1,5-Diaryl substituted pyrazoles as p38 kinase inhibitors
First Claim
Patent Images
1. A compound or a pharmaceutically-acceptable salt thereof, wherein:
- the compound corresponds in structure to Formula I;
Z is selected from the group consisting of hydrogen, C1-C12-hydrocarbyl, halogen, carboxy, cyano, azido, C1-C12-hydrocarbylsulfonyl, carbonyloxy-C1-C12-hydrocarbyl, carbonylamido, and —
X—
Y;
as to Ar1;
Ar1 is aryl optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxy, nitro, cyano, perfluoro-C1-C12-hydrocarbyl, trifluoromethyl-C1-C12-hydrocarbyl, perfluoro-C1-C12-hydrocarbyloxy, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, C1-C12-hydrocarbyl-sulfoxido, arylamino, aryl-C1-C12-hydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaryl-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-C1-C12-hydrocarbyl, heterocyclothio, heterocycloamino, C3-C12-cyclohydrocarbyloxy, C3-C12-cyclohydrocarbylthio, heteroaryl-C1-C12-hydrocarbyloxy, heteroaryl-C1-C12-hydrocarbylthio, heteroaryl-C1-C12-hydrocarbylamino, aryl-C1-C12-hydrocarbyloxy, aryl-C1-C12-hydrocarbylthio, aryl-C1-C12-hydrocarbylamino, heterocyclyl, heteroaryl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylcarbonyl, arylcarbonyl, aryl-C1-C12-hydrocarbylcarbonyl, C1-C12-hydrocarbylcarbonyloxy, aryl-C1-C12-hydrocarbylcarbonyloxy, hydroxy-C1-C12-hydrocarbyl, hydroxy-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxy-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, C1-C12-hydrocarbylhydroxycarbonyl-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbylthio, C1-C12-hydrocarbylcarbonylamino, arylcarbonylamino, C3-C12-cyclohydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbylcarbonylamino, aryl-C1-C12-hydrocarbylcarbonylainino, heteroarylcarbonylamino, heteroaryl-C1-C12-hydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylsulfonylamino, arylsulfonylamino, aryl-C1-C12-hydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroaryl-C1-C12-hydrocarbylsulfonylamino, C3-C12-cyclohydrocarbylsulfonylamino, heterocyclo-C1-C12-hydrocarbylsulfonylamino, amino and amino-C1-C12-hydrocarbyl, wherein;
the amino-C1-C12-hydrocarbyl nitrogen is substituted;
with up to two substituents independently selected from the group consisting of C1-C12-hydrocarbyl, aryl, aryl-C1-C12-hydrocarbyl, C3-C12-cyclohydrocarbyl, aryl-C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbyloxycarbonyl, and C1-C12-hydrocarbylcarbonyl, or with two substituent such that the amino-C1-C12-hydrocarbyl nitrogen and the two substituents form a 5- to 8-membered heterocyclic or heteroaryl ring, and the amino nitrogen is substituted;
with up to two substituents independently selected from the group consisting of C1-C12-hydrocarbyl, aryl, aryl-C1-C12-hydrocarbyl, C3-C12-cyclohydrocarbyl, aryl-C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbylcarbonyl, arylsulfonyl, and C1-C12-hydrocarbylsulfonyl, or with two substituents such that the amino nitrogen and the two substituents form a 5- to 8-membered heterocyclic or heteroaryl ring, and when Z is hydrogen, C1-C12-hydrocarbyl, halogen, or C1-C12-hydrocarbylcarbonyl, Ar1 is other than aryl substituted with one or more substituents independently selected from the group consisting of halogen, C1-C12-alkoxy, C1-C12-hydrocarbyl, perfluoro-C1-C12-hydrocarbyloxy, nitro, perfluoro-C1-C12-hydrocarbyl, amino, aminosulfonyl, halo-C1-C12-hydrocarbyloxy-C1-C12-hydrocarbyl, hydroxy, C1-C12-hydrocarbylsulfonylamino, C1-C12-hydrocarbylsulfonyl, acetylamino, carbonyl-C1-C12-hydrocarbylamino, perfluoro-C1-C12-hydrocarbylsulfonyl, C1-C12-hydrocarbylamino, carbonyl monosubstituted amino, carbonyl, C1-C12-hydrocarbylthio, hydroxy-C1-C12-hydrocarbyl, aryl-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxy-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbyloxyaryl-C1-C12-hydrocarbyl, halo-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxy-C1-C12-hydrocarbyl;
—
X is selected from the group consisting of —
O, —
S, and —
NQ;
—
Y is selected from the group consisting of hydrogen, C1-C12-hydrocarbyl, and C1-C12-hydrocarbylaryl;
Q is selected from the group consisting of hydrogen, C1-C12-hydrocarbyl, hydroxy-C1-C12-hydrocarbyl, 2-pyridyl-C1-C12-hydrocarbyl, 3-pyridyl-C1-C12-hydrocarbyl, 4-pyridyl-C1-C12-hydrocarbyl, and aryl-C1-C12-hydrocarbyl;
as to R;
R1 is selected from the group consisting of azido, hydrogen, C1-C12-hydrocarbyl, amido, C1-C12-hydrocarbylamino, halo-C1-C12-hydrocarbyl, and perhalo-C1-C12-hydrocarbyl, wherein;
any substitutable member of such group optionally is substituted by one or more substituents independently selected from the group consisting of halogen, C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxy, nitro, cyano, perfluoro-C1-C12-hydrocarbyl, trifluoromethyl-C1-C12-hydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, aryl-C1-C12-hydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaryl-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-C1-C12-hydrocarbyl, heterocyclothio, heterocycloamino, C3-C12-cyclohydrocarbyloxy, C3-C12-cyclohydrocarbylthio, C3-C12-cyclohydrocarbylamino, heteroaryl-C1-C12-hydrocarbyloxy, heteroaryl-C1-C12-hydrocarbylthio, heteroaryl-C1-C12-hydrocarbylamino, aryl-C1-C12-hydrocarbyloxy, aryl-C1-C12-hydrocarbylthio, aryl-C1-C12-hydrocarbylamino, heterocyclyl, heteroaryl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-alkoxycarbonyl-C1-C12-alkoxy, C1-C12-hydrocarbylcarbonyl, arylcarbonyl, aryl-C1-C12-hydrocarbylcarbonyl, C1-C12-hydrocarbylcarbonyloxy, aryl-C1-C12-hydrocarbylcarbonyloxy, hydroxy-C1-C12-hydrocarbyl, hydroxy-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxy-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, C1-C12-hydrocarbylhydroxycarbonyl-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbylthio, amino, C1-C12-hydrocarbylcarbonylamino, arylcarbonylamino, C3-C12-cyclohydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbylcarbonylamino, aryl-C1-C12-hydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroaryl-C1-C12-hydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylsulfonylamino, arylsulfonylamino, aryl-C1-C12-hydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroaryl-C1-C12-hydrocarbylsulfonylamino, C3-C12-cyclohydrocarbylsulfonylamino, heterocyclo-C1-C12-hydrocarbylsulfonylamino, and amino-C1-C12-hydrocarbyl, wherein;
the amino-C1-C12-hydrocarbyl nitrogen is substituted;
with up to two substituents independently selected from the group consisting of C1-C12-hydrocarbyl, aryl, aryl-C1-C12-hydrocarbyl, C3-C12-cyclohydrocarbyl, aryl-C1-C12-hydrocarbyloxycarbonyl, C1-C2-hydrocarbyloxycarbonyl, and C1-C12-hydrocarbylcarbonyl, or
with two substituents such that the amino-C1-C12-hydrocarbyl nitrogen and the two substituents form a 5- to 8-membered heterocyclic or heteroaryl ring, and when Z is hydrogen, C1-C12-hydrocarbyl, halogen, or C1-C12-hydrocarbylcarbonyl, R1 is other than hydrogen, C1-C12-hydrocarbyl, aryl, haloaryl, cyanoaryl, hydroxyaryl, C1-C12-hydrocarbylaryl, cyano, perfluoro-C1-C12-hydrocarbyl, hydroxy-C1-C12-hydrocarbyl, aryl-C1-C12-hydrocarbyl, carboxy, C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbylcarbonyl-C1-C12-hydrocarbyl, aminocarbonyl, aryl-C1-C12-hydrocarbyl-C1-C12-hydrocarbylcarbonyl-C1-C12-hydrocarbyl monosubstituted amino carbonyl, C1-C12-hydrocarbyl-C1-C12-hydrocarbylcarbonyl-C1-C12-hydrocarbyl monosubstituted amino carbonyl, C1-C12-hydrocarbyl-C1-C12-hydrocarbyl-C1-C12-hydrocarbylcarbonyl-C1-C12-hydrocarbyl mono substituted amino carbonyl, C1-C12-hydrocarbyl-hydroxy-disubstituted amino carbonyl-C1-C12-hydrocarbyl, and 6-member heteroaryl containing one nitrogen;
as to R2;
R2 is selected from the group consisting of azido, hydrogen, C1-C12-hydrocarbyl, amido, halo-C1-C12-hydrocarbyl, perhalo-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl, and aryl, wherein;
any substitutable member of such group optionally is substituted by one or more substituents independently selected from the group consisting of halogen, C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxy, nitro, cyano, perfluoro-C1-C12-hydrocarbyl, trifluoromethyl-C1-C12-hydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, aryl-C1-C12-hydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaryl-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-C1-C12-hydrocarbyl, heterocyclothio, heterocycloamino, C3-C12-cyclohydrocarbyloxy, C3-C12-cyclohydrocarbylthio, C3-C12-cyclohydrocarbylamino, heteroaryl-C1-C12-hydrocarbyloxy, heteroaryl-C1-C12-hydrocarbylthio, heteroaryl-C1-C12-hydrocarbylamino, aryl-C1-C12-hydrocarbyloxy, aryl-C1-C12-hydrocarbylthio, aryl-C1-C12-hydrocarbylamino, heterocyclyl, heteroaryl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylcarbonyl, arylcarbonyl, aryl-C1-C12-hydrocarbylcarbonyl, C1-C12-hydrocarbylcarbonyloxy, aryl-C1-C12-hydrocarbylcarbonyloxy, hydroxy-C1-C12-hydrocarbyl, hydroxy-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxy-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C2-hydrocarbyl, C1-C12-hydrocarbylhydroxycarbonyl-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbylthio, amino, C1-C12-hydrocarbylcarbonylamino, arylcarbonylamino, C3-C12-cyclohydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbylcarbonylamino, aryl-C1-C12-hydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroaryl-C1-C12-hydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylsulfonylamino, arylsulfonylamino, aryl-C1-C12-hydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroaryl-C1-C12-hydrocarbylsulfonylamino, C3-C12-cyclohydrocarbylsulfonylamino, heterocyclo-C1-C12-hydrocarbylsulfonylamino, and amino-C1-C12-hydrocarbyl, wherein;
the amino-C1-C12-hydrocarbyl nitrogen is substituted;
with up to two substituents independently selected from the group consisting of C1-C12-hydrocarbyl, aryl, aryl-C1-C12-hydrocarbyl, C3-C12-cyclohydrocarbyl, aryl-C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbyloxycarbonyl, and C1-C12-hydrocarbylcarbonyl, or
with two substituents such that the amino-C1-C12-hydrocarbyl nitrogen and the two substituents form a 5- to 8-membered heterocyclic or heteroaryl ring, and when Z is hydrogen, C1-C12-hydrocarbyl, halogen, or C1-C12-hydrocarbylcarbonyl, R2 is other than hydrogen, carboxy, C1-C12-hydrocarbyloxycarbonyl, halogen, or aryl;
each heterocyclyl is a saturated, partially unsaturated or aromatic unsaturated heteroatom-containing ring-shaped radical, wherein the heteroatoms are selected from the group consisting of nitrogen, sulfur, and oxygen;
each heteroaryl is a unsaturated 5- to 10-membered heteromonocyclic ring; and
each aryl is a carbocyclic aromatic system of 1, 2 or 3 rings.
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Abstract
The present invention contemplates 1,5-diaryl-substituted pyrazole compounds that, inter alia, inhibit the activity of p38 MAP kinase. Also contemplated by the invention are processes for the preparation of the contemplated compounds and for the use of a contemplated compound in treating a mammalian host having a p38 kinase- or TNF-mediated disease.
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Citations
57 Claims
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1. A compound or a pharmaceutically-acceptable salt thereof, wherein:
-
the compound corresponds in structure to Formula I;
Z is selected from the group consisting of hydrogen, C1-C12-hydrocarbyl, halogen, carboxy, cyano, azido, C1-C12-hydrocarbylsulfonyl, carbonyloxy-C1-C12-hydrocarbyl, carbonylamido, and —
X—
Y;
as to Ar1;
Ar1 is aryl optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxy, nitro, cyano, perfluoro-C1-C12-hydrocarbyl, trifluoromethyl-C1-C12-hydrocarbyl, perfluoro-C1-C12-hydrocarbyloxy, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, C1-C12-hydrocarbyl-sulfoxido, arylamino, aryl-C1-C12-hydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaryl-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-C1-C12-hydrocarbyl, heterocyclothio, heterocycloamino, C3-C12-cyclohydrocarbyloxy, C3-C12-cyclohydrocarbylthio, heteroaryl-C1-C12-hydrocarbyloxy, heteroaryl-C1-C12-hydrocarbylthio, heteroaryl-C1-C12-hydrocarbylamino, aryl-C1-C12-hydrocarbyloxy, aryl-C1-C12-hydrocarbylthio, aryl-C1-C12-hydrocarbylamino, heterocyclyl, heteroaryl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylcarbonyl, arylcarbonyl, aryl-C1-C12-hydrocarbylcarbonyl, C1-C12-hydrocarbylcarbonyloxy, aryl-C1-C12-hydrocarbylcarbonyloxy, hydroxy-C1-C12-hydrocarbyl, hydroxy-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxy-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, C1-C12-hydrocarbylhydroxycarbonyl-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbylthio, C1-C12-hydrocarbylcarbonylamino, arylcarbonylamino, C3-C12-cyclohydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbylcarbonylamino, aryl-C1-C12-hydrocarbylcarbonylainino, heteroarylcarbonylamino, heteroaryl-C1-C12-hydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylsulfonylamino, arylsulfonylamino, aryl-C1-C12-hydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroaryl-C1-C12-hydrocarbylsulfonylamino, C3-C12-cyclohydrocarbylsulfonylamino, heterocyclo-C1-C12-hydrocarbylsulfonylamino, amino and amino-C1-C12-hydrocarbyl, wherein;
the amino-C1-C12-hydrocarbyl nitrogen is substituted;
with up to two substituents independently selected from the group consisting of C1-C12-hydrocarbyl, aryl, aryl-C1-C12-hydrocarbyl, C3-C12-cyclohydrocarbyl, aryl-C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbyloxycarbonyl, and C1-C12-hydrocarbylcarbonyl, or with two substituent such that the amino-C1-C12-hydrocarbyl nitrogen and the two substituents form a 5- to 8-membered heterocyclic or heteroaryl ring, and the amino nitrogen is substituted;
with up to two substituents independently selected from the group consisting of C1-C12-hydrocarbyl, aryl, aryl-C1-C12-hydrocarbyl, C3-C12-cyclohydrocarbyl, aryl-C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbylcarbonyl, arylsulfonyl, and C1-C12-hydrocarbylsulfonyl, or with two substituents such that the amino nitrogen and the two substituents form a 5- to 8-membered heterocyclic or heteroaryl ring, and when Z is hydrogen, C1-C12-hydrocarbyl, halogen, or C1-C12-hydrocarbylcarbonyl, Ar1 is other than aryl substituted with one or more substituents independently selected from the group consisting of halogen, C1-C12-alkoxy, C1-C12-hydrocarbyl, perfluoro-C1-C12-hydrocarbyloxy, nitro, perfluoro-C1-C12-hydrocarbyl, amino, aminosulfonyl, halo-C1-C12-hydrocarbyloxy-C1-C12-hydrocarbyl, hydroxy, C1-C12-hydrocarbylsulfonylamino, C1-C12-hydrocarbylsulfonyl, acetylamino, carbonyl-C1-C12-hydrocarbylamino, perfluoro-C1-C12-hydrocarbylsulfonyl, C1-C12-hydrocarbylamino, carbonyl monosubstituted amino, carbonyl, C1-C12-hydrocarbylthio, hydroxy-C1-C12-hydrocarbyl, aryl-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxy-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbyloxyaryl-C1-C12-hydrocarbyl, halo-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxy-C1-C12-hydrocarbyl;
—
X is selected from the group consisting of —
O, —
S, and —
NQ;
—
Y is selected from the group consisting of hydrogen, C1-C12-hydrocarbyl, and C1-C12-hydrocarbylaryl;
Q is selected from the group consisting of hydrogen, C1-C12-hydrocarbyl, hydroxy-C1-C12-hydrocarbyl, 2-pyridyl-C1-C12-hydrocarbyl, 3-pyridyl-C1-C12-hydrocarbyl, 4-pyridyl-C1-C12-hydrocarbyl, and aryl-C1-C12-hydrocarbyl;
as to R;
R1 is selected from the group consisting of azido, hydrogen, C1-C12-hydrocarbyl, amido, C1-C12-hydrocarbylamino, halo-C1-C12-hydrocarbyl, and perhalo-C1-C12-hydrocarbyl, wherein;
any substitutable member of such group optionally is substituted by one or more substituents independently selected from the group consisting of halogen, C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxy, nitro, cyano, perfluoro-C1-C12-hydrocarbyl, trifluoromethyl-C1-C12-hydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, aryl-C1-C12-hydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaryl-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-C1-C12-hydrocarbyl, heterocyclothio, heterocycloamino, C3-C12-cyclohydrocarbyloxy, C3-C12-cyclohydrocarbylthio, C3-C12-cyclohydrocarbylamino, heteroaryl-C1-C12-hydrocarbyloxy, heteroaryl-C1-C12-hydrocarbylthio, heteroaryl-C1-C12-hydrocarbylamino, aryl-C1-C12-hydrocarbyloxy, aryl-C1-C12-hydrocarbylthio, aryl-C1-C12-hydrocarbylamino, heterocyclyl, heteroaryl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-alkoxycarbonyl-C1-C12-alkoxy, C1-C12-hydrocarbylcarbonyl, arylcarbonyl, aryl-C1-C12-hydrocarbylcarbonyl, C1-C12-hydrocarbylcarbonyloxy, aryl-C1-C12-hydrocarbylcarbonyloxy, hydroxy-C1-C12-hydrocarbyl, hydroxy-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxy-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, C1-C12-hydrocarbylhydroxycarbonyl-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbylthio, amino, C1-C12-hydrocarbylcarbonylamino, arylcarbonylamino, C3-C12-cyclohydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbylcarbonylamino, aryl-C1-C12-hydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroaryl-C1-C12-hydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylsulfonylamino, arylsulfonylamino, aryl-C1-C12-hydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroaryl-C1-C12-hydrocarbylsulfonylamino, C3-C12-cyclohydrocarbylsulfonylamino, heterocyclo-C1-C12-hydrocarbylsulfonylamino, and amino-C1-C12-hydrocarbyl, wherein;
the amino-C1-C12-hydrocarbyl nitrogen is substituted;
with up to two substituents independently selected from the group consisting of C1-C12-hydrocarbyl, aryl, aryl-C1-C12-hydrocarbyl, C3-C12-cyclohydrocarbyl, aryl-C1-C12-hydrocarbyloxycarbonyl, C1-C2-hydrocarbyloxycarbonyl, and C1-C12-hydrocarbylcarbonyl, or
with two substituents such that the amino-C1-C12-hydrocarbyl nitrogen and the two substituents form a 5- to 8-membered heterocyclic or heteroaryl ring, andwhen Z is hydrogen, C1-C12-hydrocarbyl, halogen, or C1-C12-hydrocarbylcarbonyl, R1 is other than hydrogen, C1-C12-hydrocarbyl, aryl, haloaryl, cyanoaryl, hydroxyaryl, C1-C12-hydrocarbylaryl, cyano, perfluoro-C1-C12-hydrocarbyl, hydroxy-C1-C12-hydrocarbyl, aryl-C1-C12-hydrocarbyl, carboxy, C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbylcarbonyl-C1-C12-hydrocarbyl, aminocarbonyl, aryl-C1-C12-hydrocarbyl-C1-C12-hydrocarbylcarbonyl-C1-C12-hydrocarbyl monosubstituted amino carbonyl, C1-C12-hydrocarbyl-C1-C12-hydrocarbylcarbonyl-C1-C12-hydrocarbyl monosubstituted amino carbonyl, C1-C12-hydrocarbyl-C1-C12-hydrocarbyl-C1-C12-hydrocarbylcarbonyl-C1-C12-hydrocarbyl mono substituted amino carbonyl, C1-C12-hydrocarbyl-hydroxy-disubstituted amino carbonyl-C1-C12-hydrocarbyl, and 6-member heteroaryl containing one nitrogen;
as to R2;
R2 is selected from the group consisting of azido, hydrogen, C1-C12-hydrocarbyl, amido, halo-C1-C12-hydrocarbyl, perhalo-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl, and aryl, wherein;
any substitutable member of such group optionally is substituted by one or more substituents independently selected from the group consisting of halogen, C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxy, nitro, cyano, perfluoro-C1-C12-hydrocarbyl, trifluoromethyl-C1-C12-hydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, aryl-C1-C12-hydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaryl-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-C1-C12-hydrocarbyl, heterocyclothio, heterocycloamino, C3-C12-cyclohydrocarbyloxy, C3-C12-cyclohydrocarbylthio, C3-C12-cyclohydrocarbylamino, heteroaryl-C1-C12-hydrocarbyloxy, heteroaryl-C1-C12-hydrocarbylthio, heteroaryl-C1-C12-hydrocarbylamino, aryl-C1-C12-hydrocarbyloxy, aryl-C1-C12-hydrocarbylthio, aryl-C1-C12-hydrocarbylamino, heterocyclyl, heteroaryl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylcarbonyl, arylcarbonyl, aryl-C1-C12-hydrocarbylcarbonyl, C1-C12-hydrocarbylcarbonyloxy, aryl-C1-C12-hydrocarbylcarbonyloxy, hydroxy-C1-C12-hydrocarbyl, hydroxy-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxy-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C2-hydrocarbyl, C1-C12-hydrocarbylhydroxycarbonyl-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbylthio, amino, C1-C12-hydrocarbylcarbonylamino, arylcarbonylamino, C3-C12-cyclohydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbylcarbonylamino, aryl-C1-C12-hydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroaryl-C1-C12-hydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylsulfonylamino, arylsulfonylamino, aryl-C1-C12-hydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroaryl-C1-C12-hydrocarbylsulfonylamino, C3-C12-cyclohydrocarbylsulfonylamino, heterocyclo-C1-C12-hydrocarbylsulfonylamino, and amino-C1-C12-hydrocarbyl, wherein;
the amino-C1-C12-hydrocarbyl nitrogen is substituted;
with up to two substituents independently selected from the group consisting of C1-C12-hydrocarbyl, aryl, aryl-C1-C12-hydrocarbyl, C3-C12-cyclohydrocarbyl, aryl-C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbyloxycarbonyl, and C1-C12-hydrocarbylcarbonyl, or
with two substituents such that the amino-C1-C12-hydrocarbyl nitrogen and the two substituents form a 5- to 8-membered heterocyclic or heteroaryl ring, andwhen Z is hydrogen, C1-C12-hydrocarbyl, halogen, or C1-C12-hydrocarbylcarbonyl, R2 is other than hydrogen, carboxy, C1-C12-hydrocarbyloxycarbonyl, halogen, or aryl;
each heterocyclyl is a saturated, partially unsaturated or aromatic unsaturated heteroatom-containing ring-shaped radical, wherein the heteroatoms are selected from the group consisting of nitrogen, sulfur, and oxygen;
each heteroaryl is a unsaturated 5- to 10-membered heteromonocyclic ring; and
each aryl is a carbocyclic aromatic system of 1, 2 or 3 rings. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 54, 55, 56, 57)
Ar1 is aryl substituted by a substituent selected from the group consisting of fluorine and C1-C6-hydrocarbyl;
R1 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl;
R2 is selected from the group consisting of hydrogen, C1-C6-hydrocarbyl, and aminocarbonyl;
Z is —
X—
Y;
—
X is selected from the group consisting of —
O and —
NQ;
Q is aryl-C1-C6-hydrocarbyl; and
—
Y is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl.
-
-
3. The compound or salt according to claim 1, wherein:
-
Ar1 is aryl substituted by one or more substituents independently selected from the group consisting of C1-C6-hydrocarbyl and halogen;
R1 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl;
R2 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl;
Z is —
X—
Y;
—
X is —
NQ;
Q is selected from the group consisting of C1-C6-hydrocarbyl and hydroxy-C1-C6-hydrocarbyl; and
—
Y is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl.
-
-
4. The compound or salt according to claim 1, wherein:
-
Ar1 is aryl substituted by one or more substituents independently selected from the group consisting of C1-C6-hydrocarbyl and halogen;
R1 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl;
R2 is hydrogen;
Z is selected from the group consisting of cyano and —
X—
Y;
—
X is selected from the group consisting of —
O and —
NQ;
Q is selected from a group consisting of hydrogen, C1-C6-hydrocarbyl, aryl-C1-C6-hydrocarbyl, hydroxy-C1-C6-hydrocarbyl, and 3-pyridyl-C1-C6-hydrocarbyl; and
—
Y is selected from the group consisting of hydrogen, C1-C6-hydrocarbyl, and aryl-C1-C6-hydrocarbyl.
-
-
5. A compound or salt according to claim 1, wherein:
-
the compound corresponds in structure to Formula II;
R3 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl;
R4 is selected from the group consisting of hydrogen, C1-C6-hydrocarbyl, aryl-C1-C6-hydrocarbyl, hydroxy-C1-C6-hydrocarbyl, 2-pyridyl-C1-C6-hydrocarbyl, 3-pyridyl-C1-C6-hydrocarbyl, and 4-pyridyl-C1-C6-hydrocarbyl;
Ar1 is aryl substituted by a substituent selected from the group consisting of halogen, C1-C6-hydrocarbyl, and C1-C12-hydrocarbyloxy;
R1 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl; and
R2 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl.
-
-
6. The compound or salt according to claim 5, wherein:
-
Ar1 is aryl substituted by C1-C6-hydrocarbyl;
R1 is C1-C6-hydrocarbyl;
R2 is hydrogen;
R3 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl; and
R4 is selected from the group consisting of C1-C6-hydrocarbyl and aryl-C1-C6-hydrocarbyl.
-
-
7. The compound or salt according to claim 5, wherein:
-
Ar1 is aryl substituted by C1-C6-hydrocarbyl;
R1 is C1-C6-hydrocarbyl;
R2 is hydrogen;
R3 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl; and
R4 is selected from the group consisting of C1-C6-hydrocarbyl and hydroxy-C1-C6-hydrocarbyl.
-
-
8. The compound or salt according to claim 5, wherein:
-
Ar1 is aryl substituted with a substituent selected from the group consisting of C1-C6-hydrocarbyl and halogen;
R1 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl;
R2 is hydrogen;
R3 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl; and
R4 is selected from the group consisting of aryl-C1-C6-hydrocarbyl, hydroxy-C1-C6-hydrocarbyl, and 3-pyridyl-C1-C6-hydrocarbyl.
-
-
9. A compound or salt according to claim 1, wherein:
-
the compound corresponds in structure to Formula III;
R5 is selected from the group consisting of hydrogen, C1-C6-hydrocarbyl, and aryl-C1-C6-hydrocarbyl;
Ar1 is aryl substituted with a substituent selected from the group consisting of halogen, C1-C6-hydrocarbyl, and C1-C12-hydrocarbyloxy;
R1 is C1-C6-hydrocarbyl; and
R2 is hydrogen.
-
-
10. The compound or salt according to claim 9, wherein:
-
Ar1 is aryl substituted by C1-C6-hydrocarbyl;
R1 is C1-C6-hydrocarbyl;
R2 is hydrogen; and
R5 is selected from the group consisting of C1-C6-hydrocarbyl and aryl-C1-C6-hydrocarbyl.
-
-
11. A compound or salt according to claim 1, wherein:
-
the compound corresponds in structure to Formula IV;
Ar1 is aryl substituted by a substituent selected from the group consisting of halogen, C1-C6-hydrocarbyl, and C1-C12-hydrocarbyloxy;
R1 is C1-C6-hydrocarbyl; and
R2 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl.
-
-
12. The compound or salt according to claim 11, wherein:
-
Ar1 is aryl substituted by C1-C6-hydrocarbyl;
R1 is C1-C6-hydrocarbyl; and
R2 is hydrogen.
-
-
13. A compound according to claim 1 corresponding in structure to the formula
-
14. A compound according to claim 1 corresponding in structure to the formula
-
15. A compound according to claim 1 corresponding in structure to the formula
-
16. A compound according to claim 1 corresponding in structure to the formula
-
17. A compound according to claim 1 corresponding in structure to the formula
-
18. A compound according to claim 1 corresponding in structure to the formula
-
19. A compound according to claim 1 corresponding in structure to the formula
-
20. A compound according to claim 1 corresponding in structure to the formula
-
21. A compound according to claim 1 corresponding in structure to the formula
-
22. A compound according to claim 1 corresponding in structure to the formula
-
23. A compound according to claim 1 corresponding in structure to the formula
-
24. A compound according to claim 1 corresponding in structure to the formula
-
25. A compound according to claim 1 corresponding in structure to the formula
-
26. A compound according to claim 1 corresponding in structure to the formula
-
27. A compound according to claim 1 corresponding in structure to the formula
-
28. A compound according to claim 1 corresponding in structure to the formula
-
29. A compound according to claim 1 corresponding in structure to the formula
-
30. A compound according to claim 1 corresponding in structure to the formula
-
31. A compound according to claim 1 corresponding in structure to the formula
-
32. A compound according to claim 1 corresponding in structure to the formula
-
34. A compound according to claim 1 corresponding in structure to the formula
-
35. A compound according to claim 1 corresponding in structure to the formula
-
36. A compound according to claim 1 corresponding in structure to the formula
-
37. A compound according to claim 1 corresponding in structure to the formula
-
38. A compound according to claim 1 corresponding in structure to the formula
-
39. A compound according to claim 1 corresponding in structure to the formula
-
40. A compound according to claim 1 corresponding in structure to the formula
-
41. A compound according to claim 1 corresponding in structure to the formula
-
54. A pharmaceutical composition for the treatment of a condition associated with pathological p38 MAP kinase activity, wherein the composition comprises:
-
a therapeutically-effective amount of a compound of claim 1 or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable diluent.
-
-
55. A pharmaceutical composition for the treatment of a condition associated with pathological p38 MAP kinase activity, wherein the composition comprises:
-
a therapeutically-effective amount of a compound of claim 5 or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable diluent.
-
-
56. A pharmaceutical composition for the treatment of a condition associated with pathological p38 MAP kinase activity, wherein the composition comprises:
-
a therapeutically-effective amount of a compound of claim 9 or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable diluent.
-
-
57. A pharmaceutical composition for the treatment of a condition associated with pathological p38 MAP kinase activity, wherein the composition comprises:
-
a therapeutically-effective amount of a compound of claim 11 or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable diluent.
-
-
33. A compound corresponding in structure to the formula
-
42. A method for treating a mammal having a condition associated with pathological p38 MAP kinase activity, wherein:
-
the method comprises administering to the mammal having such a condition an effective amount of a p38 MAP kinase inhibitor compound or a pharmaceutically-acceptable salt thereof;
the compound corresponds in structure to Formula I;
Z is selected from the group consisting of hydrogen, C1-C12-hydrocarbyl, halogen, carboxy, cyano, azido, C1-C12-hydrocarbylsulfonyl, carbonyloxy-C1-C12-hydrocarbyl, carbonylamido, and —
X—
Y;
as to Ar1;
Ar1 is aryl optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxy, nitro, cyano, perfluoro-C1-C12-hydrocarbyl, trifluoromethyl-C1-C12-hydrocarbyl, perfluoro-C1-C12-hydrocarbyloxy, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, C1-C12-hydrocarbyl-sulfoxido, arylamino, aryl-C1-C2-hydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaryl-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-C1-C12-hydrocarbyl, heterocyclothio, heterocycloamino, C3-C12-cyclohydrocarbyloxy, C3-C12-cyclohydrocarbylthio, heteroaryl-C1-C12-hydrocarbyloxy, heteroaryl-C1-C12-hydrocarbylthio, heteroaryl-C1-C12-hydrocarbylamino, aryl-C1-C12-hydrocarbyloxy, aryl-C1-C12-hydrocarbylthio, aryl-C1-C12-hydrocarbylamino, heterocyclyl, heteroaryl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylcarbonyl, arylcarbonyl, aryl-C1-C12-hydrocarbylcarbonyl, C1-C12-hydrocarbylcarbonyloxy, aryl-C1-C12-hydrocarbylcarbonyloxy, hydroxy-C1-C12-hydrocarbyl, hydroxy-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxy-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, C1-C2-hydrocarbylhydroxycarbonyl-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbylthio, C1-C12-hydrocarbylcarbonylamino, arylcarbonylamino, C3-C12-cyclohydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbylcarbonylamino, aryl-C1-C12-hydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroaryl-C1-C12-hydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylsulfonylamino, arylsulfonylamino, aryl-C1-C12-hydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroaryl-C1-C12-hydrocarbylsulfonylamino, C3-C12-cyclohydrocarbylsulfonylamino, heterocyclo-C1-C12-hydrocarbylsulfonylamino, amino and amino-C1-C12-hydrocarbyl, wherein;
the amino-C1-C12-hydrocarbyl nitrogen is substituted;
with up to two substituents independently selected from the group consisting of C1-C12-hydrocarbyl, aryl, aryl-C1-C12-hydrocarbyl, C3-C12-cyclohydrocarbyl, aryl-C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbyloxycarbonyl, and C1-C12-hydrocarbylcarbonyl, or two substituents such that the amino-C1-C12-hydrocarbyl nitrogen and the two substituents form a 5- to 8-membered heterocyclic or heteroaryl ring, and the amino nitrogen is substituted;
with up to two substituents independently selected from the group consisting of C1-C12-hydrocarbyl, aryl, aryl-C1-C12-hydrocarbyl, C3-C12-cyclohydrocarbyl, aryl-C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbylcarbonyl, arylsulfonyl, and C1-C12-hydrocarbylsulfonyl, or with two substituents such that the amino nitrogen and the two substituents form a 5- to 8-membered heterocyclic or heteroaryl ring, and when Z is hydrogen, C1-C12-hydrocarbyl, halogen, or C1-C12-hydrocarbylcarbonyl, Ar1 is other than aryl substituted with one or more substituents independently selected from the group consisting of halogen, C1-C12-alkoxy, C1-C12-hydrocarbyl, perfluoro-C1-C12-hydrocarbyloxy, nitro, perfluoro-C1-C12-hydrocarbyl, amino, aminosulfonyl, halo-C1-C12-hydrocarbyloxy-C1-C12-hydrocarbyl, hydroxy, C1-C12-hydrocarbylsulfonylamino, C1-C12-hydrocarbylsulfonyl, acetylamino, carbonyl-C1-C12-hydrocarbylamino, perfluoro-C1-C12-hydrocarbylsulfonyl, C1-C12-hydrocarbylamino, carbonyl monosubstituted amino, carbonyl, C1-C12-hydrocarbylthio, hydroxy-C1-C12-hydrocarbyl, aryl-C, -C12-hydrocarbyl, C1-C12-hydrocarbyloxy-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbyloxyaryl-C1-C12-hydrocarbyl, halo-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxy-C1-C12-hydrocarbyl;
—
X is selected from the group consisting of —
O, —
S, and —
NQ;
—
Y is selected from the group consisting of hydrogen, C1-C12-hydrocarbyl, and C1-C12-hydrocarbylaryl;
Q is selected from the group consisting of hydrogen, C1-C12-hydrocarbyl, hydroxy-C1-C12-hydrocarbyl, 2-pyridyl-C1-C12-hydrocarbyl, 3- pyridyl-C1-C12-hydrocarbyl, 4-pyridyl-C1-C12-hydrocarbyl, and aryl-C1-C12-hydrocarbyl;
as to R1;
R1 is selected from the group consisting of azido, hydrogen, C1-C12-hydrocarbyl, amido, C1-C12-hydrocarbylamino, halo-C1-C12-hydrocarbyl, and perhalo-C1-C12-hydrocarbyl, wherein;
any substitutable member of such group optionally is substituted by one or more substituents independently selected from the group consisting of halogen, C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxy, nitro, cyano, perfluoro-C1-C12-hydrocarbyl, trifluoromethyl-C1-C12-hydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, aryl-C1-C12-hydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaryl-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-C1-C12-hydrocarbyl, heterocyclothio, heterocycloamino, C3-C12-cyclohydrocarbyloxy, C3-C12-cyclohydrocarbylthio, C3-C12-cyclohydrocarbylamino, heteroaryl-C1-C12-hydrocarbyloxy, heteroaryl-C1-C12-hydrocarbylthio, heteroaryl-C1-C12-hydrocarbylamino, aryl-C1-C12-hydrocarbyloxy, aryl-C1-C12-hydrocarbylthio, aryl-C1-C12-hydrocarbylamino, heterocyclyl, heteroaryl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-alkoxycarbonyl-C1-C12-alkoxy, C1-C12-hydrocarbylcarbonyl, arylcarbonyl, aryl-C1-C12-hydrocarbylcarbonyl, C1-C12-hydrocarbylcarbonyloxy, aryl-C1-C12-hydrocarbylcarbonyloxy, hydroxy-C1-C12-hydrocarbyl, hydroxy-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxy-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, C1-C12-hydrocarbylhydroxycarbonyl-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbylthio, amino, C1-C12-hydrocarbylcarbonylamino, arylcarbonylamino, C3-C12-cyclohydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbylcarbonylamino, aryl-C1-C12-hydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroaryl-C1-C12-hydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylsulfonylamino, arylsulfonylamino, aryl-C1-C12-hydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroaryl-C1-C12-hydrocarbylsulfonylamino, C3-C12-cyclohydrocarbylsulfonylamino, heterocyclo-C1-C12-hydrocarbylsulfonylamino, and amino-C1-C12-hydrocarbyl, wherein;
the amino-C1-C12-hydrocarbyl nitrogen is substituted;
with up to two substituents independently selected from the group consisting of C1-C12-hydrocarbyl, aryl, aryl-C1-C12-hydrocarbyl, C3-C12-cyclohydrocarbyl, aryl-C1-C12-hydrocarbyloxycarbonyl, Cl-C12-hydrocarbyloxycarbonyl, and C1-C12-hydrocarbylcarbonyl, or
with two substituents such that the amino-C1-C12-hydrocarbyl nitrogen and the two substituents form a 5- to 8-membered heterocyclic or heteroaryl ring, andwhen Z is hydrogen, C1-C12-hydrocarbyl, halogen, or C1-C12-hydrocarbylcarbonyl, R1 is other than hydrogen, C1-C12-hydrocarbyl, aryl, haloaryl, cyanoaryl, hydroxyaryl, C1-C12-hydrocarbylaryl, cyano, perfluoro-C1-C12-hydrocarbyl, hydroxy-C1-C12-hydrocarbyl, aryl-C1-C12-hydrocarbyl, carboxy, C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, aminocarbonyl, aryl-C1-C12-hydrocarbyl-C1-C12-hydrocarbylcarbonyl-C1-C12-hydrocarbyl monosubstituted amino carbonyl, C1-C12-hydrocarbyl-C1-C12-hydrocarbylcarbonyl-C1-C12-hydrocarbyl monosubstituted amino carbonyl, C1-C12-hydrocarbyl-C1-C12-hydrocarbyl-C1-C12-hydrocarbylcarbonyl-C1-C12-hydrocarbyl monosubstituted amino carbonyl, C1-C12-hydrocarbyl-hydroxy-disubstituted amino carbonyl-C1-C12-hydrocarbyl, and 6-member heteroaryl containing one nitrogen;
as to R2;
R2 is selected from the group consisting of azido, hydrogen, C1-C12-hydrocarbyl, amido, halo-C1-C12-hydrocarbyl, perhalo-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl, and aryl, wherein;
any substitutable member of such group optionally is substituted by one or more substituents independently selected from the group consisting of halogen, C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxy, nitro, cyano, perfluoro-C1-C12-hydrocarbyl, trifluoromethyl-C1-C12-hydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, aryl-C1-C12-hydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaryl-C1-C12-hydrocarbyl, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-C1-C12-hydrocarbyl, heterocyclothio, heterocycloamino, C3-C12-cyclohydrocarbyloxy, C3-C12-cyclohydrocarbylthio, C3-C12-cyclohydrocarbylamino, heteroaryl-C1-C12-hydrocarbyloxy, heteroaryl-C1-C12-hydrocarbylthio, heteroaryl-C1-C12-hydrocarbylamino, aryl-C1-C12-hydrocarbyloxy, aryl-C1-C12-hydrocarbylthio, aryl-C1-C12-hydrocarbylamino, heterocyclyl, heteroaryl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylcarbonyl, arylcarbonyl, aryl-C1-C12-hydrocarbylcarbonyl, C1-C12-hydrocarbylcarbonyloxy, aryl-C1-C12-hydrocarbylcarbonyloxy, hydroxy-C1-C12-hydrocarbyl, hydroxy-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxy-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl, hydroxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyl, C1-C12-hydrocarbylhydroxycarbonyl-C1-C12-hydrocarbylthio, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbyloxycarbonyl-C1-C12-hydrocarbylthio, amino, C1-C12-hydrocarbylcarbonylamino, arylcarbonylamino, C3-C12-cyclohydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbylcarbonylamino, aryl-C1-C12-hydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroaryl-C1-C12-hydrocarbylcarbonylamino, heterocyclo-C1-C12-hydrocarbyloxy, C1-C12-hydrocarbylsulfonylamino, arylsulfonylamino, aryl-C1-C12-hydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroaryl-C1-C12-hydrocarbylsulfonylamino, C3-C12-cyclohydrocarbylsulfonylamino, heterocyclo-C1-C12-hydrocarbylsulfonylamino, and amino-C1-C12-hydrocarbyl, wherein;
the amino-C1-C12-hydrocarbyl nitrogen is substituted;
with up to two substituents independently selected from the group consisting of C1-C12-hydrocarbyl, aryl, aryl-C1-C12-hydrocarbyl, C3-C12-cyclohydrocarbyl, aryl-C1-C12-hydrocarbyloxycarbonyl, C1-C12-hydrocarbyloxycarbonyl, and C1-C12-hydrocarbylcarbonyl, or
with two substituents such that the amino-C1-C12-hydrocarbyl nitrogen and the two substituents form a 5- to 8-membered heterocyclic or heteroaryl ring, andwhen Z is hydrogen, C1-C12-hydrocarbyl, halogen, or C1-C12-hydrocarbylcarbonyl, R2 is other than hydrogen, carboxy, C1-C12-hydrocarbyloxycarbonyl, halogen, or aryl;
each heterocyclyl is a saturated, partially unsaturated or aromatic unsaturated heteroatom-containing ring-shaped radical, wherein the heteroatoms are selected from the group consisting of nitrogen, sulfur, and oxygen;
each heteroaryl is a unsaturated 5- to 10-membered heteromonocyclic ring; and
each aryl is a carbocyclic aromatic system of 1, 2 or 3 rings. - View Dependent Claims (43, 44, 45)
Ar1 is aryl substituted by a substituent selected from the group consisting of fluorine and C1-C6-hydrocarbyl;
R1 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl;
R2 is selected from the group consisting of hydrogen, C1-C6-hydrocarbyl, and aminocarbonyl;
Z is —
X—
Y;
—
X is selected from the group consisting of —
O and —
NQ;
Q is aryl-C1-C6-hydrocarbyl; and
—
Y is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl.
-
-
44. The method according to claim 42, wherein:
-
Ar1 is aryl substituted by one or more substituents independently selected from the group consisting of C1-C6-hydrocarbyl and halogen;
R1 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl;
R2 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl;
Z is —
X—
Y;
—
X is —
NQ;
Q is selected from the group consisting of C1-C6-hydrocarbyl and hydroxy-C1-C6-hydrocarbyl; and
—
Y is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl.
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45. The method according to claim 42, wherein:
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Ar1 is aryl substituted by one or more substituents independently selected from the group consisting of C1 -C6-hydrocarbyl and halogen;
R1 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl;
R2 is hydrogen;
Z is selected from the group consisting of cyano and —
X—
Y;
—
X is selected from the group consisting of —
O and —
NQ;
Q is selected from a group consisting of hydrogen, C1-C6-hydrocarbyl, aryl-C1-C6-hydrocarbyl, hydroxy-C1-C6-hydrocarbyl, and 3-pyridyl-C1-C6-hydrocarbyl; and
—
Y is selected from the group consisting of hydrogen, C1-C6-hydrocarbyl, and aryl-C1-C6-hydrocarbyl.
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46. A method for treating a mammal having a condition associated with pathological p38 MAP kinase activity, wherein:
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the method comprises administering to the mammal having such a condition an effective amount of a p38 MAP kinase inhibitor compound or a pharmaceutically-acceptable salt thereof;
the compound corresponds in structure to Formula II;
R3 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl;
R4 is selected from the group consisting of hydrogen, C1-C6-hydrocarbyl, aryl-C1-C6-hydrocarbyl, hydroxy-C1-C6-hydrocarbyl, 2-pyridyl-C1-C6-hydrocarbyl, 3-pyridyl-C1-C6-hydrocarbyl, and 4-pyridyl-C1-C6-hydrocarbyl;
Ar1 is aryl substituted by a substituent selected from the group consisting of halogen, C1-C6-hydrocarbyl, and C1-C12-hydrocarbyloxy;
R1 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl; and
R2 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl. - View Dependent Claims (47, 48, 49)
Ar1 is aryl substituted by C1-C6-hydrocarbyl;
R1 is C1-C6-hydrocarbyl;
R2 is hydrogen;
R3 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl; and
R4 is selected from the group consisting of C1-C6-hydrocarbyl and aryl-C1-C6-hydrocarbyl.
-
-
48. The method according to claim 46, wherein:
-
Ar1 is aryl substituted by C1-C6-hydrocarbyl;
R1 is C1-C6-hydrocarbyl;
R2 is hydrogen;
R3 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl; and
R4 is selected from the group consisting of C1-C6-hydrocarbyl and hydroxy-C1-C6-hydrocarbyl.
-
-
49. The method according to claim 46, wherein:
-
Ar1 is aryl substituted with a substituent selected from the group consisting of C1-C6-hydrocarbyl and halogen;
R1 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl;
R2 is hydrogen;
R3 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl; and
R4 is selected from the group consisting of aryl-C1-C6-hydrocarbyl, hydroxy-C1-C6-hydrocarbyl, and 3-pyridyl-C1-C6-hydrocarbyl.
-
-
50. A method for treating a mammal having a condition associated with pathological p38 MAP kinase activity, wherein:
-
the method comprises administering to the mammal having such a condition an effective amount of a p38 MAP kinase inhibitor compound or a pharmaceutically-acceptable salt thereof;
the compound corresponds in structure to Formula III;
R5 is selected from the group consisting of hydrogen, C1-C6-hydrocarbyl, and aryl-C1-C6-hydrocarbyl;
Ar1 is aryl substituted with a substituent selected from the group consisting of halogen, C1-C6-hydrocarbyl, and C1-C12-hydrocarbyloxy;
R1 is C1-C6-hydrocarbyl; and
R2 is hydrogen. - View Dependent Claims (51)
Ar1 is aryl substituted by C1-C6-hydrocarbyl;
R1 is C1-C6-hydrocarbyl;
R2 is hydrogen; and
R5 is selected from the group consisting of C1-C6-hydrocarbyl and aryl-C1-C6-hydrocarbyl.
-
-
52. A method for treating a mammal having a condition associated with pathological p38 MAP kinase activity, wherein:
-
the method comprises administering to the mammal having such a condition an effective amount of a p38 MAP kinase inhibitor compound or a pharmaceutically-acceptable salt thereof;
the compound corresponds in structure to Formula IV;
Ar1 is aryl substituted by a substituent selected from the group consisting of halogen, C1-C6-hydrocarbyl and C1-C12-hydrocarbyloxy;
R1 is C1-C6-hydrocarbyl; and
R2 is selected from the group consisting of hydrogen and C1-C6-hydrocarbyl. - View Dependent Claims (53)
Ar1 is aryl substituted by C1-C6-hydrocarbyl;
R1 is C1-C6-hydrocarbyl; and
R2 is hydrogen.
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Specification
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- Resources
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Current AssigneeGD Searle LLC (Pfizer Inc.)
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Original AssigneePharmacia Corporation (Pfizer Inc.)
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InventorsCrich, Joyce Z., Collins, Paul W., Xu, Xiang Dong, Weier, Richard M.
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Primary Examiner(s)AULAKH, CHARANJIT
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Application NumberUS09/674,653Time in Patent Office708 DaysField of Search514/341, 514/252, 514/333, 546/275.4, 546/256, 544/360US Class Current514/341CPC Class CodesC07D 231/12 with only hydrogen atoms, h...C07D 401/04 directly linked by a ring-m...C07D 401/14 containing three or more he...
