HETEROARYL COMPOUNDS FOR KINASE INHIBITION

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.