Glucokinase activator compounds, compositions containing such compounds, and methods of treatment

Patent metadata

Field	Value
Publication number	US-9453038-B2
Application number	US-201314652883-A
Country	US
Kind code	B2
Filing date	Dec 12, 2013
Priority date	Dec 17, 2012
Publication date	Sep 27, 2016
Grant date	Sep 27, 2016

Abstract

Novel pyridine-2-carboxamide derivatives of formula I: and pharmaceutically acceptable salts thereof are disclosed as useful for treating or preventing type 2 diabetes and similar conditions. The compounds are effective as glucokinase activating agents. Pharmaceutical compositions and methods of treatment are also included.

First claim

What is claimed is:

1. A compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
X 1 , X 2 , X 3 and X 4 individually represent CH or N wherein X 3 and X 4 cannot both be N;
M represents a 6- to 10-membered aryl group, a 5- to 7-membered heteroaryl group, a 5- to 7- membered cycloalkyl group, or a 5- to 7-membered aliphatic heterocyclic group, optionally substituted with 1-4 substituents independently selected from: halogen, hydroxy, oxo, C 1-6 alkylOC 1-6 alkyl, C 1-6 alkoxy, CN, NR 2 R 4 , C 1-6 alkylNR 2 R 4 , C(O) 1-2 C 1-6 alkyl, C 1-6 alkylC(O) 1-2 C 1-6 alkyl, C(O)OH, C 1-6 alkylCOOH, S(O) 0-2 C 1-6 alkyl, S(O) 0-2 or arylC 1-6 alkyl, wherein the alkyl and alkoxy substituents are further optionally substituted by 1-4 substituents independently selected from: halogen or C 1-6 alkyl where said C 1-6 alkyl is optionally substituted by 1-6 halogens;
L 1 represents O or S(O) 0-2 ;
L 2 represents a single bond, O, S(O) 0-2 or CR 2 R 4 ;
L 3 represents C 1-6 alkyl, OC 1-6 alkyl, S(O) 0-2 C 1-6 alkyl, C 1-6 alkylOC 1-6 alkyl, C 1-6 alkylS(O) 0-2 C 1-6 alkyl or CONHC 1-6 alkyl;
Z 1 , Z 2 and Z 3 individually represent -L 3 -COOR, -P(O)R 3 OR, -L 3 -P(O)R 3 OR or null; provided that Z 1 , Z 2 and Z 3 cannot all three be null together;
R individually represents H, C 1-6 alkyl or C 1-6 cycloalkyl, optionally substituted with 1-4 substituents independently selected from: halogen or hydroxy;
R 2 and R 4 individually represent H or C 1-6 alkyl, optionally substituted with 1-4 substituents independently selected from: halogen or hydroxy;
R 1 represents H, halogen, C 1-6 alkyl, C 1-6 cycloalkyl, OC 1-6 alkyl, S(O) 0-2 C 1-6 alkyl, C 1-6 alkylOC 1-6 alkyl, C 1-6 alkylS(O) 0-2 C 1-6 alkyl, NR 2 R 4 , C 1-6 alkylNR 2 R 4 or C(O)NR 2 R 4 , wherein the alkyl substituents are optionally substituted with 1-4 substituents independently selected from: halogen or hydroxy; and further wherein the R 2 and R 4 on the C(O)NR 2 R 4 can together form a 4- to 6-membered saturated heterocyclic ring having 1 nitrogen atom which 4- to 6-membered ring may be optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy or CO 2 C 1-6 alkyl where the alkyl or alkoxy substituents are optionally substituted by 1-6 halogens;
R 3 represents C 1-6 alkyl or OC 1-6 alkyl,
n represents 1-4, and
ring A is a substituted phenyl, isothiazolyl group, imidazolyl group, oxazolyl group, thiadiazolyl group, thienyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrimidinyl group, furyl group, thiazolyl group, isoxazolyl group or pyrazolyl group; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein M is a phenyl group, isothiazolyl group, imidazolyl group, oxazolyl group, thiadiazolyl group, thienyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrimidinyl group, furyl group, thiazolyl group, isoxazolyl group or pyrazolyl group, optionally substituted with halogen, hydroxy, oxo, C 1-6 alkyl, C 1-6 alkylOC 1-6 alkyl, C 1-6 alkoxy, CN, NR 2 R 4 , C 1-6 alkylNR 2 R 4 , C(O) 1-2 C 1-6 alkyl, C 1-6 alkylC(O) 1-2 C 1-6 alkyl, C(O)OH, C 1-6 alkylCOOH, S(O) 0-2 C 1-6 alkyl, S(O) 0-2 or arylC 1-6 alkyl, wherein the alkyl and alkoxy substituents are further optionally substituted by 1-4 substituents independently selected from: halogen or C 1-6 alkyl where said C 1-6 alkyl is optionally substituted by 1-6 halogens; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein M is phenyl, pyrrolidine or pyridyl, optionally substituted with 1-4 substituents independently selected from: halogen, oxo, C 1-6 alkyl, C 1-6 alkylOC 1-6 alkyl, C 1-6 alkoxy, C(O) 1-2 C 1-6 alkyl, C 1-6 alkylC(O) 1-2 C 1-6 alkyl, C(O)OH or C 1-6 alkylCOOH, wherein the alkyl is further optionally substituted by 1-6 halogen substituents; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein M is phenyl or pyrrolidine, optionally substituted with 1-4 substituents independently selected from: halogen, oxo, C 1-6 alkyl, C 1-6 alkylOC 1-6 alkyl, C 1-6 alkoxy, C(O) 1-2 C 1-6 alkyl, C 1-6 alkylC(O) 1-2 C 1-6 alkyl, C(O)OH or C 1-6 alkylCOOH, wherein the alkyl is further optionally substituted by 1-6 halogen substituents; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein L 1 is O; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein L 2 is a single bond or CR 2 R 4 ; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 wherein L 3 is C 1-6 alkyl, OC 1-6 alkyl or CONHC 1-6 alkyl; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 wherein one of Z 1 , Z 2 and Z 3 is -L 3 -COOR, -P(O)R 3 OR or -L 3 -P(O)R 3 OR, and the other two are null; or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 wherein R individually represents H or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with 1-6 halogen substituents; or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 wherein R 1 is individually selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkylOC 1-6 alkyl, S(O) 0-2 C 1-6 alkyl or C(O)NR 2 R 4 , wherein the alkyl substituents are optionally substituted with 1-4 substituents independently selected from: halogen or hydroxy; and further wherein the R 2 and R 4 on the C(O)NR 2 R 4 together form a 4-membered saturated heterocyclic ring having 1 nitrogen atom which 4-membered ring may be optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, oxo, C 1-6 alkoxy or CO 2 C 1-6 alkyl where the alkyl or alkoxy substituents are optionally substituted by 1-6 halogens; or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 wherein ring A is a substituted pyridyl, pyrazinyl or phenyl group; or a pharmaceutically acceptable salt thereof.

12. The compound which is:
methyl 3-(6-{5-[4-(ethylsulfonyl)phenoxy]-6-(1-methyl-5-oxopyrrolidin-2-yl)-1H-indol-2-yl}pyridin-3-yl)propanoate;
3-(6-{5-[4-(ethylsulfonyl)phenoxy]-6-(1-methyl-5-oxopyrrolidin-2-yl)-1H-indol-2-yl}pyridin-3-yl)propanoic acid;
(2-{5-[4-(ethylsulfonyl)phenoxy]-2-[5-(trifluoromethyl)pyridin-2-yl]-1H-indol-6-yl}-5-oxopyrrolidin-1-yl)acetic acid;
methyl 3-[4-({6-(1-methyl-5-oxopyrrolidin-2-yl)-2-[5-(trifluoro-methyl)pyridin-2-yl]-1H-indol-5-yl}oxy)phenyl]propionate;
3-[4-({6-(1-methyl-5-oxopyrrolidin-2-yl)-2-[5-(trifluoro-methyl)pyridin-2-yl]-1H-indol-5-yl}oxy)phenyl]propanoic acid;
methyl 3-(6-{6-(2-fluorophenoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}pyridin-3-yl)propanoate;
3-(6-{6-(2-fluorophenoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}pyridin-3-yl)propanoic acid;
n-({6-[6-(1-methyl-5-oxopyrrolidin-2-yl)-5-{[6-(methyl-sulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]pyridin-3-yl}-carbonyl)-β-alanine;
3-[6-(5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-6-[(2-oxopyrrolidin-1-yl)methyl]-1H-pyrrolo[2,3-b]pyridin-2-yl)pyridin-3-yl]propanoic acid;
methyl 3-{6-[6-(1-acetylpyrrolidin-2-yl)-5-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]pyridin-3-yl}propanoate;
3-{6-[6-(1-acetylpyrrolidin-2-yl)-5-{-[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]pyridin-3-yl}propanoic acid;
(6-(5-(4-(ethylsulfonyl)phenoxy)-6-(1-methyl-5-oxopyrrolidin-2-yl)-1H-indol-2-yl)pyridin-3-yl)(methyl)phosphinic acid;
methyl 3-(6-(6-(1-methyl-5-oxopyrrolidin-2-yl)-5-((6-(methylsulfonyl)pyridin-3-yl)oxy)-1H-indol-2-yl)pyridin-3-yl)propanoate;
3-(6-(6-(1-methyl-5-oxopyrrolidin-2-yl)-5-

Assignees

• Merck Sharp & Dohme

Inventors

• Lin Songnian
• Zhang Rui
• Campbell Brian
• Dewnani Sunita V
• Xu Jiayi
• Xu Libo
• Parmee Emma R
• Kats-Kagan Roman

Classifications

• C07F9/58

  Pyridine rings · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title