US2009264346A1PendingUtilityA1
Macrocyclic peptides active against the hepatitis c virus
Est. expiryJan 21, 2024(expired)· nominal 20-yr term from priority
Inventors:Montse Llinas-BrunetMurray D. BaileyFrancois BilodeauPasquale ForgioneElise GhiroNathalie GoudreauTeddy HalmosJean Rancourt
A61P 31/12A61P 31/00A61P 31/20A61P 31/14A61P 43/00C07K 5/0827A61K 38/00C07K 5/0812C07K 5/0808
60
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Claims
Abstract
Compounds of formula (I): wherein R 1 , R 2 , X, R 3 , D, and the dotted line b are as defined herein; or a pharmaceutically acceptable salt or ester thereof, are useful as inhibitors of the HCV NS3 protease.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I):
wherein R 1 is hydroxy;
R 2 is a group of formula:
wherein
R 20 is H, OH, halogen, or Y 1 —R 20a wherein Y 1 is a bond, O, S, or NR 20b and wherein:
R 20a is selected from the group consisting of: (C 1-8 )alkyl, (C 1-6 )alkyl-C≡N, (C 2-8 )alkenyl, (C 2-8 )alkynyl and (C 3-7 )cycloalkyl, each of said alkyl, alkenyl, alkynyl and cycloalkyl being optionally substituted with one, two or three substituents, each independently selected from:
halogen, (C 1-6 )alkyl optionally substituted with —O—(C 1-6 )alkyl or —O—(C 3-6 )cycloalkyl, (C 3-7 )cycloalkyl, —O—(C 1-6 )alkyl, Het, —O—(C 3-6 )cycloalkyl, —NH 2 , —NH(C 1-4 )alkyl and —N((C 1-4 )alkyl) 2 ; and
R 20b is H, (C 1-6 )alkyl or (C 3-6 )cycloalkyl;
and W is N; and the dotted line “a” is a double bond; or
R 20 is oxo, and W is NR 23 wherein R 23 is H, (C 1-6 )alkyl, (C 2-6 )alkenyl or (C 2-6 )alkynyl; and the dotted line “a” is a single bond;
R 21 is halogen or Y 2 —R 21a , wherein Y 2 is a bond, O, S, SO or SO 2 , and R 21a is (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 3-7 )cycloalkyl or (C 3-7 )cycloalkyl-(C 1-6 )alkyl-;
R 22 is H, —OH, —O—(C 1-4 )alkyl, —NH 2 , —NH(C 1-4 )alkyl or —N((C 1-4 )alkyl) 2 ;
or R 2 is a group of formula:
wherein
R 20 , W and the dotted line “a” are as defined above;
R 24 is H or R 21 as defined above; and
R 25 is H or (C 1-6 )alkyl;
X is O or NH;
R 3 is (C 1-10 )alkyl, (C 3-7 )cycloalkyl or (C 3-7 )cycloalkyl-(C 1-4 )alkyl-,
a) wherein the cycloalkyl and cycloalkyl-alkyl- may be mono-, di- or tri-substituted with (C 1-3 )alkyl;
b) wherein the alkyl, cycloalkyl and cycloalkyl-alkyl- may be mono- or di-substituted with substituents each independently selected from hydroxy and O—(C 1-6 )alkyl;
c) wherein each alkyl group may be mono-, di- or tri-substituted with halogen; and
d) wherein in each cycloalkyl group being 5-, 6- or 7-membered, one or two —CH 2 -groups not being directly linked to each other may be replaced by —O— such that the O-atom is linked to the group X via at least two C-atoms;
D is a 3 to 8 atom saturated or unsaturated alkylene chain; and
the dotted line “b” is a single bond or a double bond;
wherein Het as used herein is defined as a 3- to 7-membered heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S, which may be saturated, unsaturated or aromatic, and which is optionally fused to at least one other cycle to form a 4- to 14-membered heteropolycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O, N and S, said heteropolycycle being saturated, unsaturated or aromatic;
or a pharmaceutically acceptable salt or ester thereof.
2 . The compound according to claim 1 wherein R 2 is a group of formula:
wherein
W, R 20 , R 21 , R 22 and the dotted line “a” are defined as in claim 1 .
3 . The compound according to claim 2 wherein R 20 is oxo; W is NR 23 wherein R 23 is Me, Et, —CH 2 CH═CH 2 or H; and the dotted line “a” is a single bond.
4 . The compound according to claim 2 wherein W is N; the dotted line “a” is a double bond; and R 20 is H, OH, halogen, or Y 1 —R 20a wherein
Y 1 is a bond, O, S, or NR 20b ; R 20a is selected from the group consisting of: (C 1-8 )alkyl, (C 2-8 )alkenyl, (C 2-8 )alkynyl and (C 3-7 )cycloalkyl, each of said alkyl, alkenyl, alkynyl and cycloalkyl being optionally substituted with one, two or three substituents, each independently selected from:
halogen, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, Het, —O—(C 1-6 )alkyl, —O—(C 3-6 )cycloalkyl, —NH 2 , —NH(C 1-4 )alkyl and —N((C 1-4 )alkyl) 2 ; and
R 20b is H, (C 1-6 )alkyl or (C 3-6 )cycloalkyl.
5 . The compound according to claim 2 wherein W is N; the dotted line “a” is a double bond; and R 20 is H, (C 1-6 )alkyl, OH, —O—(C 1-6 )alkyl, —S—(C 1-6 )alkyl, —(CH 2 ) 0-4 —CH═CH 2 , —(CH 2 ) 0-4 —C≡CH, —O—(CH 2 ) 0-4 —CH═CH 2 , —O—(CH 2 ) 0-4 —C≡CH, —O—(CH 2 ) 1-4 —OMe; —O—(CH 2 ) 1-4 —N(Me) 2 ; —O—(CH 2 ) 1-4 -Het; —S—(CH 2 ) 0-4 —CH═CH 2 , —S—(CH 2 ) 0-4 —C≡CH, —S—(CH 2 ) 1-4 —OMe; —S—(CH 2 ) 1-4 —N(Me) 2 , —S—(CH 2 ) 1-4 -Het; (C 3-6 )cycloalkyl, —O—(C 3-6 )cycloalkyl, O—(C 1-6 )alkyl-(C 3-6 )cycloalkyl, —S—(C 3-6 )cycloalkyl, or —S—(C 1-6 )alkyl-(C 3-6 )cycloalkyl; wherein Het is 5- or 6-membered monocyclic heteroaryl containing from one to three heteroatoms each independently selected from N, O and S;
each of said (C 1-6 )alkyl, —O—(C 1-6 )alkyl, —S—(C 1-6 )alkyl, —(CH 2 ) 0-4 —CH═CH 2 , —(CH 2 ) 0-4 —C≡CH, —O—(CH 2 ) 0-4 —CH═CH 2 , —O—(CH 2 ) 0-4 —C≡CH, —S—(CH 2 ) 0-4 —CH═CH 2 , —S—(CH 2 ) 0-4 —C≡CH, (C 3-6 )cycloalkyl, —O—(C 3-6 )cycloalkyl, and —S—(C 3-6 )cycloalkyl being optionally substituted with one, two or three substituents, each independently selected from (C 1-4 )alkyl, —O—(C 1-4 )alkyl, and halo; or R 20 is NR 20a R 20b wherein R 20a is (C 1-4 )alkyl, and R 20b is H, (C 1-4 )alkyl or (C 3-5 )cycloalkyl.
6 . The compound according to claim 5 wherein R 20 is H, methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH═CH 2 , —C≡CH, O-methyl, O-ethyl, O-propyl, O—CH(CH 3 ) 2 , 0-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, O—CH 2 CH 2 CF 3 , —O—CH═CH 2 , —O—CH 2 —CH═CH 2 , O—C≡CH, —O—CH 2 —C≡CH, —O—CH 2 —C≡CCH 3 , —O—CH 2 —CH 2 —OMe, —O—CH 2 —CH 2 —N(Me) 2 ,S-methyl, S-ethyl, S-propyl, S—CH(CH 3 ) 2 , S-cyclopropyl, S-cyclobutyl, S-cyclopentyl, S-cyclohexyl, —S—CH═CH 2 , —S—CH 2 —CH═CH 2 , S—C≡CH, —S—CH 2 —C≡CH, —S—CH 2 —CH 2 —OMe, —S—CH 2 —CH 2 —N(Me) 2 ,
7 . The compound according to claim 2 wherein R 21 is selected from: fluorine, chlorine, bromine, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —SCH 3 , —SCH 2 CH 3 , —SCH 2 CH 2 CH 3 , —(SO)CH 3 , —(SO)CH 2 CH 3 , —(SO)CH 2 CH 2 CH 3 , —(SO 2 )CH 3 , —(SO 2 )CH 2 CH 3 , —(SO 2 )CH 2 CH 2 CH 3 ,
and —C≡CH.
8 . The compound according to claim 2 wherein R 22 is selected from: H, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —NHCH 3 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 and —N(CH 3 )CH 2 CH 2 CH 3 .
9 . The compound according to claim 8 wherein R 22 is H or —OCH 3 .
10 . The compound according to claim 1 wherein R 2 is a group of formula:
wherein
W, R 20 , R 24 , R 25 and the dotted line “a” are defined as in claim 1 .
11 . The compound according to claim 10 wherein W is N; the dotted line “a” is a double bond; and R 20 is H, OH, halogen, or Y 1 —R 20a wherein
Y 1 is a bond, O, S, or NR 20b ; R 20a is selected from the group consisting of: (C 1-8 )alkyl, (C 2-8 )alkenyl, (C 2-8 )alkynyl and (C 3-7 )cycloalkyl, each of said alkyl, alkenyl, alkynyl and cycloalkyl being optionally substituted with one, two or three substituents, each independently selected from:
halogen, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, Het, —O—(C 1-6 )alkyl, —O—(C 3-6 )cycloalkyl, —NH 2 , —NH(C 1-4 )alkyl and —N((C 1-4 )alkyl) 2 ; and
R 20b is H, (C 1-6 )alkyl or (C 3-6 )cycloalkyl.
12 . The compound according to claim 11 wherein R 20 is Y 1 —R 20a , wherein Y 1 is 0 and R 20a is (C 1-8 )alkyl.
13 . The compound according to claim 10 wherein R 24 is H or (C 1-6 )alkyl.
14 . The compound according to claim 10 wherein R 25 is H.
15 . The compound according to claim 1 wherein X is O.
16 . The compound according to claim 1 wherein R 3 is selected from (C 2-8 )alkyl, (C 3-7 )cycloalkyl and (C 3-7 )cycloalkyl-(C 1-3 )alkyl-,
a) wherein said cycloalkyl and cycloalkyl-alkyl- may be mono-, di- or tri-substituted with (C 1-3 )alkyl; and b) wherein said alkyl, cycloalkyl and cycloalkyl-alkyl- may be mono- or di-substituted with substituents each independently selected from hydroxy and O—(C 1-4 )alkyl; and c) wherein each of said alkyl groups may be mono-, di- or tri-substituted with fluorine or mono-substituted with chlorine or bromine; and d) wherein in each of said cycloalkyl groups being 5-, 6- or 7-membered, one or two —CH 2 -groups not being directly linked to each other may be replaced by —O— such that the O-atom is linked to the group X via at least two C-atoms.
17 . The compound according to claim 16 wherein R 3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a group selected from:
18 . The compound according to claim 1 wherein linker D is a 5 carbon atom chain.
19 . The compound according to claim 1 wherein the dotted line “b” is a single bond or a double bond in the Z (cis) configuration.
20 . The compound according to claim 1 of formula (Ia):
wherein R 1 is hydroxy;
R 20 is H, OH, halogen, or Y 1 —R 20a wherein Y 1 is a bond, O, S, or NR 20b wherein:
R 20a is selected from the group consisting of: (C 1-8 )alkyl, (C 1-6 )alkyl-C≡N, (C 2-8 )alkenyl, (C 2-8 )alkynyl, all of said alkyl, alkenyl and alkynyl being optionally mono- or di-substituted with:
halogen, (C 1-6 )alkyl, —O—(C 1-6 )alkyl, (C 1-4 )alkyl-O—(C 1-6 )alkyl, —O—(C 3-6 )cycloalkyl, (C 1-4 )alkyl-O—(C 3-6 )cycloalkyl, amino, (C 1-4 )alkylamino, or di((C 1-4 )alkyl)amino; and
R 20b is H, (C 1-6 )alkyl or (C 3-6 )cycloalkyl;
and W is N; and the dotted line “a” is a double bond; or
R 20 is oxo, and W is NR 23 wherein R 23 is H, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl; and the dotted line “a” is a single bond;
R 21 is halogen, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, —O—(C 1-6 )alkyl, —O—(C 2-6 )alkenyl, —O—(C 2-6 )alkynyl, —S—(C 1-6 )alkyl, —S—(C 2-6 )alkenyl, and —S—(C 2-6 )alkynyl, wherein the sulfur is in any oxidized state;
R 22 is H, —OH, —O—(C 1-4 )alkyl, —NH 2 , —NH(C 1-4 )alkyl or —N((C 1-4 )alkyl) 2 ;
X is O or NH;
R 3 is (C 1-10 )alkyl, (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl-(C 1-4 )alkyl-,
a) wherein the cycloalkyl and cycloalkyl-alkyl- may be mono-, di- or tri-substituted with (C 1-3 )alkyl;
b) wherein the alkyl, cycloalkyl and cycloalkyl-alkyl- may be mono- or di-substituted with substituents selected from hydroxy and O—(C 1-6 )alkyl;
c) wherein all the alkyl groups may be mono-, di- or tri-substituted with halogen; and
d) wherein in the cycloalkyl groups, being 5-, 6- or 7-membered, one or two —CH 2 -groups not being directly linked to each other may be replaced by —O—;
D is a 3 to 8 atom saturated or unsaturated alkylene chain; and
the dotted line “b” is a single bond or a double bond;
or a pharmaceutically acceptable salt or ester thereof.
21 . The compound according to claim 1 wherein R 1 is hydroxy;
R 2 is a group of formula
wherein
R 20 is oxo, W is NR 23 wherein R 23 is Me, Et, —CH 2 CH═CH 2 or H and the dotted line “a” is a single bond; or
W is N, the dotted line “a” is a double bond; and R 20 is H, OH, halogen, or
Y 1 —R 20a wherein
Y 1 is a bond, O, S, or NR 20b ;
R 20a is selected from the group consisting of: (C 1-8 )alkyl, (C 2-8 )alkenyl, (C 2-8 )alkynyl and (C 3-7 )cycloalkyl, each of said alkyl, alkenyl, alkynyl and cycloalkyl being optionally substituted with one, two or three substituents, each independently selected from:
halogen, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, Het, —O—(C 1-6 )alkyl, —O—(C 3-6 )cycloalkyl, —NH 2 , —NH(C 1-4 )alkyl and —N((C 1-4 )alkyl) 2 ; wherein Het is defined as in claim 1 ; and
R 20b is H, (C 1-6 )alkyl or (C 3-6 )cycloalkyl; and
R 21 is selected from: fluorine, chlorine, bromine, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —SCH 3 , —SCH 2 CH 3 , —SCH 2 CH 2 CH 3 , —(SO)CH 3 , —(SO)CH 2 CH 3 , —(SO)CH 2 CH 2 CH 3 , —(SO 2 )CH 3 , —(SO 2 )CH 2 CH 3 , —(SO 2 )CH 2 CH 2 CH 3 ,
and —C≡CH; and
R 22 is selected from: H, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —NHCH 3 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 and —N(CH 3 )CH 2 CH 2 CH 3 ;
or R 2 is a group of formula
wherein
W is N; the dotted line “a” is a double bond; and R 20 is H, OH, halogen, or
Y 1 —R 20a wherein
Y 1 is a bond, O, S, or NR 20b ;
R 20a is selected from the group consisting of: (C 1-8 )alkyl, (C 2-8 )alkenyl, (C 2-8 )alkynyl and (C 3-7 )cycloalkyl, each of said alkyl, alkenyl, alkynyl and cycloalkyl being optionally substituted with one, two or three substituents, each independently selected from:
halogen, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, Het, —O—(C 1-6 )alkyl, —O—(C 3-6 )cycloalkyl, —NH 2 , —NH(C 1-4 )alkyl and —N((C 1-4 )alkyl) 2 ; wherein Het is defined as in claim 1 ; and
R 20b is H, (C 1-6 )alkyl or (C 3-6 )cycloalkyl; and
R 24 is H or (C 1-6 )alkyl; and
R 25 is H; and
X is O or NH; and
R 3 is selected from (C 2-8 )alkyl, (C 3-7 )cycloalkyl and (C 3-7 )cycloalkyl-(C 1-3 )alkyl-,
a) wherein said cycloalkyl and cycloalkyl-alkyl- may be mono-, di- or tri-substituted with (C 1-3 )alkyl; and
b) wherein said alkyl, cycloalkyl and cycloalkyl-alkyl- may be mono- or di-substituted with substituents each independently selected from hydroxy and O—(C 1-4 )alkyl; and
c) wherein each of said alkyl groups may be mono-, di- or tri-substituted with fluorine or mono-substituted with chlorine or bromine; and
d) wherein in each of said cycloalkyl groups being 5-, 6- or 7-membered, one or two —CH 2 -groups not being directly linked to each other may be replaced by —O— such that the O-atom is linked to the group X via at least two C-atoms; and
linker D is a 3 to 8 atom saturated or unsaturated alkylene chain; and
the dotted line “b” is a single bond or a double bond.
22 . The compound according to claim 1 wherein
R 1 is hydroxy; R 2 is a group of formula
wherein
R 20 is oxo, W is NR 23 wherein R 23 is Me, Et, —CH 2 CH═CH 2 or H and the dotted line “a” is a single bond; or
W is N, the dotted line “a” is a double bond, and R 20 is H, (C 1-6 )alkyl, OH, —O—(C 1-6 )alkyl, —S—(C 1-6 )alkyl, —(CH 2 ) 0-4 —CH═CH 2 , —(CH 2 ) 0-4 —C≡CH, —O—(CH 2 ) 0-4 —CH═CH 2 , —O—(CH 2 ) 0-4 —C≡CH, —O—(CH 2 ) 1-4 —OMe; —O—(CH 2 ) 1-4 —N(Me) 2 ; —O—(CH 2 ) 1-4 -Het; —S—(CH 2 ) 0-4 —CH═CH 2 , —S—(CH 2 ) 0-4 —C≡CH, —S—(CH 2 ) 1-4 —OMe; —S—(CH 2 ) 1-4 —N(Me) 2 , —S—(CH 2 ) 1-4 -Het; (C 3-6 )cycloalkyl, —O—(C 3-6 )cycloalkyl, O—(C 1-6 )alkyl-(C 3-6 )cycloalkyl, —S—(C 3-6 )cycloalkyl, or —S—(C 1-6 )alkyl-(C 3-6 )cycloalkyl; wherein Het is 5- or 6-membered monocyclic heteroaryl containing from one to three heteroatoms each independently selected from N, O and S;
each of said (C 1-6 )alkyl, —O—(C 1-6 )alkyl, —S—(C 1-6 )alkyl, —(CH 2 ) 0-4 —CH═CH 2 , —(CH 2 ) 0-4 —C≡CH, —O—(CH 2 ) 0-4 —CH═CH 2 , —O—(CH 2 ) 0-4 —C≡CH, —S—(CH 2 ) 0-4 —CH═CH 2 , —S—(CH 2 ) 0-4 —C≡CH, (C 3-6 )cycloalkyl, —O—(C 3-6 )cycloalkyl, and —S—(C 3-6 )cycloalkyl being optionally substituted with one, two or three substituents, each independently selected from (C 1-4 )alkyl, —O—(C 1-4 )alkyl, and halo;
or R 20 is NR 20a R 20b wherein R 20a is (C 1-4 )alkyl, and R 20 b is H, (C 1-4 )alkyl or (C 3-5 )cycloalkyl; and
R 21 is selected from: fluorine, chlorine, bromine, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —SCH 3 , —SCH 2 CH 3 , —SCH 2 CH 2 CH 3 , —(SO)CH 3 , —(SO)CH 2 CH 3 , —(SO)CH 2 CH 2 CH 3 , —(SO 2 )CH 3 , —(SO 2 )CH 2 CH 3 , —(SO 2 )CH 2 CH 2 CH 3 ,
and —C≡CH; and
R 22 is selected from H, —OCH 3 and —N(CH 3 ) 2 ;
or R 2 is a group of formula
wherein
W is N; the dotted line “a” is a double bond;
R 20 is Y 1 —R 20a , wherein Y 1 is O and R 20a is (C 1-8 )alkyl;
R 24 is H or (C 1-6 )alkyl; and
R 25 is H; and
X is O or NH; and
R 3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a group selected from:
and
linker D is a 3 to 8 atom saturated or unsaturated alkylene chain; and
the dotted line “b” is a single bond or a double bond.
23 . The compound according to claim 1 wherein
R 1 is hydroxy; R 2 is a group of formula
wherein
R 20 is oxo, W is NR 23 wherein R 23 is Me, Et, —CH 2 CH═CH 2 or H and the dotted line “a” is a single bond; or
W is N, the dotted line “a” is a double bond, and R 20 is H, methyl, ethyl, 1-methylethyl, —C≡CH, O-methyl, O-ethyl, O— propyl, O—CH(CH 3 ) 2 , O-cyclopentyl, O—CH 2 CH 2 CF 3 , —O—CH═CH 2 , —O—CH 2 —CH═CH 2 , —O—CH 2 —C≡CH, —O—CH 2 —C≡CCH 3 , —O—CH 2 CH 2 OMe, —O—CH 9 CH 9 N(Me) 2 , S-methyl, S-ethyl, S-propyl, S—CH(CH 3 ) 2 ,
and
R 21 is selected from fluorine, chlorine, bromine, —CH 3 , —OCH 3 , —SCH 3 , —SCH 2 CH 3 , (SO)CH 3 , (SO 2 )CH 3 , —(SO 2 )CH 2 CH 3 ,
and —C≡CH; and
R 22 is H or —OCH 3 ;
or R 2 is a group of formula
wherein
W is N; the dotted line “a” is a double bond;
R 20 is —O—CH 2 CH 3 ;
R 24 is H or CH 3 ; and
R 25 is H; and
X is O; and
R 3 is selected from cyclopentyl,
and
linker D is a 5 carbon atom chain; and
the dotted line “b” is a single bond or a double bond in the Z (cis) configuration.
24 . The compound according to claim 1 of the formula:
wherein R 1 , R 20 , R 21 and R 22 are defined as in the table below:
Cpd
R 22
R 21
R 20
R 1
101
OMe
Br
OEt
OH
102
OMe
Me
OEt
OH
103
H
Br
OEt
OH
104
H
Cl
OEt
OH
105
H
Br
OMe
OH
106
H
Cl
OMe
OH
107
H
F
OMe
OH
108
OMe
Me
OMe
OH
109
OMe
Me
H
OH
110
H
Cl
H
OH
111
H
Br
H
OH
112
H
Cl
Me
OH
113
H
F
OEt
OH
114
H
Me
OEt
OH
115
H
Br
Me
OH
116
H
Cl
Et
OH
117
H
Cl
—CH(CH 3 ) 2
OH
118
H
SMe
OEt
OH
119
H
Me
O—CH(CH 3 ) 2
OH
120
OMe
Me
O—CH(CH 3 ) 2
OH
121
H
Cl
O—CH(CH 3 ) 2
OH
122
H
Br
O—CH(CH 3 ) 2
OH
123
H
F
O—CH(CH 3 ) 2
OH
124
H
SO 2 ME
OEt
OH
125
H
Cl
SMe
OH
126
OMe
Br
OMe
OH
127
H
SMe
H
OH
128
H
SOMe
H
OH
129
H
SO 2 Me
H
OH
130
H
Cl
SEt
OH
131
H
Cl
OCH 2 CH(CH 3 ) 2
OH
132
H
Cl
OCH 2 CH 2 CH 3
OH
133
H
OMe
OEt
OH
134
H
—C≡CH
OEt
OH
137
H
Cl
SCH 2 CH 2 CH 3
OH
138
H
Cl
SCH(CH 3 ) 2
OH
139
H
Cl
OCH 2 C(CH 3 ) 3
OH
140
H
Cl
OCH 2 CH 2 CF 3
OH
141
H
Cl
OH
142
H
Cl
OH
143
H
Cl
OH
144
H
Cl
OH
145
H
Cl
—C≡CH
OH
146
OMe
Br
—OCH 2 C≡CH
OH
147
OMe
Br
—OCH 2 CH═CH 2
OH
148
H
Cl
OH
149
OMe
CH 3
—OCH 2 CH═CH 2
OH
150
OMe
CH 3
—OCH 2 C≡CH
OH
151
OMe
Cl
—OEt
OH
152
OMe
Cl
—O—CH(CH 3 ) 2
OH
153
OMe
Cl
—OMe
OH
154
OMe
Cl
—OCH 2 CH≡CH 2
OH
155
OMe
Cl
—OCH 2 C≡CH
OH
156
OMe
Br
—OCH 2 C≡CCH 3
OH
157
H
Cl
OH
158
H
Cl
OH
159
H
Cl
—OCH═CH 2
OH
160
OMe
Br
—O—CH(CH 3 ) 2
OH
161
H
—SEt
—OEt
OH
162
H
—SO 2 Et
—OEt
OH
163
H
—OEt
OH
25 . The compound according to claim 1 of the formula:
wherein R 1 , R 20 , R 21 , R 22 and R 3 are defined as in the table below:
Cpd
R 3
R 22
R 21
R 20
R 1
201
Et
H
F
OEt
OH
202
H
F
OEt
OH
203
—CH 2 CH 2 CH 3
H
F
OEt
OH
204
H
F
OEt
OH
205
H
F
OEt
OH
206
H
Cl
OEt
OH
207
—CH 2 CH 2 CH 3
H
Cl
OEt
OH
208
H
Cl
OEt
OH
209
H
Cl
OEt
OH
210
Et
H
Me
OEt
OH
211
H
Me
OEt
OH
212
—CH 2 CH 2 CH 3
H
Me
OEt
OH
213
H
Me
OEt
OH
214
H
Me
OEt
OH
215
H
Cl
OEt
OH
216
H
Me
OEt
OH
26 . The compound according to claim 1 of the formula:
wherein R 1 , R 20 , R 21 and R 22 are defined as in the table below:
Cpd
R 22
R 21
R 20
R 1
301
OMe
Br
OEt
OH
302
H
Br
OEt
OH
303
H
Cl
OEt
OH
304
H
F
OEt
OH
305
OMe
Me
OEt
OH
306
H
Me
OEt
OH
307
H
F
OMe
OH
308
OMe
Me
OMe
OH
309
H
Cl
SEt
OH
27 . The compound according to claim 1 of the formula:
wherein R 21 , R 22 and R 23 are defined as in the table below:
Cpd
R 22
R 21
R 23
401
OMe
Br
H
402
OMe
Br
Me
403
OMe
Br
Et
404
OMe
Cl
Me
405
OMe
Cl
—CH 2 CH═CH 2
406
OMe
CH 3
H
28 . The compound according to claim 1 of the formula:
wherein R 24 is defined as in the table below:
Cpd
R 24
501
H
502
CH 3
29 . A pharmaceutical composition comprising an anti-hepatitis C virally effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier medium or auxiliary agent.
30 . The pharmaceutical composition according to claim 29 further comprising a therapeutically effective amount of at least one other antiviral agent.
31 . The pharmaceutical composition according to claim 30 , wherein said antiviral agent is ribavirin.
32 . The pharmaceutical composition according to claim 30 , wherein said antiviral agent is selected from an other anti-HCV agent, HIV inhibitor, HAV inhibitor and HBV inhibitor.
33 . The pharmaceutical composition according to claim 32 , wherein said other anti-HCV agent is selected from the group consisting of immunomodulatory agents, other inhibitors of HCV NS3 protease, inhibitors of HCV polymerase and inhibitors of another target in the HCV life cycle.
34 . The pharmaceutical composition according to claim 33 , wherein said immunomodulatory agent is selected from α-interferon, γ-interferon and pegylated α-interferon.
35 . The pharmaceutical composition according to claim 33 , wherein said inhibitor of another target in the HCV life cycle is selected from inhibitors of: helicase, NS2/3 protease and internal ribosome entry site (IRES).
36 . A method for the treatment or prevention of a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof.
37 . A method for the treatment or prevention of a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of a combination of a compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof, and at least one other antiviral agent.
38 . The method according to claim 37 , wherein said antiviral agent is ribavirin.
39 . The method according to claim 37 wherein said other antiviral agent is selected from another anti-HCV agent, HIV inhibitor, HAV inhibitor and HBV inhibitor.
40 . The method according to claim 39 , wherein said other anti-HCV agent is selected from immunomodulatory agents, other inhibitors of HCV NS3 protease, inhibitors of HCV polymerase and inhibitors of another target in the HCV life cycle.
41 . The method according to claim 40 , wherein said immunomodulatory agent is selected from α-interferon, γ-interferon and pegylated α-interferon.
42 . The method according to claim 40 , wherein said inhibitor of another target in the HCV life cycle is selected from inhibitors of: helicase, NS2/3 protease and internal ribosome entry site (IRES).
43 . A method of inhibiting the replication of hepatitis C virus by exposing the virus to a hepatitis C viral NS3 protease inhibiting amount of a compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof.
44 . An article of manufacture comprising a composition effective to treat an HCV infection or to inhibit the NS3 protease of HCV and packaging material comprising a label which indicates that the composition can be used to treat infection by the hepatitis C virus, wherein said composition comprises a compound according to claim 1 or a pharmaceutically acceptable salt or ester thereof.Cited by (0)
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