Pro-neurogenic compounds

1. A method of treating a disease, disorder, or condition associated with insufficient neurogenesis or unwanted neuronal cell death in a subject in need thereof, comprising administering an effective amount of a compound having formula (III), or a pharmaceutically acceptable salt thereof:

wherein:

each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro;

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 hydrogen, halo, OR 9 or C 1 -C 3 alkyl; wherein R 9 is C 1 -C 3 alkyl that is optionally substituted with hydroxyl or C 1 -C 3 alkoxy;

Z is:

(i) —NR 10 R 11 ;

(ii) —OR 12 ; or

(iii) —S(O) n R 13 , wherein n is 0, 1, or 2;

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 alkyl), O, and S, wherein said heteroaryl is optionally substituted with from 1-4 R b ;

(d) C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, each of which is optionally substituted with from 1-3R d ;

(e) —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), or —C(O)O(C 1 -C 6 alkyl);

(f) C 2 -C 6 alkenyl or C 2 -C 6 alkenyl;

wherein one of R 10 and R 11 is (b) or (c);

R 12 1s:

(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 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;

R 13 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 13 alkyl), O, and S; and wherein said heteroaryl 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 ; —NHC(O)(C 1 -C 6 alkyl);

wherein the alkyl portion of each is optionally 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 alkenyl;

—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 ; (cc) C 3 -C 6 cycloalkyl or heterocyclyl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S; and

(dd) phenyl or heteroaryl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heteroaryl is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S;

wherein each of said phenyl and heteroaryl is optionally substituted with from 1-3 substituents independently selected from halo; hydroxyl; cyano; nitro; —NH 2 ; —NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), 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, and C 1 -C 6 haloalkyl; 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) 22 n-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 1 C(O)—, and Cy is a saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring system.

2. The method of claim 1 , wherein the disease, disorder, or condition is selected from the group consisting of:

schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, and abuse of a neuro-active drug.

3. The method of claim 1 , wherein R 3 is halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , or nitro; and each of R 1 , R 2 , and R 4 is hydrogen.

4. The method of claim 3 , wherein R 6 is halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , or nitro; and each of R 5 , R 7 , and R 8 is hydrogen.

5. The method of claim 1 , wherein Z is —NR 10 R 11 .

6. The method of claim 5 , wherein one of R 10 and R 11 is (b) 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 method of claim 5 , wherein one of R 10 and R 11 is (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 alkyl), O, and S, wherein said heteroaryl is optionally substituted with from 1-4 R b ; and the other is hydrogen or C 1 -C 6 alkyl.

8. The method of claim 1 , wherein Z is —OR 12 .

9. The method of claim 8 , wherein R 12 is C 6 -C 10 aryl that is optionally substituted with 1 R b .

10. The method of claim 1 , wherein R 12 is 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 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with 1 R b .

11. The method of claim 1 , wherein Z is —S(O) n R 13 , wherein n is 0 or 2.

12. The method of claim 11 , wherein R 13 is C 6 -C, 10 aryl that is optionally substituted with 1 R b .

13. The method of claim 11 , wherein R 13 is 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 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with 1 R b .

14. The method of claim 1 , wherein the compound is selected from:

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;

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxy-N-methylaniline; and

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2,2-difluoropropyl)-3-methoxyaniline.

15. A method of treating a disease, disorder, or condition associated with insufficient neurogenesis or unwanted neuronal cell death in a subject in need thereof, comprising administering an effective amount of a compound having formula (III), or a pharmaceutically acceptable salt thereof:

wherein:

each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro;

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 hydrogen, halo or C 1 -C 3 alkyl; wherein R 9 is hydrogen or C 1 -C 3 alkyl that is optionally substituted with hydroxyl or C 1 -C 3 alkoxy;

Z is:

(i) —NR 10 R 11 ;

(ii) —OR 12 ; or

(iii) —S(O) n R 13 , wherein n is 0, 1, or 2;

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 alkyl), O, and S, wherein said heteroaryl is optionally substituted with from 1-4 R b ;

(d) C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, each of which is optionally substituted with from 1-3R d ;

(e) -C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), or -C(O) 0 (C 1 -C 6 alkyl);

(f) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;

wherein one of R 10 and R 11 is (c);

R 12 is 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 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;

R 13 is 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 alkyl), O, and S; and wherein said heteroaryl 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 l -C 6 alkyl; C 1 -C 6 haloalkyl; —NH(C 1 -C 6 alkyl); N(C 1 -C 6 alkyl) 2 ; —NHC(O)(C 1 -C 6 alkyl);

wherein the alkyl portion of each is optionally 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)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 ;

(cc) C 3 -C 6 cycloalkyl or heterocyclyl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S; and

(dd) phenyl or heteroaryl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heteroaryl is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S;

wherein each of said phenyl and heteroaryl is optionally substituted with from 1-3 substituents independently selected from halo; hydroxyl; cyano; nitro; —NH 2 ; —NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), 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, and C 1 -C 6 haloalkyl; 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.

16. The method of claim 15 , wherein the disease, disorder, or condition is selected from the group consisting of: schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, and abuse of a neuro-active drug.

17. The method of claim 15 , wherein R 3 is halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , or nitro; and each of R 1 , R 2 , and R 4 is hydrogen.

18. The method of claim 17 , wherein R 6 is halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , or nitro; and each of R 5 , R 7 , and R 8 is hydrogen.

19. The method of claim 15 , wherein Z is —NR 10 R 11 .

20. The method of claim 19 , wherein one of R 10 and R 11 is heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C,-C 3 alkyl), O, and S, wherein said heteroaryl is optionally substituted with 1-4 R b ; and the other is hydrogen or C 1 -C 6 alkyl.

21. The method of claim 15 , wherein Z is —OR 12 .

22. The method of claim 21 , wherein R 12 is 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 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with 1 R b .

23. The method of claim 15 , wherein Z is —S(O) n R 13 .

24. The method of claim 23 , wherein R 13 is 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 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with 1R b .

25. The method of claim 15 , wherein the compound is selected from:

1-(3 ,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-2-ylamino)propan-2-ol;

1-(3 ,6-dibromo-9H-carbazol-9-yl)-3-(pyrimidin-2-ylamino)propan-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; and

1-(4-bromophenylamino)-3-(2,3 -dimethyl-1H-indol-1-yl)propan-2-ol.