Hepatitis C inhibitor tri-peptides
First Claim
1. A racemate, diastereoisomer or optical isomer of a compound of formula (I):
-
whereinB is H, a C6 or C10 aryl, C7-16 aralkyl;
Het or (lower alkyl)-Het, all of which optionally substituted with C1-6 alkyl;
C1-6 alkoxy;
C1-6 alkanoyl;
hydroxy;
hydroxyalkyl;
halo;
haloalkyl;
nitro;
cyano;
cyanoalkyl;
amino optionally substituted with C1-6 alkyl;
amido;
or (lower alkyl)amide;
or B is an acyl derivative of formula R4—
C(O)—
;
a carboxyl derivative formula R4—
O—
C(O)—
;
an amide derivative of formula R4—
N(R5)—
C(O)—
;
a thioamide derivative of formula R4—
N(R5)—
C(S)—
;
or a sulfonyl derivative of formula R4—
SO2 wherein R4 is (i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amino optionally mono- or di-substituted with C1-6 alkyl, amido, or (lower alkyl) amide;
(ii) C3-7 cycloalkyl, C3-7 cycloalkoxy, or C4-10 alkylcycloalkyl, all optionally substituted with hydroxy, carboxyl, (C1-6 alkoxy)carbonyl, amino optionally mono- or di-substituted with C1-6 alkyl, amido, or (lower alkyl) amide;
(iii) amino optionally mono- or di-substituted with C1-6 alkyl;
amido;
or (lower alkyl)amide;
(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl;
or (v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl) amide, or amino optionally mono- or di-substituted with C1-6 alkyl;
R5 is H or C1-6 alkyl;
with the proviso that when B is a carboxyl derivative, an amide derivative or a thioamide derivative, R4 is not a cycloalkoxy;
Y is H or C1-6 alkyl;
R3 is C1-8 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C1-6 alkoxy, C1-6 thioalkyl, amido, (lower alkyl)amido, C6 or C10 aryl, or C7-16 aralkyl;
R2 is CH2—
R20, NH—
R20, O—
R20 or S—
R20, wherein R20 is a saturated or unsaturated C3-7 cycloalkyl or C4-10 (alkylcycloalkyl), all of which being optionally mono-, di- or tri-substituted with R21, or R20 is a C6 or C10 aryl or C7-14 aralkyl, all optionally mono-, di- or tri-substituted with R21, or R20 is Het or (lower alkyl)-Het, both optionally mono-, di- or tri-substituted with R21, wherein each R21 is independently C1-6 alkyl;
C1-6 alkoxy;
lower thioalkyl;
sulfonyl;
NO2;
OH;
SH;
halo;
haloalkyl;
amino optionally mono- or di-substituted with C1-6 alkyl, C6 or C10 aryl, C7-14 aralkyl, Het or (lower alkyl)-Het;
amido optionally mono-substituted with C1-6 alkyl, C6 or C10 aryl, C7-14 aralkyl, Het or (lower alkyl)-Het;
carboxyl;
carboxy(lower alkyl);
C6 or C10 aryl, C7-14 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted with R22;
wherein R22 is C1-6 alkyl;
C3-7 cycloalkyl;
C1-6 alkoxy;
amino optionally mono- or di-substituted with C1-6 alkyl;
sulfonyl;
(lower alkyl)sulfonyl;
NO2;
OH;
SH;
halo;
haloalkyl;
carboxyl;
amide;
(lower alkyl)amide;
or Het optionally substituted with C1-6 alkyl;
R1 is H;
C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, or C2-6 alkynyl, all optionally substituted with halogen;
or a pharmaceutically acceptable salt or ester thereof;
wherein “
Het”
is defined as a five-, six-, or seven-membered saturated or unsaturated, aromatic or non-aromatic, heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur, wherein said heterocycle is optionally fused to a benzene ring.
0 Assignments
0 Petitions
Accused Products
Abstract
Racemates, diastereoisomers and optical isomers of a compound of formula (I):
wherein
B is H, a C6 or C10 aryl, C7-16 aralkyl; Het or (lower alkyl)-Het, all of which optionally substituted with C1-6 alkyl; C1-6 alkoxy; C1-6 alkanoyl; hydroxy; hydroxyalkyl; halo; haloalkyl; nitro; cyano; cyanoalkyl; amino optionally substituted with C1-6 alkyl; amido; or (lower alkyl)amide; or
B is an acyl derivative of formula R4—C(O)—; a carboxyl of formula R4—O—C(O)—; an amide of formula R4—N(R5)—C(O)—; a thioamide of formula R4—N(R5)—C(S)—; or a sulfonyl of formula R4—SO2; R5 is H or C1-6 alkyl; and
Y is H or C1-6 alkyl;
R3 is C1-8 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C1-6 alkoxy, C1-6 thioalkyl, amido, (lower alkyl)amido, C6 or C10 aryl, or C7-16 aralkyl;
R2 is CH2—R20, NH—R20, O—R20 or S—R20, wherein R20 is a saturated or unsaturated C3-7 cycloalkyl or C4-10 (alkylcycloalkyl), all of which being optionally mono-, di- or tri-substituted with R21,
or R20 is a C6 or C10 aryl or C7-14 aralkyl optionally substituted, or R20 is Het or (lower alkyl)-Het, both optionally substituted, Het or (lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C6 or C10 aryl, C7-14 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted; and
R1 is H; C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, or C2-6 alkynyl, all optionally substituted with halogen; or a pharmaceutically acceptable salt or ester thereof.
-
Citations
96 Claims
-
1. A racemate, diastereoisomer or optical isomer of a compound of formula (I):
-
wherein B is H, a C6 or C10 aryl, C7-16 aralkyl;
Het or (lower alkyl)-Het, all of which optionally substituted with C1-6 alkyl;
C1-6 alkoxy;
C1-6 alkanoyl;
hydroxy;
hydroxyalkyl;
halo;
haloalkyl;
nitro;
cyano;
cyanoalkyl;
amino optionally substituted with C1-6 alkyl;
amido;
or (lower alkyl)amide;
or B is an acyl derivative of formula R4—
C(O)—
;
a carboxyl derivative formula R4—
O—
C(O)—
;
an amide derivative of formula R4—
N(R5)—
C(O)—
;
a thioamide derivative of formula R4—
N(R5)—
C(S)—
;
or a sulfonyl derivative of formula R4—
SO2 whereinR4 is (i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amino optionally mono- or di-substituted with C1-6 alkyl, amido, or (lower alkyl) amide;
(ii) C3-7 cycloalkyl, C3-7 cycloalkoxy, or C4-10 alkylcycloalkyl, all optionally substituted with hydroxy, carboxyl, (C1-6 alkoxy)carbonyl, amino optionally mono- or di-substituted with C1-6 alkyl, amido, or (lower alkyl) amide;
(iii) amino optionally mono- or di-substituted with C1-6 alkyl;
amido;
or (lower alkyl)amide;
(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl;
or(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl) amide, or amino optionally mono- or di-substituted with C1-6 alkyl;
R5 is H or C1-6 alkyl;
with the proviso that when B is a carboxyl derivative, an amide derivative or a thioamide derivative, R4 is not a cycloalkoxy;
Y is H or C1-6 alkyl;
R3 is C1-8 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C1-6 alkoxy, C1-6 thioalkyl, amido, (lower alkyl)amido, C6 or C10 aryl, or C7-16 aralkyl;
R2 is CH2—
R20, NH—
R20, O—
R20 or S—
R20, wherein R20 is a saturated or unsaturated C3-7 cycloalkyl or C4-10 (alkylcycloalkyl), all of which being optionally mono-, di- or tri-substituted with R21,or R20 is a C6 or C10 aryl or C7-14 aralkyl, all optionally mono-, di- or tri-substituted with R21, or R20 is Het or (lower alkyl)-Het, both optionally mono-, di- or tri-substituted with R21, wherein each R21 is independently C1-6 alkyl;
C1-6 alkoxy;
lower thioalkyl;
sulfonyl;
NO2;
OH;
SH;
halo;
haloalkyl;
amino optionally mono- or di-substituted with C1-6 alkyl, C6 or C10 aryl, C7-14 aralkyl, Het or (lower alkyl)-Het;
amido optionally mono-substituted with C1-6 alkyl, C6 or C10 aryl, C7-14 aralkyl, Het or (lower alkyl)-Het;
carboxyl;
carboxy(lower alkyl);
C6 or C10 aryl, C7-14 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted with R22;
wherein R22 is C1-6 alkyl;
C3-7 cycloalkyl;
C1-6 alkoxy;
amino optionally mono- or di-substituted with C1-6 alkyl;
sulfonyl;
(lower alkyl)sulfonyl;
NO2;
OH;
SH;
halo;
haloalkyl;
carboxyl;
amide;
(lower alkyl)amide;
or Het optionally substituted with C1-6 alkyl;
R1 is H;
C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, or C2-6 alkynyl, all optionally substituted with halogen;
or a pharmaceutically acceptable salt or ester thereof; wherein “
Het”
is defined as a five-, six-, or seven-membered saturated or unsaturated, aromatic or non-aromatic, heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur, wherein said heterocycle is optionally fused to a benzene ring.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79)
B is a C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C1-6 alkyl; - or
B is Het or (lower alkyl)-Het, all optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C1-6 alkyl.
-
-
3. A compound of formula I according to claim 1, wherein B is R4—
- SO2 wherein R4 is C1-6 alkyl;
amido;
(lower alkyl)amide;
C6 or C10 aryl, C7-14 aralkyl or Het, all optionally substituted with C1-6 alkyl.
- SO2 wherein R4 is C1-6 alkyl;
-
4. A compound of formula I according to claim 1, wherein B is an acyl derivative of formula R4—
- C(O)—
wherein R4 is(i) C1-10 alkyl optionally substituted with carboxyl, hydroxy or C1-6 alkoxy, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl;
(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C1-6 alkyl;
(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amino optionally substituted with C1-6 alkyl, amido, (lower alkyl)amide, or amino optionally substituted with C1-6 alkyl.
- C(O)—
-
5. A compound of formula I according to claim 1, wherein B is a carboxyl derivative of formula R4—
- O—
C(O)—
, wherein R4 is(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amino optionally mono- or di-substituted with C1-6 alkyl, amido or (lower alkyl)amide;
(ii) C3-7 cycloalkyl, C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amino optionally mono- or di-substituted with C1-6 alkyl, amido or (lower alkyl)amide;
(iv) C6 or C10 aryl or C7-16 aralkyl optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C1-6 alkyl;
or(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amino optionally mono- or di-substituted with C1-6 alkyl, amido or (lower alkyl)amido.
- O—
-
6. A compound of formula I according to claim 1, wherein B is an amide derivative of formula R4—
- N(R5)—
C(O)—
wherein R4 is(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C1-6 alkyl;
(iii) amino optionally mono- or di-substituted with C1-3 alkyl;
(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C1-6 alkyl;
or(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amino optionally substituted with C1-6 alkyl, amido or (lower alkyl)amide; and
R5 is H or methyl.
- N(R5)—
-
7. A compound of formula I according to claim 1, wherein B is a thioamide derivative of formula R4—
- NH—
C(S)—
;
wherein R4 is(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl or C1-6 alkoxy;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amino or amido.
- NH—
-
8. A compound of formula I according to claim 2, wherein B is a C6 or C10 aryl optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl.
-
9. A compound of formula I according to claim 2, wherein B is Het optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, halo, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl.
-
10. A compound of formula I according to claim 4, wherein B is an acyl derivative of formula R4—
- C(O)—
wherein R4, is(i) C1-10 alkyl optionally substituted with carboxyl, hydroxy or C1-6 alkoxy;
or(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C1-6 alkoxy)carbonyl, or (iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, or (v) Het optionally substituted with C1-6 alkyl, hydroxy, amido or amino.
- C(O)—
-
11. A compound of formula I according to claim 5, wherein B is a carboxyl derivative of formula R4—
- O—
C(O)—
, wherein R4 is(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy or amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl, C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl, or (iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amino optionally substituted with C1-6 alkyl;
or(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amido, or amino optionally mono-substituted with C1-6 alkyl.
- O—
-
12. A compound of formula I according to claim 6, wherein B is an amide derivative of formula R4—
- N(R5)—
C(O)—
wherein R4 is(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(iii) amino optionally mono- or di-substituted with C1-3 alkyl, or (iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amino or amido optionally substituted with C1-6 alkyl;
or(v) Het optionally substituted with C1-6 alkyl, hydroxy, amino or amido, and R5 is H.
- N(R5)—
-
13. A compound of formula I according to claim 7, wherein B is a thioamide derivative of formula R4—
- NH—
C(S)—
;
wherein R4 is (i) C1-10 alkyl;
or (ii) C3-7 cycloalkyl.
- NH—
-
14. A compound of formula I according to claim 12, wherein B is an amide derivative of formula R4—
- NH—
C(O)—
wherein R4 is(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(iv) C6 or C10 aryl or C7-16 aralkyl optionally substituted with C1-6 alkyl, hydroxy, amino or amido.
- NH—
-
15. A compound of formula I according to claim 1, wherein B is
-
16. A compound of formula I according to claim 1, wherein Y is H or methyl.
-
17. A compound of formula I according to claim 16, wherein Y is H.
-
18. A compound of formula I according to claim 1, wherein R3 is C1-8 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C1-6 alkoxy, C1-6 thioalkyl, acetamido, C6 or C10 aryl, or C7-16 aralkyl,.
-
19. A compound of formula I according to claim 18, wherein R3 is the side chain of Tbg, He, Val, Chg or:
-
20. A compound of formula I according to claim 19, wherein R3 is the side chain of Tbg, Chg or Val.
-
21. A compound of formula I according to claim 1, wherein R2 is S—
- R20 or O—
R20 wherein R20 is a C6 or C10 aryl, C7-16 aralkyl, Het or —
CH2—
Het, all optionally mono-, di- or tri-substituted with R21, whereinR21 is C1-6 alkyl;
C1-6 alkoxy;
lower thioalkyl;
amino or amido optionally mono-or di-substituted with C1-6 alkyl, C6 or C10 aryl, C7-16 aralkyl, Het or (lower alkyl)-Het;
NO2;
OH;
halo;
trifluoromethyl;
carboxyl;
C6 or C10 aryl, C7-16 aralkyl, or Het, said aryl, aralkyl or Het being optionally substituted with R22, whereinR22 is C1-6 alkyl;
C3-7 cycloalkyl;
C1-6 alkoxy;
amino;
mono- or di-(lower alkyl)amino;
(lower alkyl)amide;
sulfonylalkyl;
NO2;
OH;
halo;
trifluoromethyl;
carboxyl or Het.
- R20 or O—
-
22. A compound of formula I according to claim 21, wherein R21 is C1-6 alkyl;
- C1-6 alkoxy;
amino;
di(lower alkyl)amino;
(lower alkyl)amide;
C6 or C10 aryl, or Het, said aryl or Het being optionally substituted with R22, wherein R22 is C1-6 alkyl;
C3-7 cycloalkyl;
C1-6 alkoxy;
amino;
mono- or di(lower alkyl)amino;
amido;
(lower alkyl)amide;
halo;
trifluoromethyl or Het.
- C1-6 alkoxy;
-
23. A compound of formula I according to claim 22, wherein R22 is C1-6 alkyl;
- C1-6 alkoxy;
halo;
amino optionally mono- or di-substituted with lower alkyl;
amido;
(lower alkyl)amide;
or Het.
- C1-6 alkoxy;
-
24. A compound of formula I according to claim 23, wherein R22 is methyl;
- ethyl;
isopropyl;
tert-butyl;
methoxy;
chloro;
amino optionally mono- or di-substituted with lower alkyl;
amido, (lower alkyl)amide;
or (lower alkyl) 2-thiazole.
- ethyl;
-
25. A compound of formula I according to claim 21, wherein R2 is selected from the group consisting of:
-
26. A compound of formula I according to claim 21, wherein R2 is 1-naphthylmethoxy;
- 2-naphthylmethoxy;
benzyloxy, 1-naphthyloxy;
2-naphthyloxy;
or quinolinoxy unsubstituted, mono- or di-substituted with R21 as defined in claim 21.
- 2-naphthylmethoxy;
-
27. A compound of formula I according to claim 26, wherein R2 is 1-naphtylmethoxy;
- or quinolinoxy unsubstituted, mono- or di-substituted with R21 as defined in claim 26.
-
28. A compound of formula I according to claim 27, wherein R2 is selected from the group consisting of:
-
29. A compound of formula I according to claim 26, wherein R2 is
wherein R21A is C1-6 alkyl; - C1-6 alkoxy;
lower thioalkyl;
halo;
amino optionally mono-substituted with C1-6 alkyl;
or C6, C10 aryl, C7-16 aralkyl, or Het, said aryl, aralkyl or Het optionally substituted with R22 wherein R22 is C1-6 alkyl, C1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl, or Het; and
R21B is C1-6 alkyl, C1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO2, OH, halo, trifluoromethyl, or carboxyl.
- C1-6 alkoxy;
-
30. A compound of formula I according to claim 29, wherein R21A is C6, C10 aryl or Het, all optionally substituted with R22 as defined in claim 29.
-
31. A compound of formula I according to claim 30, wherein R21A is selected from the group consisting of:
-
32. A compound of formula I according to claim 21, wherein R2 is:
-
wherein R22A is C1-6 alkyl;
C1-6 alkoxy;
or halo; and
R21B is C1-6 alkyl, C1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO2, OH, halo, trifluoromethyl, or carboxyl.
-
-
33. A compound of formula I according to claim 29, wherein R2 is:
-
wherein R22B is C1-6 alkyl, amino optionally mono-substituted with C1-6 alkyl, amido, or (lower alkyl)amide;
; and
R21B is C1-6 alkyl, C1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO2, OH, halo, trifluoromethyl, or carboxyl.
-
-
34. A compound of formula I according to claim 32 or 33, wherein R21B is C1-6 alkoxy, or di(lower alkyl)amino.
-
35. A compound of formula I according to claim 32 or, 33, wherein R21B is methoxy.
-
36. A compound of formula I according to claim 1, wherein R1 is H, C1-3 alky, C3-5 cycloalkyl, or C2-4 alkenyl, all optionally substituted with halo
-
37. A compound of formula I according to claim 36, wherein P1 is
and R1 is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl. -
38. A compound of formula I according to claim 37, wherein R1 is vinyl.
-
39. A compound of formula I according to claim 37, wherein R1 at carbon 2 is orientated syn to the carbonyl at position 1, represented by the radical:
-
40. A compound of formula I according to claim 37, wherein R1 at position 2 is orientated anti to the carbonyl at position 1, represented by the radical:
-
41. A compound of formula I according to claim 37, wherein carbon 1 has the R configuration:
-
42. An optical isomer of a compound of formula I according to claim 41, wherein said R1 substituent and the carbonyl in a syn orientation in the following absolute configuration:
-
43. A compound of formula I according to claim 42, wherein R1 is ethyl, hence the asymmetric carbon atoms at positions 1 and 2 have the R,R configuration.
-
44. A compound of formula I according to claim 42, wherein R1 is vinyl, hence the asymmetric carbon atoms at positions 1 and 2 have the R,S configuration.
-
45. A compound of formula I according to claim 1, wherein
B is a C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C1-6 alkyl; - or
Het or (lower alkyl)-Het, all optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C1-6 alkyl, or B is R4—
SO2 wherein R4 is preferably amido;
(lower alkyl)amide;
C6 or C10 aryl, C7-14 aralkyl or Het, all optionally substituted with C1-6 alkyl, orB is an acyl derivative of formula R4—
C(O)—
wherein R4 is(i) C1-10 alkyl optionally substituted with carboxyl, hydroxy or C1-6 alkoxy, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl;
(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C1-6 alkyl;
(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amino optionally substituted with C1-6 alkyl, amido, (lower alkyl)amide, or amino optionally substituted with C1-6 alkyl, or B is a carboxyl derivative of formula R4—
O—
C(O)—
, wherein R4 is(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amino optionally mono- or di-substituted with C1-6 alkyl, amido or (lower alkyl)amide;
(ii) C3-7 cycloalkyl, C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amino optionally mono- or di-substituted with C1-6 alkyl, amido or (lower alkyl)amide;
(iv) C6 or C10 aryl or C7-16 aralkyl optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C1-6 alkyl;
or(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amino optionally mono- or di-substituted with C1-6 alkyl, amido or (lower alkyl)amido, or B is an amide derivative of formula R4—
N(R5)—
C(O)—
wherein R4 is(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C1-6 alkyl;
(iii) amino optionally mono- or di-substituted with C1-3 alkyl;
(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C1-6 alkyl;
or(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amino optionally substituted with C1-6 alkyl, amido or (lower alkyl)amide; and
R5 is H or methyl, or B is thioamide derivative of formula R4—
NH—
C(S)—
;
wherein R4 is(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl or C1-6 alkoxy;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amino or amido;
Y is H or methyl;
R3 is C1-8 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C1-6 alkoxy, C1-6 thioalkyl, acetamido, C6 or C10 aryl, or C7-16 aralkyl;
R2 is S—
R20 or O—
R20 wherein R20 is a C6 or C10 aryl, C7-16 aralkyl, Het or —
CH2-Het, all optionally mono-, di- or tri-substituted with R21, whereinR21 is C1-6 alkyl;
C1-6 alkoxy;
lower thioalkyl;
amino or amido optionally mono-or di-substituted with C1-6 alkyl, C6 or C10 aryl, C7-16 aralkyl, Het or (lower alkyl)-Het;
NO2;
OH;
halo;
trifluoromethyl;
carboxyl;
C6 or C10 aryl, C7-16 aralkyl, or Het, said aryl, aralkyl or Het being optionally substituted with R22, whereinR22 is C1-6 alkyl;
C3-7 cycloalkyl;
C1-6 alkoxy;
amino;
mono- or di-(lower alkyl)amino;
(lower alkyl)amide;
sulfonylalkyl;
NO2;
OH;
halo;
trifluoromethyl;
carboxyl or Het;
orR2 is selected from the group consisting of;
or R2 is 1-naphthylmethoxy;
2-naphthylmethoxy;
benzyloxy, 1-naphthyloxy;
2-naphthyloxy;
or quinolinoxy unsubstituted, mono- or di-substituted with R21, as defined above; and
P1 is;
wherein R1 is H, C1-3 alkyl, C3-5 cycloalkyl, or C2-4 alkenyl optionally substituted with halo, and said R1 at carbon 2 is orientated syn to the carbonyl at position 1, represented by the radical;
or a pharmaceutically acceptable salt or ester thereof.
- or
-
46. A compound of formula I according to claim 45, wherein B is a C6 or C10 aryl optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl;
- or B is Het optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, halo, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl;
or B is R4—
SO2 wherein R4 is C6 or C10 aryl, a C7-14 aralkyl or Het all optionally substituted with C1-6 alkyl;
amido, (lower alkyl)amide;
B is an acyl derivative of formula R4—
C(O)—
wherein R4 is(i) C1-10 alkyl optionally substituted with carboxyl, hydroxy or C1-6 alkoxy;
or(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C1-6 alkoxy)carbonyl;
or(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy;
or(v) Het optionally substituted with C1-6 alkyl, hydroxy, amido or amino;
or B is a carboxyl derivative of formula R4—
O—
C(O)—
, wherein R4 is(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy or amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl, C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl;
or(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amino optionally substituted with C1-6 alkyl;
or(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amido, or amino optionally mono-substituted with C1-6 alkyl;
or B is an amide derivative of formula R4—
N(R5)—
C(O)—
wherein R4 is(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl; and
R5 is H or methyl;
orR4 is (iii) amino optionally mono- or di-substituted with C1-3 alkyl;
or(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amino or amido optionally substituted with C1-6 alkyl;
or(v) Het optionally substituted with C1-6 alkyl, hydroxy, amino or amido;
or B is a thioamide derivative of formula R4—
NH—
C(S)—
;
wherein R4 is;
(i) C1-10 alkyl;
or (ii) C3-7 cycloalkyl;
orY is H;
R3 is the side chain of Tbg, He, Val, Chg or;
R2 is 1-naphtylmethoxy;
or quinolinoxy unsubstituted, mono- or di-substituted with R21 as defined above, orR2 is;
wherein R21A is C1-6 alkyl;
C1-6 alkoxy;
C6, C10 aryl or Het;
lower thioalkyl;
halo;
amino optionally mono-substituted with C1-6 alkyl;
or C6, C10 aryl, C7-16 aralkyl or Het, optionally substituted with R22 wherein R22 is C1-6 alkyl, C1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl, or Het; and
R21B is C1-6 alkyl, C1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO2, OH, halo, trifluoromethyl, or carboxyl;
P1 is;
R1 is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl.
- or B is Het optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, halo, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl;
-
47. A compound of formula I according to claim 46, wherein
B is an amide derivative of formula R4— - NH—
C(O)—
wherein R4 isi) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(iv) C6 or C10 aryl or C7-16 aralkyl optionally substituted with C1-6 alkyl, hydroxy, amino or amido;
R3 is the side chain of Tbg, Chg or Val;
R1 is;
wherein R22A is C1-6 alkyl;
C1-6 alkoxy;
or halo;
R22B is C1-6 alkyl, amino optionally mono-substituted with C1-6 alkyl, amido, or (lower alkyl)amide; and
R21B is C1-6 alkyl, C1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO2, OH, halo, trifluoromethyl, or carboxyl; and
P1 is;
- NH—
-
48. A compound according to claim 45 represented by the formula:
-
wherein B, R3,R2 as defined below;
-
-
49. Compound #111 according to claim 48.
-
50. A compound according to claim 45 represented by the formula:
-
wherein B,R3, R1 are as defined below;
-
-
51. Compound #203 according to claim 49.
-
52. A compound cccording to claim 45 represented by the formula:
-
wherein B, R3, R2 and R1 are as defined below;
-
-
53. A compound according to claim 52, selected from the group consisting of compound #307, 314, 317, 319, 321, 324, 325, 326, 327, 329, 331, 332, 333, and 334.
-
54. A compound according to claim 45 represented by the formula:
-
wherein B, R3, R2 and R1 are as defined below;
-
-
55. A compound according to claim 54, selected from the group consisting of compound #:
- 403, 405, and 406.
-
56. A compound according to claim 45 represented by the formula:
-
wherein R3 is as defined below;
-
-
57. A compound according to claim 56, selected from the group consisting of compound #:
- 501, 509, and 510.
-
58. A compound according to claim 46 represented by the formula:
-
wherein R3, R21A and R21B are as defined below;
-
-
59. A compound according to claim 58, selected from the group consisting of compound #:
- 601, 602, 603, 604, 605, 606, 607, 610, 611, 612, 615, 616, 617, 620, 621, 622, 625, 626, 627, 628, 629, and 630.
-
60. A compound according to claim 46 represented by the formula:
-
wherein R3 and R21A are as defined below;
-
-
61. A compound according to claim 60, selected from the group consisting of compound #:
- 701, 702, 703, 704, 705, 706, 707, 708, 709, and 711 to 737.
-
62. A compound according to claim 45 represented by the formula:
-
wherein B, R3, and R22 are as defined below;
-
-
63. A compound according to claim 62, selected from the group consisting of compound #:
- 801 to 825, 827 to 858, and 860 to 873.
-
64. A compound according to claim 45 represented by the formula:
-
wherein B is as defined below;
-
-
65. A compound according to claim 45 represented by the formula:
-
wherein B, X, R3, z and R21B are as defined below;
-
-
66. A pharmaceutical composition comprising an anti-hepatitis C virally effective amount of a compound of formula I according to claim 1, or a therapeutically acceptable salt or ester therof, in admixture with a pharmaceutically acceptable carrier medium or auxiliary agent.
-
67. A method of treating a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof.
-
68. A method of treating a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of the composition according to claim 66.
-
69. A method of inhibiting the replication of hepatitis C virus comprising exposing the virus to a hepatitis C viral NS3 protease inhibiting amount of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof.
-
70. A method of treating a hepatitis C viral infection in a mammal comprising administering thereto an anti-hepatitis C virally effective amount of a combination of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof with another anti-HCV agent.
-
71. A method according to claim 70, wherein said other anti-HCV agent is selected from the group consisting of:
- α
- or β
-interferon, ribavirin and amantadine.
- α
-
72. A method according to claim 70, wherein said other anti-HCV agent comprises an inhibitor of other targets in the HCV life cycle, selected from:
- helicase, polymerase, metalloprotease or IRES.
-
73. A process for the preparation of a peptide analog of formula (I) according to claim 1 wherein P1 is a substituted aminocyclopropyl carboxylic acid residue, comprising the step of:
-
coupling a peptide selected from the group consisting of;
APG-P3-P2;
or APG-P2;
with a P1 intermediate of formula;
wherein R1 is C1-6 alkyl, cycloalkyl or C2-6 alkenyl, all optionally substituted with halogen, CPG is a carboxyl protecting group and APG is an amino protecting group and P3 and P2 are as defined above.
-
-
74. A process for the preparation of:
- a peptide analog of formula (I) according to claim 1, this process comprising the step of;
coupling a suitably protected amino acid, peptide or peptide fragment with a P1 intermediate of formula;
wherein R1 is C1-6 alkyl, cycloalkyl or C2-6 alkenyl, all optionally substituted with halogen, and CPG is a carboxyl protecting group.
- a peptide analog of formula (I) according to claim 1, this process comprising the step of;
-
75. A process for the preparation of:
- a peptide analog of formula (I) according to claim 1, this process comprising the step of;
coupling a suitably protected amino acid, peptide or peptide fragment with a P1 intermediate of formula;
wherein CPG is a carboxyl protecting group.
- a peptide analog of formula (I) according to claim 1, this process comprising the step of;
-
76. A process according to claim 73, 74 or 75 wherein said carboxyl protecting group (CPG) is selected from the group consisting of:
- alkyl esters, aralkyl esters, and esters being cleavable by mild base treatment or mild reductive means.
-
77. Method of preparing a composition for treating a hepatitis C viral infection in a mammal comprising combining an anti-hepatitis C virally effective amount of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof, with a pharmaceutically acceptable carrier medium or auxiliary agent.
-
78. Method of preparing a composition for inhibiting the replication of hepatitis C virus comprising combining a hepatitis C viral NS3 protease inhibiting amount of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof, with a pharmaceutically acceptable carrier medium or auxiliary agent.
-
79. Method of preparing a composition for treating a hepatitis C viral infection in a mammal comprising combining an anti-hepatitis C virally effective amount of a combination of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof, and an interferon with a pharmaceutically acceptable carrier medium or auxiliary agent.
-
80. A compound of the formula:
-
wherein R2 is wherein R21A is C1-6 alkyl;
C1-6 alkoxy;
lower thioalkyl;
halo;
amino optionally mono-substituted with C1-6 alkyl;
or C6, C10 aryl, C7-16 aralkyl, or Het, said aryl, aralkyl or Het optionally substituted with R22 wherein R22 is C1-6 alkyl, C1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl, or Het; and
R21B is C1-6 alkyl, C1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO2, OH, halo, trifluoromethyl, or carboxyl;
R1 is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl;
APG is an amino protecting group selected from;
1) acyl groups,
2) aromatic carbamate groups,
3) aliphatic carbamate groups,
4) cyclic alkyl carbamate groups,
5) alkyl groups,
6) trialkylsilyl, and
7) thiol containing groups; and
CPG is a carboxyl protecting group selected from;
alkyl esters, aralkyl esters, and esters being cleavable by mild base treatment or mild reductive means.- View Dependent Claims (81, 82, 83, 84, 87, 90, 91, 92, 93, 94, 95, 96)
wherein R22B is C1-6 alkyl, amino optionally mono-substituted with C1-6 alky, amido, or (lower alkyl)amide; and
R21B is C1-6 alkyl, C1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO2, OH, halo, trifluoromethyl, or carboxyl.
-
-
90. A compound of formula I according to claim 80, wherein R1 is vinyl.
-
91. A compound of formula I according to claim 80, wherein R1 at carbon 2 is orientated syn to the carbonyl at position 1, represented by the radical:
-
92. A compound of formula I according to claim 80, wherein R1 at position 2 is orientated anti to the carbonyl at position 1, represented by the radical:
-
93. A compound of formula I according to claim 80, wherein carbon 1 has the R configuration:
-
94. An optical isomer of a compound of formula I according to claim 93, wherein said R1 substituent and the carbonyl are in a syn orientation in the following absolute configuration:
-
95. A compound of formula I according to claim 94, wherein R1 is ethyl, hence the asymmetric carbon atoms at positions 1 and 2 have the R,R configuration.
-
96. A compound of formula I according to claim 94, wherein R1 is vinyl, hence the asymmetric carbon atoms at positions 1 and 2 have the R,S configuration.
-
85. A compound of formula I according to claimwherein R21A is selected from the group consisting of:
-
86. A compound of the formula:
-
wherein R2 is wherein R22A is C1-6 alkyl;
C1-6 alkoxy;
or halo; and
R21B is C1-6 alkyl, C1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO2, OH, halo, trifluoromethyl, or carboxyl;
R1 is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl;
APG is an amino protecting group selected from;
1) acyl groups,
2) aromatic carbamate groups,
3) aliphatic carbamate groups,
4) cyclic alkyl carbamate groups,
5) alkyl groups,
6) trialkylsilyl, and
7) thiol containing groups; and
CPG is a carboxyl protecting group selected from;
alkyl esters, aralkyl esters, and esters being cleavable by mild base treatment or mild reductive means.- View Dependent Claims (88, 89)
-
Specification