Substituted 4-phenylpiperidines, their preparation and use

1. A compound having the structure:

wherein

R 1 is CF 3 , R 2 is F, R 3 is F, R 4 is H, and R 5 is H,

R 1 is CF 3 , R 2 is F, R 3 is H, R 4 is F, and R 5 is H, or

R 1 is CF 3 , R 2 is F, R 3 is H, R 4 is H, and R 5 is H;

R 6 is H; and

B is a substituted or unsubstituted heterobicycle having the structure:

wherein

n is an integer from 0-2;

α, β, χ, δ, ε, and ϕ are each independently absent or present, and when present each is a bond;

Z 1 is N;

Z 2 is N or N—R 7 ,

wherein R 7 is H, C 1 -C 10 alkyl, or oxetane;

X is C or N; and

Y 1 , Y 2 , Y 3 , and each occurrence of Y 4 are each independently CR 8 , CH 2 , or N—R 9 ,

wherein

R 8 is H, halogen, OCH 3 , CN, or CF 3 ; and

R 9 is H, CN, oxetane, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 4 alkyl) (C 3 -C 6 cycloalkyl), (C 1 -C 6 alkyl)-OCH 3 , (C 1 -C 6 alkyl)-CF 3 , C(O)—(C 1 -C 6 alkyl), C(O) 2 —(C 1 -C 6 alkyl), C(O)—NH 2 C(O)NH—(C 1 -C 6 alkyl), C(O)—(C 6 aryl), C(O)—(C 6 heteroaryl), C(O)-pyrrolidine, C(O)-piperidine, C(O)-piperazine, (C 1 -C 6 alkyl)-CO 2 H, (C 1 -C 6 alkyl)-CO 2 (C 1 -C 6 alkyl) or SO 2 —(C 1 -C 6 alkyl),

wherein when R 1 is CF 3 , R 2 is F, R 3 is H, R 4 is H, and R 5 is H, then B is other than

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein B has the structure:

wherein

n is 0;

R 7 is H, C 1 -C 4 alkyl, or oxetane;

Y 1 and Y 3 are each CH 2 ; and

Y 2 is N—R 9 ,

wherein

R 9 is H, CN, oxetane, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 4 alkyl)(C 3 -C 6 cycloalkyl), (C 1 -C 6 alkyl)-OCH 3 , (C 1 -C 6 alkyl)-CF 3 , C(O)—(C 1 -C 6 alkyl), C(O) 2 —(C 1 -C 6 alkyl), C(O)—NH 2 C(O)NH—(C 1 -C 6 alkyl), C(O)—(C 6 aryl), C(O)—(C 6 heteroaryl), C(O)-pyrrolidine, C(O)-piperidine, C(O)-piperazine, (C 1 -C 6 alkyl)-CO 2 H, (C 1 -C 6 alkyl)-CO 2 (C 1 -C 6 alkyl) or SO 2 —(C 1 -C 6 alkyl),

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein B has the structure:

wherein

n is 1;

R 7 is H, C 1 -C 4 alkyl, or oxetane;

Y 1 , Y 2 and Y 4 are each CH 2 ; and

Y 3 is N—R 9 ,

wherein

R 9 is H, CN, oxetane, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 4 alkyl)(C 3 -C 6 cycloalkyl), (C 1 -C 6 alkyl)-OCH 3 , (C 1 -C 6 alkyl)-CF 3 , C(O)—(C 1 -C 6 alkyl), C(O) 2 —(C 1 -C 6 alkyl), C(O)—NH 2 C(O)NH—(C 1 -C 6 alkyl), C(O)—(C 6 aryl), C(O)—(C 6 heteroaryl), C(O)-pyrrolidine, C(O)-piperidine, C(O)-piperazine, (C 1 -C 6 alkyl)-CO 2 H, (C 1 -C 6 alkyl)-CO 2 (C 1 -C 6 alkyl) or SO 2 —(C 1 -C 6 alkyl),

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein B has the structure:

wherein

n is 1;

R 7 is H, C 1 -C 4 alkyl, or oxetane;

Y 1 , Y 3 and Y 4 are each CH 2 ; and

Y 2 is N—R 9 ,

wherein

R 9 is H, CN, oxetane, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 4 alkyl)(C 3 -C 6 cycloalkyl), (C 1 -C 6 alkyl)-OCH 3 , (C 1 -C 6 alkyl)-CF 3 , C(O)—(C 1 -C 6 alkyl), C(O) 2 —(C 1 -C 6 alkyl), C(O)—NH 2 C(O)NH—(C 1 -C 6 alkyl), C(O)—(C 6 aryl), C(O)—(C 6 heteroaryl), C(O)-pyrrolidine, C(O)-piperidine, C(O)-piperazine, (C 1 -C 6 alkyl)-CO 2 H, (C 1 -C 6 alkyl)-CO 2 (C 1 -C 6 alkyl) or SO 2 —(C 1 -C 6 alkyl),

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein B has the structure:

wherein

R 9 is H, CN, oxetane, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 4 alkyl)(C 3 -C 6 cycloalkyl), (C 1 -C 6 alkyl)-OCH 3 , (C 1 -C 6 alkyl)-CF 3 , C(O)—(C 1 -C 6 alkyl), C(O) 2 —(C 1 -C 6 alkyl), C(O)—NH 2 C(O)NH—(C 1 -C 6 alkyl), C(O)—(C 6 aryl), C(O)—(C 6 heteroaryl), C(O)-pyrrolidine, C(O)-piperidine, C(O)-piperazine, (C 1 -C 6 alkyl)-CO 2 H, (C 1 -C 6 alkyl)-CO 2 (C 1 -C 6 alkyl) or SO 2 —(C 1 -C 6 alkyl).

6. The compound of claim 5 , wherein

wherein R 9 is SO 2 —CH 3 , C(O)—CH 3 , C(O)—CH 2 CH 3 , C(O)—CH 2 CH 2 CH 3 , C(O)—CH(CH 3 ) 2 , C(O)—CH 2 CH(CH 3 ) 2 , C(O)-t-Bu, C(O)—OCH 3 , C(O)—NHCH 3 ,

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein B has the structure:

wherein

Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 8 or N,

wherein each R 8 is independently H, halogen, OCH 3 , CN, or CF 3 ,

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt of the compound.

9. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt of the compound.

10. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt of the compound.

11. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt of the compound.

12. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt of the compound.

13. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt of the compound.

14. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt of the compound.

15. The compound of claim 1 , wherein R 1 is CF 3 , R 2 is F, R 3 is F, R 4 is H, and R 5 is H, or a pharmaceutically acceptable salt of the compound.

16. The compound of claim 1 , wherein R 1 is CF 3 , R 2 is F, R 3 is H, R 4 is F, and R 5 is H, or a pharmaceutically acceptable salt of the compound.

17. The compound of claim 1 , wherein R 1 is CF 3 , R 2 is F, R 3 is H, R 4 is H, and R 5 is H, or a pharmaceutically acceptable salt of the compound.

18. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

19. A method for treating a disease characterized by excessive lipofuscin accumulation in the retina in a mammal afflicted therewith comprising administering to the mammal an effective amount of the compound of claim 1 , wherein the disease characterized by excessive lipofuscin accumulation in the retina is Age-Related Macular Degeneration,dry (atrophic) Age-Related Macular Degeneration, Stargardt Disease, Best disease, adult vitelliform maculopathy or Stargardt-like macular dystrophy.