Small-molecule modulators of hepatocyte growth factor / scatter factor activities

A method for modulating HGF/SF activity in a mammal comprising administering to said mammal an effective HGF/SF activity modulating amount of a compound selected from the group consisting of

• 3-(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)-1-(4-chlorophenyl)prop-2-en-1-one;
• [4-(2,6-dichlorobenzyl)-3,5-dimethyl-1H-pyrazol-1-yl][3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]methanone;
• (4-(2-chloro-6-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-1-yl)(3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl)methanone;
• 4-(2-chloro-6-fluorobenzyl)-1-((3,4-dichlorophenyl)sulfonyl)-3,5-dimethyl-1H-pyrazole;
• 4-(2-chloro-6-fluorobenzyl)-1,3,5-trimethyl-1H-pyrazole;
• 4-(2-chloro-6-fluorobenzyl)-3,5-dimethyl-1H-pyrazole;
• (4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)(3-(2,6-dichlorophenyl)isoxazole-4-carbohydrazide);
• 3-(4-(2,6-dichlorobenzyl)-3,5-dimethyl-1H-pyrazol-1-yl)propanenitrile;
• 3,5-di(tert-butyl)-4-(2-chloro-6-fluorobenzyl)-1H-pyrazole;
• (4-(2-chloro-6-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-1-yl)(2,6-dichlorophenyl)methanone;
• 1-(4-(2-chloro-6-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-1-yl)2,2-dimethylpropan-1-one;
• (4-(2-chloro-6-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-1-yl)(4-chlorophenyl)methanone;
• (4-(2-chloro-6-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-1-yl)(2-thienyl)methanone;
• and
• (4-chlorophenyl)(3,5-dimethyl-4-((1-methyl-1H-imidazol-2-yl)thio)-1H-pyrazol-1-yl)methanone.

A pharmaceutical composition comprising a compound with the general formula I:

• 10
• wherein
• R3 and R5 are independently or together methyl, t-butyl or chloro groups;
• R1 is CO-Aryl, SO2-Aryl, CO-heteroaryl, or CO-alkyl, wherein said Aryl is phenyl, naphthyl or diphenyl, said Aryl substituted with one or more halogen, C1 to C4 alkyl, or C1 to C4 alkyloxy groups, or said heteroaryl is a 3-aryl-substituted isoxazole or a 3-aryl substituted thienyl group, or said alkyl group is a t-butyl;
• and
• R4 is CH2-Aryl, halogen, arylcarbonylvinyl or S-heteroaryl;
• And a pharmaceutically-acceptable carrier.

A method for modulating HGF/SF activity in a mammal comprising administering to said mammal an effective HGF/SF activity modulating amount of a compound with the general formula II:

• 11
• wherein
• R5 is methyl;
• R3 is an alkyl-, halogen- or alkyloxy-substituted phenyl group;
• R1 is hydrogen or methyl;
• and
• R2 is a substituted pyridyl or arylthiocarbonyl group or a 4-aryl-substituted 5-methylisoxazonecarbonyl group.

A method for modulating HGF/SF activity in a mammal comprising administering to said mammal an effective HGF/SF activity modulating amount of a compound selected from the group consisting of

• N′4,5-dimethyl-N′4-(5-nitro-2-pyridyl)-3-(2,6-dichlorophenyl)isoxazole-4-carbohydrazide;
• N′4-(2-(((2,4-dichlorobenzylidene)amino)oxy)acetyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide;
• N′4-(3-(3,4,5-trimethoxyphenyl)propanoyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide;
• 2-nitrophenyl 2-((3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl)carbonyl)hydrazine-1-carbothioate;
• N′4-((2-methyl-1,3-thiazol-4-4yl)carbonyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-4carbohydrazide;
• N1-((2-((3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl)carbonyl)hydrazino)(methylthio)methylidene)benzene-1-sulfonamide;
• N′4-(2,4,6-trichlorophenyl)-3-3(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide;
• N′4,3-di(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide;
• N′4-(3,5-dichloro-4-pyridyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide;
• N′4-phenyl-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide;
• N′4,N′4,5-trimethyl-3-(2,6-dichlorophenyl)isoxazole-4-carbohydrazide;
• N4-azepan-1-yl-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxamide;
• N′4-(6-(trifluoromethyl)-2-pyridyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide;
• and
• N′4-(3,3-diethoxypropanoyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide.

A pharmaceutical composition comprising a compound with the general formula II:

• 12
• wherein
• R5 is methyl;
• R3 is an alkyl-, halogen- or alkyloxy-substituted phenyl group;
• R1 is hydrogen or methyl;
• and
• R2 is a substituted pyridyl or arylthiocarbonyl group or a 4-aryl-substituted 5-methylisoxazonecarbonyl group;
• And a pharmaceutically-acceptable carrier.

A method for modulating HGF/SF activity in a mammal comprising administering to said mammal an effective HGF/SF activity modulating amount of a compound with the general formula III:

• 13
• Wherein
• R1 is SO2Alkyl, wherein alkyl is a C1 to C4 straight-chain, branched or cycloalkyl group;
• SO2-Aryl, wherein aryl is halo, C1 to C4 alkyl- or alkyloxy-substituted phenyl;
• COAlkyl, wherein alkyl is C1 to C6 straight-chained alkyl, branched alkyl or cycloalkyl;
• COAryl, wherein Aryl is phenyl substituted with halo, C1-C4 alkyl or alkyloxy;
• CONHAlkyl wherein alkyl is C1 to C6 straight-chained alkyl, branched alkyl or cycloalkyl;
• or CONHAryl, wherein aryl is phenyl substituted with halo, C1 to C4 alkyl or C1 to C4 alkyloxy;
• R3 is CHCH-heteroaryl, where in heteroaryl is cis or trans CHCH-3-thienyl, CHCH-2-furyl, CHCH-3-furyl, substituted CHCH-thienyl, or CHCH-furyl;
• phenoxyphenyl;
• heteroaryl;
• or aryl substituted heteroaryl.

A method for modulating HGF/SF activity in a mammal comprising administering to said mammal an effective HGF/SF activity modulating amount of a compound selected from the group consisting of

• (4-chlorophenyl)[3-(2-(2-thienyl)vinyl)-1H-pyrazol-1-yl]methanone;
• 1-(methylsulfonyl)-3-(2-(2-thienyl)vinyl)-1H-pyrazole;
• 2,2-dimethyl-1-(3-(2-(2-thienyl)vinyl)-1H-pyrazole-1-yl)propan-1-one;
• N-methyl-3-(2-(2-thienyl)vinyl)-1H-pyrazole-1-carboxamide;
• (4-chlorophenyl)(3-(3-phenylisoxazol-5-yl)-1H-pyrazol-1-yl)methanone;
• (4-chlorophenyl)(3-(3-(4-chlorophenyl)-5-methylisoxazol-4-yl)-1H-pyrazol-1-yl)methanone;
• (4-chlorophenyl)(3-(5-(2-thienyl)-2-thienyl)-1H-pyrazol-1-yl)methanone;
• (2,4-dichlorophenyl)(3-(5-(2,4-difluorophenyl)-2-furyl)-1H-pyrazol-1-yl)methanone;
• N1-phenyl-3-(2-(2-thienyl)vinyl)-1H-pyrazole-1-carboxamide;
• (4-chlorophenyl)(3-(2-(5-(2-thienyl)-2-thienyl)-4-methyl-1,3-thiazol-5-yl)-1H-pyrazol-1-yl)methanone;
• (3-benzhydryl-1H-pyrazol-1-yl)(4-chlorophenyl)methanone;
• N1-(4-chlorophenyl)-3-(2-(2-thienyl)vinyl)-1H-pyrazole-1-carboxamide;
• (4-chlorophenyl)(3-(2-methylimidazo(1,2-a)pyridin-3-yl)-1H-pyrazol-1-yl)methanone;
• 2-chloro-6-(4-(1-(4-chlorobenzyl)-1H-pyrazol-3-yl)phenoxy)benzonitrile;
• and
• 1-((4-chlorophenyl)sulfonyl)-3-(2-(2-thienyl)vinyl)-1H-pyrazole.

A pharmaceutical composition comprising a compound with the general formula III:

• 14
• wherein
• R1 is SO2Alkyl, wherein alkyl is a C1 to C4 straight-chain, branched or cycloalkyl group;
• SO2-Aryl, wherein aryl is halo, C1 to C4 alkyl- or alkyloxy-substituted phenyl;
• COAlkyl, wherein alkyl is C1 to C6 straight-chained alkyl, branched alkyl or cycloalkyl;
• COAryl, wherein Aryl is phenyl substituted with halo, C1-C4 alkyl or alkyloxy;
• CONHAlkyl wherein alkyl is C1 to C6 straight-chained alkyl, branched alkyl or cycloalkyl;
• or CONHAryl, wherein aryl is phenyl substituted with halo, C1 to C4 alkyl or C1 to C4 alkyloxy;
• R3 is CHCH-heteroaryl, where in heteroaryl is cis or trans CHCH-3-thienyl, CHCH-2-furyl, CHCH-3-furyl, substituted CHCH-thienyl, or CHCH-furyl;
• phenoxyphenyl;
• heteroaryl;
• or aryl substituted heteroaryl;
• and a pharmaceutically-acceptable carrier.

A method for modulating HGF/SF activity in a mammal comprising administering to said mammal an effective HGF/SF activity modulating amount of a compound with the general formula IV:

• 15
• wherein
• R1 is a phenyl group substituted with hydrogen, a halogen, C1 to C4 alkyl, or C1 to C4 alkyloxy, or is a heteroaryl group selected from the group consisting of 4-bromo-2-thienyl, 4-pyridyl, 2-furyl, 3-thienyl, optionally substituted with halogens and/or C1 to C4 alkyl;
• and
• R2 is one or more hydrogen, C1 to C4 alkyl, halogen, or C1 to C4 alkyloxy groups.

A method for modulating HGF/SF activity in a mammal comprising administering to said mammal an effective HGF/SF activity modulating amount of a compound selected from the group consisting of

• 1-(4-chloro-3-methylphenyl)-3-(2,6-dichlorophenyl)-prop-2-en-1-one
• 1-(4-chloro-3-methylphenyl)-3-(2-chlorophenyl)prop-2-en-1-one
• 3-(2-chloro-6-fluorophenyl)-1-(4-chloro-3-methylphenyl)prop-2-en-1-one
• 3-(4-bromo-2-thienyl)-1-(3,4-dichlorophenyl)prop-2-en-1-one
• 3-(4-bromo-2-thienyl)-1-(4-chloro-3-methylphenyl)prop-2-en-1-one
• 3-(4-bromo-2-thienyl)-1-(4-fluorophenyl)prop-2-en-1-one
• 3-(4-bromo-2-thienyl)-1-(4-chlorophenyl)prop-2-en-1-one
• 1-(4-chlorophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one
• 3-(1,3-benzodioxol-5-yl)-1-(4-bromophenyl)prop-2-en-1-one
• 3-(3-phenoxy-2-thienyl)-1-(2-thienyl)prop-2-en-1-one
• 3-(3-bromo-4-methoxyphenyl)-1-phenylprop-2-en-one
• 3-(3,4-dichlorophenyl)-1-(2-nitrophenyl)prop-2-en-1-one
• 1-(4-chlorophenyl)-3-(3,4-dichlorophenyl)prop-2-en-1-one
• 1-(4-chlorophenyl)-3-(3,5-dichloro-2-hydroxyphenyl)prop-2-en-1-one
• 1-(2-chlorophenyl)-3-(3,5-dichloro-2-hydroxyphenyl)prop-2-en-1-one
• 3-(4-chlorophenyl)-1-(2,6-dichlorophenyl)prop-2-en-1-one
• 1-(4-bromophenyl)-3-(4-chlorophenyl)prop-2-en-1-one
• 1-(2-chlorophenyl)-3-(2,6-dichlorophenyl)prop-2-en-1-one
• 1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)prop-2-en-1-one
• 3-(2,6-dichlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one
• 3-(4-chloro-1-methyl-1H-pyrazol-3-yl)-1-[4-(trifluoromethyl)phenyl]prop-2-en-1-one
• 3-(2,4-dichlorophenyl)-1-(2-methylphenyl)prop-2-en-1-one
• 3-(2,6-dichlorophenyl)-1-(2-methylphenyl)prop-2-en-1-one
• 3-(3,4-dichlorophenyl)-1-(2-methylphenyl)prop-2-en-1-one
• 3-(5-bromo-2-hydroxyphenyl)-1-(3-methylphenyl)prop-2-en-1-one
• 3-(5-bromo-2-hydroxyphenyl)-1-(4-methylphenyl)prop-2-en-1-one
• 3-(2,4-dichlorophenyl)-1-(3-methylphenyl)prop-2-en-1-one
• 3-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one
• 1-[4-amino-2-(methylthio)-1,3-thiazol-5-yl]-3-(4-chlorophenyl)prop-2-en-1-one
• 1-(4-chlorophenyl)-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one
• 1-benzo[b]thiophen-3-yl-3-(4-chlorophenyl)prop-2-en-1-one
• 1,3-di(5-nitro-3-thienyl)prop-2-en-1-one
• 1-(4-bromophenyl)-3-(3,5-difluorophenyl)prop-2-en-1-one
• 3-(3,5-difluorophenyl)-1-(3-nitrophenyl)prop-2-en-1-one

A pharmaceutical composition comprising a compound with the general formula IV:

• 16
• wherein
• R1 is a phenyl group substituted with hydrogen, a halogen, C1 to C4 alkyl, or C1 to C4 alkyloxy, or is a heteroaryl group selected from the group consisting of 4-bromo-2-thienyl, 4-pyridyl, 2-furyl, 3-thienyl, optionally substituted with halogens and/or C1 to C4 alkyl;
• and
• R2 is one or more hydrogen, C1 to C4 alkyl, halogen, or C1 to C4 alkyloxy groups;
• and a pharmaceutically-acceptable carrier.

A method for increasing hepatocyte growth factor/scatter factor (HGF/SF) activities in a mammal comprising administration to said mammal an effective amount of a compound having a molecular weight below about 1,000 Daltons, said compound exhibiting HGF/SF-like activity in at least one HGF/SF activity assay selected from the group consisting of

• induction of proliferation of endothelial cells in vitro or in vivo;
• induction of angiogenesis in vitro or in vivo;
• increasing angiogenesis in wounds in vivo;
• promoting tumor growth;
• inducing gene expression of angiogenic-cascade-related genes such as but not limited to IL-8 and angiopoietin-2;
• inducing anti-apoptotic activity;
• and
• inducing scatter activity.

A method for the prophylaxis or treatment in a mammal of hepatic disease, renal disease, bone regeneration, hair growth, promoting wound or tissue healing, promoting vascularization of a tissue, promoting wound healing, promoting vascularization of an ischemic tissue, promoting vascularization of a tissue susceptible to ischemia, or augmenting or restoring blood flow to ischemic tissues such as the heart following myocardial infarction comprising administered systemically or locally to particular tissues or organ in need thereof a an effective amount of a compound having a molecular weight below about 1,000 Daltons, said compound exhibiting HGF/SF-like activity in at least one HGF/SF activity assay selected from the group consisting of

• induction of proliferation of endothelial cells in vitro or in vivo;
• induction of angiogenesis in vitro or in vivo;
• increasing angiogenesis in wounds in vivo;
• promoting tumor growth;
• inducing gene expression of angiogenic-cascade-related genes such as but not limited to IL-8 and angiopoietin-2;
• inducing anti-apoptotic activity;
• and
• inducing scatter activity.

A method for inhibiting the activity of hepatocyte growth factor/scatter factor (HGF/SF) in a mammal comprising administering to said mammal an effective amount of a compound having a molecular weight below about 1,000 Daltons, said compound exhibiting HGF/SF inhibitory or antagonistic activity in at least one HGF/SF activity assay selected from the group consisting of

• inhibiting proliferation of endothelial cells in vitro or in vivo;
• inhibiting the growth of tumor cells in vitro or in vivo;
• inhibiting scatter of normal or tumor cells in vitro or in vivo;
• and
• inhibiting anti-apoptotic activity.

A method for the prophylaxis or treatment in a mammal of a condition of disease selected from the group consisting of excessive cellular proliferation, angiogenesis, a dysproliferative disease, cancer, metastasis, inflammatory disease, diabetic retinopathy, inflammatory joint disease, and inflammatory skin disease comprising administering to said mammal an effective amount of a compound having a molecular weight below about 1,000 Daltons, said compound exhibiting HGF/SF inhibitory or antagonistic activity in at least one HGF/SF activity assay selected from the group consisting of

• inhibiting proliferation of endothelial cells in vitro or in vivo;
• inhibiting the growth of tumor cells in vitro or in vivo;
• inhibiting scatter of normal or tumor cells in vitro or in vivo;
• and
• inhibiting anti-apoptotic activity.