Hedgehog pathway antagonists and therapeutic applications thereof

• US 8,835,648 B2
• Filed: 06/09/2010
• Issued: 09/16/2014
• Est. Priority Date: 06/11/2009
• Status: Expired due to Fees

• Current Assignee: Siena Biotech S.p.A.
• Original Assignee: Siena Biotech S.p.A.
• Inventors: Thomas, J. Russell, Pericot Mohr, Gal.la, Caramelli, Chiara, Minetto, Giacomo, Bellini, Marta
• Primary Examiner(s): STOCKTON, LAURA LYNNE
• Application Number:
  US13/377,290
• Publication Number:
  US 20120088752A1
• Time in Patent Office: 1,560 Days
• Field of Search: 548/310.7
• US Class Current: 548/310.7
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Heterocyclic compounds that modulate the hedgehog signaling pathway, pharmaceutical composition thereof and their therapeutic applications.

Claims

1. Compounds of formula I and pharmaceutically acceptable salts thereof

2. Compounds according to claim 1 wherein i equals 2 and —

C(═

O)—

Y stands in the 4 position of the ensuing piperidine ring and wherein R₁, R₂, X, R₃, Y, Z, Rx, k, n, p, T, T′

, r and R′

are as defined in claim 1.

3. Compounds according to claim 1 wherein i equals 2 and —

C(═

O)—

Y stands in the 3 position of the ensuing piperidine ring and wherein R₁, R₂, X, R₃, Y, Z, Rx, k, n, p, T, T′

, r and R′

are as defined in claim 1.

4. Compounds according to claim 1 wherein i equals 1 and wherein R₁, R₂, X, R₃, Y, Z, Rx, k, n, p, T, T′

, r and R′

are as defined in claim 1.

5. Compounds according to claim 1 wherein R₁ is H, R₂ is Cl or F and wherein i, X, R₃, Y, Z, Rx, k, n, p, T, T′

, r and R′

are as defined in claim 1.

6. Compounds according to claim 1 wherein R₂ is H, R₁ is linear (C₁-C₄) alkyl group, branched or cyclic (C₃-C₄) alkyl group and wherein i, X, R₃, Y, Z, Rx, k, n, p, T, T′

, r and R′

are as defined in claim 1.

7. Compounds according to claim 1 wherein X is N and wherein i, R₁, R₂, R₃, Y, Z, Rx, k, n, p, T, T′

, r and R′

are as defined in claim 1.

8. Compounds according to claim 1 wherein X is CR₃ and wherein i, R₁, R₂, R₃, Y, Z, Rx, k, n, p, T, T′

, r and R′

are as defined in claim 1.

9. Compounds according to claim 8 wherein R₃ is H and wherein i, R₁, R₂, Y, Z, Rx, k, n, p, T, T′

, r and R′

are as defined in claim 8.

10. Compounds according to claim 1 wherein R₃ is Cl, F, OMe or Me and wherein i, R₁, R₂, Y, Z, Rx, k, n, p, T, T′

, r and R′

are as defined in claim 1.

11. Compounds according to claim 1 wherein r equals zero.

12. Compounds according to claim 1 wherein Y is

13. Compounds according to claim 1 wherein Y is

14. Compounds according to claim 1 wherein i equals 2 and —

C(═

O)—

Y stands in the 4 position of the ensuing piperidine ring, X is C R₃, R₃ is methyl, R₂ is F and wherein R₁, Y, Z, Rx, k, n, p, T, T′

, r and R′

are as defined in claim 1.

15. A compound according to claim 1, which is selected from the group of:

{1-[4-Fluoro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-yl}-piperazin-1-yl-methanone;

Azepan-1-yl-{1-[4-fluoro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-yl}-methanone;

{1-[4-Fluoro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-yl}-pyrrolidin-1-yl-methanone,

{1-[4-Fluoro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-yl}-piperidin-1-yl-methanone;

{(S)-1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-piperidin-3-yl}-morpholin-4-yl-methanone;

{1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-piperidin-4-yl}-morpholin-4-yl-methanone;

1-[4-Fluoro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-4-carboxylic acid (3-dimethylamino-propyl)-methyl-amide;

{1-[4-Fluoro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-yl}-(4-methyl-piperazin-1-yl)-methanone;

{1-[4-Fluoro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-yl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;

{1-[4-Fluoro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-yl}-morpholin-4-yl-methanone;

{1-[4-Chloro-3-(5-methoxy-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-yl}-morpholin-4-yl-methanone;

{(R)-1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-piperidin-3-yl}-morpholin-4-yl-methanone;

{(S)-1-[3-(1-Methyl-1H-Benzoimidazol-2-yl)-phenyl]-piperidin-3-yl}-morpholin-4-yl-methanone;

{(R)-1-[3-(1-Methyl-1H-Benzoimidazol-2-yl)-phenyl]-piperidin-3-yl}-morpholin-4-yl-methanone;

{1-[4-Fluoro-3-(5-fluoro-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-yl}-morpholin-4-yl-methanone;

(3-Dimethylaminopyrrolidin-1-yl)-{(R)-1-[3-(1-methyl-1H-benzoimidazol-2-yl-) -phenyl]-piperidin-3-yl}-methanone;

{(R)-1-[4-Chloro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-3-yl}-(3-dimethylamino-pyrrolidin-1-yl)-methanone;

{(S)-1-[4-Chloro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-3-yl}-morpholin-4-yl-methanone;

{1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-pyrrolidin-3-yl}-(3-dimethylamino-pyrrolidin-1-yl)-methanone,

(3-Dimethylamino-pyrrolidin-1-yl)-{(S)-1-[3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-3-yl}-methanone;

(3-Dimethylamino-pyrrolidin-1-yl)-{(R)-1-[3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-3-yl}-methanone;

{(R)-1-[4-Chloro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-3-yl}-(3-dimethylamino-pyrrolidin-1-yl)-methanone;

{1-[4-Chloro-3-(5-methoxy-1H-benzoimidazol-2-yl)-phenyl]-pyrrolidin-3-yl}-morpholin-4-yl-methanone;

(3-Dimethylamino-pyrrolidin-1-yl)-{1-[3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-pyrrolidin-3-yl}-methanone;

{(R)-1-[4-Chloro-3-(5-fluoro-1H-benzoimidazol-2-yl)-phenyl]-piperidin-3-yl}-(3-dimethylamino-pyrrolidin-1-yl)-methanone, {(R)-1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-piperidin-3-yl}-(3-dimethylamino-pyrrolidin-1-yl)-methanone;

{(R)-1-[4-Chloro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-3-yl}-morpholin-4-yl-methanone;

{1-[4-Chloro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-pyrrolidin-3-yl}-(3-dimethylamino-pyrrolidin-1-yl)-methanone,

{(S)-1-[4-Chloro-3-(5-fluoro-1H-benzoimidazol-2-yl)-phenyl]-piperidin-3-yl}-morpholin-4-yl-methanone,

{(S)-1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-piperidin-3-yl}-(3-dimethylamino-pyrrolidin-1-yl)-methanone;

{1-[4-Chloro-3-(−

1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-piperidin-4-yl}-morpholin-4-yl-methanone,

{(R)-1-[4-Chloro-3-(−

1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-piperidin-3-yl}-morpholin-4-yl-methanone;

{(S)-1-[4-Chloro-3-(−

1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-piperidin-3-yl}-morpholin-4-yl-methanone;

{1-[4-Chloro-3-(−

1H-imidazo[4,5-c]pyridin-2-yl)-phenyl}-piperidin-4-yl]-(3-dimethylamino-pyrrolidin-1-yl)-methanone;

{(S)-1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-piperidin-3-yl}-(3-dimethylamino-pyrrolidin-1-yl)-methanone,

{1-[4-Chloro-3-(5-fluoro-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-yl}-morpholin-4-yl-methanone,

{1-[4-Chloro-3-(5-fluoro-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-yl}-(3-dimethylamino-pyrrolidin-1-yl)-methanone; and

{1-[4-Chloro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-yl}-morpholin-4-yl-methanone,

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition containing a compound according to claim 1 with a pharmaceutically acceptable carrier or excipient.

17. A method for treating osteoporosis comprising administering a pharmaceutical composition comprising a compound according to claim 1.