US 2006/0235017 A1 · Cytokine Inhibitors

Abstract

Disclosed are compounds of formula (I) Where Ar1, X, Y, Q, W, R3, R4, R5, R6 and Ry are defined herein. The compounds of the invention inhibit production of cytokines involved in inflammatory processes and are thus useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease. The compounds are also useful for treating diseases or conditions related to oncology and anticoagulant or fibrinolytic therapy. Also disclosed are processes for preparing these compounds and pharmaceutical compositions comprising these compounds.

A compound of the formula (I)

wherein:
Ar1 is an aromatic carbocycle substituted with one R1, and wherein Ar1 is independently substituted with two R2 groups and wherein one R1 and one R2 on adjacent ring atoms optionally form a 5- or 6-membered carbocyclic or heterocyclic ring;
R1 is halogen, NO2, NH2, J-N(Ra)—(CH2)m—, N(J)2—(CH2)m—, NH2C(O)—, J-N(Ra)—C(O)—, J-S(O)m—N(Ra)—, J-N(Ra)—S(O)m— or heterocycle-(CH2)m— wherein the heterocyclic group is optionally substituted by C1-5 alkyl;
Q is a N or CRp;
Y is >CRpRv, —CRp═C(Rv)—, —O—, —N(Rx)— or >S(O)m;
wherein Ra, Rp, Rv, Rx and Ry are each independently hydrogen or C1-5 alkyl;
X is —CH2—, —N(Ra)—, —O— or —S—;
W is N or CH;
each m is independently 0, 1 or 2;
J is chosen from C1-10 alkyl and carbocycle each optionally substituted by Rb;
R2 is chosen from C1-6 alkyl, C3-7 cycloalkyl optionally substituted by C1-5 alkyl, C1-4 acyl, aroyl, C1-4 alkoxy, each being optionally partially or fully halogenated, halogen, C1-6 alkoxycarbonyl, carbocyclesulfonyl and —SO2—CF3;
each R3, R4 and R5 are independently chosen from hydrogen, C1-6 alkyl and halogen;
R6 is optionally attached at a position ortho or meta to the N atom of the indicated ring, and is chosen from
a bond, —O—, —O—(CH2)1-5—, >C(O), —NH—, —C(O)—NH—, —S—, C1-5 alkyl branched or unbranched, C2-5 alkenyl, C1-3 acyl, C1-3 alkyl(OH), heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl and tetrahydrofuranyl, heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, thiazolyl, oxazolyl and isothiazolyl or aryl each alkyl, alkenyl, acyl, heterocycle, heteroaryl and aryl are optionally substituted by one to three hydroxy, oxo, C1-3 alkyl, C1-3 alkoxy, C1-5 alkoxycarbonyl, —NR7R8 or NR7R8—C(O)—;
wherein each R6 is further optionally covalently attached to groups chosen from:
hydrogen, —NR7R8, C1-3 alkyl, C3-6 cycloalkylC0-2alkyl, hydroxy, C1-3 alkoxy, phenoxy, benzyloxy, arylC0-4 alkyl, heteroaryl C0-4 alkyl and heterocycle C0-4alkyl, each above-listed heterocycle, heteroaryl and aryl group is optionally substituted by one to three hydroxy, oxo, C1-4 alkyl, C1-3 alkoxy, C1-5 alkoxycarbonyl, NR7R8—C(O)— or C1-4 acyl;
each R7 and R8 are independently hydrogen, phenylC0-3alkyl optionally subtituted by halogen, C1-3 alkyl or diC1-5 alkyl amino, or R7 and R8 are C1-2 acyl, benzoyl or C1-5 branched or unbranched alkyl optionally substituted by C1-4 alkoxy, hydroxy or mono or diC1-3 alkyl amino;
and
Rb is chosen from hydrogen, C1-5 alkyl, hydroxyC1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, carbocycle, heterocycle, heteroaryl, C1-5 alkoxy, C1-5 alkylthio, amino, C1-5 alkylamino, C1-5 dialkylamino, C1-5 acyl, C1-5 alkoxycarbonyl, C1-5 acyloxy, C1-5 acylamino, each of the aforementioned are optionally partially or fully halogenated, or Rb is chosen from C1-5 alkylsulphonylamino, hydroxy, oxo, halogen, nitro and nitrile;
or the pharmaceutically acceptable salts, acids or isomers thereof.

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Cytokine Inhibitors

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Cytokine Inhibitors

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Abstract

Claims18