Pteridines useful as HCV inhibitors and methods for the preparation thereof

Patent metadata

Field	Value
Publication number	US-9951075-B2
Application number	US-201615042299-A
Country	US
Kind code	B2
Filing date	Feb 12, 2016
Priority date	May 12, 2005
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

The present invention relates to the use of pteridines as inhibitors of HCV replication as well as their use in pharmaceutical compositions aimed to treat or combat HCV infections. In addition, the present invention relates to compounds per se and their use as medicines. The present invention also concerns processes for the preparation of such compounds, pharmaceutical compositions comprising them, and combinations of said compounds with other anti-HCV agents.

First claim

The invention claimed is:

1. A method of diminishing hepatitis C virus viral load in a mammal infected with hepatitis C virus comprising administering to the mammal
a compound having the formula (I), for a time and in an amount effective to diminish the HCV viral load in the mammal:

or an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof, wherein
R 1 is hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxyC 1-4 alkyl, diC 1-4 alkylaminoC 1-4 alkyl, piperidin-1-yl-C 1-4 alkyl, arylC 1-6 alkyl, wherein the aryl group may be further substituted with C 1-4 alkyl, or C 1-4 alkoxy;
L is —NR 8 —, —NR 8 —C 1-6 alkanediyl-, —NR 8 —CO—C 1-6 alkanediyl-, —NR 8 —SO 2 —C 1-6 alkanediyl-, —O—, —O—C 1-6 alkanediyl-, —O—CO—, —O—CO—C 1-6 alkanediyl-, —S—, —S—C 1-6 alkanediyl-, or

wherein the dotted ring together with N and Z form a Het 1 cycle having 5 to 8 members including ring members N and Z, and wherein said L ring is attached to the pteridine ring by the nitrogen atom;
Z is N or CH;
R 2 is hydrogen, hydroxyC 1-6 alkyl, C 3-7 cycloalkyl, aryl, Het 1 , or Het 2 , wherein said C 3-7 cycloalkyl, aryl, Het 1 , and Het 2 are each independently optionally substituted with one or more substituents selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, polyhaloC 1-4 alkyl, halo, cyano, nitro, —COR 6 , —COOR 7 , —CONR 4a R 4b , —OR 7 , —OCOR 6 , —OCONR 4a R 4b , —NR 4a R 4b , —NR 4a COR 6 , —NR 4a CONR 4a R 4b , —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SR 5 , —SOR 7 , —SO 2 R 5 , —SO 3 R 7 , —SO 2 NR 4a R 4b , morpholin-4-yl, phenyl, aminophenyl, or aminophenylcarbonyl, and wherein the C 1-4 alkyl may be further substituted with —COOR 7 ;
R 3 is a C 1-6 alkyl, C 3-7 cycloalkyl, aryl, arylC 1-6 alkyl, Het 1 , Het 2 or Het 2 -C 1-6 alkyl, each independently optionally substituted with one or more substituents selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, polyhaloC 1-4 alkyl, halo, cyano, nitro, —COR 6 , —COOR 7 , —CONR 4a R 4b , —OR 7 , —OCOR 6 , —OCONR 4a R 4b , —NR 4a R 4b , —NR 4a COR 6 , —NR 4a COOR 7 , —NR 4a CONR 4a R 4b , —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SR 5 , —SOR 7 , —SO 2 R 5 , —SO 3 R 7 , or —SO 2 NR 4a R 4b ; and wherein R 4a and R 4b may optionally form, together with the nitrogen atom to which they are bound, a 5 to 8 membered saturated, unsaturated or partially unsaturated ring, optionally comprising one or two additional heteroatoms;
each R 4a and R 4b is independently hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, Het 1 -C 1-4 alkyl, polyhaloC 1-4 alkyl, cyano, or nitro;
each R 5 is independently hydrogen, or C 1-4 alkyl;
each R 6 is independently hydrogen, or C 1-4 alkyl;
each R 7 is independently hydrogen or C 1-4 alkyl; and
R 8 is hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylcarbonyl, amino-C 1-10 alkyl, aryl, arylcarbonyl, arylC 1-10 alkyl, Het 1 , Het 1 C 1-6 alkyl, or a protecting group, wherein the aryl is optionally substituted with 1 to 3 substituents selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylcarbonyl, phenyl, C 1-4 alkylphenyl, phenylcarbonyl, aminophenyl, aminoC 1-4 alkylphenyl, aminophenylcarbonyl, halo, —OR 6 , —NR 4a R 4b , —SR 5 , —SOR 5 , —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SO 2 R 5 , —OCOR 6 , —NR 4a COR 6 , —NR 4a CONR 4a R 4b , —NR 4a COOR 6 , —OCONR 4a R 4b , —COOR 6 , —SO 3 R 6 , —CONR 4a R 4b , —SO 2 NR 4a R 4b , cyano, polyhalo-C 1-4 alkyl, and nitro;
Het 1 as a group or part of a group is defined as a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 12 ring members, more preferably 5 to 10 ring members and more preferably 5 to 8 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by C 1-6 alkyl, C 1-6 alkoxy, halo, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, polyhaloC 1-4 alkyl, carboxyl, C 1-6 alkoxy-carbonyl, C 3-7 cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl and a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and whereby the optional substituents on any amino function are hydrogen, or C 1-4 alkyl;
Het 2 as a group or part of a group is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members, preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members each independently selected from nitrogen, oxygen or sulfur, and which is optionally substituted on one or more carbon atoms by C 1-6 alkyl, optionally mono- or disubstituted aminoC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, halo, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, polyhaloC 1-4 alkyl, carboxyl, C 1-6 alkoxycarbonyl, C 3-7 cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het 1 and an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members; whereby the optional substituents on any amino function are hydrogen, or C 1-4 alkyl; and
aryl as a group or part of a group is phenyl.

2. The method of claim 1 , wherein the compound has the formula (II)

or an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof, and further wherein
R 9 is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, polyhaloC 1-4 alkyl, halo, cyano, nitro, —COR 6 , —COOR 7 , —CONR 4a R 4b , —OR 7 , —OCOR 6 , —OCONR 4a R 4b , —NR 4a R 4b , —NR 4a COR 6 , —NR 4a CONR 4a R 4b , —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SR 5 , —SOR 7 , —SO 2 R 5 , —SO 3 R 7 , —SO 2 NR 4a R 4b , morpholin-4-yl, phenyl, aminophenyl, or aminophenyl-carbonyl, and wherein the C 1-4 alkyl may be further substituted with —COOR 7 ; and
n is 0, 1, 2, 3, or 4.

3. The method of claim 1 , wherein the compound has the formula (III):

or an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof, and further wherein
R 10 is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, polyhaloC 1-4 alkyl, halo, cyano, nitro, —COR 6 , —COOR 7 , —CONR 4a R 4b , —OR 7 , —OCOR 6 , —OCONR 4a R 4b , —NR 4a R 4b , —NR 4a COR 6 , —NR 4a COOR 7 , —NR 4a CONR 4a R 4b , —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SR 5 , —SOR 7 , —SO 2 R 5 , —SO 3 R 7 , or —SO 2 NR 4a R 4b ; and
m is 0, 1, 2, 3, or 4.

4. The method of claim 1 , wherein the compound has the formula (IV):

or an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof, and further wherein
R 9 is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, polyhaloC 1-4 alkyl, halo, cyano, nitro, —COR 6 , —COOR 7 , —CONR 4a R 4b , —OR 7 , —OCOR 6 , —OCONR 4a R 4b , —NR 4a R 4b , —NR 4a COR 6 , —NR 4a CONR 4a R 4b , —R 4a SOR 5 , —NR 4a SO 2 R 5 , —SR 5 , —SOR 7 , —SO 2 R 5 , —SO 3 R 7 , —SO 2 NR 4a R 4b , morpholin-4-yl, phenyl, aminophenyl, or

Assignees

• Janssen Sciencies Ireland UC
• Janssen Sciences Ireland Uc

Inventors

• Raboisson Pierre Jean-Marie Bernard
• Surleraux Dominique Louis Nestor Ghislain
• Lin Tse-I
• Lenz Oliver
• Simmen Kenneth Alan

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title