Naphthalene and quinoline sulfonylurea derivatives as EP4 receptor antagonists

1. A compound according of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from the group consisting of N or CH;

R 1 and R 2 are independently selected from the group consisting of: C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 fluoroalkyl;

R 3 is selected from the group consisting of: halogen, C 1-6 alkyl and C 1-6 haloalkyl;

R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of: hydrogen, halogen, C 1-6 alkyl and C 3-6 cycloalkyl; or R 4 and R 5 or R 6 and R 7 can join to make a 3-6 membered monocyclic cycloalkane ring;

Ar is 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; and

each Y is independently selected from the group consisting of: halo, methyl, ethyl, methoxy, CF 3 , CF 3 O— and hydroxy.

2. The compound according to claim 1 wherein Ar is phenyl or naphthyl.

3. The compound according to claim 2 wherein Ar is phenyl.

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

5. The compound according to claim 1 wherein: R 4 and R 5 are hydrogen and R 6 and R 7 are joined to make a cyclopropyl ring.

6. The compound according to claim 1 wherein X is N.

7. The compound according to claim 1 wherein X is CH.

8. The compound according to claim 1 according to Formula Ia

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from the group consisting of N or CH;

R 1 and R 2 are the same and selected from the group consisting of: ethyl, 2,2,2-trifluoroethyl and difluoromethyl; and

one or two Y groups are present and each Y is independently selected from the group consisting of F, Cl, Br, methyl, ethyl, methoxy, CF 3 , CF 3 O— and hydroxy.

9. The compound according to claim 8 wherein X is N.

10. The compound according to claim 8 wherein X is CH.

11. The compound according to claim 1 selected from the following group:

2,6-dichloro-N-[({1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)-3-methylbenzyl]cyclopropyl}amino)carbonyl]benzenesulfonamide;

N-[({1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)-3-methylbenzyl]cyclopropyl}amino)carbonyl]-4-methylbenzenesulfonamide;

2-chloro-N-[({1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)-3-methylbenzyl]cyclopropyl}amino)carbonyl]benzenesulfonamide;

N-[({1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)-3-methylbenzyl]cyclopropyl}amino)carbonyl]-2-methylbenzenesulfonamide;

N-[({1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)-3-methylbenzyl]cyclopropyl}amino)carbonyl]-2-methoxybenzenesulfonamide;

2-bromo-N-[({1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)-3-methylbenzyl]cyclopropyl}amino)carbonyl]benzenesulfonamide;

N-[({1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)-3-methylbenzyl]cyclopropyl}amino)carbonyl]-2,6-dimethoxybenzenesulfonamide;

N-[({1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)-3-methylbenzyl]cyclopropyl}amino)carbonyl]-2-(trifluoromethyl)benzenesulfonamide;

N-[({1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)-3-methylbenzyl]cyclopropyl}amino)carbonyl]naphthalene-2-sulfonamide;

N-[({1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)-3-methylbenzyl]cyclopropyl}amino)carbonyl]-2,6-bis(trifluoromethyl)benzenesulfonamide;

N-[({1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)-3-methylbenzyl]cyclopropyl}amino)carbonyl]-2,6-dimethylbenzenesulfonamide;

2,3-dichloro-N-[({1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)-3-methylbenzyl]cyclopropyl}amino)carbonyl]benzenesulfonamide;

N-[({1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)-3-methylbenzyl]cyclopropyl}amino)carbonyl]-4-fluorobenzenesulfonamide;

N-[({1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)-3-methylbenzyl]cyclopropyl}amino)carbonyl]-4-(trifluoromethoxy)benzenesulfonamide;

N-{[(2-{4-[4,9-bis(difluoromethoxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-methylphenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

2-chloro-N-{[(1-{3-methyl-4-[6-oxo-5,9-bis(2,2,2-trifluoroethoxy)-6,8-dihydro-7H-pyrrolo[3,4g]quinolin-7yl]benzyl}cyclopropyl)amino]carbonyl}benzenesulfonamide;

2-chloro-N-[({2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)-3-methylphenyl]-2,2-difluoroethyl}amino)carbonyl]benzenesulfonamide;

N-{[(1-{3-methyl-4-[6-oxo-5,9-bis(2,2,2-trifluoroethoxy)-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl]benzyl}cyclopropyl)amino]carbonyl}naphthalene-2-sulfonamide; and

2-methoxy-4-methyl-N-{[(1-[3-methyl-4-[6-oxo-5,9-bis(2,2,2-trifluoroethoxy)-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl]benzyl}cyclopropyl)amino]carbonyl}benzenesulfonamide;

or a pharmaceutically acceptable salt of any of the foregoing compounds.

12. The compound according to claim 1 which is the hydrochloride salt of 2-chloro-N-{[(1-{3-methyl-4-[6-oxo-5,9-bis(2,2,2-trifluoroethoxy)-6,8-dihydro-7H-pyrrolo[3,4g]quinolin-7-yl]benzyl}cyclopropyl)amino]carbonyl}benzenesulfonamide.

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

14. A method for treating acute or chronic pain, migraine, osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea, or atherosclerosis in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.