Indole amide derivatives as EP4 receptor antagonists

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

each of A, B and C is independently selected from CH and C(R 1 );

-D-E-F- is selected from the group consisting of:

—C(R 5 )═C(R)—N—,

—C(R)═N—C(R)—,

—C(R)═N—N—,

—N═C(R)—N—,

—N═N—N—,

—C(R) 2 —N═C—,

—N(R)—C(R)═C—,

—N(R)—N═C—,

—O—N═C— and

—S—N═C—

wherein each R is independently selected from the group consisting of: hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy and acetyl;

R 5 is selected from the group consisting of: hydrogen, halo, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 -alkoxy, C 1-4 -fluoroalkoxy and acetyl;

X is a bond, —CH 2 — or —CH 2 —CH 2 —, and X may additionally be —S—when -D-E-F- is —C(R 5 )═N—C(R)—;

Ar 1 and Ar 2 are independently selected from the group consisting of: C 3-6 cycloalkyl, aryl, heteroaryl and heterocyclyl, or a fused analog of C 3-6 cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein Ar 2 is optionally substituted with one to three R 2 groups and Ar 1 is optionally substituted with one to three R 4 groups; and

R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of: halo, C 1-4 alkyl, C 1-4 -fluoroalkyl, C 1-4 alkoxy, C 1-4 -fluoroalkoxy and acetyl.

2. The compound according to claim 1 wherein R 3 is methyl.

3. The compound according to claim 1 wherein Ar 1 is phenyl, optionally substituted with one to three R 4 groups.

4. The compound according to claim 1 wherein Ar 2 is phenyl, optionally substituted with one to three R 2 groups.

5. The compound according to claim 1 of Formula Ia

or a pharmaceutically acceptable salt thereof, wherein:

-D-E-F- is selected from the group consisting of:

—C(R 5 )═C(R)—N—,

—C(R)═N—N—,

—N(R)—C(R)═C—,

—N═C(R)—N— and

—N═N—N—,

wherein each R is independently selected from the group consisting of: hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy and acetyl;

R 5 is selected from the group consisting of: hydrogen, halo, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy and acetyl;

X is a bond or —CH 2 —; and

R 1 and R 2 are independently selected from the group consisting of: halo, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy and acetyl.

6. The compound according to claim 5 wherein X is —CH 2 —.

7. The compound according to claim 5 wherein

each R is independently selected from the group consisting of: hydrogen, methyl, thrifluoromethyl, trifluoromethoxy and acetyl;

R 5 is selected from the group consisting of hydrogen, chloro, methyl, thrifluoromethyl, trifluoromethoxy and acetyl; and

R 1 and R 2 are independently selected from the group consisting of: chloro, methyl, thrifluoromethyl, trifluoromethoxy and acetyl.

8. The compound according to claim 5 wherein -D-E-F- is —C(R 5 )═C(R)—N—.

9. The compound according to claim 5 wherein -D-E-F- is —C(R)=N—N—.

10. The compound according to claim 5 wherein -D-E-F- is: —N(R)—C(R)═C—.

11. The compound according to claim 5 wherein -D-E-F- is —N═C(R)—N—.

12. The compound according to claim 5 wherein -D-E-F- is —N═N—N—.

13. A compound according to claim 1 selected from the following:

(1) 4-{(1S)-1-[({1-[3-(trifluoromethyl)benzyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid;

(2) 4-[(1S)-1-({[1-(3-chlorobenzyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid;

(3) 4-{(1S)-1-[({1-[3-chloro-4-(trifluoromethoxy)benzyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid;

(4) 4-{(1S)-1-[({1-[2-(3-chlorophenyl)ethyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid;

(5) 4-[(1S)-1-({[1-(3-chlorobenzyl)-3-methyl-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid;

(6) 4-[(1S)-1-({[3-chloro-1-(3-chlorobenzyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid;

(7) 4-[(1S)-1-({[3-acetyl-1-(3-chlorobenzyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid;

(8) 4-[(1S)-1-({[5-chloro-1-(3-chlorobenzyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid;

(9) 4-[(1S)-1-({[5-chloro-1-(3-chlorobenzyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid;

(10) 4-[(1S)-1-({[1-(3-chlorobenzyl)-2-methyl-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid;

(11) 4-[(1S)-1-({[1-(3-chlorobenzyl)-1H-indazol-7-yl]carbonyl}amino)ethyl]benzoic acid;

4-[(1S)-1-({[5-chloro-1-(3-chlorobenzyl)-1H-indazol-7-yl]carbonyl}amino)ethyl]benzoic acid;

(12) 4-{(1S)-1-[({3-[(3-chlorophenyl)thio]-1H-indol-4-yl}carbonyl)amino]ethyl}benzoic acid;

(13) 4-[(1S)-1-({[3-(3-chlorobenzyl)-1H-indol-4-yl]carbonyl}amino)ethyl]benzoic acid;

(14) 4-[(1S)-1-({[5-chloro-1-(3-chlorobenzyl)-1H-benzimidazol-7-yl]carbonyl}amino)ethyl]benzoic acid; and

(15) 4-[(1S)-1-({[5-chloro-1-(3-chlorobenzyl)-1H-1,2,3-benzotriazol-7-yl]carbonyl}amino)ethyl]benzoic acid;

or a pharmaceutically acceptable salt of any of the aforementioned.

14. A pharmaceutical composition comprising a compound according to claim 1 in admixture with one or more physiologically acceptable carriers or excipients.