Patent EA-004049-B1 (EA)
Title: Hiv replication pyrimidines
Inventor: CORTE BART DE
IPC: C07D239/50
Filed: 1999-09-24
Abstract: 1. A compound having the formula a N-oxide, additive salt, a quaternary amine or a stereochemically isomeric form thereof, wherein R<1> 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; R<2A> is cyano and aminocarbonyl; L is -X-R<3> wherein R<3> is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R<2>; and each R<2> is hydroxy, halogen, C1-6alkyl optionally substituted with cyano or -C(=O)R<6>, 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, C1-6alkyloxy, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, -S(=O)pR<6>, -NH-S(=O)pR<6>, -C(=O)R<6>, -NHC(=O)H, -C(=O)NHNH2, -NHC(=O)R<6>,-C(=NH)R<6> or a radical of formula wherein each A independently is N, CH or CR<6>; B is NH, O, S or NR<6>; p is 1 or 2; and R<6> is methyl, amino, mono- or dimethylamino or polyhalomethyl; X is -NR<1>-, -O-, or -S-; Q represents hydrogen, C1-6alkyl, halo, polyhaloC1-6alkyl or -NR<4>R<5>; and R<4> and R<5> are each independently selected from hydrogen, hydroxy, C1-12alkyl, C1-12alkyloxy, C1-12alkylcarbonyl, C1-12alkyloxycarbonyl, aryl, amino, mono or di(C1-12alkyl)amino, mono- or di(C1-12alkyl)aminocarbonyl wherein each of the aforementioned C1-12alkyl 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(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, -S(=O)pR<6>, -NH-S(=O)pR<6>, -C(=O)R<6>, -NHC(=O)H, C(=O)NHNH2, -NHC(=O)R<6>,-C(=NH)R<6>, aryl and Het; or R<4> and R<5> taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C1-12alkyl)aminoC1-4alkylidene; Y represents hydroxy, halo, C3-7cycloalkyl, C2-6alkenyl optionally substituted with one or more halogen atoms, C2-6alkynyl optionally substituted with one or more halogen atoms, C1-6alkyl substituted with cyano or -C(=O)R<6>, C1-6alkyloxy, C1-6alkyloxycarbonyl, carboxyl, cyano, vitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, -S(=O)pR<6>, -NH-S(=O)pR<6>, -C(=O)R<6>, -NHC(=O)H, -C(=O)NHNH2, -NHC(=O)R<6>,-C(=NH)R<6> or aryl; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl and polyhaloC1-6alkyloxy; Het is an aliphatic or aromatic heterocyclic radical; said aliphatic heterocyclic radical is selected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothienyl wherein each of said aliphatic heterocyclic radical may optionally be substituted with an oxo group; and said aromatic hetero-cyclic radical is selected from pyrrolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclic radical may optionally be substituted with hydroxy. 2. A compound as claimed in claim 1, wherein R<1> is hydrogen, aryl, formyl, C1-6alkylcarbonyl, C1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkyl substituted with formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl. 3. A compound as claimed in claim 1 or 2, wherein L is -X-R<3> wherein R<3> is 2,4,6-trisubstituted phenyl. 4. A compound as claimed in any one of claims 1 to 3, wherein Y is cyano, -C(=O)NH2 or a halogen. 5. A compound as claimed in any one of claims 1 to 4, wherein Q is hydrogen or NR<4>R<5>. 6. A compound as claimed in any one of claims 1 to 5, wherein the compound is 4[[4-amino-5-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino)-benzonitrile;4-[[5-chloro-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile; 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile; 4-[[4-amino-5-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino] benzonitrile; 4-[[5-bromo-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile; 4-[[4-amino-5-chloro-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile; or 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]-benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof. 7. A compound according to claim 6, which is 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]-benzonitrile, a N-oxide, a pharmaceutically acceptable addition salt. 8. A compound as claimed in any one of claims 1 to 7 for use as a medicine. 9. The use of a compound of formula a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein R<1> 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; R<2A> is cyano or aminocarbonyl; L is -X-R<3> wherein R<3> is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R<2>; and and each R<2> 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, C1-6alkyloxy, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, -S(=O)pR<6>, -NH-S(=O)pR<6>, -C(=O)R<6>, -NHC(=O)H, -C(=O)NHNH2, -NHC(=O)R<6>,-C(=NH)R<6> or a radical of formula wherein each A independently is N, CH or CR<6>; B is NH, O, S or NR<6>; p is 1 or 2; and R<6> is methyl, amino, mono- or dimethylamino or polyhalomethyl X is -NR<1>-, -O-, or -S-; Q represents hydrogen, C1-6alkyl, halo, polyhaloC1-6alkyl or -NR<4>R<5>; and R<4> and R<5> are each independently selected from hydrogen, hydroxy, C1-12alkyl, C1-12alkyloxy, C1-12alkylcarbonyl, C1-12alkyloxycarbonyl, aryl, amino, mono- or di(C1-12alkyl)amino, mono- or di(C1-12alkyl)aminocarbonyl wherein each of the aforementioned C1-12alkyl 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(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, -S(=O)pR<6>, -NH-S(=O)pR<6>, -C(=O)R<6>, -NHC(=O)H, C(=O)NHNH2, -NHC(=O)R<6>,-C(=NH)R<6>, aryl and Het; or R<4> and R<5> taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C1-12alkyl)aminoC1-4alkylidene; Y represents hydroxy, halo, C3-7cycloalkyl, C2-6alkenyl optionally substituted with one or more halogen atoms, C2-6alkynyl optionally substituted with one or more halogen atoms, C1-6alkyl substituted with cyano or -C(=O)R<6>, C1-6alkyloxy, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, -S(=O)pR<6>, -NH-S(=O)pR<6>, -C(=O)R<6>, -NHC(=O)H, -C(=O)NHNH2, -NHC(=O)R<6>,-C(=NH)R<6> or aryl; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl and polyhaloC1-6alkyloxy; Het is an aliphatic or aromatic heterocyclic radical; said aliphatic heterocyclic radical is selected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothienyl wherein each of said aliphatic heterocyclic radical may optionally be substituted with an oxo group; and said aromatic hetero-cyclic radical is selected from pyrrolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclic radical may optionally be substituted with hydroxy; for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection. 10. The use of a compound as claimed in any one of claims 1 to 7 for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection. 11. The use of a compound as claimed in any one of claims 1 to 7 for the manufacture of a medicine for the HIV-1 infection resistant to non-nucleoside inhibitors of reverse transcriptase by other than compounds defined in claims 1-7. 12. The use of a compound as claimed in any one of claims 1 to 7, wherein R<1> is hydrogen, aryl, formyl, C1-6alkylcarbonyl, C1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkyl substituted with formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl for the manufacture of a medicine for the treatment of patients suffering from HIV (Human Immunodeficiency Virus) infection. 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in any one of claims 1 to 7. 14. A process for preparing a pharmaceutical composition as claimed in claim 13 characterized in that a therapeutically effective amount of a compound as claimed in any one of claims 1 to 7 is intimately mixed with a pharmaceutically acceptable carrier. 15. A proc