US 9,802,943 B2 · HIV inhibiting bicyclic pyrimidine derivatives

Abstract

HIV replication inhibitors of formula N-oxides, pharmaceutically acceptable addition salts, quaternary amines or stereoisomeric forms thereof, wherein -a1=a2-a3=a4- is —CH═CH—CH═CH—, —N═CH—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—, —N═N—CH═CH—; -b1=b2-b3=b4- is —CH═CH—CH═CH—, —N═CH—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—, —N═N—CH═CH—; n and m is 0, 1, 2, 3 and in certain cases also 4; R1 is hydrogen; aryl; formyl; C1-6alkylcarbonyl; optionally substituted C1-6alkyl; C1-6alkyloxycarbonyl; R2 is OH; halo; optionally substituted C1-6alkyl, C2-6alkenyl or C2-6alkynyl; substituted carbonyl; carboxyl; CN; nitro; amino; substituted amino; polyhalomethyl; polyhalomethylthio; —S(═O)pR6; C(═NH)R6; R2a is CN; amino; substituted amino; optionally substituted C1-6alkyl; halo; optionally substituted C1-6alkyloxy; substituted carbonyl; —CH═N—NH—C(═O)—R16; optionally substituted C1-6alkyloxyC1-6alkyl; substituted C2-6alkenyl or C2-6alkynyl; —C(═N—O—R8)—C1-4alkyl; R7 or —X—R7; R3 is CN; amino; C1-6alkyl; halo; optionally substituted C1-6alkyloxy; substituted carbonyl; —CH═N—NH—C(═O)—R16; substituted C1-6alkyl; optionally substituted C1-6alkyloxyC1-6alkyl; substituted C2-6alkenyl or C2-6alkynyl; —C(═N—O—R8)—C1-4alkyl; R7; —X—R7; R4 is halo; OH; optionally substituted C1-6alkyl, C2-6alkenyl or C2-6alkynyl; C3-7cycloalkyl; C1-6alkyloxy; CN; nitro; polyhaloC1-6alkyl; polyhaloC1-6alkyloxy; substituted carbonyl; formyl; amino; mono- or di(C1-4alkyl)amino or R7; -A-B— is —CR5═N—, —N═N—, —CH2—CH2—, —CS—NH—, —CO—NH—, —CH═CH—; pharmaceutical compositions comprising these; methods for the preparation of these compounds and compositions; the use of these compounds for the prevention or the treatment of HIV infection.

A compound of formula

a N-oxide;
a pharmaceutically acceptable addition salt;
a quaternary amine;
or a stereochemically isomeric form thereof, wherein
-a1=a2-a3=a4- represents a bivalent radical of a formula selected from the group consisting of:
—CH═CH—CH═CH— (a-1);
—N═CH—CH═CH— (a-2);
—N═CH—N═CH— (a-3);
—N═CH—CH═N— (a-4);
and
—N═N—CH═CH— (a-5);
-b1=b2-b3=b4- represents a bivalent radical of a formula selected from the group consisting of:
—CH═CH—CH═CH— (b-1);
—N═CH—CH═CH— (b-2);
—N═CH—N═CH— (b-3);
—N═CH—CH═N— (b-4);
and
—N═N—CH═CH— (b-5);
n is 0, 1, 2, 3 and in case -a1=a2-a3=a4- is (a-1), then n may also be 4;
m is 0, 1, 2, 3 and in case -b1=b2-b3=b4- is (b-1), then m may also be 4;
-A-B— represents a bivalent radical of a formula:
—CH2—CH2— (c-3);
or
—CH═CH— (c-6);
R1 is a member selected from the group consisting of:
hydrogen;
aryl;
formyl;
C1-6alkylcarbonyl;
C1-6alkyl;
C1-6alkyloxycarbonyl;
and C1-6alkyl substituted with a member selected from the group consisting of:
formyl, C1-6alkylcarbonyl, and C1-6alkyloxycarbonyl;
each R2 independently is selected from the group consisting of:
hydroxy;
halo;
C1-6alkyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R6;
C3-7cycloalkyl;
C2-6alkenyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R6;
C2-6alkynyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R6;
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;
and C(═NH)R6;
R2a is a member selected from the group consisting of:
cyano;
aminocarbonyl;
amino;
C1-6alkyl;
halo;
C1-6alkyloxy wherein the C1-6alkyl moiety of the C1-6alkyloxy may optionally be substituted with cyano;
NHR13;
NR13R14;
—C(═O)—NHR13;
—C(═O)—NR13R14;
C(═O)—R15;
—CH═N—NH—C(═O)—R16;
C1-6alkyl substituted with one, two or three substituents each independently selected from halo, cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl and R7;
C1-6alkyl substituted with hydroxy and a second substituent selected from halo, cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl and R7;
C1-6alkyloxyC1-6alkyl optionally substituted with one, two or three substituents each independently selected from halo, cyano, NR9R10;
—C(═O)—NR9R10, —C(═O)—C1-6alkyl and R7;
C2-6alkenyl substituted with one, two or three substituents each independently selected from halo, cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl and R7;
C2-6alkynyl substituted with one, two or three substituents each independently selected from halo, cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl and R7;
—C(═N—O—R8)—C1-4alkyl;
R7;
and —X—R7;
R3 is a member selected from the group consisting of:
cyano;
aminocarbonyl;
amino;
C1-6alkyl;
halo;
C1-6alkyloxy wherein the C1-6alkyl moiety of the C1-6alkyloxy may optionally be substituted with cyano;
NHR13;
NR13R14;
—C(═O)—NHR13;
—C(═O)—NR13R14;
—C(═O)—R15;
—CH═N—NH—C(═O)—R16;
C1-6alkyl substituted with one, two or three substituents each independently selected from halo, cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl and R7;
C1-6alkyl substituted with hydroxy and a second substituent selected from halo, cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl and R7;
C1-6alkyloxyC1-6alkyl optionally substituted with one, two or three substituents each independently selected from halo, cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl and R7;
C2-6alkenyl substituted with one, two or three substituents each independently selected from halo, cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl and R7;
C2-6alkynyl substituted with one, two or three substituents each independently selected from halo, cyano, NR9R10, —C(═O)—NR9R10, —C(═O)—C1-6alkyl and R7;
—C(═N—O—R8)—C1-4alkyl;
R7;
and —X—R7;
X is a member selected from the group consisting of:
—NR1—, —O—, —C(═O)—, —S—, and —S(═O)p—;
each R4 independently is a member selected from the group consisting of:
halo;
hydroxy;
C1-6alkyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R6;
C2-6alkenyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R6;
C2-6alkynyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R6;
C3-7cycloalkyl;
C1-6alkyloxy;
cyano;
nitro;
polyhaloC1-6alkyl;
polyhaloC1-6alkyloxy;
aminocarbonyl;
mono- or di(C1-4alkyl)aminocarbonyl;
C1-6alkyloxycarbonyl;
C1-6alkylcarbonyl;
formyl;
amino;
mono- or di(C1-4alkyl)amino;
and R7;
Q is a member selected from the group consisting of:
hydrogen, C1-6alkyl, halo, polyhaloC1-6alkyl, and —NR9R10;
R6 is a member selected from the group consisting of:
C1-4alkyl, amino, mono- or di(C1-4alkyl)amino, and polyhaloC1-4alkyl;
R7 is a member selected from the group consisting of:
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 the group consisting of:
halo, hydroxy, mercapto, C1-6alkyl, hydroxy C1-6alkyl, aminoC1-6alkyl, mono and di(C1-6alkyl)aminoC1-6 alkyl, formyl, C1-6alkylcarbonyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, —CH(═N—O—R8), R7a, —X—R7a and R7a—C1-4alkyl;
R7a is a member selected from the group consisting of:
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 the group consisting of:
halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)amino C1-6alkyl, formyl, C1-6alkylcarbonyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, and —CH(═N—O—R8);
R8 is a member selected from the group consisting of:
hydrogen, C1-4alkyl, aryl or arylC1-4alkyl;
R9 and R10 each independently are a member selected from the group consisting of:
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) and 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 the group consisting of:
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, and R7;
or
R9 and R10 may be taken together to form a bivalent or trivalent radical of a formula selected from the group consisting of:
—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);
and
═CH—CH═CH—CH═CH— (d-7);
R11 is a member selected from the group consisting of:
cyano;
C1-4alkyl optionally substituted with C1-4alkyloxy, cyano, amino, mono- or di(C1-4alkyl)amino or aminocarbonyl;
C1-4alkylcarbonyl;
C1-4alkyloxycarbonyl;
aminocarbonyl;
and mono- or di(C1-4alkyl)aminocarbonyl;
R12 is hydrogen or C1-4alkyl;
R13 and R14 each independently are a member selected from the group consisting of:
C1-6alkyl optionally substituted with cyano or aminocarbonyl;
C2-6alkenyl optionally substituted with cyano or aminocarbonyl;
and 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, aminocarbonyl, or R7;
each p is 1 or 2;
each aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from the group consisting of:
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, a radical Het and —X-Het;
and
Het is a member selected from the group consisting of:
pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl quinolinyl, benzothienyl, and benzofuranyl;
wherein each of the aforementioned Het may optionally be substituted with one or two C1-4alkyl radicals.

175 more elements

HIV inhibiting bicyclic pyrimidine derivatives

Life of this patent

HIV inhibiting bicyclic pyrimidine derivatives

Life of this patent

Abstract

Claims17