Hepatitis C inhibitor tri-peptides

• US 6,410,531 B1
• Filed: 05/04/2001
• Issued: 06/25/2002
• Est. Priority Date: 08/10/1998
• Status: Expired due to Term

• Current Assignee: Boehringer Ingelheim Limited (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Limited (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Llinas-Brunet, Montse, Cameron, Dale R., Bailey, Murray D., Rancourt, Jean, Halmos, Teddy, Tsantrizos, Youla S., Goudreau, Nathalie, Ghiro, Elise, Wernic, Dominik M., Faucher, Anne-Marie, Poupart, Marc-Andre
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US09/849,057
• Publication Number:
  US 20020037998A1
• Time in Patent Office: 417 Days
• Field of Search: 514/235.5, 514/312, 514/340, 544/128, 546/153, 546/278.4
• US Class Current: 514/235.5
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07K 5/0806 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/0808 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/081 the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• CPC Class Codes: C07K 5/0812 and aromatic or cycloaliphatic
• CPC Class Codes: C12P 13/02 Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes peptides C12P21/00 or C07K
• CPC Class Codes: C12P 41/005 : by esterification of carboxylic acid groups in the enantiomers or the inverse reaction

Abstract

Racemates, diastereoisomers and optical isomers of a compound of formula (I):

wherein

B is H, a C₆ or C₁₀ aryl, C_7-16 aralkyl; Het or (lower alkyl)-Het, all of which optionally substituted with C_1-6 alkyl; C_1-6 alkoxy; C_1-6 alkanoyl; hydroxy; hydroxyalkyl; halo; haloalkyl; nitro; cyano; cyanoalkyl; amino optionally substituted with C_1-6 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 C_1-6 alkyl; and

Y is H or C_1-6 alkyl;

R³ is C_1-8 alkyl, C_3-7 cycloalkyl, or C_4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C_1-6 alkoxy, C_1-6 thioalkyl, amido, (lower alkyl)amido, C₆ or C₁₀ aryl, or C_7-16 aralkyl;

R² is CH₂—R₂₀, NH—R₂₀, O—R₂₀ or S—R₂₀, wherein R₂₀ is a saturated or unsaturated C_3-7 cycloalkyl or C_4-10 (alkylcycloalkyl), all of which being optionally mono-, di- or tri-substituted with R₂₁,

or R₂₀ is a C₆ or C₁₀ aryl or C_7-14 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, C_7-14 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted; and

R¹ is H; C_1-6 alkyl, C_3-7 cycloalkyl, C_2-6 alkenyl, or C₂₆ alkynyl, all optionally substituted with halogen; or a pharmaceutically acceptable salt or ester thereof.

Claims

1. The racemates, diastereoisomers or optical isomers of a compound of formula (I):

wherein

B is H, a C₆ or C₁₀ aryl, C_7-16 aralkyl;

Het or (lower alkyl)-Het, all of which optionally substituted with C_1-6 alkyl;

C_1-6 alkoxy;

C_1-6 alkanoyl;

hydroxy;

hydroxyalkyl;

halo;

haloalkyl;

nitro;

cyano;

cyanoalkyl;

amino optionally substituted with C_1-6 alkyl;

amido;

or (lower alkyl)amide;

or B is an acyl derivative of formula R₄—

C(O)—

;

a carboxyl derivative of 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) C_1-10 alkyl optionally substituted with carboxyl, C_1-6 alkanoyl, hydroxy, C_1-6 alkoxy, amino optionally mono-or di-substituted with C_1-6 alkyl, amido, or (lower alkyl) amide;

(ii) C_3-7 cycloalkyl, C_3-7 cycloalkoxy, or C_4-10 alkylcycloalkyl, all optionally substituted with hydroxy, carboxyl, (C_1-6 alkoxy)carbonyl, amino optionally mono-or di-substituted with C_1-6 alkyl, amido, or (lower alkyl) amide;

(iii) amino optionally mono- or di-substituted with C_1-6 alkyl;

amido;

or (lower alkyl)amide;

(iv) C₆ or C₁₀ aryl or C_7-16 aralkyl, all optionally substituted with C_1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally mono-or di-substituted with C_1-6 alkyl;

or

(v) Het or (lower alkyl)-Het, both optionally substituted with C_1-6 alkyl, hydroxy, amido, (lower alkyl) amide, or amino optionally mono-or di-substituted with C_1-6 alkyl;

R₅ is H or C_1-6 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 C_1-6 alkyl;

R³ is C_1-8 alkyl, C_3-7 cycloalkyl, or C_4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C_1-6 alkoxy, C_1-6 thioalkyl, amido, (lower alkyl)amido, C₆ or C₁₀ aryl, or C_7-16 aralkyl;

R² is CH₂—

R₂₀, NH—

R₂₀, O—

R₂₀ or S—

R₂₀, wherein R₂₀ is pyridinyl, quinolyl, (lower alkyl)-pyridinyl or (lower alkyl)-quinolyl, each optionally mono-, di- or tri-substituted with R₂₁,

wherein each R₂₁ is independently C_1-6 alkyl;

C_1-6 alkoxy;

lower thioalkyl;

sulfonyl;

NO₂;

OH;

SH;

halo;

haloalkyl;

amino optionally mono-or di-substituted with C_1-6 alkyl, C₆ or C₁₀ aryl, C_7-14 aralkyl, Het or (lower alkyl)-Het;

amido optionally mono-substituted with C_1-6 alkyl, C₆ or C₁₀ aryl, C_7-14 aralkyl, Het or (lower alkyl)-Het;

carboxyl;

carboxy(lower alkyl);

C₆ or C₁₀ aryl, C_7-14 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted with R₂₂;

wherein R₂₂ is C_1-6 alkyl;

C_3-7 cycloalkyl;

C_1-6 alkoxy;

amino optionally mono- or di-substituted with C_1-6 alkyl;

sulfonyl;

(lower alkyl)sulfonyl;

NO₂;

OH;

SH;

halo;

haloalkyl;

carboxyl;

amide;

(lower alkyl)amide;

or Het optionally substituted with C_1-6 alkyl;

R¹ is H;

C_1-6 alkyl, C_3-7 cycloalkyl, C_2-6 alkenyl, or C_2-6 alkynyl, all optionally substituted with halogen;

or a pharmaceutically acceptable salt or ester thereof;

wherein at least one “

Het”

group is present in the compound of formula (I) and “

Het”

is defined as a six- or seven-membered saturated or unsaturated aromatic or heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur, wherein said heterocycle is optionally fused to a benzene ring.

2. A compound of formula I according to claim 1, wherein B is a C₆ or C₁₀ aryl or C_7-16 aralkyl, all optionally substituted with C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C_1-6 alkyl;

or

B is Het or (lower alkyl)-Het, all optionally substituted with C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C_1-6 alkyl.

3. A compound of formula I according to claim 1, wherein B is R₄—

SO₂ wherein

R₄ is C_1-6 alkyl;

amido;

(lower alkyl)amide;

C₆ or C₁₀ aryl, C_7-14 aralkyl or Het, all optionally substituted with C_1-6 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) C_1-10 alkyl optionally substituted with carboxyl, hydroxy or C_1-6 alkoxy, amido, (lower alkyl)amide, or amino optionally mono-or di-substituted with C_1-6 alkyl;

(ii) C_3-7 cycloalkyl or C_4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C_1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, or amino optionally mono-or di-substituted with C_1-6 alkyl;

(iv) C₆ or C₁₀ aryl or C_7-16 aralkyl, all optionally substituted with C_1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C_1-6 alkyl;

(v) Het or (lower alkyl)-Het, both optionally substituted with C_1-6 alkyl, hydroxy, amino optionally substituted with C_1-6 alkyl, amido, (lower alkyl)amide, or amino optionally substituted with C_1-6 alkyl.

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) C_1-10 alkyl optionally substituted with carboxyl, C_1-6 alkanoyl, hydroxy, C_1-6 alkoxy, amino optionally mono-or di-substituted with C_1-6 alkyl, amido or (lower alkyl)amide;

(ii) C_3-7 cycloalkyl, C_4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C_1-6 alkoxy)carbonyl, amino optionally mono- or di-substituted with C_1-6 alkyl, amido or (lower alkyl)amide;

(iv) C₆ or C₁₀ aryl or C_7-16 aralkyl optionally substituted with C_1-6 alkyl, hydroxy, amido, (lower alkyl)amido, or amino optionally mono-or di-substituted with C_1-6 alkyl;

or

(v) Het or (lower alkyl)-Het, both optionally substituted with C_1-6 alkyl, hydroxy, amino optionally mono-or di-substituted with C_1-6 alkyl, amido or (lower alkyl)amido.

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) C_1-10 alkyl optionally substituted with carboxyl, C_1-6 alkanoyl, hydroxy, C_1-6 alkoxy, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C_1-6 alkyl;

(ii) C_3-7 cycloalkyl or C_4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C_1-6 alkoxy)carbonyl, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C_1-6 alkyl;

(iii) amino optionally mono- or di-substituted with C_1-3 alkyl;

(iv) C₆ or C₁₀ aryl or C_7-16 aralkyl, all optionally substituted with C_1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C_1-6 alkyl;

or

(v) Het or (lower alkyl)-Het, both optionally substituted with C_1-6 alkyl, hydroxy, amino optionally substituted with C_1-6 alkyl, amido or (lower alkyl)amide; and

R₅ is H or methyl.

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) C_1-10 alkyl optionally substituted with carboxyl, C_1-6 alkanoyl or C_1-6 alkoxy;

(ii) C_3-7 cycloalkyl or C_4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C_1-6 alkoxy)carbonyl, amino or amido.

8. A compound of formula I according to claim 2, wherein B is a C₆ or C₁₀ aryl optionally substituted with C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C_1-6 alkyl.

9. A compound of formula I according to claim 2, wherein B is Het optionally substituted with C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkanoyl, hydroxy, halo, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C_1-6 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) C_1-10 alkyl optionally substituted with carboxyl, hydroxy or C_1-6 alkoxy;

or

(ii) C_3-7 cycloalkyl or C_4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C_1-6 alkoxy)carbonyl, or

(iv) C₆ or C₁₀ aryl or C_7-16 aralkyl, all optionally substituted with C_1-6 alkyl, hydroxy, or

(v) Het optionally substituted with C_1-6 alkyl, hydroxy, amido or amino.

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) C_1-10 alkyl optionally substituted with carboxyl, C_1-6 alkanoyl, hydroxy, C_1-6 alkoxy or amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C_1-6 alkyl;

(ii) C_3-7 cycloalkyl, C_4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C_1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C_1-6 alkyl, or

(iv) C₆ or C₁₀ aryl or C_7-16 aralkyl, all optionally substituted with C_1-6 alkyl, hydroxy, amino optionally substituted with C_1-6 alkyl;

or

(v) Het or (lower alkyl)-Het, both optionally substituted with C_1-6 alkyl, hydroxy, amido, or amino optionally mono-substituted with C_1-6 alkyl.

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) C_1-10 alkyl optionally substituted with carboxyl, C_1-6 alkanoyl, hydroxy, C_1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C_1-6 alkyl;

(ii) C_3-7 cycloalkyl or C_4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C_1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C_1-6 alkyl;

(iii) amino optionally mono- or di-substituted with C_1-3 alkyl, or

(iv) C₆ or C₁₀ aryl or C_7-16 aralkyl, all optionally substituted with C_1-6 alkyl, hydroxy, amino or amido optionally substituted with C_1-6 alkyl;

or

(v) Het optionally substituted with C_1-6 alkyl, hydroxy, amino or amido, and R₅ is H.

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) C_1-10 alkyl;

or (ii) C_3-7 cycloalkyl.

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) C_1-10 alkyl optionally substituted with carboxyl, C_1-6 alkanoyl, hydroxy, C_1-6 alkoxy amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C_1-6 alkyl;

(ii) C_3-7 cycloalkyl or C_4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C_1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C_1-6 alkyl;

(iv) C₆ or C₁₀ aryl or C_7-16 aralkyl optionally substituted with C_1-6 alkyl, hydroxy, amino or amido.

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 C_1-8 alkyl, C_3-7 cycloalkyl, or C_4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C_1-6 alkoxy, C_1-6 thioalkyl, acetamido, C₆ or C₁₀ aryl, or C_7-16 aralkyl.

19. A compound of formula I according to claim 18, wherein R³ is the side chain of Tbg, IIe, 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 pyridinyl, quinolyl, —

CH₂-pyridinyl or —

CH₂-quinolyl, all optionally mono-, di-or tri-substituted with R₂₁, wherein

R₂₁ is C_1-6 alkyl;

C_1-6 alkoxy;

lower thioalkyl;

amino or amido optionally mono- or di-substituted with C_1-6 alkyl, C₆ or C₁₀ aryl, C_7-16 aralkyl, Het or (lower alkyl)-Het;

NO₂;

OH;

halo;

trifluoromethyl;

carboxyl;

C₆ or C₁₀ aryl, C_7-16 aralkyl, or Het, said aryl, aralkyl or Het being optionally substituted with R₂₂, wherein

R₂₂ is C_1-6 alkyl;

C_3-7 cycloalkyl;

C_1-6alkoxy;

amino;

mono- or di-(lower alkyl)amino;

(lower alkyl)amide;

sulfonylalkyl;

NO₂;

OH;

halo;

trifluoromethyl;

carboxyl or Het.

22. A compound of formula I according to claim 21, wherein R₂₁ is C_1-6 alkyl;

C_1-6 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 C_1-6 alkyl;

C_3-7 cycloalkyl;

C_1-6 alkoxy;

amino;

mono- or di(lower alkyl)amino;

amido;

(lower alkyl)amide;

halo;

trifluoromethyl or Het.

23. A compound of formula I according to claim 22, wherein R₂₂ is C_1-6 alkyl;

C_1-6 alkoxy;

halo;

amino optionally mono- or di-substituted with lower alkyl;

amido;

(lower alkyl)amide;

or Het.

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.

25. A compound of formula I according to claim 21, wherein R² is

26. A compound of formula I according to claim 21, wherein R² is quinolinoxy unsubstituted, mono- or di-substituted with R₂₁ as defined in claim 21.

27. A compound of formula I according to claim 26, wherein R² is selected from the group consisting of:

28. A compound of formula I according to claim 26, wherein R² is:

wherein

R_21A is C_1-6 alkyl;

C_1-6 alkoxy;

lower thioalkyl;

halo;

amino optionally mono-substituted with C_1-6 alkyl;

or C₆, C₁₀ aryl, C_7-16 aralkyl, or Het, said aryl, aralkyl or Het optionally substituted with R₂₂ wherein R₂₂ is C_1-6 alkyl, C_1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C_1-6 alkyl, or Het; and

R_21B is C_1-6 alkyl, C_1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO₂, OH, halo, trifluoromethyl, or carboxyl.

29. A compound of formula I according to claim 28, wherein R_21A is C₆, C₁₀ aryl or Het, all optionally substituted with R₂₂ as defined in claim 28.

30. A compound of formula I according to claim 21, wherein R² is:

wherein

R_22A is C_1-6 alkyl;

C_1-6 alkoxy;

or halo; and

R_21B is C_1-6 alkyl, C_1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO₂, OH, halo, trifluoromethyl, or carboxyl.

31. A compound of formula I according to claim 30, wherein R_21B is C_1-6 alkoxy, or di(lower alkyl)amino.

32. A compound of formula I according to claim 30, wherein R_21B is methoxy.

33. A compound of formula I according to claim 1, wherein R¹ is H, C_1-3 alkyl, C_3-5 cycloalkyl, or C_2-4 alkenyl, all optionally substituted with halo.

34. A compound of formula I according to claim 33, wherein P1 is:

and R¹ is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl.

35. A compound of formula I according to claim 34, wherein R¹ is vinyl.

36. A compound of formula I according to claim 34, wherein R¹ at carbon 2 is orientated syn to the carbonyl at position 1, represented by the radical:

37. A compound of formula I according to claim 34, wherein R¹ at position 2 is orientated anti to the carbonyl at position 1, represented by the radical:

38. A compound of formula I according to claim 34, wherein carbon 1 has the R configuration:

39. An optical isomer of a compound of formula I according to claim 38, wherein said R¹ substituent and the carbonyl in a syn orientation in the following absolute configuration:

40. A compound of formula I according to claim 39, wherein R¹ is ethyl, hence the asymmetric carbon atoms at positions 1 and 2 have the R,R configuration.

41. A compound of formula I according to claim 39, wherein R¹ is vinyl, hence the asymmetric carbon atoms at positions 1 and 2 have the R,S configuration.

42. A compound of formula I according to claim 1, wherein

B is a C₆ or C₁₀ aryl or C_7-16 aralkyl, all optionally substituted with C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C_1-6 alkyl;

or Het or (lower alkyl)-Het, all optionally substituted with C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C_1-6 alkyl,. or

B is R₄—

SO₂ wherein R₄ is preferably amido;

(lower alkyl)amide;

C₆ or C₁₀ aryl, C_7-14 aralkyl or Het, all optionally substituted with C_1-6 alkyl, or

B is an acyl derivative of formula R₄—

C(O)—

wherein R₄ is

(i) C_1-10 alkyl optionally substituted with carboxyl, hydroxy or C_1-6 alkoxy, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C_1-6 alkyl;

(ii) C_3-7 cycloalkyl or C_4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C_1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C_1-6 alkyl;

(iv) C₆ or C₁₀ aryl or C_7-16 aralkyl, all optionally substituted with C_1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C_1-6 alkyl;

(v) Het or (lower alkyl)-Het, both optionally substituted with C_1-6 alkyl, hydroxy, amino optionally substituted with C_1-6 alkyl, amido, (lower alkyl)amide, or amino optionally substituted with C_1-6 alkyl, or

B is a carboxyl derivative of formula R₄—

O—

C(O)—

, wherein R₄ is

(i) C_1-10 alkyl optionally substituted with carboxyl, C_1-6 alkanoyl, hydroxy, C_1-6 alkoxy, amino optionally mono- or di-substituted with C_1-6 alkyl, amido or (lower alkyl)amide;

(ii) C_3-7 cycloalkyl, C_4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C_1-6 alkoxy)carbonyl, amino optionally mono- or di-substituted with C_1-6 alkyl, amido or (lower alkyl)amide;

(iv) C₆ or C₁₀ aryl or C_7-16 aralkyl optionally substituted with C_1-6 alkyl, hydroxy, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C_1-6 alkyl;

or

(v) Het or (lower alkyl)-Het, both optionally substituted with C_1-6 alkyl, hydroxy, amino optionally mono- or di-substituted with C_1-6 alkyl, amido or (lower alkyl)amido, or

B is an amide derivative of formula R₄—

N(R₅)—

C(O)—

wherein R₄ is

(i) C_1-10 alkyl optionally substituted with carboxyl, C_1-6 alkanoyl, hydroxy, C_1-6 alkoxy, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C_1-6 alkyl;

(ii) C_3-7 cycloalkyl or C_4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C_1-6 alkoxy)carbonyl, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C_1-6 alkyl;

(iii) amino optionally mono- or di-substituted with C_1-3 alkyl;

(iv) C₆ or C₁₀ aryl or C_7-16 aralkyl, all optionally substituted with C_1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C_1-6 alkyl;

or

(v) Het or (lower alkyl)-Het, both optionally substituted with C_1-6 alkyl, hydroxy, amino optionally substituted with C_1-6 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) C_1-10 alkyl optionally substituted with carboxyl, C_1-6 alkanoyl or C_1-6 alkoxy;

(ii) C_3-7 cycloalkyl or C_4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C_1-6 alkoxy)carbonyl, amino or amido;

Y is H or methyl;

R³ is C_1-8 alkyl, C_3-7 cycloalkyl, or C_4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C_1-6 alkoxy, C_1-6 thioalkyl, acetamido, C₆ or C₁₀ aryl, or C_7-16 aralkyl;

R² is S—

R₂₀ or O—

R₂₀ wherein R₂₀ is pyridinyl, quinolyl, —

CH₂-pyridinyl or —

CH₂-quinolyl, all optionally mono-, di- or tri-substituted with R₂₁, wherein

R₂₁ is C_1-6alkyl;

C_1-6 alkoxy;

lower thioalkyl;

amino or amido optionally mono- or di-substituted with C_1-6 alkyl, C₆ or C₁₀ aryl, C_7-16 aralkyl, Het or (lower alkyl)-Het;

NO₂;

OH;

halo;

trifluoromethyl;

carboxyl;

C₆ or C₁₀ aryl, C_7-16 aralkyl, or Het, said aryl, aralkyl or Het being optionally substituted with R₂₂, wherein

R₂₂ is C_1-6 alkyl;

C_3-7 cycloalkyl;

C_1-6 alkoxy;

amino;

mono- or di-(lower alkyl)amino;

(lower alkyl)amide;

sulfonylalkyl;

NO₂;

OH;

halo;

trifluoromethyl;

carboxyl or Het;

or

R² is

or R² is quinolinoxy unsubstituted, mono- or di-substituted with R₂ as defined above; and

P1 is;

 

wherein R¹ is H, C_1-3 alkyl, C_3-5 cycloalkyl, or C_2-4 alkenyl optionally substituted with halo, and said R¹ at carbon 2 is orientated syn to the carbonyl at position 1, represented by the radical;

wherein at least one “

Het”

group is present in the compound of formula (I) and “

Het”

is as defined in claim 1;

or a pharmaceutically acceptable salt or ester thereof.

43. A compound of formula I according to claim 42, wherein B is a C₆ or C₁₀ aryl optionally substituted with C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C_1-6 alkyl;

or B is Het optionally substituted with C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkanoyl, hydroxy, halo, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C_1-6 alkyl;

or

B is R₄—

SO₂ wherein R₄ is C₆ or C₁₀ aryl, a C_7-14 aralkyl or Het all optionally substituted with C_1-6 alkyl;

amido, (lower alkyl)amide;

or

B is an acyl derivative of formula R₄—

C(O)—

wherein R₄ is

(i) C_1-10 alkyl optionally substituted with carboxyl, hydroxy or C_1-6 alkoxy;

or

(ii) C_3-7 cycloalkyl or C_4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C_1-6 alkoxy)carbonyl;

or

(iv) C₆ or C₁₀ aryl or C_7-16 aralkyl, all optionally substituted with C_1-6 alkyl, hydroxy;

or

(v) Het optionally substituted with C_1-6 alkyl, hydroxy, amido or amino;

or B is a carboxyl derivative of formula R₄—

O—

C(O)—

, wherein R₄ is

(i) C_1-10 alkyl optionally substituted with carboxyl, C_1-6 alkanoyl, hydroxy, C_1-6 alkoxy or amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C_1-6 alkyl;

(ii) C_3-7 cycloalkyl, C_4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C_1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C_1-6 alkyl;

or

(iv) C₆ or C₁₀ aryl or C_7-16 aralkyl, all optionally substituted with C_1-6 alkyl, hydroxy, amino optionally substituted with C_1-6 alkyl;

or

(v) Het or (lower alkyl)-Het, both optionally substituted with C_1-6 alkyl, hydroxy, amido, or amino optionally mono-substituted with C_1-6 alkyl;

or B is an amide derivative of formula R₄—

N(R₅)—

C(O)—

wherein R₄ is

(i) C_1-10 alkyl optionally substituted with carboxyl, C_1-6 alkanoyl, hydroxy, C_1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C_1-6 alkyl;

(ii) C_3-7 cycloalkyl or C_4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C_1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C_1-6 alkyl; and

R₅ is H or methyl;

or R₄ is (iii) amino optionally mono- or di-substituted with C_1-3 alkyl;

or (iv) C₆ or C₁₀ aryl or C_7-16 aralkyl, all optionally substituted with C_1-6 alkyl, hydroxy, amino or amido optionally substituted with C_1-6 alkyl;

or (v) Het optionally substituted with C_1-6 alkyl, hydroxy, amino or amido;

or

B is a thioamide derivative of formula R₄—

NH—

C(S)—

;

wherein R₄ is;

(i) C_1-10 alkyl;

or (ii) C_3-7 cycloalkyl;

or

Y is H;

R³ is the side chain of Tbg, IIe, Val, Chg or;

R² is quinolinoxy unsubstituted, mono- or di-substituted with R₂₁ as defined in claim 42, or

R² is;

wherein R_21A is C_1-6 alkyl;

C_1-6 alkoxy;

C₆, C₁₀ aryl or Het;

lower thioalkyl;

halo;

amino optionally mono-substituted with C_1-6 alkyl;

or C₆, C₁₀ aryl, C_7-16 aralkyl or Het, optionally substituted with R₂₂ wherein R₂₂ is C_1-6 alkyl, C_1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C_1-6 alkyl, or Het;

R_21B is C_1-6 alkyl, C_1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO₂, OH, halo, trifluoromethyl, or carboxyl;

P1 is;

and

R¹ is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl.

44. A compound according to claim 42 represented by the formula:

wherein B, R³, R², R¹ are as defined below;

45. A compound according to claim 42 represented by the formula:

wherein R³, R_21A and R_21B are as defined below;

46. A compound according to claim 45, selected from the group consisting of compound #612, 617, and 620.

47. A compound according to claim 42 represented by the formula:

wherein R³ and R_21A are as defined below;

48. A compound according to claim 47, which is compound #715.

49. 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 thereof, in admixture with a pharmaceutically acceptable carrier medium or auxiliary agent.

50. A method of treating a hepatitis C viral infection in a mammal by 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.

51. A method of treating a hepatitis C viral infection in a mammal by administering to the mammal an anti-hepatitis C virally effective amount of the composition according to claim 49.

52. A method of inhibiting the replication of hepatitis C virus by 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.

53. A method of treating a hepatitis C viral infection in a mammal by 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.

54. A method according to claim 53, wherein said other anti-HCV agent is selected from the group consisting of:

α

-or β

-interferon, ribavirin and amantadine.

55. A method according to claim 53, wherein said other anti-HCV agent comprises an inhibitor of other targets in the HCV life cycle, selected from:

helicase, polymerase, metalloprotease or IRES.

56. 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 C_1-6 alkyl, cycloalkyl or C_2-6 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.

57. 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 C_1-6 alkyl, cycloalkyl or C_2-6 alkenyl, all optionally substituted with halogen, and CPG is a carboxyl protecting group.

58. 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.

59. The process according to claim 56, 57 or 58 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.

60. 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.

61. 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.

62. 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.

63. A compound of formula (I) according to claim 1, wherein each Het group is independently selected from the group consisting of diazepine, piperidine, 1,4-dioxane, 4-morpholine, pyridine, pyrimidine, or quinoline.