Pro-neurogenic compounds
This invention relates generally to stimulating neurogenesis (e.g., post-natal neurogenesis, e.g., post-natal hippocampal neurogenesis) and protecting from neuron cell death.
1. A compound having formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
each of R 1 , R 2 , and R 4 is independently selected from hydrogen, halo, C 1 -C 6 unsubstituted alkoxy, C 1 -C 6 unsubstituted alkyl, and cyano; R 3 is selected from fluoro, chloro, bromo, C 1 -C 6 unsubstituted alkoxy, C 1 -C 6 unsubstituted alkyl, and cyano;
R and R′ together with C 2 and C 3 , respectively, form:
(1) a fused phenyl ring having formula (II):
wherein each of R 5 , R 6 , R 7 , and R 8 is independently selected from hydrogen, halo, C 1 -C 6 unsubstituted alkoxy, C 1 -C 6 unsubstituted alkyl, and cyano; or
(2) a fused heteroaryl ring containing 6 ring atoms, wherein 1 of the ring atoms is N; and wherein said heteroaryl ring is optionally substituted with from 1-3 independently selected from hydrogen, halo, C 1 -C 6 unsubstituted alkoxy, C 1 -C 6 unsubstituted alkyl, and cyano;
each of L 1 and L 2 is CH 2 ;
A is CR A1 R A2 , wherein one of R A1 and R A2 is halo or OR 9 , and the other of R A1 and R A2 is halo, hydrogen or C 1 -C 3 unsubstituted alkyl;
Z is:
(i) —NR 10 R 11 ;
(ii) —OR 12 ; or
(iii) —S(O) n R 13 , wherein n is 0, 1, or 2;
R 9 is hydrogen; or C 1 -C 3 alkyl that is optionally substituted with hydroxyl or C 1 -C 3 unsubstituted alkoxy;
each of R 10 and R 11 is independently selected from:
(a) hydrogen;
(b) C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ;
(c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 unsubstituted alkyl), O, and S, wherein said heteroaryl is optionally substituted with from 1-4 R b ;
(d) C 1 -C 6 unsubstituted alkyl or C 1 -C 6 haloalkyl;
(e) —C(O)(C 1 -C 6 unsubstituted alkyl), —C(O)(C 1 -C 6 haloalkyl), or —C(O)O(C 1 -C 6 unsubstituted alkyl); and
(f) C 2 -C 6 unsubstituted alkenyl or C 2 -C 6 unsubstituted alkynyl;
wherein one of R 10 and R 11 is (b) or (c), and the other of R 10 and R 11 is (a) or (d) or (e) or (f);
R 12 is:
(i) C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ; or
(ii) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 unsubstituted alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;
R 13 is:
C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ;
R b at each occurrence is independently selected from:
(aa) C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 thiohaloalkoxy; C 1 -C 6 alkyl; C 1 -C 6 haloalkyl; —NH(C 1 -C 6 alkyl); N(C 1 -C 6 alkyl) 2 ; wherein the alkyl portion of each of the foregoing is unsubstituted or substituted with from 1-3 independently selected R e ;
(bb) halo; hydroxyl; cyano; nitro; —NH 2 ; azido; sulfhydryl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; —C(O)(C 1 -C 6 alkyl); —C(O)(C 1 -C 6 haloalkyl); C(O)OH; —C(O)O(C 1 -C 6 alkyl); —C(O)NH 2 ; —C(O)NH(C 1 -C 6 alkyl); C(O)N(C 1 -C 6 alkyl) 2 ; —SO 2 (C 1 -C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); —SO 2 N(C 1 -C 6 alkyl) 2 ; wherein the alkyl portion of each of the foregoing, where applicable, is unsubstituted; and
R e at each occurrence is, independently selected from hydroxyl, C 1 -C 6 alkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thiohaloalkoxy; —NH 2 ; —NH(C 1 -C 6 alkyl); N(C 1 -C 6 alkyl) 2 ; —NHC(O)(C 1 -C 6 alkyl); cyano; —C(O)H; —C(O)(C 1 -C 6 alkyl); —C(O)(C 1 -C 6 haloalkyl); C(O)OH; —C(O)O(C 1 -C 6 alkyl); —C(O)NH 2 ; —C(O)NH(C 1 -C 6 alkyl); C(O)N(C 1 -C 6 alkyl) 2 ; —SO 2 (C 1 -C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); —SO 2 N(C 1 -C 6 alkyl) 2 ; and L 3 -(C 1 -C 6 alkylene)-Cy, where in L 3 is a —O—, —NH—, —NCH 3 —, —C(O)—, —C(O)NH—, —C(O)NCH 3 —, —NHC(O)—, or —NCH 3 C(O)—, and Cy is a saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring system; wherein the alkyl portion of each of the foregoing, where applicable, is unsubstituted;
wherein when R and R′ are (1), one of R A1 and R A2 is OH and the other is hydrogen, Z is —NHR 10 , R 3 and R 6 are both halo, each of R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 is hydrogen, and R 10 is C 6 -C 10 aryl that is optionally substituted with 1 to 4 R b , then R 10 is unsubstituted phenyl or phenyl substituted with 1 R b .
2. The compound or salt of claim 1 , wherein Z is —NR 10 R 11 .
3. The compound or salt of claim 2 , wherein R and R′ together with C 2 and C 3 , respectively, form a fused phenyl ring having formula (II):
4. The compound or salt of claim 3 , wherein R 3 is halo, C 1 -C 6 alkoxy, or cyano, and each of R 1 , R 2 , and R 4 is hydrogen.
5. The compound or salt of claim 4 , wherein R 6 is halo, C 1 -C 6 alkoxy, or cyano.
6. The compound or salt of claim 5 , wherein one of R 10 and R 11 is C 6 -C 10 aryl that is optionally substituted with from 1-4 R b , and the other is hydrogen or C 1 -C 6 alkyl.
7. The compound or salt of claim 5 , wherein one of R 10 and R 11 is C 6 -C 10 aryl that is optionally substituted with from 1-4 R b , and the other is hydrogen.
8. The compound or salt of claim 5 , wherein one of R 10 and R 11 is unsubstituted phenyl, and the other is hydrogen.
9. The compound or salt of claim 5 , wherein one of R 10 and R 11 is phenyl that is substituted with 1 R b , and the other is hydrogen.
10. The compound or salt of claim 9 , wherein R b is C 1 -C 6 alkoxy.
11. The compound or salt of claim 9 , wherein R b is OCH 3 .
12. The compound or salt of claim 5 , wherein one of R 10 and R 11 is 3-methoxyphenyl, and the other is hydrogen.
13. The compound or salt of claim 1 , wherein Z is —OR 12 .
14. The compound or salt of claim 13 , wherein R′ 2 is C 6 -C 10 aryl.
15. The compound or salt of claim 14 , wherein R and R′ together with C 2 and C 3 , respectively, form a fused phenyl ring having formula (II):
16. The compound or salt of claim 15 , wherein R 3 is halo, C 1 -C 6 alkoxy, or cyano, and each of R 1 , R 2 , and R 4 is hydrogen.
17. The compound or salt of claim 16 , wherein R 6 is halo, C 1 -C 6 alkoxy, or cyano.
18. The compound or salt of claim 1 , wherein Z is —S(O) n R 13 , wherein n is 0 or 2.
19. The compound or salt of claim 1 , selected from:
R-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol;
S-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol;
1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylthio)propan-2-ol;
N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)acetamide;
N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline;
N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-methoxypropyl)-3-methoxyaniline;
1-(3,6-Dimethyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;
1-(3-Bromo-6-methyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol;
1-(3,6-Dichloro-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;
1-(3,6-Dibromo-9H-pyrido[3,4-b]indol-9-yl)-3-(phenylamino)propan-2-ol;
1-(3-Azidophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;
1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-2-ylamino)propan-2-ol;
1-(3,6-dibromo-9H-carbazol-9-yl)-3-((3-methoxyphenyl)(methyl)-amino)propan-2-ol;
1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyrimidin-2-ylamino)propan-2-ol;
N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxy-N-methylaniline;
1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-ethoxyphenylamino)propan-2-ol;
1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfinyl)propan-2-ol;
1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol;
1-(3-bromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;
1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol;
1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-3-ylamino)propan-2-ol;
1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-4-ylamino)propan-2-ol;
N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2,2-difluoropropyl)-3-methoxyaniline; and
1-(3,6-dibromo-9H-carbazol-9-yl)-3-(naphthalen-1-ylamino)propan-2-ol.
20. A compound having formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
each of R 1 , R 2 , and R 4 is independently selected from hydrogen, halo, C 1 -C 6 unsubstituted alkoxy, C 1 -C 6 unsubstituted alkyl, and cyano; R 3 is selected from fluoro, chloro, bromo, C 1 -C 6 unsubstituted alkoxy, C 1 -C 6 unsubstituted alkyl, and cyano;
R and R′ together with C 2 and C 3 , respectively, form a fused phenyl ring having formula (II):
wherein each of R 5 , R 6 , R 7 , and R 8 is independently selected from hydrogen, halo, C 1 -C 6 unsubstituted alkoxy, C 1 -C 6 unsubstituted alkyl, and cyano;
each of L 1 and L 2 is CH 2 ;
A is CR A1 R A2 , wherein one of R A1 and R A2 is halo or OR 9 , and the other of R A1 and R A2 is halo, hydrogen or C 1 -C 3 unsubstituted alkyl;
Z is:
(i) —NR 10 R 11 ;
(ii) —OR 12 ; or
(iii) —S(O) n R 13 , wherein n is 0, 1, or 2;
R 9 is hydrogen; or C 1 -C 3 alkyl that is optionally substituted with hydroxyl or C 1 -C 3 unsubstituted alkoxy;
each of R 10 and R 11 is independently selected from:
(a) hydrogen;
(b) C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ;
(c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 unsubstituted alkyl), O, and S, wherein said heteroaryl is optionally substituted with from 1-4 R b ;
(d) C 1 -C 6 unsubstituted alkyl or C 1 -C 6 haloalkyl;
(e) —C(O)(C 1 -C 6 unsubstituted alkyl), —C(O)(C 1 -C 6 haloalkyl), or —C(O)O(C 1 -C 6 unsubstituted alkyl); and
(f) C 2 -C 6 unsubstituted alkenyl or C 2 -C 6 unsubstituted alkynyl;
wherein one of R 10 and R 11 is (b) or (c), and the other of R 10 and R 11 is (a) or (d) or (e) or (f);
R 12 is:
(i) C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ; or
(ii) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 unsubstituted alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;
R 13 is:
C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ;
R b at each occurrence is independently selected from:
(aa) C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 thiohaloalkoxy; C 1 -C 6 alkyl; C 1 -C 6 haloalkyl; —NH(C 1 -C 6 alkyl); N(C 1 -C 6 alkyl) 2 ; wherein the alkyl portion of each of the foregoing is unsubstituted or substituted with from 1-3 independently selected R e ;
(bb) halo; hydroxyl; cyano; nitro; —NH 2 ; azido; sulfhydryl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; —C(O)(C 1 -C 6 alkyl); —C(O)(C 1 -C 6 haloalkyl); C(O)OH; —C(O)O(C 1 -C 6 alkyl); —C(O)NH 2 ; —C(O)NH(C 1 -C 6 alkyl); C(O)N(C 1 -C 6 alkyl) 2 ; —SO 2 (C 1 -C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); —SO 2 N(C 1 -C 6 alkyl) 2 ; wherein the alkyl portion of each of the foregoing, where applicable, is unsubstituted; and
R e at each occurrence is, independently selected from hydroxyl, C 1 -C 6 alkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thiohaloalkoxy; —NH 2 ; —NH(C 1 -C 6 alkyl); N(C 1 -C 6 alkyl) 2 ; —NHC(O)(C 1 -C 6 alkyl); cyano; —C(O)H; —C(O)(C 1 -C 6 alkyl); —C(O)(C 1 -C 6 haloalkyl); C(O)OH; —C(O)O(C 1 -C 6 alkyl); —C(O)NH 2 ; —C(O)NH(C 1 -C 6 alkyl); C(O)N(C 1 -C 6 alkyl) 2 ; —SO 2 (C 1 -C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); —SO 2 N(C 1 -C 6 alkyl) 2 ; and L 3 -(C 1 -C 6 alkylene)-Cy, where in L 3 is a —O—, —NH—, —NCH 3 —, —C(O)—, —C(O)NH—, —C(O)NCH 3 —, —NHC(O)—, or —NCH 3 C(O)—, and Cy is a saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring system; wherein the alkyl portion of each of the foregoing, where applicable, is unsubstituted;
wherein when one of R A1 and R A2 is OH and the other is hydrogen, Z is —NHR 10 , R 3 R 6 are both halo, each of R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 is hydrogen, and R 10 is C 6 -C 10 aryl that is optionally substituted with 1 to 4 R b , then R 10 is unsubstituted phenyl or phenyl substituted with 1 R b .