Dihydro-6-azaphenalene derivatives for the treatment of CNS, oncological diseases and related disorders
In one embodiment, the present application discloses 2-aza-, 2-oxa- and 2-thia-2,3-dihydro-6-azaphenalene compounds and compositions, and methods for treating a neurological disease in a patient in need thereof using the compounds and compositions as disclosed herein.
1. A compound of the formula I:
wherein:
X 1 is —OH or —NR 1 R 2 ;
X 2 is selected from the group consisting of —NR 3 —, —O— and —S(O) 1-2 —;
A 1 is selected from the group consisting of —C(O)— and —CH 2 ;
A 2 is selected from the group consisting of —C(O)— and —CH 2 ;
R 1 and R 2 are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, X—C 1 -C 6 alkyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted —C 1-6 alkyl-C 6-10 aryl, substituted or unsubstituted C 1-6 alkylC(O)—, X—C 1-6 alkylC(O)—, substituted or unsubstituted C 1-6 alkylS(O) 1-2 —, substituted or unsubstituted C 1-6 alkylNR′C(O)—, X—C 1-6 alkylNR′C(O)—, X—C 1-6 alkoxyC(NR″)— and substituted or unsubstituted C 1-6 alkoxyC(NR″)—;
R′ and R″ are each independently selected from the group consisting of H, substituted or unsubstituted C 1-6 alkyl and substituted and unsubstituted —C 1-6 alkyl-C 6-10 aryl;
R 3 is H or selected from the group consisting of substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted —C 1-6 alkyl-C 6-10 aryl, substituted or unsubstituted —C 1-6 alkyl-C 5-10 heteroaryl, substituted or unsubstituted C 1-6 alkylC(O)—, substituted or unsubstituted C 1-6 alkyl-S(O) 1-2 —, substituted or unsubstituted C 1-6 alkylNHC(O)— and substituted or unsubstituted C 1-6 alkoxyC(NR′)—;
R 10 , R 11 and R 12 are each independently H or substituted or unsubstituted C 1-6 alkyl;
R 13 is H or is selected from the group consisting of X, halo, substituted or unsubstituted C 1-6 alkyl;
each X is independently selected from the group consisting of 131 I, 124 I, 125 I, 3 H, 123 I 18 F, 19 F, 75 Br and 76 Br;
or
a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein X 1 is —OH.
3. The compound of claim 1 , wherein X 2 is —NR 3 , wherein R 3 is substituted or unsubstituted C 1-6 alkyl or a substituted or unsubstituted —C 1-6 alkyl-C 6-10 aryl.
4. The compound of claim 3 , wherein R 3 is C 1-6 alkyl-X, wherein X is selected from the group consisting of 131 I, 124 I, 125 I, 3 H 123 I, 18 F, 19 F, 75 Br and 76 Br.
5. The compound of claim 4 , wherein X is 18 F.
6. The compound of claim 1 , wherein A 1 and A 2 are each independently —C(O)—.
7. The compound of claim 1 , wherein R 10 , R 11 , R 12 and R 13 are hydrogen.
8. The compound of claim 1 , wherein R 3 is N-benzyl.
9. A compound of the formula II:
wherein:
X 1 is —OH or —NHR 2 ;
R 1 and R 2 are each independently H, X—C 1-6 alkyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted —C 1-6 alkyl-C 6-10 aryl, X—C 1-6 alkylC(O)—, substituted or unsubstituted C 1-6 alkylC(O)—, X—C 1-6 alkyl-S(O) 1-2 —, substituted or unsubstituted C 1-6 alkyl-S(O) 1-2 —, X—C 1-6 alkylNHC(O)—, substituted or unsubstituted C 1-6 alkylNHC(O)—, X—C 1-6 alkoxyC(NH)— and substituted or unsubstituted C 1-6 alkoxyC(NH)—;
R 3 is H or selected from the group consisting of X—C 1-6 alkyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted —C 1-6 alkyl-C 6-10 aryl, X—C 1-6 alkylC(O)—, substituted or unsubstituted C 1-6 alkylC(O)—, X—C 1-6 alkylS(O) 1-2 substituted or unsubstituted C 1-6 alkylS(O) 1-2 —, substituted or unsubstituted C 1-6 alkylNHC(O)—, X—C 1-6 alkoxyC(NH)— and substituted or unsubstituted C 1-6 alkoxyC(NH)—;
R 10 , R 11 and R 12 are each independently H, X or substituted or unsubstituted C 1-6 alkyl;
R 13 is H or is selected from the group consisting of X, halo, substituted or unsubstituted C 1-6 alkyl;
R′ and R″ are each independently selected from the group consisting of H, substituted or unsubstituted C 1-6 alkyl and substituted or unsubstituted —C 1-6 alkyl-C 6-10 aryl;
each X is independently selected from the group consisting of 131 I, 124 I, 125 I, 3 H, 123 I, 18 F, 19 F, 75 Br and 76 Br;
or
a pharmaceutically acceptable salt thereof.
10. The compound of claim 9 , wherein X 1 is OH and R 10 , R 11 , R 12 and R 13 are hydrogen.
11. The compound of claim 10 , wherein R 3 is substituted or unsubstituted —C 1-6 alkyl-C 6-10 aryl.
12. The compound of claim 9 , wherein:
X 1 is —OH;
R 10 , R 11 and R 12 are hydrogen;
R 3 is C 1-6 alkyl-C 6-10 aryl-X; and
R 13 is H.
13. The compound of claim 9 , wherein R 3 is C 1-6 alkyl-X, wherein X is selected from the group consisting of 131 I, 124 I, 125 I, 3 H, 123 I, 18 F, 19 F, 75 Br and 76 Br.
14. The compound of claim 9 , wherein at least one of R 10 , R 11 , R 12 and R 13 is X.
15. A compound of the formula III:
wherein:
X 1 is —OR 1 or —NHR 2 ;
R 1 is H and R 2 is H, X—C 1-6 alkyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted —C 1-6 alkyl-C 6-10 aryl, X—C 1-6 alkylC(O)—, substituted or unsubstituted C 1-6 alkylC(O)—, X—C 1-6 alkyl-S(O) 1-2 —, substituted or unsubstituted C 1-6 alkyl-S(O) 1-2 —, X—C 1-6 alkylNHC(O)—, substituted or unsubstituted C 1-6 alkylNHC(O)— and substituted, X—C 1-6 alkoxyC(NH)—, or unsubstituted C 1-6 alkoxyC(NH)—;
R 3 is H or selected from the group consisting of X—C 1-6 alkyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted —C 1-6 alkyl-C 6-10 aryl, X—C 1-6 alkylC(O)—, substituted or unsubstituted C 1-6 alkylC(O)—, X—C 1-6 alkylS(O) 1-2 —, substituted or unsubstituted C 1-6 alkylS(O) 1-2 —, X—C 1-6 alkylNHC(O)—, substituted or unsubstituted C 1-6 alkylNHC(O)—, X—C 1-6 alkoxyC(NH)— and substituted or unsubstituted C 1-6 alkoxyC(NH)—;
R 7 is H or is selected from the group consisting of substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkylC(O)—, substituted or unsubstituted C 1-6 alkoxyC(O)—, substituted or unsubstituted —C 1-6 alkyl-C 6-10 aryl and substituted or unsubstituted C 5-10 aryl;
R 10 , R 11 and R 12 are each independently H, X or selected from the group consisting of substituted or unsubstituted C 1-6 alkyl and substituted or unsubstituted C 1-6 alkylC(O)—;
R 13 is H or is selected from the group consisting of X, halo, —OR′, —CN, —SR′, —NR′R″, —NO 2 , —CO 2 R′, —SO 3 R′, substituted or unsubstituted C 1-6 alkyl, —C 1-6 alkyl-SH, substituted or unsubstituted C 1-6 alkoxy-, substituted or unsubstituted C 1-6 alkylC(O)—, substituted or unsubstituted C 1-6 alkylC(S)—, —(CH 2 ) n —NH—(CH 2 ) m —NR′R″, C 1-6 alkylC(NR′)—, C 1-6 alkylC(NOH)—, —(CH 2 ) n —C(NOH)—C 1-6 alkyl, C 6-10 aryl, —C 1-6 alkyl-C 6-10 aryl, —C 1-6 alkyl-C 3-10 heteroaryl and —C 3-10 heteroaryl;
R′ and R″ are each independently selected from the group consisting of H, substituted or unsubstituted C 1-6 alkyl and substituted or unsubstituted —C 1-6 alkyl-C 6-10 aryl;
each X is independently selected from the group consisting of 131 I, 124 I, 125 I, 3 H, 123 I, 18 F, 19 F, 75 Br and 76 Br;
m and n are each independently 1, 2 or 3; or
a pharmaceutically acceptable salt thereof;
provided that when R 7 is phenyl and X 1 is —OH, then R 3 is not benzyl.
16. The compound of claim 15 , wherein X 1 is OH and R 10 , R 11 , R 12 and R 13 are hydrogen.
17. The compound of claim 15 , wherein R 3 is C 1-6 alkyl-C 6-10 aryl.
18. The compound of any claim 15 , wherein:
X 1 is —OH;
R 10 , R 11 and R 12 are hydrogen;
R 3 is —C 1-6 alkyl-C 6-10 aryl; and
R 13 is H or substituted or unsubstituted C 1-6 alkyl.
19. The compound of claim 15 , wherein at least one of R 10 , R 11 , R 12 and R 13 is X.
20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claim 1 , 9 or 15 , and a pharmaceutically acceptable excipient.