Pyrrolotriazine compounds useful as kinase inhibitors and methods of treating kinase-associated conditions therewith

Abstract

The invention relates to at least one pyrrolotriazine derivative, at least one pharmaceutical composition comprising at least one pyrrolotriazine derivative, and at least one method of using at least one pyrrolotriazine derivative to treat at least one kinase associated condition.

1 . A compound of Formula (I) 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts thereof, wherein:
 Q 1  is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 
 R 1  is H, —NR 6 C(═O)R 7 , —OR 7 , or —C(═O)NR 7 R 8 ; 
 Q 2  is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 
 R 2  is H, alkyl, substituted alkyl, hydroxy (—OH), alkoxy, halogen, haloalkyl, haloalkoxy, oxo, aryloxy, arylalkyl, arylalkyloxy, alkanoyl, substituted alkanoyl, alkanoyloxy, amino, aminoalkyl, substituted aminoalkyl, alkylamino, substituted alkylamino, hydroxyalkyl, disubstituted amino, amide, substituted amide, carbamate, substituted carbamate, ureido, cyano, sulfonamide, substituted sulfonamide, alkylsulfone, heterocycloalkyl, substituted heterocycloalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, —NR 6 (C═O)R 9 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaryloxy, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, heterocycle, substituted heterocycle, alkylcarbonyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, arylamino, arylalkylamino, alkanoylamino, arylamino, arylalkanoylamino, arylthio, arylalkylthio, arylsulfonyl, arylalkylsulfonyl, alkylsulfonyl, arylcarbonylamino, or alkylaminocarbonyl; 
 R 3 , R 4 , and R 5  are independently selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, alkanoyl, substituted alkanoyl, amino, aminoalkyl, substituted aminoalkyl, alkylamino, substituted alkylamino, amide, substituted amide, carbamate, ureido, cyano, sulfonamide, substituted sulfonamide, alkylsulfone, cycloalkyl, substituted cycloalkyl, nitro, thio, thioalkyl, alkylthio, disubstituted amino, alkylsulfonyl, alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, —NR 6 (C═O)R 9 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and alkylcarbonyl. 
 R 6  is H, lower alkyl, or substituted lower alkyl; 
 R 7  and R 8  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, hetroalkynyl, or substituted heteroalkynyl; 
 R 9  is H, alkyl, substituted alkyl, alkoxy, aminoalkyl, substituted aminoalkyl, alkylamino, substituted alkylamino, aryl, or substituted aryl. 
 
   
   
       2 . A compound according to  claim 1 , wherein Q 2  is heteroaryl or substituted heteroaryl. 
   
   
       3 . A compound according to  claim 1 , wherein Q 2  is pyrazole, thiazole, or pyrimidine. 
   
   
       4 . A compound according to  claim 1 , wherein R 2  is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl. 
   
   
       5 . A compound according to  claim 1 , wherein Q 1  is aryl or substituted aryl. 
   
   
       6 . A compound according to  claim 1 , wherein Q 1  is phenyl or substituted phenyl. 
   
   
       7 . A compound according to  claim 1 , wherein R 3 , R 4 , and R 5  are independently selected from H, alkyl, substituted alkyl, alkoxy, and halogen. 
   
   
       8 . A compound according to  claim 1 , wherein R 7  and R 8  are independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyt, or substituted cycloalkyl. 
   
   
       9 . A compound according to  claim 1 , wherein R′ is —NR 6 C(═O)R 7  and R 2  is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl. 
   
   
       10 . A compound according to  claim 1 , having the formula 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
       Q 1 , R 1 , R 2 , R 3 , R 4 , R 5 , and R 7  are as defined hereinabove. 
     
   
   
       11 . The compound according to  claim 10 , wherein Q 1  is aryl or substituted aryl. 
   
   
       12 . A compound according to  claim 10 , having the formula 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
       Q 1 , R 1 , R 2 , R 3 , R 4 , and R 5  are as defined hereinabove. 
     
   
   
       13 . A compound according to  claim 12 , wherein R 1  is —NR 6 C(═O)R 7  and R 2  is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl. 
   
   
       14 . A pharmaceutical composition comprising
 a) at least one compound according to  claim 1 ;   b) optionally at least one pharmaceutically-acceptable carrier and/or diluent; and   c) optionally at least one other anti-cancer agent   
   
   
       15 . A method for treating at least one proliferative disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound according  claim 1 ; optionally administering either simultaneously or sequentially at least one other anti-cancer agent, and optionally administering either simultaneously or sequentially at least one other anti-cancer treatment. 
   
   
       16 . The method according to  claim 15 , wherein the proliferative disease is selected from cancer, bone disease, inflammatory disease, autoimmune disease, metabolic disease, viral disease, fungal disease, neurological and neurodegenerative disorders, Alzheimer's disease, allergies and asthma, cardiovascular disease, and hormone related disease. 
   
   
       17 . The method according to  claim 15 , wherein the proliferative disease is cancer. 
   
   
       18 . The method according to  claim 17 , wherein the patient is a human. 
   
   
       19 . The method according to  claim 15 , wherein the patient is a human. 
   
   
       20 . A compound according to  claim 1  selected from
 (i) N-[4-({4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide;
 N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-{[3-(methyloxy)phenyl]sulfanyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine; 
 N-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}sulfanyl)phenyl]acetamide; 
 3-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-J][1,2,4]triazin-2-yl}sulfanyl)-N-methylbenzamide; 
 N-(5-methyl-1H-pyrazol-3-yl)-2-(phenylsulfanyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine; and 
 N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)sulfanyl)phenyl)benzamide; and 
   (ii) a pharmaceutically acceptable salt thereof.