PRO-NEUROGENIC COMPOUNDS

摘要

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.

主权项

1. A method for promoting post-natal mammalian neurogenesis and/or reducing neuronal cell death in a subject in need thereof, the method comprising administering an effective amount of a compound having formula (III) or a pharmaceutically acceptable salt thereof: wherein: each of R1, R2, R4, R5, R7, and R8 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, and cyclopropyl; R3 is selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cyclopropyl, —N3, and cyano; R6 is selected from hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cyclopropyl, —N3, and cyano; each of L1 and L2 is, independently, C1-C3 alkylene, which is optionally substituted with from 1-2 independently selected Rc; A is CRA1RA2, wherein one of RA1 and RA2 is halo, and the other of RA1 and RA2 is hydrogen or C1-C3 alkyl; Z is —NR10R11 or —OR12 or —S(O)nR12, wherein n is 0, 1, or 2; each of R10 and R11 is independently selected from:
(a) hydrogen;(b) C6-C10 aryl that is optionally substituted with from 1-4 Rb; or(c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C1-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 Rb; wherein one of R10 and R11 is (b) or (c); each of R12 and R3 is:
(i) C6-C10 aryl that is optionally substituted with from 1-4 Rb; or(ii) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C1-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 Rb; Rb at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:
(aa) C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 thioalkoxy; C1-C6 thiohaloalkoxy; —O—(CH2)1-3[O(CH2)1-3]1-3H; C1-C6 alkyl, C1-C6 haloalkyl, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6 alkyl);(bb) halo; hydroxyl; cyano; nitro; —NH2; azido; sulfhydryl; C2-C6 alkenyl; C2-C6 alkynyl; —C(O)H; —C(O)(C1-C6 alkyl); —C(O)(C1-C6 haloalkyl); C(O)OH; —C(O)O(C1-C6 alkyl); —C(O)NH2; —C(O)NH(C1-C6 alkyl); —C(O)N(C1-C6 alkyl)2; —SO2(C1-C6 alkyl); —SO2NH2; —SO2NH(C1-C6 alkyl); —SO2N(C1-C6 alkyl)2;(cc) C3-C6 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(C1-C6 alkyl), NC(O)(C1-C6 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(C1-C3 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; —NH2; —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6 alkyl), C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 thioalkoxy; C1-C6 thiohaloalkoxy; C1-C6 alkyl, and C1-C6 haloalkyl; and Rc at each occurrence is, independently selected from halo, C1-C6 alkoxy, C1-C6 thioalkoxy, C1-C6 haloalkoxy, C1-C6 thiohaloalkoxy, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6 alkyl), and cyano.