HIV inhibiting 5,6-substituted pyrimidines

1. A compound of formula

a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein:

each R 1 independently is hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; C 1-6 alkyl; C 1-6 alkyloxycarbonyl;

R 2 , R 3 , R 7 and R 8 independently are hydrogen; hydroxy; halo; C 3-7 cycloalkyl; C 1-6 alkyloxy; carboxyl; C 1-6 alkyloxycarbonyl; cyano; nitro; amino; mono- or di(C 1-6 alkyl)amino; polyhaloC 1-6 alkyl; polyhaloC 1-6 alkyloxy; —C(═O)R 10 ; C 1-6 alkyl optionally substituted with halo, cyano or —C(═O)R 10 ; C 2-6 alkenyl optionally substituted with halo, cyano or —C(═O)R 10 ; C 2-6 alkynyl optionally substituted with halo, cyano or —C(═O)R 10 ;

R 4 and R 9 independently are hydroxy; halo; C 3-7 cycloalkyl; C 1-6 alkyloxy; carboxyl; C 1-6 alkyloxycarbonyl; formyl; cyano; nitro; amino; mono- or di(C 1-6 alkyl)amino; polyhaloC 1-6 alkyl; polyhaloC 1-6 alkyloxy; —C(═O)R 10 ; cyano; —S(═O) r R 10 ; —NH—S(═O) 2 R 10 ; —NHC(═O)H; —C(═O)NHNH 2 ; —NHC(═O)R 10 ; Het; C 1-6 alkyl optionally substituted with halo, cyano, amino, mono- or di(C 1-6 alkyl)amino, —C(═O)—R 10 , Het or with C 1-6 alkyloxy; C 2-6 alkenyl optionally substituted with halo, cyano, amino, mono- or di(C 1-6 alkyl)amino, —C(═O)—R 10 , Het or with C 1-6 alkyloxy; C 2-6 alkynyl optionally substituted with halo, cyano, amino, mono- or di(C 1-6 alkyl)amino, —C(═O)—R 10 , Het or with C 1-6 alkyloxy;

R 5 is C 2-6 alkenyl or C 2-6 alkynyl both substituted with cyano, aminocarbonyl, mono- or di(C 1-6 alkyl)aminocarbonyl, aryl, pyridyl, thienyl, furanyl, or with one or two C 1-6 alkyloxy groups; or R 5 is Het; —C(═O)NR 5a R 5b ; or —CH(OR 5c )R 5d ; wherein

R 5a is C 1-6 alkyloxy; C 2-6 alkenyl; C 3-7 cycloalkyl; or C 1-6 alkyl substituted with hydroxy, amino, mono- or di(C 1-6 alkyl)amino, C 1-6 alkylcarbonylamino, halo, cyano, aryl, pyridyl, thienyl, furanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, piperazinyl optionally substituted with C 1-6 alkyl, C 1-6 alkylcarbonyl, or with hydroxyC 1-6 alkyl; or R 5a is C 1-6 alkyl substituted with one or two C 1-6 alkyloxy;

R 5b is hydrogen or C 1-6 alkyl; or

R 5a and R 5b taken together with the nitrogen atom to which they are substituted form pyrrolidinyl; piperidinyl optionally substituted with aminocarbonyl, hydroxy, or with C 1-6 alkyloxy; morpholinyl; piperazinyl; piperazinyl optionally substituted with C 1-6 alkyl, C 1-6 alkylcarbonyl, or with hydroxyC 1-6 alkyl;

R 5c is hydrogen, C 1-6 alkyl, Het;

R 5d is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, or Het;

R 6 is C 1-6 alkoxyC 1-6 alkyl;

each R 10 independently is C 1-6 alkyl, amino, mono- or di(C 1-6 alkyl)amino or polyhaloC 1-6 alkyl;

X is —NR 1 —, —O—, —CH 2 —, or —S—;

each r independently is 1 or 2;

each Het independently is pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, quinolinyl, benzothienyl, benzofuranyl; which each may optionally be substituted with one or two substituents each independently selected from C 1-6 alkyl, halo, hydroxy, cyano, C 1-6 alkyloxy, and C 2-6 alkenyl substituted with halo, hydroxy or with cyano;

each aryl independently is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)amino-C 1-6 alkyl, C 1-6 alkylcarbonyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, phenylC 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, aminosulfonyl, C 1-6 alkylsulfonyl, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, phenyl or Het.

2. The compound of claim 1 wherein the compound of formula (I) has the following structure:

3. The compound of claim 1 , wherein R 4 and R 9 independently are cyano; C 1-6 alkyl substituted with cyano; C 2-6 alkenyl substituted with cyano.

4. The compound of claim 1 , wherein R 2 , R 3 , R 7 and R 8 independently are hydrogen; halo; C 1-6 alkyl; cyano.

5. The compound of claim 1 , wherein R 9 is a radical —CH 2 —CH 2 —CN, —CH═CH—CN, or —C≡C—CN.

6. The compound of claim 5 , wherein R 9 is a radical (E)-CH═CH—CN.

7. The compound of claim 1 , wherein R 4 is cyano.

8. The compound of claim 1 , wherein R 1 is hydrogen.

9. The compound of claim 1 , wherein (a) R 5 is C 2-6 alkenyl or C 2-6 alkynyl both substituted with cyano, aminocarbonyl, mono- and di(C 1-6 alkyl)aminocarbonyl, aryl, pyridyl, or with one or two C 1-6 alkyloxy groups; Het; —C(═O)NR 5a R 5b ; —CH(OR 5c )R 5d ;

wherein

R 5a is C 1-6 alkyloxy; C 2-6 alkenyl; C 3-7 cycloalkyl; or C 1-6 alkyl substituted with mono- and di(C 1-6 alkyl)amino, C 1-6 alkylcarbonylamino, cyano, aryl, pyridyl, thienyl, tetrahydrofuranyl, morpholinyl, piperazinyl, piperazinyl optionally substituted with C 1-6 alkyl or with hydroxyC 1-6 alkyl; or R 5a is C 1-6 alkyl substituted with one or two C 1-6 alkyloxy;

R 5b is hydrogen or C 1-6 alkyl; or

R 5a and R 5b taken together with the nitrogen atom to which they are substituted form piperidinyl optionally substituted with aminocarbonyl or hydroxy; piperazinyl optionally substituted with C 1-6 alkyl or hydroxyC 1-6 alkyl;

R 5c is hydrogen;

R 5d is C 1-6 alkyl, C 2-6 alkenyl, aryl, pyridyl, or thiazolyl.

10. The compound of claim 1 , wherein X is —NH—.

11. The compound of claim 1 , wherein each Het independently is pyridyl, thienyl, furanyl, oxazolyl, thiazolyl.

12. A pharmaceutical composition comprising an effective amount of a compound of formula (I) as defined in claim 1 and a carrier.