US 7,608,592 B2Granted

HCV inhibitors

AssigneeViroBay, Inc.

InventorsMichael Graupe, John O. Link, Chandrasekar Venkataramani

Life of this patent

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Abstract

The present invention is directed to compounds that are antiviral agents. Specifically the compounds of the present invention inhibit replication of HCV and are therefore useful in treating hepatitis C infections. The present invention is also directed to pharmaceutical compositions comprising these compounds and processes for preparing them.

Claims31

Dependent claims

A compound of Formula (I):

wherein
E is —COCONR5R6, —COCF2CONR5R6, —COCF2C(O)OR5, —COCOR7, —COCF2R8, —COR9, or —B(OR13)2 where R5, R6, R7, R9, and each R13 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl and R8 is halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl wherein the aliphatic, alicyclic and aromatic groups in E are optionally substituted with one, two, or three Ra independently selected from hydroxy, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, amino, monosubstituted amino, disubstituted amino, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkenylaminocarbonyl, acylamino, aminocarbonyl, halo, or cyano and further wherein the aromatic or alicyclic ring in Ra is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, carboxy, or carboxyalkyl;
R1 is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl wherein the aliphatic, alicyclic and aromatic groups in R1 are optionally substituted with one or two Rb independently selected from hydroxy, alkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, amino, monosubstituted amino, disubstituted amino, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, halo, or cyano and further wherein the aromatic ring in Rb is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, carboxy, or carboxyalkyl;
X is —O—, —NH—, —S—, —SO—, or —SO2—;
R3 is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl wherein the aliphatic, alicyclic and aromatic groups in R3 are optionally substituted with one or two Rc independently selected from hydroxy, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, amino, monosubstituted amino, disubstituted amino, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, halo, or cyano and further wherein the aromatic ring in Rc is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, carboxy, or carboxyalkyl;
Y is —C(O)NH—, —OC(O)NH—, —NR14—C(O)NH—, or —NR14C(O)O— where each R14 is selected from hydrogen, alkyl optionally substituted with halo, hydroxy, alkoxy, amino, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl;
R2 is a group of formula (a):
where
Rd1 is hydrogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, haloalkoxy or alkylsulfonyl;
Rd and Rd2 are independently hydrogen, alkyl, halo, alkoxy, alkvlthio, or alkylsulfonyl;
or
Rd1 and Rd or Rd1 and Rd2 together with the carbon atoms to which they are attached form a 4, 5, or 6- atom heterocyclyl ring wherein one or two ring atoms are replaced by oxygen or —N— where the heterocyclyl ring is optionally substituted with one or two alkyl;
Rd3 is aryl, heteroaryl, or heterocyclyl optionally substituted with halo, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkylalkycarbonylamino, alkyloxycarbonylamino, amino, alkylamino, dialkylamino, or —NHCONRR′ where R is hydrogen or alkyl and R′ is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl wherein cycloalkyl and cycloalkylalkyl are optionally substituted with one, two or three alkyl;
and
R4 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl;
provided that:
(i) when R4 is alkyl and when Y is —C(O)NH —, then Rd3 is a heteroaryl ring;
and
(ii) when R4 is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, then Rd3 is a heteroaryl ring;
wherein the aromatic or alicyclic ring in R4 is optionally substituted with one, two, or three Rf independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, carboxy, carboxyalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylcarbonyl, aryl, aralkyl, arylsulfonyl, arylcarbonyl, aryloxycarbonyl, aminosulfonyl, aminocarbonyl, heteroaryl, heteroaralkyl, heteroarylsulfonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, heterocyclyl, heterocyclylalkyl heterocyclylsulfonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl monosubstituted amino, or disubstituted amino wherein the aromatic ring in Rf is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, monosubstituted amino, disubstituted amino, or acylamino;
or
a pharmaceutically acceptable salts thereof.

19 more elements

A compound of Formula (I):

wherein
E is —COCONR5R6, —COCF2CONR5R6, —COCF2C(O)OR5, —COCOR7, —COCF2R8, —COR9, or —B(OR13)2 where R5, R6, R7, R9, and each R13 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl and R8 is halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl wherein the aliphatic, alicyclic and aromatic groups in E are optionally substituted with one, two, or three Ra independently selected from hydroxy, alkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, amino, monosubstituted amino, disubstituted amino, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkenylaminocarbonyl, acylamino, aminocarbonyl, halo, or cyano and further wherein the aromatic ring in Ra is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, carboxy, or carboxyalkyl;
R1 is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl wherein the aliphatic, alicyclic and aromatic groups in R1 are optionally substituted with one or two Rb independently selected from hydroxy, alkoxy, aryloxy. heteroaryloxy, alkylthio. arylthio, heteroarvlthio, amino, monosubstituted amino, disubstituted amino, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, halo, or cyano and further wherein the aromatic ring in Rb is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, carboxy, or carboxyalkyl;
X is —O—, —NH—, —S—, —SO—, or —SO2—;
R3 is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl wherein the aliphatic, alicyclic and aromatic groups in R3 are optionally substituted with one or two Rc independently selected from hydroxy, alkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, amino, monosubstituted amino, disubstituted amino, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, halo, or cyano and further wherein the aromatic ring in Rc is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, carboxy, or carboxyalkyl;
Y is —OC(O)NH—, —NR14—C(O)NH—, or NR14C(O)O—where each R14 selected from hydrogen, alkyl optionally substituted with hydroxy, alkoxy, amino, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl;
R2 is a group of formula (b):
where:
Rd1 is hydrogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, haloalkoxy or alkylsulfonyl;
Rd and Rd2 are independently hydrogen, alkyl, halo, alkoxy, alkylthio, or alkylsulfonyl;
or
Rd1 and Rd or Rd1 and Rd2 together with the carbon atoms to which they are attached form 4, 5, or 6-atom heterocyclyl ring wherein one or two ring atoms are replaced by oxygen or —N— where the heterocyclyl ring is optionally substituted with one or two alkyl;
Rd3 is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl;
wherein at least one of Rd, Rd1, Rd2 and R d3 is other than hydrogen;
and
R 4 is alkyl;
or a pharmaceutically acceptable salt thereof.

14 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/478,337Filed 28 Jun 2006 · us provisional application
Priority: 30 Jun 2005
Published: US 2007/0054864 A18 Mar 2007
Granted: 27 Oct 2009
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

A61K 38/05
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: dipeptides
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
A61P 31/14
Antivirals: for RNA viruses

Family

Application60/695,767Us provisional application · filed 30 Jun 2005
US 2007/0054864 A1Pre-grant publication · published 8 Mar 2007
US 7,608,592 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula (I):

wherein
E is —COCONR5R6, —COCF2CONR5R6, —COCF2C(O)OR5, —COCOR7, —COCF2R8, —COR9, or —B(OR13)2 where R5, R6, R7, R9, and each R13 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl and R8 is halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl wherein the aliphatic, alicyclic and aromatic groups in E are optionally substituted with one, two, or three Ra independently selected from hydroxy, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, amino, monosubstituted amino, disubstituted amino, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkenylaminocarbonyl, acylamino, aminocarbonyl, halo, or cyano and further wherein the aromatic or alicyclic ring in Ra is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, carboxy, or carboxyalkyl;
R1 is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl wherein the aliphatic, alicyclic and aromatic groups in R1 are optionally substituted with one or two Rb independently selected from hydroxy, alkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, amino, monosubstituted amino, disubstituted amino, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, halo, or cyano and further wherein the aromatic ring in Rb is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, carboxy, or carboxyalkyl;
X is —O—, —NH—, —S—, —SO—, or —SO2—;
R3 is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl wherein the aliphatic, alicyclic and aromatic groups in R3 are optionally substituted with one or two Rc independently selected from hydroxy, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, amino, monosubstituted amino, disubstituted amino, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, halo, or cyano and further wherein the aromatic ring in Rc is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, carboxy, or carboxyalkyl;
Y is —C(O)NH—, —OC(O)NH—, —NR14—C(O)NH—, or —NR14C(O)O— where each R14 is selected from hydrogen, alkyl optionally substituted with halo, hydroxy, alkoxy, amino, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl;
R2 is a group of formula (a):
where
Rd1 is hydrogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, haloalkoxy or alkylsulfonyl;
Rd and Rd2 are independently hydrogen, alkyl, halo, alkoxy, alkvlthio, or alkylsulfonyl;
or
Rd1 and Rd or Rd1 and Rd2 together with the carbon atoms to which they are attached form a 4, 5, or 6- atom heterocyclyl ring wherein one or two ring atoms are replaced by oxygen or —N— where the heterocyclyl ring is optionally substituted with one or two alkyl;
Rd3 is aryl, heteroaryl, or heterocyclyl optionally substituted with halo, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkylalkycarbonylamino, alkyloxycarbonylamino, amino, alkylamino, dialkylamino, or —NHCONRR′ where R is hydrogen or alkyl and R′ is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl wherein cycloalkyl and cycloalkylalkyl are optionally substituted with one, two or three alkyl;
and
R4 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl;
provided that:
(i) when R4 is alkyl and when Y is —C(O)NH —, then Rd3 is a heteroaryl ring;
and
(ii) when R4 is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, then Rd3 is a heteroaryl ring;
wherein the aromatic or alicyclic ring in R4 is optionally substituted with one, two, or three Rf independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, carboxy, carboxyalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylcarbonyl, aryl, aralkyl, arylsulfonyl, arylcarbonyl, aryloxycarbonyl, aminosulfonyl, aminocarbonyl, heteroaryl, heteroaralkyl, heteroarylsulfonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, heterocyclyl, heterocyclylalkyl heterocyclylsulfonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl monosubstituted amino, or disubstituted amino wherein the aromatic ring in Rf is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, monosubstituted amino, disubstituted amino, or acylamino;
or
a pharmaceutically acceptable salts thereof.

19 more elements

Facts

Application

11/478,337Filed 28 Jun 2006 · us provisional application

Priority

30 Jun 2005

Published

US 2007/0054864 A18 Mar 2007

Granted

27 Oct 2009

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

A61K 38/05
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: dipeptides
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
A61P 31/14
Antivirals: for RNA viruses