Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof
View Patent ↗The present invention relates to tetrahydro-azacarboline derivatives of formula (I): having the substituents as described herein which are melanin-concentrating hormone (MCH-1) receptor antagonists. The present invention also relates to pharmaceutical compositions including these compounds, and methods of preparation and use thereof.
1. A compound of formula (I):
wherein
G is —NR 8 —CR 9 R 10 —or —CR 9 R 10 —NR 8 —;
X is CR 16 ;
Y is C;
W is C;
Q is C;
Z is N;
L is —(CH 2 ) p —O—, —(CH 2 ) p —, —CH═CH—, or a bond;
A is C or CH;
B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of the aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substituted with from 1 to 3 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 optionally present and, if present, is selected from the group consisting of H, —S(O) q R 12 , —C(O) R 12 ,—C(O)NR 11 R 12 , C 6 -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 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, heterocyclyl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 14 ,—NR 14 R 15 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, alkoxy, —CN, ——OR 14, or —NR 14 R 15;
R 2 , R 3 , R 4 , R 5 , R 9 , and R 10 are each, independently, selected from the group consisting of H, halogen, —OR 11 , —NR 11 R 12 , —NR 11 C(O)R 12 , —NR 11 C(O) 2 R 12 , —NR 13 C(O)NR 12 R 13 , —S(O) q R l2 , —CN, —C(O)R 12 , —C(O)NR 11 R 12 , 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, 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, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 14 , —NR 14 R 15 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 14 , or —NR 14 R 15 ; or R 2 and R 3 or R 4 and R 5 can combine to form an oxo, thio, imine, cycloalkyl, or heterocycle group containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;
R 6 is independently selected at each location from the group consisting of H, halogen, —OR 11, —NR 11 C(O)R 12 , —NR 11 C(O) 2 R 12 , —NR 13 C(O)NR 12 R 13 , —S(O) q R 12 , —CN, —C(O)R 12 , —C(O)NR 11 R 12 , 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, 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, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 14 , —NR 14 R 15 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 14 , or —NR 14 R 15 ;
R 7 is optionally present and, if present, is selected from the group consisting of H, halogen, —OR 11 , —NR 11 R 12 , —NR 11 C(O)R 12 , —NR 11 C(O) 2 NR 12 , —NR 13 C(O)NR 12 R 13 , —S(O) q R l2 , —CN, —C(O)R 12 , —C(O)NR 11 R 12 , 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, 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, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 14 , —NR 14 R 15 , 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 14 , or —NR 14 R 15 ;
R 8 is selected from the group consisting of H, —S(O) q R 12, —C(O)R 12 , —C(O)NR 11 R 12 , 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 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, heterocyclyl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 14 , —NR 14 R 15 , 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 14 , or —NR 14 R 15;
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, —C(O)R 13 , 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 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 13 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or phenyl;
R 14 and R 15 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 13 , 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;
R 16 is selected from the group consisting of H, halogen, —OR 11 , —NR 11 R 12 —NR 11 C(O)R 12 , —NR 11 C(O) 2 R 12 , —NR 12 C(O)NR 12 R 13 ,—S(O) q R 12 , —CN, —C(O)R 12 , —C (O)NR 11 R 12 , 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, 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, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 14 , —NR 14 R 15 , 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 14 , or —NR 14 R 15 ;
n is 0, 1, 2, or 3;
p is from 1 to 4;
q is 0, 1, or 2; and
represents an optional double bond,
or a pharmaceutically acceptable salt thereof or a solvate thereof.
2. The compound according to claim 1 , wherein R 1 is H or C 1 -C 6 alkyl.
3. The compound according to claim 2 , wherein R 1 is H.
4. The compound according to claim 2 , wherein R 1 is C 1 -C 6 alkyl.
5. The compound according to claim 1 , wherein X is CH.
6. The compound according to claim 1 , wherein L is a bond.
7. The compound according to claim 1 , wherein L is —CH 2 —O—.
8. The compound according to claim 1 , wherein L is —CH 2 -CH 2 -.
9. The compound according to claim 1 , wherein B is phenyl, pyridinyl, pyridazinyl, or pyrimidinyl.
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 structure (IV):
16. The compound according to claim 1 , wherein the compound has the formula:
17. The compound according to claim 1 , wherein the compound is selected from the group consisting of:
18. The compound according to claim 1 , wherein the compound is an HC1 salt.
19. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
20. 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.
21. The method according to claim 20 further comprising:
administering to the patient a therapeutically effective amount of an anti-obesity adjunct selected from the group consisting of phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, leptin, amylin peptide, dehydroepiandrosterone, and combinations thereof.
22. A process for preparation of a product compound of formula (I):
wherein
G is —NR 8 —CR 9 R 10 —or —CR 9 R 10 —NR 8 —;
X is CR 16 ;
Y is C;
W is C;
Q is C;
Z is N;
L is —(CH 2 ) p —O—, —(CH 2 ) p —, —CH═CH—, or a bond;
A is C or CH;
B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of the aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substituted with from 1 to 3 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 optionally present and, if present, is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl;
R 2 , R 3 , R 4 , R 5 , R 9 , and R 19 are each, independently, selected from the group consisting of H, C l -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and aryl;
R 6 is independently selected at each location from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and aryl;
R 7 is optionally present and, if present, is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and aryl;
R 8 is selected from the group consisting of H, —C(O)R 12 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl;
R 11 is H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and phenyl;
R is H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and phenyl;
R 13 is C 1 -C 4 alkyl or phenyl;
R 14 and R 15 are each independently H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and phenyl;
R 16 is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and aryl;
n is 0, 1, 2, or 3;
p is from 1 to 4; and
represents an optional double bond,
said process comprising:
treating a first intermediate compound of formula V:
wherein J is a halogen, under conditions effective to form the product compound,
wherein treating comprises:
reacting the first intermediate with a second intermediate having the structure: