Thiazole, imidazole and oxazole compounds and treatments of disorders associated with protein aging

Abstract

Provided are, among other things, compounds of formula I or IA,

1 . A compound of formula I or IA,  
     
       
         
         
             
             
         
       
     
     wherein: 
 a. J is oxygen, sulfur, or N-R d ;  
 b. the carbon 2 to nitrogen bond is a double bond except when R c  is oxo;  
 c. the bond between carbons 4 and 5 is a single bond or a double bond;  
 d. R a  and R b  are 
 1. independently selected from hydrogen, acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, (C1-C3)alkylenedioxy, allyl, amino, ω-alkylenesulfonic acid, carbamoyl, carboxy, carboxyalkyl (which alkyl can be substituted with alkyloxyimino), cycloalkyl, dialkylamino, halo, hydroxy, (C2-C6)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid, alkylsulfonyl, alkylsulfinyl, alkylthio, trifluoromethyl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, piperazin-1-yl, Ar {wherein, consistent with the rules of aromaticity, Ar is C 6  or C 10  aryl or a 5- or 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heterodryl ring contains from one to three atoms of N or one atom of O or S and zero to two atoms of N, each heteroaryl ring can be fused to a substituted benzene, pyridine, pyrimidine, pyridazine, or (1,2,3)triazine (wherein the ring fusion is at a carbon-carbon double bond of Ar)}, Ar-alkyl, ArO—, ArSO 2 —, ArSO—, ArS—, ArSO 2 NH—, ArNH, (N—Ar)(N-alkyl)N—, ArC(O)—, ArC(O)NH—, ArNH—C(O)—, and (N—Ar)(N-alkyl)N C(O)—, or together R 1 , and R 2  comprise methylenedioxy-, wherein at least one of R a  and R b  is other than hydrogen; or  
 2. together with their ring carbons form a C 6 — or C 10 -aryl fused ring; or  
 3. together with their ring carbons form a C 5 -C 7  fused cycloalkyl ring having up to two double bonds including a fused double bond of the containing group, which cycloalkyl ring can be substituted by one or more, of the group consisting of alkyl, alkoxycarbonyl, amino, aminocarbonyl, carboxy, fluoro, or oxo; or  
 4. together with their ring carbons form a fused 5- or 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heteroaryl ring contains from one to three atoms of N or one atom of O or S and zero to two atoms of N; or  
 5. together with their ring carbons form a fused five to eight membered second heterocycle, wherein the fused heterocycle consists of ring atoms selected from the group consisting of carbon, nitrogen, oxygen, sulfur, and S(O) n , wherein n is 1 or 2;  
 
 e. R d  is alkyl, alkenyl, hydrogen, or Ar;  
 f. R c  is 
 1. dialkylamino(C 1 -C 5 )alkyl; or  
 2. —NHC(O)(CH 2 ) n -D-R e R f , wherein D is oxygen, sulfur or nitrogen, wherein where D is nitrogen n is 0, 1 or 2, but when D is oxygen or sulfur n=1 or 2, and R f  is present only when D is nitrogen,  
 wherein 
 (a) Re is 
 (1) Ar,  
 (2) a group of the formula  
                     
 wherein E is sulfur, oxygen, or N—R i , and R g , R h  and R i  are independently the same as R a , R b  and R d , respectively,  
 (3) a C 3 -C 8  cycloalkyl ring having up to one double bond with the proviso that the carbon linking the cyloalkyl ring to D is saturated, which cycloalkyl ring can be substituted by one or more alkyl-, alkoxycarbonyl-, amino-, aminocarbonyl-, carboxy-, fluoro-, or oxo substituents; or  
 (4) a 5- or 6-membered heteroaryl ring containing at least one, and up to three atoms of N for the 6-membered heteroaryl rings and from one to three atoms of N or one atom of O or S and zero to two atoms of N for the 5-membered heteroaryl rings; or  
 (5) hydrogen, (C 2 -C 6 )hydroxyalkyl, alkanoylalkyl, alkyl, alkoxycarbonylalkyl, alkenyl, carboxyalkyl (which alkyl can be substituted with alkoxyimino), alkoxycarbonyl, a group Ar which is C 6 — or C 10 -aryl or a 5- or 6-membered, or 9- or 10-membered heteroaryl (wherein the heteroatom is one oxygen, one sulfur or one nitrogen) or Ar Φ -alkyl; and  
 (b) R f  is independently hydrogen, (C2-C6)hydroxyalkyl, alkanoylalkyl, alkyl, alkoxycarbonylalkyl, alkenyl, carboxyalkyl (which alkyl can be substituted with alkyloxyimino), alkoxycarbonyl, Ar Φ , or Ar Φ -alkyl;  
 wherein aryl, Ar, or Ar Φ  can be substituted with, in addition to any substitutions specifically noted one or more substituents selected from the group of acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, (C1-C3)alkylenedioxy, alkylsulfonyl, alkylsulfinyl, ω-alkylenesulfonic acid, alkylthio, allyl, amino, ArC(O)—, ArC(O)NH—, carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, trifluoromethyl, hydroxy, (C2-C6)hydroxyalkyl, mercapto, nitro, ArO—, Ar—, Ar alkyl-, sulfamoyl, sulfonic acid, 1-pyrrolidinyl, 4-[C6 or C I O]arylpiperazin-1-yl-, 4-[C6 or ClOlarylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4 yl, piperazin-1-yl, piperidin-1-yl; and  
 
 
 
 heterocycles, except those of Ar and Ar Φ , can be substituted with in addition to any substitutions specifically noted one or more substituents selected from acylamino, alkanoyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, (C1 to C3)alkylenedioxy, alkylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, amino, ArC(O)—, ArO—, Ar—, Ar-alkyl, carboxy, dialkylamino, fluoro, fluoroalkyl, difluoroalkyl, hydroxy, mercapto, oxo, sulfamoyl, trifluoromethyl, 4-[C 6  or C 10 ]arylpiperidin-1-yl and 4-[C 6  or C 10 ]arylpiperazin-1-yl.  
 
   
   
       2 . The compound of  claim 1 , wherein D is oxygen or sulfur.  
   
   
       3 . The compound of  claim 2 , wherein R e  is 
 (1) Ar,    (2) a group of the formula                          wherein E is sulfur, oxygen, or N—R i , and R g , R h  and R i  are independently the same as R a , R b  and R d , respectively,    (3) a C 3 -C 8  cycloalkyl ring having up to one double bond with the proviso that the carbon linking the cyloalkyl ring to D is saturated, which cycloalkyl ring can be substituted by one or more alkyl-, alkoxycarbonyl-, amino-, aminocarbonyl-, carboxy-, fluoro-, or oxo substituents; or    (4) a 5- or 6-membered heteroaryl ring containing at least one and up to -three atoms of N for the 6-membered heteroaryl rings and from one to three atoms of N or one atom of O or S and zero to two atoms of N for the 5-membered heteroaryl rings.    
   
   
       4 . A compound of formula I or IA,  
     
       
         
         
             
             
         
       
     
     wherein: 
 a. J is sulfur;  
 b. R a  is hydroxyalkyl or alkyl omega-substituted with a tertiary amine which is dialkyl amine or (i) incorporated into a 5- or 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heteroaryl ring contains from one to three atoms of N or one atom of O or S and one to two atoms of N or (ii) incorporated into a 5- or 6-membered non-aromatic heterocyclic ring having one to two ring nitrogens; and  
 C. R b  and R c  are alkyl.  
 
   
   
       5 . A pharmaceutical composition comprising an effective amount of a compound of  claim 4 .  
   
   
       6 . A compound of formula I or IA,  
     
       
         
         
             
             
         
       
     
     wherein: 
 a. J is sulfur;  
 b. the carbon 2 to nitrogen bond is a double bond;  
 c. the bond between carbons 4 and 5 is a double bond;  
 d. R a  and R b  are independently selected from hydrogen, acylamino, alkanoyl, alkanoylalkyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, (C2-C6)hydroxyalkyl, nitro, trifluoromethyl, Ar {wherein, Ar is C 6  or C 10  aryl}, or Ar-alkyl; and  
 e. R c  is alkyl omega-substituted with a tertiary amine which is dialkyl amine or (i) incorporated into a 5- or 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heteroaryl ring contains from one to three atoms of N or one atom of O or S and one to two atoms of N or (ii) incorporated into a 5- or 6-membered non-aromatic heterocyclic ring having one to two ring nitrogens, wherein aryl can be substituted with one or more substituents selected from the group of acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, (C 1 -C 3 )alkylenedioxy, alkylthio, allyl, carboxyalkyl, cycloalkyl, dialkylamino, halo, trifluoromethyl, hydroxy, (C 2 -C 6 )hydroxyalkyl, mercapto, nitro, ArO—, Ar—, or Ar-alkyl-.  
 
   
   
       7 . A pharmaceutical composition comprising an effective amount of a compound of  claim 6 .  
   
   
       8 . A compound of formula I or IA,  
     
       
         
         
             
             
         
       
     
     wherein: 
 a. J is sulfur;  
 b. the carbon 2 to nitrogen bond is a double bond;  
 c. the bond between carbons 4 and 5 is a double bond;  
 d. R a  and R b  are independently selected from hydrogen, acylamino, alkanoyl, alkanoylalkyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, (C2-C6)hydroxyalkyl, nitro, trifluoromethyl, Ar {wherein, Ar is C 6  or C 10  aryl}, or Ar-alkyl;  
 e. R c  is (C 2 -C 5 )alkyl omega-substituted with halo, wherein aryl can be substituted with one or more substituents selected from the group of acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, (C1-C3)alkylenedioxy, alkylthio, allyl, carboxyalkyl, cycloalkyl, dialkylamino, halo, trifluoromethyl, hydroxy, (C2-C6)hydroxyalkyl, mercapto, nitro, ArO—, Ar—, or Ar-alkyl-.