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Substituted 3-cyano-[1.7], [1.5], and [1.8] naphthyridine inhibitors of tyrosine kinases

  • US 6,548,496 B2
  • Filed: 12/21/2001
  • Issued: 04/15/2003
  • Est. Priority Date: 04/21/1999
  • Status: Expired due to Fees
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Assignment
First Claim
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1. A compound of formula I having the structure embedded imagewherein:

  • X is the radical embedded imageE is Ph;

    T is substituted on E at carbon and is —

    NH(CH2)m—

    , —

    NR(CH2)m—

    , —

    CH2)mNH—

    , or —

    (CH2)mNR—

    ;

    L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatoms selected from N, O, and S;

    wherein the heteroaryl ring may be optionally mono- or di-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;

    Ph is phenyl, which may be optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;

    Z is —

    NH—

    ;

    A″

    is a diavalent moiety selected from the group embedded imageG1, G2, G3, and G4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 2-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulphonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, R2NH, embedded image 

    R7—

    (C(R6)2)g″

    Y—

    , R7—

    (C(R6)2)p—

    M—

    (C(R6)2)k—

    Y—

    , Het-(C(R6)2)q—

    W—

    (C(R6)2)k—

    Y—

    , with the proviso that G3 and G4 are not R2NH;

    Y is a divalent radical selected from the group consisting of embedded imageR7 is —

    NR6R6, —

    OR6, —

    J, —

    N(R6)3+, or —

    NR6(OR6);

    M is >

    NR6, —

    O—

    , >

    N—

    (C(R6)2)pNR6R6, or >

    N—

    (C(R6)2)p—

    OR6;

    W is >

    NR6, —

    O—

    or is a bond;

    Het is a heterocyclic radical selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane tetrahydropyran, and embedded imagewhich may be optionally mono- or di-substituted on carbon with R6, hydroxy, —

    N(R6)2, —

    OR6—

    (C(R6)2)sOR6 or —

    (C(R6)2)sN(R6)2;

    optionally mono-substituted on nitrogen with R6; and

    optionally mono or di-substituted on a saturated carbon with divalent radicals —

    O—

    or —

    O(C(R6)2)sO—

    ;

    R6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl 2-7 carbon atoms, phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms;

    with the proviso that the alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;

    R2, is selected from the group consisting of embedded imageembedded imageR3 is hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, embedded image 

    R7—

    (C(R6)2)s—

    , R7(C(R6)2)p—

    M—

    (C(R6)2)r—

    ,  

    R8R9—

    CH—

    M—

    (C(R6)2)r—

    , or Het-(C(R6)2)q—

    W—

    (C(R6)2)r—

    ;

    R5 is hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, embedded image 

    R7—

    (C(R6)2)s—

    , R7—

    (C(R6)2)p—

    M—

    (C(R6)2)r—

    ,  

    R8R9—

    CH—

    M—

    (C(R6)2)r—

    , or Het-(C(R8)2)q—

    W—

    (C(R6)2)r—

    ;

    R8, and R9 are each, independently, —

    (C(R6)2)rNR6R6, or —

    (C(R6)2)rOR6;

    J is independently hydrogen, chlorine, fluorine, or bromine;

    Q is alkyl of 1-6 carbon atoms or hydrogen;

    a=0-1;

    g=1-6;

    k=0-4;

    n is 0-1;

    m is 0-3;

    p=2-4;

    q=0-4;

    r=1-4;

    s=1-6;

    u=0-4 and v=0-4, wherein the sum of u+v is 2-4;

    or a pharmaceutically acceptable salt thereof,provided thatwhen R6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;

    and provided thatwhen R3 is bound to sulfur, it cannot be hydrogen, carboxy, carboalkoxy, or carboalkyl;

    and provided thatwhen Y is —

    NR6— and

    R7 is —

    NR6R6, —

    N(R6)3+, or —

    NR6(OR6), then g=2-6;

    when M is —

    O— and

    R7 is —

    OR6 then p=1-4;

    when Y is —

    NR6—

    then k=2-4;

    when Y is —

    O— and

    M or W is —

    O—

    then k=1-4 when W is not a bond with Het bonded through a nitrogen atom then q=2-4 and when W is a bond with Het bonded through a nitrogen atom and Y is —

    O—

    or —

    NR6—

    then k=2-4;

    and finally provided thatwhen A″

    is the moiety embedded imagen=0, Z is NH, G1 is hydrogen, halogen, alkyl, alkoxy, hydroxy, alkanoyloxy of 2-6 carbon atoms, or phenoxy, and G2 is hydrogen, halogen, alkyl, hydroxy, carboxyalkyl, carboalkoxyalkyl, hydroxyalkyl, alkoxy, halomethyl, carboxyl, carboalkoxy, alkanoylamino, or alkenoylamino, then X can not be a phenyl ring that is substituted with a hydroxy or alkoxy group.

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