4-phenyl substituted tetrahydroisoquinolines therapeutic use thereof

1. A compound of the Formula IA, IB, IIA, IIB, IIIA or IIIB:

wherein:

R 1 is selected from the group consisting 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 benzyl, each of which is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C 1 -C 3 alkyl, halogen, —CN, —OR 8 and —NR 8 R 9 ;

R 2 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 4 -C 7 cycloalkylalkyl and C 1 -C 6 haloalkyl;

R 3 is selected from the group consisting of H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 3 -C 6 cycloalkyl, wherein C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 3 -C 6 cycloalkyl are optionally substituted with 1 to 3 substituents selected independently at each occurrence from OR 8 and NR 8 R 9 ;

R 4 , R 5 and R 6 are each independently selected at each occurrence thereof from the group consisting of H, halogen, —OR 10 , —NO 2 , NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O)NR 11 R 12 , —S(O) n R 11 , —CN, —C(O)R 11 , —C(O) 2 R 11 , —C(O)NR 11 R 12 , C 1 - 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 are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C 1 -C 3 alkyl, halogen, ═O, —CN, —OR 8 , —NR 8 R 9 and phenyl, and wherein phenyl is optionally substituted with 1-3 substituents selected independently at each occurrence from halogen, —CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —OR 8 and —NR 8 R 9 ;

alternatively R 5 and R 6 are —O—C(R 11 ) 2 —O—;

R 7 is selected from the group consisting of H, halogen and OR 10 ;

R 8 and R 9 are each independently selected from the group consisting of H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 1 -C 4 alkoxyalkylalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cylcoalkylalkyl, —C(O)R 12 , phenyl and benzyl, wherein phenyl and benzyl are optionally substituted with 1 to 3 substituents selected independently at each occurrence from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy;

R 10 is selected from the group consisting of 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 and benzyl, wherein phenyl and benzyl are optionally substituted with 1 to 3 substituents selected independently at each occurrence from halogen, —NH 2 , —OH, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy;

R 11 is selected from the group consisting of 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 and benzyl, where phenyl and benzyl are optionally substituted with 1 to 3 substituents selected independently at each occurrence from halogen, —NH 2 , —OH, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy, or R 10 and R 11 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, N-methylpiperazine, morpholine, or thiomorpholine ring, with the proviso that only one of R 8 and R 9 or R 10 and R 11 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperaine, N-methylpiperazine, morpholine, or thiomorpholine ring;

R 12 is selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and phenyl;

X is selected from the group consisting of 0, NR 13 and S, with the proviso that X is not NR 13 when a compound is of Formula (IA);

n is 0, 1, or 2; and,

R 13 is selected from the group consisting of H, C 1 -C 6 alkyl, benzyl and phenyl, wherein C 1 -C 6 alkyl, benzyl and phenyl are optionally substituted with 1-3 substituents independently at each occurrence from halogen, —NH 2 , —OH, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy.

2. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl.

3. The compound of claim 2 , wherein R 1 is CH 3 .

4. The compound of claim 1 , wherein R 2 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkyl.

5. The compound of claim 4 , wherein R 2 is H or C 1 -C 6 alkyl.

6. The compound of claim 5 , wherein R 2 is H.

7. The compound of claim 1 , wherein R 3 is at each occurrence thereof independently H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted with from 1 to 3 of OR 8 or NR 8 R 9 .

8. The compound of claim 7 , wherein R 3 is H or C 1 -C 6 alkyl.

9. The compound of claim 8 , wherein R 3 is H.

10. The compound of claim 1 , wherein R 1 is CH 3 , R 2 is H and R 3 is H.

11. The compound of claim 1 , wherein R 4 , R 5 and R 6 are each independently H, halogen, C 1 -C 6 alkyl or —OR 10 .

12. The compound of claim 11 , wherein at least one of R 4 , R 5 and R 6 is H.

13. The compound of claim 12 , wherein each of R 4 , R 5 and R 6 are H.

14. The compound of claim 12 , wherein one of R 4 , R 5 and R 6 is halogen.

15. The compound of claim 1 , wherein R 1 is CH 3 , R 2 and R 3 are each H, and at least one of R 4 , R 5 and R 6 is H.

16. A compound of Formula (10):

or a pharmaceutically acceptable salt form thereof selected from the group consisting of:

a compound of Formula (10) wherein R 4 is H, R 5 is H and R 6 is H;

a compound of Formula (10) wherein R 4 is H, R 5 is Me and R 6 is H;

a compound of Formula (10) wherein R 4 is Cl, R 5 is H and R 6 is H; and

a compound of Formula (10) wherein R 4 is H, R 5 is F and R 6 is H.

17. The compound of claim 1 , wherein the compound has a structure of Formula (20):

or a pharmaceutically acceptable salt form thereof selected from the group consisting of:

a compound of Formula (20) wherein R 4 is H, R 5 is H and R 6 is H;

a compound of Formula (20) wherein R 4 is H, R 5 is Me and R 6 is H;

a compound of Formula (20) wherein R 4 is H, R 5 is Cl and R 6 is H;

a compound of Formula (20) wherein R 4 is H, R 5 is F and R 6 is H; and

a compound of Formula (20) wherein R 4 is F, R 5 is H and R 6 is F.

18. A compound of Formula (30):

or a pharmaceutically acceptable salt form thereof selected from the group consisting of:

a compound of Formula (30) wherein R 3 is H, R 4 is H, R 5 is H and R 6 is H;

a compound of Formula (30) wherein R 3 is H, R 4 is F, R 5 is F and R 6 is H;

a compound of Formula (30) wherein R 3 is H, R 4 is F, R 5 is H and R 3 is F;

a compound of Formula (30) wherein R 3 is H, R 4 is H, R 5 is F and R 6 is H;

a compound of Formula (30) wherein R 3 is H, R 4 is Cl, R 5 is H and R 6 is H;

a compound of Formula (30) wherein R 3 is H, R 4 is H, R 5 is Cl and R 6 is H;

a compound of Formula (30) wherein R 3 is H, R 4 is H, R 5 is Cl and R 6 is F;

a compound of Formula (30) wherein R 3 is H, R 4 is H, R 5 is F and R 6 is Cl;

a compound of Formula (30) wherein R 3 is H, R 4 is F, R 5 is H and R 6 is Cl;

a compound of Formula (30) wherein R 3 is H, R 4 is H, R 5 is OMe and R 6 is H; and

a compound of Formula (30) wherein R 3 is H, R 4 is F, R 5 is H and R 6 is H.

19. The compound of claim 1 , wherein the compound has a structure of Formula (40):

or a pharmaceutically acceptable salt form thereof selected from the group consisting essentially of:

a compound of Formula (40) wherein R 3 is H, R 4 is H, R 5 is H and R 6 is H;

a compound of Formula (40) wherein R 3 is H, R 4 is F, R 5 is F and R 6 is H;

a compound of Formula (40) wherein R 3 is H, R 4 is F, R 5 is H and R 6 is F;

a compound of Formula (40) wherein R 3 is H, R 4 is F, R 5 is H and R 6 is H;

a compound of Formula (40) wherein R 3 is H, R 4 is H, R 5 is F and R 6 is H;

a compound of Formula (40) wherein R 3 is H, R 4 is Cl, R 5 is H and R 6 is H;

a compound of Formula (40) wherein R 3 is H, R 4 is H, R 5 is Cl and R 6 is H;

a compound of Formula (40) wherein R 3 is H, R 4 is H, R 5 is Cl and R 6 is F;

a compound of Formula (40) wherein R 3 is H, R 4 is H, R 5 is F and R 6 is Cl;

a compound of Formula (40) wherein R 3 is H, R 4 is F, R 5 is H and R 6 is Cl;

a compound of Formula (40) wherein R 3 is H, R 4 is H, R 5 is OMe and R 6 is H;

a compound of Formula (40) wherein R 3 is Me, R 4 is H, R 5 is H and R 6 is H;

a compound of Formula (40) wherein R 3 is Et, R 4 is H, R 5 is H and R 6 is H; and

a compound of Formula (40) wherein R 3 is CH 2 OH, R 4 is H, R 5 is H and R 6 is H.

20. A compound of Formula (80):

or a pharmaceutically acceptable salt form thereof selected from the group consisting of:

a compound of Formula (80) wherein R 4 is H, R 5 is H and R 6 is H;

a compound of Formula (80) wherein R 4 is H, R 5 is F and R 6 is H; and

a compound of Formula (80) wherein R 4 is H, R 5 is F and R 6 is F.

21. The compound of claim 1 , wherein the compound has a structure of Formula (90);

or a pharmaceutically acceptable salt form thereof selected from the group consisting of:

a compound of Formula (90) wherein R 4 is H, R 5 is H and R 6 is H,

a compound of Formula (90) wherein R 4 is H, R 5 is F and R 6 is F; and

a compound of Formula (90) wherein R 4 is H, R 5 is F and R 6 is H.

22. A compound of Formula (110):

or a pharmaceutically acceptable salt form thereof selected from the group consisting of:

a compound of Formula (110) wherein R 4 is H, R 5 is H and R 6 is H;

a compound of Formula (110) wherein R 4 is H, R 5 is F and R 6 is F;

a compound of Formula (110) wherein R 4 is H, R 5 is F and R 6 is H;

a compound of Formula (110) wherein R 4 is H, R 5 is H and R 6 is Cl;

a compound of Formula (110) wherein R 4 is H, R 5 is Cl and R 6 is F;

a compound of Formula (110) wherein R 4 is H, R 5 is F and R 6 is Cl; and

a compound of Formula (110) wherein R 4 is H, R 5 is OMe and R 6 is H.

23. The compound of claim 1 wherein the compound has a structure of Formula (120):

or a pharmaceutically acceptable salt form thereof selected from the group consisting of:

a compound of Formula (120) wherein R 4 is H, R 5 is H and R 6 is H;

a compound of Formula (120) wherein R 4 is H, R 5 is F and R 6 is F;

a compound of Formula (120) wherein R 4 is H, R 5 is F and R 6 is H;

a compound of Formula (120) wherein R 4 is H, R 5 is H and R 6 is Cl;

a compound of Formula (120) wherein R 4 is H, R 5 is Cl and R 6 is F;

a compound of Formula (120) wherein R 4 is H, R 5 is OMe and R 6 is H; and

a compound of Formula (120) wherein R 4 is H, R 5 is F and R 6 is Cl.

24. A compound of Formula (140):

or a pharmaceutically acceptable salt form thereof selected from the group consisting of:

a compound of Formula (140) wherein R 4 is H, R 5 is H and R 6 is H;

a compound of Formula (140) wherein R 4 is H, R 5 is F and R 6 is H;

a compound of Formula (140) wherein R 4 is H, R 5 is F and R 6 is Cl;

a compound of Formula (140) wherein R 4 is H, R 5 is Cl and R 6 is F;

a compound of Formula (140) wherein R 4 is H, R 5 is H and R 6 is Cl;

a compound of Formula (140) wherein R 4 is H, R 5 is OMe and R is H;

a compound of Formula (140) wherein R 4 is H, R 5 is F and R 6 is F.

25. The compound of claim 1 , wherein the compound has a structure of Formula (150);

or a pharmaceutically acceptable salt form thereof selected from the group consisting of:

a compound of Formula (150) wherein R 4 is H, R 5 is H and R 6 is H;

a compound of Formula (150) wherein R 4 is H, R 5 is F and R 6 is H;

a compound of Formula (150) wherein R 4 is H, R 5 is F and R 6 is Cl;

a compound of Formula (150) wherein R 4 is H, R 5 is Cl and R 6 is F;

a compound of Formula (150) wherein R 4 is H, R 5 is H and R 6 is Cl;

a compound of Formula (150) wherein R 4 is H, R 5 is OMe and R 6 is H; and

a compound of Formula (150) wherein R 4 is H, R 5 is F and R 6 is F.

26. A compound of Formula (170):

or a pharmaceutically acceptable salt form thereof selected from the group consisting of:

a compound of Formula (170) wherein R 4 is H, R 5 is H and R 6 is H;

a compound of Formula (170) wherein R 4 is H, R 5 is F and R 6 is H; and

a compound of Formula (170) wherein R 4 is H, R 5 is F and R 6 is F.

27. The compound of claim 1 , wherein the compound has a structure of Formula (180):

or a pharmaceutically acceptable salt form thereof selected from the group consisting of:

a compound of Formula (180) wherein R 4 is H, R 5 is H and R 6 is H;

a compound of Formula (180) wherein R 4 is H, R 5 is F and R 6 is H; and

a compound of Formula (180) wherein R 4 is H, R 5 is F and R 6 is F.

28. A compound of claim 1 selected from the group consisting of:

(R)-2-methyl-4-phenyl-1,2,3,4,8,9-hexahydro-furo[2,3-h]isoquinoline;

(S)-2-methyl-4-phenyl-1,2,3,4,8,9-hexahydro-furo[2,3-h]isoquinoline;

(R)-7-methyl-5-phenyl-5,6,7,8-tetrahydro-furo[3,2-g]isoquinoline;

(S)-7-methyl-5-phenyl-5,6,7,8-tetrahydro-furo[3,2-g]isoquinoline;

(R)-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2, 3-h]isoquinoline;

(S)-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(R)-4-(3, 4-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2, 3-h]isoquinoline;

(S)-4-(3,4-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo [2,3-h]isoquinoline;

(R)-2-methyl-4-phenyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(S)-2-methyl-4-phenyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(R)-4-(4-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(S)-4-(4-chloro-phenyl)-2-methyl-1,2,3, 4-tetrahydro-furo[2,3-h]isoquinoline;

(R)-8-methyl-6-phenyl-2,3,6,7,8,9-hexahydro-furo[3,2-h]isoquinoline;

(S)-8-methyl-6-phenyl-2,3,6,7,8,9-hexahydro-furo [3,2-h]isoquinoline;

(R)-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(S)-4-(4-fluoro-phenyl)-2-methyl-1,2,3, 4-tetrahydro-furo[2,3-h]isoquinoline;

(R)-4-(3,5-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(S)-4-(3,5-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(R)-2-methyl-4-phenyl-2,3,4,7-tetrahydro-1H-pyrrolo [2,3-h]isoquinoline; and

(S)-2-methyl-4-phenyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline.

29. A compound of claim 1 selected from the group consisting of:

(+)-2-methyl-4-phenyl-1,2,3,4,8,9-hexahydro-furo[2,3-h]isoquinoline;

(−)-2-methyl-4-phenyl-1,2,3,4,8,9-hexahydro-furo[2,3-h]isoquinoline;

(+)-7-methyl-5-phenyl-5,6,7,8-tetrahydro-furo[3,2-g]isoquinoline;

(−)-7-methyl-5-phenyl-5,6,7,8-tetrahydro-furo[3,2-g]isoquinoline;

(+)-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(−)-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(+)-4-(3,4-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(−)-4-(3,4-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(+)-2-methyl-4-phenyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(−)-2-methyl-4-phenyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(+)-4-(4-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(−)-4-(4-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(+)-8-methyl-6-phenyl-2,3,6,7,8,9-hexahydro-furo[3,2-h]isoquinoline;

(−)-8-methyl-6-phenyl-2,3,6,7,8,9-hexahydro-furo[3,2-h]isoquinoline;

(+)-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(−)-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(+)-4-(3,5-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(−)-4-(3,5-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;

(+)-2-methyl-4-phenyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline; and

(−)-2-methyl-4-phenyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline.

30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 .