HIV inhibiting 5-carbo- or heterocyclic substituted pyrimidines
View Patent ↗HIV replication inhibitors of formula (I) N-oxides, a pharmaceutically acceptable addition salts, a quaternary amines or a stereoisomeric forms thereof, wherein -a 1 =a 2 -a 3 =a 4 - is —CH═CH—CH═CH—, —N═CH—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—, —N═N—CH═CH—; -b 1 =b 2 -b 3 =b 4 - is —CH═CH—CH═CH—, —N═CH—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—, —N═N—CH═CH—; R 1 is hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; optionally substituted C 1-6 alkyl; C 1-6 alkyloxycarbonyl; R 2 is OH; halo; optionally substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; substituted carbonyl; carboxyl; CN; nitro; amino; substituted amino; polyhalomethyl; polyhalomethylthio; —S(═O)rR 6 ; C(═NH)R 6 ; R 2a is CN; amino; substituted amino; optionally substituted C 1-6 alkyl; halo; optionally substituted C 2-6 alkyloxy; substituted carbonyl; —CH═N—NH—C(═O)—R 16 ; optionally substituted C 1-6 alkyloxy C 1-6 alkyl; substituted C 2-6 alkenyl or C 2-6 alkynyl; —C(═N—O—R 8 )—C 1-4 alkyl; R 7 or —X 3 —R 7 ; X 1 is —NR 1 —, —O—, —C(═O)—, CH 2 , —CHOH—, —S—, —S(═O) r —; R 3 is CN; amino; C 1-6 alkyl; halo; optionally substituted C 1-6 alkyloxy; substituted carbonyl; —CH═N—NH—C(═O)—R 16 ; substituted C 1-6 alkyl; optionally substituted C 1-6 alkyloxy C 1-6 alkyl; substituted C 2-6 alkenyl or C 2-6 alkynyl; —C(═N—O—R 8 )—C 1-4 alkyl; R 7 ; —X 3 —R 7 ; R 4 is halo; OH; optionally substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; C 3-7 cycloalkyl; C 1-6 alkyloxy; CN; nitro; polyhalo C 1-6 alkyl; polyhalo C 1-6 alkyloxy; substituted carbonyl; formyl; amino; mono- or di(C 1-4 alkyl)amino or R 7 ; R 5 is —Y—C q H2 q -L or —C q H 2q —Y—C r H 2r -L; L is aryl or Het; processes for the preparation of these compounds, pharmaceutical compositions comprising these compounds as active ingredient and the use of these compounds for the prevention or the treatment of HIV infection.
1. A compound of formula
a N-oxide, a pharmaceutically acceptable addition salt, or a stereochemically isomeric form thereof, wherein
n is 0, 1, 2, 3;
m is 0, 1, 2, 3;
each R 1 independently 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, or with C 1-6 alkylcarbonyloxy;
each R 2 independently is hydroxy; halo; C 1-6 alkyl; C 1-6 alkyloxycarbonyl;
R 2a is cyano; aminocarbonyl; amino; C 1-6 alkyl; halo; C 1-6 alkyloxy
X 1 is —NR 1 —, —O—, —C(═O)—, —CH 2 —, —CHOH—, —S—, —S(═O)r;
R 3 is C 1-6 alkyl substituted with cyano
R 4 is halo; hydroxy; C 1-6 alkyl; C 1-6 alkyloxy; cyano; nitro; polyhaloC 1-6 alkyl; C 1-6 alkyloxycarbonyl; amino; mono- or di(C 1-4 alkyl)amino;
R 5 is a radical of formula —Y-Alk-L, -Alk′-Y-L or -Alk′-Y-Alk-L;
each Alk or Alk′ independently is a bivalent C 1-6 alkyl or C 2-6 alkenyl group;
L is aryl or Het;
Y is O, S, —S(═O) r —, NR 1 ; —CH═N—O—;
Het is a 5- or 6-membered completely unsaturated ring system wherein one, two, three or four ring members are hetero atoms each independently selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the remaining ring members are carbon atoms; and, where possible, any nitrogen ring member may optionally be substituted with C 1-6 alkyl; which ring system may optionally be annelated with a benzene ring; and wherein any ring carbon atom, including any carbon of an optionally annelated benzene ring, may, each independently, optionally be substituted with a substituent selected from halo, hydroxy, mercapto, cyano, C 1-6 alkyl, hydroxyC 1-4 alkyl, carboxyC 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyl, C 1-4 alkyloxycarbonylC 1-4 alkyl, cyanoC 1-4 alkyl, mono- and di(C 1-4 alkyl)aminoC 1-4 alkyl, Het 1 C 1-4 alkyl, arylC 1-4 alkyl, polyhaloC 1-4 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, aryl-C 2-4 alkenyl, C 1-4 alkyloxy, —OCONH 2 , polyhaloC 1-4 alkyloxy, aryloxy, amino, mono- and di-C 1-4 alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, C 1-4 alkylcarbonylamino, formyl, C 1-4 alkylcarbonyl, C 1-4 alkyloxy-carbonyl, aminocarbonyl, mono- and diC 1-4 alkylaminocarbonyl, aryl, Het 1 ;
Het 1 is pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl quinolinyl, benzothienyl, benzofuranyl; which each may optionally be substituted with one or two C 1-4 alkyl radicals;
Q is hydrogen, C 1-6 alkyl, halo, polyhaloC 1-6 alkyl, or —NR 9 R 10 ;
R 9 and R 10 each independently are hydrogen; C 1-6 alkyl
each 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, C 2-6 alkenyl, C 2-6 alkynyl, 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, phenylC 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, aminosulfonyl, C 1-6 alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, phenyl, Het 1 .
2. A compound according to claim 1 wherein Het is a heterocycle selected from pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, thiatriazolyl, thiadiazolyl oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, benzothiadiazolyl, benzofurazanyl, benzoxadiazolyl, indazolyl, quinolinyl, said heterocycle optionally being substituted on its carbon atoms with one, two or three substituents each independently selected from halo, hydroxy, mercapto, cyano, C 1-6 alkyl, hydroxyC 1-4 alkyl, carboxyC 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyl, C 1-4 alkyloxycarbonyl-C 1-4 alkyl, cyanoC 1-4 alkyl, mono- and di(C 1-4 alkyl)aminoC 1-4 alkyl, Het C 1-4 alkyl, arylC 1-4 alkyl, polyhaloC 1-4 alkyl, C 3-7 cycloalkyl, arylC 2-4 alkenyl, C 1-4 alkyloxy, —OCONH 2 , polyhaloC 1-4 alkyloxy, aryloxy, amino, mono- and di-C 1-4 alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, C 1-4 alkylcarbonylamino, formyl, C 1-4 alkylcarbonyl, aryl, C 1-4 alkyloxycarbonyl, aminocarbonyl, mono- and diC 1-4 alkylaminocarbonyl, Het 1 .
3. A compound according to claim 1 wherein Het is a heterocycle selected from pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, thiatriazolyl, to thiadiazolyl oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, indolyl, benzothiadiazolyl, quinolinyl, said heterocycle optionally being substituted on its carbon atoms with one, two or three substituents each independently selected from halo, hydroxy, cyano, C 1-6 alkyl, C 1-4 alkyloxycarbonyl-C 1-4 alkyl, amino, mono- and di-C 1-4 alkylamino, morpholinyl, C 1-4 alkylcarbonylamino, aminocarbonyl, mono- and diC 1-4 alkylaminocarbonyl, aryl, Het 1 .
4. A compound according to claim 1 wherein Het is a heterocycle selected from pyrrolyl, furanyl, thienyl, oxadiazolyl, pyridyl, said heterocycle optionally being substituted on its carbon atoms with one, two or three substituents each independently selected from halo, hydroxy, C 1-6 alkyl, phenyl, Het 1 (the latter in particular being pyridyl).
5. A compound according to claim 1 wherein
n is 0, 1 or 2;
m is 0, 1 or 2;
R 1 is hydrogen; or C 1-6 alkyl;
R 2 is hydroxy; halo; C 1-6 alkyl cyano; nitro; amino; mono- or di(C 1-6 alkyl)amino; trifluoromethyl;
R 2a is cyano; aminocarbonyl; amino; C 1-6 alkyl; halo; C 1-6 alkyloxy
X 1 is —NR 1 —, —O—, —S—, —S(═O)r-;
R 3 is C 2-6 alkenyl substituted with cyano;
R 4 is halo; hydroxy; C 1-6 alkyl C 1-6 alkyloxy; cyano; trifluoromethyl;
Q is hydrogen or —NR 9 R 10 .
6. A compound according to claim 5 wherein
R 2 is halo, C 1-6 alkyl
R 2a is halo, cyano, aminocarbonyl, C 1-6 alkyl optionally substituted with cyano or aminocarbonyl, C 2-6 alkenyl;
X 1 is —NH—, —N(CH 3 )—, —O—, —S—;
R 4 is halo, C 1-4 alkyl, C 1-4 alkyloxy, or cyano;
Y is O, NR 1 ; —CH═N—O—;
Q is hydrogen, amino, mono- or di-C 1-4 alkylamino.
7. A compound according to claim 1 wherein the compound has the formula
8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound as claimed in claim 1 .
9. A compound according to claim 1 wherein R 5 is a radical of formula —Y—C p H 2p -L or —C q H 2q —Y—C p H 2p -L; wherein L is aryl or Het; and
p is 1-6;
q is 1-6.
10. A compound according to claim 9 wherein
Y is O, S, NR 1 ; —CH═N—O—;
p is 1-4;
q is 1-4.
11. A compound according to claim 10 wherein
Y is NR 1 or —CH═N—O—;
p is 1-2;
q is 1-2.
12. A compound according to claim 4 wherein Het 1 is pyridyl.
13. A compound according to claim 6 wherein
n is 0;
m is 2;
R 4 is halo or C 1-4 alkyl;
Q is hydrogen.
14. A compound according to claim 13 wherein R 5 is a radical of formula —Y—C p H 2p -L or —C q H 2q —Y—C p H 2p -L; wherein L is aryl or Het; and
p is 1-6;
q is 1-6.
15. A compound according to claim 14 wherein
Y is O, S, NR 1 ; —CH═N—O—;
p is 1-4;
q is 1-4.
16. A compound according to claim 15 wherein
Y is NR 1 or —CH═N—O—;
p is 1-2;
q is 1-2.
17. A compound according to claim 16 wherein Het is a heterocycle selected from pyrrolyl, furanyl, thienyl, oxadiazolyl, pyridyl, said heterocycle optionally being substituted on its carbon atoms with one, two or three substituents each independently selected from halo, hydroxy, C 1-6 alkyl, phenyl, Het 1 .
18. A compound according to claim 17 wherein Het 1 is pyridyl.