Diaryl macrocycles as modulators of protein kinases

Abstract

The present invention relates to certain diaryl macrocyclic compounds, pharmaceutical compositions containing them, and methods of using them, including methods for treating cancer, pain, neurological diseases, autoimmune diseases, and inflammation.

1 - 56 . (canceled) 
     
     
         57 . A pharmaceutical composition comprising a compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         one or more additional active ingredients; and 
         a pharmaceutically acceptable excipient. 
       
     
     
         58 . The pharmaceutical composition of  claim 57 , wherein the one or more additional active ingredients is an anti-cancer agent. 
     
     
         59 . The pharmaceutical composition of  claim 57 , wherein the one or more additional active ingredients is a kinase inhibitor. 
     
     
         60 . The pharmaceutical composition of  claim 57 , wherein the one or more additional active ingredients is an EGFR inhibitor, a Raf inhibitor, or a VEGFR inhibitor. 
     
     
         61 . The pharmaceutical composition of  claim 57 , wherein the one or more additional active ingredients is a Raf inhibitor. 
     
     
         62 . The pharmaceutical composition of  claim 57 , wherein the one or more additional active ingredients is a VEGFR inhibitor. 
     
     
         63 . The pharmaceutical composition of  claim 57 , wherein the one or more additional active ingredients is a standard chemotherapy agent. 
     
     
         64 . The pharmaceutical composition of  claim 57 , wherein the standard chemotherapy agent is selected from alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, and corticosteroids. 
     
     
         65 . The pharmaceutical composition of  claim 57 , wherein the standard chemotherapy agent is an alkylating agent. 
     
     
         66 . The pharmaceutical composition of  claim 57 , wherein the standard chemotherapy agent is an antimetabolite. 
     
     
         67 . The pharmaceutical composition of  claim 57 , wherein the standard chemotherapy agent is an anti-tumor antibiotic. 
     
     
         68 . The pharmaceutical composition of  claim 57 , wherein the standard chemotherapy agent is a topoisomerase inhibitor. 
     
     
         69 . The pharmaceutical composition of  claim 57 , wherein the standard chemotherapy agent is a platinum drug. 
     
     
         70 . The pharmaceutical composition of  claim 57 , wherein the standard chemotherapy agent is a mitotic inhibitor. 
     
     
         71 . The pharmaceutical composition of  claim 57 , wherein the standard chemotherapy agent is an antibody. 
     
     
         72 . The pharmaceutical composition of  claim 57 , wherein the standard chemotherapy agent is a hormone therapy. 
     
     
         73 . The pharmaceutical composition of  claim 57 , wherein the standard chemotherapy agent is a corticosteroid. 
     
     
         74 . The pharmaceutical composition of  claim 57 , wherein the one or more additional active ingredients is an anti-inflammatory. 
     
     
         75 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         one or more additional active ingredients; and 
         a pharmaceutically acceptable excipient. 
       
     
     
         76 . The method of  claim 75 , wherein the cancer is selected from lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma.