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

Abstract

Provided herein are compounds and compositions useful in inhibiting a 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., cancers, autoimmune diseases, allergic diseases, inflammatory diseases, fibrosis, metabolic disorders, and neurodegenerative diseases).

Description

KIT INHIBITORS, COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF

[0001] This application is directed to inhibitors of a receptor tyrosine kinase, KIT (c-KIT), and methods for their use, such as to prevent or treat one or more KIT mediated diseases or conditions.

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

[0003] Abnormalities in the expression and function of KIT are associated with several human diseases. KIT activation has been implicated in various human cancers, including mastocytosis, germ cell tumors, small-cell lung carcinoma, gastrointestinal stromal tumors (GIST), acute myelogenous leukemia, neuroblastoma, melanoma, ovarian carcinoma, and breast carcinoma (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 accomplished by one or more of three mechanisms: autocrine and / or paracrine stimulation by SCF, cross-activation by other kinases, and / or the acquisition of activating mutations (Hirota et al., Science (Wash DC) 1998, 279: 577-580; Heinrich et al. 2002). Pharmacological inhibition of KIT or SCF with small molecule inhibitors or specific antibodies can also affect the function of healthy and carcinogenic cells expressing KIT receptor (Valent et al., J Allergy Clin Immunol 2022, 149:1866-74). Indeed, several kinase inhibitors are approved for the treatment of GIST and other malignancies with KIT activation in both humans and non-human mammals.

[0004] It has become evident that KIT and its ligand participate in the development and function of multiple distinct cell lineages. These include cells in parts of the central nervous system, the interstitial cells of Cajal in the gut, taste cells, as well as several hematopoietic cell lineages in addition to MCs, including dendritic cells, eosinophils, and ILC2s (Tsai M et al., J. Allergy Clin. Immunol. 2022, 149:1845-54). While most lineages lose KIT 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 myeloid cells, MCs are long-lived. This is because the development of fully mature MCs from stem cells through pluripotent and committed MC progenitor cells may take several months. In addition, some mature tissue MCs survive months or perhaps years when residing within local tissue microenvironments (Cerny-Reiterer S et al., Oncotarget 2015, 6:3071-84). At maturation, MCs reside in local tissue sites at which SCF and other growth factors and cytokines are expressed, supporting long-term survival as well as effector cell functions.

[0006] As multifunctional cells of the innate immune system, MCs contribute to adaptive immune responses, and they play a role in allergic and other inflammatory reactions, as well. 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 allergens through IgE and IgE receptors; by IgG immune complexes; by complement and cytokines; by toxins, venom, and bacterial byproducts, as well as by certain medications (Valent et al. 2020). MC activation occurs in a number of different disease states and pathologies. Clinical symptoms may be severe, resulting in challenges to everyday life. In patients with allergic (atopic) disorders and in those with mastocytosis, MC activation may be substantial and systemic, even resulting in overt anaphylaxis.

[0007] Imatinib is a small molecule TKI which blocks KIT and other kinases including ABL1, ABL2, PDGFRs, and many more. Initially developed as a targeted cancer drug, Imatinib is approved by both the US Food and Drug Administration and European Medicines Agency for the treatment of systemic mastocytosis (SM), where the numbers of MCs are excessively elevated. The rationale for the use of imatinib in SM came from several studies. In one report, patients with chronic myeloid leukemia were treated with imatinib for several years. During this therapy, the number of MCs in the bone marrow were found to have decreased after 12 months; and after 24 months, MCs were almost completely absent in bone marrow sections (Cerny-Reiterer S et al. 2015). Simultaneously, serum tryptase levels, a MC activation marker, decreased to the point where they were low to undetectable (Cerny-Reiterer S et al. 2015). In a different study, 62 patients with poorly controlled or uncontrolled severe asthma who had airway hyperresponsiveness despite receiving maximal medical therapy were treated with imatinib (400 mg per day orally) for 24 weeks. Therapy with imatinib was found to reduce airway hyperresponsiveness and bronchoalveolar lavage tryptase levels more effectively in these patients than in the placebo control (Cahill KN et al., N Engl J Med 2017, 376:1911-20). Taken together, these data suggest that therapy with KIT-targeting drugs may lead to partial or even complete eradication of the MC lineage in patients with various MC diseases. In addition, some of these TKIs can also 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 diseases.

[0008] Provided herein, inter alia, are compounds and compositions comprising such compounds that are useful for inhibiting KIT. In particular, disclosed herein are methods inhibiting the activity of KIT for the prevention or treatment of KIT mediated diseases or conditions associated with improperly regulated kinase signal transduction of MCs such as cancers, 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.

[0009] In one embodiment, provided herein is a compound represented by the following Formula (I):

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen; C1-3-deuteroalkyl; C1-6-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, oxo, -NH-CO-(C1-4-alkyl), carbamoylamino, mono- or di-(C1-4-alkyl)carbamoylamino, -NH-CO-O-(C1-4-alkyl), and aryl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, and -O-(C1-4-haloalkyl), in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, and heterocyclyl; aryl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, and heterocyclyl; heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, and heterocyclyl; or heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, and heterocyclyl; R2is hydrogen, halogen, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, nitro, amino, or mono- or di-(C1-4-alkyl)amino, R3is hydrogen, hydroxy, or C1-4-alkyl, R4is halogen, hydroxy, nitro, amino, pentafluorothio, RA, -O-RA, -S(O)m-RA, -N(RA)(RB), or -CO-N(RA)(RC), and R5is hydrogen, halogen, hydroxy, nitro, amino, RA, -O-RA, -N(RA)(RB), or -CO-N(RA)(RC), or R4and R5are taken together to form a group of the formula:

[0012]

[0013] the wavy line indicates a point of attachment to the rest of molecule, R6is hydrogen, halogen, or C1-4-alkyl, R7is hydrogen or RA, R8is hydrogen, RA, or -N(RA)(RB), R9is hydrogen, halogen, or C1-4-alkyl, R10is hydrogen, halogen, or C1-4-alkyl, R11is hydrogen, halogen, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, nitro, amino, or mono- or di-(C1-4-alkyl)amino, R12is hydrogen, halogen, or C1-4-alkyl, L is a group of the formula:

[0014]

[0015] Q1is O or S, Q2is O, S, or NH, X1and X2are each independently N or C-R11, Y1and Y2are each independently N or C-R12, m is an integer having a value of 0, 1, or 2, n is an integer having a value of 0 or 1, RAis C1-4-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, -O-(C1-4-alkyl), mono- or di-(C1-4-alkyl)amino, C3-6-cycloalkyl, aryl, heterocyclyl, and heteroaryl, in which said C3-6-cycloalkyl, aryl, heterocyclyl, and heteroaryl may be further substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; C3-7-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino, in which said C1-4-alkyl group and C1-4-alkyl moieties may be further substituted with heterocyclyl optionally substituted with halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, or mono- or di-(C1-4-alkyl)amino; aryl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino, in which said C1-4-alkyl group and C1-4-alkyl moieties may be further substituted with heterocyclyl optionally substituted with halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, or mono- or di-(C1-4-alkyl)amino; heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino, in which said C1-4-alkyl group and C1-4-alkyl moieties may be further substituted with heterocyclyl optionally substituted with halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, or mono- or di-(C1-4-alkyl)amino; or heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino, in which said C1-4-alkyl group and C1-4-alkyl moieties may be further substituted with heterocyclyl optionally substituted with halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, or mono- or di-(C1-4-alkyl)amino; RBis hydrogen, C1-4-alkyl, or C3-6-cycloalkyl, and RCis C1-4-alkyl or C3-6-cycloalkyl, or RAand RCat the -CO-N(RA)(RC) are taken together with the nitrogen atom to form an N-containing heterocyclic ring optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino.

[0016] In another embodiment, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and one or more of the disclosed compounds, or a pharmaceutically acceptable salt thereof. 　　　Another embodiment comprises method for 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound(s). 　　　Also provided herein is use of one or more of the disclosed compounds, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of a KIT mediated disease or condition. 　　　In another embodiment, provided herein is one or more of the disclosed compounds, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the disclosed compound(s) for use in preventing or treating a KIT mediated disease or condition.

[0017] <Definitions> 　　　　The term “alkyl" used alone or as part of a larger moiety, such as “haloalkyl”, "cycloalkyl", “alkylamino”, and the like, means saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 4 carbon atoms, i.e., C1-4-alkyl. As used herein, a “C1-4-alkyl” group and “C1-4alkyl” moiety of -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), mono- or di-(C1-4-alkyl)amino, -CO-O-(C1-4-alkyl), -NH-CO-(C1-4-alkyl), mono- or di-(C1-4-alkyl)carbamoylamino, -NH-CO-O-(C1-4-alkyl), and the like, mean a radical having from 1 to 4 carbon atoms in a linear or branched arrangement, and includes methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2-methylpropyl, and tert-butyl. 　　　　The term “deuteroalkyl” means an alkyl having one or more deuterium atoms. For example, the term “C1-3-deuteroalkyl” means a radical having from 1 to 3 carbon atoms, and includes mono, di, and trideuteromethyl.

[0018] The term “alkylamino” means amino substituted with one or more alkyl groups. For example, “mono- or di-(C1-4-alkyl)amino” includes methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, (ethyl)(methyl)amino, (isopropyl)(methyl)amino, and (tert-butyl)(methyl)amino. 　　　　The term “alkylcarbamoylamino” means carbamoylamino substituted with one or more alkyl groups. For example, “mono- or di-(C1-4-alkyl)carbamoylamino” includes methylcarbamoylamino, ethylcarbamoylamino, isopropylcarbamoylamino, dimethylcarbamoylamino, diethylcarbamoylamino, (ethyl)(methyl)carbamoylamino, (isopropyl)(methyl)carbamoylamino, and (tert-butyl)(methyl)carbamoylamino.

[0019] The term “haloalkyl” means alkyl substituted with one or more halogen atoms. For example, “C1-4-haloalkyl” includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, bromomethyl, fluoroethyl, difluoroethyl, dichloroethyl and chloropropyl. In one aspect, an example of C1-4-haloalkyl includes difluoromethyl, trifluoromethyl, fluoroethyl, and difluoroethyl, and in another aspect, an example of C1-4-haloalkyl includes trifluoromethyl. 　　　　The term “halogen” or “halo” means fluorine or fluoro (F), chlorine or chloro (Cl), bromine or bromo (Br), or iodine or iodo (I).

[0020] The term “aryl” means 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, an example of aryl includes phenyl or naphthyl, and in another aspect, an example of aryl includes phenyl. 　　　　The term "cycloalkyl" means a 3-12 membered saturated aliphatic cyclic hydrocarbon radical. It can be monocyclic, bicyclic (e.g., a bridged, spirofused, or fused bicyclic ring), or tricyclic. For example, monocyclic C3-6-cycloalkyl means a radical having from 3 to 6 carbon atoms arranged in a monocyclic ring. For example, “C3-6-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. For example, “C3-7-cycloalkyl” includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, spiro[2.3]hexyl, and spiro[3.3]heptyl.

[0021] The term "heteroaryl" refers to 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, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalyl, indolizinyl, pyrazolo[1,5-a]pyridyl, 1H-imidazo[1,2-a]imidazolyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, [1,2,4]triazolo[1,5-a]pyridyl, [1,2,3]triazolo[1,5-a]pyridyl, tetrazolo[1,5-a]pyridyl, 1H-pyrrolo[1,2-a]imidazolyl, 1H-pyrrolo[1,2-c]imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzoxazolyl, benzothiazolyl, furyl, thienyl, benzofuryl, and benzothienyl. In one aspect, an example of heteroaryl includes 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In one aspect, an example of heteroaryl includes 8- to 10-membered heteroaryl having 1 to 4 nitrogen atoms such as indolyl, isoindolyl, indazolyl, benzotriazolyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalyl, indolizinyl, pyrazolo[1,5-a]pyridyl, 1H-imidazo[1,2-a]imidazolyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, [1,2,4]triazolo[1,5-a]pyridyl, [1,2,3]triazolo[1,5-a]pyridyl, tetrazolo[1,5-a]pyridyl, 1H-pyrrolo[1,2-a]imidazolyl, and 1H-pyrrolo[1,2-c]imidazolyl. In one aspect, an example of heteroaryl includes 5-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom such as oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. In one aspect, an example of heteroaryl includes 9-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom such as benzoxazolyl and benzothiazolyl. In one aspect, an example of heteroaryl includes 5-membered heteroaryl having 1 oxygen or sulfur atom such as furyl and thienyl. In one aspect, an example of heteroaryl includes 9-membered heteroaryl having 1 oxygen or sulfur atom such as benzofuryl and benzothienyl.

[0022] 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) heteroatoms (e.g., oxygen, nitrogen, or sulfur). Each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO); oxygen; and sulfur, including sulfoxide and sulfone. Some of bonds that constitute the heterocyclyl may be unsaturated bonds. A part of the bicyclic heterocyclyl may have aromaticity. Examples thereof include aspects in a state where the monocyclic heterocyclyl having a 5- and 6-membered ring is fused with a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, an oxazole ring, a thiazole ring, or a pyridine ring, and a state where at least a partially unsaturated hydrocarbon ring radical having a 5- and 6-membered ring is fused with a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, an oxazole ring, a thiazole ring, or a pyridine ring. Examples of such heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, dihydropyridyl, tetrahydropyridyl, dihydropyridazinyl, tetrahydropyridazinyl, hexahydropyridazinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, hexahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzimidazolyl, tetrahydroquinolyl such as 5,6,7,8-tetrahydroquinolyl, dihydro-1H-pyrrolo[2,3-b]pyridyl, dihydro-1H-imidazo[1,2-a]imidazolyl such as 2,3-dihydro-1H-imidazo[1,2-a]imidazolyl, dihydro-1H-pyrrolo[1,2-a]imidazolyl, dihydro-1H-pyrrolo[1,2-c]imidazolyl, morpholinyl, thiomorpholinyl, dihydrobenzoxazolyl, tetrahydrobenzoxazolyl, dihydrofuro[2,3-b]pyridyl such as 2,3-dihydrofuro[2,3-b]pyridyl, dihydrofuro[3,4-b]pyridyl such as 5,7-dihydrofuro[3,4-b]pyridyl, dihydro-2H-pyrano[2,3-b]pyridyl such as 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 2-oxaspiro[3.3]heptyl, tetrahydrothienyl, tetrahydrothiopyranyl, dihydrothiopyranyl, 2-oxaspiro[3.5]nonyl, dihydrobenzofuryl, dihydroisobenzofuryl, and dihydrobenzopyranyl such as 3,4-dihydro-2H-1-benzopyranyl. In one aspect, an example of heterocyclyl includes 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms such as azetidinyl, pyrrolidinyl, piperidinyl, dihydropyridyl, tetrahydropyridyl, dihydropyridazinyl, tetrahydropyridazinyl, hexahydropyridazinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, hexahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, and piperazinyl. In one aspect, an example of heterocyclyl includes 8- to 10-membered heterocyclyl having 1 to 4 nitrogen atoms such as dihydroindolyl, dihydroisoindolyl, dihydrobenzimidazolyl, tetrahydroquinolyl such as 5,6,7,8-tetrahydroquinolyl, dihydro-1H-pyrrolo[2,3-b]pyridyl, dihydro-1H-imidazo[1,2-a]imidazolyl such as 2,3-dihydro-1H-imidazo[1,2-a]imidazolyl, dihydro-1H-pyrrolo[1,2-a]imidazolyl, and dihydro-1H-pyrrolo[1,2-c]imidazolyl. In one aspect, an example of heterocyclyl includes 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom such as morpholinyl and thiomorpholinyl. In one aspect, an example of heterocyclyl includes 9- or 10-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom such as dihydrobenzoxazolyl, tetrahydrobenzoxazolyl, dihydrofuro[2,3-b]pyridyl such as 2,3-dihydrofuro[2,3-b]pyridyl, dihydrofuro[3,4-b]pyridyl such as 5,7-dihydrofuro[3,4-b]pyridyl, and dihydro-2H-pyrano[2,3-b]pyridyl such as 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl. In one aspect, an example of heterocyclyl includes 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom such as oxiranyl, oxetanyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 2-oxaspiro[3.3]heptyl, tetrahydrothienyl, tetrahydrothiopyranyl, and dihydrothiopyranyl. In one aspect, an example of heterocyclyl includes 9- or 10-membered heterocyclyl having 1 oxygen or sulfur atom such as 2-oxaspiro[3.5]nonyl, dihydrobenzofuryl, dihydroisobenzofuryl, and dihydrobenzopyranyl such as 3,4-dihydro-2H-1-benzopyranyl.

[0023] Examples of "N-containing heterocyclic ring" formed by taken together RAand RCat the -CO-N(RA)(RC) with the nitrogen atom include azetidine, pyrrolidine, pyrazole, imidazole, triazole, tetrazole, piperidine, dihydropyridine, tetrahydropyridine, piperazine, morpholine, and thiomorpholine.

[0024] The terms “optionally substituted” and "which may be substituted" mean which is unsubstituted or which has one or more substituents. In a case of having a substituent, unless otherwise noted, it is possible to have a plurality of substituents as long as chemical structures are allowed. In the case of having the plurality of substituents, individual substituents may be the same or different from each other.

[0025] Compounds having one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. The term "geometric isomer" refers to compounds having at least one double bond, wherein the double bond(s) may exist in cis (also referred to as syn or entgegen (E)) or trans (also referred to as anti or zusammen (Z)) forms 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 the structure encompasses one or more of the possible stereoisomers, or geometric isomers, or a mixture of the encompassed stereoisomers or geometric isomers.

[0026] When a geometric isomer is depicted by name or structure, it is to be understood that the named or depicted isomer exists to a greater degree than another isomer, that is that the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by weight. 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 of the geometric isomers in the mixture.

[0027] Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer. When a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms (e.g., both enantiomerically-pure, enantiomerically-enriched or racemic) of the compound. When a compound with two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral centers, it is understood that the name or structure encompasses all possible diastereomeric forms (e.g., diastereomerically pure, diastereomerically enriched and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures) of the compound.

[0028] 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 compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers also can be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0029] When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated othe1wise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as "enantiomerically pure"). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

[0030] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

[0031] It is to be understood that when a compound herein is represented by a structural formula or designated by a chemical name herein, all other tautomeric forms which may exist for the compound are encompassed by the structural formula.

[0032] As used herein, the term "pharmaceutically acceptable salt" refers to pharmaceutical salts that are, 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 response, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66:1-19. 　　　　Included in the present teachings are pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having basic amine groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, e.g., acetic, trifluoroacetic, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).

[0033] Furthermore, the present invention also includes various hydrates or solvates, and any of crystalline polymorphs of the compound of Formula (I) and a pharmaceutically acceptable salt thereof. In addition, the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes. 　　　　It is to be noted that the compounds of Formulas (Ia) and (Ib) are included within the scope of the compound of Formula (I), and accordingly suitable examples or embodiments of the compounds of Formulas (Ia) and (Ib) are to be referred to those as exemplified for the compound of Formula (I).

[0034] <Compounds of the Invention> 　　　In a first embodiment, the invention provides a compound represented by the following Formula (I).

[0035]

[0036] or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen; C1-3-deuteroalkyl; C1-6-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, oxo, -NH-CO-(C1-4-alkyl), carbamoylamino, mono- or di-(C1-4-alkyl)carbamoylamino, -NH-CO-O-(C1-4-alkyl), and aryl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, and -O-(C1-4-haloalkyl), in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, and heterocyclyl; aryl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, and heterocyclyl; heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, and heterocyclyl; or heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, and heterocyclyl; R2is hydrogen, halogen, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, nitro, amino, or mono- or di-(C1-4-alkyl)amino, R3is hydrogen, hydroxy, or C1-4-alkyl, R4is halogen, hydroxy, nitro, amino, pentafluorothio, RA, -O-RA, -S(O)m-RA, -N(RA)(RB), or -CO-N(RA)(RC), and R5is hydrogen, halogen, hydroxy, nitro, amino, RA, -O-RA, -N(RA)(RB), or -CO-N(RA)(RC), or R4and R5are taken together to form a group of the formula:

[0037]

[0038] the wavy line indicates a point of attachment to the rest of molecule, R6is hydrogen, halogen, or C1-4-alkyl, R7is hydrogen or RA, R8is hydrogen, RA, or -N(RA)(RB), R9is hydrogen, halogen, or C1-4-alkyl, R10is hydrogen, halogen, or C1-4-alkyl, R11is hydrogen, halogen, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, nitro, amino, or mono- or di-(C1-4-alkyl)amino, R12is hydrogen, halogen, or C1-4-alkyl, L is a group of the formula:

[0039]

[0040] Q1is O or S, Q2is O, S, or NH, X1and X2are each independently N or C-R11, Y1and Y2are each independently N or C-R12, m is an integer having a value of 0, 1, or 2, n is an integer having a value of 0 or 1, RAis C1-4-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, -O-(C1-4-alkyl), mono- or di-(C1-4-alkyl)amino, C3-6-cycloalkyl, aryl, heterocyclyl, and heteroaryl, in which said C3-6-cycloalkyl, aryl, heterocyclyl, and heteroaryl may be further substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; C3-7-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino, in which said C1-4-alkyl group and C1-4-alkyl moieties may be further substituted with heterocyclyl optionally substituted with halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, or mono- or di-(C1-4-alkyl)amino; aryl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino, in which said C1-4-alkyl group and C1-4-alkyl moieties may be further substituted with heterocyclyl optionally substituted with halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, or mono- or di-(C1-4-alkyl)amino; heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino, in which said C1-4-alkyl group and C1-4-alkyl moieties may be further substituted with heterocyclyl optionally substituted with halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, or mono- or di-(C1-4-alkyl)amino; or heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino, in which said C1-4-alkyl group and C1-4-alkyl moieties may be further substituted with heterocyclyl optionally substituted with halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, or mono- or di-(C1-4-alkyl)amino; RBis hydrogen, C1-4-alkyl, or C3-6-cycloalkyl, and RCis C1-4-alkyl or C3-6-cycloalkyl, or RAand RCat the -CO-N(RA)(RC) are taken together with the nitrogen atom to form an N-containing heterocyclic ring optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino.

[0041] In a 2ndembodiment, the invention provides a compound according to the 1stembodiment, or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen; C1-3-deuteroalkyl; C1-6-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, oxo, -NH-CO-(C1-4-alkyl), carbamoylamino, mono- or di-(C1-4-alkyl)carbamoylamino, -NH-CO-O-(C1-4-alkyl), and phenyl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, and -O-(C1-4-haloalkyl), in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; phenyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms or 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; or 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms, 5-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, or 9-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; RAis C1-4-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, -O-(C1-4-alkyl), and mono- or di-(C1-4-alkyl)amino; C3-7-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; phenyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms or 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; or 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms or 5-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; RBis C1-4-alkyl, and RCis C1-4-alkyl or C3-6-cycloalkyl, or RAand RCat the -CO-N(RA)(RC) are taken together with the nitrogen atom to form an N-containing heterocyclic ring optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino.

[0042] In a 3rdembodiment, the invention provides a compound according to the 2ndembodiment, or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen; C1-3-deuteroalkyl; C1-6-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, oxo, -NH-CO-(C1-4-alkyl), carbamoylamino, mono- or di-(C1-4-alkyl)carbamoylamino, -NH-CO-O-(C1-4-alkyl), and phenyl.

[0043] In a 4thembodiment, the invention provides a compound according to the 2ndor 3rdembodiment, or a pharmaceutically acceptable salt thereof, wherein: R4is pentafluorothio; C1-4-haloalkyl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; or -N(RA)(RB); and R5is hydrogen, halogen, or C1-4-alkyl, or R4and R5are taken together to form a group of the formula:

[0044]

[0045] In a 5thembodiment, the invention provides a compound according to the 4thembodiment, or a pharmaceutically acceptable salt thereof, wherein: R4is C1-4-haloalkyl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; or -N(RA)(RB); and R5is hydrogen, halogen, or C1-4-alkyl, or R4and R5are taken together to form a group of the formula:

[0046]

[0047] RAis isopropyl; C1-4-haloalkyl; C3-7-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; phenyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms or 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; or 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms or 5-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; and RBis methyl.

[0048] In a 6thembodiment, the invention provides a compound according to the 5thembodiment, or a pharmaceutically acceptable salt thereof, wherein: R4is trifluoromethyl; fluoroethyl; difluoroethyl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; azetidinyl or pyrrolidinyl, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; pyrazolyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; or -N(RA)(RB); R5is hydrogen, RAis isopropyl; C1-4-haloalkyl; C3-7-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; phenyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; or 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms or 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; and RBis methyl.

[0049] In a 7thembodiment, the invention provides a compound according to the 1stembodiment, or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen; C1-3-deuteroalkyl; C1-6-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, oxo, -NH-CO-(C1-4-alkyl), carbamoylamino, mono- or di-(C1-4-alkyl)carbamoylamino, -NH-CO-O-(C1-4-alkyl), and phenyl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, and -O-(C1-4-haloalkyl), in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; phenyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms or 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; or 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms, 5-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, or 9-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; R4is -N(RA)(RB); and R5is hydrogen, or R4and R5are taken together to form a group of the formula:

[0050]

[0051] RAis C1-4-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, -O-(C1-4-alkyl), and mono- or di-(C1-4-alkyl)amino; C3-7-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; phenyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms or 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; or 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms or 5-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; and RBis C1-4-alkyl.

[0052] In an 8thembodiment, the invention provides a compound according to the 7thembodiment, or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen; C1-3-deuteroalkyl; C1-6-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, oxo, -NH-CO-(C1-4-alkyl), carbamoylamino, mono- or di-(C1-4-alkyl)carbamoylamino, -NH-CO-O-(C1-4-alkyl), and phenyl.

[0053] In a 9thembodiment, the invention provides a compound according to the 8thembodiment, or a pharmaceutically acceptable salt thereof, wherein: RAis isopropyl; C1-4-haloalkyl; C3-7-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; phenyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; or 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms or 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; and RBis methyl.

[0054] In a 10thembodiment, the invention provides a compound according to the 9thembodiment, or a pharmaceutically acceptable salt thereof, wherein: RAis isopropyl and RBis methyl.

[0055] In an 11thembodiment, the invention provides a compound according to the 1stto 10thembodiments, or a pharmaceutically acceptable salt thereof, wherein: X1and X2are each independently C-R11, Y1is N or C-R12, and Y2is C-R12.

[0056] In a 12thembodiment, the invention provides a compound according to the 1stto 11thembodiments, or a pharmaceutically acceptable salt thereof, wherein: R2is hydrogen, halogen, or C1-4-alkyl, and R11is hydrogen, halogen, or C1-4-alkyl.

[0057] In a 13thembodiment, the invention provides a compound according to the 1stto 12thembodiments, or a pharmaceutically acceptable salt thereof, wherein: L is a group of the formula:

[0058]

[0059] In a 14thembodiment, the invention provides a compound according to the 13thembodiment, or a pharmaceutically acceptable salt thereof, wherein n is an integer having a value of 1.

[0060] In a 15thembodiment, the invention provides a compound according to the 1stto 12thembodiments, or a pharmaceutically acceptable salt thereof, wherein: L is a group of the formula:

[0061]

[0062] In a 16thembodiment, the invention provides a compound according to the 15thembodiments, or a pharmaceutically acceptable salt thereof, wherein n is an integer having a value of 1.

[0063] In a 17thembodiment, the invention provides a compound according to the 1stto 12thembodiments, or a pharmaceutically acceptable salt thereof, wherein: L is a group of the formula:

[0064]

[0065] In an 18thembodiment, the invention provides a compound according to the 17thembodiments, or a pharmaceutically acceptable salt thereof, wherein n is an integer having a value of 0.

[0066] In a 19thembodiment, the invention provides a compound according to the 2ndor 3rdembodiment, or a pharmaceutically acceptable salt thereof, wherein: R4is pentafluorothio; C1-4-haloalkyl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms, which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; or -N(RA)(RB); and R5is hydrogen, halogen, or C1-4-alkyl, or R4and R5are taken together to form a group of the formula:

[0067]

[0068] L is a group of the formula:

[0069]

[0070] n is an integer having a value of 1.

[0071] In a 20thembodiment, the invention provides a compound according to the 19thembodiment, or a pharmaceutically acceptable salt thereof, wherein: R4is C1-4-haloalkyl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms, which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; or -N(RA)(RB); and R5is hydrogen, halogen, or C1-4-alkyl, or R4and R5are taken together to form a group of the formula:

[0072]

[0073] RAis isopropyl; C1-4-haloalkyl; C3-7-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; phenyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms or 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; or 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms or 5-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; and RBis methyl.

[0074] In a 21stembodiment, the invention provides a compound according to the 20thembodiment, or a pharmaceutically acceptable salt thereof, wherein: R4is trifluoromethyl; fluoroethyl; difluoroethyl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; azetidinyl or pyrrolidinyl, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; pyrazolyl, which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; or -N(RA)(RB); R5is hydrogen, RAis isopropyl; C1-4-haloalkyl; C3-7-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; phenyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; or 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms or 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; and RBis methyl.

[0075] In a 22ndembodiment, the invention provides a compound according to the 2ndor 3rdembodiment, or a pharmaceutically acceptable salt thereof, wherein: R4is pentafluorothio; C1-4-haloalkyl; or -N(RA)(RB); and R5is hydrogen, halogen, or C1-4-alkyl, or R4and R5are taken together to form a group of the formula:

[0076]

[0077] L is a group of the formula:

[0078]

[0079] n is an integer having a value of 1.

[0080] In a 23rdembodiment, the invention provides a compound according to the 1stembodiment, wherein the compound is selected from the group consisting of 　　　5-(1-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 1), 　　　(S)-5-(1-((6-((3,3-Difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 2), 　　　5-(1-(1-(4-(Isopropyl(methyl)amino)phenyl)ethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzimidazol-2-one (Compound 3), 　　　5-(1-((6-((3,3-Difluorocyclobutyl)(methyl)amino)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxypropyl)-1,3-dihydro-2H-benzimidazol-2-one (Compound 4), 　　　1-Methyl-5-(5-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-1,3,4-oxadiazol-2-yl)-1,3-dihydro-2H-benzimidazol-2-one (Compound 5), 　　　5-(4-((6-((3,3-Difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1H-1,2,3-triazol-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 6), 　　　5-(4-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1H-1,2,3-triazol-1-yl)-1,3-dihydro-2H-benzimidazol-2-one (Compound 7), 　　　5-(1-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 8), 　　　5-(6'-(Isopropyl(methyl)amino)-2-oxo-[3,3'-bipyridin]-1(2H)-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 9), 　　　5-(6'-(Isopropyl(methyl)amino)-2-oxo-2H-[1,3'-bipyridin]-3-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 10), 　　　5-(2-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-2H-tetrazol-5-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 11), 　　　5-(4-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)thiazol-2-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 12), 　　　5-(3-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1,2,4-oxadiazol-5-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 13), 　　　5-(5-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1,2,4-oxadiazol-3-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 14), 　　　and 　　　5-(4-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1H-imidazol-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 56), 　　　or a pharmaceutically acceptable salt thereof.

[0081] In certain embodiments, the invention is any one of the compounds depicted in the exemplification section of the instant application; and pharmaceutically acceptable salts as well as the neutral forms of these compounds also are included in the invention. Specifically, the invention is any one of the compounds depicted in Examples 1-57; and pharmaceutically acceptable salts as well as the neutral forms of these compounds also are included in the invention. In preferred embodiments, the invention is any one of Compounds 1-57; and pharmaceutically acceptable salts as well as the neutral forms of these compounds also are included in the invention.

[0082] <Methods of Preparing Compounds of the Invention> 　　　Methods of preparing compounds of Formula (I) are disclosed.

[0083] Preparation process A 　　　In one embodiment, a compound of Formula (Ia)

[0084]

[0085] or a pharmaceutically acceptable salt thereof may be prepared by reacting a compound of Formula (IIa)

[0086]

[0087] or its salt with a compound of Formula (IIIa)

[0088]

[0089] or its salt, or reacting a compound of Formula (IIb)

[0090]

[0091] or its salt with a compound of Formula (IIIb)

[0092]

[0093] or its salt, wherein: L1is a group of the formula:

[0094]

[0095] Z is borono (-B(OH)2) or 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl. 　　　Suitable salts of the compounds of Formulas (IIa), (IIb), (IIIa), and (IIIb) can be referred to the salts as exemplified for the compound (I).

[0096] The reaction is usually carried out in the presence of a conventional inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, and sodium hydride, and a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (PdCl2(dppf).DCM) and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), in a conventional solvent such as dichloromethane, chloroform, acetonitrile, dioxane, tetrahydrofuran, dimethyl sulfoxide, and N,N-dimethylformamide. 　　　The reaction temperature is not critical and the reaction can be carried out under room temperature or under heating. 　　　In a case where another functional group in a molecule complicates the reaction, the group may be protected by a conventional protecting group, the reaction may be carried out by reacting the compound of Formula (IIa) or Formula (IIb) with the compound of Formula (IIIa) or Formula (IIIb), respectively, and thereafter, the protecting group may be deprotected, and as a result, the compound of the present invention may be led.

[0097] Preparation process B 　　　In one embodiment, a compound of Formula (Ib)

[0098]

[0099] or a pharmaceutically acceptable salt thereof may be prepared by reacting a compound of Formula (IIc)

[0100]

[0101] or its salt with a compound of Formula (IIIb)

[0102]

[0103] or its salt, wherein: L2is a group of the formula:

[0104]

[0105] Suitable salts of the compounds of Formulas (IIc) and (IIIb) can be referred to the salts as exemplified for the compound of Formula (I). 　　　The reaction is usually carried out in the presence of a conventional inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, and sodium hydride, and, optionally, a catalyst derived from copper(I) iodide and 8-hydroxyquinoline, in a conventional solvent such as dichloromethane, chloroform, acetonitrile, dioxane, tetrahydrofuran, dimethyl sulfoxide, and N,N-dimethylformamide. 　　　The reaction temperature is not critical and the reaction can be carried out under room temperature or under heating. 　　　In a case where another functional group in a molecule complicates the reaction, the group may be protected by a conventional protecting group, the reaction may be carried out by reacting the compound of Formula (IIc) with the compound of Formula (IIIb), and thereafter, the protecting group may be deprotected, and as a result, the compound of the present invention may be led. 　　　As the protecting group in the Preparation processes, a group usually used by those skilled in the art can be applied, and for example, the groups described in the above described "Greene's Protective Groups in Organic Synthesis (4th edition, 2006)" can be used. 　　　The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, chromatography, and reprecipitation. 　　　Detailed synthetic protocols for preparing exemplary compounds of Formula (I) and their intermediate compounds can be referred to Examples and Preparations below or similar manners thereto or conventional manners.

[0106] <Pharmaceutical Compositions> 　　　The compounds of Formula (I) disclosed therein are KIT inhibitors. The pharmaceutical composition of the present invention comprises one or more KIT inhibitors, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0107] "Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to a substance that aids the formulation and / or administration of an active agent to and / or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds.

[0108] The 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 flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5thEd., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003 -20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. The carriers, diluents and / or excipients are "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0109] The pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. In an embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings. In preferred embodiments, the pharmaceutical composition is formulated for oral or intravenous administration.

[0110] Typically, for oral therapeutic administration, a compound of the present teachings may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. 　　　Typically for parenteral administration, solutions of a compound of the present teachings can generally be prepared in water 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 a preservative to prevent the growth of microorganisms. 　　　Typically, for injectable use, sterile aqueous solutions, or dispersion of, and sterile powders of, a compound described herein for the extemporaneous preparation of sterile injectable solutions or dispersions are appropriate.

[0111] <Methods of Treatment> 　　　Methods of preventing or treating a KIT mediated disease or condition, especially, the KIT mediated disease or condition associated with improperly regulated kinase signal transduction of mast cells, in a subject are disclosed. The methods can include administering to the subject a therapeutically effective amount of one or more compounds of Formula (I) or compositions provided herein. 　　　A "subject" is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).

[0112] In one embodiment, the KIT mediated disease or condition is a cancer. Examples of cancers include, but are not limited to, mastocytosis, mastocytoma, solid tumor, gastrointestinal stromal tumor ("GIST"), small cell lung cancer, non-small cell lung cancer, acute myelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, colorectal carcinoma, gastric carcinoma, testicular cancer, glioblastoma, astrocytoma, melanoma, mast cell tumor, neuroblastoma, sarcoma, and seminoma.

[0113] In other embodiments, the KIT mediated disease or condition is an autoimmune disease. Examples of autoimmune diseases include, but are not limited to, multiple sclerosis, psoriasis, intestine inflammatory disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, local and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome, nodular panarteritis, autoimmune enteropathy, and proliferative glomerulonephritis.

[0114] 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 allergy, seasonal allergy, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis, insect bite skin inflammation, and blood sucking parasitic infestation.

[0115] In other embodiments, the KIT mediated disease or condition is an inflammatory disease. Examples of inflammatory diseases include, but are not limited to, rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and eosinophilic esophagitis.

[0116] In yet other embodiments, the KIT mediated disease or condition is fibrosis. Examples of fibrosis includes, but are not limited to, pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, and myelofibrosis.

[0117] In still other embodiments, the KIT mediated disease or condition is a metabolic disorder. Examples of metabolic disorders include, but are not limited to, diabetes mellitus and its chronic complications; obesity; type I diabetes or type II diabetes; hyperlipidemias and dyslipidemias; atherosclerosis; hypertension; and cardiovascular disease.

[0118] 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, the prion diseases, motor neuron disease (MND), and amyotrophic lateral sclerosis (ALS).

[0119] 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).

[0120] <Methods of Administration and Dosage Forms> 　　　The terms "administer", "administering", "administration", and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in 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.

[0121] The term "effective amount" means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses, or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, a therapeutically effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg to about 5 grams per day; and in another alternatively from 10 mg to 1 gram per day). In a case of usual oral administration, the daily dose can be 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, and more preferably 0.1 to 10 mg / kg, per body weight. The above dose is administered in a single portion or divided into 2 to 4 portions. In a case of intravenous administration, the appropriate daily dose can be 0.0001 to 10 mg / kg, per body weight. The above dose is administered in a single portion or divided into 2 to 4 portions. In a case of being transmucosally administered, the appropriate daily dose can be 0.001 to 100 mg / kg, per body weight. The above dose is administered in a single portion or divided into 2 to 4 portions.

[0122] Depending on the kinds of administration routes, dosage forms, administration sites, excipients, and additives, the pharmaceutical composition of the present invention contains one or more compounds of Formula (I) or salts thereof as active ingredients in an amount of 0.01% to 100% by mass, preferably 0.01% to 50% by mass. 　　　The precise amount of compound administered to provide an "effective amount" to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.

[0123] In addition, the compounds of Formula (I) can be co-administered with other therapeutic agents. As used herein, the terms "co-administration", "administered in combination with", and their grammatical equivalents, are meant to encompass administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times. In some embodiments the one or more compounds described herein will be co-administered with other agents. These terms encompass administration of two or more agents to the subject so that both agents and / or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and / or administration in a composition in which both agents are present. Thus, in some embodiments, the compounds described herein and the other agent(s) are administered in a single composition. In some embodiments, the compounds described herein and the other agent(s) are admixed in the composition. In some embodiments, the compounds of Formula (I) can be used in combination with other agents known to have beneficial activity with the compounds of Formula (I) for treating or preventing the KIT mediated diseases or conditions. For example, the compounds of Formula (I) can be administered alone or in combination with one or more other anticancer agents, immunomodulatory agents, antiallergic agents, anti-inflammatory agents, antifibrotic agents, antimetabolites, and anti-neurodegenerative disease agents for treating or preventing the KIT mediated diseases or conditions. When administered in combination with other therapeutic agents, e.g., when administered in combination with an anti-cancer agent, an "effective amount" of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the invention being used by following, for example, dosages reported in the literature and recommended in the Physician 's Desk Reference (57th ed., 2003).

[0124] <Synthetic Preparation of Compound Embodiments> Abbreviations

[0125]

[0126] Example-1

[0127]

[0128] Step-1: Methyl 6-(isopropylamino)nicotinate 　　　To a stirred solution of methyl 6-chloronicotinate (1.5 g, 8.74 mmol) in DMSO (15 mL) was added DIPEA (6.78 g, 52.4 mmol) followed by propan-2-amine hydrochloride (4.17 g, 43.6 mmol) at RT and stirred at 100℃ for 12 h. The reaction mass was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 30% EtOAc in hexane as an eluent to get the title compound (1 g, 59%). LC-MS: 195 [M+H]+.

[0129] Step-2: Methyl 6-(isopropyl(methyl)amino)nicotinate 　　　To a stirred solution of methyl 6-(isopropylamino)nicotinate (1 g, 5.15 mmol) in DMF (10 mL) was added NaH (60% dispersion in mineral oil)(0.31 g, 7.8 mmol) followed by iodomethane (1.1 g, 7.8 mmol) at 0℃ and stirred at RT for 2 h. The reaction mass was quenched with ice cold water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 10% EtOAc in hexane as an eluent to get the title compound (1 g, 93.2%). LC-MS: 209 [M+H]+.

[0130] Step-3: (6-(Isopropyl(methyl)amino)pyridin-3-yl)methanol 　　　To a stirred solution of methyl 6-(isopropyl(methyl)amino)nicotinate (1 g, 4.8 mmol) in THF (10 mL) was added LiBH4(0.42 g, 19.2 mmol) in portions at 0℃ and stirred at 65℃ for 16 h. To the reaction mixture was added saturated ammonium chloride solution, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to afford the title compound. (0.85 g, 98.2%). LC-MS: 181 [M+H]+

[0131] Step-4: 5-(Chloromethyl)-N-isopropyl-N-methylpyridin-2-amine 　　　To a stirred solution of (6-(isopropyl(methyl)amino)pyridin-3-yl)methanol (0.2 g, 1.11 mmol) in DCM (5 mL) was added SOCl2(0.26 g, 2.18 mmol) at 0℃ and stirred at 65℃ for 3 h. The reaction mixture was concentrated to get the title compound (0.21 g, 95.5%).1H-NMR (400 MHz, DMSO-D6) δ 8.12-8.11 (d, 1H), 8.04-8.00 (dd, 1H), 7.40-7.38 (d, 1H), 4.81 (s, 2H), 4.54-4.50 (m, 1H), 3.04 (s, 3H), 1.22-1.20 (d, 6H).

[0132] Step-5: N-Isopropyl-N-methyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-amine 　　　To a stirred solution of 5-(chloromethyl)-N-isopropyl-N-methylpyridin-2-amine (0.2 g, 1.0 mmol) in MeCN (5 mL) was added cesium carbonate (0.65 g, 2.0 mmol) followed by 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.13 g, 0.67 mmol) at RT and stirred at 65℃ for 5 h. The reaction mass was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 30% EtOAc in hexane as an eluent to get the title compound (0.21 g, 58.9%). LC-MS: 357 [M+H]+.

[0133] Step-6: 5-(1-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 1) 　　　To a stirred solution of N-isopropyl-N-methyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-amine (0.16 g, 0.45 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added 5-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.08 g, 0.35 mmol) followed by sodium carbonate (0.12 g, 1.13 mmol). The reaction mass was degassed with purging argon for 15 min then PdCl2(dppf).DCM (0.03 g, 0.03 mmol) was added thereto and stirred at 100℃ for 12 h. The reaction mass was diluted with EtOAc, filtered through Celite, and the filtrate was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 80% EtOAc in hexane as an eluent to get the title compound (0.08 g, 60.3%). LC-MS: 377 [M+H]+;1H-NMR (400 MHz, CD3OD) δ 8.04-8.03 (d, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 7.48-7.46 (dd, 1H), 7.29-7.26 (dd, 1H), 7.20-7.19 (d, 1H), 7.07-7.05 (d, 1H), 6.64-6.62 (d, 1H), 5.18 (s, 2H), 4.86-4.67 (m, 1H), 3.36 (s, 3H), 2.82 (s, 3H), 1.16-1.14 (d, 6H).

[0134] Example-2

[0135]

[0136] Step-1: Methyl (S)-6-((3,3-difluorocyclopentyl)amino)nicotinate 　　　To a stirred solution of methyl 6-chloronicotinate (1 g, 5.82 mmol) in DMSO (10 mL) was added DIPEA (4.5 g, 34.8 mmol) followed by (S)-3,3-difluorocyclopentan-1-amine hydrochloride (1 g, 6.34 mmol) at RT and stirred at 120℃ for 16 h. The reaction mass was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 30% EtOAc in hexane as an eluent to get the title compound (1 g, 67.1%). LC-MS: 257 [M+H]+.

[0137] Step-2: Methyl (S)-6-((3,3-difluorocyclopentyl)(methyl)amino)nicotinate 　　　To a stirred solution of methyl (S)-6-((3,3-difluorocyclopentyl)amino)nicotinate (1 g, 3.9 mmol) in DMF (5 mL) was added NaH (60% dispersion in mineral oil)(0.23 g, 5.85 mmol) followed by dropwise addition of iodomethane (0.66 g, 4.65 mmol) at 0℃ and stirred at RT for 2 h. The reaction mass was quenched with ice cold water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 20% EtOAc in hexane as an eluent to get the title compound (0.9 g, 85.3%). LC-MS: 271 [M+H]+.

[0138] Step-3: (S)-(6-((3,3-Difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methanol 　　　To a stirred solution of methyl (S)-6-((3,3-difluorocyclopentyl)(methyl)amino)nicotinate (0.9 g, 3.3 mmol) in THF (10 mL) was added LiBH4(0.29 g, 13.2 mmol) in portions at 0℃ and stirred at RT for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to get the title compound. (0.8 g, 99.2%). LC-MS: 243 [M+H]+

[0139] Step-4: (S)-5-(Chloromethyl)-N-(3,3-difluorocyclopentyl)-N-methylpyridin-2-amine 　　　To a stirred solution of (S)-(6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methanol (0.8 g, 3.3 mmol) in DCM (8 mL) was added SOCl2(3.9 g, 32.7 mmol) at 0℃ and stirred at 65℃ for 16 h. The reaction mixture was concentrated to get the title compound (0.8 g, 93%).1H-NMR (400 MHz, CDCl3) δ 8.26-8.24 (d, 1H), 7.97-7.95 (dd, 1H), 7.02-7.00 (d, 1H), 5.28-5.26 (m, 1H), 4.54 (s, 2H), 3.24 (s, 3H), 2.80-1.90 (m, 6H).

[0140] Step-5: (S)-N-(3,3-Difluorocyclopentyl)-N-methyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-amine 　　　To a stirred solution of (S)-5-(chloromethyl)-N-(3,3-difluorocyclopentyl)-N-methylpyridin-2-amine (0.6 g, 2.3 mmol) in MeCN (10 mL) was added cesium carbonate (2.2 g, 6.75 mmol) followed by 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.45 g, 2.3 mmol) at RT and stirred at 65℃ for 5 h. The reaction mass was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 40% EtOAc in hexane as an eluent to get the title compound (0.7 g, 73%). LC-MS: 419 [M+H]+.

[0141] Step-6: (S)-5-(1-((6-((3,3-Difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of (S)-N-(3,3-difluorocyclopentyl)-N-methyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-amine (0.32 g, 0.76 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL) was added 5-bromo-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (0.27 g, 0.76 mmol) followed by sodium carbonate (0.16 g, 1.52 mmol). The reaction mass was degassed with purging argon for 15 min. Then PdCl2(dppf).DCM (0.12 g, 0.14 mmol) was added thereto and stirred at 110℃ for 18 h. The reaction mass was diluted with EtOAc, filtered through Celite, and the filtrate was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 50% EtOAc in hexane as an eluent to get the title compound (0.18 g, 41.7%). LC-MS: 569 [M+H]+.

[0142] Step-7: (S)-5-(1-((6-((3,3-Difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 2) 　　　To a stirred solution of (S)-5-(1-((6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (0.17 g, 0.3 mmol) in DCM (4 mL) was added TFA (2 mL) at 0℃ and stirred at RT for 2 h. The reaction mixture was concentrated to remove TFA and DCM. To the residue was added 1,4-dioxane (3 mL) followed by 25% aqueous solution of NH4OH (3 mL) and stirred at 55°C for 2 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC using Method A to afford the title compound (0.05 g, 38%). LC-MS: 439 [M+H]+;1H-NMR (400 MHz, CD3OD) δ 8.12-8.11 (d, 1H), 7.99-7.98 (d, 1H), 7.81-7.80 (d, 1H), 7.56-7.53 (dd, 1H), 7.34-7.30 (dd, 1H), 7.24-7.23 (d, 1H), 7.10-7.09 (dd, 1H), 6.71-6.69 (d, 1H), 5.31-5.29 (m, 1H), 5.24 (s, 2H), 3.41 (s, 3H), 2.92 (s, 3H), 2.39-2.29 (m, 1H), 2.26-2.15 (m, 2H), 2.13-1.98 (m, 3H).

[0143] Example-3

[0144]

[0145] Step-1: 1-(4-(Isopropyl(methyl)amino)phenyl)ethan-1-ol 　　　To a stirred solution of 4-(isopropyl(methyl)amino)benzaldehyde (0.7 g, 3.94 mmol) in THF (20 mL) was added methyl magnesium chloride (0.59 g, 7.89 mmol, 3 M in THF) at 0℃ and stirred at RT for 1 h. To the reaction mass was added aqueous solution of NH4Cl and extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 20% EtOAc in hexane as an eluent to get the title compound (0.4 g, 52.3%). LC-MS: 194 [M+H]+

[0146] Step-2: N-Isopropyl-N-methyl-4-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)aniline 　　　To a stirred solution of 1-(4-isopropyl(methyl)amino)phenyl)ethan-1-ol (0.2 g, 1.04 mmol) in THF (5 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.17 g, 0.87 mmol). To the mixture was added TPP (0.23 g, 0.87 mmol) followed by dropwise addition of DIAD (0.21 g, 1.05 mmol) at 0℃ and stirred at RT for 4 h. The reaction mass was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 50% EtOAc in hexane as an eluent to get the title compound (0.03 g, 7.8%). LC-MS: 370 [M+H]+.

[0147] Step-3: 5-(1-(1-(4-(Isopropyl(methyl)amino)phenyl)ethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzimidazol-2-one (Compound 3) 　　　 To a stirred solution of N-isopropyl-N-methyl-4-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)aniline (0.2 g, 0.54 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was added 5-bromo-1,3-dihydro-2H-benzimidazol-2-one (0.14 g, 0.65 mmol) followed by sodium carbonate (0.12 g, 1.1 mmol). The reaction mass was degassed with purging argon for 15 min. Then PdCl2(dppf).DCM (0.03 g, 0.03 mmol) was added thereto and stirred at 110℃ for 18 h. The reaction mass was diluted with EtOAc, filtered through Celite, and the filtrate was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC using Method A to afford the title compound (0.01 g, 4.9%). LC-MS: 376 [M+H]+;1H-NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.79-7.78 (d, 1H), 7.26-7.23 (d, 1H), 7.21-7.17 (m, 3H), 7.04-7.02 (d, 1H), 6.86 (bs, 2H), 5.51-5.50 (m, 1H), 4.12-4.10 (m, 1H), 2.75 (s, 3H), 1.90-1.88 (d, 3H), 1.86-1.82 (d, 6H). Example-4

[0148]

[0149] Step-1: Methyl 6-((3,3-difluorocyclobutyl)amino)nicotinate 　　　To a stirred solution of methyl 6-chloronicotinate (0.5 g, 2.92 mmol) in DMSO (8 mL) was added DIPEA (1.13 g, 8.78 mmol) followed by 3,3-difluorocyclobutan-1-amine hydrochloride (0.42 g, 2.92 mmol) and stirred at 120℃ for 3 h under microwave irradiation. The reaction mass was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 20% EtOAc in hexane as an eluent to get the title compound (0.2 g, 28.2%), LC-MS: 243 [M+H]+

[0150] Step-2: Methyl 6-((3,3-difluorocyclobutyl)(methyl)amino)nicotinate 　　　To a stirred solution of methyl 6-((3,3-difluorocyclobutyl)amino)nicotinate (0.4 g, 1.65 mmol) in DMF (8 mL) was added NaH (60% dispersion in mineral oil)(0.1 g, 2.4 mmol) followed by dropwise addition of iodomethane (0.28 g, 1.98 mmol) at 0℃ and stirred at RT for 1 h. The reaction mass was quenched with ice cold water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 20% EtOAc in hexane as an eluent to get the title compound (0.3 g, 70.9%), LC-MS: 257 [M+H]+ Step-3: (6-((3,3-Difluorocyclobutyl)(methyl)amino)pyridin-3-yl)methanol 　　　To a stirred solution of methyl 6-((3,3-difluorocyclobutyl)(methyl)amino)nicotinate (0.27 g, 1.05 mmol) in THF (8 mL) was added LiBH4(0.09 g, 4.2 mmol) in portions at 0℃ and stirred at RT for 12 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to afford the title compound (0.2 g, 83.3%). LC-MS: 229 [M+H]+

[0151] Step-4: 5-(Chloromethyl)-N-(3,3-difluorocyclobutyl)-N-methylpyridin-2-amine 　　　To a stirred solution of (6-((3,3-difluorocyclobutyl)(methyl)amino)pyridin-3-yl)methanol (0.2 g, 0.88 mmol) in DCM (4 mL) was added SOCl2(1.05 g, 8.7 mmol) at 0°C and stirred at RT for 2 h. The reaction mixture was concentrated to get the title compound (0.2 g, 92.1%).1H-NMR (400 MHz, DMSO-D6) δ 8.12-8.10 (d, 1H), 7.98-7.96 (dd, 1H), 7.12-7.10 (d, 1H), 4.78 (s, 2H), 4.64-4.62 (m, 1H), 3.06 (s, 3H), 3.02-3.0 (m, 2H), 2.98-2.96 (m, 2H).

[0152] Step-5: N-(3,3-Difluorocyclobutyl)-N-methyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-amine 　　　To a stirred solution of 5-(chloromethyl)-N-(3,3-difluorocyclobutyl)-N-methylpyridin-2-amine (0.2 g, 0.81 mmol) in MeCN (6 mL) was added cesium carbonate (0.53 g, 1.62 mmol) followed by addition of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.16 g, 0.81 mmol) at RT and stirred at 65℃ for 16 h. The reaction mass was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 50% EtOAc in hexane as an eluent to get the title compound (0.19 g, 57.9%). LC-MS: 405 [M+H]+

[0153] Step-6: 1-(3-((tert-Butyldimethylsilyl)oxy)propyl)-5-(1-((6-((3,3-difluorocyclobutyl) (methyl)amino)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzimidazole-2-one 　　　To a stirred solution of N-(3,3-difluorocyclobutyl)-N-methyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-amine (0.29 g, 0.72 mmol) in 1,4-dioxane (8 mL) and water (1 mL) was added 5-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1,3-dihydro-2H-benzimidazol-2-one (0.42 g, 1.08 mmol) followed by sodium carbonate (0.16 g, 1.49 mmol). The reaction mass was degassed with purging argon for 15 min. Then PdCl2(dppf).DCM (0.06 g, 0.07 mmol) was added thereto and stirred at 110℃ for 12 h. The reaction mass was diluted with EtOAc, filtered through Celite, and the filtrate was washed with water, dried over anhydrous Na2SO4, and concentrated to get the title compound. (0.4 g, 95.5%). LC-MS: 583 [M+H]+

[0154] Step-7: 5-(1-((6-((3,3-Difluorocyclobutyl)(methyl)amino)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxypropyl)-1,3-dihydro-2H-benzimidazol-2-one (Compound 4) 　　　To a stirred solution of 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-(1-((6-((3,3-difluorocyclobutyl)(methyl)amino)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzimidazol-2-one (0.4 g, 0.69 mmol) in 1,4-dioxane (5 mL) was added 4 M HCl in 1,4-dioxane (4 mL) at 0℃ and stirred at RT for 2 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC using Method A to afford the title compound (0.02 g, 6.2%). LC-MS: 469 [M+H]+;1H-NMR (400 MHz, CD3OD) δ 8.15-8.14 (d, 1H), 7.99-7.98 (d, 1H), 7.81-7.80 (d, 1H), 7.57-7.54 (dd, 1H), 7.32-7.29 (dd, 1H), 7.24-7.20 (d, 1H), 7.18-7.16 (d, 1H), 6.73-6.70 (d, 1H), 5.25 (s, 2H), 4.87-4.63 (m, 1H), 4.01-3.99 (t, 2H), 3.63-3.60 (t, 2H), 3.01 (s, 3H), 2.93-2.90 (m, 2H), 2.88-2.72 (m, 2H), 1.99-1.94 (m, 2H).

[0155] Example-5

[0156]

[0157] Step-1: 5-Bromo-N-(cis-3-(trifluoromethyl)cyclobutyl)pyridin-2-amine 　　　To a stirred solution of 5-bromo-2-fluoropyridine (0.5 g, 2.84 mmol) in DMSO (3 mL) was added DIPEA (1.1 g, 8.52 mmol) followed by cis-3-(trifluoromethyl)cyclobutan-1-amine hydrochloride (0.65 g, 3.69 mmol) at RT and stirred at 100℃ for 12 h. The reaction mixture was poured into ice cold water, and the solid precipitated was collected by filtration and dried. The solid was purified by combi flash column chromatography using 10% EtOAc in hexane as an eluent to get the title compound (0.42 g, 50.1%). LC-MS: 295 [M+H]+

[0158] Step-2: 5-Bromo-N-methyl-N-(cis-3-(trifluoromethyl)cyclobutyl)pyridin-2-amine 　　　To a stirred solution of 5-bromo-N-(cis-3-(trifluoromethyl)cyclobutyl)pyridin-2-amine (0.4 g, 1.35 mmol) in DMF (2 mL) was added NaH (60% dispersion in mineral oil)(0.16 g, 4.06 mmol) followed by dropwise addition of iodomethane (0.39 g, 2.71 mmol) at 0℃ and stirred at RT for 2 h. The reaction mass was quenched with ice cold water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 10% EtOAc in hexane as an eluent to get the title compound (0.36 g, 83.9%). LC-MS: 309 [M+H]+

[0159] Step-3: Ethyl 2-(6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)acetate 　　　To a stirred solution of 5-bromo-N-methyl-N-(cis-3-(trifluoromethyl)cyclobutyl)pyridin-2-amine (0.36 g, 1.13 mmol) in 1,3,5-trimethylbenzene (5 mL), was added DMAP (0.01 g, 0.11 mmol) followed by monoethyl potassium malonate (0.3 g 1.76 mmol). The reaction mass was degassed with purging argon for 15 min. Then BINAP (0.04 g, 0.06 mmol) was added thereto followed by allylpalladium (II) chloride dimer (0.04 g, 0.11 mmol) and stirred at 140℃ for 12 h. The reaction mass was diluted with DCM, filtered through Celite, and the filtrate was concentrated. The residue was purified by combi flash chromatography using 10% EtOAc in hexane as an eluent to get the title compound (0.13 g, 36.4%), LC-MS: 317 [M+H]+

[0160] Step-4: 2-(6-(Methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)acetohydrazide 　　　To a stirred solution of ethyl 2-(6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)acetate (0.13 g, 0.41 mmol) in EtOH (5 mL) was added hydrazine hydrate (0.06 g, 1.23 mmol) at RT and stirred at 70℃ for 12 h. The reaction mass was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4and concentrated to get the title compound (0.12 g, 96.7%). LC-MS: 303 [M+H]+

[0161] Step-5: 1-Methyl-N'-(2-(6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)acetyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbohydrazide 　　　To a stirred solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.08 g, 0.41 mmol) in DMF (4 mL) was added EDC.HCl (0.08 g, 0.41 mmol), HOBt (0.05 g, 0.41 mmol) and stirred at RT for 10 min. To the mixture was added 2-(6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)acetohydrazide (0.12 g, 0.41 mmol) followed by triethylamine (0.16 g, 1.64 mmol) and stirred at RT for 12 h. The reaction mixture was diluted with ice cold water, and the solid precipitated was collected by filtration and dried to get the title compound. (0.07 g, 36%). LC-MS: 477 [M+H]+

[0162] Step-6: 1-Methyl-5-(5-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-1,3,4-oxadiazol-2-yl)-1,3-dihydro-2H-benzimidazol-2-one (Compound 5) 　　　To a stirred solution of 1-methyl-N'-(2-(6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)acetyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbohydrazide (0.05 g, 0.1 mmol) in THF (5 mL) was added (1E)-1-methoxy-N-(triethylazaniumyl)sulfonylmethanimidate (Burgess reagent) (0.08 g, 0.31 mmol) and stirred at 150℃ for 2 h under microwave irradiation. The reaction mass was concentrated and the residue was purified by Preparative TLC using 4% MeOH in DCM as an eluent to get the title compound (0.02 g, 41.5%), LC-MS: 459 [M+H]+1H-NMR (400 MHz, CD3OD) δ 8.15-8.12 (d, 1H), 7.80-7.77 (dd, 1H), 7.68-7.67 (d, 1H), 7.61-7.58 (dd, 1H), 7.28-7.26 (d, 1H), 6.74-6.71 (d, 1H), 4.84-4.82 (m, 1H), 4.22 (s, 2H), 3.45 (s, 3H), 3.01 (s, 3H), 3.83-2.81 (m, 1H), 2.52-2.45 (m, 2H), 2.37-2.35 (m, 2H).

[0163] Example-6

[0164]

[0165] Step-1: Methyl 6-((3,3-difluorocyclopentyl)amino)nicotinate 　　　To a stirred solution of methyl 6-chloronicotinate (0.5 g, 2.91 mmol) in DMSO (5 mL) was added DIPEA (1.13 g, 8.74 mmol) followed by 3,3-difluorocyclopentan-1-amine hydrochloride (0.55 g, 3.5 mmol) at RT and stirred at 100℃ for 12 h. The reaction mixture was poured into ice cold water, and the solid precipitated was collected by filtration and dried. The solid was purified by combi flash column chromatography using 20% EtOAc in hexane as an eluent to get the title compound (0.6 g, 80.5%). LC-MS: 257 [M+H]+

[0166] Step-2: Methyl 6-((3,3-difluorocyclopentyl)(methyl)amino)nicotinate 　　　To a stirred solution of methyl 6-((3,3-difluorocyclopentyl)amino)nicotinate (0.6 g, 2.34 mmol) in DMF (5 mL) was added NaH (60% dispersion in mineral oil)(0.28 g, 7.02 mmol) followed by dropwise addition of iodomethane (0.5 g, 3.51 mmol) at 0℃ and stirred at RT for 1 h. The reaction mass was quenched with ice cold water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to get the title compound (0.6 g, 95.2%). LC-MS: 271 [M+H]+

[0167] Step-3: (6-((3,3-Difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methanol 　　　To a stirred solution of methyl-6-((3,3-difluorocyclopentyl)(methyl)amino)nicotinate (0.6 g, 2.22 mmol) in THF (15 mL) was added LiBH4(0.19 g, 8.88 mmol) in portions at 0℃ and stirred at RT for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 40% EtOAc in hexane as an eluent to get the title compound (0.47 g, 87.5%). LC-MS: 243 [M+H]+

[0168] Step-4: 6-((3,3-Difluorocyclopentyl)(methyl)amino)nicotinaldehyde 　　　To a stirred solution of (6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methanol (0.47 g, 1.94 mmol) in DMSO (10 mL) was added SIBX (1.08 g, 3.88 mmol) in portions at 0℃ and stirred at RT for 4 h. The reaction mass was quenched with saturated sodium bicarbonate solution, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to get the title compound (0.45 g, 96.7%). LC-MS: 241 [M+H]+.

[0169] Step-5: 1-(6-((3,3-Difluorocyclopentyl)(methyl)amino)pyridin-3-yl)-3-(trimethylsilyl)prop-2-yn-1-ol 　　　To a stirred solution of ethynyltrimethylsilane (0.37 g, 3.74 mmol) in THF (5 mL) was added n-BuLi in THF(0.36 g, 5.61 mmol, 1.6 M solution) at -78℃. Then 6-((3,3-difluorocyclopentyl)(methyl)amino)nicotinaldehyde (0.45 g, 1.87 mmol) was added thereto and stirred at RT for 12 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 20% EtOAc in hexane as an eluent to get the title compound (0.4 g, 63.3%). LC-MS: 339 [M+H]+.

[0170] Step-6: 5-(4-((6-((3,3-Difluorocyclopentyl)(methyl)amino)pyridin-3-yl)(hydroxy)methyl)-1H-1,2,3-triazol-1-yl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (0.28 g, 0.69 mmol) in MeOH (20 mL) was added Cu(OAc)2(0.01 g, 0.07 mmol) followed by NaN3(0.09 g 1.38 mmol) and stirred at 55℃ for 2 h. The reaction mass was cooled to RT and to the mixture were added 1-(6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)-3-(trimethylsilyl)prop-2-yn-1-ol (0.24 g, 0.69 mmol) and sodium ascorbate (0.03 g, 0.13 mmol) followed by sodium methoxide (0.04 g, 0.69 mmol). The mixture was stirred at RT for 24 h under oxygen atmosphere. The reaction mass was diluted with MeOH, filtered through Celite and the filtrate was concentrated. The residue was purified by combi flash chromatography using 40% EtOAc in hexane as an eluent to get the title compound (0.32 g, 79.4%), LC-MS: 586 [M+H]+.

[0171] Step-7: 5-(4-((6-((3,3-Difluorocyclopentyl)(methyl)amino)pyridin-3-yl)(hydroxy)methyl)-1H-1,2,3-triazol-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 5-(4-((6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)(hydroxy)methyl)-1H-1,2,3-triazol-1-yl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (0.32 g, 0.55 mmol) in 1,4-dioxane (5 mL) was added TFA (5 mL) at 0℃ and stirred at RT for 1 h. The reaction mixture was concentrated to remove TFA. To the residue was added 1,4-dioxane (5 mL) followed by 25% aqueous solution of NH4OH (5 mL) and stirred at 60°C for 3 h. The reaction mixture was concentrated to get the title compound. (0.23 g, 92%). LC-MS: 456 [M+H]+.

[0172] Step-8: 5-(4-((6-((3,3-Difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1H-1,2,3-triazol-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 6) 　　　To a stirred solution of 5-(4-((6-((3,3-difluorocyclopentyl)(methyl)amino)pyridin-3-yl)(hydroxy)methyl)-1H-1,2,3-triazol-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.23 g, 0.5 mmol) in acetic acid (5 mL) were added aqueous 37% HCl (2 mL) and Pd / C (0.07 g) and stirred at RT for 12 h under hydrogen bladder pressure. The reaction mass was filtered through Celite, and the filtrate was concentrated. The residue was purified by preparative HPLC using Method A to afford the title compound (0.06 g, 27.3%). LC-MS: 440 [M+H]+;1H-NMR (400 MHz, DMSO-D6) δ 11.18 (s, 1H), 8.51 (s, 1H), 8.07-8.06 (d, 1H), 7.53-7.44 (m, 3H), 7.25-7.24 (d, 1H), 6.71-6.69 (bs, 1H), 5.29-5.25 (m, 1H), 3.94 (s, 2H), 3.34 (s, 3H), 2.84 (s, 3H), 2.33-2.16 (m, 4H), 2.15-2.07 (m, 2H). Example-7

[0173]

[0174] Step-1: 6-(Isopropyl(methyl)amino)nicotinaldehyde 　　　To a stirred solution of (6-(isopropyl(methyl)amino)pyridin-3-yl)methanol (1 g, 5.54 mmol) in DMSO (10 mL) was added SIBX (3.1 g, 11.08 mmol) in portions at 0℃ and stirred at RT for 12 h. The reaction mass was quenched with saturated sodium bicarbonate, solution, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by combi flash column chromatography using 20% EtOAc in hexane as an eluent to get the title compound (0.95 g, 96.4%).1H-NMR (400 MHz, DMSO-D6) δ 9.65 (s, 1H), 7.68-7.66 (d, 1H), 6.87-6.86 (d, 2H), 4.28-4.26 (m, 1H), 2.82 (s, 3H), 1.19-1.18 (d, 6H).

[0175] Step-2: 1-(6-(Isopropyl(methyl)amino)pyridin-3-yl)-3-(trimethylsilyl)prop-2-yn-1-ol 　　　To a stirred solution of 6-(isopropyl(methyl)amino)nicotinaldehyde (0.5 g, 2.82 mmol) in THF (7 mL) was added n-BuLi in THF(0.54 g, 8.46 mmol, 1.6 M solution) at 0℃ and stirred at RT for 1 h. Then ethynyltrimethylsilane (0.55 g, 5.64 mmol) was added thereto at -78℃ and stirred at RT for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 15% EtOAc in hexane as an eluent to get the title compound (0.45 g, 57.8%). LC-MS: 277 [M+H]+.

[0176] Step-3: 5-(4-(Hydroxy(6-(isopropyl(methyl)amino)pyridin-3-yl)methyl)-1H-1,2,3-triazol-1-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 1-(6-(isopropyl(methyl)amino)pyridin-3-yl)-3-(trimethylsilyl)prop-2-yn-1-ol (0.5 g, 1.81 mmol) in MeOH (7 mL) was added Cu(OAc)2(0.03 g, 0.18 mmol) followed by NaN3(0.12 g 1.81 mmol) and stirred at 55℃ for 2 h. The reaction mass cooled to RT and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (0.94 g, 1.81 mmol) and sodium ascorbate (0.04 g, 0.18 mmol) were added thereto followed by sodium methoxide (0.09 g, 1.81 mmol). The reaction mixture was stirred at RT for 24 h under oxygen atmosphere. The reaction mass was filtered through Celite, and the filtrate was concentrated. The residue was purified by combi flash column chromatography using 40% EtOAc in hexane as an eluent to get the title compound (0.25 g, 21.6%), LC-MS: 640 [M+H]+.

[0177] Step-4: 5-(4-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1H-1,2,3-triazol-1-yl)-1,3-dihydro-2H-benzimidazol-2-one (Compound 7) 　　　To a stirred solution of 5-(4-(hydroxy(6-(isopropyl(methyl)amino)pyridin-3-yl)methyl)-1H-1,2,3-triazol-1-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (0.22 g, 0.34 mmol) in 1,2-dichloroethane (4 mL) were added triethylsilane (0.16 g, 1.36 mmol) and TFA (0.31 g, 2.72 mmol) at RT and stirred at 70℃ for 2 h under microwave irradiation. The reaction mixture was concentrated to remove TFA. To the residue was added 1,4-dioxane (5 mL) followed by 25% aqueous solution of NH4OH (2 mL) and stirred at 55℃ for 1 h. The reaction mixture was concentrated and the residue was purified by preparative TLC using 5% MeOH in DCM to afford the title compound (0.03 g, 24.4%). LC-MS: 364 [M+H]+;1H-NMR (400 MHz, CD3OD) δ 8.20 (s, 1H), 8.02-8.01 (d, 1H), 7.52-7.44 (m, 3H), 7.19-7.17 (d, 1H), 6.68-6.65 (d, 1H), 4.75-4.60 (m, 1H), 4.01 (s, 2H), 2.85(s, 3H), 1.20-1.18 (d, 6H).

[0178] Example-8

[0179]

[0180] Step-1: Methyl 6-(isopropylamino)nicotinate 　　　To a stirred solution of methyl 6-chloronicotinate (10 g, 58.28 mmol) in DMSO (125 mL) was added DIPEA (37.66 g, 291.4 mmol) followed by propan-2-amine hydrochloride (16.71 g, 174.85 mmol) at RT and stirred at 100℃ for 12 h. The reaction mass was diluted with ice cold water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to get the title compound. (10.1 g, 89.3%). LC-MS: 195 [M+H]+.

[0181] Step-2: Methyl 6-(isopropyl(methyl)amino)nicotinate 　　　To a stirred solution of methyl 6-(isopropylamino)nicotinate (10 g, 51.48 mmol) in DMF (150 mL) was added NaH (60% dispersion in mineral oil)(3.1 g, 77.21 mmol) followed by dropwise addition of iodomethane (8.76 g, 61.78 mmol) at 0℃ and stirred at RT for 1 h. The reaction mass was quenched with ice cold water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 20% EtOAc in hexane as an eluent to get the title compound (10.65 g, 99.5%). LC-MS: 209 [M+H]+

[0182] Step-3: (6-(Isopropyl(methyl)amino)pyridin-3-yl)methanol 　　　To a stirred solution of methyl 6-(isopropyl(methyl)amino)nicotinate (10.5 g, 50.5 mmol) in THF (230 mL) was added LiBH4(4.38 g, 202.0 mmol) in portions at 0℃ and stirred at RT for 5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to get the title compound. (8.5 g, 93.1%). LC-MS: 181 [M+H]+.

[0183] Step-4: 5-(Chloromethyl)-N-isopropyl-N-methylpyridin-2-amine 　　　To a stirred solution of (6-(isopropyl(methyl)amino)pyridin-3-yl)methanol (0.6 g, 3.32 mmol) in DCM (10 mL) was added SOCl2(1.19 g, 9.98 mmol) at 0℃ and stirred at 65 °C for 16 h. The reaction mixture was concentrated to get the title compound (0.61 g, 92.4%).1H-NMR (400 MHz, DMSO-D6) δ 8.12-8.11 (d, 1H), 8.04-8.00 (dd, 1H), 7.40-7.38 (d, 1H), 4.81 (s, 2H), 4.54-4.50 (m, 1H), 3.04 (s, 3H), 1.22-1.20 (d, 6H).

[0184] Step-5: 1-Methyl-5-((triisopropylsilyl)ethynyl)-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 5-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.5 g, 2.2 mmol) in DMF (8 mL) was added NaHCO3(0.55 g, 6.6 mmol) followed by ethynyltriisopropylsilane (1.2 g, 6.6 mmol). The reaction mass was degassed with purging argon for 15 min then bis(triphenylphosphine)palladium(II) dichloride (0.15 g, 0.22 mmol) was added thereto and stirred at 120℃ for 16 h. The reaction mass was diluted with EtOAc, filtered through Celite, and the filtrate was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 50% EtOAc in hexane as an eluent to get the title compound (0.42 g, 58.3%). LC-MS: 329 [M+H]+.

[0185] Step-6: 5-Ethynyl-1-methyl-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 1-methyl-5-((triisopropylsilyl)ethynyl)-1,3-dihydro-2H-benzimidazol-2-one (0.42 g, 1.28 mmol) in THF (6 mL) was added TBAF (0.5 g, 1.91 mmol) at RT and stirred at 80℃ for 12 h. The reaction mass was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4, and concentrated to get the title compound. (0.21 g, 95.9%). LC-MS: 173 [M+H]+.

[0186] Step-7: 5-(1-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 8) 　　　To a stirred solution of 5-ethynyl-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.21 g, 1.22 mmol) in MeOH (15 mL) was added Cu(OAc)2(0.02 g, 0.12 mmol) followed by NaN3(0.12 g 1.83 mmol) and stirred at 55℃ for 2 h. The reaction mass was cooled to RT then 5-(chloromethyl)-N-isopropyl-N-methylpyridin-2-amine (0.24 g, 1.22 mmol) and sodium ascorbate (0.05 g, 0.25 mmol) were added thereto followed by sodium methoxide (0.06 g, 1.22 mmol) and stirred at 55℃ for 24 h under oxygen atmosphere. The reaction mass was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative TLC using 5% MeOH in DCM as an eluent to get the title compound (0.07 g, 15.2%), LC-MS: 378 [M+H]+;1H-NMR (400 MHz, CDCl3) δ 8.23-8.22 (d, 1H), 7.89 (bs, 1H), 7.61-7.51(d, 2H), 7.51-7.43 (dd, 2H), 6.99-6.97 (d, 1H), 6.53-6.51 (d, 1H), 5.44 (s, 2H), 4.89-4.85 (m, 1H), 3.44 (s, 3H), 2.83(s, 3H), 1.23-1.20 (d, 6H).

[0187] Example-9

[0188]

[0189] Step-1: 5-Bromo-N-isopropylpyridin-2-amine 　　　To a stirred solution of 5-bromo-2-fluoropyridine (1 g, 5.68 mmol) in DMSO (10 mL) was added potassium carbonate (1.57 g, 11.36 mmol) followed by propan-2-amine (0.5 g, 8.52 mmol) at RT and stirred at 120℃ for 16 h. The reaction mass was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to get the title compound (1.2 g, 98.7%). LC-MS: 215 [M+H]+.

[0190] Step-2: 5-Bromo-N-isopropyl-N-methylpyridin-2-amine 　　　To a stirred solution of 5-bromo-N-isopropylpyridin-2-amine (1.2 g, 5.60 mmol) in DMF (10 mL) was added NaH (60% dispersion in mineral oil)(0.27 g, 6.72 mmol) followed by dropwise addition of iodomethane (0.95 g, 6.72 mmol) at 0℃ and stirred at RT for 2 h. The reaction mass was quenched with ice cold water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 10% EtOAc in hexane as an eluent to get the title compound (1.25 g, 98.4%). LC-MS: 229 [M+H]+.

[0191] Step-3: (6-(Isopropyl(methyl)amino)pyridin-3-yl)boronic acid 　　　To a stirred solution of 5-bromo-N-isopropyl-N-methylpyridin-2-amine (0.1 g, 0.43 mmol) in 1,4-dioxane (3 mL) was added bis(pinacolato)diboron (0.11 g, 0.43 mmol) followed by potassium acetate (0.09 g, 0.87 mmol). The reaction mass was degassed with purging argon for 15 min then PdCl2(dppf).DCM (0.02 g, 0.02 mmol) was added thereto and stirred at 80℃ for 4 h. The reaction mass was diluted with EtOAc, filtered through Celite, and the filtrate was washed with water, dried over anhydrous Na2SO4, and concentrated to get the title compound. (0.08 g, 96.4%).1H-NMR (400 MHz, CD3OD) δ 8.12-8.11 (d, 1H), 7.63-7.60 (d, 1H), 6.61-6.59 (d, 1H), 4.78-4.72 (m, 1H), 2.76 (s, 3H), 1.10-1.09 (d, 6H).

[0192] Step-4: 6'-(Isopropyl(methyl)amino)-1-(4-methoxybenzyl)-[3,3'-bipyridin]-2(1H)-one 　　　To a stirred solution of (6-(isopropyl(methyl)amino)pyridin-3-yl)boronic acid (0.42 g, 2.16 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added 3-bromo-1-(4-methoxybenzyl)pyridin-2(1H)-one (0.64 g, 2.16 mmol) followed by sodium carbonate (0.68 g, 6.48 mmol). The reaction mass was degassed with purging argon for 15 min then PdCl2(dppf).DCM (0.09 g, 0.11 mmol) was added thereto and stirred at 100℃ for 16 h. The reaction mass was diluted with EtOAc, filtered through Celite, and the filtrate was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 40% EtOAc in hexane as an eluent to get the title compound (0.21 g, 26.8%). LC-MS: 364 [M+H]+.

[0193] Step-5: 6'-(Isopropyl(methyl)amino)-[3,3'-bipyridin]-2(1H)-one 　　　To TFA (2 mL) was added 6'-(isopropyl(methyl)amino)-1-(4-methoxybenzyl)-[3,3'-bipyridin]-2(1H)-one (0.35 g, 0.96 mmol) at 0℃ and stirred at 110°C for 16 h. The reaction mixture was concentrated to get the title compound. (0.2 g, 85.1%). LC-MS: 244 [M+H]+.

[0194] Step-6: 5-(6'-(Isopropyl(methyl)amino)-2-oxo-[3,3'-bipyridin]-1(2H)-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 9) 　　　To a stirred solution of 6'-(isopropyl(methyl)amino)-[3,3'-bipyridin]-2(1H)-one (0.41 g, 1.68 mmol) in DMSO (10 mL) were added potassium carbonate (0.35 g, 2.52 mmol) and CuI (0.06 g, 0.33 mmol) followed by 8-hydroxyquinoline (0.05 g, 0.33 mmol) and tert-butyl 6-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (0.7 g, 2.13 mmol) at RT and stirred at 120℃ for 96 h. The reaction mass was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC using Method B to afford the title compound (0.02 g, 3.0%). LC-MS: 390 [M+H]+;1H-NMR (400 MHz, CD3OD) δ 8.62-8.61 (d, 1H), 8.40-8.37 (dd, 1H), 7.41-7.39 (dd, 1H), 7.75-7.73 (dd, 1H), 7.44-7.42 (d, 1H), 7.29-7.27 (d, 1H), 7.18-7.14 (m, 2H), 6.65-6.62 (t, 1H), 4.49-4.47 (m, 1H), 3.47 (s, 3H), 3.14 (s, 3H), 1.39-1.37 (d, 6H).

[0195] Example-10

[0196]

[0197] Step-1: 3-Bromo-6'-(isopropyl(methyl)amino)-2H-[1,3'-bipyridin]-2-one 　　　To a stirred solution of 5-bromo-N-isopropyl-N-methylpyridin-2-amine (2.63 g, 11.49 mmol) in DMF (20 mL) were added 3-bromopyridin-2(1H)-one (2.0 g, 11.49 mmol), cesium carbonate (11.23 g, 34.48 mmol), CuI (0.43 g, 2.28 mmol) followed by 8-hydroxyquinoline (0.33 g, 2.28 mmol) at RT and stirred at 120℃ for 16 h. The reaction mass was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 50% EtOAc in hexane as an eluent to get the title compound (0.5 g, 13.6%). LC-MS: 322 [M+H]+.

[0198] Step-2: 5-(6'-(Isopropyl(methyl)amino)-2-oxo-2H-[1,3'-bipyridin]-3-yl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 3-bromo-6'-(isopropyl(methyl)amino)-2H-[1,3'-bipyridin]-2-one (0.9 g, 2.80 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (0.79 g, 1.95 mmol) followed by sodium carbonate (0.59 g, 5.57 mmol). The reaction mass was degassed with purging argon for 15 min then PdCl2(dppf).DCM (0.22 g, 0.27 mmol) was added thereto and stirred at 100℃ for 16 h. The reaction mass was diluted with EtOAc, filtered through Celite, and the filtrate was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 50% EtOAc in hexane as an eluent to get the title compound (0.32 g, 31.6%). LC-MS: 520 [M+H]+.

[0199] Step-3: 5-(6'-(Isopropyl(methyl)amino)-2-oxo-2H-[1,3'-bipyridin]-3-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 10) 　　　To a stirred solution of 5-(6'-(isopropyl(methyl)amino)-2-oxo-2H-[1,3'-bipyridin]-3-yl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (0.35 g, 0.67 mmol) in DCM (4 mL) was added TFA (2 mL) at 0℃ and stirred at RT for 1 h. The reaction mixture was concentrated to remove TFA and DCM. To the residue was added 1,4-dioxane (5 mL) followed by 25% aqueous solution of NH4OH (2 mL) and stirred at 60℃ for 4 h. The reaction mixture was concentrated. The residue was purified by preparative HPLC using Method A to afford the title compound (0.15 g, 57.1%). LC-MS: 390 [M+H]+;1H-NMR (400 MHz, CD3OD) δ 8.12-8.11 (d, 1H), 7.75-7.73 (dd, 1H), 7.62-7.59 (m, 2H), 7.48-7.47 (d, 1H), 7.41-7.39 (dd, 1H), 7.17-7.15 (d, 1H), 6.78-6.76 (d, 1H), 6.58-6.55 (t, 1H), 4.91-4.89 (m, 1H), 3.43 (s, 3H), 2.93 (s, 3H), 1.24-1.22 (d, 6H).

[0200] Example-11

[0201]

[0202] Step-1: 5-Bromo-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 5-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (1 g, 4.4 mmol) in THF (10 mL) was added NaH (60% dispersion in mineral oil)(0.18 g, 4.62 mmol) followed by dropwise addition of 2-(trimethylsilyl)ethoxy)methyl chloride (0.95 g, 5.7 mmol) at 0℃ and stirred at RT for 16 h. The reaction mass was quenched with ice cold water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was further purified by combi flash column chromatography using 10% EtOAc in hexane as an eluent to get the title compound (1 g, 63.7%).1H-NMR (400 MHz, DMSO-D6) δ 7.45-7.44 (d, 1H), 7.3-7.25 (dd, 1H), 7.17-7.14 (dd, 1H), 5.26 (s, 2H), 3.60 (s, 3H), 3.55-3.50 (m, 4H), 0.01 (s, 9H).

[0203] Step-2: 1-Methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzimidazole-5-carbonitrile 　　　To a stirred solution of 5-bromo-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (1 g, 2.79 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added KOAc (0.55 g, 5.6 mmol) followed by K4[Fe(CN)6] (0.46 g, 1.4 mmol). The reaction mass was degassed with purging argon for 15 min then XPhos (0.03 g, 0.06 mmol) was added thereto followed by Pd2(dba)3(0.03 g, 0.03 mmol) and stirred at 90°C for 16 h. The reaction mass was diluted with EtOAc, filtered through Celite, and the filtrate was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by combi flash column chromatography using 20% EtOAc in hexane as an eluent to get the title compound (0.8 g, 94.7%). LC-MS: 304 [M+H]+.

[0204] Step-3: 1-Methyl-5-(2H-tetrazol-5-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzimidazole-5-carbonitrile (0.85 g, 2.8 mmol) in DMF (5 mL) was added NH4Cl (0.6 g, 11.2 mmol) followed by NaN3(0.54 g, 8.4 mmol) at 0℃ and stirred at 120°C for 5 h. The reaction mass was quenched with 1N aqueous HCl solution, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to get the title compound. (0.78 g, 80.6%). LC-MS: 347 [M+H]+.

[0205] Step-4: 5-(2-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-2H-tetrazol-5-yl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 1-methyl-5-(2H-tetrazol-5-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (0.78 g, 2.25 mmol) in DMF (8 mL) was added K2CO3(1.09 g, 7.89 mmol) followed by 5-(chloromethyl)-N-isopropyl-N-methylpyridin-2-amine (0.61 g, 3.07 mmol) at RT and stirred at 80°C for 16 h. The reaction mass was quenched with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to get the title compound. (0.9 g, 78.9%). LC-MS: 509 [M+H]+.

[0206] Step-5: 5-(2-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-2H-tetrazol-5-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 11) 　　　To a stirred solution of 5-(2-((6-(isopropyl(methyl)amino)pyridin-3-yl)methyl)-2H-tetrazol-5-yl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (0.45 g, 0.88 mmol) in DCM (5 mL) was added TFA (4 mL) at 0℃ and stirred at RT for 3 h. The reaction mixture was concentrated to remove TFA. To the residue was added 1,4-dioxane (5 mL) followed by 25% aqueous solution of NH4OH (2 mL) and stirred at 55℃ for 1 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC using Method A to afford the title compound (0.03 g, 8.9%). LC-MS: 379 [M+H]+;1H-NMR (400 MHz, CD3OD) δ 8.22-8.21 (d, 1H), 7.91-7.88 (dd, 1H), 7.79-7.78 (d, 1H), 7.75-7.72 (dd, 1H), 7.25-7.22 (d, 1H), 6.84-6.82 (d, 1H), 5.79 (s, 2H), 4.72-4.69 (m, 1H), 3.44 (s, 3H), 2.91 (s, 3H), 1.23-1.22 (d, 6H).

[0207] Example-12

[0208]

[0209] Step-1: 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2-(trimethylsilyl) ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 5-bromo-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (5.5 g, 15.39 mmol) in 1,4-dioxane (60 mL) was added bis(pinacolato)diboron (7.81 g, 30.78 mmol) followed by potassium acetate (6.02 g, 61.33 mmol). The reaction mass was degassed with purging argon for 15 min then PdCl2(dppf).DCM (1.25 g, 1.53 mmol) was added thereto and stirred at 100℃ for 12 h. The reaction mass was diluted with EtOAc and filtered on Celite and the filtrate was concentrated. The residue was purified by combi flash column chromatography using 30% EtOAc in hexane as an eluent to get the title compound (5.2 g, 83.5%).1H-NMR (400 MHz, DMSO-D6) δ 7.93 (s, 1H), 7.46-7.45 (d, 1H), 7.19-7.17 (d, 1H), 5.27 (s, 2H), 3.53-3.49 (t, 2H), 3.34 (s, 3H), 1.16 (s, 12H), 0.85-0.82 (t, 2H), 0.01 (s, 9H).

[0210] Step-2: 5-(4-(((tert-Butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-1-methyl-3-((2-(trimethyl silyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (0.7 g, 1.73 mmol) in 1,2-dimethoxyethane (20 mL) was added 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (0.77 g, 2.59 mmol) followed by Cs2CO3(1.69 g, 5.19 mmol). The reaction mass was degassed with purging argon for 15 min then Pd(PPh3)4(0.2 g, 0.17 mmol) was added thereto and stirred at 95℃ for 12 h. The reaction mass was diluted with EtOAc and filtered through Celite and the filtrate was concentrated. The residue was purified by combi flash column chromatography using 30% EtOAc in hexane as an eluent to get the title compound (0.4 g, 45.7%).1H-NMR (400 MHz, CD3OD) δ 7.85-7.84 (d, 1H), 7.80-7.78 (dd, 1H), 7.34 (s, 1H), 7.26-7.25 (d, 1H), 5.40 (s, 2H), 4.89-4.88 (d, 2H), 3.69-3.65 (t, 2H), 3.48 (s, 3H), 0.99 (s, 9H), 0.95-0.92 (m, 2H), 0.18-0.17 (s, 6H), 0.15-0.03 (s, 9H).

[0211] Step-3: 5-(4-(Hydroxymethyl)thiazol-2-yl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (0.4 g, 0.79 mmol) in THF (7 mL) was added TBAF (0.41 g, 1.58 mmol) and stirred at RT for 2 h. The reaction mass was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4, and concentrated to get the title compound. (0.3 g, 97.1%). LC-MS: 392 [M+H]+.

[0212] Step-4: 5-(4-(Hydroxymethyl)thiazol-2-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 5-(4-(hydroxymethyl)thiazol-2-yl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (0.34 g, 0.87 mmol) in DCM (4 mL) was added TFA (2 mL) at 0℃ and stirred at RT for 1 h. The reaction mixture was concentrated to remove TFA and DCM. To the residue was added 1,4-dioxane (5 mL) followed by 25% aqueous solution of NH4OH (2 mL) and stirred at 60℃ for 1 h. The reaction mixture was concentrated to get the title compound. (0.02 g, 8.8%). LC-MS: 262 [M+H]+.

[0213] Step-5: 5-(4-(Bromomethyl)thiazol-2-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 5-(4-(hydroxymethyl)thiazol-2-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.3 g, 1.14 mmol) in DCM (10 mL) was added PBr3(0.15 g, 0.57 mmol) at 0℃ and stirred at RT for 4 h. The reaction mass was further diluted with DCM, washed with saturated Na2CO3,dried over anhydrous Na2SO4, and concentrated to get the title compound. (0.28 g, 76%). LC-MS: 324 [M+H]+.

[0214] Step-6: 5-(4-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)thiazol-2-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 12) 　　　To a stirred solution of 5-(4-(bromomethyl)thiazol-2-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.08 g, 0.25 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was added (6-(isopropyl(methyl)amino)pyridin-3-yl)boronic acid (0.05 g, 0.25 mmol) followed by K2CO3(0.07 g, 0.51 mmol). The reaction mass was degassed with purging argon for 15 min then Pd(PPh3)4(0.03 g, 0.03 mmol) was added thereto and stirred at 80℃ for 12 h. The reaction mass was diluted with EtOAc and filtered through Celite and the filtrate was concentrated. The residue was purified by preparative HPLC using Method B to get the title compound (0.03 g, 30.5%). LC-MS: 394 [M+H]+;1H-NMR (400 MHz, CD3OD) δ 8.05-8.04 (dd, 1H), 7.93-7.92 (d, 1H), 7.78-7.77 (dd, 1H), 7.71-7.70 (d, 1H), 7.45 (s, 1H), 7.38-7.36 (d, 1H), 7.28-7.26 (d, 1H), 4.47-4.40 (m, 1H), 4.20 (s, 2H), 3.45 (s, 3H), 3.01 (s, 3H), 1.36-1.34 (d, 6H).

[0215] Example-13

[0216]

[0217] Step-1: N'-Hydroxy-2-(6-(isopropyl(methyl)amino)pyridin-3-yl)acetimidamide 　　　To 2-(6-(Isopropyl(methyl)amino)pyridin-3-yl)acetonitrile (0.25 g, 1.32 mmol) was added hydroxylamine solution (0.18 g, 2.64 mmol, 50 wt. % in H2O) at RT and stirred at 65℃ for 12 h. The reaction mass was concentrated to get the title compound (0.24 g, 81.9%). LC-MS: 223 [M+H]+.

[0218] Step-2: 2-(6-(Isopropyl(methyl)amino)pyridin-3-yl)-N'-((1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonyl)oxy)acetimidamide 　　　To a stirred solution of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (0.17 g, 0.9 mmol) in DMF (6 mL) was added EDC.HCl (0.16 g, 0.86 mmol) followed by HOBt (0.05 g, 0.4 mmol) and stirred at RT for 10 min. Then N'-hydroxy-2-(6-(isopropyl(methyl)amino)pyridin-3-yl)acetimidamide (0.2 g, 0.9 mmol) was added thereto followed by triethylamine (0.45 g, 4.5 mmol) and stirred at RT for 12 h. The reaction mixture was diluted with ice cold water, and the solid precipitated was collected by filtration and dried to get the title compound (0.25 g, 71.4%). LC-MS: 397 [M+H]+

[0219] Step-3: 5-(3-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1,2,4-oxadiazol-5-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 13) 　　　To a stirred solution of 2-(6-(isopropyl(methyl)amino)pyridin-3-yl)-N'-((1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonyl)oxy)acetimidamide (0.25 g, 0.63 mmol) in THF (5 mL) was added TBAF (0.33 g, 1.26 mmol) at RT and stirred at 120℃ in microwave for 1 h. The reaction mass was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4, and concentrated to get crude compound. This was purified by preparative HPLC using Method A to afford the title compound (0.04 g, 16.8%). LC-MS: 379 [M+H]+;1H-NMR (400 MHz, DMSO-D6) δ 11.23 (s, 1H), 8.07-8.06 (d, 1H), 7.81-7.78 (dd, 1H), 7.58-7.57 (d, 1H), 7.48-7.45 (dd, 1H), 7.31-7.29 (d, 1H), 6.60-6.58 (d, 1H), 4.82-4.79 (m, 1H), 3.97 (s, 2H), 3.34 (s, 3H), 2.76 (s, 3H), 1.10-1.09 (d, 6H).

[0220] Example-14

[0221]

[0222] Step-1: N'-Hydroxy-1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzimidazole-5-carboximidamide 　　　To 1-Methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzimidazole-5-carbonitrile (0.4 g, 1.31 mmol) was added hydroxylamine solution (0.43 g, 6.55 mmol, 50 wt. % in H2O ) at RT and stirred at 65℃ for 12 h. The reaction mass concentrated to get the title compound (0.41 g, 93.2%). LC-MS: 337 [M+H]+.

[0223] Step-2: N'-(2-(6-(Isopropyl(methyl)amino)pyridin-3-yl)acetoxy)-1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzimidazole-5-carboximidamide 　　　To a stirred solution of 2-(6-(isopropyl(methyl)amino)pyridin-3-yl)acetic acid (0.18 g, 0.89 mmol) in DMF (6 mL) was added EDC.HCl (0.16 g, 0.84 mmol) followed by HOBt (0.04 g, 0.26 mmol) and stirred at RT for 10 min. Then N'-hydroxy-1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzimidazole-5-carboximidamide (0.3 g, 0.89 mmol) was added thereto followed by triethylamine (0.45 g, 4.46 mmol) and stirred at RT for 12 h. The reaction mixture was added into ice cold water, and the precipitate formed was collected by filtration and dried to afford the title compound. (0.2 g, 42.7%) LC-MS: 527 [M+H]+

[0224] Step-3: 5-(5-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1,2,4-oxadiazol-3-yl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of N'-(2-(6-(isopropyl(methyl)amino)pyridin-3-yl)acetoxy)-1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzimidazole-5-carboximidamide (0.12 g, 0.23 mmol) in DMF (4 mL) was added p-toluenesulfonic acid (0.08 g, 0.46 mmol) at RT and stirred at 80℃ for 2 h. The reaction mass was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to get the title compound. (0.09 g, 82.9%). LC-MS: 509 [M+H]+.

[0225] Step-4: 5-(5-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1,2,4-oxadiazol-3-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 14) 　　　To a stirred solution of 5-(5-((6-(isopropyl(methyl)amino)pyridin-3-yl)methyl)-1,2,4-oxadiazol-3-yl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (0.15 g, 0.29 mmol) in DCM (4 mL) was added TFA (2 mL) at 0℃ and stirred at RT for 1 h. The reaction mixture was concentrated to remove TFA and DCM. To the residue, 1,4-dioxane (5 mL) was added followed by 25% aqueous solution of NH4OH (2 mL) and stirred at 60℃ for 1 h. The reaction mixture was concentrated to get a crude compound. This was purified by preparative HPLC using Method A to afford the title compound (0.02 g, 17.9%). LC-MS: 379 [M+H]+;1H-NMR (400 MHz, CD3OD) δ 8.06-8.05 (d, 1H), 7.86-7.82 (dd, 1H), 7.78-7.75 (dd, 1H), 7.72-7.71 (d, 1H), 7.22-7.19 (d, 1H), 6.96-6.94 (d, 1H), 4.63-4.59 (m, 1H), 4.27 (s, 2H), 3.44 (s, 3H), 2.96 (s, 3H), 1.27-1.25 (d, 6H).

[0226] Preparation-1

[0227]

[0228] Step-1: 2-(6-(Isopropyl(methyl)amino)pyridin-3-yl)acetonitrile 　　　To a stirred solution of (6-(isopropyl(methyl)amino)pyridin-3-yl)methanol (1 g, 5.54 mmol) in THF (15 mL) was added 2-hydroxy-2-methylpropanenitrile (1.41 g, 16.64 mmol) at RT. Then TPP (3.63 g, 13.87 mmol) was added thereto followed by dropwise addition of DIAD (2.8 g, 13.87 mmol) at 0℃ and stirred at RT for 16 h. The reaction mass was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to get a crude compound. This was purified by combi flash column chromatography using 50% EtOAc in hexane as an eluent to get the title compound (1.01 g, 96.2%). LC-MS: 190 [M+H]+

[0229] Step-2: 5-((2H-Tetrazol-5-yl)methyl)-N-isopropyl-N-methylpyridin-2-amine 　　　To a stirred solution of 2-(6-(isopropyl(methyl)amino)pyridin-3-yl)acetonitrile (1 g, 5.28 mmol) in DMF (10 mL) was added NH4Cl (1.13 g, 21.14 mmol) followed by NaN3(1.03 g, 15.84 mmol) at 0℃ and stirred at 120°C for 16 h. The reaction mass was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to get a crude compound. This was purified by combi flash column chromatography using 50% EtOAc in hexane as an eluent to get the title compound (0.4 g, 32.6%). LC-MS: 233 [M+H]+

[0230] Preparation-2

[0231]

[0232] Step-1: 4-Iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole 　　　To a stirred solution of 4-iodo-1H-imidazole (0.5 g, 2.57 mmol) in THF (5 mL) was added NaH (60% dispersion in mineral oil)(0.12 g, 3.09 mmol) at 0℃ and stirred at RT for 15 min. Then 2-(trimethylsilyl)ethoxy)methyl chloride (0.55 g, 3.35 mmol) was added thereto at RT and stirred for 16 h. The reaction mass was quenched with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to get a crude compound. This was purified by combi flash column chromatography using 30% EtOAc in hexane as an eluent to get the title compound (0.8 g, 96.0%).1H-NMR (400 MHz, CDCl3) δ 7.51-7.50 (d, 1H), 7.16-7.15 (d, 1H), 5.26 (s, 2H), 3.51-3.50 (t, 2H), 0.94-0.93 (t, 2H), 0.09 (s, 9H).

[0233] Step-2: (6-(Isopropyl(methyl)amino)pyridin-3-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanol 　　　To a stirred solution of 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (0.03 g, 0.09 mmol) in diethyl ether (3 mL) was added ethyl magnesium bromide (0.01 g, 0.11 mmol, 3 M in THF) followed by 6-(isopropyl(methyl)amino)nicotinaldehyde (0.02 g, 0.09 mmol) at 0℃ and stirred at RT for 16 h. The reaction mass was quenched with saturated ammonium chloride, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to get a crude compound. This was purified by combi flash column chromatography using 5% MeOH in DCM as an eluent to get the title compound (0.01 g, 29.4%). LC-MS: 377 [M+H]+

[0234] Step-3: 5-((1H-Imidazol-4-yl)methyl)-N-isopropyl-N-methylpyridin-2-amine 　　　To a stirred solution of (6-(isopropyl(methyl)amino)pyridin-3-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanol (1.2 g, 3.18 mmol) in TFA (2.90 g, 25.49 mmol) was added triethyl silane (2.21 g, 19.11 mmol) at RT and stirred at 65℃ for 16 h. The reaction mixture was concentrated to get the tile compound. (0.6 g, 81.8%). LC-MS: 231 [M+H]+

[0235] Preparation-3

[0236]

[0237] Step-1: 5-(2-(((tert-Butyldimethylsilyl)oxy)methyl)thiazol-4-yl)-1-methyl-3-((2-(trimethylsilyl) ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (2.5 g, 6.18 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added 4-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (1.96 g, 6.18 mmol) followed by sodium carbonate (2.62 g, 24.72 mmol). The reaction mass was degassed with purging argon for 15 min. Then PdCl2(dppf).DCM (0.4 g, 0.49 mmol) was added thereto and stirred at 100℃ for 20 h. The reaction mass was diluted with EtOAc, filtered through Celite, and the filtrate was washed with water, dried over anhydrous Na2SO4, and concentrated to get a crude compound. This was purified by combi flash column chromatography using 15% EtOAc in hexane as an eluent to get the title compound (1.4 g, 44.8%). LC-MS: 506 [M+H]+.

[0238] Step-2: 5-(2-(Hydroxymethyl)thiazol-4-yl)-1-methyl-3-((2-(trimethylsilyl)ethoxy) methyl)-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 5-(2-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-4-yl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzimidazol-2-one (0.8 g, 1.58 mmol) in 1,4-dioxane (5 mL) was added 4 M HCl in 1,4-dioxane (5 mL) at 0℃ and stirred at RT for 2 h. The reaction mixture was concentrated to get the title compound (0.36 g, 58%). LC-MS: 392 [M+H]+.

[0239] Preparation-4

[0240]

[0241] Step-1: 4-Bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-nitroaniline 　　　To a stirred solution of 4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.09 mmol) in DCM (10 mL) was added DIPEA (1.76 g, 13.63 mmol) followed by 3-((tert-butyldimethylsilyl)oxy)propan-1-amine (2.07 g, 10.91 mmol) and stirred at RT for 16 h. The reaction mass was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4and concentrated to get a crude compound. This was further purified by combi flash column chromatography using 2% EtOAc in hexane as an eluent to get the title compound (3.0 g, 84.7%). LC-MS: 389 [M+H]+.

[0242] Step-2: 4-Bromo-N1-(3-((tert-butyldimethylsilyl)oxy)propyl)benzene-1,2-diamine 　　　To a stirred solution of 4-bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-nitroaniline (1.9 g, 4.88 mmol) in THF (20 mL) was added ammonium chloride(2.09 g, 39.04 mmol) in water (8 mL) followed by zinc dust (1.28 g, 19.43 mmol) and stirred at RT for 1 h. The reaction mass was diluted with EtOAc, filtered through Celite, and the filtrate was washed with water, dried over anhydrous Na2SO4and concentrated to afford the title compound (1.5 g, 85.6%). LC-MS: 359 [M+H]+.

[0243] Step-3: 5-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1,3-dihydro-2H-benzimidazol-2-one 　　　To a stirred solution of 4-bromo-N1-(3-((tert-butyldimethylsilyl)oxy)propyl)benzene-1,2-diamine (1.5 g, 4.17 mmol) in THF (20 mL) was added 1,1'-carbonyldiimidazole (1.01 g, 6.26 mmol) and stirred at 70℃ for 8 h. The reaction mixture was concentrated and diluted with ice cold water, and the solid precipitated was collected by filtration and dried to get a crude compound. This was further purified by combi flash column chromatography using 40% EtOAc in hexane as an eluent to get the title compound (0.7 g, 43.5%). LC-MS: 385 [M+H]+.

[0244] Prep HPLC methods: Method A: Column- Waters, Xselect, c18 (250 mm x 21.2 mm), 5.0μ; Eluent-A 0.05% HCOOH in water, B-MeCN, gradient-10% B at 0 min, 30% B at 2 min, 70% B at 8 min), Flow: 13 mL / min. Method B: Column-LUNA C18 (250 mm x 19 mm), 5.0μ; Eluent-A 0.05% HCl in water, B-MeCN, gradient-10% B at 0 min, 20% B at 2 min, 50% B at 10 min, 70% B at 15 min), Flow: 18 mL / min.

[0245] Examples-15 to 57 　　　Compounds of Examples (Ex.)-15 to 57 shown in Tables 2 to 27 were prepared according to a similar manner to that of the referred Example and step. For example, the term “E1-S2” in the column “Ref.” of the table shows that the compound was prepared according to a similar manner to that of referred “E”xample- “1” - “S”tep-“2” above. It is understood that compounds can be obtained as a free form or a salt form due to isolation condition.

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272] <Biological Assays> Example-58 KIT Tyrosine Kinase Assay 　　　An in vitro assay utilizing the recombinant human KIT tyrosine kinase protein was developed to measure compound inhibition of KIT. KIT tyrosine kinase activity was measured by the ADP-Glo Kinase Assay system with poly (Glu4-Tyr) peptide substrate. Kinase Assay was performed in white 384-well plates and the luminescence was measured by Victor X5 Multilabel Counter (Perkin Elmer).

[0273] Materials and Method 　　　Recombinant intracellular domain of human KIT protein was purchased from Carna Biosciences (Kobe, Japan). Poly (Glu4-Tyr) peptide was purchased from Sigma-Aldrich (St. Louis, Missouri, USA). ADP-Glo Kinase Assay reagent was purchased from Promega (Madison, Wisconsin, USA). Each test compound was dissolved in 100% DMSO to prepare 10 mM stock solutions. Stock solutions were diluted to 400 μM, then serially diluted 1:3 in 100% DMSO to make a 9-point serial dilution. To prepare compound working solutions, each serially diluted solution 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, 50 μM Dithiothreitol (DTT). 　　　Recombinant KIT protein was diluted to 1 μM with Assay Buffer. Poly (Glu4-Tyr) peptide and ATP were diluted to 300 microgram / mL and 250 μM, respectively, with Assay Buffer, then mixed to make the substrate solution. In a 384-well plate, 2 μL of working compounds and 5 μL of recombinant KIT protein were mixed and incubated for 30 minutes at room temperature. After the preincubation, 3 μL of substrate / ATP mixture was added and incubated for 1 hour at room temperature. The tyrosine phosphorylation by KIT kinase was quantified by ADP-Glo kinase assay kit following the manufacturer’s protocol. Briefly, the phosphorylation reaction was terminated by adding 10 μL ADP-Glo reagent and incubated for 60 minutes at room temperature. 20 μL of Kinase Detection Reagent was added to each well and luminescence was measured by plate reader. The assay control for this experiment was 2.5% DMSO and Assay Buffer was used as the blank. Half maximal inhibitory concentration (IC50) was calculated by a Four Parameters Logistic Regression model using GraphPad Prism (GraphPad Software). The value without recombinant KIT protein and without test compound was used as a negative control (assay background). The value with recombinant KIT protein without test compound was a positive control (100% activity). 　　　The Table 28 below lists inhibitory effects of representative compounds of the present invention against KIT.

[0274]

[0275] Notably, the representative compounds of the present invention showed selective inhibitory activities against KIT while not exhibiting significant inhibition against other kinases.

[0276] Example-59 SCF-dependent M-07e Cell Proliferation Assay 　　　SCF-dependent cell proliferation assay was developed to measure the inhibitory potency of the compounds in M-07e cells, which express wild-type human KIT protein. The assay was performed in 96-well plates and the IC50 of each KIT inhibitor was determined by CellTiter Glo Assay reagent and Victor X5 Multilabel Counter (Perkin Elmer). Materials and Methods

[0277] M-07e cells were purchased from AcceGen Biotechnology. Cells were maintained with M-07e Growth medium: RPMI-1640 containing 20% FBS, 100 U / mL penicillin and 100 microgram / mL streptomycin, 10 ng / mL rhGM-CSF, 10 ng / mL rhSCF. M-07e cells were seeded at a density of 5000 cells / 90μL / well in 96-well plates. Test compounds were dissolved in 100% DMSO to make 20 mM stock solution and serially diluted 1:3 with 100% DMSO to make an 11-point dilution series with concentrations from 15 mM to 0.024 μM. The serially diluted compounds were then each diluted 1:50 with culture medium to obtain assay compound solutions containing 2% DMSO. Ten μL of assay compound solutions were added to the 90 μL of culture cell suspension in the 96-well plate, with a final DMSO concentration of 0.2%. The plates were then incubated in a 5% CO2incubator at 37℃ for 3 days. To obtain Day Zero Controls for background calculation, cells were seeded at 5000 cells / 100 μL in a new 96-well plate and processed on the same day. Both Day Zero controls and 3 day 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 for 15 min on a shaker at 200-300 RPM. Then 100 μL of cell lysate samples were transferred to white wall 96-well plates and luminescence was measured by a plate reader. The luminescence of Day Zero Control was subtracted from the luminescence intensity of 3 day culture readings. The assay control for this experiment was cells treated with 0.2% DMSO in culture medium and wells with 100 μL of culture medium (0.2% DMSO without cells) were used as the blank for data analysis.

[0278] The IC50 value of each compound was determined by using % inhibition by normalizing inhibition in DMSO treated control wells to 0% using the following formula method: % inhibition=100-[(Blanks subtracted L of experimental wells) / (Blanks subtracted L of 0.2% DMSO control wells )×100] *Where L is luminescence

[0279] Plot percent inhibition in proliferation of triplicates against the respective concentrations of compound and fit the dose response curve using the sigmoidal dose response equation to generate the IC50 in GraphPad Prism 8 software. 　　　The Table 29 below lists inhibitory effects of representative compounds of the present invention against the M-07e cells.

[0280]

Claims

1. A compound represented by the following Formula (I): 　or a pharmaceutically acceptable salt thereof, wherein: 　R1is hydrogen; C1-3-deuteroalkyl; C1-6-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, oxo, -NH-CO-(C1-4-alkyl), carbamoylamino, mono- or di-(C1-4-alkyl)carbamoylamino, -NH-CO-O-(C1-4-alkyl), and aryl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, and -O-(C1-4-haloalkyl), in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, and heterocyclyl; aryl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, and heterocyclyl; heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, and heterocyclyl; or heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, and heterocyclyl; 　R2is hydrogen, halogen, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, nitro, amino, or mono- or di-(C1-4-alkyl)amino, 　R3is hydrogen, hydroxy, or C1-4-alkyl, 　R4is halogen, hydroxy, nitro, amino, pentafluorothio, RA, -O-RA, -S(O)m-RA, -N(RA)(RB), or -CO-N(RA)(RC), and 　R5is hydrogen, halogen, hydroxy, nitro, amino, RA, -O-RA, -N(RA)(RB), or -CO-N(RA)(RC), or 　R4and R5are taken together to form a group of the formula: 　the wavy line indicates a point of attachment to the rest of molecule, 　R6is hydrogen, halogen, or C1-4-alkyl, 　R7is hydrogen or RA, 　R8is hydrogen, RA, or -N(RA)(RB), 　R9is hydrogen, halogen, or C1-4-alkyl, 　R10is hydrogen, halogen, or C1-4-alkyl, 　R11is hydrogen, halogen, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, nitro, amino, or mono- or di-(C1-4-alkyl)amino, 　R12is hydrogen, halogen, or C1-4-alkyl, 　L is a group of the formula: 　Q1is O or S, 　Q2is O, S, or NH, 　X1and X2are each independently N or C-R11, 　Y1and Y2are each independently N or C-R12, 　m is an integer having a value of 0, 1, or 2, 　n is an integer having a value of 0 or 1, 　RAis C1-4-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, -O-(C1-4-alkyl), mono- or di-(C1-4-alkyl)amino, C3-6-cycloalkyl, aryl, heterocyclyl, and heteroaryl, in which said C3-6-cycloalkyl, aryl, heterocyclyl, and heteroaryl may be further substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; C3-7-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino, in which said C1-4-alkyl group and C1-4-alkyl moieties may be further substituted with heterocyclyl optionally substituted with halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, or mono- or di-(C1-4-alkyl)amino; aryl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino, in which said C1-4-alkyl group and C1-4-alkyl moieties may be further substituted with heterocyclyl optionally substituted with halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, or mono- or di-(C1-4-alkyl)amino; heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino, in which said C1-4-alkyl group and C1-4-alkyl moieties may be further substituted with heterocyclyl optionally substituted with halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, or mono- or di-(C1-4-alkyl)amino; or heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino, in which said C1-4-alkyl group and C1-4-alkyl moieties may be further substituted with heterocyclyl optionally substituted with halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, or mono- or di-(C1-4-alkyl)amino; 　RBis hydrogen, C1-4-alkyl, or C3-6-cycloalkyl, and 　RCis C1-4-alkyl or C3-6-cycloalkyl, or 　RAand RCat the -CO-N(RA)(RC) are taken together with the nitrogen atom to form an N-containing heterocyclic ring optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen; C1-3-deuteroalkyl; C1-6-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, oxo, -NH-CO-(C1-4-alkyl), carbamoylamino, mono- or di-(C1-4-alkyl)carbamoylamino, -NH-CO-O-(C1-4-alkyl), and phenyl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, and -O-(C1-4-haloalkyl), in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; phenyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms or 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; or 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms, 5-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, or 9-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; RAis C1-4-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, -O-(C1-4-alkyl), and mono- or di-(C1-4-alkyl)amino; C3-7-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; phenyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms or 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; or 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms or 5-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; RBis C1-4-alkyl, and RCis C1-4-alkyl or C3-6-cycloalkyl, or 　RAand RCat the -CO-N(RA)(RC) are taken together with the nitrogen atom to form an N-containing heterocyclic ring optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein: 　R1is hydrogen; C1-3-deuteroalkyl; C1-6-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, oxo, -NH-CO-(C1-4-alkyl), carbamoylamino, mono- or di-(C1-4-alkyl)carbamoylamino, -NH-CO-O-(C1-4-alkyl), and phenyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein: R4is pentafluorothio; C1-4-haloalkyl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; or -N(RA)(RB); and R5is hydrogen, halogen, or C1-4-alkyl, or R4and R5are taken together to form a group of the formula:

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: R4is C1-4-haloalkyl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; or -N(RA)(RB); and R5is hydrogen, halogen, or C1-4-alkyl, or R4and R5are taken together to form a group of the formula: RAis isopropyl; C1-4-haloalkyl; C3-7-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; phenyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms or 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; or 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms or 5-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; and RBis methyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein: R4is trifluoromethyl; fluoroethyl; difluoroethyl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; azetidinyl or pyrrolidinyl, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; pyrazolyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; or -N(RA)(RB); R5is hydrogen, RAis isopropyl; C1-4-haloalkyl; C3-7-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; phenyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; or 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms or 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; and RBis methyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen; C1-3-deuteroalkyl; C1-6-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, oxo, -NH-CO-(C1-4-alkyl), carbamoylamino, mono- or di-(C1-4-alkyl)carbamoylamino, -NH-CO-O-(C1-4-alkyl), and phenyl; C3-6-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, and -O-(C1-4-haloalkyl), in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; phenyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms or 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; or 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms, 5-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, or 9-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), and C3-6-cycloalkyl, in which said C1-4-alkyl group and C1-4-alkyl moieties may be substituted with one or more groups selected from the group consisting of cyano, hydroxy, -O-(C1-4-alkyl), -O-(C1-4-haloalkyl), amino, mono- or di-(C1-4-alkyl)amino, 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms, and 5- or 6-membered heterocyclyl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom; R4is -N(RA)(RB); and R5is hydrogen, or R4and R5are taken together to form a group of the formula: RAis C1-4-alkyl optionally substituted with one or more groups selected from the group consisting of halogen, -O-(C1-4-alkyl), and mono- or di-(C1-4-alkyl)amino; C3-7-cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), amino, and mono- or di-(C1-4-alkyl)amino; phenyl optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; 4- to 6-membered heterocyclyl having 1 to 3 nitrogen atoms or 3- to 7-membered heterocyclyl having 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, -CO-O-(C1-4-alkyl), amino, and mono- or di-(C1-4-alkyl)amino; or 5- or 6-membered heteroaryl having 1 to 4 nitrogen atoms or 5-membered heteroaryl having 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, each of which may be substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-4-alkyl, -O-(C1-4-alkyl), C1-4-haloalkyl, -O-(C1-4-haloalkyl), C3-6-cycloalkyl, amino, and mono- or di-(C1-4-alkyl)amino; and RBis C1-4-alkyl.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein: L is a group of the formula:

9. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein: L is a group of the formula:

10. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein: L is a group of the formula:

11. The compound of claim 1, wherein the compound is selected from the group consisting of 　　　5-(1-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, 　　　(S)-5-(1-((6-((3,3-Difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, 　　　5-(1-(1-(4-(Isopropyl(methyl)amino)phenyl)ethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzimidazol-2-one, 　　　5-(1-((6-((3,3-Difluorocyclobutyl)(methyl)amino)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxypropyl)-1,3-dihydro-2H-benzimidazol-2-one, 　　　1-Methyl-5-(5-((6-(methyl(cis-3-(trifluoromethyl)cyclobutyl)amino)pyridin-3-yl)methyl)-1,3,4-oxadiazol-2-yl)-1,3-dihydro-2H-benzimidazol-2-one, 　　　5-(4-((6-((3,3-Difluorocyclopentyl)(methyl)amino)pyridin-3-yl)methyl)-1H-1,2,3-triazol-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, 　　　5-(4-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1H-1,2,3-triazol-1-yl)-1,3-dihydro-2H-benzimidazol-2-one, 　　　5-(1-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, 　　　5-(6'-(Isopropyl(methyl)amino)-2-oxo-[3,3'-bipyridin]-1(2H)-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, 　　　5-(6'-(Isopropyl(methyl)amino)-2-oxo-2H-[1,3'-bipyridin]-3-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, 　　　5-(2-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-2H-tetrazol-5-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, 　　　5-(4-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)thiazol-2-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, 　　　5-(3-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1,2,4-oxadiazol-5-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, 　　　5-(5-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1,2,4-oxadiazol-3-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, and 　　　5-(4-((6-(Isopropyl(methyl)amino)pyridin-3-yl)methyl)-1H-imidazol-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, 　or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition according to claim 12, which is a pharmaceutical composition for a treatment of a KIT mediated disease or condition.

14. Use of a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof for manufacturing a medicament for a treatment of a KIT mediated disease or condition.

15. Use of a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof for a treatment of a KIT mediated disease or condition.

16. A compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof for a treatment of a KIT mediated disease or condition.

17. 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 compounds of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

18. The method of claim 17, wherein the KIT mediated disease or condition is a 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).

19. The method of claim 18, wherein: the cancer is selected from mastocytosis, mastocytoma, solid tumor, gastrointestinal stromal tumor ("GIST"), small cell lung cancer, non-small cell lung cancer, acute myelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, colorectal carcinoma, gastric carcinoma, testicular cancer, glioblastoma, astrocytoma, melanoma, mast cell tumor, neuroblastoma, sarcoma, and seminoma; the autoimmune disease is selected from multiple sclerosis, psoriasis, intestine inflammatory disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, local and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome, nodular panarteritis, 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 venulitis, insect bite skin inflammation, and blood sucking parasitic infestation; the inflammatory disease is selected from rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and eosinophilic esophagitis; the fibrosis is selected from pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, and myelofibrosis; the metabolic disorder is selected from diabetes mellitus and its chronic complications; obesity; type I diabetes or type II diabetes; hyperlipidemias and dyslipidemias; atherosclerosis; hypertension; and cardiovascular disease; and the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, the prion diseases, motor neuron disease (MND), and amyotrophic lateral sclerosis (ALS).

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