Pyrrolidine GPR40 modulators

1. A compound of Formula (I):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

X is selected from the group consisting of: O, S, CH 2 , CH(C 1-4 alkyl), C(C 1-4 alkyl) 2 , CH(C 1-4 alkoxy-phenyl), and C(O);

ring A is phenyl substituted with 0-2 R 5 , pyridinyl substituted with 0-2 R 5 , or pyrimidinyl substituted with 0-2 R 5 ;

R 1 is —(CH 2 ) n -phenyl substituted with 0-3 R 2 , —(CH 2 ) n -naphthyl substituted with 0-3 R 2 , or —(CH 2 ) n -5- to 6-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O) p ; wherein said heteroaryl is substituted with 0-3 R 2 ;

R 2 , at each occurrence, is independently selected from the group consisting of: halo, CF 3 , CN, NO 2 , OCF 3 , SCF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , —(CH 2 ) n —C 3-10 carbocycle, —(CH 2 ) n —O—C 3-10 carbocycle, and —(CH 2 ) n -3- to 10-membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O) p ; wherein said carbocycle and heterocycle are substituted with 0-3 R 6 ;

R 3 and R 4 , at each occurrence, are independently selected from the group consisting of: H, OH, halo, CF 3 , C 1-4 alkyl, and C 1-4 alkoxy;

R 5 , at each occurrence, is independently selected from the group consisting of: halo and C 1-4 alkyl;

R 6 , at each occurrence, is independently selected from the group consisting of: halo, CF 3 , C 1-4 alkyl, and C 1-4 alkoxy;

n, at each occurrence, is independently 0, 1, 2 or 3; and

p, at each occurrence, is independently 0, 1 or 2.

2. A compound according to claim 1 , wherein:

X is selected from the group consisting of: O, S, CH 2 , CH(C 1-4 alkyl), CH(C 1-4 alkoxy-phenyl), and C(O);

R 1 is —(CH 2 ) n -phenyl substituted with 0-3 R 2 , —(CH 2 ) n -naphthyl substituted with 0-3 R 2 , or —(CH 2 ) n -pyridyl substituted with 0-3 R 2 ;

R 2 , at each occurrence, is independently selected from the group consisting of: halo, CF 3 , CN, NO 2 , OCF 3 , SCF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , —(CH 2 ) n —C 3-6 cycloalkyl, —(CH 2 ) n —C 4-6 cycloalkenyl, —(CH 2 ) n -phenyl, —(CH 2 ) n —O-phenyl, and —(CH 2 ) n -5- to 6-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O) p ; wherein said cycloalkyl, cycloalkenyl, phenyl and heteroaryl are substituted with 0-2 R 6 ; and

n, at each occurrence, is independently 0, 1 or 2.

3. A compound according to claim 1 , wherein the compound is of Formula (II):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

X is selected from the group consisting of: O, S, CH 2 , CH(C 1-4 alkyl), CH(2-(methoxy)-phenyl), and C(O);

ring A is selected from the group consisting of:

R 2 , at each occurrence, is independently selected from the group consisting of: halo, CF 3 , CN, NO 2 , OCF 3 , SCF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, NH, NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , cyclopentenyl substituted with 0-2 R 6 , phenyl substituted with 0-2 R 6 , benzyl substituted with 0-2 R 6 , phenoxy substituted with 0-2 R 6 , benzoxy substituted with 0-2 R 6 , and pyrazol-1-yl; and

R 3 is selected from the group consisting of: H, OH, halo, CF 3 , C 1-4 alkyl, and C 1-4 alkoxy.

4. A compound according to claim 3 wherein:

R 1 is selected from the group consisting of: phenyl, 2-halophenyl, 3-halophenyl, 4-halophenyl, 2-(C 1-4 alkyl)phenyl, 3-(C 1-4 alkyl)phenyl, 4-(C 1-4 alkyl)phenyl, 2-(C 1-4 alkoxy)phenyl, 4-(C 1-4 alkoxy)phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-cyanophenyl, 3-(N,N-dimethylamino)-phenyl, 4-phenoxyphenyl, 3-(2-halophenyl)phenyl, 3-(4-halophenoxy)phenyl, 3-(2-halobenzyl)phenyl, 3-(2-(C 1-4 alkyl)benzyl)phenyl, 4-(2-halobenzoxy)phenyl, 3-(2-halo-5-(C 1-4 alkoxy)-phenyl)phenyl, 2-biphenyl, 2-benzylphenyl, 4-benzylphenyl, 3-benzoxyphenyl, 4-benzoxyphenyl, 2-(C 1-4 alkyl)-3-(C 1-4 alkyl)-phenyl, 2-(C 1-4 alkyl)-4-(C 1-4 alkyl)-phenyl, 2-(C 1-4 alkyl)-6-(C 1-4 alkyl)-phenyl, 2-halo-3-halophenyl, 2-halo-4-halo-phenyl, 3-halo-4-halophenyl, 3-halo-5-halophenyl, 2-halo-6-halophenyl, 2-(C 1-4 alkyl)-4-(C 1-4 alkoxy)-phenyl, 2-(C 1-4 alkyl)-3-halo-phenyl, 2-(C 1-4 alkyl)-4-halo-phenyl, 2-halo-3-(C 1-4 alkyl)-phenyl, 3-halo-4-(C 1-4 alkyl)-phenyl, 2,4-ditrifluoromethyl-phenyl, 2-halo-3-trifluoromethyl-phenyl, 2-halo-4-trifluoromethyl-phenyl, 2-(C 1-4 alkyl)-4-benzoxy-phenyl, 2-trifluoromethyl-4-cyano-phenyl, 2-cyano-4-trifluoromethyl-phenyl, 3-cyano-4-trifluoromethyl-phenyl, 3-trifluoromethyl-4-cyano-phenyl, 2-halo-4-cyano-phenyl, 2-(C 1-4 alkyl)-3-(2-halo-5-(C 1-4 alkoxy)-phenyl)-phenyl, benzyl, 2-halobenzyl, 3-halobenzyl, 4-halobenzyl, 2-(C 1-4 alkyl)benzyl, 4-(C 1-4 alkyl)benzyl, 4-(C 1-4 alkylthio)benzyl, 2-trifluoromethyl-benzyl, 3-trifluoromethyl-benzyl, 4-trifluoromethyl-benzyl, 2-trifluoromethoxy-benzyl, 3-trifluoromethoxy-benzyl, 4-trifluoromethoxy-benzyl, 2-trifluoromeththio-benzyl, 2-cyanobenzyl, 2-phenylbenzyl, 3-phenylbenzyl, 4-phenylbenzyl, 2-halo-3-halo-benzyl, 2-halo-4-halo-benzyl, 2-halo-5-halo-benzyl, 3-halo-4-halo-benzyl, 2-halo-3-(C 1-4 alkyl)-benzyl, 3-(C 1-4 alkyl)-4-halo-benzyl, 3-(2-halophenoxy)-benzyl, 3-(C 1-4 alkyl)-4-(2-halophenyl)-benzyl, 4-(pyrazol-1-yl)-benzyl, 3-(C 1-4 alkyl)-5-(C 1-4 alkyl)-benzyl, 3-(C 1-4 alkyl)-4-(2-halo-5-(C 1-4 alkoxy)-phenyl)-benzyl, 3-(2-halo-5-(C 1-4 alkoxy)-phenyl)-4-(C 1-4 alkyl)-benzyl, 3-(5,5-dimethylcyclopent-1-enyl)-4-(2-halo-5-(C 1-4 alkoxy)-phenyl)benzyl, 3-halo-5-trifluoromethylpyrid-3-yl, (2-(C 1-4 alkyl)-6-trifluoromethyl-pyrid-3-yl)methyl, and (2-(C 1-4 alkylthio)-pyrid-3-yl)methyl, and 2-naphthyl.

5. A compound according to claim 1 , wherein the compound is of Formula (III):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

X is selected from the group consisting of: O, S, CH 2 , CH(CH 3 ), CH(CH 2 CH 3 ), CH(2-methoxyphenyl), and C(O);

R 1 is selected from the group consisting of: phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-(t-butyl)phenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-cyanophenyl, 3-(N,N-dimethylamino)phenyl, 4-phenoxyphenyl, 3-(4-fluorophenoxy)-phenyl, 2-biphenyl, 2-benzylphenyl, 4-benzylphenyl, 3-benzoxyphenyl, 4-benzoxyphenyl, 3-(2-fluorophenyl)phenyl, 3-(2-fluorobenzyl)phenyl, 3-(2-methylbenzyl)phenyl, 4-(2-fluorobenzoxy)phenyl, 3-(2-fluoro-5-methoxy-phenyl)phenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4-ditrifluoromethylphenyl, 3-fluoro-4-methyl-phenyl, 2-methyl-4-methoxy-phenyl, 2-methyl-3-chloro-phenyl, 2-methyl-4-chloro-phenyl, 2-fluoro-4-chloro-phenyl, 2-chloro-3-trifluoromethyl-phenyl, 2-chloro-4-trifluoromethyl-phenyl, 2-methyl-4-benzoxy-phenyl, 2-fluoro-4-cyano-phenyl, 2-chloro-4-cyano-phenyl, 2-cyano-4-trifluoromethyl-phenyl, 3-cyano-4-trifluoromethyl-phenyl, 2-trifluoromethyl-4-cyano-phenyl, 3-trifluoromethyl-4-cyano-phenyl, 2-methyl-3-(2-fluoro-5-methoxy-phenyl)-phenyl, benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-(n-butyl)benzyl, 4-(t-butyl)benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 4-methylthiobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2-trifluoromethoxybenzyl, 3-trifluoromethoxybenzyl, 2-trifluoromethylthiobenzyl, 2-cyanobenzyl, 2-phenylbenzyl, 3-phenylbenzyl, 4-phenylbenzyl, 3-(2-fluorophenoxy)benzyl, 4-(pyrazol-1-yl)benzyl, 3,5-dimethylbenzyl, 2,4-difluorobenzyl, 3,4-difluorobenzyl, 2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 2,5-dichlorobenzyl, 3,4-dichlorobenzyl, 2-fluoro-3-methyl-benzyl, 3-methyl-4-bromo-benzyl, 3-methyl-4-(2-fluorophenyl)-benzyl, 3-methyl-4-(2-fluoro-5-methoxy-phenyl)-benzyl, 3-(2-fluoro-5-methoxy-phenyl)-4-(t-butyl)-benzyl, 3-(5,5-dimethylcyclopent-1-enyl)-4-(2-fluoro-5-methoxy-phenyl)benzyl, 3-chloro-5-trifluoromethylpyrid-2-yl, (2-(isopropylthio)-pyrid-3-yl)methyl, (2-methyl-6-trifluoromethylpyrid-3-yl)methyl, and 2-naphthyl; and

R 3 is selected from the group consisting of: H, F, OH, CH 3 , CH 2 CH 3 , OCH 3 , and CF 3 .

6. A compound according to claim 5 , wherein:

X is selected from the group consisting of: 0, S and CH 2 ;

R 1 is selected from the group consisting of: phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-phenoxyphenyl, 2-benzylphenyl, 3-benzoxyphenyl, 4-benzoxyphenyl, 3-(2-fluorophenyl)phenyl, 3-(2-fluorobenzyl)phenyl, 4-(2-fluorobenzoxy)phenyl, 3-(2-fluoro-5-methoxy-phenyl)phenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,5-difluorophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4-ditrifluoromethylphenyl, 3-fluoro-4-methyl-phenyl, 2-methyl-4-methoxy-phenyl, 2-methyl-3-chloro-phenyl, 2-methyl-4-chloro-phenyl, 2-fluoro-4-chloro-phenyl, 2-chloro-3-trifluoromethyl-phenyl, 2-chloro-4-trifluoromethyl-phenyl, 2-methyl-4-benzoxy-phenyl, 2-chloro-4-cyano-phenyl, 3-cyano-4-trifluoromethyl-phenyl, 2-trifluoromethyl-4-cyano-phenyl, 3-trifluoromethyl-4-cyano-phenyl, 2-methyl-3-(2-fluoro-5-methoxy-phenyl)-phenyl, benzyl, 2-methylbenzyl, 4-methylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 4-methylthiobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 2-trifluoromethoxybenzyl, 3-trifluoromethoxybenzyl, 2-trifluoromethylthiobenzyl, 2-cyanobenzyl, 2-phenylbenzyl, 4-phenylbenzyl, 3-(2-fluorophenoxy)benzyl, 3,5-dimethylbenzyl, 2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 2-fluoro-3-methyl-benzyl, 3-methyl-4-bromo-benzyl, 3-(5,5-dimethylcyclopent-l-enyl)-4-(2-fluoro-5-methoxy-phenyl)benzyl, (2-(isopropylthio)-pyrid-3-yl)methyl, (2-methyl-6-trifluoromethylpyrid-3-yl)methyl, and 2-naphthyl; and

R 3 is selected from the group consisting of: H, F, CH 3 , CH 2 CH 3 , and CF 3 .

7. A compound according to claim 5 , wherein:

X is selected from the group consisting of: O, S and CH 2 ;

R 1 is selected from the group consisting of: phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-fluorophenyl, 4-chlorophenyl, 3-bromophenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-phenoxyphenyl, 4-benzoxyphenyl, 3-(2-fluorophenyl)phenyl, 4-(2-fluorobenzoxy)phenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 2-methyl-4-methoxy-phenyl, 2-methyl-3-chloro-phenyl, 2-methyl-4-chlorophenyl, 2-methyl-4-benzoxy-phenyl, 3-cyano-4-trifluoromethyl-phenyl, 2-chloro-4-trifluoromethyl-phenyl, 2-methyl-3-(2-fluoro-5-methoxy-phenyl)-phenyl, 2-methylbenzyl, 2-chlorobenzyl, 2-trifluoromethylbenzyl, 2-trifluoromethoxybenzyl, 2-trifluoromethylthiobenzyl, 2-phenylbenzyl, 3-(2-fluorophenoxy)benzyl, 2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 2-methyl-4-chloro-benzyl, 2-methyl-3-trifluoromethyl-benzyl, and (2-(isopropylthio)-pyrid-3-yl)methyl; and

R 3 is selected from the group consisting of: H, F, CH 3 , CH 2 CH 3 , and CF 3 .

8. A compound according to claim 5 , wherein the compound is of Formula (III):

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

X, R 1 and R 3 are selected in concert from the group consisting of:

X

R 1

R 3

O

2-methyl-4-methoxy-phenyl

CF 3

O

2-methylphenyl

CF 3

CH 2

2-methylphenyl

CF 3

O

2-trifluoromethoxybenzyl

H

O

2-methylphenyl

H

O

2,3-dimethylphenyl

CF 3

CH 2

2-methylphenyl

F

O

2-methyl-3-chloro-phenyl

CF 3

O

2-fluorophenyl

CF 3

O

2,6-dimethylphenyl

H

O

2,4-dimethylphenyl

H

O

2-methylphenyl

F

O

2-fluorophenyl

F

O

2-methylbenzyl

CF 3

O

2-trifluoromethylthiobenzyl

H

O

2,3-dimethylphenyl

H

O

2-methylphenyl

F

O

2-methyl-4-benzoxy-phenyl

CF 3

CH 2

2-methylphenyl

H

O

2-methyl-4-methoxy-phenyl

H

CH 2

2-methylphenyl

CH 3

O

2-fluorophenyl

H

O

2-methylbenzyl

F

O

4-benzoxyphenyl

H

O

2-trifluoromethoxybenzyl

CF 3

O

2-trifluoromethoxyphenyl

CF 3

O

2-methylphenyl

CH 3

O

2-methylbenzyl

H

O

2-trifluoromethylbenzyl

H

O

2-trifluoromethylbenzyl

CH 3

O

3-trifluoromethoxyphenyl

H

O

4-benzoxyphenyl

H

O

2,4-dichlorobenzyl

H

CH 2

4-chlorophenyl

H

CH 2

3-methylphenyl

H

O

3,4-dichlorobenzyl

H

O

3-methylphenyl

H

O

(2-(isopropylthio)-pyrid-3-yl)methyl

H

CH 2

2-fluorophenyl

H

CH 2

2,6-difluorophenyl

H

O

4-chlorophenyl

H

O

2-phenylbenzyl

H

O

2-chloro-4-trifluoromethyl-phenyl

CF 3

O

2-trifluoromethylphenyl

CF 3

CH 2

4-methylphenyl

H

O

3,5-dichlorophenyl

H

O

2-methyl-3-(2-fluoro-5-methoxy-

H

phenyl)-phenyl

O

3-(2-fluorophenyl)phenyl

H

O

4-phenoxyphenyl

H

CH 2

2-trifluoromethylphenyl

H

O

3-bromophenyl

H

CH 2

4-benzoxyphenyl

H

O

3-(2-fluorophenoxy)benzyl

H

O

2,3-dichlorobenzyl

H

S

2-methylphenyl

H

O

2-trifluoromethylbenzyl

H

O

2-methylphenyl

Et

O

2,4-dichlorophenyl

H

CH 2

2,4-dimethylphenyl

H

CH 2

2-methyl-4-chloro-phenyl

H

O

3-cyano-4-trifluoromethyl-phenyl

H

O

4-methylphenyl

H

CH 2

3-fluoro-4-methyl-phenyl

H

O

4-methoxyphenyl

H

CH 2

2-naphthyl

H

O

4-methylthiobenzyl

H

O

(2-methyl-6-trifluoromethylpyrid-3-

H

yl)methyl

O

phenyl

H

O

4-methylbenzyl

H

CH 2

2,4-difluorophenyl

H

O

2-chloro-4-cyano-phenyl

H

O

2-trifluoromethyl-4-cyano-phenyl

H

CH 2

2-chlorophenyl

H

CH 2

2-fluoro-4-chloro-phenyl

H

O

2-fluoro-3-methyl-benzyl

H

O

3-(2-fluorobenzyl)phenyl

H

O

3-chlorophenyl

H

CH 2

phenyl

H

O

2-fluorobenzyl

H

O

3-trifluoromethyl-4-cyano-phenyl

H

CH 2

2-chloro-3-trifluoromethyl-phenyl

H

O

2-benzylphenyl

H

O

3-(5,5-dimethylcyclopent-1-enyl)-4-(2-

H

fluoro-5-methoxy-phenyl)benzyl

O

benzyl

H

O

3-fluorobenzyl

H

CH 2

3,5-difluorophenyl

H

O

3-benzoxyphenyl

H

CH 2

4-trifluoromethylphenyl

H

CH 2

2,4-ditrifluoromethylphenyl

H

O

3-(2-fluoro-5-methoxy-phenyl)phenyl

H

CH 2

3-trifluoromethylphenyl

H

O

3-methyl-4-bromo-benzyl

H

O

4-phenylbenzyl

H

O

3-trifluoromethoxybenzyl

H

O

2-cyanobenzyl

H

9. A compound according to claim 1 , wherein the compound is selected from the group consisting of:

or a stereoisomer or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of claim 1 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of claim 2 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of claim 3 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of claim 4 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of claim 5 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of claim 6 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of claim 7 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of claim 8 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of claim 9 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.