HDAC inhibitors and therapeutic methods using the same

Abstract

Histone deacetylases inhibitors (HDACIs) and compositions containing the same are disclosed. Methods of treating diseases and conditions wherein inhibition of HDAC provides a benefit, like a cancer, a neurodegenerative disorder, a peripheral neuropathy, a neurological disease, traumatic brain injury, stroke, hypertension, malaria, an autoimmune disease, autism, autism spectrum disorders, and inflammation, also are disclosed.

What is claimed: 
     
       1. A compound having a structural formula
   Cap-L-M 
 wherein Cap is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         wherein ring 
       
       
         
           
           
               
               
           
         
          is an aliphatic or aromatic five or six membered ring, 
         W, X, Y, and Z independently are selected from the group consisting of null, C(R 1 ) 2 , O, S, and NR 1 , 
         ring 
       
       
         
           
           
               
               
           
         
          is an aliphatic or aromatic six membered ring, 
         wherein D, E, F, and G independently are selected from the group consisting of C(R 1 ) 2 , O, and S, 
         or ring 
       
       
         
           
           
               
               
           
         
          is an aliphatic or aromatic five membered ring, wherein D, E, F, and G are selected from the group consisting of null, C(R 1 ) 2 , and NR 1 , 
         R 1 , independently, is selected from the group consisting of null, hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 1-6 perfluoroalkyl, C 1-6 perfluoroalkoxy, aryl, heteroaryl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-6 alkylenearyl, C 1-6 alkyleneheteroaryl, C 1-6 alkyleneheterocycloalkyl, C 1-6 alkylenecycloalkyl, 
       
       
         
           
           
               
               
           
         
          OR a , halo, N(R a ) 2 , SR a , SOR a , SO 2 R a , CN, C(═O)R a , CF 3 , OCF 3 , NO 2 , OC(═O)R a , SO 2 N(R a ) 2 , OSO 2 CF 3 , C(═O)OR a , C(═O)N(R a ) 2 , C 1-6 alkyleneN(R a ) 2 , C 1-6 alkyleneC(═O)R a , C 1-6 alkyleneOR a , C 1-6 alkyleneSR a , C 1-6 alkyleneNR a SO 2 R a , C 1-6 alkyleneSOR a , C 1-6 alkyleneCN, C 1-6 heteroalkyleneCN, C 1-6 alkyleneC(═O)OR a , C 1-6 alkyleneOC(═O)N(R a ) 2 , C 1-6 alkyleneNR a C(═O)OR a , C 1-6 alkyleneNR a C(═O)R a , C 1-6 alkylene C(═O)N(R a ) 2  C 1-6 alkyleneC(═O)N(R a ) 2 , C 1-6 alkyleneOC 1-6 alkyleneC(═O)OR a , C(═O)NR a SO 2 R a , C(═O)C 1-6 alkylenearyl, C(═O)NR a C 1-6 alkyleneOR a , OC 1-6 alkyleneC(═O)OR a , OC 1-6 alkyleneN(R a ) 2 , OC 1-6 alkyleneOR a , OC 1-6 alkyleneNR a C(═O)OR a , NR a C 1-6 alkyleneN(R a ) 2 , NR a C(═O)R a , NR a C(═O)N(R a ) 2 , N(SO 2 C 1-6 alkyl) 2 , and NR a (SO 2 C 1-6 alkyl), and 
         R a , independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkyleneNH 2 , C 1-6 alkyleneNH(C 1-6 alkyl), C 1-6 alkyleneN(C 1-6 alkyl) 2 , C 1-6 alkyleneNH(C 1-6 alkyl) 2 , C 1-6 alkyleneNHC(═O)(C 1-6 alkyl), C 1-6 alkyleneC(═O)NH 2 , C 1-6 alkyleneOH, C 1-6 alkyleneCN, C 1-6 heteroalkyleneCN, C 1-6 alkyleneOC 1-6 alkyl, C 1-6 alkyleneSH, C 1-6 alkyleneSC 1-6 alkyl, C 1-6 alkyleneNH(SO 2 C 1-6 alkyl), aryl, heteroaryl, C 3-8 cycloalkyl, and C 3-10 heterocycloalkyl, 
         wherein linker L is attached to any atom D, E, F, or G, and  
       
       
         
           
           
               
               
           
         
         wherein ring 
       
       
         
           
           
               
               
           
         
          is an aliphatic or aromatic five or six membered ring, 
         E, F, W, X, Y, Z, R 1 , and R a  are as defined above, and 
       
       
         
           
           
               
               
           
         
         wherein A is C, N, O, S, B, or P, and L is attached to A, 
         R 2 , R 3  and R 4  independently are selected from the group consisting of null, hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 1-6 perfluoroalkyl, C 1-6 perfluoroalkoxy, aryl, heteroaryl, C 3-10 cycloalkyl, C 3-8 heterocycloalkyl, C 1-6 alkylenearyl, C 1-6 alkyleneheteroaryl, C 1-6 alkyleneheterocycloalkyl, C 1-6 alkylenecycloalkyl, 
       
       
         
           
           
               
               
           
         
          OR a , halo, N(R a ) 2 , SR a , SOR a , SO 2 R a , CN, C(═O)R a , OC(═O)R a , C(═O)OR a , C 1-6 alkyleneN(R a ) 2 , C 1-6 alkyleneOR a , C 1-6 alkyleneSR a , C 1-6 alkyleneC(═O)OR a , C(═O)N(R a ) 2 , C(═O)NR a C 1-6 alkyleneOR a , OC 1-6 alkyleneC(═O)OR a , OC 1-6 alkyleneN(R a ) 2 , OC 1-6 alkyleneOR a , OC 1-6 alkyleneNR a C(═O)OR a , NR a C 1-6 alkyleneN(R a ) 2 , NR a C(═O)R a , NR a C(═O)N(R a ) 2 , N(SO 2 C 1-6 alkyl) 2 , NR a (SO 2 C 1-6 alkyl), nitro, and SO 2 N(R a ) 2 , and 
         R a  is defined above; wherein at least one of E, F, W, X, Y, and Z is NR 1 ;  
         L is selected from the group consisting of null, C 1-8 alkylene, R a  substituted C 1-8 alkylene, NR a , C(═O), aryl, C(═O)aryl, C(═O)C 1-6 alkylene, C 1-8 alkyleneNR a , C 1-6 alkylenearyleneC 1-6 alkylene, C 2-6 alkenylene, C 4-8 alkdienylene, C 1-6 alkylenearylene, C 1-6 alkyleneheteroarylene, R a  substituted C 1-6 alkyleneheteroarylene, and C 2-6 alkenylenearyleneC 1-6 alkylene, and R a  is defined above CH 2 —C 6 H 5 ; 
         M is  
       
       
         
           
           
               
               
           
         
        
          selected from the group consisting of —C(═O)N(R b )OH, 
         —O(CH 2 ) 1-6 C(═O)N(R b )OR b , 
         —N(R b )(CH 2 ) 1-6 C(═O)N(R b )OR b , 
         —N(R b )(CH 2 ) 1-6 C(═O)N(R b )OR b , 
         arylC(═O)NHOH, 
         —N(OH)C(═O)R b , 
         heteroarylC(═O)NHOH, 
         —C 3-6 cycloalkylN—C(═O)CH 2 SH, 
         —B(OR b ) 2 , 
         SO 2 NHR b , 
         —NHSO 2 NHR b , 
         NHSO 2 C 1-6 alkyl, 
         —SO 2 C 1-6 alkyl, 
         —SR c , 
       
       
         
           
           
               
               
           
         
         —C(═O)R e , 
         —P(═O)(OR f ) 2 , 
         —NH—P(═O)(OR f ) 2 , 
       
       
         
           
           
               
               
           
         
         —C(═O)(C(R b ) 2 ) 1-6 SH, 
         —C(═O)C(═O)NHR b , 
         —C(═O)NHN(R b ) 2 , 
         —C(═O)NH(CH 2 ) 1-3 N(R b ) 2 , 
       
       
         
           
           
               
               
           
         
         —S—(C═O)C 1-6 alkyl, 
         C 3-10 heterocycloalkyl optionally substituted with oxo (═O), thioxo (═S), or both, 
         aryl optionally substituted with one or more of C 1-6 alkyl, —C(═O)R d , —NH 2 , and —SH, 
         heteroaryl optionally substituted with —NH 2 , —SH, or both, 
         —N(H)C(═O)SH, 
         —NHC(═O)NHR d , 
         —NHC(═O)CH 2 R d , 
         —NHC(═O)(CH 2 ) 1-6 SH, 
         —NHC(═O)CH 2 Hal, 
         —NHC(═S)NHR d , 
         —NHC(═S)CH 2 R d , 
         —C(═S)NHR d , 
         —C(═S)CH 2 R d , 
         —NHC(═S)CH 2 R d , 
         —NHC(═S)CH 2 Hal, and 
         —(C═O)C 1-6 alkyl; 
         R b , independently, is selected from the group consisting of hydrogen, (C═O)CH 3 , C 1-6 alkyl, CF 3 , CH 2 F, and aryl, or two R b  groups are taken together with the carbon to which they attached to form a C 3-8 cycloalkyl group; 
         R c  is selected from hydrogen or (C═O)CH 3 ; 
         R d  is NH 2  or OH; 
         R e  is selected from the group consisting of OH, N(R b ) 2 , NH(OCH 3 ), N(CH 3 )OH, C 1-6 alkyl, CF 3 , aryl, heteroaryl, C 3-8 cycloalkyl, NHSO 2 CH 3 , NHSO 2 CF 3 , and C 1-6 haloalkyl; 
         R f  independently is hydrogen, methyl, or ethyl; and 
         Hal is halo, 
         or a pharmaceutically acceptable salt, hydrate, or prodrug thereof. 
       
     
     
       2. The compound of  claim 1  wherein the bicyclic ring system 
       
         
           
           
               
               
           
         
         is selected from a residue of the group consisting of thionaphthene, isothionaphthene, indole, indolenine, 1H-isoindole, cyclopenta[b]pyridine, pyrano[3,4-b]pyrrole, indazole, benzisoxazole, benzoxazole, anthranil, naphthalene, tetralin, decalin, 2H-1-benzopyran, coumarin, coumarin-4-one, isochromen-1-one, isochromen-3-one, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyrido[3,4-b]-pyridine, pyrido[3,2-b]-pyridine, pyrido[4,3-b]-pyridine, 2H-1,3-benzoxazine, 1H-2,3-benzoxazine, 4H-3,1-benzoxazine, 2H-1,2-benzoxazine, 4H-1,4-benzoxazine, purine, indoline, benzo(b)furan, indene, pteridine, quinoxaline, benzimidazole, benzthiazole, and phthalzine, 
         and wherein the linker L is attached to any atom D, E, F, G, W, X, Y, or Z. 
       
     
     
       3. The compound of  claim 1  wherein 
       
         
           
           
               
               
           
         
         is selected from the group consisting of cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, cycloheptyl, cycloheptenyl, phenyl, furanyl, 2H-pyrrolyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3,-oxadiazolyl, 1,2,3,-triazolyl, 1,2,5-oxadiazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl,oxazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 3H-pyrrolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 3H-1,2,3-dioxazolyl, 1,3,2-dioxazolyl, 1,2-dithiolyl, 5H-1,2,5-oxathiazolyl, 1,3-oxathiolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrimidinyl, piperazinyl, 2-pyronyl, 4-pyronyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 4H-1,3-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 4H-1,4-oxazinyl, 2H-1,2-oxazinyl, 1,4-oxazinyl, p-isoxazinyl, o-isoxazinyl, pyridinyl, 1,2,6-oxathiazinyl, 1,2,5-oxathiazinyl, 1,4,2-oxadiazinyl, pyridazinyl, and pyrazinyl, azacycloheptyl, azacycloheptenyl, oxacycloheptyl, and thiacycloheptyl, 
         wherein linker L is attached to any atom U, V E, F, W, X, Y, or Z. 
       
     
     
       4. The compound of  claim 1  wherein the Cap group has a structure: 
       
         
           
           
               
               
           
         
         either unsubstituted or substituted with one or more R 1 . 
       
     
     
       5. The compound of  claim 1  wherein 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       6. The compound of  claim 1  wherein R 1  is selected from the group consisting of null, hydrogen, OR a , halo, C 1-6 alkyl, aryl, heterocycloalkyl, —(CH 2 ) 1-4 heterocycloalkyl, —(CH 2 ) 1-4 N(R a ) 2 , 
       
         
           
           
               
               
           
         
       
       or —C(═O)N(CH 2 ) 1-4 N(R a ) 2 . 
     
     
       7. The compound of  claim 1  wherein R a  is selected from the group consisting of null, hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, aryl, and heteroaryl. 
     
     
       8. The compound of  claim 1  wherein L is null, —(CH 2 ) 1-6 —, 
       
         
           
           
               
               
           
         
       
       optionally substituted with halo, CF 3 , or CN, 
       
         
           
           
               
               
           
         
       
       —CH 2 —CH═CH—CH═CH—, —(CH 2 ) 2 —CH═CH—CH═CH 2 —, —(CH 2 ) 0-6 —NH—, 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       9. The compound of  claim 1  wherein M is 
       
         
           
           
               
               
           
         
       
       —SC(═O)tBu, —SC(═O)CF 3 , —S(CH 2 ) 1-3 C(═O)CF 3 , —CH 2 SAc, 
       
         
           
           
               
               
           
         
       
       —NH—C(═O)CH 2 SH, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
        
       
     
     
       10. The compound of  claim 1  wherein the Cap group is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       11. A composition comprising (a) compound of  claim 1 , (b) an optional second therapeutic agent useful in the treatment of a disease or condition wherein inhibition of histone deacetylase provides a benefit, and (c) an excipient and/or pharmaceutically acceptable carrier. 
     
     
       12. A compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       13. A compound having a structure 
       
         
           
           
               
               
           
         
       
     
     
       14. A compound having a structure 
       
         
           
           
               
               
           
         
         wherein Cap is selected from the group consisting of