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Cyclic protein tyrosine kinase inhibitors

DC
  • US 6,596,746 B1
  • Filed: 04/13/2000
  • Issued: 07/22/2003
  • Est. Priority Date: 04/15/1999
  • Status: Expired due to Term
2
Associated Cases
1
Associated Defendant
2
Product Citations
0
Petitions
184
Forward Citations
1
Assignment
First Claim
Patent Images

1. A compound of formula I or a salt thereof embedded imagewhereQ is thiazole;

  • Z is a single bond;

    X1 and X2 together form ═

    O;

    R1 is (1) hydrogen or R6, where R6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z1, Z2 and one or more groups Z3;

    (2) —

    OH or —

    OR6;

    (3) —

    SH or —

    SR6;

    (4) —

    C(O)2H, —

    C(O)qR6, or —

    O—

    C(O)qR6, where q is 1 or 2;

    (5) —

    SO3H or —

    S(O)qR6;

    (6) halo;

    (7) cyano;

    (8) nitro;

    (9) —

    Z4—

    NR7R8;

    (10) —

    Z4—

    N(R9)—

    Z5—

    NR10R11;

    (11) —

    Z4—

    N(R12)—

    Z5—

    R6;

    (12) —

    P(O)(OR6)2;

    R2 is hydrogen, R6, —

    Z4—

    R6, or —

    Z13—

    NR7R8;

    R3 is —

    Z4—

    R6 wherein Z4 is a single bond and wherein R6 is aryl substituted with at least one group Z3 where Z3 is —

    Z4—

    NZ7Z8 where Z4 is a bond Z7 is hydrogen or alkyl and Z8 is heterocyclo-substituted alkyl;

    R4 and R5 are each independently (1) hydrogen or R6;

    (2) —

    Z4—

    N(R9)—

    Z5—

    NR10R11;

    (3) —

    N(R9)Z4R6;

    or (4) together with the nitrogen atom to which they are attached complete a 3- to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z1, Z2 and Z3, which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z1, Z2 and Z3;

    R7, R8, R9, R10, R11 and R12 (1) are each independently hydrogen or R6;

    (2) R7 and R8 may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;

    or (3) any two of R9, R10 and R11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;

    R13 is (1) cyano;

    (2) nitro;

    (3) —

    NH2;

    (4) —

    NHOalkyl;

    (5) —

    OH;

    (6) —

    NHOaryl;

    (7) —

    NHCOOalkyl;

    (8) —

    NHCOOaryl;

    (9) —

    NHSO2alkyl;

    (10) —

    NHSO2aryl;

    (11) aryl;

    (12) heteroaryl;

    (13) —

    Oalkyl;

    or (14) —

    Oaryl;

    R14 is (1) —

    NO2;

    (2) —

    COOalkyl;

    or (3) —

    COOaryl;

    R15 is (1) hydrogen;

    (2) alkyl;

    (3) aryl;

    (4) arylalkyl;

    or (5) cycloalkyl;

    Z1, Z2 and Z3 are each independently (1) hydrogen or Z6, where Z6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;

    (ii) a group (i) which is itself substituted by one or more of the same or different groups (i);

    or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z1, Z2 and Z3;

    (2) —

    OH or —

    OZ6;

    (3) —

    SH or —

    SZ6;

    (4) —

    C(O)qH, —

    C(O)qZ6, or —

    O—

    C(O)qZ6;

    (5) —

    SO3H, —

    S(O)qZ6;

    or S(O)qN(Z9)Z6;

    (6) halo;

    (7) cyano;

    (8) nitro;

    (9) —

    Z4—

    NZ7Z8;

    (10) —

    Z4—

    N(Z9)—

    Z5—

    NZ7Z8;

    (11) —

    Z4—

    N(Z10)—

    Z5Z6;

    (12) —

    Z4—

    N(Z10)—

    Z5—

    H;

    (13) oxo;

    (14) —

    O—

    C(O)—

    Z6;

    (15) any two of Z1, Z2, and Z3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;

    or (16) any two of Z1, Z2, and Z3 may together be —

    O—

    (CH2)r—

    O—

    , where r is 1 to 5, completing a 4- to 8-membered ring together with the atoms to which they are attached;

    Z4 and Z5 are each independently (1) a single bond;

    (2) —

    Z11—

    S(O)q—

    Z12—

    ;

    (3) —

    Z11—

    C(O)—

    Z12—

    ;

    (4) —

    Z11—

    C(S)—

    Z12—

    ;

    (5) —

    Z11—

    O—

    Z12—

    ;

    (6) —

    Z11—

    S—

    Z12—

    ;

    (7) —

    Z11—

    O—

    C(O)—

    Z12—

    ;

    or (8) —

    Z11—

    C(O)—

    O—

    Z12—

    ;

    Z7, Z8, Z9 and Z10 (1) are each independently hydrogen or Z6;

    (2) Z7 and Z8, or Z6 and Z10, may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;

    or (3) Z7 or Z8, together with Z9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;

    Z11 and Z12 are each independently (1) a single bond;

    (2) alkylene;

    (3) alkenylene;

    or (4) alkynylene; and

    Z13 is (1) a single bond;

    (2) —

    Z11—

    S(O)q—

    Z12—

    ;

    (3) —

    Z11—

    C(O)—

    Z12—

    ;

    (4) —

    Z11—

    C(S)—

    Z12—

    ;

    (5) —

    Z11—

    O—

    Z12—

    ;

    (6) —

    Z11—

    S—

    Z12—

    ;

    (7) —

    Z11—

    O—

    C(O)—

    Z12—

    ;

    (8) —

    Z11—

    C(O)—

    O—

    Z12—

    ;

    (9) —

    C(NR13)—

    ;

    (10) —

    C(CHR14)—

    ;

    or (11) —

    C(C(R14)2)—

    .

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