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1,5-Diaryl substituted pyrazoles as p38 kinase inhibitors

  • US 6,509,361 B1
  • Filed: 02/12/2001
  • Issued: 01/21/2003
  • Est. Priority Date: 05/12/1999
  • Status: Expired due to Fees
First Claim
Patent Images

1. A compound or a pharmaceutically-acceptable salt thereof, wherein:

  • the compound corresponds in structure to Formula I;

    embedded imageZ 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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