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Heterocyclic inhibitors of p38

  • US 6,509,363 B2
  • Filed: 03/16/2001
  • Issued: 01/21/2003
  • Est. Priority Date: 09/18/1998
  • Status: Expired due to Term
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Petitions
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Forward Citations
2
Assignments
First Claim
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1. A compound having the formula:

  • embedded imagewherein;

    each of Q1 and Q2 is independently selected from the group consisting of a 5-6 membered aromatic carbocyclic or heterocyclic ring system, and an 8-10 membered bicyclic ring system comprising aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring;

    or wherein;

    Q1 is selected from the group consisting of a 5-6 membered aromatic carbocyclic or heterocyclic ring systam and an 8-10 membered bicyclic ring system comprising aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring, and Q2 is selected from the group consisting of H, CO2R′

    , CON(R′

    )2, and a (C1-C4) branched or straight-chain alkyl optionally containing 1-3 substituents independently selected from the group consisting of A, T—

    C(O)R′

    , OPO3H2,NR′

    2,OR′

    ,CO2R′

    ,CON(R′

    )2, and SO2N(R2)2;

    wherein;

    Q1 is optionally substituted with 1 to 4 substituents, each of which is independently selected from the group consisting of halo;

    C1-C4 alkyl optionally containing 1-3 substituents independently selected from the group consisting of A, T—

    C(O)R′

    ,OPO3H2, NR′

    2,OR′

    ,CO2R′ and

    CONR′

    2;

    O—

    (C1-C4)-alkyl optionally containing 1-3 substituents independently selected from the group consisting of A,T—

    C(O)R′

    ,OPO3H2,NR′

    2,OR′

    , CO2R′ and

    CONR′

    2;

    NR′

    2;

    OCF3;

    CF3;

    NO2;

    CO2R′

    ;

    CONR′

    ;

    SR′

    ;

    S(O2)N(R′

    )2;

    SCF3;

    CN;

    N(R′

    )C(O)R4;

    N(R′

    )C(O)OR4;

    N(R′

    )C(O)C(O)R4;

    N(R′

    )S(O2)R4;

    N(R′

    )R4;

    N(R4)2;

    OR4;

    OC(O)R4;

    OP(O)3H2; and

    N═

    C—

    N(R′

    )2; and

    wherein;

    Q2, when a ring system, is optionally substituted with up to 4 substituents, each of which is independently selected from the group consisting of halo;

    C1-C4 straight or branched alkyl optionally containing 1-3 substituents independently selectd from the group consisting of A, T—

    C(O)R′

    ,OPO3H2,NR′

    2,OR′

    ,CO2R′

    ,S(O2)N(R′

    )2,N═

    C—

    N(R′

    )2,R3, and CONR′

    2;

    O—

    (C1-C3)-alkyl;

    O—

    (c1-C4)-alkyl optionally containing 1-3 substituents independently selected from the group consisting of A, T—

    C(O)R′

    ,OPO3H2,NR′

    2,OR′

    , CO2R′

    , S(O2)N(R′

    )2, N=C−

    N(R′

    )2, R3, and CONR′

    2;

    OCF3;

    CF3, NO2;

    CO2R′

    ;

    CONR′

    ;

    R3;

    OR3;

    NR3;

    SR3;

    C(O)R3;

    C(O)N(R′

    )R3;

    C(O)OR3;

    SR′

    ;

    S(O2)N(R′

    )2;

    SCF3;

    N═

    C—

    N(R′

    )2; and

    CN;

    wherein A is selected from the group consisting of;

    embedded imagewherein R′

    is selected from the group consisting of hydrogen, (C1-C3)-alkyl;

    (C2-C3)-alkenyl or alkynyl; and

    phenyl or phenyl substituted with 1 to 3 substituents independently selected from the group consisting of halo, methoxy, cyano, nitro, amino, hydroxy, methyl and ethyl;

    wherein R3 is a 5-6 membered aromatic carbocyclic or heterocyclic ring system;

    wherein R4 is (C1-C4)-alkyl optionally substituted with N(R′

    )2,OR′

    ,CO2R′

    , CON(R′

    )2, or SO2N(R2)2;

    a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with a (C1-C4) branched or straight-chain alkyl group, N(R′

    )2,OR′

    , CO2R′

    ,CON(R′

    )2, or SO2N(R2)2;

    or a (C1-C4)-alkyl optionally substituted with the 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with a (C1-C4) branched or straight-chain alkyl group, N(R′

    )2,OR′

    ,CO2R′

    ,CON(R′

    )2, or SO2N(R2)2;

    wherein R2 is selected from the group consisting of hydrogen, (C1-C3)-alkyl, and (C1-C3)-alkenyl;

    each optionally substituted with —

    N(R′

    )2, —

    OR′

    , SR′

    , —

    C(O)—

    N(R′

    )2,—

    S(O2)—

    N(R′

    )2,—

    C(O)—

    OR′

    , or R3;

    wherein X is selected from the group consisting of O,S,NR and C(R)2;

    wherein Y is CR or N;

    wherein Z is CH or N;

    wherein M is C═

    O,CHOH, or CH2;

    wherein n is 0 or 1;

    wherein each R is independently selected from the group consisting of hydrogen —

    R2,—

    N(R2)2,—

    OR2,SR2,—

    C(O)—

    N(R2)2,—

    S(O2)—

    N(R2)2, and —

    C(O)—

    OR2, wherein two adjacent R are optionally bound to one another and, together with each Y to which they are respectively bound, form a 4-8 membered carbocyclic or heterocyclic ring;

    and pharmaceutically acceptable salts thereof;

    wherein when Q1 is substituted with 1 to 3 substituents, Q2 is a ring system, X is NR or C(R)2, and n is 1, then M is not —

    C(O)—

    or —

    CH2—

    ;

    when Y is N and/or X is NR, Z is CH, n is 0 and Q1 is a substituted or unsubstituted phenyl or thienyl group, then Q2 is not H; and

    when Y is CH, X is S, Z is CH, and n is 0, then Q2 is not H.

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