Pro-neurogenic compounds
This technology relates generally to compounds and methods for stimulating neurogenesis (e.g., post-natal neurogenesis, including post-natal hippocampal and hypothalamic neurogenesis) and/or protecting neuronal cell from cell death. Various compounds are disclosed herein. In vivo activity tests suggest that these compounds may have therapeutic benefits in neuropsychiatric and/or neurodegenerative diseases such as 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, abuse of a neuro-active drug, retinal degeneration, spinal cord injury, peripheral nerve injury, physiological weight loss associated with various conditions, as well as cognitive decline associated with normal aging, chemotherapy, and the like.
1. A compound having formula (III) or a pharmaceutically acceptable salt thereof:
wherein:
each of R 1 , R 2 , 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, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , 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;
R 3 is selected from 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, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , 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, independently, C 1 -C 3 alkylene, which is optionally substituted with from 1-2 independently selected R c ;
A is CR A1 R A2 , wherein one of R A1 and R A2 is halo, and the other of R A1 and R A2 is hydrogen, halo, C 1 -C 3 unsubstituted alkyl, and hydroxyl;
Z is —NR 10 R 11 or —OR 12 or —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 ; or
(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; and 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; and
(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);
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);
each of R 12 and 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 1 -C 3 unsubstituted 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 the substituents delineated in (aa) through (dd) below:
(aa) C 1 -C 6 unsubstituted alkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 unsubstituted thioalkoxy; C 1 -C 6 thiohaloalkoxy; —O—(CH 2 ) 1-3 —[O(CH 2 ) 1-3 ] 1-3 —H; C 1 -C 6 unsubstituted alkyl, C 1 -C 6 haloalkyl, —NH(C 1 -C 6 unsubstituted alkyl), —N(C 1 -C 6 unsubstituted alkyl) 2 , —NHC(O)(C 1 -C 6 unsubstituted alkyl);
(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 ; wherein the alkyl portion of each of the foregoing, where applicable, is unsubstituted;
(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 unsubstituted alkyl), NC(O)(C 1 -C 6 unsubstituted 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 unsubstituted 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 unsubstituted alkyl), —N(C 1 -C 6 unsubstituted alkyl) 2 , —NHC(O)(C 1 -C 6 unsubstituted 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 unsubstituted alkyl, and C 1 -C 6 haloalkyl;
R c at each occurrence is, independently selected from halo, C 1 -C 6 unsubstituted alkoxy, C 1 -C 6 unsubstituted thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 unsubstituted alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 unsubstituted alkyl), —N(C 1 -C 6 unsubstituted alkyl) 2 , —NHC(O)(C 1 -C 6 unsubstituted alkyl), and cyano; and
R d at each occurrence is, independently selected from hydroxyl, C 1 -C 6 unsubstituted alkoxy, C 1 -C 6 unsubstituted thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 unsubstituted alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 unsubstituted alkyl), N(C 1 -C 6 unsubstituted alkyl) 2 , —NHC(O)(C 1 -C 6 unsubstituted alkyl), and cyano.
2. The compound or salt of claim 1 , wherein R 3 is halo.
3. The compound or salt of claim 2 , wherein R 3 is bromo.
4. The compound or salt of claim 3 , wherein each of R 1 , R 2 , and R 4 is hydrogen.
5. The compound or salt of claim 4 , wherein R 6 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , and cyano.
6. The compound or salt of claim 4 , wherein R 6 is halo or C 1 -C 6 alkyl.
7. The compound or salt of claim 4 , wherein R 6 is halo.
8. The compound or salt of claim 4 , wherein R 6 is bromo.
9. The compound or salt of claim 8 , wherein each of R 5 , R 7 , and R 8 is hydrogen.
10. The compound or salt of claim 4 , wherein Z is —NR 10 R 11 .
11. The compound or salt of claim 10 , 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 ; or
(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; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;
and the other of R 10 and R 11 is hydrogen.
12. The compound or salt of claim 4 , wherein Z is —OR 12 .
13. The compound or salt of claim 12 , wherein R 12 is C 6 -C 10 aryl that is optionally substituted with from 1-4 R b .