IP Library › Granted Patent US 6,977,263

Granted Patent B2

US 6,977,263 · App. 09/843,126 · Granted Dec 20, 2005

Chemical compounds

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Quick Facts

Patent No.: US 6,977,263
App. No.: 09/843,126
Granted: Dec 20, 2005
Kind: B2

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Abstract

Provided herein are novel and useful compounds having a tryptase inhibition activity, pharmaceutical compositions comprising such compounds, and methods treating subjects suffering from a condition, disease, or disorder that can be ameliorated by the administration of an inhibitor of tryptase, e.g., asthma and inflammatory diseases, to name only a few.

Claims (169)

1. A compound of formula (I):

such that Ar is an aryl or a heteroaryl, and the

group is beta to the

on the aryl,

wherein,

is a single or a double bond;

R 1 and R 2 are each independently hydrogen or lower alkyl;

R 3 is aryl, arylalkenyl, cycloalkenyl, cycloalkyl, heteroaryl, heteroarylalkenyl, heterocycloalkenyl, a carbon linked heterocycloalkyl or alkyl optionally substituted by one or more groups selected from hydroxy, alkoxy, alkyloxycarbonylamino, cycloalkyl, heterocycloalkyl, R 6 , —OR 6 , —S(O) m R 6 or —C(═O)—R 6 ;

R 4 is hydrogen, acyl, alkoxy, alkyloxycarbonyl, carboxy, cyano, halo, hydroxy, —C(═O)—NY 1 Y 2 or alkyl optionally substituted with alkoxy, alkylcarbonylamino, alkylsulfonylamino, hydroxy, —S(O) m -alkyl or —NY 1 Y 2 ;

R 6 is aryl or heteroaryl;

Y 1 and Y 2 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl; or the group —NY 1 Y 2 may form a cyclic amine;

m is zero or an integer 1 to 2; and

n is 2; or

an N-oxide of said compound, a prodrug of said compound, a pharmaceutically acceptable salt of said compound, a solvate of said compound or a hydrate of said compound.

2. The compound of claim 1 , wherein R 1 or R 2 is hydrogen, or R 1 and R 2 are hydrogen, and R 3 is an aryl or a heteroaryl.

3. The compound of claim 2 , wherein said R 3 is a phenyl or a naphthyl.

4. The compound of claim 2 , wherein said R 3 aryl is aryl substituted with at least one substituent.

5. The compound of claim 4 , wherein said substituent is selected from the group consisting of a halo atom, an alkyl substituted by aryl, an alkyl substituted by aryloxy, an alkyl substituted by aroyl, an alkyl substituted by heteroaryl, an arylalkynyl, a heteroarylalkynyl, an aryl, a heteroaryl, an arylalkenyl and an arylalkyloxy.

6. The compound of claim 5 , wherein said aryl or heteroaryl of said substituent is further substituted by at least one aryl group substituent.

7. The compound of claim 2 , wherein said heteroaryl is a pyridyl, a quinolinyl, a thienyl, a furanyl, or an indolyl.

8. The compound of claim 7 , wherein said heteroaryl is substituted with at least one substituent.

9. The compound of claim 8 , wherein said substituent is an alkyl, an alkyl substituted by an aryl, an alkyl substituted by an aryloxy, an alkyl substituted by an aroyl, an alkyl substituted heteroaryl, an arylalkynyl, a heteroarylalkynyl, a heteroaryl, an arylalkenyl or an arylalkyoxy.

10. The compound of claim 9 , wherein said aryl of said substituent is further substituted by at least one aryl substituent.

11. The compound of claim 1 , wherein R 4 is hydrogen or a cyano group.

12. The compound of claim 1 , wherein R 5 is a hydrogen, a lower alkyl, or a halo.

13. The compound of claim 1 , wherein:

Ar comprises a phenyl group;

R 1 and R 2 are both hydrogen;

R 3 is an aryl, a naphthyl, or a heteroaryl;

R 4 is hydrogen or a cyano; and

is a single bond.

14. The compound of claim 13 , wherein R 3 as aryl or naphthyl is substituted with at least one substituent selected from the group consisting a halo atom, an alkyl substituted by aryl, an alkyl substituted by aryloxy, an alkyl substituted by aroyl, an alkyl substituted by aryloxy, an alkyl substituted aroyl, an alkyl substituted by a heteroaryl, an arylalkynyl, a heteroarylalkynyl, an aryl, a heteroaryl, an arylalkenyl, and an arylalkyloxy.

15. The compound of claim 14 , wherein said aryl or said heteroaryl of said substituent is further substituted by at least one aryl substituent.

16. The compound of claim 13 , wherein R 3 as heteroaryl is substituted by at least one substituent selected from the group consisting of a pyridyl, a quinolinyl, a thienyl, a furanyl, and an indolyl.

17. The compound of claim 16 , wherein said substituent of said heteroaryl is further substituted by at least one moiety selected from the group consisting of an alkyl substituted by an aryl, an alkyl substituted by an aryloxy, an alkyl substituted by an aroyl, an alkyl substituted heteroaryl, an arylalkynyl, a heteroarylalkynyl, a heteroaryl, an arylalkenyl, or an arylalkyloxy.

18. The compound of claim 17 , wherein an aryl of said moiety is further substituted by at least one aryl substituent.

19. A compound of formula (Ia):

wherein,

is a single or double bond;

R 1 and R 2 are each independently hydrogen or lower alkyl;

R 5 is hydrogen, acyl, alkoxy, alkyloxycarbonyl, aryl, carboxy, cyano, halo, heteroaryl, heteroaryloxy, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylalkyloxy, heteroarylalkyloxy, hydroxy, trifluoromethyl, —C(═O)—NY 1 Y 2 , —NY 1 Y 2 , —Z 1 —C 2-6 alkylene-R 7 or alkyl optionally substituted with alkoxy, alkylcarbonylamino, alkylsulfonylamino, aryl, heteroaryl, heterocycloalkyl, hydroxy, ureido, —C(═O)—NY 1 Y 2 , —SO 2 —NY 1 Y 2 , —S(O) m -alkyl or —NY 1 Y 2 , and,

R 6 is aryl or heteroaryl;

R 7 is hydroxy, alkoxy, ureido, —C(═O)—NY 1 Y 2 , —SO 2 —NY 1 T 2 , —S(O) m -alkyl or —NY 1 Y 2 ,

R 8 is hydrogen or lower alkyl;

Y 1 and Y 2 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl; or the group —NY 1 Y 2 may form a cyclic amine;

Z 1 is O, S(O) m or NR 8 ;

m is zero or an integer 1 or 2; and

n is 2; or

an N-oxide of said compound, a prodrug of said compound, a pharmaceutically acceptable salt of said compound, a solvate of said compound, an N-oxide of said solvate of said compound, or a prodrug of said solvate of said compound.

20. The compound of claim 19 , wherein R 3 is a phenyl or a naphthyl.

21. The compound of claim 20 , wherein said aryl is substituted by at least one substituent selected from the group consisting of a halo atom, an alkyl substituted by an aryl, an alkyl substituted by a heteroaryl.

22. The compound of claim 21 , wherein said aryl or heteroaryl of said substituent is further substituted by at least one aryl group substituent.

23. The compound of claim 19 , wherein R 3 is phenylC 1-3 alkylpyridyl, phenylC 1-3 alkylthienyl or indolyl.

24. The compound of claim 23 , wherein the phenylC 1-3 alkylpyridyl is 5-phenylethyl-pyrid-3-yl, the phenylC 1-3 alkylthienyl is and the indolyl is indol-6-yl.

25. The compound of claim 19 , wherein R 3 is a heteroaryl selected from the group consisting of a pyridyl, a quinolinyl, a thienyl, a furanyl, and an indolyl.

26. The compound of claim 25 , wherein said heteroaryl is substituted by at least one substituent selected from the group consisting of an alkyl substituted by an aryl, or an alkyl substituted by a heteroaryl.

27. The compound of claim 26 , wherein said aryl and said heteroaryl of said substituent are further substituted by at least one aryl group substituent.

28. The compound of claim 27 , wherein R 3 is phenylC 1-3 alkylpyridyl, phenylC 1-3 alkylthienyl or indolyl.

29. The compound of claim 28 , wherein the phenylC 1-3 alkylpyridyl is 5-phenylethyl-pyrid-3-yl, the phenylC 1-3 alkylthienyl is 5-phenylethyl-thien-2-yl and the indolyl is indol-6-yl.

30. The compound of claim 19 , wherein R 4 is a hydrogen or a cyano.

31. The compound of claim 19 , wherein R 5 is a hydrogen, a lower alkyl or a halo.

32. The compound of claim 31 , wherein R 5 methyl or a fluoro.

33. The compound of claim 31 , wherein R 5 is attached to the phenyl ring of formula (Ia) in the position para to the CH 2 NH 2 group.

34. The compound of claim 19 , wherein:

R 3 is a phenyl, a naphthyl, a heteroaryl selected from the group consisting a pyridyl, a quinolinyl, a thienyl, a furanyl, and an indolyl, a phenyl substituted by at least one substituent, a naphthyl substituted by at least one substituent, or a heteroaryl selected from the group consisting a pyridyl, a quinolinyl, a thienyl, a furanyl, and an indolyl, that is substituted by at least one substituent,

wherein said substituent is selected from the group consisting of a halo atom, an alkyl substituted by aryl, and alkyl substituted heteroaryl, wherein the aryl or heteroaryl groups are further substituted by one or more aryl group substituents;

R 4 comprises hydrogen or a cyano; and

R 5 comprises hydrogen, a lower alkyl or a halo.

35. The compound of claim 34 , wherein:

R 3 is phenylC 1-3 alkylpyridyl, phenylC 1-3 alkylthienyl or indolyl;

R 4 is a hydrogen or a cyano; and

R 5 is a methyl or a fluoro, and is attached to the phenyl ring of formula (Ia) in the position para to the CR 1 R 2 NH 2 group.

36. The compound of claim 35 , wherein the phenylC 1-3 alkylpyridyl is 5-phenylethyl-pyrid-3-yl, the phenylC 1-3 alkylthienyl is 5-phenylethyl-thien-2-yl and the indolyl is indol-6-yl.

37. A compound of claim 19 , having formula (Ib):

38. The compound of claim 37 , wherein R 3 is a phenyl or a naphthyl.

39. The compound of claim 38 , wherein said aryl is substituted by at least one substituent selected from the group consisting of a halo atom, an alkyl substituted by an aryl, and an alkyl substituted by a heteroaryl.

40. The compound of claim 39 , wherein said aryl or heteroaryl of said substituent is further substituted by at least one aryl group substituent.

41. The compound of claim 37 , wherein R 3 is a pyridyl, a quinolinyl, a thienyl, a furanyl, or an indolyl.

42. The compound of claim 40 , wherein said heteroaryl is substituted by at least one substituent selected from the group consisting of an alkyl substituted by an aryl, and an alkyl substituted by a heteroaryl.

43. The compound of claim 40 , wherein said aryl and said heteroaryl of said substituent are further substituted by at least one aryl group substituent.

44. The compound of claim 37 , wherein R 3 is phenylC 1-3 alkylpyridyl, phenylC 1-3 alkylthienyl or indolyl.

45. The compound of claim 37 , wherein R 4 is a hydrogen or a cyano.

46. The compound of claim 37 , wherein R 5 is a hydrogen, a lower alkyl or a halo.

47. The compound of claim 46 , wherein R 5 is a methyl or a fluoro.

48. The compound of claim 46 , wherein R 5 is attached to the phenyl ring of formula (Ib) in the position para to the CH 2 NH 2 group.

49. The compound of claim 37 , wherein:

R 3 is a phenyl, a naphthyl, a heteroaryl selected from the group consisting a pyridyl, a quinolinyl, a thienyl, a furanyl, and an indolyl, a phenyl substituted by at least one substituent, a naphthyl substituted by at least one substituent, or a heteroaryl selected from the group consisting of a pyridyl, a quinolinyl, a thienyl, a furanyl, and an indolyl, that is substituted by at least one substituent,

R 4 is hydrogen or a cyano; and

R 5 is hydrogen, a lower alkyl or a halo.

50. The compound of claim 49 , wherein:

R 3 is phenylC 1-3 alkylpyridyl, phenylC 1-3 alkylthienyl or indolyl;

R 4 is a hydrogen or a cyano; and

R 5 is a methyl or a fluoro.

51. The compound of claim 1 , wherein

is a single bond.

52. The compound of claim 1 , selected from the group consisting of:

3-[1-(5-phenylethynyl-pyridine-3-carbonyl)-piperidin-4-yl]-benzylamine;

3-[1-(3-phenylethyl-benzoyl)-piperidin-4-yl]-benzylamine;

3-{1-[3-(4-hydroxyphenyl)ethyl-benzoyl]-piperidin-4-yl}-benzylamine;

3-{1-[3-(6-amino-pyridin-3-yl)ethyl-benzoyl]-piperidin-4-yl}-benzylamine;

3-[1-(5-phenylethyl-thiophene-2-carbonyl)-piperidin-4-yl]-benzylamine;

4-fluoro-3-[1-(5-phenylethyl-pyridine-3-carbonyl)-piperidin-4-yl]-benzylamine;

4-methyl-3-[1-(5-phenylethyl-pyridine-3-carbonyl)-piperidin-4-yl]-benzylamine;

3-[1-(indole-6-carbonyl)-piperidin-4-yl]-benzylamine;

4-(3-aminomethyl-phenyl)-1-(5-phenethyl-pyridine-3-carbonyl)-piperidine-4-carbonitrile;

[4-(3-aminomethylphenyl)piperidin-1-yl]-(3,4-dichlorophenyl)methanone;

1-{1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-methanoyl}-3-methylsulfanyl-6,7-dihydro-5H-benzo[c]thiophen-4-one trifluoroacetate;

1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-1-(3-methylsulfanyl-6,7-dihydro-benzo[c]thiophen-1-yl)-methanone trifluoroacetate;

1-{1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-methanoyl}-3-ethylsulfanyl-6,6-dimethyl-6,7-dihydro-5H-benzo[c]thiophen-4-one trifluoroacetate;

1-{1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-methanoyl}-3-propylsulfanyl-6,7-dihydro-5H-benzo[c]thiophen-4-one trifluoroacetate;

1-{1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-methanoyl}-3-isopropylsulfanyl-6,7-dihydro-5H-benzo[c]thiophen-4-one trifluoroacetate;

1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-1-benzo[b]thiophen-2-yl-methanone-trifluoroacetate;

1-[4-(3-Aminomethyl-phenyl)-4-hydroxy-piperidin-1-yl]-1-(5-phenethyl-pyridin-3-yl)-methanone-ditrifluoroacetate;

1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-1-(1-methyl-1H-indol-3-yl)-methanone-trifluoroacetate;

1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-1-[3-(2-fluoro-phenylethynyl)-phenyl]-methanone trifluoroacetate;

1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-1-{3-[2-(2-fluoro-phenyl)-ethyl]-phenyl}-methanone trifluoroacetate;

1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-1-{3-[2-(6-amino-pyridin-3-yl)-ethyl]-phenyl}-methanone tri-trifluoroacetate;

1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-1-(6-chloro-thieno[3,2-b]thiophen-2-yl)-methanone trifluoroacetate;

(3R,4S) and (3S,4R)-4-(3-Aminomethyl-phenyl)-1-(5-phenethyl-pyridine-3-carbonyl)-piperidine-3-carboxylic acid ethyl ester dihydrochloride;

3-[1-(5-Phenylethynyl-furan-2-carbonyl)-piperidin-4-yl]-benzylamine trifluoroacetate;

4-(3-Aminomethyl-phenyl)-piperidine-1-carboxylic acid (3,4-dichloro-phenyl)-amide trifluoroacetate;

1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-1-(2,3-dihydro-benzofuran-5-yl)-methanone;

1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-1-(5,6-dichloro-pyridin-3-yl)-methanone;

1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-1-(3-bromo-4-fluoro-phenyl)-methanone;

(E)-1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-3-(2-nitro-phenyl)-propenone;

1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-1-(3-bromo-5-iodo-phenyl)-methanone; and

(E)-1-[4-(3-Aminomethyl-phenyl)-piperidin-1-yl]-3-phenyl-propenone.

53. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier thereof.

54. The pharmaceutical composition of claim 53 , wherein said compound is selected from the group consisting of: