Aminopyrrolidinone Derivatives and Uses Thereof

Abstract

The present invention provides compounds of formula I: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, T, R 2 , R 2′ , and R A is as defined and described herein and methods for treating subjects or patients with a disease, disorder, or condition.

We claim: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 Ring A is C3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, a 5-6 membered monocyclic saturated, partially unsaturated or aromatic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally substituted with 1-5 R 1  groups; 
 each R 1  is independently selected from —R, halogen, —OR, —CN, —NO 2 , —SR, —S(O)R, —SO 2 R, —C(O)R, —CO 2 R, —OC(O)R, —C(O)N(R) 2 , —OC(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, —SO 2 N(R) 2 , —N(R) 2 , —C(R) 3 , —Si(CH 3 ) 3 , or an optionally substituted group selected from phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each R is independently hydrogen, deuterium, or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or wherein:
 two R on the same nitrogen are taken together to form a 5-6 membered saturated, partially saturated, or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 
 R A  is hydrogen, deuterium, or C 1-6  aliphatic; 
 T is a valence bond or a bivalent C 1-2  alkylene chain wherein T is optionally substituted with one or two R groups, and wherein two R groups on T are optionally taken together with their intervening atom(s) to form a 3-8-membered saturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each of R 2  and R 2′  is independently hydrogen, deuterium, halogen, or optionally substituted C 1-6  aliphatic; 
 Ring B is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring B is optionally substituted with 1-5 R 3  groups; and 
 each R 3  is independently selected from —R, halogen, —OR, —CN, —NO 2 , —SR, —S(O)R, —SO 2 R, —SO 2 N(R) 2 , —C(O)R, —CO 2 R, —OC(O)R, —OC(O)N(R) 2 , —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, —N(R) 2 , —C(R) 3 , —Si(CH 3 ) 3 , or an optionally substituted group selected from phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
 
     
     
         2 . The compound of  claim 1 , wherein Ring B is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , wherein at least one of R 3  is selected from the group consisting of R, halogen, —OR, —CN, and —N(R) 2 . 
     
     
         4 . The compound of  claim 3 , wherein R 3  is CN. 
     
     
         5 . The compound of  claim 1 , wherein R A  is hydrogen. 
     
     
         6 . The compound of  claim 1 , wherein R 2  and R 2′  are each hydrogen. 
     
     
         7 . The compound of  claim 1 , wherein Ring A is selected from the group consisting of phenyl, 6-membered monocyclic saturated or partially unsaturated or aromatic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 10-membered bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each is optionally substituted with 1-5 R 1  groups. 
     
     
         8 . The compound of  claim 7 , wherein Ring A is selected from the group consisting of phenyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one, chromanyl, naphthyl, or 1,2,3,4-tetrahydronaphthalenyl, wherein each ring is optionally substituted with 1-2 R 1  groups. 
     
     
         9 . The compound of  claim 8 , wherein Ring A is selected from the group consisting of phenyl, chromanyl, and 1,2,3,4-tetrahydronaphthalenyl. 
     
     
         10 . The compound of  claim 7 , wherein at least one R 1  is selected from the group consisting of R, halogen, —OR, —CN, —N(R) 2 , —CF 3 , —CHF 2 , or CH 3 . 
     
     
         11 . The compound of  claim 10 , wherein at least one R 1  is selected from halogen, C 1 -C 6  aliphatic, —CN, —CHF 2 , —CF 3 , and phenyl. 
     
     
         12 . The compound of  claim 1 , wherein T is a valence bond or —CH 2 —. 
     
     
         13 . The compound of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 
     
     
         15 . A method of treating a proteinopathic subject, wherein the method comprises administering to the subject a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method of  claim 15 , wherein the proteinopathic subject is suffering from a neurodegenerative disease, a cognitive impairment, dementia, depression, anxiety, a lysosomal storage disease, an ocular disease, an inflammatory disease, a cardiovascular disease, a proliferative disease, immunologic disease, a myopathy, diabetes, obesity, traumatic brain injury, an immunological disease or a mitochondrial disease. 
     
     
         17 . The method of  claim 16 , wherein neurodegenerative disease is selected from Parkinson's disease, diffuse Lewy body disease, multiple system atrophy, pantothenate kinase-associated neurodegeneration, amyotrophic lateral sclerosis, Huntington's disease, and Alzheimer's disease. 
     
     
         18 . The method of  claim 16 , wherein the proteinopathic subject is suffering from a mitochondrial disease, wherein decreased mitochondrial function is responsible, wholly, or in part, for the symptoms of the disease. 
     
     
         19 . The method of  claim 18 , wherein the disease that the subject is suffering from is selected from MELAS, Leber syndrome, type 2 diabetes, Alzheimer's disease, Parkinson's disease, Crohn's disease, mitochondrial myopathy, progressive supranclear palsy, Lewy body disease, ALS (amyotophic lateral sclerosis/Lou Gehrig's disease), and Huntington's disease. 
     
     
         20 . The method of  claim 15 , wherein the amount administered is an amount sufficient to improve mitochondrial health in the subject.