HIV inhibiting bicyclic pyrimidine derivatives

Patent metadata

Field	Value
Publication number	US-9802943-B2
Application number	US-201615241615-A
Country	US
Kind code	B2
Filing date	Aug 19, 2016
Priority date	Oct 29, 2004
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

Abstract

HIV replication inhibitors of formula

N-oxides, pharmaceutically acceptable addition salts, quaternary amines or 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—; n and m is 0, 1, 2, 3 and in certain cases also 4; 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) p R 6 ; C(═NH)R 6 ; R 2a is CN; amino; substituted amino; optionally substituted C 1-6 alkyl; halo; optionally substituted C 1-6 alkyloxy; substituted carbonyl; —CH═N—NH—C(═O)—R 16 ; optionally substituted C 1-6 alkyloxyC 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—R 7 ; 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 alkyloxyC 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—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; polyhaloC 1-6 alkyl; polyhaloC 1-6 alkyloxy; substituted carbonyl; formyl; amino; mono- or di(C 1-4 alkyl)amino or R 7 ; -A-B— is —CR 5 ═N—, —N═N—, —CH 2 —CH 2 —, —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.

First claim

The invention claimed is:

1. A compound of formula

a N-oxide; a pharmaceutically acceptable addition salt; a quaternary amine; or a stereochemically isomeric form thereof, wherein
-a 1 =a 2 -a 3 =a 4 - 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);

-b 1 =b 2 -b 3 =b 4 - 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 -a 1 =a 2 -a 3 =a 4 - is (a-1), then n may also be 4;
m is 0, 1, 2, 3 and in case -b 1 =b 2 -b 3 =b 4 - is (b-1), then m may also be 4;
-A-B— represents a bivalent radical of a formula:
—CH 2 —CH 2 —  (c-3); or

—CH═CH—  (c-6);

R 1 is a member selected from the group consisting of: hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; C 1-6 alkyl; C 1-6 alkyloxycarbonyl; and C 1-6 alkyl substituted with a member selected from the group consisting of: formyl, C 1-6 alkylcarbonyl, and C 1-6 alkyloxycarbonyl;
each R 2 independently is selected from the group consisting of: hydroxy; halo; C 1-6 alkyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R 6 ; C 3-7 cycloalkyl; C 2-6 alkenyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R 6 ; C 2-6 alkynyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —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 ; and C(═NH)R 6 ;
R 2a is a member selected from the group consisting of: cyano; aminocarbonyl; amino; C 1-6 alkyl; halo; C 1-6 alkyloxy wherein the C 1-6 alkyl moiety of the C 1-6 alkyloxy 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, two or three substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl and 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 and R 7 ; C 1-6 alkyloxyC 1-6 alkyl optionally substituted with one, two or three substituents each independently selected from halo, cyano, NR 9 R 10 ; —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl and R 7 ; C 2-6 alkenyl substituted with one, two or three substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl and R 7 ; C 2-6 alkynyl substituted with one, two or three substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl and R 7 ; —C(═N—O—R 8 )—C 1-4 alkyl; R 7 ; and —X—R 7 ;
R 3 is a member selected from the group consisting of: cyano; aminocarbonyl; amino; C 1-6 alkyl; halo; C 1-6 alkyloxy wherein the C 1-6 alkyl moiety of the C 1-6 alkyloxy 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, two or three substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl and 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 and R 7 ; C 1-6 alkyloxyC 1-6 alkyl optionally substituted with one, two or three substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl and R 7 ; C 2-6 alkenyl substituted with one, two or three substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl and R 7 ; C 2-6 alkynyl substituted with one, two or three substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl and R 7 ; —C(═N—O—R 8 )—C 1-4 alkyl; R 7 ; and —X—R 7 ;
X is a member selected from the group consisting of: —NR 1 —, —O—, —C(═O)—, —S—, and —S(═O) p —;
each R 4 independently is a member selected from the group consisting of: halo; hydroxy; C 1-6 alkyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R 6 ; C 2-6 alkenyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —C(═O)R 6 ; C 2-6 alkynyl optionally substituted with one, two or three substituents each independently selected from halo, cyano and —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; and R 7 ;
Q is a member selected from the group consisting of: hydrogen, C 1-6 alkyl, halo, polyhaloC 1-6 alkyl, and —NR 9 R 10 ;
R 6 is a member selected from the group consisting of: C 1-4 alkyl, amino, mono- or di(C 1-4 alkyl)amino, and polyhaloC 1-4 alkyl;
R 7 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, C 1-6 alkyl, hydroxy C 1-6 alkyl, aminoC 1-6 alkyl, mono and 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—R 7a and R 7a —C 1-4 alkyl;
R 7a 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, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)amino C 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, and —CH(═N—O—R 8 );
R 8 is a member selected from the group consisting of: hydrogen, C 1-4 alkyl, aryl or arylC 1-4 alkyl;
R 9 and R 10 each independently are a member selected from the group consisting of: 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 ) and 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 the group consisting of: 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, —

Assignees

• Janssen Sciences Ireland Uc

Inventors

• Guillemont Jerôme Emile Georges
• Paugam Mikaël
• Delest Bruno Francois Marie
• Heeres Jan
• Lewi Paulus Joannes
• Janssen Paul Adriaan Jan

Classifications

• C07D473/00

  Heterocyclic compounds containing purine ring systems · CPC title

• C07D473/24

  one nitrogen and one sulfur atom · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D473/34

  attached in position 6, e.g. adenine · CPC title

• A61P31/18

  for HIV · CPC title