Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9822107-B2
Application number	US-201415105713-A
Country	US
Kind code	B2
Filing date	Dec 18, 2014
Priority date	Dec 20, 2013
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

The invention provides certain thiazole-substituted aminoheteroaryl compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein ring R 1 , R 2 , R 3 , R 4 , ring B, and the subscript r are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the compounds for treating diseases or conditions mediated by Spleen Tyrosine Kinase (Syk).

First claim

What is claimed is:

1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof, wherein
ring B is selected from the group consisting of indole, quinoline, indazole, and benzimidazole,
R 1 is selected from the group consisting of:
(a) H;
(b) C 1 -C 3 alkyl;
(c) C 1 -C 3 fluoroalkyl;
(d) C 1 -C 3 alkoxy; and
(e) C 3 -C 6 cycloalkyl;

R 2 is selected from the group consisting of H and halo;
R 3 is selected from the group consisting of
(a) H;
(b) C 1 -C 3 alkyl;
(c) C 1 -C 3 alkoxy; and
(d) halo; or
two R 3 when substituted on a common carbon atom together with the carbon atom form a carbonyl;

R 4 is selected from the group consisting of:

ring C y is a mono- or bicyclic carbocyclic ring system containing 4 to 12 carbon atoms;
ring C A is phenyl or C 3 -C 6 cycloalkyl;
R 5 is —C(O)OH;
R 6 is C 1 -C 3 alkyl or halo;
R 7 is H or C 1 -C 3 alkyl;
R 8 is H or F;
the subscript r is 0, 1, 2, 3, or 4;
the subscripts is 0 or 1; and
the subscript t is 0, 1, 2, 3, 4, or 5.

2. The compound of any one of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of H, methyl, —CF 3 , and —CF 2 .

3. The compound of any one of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is —CF 3 or —CF 2 .

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is H.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is H or methyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the moiety in Formula (I)

is selected from the group consisting of:

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein C y is cyclobutyl or cyclohexyl.

9. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein
C y is cyclohexyl;
R 5 is —C(O)OH;
R 6 is methyl;
the subscripts is 1; and
the subscript t is 0, 1, or 2.

10. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein
C y is cyclobutyl; and
the subscripts s and t are both 0.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein
C A is cyclohexyl;
R 5 is —C(O)OH;
R 7 is H or methyl;
the subscripts is 1; and
the subscript t is 0, 1, or 2.

13. The compound of claim 1 or a pharmaceutically acceptably salt thereof, wherein the compound is selected from the group consisting of:
(trans)-4-(1-hydroxy-1-(5-(6-((4-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-indol-4-yl)thiazol-2-yl)ethyl)cyclohexanecarboxylic acid;
1-[5-(6-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-1H-indol-4-yl)-1,3-thiazol-2-yl]cyclobutanol;
4-hydroxy-2,2-dimethyl-4-[5-(6-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-1H-indol-4-yl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;
4-hydroxy-2,2-dimethyl-4-[5-(1-methyl-6-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-1H-indol-4-yl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;
4-hydroxy-2,2-dimethyl-4-(5-(7-((4-(trifluoromethyl)pyrimidin-2-yl)amino)quinolin-4-yl)thiazol-2-yl)cyclohexanecarboxylic acid;
(trans)-1-hydroxy-1-(5-(7-((4-(trifluoromethyl)pyrimidin-2-yl)amino)quinolin-4-yl)thiazol-2-yl)ethyl)cyclohexanecarboxylic acid;
4-hydroxy-2,2-dimethyl-4-(5-(6-((4-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-indol-3-yl)thiazol-2-yl)cyclohexanecarboxylic acid;
(cis)-4-hydroxy-2,2-dimethyl-4-(5-(5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-indol-3-yl)thiazol-2-yl)cyclohexanecarboxylic acid;
(trans)-4-(1-hydroxy-1-(5-(6-((4-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-indol-3-yl)thiazol-2-yl)ethyl)cyclohexanecarboxylic acid;
(cis) 4-hydroxy-4-(5-(5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-indol-3-yl)thiazol-2-yl)cyclohexanecarboxylic acid;
(cis)-4-(5-(5-((4-(difluoromethyl)pyrimidin-2-yl)amino)-1H-indol-3-yl)thiazol-2-yl)-4-hydroxycyclohexanecarboxylic acid;
4-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-6-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-1,3-dihydro-2H-benzimidazol-2-one;
4-hydroxy-2,2-dimethyl-4-[5-(5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-1H-indazol-7-yl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;
(trans)-4-(1-hydroxy-1-[5-(5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino-1H-indazol-7-yl)-1,3-thiazol-2-yl]ethyl}-2,2-dimethylcyclohexanecarboxylic acid;
(trans)-4-(1-hydroxy-1-[5-(5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-1H-indazol-7-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid;
(trans)-4-(1-hydroxy-1-(5-(6-((4-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-indazol-4-yl)thiazol-2-yl)ethyl)cyclohexanecarboxylic acid; and
(trans)-4-(1-hydroxy-1-(5-(6-((4-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-benzo[d]imidazol-4-yl)thiazol-2-yl)ethyl)cyclohexanecarboxylic acid;

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 4-hydroxy-2,2-dimethyl-4-(5-(7-((4-(trifluoromethyl)pyrimidin-2-yl)amino)quinolin-4-yl)thiazol-2-yl)cyclohexanecarboxylic acid.

Assignees

• Andresen Brian M
• Arrington Kenneth L
• Otte Ryan D
• Ellis John Michael
• Butcher John W
• Northrup Alan B
• Robichaud Joel S
• Gauthier Jacques Yves
• Fournier Jean-Francois
• Merck Sharp & Dohme
• Merck Canada Inc

Inventors

• Andresen Brian M
• Arrington Kenneth L
• Otte Ryan D
• Ellis John Michael
• Butcher John W
• Northrup Alan B
• Robichaud Joel S
• Gauthier Jacques Yves
• Fournier Jean-Francois

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P17/06

  Antipsoriatics · CPC title

• C07D417/14 Primary

  containing three or more hetero rings · CPC title