Heteroaromatic glucokinase activators
View Patent ↗The present invention describes 2,3-di-substituted N-heteroaromatic propionamides, of Formula (I) wherein the substitution at the 3-position is an optionally substituted phenyl ring and the substitution at the 2-position is an alkyl or cycloalkyl group; pharmaceutical compositions comprising the same; and, methods of using the same. The propionamides are glucokinase activators for the treatment of type II diabetes.
1. A compound of formula I:
wherein, the * indicates an asymmetric atom;
R 1 is selected from the group consisting of H, Cl, F, Br, I, NH 2 , —NHOH, —CN, —NO 2 , C 1-6 alkyl, —OR 5 , —C(O)OR 6 , perfluoro-C 1-6 alkyl, C 1-6 alkyl-S—, perfluoro-C 1-6 alkyl-S—, C 1-6 alkyl-SO 2 —, perfluoro-C 1-6 alkyl-SO 2 —, C 1-6 alkoxy-C 1-6 alkyl-SO 2 —, C 1-6 alkyl-S(O)—, and —SO 2 NR 13 R 14 ;
R 2 is selected from the group consisting of C 1-6 alkyl-SO 2 —, C 3-6 cycloalkyl-SO 2 —, perfluoro-C 1-6 alkyl-SO 2 —, and C 1-6 alkoxy-C 1-6 alkyl-SO 2 —;
R 3 is cyclopentyl;
ring A is a mono-substituted thiazole;
wherein the substituent is selected from the group consisting of —SCN, —(CH 2 ) 0-2 —S(O) p —(CH 2 ) 1-4 —C(O)OR 7 ; —(CH 2 ) 0-2 —S(O) p —(CH 2 ) 1-4 —C(O)OH; —(CH 2 ) 0-2 —S(O) p —(CH 2 ) n —NR 10 R 11 ; —(CH 2 ) 0-2 —S(O) p —(CH 2 ) n —C(O)NR 10 R 11 ; and —(CH 2 ) n -5-6 membered heterocycle consisting of carbon atoms and 1-3 heteroatoms selected from S(O) p , O, and N and is substituted with 0-1 C 1-4 alkyl; and, R 7 , at each occurrence, is independently selected from the group consisting of C 1-4 alkyl and C 3-6 cycloalkyl;
R 5 , at each occurrence, is independently selected from the group consisting of H, C 1-6 alkyl, and perfluoro-C 1-6 alkyl;
R 6 , at each occurrence, is independently C 1-6 alkyl;
R 8 , at each occurrence, is independently selected from the group consisting of H, C 1-8 alkyl, —(CH 2 ) n —OH, —(CH 2 ) n —C(O)OH, aryl, and 5-10 membered heteroaryl consisting of carbon atoms and 1-3 heteroatoms selected from S(O) p , O, and N;
R 9 , at each occurrence, is independently selected from the group consisting of H, C 1-8 alkyl, —(CH 2 ) n —OH, —(CH 2 ) n —C(O)OH, aryl, and 5-10 membered heteroaryl consisting of carbon atoms and 1-3 heteroatoms selected from S(O) p , O, and N;
alternatively, R 8 and R 9 , together with the nitrogen to which they are attached form a 5-6 membered heterocycle, consisting of, in addition to the nitrogen atom to which R 8 and R 9 are attached, carbon atoms and 0-2 heteroatoms selected from S(O) p , O, and N;
R 10 , at each occurrence, is independently selected from the group consisting of H; C 1-6 alkyl; —(CH 2 ) n —OH; —(CH 2 ) n —C(O)OH; —(CH 2 ) n —C 3-8 cycloalkyl; —(CH 2 ) n -aryl; —(CH 2 ) n -5-10 membered heterocycle consisting of carbon atoms and 1-3 heteroatoms selected from S(O) p , O, and N; —(CH 2 ) n -5-10 membered heteroaryl consisting of carbon atoms and 1-3 heteroatoms selected from S(O) p , O, and N; —(CH 2 ) p —NHR 7 ; and —(CH 2 ) n —NR 7 R 7 ;
R 11 , at each occurrence, is independently selected from the group consisting of H; C 1-6 alkyl; —(CH 2 ) n —OH; —(CH 2 ) n —C(O)OH; —(CH 2 ) n —C 3-8 cycloalkyl; —(CH 2 ) n -aryl; —(CH 2 ) n -5-10 membered heterocycle consisting of carbon atoms and 1-3 heteroatoms selected from S(O) p , O, and N; —(CH 2 ) n -5-10 membered heteroaryl consisting of carbon atoms and 1-3 heteroatoms selected from S(O) p , O, and N; —(CH 2 ) n —NHR 7 ; and —(CH 2 ) n —NR 7 R 7 ;
alternatively, R 10 and R 11 , together with the nitrogen to which they are attached form a 5-6 membered heterocycle, consisting of, in addition to the nitrogen atom to which R 10 and R 11 are attached, carbon atoms and 0-2 heteroatoms selected from S(O) p , O, and N; and wherein the heterocycle thus formed is substituted with 0-2 R 12 ;
R 12 , at each occurrence, is independently selected from the group consisting of C 1-6 alkyl, Cl, F, Br, I, NO 2 , —CN, —(CH 2 ) n —OH, —(CH 2 ) n —C(O)OH, NR 8 R 9 , NHS(O) 2 CH 3 , S(O) 2 CH 3 , and S(O) 2 NH 2 ;
R 13 , at each occurrence, is independently selected from the group consisting of H and C 1-4 alkyl;
R 14 , at each occurrence, is independently selected from the group consisting of H and C 1-4 alkyl;
p, at each occurrence, is selected from 0, 1, and 2; and
n, at each occurrence, is independently selected from 0, 1, 2, 3, 4, 5, and 6 or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 , wherein in ring A the substituent is selected from the group consisting of: —SCN, —S(O) 2 —CH 2 —C(O)OR 7 ; —S(O) 2 —CH 2 —C(O)OH; —S—CH 2 —C(O)OR 7 ; —S—CH 2 —CH 2 —C(O)OR 7 ; —S—CH 2 —C(O)OH; —S—CH 2 —CH 2 —C(O)OH; —S—(CH 2 ) 2 —NR 10 R 11 ; —S—CH 2 —C(O)NR 10 R 11 ; and piperazine; and,
R 7 , at each occurrence, is independently selected from C 1-2 alkyl.
3. A compound of claim 1 wherein n is 1.
4. A compound of claim 1 wherein n is 2.
5. A compound of claim 1 , wherein R 8 and R 9 , together with the nitrogen to which they are attached form a heterocycle selected from: piperazine, piperidine, homopiperazine, and morpholine.
6. A compound of claim 1 , wherein R 10 and R 11 , together with the nitrogen to which they are attached form a heterocycle selected from the group consisting of: piperidine, piperazine, homopiperazine, pyrrolidine, and morpholine.
7. A compound of claim 1 , wherein the asymmetric carbon shown is in the R configuration.
8. A compound of claim 1 wherein
R 1 is selected from the group consisting of H, Cl, F, Br, I, perfluoro-C 1-6 alkyl, NO 2 , NH 2 , C 1-6 alkyl-SO 2 —, and —SO 2 NR 13 R 14 ; and,
R 2 is C 1-6 alkyl-SO 2 —.
9. A compound of claim 8 , wherein R 1 is H.
10. A compound of claim 8 , wherein R 1 is selected from the group consisting of Cl, CF 3 , and CH 3 .
11. A compound of claim 8 , wherein R 1 is H and R 2 is CH 3 —SO 2 —.
12. A compound selected from the group consisting of:
3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(4-methyl-piperazin-1-yl)-thiazol-2-yl]-propionamide
{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester
{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-5-methyl-thiazol-4-yl}-acetic acid
{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic acid
(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-thiocyanato-thiazol-2-yl)-propionamide
(R)-3-Cyclopentyl-N-[5-(2-diethylamino-ethylsulfanyl)-thiazol-2-yl]-2-(4-methanesulfonyl-phenyl)-propionamide
(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methylsulfanyl-thiazol-2-yl)-propionamide
3-Cyclopentyl-N-(5-diethylcarbamoylmethylsulfanyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide
{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-sulfonyl}-acetic acid
(R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester
(R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic acid
(R)-3-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester
(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(2-oxo-2-piperazin-1-yl-ethylsulfanyl)-thiazol-2-yl]-propionamide
(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(2-morpholin-4-yl-2-oxo-ethylsulfanyl)-thiazol-2-yl]-propionamide
(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-{5-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethylsulfanyl]-thiazol-2-yl}-propionamide
(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(2-oxo-2-piperidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-propionamide
(R)-3-Cyclopentyl-N-[5-(2-dimethylamino-ethylsulfanyl)-thiazol-2-yl]-2-(4-methanesulfonyl-phenyl)-propionamide
(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(2-morpholin-4-yl-ethylsulfanyl)-thiazol-2-yl]-propionamide
(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(2-piperidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-propionamide
(R)-3-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-propionic acid
(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(4-methyl-piperazin-1-yl)-thiazol-2-yl]-propionamide
(R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester
(R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic acid
(R)-3-Cyclopentyl-N-(5-diethylcarbamoylmethylsulfanyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising: a pharmaceutically acceptable carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.