Compounds, compositions and methods of use

Abstract

Herein, compounds, compositions and methods for modulating inclusion formation and stress granules in cells related to the onset of neurodegenerative diseases, musculoskeletal diseases, cancer, ophthalmological diseases, and viral infections are described.

1 - 73 . (canceled) 
     
     
         74 . A method of treating a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         each of Ring A and Ring B is independently cycloalkyl, heterocyclyl, aryl, or heteroaryl; 
         X is C(R′)(R″), O, or S(O) x ; 
         each of L 1  and L 2  is independently —C 1 -C 6  heteroalkyl-, —NR A —, —C(O)NR A —, —NR A C(O)—, —C(O)NR A —C 1 -C 6  alkyl-, —C 1 -C 6  alkyl-C(O)NR A —, —NR A C(O)—C 1 -C 6  alkyl-, —C 1 -C 6  alkyl-NR A C(O)—, —C(O)NR A —C 1 -C 6  heteroalkyl-, —C 1 -C 6  heteroalkyl-C(O)NR A —, —NR A C(O) C 1 -C 6  heteroalkyl-, —C 1 -C 6  heteroalkyl-NR A C(O)—, —C 1 -C 6  heteroalkyl-C(O)—, or —C(O)—C 1 -C 6  heteroalkyl-, each of which is optionally substituted with 1-5 R 4 ; 
         each of R 1  and R 3  is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 1 -C 6  haloalkyl, halo, cyano, nitro, azido, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR B , —C(O)R D , —C(O)OR B , —NR A R C , —NR A C(O)R D , —S(O) x R E , —OS(O) x R E , —C(O)NR A S(O) x R E , —NR A S(O) x R E , or —S(O) x NR A , each of which is optionally substituted with 1-5 R 5 ; or 
         each R 2  is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 1 -C 6  haloalkyl, halo, cyano, or nitro; 
         each of R′ and R″ is independently H, C 1 -C 6  alkyl, or C 1 -C 6  heteroalkyl; 
         each R 4  is independently deuterium, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 1 -C 6  haloalkyl, halo, cyano, cycloalkyl, heterocyclyl, —OR B , —C(O)R D , —C(O)OR B , —C(O)NR A R C , or —SR E , each of which is optionally substituted with 1-5 R 6 ; 
         or one R 4 , taken together with the atoms to which it is attached, forms a ring with Ring A, optionally substituted with 1-5 R 5 ; 
         or two R 4 , taken together with the atoms to which they are attached to form a ring, optionally substituted with 1-5 R 6 ; 
         each R 5  is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 1 -C 6  haloalkyl, halo, cyano, or oxo; 
         or two R 5 , taken together with the atoms to which they are attached to form a ring, optionally substituted with 1-5 R 6 ; 
         each R A , R B , R C , R D , or R E  is independently H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 1 -C 6  haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1-4 R 6 ; 
         or R A  and R C , together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R 8 ; 
         each R 6  is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 2 -C 6  heteroalkenyl, C 2 -C 6  heteroalkynyl, C 1 -C 6  haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, or nitro; 
         each of n, o, and p is independently 0, 1, 2, 3, 4, 5, or 6; and 
         x is 0, 1, or 2. 
       
     
     
         75 . The method of  claim 74 , wherein Ring A is aryl or heteroaryl. 
     
     
         76 . The method of  claim 74 , wherein Ring A is aryl. 
     
     
         77 . The method of  claim 74 , wherein ring A is. 
       
         
           
           
               
               
           
         
       
     
     
         78 . The method of  claim 74 , wherein Ring B is heteroaryl. 
     
     
         79 . The method of  claim 74 , wherein Ring B is bicyclic heteroaryl. 
     
     
         80 . The method of  claim 74 , wherein Ring B is 
       
         
           
           
               
               
           
         
       
     
     
         81 . The method of  claim 74 , wherein X is C(R′)(R″). 
     
     
         82 . The method of  claim 81 , wherein each of R′ and R″ is independently H. 
     
     
         83 . The method of  claim 74 , wherein each of L 1  and L 2  is independently —C 1 -C 6  heteroalkyl-, —C(O)NR A —, —NR A C(O)—, —C(O)NR A —C 1 -C 6  alkyl-, —C 1 -C 6  alkyl-C(O)NR A —, —NR A C(O)—C 1 -C 6  alkyl-, or —C 1 -C 6  alkyl-NR A C(O)—, each of which is optionally substituted with 1-5 R 4 . 
     
     
         84 . The method of  claim 74 , wherein L 1  is —C 1 -C 6  heteroalkyl-. 
     
     
         85 . The method of  claim 84 , wherein L 1  is —NHCH 2 —. 
     
     
         86 . The method of  claim 74 , wherein L 2  is —NR A C(O)—. 
     
     
         87 . The method of  claim 86 , wherein R A  is —CH 2 CH 3 . 
     
     
         88 . The method of  claim 74 , wherein n is 0. 
     
     
         89 . The method of  claim 74 , wherein o is 0. 
     
     
         90 . The method of  claim 74 , wherein p is 0. 
     
     
         91 . The method of  claim 74 , wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         92 . The method of  claim 74 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), frontotemporal lobar dementia with ubiquitin inclusions (FTLD-U), progranulin-deficient FTLD, frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Huntington's chorea, Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, scrapie, Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Down's syndrome, multiple system atrophy, spinal muscular atrophy (SMA) Type I, SMA Type II, SMA Type III, congenital SMA with arthrogryposis, progressive spinobulbar muscular atrophy, post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease/motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, amyotrophic lateral sclerosis-parkinsonism dementia, Guam-Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler's disease, Krabbe's disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder's disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome and other transmissible spongiform encephalopathies, hereditary spastic paraparesis, Leigh's syndrome, demyelinating diseases, neuronal ceroid lipofuscinoses, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, narcolepsy, fatal familial insomnia, stroke, head injury, autism, or any combination thereof. 
     
     
         93 . The method of  claim 90 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, FTD, ALS, and Parkinson's disease.