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Benzylidene-1,3-dihydro-indol-2-one derivatives a receptor tyrosine kinase inhibitors, particularly of Raf kinases

  • US 6,268,391 B1
  • Filed: 04/07/2000
  • Issued: 07/31/2001
  • Est. Priority Date: 08/06/1997
  • Status: Expired due to Fees
First Claim
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1. A compound of formula (I) wherein R1 is H or is optionally joined with R2 to form a fused ring selected from the group consisting of five to ten membered aryl, heteroaryl or heterocyclyl rings, said heteroaryl or said heterocyclyl rings having one to three heteroatoms where zero to three of said heteroatoms are N and zero to 1 of said heteroatoms are O or S and where said fused ring is optionally substituted by one to three of R9, where R2 and R9 are as defined below;

  • R2 and R3 are independently H, HET, aryl, C1-12 aliphatic, CN, NO2, halogen, R10, —

    OR10, —

    SR10, —

    S(O)R10, —

    SO2R10, —

    NR10R11, —

    NR11R12, —

    NR12COR11, —

    NR12CO2R11, —

    NR12CONR11R12, —

    NR12SO2R11, —

    NR12C(NR12)NHR11, —

    COR11, —

    CO2R11, —

    CONR12R11, —

    SO2NR12R11, —

    OCONR12R11, C(NR12)NR12R11 where said C1-12 aliphatic optionally bears one or two insertions of one to two groups selected from C(O), O, S, S(O), SO2 or NR12;

    with said HET, aryl or C1-12 aliphatic being optionally substituted by one to three of R10; and

    where R2 is optionally joined with R3 to form a fused ring selected from the group consisting of five to ten membered aryl, heteroaryl or heterocyclyl rings, said heteroaryl or said heterocyclyl rings having zero to three heteroatoms where zero to three of said heteroatoms are N and zero to one of said heteroatoms are O or S and where said fused ring is optionally substituted by one to three of R9;

    where HET, R9, R10, R11 and R12 are as defined below;

    or R2 and R3 are independently —

    R12NH2, —

    R12-halogen, —

    COR11NR12R11, —

    C(NH)R11, where R11 is as defined below, and R12 is H, C1-6 aliphatic, NO2, C1-6 alkoxy, halogen, aryl or HET, said C1-6 aliphatic optionally substituted by one to three of halogen or OH, where HET is as defined below;

    R4 is H, halogen, NO2 or CN;

    R5 is H or C1-12 aliphatic optionally substituted by one to three of halo, hydroxyl, or aryl;

    R6 and R7 are independently bromo or chloro;

    R8 is OH;

    each R9is independently halogen, C1-12 aliphatic, CN, —

    NO2, R10, —

    OR11, —

    SR11, —

    S(O)R10, —

    SO2R10, —

    NR10R11, —

    N11R12, —

    NR12COR11, —

    NR12CO2R11, —

    NR12CONR11R12, —

    NR12SO2R11, —

    NR12C(NR12)NHR11, —

    CO2R11, —

    CONR12R11, —

    SO2NR12R11, —

    OCONR12R11 or C(NR12)NR12R11, where R10, R11 and R12 are as defined below;

    each R10 is independently H, halogen, C1-12 aliphatic, aryl or HET, where said C1-12 aliphatic optionally bears an inserted one to two groups selected from O, S, S(O), SO2 or NR12, where said C1-12 aliphatic, aryl or HET is optionally substituted by one to three of halo, another HET, aryl, CN, —

    SR12, —

    OR12, —

    N(R2)2, —

    S(O)R12, —

    SO2R12, SO2N(R12)2, —

    NR12COR12, —

    NR12CO2R12, —

    NR12CON(R12)2, —

    NR12(NR12)NHR12, —

    CO2R12, —

    CON(R12)2, —

    NR12SO2R12, —

    OCON(R12)2, where HET and R12 are as defined below;

    or each R10 is independently C1-6 aliphatic, aryl or HET optionally substituted by one to three of NO2, R12, —

    R12N(R12)2 or trifluoro, where R12 is H, C1-6 aliphatic, NO2, C1-6 alkoxy, halogen, aryl or HET, said C1-6 aliphatic optionally substituted by one to three of halogen or OH, where HET is as defined below;

    or each R10 is oxo, cyano or amino;

    or each R9 is —

    COR10, where R10 is H, C1-6 aliphatic or amino;

    R11 is H or R10;

    R12 is H, C1-12 aliphatic or HET, said C1-12 aliphatic optionally substituted by one to three of halogen or OH where HET is as defined below;

    or R12 is NO2, C1-6 alkoxy, halogen or aryl;

    HET is a five to ten-membered saturated or unsaturated heterocyclic ring selected from the group consisting of benzofuran, benzoxazole, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, indole, indazole, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxiadiazine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline, quinazoline, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, and triazole;

    or R12 is (R11)2N—

    C1-6 aliphatic, where R11 is H, C1-6 aliphatic, hydroxy-C1-6 aliphatic, phenyl, phenyl-C, aliphatic or HET, where HET is oxazole, pyridine, tetrazole or thiazole; and

    and the pharmaceutically acceptable salts or solvates thereof.

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