NZ749951B - Novel pyrazole derivative as alk5 inhibitor and uses thereof - Google Patents

Novel pyrazole derivative as alk5 inhibitor and uses thereof

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Publication number
NZ749951B
NZ749951B NZ749951A NZ74995117A NZ749951B NZ 749951 B NZ749951 B NZ 749951B NZ 749951 A NZ749951 A NZ 749951A NZ 74995117 A NZ74995117 A NZ 74995117A NZ 749951 B NZ749951 B NZ 749951B
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New Zealand
Prior art keywords
pyrazolecarboxyamide
methylpyridinyl
benzo
thiazolyl
phenyl
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NZ749951A
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NZ749951A (en
Inventor
Seung Ah Jun
Young Hee Jung
Kyung Ik Lee
Ji Young Song
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Hanmi Pharmaceutical Co Ltd
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Publication date
Priority claimed from KR1020170082868A external-priority patent/KR102434226B1/en
Application filed by Hanmi Pharmaceutical Co Ltd filed Critical Hanmi Pharmaceutical Co Ltd
Priority claimed from PCT/KR2017/006940 external-priority patent/WO2018004290A1/en
Publication of NZ749951A publication Critical patent/NZ749951A/en
Publication of NZ749951B publication Critical patent/NZ749951B/en

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Abstract

The present invention relates to a novel substituted pyrazole derivative of Formula 1, having the effect of inhibiting the serine/threonine kinase activity, targeting the receptor ALK5 of TGF-β. A pharmaceutical composition containing a compound of Formula 1 of the present invention as an active ingredient can be usefully used in the treatment and/or prevention of cancer, an autoimmune disease, a fibrotic disease, an inflammatory disease, a neurodegenerative disease, an infectious disease, a pulmonary disease, a cardiovascular disease or a metabolic disease or other diseases associated with a decrease in TGF family signaling activity. redient can be usefully used in the treatment and/or prevention of cancer, an autoimmune disease, a fibrotic disease, an inflammatory disease, a neurodegenerative disease, an infectious disease, a pulmonary disease, a cardiovascular disease or a metabolic disease or other diseases associated with a decrease in TGF family signaling activity.

Description

【DESCRIPTION 】 【Disclosure Title 】 NOVEL PYRAZOLE DERIVATIVES AS ALK5 INHIBITORS AND USE THEREOF 【Technical Field 】
[0001] The present disclosure relates to a novel pyrazole derivative compound and use thereof, and in particular, to a novel pyrazole derivative having an ALK5 activity inhibiting effect, a pharmaceutically acceptable salt or solvate thereof, a pharmaceutical composition including such a compound as an active ingredient, and use thereof.
【Background Art 】
[0002] A transforming growth factor-β (TGF-β) signal regulates a developmental stage and cell activity in various ways, and thereby regulates various cell responses such as cell proliferation, differentiation, cell migration and cell death. TGF-β has at least 3 isoforms called TGF-β1, TGF-β2 and TGF-β3, and TGF-β1 may be divided into two well- preserved single membrane serine/threonine kinase type I (ALK5) and formulation TGF- β receptor. When oligomerization is induced by a ligand, the formulation receptor induces activation of ALK5 by hyperphosphorylating serine/threonine residues of ALK5 and producing Smad protein bonding sites. Activated ALK5 phosphorylates Smad2 and Smad3 to form a complex with Smad4, and migrates into the nucleus to regulate gene expression (Pennison, M. Pasche, B., Curr Opin Oncol (2007) 19, 579-85, Attisano, L., Wrana, JL. Science (2002) 296, 1646-47). Accordingly, abnormality in the TGF-β signaling function causes a number of human diseases (for example, deposition of extracellular matrix, inflammatory response, fibrotic dysfunction and advanced cancer).
Meanwhile, TGF-β responds to cancer formation in an early stage of cancer, and facilitates metastasis formation in cancer growing and late tumor stages. For cancer cells, TGF-β facilitates proliferation, epithelial mesenchymal transition (EMT), penetration and metastasis, acts as a major regulator of autocrine and paracrine between a cancer and microenvironments around the cancer, and acts on changes in the microenvironment, neovascularization and immunosuppression, which is effective in inhibiting tumor proliferation and cancer metastasis. An important role played by TGF- β in facilitating cancer growth also indicates a correlation between potent TGF-β expression and poor prognosis.
In addition, fibrosis of organs and tissues is considered to be well-known as a relation between the TGF-β and diseases. EMT activity has been known to be a main mechanism causing fibrosis to date. An inhibitor of intercellular signaling pathways is a useful therapeutic for fibroplasia. It is known to be centrally related to fibrosis of organs such as kidney, liver, lung, heart, bone marrow and skin. From such a point, it has become clear that inhibiting TGF-β is useful for preventing and treating all diseases accompanying fibrosis including chronic renal disease.
A compound according to the present disclosure and a salt thereof have been found to have very important pharmacological properties while being highly tolerant.
Particularly, these exhibit TGF-β receptor I kinase (ALK5)-inhibiting properties.
Accordingly, for signaling pathway ingredients of the TGF-β family, development of inhibitors in treating or preventing diseases associated with an abnormal behavior of this signaling pathway has been required.
【Disclosure 】 【Technical Problem 】 The present disclosure is directed to providing a compound capable of selectively and effectively inhibiting ALK5 and/or ALK4, or a pharmaceutically acceptable salt thereof.
The present disclosure is also directed to providing a pharmaceutical composition including the compound as an active ingredient.
The present disclosure is also directed to providing a pharmaceutical composition capable of, by including the compound as an active ingredient, selectively and effectively inhibiting ALK5 and/or ALK4 and thereby preventing or treating various diseases mediated thereby.
【Technical Solution 】 In view of the above, one embodiment of the present disclosure provides a compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] in Chemical Formula 1, X is N or CH;
[0014] a ring A is C cycloalkylene, C arylene, C heteroarylene containing 3-6 6-10 5-10 1 to 4 heteroatoms selected from among N, O and S atoms, or a non-aromatic fused heteropolycyclic ring containing 1 to 4 heteroatoms selected from among N, O and S; R s are each independently hydrogen, halogen, or linear or branched C 1 1-6 alkyl, or halo C alkyl, and when there are a plurality of R s, these are the same as or 1-6 1 different from each other; R2s are each independently , , , , , , or ; R is hydrogen, halogen, linear or branched C alkyl, linear or branched 3 1-6 halo C alkyl, C cycloalkyl, C heterocycloalkyl unsubstituted or substituted with 1-6 3-10 3-10 R4, C6-10 heterobicycloalkyl, linear or branched C2-6 alkenyl, C2-6 alkynyl, -(CH2)a-R4, - (CH2)a-OR4, -(CH2)a-O-(CH2)a-R4, -(CH2)a-S-(CH2)a-R4, -(CH2)a-O-(CH2)a-OR4, -(CH2)a- NR R , -(CH ) -NO , -(CH ) -CN, -(CH ) -COR , -(CH ) -CO R , -(CH ) -CONR R , - 4 5 2 a 2 2 a 2 a 4 2 a 2 4 2 a 4 5 (CH ) -NHCOR , -(CH ) -SR , -(CH ) -NHSO R , -(CH ) SOR , -(CH ) -SO R , - 2 a 4 2 a 4 2 a 2 4 2 a 6 2 a 2 6 (CH2)a-SO2NHR6, -(CH2)a-SO(NH)R6 or -(CH2)a-SO2NR4R5, or when there are a plurality of R3s and they are adjacent to each other, they may be linked to each other to form a 5- membered or 6-membered ring with the ring A, one or more heteroatoms selected from among N, O and S atoms may be included in the ring, and the heteroatoms may be further oxidized;
[0018] R and R are each independently hydrogen, linear or branched C alkyl, 4 5 1-6 linear or branched halo C alkyl, C cycloalkyl, C cycloalkenyl, C carbonyl, C 1-6 3-10 3-6 1-6 6-12 aryl, -(CH ) -NR R , or saturated or partially unsaturated 5-membered to 10-membered 2 b 6 7 monocyclic or bicyclic heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from among N, O and S; R and R are each independently hydrogen, hydroxy, C alkyl, halo C 6 7 1-6 1-6 alkyl or C cycloalkyl;
[0020] a and b are an integer of 0 to 4; and l, m and n are each independently an integer of 0 to 4.
Another embodiment of the present disclosure provides a preventive or therapeutic use for diseases mediated by an ALK5 and/or ALK4 receptor in a pharmaceutical composition including the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
The disease is particularly preferably selected from the group consisting of fibrotic diseases (for example, scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical trauma, spinal trauma, CNS injury, acute lung injury, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, diabetic renal disorder, hypertension-induced renal disorder, liver or biliary fibrosis, liver cirrhosis, primary biliary sclerosis, fatty liver disease, primary sclerogenous cholangitis, recurrent stenosis, cardiac fibrosis, ocular damage, fibrosclerosis, fibrous cancer, fibromyoma, fibroma, fibroadenoma, fibrosarcoma, grafted arterial disorder, and keloid); dehydration of nerve multiple sclerosis; Alzheimer’s disease; great sinus vasculophathy; and tumor cells (for example, squamous cell carcinoma, multiple myeloma, melanoma, glioma, glioblastoma, leukemia, and carcinomas of lung, breast, ovary, cervix, liver, biliary duct, gastrointestinal tract, pancreas, prostate, and head and neck).
【Advantageous Effects 】
[0024] A novel pyrazole derivative according to the present disclosure is capable of selectively or simultaneously inhibiting various diseases mediated by TGF-β, particularly ALK5 and/or ALK4. Accordingly, the novel derivative according to the present invention is useful in treating or preventing fibrotic diseases (for example, scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical trauma, spinal trauma, CNS injury, acute lung injury, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, diabetic renal disorder, hypertension- induced renal disorder, liver or biliary fibrosis, liver cirrhosis, primary biliary sclerosis, fatty liver disease, primary sclerogenous cholangitis, recurrent stenosis, cardiac fibrosis, ocular damage, fibrosclerosis, fibrous cancer, fibromyoma, fibroma, fibroadenoma, fibrosarcoma, grafted arterial disorder, and keloid); dehydration of nerve multiple sclerosis; Alzheimer’s disease; great sinus vasculophathy; and tumor cells (for example, squamous cell carcinoma, multiple myeloma, melanoma, glioma, glioblastoma, leukemia, and carcinomas of lung, breast, ovary, cervix, liver, biliary duck, gastrointestinal tract, pancreas, prostate, and head and neck).
【Mode for Disclosure 】 Definitions listed below are definitions of various terms used for describing the present disclosure. These definitions are used throughout the specification individually or as a part of terms including these unless limited otherwise.
[0026] The term ‘halogen’ used in the present specification means, unless mentioned otherwise, any one of fluorine, chlorine, bromine, iodine, or all of these.
The term ‘alkyl’ used in the present specification refers to, unless mentioned otherwise, a saturated linear or branched hydrocarbon radical expressed by C H , and specifically, refers to a saturated linear or branched hydrocarbon radical each n 2n+1 including carbon atoms between 1 to 6, 1 to 8, 1 to 10, or 1 to 20. Examples of these radicals include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals, but are not limited thereto.
The term ‘alkenyl’ used in the present specification refers to, unless mentioned otherwise, a monovalent group derived from an unsaturated linear or branched hydrocarbon moiety having at least one carbon-carbon double bond, and specifically, refers to an unsaturated linear or branched monovalent group each including carbon atoms between 2 to 6, 2 to 8, 2 to 10, or 2 to 20. Examples thereof include ethenyl, propenyl, butenyl, 1-methylbutenyl, heptenyl and octenyl radicals, but are not limited thereto.
The term ‘cycloalkyl’ used in the present specification refers to, unless mentioned otherwise, a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound. For example, examples of C3-C8-cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C3-C12-cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1]heptyl, and bicyclo[2.2.2]octyl. A monovalent group derived from a monocyclic or polycyclic carbocyclic ring compound having at least one carbon-carbon double bond obtained by removing a single hydrogen atom is also considered. Examples of such a group include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl, cyclooctenyl and the like.
[0030] The term ‘cycloalkenyl’ used in the present specification refers to, unless mentioned otherwise, a partially unsaturated carbocyclic ring containing 3 to 6 carbon atoms and having a carbon-carbon double bond in the ring. Examples of such a group include, but are not limited to, cyclopentenyl, cyclohexenyl and the like.
The term ‘aryl’ used in the present specification refers to, unless mentioned otherwise, a mono- or poly-cyclic carbocyclic ring system having fused or non-fused one or more aromatic rings, and although not limited thereto, includes phenyl, naphthyl, tetrahydronaphthyl, indenyl, idenyl and the like.
The term ‘heterocycloalkyl’ used in the present specification refers to, unless mentioned otherwise, a saturated or partially unsaturated 3-membered to 10- membered monocyclic or polycyclic substituent containing one or more, for example, 1 to 4 heteroatoms selected from among N, O and S. Examples of the monocyclic heterocycloalkyl may include piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl and groups similar thereto, but are not limited thereto.
[0033] The term ‘heteroaryl’ used in the present specification means, unless mentioned otherwise, a 5-membered to 12-membered monocyclic, or bicyclic or higher aromatic group containing one or more, for example, 1 to 4 heteroatoms selected from among O, N and S. Examples of the monocyclic heteroaryl may include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and groups similar thereto, but are not limited thereto. Examples of the bicyclic heteroaryl may include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, furinyl, furopyridinyl and groups similar thereto, but are not limited thereto.
[0034] The term ‘non-aromatic fused heteropolycyclic ring’ used in the present specification means a group having two or more rings fused to each other, including a heteroatom selected from among N, O and S as a ring-forming atom other than carbon, and having the whole molecule exhibiting non-aromacity (for example, having 5 to 10 nuclear atoms). Examples of the non-aromatic fused heteropolycyclic ring may include benzo[d][1,3]dioxol and the like, but are not limited thereto.
Hereinafter, the present disclosure will be described in more detail.
One embodiment of the present disclosure provides a compound of the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1]
[0038] in Chemical Formula 1, X is N or CH; a ring A is C3-6 cycloalkylene, C6-10 arylene, C5-10 heteroarylene containing 1 to 4 heteroatoms selected from among N, O and S atoms, or a non-aromatic fused heteropolycyclic ring containing 1 to 4 heteroatoms selected from among N, O and S; R s are each independently hydrogen, halogen, or linear or branched C 1 1-6 alkyl, or halo C alkyl, and when there are a plurality of R s, these are the same as or 1-6 1 different from each other; R2s are each independently , , , , , , or ; R is hydrogen, halogen, linear or branched C alkyl, linear or branched 3 1-6 halo C alkyl, C cycloalkyl, C heterocycloalkyl unsubstituted or substituted with 1-6 3-10 3-10 R4, C6-10 heterobicycloalkyl, linear or branched C2-6 alkenyl, C2-6 alkynyl, -(CH2)a-R4, - (CH2)a-OR4, -(CH2)a-O-(CH2)a-R4, -(CH2)a-S-(CH2)a-R4, -(CH2)a-O-(CH2)a-OR4, -(CH2)a- NR R , -(CH ) -NO , -(CH ) -CN, -(CH ) -COR , -(CH ) -CO R , -(CH ) -CONR R , - 4 5 2 a 2 2 a 2 a 4 2 a 2 4 2 a 4 5 (CH ) -NHCOR , -(CH ) -SR , -(CH ) -NHSO R , -(CH ) SOR , -(CH ) -SO R , - 2 a 4 2 a 4 2 a 2 4 2 a 6 2 a 2 6 (CH2)a-SO2NHR6, -(CH2)a-SO(NH)R6 or -(CH2)a-SO2NR4R5, or when there are a plurality of R3s and they are adjacent to each other, they may be linked to each other to form a 5- membered or 6-membered ring with the ring A, one or more heteroatoms selected from among N, O and S atoms may be included in the ring, and the heteroatoms may be further oxidized;
[0045] R and R are each independently hydrogen, linear or branched C alkyl, 4 5 1-6 linear or branched halo C alkyl, C cycloalkyl, C cycloalkenyl, C carbonyl, C 1-6 3-10 3-6 1-6 6-12 aryl, -(CH ) -NR R , or saturated or partially unsaturated 5-membered to 10-membered 2 b 6 7 monocyclic or bicyclic heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from among N, O and S; R and R are each independently hydrogen, hydroxy, C alkyl, halo C 6 7 1-6 1-6 alkyl or C cycloalkyl;
[0047] a and b are an integer of 0 to 4; and l, m and n are each independently an integer of 0 to 4.
In one specific embodiment of the present disclosure, X may be N, and R may be C alkyl.
In one specific embodiment of the present disclosure, the ring A may be phenyl, pyrazole, pyridinyl or benzo[d][1,3]dioxol.
In one specific embodiment of the present disclosure, the compound of Chemical Formula 1 may be selected from the group consisting of the following compounds, but is not limited thereto: (1) 5-(benzo[d]thiazolyl)-N-(4-methoxyphenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (2) 5-(benzo[d]thiazolyl)-N-(4-ethoxyphenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (3) 5-(benzo[d]thiazolyl)-N-(4-(cyclopropylmethoxy)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide;
[0055] (4) 5-(benzo[d]thiazolyl)-N-(4-(2-methoxyethoxy)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (5) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- (trifluoromethoxy)phenyl)-1H-pyrazolecarboxyamide; (6) 5-(benzo[d]thiazolyl)-N-(4-(benzyloxy)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (7) N-(benzo[d][1,3]dioxolyl)(benzo[d]thiazolyl)(6- methylpyridinyl)H-pyrazolecarboxyamide; (8) 5-(benzo[d]thiazolyl)-N-(4-fluoromethoxyphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide;
[0060] (9) 5-(benzo[d]thiazolyl)-N-(2-fluoromethoxyphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (10) 5-(benzo[d]thiazolyl)-N-(3-fluoromethoxyphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (11) 5-(benzo[d]thiazolyl)-N-(3-aminophenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (12) 5-(benzo[d]thiazolyl)-N-(3-(methylamino)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (13) 5-(benzo[d]thiazolyl)-N-(4-(dimethylamino)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide;
[0065] (14) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4-nitrophenyl)- 1H-pyrazolecarboxyamide; (15) 5-(benzo[d]thiazolyl)-N-(4-((2- (dimethylamino)ethyl)(methyl)amino) phenyl)(6-methylpyridinyl)-1H-pyrazole carboxyamide;
[0067] (16) 5-(benzo[d]thiazolyl)-N-(4-(3-(dimethylamino)pyrrolidin yl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (17) 5-(benzo[d]thiazolyl)-N-(3-chloro(octahydro-6H-pyrrolo[3,4- b]pyridinyl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (18) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-phenyl-1H- pyrazolecarboxyamide; (19) 5-(benzo[d]thiazolyl)-N-(3-tolyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamide; (20) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3- vinylphenyl)-1H-pyrazolecarboxyamide;
[0072] (21) 5-(benzo[d]thiazolyl)-N-(3-(trifluoromethyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (22) 5-(benzo[d]thiazolyl)-N-(3-(cyanophenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (23) 5-(benzo[d]thiazolyl)-N-(3-acetylphenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (24) ethyl 3-(5-(benzo[d]thiazolyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamido)benzoate; (25) 5-(benzo[d]thiazolyl)-N-(4-(methylcarbamoyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide;
[0077] (26) 5-(benzo[d]thiazolyl)-N-(4-acetamidophenyl)(6-methylpyridin- 2-yl)-1H-pyrazolecarboxyamide; (27) 5-(benzo[d]thiazolyl)-N-(2-fluorophenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (28) 5-(benzo[d]thiazolyl)-N-(3-fluorophenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (29) 5-(benzo[d]thiazolyl)-N-(4-fluorophenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (30) 5-(benzo[d]thiazolyl)-N-(3,4-difluorophenyl)(6-methylpyridin- 2-yl)-1H-pyrazolecarboxyamide; (31) 5-(benzo[d]thiazolyl)-N-(2-chlorophenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (32) 5-(benzo[d]thiazolyl)-N-(3-chlorophenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide;
[0084] (33) 5-(benzo[d]thiazolyl)-N-(4-chlorophenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (34) 5-(benzo[d]thiazolyl)-N-(4-bromophenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (35) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3- (methylthio)phenyl)-1H-pyrazolecarboxyamide; (36) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- (methylthio)phenyl)-1H-pyrazolecarboxyamide; (37) 5-(benzo[d]thiazolyl)-N-(4-(cyclopropylthio)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide;
[0089] (38) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3- (methylsulfinyl)phenyl)-1H-pyrazolecarboxyamide; (39) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- (methylsulfinyl)phenyl)-1H-pyrazolecarboxyamide; (40) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3- (methylsulfonyl)phenyl)-1H-pyrazolecarboxyamide; (41) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- (methylsulfonyl)phenyl)-1H-pyrazolecarboxyamide; (42) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- (propylsulfonyl)phenyl)-1H-pyrazolecarboxyamide; (43) 5-(benzo[d]thiazolyl)-N-(4-(cyclopropylsulfonyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (44) 5-(benzo[d]thiazolyl)-N-(2-fluoro(methylsulfonyl)phenyl) (6-methylpyridinyl)-1H-pyrazolecarboxyamide;
[0096] (45) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3- sulfamoylphenyl)-1H-pyrazolecarboxyamide; (46) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- sulfamoylphenyl)-1H-pyrazolecarboxyamide; (47) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3-(N- methylsulfamoyl)phenyl)-1H-pyrazolecarboxyamide; (48) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4-(N- methylsulfamoyl)phenyl)-1H-pyrazolecarboxyamide; (49) 5-(benzo[d]thiazolyl)-N-(3-(N-cyclopropylsulfamoyl)phenyl) (6-methylpyridinyl)-1H-pyrazolecarboxyamide;
[00101] (50) 5-(benzo[d]thiazolyl)-N-(4-(N-cyclopropylsulfamoyl)phenyl) (6-methylpyridinyl)-1H-pyrazolecarboxyamide; (51) 5-(benzo[d]thiazolyl)-N-(3-(N,N-dimethylsulfamoyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (52) 5-(benzo[d]thiazolyl)-N-(4-(N,N-dimethylsulfamoyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (53) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3- (methylsulfonamido)phenyl)-1H-pyrazolecarboxyamide; (54) 5-(benzo[d]thiazolyl)-N-(3-(cyclopropanesulfonamido)phenyl) (6-methylpyridinyl)-1H-pyrazolecarboxyamide; (55) 5-(benzo[d]thiazolyl)-N-(4-(cyclopropanesulfonamido)phenyl) (6-methylpyridinyl)-1H-pyrazolecarboxyamide; (56) 4-(5-(benzo[d]thiazolyl)(6-methylpyridinyl)-1H-pyrazole carboxyamido)benzenesulfonic acid;
[00108] (57) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- ((trifluoromethyl)sulfonyl)phenyl)-1H-pyrazolecarboxyamide; (58) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4-(N-(2,2,2- trifluoroethyl)sulfamoyl)phenyl)-1H-pyrazolecarboxyamide; (59) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- ((methylsulfonyl)methyl)phenyl)-1H-pyrazolecarboxyamide; (60) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3- (sulfamoylmethyl)phenyl)-1H-pyrazolecarboxyamide; (61) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- (sulfamoylmethyl)phenyl)-1H-pyrazolecarboxyamide;
[00113] (62) 5-(benzo[d]thiazolyl)-N-(4-fluoro(sulfamoylmethyl)phenyl) (6-methylpyridinyl)-1H-pyrazolecarboxyamide; (63) 5-(benzo[d]thiazolyl)-N-(4-((1,1-dioxidotetrahydrothiophen yl)amino)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (64) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(pyridinyl)- 1H-pyrazolecarboxyamide; (65) 5-(benzo[d]thiazolyl)-N-(6-methoxypyridinyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (66) 5-(benzo[d]thiazolyl)-N-(2-methoxypyridinyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (67) 5-(benzo[d]thiazolyl)-N-(6-(methylthio)pyridinyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (68) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(6- (methylsulfonyl)pyridinyl)-1H-pyrazolecarboxyamide;
[00120] (69) 5-(benzo[d]thiazolyl)-N-(6-(methylsulfonyl)pyridinyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (70) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(2- (methylsulfonyl)pyridinyl)-1H-pyrazolecarboxyamide; (71) 5-(benzo[d]thiazolyl)-N-(6-fluoropyridinyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (72) 5-(benzo[d]thiazolyl)-N-(2-fluoropyridinyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (73) 5-(benzo[d]thiazolyl)-N-(6-chloropyridinyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide;
[00125] (74) 5-(benzo[d]thiazolyl)-N-(2-chloropyridinyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (75) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(thiazolyl)- 1H-pyrazolecarboxyamide; (76) 5-(benzo[d]thiazolyl)-N-benzyl(6-methylpyridinyl)-1H- pyrazolecarboxyamide; (77) 5-(benzo[d]thiazolyl)-N-(2-fluorobenzyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (78) 5-(benzo[d]thiazolyl)-N-(3-fluorobenzyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (79) 5-(benzo[d]thiazolyl)-N-(4-fluorobenzyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (80) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(1- (methylsulfonyl)-1H-pyrazolyl)-1H-pyrazolecarboxyamide;
[00132] (81) 5-(benzo[d]thiazolyl)-N-(1-(cyclopropylsulfonyl)-1H-pyrazol yl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (82) 5-(benzo[d]thiazolyl)-N-(3-hydroxyphenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (83) 5-(benzo[d]thiazolyl)-N-(4-hydroxyphenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (84) 5-(benzo[d]thiazolyl)-N-(3-(hydroxymethyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (85) 5-(benzo[d]thiazolyl)-N-(4-(hydroxymethyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide;
[00137] (86) N-(4-aminophenyl)(benzo[d]thiazolyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (87) 5-(benzo[d]thiazolyl)-N-(4-(butylamino)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (88) 5-(benzo[d]thiazolyl)-N-(4-(cyclopropylamino)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (89) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4-(S- methylsulfonimidoyl)phenyl)-1H-pyrazolecarboxyamide; (90) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-methoxyphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (91) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-methoxyphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (92) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-methoxyphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide;
[00144] (93) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-hydroxyphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (94) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-isopropylphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (95) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(2- methoxyethoxy)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (96) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(benzo[d][1,3]dioxolyl)- 1-(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (97) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-fluoromethoxyphenyl)- 1-(6-methylpyridinyl)-1H-pyrazolecarboxyamide;
[00149] (98) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-fluoromethoxyphenyl)- 1-(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (99) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N-(2- (trifluoromethoxy)phenyl)-1H-pyrazolecarboxyamide; (100) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N- (3-(trifluoromethoxy)phenyl)-1H-pyrazolecarboxyamide; (101) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N- (4-(trifluoromethoxy)phenyl)-1H-pyrazolecarboxyamide; (102) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3- (dimethylamino)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (103) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-aminophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (104) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4- (dimethylamino)phenyl)(6-methylpyridinyl)H-pyrazolecarboxyamide;
[00156] (105) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(pyrrolidin yl)phenyl)1-(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (106) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-((2-(dimethylamino) ethyl)(methyl)amino)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (107) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(4-methylpiperazin yl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (108) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(4-acetylpiperazin yl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (109) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-((1,1- dioxidotetrahydrothiophenyl)amino)phenyl)(6-methylpyridinyl)-1H-pyrazole carboxyamide; (110) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-acetamidophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (111) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4- ((dimethylamino)methyl)phenyl)(6-methylpyridinyl)-1H-pyrazole carboxyamide; (112) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2- (methylcarbamoyl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (113) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4- (methylcarbamoyl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (114) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N- phenyl-1H-pyrazolecarboxyamide; (115) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N- (o-tolyl)-1H-pyrazolecarboxyamide;
[00167] (116) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N- (m-tolyl)-1H-pyrazolecarboxyamide; (117) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N- (p-tolyl)-1H-pyrazolecarboxyamide; (118) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N- (3-(trifluoromethyl)phenyl)-1H-pyrazolecarboxyamide; (119) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N- (4-vinylphenyl)-1H-pyrazolecarboxyamide; (120) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-cyanophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide;
[00172] (121) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-cyanophenyl)(6- methylpyridinyl)H-pyrazolecarboxyamide; (122) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-acetylphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (123) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-acetylphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (124) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-fluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (125) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-fluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (126) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-fluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (127) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-chlorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide;
[00179] (128) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-chlorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (129) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-chlorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (130) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-bromophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (131) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-bromophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (132) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-bromophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide;
[00184] (133) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2,3-difluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (134) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2,4-difluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (135) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2,5-difluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (136) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3,4-difluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (137) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3,5-difluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (138) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-chlorofluorophenyl)- 1-(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (139) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-chlorofluorophenyl)- 1-(6-methylpyridinyl)-1H-pyrazolecarboxyamide;
[00191] (140) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-chlorofluorophenyl)- 1-(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (141) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3,4-dichlorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (142) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-bromofluorophenyl)- 1-(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (143) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-(methoxythio)phenyl) (6-methylpyridinyl)-1H-pyrazolecarboxyamide; (144) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(methoxythio)phenyl) (6-methylpyridinyl)-1H-pyrazolecarboxyamide;
[00196] (145) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-(methylsulfinyl)phenyl)- 1-(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (146) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(methylsulfinyl)phenyl)- 1-(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (147) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4- (methylsulfonyl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (148) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-sulfamoylphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (149) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(S- methylsulfonimidoyl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (150) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(propylsulfonyl)phenyl)- 1-(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (151) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(propylsulfonyl)phenyl)- 1-(6-methylpyridinyl)-1H-pyrazolecarboxyamide;
[00203] (152) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(6-fluoropyridinyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (153) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(6-chloropyridinyl) (6-methylpyridinyl)-1H-pyrazolecarboxyamide; (154) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(6-methoxypyridinyl) (6-methylpyridinyl)-1H-pyrazole carboxyamide; (155) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-fluorobenzyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (156) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-fluorobenzyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide;
[00208] (157) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-fluorobenzyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (158) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-methoxybenzyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (159) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-methoxybenzyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (160) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4- (dimethylamino)benzyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (161) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(-acetamidobenzyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (162) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N- (1-(methylsulfonyl)-1H-pyrazolyl)-1H-pyrazolecarboxyamide; (163) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(1-cyclopropyl sulfonyl)- 1H-pyrazolyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide;
[00215] (164) N-(4-methoxyphenyl)(6-methylpyridinyl)(quinoxalin yl)-1H-pyrazolecarboxyamide; (165) N-(3-methoxyphenyl)(6-methylpyridinyl)(quinoxalin yl)-1H-pyrazolecarboxyamide; (166) N-(2-methoxyphenyl)(6-methylpyridinyl)(quinoxalin yl)-1H-pyrazolecarboxyamide; (167) N-(4-(2-methoxyethoxy)phenyl)(6-methylpyridinyl) (quinoxalinyl)-1H-pyrazolecarboxyamide; (168) N-(benzo[d][1,3]dioxolyl)(6-methylpyridinyl) (quinoxalinyl)-1H-pyrazolecarboxyamide;
[00220] (169) N-(2,3-dihydrobenzo[b][1,4]dioxinyl)(6-methylpyridinyl)- -(quinoxalinyl)-1H-pyrazolecarboxyamide; (170) N-(4-(dimethylamino)phenyl)(6-methylpyridinyl) (quinoxalinyl)-1H-pyrazolecarboxyamide; (171) 1-(6-methylpyridinyl)-N-(4-morpholinophenyl)(quinoxalin yl)-1H-pyrazolecarboxyamide; (172) N-(4-(4-methylpiperazinyl)phenyl)(6-methylpyridinyl) (quinoxalinyl)-1H-pyrazolecarboxyamide; (173) N-(4-(4-acetylpiperazinyl)phenyl)(6-methylpyridinyl) (quinoxalinyl)-1H-pyrazolecarboxyamide; (174) N-(4-cyanophenyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (175) N-(3-cyanophenyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide;
[00227] (176) N-(2-cyanophenyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (177) 1-(6-methylpyridinyl)-N-(4-(morpholinomethyl)phenyl) (quinoxalinyl)-1H-pyrazolecarboxyamide; (178) N-(4-acetylphenyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (179) N-(3-acetylphenyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (180) 1-(6-methylpyridinyl)(quinoxalinyl)-N-(4- (trifluoromethyl)phenyl)-1H-pyrazolecarboxyamide;
[00232] (181) 1-(6-methylpyridinyl)(quinoxalinyl)-N-(3- (trifluoromethyl)phenyl)-1H-pyrazolecarboxyamide; (182) N-(4-(methylcarbamoyl)phenyl)(6-methylpyridinyl) (quinoxalinyl)-1H-pyrazolecarboxyamide; (183) N-(4-fluorophenyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (184) N-(3-fluorophenyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (185) N-(2-fluorophenyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (186) N-(3,4-difluorophenyl)(6-methylpyridinyl)(quinoxalin yl)-1H-pyrazolecarboxyamide; (187) N-(2,4-difluorophenyl)(6-methylpyridinyl)(quinoxalin yl)-1H-pyrazolecarboxyamide;
[00239] (188) N-(2,3-difluorophenyl)(6-methylpyridinyl)(quinoxalin yl)-1H-pyrazolecarboxyamide; (189) N-(4-chlorophenyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (190) N-(2-chlorophenyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (191) N-(4-bromophenyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (192) N-(6-methoxypyridinyl)(6-methylpyridinyl)(quinoxalin- 6-yl)-1H-pyrazolecarboxyamide;
[00244] (193) N-(4-methoxybenzyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (194) N-(4-cyanobenzyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (195) N-(3-acetylbenzyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (196) N-(4-fluorobenzyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (197) N-(3-fluorobenzyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (198) N-(2-fluorobenzyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (199) N-(4-chlorobenzyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide;
[00251] (200) N-(3-chlorobenzyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (201) N-(2-chlorobenzyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (202) N-(2-fluorophenyl)(quinoxalinyl)(m-tolyl)-1H-pyrazole carboxyamide; (203) 1-(5-chlorofluorophenyl)-N-(4-methoxyphenyl)(quinoxalin yl)-1H-pyrazolecarboxyamide; (204) 1-(5-chlorofluorophenyl)-N-(4-(dimethylamino)phenyl) (quinoxalinyl)-1H-pyrazolecarboxyamide;
[00256] (205) N-(4-methoxyphenyl)(quinoxalinyl)(6- trifluoromethyl)pyridinyl)-1H-pyrazolecarboxyamide; (206) N-(4-(dimethylamino)phenyl)(quinoxalinyl)(6- trifluoromethyl)pyridinyl)-1H-pyrazolecarboxyamide; (207) 1-(6-bromopyridinyl)-N-(4-methoxyphenyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (208) 1-(6-bromopyridinyl)-N-(4-(dimethylamino)phenyl) (quinoxalinyl)-1H-pyrazolecarboxyamide; (209) N-(2-fluorophenyl)(6-methylpyridinyl)(quinolinyl)-1H- pyrazolecarboxyamide; (210) N-(4-methoxyphenyl)(6-methylpyridinyl)(quinolinyl)- 1H-pyrazolecarboxyamide; (211) 1-(6-methylpyridinyl)-N-(4-(methylsulfonyl)phenyl) (quinolinyl)-1H-pyrazolecarboxyamide;
[00263] (212) N-(6-methoxypyridinyl)(6-methylpyridinyl)(quinolin yl)-1H-pyrazolecarboxyamide; (213) N-(6-chloropyridinyl)(6-methylpyridinyl)(quinolin yl)-1H-pyrazolecarboxyamide; (214) N-(benzo[d][1,3]dioxolyl)(6-methylpyridinyl)(quinolin- 4-yl)-1H-pyrazolecarboxyamide; (215) N-(3-fluoromethoxyphenyl)(6-methylpyridinyl) (quinolinyl)-1H-pyrazolecarboxyamide; (216) N-(2-fluoromethoxyphenyl)(6-methylpyridinyl) (quinolinyl)-1H-pyrazolecarboxyamide;
[00268] (217) N-(4-(2-methoxyethoxy)phenyl)(6-methylpyridinyl) (quinolinyl)-1H-pyrazolecarboxyamide; (218) 5-(benzo[c][1,2,5]oxadiazolyl)-N-(4- (cyclopropylsulfonyl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (219) 5-(benzo[d]oxazolyl)-N-(2-fluorophenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (220) 5-(benzo[d]oxazolyl)-N-(4-(cyclopropylsulfonyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (221) N-cyclopropyl(4-fluoro(1-(2-hydroxyethyl)-1H-pyrazol yl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (222) N-(1H-pyrazolyl)(4-fluoro(1-(2-hydroxyethyl)-1H-pyrazol- 4-yl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (223) N-(1-methyl-1H-pyrazolyl)(4-fluoro(1-(2-hydroxyethyl)- 1H-pyrazolyl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide;
[00275] (224) N-(1-(methylsulfonyl)-1H-pyrazolyl)(4-fluoro(1-(2- hydroxy ethyl)-1H-pyrazolyl)phenyl)(6-methylpyridinyl)-1H-pyrazole carboxyamide; (225) N-(4-chlorophenyl)(4-fluoro(1-(2-hydroxyethyl)-1H-pyrazol- 4-yl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide;
[00277] (226) N-(4-(methylsulfonyl)phenyl)(4-fluoro(1-(2-hydroxyethyl)- 1H-pyrazolyl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; and (227) N-(2-fluorophenyl)(thieno[3,2,c]pyridinyl)(m-tolyl)-1H- pyrazolecarboxyamide.
The compound of Chemical Formula 1 according to the present disclosure may be prepared using a method representatively illustrated in the following Reaction Formula 1: <Reaction Formula 1> In Reaction Formula 1, R1, R2, R3, A, l, m and n each have the same definitions as in Chemical Formula 1.
When describing the reaction in more detail with reference to Reaction Formula 1, an acetyl compound having R , diethyl oxalate and ethoxysodium solution are refluxed in an organic solvent (for example, ethanol) to obtain Compound (4).
Compound (4) is refluxed with a hydrazinyl material having an (R1)l group and the like to obtain Compound (3), and this may be stirred under 1,4-dioxane and lithium hydroxide to obtain Intermediate Compound (2). Next, Compound (2) may be reacted with an aniline derivative having an R group together with HATU and DIPEA in N,N-dimethylformamide to obtain a target compound of Chemical Formula 1 of the present disclosure.
The compound of Chemical Formula 1 according to the present disclosure may be prepared to a pharmaceutically acceptable salt form having an inorganic acid or an organic acid added thereto, and herein, examples of the preferred salts may include salts derived from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or the like.
[00286] Specifically, the pharmaceutically acceptable salt according to the present disclosure may be prepared by dissolving the compound of Chemical Formula 1 in an organic solvent such as acetone, methanol, ethanol or acetonitrile, adding an organic acid or an inorganic acid thereto, and filtering crystals precipitated therefrom. Alternatively, the pharmaceutically acceptable salt may be prepared by vacuuming a solvent or excess acid in an acid-added reaction mixture to dry the residue, or prepared by filtering a salt precipitated from adding other organic solvents.
The compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof according to the present disclosure may have a form of a hydrate or solvate, and such compounds are also included in the present disclosure.
The compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof according to the present disclosure may effectively inhibit protein kinase. In one embodiment, the compound of the present disclosure may effectively prevent or treat diseases mediated by the ALK5 receptor or the ALK4 receptor, or both the ALK5 receptor and the ALK4 receptor. Specifically, the disease may be selected from the group consisting of kidney-, liver- or lung-fibrosis, glomerulonephritis, diabetic renal disease, erythematous nephritis, hypertension-induced renal disease, kidney interstitial fibrosis, kidney fibrosis derived from drug exposure complications, HIV-related renal disease, organ transplantation gangrene, liver fibrosis caused by all diseases, hepatic dysfunction caused by infection, alcohol-induced hepatitis, biliary disorder, pulmonary fibrosis, acute lung injury, adult respiratory pain syndrome, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, pulmonary fibrosis caused by infection or toxic factors, cardiac fibrosis after myocardial infarction, congestive heart failure, dilated cardiomyopathy, myocarditis, vascular stenosis, restenosis, atherosclerosis, visual impairment, corneal injury, proliferative vitreoretinopathy, excessive or exacerbated scar or keloid formation in the dermis occurring during wound healing from trauma or surgical wounds, peritoneum and subcutaneous adhesion, skin sclerosis, fibrosclerosis, progressive systemic sclerosis, dermatomyositis, multiple myositis, arthritis, osteoporosis, ulcer, impaired nerve function, male impotence, Alzheimer’s disease, Raynaud’s disease, fibrous cancer, metastasis growth of tumors, radiation-induced fibrosis and thrombosis, but is not limited thereto.
In one specific embodiment of the present disclosure, the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof may prevent or treat fibrotic diseases or fibrotic conditions. Herein, the fibrotic disease or the fibrotic condition may be selected from the group consisting of liver fibrosis, kidney fibrosis, pulmonary fibrosis, irritable pneumonia, interstitial fibrosis, systematic sclerodermie, macular degeneration, pancreas fibrosis, splenic fibrosis, cardiac fibrosis, species septic fibrosis, bone marrow fibrosis, vascular fibrosis, skin fibrosis, eye fibrosis, joint fibrosis, muscle fibrosis, thyroid fibrosis, endocardial myocardial fibrosis, peritoneal fibrosis, after peritoneal fibrosis, progressive congenital trophoblastic fibrosis, allogeneic systematic fibrosis, fibrotic complications of surgery and infection fibrosis, but is not limited thereto.
In one specific embodiment of the present disclosure, the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof may effectively prevent or treat cancers or tumors, and may further effectively inhibit cancer cell metastasis as well. Herein, the cancer may be selected from the group consisting of liver cancer, hepatocellular carcinoma, thyroid cancer, colorectal cancer, testicular cancer, bone cancer, oral cancer, basal cell carcinoma, ovarian cancer, brain tumor, gallbladder carcinoma, biliary tract cancer, head and neck cancer, colorectal cancer, vesical carcinoma, tongue cancer, esophageal cancer, glioma, glioblastoma, renal cancer, malignant melanoma, gastric cancer, breast cancer, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, rectal cancer, pancreatic cancer, lung cancer, skin cancer and other solid cancers, but is not limited thereto.
In one specific embodiment of the present disclosure, the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof may effectively prepvent or treat a carcinoma mediated by overexpression of TGFβ. Herein, the carcinoma may be selected from the group consisting of carcinomas of lung, breast, liver, biliary, gastrointestinal tract, head and neck, pancreas, prostate and cervix, multiple myeloma, melanoma, glioma and glioblastoma, but is not limited thereto.
[00292] The compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof according to the present disclosure may strengthen therapeutic effects by being co-administered with other drugs for treating fibrotic diseases, cancers or tumors, inflammatory diseases, autoimmune diseases, proliferative diseases, hyperproliferative diseases or immunologically-mediated diseases.
[00293] Examples of the other drugs for treating cancers or tumors may include drugs such as cell signaling inhibitors (gleevec, iressa, tarceva and the like), mitotic inhibitors (vincristine, vinblastine and the like), alkylating agents (cyclophosphamide, thiotepa, busulfan and the like), anti-metabolites (tergaflor-based, methotrexate, gemcitabine and the like), topoisomerase inhibitors (irinotecan, topotecan, amsacrine, etoposide, teniposide and the like), immunotherapeutic agents (interferon α, β, γ, interleukin and the like) or anti-hormones (tamoxifen, leuprorelin, anastrozole and the like), but are not limited thereto, and one or more drugs selected from among these may be included in the pharmaceutical composition of the present disclosure.
Examples of the other drugs for treating inflammatory diseases, autoimmune diseases, proliferative diseases, hyperproliferative diseases or immunologically-mediated diseases may include drugs such as steroid drugs (prednisone, prednisolone, methylprednisolone, cortisone, hydroxycortisone, betamethasone, dexamethasone and the like), methotrexate, leflunomide, anti-TNFα drugs (etanercept, infliximab, adalimumab and the like), calcineurin inhibitors (tacrolimus, pimecrolimus and the like) and antihistamine drugs (diphenhydramine, hydroxygene, loratadine, avastin, ketotifen, cetirizine, levocetirizine, fexofenadine and the like), but are not limited thereto, and one or more drugs selected from among these may be included in the pharmaceutical composition of the present disclosure.
The compound of Chemical Formula 1, a pharmaceutically acceptable salt thereof, or the like according to the present disclosure may be administered to a subject to prevent or treat the above-mentioned diseases. Herein, the dosage may vary depending on the subject to be treated, the severity of disease or condition, the rate of administration and the judgement of prescribing physician, however, the compound of Chemical Formula 1 may be commonly administered to a person as an active ingredient via an oral or parenteral route 1 to 4 times a day or on an on/off schedule with an amount of 0.1 mg to 2,000 mg and preferably 1 mg to 1,000 mg per day based on a body weight of 70 kg. In some cases, dosage less than the above-mentioned range may be more suited, and more dosage may be used without causing harmful side effects. More dosage may be dispensed in several smaller dosage over a day.
[00296] The pharmaceutical composition according to the present disclosure may be formulated using common methods, and may be prepared in various oral administration forms such as tablets, pills, powders, capsules, syrups, emulsions or microemulsions, or parenteral administration forms such as intramuscular, intravenous or subcutaneous administration.
[00297] When the pharmaceutical composition according to the present disclosure is prepared in the form of oral formulation, examples of a carrier to be used may include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, a surfactant, a suspension, an emulsifier, a diluent and the like. When the pharmaceutical composition according to the present disclosure is prepared in the form of an injection, water, a saline solution, an aqueous glucose solution, an aqueous pseudo-sugar solution, alcohol, glycol, ether (for example: polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, a surfactant, a suspension, an emulsifier and the like may be used as the carrier.
The compound of Chemical Formula 1 of the present disclosure may be used in studies on kinases for biological and pathological phenomena, studies on intracellular signaling pathways mediated by kinases, and comparative evaluations on novel kinase inhibitors.
Hereinafter, the present disclosure will be described in detail with reference to examples. However, the following examples are for illustrative purposes only, and the present disclosure is not limited to the following examples. <Reaction Formula 2> [Preparation Example 1] 5-(Benzo[d]thiazolyl)(6-methylpyridin- 2-yl)-1H-pyrazolecarboxylic acid
[00303] Step 1. Preparation of N-methoxy-N-methylbenzo[d]thiazole carboxyamide After adding benzothiazolecarboxylic acid (5.0 g, 27.9 mmol), HATU (15.9 g, 41.9 mmol) and DIPEA (11.7 mL, 83.7 mmol) to dichloromethane (87 mL) and N,N-dimethylformamide (22 mL), the result was stirred for 30 minutes. To the reaction solution, an N,O-dimethylhydroxylamine salt (3.0 g, 30.7 mmol) was introduced, and the result was stirred for 12 hours at room temperature. After terminating the reaction, the reaction solution was removed, and ethyl acetate was added thereto. The result was washed with water and saline, then dried using anhydrous magnesium sulfate, and filtered.
The filtrate was concentrated and purified using column chromatography to obtain a target compound (6.2 g).
[00305] H NMR spectrum (300 MHz, CDCl3) δ 9.13(s, 1H), 8.36(d, 1H), 8.16(d, 1H), 7.87(dd, 1H), 3.57(s, 3H), 3.42(s, 3H).
Step 2. 1-(Benzo[d]thiazolyl)ethanone After dissolving N-methoxy-N-methylbenzo[d]thiazolecarboxyamide (6.2 g, 27.9 mmol) synthesized in Step 1 in anhydrous tetrahydrofuran (84 mL) under argon, 3 M methyl magnesium bromide (13.9 mL, 41.8 mmol) dissolved in diethyl ether was added dropwise thereto at 0ºC. The reaction solution was warmed to room temperature and stirred for 12 hours. After terminating the reaction by introducing a saturated ammonium chloride solution thereto, ethyl acetate was introduced thereto, and the result was extracted. The organic layer was dried using anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated and then purified using column chromatography to obtain a target compound (3.1 g).
H NMR spectrum (300 MHz, CDCl3) δ 9.17(s, 1H), 8.62(s, 1H), 8.16(q, 2H), 2.71(s, 3H).
Step 3. Ethyl (Z)(benzo[d]thiazolyl)hydroxyoxobutenoate
[00310] After dissolving 1-(benzo[d]thiazolyl)ethanone (1.0 g, 5.6 mmol) synthesized in Step 2 and diethyl oxalate (1.5 mL, 11.3 mmol) in ethanol (2 mL), a 2 M ethoxysodium solution (5.6 mL, 11.3 mmol) was slowly added dropwise thereto at 50ºC, and the result was refluxed for 2 hours. After cooling the result to room temperature, the solvent was vacuum concentrated, and the result was acidified by adding 2 M HCl dropwise thereto. Dichloromethane was introduced thereto for extraction, and the organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (597 mg).
H NMR spectrum (300 MHz, CDCl ) δ 9.19(s, 1H), 8.68(s, 1H), 8.20(q, 2H), 7.17(s, 1H), 4.43(q, 2H), 1.43(t, 3H).
Step 4. Ethyl 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-1H- pyrazolecarboxylate After dissolving ethyl (Z)(benzo[d]thiazolyl)hydroxyoxo butenoate (580 mg, 2.1 mmol) synthesized in Step 3 and 2-hydrazinylmethylpyridine hydrochloric acid (350 mg, 2.2 mmol) in ethanol (10 mL), the result was refluxed for 2 hours. After terminating the reaction, the reaction solution was removed under vacuum, and ethyl acetate was added thereto. The organic layer was washed with saline and then dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated.
The filtrate was purified using column chromatography to obtain a target compound (525 mg).
H NMR spectrum (300 MHz, CDCl ) δ 9.04(s, 1H), 8.04(d, 1H), 7.97(d, 1H), 7.67(t, 1H), 7.41-7.33(m, 2H), 7.14-7.10(m, 2H), 7.47(q, 2H), 2.32(s, 3H), 1.43(t, 3H).
Step 5. 5-(Benzo[d]thiazolyl)(6-methylpyridinyl)-1H-pyrazole carboxylic acid After dissolving ethyl 5-(benzo[d]thiazolyl)(6-methylpyridinyl)- 1H-pyrazolecarboxylate (520 mg, 1.4 mmol) synthesized in Step 4 in 1,4-dioxane (11 mL), a 2 N lithium hydroxide solution dissolved in water was introduced thereto, and the result was stirred for 2 hours at 70ºC. After terminating the reaction, the reaction solution was removed under vacuum. The result was acidified by adding 12 N hydrochloric acid thereto, and then extracted by introducing chloroform/isopropanol (3:1) thereto. The organic layer was dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain Intermediate 1 (394 mg).
[00317] H NMR spectrum (300 MHz, CDCl3) δ 9.34(s, 1H), 8.09(d, 1H), 8.05(s, 1H), 7.75(t, 1H), 7.44-7.39(m, 2H), 7.21(d, 1H), 7.13(s, 1H), 2.36(s, 3H). <Reaction Formula 3> [Preparation Example 2] Preparation of 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-1H-pyrazolecarboxylic acid Step 1. Preparation of 2-hydrazinylmethylpyridine hydrochloric acid salt A hydrazine hydrate (60 mL) was added to 2-bromomethylpyridine (10.0 g, 58.1 mmol), and the result was heated under reflux for 4 hours. After terminating the reaction, the result was extracted with ethyl acetate, and the obtained organic layer was vacuum concentrated, and acidified with 4 N-hydrochloric acid/dioxane (30 mL). The produced solids were filtered, and the obtained solids were dried to obtain a target compound (9.3 g).
H NMR (300 MHz, DMSO-d6) δ 9.65 (brs, 3H), 7.60 (t, 1H), 6.75 (d, 1H), 6.69 (d, 1H), 2.41 (s, 3H).
MS (ESI ): m/z 124 [M+H] Step 2. Preparation of 1-([1,2,4]triazolo[1,5- α]pyridinyl)ethanone
[00326] After dissolving 1-bromo-[1,2,4]triazolo[1,5- α]pyridine (1.1 g, 5.6 mmol) in N,N-dimethylformamide (15 mL) in a sealed tube, n-butyl vinyl ether (3.6 mL, 27.8 mmol), 1,3-bis(diphenylphosphino)propane (161 mg, 0.4 mmol), palladium(II) acetate (37 mg, 0.2 mmol), potassium carbonate (922 mg, 6.7 mmol) and water (1.6 mL) were added thereto, and the result was heated under reflux for 16 hours. After lowering the temperature to room temperature, an aqueous 2 N-hydrochloric acid solution (10 mL) was added thereto, and the result was stirred for 30 minutes at room temperature. After terminating the reaction, the result was extracted with ethyl acetate, and the obtained organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (410 mg).
H NMR (300 MHz, CDCl ) δ 9.23 (s, 1H), 8.46 (s, 1H), 8.09 (d, 1H), 7.81 (d, 1H), 2.67 (s, 3H).
MS (ESI ): m/z 162 [M+H] Step 3. Preparation of (Z)-ethyl([1,2,4]triazolo[1,5- α]pyridinyl) hydroxyoxobutenoate After adding diethyl oxalate (1.3 mL, 9.9 mmol) to a 2 M ethoxysodium solution (5.0 mL, 9.9 mmol), a solution dissolving 1-([1,2,4]triazolo[1,5- α]pyridin yl)ethanone (400 mg, 2.5 mmol) synthesized in Step 1 in ethanol (3 mL) was added thereto, and the result was stirred for 2 hours at room temperature. The result was vacuum concentrated, and acidified by adding an aqueous 2 N hydrochloric acid solution dropwise thereto at 0℃. The result was extracted with ethyl acetate, and the obtained organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and recrystallized with ether to obtain a target compound (444 mg).
H NMR (300 MHz, DMSO-d ) δ 9.95 (s, 1H), 8.69 (s, 1H), 8.16 (d, 1H), 7.95 (d, 1H), 7.30 (brs, 1H), 4.30 (q, 2H), 1.31 (t, 3H).
MS (ESI ): m/z 262 [M+H] Step 4. Preparation of ethyl([1,2,4]triazolo[1,5- α]pyridinyl)(6- methylpyridinyl)-1H-pyrazolecarboxylate After dissolving (Z)-ethyl([1,2,4]triazolo[1,5- α]pyridinyl) hydroxyoxobutenoate (440 mg, 1.7 mmol) synthesized in Step 3 and the 2- hydrazinylmethylpyridine hydrochloric acid salt (268 mg, 1.7 mmol) synthesized in Step 1 in ethanol (6 mL), the result was stirred for 2 hours at 50℃. The result was vacuum concentrated, extracted with ethyl acetate, and the obtained organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (446 mg).
H NMR (300 MHz, CDCl ) δ 8.73 (s, 1H), 8.39 (s, 1H), 7.77-7.67 (m, 3H), 7.47 (d, 1H), 7.18-7.09 (m, 2H), 4.46 (q, 2H), 2.26 (s, 3H), 1.45 (t, 3H).
MS (ESI ): m/z 349 [M+H] Step 5. Preparation of 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6- methylpyridinyl)-1H-pyrazolecarboxylic acid After adding an aqueous 50% ethanol solution (5 mL) to ethyl ([1,2,4]triazolo[1,5-α]pyridinyl)(6-methylpyridinyl)-1H-pyrazolecarboxylate (440 mg, 1.3 mmol) synthesized in Step 4, the result was stirred for 1 hour at 50ºC. The result was vacuum concentrated and acidified with an aqueous 2 N hydrochloric acid solution, and produced solids were filtered and dried to obtain Intermediate 2 (386 mg).
H NMR (300 MHz, DMSO-d6) δ 13.2 (brs, 1H), 9.15 (s, 1H), 8.52 (s, 1H), 7.91 (t, 1H), 7.78 (d, 1H), 7.73 (d, 1H), 7.29 (d, 1H), 2.13 (s, 3H).
MS (ESI ): m/z 321 [M+H] <Reaction Formula 4>
[00342] [Preparation Example 3] Synthesis of 1-(6-methylpyridinyl) (quinoxalinyl)-1H-pyrazolecarboxylic acid Step 1. Preparation of 1-(quinoxalinyl)ethanone After adding 6-bromoquinoxaline (3.8 g, 18.2 mmol), n-butyl vinyl ether (12.3 mL, 95.2 mmol), potassium carbonate (3.1 g, 22.8 mmol), 1,3- bis(diphenylphosphino)propane (504 mg, 1.3 mmol) and palladium(II) acetate (124 mg, 0.5 mmol) to N,N-dimethylformamide (47 mL) and water (6 mL), the result was stirred and refluxed for 6 hours. After terminating the reaction, the result was cooled to room temperature, 2 N hydrochloric acid was added thereto, and the result was stirred for 0.5 hours. Ethyl acetate was added thereto, the organic layer was washed with water and sodium bicarbonate, dried using anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (2.4 g).
H NMR spectrum (300 MHz, DMSO-d6) δ 10.05(d, 1H), 9.73(t, 1H), 8.71(s, 1H), 7.97(d, 1H), 3.16(s, 3H).
Step 2. Preparation of ethyl (Z)hydroxyoxo(quinoxalinyl) butenoate
[00348] After dissolving 6-(quinoxalinyl)ethanone (4.6 g, 27.0 mmol) synthesized in Step 1 and diethyl oxalate (7.3 mL, 53.9 mmol) in ethanol (9 mL), a 2 M ethoxysodium solution (26.9 mL, 53.9 mmol) was slowly added dropwise thereto at 50ºC, and the result was refluxed for 2 hours. After cooling the result to room temperature, the solvent was vacuum concentrated, and the result was acidified by adding 2 M HCl dropwise thereto. Dichloromethane was introduced thereto for extraction, and the organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (6.7 g).
H NMR spectrum (300 MHz, CDCl3) δ 8.96(s, 2H), 8.78(s, 1H), 8.35(dd, 1H), 8.24(d, 1H), 7.27(s, 1H), 4.44(q, 2H), 1.45(t, 3H).
Step 3. Preparation of ethyl 1-(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxylate After dissolving (Z)hydroxyoxo(quinoxalinyl)butenoate (2.7 g, 10.1 mmol) synthesized in Step 2 and 2-hydrazinylmethylpyridine hydrochloric acid (1.3 g, 10.6 mmol) in ethanol, the result was refluxed for 2 hours. After terminating the reaction, the reaction solution was removed under vacuum, and ethyl acetate was added thereto. The organic layer was washed with sodium bicarbonate, dried using anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (2.7 g).
H NMR spectrum (300 MHz, CDCl3) δ 8.86(s, 2H), 8.09(d, 1H), 8.01(d, 1H), 7.73-7.62(m, 1H), 7.55(d, 1H), 7.20(s, 1H), 7.13(d, 1H), 4.48(q, 2H), 2.24(s, 3H), 1.45(s, 3H).
Step 4. Preparation of 1-(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxylic acid After dissolving ethyl 1-(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxylate (2.6 g, 7.2 mmol) synthesized in Step 3 in 1,4-dioxane (40 mL), a 2 N lithium hydroxide solution dissolved in water was introduced thereto, and the result was stirred for 3 hours at 70ºC. After terminating the reaction, the reaction solution was removed under vacuum, and water was added thereto. Ethyl acetate was introduced thereto for extraction, the water layer was acidified to a pH of 2 to 3, and the result was stirred for 1 hour at room temperature. Produced solids were filtered, washed with water, and dried to obtain Intermediate 3 (2.3 g).
H NMR spectrum (300 MHz, DMSO-d6) δ 13.17(br, 1H), 8.96(s, 2H), 8.06-7.92(m, 3H), 7.72(dd, 1H), 7.60(d, 1H), 7.35-7.32(m, 2H), 2.15(s, 3H). <Reaction Formula 5> [Preparation Example 4] 1-(6-Methylpyridinyl)(quinolinyl)- 1H-pyrazolecarboxylic acid
[00359] Step 1. Preparation of N-methoxy-N-methylquinolinecarboxyamide After adding quinolinecarboxylic acid (2.2 g, 12.8 mmol), HATU (5.8 g, 15.3 mmol) and DIPEA (6.7 mL, 38.4 mmol) to dichloromethane (25 mL), the result was stirred for 30 minutes. To the reaction solution, an N,O-dimethylhydroxylamine salt (1.9 g, 19.2 mmol) was introduced, and the result was stirred for 12 hours at room temperature. After terminating the reaction, the reaction solution was removed, and ethyl acetate was added thereto. The result was washed with water and saline, then dried using anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (2.8 g).
H NMR spectrum (300 MHz, CDCl3) δ 8.96(d, 1H), 8.15(d, 1H), 7.86(d, 1H), 7.76(t, 1H), 7.59(t, 1H), 7.39(d, 1H), 3.48-3.40(m, 6H).
Step 2. Preparation of 1-(quinolinyl)ethanone After dissolving N-methoxy-N-methylquinolinecarboxyamide (2.8 g, 12.9 mmol) synthesized in Step 1 in anhydrous tetrahydrofuran (100 mL) under argon, 3 M methyl magnesium bromide (6.5 mL, 19.4 mmol) dissolved in diethyl ether was added dropwise thereto at 0ºC. The reaction solution was warmed to room temperature, and stirred for 3 hours. 3M methyl magnesium bromide (3.0 mL, 9.0 mmol) dissolved in diethyl ether was further added dropwise thereto at 0℃. The reaction solution was warmed to room temperature and stirred for 12 hours. After terminating the reaction by introducing a saturated ammonium chloride solution thereto, ethyl acetate was introduced thereto, and the result was extracted. The organic layer was dried using anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated and then purified using column chromatography to obtain a target compound (1.8 g).
H NMR spectrum (300 MHz, CDCl ) δ 9.03(d, 1H), 8.46(d, 1H), 8.17(d, 1H), 7.77(t, 1H), 7.67-7.61(m, 2H), 2.75(s, 3H).
Step 3. Preparation of ethyl (Z)hydroxyoxo(quinolinyl)but enoate After dissolving 1-(quinolinyl)ethanone (1.0 g, 5.8 mmol) synthesized in Step 2 and diethyl oxalate (1.6 mL, 11.7 mmol) in ethanol (3 mL), a 2 M ethoxysodium solution (5.8 mL, 11.7 mmol) was slowly added dropwise thereto at 50℃, and the result was refluxed for 1 hour. After cooling the result to room temperature, the solvent was vacuum concentrated, and the result was acidified by adding 2 M hydrochloric acid dropwise thereto. Dichloromethane was introduced thereto for extraction, and the organic layer was dried using anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated and then crystallized using a 1:1 mixed solution of hexane and ether to obtain a target compound (1.1 g).
H NMR spectrum (300 MHz, CDCl ) δ 9.06(d, 1H), 8.40(d, 1H), 8.20(d, 1H), 7.81(t, 1H), 7.70-7.63(m, 2H), 6.95(s, 1H), 4.42(q, 2H), 1.41(t, 3H).
Step 4. Preparation of ethyl 1-(6-methylpyridinyl)(quinolinyl)- 1H-pyrazolecarboxylate After dissolving ethyl (Z)hydroxyoxo(quinolinyl)butenoate (1.1 g, 4.2 mmol) synthesized in Step 3 and 2-hydrazinylmethylpyridine hydrochloric acid (677 mg, 4.2 mmol) in ethanol (12 mL), the result was refluxed for 3 hours. After terminating the reaction, the reaction solution was removed under vacuum, and ethyl acetate was added thereto. The organic layer was washed with water and saline, then dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated.
The filtrate was purified using column chromatography to obtain a target compound (1.1 H NMR spectrum (300 MHz, CDCl3) δ 8.92(d, 1H), 8.13(d, 1H), 7.70- 7.56(m, 4H), 7.39(t, 1H), 7.31(t, 1H), 7.13(s, 1H), 6.89(d, 1H), 4.50(q, 2H), 1.79(s, 3H), 1.46(t, 3H).
Step 5. Preparation of 1-(6-methylpyridinyl)(quinolinyl)-1H- pyrazolecarboxylic acid After dissolving ethyl 1-(6-methylpyridinyl)(quinolinyl)-1H- pyrazolecarboxylate (1.1 g, 3.2 mmol) synthesized in Step 4 in 1,4-dioxane (11 mL), a 2 N lithium hydroxide solution (4.8 mL, 9.5 mmol) dissolved in water was introduced thereto, and the result was stirred for 2 hours at 45℃. After terminating the reaction, the reaction solution was removed under vacuum, and the result was acidified to a pH of 2 to 3 by adding 2 N hydrochloric acid thereto, and then stirred for 1 hour at room temperature.
The result was vacuum filtered to obtain Intermediate 4 (960 mg).
H NMR spectrum (300 MHz, DMSO-d6) δ 13.0(bs, 1H), 8.92(d, 1H), 8.07(d, 1H), 7.81(t, 1H), 7.71-7.65(m, 2H), 7.50-7.44(m, 3H), 7.06(s, 1H), 7.05(d, 1H), 1.64(t, 3H). <Reaction Formula 6> [Preparation Example 5] 5-(Benzo[c][1,2,5]oxadiazolyl)(6- methylpyridinyl)-1H-pyrazolecarboxylic acid
[00377] Step 5. Preparation of 5-(benzo[c][1,2,5]oxadiazolyl)(6- methylpyridinyl)-1H-pyrazolecarboxylic acid Intermediate 5 (30 mg) was obtained through the methods of Step 1 to Step of Preparation Example 4 using benzo[c][1,2,5]oxadiazolecarboxylic acid instead of quinolinecarboxylic acid of Step 1.
H NMR spectrum (300 MHz, DMSO-d ) δ 8.14(s, 1H), 7.97-7.92(m, 2H), 7.71(d, 1H), 7.40(d, 1H), 7.31-7.28(m, 2H), 2.10(s, 3H). <Reaction Formula 7> [Preparation Example 6] 5-(Benzo[d]oxazolyl)(6-methylpyridin- 2-yl)-1H-pyrazolecarboxylic acid
[00383] Step 3. Preparation of ethyl (Z)(benzo[d]oxazolyl)hydroxy oxobutenoate A target compound (1.2 g) was obtained through the methods of Step 1 to Step 3 of Preparation Example 4 using benzo[d]oxazolecarboxylic acid instead of quinolinecarboxylic acid of Step 1.
[00385] H NMR spectrum (300 MHz, CDCl ) δ 8.28-8.26(m, 2H), 8.06(d, 1H), 7.90(d, 1H), 7.27(s, 1H), 7.14(s, 1H), 4.42(q, 2H), 1.44(t, 3H).
Step 4. Preparation of ethyl 5-(4-aminohydroxyphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxylate After dissolving ethyl (Z)(benzo[d]oxazolyl)hydroxyoxobut enoate (1.2 g, 4.8 mmol) synthesized in Step 3 and 2-hydrazinylmethylpyridine hydrochloric acid (915 mg, 5.7 mmol) in ethanol (15 mL), the result was refluxed for 2 hours. After terminating the reaction, the reaction solution was removed under vacuum, and a saturated sodium bicarbonate solution was added thereto. The result was stirred for 1 hour at room temperature, and then vacuum filtered. Obtained solids were crystallized with dichloromethane and vacuum filtered to obtain a target compound (1.5 g).
[00388] H NMR spectrum (300 MHz, DMSO-d6) δ 9.11(s, 1H), 7.84(t, 1H), 7.37(d, 1H), 7.20(d, 1H), 6.83(s, 1H), 6.49-6.41(m, 3H), 4.79(bs, 2H), 4.31(q, 2H), 1.33(t, 3H).
Step 5. Preparation of ethyl 5-(benzo[d]oxazolyl)(6-methylpyridin- 2-yl)-1H-pyrazolecarboxylate
[00390] After dissolving ethyl 5-(4-aminohydroxyphenyl)(6-methylpyridin- 2-yl)-1H-pyrazolecarboxylate (1.0 g, 3.0 mmol) synthesized in Step 4 in trimethyl orthoformate (1.5 mL), the result was stirred for 2 hours at 100℃. After terminating the reaction, the reaction solution was removed under vacuum, and the result was purified using column chromatography to obtain a target compound (930 mg).
[00391] H NMR spectrum (300 MHz, CDCl ) δ 8.12(s, 1H), 7.72-7.63(m, 2H), 7.55(d, 1H), 7.36(d, 1H), 7.25(m, 1H), 7.13(d, 1H), 7.07(s, 1H), 4.46(q, 2H), 2.33(s, 3H), 1.43(t, 3H).
Step 6. Preparation of 5-(benzo[d]oxazolyl)(6-methylpyridinyl)- 1H-pyrazolecarboxylic acid
[00393] After dissolving ethyl 5-(benzo[d]oxazolyl)(6-methylpyridinyl)- 1H-pyrazolecarboxylate (300 mg, 0.9 mmol) synthesized in Step 5 in 1,4-dioxane (3 mL), a 1 N lithium hydroxide solution (1.5 mL, 1.5 mmol) dissolved in water was introduced thereto, and the result was stirred for 2 hours at room temperature. After terminating the reaction, the reaction solution was removed under vacuum, and the result was acidified to a pH of 2 to 3 by adding 1 N hydrochloric acid thereto, and then stirred for 1 hour at room temperature. The result was vacuum filtered and then purified using column chromatography to obtain Intermediate 6 (100 mg).
H NMR spectrum (300 MHz, DMSO-d ) δ 8.75(s, 1H), 7.85(t, 1H), 7.72- 7.68(m, 2H), 7.45(d, 1H), 7.24-7.17(m, 2H), 6.84(s, 1H), 2.14(s, 3H).
[00395] <Reaction Formula 8> [Preparation Example 7] 1-(6-Methylpyridinyl)(4-fluoro(1-(2- hydroxyethyl)-1H-pyrazolyl)-1H-pyrazolecarboxylic acid Step 1. Preparation of t-butyl 4-(5-acetylfluorophenyl)-1H-pyrazole carboxylate After dissolving 1-(3-bromofluorophenyl)ethanone (1.0 g, 4.6 mmol) in 1,4-dioxane (20 mL) and water (4 mL), t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran- 2-yl)-1H-pyrazolecarboxylate (2.0 g, 6.9 mmol), tripotassium phosphate (2.0 g, 9.2 mmol) and XPhos (156 mg, 0.2 mmol) were added thereto under nitrogen, and the result was heated under reflux for 5 hours at 100℃. The result was cooled to room temperature, then extracted with ethyl acetate, dried and concentrated. The result was purified using column chromatography to obtain a target compound (960 mg).
H NMR (300 MHz, CDCl ) δ 8.51 (s, 1H), 8.21 (d, 1H), 8.14 (s, 1H), 7.23 (d, 1H), 2.64 (s, 3H), 1.70 (s, 9H).
MS (ESI ): [M+H] m/z 305 Step 2. Preparation of ethyl(4-fluoro(1H-pyrazolyl)phenyl) hydroxyoxobutenoate After adding ethanol (15 mL) to diethyl oxalate (1.7 mL, 12.6 mmol), a 2 M ethoxysodium solution (6.3 mL, 12.6 mmol) was added thereto. t-Butyl 4-(5-acetyl- 2-fluorophenyl)-1H-pyrazolecarboxylate (1.0 g, 4.6 mmol) was slowly added thereto, and the result was stirred for 3 hours at room temperature. The solvent was vacuum concentrated, and the result was acidified by adding 2 N hydrochloric acid dropwise thereto. The result was extracted with ethyl acetate, the organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated to obtain a target compound (958 mg).
H NMR (300 MHz, CDCl ) δ 8.24 (d, 1H), 8.07 (s, 2H), 7.90-7.84 (m, 1H), 7.29-7.23 (m, 1H), 7.07 (s, 1H), 4.42 (q, 2H), 1.43 (t, 3H).
MS (ESI ): [M+H] m/z 305
[00406] Step 3. Preparation of ethyl 5-(4-fluoro(1H-pyrazolyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxylate After dissolving ethyl(4-fluoro(1H-pyrazolyl)phenyl)hydroxy- 4-oxobutenoate (955 mg, 3.1 mmol) and a 2-hydrazinylmethylpyridine hydrochloric acid salt (751 mg, 4.7 mmol) in ethanol (15 mL), the result was stirred for 2 hours at 50℃.
After terminating the reaction, the reaction solution was removed under vacuum. The result was extracted with ethyl acetate, dried using anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (658 mg).
H NMR (300 MHz, CDCl ) δ 7.90 (s, 2H), 7.72 (t, 1H), 7.53 (d, 1H), 7.40 (d, 1H), 7.18 (d, 1H), 7.12-7.09 (m, 3H), 4.49 (q, 2H), 2.42 (s, 3H), 1.46 (t, 3H).
MS (ESI ): [M+H] m/z 392 Step 4. Preparation of ethyl 5-(3-(1-(2-((t-butyldimethylsilyl)oxy)ethyl)- 1H-pyrazolyl)fluorophenyl)(6-methylpyridinyl)-1H-pyrazolecarboxylate After dissolving ethyl 5-(4-fluoro(1H-pyrazolyl)phenyl)(6- methylpyridinyl)-1H- pyrazolecarboxylate (650 mg, 1.7 mmol), (2-bromoethoxy)(t- butyl)dimethylsilane (477 mg, 2.0 mmol) and potassium carbonate (688 mg, 5.0 mmol) in N,N-dimethylformamide (15 mL), the result was stirred for 16 hours at 80℃. The result was cooled to room temperature, then extracted with ethyl acetate, dried using anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (740 mg).
H NMR (300 MHz, CDCl ) δ 7.88 (s, 1H), 7.75-7.70 (m, 2H), 7.51 (d, 1H), 7.41 (d, 1H), 7.19 (d, 1H), 7.11-7.08 (m, 3H), 4.51 (q, 2H), 4.29 (t, 2H), 4.00 (t, 2H), 2.44 (s, 3H), 1.47 (t, 3H), 0.88 (s, 9H), 0.02 (s, 6H).
MS (ESI ): [M+H] m/z 550
[00414] Step 5. Preparation of 5-(4-fluoro(1-(2-hydroxyethyl)-1H-pyrazol yl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxylic acid After adding an aqueous 50% ethanol solution (8 mL) to ethyl 5-(3-(1-(2- ((t-butyldimethylsilyl)oxy)ethyl)-1H-pyrazolyl)fluorophenyl)(6-methylpyridin- 2-yl)-1H-pyrazolecarboxylate (700 mg, 1.3 mmol), the result was stirred for 2 hours at 50℃. The result was vacuum concentrated and acidified with 2 N hydrochloric acid, and then produced solids were filtered and dried to obtain Intermediate 7 (460 mg).
H NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.74-7.69 (m, 2H), 7.50 (d, 1H), 7.40 (d, 1H), 7.18 (d, 1H), 7.08-7.05 (m, 3H), 4.32 (t, 2H), 4.06 (t, 2H), 2.40 (s, 3H).
MS (ESI ): m/z 408 [M+H]
[00418] <Reaction Formula 9> [Preparation Example 8] 1-(6-Methylpyridinyl)(thieno[3,2- c]pyridinyl)-1H-pyrazolecarboxylic acid Step 1. Preparation of (4-chloropyridinyl)methanol
[00422] After dissolving 4-chloronicotinic acid (7.0 g, 44.4 mmol) in tetrahydrofuran (500 mL), lithium aluminum hydride (1.68 g, 44.4 mmol) was introduced thereto, and the result was stirred for 1 hour at room temperature. After terminating the reaction, the reaction solution was removed under vacuum, and the result was extracted by introducing ethyl acetate and water thereto. The organic layer was dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain an intermediate (2.6 g).
H NMR spectrum (300 MHz, CDCl3) δ 8.62(s, 1H), 8.42(s, 1H), 7.48(s, 1H), 7.53(s, 2H).
Step 2. Preparation of 4-chloronicotinaldehyde
[00425] After dissolving (4-chloropyridinyl)methanol (2.6 g, 18.0 mmol) synthesized in Step 1 in dichloromethane (26 mL), manganese(IV) oxide (23.5 g, 270.5 mmol) was introduced thereto, and the result was stirred for 12 hours at 50℃. After terminating the reaction, the result was extracted by introducing water thereto. The organic layer was dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain an intermediate (1.37 g).
H NMR spectrum (300 MHz, CDCl ) δ 10.51(s, 1H), 9.05(s, 1H), 8.67(s, 1H), 7.42(s, 1H).
[00427] Step 3. Preparation of ethylthieno[3,2,c]pyridinecarboxylate After dissolving 4-chloronicotinaldehyde (3.3 g, 23.3 mmol) synthesized in Step 2 in N,N-dimethylformamide (33 mL) and water (3.3 mL), potassium carbonate (3.1 g, 23.3 mmol) was introduced thereto, and the result was stirred for 5 minutes at room temperature. After adding ethyl 2-mercaptoacetate (2.8 g, 23.3 mmol) dropwise thereto, the result was stirred for 12 hours at 50℃. After the reaction was completed, water was added dropwise thereto, the result was stirred for 1 hour, and solids were filtered to obtain an intermediate (2.3 g).
H NMR spectrum (300 MHz, CDCl3) δ 9.26(s, 1H), 8.54(s, 1H), 8.32(s, 1H), .13(s, 1H), 4.39(q, 2H), 1.33(t, 3H).
[00430] Step 4. Preparation of thieno[3,2-c]pyridinecarboxylic acid After dissolving ethylthieno[3,2,c]pyridinecarboxylate (2.3 g, 11.0 mmol) synthesized in Step 3 in methanol (25 mL), a 2 N lithium hydroxide solution dissolved in water was introduced thereto, and the result was stirred for 2 hours at 70℃.
After terminating the reaction, the reaction solution was removed under vacuum. The result was acidified by adding 12 N hydrochloric acid thereto, and then extracted by introducing chloroform/isopropanol (3:1) thereto. The organic layer was dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain an intermediate (1.89 g).
H NMR spectrum (300 MHz, CDCl ) δ 9.24(s, 1H), 8.52(s, 1H), 8.23(s, 1H), 8.10(s, 1H).
Step 5. Preparation of N-methoxy-N-methylthieno[3,2-c]pyridine carboxyamide After adding thieno[3,2-c]pyridinecarboxylic acid (1.9 g, 10.5 mmol), HATU (6.0 g, 15.8 mmol) and TEA (3.2 g, 31.6 mmol) to dichloromethane (38 mL) and N,N-dimethylformamide (7.5 mL), the result was stirred for 30 minutes. To the reaction solution, an N,O-dimethylhydroxylamine salt (1.1 g, 11.6 mmol) was introduced, and the result was stirred for 12 hours at room temperature. After terminating the reaction, the reaction solution was removed, and ethyl acetate was added thereto. The result was washed with water and saline, then dried using anhydrous magnesium sulfate, and filtered.
The filtrate was concentrated and purified using column chromatography to obtain a target compound (1.4 g).
H NMR spectrum (300 MHz, CDCl ) δ 9.19(s, 1H), 8.50(s, 1H), 8.27(s, 1H), 7.80(s, 1H), 3.83(s, 3H), 3.42(s, 3H).
Step 6. Preparation of 1-(thieno[3,2-c]pyridinyl)ethanone
[00437] After dissolving N-methoxy-N-methylthieno[3,2-c]pyridine carboxyamide (0.4 g, 1.7 mmol) synthesized in Step 5 in anhydrous tetrahydrofuran (5.1 mL) under argon, 3 M methyl magnesium bromide (2.8 mL, 2.5 mmol) dissolved in diethyl ether was added dropwise thereto at 0ºC. After terminating the reaction by introducing a saturated ammonium chloride solution thereto, ethyl acetate was introduced thereto, and the result was extracted. The organic layer was dried using anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated and then purified using column chromatography to obtain a target compound (250 mg).
H NMR spectrum (300 MHz, CDCl ) δ 9.19(s, 1H), 8.54(s, 1H), 7.80(s, 1H), 7.78(s, 1H), 2.68(s, 3H).
Step 7. Preparation of (Z)-ethyl 2-hydroxyoxo(thieno[3,2-c]pyridin- 2-yl)2-butenoate After dissolving 1-(thieno[3,2-c]pyridinyl)ethanone (0.3 g, 1.4 mmol) synthesized in Step 6 and diethyl oxalate (0.8 g, 5.6 mmol) in ethanol (2.5 mL), ethoxysodium (0.4 g, 5.6 mmol) was slowly added dropwise thereto at 50℃, and the result was refluxed for 2 hours. After cooling the result to room temperature, the solvent was vacuum concentrated, and the result was acidified by adding 2 M hydrochloric acid dropwise thereto. Dichloromethane was introduced thereto for extraction, and the organic layer was dried using anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (0.2 g).
H NMR spectrum (300 MHz, CDCl ) δ 9.51(s, 1H), 8.43(s, 1H), 8.16(s, 1H), 7.38(s, 1H), 7.38 (s, 1H), 4.23(q, 2H), 1.21(t, 3H).
Step 8. Preparation of ethyl 1-(6-methylpyridinyl) (thieno[3,2,c]pyridinyl)-1H-pyrazolecarboxylate After dissolving (Z)-ethyl 2-hydroxyoxo(thieno[3,2-c]pyridin yl)2-butenoate (0.2 g, 0.6 mmol) synthesized in Step 7 and 2-hydrazinylmethylpyridine hydrochloric acid (0.1 g, 0.6 mmol) in ethanol (1.5 mL), the result was refluxed for 2 hours.
After terminating the reaction, the reaction solution was removed under vacuum, and ethyl acetate was added thereto. The organic layer was washed with saline and then dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain a target compound (98 mg).
H NMR spectrum (300 MHz, CDCl ) δ 9.02(s, 1H), 8.45(s, 1H), 7.84- 7.70(m, 2H), 7.61(t, 1H), 7.52(s, 1H), 7.39-7.20(m, 2H), 4.50(q, 2H), 2.32(s, 3H), 1.43(t, 3H).
Step 9. Preparation of 1-(6-methylpyridinyl)(thieno[3,2-c]pyridin yl)-1H-pyrazolecarboxylic acid After dissolving ethyl 1-(6-methylpyridinyl)(thieno[3,2,c]pyridin yl)-1H-pyrazolecarboxylate (98 mg, 0.3 mmol) synthesized in Step 8 in 1,4-dioxane (1 mL), a 2 N lithium hydroxide solution dissolved in water was introduced thereto, and the result was stirred for 2 hours at 70℃. After terminating the reaction, the reaction solution was removed under vacuum. The result was acidified by adding 12 N hydrochloric acid thereto, and then extracted by introducing chloroform/isopropanol (3:1) thereto. The organic layer was dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain Intermediate 8 (82 mg).
H NMR spectrum (300 MHz, CDCl ) δ 9.50(s, 1H), 8.69(d, 2H), 8.06(s, 1H), 7.99(t, 1H), 7.64-7.61(m, 2H), 7.43 (d, 1H), 2.37(s, 3H).
[Example 1] 5-(Benzo[d]thiazolyl)-N-(4-methoxyphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide After dissolving 1-(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxylic acid (40 mg, 0.1 mmol) synthesized in Step 5 of Preparation Example 1 in dichloromethane, HATU (54 mg, 0.1 mmol) and DIPEA (60 μL, 0.4 mmol) were introduced thereto, and the result was stirred for 20 minutes at room temperature.
To the reaction solution, p-anisidine (16 mg, 0.1 mmol) was introduced, and the result was stirred for 12 hours at room temperature. After terminating the reaction, ethyl acetate was added thereto. The result was washed with sodium bicarbonate, then dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain a target compound (22 mg).
H NMR spectrum (300 MHz, CDCl ) δ 9.05(s, 1H), 8.76(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.66-7.63(m, 3H), 7.35(dd, 1H), 7.20(t, 3H), 7.20(dd, 2H), 3.82(s, 3H), 2.43(s, 3H).
MS (ESI ): [M+H] m/z 442.1 [Examples 2 to 81] Compounds of Examples 2 to 79 listed in the following [Table 1] were obtained in the same manner as in Step 1) of Example 1 using various amine derivatives instead of p-anisidine.
【Table 1 】 MS (ES) Actual Example H NMR Spectrum Measurement Structure Compound Name Number (300 MHz, CDCl ) δ Value[M+H] / Required Value 9.04(s, 1H), 8.73(s, 1H), -(benzo[d]thiazolyl)- 8.06(d, 1H), 7.98(d, 1H), N-(4-ethoxyphenyl) 7.69-7.60(m, 3H), 7.36(dd, 2 (6-methylpyridinyl)- 456.1/455.1 1H), 7.19(t, 3H), 6.90 (d, 1H-pyrazole 2H), 4.04(q, 2H), 2.42(s, 3H), carboxyamide 1.41(t, 3H) -(benzo[d]thiazolyl)- 9.05(s, 1H), 8.74(s, N-(4- 1H), 8.05(d, 1H), 7.98(d, (cyclopropylmethoxy)ph 1H), 7.69-7.61(m, 3H), 3 enyl)(6- 7.36(dd, 1H), 7.22(t, 3H), 482.2/481.2 methylpyridinyl)-1H- 6.92(d, 2H), 3.80(d, 2H), pyrazole 2.44(s, 3H), 1.28-1.21(m, carboxyamide 1H), 0.66(q, 2H), 0.36(q, 2H) 9.04(s, 1H), 8.77(s, 1H), -(benzo[d]thiazolyl)- 8.05(d, 1H), 7.98(d, 1H), N-(4-(2- 7.68-7.61(m, 3H), 7.36(dd, methoxyethoxy)phenyl)- 4 1H), 7.20(t, 3H), 6.95(d, 2H), 486.2/485.2 1-(6-methylpyridin 4.14-4.11(m, 2H), 3.77- yl)-1H-pyrazole 3.73(m, 2H), 3.46(s, 3H), carboxyamide 2.42(s, 3H) -(benzo[d]thiazolyl)- 9.05(s, 1H), 8.88(s, 1H), 1-(6-methylpyridin 8.05(d, 1H), 7.98(d, 1H), yl)-N-(4- 7.76(d, 2H), 7.67(t, 1H), 496.1/495.1 (trifluoromethoxy)pheny 7.36(dd, 1H), 7.25-7.19(m, l)-1H-pyrazole 5H), 2.45(s, 3H) carboxyamide -(benzo[d]thiazolyl)- (300 MHz, DMSO-d ) δ 6 N-(4- 10.15(s, 1H), 9.44(s, 1H), 518.2/517.2 (benzyloxy)phenyl) 8.26(d, 1H), 8.03(d, 1H), (6-methylpyridinyl)- 7.92(t, 1H), 7.73(d, 2H), 1H-pyrazole 7.61(d, 1H), 7.47-7.32(m, carboxyamide 6H), 7.20(s, 1H), 7.00(d, 2H), .10(s, 2H), 2.22(s, 3H) N -(benzo[d][1,3]dioxol- 9.05(s, 1H), 8.75(s, 1H), -yl)(benzo[d]thiazol- 8.05(d, 1H), 7.98(d, 1H), 6-yl)(6- 7.66(t, 1H), 7.45(d, 1H), 7 456.1/455.1 methylpyridinyl) 7.34(dd, 1H), 7.18(t, 3H), H-pyrazole 7.00(d, 1H), 6.70(d, 1H), carboxyamide 5.97(s, 2H), 2.44(s, 3H) -(benzo[d]thiazolyl)- 9.05(s, 1H), 8.81(s, 1H), N-(4-fluoro 8.05(d, 1H), 7.98(d, 1H), methoxyphenyl)(6- 8 7.74-7.64(m, 2H), 7.35(dd, 460.1/459.1 methylpyridinyl)-1H- 1H), 7.22(t, 3H), 7.02(d, 2H), pyrazole 3.94(s, 3H), 2.44(s, 3H). carboxyamide -(benzo[d]thiazolyl)- 9.04(s, 1H), 8.88(s, 1H), N-(2-fluoro 8.30(t, 1H), 8.05(d, 1H), methoxyphenyl)(6- 7.99(d, 1H), 7.69(t, 1H), 9 460.1/459.1 methylpyridinyl)-1H- 7.35(t, 2H), 7.18-7.15(m, pyrazole 2H), 6.70(d, 2H), 3.80(s, 3H), carboxyamide 2.36(s, 3H) -(benzo[d]thiazolyl)- 9.04(s, 1H), 8.77(s, 1H), 460.1/459.1 N-(3-fluoro 8.05(d, 1H), 7.98(d, 1H), methoxyphenyl)(6- 7.69-7.63(m, 2H), 7.35(d, methylpyridinyl)-1H- 2H), 7.19(t, 3H), 6.95(t, 1H), pyrazole 3.89(s, 3H), 2.43(s, 3H) carboxyamide (300 MHz, DMSO-d ) δ -(benzo[d]thiazolyl)- .50(s, 1H), 9.41(s, 1H), N-(3-aminophenyl) 8.25(s, 1H), 8.02(m, 1H), 11 (6-methylpyridinyl)- 427.1/426.1 7.91(t, 1H), 7.68(d, 1H), 1H-pyrazole 7.59(d, 1H), 7.43-7.32(m, carboxyamide 4H), 7.03(d, 1H), 2.22(s, 3H) (300 MHz, MeOD) δ 9.30(s, -(benzo[d]thiazolyl)- 1H), 8.11(s, 1H), 8.02(d, 1H), N-(3- 7.80(t, 1H), 7.42-7.37(m, (methylamino)phenyl)- 12 2H), 7.31(d, 1H), 7.17(s, 1H), 441.1/440.1 1-(6-methylpyridin 7.14-7.09(m, 2H), 7.00(d, yl)-1H-pyrazole 1H), 6.45(d, 1H), 2.80(d, carboxyamide 3H), 2.36(s, 3H) -(benzo[d]thiazolyl)- 9.04(s, 1H), 8.71(s, 1H), N-(4- 8.05(d, 1H), 7.98(d, 1H), (dimethylamino)phenyl) 7.66(t, 1H), 7.59(d, 2H), 13 455.2/454.2 (6-methylpyridin 7.36(dd, 1H), 7.23-7.16(m, yl)-1H-pyrazole 3H), 6.76(d, 2H), 2.95(s, 6H), carboxyamide 2.05(s, 3H) (300 MHz, DMSO-d ) δ -(benzo[d]thiazolyl)- .90(s, 1H), 9.45(s, 1H), 1-(6-methylpyridin 8.29-8.26(m, 3H), 8.15(d, 14 yl)-N-(4-nitrophenyl)- 457.1/456.1 2H), 8.05(d, 1H), 7.93(t, 1H), 1H-pyrazole 7.61(d, 1H), 7.38-7.34(m, carboxyamide 2H), 7.31(s, 1H), 2.27(s, 3H) -(benzo[d]thiazolyl)- 9.04(s, 1H), 8.68(s, 1H), N-(4-((2- 8.04(d, 1H), 7.98(d, 1H), (dimethylamino)ethyl)( 7.66(t, 1H), 7.56(d, 2H), N HN N methyl)amino)phenyl)- 7.35(d, 1H), 7.20(t, 3H), 490.1/489.1 1-(6-methylpyridin 6.74(d, 2H), 3.48(t, 2H), yl)-1H-pyrazole 2.96(s, 3H), 2.55(t, 2H), carboxyamide 2.43(s, 3H), 2.35(s, 6H) 9.05(s, 1H), 8.67(s, 1H), -(benzo[d]thiazolyl)- 8.07(d, 1H), 7.99(s, 1H), N-(4-(3- 7.67(t, 1H), 7.59(d, 2H), (dimethylamino)pyrrolid 7.38(d, 1H), 7.35-7.17(m, 16 inyl)phenyl)(6- 3H), 6.58(d, 2H), 3.55- 524.2/523.2 methylpyridinyl)-1H- 3.41(m,2H), 3.37-3.34(m, pyrazole 1H), 3.20(t, 1H), 2.93- carboxyamide 2.91(m, 1H), 2.43(s, 3H), 2.36(s, 6H), 2.24-2.22(m,1H) -(benzo[d]thiazolyl)- 9.04(s, 1H), 8.70(s, 1H), 17 570.1/569.1 N-(3-chloro 8.04(d, 1H), 7.97(s, 1H), (octahydro-6H- 7.74(s, 1H), 7.60(t, 1H), pyrrolo[3,4-b]pyridin 7.44(d, 1H), 7.34(d, 1H), yl)phenyl)(6- 7.24-7.15(m, 3H), 6.86(d, methylpyridinyl)-1H- 1H), 3.80-3.70(m,2H), 3.47- pyrazole 3.45(m,3 carboxyamide H), 3.30-3.06(m, 2H), 2.70(t, 1H), 2.41(s, 3H), 2.39- 2.36(m, 1 H), 1.77-1.73(m,3H) -(benzo[d]thiazolyl)- 9.08(s, 1H), 8.89(s, 1H), 1-(6-methylpyridin 8.05(d, 1H), 7.98(d, 1H), 18 yl)-N-phenyl-1H- 7.74(d, 2H), 7.66(t, 1H), 412.1/411.1 pyrazole 7.38-7.35(m, 3H), 7.22- carboxyamide 7.17(m, 4H), 2.43(s, 3H) (300 MHz, MeOD) δ 9.28(s, -(benzo[d]thiazolyl)- 1H), 8.06(s, 1H), 7.98(d, 1H), N-(3-tolyl)(6- 7.76(t, 1H), 7.56-7.53(m, 19 methylpyridinyl)-1H- 2H), 7.36(d, 2H), 7.30- 426.1/425.1 pyrazole 7.20(m, 2H), 7.13(s, 1H), carboxyamide 6.96(d, 1H), 2.34(s, 3H), 2.33(s, 3H) -(benzo[d]thiazolyl)- 9.05(s, 1H), 8.85(s, 1H), 1-(6-methylpyridin 8.05(d, 1H), 7.99(d, 1H), 438.1/437.1 yl)-N-(3-vinylphenyl)- 7.90(s, 1H), 7.70-7.62(m, 1H-pyrazole 2H), 7.34(d, 2H), 7.21(t, 3H), carboxyamide 6.73(dd, 1H), 5.80(d, 1H), .28(d, 1H), 2.43(s, 3H) -(benzo[d]thiazolyl)- 9.06(s, 1H), 9.01(s, 1H), N-(3- 8.08-8.05(m, 2H), 8.00- (trifluoromethyl)phenyl) 7.94(m, 2H), 7.68(t, 1H), 21 480.1/479.1 (6-methylpyridin 7.50(t, 1H), 7.41-7.34(m, yl)-1H-pyrazole 2H), 7.28-7.19(m, 3H), carboxyamide 2.45(s, 3H) 9.06(s, 1H), 8.95(s, 1H), -(benzo[d]thiazolyl)- 8.15(d, 1H), 8.06(d, 1H), N-(3-(cyanophenyl) 7.99(d, 1H), 7.80(dd, 1H), 22 (6-methylpyridinyl)- 437.1/436.1 7.68(t, 1H), 7.47-7.43(m, 1H-pyrazole 2H), 7.37(dd, 1H), 7.21- carboxyamide 7.18(m, 3H), 2.45(s, 3H) 9.07(s, 1H), 9.01(s, 1H), -(benzo[d]thiazolyl)- 8.27(s, 1H), 8.26-8.06(m, N-(3-acetylphenyl)(6- 2H), 8.00(s, 1H), 7.74- 23 methylpyridinyl)-1H- 454.1/453.1 7.67(m, 2H), 7.50(t, 1H), pyrazole 7.38(d, 1H), 7.25-7.20(m, carboxyamide 2H), 2.66(s, 3H), 2.45(s, 3H) ethyl 3-(5- 9.05(s, 1H), 8.95(s, 1H), 24 (benzo[d]thiazolyl) 8.21(s, 1H), 8.16(d, 1H), 484.1/483.1 (6-methylpyridinyl)- 8.06(d, 1H), 7.99(d, 1H), 1H-pyrazole 7.83(d, 1H), 7.66(t, 1H), carboxyamido)benzoate 7.46(t, 1H), 7.37(dd, 1H), 7.21 (t, 3H), 4.40(q, 2H), 2.43(s, 3H), 4.41(t, 3H) -(benzo[d]thiazolyl)- 9.05(s, 1H), 8.98(s, 1H), N-(4- 8.07(d, 1H), 7.99(d, 1H), (methylcarbamoyl)phen 7.80(s, 4H), 7.68(t, 1H), 469.1/468.1 yl)(6-methylpyridin- 7.35(dd, 1H), 7.21 (t, 3H), 2-yl)-1H-pyrazole 6.10(s, 1H), 3.03(d, 3H), carboxyamide 2.44(s, 3H) (300 MHz, DMSO-d ) δ .16(s, 1H), 9.90(s, 1H), -(benzo[d]thiazolyl)- 9.42(s, 1H), 8.85(d, 1H), N-(4- 8.39(d, 1H), 8.25(s, 1H), acetoamidophenyl)(6- 26 8.25-8.00(m, 2H), 7.90(t, 469.1/468.1 methylpyridinyl)-1H- 1H), 7.73(d, 2H), 7.60(d, pyrazole 1H), 7.53(d, 2H), 7.34(t, 2H), carboxyamide 7.19(s, 1H), 2.21(s, 3H), 2.01(s, 3H) -(benzo[d]thiazolyl)- 9.10(br, 1H), 9.05(s, 1H), N-(2-fluorophenyl)(6- 8.52(t, 1H), 8.06(d, 1H), 27 methylpyridinyl)-1H- 8.00(d, 1H), 7.70(t, 1H), 430.1/429.1 pyrazole 7.39-7.35(m, 2H), 7.20- carboxyamide 7.09(m, 5H), 2.35(s, 3H) -(benzo[d]thiazolyl)- 9.05(s, 1H), 8.91(s, 1H), N-(3-fluorophenyl)(6- 8.06(d, 1H), 7.98(d, 1H), 28 methylpyridinyl)-1H- 7.79-7.65(m, 2H), 7.37- 430.1/429.1 pyrazole 7.30(m, 3H), 7.23-7.18(m, carboxyamide 3H), 6.84(t, 1H), 2.44(s, 3H) -(benzo[d]thiazolyl)- 9.05(s, 1H), 8.84(s, 1H), N-(4-fluorophenyl)(6- 8.06(d, 1H), 7.98(d, 1H), 29 methylpyridinyl)-1H- 7.72-7.67(m, 3H), 7.36(d, 430.1 /429.1 pyrazole 1H), 7.22-7.18(m, 3H), carboxyamide 7.07(t, 2H), 2.44(s, 3H) 9.06(s, 1H), 8.86(s, 1H), -(benzo[d]thiazolyl)- 8.06(d, 1H), 7.98(d, 1H), N-(3,4-difluorophenyl)- 7.82-7.78(m, 1H), 7.67(t, 1-(6-methylpyridin 448.1/447.1 1H), 7.35(d, 1H), 7.30- yl)-1H-pyrazole 7.28(m, 1H), 7.21-7.13(m, carboxyamide 4H), 2.45(s, 3H) 9.49(s, 1H), 9.05(s, 1H), -(benzo[d]thiazolyl)- 8.60(d, 1H), 8.05(d, 1H), N-(2-chlorophenyl) 8.01(d, 1H), 7.73(t, 1H), 31 (6-methylpyridinyl)- 446.1/445.1 7.46-7.34(m, 4H), 7.19(s, 1H-pyrazole 1H), 7.15 (d, 1H), 7.07(t, carboxyamide 1H), 2.30(s, 3H) 9.05(s, 1H), 8.85(s, 1H), -(benzo[d]thiazolyl)- 8.05(d, 1H), 7.98(d, 1H), N-(3-chlorophenyl) 7.86(s, 1H), 7.67(t, 1H), 32 (6-methylpyridinyl)- 446.1/445.1 7.57(d, 1H), 7.36-7.30(m, 1H-pyrazole 2H), 7.21-7.10(m, 4H), carboxyamide 2.44(s, 3H) -(benzo[d]thiazolyl)- 9.05(s, 1H), 8.84(s, 1H), N-(4-chlorophenyl) 8.05(d, 1H), 7.98(d, 1H), 33 (6-methylpyridinyl)- 7.70-7.64(m, 3H), 7.36- 446.1/445.1 1H-pyrazole 7.30(m, 3H), 7.21-7.18(m, carboxyamide 3H), 2.44(s, 3H) -(benzo[d]thiazolyl)- 9.05(s, 1H), 8.83(s, 1H), N-(4-bromophenyl) 8.05(d, 1H), 7.98(d, 1H), 34 (6-methylpyridinyl)- 7.69-7.62(m, 3H), 7.48(d, 490.0/489.0 1H-pyrazole 2H), 7.34(d, 1H), 7.21- carboxyamide 7.18(m, 3H), 2.44(s, 3H) -(benzo[d]thiazolyl)- 9.04(s, 1H), 8.84(s, 1H), 1-(6-methylpyridin 8.05(d, 1H), 7.98(d, 1H), yl)-N-(3- 7.74(m, 1H), 7.67(t, 1H), 458.1/457.1 (methylthio)phenyl)-1H- 7.40(dd, 1H), 7.35(d, 1H), pyrazole 7.27-7.17(m, 4H), 7.01(d, carboxyamide 1H), 2.52(s, 3H), 2.43(s, 3H) -(benzo[d]thiazolyl)- 9.05(s, 1H), 8.84(s, 1H), 36 458.1/457.1 1-(6-methylpyridin 8.05(d, 1H), 7.98(d, 1H), yl)-N-(4- 7.69-7.64(m, 3H), 7.36- (methylthio)phenyl)-1H- 7.27(m, 4H), 7.21-7.18(m, pyrazole 2H), 2.49(s, 3H), 2.44(s, 3H) carboxyamide 9.04(s, 1H), 8.80(s, 1H), -(benzo[d]thiazolyl)- 8.05(d, 1H), 7.98(d, 1H), N-(4- 7.69-7.64(m, 3H), 7.40- (cyclopropylthio)phenyl) 37 7.34(m, 4H), 7.26-7.17(m, (6-methylpyridin 2H), 2.43(s, 3H), 2.23- yl)-1H-pyrazole 2.19(m, 1H), 1.08-1.03(m, carboxyamide 2H), 0.73-0.69(m, 2H) -(benzo[d]thiazolyl)- 9.09(s, 1H), 9.05(s, 1H), 1-(6-methylpyridin 8.07-7.98(m, 4H), 7.69(t, yl)-N-(3- 38 1H), 7.54(t, 1H), 7.43- 474.1/473.1 (methylsulfinyl)phenyl)- 7.34(m, 2H), 7.20-7.18(m, 1H-pyrazole 3H), 2.77(s, 3H), 2.42(s, 3H) carboxyamide -(benzo[d]thiazolyl)- 9.08(s, 1H), 9.06(s, 1H), 1-(6-methylpyridin 8.06(d, 1H), 7.98(d, 1H), N yl)-N-(4- 7.93(d, 2H), 7.69-7.64(m, N HN 39 474.1/473.1 (methylsulfinyl)phenyl)- 3H), 7.36(d, 1H), 7.22- 1H-pyrazole 7.17(m, 3H), 2.74(s, 3H), carboxyamide 2.46(s, 3H) -(benzo[d]thiazolyl)- 9.07(m, 2H), 8.24(s, 1H), 1-(6-methylpyridin 8.15(d, 1H), 8.06(d, 1H), yl)-N-(3- 7.99(d, 1H), 7.69(t, 2H), 40 490.1/489.1 (methylsulfonyl)phenyl) 7.59(t, 1H), 7.36(d, 1H), -1H-pyrazole 7.22-7.19(m, 3H), 3.10(s, carboxyamide 3H), 2.44(s, 3H) -(benzo[d]thiazolyl)- 9.12(s, 1H), 9.06(s, 1H), 1-(6-methylpyridin 8.06(d, 1H), 7.98-7.95(m, yl)-N-(4- 41 5H), 7.67(t, 1H), 7.35(d, 1H), 490.1/489.1 (methylsulfonyl)phenyl) 7.22-7.18(m, 3H), 3.07(s, -1H-pyrazole 3H), 2.46(s, 3H) carboxyamide -(benzo[d]thiazolyl)- 9.10(s, 1H), 9.06(s, 1H), 1-(6-methylpyridin 8.06(d, 1H), 7.99-7.89(m, yl)-N-(4- 5H), 7.68(t, 1H), 7.35(d, 1H), 42 518.1/517.1 (propylsulfonyl)phenyl)- 7.23-7.17(m, 3H), 3.10- 1H-pyrazole 3.05(m, 2H), 2.46(s, 3H), carboxyamide 1.80-1.72(m, 2H), 1.01(t, 3H) -(benzo[d]thiazolyl)- 9.08(s, 1H), 9.06(s, 1H), N-(4- 8.06(d, 1H), 7.98(d, 1H), 43 (cyclopropylsulfonyl)ph 7.95-7.91(m, 4H), 7.68(t, 516.1/515.1 enyl)(6- 1H), 7.35(d, 1H), 7.22- methylpyridinyl)-1H- 7.18(m, 3H), 2.49-2.46(m, pyrazole 4H), 1.37-1.35(m, 2H), 1.06- carboxyamide 1.02(m, 2H) -(benzo[d]thiazolyl)- 9.36(s, 1H), 9.07(s, 1H), N-(2-fluoro 8.86(t, 1H), 8.07(d, 1H), (methylsulfonyl)phenyl) 8.01(s, 1H), 7.82-7.70(m, 44 508.0/507.0 (6-methylpyridin 3H), 7.39-7.32(m, 3H), 7.22- yl)-1H-pyrazole 7.20(m, 2H), 3.09(s, 3H), carboxyamide 2.39(s, 3H) -(benzo[d]thiazolyl)- 9.12(s, 1H), 8.34(m, 1H), 1-(6-methylpyridin 8.08(d, 1H), 8.02(d, 1H), yl)-N-(3- 7.98(d, 1H), 7.70-7.60(m, 45 491.1/490.1 sulfamoylphenyl)-1H- 2H), 7.52(t, 1H), 7.37(d, 1H), pyrazole 7.24(d, 1H), 7.20(s, 2H), carboxyamide 6.98(d, 1H), 2.56(s, 3H) -(benzo[d]thiazolyl)- 9.12(s, 1H), 8.07(d, 1H), 1-(6-methylpyridin 8.01(d, 1H), 7.93(s, 4H), yl)-N-(4- 46 7.64(t, 1H), 7.39-7.26(m, 491.1/490.1 sulfamoylphenyl)-1H- 2H), 7.24(d, 1H), 7.21(s, 1H), pyrazole 7.00(d, 1H), 2.56(s, 3H) carboxyamide -(benzo[d]thiazolyl)- 9.06-7.05(m, 2H), 8.18(d, 1-(6-methylpyridin 1H), 8.05(d, 2H), 7.99(d, 47 505.1/504.1 yl)-N-(3-(N – 1H), 7.71-7.54(m, 3H), methylsulfamoyl)phenyl 7.35(d, 1H), 7.24-7.20(m, )-1H-pyrazole 3H), 4.41-4.39(bs, 1H), carboxyamide 2.73(s, 3H), 2.44(s, 3H) -(benzo[d]thiazolyl)- 9.06 (m, 2H), 8.06(d, 1H), 1-(6-methylpyridin 7.99(d, 1H), 7.93-7.85(m, yl)-N-(4-(N – 3H), 7.68(t, 1H), 7.35(d, 1H), 48 505.1/504.1 methylsulfamoyl)phenyl 7.22-7.18(m, 3H), 4.21- )-1H-pyrazole 4.19(bs, 1H), 2.69(s, 3H), carboxyamide 2.46(s, 3H) 9.06(s, 1H), 9.05(s, 1H), -(benzo[d]thiazolyl)- 8.19(d, 1H), 8.08(t, 2H), N-(3-(N- 7.99(d, 1H), 7.70-7.66(m, cyclopropylsulfamoyl)p 2H), 7.55(t, 1H), 7.35(d, 1H), 49 henyl)(6- 531.1/530.1 7.22-7.19(m, 3H), 4.91(s, methylpyridinyl)-1H- 1H), 2.44(s, 3H), 2.35- pyrazole 2.28(m, 1H), 0.68-0.64(m, carboxyamide -(benzo[d]thiazolyl)- 9.13(s, 1H), 9.06(s, 1H), N-(4-(N- 8.07(d, 1H), 8.00(d, 1H), cyclopropylsulfamoyl)p 7.85(d, 2H), 7.71(t, 1H), 50 henyl)(6- 7.42-7.34(m, 2H), 7.21- 531.1/530.1 methylpyridinyl)-1H- 7.17(m, 4H), 4.90(s, 1H), pyrazole 2.34(s, 3H), 2.25-2.22(m, carboxyamide 1H), 0.60-0.57(m, 4H) -(benzo[d]thiazolyl)- 9.08(s, 1H), 9.06(s, 1H), N-(3-(N,N - 8.10-8.05(m, 3H), 7.98(d, dimethylsulfamoyl)phen 1H), 7.68(t, 1H), 7.56- 51 519.1/518.1 yl)(6-methylpyridin- 7.54(m, 2H), 7.35(d, 1H), 2-yl)-1H-pyrazole 7.25-7.19(m, 3H), 2.76(s, carboxyamide 6H), 2.44(s, 3H) (300 MHz, DMSO-d ) δ -(benzo[d]thiazolyl)- .50(s, 1H), 9.23(s, 1H), N-(4-(N, N- 8.46(s, 1H), 8.02(m, 1H), dimethylsulfamoyl)phen 52 7.96(d, 2H), 7.89-7.85(m, 519.1/518.1 yl)(6-methylpyridin- 3H), 7.60(d, 2H), 7.34-7.29 2-yl)-1H-pyrazole (m, 1H), 7.25-7.22(m, 1H), carboxyamide 2.66(s, 6H), 2.51(s, 3H) 9.05(s, 1H), 8.90(s, 1H), -(benzo[d]thiazolyl)- 8.05(d, 1H), 7.98(d, 1H), 1-(6-methylpyridin 7.77(d, 1H), 7.68(t, 1H), yl)-N-(3- 53 7.48(d, 1H), 7.38-7.34(m, 505.1/504.1 (methylsulfonamide)phe 2H), 7.23-7.18(m, 3H), nyl)-1H-pyrazole 7.00(d, 1H), 6.40(s, 1H), carboxyamide 3.06(s, 3H), 2.43(s, 3H) -(benzo[d]thiazolyl)- 9.05(s, 1H), 8.89(s, 1H), N-(3- 8.05(d, 1H), 7.98(d, 1H), 54 531.1/530.1 (cyclopropanesulfonami 7.80(d, 1H), 7.67(t, 1H), do)phenyl)(6- 7.48(d, 1H), 7.35(d, 2H), methylpyridinyl)-1H- 7.23-7.18(m, 3H), 7.06(d, pyrazole 1H), 6.32(s, 1H), 2.56- carboxyamide 2.54(m, 1H), 2.43(s, 3H), 1.28-1.21(m, 2H), 1.04- 0.99(m, 2H) 9.06(s, 1H), 8.87(s, 1H), -(benzo[d]thiazolyl)- 8.05(d, 1H), 7.98(d, 1H), N-(4- 7.72(d, 2H), 7.67(t, 1H), (cyclopropanesulfonami 7.35(d, 1H), 7.30(d, 2H), 55 do)phenyl)(6- 531.1/530.1 7.23-7.18(m, 3H), 6.32(s, methylpyridinyl)-1H- 1H), 2.49-2.44(s, 4H), 1.18- pyrazole 1.15(m, 2H), 1.00-0.95(m, carboxyamide (300 MHz, DMSO-d ) δ 4-(5-(benzo[d]thiazol 10.30(s, 1H), 9.44(s, 1H), yl)(6-methylpyridin- 8.27(d, 1H), 8.03(d, 1H), 56 2-yl)-1H-pyrazole 7.93(t, 1H), 7.77(d, 2H), 492.1/491.1 carboxyamido)benzenes 7.65(d, 1H), 7.56(d, 2H), ulfonic acid 7.34(t, 2H), 7.23(s, 1H), 2.08(s, 3H) -(benzo[d]thiazolyl)- 9.23(s, 1H), 9.06(s, 1H), 1-(6-methylpyridin 57 8.08-8.04(m, 5H), 7.99(d, 544.1/543.1 yl)-N-(4- 1H), 7.68(t, 1H), 7.35(d, 1H), ((trifluoromethyl)sulfon yl)phenyl)-1H-pyrazole- 7.24-7.17(m, 3H), 2.47(s, 3-carboxyamide 3H) -(benzo[d]thiazolyl)- 9.09(s, 1H), 9.06(s, 1H), 1-(6-methylpyridin 8.06(d, 1H), 7.98(d, 1H), yl)-N-(4-(N- (2,2,2- 7.89(dd, 4H), 7.68(t, 1H), trifluoroethyl)sulfamoyl) 7.36(d, 1H), 7.22-7.19(m, phenyl)-1H-pyrazole 3H), 4.97(t, 1H), 3.73- carboxyamide 3.65(m, 2H), 2.45(s, 3H) 9.05(s, 1H), 8.93(s, 1H), -(benzo[d]thiazolyl)- 8.06(d, 1H), 7.99(d, 1H), 1-(6-methylpyridin 7.85(d, 1H), 7.75(d, 1H), yl)-N-(4- 59 7.68(t, 1H), 7.43(t, 2H), 504.1/503.1 ((methylsulfonyl)methyl 7.37(d, 1H), 7.23-7.18(m, )phenyl)-1H-pyrazole 3H), 4.27(s, 2H), 2.81(s, 3H), carboxyamide 2.43(s, 3H) (300 MHz, DMSO-d ) δ -(benzo[d]thiazolyl)- 10.31(s, 1H), 9.45(s, 1H), 1-(6-methylpyridin 8.27(d, 1H), 8.03(d, 1H), N S yl)-N-(3- 7.95-7.84(m, 3H), 7.64(d, N HN 60 505.1/504.1 (sulfamoylmethyl)pheny 1H), 7.39-7.33(m, 3H), l)-1H-pyrazole 7.24(s, 1H), 7.12(d, 1H), carboxyamide 6.88(s, 2H), 4.25(s, 2H), 2.22(s, 3H) (300 MHz, DMSO-d ) δ -(benzo[d]thiazolyl)- .32(s, 1H), 9.45(s, 1H), 1-(6-methylpyridin 8.27(d, 1H), 8.03(d, 1H), yl)-N-(4- 61 7.92(t, 1H), 7.84(d, 2H), 505.1/504.1 (sulfamoylmethyl)pheny 7.61(d, 1H), 7.35-7.33(m, l)-1H-pyrazole 4H), 7.24(s, 1H), 6.83(s, 2H), carboxyamide 4.23(s, 2H), 2.23(s, 3H) (300 MHz, DMSO-d ) δ -(benzo[d]thiazolyl)- .40(s, 1H), 9.45(s, 1H), N-(4-fluoro 8.27(d, 1H), 8.03(d, 1H), N S (sulfamoylmethyl)pheny N HN 62 7.97-7.90(m, 3H), 7.62(d, 523.1/522.1 l)(6-methylpyridin 1H), 7.35(dd, 2H), 7.23(dd, yl)-1H-pyrazole 2H), 7.06(s, 2H), 4.30(s, 2H), carboxyamide 2.23(s, 3H) 9.05(s, 1H), 8.85(s, 1H), -(benzo[d]thiazolyl)- 8.05(d, 1H), 7.98(d, 1H), N-(4-((1,1- 7.68(t, 1H), 7.62(d, 2H), dioxidotetrahydrothioph 7.37(d, 1H), 7.23-7.18(m, 63 enyl)amino)phenyl)- 545.1/544.1 3H), 6.70(d, 2H), 4.25(s, 1H), 1-(6-methylpyridin 3.45-2.98(m, 5H), 2.55- yl)-1H-pyrazole 2.50(m, 1H), 2.43(s, 3H), carboxyamide 2.33-2.30(m, 1H) -(benzo[d]thiazolyl)- 9.05(s, 1H), 8.96(s, 1H), 1-(6-methylpyridin 8.55(d, 2H), 8.05(d, 1H), 64 yl)-N-(pyridinyl)-1H- 7.98(d, 1H), 7.70-7.65(m, 413.1/412.1 pyrazole 3H), 7.35(d, 1H), 7.22- carboxyamide 7.19(m, 3H), 2.44(s, 3H) 9.05(s, 1H), 8.74(s, 1H), -(benzo[d]thiazolyl)- 8.38(d, 1H), 8.13(dd, 1H), N-(6-methoxypyridin 8.06(d, 1H), 7.98(d, 1H), 65 yl)(6-methylpyridin- 7.66(t, 1H), 7.35(d, 1H), 443.1/442.1 2-yl)-1H-pyrazole 7.21(s, 2H), 7.18(dd, 1H), carboxyamide 6.79(d, 1H), 3.94(s, 3H), 2.45(s, 3H) -(benzo[d]thiazolyl)- 9.06(s, 1H), 8.95(s, 1H), N-(2-methoxypyridin 8.11-8.04(m, 2H), 7.97(d, 66 yl)(6-methylpyridin- 1H), 7.67(t, 1H), 7.34(d, 1H), 443.1/442.1 2-yl)-1H-pyrazole 7.22-7.17(m, 5H), 3.95(s, carboxyamide 3H), 2.45(s, 3H) -(benzo[d]thiazolyl)- 9.07(s, 1H), 8.83(s, 1H), N-(6- 8.67(s, 1H), 8.18(d, 1H), (methylthio)pyridin 8.07(d, 1H), 7.99(s, 1H), 67 459.1/458.1 yl)(6-methylpyridin- 7.68(t, 1H), 7.36(d, 1H), 2-yl)-1H-pyrazole 7.24-7.20(m,4H), 2.59(s, carboxyamide 3H), 2.46(s, 3H) -(benzo[d]thiazolyl)- 9.64(s, 1H), 9.06(s, 1H), 1-(6-methylpyridin 8.68(d, 1H), 8.08-7.99(m, yl)-N-(6- 68 3H), 7.84(d, 1H), 7.73(t, 1H), 491.1/490.1 (methylsulfonyl)pyridin- 7.35(d, 2H), 7.22-7.13(m, 2-yl)-1H-pyrazole 2H), 3.22(s, 3H), 2.32(s, 3H) carboxyamide -(benzo[d]thiazolyl)- 9.16(s, 1H), 9.06(s, 1H), N-(6- 8.92(s, 1H), 8.60(d, 1H), (methylsulfonyl)pyridin- 8.12-8.05(m, 2H), 7.98(s, 69 3-yl)(6- 491.1/490.1 1H), 7.67(t, 1H), 7.34(d, 1H), methylpyridinyl)-1H- 7.23-7.16(m, 3H), 3.22(s, pyrazole 3H), 2.46(s, 3H) carboxyamide -(benzo[d]thiazolyl)- 9.30(s, 1H), 9.06(s, 1H), 1-(6-methylpyridin 8.66(d, 1H), 8.22(d, 1H), yl)-N-(2- 8.17(d, 1H), 8.06(d, 1H), 491.1/490.1 (methylsulfonyl)pyridin- 7.98(d, 1H), 7.70(t, 1H), 4-yl)-1H-pyrazole 7.35(d, 1H), 7.24-7.20(m, carboxyamide 3H), 3.24(s, 3H), 2.43(s, 3H) -(benzo[d]thiazolyl)- (300 MHz, DMSO-d ) δ N-(6-fluoropyridin 10.67(s, 1H), 9.45(s, 1H), 71 yl)(6-methylpyridin- 8.67(d, 1H), 8.38(t, 1H), 431.1/430.1 2-yl)-1H-pyrazole 8.27(d, 1H), 8.03(d, 1H), carboxyamide 7.93(t, 1H), 7.57(d, 1H), 7.37-7.32(m, 2H), 7.26- 7.20(m, 2H), 2.25(s, 3H) 9.15(s, 1H), 9.06(s, 1H), -(benzo[d]thiazolyl)- 8.16(d, 1H), 8.07(d, 1H), N-(2-fluoropyridin 7.98(d, 1H), 7.67(t, 1H), 72 yl)(6-methylpyridin- 431.1/430.1 7.52(d, 1H), 7.34(d, 1H), 2-yl)-1H-pyrazole 7.30(d, 1H), 7.23-7.16(m, carboxyamide 3H), 2.46(s, 3H) 9.05(s, 1H), 8.92(s, 1H), -(benzo[d]thiazolyl)- 8.58(d, 1H), 8.36(dd, 1H), N-(6-chloropyridin 8.06(d, 1H), 7.98(d, 1H), 73 yl)(6-methylpyridin- 447.1/446.1 7.67(t, 1H), 7.35(d, 2H), 2-yl)-1H-pyrazole 7.22-7.19(m, 3H), 2.44(s, carboxyamide 9.09(s, 1H), 9.06(s, 1H), -(benzo[d]thiazolyl)- 8.31(d, 1H), 8.06(d, 1H), N-(2-chloropyridin 7.98(d, 1H), 7.83(d, 1H), 74 yl)(6-methylpyridin- 447.1/446.1 7.67(t, 1H), 7.56(dd, 1H), 2-yl)-1H-pyrazole 7.34(d, 1H), 7.23-7.16(m, carboxyamide 3H), 2.46(s, 3H) .28(s, 1H), 9.05(s, 1H), -(benzo[d]thiazolyl)- 8.06(d, 1H), 8.00(d, 1H), 75 1-(6-methylpyridin 419.1/418.1 7.71(t, 1H), 7.51(d, 1H), yl)-N-(thiazolyl)-1H- 7.35(t, 2H), 7.21(s, 1H), pyrazole 7.20(d, 1H), 7.03(d, 1H), carboxyamide 2.34(s, 3H) -(benzo[d]thiazolyl)- 9.03(s, 1H), 8.04(d, 1H), N-benzyl(6- 7.95(d, 1H), 7.61(t, 1H), 76 methylpyridinyl)-1H- 426.1/425.1 7.40-7.30(m, 7H), 4.67(d, pyrazole 3H), 2.38(s, 3H) carboxyamide -(benzo[d]thiazolyl)- 9.03(s, 1H), 8.03(d, 1H), N-(2-fluorobenzyl)(6- 7.95(d, 1H), 7.63(t, 1H), 77 methylpyridinyl)-1H- 7.48-7.44(m, 2H), 7.34(dd, 444.2/443.1 pyrazole 1H), 7.20-7.09(m, 5H), carboxyamide 4.72(d, 2H), 2.38(s, 3H) 9.04(s, 1H), 8.04(d, 1H), -(benzo[d]thiazolyl)- 7.96(d, 1H), 7.62(t, 1H), N-(3-fluorobenzyl)(6- 7.45(t, 1H), 7.35-7.30(m, 78 methylpyridinyl)-1H- 444.1/443.1 2H), 7.19-7.13(m, 5H), pyrazole 6.97(t, 1H), 4.66(d, 2H), carboxyamide 2.39(s, 3H) -(benzo[d]thiazolyl)- 9.04(s, 1H), 8.04(d, 1H), N-(4-fluorobenzyl)(6- 7.95(d, 1H), 7.61(t, 1H), 79 methylpyridinyl)-1H- 7.38-7.31(m, 4H), 7.17- 444.1/443.1 pyrazole 7.13(m, 3H), 7.03(t, 2H), carboxyamide 4.63(d, 2H), 2.39(s, 3H) -(benzo[d]thiazolyl)- 9.06(s, 1H), 8.90(s, 1H), 1-(6-methylpyridin 8.61(s, 1H), 8.06(d, 1H), yl)-N-(1- 7.99-7.97(m, 2H), 7.66(t, 80 (methylsulfonyl)-1H- 480.1/479.1 1H), 7.35(d, 1H), 7.21- pyrazolyl)-1H- 7.14(m, 3H), 3.49(s, 3H), pyrazole 2.46(s, 3H) carboxyamide 9.05(s, 1H), 8.85(s, 1H), -(benzo[d]thiazolyl)- 8.58(s, 1H), 8.06(d, 1H), N-(1- 7.97(m, 2H), 7.66(t, 1H), (cyclopropylsulfonyl)- 7.36-7.33(m, 1H), 7.21- 81 1H-pyrazolyl)(6- 506.1/505.1 7.16(m, 3H), 2.79-2.74(m, methylpyridinyl)-1H- 1H), 2.45(s, 3H), 1.54- pyrazole 1.49(m, 2H), 1.23-1.16(m, carboxyamide [Example 82] 5-(Benzo[d]thiazolyl)-N-(3-hydroxyphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide Step 1. 5-(Benzo[d]thiazolyl)-N-(3-((tert- butyldimethylsilyl)oxy)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide A target compound (140 mg) was obtained in the same manner as in Example 1 except that 3-((tert-butyldimethylsilyl)oxy)aniline was used instead of p- anisidine.
H NMR spectrum (300 MHz, CDCl3) δ 9.04(s, 1H), 8.79(s, 1H), 8.05(d, 1H), 7.97(d, 1H), 7.66(t, 1H), 7.40(d, 1H), 7.34(d, 1H), 7.26-7.17(m, 5H), 6.64-6.61(m, 1H), 2.43(s, 3H), 1.01(s, 9H), 0.25(S, 6H).
Step 2. 5-(Benzo[d]thiazolyl)-N-(3-hydroxyphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide After dissolving 5-(benzo[d]thiazolyl)-N-(3-((tert- butyldimethylsilyl)oxy)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide (140 mg, 0.26 mmol) synthesized in Step 1 in tetrahydrofuran (2.5 mL), 1.0 M TBAF (0.78 mL, 0.78 mmol) was added dropwise thereto at room temperature, and the reaction solution was stirred for 1 hour. The reaction solution was removed under vacuum, and then ethyl acetate was added thereto. The organic layer was washed with sodium bicarbonate, and then dried using anhydrous magnesium sulfate, and after filtering, the filtrate was vacuum concentrated. The filtrate was purified using column chromatography to obtain a target compound (23 mg).
[00477] H NMR spectrum (300 MHz, CDCl ) δ 9.06(s, 1H), 8.93(s, 1H), 8.05(d, 1H), 8.00(d, 2H), 7.67(t, 1H), 7.38-7.18(m, 5H), 6.90(d, 1H), 6.68(d, 1H), 2.44(s, 3H).
MS (ESI ): [M+H] m/z 428.1 [Examples 83 to 85] Compounds of Examples 83 to 85 listed in the following [Table 2] were obtained in the same manner as in Step 2) of Example 82.
【Table 2 】 MS (ES) Example H NMR Spectrum (300 Actual Structure Compound Name Number MHz, CDCl ) δ Measurement Value[M+H] / Required Value 9.04(s, 1H), 8.71(s, 1H), -(benzo[d]thiazolyl)- 8.05(d, 1H), 7.98(d, 1H), N-(4-hydroxyphenyl) 7.66(t, 1H), 7.57(d, 2H), 83 (6-methylpyridinyl)- 428.1/427.1 7.37(d, 1H), 7.19(t, 3H), 1H-pyrazole 6.85(d, 2H), 4.93(s, 1H), carboxyamide 2.44(s, 3H) -(benzo[d]thiazolyl)- 9.05(s, 1H), 8.89(s, 1H), N-(3- 8.05(d, 1H), 7.99(d, 1H), (hydroxymethyl)phenyl) 7.77(s, 1H), 7.67(t, 2H), 84 442.1/441.1 (6-methylpyridin 7.37(t, 2H), 7.26-7.14(m, yl)-1H-pyrazole 4H), 7.43(d, 2H), 2.43(s, 3H), carboxyamide 1.80(s, 1H) -(benzo[d]thiazolyl)- 9.05(s, 1H), 8.88(s, 1H), N-(4- 8.05(d, 1H), 7.98(d, 1H), (hydroxymethyl)phenyl) 85 7.73(d, 2H), 7.67(t, 1H), 442.1/441.1 (6-methylpyridin 7.36(td, 3H), 7.20(t, 3H), yl)-1H-pyrazole 4.69(d, 2H), 2.44(s, 3H) carboxyamide [Example 86] N-(4-Aminophenyl)(benzo[d]thiazolyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide After dissolving 5-(benzo[d]thiazolyl) (6-methylpyridinyl)-N-(4- nitrophenyl)-1H-pyrazolecarboxyamide (65 mg, 0.14 mmol) synthesized in Example 14 in ethanol (1.5 mL) and dichloromethane (3mL), 20% PdOH/C (20 mg, 30% w/w) was added thereto at room temperature, and the reaction solution was stirred for 13 hours under hydrogen gas. The reaction solution was vacuum filtered through celite, and the solvent was vacuum concentrated. The result was purified using column chromatography to obtain a target compound (20 mg).
[00484] H NMR spectrum (300 MHz, CDCl3) δ 9.09(s, 1H), 8.05(d, 1H), 8.00(d, 1H), 7.63(t, 1H), 7.52(d, 2H), 7.36(d, 1H), 7.21(d, 1H), 7.18(s, 1H), 7.05(d, 1H), 6.74(d, 2H), 3.38(s, 2H), 2.51(s, 3H).
MS (ESI ): [M+H] m/z 427.1 [Example 87] 5-(Benzo[d]thiazolyl)-N-(4-(butylamino)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide Step 1. Tert-butyl(4-(5-(benzo[d]thiazolyl))(6-methylpyridinyl)- 1H-pyrazolecarboxyamido)phenyl)(butyl)-carbamate A target compound (110 mg) was obtained in the same manner as in Example 1 except that tert-butyl(4-aminophenyl)(butyl)carbamate was used instead of p- anisidine.
H NMR spectrum (300 MHz, CDCl ) δ 9.05(s, 1H), 8.85(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.71-7.64(m, 3H), 7.36(d, 1H), 7.20(td, 5H), 3.61(t, 2H), 2.44(s, 3H), 1.56-1.50(m, 2H), 1.43(s, 9H), 1.37-1.25(m, 2H), 0.90(t, 3H).
[00491] Step 2. 5-(Benzo[d]thiazolyl)-N-(4-(butylamino)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide After dissolving tert-butyl(4-(5-(benzo[d]thiazolyl))(6- methylpyridinyl)-1H-pyrazolecarboxyamido)phenyl)(butyl)-carbamate (110 mg, 0.19 mmol) synthesized in Step 1 in dichloromethane (1.5 mL), a 4.0 M hydrochloric acid 1,4-dioxane solution (0.28 mL, 1.13 mmol) was added dropwise thereto at room temperature, and the reaction solution was stirred for 13 hours at room temperature. After adding dichloromethane to the reaction solution, the organic layer was washed with sodium bicarbonate, dried using anhydrous magnesium sulfate, and after filtering, the filtrate was vacuum concentrated. The filtrate was purified using column chromatography to obtain a target compound (70 mg).
H NMR spectrum (300 MHz, CDCl ) δ 9.05(s, 1H), 8.67(s, 1H), 8.06(d, 1H), 7.99(d, 1H), 7.67(t, 1H), 7.53(d, 2H), 7.36(d, 1H), 7.20(t, 3H), 6.64(d, 2H), 3.13(t, 2H), 2.44(s, 3H), 1.65-1.51(m, 2H), 1.51-1.41(m, 2H), 0.98(t, 3H).
MS (ESI ): [M+H] m/z 483.2 [Example 88] A compound of Example 88 listed in the following [Table 3] was obtained in the same manner as in Step 2) of Example 87.
[00497] 【Table 3 】 MS (ES) Actual Example H NMR Spectrum (300 Measurement Structure Compound Name Number MHz, CDCl ) δ Value[M+H] / Required Value -(benzo[d]thiazolyl)- 9.04(s, 1H), 8.67(s, 1H), 88 N-(4- 8.05(d, 1H), 7.98(d, 1H), 467.2/466.2 (cyclopropylamino)phen 7.66(t, 1H), 7.53(d, 2H), yl)(6-methylpyridin- 7.37(d, 1H), 7.36(t, 3H), 2-yl)-1H-pyrazole 6.80(d, 2H), 2.46-2.43(m, carboxyamide 4H), 0.75-0.70(m, 2H), 0.54- 0.51(m, 2H) [Example 89] 5-(Benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4-(S- methylsulfonimidoyl)phenyl)-1H-pyrazolecarboxyamide Step 1. Ethyl-((4-(5-(benzo[d]thiazolyl))(6-methylpyridinyl)-1H- pyrazolecarboxyamido)phenyl)(methyl)(oxo)-λ -sulfanylidine)carbamate A target compound (50 mg) was obtained in the same manner as in Example 1 except that ethyl ((4-aminophenyl)(methyl)(oxo)-λ -sulfanylidine)carbamate was used instead of p-anisidine.
H NMR spectrum (300 MHz, CDCl ) δ 9.16(s, 1H), 9.06(s, 1H), 8.06(d, 1H), 8.00-7.98(m, 5H), 7.67(t, 1H), 7.35(d, 1H), 7.23-7.17(m, 3H), 4.15-4.07(m, 2H), 3.33(s, 3H), 2.46(s, 3H), 1.24(t, 3H).
Step 2. 5-(Benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4-(S- methylsulfonimidoyl)phenyl)-1H-pyrazolecarboxyamide After dissolving ethyl-((4-(5-(benzo[d]thiazolyl))(6-methylpyridin- 2-yl)-1H-pyrazolecarboxyamido)phenyl)(methyl)(oxo)-λ -sulfanylidine)carbamate (50 mg, 0.09 mmol) synthesized in Step 1 in ethanol (1.0 mL), a 1.5 M sodium ethoxide ethanol solution (0.30 mL, 0.45 mmol) was added dropwise thereto at room temperature, and the reaction solution was stirred for 5 hours at 60℃. After adding saline to the reaction solution, the result was extracted using a mixed solution of dichloromethane and methanol.
The organic layer was dried using anhydrous magnesium sulfate, and after filtering, the filtrate was vacuum concentrated. The filtrate was purified using column chromatography to obtain a target compound (10 mg).
H NMR spectrum (300 MHz, CDCl ) δ 9.16(s, 1H), 9.06(s, 1H), 8.08- 7.92(m, 6H), 7.67(t, 1H), 7.35(d, 1H), 7.23-7.15(m, 3H), 3.13(t, 2H), 2.47(s, 3H).
MS (ESI ): [M+H] m/z 489.1 [Example 90] Preparation of 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2- methoxyphenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide Step 1. Preparation of 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4- methoxyphenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide After dissolving 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6- methylpyridinyl)-1H-pyrazolecarboxylic acid (30 mg, 0.09 mmol) synthesized in Step 4) of Preparation Example 2 in N,N-dimethylformamide (1 mL), HATU (42 mg, 0.11 mmol) and DIPEA (34 μL, 0.28 mmol) were introduced thereto, and the result was stirred for 30 minutes at room temperature. To the reaction solution, p-anisidine (11 μL, 0.09 mmol) was introduced, and the result was stirred for 12 hours at room temperature. The result was extracted with ethyl acetate, and the obtained organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (20 mg, 50%).
H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.18 (s, 1H), 8.56 (s, 1H), 7.96 (m, 1H), 7.83-7.72 (m, 3H), 7.54 (m, 1H), 7.32 (br, 2H), 6.96 (d, 2H), 3.76 (s, 3H), 2.17 (s, 3H).
MS (ESI ): m/z 426 [M+H] .
[00513] [Examples 91 to 163] Compounds of Examples 91 to 163 listed in the following [Table 4] were obtained in the same manner as in Step 1) of Example 1 using various amine derivatives instead of p-anisidine.
【Table 4 】 Example Structural Formula Compound Name Analysis Data -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.79 (brs, 1H), 8.72 α]pyridinyl)-N-(3- (s, 1H), 8.38 (s, 1H), 7.76-7.69 (m, 2H), 7.57-7.47 91 methoxyphenyl)(6- (m, 3H), 7.27-7.15 (m, 4H), 6.72 (d, J = 8.1 Hz, methylpyridinyl)-1H- 1H), 3.84 (s, 3H), 2.31 (s, 3H). MS (ESI ): m/z pyrazolecarboxyamide 426 [M+H] .
H NMR (300 MHz, CDCl ) δ 9.42 (brs, 1H), 8.73 -([1,2,4]triazolo[1,5- (s, 1H), 8.54 (d, J = 7.8 Hz, 1H), 8.39 (s, 1H), α]pyridinyl)-N-(2- 7.80-7.64 (m, 3H), 7.49 (d, J = 9.0 Hz, 1H), 7.19 92 methoxyphenyl)(6- (s, 1H), 7.15-7.02 (m, 3H), 6.94 (d, J = 7.8 Hz, methylpyridinyl)-1H- 1H), 3.95 (s, 3H), 2.26 (s, 3H). MS (ESI ): m/z pyrazolecarboxyamide 426 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.0(s, 1H), 93 α]pyridinyl)-N-(4- 9.28(s, 1H), 9.18(s, 1H), 8.56(s, 1H), 7.98- hydroxyphenyl)(6- 7.93(m, 1H), 7.79(m, 2H), 7.61-7.51(m, 3H), methylpyridinyl)-1H- 7.32(d, 1H), 7.29(d, 1H), 6.77(d, 2H), 2.27(s, pyrazolecarboxyamide 3H). MS (ESI ): m/z 412 [M+H] .
H NMR (300 MHz, CDCl ) δ 8.71 (brs, 1H), 8.37 -([1,2,4]triazolo[1,5- (s, 1H), 7.74-7.68 (m, 2H), 7.61-7.53 (m, 3H), α]pyridinyl)-N-(4- 7.46 (d, J = 9.3 Hz, 1H), 7.18-7.13 (m, 2H), 6.90 94 isopropylphenyl)(6- (d, J = 8.1 Hz, 2H), 4.52 (q, J = 6.0 Hz, 1H), 2.29 methylpyridinyl)-1H- (s, 3H), 1.33 (d, J = 6.0 Hz, 6H). MS (ESI ): m/z pyrazolecarboxyamide 454 [M+H] .
H NMR (300 MHz, CDCl ) δ 8.71 (brs, 1H), 8.37 -([1,2,4]triazolo[1,5- (s, 1H), 7.74-7.68 (m, 2H), 7.62 (d, J = 9.0 Hz, α]pyridinyl)-N-(4-(2- 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 9.3 Hz, 95 methoxyethoxy)phenyl) 1H), 7.18-7.13 (m, 2H), 6.96 (d, J = 9.0 Hz, 2H), (6-methylpyridinyl)-1H- 4.12 (t, J = 4.8 Hz, 2H), 3.75 (t, J = 4.8 Hz, 2H), pyrazolecarboxyamide 3.45 (s, 3H), 2.29 (s, 3H). MS (ESI ): m/z 454 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.72 (brs, 1H), 8.39 α]pyridinyl)-N- (s, 1H), 7.76-7.69 (m, 2H), 7.56-7.44 (m, 3H), N (benzo[d][1,3]dioxolyl)- 96 7.19-7.15 (m, 2H), 7.00 (d, J = 8.1 Hz, 1H), 6.81 O 1-(6-methylpyridinyl)- (d, J = 7.8 Hz, 1H), 5.98 (s, 2H), 2.31 (s, 3H). MS 1H-pyrazole (ESI ): m/z 440 [M+H] . carboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.86 (brs, 1H), 8.73 97 (m, 1H), 8.39 (s, 1H), 8.31 (t, 1H), 7.80-7.69 (m, α]pyridinyl)-N-(2- fluoromethoxyphenyl) 2H), 7.63 (d, 1H), 7.48 (d, 1H), 7.19 (s, 1H), 7.15 (6-methylpyridinyl)-1H- (d, 1H), 6.76-6.72 (m, 2H), 3.81 (s, 3H), 2.27 (s, pyrazolecarboxyamide 3H). MS (ESI ): m/z 444.2 [M+H] -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.72-8.70 (m, 2H), α]pyridinyl)-N-(3- 8.39 (s, 1H), 7.76-7.70 (m, 2H), 7.63 (d, 1H), 7.54 98 fluoromethoxyphenyl) (d, 1H), 7.46 (d, 1H), 7.34 (d, 1H), 7.20-7.16 (m, (6-methylpyridinyl)-1H- 2H), 6.97 (t, 1H), 3.90 (s, 3H), 2.32 (s, 3H). MS pyrazolecarboxyamide (ESI ): m/z 444.2 [M+H] -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 9.33 (s, 1H), 8.75 α]pyridinyl)(6- (m, 1H), 8.60 (d, 1H), 8.39 (s, 1H), 7.79-7.68 (m, methylpyridinyl)-N-(2- 99 3H), 7.50 (d, 1H), 7.40-7.32 (m, 2H), 7.18 (s, 2H), (trifluoromethoxy)phenyl)- 7.13 (d, 1H), 2.23 (s, 3H). MS (ESI ): m/z 480.1 1H-pyrazole [M+H] carboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.86 (s, 1H), 8.73 α]pyridinyl)(6- (s, 1H), 8.39 (s, 1H), 7.80-7.70 (m, 3H), 7.62 (d, methylpyridinyl)-N-(3- 100 1H), 7.55 (d, 1H), 7.46 (d, 1H), 7.39 (t, 1H), 7.21 (trifluoromethoxy)phenyl)- (s, 1H), 7.18 (d, 1H), 7.03(d, 1H), 2.32 (s, 3H). 1H-pyrazole MS (ESI ): m/z 480.1 [M+H] carboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.86 (s, 1H), 8.73 α]pyridinyl)(6- (m, 1H), 8.39 (s, 1H), 7.80-7.70 (m, 4H), 7.54 (d, methylpyridinyl)-N-(4- 1H), 7.46 (d, 1H), 7.23-7.17 (m, 4H), 2.32 (s, 3H). (trifluoromethoxy)phenyl)- MS (ESI ): m/z 480.1 [M+H] 1H-pyrazole carboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.74 (s, 1H), 8.72 α]pyridinyl)-N-(3- (m, 1H), 8.39 (s, 1H), 7.76-7.69 (m, 2H), 7.58 (d, 102 (dimethylamino)phenyl) 1H), 7.46 (d, 1H), 7.31-7.15 (m, 4H), 6.96 (d, (6-methylpyridinyl)-1H- 1H), 6.55 (d, 1H), 2.99 (s, 6H), 2.31 (s, 3H). MS pyrazolecarboxyamide (ESI ): m/z 439.2 [M+H] -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 9.91(s, 1H), α]pyridinyl)-N-(4- 9.18(s, 1H), 8.56(s, 1H), 7.97(t, 1H), 7.82- 103 aminophenyl)(6- 7.79(m, 2H), 7.54(d, 1H), 7.45(d, 2H), 7.31(d, methylpyridinyl)-1H- 1H), 7.24(s, 1H), 6.54(d, 2H), 4.95(br, -NH ), pyrazolecarboxyamide 2.16(s, 3H) MS (ESI ): m/z 411 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 9.99(s, 1H), 9.17(s, 1H), 8.55(s, 1H), 7.95(m, 1H), 7.95- α]pyridinyl)-N-(4- 104 (dimethylamino)phenyl) 7.93(m, 2H), 7.78(d, 2H), 7.53(d, 1H), 7.30- (6-methylpyridinyl)H- 7.25(m, 2H), 6.72(d, 2H), 2.87(s, 6H), 2.16(s, pyrazolecarboxyamide 3H). MS (ESI ): m/z 439 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.72 (s, 1H), 8.60 α]pyridinyl)-N-(4- (s, 1H), 8.38 (s, 1H), 7.75-7.69 (m, 2H), 7.58-7.53 (pyrrolidinyl)phenyl)1- 105 (m, 3H), 7.47 (d, 1H), 7.19 (s, 1H), 7.15 (d, 1H), (6-methylpyridinyl)- - 6.57 (d, 2H), 3.32-3.27(m, 4H), 2.30 (s, 3H), 1H-pyrazole 2.03-1.99 (m, 4H). MS (ESI ): m/z 465.2 [M+H] carboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.71 (brs, 1H), 8.64 α]pyridinyl)-N-(4-((2- (s, 1H), 7.78-7.69 (m, 2H), 7.57-7.55 (m, 3H), (dimethylamino)ethyl)(met 7.46 (d, J = 9.3 Hz, 1H), 7.19-7.14 (m, 2H), 6.74 hyl)amino)phenyl)(6- (d, J = 9.0 Hz, 2H), 3.51 (t, J = 7.5 Hz, 2H), 3.96 methylpyridinyl)-1H- (s, 3H), 2.57 (t, J = 7.2 Hz, 2H), 2.36 (s, 6H), 2.30 pyrazolecarboxyamide (s, 3H). MS (ESI ): m/z 496 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.72 (s, 1H), 8.70 α]pyridinyl)-N-(4-(4- (s, 1H), 8.38 (s, 1H), 7.77-7.69 (m, 2H), 7.62-7.54 methylpiperazin 107 (m, 3H), 7.47 (d, 1H), 7.19-7.14 (m, 2H), 6.95 (d, yl)phenyl)(6- 2H), 3.21 (m, 4H), 2.60 (m, 4H), 2.36 (s, 3H), methylpyridinyl)-1H- 2.31 (s, 3H). MS (ESI ): m/z 494.2 [M+H] pyrazolecarboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.72 (s, 1H), 8.70 α]pyridinyl)-N-(4-(4- (s, 1H), 8.39 (s, 1H), 7.79-7.69 (m, 2H), 7.63 (d, acetylpiperazin 2H), 7.55 (d, 1H), 7.47 (d, 1H), 7.20-7.15 (m, yl)phenyl)(6- 2H), 6.95 (d, 2H), 3.80-3.77 (m, 2H), 3.65-3.62 methylpyridinyl)-1H- (m, 2H), 3.19-3.12 (m, 4H), 2.31 (s, 3H), 2.15 (s, pyrazolecarboxyamide 3H). MS (ESI ): m/z 522.2 [M+H] -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.72 (brs, 1H), 8.66 α]pyridinyl)-N-(4-((1,1- (s, 1H), 8.39 (s, 1H), 7.79-7.69 (m, 2H), 7.58-7.54 dioxidotetrahydrothiophen- (m, 3H), 7.46 (d, J = 9.0 Hz, 1H), 7.19-7.15 (m, 3-yl)amino)phenyl)(6- 2H), 6.66 (d, J = 9.0 Hz, 2H), 4.41-4.36 (m, 1H), methylpyridinyl)-1H- 4.01-3.98 (m, 1H), 3.76-3.69 (m, 1H), 3.303.28 pyrazolecarboxyamide (m, 1H), 3.04-3.00 (m, 1H), 2.70-2.50 (m, 1H), 2.36-2.31 (m, 1H), 2.31 (s, 3H). MS (ESI ): m/z 496 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.22 (brs, 1H), α]pyridinyl)-N-(4- 9.93 (s, 1H), 9.19 (s, 1H), 8.56 (s, 1H), 7.96 (d, J 110 acetamidophenyl)(6- = 7.8 Hz, 1H), 7.84-7.73 (m, 4H), 7.57-7.50 (m, methylpyridinyl)-1H- 3H), 7.32-7.29 (m, 2H), 2.17 (s, 3H), 2.03 (s, 3H). pyrazolecarboxyamide MS (ESI ): m/z 453 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.82 (s, 1H), 8.73 α]pyridinyl)-N-(4- (s, 1H), 8.39 (s, 1H), 7.79-7.69 (m, 4H), 7.56 (d, ((dimethylamino)methyl)ph 111 1H), 7.47 (d, 1H), 7.35 (d, 2H), 7.21 (s, 1H), 7.17 enyl)(6-methylpyridin (d, 1H), 3.50 (s, 2H), 2.31 (s, 9H). MS (ESI ): m/z yl)-1H-pyrazole 453.2 [M+H] carboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 12.66 (brs, 1H), α]pyridinyl)-N-(2- 9.21 (s, 1H), 8.77 (brs, 1H), 8.65 (d, J = 8.1 Hz, (methylcarbamoyl)phenyl)- 1H), 8.57 (s, 1H), 8.01 (t, J = 8.1 Hz, 1H), 7.83- 1-(6-methylpyridinyl)- 7.77 (m, 3H), 7.59-7.53 (m, 2H), 7.34-7.31 (m, 1H-pyrazole 2H), 7.23-7.18 (m, 1H), 2.83 (s, 3H), 2.15 (s, 3H). carboxyamide MS (ESI ): m/z 453 [M+H] .
H NMR (300 MHz, DMSO-d ) δ 10.46 (brs, 1H), -([1,2,4]triazolo[1,5- 9.18 (s, 1H), 8.55 (s, 1H), 8.35 (brs, 1H), 7.98- α]pyridinyl)-N-(4- 113 7.91 (m, 3H), 7.84-7.78 (m, 4H), 7.51 (d, J = 9.3 (methylcarbamoyl)phenyl)- Hz, 1H), 7.32-7.29 (m, 2H), 2.77 (s, 3H), 2.16 (s, 1-(6-methylpyridinyl)- 3H). MS (ESI ): m/z 453 [M+H] . 1H-pyrazole carboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.29(s, 1H), α]pyridinyl)(6- 9.20(s, 1H), 8.57(s, 1H), 7.95(t, 1H), 7.86- 114 methylpyridinyl)-N- 7.80(m, 4H), 7.54(d, 1H), 7.40-7.31(m, 4H), phenyl-1H-pyrazole 7.12(t, 1H), 2.18(s, 3H). MS (ESI ): m/z 396 carboxyamide [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.77 (s, 1H), 8.73 α]pyridinyl)(6- (s, 1H), 8.48 (m, 1H), 8.39 (s, 1H), 8.14-8.11 (m, 115 methylpyridinyl)-N-(o- 3H), 7.77-7.70 (m, 2H), 7.61 (d, 1H), 7.56 (d, tolyl)-1H-pyrazole 1H), 7.23-7.14 (m, 2H), 2.40 (s, 3H), 2.27 (s, 3H). carboxyamide MS (ESI ): m/z 410.2 [M+H] -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.74 (s, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 7.76-7.69 (m, 2H), 7.59-7.45 α]pyridinyl)(6- 116 methylpyridinyl)-N-(m- (m, 4H), 7.29-7.25 (m, 1H), 7.20 (s, 1H), 7.16 (d, tolyl)-1H-pyrazole 1H), 6.99 (s, 1H), 2.39 (s, 3H), 2.30 (s, 3H). MS carboxyamide (ESI ): m/z 410.2 [M+H] -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.72 (s, 2H), 8.38 α]pyridinyl)(6- (s, 1H), 7.78-7.69 (m, 2H), 7.61-7.55 (m, 3H), 117 methylpyridinyl)-N-(p- 7.46 (dd, 1H), 7.19-7.14 (m, 4H), 2.34 (s, 3H), tolyl)-1H-pyrazole 2.30 (s, 3H). MS (ESI ): m/z 410.2 [M+H] carboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.91 (s, 1H), 8.73 α]pyridinyl)(6- (s, 1H), 8.39 (s, 1H), 8.00-7.96 (m, 2H), 7.78-7.70 methylpyridinyl)-N-(3- (m, 2H), 7.58-7.40 (m, 4H), 7.21 (s, 1H), 7.18 (d, (trifluoromethyl)phenyl)- 1H), 2.32 (s, 3H). MS (ESI ): m/z 464.1 [M+H] 1H-pyrazole carboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.80 (s, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 7.80-7.70 (m, 4H), 7.61-7.56 α]pyridinyl)(6- 119 methylpyridinyl)-N-(4- (m, 2H), 7.46 (d, 1H), 7.34 (t, 1H), 7.22-7.15 (m, vinylphenyl)-1H-pyrazole- 2H), 6.73 (dd, 1H), 5.80 (d, 1H), 5.29 (d, 1H), 3-carboxyamide 2.31 (s, 3H). MS (ESI ): m/z 422.2 [M+H] -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.90 (s, 1H), 8.73 α]pyridinyl)-N-(3- (s, 1H), 8.40 (s, 1H), 8.12 (m, 1H), 7.95 (d, 1H), 120 cyanophenyl)(6- 7.78-7.71 (m, 2H), 7.55-7.44 (m, 4H), 7.22 (s, methylpyridinyl)-1H- 1H), 7.20 (d, 1H), 2.33 (s, 3H). MS (ESI ): m/z pyrazolecarboxyamide 421.1 [M+H] -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.70(s, 1H), α]pyridinyl)-N-(4- 9.18(s, 1H), 8.55(s, 1H), 8.08-8.05(m, 2H), 7.95- 121 cyanophenyl)(6- 7.92(m, 2H), 7.84-7.78(m, 3H), 7.52(d, 1H), methylpyridinyl)H- 7.35-7.30(m, 2H), 2.25(s, 3H). MS (ESI ): m/z pyrazolecarboxyamide 421 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.50(s, 1H), α]pyridinyl)-N-(3- 9.18(s, 1H), 8.55(s, 1H), 8.43(s, 1H), 8.12(d, 1H), 122 acetylphenyl)(6- 7.98-7.93(m,1H), 7.84-7.73(m,2H), 7.73(d, 1H), methylpyridinyl)-1H- 7.70-7.52(m, 2H), 7.32(br,2H), 2.58(s, 3H), pyrazolecarboxyamide 2.16(s, 3H). MS (ESI ): m/z 438 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.59(s, 1H), α]pyridinyl)-N-(4- 9.18(s, 1H), 8.55(s, 1H), 7.99-7.95(m, 5H), 7.83- 123 acetylphenyl)(6- 7.78(m,2H), 7.53(d, 1H), 7.34(br,2H), 2.54(s, methylpyridinyl)-1H- 3H), 2.25(s, 3H). MS (ESI ): m/z 438 [M+H] . pyrazolecarboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.0(s, 1H), α]pyridinyl)-N-(2- 9.20(s, 1H), 8.57(s, 1H), 7.96(t, 1H), 7.83- 124 fluorophenyl)(6- 7.78(m, 3H), 7.54(d, 1H),7.33-7.25(m, methylpyridinyl)-1H- 5H),2.18(s, 3H). MS (ESI ): m/z 414 [M+H] . pyrazolecarboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.48(s, 1H), 9.18(s, 1H), 8.55(s, 1H), 7.98(t, 1H), 7.81- α]pyridinyl)-N-(3- 125 fluorophenyl)(6- 7.78(m, 3H), 7.66(d, 1H), 7.52(d, 1H), 7.48- methylpyridinyl)-1H- 6.97(m, 3H), 6.91(t, 1H), 2.18(s, 3H). MS (ESI ): pyrazolecarboxyamide m/z 414 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.37(s, 1H), α]pyridinyl)-N-(4- 9.17(s, 1H), 8.56(s, 1H), 7.98-7.79(m, 5H), 126 fluorophenyl)(6- 7.52(d, 1H), 7.31-7.17(m, 4H), 2.25(s, 3H). MS methylpyridinyl)-1H- (ESI ): m/z 414 [M+H] . pyrazolecarboxyamide H NMR (300 MHz, DMSO-d ) δ 10.00(s, 1H), -([1,2,4]triazolo[1,5- 9.34(s, 1H), 8.57(s, 1H), 7.97(m, 2H), 7.80(m, 127 α]pyridinyl)-N-(2- 2H), 7.58(m, 3H), 7.42-7.35(m, 3H), 2.17(s, 3H). chlorophenyl)(6- MS (ESI ): m/z 430 [M+H] . methylpyridinyl)-1H- pyrazolecarboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.45(s, 1H), α]pyridinyl)-N-(3- 9.18(s, 1H), 8.55(s, 1H), 8.16(s, 1H), 7.98(t, 1H), 128 chlorophenyl)(6- 7.86-7.79(m, 3H), 7.50(d, 1H), 7.32(br, 4H), methylpyridinyl)-1H- 2.17(s, 3H). MS (ESI ): m/z 430 [M+H] . pyrazolecarboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.45(s, 1H), α]pyridinyl)-N-(4- 9.19(s, 1H), 8.57(s, 1H), 7.99-7.80(m, 5H), 129 chlorophenyl)(6- 7.53(d, 1H), 7.44(m, 2H), 7.31(br, 2H), 2.25(s, methylpyridinyl)-1H- 3H). MS (ESI ): m/z 430 [M+H] . pyrazolecarboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 9.87(s, 1H), 9.18(s, 1H), 8.56(s, 1H), 7.96-7.93(m, 2H), 7.82- α]pyridinyl)-N-(2- 130 bromophenyl)(6- 7.74(m, 2H), 7.54-7.43(m, 3H), 7.33(br, 2H), methylpyridinyl)-1H- 7.16(t, 1H), 2.16(s, 3H). MS (ESI ): m/z 474 pyrazolecarboxyamide [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.45(s, 1H), α]pyridinyl)-N-(3- 9.18(s, 1H), 8.55(s, 1H), 8.16(s, 1H), 7.98(t, 1H), 131 bromophenyl)(6- 7.86-7.79(m, 3H), 7.50(d, 1H), 7.32(br, 4H), methylpyridinyl)-1H- 2.17(s, 3H). MS (ESI ): m/z 474 [M+H] . pyrazolecarboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.44(s, 1H), α]pyridinyl)-N-(4- 9.19(s, 1H), 8.57(s, 1H), 7.99(t, 1H), 7.86- bromophenyl)(6- 7.79(m, 2H), 7.57-7.50(m, 4H), 7.31(br, 3H), methylpyridinyl)-1H- 2.25(s, 3H). MS (ESI ): m/z 474 [M+H] . pyrazolecarboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.27(s, 1H), α]pyridinyl)-N-(2,3- 9.18(s, 1H), 8.55(s, 1H), 7.97(t, 1H), 7.78(t, 2H), 133 difluorophenyl)(6- 7.48(d, 2H), 7.31-7.21(m, 4H), 2.16(s, 3H). MS methylpyridinyl)-1H- (ESI ): m/z 432 [M+H] . pyrazolecarboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.08(s, 1H), α]pyridinyl)-N-(2,4- 9.18(s, 1H), 8.55(s, 1H), 7.97(t, 1H), 7.78(t, 2H), 134 difluorophenyl)(6- 7.68-7.66(m, 1H), 7.52(d, 1H), 7.37-7.29(m, 3H), methylpyridinyl)-1H- 7.13(t, 1H), 2.06(s, 3H). MS (ESI ): m/z 432 pyrazolecarboxyamide [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.04(s, 1H), α]pyridinyl)-N-(2,5- 9.18(s, 1H), 8.55(s, 1H), 7.95(t, 1H), 7.81- 135 difluorophenyl)(6- 7.71(m, 3H), 7.52(d, 1H), 7.41-7.33(br, 3H), methylpyridinyl)-1H- 7.13-7.09(m, 1H), 2.17(s, 3H). MS (ESI ): m/z pyrazolecarboxyamide 432 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.64(s, 1H), α]pyridinyl)-N-(3,4- F 9.20(s, 1H), 8.55(s, 1H), 7.95(t, 2H), 7.65(br, 2H), N HN 136 difluorophenyl)(6- 7.49(br, 1H), 7.49-7.39(m, 2H), 7.32(br, 2H), methylpyridinyl)-1H- 2.25(s, 3H). MS (ESI ): m/z 432 [M+H] . pyrazolecarboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 9.19(s, 1H), 8.98(s, α]pyridinyl)-N-(3,5- 1H), 8.24(s, 1H), 7.80-7.73(m, 2H), 7.70-7.60(m, 137 difluorophenyl)(6- 3H, 7.55-7.44(m, 3H), 6.64-6.57(m, 1H), 2.25(s, methylpyridinyl)-1H- 3H). MS (ESI ): m/z 432 [M+H] . pyrazolecarboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.24(s, 1H), α]pyridinyl)-N-(3- 9.18(s, 1H), 8.55(s, 1H), 7.94(t, 2H), 7.78(t, 2H), 138 chlorofluorophenyl) 7.66(m, 1H), 7.51-7.43(m, 2H), 7.31-7.25(m, (6-methylpyridinyl)-1H- 3H), 2.16(s, 3H). MS (ESI ): m/z 448 [M+H] . pyrazolecarboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.33(s, 1H), α]pyridinyl)-N-(4- 9.44(s, 1H), 8.56(s, 1H), 7.83(t, 1H), 7.79- 139 chlorofluorophenyl) 7.73(m, 3H), 7.65-7.50(m, 3H), 7.32(br, 2H), (6-methylpyridinyl)-1H- 2.18(s, 3H). MS (ESI ): m/z 448 [M+H] . pyrazolecarboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.52(s, 1H), α]pyridinyl)-N-(3- 9.18(s, 1H), 8.55(s, 1H), 8.12(d, 2H), 7.95(t, 1H), 140 chlorofluorophenyl) 7.80-7.78(br, 2H), 7.52-7.40(m, 2H), 7.32(br, (6-methylpyridinyl)-1H- 2H), 2.17(s, 3H). MS (ESI ): m/z 448 [M+H] . pyrazolecarboxyamide H NMR (300 MHz, DMSO-d ) δ 10.59(s, 1H), -([1,2,4]triazolo[1,5- 9.18(s, 1H), 8.55(s, 1H), 7.98(s, 1H), 7.98- 141 α]pyridinyl)-N-(3,4- 7.78(m, 4H), 7.64(d, 1H), 7.61(d, 1H), 7.21(br, dichlorophenyl)(6- 2H), 2.17(s, 3H). MS (ESI ): m/z 464 [M+H] . methylpyridinyl)-1H- pyrazolecarboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.17(s, 1H), α]pyridinyl)-N-(2- 9.14(s, 1H), 8.49(s, 1H), 7.96(t, 1H), 7.85- 142 bromofluorophenyl) 7.70(m, 4H), 7.51(m, 1H), 7.32(br, 3H), 2.17(s, (6-methylpyridinyl)-1H- 3H). MS (ESI ): m/z 492 [M+H] . pyrazolecarboxyamide H NMR (300 MHz, CDCl ) δ 8.80 (brs, 1H), 8.73 -([1,2,4]triazolo[1,5- (s, 1H), 8.39 (s, 1H), 7.76-7.70 (m, 3H), 7.57 (d, α]pyridinyl)-N-(3- J = 7.8 Hz, 1H), 7.48-7.43 (m, 2H), 7.28 (t, J = 7.8 143 (methoxythio)phenyl)(6- Hz, 1H), 7.19-7.15 (m, 2H), 7.04 (d, J = 8.1 Hz, methylpyridinyl)-1H- 1H), 2.52 (s, 3H), 2.19 (s, 3H). MS (ESI ): m/z pyrazolecarboxyamide 442 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.77 (brs, 1H), 8.72 α]pyridinyl)-N-(4- (s, 1H), 8.39 (s, 1H), 7.77-7.66 (m, 4H), 7.56 (d, 144 (methoxythio)phenyl)(6- J = 7.8 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.32- methylpyridinyl)-1H- 7.29 (m, 2H), 7.18-7.16 (m, 2H), 2.50 (s, 3H), pyrazolecarboxyamide 2.32 (s, 3H). MS (ESI ): m/z 442 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 9.03 (brs, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 8.01-7.98 (m, 2H), 7.78-7.70 α]pyridinyl)-N-(3- 145 (methylsulfinyl)phenyl) (m, 2H), 7.60-7.37 (m, 4H), 7.20-7.16 (m, 2H), (6-methylpyridinyl)-1H- 2.77 (s, 3H), 2.30 (s, 3H). MS (ESI ): m/z 458 pyrazolecarboxyamide [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.98 (brs, 1H), 8.73 α]pyridinyl)-N-(4- (s, 1H), 8.39 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 146 (methylsulfinyl)phenyl) 7.79-7.66 (m, 4H), 7.55 (d, J= 7.8 Hz, 1H), 7.46 (6-methylpyridinyl)-1H- (d, J = 9.3 Hz, 1H), 7.21-7.17 (m, 2H), 2.74 (s, pyrazolecarboxyamide 3H), 2.32 (s, 3H). MS (ESI ): m/z 458 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 9.06 (brs, 1H), 8.75 α]pyridinyl)-N-(4- (s, 1H), 8.41 (s, 1H), 7.97 (m, 4H), 7.82-7.72 (m, 147 (methylsulfonyl)phenyl) 2H), 7.55 (d, J= 8.1 Hz, 1H), 7.48 (d, J = 9.3 Hz, (6-methylpyridinyl)-1H- 1H), 7.24-7.20 (m, 2H), 3.09 (s, 3H), 2.35 (s, 3H). pyrazolecarboxyamide MS (ESI ): m/z 474 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 10.63 (brs, 1H), 9.21 (s, 1H), 8.57 (s, 1H), 8.04-7.94 (m, 3H), α]pyridinyl)-N-(4- 148 sulfomoylphenyl)(6- 7.83-7.80 (m, 4H), 7.53 (d, J = 9.3 Hz, 1H), 7.35- methylpyridinyl)-1H- 7.30 (m, 4H), 2.19 (s, 3H). MS (ESI ): m/z 475 pyrazolecarboxyamide [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 9.05 (brs, 1H), 8.73 α]pyridinyl)-N-(4-(S- (s, 1H), 8.39 (s, 1H), 7.04-7.91 (m, 4H), 7.77-7.70 methylsulfonimidoyl)pheny 149 (m, 2H), 7.53 (d, J= 7.8 Hz, 1H), 7.46 (d, J = 9.3 l)(6-methylpyridinyl)- Hz, 1H), 7.22-7.18 (m, 2H), 3.12 (s, 3H), 2.33 (s, 1H-pyrazole 3H). MS (ESI ): m/z 473 [M+H] . carboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 9.06 (brs, 1H), 8.75 150 (s, 1H), 8.41 (d, J = 6.9 Hz, 2H), 7.80-7.48 (m, α]pyridinyl)-N-(4- (propylsulfonyl)phenyl) 4H), 7.24-7.20 (m, 2H), 7.07 (d, J = 7.2 Hz, 1H), (6-methylpyridinyl)-1H- 6.84 (s, 1H), 3.12-3.07 (m, 1H), 2.20 (s, 3H), pyrazolecarboxyamide 1.81-1.71 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H). MS (ESI ): m/z 502 [M+H] .
H NMR (300 MHz, CDCl ) δ 9.04 (brs, 1H), 8.73 -([1,2,4]triazolo[1,5- (s, 1H), 8.39 (s, 1H), 7.95-7.88 (m, 4H), 7.80-7.70 α]pyridinyl)-N-(4- (m, 2H), 7.54 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 9.3 151 (propylsulfonyl)phenyl) Hz, 1H), 7.43-7.18 (m, 2H), 2.50-2.44 (m, 1H), (6-methylpyridinyl)-1H- 2.33 (s, 3H), 1.38-1.32 (m, 2H), 1.07-1.00 (m, pyrazolecarboxyamide 3H). MS (ESI ): m/z 502 [M+H] .
H NMR (300 MHz, DMSO-d ) δ 10.68 (brs, 1H), -([1,2,4]triazolo[[1,5- 9.21 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.40 (t, J α]pyridinyl)-N-(6- = 6.9 Hz, 1H), 7.97 (t, J = 7.8 Hz, 1H), 7.83-7.78 N HN 152 fluoropyridinyl)(6- (m, 2H), 7.51 (d, J= 9.3 Hz, 1H), 7.35-7.33 (m, methylpyridinyl)-1H- 2H), 7.24 (d, J = 8.7 Hz, 1H), 2.20 (s, 3H). MS pyrazolecarboxyamide (ESI ): m/z 415 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 9.42(s, 1H), 8.74(s, 1H), 8.49(br, 2H), 7.91(t, 1H), 7.75(d, α]pyridinyl)-N-(6- 153 chloropyridinyl)(6- 1H), 7.64(d, 2H), 7.50-7.48(m, 2H), 7.37(d, 1H), methylpyridinyl)-1H- 7.27(s, 1H), 2.13(s, 3H). MS (ESI ): m/z 431 pyrazolecarboxyamide [M+H] .
H NMR (300 MHz, CDCl ) δ 8.72 (brs, 1H), 8.71 -([1,2,4]triazolo[1,5- (s, 1H), 8.68-8.36 (m, 2H), 8.11 (d, J = 9.0 Hz, 154 α]pyridinyl)-N-(6- 1H), 7.76-7.69 (m, 2H), 7.54 (d, J = 7.8 Hz, 1H0, methoxypyridinyl)(6- 7.45 (d, J = 9.0 Hz, 1H), 7.24-7.15 (m, 2H), 6.79 methylpyridinyl)-1H- (d, J = 9.0 Hz, 1H), 3.94 (s, 3H), 2.32 (s, 3H). MS pyrazolecarboxyamide (ESI ): m/z 427 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 9.25(s, 1H), α]pyridinyl)-N-(2- 9.01(t, 1H), 8.54(s, 1H), 7.89(t, 1H), 7.77(d, 1H), 155 fluorobenzyl)(6- 7.70(d, 1H), 7.51(d, 1H), 7.38-7.27(m, 3H), methylpyridinyl)-1H- 7.14(br, 2H), 4.54(d, 2H), 2.15(s, 3H). MS (ESI ): pyrazolecarboxyamide m/z 428 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 9.15(s, 1H), α]pyridinyl)-N-(3- 9.00(t, 1H), 7.95(s, 1H), 7.81(t, 1H), 7.78(d, 1H), 156 fluorobenzyl)(6- 7.71(d, 1H), 7.52(d, 1H), 7.48-7.28(m, 3H), methylpyridinyl)-1H- 7.15(br, 2H), 4.55(d, 2H), 2.15(s, 3H). MS (ESI ): pyrazolecarboxyamide m/z 428 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 9.21(s, 1H), 9.10(t, 1H), 8.61(s, 1H), 7.87(t, 1H), 7.83(d, 1H), α]pyridinyl)-N-(4- 157 fluorobenzyl)(6- 7.75(d, 1H), 7.57(d, 1H), 7.46-7.42(m, 2H), methylpyridinyl)-1H- 7.33(d, 1H), 7.18(br, 3H), 4.53(d, 2H), 2.22(s, pyrazolecarboxyamide 3H). MS (ESI ): m/z 428 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.71 (brs, 1H), 8.39 (s, 1H), 7.72-7.69 (m, 2H), 7.52-7.45 (m, 2H), α]pyridinyl)-N-(3- 158 methoxybenzyl)(6- 7.31-7.11 (m, 3H), 6.99-6.87 (m, 3H), 4.66 (d, J = methylpyridinyl)-1H- 4.0 Hz, 2H), 3.82 (s, 3H), 2.28 (s, 3H). MS (ESI ): pyrazolecarboxyamide m/z 440 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.71 (brs, 1H), 8.39 α]pyridinyl)-N-(4- (s, 1H), 7.72-7.68 (m, 2H), 7.51-7.44 (m, 2H), methoxybenzyl)(6- 7.33 (d, J = 8.7 Hz, 2H), 7.15-7.11 (m, 2H), 6.91 methylpyridinyl)-1H- (d, J = 8.7 Hz, 2H), 4.62 (d, J = 4.0 Hz, 2H), 3.82 pyrazolecarboxyamide (s, 3H), 2.28 (s, 3H). MS (ESI ): m/z 440 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, CDCl ) δ 8.70 (s, 1H), 8.37 (s, 1H), 7.70-7.66 (m, 2H), 7.47 (dd, 2H), 7.28- α]pyridinyl)-N-(4- 160 (dimethylamino)benzyl) 7.25 (m, 3H), 7.13 (s, 1H), 7.10 (d, 1H), 6.73 (d, (6-methylpyridinyl)-1H- 2H), 4.57 (d, 2H), 2.94 (s, 6H), 2.25 (s, 3H). MS pyrazolecarboxyamide (ESI ): m/z 453.2 [M+H] H NMR (300 MHz, DMSO-d ) δ 8.90 (brs, 1H), -([1,2,4]triazolo[1,5- 9.15 (s, 1H), 8.99 (t, 1H), 8.55 (s, 1H), 7.91 (t, J α]pyridinyl)-N-(- = 8.1 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.72 (d, J 161 acetamidobenzyl)(6- = 8.1 Hz, 1H), 7.53-7.47 (m, 3H), 7.29-7.24 (m, methylpyridinyl)-1H- 3H), 7.18 (s, 1H), 4.42 (d, J = 4.0 Hz, 2H), 2.15 pyrazolecarboxyamide (s, 3H), 2.01 (s, 3H). MS (ESI ): m/z 467 [M+H] . -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 8.76(s, 1H), α]pyridinyl)(6- 8.73(s, 1H), 8.62(s, 1H), 8.39(s, 1H), 8.01(s, 1H), methylpyridinyl)-N-(1- 162 7.79-7.70(m, 2H), 7.53(d, 1H), 7.45(d, 1H), 7.20- (methylsulfonyl)-1H- 7.17(m, 2H), 3.33(s, 3H), 2.33(s, 3H). MS (ESI ): pyrazolyl)-1H-pyrazole- m/z 464.1 [M+H] . 3-carboxyamide -([1,2,4]triazolo[1,5- H NMR (300 MHz, DMSO-d ) δ 8.78(s, 1H), α]pyridinyl)-N-(1- 8.73(s, 1H), 8.59(s, 1H), 8.40(s, 1H), 7.99(s, 1H), cyclopropylsulfonyl)-1H- 7.79-7.71(m, 2H), 7.53(d, 1H), 7.45(d, 1H), 7.20- pyrazolyl)(6- 7.17(m, 2H), 2.80-2.75(m, 1H), 2.33(s, 3H), 1.57- methylpyridinyl)-1H- 1.50(m, 2H), 1.19-1.14(m, 2H). MS (ESI ): m/z pyrazolecarboxyamide 506.1 [M+H] .
[Example 164] Preparation of N-(4-methoxyphenyl)(6-methylpyridin- 2-yl)(quinoxalinyl)-1H-pyrazolecarboxyamide After dissolving Intermediate 3 (50 mg, 0.15 mmol) in N,N- dimethylformamide, HATU (69 mg, 0.18 mmol) and DIPEA (79 μL, 0.45 mmol) were introduced thereto, and the result was stirred for 30 minutes at room temperature. To the reaction solution, p-anisidine (20 mg, 0.17 mmol) was introduced, and the result was stirred for 12 hours at room temperature. Produced solids were filtered, washed with ethyl acetate, and then vacuum dried to obtain a target compound (42 mg).
[00529] H NMR spectrum (300 MHz, DMSO-d ) δ 10.1(s, 1H), 8.96(s, 2H), 8.07- 7.93(m, 3H), 7.78-7.73(m, 4H), 7.37(br, 2H), 6.92(d, 2H), 3.75(s, 3H), 2.17(s, 3H).
MS (ESI ): [M+H] + m/z 437.1 [Examples 165 to 201] Compounds of Examples 161 to 198 listed in the following [Table 5] were obtained in the same manner as in Example 160 using various amine derivatives instead of p-anisidine.
【Table 5 】 MS (ES) Actual Example H NMR Spectrum (300 Measurement Structure Compound Name Number MHz, CDCl ) δ Value[M+H] / Required Value .2(s, 1H), 8.96(s, 2H), N-(3-methoxyphenyl) 8.07-8.03(m, 2H), 7.96(t, (6-methylpyridinyl)- 1H), 7.75(t, 2H), 7.53- 165 5-(quinoxalinyl)-1H- 437.1/436.1 7.46(m, 2H), 7.40-7.34(m, pyrazole 2H), 7.26(t, 1H), 6.69(d, 1H), carboxyamide 3.76(s, 3H), 2.17(s, 3H) 9.43(s, 1H), 8.97(s, 2H), N-(2-methoxyphenyl) 8.28(d, 1H), 8.07-7.95(m, (6-methylpyridinyl)- 3H), 7.78(dd, 2H), 7.43(s, 166 5-(quinoxalinyl)-1H- 437.1/436.1 1H), 7.39(d, 1H), 7.15(br, pyrazole 2H), 7.13(m, 1H), 3.91(s, carboxyamide 3H), 2.19(s, 3H) N-(4-(2- 8.87(s, 2H), 8.78(s, 1H), methoxyethoxy)phenyl)- 8.09-8.03(m, 2H), 7.70- 1-(6-methylpyridin 167 7.63(m, 4H), 7.37(d, 1H), 481.2/480.2 yl)(quinoxalinyl)- 7.29(s, 1H), 7.17(d, 1H), 1H-pyrazole 6.95(d, 2H), 4.14(q, 2H), carboxyamide 3.76(q, 2H), 3.46(s, 3H), 2.34(s, 3H) N-(benzo[d][1,3]dioxol- .19(s, 1H), 8.95(s, 2H), -yl)(6- 8.06-8.00(m, 2H), 7.94(t, methylpyridinyl) 168 1H), 7.76-7.68(m, 2H), 450.1/451.1 (quinoxalinyl)-1H- 7.48(d, 1H), 6.89(d, 1H), pyrazole .99(s, 2H), 2.16(s, 3H) carboxyamide N-(2,3- 8.87(s, 2H), 8.71(s, 1H), dihydrobenzo[b][1,4]dio 8.08-8.03(m, 2H), 7.70- xinyl)(6- 7.64(m, 2H), 7.39-7.36(m, 169 methylpyridinyl) 2H), 7.29(s, 1H), 7.18- 465.2/464.2 (quinoxalinyl)-1H- 7.10(m, 2H), 6.86(d, 1H), pyrazole 4.29-4.25(m, 4H), 2.34(s, carboxyamide 3H) N-(4- 9.97(s, 1H), 8.95(s, 2H), (dimethylamino)phenyl) 8.05-7.91(m, 3H), 7.76- (6-methylpyridin 170 7.60(m, 4H), 7.33(br, 2H), 450.2/449.2 yl)(quinoxalinyl)- 6.79-6.70(m, 3H), 2.86(s, 1H-pyrazole 6H), 2.06(s, 3H) carboxyamide 1-(6-methylpyridin 8.87(s, 2H), 8.75(s, 1H), 171 yl)-N-(4- 8.09-8.04(m, 2H), 7.71- 492.2/491.2 morpholinophenyl) 7.63(m, 4H), 7.38(d, 1H), (quinoxalinyl)-1H- 7.30(s, 1H), 7.18(d, 1H), pyrazole 6.94(d, 2H), 3.88(t, 4H), carboxyamide 3.16(t, 4H), 2.35(s, 3H) (300 MHz, DMSO-d ) δ N-(4-(4- .07(s, 1H), 8.97(s, 2H), methylpiperazin 8.07-8.03(m, 2H), 7.96(t, yl)phenyl)(6- 1H), 7.78-7.66(m, 4H), 172 methylpyridinyl) 505.2/504.2 7.36(s, 2H), 6.93(d, 2H), (quinoxalinyl)-1H- 3.31(s, 3H), 3.12-3.11(m, pyrazole 4H), 2.25-2.22(m, 4H), carboxyamide 2.17(s, 3H) 8.91(s, 2H), 8.74(s, 1H), N-(4-(4-acetylpiperazin- 8.08-8.03(m, 2H), 7.73- 1-yl)phenyl)(6- 7.63(m, 4H), 7.37(d, 1H), methylpyridinyl) 7.29(s, 1H), 7.17(d, 1H), 173 533.3/532.3 (quinoxalinyl)-1H- 6.96(d, 2H), 3.80-3.79(m, pyrazole 2H), 3.65-3.63(m, 2H), 3.19- carboxyamide 3.14(m, 4H), 2.35(s, 3H), 2.15(s, 3H) N-(4-cyanophenyl)(6- 9.05(s, 1H), 8.88(s, 2H), methylpyridinyl) 8.09-8.05(m, 2H), 7.88(d, 174 (quinoxalinyl)-1H- 2H), 7.75-7.64(m, 4H), 432.2/431.1 pyrazole 7.35(d, 1H), 7.31(s, 1H), carboxyamide 7.21(d, 1H), 2.38(s, 3H) 8.97(s, 1H), 8.88(s, 2H), N-(3-cyanophenyl)(6- 8.15(s, 1H), 8.09-8.05(m, methylpyridinyl) 2H), 7.96(d, 1H), 7.72- 175 (quinoxalinyl)-1H- 432.2/431.1 7.65(m, 2H), 7.49-7.44(m, pyrazole 2H), 7.36(d, 1H), 7.31(s, 1H), carboxyamide 7.20(d, 1H), 2.37(s, 3H) 9.56(s, 1H), 8.88(s, 2H), N-(2-cyanophenyl)(6- 8.66(d, 1H), 8.13(d, 1H), methylpyridinyl) 8.05(d, 1H), 7.78(t, 1H), 176 (quinoxalinyl)-1H- 432.2/431.1 7.71-7.64(m, 4H), 7.28(s, pyrazole 1H), 7.21(t, 1H), 7.13(d, 1H), carboxyamide 2.19(s, 3H) 1-(6-methylpyridin 8.87(s, 3H), 8.09-8.04(m, yl)-N-(4- 2H), 7.73-7.64(m, 4H), 7.38- (morpholinomethyl)phen 7.30(m, 4H), 7.18(d, 1H), 177 506.2/505.2 yl)(quinoxalinyl)- 3.76-3.71(m,4H), 3.50(s, 1H-pyrazole 2H), 2.48-2.45(m, 4H), carboxyamide 2.36(s, 3H) 9.04(s, 1H), 8.88(s, 2H), N-(4-acetylphenyl)(6- 8.10-8.00(m, 4H), 7.85(d, methylpyridinyl) 2H), 7.75-7.65(m, 2H), 178 (quinoxalinyl)-1H- 449.2/448.2 7.38(d, 1H), 7.32(s, 1H), pyrazole 7.21(d, 1H), 2.61(s, 3H), carboxyamide 2.37(s, 3H) (300 MHz, DMSO-d ) .5(s, 1H), 8.97(s, 2H), N-(3-acetylphenyl)(6- 8.46(br, 1H), 8.17(d, 1H), methylpyridinyl) 8.07-8.04(m, 2H), 7.97(t, 179 (quinoxalinyl)-1H- 449.1/ 448.1 1H), 7.79-7.76(m, 3H), pyrazole 7.56(t, 1H), 7.37(s, 1H), carboxyamide 7.35(d,1H), 2.59(s, 3H), 2.18(s, 3H) 1-(6-methylpyridin (300 MHz, DMSO-d ) yl)(quinoxalinyl)- .6(s, 1H), 8.96(s, 2H), N-(4- 180 8.11-7.93(m, 4H), 7.78- 475.1/474.1 (trifluoromethyl)phenyl) 7.72(m, 3H), 7.44(s, 1H), -1H-pyrazole 7.35(d, 1H), 2.07(s, 3H) carboxyamide (300 MHz, DMSO-d ) 1-(6-methylpyridin 10.6(s, 1H), 8.97(s, 2H), yl)(quinoxalinyl)- 8.33(br, 1H), 8.15(d, 1H), N-(3- 8.08-8.00(m, 2H), 7.94(t, 181 475.1/474.1 (trifluoromethyl)phenyl) 1H), 7.79-7.74(m, 2H), -1H-pyrazole 7.72(t, 1H), 7.43(d,1H), carboxyamide 7.38(s, 1H), 7.35(d, 1H), 2.08(s, 3H) N-(4- 182 (300 MHz, DMSO-d ) 464.1/ 463.1 (methylcarbamoyl)phen yl)(6-methylpyridin- 10.4(s, 1H), 8.94(s, 2H), 2-yl)(quinoxalin 8.34(br, 1H), 8.06-7.91(m, yl)-1H-pyrazole 5H), 7.83-7.70(m, 4H), carboxyamide 7.40(s, 1H), 7.33(d, 1H), 2.77(s, 3H), 2.05(s, 3H) N-(4-fluorophenyl)(6- 8.87-8.85(m, 3H), 8.08- methylpyridinyl) 8.04(m, 2H), 7.73-7.64(m, 183 (quinoxalinyl)-1H- 4H), 7.35(d, 1H), 7.30(s, 1H), 425.1/424.1 pyrazole 7.18(d, 1H), 7.07(t, 2H), carboxyamide 2.36(s, 3H) N-(3-fluorophenyl)(6- 10.50(s, 1H), 8.97(s, 2H), methylpyridinyl) 8.08-7.94(m, 3H), 7.84- 184 (quinoxalinyl)-1H- 7.68(m, 4H), 7.42(s, 1H), 425.2/421.1 pyrazole 7.38-7.35(m, 2H), 6.95(t, carboxyamide 1H), 2.12(s, 3H) N-(2-fluorophenyl)(6- 9.11(s, 1H), 8.87(s, 2H), methylpyridinyl) 8.53(t, 1H), 8.11-8.04(m, 185 (quinoxalinyl)-1H- 2H), 7.77-7.66(m, 2H), 425.2/424.1 pyrazole 7.51(d, 1H), 7.29(s, 1H), carboxyamide 7.20-7.11(m, 4H), 2.28(s, 3H) 8.87(s, 2H), 8.83(s, 1H), N-(3,4-difluorophenyl)- 8.08-8.04(m, 2H), 7.84- 186 1-(6-methylpyridin 443.1/442.1 7.80(m, 1H), 7.71-7.63(m, yl)(quinoxalinyl)- 2H), 7.35(d, 1H), 7.28(s, 2H), 1H-pyrazole 7.25-7.17(m, 2H), 2.36(s, carboxyamide 3H) 8.98(s, 1H), 8.87(s, 2H), N-(2,4-difluorophenyl)- 8.48-8.45(m, 1H), 8.10(d, 1-(6-methylpyridin 1H), 8.05(d, 1H), 7.74(t, 1H), 187 yl)(quinoxalinyl)- 7.66(dd, 1H), 7.48(d, 1H), 443.1/442.1 1H-pyrazole 7.28(s, 1H), 7.16(d, 1H), carboxyamide 6.96-6.91(m, 2H), 2.28(s, 9.13(s, 1H), 8.88(s, 2H), N-(2,3-difluorophenyl)- 8.30(t, 1H), 8.11-8.04(m, 1-(6-methylpyridin 2H), 7.75(t, 1H), 7.67(dd, 188 yl)(quinoxalinyl)- 443.1/442.1 1H), 7.50(d, 1H), 7.29(s, 1H), 1H-pyrazole 7.19-7.12(m, 2H), 6.94(q, carboxyamide 1H), 2.28(s, 3H) N-(4-chlorophenyl) 8.87(s, 3H), 8.08-8.04(m, (6-methylpyridinyl)- 2H), 7.73-7.63(m, 4H), 7.36- 189 5-(quinoxalinyl)-1H- 441.1/440.1 7.29(m, 4H), 7.18(d, 1H), pyrazole 2.36(s, 3H) carboxyamide 9.51(s, 1H), 8.87(s, 2H), N-(2-chlorophenyl) 8.61(d, 1H), 8.12(d, 1H), 190 (6-methylpyridinyl)- 441.1/440.1 8.05(d, 1H), 7.77(t, 1H), -(quinoxalinyl)-1H- 7.69(dd, 1H), 7.59(d, 1H), pyrazole 7.43(dd, 1H), 7.34(t, 1H), carboxyamide 7.29(s, 1H), 7.15(d, 1H), 7.09(t, 1H), 2.23(s, 1H) (300 MHz, DMSO-d ) δ N-(4-bromophenyl) 10.44 (s, 1H), 8.97(s, 2H), (6-methylpyridinyl)- 8.08-8.04(m, 2H), 7.96(t, 191 5-(quinoxalinyl)-1H- 1H), 7.84(d, 2H), 7.78- 485.1/484.1 pyrazole 7.71(m, 2H), 7.55(s, 2H), carboxyamide 7.41(s, 1H), 7.36(d, 1H), 2.18(s, 3H) (300 MHz, DMSO-d ) δ N-(6-methoxypyridin 10.40 (s, 1H), 8.96(s, 2H), yl)(6-methylpyridin- 8.59(d, 1H), 8.14-8.03(m, 192 2-yl)(quinoxalin 3H), 7.96(t, 1H), 7.77(d, 1H), 438.2/437.2 yl)-1H-pyrazole 7.70(d, 1H), 7.40(s, 1H), carboxyamide 7.36(d, 1H), 6.85(d, 1H), 3.85(s, 3H), 2.19(s, 3H) N-(4-methoxybenzyl) 8.86(s, 2H), 8.06-8.02(m, (6-methylpyridinyl)- 2H), 7.65(t, 2H), 7.33- 193 5-(quinoxalinyl)-1H- 7.24(m, 5H), 7.12(d, 1H), 451.2/450.2 pyrazole 6.89(d, 2H), 4.61(d, 2H), carboxyamide 3.81(s, 3H), 2.29(s, 3H) 8.87(s, 2H), 8.06(d, 1H), N-(4-cyanobenzyl)(6- 8.03(s, 1H), 7.69-7.62(m, methylpyridinyl) 4H), 7.51-7.49(m, 3H), 194 (quinoxalinyl)-1H- 446.2/445.2 7.30(d, 1H), 7.25(s, 1H), pyrazole 7.16(d, 1H), 4.74(d, 2H), carboxyamide 2.33(s, 3H) 8.86(s, 2H), 8.07-8.02(m, N-(3-acetylbenzyl)(6- 2H), 7.97(s, 1H), 7.88(d, 1H), methylpyridinyl) 7.66-7.61(m, 3H), 7.49- 195 (quinoxalinyl)-1H- 7.44(m, 2H), 7.32(d, 1H), 463.2/462.2 pyrazole 7.25(s, 1H), 7.14(d, 1H), carboxyamide 4.74(d, 2H), 2.62(s, 3H), 2.31(s, 3H) N-(4-fluorobenzyl)(6- 8.86(s, 2H), 8.06-8.02(m, methylpyridinyl) 2H), 7.65-7.62(m, 2H), 7.38- 196 (quinoxalinyl)-1H- 7.29(m, 4H), 7.25(s, 1H), 439.2/438.2 pyrazole 7.14(d, 1H), 7.04(t, 2H), carboxyamide 4.65(d, 2H), 2.31(s, 3H) 8.86(s, 2H), 8.07-8.03(m, N-(3-fluorobenzyl)(6- 2H), 7.66-7.63(m, 2H), methylpyridinyl) 7.42(t, 1H), 7.34-7.30(m, 197 (quinoxalinyl)-1H- 439.2/438.2 2H), 7.25(s, 1H), 7.18- pyrazole 7.13(m, 3H), 6.98(t, 1H), carboxyamide 4.68(d, 2H), 2.31(s, 3H) N-(2-fluorobenzyl)(6- 8.86(s, 2H), 8.06-8.02(m, methylpyridinyl) 2H), 7.67-7.62(m, 2H), 7.49- 198 (quinoxalinyl)-1H- 7.33(m, 3H), 7.23(s, 1H), 439.2/438.2 pyrazole 7.15-7.04(m, 3H), 4.74(d, carboxyamide 2H), 2.30(s, 3H) N-(4-chlorobenzyl)(6- 8.86(s, 2H), 8.06-8.02(m, methylpyridinyl) 2H), 7.68-7.62(m, 2H), 199 (quinoxalinyl)-1H- 7.40(t, 1H), 7.32-7.30(m, 455.1/454.1 pyrazole 3H), 7.25(d, 2H), 7.14(d, carboxyamide 1H), 4.65(d, 2H), 2.31(s, 3H) N-(3-chlorobenzyl)(6- 8.84(s, 2H), 8.05-8.01(m, methylpyridinyl) 2H), 7.67-7.61(m, 2H), 200 (quinoxalinyl)-1H- 7.36(s, 1H), 7.25-7.23(m, 455.1/454.1 pyrazole 5H), 7.13(d, 1H), 4.63(d, carboxyamide 2H), 2.78(s, 3H) 8.86(s, 2H), 8.06-8.02(m, N-(2-chlorobenzyl)(6- 2H), 7.67-7.62(m, 2H), 7.51- methylpyridinyl) 7.49(m, 2H), 7.37-7.34(m, 201 (quinoxalinyl)-1H- 455.1/454.1 2H), 7.26-7.23(m 2H), pyrazole 7.14(d, 2H), 4.78(d, 2H), carboxyamide 2.80(s, 3H) [Example 202] Preparation of N-(2-fluorophenyl)(quinoxalinyl) (m-tolyl)-1H-pyrazolecarboxyamide A target compound (3 mg) was obtained in the same manner as in Example 160 except that phenylhydrazine was used instead of 2-hydrazinylmethylpyridine hydrochloric acid in Step 3 of Preparation Example 3, and 2-fluoroaniline was used instead of p-anisidine of Example 160.
H NMR spectrum (300 MHz, CDCl3) δ 9.08(s, 1H), 8.87(s, 2H), 8.53(t, 1H), 8.07-8.03(m, 2H), 7.59(dd, 1H), 7.32(s, 2H), 7.24-7.07(m, 6H), 2.37(s, 3H).
MS (ESI ): [M+H] m/z 424.2 [Examples 203 to 208]
[00546] Compounds of Examples 203 to 208 listed in the following [Table 6] were obtained in the same manner as in Example 202.
【Table 6 】 MS (ES) Actual Example H NMR Spectrum (300 Measurement Structure Compound Name Number MHz, CDCl ) δ Value [M+H] /Required Value 1-(5-chloro 8.87-8.85(m, 2H), 8.67(s, 203 474.1/473.1 fluorophenyl)-N-(4- 1H), 8.10(d, 1H), 7.97(d, methoxyphenyl) 1H), 7.71-7.62(m, 4H), 7.40- (quinoxalinyl)-1H- 7.35(m, 1H), 7.33(s, 1H), pyrazole 7.04(t, 1H), 6.92(d, 2H), carboxyamide 3.82(s, 3H) 1-(5-chloro 8.86-8.85(m, 2H), 8.60(s, fluorophenyl)-N-(4- 1H), 8.10(d, 1H), 7.97(d, (dimethylamino)phenyl) 1H), 7.71-7.68(m, 2H), 204 487.1/486.1 (quinoxalinyl)-1H- 7.57(d, 2H), 7.43-7.40(m, pyrazole 1H), 7.32(s, 1H), 7.03(t, 1H), carboxyamide 6.75(d, 2H), 2.95(s, 3H) N-(4-methoxyphenyl) 8.89-8.86(m, 2H), 8.73(s, (quinoxalinyl)(6- 1H), 8.14-8.02(m, 4H), 205 trifluoromethyl)pyridin- 7.73(d, 1H), 7.65(d, 2H), 491.1/490.1 2-yl)-1H-pyrazole 7.60(d, 1H), 6.93(d, 2H), carboxyamide 3.82(s, 3H) N-(4- (dimethylamino)phenyl) 8.89-8.86(m, 2H), 8.65(s, (quinoxalinyl) 1H), 8.15-8.03(m, 4H), 206 (6- 504.2/503.2 7.74(d, 1H), 7.61-7.58(m, trifluoromethyl)pyridin- 3H), 6.77(d, 2H), 2.96(s, 6H) 2-yl)-1H-pyrazole carboxyamide 1-(6-bromopyridin yl)-N-(4- 8.89(s, 2H), 8.75(s, 1H), methoxyphenyl) 8.13-8.10(m, 2H), 7.72- 207 501.1/500.1 (quinoxalinyl)-1H- 7.63(m, 5H), 7.46-7.44(m, pyrazole 1H), 6.93(d, 2H), 3.82(s, 3H) carboxyamide 1-(6-bromopyridin yl)-N-(4- 8.88(s, 2H), 8.65(s, 1H), (dimethylamino)phenyl) 8.12-8.09(m, 2H), 7.70(dd, 208 514.1/513.1 (quinoxalinyl)-1H- 3H), 7.59(d, 2H), 7.44(d, pyrazole 1H), 6.77(d, 2H), 2.95(s, 6H) carboxyamide [Example 209] N-(2-Fluorophenyl)(6-methylpyridinyl) (quinolinyl)-1H-pyrazolecarboxyamide After dissolving 1-(6-methylpyridinyl)(quinolinyl)-1H-pyrazole- 3-carboxylic acid (40 mg, 0.1 mmol) synthesized in Step 5 of Preparation Example 4 in dichloromethane, HATU (55 mg, 0.1 mmol) and DIPEA (47 μL, 0.4 mmol) were introduced thereto, and the result was stirred for 20 minutes at room temperature. To the reaction solution, 2-fluoroaniline (13 mg, 0.1 mmol) was introduced, and the result was stirred for 12 hours at room temperature. After terminating the reaction, ethyl acetate was added thereto. The result was washed with sodium bicarbonate, then dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain a target compound (16 mg).
H NMR spectrum (300 MHz, CDCl ) δ 9.17(s, 1H), 8.93(d, 1H), 8.55(t, 1H), 8.15(d, 1H), 7.69-7.60(m, 4H), 7.41(t, 1H), 7.33(d, 1H), 7.25-7.12(m, 4H), 6.95(d, 1H), 1.83(s, 3H).
MS (ESI ): [M+H] m/z 424.2 [Examples 210 to 217] Compounds of Examples 210 to 217 listed in the following [Table 7] were obtained in the same manner as in Example 209 using various amine derivatives instead of 2-fluoroaniline.
【Table 7 】 Example Structure Compound Name Material Information H NMR (300 MHz, CDCl ) δ 8.92(d, N-(4-methoxyphenyl) 1H), 8.78(s, 1H), 8.15(d, 1H), 7.72- (6-methylpyridinyl)- 7.57(m, 5H), 7.48-7.40(m, 2H), 7.32(d, 210 5-(quinolinyl)-1H- 1H), 7.26(s, 1H), 6.95(d, 3H), 3.83(s, 3H), pyrazole 1.92(s, 3H). carboxyamide MS (ESI ): [M+H] m/z 436 H NMR (300 MHz, CDCl ) δ 9.13(s, 1-(6-methylpyridin 1H), 8.93(d, 1H), 8.16(d, 1H), 7.98(s, 4H), yl)-N-(4- 211 7.71(t, 1H), 7.65-7.58(m, 2H), 7.44(d, (methylsulfonyl)phenyl) 2H), 7.33-7.28(m, 2H), 6.98(d, 1H), (quinolinyl)-1H- 3.08(s, 3H), 1.96(s, 3H). pyrazole MS (ESI ): [M+H] m/z 484 carboxyamide H NMR (300 MHz, CDCl ) δ 8.92(d, N-(6-methoxypyridin 1H), 8.81(s, 1H), 8.41(d, 1H), 8.17- yl)(6-methylpyridin- 8.13(m, 2H), 7.70-7.57(m, 3H), 7.45- 212 2-yl)(quinolinyl)- 7.41(m, 2H), 7.31(d, 1H), 7.26(s, 1H), 1H-pyrazole 6.96(d, 1H), 6.81(d, 1H), 3.96(s, 3H), carboxyamide 1.95(s, 3H).
MS (ESI ): [M+H] m/z 437 N-(6-chloropyridin H NMR (300 MHz, CDCl ) δ 8.99(s, yl)(6-methylpyridin- 1H), 8.92(d, 1H), 8.62(d, 1H), 8.40(d, 1H), 213 2-yl)(quinolinyl)- 8.15(d, 1H), 7.70-7.58(m, 3H), 7.45- 1H-pyrazole 7.26(m, 5H), 6.97(d, 1H), 1.95(s, 3H). carboxyamide MS (ESI ): [M+H] m/z 441 N-(benzo[d][1,3]dioxol- H NMR (300 MHz, CDCl ) δ 8.92(d, -yl)(6- 1H), 8.80(s, 1H), 8.15(d, 1H), 7.69- methylpyridinyl) 7.56(m, 3H), 7.49-7.42(m, 3H), 7.31(d, (quinolinyl)-1H- 1H), 7.24(s, 1H), 7.05(d, 1H), 6.94(d, 1H), pyrazole 6.81(d, 1H), 5.99(s, 2H), 1.95(s, 3H). carboxyamide MS (ESI ): [M+H] m/z 450 N-(3-fluoro H NMR (300 MHz, CDCl ) δ 8.90(d, methoxyphenyl)(6- 215 1H), 8.85(s, 1H), 8.15(d, 1H), 7.70- methylpyridinyl) 7.59(m, 4H), 7.46-7.41(m, 3H), 7.32- (quinolinyl)-1H- pyrazole 7.24(m, 2H), 6.97-6.93(m, 2H), 3.93(s, carboxyamide 3H), 1.95(s, 3H).
MS (ESI ): [M+H] m/z 454 N-(2-fluoro H NMR (300 MHz, CDCl ) δ 8.94- methoxyphenyl)(6- 8.92(m, 2H), 8.34(t, 1H), 8.15(d, 1H), methylpyridinyl) 7.69-7.59(m, 4H), 7.41(t, 1H), 7.31(d, (quinolinyl)-1H- 1H), 7.23(s, 1H), 6.92(d, 1H), 6.76(d, 2H), pyrazole 3.82(s, 3H), 1.83(s, 3H). carboxyamide MS (ESI ): [M+H] m/z 454 H NMR (300 MHz, CDCl ) δ 8.92(d, N-(4-(2- 1H), 8.84(s, 1H), 8.15(d, 1H), 7.70- methoxyethoxy)phenyl)- 7.55(m, 5H), 7.48-7.41(m, 2H), 7.32- H 1-(6-methylpyridin 217 NMR (300 MHz, CDCl ) δ 7.24(m, 2H), yl)(quinolinyl)- 6.98-6.91(m, 3H), 4.15-4.10(m, 2H), 3.78- 1H-pyrazole 3.75(m, 2H), 3.46(s, 3H), 1.90(s, 3H). carboxyamide MS (ESI ): [M+H] m/z 480 [Example 218] 5-(Benzo[c][1,2,5]oxadiazolyl)-N-(4- (cyclopropylsulfonyl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide After dissolving 5-(benzo[c][1,2,5]oxadiazolyl)(6-methylpyridin yl)-1H-pyrazolecarboxylic acid (30 mg, 0.1 mmol) synthesized in Step 5 of Preparation Example 5 in dichloromethane, HATU (43 mg, 0.1 mmol) and DIPEA (48 μL, 0.3 mmol) were introduced thereto, and the result was stirred for 20 minutes at room temperature.
To the reaction solution, 4-(cyclopropylsulfonyl)aniline (21 mg, 0.1 mmol) was introduced, and the result was stirred for 12 hours at room temperature. After terminating the reaction, ethyl acetate was added thereto. The result was washed with sodium bicarbonate, then dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain a target compound (5 mg).
H NMR spectrum (300 MHz, CDCl ) δ 9.02(s, 1H), 7.93(s, 4H), 7.84- 7.75(m, 3H), 7.60(s, 1H), 7.31-7.26(m, 2H), 7.18(d, 1H), 2.50-2.45(m, 1H), 2.28(s, 3H), 1.39-1.34(m, 2H), 1.06-1.03(m, 2H).
MS (ESI ): [M+H] m/z 501 [Example 219] 5-(Benzo[d]oxazolyl)-N-(2-fluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide
[00565] After dissolving 5-(benzo[d]oxazolyl)(6-methylpyridinyl)-1H- pyrazolecarboxylic acid (50 mg, 0.2 mmol) synthesized in Step 6 of Preparation Example 6 in dichloromethane, HATU (71 mg, 0.2 mmol) and DIPEA (81 μL, 0.5 mmol) were introduced thereto, and the result was stirred for 20 minutes at room temperature.
To the reaction solution, 2-fluoroaniline (17 mg, 0.2 mmol) was introduced, and the result was stirred for 12 hours at room temperature. After terminating the reaction, ethyl acetate was added thereto. The result was washed with sodium bicarbonate, then dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain a target compound (29 mg).
H NMR spectrum (300 MHz, CDCl ) δ 9.09(s, 1H), 8.51(t, 1H), 8.13(s, 1H), 7.74-7.70(m, 2H), 7.58(d, 1H), 7.34-7.26(m, 2H), 7.18-7.11(m, 5H), 2.37(s, 3H).
[00567] MS (ESI ): [M+H] m/z 414 [Examples 220 to 227] Using compounds prepared in the preparation examples, compounds of Examples 220 to 227 listed in the following [Table 8] were obtained in the same manner as in Example 219 using various amines instead of 2-fluoroaniline.
[00570] 【Table 8 】 Example Structure Compound Name Material Information H NMR (300 MHz, CDCl ) δ 9.10(s, 1H), 8.14(s, 1H), 7.95- -(benzo[d]oxazolyl)-N-(4- 7.90(m, 4H), 7.75-7.65(m, 2H), (cyclopropylsulfonyl)phenyl)- 220 7.57(s, 1H), 7.29-7.15(m, 4H), 2.50- 1-(6-methylpyridinyl)-1H- 2.45(m, 4H), 1.37-1.35(m, 2H), pyrazolecarboxyamide 1.05-1.02(m, 2H).
MS (ESI ): [M+H] m/z 500 H NMR (300 MHz, CDCl ) δ N-cyclopropyl(4-fluoro 7.82 (s, 1H), 7.69-7.64 (m, 2H), 7.45 (1-(2-hydroxyethyl)-1H- (d, 1H), 7.20-7.15 (m, 3H), 7.05- 221 pyrazolyl)phenyl)(6- 7.02 (m, 3H), 4.28 (t, 2H), 4.03 (t, methylpyridinyl)-1H- 2H), 2.70 (q, 1H), 2.47 (s, 3H), 0.88 pyrazolecarboxyamide (q, 2H), 0.69 (q, 2H).
MS (ESI ): [M+H] m/z 447 H NMR (300 MHz, MeOD) δ 8.52 (s, 2H), 8.20 (s, 1H), 8.00 (s, N-(1H-pyrazolyl)(4- fluoro(1-(2-hydroxyethyl)- 1H), 7.94 (t, 1H), 7.69 (d, 1H), 7.53 222 1H-pyrazolyl)phenyl)(6- (d, 1H), 7.40 (d, 1H), 7.21-7.18 (m, methylpyridinyl)-1H- 3H), 4.35 (t, 2H), 3.94 (t, 2H), 2.43 pyrazolecarboxyamide (s, 3H).
MS (ESI ): [M+H] m/z 473 H NMR (300 MHz, MeOD) δ N-(1-methyl-1H-pyrazolyl)- 8.80 (s, 1H), 8.03 (s, 1H), 7.81 (s, -(4-fluoro(1-(2- 1H), 7.72-7.64 (m, 2H), 7.50-7.44 hydroxyethyl)-1H-pyrazol 223 (m, 2H), 7.19-7.03 (m, 5H), 4.26 (t, yl)phenyl)(6-methylpyridin- 2H), 4.04 (t, 2H), 3.89 (s, 3H), 2.48 2-yl)-1H-pyrazole (s, 3H). carboxyamide MS (ESI ): [M+H] m/z 487 H NMR (300 MHz, CDCl ) δ N-(1-(methylsulfonyl)-1H- 9.04 (s, 1H), 8.60 (s, 1H), 7.99 (s, pyrazolyl)(4-fluoro(1- 1H), 7.83 (s, 1H), 7.71-7.66 (m, 2H), (2-hydroxyethyl)-1H-pyrazol- 224 7.46 (d, 1H), 7.24-7.05 (m, 5H), 4.30 4-yl)phenyl)(6- (t, 2H), 4.05 (t, 2H), 3.33 (s, 3H), methylpyridinyl)-1H- 2.51 (s, 3H). pyrazolecarboxyamide MS (ESI ): [M+H] m/z 551 H NMR (300 MHz, CDCl ) δ N-(4-chlorophenyl)(4- 8.89 (s, 1H), 7.84 (s, 1H), 7.74-7.69 fluoro(1-(2-hydroxyethyl)- (m, 3H), 7.52 (d, 1H), 7.35 (d, 2H), 225 1H-pyrazolyl)phenyl)(6- 7.25-7.16 (m, 2H), 7.09 (d, 2H), 4.31 methylpyridinyl)-1H- (t, 2H), 4.06 (t, 2H), 3.33 (s, 3H), pyrazolecarboxyamide 2.52 (s, 3H).
MS (ESI ): [M+H] m/z 517 H NMR (300 MHz, CDCl ) δ N-(4-(methylsulfonyl)phenyl)- 9.13 (s, 1H), 7.96 (s, 3H), 7.84 (s, -(4-fluoro(1-(2- 1H), 7.75-7.70 (m, 2H), 7.50 (d, hydroxyethyl)-1H-pyrazol 226 1H), 7.24-6.77 (m, 6H), 4.31 (t, 2H), yl)phenyl)(6-methylpyridin- 4.06 (t, 2H), 3.08 (s, 3H), 2.53 (s, 2-yl)-1H-pyrazole 3H). carboxyamide MS (ESI ): [M+H] m/z 561 H NMR (300 MHz, CDCl ) δ N-(2-fluorophenyl) 9.98(s, 1H), 9.11(s, 1H), 8.41(s, 1H), (thieno[3,2,c]pyridinyl) 7.95(d, 2H), 7.80(s, 1H), 7.80(s, (m-tolyl)-1H-pyrazole 2H), 7.70(d, 1H), 7.50(d, 1H), 7.28- carboxyamide 7.23(m, 4H), 2.42(s, 3H) MS (ESI ): [M+H] m/z 429 Formulation Example 1: Preparation of Tablet In accordance with common methods, a single tablet for oral administration containing each of the compounds prepared in Examples 1 to 227 as an active compound was prepared using ingredients of the following Table 9 in amounts corresponding thereto.
[00574] 【Table 9 】 Ingredient Amount per Tablet Active Compound 100 mg Corn Starch 80 mg Lactose 80 mg Magnesium Stearate 5 mg Formulation Example 2: Preparation of Capsule In accordance with common methods, a hard gelatin capsule for oral administration containing each of the compounds prepared in Examples 1 to 227 as an active compound was prepared using ingredients of the following Table 10 in amounts corresponding thereto.
【Table 10 】 Ingredient Amount per Capsule Active Compound 100 mg Corn Starch 80 mg Lactose 80 mg Crystalline Cellulose 80 mg Magnesium Stearate 5 mg Formulation Example 3: Preparation of Formulation for Injection In accordance with common methods, a formulation for injection containing each of the compounds prepared in Examples 1 to 227 as an active compound was prepared using ingredients of the following Table 11 in amounts corresponding thereto. However, a pH was not adjusted when using a salt of the compound of Chemical Formula 1 as the active compound.
【Table 11 】 Ingredient Amount per Formulation for Injection Active Compound 20 mg % Glucose Solution 10 mL HCl (1 N) Suitable Amount to Make pH to 4 Formulation Example 4: Preparation of Formulation for Injection In accordance with common methods, a formulation for injection containing each of the compounds prepared in Examples 1 to 227 as an active compound was prepared using ingredients of the following Table 12 in amounts corresponding thereto.
【Table 12 】 Ingredient Amount per Formulation for Injection Active Compound 20 mg Polyethylene Glycol 400 2 mL Sterilized Water 8 mL Experimental Example 1: Activity Inhibition Test on ALK5 Enzyme For each of the compounds obtained in Examples 1 to 227, inhibitory activity against ALK5 kinase was measured.
For this, a LanthaScreen Eu binding kinase assay method was used, and ALK5 kinase, a kinase buffer, a kinase tracer 178, and a LanthaScreen Eu-GST binding antibody were all purchased from Thermo Fisher Scientific Solutions. Each of the compounds was made into a 10 mM DMSO solution, and diluted by 1/10 to a concentration of 1 μM to 0.0001 μM with an aqueous solution containing 4% DMSO. The test was performed in 384 well plates (well polystyrene low volume round-bottomed plates).
First, 5 μL of the diluted compound solution was added, then 5 μL of the kinase/antibody mixture solution was introduced thereto, and 5 μL of the tracer was introduced thereto.
Herein, these were added to each well so that the final kinase concentration became 5 nM, the final Eu-GST binding antibody concentration 2 nM, and the kinase tracer 178 concentration 10 nM, and the result was reacted in a stirrer for 60 minutes at room temperature. Then a fluorescence value was measured using a fluorescence meter (molecular device) (620 nm excitation filter, 665 nm emission filter). Herein, as for the degree of compound activity to inhibit the kinase reaction, a phosphorylate rate was calculated from 0% to100% with respect to a control group according to the protocol included in the kit, and a 50% inhibitory concentration (IC50) value was calculated by obtaining the x-axis concentration in the region where 50% activity was inhibited. The IC results for each of the compounds are shown in the following Table 13.
【Table 13 】 IC (nM) Example ALK5 Example ALK5 Example ALK5 1 5.0 41 5.2 81 1.5 2 4.7 42 2.2  82 2.7 3 12 43 4.4 83 0.7 4 4.4 44 13 84 3.9 10-100 45 2.4 85 3.8 6 11 46 1.3 86 1.1 7 < 10 47 1.2 87 9.1 8 4.7 48 4.1 88 3.5 9 19 49 5.6 89 3.5 10 50 6.6 90 5.0 11 2.2 51 6.5 91 10-100 12 6.1 52 2.5 92 10-100 13 10-100 53 2.4 93 3.9 14 17 54 2.0 94 ~10 6.4 55 4.2 95 25 16 2.3 56 2.4 96 3.5 17 14 57 45 97 10-100 18 10-100 58 5.6 98 5.3 19 10-100 59 20 99 ~10 10-100 60 13 100 10-100 21 ~100 61 10-100 101 10-100 22 10-100 62 16 102 10-100 23 ~10 63 3.7 103 9.1 24 ~100 64 < 10 104 7.0 < 10 65 < 10 105 7.0 26 10-100 66 3.2 106 14 27 6.2 67 9.6 107 10-100 28 4.5 68 65 108 ~10 29 3.9 69 4.9 109 9.7 5.8 70 4.6 110 10-100 31 > 100 71 8.0 111 > 100 32 10-100 72 11 112 10-100 33 10-100 73 5.8 113 10-100 34 10-100 74 2.3 114 9.5 10-100 75 7.4 115 10-100 36 < 10 76 -10 116 ~10 37 40 77 7.2 117 10-100 38 1.8 78 3.4 118 10-100 39 2.4 79 5.6 119 < 10 40 3.3 80 1.3 120 10-100 IC (nM) Example ALK5 Example ALK5 Example ALK5 121 10-100 157 10-100 193 ~100 122 10-100 158 10-100  194 >100 123 10-100 159 10-100 195 10-100 124 31 160 10-100 196 100 125 10-100 161 10-100 197 10-100 126 ~10 162 2.0 198 <100 127 ~100 163 4.6 199 >100 128 10-100 164 18 200 10-100 129 10-100 165 24 201 10-100 130 10-100 166 ~100 202 >1,000 131 10-100 167 ≤100 203 >100 132 ~10 168 ≤100 204 ~100 133 10-100 169 10-100 205 >100 134 10-100 170 <100 206 >100 135 10-100 171 10-100 207 10-100 136 ~10 172 10-100 208 10-100 137 10-100 173 10-100 209 > 100 138 10-100 174 <100 210 10-100 139 10-100 175 <100 211 < 10 140 ~10 176 100 212 36 141 10-100 177 ~100 213 23 142 10-100 178 10-100 214 30 143 6.6 179 <100 215 91 144 10-100 180 100-1,000 216 ~100 145 15 181 ~100 217 18 146 6.0 182 <100 218 10-100 147 3.7 183 10-100 219 27 148 8.3 184 10-100 220 3.2 149 7.7 185 <100 221 4.3 150 4.8 186 10-100 222 1.0 151 2.7 187 10-100 223 2.8 152 4.6 188 100 224 3.1 153 25 189 10-100 225 33 154 ~10 190 100-1,000 226 4.7 155 13 191 10-100 227 ~100 156 22 192 10-100 Hereinbefore, the present disclosure has been described with reference to the examples, however, these are for illustrative purposes only, and it is to be understood that various modified and equivalent other examples of the present disclosure obvious to those skilled in the art may be implemented within the scope of the attached claims. 【

Claims (3)

1. 】 【Claim 1 】 A compound of the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: 5 [Chemical Formula 1] wherein, in Chemical Formula 1, X is N or CH; a ring A is C cycloalkylene, C arylene, C heteroarylene containing 1 to 4 3-6 6-10 5-10 10 heteroatoms selected from among N, O and S atoms, or a non-aromatic fused heteropolycyclic ring containing 1 to 4 heteroatoms selected from among N, O and S; R s are each independently hydrogen, halogen, or linear or branched C alkyl, or 1 1-6 halo C alkyl, and when there are a plurality of R s, these are the same as or different 1-6 1 from each other; R s are each independently , , , , , , or ; R is hydrogen, halogen, linear or branched C alkyl, linear or branched halo C 3 1-6 1- 5 alkyl, C cycloalkyl, C heterocycloalkyl unsubstituted or substituted with R , C 6 3-10 3-10 4 6-10 heterobicycloalkyl, linear or branched C2-6 alkenyl, C2-6 alkynyl, -(CH2)a-R4, -(CH2)a-OR4, -(CH2)a-O-(CH2)a-R4, -(CH2)a-S-(CH2)a-R4, -(CH2)a-O-(CH2)a-OR4, -(CH2)a-NR4R5, - (CH ) -NO , -(CH ) -CN, -(CH ) -COR , -(CH ) -CO R , -(CH ) -CONR R , -(CH ) - 2 a 2 2 a 2 a 4 2 a 2 4 2 a 4 5 2 a NHCOR , -(CH ) -SR , -(CH ) -NHSO R , -(CH ) SOR , -(CH ) -SO R , -(CH ) - 4 2 a 4 2 a 2 4 2 a 6 2 a 2 6 2 a 10 SO2NHR6, -(CH2)a-SO(NH)R6 or -(CH2)a-SO2NR4R5, or when there are a plurality of R3s and they are adjacent to each other, they are linked to each other to form a 5-membered or 6-membered ring with the ring A, one or more heteroatoms selected from among N, O and S atoms are included in the ring, and the heteroatoms are further oxidized; R4 and R5 are each independently hydrogen, linear or branched C1-6 alkyl, linear 15 or branched halo C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkenyl, C1-6 carbonyl, C6-12 aryl, - (CH ) -NR R , or saturated or partially unsaturated 5-membered to 10-membered 2 b 6 7 monocyclic or bicyclic heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from among N, O and S; R6 and R7 are each independently hydrogen, hydroxy, C1-6 alkyl, halo C1-6 alkyl or C cycloalkyl; 5 a and b are an integer of 0 to 4; and l, m and n are each independently an integer of 0 to 4. 【Claim 2 】 The compound or a pharmaceutically acceptable salt thereof of Claim 1, wherein X is N, and R is C alkyl. 1 1-6 10 【Claim 3 】 The compound or a pharmaceutically acceptable salt thereof of Claim 1, wherein the ring A is phenyl, pyrazole, pyridinyl or benzo[d][1,3]dioxol. 【Claim 4 】 The compound or a pharmaceutically acceptable salt thereof of Claim 1, wherein 15 the compound of Chemical Formula 1 is a compound selected from the group consisting of the following compounds: (1) 5-(benzo[d]thiazolyl)-N-(4-methoxyphenyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamide; (2) 5-(benzo[d]thiazolyl)-N-(4-ethoxyphenyl)(6-methylpyridinyl)-1H- 20 pyrazolecarboxyamide; (3) 5-(benzo[d]thiazolyl)-N-(4-(cyclopropylmethoxy)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (4) 5-(benzo[d]thiazolyl)-N-(4-(2-methoxyethoxy)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (5) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- (trifluoromethoxy)phenyl)-1H-pyrazolecarboxyamide; (6) 5-(benzo[d]thiazolyl)-N-(4-(benzyloxy)phenyl)(6-methylpyridinyl)- 1H-pyrazolecarboxyamide; 5 (7) N-(benzo[d][1,3]dioxolyl)(benzo[d]thiazolyl)(6-methylpyridin yl)H-pyrazolecarboxyamide; (8) 5-(benzo[d]thiazolyl)-N-(4-fluoromethoxyphenyl)(6-methylpyridin-
2-yl)-1H-pyrazolecarboxyamide; (9) 5-(benzo[d]thiazolyl)-N-(2-fluoromethoxyphenyl)(6-methylpyridin- 10 2-yl)-1H-pyrazolecarboxyamide; (10) 5-(benzo[d]thiazolyl)-N-(3-fluoromethoxyphenyl)(6-methylpyridin- 2-yl)-1H-pyrazolecarboxyamide; (11) 5-(benzo[d]thiazolyl)-N-(3-aminophenyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamide; 15 (12) 5-(benzo[d]thiazolyl)-N-(3-(methylamino)phenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (13) 5-(benzo[d]thiazolyl)-N-(4-(dimethylamino)phenyl)(6-methylpyridin- 2-yl)-1H-pyrazolecarboxyamide; (14) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4-nitrophenyl)-1H- 20 pyrazolecarboxyamide; (15) 5-(benzo[d]thiazolyl)-N-(4-((2-(dimethylamino)ethyl)(methyl)amino) phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (16) 5-(benzo[d]thiazolyl)-N-(4-(3-(dimethylamino)pyrrolidinyl)phenyl) (6-methylpyridinyl)-1H-pyrazolecarboxyamide; (17) 5-(benzo[d]thiazolyl)-N-(3-chloro(octahydro-6H-pyrrolo[3,4- b]pyridinyl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (18) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-phenyl-1H-pyrazole carboxyamide; 5 (19) 5-(benzo[d]thiazolyl)-N-(3-tolyl)(6-methylpyridinyl)-1H-pyrazole-
3-carboxyamide; (20) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3-vinylphenyl)-1H- pyrazolecarboxyamide; (21) 5-(benzo[d]thiazolyl)-N-(3-(trifluoromethyl)phenyl)(6-methylpyridin- 10 2-yl)-1H-pyrazolecarboxyamide; (22) 5-(benzo[d]thiazolyl)-N-(3-(cyanophenyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamide; (23) 5-(benzo[d]thiazolyl)-N-(3-acetylphenyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamide; 15 (24) ethyl 3-(5-(benzo[d]thiazolyl)(6-methylpyridinyl)-1H-pyrazole carboxyamido)benzoate; (25) 5-(benzo[d]thiazolyl)-N-(4-(methylcarbamoyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (26) 5-(benzo[d]thiazolyl)-N-(4-acetamidophenyl)(6-methylpyridinyl)- 20 1H-pyrazolecarboxyamide; (27) 5-(benzo[d]thiazolyl)-N-(2-fluorophenyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamide; (28) 5-(benzo[d]thiazolyl)-N-(3-fluorophenyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamide; (29) 5-(benzo[d]thiazolyl)-N-(4-fluorophenyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamide; (30) 5-(benzo[d]thiazolyl)-N-(3,4-difluorophenyl)(6-methylpyridinyl)- 1H-pyrazolecarboxyamide; 5 (31) 5-(benzo[d]thiazolyl)-N-(2-chlorophenyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamide; (32) 5-(benzo[d]thiazolyl)-N-(3-chlorophenyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamide; (33) 5-(benzo[d]thiazolyl)-N-(4-chlorophenyl)(6-methylpyridinyl)-1H- 10 pyrazolecarboxyamide; (34) 5-(benzo[d]thiazolyl)-N-(4-bromophenyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamide; (35) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3- (methylthio)phenyl)-1H-pyrazolecarboxyamide; 15 (36) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- (methylthio)phenyl)-1H-pyrazolecarboxyamide; (37) 5-(benzo[d]thiazolyl)-N-(4-(cyclopropylthio)phenyl)(6-methylpyridin- 2-yl)-1H-pyrazolecarboxyamide; (38) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3- 20 (methylsulfinyl)phenyl)-1H-pyrazolecarboxyamide; (39) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- (methylsulfinyl)phenyl)-1H-pyrazolecarboxyamide; (40) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3- (methylsulfonyl)phenyl)-1H-pyrazolecarboxyamide; (41) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- (methylsulfonyl)phenyl)-1H-pyrazolecarboxyamide; (42) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- (propylsulfonyl)phenyl)-1H-pyrazolecarboxyamide; 5 (43) 5-(benzo[d]thiazolyl)-N-(4-(cyclopropylsulfonyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (44) 5-(benzo[d]thiazolyl)-N-(2-fluoro(methylsulfonyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (45) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3-sulfamoylphenyl)- 10 1H-pyrazolecarboxyamide; (46) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4-sulfamoylphenyl)- 1H-pyrazolecarboxyamide; (47) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3-(N- methylsulfamoyl)phenyl)-1H-pyrazolecarboxyamide; 15 (48) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4-(N- methylsulfamoyl)phenyl)-1H-pyrazolecarboxyamide; (49) 5-(benzo[d]thiazolyl)-N-(3-(N-cyclopropylsulfamoyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (50) 5-(benzo[d]thiazolyl)-N-(4-(N-cyclopropylsulfamoyl)phenyl)(6- 20 methylpyridinyl)-1H-pyrazolecarboxyamide; (51) 5-(benzo[d]thiazolyl)-N-(3-(N,N-dimethylsulfamoyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (52) 5-(benzo[d]thiazolyl)-N-(4-(N,N-dimethylsulfamoyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (53) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3- (methylsulfonamido)phenyl)-1H-pyrazolecarboxyamide; (54) 5-(benzo[d]thiazolyl)-N-(3-(cyclopropanesulfonamido)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; 5 (55) 5-(benzo[d]thiazolyl)-N-(4-(cyclopropanesulfonamido)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (56) 4-(5-(benzo[d]thiazolyl)(6-methylpyridinyl)-1H-pyrazole carboxyamido)benzenesulfonic acid; (57) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- 10 ((trifluoromethyl)sulfonyl)phenyl)-1H-pyrazolecarboxyamide; (58) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4-(N-(2,2,2- trifluoroethyl)sulfamoyl)phenyl)-1H-pyrazolecarboxyamide; (59) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- ((methylsulfonyl)methyl)phenyl)-1H-pyrazolecarboxyamide; 15 (60) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(3- (sulfamoylmethyl)phenyl)-1H-pyrazolecarboxyamide; (61) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4- (sulfamoylmethyl)phenyl)-1H-pyrazolecarboxyamide; (62) 5-(benzo[d]thiazolyl)-N-(4-fluoro(sulfamoylmethyl)phenyl)(6- 20 methylpyridinyl)-1H-pyrazolecarboxyamide; (63) 5-(benzo[d]thiazolyl)-N-(4-((1,1-dioxidotetrahydrothiophen yl)amino)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (64) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(pyridinyl)-1H- pyrazolecarboxyamide; (65) 5-(benzo[d]thiazolyl)-N-(6-methoxypyridinyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (66) 5-(benzo[d]thiazolyl)-N-(2-methoxypyridinyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; 5 (67) 5-(benzo[d]thiazolyl)-N-(6-(methylthio)pyridinyl)(6-methylpyridin- 2-yl)-1H-pyrazolecarboxyamide; (68) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(6- (methylsulfonyl)pyridinyl)-1H-pyrazolecarboxyamide; (69) 5-(benzo[d]thiazolyl)-N-(6-(methylsulfonyl)pyridinyl)(6- 10 methylpyridinyl)-1H-pyrazolecarboxyamide; (70) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(2- (methylsulfonyl)pyridinyl)-1H-pyrazolecarboxyamide; (71) 5-(benzo[d]thiazolyl)-N-(6-fluoropyridinyl)(6-methylpyridinyl)- 1H-pyrazolecarboxyamide; 15 (72) 5-(benzo[d]thiazolyl)-N-(2-fluoropyridinyl)(6-methylpyridinyl)- 1H-pyrazolecarboxyamide; (73) 5-(benzo[d]thiazolyl)-N-(6-chloropyridinyl)(6-methylpyridinyl)- 1H-pyrazolecarboxyamide; (74) 5-(benzo[d]thiazolyl)-N-(2-chloropyridinyl)(6-methylpyridinyl)- 20 1H-pyrazolecarboxyamide; (75) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(thiazolyl)-1H- pyrazolecarboxyamide; (76) 5-(benzo[d]thiazolyl)-N-benzyl(6-methylpyridinyl)-1H-pyrazole carboxyamide; (77) 5-(benzo[d]thiazolyl)-N-(2-fluorobenzyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamide; (78) 5-(benzo[d]thiazolyl)-N-(3-fluorobenzyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamide; 5 (79) 5-(benzo[d]thiazolyl)-N-(4-fluorobenzyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamide; (80) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(1-(methylsulfonyl)- 1H-pyrazolyl)-1H-pyrazolecarboxyamide; (81) 5-(benzo[d]thiazolyl)-N-(1-(cyclopropylsulfonyl)-1H-pyrazolyl)(6- 10 methylpyridinyl)-1H-pyrazolecarboxyamide; (82) 5-(benzo[d]thiazolyl)-N-(3-hydroxyphenyl)(6-methylpyridinyl)- 1H-pyrazolecarboxyamide; (83) 5-(benzo[d]thiazolyl)-N-(4-hydroxyphenyl)(6-methylpyridinyl)- 1H-pyrazolecarboxyamide; 15 (84) 5-(benzo[d]thiazolyl)-N-(3-(hydroxymethyl)phenyl)(6-methylpyridin- 2-yl)-1H-pyrazolecarboxyamide; (85) 5-(benzo[d]thiazolyl)-N-(4-(hydroxymethyl)phenyl)(6-methylpyridin- 2-yl)-1H-pyrazolecarboxyamide; (86) N-(4-aminophenyl)(benzo[d]thiazolyl)(6-methylpyridinyl)-1H- 20 pyrazolecarboxyamide; (87) 5-(benzo[d]thiazolyl)-N-(4-(butylamino)phenyl)(6-methylpyridin yl)-1H-pyrazolecarboxyamide; (88) 5-(benzo[d]thiazolyl)-N-(4-(cyclopropylamino)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (89) 5-(benzo[d]thiazolyl)(6-methylpyridinyl)-N-(4-(S- methylsulfonimidoyl)phenyl)-1H-pyrazolecarboxyamide; (90) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-methoxyphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; 5 (91) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-methoxyphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (92) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-methoxyphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (93) 5-([1,2,4] triazolo [1,5- α]pyridinyl)-N-(4-hydroxyphenyl)(6- 10 methylpyridinyl)-1H-pyrazolecarboxyamide; (94) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-isopropylphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (95) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(2-methoxyethoxy)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; 15 (96) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(benzo[d][1,3]dioxolyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (97) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-fluoromethoxyphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (98) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-fluoromethoxyphenyl)(6- 20 methylpyridinyl)-1H-pyrazolecarboxyamide; (99) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N-(2- (trifluoromethoxy)phenyl)-1H-pyrazolecarboxyamide; (100) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N-(3- (trifluoromethoxy)phenyl)-1H-pyrazolecarboxyamide; (101) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N-(4- (trifluoromethoxy)phenyl)-1H-pyrazolecarboxyamide; (102) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-(dimethylamino)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; 5 (103) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-aminophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (104) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(dimethylamino)phenyl)(6- methylpyridinyl)H-pyrazolecarboxyamide; (105) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(pyrrolidinyl)phenyl)1-(6- 10 methylpyridinyl)-1H-pyrazolecarboxyamide; (106) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-((2- (dimethylamino)ethyl)(methyl)amino)phenyl)(6-methylpyridinyl)-1H-pyrazole carboxyamide; (107) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(4-methylpiperazin 15 yl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (108) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(4-acetylpiperazin yl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (109) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-((1,1- dioxidotetrahydrothiophenyl)amino)phenyl)(6-methylpyridinyl)-1H-pyrazole 20 carboxyamide; (110) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-acetamidophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (111) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4- ((dimethylamino)methyl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (112) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-(methylcarbamoyl)phenyl) (6-methylpyridinyl)-1H-pyrazolecarboxyamide; (113) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(methylcarbamoyl)phenyl) (6-methylpyridinyl)-1H-pyrazolecarboxyamide; 5 (114) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N-phenyl- 1H-pyrazolecarboxyamide; (115) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N-(o-tolyl)- 1H-pyrazolecarboxyamide; (116) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N-(m- 10 tolyl)-1H-pyrazolecarboxyamide; (117) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N-(p-tolyl)- 1H-pyrazolecarboxyamide; (118) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N-(3- (trifluoromethyl)phenyl)-1H-pyrazolecarboxyamide; 15 (119) 5-([1,2,4]triazolo[1,5- α]pyridinyl)(6-methylpyridinyl)-N-(4- vinylphenyl)-1H-pyrazolecarboxyamide; (120) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-cyanophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (121) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-cyanophenyl)(6- 20 methylpyridinyl)H-pyrazolecarboxyamide; (122) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-acetylphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (123) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-acetylphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (124) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-fluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (125) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-fluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; 5 (126) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-fluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (127) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-chlorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (128) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-chlorophenyl)(6- 10 methylpyridinyl)-1H-pyrazolecarboxyamide; (129) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-chlorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (130) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-bromophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; 15 (131) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-bromophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (132) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-bromophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (133) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2,3-difluorophenyl)(6- 20 methylpyridinyl)-1H-pyrazolecarboxyamide; (134) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2,4-difluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (135) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2,5-difluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (136) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3,4-difluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (137) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3,5-difluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; 5 (138) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-chlorofluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (139) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-chlorofluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (140) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-chlorofluorophenyl)(6- 10 methylpyridinyl)-1H-pyrazolecarboxyamide; (141) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3,4-dichlorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (142) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-bromofluorophenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; 15 (143) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-(methoxythio)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (144) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(methoxythio)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (145) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-(methylsulfinyl)phenyl)(6- 20 methylpyridinyl)-1H-pyrazolecarboxyamide; (146) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(methylsulfinyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (147) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(methylsulfonyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (148) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-sulfamoylphenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (149) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(S- methylsulfonimidoyl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; 5 (150) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(propylsulfonyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (151) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(propylsulfonyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (152) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(6-fluoropyridinyl)(6- 10 methylpyridinyl)-1H-pyrazolecarboxyamide; (153) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(6-chloropyridinyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (154) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(6-methoxypyridinyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; 15 (155) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(2-fluorobenzyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (156) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-fluorobenzyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (157) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-fluorobenzyl)(6- 20 methylpyridinyl)-1H-pyrazolecarboxyamide; (158) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(3-methoxybenzyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (159) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-methoxybenzyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (160) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(4-(dimethylamino)benzyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (161) 5-([1,2,4]triazolo[1,5- α]pyridinyl)-N-(-acetamidobenzyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; 5 (162) 5-([1,2,4]triazolo[1,5-α]pyridinyl)(6-methylpyridinyl)-N-(1- (methylsulfonyl)-1H-pyrazolyl)-1H-pyrazolecarboxyamide; (163) 5-([1,2,4]triazolo[1,5-α]pyridinyl)-N-(1-cyclopropyl sulfonyl)-1H- pyrazolyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (164) N-(4-methoxyphenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- 10 pyrazolecarboxyamide; (165) N-(3-methoxyphenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (166) N-(2-methoxyphenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; 15 (167) N-(4-(2-methoxyethoxy)phenyl)(6-methylpyridinyl)(quinoxalin yl)-1H-pyrazolecarboxyamide; (168) N-(benzo[d][1,3]dioxolyl)(6-methylpyridinyl)(quinoxalin yl)-1H-pyrazolecarboxyamide; (169) N-(2,3-dihydrobenzo[b][1,4]dioxinyl)(6-methylpyridinyl) 20 (quinoxalinyl)-1H-pyrazolecarboxyamide; (170) N-(4-(dimethylamino)phenyl)(6-methylpyridinyl)(quinoxalin yl)-1H-pyrazolecarboxyamide; (171) 1-(6-methylpyridinyl)-N-(4-morpholinophenyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (172) N-(4-(4-methylpiperazinyl)phenyl)(6-methylpyridinyl) (quinoxalinyl)-1H-pyrazolecarboxyamide; (173) N-(4-(4-acetylpiperazinyl)phenyl)(6-methylpyridinyl) (quinoxalinyl)-1H-pyrazolecarboxyamide; 5 (174) N-(4-cyanophenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (175) N-(3-cyanophenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (176) N-(2-cyanophenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- 10 pyrazolecarboxyamide; (177) 1-(6-methylpyridinyl)-N-(4-(morpholinomethyl)phenyl)(quinoxalin- 6-yl)-1H-pyrazolecarboxyamide; (178) N-(4-acetylphenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; 15 (179) N-(3-acetylphenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (180) 1-(6-methylpyridinyl)(quinoxalinyl)-N-(4- (trifluoromethyl)phenyl)-1H-pyrazolecarboxyamide; (181) 1-(6-methylpyridinyl)(quinoxalinyl)-N-(3- 20 (trifluoromethyl)phenyl)-1H-pyrazolecarboxyamide; (182) N-(4-(methylcarbamoyl)phenyl)(6-methylpyridinyl)(quinoxalin yl)-1H-pyrazolecarboxyamide; (183) N-(4-fluorophenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (184) N-(3-fluorophenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (185) N-(2-fluorophenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; 5 (186) N-(3,4-difluorophenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (187) N-(2,4-difluorophenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (188) N-(2,3-difluorophenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- 10 pyrazolecarboxyamide; (189) N-(4-chlorophenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (190) N-(2-chlorophenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; 15 (191) N-(4-bromophenyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (192) N-(6-methoxypyridinyl)(6-methylpyridinyl)(quinoxalinyl)- 1H-pyrazolecarboxyamide; (193) N-(4-methoxybenzyl)(6-methylpyridinyl)(quinoxalinyl)-1H- 20 pyrazolecarboxyamide; (194) N-(4-cyanobenzyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (195) N-(3-acetylbenzyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (196) N-(4-fluorobenzyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (197) N-(3-fluorobenzyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; 5 (198) N-(2-fluorobenzyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (199) N-(4-chlorobenzyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (200) N-(3-chlorobenzyl)(6-methylpyridinyl)(quinoxalinyl)-1H- 10 pyrazolecarboxyamide; (201) N-(2-chlorobenzyl)(6-methylpyridinyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (202) N-(2-fluorophenyl)(quinoxalinyl)(m-tolyl)-1H-pyrazole carboxyamide; 15 (203) 1-(5-chlorofluorophenyl)-N-(4-methoxyphenyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (204) 1-(5-chlorofluorophenyl)-N-(4-(dimethylamino)phenyl)(quinoxalin- 6-yl)-1H-pyrazolecarboxyamide; (205) N-(4-methoxyphenyl)(quinoxalinyl)(6-trifluoromethyl)pyridin 20 yl)-1H-pyrazolecarboxyamide; (206) N-(4-(dimethylamino)phenyl)(quinoxalinyl)(6- trifluoromethyl)pyridinyl)-1H-pyrazolecarboxyamide; (207) 1-(6-bromopyridinyl)-N-(4-methoxyphenyl)(quinoxalinyl)-1H- pyrazolecarboxyamide; (208) 1-(6-bromopyridinyl)-N-(4-(dimethylamino)phenyl)(quinoxalin yl)-1H-pyrazolecarboxyamide; (209) N-(2-fluorophenyl)(6-methylpyridinyl)(quinolinyl)-1H- pyrazolecarboxyamide; 5 (210) N-(4-methoxyphenyl)(6-methylpyridinyl)(quinolinyl)-1H- pyrazolecarboxyamide; (211) 1-(6-methylpyridinyl)-N-(4-(methylsulfonyl)phenyl)(quinolinyl)- 1H-pyrazolecarboxyamide; (212) N-(6-methoxypyridinyl)(6-methylpyridinyl)(quinolinyl)-1H- 10 pyrazolecarboxyamide; (213) N-(6-chloropyridinyl)(6-methylpyridinyl)(quinolinyl)-1H- pyrazolecarboxyamide; (214) N-(benzo[d][1,3]dioxolyl)(6-methylpyridinyl)(quinolinyl)- 1H-pyrazolecarboxyamide; 15 (215) N-(3-fluoromethoxyphenyl)(6-methylpyridinyl)(quinolinyl)- 1H-pyrazolecarboxyamide; (216) N-(2-fluoromethoxyphenyl)(6-methylpyridinyl)(quinolinyl)- 1H-pyrazolecarboxyamide; (217) N-(4-(2-methoxyethoxy)phenyl)(6-methylpyridinyl)(quinolin 20 yl)-1H-pyrazolecarboxyamide; (218) 5-(benzo[c][1,2,5]oxadiazolyl)-N-(4-(cyclopropylsulfonyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (219) 5-(benzo[d]oxazolyl)-N-(2-fluorophenyl)(6-methylpyridinyl)-1H- pyrazolecarboxyamide; (220) 5-(benzo[d]oxazolyl)-N-(4-(cyclopropylsulfonyl)phenyl)(6- methylpyridinyl)-1H-pyrazolecarboxyamide; (221) N-cyclopropyl(4-fluoro(1-(2-hydroxyethyl)-1H-pyrazol yl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; 5 (222) N-(1H-pyrazolyl)(4-fluoro(1-(2-hydroxyethyl)-1H-pyrazol yl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (223) N-(1-methyl-1H-pyrazolyl)(4-fluoro(1-(2-hydroxyethyl)-1H- pyrazolyl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (224) N-(1-(methylsulfonyl)-1H-pyrazolyl)(4-fluoro(1-(2- 10 hydroxyethyl)-1H-pyrazolyl)phenyl)(6-methylpyridinyl)-1H-pyrazole carboxyamide; (225) N-(4-chlorophenyl)(4-fluoro(1-(2-hydroxyethyl)-1H-pyrazol yl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; (226) N-(4-(methylsulfonyl)phenyl)(4-fluoro(1-(2-hydroxyethyl)-1H- 15 pyrazolyl)phenyl)(6-methylpyridinyl)-1H-pyrazolecarboxyamide; and (227) N-(2-fluorophenyl)(thieno[3,2,c]pyridinyl)(m-tolyl)-1H-pyrazole- 3-carboxyamide. 【Claim 5 】 A pharmaceutical composition comprising the compound or pharmaceutically 20 acceptable salt thereof of Claim 1 in a pharmaceutically effective amount. 【Claim 6 】 A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of Claim 4 in a pharmaceutically effective amount. 【Claim 7 】 Use of a compound of any one of Claims 1 to 3 for the manufacture of a medicament for inhibiting a TGF-β signaling pathway in a subject or a cell, 【Claim 8 】 Use of a compound of Claim 4 for the manufacture of a medicament for inhibiting 5 a TGF-β signaling pathway in a subject or a cell, 【Claim 9 】 Use of a compound of any one of Claims 1 to 4 for the manufacture of a medicament for treating or preventing a fibrotic disease or a fibrotic condition in a subject.. 【Claim 10 】 10 The use of Claim 9, wherein the fibrotic disease or fibrotic condition is selected from the group consisting of scleroderma, idiopathic pulmonary fibrosis, glomerulonephritis, diabetic nephrosis, lupus nephrosis, hypertension-induced nephrosis, eye scar, corneal scar, liver fibrosis, biliary duct fibrosis, pulmonary fibrosis, acute lung injury, postinfarction cardiac fibrosis, fibrosclerosis, fibrous cancer, fibroid, fibroma, 15 fibroadenoma or fibrosarcoma. 【Claim 11 】 Use of a compound of any one of Claims 1 to 4 for the manufacture of a medicament for inhibiting metastasis of cancer cells in a subject, 【Claim 12 】 20 Use of a compound of any one of Claims 1 to 4 for the manufacture of a medicament for treating a carcinoma mediated by overexpression of TGFβ in a subject. . 【Claim 13 】 The use of Claim 12, wherein the carcinoma is selected from the group consisting of carcinomas of lung, breast, liver, biliary, gastrointestinal tract, head and neck, pancreas, 25 prostate and cervix, multiple myeloma, melanoma, glioma and glioblastoma. 【Claim 14 】 Use of a pharmaceutical composition of Claim 5 or 6, for the manufacture of a medicament for preventing or treating a fibrotic disease or a fibrotic condition. 【Claim 15 】 5 The use of Claim 14, wherein the fibrotic disease or the fibrotic condition includes one or more diseases selected from the group consisting of liver fibrosis, kidney fibrosis, pulmonary fibrosis, irritable pneumonia, interstitial fibrosis, systematic sclerodermie, macular degeneration, pancreas fibrosis, splenic fibrosis, cardiac fibrosis, species septic fibrosis, bone marrow fibrosis, vascular fibrosis, skin fibrosis, eye fibrosis, joint fibrosis, 10 muscle fibrosis, thyroid fibrosis, endocardial myocardial fibrosis, peritoneal fibrosis, after peritoneal fibrosis, progressive congenital trophoblastic fibrosis, allogeneic systematic fibrosis, fibrosis complications of surgery and infection fibrosis. 【Claim 16 】 Use of a pharmaceutical composition of Claim 5 or 6 for the manufacture of a 15 medicament for preventing or treating a cancer or a tumor. 【Claim 17 】 The use of Claim 16, wherein the cancer is selected from the group consisting of liver cancer, hepatocellular carcinoma, thyroid cancer, colorectal cancer, testicular cancer, bone cancer, oral cancer, basal cell carcinoma, ovarian cancer, brain tumor, gallbladder 20 carcinoma, biliary tract cancer, head and neck cancer, colorectal cancer, vesical carcinoma, tongue cancer, esophageal cancer, glioma, glioblastoma, renal cancer, malignant melanoma, gastric cancer, breast cancer, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, rectal cancer, pancreatic cancer, lung cancer, skin cancer and other solid cancers. 25 【Claim 18 】 Use of a pharmaceutical composition of Claim 5 or 6 for the manufacture of a medicament for preventing or treating a disease selected from the group consisting of kidney-, liver- or lung-fibrosis, glomerulonephritis, diabetic renal disease, erythematous nephritis, hypertension-induced renal disease, kidney interstitial fibrosis, kidney fibrosis 5 derived from drug exposure complications, HIV-related renal disease, organ transplantation gangrene, liver fibrosis caused by all diseases, hepatic dysfunction caused by infection, alcohol-induced hepatitis, biliary disorder, pulmonary fibrosis, acute lung injury, adult respiratory pain syndrome, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, pulmonary fibrosis caused by infection or toxic factors, cardiac fibrosis 10 after myocardial infarction, congestive heart failure, dilated cardiomyopathy, myocarditis, vascular stenosis, restenosis, atherosclerosis, visual impairment, corneal injury, proliferative vitreoretinopathy, excessive or exacerbated scar or keloid formation in the dermis occurring during wound healing from trauma or surgical wounds, peritoneum and subcutaneous adhesion, skin sclerosis, fibrosclerosis, progressive systemic sclerosis, 15 dermatomyositis, multiple myositis, arthritis, osteoporosis, ulcer, impaired nerve function, male impotence, Alzheimer’s disease, Raynaud’s disease, fibrous cancer, metastasis growth of tumors, radiation-induced fibrosis and thrombosis. 【Claim 19 】 20 A compound of any one of Claims 1 to 4 substantially as hereinbefore described with reference to the examples and excluding, if any, comparative examples.
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KR1020170082868A KR102434226B1 (en) 2016-06-30 2017-06-29 Novel substituted pyrazole derivatives as a alk5 inhibitors and use thereof
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