Glucokinase activators

• US 8,163,779 B2
• Filed: 12/17/2007
• Issued: 04/24/2012
• Est. Priority Date: 12/20/2006
• Status: Expired due to Fees

• Current Assignee: Takeda San Diego, Inc. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda San Diego, Inc. (Takeda Pharmaceutical Company Limited)
• Inventors: Cheruvallath, Zacharia, Feng, Jun, Guntupalli, Prasuna, Gwaltney, Stephen L., Miura, Joanne, Sabat, Mark, Tang, Mingnam, Wang, Haxia
• Primary Examiner(s): MORRIS, PATRICIA L
• Application Number:
  US11/958,271
• Publication Number:
  US 20090105255A1
• Time in Patent Office: 1,590 Days
• Field of Search: 546/270.7, 514/342
• US Class Current: 514/342
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/71 to which a second hetero atom is attached
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

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

1. A compound of the formula:

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 R₃ 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 R₃ 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 R₃ 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 R₃ 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 R₃ is selected from the group consisting of butyl, cyclohexylmethyl, benzyl, and phenyl.

8. The compound or pharmaceutically acceptable salt according to claim 1, wherein R₄ is selected from the group consisting of halo, (C_1-10)alkyl, (C_1-10)alkoxy, —

CO—

NH—

R₁₆, —

NH—

CO—

R₁₆, —

SO₂—

R₁₆, —

NH—

SO₂—

R₁₆, and —

SO₂—

NH—

R₁₆.

9. The compound or pharmaceutically acceptable salt according to claim 1, wherein R₄ is a substituted or unsubstituted (C_1-5)alkyl.

10. The compound or pharmaceutically acceptable salt according to claim 1, wherein R₄ is methyl.

11. The compound or pharmaceutically acceptable salt according to claim 1, wherein R₆ is selected from the group consisting of hydrogen, halo, (C_1-10)alkyl, (C_1-10)alkoxy, —

CO—

NH—

R₁₆, —

NH—

CO—

R₁₆, —

SO₂—

R₁₆, —

NH—

SO₂—

R₁₆, and —

SO₂—

NH—

R₁₆.

12. The compound or pharmaceutically acceptable salt according to claim 1, wherein R₆ is hydrogen.

13. The compound or pharmaceutically acceptable salt according to claim 1, wherein R₆ is a substituted or unsubstituted (C_1-5)alkyl.

14. The compound or pharmaceutically acceptable salt according to claim 1, wherein R₆ is methyl.

15. The compound or pharmaceutically acceptable salt according to claim 1, wherein R₇ is selected from the group consisting of hydrogen, halo, (C_1-10)alkyl, (C_1-10)alkoxy, —

CO—

NH—

R₁₆, —

NH—

CO—

R₁₆, —

SO₂—

R₁₆, —

NH—

SO₂—

R₁₆, and —

SO₂—

NH—

R₁₆.

16. The compound or pharmaceutically acceptable salt according to claim 1, wherein R₇ is methyl.

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

and one or more pharmaceutically acceptable excipients.

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.