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US 8,026,236 B2Granted
6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives
AssigneeN.V. Organon
InventorsJohn Stephen Robinson, Philip Stephen Jones, Jiaqiang Cai, David Jonathan Bennett
Life of this patent
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Abstract
The present invention relates to 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives having the general Formula I to pharmaceutical compositions comprising the same as well as to the use of these derivatives for the preparation of a medicament for the treatment of cathepsin S related diseases such as atherosclerosis, obesity, inflammation and immune disorders, such as rheumatoid arthritis, psoriasis, cancer, and chronic pain, such as neuropathic pain.
Claims8
A 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative having the general Formula I
- wherein
- R1 is H or (C1-3)alkyl;
- R2 is H or (C1-3)alkyl;
- R3 is halogen or (C1-4)alkyl, optionally substituted with one or more halogens;
- X is CH2, O or S;
- n is 1-3;
- Y is selected from
- NR4COR5,
- NR4SO2R5,
- R4 is H, (C1-3)alkyl or (C3-5)cycloalkyl;
- R5 is H, (C1-6)alkyl, (C3-5)cycloalkyl, NR12R13, CR16R17NR12R13, Het or a saturated
- 4-6-membered NR11 containing ring;
- R6 is (C3-5)cycloalkyl, halo(C1-6)alkyl,(C1-3)alkyloxy(C1-3)alkyl, (CH2)mCONR12R13, CO(C1-6)alkyl, COCR16R17NR12R13, SO2(C1-6)alkyl, Het, COHet or CH2Het;
- r=0-3;
- p=0-2;
- q=0-2;
- X1 and X2 are independently CH or N;
- one of R7 and R8 is selected from halogen, (C1-3)alkyloxy, NR14R15, CONR14R15, NR14COR15, COO(C1-3)alkyl and phenyl;
- the other is H or halogen;
- R9 and R10 are (C1-3)alkyl;
- or
- R9 an R10 form together with the carbon to which they are bonded a 3-5 membered saturated ring;
- R11 is H or (C1-3)alkyl;
- m is 0 or 1;
- Het is a 5- or 6 membered heteroaryl ring comprising 1-3 heteroatoms selected from O, S and N, optionally substituted with (C1-3)alkyl;
- R12 and R13 are independently H, (C1-6)alkyl, or (C1-3)alkyloxy(C1-3)alkyl;
- or
- R12 and R13 form together with the N to which they are bonded a 5-10 membered saturated heterocyclic ring, optionally comprising a further heteroatom selected form O and S;
- R14 and R15 are independently H or (C1-6)alkyl;
- or
- R14 and R15 form together with the N to which they are bonded a 5-7 membered saturated heterocyclic ring;
- R16 and R17 are independently H or (C1-3)alkyl;
- or
- R16 and R17 form together with the carbon atom to which they are bonded a cyclopropyl ring;
- with the proviso that when r is 0, R6 is not H or (C1-4)alkyl, or a pharmaceutically acceptable salt thereof.
32 more elements
A pharmaceutical composition comprising a 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative selected from
- N-(3-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)propyl)methanesulfonamide;
- 6-[4-(3-acetylaminopropoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 6-{4-[3-(N-acetyl-N-methylamino)propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 1-methyl-6-(4-(2-(N-acetyl-N-methylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 1-methyl-6-{4-[(2-(N-ethyl-N-methylamino)-pyridin-4-yl)-methoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile hydrochloride;
- 1-methyl-6-(4-(2-(1-(oxazol-2-ylmethyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile hydrochloride;
- 1-methyl-6-(4-(2-(1-((5-methylisoxazol-3-yl)methyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 6-(4-(2-(1-((3,5-dimethylisoxazol-4-yl)methyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 6-(4-(2-(1-(2-dimethylamino-2-oxo-ethyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 6-(4-(2-(1-(2-fluoroethyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 6-(4-(2-(1-(2-methoxyethyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 1-methyl-6-(4-(2-(1-(thiazol-2-ylmethyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 1-methyl-6-(4-(2-(1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 1-methyl-6-(4-(2-(1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 1-methyl-6-(4-(2-(1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 1-methyl-6-(4-(2-(1-((3-methylisoxazol-5-yl)methyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 6-(4-(3-acetylaminobenzoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 6-(4-(2-(1-(2,2-dimethylamino-2-oxoethyl)-4-fluoropiperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 6-(4-(2-(4-fluoro-1-(2-methoxyethyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 6-(4-(2-(1-ethyl-4-fluoro-piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 6-(4-(2-(4-fluoro-1-(2-fluoroethyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 6-(4-(2-(4-fluoro-1-methyl-piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 1-methyl-6-(4-(2-(1-(pyridin-2-yl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- 1-methyl-6-(4-(2-(1-(6-methyl-pyridin-2-yl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-2-(dimethylamino)-N-methylacetamide;
- N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N-methyl-2-(pyrrolidin-1-yl)acetamide;
- (S)—N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N,1-dimethylpyrrolidine-2-carboxamide;
- 2-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)-N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N-methylacetamide;
- 1-methyl-6-(4-(2-(1-(2-(pyrrolidin-1-yl)acetyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- and
- 1-methyl-6-(4-(2-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;
- or a pharmaceutically acceptable salt thereof, in admixture with one or more pharmaceutically acceptable auxilliaries.
29 more elements
Dependencies are inferred from the claim text.