HIV Replication Inhibiting Pyrimidines

摘要

This invention concerns HIV replication inhibitors of formula;;the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof, wherein the ring containing -a1=a2-a3=a4- and -b1=b2-b3=b4- represents phenyl, pyridyl, pyrimidinyl, pirazinyl, pyridazinyl; n is 0 to 5; m is 1 to 4; R1 is hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyl; C1-6alkyloxycarbonyl; substituted C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy; substituted C1-6alkyloxyC1-6alkylcarbonyl; R2 is hydroxy, halo, optionally substituted C1-6alkyl, C3-7cycloalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)pR6, —NH—S(═O)pR6, —C(═O)R6, —NHC(═O)H, —C(═O)NHNH2, —NHC(═O)R6, —C(═NH)R6 or a 5-membered heterocycle; X1 is —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, C1-4alkanediyl, —CHOH—, —S—, —S(═O)p—, —X2—C1-4alkanediyl- or —C1-4alkanediyl-X2—; R3 is NHR13; NR13R14; —C(═O)—NHR13; —C(═O)—NR13R14; —C(═O)—R15; —CH═N—NH—C(═O)—R16; substituted C1-6alkyl; optionally substituted C1-6alkyloxyC1-6alkyl; substituted C2-6alkenyl; substituted C2-6alkynyl; C1-6alkyl substituted with hydroxy and a second substituent; —C(═N—O—R8)—C1-4alkyl; R7; or —X3—R7; R4 is halo, hydroxy, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyl, formyl, amino, mono- or di(C1-4alkyl)amino; their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them.

主权项

1. A combination containing (a) a compound of formula (I)a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein-a=a2-a3=a4- represents a bivalent radical of formula
—CH═CH—CH═CH—  (a-1); —N═CH—CH═CH—  (a-2); —N═CH—N═CH—  (a-3); —N═CH—CH═N—  (a-4); —N═N—CH═CH—  (a-5);-b1=b2-b3=b4- represents a bivalent radical of formula
—CH═CH—CH═CH—  (b-1); —N═CH—CH═CH—  (b-2); —N═CH—N═CH—  (b-3); —N═CH—CH═N—  (b-4); —N═N—CH═CH—  (b-5); n is 0, 1, 2, 3 or 4; and in case -a1=a2-a3=a4- is (a-1), then n may also be 5; m is 1, 2, 3 and in case -b1=b2-b3=b4- is (b-1), then m may also be 4; R1 is hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyl; C1-6alkyloxycarbonyl; C1-6alkyl substituted with formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy; C1-6alkyloxyC1-6alkylcarbonyl substituted with C1-6alkyloxycarbonyl; each R2 independently is hydroxy, halo, C1-6alkyl optionally substituted with cyano or —C(═O)R6, C3-7cycloalkyl, C2-6alkenyl optionally substituted with one or more halogen atoms or cyano, C2-6alkynyl optionally substituted with one or more halogen atoms or cyano, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethylthio, —S(═O)pR6, —NH—S(═O)pR6, —C(═O)R6, —NHC(═O)H, —C(═O)NHNH2, —NHC(═O)R6, —C(═NH)R6 or a radical of formula wherein each A1 independently is N, CH or CR6; and
A2 is NH, O, S or NR6; X1 is —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, C1-4alkanediyl, —CHOH—, —S—, —S(═O)p—, —X2—C1-4alkanediyl- or —C1-4alkanediyl-X2—; X2 is —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)p—; R3 is NHR13; NR13R14; —C(═O)—NHR3; —C(═O)—NR13R14; —C(═O)—R15; —CH═N—NH—C(═O)—R16; C1-6alkyl substituted with one or more substituents each independently selected from cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; C1-6alkyl substituted with one or more substituents each independently selected from cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7 and wherein 2 hydrogen atoms bound at the same carbon atom are replaced by C1-4alkanediyl; C1-6alkyl substituted with hydroxy and a second substituent selected from cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; C1-6alkyloxyC1-6alkyl optionally substituted with one or more substituents each independently selected from cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; C2-6alkenyl substituted with one or more substituents each independently selected from halo, cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; C2-6alkynyl substituted with one or more substituents each independently selected from halo, cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl or R7; —C(═N—O—R8)—C1-4alkyl; R7 or —X3—R7; X3 is —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O)p—, —X2—C1-4alkanediyl-, —C1-4alkanediyl-X2a—, —C1-4alkanediyl-X2b—C1-4alkanediyl, —C(═N—OR8)—C1-4alkanediyl-;
with X2a being —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O)p—; andwith X2b being —NH—NH—, —N═N—, —C(═O)—, —S—, —S(═O)p—; R4 is halo, hydroxy, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyl, formyl, amino, mono- or di(C1-4alkyl)amino or R7; R5 is hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyl; C1-6alkyloxycarbonyl; C1-6alkyl substituted with formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl or C1-6alkylcarbonyloxy; C1-6alkyloxyC1-6alkylcarbonyl substituted with C1-6alkyloxycarbonyl; R6 is C1-4alkyl, amino, mono- or di(C1-4alkyl)amino or polyhaloC1-4alkyl; R7 is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl,
C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, —CH(═N—O—R8), R7a, —X3—R7a or R7a—C1-4alkyl; R7a is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl,
C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, —CH(═N—O—R8); R8 is hydrogen, C1-4alkyl, aryl or arylC1-4alkyl; R9 and R10 each independently are hydrogen; hydroxy; C1-6alkyl; C1-6alkyloxy; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; amino; mono- or di(C1-6alkyl)amino; mono- or di(C1-6alkyl)aminocarbonyl; —CH(═NR11) or R7, wherein each of the aforementioned C1-6alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C1-6alkyloxy, hydroxyC1-6alkyloxy, carboxyl, C1-6alkyloxycarbonyl, cyano, amino, imino, mono- or di(C1-4alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)pR6, —NH—S(═O)pR6, —C(═O)R6, —NHC(═O)H, —C(═O)NHNH2, —NHC(═O)R6, —C(═NH)R6, R7; or R9 and R10 may be taken together to form a bivalent radical of formula
—CH2—CH2—CH2—CH2—  (d-1)—CH2—CH2—CH2—CH2—CH2—  (d-2)—CH2—CH2—O—CH2—CH2—  (d-3)—CH2—CH2—S—CH2—CH2—  (d-4)—CH2—CH2—NR12—CH2—CH2—  (d-5)—CH2—CH═CH—CH2—  (d-6) R11 is cyano; C1-4alkyl optionally substituted with C1-4alkyloxy, cyano, amino, mono- or di(C1-4alkyl)amino or aminocarbonyl; C1-4alkylcarbonyl; C1-4alkyloxycarbonyl; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; R12 is hydrogen or C1-4alkyl; R13 and R14 each independently are C1-6alkyl optionally substituted with cyano or aminocarbonyl, C2-6alkenyl optionally substituted with cyano or aminocarbonyl, C2-6alkynyl optionally substituted with cyano or aminocarbonyl; R15 is C1-6alkyl substituted with cyano or aminocarbonyl; R16 is C1-6alkyl optionally substituted with cyano or aminocarbonyl, or R7; p is 1 or 2; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, C1-6alkylcarbonyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, R7 or —X3—R7; and (b) another antiretroviral compound.