Preparation of substituted pyrazines as protein kinase modulators.

Abstract

This invention relates to compds. I [R1 = H, halo, CN, etc.; R2, R3 = H, alkyl, aryl, etc.; R4 = H, alkyl, aryl, etc.; Z = N, CH; A = CO, CS, C(:NR6), R7 (when A = R7, E does not exist); R6 = H, NO2, CN, etc.; R7 = (un)substituted 5-7 membered heterocyclyl; E = NR8R9, NNR2R3, OR4, etc.; R8 = H, alkyl; R9 = H, heteroarylalkyl, etc.; NR8R9 = (un)substituted 5-7 membered heteroalicyclyl; W = 6-10 membered arylene, 5-10 membered heteroarylene; X = a bond, (un)substituted alkylene, O(CH2)2-3O, etc.; Y = H, alkyl, aryl, etc.; with provisos] for modulating protein kinase enzymic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion, and to pharmaceutical compns. contg. such compds. Even more specifically, the invention relates to compds. I that inhibit, regulate and/or modulate kinases, particularly Checkpoint Kinases, even more particularly Checkpoint Kinase 1, or Chk1. Prepn. of representative compds. I is described. Thus, amidation of 3-amino-6-phenylpyrazinecarboxylic acid (prepn. given) with benzylamine afforded 67% 3-amino-6-phenyl-N-(phenylmethyl)pyrazine-2-carboxamide which showed IC50 of 10,000 nM or greater against Chk1. Table presenting activity data with respect to Chk1 for over 1000 compds. I is given. Methods of therapeutically or prophylactically using the compds. I and compns. to treat kinase-dependent diseases and conditions are also an aspect of the invention, and include methods of treating cancer, as well as other disease states assocd. with unwanted angiogenesis and/or cellular proliferation, by administering effective amts. of such compds. [on SciFinder(R)]