Compounds and methods for kinase modulation, and indications therefor

Abstract

Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

1 .- 12 . (canceled) 
     
     
         13 . A method of treating a patient diagnosed with metastatic melanoma comprising:
 (a) identifying a metastatic melanoma patient who is positive for a  V600E BRAF mutation; and   (b) administering to the patient identified in step (a) an effective amount of a sulfonamide compound of formula IIIm or a pharmaceutically acceptable salt thereof,   
       
         
           
           
               
               
           
         
         in which R 112  is amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or lower alkyl; 
         R 83  is hydrogen, fluoro, or chloro; 
         R 81  is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —C(S)NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —OR 68 , SR 68 , —NR 69 R 68 , —C(O)R 68 , —C(S)R 68 , —C(O)OR 68 , —C(O)NR 69 R 68 , —C(S)NR 69 R 68 , —S(O) 2 NR 69 R 68 , —NR 69 C(O)R 68 , —NR 69 C(S)R 68 , —NR 69 S(O) 2 R 68 , —NR 69 C(O)NH 2 , —NR 69 C(O)NR 69 R 68 , —NR 69 C(S)NH 2 , —NR 69 C(S)NR 69 R 68 , —NR 69 S(O) 2 NH 2 , —NR 69 S(O) 2 NR 69 R 68 , —S(O)R 68 , and —S(O) 2 R 68 ; 
         R 68  is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 68  is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 68 , —SR 68 , —NR 69 R 68 , —C(O)R 68 , —C(S)R 68 , C(O)OR 68 , —C(O)NR 69 R 68 , —C(S)NR 69 R 68 , —S(O) 2 NR 69 R 68 , —NR 69 C(O)R 68 , —NR 69 C(S)R 68 , —NR 69 S(O) 2 R 68 , —NR 69 C(O)NH 2 , —NR 69 C(O)NR 69 R 68 , —NR 69 C(S)NH 2 , —NR 69 C(S)NR 69 R 68 , —NR 69 S(O) 2 NH 2 , —NR 69 S(O) 2 NR 69 R 68 , —S(O)R 68 , or —S(O) 2 R 68 , optionally substituted lower alkynyl, provided, however, that when R 68  is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 68 , —SR 68 , —NR 69 R 68 , —C(O)R 68 , —C(S)R 68 , —C(O)OR 68 , —C(O)NR 69 R 68 , —C(S)NR 69 R 68 , —S(O) 2 NR 69 R 68 , —NR 69 C(O)R 68 , —NR 69 C(S)R 68 , —NR 69 S(O) 2 R 68 , —NR 69 C(O)NH 2 , —NR 69 C(O)NR 69 R 68 , —NR 69 C(S)NH 2 , —NR 69 C(S)NR 69 R 68 , —NR 69 S(O) 2 NH 2 , —NR 69 S(O) 2 NR 69 R 68 , —S(O)R 68 , or —S(O) 2 R 68 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
         R 69  is selected from the group consisting of hydrogen and optionally substituted lower alkyl; and 
         R 79  and R 80  are independently hydrogen or optionally substituted lower alkyl, or R 79  and R 80  combine with the nitrogen to which they are attached to form optionally substituted 5-7 membered heterocycloalkyl. 
       
     
     
         14 . The method of  claim 13  in which R 112  is a substituted aryl. 
     
     
         15 . The method of  claim 14  in which the substituted aryl is a fluorobenzene radical. 
     
     
         16 . The method of  claim 14  in which the substituted aryl is a difluorobenzene radical. 
     
     
         17 . The method of  claim 14  in which R 83  is hydrogen. 
     
     
         18 . The method of  claim 13  in which R 112  is a lower alkyl. 
     
     
         19 . The method of  claim 18  in which the lower alkyl is n-propyl. 
     
     
         20 . The method of  claim 19  in which R 83  is fluoro. 
     
     
         21 . The method of  claim 13  in which R 112  is a difluorobenzene radical and R 83  is hydrogen. 
     
     
         22 . The method of  claim 13  in which the patient's cancer has metastasized to the patient's brain. 
     
     
         23 . The method of  claim 13 , wherein R 81  is halogen. 
     
     
         24 . The method of  claim 23 , wherein R 81  is Cl. 
     
     
         25 . The method of  claim 13 , wherein R 81  is optionally substituted aryl. 
     
     
         26 . The method of  claim 13 , wherein R 81  is optionally substituted phenyl. 
     
     
         27 . The method of  claim 13 , wherein R 81  is halogen substituted phenyl. 
     
     
         28 . The method of  claim 27 , wherein R 81  is chloro substituted phenyl. 
     
     
         29 . The method of  claim 13 , wherein R 81  is chloro or chloro substituted phenyl, R 83  is fluoro and R 112  is n-propyl. 
     
     
         30 . The method of  claim 13 , wherein R 81  is 4-chlorophenyl, R 83  is fluoro and R 112  is n-propyl.