HIV inhibiting 1,2,4-triazines

1. A compound of formula

a N-oxide, a pharmaceutically acceptable acid or base addition salt or a stereochemically isomeric form thereof, wherein

-a 1 =a 2 -a 3 =a 4 - represents a bivalent radical of formula

—CH═CH—CH═CH— (a-1);

-b 1 =b 2 -b 3 =b 4 - represents a bivalent radical of formula

—CH═CH—CH═CH— (b-1);

n is 0, 1, 2, 3 or 4;

m is 0, 1, 2, 3 or 4;

R 1 is hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; C 1-6 alkyl; C 1-6 alkyloxycarbonyl; C 1-6 alkyl substituted with formyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyloxy; C 1-6 alkyloxyC 1-6 alkylcarbonyl substituted with C 1-6 alkyloxycarbonyl;

each R 2 independently is hydroxy; halo; C 1-6 alkyl optionally substituted with one or more substituents each independently selected from halo, cyano or —C(═O)R 6 ; C 3-7 cycloalkyl; C 2-6 alkenyl optionally substituted with one or more substituents each independently selected from halo, cyano or —C(═O)R 6 ; C 2-6 alkynyl optionally substituted with one or more substituents each independently selected from halo, cyano or —C(═O)R 6 ; C 1-6 alkyloxycarbonyl; carboxyl; cyano; nitro; amino; mono- or di(C 1-6 alkyl)amino; polyhalomethyl; polyhalomethylthio; —S(═O) p R 6 ; —NH—S(═O) p R 6 ; —C(═O)R 6 ; —NHC(═O)H; —C(═O)NHNH 2 ; NHC(═O)R 6 ; C(═NH)R 6 ;

R 2a is cyano; aminocarbonyl; amino; C 1-6 alkyl; halo; C 1-6 alkyloxy wherein C 1-6 alkyl may optionally be substituted with cyano; NHR 13 ; NR 13 R 14 ; —C(═O)—NHR 13 ; —C(═O)—NR 13 R 14 ; —C(═O)—R 15 ; —CH═N—NH—C(═O)—R 16 ; C 1-6 alkyl substituted with one or more substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 1-6 alkyl substituted with hydroxy and a second substituent selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 1-6 alkyloxyC 1-6 alkyl optionally substituted with one or more substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 2-6 alkenyl substituted with one or more substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 2-6 alkynyl substituted with one or more substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; —C(═N—O—R 8 )—C 1-4 alkyl; R 7 or —X 3 —R 7 ;

X 1 is —NH—, —O—, or —S—;

X 2 is —NR 1 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, or —S(═O) p —;

R 3 is cyano; aminocarbonyl; amino; C 1-6 alkyl; halo; C 1-6 alkyloxy wherein C 1-6 alkyl may optionally be substituted with cyano; NHR 13 ; NR 13 R 14 ; —C(═O)—NHR 13 ; —C(═O)—NR 13 R 14 ; —C(═O)—R 15 ; —CH═N—NH—C(═O)—R 16 ; C 1-6 alkyl substituted with one or more substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 1-6 alkyl substituted with hydroxy and a second substituent selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 1-6 alkyloxyC 1-6 alkyl optionally substituted with one or more substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 2-6 alkenyl substituted with one or more substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 2-6 alkynyl substituted with one or more substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; —C(═N—O—R 8 )—C 1-4 alkyl; R 7 or —X 3 —R 7 ;

X 3 is —NR 1 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O) p —, —X 2 —C 1-4 alkanediyl-, —C 1-4 alkanediyl-X 2a —, —C 1-4 alkanediyl-X 2b —C 1-4 alkanediyl, —C(═N—OR 8 )—C 1-4 alkanediyl-; with X 2a being —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O) p —; and

with X 2b being —NH—NH—, —N═N—, —C(═O)—, —S—, —S(═O) p —;

R 4 is halo; hydroxy; C 1-6 alkyl optionally substituted with one or more substituents each independently selected from halo, cyano or —C(═O)R 6 ; C 2-6 alkenyl optionally substituted with one or more substituents each independently selected from halo, cyano or —C(═O)R 6 ; C 2-6 alkynyl optionally substituted with one or more substituents each independently selected from halo, cyano or —C(═O)R 6 ; C 3-7 cycloalkyl; C 1-6 alkyloxy; cyano; nitro; polyhaloC 1-6 alkyl; polyhaloC 1-6 alkyloxy; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyl; formyl; amino; mono- or di(C 1-4 alkyl)amino or R 7 ;

R 5 is hydrogen; halo; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl; amino; C 1-6 alkyloxycarbonyl; C 1-6 alkyloxycarbonylamino; polyhaloC 1-6 alkyl; C 1-6 alkyl optionally substituted with cyano, hydroxy, halo, C 1-6 alkyloxy, C 1-6 alkylthio or S(═O) p —C 1-6 alkyl; C 2-6 alkenyl optionally substituted with cyano, hydroxy, halo, C 1-6 alkyloxy, C 1-6 alkylthio or S(═O) p —C 1-6 alkyl; C 2-6 alkynyl optionally substituted with cyano, hydroxy, halo, C 1-6 alkyloxy, C 1-6 alkylthio or S(═O) p —C 1-6 alkyl;

R 6 is C 1-4 alkyl, amino, mono- or di(C 1-4 alkyl)amino or polyhaloC 1-4 alkyl;

R 7 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, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)aminoC 1-6 alkyl, formyl, C 1-6 alkylcarbonyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, C 1-6 alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, —CH(═N—O—R 8 ), R 7a , —X 3 —R 7a or R 7a —C 1-4 alkyl;

R 7a 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, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)aminoC 1-6 alkyl, formyl, C 1-6 alkylcarbonyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, C 1-6 alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, —CH(═N—O—R 8 );

R 8 is hydrogen, C 1-4 alkyl, aryl or arylC 1-4 alkyl;

R 9 and R 10 each independently are hydrogen; hydroxy; C 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; amino; mono- or di(C 1-6 alkyl)amino; mono- or di(C 1-6 alkyl)aminocarbonyl; —CH(═NR 11 ) or R 7 , wherein each of the aforementioned C 1-6 alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C 1-6 alkyloxy, hydroxyC 1-6 alkyloxy, carboxyl, C 1-6 alkyloxycarbonyl, cyano, amino, imino, mono- or di(C 1-4 alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O) p R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 6 , —C(═NH)R 6 , R 7 ; with the proviso that R 9 and R 10 are not simultaneously hydroxy or C 1-6 alkyloxy; or

R 9 and R 10 may be taken together to form a bivalent radical of formula

—CH 2 —CH 2 —CH 2 —CH 2 — (d-1)

—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 — (d-2)

—CH 2 —CH 2 —O—CH 2 —CH 2 — (d-3)

—CH 2 —CH 2 —S—CH 2 —CH 2 — (d-4)

—CH 2 —CH 2 —NR 12 —CH 2 —CH 2 — (d-5)

—CH 2 —CH═CH—CH 2 — (d-6)

R 11 is cyano; C 1-4 alkyl optionally substituted with C 1-4 alkyloxy, cyano, amino, mono- or di(C 1-4 alkyl)amino or aminocarbonyl; C 1-4 alkylcarbonyl; C 1-4 alkyloxycarbonyl; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl;

R 12 is hydrogen or C 1-4 alkyl;

R 13 and R 14 each independently are C 1-6 alkyl optionally substituted with cyano or aminocarbonyl, C 2-6 alkenyl optionally substituted with cyano or aminocarbonyl, C 2-6 alkynyl optionally substituted with cyano or aminocarbonyl;

R 15 is C 1-6 alkyl substituted with cyano or aminocarbonyl;

R 16 is C 1-6 alkyl optionally substituted with cyano or aminocarbonyl, or R 7 ;

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, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)aminoC 1-6 alkyl, C 1-6 alkylcarbonyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, C 1-6 alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, R 7 or —X 3 —R 7 provided the following compounds

1,2,4-triazine-6-carboxylic acid, 3,5-bis[(4-methylphenyl)amino]-, ethyl ester;

N,N′-bis(4-chlorophenyl)-6-fluoro-1,2,4-triazine-3,5-diamine;

are not included.

2. A compound according to claim 1 wherein at least one of m or n is other than 0.

3. A compound according to claim 1 wherein the compound has the formula

wherein R 1 , R 2a , R 3 , R 4 , R 5 and X 1 are as defined in claim 1 .

4. A compound as claimed in claim 1 wherein the compound has the formula

wherein R 1 , R 2a , R 3 , R 4 , R 5 and X 1 are as defined in claim 1 .

5. A compound according to claim 1 wherein R 2a is cyano, aminocarbonyl, C 1-6 alkyl, C 1-6 alkyl substituted with cyano or aminocarbonyl, C 2-6 alkenyl optionally substituted with cyano or aminocarbonyl.

6. A compound according to claim 1 wherein R 5 is hydrogen, C 1-6 alkyl or halo.

7. A compound according to claim 1 wherein R 2a or R 2 is halo, cyano, aminocarbonyl, C 1-6 alkyloxy, C 1-6 alkyl, C 1-6 alkyl substituted with cyano or C 2-6 alkenyl substituted with cyano.

8. A compound according to claim 1 wherein n is 0 or 2.

9. A compound according to claim 1 wherein R 3 is C 1-6 alkyl; cyano; aminocarbonyl; mono or di(C 1-4 alkyl)aminocarbonyl; C 1-6 alkyl substituted with cyano or aminocarbonyl; C 2-6 alkenyl substituted with cyano or aminocarbonyl or mono- or di(C 1-4 alkyl)aminocarbonyl or C(═O)NR 9 R 10 wherein R 9 and R 10 are taken together to form a bivalent radical of formula (d-1) to (d-6); halo; or C 1-6 alkyloxy optionally substituted with cyano.

10. A compound according to claim 1 wherein m is 0 and R 3 is cyano or aminocarbonyl.

11. A compound according to claim 1 wherein m is 2 and R 4 is C 1-6 alkyl, halo, C 1-6 alkyloxy, C 1-6 alkyl substituted with cyano.

12. A compound according to claim 1 wherein R 2a is cyano, m is 2 and R 3 is C 2-6 alkenyl substituted with cyano.

13. A compound according to claim 1 wherein n is 2, R 3 is cyano, m is 0 and R 2a is C 2-6 alkenyl substituted with cyano.

14. A compound according to claim 1 wherein R 1 is hydrogen.

15. A compound having the following structure:

R 2a

R 2b

R 2c

X 1

R 5

Z

CN

H

H

NH

H

CN

H

H

NH

H

CN

H

H

NH

CH 3

CN

H

H

NH

CH 3

CN

H

H

NH

CH 3

CN

H

H

NH

CH 3

CN

H

H

NH

CH 3

CN

H

H

NH

CH 3

CN

H

H

NH

CH 3

CN

H

H

NH

CH 3

CN

H

H

NH

Cl

CN

H

H

O

CH 3

CN

H

H

O

CH 3

CN

H

H

O

CH 3

a N-oxide, a pharmaceutically acceptable acid or base addition salt or a stereochemically isomeric form thereof.

16. A method for the treatment of HIV (Human Immunodeficiency Virus) infection, comprising administering to a subject in need thereof a medicament that comprises a therapeutically effective amount of a compound of claim 1 .

17. The method of claim 16 , wherein the HIV (Human Immunodeficiency Virus) infection comprises (multi)drug resistant HIV infection.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound as claimed in claim 1 .

19. A process for preparing a pharmaceutical composition comprising intimately mixing a therapeutically effective amount of a compound as claimed in claim 1 with a pharmaceutically acceptable carrier.