TW200808832A - Triazolyl macrocyclic hepatitis C serine protease inhibitors - Google Patents

Abstract

The present invention relates to compounds of Formula I or II, or pharmaceutically acceptable salts, esters or prodrugs thereof: which 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 to the subject a pharmaceutical composition comprising a compound of the present invention.

Description

200808832 IX. OBJECTS OF THE INVENTION: TECHNICAL FIELD The present invention relates to a triazolyl macrocyclic hepatitis C virus (jjcv) protease inhibitor compound which has anti-HCV activity and is useful for treating hCV sensation. Specifically, the present invention relates to a novel HCV protease inhibitor compound of a triterpene, a composition containing the same, a method of using the same, and a method of producing the compound. [Prior Art] HCV is the main cause of non-a, non-B hepatitis, and has caused increasing public health problems in developed and developed countries. It is estimated that the disease is infected more than 200 million people worldwide, almost five times more than individuals infected with human immunodeficiency virus (HIV). "CV-infected patients, because a high proportion of individuals are chronically infected, the risk of developing cirrhosis is increased, and then it is manifested as hepatocellular carcinoma and terminal liver#. Hcv $ causes the most important cause of hepatocellular carcinoma, and the cause of liver transplantation in Western countries is the main cause. In most cases, antiviral drugs that have mild infections and are prone to significant side effects in the liver. Currently, there are only two treatments for HCV infection, which usually involve a considerable number of obstacles in the development of anti-HCV therapy for 3-12 months, including Not limited to: the virus is tenacious, the genetic diversity of the virus when it replicates in the host, the chance of the virus developing into a drug resistant mutant, and the lack of reproducible infectious culture system and the small animal model for HCV replication and pathogenesis . In large complex biology, special care must be taken. Therapy has been approved. The original time course was intravenous administration of interferon H50-9072-PF; Linlin 6 200808832 -alpha (IFN-α), and a newly recognized second-generation treatment consisting of iFN-a and a k-type antiviral Nucleoside mimics, for example, ribav ir in, co-therapy. These treatments suffer from interferon-related side effects and poor efficacy against HCV infection. Due to the poor tolerance of current therapies and the poor efficacy, there is a need to develop antiviral agents that are effective against HCV infection. When most patients are chronically infected and have no symptoms, and the prognosis is unknown, an effective drug preferably has a significantly lower side effect than currently available treatments. Hepatitis C non-structural protein-3 (NS3) is a proteolytic enzyme necessary for the processing of viral polyproteins and subsequent viral replication. Although there is a large number of viral variants associated with HCV infection, the active site of NS3 protease has high retention, so its inhibition is an attractive mode of intervention. The recent success in the treatment of protease inhibitors supports the concept of NS3 inhibition as a key target in the anti-Hcv war. HCV is the Rna virus of the family Flavividae. (4) The genome has a mantle membrane and contains - about 96 (3) a pair of leg molecules. It is encoded as a polypeptide of about 3010 amino acids. The HCV polyprotein is treated with a virus and a host's skin enzyme to form a peptide having various functions. There are three structural proteins, the functions of c, M and Μ10 proteins are unknown 'and include highly mutated sequences... non-structural proteins. NS2 is a _-dependent metalloproteinase that functions as a -de-protein-partial linker. NS3 is involved in two catalytic functions (as one of the separate ends of serine protease, which requires a ship 1150-9072-PF; Linlin 7 200808832. 乍 is an auxiliary, and one of the C-terminal ATPase-dependent Helicase function. NS4A is a cofactor that is related to sputum but is a non-covalent serine protease. NS3-4A protease is responsible for the cleavage of four parts of viral polyprotein. NS3 NS4A is self-catalyzed and cleaved In the cis position, the other three hydrolases, NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B, all of which are produced in the trans position. NS3 is a serine protease, which is structurally classified as a type of pancreatic coagulation. Chymotrypsin. Although NS silky female protein has its own proteolytic activity, Η" protease is not an efficient enzyme in catalyzing XK protein cleavage. It has been confirmed that one of the central hydrophobic regions of NS4A protein shell Enhancement is necessary. The complexation of NS3 protein with NS4A appears to be necessary for the decomposition treatment, and can enhance the protein decomposition efficiency of all parts. The general strategy for developing antiviral agents is to make the virus coded. The enzyme is inactive and contains NS3, which is necessary for viral replication. Recent research on finding NS3 protease inhibitors is based on 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: w〇 00/59929 (2000); WO 99/07733 (1999); WO 00/09543

(2000); WO 99/50230 (1 999); US 5861 297 (1 999) and US 2002/0037998 (2002). SUMMARY OF THE INVENTION The present invention relates to a trimethylthiol HCV protease inhibitor compound 1150-9072-PF; Linlin 8 200808832, including pharmaceutically acceptable salts, esters, or prodrugs thereof, which inhibits serine Protease activity, especially the activity of the hepatitis C virus (hcv) NS3_NS4a protease. Thereby, the compound of the present invention interferes with the hepatitis C virus. It is a cycle and can be used as an effective antiviral agent. The invention further relates to pharmaceutical compositions comprising administering a compound, or a salt, ester or prodrug thereof, to a subject suffering from an HCV infection. 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-HCV agent, such as interferon (alpha-interferon, cold-interferon, Complex interferon, polyethylene glycol interferon, albumin or a combination of interferons), ribavarin, adamantine, an other HCV protease inhibitor or an HCv polymerase, helicase, or 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 one embodiment, the compounds disclosed herein are represented by Formula I or π, or a pharmaceutically acceptable salt, ester or precursor thereof, wherein:

Where: A is selected from - (〇〇) - 〇 - Ri, - (c = 〇) - &, -c ( = 〇) - NH_R2 or S (0) 2 - R" - S (0) 2 NHR2; 1150-9072-PF; Linlin 9 200808832 R i is selected from the following group: (i) base, substituted aryl, miscellaneous - Zhu Xi Fang, substituted heteroaryl (Π) Heterocycloalkyl or substituted heterocycloalkyl; ', earth (iii) - Ci-C8: J: a group, -C2-C8, a ruthenium or a -C2-C8 alkynyl group, each containing hydrazine 1, 2, or 3 heteroatoms selected from ruthenium and SstN; substituted 丄a 烧, 丝代 (4) L substituted 匕 block, each containing

0, l, 2 or: 3 heteroatoms selected from O, S or N η, -C3-c 〗 2 cycloalkyl or substituted -C3_Ci2 cycloalkyl; - Γ^Γ re π * (〇3 Cl2 % fine or substituted -C3-C12 cycloalkenyl; R2 is independently selected from the following salty groups: (1) hydrogen; (ii) aryl; substituted aryl; 々 sign, heteroaryl, substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; (iv) -Ci-Ce, -C2-C8, green A, ten rr L8 ~ or -C2-C8 alkynyl, each comprising hydrazine, 2 or 3 heteroatoms selected from 0, s or N; substituted _cA alkyl, substituted -c2 - c8 alkenyl or Substituted _G2-h alkynyl groups each containing hydrazine, 1, 2 or 3 selected from 0, 8 or ^[[br>[r.].r P.sub.4 π t潍 atom, —c3 —Ci2 naphthenic a substituted or substituted C3-Ci2 cycloalkyl; -ccf榼U Li2 % syl or substituted -C3-C12 cycloalkenyl; G is selected from -NHS(0)2~R3 or -龙( s 〇 2) NR 4 R 5 ; wherein R 3 is selected from ( υ aryl '. substituted aryl; heteroaryl; substituted heteroaryl; (ii) heterocycloalkyl or substituted heterocyclic (iiO-h-C8 alkyl, -C2-& alkenyl or -C2-decynyl, each containing hydrazine, 1150-9072-PF; Linlin 10 200808832 1, 2 or 3 selected from hydrazine, a hetero atom of s or n; a substituted -CrC8 alkyl group, a substituted -C2-C8 alkenyl group or a substituted ~C2-C8 alkynyl group, each containing hydrazine, 1, 2 or 3 selected from hydrazine, a hetero atom of s or n; -Cs-C12 cycloalkyl or substituted cycloalkyl; -Cs-Cu ring-dilute or substituted -C 3 - C 1 2 ring-dilute ·, but R3 is not ~CH2Ph or -CH2CH2Ph; R4 and ^ are independently selected from (1) hydrogen; (11) aryl; substituted aryl; heteroaryl; substituted heteroaryl; (in) heterocycloalkyl Or substituted heterocycloalkyl; • ) Cl C8 alkyl, -C2-C8 dilute or - C2-C8 fast radicals each comprising hydrazine, 1 2 or 3 heteroatoms selected from 0, S or N Substituted -Cl-C8 alkyl, substituted -Cz-Cs alkenyl or substituted -C2_Cs alkynyl, each containing 0, 1, 2 or 3 heteroatoms selected from ruthenium, 3 or N ; a C3_Ci2 cycloalkyl

-C3-C12 cycloalkenyl;

X and Y are independently selected from: (1) hydrogen; (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl; (Hi)heterocycloalkyl or substituted heterocycloalkyl ;

‘each contains 〇,

11 200808832 〇, 1, 2 or 3 heteroatoms selected from 〇, s*N; _C3_Ci2 ring or substituted -G-Cu cycloalkyl; -C3_Ci2 cycloalkenyl or taken -C 3 - C 1 2 ring-dilute group; (V)-W-R6, wherein w does not exist or is selected from a 〇-, -s~, N-, -N(Me)-, -C(0)NH- or —C(0)N(Me)_ ; &amp; is selected from the group consisting of: (a) nitrogen, (b) aryl; substituted aryl; heteroaryl; substituted heteroaryl (c) a heterocycloalkyl or substituted heterocycloalkyl; (d) -U8 alkyl, -C2-C8 alkenyl or -Cs alkynyl, each containing hydrazine, 1, 2 or 3 selected from Hetero atom of 〇, s or N; Alkyl, substituted -C2-&amp;alkenyl or substituted - alkynyl, each comprising 0, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; -Cs -^ Alkyl or substituted -G-Ck cycloalkyl; -o-c"cycloalkenyl or substituted -C3-Cl2 cycloaliphatic; or 'X and Y and attached carbon atom-forming ring a structure in which the cyclic structure is selected from an aryl group, a substituted aryl group; an anthracene group, a substituted heteroaryl group; =: represents a carbon-carbon single or double bond; j = 0, 1, 2 3 or 4; k = 1, 2 or 3; m=0, 1 or 2; n=l, 2 or 3 〇1150-9072-PF; Linlin 12 200808832 [Embodiment] The first embodiment of the present invention is as above </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> <RTIgt; The invention relates to a compound of the formula: Υ ν

G or a pharmaceutically acceptable salt thereof, a cool or prodrug, alone or in a pharmaceutically acceptable carrier or excipient, wherein Α, γ, χ —, —, ° ～ is defined. In another example of G, X and Y are independently selected from the group consisting of hydrogen-promoting, aryl, substituted aryl &amp; heteroaryl, substituted heteroaryl' 埤: cycloalkyl, via Substituted heterocycloalkyl, _Ci_C8 alkyl, _C2~C8 indomethan-G-C8 alkynyl, substituted Cs alkyl, substituted _8-8 substituted -C2-C8 alkynyl, -c3_Cl2 cycloalkyl, -C3_Ci2 cycloalkenyl 2 substituted -C3-C!2 cycloalkyl or substituted -C3-Ci2 cycloalkenyl, wherein -1 -Ci-Cs alkyl, -CrGalkenyl Or -h-Cs alkynyl, substituted -Ci-decyl, substituted -C2-C8 alkenyl or substituted -C2-Cs alkyne comprises 0 small 2 or 3 selected from. , SU's hetero atom. A = group consisting of -C-(0) - Ri, -c_(〇)_〇_Ri, -CCCO-NH-L, where Ri is selected from aryl, substituted aryl, hetero Aromatic 1150-9072-PF; Linlin 13 200808832, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, _Ci_Ci alkyl, -C2-C8 decyl, -CA alkynyl, substituted -Ci_C8 alkyl, substituted exo (:8 alkenyl or substituted _C2_C8 alkynyl, _C3_Ci2 cycloalkyl, -CrC12 cycloaliphatic, hydrazine-substituted _C3_Cl2 cycloalkyl or substituted cycloolefin G is -NH-S〇2-NR4R5 or -NHS〇2-R3, wherein Rs is selected from -CrCs alkyl, -CZ-C8 alkenyl or -C2 -C8 alkynyl, aryl, substituted Aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -C3-Cl2 cycloalkyl, -C3_Ci2 cycloalkenyl, substituted _C3_Ci2 = alkyl or Substituted -C3-C12 cycloalkenyl, wherein hydrazine and Rs are independently selected from nitrogen, _Cl-C8 alkyl, substituted-Ci-c8 C2 - 〇8, and -C2-C8: t fluorenyl, Alkyl, substituted -C2-C8 alkenyl or substituted -C2-Cs alkynyl, aryl, substituted heteroaryl, hetero Anthracenyl, substituted heterocycloalkyl, cycloalkyl, -c3-c12 cycloaliphatic, substituted -C3 -Ci2 cycloalkyl or substituted -C3-Cl2 cycloaliphatic. In another example , X and Y are selected from the group consisting of chlorine, aryl, substituted aryl, heteroaryl, substituted heteroaryl. A is -c-(o)-o-Rl, -C (0)_nh_Ri, where 1 is selected from _c丨一 &amp; alkyl '', ', -c2-c8 alkenyl or prepared (tetra), substituted _Gi_G old base, taken by -C2- a C8 alkenyl group, a substituted _C2_C8 alkynyl group, a _C3_Ci2 cycloalkyl group, a -G_Ci2 cycloalkenyl group, a substituted Crk cycloalkyl group or a substituted acyclic ring group. G is -NHS〇2-R3-, Wherein L is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycle

a C3-Cl2 cyclodextrin, a _C3_Cl2 cycloalkenyl group, a substituted-Ca-Cu cycloalkyl group or a substituted -C3_Cl2 cycloalkenyl group. , Bauxite S 1150-9072-PF; Linlin 14 200808832 In another case, the x and γ systems are independently selected from the following aryl groups, substituted aryl '' groups, substituted hetero-c- (0) + Rl 'wherein R1 is 〜3. 2 cycloalkyl or substituted: Α is a cycloalkyl group. G is - for example, wherein R3 is selected from _Cm^3Cl2 substituted -C3_Cl2 cycloalkyl Or in another example, X and Y are independently selected from the following aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl A · -C(0)-NH-Rl, Wherein 1?1 is -(:148 alkyl or substituted -the earth is a ^-based group. It is -NHS02-R3, and its t R3 is selected from _C3_Ci2 cycloalkyl or substituted - C3*~Cl2 ring-burning In another example, X is a substituted or unsubstituted aryl group (e.g., y), and y is a substituted or unsubstituted heteroaryl group (e.g., Η). The lanthanide system is selected from the group consisting of :-(:-(0)-1^, -(:-(〇)一〇11, _(:(0) — 1^11, where 1?1 is a square group, a substituted aryl group, a heteroaryl group Substituted, substituted heteroaryl, heterocycloalkyl, substituted heteroalkyl, -Ci-Cs alkyl, -C2-Csalkenyl, -CrC8 alkynyl, substituted -U 8-alkyl, substituted -C2-C8 alkenyl or substituted -C2-C8 alkynyl, ~C3-Cu cycloalkyl, -C3-C&quot;cycloalkenyl, substituted C3-C12 ring:) : a substituted or substituted C3-Ci2 cycloalkenyl group. G is - leg hNR4r5 or -NHS〇2_R3, wherein R3 is selected from _Ci-C8 alkyl, - 匕-Cs alkenyl or -C2-C8 alkyne Alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -C3_C12 cycloalkyl, -C3-C12 cycloalkenyl, Substituted ~C3-cycloalkyl or substituted -C3 -Ci2 cycloalkenyl, 1150-9072-PF; Linlin 15 200808832 wherein R4 and R5 are independently selected from hydrogen, a Cl-Cs alkyl group, -C2-C8 Alkenyl, -CrCs alkynyl, substituted -Cl-alkyl, substituted -C2-C8 alkenyl or substituted -C2-Cs alkynyl, aryl, substituted aryl, heteroaryl, Substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -C3-C12 cycloalkyl,

Cs Cl2 cycloalkenyl, substituted _C3_Cw cycloalkyl or substituted -CrCn cycloaliphatic.

In another example, X is a substituted or unsubstituted aryl group (such as ··Y), and γ is

Substituted or unsubstituted hetero. 'Heterogroup (eg · &gt;). A is -(:(0)-0-1 or C(〇) NH R] wherein R1-C3-Cl2 cycloalkyl or substituted -C3-C12 cycloalkyl G is NHS〇2-R3, R3 is selected from -c3 - Ci2 cycloalkyl or substituted -c3-c12 cycloalkyl. In another embodiment, the invention relates to a compound of formula IV:

A pharmaceutically acceptable carrier or excipient, wherein Α alone or in combination with a X and G are as defined above. In another example, X and γ are selected from the group consisting of: gas, aryl, substituted arylheteroaryl, substituted heteroaryl, heterocycloalkyl, substituted 1150-9072-PF; Linlin 16 200808832 Heterocyclyl, _Ci-Cs, -CrCsalkenyl or -C2-C8 fast radical, substituted -CrC8 alkyl, substituted -C2-C8 alkenyl or substituted -C2- C8 alkynyl, -Cs-Cl2 cycloalkyl, -c3-c12 cycloalkenyl, substituted -C3-Cl2 cycloalkyl or substituted -C3-Cl2 cycloalkenyl, wherein -Cl-C8 alkyl , a c2-c8 alkenyl or -CrC8 alkynyl group, a substituted -c---alkyl group, a substituted -C2 - C8 dilute group or a substituted -C^C8 alkynyl group each containing hydrazine; 2 or 3 heteroatoms selected from 〇, s or N. A is selected from the following groups: -c(〇)_〇_Ri or -C(0)-NH-Ri 'where Ri is selected from aryl, substituted aryl, heteroaryl' substituted Heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, _Ci-Cs alkyl, -CrC8 alkenyl, -C2-C8 alkynyl, substituted -Cl-C8 alkyl, substituted -c2 -c8 alkenyl, substituted -c; 2-C8 alkynyl, -C3 -monocyclic, -C3-c"cycloalkenyl, substituted -C3_Cl2 cycloalkyl or substituted -cycloalkenyl. G may be -NH-SO^NRl or -NHS〇2-R3, wherein R3 is selected from -CA alkyl, C8 alkenyl, -C2-C8 alkynyl, aryl, substituted, and hetero Aryl, substituted base, heterocyclic, substituted heterocycloalkyl, -C3-Cl2 cycloalkyl, -Cli&gt; if, knee 1 U2 % alkenyl, substituted -C3-c12

Cycloalkyl or substituted -CrC"cycloalkenyl, Lizhong R 丞 /, 甲 4 and 匕 independently selected from the wind, -CK base, each c8 dilute, each Gs alkynyl, substituted - cc alkyl, substituted _ group or substituted _C2_C8 alkynyl, aryl / substituted aryl, heteroaryl, desorbed. ^ &amp; such as heteroaryl, heterocycloalkyl , substituted heteroalkyl, -C3-C"cycloalkyl, -jr rr C12 bad, substituted -c3-Cl2 ring or substituted nGi2 cycloalkenyl. In yet another example, the X and γ systems are selected from the group consisting of ruthenium, aryl, substituted aryl, hetero 4, group, heteroaryl, substituted heteroaryl. Α 17 U50-9072-PF; Linlin 200808832 is -C-(0)-〇-Ri, -C(0) - NH - Ri, where Ri is selected from _Ci-Cs alkyl, -C2-C8 olefin Or -C2-C8 alkynyl, substituted _Cl-Cs alkyl, substituted -C2-C8 alkenyl, substituted - 匕-Cs alkynyl, _C3_Ci2 cycloalkyl, -GC! 2 cycloalkenene a substituted, L-L cycloalkyl or substituted C3-k cycloalkenyl. G is -NHS〇2_R3-, wherein R3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -C3-C !2 cycloalkyl, -cycloalkenyl, substituted -C3 -Ci2 cycloalkyl or substituted -C3 - C12 cycloaliphatic. In another example, X and Y are independently selected from the group consisting of: a aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group. A is -c(o)-o-Rl, wherein 1?1 is a 吖3412 cycloalkyl group or a substituted _C3_k ring alkyl group. G is -NHSCh-R3 wherein Rs is selected from _C3_Ci2 cycloalkyl or by: -C3-Cl2 cycloalkyl. for

An aryl group, a substituted aryl 'heteroaryl group, a substituted (tetra) group. I -CW-NH-R, 'its &quot; base or substituted - eh. alkyl. G is -NHSH, and the towel R3 is selected from the m yard or the soil. - C3-Cl2 cycloalkyl. In another embodiment, the invention relates to a compound of the formula: 1150—9072—PF/Linlin 18 200808832

Nw

G or its pharmaceutically acceptable salts, esters or pre-pharmaceutically acceptable carriers = or combinations - independent grip: 糸 independently selected from one to one independently from each of the following: (i) hydrogen, _ , -N〇2, ~CN; (11)-M-R4-, Μ is 〇, s or NH; (iii) NR4R5; (iW-CA alkyl, decyl or _C2_C8 alkynyl, each containing 〇, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; substituted _Cl-C8 alkyl, substituted C8 alkenyl or substituted each &amp; alkynyl, each containing hydrazine ', 2 or 3 selected heteroatoms; - Μ" cyclodextrin or substituted -C3-C12 cycloalkyl; -C3-Cl2 Cyclohexyl or substituted -C3-Cl2 fluorene (v) an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group; (Vi) a heterocycloalkyl group or a substituted heterocycloalkyl group; wherein A, G, R4 and R5 are the same In another example, wherein Μ4 is independently selected from, 7 or N, where R? is as defined above. A is selected from 〇, UhR, -(:(0)-0 -1 or -CCCO-NH-R!, wherein the oxime is selected from aryl, , and &amp; substituted aryl, heteroaryl, substituted Aryl, heterocycloalkyl substituted heterocycloalkyl, -Cl - C8 1150-9072-PF; Linlin 19 200808832 alkyl, -C2~C8 alkenyl or -C2-C8 alkynyl, substituted - Cl-C8 alkyl, substituted -C2-Cs alkenyl, substituted -c2-c8 alkynyl, -C3_Ci2 cycloalkyl, -C3-Cl2% alkenyl, substituted -C3 -Ci2 naphthenic Substituted or substituted - C3 - C! 2 cyclofine. G is -NH-S〇2-NR4R5- or -SCh-Rs-, wherein Rs is selected from -C "C8 alkyl, -C2-C8 olefin , -C2-c8 alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CrC 2 ring;): a terminal, -Cs-Ci2 cycloaliphatic, substituted -c3-Ci2 cycloalkyl or substituted -C3-C12 cycloalkenyl, wherein R4 and R5 are independently selected from nitrogen, -C 1 - C 8 , -C2-C8 dilute-C2-C8 alkynyl, substituted -Cl-C8 alkyl, substituted -CrC8 alkenyl, substituted -C2 -C8 alkynyl, aryl, substituted aryl Base, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -GC!2 cycloalkyl, -C3_Cl2 cycloalkenyl, substituted -CrCu Alkyl or substituted -C3 -Ci2 cycloalkenyl. In another example, wherein XrX4 is independently selected from a ^7 or N, wherein R7 is as defined above. A is -(:(0)-0- 1 or -c(0) - nh - Ri, wherein Ri is selected from -C]-C8 alkyl, -G-C8 alkenyl or -C2-C8 alkynyl, substituted -CrC8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-C!2 cycloalkyl, -C3-C-2-cycloalkenyl, substituted -G-k cycloalkyl or Substituting -C3-C!2 cycloalkenyl. G is -NH~S〇2-Rr, wherein R3 is selected from aryl, substituted aryl [heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocalcinyl, -C3 - C 1 2 ring burned, pp machine 丞, ~C3~Cl2 cycloalkenyl, substituted -CrC!2 cycloalkyl or substituted -C3 -c" ring meaning. In another example Where X "X" is independently selected from -cl or N, where R7 is as defined above. A is -C(0)-0 - Ri or a c(〇)-with-, where the ruler 1150-9072-PF; Linlin 20 200808832 is selected from -Cs-C!2 cycloalkyl or substituted - C3_Cu cycloalkyl. G is -NH-SOrR3-, wherein &amp; is selected from -C3-c 2 cycloalkyl or substituted -&amp;&lt;12 cycloalkyl. In yet another example, wherein Χι-Χ4 is independently selected from -CR7 or N, wherein R? is as defined above. A is -(:(0)-guan-1^, wherein R1 is selected from a Cl-C8 alkyl group or a substituted -Cl_c8 alkyl group. G is -NH-s〇2-Rs-, the central choice From -C3-Cl2 cycloalkyl or substituted -C3-Cl2 cycloalkyl. In another embodiment, the invention relates to a compound of formula YJ:

Or a pharmaceutically acceptable salt, ester or precursor thereof,

Can be used to drive drugs, alone or in combination with a • 4 series independently from (1), i^i X _ λΤ r\

(iii) NR4R5; (iv)~Ci-Cs alkyl, ~c2. 1, 2 or 3 selected from alkyl, substituted -C2-〇, 1, 2 or 3 selected from 〇, or Substituted -C 3 - C 1 2 ring, b

Cs alkenyl or ~C2-C8 alkynyl, each containing hydrazine,

Or a hetero atom of N; a substituted -Ci-C8 or a substituted -C2-C8 alkynyl group, each containing a hetero atom of s or N; -C3-Ci2 cycloalkyl^; -C3-C!2 cycloalkenene Substituted or substituted 1150-9072-PF; Linlin 21 200808832 -C3-C12 ring; (7) aryl "substituted aryl, heteroaryl, substituted heteroaryl (VI) heterocycloalkyl or Substituted heterocycloalkyl; wherein a, G, R4 and R5 are as defined in the first embodiment. In another example, wherein X1-X4 are independently selected from north or n, wherein R7 is as defined above. A is selected from -On(8)-〇1 or -C(8)', wherein Ri is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycle An alkyl group, a C2-C8 alkenyl group or a -C8 alkynyl group, a substituted alkyl group, a substituted C2-C8 alkenyl group, and a substituted one of the "L2 C8 alkynyl groups" —C3-(: 12 cycloalkyl, -C3-Cl 2 cycloalkenyl, exemplified by Γ Γ & 代 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 G is -NH-S〇2-NR4R5- or -NH_s〇p 4(tetra)bU2 - R3-, wherein &amp; is selected from -c-poly C8 alkyl, -c2-c8 alkenyl, -C2, chivalrous radical, Substituted aryl, heteroaryl, substituted heterozygous, skuttered alkyl, substituted heterocycloalkyl, -C3-C&quot;cycloalkyl, -Γ _ ^ ^ and C" An alkenyl group, a substituted C3-alkyl group or a substituted -C3-Ci2 ring is considered to be an alkenyl group, wherein 1 and Rs are independently selected from hydrogen, -Cl-C8 alkyl, -C2- C8 is suspected to be an alkenyl group, a C2~c8 alkynyl group, a substituted -Ci alkyl group, a substituted -c2-c8, a -t alkenyl group, a substituted -C2-C8 alkynyl group Aromatically substituted aryl, heteroaryl, terephthalic, substituted, heterocyclic alkyl, heterosubstituted heterocyclic alkyl, -C 3 C j 2 net t 2% alkyl, - C3-C! 2 cycloalkenyl, by taking -C3-Cl2 ring-based or by taking the Γ Γ — - C3 - (^12 cycloalkenyl. In another case, its 47 YV γ

Xl-h is independently selected from -CR7 or Ν, complex R? as defined above. A pendulum is selected from ~C (8)-〇nc(0) - nh~Ri, where Ri is selected from -Ci-Ce, its η thiol, -C2-c8 dilute or _C2_C8 alkynyl, Substituted by -1 1150-9072-PF; Linlin 200808832 - c-c8 alkyl, substituted -C2-C8 alkenyl, substituted -C2-Cs alkynyl, -C3~Cl2 cycloalkyl, -G- Cu cycloalkenyl, substituted -C3-C!2 ring k or or substituted _c3 - Ci2 cycloalkenyl. g is a s〇2-R3-, wherein r3 is selected from an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl 'heteroalkyl group, a substituted heterocycloalkyl group, G-Ci2 cycloalkyl, -C3 - Cl2 ring rare earth ▲ substituted - C3-C! 2 cycloalkyl or substituted _C3-C 2 cycloalkenyl. In another example, where X!-X4 is independently selected from -CR? or N, where R? is as defined above. A is selected from -C(0) - 〇R! or -CCO)-NH-Rr" wherein Ri is selected from -Cs-Ciz cycloalkyl or substituted _C3-L cycloalkyl. NH S〇2-R3— 'wherein the choice is from a cycloalkyl group or a substituted C3-Cl2 cycloalkyl group. In the example 'where Χι-X4 is independently selected from -CR? or N, where b As defined above, A is selected from _c(〇)_nh_Ri or C(〇) NH-R]' where Rl is selected from 吒广^ 炫 or substituted - 烧基. G is -NHS〇 2-R3-m3 is selected from _C3_Ci2 cycloalkyl or substituted -C3-Cu cycloalkyl. In another embodiment,

N

The present invention relates to a compound of the formula VI [or a pharmaceutically acceptable acceptable carrier or a salt, ester or prodrug thereof, alone or in combination, wherein the Y]-Y3 is independently selected from the H50- 9072-PF;Linlin 23 200808832 -CR?,N,NR?,S or 〇' where R? is independently selected from each of the following items: (i) hydrogen, halogen, -N〇2, -CN; (ii) -M-Rr, Μ is 〇, S or NH; (iii) NR4R5; (vi)-Ci-c8 alkyl, -c2-c8 alkenyl or -C2-C8 alkynyl, each containing 〇, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; substituted alkyl, substituted -CrC8 alkenyl or substituted -CrCs alkynyl, each containing 0, 1, 2 or 3 selected from 0 a hetero atom of S or N; -c3-c12 cycloalkane or substituted -CrC!2 cycloalkyl; -Cs-Ci2 cycloalkenyl or substituted -C 3 -C 1 2 cycloaliphatic; Or a substituted heterocycloalkyl group; wherein A, G, R4 and R5 are the same as the first embodiment; The example is defined. In another example, wherein Υι-Υ3 is independently selected from -CR?, N, NRt, § or 0, wherein R7 is as defined above. A is selected from -C~(〇)~Ri, -C(0)-0-1 or -C(0)-NH-Ri, where Ri is selected from aryl, substituted, and hetero Aryl, substituted heteroaryl, heterocyclic, substituted heterocycloalkyl, -C-C8 alkyl, -CrC8 alkenyl or -C2-C8 alkynyl, substituted - Ci-C8 Substituted, substituted - CrC8 fluorenyl, substituted -C2-C8 alkynyl, -C3-Cl2 cycloalkyl, -C3-Cl2 cycloalkenyl, substituted -CrC!2 cycloalkyl -C3-C"cycloalkenyl. G is -NH-S〇2-NR4R5- or -NH-SOrR3-, wherein R3 is selected from -Cl-c8 alkyl, one C2-C8 alkenyl, -C2-alkyne Alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -Clz cycloalkyl, -C3-C12 ring 1150-9072- PF;Linlin 24 200808832 Alkenyl, substituted -C3_Cl2 ring-based or substituted-c3-Cl2 ring-dense group, wherein h and R5 are selected from gas, _Ci-C8 alkyl, _C2-C8 , "heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, _C3_Cu cycloalkyl-GC] 2 cycloalkenyl, substituted _C3_Ci2 cycloalkyl or substituted -CK ring . Alkynyl, substituted -Cl-C8 alkyl, substituted _C2_C8 alkenyl, substituted -c2-c8 alkynyl, aryl, substituted aryl, heteroaryl, substituted in another Where γ-wide Y3 is independently selected from ~CR7, N, "s or 〇, where R7 is as defined above. A is selected from -c(〇)_〇- Ri or -C(0)- NH-L, wherein 1 is selected from -Cl-C8 alkyl, -C2-C8 alkenyl or -CrC8 alkynyl, substituted -Cl-C8 alkyl, substituted -C2-Cg-alkenyl, Substituted -C2-C8 alkynyl, -C3-Cl2 cycloalkyl, -C3~C12 cyclodecyl, substituted -C3-C"cycloalkyl or substituted -C3-Cn cycloalkenyl. G is -NH-SCh-R3- 'wherein R3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -C3_C12 a cycloalkyl group, a -C3-C" cycloalkenyl group, a substituted -C3-C12 cycloalkyl group or a substituted -C3-Cl2 ring-based group. In another example, wherein the YrYs are independently selected from a Cr7, N, nr7, s or 0, wherein R7 is as defined above. A is selected from _c(〇)-〇-Ri, wherein Ri is selected from -C3-Ci2 cycloalkyl or substituted - C3 -CI2 cycloalkyl. G is -NH-S〇2-R3-, wherein R3 is selected from -C3 - Ci2 cycloalkyl or substituted -匸3_〇12 bad alkyl. In another example, Υι-Y3 is independently selected from -CR7, N, NR7, S or 0, where R7 is as defined above. A is selected from -C(0)-NH-Ri, 1150-9072-PF; Linlin 25 200808832 wherein R! is selected from -CrC8 alkyl or substituted _Ci_C8 alkyl. G is -NH-SO2-R3-, wherein R3 is selected from "^^, evaluation % u Cl2 bad alkyl or Substituting -C3-C12 cycloalkyl. In another embodiment, the invention relates to a compound of formula

G (VIII) or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient, wherein Y1-Ys are independently selected from -CR7, N, NR? , S or 0, wherein R? is independently selected from the following: (i) hydrogen, element, -N〇2, -CN; (ii) -M-R4-, Μ is 〇, s or NH; (iii) NR4R5; (vO-C!-C8 alkyl, -c2-C8 alkenyl or -C2-C8 alkynyl, each containing hydrazine, 1, 2 or 3 heteroatoms selected from hydrazine, 8 or hydrazine Substituted - alkyl, substituted -CrC8 alkenyl or substituted -C2-Cs alkynyl, each containing hydrazine, 2 or 3 heteroatoms selected from hydrazine, s or N; - Cs - C"cycloalkyl or cycloalkyl; Ci2 cycloalkenyl or substituted -C3-C12 cycloaliphatic; () aryl 1 substituted aryl, heteroaryl, substituted heteroaryl (V 1) a heterocycloalkyl group or a substituted heterocycloalkyl group; wherein A, G, R4 and R5 are as defined in the first embodiment. 26 1150-9072~PF; Linlin 200808832; wherein Yl~Y3 are independently selected From -CR" N, NR7, S or 〇, where R7 is as defined above. "The choice is from _c - (8) such as (〇) 〇 L or . (0)- -!^ ' wherein Ri is selected from aryl, substituted = base, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted hetero-alkyl, -Gl-C8 (tetra), -^ Alkenyl or -C2-Cs alkynyl, substituted (IV), substituted _C2-G8 county, substituted _G2_C8 block, -c3-Cl2 ring, -C3_Cl2 cycloalkenyl, substituted _ C3_Ci2 is substituted by a ring-based group. G is a general-NR [or -NH-L, wherein R3 is selected from a silk, a κ8 alkenyl group, a aryl group, a substituted aryl group, a heteroaryl group. a substituted heterocycloalkyl, a substituted heterocycloalkyl, a C3_Ci2 cycloalkenyl group, a substituted C3-Cl2 cycloalkyl group or a substituted -c3_Cu cycloalkene, independently selected from Hydrogen K-based, prepared &amp; alkenyl, - alkynyl, substituted -QC^, substituted _G2_G8 alkenyl, 8-C2-C8 alkynyl, aryl, substituted aryl , heteroaryl, substituted adamantyl, heterocycloalkyl, substituted heterocycloalkyl, _C3_c&quot;cycloalkane-C3-C丨2 cycloalkenyl, substituted _C3_Ci2 cycloalkyl or Substituted two earth, cycloalkenyl. 3~el2 in another case, where Υι - Y3 is independently selected from -CR7, N, 盹" or 〇, where R7 is as defined above. A is selected from ~c (〇卜〇S = (8) side &quot; where R1 is selected from or C2 C8 Alkynyl, substituted-Ci-C8 alkyl, substituted - oxime-decene substituted -C2-C8 alkynyl, -LC, 2 cycloalkyl, _C3_Cl2 cycloalkenyl finely substituted -CrCu ring Alkyl or substituted _C3_Ci2 cycloolefin. Two soils. G is 1150-9072-PF; Linlin 27 200808832 -NH-S〇2-R3-, straight r ', 3 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl , hetero A p fluorenyl, substituted heterocycloalkyl, -c3-c12 % alkyl, -C3-Ci2 cycloalkenyl, sister, second-generation -Cs-Cu % alkyl or substituted -u2裱Alkenyl. In another case, Φ .π ^ ^ &quot; Yl~Y3 are independently selected from -CR?, N, NR" s or 〇,,,,,,,,,,,,,,,,,,,,,,,, A is selected from -C(0)-〇-Rl, where L is selected from a C3~c^^ group or a substituted C3-C 2 cycloalkyl group. G is -NH -S〇2-R3-, wherein &amp; 3 is selected from -C3-Ci2 cycloalkyl or substituted -C3-C12 ring:): complete.

In another example, J: towel V

, /, Υι~γ3 are independently selected from -CR7, N, NR7, S or 〇, where R? is as described above. A is selected from -C(0)-NH-L, wherein R1 is selected from a C 丨 to c 8 p 々 4 fluorenyl group or a substituted C 丨 -C 8 alkyl group. G is -NH-S〇2-R3-, wherein the search is selected from a ~C3-Cl2 cycloalkyl group or a substituted -C 3 - C 1 2 ring;): complete. Representative compounds of the present invention include, but are not limited to, the following compounds according to formula X (Table 1). Table 1 embodiment __ A ------- QG 22 people again / ^----- NVN review 23 NvN _ 1 1150-9072-PF; Linlin 28 200808832 24 ΛΛ Ν Ν Ν 25 people / VN 26 people Also / nVn 7'^V 27. — V 28 Μ 29 nnVn 'Ά 30 人又/ NVN 7'i¥v 31 人又/ NyN 32 cr1/ nVn 7fv 1150-9072-PF;Linlin 29 200808832 33 人又〆ΝγΝ /〇,ς, Ρ A r 34 people / nVn /, yN- Η 1 35 people / Ϋ Ά Η 1 36 people / N&gt;rN Η 1 37 hearts N /, Xr Η I 38 people / NyN 39 people again / / ^ 3⁄4 40 people again / N:&gt; 41 people again / γ 1150-9072-PF/Linlin 30 200808832

1150-9072-PF; Linlin 31 200808832 51 〇 Ϋ /ίϊν 52 〇 nVn Ψ^7 53 nVn 54 CX. Also Νί&gt; /ίϊν 55. , 0^0°' nVn 'Ά 56 a nVn 57 Vv Ϋ Ϋν 58 αΛ 〇V0°' ΝγΝ 59 , and / ΝνΝ 1150-9072-PF/Linlin 32 200808832 m 60 O / Ϋ 61 〇F~rA/ NyN 62 a^p0' Ϋ 63 &lt;X/ a^p°' Ϋ 64 〇ip°' Ϋ 65 CA Ϋ 66 Me a^°' Ϋ 67 a^_p°' nVn 68 〇Me^fy^y HN\e nVn 1150-9072-PF/Linlin 200808832 69 Me^7 Me 70 HN^ nVn 71 of/ Ϋ 72 Cl0A/ nVn 73 (W nVn /3⁄4 74 CX0X/ HG, cH3 75 Cl〇A/ 76 &lt;αΛ/ nVn / 3⁄4 77 Ο^Λ/ f^p° /3⁄4 ^^〇Η3 1150-9072-PF;Linlin 200808832

78 Ϋ 79 &lt;1. Also / nVn 80 OJy ΝγΝ 81 OJy noisy. , Ϋ 82 Cl. Also / Ϋ α^ύΗ^ 83 CX0 again / Ϋ AXf3 84 CX. Also / α^0°' ΝγΝ /3⁄4 85 Cl〇A/ α^Γ nVn 86 Cl. Also / Ϋ A^CI 1150-9072-PF; Linlin 35 200808832

87 CX0 again / /, know 88 CX0A / 〇 ^ p0 ' nVn people 89 H 89 OJy NvN /, A' Η H 90 CX 〇 A / nVn A%PHX'n people ί ΐ N 91 Cl〇A / nVn 92 Ο ^Λ/ nVn 'k%'V,&gt; N\ 93 〇1. Also / (SKP Ϋν 94 Cl. Also / ap Y 95 CX〇A/ Y 1150-9072-PF/Linlin 36 200808832 96 CX0 again / N, N, N 1 97 〇 ^ 〇 A / T 98 Cl. Also / % NI 99 CX. Also / NI 100 Cl〇A/ MeO NI 101 CX. Also / NY /isV 102 α. Also / 丫1150-9072-PF/Linlin 37 200808832 103 CX〇A/ '(5) 104 CX〇A/ NYN 105 〇^〇A/ MeO 106 Cl〇A/ f3co ▼ 107 〇Λ 丄108 CX〇i/ 1150-9072-PF;Linlin 38 200808832 109 ? HP ϋ A 110 (λΛ/ OMe 4 丄This invention also relates to pharmaceutical combinations A compound of the invention or a pharmaceutically acceptable salt, ester or precursor. According to yet another embodiment, the pharmaceutical composition of the invention further comprises other anti-HCV agents. Examples of anti-HCV agents, including However, it is not limited to interferon (α-interferon, 5-interferon, complex interferon, polyethylene glycol interferon, albumin or combined interferon), ribavirin, diamond-like. For other 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

(2002). The following information is hereby incorporated by reference in its entirety in its entirety by reference:::::::::::::::::::::::::::::::::::::::::::::::,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 2002/0037998 (2002). According to yet another embodiment, the pharmaceutical composition of the invention further comprises other HCV protease inhibitors. According to still another embodiment, the pharmaceutical composition of the present invention further comprises an inhibitor of other targets in the life history of HCV, including but not limited to helicase, poly 1150-9072-PF; Linlin 39 200808832 • synthase, metalloproteinase Or ires. According to still another example of the yoke, the pharmaceutical composition of the present invention further comprises other ???-, 、, 囷, antifungal or anti-cancer inhibitors, immunomodulators, or other therapeutic agents. According to still another example, the present invention further comprises treating a subject infected with an HCV subject to an effective amount of a compound of the present invention or a pharmaceutically acceptable salt for the subject against an HCV virus, A genus or precursor. According to still another embodiment, the present invention further comprises a method of treating a liCV-infected pair, wherein the subject is administered an anti-HCV virus effective amount or an inhibitory amount of the pharmaceutical composition of the present invention. According to yet 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 utilizing 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 shall apply to this specification and the scope of the patent application, unless otherwise indicated in the particular case of an individual or a larger group. The term "Cl-C6 alkyl" or rCl_C8 alkyl as used herein, means a saturated straight or branched chain hydrocarbon containing an atomic group of 丨~6 or 丨~8 carbon atoms. Examples of -Ce alkyl radicals include, but are not limited to, fluorenyl, methacrylate, isopropyl, mound: fluorenyl, decyltributyl, neopentyl, n-hexyl radical ' and Ci-Cs :): Examples of complete radicals, including but not limited to: methyl, ethyipropyl, isopropyl, benzyl, decyltributyl, neopentyl, n-hexyl, heptyl 1150-9072-PF; Linlin 40 200808832, sim Base atomic group. The use of the ancient five "Γ dream by r hit ..." or C2 ~ C8 women base", representing the second = early one atom derived from the hydrocarbon part of the - unitary base circle, one of the P knife each contains 2 ~ 6 One carbon atom or 2 to 8 carbon atoms, and there are up to = 1 double bond. The dilute base includes, but is not limited to, for example, an ethylene group, a fentanyl group, a benzyl group, a butyl group, a hexyl group, a octyl group, and the like. : ❹ ❹ 用 ❹ 用 用 用 用 用 用 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表 代表~ 8 carbon atoms, one less by removing a single Wenggong; # &quot; Its U wind atom is made of carbon-carbon triple bond. Representative thiol groups include, but are not limited to, for example: , heptyl, octynyl, and the like.乙乙卜基基基,卜丁块基, the term "C3 - C 斗 rr ^ #衣 alkyl" or C3-Ci2 ~ cycloalkyl, as used herein, except that a single chlorine atom is derived from a single ring or One of the polycyclic compounds is monoplaced, gan; human, q 1 wherein the carbocyclic ring has 3 to 8 carbon atoms or ~12 carbon atoms. C 3 - C 8 - Huanyuan L # Μ , ' 环丙美... including but not limited to: &quot;衣土, %pentyl, cyclohexyl, cyclopentyl, and cyclooctane· and C4-cycloalkyl Examples include, but are not limited to, cyclopropyl: 'cyclononyl, cyclohexyl, bicyclo[2.U]heptyl and bicyclo[22 tear^. , the term "C3_C8_cycloalkenyl" or "C3_Ci2' cycloaliphatic, as used herein, means having at least one carbon-carbon double bond W by removing a mono-hydrogen atom from a single ring or more One of the ring-saturated carbocyclic compounds is a monovalent group, and the bamboo: carbocyclic ring has 3 to 8 carbon atoms or 3 to 12 carbon atoms. Examples include but not limited to propylene, cyclobutyl, and cyclopentene. Base, m9〇72-PF; Linlin 41 200808832 cyclohexyl group, select &amp;#spoon red * Geng, ring octyl, etc.; and c3-c12-cycloalkenyl example J but not limited to · ring Aromatic, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptenyl, cyclooctenyl, etc. The term "aryl" is used to mean a mono- or polycyclic carbocyclic ring, λ, /, having 1 or 2 aromatic rings, including but not limited to phenyl, naphthyl, tetradecyl, udanyl, indenylU. = ff "aryl" used at the site, Means that a Ci_c or a fluorenyl residue is attached to an aryl ring. Examples include, but are not limited to, a phenyl group, etc. The term "heteroaryl" as used herein refers to a single ring, Bicyclic or: cyclic aromatic radical a ring having 5 to 10 ring atoms, one of which is selected from, for example, S, G, and N; wherein any nitrogen or oxygen on the ring may be emulsified with tolerance. Heteroaryl groups include, but are not limited to, biting groups...哄基基...Bite 2^ each group, fluorenyl group, fluorenyl group, (tetra) group, (tetra) group, iso. =, sedyl, decyl, fluorenyl, fluorenyl, porphyrin, iso The term "heteroarylalkyl" as used herein, refers to the attachment of a -c or Cl-C6 alkyl residue to a guolinyl group, a benzimidazolyl group, a benzoxazolyl group, a quinoxaline group, and the like. - Examples of heteroaromatic earthworms include, but are not limited to, hexylmethyl, pyrimidinylphenethyl, etc. or as used herein, "heterocyclyl" * "heterocycloalkyl" a non-aromatic 3_, 4-, 5-, 6- or 7-membered ring, or a tricyclic group fused system' wherein (1) each ring contains! to 3 heteroatoms, independently selected from oxygen, sulfur And nitrogen; ((1) each of the 5 members of the ring has a 〇 to! a booth key, and each 6 member ring has. To 2 double bonds; (1) υ the nitrogen and sulfur heteroatoms can follow H50~9072-PF; Linlin 42 200808832 ... lv The nitrogen hetero atom can optionally pass through four stages :: Top-cut can be coupled to a -benzene ring. Representative heterocyclic alkyl group, package = not (four): [1,3] di-burning, ... fixed base" ratio (tetra) base ratio:; = (four) , a hexahydro group, a (tetra) group, a sputum, a oxazolidinyl group, a morpholinyl group, a thiazolidinyl group, an isothiazolidinyl group, and a tetradecyl group. The heterocyclic group can be further substituted to obtain a Substituted "heterocyclic" as used herein, means substituted, independently substituted 1, 2 or 3 or more hydrogen atoms of the original radical, including but not limited to: F, -Π, -Br, -I, -〇H, protected hydroxyl group, _N〇2, _CN, _nh" protected amine group, _NH-Cl-c, 2-alkyl group, _NH_C2_Ci2_alkenyl group, -nh-c2- c] 2-alkenyl, -nh_C3_Ci2_cycloalkyl, _NH_aryl, _nh-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamine, -di Arylamino, -oc丨-c丨2-alkyl, -o-c2-Cw alkenyl, -〇_C2_Ci2-alkenyl, -〇-C3-C12-cycloalkyl, -O-aryl, _〇_heteroaryl, —〇_heterocycloalkyl, —C(〇)-Cl-Cu-alkyl, —C(0)-C2-Cl2-alkenyl, —C(〇)-C2-Cl2 - Dilute, -C(〇)-C3 -C12_cycloalkyl, -c(0)-aryl, -c(7)heteroaryl, -C(0)-heterocyclic alkyl, -c〇NH2, -CONH-Ci-Ci2-:l: complete , -CONH-C2-Cw fine group, -C0NH-C2-C12-alkenyl, -C〇NH-C3~Ci2-ring:): complete, -c〇NH-aryl, -C0NH_heteroaryl ,-CONH-heterocycloalkyl, -〇c〇2-Ci-C12-alkyl, -OCO2-C2-Cl2~thyl, -〇C〇2-C2-Cl2-dilute, -〇C〇2 -C3-Cl2~ cycloalkyl, -〇C〇2-aryl, -〇C〇2-heteroaryl, -〇C〇2-heterocyclic, -0C0NH2, -OCONH-Ci-Cw alkyl , -0C0NH-C2-C12-alkenyl, -0C0NH-C2-C12-dilute, -OCONH-Cs-Ci2-cycloalkyl, -0CONH-aryl 1150-9072-PF; Linlin 43 200808832 • Base, -0C0NH -heteroaryl, -0CONH-heterocycloalkyl, -NiKXOhCrCu-alkyl, _NHC(0)-C2-C12-sweet, -NHC(0)-C2-C12-sweet, -NHC(0)- C3-C12-cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCOs-CrCw alkyl, -NHCO2-C2- Ci2-alkenyl, -NHC〇2-C2-Cl2-dilute, -NHC〇2-C3-Cl2-cycloalkyl, -NHC〇2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocycle Alkyl, -nhc(o)nh2, -NHCXOnH-CrCu-alkyl, -NHC(0)NH-C2-Ci2- , -NHC(0)NH-C2-Ci2-alkenyl, -NHC(0)NH-C3-C12-cycloalkyl, -NHC(0)NH-aryl, -NHC(0)NH-hetero , -NHC(0)NH-heterocycloalkyl, NHC(S)NH2, -NHC(S)NH-C-C12-alkyl, -NHC(S)NH-C2-Cn-alkenyl, - NHC(S)NH-C2-CW alkenyl, -NHC(S)NH-C3-C&quot;-cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, - NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHCUHHH-C-C12-alkyl, -NHCXNIONH-Cs-Cw alkenyl, -NHCXNiONH-Cg-Cw alkenyl, -NHC ( NH)NH-C3-Ci2-cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHCUIO-Ci- CK-alkyl, -NHC(NH)-C2-C12-alkenyl, -NHC(NH)-C2-C!2-alkenyl, -NHC(NH)-C3-Ci2-cycloalkyl, -NHC ( NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-CrC12-alkyl, -C(NH)NH-C2-C12- Alkenyl, -C(NH)NH-C2-C!2-alkenyl, -C(NH)NH-C3-C12-cycloalkyl, -C(NH)NH-aryl, -C(NH)NH -heteroaryl, -C(NH)NH-heterocycloalkyl, -S(0)-C丨-Ci2-alkyl-NHS〇2-C2-C12-alkenyl, -NHS〇2-CrC&quot;- Alkenyl, -NHS〇2-C3-C12-cycloalkyl, -NHS〇2-aryl, -NHS〇2-heteroaryl, 11 50-9072-PF; Linlin 44 200808832, -SH, -S-CrCu-alkyl-NHS〇2-heterocycloalkyl, -eh.2, _CH2S〇2CH3, aryl, arylalkyl, _heteroaryl, -heteroaryl, -heterocyclic, _C3_Ci2_cycloalkyl Z polyalkoxyalkyl, polyalkoxy, methoxymethoxy, methoxy ethoxy

Ci2-alkenyl, -s-C2~Ci2-alkenyl, -sn2-cycloalkyl, -s-aryl, jheteroaryl, heterocycloalkyl, methylthiomethyl. It is to be understood that the sulfhydryl group, the heteroaryl group and the alkyl group may be substituted. In some cases, each substituent in the substituted structure may be additionally optionally substituted with one or more groups, each independently selected from the group -F, -C1, -Br, -I , -0H, _N〇2, -CN or _眺. In accordance with the present invention, any of the aryl, substituted aryl, heteroaryl and substituted heteroaryl groups described herein may be an anthracene aryl group. The aryl group may be substituted or unsubstituted. It is to be understood that any of the alkyl, decyl, fast-radical, cycloalkyl and cycloalkenyl structures described herein can also be an aliphatic group, an alicyclic group or a heterocyclyl group. An "aliphatic group" is a non-aromatic structure which may comprise any combination of carbon atoms, hydrogen atoms, _ atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, such as Key and / or three keys. The aliphatic group may be straight chain, branched chain or cyclic, preferably containing from about ??? to about ^ carbon atoms' more typically about! Up to about 12 carbon atoms. In addition to the aliphatic hydrocarbon group, the aliphatic group includes, for example, a polyalkoxyalkyl group such as a polyalkylene glycol, a polyamine, and a polyimine. These aliphatic groups can be further substituted. It is to be understood that the aliphatic group can be used in place of the alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene groups described herein. The term "alicyclic" as used herein refers to a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic compound by removal of a single hydrogen atom 1150-9072-PF/Linlin 45 200808832. 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 the examples of the present invention, m substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl, I-organic, and hetero- The ring-burning group is intended to be divalent or trivalent. Thus, the above definitions include: alkylene, alkenylene and alkynylene, cycloalkylene, cycloalkenylene, acetylene alkynylene, arylalkylene, heteroarylalkylene, and heterocyclic An alkylene group, and may be suitable for providing the structural formula herein at an appropriate valence. As used herein, the term "hydroxyl activating group" refers to a labile chemical structure which is known in the art to activate a hydroxyl group for detachment during a synthetic step, such as a substitution or elimination reaction. Examples of hydroxyl activating groups include, but are not limited to, mesylate, sulfonate, triflate (t r i f 1 a t e), lorazepyr benzoate, phosphonate, and the like. The term "activated hydroxyl group" as used herein, refers to a radical activation group as defined above, including, for example, mesylate, tosylate, trif late, #nitrobenzoic acid. Root, 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, triethyl decyl, methoxymethyl. , the protected hydroxyl group. "halogen" or "halogen" means an atom selected from fluorine, gas, bromine and iodine 0 1150-9072-PF; Linlin 46 200808832 The compound described herein contains one or more asymmetric centers and is therefore capable of mirroring Enantiomers, diastere mers and other stereoisomeric forms are defined as (R)- or (S)-, or amino acids by absolute stereochemistry, defined as ( D)_ or (L)_. The present invention is intended to include all such possible isomers, as well as racemates thereof, as well as optically pure forms. Optical isomers can be prepared by subjecting their respective optically active precursors to the above procedures or by resolution of the racemic mixture. This analysis can be carried out by chromatography or repeated crystallization in the presence of an agent or by a combination of techniques known to those skilled in the art. About analysis

Jacques, et al., Enantiomers, Racemates and Resolutions (John WUey &amp; - i98i). When the compounds herein contain an olefinic double bond, other unsaturated or other geometrically asymmetric centers&apos; and unless otherwise indicated&apos;, it is meant that the compound comprises both the £ and z geometric isomers or the cis and trans isomers. Similarly, all tautomeric forms are also included. The construction of any carbon-carbon double bond shown here is convenient, unless it is so prepared in this article, +, . ^ ^ • ^ This is not intended to specify a particular

Therefore, this virtual J壬咅山^., L 妷-n-double bond or carbon-heteroatom double bond is depicted as trans, possibly cis, 10,000, fly, and 4 or both a mixture of ratios. The term "to t-image" is used here to contemplate a mammal. Preferably, for example, a dog, a cat, a horse, a cow, a person, a second mouse, or the like. This object is preferably a human 0. When the object is a one-person boat ^", a human cheek, the object referred to herein may be a patient. The term used herein is "the rivet I can pick up the salt of the text". Means that the salt is located in full medical judgment ‧ and applies to humans or lower animals

The tissue contact, but not the right X θ, has unfavorable toxicity, irritation, allergic reaction, etc., 1150-9072-PF; Linlin 200808832 ' and the reasonable benefit/risk ratio is proportional. Pharmaceutically acceptable salts are well known to those skilled in the art.

Berge, 5 people detail pharmaceutically acceptable salts in j.

Pharmaceutical Sciences, 66: 1-1 9 (1 977). The salt can be prepared in situ when the compound of the invention is finally isolated and purified, or separately by reacting the free assay with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts such as amine salts, amine and inorganic acids such as hydrochloric acid, hydrobromic acid, squaric acid, sulfuric acid and perchloric acid, or organic acids, For example: acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid addition preparation 'or use other methods in the art, such as ion father preparation. Other pharmaceutically acceptable salts, including but not limited to: hexanoate, alginate, ascorbate, aspartate, besylate, benzoate, hydrogen sulfate, borate, butyrate , camphorate, camphor maye, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, Portuguese Heptanoate, glycerol phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, lactate, laurate, Laurel sulfate, malate, maleate, malonate, strontium ore, 2-naphthoate, final acid salt, acid salt, oleate, oxalate, palmitic acid Salt, pamoate, fruit acid salt, persulfate, 3-phenylpropionate, phosphate, picrate, trimethylacetate, propionate, stearate, succinic acid Salt, sulfate, tartrate, thiocyanate, p-toluene, potassium carbonate, pentane salt, and the like. Representative or soil test metal salts, including: sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts, including 1150-9072-PF; Linlin 48 200808832, including the use of counterions such as halides, hydroxides, tartrates, sulfates, phosphates, nitrates, having from 1 to 6 carbons Non-toxic ammonium, quaternary ammonium and amine cations formed by the atomic base, sulfonate and aryl sulfonate. As used herein, the term "hydroxy protecting group" refers to a restless chemical structure which is known in the art to protect the meridine from unintended reactions in the synthesis. After the synthesis process, the base groups described herein can be selectively removed. For a general description of the radical protecting groups, see Τ·Η·Greene and P.G.m. wUtS, Protective Groups in Organic Synthesis, 3rd edition, John Wiley &amp; Sons, New York (1 999). Examples of the hydroxy protecting group include: benzyloxycarbonyl, 4-nitronodooxycarbonyl, 4-bromohydrazinocarbonyl, 4-methoxyloxycarbonyl, methoxycarbonyl't-butoxycarbonyl , isopropoxycarbonyl, monophenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-mono(trimethyldecyl)ethoxycarbonyl, 2-mercaptooxycarbonyl, allyl An oxycarbonyl group, an ethyl carbonyl group, a decyl group, a chloroethenyl group, a ternary oxime group, a methoxyethyl fluorenyl group, a phenoxyacetic acid group, a benzoic acid group, a methyl group, a tert-butyl group, 2,2,2-trichloroethyl, propenyl, 3-methyl-3-2-dimethylstone, ethyl 1,1;[monodimethyl-2-phenylbutenyl, dipropyl , benzyl, p-methoxyl-diphenylmethyl, triphenylmethyl (trityl), tetrahydrofuranyl, methoxymethyl, methylthiomethyl, benzyloxy Base, 2,2,2-trichloroethoxymethyl, 2-(trimethyl hydroxy)ethoxymethyl, methyl hydrazino, p-toluene decyl, trimethyl sulphate, triethyl (4) Base, triisopropyl money base, etc. In the present day and month, the preferred base protecting group is: acetamyl (Ac or _c(8)CH〇, benzamidine (Bz or 49 115◦-9072-PF; Linlin 200808832 \ -C(0)C6H5) and Trimethyldecylalkyl (TMS or -Si(CH3) oxime. As used herein, the term "amino protecting group" refers to a restorative chemical structure, which is known in the art to protect an amine group. The group is protected from unintended reactions during the synthesis. After the synthesis process, the amine protecting groups described herein can be selectively removed. For a general description of the amine protecting groups, see Τ·Η·Greene And PGm· Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley &amp; Sons, New York (1 999). Examples of amine protecting groups including, but not limited to, third butoxycarbonyl, 9-yl Oxycarbonyl, benzyloxycarbonyl, etc. The term "pharmaceutically acceptable ester" as used herein, refers to an ester that hydrolyzes in the body and which readily disintegrates in the human body and leaves the parent compound or its salt. Suitable esters include, for example, those derived from pharmaceutically acceptable aliphatic tickers, especially The acid, the olefinic acid, the naphthenic acid and the alkanoic acid, wherein each of the alkyl or alkenyl structures is preferably not more than 6 carbon atoms. Examples of specific vinegars include, but are not limited to, formic acid vinegar, acetic acid, and C. Acidic, butyric acid, acrylate, and ethyl phenate. The term "pharmaceutically acceptable pre-drug" as used herein means the precursor of the present invention and is in full medical judgment. Within the scope of the application, it is suitable for human or lower animal contact without adverse toxicity, irritation, allergic reaction, etc., and the reasonable benefit/risk ratio is proportional and effective for its use, And when possible, a zwitterion of a compound of the invention. As used herein, "prodrug" means a compound which can be converted to a compound of the invention by metabolism (e.g., pyrolysis) in vivo. Technical fields are known, for example: discussed in Bundgaard, (ed.), Design 1150-9072-PF; Linlin 50 200808832 of Prodrug, E1sevier (1 985); Widder, et al. (ed.)-Methods in Enzymology, vol.4, Academic Press (1985); Krogsgaard-Larsen, et a L., (ed) , 1 丨 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 &amp; Joachimmayer, Hydrolysis In Drug And Prodrugmetabolism: Chemistry, Biochemistry And Enzymology, &quot; John Wiley and Sons, Ltd. (2002). 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, hydrocarbons such as hexane and toluene, such as: halogenated hydrocarbons such as dichloromethane, dichloroethane, 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 are known to those skilled in the art for specific compounds and reaction conditions, such as, for example, drug solubility, drug reactivity, and preferred response. The range 'each preferred solvent or mixture is readily apparent. Advances for aprotic solvents can be found in organic chemistry textbooks or in specific monographs such as: Organic Solvents physicai pr〇perties a&quot;1150-9072~PF; Linlin 51 200808832 - methods of Purification, 4th ed. , edited by J〇hn A. Riddick et al. , Vol. 11, in the Techniques of

Chemistry Series, John Wiley &amp; Sons, NY, 1986. The term "protonated organic solvent" or "proton solvent" as used herein refers to a solvent which tends to provide a proton, such as an alcohol, such as sterol, ethanol, propanol, isopropanol, butanol, Tributanol and the like. Such compounds are well known to those skilled in the art and are known to those skilled in the art for each particular compound and reaction conditions, such as the solubility of the agent, the reactivity of the agent, and the preferred range of reaction. Preferred solvents or mixtures are readily apparent. Further discussion of proton-solving solvents can be found in organic chemistry textbooks or in specific monographs such as:

Solvents Physical Properties and methods 〇f

Purification, 4th ed., edited by John A. Riddick ei 5/ V〇l· II, in the Techniques of Chemistry Series J〇hn W&quot;ey &amp; Sons, NY, 1 986. Combinations of substituents or variations contemplated by the present invention are only those which form a stable compound. As used herein, the term "stable" means that the compound has 2 stability to permit manufacture and can be maintained for a sufficiently long period of time as described herein (eg, for a subject therapeutically or prophylactically). Make it useful. The synthesized compound can be isolated from the reaction mixture and further purified by, for example, column chromatography, high pressure liquid chromatography or recrystallization. The ‘multiplication of the technology should be derived from the content of this specification and the synthesis of this compound. In addition, the various synthetic steps can be carried out in the order or order of substitution, ll5-9072-PF; Linlin 52 200808832 - to obtain 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 vary the various reaction conditions to produce the bridging macrocycle products of the present invention. Synthetic chemical conversion and protecting group methodology (conservation 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 Fieser1 s Reagents for

Organic Synthesis, John Wiley and Sons (1994); and L.

Paquette, ed. , Encyclopedia of Reagents for Organic

Synthesis, John Wiley and Sons (1995). The compounds of the present invention can be modified to enhance selective biological properties by any of the synthetic methods shown herein, with the addition of various functional groups. Such modifications are known to those skilled in the art and may include increased biocompatibility for a given biological system (e.g., blood, lymphatic system, central nervous system), increased oral availability, increased solubility In order to be able to be administered by injection, to change metabolism and to change the rate of excretion. Pharmaceutical Compositions The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the invention, and one or more pharmaceutically acceptable carriers together. The term "pharmaceutically acceptable carrier or excipient" as used herein means nothing! • Raw, U-solid, semi-solid or liquid fillers, thinners, encapsulated 1150-9072-PF; Linlin 53 200808832 materials, or any type of formulation. Examples of what can be used as a pharmaceutically acceptable burden are sugars such as lactose, sucrose and sucrose; starches such as corn powder and potato starch; and, and their derivatives, for example, a few f-based cellulose sodium, ethyl cellulose and "f Han, 哉, 隹 乙酸 acetate; powdered jaundice gum; malt; gelatin; talc; Fu "·, not 钊, such as cocoa butter and suppositories Butterfly; oil, such as peanut oil, cottonseed oil, a towel, Ding, Tian,, chemical oil, sesame oil, olive oil 'corn and soybean oil; diol, such as propylene glycol', such as oleic acid and vinegar + month + Ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; no pyrogen water; isotonic _ · special wave 1 trajectory, Linzhi's solution; ethanol and phosphate buffer solution, and Other non-toxic compatible chews, anti-slip agents, such as sodium lauryl sulfate and magnesium stearate, as well as the multi-Nan 丨 巳 巳 释放 release agent, filming agent, sweetener, flavor and Aromatic agents, preservatives and antioxidants, depending on the formulator's judgment, can also exist in In the composition. The pharmaceutical composition of the present invention can be obtained from the group of sputum, sputum, na.,», rectum, non-oral, transcerebral (intracisternaUy), transvaginal, transabdominal, topical (for example, powder, oil Lean or drops), sputum or oral or nasal spray. The pharmaceutical composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, by war, vaginally or via a transplant reservoir, especially by oral administration or injection. . The pharmaceutical compositions of the present invention include any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or carrier. In some instances, the pH of the formation can be adjusted by a pharmaceutically acceptable acid, base or buffer solution to enhance the stability of the compound or derivative thereof. The term "non-oral" is used herein, including subcutaneous, intradermal, intravenous, intramuscular, ankle, arteries, joints 1150-9072-PF; Linlin 54 200808832, intrasternal, intra meningeal disease or intracranial Injection or infusion technique. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, sugars, and elixirs. In addition to the active compound, the liquid dosage form may comprise (iv) dilute (iv) commonly used in the art, for example: water or other solvents, solubilizing agents, and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl Alcohol, benzyl bromide, propylene glycol, 1,3-butanediol, dimethylformamide, oil (especially, Jinxuan oil, peanut oil, corn oil, germ oil, olive oil, sesame oil and sesame oil), glycerin , tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitol needle fatty acid sl, and mixtures thereof. Besides the inert diluent, the oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweetening, flavoring, and perfuming agents. The preparation for injection, for example, a sterile injectable aqueous or oleaginous suspension, may be formulated according to the known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension or emulsion, dissolved in a non-toxic, non-oral acceptable diluent or solvent 'for example: in 1,3-butanediol Solution. Among the acceptable carriers and solvents, water, Ringer's solution, u s p., and isotonic sodium solution can be used. In addition, sterile fixed oils are conventionally used as a solvent or suspension medium. For this purpose, various brands of fixed oils can be used, including synthetic heart or diglycerin. In addition, 'fatty acids' such as oleic acid are used in the preparation of injections. The formulation for injection can be passed by bacteria.遽, or the bactericide is included in the sterile solid composition for sterilization ', the solid composition of the two bacteria can be dissolved in sterile water or other sterile injection / medium 1150-9072-PF before use; Linlin 55 200808832 body dissolution Or scattered. In order to prolong the effect of the drug, when I am shy, the subcutaneous or intramuscular injection of the drug is absorbed. For this purpose, you can achieve this by using a liquid suspension of crystallized amorphous material that is poorly soluble in water. The rate of absorption of the drug depends on the rate of dissolution and is related to the crystal size and crystalline form. Alternatively, the absorption of the parenterally administered drug can be delayed by dissolving or suspending the drug in an oil vehicle. The form of the injectable stock can be achieved by forming a microcapsule matrix of the drug onto a biodegradable polymer, such as polylactic acid-polyglycide (P〇lylactide-polyglyc〇lide). The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of that particular polymer. Examples of other biodegradable polymers include poly(raw vinegar,) and poly(anhydride). The formulation for injectables can also be prepared by capturing the drug in a liposome or microemulsion that is compatible with body tissues. A composition for rectal or vaginal administration, preferably a suppository, may be prepared by admixing a compound of the invention together with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or suppository wax, The suppository wax is solid at normal temperature but liquid at body temperature, so it can be dissolved in the rectum or vagina to release the active compound. Solid dosage forms for oral administration include capsules, lozenges, pills, powders, and granules. In such a solid dosage form, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium sulphate or sulphate di- and/or: a) filler or increment Agents such as powder, lactose, sucrose, glucose, mannitol and linalic acid, b) binders, such as 竣甲美美纤维素, alginate, gelatin, polyvinylpyrrolidone, sucrose and locust gum , 1150-9072-PF; Linlin 56 200808832 c) wetting agents, such as glycerin, d) disintegrating agents, such as agar-agar, calcium carbonate, macadamia or tapioca starch, alginic acid, certain citrates and carbonated Sodium, e) solution retaining agents, such as paraffin, f) absorption enhancers, such as quaternary ammonium compounds, g) wetting agents, such as: cetyl alcohol, and glyceryl monostearate, h) absorbents, such as kaolin And swelling clay, and i) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, lozenges and pills, the dosage form may further comprise buffer 0 in a similar type of solid composition, or as a filler in soft and hard-shell filled gelatin capsules. The excipient used in the capsule is lactose. And high molecular weight polyethylene glycol and the like. The active compound may also be in microencapsulated form with one or more excipients such as those described above. The solids of lozenges, dragees, capsules, pills and granules can be prepared by coating a film and a shell, such as a casing, a release controlling agent, and other coatings well known in the art of formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such a dosage form, in general practice, may contain substances other than inert diluents, such as: potential, ^ X I red lubricant, and other ingot auxiliaries, such as magnesium stearate and microcrystalline, day 1 king, iron vegan. In the case of capsules, tablets and pills, these dosage forms are also τ, ι J3 buffers. The opacifying agent may optionally be included and may be a single release of the composition, or the birch release or preferentially in a certain part of the intestine, optionally in a delayed manner, or a multi-active ingredient. Examples of the buried composition that can be used include polymerizable materials and waxes. The topical or transdermal coating of the compound of the present invention is applied to the dosage form, including: ointment 1150-9072-PF; Linlin 57 200808832 (ointment), paste, cream, emulsion (] 〇ti〇 n), condensate, 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. In addition to the active compounds of the present invention, the ointments, pastes, creams and gels may include excipients such as animal fats and vegetable fats, oils, waxes, waxes, starches, gum tragacanths, cellulose derivatives. , polyethylene glycol, fluorenone, bentonite, citric acid, talc and zinc oxide or a mixture thereof. Powders and sprays can include, in addition to the compounds of the present invention, excipients such as lactose, talc, anthraquinone, hydrazine, and lysine powder, or mixtures thereof. Sprays may also contain conventional propellants, such as chlorofluorocarbons. An additional advantage of wearing a patch is that the compound is delivered to the body in a controlled manner. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a matrix or gel. Oral antiviral activity The inhibitory amount or agent of the compound described herein, nn 里 "马,,, 〇 〇 · lmg / Kg to about 500mg / Kg, or about 1 to ς m〇mg / Kg. Inhibition amount or dose, or

Depending on the route to be taken, and I $ A and π can be used differently than other agents. η according to the treatment method of the present invention, the treatment of viral infection in a subject 1150-9072-PF; Linlin 58 200808832 or prevention, by administering a primary anti-c-type liver to the subject and time to achieve the desired result In the case of a clear compound, the object is, for example, a method of releasing or suppressing cockroaches, and the method is based on the amount and time of the susceptibility, and the injection is suppressed. Inventive compound. As used herein, "the term "anti-c" means a sufficient amount of "effective amount" of the present invention - the virus in the subject "can be reduced to a biological sample or in the medical technology" It is well known that the "reasonable benefit of anti-hepatitis C disease" in the compound of the present invention will be located within a ratio of π lean/risk. Below or above the above listed items. Special prescriptions for the treatment of 詈乐口 will depend on many early spears, 疋' including: the activity of the specific person used, the age of the patient, the body sputum, general health, gender and drinking order. Time, excretion rate; I drug composition used by Putian _ s KRJ ^; severity and cause of the disease; condition or disease makeup, 'heavy;; treatment of the disease by the person of the person; condition and treatment doctor Judgment. Team/Children's Diseases As used herein, "suppressing 丨丨 丄 丄 制 」 」 」 」 」 」 」 」 」 」 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本It is well known in the art that the compound of the present invention is administered to a subject which is administered by a physician and will be located in a medical treatment suitable for any medical treatment. Within the benefit/risk ratio. The term "substance derived from biological sources and its components, such as plasma, biological samples" as used herein, means the use of biological samples for a subject, including but not limited to: blood platelets, blood cells, subgroups Etc; Organ, 1150-9072-PF; Linlin 59 200808832 For example, kidney n, lung, etc.; sperm and _; bone marrow and its components; Another embodiment of the invention is a method of treating a biological sample by contacting the biological sample with an inhibitory amount of a compound of the invention or a pharmaceutical composition. μ When the condition of the patient is improved&apos; A maintenance dose of a compound, composition or combination of the present invention can be administered as needed. Then, the symptoms are reduced to the desired level, and depending on the symptoms, the dose or frequency or both can be reduced to maintain the improvement. However, patients may require long-term intermittent treatment to prevent any recurrence of the condition. Another method of the present invention is to administer a compound of the present invention in an inhibitory amount for a biological sample in an amount and for the purpose of inhibiting viral replication and/or reducing viral load. As used herein, the term "inhibitory amount" means an amount sufficient to inhibit viral replication and/or reduce the amount of hepatitis virus in a biological sample. The term "biological sample" as used herein, means a substance of biological origin for administration to a subject. Examples of biological samples include, but are not limited to, blood and its components, such as plasma, platelets, subpopulations of blood cells, etc.; Lu, such as kidney, liver, heart, lung, etc.; sperm and eggs; bone fibers and their components; or stem cells . Another embodiment of the invention is a method of treating a biological sample by contacting the biological sample with an inhibitory amount of a compound of the invention or a pharmaceutical composition. However, it is to be understood that the total daily use of the compounds and compositions of the present invention is determined by the attending physician within the scope of full medical judgment. The particular therapeutically effective dose for any particular patient will depend on a number of factors, including: the condition to be treated and the severity of the condition; the particular 1150-9072-PF employed; Linlin 60 200808832 long-lasting composition The age of the patient, the health of the body, the sex and the diet; the administration of Xia, the right to the apex, the route of administration, and the rate of the specific compound, and the use of the thousand,> the period of oral therapy· In combination with or in combination with the specific compounds used, it is a similar factor that is well known in the medical field. The compound of the present invention may be administered at a dose of, for example, 〇·1 to 25 mg/kg body weight. A single 'in order to achieve the daily dose of the compound of the invention in a single dose or multiple times per dose. ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Including about 10 mg to about 1 mg of the desired patient. Unless otherwise defined, all the techniques and sciences used herein are based on the meanings, patents, and publications common to those of ordinary skill in the art. Patent applications and other references are incorporated herein by reference. f raw language, . All out, complete introduction The following synthetic flow process and examples appear as follows: ACN: acetonitrile;

Ac : ethyl sulfhydryl;

Boc: tris-butoxycarbonyl;

Bz: benzoquinone;

Bn · · benzyl; CDI : carbonyl diimidazole; dba : diphenylacetin; 1150-9072-PF; Linlin 61 200808832 CDI : 1,1 - Weiji dimiwa; DBU · · 1,8-diaza Bicyclo[5·4·〇]decene carbon-pene, DCM: dichloromethane; DIAD: diisopropylazabiazodicarboxylate; DMAP: dimethylamino π ϋ DMF: dimethyl carbamide; DMS0: dimethyl hydrazine; dppb: diphenyl phosphine;

EtOAc: ethyl acetate; HATU · 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetradecyluronium hexafluorophosphate; iPrOH:isopropyl alcohol;

NaHMDS: sodium bis(trimethyl decyl) decylamine; NMO : N-mercaptomorpholine N-oxide;

MeOH: decyl alcohol;

Ph: phenyl; POPd: diar-dichlorodichlorobis(di-tert-butylphosphine)palladium(II); TBAHS ··tetrabutylammonium hydrogen sulfate; TEA ·· triethylamine; THF : tetrahydro sulphur TPP: triphenylphosphine;

Tris: tris(hydroxymethyl)amino decane; BME: 2 -mercaptoethanol; Β0Ρ: benzotriazole-bukioxy-tris(didecylamino) hexafluorophosphate 1150-9072-PF; Linlin 62 200808832 COD: cyclooctadiene; DAST: diethylaminosulfur trifluoride; MBCYL: 6-(N-4'-carboxy-4-(didecylamino)azobenzene)-amino Hexyl-1-0-(2-cyanoethyl)-(N,N-diisopropylphosphoryl; DCM: dichlorodecane; DIAD: diisopropylazabiazodicarboxylic acid Salt (ester); DIBAL-H: diisobutylaluminum hydride; DIEA: diisopropylethylamine; DMAP: N, N-didecylaminopyridine; DME: ethylene glycol dioxime; DMEM: Dulbecco 's modified Eagles medium; DMF ··N, N-dimethylformamide; DMS0: dimethyl sulfoxide;

EDANS: 5-(2-Amino-ethylamino)-naphthalene-1-sulfonic acid; EDCI or EDC: 1-(3-diethylaminopropyl)-3-ethylcarbodiimide Hydrochloride;

EtOAc: ethyl acetate; HATU: 0 (7-aza-1H-benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate; 1150-9072-PF/ Linlin 63 200808832 - Hoveyda's Cat.: dichloro(o-isopropoxyphenylmethylene) (tricyclohexylphosphine) ruthenium (11); KHMDS: potassium bis(trimethyldecyl) decylamine;

Ms: methylsulfonyl;

EtOAc: ethyl acetate; g: gram; h: hr; NMM · · N - 4-methyl hydrazine;

PyBrOP: tripyrrolidinyl bromide hexafluorophosphate;

Ph: phenyl; RCM: closed-loop translocation; RT: room temperature; HATU: 0 (7-aza-1H-benzotriazole-bu)-N,N,N,N-tetramethyluron hexafluoro Phosphate; HPLC: high pressure liquid chromatography;

Ph: phenyl;

Me: methyl; RT: reverse transcription; RT-PCR: reverse transcription-polymerase chain reaction; TEA: triethylamine; TFA: trifluoroacetic acid;

MeOH:methanol;mg:mg; mi η:min; 1150-9072-PF/Linlin 64 200808832 MS: mass spectrometer; 丽R · NMR, rt: room temperature; THF: tetrahydro sigma; TLC: thin Layer chromatography or PPh3 · · triphenylphosphine; tBOC or Boc: third butyloxycarbonyl;

Xantphos: 4,5-di-diphenyl fluorenyl-9,9-dimercapto-9H-occluded oxime. Synthetic Methods The compounds and treatments of the present invention will be better understood by the following synthetic schemes, and the compounds of the present invention can be prepared by the following methods. Process 1

OH

OH

Scheme 1 describes the synthesis of the intermediate (Ig). The cyclic peptide precursor (Ig) is from Boc-L-2-amino-8-decenoic acid (la) and cis-L-hydroxyproline decyl ester (lb) via steps A to D of Scheme 1. And prepared. For further details of the synthetic methods employed to produce the ring 1150-9072-PF/Linlin 65 200808832 Peptide Precursor (Ig), see U.S. Patent No. 6,600,0 2, Reference. Other amino acid derivatives containing terminal oxime may be substituted for I a to produce a different macrocyclic structure (see W0/0059929 for more details). Ring closure methathesis is provided as a key intermediate I g (for further details of closed-loop translocation, see recent literature: Grubbs et al., Acc. Chem. Res. , 1995, 28, 446; Shrock etal., Tetrahedron 1999, 55, 8141; Furstner, A. Angew

Chem. Int Ed. 2000, 39, 3012; Tmka et al., Acc. Chem. Res. 2001, 34, 18; and Hoveyda et al., Chem. Eur J. 200 1, 7, 945). Process 2

Scheme 2 describes a general method for the synthesis of triazole analogs. The triazole compound (2-2) is synthesized via an alkyne (2-oxime), and a TMSNs compound, but is not limited to TMSN". The alkyne (^) is commercially available or is derived from a primary alkyne (2-8) and an aryl halide. (2-9) prepared by a succulent coupling reaction (s〇n〇gashira 1150-9072-PF/Linlin 66 200808832 coup 1 ing react ion). Further details regarding the coupling reaction of the succulent See Son〇gashira, c〇mprehensive

Synthesis, Volume 3, Chapters 2, 4 and Sonogashira, 1 977, 777. Intermediates (2-4) and (2-5) can be converted to the appropriate leaving group via the hydroxy intermediate (ig), for example but not Limited to: 〇Ms, OTs, OTf, bromide or iodide, prepared by substituting SN2 for the reactive hydroxyl group. The ester is then hydrolyzed to give (2-6) and (2-7) compounds. Process 3

The intermediate (3 -1 ) is via the macrocyclic megendronic acid (2 - 3) and trinitrogen. The compound (2-2) is synthesized, as described in Scheme 2. Next, the intermediate (3-1) can be via Suzuki coupling reactions, Sujogasu 1150-9072-PF; Linlin 67 200808832 - Son ogashira coupling reaction or Stiller coupling (stille The coupling reaction is carried out at the position of the iS compound or OTf. For further details on the Suzuki coupling reaction, see A. Suzuki, Pure Appl. Chem. 1 991, 63, 41 9-422 and AR Martin, Y· Yang, 1 993, 47, 22 Bu 230. About Sujoga Suro For further details of the coupling reaction, see Sonogashira, Comprehensive Organic Synthesis, Volume 3, Chapters 2, 4 and Sonogashira, 1 977, 777. For a Stüler coupling reaction, a more detailed reaction is detailed in JK St i 11 e. r,

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. The 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 1998, 37, 2046-2067. Scheme 4 1150- 9072-PF; Linlin 68 200808832

Scheme 4 illustrates the modification of the N-terminus and the c-terminus of the giant loop. The Boc structure is deprotected with an acid such as, but not limited to, hydrochloric acid to give an acid of the formula (4-2). The amine structure of the formula (4-2) can be carried out by a suitable or a decyl 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). After the slave, the acid structure is activated and then treated with a suitable sulfhydryl or sulfonyl group to give a compound of formula (4-5). Process

Sulfonamide (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 elevated temperature, and then the corresponding sulfonamide R3 — s(〇) 2 —NH 2 is added in the presence of a base, wherein R 3 The definition is the same as before. EXAMPLES The compounds and treatments of the present invention will be further enhanced by the following examples. H50-9072-PF; Linlin 69 200808832 • The examples 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. This compound is also described in U.S. Patent No. 200501 53877, where G = 〇H. Example 1 Synthesis of the cyclic peptide precursor:

Step la 6 〇〇1^-2-amino~8-decenoic acid (13) (1.368, 5111〇1) and commercially available cis-L-methyl phthalate (lb) (1〇) 9 g, 6 匪〇 1) A solution of 15 ml of DMF was added, DIEA (4 iii, 4 eq.) and HATU (4 g, 2 eq.) were added. The coupling reaction was carried out at 〇C for 1 hour. The reaction mixture was diluted with 1 (10) mL of Et〇Ac, then the extract was washed with 5% EtOAc (2×20 mL), water (2×20ml), 1M NaHC 3 (4×20 ml) and brine (2×10 ml). The organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to give di-di(p) ((c. , 90% B) and 1150-9072-PF; Linli: 70 200808832 MS (421.37, M + Na+) identified. Step lb A double solution (lc) was dissolved in a solution of i5 mL of dioxane and i5 mL of 1 n LiOH. The hydrolysis reaction was carried out at room temperature for 4 hours. The reaction mixture was acidified with 5 EtOAc / EtOAc (EtOAc)EtOAc. The organic phase was dried over anhydrous sodium sulphate and then concentrated in vacuo to afford EtOAc (d) (yel. Step lc

The carboxylic acid of step lb (1.77 g, 4.64 mmol) was dissolved in 5 ml of DMF Lok solution 'Addition of D- /3-vinylcyclopropane amino acid ethyl ester (丨e) (〇·9 5g, 5mmol) , DIEA (4 ml, 4 equivalents) and HATUUg, 2 equivalents). The coupling reaction was carried out at 0 ° C for more than 5 hours. The reaction mixture was diluted with 8 mL of EtOAc, and then washed with 5% citric acid &lt;RTI ID=0.0&gt;&gt; The organic phase was dried over anhydrous sodium sulfate and then evaporated. The residue was purified by flash chromatography using celite, using hexanes: EtOAc as a solvent (5:1~·&gt; 3: 1-&gt; 1 : 2 - 1 : 5). After removal of the solvent, the isolated product was an oily linear tripeptide (1 〇 (1·59 g, 65.4%) with HPLC (residence time II 11.43 minutes) and MS (544 84.M+Na + ) identified. Step Id closed-loop metathesis (RCM) The linear dipeptide lf (1.51 g, 2.89 mmol) was dissolved in 200 ml of anhydrous DCM and degassed by &amp; foaming. The catalyst used for the ring closure metathesis (RCM), such as Hoveyda's catalyst (5 m 〇 U equivalent), was added as solid form 1150-9072-PF; Linlin 71 200808832. The reaction was refluxed for 12 hours under n2 atmosphere. Evaporation, the sub-residue was flash chromatographed on silica gel eluting with hexane. EtOAC (9:1 - 5:1~&gt; 3:1 -1:1: 2:1:5). After removing the solvent of the extract, 'the cyclic peptide precursor' was separated from the α white powder (1.24 g, 87%), and HPLC (detention time = 7 84 hearts, 3 〇 _7 (10), deleted), MS (measured value) 516.28, M + Na + ) Identification. For further details of the synthetic method for the production of the cyclic peptide precursor 1, see U.S. Patent No. 6,6,0 0,7, incorporated herein by reference. Methanesulfonate before cyclic peptide Drive

Step 2A: Dissolve the giant ring moon shovel (1) (5q 〇mg, 1 · 〇1 mm〇1) and DIEA (0.4ml, 2mmol) in a solution of 2. 〇ml DCM, slowly add the acid Gas (0.1 ml), the reaction was carried out in 〇c for 3 hours. The reaction mixture was added to 30 mL of EtOAc, and then washed with 5% citric acid 2 x 10 ml, water 2 x 10 ml, 1M NaHC 〇 3 2 x 10 ml and brine 2 x 10 ml. The organic phase was dried <RTI ID=0.0>

, G = 0H The compound of formula IX of Example 3, wherein A = Boc, the synthesis of step 3 a alkyne

Ή +

Pd (II), Cul TEA/CH3CN

1150-9072-PF; Linlin Ί2 200808832 The alkyne of this example, 2-(2-thiazole)-4-methoxyphenylacetylene was prepared from a degassed &gt; trough solution to give a solution of 4 mmol of 4 - ethynyl benzoquinone scale, 4 mmol of 2-bromothiazole and 1 ml of triethylamine were dissolved in hydrazine (10) acetonitrile, 140 mg (0.2 Å) of PdCl2 (PPh3) 2, 19 mg (0.1 mmol) w CuI. The reaction mixture was degassed and stirred at room temperature for 5 minutes and then heated to g 〇 C for 12 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography eluting eluting 〇· 6lg color liquid. MS (ESI): w/z = 2\Q. 17 [M + H] lHNMR CCDCls, 500 MHz) δ 7.765 (d, J = 3 Hz, 1H), 7· 472~7· 455 (m, 2H), 7. 277 (d, J-3. 5 Hz, 1H), 6·837~6· 820 (m, 2H), 3·768 (s, 3H). Step 3b Synthesis of triazole

The compound of step 3a (〇·3 mg), 〇·74 ml of trimethylsulfonium azide compound and 4 ml of dinonylbenzene were dissolved in a pressure tube to synthesize 4-(2-嗟α sitting)-5- (p-decyloxyphenyl) triazole ^ sit. The reaction mixture was directly separated by flash chromatography on silica gel to give a brown liquid (yield: 18 g, 5%). MS (ESI): m/z = 2b 9.27 [M+H] lHNMR (DMSO-de), 500 MHz) 5 8. 016 (d, J = 8·5 Hz, 2H), 7.929 (d, J-3Hz, 1H), 7.817 (d, J = 3 Hz, 1H), 7. 066 (d, J = 8.5 Hz, 2H), 3.824 (s, 3H) Step 3c 1150-9072-PF; Linlin 73 200808832

The sulfonated macrocyclic peptide precursor (0.041 mmol) of step 2 and the compound of step 3b (〇 i23 mmol) were dissolved in 1 ml of DMF solution, and the carbonic acid planer of 0·246匪〇1 was added. The reaction was carried out at 7 Torr for 12 hours. The reaction mixture was extracted with EtOAc (EtOAc)EtOAc. MS (ESI): λ7 / ζ = 734. 34 [M + H]. Step 3d

The title compound was prepared from the title compound of the mp. The reaction mixture was stirred at room temperature for 8 hours. The pH of the reaction mixture was adjusted to 3 with citric acid, followed by extraction with EtOAc and washed with water and brine. The organic phase was concentrated in vacuo to facilitate HPLC purification. After lyophilization, a yellow powder (1 mg, yield 34%) was obtained. MS (ESI): melon/z 706. 33 [M + H] broad, 1H) lHNMRC DMSO-de, 5 〇〇 MHz) 5 12.283 (s, 1150-9072-PF; Linlin 74 200808832 8.750 (s, broad, 1H), 8.014 (d, J: 9 Hz, 2H), 7.938 (d, J = 3.5 Hz, 1H), 7.852 (d, J = 3.5 Hz, 1H), 6.997 (d, J = 8 Hz, 2H), 6.927 (d, J = 7, 1H), 5. 555(s, broad, 1H), 5.499(m, 1H), 5.298 (t, J = 18Hz and 9Hz, 1H), 4. 643(t, J = 16 Hz and 8Hz, 1H), 4. 558(d, J = 11.5Hz, 1H), 4. 1 25-4. 093(m, 2H), 3.802(s, 3H), 2. 890-2.847(m, 1H), 2. 542-2.497(m, 2H), 2·123~2·106(m, 1H), 1.806(s, broad, 1H), 1 ·701~1·663(m, 1H), 1.519 (s, broad, 1H)' 1.460~1·435 (m, 1H), 1·314~1.074 (m, 16H). The compounds of Examples 4 to 21 are composed of different triazoles as described in Example 3. The preparation of the program.

.g-〇h 0

G two OH 0

G 二〇H 0

g: oh 实施 Example 4 Compound of formula IX, wherein A = Boc MS (ESI): π / ζ = 676 · 44 [M + H]. Example 5 Compound of Formula K wherein A = Boc MS (ESI): π / ζ = 595 · 28 [M + H]. Example 6 Compound of Formula K wherein A = Boc MS (ESI): π / ζ = 595 · 42 [Μ + Η]. Example 7 A compound of formula IX wherein A = Boc MS (ESI) · π / ζ = 690 · 42 [M + Na]. 1150-9072-PF; Linlin 75 200808832

G = 0H Example 8 Compound of formula IX, wherein A = Boc, MS (ESI): π / ζ = 677 · 88, 679 · 89 [Μ + Η].

G = 0H

n:Jn

G = 0H Example 9 Compound of formula IX, wherein oxime Boc, MS (ESI): π / ζ = 772 · 11 [M + Na]. Example 10 A compound of formula IX wherein A = Boc MS (ESI): π / ζ = 657. 99 [M + Na].

G = 0H Example 11 Compound of formula IX, wherein A = Boc, Q: MS (ESI): π / ζ = 705 · 31 [M + H].

G = 0H Example 12 Compound of formula IX, wherein A = B〇c MS (ESI): π / ζ = 695. 30 [M+H].

Embodiment 13 A compound of formula IX wherein A = Boc, Q = I, G = 0H. MS (ESI): π / ζ = 677. 25 [M+H].实施 Example 14 Formula X Compound, wherein ', Q = Ϋ , G = 0H MS (ESI): π / ζ = 700 · 34 [M + H].

Example 15 A compound of formula K, wherein A = 〇 &quot;^, ΐΝ, G = 0H 1150-9072-PF/Linlin 76 200808832 MS (ESI): m/z = HQ. 32 [M + H] (Example 1 Compound of formula K, wherein MS (ESI): 36 [M+H] (Example 1 7 Compound of formula IX, wherein MS (ESI): in/z-llh. 39 [M + H] ^ 〇

IN. A Q II i , G=OH ° 〇

Q^p°, G=OH. 〇

N Example 1 8 Compound of formula IX wherein A = MS (ESI): ζζ7 / ζ = 699 · 36 [M + H]. , G=OH. Embodiment 19 A compound of formula IX wherein A = y ' Q = ΐΐ MS (ESI): / / / / ζ = 703 · 40 [Μ + Η]. G = OH ° 实施 Example 20 Compound of formula IX, wherein Α = Vn\ MS (ESI): π / ζ = 713 · 38 [M + H]. , G=OH. 〇

Example 21 A compound of formula IX wherein A = MS(ESI)·· /ζ//ζ=7〇0·36[M + H]. Example 22 Compound of formula K, wherein A = Boc, Q = ΝίΝ, (Compound 3d compound of Example 3 (30 mg) was dissolved in DMF to add CDI (10 mg). The reaction mixture was stirred at 40 ° C, G=OH 〇 solution, J, hr, 1150-9072-PF; Linlin 77 200808832 Add cyclopropyl sulfonamide (11 mg) and DBU (12 // 1). The reaction mixture was at 40 ° C. The reaction mixture was stirred with EtOAc EtOAc EtOAc. MS (ESI): π / ζ = 809. 30 [M + H]. Compounds of Example 2 3 to 41 were prepared from different sulfonamides according to the procedure described in Example 22.

Example 23 A compound of formula IX, wherein A = Boc, Q MS (ESI): /ff/z = 779.26 [M + H]. Example 2 A compound of formula IX wherein A = B o c, Q MS (ESI): π / ζ = 698 · 36 [M + H]. Embodiment 25. A compound of formula IX, wherein A = Boc, Q MS (ESI): ζζ//ζ = 772·55 [M + H].

Embodiment 26 A compound of formula IX wherein A = Boc, Q = MS (ESI): /Z7/Z-880.51, 882.51 [M+H]〇

Example 27 A compound of formula IX wherein A = Boc, Q MS (ESI): λ / / ζ = 852 · 60 [M + H]. Example 28 A compound of formula IX, wherein A = Boc, Q 1150-9072-PF; Linlin 78 200808832. MS (ESI): w/z = 738. 55 [M+H]. Example 29 A compound of formula IX, wherein A = Boc, Q: MS (ESI): swim / z 808. 54 [M + H]. Embodiment 30 A compound of formula IX, wherein A = Boc, Q = MS (ESIh π / ζ 798. 57 [M + H]. Example 31 Compound of Formula IX, wherein A = Boc, Q MS (ESI): π/ ζ=780.51[M+H] 〇/^y Example 32 Compound of formula K, wherein A = Vi, Q MS (ESI): π / ζ = 803 · 47 [M + H]. Compound IX, wherein A = Boc, Q MS (ESI): τ ζ / / ζ = 775 · 38 [M + H]. Example 34 Compound of formula IX, wherein A = Boc, Q = MS (ESI): π / ζ = 812· 34 [M + H]. The compound of the formula IX, wherein A = Boc, Q = MS (ESI): π / ζ = 883 · 33, 885 · 31 [Μ + Η]. 1150-9072- PF; Linlin 79 200808832 Example 36 Compound of formula K, wherein A = Boc, Q MS (ESI): π / ζ = 741 · 39 [M + H].

Example 37 A compound of formula IX wherein A = -, MS (ESI): π / ζ = 806 · 30 [M + H]. Embodiment 38 A compound of formula IX, wherein A = Boc, Q: MS (ESI): / / 7 / ζ = 808 · 37 [M + H]. Embodiment 39 A compound of formula IX, wherein A = Boc, Q = MS (ESI): π / ζ = 845 · 33 [M + H].

Br Example 40 Compound of formula IX wherein A = Boc, Q = MS (ESI): two 916.31, 918.31 [Μ+Η]. Embodiment 41 A compound of formula IX, wherein A = Boc, Q = MS(ESI)··π/ζ=774·38[M + H].

Embodiment 42 A compound of formula IX wherein A =

MS (ESI): π/ζ = 839·28 [M + H]. 1150-9072-PF; Linlin 80 200808832 Example 43 Compound of formula K, wherein a = step 43a

化合物 The compound of Example 24 was dissolved in a solution of 5 ml of 4N HCl / dioxane, and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was evaporated twice with DCM. The resulting product was used directly in the next step. MS (ESI): π / ζ = 598. 26 [M + H]. Step 4 3 b A solution of the compound of Step 43a was dissolved in DCM, and DIEA (122 / / 1) and cyclobutyl chloroformate (? The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with Et EtOAc. The organic layer was washed with 1M NaHC3, water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by HPLC to give the desired material. MS (ESI): τ ζ 7 / ζ = 710·30 [Μ + Η]. 13CCCD30D): 177.9, 1 73.1, 1 69.4, 1 56.5, 143.9, 1 37 1 1 35.4, 1 25.1, 1 1 6.3, 77.5, 65.1, 60.4, 6〇. 3, 53 6 52.3, 43.9, 34.1, 32.6, 32·3,32.2,32.1,32 0,3〇7 30.2, 27.3, 27.1, 26.4, 23.3, 23.2, 22.2, 21.3, 1 9 7 The compounds of Examples 44 to 92 are according to the procedure described in Example 22 or 42 preparation. 9

(IX) 1150-9072-PF; Linlin 81 200808832 Example A Q G 44 CX. Also / V 45 CX0 again / a^p°' V 46 Ο^ι〇a^p0' V 47 o^p0' Ψ^ν 48 MeO^0^^ a^p°' A&gt;% 49 ΛΛ f^p ΝγΝ /Ά 50 〇nVn 51 〇nVn 7&gt;v 1150-9072-PF;Linlin 82 200808832 52 〇Ϋ 53 F 54 ΟχΛ /ί¥ν 55 nVn 'Ά 56 Ov nVn 7ΐ5ν 57 V/ V 'Ά 58 &lt;Vy H ' O^p0' ΝγΝ 59 \又/ Η · ύ^ρ° V 'Ά 60 &lt;3K/ ο^ρ°' ΝγΝ 1150-9072-PF;Linlin 200808832

61 〇人 / Ϋ 62 a1, a^_p°' V 63 Oy Ϋ 64 (// 〇lp〇' nVn 65 nVn 66 Me 0^°' nVn 67 CA V 68 〇Me^yV HNAMe V 69 Me a^p0 'V 1150-9072-PF;Linlin 200808832 70 Ά HN&gt; 71 of/ nVn 72 CX. Also / nVn /V s 73 CX〇A/ nVn HU) 74 〇^〇A/ Ϋ /, X. H G, CH3 75 Q^. , nVn /3⁄4 1 H 76 CX. Also / nVn 77 Cl. Also / nVn /3⁄4 78 CX〇A/ nVn /3⁄4 N:o2h 1150-9072-PF;Linlin 200808832 79 ο^Λ/ nVn 80 / gas 81 Cl〇A/ 〇^p0' ΝγΝ 82 CVy nVn 83 Cl. Also / nVn /v43 84 CX0 again / ΝγΝ /3⁄4 85 Cl. Also / NVN 1 /3⁄4 86 Ο^Λ/ ΝγΝ 87 OJy Y /, know 1150-9072-PF; Linlin 86 200808832

88 Cl〇A/ nVn /, Guan Η H 89 OJy nVn Η H 90 CX. Also / nVn people N' 91 CX. Also / Ϋ AX, H 92 CX0 again / Ν γΝ 'ΆΝ, &gt; N \ 93 〇^〇A/ NvN 1 94 CVy RP n, n'N 1 Ϋν 95 O^oA/ N 96 OJy Y 1150-9072-PF ;Linlin 87 200808832 97 &lt;λ. Also / 98 Cl. Also / % V 99 CX〇A/ γ 100 CX. Also / Me〇 ΝγΝ 101 Cl. Also / bvF νι 102 &lt;Vy Y Ψ^ν 103 CX. Also / v? HP ΝγΝ /Ά 1150-9072-PF; Linlin 88 200808832 104 Cl. Also / CN / 〇,, s//〇 Yv 105 OJy MeO ¥ 106 CX. Also / f3co ▼ 107 &lt;λ0 again / o^P Ϋ 108 CX. Also / 〇 〇vqp 109 &lt;λ. Also / % 1150-9072-PF; Linlin 89 200808832

The title compound was prepared according to the procedure described in the step lc of Example 1 from the commercially available Boc-cis-L-hydroxyproline and D-y5-vinylcyclopentanoic acid ethyl ester (le). Step 9 3 b

The title compound was prepared from the Boc-protected dipeptide (93a) according to the procedure described in step 43a of Example 43. Step 9 3 c 1150-9072-PF/Linlin 90 200808832

The title compound is derived from (S)-2-(cyclopentyloxyweiki-amino-8-decenoic acid (Organic Process Research and Development (2007), 11(1), 60-63)) and dipeptides ( 93b) Prepared according to the procedure described in step lc of Example 1. MS (ESI): yz / /z = 534. 2 [M + H] ° Step 93d

The title compound was prepared from the diene (93c) according to the procedure described in Step 1 of Example 1. MS (ESI): /Z7/Z=506. 2 [M + H] 〇 Step 93e

The title compound was obtained from the macrocycle (93(1) and BsCl according to the procedure described in Example 2. MS (ESI) · · 々 712 712 · 2 [M + H]. 1150-9072~PF; Linlin 200808832 Step 9 3 f

The title compound is a macrocyclic ring (9 3 e ) and 4-bromo-5-phenyl-1,2,3-triazide from bromobenzene (European J. of Med·Chem_ (1 983), 18 (5). 4 71) According to the procedure described in Step 3 c of Example 3, MS (ESI): m/z^l\\% 1[M+H] ° Step 93g

The title compound was prepared from the ester (9 3 f ) according to the procedure described in the procedure of Example 3, dd. MS (ESI): /z?/z-685. 5 [M + H] ° Step 93h 1150-9072~PF; Linlin 92 200808832

In a microwave glass bottle, triazolium bromide (50 mg, 0·0 73_〇1), quinoline-8-boric acid (38·Omg, 〇·219 mmol), potassium phosphate (46.6 mg, 0.2l9 mmol), Dicyclohexane (2, ,4,6,-triisopropylbiphenyl-2-yl)phosphine (3·〇〇g, 6.29# mol), Pd2(dba)3(〇. 98 0mg , 1.070 / / mol) mixture, diluted with acetonitrile (183 / zL) and butanol (i 〇〇 # L). The glass tube was microwaved at 140 ° C for 15 minutes. The reaction mixture was dissolved in dioxo with 20 0 / L 4N HCl and solvent was removed under nitrogen. The reaction mixture was purified by EtOAc (EtOAc) elute MS (ESI): 1[M+H] ° Step 93

The title compound was prepared from the acid (93 g) according to procedure 1150-9072-PF, as described in Example 22; Linlin 93 200808832. MS (ESI): π / ζ 2 835. 1 [M + H] 〇

</ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; MS (ESI): m/z =:::::::::::: MS (ESI): π / ζ = 803 · 〇 [M+H] 实施 Example 95 Compound IX, wherein α =

a 〇V Q = Ν 步骤 Step 95a The title compound was obtained from the procedure described in the step 93h of Example 93 from triazolium bromide (93 g) and 2-pyridin-4-bronic acid. MS (ESI): π / ζ = 70 〇 2 [M + H] 〇 Step 95b The title compound was obtained from the acid (95a) according to the procedure 1150-9072-PF of Example 22; Linlin 94 200808832 . MS (ESI): </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> <RTIgt;

Step 96a The title compound was obtained from the procedure of the procedure described in the procedure of s. MS (ESI): </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; MS (ESI): Λ 7 / ζ = 784. 2 [Μ + Η] 实施 Example 9 7 Compound of formula IX, where a =

Step 97a The title compound was obtained from the procedure described in step 93h of Example 93, mp. MS (ESI): ζζ//ζ: 687·2 [Μ + Η]. Step 97b The title compound was prepared from the acid (97a) according to procedure 1150-9072-PF; Linlin Qc-200808832 as described in Example 22. MS (ESI): i / / = = 79. 7 [M + H] 实施 Example 98 Compound of formula K, where A =

Step 98a 2-Naphthylboronic acid is prepared according to the procedure described in Step 93h of Example 93. MS (ESI): λ? / ζ = 731 · 2 [Μ + Η]. Step 98b The title compound was obtained from the acid (98a) according to the procedure described in Example 22. MS(ESI): τζ//ζ=834·2[Μ + Η] 〇

Embodiment 9 A compound of the formula IX wherein A =

Step 99a The title compound is obtained from the procedure described in Step 93h of Example 93, from the succinyl bromide (9 3 g) and the 3- s. MS (ESI): ni/z = QST. 2 [M+H] ° 1150-9072-PF; Linlin 96 200808832 Step 99b Procedure The title compound was prepared from acid (99a) according to Example 22. . MS (ESI): /ff/z=790. 1 [Μ + Η]-

Example 1 0 0 compound of formula IX, wherein

Step 1 0 0 a The title compound consists of triazole (93 g) and 2-methoxypyrimidine. D-5-boronic acid was prepared according to the procedure described in Step 93h of Example 93. MS (ESI): m/z =:::::::::::::: MS (ESI): z7 / z = 816. 1 [M + H] ° Example 1 01 Compound IX, where A =

Step 101a 1150-9072-PF/Linlin 97 200808832 \ The title compound was prepared from the procedure described in Step 93h of Example 93 from triazole (93s) and 4-methoxyphenyl boronic acid. MS (ESI): m/z =l.2. </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; MS (ESI): m/z = SlA. 0 [Μ+Η] 〇

Example 1 01 Formula IX compound wherein A =

The title compound was prepared from the triazole (93 g) according to the procedure described in Example 22. MS (ESI): m/z = 18Q. 0 [Μ+Η] 〇

F

Embodiment 102 Formula K compound, wherein a two

Add triazolium bromide (101) (2 〇 mg, 0·025 mmol), 3-(4-fluorophenylamine-mercapto) phthalic acid (23. 3 mg, 0.09 mmol) in a microwave tube, FibreCat a mixture of 1 007 (A1faAesar, 21 mg, 1150-9072-PF; Linlin 98 200808832 0.0075ππη〇1), 1M potassium carbonate (30/zL, 0.03 mm〇l) and ethanol (1 ml), heated under microwave conditions To 12 (microwave) for 30 minutes. The reaction mixture was dried over EtOAc (2 g, EtOAc (yield: 79 mmol/g) and diluted with methanol. After solvent concentration, the residue was purified by reverse phase HPLC. The title compound (3.5 mg, yield 15%). MS (ESI): w/z

The title compound was obtained by the procedure described in Example 021 from triazinium bromide (1 〇 1) and 3-(purpurin-2-methylcarbazinyl)benzene boronic acid. MS (ESI): π / ζ = 907·3 [M + H]. Example 1 Compound of formula K, wherein A =

The title compound was obtained by the procedure described in Example 021 from triazolium bromide (101) and 4-(cyanomethyl)benzeneboronic acid. MS (ESI): m/z = </RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt;

The title compound consists of triazole (1 〇 1) and β-methyl oxypyr. The -3-boronic acid was prepared according to the procedure described in Example 102. MS (ESI): π / ζ = 815 · 2 [Μ + Η]. Embodiment 106] a compound of the formula X, wherein Α =

The title compound was prepared according to the procedure described in Example 1 〇2, using triazolium bromide (1 01) and 6-(trifluorodecyloxy)pyridine-3-boronic acid. MS (ESI): w/z = 868. 2 [ Μ + Η].

Embodiment 107 A compound of formula IX, wherein A is di-di-H?. The title compound was prepared according to the procedure described in Example 021, using triazolium bromide (101) and 3-ethylindole boronic acid 1150-9072-PF; Linlin 1 〇〇 200808832. MS(ESI): λ?/ζ=826. 3 [Μ + Η] 〇

/^Ί Ο Example 1 08 Κ compound, wherein

The title compound was obtained from bromo-4-carbonyl)benzeneboronic acid according to the procedure of MS (ESI): π / ζ = 897 · 3 [Μ + Η]. Prepared by the procedures described for triazole (101) and 3-(oxygen nitrogen).

4' phenoxy oxo boron The title compound was obtained by the procedure described in Example 021 from triazinium bromide (1 〇 1) and acid. MS (ESI): π / ζ = 876 · 2 [Μ + Η]. Embodiment 11 0 Compound of formula IX, wherein Α =

1150-9072-PF; Linlin 101 200808832 Step 110a

The title compound is a bromobenzenesulfonated macrocycle (93e) and a commercially available 4-(4~methoxyphenyl) 211-1,2,3-triazole according to the procedure described in Step 3c of Example 3. The title compound is obtained from the compound (11Oa) according to the procedure described in Step 3d of Example 3. MS (ESI): π/ζ=635·3[Μ+Η]. The title compound was prepared from the acid (11 〇b) according to the procedure described in Example 22. MS (ESI): π / Ή 38·2 [Μ + Η]. The compound of the present invention is shown for HCV NS3 protease Effective inhibitory properties. The following examples describe analytical methods in which the compounds of the invention can be tested for anti-HCV effects. Example 111 NS3/NS4a Protease Assay HCV Protease Activity and Inhibition Are Internally Suppressed (Calculation ^6(1) Firefly The light matrix was analyzed. The -DABCyl and -EDANS groups were attached to both ends of a short peptide. In the case of protein cleavage, the inhibition of the MBCYL group on the edans fluorescence 1150~9072-PF/Linlin 102 200808832 &quot; Fluorescence is measured with a Molecular Devices Fluoromax (or equivalent) using the excitation wave The length is 355 nm and the emission wavelength is 485 nm. The analysis is in a Corning white half 96-well plate (VWR 29444-31 2 [Corning 3 6 93 ]) to which the NS4A cofactor is attached (final enzyme concentration 1 Up to 15 nM) of full-length NS3 HCV protease lb. The assay buffer was supplemented with 10//M NS4A cofactor pep 4A (Anaspec 25336 or self-made, MW 1424.8). RET Sl (Ac-AsP-GlU-Asp (EDANS) -Glu-Glu-Abu-[C00]Ala-Ser-Lys-(DABCYL)-NH2, AnaSpec 22991, MW 1 548·6) as a fluorescent peptide receptor. The assay buffer contains 50 mM Hepes (pH 7.5) ), 30 mM NaCl and 10 mM BME The enzyme reaction was carried out 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-OH is used as a reference compound. IC50 value, using equation 205: y = A+((BA)/(l + ((C/xTD)))), calculated by XLFit in the active group (Activity Base, IDBS). Example 112 cell line replicon analysis HCV Replicon RNA Quantification of Cell Lines (HCV Cell Line Analysis) HCV Replicon RNA of Cell Lines was Performed Using Huh-11-7 Cell Line (Lohmann et al, Science 285: 1 1 0- 1 1 3, 1 999) Quantification (HCV cell line analysis). Cells were seeded at 4x 103 cells/well in 96 well plate 1150-9072-PF/Linlin 103 200808832 • and provided with DMEM (high glucose), 10% fetal bovine serum, penicillin- Medium for streptomycin and non-essential amino acids. The cells were cultured in a 7.5% C〇2 incubator at 37 ° C. At the end of the culture period, the cells were extracted with Ambion RNAqueous 96 Kit (model number AMI 812). Purify the total RNA of the cells. To amplify the HCV RNA so that there is enough material to detect the HCV-specific probe (see below), use the TaqMan One-step RT-PCR master mix kit (Applied Biosystems catalog number 4309169) to HCV (see below) Specific primers are used for reverse transcription, and cDNA amplification is performed by polymerase chain reaction (PCR). The nucleotide sequence is located in the NS5B region of the HCV genome as follows: HCV forward primer "RBNS5bfor" 5' GCTGCGGCCTGTCGAGCT (SEQ ID NO: 1): HCV leader "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 fluorescent reporter dye and the dye-inhibiting probe. The increase in the amount of fluorescence per revolution to the RT reflects the increase in the RT-pcR product. In particular, the amount of enthalpy is based on a threshold round, where the magnified line exceeds the gamma threshold of the sigma. Rounds are compared to known standards and provide high-sensitivity measurements of different sample sizes (10) User Bulletin #2u, i 997). The data was analyzed using the ABI SDS program version 1.7. The relative template concentration can be converted to RM copy number (abi 1150-9072-PF; Linlin 104 200808832 • User Bu 11etiη #2 December 11,1 997) by using a HC standard curve of known copy number. The RT-PCR product was detected using the following labeled probe: 5, FAM-CGAAGCTCCAGGACTGCACGATGCT-TAMRA (SEQ ID NO: 3) FAM = fluorescent reporter dye TAMRA: = inhibitor dye was subjected to RT reaction at 48 ° C for 30 minutes , carry out pcr. The thermal cycling parameters of the PCR reactions used on the ABI Prism 7500 Sequence Detection System were: 9 5 °C for 1 round for 10 minutes, followed by 4 rounds, each including incubation at 9 5 C for 15 seconds' and at 60 The second incubation was carried out for 1 minute at °C. To normalize the data to the internal control molecule of cellular RNA, rt-PCR was applied to the cellular mRNA glycerol ternate-3-dehydrogenase (gapdh). The GAPDH copy number is very stable in the cell line used. Gapdjj —pCR is implemented in the same real RNA sample from which the Hcv copy number is determined. The AB Pre-Developed TaqMan Analysis Kit (Cat. No. 431 〇 884E) contains the above GAPDH primers and probes. The ratio of HCV/GAPDHRNA was used to evaluate the activity of compounds that inhibit HCV RNA replication. In the Huh-7 cell line containing the replicon, the activity of the compound as an Hcv replication inhibitor (cell line analysis) in Huh-11-7 cells, the effect of specific antiviral compounds on the sputum of the hcv replicon RNA, This is determined by comparing the amount of HCV RNA that the cells are exposed to with the cells exposed to the DMSO vehicle (negative control) and normalized to GAPDH (eg, HCV/GAPDH ratio). Specifically, the cells were seeded at 4×1 〇3 cells/well in a 96 well plate and cultured at 1150-9072-PF; Linlin 105 200808832 at: 1) medium containing 1% DMSO (〇% inhibition control group), or 2 Medium/1% DMS0 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 00- 1 0 0*S/C1 where s = ratio of HCV RNA copy number/GAPDH RNA copy number in the sample C1 = 0% inhibition in the control group (medium/1% 丽8〇) In the case of HCV RNA copy number/GAPDH RNA copy number, the dose-response curve is obtained by serially diluting the compound three times, from high to low concentrations across three logarithmic values. The highest concentration is set to 1·5 uM and the lowest concentration is 〇· 23 nM. If the EC50 value does not fall within the linear region of the curve, further serial dilutions (eg, 500 nM to 〇·〇8 nM). The EC50 is based on the IDBS Activity Base program, using the "XLFit" function, 4-parameter, and non-linear regression (model #205, version 4.2.1, buildl 6). In the above analysis, the compound represented by the present invention has Ηα replication inhibitory activity and HCV NS3 protease inhibitory activity. These compounds are also effective for inhibiting different HCV phenotypes, including Hcv ns3 proteases of phenotypes 2、, 2, 3 and 4. Representative compounds were tested by the above tests (Examples 111 and U2). Representative compounds disclosed herein, such as the NS3/NS4a protease assay and cell line replicon assay, are active in the range &lt;=〇·hM-丨 000 nM. [Simple description of the diagram] 1150-9072~PF; Linlin 106 200808832 - No 0 [Description of main components] No 0 1150-9072-PF; Linlin 107

Claims (1)

200808832 Patent application scope: 1 · A compound 'is represented by formula I or JJ: γ N, “N l!w Sen ((II) G , CH c(=〇)-NH-R: A is selected from R!, -(〇0)~〇~Ri, —(c = 〇) —匕 or -3 ( 0) 2-1, -S(〇)2NHR2; R i is selected from the group consisting of: (i) aryl; substituted aryl; heteroquinone • · 丞, heteroaryl, substituted Heteroaryl (ii) heterocycloalkyl or substituted heterocycloalkyl; (iii) -Cl-C8 alkyl, -c2_C8 or _C2_Cs alkynyl, each containing 2 or 3 selected from ο a hetero atom of S or N; a substituted -c alkyl group, a substituted -Cr Cs alkenyl group or a substituted -^ 〇, 1, 2 or 3 hetero atom selected from 〇, ^N, L 3 — C 1 2 ring-checked or substituted-CrC! 2 cycloalkyl; —C 3 —C ring-terminated or substituted-C3-Cl 2 cycloalkenyl; R 2 is independently selected from the following a group consisting of (1) hydrogen; (1) an aryl group; a substituted aryl group; a heteroaryl group; a substituted (iii) heterocyclic alkyl group or a substituted heterocyclic alkyl group, earth '1150-9072-PF ;Linlin 108 200808832 (1V)~C1~C8 alkyl, -C2-C8 alkenyl or -C2 -&amp; alkynyl, each containing ο, 1 2 or 3 selected from 〇, s or N Atom; substituted -Ci - c8 -Cenyl I substituted -Cr C8 alkenyl or substituted -C 2 -C8 alkynyl, each containing 〇, 1, 2 or 3 selected from 〇, § or N a heteroatom; _C3 - a Ci2 cycloalkylcycloalkenyl group or a substituted or substituted ~C3 -Ci2 cycloalkyl group; -G-L -C 3 - C 1 2 ring-based; G system selected from -NHS (〇) 2 —R 3 or —NH(s〇 2)NR 4 R 5 ·, wherein R 3 is selected from: (i) aryl, substituted aryl; heteroaryl; substituted heteroaryl; (1 Ο a heterocycloalkyl or substituted heterocycloalkyl; (11 alkyl, -C2-C8 alkenyl or -c2-c8 alkynyl, each containing 0, 1, 2 or 3 selected from 〇, 8 or N a hetero atom; a substituted alkyl group, a substituted -C 2 -C 8 alkenyl group or a substituted -C 2 -C 8 alkynyl group each containing 0, 1, 2 or 3 selected from hydrazine, S Or a hetero atom of N; _C3 - "cycloalkyl or hydrazine substituted ~C3 - Cl2 cycloalkyl; ~C3 -C" cycloalkenyl or substituted -C 3 -C 1 2 cycloalkenyl; Is -CH2ph or -CH2CH2Ph; R4 and ^ are independently selected from: (1) hydrogen; (ii) diradical, substituted aryl, heteroaryl Substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; (iv) ~Ci-C8 alkyl, -C2-C8 alkenyl or -c2-C8 alkynyl, each comprising hydrazine , 1 2 or 3 heteroatoms selected from hydrazine, s or N; substituted - 1 - c8 alkyl, substituted - CrC8 alkenyl or substituted - G - U alkynyl, each comprising 1150 -9072-PF;Linlin 109 200808832 • 0, 1, 2 or 3 heteroatoms selected from 〇, 8 or 1^; ^-(: 12 cycloalkyl or substituted -CrCu cycloalkyl; -C3 —c”cycloalkenyl or substituted -C 3 _ C 1 2 ring-based; L· is selected from -d-, -0~, -s-, §(〇)2— · X and Y independent The system is selected from: (1) hydrazine; (ii) aryl, substituted aryl; heteroaryl; substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocyclic alkyl; -Ci-C8 alkyl, -C2-C8 alkenyl or -c2-c8 alkynyl, each containing hydrazine, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; substituted ~Ci_c8 a substituted, G-C8 alkenyl group or a substituted C2-C8 alkynyl group each containing hydrazine, 1, 2 or 3 heteroatoms selected from 0, S or N; - c3-C12 naphthenic base Or substituted -CrCu cycloalkyl; -C3-Cu cycloalkenyl or substituted -Cs-C12 cycloalkenyl; (V)-W-R6' wherein W is absent or selected from a 〇-, _1, -N(Me)-, -C(0)NH- or _C(0)N(Me)-; R6 is selected from the group consisting of: (a) hydrogen (b) aryl Substituted aryl; heteroaryl; substituted heteroaryl; (c) heterocycloalkyl or substituted heterocycloalkyl; (cO-Ci-o alkyl, _CrC8 alkenyl or - 匕- Cs alkynyl, each containing hydrazine, 1, 2 or 3 heteroatoms selected from 0, S or N; substituted -Ci - Cs alkyl, substituted -CrC8 alkenyl or substituted -G - And alkynyl groups each containing hydrazine, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; ~C3 - cycloalkyl 115〇-9〇72^PF; Linlin 110 200808832 or substituted - (8) a cycloalkyl group; _c: • a C 2 cycloalkenyl group or a substituted C 3 -C 1 2 cycloalkenyl group; or, X and v together with a carbon atom to which they are attached, the ring contains ···丁t❿ into %, square, substituted aryl, heteroaryl; heteroaryl, substituted = represents a carbon-carbon single or double bond j = 〇, 1, 2, 3 or 4; k = 1, 2 or 3; mz: 0, 1 or 2; and n = l, 2 or 3 〇 2. If Γ #χ patent scope item 1 Compound, expressed as formula, IV: Or a pharmaceutically acceptable salt, a dragon or a precursor, the towels A, G, and Y are as defined in item 1 of the scope of the patent application. 3. If the compound of the patent scope 帛i is selected, it is selected from the formula v, VI: 1150-9072-PF; Linlin Hi 200808832 Χ3 ;Χ2 Χι χ:η. Ν,ζΝ 独立. An independent system is selected from -Cb and Ν, wherein R7 is independently selected from (i) hydrogen; halogen; -Ν〇2; -CN; (ii)-M-R4; μ is 〇, 8 or ' Where & same application definition; 丄 (iiUNH, where 1 and Rs are as defined in item 1 of the scope of application; (iv) Cl C8 thiol, -C2-C8 alkenyl or -C2-C8 alkynyl, each containing hydrazine, 1, 2 or 3 heteroatoms selected from hydrazine, s or N; substituted ～C alkyl, substituted _G2-alkenyl or substituted radicals, each 8 〇, 1, 2 or 3 a hetero atom selected from ruthenium, 3 or N; -μ = or substituted - (10) a ring-burning HCl2 ring or a C-C3-Cl2 cycloalkenyl group; an aryl group; a substituted aryl group, Heteroaryl; substituted heteroaryl &lt;&gt; doped % alkyl or substituted heterocycloalkyl, wherein A is defined in the scope of item 1. 八同申4. Compound, select m: , VH, 1150-9072-PF; Linlin 112 200808832 Or medicine can be fragrant, drink salt, ester or precursor, wherein: Y1 to Y3 independent of your λ. 1 糸 from CR7, N, NR7, S or 0, of which IM is selected from : (i) hydrogen; element; 〇2; _CN; (·) M 疋〇, s or NH, where R4 is defined in item 1 of the scope of application; •...) NMs where R1 2 3 4 and R5 are the same as the scope of application Definition of item 1; (iv) C! c8 alkyl, -C2-C8 alkenyl or -C2-g alkynyl, each containing hydrazine, 1150-9072-PF/Linlin 113 1 2 or 3 selected from hydrazine, 5*N heteroatoms; substituted -Cl-. 8 2 calcined, or disubstituted - C 2 -C 8 dilute or substituted - G - alkynyl, each containing 3 b 2 or 3 heteroatoms selected from 〇, uN; -ο -^ a cycloalkyl group 4 or a disubstituted C3-C12 cycloalkyl group; a c3 -Ci2 cycloalkenyl group or a substituted -C3-Cl2 cyclodecyl group; (v) an aryl group, a substituted aryl group Heteroaryl; substituted heteroaryl; (vi) heterocycloalkyl or substituted heterocycloalkyl, wherein a and 6 are as defined in the first item. 5. If the compound of the first application of the scope of application is selected from the formula, VIII, 卩 and 6 are shown in Table 1; 200808832 Q (IX) Table 1 Example A Q G 22 people again / noisy. 'V 23人又/ γ Ϋν 24 Μ 8 ΝγΝ /Ά 25 ΛΛ φ ΝγΝ 26 ΛΛ A, » 7YVV 27 乂Λ〆V ;Ψν 28 people / ΝγΝ Ϋν 1150-9072-PF;Linlin 114 200808832 29 people/ 0^°' V Ϋν 30 人又/ V 31 人又/ ΝγΝ Ϋν 32 a1, nVn 33 人又/ γ Α^Υ 34 人又/ Crd°' N: :NN /,Χ- Η 1 35 people/ nVn /, Xr Η 1 36 people and / / 〇,, &lt;, 〇 Yr 37 nVn /, x Η 1 1150-9072-PF; Linlin 115 200808832 38 people / ap NyN 39 people / Ϋ 40 people / Ϋ 41 乂. Also / ΝγΝ 42 &lt;// f^p°' ΝγΝ 43 CX0 again / h V 44 〇^〇A/ 〇lp°' V 45 nVn 46 〇^10 people / nVn 1150-9072-PF; Linlin 116 200808832 47 1 V / ν Υν 48 MeO^0^^ a^fi0' ΝγΝ 49 ΛΛ ΝγΝ 50 人Ο^Γ ΝγΝ 51 〇0^°' nVn 52 〇ΝγΝ 'ά 53 0^0°' ΝγΝ 54 CX〇^ 0^ °' γ 55 Cl into α^ρ°' V Ψ^ν 1150-9072-PF; Linlin 117 200808832 56 Ον Ϋ 57 ΝγΝ 58 αΛ ΝγΝ 59 V 60 &lt;yl/ Ϋ 'Ά 61 〇人 / nVn 62 a1, NVN 63 〇vo^p° nVn /isV 64 o1/ nVn 7&gt;v 1150-9072-PF;Linlin 200808832 65 cA nVn 66 a1, Me nVn Ϋν 67 {λ 0^°' Ϋ 'Ά 68 〇ΗΝΛΐβ nVn 69 Mei ^ Me Ϋ Ψ^7 70 HN^ 6^0 nVn 71 of7 nVn 72 Cl. Also / nVn 73 Cl. Also / Ϋ /3⁄4 1150-9072-PF; Linlin 119 200808832 74 CX. Also / 75 Cl〇A/ o^p0' V /3⁄4 and 1 Η 76 Cl〇A/ o^p0' 77 CX. Also / c^p0' VN Α«&quot;Κ 78 CUy NyN 79 CVy V Αν^ η u0CH3 80 0^0°' V / gas 81 Cl. Also / aid' n'n^n Ν 82 OJy V 1150-9072-PF; Linlin 120 200808832 83 γ AXf3 84 CX. Also / nVn 85 CX. Also / γ 43⁄4 86 CX0 again / ο^ρ0' 1 /3⁄4 87 CX0 again / Ν: &gt; 1 AK%F 88 CX. Also / γ αΧ^&gt; Η Η 89 Ν γ Ν , Ά Η Η 90 CX. Also / nVn ο 〇ην-ν Ζ, νΎ Η Η 91 nVn /γ, 1150-9072-PF; Linlin 121 200808832 92 &lt;λ. Also / nVn /US N\ 93 OJy (3⁄40 NVN 1 94 OJy ap V 95 V 96 CVy Y 97 CX〇 / π Y 98 CL. Also / % ΝγΝ 99 Cl〇A/ ΝγΝ 100 CX. Also / MeO 丫1150 -9072-PF/Linlin 122 200808832 101 NI 102 Cl. Also / ΝγΝ 103 Cl. Also / v? ΝγΝ 104 CX. Also / CN A 105 CX. Also / MeO ¥ 106 CX. Also / F3C〇1150-9072-PF ;Linlin 123 200808832 107 OJy 108 OJy 109 (λ. again / % 110 Cl. / / OMe 4 丄 6 · a compound whose chemical formula is selected from the formula I, Π, 羾, IV, V, VI described in the specification , VH, hydrazine or IX, or a pharmaceutically acceptable salt, ester or precursor. 7. A pharmaceutical composition comprising: (1) a compound selected from the formula I, π, m, as described in the specification Iv, V, VI, W, 或 or IX, (2) or a pharmaceutically acceptable salt, ester or precursor of the composition. 8. A pharmaceutical composition comprising a therapeutically effective amount of the patent range 1 1150- 9072-PF; Linlin 124 compound, or a pharmaceutically acceptable carrier acceptable carrier or excipient. &lt;, s intended or precursor and its in-process 9. Type C liver in a therapeutic object * Contains: a method for administering the drug to the subject (3) a method for virulence infection, a pharmaceutical composition of the package. &lt; Item 8 of the patent application 1〇--inhibiting hepatitis C disease Hepatitis nS3 protease treatment has the method of 欵旦&amp;, including: administration-pharmaceutical composition. In the scope of claim 8 of the patent application, the method of infection, the method of infection,浐, :, Hepatitis C virus 12 in the subject... Extra anti-hepatitis C virus rate agent 12. If the application range is the first u-mother of the application, the toxicity is reduced, and the hepatitis C disease in the treatment target The method of the eucalyptus, wherein the additional anti-c-type liver is formed by the following group: α_ 毋 』 择 from r interferon, no-interferon, ribavarin and diamond-like (adamantlne). A method of treating hepatitis G and sputum in the first treatment target, wherein the chain anti-c hepatitis virus agent is an inhibitor of hepatitis C virus, comprising: helicase, polymerization Enzyme, whole protease or IRES. H. - Method of making a compound selected from work, n, melon, shell, v, n - or IX, according to the procedures, methods or preparations described herein. A pharmaceutical composition comprising a compound of the scope of the application, or a pharmaceutically acceptable salt, ester or precursor of the compound. 1 6· The pharmaceutical composition of the scope of the application of item 5 contains another anti-H C V agent. 1150-9072-PF; Linlin 125 I7. The 15th Jg agent of the application range, selected from the following group - M pharmaceutical composition, still contains inhibition - hcv protein inhibition two: ! two rebavirin, diamond-like, another Inhibitor or "enzyme inhibitor, - (iv) helicase μ 4 ribosome entry site inhibitor. The pharmaceutical composition of claim 15 further comprises a glycolated interferon. Ethylene 19. The drug of claim 15 The composition still contains another anti-viral, anti-bacterial, anti-fungal or anti-cancer inhibitor, or immunomodulator. 1150-9072-PF; Linlin 126 200808832 VII. Designated representative map: (1) The representative representative of the case is: (2) The symbol of the symbol of this representative figure is simple: No. 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 1150-9072—PF/Linlin 5