IP Library › Granted Patent US 7,507,737

Granted Patent B2

US 7,507,737 · App. 11/731,074 · Granted Mar 24, 2009

Benzoimidazol-2-yl pyrimidines and pyrazines as modulators of the histamine H

Assignee: Janssen Pharmaceutica, N.V.

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Quick Facts

Patent No.: US 7,507,737
App. No.: 11/731,074
Granted: Mar 24, 2009
Kind: B2

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Abstract

Benzoimidazol-2-yl pyrimidines and pyrazines, pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by H 4 receptor activity, including allergy, asthma, autoimmune diseases, and pruritis.

Claims (274)

1. A chemical entity that is a compound of Formula (I):

wherein

each of R 1-4 is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, —CF 3 , —OCF 3 , —ON, halo, —NO 2 , —OC 1-4 alkyl, —SC 1-4 alkyl, —S(O)C 1-4 alkyl, —SO 2 C 1-4 alkyl, —C(O)C 14 alkyl, —C(O)phenyl, —C(O)NR a R b , —CO 2 C 1-4 alkyl, —CO 2 H, —C(O)NR a R b , or —NR a R b ;

wherein R a and R b are each independently H, C 1-4 alkyl, or C 3-7 cycloalkyl;

one of X 1 and X 2 is N and the other is C-R c ;

where R c is H, methyl, hydroxymethyl, dimethylaminomethyl, ethyl, propyl,

isopropyl, —CF 3 , cyclopropyl, or cyclobutyl;

n is 1 or 2;

Z is N, CH, or C(C 1-4 alkyl);

R 6 is H, C 1-6 alkyl, or monocyclic cycloalkyl;

R 8 is H or C 1-4 alkyl;

R 9 and R 10 are each independently H or C 1-4 alkyl; and

R 11 is H or C 1-4 alkyl; or

a pharmaceutically acceptable salt of compound of Formula (I).

2. A chemical entity as defined in claim 1 , wherein each of R 1-4 is independently H, methyl, tert-butyl, methoxy, —CF 3 , —CN, fluoro, chloro, methoxycarbonyl, or benzoyl.

3. A chemical entity as defined in claim 1 , wherein X 2 is N.

4. A chemical entity as defined in claim 1 , wherein X 1 is N.

5. A chemical entity as defined in claim 1 , wherein R c is H, methyl, ethyl, CF 3 , cyclopropyl, or cyclobutyl.

6. A chemical entity as defined in claim 1 , wherein R c is H or methyl.

7. A chemical entity as defined in claim 1 , wherein n is 1.

8. A chemical entity as defined in claim 1 , wherein Z is N or CH.

9. A chemical entity as defined in claim 1 , wherein Z is CH.

10. A chemical entity as defined in claim 1 , wherein R 6 is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl.

11. A chemical entity as defined in claim 1 , wherein R 6 is H or methyl.

12. A chemical entity as defined in claim 1 , wherein R 8 is H.

13. A chemical entity as defined in claim 1 , wherein R 9 and R 10 are each independently H or methyl.

14. A chemical entity as defined in claim 1 , wherein R 9 and R 10 are both H.

15. A chemical entity as defined in claim 1 , wherein R 11 is H or methyl.

16. A chemical entity as defined in claim 1 , wherein R 11 is methyl.

17. A chemical entity selected from:

[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(6-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4,5-Difluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4,6-Difluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-methyl-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-methyl-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4,5-Difluoro-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4-Fluoro-5-methyl-1H-benzoimidazol-2-yl)-4-propyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[4-Cyclobutyl-5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[4-Cyclobutyl-5-(4,5-difluoro-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[4-Cyclobutyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[4-Cyclobutyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-propyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; [4-Ethyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[4-Methyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(1H-Benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(5-Fluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[3-(1-Methyl-piperidin-4-yl)-propyl]-[4-methyl-5-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-amine;

[5-(5-tert-Butyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(5-Chloro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; [5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(6-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4,6-Dichloro-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(5,6-Difluoro-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; [5-(4,5-Difluoro-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(1 H-Benzoimidazol-2-yl)-pyrazin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-pyrazin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; and

pharmaceutically acceptable salts thereof.

18. A chemical entity selected from:

[5-(4,6-Bis-trifluoromethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

2-{4-Methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-1H-benzoimidazole-5-carbonitrile;

[5-(5-Methoxy-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(5-Chloro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(5,6-Dichloro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[4-Ethyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[4-Cyclopropyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[4-Cyclopropyl-5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[4-Cyclopropyl-5-(6-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[4-Cyclopropyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[4-Cyclopropyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(6-Chloro-5-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

[5-(4-Chloro-6-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;

and pharmaceutically acceptable salts thereof.

19. A chemical entity that is a compound of Formula (I):

wherein

each of R 1-4 is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, —CF 3 , —OCF 3 , —CN, halo, —NO 2 , —OC 1-4 alkyl, —SC 1-4 alkyl, —S(O)C 1-4 alkyl, —SO 2 C 14 alkyl, —C(O)C 1-4 alkyl, —C(O)phenyl, —C(O)NR a R b , —CO 2 C 1-4 alkyl, —CO 2 H, —C(O)NR a R b , or —NR a R b ;

wherein R a and R b are each independently H, C 1-4 alkyl, or C 3-7 cycloalkyl; one of X 1 and X 2 is N and the other is C—R c ;

where R c is H, methyl, hydroxymethyl, dimethylaminomethyl, ethyl, propyl, isopropyl, —OF 3 , cyclopropyl, or cyclobutyl;

n is 1or 2;

Z is N, OH, or O(C 1-4 a1alkyl);

R 6 is H, C 1-6 alkyl, or monocyclic cycloalkyl;

R 8 is H or C 1-4 alkyl;

R 9 and R 10 are each independently H or C 1-4 alkyl; and

R 11 is H or C 1-4 alkyl;

a monohydrate of a compound of Formula (I), a dihydrate of a compound of formula (I), or a hemitartrate salt of a compound of Formula (I).

20. A chemical entity selected from: