Preparation of thiazolylamino benzamide derivatives as modulators of cell proliferation and inhibitors of protein kinases.

Abstract

Aminothiazole compds. with mono-/di-substituted benzamides (shown as I; variables described below; e.g. 4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]-N-(2-morpholin-4-ylethyl)benzamide), and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of said metabolites are described. These agents modulate and/or inhibit the cell proliferation and activity of protein kinases and are useful as pharmaceuticals for treating malignancies and other disorders. Inhibitory activities towards three cyclin complexes of protein kinases, phosphorylated FGF receptor and/or LCK tyrosine kinase and/or cytotoxicity towards the HCT-116 cancer cell line are reported for hundreds of I, many of which were prepd. combinatorially. For I: R1 and R2 are each independently H, or an alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, aminoalkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group unsubstituted or substituted with ≥1 substituents listed in the claims, or R1 or R2, together with the N-C(O) and two adjacent C atoms of the Ph ring of I, forms a 5- or 6-membered ring structure fused to the Ph ring of I and unsubstituted or substituted with ≥1 substituents listed in the claims, or R1 and R2, taken together with the N atom to which they are bonded, form a monocyclic or fused or nonfused polycyclic structure which may contain 1-3 addnl. heteroatoms, the structure being unsubstituted or substituted with ≥1 substituents listed in the claims. R3 is an aryl, heteroaryl, alkyl, or cycloalkyl group, unsubstituted or substituted with ≥1 substituents listed in the claims. Y is H, alkyl, heteroalkyl, haloalkyl, halocycloalkyl, haloheterocycloalkyl, cycloalkyl, heterocycloalkyl, -NO2, -NH2, -N-OH, N-ORc, -CN, -(CH2)z-CN (z is 0-4), halogen, -OH, -O-Ra-O-, -ORb, -CO-R, -O-CO-Rc, -CO-ORc, -O-CO-OR, -O-OR, =O, =S, -NRdRe, -CO-NRdRe, -O-CO-NRdRe, -NRc-CO-Re, -NR-CO-OR, -CO-NRc-CO-Rd, -O-SO2-Re, -O-SO-R, -O-S-Re, -S-CO-Rc, -SO-CO-ORc, -SO-CO-OR, -O-SO3, -NRc-SRd, -NRc-SO-Rd, NRc-SO2-Rd, -CO-SRc, -CO-SO-Re, -CO-OSO2-Rc, -CS-Rc, -CSO-R, -CSO2-R,, -NRc-CS-Rd, -O-CS-Re, -O-CSO-Rc, -O-SO2-Re, -OS2-NRdRe, -SO-NRdRe, -S-NRdRe, -NRd-CSO2-Rd, - NRc-CSO-Rd, -NRc-CS-Rd, -SH, -S-Rb, and -PO2-ORc (Ra, etc. defined in claims). Although the methods of prepn. are not claimed, ∼80 example prepns. of I are included and directions are given for combinatorial prepn. of 396 I. [on SciFinder(R)]