400 MHz, DMSO-d6): δ 7.03-7.01 (d, 1H), 4.98-4.96 (d,1H), 3.74-3.70 (m, 1H), 3.39-3.32 (m, 1H), 2.43-2.37 (m, 2H), 2.08-2.00 (m,2H), 1.37-1.36 (d, 9H).

[0854] Step-3: tert-Butyl (3-(difluoromethoxy)cyclobutyl)carbamate

[0855] To a stirred solution of tert-butyl (3-hydroxycyclobutyl)carbamate (0.6 g, 3.2 mmol) in acetonitrile (20 mL) was added copper iodide (0.12 g, 0.64 mmol) followed by 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.68 g, 3.84 mmol) and the mixture was stirred at 50° C. for 2.5 h. The reaction mass was concentrated to remove the solvent and diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated to give the title compound (0.45 g, 59%). 1 H-NMR (400 MHz, DMSO-d6): δ 7.40 (m, 1H), 6.78-6.40 (m, 1H), 3.98-3.84 (m, 1H), 2.23-2.17 (m,2H), 1.99-1.98 (m, 1H), 1.52-1.48 (m, 2H), 1.38-1.36 (d, 9H).

[0856] Step-4: 3-(Difluoromethoxy)cyclobutane-1-amine

[0857] To a solution of tert-butyl (3-(difluoromethoxy)cyclobutyl)carbamate (0.45 g, 1.26 mmol) in DCM (15 mL) was added TFA (1.5 mL) and the mixture was stirred at RT for 4 h. The reaction mixture was concentrated to give the title compound (0.24 g, 92%). LC-MS: 138 [M+H] +

[0858] Step-5: 6-((3-(difluoromethoxy)cyclobutyl)amino)nicotinonitrile

[0859] To a stirred solution of 6-fluoronicotinonitrile (0.26 g, 2.18 mmol) in DMSO (8 mL) was added DIPEA (1.7 g, 13.1 mmol) followed by 3-(difluoromethoxy)cyclobutan-1-amine (0.3 g, 2.18 mmol) and the mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated to remove DIPEA and the residue was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by combined flash column chromatography using 30% EtOAc in n-hexane as eluent to give the cis- and trans-isomers of the title compound, yl isomer I (0.07 g, 13%) and isomer II (0.05 g, 10%). LC-MS: 240 [M+H] +

[0860] Isomer I

[0861] Step-6: 6-((3-(difluoromethoxy)cyclobutyl)(methyl)amino)nicotinonitrile

[0862] To a stirred solution of 6-((3-(difluoromethoxy)cyclobutyl)amino)nicotinonitrile (Isomer I of step-5 above: 0.06 g, 0.25 mmol) in DMF (5 mL) at 0°C was added NaH (60% dispersion in mineral oil) (0.01 g, 0.37 mmol), followed by dropwise addition of iodomethane (0.04 g, 0.28 mmol), and the mixture was stirred at RT for 3 h. The reaction mixture was quenched with water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give the title compound (0.06 g, 95%). LC-MS: 254 [M+H] + .

[0863] Step-7: 5-(Aminomethyl)-N-(3-(difluoromethoxy)cyclobutyl)-N-methylpyridin-2-amine

[0864] To a stirred solution of 6-((3-(difluoromethoxy)cyclobutyl)(methyl)amino)nicotinonitrile (0.06 g, 0.23 mmol) in EtOH (5 mL) was added Raney Nickel (0.07 g) followed by 7 M ammonia in MeOH (2 mL) and the mixture was stirred at RT under hydrogen balloon pressure for 4 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.045 g, 73.2%). LC-MS: 258 [M+H] + .

[0865] Step-8: N-((6-((3-(difluoromethoxy)cyclobutyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 106 Isomer I)

[0866] To a stirred solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.03 g, 0.18 mmol) in DMF (4 mL) was added EDC·HCl (0.03 g, 0.18 mmol) followed by HOBt (0.01 g, 0.09 mmol) and the mixture was stirred at RT for 10 min. To the reaction mixture was added 5-(aminomethyl)-N-(3-(difluoromethoxy)cyclobutyl)-N-methylpyridin-2-amine (0.04 g, 0.18 mmol) followed by triethylamine (0.07 g, 0.73 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC method C to give the title compound (0.01 g, 12.7%). LC-MS: 432 [M+H] + ; 1 H-NMR (400 MHz, CDCl3): δ 8.18-8.17 (d, 1H), 8.08 (bs, 1H), 7.56-7.45 (m, 3H), 6.99-6.97 (d, 1H), 6.54-6.51 (d, 1H), 6.39-6.02 (m, 2H), 4.6-4.54 (m, 3H), 4.53-4.41 (m, 1H), 3.45 (s, 3H), 3.05 (s, 3H), 2.78-2.73 (m, 2H), 2.37-2.30 (m, 2H).

[0867] Isomer II

[0868] Step-6A: 6-((3-(difluoromethoxy)cyclobutyl)(methyl)amino)nicotinonitrile

[0869] To a stirred solution of 6-((3-(difluoromethoxy)cyclobutyl)amino)nicotinonitrile (Isomer II of step-5 above: 0.04 g, 0.18 mmol) in DMF (5 mL) at 0°C was added NaH (60% dispersion in mineral oil) (0.01 g, 0.28 mmol), followed by dropwise addition of iodomethane (0.03 g, 0.22 mmol), and the mixture was stirred at RT for 3 h. The residue was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated to give the title compound (0.04 g, 84%). LC-MS: 254 [M+H] + .

[0870] Step-7A: 5-(Aminomethyl)-N-(3-(difluoromethoxy)cyclobutyl)-N-methylpyridin-2-amine

[0871] To a stirred solution of 6-((3-(difluoromethoxy)cyclobutyl)(methyl)amino)nicotinonitrile (0.04 g, 0.23 mmol) in EtOH (5 mL) was added Raney Nickel (0.04 g) followed by 7 M ammonia in MeOH (2 mL) and the mixture was stirred at RT under hydrogen balloon pressure for 4 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.02 g, 73.2%). LC-MS: 258 [M+H] + .

[0872] Step-8A: N-((6-((3-(difluoromethoxy)cyclobutyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 106 Isomer II)

[0873] To a stirred solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.02 g, 0.1 mmol) in DMF (4 mL) was added EDC·HCl (0.02 g, 0.1 mmol) followed by HOBt (0.01 g, 0.05 mmol) and stirred at RT for 10 min. 5-(aminomethyl)-N-(3-(difluoromethoxy)cyclobutyl)-N-methylpyridin-2-amine (0.02 g, 0.1 mmol) followed by triethylamine (0.04 g, 0.43 mmol) was then added thereto and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give the crude compound. The crude was further purified by preparative HPLC method C to give the title compound (0.003 g, 6.7%). LC-MS: 432 [M+H] + ; 1H-NMR (400 MHz, CDCl3): δ 8.58 (s, 1H), 8.20-8.19 (s, 1H), 7.56-7.51 (m, 3H), 6.99-6.97 (d, 1H), 6.52-6.50 (d, 1H), 6.28-6.05 (m, 2H), 5.05-5.01 (m, 1H), 4.76-4.75 (m, 1H), 4.54-4.53 (d, 2H), 3.45 (s, 3H), 3.03-3.01 (s, 3H), 2.58-2.55 (m, 4H).

[0874] Example-107

[0875] [Chemical formula 71]

[0876]

[0877] Step-1: tert-Butyl (3-(trifluoromethoxy)cyclobutyl)carbamate

[0878] To a stirred solution of tert-butyl (3-hydroxycyclobutyl)carbamate (0.9 g, 4.8 mmol) in EtOAc (50 mL) were added silver trifluoromethanesulfonate (4.94 g, 19.22 mmol), KF (1.11 g, 19.22 mmol), 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (2.55 g, 7.21 mmol) and 2-fluoropyridine (1.86 g, 19.22 mmol), followed by trimethyl(trifluoromethyl)silane (1.87 g, 12.01 mmol), and the mixture was stirred at RT for 16 h. The reaction mass was filtered through celite, and the filtrate was washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by combined flash column chromatography using 10% EtOAc in n-hexane as eluent to give the title compound (0.65 g, 53%). 1 H-NMR (400 MHz, DMSO-d6): δ 7.23-7.21 (d, 1H), 4.53-4.45(m, 1H), 3.65-3.61 (m, 1H), 2.67-2.50 (m, 1H), 2.45-2.43 (m, 1H), 2.34-2.23 (m, 1H), 2.15-2.07 (m, 1H), 1.40-1.37 (d, 9H).

[0879] Step-2: 3-(Trifluoromethoxy)cyclobutane-1-amine

[0880] To a solution of tert-butyl (3-(trifluoromethoxy)cyclobutyl)carbamate (0.62 g, 2.44 mmol) in DCM (25 mL) was added TFA (3 mL) and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated to give the title compound (0.3 g, 80%). 1 H-NMR (400 MHz, DMSO-d6): δ 8.17 (s, 2H), 4.67-4.63 (m, 1H), 3.38-3.37 (m, 1H), 2.58-2.57 (m, 2H), 2.38-2.30 (m, 2H).

[0881] Step-3: 6-((3-(trifluoromethoxy)cyclobutyl)amino)nicotinonitrile

[0882] To a stirred solution of 6-fluoronicotinonitrile (0.5 g, 4.09 mmol) in DMSO (20 mL) was added DIPEA (3.17 g, 24.57 mmol) followed by 3-(trifluoromethoxy)cyclobutan-1-amine (0.63 g, 4.09 mmol) and the mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated to remove DIPEA and the residue was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by combined flash column chromatography using 30% EtOAc in n-hexane as eluent to give the cis- and trans-isomers of the title compound, namely Isomer I (0.3 g, 29%) and Isomer II (0.15 g, 14%). LC-MS: 258 [M+H] + .

[0883] Isomer I

[0884] Step-4: 6-(Methyl(3-(trifluoromethoxy)cyclobutyl)amino)nicotinonitrile

[0885] To a stirred solution of 6-((3-(trifluoromethoxy)cyclobutyl)amino)nicotinonitrile (Isomer I of step-3 above: 0.3 g, 1.16 mmol) in DMF (10 mL) was added NaH (60% dispersion in mineral oil) (0.14 g, 3.49 mmol) at 0°C, followed by dropwise addition of iodomethane (0.33 g, 2.33 mmol), and the mixture was stirred at RT for 3 h. The reaction mixture was quenched with ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified by combined flash column chromatography using 10% EtOAc in n-hexane as eluent to afford the title compound (0.25 g, 79%). LC-MS: 272 [M+H] + .

[0886] Step-5: 5-(Aminomethyl)-N-methyl-N-(3-(trifluoromethoxy)cyclobutyl)pyridin-2-amine

[0887] To a stirred solution of 6-(methyl(3-(trifluoromethoxy)cyclobutyl)amino)nicotinonitrile (0.25 g, 0.92 mmol) in EtOH (10 mL) was added Raney Nickel (0.25 g) and the mixture was stirred at RT under hydrogen balloon pressure for 2 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.25 g, 98%). LC-MS: 276 [M+H] + .

[0888] Step-6: 1-Methyl-N-((6-(methyl(3-(trifluoromethoxy)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 107 Isomer I)

[0889] To a stirred solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.14 g, 0.72 mmol) in DMF (8 mL) was added EDC·HCl (0.16 g, 0.81 mmol) followed by HOBt (0.05 g, 0.4 mmol) and the mixture was stirred at RT for 10 min. To the reaction mixture was added 5-(aminomethyl)-N-methyl-N-(3-(trifluoromethoxy)cyclobutyl)pyridin-2-amine (0.25 g, 0.9 mmol) followed by triethylamine (0.45 g, 4.54 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water and the resulting solid was collected by filtration and dried. It was purified by preparative TLC using 5% MeOH in DCM as eluent to give the title compound (0.03 g, 7%). LC-MS: 450 [M+H] + ; 1 H-NMR (400 MHz, CD3OD): δ 8.16-8.11 (d, 1H), 7.66-7.58 (m,3H), 7.18-7.16 (d, 1H), 6.68-6.67 (d, 1H), 4.59-4.57 (m, 1H), 4.46 (s, 2H), 4.41-4.36 (m, 1H), 3.43 (s, 3H), 3.00 (s, 3H), 2.83-2.77 (m, 2H), 2.42-2.37(m, 2H).

[0890] Isomer II

[0891] Step-4A: 6-(Methyl(3-(trifluoromethoxy)cyclobutyl)amino)nicotinonitrile

[0892] To a stirred solution of 6-((3-(trifluoromethoxy)cyclobutyl)amino)nicotinonitrile (Isomer II of step-3 above: 0.15 g, 0.58 mmol) in DMF (5 mL) was added NaH (60% dispersion in mineral oil) (0.07 g, 1.74 mmol) at 0°C, followed by dropwise addition of iodomethane (0.16 g, 1.16 mmol), and the mixture was stirred at RT for 3 h. The reaction mixture was quenched with ice-cold water and extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified by combined flash column chromatography using 10% EtOAc in n-hexane as eluent to afford the title compound (0.11 g, 69%). LC-MS: 272 [M+H] + .

[0893] Step-5A: 5-(Aminomethyl)-N-methyl-N-(3-(trifluoromethoxy)cyclobutyl)pyridin-2-amine

[0894] To a stirred solution of 6-(methyl(3-(trifluoromethoxy)cyclobutyl)amino)nicotinonitrile (0.11 g, 0.40 mmol) in EtOH (5 mL) was added Raney Nickel (0.12 g) and stirred at RT under hydrogen balloon pressure for 2 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.08 g, 71%). LC-MS: 276 [M+H] + .

[0895] Step-6A: 1-Methyl-N-((6-(methyl(3-(trifluoromethoxy)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 107 Isomer II)

[0896] To a stirred solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.04 g, 0.72 mmol) in DMF (3 mL) was added EDC HCl (0.05 g, 0.26 mmol) followed by HOBt (0.02 g, 0.13 mmol) and the mixture was stirred at RT for 10 min. To the reaction mixture was added 5-(aminomethyl)-N-methyl-N-(3-(trifluoromethoxy)cyclobutyl)pyridin-2-amine (0.08 g, 0.9 mmol) followed by triethylamine (0.15 g, 1.45 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water to give a solid which was collected by filtration and dried. It was purified by preparative TLC using 5% MeOH in DCM as eluent to give the title compound (0.03 g, 23%). LC-MS: 450 [M+H] + ; 1 H-NMR (400 MHz, CDCl3): δ 8.64 (d, 1H), 8.20-8.19 (d,1H), 7.57-7.52 (m, 3H), 6.99-6.97 (d, 1H), 6.53-6.51 (d, 1H), 6.29 (t, 1H),5.08-5.04 (m, 1H), 4.84-4.81(m, 1H), 4.55-4.54 (d, 2H), 3.45 (s, 3H), 3.01(s, 3H), 2.64-2.59 (m, 4H).

[0897] Example-108

[0898] [Chemical formula 72]

[0899]

[0900] Step-1: 6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid methyl ester

[0901] To a stirred solution of cyclopent-3-ene-1-carboxylic acid methyl ester (3.0 g, 23.7 mmol) in diethylene glycol dimethyl ether (15 mL) was added trimethyl(trifluoromethyl)silane (9.28 g, 59.4 mmol) followed by sodium iodide (1.78 g, 11.88 mmol) at 120° C. and the mixture was stirred for 72 h. The reaction mass was diluted with DCM, washed with water, dried over anhydrous Na2SO4 and concentrated to give the title compound (2.8 g, 66.8%). 1 H-NMR (400 MHz, CD3OD): δ3.23-3.10 (m, 1H), 2.90-2.80 (m, 1H), 2.66 (d, 3H), 2.33-2.24 (m, 4H), 2.05-2.01 (dd, 1H).

[0902] Step-2: 6,6-Difluorobicyclo[3.1.0]hexane-3-carboxylic acid

[0903] To a stirred solution of methyl 6,6-difluorobicyclo[3.1.0]hexane-3-carboxylate (2.5 g, 14.15 mmol) in THF (15 mL) and MeOH (10 mL) was added LiOH (0.6 g, 14.2 mmol) in water (5 mL), and the mixture was stirred at RT for 16 h. The reaction mixture was concentrated to remove THF and MeOH, acidified with 1 N HCl and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give the title compound (2.0 g, 87.0%). 1 H-NMR (400 MHz, CDCl3): δ 3.21-3.16 (m, 1H), 2.91-2.90 (m, 1H), 2.38-2.27 (m, 4H), 2.07-2.03(dd, 2H).

[0904] Step-3: tert-Butyl (6,6-difluorobicyclo[3.1.0]hexan-3-yl)carbamate

[0905] To a stirred solution of 6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid (1.5 g, 9.25 mmol) in toluene (20 mL) was added triethylamine (1.8 g, 18.5 mmol) followed by DPPA (3.8 g, 13.8 mmol) and the mixture was stirred at RT for 10 min. To the reaction mixture was added t-BuOH (9.0 g, 120.25 mmol) and stirred at 80 °C for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified by combined flash column chromatography using 20% ​​EtOAc in n-hexane as eluent to give the title compound (1.2 g, 55.6%). 1 H-NMR (400 MHz, DMSO-d6): δ 5.70-5.60 (d, 1H), 4.25-4.15 (m, 1H), 2.25-2.15 (m, 4H), 1.90-1.75 (m, 2H), 1.38-1.37 (d, 9H).

[0906] Step-4: 6,6-Difluorobicyclo[3.1.0]hexan-3-amine hydrochloride

[0907] To a stirred solution of tert-butyl (6,6-difluorobicyclo[3.1.0]hex-3-yl)carbamate (1.2 g, 5.14 mmol) in 1,4-dioxane (5 mL) was added 4 N HCl in 1,4-dioxane (10 mL), and the mixture was stirred at RT for 4 h. The reaction mixture was concentrated to give the title compound (0.3 g, 34%). LC-MS: 134 [M+H] + .

[0908] Step-5: 6-((6,6-difluorobicyclo[3.1.0]hexan-3-yl)amino)nicotinonitrile

[0909] To a stirred solution of 6-fluoronicotinonitrile (0.2 g, 1.63 mmol) in DMSO (6 mL) was added DIPEA (1.26 g, 9.8 mmol) followed by 6,6-difluorobicyclo[3.1.0]hexan-3-amine hydrochloride (0.27 g, 1.63 mmol) and the mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated to remove DIPEA and the residue was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by combined flash column chromatography using 30% EtOAc in n-hexane as eluent to give the title compound (0.04 g, 84%). LC-MS: 236 [M+H]+ .

[0910] Step-6: 6-((6,6-difluorobicyclo[3.1.0]hex-3-yl)(methyl)amino)nicotinonitrile

[0911] To a stirred solution of 6-((6,6-difluorobicyclo[3.1.0]hex-3-yl)amino)nicotinonitrile (0.2 g, 0.85 mmol) in DMF (5 mL) at 0°C was added NaH (60% dispersion in mineral oil) (0.05 g, 1.27 mmol) followed by dropwise addition of iodomethane (0.15 g, 1.02 mmol) and the mixture was stirred at RT for 3 h. The residue was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated to give the title compound (0.2 g, 94%). LC-MS: 250 [M+H] + .

[0912] Step-7: 5-(Aminomethyl)-N-(6,6-difluorobicyclo[3.1.0]hexan-3-yl)-N-methylpyridin-2-amine

[0913] To a stirred solution of 6-((6,6-difluorobicyclo[3.1.0]hex-3-yl)(methyl)amino)nicotinonitrile (0.19 g, 0.76 mmol) in EtOH (10 mL) was added Raney Nickel (0.2 g) followed by 7 M ammonia in MeOH (5 mL) and the mixture was stirred at RT under hydrogen balloon pressure for 4 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.19 g, 98.2%). LC-MS: 254 [M+H] + .

[0914] Step-8: N-((6-((6,6-difluorobicyclo[3.1.0]hexan-3-yl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 108)

[0915] To a stirred solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.15 g, 0.78 mmol) in DMF (4 mL) was added EDC·HCl (0.15 g, 0.78 mmol) followed by HOBt (0.06 g, 0.39 mmol) and the mixture was stirred at RT for 10 min. To the reaction mixture was added 5-(aminomethyl)-N-(6,6-difluorobicyclo[3.1.0]hex-3-yl)-N-methylpyridin-2-amine (0.2 g, 0.78 mmol) followed by triethylamine (0.31 g, 3.12 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC using method C to give the title compound (0.06 g, 18.0%). LC-MS: 428 [M+H] + ; 1 H-NMR (400 MHz, CD3OD): δ 8.09-8.02 (dd, 1H),7.85 (d, 1H), 7.65-7.62 (dd, 1H), 7.57-7.50 (dd, 1H), 7.31-7.29 (dd, 1H),7.18-7.16 (dd, 1H), 4.60-4.55 (m, 1H), 4.47 (s, 2H), 3.41 (s, 3H), 3.11 (s,3H), 2.39-2.30 (m, 4H), 2.25-2.1 (m, 2H).

[0916] Example-109

[0917] [Chemical formula 73]

[0918]

[0919] Step-1: 6-(Spiro[2.3]hexan-5-ylamino)nicotinonitrile

[0920] To a stirred solution of 6-fluoronicotinonitrile (0.13 g, 1.06 mmol) in DMSO (5 mL) was added DIPEA (0.28 g, 2.12 mmol) followed by spiro[2.3]hexan-5-amine hydrochloride (0.14 g, 1.06 mmol) and the mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated to remove DIPEA, poured into ice-cold water, and the separated solid was collected by filtration and dried to give the title compound (0.20 g, 94%). LC-MS: 200 [M+H] + .

[0921] Step-2: 6-(Methyl(spiro[2.3]hexan-5-yl)amino)nicotinonitrile

[0922] To a stirred solution of 6-(spiro[2.3]hexan-5-ylamino)nicotinonitrile (0.20 g, 1.00 mmol) in DMF (8 mL) at 0°C was added NaH (60% dispersion in mineral oil) (0.06 g, 1.50 mmol) followed by dropwise addition of iodomethane (0.17 g, 1.50 mmol) and the mixture was stirred at RT for 3 h. The reaction mixture was poured into ice-cold water and the separated solid was collected by filtration and dried to give the title compound (0.16 g, 74%). LC-MS: 214 [M+H] + .

[0923] Step-3: 5-(Aminomethyl)-N-methyl-N-(spiro[2.3]hexan-5-yl)pyridin-2-amine hydrochloride

[0924] To a stirred solution of 6-(methyl(spiro[2.3]hex-5-yl)amino)nicotinonitrile (0.13 g, 0.63 mmol) in MeOH (20 mL) was added NiCl2·6H2O (0.08 g, 0.09 mmol) at 0°C followed by dropwise addition of di-tert-butyl dicarbonate (0.21 g, 0.96 mmol) and the mixture was stirred for 5 min. Maintaining the same temperature, NaBH4 (0.17 g, 4.43 mmol) was added portionwise to the reaction mixture. After stirring at RT for 4 h, the reaction mass was concentrated to remove the solvent. The residue was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by combined flash column chromatography using 20% ​​EtOAc in n-hexane as the eluent. Transferred into 1,4-dioxane (2 mL), 4 M HCl in 1,4-dioxane (2 mL) was added and then stirred at RT for 4 h. The reaction mixture was concentrated to give the title compound (0.12 g, 90.6%). LCMS: 218 [M+H] + .

[0925] Step-4: 1-Methyl-N-((6-(methyl(spiro[2.3]hexan-5-yl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide formate (Compound 109)

[0926] To a stirred solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.10 g, 0.52 mmol) in DMF (4 mL) was added EDC·HCl (0.10 g, 0.52 mmol) followed by HOBt (0.03 g, 0.26 mmol) and the mixture was stirred at RT for 10 min. To the reaction mixture was added 5-(aminomethyl)-N-methyl-N-(spiro[2.3]hexan-5-yl)pyridin-2-amine hydrochloride (0.11 g, 0.52 mmol) followed by triethylamine (0.31 g, 3.12 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified using preparative HPLC method C to give the title compound as a formate salt (0.02 g, 10.0%). LC-MS: 392 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.82-8.79(t, 1H), 8.47 (s, 1H), 8.07-8.06 (d, 1H), 7.63-7.60 (dd, 1H), 7.50-7.40 (dd,2H), 7.15-7.13 (d, 1H), 6.62-6.60 (d, 1H), 5.01 (m, 1H), 4.31-4.29 (d, 2H), 3.33-3.30 (s, 3H), 2.97 (s, 3H), 2.42-2.33 (m, 2H), 2.18-2.15 (m, 2H), 0.52-0.49 (m, 2H), 0.44-0.41 (m, 2H).

[0927] Example-110

[0928] [Chemical formula 74]

[0929]

[0930] Step-1: 6-(((1S,3R)-3-fluorocyclopentyl)amino)nicotinonitrile

[0931] To a stirred solution of 6-fluoronicotinonitrile (0.15 g, 1.22 mmol) in acetonitrile (6 mL) was added DBU (0.15 g, 0.98 mmol) followed by (1S,3R)-3-fluorocyclopentan-1-amine hydrochloride (0.17 g, 1.22 mmol) and the mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated to give the title compound (0.25 g, 99%). LC-MS: 206 [M+H] + ;

[0932] Step-2: 6-(((1S,3R)-3-fluorocyclopentyl)(methyl)amino)nicotinonitrile

[0933] To a stirred solution of 6-(((1S,3R)-3-fluorocyclopentyl)amino)nicotinonitrile (0.25 g, 1.21 mmol) in DMF (6 mL) at 0 °C was added NaH (60% dispersion in mineral oil) (0.07 g, 1.82 mmol) followed by dropwise addition of iodomethane (0.20 g, 1.46 mmol) and the mixture was stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and extracted with EtOAc. The separated organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by combined flash column chromatography using 30% EtOAc in n-hexane as eluent to give the title compound (0.18 g, 67%). LC-MS: 220 [M+H] +

[0934] Step-3: 5-(Aminomethyl)-N-((1S,3R)-3-fluorocyclopentyl)-N-methylpyridin-2-amine

[0935] To a stirred solution of 6-(((1S,3R)-3-fluorocyclopentyl)(methyl)amino)nicotinonitrile (0.1 g, 0.45 mmol) in EtOH (10 mL) was added 7 M ammonia in MeOH (4 mL) followed by Raney nickel (0.03 g) and stirred under hydrogen pressure at RT for 1 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.1 g, 98%). LC-MS: 224 [M+H] + .

[0936] Step-4: N-((6-(((1S,3R)-3-fluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 110)

[0937] To a stirred solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.09 g, 0.46 mmol) in DMF (5 mL) was added EDC·HCl (0.09 g, 0.46 mmol) followed by HOBt (0.03 g, 0.23 mmol) and the mixture was stirred at RT for 10 min. To the reaction mixture was added 5-(aminomethyl)-N-((1S,3R)-3-fluorocyclopentyl)-N-methylpyridin-2-amine (0.10 g, 0.46 mmol) followed by triethylamine (0.19 g, 1.87 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water and the formed precipitate was collected by filtration and dried. The crude product was purified using preparative HPLC method C to give the title compound (0.04 g, 22.4%). LC-MS: 398 [M+H] + ; 1 H-NMR (400 MHz, CD3OD): δ 8.07-8.06 (d, 1H), 7.67-7.64 (dd, 1H), 7.61-7.58 (dd, 2H), 7.18-7.16 (d, 1H), 6.73-6.71 (d, 1H), 5.20-5.19 (m, 1H), 5.08-5.06 (m, 1H), 4.45 (s, 2H), 3.43 (s, 3H), 2.93 (s, 3H), 2.37-2.03 (m, 1H),1.94-1.88 (m, 1H), 1.82-1.70 (m, 4H).

[0938] Example-111

[0939] [Chemical formula 75]

[0940]

[0941] Step-1: 5-Bromo-2-(1-(3,3-difluoropyrrolidin-1-yl)ethyl)pyridine

[0942] To a stirred solution of 1-(5-bromopyridin-2-yl)ethan-1-one (0.5 g, 2.5 mmol) in MeOH (10 mL) was added 3,3-difluoropyrrolidine hydrochloride (0.46 g, 3.25 mmol) followed by sodium cyanoborohydride (0.47 g, 7.5 mmol) and the mixture was stirred at RT for 12 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over Na2SO4 and concentrated. The residue was purified by combined flash column chromatography using 10% EtOAc in n-hexane as eluent to give the title compound (0.48 g, 66%). LC-MS: 291 [M+H] + .

[0943] Step-2: 6-(1-(3,3-difluoropyrrolidin-1-yl)ethyl)nicotinonitrile

[0944] To a stirred solution of 5-bromo-2-(1-(3,3-difluoropyrrolidin-1-yl)ethyl)pyridine (0.25 g, 0.85 mmol) in t-BuOH and water was added DBU (0.03 g, 0.21 mmol) followed by potassium ferrocyanide trihydrate (0.14 g, 0.34 mmol). The reaction mass was degassed with argon for 15 min and then tetrakis(triphenylphosphine)palladium (0.05 g, 0.04 mmol) was added thereto and stirred at 90 °C for 12 h. The reaction mass was concentrated and the crude compound was purified by coupled flash column chromatography using 10% EtOAc in n-hexane as eluent to obtain the title compound (0.13 g, 63.79%). LC-MS: 238[M+H] + .

[0945] Step-3: (6-(1-(3,3-difluoropyrrolidin-1-yl)ethyl)pyridin-3-yl)methanamine

[0946] To a stirred solution of 6-(1-(3,3-difluoropyrrolidin-1-yl)ethyl)nicotinonitrile (0.11 g, 0.46 mmol) in EtOH (5 mL) was added Raney Nickel (0.14 g) and stirred under hydrogen balloon pressure at RT for 2 h. The reaction mixture was filtered through celite and the filtrate was concentrated to give the title compound (0.12 g). LC-MS: 242 [M+H] + .

[0947] Step-4: N-((6-(1-(3,3-difluoropyrrolidin-1-yl)ethyl)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide hydrochloride (Compound 111)

[0948] To a stirred solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.76 g, 0.39 mmol) in DMF (3 mL) was added triethylamine (0.3 g, 2.98 mmol), EDC·HCl (0.08 g, 0.44 mmol), HOBt (0.03 g, 0.22 mmol) followed by (6-(1-(3,3-difluoropyrrolidin-1-yl)ethyl)pyridin-3-yl)methanamine (0.12 g, 0.89 mmol) and the mixture was stirred at RT for 12 h. The reaction mass was quenched with water, extracted with EtOAc, dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC using method D to afford the title compound as HCl salt (0.02 g, 41.91%). LC-MS: 416 [M+H] + ; 1 H-NMR (400 MHz, CD3OD): δ 8.75-8.74(d, 1H), 8.0-7.98 (dd, 1H), 7.72-7.69 (dd, 1H), 7.63 (d, 1H), 7.57-7.55 (d,1H), 7.21-7.19 (d, 1H), 4.72-4.70 (q, 1H), 4.65 (s, 2H), 3.87-3.84 (m, 2H), 3.70 (m, 1H), 3.60 (m, 1H), 3.43 (s, 3H), 2.66 (m, 2H), 1.69-1.68 (d, 3H).

[0949] Example-112

[0950] [Chemical formula 76]

[0951]

[0952] Step-1: 1-(5-bromopyridin-2-yl)ethan-1-ol

[0953] To a stirred solution of 1-(5-bromopyridin-2-yl)ethan-1-one (0.5 g, 2.5 mmol) in THF (5 mL) was added NaBH4 (0.19 g, 5.0 mmol) at 0°C and the mixture was stirred at RT for 2 h. The reaction mass was concentrated to remove THF, quenched with ice-cold water and extracted with EtOAc. The separated organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to get the title compound (0.4 g 79%). LC-MS: 202 [M+H] + .

[0954] Step-2: 1-(5-bromopyridin-2-yl)ethyl methanesulfonate

[0955] To a stirred solution of 1-(5-bromopyridin-2-yl)ethan-1-ol (0.4 g, 1.98 mmol) in DCM (10 mL) was added triethylamine (0.4 g, 3.96 mmol) followed by methanesulfonyl chloride (0.27 g, 2.37 mmol) and the mixture was stirred at RT for 2 h. The reaction mixture was diluted with DCM, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by combined flash column chromatography using 20% ​​EtOAc in n-hexane as eluent to give the title compound (0.48 g, 86%). LC-MS: 280 [M+H] +

[0956] Step-3: 5-Bromo-2-(1-(3-(trifluoromethyl)pyrrolidin-1-yl)ethyl)pyridine

[0957] To a stirred solution of 1-(5-bromopyridin-2-yl)ethyl methanesulfonate (0.3 g, 1.07 mmol) in DMSO (5 mL) was added triethylamine (0.32 g, 3.21 mmol) followed by 3-(trifluoromethyl)pyrrolidine hydrochloride (0.23 g, 1.28 mmol) and the mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated and the residue was purified by combined flash column chromatography using 20% ​​EtOAc in n-hexane as eluent to give the title compound (0.08 g, 23%). LC-MS: 323 [M+H] + .

[0958] Step-4: 6-(1-(3-(trifluoromethyl)pyrrolidin-1-yl)ethyl)nicotinonitrile

[0959] To a stirred solution of 5-bromo-2-(1-(3-(trifluoromethyl)pyrrolidin-1-yl)ethyl)pyridine (0.08 g, 0.25 mmol) in t-BuOH (2 mL) and water (2 mL) was added DBU (0.01 g, 0.07 mmol) followed by potassium ferrocyanide trihydrate (0.05 g, 0.12 mmol). The reaction mixture was degassed with argon for 15 min, tetrakis(triphenylphosphine)palladium (0.03 g, 0.02 mmol) was added thereto, and the mixture was stirred at 90 °C for 5 h. The reaction mixture was cooled to RT, diluted with 10% MeOH in DCM, and filtered through celite. The filtrate was concentrated and purified by combining flash column chromatography using 20% ​​EtOAc in n-hexane as eluent to give the title compound (0.06 g, 97%). LC-MS: 270 [M+H] + .

[0960] Step-5: (6-(1-(3-(trifluoromethyl)pyrrolidin-1-yl)ethyl)pyridin-3-yl)methanamine

[0961] To a stirred solution of 6-(1-(3-(trifluoromethyl)pyrrolidin-1-yl)ethyl)nicotinonitrile (0.06 g, 0.24 mmol) in EtOH (5 mL) was added Raney Nickel (0.1 g) followed by 7 M ammonia in MeOH (2 mL) and the mixture was stirred at RT under hydrogen balloon pressure for 4 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.06 g, 98%). LC-MS: 274 [M+H] + .

[0962] Step-6: 1-methyl-2-oxo-N-((6-(1-(3-(trifluoromethyl)pyrrolidin-1-yl)ethyl)pyridin-3-yl)methyl)-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 112)

[0963] To a stirred solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.04 g, 0.20 mmol) in DMF (4 mL) was added EDC·HCl (0.04 g, 0.23 mmol) followed by HOBt (0.02 g, 0.12 mmol) and the mixture was stirred at RT for 10 min. To the reaction mixture was added (6-(1-(3-(trifluoromethyl)pyrrolidin-1-yl)ethyl)pyridin-3-yl)methanamine (0.07 g, 0.25 mmol) followed by triethylamine (0.13 g, 1.3 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was further purified using preparative HPLC method C to give the title compound (0.02 g, 17%). LC-MS: 448[M+H] + ; 1 H-NMR (400 MHz, CD3OD): δ 8.5 (s, 1H), 7.86-7.84 (dd, 1H), 7.7-7.68(dd, 1H), 7.61 (d, 1H), 7.52-7.50 (dd, 1H), 7.2-7.18 (d, 1H), 4.62 (s, 2H), 3.55-3.53 (m, 1H), 3.44 (s, 3H), 3.0-2.5(m, 5H), 2.15-1.85 (m, 2H), 1.44-1.42(d, 3H).

[0964] Example-113

[0965] [Chemical formula 77]

[0966]

[0967] Step-1: 6-Chloronicotinoyl chloride

[0968] To a stirred solution of 6-chloronicotinic acid (0.5 g, 3.17 mmol) in DCM (5 mL) was added oxalyl chloride (0.8 g, 6.3 mmol) at 0 °C. A catalytic amount of DMF was added to the mixture and stirred at RT for 2 h. The reaction mixture was concentrated under an argon atmosphere to give the title compound, which was further transferred to the next step without purification.

[0969] Step-2: 6-Chloropyridin-3-yl(phenyl)methanone

[0970] To a stirred solution of 6-chloronicotinoyl chloride (0.5 g, 3.17 mmol) in benzene (15 mL) at 0 °C was added aluminum chloride (0.8 g, 6.3 mmol) and stirred at 70 °C for 16 h. The reaction mixture was poured into water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. It was purified by combined flash column chromatography using 20% ​​EtOAc in n-hexane as eluent to give the title compound (0.5 g, 80.6%). LC-MS: 218 [M+H] + .

[0971] Step-3: (6-(Isopropyl(methyl)amino)pyridin-3-yl)(phenyl)methanone

[0972] To a stirred solution of 6-chloropyridin-3-yl(phenyl)methanone (0.3 g, 1.37 mmol) in EtOH (5 mL) was added N-methylpropan-2-amine (0.5 g 6.8 mmol) and stirred at 150 °C for 2 h under microwave irradiation. The reaction mixture was poured into water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated to give the title compound (0.45 g, 128.2%). LC-MS: 255 [M+H] + .

[0973] Step-4: N-[(E)-(6-(Isopropylamino)pyridin-3-yl)(phenyl)methylene]hydroxylamine

[0974] To a stirred solution of (6-(isopropyl(methyl)amino)pyridin-3-yl)(phenyl)methanone (0.32 g, 1.25 mmol) in EtOH (3 mL) and THF (3 mL) was added hydroxylamine hydrochloride (0.28 g, 4.0 mmol) followed by DIPEA (1.03 g, 8.0 mmol) and the mixture was stirred at 80 °C for 16 h. The reaction mass was concentrated to remove EtOH and THF. The residue was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated to give the title compound (0.38 g, 112%). LC-MS: 270 [M+H] +

[0975] Step-5: 5-(Amino(phenyl)methyl)-N-isopropyl-N-methylpyridin-2-amine

[0976] To a stirred solution of N-[(E)-(6-(isopropylamino)pyridin-3-yl)(phenyl)methylene]hydroxylamine (0.3 g, 1.1 mmol) in EtOH (10 mL) was added Raney Nickel (0.32 g) followed by 7 M ammonia in MeOH (5 mL) and stirred at RT under hydrogen balloon pressure for 4 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.2 g, 70.2%). LC-MS: 256 [M+H] + .

[0977] Step-6: N-((6-(isopropyl(methyl)amino)pyridin-3-yl)(phenyl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 113)

[0978] To a stirred solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.15 g, 0.78 mmol) in DMF (4 mL) was added EDC·HCl (0.15 g, 0.78 mmol) followed by HOBt (0.06 g, 0.46 mmol) and the mixture was stirred at RT for 10 min. To the reaction mixture was added 5-(amino(phenyl)methyl)-N-isopropyl-N-methylpyridin-2-amine (0.2 g, 0.78 mmol) followed by triethylamine (0.47 g, 4.68 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC using method C to give the title compound (0.1 g, 29.7%). LC-MS: 430 [M+H] + ; 1 H-NMR (400 MHz, CD3OD): δ 7.93-7.91 (d, 1H), 7.74-7.68 (bs, 2H), 7.64(bs, 1H), 7.41-7.28 (m, 6H), 7.12-7.10 (d, 1H), 6.37 (bs, 1H), 4.43-4.34 (m,1H), 3.34 (s, 3H), 3.05 (s, 3H), 1.29-1.27 (d, 6H).

[0979] Example-114

[0980] [Chemical formula 78]

[0981]

[0982] Step-1: 1-(6-(Isopropyl(methyl)amino)pyridin-3-yl)ethan-1-one

[0983] To a stirred solution of 1-(6-chloropyridin-3-yl)ethan-1-one (2.0 g, 12.85 mmol) in EtOH (5 mL) was added N-methylpropan-2-amine (2.82 g, 38.56 mmol) and stirred at 150 °C for 2 h under microwave irradiation. The reaction mixture was concentrated and the residue was purified by combined flash column chromatography using 20% ​​EtOAc in n-hexane as eluent to give the title compound (2.0 g, 81%). LC-MS: 193 [M+H] + .

[0984] Step-2: Methyl 2-(6-(isopropyl(methyl)amino)pyridin-3-yl)-2-oxoacetate

[0985] To a stirred solution of 1-(6-(isopropyl(methyl)amino)pyridin-3-yl)ethan-1-one (0.5 g, 2.60 mmol) in DMSO (10 mL) was added iodine (1.98 g, 7.8 mmol) and then K2CO3 (2.15 g, 15.6 mmol), and the mixture was stirred at 110°C for 2 h. The reaction mixture was cooled to RT, iodomethane (0.44 g, 3.12 mmol) was added thereto, and the mixture was stirred at 35°C for 1 h. The reaction mixture was quenched with saturated sodium sulfite solution and extracted with toluene. The separated organic layer was washed with brine, dehydrated over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC using 20% ​​EtOAc in n-hexane as eluent to give the title compound (0.2 g, 32%). LC-MS: 237 [M+H] + .

[0986] Step-3: (Z)-methyl 2-(hydroxyimino)-2-(6-(isopropyl(methyl)amino)pyridin-3-yl)acetate

[0987] To a stirred solution of methyl 2-(6-(isopropyl(methyl)amino)pyridin-3-yl)-2-oxoacetate (0.2 g, 0.84 mmol) in EtOH (5 mL) was added hydroxylamine hydrochloride (0.12 g, 1.69 mmol) followed by pyridine (0.13 g, 1.69 mmol) and the mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated to give the title compound (0.22 g). LC-MS: 252 [M+H] + .

[0988] Step-4: Methyl 2-amino-2-(6-(isopropyl(methyl)amino)pyridin-3-yl)acetate

[0989] To a stirred solution of methyl (Z)-2-(hydroxyimino)-2-(6-(isopropyl(methyl)amino)pyridin-3-yl)acetate (0.22 g) in EtOH (5 mL) was added Raney nickel (0.25 g) and the mixture was stirred under hydrogen pressure at RT for 3 h. The reaction mass was filtered through celite and the filtrate was concentrated to get the title compound (0.2 g). LC-MS: 238 [M+H] + .

[0990] Step-5: Methyl 2-(6-(isopropyl(methyl)amino)pyridin-3-yl)-2-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamido)acetate (Compound 114a)

[0991] To a stirred solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.13 g, 0.67 mmol) in DMF (5 mL) was added EDC·HCl (0.14 g, 0.75 mmol) followed by HOBt (0.05 g, 0.37 mmol) and the mixture was stirred at RT for 10 min. To the reaction mixture was added methyl 2-amino-2-(6-(isopropyl(methyl)amino)pyridin-3-yl)acetate (0.2 g, 0.84 mmol) followed by triethylamine (0.42 g, 4.21 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated (0.15 g). The residue (0.1 g) was purified using preparative HPLC method C to give the title compound (0.03 g). LC-MS: 412 [M+H] + ; 1 H-NMR (400 MHz, CD3OD): δ 8.07-8.02 (dd, 2H), 7.72-7.70 (d,1H), 7.61-7.60 (d, 1H), 7.33-7.31 (d, 1H), 7.22-7.20 (d, 1H), 5.75 (s, 1H), 4.47 (m, 1H), 3.82 (s, 3H), 3.44 (s, 3H), 3.08 (s, 3H), 1.34-1.33 (s, 6H).

[0992] Step-6: N-(2-Hydroxy-1-(6-(isopropyl(methyl)amino)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 114b)

[0993] To a stirred solution of methyl 2-(6-(isopropyl(methyl)amino)pyridin-3-yl)-2-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamido)acetate (0.04 g, 0.41 mmol) in THF (2 mL) at 0°C was added LiBH4 (0.004 g, 0.19 mmol) and the mixture was stirred at RT for 3 h. The reaction mixture was quenched with saturated sodium sulfite solution and extracted with EtOAc. The separated organic layer was washed, dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC using 5% MeOH in DCM as eluent to give the title compound (0.02 g, 53%). LC-MS: 384 [M+H] + ; 1 H-NMR (400 MHz, CD3OD): δ 8.11-8.10 (d, 1H), 7.72-7.69 (dd,1H), 7.62-7.59 (dd, 2H), 7.19-7.18 (d, 1H), 6.69-6.66 (d, 1H), 5.12-5.09 (m,1H), 4.73-4.70 (m, 1H), 3.89-3.85 (m, 2H), 3.44 (s, 3H), 2.85 (s, 3H), 1.20-1.18 (d, 6H).

[0994] Example-115

[0995] [Chemical formula 79]

[0996]

[0997] Step-1: 5-(Aminomethyl)-N-(4,4-difluorocyclohexyl)-N-methylpyridin-2-amine

[0998] To a stirred solution of 6-((4,4-difluorocyclohexyl)(methyl)amino)nicotinonitrile (0.1 g, 0.39 mmol) in EtOH (5 mL) was added Raney Nickel (0.1 g) followed by 7 M ammonia in MeOH (2 mL) and stirred at RT under hydrogen balloon pressure for 1 h. The reaction mass was filtered through celite and the filtrate was concentrated to give the title compound (0.09 g, 89%). LC-MS: 256 [M+H] + .

[0999] Step-2: N-((6-((4,4-difluorocyclohexyl)(methyl)amino)pyridin-3-yl)methyl)-6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 115)

[1000] To a stirred solution of 6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.16 g, 0.78 mmol) in DMF (4 mL) was added EDC·HCl (0.15 g, 0.78 mmol) followed by HOBt (0.05 g, 0.39 mmol) and the mixture was stirred at RT for 10 min. To the reaction mixture was added 5-(aminomethyl)-N-(4,4-difluorocyclohexyl)-N-methylpyridin-2-amine (0.2 g, 0.78 mmol) followed by triethylamine (0.24 g, 2.34 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC method C to give the title compound (0.03 g, 10%). LC-MS: 448[M+H] + ; 1 H-NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 8.55-8.45 (m, 1H), 8.06 (s,1H), 7.52-7.5 (dd, 1H), 7.20-7.14 (m, 2H), 6.67-6.65 (d, 1H), 4.64-4.58 (m,1H), 4.31-4.29 (d, 2H), 3.26 (s, 3H), 2.81 (s, 3H), 2.1-2.07 (m, 4H), 1.8-1.6(m, 4H).

[1001] Example-116

[1002] [Chemical formula 80]

[1003]

[1004] Step-1: Methyl 4-((trideuteromethyl)amino)-3-nitrobenzoate

[1005] To a stirred solution of methyl 4-fluoro-3-nitrobenzoate (0.5 g, 2.51 mmol) in DMF (8 mL) at 10 °C was added K2CO3 (0.69 g, 5.02 mmol) followed by methyl-d3-amine hydrochloride (0.18 g, 2.51 mmol) and the mixture was stirred at RT for 24 h. The reaction mixture was poured into ice-cold water and the separated solid was collected by filtration and dried to give the title compound (0.5 g, 93%). LC-MS: 214 [M+H] + .

[1006] Step-2: Methyl 3-amino-4-((trideuteratedmethyl)amino)benzoate

[1007] To a stirred solution of methyl 4-((trideuteratedmethyl)amino)-3-nitrobenzoate (0.09 g, 0.42 mmol) in THF (2 mL) and water (1 mL) was added ammonium chloride (0.23 g, 4.2 mmol) followed by zinc powder (0.22 g, 3.36 mmol) and the mixture was stirred at RT for 1 h. The reaction mass was diluted with EtOAc and filtered through a celite bed. The filtrate was washed with water, dried over anhydrous Na2SO4 and concentrated to give the title compound (0.07 g, 90%). LC-MS: 184 [M+H] + .

[1008] Step-3: 1-(trideuterated methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid methyl ester

[1009] To a stirred solution of methyl 3-amino-4-((trideuteratedmethyl)amino)benzoate (0.07 g, 0.42 mmol) in THF (2 mL) was added CDI (0.13 g, 0.84 mmol), and the mixture was stirred at 65 °C for 12 h. The reaction mixture was poured into ice-cold water, and the separated solid was collected by filtration and dried to give the title compound (0.05 g, 57%). LC-MS: 210 [M+H] +

[1010] Step-4: 1-(Trideuterated methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid

[1011] To a stirred solution of methyl 1-(trideuteromethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate (0.05 g, 0.24 mmol) in THF (2 mL) and MeOH (1 mL) was added KOH (0.02 g, 0.36 mmol) in water (1 mL) and stirred at RT for 16 h. The reaction mixture was concentrated to remove THF and MeOH, diluted with water and acidified with 1 N HCl. The formed precipitate was collected by filtration and dried to give the title compound (0.04 g, 85%). LC-MS: 196 [M+H] +

[1012] Step-5: 1-(trideuterated methyl)-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 116)

[1013] To a solution of 1-(trideuterated methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.04 g, 0.2 mmol) in DMF (2 mL) were added EDC·HCl (0.04 g, 0.2 mmol), HOBt (0.01 g, 0.07 mmol), and the mixture was stirred at RT for 10 minutes. To the reaction mixture were added 5-(aminomethyl)-N-methyl-N-(cis-3-(trifluoromethyl)cyclobutyl)pyridin-2-amine (0.06 g, 0.23 mmol) and then triethylamine (0.12 g, 1.2 mmol), and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, and the formed precipitate was collected by filtration and dried. It was sonicated and stirred with 10% DCM in n-hexane (10 mL) for 30 min, then collected by filtration and dried to give the title compound (0.04 g, 36%). LC-MS: 437 [M+H] + ; 1 H-NMR (400 MHz, CD3OD): δ 8.11 (d, 1H), 7.66-7.58 (m, 3H), 7.18-7.16 (d, 1H), 6.7-6.68 (d, 1H), 4.8-4.6 (m, 1H), 4.45(s, 2H), 3.0 (s, 3H), 2.82-2.80 (m, 1H), 2.5-2.46 (m, 2H), 2.34-2.30 (m, 2H).

[1014] Preparative HPLC method:

[1015] - Method A: Column-LUNA C18 (250mm x 19mm), 5.0µ; Eluent-A 0.05% TFA in water, B-ACN, Gradient-10% B at 0 min, 20% B at 2 min, 50% at 10 min, 70% at 15 min), Flow rate: 18 mL / min

[1016] - Method B: Column - Waters, Xselect, c18 (250mm x 21.2mm), 5.0µ; Eluent - A 0.05% TFA in water, B-ACN, Gradient - 10% B at 0 min, 30% B at 2 min, 70% at 8 min), Flow rate: 13 mL / min

[1017] - Method C: Column-LUNA C18 (250mm x 19mm), 5.0µ; Eluent-A 0.1% FA in water, B-ACN, Gradient-10% B at 0 min, 20% B at 2 min, 50% at 10 min, 70% at 15 min), Flow rate: 18 mL / min

[1018] - Method D: Column-LUNA C18 (250mm x 19mm), 5.0µ; Eluent-A 0.1% HCl in water, B-ACN, Gradient-10% B at 0 min, 20% B at 2 min, 50% at 10 min, 70% at 15 min), Flow rate: 18 mL / min

[1019] Examples 28 to 102 and 117 to 147

[1020] The compounds of Examples (Ex.) -28 to 102 and 117 to 147 shown in Tables 2 to 97 were prepared in a manner similar to the examples and steps of the references. For example, the term "E4-S4" in the "Ref." column of the table indicates that the compound was prepared in a manner similar to the above-mentioned reference "Example 4" - "Step 4". Similarly, the term "P5-S1" in the "Ref." column of the table indicates that the compound was prepared in a manner similar to the above-mentioned reference "Preparation 5" - "Step 1". It should be understood that due to the separation conditions, the compound can be obtained in a free form or a salt form.

[1021] A compound having a chemical formula having "HCl" near it indicates that the compound is isolated as a hydrochloride salt.

[1022] A compound whose chemical structure is marked with "*" indicates that the compound is an isomer having the configuration of the structure indicated.

[1023] The obtained compounds 82 and 130 were separated to obtain two optical isomers of the compounds, namely, compound 82 peak 1 and compound 82 peak 2, and compound 130 peak 1 and compound 130 peak 2, respectively.

[1024] (Preparative HPLC method: column - Chiral pak-IG (250 x 21.2 mm), 5µ; eluent: A: n-hexane, B: ETOH; isocratic: A:B (50:50); flow rate: 15 mL / min).

[1025] [Table 2]

[1026]

[1027] [Table 3]

[1028]

[1029] [Table 4]

[1030]

[1031] [Table 5]

[1032]

[1033] [Table 6]

[1034]

[1035] [Table 7]

[1036]

[1037] [Table 8]

[1038]

[1039] [Table 9]

[1040]

[1041] [Table 10]

[1042]

[1043] [Table 11]

[1044]

[1045] [Table 12]

[1046]

[1047] [Table 13]

[1048]

[1049] [Table 14]

[1050]

[1051] [Table 15]

[1052]

[1053] [Table 16]

[1054]

[1055] [Table 17]

[1056]

[1057] [Table 18]

[1058]

[1059] [Table 19]

[1060]

[1061] [Table 20]

[1062]

[1063] [Table 21]

[1064]

[1065] [Table 22]

[1066]

[1067] [Table 23]

[1068]

[1069] [Table 24]

[1070]

[1071] [Table 25]

[1072]

[1073] [Table 26]

[1074]

[1075] [Table 27]

[1076]

[1077] [Table 28]

[1078]

[1079] [Table 29]

[1080]

[1081] [Table 30]

[1082]

[1083] [Table 31]

[1084]

[1085] [Table 32]

[1086]

[1087] [Table 33]

[1088]

[1089] [Table 34]

[1090]

[1091] [Table 35]

[1092]

[1093] [Table 36]

[1094]

[1095] [Table 37]

[1096]

[1097] [Table 38]

[1098]

[1099] [Table 39]

[1100]

[1101] [Table 40]

[1102]

[1103] [Table 41]

[1104]

[1105] [Table 42]

[1106]

[1107] [Table 43]

[1108]

[1109] [Table 44]

[1110]

[1111] [Table 45]

[1112]

[1113] [Table 46]

[1114]

[1115] [Table 47]

[1116]

[1117] [Table 48]

[1118]

[1119] [Table 49]

[1120]

[1121] [Table 50]

[1122]

[1123] [Table 51]

[1124]

[1125] [Table 52]

[1126]

[1127] [Table 53]

[1128]

[1129] [Table 54]

[1130]

[1131] [Table 55]

[1132]

[1133] [Table 56]

[1134]

[1135] [Table 57]

[1136]

[1137] [Table 58]

[1138]

[1139] [Table 59]

[1140]

[1141] [Table 60]

[1142]

[1143] [Table 61]

[1144]

[1145] [Table 62]

[1146]

[1147] [Table 63]

[1148]

[1149] [Table 64]

[1150]

[1151] [Table 65]

[1152]

[1153] [Table 66]

[1154]

[1155] [Table 67]

[1156]

[1157] [Table 68]

[1158]

[1159] [Table 69]

[1160]

[1161] [Table 70]

[1162]

[1163] [Table 71]

[1164]

[1165] [Table 72]

[1166]

[1167] [Table 73]

[1168]

[1169] [Table 74]

[1170]

[1171] [Table 75]

[1172]

[1173] [Table 76]

[1174]

[1175] [Table 77]

[1176]

[1177] [Table 78]

[1178]

[1179] [Table 79]

[1180]

[1181] [Table 80]

[1182]

[1183] [Table 81]

[1184]

[1185] [Table 82]

[1186]

[1187] [Table 83]

[1188]

[1189] [Table 84]

[1190]

[1191] [Table 85]

[1192]

[1193] [Table 86]

[1194]

[1195] [Table 87]

[1196]

[1197] [Table 88]

[1198]

[1199] [Table 89]

[1200]

[1201] [Table 90]

[1202]

[1203] [Table 91]

[1204]

[1205] [Table 92]

[1206]

[1207] [Table 93]

[1208]

[1209] [Table 94]

[1210]

[1211] [Table 95]

[1212]

[1213] [Table 96]

[1214]

[1215] [Table 97]

[1216]

[1217] Bioassay

[1218] Example 148 KIT tyrosine kinase assay

[1219] An in vitro assay using recombinant human KIT tyrosine kinase protein was developed to measure the inhibition of KIT by compounds. KIT tyrosine kinase activity was measured by the ADP-Glo ​​Kinase Assay System using a poly(Glu4-Tyr) peptide substrate. The kinase assay was performed in white 384-well plates and luminescence was measured by a Victor X5 Multilabel Counter (Perkin Elmer).

[1220] Materials and methods

[1221] The recombinant intracellular domain of human KIT protein was purchased from Carna Biosciences (Kobe, Japan). Poly(Glu4-Tyr) peptide was purchased from Sigma-Aldrich (St. Louis, Missouri, USA). ADP-Glo ​​kinase assay reagent was purchased from Promega (Madison, Wisconsin, USA). Each test compound was dissolved in 100% DMSO to prepare a 10 mM stock solution. The stock solution was diluted to 400 μM and then serially diluted in 100% DMSO at a ratio of 1:3 to prepare a 9-point serial dilution. To prepare the compound working solution, each serial dilution solution was further diluted 1:8 with an assay buffer consisting of 50 mMTris-HCl pH 7.5, 20 mM MgCl2, 0.01% Tween-20, 2 mM MnCl2, 50 μM dithiothreitol (DTT).

[1222] Recombinant KIT protein was diluted to 1 μM with assay buffer. Poly(Glu4-Tyr) peptide and ATP were diluted to 300 μg / mL and 250 μM with assay buffer, respectively, and then mixed to prepare substrate solution. In a 384-well plate, 2 μL of working compound and 5 μL of recombinant KIT protein were mixed and incubated at room temperature for 30 minutes. After pre-incubation, 3 μL of substrate / ATP mixture was added and incubated at room temperature for 1 hour. Tyrosine phosphorylation of KIT kinase was quantified by ADP-Glo ​​Kinase Assay Kit according to the manufacturer's protocol. Briefly, the phosphorylation reaction was terminated by adding 10 μL of ADP-Glo ​​reagent and incubated at room temperature for 60 minutes. 20 μL of Kinase Detection Reagent was added to each well, and luminescence was measured with a plate reader. The assay control for this experiment was 2.5% DMSO, and assay buffer was used as a blank.

[1223] The half maximal inhibitory concentration (IC50) was calculated by a four-parameter logistic regression model using GraphPad Prism (GraphPad Software). The values ​​without recombinant KIT protein and test compound were used as negative controls (assay background). The values ​​with recombinant KIT protein but without test compound served as positive controls (100% activity).

[1224] Tables 98 and 99 below list the inhibitory effects of representative compounds of the present invention on KIT.

[1225] [Table 98]

[1226]

[1227] [Table 99]

[1228]

[1229] Notably, the representative compounds of the present invention exhibited selective inhibitory activity against KIT, while showing no significant inhibition against other kinases.

[1230] Example 149 SCF-dependent M-07e cell proliferation assay

[1231] A SCF-dependent cell proliferation assay was developed to measure the inhibitory potency of compounds in M-07e cells expressing wild-type human KIT protein. The assay was performed in 96-well plates and the IC50 of each KIT inhibitor was determined by CellTiter Glo assay reagent and VictorX5 multilabel counter (Perkin Elmer).

[1232] Materials and methods

[1233] M-07e cells were purchased from AcceGen Biotechnology. Cells were maintained in M-07e growth medium: RPMI-1640 containing 20% ​​FBS, 100 U / mL penicillin and 100 μg / mL streptomycin, 10 ng / mL rhGM-CSF, 10 ng / mL rhSCF. M-07e cells were seeded in 96-well plates at a density of 5000 cells / 90 μL / well. Test compounds were dissolved in 100% DMSO to prepare a 20 mM stock solution and serially diluted 1:3 with 100% DMSO to prepare 11-point serial dilutions ranging from 15 mM to 0.024 μM. The serially diluted compounds were then each diluted 1:50 with culture medium to obtain a test compound solution containing 2% DMSO. 10 μL of the test compound solution was added to 90 μL of the cultured cell suspension in a 96-well plate, with a final DMSO concentration of 0.2%. The plates were then incubated at 37°C for 3 days in a 5% CO2 incubator. To obtain a day 0 control for background calculation, cells were seeded into a new 96-well plate at a density of 5000 cells / 100 μL and treated the same day. The day 0 control and 3-day culture plates were then treated as follows. 100 μL of CellTiter Glo assay reagent was added to each well and the plates were incubated on a shaker at 200-300 RPM for 15 min at room temperature. A 100 μL sample of the cell lysate was then transferred to a white wall 96-well plate and luminescence was measured using a plate reader. The luminescence of the day 0 control was subtracted from the luminescence intensity of the 3-day culture reading. The assay control for this experiment was cells treated with 0.2% DMSO in culture medium, and wells containing 100 μL of culture medium (0.2% DMSO, no cells) were used as blanks for data analysis.

[1234] The IC50 value for each compound was determined using % inhibition by normalizing the inhibition in DMSO-treated control wells to 0% using the following formula:

[1235] Inhibition % = 100 - [(blank minus L of experimental wells) / (blank minus L of 0.2% DMSO control wells) × 100]

[1236] * Where L is luminescence.

[1237] The percentage inhibition of proliferation of triplicate samples was plotted against the corresponding concentration of compound and the dose response curves were fitted using the sigmoidal dose response equation in GraphPad Prism 8 software to generate IC50s.

[1238] Table 100 below lists the inhibitory effects of representative compounds of the present invention on M-07e cells.

[1239] [Table 100]

[1240]

[1241] Example 150 GIST Cell Proliferation Assay

[1242] Gastrointestinal stromal tumors (GIST) are the most common adult sarcomas, and the majority (85-90%) of GIST cases are caused by oncogenic mutations in the receptor tyrosine kinases (RTKs), KIT or PDGFRA, which result in constitutive activation of these receptors. The inhibitory potency of the compounds was measured using a human GIST-derived cell line, GIST-T1, that carries a mutation in exon 11 of KIT.

[1243] Materials and methods

[1244] GIST-T1 cells were purchased from Cosmo Bio (Tokyo, Japan) and cultured in DMEM containing 10% FBS. The assay was performed in 96-well plates, and the IC50 of each compound was determined by CellTiter Glo assay reagent and Victor X5 multilabel counter. Cells were seeded in 96-well plates at a density of 2000 cells / 90 μL / well. Compound dilution, cell treatment, and IC50 determination were performed as described in the assay method for M-07e cell proliferation assay.

[1245] Table 101 below lists the inhibitory effects of representative compounds of the present invention on GIST-T1 cells.

[1246] [Table 101]

[1247]

Claims

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: [Chemical formula 1] in: R 1 It is hydrogen, C 1-3 -alkyl or C 1-3 -deuterated alkyl, R 2 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, R 3 is hydrogen, aryl, carboxyl, -CO-O-(C 1-4 -alkyl) or C 1-4 -alkyl, Ring A: [Chemical formula 2] is a group of the formula: [Chemical formula 3] The wavy line indicates the point of attachment to the rest of the molecule. R 4 Yes-N(R A )(R B ),-OR A or C optionally substituted by a substituent selected from the group consisting of 1-2 -Alkyl: halogen, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, R 5 is hydrogen, halogen or C 1-4 -alkyl, R 6 YesR A , X 1 and X 2 Each independently is N or CR 7 , R 7 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, X 3 is N or C(R 8 ) n , R 8 is hydrogen or a halogen, n is an integer value of 1 or 2, Y is O or S, The dashed line is a single bond or a double bond, provided that when X 3 is N or C(R 8 ) n , where n is an integer value of 1, the dashed line is a double bond, R A is C optionally substituted by one or more groups selected from the following group 1-4 -Alkyl: halogen, hydroxyl, -O-(C 1-4 -alkyl), C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroarylC 1-4 -alkyl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; C optionally substituted by one or more groups selected from the group consisting of 3-6 -Cycloalkyl: halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; aryl optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, wherein the C 1-4 -Alkyl may further optionally have halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group; a heterocyclic group optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; or heteroaryl optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group; and R B It is hydrogen, C 1-4 -alkyl or C 3-6 - cycloalkyl, or -N(R A )(R B ) at R A and R B Together with the nitrogen atom, it forms an N-containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino.

2. The pharmaceutical composition according to claim 1, which is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: [Chemical formula 4] in: R 1 is hydrogen or C 1-3 -alkyl, R 2 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, R 3 is hydrogen or C 1-4 -alkyl, Ring A: [Chemical formula 5] is a group of the formula: [Chemical formula 6] The wavy line indicates the point of attachment to the rest of the molecule. R 4 Yes-N(R A )(R B ),-OR A or C optionally substituted by a substituent selected from the group consisting of 1-2 -Alkyl: halogen, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, R 5 is hydrogen, halogen or C 1-4 -alkyl, R 6 YesR A , X 1 and X 2 Each independently is N or CR 7 , R 7 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, X 3 is N or C(R 8 ) n , R 8 is hydrogen or a halogen, n is an integer value of 1 or 2, Y is O or S, The dashed line is a single bond or a double bond, provided that when X 3 is N or C(R 8 ) n , where n is an integer value of 1, the dashed line is a double bond, R A is C optionally substituted by one or more groups selected from the following group 1-4 -Alkyl: halogen, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; C optionally substituted by one or more groups selected from the group consisting of 3-6 -Cycloalkyl: halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; aryl optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, wherein the C 1-4 -Alkyl may further optionally have halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group; a heterocyclic group optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; or heteroaryl optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group; and R B It is hydrogen, C 1-4 -alkyl or C 3-6 - cycloalkyl, or -N(R A )(R B ) at R A and R B Together with the nitrogen atom, it forms an N-containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino.

3. The pharmaceutical composition according to claim 2, wherein R 1 is hydrogen, methyl, ethyl or isopropyl, and R 3 is hydrogen or methyl.

4. The pharmaceutical composition according to claim 3, wherein the ring A: [Chemical formula 7] is a group of the formula: [Chemical formula 8] 。 5. The pharmaceutical composition according to any one of claims 1 to 4, wherein R 4 Yes-N(R A )(R B ) or -OR A , and R 5 is hydrogen, where R A is C optionally substituted by one or more groups selected from the following group 1-4 -Alkyl: halogen, C 3-6 -cycloalkyl, phenyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl and indazolyl, wherein the C 3-6 -cycloalkyl, phenyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl and indazolyl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; C optionally substituted by one or more groups selected from the group consisting of 3-6 -Cycloalkyl: halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; phenyl optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, wherein the C 1-4 -alkyl may be further substituted by tetrahydropyranyl, piperidinyl or piperazinyl, each of which may be further substituted by halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl) amino group; tetrahydropyranyl, piperidinyl or piperazinyl, each of which may be substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; or pyridyl, pyrimidinyl or indazolyl, each of which may be substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group; and R B It's methyl.

6. The pharmaceutical composition according to claim 5, wherein R A isopropyl; C substituted by one or more groups selected from the following group 3-6 -Cycloalkyl: halogen, cyano, C 1-4 -alkyl and C 1-4 -haloalkyl; phenyl substituted by one or more groups selected from the group consisting of halogen, cyano, C 1-4 -alkyl and C 1-4 -haloalkyl; or pyridyl substituted by one or more groups selected from the group consisting of halogen, cyano, C 1-4 -alkyl and C 1-4 -haloalkyl.

7. The pharmaceutical composition according to claim 1, wherein the compound is selected from the group consisting of: N-((6-(2-fluorophenoxy)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-(4-fluorophenoxy)pyridin-3-yl)methyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 6-Fluoro-N-((6-(2-fluorophenoxy)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-(2,4-difluorophenoxy)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((2-(4-fluorophenoxy)thiazol-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-(1-(6-(4-fluorophenoxy)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, (S)-N-(1-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-((4-fluorophenyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-((4-fluorophenyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-((4,4-difluorocyclohexyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-(isopropyl(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 1-methyl-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, (S)-N-(1-(6-((4-fluorophenyl)(methyl)amino)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, (S)-1-methyl-N-((6-(2-methylpyrrolidin-1-yl)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-(1-(4-fluorophenyl)ethyl)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-(fluoro(4-fluorophenyl)methyl)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((1-(4,4-difluorocyclohexyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((1-(2-fluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 1-methyl-2-oxo-N-((1-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((3-(2,6-difluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-(3-cyanophenoxy)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-(cyclopropyl(4-fluorophenyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 1-methyl-N-((6-(methyl(1-methylpiperidin-4-yl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((2-((4,4-difluorocyclohexyl)amino)thiazol-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 1-methyl-N-((6-(methyl(3-((4-methylpiperazin-1-yl)methyl)phenyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-(1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-((4,4-difluorocyclohexyl)(methyl)amino)pyrazin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 1-methyl-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyrazin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 1-methyl-N-((6-(methyl(spiro[2.3]hexan-5-yl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, (S)-N-((6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, (R)-N-((6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-((3-(difluoromethoxy)cyclobutyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide and its cis- and trans-isomers, 1-(trideuterated methyl)-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 6-fluoro-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 1-methyl-N-((6-(methyl(3-(trifluoromethoxy)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide and its cis- and trans-isomers, N-((6-(((1S,3R)-3-fluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-(((1R,3S)-3-fluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-((6,6-difluorobicyclo[3.1.0]hex-3-yl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, and N-((6-((4,4-difluorocyclohexyl)(methyl)amino)pyridin-3-yl)methyl)-6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, or a pharmaceutically acceptable salt thereof.

8. A compound represented by the following formula (Ia), or a pharmaceutically acceptable salt thereof: [Chemical formula 9] in: R 1 It is hydrogen, C 1-3 -alkyl or C 1-3 -deuterated alkyl, R 2 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, R 3 is hydrogen, aryl, carboxyl, -CO-O-(C 1-4 -alkyl) or C 1-4 -alkyl, Ring A 1 : [Chemical formula 10] is a group of the formula: [Chemical formula 11] The wavy line indicates the point of attachment to the rest of the molecule. R 4 Yes-N(R A )(R B ),-OR A or C optionally substituted by a substituent selected from the group consisting of 1-2 -Alkyl: halogen, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, R 4A Yes-N(R A )(R B ) or C optionally substituted by a substituent selected from the group consisting of 1-2 -Alkyl: halogen, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, R 5 is hydrogen, halogen or C 1-4 -alkyl, R 6 YesR A , X 1 and X 2 Each independently is N or CR 7 , R 7 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, X 3 is N or C(R 8 ) n , R 8 is hydrogen or a halogen, n is an integer value of 1 or 2, Y is O or S, The dashed line is a single bond or a double bond, provided that when X 3 is N or C(R 8 ) n , where n is an integer value of 1, the dashed line is a double bond, R A is C optionally substituted by one or more groups selected from the following group 1-4 -Alkyl: halogen, hydroxyl, -O-(C 1-4 -alkyl), C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; C optionally substituted by one or more groups selected from the group consisting of 3-6 -Cycloalkyl: halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; aryl optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, wherein the C 1-4 -Alkyl may further optionally have halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group; a heterocyclic group optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; or heteroaryl optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group; and R B It is hydrogen, C 1-4 -alkyl or C 3-6 - cycloalkyl, or -N(R A )(R B ) at R A and R B Together with the nitrogen atom, it forms an N-containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, Provided that the compound is not [Chemical formula 12] 。 9. The compound according to claim 8, which is a compound represented by the following formula (Ia), or a pharmaceutically acceptable salt thereof: [Chemical formula 13] in: R 1 is hydrogen or C 1-3 -alkyl, R 2 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, R 3 is hydrogen or C 1-4 -alkyl, Ring A 1 : [Chemical formula 14.] is a group of the formula: [Chemical formula 15] The wavy line indicates the point of attachment to the rest of the molecule. R 4 Yes-N(R A )(R B ),-OR A or C optionally substituted by a substituent selected from the group consisting of 1-2 -Alkyl: halogen, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, R 4A Yes-N(R A )(R B ) or C optionally substituted by a substituent selected from the group consisting of 1-2 -Alkyl: halogen, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, R 5 is hydrogen, halogen or C 1-4 -alkyl, R 6 YesR A , X 1 and X 2 Each independently is N or CR 7 , R 7 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, X 3 is N or C(R 8 ) n , R 8 is hydrogen or a halogen, n is an integer value of 1 or 2, Y is O or S, The dashed line is a single bond or a double bond, provided that when X 3 is N or C(R 8 ) n , where n is an integer value of 1, the dashed line is a double bond, R A is C optionally substituted by one or more groups selected from the following group 1-4 -Alkyl: halogen, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; C optionally substituted by one or more groups selected from the group consisting of 3-6 -Cycloalkyl: halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; aryl optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, wherein the C 1-4 -Alkyl may further optionally have halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group; a heterocyclic group optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; or heteroaryl optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group; and R B It is hydrogen, C 1-4 -alkyl or C 3-6 - cycloalkyl, or -N(R A )(R B ) at R A and R B Together with the nitrogen atom, it forms an N-containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, Provided that the compound is not [Chemical formula 16] 。 10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, methyl, ethyl or isopropyl, and R 3 is hydrogen or methyl.

11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Each is independently CR 7 , where R 7 is hydrogen or a halogen.

12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein the ring A 1 : [Chemical formula 17] is a group of the formula: [Chemical formula 18] 。 13. The compound according to any one of claims 8 to 12, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 4A Each is -N(R A )(R B ), R 5 is hydrogen, and R 6 YesR A , where R A is C optionally substituted by one or more groups selected from the following group 1-4 -Alkyl: halogen, C 3-6 -cycloalkyl, phenyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl and indazolyl, wherein the C 3-6 -cycloalkyl, phenyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl and indazolyl may be further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; C optionally substituted by one or more groups selected from the group consisting of 3-6 -Cycloalkyl: halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; phenyl optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, wherein the C 1-4 -alkyl may be further substituted by tetrahydropyranyl, piperidinyl or piperazinyl, each of which may be further substituted by halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl) amino group; tetrahydropyranyl, piperidinyl or piperazinyl, each of which may be substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino; or pyridyl, pyrimidinyl or indazolyl, each of which may be substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group; and R B It's methyl.

14. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R A isopropyl; C substituted by one or more groups selected from the following group 3-6 -Cycloalkyl: halogen, cyano, C 1-4 -alkyl and C 1-4 -haloalkyl; phenyl substituted by one or more groups selected from the group consisting of halogen, cyano, C 1-4 -alkyl and C 1-4 -haloalkyl; or pyridyl substituted by one or more groups selected from the group consisting of halogen, cyano, C 1-4 -alkyl and C 1-4 -haloalkyl.

15. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein: R 1 It is hydrogen, C 1-3 -alkyl or C 1-3 -deuterated alkyl, R 2 is hydrogen or a halogen, R 3 is hydrogen or C 1-4 -alkyl, Ring A 1 : [Chemical formula 19] is a group of the formula: [Chemical formula 20] The wavy line indicates the point of attachment to the rest of the molecule. R 4A Yes-N(R A )(R B ), R 5 is hydrogen or a halogen, X 1 and X 2 Each independently is N or CR 7 , R 7 is hydrogen or a halogen, R A is C substituted by one or more groups selected from the following group 3-6 -Cycloalkyl: halogen, C 1-4 -haloalkyl and -O-(C 1-4 -haloalkyl), and R B is hydrogen or C 1-4 -alkyl.

16. The compound according to claim 8, wherein the compound is selected from the group consisting of: N-((2-(4-fluorophenoxy)thiazol-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-((4-fluorophenyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-((4-fluorophenyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-((4,4-difluorocyclohexyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-(isopropyl(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 1-methyl-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, (S)-N-(1-(6-((4-fluorophenyl)(methyl)amino)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, (S)-1-methyl-N-((6-(2-methylpyrrolidin-1-yl)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-(1-(4-fluorophenyl)ethyl)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-(fluoro(4-fluorophenyl)methyl)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((1-(4,4-difluorocyclohexyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((1-(2-fluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 1-methyl-2-oxo-N-((1-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((3-(2,6-difluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-(cyclopropyl(4-fluorophenyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 1-methyl-N-((6-(methyl(1-methylpiperidin-4-yl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((2-((4,4-difluorocyclohexyl)amino)thiazol-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 1-methyl-N-((6-(methyl(3-((4-methylpiperazin-1-yl)methyl)phenyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-((4,4-difluorocyclohexyl)(methyl)amino)pyrazin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 1-methyl-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyrazin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 1-methyl-N-((6-(methyl(spiro[2.3]hexan-5-yl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, (S)-N-((6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, (R)-N-((6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-((3-(difluoromethoxy)cyclobutyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide and its cis- and trans-isomers, 1-(trideuterated methyl)-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 6-fluoro-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, 1-methyl-N-((6-(methyl(3-(trifluoromethoxy)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide and its cis- and trans-isomers, N-((6-(((1S,3R)-3-fluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-(((1R,3S)-3-fluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, N-((6-((6,6-difluorobicyclo[3.1.0]hex-3-yl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, and N-((6-((4,4-difluorocyclohexyl)(methyl)amino)pyridin-3-yl)methyl)-6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, or a pharmaceutically acceptable salt thereof.

17. A compound represented by the following formula (Ib), or a pharmaceutically acceptable salt thereof: [Chemical formula 21] in: R 1 It is hydrogen, C 1-3 -alkyl or C 1-3 -deuterated alkyl, R 2 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, R 3 is hydrogen, aryl, carboxyl, -CO-O-(C 1-4 -alkyl) or C 1-4 -alkyl, Ring A 2 : [Chemical formula 22] is a group of the formula: [Chemical formula 23] ， The wavy line indicates the point of attachment to the rest of the molecule. R 4B Yes-OR C , R 5 is hydrogen, halogen or C 1-4 -alkyl, X 1 and X 2 Each independently is N or CR 7 , R 7 is hydrogen, halogen, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino or mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino group, R C is C optionally substituted by one or more groups selected from the following group 3-6 -Cycloalkyl: halogen, cyano, hydroxyl, C 1-4 -alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino and mono(C 1-4 -alkyl)amino or di(C 1-4 -alkyl)amino.

18. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein: R 1 It is hydrogen, C 1-3 -alkyl or C 1-3 -deuterated alkyl, R 2 is hydrogen or a halogen, R 3 is hydrogen or C 1-4 -alkyl, R 5 is hydrogen or a halogen, R 7 is hydrogen or a halogen, and R C is C substituted by one or more groups selected from the following group 3-6 -Cycloalkyl: halogen, C 1-4 -haloalkyl and -O-(C 1-4 -haloalkyl).

19. The pharmaceutical composition according to claim 1, which is a pharmaceutical composition for treating a KIT-mediated disease or disorder.

20. Use of the compound according to claim 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a KIT-mediated disease or condition.

21. Use of the compound according to claim 8 or a pharmaceutically acceptable salt thereof for treating a KIT-mediated disease or condition.

22. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, for use in treating a KIT-mediated disease or condition.

23. A method of treating a KIT-mediated disease or condition in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more pharmaceutical compositions according to any one of claims 1-7 or compounds according to any one of claims 8-18, or pharmaceutically acceptable salts thereof.

24. The method of claim 23, wherein the KIT-mediated disease or condition is cancer, autoimmune disease, allergic disease, inflammatory disease, fibrosis, metabolic disorder, neurodegenerative disease, bone loss, tumor angiogenesis, interstitial cystitis, pulmonary arterial hypertension (PAH) and primary pulmonary hypertension (PPH).

25. The method of claim 24, wherein: The cancer is selected from mastocytosis, mastocytoma, solid tumors, gastrointestinal stromal tumors ("GIST"), small cell lung cancer, non-small cell lung cancer, acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myeloid leukemia, colorectal cancer, gastric cancer, testicular cancer, glioblastoma, astrocytoma, melanoma, mast cell tumors, neuroblastoma, sarcoma and seminoma; The autoimmune disease is selected from the group consisting of multiple sclerosis, psoriasis, inflammatory bowel diseases, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, localized and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjögren's syndrome, systemic arteritis nodosa, autoimmune enteropathy, and proliferative glomerulonephritis; The allergic disease is selected from asthma, severe asthma, allergic rhinitis, chronic rhinitis, allergic sinusitis, allergic syndrome, urticaria, food allergy, seasonal allergy, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, necrotizing venules of the skin, insect bite skin inflammation and blood-sucking parasite infestation; The inflammatory disease is selected from rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and eosinophilic esophagitis; The fibrosis is selected from the group consisting of pulmonary fibrosis, liver fibrosis, cardiac fibrosis and myelofibrosis; The metabolic disorder is selected from diabetes and its chronic complications, obesity, type I diabetes or type II diabetes, hyperlipidemia and dyslipidemia, atherosclerosis, hypertension and cardiovascular disease; and The neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, prion disease, motor neuron disease (MND) and amyotrophic lateral sclerosis (ALS).

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