TW200920394A - Tetrazolyl macrocyclic hepatitis C serine protease inhibitors - Google Patents

Abstract

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

Description

200920394 IX. Inventive Note: [Related Application] This application is based on the US Provisional Application No. 60/ΧΧΧΧΧ (transition of US Application 1 1/499245) on August 4, 2006. This is for reference. TECHNICAL FIELD OF THE INVENTION The present invention relates to a macrocyclic compound which has activity against hepatitis C virus (HCV) and is useful for treating HCV infection. More specifically, the present invention relates to a tetrazolyl macrocyclic compound, a composition containing the same, and a method of using the composition & and a method of producing the same. [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 speculated that the virus infects more than 200 million people worldwide, more than human immunodeficiency virus (infected individuals almost five times ... cv infection patients, due to a high proportion of chronic infection, the development of cirrhosis Increased risk, and subsequent development of hepatocellular carcinoma and terminal liver disease. (D) is the main cause of hepatocellular carcinoma, and is the main cause of liver transplantation in Western countries. In the development of anti-HCV treatment There are quite a few obstacles, including, but not: the genetic diversity of the virus (IV), the replication of the virus in the host, the high chance of developing a drug-resistant mutant, and the lack of reproducible adult culture systems and Small animal model for HCV replication and pathogenesis] 1150-9047-PF; Kai 6 200920394 Large-scale clearing, due to mild infection and complex biology of the liver, special care must be taken for antiviral drugs that are prone to significant side effects. At present, only two treatments for HCV infection have been approved. The original treatment of the soil spear hangs 'containing 3 to 2 months of time to intravenously give interferon-alpha (strand alpha), and a new The second generation of treatments, including (10) with a general antiviral nuclear mimic, such as, BavHn, (7) treatment, interferon-related side effects, and anti-HCV infection effects in each treatment Low. Due to the poor tolerance and poor efficacy of current treatments, it is necessary to develop antiviral agents that are effective for the treatment of HCV infection. Most of the patients are chronically infected and have no symptoms, and are unpredictable. The drug is preferably a significantly lower side effect than currently available treatments. (: Hepatitis non-structural protein _3 (de-), a proteolytic enzyme for the treatment of viral polyproteins and subsequent viruses Replication is necessary. Although there is a large number of viral variants (_) associated with HCV infection, the active site of the NS3 protease is highly reserving: its inhibition is an attractive mode of intervention. Recently treated with protein agents The success of ''s support for the concept of NS3 inhibition is a key target in the fight. HCV is the Rna virus of the Flaviridae family. And comprising a single strand of r difficult molecule of about 9600 base pairs. The dragon is encoded as a polypeptide of about 301 amino acid. The HCV polyprotein is treated by the virus and the host enzyme to (1) discreet The peptide is responsible for many functions. 3 ύ, clean protein '(: (7) and ^ (7) protein function is unknown' and includes height change 1150-9047-PF; Ka i 7 200920394 different sequence. There are 6 kinds Non-structural protein f. Like zinc-dependent metalloproteinase, its role is linked to the NS3 protein f. M3 is involved in two catalytic functions (separate from its association with NS2): at the n-term: a silk amine Acid protease, which requires NS4A as a cofactor, and at the c-terminus - ATPase-dependent helicase function. NS4A is a cofactor that is closely related but is a non-covalent serine protease.

The NS3 and NS4A proteases are responsible for the incision of four parts of the viral polyprotein. NS3-NS4A is cleaved to be self-catalytic and occurs in the cis position. The other three hydrolases, NS4A_NS4B, NS4B_NS5A and nS5a_ns5b, all occur in the trans position. NS3 is a leucine protease' which is structurally classified as a class of chym〇trypsin. Although Μ serine protease itself has proteolytic activity, HCV protease is not an efficient enzyme in catalyzing polyprotein cleavage. It is known that one of the central hydrophobic regions of the NS4A protein is necessary for this enhancement. The formation of a complex of NS3 protein with NS4A appears to be necessary for the treatment of events and enhances the proteolytic efficiency of all sites. Strategies for developing antiviral agents generally render the virus-encoded enzyme inactive, including NS3, which is required for viral replication. A recent review of efforts to find ns3 protease inhibitors is described in S. Tan, A. Pause, Y. Shi 'N. Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov., 1,867 -881 (2002). Other patents that disclose such synthetic HCV protease inhibitors are: W〇00/59929 (2000); WO 99/07733 (1999); WO 00/09543 (2000); WO 99/50230 (1999); 1150-9047- PF; Kai 8 200920394 US5861297 (1999); and US 2002/0037998 (2002). SUMMARY OF THE INVENTION The present invention is directed to a tetra-α-based macrocyclic compound, and a pharmaceutically acceptable salt, S- or prodrug thereof, and a method of using such a subject in need of treatment for hepatitis C virus infection therapy. Thereby, the macrocyclic compound of the present invention interferes with the life history of the hepatitis C virus and is useful as an antiviral agent. The invention further encompasses a pharmaceutical composition comprising administering a prostaglandin 5 to a subject suffering from an HCV infection, or a salt, g- or prodrug thereof. The invention further provides 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 an interferon (eg, alpha interferon # interferon, Consistent interferon, long-acting interferon, or albumin or other interferon interferon), ribavarin, adamantine, other HCV protease inhibitors or an HCV polymerase, The helicase, or the internal ribosome entry site, inhibits d. The present invention is also directed to a method of treating an individual infected with HCV. The pharmaceutical composition of the present invention is administered to the individual. The invention further provides a pharmaceutical composition comprising a compound or/or a pre-acceptable salt, ester or prodrug of the invention, and a further pharmaceutically acceptable carrier or excipient. In a specific embodiment of the present invention, a compound of the formula and the pharmaceutically acceptable salt, ester or prodrug thereof is disclosed: 1^50-9〇47-PF; Kai 9 200920394

/

Wherein -S(0)2NHR2; -(c=0)-r2, -C(=0)_NH-R2 and ~s(〇)2_Ri R1 are selected from the group consisting of: (i) aryl Substituted aryl; heteroaryl; substituted heteroaryl(11)heterocycloalkyl or substituted heterocycloalkyl; and earth (nO-C^C8 alkyl, -G-C8 alkenyl or _C2_C8 alkynyl, 2 or 3 heteroatoms selected from hydrazine, SstN; substituted = fluorenyl, substituted -C2_Cs alkenyl or substituted _C2_h alkynyl, [Η 0 1 2 or 3 a hetero atom selected from 0, S or n; -c ' or a substituted C3_Cl2 cycloalkyl group; - C3_ = Cl2 cycloalkane d - (:3_(:12cycloalkenyl; ^substituted € h independently Selected from the following group: 1150-9047-PF; Kai 10 200920394 (1) hydrogen; (11) aryl; substituted aryl; heteroaryl; substituted heteroaryl; (iii) heterocyclic a substituted or substituted cycloheterocyclyl; and (iv)-C-C8 alkyl, -C2-C8 or -C2-C8 alkynyl each having 〇, 1, 2 or 3 selected from 〇, a hetero atom of s or N; substituted, terpenoid, 'disubstituted _ c2 - cs alkenyl or substituted _ c2 _ c8 fast radical, each having 〇, 1, 2 or 3 Square, of 8 or N heteroatom; _C3_Cl2 burning cycloalkyl group

Or substituted ~C3-Cl2 cycloalkyl; -Cs-C!2 cycloalkenyl or substituted -C3_Cl2 cycloaliphatic; G, selected from the following group _nHS(〇)2~R3 - Nhcs〇2)nr4r5; K3 is selected from the following: aryl,, disubstituted aryl, heteroaryl; substituted heteroaryl (11) heterocycloalkyl or substituted heterocycloalkyl And earth (m)-匕-C8 alkyl, -C2-C8 alkenyl or _C2_C8 alkynyl, each having 12 or 3 heteroatoms selected from hydrazine, s or N; substituted, alkyl Substituted C8 dilute group or substituted C8 fast group, ... 〇, 卜 2 or 3 selected from 〇, m of miscellaneous... : or by taking ... a base - ring dilute base or by taking = - C3-Cl2% fluorenyl; oxime heart] Among the compounds of formula 1, R3 is not CH2Ph or CH2CH ph m is independently selected from the following: 2 h, (1) hydrogen; 'substituted heteroaryl is ( Ii) aryl; substituted aryl; heteroaryl 1150-9047-PF; Kai 11 200920394 (m) heterocycloalkyl or substituted heterocycloalkyl; and 〇ν)-εκ8 alkyl, _CrC8 olefin Base or —c2—Cs fast base, each of which is a hetero atom selected from 〇, ...; An alkyl, substituted C8 or substituted fast radical, each having a degree of 1, 2, or 3 heteroatoms selected from 0, UN; each Cl2 ring: a substituted or substituted C3-Cl2 ring Alkyl; each Ci2 cycloalkenyl or by: di-C3-〇12 ring-dense; L, selected from the following group - CH2_, _〇_, _s_ and s(〇) X a group consisting of: (i) hydrogen; (11) aryl, substituted aryl; heteroaryl; substituted heteroaryl (Η 〇 heterocycloalkyl or substituted heterocycloalkyl (IV)-.-Cs alkyl, -C2-C8 alkenyl or -CrC8 alkynyl, each having hydrazine, 2 or 3 heteroatoms selected from 0, S or N; substituted -Ci_C8 a substituted C-Cs-alkenyl group or a substituted _C2_C8 alkynyl group each having hydrazine, 1, 2 or 3 heteroatoms selected from 0, s or N; a C3~Cl2 cycloalkyl group or Substituted -C3-Cl2 cycloalkyl; -GC"cycloalkenyl or substituted -C3-C12 cycloalkenyl; and (v) w R6, wherein w is absent or selected from mono-, -s ~, _NH-, -N(Me)-, -C(〇)NH- or -c(〇)N(Me)_, R6 is selected from the group consisting of: (a) hydrogen; (b) aromatic Base Aryl, heteroaryl; substituted heteroaryl (c) heterocyclic or substituted heterocyclic; and 1150-9047-PF; Kai 12 200920394 (d)-Crc8 alkyl, -C2-C8 alkenyl Or -C2-C8 alkynyl, each having 0, 1, 2 or 3 heteroatoms selected from 0, S or N; substituted -Ci-Cs alkyl, substituted -C2-C8 alkenyl or Substituted -C2-Cs alkynyl groups each having 0, 1, 2 or 3 heteroatoms selected from 0, S or N; -C3-C12 cycloalkyl or substituted -C3-Cl2 cycloalkyl ;-C3-Cl2 ring-dense or substituted-C3-Cl2 ring-dilute group; =·- means carbon-carbon single or double bond j=0, 1, 2, 3 or 4; k=l, 2 or 3 ; m=0, 1 or 2; and n= 1, 2 or 3. [Embodiment] In the first embodiment of the present invention, the compound represented by the formula I-IV, or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination, a pharmaceutically acceptable carrier or form Agent. In another embodiment of the invention, the compound represented by Formula V:

(V) or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination, a pharmaceutically acceptable carrier or excipient wherein A, X and G are as in the previous examples 1150-9047-PF ;Kai 13 200920394 Definition. In one embodiment, γ is independently selected from the group consisting of hydrogen, aryl, substituted, and squat: earth, heteroaryl, substituted heteroaryl, substituted heterocycle, ~ 〇 〇 方, hetero-h-C8 alkyl, —c substituted —c wide Cs alkyl, via-C2-cs block, alkynyl, —CrCu cycloalkane 28 alkenyl, substituted ~c2-C8 soil, -C3-Cu cycloalkenyl, alkyl group and substituted -C3, C12 cycloalkenene: -cycloalkenyl, -C2-C8 alkynyl, slow-substituted hydrazine C8 base, each. 8 ^ ^ Substituted -C1 -decyl, substituted - indolyl and substituted -c2~r^^^C2~Cs c8 alkynyl independently contain hydrazine, hydrazine from 0, S or N is a mixed worker. ^ Fly 3 choices C(0) R G(8) is a group consisting of: nc is called Ri[c (called Ri, its substituted aryl, heterozygous L, square, square) Substituted heteroaryl, heterocyclic, substituted heterocyclic, -Cl-C8 alkyl, indole A i substituted C2 C8 alkenyl, ~C2-C8 alkynyl, substituted -Ci-Cs a substituted or substituted C-Cs alkenyl group, a substituted -G-C8 alkynyl group, a C3 C12% alkyl group, a fluorene 2 cycloalkenyl group, a substituted _^Ci2 cycloalkyl group or a substituted product - CK! 2 ring dilute group. G can be an NH_s〇2 - NR4R5 or -NHS 〇2-R3, wherein R ώ Μ # b I? 3 is selected from a aryl group, a substituted aryl group, a heteroaryl group Substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-C12 cycloalkyl, ketyl substituted -C 3 -C 1 2 cycloalkyl or substituted _ C 3 -C 1 2 Ienyl and R 4 and rs are each independently selected from hydrogen, —G—c8 alkyl, _c2_c8 dilute C 2 Cs, substituted _CrC 8 alkyl, substituted —c 2 —C 8 alkenyl, substituted —C 2 —C8 alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, —C3-C12 naphthenic a group, a C3-Cl2 cycloalkenyl group, a substituted-Cs-Cu cycloalkyl group or a substituted 1150-9〇47-PF; Kai 14 200920394 -C 3 _ C 1 2 ring-dilute group. In another embodiment In the example, χ is independently selected from the following group.

Hydrogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl are -C(0)-〇-r丨 or _C(0)_NH_Rl, wherein Ri is —Ci_c8 alkyl, earth c A alkenyl, -Cz-C8 alkynyl, substituted -Crb alkyl, substituted c °8 alkenyl, substituted -C2-C8 alkynyl, _c3-Ci2 cycloalkyl, Γ Γ 2 The Cs group, the substituted _C3_Cl2 cycloalkyl group or the substituted -Ca-C" cycloalkenene is -NHS〇2~r3, which is selected from an aryl group, a substituted aryl group, and a heterocyclic ring. Heteroaryl, heterocyclic, substituted heterocyclic, _C3_c"cycloalkane-CrCu cycloalkenyl, substituted _Crc]2 cycloalkyl or substituted terpene. 3~Cu In another embodiment, X is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl. A · -C(8)-o-Rl' wherein a cycloalkyl group or a substituted group is substituted. GW-R3, wherein R3 is selected from -G3 - Ci2(tetra)yl or =-C3-C12 cycloalkyl. In another embodiment, x is independently selected from the following aryl groups, substituted aryl groups, and miscellaneous pens.

Heteroaryl and substituted heteroaryl. A —C(0)-NH-Ri’ where Ri is _〇^-“p 里

Ll U- or substituted-(^-Ce alkyl. G is -NHS〇2 - R3 ' where s is selected from -C3-C12 bad or substituted -C 3 - C 1 2 ring In another embodiment, ΑΑ-γγ n, d 甘 tb η is a Λ 〇〇 — R — , , , , , , , , , / / / / / / / / / / / / / / / / / / / / / / / AA ^ « , J-based, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic red, ^ s sub-substituted hetero-, and substituted with 1150-9047-PF; Kai 15 200920394 (2)-NHC(O)-Ci-Ci2-院, -NHC(〇)-C2-C12-alkenyl, -NHC(0)-C2-C12-alkenyl, -NHC(0)_C3 ~c12-cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCCh-L-Cu-alkyl, -NHC〇 2-CrCi2-alkenyl, ~NHC〇2-C2-C12-alkenyl, -NHC〇2-C3-C12-cycloalkyl, -NHC〇2-aryl, -nhc〇2-heteroaryl or NHC〇2 - Heterocyclic base. In another embodiment, X is aryl, heteroaryl, heterocycle,

a cycloalkyl or -C3-Ci2 cycloalkenyl group and substituted with -R, wherein L, is

Ci-Ce alkylene, C2_Ce alkenylene or C2-C (5 alkynylene, R, is a aryl, heteroaryl, heterocyclic, C3-C1Z cycloalkyl or C3_C1Z cycloalkenyl.

In another embodiment, X is an upper group; VIII is _(:(0)__〇, {^, is an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl ring, substituted Heterocycle, _C]-C8 alkyl, -C2_c8 alkenyl, -Ci 1 group, hetero substituted substituted group, substituted -C2_Cs fluorenyl, via ', yl, c, alkyl or substituted C12 cycloalkenyl; and G is - depurinated R" is selected from -c3-c12 cycloalkyl (eg cyclopropyl) or substituted. 3~C!, soil 3 C12 cycloalkyl, -Cs -Ci2 cycloalkenyl, substituted η »!# _L> . V/

Ra ring 于 In another embodiment of the invention, the formula is represented by Formula VI: 1150-9047-pp; 16 200920394

N-N

The definitions of pharmaceutically and x, alone or in combination, are the same as those of the above-mentioned acceptable support or bismuth agent. In one embodiment, X is not a, , ^ is independently selected from the group consisting of substituted aryl, substituted aromatic, anthracene, earth, heterocyclyl, substituted heteroaryl, substituted Heterocycle, C Bu ^ Γ „ 衣, «Alkyl, -C2-C8~, -c2_c8 alkynyl, N-substituted -C!-C8 alkyl, 纟π,,-substituted-CrCs Substituted ~c2 -f alkynyl, -C3-CI2 cycloalkyl, -8 -C3 -c丨2 J sulphate, substituted _C3-CI2 cycloalkyl and substituted ~c3~ "Lu 咕 * 廿 AA p 衣 衣 clothing alkenyl group" wherein each -Cl_c8 alkyl, -c2 8

Alkenyl C2 C8, substituted-Ci-Cs, substituted -c2~C8 alkenyl and substituted -Gb c8 alkynyl independently comprise 0, 丨, 2 or 3 0, S or N heteroatoms. A is selected from the group consisting of c(0)_Rl, _c(0)~0~Ri and -(:(0)-0-1, where l is selected from an aryl group, a substituted aryl group, Heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -CrC8 alkyl, -CrCsalkenyl, _CrC8 alkynyl, substituted -C "C8 alkyl, substituted _C2" C8 dilute, substituted -C2_C8 alkynyl, -Cs-Cn cycloalkyl, cycloalkenyl, substituted -Ca-Cu cycloalkyl or substituted -C3-C12 cycloalkenyl. G can be _ NH-S〇2-NR4R5 or -NHS〇2-R3, wherein R3 is selected from aryl, substituted aryl, heteroaryl, 1150-9047-PF; Kai 17 200920394 substituted heterozygous. a base, a heterocyclic ring, a substituted heterocyclic ring, a -c3-c12 cyclodecene-C3-Ci2 cycloalkenyl group, a fluorenyl group, a C3-C12 alkyl group or a substituted ~c% alkenyl group and R4 and 卩3 Ci2 K5 are each independently selected from hydrogen, -C丨-C8 alkyl, phenyl, -C2~C8, kt_a: λ 2~C8 8 alkynyl, substituted -Cl_C8 alkyl, olefin Substituted, substituted _Γ-Γ** n^'C-C8 _ '2 8 alkynyl, aryl, substituted aryl, hetero# hetero-substituted heteroaryl, heterocyclic, substituted miscellaneous , ϋ戸., -C3_C12 cycloalkenyl, each C4 alkenyl group by a long alkyl group. Substituted or substituted β In another embodiment, X is independently selected from the following: hydrogen, aryl, Substituted aryl, heteroaryl and substituted heteroaryl. C(0) wherein _c-alkyl, dilute, -G2-G8 alkynyl, substituted W group, substituted /alkenyl, substituted C8 alkynyl, _C3_Ci2 cycloalkyl, _C3-8, substituted -C3_Cl2 cycloalkyl or substituted -c3-c12 cycloalkenyl.

Is -NHS〇2-R3, wherein R3 is selected from aryl, substituted aryl, hetero-di-substituted heteroaryl, heterocyclic, substituted heterocyclic ring... C3_Ci2 cycloalkyl, ~C3_Ci2 ring Dilute, substituted cycloalkyl or substituted rc soil, cycloalkenyl. 3 U2 - In another embodiment, X is independently selected from the group consisting of the following aryl group-substituted aryl, heteroaryl and substituted heteroaryl groups. A 4(0)-0-1' is a towel R1 which is a C3_Ci2 cycloalkyl group or a substituted group. - 匕 2 ring radiant base. G is -NHS0 "R3, and the towel R3 is selected from the _C3-Ci2 cycloalkyl group or the substituted -C3-C12 cycloalkyl group. In another embodiment, X is independently selected from the following _ 1150-9047-PF; Kai 18 200920394 • aryl & substituted aryl, heteroaryl and substituted heteroaryl. Artificial () R1 wherein R1 is -Ci-Cs dan or substituted -Ci -Cs alkyl. G is NHS〇2 r3, wherein R3 is selected from a cyclic group or a substituted -C3-Cl2 cycloalkyl group. In another embodiment, A is -(C = 0)-R2, wherein R2 is a substituted _Cl-C8 alkyl group substituted with a (1) aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic ring or a substituted heterocyclic ring, and substituted (2)_NHC(0)-Cl~Cl2-alkyl, -NHC(0)-C2-Ci2-alkenyl, :n-NHC(0)-C2~Cl2-alkenyl, -NHC(0)- C3-C12-cycloalkyl, -NHC(〇)-aryl, -NHC(〇)-heteroaryl, -NHC(〇)-heterocycloalkyl, -N-Cl-alkyl, -NHC〇 2-C2-Ck-alkenyl, -NHC〇2-C2-C丨2-alkenyl, -nhc〇2-c3-c12-cycloalkyl, _NHC〇2_aryl, _NHC〇2 heteroaryl or -NHC〇2-Heterocyclic alkyl. In another embodiment, X is aryl, hetero An aryl group, a heterocyclic ring, a —c3-Cu cycloalkyl group or a —Cs—Cu ring group and substituted with -l, _r', wherein l' is a JC丨-C1 2 3 alkylene group, a C2-C2 alkylene group Or a CrC2 alkynylene group & R, is an aryl group, a heteroaryl group, a heterocyclic ring, a C3_Cl2 cycloalkyl group or a C3~C12 cycloalkenyl group. 1150-9047-PF; Kai 19 1 2 in another example , X is -/vw'; A is -(^(0)-0-1, wherein Ri is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted Heterocycle, -CBuCs alkyl, -Κ4 alkenyl'-C2, C8 alkynyl, 3 substituted-Ci-c8 alkyl, substituted -C2-C8 alkenyl, substituted -〇Cs 4 alkynyl, -CrCucycloalkyl, -CK, 2 cycloalkenyl, substituted Ci2 ring 200920394 alkyl or substituted anthracene ϋ2 cycloalkenyl; and g is -nhs〇2~r3, 苴Select from -c3-Cl2 ring where r3

Gansu soil (such as % propyl) or substituted ~K base. 1/12% alkane Another embodiment of the invention is represented by the formula νπ

N-V compound,

Or a pharmaceutically acceptable salt, singly or prodrug thereof, alone or as an acceptable carrier or combination of excipients, wherein A, QX are the same as defined above: academically. Vapor Embodiment In one embodiment, X is independently selected from the group consisting of a substituted aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a second, and a substituted group. Heterocycle, each C8 top group, each heterocycle, 12-匕8 block _ substituted -C wide C8 base, substituted -C2_Cs thin base, desorbed, alkynyl, -g-Ck ring Alkyl, -C3-Cl2 cycloalkenyl, substituted $C2~Cs alkyl and substituted -C3-C!2 cycloalkenyl, 1 φ 久Γ广12环"肀各-C丨-C8 alkyl,

Alkenyl, -CrC8 alkynyl, substituted _Cl~C8 alkyl, substituted ~Bu G

The alkenyl group and the substituted _C2-C8 alkynyl group independently comprise 〇, 2 G , 1, 2 or 3 heteroatoms substantially from 0, S or N. A is selected from the following - (: (0) - 1? 1, -0 (0) - 0-1? 1 and - (: (0) - bribe - 1? 1, where 1? six r κ The aryl group, heteroaryl group, substituted heteroaryl group, _ soil, _ clothes, deuterated heterocyclic ring, -C〗-Cs sulphate, -C2-Cs dilute group , a C2-r Hr-alkynyl group, a substituted 1150-9047-PF; Kai 20 200920394

Ci Cs alkyl, substituted _[2 -& alkenyl, substituted _[2_08 alkynyl, -CrCu cycloalkyl, -C3_Cu cycloalkenyl, substituted -C3_Ci2 cycloalkyl or substituted -C3-C12 cycloalkenyl. G may be -NH-S〇2-NR4R5 or NHS〇2 R3' wherein I is selected from an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic ring, a substituted heterocyclic ring ,—C3_Ci2 cycloalkyl,

-cs-c, 2 cycloalkenyl, substituted -Cs_Ci2 cycloalkyl or substituted cycloalkenyl, and 1 and Rs are each independently selected from: hydrogen, -Ci_C8 alkyl, _C2-decenyl, -CrG alkynyl, substituted _Cl-Cs alkyl, substituted _C2 -^, substituted -C2-C8 block, aryl, substituted aryl, heteroaryl, substituted Heteroaryl, heterocyclic, substituted heterocyclic, -hi cycloalkyl, -c3-c12 cycloalkenyl, substituted-cycloalkyl or substituted -C 3 -C 1 2 cyclodecyl. In another embodiment, X is independently selected from the group consisting of: hydrogen, aryl, substituted aryl, heteroaryl, and substituted hetero.. -c(o)-o-Rl or - C(8)_NH—Ri' wherein Ri is a C8 alkyl group, a di-c-alkenyl group, a -c2-c8 alkynyl group, a substituted _Cl_C8 alkyl group, a substituted c-alkenyl group, a substituted -C2-C8 alkyne The base, -c3_Cl2 cycloalkyl, _C3_Ci2: a base, a substituted -C3-Cl2 cycloalkyl or a substituted C3_Ci2 cycloalene:. Is -NHS〇2-R3, which is selected from an aryl group, a substituted aryl group: a G-substituted heteroaryl group, a heterocyclic ring, a substituted heterocyclic ring, a _C3_C12 ring ring, a -CrC12 cycloalkene a substituted, substituted _C3_Ci2 cycloalkyl or substituted di-, cycloalkenyl. 3 to C12 In another embodiment, X is independently selected from the group consisting of a substituted aryl group, a heteroaryl group and a substituted heteroaryl group. , Group Wan A is 1150-9047-PF; Kai 21 200920394 -(:(0)-0-1' wherein R^-C3_Ci2 cycloalkyl or substituted _c;s~Ci2 cycloalkyl. G is -NHSOrR3, wherein R3 is selected from - cs-C12 cycloalkyl or substituted -C3-C12 cycloalkyl. In another embodiment, X is independently selected from the group consisting of: aryl, substituted Aryl, heteroaryl and substituted heteroaryl. A is 'wherein R' is -CrC8 alkyl or substituted -Ci-Cs alkyl. G is -NHSOrR3 'where Rs is selected from _C3_Cl2 ring Alkyl or substituted -(:3-(:12-cycloalkyl. In yet another embodiment, A is -(C=〇)-R2, wherein I is a substituted K8 alkyl group, substituted ( 1) aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic ring, and substituted with (2)-NHC(0)-Ci-Cu-alkyl ,—NHC(〇)_C2_Cl2_ dilute group, —NHC(O)-C2-C12-alkenyl, —NHC(0)_C3-C12-cycloalkyl, —NHC(〇)_aryl, —NHC(O) -heteroaryl, -nhc(0)-heterocycloalkyl, -NHCO^c^Cn alkyl, -NHC〇2-C2-Ci2-dilute, -NHC〇2 - C2_Cu_,

-nhc〇2-c3-c12-cycloalkyl, -NHC〇2-aryl, _NHC〇2-heteroaryl or -NHC〇2-heterocycloalkyl. In another embodiment, X is aryl, heteroaryl, heterocyclic, _C3_Ci2 cycloalkyl or -Cs-Ci2 cycloalkenyl, and substituted with _l, -R, wherein l, inflammatory G-C6 Alkyl, CrCe alkenylene or C2-C6 alkynylene and R' is aryl, heteroaryl, heterocyclic, cycloalkyl or C3~C12 cycloalkenyl.

In another embodiment, X

Is -0(0)-0-1 wherein 1150-9047-PF; Ka i 22 200920394 ι is an aryl group, a substituted aryl group, an I 〇 ff _ ^ engraved square group, a substituted heteroaryl group, a bad Substituted heterocyclic ring, —c-square group, hetero-substituted-based group, via:::, each. Dilute, decyl, alkynyl, each Cl2 cycloalkyl C2 c' group, substituted 4c8 _ « hC12 cycloalkenyl, substituted alkyl or substituted -C3_Ci2 ' 3~C12 ring from Γ r thiol; and G is -NHS〇2-R3,1 is selected from -C3-C]2 cycloalkyl (eg, r3 group. -propyl) or substituted -CBuCl2 ring-burning invention In another specific example, N=N is a compound represented by Formula VIII, NV'N, x,

Or a pharmaceutically acceptable salt of the party, a second or a cockroach, alone or plaque--acceptable carrier or combination of excipients, wherein the two-learnings are the same as described in the Examples. In one embodiment, hydrogen is consistently applied, x 4 I „ is selected from the following group, square, substituted aryl group, square, substituted heterogeneous ring , substituted heterocyclic ring, __c ” square group, c«alkyl group, -c2-c8 alkenyl group, _c substituted -C丨-c8 alkyl group, C8 block group, substituted ~C2-C8 alkenyl group a substituted c-alkynyl group, a -C3-Cu cycloalkyl group, a fluorene C3-alkenyl group, a substituted alkyl group, and a substituted p c12% alkenyl group, wherein each _Ci C8 alkyl group, alkenyl group, -C2-C8 alkynyl, sister c2, and, -Ci-C8 alkyl, substituted alkenyl and substituted -(Ve '~c2~U alkynyl independently comprise 0, i, 2 -乂3 1150-9047-PF; Kai 23 200920394 From the hetero atom of 〇, S or N. A is selected from the following = (〇 R Rl\—c(G)—Q~Ri and -c(g - nh'Ri, wherein selected from 1 fresh: substituted aryl, heteroaryl, substituted hetero' fluorenyl, heterocyclic ring, each Γ rt "%, substituted alkyl, -C2_C8 alkenyl , 'C2~C8 alkynylalkyl, substituted C2-C8 alkenyl, substituted _C2~-C3-Cl2 ring a radical K2 ring, a substituted "12 ring =, u C12 % alkenyl. G can be _NH_s 〇 2, such as: wherein R 3 is selected from aryl, substituted aryl, (d) or substituted Heteroaryl, heterocyclic, substituted heterocyclic, -C3-Cu:, 2 ring cycloalkenyl, substituted _C3_Cl2 cycloalkyl or substituted 7, cycloalkenyl, and R4 and Rs are each independently Selected from % dilute, -W, substituted W, thiol, substituted heteroaryl*! substituted aryl, heteroaryl heterocycle, heterocycle, substituted heterocycle, _C3, _c3-c12 cycloalkenyl, via 2 decane-C3-(: 12 ring succinyl, fluorene-substituted fluorenyl) or substituted i. In another embodiment, X ̄ » " _ The group consists of the following: 虱, 方方, substituted aryl, heteroaryl and substituted heteroaromatic AA are -C (8)-Q-HC(0), _R1, where R is W: C.: a dilute group, a - group, a substituted _C1-C8 alkyl group, an 8 decyl group, a substituted yl group, a ring group, a decyl group or a substituted group -c3 - c]2 Cycloalkenyl. Γ is -NHS〇2-R3, wherein r3 is selected from aryl, substituted aryl substituted heteroaryl, hetero 'Substituted heterocyclic ring, prepared C12 ring: II, 1150-9047-PF/Kai 24 200920394 -h-Cu cycloalkenyl, substituted -etc. cycloalkyl or substituted cycloalkenyl. - In the examples, 'x is independently selected from the aryl, heteroaryl and substituted heteroaryl groups substituted by the following constituents. a : a (ο) 〇 l ' wherein l is _c3_Ci2 cycloalkyl or substituted -C3-h = alkyl. G is -NHS〇2_R3, and the oxime is selected from the group consisting of -c3-c!2 cycloalkyl. "In another implementation, x is independently selected from the following group of radicals, 'substituted aryl, heteroaryl and substituted heteroaryl. A is C(〇) NH R, 'where L Is a Ci_C{yl or substituted -O-alkyl. G is NHS〇2-r3, wherein R3 is selected from _C3 -c" cycloalkyl or substituted _(:3-(:12 ring Alkyl. In another embodiment, A is -(〇0)-R2, wherein r2 is substituted -8-8 alkyl, substituted with (1) aryl, substituted aryl, heteroaryl, Substituted heteroaryl, heterocyclic or substituted heterocyclic ring, and substituted with (7)-NHC(〇)-Cl_Cl21 group, -NHC(〇)-C2-C12-alkenyl, leg C(〇) c2-c12 -alkenyl, _NHC(〇)_C3_Ci2—cycloalkyl, —NHc(〇)yl, —NHC(0)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHC〇2_Cl_C丨2- Alkyl, -NHC〇2-C2~C12-alkenyl, _NHC〇2_C2_Ci2_ alkenyl, NHC〇2 G-Cu-i singyl, -NHC〇2-aryl, jHC〇2_heteroaryl- NHCCh-heterocycloalkyl. In another embodiment, X is aryl, heteroaryl, heterocycle, fluorenylcycloalkyl or ~C3-Cl2 cycloalkenyl, and substituted with -L, R, wherein L, Ci-匕alkylene, (: 2_(:6 alkenylene or C2_Ce alkynylene and r' is aryl, 1150-9〇47~ργ. PF; Kai 25 200920394 heteroaryl, heterocyclic, (: 3_(: 12 cycloalkyl or (: 3-(: 12 cycloalkenyl. 0

In yet another embodiment, X is 丄-; A is -C(0)-Ο-Ri, wherein I is aryl, substituted aryl, heteroaryl 'substituted heteroaryl' heterocycle, Substituted heterocyclic ring, -Cl-C8 alkyl group, -C2-C8 dilute group, -C2-C8 fast group, substituted -CrCs alkyl group, substituted -C2-Cs alkenyl group, substituted -C2 -C8 alkynyl, -(: 3-(:12-cycloalkyl, -C3-C12 cycloalkenyl, substituted-(:3-(:12-cycloalkyl or substituted-C3-C12 cycloalkenyl) And G is -NHS〇2-R3, wherein R3 is selected from -c3-C12 cycloalkyl (eg cyclopropyl) or substituted -c3-C12 cycloalkyl. Representative compounds of the invention, including but not Limited to compounds according to formula IX below (Table 1):

Q

(IX) Table 1

Example # AQG 15 person / AV 1150-9047-PF/Kai 26 200920394 16 ΛΛ _/°~· V 17 ΛΛ ΝγΝ 'Ά 18 person / jrr N 19 person again / / ίϊν 20 person / ^τ〇 ΝγΝ 21 乂Λ / 7CF3 ΝγΝ Ϋν 22 丫23 ρ- ν 24 乂Λ, ρ- ΝΥΝ 25 person / νΝ 1150-9047-PF/Kai 27 200920394 26 person / li N / "ΡΝ-Η 1 27 people again / > v /X- Η 1 28 people / NYN Ά Η 1 29 people / v /X- Η 1 30 people / Ν Ν Ν / "ΡΝ-Η 1 31 people again / ν 32 乂Λ / jrr ν* ΊΓ Ν 43⁄4 33 person / Ν γΝ 'Κ〇34 person / νΝ 43⁄4 1150-9047-PF; Kai 28 200920394 35 too / v /}3⁄4 36 CX〇A/ β~ V 37 <λ0 again / V 38 0^1 0 4 people / ΝγΝ /^ν 39 Ρ- v 40 MeO^C^0"^ ρ- ν 41 λΛ ρ- γ /ί¥ν 42 〇人V 43 vjy ν 1150-9047-PF;Kai 29 200920394

44 〇N /Ά 45 ΝγΝ /Ά 46 CXA v AS5% 47 NYN /Ά 48 av 49 V/ ?- NYN /, & 50 αΛ :β~ v 51 , / / P~~ Y 'Ά 52 (// ^p- VN 1150— 9〇4 7-PFVKai 30 200920394 53 〇f~n人/ _p- V 1 54 a1, p- V 1 55 <X/ p- V 1 Ϋν 56 p N^lT 57 < ^Λ/ p- V 1 58 A Me _p- V \ 59 cA p- !L 'ϋ 60 0 Me-^yV ΗΝΛΜβ V 1 61 Me p- V 1 1150-9047-PF; Kai 31 200920394 62 HN-^ ΝΥΝ 63 A _/°~~ ν 64 ΝγΝ 65 Ν 66 N>rN 67 CX0 again / ¥ ΝγΝ Η Ο^0Η3 68 CX. Also / Ρ- ΝγΝ α^λ Η 69 CX0 / / ΝΥΝ Λί51> 70 <λ Also / ΝγΝ Η UCH3 1150-9047-PF; Kai 32 200920394

71 CX〇A/ ΝΥΝ 5:3⁄4 ^^co2h 72 〇Jy N>rN och3 73 CX. Also / ΝγΝ gas 3 74 C^〇A/ ρ- ΝγΝ 75 CX. Also / ΝγΝ 76 OJy ΝγΝ aXf3 77 CX. Also / :β~ ΝγΝ a«V, 78 <λ. Also / Ρ~ ΝγΝ 43⁄4 79 CX. Also / ρ~ ΝγΝ aXh2 H 1150-9047~PF; Kai 33 200920394

80 CX. Also / P~ ΝγΝ A^x, 81 OJy γ Ai"X7F 82 CX. Also / _Ρ~ ΝγΝ /, xa Η H 83 (λ.又 / Ν Η H 84 〇^〇A/ ρ- ΝγΝ 人 XS Η H 85 CX. Also / _y°- VN /, Xf3 H 86 (λ. / ρ- ΝγΝ A^cl 87 CX〇A/ y VN 43⁄4 88 <λ. Also / p- v AX, H 1150-9047-PF; Kai 34 200920394 89 CX0 again / ΝγΝ A^x, 90 CX0 again / N a?Vf 91 CX. Also / p- v /, χα Η Η 92 <λ. / /p-VN , Α力Η Η 93 CX0 again / v ο 0 ΗΝ-Ν% WvN Η Η 94 CX / / NYN /}3⁄4 Ν\ 96 ΛΛ 0°' NN ΝγΝ 98 people again / ^7 100 people again / Ν γ Ν 1150-9047-PF; Kai 35 200920394 101 CX0 again / 0., NN Ν γ Ν /V Yv 102 0 °' NN ΝγΝ 103 °0 0., NN ΝγΝ 104. 0 0., NN ΝγΝ 105. (〇0°' NN ΝγΝ 107 ΛΛ Cl V 108 N^TN /Ά 110 people again / > v 111 Cl. / > N 'Ά 1150-9047-PF; Kai 36 200920394 People again / --~~~-- V 1 — \ 人又/ -----_____ —茨ν¥ν 1 ---- α. / -----___ J % — People again / -- ΝγΝ —------ / 0兮0 /γ~ α. Also / ----. > ΝγΝ ---- --- - 1 χ^7 证禾予扭风视,巴枯丰A compound of the formula or a pharmaceutically acceptable salt thereof, vinegar, or a prodrug. 113 114 116 117 119 120 l. 121 Bean 2 Inventive Illustrator, the pharmaceutical composition of the present invention further includes other anti-HCV agents. Examples of agents, including, but not limited to, interferons (such as '" interferon interferon... agonist interferon ((10) Nate mterfe (10)), long-acting interferon, or interference with albumin or other junctions 1150-9047- PF; Kai 37 200920394 *. 素), ribavarin and adamantine. For further details see S. Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov., 1, 867-881 (2002); WO 00/59929 (2000); WO 99/07733 (1999); WO 00/09543 (2000); WO 99/50230 (1999) US Pat. No. 5,861,297 (1,999); and US 2002/0037998 (2002), incorporated herein by reference. In another embodiment, the pharmaceutical composition of the invention further comprises other HCV protease inhibitors. In another embodiment, the pharmaceutical composition of the present invention further comprises one or more inhibitors of other targets in the life history of HCV, including, but not limited to, helicase, polymerase, metalloproteinase, and internal ribosome entry sites. (IRES). In another embodiment, the pharmaceutical composition of the present invention further comprises other antiviral, antibacterial, antifungal or anticancer agents or immunomodulators or other therapeutic agents. In another embodiment, the invention includes a method of treating a subject in need of treatment for a hepatitis C infection, the subject being administered an anti-HCV virus effective amount of a pharmaceutical compound of the invention, or a pharmaceutically acceptable salt thereof, or Precursor. In another embodiment, the invention includes a method of treating an individual infected with a type C hepatitis in need of treatment, the subject being administered an anti-viral effective amount or an inhibitory amount of a pharmaceutical composition of the invention. In another embodiment, the invention includes a 1150-9047-PF for treating a biological sample; and the method of Kai 38 200920394 is by contacting the biological sample with a compound of the invention. Still another aspect of the invention is the treatment of any of the compounds shown herein, using any of the synthetic methods indicated herein. Definitions The following is a list of the owed money used to describe the present invention. The definitions of these terms apply to this specification and the scope of the patent application, except in the case of a particular product or a part of a larger group. As used herein, the term "CrCe alkyl" or "(^-(:8; | 疋I"" means a saturated straight or branched hydrocarbon containing a group of 6 or 8 carbon atoms. -(: Examples of 6-alkyl radicals, including but not limited to: methyl, propyl, isopropyl m-tributyl, neopentyl, hexyl, and Ci-Cs alkyl radicals, including But not limited to: Jiameimei: base propyl, " base, heart butyl, neopentyl, positive V base: G

The radical, octyl radical D, by means of "C, yl" or "C2, yl", represents a monovalent group derived from the hydrocarbon moiety of the a I-wind atom, and each of the two groups contains 2 to 6 carbon atoms. Or 2 to 8 carbon atoms, and having; v - a slave-carbon double bond. Alkenyl groups include, but are not limited to, alkenyl, butenyl, methyl 1, butyridyl, alkenyl, and propyl. The term "C2 - 1 octyl, etc., W disgusting" or 1 C2-C8 alkyne is used herein. The chemist removes the single-dance; the g-work π, the soil"' represents one of the hydrocarbons derived from the hydrocarbon moiety. The hydrocarbon moiety contains -... carbon:: Γ::: removes a single hydrogen atom It is a carbon-carbon triple bond. Substituents=, including but not limited to, for example, an alkenyl group, a propanyl group, a butyne: block 1150-9047-PF; Kai 39 200920394 heptynyl, octynyl, and the like. Terms used here Γ C3 — c

J represents a monovalent group by removing a single hydrogenogen to a base or a C3 - Cl2 - cycloalkyl compound, a/a monocyclic or polycyclic saturated carbocyclic ring or 3 to 12 carbon atoms. c3_C8_ Atomic ring and its s _ children's examples, including but not limited to: propyl, butyl, cyclopentyl, pentacene, cyclopentyl, and cyclooctyl. and c3-c丨2-ring Examples of alkyl groups, inclusions, and production of A, are not limited to · cyclopropyl, cyclobutyl, %: pentyl, oxime, double ring "? _.] heptyl and bicyclo [2.2.2]辛基. The term "c3~r _ 〇8 % alkenyl" or "C3-CI2-cycloalkenyl" as used herein, means having at least one carbon-carbon by removing a single hydroquinone early π ligament. The double bond is derived from a monovalent group of a single ring or a polycyclic saturated saturating spear. The carbocyclic ring has 3 to 8 carbons and 7 D times of 妷 atoms. Examples of C3-C8-cycloalkenyl include, but are not limited to, earn & π # a ^(tetra)yl, cyclobutenyl, cyclopentenyl, %hexenyl, cycloheptenyl, ring-clothing And examples of Cs-Cu-cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutene, oxime-salt, succinyl, butenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, ring Octenyl and the like. As used herein, the term "aryl J' refers to a mono- or polycyclic carbocyclic ring," which has one or two aromatic rings, including but not limited to phenyl, zeoliyl, tetradecylnaphthyl, anthracene.满基(五)时川, 茚基 (indenyi), etc. The term "arylalkyl" as used herein means -CrC3 alkyl or

The Cl- & alkyl residue is attached to an aryl ring. Examples include, but are not limited to, benzyl, phenethyl and the like. The term "heteroaryl" as used herein, refers to a monocyclic, bicyclic or trihydrazone radical or ring having 5 to iq ring atoms, one of which is H50-9047-PF; Kai 40 200920394 Atoms are selected, for example, from ς, . . . S ^ N, G, 1 or 2 ring atoms are additional 'grounds from, for example, S, 0, and N; and the other ring atoms are carbon. Heteroaryl groups include, but are not limited to, hydrazino groups, thiol groups, thiophene groups, stilbenyl groups, snail groups, oxime groups, thiol groups, isoindolyl groups, thiazolazole groups, Oxadiazolyl, thienyl, furyl, quinolyl, isoquinolyl, phenylidene, stupid and sulfhydryl, hydrazine, etc. The term used herein is a " The use of π-heteroarylalkyl" means that one (: 丨-^ alkyl or (iv)-based residue is attached to a heteroaryl ring. Examples include, but are not limited to, pyridylmethyl, pyrimidinyl phenyl Use, means a non-aromatic 3-, 4- as used herein, the terms "heterocycle" and "heterocyclic alkyl", which may be alternated or a 7-membered ring, or a di- or bi-cyclic group. The fused system, and the middle (·) TU ) each contains 1 to 3 heteroatoms, independently selected from oxygen, sulfur and nitrogen; m J Valley 5 shellfish has 〇 to 1 double bond, and each 6 members The ring has 〇 to 2 double bonds. (彳彳·, — > a 1U and a bond, (111) the nitrogen and sulfur heteroatoms can be oxidized at will; (iv) the aza-purine Tertiary, and (iv) any of the above rings may be fused - laughs iS2 t as an example of a typical heterocycloalkyl group, including but not limited to: [1,3] dioxane, steroidal pirazolidine, pyrazolinyl, pyridyl Oxazide, 0, 0, σ, 疋, 虱, pyridyl, piperidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, g ^ . ^ κ 卜 #坐定基,异0塞. sitbit and tetrahydrofuranyl. The term "binding" in this context means replacing 1, 2 or 3 or #容 on the original atom. The atom is a substituent, including but not limited to: -F, -C1, -Br, -I, -oh, scorpion scorpion, _ _, 保 s 蔓 羟基 羟基, -N 〇 2 -CN, - leg 2, protected amine group, -NH-C]-rp, «. (4) U Ci2-alkyl, - title - C2_C〗 2_alkenyl, 1150-9047-PF; Kai 41 200920394 ' NH-C2-C12-alkenyl, _NH_C3_Ci2-cycloalkyl, _NH-aryl, _NH heteroaryl, -NH-heterocycloalkyl, -dialkylamino,-diarylamino, -di Aryl base, -0~Cl-Cl2-alkyl, -O-C2-C12-alkenyl, -〇-C2-Cl2-alkenyl, -0-C3-Cl2-cycloalkyl, _〇_ Aryl Heteroaryl, heterocycloalkyl, -CXOXi-Cw-alkyl, -c(0)-c2-c12-alkenyl, -C(0)-C2-Ci2-alkenyl, -c(0)-Cs -Cu_cycloalkyl, _c(0)-aryl, -c(〇)-heteroaryl, -c(o)-heterocycloalkyl, -(3)NH2, -CONH_Ci-Ci2-alkyl, -C0NH C2_Ci2_ Alkenyl, -CONH-C2-C12-alkenyl, -CONH-C3-Ci2-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -ocOz-CrCu- Alkyl, -0C02-C2-C12-alkenyl, -〇C〇2-C2-Cl2-alkenyl, -〇C〇2-C3-C12-cycloalkyl, -〇C〇2-aryl, - 〇C〇2-heteroaryl, -〇C〇2-heterocyclic alkyl, -0C0NH2, -0CONH-Ci-C12-alkyl, -〇c〇NH-C2-C12-alkenyl, -OCONH-C2 -C12-alkenyl, -OCONH-C3-C12-cycloalkyl,-0CONH-aryl, -0CONH-heteroaryl, -0CONH-heterocycloalkyl, -NHCCOhCrC-alkyl, -NHC(0) -C2-C12-alkenyl, -NHC(0)-C2-C12-alkenyl, /, -NH with 0) -C3 -Cl2_cycloalkyl, -NHC(O)-aryl, -NHC(O )-heteroaryl, -NHC(O)-heterocycloalkyl, -NHC〇2-C!-C!2-alkyl, -NHC〇2-C2-C12-alkenyl, -NHC〇2-C2 -C12-alkenyl, -NHCOrC3-C12-cycloalkyl, -NHC〇2-aryl, -NHCOrheteroaryl, -NHC〇2-heterocycle , -NHC(0)NH2, -NHC(0)NH-CrCu-alkyl, -NHC(0)NH-C2-C12-alkenyl, -NHC(0)NH-C2-C12-alkenyl, - NHC(0)NH-C3-C12-cycloalkyl, -NHC(0)NH-aryl, -NHC(0)NH-heteroaryl, -NHC(0)NH-heterocyclic alkyl, NHiXS^m '-NHCXSMH-Ci-Cu-alkyl, -NHC(S)NH-C2-C12-alkenyl, -NHC(S)NH-C2-C12-alkenyl, -NHC(S)NH-C3-C12- Cycloalkyl, 1150-9047-PF; Kai 42 200920394: -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC ( NH)NH2, -NHCXNtONH-G-Cu-alkyl, -NHC(NH)NH-C2-C12-alkenyl, -NHC(NH)NH-C2-C12-sweet, -NHC(NH)NH-C3 -C12-cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-Ci-Ci2- Alkyl, -NHC(NH)-C2-C丨2-alkenyl, -NHC(NH)-C2-C12-alkenyl, -NHC(NH)-C3-C12-cycloalkyl, -NHC(NH) -aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, .... -C(NH)NH-CrCu-alkyl, -C(NH)NH-C2- C12-alkenyl, -C(NH)NH-C2-Ci2-alkenyl, -C(NH)NH-C3-C12-cycloalkyl, -C(NH)NH-aryl, -C(NH)NH -heteroaryl, -C(NH)NH-heterocycloalkyl, -S(0)-Ci-Ci2-alkyl, _s(〇)-C2-Ci2-alkenyl, _S(0) -C2~Ci2-alkenyl, -S(0)-C3-Ci2 -cycloalkyl, -s(o)-aryl, _s(o)-heteroaryl, -S(0)-heterocyclic alkyl -SO2NH2, -SO2NH-C1-C12-calcin, -SO2NH-C2-C12-alkenyl, -S〇2NH-C2-Ci2-alkenyl, -SChNH~C3-C12-f cycloalkyl, -S〇 2NH-aryl, -s〇2NH-heteroaryl, -S〇2NH-heterocycloalkyl, -NHS〇2-Ci-Ci2-cathylene, -NHSO2-C2-C12-alkenyl, -NHS〇2 ~c2-Ci2-alkenyl, -NHSOrC3-c^-cycloalkyl, -NHS〇2-aryl, -NHS〇2-heteroaryl, -NHS02-heterocycloalkyl, -CH2NH2, _CH2S〇2CH3, —aryl, arylalkyl, —heteroaryl, —heteroarylalkyl, —heterocycloalkyl,吖3-C12-cycloalkyl, polyalkoxyalkyl, polyalkoxy, —oxygen Methoxy, -methoxyethoxyethoxy, -SH, -S-CrCu-alkyl, -S-c2-c12-alkenyl, -s~c2-C12-alkenyl, -S-Cs-Cu -cycloalkyl, -s_aryl, -s_heteroaryl, ~s-heterocycloalkyl, methylthiomethyl or -L, -R', wherein L' is Ci-C6 alkylene, 1150-9047-PF; Kai 43 200920394 C2-Ce alkenylene or CS-C6 alkynylene and R, aryl 'heteroaryl, heterocyclic, Cs-Cu cycloalkyl or Cs-Cu cycloalkenyl. It is to be understood that an aryl group, a heteroaryl group, an alkyl group or the like can be further substituted. In some cases, each substituent in the substituted structure may be additionally optionally substituted with i or more groups, each group being independently selected from: -F, _C1, -Br, -1... 〇H, _N〇2, _CN or ~NH2. Any of the aryl, substituted aryl, heteroaryl and substituted heteroaryl groups described herein may be any aryl group in accordance with the present invention. The aryl group may be substituted or unsubstituted. It is to be understood that any of the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl structures described herein may 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, halogen atoms, 1, nitrogen or other atoms, and contemplates one or more unsaturated units, such as Key and / or three keys. The aliphatic group may be linear, branched or cyclic, preferably containing from about i to about 24 stone anodic atoms, more typically from about j to about 丄2 carbon atoms. In addition to the aliphatic hydrocarbon group, the aliphatic group contains, for example, a polyalkoxyalkyl group such as a polyalkylene glycol, a polyamine, and a polyimine. These aliphatic groups can be further substituted. It is 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. Examples include but not (d): cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2. U heptyl and bicyclo [2.2.2] octyl. These alicyclic groups can be substituted into 1150-9047-PF; Kai 44 200920394 - one step substituted. It is apparent that in each of the specific examples of the invention, the substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl 'heteroaryl group Alkyl, and heterocycloalkyl, are intended to be monovalent or divalent. Thus, alkylene, alkenylene and alkynylene, cycloalkylene, cycloalkenylene, cycloalkynylene, arylalkylene, heteroarylalkylene and heterocycloalkylene groups, It is included in the above definition and can be applied to provide the appropriate valence of the structural formula herein. r : The term "(iv) activating group" as used herein refers to a chemical structure that is unstable, which is known in the art to activate a hydroxyl group to liberate during a synthesis step, such as a substitution or elimination reaction. Examples of hydroxyl activating groups include, but are not limited to, mesylate, tosylate, tnfluoromethanesuHonate, potential nitrobenzoate, phosphonate, and the like. As used herein, the term "activated hydroxy" means a hydroxy-activated group (including, for example, mesylate, tosylate, trifluormethanesulfonate, sternyl) Benzoate, phosphonate, activated radical. As used herein, the term "protected hydroxy" refers to a hydroxy protecting group as defined below, including, for example, benzamidine, ethyl-trimethyl decane. Alkyl group, triethyl decyl group, methoxymethyl group, protected hydroxy group. The terms "halogen" and "halogen" as used herein mean an atom selected from the group consisting of fluorine, chlorine, bromine and iodine. The compound contains one or more asymmetric centers, thus producing 1150-9047-PF; Kai 45 200920394 enantiomers, diastereomers, and other stereoisomeric forms , defined by absolute stereochemistry as (R)- or (S)-, or an amino acid, defined as (D)- or (L)-. The present invention is intended to include all such possible isomers, as well as Spiral and optically pure forms. Optical isomers can be made by their respective The optically active precursor is prepared by the above procedure or by resolution of the racemic mixture. This analysis can be carried out in the presence of an analytical agent by chromatography or a combination of techniques known to those skilled in the art. Implementation. About analysis

Jacques, et al., Enanti〇mers, Racemates and Res〇lutions (J〇hn WUey & s〇ns, 1981). When the compounds described herein contain olefinic double bonds, other sites of unsaturation or other geometric asymmetry, and unless otherwise specified, means that the compounds comprise E and z geometries, structures or cis and trans isomers. . Similarly, all tautomeric forms are also included. The configuration of any carbon-carbon double bond shown herein is convenient, unless it is recited herein, and is not intended to specify a particular structure, therefore, any carbon-carbon double bond or carbon herein. - A hetero atom double bond is depicted as a trans-'may be cis, and 4, or a mixture of the two in any ratio. The term "individual" as used herein, means - mammal. Thus, - individual 'for example, for example, a dog, a cat, a horse, a cow, a pig, a guinea pig, and the like. Preferably, the individual is a human. When the individual is a human, this may refer to a patient. The term "pharmaceutically acceptable salt" as used herein is used in the context of medical judgment and is suitable for use in human or lower-eating tissues without adverse toxicity or irritation. Allergic reaction 彳 1150-9047-pf; Kai 46 200920394 and the reasonable benefit/risk ratio is proportional. Pharmaceutically acceptable salts are well known to those skilled in the art.

At T.H. Greene and P.G.m. Wuts, Pr〇tecUve Gr〇ups in 1, John Wiley & Sons, New, including. oxy-based groups, 4 - nitrate

Organic Synthesis, 3rd edition York (1 999). Examples of hydroxy protecting groups, mercaptobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, second butoxycarbonyl, isopropoxy, diphenyl Methoxycarbonyl, 2, 2, 2-dichloroethoxycarbonyl, 2-(trimethylsulfonyl)ethoxycarbonyl, 2-mercaptooxycarbonyl, allyloxycarbonyl, ethylidene , formazan, chloroethyl, trifluoroethyl, methoxyethyl, phenoxyethyl, benzhydryl, decyl, tert-butyl, 2, 2, 2-three Glycol, 2-trimethyldecylethyl, 1,1-dimercapto-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl, p-methoxybenzyl Diphenylmethyl, triphenylmethyl (trityl), tetrahydrofuranyl, decyloxymethyl, decylthiomethyl, benzyloxymethyl, 2, 2, 2-triethoxyethoxy Base group, 2-(trimethyldecyl)ethoxymethyl, sulfonyl, p-toluenesulfonyl, trimethyldecyl, triethyltin, triisopropyldecyl, etc. . In the present invention, the preferred hydroxy protecting group is: an ethylene-based group (Ac or -c(〇)CH3), a benzamidine group (Bz or -C(0)C6H5), and a sulfhydryl group (TMS or - Si(CH3)3) ° Berge et al. detail pharmaceutically acceptable salts in j. Pharmaceutical Sciences, 66: 1150-9047-PF; Kai 47 200920394 • 1 1 9 (1 977). The phosphonium salt can be prepared in situ when the compound of the present invention is finally isolated and purified, and 4 is separately prepared by reacting the free test with an organic acid of hydrazine. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, salts of amine groups, and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and peroxyacids, or organic acids, for example : Acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid addition preparation, or using other methods in the art, such as ion father preparation. Other pharmaceutically acceptable salts, including but not limited to: hexanoate, alginate, ascorbate, aspartate (salt, benzoate, benzoate, hydrogen sulphate, sulphonate, butyl Acid salt, camphorate, camphor sulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, Glucoheptanoate, glycerol sulphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, lactate, lauric acid Salt, laurate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinic acid, nitrate, oleate, oxalate, palm Acid salt, pamoate, acid salt, persulphate, lut-3-phenylpropionate, phosphate, picrate, trimethylacetate, propionate, stearate, Succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, eleven carbonate, pentane salt, etc. Representative alkali or alkaline earth metal salts, including: sodium, lithium, potassium, , magnesium, etc. Other pharmaceutically acceptable salts, including the appropriate use of counter ions such as vapors, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl groups having 1 to 6 carbon atoms, sulphur Acid-free and aryl sulfonate, forming non-toxic ammonium, quaternary ammonium and amine cations. 1150-9047-PF; Kai 48 200920394 The term "amino protecting group" as used herein refers to an unstable chemical structure. It is known in the art to protect an amine group from undesired reactions during the synthesis. After the synthesis process, the amine protecting groups described herein can be selectively removed. The base protecting group is generally described in Τ·Η·Greene and PGm· Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,

Mew Y〇rk (1 999). Examples of the amine protecting group include, but are not limited to, a third butoxycarbonyl group, a 9-fluorenyloxycarbonyl group, a benzyloxycarbonyl group and the like. As used herein, the term "pharmaceutically acceptable ester" means an ester which is hydrolyzed in vivo and which comprises an ester which readily disintegrates in the human body and leaves the parent compound or a salt thereof. Suitable esters include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, especially alkanoic acids, enoic acids, naphthenic acids and alkanoic acids, wherein each alkyl or alkenyl structure is preferably no more than 6 One carbon atom. Examples of specific esters include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, and ethyl succinate. The term "pharmaceutically acceptable pre-drug" as used herein means that the prodrugs of the present invention are within the scope of adequate medical judgment and are suitable for tissue contact of humans or lower animals, without Unfavorable toxicity, irritation, allergic reaction, etc., and the reasonable benefit/risk ratio is commensurate, and is effective for its use, and when possible, the "precursor" used by the two ions of the compound of the present invention, It means that it can be converted into a form by metabolism (eg hydrolysis) in the body! The compound. Many forms of pre-drugs are known in the art, for example: discussed in Bundgaard, (ed.), Design 〇f Prodrug, Elsevier (1985); Widder, et al. (ed.)^

1150-9047-PF; Kai 4Q 200920394

Methods in Enzymology, vol. 4, Academic Press (1 985); Krogsgaard-Larsen, eta 1., (ed), "Design and Application of Prodrug, Textbook of Drug Design and Development, Chapter 5 '113-191 (1991 Bundgaard, et al., Journal of Drug De1iver Reviews, 8:1-38 (1992);

Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrug as Novel Drug Delivery System, American Chemical

Society (1 975); and Bernard Testa & Joachimmayer,

Hydro lysis In Drug And Prodrugmetabolism: Chemistry, Biochemistry And Enzymology, " John Wiley and Sons, Ltd. (2002) The term "mercapto" as used herein, includes residues derived from an acid, including but not limited to Tannic acid, carbamate 'carbonic acid, acid and acid. Examples include aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl, aromatic

Groups of sulfhydryl groups, aliphatic sulfinyl groups, aromatic phosphates and aliphatic phosphates. Examples of the aliphatic carbonyl group include, but are not limited to, an ethyl fluorenyl group, a propyl fluorenyl group, a 2-fluoroethyl fluorenyl group, a butyl group, a 2-hydroxyethyl group, and the like. The term "aprotic solvent" as used herein refers to a solvent that is relatively inert to proton activity, and τ# hl is not a proton donor. Examples include, but are not limited to, hydrocarbons, such as ρ ρ 院 院 and 甲本, for example: halogenated hydrocarbons, for example: 乳乳院, 二气 ",)·*· /a ^ G rolling of alkane, imitation, etc. Heterocyclic compounds, for example, tetrahydrofuran and N-methyl η-pironidone and ethers, such as diethyl ether, dimethoxy fluorenyl, are well known to those skilled in the art. Pairs 1150-9047-PF; Kai 50 200920394 • For those skilled in the art, preferred solvents for specific compounds and reaction conditions, such as such solubility, reagent reactivity, and preferred reaction range Or mixtures are readily apparent. Further discussion of aprotic solvents can be found in organic chemistry textbooks or in specific monographs, such as. Organic Solvents Physical Properties and methods of Purification, 4th ed., edited by John A. Riddick et Al. , V〇l. II, in the Techniques of

Chemistry Series, John Wiley & 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 decyl alcohol, ethanol, propanol, isopropanol, butanol, and third. Butanol and the like. Compounds such as & are well known to those skilled in the art, and to those skilled in the art, for specific compounds and reaction conditions, such as such solubility, reagent reactivity, and preferred reaction range Preferably, each of the preferred solvents or mixtures is readily apparent. Further discussion of proton-solving solvents can be found (in organic chemistry textbooks or on specific monographs) eg 〇rganic

Solvents Physical Properties and methods of

Purification, 4th ed., edited by John A. Riddick V〇l. II, in the Techniques of Chemistry Series, John Wi1ey & Sons, NY, 1986. 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 is sufficiently stable to permit manufacture and can be maintained for a sufficient period of time for the use described herein (for example, for a therapeutic or prophylactic administration). It has 1150-9047-PF; Kai 51 200920394 - 〇3, used. The synthesized compound can be isolated from the reaction mixture and further purified by, for example, column chromatography, high pressure liquid chromatography or recrystallization. Those skilled in the art will appreciate that other methods of synthesizing the structural compounds herein will be apparent to those of ordinary skill in the art. In addition, the various synthetic steps can be carried out in an alternate order or order to yield the desired compound. Useful synthetic chemical conversion and sulfhydryl-based methods for the synthesis of the compounds described herein (protection and deprotection are well known to those skilled in the art including, for example, described in R. Larock, Comprehensi ve Organic Transformations, VCH Publishers ( 1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. ieser andm. Fieser, Fieser and Fieser, s Reagents for Organic Synthesis, John Wiley and Sons ( 1994); and L. quette, ed., Encyclopedia of Reagents for Organic

Synthesis, John Wiley and Sons (1995). The compounds of the invention may be modified by the addition of appropriate functional groups to enhance selective biological properties. 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 administration, increased solubility so that injection can be administered by injection. Change metabolism and change excretion rate. Pharmaceutical Composition The pharmaceutical composition of the present invention comprises a therapeutically effective amount of a compound of the invention, and one or more pharmaceutically acceptable carriers or forms of a formulation 1150-9047-PF; Kai 52 200920394 :. The term "pharmaceutically acceptable carrier or ageing agent" as used herein means - non-toxic, inert solid, semi-solid or liquid-filled material, or any type of formulation. Some examples of pharmaceutically acceptable carriers are sugars such as lactose, glucose and yanthanum: starches such as corn starch and horse yam starch; cellulose and resurrection organisms, for example, methicone , ethyl cellulose and cellulose acetate brewing: finalized xanthine gum · malt, · gelatin; talc; excipients, for example: and suppositories n such as peanut oil, cottonseed oil m H ^ oyster sauce, corn and yellow Soybean oil; glycol, such as propylene glycol; vinegar, such as oleic acid ethyl vinegar and lauric acid; rouge; buffering agent 'such as magnesium hydroxide and aluminum hydroxide; alginic acid; no pyrogen water; isotonic saline; Grignard solution; and acid buffer solution, and other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate 'and coloring agents, release film agents' sweeteners, flavors and The judgment of the aromatic medicinal agent, the preservative and the anti-oxidant diagnosing formula can also be present in the present composition. The composition of the present invention may be administered orally, rectally, parenterally, intracisternally, vaginally, intraperitoneally, topically (for example, powder, ointment or drops), sputum or oral or Nasal spray. 77 The pharmaceutical composition of the invention may be administered orally or parenterally via oral, parenteral, inhalation spray, topical, rectal, nasal, warp, transvaginal, or via an implanted reservoir. Cast. The pharmacy of the present invention, and the product' may comprise any conventionally non-toxic pharmaceutically acceptable carrier, adjuvant (10) brain (4) or carrier. In some cases, the pH of the formulation can be adjusted with a pharmaceutically acceptable acid, test or buffer to enhance the stability of the formulation of the formulation compound or 1150-9047-PF; Kai 53 200920394. The terminology used herein is not oral (parenteral), including: subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, synovial fluid, non-connected sternum, intraorbital, intracranial, and Internal injection or perfusion techniques. Microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents conventional in the art, such as: water or other solvents, solubilizing agents, and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl Alcohol, benzyl benzoate, propylene glycol,! 3 - Butanediol, dimethyl decylamine, oil (especially, cottonseed oil, peanut oil, corn oil, germ oil, eucalyptus oil, castor oil and oil), glycerin, tetrahydrofurfuryl alcohol /: polyethylene Alcohol and sorbitan fatty acid vinegar, and mixtures thereof. In addition to the diluent, the oral composition may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweetening agents, flavoring agents, and flavoring agents. Preparations for injection, for example, sterile water for injection or liquid, can be used according to the known techniques, in formula or wet (four) and suspending agent to prepare the main injection preparation, which can be - sterile injection solution, ... attack Or liquefied liquid, soluble in non-toxic non-mouth solvents, for example: for! 3 "In addition to the diluent or solvent, a solution of p can be used in acceptable carriers and sodium solutions. In addition, helmet - + m - U. s. p• and special gasification for this purpose, The oil is used as a solvent or a suspension medium. 'According to various brands of &, 丄^, diglyceride. In addition, the monthly H 疋 oil 'includes β into a single or use. 曰-夂 such as 'oleic acid 'Used in the preparation of injection H50-9047-pF; Kai 54 200920394 The formulation for injection, or the sterilization of the bacteria can not pass through the membrane and the sterile solid composition can be used:: Solid composition order In the case of sterilization, the in vivo dissolution or dispersion is carried out by using sterile water or other sterile injectable media: drug action, and it is often desirable to slow down the subcutaneous or intramuscular injection for the day. This purpose can be achieved by using water in poor solubility. The crystallization is achieved by a liquid suspension of the bismuth material. The rate of absorption of the drug depends on the rate and is related to the crystal size and crystalline form. Or dissolve or suspend the drug in an oily carrier to achieve a delay in the absorption of the drug. The form of the injectable stock can be achieved by using the microcapsule matrix of the drug as a bioactive drug, such as polylactic acid-polyglycolic acid (p〇1ylactlde i). Depending on the drug, the “ratio of the substance, and the nature of the particular polymer, the release rate of the drug can be controlled. Examples of other biodegradable polymers include poly(raw vinegar) anhydrate.) It can be prepared by capturing a drug, a body-compatible microlipid or a microemulsion. A composition for rectal or vaginal administration, preferably a test, which can be combined with the compound of the present invention by Suitable non-irritating excipients or supports: For example: cocoa butter, polyethylene glycol or suppository sputum is prepared by mixing. The suppository worm is solid at room temperature but is liquid at body temperature, so it can be dissolved in the rectum or vaginal. A solid dosage form for oral administration, comprising: a capsule, a lozenge, a pill, a powder, and a granule. In such a solid dosage form, the active compound is mixed to i an inert pharmaceutically acceptable ingredient or The carrier, for example, sodium sulphate H50-9047-PF; Kai 55 200920394 or sulphonate and/or: a) filler or extender such as starch, lactose, sucrose, glucose, mannitol and citric acid , b) binder, For example: carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and locust gum, C) wetting agent 'eg glycerin, d) disintegrating agent, such as agar-agar, carbonic acid, potato or tree Potato starch, alginic acid, certain oxalates and sodium carbonate, e) solution retention agents 'eg 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 swellable clay ' and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and the like a mixture of capsules, troches, and pills. The dosage form may also contain a solid composition of a similar type of buffer 0, or a filler filled with a soft and hard-shell filled gelatin capsule. It is lactose, as well as high molecular weight polyethylene glycol, etc. The active compound can also be prepared in one form. Tablets, dragees, capsules are prepared from coated garments and outer shells, such as enteric coatings. Give priority to a certain release in the intestine Or a plurality of active ingredients, which may comprise a polymeric substance and a wax. Or more of the above-mentioned excipients may form a solid such as microencapsulation, granules and granules, which may be known as an opaque agent and may be a composition. The portion of the material, optionally in a delayed manner, comprising a topical or transdermal dosage form of a compound of the invention, including: ointment, paste, cream , emulsion, gel, powder, solution, spray, inhalant or patch. The active ingredient is in sterile H50-9047-PF; Kai 56 200920394 condition and pharmaceutically acceptable carrier And, if necessary, a preservative or buffer mixture. Ophthalmic formulations, ear drops, ophthalmic ointments, powders and solutions are also considered to be within the scope of the present 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, woven, rocky soils, flouricides, gum tragacanth, cellulose. Derivatives, polyethylene glycol, linaloic acid, bentonite, citric acid, talc, and oxidized or mixtures thereof. In addition to the compounds of the present invention, the powders and sprays may include excipients such as lactose, talc, citric acid, aluminum hydroxide, calcium citrate, and polyamidamine powders 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 used to increase the flux of the compound across the skin by dissolving or dispersing the compound in a suitable medium to prepare an absorption enhancer. The rate can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. Antiviral Activity The compound of the present invention may be from about 1 mg/kg to about 500 mg/kg, or from about 1 to about 50 mg/kg, depending on the compound of the present invention. The amount or dose of inhibition may also depend on the route of administration, and whether the county + 疋 can be used with other agents, but is different. The method of treatment or prevention according to the present invention is to treat the individual and the time, and to treat the viral infection of the primary antibody in the individual, the amount of the desired result is to achieve a desired amount of toxic effective amount or a inhibiting amount. The present invention is 1150-9047-PF; Kai 57 200920394. The compound 'this individual is, for example, a lower mammal. Another method of the present invention is to administer a compound of the invention inhibited by a sample of — 物, in a time and time required to achieve the desired result. As used herein, "an effective amount of a compound of the invention" means a sufficient amount of a compound to reduce the amount of virus in a biological sample or a body. As is well known in the art, the "anti-c hepatitis disease table is effective and the mother is effective I" in the compound of the present invention, and will be applicable to any

Within the reasonable benefit/risk ratio of Italian medical treatment. As used herein, "inhibiting amount", a compound of the invention, means a sufficient amount which is reduced by the amount of virus in a biological sample or individual. It is well known in the art of stomach medicine that the "inhibitory amount" of the compound of the invention will be within the reasonable benefit/risk ratio determined by the physician for any medical treatment. The term "biological sample" as used herein, refers to a substance of biological origin that is administered to a body. Examples of biological samples: including but not limited to: blood and its components, such as blood m, blood small & subpopulations of blood cells; organs such as kidney, liver, heart, lung, etc.; sperm and India; bone marrow and its 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. When the condition of the patient is improved, a maintenance dose of the compound, composition or combination of the present invention can be administered as needed. Then, when the symptoms are alleviated to the desired level, depending on the symptoms, the dosage or frequency of administration or both can be reduced to maintain the improved condition. However, patients may require long-term intermittent treatment to prevent any recurrence of the condition. 1150-9047-PF; Kai 58 200920394 β2 and 'It should be understood that the total daily use of the compounds and compositions of the present invention is determined by the master physician within the scope of full medical judgment. The sputum dose for a particular treatment of a particular patient will depend on a number of factors, including: the condition of the desired 'oral therapy' and the severity of the condition; the activity of the particular compound employed; Special composition; age, weight, health, sex and diet; & time, route of administration, and rate of excretion of sputum sputum used; duration of treatment; A combination of specific compounds or a drug that is used at the same time; and a similar factor that is well known in the medical field. The compound of the present invention is administered to the individual, and the total dose per sputum may be, for example, a single dose or a dose of f. For example, 〇 〇 〇 5 〇 heart weight, or usually 0. 卜 25 mg / kg body weight. The single-dose composition may contain this amount or be divided into multiples to achieve the daily dose. Generally, the treatment course of the present invention comprises administering about 10,000 to about 1 ounce per patient in a single dose or multiple times. The compound of the invention. If there is no other A, all the technical and scientific terms used herein are based on the meanings common to those skilled in the art. All publications, patents, published patent applications, and other references are hereby incorporated by reference. Abbreviations The following synthetic procedures and examples appear as follows: ACN: acetonitrile;

Ac : ethyl sulfhydryl;

Boc: tert-butoxycarbonyl; 1150-9047-PF; Kai 59 200920394 . Bz : benzoin;

Bn: benzyl; CDI: carbonyl diimidazole; dba: dibenzylideneacetone; CDI: 1, fluorene-carbonyldiimidazole; DBU: 1,8-diazabicyclo[5.4.0] eleven-7- Alkene; DCM: dioxane; DIAD: diisopropylazodicarboxylate; f DMAP: dimethylaminopyridine; DMF: dimethylformamide; DMS0: dimercaptosulfoxide; dppb : diphenylphosphinobutane;

EtOAc: ethyl acetate; HATU: 2-(7-aza-1H-benzotriazol-bu)-l,l,3,3-ylurea hexafluorophosphate; iPrOH: isopropanol; . 11 NaHMDS : sodium bis(trimethyldecyl) decylamine; NMO : N-oxidized N-methylmorpholine;

MeOH: decyl alcohol;

Ph: phenyl; POPd: dihydrodichlorobis(di-t-butylphosphino)palladium(II); TBAHS ·• tetradecyl ammonium hydrogen sulfate; TEA: triethylamine; THF: tetrahydrofuran; 1150-9047 ~PF; Kai 60 200920394 ·· TPP: trisylphosphine;

Tris: tris(hydroxymethyl)amino decane; BME: 2-mercaptoethanol; Β0Ρ: benzotriazole-buquino-tris(dimethylamino)phosphine hexafluorophosphate; C0D: cyclooctane Aene; DAST: diethylaminosulfur trifluoride; MBCYL: 6-(N-4'-carboxy-4-(didecylamino)azobenzene)-aminof hexyl-1-0-( 2-cyanoethyl)-(n,N-diisopropyl)-subdoxime; DCM: dioxane; DIAD: diisopropylazodicarboxylate; DIBAL-H: diiso Butyl hydrogenation; DIEA: diisopropylethylamine; MAP: N,N-dimethylamino. DME: ethylene glycol dimethyl mystery; DMEM. Dulbecco's modified Eagles medium; V 'DMF: N,N-dimethylformamide; DMS0: dimethyl hydrazine;

EDANS : 5-(2-Amino-ethylamino)-naphthalene-1-sulfonic acid; EDCI or EDC: Bu (3-diethylaminopropyl)-3-ethylcarbodiate 1150- 9047-PF; Kai 61 200920394 : Amine hydrogen chloride;

EtOAc: ethyl acetate; HATU: 0 (7-azabenzotriazol-1-yl)-oxime, oxime, Ν', Ν'-tetradecylurea hexafluoroacetic acid vinegar;

Hoveyda' sCat.: dioxo (o-isopropoxyphenyl sulfenyl) (tricyclohexylphosphine) ruthenium (11); KHMDS · · bis(tridecylfluorenyl) guanamine potassium;

Ms : methylsulfonyl; f'

EtOAc: ethyl acetate; g: gram; h: hour; NMM: N - 4 - fluorenyl?

PyBrOP: bromo-tri-pyrrolidino-square hexafluorophosphate;

Ph: phenyl; RCM: ring-closing translocation; RT: reverse transcription; RT-PCR: reverse transcription-polymerase chain reaction; TEA: triethylamine; TFA: trifluoroacetic acid;

MeOH:methanol; mg: milligrams (s); mi η:min (s); MS: mass spectrum; NMR. nuclear magnetic resonance, 1150-9047-PF; Kai 62 200920394 rt: room temperature; THF: tetrahydrofuran; TLC : thin layer chromatography; TPP or PPh3: triphenylphosphine; tBOC or Boc: a third butoxycarbonyl group;

Xantphos: 4, 5-di-diphenylphosphinoalkyl-9,9-dimercapto-9H-occluded with oxygen. 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

Bocr^

La

Ig

Scheme 1 reveals the synthesis of intermediate IG. The cyclic peptide precursor I g was prepared from Boc-L-2-amino-8-decenoic acid la and cis-L-hydroxyproline oxime Ib through steps A-D shown in Scheme 1. For further procedures for the production of the cyclic peptide precursor Ig, see U.S. Patent No. 6,6, 8, 0, the entire disclosure of which is incorporated herein by reference. To make a variety of macrocyclic knots 1150-9047-PF; Kai 63 200920394 can be substituted for la using other amino acid-containing derivatives containing terminal olefins (for further details, see WO/0059929). The ring-opening translocation is carried out with a guanidine catalyst to obtain the desired key intermediate Ig (for further details on the ring-opening translocation, see recent comments: Grubbs et a 1., Jcc. Aes., 1995, 28, 446 Shrock et al., Tetrahedron 1999, 55, 8141; Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012; Tmka et al., jcc. to (iv).vPes.. 200 1,18 ; and Hoveyda et al., price /r. /. 200 1,7,945). Process 2

(2·6) (2-4) (2-5) Scheme 2 discloses a method for synthesizing a tetrazole analog. 5 - Substituted tetraindole (2-2) is synthesized from a nitrile compound (2-1) and an azide, but not limited to sodium azide. The intermediates (2-4) and (2-5) can be suitably removed by substitution of the hydroxy intermediate Ig via SN2 of the surface-activated hydroxyl group, such as, but not limited to, OMs, OTs, OTf, bromide Or iodide. Upon subsequent hydrolysis of the ester, a compound of the formula (2-6) or (2-7) can be obtained. Process 3 1150-9047-PF; Kai 64 200920394

w

(2-3) N^Ar-Y N, 丨 (2-2) V= halide, OTf

The intermediate (3-1) is synthesized under the conditions of the macrocyclic carbaryl ester (2-3) and the 5-substituted tetrazole of Scheme 2. The intermediate (3-1) can be followed by a Suzuki coupling reaction at the position occupied by the dentate or 、, Sonogashira

Reaction or St i 11 e coupling. For further details on the Suzuki coupling reaction, see: A. Suzuki, 厶 (3) Ba Jian 1991, 419-422 and A. R. Martin, Y. Yang, 1 993, 47, 221-230. For further details on the Sonogashira reaction, see: Sonogashira. Comprehensive Organic Synthesis, Volume 3, Chapters 2, 4 A Sonogashira, Synthesis 1977, 777. For further details on the S ti 11 e coupling reaction, see: j. κ. S ti 11 e, Angew. Chem. Int. Ed. 1 986, 25, 508-524, M. Pereyre 1150-9047-PF; Kai 65 200920394 et a 1., Tin in Organic Synthesis (Butterworths, Boston, 1987) pp 185-207 pa and a review of synthetic applicationsΤ N. Mitchell, 1 992, 803-815. This Buchwald reaction can replace the 1st and 2nd amines and the 1 nitrogen heterocycle under the aryl bromide. For further details on the Buchwald reaction, see J. F. Hartwig,

Angew. Chem. Int. Ed. 1998, 37, 2046-2067 ° Process 4

Scheme 4 reveals the n-terminus and C-terminus of the modified macrocycle. Boc structure

Deprotection of an acid such as hydrochloric acid gives a compound of the formula (4-2). The amine structure of formula (4-2) can be alkylated or deuterated by a suitable halogenated or mercapto group to give a compound of formula (4-3). The compound of the formula (4-3) can be hydrolyzed by a base such as a hydrazine hydroxide to release the acid structure of the formula (4-4). Next, the compound of the formula (4-5) is obtained by activating the acid structure with an appropriate sulfhydryl group or a sulfonyl group. Process 5 1150-9047-PF; Kai 66 200920394 Q 9

X

N-N N=N /< « ' '

The sulfonamide (5-2) is prepared with the corresponding acid (5-1), allowing the acid to interact with a coupling agent (ie, CDI, HATU, DCC, EDC, etc.) at room temperature or elevated temperature. And in the presence of the test, the corresponding synthetic amine R3-S(0)2-NH2 is added, wherein R3 has the same definition as above. Process 6

The carbon-linked tetrazole (6-6) was prepared from the commercially available starting material (6-1) by the procedure described in Scheme 6. Compound (6-6) can be easily converted to the corresponding acid and sulfonamide using the procedures described in Scheme 4 and Scheme 5. Process 7 1150-9047-PF; Kai 67 200920394

N-NH η \ N^N

BocN~ 2) HATU, DIEA 0 〇〇2Μθ

1) LiOH/THF/MeOH

(6-2)

Tetrazolium (6-6) can be prepared by the alternative route described in Scheme 7. Synthetic meaning

Starting with the common intermediate (6-2), the addition aromatic group is substituted on the tetra-salt ring, and the compound (6-2) is coupled with P1, followed by coupling with p3 to obtain (7-3). Under the substitution conditions, a macrocyclic compound (7_4) is formed. Octa (7-4) is used as a common intermediate for further modification in the tetrazole ring to give (6-6). [Embodiment] The present invention will be further understood by the following examples. The examples are intended to be illustrative and not limiting. 'Various changes and modifications to those skilled in the art are manifested as four (4), and such changes and modifications 'including but not limited to: chemical structures, substituents, organisms, formulations and/or methods of the invention' may not be scared It is implemented within the scope of the spirit of the invention and the scope of the patent application. U.S. Patent Application Publication No. 20050 1 53877 also describes compound 1150-9047-PF; Kai 68 200920394 wherein G = 〇H, the entire disclosure of which is incorporated herein by reference. Example 1. Synthesis of cyclic peptide precursors

Boc^

OH

La

1Α·p-b〇cL-2-amino-8-indole acid la (1.36g, 5mol) and commercially available cis-L-hydroxy decyl decyl lb (l. 09g, 6_ol) Dissolve in 15ml of DMF solution, add DIEA (4ml, 4eq.) and HATU (4g,

2 eq) ° The coupling was carried out at 0 ° C for 1 hour. The reaction mixture was i〇〇mL

Diluted with EtOAc and then washed with 5% citric acid 2 x 20 ml, water 2 x 20 ml, 1 M NaHC s. 3 4 x 20 ml and brine. The organic phase was dried over Na 2 S 〇 4 and then evaporated to give the dipeptide lc (1.91 g, 95.8%), W Η ριχ (retention time = 8.9 min, 30-70%, 90% B) and MS (measured) 421. 37, M + Na+)

Identification. 1B. The dipeptide ic (1.91 g) was dissolved in a 15% aqueous solution of 15% dioxane and i5mLiN, and hydrolyzed at room temperature for 4 hours. The reaction mixture was acidified with 5% citric acid and was taken up in 1 mL of Ftn Ar uum L·LtUAc, followed by washing with 2 x 20 ml of water and 2 x 20 ml of saline. Will be right-handed gentleman. Jiu Cai and the organic phase are anhydrous Na2S〇4 dry comprehensive ‘and the splicer moves in the vacuum, 彳 纠 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

Ld (1.79 g, 97%), which was used for subsequent purification without further purification. 1C. A solution of the above-obtained free acid (1.77, 4.64 mm〇l) in 5 ml of DMF was added, and D-/5-vinylcyclopropanoic acid ethyl ester (0.95 g, 5 mmol) was added. DIEA (4 ml, 4 eq.) and HATU (4 g, 2 eq). The coupling reaction was carried out at 0 ° C for 5 hours. The reaction mixture was taken to 80 mL

Diluted with EtOAc and then at 5 °/. Wash citric acid 2x20m water 2x20ml, 1M NaHCCh 4x20ml and concentrated brine 2x10ml. The organic phase was dried as anhydrous NazS 4 and then evaporated. The residue was purified by silica gel flash chromatography.

Different ratios of hexane: EtOAc were used as the elution phase (5: 1 - 3 : 1 - 1 : 1 - 1 : 2 - 1 : 5). The linear tripeptide 1 f was isolated in oil form after removal of the elution solution (1·59 g, 65·4%) by HPLC (residence time = 11.43 min) and MS (measured 544.84, M + Na+) Identification. 1D. Ring-opening translocation (RCM). The linear tripeptide lf (1.51 g, 2.89_〇1) was dissolved in a solution of 20 ml of anhydrous DCM, and deoxidized by & foaming. Then add Hoveyda's first generation catalyst (5m 〇 1% eq.) solid. The reaction was refluxed for 12 hours under N2. The solution was evaporated, and the residue was purified by silica gel flash chromatography using different ratios of hexane: Μ - # as the elution phase (9:1 - 5:1 - 3:141:1~1:2~1: 5). After removal of the eluting solvent, the cyclic precursor 1 was isolated as a white powder (1.24 g, 87%) by HPLC (residence time = 7.84 min 30-70% 90% B) and MS ( 516.28, M + Na + ) were identified. Further details of the first embodiment of the invention are described in the U.S. Patent No. 6,608,027, the entire disclosure of which is incorporated herein by reference. Example 2 - Synthesis of the cyclic peptide precursor Mesylate 1150-9047-PF; Kai 70 200920394

2A. A solution of macrocyclic peptide precursor 1 (50Omg, 1. 01 mmo 1) and DIEA (0.4 ml, 2 mmol) dissolved in 2.0 ml of DCM, slowly at 0. (: Add methanesulfonic acid gas (〇·1 mi), wherein the reaction was continued for 3 hours. Then add 30 mL of EtOAc, each with 5% citric acid 2 x 10 ml, water 2 x 10 ml, 1 M NaHC 〇 3 2 x 10 ml and concentrated brine 2 x l 〇 The organic phase was dried over anhydrous Nad.sub.4 and evaporated to give the title compound methanesulfonate, which was used directly in the next step without further purification. Example 3. Tetraazole synthesis for the preparation of the tetrazole of the present invention The tetrazolium Illa-IIIq' which differs in the structure of the megaring is synthesized from the commercially available nitrile (niti_ile) compound:

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

To a closed tube containing 5 ml of diphenylbenzene, 3_C1_4 monohydroxy-benzoacetonitrile (〇·31g, 5 mol), NaN3 (〇.65g, 10_〇1), and triethylamine hydrochloride (0. 52g) were added. , 3mmol). Mix the mixture vigorously on i4 (rc

3f

3k 1150-9047-PF; Kai 71 200920394 20-3 0 hours. The reaction mixture is then cooled and poured to

Mixture of EtOAc (30 mL) and EtOAc (20 mL). After washing with water 2xl〇mi and water brine 2 X1 0 m 1 'the organic layer was dried over anhydrous n a 2 S 0 4 and evaporated to a color solid. After recrystallization from EtOAc-hexanes, tetramethylene compound 3a was obtained in good yield (〇_4g'86V/.), high purity (>90% 'HPLC), and was analyzed by NMR and MS (measured 197. And 1 99. 38, M + H + ) identification.

Embodiment 4. A compound of formula IX wherein a = Boc, Q = Y and G = 0H. Step 4 a: The substituted method β hai compound was prepared by substituting the sucrose from Example 2 and 4 s. This substitution method was performed by dissolving 〇. 〇41_〇1 macrocyclic peptide precursor. 3 g of hydrazine sulfonate 2 and hydrazine 123 mmol tetrazole in 3 ml of DMF, and 0.246_〇1 sodium carbonate (6 〇mg) was added. The obtained reaction mixture was stirred at 60 C for 4-1 0 hours, and then It was cooled and extracted with EtOAc. EtOAc (EtOAc) 688·29 [M + Na]. Step 4b The title compound was obtained by dissolving the compound from Example 4 of Step 4a (2 〇mg) in 2 of dioxane and lraL. The reaction mixture was acidified with 4 - 8 ^ 5% citric acid at room temperature, extracted with 10 mL of Et〇Ac, the solution was evaporated, and the residue was purified by HpLAQ12S1 1 -0520 WT;® qn-fi and the residue was purified by HPLC. 4 to 8 hours. The reaction mixture was taken as a guest's and washed with water 2 X 2 0 m 1. HPLC purification using VMr 0520WT column and 30 — 80% (1% acetonitrile) gradient of YMC was used for 20 1150-9047-PF; Kai 72 2009 20394 min. After freezing, the title compound was obtained as a white amorphous solid. MS (ESI): / / 7/π. 92 [M + Na]. Example 5 to Example 14 were prepared according to procedures analogous to Example 4, using different 5-substituted tetrazole.

And G = 0H.

And G = 0H. Example 5. A compound of formula IX wherein A = B 〇 c, Q = MS (ESI): τ ζ 7 / ζ = 612 · 31 [M + H]. Example 6. A compound of formula IX wherein A = B 〇 c, Q = MS (ESI) : τζ7 / ζ = 672 · 32, 6 74. 31 [M + H].

And G = 0H. Example 7. A compound of formula IX wherein A = B 〇c, MS (ESI): >77/^678. 27 ' 680. 27 [Μ + Η] Example 8. A compound of formula IX wherein A = Boc, MS (ESI): /ζ//ζ=692· 38 [M + Na].

And G = 0H. Example 9. A compound of formula IX wherein A = Boc, MS (ESI): Λ7/ζ = 630. 35 [M + Na].

And G = 0H.

And G=OH. Example 10. A compound of formula IX wherein A = Boc MS (ESI): /z?/z = 684.32 [M + Na]. Embodiment 11. A compound of formula IX, wherein A = Boc,

And G = 0H. 1150-9047-PF; Kai 73 200920394 MS (ESI): π/>=698.32 [M+Na].

And G=〇H. Example 12. A compound of Formula IX wherein A = Boc, Q MS (ESI): π 々 = 702 · 33, 704. 33 [M + H]. Example 13. A compound of formula IX wherein A = Boc, Q MS (ESI): π / ζ = 658. 37, 660.37 [M + H].

And G=OH.

Embodiment 14. A compound of Formula IX wherein A = B〇c, Q = and G = 0H. M S (E SI ) : 6 9 6 · 4 4 [ Μ + Η ].

Example 15. A compound of formula IX, wherein A = Boc, Q = i and a solution of the compound of Example 4 (33 mg) dissolved in DMF, was added CDI (12 mg). The reaction mixture was stirred at 40 ° C for 1 hour, followed by cyclopropyl decylamine (1 2 mg) and DBU (1 5 #1). The reaction mixture was stirred at 40 ° C overnight. The reaction mixture was extracted with EtOAc. The organic extract was washed with 1M NaHCCh, brine, dried over Na.sub.2.sub.4, filtered and concentrated. The residue was purified by EtOAc EtOAc (EtOAc) MS (ESI) ·· /»/>=741. 40 [M + H]. 13CCCD30D): 6 177_ 5, 173.7, 169.4, 165. 〇, 161·1, 155.9, 135.4, 128.2, 125_ 1, 119.7, 114.6, 79.0, 63.5, 63.4, 60. 1, 53.6, 52.3, 43.8, 33.6, 32.0, 30 7, 30.3, 1150-9047-PF; Kai 74 200920394 27. 3 ' 27. Example 16 Preparation. Example 16. 〇MS (ESI): Example 17. 〇MS (ESI): Example 18. s MS (ESI): Example 19.., 26. 3, 22. 2, 21. 5, 13. 9, 5. 6, 5. 4. To the embodiment 3 5 is in accordance with the procedure similar to the embodiment 15

A compound of formula IX wherein A = Boc, Q = Y and G = /'iiS; V ζζ//ζ = 727·27 [M + H]. A compound of formula IX wherein A = Boc, Q = m/z = n^0. 41 > 777. 39 [M + H] °

a compound of formula IX wherein A = Boc, Q = i and

a compound of formula IX, wherein A = Boc

MS (ESI): mp. (m.). a compound of formula IX, wherein A = Boc,

</ RTI> <RTIgt;

And

Example 22. A compound of formula IX wherein A = Boc, Q = Y and 〇 MS (ESI): /z7/z = 779. 45 [M + H].

Example 23. A compound of formula IX wherein A = Boc, Q = 〇 MS (ESI): π / ζ = 8 0 5. 37, 8 〇 7 · 38 [M + H].

Example 2 4. A compound of formula IX, wherein A = Β ο c,

MS (ESI): π / ζ = 761 · 47, 763_47 [M + H]. x Example 25. A compound of formula IX wherein A = Boc, Q = soil and G =

/☆V M S (E SI) : z7/z= 799.45 [M + H]. , 'Ά Example 26. Compound of formula IX, wherein A di Boc, Q = Y and G = ϊ 'ϊ 1150-9047-PF; Kai 76 200920394 MS (ESI): Example 27. ο MS (ESI): Example 28. o MS (ESI): Example 29. o MS (ESI): Example 30. o MS (ESI): Example 31. o MS (ESI): Example 3 2. m/z = 730 . 33 [M+H] °

A compound of formula IX, wherein A = Boc, Q = i and /π/ζ = ΊΊ 84. 21 ' 786. 1 9 [Μ + Η]

A compound of formula IX, wherein A = Boc, Q = i λ / / ζ = 808. 25, 810. 26 [M + H].

A compound of formula IX, wherein A = Boc, Q=i and /X·zff/^764. 31 ' 766. 32 [M + H] a compound of formula IX, wherein A = Boc, Q: in/z = S02. 38 [M + H]

/ Compound of formula IX, wherein A = Boc, Q = I and G: calendar / ζ = 763. 33 [Μ + Η]. A compound of formula IX, wherein A = Boc, Q = I and G: 115〇-9047-PF; Kai 77 200920394 MS (ESI): Example 33. ο MS (ESI): Example 34. ο MS (ESI) : 诏/ζ=817· 19,819·21 [M + H]. A compound of formula IX, wherein A = Boc, Q = τζ//ζ=841·25, 843·25 [M + H] 〇

A compound of formula IX, wherein A = B〇c, Q = imitation / = 797 · 30, 799.30 [M + H].

Embodiment 35. A compound of formula IX wherein A = Boc

MS (ESI): Example 36. 诏/z = 835. 37 [M + H] 化合物 Compound of formula IX, where A =

Step 3 6 a will be from the alkane solution and condensed. The residue is stopped. MS (ESI): The compound obtained in Example 16 was dissolved in 5 ml of 4NH?? The reaction mixture was concentrated in vacuo and evaporated twice with DCM. The obtained product was used directly in the next step /&gt;=627·33 [M + H]. 1150-9047-PF; Kai 78 200920394; Step 36b A solution of the compound from step 36a dissolved in 2 ml of DCM, adding DIEA (143/z 1)) and cyclopentyl carbonitrile (0. 246 mmol)) . The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with EtOAc. The organic layer was washed with 1M NaHCOs, water, brine, dried with NadCU, filtered and concentrated. The residue was purified by HPLC to give 42 mg of desired product. MS (ESI): /ζ?/ζ=739· 32 [M + H]. 13CCCD30D): 5 177.5, 173.4, 169.4, 165. 1, 161.8, 156.6, 135.4, 128.2, 125.1, 119.9, 114.1, 77.5, 63.3 ' 60. 2, 54.7, 53.4, 52, 5, 43. 9, 43. 8, 33. 7, 32·3, 32. 2, 32.0, 30.7, 30.3, 27.3, 27. 0, 26.3, 23.2, 22.2, 21.5, 5. 6 , 5. 4 〇Example 3 7 to Example 9 4 (Formula IX) was prepared according to the procedure described in Example 15 or 36.

Q

1150-9047-PF; Ka 79 200920394 38 0^1〇^p- V \ 39 p- V 1 40 MeO^0 / p- , PV 1 /^V 41 ΛΛ V 1 42 p人p- 0 43 0 V 1 /Ά 44 〇V 1 /Ά 45 P~ p N* Λ 'Ά 46 CXA %,N 1 1150-9047-PF;Kai 80 200920394 47 (λ., &gt;Ν 'Ά 48 〇yy V 49 ν 50 A / Η _ρ- 0 Ν 'Ά 51 Η f ΝγΝ 52 &lt;yl/ ΝγΝ 53 Fv^n person / ν λΐ5% 54 ο1, ρ- ΝγΝ 55 〇ν ¥ V Ψ^ν 1150-9047-PF; Kai 81 200920394

56 ΝγΝ /Ά 57 &lt;// p- ΝγΝ 58 Me P ν·Λ N /fv 59 VN /Ά 60 0 Me&gt;^yV ΗΝΛβ _/0- ΝγΝ /fv 61 Mei^ Me 0 N^TN 'Ά 62 Ά HN-^ ?- NYN 63 a1, p- VN 64 &lt;Cr^y fsj-NH p- NYN 1150-9047-PF; Kai 82 200920394

65 &lt; λ. Also / V 1 43⁄4 66 CX0 again / V 1 43⁄4 67 〇^〇A/ V 1 68 &lt;λ. Also / p Ν-Λ α^λ 1 Η 69 CX. Also / V 1 AhN: '1&gt; 70 CX. Also / ¥ V 1 a«VCHs 71 CX. Also / J, 0 N^lT gas 72 &lt;^〇A/ p- V \ An^ HU〇CH3 73 again / VN 1 I 1150-9047-PF; Kai 83 200920394 74 CX0 again / V i 75 CX0 again / V 1 76 &lt; λ. Also / _ρ- V 1 /Ί Η 3 77 &lt;λ. Also / V 1 78 CX. Also / V 1 43⁄4 79 CX. Also / _y°- 0 Ν'^Ν !_ ΑΧ, Η 80 Cl0 again / _ρ-~ 0 Ν^Λ !_ /3⁄4 81 &lt;λ. Also / ρ- Ρ a 82 Cl. Also / ν, νγν 1 /ν« Η Η 84 1150-9047-PF; Kai 200920394 83 CX. Also / V 1 /, A &gt; Η H 84 CX〇 and / _ρ-~ V 1 person view Η Η 85 CX. Also / V 1 aXf3 86 Cl. Also / _p- VN 1 /, ~ 87 &lt; λ. Also / V \ 43⁄4 88 Cl. Also / _p~- NP V 1 αΧη2 89 CX0 again / 0 Ν-ΐΓ /3⁄4 90 CX0 again / NVN 1 /, ^rF 91 &lt;! 〇 / / ^Ρ~~ V 1 /, χ巧Η Η 85 115 〇-9047-PF; Kai 200920394

Embodiment 95. A compound of Formula IX wherein G = 0H.

92 CX. Also / P- Ν, ΝΤΝ 1 93 CX. Also / Ρ~ %/Ν 1 Η Η 94 Cl. Further / VI Ν, Step 95A. For a sealed tube containing 95a (2.54g, lOmmol) and toluene (3〇mL), pass NaN3 (1.95g, 30mmol) and Et3N.HCl (4. 13g, 30mmol) ). The reaction mixture was stirred at 1 ° C for 2 hrs. A solution of saturated NaHC 3 (10 mL) was added to the reaction mixture, followed by Me0H (3 mL). The resulting mixture was stirred at room temperature for 3 minutes. Slowly add 10% citric acid to adjust the pH to 6. The mixture was extracted 3 times with EtOAc 1150-9 〇 47-PF; Kai 86 200920394. The combined organic phases were dried over anhydrous NazSO4 and evaporated. The residual residue was purified by a flash-flash chromatography using EtOAc (yield: EtOAc). Step 95B. A solution of 95b (350mg, leq) in CH2Cl2 (12mL), (4-methoxyphenyl)organic boronic acid (232mg, 2eq), pyridine (198 &quot; L, 2eq), Cu (OAc 2 (244 mg, 1.5 eq), molecular sieve 4A (〇. 95g) treatment. The reaction mixture was stirred at room temperature under air for 24 hours and then filtered through Celite. The resulting solution was concentrated, and Q:EtGAG = 2:3) was purified by flash chromatography to give compound (oil). , Step 95C - F. The title compound was obtained according to the procedure of the procedure (Step 1A-D). MS (ESI): / / / / = 624.29 [M + H] Example 96. Where A: :B〇

c, Q

N-N and G: This compound was prepared from compound 95 according to a procedure similar to that of Example A. MS (ESI): -= 727 · 25 [M + H].

Example 97. A compound of formula IX, in the pot A - Τ Λ jj〇c Ν Q = γ and G = 〇H. U50-9047-PF; Kai 87 200920394

Step 97A. To a solution of 95b in THF (3 mL), BnBr (48 / /L, </ RTI> 40 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> was added, followed by K2C 〇3 (138 mg, 1.0 mmol). The reaction mixture was stirred at 65 ° C for 16 hours. Remove the solvent. The residue was purified by silica gel flash chromatography (MeOH: CH2Cl2=l: 10) to yield 97a (1 〇 8 mg). Step 97B-E. The title compound was prepared in a procedure similar to that described in Example 95 (steps 95C-F). MS (ESI): 茁々 = 6 〇 8.29 [M + H]. N-^~/ 0兮0

Example 98. A compound of formula IX wherein a = Boc, Q = 1 and G = h 'V This compound was prepared from compound 97 according to procedures analogous to those described in Example 15. MS (ESI): 々 711 711 · 06 [M+H] 实施 Example 9 9 • Compound of formula IX, where A = Boc, Q

And G = 0H. 1150-9047-PF; Kai 88 200920394 This compound is prepared according to the procedure MS (ESI): ^/^= 658.30 as described in Example 9 7 [M+H] °

Compound of G = wherein A = Boc, this compound is prepared according to 99. Following the procedure described in Example 15, 5, from the compound MS): heart _-783.37 [m. Example 101. A compound of formula IX, &lt;Cl〇jy, Q = l 〇. .〇6 times 0°' and G =

This compound was prepared from compound 96 according to procedure analogous to that described in Example 36. MS (ESI): Μ = 739.25 [M + H]. ο 0. Example 1 〇 2. The compound of the formula 〇 〇 〇 / / q = ¥ and g = ^ /, this compound was prepared according to the procedure similar to Example 36, from compound 96 and cyclobutyl chloroformic acid vinegar . MS (ESI)·· π/Ή 25.23 [M+H]. Ο.〇- Ν_0 Example 103. Compound of formula IX where α = °〇, Q = ¥ and g = 1150-9047-PF; Kai 89 200920394 /

QwO V. 4 ° according to procedures similar to those described in Example 36, 96 and 0. MS (ESI): π 々 = 866.43 [μ + η]. Example 104. A compound of the formula wherein, from the compound; ν and G: this compound was prepared from the compound 103 according to procedures similar to those described in Example 36. MS (ESI) : /»/&gt;=824. 58 [M + H]. (γΛ Ν.^ and G: Example 105. A compound of the formula wherein Α = Η °0, Q = ¥ 〇 This compound is in accordance with the procedure described in Example 36, from the compound

1 03 and Η 制备 Preparation of HATU as a coupling agent MS (ESI): /»/ζ=872·80 [Μ + Η]. Examples 106 to 121 (Formula IX) were prepared as described in Example 4, 15 or 36. Embodiment 106. A compound of Formula IX wherein A = Boc

1 and -0Η·1150-9047-PF; Kai 90 200920394 MS (ESI): π/ζ=662·36, 664.36 [M + H].

Embodiment 107. A compound of Formula IX wherein A = Boc, Q = i and G

MS (ESI): ^=765. 27 ' 767. 27 [M + H] °

Embodiment 108. A compound of Formula IX wherein A =

MS (ESI): π / ζ = 777. 32, 779.32 [M + H]. 13C(CD30D): δ 177.5, 177.4, 173.6, 169. 3, 162.9, 156.6, 135.8, 135.4, 130.9, 129.9, 125·1, 125.0, 77.4, 63.8, 60·1, 60.0, 53·7, 52.6, 43.9, 33·5, 32.3, 32.0, 30.7, 30.3, 27.3, 27.0, 26.3, 23.2, 23·1, 22.2, 21·4, 5·6, 5·4.

Example 1 0 9. A compound of the formula IX, wherein A = Β ο c, MS (ESI): ^=630. 35 [M + H] °

Example 110. A compound of formula IX wherein A = Boc, Q =: MS (ESI): m/z = lZ2 &gt; 31 [M + H] ° 1150-9047-PF; Kai 91 200920394

&lt;ΓΊ ο ,, Example 111. A compound of formula IX wherein AsUoA/, Q = Nr and G = . MS (ESI): /z//z = 745. 30 [M + H]. 13C (CD30D): 5177.4, 173.5, 169.4, 163.4, 156.6, 135.3, 125", 123·6, 123·5, 118", 118.0, 115·9, 115·7, 77.4, 63.6, 60.0, 53.5, 52_5 , 43.8, 33_7, 32.3, 32.2, 32.0, 30·7, 30.3, 27.3, 27.0, 26·3, 23·1, 23·: 1'22·2, 21. 5, 5·6, 5· 4 °

And G=-〇H. Embodiment 112. A compound of Formula IX wherein A = Boc, Q: MS (ESI): /! / / ζ = 630 · 36 [M + H]. / Example 113. A compound of formula IX wherein A = Boc, Q = I and MS (ESI): /zz/z = 733. 31 [Μ + Η] ° Example 11 4. A compound of formula IX, wherein A =

F

real

MS (ESI): π / ζ = 745. 35 [M + H]. 13C(CD30D): 5177.4, 173_6, 169.4, 164.7, 164.3, 163.3, 162.7, 162.6, 156.6, 135.3, 131.0, 125. Bu 109.7, 109. 6, 109. 5, 105. 5, 105. 3, 105. ; 1, 77. 4, 63. 7, 60. 0, 1150-9047-PF; Kai 92 200920394 53.5, 52.5, 43.8, 33.7, 32.3, 32.2, 32.0, 30.7, 30.4, 27.3, 27.0, 26.3, 23_1, 22.2, 21.5, 5.6, 5.4. Example 11 5. A compound of formula IX wherein A = B o c, Q = MS (ESI): /z?/&gt; =644. 41 [M + H].

O. Embodiment 116. A compound of formula IX wherein A = Boc, Q =

MS (ESI): ιπ / ζ = ΊΑΊ. 53 [M + H] Example 117. Compound of formula IX, wherein A:

r, 'N. .N Q= 1 and MS (ESI): /z?/z=759. 3 1 [M + H]. 13CCCD30D): 5 176.8 ' 173. 1 &gt; 168.3 ' 165.7 &gt; 155.9 ί.. 136·5, 134”, 131.3, 130.6, 128.8, 128_7, 127.6, 126.5 125.9, 125.3, 124.7, 124.0, 78.2, 67.3, 62·7, 59.9 53.2, 52.5, 44·6, 33.9, 32.9, 32.8, 32.4, 31.3, 30·0 27_4, 27.2, 2·1, 23.6, 22.6, 21.0, 6.9, 6.3.

Example 118. A compound of formula IX wherein A = Boc, Q = and G = -0H &lt; M S (E SI): 644.41 [M + H].

Example 119. A compound of formula IX wherein A = Boc, Q = NiN 1150-9047-PF; Kai 93 200920394 MS (ESI): m/z = M. 53 [M + H] °

IN. -I Q = i and Embodiment 120. A compound of formula IX wherein A: /〇, s~〇 gA Nz. MS (ESI): π / ζ = 759. 44 [M + H]. 13CCCD30D) : (5 17 7. 6 ' 177. 5 ' 173. 6 ' 16 9. 4 ' 165. 2 156. 6, 135. 4, 134. 5, 133. 4, 128. 6, 128· 4. 127. 7, 127.2, 126.7, 126.4, 125.1, 124.8, 123.7, 77.4, 63.5, 60·2 60·:, 53.6, 52.5, 43.8, 33.7, 32.2, 32.0, 30.7, 30.3 2 7. 3, 27.0 , 2·3' 23.0, 22.9, 22·3, 21.5, 5.6, 5.4 Example 1 21. A compound of the formula IX, wherein A: Ο// Q: N: „ and MS (ESI): π/ζ=753 42 [M + H] 13C(CD30D) : (5 177. 5, 173.4, 169_ 3, 165·1, 161.1, 156.6, 135.4, 128.2, 125. 1, 119.8, 114.7, 77.5, 63.5, 63.3, 60. Bu 60.0, 53.4, 52.5, 43.9, 43.8, 33.7, 32.3, 32. 2, 32.0, 30.7, 30.3, 27.3, 27.0, 26.3, 23.2, 22.3, 21. 3, 13. 9 6. The compound of the present invention exhibits an effective inhibitory property against the HCVNS 3 protease. The following examples describe the test of the compound of the present invention, and the anti-HCV effect can be tested. 1150-9047-PF; Kai 94 200920394 : Examples 122. NS3/NS4a protease assay HCV protease activity and inhibition are called internaUy (9) to receive fluorescence Detection. DABCYL and an EDANS group are attached to the opposite end of the short peptide. The EDANS fluorescence is inhibited by the DABCYL group and will be released upon proteination. Fluorescence is a Molecular Devices Fluoromax (or equivalent) The excitation wavelength 355 nm 'emission wavelength 485 nm was used. The full length NS3 HCV protease lb was placed in a white half 96-well plate (VWR 29444-312 [Corning 3693]) with the NS4A cofactor (final enzyme concentration 1 to 15 nM). The assay buffer contains 1 NS4a

Cofactor Pep 4A (Anaspec 25336 or homemade MW 1424.8). RETSl(Ac-Asp-Glu-Asp(EDANS)-Glu-Glu-Abu-[COO]Ala-S

61'-1^3-(0 8 60丫1)-_2, 八1^3?6.22991, 1^ 1548.6) as a fluorescent peptide acceptor. The assay buffer contained 5 mM Hepes (pH 7.5), 3 mM mM NaCl, and 10 mM BME. The enzyme reaction is followed by a 3 〇 minute time interval at room temperature, and D is carried out in the absence and presence of an inhibitor.

Peptide inhibitor HCV Inh l (Anaspec 25345 ' MW

796.8) Ac-Asp-Glu-Met-Glu-Glu-Cys-〇H, [-20 °C] and HCV

Inh 2 (Anaspec 25346 'MW 913. 1) Ac-Asp-Glu-Dif-Cha-Cys -0 H was used as a reference compound. The IC50 value 'is calculated using the formula 205: y = A+((B-AV(l + ((C/xVD)))), XFit in the active group (Activity Base, IDBS). Example 1 23-cell line replicon HCV replicon rnA quantification (HCV cell line analysis) analyzed in cell lines using Huh-11-7 cell line (Lohmann et al 1, Science 1150-9047-PF/Kai 95 200920394 285: 1 1 0-1 1 3, 1 999). The cells were seeded at 4×103 cells/well in a 96 well plate and a medium containing DMEM (high glucose), 1% fetal bovine serum, penicillin-streptomycin and non-essential amino acids was provided. 37乞 was cultured in a 7.5% C〇2 incubator. At the end of the culture period, total rnA was extracted and purified from the cells using the Ambion RNAqueous 96 Kit (model number AM1812). The HCV RNA was amplified to allow sufficient material for HCV. Specific probe detection (described below) 'HCV (described below) specific probe vector HCV RNA reverse transcription, and polymerase chain reaction using TaqMan One-step RT-PCR master mix kit (Applied Biosystems catalog number 4309169) cDNA amplification by (pcr). The nucleotide sequence of the RT-PCR primer is located in the NS 5 B region of the HCV genome. As shown below: HCV forward primer "RBNS5bfor" 5 (GCTGCGGCCTGTCGAGCT (SEQ ID NO: 1): HCV retroprobe "RBNS5Brev" 5, CAAGGTCGTCTCCGCATACCSEQ ID NO 2). Applied Bi〇SystemS (ABI) Prism 75〇〇 sequence The detection system (SDS) detects the RT-PCR product, marks the fluorescent reporter dye and the dye-inhibiting probe, and emits fluorescence during the PCR reaction. The increase in the amount of fluorescence measured in each round of pcR reflects the RT-PCR product. In particular, the quantification is based on a threshold round, wherein the magnified line exceeds the established illumination threshold. Comparing the threshold of the sample to a known standard provides a high-sensitivity measure of relative template concentration among different samples ( ΑΒι

Bulletin #2 December 11,1 997). The data was analyzed using the abi SDS program version 1. 7. The relative template concentration can be converted to RNA copy number by using a known copy number of 1150-9047-PF; Kai 96 200920394: HCV RNA standard curve' (ABI User Bulletin #2 December 11, 1997). The RT-PCR product was detected using the following labeled probe: 5' FAM-CGAAGCTCCAGGACTGCACGATGCT-TAMRA (SEQ ID NO: 3) FAM = fluorescent reporter dye TAMRA: = inhibited dye RT reaction after 30 minutes at 48 ° C , implement pcr. The thermal cycling parameters of the PCR reaction used on the ABI Pr i sm 7500 Sequence Detection system are: 9 5 °C for 1 turn 1 〇 minutes, followed by 40 rounds, each including reaction at 95 ° C for 15 seconds, and The second reaction was carried out for 1 minute at 60 °C.

To normalize the data to the internal control molecule of cellular RNA, rt-pcR is implemented in the cellular mRNA glycerol awake-3-phosphate dehydrogenase (GAPDH). The GAPDH copy number is very stable in the cell line used. GAPDH RT-PCR implementation

The HCV copy number is determined from the same real RNA sample. The GAPDH primer and probe, and the standard used to determine the copy number, are included in ABi,

Pre-Developed TaqMan Analysis Kit (Cat. No. 431〇884E). The ratio of HCV/GAPDHRNA was used to calculate the activity of a compound which inhibits RNA replication of HCV. Activity of compounds as hcv replication inhibitors in a Huh_7 cell containing replicon (cell analysis) in the influence of 'specific antiviral compounds on η[v replicon RNA level' in Huhn-11-7 cells By comparing cell exposure to the compound and cells exposed to the DMSO vehicle (negative control) and often to 1150-9047-PF; Kai 97 200920394 GAPDH (eg, HCV/GAPDH ratio) of HCV RNA amount Decide. Specifically, cells were seeded at 4x1 03 cells/well in a 96 well plate and cultured in: 1) medium containing UMDSO (〇% inhibition control), or 2) medium/1% DMS0' containing a fixed concentration of compound. The 96 well plate was then incubated at 37 ° C for 4 曰 (IC50 decision). The percent inhibition is defined as: % inhibition = 1 00-1 00*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% DMS 〇) In the case of HCV RNA copy number/GAPDH RNA copy number, the dose-response curve is added by adding the compound to a logarithmic value of three times from a series of dilutions from high to low. The maximum concentration for a particular compound is 丨.5uM, and the lowest concentration is 0.23nM. If the IC50 value does not fall in the linear region of the curve, implement one

The dilution series of steps (eg 50 0nM to 〇.〇8nM). IC5 is based on the IDBS Activity Base program, using the "XLFit" function, 4 parameters, and nonlinear regression (model #2〇5, version 4.2.1, bui ldl6). In the above analysis, the measured values of the compounds represented by the present invention have Hcv replication inhibitory activity and HCV NS3 protease inhibitory activity. These compounds

Proteases are also effective. And 4, the HCV NS3

122 and real: in the NS3/NS4a egg 1150-9047-PF; Kai 98 200920394 white enzyme enzyme test, in the range of &lt;= 〇. 2nM-10 0Nm active 'in cell line replicon analysis, in &lt; = 2. 2nM- 1 00 0nM is active. For example, the compounds of Example 36, 〇1 and in, in the NS3/NS4a protease assay showed IC50 of 〇. ΙηΜ, 0.4 nM and 0·2 nM, in the cell line replicon analysis, each showed an EC50 of 0. 8nM. Pharmacokinetic analysis of representative compounds, showing high liver drug levels, for example, 36 compounds showed 16'1/Zg/mi and a single oral dose of 20 mg / kg in rats, the sample bioavailability was 76%, Cmax and AUC is each

5 2 · 9 // g · h r / m 1 ° Pigments These compounds have also been tested and found to have no inhibitory effect on the Cytochrome P450 enzyme. [Simple description of the diagram] None. [Main component symbol description] 〇 &lt;**, 1150-9047-PF; Kai 99

Claims (1)

200920394 : X. Applying for a patent garden: 1. The compound is expressed by formula 1, II, III or IV: X N-N N-N , month IJ stolen goods, with armor, A selected from the following group of warriors: R,, - (C = 0) ~ - (C = 0) - R2 ' -C (=0) - NH ~ R2 « Kl 久~S(0)2-R,, -S(〇)2NHR2 ; R1 is selected from the following groups: (i) aryl; substituted aryl; violent, heteroaryl Substituted heteroaryl. (1)) Hetero-Wei or silk (4) (tetra); ^ Soil '(1 n )-C--C8 alkyl, -C2-C:8 alkenyl or _C2-Cs alkynyl, Each having 〇, 1, 2 or 3 heteroatoms selected from hydrazine, 3 or N; substituted fluorenyl, substituted C2-C8 alkenyl or substituted -C2-Cs alkynyl, each Having 1, 2 or 3 heteroatoms selected from hydrazine, s or N; -C3-CI2 cycloalkyl or substituted -a-C" cycloalkyl; - ο-cycloalkenyl or substituted 1150-9047-PF; Kai 100 200920394 -C 3 - C 1 2 ring-dilute group; R: independently selected from the group consisting of: (1) hydrogen; (1 1 ) a square group; a substituted aryl group; Heteroaryl; substituted heteroaryl; (·1) hetero- or substituted heterocyclic; and (lv) Cl Cs alkyl, -C2~C8 alkenyl or -c2-c8 alkynyl , each with 〇, 1 2 or 3 choices From the hetero atom of 〇, s^N; substituted ". meta-soil, k-substituted _c2_C8 alkenyl or substituted -ca fast radical, each having, &lt; 3 from 0, 8 or N a hetero atom; a C3-C12 cycloalkyl group or a substituted ί梦, k 甘衣基; _C3_Ci2 cycloalkenyl or substituted -C 3 - C 1 2 cycloalkenyl; G is selected from the following Groups: -NHS(〇)2_R3 and -NH(S〇2)NR4R5; R3 is selected from the group consisting of: (I) a square group, a substituted aryl group; a heteroaryl group; a substituted heteroaryl group a (II) hetero- or alkyl-substituted heterocycloalkyl; and (III) a Cl-C8 alkyl group, a -G-C8 alkenyl group or a _C2_Cs alkynyl group each having a hydrazine, '2 or 3 selected from a hetero atom at 0, s or N; a substituted _Ci_c8 alkyl group; a substituted _C2_C8 dilute group or a substituted _^_C8 fast group, each having 〇, 1, 2 or 3 selected from 0' a hetero atom of S or N, C3-C" cycloalkyl or substituted C2 cycloalkyl; 〜Lb cycloalkenyl or substituted -C 3 -C 1 2 ring; /, R3 is not CHzPh or CihCfhPh; I and Rs are independently selected from: 1150-9047-PF; Kai 101 2ϋϋ^2ϋ3^4 (1) hydrogen; (1 1) an aryl group; a substituted aryl(fluorene)heterocyclic fluorenyl group or a fine aryl group; a substituted heteroaryl group; (5) a fluorenyl group; a heterocyclic alkyl group; and 1, 2 or 3 selected from Yu Yu,. Or a ~Cz-C8 alkynyl group, each having a hydrazine, an alkyl group, a substituted heteroatom of C2 S or N; a substituted gas concentrating 0, 2 or 3 h 2 8 or substituted CA alkynyl groups each having 3 hydrazines selected from the cesium having or substituted by ~c ^; -C3~c12 cycloalkyl fluorene 12 cycloalkyl.~G-C3-Cucycloalkenyl ; soil, 'C3'cu cycloalkenyl or substituted L is selected from the group consisting of CX selected from 丨砰LH2—, —〇—, —S— and ~s(0)2—; The following group consists of: (1) hydrogen; (ii) ^' group; substituted aryl · 〆 · ·, further aryl 'heteroaryl; substituted heteroaryl; (1 1 1 ) heterocycloalkane Or a substituted heterocycloalkyl group; Civ)-Ci-C8^AP. V.. C2 - Cs alkenyl or -C2-C8 alkynyl, each having hydrazine, 1 2 or 3 heteroatoms selected from hydrazine, $+, μ, s or hydrazine; substituted -Ci-c8~ , a 'K8 dilute group or a substituted C-C8 alkynyl group, each having or 3 selected from. a hetero atom of s or N; a cycloalkyl or substituted ~m CtC&quot; decyl group; a _C3_Ci2 cycloalkenyl or a substituted -C3-Cl2 cycloalkenyl; and () WR6 wherein w is absent or selected - 〇一, -, - bribe -, (e) C (〇) NH- and -C(〇)N(Me)-; r6 is selected from the following group: (a) hydrogen; 1150-9047 -PF; Kai 102 200920394 f (b) aryl; substituted aryl; heteroaryl; substituted heteroaryl (c) heterocyclic or substituted heterocyclic; and (d) _Cl-C8 alkyl , -C2-Cs alkenyl or -C2-C8 alkynyl, each having fluorene, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; substituted -Cl-C8, substituted, -C2-C8 alkenyl or substituted -Cz-Cs alkynyl, each having 0, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; -C3-C12 cyclodecyl or substituted -C3-C12 cycloalkyl; -C3-Cu cycloalkenyl or substituted -C3~&quot;Cl2 ring-dense; = represents carbon-carbon single or double bond; j=0, 1, 2, 3 or 4 ; k = l , 2 or 3 ; m = 0, 1 or 2; n = l , 2 or 3. 2. The compound of claim 1, wherein the compound of the formula V, VI, VII or VIII is: // \ nn^n 1150-9047-PF; Kai 103 200920394, or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein A, G and X are as defined in claim 1 of the scope of the patent application. 3. The compound of claim 1, wherein the compound of formula IX is selected from the group consisting of compounds of formula IX, wherein A, Q and G are listed in Table 1: Table 1 Example # AQG 15 person / V 1 16 person / P~~ V 1 17 person / V 1 18 ΛΛ JTr V 1 19 person / V .〇ν /0 /d Μ V 20 ^Γ〇 V 1 1150-9047-PF; Kai 104 200920394 21 人又 / 7CF3 0 Ν^ΐΓ Ν 'Ά 22 人又 / ν 23 ΛΛ ρ- Ν 'Ά 24 ΛΛ ν A 25 ΛΛ Ο^Ρ ν /ίϊν 26 ΛΛ _Ρ ~ Ρ Ν /, Χτ Η 1 27 people again / &gt; Ν γ Ν /, Χ - Η 1 28 乂Λ, _ρ- Ν γ Ν /, Χ - Η 1 29 person / ρ- Ν γ Ν /, Χ - Η 1 1150-9047 -PF; Kai 105 200920394 30 ΛΛ vn /〇.νΡ Yr 31 人 / NYN 32 人 / JT Ν^ΐΓ Ν 33 ΛΛ ΝγΝ 43⁄4 34 people / tfc, Ν 43⁄4 35 people / ^γΝ 43⁄4 36 Cl. Also / ρ- ν /isV 37 €1. / V 38 〇人 / γ 'Ά 1150-9047-PF/Kai 106 200920394 39 V 1 40 MeO^C^°^^ 41 l. 42 43人43 〇_ρ- p 44 〇^p- V 1 45 %'N 1 /^7 46 CXA ,0- V \ /isV 47 p 'Ά 1150-9047-PF;Kai 107 200920394 48 Ον VN 49 ΝγΝ 'Ά 50 αΛ ΝΥΝ 51 li Ν 52 Also / ΝγΝ 53 〇Fv^ n person / ν 54 ΝγΝ 55 &lt;Χ/ ρ- Ρ ν·Λ Ν /, (5) 56 1150-9047-PF; Kai 108 200920394 57 f li N 58 Me 0 N 59 0*^ v Ϋν 60 0 ΗΝΛβ v 61 Me v 62 HN-^ 0 Λ N 63 a1, p- ΝγΝ 64 ΝγΝ 65 &lt;^〇A/ :P~ v 1150-9047-PF; Kai 109 200920394 66 CX0 again / VN H k^o 67 YA^. H3 68 〇-〇A/ V /, ~ and 69 CX. Also / V 70 CX0 again / p- γ ^N: H3 71 Cl〇A / p- Ν γ Ν 72 CX. Also / 73 Cl〇A / Y / gas 74 CX. Also / Ν Ν Ν 1150-9047-PF/Kai 110 200920394 75 CX. Also / %/N I 76 CX0 again / p- , Ρ V 1 aXf3 77 Ο ^ Λ / %, N 1 /? XX 78 CX. Also / V 1 43⁄4 79 &lt; λ. Also / V 1 aXh2 80 CX. Also / V 1 A^x, 81 CX. Also / _ρ- V 1 82 &lt;λ0 again / _p- V 1 /, XQ Η H 83 Cl. Also / P- V 1 Η H 1150-9047-PF; Kai 111 200920394 84 &lt;λ01/ V 1 / %?T'N 85 Cl〇A/ V 1 /, XF3 H 3 86 Cl. Also / V 1 A^CI 87 CX. Also / V &gt; 43⁄4 88 &lt;^〇A/ ^p- V 1 aXh2 H 89 CX. Also / _y〇- V 1 A^X 90 CX0 again / _p- V 1 々V 91 Cl0 again / 0 N^lT !_ /, XQ Η H 92 OJy p- V 1 /, X force Η H 1150-9047 -PF/Kai 112 200920394 93 CX. Also / _/°~· I v / /, νΆ, Η Η 94 CX. Also / v Ν , Example # A Q G 96 person again / 0° ' N-N Ν γ Ν 98 person / N-N ^ ^ Ν γ Ν 100 ΛΛ Ν γ Ν 101 ex. Again / 0. , N-N ΝγΝ 102 0°' N-N ΝγΝ 103 °0 0°' N-N ΝγΝ 1150-9047-PF; Kai 113 200920394 104 . 0 0. ~ Ν-Ν ΝγΝ 105 °0 0°' Ν-Ν ΝγΝ 107 ΛΛ &gt; Ν 108 &lt;λ. Also / &gt; ΝγΝ 110 ΛΛ &gt; Ν^ΐΓ Ν ΆΆ 111 οΐΛ/ &gt; Ν々'Ν ΆΆ 113 people again / V I 114 CX. /V I 1150-9047-PF; Kai 114 200920394 4. A compound selected from formula I, hydrazine, 111, IV, V, VI, VII, VIII or IX as described in the specification, or a pharmaceutically acceptable salt thereof, t^0 or a prodrug. A pharmaceutical composition comprising: (1) a compound having the structural formula I, II, m, IV, V, VI, VII, vm or IX as described herein, or (7) pharmaceutically acceptable compound Acceptable salt, vinegar or prodrug. 6. A pharmaceutical composition comprising: a compound that is too inhibiting I of claim 1, or a pharmaceutically acceptable z-substance, a s- or a precursor, and a combination of a musically acceptable Support or excipient. Pharmacology Pharmacy 1150-9047-PF for treating hepatitis C virus infection in one body; Pharma composition of the composition of Kai 115 200920394 6 Included - Inhibition amount of the patent application. 8. A pharmaceutical composition for inhibiting hepatitis C 疝 葙 枇 Γ Γ Γ Γ “ “ “ 、 、 、 、 、 、 、 、 、 、 、 9. 9. 9. 9. 9. 9. 9. 9. 9. 9. 9. 9. 9. 9. 9. 9. 9. 9. 9. 9. The medicinal composition according to the above item 7, further comprising an additional anti-hepatitis C virus agent. The pharmaceutical composition according to claim 9, wherein the external anti-hepatitis C virus agent , selected from the group consisting of: α-interferon,/5-interferon, ribavarin, and adamantine. 11. The pharmaceutical composition as described in claim 9 Wherein the additional anti-hepatitis C virus agent is an inhibitor of helicase of the hepatitis C virus, a polymerase, a metalloproteinase or a ruthenium RES. 12. The article has the formula I, π, as described in the specification. The process of the compounds of ΠΙ, IV, V, VI, VII, VIII or Ix is in accordance with the procedures and examples described herein. 1. 3. A pharmaceutical composition comprising the pharmacy as described in claim 1 a composition or a pharmaceutically acceptable salt thereof, Or a prodrug. 14. The pharmaceutical composition according to claim 13 of the patent application, further comprising another anti-HCV agent. 1 5 · The pharmaceutical composition according to claim 13 of the patent application, further comprising a An agent selected from the group consisting of: interferon, ribavirin, amantadine, other HCV protease inhibitors, an HCV polymerase inhibitor, an HCV solution 1150-9047-PF; Kai 116 200920394 j Cyclonease inhibitor or an internal ribosome entry A site inhibitor. 16. The pharmaceutical composition of claim 13 is a pegylated interferon. 17. The pharmaceutical composition of claim 13 is additionally resistant to viruses, bacteria, and fungi. Or an anti-cancer agent. The substance, including 'more includes one, or one immunization 1150-9047-PF; Kai 117 200920394 VII. Designated representative map: (1) The representative representative of the case is: No. (II) Representative The symbol of the symbol of the figure is simple: No. 8. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: X 1150-9047-PF/Kai 5