Oxopiperazine-azetidine amides and oxodiazepine-azetidine amides as monoacylglycerol lipase inhibitors

1. A compound of Formula (Ia)

wherein

Y is

i) a C 6-10 aryl or

ii) a heteroaryl selected from the group consisting of thiazolyl, oxazolyl, pyridinyl, and pyrimidinyl,

wherein Y is unsubstituted or substituted with one or two substituents each of which is independently selected from the group consisting of fluoro, chloro, C 1-4 alkyl, C 1-4 alkoxy, cyano, and trifluoromethyl;

Z is selected from the group consisting of

i) a C 6-10 aryl,

ii) a heteroaryl selected from the group consisting of benzoxazolyl, benzothiazolyl, benzothienyl, indazolyl, and indolyl, or

iii) phenylmethyl-phenyl; wherein the phenyl of phenylmethyl is unsubstituted or substituted with one or two substituents each of which is independently selected from the group consisting of bromo, chloro, fluoro, iodo, C 1-4 alkyl, C 1-4 alkoxy, and trifluoromethyl;

wherein the C 6-10 aryl and the heteroaryl of Z are unsubstituted or substituted with one or two substitutents each of which is independently selected from the group consisting of bromo, chloro, fluoro, iodo, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, and phenyl,

provided that no more than one substituent of Z is phenyl and said phenyl is unsubsituted or substituted with one or two subsituents each of which is independently selected from the group consisting of trifluoromethyl, chloro, cyano, and fluoro;

n is 1 or 2; and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein Y is phenyl, thiazolyl, or pyrimidinyl.

3. The compound of claim 2 wherein Y is thiazolyl or pyrimidinyl.

4. The compound of claim 1 wherein

Z is

i) a C 6-10 aryl or

ii) a heteroaryl selected from the group consisting of benzoxazolyl, benzothiazolyl, benzothienyl, and indolyl,

wherein the C 6-10 aryl and the heteroaryl of Z are unsubstituted or substituted with one or two substitutents each of which is independently selected from the group consisting of chloro, fluoro, C 1-4 alkyl, trifluoromethyl, and phenyl,

provided that no more than one substituent of Z is phenyl and said phenyl is unsubstituted or substituted with one or two substituents each of which is trifluoromethyl or fluoro.

5. The compound of claim 4 wherein Z is a heteroaryl selected from the group consisting of benzoxazolyl, benzothiazolyl, benzothienyl, and indolyl,

wherein the heteroaryl of Z is unsubstituted or substituted with one or two substitutents each of which is independently selected from the group consisting of chloro, trifluoromethyl, and phenyl,

provided that no more than one substituent of Z is phenyl and said phenyl is unsubstituted or substituted with one or two substituents each of which is trifluoromethyl or fluoro.

6. The compound of claim 1 wherein n is 1.

7. The compound of claim 1 wherein n is 2.

8. A compound of Formula (Ia)

wherein:

Y is

i) phenyl or

ii) a heteroaryl that is thiazolyl or pyrimidinyl;

Z is

i) a C 6-10 aryl or

ii) a heteroaryl selected from the group consisting of benzoxazolyl, benzothiazolyl, benzothienyl, and indolyl,

wherein the C 6-10 aryl and the heteroaryl of Z are unsubstituted or substituted with one or two substitutents each of which is independently selected from the group consisting of chloro, fluoro, C 1-4 alkyl, trifluoromethyl, and phenyl,

provided that no more than one substituent of Z is phenyl and said phenyl is unsubstituted or substituted with one or two substituents each of which is trifluoromethyl or fluoro;

n is 1 or 2; and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

9. The compound of claim 8 wherein n is 1.

10. The compound of claim 8 wherein n is 2.

11. A compound of Formula (Ia)

wherein:

Y is thiazolyl or pyrimidinyl;

Z is a heteroaryl selected from the group consisting of benzoxazolyl, benzothiazolyl, benzothienyl, and indolyl,

wherein the heteroaryl of Z is unsubstituted or substituted with one or two substitutents each of which is independently selected from the group consisting of chloro, trifluoromethyl, and phenyl,

provided that no more than one substituent of Z is phenyl, and said phenyl is unsubstituted or substituted with one or two substitutents each of which is trifluoromethyl or fluoro;

n is 1 or 2;

and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

12. The compound of claim 11 wherein n is 1.

13. A compound of Formula (Ia)

selected from the group consisting of

the compound wherein Y is phenyl, Z is 4-(phenylmethyl)-phenyl, and n is 1;

the compound wherein Y is phenyl, Z is 4-phenyl-phenyl, and n is 1;

the compound wherein Y is pyrimidin-2-yl, Z is 1-(4-trifluoromethyl-phenyl)-1H-indol-5-yl, and n is 1;

the compound wherein Y is pyrimidin-2-yl, Z is 1-(4-fluoro-phenyl)-1H-indol-5-yl, and n is 1;

the compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoro-phenyl)-1H-indol-5-yl, and n is 1;

the compound wherein Y is thiazol-4-yl, Z is 1-(4-fluoro-phenyl)-1H-indol-5-yl, and n is 1;

the compound wherein Y is thiazol-4-yl, Z is 3-chloro-6-trifluoromethyl-benzothien-2-yl, and n is 1;

the compound wherein Y is pyrimidin-2-yl, Z is 3-chloro-6-trifluoromethyl-benzothien-2-yl, and n is 1;

the compound wherein Y is pyrimidin-2-yl, Z is 4-phenyl-phenyl, and n is 1;

the compound wherein Y is pyrimidin-2-yl, Z is 2-phenyl-benzothiazol-6-yl, and n is 1;

the compound wherein Y is thiazol-2-yl, Z is 3-chloro-6-trifluoromethyl-benzothien-2-yl, and n is 1;

the compound wherein Y is thiazol-2-yl, Z is 2-phenyl-benzothiazol-6-yl, and n is 1;

the compound wherein Y is phenyl, Z is 1-(4-trifluoromethyl-phenyl)-1H-indol-5-yl, and n is 1;

the compound wherein Y is phenyl, Z is 3-chloro-6-trifluoromethyl-benzothien-2-yl, and n is 1;

the compound wherein Y is phenyl, Z is 1-(3,4-difluoro-phenyl)-1H-indol-5-yl, and n is 1;

the compound wherein Y is thiazol-2-yl, Z is 2-phenyl-benzoxazol-6-yl, and n is 1;

the compound wherein Y is pyrimidin-2-yl, Z is 3-chloro-6-trifluoromethyl-benzothien-2-yl, and n is 2;

the compound wherein Y is thiazol-2-yl, Z is 4-phenyl-phenyl, and n is 1;

the compound wherein Y is thiazol-2-yl, Z is 3-chloro-6-trifluoromethyl-benzothien-2-yl, and n is 2;

the compound wherein Y is pyrimidin-2-yl, Z is 1-(4-fluoro-phenyl)-1H-indol-5-yl, and n is 2;

the compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoro-phenyl)-1H-indol-5-yl, and n is 2;

the compound wherein Y is thiazol-2-yl, Z is 2-phenyl-benzoxazol-6-yl, and n is 2;

and pharmaceutically acceptable salt forms thereof.

14. A compound of Formula (Ib)

wherein:

Y b is

i) a C 6-10 aryl or

ii) a heteroaryl selected from the group consisting of thiazolyl, oxazolyl, pyridinyl, and pyrimidinyl,

wherein Y b is unsubstituted or substituted with one or two substituents each of which is selected from the group consisting of fluoro, chloro, C 1-4 alkyl, C 1-4 alkoxy, cyano, and trifluoromethyl;

Z b is

i) a C 6-10 aryl,

ii) a heteroaryl selected from the group consisting of benzoxazolyl, benzothiazolyl, benzothienyl, and indolyl, or

iii) phenylmethyl-phenyl; wherein the phenyl of phenylmethyl is unsubstituted or substituted with one or two substituents each of which is selected from the group consisting of bromo, chloro, fluoro, iodo, C 1-4 alkyl, C 1-4 alkoxy, and trifluoromethyl,

wherein the C 6-10 aryl and the heteroaryl of Z b are unsubstituted or substituted with one or two substitutents each of which is selected from the group consisting of bromo, chloro, fluoro, iodo, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, and phenyl,

provided that no more than one substituent of Z b is phenyl and said phenyl is unsubstituted or substituted with one or two substituents each of which is selected from the group consisting of trifluoromethyl, chloro, cyano, and fluoro;

and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

15. The compound of claim 14 wherein Y b is thiazolyl or pyrimidinyl.

16. The compound of claim 14 wherein Z b is the heteroaryl selected from the group consisting of benzoxazolyl, benzothiazolyl, benzothienyl, and indolyl;

wherein the heteroaryl of Z b is unsubstituted or substituted with one or two substitutents each of which is independently selected from the group consisting of bromo, chloro, fluoro, trifluoromethyl, and phenyl;

provided that no more than one substituent of Z b is phenyl and said phenyl is unsubstituted or substituted with one or two substituents each of which is trifluoromethyl or fluoro.

17. The compound of claim 16 wherein Z b is benzothienyl or indolyl,

wherein Z b is unsubstituted or substituted with one or two substitutents each of which is trifluoromethyl or phenyl,

provided that no more than one substituent of Z b is phenyl and said phenyl is unsubstituted or substituted with one trifluoromethyl or fluoro substituent.

18. A compound of Formula (Ib)

wherein:

Y b is thiazolyl or pyrimidinyl;

Z b is a heteroaryl selected from the group consisting of benzoxazolyl, benzothiazolyl, benzothienyl, and indolyl,

wherein the heteroaryl of Z b is unsubstituted or substituted with one or two substitutents each of which is selected from the group consisting of bromo, chloro, fluoro, trifluoromethyl, and phenyl,

provided that no more than one substituent is phenyl and said phenyl is unsubstituted or substituted with one or two substituents each of which is trifluoromethyl or fluoro;

and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

19. A compound of Formula (Ib)

wherein:

Y b is thiazolyl or pyrimidinyl;

Z b is benzothienyl or indolyl,

wherein Z b is unsubstituted or substituted with one or two substitutents each of which is trifluoromethyl or phenyl,

provided that no more than one substituent of Z b is phenyl and said phenyl is unsubstituted or substituted with one trifluoromethyl or fluoro substituent;

and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

20. A compound of Formula (Ib)

selected from the group consisting of:

the compound wherein Y b is pyrimidin-2-yl, and Z b is 6-trifluoromethyl-benzothien-2-yl;

the compound wherein Y b is pyrimidin-2-yl, and Z b is 1-(4-trifluoromethyl-phenyl)-1H-indol-5-yl;

and pharmaceutically acceptable salts thereof.

21. A pharmaceutical composition comprising the compound of claim 1 or 13 and a member selected from the group consisting of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

22. A pharmaceutical composition of claim 21 , wherein the composition is a solid oral dosage form.

23. A pharmaceutical composition of claim 21 , wherein the composition is selected from the group consisting of a syrup, an elixir, and a suspension.

24. A method for treating inflammatory pain in a subject in need thereof comprising administering a therapeutically effective amount of the compound of claim 1 or 13 to the subject.

25. The method of claim 24 wherein the inflammatory pain is due to inflammatory bowel disease, visceral pain, migraine, post operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases, skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomous snake bite, spider bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, pain, pain due to physical trauma, headache, sinus headache, tension headache, or arachnoiditis.

26. A pharmaceutical composition comprising the compound of claim 14 or 20 and a member selected from the group consisting of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

27. A pharmaceutical composition of claim 26 , wherein the composition is a solid oral dosage form.

28. A pharmaceutical composition of claim 26 , wherein the composition is selected from the group consisting of a syrup, an elixir, and a suspension.

29. A method for treating inflammatory pain in a subject in need thereof comprising administering a therapeutically effective amount of the compound of claim 14 or 20 to the subject.

30. The method of claim 29 wherein the inflammatory pain is due to inflammatory bowel disease, visceral pain, migraine, post operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases, skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomous snake bite, spider bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, pain, pain due to physical trauma, headache, sinus headache, tension headache, or arachnoiditis.