IP Library › Granted Patent US 8,476,457
Granted Patent B2
US 8,476,457 · App. 12/820,748 · Granted Jul 2, 2013

Indole, indazole and benzimidazole arylamides as P2X

Inventors: Michael Patrick Dillon (San Francisco, CA); Nancy Elisabeth Krauss (Los Gatos, CA)
Assignee: Roche Palo Alto LLC
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Quick Facts
Patent No.
US 8,476,457
App. No.
12/820,748
Granted
Jul 2, 2013
Kind
B2
Abstract

Compounds of the formula I: or a pharmaceutically acceptable salt thereof, wherein, X, Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein. Also disclosed are methods of using the compounds for treating diseases associated with P2X 3 and/or a P2X 2/3 receptor antagonists and methods of making the compounds.

Claims (56)

1. A compound of formula III:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is:

C 1-6 alkyl; or

halo;

R 2 is:

C 3-6 cycloalkyl;

C 1-6 alkoxy-C 1-6 alkyl;

hydroxy-C 1-6 alkyl; or

heteroaryl-C 1-6 alkyl selected from: pyrazinyl-methyl; pyridazinyl-methyl; pyrimidinyl-methyl; 1-pyrazinyl-ethyl; 1-pyridazinyl-ethyl; and 1-pyrimidinyl-ethyl; wherein the pyrazinyl, pyridazinyl and pyrimidinyl portions thereof may be optionally substituted once with methyl;

R 3 is:

C 1-6 alkyl;

hydroxy-C 1-6 alkyl;

C 1-6 alkoxy-C 1-6 alkyl;

halo-C 1-6 alkyl;

C 3-6 cycloalkyl;

C 3-6 cycloalkyl-C 1-6 alkyl;

phenyl optionally substituted with: halo, C 1-6 alkyl, C 1-6 alkoxy or halo-C 1-6 alkyl; or

phenyl-C 1-6 alkyl wherein the phenyl portion thereof is optionally substituted with: halo, C 1-6 alkyl, C 1-6 alkoxy or halo-C 1-6 alkyl; and

X is: N or CR a wherein R a is hydrogen, C 1-6 alkyl or halo.

2. The compound of claim 1 , wherein R 1 is methyl.

3. The compound of claim 1 , wherein R 2 is: cyclopropyl; 2-methoxy-1-methyl-ethyl; 2-hydroxy-1-methyl-ethyl; 5-methylpyrazin-2-yl-methyl; 1-pyrazin-2-yl-ethyl; pyrimidin-5-yl-methyl; 6-methyl-pyridazin-3-yl-methyl; pyridazin-3-yl-methyl; 5-methyl-pyrimidin-yl-methyl; or 2-methyl-pyrimidin-5-yl-methyl.

4. The compound of claim 1 , wherein R 2 is 2-hydroxy-1-methyl-ethyl; 5-methylpyrazin-2-yl-methyl; or 1-pyrazin-2-yl-ethyl.

5. The compound of claim 1 , wherein R 3 is C 1-6 alkyl; halo-C 1-6 alkyl; phenyl optionally substituted with C 1-6 alkyl; or phenyl-C 1-6 alkyl wherein the phenyl portion thereof is optionally substituted with C 1-6 alkyl.

6. The compound of claim 1 , wherein R 3 is isopropyl, isobutyl, n-propyl, 3-methyl-butyl, 222-trifluoroethyl, 2-methoxyethyl, phenyl, benzyl, 2-methyl-phenyl; 4-methyl-phenyl; or 2-isopropyl-phenyl.

7. The compound of claim 1 , wherein R 3 is isopropyl, isobutyl, n-propyl, or 3-methyl-butyl.

8. The compound of claim 1 , wherein R 3 is phenyl, 2-methyl-phenyl; 4-methyl-phenyl; or 2-isopropyl-phenyl.

9. The compound of claim 1 , wherein X is —N—.

10. The compound of claim 1 , wherein X is —CR a —.

11. The compound of claim 10 , wherein R a is hydrogen or halo.

12. The compound of claim 1 , wherein X is CR a , and R a is hydrogen.

13. The compound of claim 1 , wherein said compound is selected from:

1-Isobutyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

1-Butyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

1-Butyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;

1-Isopropyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

1-Isopropyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;

1-(2-Methoxy-ethyl)-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

1-(3-Methyl-butyl)-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

1-(3-Methyl-butyl)-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid (6-methyl-pyridazin-3-ylmethyl)-amide;

1-Benzyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

1-Benzyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;

1-Benzyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid (6-methyl-pyridazin-3-ylmethyl)-amide;

4-(5-Methyl-pyridin-2-yl)-1-(2,2,2-trifluoro-ethyl)-1H-indazole-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

4-(5-Methyl-pyridin-2-yl)-1-(2,2,2-trifluoro-ethyl)-1H-indazole-6-carboxylic acid (6-methyl-pyridazin-3-ylmethyl)-amide;

4-(5-Methyl-pyridin-2-yl)-1-phenyl-1H-indazole-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

4-(5-Methyl-pyridin-2-yl)-1-phenyl-1H-indazole-6-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;

4-(5-Methyl-pyridin-2-yl)-1-p-tolyl-1H-indazole-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

4-(5-Methyl-pyridin-2-yl)-1-p-tolyl-1H-indazole-6-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;

4-(5-Methyl-pyridin-2-yl)-1-o-tolyl-1H-indazole-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

4-(5-Methyl-pyridin-2-yl)-1-o-tolyl-1H-indazole-6-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;

1-(2-Isopropyl-phenyl)-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide.

14. A composition comprising:

(a) a pharmaceutically acceptable carrier; and

(b) a compound of claim 1 .

Continuity (2)
Provisional Application 61219177 · Jun 22, 2009
Related Publication 20100324070A1 · Dec 23, 2010