US2012269769A1PendingUtilityA1
Hepatitis C Inhibitor Compounds
Est. expiryMay 21, 2023(expired)· nominal 20-yr term from priority
Inventors:Montse Llinas-BrunetMurray D. BaileyPunit BhardwajJosee BordeleauPasquale ForgioneElise GhiroVida GorysNathalie GoudreauSylvie GouletTeddy HalmosJean Rancourt
A61P 43/00A61P 31/14A61P 31/00A61P 31/12A61P 1/16C07K 5/0827A61K 38/06A61K 38/212C07K 5/0808A61K 31/4709C07D 417/14Y02A50/30
55
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Claims
Abstract
Compounds of formula (I): wherein B, X, R 3 , L 0 , L 1 , L 2 , R 2 , R 1 and R C are defined herein. The compounds are useful as inhibitors of HCV NS3 protease for the treatment of hepatitis C viral infection.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (I) or a racemate, diastereoisomer, or optical isomer thereof:
wherein
B is (C 1-10 )alkyl, (C 3-7 )cycloalkyl, or (C 1-4 )alkyl-(C 3-7 )cycloalkyl,
a) wherein said alkyl, cycloalkyl, and alkyl-cycloalkyl may be mono-, di- or tri-substituted with (C 1-3 )alkyl; and
b) wherein said alkyl, cycloalkyl, and alkyl-cycloalkyl may be mono- or di-substituted with substituents 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 halogen; and
d) wherein each of said cycloalkyl groups being 4-, 5-, 6- or 7-membered having optionally one (for the 4-, 5, 6, or 7-membered) or two (for the 5-, 6- or 7-membered)-CH 2 -groups not directly linked to each other replaced by —O— such that the O-atom is linked to the group X via at least two C-atoms;
X is O or NH;
R 3 is (C 2-8 )alkyl, (C 3-7 )cycloalkyl or (C 1-3 )alkyl-(C 3-7 )cycloalkyl, wherein said alkyl, cycloalkyl, and alkyl-cycloalkyl groups may be mono-, di- or tri-substituted with (C 1-4 ) alkyl;
L 0 is H;
L 1 , L 2 are each independently halogen, cyano, (C 1-4 )alkyl, —O—(C 1-4 )alkyl, —S—(C 1-4 )alkyl, —SO—(C 1-4 )alkyl, or —SO 2 —(C 1-4 )alkyl, wherein each of said alkyl groups is optionally substituted with from one to three halogen atoms; and
either L 1 or L 2 (but not both at the same time) may also be H;
R 2 is R 20 , —NR 22 COR 20 , —NR 22 COOR 20 —NR 22 R 21 or —NR 22 CONR 21 R 23 , wherein
R 20 is selected from (C 1-8 )alkyl, (C 3-7 )cycloalkyl and (C 1-4 )alkyl-(C 3-7 )cycloalkyl, wherein said cycloalkyl and alkyl-cycloalkyl may be mono-, di- or tri-substituted with (C 1-3 )alkyl;
R 21 is H or R 20 as defined above,
R 22 and R 23 are independently selected from H and methyl,
R 1 is ethyl or vinyl;
R C is hydroxy or NHSO 2 R S wherein R S is (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, phenyl, naphthyl, pyridinyl, (C 1-4 )alkyl-phenyl, (C 1-4 )alkyl-naphthyl or (C 1-4 )alkyl-pyridinyl; each of which optionally being mono-, di- or tri-substituted with substituents selected from halogen, hydroxy, cyano, (C 1-4 )alkyl, O—(C 1-6 )alkyl, —CO—NH 2 , —CO—NH(C 1-4 )alkyl, —CO—N((C 1-4 )alkyl) 2 , —NH 2 , —NH(C 1-4 )alkyl and —N((C 1-4 ) alkyl) 2 , wherein (C 1-4 )alkyl and O—(C 1-6 )alkyl are optionally substituted with one to three halogen atoms; and each of which optionally being monosubstituted with nitro;
or R S is —N(R N2 )R N1 ), wherein R N1 and R N2 are independently selected from H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl and (C 1-6 )alkyl-aryl; wherein said (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl and (C 1-6 )alkyl-aryl are optionally substituted with one or more substituents independently selected from halogen, (C 1-6 )alkyl, hydroxy, cyano, O—(C 1-6 )alkyl, —NH 2 , —NH(C 1-4 )alkyl, —N((C 1-4 )alkyl) 2 , —CO—NH 2 , —CO—NH(C 1-4 )alkyl, —CO—N((C 1-4 )alkyl) 2 , —COOH, and —COO(C 1-6 )alkyl; or
R N2 and R N1 are linked, together with the nitrogen to which they are bonded, to form a 3- to 7-membered monocyclic saturated or unsaturated heterocycle or a 9- or 10-membered bicyclic saturated or unsaturated heterocycle, each of which optionally containing from one to three further heteroatoms independently selected from N, S and O, and each of which being optionally substituted with one or more substituents independently selected from halogen, (C 1-6 )alkyl, hydroxy, cyano, O—(C 1-6 )alkyl, —NH 2 , —NH(C 1-4 )alkyl, —N((C 1-4 )alkyl) 2 , —CO—NH 2 , —CO—NH(C 1-4 )alkyl, —CO—N((C 1-4 )alkyl) 2 , —COOH, and —COO(C 1-6 )alkyl;
or a pharmaceutically acceptable salt or ester thereof.
2 . The compound according to claim 1 , wherein
B is (C 1-10 )alkyl, (C 3-7 )cycloalkyl, or (C 1-4 )alkyl-(C 3-7 )cycloalkyl,
a) wherein said cycloalkyl, and alkyl-cycloalkyl may be mono-, di- or tri-substituted with (C 1-3 )alkyl; and
b) wherein said alkyl, cycloalkyl, and alkyl-cycloalkyl may be mono- or di-substituted with substituents selected from hydroxy and O—(C 1-4 )alkyl; and
c) wherein all said alkyl-groups may be mono-, di- or tri-substituted with halogen; and
d) wherein all said cycloalkyl-groups being 4-, 5-, 6- or 7-membered having optionally one (for the 4-, 5, 6, or 7-membered) or two (for the 5-, 6- or 7-membered)-CH 2 -groups not directly linked to each other replaced by —O— such that the O-atom is linked to the group X via at least two C-atoms;
X is O or NH; R 3 is (C 2-8 )alkyl, (C 3-7 )cycloalkyl or (C 1-3 )alkyl-(C 3-7 )cycloalkyl, wherein said cycloalkyl groups may be mono-, di- or tri-substituted with (C 1-4 )alkyl; L 0 is H; L 1 , L 2 are each independently halogen, (C 1-4 )alkyl, —O—(C 1-4 )alkyl or —S—(C 1-4 )alkyl (in any oxidized state such as SO or SO 2 ); and
either L 1 or L 2 (but not both at the same time) may also be H;
R 2 is R 20 , —NR 22 COR 20 , —NR 22 COOR 20 —NR 22 R 21 and —NR 22 CONR 21 R 23 , wherein
R 20 is selected from (C 1-8 )alkyl, (C 3-7 )cycloalkyl and (C 1-4 )alkyl-(C 3-7 )cycloalkyl, wherein said cycloalkyl and alkyl-cycloalkyl may be mono-, di- or tri-substituted with (C 1-3 )alkyl;
R 21 is H or has one of the meanings of R 20 as defined above,
R 22 and R 23 are independently selected from H and methyl,
R 1 is ethyl or vinyl; R C is hydroxy or NHSO 2 R S wherein R S is (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, phenyl, naphthyl, pyridinyl, (C 1-4 )alkyl-phenyl, (C 1-4 )alkyl-naphthyl or (C 1-4 )alkyl-pyridinyl; all of which optionally being mono-, di- or tri-substituted with substituents selected from halogen, hydroxy, cyano, (C 1-4 )alkyl, O—(C 1-6 )alkyl, —CO—NH 2 , —CO—NH(C 1-4 )alkyl, —CO—N((C 1-4 )alkyl) 2 , —NH 2 , —NH(C 1-4 )alkyl and —N((C 1-4 )alkyl) 2 ; and all of which optionally being monosubstituted with nitro;
or R S can be further selected from: —NH(C 1-8 )alkyl, N((C 1-8 )alkyl) 2 ,
or a pharmaceutically acceptable salt or ester thereof.
3 . The compound according to claim 2 , or a pharmaceutically acceptable salt or ester thereof, wherein B is selected from (C 2-8 )alkyl, (C 3-7 )cycloalkyl and (C 1-3 )alkyl-(C 3-7 )cycloalkyl,
a) wherein said alkyl, cycloalkyl, and alkyl-cycloalkyl may be mono-, di- or tri-substituted with (C 1-3 )alkyl; and b) wherein said alkyl, cycloalkyl, and alkyl-cycloalkyl may be mono- or di-substituted with substituents 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.
4 . The compound according to claim 3 , or a pharmaceutically acceptable salt or ester thereof, wherein B is selected from ethyl, n-propyl, tert-butyl, 2-methylpropyl, 1,2-dimethylpropyl, 1,2,2-trimethylpropyl, 2-fluoroethyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopentyl and 1-methylcyclohexyl, and a group selected from:
5 . The compound according to claim 4 , or a pharmaceutically acceptable salt or ester thereof, wherein B is selected from ethyl, n-propyl, tert-butyl, cyclopentyl, 1-methylcyclopentyl, 2-fluoroethyl or 3-fluoropropyl.
6 . The compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof, wherein X is O.
7 . The compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof, wherein X is NH.
8 . The compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof, wherein R 3 is (C 2-6 )alkyl, (C 3-7 )cycloalkyl or (C 1-3 )alkyl-(C 3-7 )cycloalkyl, each of which being optionally substituted with 1 to 3 substituents selected from (C 1-4 ) alkyl.
9 . The compound according to claim 8 , or a pharmaceutically acceptable salt or ester thereof, wherein R 3 is selected from 1,1-dimethylethyl, cyclopentyl, cyclohexyl and 1-methylcyclohexyl.
10 . The compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof, wherein L 1 and L 2 are each independently selected from: halogen, —CH 3 , —C 2 H 5 , —OCH 3 , —OC 2 H 5 , —OC 3 H 7 , —OCH(CH 3 ) 2 , CF 3 , —SMe, —SOMe, and SO 2 Me whereby either L 1 or L 2 may be H.
11 . The compound according to claim 10 , or a pharmaceutically acceptable salt or ester thereof, wherein either one of L 1 and L 2 is —CH 3 , —F, —Cl, —Br, —OMe, —SMe, or —SO 2 Me and the other of L 1 and L 2 is H.
12 . The compound according to claim 11 , or a pharmaceutically acceptable salt or ester thereof, wherein L 1 is CH 3 , —F, —Cl, —Br, —OMe, —SMe, or —SO 2 Me and L 2 is H.
13 . The compound according to claim 12 wherein L 1 is CH 3 , —Cl or —Br and L 2 is H.
14 . The compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof, wherein R 2 is R 20 , —NHCOR 20 , —NHCOOR 20 , —NHR 21 or —NHCONR 21 R 23 , wherein
R 20 is selected from (C 1-8 )alkyl, (C 3-7 )cycloalkyl, and (C 1-3 )alkyl-(C 3-7 )cycloalkyl, wherein each of said cycloalkyl and alkyl-cycloalkyl groups may be mono-, di- or tri-substituted with (C 1-3 )alkyl; and
R 21 is H or R 20 as defined above; and
R 23 is H or methyl.
15 . The compound according to claim 14 , or a pharmaceutically acceptable salt or ester thereof, wherein R 2 is —NHCOR 20 , —NHCOOR 20 , or —NHR 21 .
16 . The compound according to claim 15 , or a pharmaceutically acceptable salt or ester thereof, wherein R 20 and R 21 are independently selected from: methyl, ethyl, n-propyl, i-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, 2,2-dim ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1,2,2-trimethylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, each of said cycloalkyl or alkyl-cycloalkyl groups optionally being mono- or di-substituted with methyl or ethyl.
17 . The compound according to claim 16 , or a pharmaceutically acceptable salt or ester thereof, wherein R 20 and R 21 are independently selected from methyl, ethyl, n-propyl, i-propyl, 2,2-dimethylpropyl, cyclopentyl and cyclopentylmethyl.
18 . The compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof, wherein R 1 is vinyl.
19 . The compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof, wherein R C is hydroxy, NHSO 2 -methyl, NHSO 2 -ethyl, NHSO 2 -(1-methyl)ethyl, NHSO 2 -propyl, NHSO 2 -cyclopropyl, NHSO 2 —CH 2 -cyclopropyl, NHSO 2 -cyclobutyl, NHSO 2 -cyclopentyl or NHSO 2 -phenyl.
20 . The compound according to claim 19 , or a pharmaceutically acceptable salt or ester thereof, wherein R C is hydroxy.
21 . The compound according to claim 19 , or a pharmaceutically acceptable salt or ester thereof, wherein R C is NHSO 2 -cyclopropyl.
22 . The compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof, wherein R C is NHSO 2 N(R N2 )R N1 ), wherein R N1 and R N2 are independently selected from H, (C 1-4 )alkyl, (C 3-7 )cycloalkyl, (C 1-3 )alkyl-(C 3-7 )cycloalkyl, phenyl, and (C 1-3 )alkyl-phenyl; wherein said (C 1-4 )alkyl, (C 3-7 )cycloalkyl, (C 1-3 )alkyl-(C 3-7 )cycloalkyl, phenyl and (C 1-3 )alkyl-phenyl are optionally substituted with one, two or three substituents independently selected from halogen, (C 1-6 ) alkyl, hydroxy, cyano, O—(C 1-6 )alkyl, —NH 2 , —NH(C 1-4 )alkyl, —N((C 1-4 )alkyl) 2 , NH 2 , —CO—NH(C 1-4 )alkyl, —CO—N((C 1-4 )alkyl) 2 , —COOH, and —COO(C 1-6 )alkyl; or
R N2 and R N1 are linked, together with the nitrogen to which they are bonded, to form a 5 or 6-membered monocyclic heterocycle which may be saturated or unsaturated, optionally containing from one to three further heteroatoms independently selected from N, S and O, and optionally substituted with one, two or three substituents independently selected from halogen, (C 1-6 )alkyl, hydroxy, cyano, O—(C 1-6 )alkyl, —NH 2 , —NH(C 1-4 )alkyl, —N((C 1-4 )alkyl) 2 , —CO—NH 2 , —CO—NH(C 1-4 )alkyl, —CO—N((C 1-4 )alkyl) 2 , —COOH, and —COO(C 1-6 )alkyl.
23 . The compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof, wherein
B is (C 2-8 )alkyl, (C 3-7 )cycloalkyl or (C 1-3 )alkyl-(C 3-7 )cycloalkyl,
a) wherein said alkyl, cycloalkyl, and alkyl-cycloalkyl may be mono-, di- or tri-substituted with (C 1-3 )alkyl; and
b) wherein said alkyl, cycloalkyl, and alkyl-cycloalkyl may be mono- or di-substituted with substituents 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;
X is O or NH; R 3 is (C 2-6 )alkyl or (C 3-7 )cycloalkyl, both of which being optionally substituted with 1 to 3 substituents selected from (C 1-4 )alkyl; L 0 is H; L 1 and L 2 are each independently selected from: halogen, —CH 3 , —C 2 H 5 , —OCH 3 , —OC 2 H 5 , —OC 3 H 7 , —OCH(CH 3 ) 2 , CF 3 , —SMe, —SOMe, and SO 2 Me, whereby either L 1 or L 2 may be H; R 2 is R 20 , —NHCOR 20 , —NHCOOR 20 , —NHR 21 and —NHCONR 21 R 23 ,
wherein
R 20 is selected from (C 1-8 )alkyl, (C 3-7 )cycloalkyl, (C 1-3 )alkyl-(C 3-7 )cycloalkyl, wherein said cycloalkyl and alkyl-cycloalkyl may be mono-, di- or tri-substituted with (C 1-3 )alkyl; and
R 21 is H or R 20 as defined above; and
R 23 is H or methyl;
R 1 is ethyl or vinyl; and R C is hydroxy, NHSO 2 -methyl, NHSO 2 -ethyl, NHSO 2 -(1-methyl)ethyl, NHSO 2 -propyl, NHSO 2 -cyclopropyl, NHSO 2 —CH 2 -cyclopropyl, NHSO 2 -cyclobutyl, NHSO 2 -cyclopentyl or NHSO 2 -phenyl.
24 . The compound according to claim 23 , or a pharmaceutically acceptable salt or ester thereof, wherein
B is selected from: ethyl, n-propyl, tert-butyl, 2-methylpropyl, 1,2-dimethylpropyl, 1,2,2-trimethylpropyl, 2-fluoroethyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopentyl and 1-methylcyclohexyl, and a group selected from:
R 3 is selected from 1,1-dimethylethyl, cyclopentyl, cyclohexyl and 1-methylcyclohexyl; L 1 is CH 3 , —F, —Cl, —Br, —OMe, —SMe, or —SO 2 Me; L 2 is H;
R 2 is —NHCOR 20 , —NHCOOR 20 or —NHR 21 , wherein R 20 and R 21 are independently selected from methyl, ethyl, n-propyl, i-propyl, 2,2-dimethylpropyl, cyclopentyl and cyclopentylmethyl;
R 1 is vinyl; and R C is hydroxy or NHSO 2 -cyclopropyl.
25 . The compound according to claim 24 , or a pharmaceutically acceptable salt or ester thereof, wherein B is selected from ethyl, n-propyl, tert-butyl, cyclopentyl, 1-methylcyclopentyl, 2-fluoroethyl and 3-fluoropropyl; R 3 is selected from 1,1-dimethylethyl and cyclohexyl; L 1 is —CH 3 , —Cl, or —Br; L 2 is H; and R C is hydroxy.
26 . The compound according to claim 1 of the formula
wherein B, L 0 , L 1 and R 2 are defined as in the table below
Cpd.
B
L 0
L 1
R 2
1059
H
Br
1060
H
Br
1061
H
Br
1062
H
Br
1082
H
Cl
1083
H
Cl
1084
H
Cl
1085
H
Cl
1086
H
Cl
1087
H
Cl
1088
H
Cl
1089
H
Cl
1098
H
Br
1157
H
—SMe
1158
H
—SMe
1159
H
—SMe
1160
H
—SMe
1161
H
—SMe
1162
H
—SMe
1163
H
—SMe
1164
H
—CF 3
1165
H
—CF 3
1166
H
—CF 3
1171
H
—SO 2 Me
1172
H
—SO 2 Me
1173
H
Me—
1174
H
Me—
1175
H
Me—
1176
H
Me—
1177
H
Me—
1178
H
Me—
1179
H
—SO 2 Me
1180
H
—SO 2 Me
1181
H
—OMe
or a pharmaceutically acceptable salt or ester thereof.
27 . The compound according to claim 1 of the formula
wherein B, L 0 , L 1 , L 2 and R 2 are defined as in the table below
Cpd.
#
B
L 2
L 0
L 1
R 2
6001
MeO—
H
Me
6002
MeO—
H
Me
6003
MeO—
H
Me
6004
MeO—
H
Me
6005
Me
H
Br
6006
Me
H
Br
6007
Me
H
Br
6008
Me
H
Br
6009
Me
H
Br
6010
Me
H
Br
6011
Me
H
Me
6012
Me
H
Me
6013
Me
H
Me
6014
Me
H
Me
6017
Br
H
Br
6018
Br
H
Br
6019
Br
H
Cl
6020
Br
H
Cl
or a pharmaceutically acceptable salt or ester thereof.
28 . A pharmaceutical composition comprising an anti-hepatitis C virally effective amount of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt or ester thereof, in admixture with a pharmaceutically acceptable carrier medium or auxiliary agent.
29 . The pharmaceutical composition according to claim 28 further comprising a therapeutically effective amount of at least one other antiviral agent.
30 . The pharmaceutical composition according to claim 29 wherein said antiviral agent is ribavirin (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide).
31 . The pharmaceutical composition according to claim 29 , wherein said antiviral agent is selected from α-interferon and pegylated α-interferon.
32 . A method for the treatment of a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of a compound of formula I according to claim 1 , or a pharmaceutically acceptable salt or ester thereof.
33 . A method for the treatment of a hepatitis C viral infection in a mammal comprising administering thereto an anti-hepatitis C virally effective amount of a compound of formula I according to claim 1 , or a pharmaceutically acceptable salt or ester thereof in combination with at least one other antiviral agent.
34 . The method according to claim 33 , wherein said antiviral agent is ribavirin (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide).
35 . The method according to claim 33 , wherein said antiviral agent is selected from α-interferon and pegylated α-interferon.
36 . The method according to claim 33 , wherein said antiviral agent is selected from inhibitors of: helicase, NS2/3 protease and internal ribosome entry site (IRES).
37 . An article of manufacture comprising packaging material contained within which is a composition effective to treat an HCV infection and the packaging material comprises a label which indicates that the composition can be used to treat infection by the hepatitis C virus, and wherein said composition comprises a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt or ester thereof, in admixture with a pharmaceutically acceptable carrier medium or auxiliary agent.Cited by (0)
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