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1N-alkyl-n-arylpyrimidinamines and derivatives thereof

  • US 6,342,503 B1
  • Filed: 01/07/1998
  • Issued: 01/29/2002
  • Est. Priority Date: 10/12/1993
  • Status: Expired due to Term
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Assignment
First Claim
Patent Images

1. A compound of formula (I):

  • embedded imageor a pharmaceutically acceptable salt thereof, wherein;

    R1 is independently selected, at each occurrence from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C1-C2 haloalkyl;

    R3 is C1-C4 alkyl, C3-C6 cycloalkyl, C1-C2 haloalkyl, nitro, NR6R7, OR8, S(O)nR8, C(═

    O)R9, C(═

    O)NR6R7, C(═

    S)NR6R7, —

    (CHR16)kNR6R7, (CH2)kOR8, C(═

    O)NR10CH(R11)CO2R12, —

    C(OH)(R25)(R25a), —

    (CH2)pS(O)n-alkyl, —

    (CHR16)R25, —

    C(CN)(R25)(R16), —

    C(═

    O)R25, —

    CH(CO2R16)2, NR10C(═

    O)CH(R11)NR10R12, NR10CH(R11)CO2R12;

    K and L are each independently CX′

    ;

    R2 is independently selected at each occurrence from the group consisting of hydrogen, halo, halomethyl, C1-C3 alkyl, and cyano;

    R4 is (CH2)mOR16, C1-C4 alkyl, allyl, propargyl, (CH2)mR13, or —

    (CH2)mOC(O)R16;

    X is halogen, S(O)2R8, SR8, halomethyl, —

    (CH2)pOR8, cyano, —

    (CHR16)pNR14R15, —

    C(═

    O)R8, C1-C6 alkyl, C4-C10 cycloalkylalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C3-C6 cycloalkyl, nitro, thio-(C1-C10)-alkyl, —

    C(═

    NOR16)—

    C1-C4-alkyl, —

    C(═

    NOR16)H, or —

    C(═

    O)NR14R15 where substitution by R18 can occur on any carbon containing substituents;

    X′

    is independently selected at each occurrence from the group consisting of hydrogen, halogen, S(O)nR8, halomethyl, —

    (CHR16)pOR8, cyano, —

    (CHR16)pNR14R15, C(═

    O)R8, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C3-C6 cycloalkyl, nitro, thio-(C1-C10)-alkyl, —

    C(═

    NOR16)—

    C1-C4-alkyl, —

    C(═

    NOR16)H, or —

    C(═

    O)NR14R15 where substitution by R18 can occur on any carbon containing substituents;

    R5 is halo, —

    C(═

    NOR16)—

    C1-C4-alkyl, C1-C6 alkyl, C1-C3 haloalkyl, C1-C6 alkoxy, —

    (CHR16)pOR8, (CHR16)pS(O)nR8, —

    (CHR16)pNR14R15, C3-C6 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, C3-C6 cycloalkoxy, nitro, amino-(C2-C10)-alkyl, thio-(C2-C10)-alkyl, SOn(R8), C(═

    O)R8, —

    C(═

    NOR16)H, or C(═

    O)NR14R15, where substitution by R18 can occur on any carbon containing substituents;

    R6 and R7 are independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, (C4-C12)-cycloalkylalkyl, —

    (CH2)kR13, (CHR16)pOR8, —

    (C1-C6 alkyl)-aryl, phenyl, heteroaryl, —

    S(O)z-aryl or —

    (C1-C6 alkyl)-heteroaryl, wherein the aryl or heteroaryl groups are optionally substituted with 1-3 groups selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, NHC(═

    O)(C1-C6 alkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)2, nitro, carboxy, CO2(C1-C6 alkyl), cyano, S(O)z—

    (C1-C6 alkyl);

    or can be taken together to form —

    (CH2)qA(CH2)r—

    , optionally substituted with 0-3 R17;

    A is CH2, O, NR25, C(═

    O), S(O)n, N(C(═

    O)R17), N(R19), C(H)(NR14R15), C(H)(OR20), C(H)(C(═

    O)R21), N(S(O)nR21);

    R8 is independently selected at each occurrence from the group consisting of hydrogen;

    C1-C6 alkyl;

    —

    (C4-C12) cycloalkylalkyl;

    (CH2)tR22;

    C3-C10 cycloalkyl;

    —

    NR6R7;

    aryl;

    heteroaryl;

    —

    NR16(CH2)nNR6R7;

    —

    (CH2)kR25; and

    (CH2)theteroaryl or (CH2)taryl, either of which can be optionally substituted with 1-3 groups selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, NHC(═

    O)(C1-C6 alkyl), NH(C1-C6 alkyl) N(C1-C6 alkyl)2, nitro, carboxy, CO2(C1-C6 alkyl), cyano, and S(O)z(C1-C6-alkyl);

    R9 is independently selected at each occurrence from R10, hydroxy, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C4 alkenyl, phenyl substituted with 0-3 R18, and —

    (C1-C6 alkyl)-aryl substituted with 0-3 R18;

    R10, R16, R23, and R24 are independently selected at each occurrence from hydrogen or C1-C4 alkyl;

    R11 is C1-C4 alkyl substituted with 0-3 groups chosen from the following;

    keto, amino, sulfhydryl, hydroxyl, guanidinyl, p-hydroxyphenyl, imidazolyl, phenyl, indolyl, and indolinyl, or, when taken together with an adjacent R10, are (CH2)t;

    R12 is hydrogen or an appropriate amine protecting group for nitrogen or an appropriate carboxylic acid protecting group for carboxyl;

    R13 is independently selected at each occurrence from the group consisting of CN, OR19, SR19, and C3-C6 cycloalkyl;

    R14 and R15 are independently selected at each occurrence from the group consisting of hydrogen, C4-C10 cycloalkyl-alkyl, and R19;

    R17 is independently selected at each occurrence from the group consisting of R10, C1-C4 alkoxy, halo, OR23, SR23, NR23R24, and (C1-C6) alkyl (C1-C4) alkoxy;

    R18 is independently selected at each occurrence from the group consisting of R10, hydroxy, halogen, C1-C2 haloalkyl, C1-C4 alkoxy, C(═

    O)R24, and cyano;

    R19 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, (CH2)wR22, and phenyl substituted with 0-3 R18;

    R20 is independently selected at each occurrence from the group consisting of R10, C(═

    O)R31, and C2-C4 alkenyl;

    R21 is independently selected at each occurrence from the group consisting of R10, C1-C4 alkoxy, NR23R24, and hydroxyl;

    R22 is independently selected at each occurrence from the group consisting of cyano, OR24, SR24, NR23R24, C1-C6 alkyl, C3-C6 cycloalkyl, —

    S(O)nR31, and —

    C(═

    O)R25;

    R25, which can be optionally substituted with 0-3 R17, is independently selected at each occurrence from the group consisting of phenyl, and pyridyl;

    R25a, which can be optionally substituted with 0-3 R17, is independently selected at each occurrence from the group consisting of H and R25;

    R27 is independently selected at each occurrence from the group consisting of C1C3 alkyl, C2-C4 alkenyl, C2-4 alkynl, C2-4 alkoxy, aryl, nitro, cyano, halogen, and phenyloxy;

    R31 is independently selected at each occurrence from the group consisting of C1-C4 alkyl, C3-C7 cycloalkyl, C4-C10 cycloalkyl-alkyl, and aryl-(C1-C4) alkyl;

    k, m, and r are independently selected at each occurrence from 1-4;

    n is independently selected at each occurrence from 0-2;

    p, q, and z are independently selected at each occurrence from 0-3;

    t and w are independently selected at each occurrence from 1-6;

    provided that when K and L are both CH, then (A) when R2 is H and R1 and R3 are methyl, (1) and R4 is methyl, then (a) R5 can not be C1-C6 alkyl when X is OH and X′

    is H;

    (b) R5 can not be (CHR16)pNR14R15 wherein p is 0 when X and X′

    are —

    OCH3; and

    (c) R5 can not be (CHR 16)pNR14R15 when X and X′

    are —

    OCH2CH3; and

    (2) and R4 is ethyl, then (a) R5 can not be (CHR16)pNR14R15 when X and X′

    are —

    OCH3;

    (b) R5 can not be (CHR16)pOR18 with p=0 and R18=H when X is Br and X′

    is OH; and

    (c) R5 can not be C1-C6 alkyl substituted with OH;

    or (CHR16)pNR14R15 wherein R16=H and p=1-3 and R14 and R15 are H or C1-C6 alkyl when X is —

    SCH3 and X′

    is H;

    (B) when R2 is H, R4 is ethyl, R5 is iso-propyl, X is Br, X′

    is H, and (1) R1 is CH3;

    then (a) R3 can not be OR8, CO2R12, C(═

    O)NR6R7, (CH2)kOR8;

    (CHR16)kNR6R7;

    (2) R1 is —

    CH2CH2CH3 then R3 can not be C1-C6 alkyl;

    further provided that when X′

    is H, and K and L are both CH, then (D) when R2 is H or C1-C3 alkyl;

    R4 is C1-C4 alkyl;

    R5, X and/or X′

    are OH, halo, CF3, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, cyano, amino, carbamoyl, or C1-C4 alkanoyl; and

    R1 is C1-C4 alkyl, then R3 can not be —

    NH(substituted phenyl) or —

    N (C1-C4 alkyl) (substituted phenyl) and further provided that when R3 is S(O)nR8, R8 is not hydrogen;

    and when R3 is —

    C(CN)(R25)(R16), R25 is not pyridyl and when R3 is S(O)nR8, R8 is not H;

    wherein the term “

    heterocycle”

    is defined as pyridyl, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl or benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thiophenyl, thianthrenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrole, imidazolyl, pyrazolyl, isothiazolyl, isoxazole, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindole, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β

    -carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl;

    wherein the term “

    aryl”

    is defined as phenyl, biphenyl or naphthyl; and

    wherein the term “

    heteroaryl”

    is defined as 2-, or 3-, or 4-pyridyl;

    2- or 3-furyl;

    2- or 3-benzofuranyl;

    2-, or 3-thiophenyl;

    2- or 3-benzo[b]thiophenyl;

    2-, or 3-, or 4-quinolinyl;

    1-, or 3-, or 4-isoquinolinyl;

    2- or 3-pyrrolyl;

    1- or 2- or 3-indolyl;

    2-, or 4-, or 5-oxazolyl;

    2-benzoxazolyl;

    2- or 4- or 5-imidazolyl;

    1- or 2-benzimidazolyl;

    2- or 4- or 5-thiazolyl;

    2-benzothiazolyl;

    3- or 4- or 5-isoxazolyl;

    3- or 4- or 5-pyrazolyl;

    3- or 4- or 5-isothiazolyl;

    3- or 4-pyridazinyl;

    2- or 4- or 5-pyrimidinyl;

    2-pyrazinyl;

    2-triazinyl;

    3- or 4- cinnolinyl;

    1-phthalazinyl;

    2- or 4-quinazolinyl;

    or 2-quinoxalinyl ring.

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