TW200813024A - Tetrazolyl acyclic hepatitis C serine protease inhibitors - Google Patents

Abstract

The present invention relates to compounds of Formula I, II, III or IV, or pharmaceutically acceptable salts, esters or prodrugs thereof: which can inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising a compound of the present invention.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel hepatitis C virus (HCV) protease inhibitor compound which has anti-HCV activity and is useful for treating HCV infection. More specifically, the present invention relates to a novel tetradecyl acyclic compound, a composition containing the same, a method of using the composition, and a method of producing the compound. f [Prior Art] HCV is the main cause of non-A, non-B hepatitis, and it has caused more and more serious public health problems in developed and developed countries. The virus is estimated to be infected more than 200 million people worldwide, more than five times more likely to be infected by human immunodeficiency virus (HIV). Patients with HCV infection have a higher risk of developing cirrhosis due to a higher proportion of individuals with chronic sensation, and subsequently develop hepatocellular carcinoma and terminal liver disease. HCV is the leading cause of hepatocellular carcinoma and is the leading cause of liver transplant in Western countries. There are considerable barriers to the development of anti-HCV therapies, including but not limited to: the virus is tenacious, the genetic diversity of the virus when replicated in the host, the chance of the virus developing into a drug resistant mutant, and the reproducible infection. Sex culture system and small animal model for HCV replication and pathogenesis. In the case of a large number of cases, due to the slight infection and the complex biology of the liver, special care must be taken for antiviral drugs that are prone to significant side effects.

At present, there are only two kinds of HCV salty, Zhi, Zhi, X, and the oral therapy has been recognized. The original course of treatment usually involves intravenous administration of interferon 1150-9065-PF in the time course of Putian + ours; Linlin 6 200813024 - a 1 pha ( IFN - α ), and a 1, _ - new ^ The second generation of treatment, including IFN-α and - general antiviral nuclear mimics, for example, Ribavidn, common / oral therapy ^ two 'oral therapy have encountered interferon-related side effects, and confrontation The problem of poor efficacy of HCV infection. Due to the poor tolerance of current treatments and poor efficacy, Yun 1M has developed antiviral agents that are effective against HCV infection. Tian Da. Patients with P-knife are sputum infections with no symptoms, and the prognosis is not (, ^ 彳 的 的 最好 最好 最好 最好 最好 最好 最好 最好 最好 最好 最好 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Since f _3 (NS3) is a proteolytic enzyme necessary for the treatment of viral polyproteins and subsequent viral replication, although 'a large number of viral variants are associated with Hcv infection', the active site of NS3 protease has Highly retained, so its inhibition is "attractive". The recent success in the treatment of ΗI v with protease inhibitors supports the concept of NS3 inhibition as a key target in the anti-Hcv war. " Feet are yellow The RNA virus of the family Flaviidae. The Hcv gene has a mantle membrane and contains a single-stranded molecule of about 96 Å. It encodes a polypeptide of about 30 1 amino acid. The protein is processed by the virus and host enzymes into peptides with various functions. There are three structural proteins, c, ei & e2qP70. The function of the substance is unknown, and includes highly mutated sequences. There are 6 kinds of non-structural proteins. NS2 is - A dependent metalloproteinase that acts to link to the deproteinized-part. NS3 is involved in two catalytic functions (separate from its association with de- cleavage). · Μ---------- - PF; Linlin 7 200813024 as a helper' and at the C-terminus - ATPase-dependent helicase function. NS4A is a closely related but non-covalent serine protease cofactor. NS3-4A protease Responsible for incision of the viral polyprotein. NS3-NS4A is self-catalyzed and occurs in the cis position. The other three hydrolases, NS4A_NS4B, NS4B_NS5A and ns5a_ns讥 occur in trans (trans Position: NS3 is a serine protease, which is structurally classified as a type of chymase (chym〇trypsin). Although Μ = amino acid protease itself has proteolytic activity, & Ηα protease is not a catalytic polyprotein cleavage As an efficient enzyme, it has been confirmed that one of the central hydrophobic regions of ns" protein shell is necessary for this enhancement. The formation of a complex with NS4A seems to be necessary for decomposition treatment. The protein decomposing potency of the site. The general strategy for the development of antiviral agents is to make the virus-encoded enzyme inactive, including NS3, which is necessary for viral replication. Recent research on finding protease inhibitors refers to s Tan, Α· pause, γ. shi, N.

Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov., 1 867-881 (2002). Patents relating to the synthesis of HCV protease inhibitors are: 卯00/59929 (2000); WO 99/07733 (1999); WO OO/09543 (2000); WO 99/50230 (1999); US5861297 (1999) and US2002/0037998 (2002) 〇 [Summary of the Invention] The present invention relates to novel HCV protease inhibitor compounds, including 1150-9065-PF; Linlin 8 200813024, a pharmaceutically acceptable salt, ester' or prodrug thereof, which inhibits serine protease The activity 'especially the live hepatitis IV virus (HCV) NS3-NS4A protease, whereby the compounds of the present invention interfere with the life cycle of the hepatitis C virus and act as an effective antiviral agent. The present invention is also directed to a pharmaceutical composition which comprises administering the aforementioned compound, or a salt, ester or cockroach thereof, to a subject infected with HCV. The invention is also a pharmaceutical composition comprising a compound of the invention (or a pharmaceutically acceptable salt, ester or prodrug thereof) and a further anti-agent, such as interferon U-interferon, stone-interferon , a combination of interferon, 'ethylene-alcoholized interferon, albumin or a combination of interferons), ribaVaHn, diamond-like (ada_tine), a further Hcv egg inhibitor or -HCV polymerase, helicase, Or an internal ribosome entry site inhibitor. The present invention is also directed to a method of treating a subject infected with HCV, which is administered to a pharmaceutical composition of the present invention. In the examples, 'the compounds disclosed in the present invention are represented by < I, melon or IV, or JL, X, /, table-acceptable salts, esters or precursors: (II)), . (m) (IV) 2 1150-9065-PF; Linlin 9 200813024 where: (〇0)-R2, -C(>〇)n A is selected from Ri, -(〇= 〇) — 〇— 1 or -S(0)2-Ri, -S(0)2NHR2; L is selected from the group consisting of: (1) aryl, substituted aryl; heteroaryl; substituted heteroaryl (ii) a heterocycloalkyl or substituted heterocyclic alkyl group; soil f

(iii) -CrC8 alkyl, -C2-C8 alkenyl or -C2-Cs alkynyl, each comprising hydrazine, 1, 2 or 3 heteroatoms selected from 0, S or N; substituted L 1 〜 L 8 alkyl, substituted -C 2 -C 8 alkenyl or substituted -C 2 -alkynyl, each containing hydrazine, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; -c3-C12 a cycloalkyl or substituted -C3-Cu cycloalkyl; -GC"cycloalkenyl or substituted -C3-Cl2 cycloalkenyl; R2 is independently selected from the group consisting of: (1) hydrogen; Aryl; substituted aryl; heteroaryl; substituted heteroaryl; (i Η)heterocycloalkyl or substituted heterocycloalkyl; (ivhCrC8 alkyl, _C2 -Cs alkenyl or C2-C8 alkynyl groups each containing hydrazine, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; substituted -CrCs alkyl, substituted _C2-Cs alkenyl or substituted - CrC8 alkynyl groups each containing hydrazine, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; -C3-Ci2 cyclodyl or substituted -C3_Cl2 cycloalkyl; -G-Ci2 cycloalkenyl Or substituted -C3-C12 cycloalkenyl; B is selected from [{ or CH3, G is selected from -NHS(O)2-R3 or -NH(S〇2)NR4R5; 1150-9065-PF ;Linlin 10 200813024 wherein R3 is selected from the group consisting of: (i) a radical of a substituted radical, a heteroaryl; a substituted heteroaryl; (ii) a heterocycloalkyl or a substituted heterocycloalkyl; -Ci-C8 alkyl, -C2~C8 alkenyl or -c2-C8 alkynyl, each comprising 〇1, 2 or 3 heteroatoms selected from hydrazine, S or N; substituted ~Ci. a substituted, CrC8 alkenyl group or a substituted -G-C8 alkynyl group, each of which contains 0, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; _C3 —c"cycloalkane 1

Or substituted -C3-Ci2 cycloalkyl; -C3-C!2 cycloalkenyl or substituted -C3-C12 cycloalkenyl; but R3 is not -CH2(C5H9); R4 and R5 are independently selected From: (1) hydrogen; (ii) aryl, substituted aryl; heteroaryl; substituted heteroaryl (iii) heterocycloalkyl or substituted heterocycloalkyl; (iv)-C -C8 alkyl, -C2-decenyl or -C2-C8 alkynyl, each comprising 1, 2 or 3 heteroatoms selected from hydrazine, 3 or N; substituted oxime. An alkyl group, a substituted C2-C8 alkenyl group or a substituted C2-Cs alkynyl group, each containing eight, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; Or substituted -Gk cycloalkyl; -C3 -cycloalkenyl or by -C3-indole 12; the L and Z series are independently selected from: (1) hydrogen; (u) aryl; substituted Aryl; heteroaryl; substituted heteroaryl (iii) heterocycloalkyl or substituted heterocycloalkyl; 1150-9065-PF; Linlin 11 200813024 (iv)-Cl-C, c8 Anthracenyl or _C2_C8 alkynyl, each of which contains 1, 2 or 3 heteroatoms selected from hydrazine, UN; substituted c, alkyl, substituted -C2_C8 dilute or substituted fluorenyl, Each ^ 〇, 卜 2 or 3 hetero atoms selected from 0, SstN; A -. Heart: or substituted - c3_Cl2 cycloalkyl; _C3_Ci2 cycloalkenyl or taken: - C 3 - C 1 2 cycloalkenyl; X is selected from: (1) hydrogen; (8) aryl; substituted aryl Heteroaryl; substituted heteroaryl. (iii) heterocycloalkyl or substituted heterocycloalkyl; earth, (i W-CrC8 alkyl, -C2-C8 alkenyl or _C2_C8 alkynyl, Each contains 〇,

1, 2 or 3 heteroatoms selected from 0, S or N; substituted -C alkyl, substituted -C2 - (:8 alkenyl or substituted _C2_C8 block, each ^8 8 〇, 1, 2 or 3 heteroatoms selected from 0, UN; -c heart ring = or substituted - C3_Cl2 cycloalkyl fluorenyl-hydrazine" cycloalkenyl, · ^ or substituted (1) H, Where W does not exist or is selected from _〇...s_, -N(Me)-, -C(8)NH_ or _c(8)N(Me)_ ; r" is the selected ethnic group · 堺 constitutes (a) hydrogen; (7) Fang Substituted aryl; heteroaryl; substituted heteroaryl; (c) heterocycloalkyl or substituted heterocycloalkyl; () Ci C group, —C 2 —C 8 alkenyl or — Q —& fast radicals, each containing 1 2 or 3 heteroatoms selected from ., q bucket, or oxime; substituted—Ci-Cs H50~9065-PF; Linlin 12 200813024 alkyl, via Substituted _C2_C8 0, sub-substituted -C2-C8 alkynyl group, each containing ° 1 2 or 3 heteroatoms selected from hydrazine, s or hydrazine; -C3-Cl2 cycloalkyl Or, disubstituted-C3 - Cl2 cycloalkyl; -Crk cycloaliphatic; LCu% fine or substituted m=〇, 1 or 2; n=l, 2 or 3 [Embodiment] The first embodiment of the present invention is a compound represented by Formula I of the above + #^一η月, or a pharmaceutically acceptable hydrazine, a slightly ambiguous or a pharmaceutically acceptable drug, alone or in combination with a pharmaceutical Acceptable carrier or excipient. In another embodiment, after the present invention

X x 呶明 relates to the compound of formula V:

N

A commercially acceptable carrier or excipient wherein a, l, X, W G are as defined above. In another example, the X system is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl. , -Cl-C8 calcined, r Γ π group, -C2-C8 alkenyl or -C2 - C8 alkynyl group, each containing 0, 1, 2 or 3 selected from 八 Q. λτ with a target of 0, S Or a hetero atom, substituted 1150-9065~PF; Linlin 13 200813024

Ci-Cs alkyl, substituted - C2-Cs alkenyl or substituted - c2_c each comprise ο, 1, 2 or 3 heteroatoms selected from ο, S or N, -C3 - Ci alkynyl ▲攻〇〇评(二)々;u〇JN hetero atom,—C3—C” cycloalkyl, -c3-Cl2 cycloalkenyl, substituted each & 2 ring or substituted -C3- Cu cycloalkenyl. A is selected from the group consisting of: -C-(〇)-匕, -C-(0)-0-R5, -c(〇)_NH-R5, wherein Rs is selected from Aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted hetero-alkyl, -Cl-G alkyl, _C2-decenyl, -G-匕Alkynyl, substituted-CrL alkyl, substituted-Cr&alkenyl or substituted _c2-&alkynyl, -G-Cucycloalkyl, -Cl2 cycloalkenyl, substituted -C3 —Ci 2 cycloalkyl or substituted —C 3 —Cl 2 cycloalkenyl. L and z are independently selected from —alkyl — —C 2 -C 8 alkenyl or —C 2 —C 8 alkynyl, substituted —Ci — C8 alkyl, substituted -G2—G8 alkenyl, substituted K8 alkynyl, —(;3-Cl 2 cycloalkyl, —C3-C!2 cycloalkenyl, substituted—C3 _Ci2 cycloalkyl or substituted cyclopentene can be -NH-S02-NH-n_2-R3, and R3 is selected from aryl, heteroaryl, substituted by nitrogen aryl M. a heteroaryl group, a heterocyclic alkyl group, a substituted heterocyclic alkyl group, a C3-Ci2 cycloalkyl group, a cycloalkenyl group, a substituted G12 ring county or a substituted ring of a 2 ring ring. Alternatively, X is selected from the group consisting of aryl, substituted aryl, heteroaryl or substituted heteroaryl. A is -(:(〇) -〇_15 or C(〇)腾5, wherein R5 is a Cl-C8 yard, -c2-c8 fluorenyl or a c2-c8 alkynyl group, substituted -c"p^^uh alkyl, substituted-C2-Cs alkenyl, Substituted C2 C8 alkynyl, -C3~Cl2 cycloalkyl, -Cs-C!2 cycloalkenyl, substituted C2 cycloalkyl or substituted C2 cyclohexane. L is selected from - Ci_C8 alkyl, -c2-c8 alkenynynyl, substituted c-channel, substituted by 1150-9065-PF; Linlin 14 200813024 - C2~Cs alkenyl or substituted -CrCs alkynyl, ~ C3-Ci2 cyclodextrin, -C3-Cu cyclodecyl, substituted _c3-Ci2 cycloalkyl or substituted -C3~Ci2 cycloalkenyl Z is selected from the group consisting of -κ8 alkyl, ~C2_Cs alkenyl, substituted alkyl, substituted -C2-Cs alkenyl. G is -NHS〇2-R3, wherein R3 is derived from aryl, Substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -Cs-Ci2 cycloalkyl, -C3-Ci2 ring cyclized, substituted - C3 -C! 2 cycloalkyl or substituted -C3-C!2 cycloalkenyl. In yet another example, the X group is selected from the group consisting of an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group. A is -C(0)-〇-r5, wherein only 5 is -C3-Ci2 cycloalkyl or substituted -C3-Ci2 cycloalkyl. l is selected from - Ci-C8 alkyl or substituted - Ci-C8 leuco. The Z series is selected from -C2-C8 fluorenyl or substituted -C2_C8 alkenyl. G is -NHS〇2-R3, wherein r3 is selected from -C3-C12 cycloalkyl or substituted -G-Cu cycloalkyl. In still another example, X is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl. A is -C(0)-NH-R5, wherein r5 is -Ci_C8 alkyl or substituted _Ci-C8 alkyl. The L system is selected from a -Ci-Cs alkyl group or a substituted -Ci-C8 alkyl group. The Z series is selected from the _C2-C8 dilute group or the substituted -C2-C8 fine group. G is ·"NHS〇2-R3' wherein R3 is a -C3-Cl2 cycloalkyl group or a substituted -C3-Ci2 cycloalkyl group. In another embodiment, the invention relates to a compound of formula VI: 1150-9065-Pf^ Linlin 15 x200813024

Or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier or a pharmaceutically acceptable agent.酉曰 or prodrug, alone or in combination with a 'where A, L, Z, r, v and X are the same as before

Heteroaryl-Cl-C8 alkyl, -C2-Cs, "Γα# π丞 or -C2-C8 alkynyl, each containing 〇3 selected from 0, S or Ν; a hetero atom, a substituted C8 alkyl group, a substituted C2-C8 alkenyl group or a substituted disubstituted C2-C8 alkynyl group, each containing 〇, i, or 3 selected from 0, 8 or ^[夕左四搭0 ^ X n of heteroatoms, -c3-c12 cycloalkyl, -C3—Ci2 ring dilute, substituted ~ Γ r r I into w #上u Cl2 J 烷基 alkyl or Substituted -C3-C-2-cycloalkenyl. A is selected from the following · · · a 軚 軚 · · -C (〇)-R5, - 〇) - 〇 - Rs and

For example, X is selected from the group consisting of an aryl group, a substituted heteroaryl group, and a substituted heterocycloalkyl group by C(0) NH R5 r in the r5 system. Aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -Cl-C8 alkyl, -C2-C8 dilute, ~c2_C8 alkyne Substituted, substituted -Ci-C8 alkyl, substituted -C2-C8 dilute, substituted -o-Cs alkynyl, -C3 -cycloalkyl, -C3-Cl2 cycloaliphatic -C3 - Ci2 cycloalkyl or substituted _Cs - ring dilute. L and Z are independently selected from _Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8 fast radical, substituted -CBu cs alkyl, substituted C2-C8 alkenyl, via Substituted -CrC8 alkynyl, -C3~Cl2 cycloalkyl, -C3-Ci2 cycloalkenyl, substituted -Cs-c. % alkyl or substituted - C3_Ci2 cycloalkenyl. G can be 1150-9065-PF; Linlin 16 200813024: _NH-S〇2_NH-R3 or -NHS〇2-R3 'where r3 is selected from chlorine, aryl, substituted aryl, heteroaryl, Substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -C3-Cu cycloalkyl, -C3-Cl2 cyclodext, substituted -C 3 -C 1 2 i alkyl or Substituted -C 3 -C 1 2 ring-dilute group. In yet another example, the X family is selected from the group consisting of an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group. Α is —C(0)-0_R5 or C-(0)-NH-R5 ' wherein R5 is -Ci-Cs alkyl, -c2-c8 alkenyl, -C2-c8 alkynyl, substituted-CrC8 alkane Substituted, substituted C2-C8 dilute group, substituted C--C 2 -C 8 fast group, -C 3 - C12 per alkyl group, -c 3 - C12 ring dilute group, substituted -Cs- Cu cycloalkyl or substituted -CrCu cycloalkenyl. L is selected from -CrC8 alkyl, -CrC8 alkenyl, -C2-C8 alkynyl, substituted -G-c8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkyne Base, -C3_Cl2 cycloalkyl, -C3-. 2 cycloalkenyl, substituted -G-Cl2 cycloalkyl or substituted -C3_Cl2 jade. The Z series is selected from a Ci-C8 alkyl group, a -C2-C8 dilute group, a substituted -Ci-C8 alkyl group or a substituted -C2-C8 alkenyl group. G is -NHS〇2~R3, wherein R3 is an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heterocycloalkyl group, a substituted heterocycloalkyl group, —C 3 —c 12 cycloalkyl, —c3-C 12 cycloalkenyl, substituted —Cs—Cu cycloalkyl or substituted —C 3 —Cl 2 cycloalkenyl. In still another example, X is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl. A is -C(0)-〇-R5, wherein R5 is -G-Cu cycloalkyl or substituted -C3-CH cycloalkyl. The L system is selected from a Ci-C8 alkyl group or a substituted C1-Cs alkyl group. z is selected from _C2_C8 alkenyl or substituted -C2-C8 alkenyl. G is _NHS〇2-R3, wherein r3 is selected from a -G-Cn cycloalkyl group or a substituted C3__Cl2 cycloalkyl group. 1150-9065-PF; Lirilin 17 200813024 In another example, x is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl. A is ~C(〇)-NH-R5, wherein R5 is c!-C8 alkyl or substituted-CrC8 alkyl. The L system is selected from a Ch-C8 alkyl group or a substituted -Ci-C8 leuco group. The Z series is selected from -G-C8 fluorenyl or substituted - c2 - Cs alkenyl. G is -NHSOrR3, wherein R3 is -C3-CH cycloalkyl or substituted -C 3 -C 1 2 cycloalkyl. In another embodiment, the present invention relates to a compound of the formula

Or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient, wherein A, L, z, G and hydrazine are as defined above.

In another example, X is selected from the lower stone, 丨谂 · · #付, (3) 歹 歹] no group · square, substituted aryl, heteroaryl, substituted heteroaryl, miscellaneous ^ ^, a hetero-J-alkyl group, a substituted heterocyclic alkyl group, a -Cl-C8 alkyl group, a -C2-C8 dilute hydrazine-r9r Wrl^, a ΜA A-Cs alkynyl group, each containing 〇, 1, 2 Or a cycloalkenyl group, a substituted - c3 - Cl2 group. The A line is selected from the group -C(0)-NH-R5, where r5 is selected from the hetero atom of 〇 s or N, substituted A —. An alkyl group, a substituted -c2-c8 alkenyl group or a substituted decynyl group each containing i 2 or 3 hetero atoms selected from 0, _, (10) cycloalkyl, naphthyl or Substituted - C3-C12 cyclic olefin group: -C(0)-R5, -c(0)-0-R5 and from aryl, substituted aryl, heteroaryl 1150-9065-PF; Linlin 18 200813024 " Substituted heterocyclyl, heterocycloalkyl, substituted heterocycloalkyl, -CrCs alkyl, -c2-C8 dilute, ~Γ" ^ 2 C 8 fast radical, substituted -C i—C 8 alkyl, substituted—C2-Cs fluorenyl, hydrazine, C 2 -C 8 alkynyl, —C 3 —C 1 2 cycloalkyl, —c3-c12 cycloalkenyl, Take the C3-Cl2 alkyl group of S n or the substituted -c3-C12 group. L and Z alone> (each 4w) is selected from -C!-c8 alkyl, -C2-C8 alkenyl, -c2-C8 alkynyl, substituted - "Γ 8, aryl, substituted —C 2 —C 8 dilute, substituted C 2 c 8 alkynyl, —c 3 —Ci 2 cycloalkyl, —C 3 —Ci 2 cycloalkenyl, substituted f. % —C 3 —Cl 2 cycloalkyl or substituted Ci 2 ring Alkenyl. G can be NH S〇2 NH R3 or ~NHS〇2-r3, wherein r3 is selected from hydrogen, aryl, substituted radical, heteroaryl, substituted heteroaryl, heterocyclic An alkyl group, a substituted heterocarbyl group, a Cl2 cycloalkyl group, a C3-Ci2 cyclodecyl group, a substituted C3 Cu% alkyl group or a substituted -Q-Ci2 cycloalkenyl group. In yet another example, In yet another example, the X group is selected from the group consisting of an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group. A is -C(0)-〇-r5 or C-(〇)-NH -R5, wherein Rs is a Ci-C8 alkyl group, a _C2-Cs alkenyl group, a -u alkynyl group, a substituted -Cl-Cs alkyl group, a substituted C2_C8 alkenyl group, a substituted c2-C8 alkyne a group, a c3—Cl 2 cycloalkyl group, a —C 3 —Ci 2 ring dilute group, a substituted C 3 -Cu cycloalkyl group or a substituted C 3 —cycloalkenyl group Select from - ClA alkyl, -C2-G8 alkenyl, -c2_G8 alkynyl, substituted -Gi-G8 alkyl, substituted -CrC8 alkenyl, substituted -Cz-Cs alkynyl, _C3 a cycloalkyl, C3 c" cycloalkenyl, substituted _C3-cycloalkyl or substituted - aryl, substituted aryl, heteroaryl, substituted heteroarylcycloalkenyl. The Z series is selected from a C1-C8 alkyl group, a -C2-alkenyl group, a substituted -= alkyl group or a substituted -C2-C8 alkenyl group. G is -NHS〇2-R3, wherein R3 is a heterozygous 1150 -9065-PF;Linlin 19 200813024 - cycloalkyl, substituted heterocycloalkyl, -C3-c12 cycloalkyl, -C3-c"cycloalkenyl, substituted -C3-c12 cycloalkyl or Substituted -C3-C12 cycloalkenyl. In yet another example, X is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl. A is -c(0)- 0-R5, wherein R5 is -C3_C"cycloalkyl or substituted -C3-c12 cycloalkyl. L is selected from Ci-Cs alkyl or substituted -CrC8 leuco. The z series is selected from - C2-C8 alkenyl or substituted -c2-c8 alkenyl. G is -NHS〇2-R3, wherein r3 is -(:3-(:12 cycloalkyl or substituted) -C3-Cl2 cycloalkyl. In another example, X is selected from the group consisting of aryl, substituted aryl 'heteroaryl, substituted heteroaryl. △ is "C(〇)-NH- R5, wherein Cl-C8 is substituted or substituted with -C丨-Cs alkyl. The L system is selected from a Cl-C8 alkyl group or a substituted -CrC8 alkyl group. z is selected from —C 2 —C 8 alkenyl or substituted —C 2 —C 8 alkenyl. G is -NHS〇2-R3 wherein Rs is selected from -C3_Ci2 cycloalkyl or substituted -C3-C12 cycloalkyl. In another embodiment, the invention is directed to a compound of the formula:

(VIII) Ν=Ν NVN, x or a pharmaceutically acceptable salt thereof, a slight or a prodrug, alone or in combination ~ a pharmaceutically acceptable carrier or excipient, wherein A, L, Z, G and X As defined above. In another example, the X series is selected from the following groups: aryl, substituted aryl, 1150-9065-PF; Linlin 20 200813024 heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted Cyclone, -CrC8 alkyl, -C2-C8 alkenyl or -C2-C8 alkynyl, each containing hydrazine, i, 2 or 3 heteroatoms selected from 0, S or N, substituted - Cl - Cs alkyl, substituted -CrC8 alkenyl or substituted -C2_Cs alkynyl, each comprising hydrazine, 1, 2 or 3 heteroatoms selected from 0, S or N, -c3-C12 cycloalkyl — —c3-Cw cycloalkenyl, substituted —C 3 -Cu cycloalkyl or substituted —C 3 —Cl 2 cycloalkenyl. A is selected from the following groups: -c(〇) -&, -c(〇) -〇_R5 and f. -C(0)-NH-R5, wherein Rs is selected from aryl, substituted Aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -Ci - C8 alkyl, -CrC8 alkenyl, -C2 -C8 alkynyl, substituted _Ci-C8 alkyl, substituted -C2-decenyl, substituted -o-alkynyl, -Ci2 cycloalkyl, -C3_C12 cycloalkenyl, substituted -o-Cl2 cycloalkyl or Substituted - C3-Ci2 cycloalkenyl. L and Z are independently selected from _Cl-Cs alkyl, -C2-alkenyl, -C2-^ alkynyl, substituted-K8 alkyl, substituted -Ο2. Alkenyl, substituted-Crh alkynyl, -G-Cucycloalkyl, -C!2 cycloalkenyl, substituted -Cs-Cu cycloalkyl or substituted -C3-Cucycloalkenyl. G may be -NH-S〇2-NH-R3 or -NHS〇2-&, wherein & is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl , heterocycloalkyl, substituted heterocycloalkyl, -C3-(: 12cyclohexyl, anthracenyl, substituted -C3-Ci2 cycloalkyl or substituted - ο - Ci2 ring In another example, X is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl. Eight is _C(0) (H^ or -c(0) -nh-r5, wherein hydrazine is fluorenyl-fluorenyl, _C2_C8 alkenyl, alkynyl, substituted-Cl-C8 alkyl, substituted _C2_Cs alkenyl, substituted 8 1150-9065-PF; Linlin 21 200813024 ; -C2_C8 block, -C3~Cn cycloalkyl, ~C3-C12 cycloalkenyl, substituted -Cs-C!2 cycloalkyl or substituted -CrCl2 cycloalkenyl. From -Ci - C8 alkyl, -C2-C8 alkenyl, ~C2-C8 alkynyl, substituted -Ci_Cs alkyl, substituted -C2_C8 alkenyl, substituted -C2~C8 alkynyl, - Cs-Ci2 cycloalkyl, -C3-C12 cycloalkenyl, substituted -c12 cycloalkyl or substituted -c3_c12 cycloalkenyl. Z is selected from -Ci-C8 alkyl, -C2-C8 Alkenyl, substituted-CrCs alkyl or substituted -C2-C8 alkenyl. G is -NHS〇2-R3, wherein R3 is aryl, substituted aryl, heteroaryl, substituted Aryl, heterocycloalkyl, /substituted heterocycloalkyl, ~C3-Ci2 cycloalkyl, -c3-C12 cycloalkenyl, substituted -C3-Cl2 cycloalkyl or substituted -C3- Cl2 cyclodecyl. In another example, X is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl. A is -C(0) - 〇-r5, where R5 Is _C3_Cl2 % alkyl or substituted -C3-Ci2 cycloalkyl. L is selected from Ci-c8 alkyl or substituted -Ci-C8 alkyl. Z is selected from -C2-C8 alkenyl Or substituted -C2-C8 alkenyl. G is -NHS〇2-R3, wherein R3 is selected from -c3_Ci2 cycloalkyl or substituted -(: 3-(:12 cycloalkyl. In one example, the X group is selected from the group consisting of an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group. A is ~c(0)-NH-R5, wherein R5 is a Cl-C8 alkyl group or Substituted -Cl-C8 alkyl. L is selected from Ci-c8 alkyl or substituted -Ci-Cs alkyl. Z is selected from -c8 alkenyl or substituted -C2-c8 alkenyl . G is -NHS〇2-R3, wherein R3 is -C3_Ci2 cycloalkyl or substituted -C3-Cl2 cycloalkyl. The representative compound of the invention 'includes, but is not limited to, the following compounds according to formula IX (Table 1). 1150~9065-PF; Linlin 22 200813024 Table 1 Example ALQ z G 8 person again / ,,, ( !L -CH=CH2 9 people / V - CH=CH2 -w 10 people / Λ 1 < V 1 - Ch=ch2 /^v 11 Λ1< P -ch=ch2 /^v 12 people again / winter -f - CH=CH2 /°V〇Yr 13 people again / > -ch=ch2 /nts, n〆HI 14人又/ 卜多I η -ch=ch2 /〇,,〆/〇'hn r 15 people again / , -PV 1 -ch=ch2 /, Xr H | 16 people again / Λ 1< p- V 1 - Ch=ch2 1150-9065-PF;Linlin 23 200813024 17 person / V 1 -CH=CH2 18 people / ,, winter cf. l. -ch=ch2 19 people / Ν-Ρ V 1 -ch=ch2 43⁄4 20 乂. Also / ρ- 0 (:Ν IN -ch=ch2 /, gas 21 乂Jy .AVI -CH-CH2 /3⁄4. 22 乂. Also / Λ -CH 2 CH2 ^^CHs 23 person / VN 1 -ch=ch2 ^^ch3 24 people again / /, f ρ- , ρ V 1 -ch=ch2 /3⁄4 N, 25 people again / V 1 - ch=ch2 Hn, > N \ 26 people again / ρ - ΝνΝ 1 -ch=ch2 N \ 1150-9065-PF;Linlin 24 200813024 27 人又 / ,,冬ΝΥΝ -CH=CH2 /斤,〉 N \ 28 ,r Jr η -ch=ch2 29 iQkA/ -f N -ch=ch2 Λίί'ν 30 Cl〇A/ 丨冬>. — V -CH-CH2 /^v 31 ς again / v -ch=ch2 /, 八32 CX0 again / λ N -CH di CH2 33 〇y N -ch=ch2 34 V -ch=ch2 35 VN -ch=ch2 w 1150-9065-PF;Linlin 25 200813024 36 人Λ1< li -CH=CH2 /, ^v 37 〇0 -ch=ch2 //v 38 -ch=ch2 39 F _ 0 f fire v eight. Meaning y 1 .0°' Λ N -CH=CH9 /, 八 40 cx and V, Λ -ch=ch2 41 Ο^Λ -ch=ch2 42 /丫-f !L -ch=ch2 //v 43 α Xr p- 0 V 1 -ch=ch2 44 1 -ch=ch2 Λίί^ν 1150-9065-PF;Linlin ^ 6 200813024 45 αΛ -CH=CH2 46 , and / li -ch=ch2 /, ί^ν 47 <yl/ -ch=ch2 Λίν 48 , 'J'/ 0. , Λ !L -CH=CH2 / 八49 <// p- fi λ - CH=CH2 /, & 50 <X/ /r Review -ch=ch2 /, ί^ν 51 a -ch=ch2 /^ν 52 p- V 1 -ch=ch2 Λίί'ν 53 A Me ,, winter p- NVN 1 -CH-CH2 1150-9065-PF;Linlin 27 200813024 54 {Λ Λ1< V -ch=ch2 55 〇 ΗΝΛβ Y -ch=ch2 /^v 56 Mei^ Me 0 N -ch=ch2 57 InV ^ /, < 1 .0°' η Ν -ΓΗ=ΓΗ9 /Ί Η V 58 a1, y Ν _ch=ch2 59 ~ y π -ch=ch2 //v 60 Change. Also / /丫-CH di CH2 61 /, r a general N -ch=ch2 /, & 62 /, 〇V 1 -ch=ch2 /, ί^ν 28 1150-9065-PF/Linlin 200813024 63 ^〇 A/ aJ〇V 1 -ch=ch2 64 p- fi !L -ch=ch2 ^N^SYSv_ H 65 ^〇A/ p- fi N^T -ch=ch2 /, N meaning N, 1 H kj) Fifi αΛ· /< 0. — Λ N -Γ,Η=Γ,Η9 AN^N^j n,^,ch3 67 ^〇A/ -ch=ch2 α^λ 1 H 68 Change. Also / Al< -f -CH=CH2 /, production 1> 69 ^〇A/ ', winter-f 1% -ch=ch2 /3⁄4 70 1 -ch=ch2 /3⁄4 ^^co2h 71 ^〇A/ p - V 1 -ch=ch2 An^ HU〇CH3 1150-9065-PF;Linlin 200813024

72 v -CH-CH2 73 Wen. Also / Λ1< γ -ch=ch2 74 Λ1< p- γ -ch=ch2 75 a Iy σ 7 /< 1 ..0°' Λ -ΓΗ=ΓΗ9 IN N in Η H 76 ^〇A/ -f Ν -ch=ch2 /, ΧΛ> Η H 77 汶Λ / Λ1< ΝγΝ -CH-CH2 /, Xf3 H 3 78 Λ1< ΝγΝ -ch=ch2 79 Also / Bu, winter y Ν -ch=ch2 80 y -ch=ch2 A 1150-9065-PF;Linlin 30 200813024 81 'Winter V -ch=ch2 A^F 82 :, V -ch=ch2 /, x people Η H 83 Wen. Also / y λ Ν -ch=ch2 Η H 84 α 2. ——0,, / /, f 0°' -CH=CH9 人》?丄ΙΊ 会' Η 85 again / Λτ< V -CH=CH2 / %° ', ί, N\3 86 ^〇Α/ ~ >0' V -ch=ch2 / %? η Hcy 87 汄. Also / /卞 >0' νΝ -H //ν 88 Wen. Also / >0' Ν, -CH2CH3 /, iFv 89 汄. Also / /, f > 0' γ -CF2 /^v 1150-9065-PF; Linlin 200813024 90 V -ch=ch2ch 3 //v 91 ΛΛ 0. , N-N ΝγΝ -CH=CH2 / 八 92 ΛΛ 0^°\ Ν-Ν ΝγΝ -ch=ch2 93 people again / ,.夕Ν-Ν nUn -ch=ch2 Λίίδν 94 ΛΛ 0C, Ν-Ν ΝγΝ -CH:CH2 /, iFv 95 person / 0S' Ν-Ν ΝγΝ -ch=ch2 z/v 96 person / 丨'' winter Ν-Ν ΝγΝ -CH=CH2 97 人又/ Φ Ν-Ν ΝγΝ -ch=ch2 98人又/ Λ1< Ν-Ν ΝγΝ _ch=ch2 //v 1150-9065-PF;Linlin 32 200813024 99 CP NN ΝγΝ -ch=ch2 /, & 100 <λ0 again / 0. ~ Ν-Ν ΝγΝ -CH=CH2 w 101 乂Λ, ^C, -ch=ch2 102 OJy ¥ V -ΓΗ 二Γΐίο 'W ▲ JL ▲ JL u •A^V 103 乂Λ/ yr -ch=ch2 ' iFv 104 Cl0 again / jr 1 -CH=CH2 /, & 105 γ -ch=ch2 106 α. Also / /丫 C^p γ -ch=ch2 107 αΛ ο^ρ NVN -ch=ch2 108 CX. And / / 丫 <^Ρ -ch=ch2 1150-9065-PF; Linlin 200813024 109 €10 again / γ -CH=CH2 110 CX. ^/ / 丫 ν >τν 1 -CH=CH2 The present invention also relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, ester or precursor. According to still another embodiment, the pharmaceutical composition of the present invention further comprises other anti-HCV agents. Examples of anti-HCV agents, including but not limited to interferon (alpha-interferon,/5-interferon, complex interferon, polyethylene glycolated interferon, albumin or combined interferon), ribavirin Like diamonds. For additional details, please refer to S. Tan, A. Pause, Υ. Shi, Ν· Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging

Strategies, Nature Rev. Drug Discov·, 1, 867-881

(20 02). The following information is hereby incorporated by reference in its entirety by reference in its entirety by reference in its entirety in the the the the the the the the the the the the the the the the the the the the the the US 2002/0037998 (2002). According to yet another embodiment, the pharmaceutical composition of the invention further comprises other HCV protease inhibitors. According to yet another embodiment, the pharmaceutical compositions of the present invention further comprise inhibitors of other targets in the life history of HCV, including but not limited to helicases, polymerases, metalloproteinases or IRES. According to still another embodiment, the pharmaceutical composition of the present invention further comprises other 34 1150-9065-PF; Linlin 200813024 - an antiviral, antibacterial, antifungal or anticancer inhibitor, immunomodulator, or other therapeutic agent. According to still another embodiment, the invention further comprises a method of treating an Hcv-infected subject, wherein the subject is administered an anti-HCV virus effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester or precursor. In accordance with yet another embodiment, the invention further comprises a method of treating an object that is infected with Hcv, the subject being administered an anti-HCV virus effective amount or an inhibitory amount of the pharmaceutical composition of the invention. According to still another embodiment, the invention further comprises a method of treating a biological sample by contacting the biological sample with a compound of the invention. According to another embodiment, the invention includes a method of making any of the compounds herein, using any of the synthetic methods described herein. Definitions The definitions used to describe the various terms of the invention are set forth below. The definitions of these terms apply to this specification and the scope of the patent application, unless otherwise specified in the particular case of an individual or a larger group. The term "CrC6 alkyl" or "Ci-C8 alkyl" as used herein, means a saturated straight or branched chain hydrocarbon containing a group of 6 or 8 carbon atoms. Examples of the Cl-C6 alkyl group include, but are not limited to, methyl, ethyl, propyl, isopropyl, aryl, ternary tributyl, neopentyl, n-hexyl radical; and Cl-C8 alkyl Examples of the atomic group include, but are not limited to, methyl, ethyl, propyl, isopropyl, fluorenyl, aryltributyl, neopentyl, n-hexyl, heptyl, octyl radicals. The term "C2-C6 alkenyl" or "C2-C8 dilute" as used herein, denotes 1150-9065-PF; Linlin 35 200813024 is derived from a monovalent group derived from a hydrocarbon moiety by removal of a mono-hydrogen atom, Wherein the tobacco moieties each comprise 2 to 6 carbon atoms or 2 to 8 carbon atoms and have a double anti-double bond. The alkenyl group includes, but is not limited to, for example, an ethylene group, a propenyl group, a butylene group, a diphenyl group, a 2-butylene group, a heptyl group, a octyl group, and the like. - The term "c2-C6 fast radical" or "C2_C8 alkynyl" as used herein, denotes a monovalent group derived from a hydrocarbon moiety by removal of a mono-hydrogen atom (tetra), wherein the hydrocarbon moiety: each comprises 2 to 6 One carbon atom or 2 to 8 carbon atoms, and has a carbon-carbon triple bond formed by removing a single hydrogen atom. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, butynynyl, heptynyl, octynyl and the like. , the term "c3-c8_cycloalkyl" or "C3_Ci2_cycloalkyl" used in the term "," represents a monovalent group derived from a mono- or polycyclic saturated carbocyclic compound from which an early-hydrogen atom is removed. In H, the carbon ring has 3 8 carbon atoms ^ 3 to 12 carbon atoms. Examples of c3_c8-cycloalkyl groups, including but not limited to: propyl propyl butyl, j ahylpentyl, cyclohexyl, cyclopentyl, and cyclooctyl; and examples of C3-Cl2-cycloalkyl, including However, it is not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2. 2.1] heptyl and bicyclo [2.2.2] octyl. The term "c3-c8_if" or "C3_Ci2_cyclo", as used herein, refers to a derivative derived from the mono- or polycyclic ring having at least one carbon-carbon double bond removed by a single-hydrogen atom. One of the monovalent groups of the saturated carbocyclic compound, in the pot, each of the carbon rings has one carbon atom or three to two carbon atoms. Examples of the G_C8_ring rare earth include but are not limited to .% propylene, cyclobutenyl, cyclopentenyl, hexenyl, gheptenyl, cyclooctyl, and the like; and examples of cycloalkenyl include but not It is limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexene 1150-9065-PF/Linlin 36 200813024, cycloheptenyl, cyclooctenyl and the like. / The term "aryl" as used herein means: a mono- or polycyclic carbocyclic ring system which has one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrastearyl, indane Indanyl, indenyl, and the like. As used herein, *"arylalkyl" means _u-based or

The Cl—C6 alkyl residue is attached to an aryl ring. Examples include, but are not limited to, a benzyl group, a hexyl group, and the like. As used herein, the term "heteroaryl" means a monocyclic, bicyclic or trihydric aromatic radical or ring having from 5 to 10 ring atoms, one of which is selected from, for example: S, G and Ν, 〇, Μ 2 ring atoms are additional heteroatoms, independently selected from, for example, s, 〇, and Ν; and other ring atoms are anti-hetero squares including but not limited to σ σ base, It is more specific than sulfhydryl, glucosinolate, and oral than 11 bases, salivary, and salivary.唾 基 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐The phenyl group and the like. The term "Μ- σheteroarylalkyl" as used herein means that a Ci-c3 alkyl C6 compound residue is attached to the -heteroaryl ring. Examples include, but are not limited to, ° dimethyl group, decyl phenethyl, and the like. Intercommunication means a non-aromatic 3_, as used herein, the term "heterocyclyl" & "heterocyclic alkyl", which may be a 5-, 6- or 7-membered ring or a di- or tricyclic group. In the system, the basin, a (1) each ring contains 1 to 3 heteroatoms, independently selected from oxygen, furnace / 虱 & and 虱; (丨丨) each 5 member ring has 〇 to 丨a double bond, and each 6-membered ring has a 〇-to-one double bond; (iii) the nitrogen and sulfur heteroatoms can be oxidized as desired; (iv) ^) μ mouse heteroatoms can be optionally quaternized, and (iv) 1 trace 9〇65-PF; Linlin 37 200813024 Any of the above rings may be fused to a benzene ring. Representative heterocycloalkyl groups, including but not limited to: [丨, 3] ditropanol, Pyrrolidinyl, pyrazolinyl, pyrazole cryptyl, imidazolinyl, imidazolidinyl, hexahydropyridyl, piperidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidine And isohydrothiazolidinyl and tetrahydrofuranyl. The term "substituted" as used herein, means independently replacing 1, 2 or 3 or more hydrogen atoms of the original radical as a substituent, including but not limited to: -F, -C1, -Br - I, -0H, protected hydroxy group, -N〇2, -CN, _ off 2, protected amine group, -NH-CrCu-alkyl group, -NH-C2-C12-alkenyl group, -nh- C2-c12-alkenyl, —NH—c 3 —Cl 2 —cycloalkyl, —NH—aryl, —NH heteroaryl, —NH—heterocycloalkyl, —dialkylamino, —diarylamino ,-diheteroarylamino,-0-Ci-C"-alkyl,-0-C2-C12-dense, -〇-C2-C12-alkenyl,-0-C3-C12-cycloalkyl , -〇-aryl, -〇-heteroaryl, -oxime-heterocycloalkyl, -(:(0)-〇-C12-alkyl, -C(0)-C2-C12-alkenyl, - C(〇)-C2-C12-alkenyl, -c(0)-C3-c"-cycloalkyl, -c(0)-aryl, -C(〇)-heteroaryl, -c(0 )-heterocycloalkyl, -C0NH2, _C0NH-Cl-Ci2_alkyl, -c〇NH-C2_Ci2-alkenyl, -C0NH-C2-C12-alkenyl, -C0NH-C3-C12-cycloalkyl, - C0NH-aryl, -C0NH-heteroaryl, -CONH-heterocycloalkyl, _OC〇2 -Ci-Ci2-alkyl, -〇C〇2-c2-C12-sweet, -〇C〇2- C2-C12-fluorenyl, -〇C〇2-C3-C12~cycloalkyl, -OC〇2-aryl, -〇C〇2_heteroaryl, -〇c〇2-heterocycloalkyl, -0C0NH2, -0C0NH-C!-C12-alkyl, -0CONH_C2 - Cl2 Alkenyl, -0C0NH-C2-C12-alkenyl, -0CONH-C3-Cl2-cycloalkyl, -〇c〇NH_ aryl, -0CONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC ( 〇) —Ci_Ci2~alkyl, _NHC(0)-C2-C12-alkenyl, —NHC(0)_C2—Cl2-alkenyl, 1150-9065-PF; Linlin 38 200813024 -NHC(O)-C3-Ci2 -cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(0)-heterocycloalkyl, -NHCOrCi-C12-alkyl, -NHC〇2-C2- C12-alkenyl, -NHC〇2-C2-C12-alkenyl, -NHC〇2-Cs-Cw-cycloalkyl, -NHC〇2-aryl, -NHC〇2-heteroaryl, -NHC〇 2-heterocycloalkyl, _NHC(0)NH2, -NHC(0)NH-Ci-C"-alkyl, -NHC(0)NH-C2-C12-alkenyl, -NHC(0)NH-C2 -C12-alkenyl, -NHC(0)NH-C3-C12-cycloalkyl, -NHC(0)NH-aryl, -NHC(0)NH-heteroaryl, -NHC(0)NH- Cycloalkyl, NHC(S)NH2, -NHCCSHH-CrCu-alkyl, -NHC(S)NH-C2-C!2-fine, _NHC(S)NH-C2-Ci2-sweet, -NHC( S) NH-C3-Ci2-cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH) NH2, -NHCUIONH-Ci-Cu-alkyl, -NHC(NH)NH-C2-C12-alkenyl, -NHC(NH)NH-C2-C12-alkenyl, -NHC(NH)NH-C3-C12 -cycloalkyl -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHCCNH)·^-C"-alkyl, -NHC(NH) -GC"-alkenyl, Bu-NHC(NH)-C2-C12-alkenyl, -NHC(NH)-C3-C12_cycloalkyl, -NHC(NH)-aryl, -NHC(NH)- Aryl, -NHC(NH)-heterocycloalkyl, -CXNIONH-Ci-Ci2-alkyl, -C(NH)NH-C2-Ci2-alkenyl, -C(NH)NH-C2-C12-ene , -C(NH)NH-C3-C12-cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -SCOhCrCu-alkyl-NHS〇2-C2-C12-alkenyl, -NHS〇2-C2-C12-dilute, -NHSO2-C3-C12-cycloalkyl, -NHS〇2-aryl, -NHS 〇2-heteroaryl, -NHS〇2-heterocyclic, -CH2NH2, -CH2SO2CH3, -aryl, ~arylalkyl, -heteroaryl,-heteroarylalkyl,-heterocyclic alkyl , _C3-Ci2-cycloalkyl, 1150-9065-PF; Linlin 39 200813024 polyoxyalkylene, polyglycol hydrazine, methoxymethoxy its m ^ group, -SH-C4 Base, mono-, - mercapto, -S-C3-Ci2-cycloalkyl, {aryl, j-C2-C1-alkenyl, methylthiomethyl, or -I, fluorene, aryl, -S -heterocycloalkane (tetra)ceneene, (^ sub-blocky, R, for its aromatic ^ , which is a Cl-h alkylene, a -Cs-Ci2-cycloalkyl or a c3", a heterocyclyl group, a heterocyclic group, and an alkyl group, etc., which can be further in a surface group or a hetero group structure. Each substituent is opened, and AL is opened 7. After being replaced, the group is randomly selected from the outside, and each group is independently selected from the group of -F or a group of -CN or "hop." Γ, -I, -〇Η, -Ν〇2, according to the present invention, any of the aromatics, and #aryl groups and substituted residues described herein are! The substituted aryl 'heteroaromatic group may be any aromatic group. The aryl group may be substituted or unsubstituted. """, "work" = = any of the bases, bases, block bases, ring bases and ring bases described herein, and the structure may also be an aliphatic group, an alicyclic group or - Heterocyclyl group. - "aliphatic group" is a non-aromatic structure which may comprise any combination of carbon atoms, hydrogen atoms, imine atoms, oxygen, nitrogen or other atoms, and optionally contains - or more unsaturated units, such as Key and / or three keys. The aliphatic group can be straight chain, branched or cyclic, preferably containing from about 丨 to about 24 carbon atoms, more typically from about i to about 12 carbon atoms. In addition to the aliphatic hydrocarbon-free group, the aliphatic group contains, for example, a polyalkoxyalkyl group such as a polyalkylene glycol, a polyamine, and a polyimine. These aliphatic groups can be further substituted. It is understood that the aliphatic group can be used in place of the alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene groups described herein. 1150-9065-PF; Linlin 40 200813024: The term "alicyclic" as used herein, denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic compound by the removal of a single hydrogen atom. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2. 2.1] heptyl and bicyclo [2.2. 2] octyl. These alicyclic groups can be further substituted. It is to be understood that in various embodiments of the invention, the substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl group and Heterocycloalkyl is intended to be divalent or trivalent. Therefore, the meaning of r includes: alkylene, alkenylene and alkynylene, cycloalkylene, cycloalkenylene, cyclohexylidene, arylalkylene, heteroarylalkylene, and hetero A cycloalkylene group, and may be suitable for providing the structural formula herein at an appropriate valence. "i" or "halogen" means an atom selected from the group consisting of fluorine, chlorine, bromine and iodine. As used herein, the term "radio-based activating group" refers to a restless chemical structure which is known in the art to activate a substrate such that it is detached during the incorporation step, such as substitution or elimination. Examples of hydroxyl activating groups, including but not limited to: mesylate, tosylate, trif late, nitrobenzoate, phosphonate, and the like. The term "activated hydroxyl group" as used herein, refers to a hydroxy-activated group as defined above, including, for example, mesylate, sulfonate, trif, nitrobenzoate, Phosphonate, activated radical. The term "protected hydroxy" as used herein, refers to a hydroxy protecting group as defined below, including, for example, benzamidine, ethyl hydrazino, trimethyl decyl, 1150-9065-PF; Linlin 41 200813024 • Ethyl group, methoxymethyl, protected hydroxyl group. As used herein, the term "hydroxy protecting group" refers to an unstable chemical structure which is known in the art to protect a hydroxyl group from undesired reactions during the synthesis. The hydroxy protecting group described herein can be selectively removed after the synthesis process. A general description of the hydroxy protecting group can be found in T. H. Greene and P. G. m. ffuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1 999). Examples of the hydroxy protecting group include dibenzyl, oxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, and third butoxy Carbonyl, isopropoxycarbonyl, monophenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(tridecylfluorenyl)ethoxycarbonyl, 2-mercaptooxycarbonyl, allyl An oxycarbonyl group, an ethyl carbonyl group, a decyl group, a chloroethyl fluorenyl group, a trifluoroethyl fluorenyl group, a methoxyethyl fluorenyl group, a phenoxyethyl fluorenyl group, a benzhydryl group, a methyl group, a tert-butyl group, 2,2,2-trichloroethyl, 2-trimethyldecylethyl, i, bisdimethyl-2-propenyl, 3-methyl-3-( (butenyl, allyl, benzyl) , p-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuranyl, methoxymethyl, methylthiomethyl, decyloxymethyl, 2, 2 , 2-trichloroethoxymethyl, 2-mono(trimethyldecyl)ethoxymethyl, sulphate, p-toluene xanthyl, trimethyl sulphate, monoethyl decyl, two Isopropyl decyl group, etc. In the present invention, a preferred hydroxy protecting group is: Mercapto (Ac or a C(0)CH3), benzamidine (Bz or -C(〇)C6H5) and trimethyldecyl (TMS or -Si(CH〇3). The term used herein" "Amino-protecting group" means a restless chemical structure which is known in the art to protect an amine group from undesired reactions during the synthesis of 42 1150-9065-PF; Linlin 200813024 After the synthesis process, the amine protecting group described herein can be selectively removed. For a general description of the amine protecting group, refer to Τ·H. Greene and PG m. Wuts, Protective Groups in Organic Synthesis 3rd edition, John Wiley & Sons, New York (1 999). Examples of amine protecting groups include, but are not limited to, a third butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a benzyloxycarbonyl group, and the like. The term "protected amine group" as used herein, refers to an amine group protected by an amine protecting group as defined above. The term "alkylamino group" as used herein means having -NH(Cl - Cl2) A group of structures in which the Cl-Cl 2 alkyl group is as defined above.

The term "mercapto" as used herein, includes residues derived from acids including, but not limited to, carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and phosphoric acids. Examples include aliphatic carbonyl groups, aromatic carbonyl groups, aliphatic sulfonyl groups, aromatic sulfinylene groups, aliphatic sulfinyl groups, aromatic phosphate groups, and aliphatic phosphate groups. Examples of the aliphatic carbonyl group include, but are not limited to, ethyl hydrazino, propyl fluorenyl 2-fluoroethyl fluorenyl, butyl fluorenyl, 2-hydroxyethyl fluorenyl and the like. As used herein, the term "aprotic solvent" means a solvent which is relatively inert to proton activity, i.e., not a proton donor. Examples include, but are not limited to, k' such as hexane and toluene, such as: functional hydrocarbons, such as: di-methane, di-ethane, gas, etc., heterocyclic compounds such as tetrahydrofuran and N-methylpyrrolidine Ketones and ethers, such as diethyl ether, dimethoxymethyl ether. Such compounds are well known to those skilled in the art, and to those skilled in the art, for specific compounds and reaction conditions, such as such drug solubility, agent reactivity, and preferred response range 1150- 9065-PF; Linlin 43 200813024 The preferred solvents or mixtures are well known. Further discussion of aprotic solvents can be found in organic chemistry textbooks or in specific monographs, such as · Organic Solvents Physical Properties and methods of Purification, 4th ed. , edited by John A. Riddick et al., Vol. II, in the Techniques of

Chemistry Series, John Wiley & Sons, NY, 1986 〇 The term "protonated organic solvent" as used herein refers to a solvent that tends to provide protons such as alcohols such as methanol, ethanol, propanol, and isopropyl. Alcohol, butanol, tert-butanol, and the like. Such compounds are well known to those skilled in the art and are well known to those skilled in the art, and to the particular compounds and reaction conditions, such as the solubility of the agents, the reactivity of the agents, and the preferred range of reaction, Each of the preferred solvents or mixtures is readily apparent. Further discussion of proton-solving solvents can be found in organic chemistry textbooks or in specific monographs such as: Organic Solvents Physical Properties and methods of Purification, 4th ed., "edited by John A.Riddick et aJ.y Vol. II, in The Techniques of Chemistry Series, John Wi 1 ey & Sons, NY, 1 98 6. The compounds described herein contain one or more asymmetric centers and are capable of producing enantiomers, non-image isomers (diastereomer), and other stereoisomeric forms, defined by absolute stereochemistry as (R)- or (S)-' or an amino acid, defined as (D)- or (L)-. The invention is intended to include all Such possible isomers, as well as their racemates and optically pure forms. Optical isomers can be obtained by their respective optical activities 1150-9065-PF; Linlin 44 200813024: precursors in the above procedure or The racemic mixture is prepared by analysis. This analysis can be carried out by chromatography or repeated crystallization in the presence of an analytical agent or a combination of techniques known to those skilled in the art. See Jacques, etal, E_ti〇mers, Racemates and ReS〇lutions (John Wiley & s〇ns, 1981). When the compounds described herein contain olefinic double bonds, other unsaturated or other geometrically asymmetric centers, and Unless specifically referenced to the sun and the moon, it is meant that the compound comprises the £ and z geometric isomers or the cis and trans isomers. Likewise, all tautomeric forms are also included. Any carbon-carbon shown here The construction of the double bond is convenient, unless it is described in this article, it is not used to specify a specific configuration. Here, the rabbit-shout double bond or the carbon-hetero atom double bond green The trans-type 'may be cis, and 4' or a mixture of the two in any ratio. The term "object" as used herein means - mammal. Preferably, for example, dogs, miscellaneous, horses, cows, pigs, scorpio gas, and the like. This object is preferably a human. When the subject is a human, the subject referred to herein may be a patient. The term "pharmaceutically acceptable salts" as used herein means that the salts are within the scope of adequate medical judgment and are suitable for tissue contact in humans or lower animals without adverse toxicity or irritation. , allergic reactions, etc., and reasonable benefits / risk ratio is proportional. Pharmaceutically acceptable salts are well known to those skilled in the art. For example: s.m. Berge, a pharmaceutically acceptable salt described in J. Pharmaceutical Sciences, Bu 1 9 (1 977). The salt can be prepared in situ upon final isolation and purification of the compound of the invention, or separately by reacting the free base with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid additions 45 H50 >9065-PF; Linlin 200813024

, amine salts, amine and inorganic acids, such as hydrochloric acid, hydrochloric acid, squaric acid, sulfuric acid and perchloric acid, or organic acids, such as: acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid Addition is prepared or prepared using other methods in the art, such as ion exchange. Other pharmaceutically acceptable salts, including but not limited to: [acid salts, alginate, ascorbate, aspartate, besylate, #carboxylate, hydrogen sulfate, borate, butyl scorpion Know as ' shisha, camphor hydrochloride, citrate, cyclopentate propionate, monogluconate, lauryl sulfate, ethanesulfonate, formate, fumarate salt, Portuguese Heptanoate, glycerol sulphate, gluconate, sulphate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, lactate, laurate , laurel sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinic acid, nitrate, oleate, oxalate, palmitate , pamoate, pectate, persulphate, 3-phenylpropionate, phosphate, picrate, trimethylacetate, propionate, stearate, succinate , sulfate, tartrate, thiocyanate, p-toluenesulfonate, eleven carbonate, pentane salt, and the like. Representative or soil test metal salts, including: sodium, chain, potassium, mother, town, etc. Other pharmaceutically acceptable salts, including the appropriate use of counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl groups having from 1 to 6 carbon atoms, sulfonates and aryl groups Non-toxic ammonium, quaternary ammonium and amine cations formed by sulfonate. As used herein, the term "pharmaceutically acceptable ester" means an ester which hydrolyzes in the body and which comprises an ester which readily disintegrates in the human body and leaves the parent compound or a salt thereof. Suitable esters include, for example, those derived from pharmaceutically acceptable lipids 1150-9065-PF; Linlin 46 200813024, which are alkanoic acid, alkenoic acid, naphthenic acid and alkanoic acid, each of which is alkylated. The or alkenyl structure is preferably no more than 6 carbon atoms. Examples of specific vinegars include, but are not limited to, phthalate, acetate, propionate, butyrate, propionate® and a succinic acid. The term "pharmaceutically acceptable pre-drug" as used herein means that the prodrugs of the present invention are within the scope of adequate medical judgment and are suitable for tissue contact by humans or lower animals, and not There are unfavorable toxicity, irritation, allergic reactions, etc., and reasonable benefits/risk ratios are commensurate, and are effective for their use, and when possible, zwitterions of the compounds of the invention. As used herein, "precursor" means a compound which can be converted to a compound of the invention by metabolism (e.g., hydrolysis) in the body. Many forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrug, Elsevier (1985); Widder, et al. (ed.),

Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed), n Design and Application of Prodrug, Textbook of Drug Design and Development, Chapter 5 ^ 113-191 (1991); Bundgaard, et al, Journal of Drug Deliver Reviews, 8: 1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1 988); Higuchi and Stella (eds.) Prodrug as Novel Drug Delivery System, American Chemical Society (1 975); and Bernard Testa & Joachimmayer, "Hydrolysis In Drug And Prodrugmetabolism: Chemistry, Biochemistry And Enzymology," John Wiley 1150-9065-PF; Linlin 47 200813024 and Sons, Ltd. (2002 ). Combinations of substituents or variations contemplated by the present invention, 1 heavy system; I. As used herein, the term "stable" means that the compound is sufficiently stable to permit manufacture and can be maintained for a sufficient period of time for the use described herein (for example, for a subject to be treated therapeutically or prophylactically). The compound synthesized can be isolated from the reaction mixture and further purified by, for example, column chromatography, high pressure liquid chromatography or recrystallization. Those skilled in the art and the art should be able to deduce the other methods of synthesizing this compound by the teachings of this specification. In addition, the various synthetic steps can be carried out in an alternate order or order to give the desired compound. In addition, the solvents, temperatures, reaction times, and the like shown herein are for illustrative purposes only, and those skilled in the art will be able to modify various reaction conditions to produce the bridging macrocycle products of the present invention. Synthetic chemical conversion and protecting group methodology (protection and deprotection) useful for the synthesis of the compounds described herein are well known to those skilled in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers ( 1989); TW· Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser andm. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and [· Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995). The compounds of the present invention may be modified by any of the synthetic methods shown herein, attached to 1150-9065-PF; Linlin 48 200813024, with various oxo groups to enhance selective biological properties. This is equivalent to being known to those skilled in the art and may include increased biocompatibility for a given biological system (eg, blood, lymphatic system, central nervous system), increased oral utilization (oral avaUabiu y), plus dissolution Sexuality so that it can be administered by injection, altering metabolism and changing the rate of excretion. Pharmaceutical Compositions The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of an embodiment of the invention, and one or more pharmaceutically acceptable carriers of the formula. (4) The term "pharmaceutically available for the connection of ten or four ships and supports or excipients" means a non-toxic, inert solid, semi-solid or liquid-filled liquid filler, thinner or capsule. Chemical materials, or any type of formula. As an example of a tangible acceptable carrier, sugars such as milk, wrinkles and sucrose; starches such as corn granules and horse yam starch, y, y, and y Derivatives thereof, for example, sodium carboxymethylcellulose, ethylcellulose octanoate and cellulose acetate; powdered yellow gum; malt, sedative; talc, ^ ^ ^ such as cocoa butter and Suppository wax, oil, such as chemical oil, bromine / + not good erect -, mountain oil, sesame oil, olive oil, ^ alcohol 'such as propylene glycol; 酉 ,, such as oleic acid and laurel S 夂 _; Agar; buffer medicine #卜@藻酸; no pyrogen water; isotonic saline; Ringer's buffer solution, and other helmet toxicity # and ~S夂 salt, 4k compatible lubricant, such as Laurel:: Neutral and hard: acid:, as well as coloring agent, release agent, coating agent, η agent, flavor and aromatic agent, preservative and anti-oxidation judgment, can also exist in this group of people - square m ° . The pharmaceutical composition of the present invention can be administered orally, transrectally, orally, through the cerebral cistern

1150-9065-PF; Linlin, Q 4 y 200813024 (intracisternal ly), transvaginal, transabdominal, tableting; sputum (eg, powder, ointment or drops), wart or oral or nasal spray. Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups and elixirs which are pharmaceutically acceptable. In addition to the active person, the liquid dosage form may comprise inert dilutions commonly used in the art, two: water or other solvents, solubilizing agents, and emulsifiers, such as beta-s, propyl alcohol, ethyl carbonate, ethyl acetate Ester, benzyl alcohol, benzyl benzoate, propylene glycol, butanediol, dimethylformamide, oil (especially, cottonseed oil, peanut oil, oil, germ oil, olive oil, castor oil and sesame oil), Wang Mi ^ / From tetradecyl alcohol, 5 ^ ethyl alcohol and sorbitol @ f fatty acid g, and sigh a total of this compound. Besides the inert diluent, the oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweetening, flavoring, and perfuming agents. Ingredients for injection, such as: Helmets, ..., cockroaches, aqueous or oily suspensions, can be formulated according to known techniques using appropriate sizing or wetting agents and suspending agents. The sterile injectable preparation, ^ 4 ^ without injection solution, suspension or emulsion 'dissolved in Yi Xi Xi non..., parental non-oral acceptable dilution: ::::: for... a solution in an alcohol. In acceptable carriers and medium: water, Ringer's solution, usp. and isotonic sodium chloride solution are used. In addition, sterile fixed oils are used as solvents or suspension media. For this purpose, various brands of solid oils, including synthetic mono- or diglycerides, can be used. Further, fatty acid 1, such as oleic acid, is used in the preparation of injectables. The formulation for injection can be filtered by the filter film which cannot be passed through #, ,, 田, or the bactericide can be contained in the sterile 圆W round body composition for sterilization, the 1150-9065-PF; Linlin 50 200813024 The bacterial solid composition can be dissolved or dispersed in sterile water or other sterile injectable preparations using hydrazine. ί In order to prolong the action of the drug, it is often desirable to slow down the absorption of the drug by subcutaneous or intramuscular injection. This object can be achieved by using a liquid suspension of crystallized or amorphous material which is poorly soluble in water. The rate depends on the rate of dissolution, and is related to the crystal size and crystalline form. Alternatively, the absorption of the non-oral administration of the drug can be delayed by dissolving or suspending the drug in an oily carrier. It can be achieved by forming a microcapsule matrix of the drug onto a biodegradable polymer, such as polylactic acid-polyglycolic acid (P〇lylactide-polyglyc〇lide). Depending on the ratio of drug to polymer' and the specific polymer The nature of the drug release rate can be controlled. Other examples of biodegradable polymers include poly(4) and poly(acid liver). The formula for injectable injection can also be captured by the drug to be compatible with body tissues. Prepared by a liposome or microemulsion. A composition for rectal or vaginal administration, preferably a suppository, by mixing a compound of the invention and a suitable non-sting Excitable excipients or carriers: For example: cocoa butter, $ethylene glycol or suppository _ mixed preparation, suppository _ at room temperature is solid but at body temperature is liquid 'so can dissolve in the rectum or vaginal release of active compound. Oral The solid dosage forms to be administered include: capsules, capsules, pills, powders, and granules. In such a solid dosage form, the elbow/tongue compound is mixed with at least one inert pharmaceutical acceptable ingredient. Shape agent or push, r L ^ uA support, such as sodium citrate or dicalcium phosphate and / or: a) filler or granules, ... daily granules, such as starch, lactose, sucrose, glucose , mannitol and citric acid, b) zebrafish i丨 /, D; binder, for example: carboxymethyl 1150-9065-PF; Linlin 51 200813024 cellulose, alginate, gelatin, polyglycoside , #'糖和刺槐, C) wetting agent, such as glycerin, d) disintegrating agent, such as agar agar, calcium carbonate, potato or tapioca starch, sorghum, some citrate and sodium carbonate, e) Solution retention agent 'eg paraffin, f) absorption enhancer, such as quaternary ammonium compound, g) wetting agent, eg cetyl alcohol And glyceryl monostearate, h) absorbents such as kaolin and swellable clay' and lubricants such as talc, hard moon: acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and Mixtures of these. In the case of capsules, ingots and virgins, the dosage form may still contain a buffer. Solid compositions of a similar type may also be filled with soft and hard shells. A filling agent for gelatin capsules, wherein the excipient used is lactose, and a high molecular weight polyethylene glycol, etc. The active compound can also be used as a micro-I encapsulation form. Solids such as lozenges, dragees, films, bismuth pellets and granules can be coated by coatings and shells, such as intestines, such as casings, release control agents and other coatings. The tabulation is in this 4 solid dosage form, which may be combined with at least one inert dilution, such as a sugar, lactose powder. Such a dosage form, as a practical matter, may contain substances other than inert diluents t U · I. Lubricants and other I red aids, such as stearic acid town + σ day cellulose. In the case of capsules, ingots and sap, these dosage forms ^ ^ ^ 』s buffer. You can arbitrarily lick the opacifier and can be a combination of Qiu Ba @ i ^ Qiao eight only release or give priority to a sickle in the intestine, Ik thought to use the soil in a delayed way... Ten thousand release - or Multiple active ingredients. Examples of the entangled composition include polymeric substances and waxes. 1150~9065-PF/Linli 52 200813024 A topical or transdermal dosage form of a compound of the invention comprising: ointment, paste, cream, lotion (1〇ti〇n), gel , powder, solution, spray, inhalant or patch. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and optionally a preservative or buffer. Ophthalmic formulations, ear drops, ophthalmic ointments, powders and solutions are also considered to be within the scope of the invention. ~ r ... In addition to the active compound of the present invention, the ointment, paste, cream and linger may include excipients such as animal fats and vegetable fats, oils, earth, paraffin, starch, gum tragacanth, fibers A derivative, polyethylene glycol, anthrone, bentonite, citric acid, talc, and zinc oxide or a mixture thereof. In addition to the compounds of the present invention, the powders and sprays may include an excipient such as lactose, talc, anthraquinone, chlorinated acid, alkaloid, and: a guanamine powder or a mixture thereof. Sprays may also contain conventional propellants, such as chlorofluorocarbons. An extra-head advantage of a dental patch is that the compound is administered to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can be used to increase the passage of the compound through the skin. The rate can be controlled by providing a rate and controlling the cockroach, controlling the cockroach or dispersing the compound in a matrix or gel. ▲ 5 Antiviral activity The inhibitory amount or dose of the compound of the present invention may be about 5 〇〇, or about 1 to about the inhibitory amount or dose, depending on the route of administration, and whether it can be combined with other agents. Use: Different.叨1150-9065-PF;Linlin 53 200813024 According to the invention, the method or method for treating or preventing a viral infection in a subject is achieved by the amount of the desired result for the child image and the daytime Administration of a primary antibody, C-type 卞X disease, effective 3: or an inhibitory amount of a compound of the invention, such as a native or a lower mammal. Another method of the present invention is to administer an inhibitory amount of a compound of the present invention to a biological sample for a desired period of time and time. f As used herein, "anti-c hepatitis virus effective amount" of the present invention = sufficient compound can be reduced in - biological sample: As is well known in the art, the "anti-C-hepatitis disease volume" will be located within a reasonable benefit/risk ratio applicable to the intended medical treatment. As used herein, "inhibiting amount" of a compound of the invention means a viral amount in a sample or a subject. It is well known in the medical art that 'for a slanting + rL fork', "the amount of inhibition" administered by the subject, the compound of the invention will be at a reasonable benefit for any medical treatment as determined by the physician/ Within the risk ratio. The term "biological sample" as used herein, means a substance of biological origin for administration to an object. Examples of biological samples include, but are not limited to, blood: and its components, such as plasma, platelets, subpopulations of blood cells, etc.; crying officials / such as kidney, #, heart, lung, etc.; sperm and eggs; bone and its components ^ stem cells . The invention is directed to a method of treating a biological sample by contacting the biological sample with an inhibitory amount of a compound or composition of the invention. Μ When the condition of the patient is improved, a maintenance dose of 1150-9065-PF can be administered as needed; Linlin 54 200813024 The compound, composition or combination. Then, the symptoms are reduced to a desired level, and depending on the symptoms, the dosage or frequency of administration or both can be reduced to maintain the intermittent treatment period to prevent the disease from recurring. However, it is to be understood that the total daily usage of the compounds of the invention and the milk and compositions will be determined by the attending physician within the scope of full medical judgment. The specific therapeutically effective dose for a particular patient will depend on a number of factors, including: the condition to be treated and the activity of the severity of the condition; (4) the composition of the substance "patient age, ^" General health, sex and diet; the time of administration, the route of administration, and the rate of excretion of the particular compound used; the period of treatment; the combination or combination of the specific compounds used; and The field is well known for its similar factors. 'The compound of the present invention is administered to the sputum--the total daily dose of the sputum, sputum, and the dose of a single or divided dose can be, for example, 戈·〇·〇1 ~50rng / kg body weight, or usually 〇 1 ~ 25mg / kg body weight. 覃一制曰早剂 $ composition can contain this amount or divided into - to achieve 4 daily dose 1. _ like, the treatment of the present invention In the course of the present invention, the mother is administered with about 10 mg to about 100 mg of the compound of the present invention in an earlier dose or multiple times. [, All technical and scientific terms used herein are based on the art of the art. Common to all . Meaning All publications products, patents, published < patent applications and other references, the complete arch Shu herein by reference shorthand 1150-9065-PF; abbreviated Linlin 55 200813024 following synthetic flow and procedure of Example occurred as follows:

Ac : ethyl acetate, CAN: acetonitrile;

Boc ··茗Tributoxycarbonyl;

Bz · · Benzoyl group,

Bn : benzyl; CDI : carbonyl diimidazole; dba : diphenylacetin; ' DBU : 1,8-diazabicyclo [5· 4. 〇] eleven post-ene; DIAD·diisopropyl aza Diazodicarboxylate (vinegar); DMAP: dimethylamino acridine; DMF: dimethyl decylamine; DMS0: dimethyl sulfoxide; dppb: diphenylphosphine;

EtOAc: ethyl acetate; f: HATU: 2_(7-aza-1H-benzotriazol-bu) q,i 3,3-tetramethyluronium hexafluorophosphate; iPrOH: isopropanol;

NaHMDS: sodium bis(trimethyl decyl) decylamine; ΝΜ0 ··N-methylmorpholine N-oxide;

MeOH: methanol;

Ph: phenyl; POPd: dihydrodichlorobis(di-tert-butylphosphine)palladium (π); TBAHS: tetrabutylammonium hydrogen sulfate; 1150-9065-PF; Linlin 56 200813024 — TEA: triethyl Amine; THF: tetrazole; TPP: triphenylphosphine;

Tris: tris(hydroxymethyl)aminomethane; BME: 2-mercaptoethanol; Β0Ρ: benzotris-l-yloxy-tris(didecylamino)scale hexafluoro-iriate; C0D: ring Octadiene; 'DAST ··Triethylammonium trifluoride; DABCYL: 6-(N-4'-carboxy-4-(didecylamino)azobenzene)-aminohexyl-1 〇-(2-Nylideneethyl)-(N,N-diisopropyl)-arthracene ruthenium, DCM: dichloromethane; DIAD: diisopropylazadiazodicarboxylate ( Ester); DIBAL-H: diisobutylaluminum hydride; DIEA: diisopropylethylamine; MAP: N,N-didecylaminopyridine; DME: ethylene glycol dioxime; DMEM: Dulbecco's Modified Eagles medium; DMF: N,N-dimercaptodecylamine; DMS0: dimethyl hydrazine;

1150-9065-PF/Linlin 57 200813024 EDANS : 5-(2-Amino-ethylamino)-naphthalene-1-sulfonic acid; EDCI or EDC: 1_(3~"-monoethylaminopropyl -3 - ethyl carbo-imine hydrochloride;

EtOAc: ethyl acetate; HATU: 0-(7-aza-1H-benzotriazol-bu)-N,N,N,N-tetramethyluronium hexafluorophosphate;

Hoveyda’ s Cat. · Digas (o-isopropoxyphenyl sulfenyl) (tricyclohexylphosphine) ruthenium (II); KHMDS: potassium bis(trimethyl decyl) decylamine;

Ms: methylsulfonyl; NMM · N-4-methylmorpholine;

PyBrOP: tripyrrolidinyl bromide hexafluorophosphate;

Ph: phenyl; RCM: closed-loop translocation; RT: reverse transcription; ;, RT-PCR • reverse transcription-polymerase chain reaction; TEA · triethylamine; TFA: trifluoroacetic acid; THF ··tetrahydrofuran; TLC : thin layer chromatography TPP or PPh3: triphenylphosphine; tBOC or Boc: third butyloxycarbonyl;

Xantphos · 4,5-di-diphenylphosphinoalkyl-9,9-dimethyl-9H-argon. 1150-9065-PF; Linlin 58 200813024 Synthetic Methods The compounds and treatments of the present invention will be better understood from the following synthetic schemes, and the compounds of the present invention can be prepared by the following methods.

1-3)

(1-1) (1-2) HATU, 1.2 eq DIEA, 4 eq

DMF

HATU.1.2 eq DIEA, 4 eq DMF

(1-5)

1N LiOH p-dioxane ,r_t” 3 h OH

(1-4) Scheme 1 describes the synthesis of intermediates (1-6). The acyclic peptide precursor U-6) is prepared from Boc-L-third-leucine (1 - hydrazine and cis-L-hydroxyproline methyl ester (1-2)' via the 3 step of Scheme 1 For further details of the synthetic methods employed to produce the acyclic peptide precursor (1-6), see U.S. Patent 5,0,8,4,1,7,7, incorporated herein by reference.

Process 2

1150-9065~PF; Linlin 59 200813024: Scheme 2 describes a general method for the synthesis of tetrazole analogs. The 5-substituted tetrazole compound (2-2) is obtained via a nitrite compound (2_υ, and an azide compound a. The intermediates (2-4) and (2-5) can be via a hydroxyl intermediate U- 6) Convert to an appropriate leaving group, such as but not limited to: ο. , 〇Tf, bromide or iodide, prepared by substituting SN2 for the reactive hydroxyl group. Thereafter, the vinegar is hydrolyzed to obtain (2-6) and (2-7) compounds. Process 3

W= OMs, OTf, OTs, Halide (2-3) f

Ar-R

(3-2)

ΎΎ ''>-Ar-Y N, n w H (2-2) Ar-Y

(3-1) Stille Coupling

Y= halide, OTf Ar-R

(3-3)

Sonogashira Reaction /

The intermediate (3-1) is synthesized via acyclic methanesulfonic acid (2-3) and a 5-substituted tetrazole compound as described in Scheme 2. Next, the intermediate (3-1) will be via Suzuki coupling reactions, Sonogashira coup 1 ing reaction or Stiller couple 60 1150-9〇65-PF; Linlin 200813024 stille coupling reaction is carried out at the position of the halide or OTf. For further details on the Suzuki coupling reaction, see A. Suzuki, Pure App 1 · Chen. 1991, 63^ 419-422 and AR Martin, Y· Yang, 5^5/7A 1 9 93, 47, 221 - 230. For further details on the Sorocene Siro coupling reaction, see Sonogashira, Comprehensive Organic Synthesis, Volume 3, Chapters 2, 4 and Sonogashira, tSyeMes/s 1 977, 777. For a detailed reaction of the Stüler coupling reaction, see in detail JK St i 11 e, d/?

Int. Ed. 1986, 25, 508-524, M. Pereyre et al., Tin in Organic Synthesis (Butterworths, Boston, 1987) pp 185-207 passim, and a review of synthetic applications in TN Mitchell, Synthesis 1992, 803 - 815 · Buchwald reaction allows substitution of primary and secondary amine groups, such as the position of the 1H-nitrogen heterocycle at the aryl bromide, further details of the reaction 'see JF Hartwig, [力复//?i iW. 1998, 37, 2046-2067. Process 4

Hydrolysis Q

Q

(4-4) 1150-9065-PF; Linlin 61 200813024 ‘ 壬4 5 儿明 modifies the N-terminus and C-terminus of the dipeptide. The B〇c structure is deprotected with an acid such as, but not limited to, hydrochloric acid to yield a compound of formula G-2). The amino group structure of the formula (4-2) can be alkylated or thiolated with a suitable benzene or fluorenyl group to give a compound of the formula (4-3). The compound of the formula (4-3) can be hydrolyzed with a base such as lithium hydroxide to release the acid structure of the formula (4-4). Subsequently, the acid structure is activated, followed by treatment with an appropriate sulfhydryl or sulfonyl group to give a compound of formula (4-5). Process 5

Anthraquinone (5 - 2 ) is obtained from the corresponding acid (5 -1). The acid is reacted with a coupling reagent (ie, CDI, HATU, DCC, EDC, etc.) at room temperature or at a temperature, and then the corresponding phthalamide-s(〇)2-NH2 is added in the presence of the test, wherein R3 The definition is the same as before. Process 6 62 1150-9065-PF; Linlin 200813024

BocN- C02Me (6-1)

Ar-B(OH)2 Cu(OAc)2

NaN3

BocN 1)HC| '------- 2) HATU t〇2Me °<y.〇H 〇 (6-2) BocHN-T BocHN A C〇2Me (6-3) N-N // \

1) LiOH

BocHN one

2) HATU, C02Me H2N (6-4)

N-n" v ,Ar

Naicheng will sell cyanide on the market

Scheme 6 describes the synthesis of the tetrazole C6-1) and the azide at ll 〇 °C for a long time, and the tetrazolium (6-2). After the 俚-仃 coupling with B〇c-L-t-butyl-glycine, the Cu (〇Ac) 2 is used as a catalyst, and an additional pen-based aryl group is attached to the tetrazole ring. The obtained compound (6-4) is first reacted with Li 0H, followed by the labeling-known 竿 peptide coupling reaction to obtain the compound (6 - 5 ). Example

The compounds of the present invention and the treatments will be more apparent from the following examples, which are intended to illustrate and not to limit the scope of the invention. Various changes and modifications are apparent to those skilled in the art, and such changes and modifications include, but are not limited to, the chemical structures, substituents, derivatives, formulations, and/or methods of the present invention. It is implemented within the scope of the spirit of the invention and the scope of the patent application. Chemical Formula I, n, Melon, 1 ¥, ¥, 贝, ¥ [1, 稳和汉, where G is a base] is described in U.S. Patent No. 2,5,26,12, the entire disclosure of which is incorporated herein by reference. 1150-9065-PF; Linlin 63 200813024 - Example 1 Synthesis of the acyclic peptide precursor:

(1·6) (1-5) / Step 1 a Dissolve BoC-L-t-butylglycine (2.78g) and commercially available cis-L-hydroxyproline methacrylate (3.3g) In a solution of 15 ml of DMF, add 01 £8 (1〇1111) and 1^1111 (5.92). Coupling overnight at room temperature. The reaction mixture was diluted with 200 mL of EtOAc and then extracted with 5% EtOAc (2.times.20ml), water (2x20ml), 1M NaHC3 (4x20ml) and brine (2x10ml). The organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo. I MS (ESI): ^ = 359. 20 [M + Na] ° Step lb A solution of the dipeptide of step la dissolved in i5 mL of dioxane and i5 mL of 1 N Li〇H was reacted at room temperature for 4 hours. The reaction mixture was acidified with 5% citric acid and extracted with EtOAc (EtOAc) (EtOAc) The organic phase is dried over anhydrous sodium sulfate and then condensed in vacuo to give the carboxylic acid compound (4·g). The crude product will be used in step 1150-9065-PF; Linlin 64 200813024 - MS (ESI ): /^/^=345. 28 [ M + Na ] ° Step lc The carboxylic acid of step lb (1.5 g) was dissolved in 5 ml of dMF solution, and D-β-vinylcyclopropane amino acid ethyl ester was added. (i 〇g), DIEA (3.8 ml) and HATU (2·15g). The coupling reaction was carried out at 〇 °c for more than 5 hours. The reaction mixture was diluted with 200 mL of EtOAc and then washed with 5% citric acid 2 x 20 ml, water 2 x 20 ml, 1M NaHC s. The organic phase was dried over anhydrous sodium sulfate and then evaporated. The residue was purified by flash chromatography using EtOAc (EtOAc) eluting with EtOAc (EtOAc: EtOAc). After removal of the solvent, the isolated product was an oily linear tripeptide (1.4 g, 66%). MS (ESI): tz7 / z = 482. 36 [M + Na] ° Example 2 Synthesis of the mesylate-initiated acyclic peptide precursor The acyclic peptide precursor of step lc of Example 1 (5 〇〇 mg,

1.04 mmol) and DIEA (0.543 ml, 3.12_〇1) were dissolved in a solution of i〇.〇ml DCM, and methanesulfonic acid chloride (〇·122 ml) was slowly added, and the reaction was allowed to react for 3 hours. The reaction mixture was added to 1 mL of EtOAc, followed by 5% citric acid 2 x 20 m water, lx2 〇ml, iMNaHC 〇3 2 x 20 ml, and brine ix2 〇ml. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The title product methanesulfonic acid (590 mg) was obtained which was used directly in the next step without further purification. MS (ESI): π/ζ:=560·32 [Μ + Η]. Example 3 Synthesis of a tetrazine port. The tetrazine oxime prepared by the present invention is synthesized from a tetrazine salin derivative derivative, a melon q 1150-9065-PF; Linlin 65 200813024, and a commercially available nitrite. The reaction is as follows. Said:

3a 1. NaN3, 5 eq 2. Et3N.HCl, 3 eq Xylene 140 °C, 12 h

3f

3k containing 5ml - one-piece of the sealed tube, adding 3-gas-4-p-phenylene

Nitrile (0·31 g, 5 mol), NaN3 (〇·65 g, 10 mmol) and triethylamine hydrochloride (〇.52 g, 3 mmol). The resulting reaction mixture was stirred vigorously for <"(^) over 20-30 hours. The reaction was then cooled and then poured into a solution containing EtOAc (30 mL) and aqueous citric acid (2 mL). 2xl〇mi and 2x1ml of brine were washed, and the organic phase was dried over anhydrous sodium sulfate and evaporated to give a yel-yellow solid. After recrystallization from EtOAc and hexanes, a good yield (0.4 g, 86%) The tetrazolium compound 3a of high purity (> 90%, known from HpLC) was identified by NMR and MS (197·35 and 1 99.38, Μ + Γ).

Embodiment 4 A compound of formula IX wherein a = Boc, L = tBytyl, Z = CH = CH2, G diOH

Step 4a Substitution Method The title product can be prepared by substituting the oxime sulfonic acid of Step 2 and 5-(4-methyloxyphenyl)-1H-tetra-1150-9065-PF; Linlin 66 200813024 azole. The acyclic peptide and 0.23 mmol of 5-propion were dissolved in 2 ml of DMF, followed by addition of the reaction mixture at 60 ° C for stirring 12 . The substitution method is to dissolve the sulfonic acid 5 (4-methyloxyphenyl)-iH-tetragen in step 2 into sodium carbonate of 〇·6_〇ι. This was obtained for 12 hours, then the reaction was cooled and extracted with ethyl acetate. The organic extract was then washed with 2 x 3 ml of water and dried in vacuo to facilitate hydrolysis of the ethyl ester of the crude compound. MS (ESI): π / ζ 640 · 25 [Μ + Η]. Step 4b The title compound can be prepared by dissolving the compound from step 4a (13 〇 1 s) in hexanes and 2 ml of aq. The resulting reaction mixture was stirred at room temperature overnight. The reaction was then acidified with 5% citric acid and extracted with EtOAc EtOAc EtOAc. After the solvent was evaporated, the residue was purified by HPLC. After lyophilization, the title compound was obtained as a white crystalline solid. MS (ESI): π / ζ = 612·31 [Μ + Η] 化合物 The compounds of Examples 5 to 7 were prepared according to the procedure described in Example 4, using different 5-substituted tetrazolium.

Example 5 A compound of formula IX wherein a = Boc, L = tBytyl, Q = ¥, Z di CH 2 CH2, G = 0H 〇 MS (ESI): [M+H] 〇

Embodiment 6. A compound of formula IX wherein a = B〇c, L^tBytyl, Q = Y, Z = CH = CH2, G = 0H. 1150-9065-PF; Linlin 67 200813024 MS(ESI): m/z- [M+H] °

Embodiment 7 A compound of formula IX wherein A Z = CH 2 CH 2 , G = 0H. MS (ESI): m/z- [M+H] °

Embodiment 8 A compound of formula IX wherein A = Boc, L = tBytyl, Q

A solution of the compound 4 (5 G κι ) dissolved in D M F was added; CDI (19.5 mg) was added. The reaction mixture was stirred at 40 ° C for 1 hour, followed by the addition of cyclopropylsulfonamide (20 mg) and DBU (22. 5 #1). The reaction mixture was stirred at 40 ° C overnight. The reaction mixture was extracted with EtOAc. The organic extract was washed with 1M NaHC.sub.3, brine, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel to give the desired product. MS (ESI): ζζ / / ζ = 715. 47 [M + H]. 13CCCD30D) : 5 1 73. 6, 1 71.9, 1 69.4, 1 65.2, 161.9, 156.6, 133.1, 128.3, 119.7, 117_4, 114.2, 79.3, 62.9, 60.0, 59.0, 54.7, 54.0, 41.5, 41.4, 35.2, 34.7, 30.9, 27.3, 25.8, 22.3, 5.5, 5.4 The compounds of Examples 9 to 27 were prepared from the different sulfonamides according to the procedure described in Example 8.

Example 9 A hydrazone compound, wherein A = B〇c, L = tBytyl, 1150-9065-PF; Linlin 68 200813024 Z=CH=CH2, MS (ESI): Example 10 z=ch=ch2, MS (ESI Example 11 Z=CH=CH2, MS (ESI): Example 12 Z=CH=CH2, MS (ESI): Example 13 Z=CH=CH2, MS (ESI): Example 14 Z=CH =CH2, G: melon/ζ=719.46, 721.45 [M + H]. N:

A compound of formula IX, wherein A = Boc, L = tBytyl, Q = I 〇 w 〇 / G: π / ζ = 749 · 47, 751 · 47 [M + H]. A compound of formula IX, wherein A^Boc, L^tBytyl r\r\ G= H V 〇 π/ζ = 685. 49 [M + H]. N:., Compound of formula IX, where A = Boc, L = tBytyl, Q = G: ^=718. 37[M + H] N*

A compound of formula IX, wherein A = Boc, L^tBytyl, Q = work Ά G = Η I 〇 tz7/z = 722. 32, 724· 34 [M + H]. A compound of formula IX, wherein A = Boc, L = tBytyl G: /, Xr nI,

1150-9065-PF; Linlin 69 200813024 MS(ESI): )77/^=752. 34, 754.33 [M + H] Example 15 Formula IX compound wherein A = Boc, L = tByty 1

/, NTb'N Z=CH=CH2, G= Η I 〇 MS(ESI): i»/z=688_ 36[M + H].

Embodiment 16. A compound of formula IX wherein A = Boc, L = tBytyl / X N* Ό. MS (ESI): m/z = lhl. 36 [M+H]

Embodiment 17 A compound of formula IX wherein A = Boc, L = tBytyl, Z = CH = CH2, G = H ^ ° MS (ESI) · you /> = 755.32, 757.32 [M + H]. N:,

Example 18 A compound of formula IX wherein A = Boc, L = tBytyl, Q = Z = CH = CH2, G = H ^ ° MS (ESI): you />: 785.33, 787.35 [M+H]. Embodiment 19 A compound of the formula IX, wherein A = Boc, L = tBytyl, Q: Z di CH=CH MS (ESI): m/z = T21. 35 [M + H], y. 1150-9065-PF; Linlin 70 200813024 Example 20 Compound of formula IX, wherein A = Boc, L = tBytyl, Q:

Z = CH = CH" G = MS(ESI): you /ζ=766· 38[M + H]. Example 21 Compound of formula IX, where A = Boc, L = tBytyl, Q: valence r Z = CH = CH2, G = ^ ° MS (ESI): melon / = 770.34, 772.33 "M + H1. Example 22 Formula IX compound, where A = Boc, L = tBytyl, Q: N:,

:CH = CIL· MS(ESI): You / = 800.35, 802.35 [Μ +Η]. Embodiment 23 A compound of formula IX wherein A = Boc, L = tBytyl Ζ CH = CH2, G = H W .

*N MS(ESI): ^/z-736. 36 [M + H]

Embodiment 24 A compound of formula IX wherein A = Boc, L = tBytyl, Q = Y

MS (ESI): m/z = 7lS. 37 [M+H] ° 1150-9065-PF; Linlin 71 200813024

Embodiment 25. A compound of formula IX, wherein A = Boc, L = tBytyi

MS (ESI): w/z = 722.32, 724.34 [M+H] 〇

Embodiment 26. A compound of formula IX, wherein A = Boc, L = tBytyl Z = CH: CH2, G = N\.

MS (ESI): /»/z-752.34, 754.33 [M + H]〇

Embodiment 27. A compound of formula K wherein A = Boc, UtBytyl Z di CH = CH2, G = N\. MS (ESI): π / ζ = 688. 36 [M + H]. Example 28 A compound of formula IX wherein a = Z = CH = CH2, G = 9 \. Step 2 8 a

L: :tByty 1 > Q:

The compound of Example 8 was dissolved in 5 mi of 4N HCl / - oxime, and the solution of ruthenium was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was evaporated twice with DCM. The desired product can be obtained after the next step of the reaction. MS (ESI): /ff/z = 625. 24 [M + H] 〇 1150-9065-PF; Linlin 72 200813024 Step 28b The solution of the compound of step 28a was dissolved in DCM, DIEA ( 143 // 1) and Cyclobutyl chloroformate (〇. 246 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with EtOAc. The organic layer was washed with EtOAc EtOAc m. The residue was purified by HPLC to give 42 mg of desired material. MS (ESI): π/π 713· 20 [M + H]. 13C(CD30D): 5 173· 6, 171· 7, 1 69. 4, 1 65· 2, 161.9, 156.8, 133_0, 128.3, 119.7, 117.4, 114_2, 69.1, 62.9, 59.9, 59.3, 54.7, 53.9, 41.4, 35.1, 34.7, 34.2, 30.9, 30.2, 29.8, 25.8, 25.7, 22.3, 5.5, 5.4. Example 2 9 to 90 compounds were prepared according to the procedure described in Example 8 or 28. Example A L Q Z 7 29 0 1 -CH=CH2 - - A 30 OJy >. — Y — —CH—CH2 '~—--- 31 CVy 0 -L- -CH=CH2 -----_ 32 α. Also / Λ1< 0 ” -CH-CH2 ------ __________--_ 1150-9065-PF; Linlin 73 200813024 33 O^i〇4 people / w〇 — V 1 -CH=CH2 z/v 34 MeO^0^^ 0 N^lT -CH Two CH2 /^v 35 A〇^ ', winter p- fi -ch=ch2 36 1... /< 0°' -CH Two CH2 A??v 37 〇p ' -CH=CH2 /, ^v 38 〇0 -ch=ch2 ah:sv 39 a f 1 -ch=ch2 //v 40 p- NVN 1 -ch=ch2 w 41 Ο^Λ p- VN i -ch =ch2 /^v 1150-9065-PF;Linlin 74 200813024 42 /卞V 1 -ch=ch2 /^v 43 a Bu, winter%'N -CH-CH2 /^v 44 VN -ch=ch2 Aff'v 45 〇L again, h / ,, < 1 ..0°' η -cM=m A?v 46 , and / ΝγΝ -ch=ch2 Ύν 47 ol/ Λ1< 0 Ά Ν -CH-CH2 Λίί^ν 〇 / / / / / / / / / / / / / -ch=ch2 /,^v 52 A 0 ν"Λ N -ch=ch2 53 a1, Me p- fi -ch=ch2 54 〇IJJ Λ 0°' n N -CH-CH2 55 〇Me^yV HNAMe &gt ; NWN -CH=CH2 56 Me^7 Me NYN -CH=CH2 A/v 57 HN*^ V -CH-CH2 /^v 58 a1, Y -ch=ch2 /, ^v 59 p- Y -ch= Ch2 A/v 1 150-9065-PF; Linlin 76 200813024 60 ^〇A/ /, f -CH 二CH2 /, K~ 61 ^〇A/ /, 广ρ- 0 V 1 -ch=ch2 w 62 /, 0 ρ- Ρ Ν^Γ -ch=ch2 Z, iFv 63 α I. σ / , η • 0. — Λ Ν -Πί=Γ//, & 64 汊. Also / y -CH=CH2 /3⁄43⁄4 65 汊. Also / Λ1< ρ- 0 η - CH=CH2 /3⁄4 66 wen. Also / !L -CH=CH2 An^'n^i h g,ch3 67 ρ- V 1 -ch=ch2 /3⁄4 1 H 68 Also / I -ch=ch2 77 1150-9065-PF; Linlin 200813024 69 li N -ch=ch2 70 Λ1< v -CH=CH2 71 ^〇A/ η N -ch=ch2 /3⁄4 ^^Sdch3 72 o, . Again / 0. — N —ΓΗ=ρμ〇 x_^ xx v-/ xx<-> a and H V 73 ^〇A/ N^T N -ch=ch2 74 Wen. Also / N, -ch=ch2 aXh2 H 75 , winter NVN -ch=ch2 /V« Η H 76 ^〇A/ V -ch=ch2 ΧΗΛ> Η Η 77 p- Y -ch=ch2 /-Χρ3 1150 -9065-PF;Linlin 78 200813024 78 p- 0 !L -ch=ch2 79 V 1 -CH 2 CH2 80 ^〇A/ Λ1< p- V 1 -ch=ch2 /3⁄4 81 as, ◦ y A< 0 . — Λ 1. -ΓΗ=ΓΗ〇Λ. Λ. ^/Λ.Λ.1^ 82 /r p- NvN 1 -ch=ch2 /, X Η H 83 V 1 -ch=ch2 Η H 84 p - p -ch=ch2 Η 85 汊. Further /V 1 -ch=ch2 86 ^〇A/ V 1 -CH-CH2 /3⁄4 1150-9065-PF; Linlin 79 200813024 Example 91 A compound of formula IX, wherein A = Boc, L = tBytyl, Q = Z= CH=CH2

A

87 V -H 88 w Al< V -CH2CH3 89 ΝγΝ -CF2 90 n 8 a 〇/, / 0°' -CH-CH2CH 3

N-NH

N-NH

91b

B 1) HCI

CN r NaN3 o——

BocN—<^ 110 °C C02Me 91a

Step 91a Add NaN3 (1.95 g, 30 mmol) and Et3N.HCl (4.13 g, 30 mmol) 1150-9065-PF; Linlin 80 200813024 to a compound containing 91a (2.54 g, 10 mmol) and toluene (3〇mi) tube. The reaction mixture was stirred at 110 ° C for 20 hours. A saturated NaHC 3 (10 ml) was added to the reaction mixture followed by Me 〇H (3mi). The reaction mixture was stirred at room temperature for 30 minutes. Slowly add ι〇% of the sample to adjust the pH to 6. The reaction mixture was extracted three times with Et EtOAc. The combined organic phase was dried over sodium sulfate and evaporated. The residue was purified by chromatography on EtOAc (EtOAc) eluted eluted eluted eluted eluted with Got it. Step 91c A solution of the compound from step 91c (63 mg, 1 eq.) in CH2Cl2 (12 ml), and 4-methyl oxyphenyl-boric acid (45 mg, 2 eq.), pyridine (24//L, 2 eq.) Cu(0Ac)2 (42 mg, 1.5 eq.) and molecular sieve 4A (0.13 g). The reaction mixture was stirred at room temperature for 24 hours in air then filtered over Celite. After concentrating the solution, it was purified by chromatography (yield: EtOAc = 1:1) to afford compound 91d (29 mg). Step 91 d Compound 91 is prepared from compound 91 d according to the procedures described in steps 1 b and 1 c. MS (ESI): π / ζ = 737. 38 [M + H]. The compounds of Examples 9 to 9 9 were prepared from different boronic acids according to the procedure described in Example 91. 81 1150-9065-pF; Linlin 200813024 Example 92 A compound of formula IX wherein A = Boc, L = tBytyl, Z = CH di CH2, G = Η V. MS (ESI) · · π / ζ = 737 · 38 [M + Na]. Embodiment 93 A compound of formula IX wherein A = Boc, L = tByty 1 Z = CH = CH2, G/fV.

MS(ESI) : ιη/ζ=Ί3Ί. 43[M + Na] 〇 L=tByty1

N-N Q = V Example 94 Compound of formula IX, wherein A = Boc Z = CH = CH2, G = W MS (ESI): π / ζ = 719 · 07 [M + H]. Embodiment 95 A compound of formula IX, wherein A = Boc, L = tBytyl, Q = Z = CH = CH2, gH MS (ESI): /ζ//ζ=753·38[M + Na] 〇NN厂•t » Embodiment 96 A compound of formula IX wherein A = Boc, L = tBytyl, Q = 士. Z = CH = CIL · MS (ESI): w / z = 761 · 10 [M + H]. 1150-9065-PF; Linlin 82 200813024

Embodiment 97 A compound of formula IX wherein A = Boc, L = tBytyl Z = CH = CH2, G = /, iiS; V. MS (ESI): π / ζ = 735· 13 [M + H]. Embodiment 98 A compound of formula IX wherein A = Boc, L = tBytyl Z = CH di CH2. MS (ESI): w/z = 735· 12 [M + H]. Embodiment 99 A compound of formula IX, wherein A is 2 Boc, L^tBytyl /Γ " Z=CH=CH^

Ν-Ν NUN .〇= X

N-N丨々

fP MS (ESI): π / ζ = 735. 98 [M + H].

Boc > L-tBytyl Example 1 0 Compound of formula K, wherein A = again / 0.

N-N Z = CH = CH: :v The title compound was obtained from compound 91 and cyclopentyl chloroformate according to the procedure described in Example 28. MS (ESI): see />=749.38 [M + Na] 实施 Example 1 01 to 11 化合物 Compound (Formula) was prepared according to the procedure described in Example 4, 8 or 28. Example 1 IX compound of formula IX, wherein, [two tByty 1, 1150 ~ 9065-PF; Linlin 83 200813024 N:,

, Z = CH = CH" G: MS (ESI): π / ζ = 753. 35 [M + H]. Example 102 Compound of formula IX, wherein A: tByty1

Z-CH=CH^ /n

Qw 〇 MS (ESI): w/z = 765.26, 767.26 [M+Na]. 13C(CD30D): (5 173.6, 171.9, 169.3, 163.0, 157.4, 135.8, 133-0, 130.6, 130.0, 125.0, 117.4, 77.7, 63.4, 59·9, 59.4, 54.3, 41.5, 34.8, 34.6, 33.8 , 32.4, 32.3, 30.9, 25.8, 23.3, 22.2, 5.5, 5.4.

Example 1 03 Compound of Formula IX wherein A: /X Z = CH = CH2 > G:

tByty1, Q =

MS (ESI): /ff/z=725. 34, 727.34[M + H] 〇

, L=tBytyl, real

Example 1 Compound of formula IX wherein A = Z di CH 2 CH 2

MS (ESI): π / ζ 2 737_27, 739 · 27 [Μ + Η]. 13CCCD30D) : (5 173.5, 171.8, 169.3, 160.4, 157.4, 148.6, 133.0, 132_6, 127.8, 127.5, 117.4, 83.8, 77.8, 63.3, 59.8, 59.4, 54.0, 41.4, 35.0, 34.6, 34.0, 32.4, 32.1 , 30.9, 25.8, 23.3, 23.2, 22.2, 5.5, 5.4. 1150-9065-PF; Linlin 84 200813024

acA /, L = /r, the compound of the formula IX of Example 105, wherein A:

/V Z = CH = CH2, G2, Μ "v. MS (ESI): π / ζ = 797. 38 [M + H]. 13CCCD30D): 5 170.5, 170.0, 166.2, 162.8, 154.5, /

132.0, 130.6, 129·6, 128.0, 127.4, 127.1, 126.9, 126.6, 126.2, 121.4, 119.8, 116.6, 114.4, 91.4, 86·7, 76.2, 60.1, 58.0, 57.1, 51.8, 39.7, 33.7, 33· 4,31.6, 30.7,30.5,29.4,24.4,21·6,20_5,4.3,4·3

Embodiment 106 A compound of Formula IX wherein Α = acA/, L = /r, Q Z = CH 2 CH 2 , G = K V . MS (ESI): π / ζ = 783. 45 [M + H]. 13CCCD30D) : 5 172.9, 172.3, 168.6, 164.9, 156.7, 134.3, 132.8, 131.8, 130.1, 129.5, 129.1, 129.0, 128.8, 128.2, 123.5, 121.9, 118.5, 93.5, 88.9, 78.2, 62.3, 60.6, 58.2, 53·3,41·5,35.9,33.8,32.8,32·7, 31.4, 30.8, 23.8, 1 9.5, 18.2, 6.5, 6.2

Embodiment 107 A compound of the formula IX, wherein Α = a//, L = / '" = Ύ,

/X Z = CH = CH2, G = Η V 〇 MS(ESI)·· π/ζ=799· 44[M + H]. 13C(CD30D): 5 172.5, 172.3, 168.5, 165.7, 156.7, 1150-9065-PF; Linlin 85 200813024 137.7, 137.3, 132.7, 131.3, 130.6, 130.0, 129.3, 128.3, 127_9, 127.3, 127.0, 125.2, 118.8 , 78.3, 62·3, 60.3, 59.3, 54·1, 41.8, 35·8, 35.3, 33.6, 32.9, 32.6, 31.5, 26.6, 23.7, 22.8, 6.5, 6.4.

Embodiment 1 A compound of the formula IX, wherein A:, rH Z = CH = CH2, G: a 〇 VL = / 丫,

MS (ESI): ζζ / / ζ = 785 46 [M + H]. 13t (,υιΐύυυ;: oiicLi, i "B.z, ido·/, add. d, lao.i, 137-7, 137.3, 132.8, 131.4, 130.6, 129.9, 129.3, 128.6, 128.3, 128.0, 127.5, 127_1,125.2,118.6,78.1,62.4,60.9,58.4,53.6,41.4,35.9,33.7,32.8,32.7,31.5, 30.0, 24.0, 23.7, 19.5, 18_4, 6.5, 6·2· Example 109 Compound IX , where A: / Q,, Ρ

:ch=ch2,gH

MS (ESI): w/z = 810. 5 [M + H]. 13CCCD30D): 5 170.4, 170.2, 166.3, 163.6, 154.4, 140.0, 139.1, 130.6, 128.9, 128.4, 128.0, 126.6, 126.4, 124.5, 124.2, 123.7, 116.6, 114.4, 76.1, 60.0, 57.8, 57.1, 51_8, 39.7, 35.1, 33.7, 33·2, 31.4, 30.7, 30.4, 29.4, 24.5, 21.6, 20.4, 4.3, 4.3. 1150-9065-PF; Linlin 86 200813024

Embodiment 110 A compound of formula K wherein 丫 Z: CH: CH 2 , gAsV. MS (ESI): ^/^=787. 47[M + H] ° 13CCCD30D): 5 173.2, i?2.4, 168.7, 165.8, 156.7, 142.1, 1 41.3, 1 32.7, 1 31.0, 1 30.6, 1 30.1 , 1 28.7, 1 28.6, 1 26.7, 1 26.3, 1 25.7, 1 18.7, 78.3, 62.3, 60.5,

58.3, 53.3, 41.5, 37.2, 35.8, 35.4, 33.8, 32.8, 32.6, 31·4, 30, 7, 23.7, 19·4, 〗 8·4, 6·5, 6·3· HCV NS3 protease, showing potent inhibitory properties. The following examples describe analytical methods in which the compounds of the invention are tested for anti-HCV effects. Example 111 NS3/NS4a Protease Test HCV protease activity and inhibition were analyzed using an internal inhibitory (fluorescent substrate) fluorescent matrix. A DABCYL and an EDANS group are attached to both ends of a short peptide. In the case of proteinaceous cleavage, the DABCYL group is released from the inhibition of edans fluorescence. Fluorescence is measured with a Molecular Devices Fluoromax (or equivalent) using an excitation wavelength of 355 nm and an emission wavelength of 485 nm. The analysis is in a Corning white half 96-well plate (VWR). 29444-312 [Corning 3693 ]), performed with a full length NS3 HCV protease lb linked to the NS4A cofactor (final enzyme concentration 1 to 15 nM). The assay buffer is supplemented with 10//M NS4A cofactor Pep 4A (Anaspec 25336 or homemade, MW 1424·8) £>REt sl (Ac_Asp — Glu —Asp(EDANS) 87 115〇-9〇65-PF ;Linlin 200813024; -Glu-Glu-Abu-[CO〇]Ala-Ser-Lys-(DABCYL)-NH2, AnaSpec 22991, MW 1548·6) as a fluorescent peptide receptor. The assay buffer contained 50 mM Hepes (pH 7.5), 30 mM NaCl, and 10 mM BME. The enzyme was applied at room temperature for a period of 30 minutes in the absence and presence of an inhibitor. The peptide inhibitor HCV Inh 1 (Anaspec 25345, MW 796 8) Ac-Asp-Glu-Met-Glu-Glu_Cys-OH, [-20 ° C] and HCV Inh 2 (Anaspec 25346, MW 913.1) Ac-Asp- Glu-Dif-Cha-Cys- ΩΗ is used as a reference compound. 1匸50 value, using the formula 205:7 = eight + ((6-eight) / (1 + ((: / /)))))), calculated by XLFit in the active base (ActivityBase, IDBS). Example 11 2 Cell line replicon analysis HCV replicon RNA quantification of cell lines (HCV cell line analysis) Huh-11-7 cell line was used (Lohmann et al, Science 285: 1 1 0-1 1 3, 1 999) The HCV replicon RNA of the cell strain was quantified (HCV cell line analysis). The cells were seeded at 4 x 103 cells/well in a 96 well plate and a medium containing DMEM (high glucose), 1% fetal bovine serum, penicillin-key and non-essential amino acids was provided. The cells were cultured in a 7 5 % C 0 2 incubator at 37 °C. At the end of the culture period, the total rnA of the cells was extracted and purified with Ambion RNAqueous 96 K i t (model number AM 1 81 2 ). To amplify HCV RNA so that there is enough material to detect HCV-specific probes (see below), use the TaqMan One-step RT-PCR master mix kit (Applied)

Biosystems catalogue number 43091 69) was reverse transcribed with HCV (see below) specific primers and subjected to PCR amplification by polymerase chain reaction (PCR). 1150-9065-PF/Linlin 88 200813024, the nucleotide sequence of the RT-PCR primer, located in the NS5B region of the HCV genome, as shown below: HCV forward primer "RBNS5bfo:r" GCTGCGGCCTGTCGAGCT (SEQ ID NO: 1): HCV is introduced later "RBNS5Brev" 5' CAAGGTCGTCTCCGCATAC (SEQ ID NO 2). The product of RT-PCR was detected using an Applied Biosystems (ABI) Prism 7500 Sequence Detection System (SDS), which detects the fluorescent light emitted by the PCR reaction between the labeled fluorescent reporter stain and the dye-inhibiting probe. An increase in the RT-PCR product is reflected when the amount of fluorescence measured for each round of PCR is increased. In particular, the quantification is based on a threshold round where the magnified line exceeds the established fluorescence threshold. Comparing this threshold round of samples to known standards provides a high-sensitivity measure of relative template concentration among different samples (ABI User Bulletin #2 December 11, 1997). The data was analyzed using the ABI SDS program version 1. 7. The relative template concentration can be converted to RNA copy number by using a known copy number of the HCV RNA standard curve (ABI \ .

User Bulletin #2 December 11, 1997). The RT-PCR product was detected using the following labeled probe: 5, FAM-CGAAGCTCCAGGACTGCACGATGCT-TAMRA (SEQ ID NO: 3) FAM = Fluorescent reporter dye TAMRA: = Suppress dye after 30 minutes of RT reaction at 48 ° C , performing PCR. The heat of the PCR reaction used on the ABI Prism 7500 Sequence Detection System was 1150-9065-PF; Linlin 89 200813024 „ Ring parameters: 95°C for 1 round for 10 minutes, followed by 40 rounds, each including 95 °C temperature Breed for 15 seconds and perform the second incubation for 1 minute at 60 ° C. To normalize the data into internal control molecules of cellular RNA, RT-PCR was performed on the cellular mRNA glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The GAPDH copy number is very stable in the cell strain used. GAPDH RT-PCR is performed on the same real RNA sample from which the HCV copy number is determined. The ABI Pre-Developed TaqMan Analysis Kit (Cat. No. 4310884E) contains the above GAPDH. Primer and probe. The ratio of HCV/GAPDHRNA to evaluate the activity of compounds that inhibit HCV RNA replication. Among the Huh-7 cell strains containing replicons, the activity of compounds as HCV replication inhibitors (cell line analysis) In Huh-11-7 cells, the effect of specific antiviral compounds on HCV replicon RNA content was achieved by comparing cells exposed to the compound and cells exposed to the DMS0 vehicle (negative control) and normalized to GAPDH. ( For example, the ratio of HCV/GAPDH is determined by the amount of HCV RNA. Specifically, cells are seeded at 4×10 3 cells/well in a 96 well plate and cultured in a medium containing UDMS0 (0% inhibition control group). , or 2) medium/UDMS0, containing a fixed concentration of compound. The above 96 well plate was then incubated at 37 ° C for 4 days (IC50 decision). The percent inhibition is defined as: % inhibition = 1 00-1 00 * S / C1 where S The ratio of HCV RNA copy number/GAPDH RNA copy number in the two samples C1 = 0% inhibition in the control group (medium/1% DMS0), the ratio of HCV RNA copy number/GAPDH RNA copy number 1150-9065-PF; Linlin 90 200813024 The dose-response curve of the inhibitor is set to 1.5uM by the serial dilution of the character by three times, from high to low, and the highest concentration of the specific compound is set to 1.5uM. The lowest concentration is 〇·23ηΜ. If the EC50 value does not fall in the linear region of the curve, then further serial dilution (for example, 5〇〇ηΜ to 0·08ηΜ). EC50 is based on the IDBS Activity Base program, using the “xLFit” function, 4 parameters, non-linear regression suitable (model #205, version 4.2.1, buildl6). The compounds represented by the above analysis were found to be active. [Simple description of the diagram] Benefits 〇 [Main component symbol description]

No 0 1150-9065-PF/Linlin 91

Claims (1)

200813024 Patent application scope: 1.------ , π, m means: ν-ν A is selected from Rl, -(C = 0) - 〇 ~ Ri, - (c = 〇) - & ^ or -S(0)2-Ri, -s(0)2NHR2; Ri is selected from the following a group consisting of: (1) aryl; substituted aryl; heteroaryl; substituted heteroaryl (ii) heterocycloalkyl or substituted heterocycloalkyl; (iiO-Ci-C8 alkyl, - The C2-C8 alkenyl or _Κ8 alkynyl group each contains hydrazine, 1, 2 or 3 heteroatoms selected from 0, s or N; substituted alkyl, substituted -CrC8 alkenyl or substituted fluorene Alkynyl, each containing hydrazine, 2 or 3 heteroatoms selected from 0, UN; _^12 ring or substituted -C3 - Cl2 cycloalkyl; ~Γ r ^ cycloalkenyl or substituted - C 3 - C 1 2 ring-dilute group; R 2 is independently selected from the group consisting of 1150-9065-PF; Linlin 92 200813024 . (1) gas; (ii) a group, a substituted aryl group; a heteroaryl group; Substituted hydroxy group '(iii)heterocycloalkyl or substituted heterocycloalkyl; (lv)-(:Bu & alkyl, -C2-C8 alkenyl or -(:2-(:8) Alkynyl groups each containing 0, 1, 2 or 3 heteroatoms selected from hydrazine, s or N; substituted alkyl, substituted fluorenyl-decenyl or substituted - 匕-Cs alkynyl, each containing hydrazine, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; _C3 - c12 cycloalkyl or substituted - G-Ci2 cycloalkyl; - C3- C"cycloalkenyl or substituted -C 3 -C 1 2 ring dilute; B is selected from hydrazine or CH 3 ; G is selected from ~NHS(0)2-R3 or -nh(S〇2)NR4R5; Wherein R3 is selected from: (fluorenyl aryl; substituted aryl; heteroaryl; substituted heteroaryl; (Η)heterocycloalkyl or substituted heterocycloalkyl; (ill)-CrC8 An alkyl group, a -CrC8 alkenyl group or a -c2-c8 alkynyl group, each comprising 0, 1, 2 or 3 heteroatoms selected from hydrazine, s or N; substituted -(^-(8)alkyl, Substituted -CrC8 alkenyl or substituted -C2_Cs alkynyl, each containing 0, 1, 2 or 3 heteroatoms selected from hydrazine, s or N; -C3-c12 cycloalkyl or substituted ~ C3-Cu cycloalkyl; -C3-C"cycloalkenyl or substituted -C3-C12 cycloaliphatic; but R3 is not -CH2(C5H9); R4 and R5 are independently selected from: (i) Hydrogen; (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl · 1150-9065-PF; Linlin 93 200813024 (iii) heterocycloalkyl or substituted heterocycloalkane , · ()Cl'C8 alkyl, -C2-C8 alkenyl or -C2-C8 block, each containing 〇, 择 selected from 0, S戋N complex, substituted Γ 4 hetero atom, silk Instead, "2 Cs alkenyl or substituted -C2-C8 alkynyl, each containing or 3 heteroatoms selected from 0, s or N; - c3 - Ci2 cycloalkyl or substituted ~ Γ pm 3 12 % alkyl; _C3-C12 cycloalkenyl or substituted -C3-C12 cyclodecyl; L and Z are independently selected from: (i) hydrogen; • aryl 'substituted aryl; a heteroaryl group; a substituted heteroaryl group; (ill) a heterocycloalkyl group or a substituted heterocycloalkyl group; (lv) a Cl~C8 alkyl group, a C2-C8 alkenyl group or a -c2-c8 alkynyl group, Each comprising 0, 1, 2 or 3 heteroatoms selected from 〇' δ or N; substituted -Ci - C8 alkyl, substituted -C2_C8 alkenyl or substituted -C2-C8 alkynyl, Each containing hydrazine, 1, 2 or 3 heteroatoms selected from hydrazine, s or N; _c3-C12 cycloalkyl or aryl substituted ~C3 - Cl2 cycloalkyl; -C3-C"cycloalkenyl or Substituted -C 3 -C 1 2 cyclodecyl; X is selected from: (1) hydrogen; (ii) aryl; substituted aryl; heteroaryl; substituted a heteroaryl group; (iii) a heterocyclic alkyl group or a substituted heterocyclic alkyl group; (lv) - Cl - C8 alkyl group, -C 2 -C 8 alkenyl group or - c 2 - c 8 alkynyl group each containing hydrazine, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; substituted -Ci~c8 alkyl, substituted -C2-Cs alkenyl or substituted -c2 - ο fast radicals each comprising 1150- 9065-PF;Linlin 94 200813024 〇, 1, 2 or 3 heteroatoms selected from ruthenium, 3 or N; anthracene or substituted _C3_Ci2 cycloalkyl; _C3_Ci2 cycloalkenyl or substituted -C3-C12 cycloalkenyl; (〇1 such as 1 does not exist or is selected from -0_, ^, ._, -NUe)-, ~c(〇)NH_ or _c(〇)N(Me) _ ; R6 is selected from the group consisting of * (a) gas; (b) aryl; substituted aryl; heteroaryl; substituted heteroaryl · (c) heterocycloalkyl or substituted Heterocycloalkyl; soil '(d)~Ci-C8 alkyl, -C2-C8 alkenyl or -C2-C8 alkynyl, each containing 1, 2 or 3 heteroatoms selected from hydrazine, s or N Substituted alkyl, substituted - C2_C8 dilute or substituted - c 1 Cs ο, 1, ... selected from. a hetero atom; or a substituted -C-...a dilute or a base -C3-C12 cycloalkenyl; substituted by m=〇, 1 or 2; n=l, 2 or 3. Formula V, VI 2. The compound W or VDI as described in the scope of the patent application: Ν-Ν 1150-9065-PF; Linlin 95 200813024 Nv^N N9N, X (VII) (VIII) where A, G, L, X and Z are as defined in item 1 of the scope of the patent application. 3. The compound of claim 1 is selected from the formula IX, wherein A, L, Q, Z and G are shown in Table 1; (IX) Table 1 Example ALQ z G 8 person again / /丫V 1 -CH=CH2 9 person / 1 -CH-CH2 -//v 10 person again / p- V 1 -ch=ch2 11 V 1 - CH 2 CH2 A?v 1150-9065-PF; Linlin 96 200813024 12 ΛΛ -ch=ch2 /, Xr Η 1 13 乂Λ, > V 1 -ch=ch2 /, Xr Η 1 14 people again / -ch =ch2 /, X〆Η 1 15 people / N,, N Ϊ -ch=ch2 /iXr Η 1 16 people again / ,, winter -CH=CH2 17 people / /,,, winter > NVN 1 -ch =ch2 43⁄4 18 people again / n^IT -ch=ch2 19 people again / %'N 1 -ch=ch2 43⁄4 20 ΛΛ Λ1< -ch=ch2 21 乂Λ/ ,·'( 1 -CH-CH2 / gas 1150-9065-PF;Linlin 97 200813024 22 person / Ρ- Ν -CH=CH2 / gas 23 乂Λ / , Ρ Υ -ch=ch2 gas 3 24 乂Λ, Jr Ν^Γ Ν -ch=ch2 /+ 3⁄4 \ 25 people again / Ν, μ'Ν 1_, -CH=CH2 'ϋΝ, > Ν V 26 people / C^ci N -CH=CH2 Ν \ 27 people again / nP -CH=CH2 'ϋΝ, > Ν \ 28 to . / / NyN -ch=ch2 /, ί??νν 29 iQkA/ y -ch=ch2 /, [^ν 30 CX. Also / Λ1< p- fi N^TN -CH-CH2 //ν 31 Ος和 / ', winter ya N -CH=CH2 Vv 1150-9065-PF; Linlin 200813024 3 2 <λ0 again / !L -ch=ch2 /,^v 33 0^1〇^〇A/ p- V 1 -ch=ch2 /^v 34 MeO^〇X^ -f -CH-CH2 'Ά 35 A 8 . <,cr y /< 0°' Ή VN 1 -CH=CH9 Aif^ 36 〇人-f - ch=ch2 /^v 37 -f -CH=CH2 /Ά 38 〇-ch= Ch2 /, & 39 li -ch=ch2 /^v 40 丨, winter p' 1. -ch=ch2 Λίί'ν 1150-9065-PF;Linlin 99 200813024 41 Οςλ -ch=ch2 /^v 42 Λ ! L -ch=ch2 /八43 α -ch=ch2 44 1 〇太义 / Η f /, f 0°' n -CH=CH9 /, & 45 αΛ li -CH-CH2 w 46 , and / Al< -CH=CH2 Vv 47 Ο again / A1< p' -ch=ch2 w 48 〇人 / 0 V; 1 -ch=ch2 /, i??vv 49 -f li !L -ch=ch2 /,& 100 1150-9065-PF; Linlin 200813024 50 N -ch=ch2 /, iFv 51 NVN -ch=ch2 /^v 52 CA VN -ch=ch2 /, & RQ Me />< 0. — Λ N -ΓΗ=ΓΗ〇X»/ JL ▲ ▲ u Λίί^ν 54 CA Al< y N^TN -CH=CH2 55 〇Me^yV ΗΝΛΐε V -CH:CH2 56 Me^7 Me h Winter N, -ch=ch2 /, & 57 HN*^ /丫NyN -ch=ch2 58 a1, /丫ya N -ch=ch2 //v 1150-9065-PF;Linlin 101 200813024 59 0 -ch=ch2 60 /丫N -ch=ch2 61 /, wide y N -ch=ch2 62 ~Sy /, 〇0. —VN —ch=ch2 /,& 63 汊Λ/ aJ〇N -ch=ch2 64 w V' Λ N -CH-CH2 /Nq<3 H 65 V -ch=ch2 /, X, H kJ 66 汊. Also / >0' V -ch=ch2 An^N^ H d'CH3 67 γ -ch=ch2 1 H 1150-9065-PF;Linlin 102 200813024 68 ΛΤ< V -CH=CH2 69 ^〇A/ Λ1&lt ; >0' NVN -ch=ch2 H UCH3 70 again / /, f >0' ΝγΝ -CH-CH2 /3⁄4 ^^co2h 71 /γ: 0. — Λ Ν -CH=CH2 /Ί H ^och3 72 ^〇A/ ~ NvN 1 -ch=ch2 73 Λ1< V -ch=ch2 74 II. And / , , , winter Y -ch=ch2 75 p- v -ch=ch2 /V« Η H 76 ^〇A/ Ν -ch=ch2 ox/〇hn-n person NTS, N person Ν' Η Η 1150 -9065-PF;Linlin 103 200813024 77 ^〇A/ ,,冬ΝΥΝ-CH=CH2 aXF3 78 /,!< N -ch=ch2 a^Olci 79 V' N^TN -ch=ch2 /3⁄4 80 a 8, —, 0,, / / < 0. — N^N !L -CH=CH? /, Xr^ H V people c, 81. Also / li N -CH=CH2 A^F 82 汄. Also / V' N -ch=ch2 /, x people Η H 83. Also / Bu, winter p- V -CH=CH2, Ά' Η H 84 for a long time. Also / y N^T N -ch=ch2 /^a H 85 汊. Also / 1 -ch=ch2 AX0 1150-9065-PF; Linlin 104 200813024 86 ΝγΝ -CH=CH2 /3⁄4 87 ^〇A/ ', winter y -H A?v 88 仏. Also / y N^T N -CH2CH3 / eight 89 n u, ...〇, / / γ: 0. , N -CF2 / eight 90 仏. Also / NYN -CH=CH2CH 3 Z, iFv 91 person / Λ 1 < 0. , NN ΝγΝ -ch=ch2 Λίί^ 92 people again / Q^°\ NN ΝγΝ -CH=CH2 -Λ!ί2ν 93 ΛΛ /'f NN ΝγΝ -CH-CH2 /,^v 94 乂Λ/ 0C, NN ΝγΝ -ch=ch2 1150-9065-PF;Linlin 105 200813024 95 ΛΛ 0S— NN ΝγΝ -ch=ch2 96 ΛΛ NN ΝγΝ -ch=ch2 97 person / fP NN ΝγΝ -ch=ch2 /^v 98 person / CK V NN N^N -CH-CH2 /^v 99 乂Λ/ Λ1< εΡ NN ΝγΝ -CH=CH2 Λίί^ν 100 CX〇A/ Bu,冬0°' NN ΝγΝ -CH=CH2 101 人又/ Vo Λ -ch=ch2 /八102 CX0A/ ',冬> Ν -ch:ch2 103 乂Λ/ ,, winter yr η 1 -ch=ch2 1150-9065-PF;Linlin 106 200813024 4. A pharmaceutical composition which is a pharmaceutically acceptable salt, body or excipient. 'A method comprising a patented range 1st ester or precursor and a pharmaceutical product or a method acceptable for a hepatitis C viral infection in a subject, comprising: administering a therapeutically effective amount to the subject Patent No. 4 of the patent scope. 6. A method for inhibiting replication of hepatitis C virus, comprising: administration of 1150-9065-PF; Linlin 107 ^u6UU24, a hepatitis C NS3 protease therapeutically effective denim. In the scope of application for patents, the fourth item is 7th. If the application scope is the fifth item, the tenth, the + v toxic infection method is still included in the treatment target + [hepatitis disease ^ s only given an amount of ice 8. Such as towel 7 s Beb anti-hepatitis C virus agent. τ 明 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固 固From the following (adamantine). Wood (ribavarin) and diamond-like 9 · As in the scope of application, the method of infection, the extra wide range of hepatitis C virus / hepatitis virus agent is a type C liver IRES ( (four) polymerase, metal A method or method for producing a protease or a species derived from I, n iV, V, VI, νπ or 丄ν, ν, VI is performed according to the procedures, methods or processes described herein. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, vinegar or precursor of the chemical. 12. The pharmaceutical composition of claim 5, wherein the primary anti-HCV agent. 3 is 13 The pharmaceutical composition as described in the scope of application of claim 5, which still contains the following inhibitors, selected from the group - (4) under the group. Interferon, t-Bavirin, diamond-like, :- HCV protein inhibitor An HCV polymerase inhibitor, a _ helicase inhibitor or an internal ribosome entry site inhibitor. I4. The pharmaceutical composition of claim U, which further comprises a polyethylene glycolated interferon. ll50-9065-PF; Linlin 108 200813024 1 5. The pharmaceutical composition of claim 11, which further comprises another antiviral, antibacterial, antifungal or anticancer inhibitor, or immunomodulator. 1150-9065-PF; Linlin 109 200813024 VII. Designated representative map (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: None. 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 1150-9065-PF; Linlin 5