TW200817031A - Triazolyl acyclic hepatitis C serine protease inhibitors - Google Patents

Abstract

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

Description

200817031 IX. Description of invention: m [Reciprocal Reference Related Application] This application is based on the US Provisional Application No. 6〇/921,503 (usll/5〇3, 872 conversion) issued in August 2006. , advocated the offer of its inner valley completely introduced here as a reference. TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel hepatitis C virus (Hcv) protein depleted anti-inhibitor compound having antiviral/sexuality against Hepatitis B virus (HCV), and for > Oral therapy for HCV infection is useful. Further, the gentleman ^. 旯, 体, a, the present invention relates to a triazolyl acyclic HCV protein inhibitor compound, 3 combinations of such compounds, and methods of using the same, and the treatment of such compounds 0 [Prior Art] HCV is the main cause of non-a, non-B hepatitis | silk production 広Η ^ m ^ To cause the disease, and has been developed and opened in China, causing more and more serious people. People 4 ★ A Public health issues. It is speculated that this disease f is more than 200 million in the infection of the king's ball, more than five times more than the individual infected with the human immunodeficiency virus (HIV). Patients with HCV-sensitive patients have a higher risk of cirrhosis due to a high proportion of chronic infections, and subsequently develop hepatocellular carcinoma and end-stage liver disease. V is the most important cause of hepatocellular carcinoma, and it is the main cause of liver transplantation in Western countries. The main port of the development of anti-HCV treatment is limited to the main cause of the P-A, including but not limited to, the disease is tenacious, the virus is in - the genetic diversity in the replication of the host, the disease 1150- 9073-pF; Kai 6 200817031 The opportunity for the development of drug-resistant mutants and the lack of reproducible infectivity: the feeding system and small animal models for HCV replication and pathogenesis. In most cases, due to mild infections and complex biology of the liver, special care must be taken with antiviral drugs that are prone to significant side effects. Only two treatments for HCV infection were approved. The original treatment of the spear pack 3 was given intravenously with interferon ilpha (IFN-a) over a 3-12 month schedule, while the newly recognized second-generation treatment, including iFN_a and a general antiviral nuclear mimic simulation For example, Ribavirin, co-treatment. These treatments are all associated with interferon-related side effects and low efficacy against HCV infection. The poor tolerance and poor efficacy of the protocol is lower than that of the target treatment. It is necessary to develop an antiviral agent effective for the treatment of Hcv infection. In the case of the disease, most of the strains are chronically infected and have no symptoms, and it is impossible to predict that the effective drug is preferably a significantly lower side effect than the currently available treatment. Hepatitis C non-structural protein f_3 (Ns3), a protein f-resolving enzyme, is necessary for the processing of viral polyproteins and subsequent viral replication. Although there are a large number of viral variants (variant #HCV infection related to 'the active site of A NS3 protease is highly retained, it inhibits: ·, , /, attractive " entry mode. Recently treated with protease inhibitors The success of the claws' concept of restraining is a level in the anti-Hcv war

Hcv is the rna virus of the family Flaviridae. The genome has a mantle and contains a single-stranded molecule of about 9 Å. It is encoded as a polypeptide of about 30 1 amino acid. The HCV polyprotein is treated with a virus and a host peptidase, and the peptide does not exhibit 1150-9073-PF; Ka i 7 200817031 eye (4) screet, which performs many functions. There are three structural proteins, ^(10) ten proteins that function... and include highly mutated sequences.彳 6 kinds of non-structural protein f. NS2 is a word-dependent metalloproteinase that acts as a part of the NS3 I a μ ~ W protein shell. NS3 is involved in two catalytic functions (separate from its association with NS2): one of the N-terminal serine proteases, which requires the NS4A^ cofactor, and one of the g-ends, the enzyme-dependent helicase function. NS4 "-a cofactor that is closely related but is a non-covalent serine protease.

NS3-NS4A protease _ sound seven ppq & main L 赆 babe cut four parts of viral polyprotein. NS3-NS4A is cleaved to be self-catalytic and occurs in the cis (ci s) position. The other three hydrolases, NS4A_NS4B, NS4Ms5a, and (four)-(iv), all occur in the trans position. It is a leucine protease, which is structurally classified as chymotrypsin (Cai (4). (4). Although Μ lysin itself has proteolytic activity, hcv protease is not a catalyzed: polyprotein cleavage An enzyme of efficiency. It is known that a central hydrophobic region of MU protein is necessary for this enhancement. The formation of a complex of NS3 protein with NS4A seems to be necessary for the treatment of events, and can enhance the proteolytic efficiency of all sites. General strategy for the development of antiviral agents , the virus-encoded enzyme is not activated 'contains NS3, which is necessary for viral replication. Recent comments on efforts to find deprotease inhibitors are described in s. Tan, A. pause, γ.

Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov., 1' 867_881 (2〇〇2). Other descriptions of hcv protease inhibitor 1150-9073-PF; Kai 8 200817031 Synthetic patents are: WO 00/5 9929 (20 00 ); WO 99/07733 (1 999); W〇00/09543 (2000); WO 99 /50230 (1999); US5861297 (1999); and US2002/0037998 (2002). SUMMARY OF THE INVENTION The present invention relates to a novel HCV protease inhibitor compound, and a pharmaceutically acceptable salt, ester, or prodrug thereof, which inhibits serine protease activity, particularly hepatitis C virus (HCV) NS3 - NS4A protease activity. Thereby, the compound of the present invention interferes with the life history of the hepatitis C virus and is useful as an antiviral agent. More specifically, the present invention relates to a pharmaceutical composition comprising a compound of the foregoing compound administered to an individual infected with HCV by k. The invention further provides a pharmaceutical composition comprising a compound of the invention (or a pharmaceutically acceptable salt, ester or prodrug thereof) and other anti-HCV agents, such as interferons (eg, alpha-interferon, /3-interferon) , consistent interferon (c〇nsensus interferon), long-acting interferon, or albumin or other interferon), ribavarin, adamantine, other HCV protease inhibitors or HCV polymerization Enzyme, helicase, or internal ribosome entry site inhibitor. The present invention is also directed to a method of treating & an infected individual by administering to the subject a pharmaceutical composition of the present invention. In a specific example of the present invention, a compound is disclosed, which is represented by Formula I or j j , or a pharmaceutically acceptable salt, ester or prodrug thereof: 1150-9073-PF; Ka ΐ 9

X 200817031

¥

(II) A is selected from the group consisting of -(〇〇)-r2, -c(=0)-nh Kl n R2 and ~S(〇)2 - Rl, -s(0)2NHR2;

R1 is selected from the group consisting of: 1) a square group; a substituted aryl group; a heteroaryl group; a substituted hetero(11) a hetero (tetra) group or a substituted heterocyclic group; and A ' ( Ii〇—Ci-Cs alkyl, —c2-r, stannous, C8 alkenyl or —C2-Cs alkynyl, each 1, 2 or 3 selected from 〇, s I 〇, 4 N Atom; substituted alkyl, substituted -C2-C8 is exemplified by its ten r Ll~c8 u alkenyl or substituted -C2-C8 alkynyl group, long 4 〇, 1, 2 or 3 selected from 〇 , 弋 匕 匕 匕 匕 匕 或 或 或 或 或 或 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; 或 ; 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或Alkenyl; Disubstituted R2 is independently selected from the group consisting of: (1) hydrogen; ((1) aryl; substituted aryl; heteroaryl; substituted hetero(1i)hecycloalkyl or Substituted heterocycloalkyl, · aryl, (iv)-C丨-C8 alkyl, -C2-C8 alkenyl or -CrC8 alkynyl, each scoop 1, 2 or 3 selected from 〇, S Or a hetero atom of N; substituted: -3 〇, alkyl, substituted _C2-C8 fluorenyl or substituted _c2_c8 alkyne, C8 0, 1, 2 or 3 O, S or N" each containing a hetero atom, -Ca~Cl2 cycloalkyl 1150-9073-PF/Kai 10 200817031 or substituted -GC!2 cycloalkyl-C 3 - C 1 2 cycloalkenyl C3 - Cl2 cycloalkenyl or substituted B is selected from the group consisting of η and cH3; NHS(0)2-r3 and G are selected from the group consisting of: -NH(S〇2 NR4R5; R3 is selected from: substituted heteroaryl; and (i) aryl; substituted aryl; heteroaryl (11) heterocycloalkyl or substituted heterocycloalkyl «8 alkyl ,—c2_c8 dilute group or _C2-C8 alkynyl group, each containing 111 1, 2 or 3 heteroatoms selected from 0, UN,

An alkyl group, a substituted _C2_C8 olefin, a G 2 W group or a substituted seven rhyme group of Cl U of the seven γ η, each containing 〇, 2 or 3 hetero atoms selected from 〇, S 4 n; or substituted -c3-Cl2 cycloalkyl; 2 alkyl-C3-. 2 ring dilute · c group or substituted but R 3 is not CH 2 CH 2 Ph ; R 4 and R 5 are independently selected from: (1) hydrogen; (1) aryl: substituted aryl; heteroaryl; substituted heteroaryl; 111% by mole or a heterocyclic group of A; and 2 (:V): 1 C8 alkyl-C2-. Alkenyl or -c2-c8 alkynyl, each containing 0, a base of two! a hetero atom selected from °, s or N; a substituted C-alkenyl group or a substituted C-alkenyl group or a substituted -c2-c8 alkynyl group each containing a substituent selected from: 0, N Atom~cyclosqualyl", C3-CI2 % alkyl '·-C3-C12 cycloalkenyl or substituted 1150-9073-Pp; f<;a j_ 11 200817031 -C3-Cl2 cycloaliphatic; L· And Z are independently selected from: (1) hydrogen; V丄丄/ • # π φ, substituted heteroaryl. (iii) heterocycloalkyl or substituted heterocyclic alkyl and (iv)-Cl -C8 alkyl, -C2_Cs alkenyl or - oxime-amp; alkynyl, each containing 〇 1, 2 or 3 heteroatoms selected from 〇, s or N; substituted ~c/

An alkyl group, a substituted _CrC8 alkenyl group or a substituted -G-G alkynyl group, each package = 0, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; - C3~Ci2 ring-fired ^ or substituted -CrC"cycloalkyl; -ClC!2 cycloalkenyl or substituted = -C3-C12 cycloaliphatic; 'X and Y are independently selected from: (1) hydrogen; (ii) aryl; Substituted aryl; heteroaryl; substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; (iv) -C!-C8 alkyl, -C2-C8 alkenyl Or —C2-Cs alkynyl, each comprising 〇, 1, 2 or 3 heteroatoms selected from 〇, 8 or n; substituted ——alkyl, substituted —ο-C8 alkenyl or via Substituted -C2_Cs alkynyl groups each containing 0, 1, 2 or 3 heteroatoms selected from hydrazine, s or N; _c3~c12 cycloalkyl or substituted -G-Ci2 cycloalkyl; -C. a cycloalkenyl group or a substituted -C3-Ci2 ring-based group; and (v) -W-R6, wherein W is absent or selected from: -〇1, -s~, __NH_, -N(Me)-, -C(〇)NH- and -C(0)N(Me)- ; r6 are selected from the group consisting of: 1150-9073-PF/Kai 12 200817031 (a) hydrogen; (b) aryl; Substituting .λ square; heteroaryl; Heteroaryl (fluorene heterocycloalkyl or bismuth, disubstituted heterocycloalkyl fluorene and (d)-Ci-Cs alkyl, Γ 2 Cs alkenyl or -c 2 - c8 alkynyl, each containing hydrazine , 1, 2 or 3 heteroatoms selected from ^, S or hydrazine; substituted _Ci_C8 alkyl, substituted -C2< ordinated or substituted -C2-C8 alkynyl, each comprising hydrazine , 1, 2 or 3 heteroatoms selected from hydrazine, or N; -C3-C12 cycloalkyl

Or substituted -C3-C12 ring p A alkyl; -C3 -C"cycloalkenyl or substituted. 3-Cl2 bad alkenyl; or X and Y blood hair &...-^ /, /, inch carbon atoms together form a ring structure, 忒% π is chosen from the following private group, square base, Substituted aryl, heteroaryl and substituted heteroaryl; m: , 1 or 2; and η: , 2 or 3 〇 [Embodiment] In the first embodiment of the invention, the formula is as described above ! Or Π means a pharmaceutically acceptable carrier or excipient, alone or in combination, with a pharmaceutically acceptable salt, ester or prodrug thereof. In the present invention - a specific example, the compound represented by Formula III described herein: 1150-9〇73-PF; Kai 13 200817031 x Ν'/

(III) or its musically acceptable Xt. -P ffio -1⁄2 σ mouth dish, 酉曰 or 刖 drive, as soon as possible or in combination with an acceptable carrier or excipient, where A, The definitions of the specific examples of γ, X, L, and : ' are the same. And pre-production: an example 'X and Y are independently selected from the following: a hydrogen aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl ring, a substituted heterocyclic ring, each a C8 alkyl group, a _C2-C8 dilute group, a heterocyclic substituted -Crc8 alkyl group, a substituted C2-C8 alkenyl group, a substituted alkynyl C3Cl2% alkyl group, a -C3-Cl2 ring Alkenyl, substituted fluorenyl and substituted -c3-Gl2 cycloalkenyl, wherein each -Gi-G group, alkenyl, -C2-c8, substituted-Ci_C8 alkyl, Substitute, f8

The alkenyl group and the substituted -C2-Cs alkynyl group independently comprise 〇 2 G 乂 乂 d hetero atoms selected from 0, S or N. A is selected from the group consisting of -c(〇)-, -C(0)+Kl and a c(8)_nh_Ri, where R is selected from the substituted aryl, heteroaryl, substituted heteroaryl Base, heterocyclic ring, decarburized, heterocyclic ring, -CK group, -CK8 dilute group, -C2_C8 alkynyl group, decyl group, substituted-dilute group, substituted Cg block group, -c3 a -Cl2 ring-form, a Cl2 ring, a substituted _C3_Ci2 ring, or a substituted pentacyclic group. L and z can be independently selected from the group consisting of -C2-C8, -G2-C8, substituted _Gi_G, and 1150-9073-PF; Kai 14 200817031 - C2-C8 alkenyl, substituted-C2_C8 alkynyl, -G-Cu ring-sintered, -C3-Cl2 ring-dense, substituted-C3_Ci2 cycloalkyl, or substituted ~cycloalkyl. G may be -NH-S〇2-NR4R5 or -NHS〇2-R3, wherein R3 is selected from -CrC8 alkyl, -CrC8 alkenyl, -CrC8 alkynyl, aryl, substituted aryl, heteroaryl Substituted, substituted heteroaryl, heterocyclic, substituted heterocyclic, indole C cycloalkyl, -GC! 2 cyclodecyl, substituted -C3 - Cl2 cycloalkyl, or substituted -Cs -Cucycloalkenyl, and R4 and R5 are each independently selected from hydrogen, L1 8 alkyl, -CrCs, -C2-Cs alkynyl, substituted -h - C8, Finely substituted -C2-C8 alkenyl, substituted -C2-Cs alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocycle, ' ~C3-C"2cycloalkyl, -C3-C!2 cycloalkenyl, substituted -G-c" cycloalkyl, or substituted -C3-C12 cycloalkenyl. In another embodiment, X and Y are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl i A -C(0)- 〇-Ri or - as 0)---R丨, wherein 1 is -Ci - C8 alkyl, -^ alkenyl, -CrC8 alkynyl, substituted -Ci-C8 alkyl, substituted -C2 . Alkenyl, substituted -C2-C8 alkynyl, -C3-Cu cycloalkyl, _C3 - Ci2 cycloalkenyl, substituted -CrCn cycloalkyl, or substituted -CrCu cycloalkenyl l L And -CrC8 alkyl, -CrC8 alkenyl, -CrC8 alkynyl, substituted -Ci~. Alkyl, substituted -CrC8 alkenyl, substituted -C2_C8 alkynyl, _Cs~Ci2 cycloalkyl, -Cs-Cn cycloalkenyl, substituted ~C3 -cycloalkyl, or substituted -Cs -Cn cycloalkenyl. Z is selected from -C8 alkyl, _C2-Cs alkenyl, substituted -CrCs alkyl, or substituted -c2-c8 alkenyl. G is -NHS〇2~R3, wherein R3 is selected from aryl, substituted aryl, heteroaryl, substituted hetero 1150~9073-PF; Kai 15 200817031 -C3-C12 cycloalkyl, -C3 -k ring oxime or substituted ~C3-Cu cycloalkenyl. It is independently selected from the following heteroaryl and substituted heteroaryl groups. Aryl, heterocyclic, substituted heterocyclic, benzyl, substituted -C3 -C12 cycloalkyl, in yet another embodiment, X and) aryl, substituted aryl, C ( 0) 0 Ri, the towel 1 is -c3 - Ci2 cycloalkyl or substituted -^ cycloalkyl. l Select the _Gi_g channel base substituted by n-G8m. 2 is selected from -C2-C8 alkenyl or substituted C8 alkenyl. G is _NHSn, and t R3 is selected from _C3-C12 cycloalkyl or substituted C3_Ci2 cycloalkyl. Further, the examples 'X and Y are independently selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl. A is CCOhNH-Ri', and its R4_Ci_C8; or a substituted -[I-^ alkyl group. L is selected from {-(: ortho- or substituted sub-group. z is selected from ία-diluted or substituted-C2-C8 dilute group. g is m, where L is selected from -C3-C12 ring-burning A substituted or substituted _C3_Ci2 cycloalkyl group.

In another embodiment, X is a substituted or unsubstituted aryl group (for example, 'and oxime is a substituted or unsubstituted heteroaryl group (for example, \). Eight is selected from the following, &gt ; & ^ . Re-established private group · C(0)-Rl, -c(0)-〇, Ri and c(0) NH Ri, where b is selected from aryl, substituted aryl, Heteroaryl substituted heteroaryl, heterocyclic, substituted heterocyclic, prepared (10), ^& divalent U8 alkynyl, substituted anthracenyl, substituted c8 dilute, substituted alkyne Base...ring base, each Ci2 8

The substituted, substituted U ring group, or substituted _e3_el2 ′ H and Z can be independently selected from the group of 匕rh Gan · · · Cl-Cd, CC2_C8 alkenyl, —C2~Cs Alkyne 1150-9073-PF; Kai 16 200817031 yl, substituted-C-C8 alkyl, substituted _C2_C8 alkenyl, substituted-c2-c8 alkynyl, -c3~c12 cycloalkyl, -C3_Ci2 a cycloalkenyl group, a substituted cycloalkyl group, or a substituted _G3_Gi2 cycloalkenyl group. G may be _NHH or -nhs〇2-r3, wherein r3 is selected from _Ci_C8 leukoxene, C2_C8 refractory ,

Alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 8-heterocyclic, substituted heterocyclic, _C3-Ci2 ring, -C3_Ci2 ring, substituted -C3-c12 cyclodecyl, or substituted _C3_Ci2 cycloaliphatic, and ^ and R5 are each independently selected from: chloro, _Ci_C8 alkyl, C2_C8, -C4 alkynyl, substituted ~Cl- C8 alkyl, substituted -C2-C8 alkenyl, substituted -c2-c8 alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted Heterocyclic ring, -C3_C12 cycloalkyl, _C3_C12 cycloalkenyl, substituted ^-c3-Cl2 cycloalkyl, or substituted - ring dilute. Another f%, X 4 substituted or unsubstituted aryl (such as X) di Y is a substituted or unsubstituted heteroaryl (4) such as a): for the book r Rl or Qing H-R " Wherein: -Cl2 ring-based or substituted -C3-CU cycloalkyl 吖Γ A ^ A 7 ^ , from -C1~decyl or substituted -Ci-C8 alkyl. Z is selected from -C2 - C8 fluorenyl is -nhs 〇2-R3, wherein r3 is selected from - C2 - C8 alkenyl. G-C3-Cl2 cycloalkyl. , a 3~Cl2 cycloalkyl group or a substituted one in the present invention, which is a compound of the formula:

1150-9073-PF; Kai 17 200817031 (IV) or its pharmaceutically acceptable, ^ ^ I, ester or prodrug, alone or in combination - acceptable acceptable support for the 懿t or Where A, X, Z, and G are the same as the definitions of the specific examples above. In an embodiment, X is ν υ .^ γ is independently selected from the following group, square, substituted parent * ^ group: ^, square, heteroaryl, substituted Heteroaryl, substituted heterocycle, &, hetero-Cl~C8 alkyl, -c2-c8 alkenyl, -c2_c substituted -Cl-c8 alkyl, 8-block, di-, di-substituted -C2-C8 alkenyl, substituted alkynyl, -c3-c12 cycloalkyl, -c Γ γ| substituted ~c2, c8 C3 - (^23⁄4 alkenyl, substituted alkyl and substituted —c3 —Ci2 卜k cycloalkenyl, wherein each —C1-Cs alkyl, dilute, —C 2 —C 8 block, substituted 2C8, work-substituted-Ci-c8 alkyl, substituted alkenyl, and Substituted "alkynyl groups" independently comprise a hetero atom of 1 , c2, c8 from 0, .... a is selected from the group consisting of: = substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic ,: a heterocyclic ring, a -C, -C8 alkyl group, a fluorene-decene oxime substituted -C1-c8 alkyl group, a substituted C8 alkenyl group, a substituted Γ Γ ^ ^ ^ , an industrially substituted -C2~8 alkyne | -C3-C4 alkyl, -c3_Cl2 cycloalkenyl, ketone, or substituted (12 ring) L. and 7" of the C12 cycloalkyl group, which can be independently selected from the alkyl group, the -C2-C8 dilute group, the -c2 - c8 alkynyl group, the Ci~C8 group, and the -c丨- Cs alkyl, fine 1150-9073-PF; Kai 18 200817031 substituted -c2-c8 alkenyl, substituted _G eu ana I, -c3-C12 cycloalkyl, -Cs-Cn ring dilute, substituted -c3-c12 net, p A + ^ W alkyl, or substituted -C3_Ci2 cycloalkenyl. G may be -NH~S〇2 - nr4R5 of the formula MHQn η Κ4Κ5 or an NHS〇2 -& R3 is selected from -Cl-Cs alkyl, -C2-C8 alkenyl, -C c class I, substituted aryl, heteroaryl, substituted heteroaryl, alkaloid & a doped %, a substituted heterocyclic ring, a _C3-Ci2 cycloalkyl group, a C12 cycloalkenyl group, a substituted Ci2 cycloalkyl group, or a substituted -C3-C12 cycloalkenyl group, and each of 1 and 1 is independently Select from: hydrogen, sulphonyl, -CA alkenyl, each (8 fast-group, substituted benzyl group, substituted -C2-C8 alkenyl, substituted -cc 8 , a aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a hetero γ 、, a 10,000%, a substituted heterocyclic ring, -( : 3-(: 12cyclohexyl, -C3-C12 cycloaliphatic, substituted -C3 -Ci2 cycloalkyl, or substituted -C3 -C12 cyclophosphazene. In still another embodiment, X and γ is independently selected from the group consisting of a group thiol group, a substituted aryl group, a heteroaryl group, and a substituted group. A is -C(8)-〇-Rl or a C(8)_NH_Rl, wherein Ri is _^匕 基-c2-C8 dilute group, —c2_C8 block group, substituted _Ci_c8 alkyl group, taken-ca-alkenyl group, Substituted hexaacetylenyl...Μ"cycloalkyl, iridoid, substituted -C3_Cl2 cycloalkyl, or substituted C". L is selected from -C-C8 alkyl, -C2_C8 alkenyl'-C2_C8 alkynyl, :--c!-c8 alkyl, substituted-CrC8 alkenyl, substituted gan 2 C 8 fast radical, - (: 3-(: 12 cycloalkyl, _C3-Cl2 cycloalkenyl, substituted {a cycloalkyl, or substituted -Crk cycloalkenyl d selected from _Ci_C8 alkyl, ^^ thiol, Substituted -Cl_C8^, or substituted _C2_(tetra)yl^8'NHS〇2-R3' wherein R3 is selected from aryl, substituted aryl, heteroaryl': 150-9073-PF; Kai 19 200817031 Substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -C^cycloalkane-Cs-C!2 cycloalkenyl, substituted -G-L cycloalkyl, or substituted γ 环cycloalkenyl. 3 e 1 In yet another embodiment, X and γ are independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl. 1

Is -c(o)-0-Rl, wherein Ri is a "C3-c" cycloalkyl group or a substituted gas C 裱 alkyl group. L is selected from a -CrC8 alkyl group or a substituted -Ci-c8 alkane.乙 7 7 7 7 7 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 7 7 7 7 7 C3-Ci2 cycloalkyl. In another embodiment, X and γ are independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl. A is - C(0)~NH-Ri, wherein _ l is -Us alkyl or substituted - 1 乂8 alkyl. L is selected from -G-Cs alkyl or substituted -CrCs alkyl. -CrCs alkenyl or substituted -C2 -Cs alkenyl.g is -NHS〇2-R3, reoccupied ^ /, A R3 is selected from ~C3~Cl2% alkyl or substituted _C3-Cl2 Cycloalkyl. In one embodiment of the invention, a compound of the formula v: X3-X2 VI'

%,N

(V) or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination, a pharmaceutically acceptable carrier or excipient wherein X!-X4 is independently selected from

, I and N, wherein R7 is independently selected from 1150-9073-PF; Kai 20 200817031 (i) gas, halogen; -N 0 2 ;~c N · (i〇-M-R4, M is 0, s , NH(iii)NR4R5; (iv) -Ci-C8 alkyl-C2~c8 sharp i + pp (4) gan-8-yl or -C2-Cs alkynyl, each containing 〇, 1, 2 or 3 selected from 〇, 8痞\丨七灿店 2 / AN heteroatoms, substituted -Ci-C8 alkyl, substituted -C2_C8 alkenyl, tena said pp or substituted -C2 - C8 alkynyl Each comprising 〇, 1, 2 or 3 heteroatoms selected from 〇, 弋, an S or N; -C3-C12 cycloalkyl, or substituted -C3-Ci2 ring pn ^ , -Cs-Ci2% alkenyl, or substituted -C3-C12 cycloalkenyl; (v) aryl; substituted aromatic - earth, heteroaryl; substituted heteroaryl; and (vi) Heterocycloalkyl or substituted heterocycloalkyl;

Amt and R5 are the same as defined in the first specific example. In the embodiment - wherein X1 - X4 are independently selected from the definition of _CR4N, the same as described above. A is selected from the group consisting of -C(8), -c(0)-mc(0)_NH_Ri, where Ri is selected from an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group. a heterocyclic ring, a heterocyclic ring, a heterocyclic ring, a -CrG alkyl group, a -8 alkenyl group, a G-alkynyl group, a substituted -CrCs alkyl group, a substituted _C2_Cs alkenyl group, a substituted -CrG alkynyl group γ -G-Ci2, a -C3-C"cycloalkenyl group, a substituted _C3_Ci2 cycloalkyl group, or a substituted -Cs-Cu cycloalkenyl group. L and z can be independently selected from: alkyl , -CrC8 alkenyl, -C2-C8 alkynyl, substituted _Ci_C8 alkyl, face-substituted-C2-C8 alkenyl, substituted -C2-C8 alkynyl, -C3-Cl2 cycloalkyl-C3 -Ck cycloalkenyl, substituted -Crk cycloalkyl, or substituted ~ 1150-9073-PF; Kai 21 200817031

Cycloalkenyl. G can be -NH -s〇2 - NR R μ : 3⁄4 dragon b〇2 - r3, where & is selected from -Ch-C8 alkyl, -C2-C8 dilute, -C2 -c cautious * U Alkynyl, aryl, substituted aryl, heteroaryl, substituted heterocyclic, substituted four' anthracene, heterozygous, substituted heterocycle, -G - "% alkyl, C3 - C 1 2 cycloalkenyl, substituted γ h-glycol 1. % octagonal L3-(^23⁄4 alkyl, or substituted -C3 -Cl2 ring-dilute, and R and, respectively, the heart and the oxime are independent The choice is: hydrogen, a ο-^ alkyl, 〇2_〇8 alkenyl, -C2-sex Α λ- ^, u alkynyl, substituted -Ci-C8 alkyl, substituted - C2-C8 alkenyl, substituted _cc K wu U alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Cl2 a cycloalkyl K12 cycloalkenyl group, a substituted each of the k ring groups, or a substituted -C3-Cl2 cycloalkenyl group. In yet another embodiment, wherein X1 - X4 are independently selected from _CR7 and N, Wherein R? has the same definition as above. A is _c(〇)_〇_Ri or -CXCO-NH-Ri, wherein R1 is -匕-alkylene, _c2_C8 alkenyl, -G alkynyl, Substituted -CrCs alkyl, substituted -C2_C8 alkenyl, substituted -CA fast radical, "2 cycloalkyl, H2 cycloalkenyl, substituted -Cs-Ci2 cycloalkyl, or substituted" Cs-Ci2 cycloalkenyl. l is selected from - [丨-c alkyl, _C2 - C8 benzyl, -C2 - C8 alkynyl, substituted _ ς丨 - [8 burned _ substituted -CrC8 olefin A substituted C-C8 alkynyl group, a -G-Cis cycloalkyl group, a -c3-C12 cycloalkenyl group, a substituted -c3-C12 cyclodecyl group, or a substituted C12 cycloalkenyl group. Z is selected from -C1-C8 alkyl, -C2-C8 alkenyl, substituted -C1-C alkyl, or substituted -C2-C8 alkenyl. G is -NHS〇2 - Rs, wherein R3 Selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Ci2 cycloalkyl, -G-Cu ring, dry substituted -C3-Cl2 cycloalkyl, or substituted ~C3~Cl2 cycloalkenyl. 1150-9073-PF; Kai 22 200817031 In yet another embodiment, "independently selected from -CR? and N, wherein R7 is as defined by Xianli. A is _C(8)+1' where Ri is _C3_Cl2 cycloalkyl or substituted 1C, 2 ring alkyl. L is selected from Or substituted C8 base. z is selected from alkenyl or substituted C2 C8 alkenyl. G is an NHS〇2_R3 wherein L is selected from _C3_Ci2 cycloalkyl or substituted _C3_Cl2 cycloalkyl . In another embodiment, wherein Xl_X4 is independently selected from _ by 7 and N, and complex "7 is as previously defined. A is _c(〇)_NH_Ri, which is "winter. Dicalcinated or obtained - "彳-p Μ廿τ, 8 yuan soil. L is selected from -Ci-Cs alkyl or substituted A-C8 yard. z is selected from each G8 alkenyl or Substituted C8 dilute group. G is -NHS〇2-R3, wherein R柽 is selected from -G-Cu cycloalkyl or substituted -C3-C12 cycloalkyl. One embodiment of the present invention , V. J horse type VI is not a compound:

(VI) or a pharmaceutically acceptable pharmaceutically acceptable pharmaceutically acceptable pharmaceutically acceptable carrier or a proton thereof, or a combination thereof, wherein R7 is independently selected from ""Xl'X4 is independently selected from -(10) (1) hydrogen; spectrin; 2; _cn; (ii) H Μ is 〇, s, NH; (iii) NR4R5; H50-9073-PF; Kai 23 200817031 (ivkCrC8 alkyl, -h-C8 alkenyl or -C2_C8 alkynyl, each comprising hydrazine, 1, 2 or 3 heteroatoms selected from hydrazine, S or N; substituted -c"c8 alkyl, Substituted -c2-c8 alkenyl, or substituted ethynyl, each comprising hydrazine, 1 '2 or 3 heteroatoms selected from hydrazine, S or N; _C3_Ci2_ group, or substituted group; Ci2 ring-dense, or substituted-C3-Cl2 cyclodecyl; and (v) aryl; substituted aryl; heteroaryl; substituted heteroaryl; (vi) heterocycloalkyl or Substituted heterocyclic alkyl group; A, G, L, Z, 1 and R5 are the same as defined in the i-th embodiment. In one embodiment, the towels Xl-X4 are independently selected from _CR4N, in the bean ^ As just defined, A is chosen from the following group: -C(0)-R1, -C(0)-0-Rl&_c( _NH_Ri, wherein r is selected from substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, via heterocycle, -QC: cyclyl, -c2-c8 alkenyl u8 Substituted-C1-C8 leukoxyl, substituted (tetra)yl, substituted _C2_C8 block, -C3-C12 cycloalkyl, -C3-C12 cyclodecyl, substituted -C3_C12 cycloalkyl Or substituted -C3-Cl2 cycloalkenyl. L and z can be independently selected from: ca alkyl, -c2-c8 alkenyl, C8 alkynyl, substituted _c wide c, Substituted -CrC8 alkenyl, substituted _C2_C8 alkynyl, -G-c"cycloalkyl, -C"C,2 cycloalkenyl, substituted core 2 ring-form, or substituted H-cycloalkenyl G. may be -NH-SG2 - NR4R5 or _NHSQ2_R3, wherein R3 is selected from 2 _C1-C8f-based K8 alkenyl, G-block, aryl, substituted aryl, heteroaryl, substituted Heteropoly, heterocyclic, heterocyclic, heterocyclic, substituted, heterocyclic, -c3_c"1150-9073-PF; Kai 24 200817031, -c3 -Cl2 cycloalkenyl, substituted _C3 - Ci2 cycloalkyl, or substituted -C3~Cl2 cycloalkenyl, and R4 and R5 are each independently selected from Hydrogen, decylalkyl, -C^C8 alkenyl, -C2-C8 alkynyl, substituted-Ci_C8 alkyl, oxime-substituted-C-Csalkenyl, substituted _C2_C8 alkynyl, aryl, Second generation = aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Cuil alkyl, _C3_Ci2 cycloalkenyl, substituted -C3_c or substituted _C3_Ci2 Cycloalkenyl. 70, /: 3⁄4 In yet another embodiment, wherein X1-X4 are independently selected from _CR7 and N, where b is as previously defined. VIII is -c(8)_〇_Ri or -C(8)-NH-Rl, wherein RnC8 alkyl, _C2{alkenyl, 'c alkynyl, substituted-Cl-C group, substituted-C2_C8·, substituted a C8 alkynyl group, a C3_Cl2 cycloalkyl group, a C3_Ci2 ring group, a substituted -C3-C12 ring group, or a substituted _κΐ2 cycloalkenyl group. L is selected from -w alkyl, -c2-c8 dilute, c2_C8 alkynyl, substituted c-group, sister 8 substituted, phenyl group, substituted -C2-C8 block, =, substituted a cycloalkyl group, or substituted ... 2 ^ \ from -Cl-C8m'C8 alkenyl, substituted -Ci-h alkyl, or substituted indole 2-(;8 dilute. From aryl The substituted aryl group and the heteroaromatic odor are called I, and the substituents are substituted, the substituted heterocycle, the C12 cycloalkyl, and the C3_-hetero-c3- C12 cycloalkyl, or substituted 12 clothes, soil, n-doped ~C3-(:12 cycloalkenyl. In yet another embodiment - wherein Χι~Χ4 is independently selected from -C, wherein R? Previously defined. A , ^ _ horse C (〇) —〇-Ri, where p helmet-c3-CI2 cycloalkyl or substituted _c, "1 is the appearance of the base L from -C !-C8 1150-9073-PF; Kai 25 200817031 alkyl or substituted-Ci-C8 alkyl. z is selected from -c2-C8 alkenyl or substituted -c2-c8 alkenyl. G is -NHS 〇2-R3, wherein R3 is selected from —C3_Ci2 cycloalkyl or substituted —(:3-(:12-cycloalkyl. In another embodiment, wherein XhX4 is independently selected from _CR7 &a Np, where R7 is as previously defined. Man-made is 0)_肫_1?1, where 匕 is ^^^^^^^^^^^^^^^^^^^^^^ Substituted Ci c8. Z is selected from -c2-c8 alkenyl or substituted _C2_C8 dilute. G is -NHSO2-R3, wherein 淫六士人p-C3-C12 cycloalkyl. A specific example of the present invention

Κ3 is selected from -Cs-Ciz cycloalkyl or substituted by a compound of formula VII: or a pharmaceutically acceptable salt acceptable acceptor or excipient thereof, "two:: or combination - Pharmacy N, swollen 7, s, and sputum, φ D 1 3 independently selected from: CR7, /, and 1 independently selected from: (1) hydrogen; glutinin; 2; _CN; (ii)|R4 , 〇, s, NH; (iii) NR4R5; (iv)-C1-C8 alkyl 1, 2 or 3 selected from alkyl, substituted ~ dilute or alkynyl, each containing hydrazine, .8 Dilute: a hetero atom of N; substituted -Cl-C8 or substituted block, each package 1150-9073-PF; Kai 26 200817031

a fluorene, 1, 2 or 3 -C3-C12 cycloalkenyl group selected from a fluorene, a S group, or a substituted C 3 -C 2 cycloalkyl group; (v) an aryl group; a substituted aryl group; Or a hetero atom of N; - C3 - C12 naphthenic; - C3 - C12 cycloalkenyl, or substituted heteroaryl, substituted heteroaryl; (vi) heterocycloalkyl or substituted heterocycloalkyl ; A, G, l, Z, R4 and as defined in the first specific example. In one embodiment, wherein Υ!-Y3 is independently selected from -Cr7, N, s, and 〇, where R7 is as defined. A is selected from the group consisting of -C(〇)-, -c(0)-0-Ri and -(:(〇)-龙-1^, where Rl is selected from aryl, substituted Aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Cl-C8 alkyl, -CrGalkenyl, a-C8 alkynyl, substituted c8 alkyl, substituted -crc8 alkenyl, substituted -C2-C8 alkynyl, -G-Ci2 cycloalkyl, -C3-C"cycloalkenyl, substituted -Cs-Ci2 cycloalkyl, or substituted -G -Cucycloalkenyl. L and Z can be independently selected from: Cl - C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, substituted -Ci - 8 alkyl, substituted -CrC8 alkenyl, substituted -CrCs alkynyl, -Cs_Ci2 cycloalkyl, -C3-C"cycloalkenyl, substituted -G-Cl2 cycloalkyl, or substituted -C3 - c12 cycloalkenyl G may be an NH-S〇2-NR4R5 or -NHS〇2-R3, wherein r3 is selected from -Cl-Cs leucoyl, ~C2-Cs alkenyl, -C2-C8 alkynyl, aryl, Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C3-Cl2 cyclodextrin, -C3-C"cyclodecyl, substituted -c3 - C12 ring Burn a substituted or cycloalkenyl group, and R4 and fluorene are each independently selected from hydrogen, -CrCs alkyl, -C2-Cs, -C2-C8 alkynyl, substituted 1150-9073- PF; Kai 27 200817031

Ci C8 alkyl, substituted -C2_cs alkenyl, substituted -C2 - c8 alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted hetero Ring, -C3-C"cycloalkyl, -Cs-Cucycloalkenyl, substituted C3-Cl2 cycloalkyl, or substituted -c3-(:12cycloalkenyl. In yet another embodiment Where Υι-Y3 is independently selected from -CR7, N, NR?, S and 〇, where Rt is as previously defined. a is ~c(〇)Hi or -C(0)-NH-b, where 1 is -Cl-C8 alkyl, -C2_C8 alkenyl, -C2 -a fast radical, substituted -Cl-C8 alkyl, substituted _C2_Cs alkenyl, substituted -CrC8 alkynyl, -ο c"cycloalkyl, -Cs-cycloalkenyl, substituted -C3-C12 cycloalkyl, or substituted -C3_Cl2 cycloalkenyl. L is selected from -Ci - C8 alkyl, _C2-C8 alkenyl , -C2-C8 alkynyl, substituted -c-c8 alkyl, anthracene-substituted C2-C8 roasted group, substituted -C2-C8 fast group, -〇3~Ci2 ring-bright-C3-Cn ring Alkenyl, substituted -C3-C"cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. Z is selected from -CrC8 alkyl, -CrC8 alkenyl Substituted -C1_C8 alkyl, or substituted -CrC8 alkenyl. G is -NHS〇2-R3, 1 士 n-Nordan K3 is selected from aryl, substituted aryl, heteroaryl, Substituted heterogeneous, miscellaneous

Ring, substituted heterocyclic ring, -Cs-Cn cycloalkyl, -C3-c12A, oxime, substituted -C3_Ci2 cycloalkyl, or substituted -Cs-Ci2 cyclodecyl.

In still another embodiment, wherein YrY3 is independently selected from N NR7, S, and 0, wherein R? is as previously defined. A is sC(〇)n wherein Ri is a -C3-Ci2 cycloalkyl or a substituted -C3-Ci2 ring. 70丞. L is selected from -Ci-C8 alkyl or substituted -Ci-C8 alkyl. Z is selected from r 曰 - C2-C8 alkenyl

Or substituted -C2-C8 alkenyl. G is -NHS〇2-R3, and D L is selected from -C3-C12 cycloalkyl or substituted -c3-C12 cycloalkyl. 1150-9073-PF; Kai 28 200817031 In another embodiment, wherein iw3 is independently selected from _C]?7m, s and 〇, where b is as previously defined. A4_c(〇)u" wherein L is -C丨-C8 alkyl or substituted-C-Cs alkyl. L is selected from a decyl or substituted - Cl-C8 alkyl group. Z is selected from 彳 8 to evaluate the π U-C8 alkenyl group or the substituted -c2-c8 alkenyl group of the cycloalkane. G is - a foot such as ^, and its methyl group R3 is selected from a _c^ group or a substituted -C3-c12 cycloalkyl group. Compound:

In one embodiment of the present invention, it is represented by Formula VIII (VIII) or a pharmaceutically acceptable, pharmaceutically acceptable or prodrug thereof; 4, pharmaceutically acceptable cr7 > acceptable acceptor or beam alone or in combination a shape agent, wherein y N, NR?, S and 〇, the enemy, 3 are independently selected from r., and the reverse 7 is independently selected from (1) hydrogen; halogen · Millennium", , I·,;

(ιι)-Μ-R4 , M υ s, 龙· (iii)NR4R5 ; ' (iv)-C!-C8 Burn j, 1, 2 or 3 choices: C:, C: alkenyl or a C8 alkynyl group, each comprising a hydrazine, a decyl group, a substituted prosthetic or a hetero atom of N; substituted by a "π-containing quinone, a bis- or a ternary-substituted -G2-G8 block, or Substituted, C Γ from the hetero atom of W~" ί - (: 3-(: 丨 2 cycloalkenyl; earth, 2-cycloalkenyl, or substituted 1150-9073-PF; Kai 29 200817031 (v) aryl; substituted aryl; heteroaryl; substituted heteroaryl; or (vi) heterocycloalkyl or substituted heterocycloalkyl; A, G, L, Z, I and I is as defined in the specific example. In one embodiment, Υι-Y3 is independently selected from -CR7, N, nr"s and 〇, where R7 is as defined immediately. A is selected from the following The group consisting of: -C(〇)-h, -C(0)-〇-1 and -c(〇)-Off-Ri, which are selected from aryl, substituted aryl, heteroaryl, Substituted heteroaryl, heterocycle, substituted heterocycle, G group, each G8 alkenyl, -G-& alkynyl, substituted-c-C8 alkyl, substituted —C 2 —Cs alkenyl, substituted —C 2—C 8 alkynyl, —C 3−Ci 2 cycloalkyl, —C 3 —cls cycloalkenyl, substituted —C 3 —Ci 2 cycloalkyl, or substituted — GC! 2 cycloalkenyl. L and Z can be independently selected from: Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, substituted-Ci-Cs alkyl, substituted -C2-CS alkenyl, substituted-Cr Cs alkynyl, cycloalkyl, -C3-C" cycloalkenyl, substituted -G-cycloalkyl, or substituted C3-. cycloolefin G can be -NH-S〇2 - or _NHS 〇 2 - Ra, wherein the choice is from -CrC8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, aryl, Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted hetero, -C3-C!2 cycloalkyl, -C3-C"cycloalkenyl, substituted -C3 - Ci2 cycloalkyl, or substituted -G-C"cycloalkenyl, and R4 and R5 are each independently selected from hydrogen, -Cl-C8 alkyl, -C2-C8 alkenyl, -CrCs alkynyl, Substituted — C!—C8 alkyl, substituted —C 2 —Cs alkenyl, substituted —alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic , Substituted heterocyclic ring, -GC!2 cycloalkyl, -G-Cu cycloalkenyl, substituted 1150-9073-PF; Kai 30 200817031 -ο-c"cycloalkyl, or substituted-ο- . Cycloalkenyl. In yet another embodiment, wherein Υι_Υ3 is independently selected from _cr"n, and +[+7] is as previously defined. a is -(:(〇)ϋ or -C(0)-NH-Rl, Its towel nCi_C8 alkyl, _C2_C8 dilute, alkynyl, substituted -f ^ "alkyl, substituted -g-. alkenyl, substituted -c2-c8 alkynyl, -c3 - Cl2 a cycloalkyl group, a C3-Ci2 cycloalkenyl group, a substituted -C3-Cl2 cycloalkyl group, or a substituted -C3 - Ci2 cycloalkenyl group. L is selected from the group consisting of -CrC8 alkyl group, -C2-(tetra) group, —c 2 —c 8 alkynyl, substituted —Ci—c cyclyl, substituted —C 2−c8 alkenyl, substituted heptaynynyl, —C 3 —Ci 2 cycloalkyl, —C 3 —Cn cycloalkyl , substituted -Cs -^cycloalkyl, or substituted -C3-Ci2 cycloalkenyl. Z is selected from -c-polyc8 fluorenyl, a C2_Cs dilute, substituted -c "C8 alkyl, Or substituted -C2-Cs alkenyl. G is -NHS〇2-R3, wherein r3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted Heterocycle, each Ci2 cyclodextrin, -G-^ ring-dense, substituted-C3_Ci2 cycloalkyl, or substituted-Ci2 cycloalkenene In still another embodiment, wherein YrY3 is independently selected from -CR7, N, NR?, S, and 0, wherein R7 is as previously defined. A is _c(〇) - 〇 Ri, where Ri is -C3-Ci2 cycloalkyl or substituted -Cs-Ci2 cycloalkyl. L is selected from -CrCs alkyl or substituted -Cl-Cs alkyl. z is selected from -C2 - C8 alkenyl or via Substituted -C2-C8 alkenyl. G is _NHS〇2 - fluorene, wherein R3 is selected from -Cs-Ci2 cycloalkyl or substituted C3-C!2 cycloalkyl. In another embodiment, Wherein Yi - Y3 are independently selected from -CR7, N, NR7, S and 0, wherein R7 is as previously defined. a is a c(〇) off, where 1 is -(: 1-C8 alkyl or Substituted _Ci-Cs alkyl. L is selected from -CrCs 1150-9073-PF; Kai 31 200817031 «·*Acyl or substituted-C 1 _ C 8 alkyl. Z is selected from _C2-〇 8 unsubstituted or substituted -C2-C8 alkenyl. G is -NHS〇2-R3 wherein R3 is selected from -C3-C12 cycloalkyl or substituted -C 3 -C 1 2 cycloalkyl. Representative compounds of the invention, including, but not limited to, compounds of formula IX below (Table 1): 9

(IX) Table 1 Example ALQ ζ G 11 V -CH=CH2 Λ?ν 12 person / ΝγΝ -CH=CH2 13 person / ', winter v -ch=ch2 /, ^v 14 丨, winter - CH Two CH2 Λ?ν 15 people / V -ch=ch2 //v 1150-9073-PF; Kai 32 200817031 16 乂Jy V -CH-CH2 /, ^v 17 person / V 1 -ch=ch2 18 ΛΛ Y -ch=ch2 19 people again / /丫NvN -ch=ch2 /, Xr Η 1 20 From yr V -ch=ch2 /iXr Η I 21 ΛΛ N, -ch=ch2 /X- H | 22 people/ B heart n, n, n 1 -ch=ch2 /〇, vp Yr 23 ΛΛ ΝγΝ -ch=ch2 Yr 24 person again / NVN -ch=ch2 25 ΛΛ -ch=ch2 1150-9073-PF/Kai 33 200817031 26 People again / ,, winter NVN -ch=ch2 43⁄4 27 乂Λ, B heart V 1 -ch=ch2 28 people / γ -ch=ch2 43⁄4 29 people again / V -ch=ch2 gas 3 30 V -ch= Ch2 31 φ V -ch=ch2 / gas 32 ΛΛ , ,, Β Β heart%, Ν 1 -CH-CH2 / gas 33 Λ1< γ -CH=CH2 / gas 34 person / Νί> -CH-CH2 /汾Ν, 35 people again / ηΡ γ -ch=ch2 bamboo, > Ν \ 1150-9073-PF/Kai 34 200817031 36 乂. Also / HP V -CH=CH2 'ϋ,〉 N \ 37人又/ V -ch=ch2 'HN,> N \ 38 people again / > VN 1 -ch=ch2 'ϋ,> N \ 39 NVN 1 -ch=ch2 /^v 40 ^Λ/ V 1 -CH-CH2 41 Wen. Also / !L -ch=ch2 42 iQkA/ nVn -ch=ch2 Vv 43 Λ1< o^T nVn -ch=ch2 /^v 44 〇^〇A/ /, f nVn - ch=ch2 45 <Vy /丫nVn -ch=ch2 1150 — 907 3 — PE1,· Kai 35 200817031 46 〇kA, / V -ch=ch2 47 MeO^0^^ a^p°' nVn -ch=ch2 Λίί'ν 48 ΛΛ , , Winter t^. , V -ch=ch2 49 〇人/, fo^p°' Y -ch=ch2 Λ?ν 50 〇〇lp〇' V -CH-CH2 w 51 a^fi0' γ -CH=CH2 52 Al< o ^TY -ch=ch2 /7v 53 a. Also o^fi0' V -ch=ch2 54 CXA V -CH-CH2 1150-9073-PF; Kai 36 200817031 55 (λ., -CH-CH2 56 a Λ1< o^p0' nVn -ch=ch2 57 , Also / /, f ΝγΝ -ch=ch2 /7v 58 αΛ Winter γ -ch=ch2 /, ^v 59 , and / UjS' V -ch=ch2 /, ^v 60 0 again / ύ^ρ°' V -ch=ch2 A?v 61 〇Fv^n person / o^p0' V -ch=ch2 //v 62 o^fi0' V -ch:ch2 W 63 <X/ Λ1< γ -ch=ch2 1150 -9073-PF; Kai 37 200817031

64 o^p0' V -ch=ch2 65 CA/ Al< a^p0' V -ch=ch2 /^v 66 Me ο^ρ0' ΝγΝ -ch=ch2 A?v 67 ',冬ο^ρ0' V -ch=ch2 68 〇Me^yV ΗΝΛ/1β ,,, winter fj^p0' V -ch=ch2 /^v 69 Mei^ Me 〇lp°' nVn -ch=ch2 70 HN^ Λ1< V -CH- CH2 71 a1, Λ1< o^p -ch=ch2 z/v 72 Λ1< a^p°' ΝγΝ -ch=ch2 W 1150-9073-PF; Kai 38 200817031 73 Af nVn -ch=ch2 //v 74 Ap nVn -ch=ch2 /^v 75 ', 〇Ϋ -ch=ch2 //v 76 aJ〇Ϋ -ch=ch2 w 77 again / t\p°' Ϋ -ch=ch2 78 afi0' ΝγΝ -ch= Ch2 /, ν) Ί H kj) 79 0^, V -CH 2 CH2 /, N meaning N~| H Ο^0Η3 80 V -ch=ch2 /)^0 H, 1 H 81 ^〇A/ V -ch=ch2 39 1150-9073-PF/Kai 200817031

82 A1< afi0' ΝγΝ -CH-CH2 83 ^〇A/ ,, winter nVn -CH-CH2 84 /, f nVn - CH=CH2 85 /, f noisy. — Ϋ -ch=ch2 86 ,, winter V -ch=ch2 87 Al< 〇lp〇' V -ch=ch2 aXh2 H 88 /, fo^T nVn -ch=ch2 /v« Η H 89 Ϋ -ch= Ch2 /, ΧΛ > Η H 90 /, f V -CH 2 CH2 aXF3 H 1150-9073-PF; Kai 40 200817031 91 ^〇A/ A1< -ch=ch2 /3⁄4 92 ύ^ρ0' V -ch=ch2 93 ^〇A/ /卞ο^ρ V -ch=ch2 94 ο^ρ°' γ -ch=ch2 /^rF 95 ^〇A/ ο^ρ°' V -ch=ch2 /, x人Η H 96 ύ^ρ° V -ch=ch2 /, N Η H 97 ύ^ρ°' V -ch=ch2 /'ΧΛ H 98 ,, winter α^ρ°' V -ch=ch2 /3⁄4 99 /, f ύ^°' -ch=ch2 /3⁄4 1150-9073-PF; Kai 41 200817031 100 a〇A/ Ϋ - H /, heart Η V 101 V -CH2CH3 102 a〇A/ Λ1< nVn -CHF2 /, [ ^v 103 -CH=CH2CH3 /, [?Pv The present invention is a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, ester or prodrug thereof. According to another embodiment of the present invention, the pharmaceutical composition of the present invention further comprises other anti-HCV agents. Examples of anti-HCV agents include, but are not limited to, dry k (eg, alpha-interferon, /?-interferon, consensus interferon, long-acting interferon, or interference with albumin or other conjugation)素), ribavarin and amantadine. 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); US5861297 (1999); and US2002/0037998 (2002), 1150-9073-PF/Kai 42 200817031 Complete This is incorporated herein by reference. According to another embodiment, the pharmaceutical composition of the present invention may further comprise other HCV protease inhibitors. According to still another embodiment, the pharmaceutical composition of the present invention may further comprise 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). According to another embodiment, the pharmaceutical composition of the present invention may further comprise other anti-bacterial, anti-fungal or anti-cancer agents or immunomodulators or other therapeutic agents. According to 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 compound of the invention or a pharmaceutically acceptable salt, ester or prodrug thereof . According to another embodiment, the present invention comprises a method of treating an individual infected with a type C hepatitis in need of treatment, which comprises administering to the individual an effective amount or an amount of the pharmaceutical composition of the present invention against an anti-Hcv virus. In accordance with another embodiment of the invention, the invention includes a method of treating a biological sample by contacting the biological sample with a compound of the invention. In accordance with another aspect of the invention, the invention includes the use of any of the synthetic methods described herein for the manufacture of any of the compounds represented herein. Definitions The definitions used to describe the various terms of the invention are set forth below. These are defined by the terms 1150-9073-PF; Kai 43 200817031, unless otherwise stated in the particular case of an individual or a larger group, which applies to this specification and the scope of the patent application. The term "r Cl_C6 炫基" or "Ci_C8 院基基", as used herein, means a saturated straight or branched chain hydrocarbon containing a group of 6 or 8 carbon atoms. Examples of the Ci-C6 alkyl group include, but are not limited to, an anthracene group, an ethyl group, a propyl group, an isopropyl mtributyl group, a neodecyl group, a n-hexyl group, and an example of a G-C8 alkyl group. Including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, ternary tributyl, neopentyl, n-hexyl, heptyl, octyl radicals. The term "C2_C6 alkenyl" or "C2_C8 dilute" as used herein refers to a monovalent group derived from a hydrocarbon moiety by removal of a single hydrogen atom, wherein the moiety each contains 2 to 6 carbon atoms or 2 to 8 carbon atoms and having up to two slave-carbon double bonds. The alkenyl group includes, but is not limited to, for example, an ethylene group, a propyl group, a butenyl group, a methyl-2-butene+ group, a heptenyl group, an octenyl group or the like. The term "C2_Ce block base" or "C2_c8 block = single-chloride atom is derived from a monovalent group derived from the smoke moiety, and its J ° "" each contains 2 to 6 carbon atoms or 2 to 8 One carbon atom, and: - a dish - carbon triple bond. Representative block bases include, but are not limited to, for example: base, b-block, b-block, heptyl, octyl, and the like. , : The term "C3 - C8_cycloalkyl" or "Μ" - ring, !: derived from a mono- or polycyclic saturated carbocycle = monovalent group derived from the removal of a mono-chloro atom 'In the oxime, the carbon ring has 3 to 8 carbon atoms per carbon-mono-alkyl group. Examples include, but are not limited to, propyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl. And cyclooctyl; 1150-9073-PF; Kai 44 200817031 and c3 - c 12 - cycloalkyl, for example, to red hydrazine including but not limited to: cyclopropyl, cyclobutyl, decyl, cyclohexyl, Bicyclo [221] heptyl and bicyclo [2·22] octyl. For this purpose, use 5 "C3'C8~cycloalkenyl" or "C3-C12-cycloalkenyl", which means that it is removed from the earlier atom and has at least one carbon-carbon double bond. a monovalent group of a monocyclic or polycyclic saturated carbocyclic compound, wherein the carbocyclic ring has 3 to 8 carbon atoms or 3 to 12 carbon atoms each.

Examples of the group include, but are not limited to, 1 propylene, cyclobutyl, cyclopentyl, hexenyl, cycloheptenyl, cyclo (tetra), and the like; and examples of the mino group include, but are not limited to, cyclopropyl A group, a cyclobutenyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptenyl group, a cyclooctenyl group or the like. / The term "aryl" as used herein means: a monocyclic or polycyclic carbocyclic ring, which has one or two aromatic rings, including but not limited to phenyl, zeyl, tetrahydronaphthyl, Indanyl, indenyl W (soil) refers to a Cl-C3 alkyl group or examples include, but are not limited to, the term "arylalkyl C1 - C e burned residue" as used herein. The group is attached to an aryl ring, a phenylethyl group, etc. The term "heteroaryl" as used herein means a monocyclic, bicyclic or tricyclic aromatic radical or a ring having 5 to 1G rings. An atom, one of which is selected from, for example, S, 〇, and N; Q, ! or 2 ring atoms are additional heteroatoms, independently selected from, for example, s, 〇, and N; and the other ring atoms are carbon Heteroaryl groups include, but are not limited to, pyridinyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl , thienyl, furyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, quinoxalinyl, etc. 1150-9073-PF/Kai 45 200817031 used here The term "hetero, heterocyclic base" means that a Ci-G alkyl or CcC6 fluorenyl residue is attached to __^, and the α^ heteroaryl group is bad. Examples include, but are not limited to, pyridyl The base, pyrimidinyl, ethyl, etc. The term "hetero" and "heterocycloalkyl" as used herein can be used interchangeably with each other. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ a ring, or a di- or tricyclic group fused system, wherein (1) each ring contains U 3 heteroatoms' independently selected from hexamethylene and nitrogen, and (11) each 5-membered ring has 〇 to 1 double bond And each of the 6-membered rings has U to 2 double bonds; (iii) the nitrogen and sulfur heteroatoms can be optionally oxidized. > 1 v) The δ-helium heteroatoms can be optionally quaternized 'and ν) Any of the above rings can be a little 5 in one ring. Representative heterocycloalkyl groups, including but not limited to: [丨L, ό", 戍 戍, π 嘻 嘻 定 、, σ 唑 琳 琳 、 、 、 口 唾 唾 唾 唾 唾 唾 咪 咪 咪 咪 土Not decyl, hexahydropyridyl, piperidinyl, aziridine, isoxazolyl, marinyl, thiazolidinyl, isothiazolidinyl and tetrahydrofuranyl. These ^ Temple coat groups can be further substituted to the substituted heterocyclic ring. As used herein, the term "deuterium" refers to the substitution of the original _ ρ 2 or 3 or more hydrogen atoms as a substituent, including but not limited to, a protected amine group, an off-alkyl group, —·, must, —NH—C2-Ci2-alkenyl, a nh — c #Cl 2 alkyl, —NH—aryl, —off—heterocyclyl, —NH—heterocycloalkyl, —alkyl Month-female, diarylamino, -diheteroarylamino, -〇-C丨-Ci2-calcined lanthanum L2 Ll2-alkenyl,-0-C2-C12-ene di-C:-Cl2 'Alkyl, ~fluorene-aryl, -heteroaryl*,-0-heterocycloalkane i - (8) alkenyl, -c(8)_C2_Ci2_ _ C1 Br, ~1, -〇Η, protected hydroxy, -Ν〇2, - CN,-brain, 1 2-dilutyl 1150-9073-PF; Kai 46 200817031 alkenyl, cycloalkyl, -c(0)-aryl, -c(〇)_heteroaryl, -C(0 - heterocycloalkyl, -CONH2, -CONH-Cl-Cl2 - alkyl, -C〇NH_C2 - Ci2_ alkenyl, -c〇NH-c2, Cl2_alkenyl, -CONH-C3~Ci2 - cycloalkane , -c〇NH-aryl, -CONH-heteroaryl, -C0NH_heterocycloalkyl, _〇c〇2 - Ci_Ci2-alkyl, -〇C〇2-C2-c12~alkenyl, - OC〇2-c2 —Cl2—alkenyl, _ C〇2_c3 —Ci2_cycloalkyl, —OC〇2~aryl, —〇c〇2-heteroaryl, —〇c〇2—heterocycloalkyl, —0C0NH2, —0CONH-CrCu—alkyl,- 0C0NH-C2-C12-alkenyl, -0C0NH-C2-C12-alkenyl, -0CONH-c3-Cl2-cycloalkyl, -〇c〇NH_ aryl, -0CONH-heteroaryl, -0CONH_heterocycle Alkyl, -NHC(〇)_Ci -Ci2_alkyl, -NHC(O)-c2-C12-alkenyl, -NHC(0)-C2-C12-alkenyl, -NHC(O)-C3-C12- Cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHC〇2 - Cl-Cl2 -alkyl, -NHC〇2_C2 -Ci2_alkenyl, -NHC〇2-C2-C12-alkenyl, -NHC02-C3-C"-cycloalkyl, -NHC〇2-aryl, -NHC〇2-heteroaryl, -NHCO2- Heterocycloalkyl, -NHC(0)NH2, -NHC(0)NH-Κ12-alkyl, -NHC(0)NH-C2-C12-alkenyl, -NHC(0)NH-C2-c12-ene , -NHC(0)NH-C3-C12-cycloalkyl, -NHC(0)NH-aryl, -NHC(0)NH-heteroaryl, -NHC(0)NH-heterocycloalkyl, NHC(S)NH2, -NHC(S)NH-CrCu-alkyl, -NHC(S)NH-c2-C12-alkenyl, -NHCCS^H-C2-. - alkenyl, -NHC(S)NH-C3-C12-cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocyclic , -NHC(NH)NH2, -NHC(NH)NH-CrC!2-alkyl, -NHC(NH)NH-C2-C12-alkenyl, -NHCUIONH-Cg-Cu-alkenyl, -NHC( NH)NH-G-Cu-cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, 1150-9073-PF /Kai 47 200817031 -NHC(NH)-Ci-C12-alkyl, -NHC(NH)-C2_Cl2-alkenyl, -NHC(NH)-C2-C12-alkenyl, -NHC(NH)-C3-C12 -cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -CXNIONH-CrC12-alkyl, -C(NH)NH_C2_Cl2- Alkenyl, -C(NH)NH-C2-C12-alkenyl, -c(NH)NH-C3-C12-cycloalkyl, -C(NH)NH-aryl, -c(NH)NH- Aryl, —c(NH)NH-heterocycloalkyl, _s(o)-CrC12-alkyl, —S(0)—C 2 —Cl 2 —alkenyl, —s(〇)—C 2 —alkenyl, —S (0)-C3-C12-cycloalkyl, -S(0)-aryl, -S(〇)-heteroaryl, -S(0)-heterocyclic alkyl-s〇2NH2, -S〇2NH -Ci-Ci2-alkyl, -S〇2NH-C2-C12-alkenyl, -s〇2NH-c2-C12-alkenyl, _S〇2NH-c3-c12~cycloalkyl, -SChNH-aryl, Heteroaryl -s〇2NH-heterocycloalkyl, -NHS〇2-Ci-Ci2-alkyl, -NHSO2-C2-C12-alkenyl, -NHS〇2-C2-Ci2~ alkenyl, -NHSOrC3-Cu- Cycloalkyl, -NHS〇2-aryl, -NHS〇2-heteroaryl, -NHSOr heterocycloalkyl, -CH2NH2, -CH2S〇2CH3, -aryl, arylalkyl, -heteroaryl, —heteroarylalkyl, —heterocycloalkyl, —C 3 —Ci 2 —cycloalkyl, polyalkoxyalkyl, polyalkoxy, —methoxymethoxy, —methoxyethoxy, —SH , ~S-CrC12-alkyl, -S-C2-C12-alkenyl, -S-C2-C12~ alkenyl, -s-c3-c12-cycloalkyl, -s_aryl, -s- Aryl, -s-heterocycloalkyl or mercaptothiomethyl. 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 a substituted structure may be additionally optionally substituted with one or more groups, each group being independently selected from: -F, -π, -Br, -I, -0H, -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 can be substituted 1150-9073~PF; Kai 48 200817031 or unsubstituted. * It is to be understood that any of the alkyl, alkenyl, fast-radical, cycloalkyl and cyclo-radical 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 contain any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, orthopax, or his atoms, and

Intentionally includes one or more of the two keys and/or three keys. The aliphatic group may be linear, branched or cyclic, preferably containing from about up to about 24 broken atoms, more typically from about i to about _ carbon atoms. In addition to the aliphatic hydrocarbon group, the aliphatic group includes, for example, a polyalkylene group, such as a polyalkylene glycol, a polyamine, and a polyimine. These aliphatic groups can be further substituted. It is understood that the aliphatic group can be used in place of the alkyl, dilute, 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 gas atom. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bis-[2.2.1]heptyl, and biguanide [2.2.2] octyl. These alicyclic groups can be further substituted. Obviously, in each of the embodiments of the present invention, the substituted or unsubstituted alkyl, fluorenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryloxy, heteroaryl The base and the heterocyclic group are intended to be monovalent or divalent. Thus a alkylene, alkenylene and alkynylene group, a cycloalkylene group, a cycloalkenylene group, a cycloalkylene group, an arylalkylene group, a heteroarylalkylene group and a heterocyclic alkylene group, The above definitions and can be applied to provide structural formulas here at appropriate valences. As used herein, the terms "halogen" and "halogen" refer to atoms selected from the gas, 49 1150-9073-PF; Kai 200817031 gas, bromine and iodine. As used herein, the term "hydroxyl activating group" refers to a labile chemical structure which is known in the art to activate a hydroxyl group for detachment during a synthetic step, such as a substitution or elimination reaction. Examples of hydroxyl activating groups include, but are not limited to, sulfonate, tosylate, trif luoromethanesul fonate, nitrostanoate, phosphonate, and the like. The term "activated hydroxyl group" as used herein, refers to a radical activation group as defined above, including, for example, fluorite, toluene, triflate, launobenzoate, phosphonate, Activated hydroxyl group. The term "protected hydroxy" as used herein, refers to a radical protecting group as defined below, including, for example, benzamidine, ethenyl, trimethylsulfanyl, triethyldecyl, methoxy. Methyl, the protected hydroxyl group. The term "radioprotective group" as used herein refers to a restless chemical structure which is known in the art to protect the meridine from undesired reactions during the synthesis. The base protecting group described herein can be selectively removed after the synthesis process. Hydroxy protecting groups are generally described in Τ·Η·Greene and P.G.m. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New

York (l 999). Examples of the hydroxy protecting group include a benzyloxycarbonyl group, a 4-nitrobenzyloxycarbonyl group, a 4-bromobenzyloxycarbonyl group, a 4-decyloxybenzyloxycarbyl group, a methyl lactyl group, and an anthraquinone group. Dibutoxy, isopropoxy, diphenylmethoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl '2-(trimethyldecyl)ethoxycarbonyl, 2-oxime Oxycarbonyl, allyloxycarbonyl, ethyl fluorenyl, carbhydryl, 1150-9073-PF/Kai 50 200817031 chloroethinyl, triethylene ethane, methoxyethyl, phenoxy Base, phenyl fluorenyl, methyl, tert-butyl, 2,2,2-trichloroethyl ' 2-trimethyldecylethyl, 1, dimethylene-2-propenyl, 3_ Methyl-3-butenyl, :propyl, benzyl, p-methoxyl-diphenylmethyl, triphenylmethyl(trityl), tetrahydrofuranyl, anthracene Base, methylthiomethyl, benzyloxymethyl, 2,2'2-dichloroethoxymethyl, 2-(trimethyldecyl)ethoxymethyl, methylsulfonyl, p-nonyl Sulfhydryl, tridecylalkyl, triethyldecyl, diisopropyldecyl, and the like. In the present invention, preferred hydroxy protecting groups are: ethyl hydrazino (Ac or -C(0)CH3), benzamidine (with or ruthenium (7) crystal) and trimethyl decyl (TMS or -Si (CH3) ) 3). The term "amino protecting group" as used herein, refers to a restless chemical structure which is known in the art to protect an amine group from undesired reactions during the synthesis. The amine protecting groups described herein can be selectively removed after the synthesis process. Amino protecting groups are known generally as described in Τ·Η·Greene and P.G.m. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New Y〇rk (1 999). Examples of the amine protecting group include, but are not limited to, a third butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a benzyloxycarbonyl group and the like. The term "protected amine group" as used herein, refers to an amine group protected by an amine protecting group as defined above. The term "alkylamino" as used herein, means a group having a C!2 alkyl) structure, wherein the Ci-C!2 alkyl group is as defined above. The term "mercapto" as used herein, includes residues derived from acids including, but not limited to, carboxylic acids, carbamic acids, carbonic acid, tartaric acid, and squaric acid.实1150-9073-PF; Kai 51 200817031 Examples include aliphatics, ^, earth, scented carbonyl, aliphatic sulfonyl, aromatic sulfhydryl, aliphatic & s, aromatic phosphoric acid Roots 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 9- to 2-hydroxy acetyl group, and the like. As used herein, the term "north π〇 non-bean solvent" means a solvent which is quite inert to proton activity, and also does not recognize P as a proton donor. Examples include, but are not limited to, hydrocarbons, for example? # 曱本' For example, · Halogenated hydrocarbons, for example, ··············································

: Dedicated 'heterocyclic compounds, such as tetrahydrofuran and "pyrrolidone and screaming, such as bis- succinyl, dimethoxymethyl, such pharmaceutically acceptable, are well known to those skilled in the art, and For those skilled in the art, each of the preferred solvents or mixtures is readily available for the particular compound and reaction conditions, such as the solubility of the agent, the reactivity of the agent, and the preferred range of reaction. Further discussion of aprotic solvents can be found in organic chemistry textbooks or in specific monographs such as: Organic Solvents Physical Pr〇perties and methods of Purification, 4th ed. , edited by John A.Riddick et aL, Vol. II, in The Techniques 〇f Chemistry Series, John Wiley & Sons, Νγ, 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 methanol, ethanol, propanol, isopropanol, butanol, Tributanol and the like. Such compounds are well known to those skilled in the art and are known to those skilled in the art for each particular compound and reaction conditions, such as the solubility of the agent, the reactivity of the agent, and the preferred range of reaction. Preferred solvents or 1150-9073-PF; Kai 52 200817031 Mixtures are readily apparent. Further discussion of proton-solving solvents can be found in organic chemistry textbooks or in specific monographs such as: 〇rganic Solvents Physical Properties and methods of Purification, 4th ed. , edited by John A. Riddick ei , Vol. II, in the Techniques Of Chemistry Series, John Wiley & Sons, NY, 1986. The compounds described herein contain one or more asymmetric centers and are capable of producing enantiomers, diastereomers, and other stereoisomeric forms, as defined by absolute stereochemistry. (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 racemates thereof, as well as optically pure forms. Optical isomers can be prepared by subjecting their respective optically active precursors to the above procedures or by resolution of the racemic mixture. This analysis can be carried out in the presence of an analytical agent by chromatography or repeated crystallization or a combination of techniques known to those skilled in the art. For more details on analysis, see Jacques, etal·, Enantiomers, Racemates and ReS〇luti〇ns (John Wiley & s〇ns, 1981). When the compounds herein contain olefinic double bonds, other unsaturated or other geometric asymmetric centers' and unless otherwise indicated', it is meant that the compounds comprise E and Z geometric isomers or cis and trans isomers. Similarly, all tautomeric forms are also included. The construction of any carbon-carbon double bond shown herein is convenient, unless so recited herein, and is not intended to specify a particular structure'. Thus, any carbon-carbon double bond or carbon herein. - The hetero atom double bond is depicted as a trans-'may be cis, and 4, or a mixture of the two in any ratio. 1150-9073-PF; Kai 53 200817031 The term "individual" as used herein, means - mammal. - Individuals refer to, for example, dogs, I seedlings, horses, cattle, pigs, one person, _ m, two milk special. The individual is preferably a human. The individual is a human, and the individual may refer to a patient herein. The term "pharmaceutically acceptable salt" as used herein means that the _ is in the scope of adequate medical judgment ^ is suitable for tissue contact in humans or lower animals without adverse toxicity, irritation, Allergic reactions, etc., and the proportion of the cup/risk of the mouth is proportional. Pharmaceutically acceptable practices are well known to those skilled in the art. For example: S m. Berge, the minds of the pharmacy can be connected to the salt in the case of j. Pharmaceutical Scie (4) Bu 19 (1977). The salt can be prepared in situ when the final isolation and purification of the compound of the invention is carried out or separately by reacting the free base with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, salts of amine groups, and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids, for example Preparation of acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by other methods in the art, such as ion exchange. Other pharmaceutically acceptable salts, including but not limited to: hexanoate, alginate, ascorbate, aspartate, besylate, benzoate, hydrogen sulfate, borate, butyrate , camphorate, camphor sulfonate, citrate, cyclopentane propionate, digluconate 'dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptane Acid salt, glycerin phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, lactate, laurate, laurel Sulfate, malate, maleate, malonate, sulfonate, 2-naphthalenesulfonate, nicotinic acid, nitrate, oleate, grass 1150-9073-PF; Kai 54 200817031

Acid, salt, palmitate, Pamoate, acidate 'persulfate, 3-peptidyl propionate, phosphate, picrate, trimethylacetate, propionate, hard a fatty acid salt, a phlemate salt, a sulfate salt, a tartrate salt, a thiocyanate salt, a p-toluenesulfonate salt, an eleven carbonate salt, a pentane salt, and the like. Representative alkali or alkaline earth metal salts, including: sodium, bell, bell, #5, magnesium, and the like. Other pharmaceutically acceptable salts, including the appropriate use of counterions such as vapors, hydroxides, sulphate, sulfate, sulphonate, bowl acid, alkyl groups having from 1 to 6 carbon atoms, sulfonates and aryl groups Acidic acid, formed of non-toxic ammonium, quaternary ammonium and amine cations. The term "pharmaceutically acceptable ester" as used herein, refers to an ester which hydrolyzes in the body and which comprises an ester which readily disintegrates in the human body and leaves the parent compound or a salt thereof. Suitable esters include, for example, those derived from pharmaceutically acceptable 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, citric acid, acetic acid vinegar, propionic acid vinegar, butyric acid vinegar, acrylate, and ethyl succinate. The term "pharmaceutically acceptable pre-drugs" as used herein means that such sputum-driving drugs of the month are within the scope of adequate medical judgment and are suitable for tissue contact of humans or lower animals, without There will be unfavorable toxicity, irritation, allergies, and a reasonable benefit/risk ratio is commensurate, and:: it is effective in use, and when possible, a zwitterion of the compound of the present invention. As used herein, "as hydrolyzed" can be converted to the body by metabolism (for example, in any compound of Taigu. Many forms of prior beams are known in the art, for example: discussed in Bundgaard, (ed), H50~9073-PF; Kai 55 200817031

Design of Prodrug, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol_ 4, Academic Press (1 985); Krogsgaard-Larsen, etal·, (ed), ''Design and Application of Prodrug, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8: 1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et Seq. ( 1 988); Higuchi and Stella (eds. ) Prodrug as Novel

Drug Delivery System, American Chemical Soci ety (1 975); and Bernard Testa & Joachiininayer, "Hydrolysis In Drug And Prodrugmetabolism:

Chemistry, Biochemistry And Enzymology,,, j〇hn Wiley and Sons, Ltd. (2002) 组合 The combinations of substituents or variations contemplated by the present invention are only those which form stable compounds. As used herein, the term "stabilized" means that the compound is sufficiently stable to permit manufacture and can be used for the purposes described herein (for example, for a

To understand. In addition, the synthetic chemical conversions and methods that are expected to have the desired knowledge of the technical field have common knowledge.

Compound. . Useful for the synthesis of the compounds described herein is 1150-9073-PF; Kai 56 200817031 Protective group methodology (protection and deprotection), well known to those skilled in the art, including, for example, as described in R. Larock, Comprehensive Organic Transformations , VCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser andm. Fieser, Fieser and Fieser, s Reagents for

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

Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1955) and later. 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 (eg, blood, lymphatic system, mediastinal nervous system), increased oral administration, increased solubility so that injection can be administered Give, change metabolism and change excretion rate. Pharmaceutical Composition + The pharmaceutically acceptable composition comprises one or more of the formulas, or one or more pharmaceutically acceptable elixirs. The term "筚 and .../ - the support or shape of the body / the acceptable acceptor or the meaning of a non-toxic, inert solid, β", encapsulated material, bite 咅 咅 a Liquid fillers, thinners, & "types of formulas. An acceptable example of a carrier, A as a learning starch, such as jade #妒私K j 糖糖 and 庶糖; 王"粉和马钤Potato starch; cellulose, for example, betray methyl fiber to "bamboo organism, earthworm, sodium, ethylcellulose, finalized xanthine gum; malt; f acetyl ester; powdered moon, talc: Excipients such as cocoa r 1150-9073-PF; Kai 57 200817031 Mian Xuan oil, safflower oil such as propylene glycol; 酉 oil, withdrawal of oleic acid and suppository wax; oils such as peanut oil, linseed oil, corn and soybean oil Glycol, ethyl vinegar and lauric acid; qiongyue; buffering agents, such as oxidized water and oxidized m-pyrogenic water; isotonic saline; Ringer's solution; ethanol and sulphate buffer solution, And the cardamom & main alpha, ^ and its non-toxic compatible lubricant, depending on the formulation of the formula _ It can also be present in the present compositions. The pharmaceutical composition of the invention may be administered orally, rectally, parenterally, via the brain pool such as sodium lauryl sulfate and magnesium stearate, as well as a coloring agent, a release agent, a filming agent, a sweetener, a flavoring agent and Aromatic agents, preservatives and antioxidants, (intracisternally), transvaginal, transabdominal, topical "column, powder ointment or drops", sputum or oral or nasal spray. Oral administration of liquid dosage forms, including Pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may comprise inert diluents conventionally used in the art, for example: water or other solvents, solubilizing agents And emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, butanediol, dimethylformamide, oil (especially, cottonseed oil, Peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, and mixtures thereof, in addition to inert diluents, orally The compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Preparations for injection, for example, sterile aqueous or oily suspensions, may be known The technique is formulated with a suitable dispersing or moisturizing agent and a suspending agent. The sterile injectable preparation can be a sterile injectable solution, 1150-9073-PF; Kai 58 200817031 suspension or emulsion, dissolved in the helmet Toxic solvents, for example: 3~ Among the acceptable diluents or solvents for oral administration, the liquids may be used. The acceptable carriers and users are water, Ringer's solution, USP and isotonic chloride. In addition, sterile fixed oils are conventionally used as a solvent or suspension medium. L. This h 'can be used in various brands of fixed oils, including synthetic single or monoglycerin. In addition, lipase - for example, oil The acid is used in the preparation of an injectable preparation. The formulation for the injection can be passed through a filter membrane which cannot pass through the bacteria, or the edge-killing agent is packaged in a solid composition which is not read. In the sterilization, the solid composition can be Dissolve or disperse in sterile water or other sterile injectable media before use. In order to prolong the action of the drug, it is often desirable to slow down the absorption of (4) substances by subcutaneous or intramuscular injection. This purpose can be achieved by using poor solubility in water or A liquid suspension of a non-crystalline material is achieved. The rate of absorption of the drug depends on the rate of dissolution, and is related to the crystal size and crystalline form. Or 'fine can be dissolved or suspended in an oil carrier, The absorption of the drug. In the form of an injectable storage, 4 = the microcapsule matrix of the fungus is in a biodegradable polymer, such as polylactic acid - polyacetic acid (pc) lylactlde_pc) lyglycolide ^^1_ with a polymer The ratio, as well as the nature of the particular polymer, can control the rate of drug release. Examples of other biodegradable polymers include poly(original (6) and poly(anhydrous). Formulations for injectable solutions can also be prepared by capturing the drug in a body-compatible microlipid or microemulsion. A composition for rectal or vaginal administration, preferably a suppository, may be prepared by mixing 1150-9073-PF; Kai 59 200817031 σ = compound, and a suitable non-irritating excipient or carrier, such as cocoa * Prepared by mixing ethylene glycol or suppository pests. The test pests are liquid in the body at room temperature, so they can dissolve in the rectum or vaginal and release the active compound. Solid dosage forms for oral administration, including capsules 'Plates, pills, powders and granules. In such a solid dosage form, the active compound is mixed with at least one blunt pharmaceutically acceptable excipient or carrier, for example, sodium citrate or phosphate And / or · a) Fillers or extenders, such as temple powder: sugar, sugar, glucose, mannitol and tannic acid (siHcic shape ^), b) binders such as · Wei Ke methyl cellulose, algae Acid salt, gelatin, polyethylene soil than ketone, cane And gum arabic (acac ia), c) humectants, such as glycerin, d) disintegrating agents, such as agar-agar, calcium carbonate, tapioca or tapioca starch, alginic acid, certain tannins Salt, and sodium carbonate, e) solution blockers, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, G) wetting agents, such as cetyl alcohol, and glyceryl monostearyl ester, h) Knowing, for example, two-soil and soap clay (匕(9)七(10)丨ciay), and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and a mixture of these. In the case of capsules, lozenges, and pills, the dosage form may also contain a buffer. For a solid composition of a similar type, a filler which is a soft and hard-shell filled gelatin capsule, which is an excipient of lactose, a high molecular weight polyethylene glycol or the like, may also be used. The active compound may also be in microencapsulated form with one or more excipients such as those described above. Lozenges, dragees, capsules, pills and granules, solids, 1150-9073-PF; Kai 60 200817031 can be known by coating film and outer casings, such as gut-J casing, release control agents and other formulas. Prepared by coating. In such solid dosage forms, the active compound may be at least one sample from the _ 乂 / to the V species ["raw diluent mix, the inert diluent such as vegetable sugar, lactose or starch. This dosage form, general practice In addition, it may contain substances other than inert diluents. (Example) (4) Ingot lubricants...He makes key additives such as magnesium stearate and microcrystalline cellulose. In the case of capsules, lozenges and pills, etc. Buffering agents may also be included. The opaque agent may be included with the sputum and may be a composition that releases only one of the intestines to arbitrarily release one or more active ingredients in a delayed manner. Examples of the composition include a polymeric substance and a wax. A topical or transdermal dosage form of the compound of the present invention, including: ointment, paste, cream, lotion (1〇ti〇n) , gel 1 powder, solution, spray, inhalation or patch. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and optionally a preservative or buffer. Ophthalmic formula, peony water Eye ointment, powder and dissolve It is also considered to be within the scope of the present invention. 3 In addition to the active compound of the present invention, the ointments, pastes, creams and gels may include excipients such as animal fats and vegetable fats, oils, waxes, paraffins, Starch, gum tragacanth, cellulose derivative, polyethylene glycol, hydrazine, turbid earth, citric acid, talc, and oxidized or mixtures thereof. In addition to the compounds of the present invention, powders and sprays may include excipients. For example, lactose, talc, citric acid, aluminum hydroxide, calcium citrate, and polyamide powder or mixtures thereof. Sprays may also contain conventional propellants, such as chlorinated hydrocarbons. 61 1150~9073 - PF; Kai 200817031 The additional advantage of wearing a skin patch is that 庵lL ^ ^ f σ is controlled by the body to dissolve or disperse the compound in a suitable medium: 2: The agent can be used to add compounds The flux through the skin is controlled by a rate controlling membrane or by dispersing the compound in a parent or gel. ▲ Oral antiviral activity The inhibitory amount or dose of the compound of the present invention may be about 〇· (10) / Kg to about 500mg / Kg, or The dosage or dosage may be about 1 to about 50 mg/Kg. The amount or dose of inhibition may also depend on the route of administration, and η and 疋 may be used together with other agents, but differently. According to the treatment method of the present invention, the virus The treatment or prevention of a sexual infection in an individual is by administering to the individual a compound of the invention in an amount effective to achieve an anti-hepatitis C virus in an amount sufficient to achieve the desired result, such as i xh Μ U female is a human or a lower mammal. In another method of the invention, an inhibitory amount of a compound of the invention is administered by a biological sample in an amount and for a desired amount to achieve the desired result. "Anti-C Hepatitis Virus Effective Amount" The term 'a compound' of the present invention means a sufficient amount of a compound which reduces the amount of virus in a biological sample or a body. As is well known in the art of τ Yin and 1 > M W, the "anti-hepatitis C virus effective amount" of the compounds of the present invention will be within a reasonable benefit/risk ratio applicable to any medical treatment. As used herein, "inhibiting amount" of a compound of the invention means a sufficient amount to reduce the amount of virus in a biological sample or a body. It is well known in the medical art that the "inhibiting amount" administered by an individual is 1150-9073-PF of the present invention; the Kai 62 200817031 compound will be at a reasonable interest for any medical treatment as determined by a physician. / Risk ratio within. The term "biological sample" is used herein to refer to a substance of biological origin that is administered to an individual. Examples of biological samples include, but are not limited to, blood and its components, such as plasma, platelets, blood cells, ethnic groups, etc.; organs such as kidney, liver, heart, lung, etc.; sperm and print; bone marrow and its components' or stem cells. Alternatively, 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 present invention, a monthly composition or a combination may be administered as needed. Then, when the symptoms are alleviated to a desired level of water + m, the dosage or frequency of administration can be reduced to maintain an improved condition. However, the patient may require long-term intermittent treatment to prevent any recurrence of the condition. It will be understood that the total use of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The amount of a particular inhibitor for any particular patient depends on a number of factors, and is well known in the medical arts 'comprising: the condition to be treated and the severity of the condition, the activity of the particular compound employed, the particular composition of the sputum The age, weight, general health, sex and diet of the patient; the time of administration, the route of administration, and the rate of excretion of the particular compound used; the period of treatment, in combination with or in combination with the particular compound used Drugs, etc. 2 The compound of the invention is administered in a single or divided dose of the total inhibitor of a patient, for example, from 0.01 to 50 mg/kg body weight, or more usually from 1 to 25 mg/kg body weight. The single dose composition may comprise this amount or multiples up to 1150-9073-PF; Kai 63 200817031 to the dose per dose. Typically, t, in the course of treatment of the present invention, comprises administering to the patient in need thereof from about 1 mg to about 1000 mg of the compound of the invention in a single or multiple doses per day. Unless otherwise defined, all technical and scientific terms used herein are used in accordance with the meaning of the ordinary skill in the art. All publications, patents, published patent applications, and other references are hereby incorporated by reference. Abbreviation The following synthetic process and examples appear as follows: ACN: acetonitrile;

Boc: a third butoxycarbonyl group;

Bz: benzamidine;

Bn: node base; C DI · woven base two glutinous rice σ sitting; dba: two knots and propylene _; DBU: 1,8-diazabicyclo[5·4_〇] eleven-7-ene; DIAD : diisopropyl azodicarboxylate; DMAP · monomethylamine ο ratio bite; DMF: dimethylformamide; DMS0: dimercaptopurine; dppb: diphenylphosphinobutane;

EtOAc: ethyl acetate; HATU: 2 (7-aza-1H-benzotriazol-yl)-m, hydrazine, 3,3-tetramethyluron hexafluoroate; 1150-9073-PF; Kai 64 200817031 iPrOH : isopropanol;

NaHMDS: sodium bis(trimethyldecyl)decylamine; NMO: N-oxidized-N-methylmorpholine;

MeOH: methanol;

Ph: phenyl; POPd: dihydrodichlorobis(di-tert-butylphosphino)palladium (n); TBAHS: tetrabutylammonium hydrogen sulfate; TEA · triethylamine; THF: tetrahydrofuran; TPP: triphenyl Phosphine

Tris·•Tris(hydroxymethyl)aminomethane; BME: 2-mercaptoethanol; Β0Ρ: benzotriazole-bukioxy-tris(dimethylamino)scale hexafluorophosphate; C0D·ring Dioctyl; DAST: diethylaminosulfur trifluoride; u D ABC YL : 6-(N-4'-carboxy-4-(dimethylamino)azobenzene)-aminohexyl-1 -0-(2-cyanoethyl)-(N,N-diisopropyl)-phosphonium; DCM: dichlorodecane; DIAD: diisopropylazodicarboxylate; DIBAL- Η: diisobutylaluminum hydride; DIEA: diisopropylethylamine; DMAP: hydrazine, hydrazine-didecylaminopyridine; DME: ethylene glycol dioxin; 1150-9073-PF; Kai 65 200817031 DMEM : Dulbecco's modified Eagles medium; DMF: N,N-dimethylformamide; DMS0: dimethyl submilling;

EDANS : 5-(2-Amino-ethylamino)-naphthalene-b sulfonic acid; EDCI or EDC: bis(3-diethylaminopropyl)-3-ethoxycarbonyldiamine hydrochloride;

EtOAc: ethyl acetate; HATU: hydrazine (7-azabenzotriazol-bry)-v, ν, hydrazine, N,-tetramethylurea hexafluorophosphate;

Hoveyda's Cat·: dichloro(o-isopropoxyphenylmethylene) (tricyclohexylphosphine) ruthenium (11); KHMDS: potassium bis(trimethylsulfonyl) decylamine; M s :methyst Yellow wine, ΝΜΜ ··Ν-4-methylmorpholine

PyBrOP: bromo-tri-pyrrolidino-square hexafluorophosphate;

Ph: phenyl; RCM: ring-closing translocation; RT: reverse transcription; RT-PCR: reverse transcription polymerase chain reaction; TEA: triethylamine; 1150-9073-PF; Kai 66 200817031 TFA: trifluoroacetic acid; : tetrahydrofuran; TLC: thin layer chromatography; TPP or PPhs: triphenylphosphine;

Tboc or Boc: a third butoxycarbonyl group;

Xantphos: 4,5-di-diphenylphosphinoalkyl-9,9-dimethyl-911 one-clip. The synthesis method, and more preferably the compound of the present invention and treatment, will be understood from the following synthesis scheme, and the compound of the present invention can be produced by the following method. Process 1

Scheme 1 describes the synthesis of intermediates (1-6). The acyclic peptide precursor (1 is from Boc-L-third-leucine (1-1) and cis-L-hydroxy gambling...) Which version of the syllabus (1 -2), via Process 1 Prepared in the usual three steps shown. </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Process 2 1150-9073-PF; Kai 67 200817031

Scheme 2 illustrates the general synthesis of triazole analogs. Triazole (2-2) is synthesized from alkyne (2-1) and TMSNs, but is not limited to TMSN3. The alkyne (2-1) is commercially available or can be prepared according to the Sonogashira reaction with an alkyne (2-8) and an aryl halide (2-9). For further details on the Sonogashira reaction, see:

Sonogashira, Comprehensive Organic Synthesis, Volume 3, Chapters 2, 4 and Sonogashira, 1 977,777. The intermediates (2-4) and (2-5) can be obtained by converting the hydroxy intermediate U-6) to a suitable leaving group and subjecting the activated hydroxyl group to SN2 substitution, and the leaving group is, for example, not limited to: 〇Ms, 〇Ts, OTf, bromide or iodide. The vinegar is hydrolyzed to obtain a compound of the formula (2-6) or (2-7). Process 3 U50-9073-PF; Kai 68 200817031

Intermediate (3-1) was prepared as acyclic mesylate (2-3) and triazole (2-2) using the conditions described in Scheme 2. Intermediate (3-1) can be followed by a halide 〇Tf

The occupied position is subjected to a Suzuki coupling reaction, a Sonogashira reaction or a Sti 1 le coupling. For further details on the Suzuki coupling reaction, see: A. Suzuki, Pure Appl. Chem. 1991, 63, 41 9-422 and A. R. Martin, Y. Yang, Acta Chem. Scand. 1993, 47, 221-230. For further details on the Sonogashira reaction, see: Sonogashira, Comprehensive Organic Synthesis, Volume 3, Chapters 2, 4 and Sonogashira, Synthesis 1 977, 7 7 7. For further details on the S ti 11 e coupling reaction, see: J. K. Stille, Angew. Chem. Int. Ed. 1986, 25, 508-524 ^ M. Pereyre et a 1., Tin in Organic Synthesis 1150-9073 -PF;Kai 69 200817031 (Butterworths,Boston,1 987) pp 1 85-207 pass1////, and Τ· N. Mitchell, 1 992, 803-81 5 Comments on synthetic applications. The Buchwa 1 d reaction allows for the substitution of an amine in an aryl desert, a primary amine and a secondary amine, and a 1#-nitrogen heterocycle. For further details on the Buchwald reaction, see J. F. Hartwig, such as the team //7ί,

Ed. 1998, 37, 2046-2067 流程 Process 4

(4-3) ORp

Hydrolysis

Scheme 4 illustrates the modification of the N-terminus and C-terminus of the tripeptide. The b〇c structure is deprotected with an acid such as, but not limited to, hydrochloric acid to give a compound of the formula (4-2). The amino group structure of the formula (4-2) can be alkylated or thiolated by a suitable halo or fluorenyl group to give a compound of the formula (4-3). The compound of the formula (4-3) utilizes, for example, a base of lithium hydroxide to free the acid structure of the formula (4-4). The acid structure is activated and treated with a suitable saccharide or sulfonyl group to give a compound of formula (4-5). Process 5 1150-9073-PF/Kai 70 200817031

The sulfonamide (5-2) is prepared by reacting the corresponding acid (5-oxime) with a coupling agent (ie, CDI, HATU, DCC, EDC, etc.) at room temperature or elevated temperature, followed by the presence of a base. Next, the corresponding sulfonamide Rs — s(〇) 2 —NH 2 is added, wherein R 3 is as defined previously. EXAMPLES The compounds and treatments of the present invention will be more fully understood from the following examples. This specific example is intended to illustrate and not to limit the scope of the invention. Various changes and modifications are obvious to those skilled in the art, and such changes and modifications, including but not limited to, the chemical structures, substituents, derivatives, formulations and/or methods of the present invention may be It is implemented within the scope of the spirit of the invention and the scope of the appended claims. Certain compounds in which g = 〇h are also described in U.S. Patent Publication No. 2005026 1 200. Example 1 - Synthesis of the acyclic peptide precursor

1150-9073-PF; Kai 71 200817031 Step la. Soluble in Boc-L-t-butylglycine (2.77 g) and commercial product cis-L-hydroxyproline (3.3 g) A solution of l5 ml of DMF was added with DIEA (1 〇 ml) and HATU (5.9 g). The coupling was carried out overnight at room temperature. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) (EtOAc) The organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo, and the obtained dipeptide was used directly in the next step. MS (ESI): π / ζ = 359.20 [M+Na]. Step lb The dipeptide from step la was dissolved in 15 mL of dioxane and 15 mL of 1 N L10H water bath and allowed to stand at room temperature for 4 hours. The reaction mixture was acidified with 5% EtOAc and EtOAc (EtOAc)EtOAc. The organic phase was dried over anhydrous sodium sulfate and then dried in vacuo to give a free carboxylic compound (4·g) which was used in the crude form of step 1 c. MS (ESI): /^=345·28 [M + Na]. Step 1 c In a solution of the free acid (15 g) obtained in step lb dissolved in 5 ml of DMF 'add D- /3 -vinylcyclopropane amino acid ethyl ester (丨· 〇g), DIEA (3.8 ml) and HATU (215g). This coupling was carried out for 5 hours. The hydrazine reaction mixture was diluted with 2 mL of Et〇Ac, followed by 2×20 ml of citric acid, 2×2 〇mi of water, iM NaHC® 3 4×20 ml, and 2×10 ml of concentrated brine. The organic phase was dried over anhydrous sodium sulfate and evaporated. The residue 1150-9073-PF; Kai 72 200817031 was flash chromatographed with different ratios of hexane:Et〇Ac as the elution phase (5:1 -&gt; 3 : 14 1 : 1 _&gt; 1 : 2) Refined. After removal of the eluting solvent, the desired linear tripeptide oil (1.4 g, 66%) was separated. MS (ESI): π / ζ = 482. 36 [M + Na]. Example 2 Synthesis of the acyclic peptide precursor mesylate

The acyclic peptide precursor from step 1c of Example 1 (500 mg, 1.04 mmol) and DIEA (0.543 ml, 3.12 mmol) were dissolved in 10.0 ml of DCM and the methanesulfonyl chloride was slowly added at 〇 °C ( 0_122ml), continuous reaction for 3 hours. Then, 100 mL of EtOAc was added, and washed with 5% citric acid 2 x 20 ml, water 1 x 20 ml, 1 M NaHC 〇 3 2 x 20 ml, and concentrated brine 1 x 20 ml, respectively. The organic phase was dried with EtOAc (EtOAc m. MS (ESI): λ? / ζ = 560. 32 [Μ + Η] ύρ〇 Example 3. Compound of formula IX, where A = Boc, L = tButyl, Q: , Z = CH = CH2 and G = 0H . Step 3 a · · Quick formation of the alkyne, 2-(2-thiazolyl)-4-methoxyphenylacetylene of the present example, by degassing 4 mmol of 4-ethynylanisole, 4 mmol 2-Bromothiazol 1150-9073-PF/Kai 73 200817031 Azole and 1 m of triethylamine are dissolved in a solution of 1 〇m 1 acetonitrile, 140 mg (0.2 mmol) of PdCl 2 (PPh 3 ) 2 and 19 mg (01 mm 〇 1 ) ) CuI manufacturing. The mixture was degassed and stirred at room temperature for 5 minutes and heated to 9 ° C for 12 hours. The reaction mixture was concentrated in vacuo and purified with EtOAc EtOAc (EtOAc) MS (ESI): m/z = 2\Q. 17 [M + H] 1HNMR (CDCh, 500 MHz) 5 7. 765 (d, J = 3 Hz, 1H), 7· 472~7. 455 (m, 2H ), 7. 277 (d, J = 3. 5Hz, 1H), 6.837~6.820 (m, 2H), 3.768 (s, 3H). Step 3b: Formation of triazole

Preparation of the 4-(2-thialyl)-5-(p-methoxyphenyl)triazole, the straw is added by adding the compound from step 3a (0.3 g), 0. 74 ml in a pressure tube. Methyl decyl azide and 4 mi of xylene were heated to 140 ° C for 48 hours. The reaction mixture was directly separated on a silica gel column and purified to give a brown liquid (yel. 18 g, 50%). MS (ESI): m/z = 2b 9.21. [M+H] 1HNMR (DMSO-de), 500 MHz) ά 8. 016 (d, J = 8. 5 Hz, 2H), 7.929 (d, J = 3 Hz, 1H), 7.817 (d, J = 3 Hz, 1H), 7.066 (d, J = 8.5 Hz, 2H), 3·824 (s, 3H). Step 3c 1150-9073-PF; Kai 7 4 200817031

In the solution of 0. 041 mmo 1 phthalate ester from Example 2 and the compound from step 3b (0.123 mmol) dissolved in 1 ml of DMF, 0. 246 mmol of carbonic acid planer was added, and the reaction mixture was stirred at 70 ° C. 12 hours. The reaction mixture was extracted with EtOAc EtOAc (EtOAc)EtOAc. MS (ESI): m/z-122. 34 [M+H] Step 3d

The preparation of the title compound is carried out by the face Α ^ h ^ you 甶 甶 will be from the title of step 3c compound dissolved in 2mL of dioxane to another! T n , λ $ reverse and 1 mL of 1 N Li〇H aqueous solution. The resulting reaction mixture was rubbed in the chamber black, and the + to / dish was searched for 8 hours. The pH of the reaction mixture was adjusted to 3 with citric acid and the mixture was extracted with EtOAc and washed with brine and water. The organic solution was concentrated in vacuo and purified by HPLC to give the title compound (yield: 34%) MS (ESI): π / ζ 694 _ _ _ _ _ _ _ _ _ _ _ _ _ (10 mg, 1150-9073-PF; Kai 200817031 Example 4 to Example 10 were prepared in a similar procedure to that described in Example 3 using different triazoles.

Example 4. A compound of formula IX wherein A = Boc, L = tButyl, Q = , Z = CH = CH2 and G = OH. MS (ESI): ^/z-693. 31 [M + H]

Example 5. A compound of formula IX wherein A = Boc, L = tButyl, Q = Z di CH = CH2 and G = OH.

MS (ESI): m/z^U. 33 [M + H]

Embodiment 6. A compound of formula IX wherein A = Boc, L = tButyl, Q = Z = CH = CH2 and G = OH. MS (ESI): 33 [M+H]

Embodiment 7. A compound of formula IX wherein A = Boc, L = tButyl, Z = CH = CH2 and G = OH.

MS (ESI): / ζ / / ζ = 623. 41 [M + H] % Example 8. Compound of formula IX, where A = Boc, L = tButyl, Q = ΐΐ, Z = CH = CH2 and G = OH. MS (ESI): m/ζ-^Ί. 40 [M + H] 1150-9073-PF; Kai 76 200817031

Example 9. A compound of formula IX wherein A = Boc, L = tButyl, Q = V, Z = CH = CH2 and G = 0H 〇 MS (ESI): you ///==735.31, 737.31 [Μ+Η]

Embodiment 10. A compound of formula IX wherein A = Boc, L = tButyl, Q, Z = CH di CH2 and G = 0H. MS (ESI): </RTI> </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt;

-, Z:CH = CH2 and G = a solution of the compound of Example 4 (50 mg) dissolved in DMF, and CDI (16 mg) was added. The reaction mixture was stirred at 4 (TC for 1 h, then cyclopropyl sulfonamide (18 mg) and DBU (22 // 1) was added. The reaction mixture was stirred at 40 ° C overnight. The extract was extracted with aq. EtOAc (EtOAc). · yz?/z=797· 30 [M + H]. 13C(CD30D): 173.8, 171.8, 169.5, 160.8, 159.2, 156 6 145.6, 142.9, 138.5, 133.1, 130·2, 122 2 120 7 117.4, 113.4,79·3,64.1,60.1,58·9,54.5,54.1,41·3 35.4,34·8,34.3,30_9,27.3,25.8,22 4. Example 1 2 to 3 3 Manufactured according to procedures analogous to those described in Example 1150-9073-PF; Kai 77 200817031 11. Example 12. Compounds of formula IX wherein A = Boc, L = tButyl, Q =

Z = CH = CH2 and G =

MS (ESI)·· yz//z=796. 30 [M + H]. 13C(CD30D): 173.8, 171.8, 169.5, 160.4, 156.6, 144.8, 140.7, 133.1, 131.7, 129.7, 127.2, 125.7, 123.4, 1 23.3, 1 1 7.4, 1 1 3.8, 79.3, 63.5, 60.2, 58.9, 54.6, 54. 1, 51.3, 35. 5, 34. 8, 34.3, 30. 9, 27. 4, 25. 8, 22.5° Ν, Ν Example 13. A compound of formula IX, wherein A = Boc, L = tButyl, /Λρ Z = CH = CH2 and G= Κ V. MS (ESI) : /ζ?/ζ=686· 47 [Μ + Η].

Example 14. A compound of formula IX wherein A = Boc, L = tButyl, Q =

, Z=CH=CH2 and

MS (ESI): π / ζ = 686. 46 [M + H]. Q = Example 15. A compound of formula IX wherein A = Boc, L = tButyl,

:CH = CH2 and . 1150-9073-PF; Kai 78 200817031

N,, N Example 16. A compound of formula IX wherein A = Boc, L = tButyl, Q: , Z = CH = CH2 and G = ii &quot; v. MS (ESI): m/z =::::::::::::

CH = CH2 and G:

Example 18. A compound of formula IX wherein eight = 6 〇〇, 1^ = seven 611 士 71, 〇 = -1-, Z = CH = CH2 and G = W. MS (ESI): tz7/z = 684. 40 [M + H] </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; MS (ESI): m/z = S.21. [M+H] </RTI> <RTI ID=0.0></RTI>

Z = CH = CH2 and G:

Embodiment 21. A compound of Formula IX wherein A = Boc, L = tButyl, Q: 1150-9073-PF; Kai 79 200817031

, Z = CH = CHd gH MS (ESI): w/z 2 763. 43 [M + H] Example 22. Compound of formula IX wherein A = Boc, L = tButyl, Q =

Br,

/ 0, , ς &lt;Ρin in ,, NT~N〆 ^ , Z = CH = CH2 and G= κ Ϊ. MS (ESI): ^/z-841.38, 843.35 [M+H]

Example 23. A compound of formula IX wherein A = B〇c, L = tButyl, Q = i 八, 〇, Z = CH = CH2 and G = Η V ° MS (ESI): m/z = ^Sl 39 [M+H] Example 24. Compound of formula IX wherein A = Boc, L = tButyl, Q = NN, \Y, Z = CH2CH2 and G=1

MS (ESI): m/z = S21.21. [M+H] </RTI> </RTI>

:CH = CH2 and G: /

Qw〇

Embodiment 26. A compound of Formula IX wherein A = Boc, L = tButyl, Z = CH = CH2 and G = H. </ RTI> </ RTI> <RTIgt;

Example 28. A compound of formula IX wherein A = Boc, L = tButyl, Q: /

Qw〇 , Z = CH = CHh and G = MS (ESI): m/z-12^. 39 [M+H] Example 29. Compound of formula IX, where A^Boc, L = tButyl, Q =

i, Z = CH = CH2 and G = MS (ESI): ^/^=848. 33 [M + H] Example 30. Compound of formula IX wherein A = Boc, L = tButyl, Q =

/

Qw〇 i , Z = CH = CH2 and G = MS (ESI): m/ζ-ΊΊΊ. 45 [M+H]

Embodiment 31. A compound of formula IX wherein A = Boc, L = tButyl, /

Qw〇Z = CH = CH2 and G: 1150-9073-PF; Kai 81 200817031 MS (ESI): m/z = 8ll. 44 [M+H] Example 32. Compound of formula IX, where A = Boc, L = tButyl, Q =

Br,

/ 1 , Z = CH = CH2 and (l· MS (ESI): &gt;t//z=889.41, 891.36 [M + H] Example 33. Compound of formula IX, wherein A = Boc, L = tButyl, Q:

Si., Ν Z = CH = CH2 and MS (ESI): m/z = 72A. 39 [M + H] Example 34. Compound of formula IX, where A = Boc, L = tButyl, Q =

Afl° N ( . : N / , &gt; 1 , Z = CH = CH 2 and G: MS (ESI): yz7/z = 837. 22 [M + H] Example 35. Compound of formula IX, wherein A = Boc, L = tButyl, Q =

〉 i , Z = CH = CH2 and G= N\. MS (ESI): / / = = 766. 44 [M + H] Example 36. Compound of formula IX, where A = Boc, L = tButyl, Q, 〆〇

Z = CH2CH2 and MS (ESI): m/z = 800.43 [M+H] 1150-9073-PF; Kai 82 200817031 Example 37. Compound of formula IX, wherein A = Boc, L = tButyl, Φ

CH = CH2 and

N, · Example 38. A compound of formula IX wherein A is 2 Boc, L = tButy 1, Q: / vapor, &gt;, Z = CH = CH2 and G = '. MS (ESI): m/z = 12m. 39 [M+H] </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The compound from Example 11 was dissolved in 5 ml of 4N HCl / Dioxne and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was evaporated twice with DCM. The desired product is used directly in the next step. MS (ESI): π / ζ = 697· 33 [M + H]. Step 3 9 b For the solution of the compound from step 39a dissolved in 2m 1 DCM, add DIE A (8 7 // 1)) and gas formic acid ρ τ π 彳 0 [ 1 λ ^ ^ τ 鲛 % propyl ester (0· 125nunol)). The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with EtOAc. Wash with water and brine, dry with NadO4, 1150-9073-PF; The residue &gt; was purified by HPLC to give 35 mg of desired product. MS (ESIh π / ζ 809. 21 [M + H] 〇 13C (CD30D): 173.7, 171.7, 169.4, 160.6, 159.3, 157.3, 145.6, 142.9, 138.5, 133.1, 130.2, 122.3, 120.7, 117.4, 113.4 , 77.8, 64.1, 60·〇, 59.3, 54·, 54.1, 48·6, 41.4, 35.3, 34.7, 34·3, 32.5, 32.3, 30.9, 25.8, 23.3, 22·4.

Example 40 and Example 41 were prepared according to procedures analogous to those described in Example 39. Example 4 0. Compound of formula IX, wherein Α =

, L = tButy 1,

, Z = CH = CH2 and MS (ESI)·· π/ζ=684· 29 [M + H].

Example 41. A compound of formula IX wherein A =

L=tButyl, q=

, Z = CH = CH2 and G =

MS (ESI): π 々 = 684 · 30 [M + H]. 13CCCD30D): 1 73.9, 1 71.4, 1 69.4, 1 56.7, 144.7, 1 38.6, 135.0, 133.0, 131.9, 117.7, 117.4, 109.4, 69·2, 60·4, 59.2, 57.6, 53.9, 41.4, 35.3, 34·6,5·5,30.9,30.1, 29· 9,25. 7,22·3,19. 7,19· 2,12. 7 ° Example 42 and Example 103 (Formula IX) according to the embodiment The procedure described in 11 or 39 is made. 1150-9073-PF; Kai 84 200817031

Q

Table 2 Example A L Q ζ G 42 Al&lt; ΝνΝ -CH-CH2 Aif'v 43 丨, winter nVn -ch=ch2 Λ?ν 44 O; again / Λ1&lt; noisy. , nVn -ch=ch2 45 Cl0 /nVn -ch:ch2 /,&amp; 46 〇V -ch=ch2 47 MeO^0^^ a^p0' V -ch=ch2 ', /v 48 ΛΛ V -ch =ch2 /, &amp;1150-9073-PF; Kai 85 200817031 49 O人 O^fi0' V -CH=CH2 W 50 〇', winter 〇^p0' γ -CH-CH2 51 〇α^Γ V -ch =ch2 A?v 52 , winter o^p0' γ -ch=ch2 w 53 α. Also, winter, ύ^ρ°' Νί&gt;_ -CH-CH2 Λ^ν 54 ύ^ρ° ΝγΝ -ch=ch2 55 a. , γ -ch=ch2 ΛίΓ^ 56 a ύ^ρ0' V -CH-CH2 W 57 , person / ύ^ρ°' V -ch=ch2 //v 1150-9073-PF/Kai 86 200817031 58 Η , ^ 0°' NyN - CH=CH2 //v 59 , and / 0^°' nVn -ch=ch2 w 60 σ1/ nVn -CH II CH2 A?v 61 〇Fv^N person / V -ch=ch2 // v 62 〇lp°' nVn -ch=ch2 /^v 63 &lt;Χ/ Λτ&lt; NyN -ch=ch2 //v 64 0^°' Ϋ -CH 2 CH2 //v 65 Q^T nVn -ch= Ch2 /^v 66 a1, Me γ -ch=ch2 //v 1150-9073-PF;Kai 87 200817031 67 {Λ o^p°' Y -CH=CH2 w 68 〇ΗΝΛβ /, fo^p°' V -ch=ch2 Aii^v 69 Mei^ Me o^p°' nVn -ch=ch2 ', ί!^ν 70 HN·^ &lt;0^' nVn -ch=ch2 71 a1, 丨冬nVn -CH= CH2 /, &amp; 72 nVn -ch=ch2 73 Ar o^p V -CH=CH2 74 '广〇^p0' V -CH=CH2 Λ?ν 75 /,〇a^p°' ΝγΝ -ch=ch2 / 八1150-9073-PF; Kai 88 200817031 76 aJD V -ch=ch2 Λ?ν 77 /'fa^p' ΝγΝ -ch=ch2 /^3⁄4 78 α^. , nVn -ch=ch2 /, x. H U) 79, winter nVn -ch=ch2 80 winter 0^. , V -ch=ch2 1 H 81 ^〇A/ ', winter 0^°' V -ch=ch2 82 ύ^ρ°' V -ch=ch2 / gas 83 ^〇A/ fj^p0' V -ch =ch2 84 ^〇A/ /, f ύ^ρ0' V -ch=ch2 1150-9073-PF; Kai 89 200817031 85 ^〇A/ ,,冬-ch=ch2 N 86 o^p0' γ -ch= Ch2 87 ^〇A/ nVn -ch=ch2 /, |^, ΝΗ2 88 汊. Also / 0^. — γ -ch=ch2 /, X on) Η H 89 Wen. Also / 〇ip°' V -ch=ch2 /, ΧΛ&gt; Η H 90 ο^ρ0' γ -ch=ch2 H 91 汄. Also / Λ1&lt; o^fi0' V -ch=ch2 AH%sacl 92 Λ Λ / ο^ρ°' γ -ch=ch2 /3⁄4 93 ^〇Α/ ύ^ρ°' V -CH-CH2 1150-9073 -PF;Kai 90 200817031 94 汄Λ/ -ch=ch2 A^F 95 ύ^ρ°' nVn -ch=ch2 /, x person Η H 96 汄Λ / h winter V -ch=ch2 Η H 97 V - Ch=ch2 /,ΧΛ H 98 ^〇Α/ V -ch=ch2 AX〇99 ^〇Α/ α^ρ°' V -ch=ch2 aX〇100 ύ^ρ°' V -H /^v 101 ^ 〇Α/ Λ1&lt; ύ^ρ0' γ -CH2CH3 /, &amp; 102 O^fl0' γ -CF2 A?v 1150-9073-PF; Kai 91 200817031

Example 104. NS3/NS4a Protease Test

HCV protease activity and inhibition use an internally quenched fluorescent ventricle. DABCYL and an EDANS group are attached to the opposite end of a short peptide. EDANS fluorescence is inhibited by the DABCYL group and is removed during protein cleavage. The fluorescence was measured by a Molecular Devices Flu〇r〇max (or equivalent) using an excitation wavelength of 355 nm and an emission wavelength of 485 nm. The assay was carried out in a white half 96-well plate (VWR 29444-31 2 [Corning 3693]) and the full length NS3 HCV protease lb was NS4A cofactor (final enzyme concentration 1 to 15 nM). The assay buffer was supplemented with 1 〇 (10) NS4A cofactor pep 4A (Anaspec 25336 or homemade, MW 1424. 8).

RET SI (Ac-Asp-Glu-Asp(EDANS)-Glu-Glu-Abu-[COO]Ala-Ser-Lys-(DABCYL)-NH2, AnaSpec 22991, MW 1 548. 6) as a fluorescent peptide Receptor. The assay buffer contained 5 mM Hepes (pH 7.5), 30 mM NaCl, and 1 mM BME. The enzyme reaction was followed at room temperature for a 30 minute time course and was carried out in the absence and presence of the inhibitor.

The peptide inhibitor HCV Inh 1 (Anaspec 25345, MW 796·8) Ac-Asp-Glu-Met-Glu-Glu_Cys_0H, [-2 (TC] and HCV 1150-9073-PF; Kai 92 200817031

Inh 2 (Anaspec 25346, MW 913.1)

Ac-Asp-Glu-Dif-Cha-Cys-OH was used as a reference compound. IC50 value, using equation 205: y = A+((BA)/(l + ((C/xrD)))), calculated by XLFit in the active base (ActivityBase, IDBS). Example 1 0 5 cell replicon analysis The HCV replicon RNA of the cell line was quantified (HCV cell line analysis) using Huh-11-7 cell line (Lohmann et al 1, Science 285: 1 1 0-1 1 3, 1 999). The cells were 4χΐ 〇 3 cells. 5% C。 The well was inoculated in a 96 well plate and provided a medium containing DMEM (high glucose), 1% fetal bovine serum, penicillin-streptomycin and non-essential amino acid. The cells were cultured at 37 ° C at 7. 5% C 〇2 incubator. At the end of the culture period, total RNA was extracted and purified from the cells in the Ambion RNAqueous 96 kit (model number AM1812). To amplify HCV RNA so that there is sufficient material for HCV-specific probe detection (see below) ), HCV (described below) specific probe media HCV RNA reverse transcription and use

The TaqMan One-step RT-PCR master mix kit (Applied Biosystems catalog number 43091 69) was amplified by polymerase chain reaction (PCR). The nucleotide sequence of the RT-PCR primer is located in the NS5B region of the HCV genome as follows: HCV forward primer "RBNS5bfor" 5, GCTGCGGCCTGTCGAGCT (SEQ ID NO: 1): HCV backward primer "RBNS5Brev" 5' CAAGGTCGTCTCCGCATAC (SEQ ID NO 2). Detection of RT-PCR products using Applied Biosystems (ABI)

The Prism 7500 Sequence Detection System (SDS), which detects the fluorescent light emitted by the PCR reaction when labeled with the fluorescent reporter 1150-9073-PF; Kai 93 200817031 sub-dye and dye-inhibiting dye. An increase in the amount of fluorescence was measured at each round of the PCR, reflecting an increase in the RT-pcR product. In particular, the quantification is based on a threshold round where the magnified line exceeds the established fluorescence threshold. Comparing this threshold round of samples to known standards provides a high-sensitivity measure of relative template concentration among different samples (ABI User Bui let in #2 December 11,1 997). Data is based on

ABI SDS program version 1 · 7 analysis. The relative template concentration can be converted to rNA copy number (ABI) using a known copy number of HCV RNA standard curve.

User Bulletin #2 December 11, 1997). The RT-PCR product was detected using the following labeled probes:

5' FAM-CGAAGCTCCAGGACTGCACGATGCT-TAMRA (SEQ ID NO: 3) FAM = Fluorescent reporter dye TAMRA := Suppress dye

After the RT reaction was carried out at 48 ° C for 30 minutes, the PCR was carried out. At ABI

The thermal cycling parameters of the PCR reactions used on the Prism 7500 Sequence Detection system are: 9 5 °C for 1 turn 1 〇 minutes, followed by 4 回 rounds, each including reaction at 95 ° C for 15 seconds, and at 60 ° C 2 reactions for 1 minute. To normalize the data to the internal control molecules of cellular RNA, RT-PCR was performed on the cellular mRNA glyceraldehyde-3-disc dehydrogenase (GApDH). The GAPDH copy number is very stable in the cell line used. The gapdH RT-PCR was performed on the same real RNA sample from which the HCV copy number was determined. The GAPDH primer and probe, and the standard used to determine the copy number, are included in AB I 1150—9073—PF/Kai 200817031

Pre-Developed TaqMan Analysis Kit (Cat. No. 4310884E). The ratio of HCV/GAPDHRNA was used to calculate the activity of the compound which inhibits RNA replication of HCV. Among the Huh-7 cell lines containing replicons, the activity of the compound as an HCV replication inhibitor (cell line analysis) in H uh -11 - 7 cells 'a specific antiviral compound for η c V replicon RNA level The effect is determined by comparing the amount of HCV RNA that the cells are exposed to with the cells exposed to the DMS0 vehicle (negative control) and normalized to GAPDH (eg, HCV/GAPDH ratio). Specifically, the cells were seeded at 4×10 3 cells/well in a 96 well plate and cultured in: 1) medium containing 1% DMSO (0% inhibition control), or 2) medium/UDMS0, containing 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: ° / 〇 inhibition = 100 - l 〇〇 * S / Cl where S = the ratio of HCV RNA copy number / GAPDH RNA copy number in the sample C1 = 0% inhibition in the control group (medium / i / / In qDMS0), the proportion of HCV rna copy number/GAPDH RNA copy number is proportional to the dose-response curve by dividing the compound by a series of three-fold dilutions from high to low concentrations across three logarithmic values. The highest concentration for adding a specific compound is 1 · 5 uM, and the lowest concentration is 〇 · 23ηΜ. If the IC5 threshold does not fall within the linear region of the curve, then a further dilution series (e.g., 500 nM to 0. 08 nM) is implemented. The IC50 is determined according to the IDBS Activity Base program using the "XLFit" function, 4 1150-&gt;9073^PF; Kai 95 200817031 parameters, and nonlinear regression suitable (model #205, version 4.2 i, buiidi6). In the above-mentioned cleavage, the measured values of the compounds represented by the present invention have HCV replication inhibitory activity and HCV NS3 protein 醢 卩 卩 、 i i i i i 。 。 。 。 。 。. These compounds are also effective for inhibiting different HCV phenotypes, including HCV NS3 proteases of Tables 3, 2, 3 and 4. Representative compounds were tested in the above-mentioned fractions (Example 10 4 and Example 105). The revealed 彳 丨 丨 化合物 · · · NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS InM-1 OOOnM is active. A brief description of the schema] benefits. [Main component symbol description] 益 〇 H50-9073-PF/Kai 96

Claims (1)

200817031 Patent application scope: 4 11 means: A (ιι) 1 · A compound with the formula W where / A is selected from Ri, -(〇〇), 〇 and -s(0)2-Rl, -s(0 2NHR2 ; 1 —(C = 0)—R2——C( = 〇)-NH-R2 h is selected from the group consisting of: (1) aryl; substituted aryl; heterozygous. (Π)heterocycloalkyl or substituted, earth, substituted heteroaryl; (11Π Γ deuterated heterocycloalkyl fluorene and (ill)-Cl-C8 alkyl, -c2~C8 1, 2 or 3 selected from 〇, s or 5 C2C8 alkynyl groups, each containing a hydrazine, or a heterocyclic group of 1. A alkyl, substituted -CrC8 alkenyl, ',, substituted ~Ci-C8 〇, 卜, 2 or 3 selected from 〇, :: substituted-alkynyl, each group, or substituted -c3-c12 ring-burning a or N hetero atom, -C3 - Cl2 ring-burning "2 Cycloalkenyl; ^ ; —C 3 —Cl 2 cycloalkenyl, or substituted R 2 , independently selected from the group consisting of: (1) hydrogen; (ii) aryl, substituted aryl; heteroaryl; Substituted heteroquinone and (1 1 1) hetero-organic or by the removal of μ" square earth, human disubstituted heterocycloalkyl; And (iO-CrG alkyl, -C2-C8 or -C2-C8 alkynyl, each package 1150-9073-PF; Kai 97 200817031 1, 2 or 3 heteroatoms selected from 〇, s or n Substituted -Ci - C8 = group, substituted -C2 - C8 dilute group, or substituted -C2 - C8 fast group, each group of 12 or 3 heteroatoms selected from 〇, S or N ;_C3 - Ci2 cycloalkyl or, -, - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - H,CH3; G is selected from ~NHS(〇)2-R3 and -NH(S〇2)NR4R5; 匕 from: (I) aryl; substituted aryl; heteroaryl; substituted Heteroaryl (II) heterocycloalkyl or substituted heterocycloalkyl; and (III)-Ci-C8 alkyl, -C2-C8 alkenyl or -C2_Cs alkynyl, each containing hydrazine, 1, 2 Or a hetero atom selected from G, s or N, a substituted alkyl group, a substituted _G2_C8 alkenyl group, or a substituted alkynyl group, each containing 2, 3 or 3 selected from 0, s〇 of a hetero atom; _c heart ring diyl, or substituted -C3 -Ci2 cycloalkyl · -C3-(:12 cycloalkenyl; substituted but R3 is not CH2CH2Ph; R4 and Rs are independently selected from: (1) hydrogen; (ii) aryl; substituted aryl... I, heteroaryl; substituted heteroaryl (iii) heterocycloalkyl or Substituted soil, 1% heteroalkyl; and (iv)-Ci-C8 alkyl, -C2~(:8-ene | + rp decyl or -C2-Cs alkynyl, each containing 1, 2 or 3 a hetero atom selected from 〇, 8 or 七七広広0, N; a substituted ～alkyl group, a substituted C2-C8 alkenyl group, a decene group or a substituted —C2-Cs alkynyl group, each Package 1150-9073-PF; Kai 98 200817031 Hetero atom of 〇, S or N; -C3~Ci2 cycloalkylalkyl; ~C3-Cu cycloalkenyl, or substituted with 0, 1, 2 or 3 a -C3-Cl2 ring-dense group of a substituted or substituted _C3-Cl2 ring, L and Z are independently selected from (1) hydrogen; (ii) an aryl group; a substituted arylheterocyclic group, substituted a heteroaryl group; (m) a heterocyclic alkyl group or a substituted heterocyclic alkyl group; .1.. (iV) prepared C8 alkyl K8 alkenyl or -Κ8 alkynyl group, each containing hydrazine, 1, 2 or 3 heteroatoms selected from 0, s or Ν 広 ; ;; -CrCs alkyl, substituted -C2 - C8, sulfenyl or substituted -C2-C8 alkynyl, each containing 〇, 1, 2 or 3 selected from 〇, s or N7 ύ or N a hetero atom; - C3 - Ci2 cycloalkyl, or substituted -C3-C12 cycloalkyl; - Γ 匕 匕 3-Cl2, or substituted -c3-c12 cycloalkenyl; X and Y Independently selected from: (1) hydrogen; (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl; (Hi)heterocycloalkyl or substituted heterocycloalkyl; -Ci-C8 alkyl, -C2-Csalkenyl or -c2-c8 alkynyl, each comprising hydrazine, 1, 2 or 3 heteroatoms selected from hydrazine, s or N; substituted _Ci- Ci calcined, substituted -Cr C8 alkenyl, or substituted -C2-C8 alkynyl, each containing 0, 1,? Or 3 heteroatoms selected from 0, S or N; -C3 - Ci2 cycloalkyl, or substituted -C3-Ci2 cycloalkyl; -Cs-Ci2 cycloalkenyl, or substituted -C3 - Cl2 cycloalkenyl; and (v)-W-R6, wherein w is absent or selected from: -0-, -s-, -NH-, 1150-9073-PF; Kai 99 200817031; R6 is selected from a group of -N(Me)-, -C(〇)NH_ or -c(〇)N(Me)-: (b) aryl; substituted aryl; heteroaryl; substituted hetero Aryl (C)heterocycloalkyl or substituted heterocycloalkyl; and (d)-Ci-C8 alkyl, -C2-C8 alkenyl or -C2-C8 alkynyl, each containing hydrazine, 2 or 3 a hetero atom selected from hydrazine, S or N; a substituted -&amp;-an alkyl group, a substituted -C2 -&amp;alkenyl group, or a substituted -C2_C8 alkynyl group, each containing hydrazine, Or 3 heteroatoms selected from hydrazine, S or N; -C3 -^cycloalkyl, or substituted -C3-Cl2 cycloalkyl; -C3-Ci2 cycloalkenyl, or substituted -C3- Cl2 cycloalkenyl; or X and Y together with the carbon atom to which they are attached form a ring structure selected from aryl, substituted aryl, heteroaryl and Substituted heteroaryl; 2. The compound according to item 1 of the scope of the patent application, wherein the compound of Formula 111 or I v: (called or (IV) where A, G, L, X, y and z are the same as those specified in the third paragraph of the scope of application for patents! 5〇-9〇73-PF; Kai 100 200817031. 3. If the patent application scope The compound according to item 1, wherein the compound is of the formula V or VI: (VI) It makes X 1 - X 4 alone ☆ recognize 4 A is also selected from -CR? and Ν, where R7 is independently selected from CN; (i) hydrogen; ι | prime; - Ν〇 2 (ii ) -Μ-R4, μ is the same as 〇, s, and the term is the same; NH 'where I and the scope of patent application (iii) NR4Rs5 Μι Φ pr? D. /, T R4 and R5 and the scope of the patent application The terms are the same; (IV) Ci c8 alkyl, _C2_C8 or _c2_C8, each containing 2 or 3 selected from. a hetero atom; a substituted c alkyl group, a substituted C8 alkenyl group, or a substituted _C2_C8 alkynyl group, each: contained. , 2 or 3 heteroatoms selected from the group; $-heart group, or substituted cyclamate; _c heart ring, or: -C3-Cl2 cycloalkenyl; and (V) Aryl; substituted aryl; heteroaryl; substituted heteroaryl; 1150-9073-PF/Kai 101 200817031 (vi) heterocycloalkyl or substituted heterocycloalkyl; wherein A, G, L and Z are the same as defined in item 1 of the scope of application. 4. The compound of claim 1, wherein the compound is of formula VII or VIII: Wherein YrY3 is independently selected from CR7, N, NR?, S and 0; wherein R?, A and G are the same as defined above. 5. The compound of claim 1, which is selected from the compounds of formula IX of Table 1. Q (IX) Table 1 Example ALQZG 11 person / 丨, winter V -ch = ch2 1150-9073-PF; Kai 102 200817031 12 NVN 1 -ch=ch2 /, & 13 person / V 1 -ch=ch2 A?v 14 people again / 1 -ch=ch2 /, ^v 15 乂Λ, /卞hP ΝνΝ -ch=ch2 16 people / 丨, winter &lt; Ρ V -CH-CH2 17 From 丨,,冬ν 'ν'ν 1 -ch=ch2 /,&amp; 18 people again / %'Ν I -ch=ch2 /,^v 19 ', winter α^Γ Heart:Ν -ch=ch2 /〇%〇Yr 20 people Also / %'Ν -ch=ch2 /°1⁄20 Yr 21 person / ΝγΝ -ch=ch2 /, Xr Η 1 1150-9073-PF; Kai 103 200817031 22 %'N 1 -ch=ch2 Η 1 23 / ΝγΝ -ch=ch2 Η 1 24 ΛΛ ΝγΝ -CH=CH2 25 people again / ,, winter ^λΡ NVN -CH=CH2 /}3⁄4 26 乂Λ / ,, winter φ N&gt;rN -ch=ch2 43⁄4 27 people Also / 'Winter VI -ch=ch2 43⁄4 28 ΝγΝ -ch=ch2 29 乂Λ, 0^. , nVn -ch=ch2 A^CH3 30 people / ', winter ^λΡ V -ch=ch2 /3⁄4. 31 people again / -ch=ch2 A^ch3 1150-9073-PF/Kai 104 200817031 32 乂Λ/丨冬-ch=ch2 33 From &gt; %'Ν 1 -ch=ch2 34 ΛΛ A, -ch=ch2 /}3⁄4 \ 35 people again / V -CH=CH2 /3⁄4 N \ 36 people again / Λ1&lt; ΝγΝ -ch=ch2 N \ 37 From 汴B\ p- V 1 -ch=ch2 /}3⁄4 N \ 38 /, f ip V 1 -ch=ch2 N \ 39 Cl〇A/ 丨, winter n!&gt; - Ch=ch2 w 40 Λ1&lt; V 1 -CH 2 CH 2 41 /, f 1 -CH 2 CH 2 1150-9073-PF; Kai 105 200817031 42 Take again / noisy. — nVn -CH=CH2 43 V -ch=ch2 /^v 44 O; again / o^p0' nVn -ch=ch2 /^v 45 CX. Also / α^Γ V -ch=ch2 46 〇^〇Α/ V -CH=CH2 47 MeO^0^^ a^p0' V -ch=ch2 48 A〇^ ο^Γ γ -ch=ch2 49 〇 Person ο^ρ°' V -ch=ch2 50 〇, '冬〇ΐΡ°' nVn -ch=ch2 1150-9073-PF; Kai 106 200817031 51 〇nVn -CH 2 CH2 /, ^v 52 o^p° ' nVn -ch=ch2 53 a. Also, winter-ch=ch2 54 Ο^Λ ,, winter o^fi0' Y -ch=ch2 55 〇^p0' nVn -CH two CH2 w 56 V -ch=ch2 Λίί'ν 57 a^p°' -ch=ch2 58 αΛ o^p°' V -ch=ch2 59 , and / 丨, winter o^p°' Y -ch=ch2 1150-9073-PF; Kai 107 200817031 60 〇又 / -ch=ch2 /, &amp; 61 people / Al&lt; V -ch=ch2 ah:sv 62 a^p0' V -ch=ch2 A?v 63 O^TY -ch=ch2 w 64 0^p°' -ch=ch2 A ?v 65 c^/ o^p° nVn -ch=ch2 /^v 66 a1, Me Y -ch=ch2 Λ?ν 67 €A /, f 〇lp〇' NvN -ch=ch2 //v 68 〇 HN\e 丨冬o^_p V -ch=ch2 1150-9073-PF; Kai 108 200817031 69 Me /, f V -ch=ch2 70 HN^ /, fc^p°' Ϋ -ch=ch2 /, ^ v 71 丨, winter V -ch=ch2 /^v 72 丨, winter α^. , Ϋ -ch=ch2 73 / 丫f^p°' V -CH=CH2 //v 74 /, r Ϋ -ch=ch2 A?v 75 /, 0 V -ch=ch2 A?v 76 aJ〇〇 1_ρ°' V -ch=ch2 /^v 77 Λ1&lt; f^p°' Ϋ -ch=ch2 1150-9073-PF/Kai 109 200817031 78 ^〇A/ nVn -CH-CH2 /3⁄4 79 Also / -CH -CH2 /, ~ 80 Wen. Also / V -ch=ch2 /3⁄4 1 H 81 a^p0' -ch=ch2 82 Λ1&lt; o^p°' -ch=ch2 /,~H3 83 Q^T ΝγΝ -ch=ch2 / gas 84 Y - Ch=ch2 85 /'fo^p0' V -ch=ch2 86 o^p°' V -ch=ch2 1150-9073-PF; Kai 110 200817031 87 ,, winter-CH=CH2 /^N&quot;'S, xNH2 88 ο^ρ0' V -ch=ch2 /, X々Η H 89 ^〇A/ 〇^p°' V -ch=ch2 /,ΧΗΛ&gt; Η H 90 丨, winter a^fl0' V -ch= Ch2 /, Xf3 H 91 o^p0' nVn -ch=ch2 /, ~ 92 Wen. Also / V -ch=ch2 93 ,,, winter nVn -CH-CH2 /3⁄4 94 /卞〇lp〇' Y -ch=ch2 Ai%F 95 0^°' nVn -ch=ch2 ΑΧλ Η H 1150-9073 -PF; Kai 111 200817031 96 -ch=ch2 Η H 97 丨, winter nVn -ch=ch2 /)? Person H 98 nVn -ch=ch2 99 仏. Also / nVn -ch=ch2 /3⁄4 100 V -H 101 Wen. Also / /, f -CH2CH3 /, i??vv 102 汊. And /O^p γ -CF2 Λίί2ν 103 ,, γ-CH=CH2CH3 w 6. a compound or a pharmaceutically acceptable salt, ester or precursor thereof, which has the formula I as described in the specification Structures of 11, 111, IV, V, VI, VII, VIII and IX. 1150-9073-PF; Kai 112 200817031 • 7. A pharmaceutical composition comprising (1)- selected from the formulas described in the specification, π, Ιπ, Ιν, ν, π, νπ, ΠΠ and (1) conjugates Or (2) a pharmaceutically acceptable salt, vinegar or prodrug of one of the compounds. 8. A pharmaceutical composition comprising an inhibitory amount of a sigma sigma of claim 1 or a pharmaceutically acceptable salt, ester or prodrug thereof, and a pharmaceutically acceptable carrier or excipient . A pharmaceutically acceptable composition for hepatitis C virus infection in a serotherapy individual, comprising an inhibitory amount of the pharmaceutically acceptable composition of claim 8. A method for inhibiting replication of hepatitis C virus, the method comprising the pharmaceutical composition of claim 8 in which the inhibitory amount of hepatic canine virus NS3 protease is increased. 11. The pharmaceutical composition of claim 9 further comprising an additional anti-hepatitis C agent. The pharmaceutical composition according to the invention of claim 1, wherein the additional anti-hepatitis C agent is selected from the group consisting of interferon,/5-interferon, and ribavirin ( ribavarin) and a diamond-like stone (adamantine). The pharmaceutical composition according to claim 11, wherein the additional anti-hepatitis C virus agent comprises a hepatic hepatitis C virus, S#, polymerization Inhibitor of stalk, metalloproteinase or I res. 14. A process for the manufacture of compounds of ί, η, In, n, v, VI, vn, VIn and IX, in accordance with the processes, methods or processes of the present invention. A pharmaceutical composition comprising the compound of claim 3 or a pharmaceutically acceptable salt, ester or precursor thereof. 1150-9073—PF/Kai 113 200817031 1 6 The pharmaceutical composition of claim 15 further comprising an anti-HCV agent. 1 7 The pharmaceutical composition of claim 15 further comprising one of the following agents: interferon, ribavirin, amantadine, other HCV protein inhibitors, an HCV polymerase inhibitor An HCV helicase inhibitor or an internal ribosome entry site inhibitor. The pharmaceutical composition according to claim 15 of the patent application, further comprising a long-acting interferon. 1 9 · The pharmaceutical composition as described in claim 15 of the patent application, further including other antiviral, antibacterial, antifungal or anticancer agents or an immunomodulator 0 114 1150-9073-PF; Kai 200817031 VII. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: None. 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 1150-9073-PF; Kai