IP Library › Granted Patent US 8,026,236

Granted Patent B2

US 8,026,236 · App. 12/686,692 · Granted Sep 27, 2011

6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 8,026,236
App. No.: 12/686,692
Granted: Sep 27, 2011
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

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.

Claims (97)

1. A 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative having the general Formula I

wherein

R 1 is H or (C 1-3 )alkyl;

R 2 is H or (C 1-3 )alkyl;

R 3 is halogen or (C 1-4 )alkyl, optionally substituted with one or more halogens;

X is CH 2 , O or S;

n is 1-3;

Y is selected from

NR 4 COR 5 ,

NR 4 SO 2 R 5 ,

R 4 is H, (C 1-3 )alkyl or (C 3-5 )cycloalkyl;

R 5 is H, (C 1-6 )alkyl, (C 3-5 )cycloalkyl, NR 12 R 13 , CR 16 R 17 NR 12 R 13 , Het or a saturated

4-6-membered NR 11 containing ring;

R 6 is (C 3-5 )cycloalkyl, halo(C 1-6 )alkyl,(C 1-3 )alkyloxy(C 1-3 )alkyl, (CH 2 ) m CONR 12 R 13 , CO(C 1-6 )alkyl, COCR 16 R 17 NR 12 R 13 , SO 2 (C 1-6 )alkyl, Het, COHet or CH 2 Het;

r=0-3; p=0-2; q=0-2;

X 1 and X 2 are independently CH or N;

one of R 7 and R 8 is selected from halogen, (C 1-3 )alkyloxy, NR 14 R 15 , CONR 14 R 15 , NR 14 COR 15 , COO(C 1-3 )alkyl and phenyl; the other is H or halogen;

R 9 and R 10 are (C 1-3 )alkyl; or

R 9 an R 10 form together with the carbon to which they are bonded a 3-5 membered saturated ring;

R 11 is H or (C 1-3 )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 (C 1-3 )alkyl;

R 12 and R 13 are independently H, (C 1-6 )alkyl, or (C 1-3 )alkyloxy(C 1-3 )alkyl; or

R 12 and R 13 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;

R 14 and R 15 are independently H or (C 1-6 )alkyl; or

R 14 and R 15 form together with the N to which they are bonded a 5-7 membered saturated heterocyclic ring;

R 16 and R 17 are independently H or (C 1-3 )alkyl; or

R 16 and R 17 form together with the carbon atom to which they are bonded a cyclopropyl ring;

with the proviso that when r is 0, R 6 is not H or (C 1-4 )alkyl, or a pharmaceutically acceptable salt thereof.

2. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 1 wherein R 1 is methyl.

3. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 2 , wherein R 3 is CF 3 .

4. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 3 , wherein X is O and n is 1 or 2or 3.

5. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 4 , wherein Y is NR 4 COR 5 .

6. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 1 which is 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; and

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.

7. A pharmaceutical composition comprising a 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 1 or a pharmaceutically acceptable salt thereof, in admixture with one or more pharmaceutically acceptable auxilliaries.

8. A pharmaceutical composition comprising a 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative selected from