This invention relates to use of inhibitors of the transforming growth factor-β (tgf-β) type I receptor (ALK5) and/or the activin type I receptor (ALK4) in treating, preventing, or reducing fibrosis, cancer, and vascular injuries.
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2. A method of treating a metastasis of breast cancer tumor cells in a human, comprising administering to the human in need of treatment, a therapeutically effective amount of one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) has the structure:
##STR00156##
wherein:
each Ra is independently H, halo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, OH, —O—C1-6alkyl, —O—C1-6haloalkyl, —O—C3-6cycloalkyl, NH2, —NH—C1-6alkyl, —NH—C1-6haloalkyl, —NH—C3-6cycloalkyl, —S—C1-6alkyl, —S—C1-6haloalkyl, —S—C3-6cycloalkyl, CN, or NO2;
m is 0, 1, 2, 3, or 4;
one of A1 and A2 is N and the other is NR1, wherein R1 is H, OH, C1-6alkyl, C1-6 haloalkyl, or C3-6cycloalkyl;
X is —NR2—, —O—, or —S—, wherein R2 is H or C1-3alkyl;
each Rb is independently H, halo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6alkynyl, —(CH2)q—OR3, —(CH2)q—NR3R4, —(CH2)q—SR3, —(CH2)q—NO2, —(CH2)q—CONHOH, —(CH2)q—CN, —(CH2)q—COR3, —(CH2)q—CO2R3, —(CH2)q—CONR3R4, —(CH2)q-tetrazole, —(CH2)q—CH═CH—CN, —(CH2)q—CH═CH—CO2R3, —(CH2)q—CH═CH—CONR3R4, —(CH2)q—CH═CH-tetrazole, —(CH2)q—NHCOR3, —(CH2)q—NHCO2R3, —(CH2)q—CONHSO2R3, —(CH2)q—NHSO2R3, —(CH2)q—C≡C—CN, —(CH2)q—C≡C—CO2R3, —(CH2)q—C≡C—CONR3R4, —(CH2)q—C≡C-tetrazole, —(CH2)q—SOR5, —(CH2)q—SO2R5, or —(CH2)—(OR3)2, wherein R3 and R4 are independently H, C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; or taken together with the nitrogen atom to which they are attached form a mono-cyclic ring such as imidazole, pyrrolidine, piperidine, morpholine, piperazine and homopiperazine; R5 is C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; q is 0, 1, 2, 3, or 4; and r is 1, 2, 3, or 4;
n is 0, 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof.
1. A method of inhibiting tgf-β or activin signaling pathways or both in a human, comprising administering to the human in need of treatment, a therapeutically effective amount of the one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) has the structure:
##STR00155##
wherein:
each Ra is independently H, halo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, OH, —O—C1-6alkyl, —O—C1-6haloalkyl, —O—C3-6cycloalkyl, NH2, —NH—C1-6alkyl, —NH—C1-6haloalkyl, —NH—C3-6cycloalkyl, —S—C1-6alkyl, —S—C1-6haloalkyl, —S—C3-6cycloalkyl, CN, or NO2;
m is 0, 1, 2, 3, or 4;
one of A1 and A2 is N and the other is NR1, wherein R1 is H, OH, C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl;
X is —NR2—, —O—, or —S—, wherein R2 is H or C1-3alkyl;
each Rb is independently H, halo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6alkynyl, —(CH2)q—OR3, —(CH2)q—NR3R4, —(CH2)q—SR3, —(CH2)q—NO2, —(CH2)q—CONHOH, —(CH2)q—CN, —(CH2)q—COR3, —(CH2)q—CO2R3, —(CH2)q—CONR3R4, —(CH2)q-tetrazole, —(CH2)q—CH═CH—CN, —(CH2)q—CH═CH—CO2R3, —(CH2)q—CH═CH—CONR3R4, —(CH2)q—CH═CH-tetrazole, —(CH2)q—NHCOR3, —(CH2)q—NHCO2R3, —(CH2)q—CONHSO2R3, —(CH2)q—NHSO2R3, —(CH2)q—C≡C—CN, —(CH2)q—C≡C—CO2R3, —(CH2)q—C≡C—CONR3R4, —(CH2)q—C≡C-tetrazole, —(CH2)q—SOR5, —(CH2)q—SO2R5, or —(CH2)r—(OR3)2, wherein R3 and R4 are independently H, C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; or taken together with the nitrogen atom to which they are attached form a mono-cyclic ring such as imidazole, pyrrolidine, piperidine, morpholine, piperazine and homopiperazine; R5 is C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; q is 0, 1, 2, 3, or 4; and r is 1, 2, 3, or 4;
n is 0, 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof.
3. A method for treating liver fibrosis due to all etiologies, pulmonary fibrosis, wound healing and breast cancer, comprising administering to a human in need of treatment, a therapeutically effective amount of one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) has the structure:
##STR00157##
wherein:
each Ra is independently H, halo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, OH, —O—C1-6alkyl, —O—C1-6haloalkyl, —O—C3-6cycloalkyl, NH2, —NH—C1-6alkyl, —NH—C1-6haloalkyl, —NH—C3-6cycloalkyl, —S—C1-6alkyl, —S—C1-6haloalkyl, —S—C3-6cycloalkyl, CN, or NO2;
m is 0, 1, 2, 3, or 4;
one of A1 and A2 is N and the other is NR1, wherein R1 is H, OH, C1-6alkyl, C1-6 haloalkyl, or C3-6cycloalkyl;
X is —NR2—, —O—, or —S—, wherein R2 is H or C1-3alkyl;
each Rb is independently H, halo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6alkynyl, —(CH2)q—OR3, —(CH2)q—NR3R4, —(CH2)q—SR3, —(CH2)q—NO2, —(CH2)q—CONHOH, —(CH2)q—CN, —(CH2)q—COR3, —(CH2)q—CO2R3, —(CH2)q—CONR3R4, —(CH2)q-tetrazole, —(CH2)q—CH═CH—CN, —(CH2)q—CH═CH—CO2R3, —(CH2)q—CH═CH—CONR3R4, —(CH2)q—CH═CH-tetrazole, —(CH2)q—NHCOR3, —(CH2)q—NHCO2R3, —(CH2)q—CONHSO2R3, —(CH2)q—NHSO2R3, —(CH2)q—C≡C—CN, —(CH2)q—C≡C—CO2R3, —(CH2)q—C≡C—CONR3R4, —(CH2)q—C≡C-tetrazole, —(CH2)q—SOR5, —(CH2)q—SO2R5, or —(CH2)— (OR3)2, wherein R3 and R4 are independently H, C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; or taken together with the nitrogen atom to which they are attached form a mono-cyclic ring such as imidazole, pyrrolidine, piperidine, morpholine, piperazine and homopiperazine; R5 is C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; q is 0, 1, 2, 3, or 4; and r is 1, 2, 3, or 4;
n is 0, 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof.
4. The method of
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2,3-difluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,4-difluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,5-difluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-chloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-chloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-chloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2,3-dichloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,4-dichloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,5-dichloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-bromoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-bromoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-bromoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-methylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-methylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-methylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2,3-dimethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,4-dimethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,5-dimethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-ethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-ethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-isopropylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-isopropylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-isopropylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-vinylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-vinylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-vinylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-ethynylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-methoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-methoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-methoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2,3-dimethoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,4-dimethoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,5-dimethoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(methoxymethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(methoxymethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-(methoxymethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(trifluoromethoxy)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(trifluoromethoxy)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-(trifluoromethoxy)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(methylthio)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(methylthio)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-(methylthio)aniline;
2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile;
4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phthalonitrile;
2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-n yl)methylamino)benzamide;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzamide;
4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzamide;
2-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)acetonitrile;
2-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)acetonitrile;
1-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)ethanone;
1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)ethanone;
Methyl 3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzoate;
Methyl 4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzoate;
N-(2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)acetamide;
N-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)acetamide;
N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)acetamide;
N-(2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)methanesulfonamide;
N-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)methanesulfonamide;
N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)methanesulfonamide;
N1-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-N2,N2-dimethylbenzene-1,2-diamine;
N1-((4-([1,2,4]triazolo[15-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-N3,N3-dimethylbenzene-1,3-diamine;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(pyrrolidin-1-yl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-morpholinoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-morpholinoaniline;
N3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-fluoro-N1,N1-dimethylbenzene-1,3-diamine;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-5-(dimethylamino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-4-(dimethylamino)benzonitrile;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-((dimethylamino)methyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-((dimethylamino)methyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(pyrrolidin-1-ylmethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(pyrrolidin-1-ylmethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(morpholinomethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(morpholinomethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-5-((dimethylamino)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-((dimethylamino)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoro-3-(pyrrolidin-1-ylmethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoro-3-(morpholinomethyl)aniline;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-4-((dimethylamino)methyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-2-((dimethylamino)methyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-5-((dimethylamino)methyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-4-(pyrrolidin-1-ylmethyl)benzonitrile;
3-((4-([1,2,4]triazlo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-2-(pyrrolidin-1-ylmethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-5-(pyrrolidin-1-ylmethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-4-(morpholinomethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-2-(morpholinomethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-5-(morpholinomethyl)benzonitrile;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(2-(dimethylamino)ethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(2-(dimethylamino)ethylaniline;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-ethylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-ethylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoro-N-methylaniline;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)(methyl)amino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)(methyl)amino)benzamide;
6-(5-(6-methylpyridin-2-yl)-2-(phenoxymethyl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine;
6-(2-((2-fluorophenoxy)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methoxy)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methoxy)benzamide;
6-(5-(6-methylpyridin-2-yl)-2-(phenylthiomethyl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine;
6-(2-((2-fluorophenylthio)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine,
and or pharmaceutically acceptable salts thereof.
5. The method of
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2,3-difluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,4-difluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,5-difluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-chloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-chloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-chloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2,3-dichloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,4-dichloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,5-dichloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-bromoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-bromoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-bromoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-methylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-methylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-methylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2,3-dimethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,4-dimethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,5-dimethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-ethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-ethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-isopropylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-isopropylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-isopropylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-vinylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-vinylaniline;
N-((4-([1,2,4]triazlo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-vinylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-ethynylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-methoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-methoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-methoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2,3-dimethoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,4-dimethoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,5-dimethoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(methoxymethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(methoxymethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-(methoxymethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(trifluoromethoxy)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(trifluoromethoxy)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-(trifluoromethoxy)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(methylthio)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(methylthio)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-(methylthio)aniline;
2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile;
4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phthalonitrile;
2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzamide;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzamide;
4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzamide;
2-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)acetonitrile;
2-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)acetonitrile;
1-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)ethanone;
1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)ethanone;
Methyl 3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzoate;
Methyl 4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzoate;
N-(2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)acetamide;
N-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)acetamide;
N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)acetamide;
N-(2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)methanesulfonamide;
N-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)methanesulfonamide;
N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)methanesulfonamide;
N1-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-N2,N2-dimethylbenzene-1,2-diamine;
N1-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-N3,N3-dimethylbenzene-1,3-diamine;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(pyrrolidin-1-yl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-morpholinoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-morpholinoaniline;
N3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-fluoro-N′,N′-dimethylbenzene-1,3-diamine;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-5-(dimethylamino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-4-(dimethylamino)benzonitrile;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-((dimethylamino)methyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-((dimethylamino)methyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(pyrrolidin-1-ylmethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(pyrrolidin-1-ylmethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(morpholinomethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(morpholinomethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-5-((dimethylamino)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-((dimethylamino)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoro-3-(pyrrolidin-1-ylmethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoro-3-(morpholinomethyl)aniline;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-4-((dimethylamino)methyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-2-((dimethylamino)methyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-5-((dimethylamino)methyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-4-(pyrrolidin-1-ylmethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-2-(pyrrolidin-1-ylmethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-5-(pyrrolidin-1-ylmethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-4-(morpholinomethyl)benzonitrile;
3-((4-([1,2,4]triazlo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-2-(morpholinomethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-5-(morpholinomethyl)benzonitrile;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(2-(dimethylamino)ethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(2-(dimethylamino)ethylaniline;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-ethylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-ethylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoro-N-methylaniline;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)(methyl)amino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)(methyl)amino)benzamide;
6-(5-(6-methylpyridin-2-yl)-2-(phenoxymethyl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine;
6-(2-((2-fluorophenoxy)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methoxy)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methoxy)benzamide;
6-(5-(6-methylpyridin-2-yl)-2-(phenylthiomethyl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine;
6-(2-((2-fluorophenylthio)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine,
or pharmaceutically acceptable salts thereof.
6. The method of
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2,3-difluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,4-difluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,5-difluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-chloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-chloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-chloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2,3-dichloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,4-dichloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,5-dichloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-bromoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-bromoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-bromoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-methylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-methylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-methylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2,3-dimethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,4-dimethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,5-dimethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-ethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-ethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-isopropylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-isopropylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-isopropylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-vinylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-vinylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-vinylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-ethynylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-methoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-methoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-methoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2,3-dimethoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,4-dimethoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3,5-dimethoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(methoxymethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(methoxymethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-(methoxymethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(trifluoromethoxy)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(trifluoromethoxy)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-(trifluoromethoxy)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(methylthio)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(methylthio)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-(methylthio)aniline;
2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile;
4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phthalonitrile;
2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-n yl)methylamino)benzamide;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzamide;
4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzamide;
2-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)acetonitrile;
2-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)acetonitrile;
1-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)ethanone;
1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)ethanone;
Methyl 3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzoate;
Methyl 4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzoate;
N-(2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)acetamide;
N-(3-((4-([1,2,4]triazolo[15-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)acetamide;
N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)acetamide;
N-(2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)methanesulfonamide;
N-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)methanesulfonamide;
N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)phenyl)methanesulfonamide;
N1-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-N2,N2-dimethylbenzene-1,2-diamine;
N1-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-N3,N3-dimethylbenzene-1,3-diamine;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(pyrrolidin-1-yl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-morpholinoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-morpholinoaniline;
N3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-4-fluoro-N,N′-dimethylbenzene-1,3-diamine;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-5-(dimethylamino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-4-(dimethylamino)benzonitrile;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-((dimethylamino)methyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-((dimethylamino)methyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(pyrrolidin-1-ylmethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-H-imidazol-2-yl)methyl)-3-(pyrrolidin-1-ylmethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(morpholinomethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(morpholinomethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-5-((dimethylamino)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-((dimethylamino)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoro-3-(pyrrolidin-1-ylmethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoro-3-(morpholinomethyl)aniline;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-4-((dimethylamino)methyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-2-((dimethylamino)methyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-5-((dimethylamino)methyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-4-(pyrrolidin-1-ylmethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-2-(pyrrolidin-1-ylmethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-5-(pyrrolidin-1-ylmethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-4-(morpholinomethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-2-(morpholinomethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)-5-(morpholinomethyl)benzonitrile;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-(2-(dimethylamino)ethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-(2-(dimethylamino)ethylaniline;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-ethylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-ethylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoro-N-methylaniline;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)(methyl)amino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)(methyl)amino)benzamide;
6-(5-(6-methylpyridin-2-yl)-2-(phenoxymethyl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine;
6-(2-((2-fluorophenoxy)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methoxy)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methoxy)benzamide;
6-(5-(6-methylpyridin-2-yl)-2-(phenylthiomethyl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine;
6-(2-((2-fluorophenylthio)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine,
or pharmaceutically acceptable salts thereof.
0. 7. The method of claim 1, wherein the compound is selected from the group consisting of:
##STR00158##
0. 8. The method of claim 1, wherein the compound is selected from the group consisting of:
##STR00159##
##STR00160##
##STR00161##
##STR00162##
0. 9. The method of claim 1, wherein the compound is selected from the group consisting of:
##STR00163##
##STR00164##
0. 10. The method of claim 1, wherein the compound is selected from the group consisting of:
##STR00165##
0. 11. The method of claim 1, wherein the compound is selected from the group consisting of:
##STR00166##
##STR00167##
0. 12. The method of claim 1, wherein the compound is selected from the group consisting of:
##STR00168##
0. 13. The method of claim 1, wherein the compound is selected from the group consisting of:
##STR00169##
##STR00170##
##STR00171##
0. 14. The method of claim 1, wherein the compound is selected from the group consisting of:
##STR00172##
##STR00173##
0. 15. The method of claim 1, wherein the compound is selected from the group consisting of:
##STR00174##
0. 16. The method of claim 1, wherein the compound is selected from the group consisting of:
##STR00175##
0. 17. The method of claim 1, wherein the compound is selected from the group consisting of:
##STR00176##
##STR00177##
##STR00178##
0. 18. The method of claim 8, wherein the compound is
##STR00179##
0. 19. The method of claim 1,
wherein,
each Ra is independently C1-6alkyl;
m is 1 or 2;
one of A1 and A2 is N and the other is NR1, wherein R1 is H;
X is —NR2—, —O—, or —S—, and R2 is H or CH3;
each Rb is independently H, F, Cl, Br, CH3, CH2CH3, CH(CH3)2, CH═CH2 (Alkenyl), CCH (alkynyl), OCH3, CH2OCH3, OCF3, SCH3, CN, C(═O)CH3, C(═O)OCH3, C(═O)NH2, NHC(═O)CH3, NHSO2CH3, N(CH3)2, CH2N(CH3)2, (CH2)2N(CH3)2, —(CH2)q—NR3R4,
wherein,
q is 0, 1 or 2;
R3 and R4 are taken together with the nitrogen atom to which they are attached form a monocyclic ring being either pyrrolidine or morpholine.
0. 20. The method of claim 19,
wherein,
Ra is CH3 or CH2CH3;
m is 1;
X is —NR2, and R2 is H; and
one of Rb is F, Cl or Br and the remaining Rb are H.
0. 21. The method of claim 20, wherein Ra is CH3 and one of Rb is F.
0. 22. The method of claim 2, wherein the compound is selected from the group consisting of:
##STR00180##
0. 23. The method of claim 2, wherein the compound is selected from the group consisting of:
##STR00181##
##STR00182##
##STR00183##
##STR00184##
0. 24. The method of claim 2, wherein the compound is selected from the group consisting of:
##STR00185##
##STR00186##
0. 25. The method of claim 2, wherein the compound is selected from the group consisting of:
##STR00187##
0. 26. The method of claim 2, wherein the compound is selected from the group consisting of:
##STR00188##
##STR00189##
0. 27. The method of claim 2, wherein the compound is selected from the group consisting of:
##STR00190##
0. 28. The method of claim 2, wherein the compound is selected from the group consisting of:
##STR00191##
##STR00192##
##STR00193##
0. 29. The method of claim 2, wherein the compound is selected from the group consisting of:
##STR00194##
##STR00195##
0. 30. The method of claim 2, wherein the compound is selected from the group consisting of:
##STR00196##
0. 31. The method of claim 2, wherein the compound is selected from the group consisting of:
##STR00197##
0. 32. The method of claim 2, wherein the compound is selected from the group consisting of:
##STR00198##
##STR00199##
##STR00200##
0. 33. The method of claim 23, wherein the compound is
##STR00201##
0. 34. The method of claim 2,
wherein,
each Ra is independently C1-6alkyl;
m is 1 or 2;
one of A1 and A2 is N and the other is NR1, wherein R1 is H;
X is —NR2—, —O—, or —S—, and R2 is H or CH3;
each Rb is independently H, F, Cl, Br, CH3, CH2CH3, CH(CH3)2, CH═CH2 (Alkenyl), CCH (alkynyl), OCH3, CH2OCH3, OCF3, SCH3, CN, C(═O)CH3, C(═O)OCH3, C(═O)NH2, NHC(═O)CH3, NHSO2CH3, N(CH3)2, CH2N(CH3)2, (CH2)2N(CH3)2, —(CH2)q—NR3R4,
wherein,
q is 0, 1 or 2;
R3 and R4 are taken together with the nitrogen atom to which they are attached form a monocyclic ring being either pyrrolidine or morpholine.
0. 35. The method of claim 34,
wherein,
Ra is CH3 or CH2CH3;
m is 1;
X is —NR2, and R2 is H; and
one of Rb is F, Cl or Br and the remaining Rb are H.
0. 36. The method of claim 35, wherein Ra is CH3 and one of Rb is F.
0. 37. The method of claim 3, wherein the compound is selected from the group consisting of:
##STR00202##
0. 38. The method of claim 3, wherein the compound is selected from the group consisting of:
##STR00203##
##STR00204##
##STR00205##
##STR00206##
0. 39. The method of claim 3, wherein the compound is selected from the group consisting of:
##STR00207##
##STR00208##
0. 40. The method of claim 3, wherein the compound is selected from the group consisting of:
##STR00209##
0. 41. The method of claim 3, wherein the compound is selected from the group consisting of:
##STR00210##
##STR00211##
0. 42. The method of claim 3, wherein the compound is selected from the group consisting of:
##STR00212##
0. 43. The method of claim 3, wherein the compound is selected from the group consisting of:
##STR00213##
##STR00214##
##STR00215##
0. 44. The method of claim 3, wherein the compound is selected from the group consisting of:
##STR00216##
##STR00217##
0. 45. The method of claim 3, wherein the compound is selected from the group consisting of:
##STR00218##
0. 46. The method of claim 3, wherein the compound is selected from the group consisting of:
##STR00219##
0. 47. The method of claim 3, wherein the compound is selected from the group consisting of:
##STR00220##
##STR00221##
##STR00222##
0. 48. The method of claim 38, wherein the compound is
##STR00223##
0. 49. The method of claim 3,
wherein,
each Ra is independently C1-6alkyl;
m is 1 or 2;
one of A1 and A2 is N and the other is NR1, wherein R1 is H;
X is —NR2—, —O—, or —S—, and R2 is H or CH3;
each Rb is independently H, F, Cl, Br, CH3, CH2CH3, CH(CH3)2, CH═CH2 (Alkenyl), CCH (alkynyl), OCH3, CH2OCH3, OCF3, SCH3, CN, C(═O)CH3, C(═)OCH3, C(═O)NH2, NHC(═O)CH3, NHSO2CH3, N(CH3)2, CH2N(CH3)2, (CH2)2N(CH3)2, —(CH2)q—NR3R4,
wherein,
q is 0, 1 or 2;
R3 and R4 are taken together with the nitrogen atom to which they are attached form a monocyclic ring being either pyrrolidine or morpholine.
0. 50. The method of claim 49,
wherein,
Ra is CH3 or CH2CH3;
m is 1;
X is —NR2, and R2 is H; and
one of Rb is F, Cl or Br and the remaining Rb are H.
0. 51. The method of claim 50, wherein Ra is CH3 and one of Rb is F.
|
This application is a continuation-in-part of U.S. patent application Ser. No. 12/826,338 filed Jun. 29, 2010 entitled “2-Pyridyl Substituted Imidazoles as Therapeutic ALK5 and/or ALK 4 Inhibitors”, the disclosure of which is incorporated herein by reference.
Examples 2, 3, and 61 significantly reduced the number of metastastic nodules on the lung.
In Experiment 3, Western blot analysis was performed to examine the effect of Example 2 on the Smad2 phosphorylation in tumor tissues. Either vehicle buffer (4 mM HCl, 1 mg/mL BSA) or TGF-β1 (50 ng/mouse) in vehicle buffer was given to mice intravenously at 2 h before mice were sacrificed. Tumor tissues from mice were lysed in RIPA buffer [50 mM Tris, pH 7.5, 150 mM NaCl, 0.1% sodium dodecyl sulfate, 0.5% sodium deoxycholate, 1% NP-40, 1 mM NaF, 1 mM Na3VO4, 1 mM PMSF, a protease inhibitor cocktail (1 tablet of Roche Diagnostics GmbH protease inhibitor cocktail/10 mL) (Roche)] for 20 min on ice. Lysates were cleared by centrifugation at 13000 rpm at 4° C. for 20 min. Protein content of supernatants was determined using Micro-BCA (bicinchoninic acid) protein assay kit (Thermo Scientific). Lysates containing 20-50 μg total protein were separated by electrophoresis on polyacrylamide gel and then electrophoretically transferred to polyvinylidene difluoride transfer membranes (Millipore, Billerica, Mass., USA). Membranes were blocked with 5% BSA (Sigma-Aldrich) in PBS containing 0.5% Tween-20 (PBST) for 1 h and incubated overnight at 4° C. with one of following antibodies: anti-phospho-Smad2 (Millipore), anti-Smad2/3 (BD Transduction Laboratories, NJ, USA), or anti-β-actin (Sigma-Aldrich) in PBST containing 1% BSA. Membranes were washed three times with PBST and incubated with either horseradish peroxidase (HRP)-conjugated goat anti-mouse antibody or HRP-conjugated goat anti-rabbit antibody (SantaCruz Biotechnology, Santa Cruz, Calif., USA) at room temperature for 1 h. Bound antibodies were detected using Western Blotting Luminol Reagent (SantaCruz Biotechnology). Band intensities were analyzed using a densitometer LAS-3000 imager (FUJIFILM, Tokyo, Japan).
Example 2 suppressed TGF-β1-induced Smad2 phosphorylation in tumor tissues.
Anti-metastatic Effect on MMTV/c-Neu mice breast cancer model MMTV/c-Neu female transgenic mice were purchased from Jackson Laboratory (Bar Harbor, Me., USA). Animals were maintained in a temperature-controlled SPF room (22° C.) and supplied with food and water ad libitum. In Experiment 1, Example 61 (43.6 mg/kg) dissolved in saline was given to thirty two-week-old MMTV/c-Neu mice intraperitoneally every other day for three weeks. In Experiment 2, Example 3 (43.6 mg/kg) dissolved in saline was given to thirty two-week-old MMTV/c-Neu mice intraperitoneally every other day for ten weeks. Mice were sacrificed at 24 h after the last dosing, and tissues of mammary tumor and lung were analyzed by hematoxylin and eosin (H&E) staining To analyse β-casein mRNA level in tissues of mammary tumor and lung, total RNAs were isolated from these tissues using TRIzol reagent (Invitrogen Corporation) and RNeasy Mini kit (Qiagen) according to the manufacturer's instruction. The cDNAs were synthesized from 2 μg of total RNAs using random primer (Invitrogen Corporation) by MMLV RTase (Invitrogen Corporation) for 1 h at 37° C. and subjected to PCR amplification using Taq polymerase (Promega) and following gene-specific primers: mouse GAPDH (forward) 5′-ATG TGT CCG TCG TGG ATC TGA-3′ and (reverse) 5′-TTG AAG TCG CAG GAG ACA ACC-3′, mouse β-casein (forward) 5′-TCC CAC AAA ACA TCC AGC C-3′ and (reverse) 5′-ACG GAA TGT TGT GGA GTG G-3′. Amplified DNA was analyzed by agarose gel electrophoresis.
Example 61 significantly reduced the number of metastastic lesions in the lung. Significant level of β-casein (a mammary differentiation marker) mRNA was detected in the lung of MMTV/c-Neu mice. Examples 3 and 61 significantly inhibited β-casein mRNA expression level in the lung, demonstrating their anti-metastatic effect.
Activity of MMP-9 and MMP-2 in the primary mammary tumor was measured by gelatin zymography. Tumor tissues from mice (30 mg) was lysed in 500 μL RIPA buffer (50 mM Tris, 150 mM NaCl, 0.1% sodium dodecyl sulfate, 0.5% sodium deoxycholate, 1% NP-40, protease inhibitor without EDTA) for 10-20 min on ice. Lysates were cleared by centrifugation at 13000 rpm at 4° C. for 10 min. Protein content of supernatants was determined using Micro-BCA protein assay kit (Thermo Scientific). Loading samples were prepared by adding loading buffer (0.5 M Tris, pH 6.8, 50% glycerol, 10% SDS, and 1% bromophenol blue solution) into lysates containing 15 μg of total protein. Loading samples were heated at 60° C. for 5 min and separated by electrophoresis on 10% polyacrylamide gel containing 0.2% gelatin. Gel was washed twice with washing buffer [2.5% Triton-X100, 0.05 M Tris-HCl, pH 7.5, and 0.1 M NaCl] for 30 min at room temperature. Then, the gel was incubated in incubation buffer [0.05 M Tris-HCl, pH 7.5, 0.15 M NaCl, 0.01 M CaCl2, 0.02% NaN3, and 1 μM ZnCl2] at 37° C. for 16-18 h with shaking Gel was stained by 0.5% Coomassie blue 8250 solution containing 5% methanol and 10% acetic acid for 2-4 h at room temperature and destained twice by destaining solution (5% methanol and 10% acetic acid) for 30 min at room temperature. Gel image was obtained using a densitometer LAS-3000 imager (FUJIFILM) in cybergreen mode.
Example 3 significantly inhibited activity of MMP-9 and MMP-2 in the primary mammary tumor.
Anti-Fibrotic Effect on Bile Duct-Ligated Liver Fibrosis Model
Six-week-old male Sprague-Dawley (SD) rats were purchased from Orient Bio Inc. In Experiment 1, SD rats weighing 180-200 g were randomly divided into five experimental groups: sham-operated control rats (n=5), sham-operated rats treated with Example 3 (43.6 mg/kg, n=5), bile duct-ligated (BDL) rats (n=10), BDL rats treated with either 21.8 or 43.6 mg/kg of Example 3 (n=10). In Experiment 2, SD rats weighing 180-200 g were randomly divided into five experimental groups: sham-operated control rats (n=5), BDL rats (n=10), BDL rats treated with either 5, 10, or 20 mg/kg of Example 2 (n=10). For BDL, the animals were anesthetized with zoletil (20 mg/kg) and xylazine (10 mg/kg), and the common bile duct was exposed and double-ligated using 3-0 silk. The first ligature was placed below the junction of the hepatic duct, and the second was placed above the entrance of the pancreatic duct. The common bile duct was then cut between the double ligatures. In sham-operated rats, an incision was made in the abdomen and then closed without any treatment. Treatment was started within 2 h after surgical procedure. Either Example 3 dissolved in saline (Experiment 1) or Example 2 dissolved in artificial gastric fluid formulation (Experiment 2) was given to rats orally three times per week for four weeks starting from BDL surgery. Animals were maintained in a temperature controlled room (at 21° C.) and supplied with autoclaved food and water. At 48 h after the last dosing, animals were killed, and the serum, spleens and livers were removed. The livers were sagittally sliced into several parts, snap frozen in liquid nitrogen, and kept at −70° C. A part of livers was immersed into 10% neutral buffered-formalin for histopathological examinations. All experimental procedures were conducted in accordance with our institutional guidelines. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was determined using a spectrophotometric enzyme assay kit (Asan Pharm. Co., Ltd., Hwaseong-si, Korea) according to the manufacturer's instruction. Automated instrument was also used to assay general serum biochemistry. Liver specimens were fixed in 10% neutral buffered-formalin prior to routine processing in paraffin-embedded blocks. Sections (5 μm thick) were cut and stained using hematoxylin and eosin (H&E), and examined by light microscopy. Liver tissues were lysed in RIPA buffer [50 mM Tris, pH 7.5, 150 mM NaCl, 1 mM EDTA, 0.1% sodium dodecyl sulfate, 0.5% sodium deoxycholate, 1% NP-40, 50 mM NaF, 1 mM Na3VO4, 1 mM PMSF, a protease inhibitor cocktail (1 tablet of Roche Diagnostics GmbH protease inhibitor cocktail/10 mL) (Roche)] for 20 min on ice. Lysates were cleared by centrifugation at 13000 rpm at 4° C. for 20 min. Protein content of supernatants was determined using Micro-BCA protein assay kit (Thermo Scientific). Lysates containing 20-60 μg total protein were separated by electrophoresis on 6-10% sodium dodecyl sulfate-polyacrylamide gel and then transferred to nitrocellulose (Whatman®, Germany) or polyvinylidene difluoride membranes (Millipore). Membranes were blocked with 5% BSA (Sigma-Aldrich) or 5% nonfat dry milk solution for 1 h and incubated overnight at 4° C. with one of following antibodies: rabbit antiphospho-Smad3 (Cell Signaling Technology, Beverly, Mass., USA), rabbit anti-α-SMA (Millipore), mouse anti-fibronectin, mouse anti-vimentin (BD Biosciences), or mouse anti-β-actin (Sigma-Aldrich). Membranes were washed three times with Tris-buffered saline and incubated with either HRP-conjugated goat anti-rabbit antibody or HRP-conjugated goat anti-mouse antibody (SantaCruz Biotechnology) at room temperature for 1 h. Bound antibodies were detected using an ECL kit (GE Healthcare, Princeton, N.J., USA). Band intensities were analyzed using a densitometer LAS-3000 imager (FUJIFILM).
BDL rats showed body weight loss and organ (liver and spleen) weight increase compared with sham-operated control rats. Examples 2 and 3 recovered body weight loss and decreased organ (liver and spleen) weight in BDL rats. A significant increase in serum ALT and AST was observed in BDL rats as compared with sham-operated animals. Examples 2 and 3 improved serum ALT and AST in BDL rats. Examples 3 inhibited Smad signaling and suppressed α-SMA, fibronectin, and vimentin in BDL rat liver. Examples 2 suppressed α-SMA and fibronectin in BDL rat liver. BDL rat livers showed typical histological changes characterized by central±central architecture disruption and bridge fibrosis formation compared with that of normal rat livers. Examples 2 and 3 greatly abolished BDL-induced histological change.
TABLE 4
Body
Organ weight
Groups (mg/kg)
weight (g)
Liver (g)
Spleen (g)
Liver/Body (%)
Spleen/Body (%)
Sham
vehicle
357 ± 5.2
11.7 ± 0.36
0.78 ± 0.06
3.28 ± 0.07
0.22 ± 0.02
Example 3 (43.6)
354 ± 12.2##
11.8 ± 0.71
0.81 ± 0.04
3.34 ± 0.12
0.23 ± 0.01
BDL
vehicle
308 ± 6.1**
22.8 ± 1.30**
2.01 ± 0.14**
7.43 ± 0.44**
0.65 ± 0.04**
Example 3 (21.8)
340 ± 0.6#
16.4 ± 0.72**,##
1.30 ± 0.07**
4.85 ± 0.26**,##
0.39 ± 0.03**,##
Example 3 (43.6)
335 ± 8.4
16.1 ± 0.57**,##
1.19 ± 0.09**
4.84 ± 0.26**,##
0.36 ± 0.03**,##
Data represents the mean ± S.E. (n = 5-8).
**p < 0.01 vs. sham.
#p < 0.05 vs. BDL.
##p < 0.01 vs. BDL.
TABLE 5
Body
Organ weight
Groups (mg/kg)
weight (g)
Liver (g)
Spleen (g)
Liver/Body (%)
Spleen/Body (%)
Sham
vehicle
345 ± 6.3
12.1 ± 0.77
0.83 ± 0.05
3.51 ± 0.21
0.24 ± 0.02
BDL
vehicle
315 ± 16.1*
20.3 ± 2.45**
2.54 ± 0.29**
6.39 ± 0.51**
0.80 ± 0.05**
Example 2 (5)
324 ± 7.3
17.5 ± 1.82
2.00 ± 0.28**
5.46 ± 0.62
0.63 ± 0.09**
Example 2 (10)
312 ± 10.4
15.8 ± 1.88
1.57 ± 0.12#
5.08 ± 0.60
0.51 ± 0.05#
Example 2 (20)
312 ± 8.4*
15.2 ± 1.80
1.50 ± 0.16#
4.88 ± 0.63
0.48 ± 0.05#
Data represents the mean ± S.E. (n = 5-8).
*p < 0.05 vs. sham.
**p < 0.01 vs. sham.
#p < 0.05 vs. BDL.
Anti-Fibrotic Effect on Bleomycin-Induced Lung Fibrosis Model
Six-week-old male ICR mice were purchased from Orient Bio Inc. Mice weighing 31-35 g were randomly divided into five experimental groups: sham-operated control mice (saline, n=6), bleomycin (BLM)-treated mice (n=10), BLM-treated mice treated with either 5, 10, or 20 mg/kg of Example 2 (n=10). For the induction of lung fibrosis, mice were anesthetized with zoletil (10 mg/kg) and xylazine (5 mg/kg) and were given BLM (given as BLM sulfate, 1 mg/kg) (MBcell, Los Angeles, Calif., USA) dissolved in 60 μL of saline once on day 0 through intratracheal instillation. Example 2 dissolved in artificial gastric fluid formulation was given to mice orally five times per week for two weeks starting from day 7. Animals were maintained in a temperature controlled room (at 21° C.) and supplied with autoclaved food and water. At three weeks post-surgery, animals were killed, and the lungs were removed. The lungs were sagittally sliced into several parts, snap frozen in liquid nitrogen, and kept at −70° C. A part of lungs was immersed into 10% neutral buffered-formalin for histopathological examinations. All experimental procedures were conducted in accordance with our institutional guidelines. Lung specimens were fixed in 10% neutral buffered-formalin prior to routine processing in paraffin-embedded blocks. Sections (5 μm thick) were cut, stained using hematoxylin and eosin (H&E), and examined by light microscopy. Lung tissues were lysed in RIPA buffer [50 mM Tris, pH 7.5, 150 mM NaCl, 1 mM EDTA, 0.1% sodium dodecyl sulfate, 0.5% sodium deoxycholate, 1% NP-40, 50 mM NaF, 1 mM Na3VO4, 1 mM PMSF, a protease inhibitor cocktail (1 tablet of Roche Diagnostics GmbH protease inhibitor cocktail/10 mL) (Roche)] for 20 min on ice. Lysates were cleared by centrifugation at 13000 rpm at 4° C. for 20 min. Protein content of supernatants was determined using Micro-BCA protein assay kit (Thermo Scientific). Lysates containing 20-50 μg total protein were separated by electrophoresis on 6-10% sodium dodecyl sulfate-polyacrylamide gel and then transferred to nitrocellulose (Whatman®). Membranes were blocked with 5% nonfat dry milk solution for 1 h and incubated overnight at 4° C. with either rabbit anti-α-SMA (Millipore) or mouse anti-fibronectin (BD Biosciences). Membranes were washed three times with Tris-buffered saline and incubated with either HRP-conjugated goat anti-rabbit antibody or HRP-conjugated goat anti-mouse antibody (SantaCruz Biotechnology) at room temperature for 1 h. Bound antibodies were detected using an ECL kit (GE Healthcare). Band intensities were analyzed using a densitometer LAS-3000 imager (FUJIFILM).
BLM-induced fibrotic lungs showed the elevated levels of α-SMA and fibronectin compared with those of sham-operated animals. Example 2 suppressed α-SMA and fibronectin in BLM-induced fibrotic lung. Lung tissues from the BLM-treated mice showed typical histology that pulmonary interalveolar septa became thickened and infiltrated by inflammatory cells with collagen depositions in the interstitium disclosed. Example 2 greatly reduced BLM-induced histological changes at all dose levels tested.
Kim, Dae-Kee, Sheen, Yhun Yhong, Jin, Chenghua, Park, Chul-Yong, Domalapally, Sreenu, Kota, Sudhakar Rao, Maddeboina, Krishnaiah, Vura Bala, Subrahmanyam
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