Opioid antagonists
View Patent ↗Certain quinolizidine and octahydropyridopyrazine compounds, pharmaceutical compositions, and methods of their use, inter alia, as opioid receptor antagonists are disclosed.
1. A compound of formula I:
wherein:
R 1 is —OH, —OR a , —CH 2 OH, —C(═O)OR 6 , —C(═O)NR 6 R 7 , or —NR 6 R 7 ;
R 2 and R 3 are each independently alkyl or alkenyl;
R 4 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;
R 5 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl, —C(═O)OR 8a , —S(═O) 2 R 8a , —C(═O)R 8b , or —C(═O)NR 8b R 8c ;
R 6 is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;
R 7 is H, alkyl, aralkyl, or aryl;
R 8a is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aralkyl, or aryl;
R 8b and R 8c are each independently H, alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aralkyl, or aryl; or R 8b and R 8c taken together with the nitrogen atom to which they are connected form a 4- to 8-membered heterocycloalkyl ring;
R a is a hydroxyl protecting group; and
m and n are each 1;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein R 1 is —OH, —CH 2 OH, —C(═O)OR 6 , —C(═O)NR 6 R 7 , or —NR 6 R 7 .
3. A compound according to claim 1 , having the structure of formula IIa:
4. A compound according to claim 3 , having the structure of formula IIb:
5. A compound according to claim 2 , wherein R 1 is —OH, —NR 6 R 7 , or —C(═O)NR 6 R 7 .
6. A compound according to claim 5 , wherein R 1 is —OH, —NHR 7 , or —C(═O)NHR 7 .
7. A compound according to claim 6 , wherein R 1 is —OH or —C(═O)NH 2 .
8. A compound according to claim 1 , wherein R 2 and R 3 are each independently C 1 -C 3 alkyl.
9. A compound according to claim 8 , wherein R 2 and R 3 are each methyl.
10. A compound according to claim 1 , wherein R 4 is H, alkyl, cycloalkyl, aryl, or aralkyl.
11. A compound according to claim 10 , wherein R 4 is H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, or C 6 -C 10 arylC 1 -C 3 alkyl.
12. A compound according to claim 11 , wherein R 4 is H.
13. A compound according to claim 11 , wherein R 4 is cyclohexyl, phenyl, or benzyl, each of which is optionally substituted.
14. A compound according to claim 1 , wherein R 5 is H, alkyl, aryl, cycloalkylalkyl, aralkyl, alkylaralkyl, heteroarylalkyl, —C(═O)R 8b , —S(═O) 2 R 8a , or —C(═O)NR 8b R 8c .
15. A compound according to claim 14 , wherein R 5 is —C(═O)R 8b or —S(═O) 2 R 8a .
16. A compound according to claim 15 , wherein R 5 is —C(═O)R 8b .
17. A compound according to claim 14 , wherein R 8b and R 8c , taken together with the nitrogen atom to which they are connected, form a 4- to 8-membered heterocycloalkyl ring.
18. A compound according to claim 17 , wherein R 8b and R 8c , taken together with the nitrogen atom to which they are connected, form an optionally substituted morpholine ring.
19. A compound according to claim 16 , wherein R 8b is aryl or aralkyl.
20. A compound according to claim 14 , wherein R 5 is H.
21. A compound according to claim 14 , wherein R 5 is H, alkyl, aryl, cycloalkylalkyl, aralkyl, alkylaralkyl, or heteroarylalkyl.
22. A compound according to claim 21 , wherein R 5 is alkyl, aryl, cycloalkylalkyl, aralkyl, alkylaralkyl, or heteroarylalkyl.
23. A compound according to claim 22 , wherein R 5 is C 1 -C 3 alkyl, C 6 aryl, C 3 -C 6 cycloalkylC 1 -C 3 alkyl, C 6 -C 10 arylC 1 -C 3 alkyl, C 1 -C 3 alkylC 6 -C 10 arylC 1 -C 3 alkyl, or C 5 -C 10 heteroarylC 1 -C 3 alkyl.
24. A compound according to claim 23 , wherein R 5 is methyl, cyclohexylmethyl, benzyl, or thienylmethyl, each of which is optionally substituted.
25. A compound according to claim 24 , wherein R 5 is benzyl, optionally substituted with C 1 -C 6 alkyl, halo, hydroxy, or heteroaryl.
26. A compound according to claim 25 , wherein R 5 is 2-chlorobenzyl, 3-chlorobenzyl, 2-hydroxylbenzyl, 2-methylbenzyl, 3-methylbenzyl, 2,4,5-trimethylbenzyl, or 2-(pyrid-4-yl)benzyl.
27. A compound according to claim 24 , wherein R 5 is methyl substituted with carboxy.
28. A compound according to claim 1 , wherein R 6 is H, alkyl, alkylcycloalkyl, or aralkyl.
29. A compound according to claim 1 , wherein one of R 4 and R 5 is H.
30. A compound according to claim 1 , wherein the compound is:
1-(8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)-2-phenylethanone;
3-(7,8-dimethyl-2-phenethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
(8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)(phenyl)methanone;
3-(2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(phenylsulfonyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2,7,8-trimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
2-(8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)acetic acid;
3-(8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)propanoic acid;
3-(2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;
3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;
3-(3-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(3-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(3-cyclohexyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(3-methoxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(pyridin-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(cyclohexylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(4-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(2,5-dimethylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(thiophen-3-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(furan-3-ylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(pyridin-3-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(4-tert-butylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(2-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(4-phenoxybenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(pyridin-4-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(3-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(3-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(3-phenoxybenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(thiophen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(4-methoxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(4-ethylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(naphthalen-1-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
2-(8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)phenol;
3-(2-(4-isopropylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(furan-2-ylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(2-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(3-hydroxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(4-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(naphthalen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(3-(benzyloxy)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(4-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(2,3-dichlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(quinolin-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(2-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(4-(benzyloxy)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(3-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
methyl 4-((8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)benzoate;
3-(2-(4-(dimethylamino)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(4-(pyridin-3-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(quinolin-3-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
methyl 3-((8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)benzoate;
3-(2-(4-1H-imidazol-1-yl)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(biphenyl-4-ylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(quinolin-4-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(2,4,5-trimethylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(4-hydroxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(4-hydroxyphenyl)-1-(8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)propan-1-one; or
(7-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)(8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methanone;
or a pharmaceutically acceptable salt thereof.
31. A compound according to claim 30 , wherein the compound is:
1-((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)-2-phenylethanone;
3-((7R,8R,9αR)-7,8-dimethyl-2-phenethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)(phenyl)methanone;
3-((7R,8R,9αR)-2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(phenylsulfonyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((3S,7R,8R,9αR)-2,7,8-trimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
2-((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)acetic acid;
3-((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)propanoic acid;
3-((3S,7R,8R,9αR)-2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((3S,7R,8R,9αR)-2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;
3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;
3-((3S,7R,8R,9αR)-3-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((3R,7R,8R,9αR)-3-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((3S,7R,8R,9αR)-3-cyclohexyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(3-methoxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(pyridin-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(cyclohexylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(4-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(2,5-dimethylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(thiophen-3-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(furan-3-ylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(pyridin-3-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(4-tert-butylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(2-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(4-phenoxybenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(pyridin-4-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(3-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(3-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(3-phenoxybenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(thiophen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(4-methoxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(4-ethylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(naphthalen-1-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
2-(((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)phenol;
3-((7R,8R,9αR)-2-(4-isopropylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(furan-2-ylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(2-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(3-hydroxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(4-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(naphthalen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(3-(benzyloxy)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(4-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(2,3-dichlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(quinolin-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(2-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(4-(benzyloxy)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(3-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
methyl 4-(((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)benzoate;
3-((7R,8R,9αR)-2-(4-(dimethylamino)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(4-(pyridin-3-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(quinolin-3-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
methyl 3-(((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)benzoate;
3-((7R,8R,9αR)-2-(4-(1H-imidazol-1-yl)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(biphenyl-4-ylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(quinolin-4-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(2,4,5-trimethylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(4-hydroxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(4-hydroxyphenyl)-1-((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)propan-1-one; or
((R)-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)methanone;
or a pharmaceutically acceptable salt thereof.
32. A compound according to claim 30 , wherein the compound is:
(8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)(phenyl)methanone;
3-(2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;
3-(3-cyclohexyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(cyclohexylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(thiophen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(2-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(2-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
2-(8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)acetic acid;
3-(7,8-dimethyl-2-(2-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(3-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(3-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
2-((8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)phenol;
3-(2-(4-hydroxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(4-hydroxyphenyl)-1-((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)propan-1-one; or
((R)-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)methanone;
or a pharmaceutically acceptable salt thereof.
33. A compound according to claim 31 , wherein the compound is:
((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)(phenyl)methanone;
3-((7R,8R,9αR)-2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;
3-((3S,7R,8R,9αR)-3-cyclohexyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(cyclohexylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(thiophen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(2-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(2-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
2-((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)acetic acid;
3-((7R,8R,9αR)-7,8-dimethyl-2-(2-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(3-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(3-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol; or
2-(((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)phenol;
or a pharmaceutically acceptable salt thereof.
34. A compound according to claim 32 , wherein the compound is:
(8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)(phenyl)methanone;
3-(2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;
3-(3-cyclohexyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2-(cyclohexylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(thiophen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(2-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol; or
3-(2-(2-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
or a pharmaceutically acceptable salt thereof.
35. A compound according to claim 33 , wherein the compound is:
((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)(phenyl)methanone;
3-((7R,8R,9αR)-2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;
3-((3S,7R,8R,9αR)-3-cyclohexyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2-(cyclohexylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(thiophen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(2-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol; or
3-((7R,8R,9αR)-2-(2-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
or a pharmaceutically acceptable salt thereof.
36. A compound according to claim 34 , wherein the compound is:
(8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)(phenyl)methanone;
3-(2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol; or
3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;
or a pharmaceutically acceptable salt thereof.
37. A compound according to claim 35 , wherein the compound is:
((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)(phenyl)methanone;
3-((7R,8R,9αR)-2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol; or
3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;
or a pharmaceutically acceptable salt thereof.
38. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier; and
an effective amount of a compound according to claim 2 .
39. A compound of formula III:
wherein:
R 1 is —OH, —OR a , —CH 2 OH, —C(═O)OR 6 , —C(═O)NR 6 R 7 , or —NR 6 R 7 ;
R 2 and R 3 are each independently alkyl or alkenyl;
R 4 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;
R 5 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl, heterocycloalkylalkyl, —C(═O)OR 8a , —S(═O) 2 R 8a , —C(═O)R 8b , or —C(═O)NR 8b R 8c ;
R 6 is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;
R 7 is H, alkyl, aralkyl, or aryl;
R 8a is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aralkyl, or aryl;
R 8b and R 8c are each independently H, alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, heteroarylalkyl, aralkyl, or aryl; or R 8b and R 8c taken together with the nitrogen atom to which they are connected form a 4- to 8-membered heterocycloalkyl ring;
R a is a hydroxyl protecting group; and
m and n are each 1;
or a pharmaceutically acceptable salt thereof.
40. A compound according to claim 39 , wherein R 1 is —OH, —CH 2 OH, —C(═O)OR 6 , —C(═O)NR 6 R 7 , or —NR 6 R 7 .
41. A compound according to claim 39 , having the structure of formula IVa:
42. A compound according to claim 41 , having the structure of formula IVb:
43. A compound according to claim 40 , wherein R 1 is —OH, —NR 6 R 7 , or —C(═O)NR 6 R 7 .
44. A compound according to claim 43 , wherein R 1 is —OH, —NHR 7 , or —C(═O)NHR 7 .
45. A compound according to claim 44 , wherein R 1 is —OH or —C(═O)NH 2 .
46. A compound according to claim 39 , wherein R 2 and R 3 are each Independently C 1 -C 3 alkyl.
47. A compound according to claim 46 , wherein R 2 and R 3 are each methyl.
48. A compound according to claim 39 , wherein R 5 is —C(═O)R 8b .
49. A compound of claim 48 , wherein R 8b is heterocycloalkyl or aralkyl.
50. A compound according to claim 49 , wherein R 8b is heterocycloalkyl.
51. A compound according to claim 50 wherein R 8b is C 5 -C 15 heterocycloalkyl.
52. A compound according to claim 51 wherein R 8b is C 9 -C 14 heterocycloalkyl.
53. A compound according to claim 52 , wherein R 8b is tetrahydroquinolinyl or tetrahydroisoquinolinyl, each optionally substituted.
54. A compound according to claim 53 , wherein R 8b is 1,2,3,4-tetrahydroisoquinolin-3-yl or 1,2,3,4-tetrahydroquinolin-3-yl, each optionally substituted.
55. A compound according to claim 54 , wherein R 8b is optionally substituted with at least one hydroxy, alkyl, or C(═O)N(alkyl)(alkyl).
56. A compound according to claim 55 , wherein the 3-yl stereocenter of the 1,2,3,4-tetrahydroisoquinolin-3-yl or 1,2,3,4-tetrahydroquinolin-3-yl is optically enriched in one of its two enantiomeric forms.
57. A compound according to claim 56 , wherein the 3-yl stereocenter of the 1,2,3,4-tetrahydroisoquinolin-3-yl or 1,2,3,4-tetrahydroquinolin-3-yl is optically enriched in its (R)-enantiomeric form.
58. A compound according to claim 57 , wherein the 3-yl stereocenter of the 1,2,3,4-tetrahydroisoquinolin-3-yl or 1,2,3,4-tetrahydroquinolin-3-yl is substantially optically enriched in its (R)-enantiomeric form.
59. A compound according to claim 58 , wherein R 8b is substantially optically pure:
60. A compound according to claim 39 , wherein R 5 is heterocycloalkylalkyl or aralkyl.
61. A compound according to claim 60 , wherein R 5 is heterocycloalkylalkyl.
62. A compound according to claim 61 wherein R 5 is C 6 -C 20 heterocycloalkylalkyl.
63. A compound according to claim 62 wherein R 5 is C 9 -C 14 heterocycloalkylalkyl.
64. A compound according to claim 63 , wherein R 5 is tetrahydroquinolinylmethyl or tetrahydroisoquinolinylmethyl, each optionally substituted.
65. A compound according to claim 64 , wherein R 5 is 1,2,3,4-tetrahydroisoquinolin-3-ylmethyl or 1,2,3,4-tetrahydroquinolin-3-ylmethyl, each optionally substituted.
66. A compound according to claim 65 wherein R 5 is optionally substituted with at least one hydroxy, alkyl, or C(═O)N(alkyl)(alkyl).
67. A compound according to claim 66 , wherein the 3-yl stereocenter of the 1,2,3,4-tetrahydroisoquinolin-3-yl or 1,2,3,4-tetrahydroquinolin-3-yl is optically enriched in one of its two enantiomeric forms.
68. A compound according to claim 67 , wherein the 3-yl stereocenter of the 1,2,3,4-tetrahydroisoquinolin-3-yl or 1,2,3,4-tetrahydroquinolin-3-yl is optically enriched in its (R)-enantiomeric form.
69. A compound according to claim 68 , wherein the 3-yl stereocenter of the 1,2,3,4-tetrahydroisoquinolin-3-yl or 1,2,3,4-tetrahydroquinolin-3-yl is substantially optically enriched in its (R)-enantiomeric form.
70. A compound according to claim 69 , wherein R 5 is substantially optically pure:
71. A compound according to claim 39 , wherein R 4 is H, alkyl, cycloalkyl, aryl, or aralkyl.
72. A compound according to claim 71 , wherein R 4 is C 1 -C 3 alkyl.
73. A compound according to claim 72 , wherein R 4 is isopropyl.
74. A compound according to claim 48 , wherein R 8b is aryl or aralkyl.
75. A compound according to claim 74 , wherein R 8b is aryl or optionally substituted phenethyl.
76. A compound according to claim 75 , wherein R 8b is optionally substituted phenethyl.
77. A compound according to claim 76 , wherein R 8b is 2-(4-hydroxyphenyl)ethyl.
78. A compound according to claim 39 , wherein the compound is:
3-(4-hydroxyphenyl)-1-(8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)propan-1-one; or
(7-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)-(8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)methanone;
or a pharmaceutically acceptable salt thereof.
79. A compound according to claim 78 , wherein the compound is:
3-(4-hydroxyphenyl)-1-((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)propan-1-one; or
((R)-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)methanone;
or a pharmaceutically acceptable salt thereof.
80. A compound according to claim 39 , wherein the compound is:
3-(4-hydroxyphenyl)-1-(8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)propan-1-one;
(7-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)-(8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)methanone;
1-(8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)ethanone;
methyl-3-(2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzoate;
3-(2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzoic acid;
3-(7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(3-isopropyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(2,7,8-trimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
1-(8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)ethanone;
1-(8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)-3-phenylpropan-1-one;
3-(7,8-dimethyl-2-(3-phenylpropyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-(7,8-dimethyl-2-(methylsulfonyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol; or
8-(3-hydroxyphenyl)-7,8-dimethyl-N-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazine-2(6H)-carboxamide;
or a pharmaceutically acceptable salt thereof.
81. A compound according to claim 39 , wherein the compound is:
3-(4-hydroxyphenyl)-1-((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)propan-1-one;
((R)-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methanone;
1-((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)ethanone;
methyl-3-((3S,7R,8R,9αR)-2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzoate;
3-((3S,7R,8R,9αR)-2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzoic acid;
3-((3R,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((3S,7R,8R,9αR)-3-Isopropyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-2,7,8-trimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
1-((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)ethanone;
1-((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)-3-phenylpropan-1-one;
3-((7R,8R,9αR)-7,8-dimethyl-2-(3-phenylpropyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;
3-((7R,8R,9αR)-7,8-dimethyl-2-(methylsulfonyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol; or
(7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-N-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazine-2(6H)-carboxamide;
or a pharmaceutically acceptable salt thereof.
82. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier; and
an effective amount of a compound according to claim 40 .
83. A compound according to claim 1 , wherein R 5 is —C(═O)R 8b .
84. A compound according to claim 83 , wherein R 8b is aryl.
85. A compound according to claim 84 , wherein R 8b is aryl substituted with halo.
86. A compound according to claim 85 , wherein R 8b is aryl substituted with fluoro.
87. A compound according to claim 85 , wherein R 8b is phenyl substituted with halo
88. A compound according to claim 87 , wherein R 8b is phenyl substituted with fluoro.
89. A compound according to claim 1 , wherein R 5 is H.
90. A compound according to claim 37 , which is ((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)(phenyl)methanone.