1N-alkyl-N-arylpyrimidinamines and derivatives thereof

A compound of formula (I):

• ##STR73## or a pharmaceutically acceptable salt thereof, wherein Y is CR.sup.29 ;
• R.sup.1 is C.sub.1 -C.sub.2 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C.sub.2 -C.sub.4 alkoxy, halogen, amino, methylamino, dimethylamino, aminomethyl, or N-methylaminomethyl;
• CO.sub.2 H, CO.sub.2 -alkyl, acyl, alkoxy, OH, or --(CH.sub.2).sub.m Oalkyl;
• R.sup.3 is aryl, C.sub.1 -C.sub.2 haloalkyl, NR.sup.6 R.sup.7, OR.sup.8, S(O).sub.n R.sup.8, C(.dbd.O)R.sup.9, C(.dbd.O)NR .sup.6 R.sup.7, C(.dbd.S)NR.sup.6 R.sup.7, --(CHR.sup.16).sub.k NR.sup.6 R.sup.7, (CH.sub.2).sub.k OR.sup.8, C(.dbd.O)NR.sup.10 CH(R.sup.11)CO.sub.2 R.sup.12, --C(OH)(R.sup.25)(R.sup.25a), --(CH.sub.2).sub.p S(O).sub.n -alkyl, --(CHR.sup.16)R.sup.25,--C(CN)(R.sup.25)(R.sup.16) provided that R.sup.25 is not --NH-- containing rings, --C(.dbd.O)R.sup.25, --CH(CO.sub.2 R.sup.16).sub.2, NR.sup.10 C(.dbd.O)CH(R.sup.11)NR.sup.10 R.sup.12, NR.sup.10 CH(R.sup.11)CO.sub.2 R.sup.12 ;
• substituted C.sub.1 -C.sub.4 alkyl, substituted C.sub.2 -C.sub.4 alkenyl, substituted C.sub.2 -C.sub.4 alkynyl, substituted C.sub.1 -C.sub.4 alkoxy, aryl-(substituted C.sub.1 -C.sub.4) alkyl, aryl-(substituted C.sub.1 -C.sub.4) alkoxy, substituted C.sub.3 -C.sub.6 cycloalkyl, amino-(substituted C.sub.1 -C.sub.4) alkyl, substituted C.sub.1 -C.sub.4 alkylamino, where substitution by R.sup.27 can occur on any carbon containing substituent, or R.sup.3 is 2-pyridinyl, imidazolyl, 3-pyridinyl, 4-pyridinyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyrindyl, furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4pyrazinyl, azetidinyl, phenyl, 1H-indazolyl, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, azepinyl, benzofuranyl, benzothiophenyl, carbazolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl, imidazolidinyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, benzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, phenanthridinyl, phenathrolinyl, phenazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, .beta.-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thianthrenyl, thiazolyl, thiophenyl, triazinyl, xanthenyl;
• or 1tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl or either of which can be substituted with 0-3 groups cxhosen from keto and C.sub.1 -C.sub.4 alkyl, provided that R.sup.3 is not NH.sub.2, CF.sub.3, CO.sub.2 H, CO.sub.2 -alkyl, acyl, alkoxy, OH or (CH.sub.2).sub.m --O-alkyl;
• J, K, and L are independently selected at each occurrence from the group of CH and CX';
• M is CR.sup.5 ;
• V is N;
• Z is N;
• R.sup.2 is independently selected at each occurrence from the group consisting of hydrogen, halo, halomethyl, cyano, C.sub.1 -C.sub.3 alkyl, nitro, amino, --CO.sub.2 R.sup.10 ;
• R .sup.4 is taken together with R.sup.29 to form a 5-membered ring and is --N.dbd.;
• X is Cl, Br, I, S(O).sub.n R.sup.8, halomethyl, --(CHR.sup.16).sub.p OR.sup.8, cyano, --(CHR.sup.16).sub.p NR.sup.14 R.sup.15, C(.dbd.O)R.sup.8, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 alkoxy, aryl-(C.sub.1 -C.sub.10)-alkyl, C.sub.3 -C.sub.6 cycloalkyl, aryl-(C.sub.1 -C.sub.10)-alkoxy, nitro, thio-(C.sub.1 -C.sub.10)-alkyl, --C(.dbd.NOR.sup.16)-C.sub.1 -C.sub.4 -alkyl, --C(.dbd.NOR.sup.16)H, or C(.dbd.O)NR.sup.14 R.sup.15 when substitution by R.sup.18 can occur on any carbon containing substituents;
• X' is hydrogen, Cl, Br, I, S(O).sub.n R.sup.8, --(CHR.sup.16).sub.p OR.sup.8, halomethyl, cyano, --(CHR.sup.16).sub.p NR.sup.14 R.sup.15, C(.dbd.O)R.sup.8, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 alkoxy, aryl-(C.sub.1 -C.sub.10)-alkyl, C.sub.3 -C.sub.6 cycloalkyl, aryl-(C.sub.2 -C.sub.10)-alkoxy, nitro, thio-(C.sub.2 -C.sub.10)-alkyl, --C(.dbd.NOR.sup.16)-C.sub.1 -C.sub.4 -alkyl, --C(.dbd.NOR.sup.16)H, or C(.dbd.O)NR.sup.8 R.sup.15 where substitution by R.sup.18 can occur on any carbon containing substituents;
• R.sup.5 is halo, --C(.dbd.NOR.sup.16)-C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.6 alkyl, C1-C3 haloalkyl, C.sub.1 -C.sub.6 alkoxy, (CHR.sup.16).sub.p OR.sup.8, (CHR.sup.16).sub.p S(O).sub.n R.sup.8, (CHR.sup.16).sub.p NR.sup.14 R.sup.15, C.sub.3 -C.sub.6 cycloalkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, aryl-(C.sub.2 -C.sub.10)-alkyl, aryl-(C.sub.1 -C.sub.10)-alkoxy, cyano, C.sub.3 -C.sub.6 cycloalkoxy, nitro, amino-(C.sub.1 -C.sub.10)-alkyl, thio-(C.sub.1 -C.sub.10)-alkyl, SO.sub.n (R.sup.8), C(.dbd.O)R.sup.8, --C(.dbd.NOR.sup.16)H, or C(.dbd.O)NR.sup.8 R.sup.15 where substitution by R.sup.18 can occur on any carbon containing substituents;
• R.sup.6 and R.sup.7 are independently selected at each occurrence from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.10 cycloalkyl, --(CH.sub.2).sub.k R.sup.13, (CHR.sup.16).sub.p OR.sup.8, (C.sub.4 -C.sub.12)-cycloalkylalkyl, C.sub.1 -C.sub.6 alkoxy, --(C.sub.1 -C.sub.6 alkyl)-aryl, hetoaryl, aryl, --S(O).sub.Z -aryl or --(C.sub.1 -C.sub.6 alkyl)-heteroaryl or aryl wherein the aryl or heteroaryl groups are optionally substituted with 1-3 groups selected from hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, amino, NHC(.dbd.O) (C.sub.1 -C.sub.6 alkyl), NH(C.sub.1 -C.sub.6 alkyl) N (C.sub.1 -C.sub.6 alkyl).sub.2, nitro, carboxy, CO.sub.2 (C.sub.1 -C.sub.6 alkyl), and cyano;
• or can be taken together to form --(CH.sub.2).sub.q A(CH.sub.2).sub.r --, optionally substituted with 0-3 R.sup.17 ;
• or, when considered with the commonly attached nitrogen, can be taken together to form a heterocycle, said heterocycle being substituted on carbon with 1-3 groups consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, hydroxy, or C.sub.1 -C.sub.6 alkoxy;
• A is CH.sub.2, O, NR.sup.25, C(.dbd.O), S(O).sub.n, N(C(.dbd.O)R.sup.17), N(R.sup.19), C(H)(NR.sup.14 R.sup.15), C(H)(OR.sup.20), C(H)(C(.dbd.O)R.sup.21), or N(S(O).sub.n R.sup.21);
• R.sup.8 is independently selected at each occurrence from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, --(C.sub.4 -C.sub.12) cycloalkylalkyl, (CH.sub.2).sub.t R.sup.22, C.sub.3 -C.sub.10 cycloalkyl, --(C.sub.1 -C.sub.6 alkyl)-aryl, heteroaryl, --NR.sup.16, --N(CH.sub.2).sub.n NR.sup.6 R.sup.7 ;
• (CH.sub.2).sub.k R.sup.25, --(C.sub.1 -C.sub.6 alkyl)-heteroaryl or aryl optionally substituted with 1-3 groups selected from hydrogen, halogen, C.sub.1 -C.sub.6 alkyl C.sub.1 -C.sub.6 alkoxy, amino, NHC(.dbd.O)(C.sub.1 -C.sub.6 alkyl), NH(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.6 alkyl).sub.2, nitro, carboxy, CO.sub.2 (C.sub.1 -C.sub.6 alkyl), and cyano;
• R.sup.9 is independently selected at each occurrence from R.sup.10, hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.3 -C.sub.6 cycloalkyl, C.sub.2 -C.sub.4 alkenyl, or aryl substituted with 0-3 R.sup.18 ;
• R.sup.10, R.sup.16, R.sup.23, and R.sup.24 are independently selected at each occurrence from hydrogen or C.sub.1 -C.sub.4 alkyl;
• R.sup.11 is C.sub.1 -C.sub.4 alkyl substituted with 0-3 groups independently selected at each occurrence from the group consisting of keto, amino, sulfhydryl, hydroxyl, guanidinyl, p-hydroxyphenyl, imidazolyl, phenyl, indolyl, and indolinyl, or, when taken together with an adjacent R.sup.10, are (CH.sub.2);
• R.sup.12 is hydrogen or an appropriate amine protecting group for nitrogen or an appropriate carboxylic acid protecting group for carboxyl;
• R.sup.13 is independently selected at each occurrence from the group consisting of CN, OR.sup.19, SR.sup.19, and C.sub.3 -C.sub.6 cycloalkyl;
• R.sup.14 and R.sup.15 are independently selected at each occurrence from the group consisting of hydrogen, C.sub.4 -C.sub.10 cycloalkyl-alkyl, and R.sup.19 ;
• R.sup.17 is independently selected at each occurrence from the group consisting of R.sup.10, C.sub.1 -C.sub.4 alkoxy, halo, OR.sup.23, SR.sup.23, and NR.sup.23 R.sup.24 ;
• R.sup.18 is independently selected at each occurrence from the group consisting of R.sup.10, hydroxy, halogen, C.sub.1 -C.sub.2 haloalkyl, C.sub.1 -C.sub.4 alkoxy, C(.dbd.O)R.sup.24, and cyano;
• R.sup.19 is independently selected at each occurrence from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, (CH.sub.2).sub.W R.sup.22, and aryl substituted with 0-3 R.sup.18 ;
• R.sup.20 is independently selected at each occurrence from the group consisting of R.sup.10 and C(.dbd.O)R.sup.31 ;
• R.sup.21 is independently selected at each occurrence from the group consisting of R.sup.10, C.sub.1 -C.sub.4 alkoxy, NR.sup.23 R.sup.24, and hydroxyl;
• R.sup.22 is independently selected at each occurrence from the group consisting of cyano, OR.sup.24, SR.sup.24, NR.sup.23 R.sup.24, C.sub.3 -C.sub.6 cycloalkyl, --S(O).sub.n R.sup.31, and --C(.dbd.O)R.sup.25 ;
• R.sup.25, which can be optionally substituted with 0-3 R.sup.17, is independently selected at each occurrence from the group consisting of phenyl, pyrazolyl, imidazolyl, 2-methyl-3-pyrindinyl, 4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl, azetidinyl, 1H-indazolyl, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, azepinyl, benzofuranyl, benzothiophenyl, carbazolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl;
• benzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, 62-carbolinyl, tetrahydrofuranyl, tetrazolyl, thianthrenyl, thiazolyl, thiophenyl, triazinyl, xanthenyl;
• and 1-tetrahydroquinolinyly or 2-tetrahydroisoquinolinyl either of which can be substituted with 0-3 groups chosen from keto and C.sub.1 -C.sub.4 alkyl;
• R.sup.25a, which can be optionally substituted with 0-3 R.sup.17, is independently selected at each occurrence from the group consisting of R.sup.10 and R.sup.25 ;
• R.sup.26 is H or halogen;
• R.sup.27 is independently selected at each occurrence from the group consisting of C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2-4 alkynl, C.sub.2-4 alkoxy, aryl, nitro, cyano, halogen, aryloxy, and heterocycle optionally lined through 0;
• R.sup.28 is C.sub.1 -C.sub.2 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, hydrogen, C.sub.1 -C.sub.2 alkoxy, halogen, or C.sub.2 -C.sub.4 alkylamino;
• R.sup.29 is taken together with R.sup.4 to form a five membered ring and is --N.dbd.;
• R.sup.30 is hydrogen, cyano, C.sub.1 -C.sub.2 alkyl, C.sub.1 -C.sub.2 alkoxy, halogen, C.sub.1 -C.sub.2 alkenyl, nitro, amido, carboxy, or amino;
• R.sup.31 is C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.7 cycloalkyl, or aryl-(C.sub.1 -C.sub.4) 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 and q are independently selected at each occurrence from 0-3;
• t and w are independently selected at each occurrence from 1-6;
• wherein aryl means phenyl, biphenyl or napthylyl;
• heteroaryl means an unsubstituted, monosubstituted or disubstituted 5, 6 or 10 membered mono or bicyclic aromatic ring which can optionally contain from one to three heteroatoms selected from the group consisting of O, N or S wherein said heteroaryls are selected from 2-, or 3-, or 4-pyridyl;
• 2- or 3-furyl;
• 2- or 3-benzofuranyl;
• 2-, or 3-thiophenyl;
• 2- or 3-benzothiophenyl;
• 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;
• acyl means CHO or CO-alkyl wherein alkyl means a straight or branched one to six carbon atom moiety or a cyclic alkyl from three to seven carbon atoms;
• and
• heterocycle means a stable 5 to 7 membered monocyclic or bicyclic ring or a stable 7 to 10 membered bicyclic heterocyclic ring which is either saturated or unsaturated and which consists of carbon atoms and one to four heteroatoms independently selected from N, O or S and wherein the O and S atoms may optionally be oxidized and the N atom may be quaterinized and including any of the above groups fused to a benzene ring wherein said heterocycles are selected from pyridyl, pyrimidinyl, 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, triazinyl, 6H-1,2,5-thiazidazinyl, 2H,6H-1,5,2,-dithiazinyl, thiophenyl thiathrenyl, 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-carbazole, carbazole, .beta.-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl;
• provided that when R.sup.1 is CH.sub.3 and R.sup.3 is amino;
• then R.sup.5 is not halogen, or methyl.