Selective inhibitors of histone deactylase

Abstract

Described herein are compounds and pharmaceutical compositions containing such compounds, which inhibit the activity of histone deacetylase 8 (HDAC8). Also described herein are methods of using such HDAC8 inhibitors, alone and in combination with other compounds, for treating diseases or conditions that would benefit from inhibition of HDAC8 activity.

1 .- 56 . (canceled) 
     
     
         57 . A method of treating a disease or condition mediated by interleukin-1 beta (IL-1b) or IL-18 in a mammal in need thereof, comprising administering to the mammal a composition comprising a therapeutically effective amount of a compound having a structure of Formula I, Formula II, Formula V, or Formula B: 
       
         
           
           
               
               
           
         
         wherein: 
         each X is CR 3  or N, wherein one X is N; 
         X 2  is a bond, —C 1 -C 6 alkylene-, —C 2 -C 6 alkenylene-, —C 2 -C 6 alkynylene-, —C 1 -C 6 heteroalkylene-, C 1 -C 6 fluoroalkylene, C 2 -C 6 fluoroalkenylene, C 1 -C 6 haloalkylene, C 2 -C 6 haloalkenylene, —C 1 -C 6 alkylene-O—, —C 1 -C 3 alkylene-O—C 1 -C 3 alkylene-, —C 1 -C 6 alkylene-NH—, —C 1 -C 3 alkylene-NH—C 1 -C 3 alkylene-, —C 1 -C 6 alkylene-C(═O)NH—, —C 1 -C 3 alkylene-C(═O)NH—C 1 -C 3 alkylene-, —C 1 -C 6 alkylene-NHC(═O)—, —C 1 -C 3 alkylene-NHC(═O)—C 1 -C 3 alkylene-, —C 1 -C 6 alkylene-S—, —C 1 -C 3 alkylene-S—C 1 -C 3 alkylene-, —C 1 -C 6 alkylene-S(═O)—, —C 1 -C 3 alkylene-S(═O)—C 1 -C 3 alkylene, —C 1 -C 6 alkylene-S(═O) 2 —, —C 1 -C 3 alkylene-S(═O) 2 —C 1 -C 3 alkylene, —C(═O)—, or —C(═O)—C 1 -C 6 alkylene; 
         R 1  is —C(═O)NHOH; 
         R 2  is a substituted or unsubstituted group selected from among aryl, heteroaryl, C 3 -C 10 cycloalkyl, and C 2 -C 10 heterocycloalkyl; where if R 2  is substituted, then R 2  is substituted with 1, 2, or 3 groups selected from among halogen, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkoxy, aminoC 1 -C 6 alkoxy, C 1 -C 3 alkylaminoC 1 -C 3 alkoxy, hydroxyC 1 -C 3 alkylaminoC 1 -C 3 alkoxy, C 2 -C 8 heterocycloalkylC 1 -C 3 alkoxy, C 2 -C 8 heterocycloalkylC 1 -C 2 alkyl, —CN, —NO 2 , —CO 2 R 10 , —C(═O)R 11 , —S—R 11 , —S(═O)—R 11 , —S(═O) 2 —R 11 , —NR 10 C(═O)—R 11 , —C(═O)N(R 10 ) 2 , —S(═O) 2 N(R 10 ) 2 , —NR 10 S(═O) 2 —R 11 , —OC(═O)N(R 10 ) 2 , —NR 10 C(═O)O—R 11 , —OC(═O)O—R 11 , —NHC(═O)NH—R 11 , —OC(═O)—R 11 , —N(R 10 ) 2 , —C 1 -C 2 alkylN(R 10 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 
         R 10  is hydrogen, or a substituted or unsubstituted group selected from among C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, and heteroaryl; 
         R 11  is a substituted or unsubstituted group selected from among C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, and heteroaryl; and 
         each R 3  is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkoxy, C 1 -C 6 heteroalkyl, substituted or unsubstituted phenyl, or C 1 -C 6 aminoalkyl; 
         or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof. 
       
     
     
         58 . The method of  claim 57 , wherein the compound has the structure of Formula B: 
       
         
           
           
               
               
           
         
       
     
     
         59 . The method of  claim 58 , wherein:
 each R 3  is independently hydrogen or C 1 -C 4 alkyl.   
     
     
         60 . The method of  claim 59 , having the structure of Formula IIIb: 
       
         
           
           
               
               
           
         
       
     
     
         61 . The method of  claim 60 , wherein:
 X 2  is a bond, —C 1 -C 6 alkylene-, —C 1 -C 6 alkylene-O—, —C 1 -C 3 alkylene-O—C 1 -C 3 alkylene-, —C 1 -C 6 alkylene-NH—, —C 1 -C 3 alkylene-NH—C 1 -C 3 alkylene-, —C 1 -C 6 alkylene-C(═O)NH—, —C 1 -C 3 alkylene-C(═O)NH—C 1 -C 3 alkylene-, —C 1 -C 6 alkylene-NHC(═O)—, —C 1 -C 3 alkylene-NHC(═O)—C 1 -C 3 alkylene-, —C 1 -C 6 alkylene-S—, —C 1 -C 3 alkylene-S—C 1 -C 3 alkylene-, —C 1 -C 6 alkylene-S(═O)—, —C 1 -C 3 alkylene-S(═O)—C 1 -C 3 alkylene, —C 1 -C 6 alkylene-S(═O) 2 —, —C 1 -C 3 alkylene-S(═O) 2 —C 1 -C 3 alkylene, —C(═O)—, or —C(═O)—C 1 -C 6 alkylene.   
     
     
         62 . The method of  claim 61 , wherein:
 R 2  is a substituted or unsubstituted group selected from phenyl, monocyclic heteroaryl, C 3 -C 6 cycloalkyl, and monocyclic C 2 -C 6 heterocycloalkyl; where if R 2  is substituted, then R 2  is substituted with 1 or 2 groups selected from among halogen, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, C 3 -C 6 heterocycloalkylC 1 -C 2 alkyl, —CN, —NO 2 , —CO 2 R 10 , —C(═O)R 11 , —S—R 11 , —S(═O)—R 11 , —S(═O) 2 —R 11 , —NHC(═O)—R 11 , —C(═O)N(R 10 ) 2 , —S(═O) 2 N(R 10 ) 2 , —NHS(═O) 2 —R 11 , —OC(═O)N(R 10 ) 2 , —NHC(═O)O—R 11 , —OC(═O)O—R 11 , —NHC(═O)NH—R 11 , —OC(═O)—R 11 , —N(R 10 ) 2 , —C 1 -C 2 alkylN(R 10 ) 2 , C 1 -C 1 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 heteroalkyl, C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl.   
     
     
         63 . The method of  claim 62 , wherein:
 X 2  is a bond, —C 1 -C 4 alkylene-, —C 1 -C 4 alkylene-O—, —C 1 -C 4 alkylene-C(═O)NH—, —C 1 -C 4 alkylene-NHC(═O)—, —C 1 -C 4 alkylene-S—, —C 1 -C 4 alkylene-S(═O)—, —C 1 -C 4 alkylene-S(═O) 2 —, —C(═O)—, or —C(═O)—C 1 -C 4 alkylene.   
     
     
         64 . The method of  claim 63 , wherein:
 X 2  is —C 1 -C 4 alkylene- or —C 1 -C 4 alkylene-O—; and   R 2  is a substituted or unsubstituted group selected from among phenyl and monocyclic heteroaryl.   
     
     
         65 . The method of  claim 64 , wherein:
 R 2  is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group; where if R 2  is substituted, then R 2  is substituted with 1 or 2 groups selected from among halogen, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, C 3 -C 6 heterocycloalkylC 1 -C 2 alkyl, —CN, —CO 2 R 10 , —C(═O)R 11 , —NHC(═O)—R 11 , —C(═O)N(R 10 ) 2 , —S(═O) 2 N(R 10 ) 2 , —NHS(═O) 2 —R 11 , —N(R 10 ) 2 , —C 1 -C 2 alkylN(R 10 ) 2 , C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, and C 1 -C 4 heteroalkyl.   
     
     
         66 . The method of  claim 65 , wherein:
 R 2  is a substituted or unsubstituted group selected from phenyl, pyridinyl, pyrimidinyl, triazinyl, pyrrolyl, thiophenyl, and furanyl.   
     
     
         67 . The method of  claim 65 , wherein:
 R 2  is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group.   
     
     
         68 . The method of  claim 66 , wherein:
 R 2  is a substituted or unsubstituted phenyl.   
     
     
         69 . The method of  claim 68 , wherein:
 X 2  is —C 1 -C 4 alkylene-.   
     
     
         70 . The method of  claim 68 , wherein:
 X 2  is C 1 -C 4 alkylene-O—.   
     
     
         71 . The method of  claim 57  or  58 , further comprising administering to the mammal a second therapeutic agent, selected from among abarelix; aldesleukin; Alemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; asparaginase; azacitidine; bevacizumab; bexarotene; bleomycin; bortezomib; busulfan; busulfan; calusterone; capecitabine; carboplatin; carmustine; carmustine; celecoxib; cetuximab; chlorambucil; cisplatin; cladribine; clofarabine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin; Darbepoetin alfa; dasatinib; daunorubicin liposomal; daunorubicin; daunorubicin; decitabine; denileukin; dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; dromostanolone propionate; epirubicin; Epirubicin; Epoetin alfa; erlotinib; estramustine; etoposide phosphate; etoposide; exemestane; Filgrastim; floxuridine; fludarabine; fluorouracil; fulvestrant; gefitinib; gemcitabine; gemtuzumab ozogamicin; goserelin acetate; histrelin acetate; hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide; imatinib mesylate; interferon alfa 2a; Interferon alfa-2b; irinotecan; lenalidomide; letrozole; leucovorin; Leuprolide Acetate; levamisole; lomustine; meclorethamine, nitrogen mustard; megestrol acetate; melphalan; mercaptopurine; methotrexate; methoxsalen; mitomycin C; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; nelarabine; Nofetumomab; Oprelvekin; oxaliplatin; paclitaxel; paclitaxel; paclitaxel protein-bound particles; palifermin; pamidronate; panitumumab; pegademase; pegaspargase; Pegfilgrastim; pemetrexed disodium; pentostatin; pipobroman; plicamycin, mithramycin; porfimer sodium; procarbazine; quinacrine; Rasburicase; rituximab; sargramostim; Sargramostim; sorafenib; streptozocin; sunitinib maleate; tamoxifen; temozolomide; teniposide; testolactone; thalidomide; thioguanine; thiotepa; topotecan; toremifene; tositumomab; tositumomab/I-131 tositumomab; trastuzumab; tretinoin; Uracil Mustard; valrubicin; vinblastine; vincristine; vinorelbine; vorinostat; zoledronate; and zoledronic acid. 
     
     
         72 . The method of  claim 57  or  58 , wherein the composition further comprises a pharmaceutically acceptable excipient. 
     
     
         73 . The method of  claim 57  or  58 , wherein the composition is formulated for intravenous injection, subcutaneous injection, oral administration, inhalation, nasal administration, topical administration, ophthalmic administration or otic administration.