Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof

1. A compound of formula (I):

wherein

G is —NR 7 —CR 8 R 9 — or —CR 8 R 9 —NR 7 —;

L is —(CH 2 ) p —, —CH═CH—, or a bond;

B is phenyl, pyridinyl, pyridazinyl, or pyrimidinyl, wherein each of the phenyl, pyridinyl, pyridazinyl, or pyrimidinyl is optionally substituted from 1 to 3 times with substituents selected from the group consisting of H, alkoxy, —S-alkyl, optionally substituted C 1 -C 6 alkyl, halogen, —CF 3 , and —CN;

R 1 is selected from the group consisting of H, —S(O) q R 11 , —C(O)R 11 , —C(O)NR 10 R 11 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 13 , —NR 13 R 14 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 13 , or —NR 13 R 14 ;

R 2 -R 5 and R 8 -R 9 are each, independently, selected from the group consisting of H, halogen, —OR 10 , —NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O) 2 R 11 , —NR 10 C(O)NR 11 R 12 , S(O) q R 11 , —CN, —C(O)R 11 , —C(O)NR 10 R 11 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and aryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and aryl, is optionally substituted from 1 to 3 times with substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 13 , —NR 13 R 14 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 13 , or

—NR 13 R 14 ;

R 6 is independently selected at each location from the group consisting of H, halogen, —OR 10 , —NR 10 R 11 , NR 10 C(O)R 11 , —NR 10 C(O) 2 R 11 , —NR 10 C(O)NR 11 R 12 , —S(O) q R 11 , —CN, —C(O)R 11 , —C(O)NR 10 R 11 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and aryl, is optionally substituted from 1 to 3 times with substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 13 , —NR 13 R 14 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 13 , or —NR 13 R 14 ;

R 7 is selected from the group consisting of H, —S(O) q R 11 , —C(O)R 11 , —C(O)NR 10 R 11 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, is optionally substituted from 1 to 3 times with substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 13 , —NR 13 R 14 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 13 , or —NR 13 R 14 ;

R 10 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 12 , phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;

R 11 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;

R 12 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or phenyl;

R 13 and R 14 are each independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 12 , phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;

n is 0, 1, 2, or 3;

p is from 2 to 4; and

q is 0, 1, or 2;

with the proviso that when G is —CR 8 R 9 —NR 7 — and B is pyridin-2-yl, L cannot be a bond;

or an oxide thereof, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 is H.

3. The compound according to claim 1 , wherein R 1 is optionally substituted C 1 -C 6 alkyl.

4. The compound according to claim 1 , wherein R 1 is selected from the group consisting of H, —S(O) q R 11 , —C(O)R 11 , —C(O) NR 10 R 11 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl.

5. The compound according to claim 1 , wherein R 7 is H, —C(O)R 11 , or optionally substituted C 1 -C 6 alkyl.

6. The compound according to claim 1 , wherein each of R 8 and R 9 is, independently, H.

7. The compound according to claim 1 , wherein each of R 8 and R 9 is, independently, optionally substituted C 1 -C 6 alkyl.

8. The compound according to claim 1 , wherein L is a bond.

9. The compound according to claim 1 , wherein L is —CH 2 —CH 2 —.

10. The compound according to claim 1 , wherein B is unsubstituted.

11. The compound according to claim 1 , wherein B is substituted with at least one substituent selected from trifluoromethyl, chloro, fluoro, methyl, and methanethio.

12. The compound according to claim 1 , wherein B is selected from the group consisting of phenyl, 4-(trifluoromethyl)phenyl, 4-(methylthio)-phenyl, 5-(trifluoromethyl)pyridin-2-yl, 2-(trifluoromethyl)-pyrimidin-5-yl, 6-(trifluoromethyl)pyridazin-3-yl, 5-fluoro-pyridin-2-yl, 6-methylpyridin-3-yl, 6-(trifluoromethyl)pyridin-3-yl, 5-chloro-pyridin-2-yl, 2,4-dichloro-phenyl, 2,4-difluoro-phenyl, 4-chloro-phenyl, 4-chloro-2-fluoro-phenyl, 3,5-dichloro-pyridin-2-yl, 4-fluoro-phenyl, pyridin-2-yl, and 3,5-difluoro-pyridin-2-yl.

13. The compound according to claim 1 , wherein n is 1.

14. The compound according to claim 1 , wherein n is 2.

15. The compound according to claim 1 , wherein the compound has the formula:

16. The compound according to claim 1 , wherein the compound is selected from the group consisting of

17. The compound according to claim 1 , wherein the compound is an HCl salt.

18. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.

19. A method of treating obesity in a subject in need of weight loss comprising:

selecting a patient in need of weight loss, and

administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

20. The method according to claim 19 further comprising:

administering to the patient a therapeutically effective amount of an anti-obesity adjunct.

21. The method according to claim 20 , wherein the anti-obesity adjunct is selected from the group consisting of phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a serotonergic agent, a dopamine agonist, a melanocyte-stimulating hormone receptor agonist or mimetic, a melanocyte-stimulating hormone analog, a cannabinoid receptor antagonist or inverse agonist, a melanin concentrating hormone receptor antagonist, a serotonin 5-HT 6 receptor antagonist, a serotonin 5-HT 2C receptor agonist, leptin, a leptin analog, a leptin receptor agonist, amylin peptide, an amylin analog, an amylin receptor agonist, a neuropeptide Y receptor modulator, a galanin antagonist, a GI lipase inhibitor or decreaser, a bombesin agonist, dehydroepiandrosterone, a glucocorticoid receptor agonist, a glucocorticoid receptor antagonist, an orexin receptor antagonist, an urocortin binding protein antagonist, an agonist of the glucagon-like peptide-1 receptor, a ciliary neurotrophic factor, and combinations thereof.

22. A method of treating obesity in a subject who has experienced weight loss comprising:

selecting a patient who has experienced weight loss, and

administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

23. A process for preparation of a compound of formula (I):

wherein

G is —NR 7 —CR 8 R 9 — or —CR 8 R 9 —NR 7 —;

L is —(CH 2 ) p —, —CH═CH—, or a bond;

B is phenyl, pyridinyl, pyridazinyl, or pyrimidinyl, wherein each of the phenyl, pyridinyl, pyridazinyl, or pyrimidinyl is optionally substituted from 1 to 3 times with substituents selected from the group consisting of H, alkoxy, —S-alkyl, optionally substituted C 1 -C 6 alkyl, halogen, —CF 3 , and —CN;

R 1 is selected from the group consisting of H, —S(O) q R 11 , —C(O)R 11 , —C(O)NR 10 R 11 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 13 , —NR 13 R 14 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 13 , or —NR 13 R 14 ;

R 2 -R 5 and R 8 -R 9 are each, independently, selected from the group consisting of H, halogen, —OR 10 , —NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O) 2 R 11 , —NR 10 C(O)NR 11 R 12 , —S(O) q R 11 , —CN, —C(O)R 11 , —C(O)NR 10 R 11 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and aryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and aryl, is optionally substituted from 1 to 3 times with substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 13 , —NR 13 R 14 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 13 , or

—NR 13 R 14 ;

R 6 is independently selected at each location from the group consisting of H, halogen, —OR 10 , —NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O) 2 R 11 , —NR 10 C(O)NR 11 R 12 , —S(O) q R 11 , —CN, —C(O)R 11 , —C(O)NR 10 R 11 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, and aryl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and aryl, is optionally substituted from 1 to 3 times with substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 13 , —NR 13 R 14 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 13 , or —NR 13 R 14 ;

R 7 is selected from the group consisting of H, —S(O) q R 11 , —C(O)R 11 , —C(O)NR 10 R 11 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, is optionally substituted from 1 to 3 times with substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 13 , —NR 13 R 14 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 13 , or —NR 13 R 14 ;

R 10 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 12 , phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;

R 11 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;

R 12 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or phenyl;

R 13 and R 14 are each independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 12 , phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;

n is 0, 1, 2, or 3;

p is from 2 to 4; and

q is 0, 1, or 2;

said process comprising:

treating a first intermediate compound of formula II:

wherein J is halogen, under conditions effective to form the product compound,

wherein treating comprises:

reacting the first intermediate with a second intermediate having the structure: