US 7,741,479 B2 · Urea inhibitors of MAP kinases

Urea inhibitors of MAP kinases

AssigneeLocus Pharmaceuticals, Inc.

InventorsEnrique Luis Michelotti, Eric Bruce Springman, Duyan Nguyen, Rupa S. Shetty, Younghee Lee, Kristofer Kent Moffett, Jennifer Lee Ludington, Ted Tsutomis Fujimoto, Zenon D. Konteatis, Bin Liu, Frank Hollinger, Bruce D. Dorsey

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Abstract

The present invention is directed to a compound having the formula wherein R1, R2, G, and Q are defined herein. The compounds of the present invention are useful as inhibitors of protein kinases such as MAP kinases, in particular p38 kinases. The present invention is also directed to compositions comprising a compound according to the above formula. The compounds and compositions described herein are useful for treating and preventing an inflammatory condition or disease. The present invention is also directed to a method of treating or preventing a protein kinase-mediated condition.

A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein
R1 is an aryl group, which is optionally substituted with one or more R3 groups;
Q is thienyl which is substituted with one or more of R4 or R5;
G is —C(O)—;
R2 is
—wherein X1 and X2 are independently (CR6R7)n, wherein n is independently at each occurrence 1, 2, or 3;
and Z is —NR8—S(O)2—, —NR8C(O)—, —S—, —S(O)—, —S(O)2—, or —C(O)—;
or
R2 is heteroarylamino, or heteroarylalkylamino, each of which is optionally substituted with 1, 2, or 3 substituents selected from R6;
each R3 is independently C1-4 alkyl, halogen, hydroxy, alkoxy, amino, C1-4 alkylamino, di(C1-4)alkylamino, optionally substituted phenyl, ar(C1-3)alkyl, optionally substituted phenoxy, C1-4 haloalkyl, CONRaRb, or COORa, wherein Ra and Rb are independently H or C1-4 alkyl;
each R4 is independently C3-10 alkyl or C3-10 haloalkyl, each of which is optionally substituted with one to three phenyl groups;
C3-7 cycloalkyl, which is optionally substituted with one or more C1-3 alkyl, halogen, hydroxy, oxo, or thioketo;
optionally substituted C3-10 cycloheteroalkyl;
C3-10 branched alkenyl which is optionally partially or fully halogenated, and which is optionally substituted with one to three C1-5 alkyl or a phenyl group;
C5-7 cycloalkenyl optionally substituted with one to three C1-3 alkyl groups;
cyano;
or C1-4 alkoxycarbonyl;
each R5 is independently hydrogen, alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, phenyl, or substituted phenyl;
each R6 and R7 are independently hydrogen, C1-4 alkyl, halogen, amino, C1-4 alkylamino, C1-4 hydroxyalkyl, NH—CO—(C1-4)alkyl, —COO—(C1-4)alkyl, —CONH2, —CONH—(C1-4)alkyl, —CH2NH2, —CH2NH—(C1-4)alkyl, CH2NH—CO—(C1-4)alkyl, CH2COOH, CH2COO—(C1-4)alkyl, —C1-4alkyl(C6-10)aryl, or —C1-4alkyl(5-6 membered)heteroaryl;
or R6 and R7 together form a C3-5 cycloalkyl group or an oxo group;
and
R8 is hydrogen, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, optionally substituted with one or more of hydroxyl, halogen, cyano, amino, mono(C1-6)alkylamino, di(C1-6)alkylamino, C1-6 alkoxy, aminocarbonyl, C1-6 alkylaminocarbonyl, C6-10 arylaminocarbonyl, aralkylaminocarbonyl, C1-6 alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, C1-6 cycloalkyl, 3-7 membered cycloheteroalkyl, hydroxy(C1-6)alkyl, nitro, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, formylamino, (C1-6)alkylcarbonylamino, carboxy, (C1-6)alkoxycarbonyl, aminocarbonyl, mono(C1-6)alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, carboxy(C1-6)alkyl, (C1-6)alkoxycarbonyl(C1-6)alkyl, aminocarbonyl(C1-6)alkyl, mono(C1-6)alkylaminocarbonyl(C1-6)alkyl, di(C1-6)alkylaminocarbonylalkyl(C1-6), sulfonylamino, (C1-6)alkylsulfonylamino, aminosulfonyl, mono(C1-6)alkylaminosulfonyl, (di(C1-6)alkylaminosulfonyl, (C1-6)alkoxycarbonylamino, aminocarbonylamino, mono(C1-6)alkylaminocarbonylamino, di(C1-6)alkylaminocarbonylamino, C6-10 aryl, 5-10 membered heteroaryl, N-hydroxyaminocarbonyl, N-alkoxyaminocarbonyl, and N-alkoxy-N-alkylaminocarbonyl.

19 more elements

Facts

Application

11/295,638Filed 7 Dec 2005 · us provisional application

Priority

7 Dec 2004

Published

US 2006/0167247 A127 Jul 2006

Granted

22 Jun 2010

Term ends

Not estimatedThe source records don’t support an estimate.

Classification39 codes

C07D 333/38
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
A61P 9/04
Drugs for disorders of the cardiovascular system: inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Abstract

Claims19