Heteroaryl compounds for kinase inhibition

Abstract

Compounds and pharmaceutical compositions that modulate kinase activity, including mutant EGFR and mutant HER2 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including mutant EGFR and mutant HER2 activity, are described herein.

1 .- 213 . (canceled) 
     
     
         214 . A method of preparing a compound of Formula II-1, comprising:
 a) combining a compound of Formula I-1 with a compound of Formula I-2 to form a compound of Formula II-1:   
       
         
           
           
               
               
           
         
       
       wherein:
 A is selected from 
 
       
         
           
           
               
               
           
         
         
           X 1  is selected from N and CR 1 ; 
           X 2  is selected from N and CR 2 ; 
           each X 4  is independently selected from N and CR 7 ; 
           X 5  is selected from N and CR 8 ; 
           X 6  is selected from N and CR 9 ; 
           R 1  is selected from H, acyl, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkoxycarbonyl, amido, amino, carbonate, carbamate, carbonyl, carboxyl, ester, halo, CN, NO 2 , hydroxy, phosphate, phosphonate, phosphinate, phosphine oxide, mercapto, thio, alkylthio, arylthio, thiocarbonyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is substituted with 0, 1, 2, or 3 R 12 ; 
           each R 7  is independently selected from H, alkyl, alkenyl, alkynyl, alkoxy, amido, amino, carbonyl, ester, halo, CN, and NO 2 , each of which is substituted with 0, 1, 2, or 3 R 12 ; and wherein any two adjacent R 7  groups can be taken together with the carbon atoms to which they are attached to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, each of which is substituted with 0, 1, 2, or 3 R 12 ; 
           R 8  is selected from H, acyl, alkyl, amido, amino, carbamate, carbonyl, and urea, each of which is substituted with 0, 1, 2, or 3 R 12 ; 
           R 9  is selected from H, alkyl, alkenyl, alkynyl, alkoxy, amino, amido, ester, halo, CN, NO 2 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is substituted with 0, 1, 2, or 3 R 12 ; and 
         
       
       each R12 is independently selected from acyl, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkoxycarbonyl, amido, amino, carbonate, carbamate, carbonyl, ester, halo, CN, NO 2 , hydroxyl, phosphate, phosphonate, phosphinate, phosphine oxide, thio, alkylthio, arylthio, thiocarbonyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. 
     
     
         215 . The method according to  claim 214 , further comprising:
 b) combining the compound of Formula II-1 with a compound of Formula II-2 to form a compound of Formula III-1:   
       
         
           
           
               
               
           
         
       
       wherein:
 X 3  is selected from N and CR 4 ; 
 R 3  and R 4  are each independently selected from H, alkyl, alkoxy, halo, CN, and NO 2 , each of which is substituted with 0, 1, 2, or 3 R 12 ; and 
 R 5  is selected from H, alkyl, alkenyl, alkynyl, —NR 10 R 11 , —OR 11 , and —SR 11 , each of which is independently substituted with 0, 1, 2, or 3 R 12 ; or when R 5  is —NR 10 R 11 , then R 10  and R 11  can be taken together with the nitrogen atom to which they are attached to form a heterocyclyl or heteroaryl group, each of which is substituted with 0, 1, 2, or 3 R 12 ; and R 4  and R 5  can be taken together with the carbon atoms to which they are attached to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl group, each of which is substituted with 0, 1, 2, or 3 R 12 . 
 
     
     
         216 . The method according to  claim 214 , further comprising:
 c1) combining the compound of Formula III-1 and HNR 10 R 11  to form a compound of Formula IV-1:   
       
         
           
           
               
               
           
         
       
       wherein:
 R 5  is halo. 
 
     
     
         217 . The method according to  claim 214 , further comprising:
 c2) combining the compound of Formula III-1 and HOR 11  to form a compound of Formula IV-2:   
       
         
           
           
               
               
           
         
       
       wherein:
 R 5  is halo. 
 
     
     
         218 . The method according to  claim 214 , further comprising:
 d) forming a compound of Formula V-1 from a compound of any one of Formulae III-1, IV-1, or IV-2:   
       
         
           
           
               
               
           
         
       
     
     
         219 . The method according to  claim 214 , further comprising:
 e) combining a compound of Formula V-1 with a compound of either Formula V-2 or V-3 to form a compound of Formula I:   
       
         
           
           
               
               
           
         
       
       wherein:
 R 6  can be selected from H, acyl, alkyl, amino, halo, CN, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which is substituted with 0, 1, 2, or 3 R 12 . 
 
     
     
         220 . The method according to  claim 219 , wherein the compound of Formula V-1 is combined with the compound of Formula V-2 to form the compound of Formula I. 
     
     
         221 . The method according to  claim 219 , wherein the compound of Formula V-1 is combined with the compound of Formula V-3 to form the compound of Formula I. 
     
     
         222 . The method according to  claim 214 , wherein step a) is performed in the presence of AlCl 3  or FeCl 3 . 
     
     
         223 . The method according to  claim 222 , wherein step a) is performed in the presence of AlCl 3 . 
     
     
         224 . The method according to  claim 215 , wherein step b) is performed in the presence of a palladium catalyst and a base. 
     
     
         225 . The method according to  claim 224 , wherein the Pd-catalyst is selected from Pd(OAc) 2  and XantPhos, Pd 2 dba 3  and XantPhos, and PdCl 2 (dppf); and the base is selected from Cs 2 CO 3 , NaO t Bu, LiHMDS, K 3 PO 4 , K 2 CO 3 , NaOMe and KOH. 
     
     
         226 . The method according to  claim 225 , wherein the palladium catalyst is Pd(OAc) 2  and XantPhos, and the base is Cs 2 CO 3 . 
     
     
         227 . The method according to  claim 215 , wherein step b) is performed in the presence of an acid catalyst. 
     
     
         228 . The method according to  claim 227 , wherein the acid catalyst is selected from TFA, PTSA and HCl. 
     
     
         229 . The method according to  claim 228 , wherein the acid catalyst is TFA. 
     
     
         230 . The method according to  claim 215 , wherein step b) is performed in the presence of a base. 
     
     
         231 . The method according to  claim 230 , wherein the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, and potassium carbonate. 
     
     
         232 . The method according to  claim 231 , wherein the base is potassium carbonate. 
     
     
         233 . The method according to  claim 216 , wherein step c1) is performed in the presence of a base. 
     
     
         234 . The method according to  claim 233 , wherein the base is selected from K 2 CO 3 , Na 2 CO 3 , K 3 PO 4  and Cs 2 CO 3 . 
     
     
         235 . The method according to  claim 234 , wherein the base is K 2 CO 3 . 
     
     
         236 . The method according to  claim 217 , wherein step c2) is performed in the presence of a base. 
     
     
         237 . The method according to  claim 236 , wherein the base is selected from NaH, KH and LiH. 
     
     
         238 . The method according to  claim 237 , wherein the base is NaH. 
     
     
         239 . The method according to  claim 218 , wherein step d) is performed in the presence of a hydrogenation catalyst selected from Pd/C, Raney nickel, Pd(OH) 2 , and PtO 2 , and an H 2  source. 
     
     
         240 . The method according to  claim 239 , wherein the hydrogenation catalyst is Pd/C. 
     
     
         241 . The method according to  claim 218 , wherein step d) is performed in the presence of an oxidizable metal and a proton source. 
     
     
         242 . The method according to  claim 241 , wherein the oxidizable metal is selected from zinc, stannous chloride, iron and Raney nickel; and the proton source is selected from hydrochloric acid, acetic acid, formic acid, and ammonium chloride. 
     
     
         243 . The method according to  claim 242 , wherein the oxidizable metal is zinc and the proton source is ammonium chloride. 
     
     
         244 . The method according to  claim 220 , wherein step e) is performed in the presence of a coupling reagent and a base. 
     
     
         245 . The method according to  claim 244 , wherein the coupling reagent is selected from DCC, EDCI, HATU, HBTU, TBTU and T3P; and the base is selected from piperidine, triethylamine, diisopropylamine, and diisopropylethylamine. 
     
     
         246 . The method according to  claim 245 , wherein the coupling reagent is EDCI and the base is diisopropylethylamine. 
     
     
         247 . The method according to  claim 221 , wherein step f) is optionally performed in the presence of a base selected from triethylamine, diisopropylamine, diisopropylethylamine and piperidine. 
     
     
         248 . The method according to  claim 247 , wherein the base is triethylamine. 
     
     
         249 . The method according to  claim 214 , further comprising:
 f) combining the compound of Formula I with an acid of Formula H m Z to form an acid addition salt of Formula VI-1:   
       
         
           
           
               
               
           
         
       
       wherein:
 A is an anionic form of a Bronsted-Lowry acid; 
 m is 1, 2, or 3; and 
 n is 1, 2, or 3. 
 
     
     
         250 . The method according to  claim 249 , wherein Z and m are selected from:
 Z is Cl −  and m is 1;   Z is Br −  and m is 1;   Z is MeSO 2   −  and m is 1;   Z is PhSO 2   −  and m is 1;   Z is 4-methylphenylSO 2   −  and m is 1;   Z is —OC(O)—C(O)O −  and m is 2;   Z is —OC(O)—CH 2 —C(O)O −  and m is 2;   Z is   
       
         
           
           
               
               
           
         
       
       and m is 3;
 Z is SO 4   3−  and m is 3; and 
 Z is PO 4   3−  and m is 3. 
 
     
     
         251 . The method according to  claim 249 , wherein Z is Cl − , m is 1, and n is 1 or 2. 
     
     
         252 . The method according to  claim 249 , wherein Z is Cl − , m is 1, and n is 1 or 2. 
     
     
         253 . The method according to  claim 249 , wherein Z is MeSO 2   − , m is 1, and n is 1 or 2. 
     
     
         254 . The method according to  claim 249 , wherein Z is 
       
         
           
           
               
               
           
         
       
       m is 1, and n is 1 or 2.