Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof

Abstract

The present invention relates to novel pyrimidine hydroxy amide compounds, and the use of such compounds in the inhibition of HDAC6 and in the treatment of various diseases, disorders or conditions related to HDAC6.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester or prodrug thereof, 
       
       wherein,
 the ring comprising X 1 , X 2 , X 3 , and X 4  is selected from the following: 
 
       
         
           
           
               
               
           
         
         R 1  is H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl optionally substituted heteroarylalkyl, or optionally substituted heteroaryl; and 
         R 2  is H or alkyl; 
         wherein R 1  and R 2  are both not simultaneously H. 
       
     
     
         2 - 4 . (canceled) 
     
     
         5 . The compound of claim  4 , wherein R 1  is H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, phenyl, benzyl, phenethyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, thiophenyl, or tetrahydrofuranyl, each of which may be optionally substituted. 
     
     
         6 . The compound of  claim 5 , wherein R 1  is substituted with 1-4 groups independently selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, and nitro. 
     
     
         7 . The compound of  claim 6 , wherein R 1  is substituted with 1-4 groups independently selected from methyl, phenyl, pyridyl, morpholino, indolyl, pyrazinyl, F, Cl, Br, methoxy, OCF 3 , and trifluoromethyl; each of which may be further substituted by alkyl, aryl, haloalkyl, haloalkoxy, halo, or alkoxy. 
     
     
         8 - 16 . (canceled) 
     
     
         17 . The compound of  claim 1 , of formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester or prodrug thereof, 
       
       wherein,
 R 2  is H or methyl; 
 R 1  is H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, benzyl, phenethyl, pyridyl, or phenyl, each of which may be optionally substituted with 1-4 groups independently selected from methyl, phenyl, pyridyl, morpholino, indolyl, pyrazinyl, F, Cl, Br, methoxy, OCF 3 , trifluoromethyl, OH, NH 2 , CN, and NO 2 , each of which may be further substituted by alkyl, aryl, haloalkyl, halo, or alkoxy. 
 
     
     
         18 - 21 . (canceled) 
     
     
         22 . The compound of  claim 17 , wherein R 1  is phenyl or pyridyl. 
     
     
         23 . (canceled) 
     
     
         24 . The compound of  claim 22 , wherein R 1  is further substituted with 1-4 substituents independently selected from methyl, F, Cl, OCH 3 , CF 3 , OCF 3 , phenyl, pyridyl, morpholinyl, or NO 2 . 
     
     
         25 . The compound of  claim 1 , of formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester or prodrug thereof, 
       
       wherein,
 R 2  is H or methyl; 
 R x  is H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroarylalkyl, heteroaryl, heterocyclic, carbocyclic, —C(O)R 5 , or —S(O) p R 5 ; each of which may be optionally substituted; 
 R y  is H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroarylalkyl, heteroaryl, heterocyclic, carbocyclic, —C(O)R 5 , or —S(O) p R 5 ; each of which may be optionally substituted; or 
 R x  and R y  together with the carbon to which each is attached, forms a cycloalkyl or heterocycloalkyl, each of which is optionally substituted; 
 each R A  is independently alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl, heteroarylalkyl, haloalkyl, haloalkoxy, halo, OH, —NO 2 , —CN, or —NH 2 ; or two R A  groups together with the atoms to which each is attached, can form an optionally substituted ring; 
 each R 5  is independently H, alkyl, carbocycle, heterocycle, aryl, or optionally substituted heteroaryl; 
 m is 0, 1, 2, 3, or 4; and 
 p is 0, 1, 2, or 3. 
 
     
     
         26 - 37 . (canceled) 
     
     
         38 . The compound of  claim 1 , of formula VI: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester or prodrug thereof, 
       
       wherein,
 R x  is H, alkyl, or aryl; each of which is optionally substituted; 
 R y  is H or alkyl; each of which is optionally substituted; 
 each R A  is independently alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl, heteroarylalkyl, haloalkyl, haloalkoxy, halo, OH, —NO 2 , —CN, or —NH 2 ; and 
 m is 0, 1, or 2. 
 
     
     
         39 . The compound of  claim 38 , wherein R x  is H, methyl, ethyl, or phenyl. 
     
     
         40 . The compound of  claim 38 , wherein R y  is H, methyl or ethyl. 
     
     
         41 . The compound of  claim 38 , wherein m is 1 or 2, and each R A  is independently methyl, phenyl, F, Cl, methoxyl, or CF 3 . 
     
     
         42 . (canceled) 
     
     
         43 . The compound of  claim 1 , of formula VII-A: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester or prodrug thereof, 
       
       wherein,
 ring A is a heteroaryl or heterocyclic; 
 R 2  is H or methyl; 
 R x  is H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroarylalkyl, heteroaryl, heterocyclic, carbocyclic, —C(O)R 5 , or —S(O) p R 5 ; each of which may be optionally substituted; 
 R y  is H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroarylalkyl, heteroaryl, heterocyclic, carbocyclic, —C(O)R 5 , or —S(O) p R 5 ; each of which may be optionally substituted; or 
 R x  and R y  together with the carbon to which each is attached, form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted; 
 each R A  is independently alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl, heteroarylalkyl, haloalkyl, haloalkoxy, halo, OH, —NO 2 , —CN, or —NH 2 ; 
 each R 5  is independently H, alkyl, carbocycle, heterocycle, aryl, or optionally substituted heteroaryl; and 
 m is 0, 1, 2, 3, or 4. 
 
     
     
         44 . The compound of  claim 43 , wherein ring A is acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, or xanthenyl. 
     
     
         45 . (canceled) 
     
     
         46 . The compound of  claim 43 , wherein R x  is H, alkyl, aryl, or heteroaryl. 
     
     
         47 . The compound of  claim 43 , wherein R y  is H, alkyl, aryl, or heteroaryl. 
     
     
         48 . The compound of  claim 43 , wherein R x  is H, methyl or pyridine, and R y  is H. 
     
     
         49 . The compound of  claim 43 , wherein R x  and R y  together with the carbon to which each is attached, forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, each of which is optionally substituted. 
     
     
         50 . The compound of  claim 49 , wherein R x  and R y  together with the carbon to which each is attached, forms tetrahydropyran, piperidine, piperazine, morpholine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxozolidine, or imidazolidine, each of which is optionally substituted. 
     
     
         51 . The compound of  claim 43 , wherein R A  is H, alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl, heteroarylalkyl, haloalkyl, haloalkoxy, halo, OH, —NO 2 , —CN, or —NH 2 ; and m is 0 or 1. 
     
     
         52 - 56 . (canceled) 
     
     
         57 . The compound of  claim 1 , selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         58 . (canceled) 
     
     
         59 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable ester, salt, or prodrug thereof, together with a pharmaceutically acceptable carrier. 
     
     
         60 . A method of selectively inhibiting HDAC6 over other HDACs in a subject, comprising administering to the subject a compound of  claim 1   or a pharmaceutically acceptable salt, ester or prodrug thereof.   
     
     
         61 - 63 . (canceled) 
     
     
         64 . A method of treating a disease mediated by HDAC6 in a subject comprising administering to the subject a compound of  claim 1   or a pharmaceutically acceptable salt, ester or prodrug thereof.   
     
     
         65 - 74 . (canceled)