The present invention relates to imidazo[1,2-a]pyrimidine derivatives, that are useful for treating cellular proliferative diseases, for treating disorders associated with MET activity, and for inhibiting the receptor tyrosine kinase MET. The invention also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

Tyrosine kinase inhibitors

This invention describes novel pyrazole compounds of formula (IV) wherein Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl; R?x and Ry? are independently selected from T-R3, or taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 1-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen; and R2, R2', and T, and R3 are as described in the specification. The compounds are useful as protein kinase inhibitors, especially as inhibitors of aurora-2 and GSK-3, for treating diseases such as cancer, diabetes and Alzehimer's disease.

Pyrazole compounds useful as protein kinase inhititors

The present invention provides a compound of formula I: or a pharmaceutically acceptable salt or mixtures thereof. These compounds are inhibitors of protein kinases, particularly inhibitors of GSK mammalian protein kinase, and more particularly inhibitors of GSK-3 mammalian protein kinase. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of utilizing those compounds and compositions in the treatment of various protein kinase mediated disorders.

Compositions useful as inhibitors of protein kinases

Leukocyte trafficking into pulmonary tissue and airspaces is a critical component of the host defense response. Activation and migration of polymorphonuclear leukocytes (PMNs) into lungs also contribute to inflammatory tissue injury and remodeling of tissue architecture. There have been considerable advances in our understanding of the mechanisms that control PMN adhesion and transendothelial migration (TEM). Mechanisms of migration unique to the lungs have been described with regard to the profile of adhesion molecules, cytokines, and chemokines elicited during PMN emigration from blood vessels. This work reviews general mechanisms of TEM of PMNs and discusses the nature of PMN recruitment in several models of airway inflammation that illustrate how various stimuli elicit different responses. Pharmacologic manipulation of adhesive interactions between PMNs and endothelial cells is a current area of research aimed at developing pharmacologic agents to control inflammation during pulmonary and other inflammatory diseases. A summary of some of these agents and their actions is presented.

Neutrophil Migration Mechanisms, with an Emphasis on the Pulmonary Vasculature

This invention relates to inhibitors of p38, and methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing the inhibitors and pharmaceutical compositions in the treatment and prevention of various disorders mediated by p38.

P38 inhibitors and methods of use thereof

The invention is directed to methods to inhibit TGF-β and/or p38-α kinase using compounds of formula (1) or the pharmaceutically acceptable salts thereof wherein R3 is a noninterfering substituent; each Z is CR2 or N, wherein no more than two Z positions in ring A are N, and wherein two adjacent Z positions in ring A cannot be N; each R2 is independently a noninterfering substituent; L is a linker; n is 0 or 1; and Ar' is the residue of a cyclic aliphatic, cyclic heteroaliphatic, aromatic or heteroaromatic moiety optionally substituted with 1-3 noninterfering substituents.

Quinazoline derivatives as medicaments

The invention is directed to methods to inhibit p38-α kinase using compounds comprising a phenyl or thienyl coupled through a piperidine or piperazine nucleus to an indole residue wherein the indole residue mandatorily has a substituent on the ring nitrogen which is an amino or substituted amino group.

Indole-type derivatives as inhibitors of p38 kinase

The invention is directed to methods to inhibit p38-α kinase using compounds comprising saturated heterocycles coupled to a fused ring system.

Inhibitors of p38 kinase

The invention describes compounds of the formulaand the pharmaceutically acceptable salts thereofand the pharmaceutically acceptable salts thereofwherein each R2 is independently a noninterfering substituent;m is an integer of 0-4;Z is CH or N;R1 is H, alkyl (1-6C) or arylalkyl optionally substituted on the aryl group with 1-3 substituents independently selected from alkyl (1-6C), halo, OR, NR2, SR, -OOCR, -NROCR, RCO, -COOR, -CONR2, -SO2NR2, CN, CF3, and NO2, wherein each R is independently H or lower alkyl (1-4C);n is 0, 1 or 2;Ar is phenyl, pyridyl, indolyl, or pyrimidyl, each optionally substituted with a group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR2, SR, -OOCR, -NROCR, RCO, -COOR, -CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or lower alkyl (1-4C); andR3 is a branched or cyclic alkyl group (5-7C) or is phenyl optionally substituted with 1-2 substituents which substituents are selected from the group consisting of alkyl (1-6C), halo, OR, NR2, SR, -OOCR, -NROCR, RCO, -COOR, -CONR2, -SO2NR2, CN, CF3, and NO2, wherein each R is independently H or lower alkyl (1-4C) which are useful as antiinflammatories and in treating cardiac disorders.

John J. Perumattam

Papers

Quinazoline derivatives as medicaments

Indole-type derivatives as inhibitors of p38 kinase

Inhibitors of p38 kinase

Quinazoline derivatives as inhibitors of P-38 alpha

Indole-based heterocyclic inhibitors of p38α MAP kinase: designing a conformationally restricted analogue