IP Library › Granted Patent US 7,932,251

Granted Patent B2

US 7,932,251 · App. 12/173,623 · Granted Apr 26, 2011

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

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Quick Facts

Patent No.: US 7,932,251
App. No.: 12/173,623
Granted: Apr 26, 2011
Kind: B2

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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.

Claims (86)

1. 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;

R4 is H, halogen or CN;

X is CH2, O or S;

n is 1-5;

Y is selected from OH, CN, (C1-3)alkylcarbonyl, NR5R6 and Z, wherein

Z is a saturated 5-or-6-membered heterocyclic ring containing 1-3 heteroatoms selected from O, S and NR7, which ring may be substituted by OH, oxo, (C1-3)alkyl, hydroxy(C1-3)alkyl or (C1-3)alkoxy(C1-3)alkyl; or wherein

Z is an aromatic 5- or 6-membered heterocyclic ring containing 1-3 heteroatoms selected from O, S and N, which ring may be substituted by OH, (C1-3)alkyl or hydroxy(C1-3)alkyl;

R5 and R6 are independently H, (C3-8)cycloalkyl or (C1-6)alkyl, optionally substituted with halogen, OH, CF3, (C3-8)cycloalkyl, (C1-6)alkyloxy, CONR14R15, NR14R15, SO2R16, a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, S and N, or a 5-or-6-membered saturated heterocyclic group containing a heteroatom selected from O, S or NR8; or

R5 and R6 together with the nitrogen to which they are bound form a 4-10 membered saturated heterocyclic ring, optionally further comprising 1-3 heteroatoms selected from O, S and NR9, the ring being optionally substituted with OH, oxo, (C1-4)alkyl, hydroxy(C1-3)alkyl, (C3-8) cycloalkyl, CONR10R11 or NR10R11;

R7 is H, (C1-3)alkyl or hydroxy(C1-3)alkyl;

R8 is H, (C1-3)alkyl or hydroxy(C1-3)alkyl;

R9 is H, (C1-3)alkyl, (C3-7)cycloalkyl, hydroxy(C1-3)alkyl, (C1-3)alkoxy(C1-3)alkyl, (C1-6)alkylcarbonyl, (C1-6)alkyloxycarbonyl, CONR12R13, CH2CONR12R13 or a 5-or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, S and N;

R10 and R11, are independently H or (C1-3)alkyl;

R12 and R13 are independently H or (C1-3)alkyl; or

R12 and R13 together with the nitrogen to which they are bound form a 4-8 membered saturated heterocyclic ring, optionally further comprising a heteroatom selected from O and S;

R14 and R15 are independently H or (C1-3)alkyl; or

R14 and R15 together with the nitrogen to which they are bound form a 4-8 membered saturated heterocyclic ring, optionally further comprising a heteroatom selected from O and S;

R16 is (C1-3)alkyl; or a pharmaceutically acceptable salt thereof.

2. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 1 wherein R1 is H.

3. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4carbonitrile derivative of claim 2 , wherein R3 is CF3 and R4 is H.

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 2 or 3.

5. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 4 , wherein Y is NR5R6.

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

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

6-[4-(3-dimethylaminopropoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-[4-(3-pyrrolidin-1-ylpropoxy)-3-(trifluoromethyl)-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-[4-(3-N,N-diethylamino-propoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-[3-(trifluoromethyl)-4-(3-(3,3,4-trimethylpiperazin-1-yl)-propoxy)-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(3,3-dimethylpiperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(cis-3,5-dimethylpiperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-{4-[3-(4-methylpiperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(4-ethylpiperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-(4-{3-[4-(N-methylaminocarbonyl)-piperidin-1-yl]-propoxy}-3-(trifluoromethyl)-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(2-ethyl-imidazol-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-[1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[2-(cis-3,5-dimethyl-piperazin-1-yl)-ethoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-{4-[2-(8-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-3-yl)-ethoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-[4-(pyridin-2-yl-methoxy)-3-(trifluoromethyl)-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(4-ethyl-piperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-{3-(trifluoromethyl)-4-[(3-(S)-isopropylpiperazin-1-yl)-propoxy]-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile hydrochloride;

6-(4-(2-(1-ethylpiperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile 2,2,2-trifluoroacetate; and

1-methyl-6-[4-(6-methyl-pyridin-2-ylmethoxy)-3-trifluoromethyl-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile; or a pharmaceutically acceptable salt thereof.

8. 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 pharmaceutically acceptable auxilliaries.

9. The pharmaceutical composition of claim 8 , wherein the 6phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative is selected from the group consisting of