Heterocyclic compounds and methods of use

Abstract

Heterocyclic compounds derived from benzotriazine, triazines, triazoles and oxadiazoles are disclosed. The methods of synthesis and of use of such heterocyclic compounds are also provided.

1 - 63 . (canceled) 
     
     
         64 . A method for treating a disorder, comprising administering to a subject in need thereof an effective amount of a compound having the structure (B): 
       
         
           
           
               
               
           
         
       
       wherein:
 Z 1  and Z 2  are N; Z 3  is N—R 4 , wherein R 4  is hydrogen; 
 X is absent or is NH; and 
 Y is absent or is selected from a group consisting of the following moieties: 
 
       
         
           
           
               
               
           
         
         R 1  is an unsubstituted or a substituted C 3 -C 12  heteroaryl having 1-3 heteroatoms; 
         R 2  is selected from a group consisting of hydrogen, halogen, C 1 -C 18  alkyl, —OH, —NO 2 , —CN, C 1 -C 18  alkoxy, —NHSO 2 R 5 , —SO 2 NHR 5 , —NHCOR 5 , —NH 2 , —NR 5 R 6 , —S(O)R 5 , —S(O) 2 R 5 , —CO 2 R 5 , —CONR 5 R 6 , wherein R 5  and R 6  are independently selected from a group consisting of hydrogen, a C 1 -C 18  alkyl, and a substituted C 1 -C 12  alkyl; and 
         R 3  is selected from a group consisting of hydrogen, a C 1 -C 18  alkyl, a substituted C 1 -C 12  alkyl, a C 1 -C 12  cycloalkyl, a substituted C 1 -C 12  cycloalkyl, a substituted C 3 -C 10  cycloalkyl having 0-3 heteroatoms, an C 6 -C 12  aryl, a substituted C 6 -C 12  aryl, a heterocycle, a substituted heterocycle, a C 3 -C 12  heteroaryl having 1-3 heteroatoms, a substituted C 3 -C 12  heteroaryl having 1-3 heteroatoms, a C 7 -C 24  aralkyl, a substituted C 7 -C 24  aralkyl, a C 7 -C 24  alkylaryl, and a substituted C 7 -C 24  alkaryl; 
       
       or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or a pharmaceutically acceptable salt thereof. 
     
     
         65 . The method of  claim 64 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 3  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       n is an integer selected from a group consisting of 0, 1, 2, and 3, and 
       R′ is selected from a group consisting of hydrogen, a C 1 -C 8  alkyl, and a substituted C 1 -C 18  alkyl. 
     
     
         66 . The method of  claim 64 , wherein the compound having structure (B) is selected from a group consisting of compounds having the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         67 . The method of  claim 64 , wherein the disorder is selected from a group consisting of cancer, eye disease, inflammation, psoriasis, and a viral infection. 
     
     
         68 . The method of  claim 67 , wherein the cancer is an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer. 
     
     
         69 - 74 . (canceled) 
     
     
         75 . The method of  claim 64 , wherein the compound of structure B is administered in combination with a chemotherapeutic agent, immunomodulatory agent, therapeutic antibody or a protein kinase inhibitor. 
     
     
         76 . A method of treating a subject having cancer comprising administering to the subject a therapeutically effective amount of a compound having the structure (B): 
       
         
           
           
               
               
           
         
       
       wherein:
 Z 1  and Z 2  are N; Z 3  is N—R 4 , wherein R 4  is hydrogen; 
 X is absent or is NH; and 
 Y is absent or is selected from a group consisting of the following moieties: 
 
       
         
           
           
               
               
           
         
         R 1  is an unsubstituted or a substituted C 3 -C 12  heteroaryl having 1-3 heteroatoms; 
         R 2  is selected from a group consisting of hydrogen, halogen, C 1 -C 18  alkyl, —OH, —NO 2 , —CN, C 1 -C 18  alkoxy, —NHSO 2 R 5 , —SO 2 NHR 5 , —NHCOR 5 , —NH 2 —NR 5 R 6 , —S(O)R 5 , —S(O) 2 R 5 , —CO 2 R 5 , —CONR 5 R 6 , wherein R 5  and R 6  are independently selected from a group consisting of hydrogen, a C 1 -C 18  alkyl, and a substituted C 1 -C 12  alkyl; and 
         R 3  is selected from a group consisting of hydrogen, a C 1 -C 18  alkyl, a substituted C 1 -C 12  alkyl, a C 1 -C 12  cycloalkyl, a substituted C 1 -C 12  cycloalkyl, a substituted C 3 -C 10  cycloalkyl having 0-3 heteroatoms, an C 6 -C 12  aryl, a substituted C 6 -C 12  aryl, a heterocycle, a substituted heterocycle, a C 3 -C 12  heteroaryl having 1-3 heteroatoms, a substituted C 3 -C 12  heteroaryl having 1-3 heteroatoms, a C 7 -C 24  aralkyl, a substituted C 7 -C 24  aralkyl, a C 7 -C 24  alkylaryl, and a substituted C 7 -C 24  alkaryl; 
       
       or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or a pharmaceutically acceptable salt thereof. 
     
     
         77 - 82 . (canceled) 
     
     
         83 . The method of  claim 76 , wherein the compound having the structure B is administered in combination with an effective amount of a therapeutic antibody, chemotherapeutic agent or an immunotoxic agents. 
     
     
         84 - 86 . (canceled) 
     
     
         87 . The method of  claim 83 , wherein the therapeutic agent is an antimetabolite; a DNA cross-linking agent; an alkylating agent; a topoisomerase I inhibitor; a microtubule inhibitor; a vinca alkaloid; a mitomycin-type antibiotic; or a bleomycin-type antibiotic. 
     
     
         88 . The method of  claim 83 , wherein the therapeutic agent is methotrexate, cisplatin/carboplatin, canbusil, dactinomycin, taxol (paclitaxel), antifolate, colchicine, demecolcine, etoposide, taxane/taxol, docetaxel, doxorubicin, anthracycline antibiotic, doxorubicin, daunorubicin, caminomycin, epirubicin, idarubicin, mitoxanthrone, 4-dimethoxy-daunomycin, 11-deoxydaunorubicin, 13-deoxydaunorubicin, adriamycin-14-benzoate, adriamycin-14-octanoateadriamycin-14-naphthaleneacetate, irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, or trastuzumab. 
     
     
         89 . The method of  claim 88 , wherein the therapeutic agent is doxorubicin, docetaxel, or taxol. 
     
     
         90 . The method of  claim 83 , wherein the therapeutic agent is trastuzumab, bevacizumab, OSI-774, or Vitaxin. 
     
     
         91 . The method of  claim 64 , wherein the compound has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         92 . The method of  claim 64 , wherein the disorder is associated with a kinase. 
     
     
         93 . The method of  claim 92 , wherein the kinase is a MAPK kinase.