Activators of class i histone deacetylases (hdacs) and uses thereof

Abstract

The present invention provides compounds of Formulae (A), (B), (C), and (D), pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, pharmaceutical compositions thereof, and kits thereof. The present invention further provides methods of using the compounds to treat or prevent neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis), traumatic brain injury, ischemic brain injury, stroke, frontal temporal dementia, Pick's disease, corticobasal degeneration, supra cerebral palsy, prion diseases (e.g., Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia, and Kuru), Nieman Pick type C, spinal cerebellar ataxia, spinal muscular dystrophy, ataxia telangiectasia, hippocampal sclerosis, Cockayne syndrome, Werner syndrome, xeroderma pigmentosaum, and Bloom syndrome. In one aspect, the methods include administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of DAC-001, DAC-002, DAC-003, DAC-009, or DAC-012, or a compound of Formula (A), (B), (C), or (D).

1 . A compound of Formula (A): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein
 each instance of X A1 , X A2 , and X A3  is independently oxygen or sulfur; 
 each instance of R A1  and R A2  is independently hydrogen, a nitrogen protecting group, or C 1-6  alkyl; 
 Ar is optionally substituted aryl or optionally substituted heteroaryl; 
 each instance of R A3  and R A4  is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A3a , —N(R A3b ) 2 , —SR A3a , —C(═O)R A3a , —C(═O)OR A3a , —C(═O)SR A3a , —C(═O)N(R A3b ) 2 , —OC(═O)R A3a , —OC(═O)OR A3a , —OC(═O)SR A3a , —OC(═O)N(R A3b ) 2 , —NR A3b C(═O)R A3b , —NR A3b C(═O)OR A3a , —NR A3b C(═O)SR A3a , —NR A3b C(═O)N(R A3b ) 2 , —SC(═O)R A3a , —SC(═O)OR A3a , —SC(═O)SR A3a , —SC(═O)N(R A3b ) 2 , —C(═NR A3b )R A3a , —C(═NR A3b )OR A3a , —C(═NR A3b )SR A3a , —C(═NR A3b )N(R A3b ) 2 , —OC(═NR A3b )R A3a , —OC(═NR A3b )OR A3a , —OC(═NR A3b )SR A3a , —OC(═NR A3b )N(R A3b ) 2 , —NR A3b C(═NR A3b )R A3b , —NR A3b C(═NR A3b )OR A3a , —NR A3b C(═NR A3b )SR A3a , —NR A3b C(═NR A3b )N(R A3b ) 2 , —SC(═NR A3b )R A3a , —SC(═NR A3b )OR A3a , —SC(═NR A3b )SR A3a , —SC(═NR A3b )N(R A3b ) 2 , —C(═S)R A3a , —C(═S)OR A3a , —C(═S)SR A3a , —C(═S)N(R A3b ) 2 , —OC(═S)R A3a , —OC(═S)OR A3a , —OC(═S)SR A3a , —OC(═S)N(R A3b ) 2 , —NR A3b C(═S)R A3b , —NR A3b C(═S)OR A3a , —NR A3b C(═S)SR A3a , —NR A3b C(═S)N(R A3b ) 2 , —SC(═S)R A3a , —SC(═S)OR A3a , —SC(═S)SR A3a , —SC(═S)N(R A3b ) 2 , —S(═O)R A3a , —SO 2 R A3a , —NR A3b SO 2 R A3a , —SO 2 N(R A3b ) 2 , —CN, —SCN, and —NO 2 , wherein each occurrence of R A3a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R A3b  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R A3b  groups are joined to form an optionally substituted heterocyclic ring; 
 m is 0, 1, 2, 3, or 4; and 
 n is 0, 1, 2, or 3. 
 
     
     
         2 . The compound of  claim 1 , wherein the compound of Formula (A) is not of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein
 X A1  is oxygen; and   X A2  is sulfur.   
     
     
         4 . The compound of  claim 1 , wherein X A3  is oxygen. 
     
     
         5 . The compound of  claim 1 , wherein R A1  and R A2  are hydrogen. 
     
     
         6 . The compound of  claim 1 , wherein
 X A1  and X A3  are oxygen;   X A2  is sulfur; and   R A1  and R A2  are hydrogen.   
     
     
         7 . The compound of  claim 1 , wherein Ar is optionally substituted aryl. 
     
     
         8 . The compound of  claim 7 , wherein the compound is of formula: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein 
       each instance of R AI  is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR AIa , —N(R AIb ) 2 , —SR AIa , —C(═O)R AIa , —C(═O)OR AIa , —C(═O)SR AIa , —C(═O)N(R AIb ) 2 , —OC(═O)R AIa , —OC(═O)OR AIa , —OC(═O)SR AIa , —OC(═O)N(R AIb ) 2 , —NR AIb C(═O)R AIb , —NR AIb C(═O)OR AIa , —NR AIb C(═O)SR AIa , —NR AIb C(═O)N(R AIb ) 2 , —SC(═O)R AIa , —SC(═O)OR AIa , —SC(═O)SR AIa , —SC(═O)N(R AIb ) 2 , —C(═NR AIb )R AIa , —C(═NR AIb )OR AIa , —C(═NR AIb )SR AIa , —C(═NR AIb )N(R AIb ) 2 , —OC(═NR AIb )R AIa , —OC(═NR AIb )OR AIa , —OC(═NR AIb )SR AIa , —OC(═NR AIb )N(R AIb ) 2 , —NR AIb C(═NR AIb )R AIb , —NR AIb C(═NR AIb )OR AIa , —NR AIb C(═NR AIb )SR AIa , —NR AIb C(═NR AIb )N(R AIb ) 2 , —SC(═NR AIb )R AIa , —SC(═NR AIb )OR AIa , —SC(═NR AIb )SR AIa , —SC(═NR AIb )N(R AIb ) 2 , —C(═S)R AIa , —C(═S)OR AIa , —C(═S)SR AIa , —C(═S)N(R AIb ) 2 , —OC(═S)R AIa , —OC(═S)OR AIa , —OC(═S)SR AIa , —OC(═S)N(R AIb ) 2 , —NR AIb C(═S)R AIb , —NR AIb C(═S)OR AIa , —NR AIb C(═S)SR AIa , —NR AIb C(═S)N(R AIb ) 2 , —SC(═S)R AIa , —SC(═S)OR AIa , —SC(═S)SR AIa , —SC(═S)N(R AIb ) 2 , —S(═O)R AIa , —SO 2 R AIa , —NR AIb SO 2 R AIa , —SO 2 N(R AIb ) 2 , —CN, —SCN, and —NO 2 , wherein each occurrence of R Ala  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or each occurrence of R AIb  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R AIb  groups are joined to form a heterocyclic ring; and 
       j is 0, 1, 2, 3, 4, or 5. 
     
     
         9 . The compound of  claim 8 , wherein the compound is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 9 , wherein the compound is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , wherein Ar is optionally substituted heteroaryl. 
     
     
         12 . The compound of  claim 11 , wherein the compound is of formula: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein
 each instance of R AII  is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR AIIa , —N(R AIIb ) 2 , —SR AIIa , —C(═O)R AIIa , —C(═O)OR AIIa , —C(═O)SR AIIa , —C(═O)N(R AIIb ) 2 , —OC(═O)R AIIa , —OC(═O)OR AIIa , —OC(═O)SR AIIa , —OC(═O)N(R AIIb ) 2 , —NR AIIb C(═O)R AIIb , —NR AIIb C(═O)OR AIIa , —NR AIIb C(═O)SR AIIa , —NR AIb C(═O)N(R AIIb ) 2 , —SC(═O)R AIIa , —SC(═O)OR AIIa , —SC(═O)SR AIa , —SC(═O)N(R AIIb ) 2 , —C(═NR AIIb )R AIIa , —C(═NR AIIb )OR AIIa , —C(═NR AIIb )SR AIIa , —C(═NR AIIb )N(R AIIb ) 2 , —OC(═NR AIIb )R AIIa , —OC(═NR AIIb )OR AIIa , —OC(═NR AIIb )SR AIIa , —OC(═NR AIIb )N(R AIIb ) 2 , —NR AIIb C(═NR AIIb )R AIIb , —NR AIIb C(═NR AIIb )OR AIIa , —NR AIIb C(═NR AIIb )SR AIIa , —NR AIIb C(═NR AIIb )N(R AIIb ) 2 , —SC(═NR AIIb )R AIIa , —SC(═NR AIIb )OR AIIa , —SC(═NR AIIb )SR AIIa , —SC(═NR AIIb )N(R AIIb ) 2 , —C(═S)R AIIa , —C(═S)OR AIIa , —C(═S)SR AIIa , —C(═S)N(R AIIb ) 2 , —OC(═S)R AIIa , —OC(═S)OR AIIa , —OC(═S)SR AIa , —OC(═S)N(R AIIb ) 2 , —NR AIIb C(═S)R AIIb , —NR AIIb C(═S)OR AIIa , —NR AIIb C(═S)SR AIIa , —NR AIIb C(═S)N(R AIIb ) 2 , —SC(═S)R AIIa , —SC(═S)OR AIIa , —SC(═S)SR AIa , —SC(═S)N(R AIIb ) 2 , —S(═O)R AIIa , —SO 2 R AIIa , —NR AIIb SO 2 R AIIa , —SO 2 N(R AIIb ) 2 , —CN, —SCN, and —NO 2 , wherein each occurrence of R AIIa  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and each occurrence of R AIIb  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R AIIb  groups are joined to form a heterocyclic ring; and 
 k is 0, 1, 2, or 3. 
 
     
     
         13 . The compound of  claim 12 , wherein the compound is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         14 - 46 . (canceled) 
     
     
         47 . A compound of Formula (D): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein
 each instance of X D1  is independently oxygen, sulfur, —NR D1a , or C(R D1b ) 2 , wherein R D1a  is hydrogen or C 1-6  alkyl, and each occurrence of R D1b  is hydrogen, halogen, or C 1-6  alkyl, or two R D1b  groups are joined to form an optionally substituted carbocyclic or heterocyclic ring; 
 s is 0, 1, 2, 3, 4, 5, or 6; 
 each instance of R D1  and R D2  is independently hydrogen, an oxygen protecting group, C 1-6  alkyl, —C(═O)R D2a , —C(═O)OR D2a , —C(═O)SR D2a , —C(═O)N(R D2b ) 2 , —S(═O)R D2a , or —S(═O) 2 R D2a  wherein each occurrence of R D2a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R D2b  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R D2b  groups are joined to form an optionally substituted heterocyclic ring; 
 each instance of R D3  and R D4  is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR D4a , —N(R D4b ) 2 , —SR D4a , —C(═O)R D4a , —C(═O)OR D4a , —C(═O)SR D4a , —C(═O)N(R D4b ) 2 , —OC(═O)R D4a , —OC(═O)OR D4a , —OC(═O)SR D4a , —OC(═O)N(R D4b ) 2 , —NR D4b C(═O)R D4b , —NR D4b C(═O)OR D4a , —NR D4b C(═O)SR D4a , —NR D4b C(═O)N(R D4b ) 2 , —SC(═O)R D4a , —SC(═O)OR D4a , —SC(═O)SR D4a , —SC(═O)N(R D4b ) 2 , —C(═NR D4b )R D4a , —C(═NR D4b )OR D4a , —C(═NR D4b )SR D4a , —C(═NR D4b )N(R D4b ) 2 , —OC(═NR D4b )R D4a , —OC(═NR D4b )OR D4a , —OC(═NR D4b )SR D4a , —OC(═NR D4b )N(R D4b ) 2 , —NR D4b C(═NR D4b )R D4b , —NR D4b C(═NR D4b )OR D4a , —NR D4b C(═NR D4b )SR D4a , —NR D4b C(═NR D4b )N(R D4b ) 2 , —SC(═NR D4b )R D4a a, —SC(═NR D4b )OR D4a , —SC(═NR D4b )SR D4a , —SC(═NR D4b )N(R D4b ) 2 , —C(═S)R D4a , —C(═S)OR D4a , —C(═S)SR D4a , —C(═S)N(R D4b ) 2 , —OC(═S)R D4a , —OC(═S)OR D4a , —OC(═S)SR D4a , —OC(═S)N(R D4b ) 2 , —NR D4b C(═S)R D4b , —NR D4b C(═S)OR D4a , —NR D4b C(═S)SR D4a , —NR D4b C(═S)N(R D4b ) 2 , —SC(═S)R D4a , —SC(═S)OR D4a , —SC(═S)SR D4a , —SC(═S)N(R D4b ) 2 , —S(═O)R D4a , —SO 2 R D4a , —NR D4b SO 2 R D4a , —SO 2 N(R D4b ) 2 , —CN, —SCN, and —NO 2 , wherein each occurrence of R D4a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R D4b  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R D4b  groups are joined to form an optionally substituted heterocyclic ring; 
 t is 0, 1, 2, or 3; and 
 u is 0, 1, 2, 3, 4 or 5. 
 
     
     
         48 - 57 . (canceled) 
     
     
         58 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. 
     
     
         59 . (canceled) 
     
     
         60 . A method for treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. 
     
     
         61 - 121 . (canceled) 
     
     
         122 . A method for treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (B): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein
 each instance of X B1 , X B3 , and X B4  is independently oxygen, sulfur, —NR B4a , or C(R B4b ) 2 , wherein R B4a  is hydrogen, a nitrogen protecting group, or C 1-6  alkyl, and each occurrence of R B4b  is hydrogen, halogen, or C 1-6  alkyl, or two R B4b  groups are joined to form an optionally substituted carbocyclic or heterocyclic ring; 
 X B2  is nitrogen or CR B2a , wherein R B2a  is hydrogen, halogen, or C 1-6  alkyl; 
 each instance of R B1  is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR B1a , —N(R B1b ) 2 , —SR B1a , —C(═O)R B1a , —C(═O)OR B1a , —C(═O)SR B1a , —C(═O)N(R B1b ) 2 , —OC(═O)R B1a , —OC(═O)OR B1a , —OC(═O)SR B1a , —OC(═O)N(R B1b ) 2 , —NR B1b C(═O)R B1b , —NR B1b C(═O)OR B1a , —NR B1b C(═O)SR B1a , —NR B1b C(═O)N(R B1b ) 2 , —SC(═O)R B1a , —SC(═O)OR B1a , —SC(═O)SR B1a , —SC(═O)N(R B1b ) 2 , —C(═NR B1b )R B1a , —C(═NR B1b )OR B1a , —C(═NR B1b )SR B1a , —C(═NR B1b )N(R B1b ) 2 , —OC(═NR B1b )R B1a , —OC(═NR B1b )OR B1a , —OC(═NR B1b )SR B1a , —OC(═NR B1b )N(R B1b ) 2 , —NR B1b C(═NR B1b )R B1b , —NR B1b C(═NR B1b )OR B1a , —NR B1b C(═NR B1b )SR B1a , —NR B1b C(═NR B1b )N(R B1b ) 2 , —SC(═NR B1b )R B1a , —SC(═NR B1b )OR B1a , —SC(═NR B1b )SR B1a , —SC(═NR B1b )N(R B1b ) 2 , —C(═S)R B1a , —C(═S)OR B1a , —C(═S)SR B1a , —C(═S)N(R B1b ) 2 , —OC(═S)R B1a , —OC(═S)OR B1a , —OC(═S)SR B1a , —OC(═S)N(R B1b ) 2 , —NR B1b C(═S)R B1b , —NR B1b C(═S)OR B1a , —NR B1b C(═S)SR B1a , —NR B1b C(═S)N(R B1b ) 2 , —SC(═S)R B1a , —SC(═S)OR B1a , —SC(═S)SR B1a , —SC(═S)N(R B1b ) 2 , —S(═O)R B1a , —SO 2 R B1a , —NR B1b SO 2 R B1a , —SO 2 N(R B1b ) 2 , —CN, —SCN, and —NO 2 , wherein each occurrence of R B1a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R B1b  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R B1b  groups are joined to form an optionally substituted heterocyclic ring; 
 each instance of R B2 , R B3 , R B4 , and R B5  is independently hydrogen, halogen, or C 1-6  alkyl; 
 R B6  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR B6a , —N(R B6b ) 2 , or —SR B6a , wherein each occurrence of R B6a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R B6b  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R B6b  groups are joined to form an optionally substituted heterocyclic ring; and 
 p is 0, 1, 2, 3, or 4. 
 
     
     
         123 . A pharmaceutical composition comprising a compound of  claim 47 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. 
     
     
         124 . A method for treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of  claim 47 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.