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

Abstract

Provided herein are compounds and compositions useful for inhibiting the 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 conditions (e.g., cancer, autoimmune diseases, allergic diseases, inflammatory diseases, fibrosis, metabolic disorders, and neurodegenerative diseases).

Description

[Technical Field]

[0001] FIELD OF THE INVENTION This application relates to inhibitors of the receptor tyrosine kinase KIT (c-KIT) and methods of their use, such as for preventing or treating one or more KIT-mediated diseases or conditions. [Background technology]

[0002] Protein phosphorylation is an important cellular regulatory mechanism, as many enzymes and receptors are activated / inactivated by phosphorylation and dephosphorylation events mediated by kinases and phosphatases. Receptor tyrosine kinases (RTKs) play important roles in various cellular processes, including growth, motility, differentiation, and metabolism. KIT (c-KIT) is a tyrosine kinase receptor that acts as a conditional oncoprotein and regulates the development and function of multiple distinct cell lineages. These include hematopoietic progenitor cells, 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 have been associated with several human diseases. KIT activation has been implicated in a variety of human cancers, including mastocytosis, germ cell tumors, small cell lung cancer, gastrointestinal stromal tumors (GISTs), acute myeloid leukemia, neuroblastoma, malignant 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 generally achieved by one or more of three mechanisms: autocrine and / or paracrine stimulation by SCF, cross-activation by 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). Indeed, several kinase inhibitors have been approved for the treatment of GIST and other malignancies associated with KIT activation in both humans and non-human mammals.

[0004] KIT and its ligands have been shown to be involved in the development and function of several different cell lineages, including some cells of the central nervous system, interstitial cells of Cajal in the intestine, taste cells, and several hematopoietic cell lineages, including dendritic cells, eosinophils, and ILC2s in addition to MCs (Tsai M et al., J. Allergy Clin. Immunol. 2022, 149:1845-54). While most lineages lose KIT expression as they differentiate, 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 dominant role in the development and maturation of tissue MCs. In contrast to other bone marrow cells, MCs are long-lived. This is because it can take several months for fully mature MCs to develop from stem cells via multipotent MC progenitors and committed MC progenitors. Furthermore, some mature tissue MCs survive for months or even years when present within the local tissue microenvironment (Cerny-Reiterer S et al., Oncotarget 2015, 6:3071-84). Upon maturation, MCs reside at local tissue sites where SCF and other growth factors and cytokines are expressed, supporting long-term survival and effector cell function.

[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 reactions. MCs express high-affinity receptors for IgE and produce numerous biologically active 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 IgE and allergens via IgE receptors; IgG immune complexes; complement and cytokines; toxins, venoms, and bacterial by-products; and certain drugs (Valent et al., 2020). MC activation occurs in several different disease contexts and pathologies. Clinical symptoms can be severe and disabling. In patients with allergic (atopic) diseases and mastocytosis, MC activation is substantial and systemic, even resulting in overt anaphylaxis.

[0007] Imatinib is a small-molecule TKI that blocks KIT and other kinases, including ABL1, ABL2, and PDGFR. It was initially developed as a targeted anticancer drug and is approved by both the US Food and Drug Administration and the European Medicines Agency for the treatment of systemic mastocytosis (SM), a condition characterized by excessive proliferation of macrophages (MCs). The rationale for its use in SM comes from several studies. In one study, patients with chronic myeloid leukemia were treated with imatinib for several years. During this treatment, the number of MCs in the bone marrow was found to decrease after 12 months. After 24 months, MCs were almost completely absent from bone marrow sections (Cerny-Reiterer S et al., 2015). Concurrently, serum tryptase levels, a marker of MC activation, decreased from low to undetectable (Cerny-Reiterer S et al., 2015). In another study, 62 patients with poorly controlled or uncontrolled severe asthma who had airway hyperresponsiveness despite maximal medical therapy were treated with imatinib (400 mg / day orally) for 24 weeks. Treatment with imatinib was found to reduce airway hyperresponsiveness and bronchoalveolar lavage tryptase levels more effectively in these patients than placebo controls (Cahill KN et al., N Engl J Med, 2017, 376:1911-20). Collectively, these data suggest that treatment with KIT-targeted drugs may result in partial or complete eradication of the MC lineage in patients with various MC disorders. Furthermore, some of these TKIs can also suppress IgE-dependent activation of MCs and basophils (Valent et al., 2022). Therefore, highly specific KIT inhibitors may offer a new, safer treatment option for patients with severe MC disorders. Summary of the Invention [Problem to be solved by the invention]

[0008] Provided herein are, inter alia, compounds useful for inhibiting KIT and compositions comprising such compounds. In particular, disclosed herein are methods for inhibiting the activity of KIT to prevent or treat KIT-mediated diseases or conditions associated with inappropriately regulated kinase signaling in MCs, such as cancer, autoimmune diseases, allergic diseases, inflammatory diseases, fibrosis, metabolic disorders, and neurodegenerative diseases, by administering to a subject a therapeutically effective amount of one or more compounds or compositions provided herein. [Means for solving the problem]

[0009] In one embodiment, provided herein is a compound of formula (I) comprising a compound of formula (I) containing a pharmaceutically acceptable carrier or diluent and a compound of formula (I):

[0010] [ka]

[0011] or a pharmaceutically acceptable salt thereof, R 1 is hydrogen or C 1-3 -alkyl, R 2 is hydrogen, halogen, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino, or mono- or di-(C 1-4 -alkyl)amino, R 3 is hydrogen or C 1-4 -alkyl, Ring A:

[0012] [ka]

[0013] is the expression:

[0014] [ka] is the basis of

[0015] The wavy line indicates the point of attachment to the rest of the molecule, R 4 is -N(R A )(R B ), -OR A , or halogen, C 3-6 -C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl 1-2 -alkyl, wherein said C 3-6 Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino, R 5 is hydrogen, halogen, or C 1-4 -alkyl, R 6 is R A and X 1 and X 2 are each independently N or CR 7 and R 7 is hydrogen, halogen, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino, or mono- or di-(C 1-4 -alkyl)amino, X 3 is N or C(R 8 ) n and R 8 is hydrogen or halogen, n is an integer having a value of 1 or 2; Y is O or S; The dotted lines represent single or double bonds, except that X 3 is N or C(R 8 ) n where n is an integer having a value of 1, the dotted line is a double bond; R A is a halogen, C 3-6 -C optionally substituted with one or more groups selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl 1-4 -alkyl, wherein said C 3-6 Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 C optionally substituted with one or more groups selected from the group consisting of 3-6 -Cycloalkyl; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -aryl optionally substituted with one or more groups selected from the group consisting of (-alkyl)amino, wherein said C 1-4 -Alkyl is halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, or mono- or di-(C 1-4 -alkyl)amino, optionally further substituted with heterocyclyl; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4-alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino; or halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -(-alkyl)amino; R B is hydrogen, C 1-4 -alkyl, or C 3-6 -cycloalkyl, or -N(R A )(R B ) in R A and R B together with the nitrogen atom, halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino.

[0016] In another embodiment, provided herein is a compound of formula (Ia):

[0017] [ka]

[0018] or a pharmaceutically acceptable salt thereof, R 1 is hydrogen or C 1-3 -alkyl, R 2 is hydrogen, halogen, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4-haloalkyl, nitro, amino, or mono- or di-(C 1-4 -alkyl)amino, R 3 is hydrogen or C 1-4 -alkyl, Ring A 1 :

[0019] [ka]

[0020] is the expression:

[0021] [ka] is the basis of

[0022] The wavy line indicates the point of attachment to the rest of the molecule, R 4 is -N(R A )(R B ), -OR A , or halogen, C 3-6 -C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl 1-2 -alkyl, wherein said C 3-6 Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino, R 4A is -N(R A )(R B ), or halogen, C 3-6 -C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl 1-2 -alkyl, wherein said C3-6 Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino, R 5 is hydrogen, halogen, or C 1-4 -alkyl, R 6 is R A and X 1 and X 2 are each independently N or CR 7 and R 7 is hydrogen, halogen, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino, or mono- or di-(C 1-4 -alkyl)amino, X 3 is N or C(R 8 ) n and R 8 is hydrogen or halogen, n is an integer having a value of 1 or 2; Y is O or S; The dotted lines represent single or double bonds, except that X 3 is N or C(R 8 ) n where n is an integer having a value of 1, the dotted line is a double bond; R A is a halogen, C 3-6 -C optionally substituted with one or more groups selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl 1-4 -alkyl, wherein said C 3-6Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 C optionally substituted with one or more groups selected from the group consisting of 3-6 -Cycloalkyl; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -aryl optionally substituted with one or more groups selected from the group consisting of (-alkyl)amino, wherein said C 1-4 -Alkyl is halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, or mono- or di-(C 1-4 -alkyl)amino, optionally further substituted with heterocyclyl; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino; or halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4-(-alkyl)amino; R B is hydrogen, C 1-4 -alkyl, or C 3-6 -cycloalkyl, or -N(R A )(R B ) in R A and R B together with the nitrogen atom, halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -(-alkyl)amino, forming an N-containing heterocycle optionally substituted with one or more groups selected from the group consisting of However, the compound is

[0023] [ka] isn't it.

[0024] 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.

[0025] Also provided herein is the use of one or more of the disclosed compounds, or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for preventing or treating a KIT-mediated disease or condition.

[0026] In another embodiment, provided herein is one or more of the disclosed compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the disclosed compounds, for use in the prevention or treatment of a KIT-mediated disease or condition. DETAILED DESCRIPTION OF THE INVENTION

[0027] <Definition> The term "alkyl," used alone or as part of a larger moiety such as "haloalkyl," "cycloalkyl," "alkylamino," etc., means a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, alkyl groups typically contain 1 to 4 carbon atoms, i.e., C 1-4 As used herein, "C 1-4 An "alkyl" group means a group having from 1 to 4 carbon atoms in a straight or branched configuration and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0028] The term "deuteroalkyl" means an alkyl having one or more deuterium atoms. For example, "C 1-3 The term "-deuteroalkyl" means groups having 1 to 3 carbon atoms and includes mono-, di-, and tri-deuteromethyl.

[0029] The term "alkylamino" refers to an amino substituted with one or more alkyl groups. For example, "mono- 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.

[0030] The term "haloalkyl" means an alkyl substituted with one or more halogen atoms. For example, "C 1-4 "-haloalkyl" includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, bromomethyl, fluoroethyl, difluoroethyl, dichloroethyl, and chloropropyl. 1-4 Examples of -haloalkyl include difluoromethyl or trifluoromethyl, and in another embodiment, C 1-4 Examples of -haloalkyl include trifluoromethyl.

[0031] The term "halogen" or "halo" means fluorine or fluoro (F), chlorine or chloro (Cl), bromine or bromo (Br), or iodine or iodo (I).

[0032] The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon radical, 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.

[0033] The term "cycloalkyl" means a 3- to 12-membered saturated aliphatic cyclic hydrocarbon radical. It can be monocyclic, bicyclic (e.g., bridged, spiro-fused, or fused bicyclic rings), or tricyclic. For example, monocyclic C 3-6 -Cycloalkyl means a group having 3 to 6 carbon atoms arranged in a monocyclic 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.

[0034] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring radical having at least one (typically 1 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen, or sulfur). Examples of such heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalyl, pyrrolopyridyl, and imidazolopyridyl.

[0035] The term "heterocyclyl" refers to a monocyclic or bicyclic non-aromatic ring radical having at least one (typically 1 to 4, more typically 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 sulfoxide and sulfone). Some of the bonds comprising the heterocyclyl may be unsaturated. Some bicyclic heterocyclyls may have aromatic character. Examples include monocyclic heterocyclyls having 5- and 6-membered rings fused to a benzene ring, pyrrole ring, furan ring, thiophene ring, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, or pyridine ring, and at least partially unsaturated hydrocarbon ring radicals having 5- and 6-membered rings fused to a pyrrole ring, furan ring, thiophene ring, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, or pyridine ring. Examples of such heterocyclyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, dihydropyridyl, tetrahydropyridyl, dihydropyridazinyl, tetrahydropyridazinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, oxetanyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, dihydro Examples include thiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuryl, dihydroisobenzofuryl, tetrahydrobenzoxazolyl, dihydrofuropyridyl, dihydropyrazolomorpholinyl, pyridinodioxanyl, dihydroazabenzofuryl, dihydroazaisobenzofuryl, dihydroazaindolyl, 2-oxaspiro[3.5]nonyl, and 2-oxaspiro[3.3]heptyl.

[0036] -N(R A )(R B ) in R A and R BExamples of the "N-containing heterocycle" formed by combining these include azetidine, pyrrolidine, pyrazole, imidazole, triazole, tetrazole, piperidine, dihydropyridine, tetrahydropyridine, piperazine, morpholine, and thiomorpholine.

[0037] When a group is described as being "substituted", a non-hydrogen substituent is present in place of a hydrogen substituent on the carbon, sulfur, or nitrogen of the substituent. Thus, for example, a substituted alkyl is an alkyl in which at least one non-hydrogen substituent is present in place of a hydrogen substituent on the alkyl substituent. For example, a monofluoroalkyl is an alkyl substituted with a fluoro substituent, and a difluoroalkyl is an alkyl substituted with two fluoro substituents. When there are two or more substitutions on a substituent, it should be recognized that each non-hydrogen substituent may be the same or different (unless otherwise specified).

[0038] Compounds with one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial configuration. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms, as well as racemates and mixtures thereof. When a compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. The term "geometric isomer" refers to a compound having at least one double bond, where the double bond may exist in cis (also called syn or entgegen (E)) or trans (also called anti or zusammen (Z)) form, as well as mixtures thereof. When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or structure encompasses one or more possible stereoisomers, or geometric isomers, or mixtures of the encompassed stereoisomers or geometric isomers.

[0039] When a geometric isomer is designated by name or structure, it is to be understood that the named or designated isomer is present to a greater extent than another isomer, i.e., the geometric isomeric purity of the named or designated geometric isomer is greater than 50%, e.g., at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.

[0040] A racemic mixture means 50% of one enantiomer and 50% of the corresponding enantiomer. When a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, the name or structure is understood to encompass both possible enantiomeric forms of the compound (e.g., both enantiomerically pure, enantiomerically enriched, or racemic). When a compound with two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral centers, the name or structure is understood to encompass all possible diastereomeric forms (e.g., diastereomerically pure, diastereomerically enriched, equimolar mixtures of one or more diastereomers of the compound (e.g., racemic mixtures).

[0041] Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallizing the compounds as chiral salt complexes, or crystallizing the compounds in chiral solvents. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0042] If a compound is designated by a name or structure denoting a single enantiomer, unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure "enantiomerically pure." Optical purity is the weight of the named or designated enantiomer in a mixture divided by the total weight of both enantiomers in the mixture.

[0043] When the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in the case of a diastereomeric pair), it is understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0044] When a compound herein is represented by a structural formula or designated by a chemical name herein, it is understood that all other tautomeric forms that may exist for the compound are encompassed by the structural formula.

[0045] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic reaction, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in J. Pharm. Sci., 1977, 66:1-19.

[0046] The present teachings include pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having a basic amine 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 (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, etc.) and organic acids (such as acetic acid, trifluoroacetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid, etc.). Compounds having an acidic group, such as a carboxylic acid, can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (such as sodium salts and potassium salts), and alkaline earth metal salts (such as magnesium salts and calcium salts).

[0047] Furthermore, the present invention also includes any of various hydrates or solvates, and crystalline polymorphs, of the compounds of formula (I) and their pharmaceutically acceptable salts. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

[0048] It should be noted that the compounds of formula (Ia) and (Ib) are included within the scope of the compounds of formula (I), and therefore, suitable examples or embodiments of the compounds of formula (Ia) and (Ib) shall refer to those exemplified for the compounds of formula (I).

[0049] <Compositions and Compounds of the Present Invention> In a first embodiment, the present invention provides a compound represented by formula (I) comprising a pharmaceutically acceptable carrier or diluent and a compound represented by formula (I):

[0050] [ka]

[0051] or a pharmaceutically acceptable salt thereof, R 1 is hydrogen, C 1-3 -alkyl, or C 1-3-deuterated alkyl, R 2 is hydrogen, halogen, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino, or mono- or di-(C 1-4 -alkyl)amino, R 3 is hydrogen, aryl, carboxy, -CO-O-(C 1-4 -alkyl), or C optionally substituted with hydroxy 1-4 -alkyl, Ring A:

[0052] [ka]

[0053] is the expression:

[0054] [ka] is the basis of

[0055] The wavy line indicates the point of attachment to the rest of the molecule, R 4 is -N(R A )(R B ), -OR A , or halogen, C 3-6 -C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl 1-2 -alkyl, wherein said C 3-6 Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, and mono- or di-(C 1-4-alkyl)amino, R 5 is hydrogen, halogen, or C 1-4 -alkyl, R 6 is R A and X 1 and X 2 are each independently N or CR 7 and R 7 is hydrogen, halogen, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino, or mono- or di-(C 1-4 -alkyl)amino, X 3 is N or C(R 8 ) n and R 8 is hydrogen or halogen, n is an integer having a value of 1 or 2; Y is O or S; The dotted lines represent single or double bonds, except that X 3 is N or C(R 8 ) n where n is an integer having a value of 1, the dotted line is a double bond; R A is halogen, hydroxy, -O-(C 1-4 -alkyl), C 3-6 -C optionally substituted with one or more groups selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl 1-4 -alkyl, wherein said C 3-6 Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4-haloalkyl), amino, and mono- or di-(C 1-4 -alkyl)amino; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, and mono- or di-(C 1-4 C optionally substituted with one or more groups selected from the group consisting of 3-6 -Cycloalkyl; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, and mono- or di-(C 1-4 -aryl optionally substituted with one or more groups selected from the group consisting of (-alkyl)amino, wherein said C 1-4 -Alkyl is halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, or mono- or di-(C 1-4 -alkyl)amino, optionally further substituted with heterocyclyl; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, and mono- or di-(C 1-4 -alkyl)amino; or halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, and mono- or di-(C 1-4-(-alkyl)amino; R B is hydrogen, C 1-4 -alkyl, or C 3-6 -cycloalkyl, or -N(R A )(R B ) in R A and R B together with the nitrogen atom, halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, and mono- or di-(C 1-4 The present invention provides pharmaceutical compositions comprising an N-containing heterocycle optionally substituted with one or more groups selected from the group consisting of: -alkyl)amino.

[0056] In a second embodiment, the present invention provides a compound represented by formula (I) comprising a pharmaceutically acceptable carrier or diluent and a compound represented by formula (I):

[0057] [ka]

[0058] or a pharmaceutically acceptable salt thereof, R 1 is hydrogen or C 1-3 -alkyl, R 2 is hydrogen, halogen, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino, or mono- or di-(C 1-4 -alkyl)amino, R 3 is hydrogen or C 1-4 -alkyl, Ring A:

[0059] [ka]

[0060] is the expression:

[0061] [ka] is the basis of

[0062] The wavy line indicates the point of attachment to the rest of the molecule, R 4 is -N(R A )(R B ), -OR A , or halogen, C 3-6 -C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl 1-2 -alkyl, wherein said C 3-6 Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino, R 5 is hydrogen, halogen, or C 1-4 -alkyl, R 6 is R A and X 1 and X 2 are each independently N or CR 7 and R 7 is hydrogen, halogen, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino, or mono- or di-(C 1-4 -alkyl)amino, X 3 is N or C(R 8 ) n and R 8 is hydrogen or halogen, n is an integer having a value of 1 or 2; Y is O or S; The dotted lines represent single or double bonds, except that X 3 is N or C(R 8 ) n where n is an integer having a value of 1, the dotted line is a double bond; R A is a halogen, C 3-6 -C optionally substituted with one or more groups selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl 1-4 -alkyl, wherein said C 3-6 Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 C optionally substituted with one or more groups selected from the group consisting of 3-6 -Cycloalkyl; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -aryl optionally substituted with one or more groups selected from the group consisting of (-alkyl)amino, wherein said C 1-4 -Alkyl is halogen, cyano, hydroxy, C 1-4-Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, or mono- or di-(C 1-4 -alkyl)amino, optionally further substituted with heterocyclyl; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino; or halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -(-alkyl)amino; R B is hydrogen, C 1-4 -alkyl, or C 3-6 -cycloalkyl, or -N(R A )(R B ) in R A and R B together with the nitrogen atom, halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 In another embodiment, the pharmaceutical composition is provided in which the N-containing heterocycle is optionally substituted with one or more groups selected from the group consisting of: -alkyl)amino;

[0063] In a third embodiment, the present invention provides a compound comprising R 1 is hydrogen, methyl, ethyl, or isopropyl, and R 3 is hydrogen or methyl.

[0064] In a fourth embodiment, the present invention provides a compound comprising ring A:

[0065] [ka]

[0066] But the expression:

[0067] [ka] The present invention provides a pharmaceutical composition according to a third embodiment, wherein

[0068] In a fifth embodiment, the present invention provides a compound comprising R 4 -N(R A )(R B ) OR -OR A and R 5 is hydrogen, where R A But halogen, C 3-6 -C optionally substituted with one or more groups selected from the group consisting of cycloalkyl, phenyl, tetrahydropyranyl, piperidyl, piperazinyl, pyridyl, pyrimidyl, and indazolyl 1-4 -alkyl, wherein said C 3-6 -cycloalkyl, phenyl, tetrahydropyranyl, piperidyl, piperazinyl, pyridyl, pyrimidyl, and indazolyl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 C optionally substituted with one or more groups selected from the group consisting of 3-6 -Cycloalkyl; halogen, cyano, hydroxy, C1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino, wherein said C 1-4 - alkyl is tetrahydropyranyl, piperidyl, or piperazinyl (each of which is selected from the group consisting of halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, or mono- or di-(C 1-4 -alkyl)amino; tetrahydropyranyl, piperidyl, or piperazinyl, each of which is substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino and mono- or di-(C 1-4 -alkyl)amino; or pyridyl, pyrimidyl, or indazolyl, each of which is optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino; B The pharmaceutical composition of embodiments 1-4, wherein is methyl.

[0069] In a sixth embodiment, the present invention provides a compound comprising R A But isopropyl; halogen, cyano, C 1-4 -alkyl, and C 1-4 -C substituted with one or more groups selected from the group consisting of haloalkyl 3-6 -Cycloalkyl; halogen, cyano, C 1-4 -alkyl, and C 1-4-phenyl substituted with one or more groups selected from the group consisting of haloalkyl; or halogen, cyano, C 1-4 -alkyl, and C 1-4 -haloalkyl.

[0070] In a seventh embodiment, the present invention relates to a compound comprising: 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-(trideuteromethyl)-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]hexan-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.

[0071] In an eighth embodiment, the present invention provides a compound of formula (Ia):

[0072] [ka]

[0073] or a pharmaceutically acceptable salt thereof, R 1 is hydrogen, C 1-3 -alkyl, or C 1-3 -deuterated alkyl, R 2 is hydrogen, halogen, hydroxy, C 1-4 -Alkyl, -O-(C1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino, or mono- or di-(C 1-4 -alkyl)amino, R 3 is hydrogen, aryl, carboxy, -CO-O-(C 1-4 -alkyl), or C optionally substituted with hydroxy 1-4 -alkyl, Ring A 1 :

[0074] [ka]

[0075] But the expression:

[0076] [ka] is the basis of

[0077] The wavy line indicates the point of attachment to the rest of the molecule, R 4 is -N(R A )(R B ), -OR A , or halogen, C 3-6 -C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl 1-2 -alkyl, wherein said C 3-6 -Cycloalkyl, aryl, heterocyclyl and heteroaryl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, and mono- or di-(C 1-4 -alkyl)amino, R 4A is -N(R A )(R B), or halogen, C 3-6 -C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl 1-2 -alkyl, wherein said C 3-6 Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, and mono- or di-(C 1-4 -alkyl)amino, R 5 is hydrogen, halogen, or C 1-4 -alkyl, R 6 is R A and X 1 and X 2 are each independently N or CR 7 and R 7 is hydrogen, halogen, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino, or mono- or di-(C 1-4 -alkyl)amino, X 3 is N or C(R 8 ) n and R 8 is hydrogen or halogen, n is an integer having a value of 1 or 2; Y is O or S; The dotted lines represent single or double bonds, except that X 3 is N or C(R 8 ) n where n is an integer having a value of 1, the dotted line is a double bond; R A is halogen, hydroxy, -O-(C1-4 -alkyl), C 3-6 -C optionally substituted with one or more groups selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl 1-4 -alkyl, wherein said C 3-6 Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, and mono- or di-(C 1-4 -alkyl)amino; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, and mono- or di-(C 1-4 C optionally substituted with one or more groups selected from the group consisting of 3-6 -Cycloalkyl; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, and mono- or di-(C 1-4 -aryl optionally substituted with one or more groups selected from the group consisting of (-alkyl)amino, wherein said C 1-4 -Alkyl is halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, or mono- or di-(C 1-4 -alkyl)amino, optionally further substituted with heterocyclyl; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, and mono- or di-(C 1-4 -alkyl)amino; or halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, and mono- or di-(C 1-4 -(-alkyl)amino; R B is hydrogen, C 1-4 -alkyl, or C 3-6 -cycloalkyl, or -N(R A )(R B ) in R A and R B together with the nitrogen atom, halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, and mono- or di-(C 1-4 -(-alkyl)amino, forming an N-containing heterocycle optionally substituted with one or more groups selected from the group consisting of However, the compound is

[0078] [ka] or a pharmaceutically acceptable salt thereof, wherein

[0079] In a ninth embodiment, the present invention provides a compound of formula (Ia):

[0080] [ka]

[0081] or a pharmaceutically acceptable salt thereof, R 1 is hydrogen or C 1-3 -alkyl, R 2 is hydrogen, halogen, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino, or mono- or di-(C 1-4 -alkyl)amino, R 3 is hydrogen or C 1-4 -alkyl, Ring A 1 :

[0082] [ka]

[0083] But the expression:

[0084] [ka] is the basis of

[0085] The wavy line indicates the point of attachment to the rest of the molecule, R 4 is -N(R A )(R B ), -OR A , or halogen, C 3-6 -C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl 1-2 -alkyl, wherein said C 3-6 Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4-alkyl)amino, R 4A is -N(R A )(R B ), or halogen, C 3-6 -C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl 1-2 -alkyl, wherein said C 3-6 Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino, R 5 is hydrogen, halogen, or C 1-4 -alkyl, R 6 is R A and X 1 and X 2 are each independently N or CR 7 and R 7 is hydrogen, halogen, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino, or mono- or di-(C 1-4 -alkyl)amino, X 3 is N or C(R 8 ) n and R 8 is hydrogen or halogen, n is an integer having a value of 1 or 2; Y is O or S; The dotted lines represent single or double bonds, except that X 3 is N or C(R 8 ) nwhere n is an integer having a value of 1, the dotted line is a double bond; R A is a halogen, C 3-6 -C optionally substituted with one or more groups selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl 1-4 -alkyl, wherein said C 3-6 Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 C optionally substituted with one or more groups selected from the group consisting of 3-6 -Cycloalkyl; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -aryl optionally substituted with one or more groups selected from the group consisting of (-alkyl)amino, wherein said C 1-4 -Alkyl is halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, or mono- or di-(C 1-4 -alkyl)amino, optionally further substituted with heterocyclyl; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4-alkyl)amino; or halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -(-alkyl)amino; R B is hydrogen, C 1-4 -alkyl, or C 3-6 -cycloalkyl, or -N(R A )(R B ) in R A and R B together with the nitrogen atom, halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -(-alkyl)amino, forming an N-containing heterocycle optionally substituted with one or more groups selected from the group consisting of However, the compound is

[0086] [ka] or a pharmaceutically acceptable salt thereof, wherein:

[0087] In a tenth embodiment, the present invention provides a compound comprising R 1 is hydrogen, methyl, ethyl, or isopropyl, and R 3 is hydrogen or methyl, or a pharmaceutically acceptable salt thereof. In an eleventh embodiment, the present invention provides a compound comprising X 1 and X 2 are each independently CR 7 where R 7is hydrogen or halogen, or a pharmaceutically acceptable salt thereof. In a twelfth embodiment, the present invention provides a compound comprising ring A 1 :

[0088] [ka]

[0089] But the expression:

[0090] [ka] or a pharmaceutically acceptable salt thereof.

[0091] In a thirteenth embodiment, the present invention provides a compound comprising R 4 and R 4A are -N(R A )(R B ) and R 5 is hydrogen and R 6 R A where R A But halogen, C 3-6 -C optionally substituted with one or more groups selected from the group consisting of cycloalkyl, phenyl, tetrahydropyranyl, piperidyl, piperazinyl, pyridyl, pyrimidyl, and indazolyl 1-4 -alkyl, wherein said C 3-6 -cycloalkyl, phenyl, tetrahydropyranyl, piperidyl, piperazinyl, pyridyl, pyrimidyl, and indazolyl are substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4-haloalkyl, amino, and mono- or di-(C 1-4 C optionally substituted with one or more groups selected from the group consisting of 3-6 -Cycloalkyl; halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino, wherein said C 1-4 - alkyl is tetrahydropyranyl, piperidyl, or piperazinyl, each of which may be substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, or mono- or di-(C 1-4 -alkyl)amino); tetrahydropyranyl, piperidyl, or piperazinyl, each of which is optionally substituted with halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino; or pyridyl, pyrimidyl, or indazolyl, each of which is optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, amino, and mono- or di-(C 1-4 -alkyl)amino; B is methyl, or a pharmaceutically acceptable salt thereof.

[0092] In a fourteenth embodiment, the present invention provides a compound comprising R A But isopropyl; halogen, cyano, C 1-4-alkyl, and C 1-4 -C substituted with one or more groups selected from the group consisting of haloalkyl 3-6 -Cycloalkyl; halogen, cyano, C 1-4 -alkyl, and C 1-4 -phenyl substituted with one or more groups selected from the group consisting of haloalkyl; or halogen, cyano, C 1-4 -alkyl, and C 1-4 -haloalkyl; or a pharmaceutically acceptable salt thereof.

[0093] In a fifteenth embodiment, the present invention provides a method for manufacturing a semiconductor device comprising: R 1 is hydrogen, C 1-3 -alkyl, or C 1-3 -deuterated alkyl, R 2 is hydrogen or halogen, R 3 is hydrogen or C1-4-alkyl, Ring A 1 :

[0094] [ka]

[0095] is the expression:

[0096] [ka] is the basis of

[0097] The wavy line indicates the point of attachment to the rest of the molecule, R 4A is -N(R A )(R B ) and R 5 is hydrogen or halogen, X 1 and X 2 are each independently N or CR7 and R 7 is hydrogen or halogen, R A is a halogen, C 1-4 -haloalkyl, and -O-(C 1-4 -haloalkyl) 3-6 -cycloalkyl, R B is hydrogen or C 1-4 - alkyl, There is provided a compound according to an eighth embodiment, or a pharmaceutically acceptable salt thereof.

[0098] In a sixteenth embodiment, the present invention provides a compound according to the eighth embodiment, wherein the compound is 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-(trideuteromethyl)-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]hexan-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.

[0099] In a seventeenth embodiment, the present invention provides a compound of formula (Ib):

[0100] [ka]

[0101] or a pharmaceutically acceptable salt thereof, R 1 is hydrogen, C 1-3 -alkyl, or C 1-3 -deuterated alkyl, R 2 is hydrogen, halogen, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino, or mono- or di-(C 1-4 -alkyl)amino, R 3 is hydrogen, aryl, carboxy, -CO-O-(C 1-4 -alkyl), or C optionally substituted with hydroxy 1-4 -alkyl, Ring A 2 :

[0102] [ka]

[0103] is the expression:

[0104] [ka] is the basis of

[0105] The wavy line indicates the point of attachment to the rest of the molecule, R 4B -OR C and R 5 is hydrogen, halogen, or C 1-4 -alkyl, X 1and X 2 are each independently N or CR 7 and R 7 is hydrogen, halogen, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, nitro, amino, or mono- or di-(C 1-4 -alkyl)amino, R C is halogen, cyano, hydroxy, C 1-4 -Alkyl, -O-(C 1-4 -alkyl), C 1-4 -haloalkyl, -O-(C 1-4 -haloalkyl), amino, and mono- or di-(C 1-4 C optionally substituted with one or more groups selected from the group consisting of 3-6 -cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0106] In an eighteenth embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: R 1 is hydrogen, C 1-3 -alkyl or C 1-3 -deuterated alkyl, R 2 is hydrogen or halogen, R 3 is hydrogen or C 1-4 -alkyl, R 5 is hydrogen or halogen, R 7 is hydrogen or halogen, R C is a halogen, C 1-4 -haloalkyl, and -O-(C 1-4 -haloalkyl) 3-6 -cycloalkyl, A compound according to a seventeenth embodiment, or a pharmaceutically acceptable salt thereof, is provided.

[0107] In certain embodiments, the present invention includes any one of the compounds shown in the Exemplification section of this application, including pharmaceutically acceptable salts and neutral forms of these compounds. Specifically, the present invention includes any one of the compounds shown in Examples 1-147, including pharmaceutically acceptable salts and neutral forms of these compounds. In a preferred embodiment, the present invention includes any one of Compounds 1-147, including pharmaceutically acceptable salts and neutral forms of these compounds.

[0108] <Method of producing the compound of the present invention> Disclosed are methods for preparing compounds of formula (I). Generally, compounds of formula (I) or pharmaceutically acceptable salts thereof can be prepared by reacting compounds of formula (II)

[0109] [ka]

[0110] or a salt thereof,

[0111] [ka]

[0112] or a salt thereof.

[0113] Suitable salts of compounds (II) and (III) can refer to the salts exemplified for compound (I).

[0114] 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 methylene chloride, chloroform, pyridine, dioxane, tetrahydrofuran or N,N-dimethylformamide.

[0115] The reaction temperature is not critical, and the reaction can be carried out under cooling, room temperature or under heating. The reaction is preferably carried out in the presence of a conventional inorganic base or in the presence of a conventional organic base. The compound obtained by the above method can be isolated and purified by conventional methods such as pulverization, recrystallization, chromatography, and reprecipitation.

[0116] For detailed synthesis protocols for producing exemplary compounds of formula (I) and intermediate compounds thereof, reference may be made to the following Examples and Preparations, or methods similar thereto, or conventional methods.

[0117] <Pharmaceutical Composition> The compounds of formula (I) disclosed therein are KIT inhibitors. Pharmaceutical compositions of the present invention comprise one or more KIT inhibitors or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or diluent.

[0118] "Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to substances that aid in the formulation and / or administration of and / or absorption of an active agent by a subject and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations are sterilized and, if necessary, can be mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, coloring agents, and / or aromatic substances, which do not deleteriously react with or interfere with the activity of the compounds provided herein. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds.

[0119] Pharmaceutical compositions of the present teachings optionally include one or more pharmaceutically acceptable carriers and / or diluents therefor, such as lactose, starch, cellulose, and dextrose. Other excipients, such as flavorings; sweeteners; and preservatives, e.g., methyl, ethyl, propyl, and butyl parabens, may also be included. A more complete list of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5th ed., Pharmaceutical Press (2005)). Those skilled in the art will know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of appropriate formulations are described, for example, in Remington's Pharmaceutical Sciences (2003-20th edition) and The United States Pharmacopeia: The National Formulary, published in 1999 (USP 24 NF19). A 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.

[0120] <Treatment method> Disclosed are methods for preventing or treating a KIT-mediated disease or condition in a subject, particularly a KIT-mediated disease or condition associated with inappropriately regulated kinase signaling in mast cells, which can include administering to the subject a therapeutically effective amount of one or more compounds of formula (I) or compositions provided herein.

[0121] A "subject" is a mammal, preferably a human, but may also be an animal in need of veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0122] 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 ("GISTs"), small cell lung cancer, non-small cell lung cancer, acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes, chronic myeloid leukemia, colorectal cancer, gastric cancer, testicular cancer, glioblastoma, astrocytoma, melanoma, mast cell tumor, neuroblastoma, sarcoma, and seminoma.

[0123] In another embodiment, the KIT-mediated disease or condition is an autoimmune disease, examples of which include, but are not limited to, multiple sclerosis, psoriasis, intestinal inflammatory disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, localized and systemic sclerosis, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome, panarteritis nodosa, autoimmune enteropathy, and proliferative glomerulonephritis.

[0124] 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, anaphylactic syndrome, urticaria, food allergies, seasonal allergies, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrotizing phlebitis, insect bite skin inflammation, and blood-sucking parasitic infection.

[0125] In another embodiment, the KIT-mediated disease or condition is an inflammatory disease, including, but 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.

[0126] In yet another embodiment, the KIT-mediated disease or condition is fibrosis. Examples of fibrosis include, but are not limited to, pulmonary fibrosis, liver fibrosis, cardiac fibrosis, and bone marrow fibrosis.

[0127] In yet other embodiments, the KIT-mediated disease or condition is a metabolic disorder, including, but not limited to, diabetes and its chronic complications, obesity, type I or type II diabetes, hyperlipidemia and dyslipidemia, atherosclerosis, hypertension, and cardiovascular disease.

[0128] 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 diseases, motor neuron diseases (MND), and amyotrophic lateral sclerosis (ALS).

[0129] In yet other embodiments, the KIT-mediated disease or condition includes bone loss, tumor angiogenesis, interstitial cystitis, pulmonary arterial hypertension (PAH), and primary pulmonary hypertension (PPH).

[0130] <Administration method and dosage form> The exact amount of compound administered to provide an "effective amount" to a subject depends on the mode of administration, the type and severity of the disease or condition, and the subject's characteristics, such as general health, age, sex, weight, and tolerance to the drug. One skilled in the art would be able to determine the appropriate dosage depending on these and other factors. When administered in combination with other therapeutic agents, for example, in combination with an anti-cancer agent, the "effective amount" of any additional therapeutic agent will depend on the type of drug used. Appropriate dosages are known for approved therapeutic agents and can be adjusted by one skilled in the art according to the condition of the subject, the type of condition being treated, and the amount of compound of the present invention being used, for example, according to dosages reported in the literature and recommended in the Physician's Desk Reference (57th ed., 2003).

[0131] The term "effective amount" means an amount that, when administered to a subject, produces beneficial or desired results, including clinical results, e.g., inhibits, suppresses, or reduces the symptoms of the condition being treated in the subject compared to a control. For example, a therapeutically effective amount can be provided in a unit dosage form (e.g., 0.1 mg to about 50 g / day, or 1 mg to about 5 grams / day; or, alternatively, 10 mg to 1 gram / day).

[0132] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a composition to a desired site of biological effect. These methods include, but are not limited to, intra-articular (intra-articular), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. For administration techniques that can be used with the agents and methods described herein, see, e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed., Pergamon; and Remington's Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0133] Additionally, a compound of Formula (I) can be co-administered with other therapeutic agents. As used herein, the terms "co-administered," "administered in combination with," and their grammatical equivalents are meant to encompass the administration of two or more therapeutic agents to a single subject and are intended to include therapeutic 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 encompass administering two or more agents to a subject so that both agents and / or their metabolites are present in the subject at the same time. These include co-administration in separate compositions, administration at different times in separate compositions, and / or administration in a composition in which both agents are present. Thus, in some embodiments, a compound described herein and other agents are administered in a single composition. In some embodiments, a compound described herein and other agent(s) are mixed in a composition. In some embodiments, a compound of Formula (I) can be used in combination with other agents known to have beneficial activity with a compound of Formula (I) to treat or prevent a KIT-mediated disease or condition. For example, compounds of formula (I) can be administered alone or in combination with one or more other anti-cancer, immunomodulatory, anti-allergic, anti-inflammatory, anti-fibrotic, antimetabolite, and anti-neurodegenerative disease agents to treat or prevent a KIT-mediated disease or condition.

[0134] The particular mode of administration and dosage regimen will be selected by the attending physician, taking into account the specifics of the case (e.g., the subject, the disease, the disease state involved, the particular treatment). Treatment may involve daily or multi-day or sub-daily (e.g., weekly or monthly) doses over a period of several days to several months, or even years. However, one of ordinary skill in the art will readily recognize appropriate and / or equivalent doses, using the compounds of Formula (I) for guidance and reviewing the dosages of approved compositions for preventing or treating KIT-mediated diseases or conditions.

[0135] The compounds taught herein or corresponding pharmaceutical compositions can be administered to patients in various forms depending on the selected administration route, as will be understood by those skilled in the art. The compounds of the present teachings may be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, by patch, pump, or transdermal administration, and the pharmaceutical compositions are formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.

[0136] 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 routine procedures as a pharmaceutical composition adapted 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.

[0137] Typically, for oral therapeutic administration, compounds of the present teachings can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0138] Typically, for parenteral administration, solutions of the compounds of the present teachings can be prepared in water, generally suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0139] Typically, for injectable use, sterile aqueous solutions or dispersions and sterile powders of the compounds described herein are suitable for the extemporaneous preparation of sterile injectable solutions or dispersion. [Example]

[0140] <Synthesis of Compound Embodiments> Abbreviation

[0141] [Table 1]

[0142] Example 1 [ka]

[0143] Step 1: 6-(2-fluorophenoxy)nicotinonitrile 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 room temperature for 2 hours. The reaction mixture was poured into ice-cold water and stirred for another 2 hours. The separated solid was collected by filtration and dried to give the title compound (10 g, 58.1%). LC-MS: 215 [M+H] +

[0144] Step-2: tert-butyl ((6-(2-fluorophenoxy)pyridin-3-yl)methyl)carbamate To a solution of 6-(2-fluorophenoxy)nicotinonitrile (3 g, 14 mmol) in MeOH (40 mL), NiCl2.6H2O (1.66 g, 7 mmol) was added, followed by dropwise addition of di-tert-butyl dicarbonate (4.58 g, 21 mmol) at 0 °C and stirring for 5 min. Then, NaBH4 (1.06 g, 28.01 mmol) was added portionwise by maintaining the same temperature. After stirring at room temperature for 2 h, the reaction mass was concentrated to remove the solvent, 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 (3.5 g, 78.6%). LC-MS: 319 [M+H] +

[0145] Step-3: (6-(2-fluorophenoxy)pyridin-3-yl)methanamine hydrochloride 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), a solution of 4N HCl in 1,4-dioxane (20 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was then concentrated, diethyl ether was added, and the solid was collected by filtration to give the title compound (2.35 g, 97.9%). LC-MS: 219 [M+H] +

[0146] Step-4: N-((6-(2-fluorophenoxy)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 1) 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), HATU (4.99 g, 13.11 mmol) and triethylamine (5.53 g, 54.64 mmol) were added and stirred at room temperature for 10 minutes. Then, (6-(2-fluorophenoxy)pyridin-3-yl)methanamine hydrochloride (2.38 g, 9.34 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ice-cold water and extracted with EtOAc. The separated organic layer was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to give the crude compound. The crude compound was purified by combiflash column chromatography using 10% MeOH in DCM as the eluent to give 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).

[0147] Example 2 [ka]

[0148] Step 1: 4-(isopropylamino)-3-nitrobenzoic acid To a solution of 4-fluoro-3-nitrobenzoic acid (1 g, 5.4 mmol) in 1,4-dioxane (10 ml), DIPEA (2.09 g, 16.2 mmol) was added followed by propan-2-amine (0.32 g, 5.4 mmol) and stirred at 80° C. for 12 hours. The reaction mixture was then cooled to room temperature, 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 [M−H] -

[0149] Step 2: 3-amino-4-(isopropylamino)benzoic acid 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) at room temperature under a nitrogen atmosphere, and the reaction mixture was stirred under hydrogen bladder pressure for 16 hours. 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).

[0150] Step-3: 1-Isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid To a solution of 3-amino-4-(isopropylamino)benzoic acid (0.2 g, 1.03 mmol) in THF (8 ml), CDI (0.33 g, 2.06 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was poured into ice-cold water and acidified with 1N HCl, which was extracted with EtOAc, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to give the title compound (0.2 g, 88.4%). LC-MS: 221 [M+H] +

[0151] Step-4: N-((6-(4-fluorophenoxy)pyridin-3-yl)methyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 2) 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), DIPEA (0.17 g, 1.36 mmol) was added, followed by PyBOP (0.35 g, 0.68 mmol), and the mixture was stirred at room temperature for 10 minutes. Then, (6-(4-fluorophenoxy)pyridin-3-yl)methanamine (0.11 g, 0.49 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, washed with saturated 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 the 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),7.33-7.3 1(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).

[0152] Example 3 [ka]

[0153] Step 1: 4-Bromo-5-fluoro-N-methyl-2-nitroaniline To a stirred solution of 1-bromo-2,4-difluoro-5-nitrobenzene (4 g, 16.80 mmol) in THF (40 mL), KCO (5.8 g, 42.01 mmol) was added, followed by methylamine hydrochloride (1.36 g, 20.16 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and poured into ice-cold water, which was extracted with EtOAc, washed with saturated brine, dried over anhydrous NaSO, and concentrated to give the crude compound. This was purified by combiflash column chromatography using 10% EtOAc in hexane as the eluent to give the title compound (2.7 g, 64.6%). 1 H-NMR(400 MHz,DMSO-D6)δ 8.35-8.31(m,2H),7.01-6.98(d,1H)2.92-2.91(d,3H).

[0154] Step-2: 4-Bromo-5-fluoro-N 1 -Methylbenzene-1,2-diamine 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), ammonium chloride (2.14 g, 40.15 mmol) was added, followed by iron powder (2.24 g, 40.15 mmol), and the mixture was stirred at 80° C. for 8 hours. The reaction mixture was filtered through a bed of Celite, and the filtrate was poured into ice-cold water, extracted with EtOAc, washed with saturated brine, dried over anhydrous NaSO, and concentrated to give the title compound (1.5 g, 85.2%). LC-MS: 219 [M+H] +

[0155] Step-3: 5-Bromo-6-fluoro-1-methyl-1,3-dihydro-2H-benzimidazol-2-one 4-Bromo-5-fluoro-N 1To a solution of 1,2-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 hours. The reaction mixture was cooled to room temperature, acidified with 1N 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] +

[0156] Step-4: 6-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile 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), zinc cyanide (0.24 g, 2.04 mmol) was added, followed by tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.2 mmol), and the mixture was stirred at 100 °C for 12 hours. The reaction mixture was poured into ice-cold water, extracted with 10% MeOH in DCM, washed with saturated brine, dried over anhydrous NaSO, and concentrated to give the crude compound. This was purified by CombiFlash column chromatography using 5% MeOH in DCM as the 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).

[0157] Step-5: 6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid 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 hours. The reaction mixture was then concentrated, diluted with water, and acidified with 1N HCl. The precipitate that formed was collected by filtration and dried to give the title compound (0.12 g, 73%). LC-MS: 209 [M−H] - ; 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).

[0158] 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) 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), EDC.HCl (0.066 g, 0.34 mmol) and HOBt (0.047 g, 0.34 mmol) were added and stirred at room temperature for 10 minutes. Then, (6-(2-fluorophenoxy)pyridin-3-yl)methanamine (0.05 g, 0.23 mmol) was added, followed by triethylamine (0.087 g, 0.85 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give the crude compound. This was purified by preparative HPLC using Method A to give the title compound as a TFA salt (0.022 g, 23.4%). LC-MS: 411 [M+H] + ; 1H-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).

[0159] Example 4 [ka]

[0160] Step 1: 6-(2,4-difluorophenoxy)nicotinonitrile 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 room temperature for 2 hours. The reaction mixture was poured into ice-cold water and stirred for an additional 2 hours. The separated solid was collected by filtration and dried. This was purified by CombiFlash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (0.8 g, 48%). 1 H-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).

[0161] Step-2: tert-butyl ((6-(2,4-difluorophenoxy)pyridin-3-yl)methyl)carbamate 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), followed by dropwise addition of di-tert-butyl dicarbonate (0.75 g, 3.44 mmol) at 0 °C and stirring for 5 min. Then NaBH4 (0.098 g, 2.58 mmol) was added portionwise by maintaining the same temperature. After stirring at room temperature for 1 h, the reaction mass was concentrated to remove the solvent, 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 (0.55 g, 95%). LC-MS: 337 [M+H] +

[0162] Step-3: (6-(2,4-difluorophenoxy)pyridin-3-yl)methanamine hydrochloride 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), a solution of 4N HCl in 1,4-dioxane (30 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was then concentrated, diethyl ether was added, and the solid was collected by filtration to give the title compound (2.7 g, 98.9%). LC-MS: 237 [M+H] +

[0163] Step-4: N-((6-(2,4-difluorophenoxy)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 4) 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), HATU (2.84 g, 7.49 mmol) and triethylamine (1.89 g, 18.73 mmol) were added and stirred at room temperature for 10 minutes. Then, (6-(2,4-difluorophenoxy)pyridin-3-yl)methanamine hydrochloride (1.03 g, 3.77 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to ice-cold water, and the precipitate formed was collected by filtration and dried. This was further purified by CombiFlash column chromatography using 5% MeOH in DCM as the 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).

[0164] Example 5 [ka]

[0165] Step-1: (2-bromothiazol-5-yl)methanol To a solution of 2-bromothiazole-5-carbaldehyde (2 g, 10.41 mmol) in MeOH (20 mL) was added NaBH (0.59 g 15.62 mmol) and stirred at room temperature for 1 hour. The reaction mass was concentrated to remove the solvent, and the residue was dissolved in EtOAc, washed with water, dried over anhydrous NaSO, and concentrated to give the title compound (2 g, 99%). LC-MS: 194 [M+H] +

[0166] Step-2: (2-(4-fluorophenoxy)thiazol-5-yl)methanol 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, then (2-bromothiazol-5-yl)methanol (2.13 g, 15.46 mmol) was added 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 combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (1 g, 35.9%). LC-MS: 226 [M+H]+

[0167] Step-3: 5-(azidomethyl)-2-(4-fluorophenoxy)thiazole 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 room temperature for 16 h. The reaction mixture was poured into ice-cold water, extracted with DCM, dried over anhydrous NaSO, and concentrated to give a residue. This was purified by combiflash column chromatography using 10% EtOAc in hexane as the 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).

[0168] Step 4 (2-(4-fluorophenoxy)thiazol-5-yl)methanamine hydrochloride 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 room temperature for 12 hours. Then, 4N HCl in 1,4-dioxane (1 mL) was added to the reaction mixture at 0° C. and stirred for 1 hour. The reaction mass was concentrated, diethyl ether was added, and the solid was collected by filtration to give the title compound (0.04 g, 96%). LC-MS: 225 [M+H] +

[0169] Step-5: N-((2-(4-fluorophenoxy)thiazol-5-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide trifluoroacetate (Compound 5) 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), HATU (0.59 g, 1.56 mmol) and triethylamine (0.65 g, 6.5 mmol) were added and stirred at room temperature for 10 minutes. Then, (2-(4-fluorophenoxy)thiazol-5-yl)methanamine hydrochloride (0.27 g, 1.04 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to give the crude compound. This 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,2 H),7.32-7.26(m,2H),7.18-7.13(m,2H),4.47-4.46(d,2H),3.46(s,3H).

[0170] Example 6 [ka]

[0171] Step-1: 1-(6-(4-fluorophenoxy)pyridin-3-yl)ethan-1-one 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] +

[0172] Step-2: 1-(6-(4-fluorophenoxy)pyridin-3-yl)ethan-1-amine 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 room temperature for 16 hours. The reaction mixture was concentrated to remove the solvent, and the residue was diluted with water and basified with sodium hydroxide until the pH was about 12, which was then 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] +

[0173] Step-3: N-(1-(6-(4-fluorophenoxy)pyridin-3-yl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 6) 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), T3P (0.745 g, 2.34 mmol) was added and stirred at room temperature for 10 minutes. Then, 1-(6-(4-fluorophenoxy)pyridin-3-yl)ethan-1-amine (0.36 g, 1.56 mmol) was added, followed by DIPEA (0.30 g, 2.34 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added to ice-cold water, extracted with ethyl acetate, dried over anhydrous Na2SO4, and concentrated to give the crude product. This was purified by combiflash column chromatography using 4% MeOH in DCM as the eluent to give the title compound (0.14 g, 24.6%). LC-MS: 407 [M+H] + .

[0174] 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 (Peak 1 and Peak 2 of Compound 6) The obtained compound 6 was further subjected to chiral separation to obtain two optical isomers, peak 1 of compound 6 (0.025 g, 4.38%) and peak 2 of compound 6 (0.025 g, 4.38%). (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) 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. Compound 6 peak 2: LC-MS: 407 [M+H]+; 1H-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.

[0175] Example 7 [ka]

[0176] Step-1: 1-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethan-1-one To a stirred solution of 3,4-difluorophenol (1.61 g, 12.49 mmol) in DMF (3 mL) was added CsCO (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 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, washed with saturated brine, dried over anhydrous NaSO, and concentrated to give the crude compound. The compound was purified by combiflash column chromatography using 30% EtOAc in hexane as the eluent to give the title compound (2 g, 64.3%). LC-MS: 250 [M+H] +

[0177] Step-2: (R)—N-((S)-1-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide To a solution of 1-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethan-1-one (1 g, 4.04 mmol) in THF (15 ml) were added titanium tetraethoxide (1.83 g, 8.02 mmol) and (R)-2-methylpropane-2-sulfinamide (0.48 g, 4.01 mmol) under inert atmosphere. The reaction mass was heated to reflux for 18 hours. The reaction mass was cooled to -60 °C, NaBH (0.60 g, 16.05 mmol) was added, stirred at the same temperature for 30 minutes, and then stirred at room temperature for 12 hours. The reaction mass was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give the title compound. (1.4 g, 97%) LC-MS: 355 [M+H] +

[0178] Step-3: (S)-1-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethan-1-amine hydrochloride To a solution of (R)-N-((S)-1-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.4 g, 3.95 mmol) in DCM (10 mL) was added 4N HCl in 1,4-dioxane (8 mL) and stirred at room temperature for 3 hours. The reaction mass was then concentrated, diethyl ether was added, and the precipitate was collected by filtration to give the title compound (0.95 g, 96%). LC-MS: 249 [M−H] -

[0179] 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) 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), HATU (0.35 g, 0.93 mmol) and triethylamine (0.39 g, 3.9 mmol) were added and stirred at room temperature for 10 minutes. Then, (S)-1-(6-(3,4-difluorophenoxy)pyridin-3-yl)ethan-1-amine hydrochloride (0.22 g, 0.78 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give the crude compound. This was purified by combiflash column chromatography using 100% EtOAc as the 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,2H),7.4-7.3(m, 1H),7.19-7.17(d,1H),7.1-7.07(d,1H),7.04-7.01(d,1H),5.22-5.18(m,2H),3.36-3.34(s,3H),1.53-1.51(d,2H).

[0180] Example 8 [ka]

[0181] Step-1: 6-((4-fluorophenyl)amino)nicotinonitrile To a stirred solution of 6-chloronicotinonitrile (0.686 g, 4.95 mmol) in DMSO (5 mL), DIPEA (1.454 g, 11.25 mmol) was added, followed by 4-fluoroaniline (0.5 g, 4.5 mmol), and stirred at 100° C. for 12 hours. The reaction mixture was concentrated to remove DIPEA and then poured into ice-cold water, and the discarded solid was collected by filtration and dried. The crude residue was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the pure title compound (0.5 g, 52.11%). LC-MS: 214.05 [M+H] +

[0182] Step-2: tert-butyl ((6-((4-fluorophenyl)amino)pyridin-3-yl)methyl)carbamate A solution of 6-((4-fluorophenyl)amino)nicotinonitrile (0.4 g, 1.88 mmol) in MeOH (8 mL) was cooled to 0 °C, and NiCl2.6H2O (0.22 g, 0.93 mmol) was added, followed by dropwise addition of di-tert-butyl dicarbonate (0.61 g, 2.81 mmol) and stirring for 5 min. Then NaBH4 (0.14 g, 3.75 mmol) was added portionwise by maintaining the same temperature. After stirring at room temperature for 2 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 to give the title compound (crude 0.5 g). LC-MS: 318 [M+H] +

[0183] Step-3: 5-(aminomethyl)-N-(4-fluorophenyl)pyridin-2-amine hydrochloride 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 a solution of 4N HCl in 1,4-dioxane (4 mL) and stirred at room temperature for 2 hours. The reaction mass was concentrated, diethyl ether was added and the solid was collected by filtration to give the title compound (0.4 g). LC-MS: 218 [M+H] +

[0184] Step-4: N-((6-((4-fluorophenyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide trifluoroacetate (Compound 8) To a solution of 2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.18 g, 1.01 mmol) in DMF (6 mL), EDC.HCl (0.23 g, 1.21 mmol) and HOBt (0.16 g, 1.21 mmol) were added and stirred at room temperature for 10 minutes. 5-(aminomethyl)-N-(4-fluorophenyl)pyridin-2-amine hydrochloride (0.22 g, 0.86 mmol) was then added, followed by triethylamine (0.51 g, 5.05 mmol), and the mixture was stirred at room temperature for 16 hours. 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 the TFA salt (0.07 g, 16.5%). LC-MS: 378 [M+H] + 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).

[0185] Example 9 [ka]

[0186] Step-1: 6-((4-fluorophenyl)amino)nicotinonitrile To a stirred solution of 6-chloronicotinonitrile (13.7 g, 98.99 mmol) in DMSO (100 mL), DIPEA (29.08 g, 225.0 mmol) was added, followed by 4-fluoroaniline (10 g, 89.99 mmol), and stirred at 100° C. for 12 hours. The reaction mixture was concentrated to remove DIPEA and then poured into ice-cold water, and the separated solid was collected by filtration and dried. This was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (9.0 g, 46.91%). LC-MS: 214 [M+H] +

[0187] Step-2: 6-((4-fluorophenyl)(methyl)amino)nicotinonitrile 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 room temperature for 2 hours. The reaction mixture was poured into ice-cold water and the separated solid was collected by filtration and dried. This was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (8 g, 83.40%). LC-MS: 228 [M+H] +

[0188] Step-3: 5-(aminomethyl)-N-(4-fluorophenyl)-N-methylpyridin-2-amine hydrochloride A solution of 6-((4-fluorophenyl)(methyl)amino)nicotinonitrile (2.5 g, 11.00 mmol) in MeOH (25 mL) was cooled to 0° C., and a solution of 7N ammonia in MeOH (2.5 mL) was added, followed by Raney nickel (2.5 g), and stirred at room temperature for 1 hour under hydrogen bladder pressure. The reaction mass was filtered through Celite, and the filtrate was concentrated. The material was taken in 1,4-dioxane (10 mL), and 4N HCl in 1,4-dioxane (10 mL) was added at 0° C. and stirred at room temperature for 2 hours. The reaction mass was concentrated, washed with diethyl ether, and collected by filtration to give the title compound (2.3 g, 78.2%). LC-MS: 232 [M+H] +

[0189] 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) 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), HATU (2.66 g, 6.99 mmol) was added and stirred at room temperature for 10 minutes. 5-(aminomethyl)-N-(4-fluorophenyl)-N-methylpyridin-2-amine hydrochloride (1.6 g, 5.94 mmol) was then added, followed by DIPEA (2.95 g, 22.82 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added to ice-cold water, and the precipitate formed was collected by filtration and dried. This 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).

[0190] Example 10 [ka]

[0191] Step 1: 6-((4,4-difluorocyclohexyl)amino)nicotinonitrile 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-difluorocyclohexane-1-amine hydrochloride (5.57 g, 32.47 mmol) and stirred at 100° C. for 12 hours. The reaction mixture was concentrated to remove DIPEA and then poured into ice-cold water, and the separated solid was collected by filtration and dried. This was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (5.2 g, 67.48%). LC-MS: 236 [M−H] - .

[0192] Step-2: 6-((4,4-difluorocyclohexyl)(methyl)amino)nicotinonitrile 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 room temperature for 2 h. The reaction mixture was poured into ice-cold water and the separated solid was collected by filtration and dried. This was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (5 g, 90.9%). LC-MS: 252 [M+H] +

[0193] Step-3: 5-(aminomethyl)-N-(4,4-difluorocyclohexyl)-N-methylpyridin-2-amine To a solution of 6-((4,4-difluorocyclohexyl)(methyl)amino)nicotinonitrile (2 g, 7.95 mmol) in EtOH (40 mL), Raney nickel (2 g) was added and stirred under hydrogen bladder pressure at room temperature for 24 hours. 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] +

[0194] 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) 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), EDC.HCl (1.52 g, 7.92 mmol) and HOBt (0.80 g, 5.92 mmol) were added and stirred at room temperature for 10 minutes. 5-(aminomethyl)-N-(4,4-difluorocyclohexyl)-N-methylpyridin-2-amine (1.52 g, 5.96 mmol) was then added, followed by triethylamine (3.57 g, 35.25 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold water, and the precipitate formed was collected by filtration and dried. This was purified by CombiFlash column chromatography using 5% MeOH in DCM as the 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).

[0195] Example 11 [ka]

[0196] Step 1: 6-(isopropylamino)nicotinonitrile 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 hours. The reaction mixture was concentrated to remove DIPEA and then poured into ice-cold water, and the separated solid was collected by filtration and dried. This was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (2.8 g, 68.8%). LC-MS: 162 [M+H] +

[0197] Step 2: 6-(isopropyl(methyl)amino)nicotinonitrile 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 stirring at room temperature for 2 hours. The reaction mixture was poured into ice-cold water, and the separated solid was collected by filtration and dried. This was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (2.5 g, 68.8%). LC-MS: 176 [M+H] +

[0198] Step-3: tert-butyl ((6-(isopropyl(methyl)amino)pyridin-3-yl)methyl)carbamate A solution of 6-(isopropyl(methyl)amino)nicotinonitrile (2.5 g, 14.26 mmol) in MeOH (500 mL) was cooled to 0 °C, and NiCl2.6H2O (0.51 g, 2.13 mmol) was added, followed by dropwise addition of di-tert-butyl dicarbonate (6.22 g, 28.53 mmol) and stirring for 5 minutes. Then, NaBH4 (0.81 g, 21.39 mmol) was added portionwise by maintaining the same temperature. After stirring at room temperature for 1 hour, 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 combiflash chromatography using 20% EtOAc in hexane as the eluent to give the title compound (1.6 g, 40.9%). LC-MS: 280 [M+H] +

[0199] Step-4: 5-(aminomethyl)-N-isopropyl-N-methylpyridin-2-amine hydrochloride 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 a solution of 4N HCl in 1,4-dioxane (10 mL) and stirred at room temperature for 2 hours. The reaction mixture was then concentrated, diethyl ether was added, and the resulting residue was collected by filtration to give the crude title compound (1.6 g). LC-MS: 180 [M+H] +

[0200] 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) 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), EDC.HCl (1.77 g, 9.26 mmol) and HOBt (0.63 g, 4.63 mmol) were added and stirred at room temperature for 10 minutes. 5-(aminomethyl)-N-isopropyl-N-methylpyridin-2-amine hydrochloride (1.6 g, 7.41 mmol) was then added, followed by triethylamine (5.61 g, 55.56 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added to ice-cold water, and the precipitate formed was collected by filtration, washed with water, and dried. This was further purified by preparative HPLC using Method A to give the title compound as the TFA salt (0.7 g, 20.2%). LC-MS: 354 [M+H] +

[0201] 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) 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% HCl in water:acetonitrile (60:40) (700 mL) and completely concentrated at room temperature to give the title compound as the 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).

[0202] Example 12 [ka]

[0203] Step-1: 6-((cis-3-(trifluoromethyl)cyclobutyl)amino)nicotinonitrile To a stirred solution of 6-chloronicotinonitrile (1.42 g, 10.24 mmol) in DMSO (20 mL), DIPEA (7.95 g, 61.49 mmol) was added, followed by cis-3-(trifluoromethyl)cyclobutan-1-amine hydrochloride (2.00 g, 11.40 mmol), and stirred at 100° C. for 12 hours. The reaction mixture was concentrated to remove DIPEA and then poured into ice-cold water. The separated solid was collected by filtration and dried. This was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (2.32 g, 93.9%). LC-MS: 242 [M+H] + .

[0204] Step-2: 6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)nicotinonitrile 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 room temperature 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] +

[0205] Step-3: 5-(aminomethyl)-N-methyl-N-(cis-3-(trifluoromethyl)cyclobutyl)pyridin-2-amine To a solution of 6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)nicotinonitrile (2.4 g, 9.40 mmol) in EtOH (25 mL) was added 7N ammonia in MeOH (2.3 mL), followed by Raney nickel (2.4 g) and stirred under hydrogen bladder pressure at room temperature for 12 hours. 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] +

[0206] 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) 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 room temperature for 10 minutes. 5-(aminomethyl)-N-methyl-N-(cis-3-(trifluoromethyl)cyclobutyl)pyridin-2-amine (2.3 g, 8.87 mmol) was then added, followed by triethylamine (4.48 g, 44.35 mmol), and the mixture was stirred at room temperature for 16 hours. 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 × 25 mL) followed by pentane (25 mL) to give the title compound (1.28 g, 39.26%). LC-MS: 434 [M+H] + 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).

[0207] Example 13 [ka]

[0208] Step-1: 6-((4-fluorophenyl)amino)nicotinonitrile 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 hours. The reaction mixture was concentrated to remove DIPEA and then poured into ice-cold water, and 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] +

[0209] Step-2: 6-((4-fluorophenyl)(methyl)amino)nicotinonitrile 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 room temperature 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 combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the pure title compound (2.5 g, 46.92%). LC-MS: 228.0 [M+H] +

[0210] Step-3: 6-((4-fluorophenyl)(methyl)amino)nicotinic acid 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 with 1N HCl. The precipitated solid was collected by filtration and dried to give the title compound (1.7 g, 78.7%). LC-MS: 245 [M−H] -

[0211] Step-4: 6-((4-fluorophenyl)(methyl)amino)-N-methoxy-N-methylnicotinamide 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 room temperature for 10 minutes. Then, N,O-dimethylhydroxylamine hydrochloride (0.95 g, 9.74 mmol) was added, followed by DIPEA (2.46 g, 19.03 mmol), and the mixture was stirred at room temperature for 16 hours. 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 without further purification. LC-MS: 290 [M+H] +

[0212] Step-5: 1-(6-((4-fluorophenyl)(methyl)amino)pyridin-3-yl)ethan-1-one To a stirred solution of 6-((4-fluorophenyl)(methyl)amino)-N-methoxy-N-methylnicotinamide (2.7 g, 9.33 mmol) in THF (15 mL) was added methylmagnesium bromide (2.22 g, 18.66 mmol) at 0° C., and the mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated ammonium chloride, diluted with water, and extracted with DCM. This was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (1.85 g, 81.5%). LC-MS: 245 [M+H] +

[0213] Step-6: (R)—N-((S)-1-(6-((4-fluorophenyl)(methyl)amino)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide 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 titanium tetraethoxide (1.86 g, 8.18 mmol) at 0 °C, followed by (R)-2-methylpropane-2-sulfinamide (0.50 g, 4.09 mmol), and the mixture was refluxed for 36 h. The reaction mixture was cooled to -60 °C, and sodium borohydride (0.62 g, 16.37 mmol) was added and stirred at the same temperature for 0.5 h. The reaction mixture was then warmed to room temperature and stirred for 12 h. The reaction mixture was filtered, and the filtrate was diluted with water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated under reduced pressure to give a crude residue. This was purified by combi-flash column chromatography using 30% EtOAc in hexane as the eluent to give the title compound (1.1 g, 76.9%). LC-MS: 350 [M+H] +

[0214] Step-7: (S)-5-(1-aminoethyl)-N-(4-fluorophenyl)-N-methylpyridin-2-amine hydrochloride To a solution of (R)-N-((S)-1-(6-((4-fluorophenyl)(methyl)amino)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.2 g, 3.43 mmol) in 1,4-dioxane (5 mL) was added 4N HCl in 1,4-dioxane (10 mL) and stirred at room temperature for 2 hours. 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 taken further as such. LC-MS: 246 [M+H] +

[0215] 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) 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), HATU (0.59 g, 1.56 mmol) and HOAt (0.21 g, 1.56 mmol) were added and stirred at room temperature for 10 minutes. Then, (S)-5-(1-aminoethyl)-N-(4-fluorophenyl)-N-methylpyridin-2-amine hydrochloride (0.29 g, 1.04 mmol) was added, followed by triethylamine (0.66 g, 6.5 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give a crude residue. This was purified by CombiFlash column chromatography using 10% MeOH in DCM as the 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).

[0216] Example 14 [ka]

[0217] Step-1: (S)-6-(2-methylpyrrolidin-1-yl)nicotinonitrile To a stirred solution of 6-fluoronicotinonitrile (2.2 g, 18.02 mmol) in acetonitrile (10 mL), DIPEA (13.97 g, 108.1 mmol) was added, followed by (S)-2-methylpyrrolidine (2.41 g, 28.3 mmol), and stirred at 100° C. for 12 hours. The reaction mixture was concentrated to remove DIPEA and then poured into ice-cold water, and the separated solid was collected by filtration and dried. This was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (3.3 g, 97.82%). LC-MS: 188 [M+H] +

[0218] Step-2: (S)-((6-(2-methylpyrrolidin-1-yl)pyridin-3-yl)methyl)carbamate tert-butyl 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, and NiCl2.6H2O (0.22 g, 0.93 mmol) was added, followed by dropwise addition of di-tert-butyl dicarbonate (4.08 g, 18.69 mmol) and stirring for 5 minutes. Then, NaBH4 (2.48 g, 65.42 mmol) was added portionwise by maintaining the same temperature. After stirring at room temperature for 1 hour, 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 crude compound was purified by combi-flash chromatography using 20% EtOAc in hexane as the eluent to give the title compound (2.2 g, 80.8%). LC-MS: 292 [M+H] +

[0219] Step-3: (S)-(6-(2-methylpyrrolidin-1-yl)pyridin-3-yl)methanamine hydrochloride 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 a solution of 4N HCl in 1,4-dioxane (20 mL) and stirred at room temperature for 2 hours. 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] +

[0220] 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) 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 room temperature for 10 minutes. (S)-(6-(2-methylpyrrolidin-1-yl)pyridin-3-yl)methanamine hydrochloride (1.2 g, 5.27 mmol) was then added, followed by triethylamine (4.44 g, 43.91 mmol), and the mixture was stirred at room temperature for 16 hours. 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 (3 × 25 mL) to give the title compound (0.71 g, 37.1%). LC-MS: 366 [M+H] + ; 1 H-NMR(400 MHz,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).

[0221] Example 15 [ka]

[0222] Step 1: 5-Bromo-N-methoxy-N-methylpicolinamide To a solution of 5-bromopicolinic acid (4.0 g, 19.8 mmol) in DMF (20 mL), HATU (6.78 g, 17.82 mmol) was added and stirred at room temperature for 10 minutes. N,O-dimethylhydroxylamine hydrochloride (2.32 g, 23.76 mmol) was then added, followed by triethylamine (7.51 g, 74.25 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give a residue. This was purified by combi-flash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (3.8 g, 84.45%). LC-MS: 245 [M+H] +

[0223] Step-2: 1-(5-bromopyridin-2-yl)ethan-1-one To a stirred solution of 5-bromo-N-methoxy-N-methylpicolinamide (3.8 g, 15.5 mmol) in THF (40 mL) was added methylmagnesium bromide (2.77 g, 23.25 mmol) at 0° C. and stirred at room temperature for 12 hours. The reaction mixture was quenched with a saturated solution of ammonium chloride, extracted with DCM, dried over anhydrous NaSO, and concentrated to give the title compound (2.8 g, 90.3%). LC-MS: 200 [M+H] +

[0224] Step-3: 1-(5-bromopyridin-2-yl)-1-(4-fluorophenyl)ethan-1-ol To a stirred solution of 1-(5-bromopyridin-2-yl)ethan-1-one (2.8 g, 14.45 mmol) in THF (25 mL), (4-fluorophenyl)magnesium bromide (4.32 g, 21.67 mmol) was added at 0° C. and stirred at room temperature for 12 hours. The reaction mixture was quenched with a saturated solution of ammonium chloride, extracted with DCM, dried over anhydrous NaSO, and concentrated to give a residue. This was purified by combiflash column chromatography using 30% EtOAc in hexane as the eluent to give the title compound (1.5 g, 35.12%). LC-MS: 296 [M+H] +

[0225] Step-4: 5-bromo-2-(1-(4-fluorophenyl)vinyl)pyridine 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), PTSA (0.096 g, 0.50 mmol) was added at 0° C. and stirred at 100° C. for 16 hours. The reaction mixture was quenched with water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give a residue. This was purified by combiflash column chromatography using 10% EtOAc in hexane as the eluent to give the title compound (0.9 g, 69.23%). LC-MS: 280 [M+H] +

[0226] Step-5: 6-(1-(4-fluorophenyl)vinyl)nicotinonitrile 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 minutes, tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.25 mmol) was added, and heated at 120 °C for 10 hours. The reaction mixture was quenched with KMnO solution, and EtOAc was added. The organic layer was separated, dried over anhydrous NaSO, and concentrated to give a residue. This was purified by combiflash column chromatography using 30% EtOAc in hexane as the eluent to give the title compound (0.45 g, 79.73%). LC-MS: 225 [M+H] +

[0227] Step-6: (6-(1-(4-fluorophenyl)ethyl)pyridin-3-yl)methanamine To a stirred solution of 6-(1-(4-fluorophenyl)vinyl)nicotinonitrile (0.35 g, 1.56 mmol) in MeOH (8 mL), Raney nickel (0.092 g, 1.56 mmol) was added followed by methanolic ammonia (0.027 g, 1.56 mmol) and stirred under hydrogen bladder pressure at room temperature 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] +

[0228] 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) 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), HATU (0.24 g, 0.62 mmol) was added and stirred at room temperature for 10 minutes. Then, (6-(1-(4-fluorophenyl)ethyl)pyridin-3-yl)methanamine (0.11 g, 0.47 mmol) was added, followed by triethylamine (0.26 g, 2.6 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to give a residue. This 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).

[0229] Example 16 [ka]

[0230] Step 1: 5-Bromo-N-methoxy-N-methylpicolinamide To a solution of 5-bromopicolinic acid (2.0 g, 9.9 mmol) in DMF (20 mL), HATU (4.52 g, 11.88 mmol) was added and stirred at room temperature for 10 minutes. N,O-dimethylhydroxylamine hydrochloride (1.16 g, 11.88 mmol) was then added, followed by triethylamine (3.00 g, 29.69 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added to ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give a residue. This was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (0.75 g, 30.91%). LC-MS: 245 [M+H] +

[0231] Step-2: (5-bromopyridin-2-yl)(4-fluorophenyl)methanone To a stirred solution of 5-bromo-N-methoxy-N-methylpicolinamide (0.75 g, 3.06 mmol) in THF (10 mL), (4-fluorophenyl)magnesium bromide (1.22 g, 6.12 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was quenched with ammonium chloride, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give a residue. This was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (0.68 g, 79.34%). LC-MS: 280 [M+H] +

[0232] Step-3: (5-bromopyridin-2-yl)(4-fluorophenyl)methanol To a stirred solution of (5-bromopyridin-2-yl)(4-fluorophenyl)methanone (0.68 g, 2.42 mmol) in MeOH (5 mL) was added NaBH (0.14 g, 3.65 mmol) at 0 °C and stirred at room temperature for 1 h. The reaction mass was concentrated and diluted with EtOAc and water. The organic layer was dried over anhydrous NaSO and concentrated to give a residue. This was purified by combiflash column chromatography using 30% EtOAc in hexane as the eluent to give the title compound (0.5 g, 73.03%). LC-MS: 282 [M+H] +

[0233] Step-4: 5-Bromo-2-(fluoro(4-fluorophenyl)methyl)pyridine 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 room temperature for 1 hour. The reaction mixture was quenched with sodium bicarbonate solution, extracted with DCM, dried over anhydrous NaSO, and concentrated to give a residue. This was purified by combiflash column chromatography using 1% EtOAc in hexane as the eluent to give the title compound (0.35 g, 69.52%). LC-MS: 286 [M+H] +

[0234] Step 5: 6-(fluoro(4-fluorophenyl)methyl)nicotinonitrile 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 minutes, after which tetrakis(triphenylphosphine)palladium(0) (0.14 g, 0.12 mmol) was added and heated in a microwave at 100 °C for 1 hour. The reaction mixture was quenched with KMnO solution and EtOAc was added. The organic layer was separated, dried over anhydrous NaSO and concentrated to give a residue. This was purified by combiflash column chromatography using 10% EtOAc in hexane as the eluent to give the title compound (0.22 g, 77.57%). LC-MS: 231 [M+H] +

[0235] Step-6: tert-butyl ((6-(fluoro(4-fluorophenyl)methyl)pyridin-3-yl)methyl)carbamate 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). NaBH4 (0.054 g, 1.43 mmol) was then added portionwise at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mass was concentrated, and the residue was diluted with EtOAc and filtered through a Celite pad. The filtrate was concentrated and purified by Combi-Flash column chromatography using 8% EtOAc in hexane as the eluent to give the title compound (0.14 g, 42.23%). LC-MS: 335 [M+H] +

[0236] Step-7: (6-(fluoro(4-fluorophenyl)methyl)pyridin-3-yl)methanamine hydrochloride 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) at 0° C. was added 4N HCl in 1,4-dioxane (2 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mass was concentrated and the solid was washed with diethyl ether to give the title compound (0.11 g, 42.23%). LC-MS: 235 [M+H] +

[0237] 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) 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), EDC.HCl (0.108 g, 0.56 mmol) and HOBt (0.076 g, 0.55 mmol) were added and stirred at room temperature for 10 minutes. Then, (6-(fluoro(4-fluorophenyl)methyl)pyridin-3-yl)methanamine hydrochloride (0.11 g, 0.42 mmol) was added, followed by triethylamine (0.14 g, 1.4 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give a residue. This was purified by washing with diethyl ether (3 × 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).

[0238] Example 17 [ka]

[0239] Step-1: 5-Bromo-1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine 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 minutes. 2-Iodopropane (4.44 g, 26.12 mmol) was then added to it at 0° C., and the reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was quenched with ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give a residue. This was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (2.8 g, 57.79%). LC-MS: 241 [M+H] +

[0240] Step-2: 1-Isopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 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].3HO (0.77 g, 1.82 mmol) and DBU (0.17 g, 1.14 mmol). The reaction mixture was degassed with argon for 15 minutes, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.22 mmol), and the reaction mixture was heated to 85 °C for 4 hours. The reaction mixture was cooled to room temperature, diluted with 10% MeOH in DCM, and filtered through Celite. The filtrate was concentrated and purified by CombiFlash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (0.5 g, 58.54%). LC-MS: 188 [M+H] +

[0241] Step-3: (1-Isopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine 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), Raney nickel (0.019 g, 0.32 mmol) was added, followed by methanolic ammonia (1 mL), and stirred under hydrogen bladder pressure at room temperature for 1 hour. The reaction mass was filtered through a Celite pad, and the filtrate was concentrated to give the title compound (0.3 g, 98%). LC-MS: 192.15 [M+H] +

[0242] 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) 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), HATU (3.087 g, 8.11 mmol) was added and stirred at room temperature for 10 minutes. Then, (1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine (1.16 g, 6.09 mmol) was added, followed by triethylamine (3.42 g, 33.82 mmol), and stirred at room temperature for 16 hours. The reaction mixture was added to ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give a residue. This 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)δ 11.01(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,2) H),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)

[0243] Example 18 [ka]

[0244] Step-1: 5-Bromo-1-(4,4-difluorocyclohexyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine 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-picoline borane complex (3.525 g, 33.91 mmol) at 0 °C and stirred at room temperature for 16 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give a residue. This was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (3.6 g, 83.68%). LC-MS: 319 [M+H] +

[0245] Step-2: 1-(4,4-difluorocyclohexyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 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 ferricyanide (1.92 g, 4.54 mmol). The reaction mass was degassed with argon for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.66 g, 0.56 mmol) was then added thereto and heated at 100° C. for 4 hours. The reaction mass was concentrated to remove t-BuOH, and the residue was diluted with water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated. The crude residue was purified by combi-flash column chromatography using 30% EtOAc in hexane as the eluent to give the title compound (2.4 g, 80.32%). LC-MS: 264 [M+H] +

[0246] Step-3: (1-(4,4-difluorocyclohexyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine 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), Raney nickel (2.4 g) was added followed by methanolic ammonia (2.4 mL) and stirred under hydrogen bladder pressure at room temperature for 30 minutes. The reaction mass was filtered through a Celite pad and the filtrate was concentrated to give the title compound (2.4 g, 98.49%). LC-MS: 268 [M+H] +

[0247] 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) 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), EDC.HCl (1.72 g, 8.97 mmol) and HOBt (1.09 g, 8.07 mmol) were added and stirred at room temperature for 10 minutes. Then, (1-(4,4-difluorocyclohexyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine (2.4 g, 8.97 mmol) was added, followed by triethylamine (4.54 g, 44.85 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added to ice-cold water, and the precipitate formed was collected by filtration and dried. The crude compound obtained was washed with diethyl ether (3 × 50 mL) to give the title compound (1.2 g). LC-MS: 442 [M+H] + ; 1 H-NMR(400 MHz,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).

[0248] Example 19 [ka]

[0249] Step-1: 1-(2-fluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 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 minutes. Xphos (0.082 g, 0.17 mmol) and Pd2(dba)3 (0.079 g, 0.08 mmol) were added and heated to 100 °C for 6 hours. The reaction mass was filtered through a bed of Celite and concentrated to give a residue, which was purified by CombiFlash chromatography using 40% EtOAc in hexane as the eluent to give the title compound (0.26 g, 61.89%). LC-MS: 240 [M+H] +

[0250] Step-2: (1-(2-fluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine 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), Raney nickel (0.13 g) was added and stirred at room temperature under hydrogen bladder pressure for 30 minutes. 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] +

[0251] 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) 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), EDC.HCl (0.12 g, 0.64 mmol) and HOBt (0.098 g, 0.64 mmol) were added and stirred at room temperature for 10 minutes. Then, (1-(2-fluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine (0.13 g, 0.53 mmol) was added, followed by triethylamine (0.22 g, 2.13 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold water, and the precipitate formed was collected by filtration and dried to give a residue. This 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).

[0252] Example 20 [ka]

[0253] Step-1: 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 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). After degassing the reaction mixture with argon for 15 minutes, tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol) was added, and the reaction mixture was heated in a microwave at 100 °C for 1 hour. The reaction mixture was quenched with KMnO solution, added with ice-cold water mixture, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give a residue. This was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (0.4 g, 84.7%). LC-MS: 144 [M+H] +

[0254] Step-2: 1-phenyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 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 KPO (0.38 g, 2.79 mmol) and degassed with argon for 15 minutes. The reaction mixture was then heated to 100 °C in a microwave for 6 hours. The reaction mixture was diluted with water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give a residue. This was purified by combi-flash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (0.38 g, 62.04%). LC-MS: 220 [M+H] +

[0255] Step-3: (1-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine 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), Raney nickel (0.4 g) was added followed by methanolic ammonia (0.5 mL) and stirred under hydrogen bladder pressure at room temperature for 30 minutes. The reaction mass was filtered through a Celite pad and concentrated to give the title compound (0.4 g, 99%). LC-MS: 224 [M+H] +

[0256] 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) 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), EDC.HCl (0.26 g, 1.34 mmol) and HOBt (0.18 g, 1.34 mmol) were added and stirred at room temperature for 10 minutes. Then, (1-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine (0.2 g, 0.90 mmol) was added, followed by triethylamine (0.34 g, 3.35 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give a residue. This was purified by CombiFlash column chromatography using 60% EtOAc in hexane as the 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).

[0257] Example 21 [ka]

[0258] Step-1: 6-((2,6-difluorophenyl)amino)-5-nitronicotinonitrile To a stirred solution of 6-chloro-5-nitronicotinonitrile (0.25 g, 1.36 mmol) in DMF (28 mL), NaH (60% dispersion in mineral oil) (0.082 g, 2.04 mmol) was added at 0° C. and stirred at room temperature for 1 h. 2,6-difluoroaniline (0.22 g, 1.70 mmol) was then added and refluxed for 16 h. The reaction mixture was diluted with EtOAc, washed with water, dried over anhydrous NaSO, and concentrated. The crude compound obtained was purified by Combiflash chromatography using 20% EtOAc in hexane as the eluent to give the title compound (0.13 g, 34.56%). LC-MS: 275 [M−H] -

[0259] Step-2: 5-amino-6-((2,6-difluorophenyl)amino)nicotinonitrile To a solution of 6-((2,6-difluorophenyl)amino)-5-nitronicotinonitrile (0.13 g, 0.45 mmol) in ethanol (4 mL) under nitrogen atmosphere, Pd / C (0.025 g) was added and stirred at room temperature under hydrogen bladder pressure for 1 hour. The reaction mass was filtered through Celite and concentrated to give the title compound (0.1 g, 90%). LC-MS: 247 [M+H] + .

[0260] Step-3: 3-(2,6-difluorophenyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile 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 hours. The reaction mixture was concentrated and the residue was purified by column chromatography using 40% EtOAc in hexane as the eluent to give the title compound (0.09 g, 86.52%). LC-MS: 257 [M+H] + .

[0261] Step-4: (3-(2,6-difluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)methanamine 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), Raney nickel (0.080 g) was added and stirred under hydrogen bladder pressure at room temperature for 2 hours. 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] + .

[0262] 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) 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), EDC.HCl (0.084 g, 0.43 mmol) and HOBt (0.059 g, 0.43 mmol) were added and stirred at room temperature for 10 minutes. (3-(2,6-difluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)methanamine (0.065 g, 0.25 mmol) was then added, followed by triethylamine (0.15 g, 1.45 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold water, and the precipitate formed was collected by filtration and dried. This 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).

[0263] Example 22 [ka]

[0264] Step 1: 6-(3-iodophenoxy)nicotinonitrile 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 room temperature for 12 hours. The reaction mixture was poured into ice-cold water and stirred for an additional 2 hours. The separated solid was collected by filtration and dried to give the title compound (2.2 g, 75.7%). LC-MS: 323 [M+H] +

[0265] Step-2: tert-butyl ((6-(3-iodophenoxy)pyridin-3-yl)methyl)carbamate To a solution of 6-(3-iodophenoxy)nicotinonitrile (2.2 g, 6.83 mmol) in MeOH (20 mL), NiCl2.6H2O (0.81 g, 3.42 mmol) was added, followed by dropwise addition of di-tert-butyl dicarbonate (2.99 g, 13.70 mmol) at 0 °C and stirring for 5 minutes. Then, NaBH4 (0.39 g, 10.26 mmol) was added portionwise by maintaining the same temperature. After stirring at room temperature for 3 hours, the reaction mass was concentrated to remove the solvent, diluted with EtOAc, and filtered through Celite. The filtrate was washed with water, dried over anhydrous Na2SO4, and concentrated to give the crude compound, which was purified by combiflash column chromatography using 10% EtOAc in hexane as the eluent to give the title compound (1.3 g, 44.8%). LC-MS: 427 [M+H] +

[0266] Step-3: tert-butyl ((6-(3-cyanophenoxy)pyridin-3-yl)methyl)carbamate 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 saturated brine, dried over anhydrous NaSO, and concentrated to give the crude compound. This was purified by combiflash column chromatography using 23% EtOAc in hexane as the eluent to give the title compound (0.26 g, 28.5%). LC-MS: 326 [M+H] +

[0267] Step-4: 3-((5-(aminomethyl)pyridin-2-yl)oxy)benzonitrile hydrochloride 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 a solution of 4N HCl in 1,4-dioxane (2.85 mL) and stirred at room temperature for 1 hour. 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 further used without purification. LC-MS: 226 [M+H] +

[0268] Step-5: N-((6-(3-cyanophenoxy)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide trifluoroacetate (Compound 22) 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), HATU (0.55 g, 1.43 mmol) and triethylamine (0.61 g, 5.98 mmol) were added and stirred at room temperature for 10 minutes. 3-((5-(aminomethyl)pyridin-2-yl)oxy)benzonitrile hydrochloride (0.25 g, 0.95 mmol) was then added, and the mixture was stirred at room temperature for 6 hours. 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 (0.03 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)

[0269] Example 23 [ka]

[0270] Step 1: 6-(cyclopropyl(4-fluorophenyl)amino)nicotinonitrile To a solution of 6-((4-fluorophenyl)amino)nicotinonitrile (1 g, 4.68 mmol) in acetonitrile (10 mL), 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) were added, followed by stirring at 45° C. for 40 hours. The reaction mixture was poured into water and extracted with EtOAc. The separated organic layer was washed with saturated brine, dried over anhydrous NaSO, and concentrated to give the crude compound. The crude compound was purified by combiflash column chromatography using 20% EtOAc in hexane as the 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).

[0271] Step-2: 5-(aminomethyl)-N-cyclopropyl-N-(4-fluorophenyl)pyridin-2-amine 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 this solution was added 7N ammonia in MeOH (0.3 mL), followed by Raney nickel (0.22 g) and stirred under hydrogen bladder pressure at room temperature for 2 hours. The reaction mass was filtered through Celite and the filtrate was concentrated to give the crude title compound (0.22 g), which was further used without purification. LC-MS: 258 [M+H] + .

[0272] 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) 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), EDC.HCl (0.23 g, 1.2 mmol) and HOBt (0.16 g, 1.2 mmol) were added and stirred at room temperature for 10 minutes. Then, 5-(aminomethyl)-N-cyclopropyl-N-(4-fluorophenyl)pyridin-2-amine (0.21 g, 0.8 mmol) was added, followed by triethylamine (0.31 g, 3.12 mmol), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give the crude compound. This was purified by CombiFlash column chromatography using 5% MeOH in DCM as the eluent to give the title compound. (0.01g, 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).

[0273] Example 24 [ka]

[0274] Step-1: 6-(methyl(1-methylpiperidin-4-yl)amino)nicotinonitrile 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 minutes. Xantphos (0.17 g, 0.28 mmol) and Pd2(dba)3 (0.07 g, 0.07 mmol) were added, and the mixture was heated to 100 °C in a microwave for 2 hours. 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 saturated brine, dried over anhydrous Na2SO4, and concentrated to give the crude compound. The crude compound was purified by Combiflash chromatography using 10% MeOH in DCM as the eluent to give the title compound (0.33 g, 99.4%). LC-MS: 231 [M+H] +

[0275] Step-2: 5-(aminomethyl)-N-methyl-N-(1-methylpiperidin-4-yl)pyridin-2-amine 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., and Raney nickel (0.33 g) was added, followed by 7 N ammonia in MeOH (0.4 mL), and stirred under hydrogen bladder pressure at room temperature for 3 hours. The reaction mass was filtered through Celite, and the filtrate was concentrated to give the crude compound. The crude compound was purified by washing with diethyl ether to give the title compound (0.3 g, 89.5%). LC-MS: 235 [M+H] +

[0276] 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) 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), EDC.HCl (0.18 g, 0.93 mmol) and HOBt (0.13 g, 0.96 mmol) were added and stirred at room temperature for 10 minutes. Then, 5-(aminomethyl)-N-methyl-N-(1-methylpiperidin-4-yl)pyridin-2-amine (0.15 g, 0.64 mmol) was added, followed by triethylamine (0.24 g, 2.34 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated. This was purified by preparative HPLC using Method B to obtain 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).

[0277] Example 25 [ka]

[0278] Step-1: 2-((4,4-difluorocyclohexyl)amino)thiazole-5-carbonitrile To a stirred solution of 2-chlorothiazole-5-carbonitrile (0.50 g, 3.46 mmol) in DMSO (5 mL), DIPEA (1.34 g, 10.37 mmol) was added followed by 4,4-difluorocyclohexane-1-amine hydrochloride (0.59 g, 3.46 mmol) and stirred at 100° C. for 16 hours. The reaction mixture was poured into ice-cold water and extracted with EtOAc. The separated organic layer was washed with saturated brine, dried over anhydrous NaSO, and concentrated to give the crude compound. The crude compound was purified by combiflash column chromatography using 20% EtOAc in hexane as the eluent to give the title compound (0.40 g, 47.56%). LC-MS: 242 [M−H] - .

[0279] Step-2: tert-butyl (5-cyanothiazol-2-yl) (4,4-difluorocyclohexyl)carbamate 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 dropwise addition of di-tert-butyl dicarbonate (0.21 g, 0.98 mmol) at 0° C. The reaction mixture was stirred at room temperature for 12 hours, then poured into water and extracted with EtOAc. The separated organic layer was washed with saturated brine, dried over anhydrous NaSO, and concentrated to give the crude compound. The crude compound was purified by combiflash column chromatography using 30% EtOAc in hexane as the eluent to give the title compound (0.16 g, 56.93%). LC-MS: 344 [M+H] + .

[0280] Step-3: tert-butyl (5-(aminomethyl)thiazol-2-yl)(4,4-difluorocyclohexyl)carbamate To a solution of tert-butyl (5-cyanothiazol-2-yl) (4,4-difluorocyclohexyl)carbamate (0.29 g, 0.84 mmol) in EtOH (5 mL), Raney nickel (0.29 g) was added and stirred under hydrogen bladder pressure at room temperature for 12 hours. 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] + .

[0281] Step-4: tert-butyl(4,4-difluorocyclohexyl)(5-((1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamido)methyl)thiazol-2-yl)carbamate 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), EDC.HCl (0.19 g, 0.99 mmol) and HOBt (0.13 g, 0.96 mmol) were added and stirred at room temperature for 10 minutes. tert-Butyl (5-(aminomethyl)thiazol-2-yl)(4,4-difluorocyclohexyl)carbamate (0.25 g, 0.72 mmol) was then added, followed by triethylamine (0.33 g, 3.24 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold water, and the precipitate formed was collected by filtration and dried to give the crude title compound (0.15 g, 39.94%). LC-MS: 522 [M+H] + .

[0282] 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) To a solution of tert-butyl (4,4-difluorocyclohexyl) (5-((1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamido)methyl)thiazol-2-yl)carbamate (0.15 g, 0.29 mmol) in 1,4-dioxane (2 mL) was added a solution of 4 N HCl in 1,4-dioxane (4 mL) and stirred at room temperature for 2 hours. The reaction mass was concentrated to give the crude compound. This was purified by preparative HPLC using Method B to give 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).

[0283] Example 26 [ka]

[0284] Step 1: 1-methyl-4-(3-nitrobenzyl)piperazine 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 saturated brine, dried over anhydrous Na2SO4, and concentrated to give the title compound (5.6 g, 73.56%). LCMS: 236 [M+H] +

[0285] Step-2: 3-((4-methylpiperazin-1-yl)methyl)aniline To a stirred solution of 1-methyl-4-(3-nitrobenzyl)piperazine (5.0 g, 21.25 mmol) in HCl (15 mL) was added tin powder (5.04 g, 42.50 mmol) at 0° C. and stirred at 100° C. for 12 hours. 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] + .

[0286] Step-3: N-methyl-3-((4-methylpiperazin-1-yl)methyl)aniline 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 hours. The reaction mixture was concentrated, the residue was diluted with THF (10 mL), and a 2 M solution of lithium aluminum hydride in THF (0.18 g, 4.74 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 2 hours and then quenched with EtOAc. The reaction mass was filtered through Celite and the filtrate was concentrated. The crude compound was purified by CombiFlash column chromatography using 10% MeOH in DCM as the eluent to give the title compound (0.6 g, 70.22%). LCMS: 220 [M+H] +

[0287] Step-4: 6-(methyl(3-((4-methylpiperazin-1-yl)methyl)phenyl)amino)nicotinonitrile 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 minutes. 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 hours. The reaction mixture was concentrated to give the crude compound, which was further purified by preparative HPLC using Method B to give the title compound (0.21 g, 39.80%). LCMS: 322 [M+H] + .

[0288] Step-5: 5-(aminomethyl)-N-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-2-amine 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), Raney nickel (0.07 g) was added followed by methanolic ammonia (1 mL) and stirred under hydrogen bladder pressure at room temperature 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] + .

[0289] 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) 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), EDC.HCl (0.07 g, 0.39 mmol) and HOBt (0.05 g, 0.35 mmol) were added and stirred at room temperature for 10 minutes. 5-(aminomethyl)-N-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-2-amine (0.13 g, 0.40 mmol) was then added, followed by triethylamine (0.24 g, 2.39 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to give the crude compound, which 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)δ 8.03-8.00(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),7.0 4-7.01(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).

[0290] Example 27 [ka]

[0291] Step-1: 1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethan-1-one 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 CsCO (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] + .

[0292] Step-2: (E)-1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethan-1-one oxime 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 room temperature for 7 hours. The reaction mixture was concentrated to remove the solvent, water was added, and then extracted with ethyl acetate, which was dried over anhydrous NaSO and concentrated under reduced pressure to give the crude compound (0.55 g, 83.45%). LC-MS: 265 [M+H] + .

[0293] Step-3: tert-butyl (1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethyl)carbamate 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, and NiCl2.6H2O (0.25 g, 1.04 mmol) was added, followed by dropwise addition of di-tert-butyl dicarbonate (0.68 g, 3.12 mmol) and stirring for 5 minutes. Then, NaBH4 (0.12 g, 3.12 mmol) was added portionwise by maintaining the same temperature. After stirring at room temperature for 1 hour, the reaction mass was concentrated to remove methanol. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous Na2SO4, and concentrated to give the title compound (0.5 g, 68.59%). LC-MS: 351 [M+H]+ .

[0294] Step-4: 1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethan-1-amine hydrochloride 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 4M HCl in 1,4-dioxane (2 mL) and stirred at room temperature for 2 hours. The reaction mixture was then concentrated, diethyl ether was added, and the solid was collected by filtration to give the title compound (0.16 g, 78.43%). LC-MS: 251.05 [M+H] + . 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) To a solution of 2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.10 g, 0.52 mmol) in DMF (3 mL), HATU (0.122 g, 0.57 mmol) was added and stirred at room temperature for 10 minutes. Then, 1-(6-(2,4-difluorophenoxy)pyridin-3-yl)ethan-1-amine hydrochloride (0.15 g, 0.52 mmol) was added, followed by triethylamine (0.21 g, 2.08 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added to ice-cold water, and the precipitate formed was collected by filtration, washed with water, and dried. This was purified by combiflash column chromatography using 5% MeOH in DCM as the eluent to give the title compound (0.02 g, 11.4%). LC-MS: 425 [M+H] + . 1HNMR(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).

[0295] Manufacturing example 1 [ka]

[0296] Step-1: 6-((1,3-dihydroisobenzofuran-5-yl)amino)nicotinonitrile 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 hours. The reaction mass was concentrated and the residue was purified by column chromatography using 40% EtOAc in n-hexane as eluent to give the title compound (0.02 g, 37%). LC-MS: 238 [M+H] + .

[0297] Manufacturing Example 2 [ka]

[0298] Step 1: 1,1-difluorospiro[2.3]hexane-5-carbonitrile 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 NaSO, and concentrated. The residue was purified by combiflash column chromatography using 20% EtOAc in n-hexane as the 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).

[0299] Step 2: 1,1-difluorospiro[2.3]hexane-5-carboxylic acid 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 NaSO, and concentrated to give the title compound (0.5 g, 88.0%). 1 H-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).

[0300] Step-3: tert-butyl (1,1-difluorospiro[2.3]hexan-5-yl)carbamate 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 room temperature for 10 minutes. t-BuOH (1 mL) was then added and stirred at 80 °C for 16 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated. The residue was purified by combiflash column chromatography using 20% EtOAc in n-hexane as the eluent to give the title compound (0.5 g, 69.5%). 1 H-NMR (400 MHz, 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).

[0301] Step 4: 1,1-difluorospiro[2.3]hexane-5-amine hydrochloride 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 4N HCl in 1,4-dioxane (5 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to give the title compound (0.3 g, 82%). LC-MS: 134 [M+H] + .

[0302] Manufacturing Example 3 [ka]

[0303] Step-1: Methyl (5-cyanopyridin-2-yl)alaninate 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 methyl alaninate 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 and 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 [M−H] - .

[0304] Step-2: Methyl N-(5-cyanopyridin-2-yl)-N-methylalaninate To a stirred solution of methyl (5-cyanopyridin-2-yl)alaninate (0.58 g, 2.82 mmol) in DMF (6 mL) 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) at 0° C., and the mixture was stirred at room temperature for 1 hour. 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] + .

[0305] Step-3: 6-((1-hydroxypropan-2-yl)(methyl)amino)nicotinonitrile To a stirred solution of methyl N-(5-cyanopyridin-2-yl)-N-methylalaninate (0.09 g, 0.41 mmol) in THF (2 mL) was added LiBH (0.03 g, 1.64 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated sodium sulfate solution and extracted with EtOAc. The separated organic layer was washed with saturated brine, dried over anhydrous NaSO, and concentrated to give the title compound (0.09 g, 114.6%). LC-MS: 192 [M+H] + .

[0306] Step-4: 2-((5-(aminomethyl)pyridin-2-yl)(methyl)amino)propan-1-ol 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 room temperature for 3 hours. 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] + .

[0307] Manufacturing Example 4 [ka]

[0308] Step 1: 4,5-Diamino-2-fluorobenzonitrile 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 bladder pressure at room temperature for 1 hour. The reaction mass was filtered through Celite and the filtrate was concentrated to give the title compound (0.65 g, 97%). LC-MS: 152 [M+H] + .

[0309] Step-2: 6-Fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile 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 hours. 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] + .

[0310] Step-3: 6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid 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 hours. The reaction mixture was concentrated to remove EtOH, diluted with water, and acidified with 1N HCl. The precipitate that formed was collected by filtration and dried to give the title compound (0.55 g, 76%). LC-MS: 197 [M+H] + .

[0311] Manufacturing Example 5 [ka]

[0312] Step-1: Methyl 3,4-diamino-5-chlorobenzoate 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 dust (0.64 g, 3.36 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mass was diluted with EtOAc and filtered through a bed of celite. 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] + .

[0313] Step-2: Methyl 7-chloro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate 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 hours. 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] + .

[0314] Step-3: 7-chloro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid 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 room temperature for 12 hours. The reaction mixture was concentrated to remove THF and MeOH, diluted with water, and acidified with 1N HCl. The precipitate that formed was collected by filtration and dried to give the title compound (0.65 g, 99%). LC-MS: 213 [M+H] + .

[0315] Manufacturing Example 6 [ka]

[0316] Step 1: 4-Bromo-2,3-difluoro-6-nitroaniline 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 room temperature for 12 hours. After completion of the reaction, ice-cold water was added to the reaction mixture, 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] + .

[0317] Step 2: 5-bromo-3,4-difluorobenzene-1,2-diamine To a stirred solution of 4-bromo-2,3-difluoro-6-nitroaniline (1.0 g, 3.95 mmol) in THF (30 mL) was added a solution of ammonium chloride (1.26 g, 23.71 mmol) in water (10 mL), followed by zinc dust (0.77 g, 11.85 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was extracted with EtOAc. The organic layer was dried over anhydrous NaSO and concentrated to give the title compound (0.83 g, 94.1%). LC-MS: 221 [M−H] - .

[0318] Step-3: 6-Bromo-4,5-difluoro-1,3-dihydro-2H-benzimidazol-2-one 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 hours. The reaction mixture was concentrated to remove THF and then poured into ice-cold water, and the precipitated solid was collected by filtration and dried to give the title compound (0.9 g, 98.30%). LC-MS: 247 [M−H] - .

[0319] Step-4: Methyl 6,7-difluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate 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 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.35 g, 0.48 mmol) was added and stirred with 80 psi of carbon monoxide at 80 °C for 12 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated to give the title compound (0.4 g, 87%). LC-MS: 227 [M−H] - .

[0320] Step-5: 6,7-difluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid 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 hours. The reaction mixture was concentrated to remove THF and acidified with 1N HCl. The precipitate that formed was collected by filtration and dried to give the title compound (0.28 g, 85.24%). LC-MS: 213 [M−H] - .

[0321] Manufacturing Example 7 [ka]

[0322] Step 1: 3-Fluoro-N-methyl-2-nitroaniline To a stirred solution of 1,3-difluoro-2-nitrobenzene (2.0 g, 12.57 mmol) in MeOH (40 mL) was added 2M methylamine in THF (0.39 g, 12.57 mmol) at 0° C., and the mixture was stirred at room temperature for 16 hours. The reaction mass was concentrated and diluted with ice-cold water. The mixture was extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give the title compound (1.5 g, 70.13%). LC-MS: 171 [M+H] + .

[0323] Step-2: 4-Bromo-3-fluoro-N-methyl-2-nitroaniline To a stirred solution of 3-fluoro-N-methyl-2-nitroaniline (1.5 g, 8.81 mmol) in DMF (20 mL), N-bromosuccinimide (1.56 g, 8.81 mmol) was added at 0° C., and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, ice-cold water was added to the reaction mass, extracted with EtOAc, dried over anhydrous NaSO, and concentrated. The residue was purified by column chromatography using 15% EtOAc in n-hexane as the eluent to give the title compound (1.0 g, 45.55%). LC-MS: 249 [M+H] + .

[0324] Step-3: 4-Bromo-3-fluoro-N 1 -Methylbenzene-1,2-diamine 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 a solution of ammonium chloride (1.29 g, 24.09 mmol) in water (5 mL), followed by zinc dust (0.78 g, 12.04 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was extracted with EtOAc. The organic layer was dried over anhydrous NaSO and concentrated to give the title compound (0.8 g, 90.95%). LC-MS: 219 [M+H] + .

[0325] Step-4: 5-Bromo-4-fluoro-1-methyl-1,3-dihydro-2H-benzimidazol-2-one 4-Bromo-3-fluoro-N 1 To a stirred solution of 1,2-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 hours. 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] + .

[0326] Step-5: 4-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile 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 the mixture was degassed with argon for 15 minutes. Palladium diacetate (0.07 g, 0.32 mmol) was added to the reaction mixture, which was then stirred at 120 °C for 4 hours. The reaction mass was filtered through Celite, and the filtrate was diluted with water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated. The residue was purified by column chromatography using 70% EtOAc in n-hexane as the eluent to give the title compound (0.36 g, 57.68%). LC-MS: 190 [MH] - .

[0327] Step-6: 4-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid 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 hours. The reaction mixture was then concentrated and acidified with 1N 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] + .

[0328] Example 103 [ka]

[0329] Step 1: 6-(3-(trifluoromethyl)cyclobutyloxy)nicotinonitrile 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 room temperature for 12 hours. The reaction mixture was quenched with ice-cold water and extracted with EtOAc. The separated organic layer was dried over anhydrous NaSO and concentrated to give the title compound (0.3 g, 95%). LC-MS: 243 [M+H] + .

[0330] Step-2: (6-(3-(trifluoromethyl)cyclobutyloxy)pyridin-3-yl)methanamine 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 under hydrogen bladder pressure at room temperature for 3 hours. 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] + .

[0331] Step-3: 1-methyl-2-oxo-N-((6-(3-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 103) 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), EDC.HCl (0.24 g, 1.29 mmol) was added, followed by HOBt (0.08 g, 0.6 mmol), and the mixture was stirred at room temperature for 10 minutes. Triethylamine (0.98 g, 9.7 mmol) was added to the reaction mixture, followed by (6-(3-(trifluoromethyl)cyclobutyloxy)pyridin-3-yl)methanamine (0.4 g, 1.62 mmol), and the mixture was stirred at room temperature for 12 hours. 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%). 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).

[0332] Example 104 [ka]

[0333] Step 1: 3-((tert-butyldimethylsilyl)oxy)cyclohexane-1-amine 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 room temperature for 4 hours. The reaction mixture was quenched with ice-cold water and extracted with DCM. The separated organic layer was dried over anhydrous NaSO and concentrated to give the title compound (2.5 g, 96%). LC-MS: 230 [M+H] + .

[0334] Step-2: 6-((3-((tert-butyldimethylsilyl)oxy)cyclohexyl)amino)nicotinonitrile 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 dried over anhydrous NaSO and concentrated. The residue was purified by column chromatography using 10% EtOAc in n-hexane as the eluent to give the title compound (1.0 g, 27.86%). LC-MS: 332 [M+H] + .

[0335] Step-3: 6-((3-((tert-butyldimethylsilyl)oxy)cyclohexyl)(methyl)amino)nicotinonitrile To a stirred solution of 6-((3-((tert-butyldimethylsilyl)oxy)cyclohexyl)amino)nicotinonitrile (1.0 g, 3.01 mmol) in DMF (10 mL) 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) at 0° C., and the mixture was stirred at room temperature 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 the eluent to give the title compound (0.8 g, 76.7%). LC-MS: 346 [M+H] + .

[0336] Step-4: 5-(aminomethyl)-N-(3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-N-methylpyridin-2-amine 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 bladder pressure at room temperature 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] + .

[0337] 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 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 room temperature for 10 minutes. To the mixture were added 5-(aminomethyl)-N-(3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-N-methylpyridin-2-amine (0.8 g, 2.29 mmol), followed by triethylamine (1.15 g, 11.44 mmol), and the mixture was stirred at room temperature for 12 hours. 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 the eluent to give the title compound (0.23 g, 19.2%). LC-MS: 524 [M+H] + .

[0338] 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) 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 room temperature for 12 hours. The reaction mixture was concentrated to remove the solvent. The residue was dissolved with 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%). LC-MS: 410 [M+H] + ; 1H-NMR (400 MHz, DMSO-d): 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,2 H),4.09(bs,1H),3.59-3.51(bs,2H),3.31(s,3H),3.01(s,3H),1.88-1.80(m,2 H),1.73-1.70(d,1H),1.60-1.58(d,1H),1.51-1.37(m,3H),1.10-1.06(q,1H).

[0339] Example 105 [ka]

[0340] Step-1: (S)-6-((3,3-difluorocyclopentyl)amino)nicotinonitrile 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 hours. 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] +

[0341] Step-2: (S)-6-((3,3-difluorocyclopentyl)(methyl)amino)nicotinonitrile To a stirred solution of (S)-6-((3,3-difluorocyclopentyl)amino)nicotinonitrile (0.2 g, 0.89 mmol) in DMF (8 mL) 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) at 0° C., and the mixture was stirred at room temperature 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] +

[0342] Step-3: tert-butyl (S)-((6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)carbamate 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), followed by dropwise addition of di-tert-butyl dicarbonate (0.27 g, 1.26 mmol) at 0 °C, and the mixture was stirred for 5 min. To the reaction mixture was added NaBH4 (0.22 g, 5.82 mmol) portionwise by maintaining the same temperature. After stirring at room temperature for 2 h, the reaction mass was concentrated to remove solvent, diluted with EtOAc, and filtered through a celite bed. The filtrate was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combiflash column chromatography using 20% EtOAc in n-hexane as the eluent to give the title compound (0.17 g, 59%). LC-MS: 342 [M+H] +

[0343] Step-4: (S)-5-(aminomethyl)-N-(3,3-difluorocyclopentyl)-N-methylpyridin-2-amine hydrochloride To a stirred solution of tert-butyl (S)-((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 a solution of 4 N HCl in 1,4-dioxane (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the title compound (0.1 g, 95%). LC-MS: 242 [M+H] +

[0344] 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) 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 room temperature for 10 minutes. (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 then added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, 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(400MHz,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).

[0345] Example 106 [ka]

[0346] Step-1: tert-butyl (3-oxocyclobutyl)carbamate 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 room temperature for 12 hours. The reaction mixture was concentrated to remove the solvent. The residue was purified by CombiFlash column chromatography using 5% MeOH in DCM as the eluent to give the title compound (1.7 g, 74.3%). 1 H-NMR (400 MHz, 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).

[0347] Step-2: tert-butyl (3-hydroxycyclobutyl)carbamate To a stirred solution of tert-butyl (3-oxocyclobutyl)carbamate (0.7 g, 3.77 mmol) in EtOH (20 mL) at 0 °C was added NaBH (0.07 g, 1.78 mmol), and the mixture was stirred at room temperature for 1 h. The reaction mass was concentrated to remove EtOH. The residue was diluted with EtOAc, washed with water, dried over anhydrous NaSO, 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).

[0348] Step-3: tert-butyl (3-(difluoromethoxy)cyclobutyl)carbamate 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 for 2.5 h at 50° C. The reaction mass was concentrated to remove the solvent, diluted with EtOAc, washed with water, dried over anhydrous NaSO, 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).

[0349] Step-4: 3-(difluoromethoxy)cyclobutan-1-amine 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 room temperature for 4 hours. The reaction mixture was concentrated to give the title compound (0.24 g, 92%). LC-MS: 138 [M+H] +

[0350] Step-5: 6-((3-(difluoromethoxy)cyclobutyl)amino)nicotinonitrile 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 NaSO, and concentrated. The residue was purified by combiflash column chromatography using 30% EtOAc in n-hexane as the eluent to give both cis- and trans-isomers of the title compound, Isomer I (0.07 g, 13%) and Isomer II (0.05 g, 10%). LC-MS: 240 [M+H] +

[0351] Isomer I Step-6: 6-((3-(difluoromethoxy)cyclobutyl)(methyl)amino)nicotinonitrile To a stirred solution of 6-((3-(difluoromethoxy)cyclobutyl)amino)nicotinonitrile (isomer I from step-5 above: 0.06 g, 0.25 mmol) in DMF (5 mL) 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) at 0° C., and the mixture was stirred at room temperature for 3 hours. 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] + .

[0352] Step-7: 5-(aminomethyl)-N-(3-(difluoromethoxy)cyclobutyl)-N-methylpyridin-2-amine 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 under hydrogen bladder pressure at room temperature 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] + .

[0353] 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) 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 room temperature for 10 minutes. 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 room temperature for 16 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, 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).

[0354] Isomer II Step-6A: 6-((3-(difluoromethoxy)cyclobutyl)(methyl)amino)nicotinonitrile To a stirred solution of 6-((3-(difluoromethoxy)cyclobutyl)amino)nicotinonitrile (isomer II from step-5 above: 0.04 g, 0.18 mmol) in DMF (5 mL) 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) at 0° C., and the mixture was stirred at room temperature for 3 hours. 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] + .

[0355] Step-7A: 5-(aminomethyl)-N-(3-(difluoromethoxy)cyclobutyl)-N-methylpyridin-2-amine 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 under hydrogen bladder pressure at room temperature 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] + .

[0356] 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) 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), EDC.HCl (0.02 g, 0.1 mmol) was added, followed by HOBt (0.01 g, 0.05 mmol), and the mixture was stirred at room temperature for 10 minutes. 5-(aminomethyl)-N-(3-(difluoromethoxy)cyclobutyl)-N-methylpyridin-2-amine (0.02 g, 0.1 mmol) was then added, followed by triethylamine (0.04 g, 0.43 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give the crude compound. The crude product was further purified by preparative HPLC method C to give the title compound (0.003 g, 6.7%). LC-MS: 432 [M+H] + ; 1 H-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).

[0357] Example 107 [ka]

[0358] Step-1: tert-butyl (3-(trifluoromethoxy)cyclobutyl)carbamate To a stirred solution of tert-butyl(3-hydroxycyclobutyl)carbamate (0.9 g, 4.8 mmol) in EtOAc (50 mL) was added silver trifluoromethanesulfonate (4.94 g, 19.22 mmol), KF (1.11 g, 19.22 mmol), 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[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 room temperature for 16 hours. 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 combiflash column chromatography using 10% EtOAc in n-hexane as the 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).

[0359] Step-2: 3-(trifluoromethoxy)cyclobutan-1-amine 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 room temperature for 2 hours. 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).

[0360] Step-3: 6-((3-(trifluoromethoxy)cyclobutyl)amino)nicotinonitrile 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 NaSO, and concentrated. The residue was purified by combiflash column chromatography using 30% EtOAc in n-hexane as the eluent to give both cis- and trans-isomers of the title compound, Isomer I (0.3 g, 29%) and Isomer II (0.15 g, 14%). LC-MS: 258 [M+H] + .

[0361] Isomer I Step-4: 6-(methyl(3-(trifluoromethoxy)cyclobutyl)amino)nicotinonitrile To a stirred solution of 6-((3-(trifluoromethoxy)cyclobutyl)amino)nicotinonitrile (isomer I from 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), followed by dropwise addition of iodomethane (0.33 g, 2.33 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combiflash column chromatography using 10% EtOAc in n-hexane as the eluent to give the title compound (0.25 g, 79%). LC-MS: 272 [M+H] + .

[0362] Step-5: 5-(aminomethyl)-N-methyl-N-(3-(trifluoromethoxy)cyclobutyl)pyridin-2-amine 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 under hydrogen bladder pressure at room temperature for 2 hours. 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] + .

[0363] 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) 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 room temperature for 10 minutes. 5-(aminomethyl)-N-methyl-N-(3-(trifluoromethoxy)cyclobutyl)pyridin-2-amine (0.25 g, 0.9 mmol) was added to the reaction mixture, followed by triethylamine (0.45 g, 4.54 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold water, and the discarded solid was collected by filtration and dried. This was purified by preparative TLC using 5% MeOH in DCM as the eluent to give the title compound (0.03 g, 7%). LC-MS: 450 [M+H] + ; 1 H-NMR(400MHz,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).

[0364] Isomer II Step-4A: 6-(methyl(3-(trifluoromethoxy)cyclobutyl)amino)nicotinonitrile To a stirred solution of 6-((3-(trifluoromethoxy)cyclobutyl)amino)nicotinonitrile (isomer II from 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), followed by dropwise addition of iodomethane (0.16 g, 1.16 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with ice-cold water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combiflash column chromatography using 10% EtOAc in n-hexane as the eluent to give the title compound (0.11 g, 69%). LC-MS: 272 [M+H] + ;

[0365] Step 5A: 5-(aminomethyl)-N-methyl-N-(3-(trifluoromethoxy)cyclobutyl)pyridin-2-amine 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 under hydrogen bladder pressure at room temperature for 2 hours. 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] + .

[0366] 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) 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 room temperature for 10 minutes. 5-(aminomethyl)-N-methyl-N-(3-(trifluoromethoxy)cyclobutyl)pyridin-2-amine (0.08 g, 0.9 mmol) was added to the reaction mixture, followed by triethylamine (0.15 g, 1.45 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold water to give a solid, which was collected by filtration and dried. This was purified by preparative TLC using 5% MeOH in DCM as the 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).

[0367] Example 108 [ka]

[0368] Step-1: Methyl 6,6-difluorobicyclo[3.1.0]hexane-3-carboxylate To a stirred solution of methyl cyclopent-3-ene-1-carboxylate (3.0 g, 23.7 mmol) in diglyme (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 NaSO, and concentrated to give the title compound (2.8 g, 66.8%). 1 H-NMR (400 MHz, CD3OD): δ 3.23-3.10(m,1H),2.90-2.80(m,1H),2.66(d,3H),2.33-2.24(m,4H),2.05-2.01(dd,1H).

[0369] Step-2: 6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid 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 a stirred solution of LiOH (0.6 g, 14.2 mmol) in water (5 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to remove THF and MeOH, acidified with 1N HCl, and extracted with DCM. The combined organic layers were dried over anhydrous NaSO 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).

[0370] Step-3: tert-butyl (6,6-difluorobicyclo[3.1.0]hexan-3-yl)carbamate 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 room temperature for 10 minutes. t-BuOH (9.0 g, 120.25 mmol) was added to the reaction mixture, which was then stirred at 80 °C for 16 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated. The residue was purified by combiflash column chromatography using 20% EtOAc in n-hexane as the 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).

[0371] Step-4: 6,6-difluorobicyclo[3.1.0]hexane-3-amine hydrochloride To a stirred solution of tert-butyl (6,6-difluorobicyclo[3.1.0]hexan-3-yl)carbamate (1.2 g, 5.14 mmol) in 1,4-dioxane (5 mL) was added 4N HCl in 1,4-dioxane (10 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to give the title compound (0.3 g, 34%). LC-MS: 134 [M+H] +

[0372] Step-5: 6-((6,6-difluorobicyclo[3.1.0]hexan-3-yl)amino)nicotinonitrile 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]hexane-3-amine hydrochloride (0.27 g, 1.63 mmol), and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated to remove DIPEA, and the residue was diluted with EtOAc, washed with water, dried over anhydrous NaSO, and concentrated. The residue was purified by combiflash column chromatography using 30% EtOAc in n-hexane as the eluent to give the title compound (0.04 g, 84%). LC-MS: 236 [M+H] + .

[0373] Step-6: 6-((6,6-difluorobicyclo[3.1.0]hexan-3-yl)(methyl)amino)nicotinonitrile To a stirred solution of 6-((6,6-difluorobicyclo[3.1.0]hexan-3-yl)amino)nicotinonitrile (0.2 g, 0.85 mmol) in DMF (5 mL) 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) at 0° C., and the mixture was stirred at room temperature 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] + .

[0374] Step-7: 5-(aminomethyl)-N-(6,6-difluorobicyclo[3.1.0]hexan-3-yl)-N-methylpyridin-2-amine To a stirred solution of 6-((6,6-difluorobicyclo[3.1.0]hexan-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 under hydrogen bladder pressure at room temperature 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] + .

[0375] 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) 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 room temperature for 10 minutes. To the reaction mixture was added 5-(aminomethyl)-N-(6,6-difluorobicyclo[3.1.0]hexan-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 room temperature for 16 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, 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] + ; 1H-NMR(400MHz,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).

[0376] Example 109 [ka]

[0377] Step 1: 6-(spiro[2.3]hexan-5-ylamino)nicotinonitrile 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]hexane-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 and 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] + .

[0378] Step-2: 6-(methyl(spiro[2.3]hexan-5-yl)amino)nicotinonitrile To a stirred solution of 6-(spiro[2.3]hexan-5-ylamino)nicotinonitrile (0.20 g, 1.00 mmol) in DMF (8 mL) 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) at 0° C., and the mixture was stirred at room temperature for 3 hours. 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] + .

[0379] Step-3: 5-(aminomethyl)-N-methyl-N-(spiro[2.3]hexan-5-yl)pyridin-2-amine hydrochloride To a stirred solution of 6-(methyl(spiro[2.3]hexan-5-yl)amino)nicotinonitrile (0.13 g, 0.63 mmol) in MeOH (20 mL) was added NiCl2.6H2O (0.08 g, 0.09 mmol), followed by dropwise addition of di-tert-butyl dicarbonate (0.21 g, 0.96 mmol) at 0 °C, and the mixture was stirred for 5 min. To the reaction mixture was added NaBH4 (0.17 g, 4.43 mmol) in small portions by maintaining the same temperature. After stirring at room temperature 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 combiflash column chromatography using 20% EtOAc in n-hexane as the eluent. This was taken up in 1,4-dioxane (2 mL), 4M HCl in 1,4-dioxane (2 mL) was added, and then stirred at room temperature for 4 hours. The reaction mixture was concentrated to give the title compound (0.12 g, 90.6%). LCMS: 218 [M+H] + .

[0380] 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) 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 room temperature for 10 minutes. 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 room temperature for 16 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated. The residue was purified using preparative HPLC method C to give the title compound as the 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).

[0381] Example 110 [ka]

[0382] Step-1: 6-(((1S,3R)-3-fluorocyclopentyl)amino)nicotinonitrile 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 hours. The reaction mixture was concentrated to give the title compound (0.25 g, 99%). LC-MS: 206 [M+H] + .

[0383] Step-2: 6-(((1S,3R)-3-fluorocyclopentyl)(methyl)amino)nicotinonitrile To a stirred solution of 6-(((1S,3R)-3-fluorocyclopentyl)amino)nicotinonitrile (0.25 g, 1.21 mmol) in DMF (6 mL) 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) at 0° C., and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ice-cold water and extracted with EtOAc. The separated organic layer was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combiflash column chromatography using 30% EtOAc in n-hexane as the eluent to give the title compound (0.18 g, 67%). LC-MS: 220 [M+H] + .

[0384] Step-3: 5-(aminomethyl)-N-((1S,3R)-3-fluorocyclopentyl)-N-methylpyridin-2-amine 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 room temperature 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] + .

[0385] 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) 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 room temperature for 10 minutes. 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 room temperature for 16 hours. The reaction mixture was poured into ice-cold water, and the precipitate formed 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(400MHz,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).

[0386] Example 111 [ka]

[0387] Step-1: 5-bromo-2-(1-(3,3-difluoropyrrolidin-1-yl)ethyl)pyridine To a stirred solution of 1-(5-bromopyridin-2-yl)ethan-1-one (0.5 g, 2.5 mmol) in MeOH (10 mL), 3,3-difluoropyrrolidine hydrochloride (0.46 g, 3.25 mmol) was added, followed by sodium cyanoborohydride (0.47 g, 7.5 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over Na2SO4, and concentrated. The residue was purified by combiflash column chromatography using 10% EtOAc in n-hexane as the eluent to give the title compound (0.48 g, 66%). LC-MS: 291 [M+H] + .

[0388] Step-2: 6-(1-(3,3-difluoropyrrolidin-1-yl)ethyl)nicotinonitrile 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 minutes, then tetrakis(triphenylphosphine)palladium (0.05 g, 0.04 mmol) was added and stirred at 90° C. for 12 hours. The reaction mass was concentrated and the crude compound was purified by combiflash column chromatography using 10% EtOAc in n-hexane as the eluent to give the title compound (0.13 g, 63.79%). LC-MS: 238 [M+H] + .

[0389] Step-3: (6-(1-(3,3-difluoropyrrolidin-1-yl)ethyl)pyridin-3-yl)methanamine To a stirred solution of 6-(1-(3,3-difluoropyrrolidin-1-yl)ethyl)nicotinonitrile (0.11 g, 0.46 mmol) in EtOH (5 mL), Raney nickel (0.14 g) was added and stirred under hydrogen bladder pressure at room temperature for 2 hours. 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] + .

[0390] 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) 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 room temperature for 12 hours. 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 give the title compound as the HCl salt (0.02 g, 41.91%). LC-MS: 416 [M+H] + ; 1 H-NMR(400MHz,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).

[0391] Example 112 [ka]

[0392] Step-1: 1-(5-bromopyridin-2-yl)ethan-1-ol 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 NaBH (0.19 g, 5.0 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mass was concentrated to remove THF, quenched with ice-cold water, and extracted with EtOAc. The separated organic layer was washed with saturated brine, dried over anhydrous NaSO, and concentrated to give the title compound (0.4 g, 79%). LC-MS: 202 [M+H] + .

[0393] Step-2: 1-(5-bromopyridin-2-yl)ethyl methanesulfonate 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 room temperature for 2 hours. The reaction mixture was diluted with DCM, washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combiflash column chromatography using 20% EtOAc in n-hexane as the eluent to give the title compound (0.48 g, 86%). LC-MS: 280 [M+H] +

[0394] Step-3: 5-bromo-2-(1-(3-(trifluoromethyl)pyrrolidin-1-yl)ethyl)pyridine 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 hours. The reaction mixture was concentrated, and the residue was purified by combiflash column chromatography using 20% EtOAc in n-hexane as the eluent to give the title compound (0.08 g, 23%). LC-MS: 323 [M+H] + .

[0395] Step-4: 6-(1-(3-(trifluoromethyl)pyrrolidin-1-yl)ethyl)nicotinonitrile 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 minutes, tetrakis(triphenylphosphine)palladium (0.03 g, 0.02 mmol) was added, and the mixture was stirred at 90° C. for 5 hours. The reaction mixture was cooled to room temperature, diluted with 10% MeOH in DCM, and filtered through Celite. The filtrate was concentrated and purified by combiflash column chromatography using 20% EtOAc in n-hexane as the eluent to give the title compound (0.06 g, 97%). LC-MS: 270 [M+H] + .

[0396] Step-5: (6-(1-(3-(trifluoromethyl)pyrrolidin-1-yl)ethyl)pyridin-3-yl)methanamine 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 under hydrogen bladder pressure at room temperature 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] + .

[0397] 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) 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 room temperature for 10 minutes. 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 room temperature for 16 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated. The residue was further purified by preparative HPLC method C to give the title compound (0.02 g, 17%). LC-MS: 448 [M+H] + ; 1 H-NMR(400MHz,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).

[0398] Example 113 [ka]

[0399] Step 1: 6-chloronicotinoyl chloride 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 room temperature for 2 h. The reaction mixture was concentrated under an argon atmosphere to give the title compound, which was carried on to the next step without purification.

[0400] Step-2: 6-chloropyridin-3-yl(phenyl)methanone To a stirred solution of 6-chloronicotinoyl chloride (0.5 g, 3.17 mmol) in benzene (15 mL), aluminum chloride (0.8 g, 6.3 mmol) was added at 0° C. and stirred at 70° C. for 16 hours. The reaction mixture was poured into water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated. This was purified by combiflash column chromatography using 20% EtOAc in n-hexane as the eluent to give the title compound (0.5 g, 80.6%). LC-MS: 218 [M+H] + .

[0401] Step-3: (6-(isopropyl(methyl)amino)pyridin-3-yl)(phenyl)methanone 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 hours under microwave irradiation. The reaction mixture was poured into water, extracted with EtOAc, dried over anhydrous NaSO, and concentrated to give the title compound (0.45 g, 128.2%). LC-MS: 255 [M+H] + .

[0402] Step-4: N-[(E)-(6-(isopropylamino)pyridin-3-yl)(phenyl)methylidene]hydroxylamine 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 NaSO, and concentrated to give the title compound (0.38 g, 112%). LC-MS: 270 [M+H] +

[0403] Step-5: 5-(amino(phenyl)methyl)-N-isopropyl-N-methylpyridin-2-amine To a stirred solution of N-[(E)-(6-(isopropylamino)pyridin-3-yl)(phenyl)methylidene]hydroxylamine (0.3 g, 1.1 mmol) in EtOH (10 mL), Raney nickel (0.32 g) was added followed by 7 M ammonia in MeOH (5 mL) and stirred under hydrogen bladder pressure at room temperature for 4 hours. 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] + .

[0404] 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) 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 room temperature for 10 minutes. 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 room temperature for 16 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, 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(400MHz,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).

[0405] Example 114 [ka]

[0406] Step-1: 1-(6-(isopropyl(methyl)amino)pyridin-3-yl)ethan-1-one To a stirred solution of 1-(6-chloropyridin-3-yl)ethan-1-one (2.0 g, 12.85 mmol) in EtOH (5 mL), N-methylpropan-2-amine (2.82 g, 38.56 mmol) was added and stirred at 150° C. under microwave irradiation for 2 hours. The reaction mixture was concentrated and the residue was purified by combiflash column chromatography using 20% EtOAc in n-hexane as the eluent to give the title compound (2.0 g, 81%). LC-MS: 193 [M+H] +.

[0407] Step-2: Methyl 2-(6-(isopropyl(methyl)amino)pyridin-3-yl)-2-oxoacetate 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), followed by K2CO3 (2.15 g, 15.6 mmol), and the mixture was stirred at 110 °C for 2 h. The reaction mixture was cooled to room temperature, iodomethane (0.44 g, 3.12 mmol) was added, 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 saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative TLC using 20% EtOAc in n-hexane as the eluent to give the title compound (0.2 g, 32%). LC-MS: 237 [M+H] + .

[0408] Step-3: Methyl (Z)-2-(hydroxyimino)-2-(6-(isopropyl(methyl)amino)pyridin-3-yl)acetate 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] + .

[0409] Step-4: Methyl 2-amino-2-(6-(isopropyl(methyl)amino)pyridin-3-yl)acetate 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 room temperature for 3 hours. The reaction mass was filtered through Celite and the filtrate was concentrated to give the title compound (0.2 g). LC-MS: 238 [M+H] + .

[0410] Step-5: Methyl 2-(6-(isopropyl(methyl)amino)pyridin-3-yl)-2-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide)acetate (Compound 114a) 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 room temperature for 10 minutes. 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 room temperature for 16 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, 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(400MHz,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).

[0411] 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) 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-carboxamide)acetate (0.04 g, 0.41 mmol) in THF (2 mL) was added LiBH (0.004 g, 0.19 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated sodium sulfite solution and extracted with EtOAc. The separated organic layer was washed, dried over anhydrous NaSO, and concentrated. The residue was purified by preparative TLC using 5% MeOH in DCM as the eluent to give the title compound (0.02 g, 53%). LC-MS: 384 [M+H] + ; 1 H-NMR(400MHz,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).

[0412] Example 115 [ka]

[0413] Step-1: 5-(aminomethyl)-N-(4,4-difluorocyclohexyl)-N-methylpyridin-2-amine To a stirred solution of 6-((4,4-difluorocyclohexyl)(methyl)amino)nicotinonitrile (0.1 g, 0.39 mmol) in EtOH (5 mL), Raney nickel (0.1 g) was added followed by 7 M ammonia in MeOH (2 mL) and stirred under hydrogen bladder pressure at room temperature 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] + .

[0414] 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) 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 room temperature for 10 minutes. 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), was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold water, extracted with EtOAc, dried over anhydrous NaSO, 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).

[0415] Example 116 [ka]

[0416] Step-1: Methyl 4-((trideuteromethyl)amino)-3-nitrobenzoate To a stirred solution of methyl 4-fluoro-3-nitrobenzoate (0.5 g, 2.51 mmol) in DMF (8 mL) was added K2CO3 (0.69 g, 5.02 mmol) followed by methan-d3-amine hydrochloride (0.18 g, 2.51 mmol) at 10 °C, and the mixture was stirred at room temperature 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] + .

[0417] Step-2: Methyl 3-amino-4-((trideuteromethyl)amino)benzoate To a stirred solution of methyl 4-((trideuteromethyl)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 dust (0.22 g, 3.36 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mass was diluted with EtOAc and filtered through a bed of celite. 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] + .

[0418] Step-3: Methyl 1-(trideuteromethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate To a stirred solution of methyl 3-amino-4-((trideuteromethyl)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] +

[0419] Step-4: 1-(trideuteromethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid 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 room temperature for 16 hours. The reaction mixture was concentrated to remove THF and MeOH, diluted with water, and acidified with 1N HCl. The formed precipitate was collected by filtration and dried to give the title compound (0.04 g, 85%). LC-MS: 196 [M+H] +

[0420] Step-5: 1-(trideuteromethyl)-N-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide (Compound 116) To a solution of 1-(trideuteromethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.04 g, 0.2 mmol) in DMF (2 mL) was added EDC.HCl (0.04 g, 0.2 mmol) and HOBt (0.01 g, 0.07 mmol), and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 5-(aminomethyl)-N-methyl-N-(cis-3-(trifluoromethyl)cyclobutyl)pyridin-2-amine (0.06 g, 0.23 mmol), followed by triethylamine (0.12 g, 1.2 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold water, and the formed precipitate was collected by filtration and dried. This 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(400MHz,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).

[0421] Preparative HPLC method: Method A: Column - LUNA C18 (250 mm x 19 mm), 5.0 μ; 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 - Method B: Column - Waters, Xselect, c18 (250 mm x 21.2 mm), 5.0 μ; Eluent - A 0.05% TFA in water, B - ACN, Gradient - 10% B at 0 min, 30% B at 2 min, 70% B at 8 min, Flow rate: 13 mL / min Method C: Column: LUNA C18 (250 mm x 19 mm), 5.0 μm; Eluent: A 0.1% FA in water, B ACN; Gradient: 10% B in 0 min, 20% B in 2 min, 50% in 10 min, 70% in 15 min; Flow rate: 18 mL / min Method D: Column: LUNA C18 (250 mm x 19 mm), 5.0 μm; 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

[0422] Examples 28 to 102 and 117 to 147 Compounds of the Examples (Examples) -28 to 102 and 117 to 147 shown in Tables 2 to 97 were prepared in the same manner as the referenced Examples and processes. For example, the term "E4-S4" in the "Ref." column in the tables indicates that the compound was prepared by a method similar to the above-referenced "E" example-"4"-"S" step-"4" (Example-4-Step-4). Similarly, the term "P5-S1" in the "Ref." column in the tables indicates that the compound was prepared by a method similar to the above-referenced "P" preparation-"5"-"S" step-"1" (Preparation Example-5-Step-1). It is understood that the compounds can be obtained in free form or salt form depending on the isolation state.

[0423] In addition, compounds with "HCl" adjacent to them in the chemical structure indicate that the compound was isolated as the hydrochloride salt. Compounds with chemical structural formulas marked with "*" represent isomers having the constitution of the structure shown. The resulting compounds 82 and 130 were separated to give two optical isomers, compound 82 peak 1 and compound 82 peak 2; and compound 130 peak 1 and compound 130 peak 2, respectively. (Preparative HPLC method: column - Chiralpak-IG (250 x 21.2 mm) 5μ; eluent: A: n-hexane, B: ETOH; isocratic: A:B (50:50); flow rate: 15 mL / min).

[0424] [Table 2]

[0425] [Table 3]

[0426]

Table 4

[0427]

Table 5

[0428]

Table 6

[0429]

Table 7

[0430]

Table 8

[0431]

Table 9

[0432]

Table 10

[0433]

Table 11

[0434]

Table 12

[0435]

Table 13

[0436]

Table 14

[0437]

Table 15

[0438] Table 16

[0439]

Table 17

[0440] Table 18

[0441]

Table 19

[0442] Table 20

[0443] Table 21

[0444] Table 22

[0445] Table 23

[0446] Table 24

[0447] Table 25

[0448] Table 26

[0449] Table 27

[0450] Table 28

[0451] Table 29

[0452]

Table 30

[0453] Table 31

[0454] Table 32

[0455] Table 33

[0456] Table 34

[0457] Table 35

[0458] Table 36

[0459] Table 37

[0460] Table 38

[0461] Table 39

[0462] Table 40

[0463] Table 41

[0464] Table 42

[0465] Table 43

[0466] Table 44

[0467] Table 45

[0468] Table 46

[0469] Table 47

[0470] Table 48

[0471] Table 49

[0472]

Table 50

[0473] Table 51

[0474] Table 52

[0475] Table 53

[0476] Table 54

[0477] Table 55

[0478] Table 56

[0479] Table 57

[0480] Table 58

[0481] Table 59

[0482] Table 60

[0483] Table 61

[0484] Table 62

[0485] Table 63

[0486] Table 64

[0487] Table 65

[0488] Table 66

[0489] Table 67

[0490] Table 68

[0491] Table 69

[0492] Table 70

[0493] Table 71

[0494] Table 72

[0495] Table 73

[0496] Table 74

[0497] Table 75

[0498] Table 76

[0499] Table 77

[0500] Table 78

[0501] Table 79

[0502] Table 80

[0503] Table 81

[0504] Table 82

[0505] Table 83

[0506] Table 84

[0507] Table 85

[0508] Table 86

[0509] Table 87

[0510] Table 88

[0511] Table 89

[0512] Table 90

[0513]

Table 91

[0514] Table 92

[0515] Table 93

[0516] Table 94

[0517]

Table 95

[0518] Table 96

[0519] [Table 97]

[0520] Biological Assays Example 148 KIT Tyrosine Kinase Assay An in vitro assay utilizing recombinant human KIT tyrosine kinase protein was developed to measure compound inhibition of KIT. KIT tyrosine kinase activity was measured using the ADP-Glo kinase assay system with a poly(Glu4-Tyr) peptide substrate. Kinase assays were performed in white 384-well plates, and luminescence was measured using a Victor X5 Multilabel Counter (Perkin Elmer).

[0521] Materials and Methods 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, MO, USA). ADP-Glo kinase assay reagent was purchased from Promega (Madison, WI, 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 1:3 with 100% DMSO to prepare nine serial dilutions. To prepare compound working solutions, each serial dilution was further diluted 1:8 with assay buffer consisting of 50 mM Tris-HCl pH 7.5, 20 mM MgCl2, 0.01% Tween-20, 2 mM MnCl2, and 50 μM dithiothreitol (DTT).

[0522] Recombinant KIT protein was diluted to 1 μM in assay buffer. Poly(Glu4-Tyr) peptide and ATP were diluted to 300 micrograms / mL and 250 μM in assay buffer, respectively, and then mixed to form a substrate solution. In a 384-well plate, 2 μL of agonist compound and 5 μL of recombinant KIT protein were mixed and incubated at room temperature for 30 minutes. After preincubation, 3 μL of the substrate / ATP mixture was added and incubated at room temperature for 1 hour. Tyrosine phosphorylation by KIT kinase was quantified using an ADP-Glo kinase assay kit according to the manufacturer's protocol. Briefly, the phosphorylation reaction was stopped 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 using a plate reader. The assay control in this experiment was 2.5% DMSO, and assay buffer was used as a blank.

[0523] The half-maximal inhibitory concentration (IC50) was calculated by a four-parameter logistic regression model using GraphPad Prism (GraphPad Software). Values without recombinant KIT protein and without test compound were used as negative controls (assay background). Values using recombinant KIT protein without test compound were positive controls (100% activity).

[0524] Tables 98 and 99 below list the inhibitory effects of representative compounds of the present invention on KIT.

[0525] [Table 98]

[0526] [Table 99]

[0527] In particular, representative compounds of the present invention exhibited selective inhibitory activity against KIT, but did not exhibit significant inhibition against other kinases.

[0528] Example 149 SCF-dependent M-07e cell proliferation assay An 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 a 96-well plate, and the IC50 of each KIT inhibitor was determined using CellTiter Glo Assay reagent and a Victor X5 Multilabel Counter (Perkin Elmer).

[0529] Materials and Methods 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 micrograms / mL streptomycin, 10 ng / mL rhGM-CSF, and 10 ng / mL rhSCF. M-07e cells were seeded into 96-well plates at a density of 5000 cells / 90 μL / well. Test compounds were dissolved in 100% DMSO to prepare 20 mM stock solutions and serially diluted 1:3 with 100% DMSO to generate an 11-point dilution series ranging from 15 mM to 0.024 μM. Each serially diluted compound was then diluted 1:50 with culture medium to obtain an assay compound solution containing 2% DMSO. 10 μL of the assay compound solution was added to 90 μL of the cultured cell suspension in a 96-well plate for a final DMSO concentration of 0.2%. The plates were then incubated at 37°C in a 5% CO2 incubator for 3 days. To obtain a day 0 control for background calculations, cells were seeded into a new 96-well plate at 5000 cells / 100 μL and processed on the same day. Both the day 0 control and day 3 culture plates were then treated as follows: 100 μL of CellTiter Glo Assay reagent was added to each well, and the plate was incubated at room temperature on a shaker at 200-300 RPM for 15 minutes. A 100 μL cell lysate sample was then transferred to a white-walled 96-well plate, and luminescence was measured using a plate reader. The luminescence of the day 0 control was subtracted from the luminescence intensity readings for the 3-day culture. The assay control for this experiment was cells treated with 0.2% DMSO in culture medium; wells containing 100 μL of culture medium (0.2% DMSO without cells) were used as blanks for data analysis.

[0530] The IC50 value for each compound was determined by using the % inhibition by normalizing the inhibition in DMSO-treated control wells to 0% using the following formula: % Inhibition = 100 - [(L of experimental wells minus blank) / (L of 0.2% DMSO control wells minus blank) x 100] *In the formula, L is luminescence.

[0531] Percent growth inhibition in triplicates is plotted against each concentration of compound and dose-response curves are fitted using a sigmoidal dose-response equation to generate IC50 values in GraphPad Prism 8 software.

[0532] Table 100 below lists the inhibitory effects of representative compounds of the present invention on M-07e cells.

[0533] [Table 100]

[0534] Example 150 GIST Cell Proliferation Assay Gastrointestinal stromal tumor (GIST) is the most common adult sarcoma, and the majority of GIST cases (85-90%) are caused by oncogenic mutations in the receptor tyrosine kinases (RTKs), KIT or PDGFRA, which result in constitutive activation of these receptors. To measure the inhibitory potency of compounds, we used a human GIST-derived cell line, GIST-T1, which harbors a mutation in exon 11 of KIT.

[0535] Materials and Methods GIST-T1 cells were purchased from Cosmo Bio (Tokyo, Japan) and cultured in DMEM containing 10% FBS. Assays were performed in 96-well plates, and the IC50 of each compound was determined using the CellTiter Glo Assay reagent and a Victor X5 Multilabel Counter. Cells were seeded into 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 the M-07e cell proliferation assay. Table 101 below lists the inhibitory effects of representative compounds of the present invention on GIST-T1 cells.

[0536] [Table 101]

Claims

1. a pharmaceutically acceptable carrier or diluent and a compound of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, R １ is hydrogen, C １－３ - alkyl, or C １－３ -deuterated alkyl, R ２ is hydrogen, halogen, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, nitro, amino, or mono- or di-(C １－４ -alkyl)amino, R ３ is hydrogen, aryl, carboxy, —CO—O—(C １－４ -alkyl), or C optionally substituted with hydroxy １－４ - alkyl, Ring A: 【Chemistry 2】 is the formula: 【Chemistry 3】 is the basis of The wavy line indicates the point of attachment to the rest of the molecule, R ４ is -N(R Ａ ) (R Ｂ ), -O-R Ａ , or halogen, C ３－６ -C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl １－２ -alkyl, wherein said C ３－６ Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ -alkyl)amino; R ５ is hydrogen, halogen, or C １－４ - alkyl, R ６ is R Ａ and X １ and X ２ are each independently N or C-R ７ and R ７ is hydrogen, halogen, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, nitro, amino, or mono- or di-(C １－４ -alkyl)amino, X ３ is N or C(R ８ ) ｎ and R ８ is hydrogen or halogen, n is an integer having a value of 1 or 2; Y is O or S; The dotted line represents a single or double bond, provided that X ３ is N or C(R ８ ) ｎ where n is an integer having a value of 1, the dotted line is a double bond; R Ａ is halogen, hydroxy, —O—(C １－４ -alkyl), C ３－６ -C optionally substituted with one or more groups selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl １－４ -alkyl, wherein said C ３－６ Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ -alkyl)amino; halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ C optionally substituted with one or more groups selected from the group consisting of ３－６ -cycloalkyl; halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ -aryl optionally substituted with one or more groups selected from the group consisting of (-alkyl)amino, wherein said C １－４ - alkyl is halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, or mono- or di-(C １－４ -alkyl)amino; １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ -alkyl)amino; or halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ -(-alkyl)amino; R Ｂ is hydrogen, C １－４ - alkyl, or C ３－６ -cycloalkyl, or -N(R Ａ ) (R Ｂ ) in R Ａ and R Ｂ together with the nitrogen atom, halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ -alkyl)amino, forming an N-containing heterocycle optionally substituted with one or more groups selected from the group consisting of Pharmaceutical compositions.

2. a pharmaceutically acceptable carrier or diluent and a compound of formula (I): 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, R １ is hydrogen or C １－３ - alkyl, R ２ is hydrogen, halogen, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, nitro, amino, or mono- or di-(C １－４ -alkyl)amino, R ３ is hydrogen or C １－４ - alkyl, Ring A: 【Chemistry 5】 is the formula: 【Chemistry 6】 is the basis of The wavy line indicates the point of attachment to the rest of the molecule, R ４ is -N(R Ａ ) (R Ｂ ), -O-R Ａ , or halogen, C ３－６ -C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl １－２ -alkyl, wherein said C ３－６ Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino; R ５ is hydrogen, halogen, or C １－４ - alkyl, R ６ is R Ａ and X １ and X ２ are each independently N or C-R ７ and R ７ is hydrogen, halogen, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, nitro, amino, or mono- or di-(C １－４ -alkyl)amino, X ３ is N or C(R ８ ) ｎ and R ８ is hydrogen or halogen, n is an integer having a value of 1 or 2; Y is O or S; The dotted line represents a single or double bond, provided that X ３ is N or C(R ８ ) ｎ wherein n is an integer having a value of 1, the dotted line is a double bond; R Ａ is a halogen, C ３－６ -C optionally substituted with one or more groups selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl １－４ -alkyl, wherein said C ３－６ Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino; halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ C optionally substituted with one or more groups selected from the group consisting of ３－６ -cycloalkyl; halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -aryl optionally substituted with one or more groups selected from the group consisting of (-alkyl)amino, wherein said C １－４ - alkyl is halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, or mono- or di-(C １－４ -alkyl)amino; １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino; or halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -(-alkyl)amino; R Ｂ is hydrogen, C １－４ - alkyl, or C ３－６ -cycloalkyl, or -N(R Ａ ) (R Ｂ ) in R Ａ and R Ｂ together with the nitrogen atom, halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino, forming an N-containing heterocycle optionally substituted with one or more groups selected from the group consisting of The pharmaceutical composition of claim 1.

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

4. The ring A: 【Chemistry 7】 But the formula: 【Chemistry 8】 The basis of The pharmaceutical composition according to claim 3.

5. R ４ -N (R Ａ ) (R Ｂ ) or -O-R Ａ and R ５ is hydrogen, where R Ａ But halogen, C ３－６ C optionally substituted with one or more groups selected from the group consisting of cycloalkyl, phenyl, tetrahydropyranyl, piperidyl, piperazinyl, pyridyl, pyrimidyl, and indazolyl １－４ -alkyl, wherein said C ３－６ Cycloalkyl, phenyl, tetrahydropyranyl, piperidyl, piperazinyl, pyridyl, pyrimidyl, and indazolyl are substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino; halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ C optionally substituted with one or more groups selected from the group consisting of ３－６ -cycloalkyl; halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino, wherein said C １－４ - alkyl is tetrahydropyranyl, piperidyl, or piperazinyl, each of which may be substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, or mono- or di-(C １－４ -alkyl)amino); tetrahydropyranyl, piperidyl, or piperazinyl, each of which is optionally further substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino; or pyridyl, pyrimidyl, or indazolyl, each of which is optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino; Ｂ The pharmaceutical composition according to any one of claims 1 to 4, wherein is methyl.

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

7. The compound is 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-(trideuteromethyl)-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]hexan-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; The pharmaceutical composition of claim 1.

8. The following formula (Ia): 【Chemistry 9】 A compound represented by or a pharmaceutically acceptable salt thereof, wherein R １ is hydrogen, C １－３ - alkyl, or C １－３ -deuterated alkyl, R ２ is hydrogen, halogen, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, nitro, amino, or mono- or di-(C １－４ -alkyl)amino, R ３ is hydrogen, aryl, carboxy, —CO—O—(C １－４ -alkyl), or C optionally substituted with hydroxy １－４ - alkyl, Ring A １ : 【Chemistry 10】 is the formula: 【Chemistry 11】 is the basis of The wavy line indicates the point of attachment to the rest of the molecule, R ４ is -N(R Ａ ) (R Ｂ ), -O-R Ａ , or halogen, C ３－６ -C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl １－２ -alkyl, wherein said C ３－６ Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ -alkyl)amino; R ４Ａ is -N(R Ａ ) (R Ｂ ), or halogen, C ３－６ -C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl １－２ -alkyl, wherein said C ３－６ Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ -alkyl)amino; R ５ is hydrogen, halogen, or C １－４ - alkyl, R ６ is R Ａ and X １ and X ２ are each independently N or C-R ７ and R ７ is hydrogen, halogen, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, nitro, amino, or mono- or di-(C １－４ -alkyl)amino, X ３ is N or C(R ８ ) ｎ and R ８ is hydrogen or halogen, n is an integer having a value of 1 or 2; Y is O or S; The dotted line represents a single or double bond, provided that X ３ is N or C(R ８ ) ｎ where n is an integer having a value of 1, the dotted line is a double bond; R Ａ is halogen, hydroxy, —O—(C １－４ -alkyl), C ３－６ -C optionally substituted with one or more groups selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl １－４ -alkyl, wherein said C ３－６ Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ -alkyl)amino; halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ C optionally substituted with one or more groups selected from the group consisting of ３－６ -cycloalkyl; halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ -aryl optionally substituted with one or more groups selected from the group consisting of (-alkyl)amino, wherein said C １－４ - alkyl is halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, or mono- or di-(C １－４ -alkyl)amino; １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ -alkyl)amino; or halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ -(-alkyl)amino; R Ｂ is hydrogen, C １－４ - alkyl, or C ３－６ -cycloalkyl, or -N(R Ａ ) (R Ｂ ) in R Ａ and R Ｂ together with the nitrogen atom, halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ -alkyl)amino, forming an N-containing heterocycle optionally substituted with one or more groups selected from the group consisting of However, the compound is 【Chemistry 12】 or a pharmaceutically acceptable salt thereof, which is not

9. The following formula (Ia): 【Chemistry 13】 A compound represented by or a pharmaceutically acceptable salt thereof, wherein R １ is hydrogen or C １－３ - alkyl, R ２ is hydrogen, halogen, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, nitro, amino, or mono- or di-(C １－４ -alkyl)amino, R ３ is hydrogen or C １－４ - alkyl, Ring A １ : 【Chemistry 14】 is the formula: 【Chemistry 15】 is the basis of The wavy line indicates the point of attachment to the rest of the molecule, R ４ is -N(R Ａ ) (R Ｂ ), -O-R Ａ , or halogen, C ３－６ -C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl １－２ -alkyl, wherein said C ３－６ Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino; R ４Ａ is -N(R Ａ ) (R Ｂ ), or halogen, C ３－６ -C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl １－２ -alkyl, wherein said C ３－６ Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino; R ５ is hydrogen, halogen, or C １－４ - alkyl, R ６ is R Ａ and X １ and X ２ are each independently N or C-R ７ and R ７ is hydrogen, halogen, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, nitro, amino, or mono- or di-(C １－４ -alkyl)amino, X ３ is N or C(R ８ ) ｎ and R ８ is hydrogen or halogen, n is an integer having a value of 1 or 2; Y is O or S; The dotted line represents a single or double bond, provided that X ３ is N or C(R ８ ) ｎ where n is an integer having a value of 1, the dotted line is a double bond; R Ａ is a halogen, C ３－６ -C optionally substituted with one or more groups selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl １－４ -alkyl, wherein said C ３－６ Cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino; halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ C optionally substituted with one or more groups selected from the group consisting of ３－６ -cycloalkyl; halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -aryl optionally substituted with one or more groups selected from the group consisting of (-alkyl)amino, wherein said C １－４ - alkyl is halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, or mono- or di-(C １－４ -alkyl)amino; １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino; or halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -(-alkyl)amino; R Ｂ is hydrogen, C １－４ - alkyl, or C ３－６ -cycloalkyl, or -N(R Ａ ) (R Ｂ ) in R Ａ and R Ｂ together with the nitrogen atom, halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino, forming an N-containing heterocycle optionally substituted with one or more groups selected from the group consisting of However, the compound is 【Chemistry 16】 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, which is not:

10. R １ is hydrogen, methyl, ethyl, or isopropyl, and R ３ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or methyl.

11. X １ and X ２ are each independently C-R ７ where R ７ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or halogen.

12. The ring A １ : 【Chemistry 17】 But the formula: 【Chemistry 18】 12. The compound of claim 11, wherein:

13. R ４ and R ４Ａ are -N(R Ａ ) (R Ｂ ) and R ５ is hydrogen, and R ６ is R Ａ where R Ａ But halogen, C ３－６ C optionally substituted with one or more groups selected from the group consisting of cycloalkyl, phenyl, tetrahydropyranyl, piperidyl, piperazinyl, pyridyl, pyrimidyl, and indazolyl １－４ -alkyl, wherein said C ３－６ Cycloalkyl, phenyl, tetrahydropyranyl, piperidyl, piperazinyl, pyridyl, pyrimidyl, and indazolyl are substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino; halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ C optionally substituted with one or more groups selected from the group consisting of ３－６ -cycloalkyl; halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino, wherein said C １－４ - alkyl is tetrahydropyranyl, piperidyl, or piperazinyl, each of which may be substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, or mono- or di-(C １－４ -alkyl)amino); tetrahydropyranyl, piperidyl, or piperazinyl, each of which is optionally further substituted with halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino; or pyridyl, pyrimidyl, or indazolyl, each of which is optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, amino, and mono- or di-(C １－４ -alkyl)amino; Ｂ The compound according to any one of claims 8 to 12, or a pharmaceutically acceptable salt thereof, wherein is methyl.

14. R Ａ isopropyl; halogen, cyano, C １－４ - alkyl, and C １－４ -C substituted with one or more groups selected from the group consisting of haloalkyl ３－６ -cycloalkyl; halogen, cyano, C １－４ - alkyl, and C １－４ -phenyl substituted with one or more groups selected from the group consisting of haloalkyl; or halogen, cyano, C １－４ - alkyl, and C １－４ -haloalkyl; or a pharmaceutically acceptable salt thereof.

15. R １ is hydrogen, C １－３ - alkyl, or C １－３ -deuterated alkyl, R ２ is hydrogen or halogen, R ３ is hydrogen or C １－４ - alkyl, Ring A １ : 【Chemistry 19】 is the formula: 【Chemistry 20】 is the basis of The wavy line indicates the point of attachment to the rest of the molecule, R ４Ａ is -N(R Ａ ) (R Ｂ ) and R ５ is hydrogen or halogen, X １ and X ２ are each independently N or C-R ７ and R ７ is hydrogen or halogen, R Ａ is a halogen, C １－４ -haloalkyl, and -O-(C １－４ -haloalkyl) ３－６ -cycloalkyl, R Ｂ is hydrogen or C １－４ - is alkyl, 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof.

16. The compound is 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-(trideuteromethyl)-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]hexan-3-yl)(methyl)amino)pyridin-3-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, and 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, selected from the group consisting of N-((6-((4,4-difluorocyclohexyl)(methyl)amino)pyridin-3-yl)methyl)-6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide.

17. The following formula (Ib): 【Chemical 21】 A compound represented by or a pharmaceutically acceptable salt thereof, wherein R １ is hydrogen, C １－３ - alkyl, or C １－３ -deuterated alkyl, R ２ is hydrogen, halogen, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, nitro, amino, or mono- or di-(C １－４ -alkyl)amino, R ３ is hydrogen, aryl, carboxy, —CO—O—(C １－４ -alkyl), or C optionally substituted with hydroxy １－４ - alkyl, Ring A ２ : 【Chemical 22】 is the formula: 【Chemical 23】 is the basis of The wavy line indicates the point of attachment to the rest of the molecule, R ４Ｂ is -O-R Ｃ and R ５ is hydrogen, halogen, or C １－４ - alkyl, X １ and X ２ are each independently N or C-R ７ and R ７ is hydrogen, halogen, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, nitro, amino, or mono- or di-(C １－４ -alkyl)amino, R Ｃ is halogen, cyano, hydroxy, C １－４ -alkyl, -O-(C １－４ -alkyl), C １－４ -haloalkyl, -O-(C １－４ -haloalkyl), amino, and mono- or di-(C １－４ C optionally substituted with one or more groups selected from the group consisting of ３－６ -cycloalkyl, or a pharmaceutically acceptable salt thereof.

18. R １ is hydrogen, C １－３ - alkyl, or C １－３ -deuterated alkyl, R ２ is hydrogen or halogen, R ３ is hydrogen or C １－４ - alkyl, R ５ is hydrogen or halogen, R ７ is hydrogen or halogen, R Ｃ is a halogen, C １－４ -haloalkyl, and -O-(C １－４ -haloalkyl) ３－６ -cycloalkyl, 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof.

19. 10. The pharmaceutical composition of claim 1, which is a pharmaceutical composition for the treatment of a KIT-mediated disease or condition.

20. 10. Use of a compound of claim 8, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a KIT-mediated disease or condition.

21. 10. Use of a compound of claim 8, or a pharmaceutically acceptable salt thereof, for the treatment of a KIT-mediated disease or condition.

22. 10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, for the treatment of a KIT-mediated disease or condition.

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

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

25. the cancer is selected from mastocytosis, mast cell tumor, solid tumor, gastrointestinal stromal tumor ("GIST"), small cell lung cancer, non-small cell lung cancer, acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia, colorectal cancer, gastric cancer, testicular cancer, glioblastoma, astrocytoma, malignant melanoma, mast cell tumor, neuroblastoma, sarcoma, and seminoma; the autoimmune disease is selected from multiple sclerosis, psoriasis, intestinal inflammatory disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, localized and systemic sclerosis, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome, panarteritis nodosa, autoimmune enteropathy, and proliferative glomerulonephritis; the allergic disease is selected from asthma, severe asthma, allergic rhinitis, chronic rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria, food allergy, seasonal allergy, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrotizing phlebitis, insect bite skin inflammation, and blood-sucking parasitic infection; 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 pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, and bone marrow fibrosis; the metabolic disorder is selected from diabetes and its chronic complications; obesity; type I or type II diabetes; hyperlipidemia and dyslipidemia; atherosclerosis; hypertension; and cardiovascular disease; and The neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, prion disease, motor neuron disease (MND), and amyotrophic lateral sclerosis (ALS).

25. The method of claim 24.

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