IP Library › Granted Patent US 8,163,779
Granted Patent B2
US 8,163,779 · App. 11/958,271 · Granted Apr 24, 2012

Glucokinase activators

Assignee: Takeda San Diego, Inc.
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Quick Facts
Patent No.
US 8,163,779
App. No.
11/958,271
Granted
Apr 24, 2012
Kind
B2
Abstract

Compounds of the following formula are provided for use with glucokinase: wherein the variables are as defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.

Claims (86)

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

t is selected from the group consisting of 0, 1 and 2;

Q is selected from the group consisting of O and CH 2 ;

R 3 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, halo(C 1-10 )alkyl, amino (C 1-10 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, aryl, and (C 9-12 )bicycloaryl, each substituted or unsubstituted;

R 4 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, alkoxy, aryloxy, amino, (C 1-10 )alkylamino, —CO—NH—R 16 , —NH—CO—R 16 , —SO 2 —R 16 , —NH—SO 2 —R 16 , —SO 2 —NH—R 16 , (C 1-10 )alkyl, halo(C 1-10 )alkyl, amino(C 1-10 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, aryl, and (C 9-12 )bicycloaryl, each substituted or unsubstituted;

each R 13 is independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, alkoxy, aryloxy, amino, (C 1-10 )alkylamino, (C 1-10 )alkyl, halo(C 1-10 )alkyl, amino(C 1-10 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, aryl, and (C 9-12 )bicycloaryl, each substituted or unsubstituted; and

each R 16 is independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, (C 1-10 )alkoxy, (C 4-12 )aryloxy, aminocarbonyl, amino, (C 1-10 )alkylamino, (C 1-10 )alkyl, halo(C 1-10 )alkyl, hydroxy(C 1-10 )alkyl, aza(C 1-10 )alkyl, (C 1-10 )oxaalkyl, (C 1-10 )oxoalkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, (C 4-12 )aryl, and (C 9-12 )bicycloaryl, each substituted or unsubstituted,

wherein each optional substituent is independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C 1-10 )alkoxy, (C 4-12 )aryloxy, aminocarbonyl, amino, (C 1-10 )alkylamino, (C 1-10 )alkyl, halo(C 1-10 )alkyl, hydroxy(C 1-10 )alkyl, (C 1-10 )azaalkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, (C 4-12 )aryl, and (C 9-12 )bicycloaryl.

2. The compound or pharmaceutically acceptable salt according to claim 1 , wherein the thiazolyl ring is:

3. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is selected from the group consisting of (C 1-10 )alkyl, halo(C 1-10 )alkyl, amino(C 1-10 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, aryl, and (C 9-12 )bicycloaryl, each substituted or unsubstituted.

4. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, and aryl(C 1-10 )alkyl, each substituted or unsubstituted.

5. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, and aryl(C 1-10 )alkyl, each substituted or unsubstituted.

6. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is selected from the group consisting of hydrogen, butyl, cyclohexylmethyl, benzyl, and phenyl.

7. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is selected from the group consisting of butyl, cyclohexylmethyl, benzyl, and phenyl.

8. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 4 is selected from the group consisting of halo, (C 1-10 )alkyl, (C 1-10 )alkoxy, —CO—NH—R 16 , —NH—CO—R 16 , —SO 2 —R 16 , —NH—SO 2 —R 16 , and —SO 2 —NH—R 16 .

9. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 4 is a substituted or unsubstituted (C 1-5 )alkyl.

10. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 4 is methyl.

11. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 6 is selected from the group consisting of hydrogen, halo, (C 1-10 )alkyl, (C 1-10 )alkoxy, —CO—NH—R 16 , —NH—CO—R 16 , —SO 2 —R 16 , —NH—SO 2 —R 16 , and —SO 2 —NH—R 16 .

12. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 6 is hydrogen.

13. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 6 is a substituted or unsubstituted (C 1-5 )alkyl.

14. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 6 is methyl.

15. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 7 is selected from the group consisting of hydrogen, halo, (C 1-10 )alkyl, (C 1-10 )alkoxy, —CO—NH—R 16 , —NH—CO—R 16 , —SO 2 —R 16 , —NH—SO 2 —R 16 , and —SO 2 —NH—R 16 .

16. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 7 is methyl.

17. A compound selected from the group consisting of:

3-cyclohexyl-2- (6-methyl-4- (methylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(4-(ethylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(4-(cyclopentylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-N-(thiazol-2-yl)propanamide;

2-(6-methyl-4-(methylsulfonyl)-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(4-(cyclopentylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(cyclopentylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(thiazol-2-yl)propanamide;

2-(4-(cyclopentylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl) -N-(thiazol-2-yl)propanamide;

(R)-N-(5-chlorothiazol-2-yl)-2-(4-(methylsulfonyl)-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-N-(5-chlorothiazol-2-yl)-2-(4-(methylsulfonyl)-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopentylsulfonyl)-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopentylsulfonyl)-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-2-(4-(cyclopentylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-2-(4-(cyclopentylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-2-(4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-2-(4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopentylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopentylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-2-(4-(cyclopentylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-2-(4-(cyclopentylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-methyl 2-(2-(4-(cyclopentylsulfonyl)-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamido)thiazole-5-carboxylate;

(S)-methyl 2-(2-(4-(cyclopentylsulfonyl)-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamido)thiazole-5-carboxylate;

3-(2-(2-(4-(methylsulfonyl)-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamido)thiazol-5-yl)propanoic acid;

(R)-N-(5-cyanothiazol-2-yl)-2-(4-(cyclopentylsulfonyl)-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-N-(5-cyanothiazol-2-yl)-2-(4-(cyclopentylsulfonyl)-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-2-(3-chloro-4-(cyclopropylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-N-(5-chlorothiazol-2-yl)-3-cyclohexylpropanamide;

(R)-2-(3-chloro-4-(cyclopropylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-N-(5-chlorothiazol-2-yl)-3-cyclohexylpropanamide;

3-cyclohexyl-2-(4-(cyclopentylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-N-(5-(4-fluorobenzyl)thiazol-2-yl)propanamide;

ethyl 2-(2-(4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamido)thiazole-5-carboxylate;

2-(4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(5-(2-hydroxypropan-2-yl)thiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

N-(5-chlorothiazol-2-yl)-2-(4-(cyclopentylsulfonyl)-3,5,6-trimethyl-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-2-(4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(5-(2-methoxypropan-2-yl) thiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-2-(4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(5-(2-methoxypropan-2-yl)thiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopentylsulfonyl)-3,5,6-trimethyl-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopentylsulfonyl)-3,5,6-trimethyl-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

2-(4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(5-(4-fluorobenzyl)thiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

N-(5-chlorothiazol-2-yl)-2-(2-oxo-4-(2,2,2-trifluoroethylsulfonyl)pyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-N-(5-chlorothiazol-2-yl)-2-(2-oxo-4-(2,2,2-trifluoroethylsulfonyl)pyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-N-(5-chlorothiazol-2-yl)-2-(2-oxo-4-(2,2,2-trifluoroethylsulfonyl)pyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-2-(4-(cyclopentylsulfonyl)-5,6-dimethyl-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

2-(4-(cyclopropylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-2-(4-(cyclopentylsulfonyl)-5,6-dimethyl-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

N-(5-chlorothiazol-2-yl)-2-(4-(3-fluorophenylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

2-(4-(3-fluorophenylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-2-(4-(3-chlorophenylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-2-(4-(3-chlorophenylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

2-(5-chloro-4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(5-chlorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

2-(5-chloro-4-(cyclopentylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(5-chlorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

2-(5-chloro-4-(cyclopentylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-2-(4-(3-fluorophenylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-2-(4-(3-fluorophenylsulfonyl)-6-methyl-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-2-(5-chloro-4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(5-chlorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-2-(5-chloro-4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(5-chlorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-2-(5-chloro-4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-2-(5-chloro-4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide; and

a pharmaceutically acceptable salt of any one of the aforementioned compounds.

18. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt as defined in claim 1 ; and one or more pharmaceutically acceptable excipients.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 9, 2008
From: CHERUVALLATH, ZACHARIA; FENG, JUN; GUNTUPALLI, PRASUNA; GWALTNEY, STEPHEN L.; MIURA, JOANNE; SABAT, MARK; TANG, MINGNAM; WANG, HAXIA
To: TAKEDA SAN DIEGO, INC.
Reel/Frame 021215/0854 →
Continuity (2)
Provisional Application 60870929 · Dec 20, 2006
Related Publication 20090105255A1 · Apr 23, 2009