Indoline amide derivatives as EP4 receptor ligands

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

X is —COOH or tetrazol-5-yl;

each of A, B and C is independently selected from N, CH and C(R 3 ), with the proviso that not more than one of A, B or C may be N;

D is —C(R) 2 —, 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;

Ar 1 and Ar 2 are independently selected from the group consisting of: aryl, heteroaryl and heterocyclyl, wherein

the aryl of Ar 1 and Ar 2 is independently selected from phenyl and naphthyl, the heteroaryl of Ar 1 and Ar 2 is independently selected from pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl and isoquinolyl, and

the heterocyclyl of Ar 1 and Ar 2 is independently selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, and dihydroindolyl, and

wherein Ar 1 is optionally substituted with one to three R 1 groups and Ar 2 is optionally substituted with one to three R 2 groups; and

each R 1 , R 2 and R 3 is independently selected from the group consisting of: halo, —CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, acetyl, aminocarbonyl and phenyl,

R 4 and R 5 are selected from the group consisting of: hydrogen and C 1-4 alkyl, or R 4 and R 5 may be joined together with the atom to which they are attached to form a C 3-6 cycloalkyl group.

2. The compound according to claim 1 wherein R 4 is methyl and R 5 is hydrogen or R 4 and R 5 are joined together with the atom to which they are attached to form cyclopropyl.

3. The compound according to claim 1 wherein Ar 1 is phenyl, optionally substituted with one to three R 1 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 wherein each of A, B and C is independently selected from CH and C(R 3 ).

6. The compound according to claim 1 wherein X is —COOH.

7. A compound of Formula Ia

or a pharmaceutically acceptable salt thereof, wherein:

R 2 is selected from the group consisting of: halo, —CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, acetyl, aminocarbonyl and phenyl.

8. The compound according to claim 7 wherein at least one R 2 group is present.

9. A compound selected from the following group:

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

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

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

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

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

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

4-[(1S)-1-({[1-(3,5-dibromobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid;

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

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

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

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

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

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

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

4-[(1S)-1-({[1-(2,5-dichlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid;

4-[1-({[1-(3,4-dichlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)cyclopropyl]benzoic acid;

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

1-(3,4-dichlorobenzyl)-N-{1-[4-(1H-tetrazol-5-yl)phenyl]cyclopropyl}indoline-7-carboxamide;

4-{(1S)-1-[({1-[2-bromo-4-(trifluoromethyl)benzyl]-2,3-dihydro-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid;

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

N-{(1S)-1-[4-(1H-tetrazol-5-yl)phenyl]ethyl}-1-[4-(trifluoromethyl)benzyl]indoline-7-carboxamide; and

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

or a pharmaceutically acceptable salt of any of the aforementioned.

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

11. A pharmaceutical composition comprising a compound according to claim 7 in admixture with one or more physiologically acceptable carriers or excipients.