G-lactam derivatives as prostaglandin agonists

1. A gamma-lactam diene of Formula I:

wherein A is selected from the group consisting of C 1 -C 4 alkyl, aryl, heteroaryl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl;

B is C(O)Z wherein Z is selected from the group consisting of hydroxy, alkoxy, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl and NR 1 R 2 , wherein R 1 and R 2 are independently selected from the group consisting of H, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl C 1 -C 6 alkyl and heteroaryl C 1 -C 6 alkyl;

D is selected from the group consisting of H, halogen and C 1 -C 6 alkyl;

E is selected from the group consisting of H and C 1 -C 6 alkyl;

G is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl C 1 -C 6 alkyl, heteroaryl C 1 -C 6 alkyl, aryl and heteroaryl; or E and G form, together with the carbon atom they are attached to, a C 3 -C 6 cycloalkyl ring;

J, K and L are independently selected from the group consisting of H, halogen, C 1 -C 6 alkyl, aryl and heteroaryl;

M is selected from the group consisting of OR and H,

n is 0 or 1;

wherein the (a) and (b) double bonds can be independently in Z or E conformation.

2. A gamma-lactam diene of claim 1 having the following Formula II:

wherein A is selected from the group consisting of C 1 -C 4 alkyl, aryl, heteroaryl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl;

B is C(O)Z wherein Z is selected from the group consisting of hydroxy, alkoxy, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl and NR 1 R 2 , wherein R 1 and R 2 are independently selected from the group consisting of H, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl C 1 -C 6 alkyl and heteroaryl C 1 -C 6 alkyl;

D is selected from the group consisting of H, halogen and C 1 -C 6 alkyl;

E is selected from the group consisting of H and C 1 -C 6 alkyl;

G is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl C 1 -C 6 alkyl, heteroaryl C 1 -C 6 alkyl, aryl and heteroaryl; or E and G form, together with the carbon atom they are attached to, a C 3 -C 6 cycloalkyl ring;

n is 0 or 1; and

wherein the (a) and (b) double bonds can be independently in Z or E conformation.

3. A gamma-lactam diene according to claim 1 , wherein A is selected from the group consisting of aryl and heteroaryl.

4. A gamma-lactam diene according to claim 1 , wherein A is phenyl.

5. A gamma-lactam diene according to claim 1 , wherein A is thiophenyl.

6. A gamma-lactam diene according to claim 1 , wherein A is furanyl.

7. A gamma-lactam diene according to claim 1 , wherein B is C(O)Z, wherein Z is selected from the group consisting of hydroxy, alkyloxy and C 1 -C 6 alkyl.

8. A gamma-lactam diene according to claim 1 , wherein D is H.

9. A gamma-lactam diene according to claim 1 , wherein D is methyl.

10. A gamma-lactam diene according to claim 1 , wherein D is fluorine.

11. A gamma-lactam diene according to claim 1 , wherein G is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C 3 -C 6 cycloalkyl C 1 -C 6 alkyl.

12. A gamma-lactam diene according to claim 1 , wherein G is selected from the group consisting of C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl C 1 -C 6 alkyl, heteroaryl C 1 -C 6 alkyl, aryl and heteroaryl.

13. A gamma-lactam diene according to claim 1 , wherein E and G form, together with the carbon atom they are attached to, an optionally substituted C 3 -C 6 cycloalkyl ring.

14. A gamma-lactam diene according to claim 1 , wherein the bond (a) is in the “Z” conformation.

15. A gamma-lactam diene according to claim 1 , wherein A is phenyl, thiophenyl or furanyl, B is COOH, and bond (a) is in the “Z” conformation.

16. A gamma-lactam diene according to claim 1 , wherein A is phenyl, thiophenyl or furanyl, B is COOH, D is selected from the group consisting of H, methyl and fluorine, and bond (a) is in the “Z” conformation.

17. A gamma-lactam diene according to claim 1 , wherein A is phenyl or thiophenyl, B is COOH, and D is H.

18. A gamma-lactam diene according to claim 1 , wherein A is phenyl or thiophenyl, B is COOH, D is H, and E is selected from the group consisting of H and methyl.

19. A gamma-lactam diene according to claim 1 , wherein A is phenyl or thiophenyl, B is COOH, D is H, E is selected from the group consisting of H and methyl, and G is selected from the group consisting of C 1 -C 6 alkyl and C 2 -C 6 alkenyl.

20. A gamma-lactam diene according to claim 1 , wherein A is phenyl or thiophenyl, B is COOH, D is H, E is selected from the group consisting of H and methyl, and G is selected from the group consisting of C 3 -C 6 cycloalkyl C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl C 1 -C 6 alkyl, heteroaryl C 1 -C 6 alkyl, aryl and heteroaryl.

21. A gamma-lactam diene according to claim 1 , wherein A is phenyl or thiophenyl, B is COOH, D is H, and E and G form, together with the carbon atom they are attached to, a C 3 -C 6 cycloalkyl ring.

22. A gamma-lactam diene according to claim 1 selected from the group consisting of:

4-(2-{(2R)-2-[(1Z,3E)-octa-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-octa-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1Z,3E)-4-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-4-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1Z)-4-methylpenta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E)-4-methylpenta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1Z,3E)-hexa-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-hexa-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1Z,3E)-hepta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-hepta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1Z,3E)-4,8-dimethylnona-1,3,7-trienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-4,8-dimethylnona-1,3,7-trienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

5-(3-{(2R)-2-[(1Z,3E)-4-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)thiophene-2-carboxylic acid;

5-(3-{(2R)-2-[(1E,3E)-4-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)thiophene-2-carboxylic acid;

4-(2-{(2R)-2-[(1Z,3Z)-hepta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1Z and 1E,3Z)-hexa-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

5-(3-{(2R)-2-[(1Z,3E)-octa-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)thiophene-2-carboxylic acid,

5-(3-{(2R)-2-[(1E,3E)-octa-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)thiophene-2-carboxylic acid;

5-(3-{(2R)-2-[(1Z,3E)-octa-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)thiophene-2-carboxylic acid;

5-(3-{(2R)-2-[(1E,3E)-3-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)thiophene-2-carboxylic acid;

4-(2-{(2R)-2-[(1Z,3E)-3-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-3-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

5-(3-{(2R)-2-[(1E,3E)-3-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)thiophene-2-carboxylic acid;

5-(3-{(2R)-2-[(1Z,3E)-3-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)-2-furoic acid;

5-(3-{(2R)-2-[(1E,3E)-3-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)-2-furoic acid;

4-(2-{(2R)-2-[(1Z,3E)-6-cyclopropyl-4-methylhexa-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-6-cyclopropyl-4-methylhexa-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1Z,3E)-4,7-dimethylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-4,7-dimethylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1Z,3E)-5-cyclopentyl-4-methylpenta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-5-cyclopentyl-4-methylpenta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1Z,3E)-4-phenylpenta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-4-phenylpenta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1Z,3Z)-4-phenylpenta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3Z)-4-phenylpenta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

5-(3-{(2R)-2-[(1Z,3E)-octa-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)-2-furoic acid;

5-(3-{(2R)-2-[(1E,3E)-octa-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)-2-furoic acid;

4-(3-{(2R)-2-[(1Z,3E)-octa-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)benzoic acid;

4-(3-{(2R)-2-[(1E,3E)-octa-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)benzoic acid;

4-(2-{(2R)-2-[(1Z,3Z)-3-fluoro-4-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4(2-{(2R)-2-[(1E,3Z)-3-fluoro-4-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4(2-{(2R)-2-[(1Z,3E)-3-fluoro-4-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4(2-{(2R)-2-[(1E,3E)-3-fluoro-4-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4(2-{(2R)-2-[(1Z,3E)-4-methylhepta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4(2-{(2R)-2-[(1E,3E)-4-methylhepta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4(2-{(2R)-2-[(1Z,3E)-4-methylhexa-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-4-methylhexa-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

6-(3-{(2R)-2-[(1Z,3E)-4-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)pyridine-2-carboxylic acid;

6-(3-{(2R)-2-[(1E,3E)-4-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)pyridine-2-carboxylic acid;

4(2-{(2R)-2-[(1Z,3E)-4,6-dimethylhepta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-4,6-dimethylhepta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4(2-{(2R)-2-[(1Z,3E)-4,7,7-trimethylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-4,7,7-trimethylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1Z,3E)-4,5-dimethylhexa-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-4,5-dimethylhexa-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1Z,3E)-4-cyclohexylbuta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-((2R)-2-[(1E,3E)-4-cyclohexylbuta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1Z,3E)-4-phenyl-4-triflurobuta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-4-phenyl-4-triflurobuta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1Z,3Z)-4-phenyl-4-triflurobuta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4(2-{(2R)-2-[(1E,3Z)-4-phenyl-4-triflurobuta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1Z,3E)-4-cyclopropylpenta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

4-(2-{(2R)-2-[(1E,3E)-4-cyclopropylpenta-1,3-dienyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid;

5-(3-{(2R)-2-[(1Z,3E)-4-methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)nicotinic acid; and

5-(3-{(2R)-2-[(1E,3E)-4 methylocta-1,3-dienyl]-5-oxopyrrolidin-1-yl}propyl)nicotinic acid.

23. A method for treating a disease in a mammal selected from the group consisting of dysmenorrheal, undesired bone loss, inflammation resulting from Chronic Obstructive Pulmonary Disorder, a gastric ulcer, asthma, and an ovulatory disorder in a female undergoing ovulation induction or ART treatment, comprising:

administering to the mammal an effective amount of a compound of claim 1 .

24. The method according to claim 23 wherein the mammal is suffering from dysmenorrheal.

25. The method according to claim 23 wherein the mammal is suffering from a gastric ulcer.

26. The method according to claim 23 wherein the mammal is suffering from asthma.

27. The method according to claim 23 wherein the mammal is suffering from inflammation resulting from Chronic Obstructive Pulmonary Disorder.

28. The method according to claim 23 wherein the mammal is suffering from an ovulatory disorder in a female undergoing ovulation induction or ART treatment.

29. The method according to claim 23 wherein the mammal is suffering from undesired bone loss.

30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds of claim 1 .

31. A pharmaceutical composition of claim 30 wherein the compound is packaged together with instructions for use of the compound for the treatment of dysmenorrheal, undesired bone loss, inflammation resulting from Chronic Obstructive Pulmonary Disorder, a gastric ulcer, asthma, and an ovulatory disorder wherein the female is undergoing ovulation induction or ART treatment.