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Nitrogen containing heteroaromatics with ortho-substituted P1's as factor Xa inhibitors

  • US 6,548,525 B2
  • Filed: 04/12/2001
  • Issued: 04/15/2003
  • Est. Priority Date: 12/22/1997
  • Status: Expired due to Term
First Claim
Patent Images

1. A compound of formula I:

  • embedded imageor a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

    ring M contains, in addition to J, 2 N atoms and R1b is not present;

    J is N or NH;

    D is selected from CN, C(═

    NR8)NR7R9, NHC(═

    NR8)NR7R9, NR8CH(═

    NR7), C(O)NR7R8, and (CR8R9)tNR7R8, provided that D is substituted ortho to G on E;

    E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and piperidinyl substituted with 1-2 R;

    R is selected from H, Cl, F, Br, I, (CH2)tOR3, C1-4 alkyl, OCF3, CF3, C(O)NR7R8, and (CR8R9)tNR7R8;

    G is absent or is selected from NHCH2, OCH2, and SCH2, provided that when s is 0, then G is attached to a carbon atom on ring M;

    Z is selected from a C1-4 alkylene, (CH2)rO(CH2)r, (CH2)rNR3(CH2)r, (CH2)rC(O)(CH2)r, (CH2)rC(O)O(CH2)r, (CH2)rOC(O)(CH2)r, (CH2)rC(O)NR3(CH2)r, (CH2)rNR3C(O)(CH2)r, (CH2)rOC(O)O(CH2)r, (CH2)rOC(O)NR3(CH2)r, (CH2)rNR3C(O)O(CH2)r, (CH2)rNR3C(O)NR3(CH2)r, (CH2)rS(O)p(CH2)r, (CH2)rSO2NR3(CH2)r, (CH2)rNR3SO2(CH2)r, and (CH2)rNR3SO2NR3(CH2)r, provided that Z does not form a N—

    N, N—

    O, N—

    S, NCH2N, NCH2O, or NCH2S bond with ring M or group A;

    R1a and R1b are independently absent or selected from —

    (CH2)r—

    R
    1′

    , —

    CH═

    CH—

    R1′

    , NCH2R1″

    , OCH2R1″

    , SCH2R1″

    , NH(CH2)2(CH2)tR1′

    , O(CH2)2(CH2)tR1′

    , and S(CH2)2(CH2)tR1′

    ;

    alternatively, R1a and R1b, when attached to adjacent carbon atoms, together with the atoms to which they are attached form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4 and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;

    R1′

    is selected from H, C1-3 alkyl, F, Cl, Br, I, —

    CN, —

    CHO, (CF2)rCF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O)R2, (CF2)rCO2R2c, S(O)pR2b, NR2(CH2)rOR2, C(═

    NR2c)NR2R2a, NR2C(O)R2b, NR2C(O)NHR2b, NR2C(O)2R2a, OC(O)NR2aR2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2b, C3-6 carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;

    R1″

    is selected from H, CH(CH2OR2)2, C(O)R2c, C(O)NR2R2a, S(O)R2b, S(O)2R2b, and SO2NR2R2a;

    R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;

    R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;

    R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;

    R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;

    alternatively, R2 and R2a combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

    alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

    R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

    R3a, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

    R3c, at each occurrence, is selected from C1-4 alkyl, and phenyl;

    A is selected from;

    C3-10 carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;

    B is selected from;

    Y, X—

    Y, NR2R2a, C(═

    NR2)NR2R2a, NR2C(═

    NR2)NR2R2a, C3-10 carbocyclic residue substituted with 0-2 R4a, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;

    X is selected from C1-4 alkylene, —

    CR2(CR2R2b) (CH2)t

    , —

    C(O)—

    , —

    C(═

    NR1″

    )—

    , —

    CR2(NR1″

    R2)—

    , —

    CR2(OR2)—

    , —

    CR2(SR2)—

    , —

    C(O)CR2R2a

    , —

    CR2R2aC(O), —

    S(O)p

    , —

    S(O)pCR2R2a

    , —

    CR2R2aS(O)p

    , —

    S(O)2NR2

    , —

    NR2S (O)2

    , —

    NR2S(O)2CR2R2a

    , —

    CR2R2aS(O)2NR2

    , —

    NR2S(O)2NR2

    , —

    C(O)NR2

    , —

    NR2C(O)—

    , —

    C(O)NR2CR2R2a

    , —

    NR2C(O)CR2R2a

    , —

    CR2R2aC(O)NR2

    , —

    CR2R2aNR2C(O)—

    , —

    NR2C(O)O—

    , —

    OC(O)NR2

    , —

    NR2C(O)NR2

    , —

    NR2

    , —

    NR2CR2R2a

    , —

    CR2R2aNR2

    , O, —

    CR2R2aO—

    , and —

    OCR2R2a

    ;

    Y is selected from;

    (CH2)rNR2R2a, provided that X—

    Y do not form a N—

    N, O—

    N, or S—

    N bond, C3-10 carbocyclic residue substituted with 0-2 R4a, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;

    R4, at each occurrence, is selected from H, ═

    O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —

    CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, C(═

    NR2)NR2R2a, C(═

    NS(O)2R5)NR2R2a, NHC(═

    NR2)NR2R2a, C(O)NHC(═

    NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2

    C1-4 alkyl, NR2SO2R5, S(O)pR5, (CF2)rCF3, NCH2R1″

    , OCH2R1″

    , SCH2R1″

    , N(CH2)2(CH2)tR1′

    , O(CH2)2(CH2)tR1′

    , and S(CH2)2(CH2)tR1′

    , alternatively, one R4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

    R4a, at each occurrence, is selected from H, ═

    O, (CH2)rOR2, (CH2)r

    F, (CH2)r

    Br, (CH2)r

    Cl, Cl, Br, F, I, C1-4 alkyl, —

    CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(O)NH(CH2)2NR2R2a, NR2C(O)NR2R2a, C(═

    NR2)NR2R2a, NHC(═

    NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2

    C1-4 alkyl, C(O)NHSO2

    C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3;

    alternatively, one R4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R5;

    R4b, at each occurrence, is selected from H, ═

    O, (CH2)rOR3, F, Cl, Br, I, C1-4 alkyl, —

    CN, NO2, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, C(═

    NR3)NR3R3a, NR3C(═

    NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2

    C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)p

    C1-4 alkyl, S(O)p-phenyl, and (CF2)rCF3;

    R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;

    R6, at each occurrence, is selected from H, OH, (CH2)rOR2, halo, C1-4 alkyl, CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, C(═

    NH)NH2, NHC(═

    NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl;

    R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, (CH2)n-phenyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;

    R8, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;

    alternatively, R7 and R8 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

    R9, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;

    n, at each occurrence, is selected from 0, 1, 2, and 3;

    p, at each occurrence, is selected from 0, 1, and 2;

    r, at each occurrence, is selected from 0, 1, 2, and 3;

    s, at each occurrence, is selected from 0, 1, and 2; and

    , t, at each occurrence, is selected from 0, 1, 2, and 3;

    provided that D—

    E—

    G—

    (CH2)s— and



    Z—

    A—

    B are not both benzamidines.

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