Neuroprotective Compounds and Use Thereof

Abstract

Provided herein is compositions and methods for reducing one or both of axonal degeneration and neuronal cell death associated with a disease.

1 . (−)-(S)—N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine, or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A pharmaceutical composition comprising (−)-(S)—N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         3 . A method for treating a disease, comprising administering (−)-(S)—N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine, or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease is selected from schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury and/or a visual symptom associated therewith, 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, cognitive decline and/or general frailty associated with normal aging and/or chemotherapy, chemotherapy induced neuropathy, concussive injury, crush injury, peripheral neuropathy, diabetic neuropathy, post-traumatic headache, multiple sclerosis, retinal degeneration and dystrophy (such as Leber congenital amaurosis, retinitis pigmentosa, cone-rod dystrophy, microphthalmia, anophthalmia, myopia, and hyperopia), spinal cord injury, traumatic spinal cord injury, peripheral nerve injury (such as peripheral nerve crush injury, neonatal brachial plexus palsy, and traumatic facial nerve palsy), retinal neuronal death related diseases (such as glaucoma and age related macular degeneration, diabetic retinopathy, retinal blood vessel occlusions, retinal medication toxicity (such as what amino glycosides or plaquenil can cause), retinal trauma (e.g., post-surgical), retinal infections, choroidal dystrophies, retinal pigmentary retinopathies, inflammatory and cancer mediated auto immune diseases that result in retinal neuronal cell death), Autism, Stargardt disease, Kearns-Sayre syndrome, Pure neurosensory deafness, Hereditary hearing loss with retinal diseases, Hereditary hearing loss with system atrophies of the nervous system, Progressive spinal muscular atrophy, Progressive bulbar palsy, Primary lateral sclerosis, Hereditary forms of progressive muscular atrophy and spastic paraplegia, Frontotemporal dementia, Dementia with Lewy bodies, Corticobasal degeneration, Progressive supranuclear palsy, Prion disorders causing neurodegeneration, Multiple system atrophy (olivopontocerebellar atrophy), Hereditary spastic paraparesis, Friedreich ataxia, Non-Friedreich ataxia, Spinocerebellar atrophies, Amyloidoses, Metabolic-related (e.g., Diabetes) neurodegenerative disorders, Toxin-related neurodegenerative disorders, Multiple sclerosis, Charcot Marie Tooth, Diabetic neuropathy, Metabolic neuropathies, Endocrine neuropathies, Orthostatic hypotension, Creutzfeldt-Jacob Disease, Primary progressive aphasia, Frontotemporal Lobar Degeneration, Cortical blindness, Shy-Drager Syndrome (Multiple, System Atrophy with Orthostatic Hypotension), Diffuse cerebral cortical atrophy of non-Alzheimer type, Lewy-body dementia, Pick disease (lobar atrophy), Thalamic degeneration, Mesolimbocortical dementia of non-Alzheimer type, Nonhuntingtonian types of chorea and dementia, Cortical-striatal-spinal degeneration, Dementia-Parkinson-amyotrophic lateral sclerosis complex, Cerebrocerebellar degeneration, Cortico-basal ganglionic degeneration, Familial dementia with spastic paraparesis or myoclonus, and Tourette syndrome. 
     
     
         4 . A method of treating chronic TBI or a long-term symptom associated with TBI, comprising administering an effective amount of (−)-(S)—N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. 
     
     
         5 . The method of  claim 4 , wherein the (−)-(S)—N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine or salt is administered after an extended period following an injury, and/or for an extended period following an injury. 
     
     
         6 . The method of  claim 5 , wherein the extended period is 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, or longer or shorter. 
     
     
         7 . A method for reducing or slowing axonal degeneration, comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         each of R 1 , R 2 , R 3 , and R 4  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), nitro, —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 , —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6  alkyl), and —S(O) 2 N(C 1 -C 6  alkyl) 2 ; 
         R and R′ are defined according to (1), (2), (3) or (4) below: 
         (1) 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, 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), nitro, —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 , —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6  alkyl), and —S(O) 2 N(C 1 -C 6  alkyl) 2 ; or 
         (2) R and R′ together with C 2  and C 3 , respectively, form a fused heteroaryl ring containing 6 ring atoms, wherein from 1-2 independently selected ring atoms is N; and wherein said heteroaryl ring is optionally substituted with from 1-2 independently selected R b ; or 
         (3) R and R′ together with C 2  and C 3 , respectively, form a fused heterocyclic ring containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(C 1 -C 6  alkyl), NC(O)(C 1 -C 6  alkyl), O, and S; and wherein said heterocyclic ring is optionally substituted with from 1-3 independently selected R a ; or 
         (4) each of R and R′ is, independently, hydrogen, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
         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:
 (i) CR A1 R A2 , wherein each of R A1  and R A2  is independently selected from hydrogen, halo, C 1 -C 3  alkyl, OR 9 , wherein R 9  is hydrogen or C 1 -C 3  alkyl that is optionally substituted with hydroxyl or C 1 -C 3  alkoxy, or a double bond formed between A and one of L 1  and L 2 ; or 
 (ii) C═O; or 
 (iii) C 3 -C 5  cycloalkylene that is (a) substituted with 1 oxo; and (b) optionally further substituted with from 1-4 independently selected R a ; or 
 (iv) heterocycloalkylene containing from 3-5 ring atoms, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(C 1 -C 3  alkyl), O, and S; and wherein said heterocycloalkylene is (a) substituted with 1 oxo; and (b) is optionally further substituted with from 1-4 independently selected R a ; 
 
         Z is:
 (i) —NR 10 R 11 ; or 
 (ii) —C(O)NR 10 R 11 ; or 
 (iii) —OR 12 ; or 
 (iv) —S(O) n R 13 , wherein n is 0, 1, or 2; or 
 (v) heterocycloalkenyl containing from 5-6 ring atoms, wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C 1 -C 6  alkyl), NC(O)(C 1 -C 6  alkyl), O, and S; and wherein said heterocycloalkenyl is optionally substituted with from 1-4 independently selected R a ; or 
 (vi) C 6 -C 10  aryl that is optionally substituted with from 1-4 independently selected R b ; or 
 (vii) 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 independently selected R b ; or 
 (viii) C 8 -C 14  arylcycloalkyl, wherein:
 (1) the aryl portion is optionally substituted with from 1-4 independently selected R b , and 
 (2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ; or 
 
 (ix) arylheterocyclyl containing from 8-14 ring atoms, wherein:
 (1) the aryl portion from is optionally substituted with from 1-4 independently selected R b , and 
 (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C 1 -C 6  alkyl), NC(O)(C 1 -C 6  alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ; or 
 
 (x) heteroarylheterocyclyl containing from 8-14 ring atoms, wherein:
 (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C 1 -C 3  alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently selected R b ; and 
 (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C 1 -C 6  alkyl), NC(O)(C 1 -C 6  alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ; or 
 
 (xi) heteroarylcycloalkyl containing from 8-14 ring atoms, wherein:
 (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C 1 -C 3  alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently selected R b ; and 
 (2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ; 
 
 
         each of R 10  and R 11  is independently selected from the substituents delineated collectively in (a) through (I) below:
 (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; and 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 1-3 R d ; 
 (e) —C(O)(C 1 -C 6  alkyl), —C(O)(C 1 -C 6  haloalkyl), —C(O)O(C 1 -C 6  alkyl), —S(O) 2 (C 1 -C 6  alkyl), —S(O) 2 (C 6 -C 10  aryl), or —S(O) 2 (C 1 -C 13  heteroaryl), wherein the C 6 -C 10  aryl and C 1 -C 13  heteroaryl are each independently optionally substituted with 1-4 R b ; 
 (f) C 2 -C 6  alkenyl or C 2 -C 6  alkynyl; 
 (g) C 8 -C 14  arylcycloalkyl, wherein:
 (1) the aryl portion is optionally substituted with from 1-4 independently selected R b , and 
 (2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ; 
 
 (h) arylheterocyclyl containing from 8-14 ring atoms, wherein:
 (1) the aryl portion from is optionally substituted with from 1-4 independently selected R b , and 
 (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C 1 -C 6  alkyl), NC(O)(C 1 -C 6  alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ; 
 
 (i) heteroarylheterocyclyl containing from 8-14 ring atoms, wherein:
 (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C 1 -C 3  alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently selected R b ; and 
 (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C 1 -C 6  alkyl), NC(O)(C 1 -C 6  alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ; 
 
 (j) heteroarylcycloalkyl containing from 8-14 ring atoms, wherein:
 (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C 1 -C 3  alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently selected R b ; and 
 (2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ; 
 
 (k) C 3 -C 8  cycloalkyl or C 3 -C 8  cycloalkenyl, each of which is optionally substituted with from 1-4 independently selected R a ; and 
 (l) C 7 -C 12  aralkyl, wherein the aryl portion is optionally substituted with from 1-4 independently selected R b , 
 provided that one of R 10  and R 11  must be selected from (b), (c), (g), (h), (i), (j), and (k); 
 
         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  alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ; or 
 (iii) C 1 -C 6  alkyl or C 1 -C 6  haloalkyl, each of which is substituted with from 1-3 R d ; or 
 (iv) C 8 -C 14  arylcycloalkyl, wherein:
 (1) the aryl portion is optionally substituted with from 1-4 independently selected R b , and 
 (2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ; or 
 
 (v) arylheterocyclyl containing from 8-14 ring atoms, wherein:
 (1) the aryl portion from is optionally substituted with from 1-4 independently selected R b , and 
 (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C 1 -C 6  alkyl), NC(O)(C 1 -C 6  alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ; or 
 
 (vi) heteroarylheterocyclyl containing from 8-14 ring atoms, wherein:
 (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C 1 -C 3  alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently selected R b ; and 
 (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C 1 -C 6  alkyl), NC(O)(C 1 -C 6  alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ; 
 
 or 
 (vii) heteroarylcycloalkyl containing from 8-14 ring atoms, wherein:
 (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C 1 -C 3  alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently selected R b ; and 
 (2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ; 
 
 
         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  alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ; or 
 (iii) C 8 -C 14  arylcycloalkyl, wherein:
 (1) the aryl portion is optionally substituted with from 1-4 independently selected R b , and 
 (2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ; 
 
 or 
 (iv) arylheterocyclyl containing from 8-14 ring atoms, wherein:
 (1) the aryl portion from is optionally substituted with from 1-4 independently selected R b , and 
 (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C 1 -C 6  alkyl), NC(O)(C 1 -C 6  alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ; 
 
 or 
 (v) heteroarylheterocyclyl containing from 8-14 ring atoms, wherein:
 (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C 1 -C 3  alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently selected R b ; and 
 (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C 1 -C 6  alkyl), NC(O)(C 1 -C 6  alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ; 
 
 or 
 (vi) heteroarylcycloalkyl containing from 8-14 ring atoms, wherein:
 (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C 1 -C 3  alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently selected R b ; and 
 (2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ; 
 
 
         R a  at each occurrence is, independently selected from halo, hydroxyl, C 1 -C 6  alkoxy, C 1 -C 6  thioalkoxy, C 1 -C 6  haloalkoxy, C 1 -C 6  thiohaloalkoxy, oxo, thioxo, ═NH, ═N(C 1 -C 6  alkyl), C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —NH 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2 , —NHC(O)(C 1 -C 6  alkyl), and cyano; 
         R b  at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:
 (aa) C 1 -C 6  alkoxy; C 1 -C 6  haloalkoxy; C 1 -C 6  thioalkoxy; C 1 -C 6  thiohaloalkoxy; —O—(CH 2 ) 1-3 —[O(CH 2 ) 1-3 ] 1-3 —H; —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  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 wherein each of said phenyl and heterocyclyl is optionally substituted with from 1-3 independently selected R a ; 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; 
 
         R c  at each occurrence is, independently selected from halo, 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, —NH 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2 , —NHC(O)(C 1 -C 6  alkyl), and cyano; 
         R d  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, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —NH 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2 , —NHC(O)(C 1 -C 6  alkyl), and cyano; 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)-biotin, 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)—. 
       
     
     
         8 . The method of  claim 7 , further comprising treating a disease or condition selected from the group consisting of: chemotherapy induced neuropathy, concussive injury, crush injury, peripheral neuropathy, diabetic neuropathy, post-traumatic headache, multiple sclerosis, retinal degeneration and dystrophy (such as Leber congenital amaurosis, retinitis pigmentosa, cone-rod dystrophy, microphthalmia, anophthalmia, myopia, and hyperopia), spinal cord injury, traumatic spinal cord injury, peripheral nerve injury (such as peripheral nerve crush injury, neonatal brachial plexus palsy, and traumatic facial nerve palsy), retinal neuronal death related diseases (such as glaucoma and age related macular degeneration, diabetic retinopathy, retinal blood vessel occlusions, retinal medication toxicity (such as what amino glycosides or plaquenil can cause), retinal trauma (e.g., post-surgical), retinal infections, choroidal dystrophies, retinal pigmentary retinopathies, inflammatory and cancer mediated auto immune diseases that result in retinal neuronal cell death), Autism, Stargardt disease, Kearns-Sayre syndrome, Pure neurosensory deafness, Hereditary hearing loss with retinal diseases, Hereditary hearing loss with system atrophies of the nervous system, Progressive spinal muscular atrophy, Progressive bulbar palsy, Primary lateral sclerosis, Hereditary forms of progressive muscular atrophy and spastic paraplegia, Frontotemporal dementia, Dementia with Lewy bodies, Corticobasal degeneration, Progressive supranuclear palsy, Prion disorders causing neurodegeneration, Multiple system atrophy (olivopontocerebellar atrophy), Hereditary spastic paraparesis, Friedreich ataxia, Non-Friedreich ataxia, Spinocerebellar atrophies, Amyloidoses, Metabolic-related (e.g., Diabetes) neurodegenerative disorders, Toxin-related neurodegenerative disorders, Multiple sclerosis, Charcot Marie Tooth, Diabetic neuropathy, Metabolic neuropathies, Endocrine neuropathies, Orthostatic hypotension, Creutzfeldt-Jacob Disease, Primary progressive aphasia, Frontotemporal Lobar Degeneration, Cortical blindness, Shy-Drager Syndrome (Multiple, System Atrophy with Orthostatic Hypotension), Diffuse cerebral cortical atrophy of non-Alzheimer type, Lewy-body dementia, Pick disease (lobar atrophy), Thalamic degeneration, Mesolimbocortical dementia of non-Alzheimer type, Nonhuntingtonian types of chorea and dementia, Cortical-striatal-spinal degeneration, Dementia-Parkinson-amyotrophic lateral sclerosis complex, Cerebrocerebellar degeneration, Cortico-basal ganglionic degeneration, Familial dementia with spastic paraparesis or myoclonus, and Tourette syndrome. 
     
     
         9 . The method of  claim 8 , wherein the compound or salt is 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol, N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline, N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine, and/or (−)-N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine. 
     
     
         10 . The method of  claim 8 , wherein the compound or salt is N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine, and/or (−)-N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine. 
     
     
         11 . A method of treating chronic TBI or a long-term symptom associated with TBI, comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the compound or salt is administered after an extended period of time following an injury. 
     
     
         12 . The method of  claim 11 , wherein the extended period is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, or longer or shorter, or any duration therebetween. 
     
     
         13 . A method of treating chronic TBI or a long-term symptom associated with TBI, comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof, for an extended period of time. 
     
     
         14 . The method of  claim 11 , wherein the extended period is about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, or longer or shorter, or any duration therebetween.