IP Library › Granted Patent US 7,687,515

Granted Patent B2

US 7,687,515 · App. 11/653,600 · Granted Mar 30, 2010

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

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Quick Facts

Patent No.: US 7,687,515
App. No.: 11/653,600
Granted: Mar 30, 2010
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 wherein each of the substituents is given the definition as set forth in the specification and claims, 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 and/or cathepsin K related diseases such as osteoporosis, atherosclerosis, inflammation and immune disorders, such as rheumatoid arthritis, and chronic pain, such as neuropathic pain.

Claims (117)

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

wherein

R is an optional ortho- or meta-substituent selected from halogen and (C 1-4 )alkyloxy;

R 1 is (C 1-4 )alkyl, (C 1-4 )alkyloxy, halogen or CF 3 ;

R 2 is H, (C 1-4 )alkyl, (C 1-4 )alkyloxy or halogen;

R 3 is H or (CH 2 ) n —NR 5 R 6 ;

R 4 is H or (C 1-6 )alkyl, optionally substituted with COOR 7 or NR 8 R 9 ;

R 5 and R 6 are independently H, (C 3-8 )cycloalkyl, quinuclidin-3-yl, (C 2-6 )alkenyl or (C 1-6 )alkyl, optionally substituted with halogen, CF 3 , (C 3-8 )cycloalkyl, (C 6-10 )aryl, a 5- or 6-membered heteroaryl group, OH, (C 1-6 )alkyloxy, (C 6-10 )aryloxy, COOR 10 , CONR 11 ,R 12 , NR 13 R 14 or NR 13 SO 2 (C 1-4 )alkyl; or

R 5 and R 6 together with the nitrogen to which they are bound form a 4-8 membered saturated heterocyclic ring, optionally further comprising 1 or more heteroatoms selected from O, S, SO 2 and NR 15 , the ring being optionalily substituted with oxo, (C 1-4 )alkyl, (C 3-8 )cycloalkyl, NR 16 ,R 17 or CONR 18 ,R 19 ;

R 7 is H or (C 1-4 )alkyl;

R 8 and R 9 are independently H, (C 1-4 )alkyl (optionally substituted with di(C 1-4 )alkylamino) or (C 3-8 )cycloalkyl; or

R 8 and R 9 form together with the nitrogen to which they are bound a 4-8-membered saturated heterocyclic ring, optionally further comprising a heteroatom selected from O and S;

R 10 is H or (C 1-4 )alkyl;

11 and R 12 are independently H or (C 1-4 )alkyl; or

R 11 and R 12 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;

R 13 and R 14 are independently H or (C 1-4 )alkyl; or

R 13 and R 14 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;

R 15 is H, (C 1-4 )alkyl (optionally substituted with OH, (C 1-4 )alkyloxy, di(C 1-4 )alkylamino, or CONR 21 ,R 22 ), phenyl, pyridyl, COR 20 or CONR 21 ,R 22 ;

R 16 and R 17 are independently H or (C 1-4 )alkyl; or

R 16 and R 17 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;

R 18 and R 19 are independently H or (C 1-4 )alkyl;

R 20 is H, (C 1-4 )alkyl, (C 3-8 )cycloalkyl, (C 1-4 )alkyloxy or furyl;

R 21 and R 22 are independently H or (C 1-4 )alkyl; or

R 21 and R 22 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; and

n is 0 or 1; or a pharmaceutically acceptable salt thereof.

2. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives according to Formula I of claim 1 , wherein R is absent;

R 1 is (C 1-4 )alkyl, (C 1-4 )alkyloxy or CF 3 ;

R 2 is H, (C 1-4 )alkyl or (C 1-4 )alkyloxy;

R 3 is H or (CH 2 ) n —NR 5 R 6 ;

R 4 is H or (C 1-6 )alkyl, optionally substituted with COOR 7 or NR 8 R 9 ;

R 5 and R 6 are independently H, (C 3-8 )cycloalkyl, (C 2-6 )alkenyl or (C 1-6 )alkyl, optionally substituted with halogen, CF 3 , (C 3-8 )cycloalkyl, (C 6-10 )aryl, a 5- or 6-membered heteroaryl group, OH, (C 16 )alkyloxy, (C 6-10 )aryloxy, COOR 10 , CONR 11 ,R 12 or NR 13 R 14 ; or

R 5 and R 6 together with the nitrogen to which they are bound form a 4-8 membered saturated heterocyclic ring, optionally further comprising 1 or more heteroatoms selected from O, S, SO 2 and NR 15 , the ring being optionally substituted with oxo, (C 1-4 )alkyl, NR 16 ,R 17 or CONR 18 ,R 19 ;

R 7 is H or (C 14 )alkyl;

R 8 and R 9 are independently H, (C 1-4 )alkyl or (C 3-8 )cycloalkyl; or

R 8 and R 9 form together with the nitrogen to which they are bound a 4-8-membered saturated heterocyclic ring, optionally further comprising a heteroatom selected from O and S;

R 10 is H or (C 1-4 )alkyl;

R 11 and R 12 are independently H or (C 1-4 )alkyl; or

R 11 and R 12 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;

R 13 and R 14 are independently H or (C 1-4 )alkyl; or

R 13 and R 14 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;

R 15 is H, phenyl, pyridyl, COR 20 or CONR 21 ,R 22 ;

R 16 and R 17 are independently H or (C 1-4 )alkyl; or

R 16 and R 17 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;

R 18 and R 19 are independently H or (C 1-4 )alkyl;

R 20 is H, (C 1-4 )alkyl or furyl;

R 21 and R 22 are independently H or (C 1-4 )alkyl; or

R 21 and R 22 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;

n is 0 or 1;

with the proviso that one of R 3 and R 4 is H;

or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

8. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 4 , wherein R 2 is (C 1-4 )alkyloxy.

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

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

11. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 7 , wherein R 2 is ethoxy.

12. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 8 , wherein R 2 is ethoxy.

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

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

[4-cyano-6-(4-ethoxy-3-trifluoromethyl-phenyl)-imidazo[4,5-c]pyridin-1-yl]-acetic acid;

[4-cyano-6-(4-ethoxy-3-trifluoromethyl-phenyl)-imidazo[4,5-c]pyridin-1-yl]-butyric acid;

6-(4-ethoxy-3-trifluoromethyl-phenyl)-2-(3-oxo-piperazine-1-ylmethyl)-1H-imidazo-[4,5,c]pyridine-4-carbonitrile;

2-(1,1-dioxo-thiazolidin-3-ylmethyl)-methyl]-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-Imidazo[4,5-c]pyridine-4-carbonitrile;

6-(4-ethoxy-3-trifluoromethyl-phenyl)-1-(2-morpholin-4-yl-ethyl)-1H-imidazo-[4,5-c]pyridine-4-carbonitrile;

6-(4-ethoxy-3-trifluoromethyl-phenyl)-1-(2-piperidin-1-yl-ethyl)-1H-imidazo-[4,5-c]pyridine-4-carbonitrile;

1-(2-dimethylamino-ethyl)-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-(4-ethoxy-3-trifluoromethyl-phenyl)-1-(3-morpholin-4-yl-propyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-(3-dimethylamino-propyl)-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

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

6-(4-ethoxy-3-trifluoromethyl-phenyl)-2-[(2-hydroxy-ethylamino)-methyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

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

6-(4-ethoxy-3-trifluoromethyl-phenyl)-2-[4-(2-hydroxy-ethyl)-3-oxo-piperazin-1-ylmethyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-(4-ethoxy-3-trifluoromethyl-phenyl)-2-(4-oxo-imidazolidin-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

or a pharmaceutically acceptable salt thereof.

14. A method of treating a disease or disorder selected from myasthenia gravis, and chronic pain in a human, the method comprising administering to the human an effective amount of the 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 1 or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 , wherein the 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative is selected from:

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

[4-cyano-6-(4-ethoxy-3-trifluoromethyl-phenyl)-imidazo[4,5-c]pyridin-1-yl]-acetic acid;

[4-cyano-6-(4-ethoxy-3-trifluoromethyl-phenyl)-imidazo[4,5-c]pyridin-1-yl]-butyric acid;

6-(4-ethoxy-3-trifluoromethyl-phenyl)-2-(3-oxo-piperazine-1-ylmethyl) -1H-imidazo-[4,5,c]pyridine-4-carbonitrile;

2-(1,1-dioxo-thiazolidin-3-ylmethyl)-methyl]-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-Imidazo [4,5-c]pyridine-4-carbonitrile;