Heteroaryl-fused pyrimidinyl compounds as anticancer agents

Abstract

Heteroaryl-fused pyrimidinyl compounds, pharmaceutically acceptable salts, and prodrugs thereof; compositions that include a pharmaceutically acceptable carrier and one or more of the heteroaryl-fused pyrimidinyl compounds, either alone or in combination with at least one additional therapeutic agent. Methods of using the heteroaryl-fused pyrimidinyl compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases.

1 . A compound having the formula:  
       
         
           
           
               
               
           
         
         wherein, A, B, D, and E are independently selected from N, CH, or CR 6 , with the proviso that at least one, but no more than two of A, B, D, or E are N;  
         R 1  is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkylsulfonyl, or arylsulfonyl;  
         R 2  is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkylsulfonyl, arylsulfonyl, alkylcarboxy, aminocarboxy, aminocarbonyl, or alkylsulfonamido; or COR 7 , CO 2 R 7 , CONR 8 R 9 , S(O) m R 10 , or SO 2 NR 11 R 12 ;  
         R 3  is cyano, substituted or unsubstituted arylsulfonyl, or CONR 8 R 9 ;  
         R 4  is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl; or L-R 13 , wherein L is a C1-C10 saturated or unsaturated branched or unbranched carbon chain comprising one or more methylene groups, wherein one or more methylene groups are optionally independently replaced by O, N, or S; and  
         wherein L is optionally substituted with one or two oxo groups and one or more C1-C10 branched or unbranched alkyl optionally substituted by one or more halogen atoms;  
         R 5  is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl; or COR 7 , CO 2 R 7 , CONR 8 R 9 , or SO (m) R 10 ;  
         R 6  is hydrogen, halogen, hydroxy, nitro, amino, cyano, alkoxy, alkylthio, methylenedioxy, or haloalkoxy; or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylamino, dialkylamino, alkylsulfonyl, arylsulfonyl, alkylcarboxy, carboxyamino, carboxyamido, aminocarboxy, aminocarbonyl, or alkylsulfonamido;  
         R 7 , R 8 , R 9 , R 10 , R 11 , and R 12  are independently selected from hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl; or R 8  and R 9 , or R 11  and R 12  taken together form a 3- to 7-membered carbocyclic or heterocyclic ring;  
         R 13  is amino, alkylamino, or dialkylamino; or substituted or unsubstituted guanidino or heterocyclyl;  
         m=0, 1, or 2; and  
         p=0, 1, 2, or 3; or  
         the tautomers, pharmaceutically acceptable salts, or prodrugs thereof.  
       
     
     
         2 . The compound of  claim 1 , wherein A is N.  
     
     
         3 . The compound of  claim 2 , wherein D is CR 6  and R 6  is chloro.  
     
     
         4 . The compound of  claim 1 , wherein A is N, B and E are CH, D is CR 6 , and R 6  is chloro.  
     
     
         5 . A compound of  claim 1 , wherein substituted alkyl comprises arylalkyl, heteroarylalkyl, heterocyclyalkyl, aminoalkyl, alkylaminoalkyl, dialkyaminoalkyl, or sulfonamidoalkyl.  
     
     
         6 . A compound of  claim 1 , wherein X is O.  
     
     
         7 . A compound of  claim 1 , wherein R 1  is arylalkyl.  
     
     
         8 . A compound of  claim 1 , wherein R 1  is benzyl.  
     
     
         9 . A compound of  claim 1 , wherein R 2  is hydrogen and R 3  is CONR 8 R 9 .  
     
     
         10 . A compound of  claim 9 , wherein R 8  and R 9  are independently selected from hydrogen, methyl, ethyl, or isopropyl.  
     
     
         11 . A compound of  claim 1 , wherein R 4  is L-R 13 .  
     
     
         12 . A compound of  claim 11 , wherein L-R 13  is aminoalkyl.  
     
     
         13 . A compound of  claim 11 , wherein L-R 13  is aminopropyl, alkylaminopropyl, or dialkylaminopropyl.  
     
     
         14 . A compound of  claim 11 , wherein L-R 13  is aminopropyl.  
     
     
         15 . A compound of  claim 1 , wherein R 5  is hydrogen, alkyl, aryl, or COR 7 .  
     
     
         16 . A compound of  claim 4 , wherein R 5  is COR 7 .  
     
     
         17 . A compound of  claim 16 , wherein R 7  is substituted or unsubstituted aryl or heteroaryl.  
     
     
         18 . A compound of  claim 16 , wherein R 7  is alkyl- or halogen-substituted aryl.  
     
     
         19 . A compound of  claim 16 , wherein R 7  is substituted or unsubstituted phenyl, pyridyl, or pyrazinyl.  
     
     
         20 . A compound of  claim 1 , wherein R 6  is hydrogen, alkyl, chloro, or bromo.  
     
     
         21 . A composition, comprising a pharmaceutically acceptable carrier and an amount of a compound of  claim 1  effective to inhibit KSP activity in a human or animal subject when administered thereto.  
     
     
         22 . The composition of  claim 21  further comprising at least one additional agent for the treatment of cancer.  
     
     
         23 . The composition of  claim 22 , wherein the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, imatinib, 5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel, paclitaxel, tezacitabine, cyclophosphamide, vinca alkaloids, anthracyclines, rituximab, and trastuzumab.  
     
     
         24 . A method for treating a condition by modulation of KSP protein activity comprising administering to a human or animal subject in need of such treatment an effective amount of a compound of  claim 1 .  
     
     
         25 . The method of  claim 24 , wherein the compound has an IC 50  value of less than about 25 μM in a cell proliferation assay.  
     
     
         26 . The method of  claim 25 , wherein the condition is cancer.  
     
     
         27 . A method for inhibiting KSP activity in a human or animal subject, comprising administering to the human or animal subject a composition comprising an amount of a compound of  claim 1  effective to inhibit KSP activity the human or animal subject.  
     
     
         28 . A method for treating a cancer disorder in a human or animal subject, comprising administering to the human or animal subject a composition comprising an amount of a compound of  claim 1  effective to inhibit KSP activity the human or animal subject.  
     
     
         29 . The method of  claim 28  further comprising administering to the human or animal subject at least one additional agent for the treatment of cancer.  
     
     
         30 . The method of  claim 29 , wherein the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, gleevec, herceptin, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, or trastuzumab.  
     
     
         31 . A kit, comprising a compound of  claim 1  and a package insert or other labeling including directions for treating a cellular proliferative disease by administering an KSP inhibitory amount of the compound.