TW200427684A - Inhibitors of serine proteases, particularly HCV ns3-ns4a protease - Google Patents

Abstract

The present invention relates to compounds of formula I: ,or a pharmaceutically acceptable salt, or mixtures thereof, that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are useful as antiviral agents. The invention further relates to pharmaceutically acceptable compositions comprising said compounds either for ex vivo use or for administration to a patient suffering from HCV infection and processes for preparing the compounds. The invention also relates to methods of treating an HCV infection in a patient by administering a pharmaceutical composition comprising a compound of this invention.

Description

200427684 发明 Description of the invention: Cross-reference to related applications This application claims US provisional application serial number 60/5 13,765 (filed on October 23, 2003), named 'f, especially Hepatitis C virus (HCV) NS3- The rights of NS4A protease inhibitors (INHIBITORS OF SERINE PROTEASES, PARTICULARLY HCV NS3-NS4A PROTEASE), the disclosure of which has been incorporated herein by reference. This application also claims the US provisional application case number 10 / 412,600 (filed on April 11, 2003), named `` especially the hepatitis C virus (HCV) NS3-NS4A protease serine protease inhibitor (INHIBITORS OF SERINE PROTEASES, PARTICULARLY HCV NS3-NS4A PROTEASE), the disclosure of which has been fully incorporated herein by reference. [Technical field to which the present invention belongs] The present invention relates to compounds which can inhibit serine protease activity, and specifically, can inhibit hepatitis C virus NS3-NS4A protease activity. Therefore, its role is to interfere with the life cycle of hepatitis C virus, and it is suitable as an antiviral agent. The invention also relates to a pharmaceutically acceptable composition comprising the compound, which can be used in vitro or for administration to a patient suffering from HCV infection, and a method for preparing the compound. The invention also relates to a method for treating a patient with an HCV infection by administering a pharmaceutical composition comprising a compound of the invention. [Prior art] Hepatitis C virus (f'HCVn) infection is an amazing human medical problem. HCV is known to be the main cause of most non-A and non-B hepatitis, and an estimated 3% of people worldwide have a seropositive reaction [A · Alberti with a /., NC liver 92589.doc -7- 200427684 inflammation Natural History of Hepatitis C. "J. Hepatology, 31. (Suppl. 1), pp. 17-24 (1999)]. Nearly 4 million people are infected in the United States alone [MJ Alter W α /., "The Epidemiology of Viral Hepatitis in the United States, Gastroenterol. Clin. North Am ·, 23 , Pp. 437-455 (1994); MJ Alter "Hepatitis C Virus Infection in the United States

Infection in the United States), ’’ J. Hepatology, 31 (Suppl. 1), pp. 88_91 (1999)]. When first exposed to HCV, only about 20% of infected people will develop acute clinical hepatitis, while others will spontaneously release the infection. However, in nearly 70% of cases, chronic infections established by the virus will persist for decades [S. Iwarson, π The Natural Course of Chronic Hepatitis, "FEMS Microbiology Reviews, 14, pp. 201 -204 (1994); D. Lavanchy, Global Surveillance and Control of Hepatitis C, " J. Viral Hepatitis, 6, pp. 3 5-47 (1999)]. Therefore It often causes recurrence and progressive deterioration of liver inflammation, often leading to more serious diseases, such as: cirrhosis and hepatocellular carcinoma [MC Kew, 'Hepatitis C and Hepatocellular Carcinoma' ", FEMS Microbiology Reviews, 14, pp. 211-220 (1994); I. Saito et al., "Hepatitis C Virus Infection is Associated with the Development of Hepatocellular Carcinoma", '' Proc. Natl. Acad. Sci. USA, 87, pp. 6547-6549 (1990)]. Unfortunately, there is no widespread effective treatment for chronic HCV 200427684 weakness. HCV Gene group encodes 3010-3033 polyamino acids [QL Choo, et al., "Genetic Organization and Diversity of the Hepatitis C Virus" '1, Proc. Natl Acad · Sci · USA, 88, pp. 2451-2455 (1991); N. Kato et al ·, "Human Hepatitis C Virus Genome Selected Molecularly from Japanese Non-A and Non-B Hepatitis Patients ( Molecular Cloning of the Human Hepatitis C Virus Genome From Japanese Patients with Non-A, Non-B Hepatitis), '' Proc. Natl. Acad. Sci · USA · 87, pp. 9524-9528 (1990); A. Takamizawa et al., "Structure and Organization of the Hepatitis C Virus Genome Isolated From Human Carriers," isolated from human carriers, "J. Virol., 65, pp. 1105-1113 (1991)]. HCV non-structural (NS) proteins have been postulated to provide the basic catalytic mechanism necessary for viral replication. NS protein derived from proteolytic action of polyproteins [R. Bartenschlager et al., N Nonstructural protein of hepatitis C virus encoding a serine protease required for cleavage at the junction of NS3 / 4 and NS4 / 5 3 (Nonstructural Protein 3 of the Hepatitis C Virus Encodes a Serine-Type Proteinase Required for Cleavage at the NS3 / 4 and NS4 / 5 Junctions) '' J. Virol. 67, pp. 3835-3844 (1993); A. Grakoui et al., Characterization of the Hepatitis C Virus-Encoded Serine Proteinase: Determination of Proteinase-Dependent Polyprotein 92593.doc -9- 200427684

Cleavage Sites) '' J. Virol., 67, pp. 2832-2843 (1993); A. Grakoui et al., Expression and Identification of Hepatitis C Virus Polyprotein Cleavage Products) '' J. Virol .. 67, pp. 1385-1395 (1993); L. Tomei et al., &Quot; NS3 is a serine protease (NS3 is a serine protease required for processing of hepatitis C virus polyprotein) ", J. Virol · 67, pp. 4017-4026 (1993)] °

The serine protease activity contained in HCV NS protein 3 (NS3) helps to process most viral enzymes and is necessary for viral replication and infectivity. Mutations in the yellow fever virus NS3 protease are known to reduce viral infectivity [Chambers, TJ · et. Al ·, "There is evidence that the N-terminal functional site of the non-structural protein NS3 of yellow fever virus is in the viral polyprotein Evidence that the N-terminal Domain of Nonstructural Protein NS3 From Yellow Fever Virus is a Serine Protease Responsible for Site-Specific Cleavages in the Viral Polyprotein '', Proc. Natl · Acad. Sci. USA, 87, pp. 8898-8902 (1990)) ° 181 amino acids (residues of viral polyproteins 1027-1207) before NS3 are known to contain serine protease functional sites of NS3, which have HCV polymer All four downstream positions of the protein [C. Lin et al., Hepatitis C Virus NS3 Serine Proteinase: TV ㈣ 5-Cleavage Requirements and

Processing Kinetics) '', J. Virol. 68, pp. 8 147-8157 (1994)]. 92593.doc -10-200427684 The HCV NS3 serine protease and its related cofactor NS4A assist in processing all viral enzymes and are considered necessary for viral replication. This process is similar to the human immunodeficiency virus aspartyl protease that also involves the process of viral enzymes. HIV protease inhibitors can inhibit the processing of viral proteins and are powerful antiviral agents for humans. This means that they interfere with the viral life cycle at this stage and can be used as medical active agents. Therefore, HCV NS3 serine protease is also an attractive target for drug development. In addition, current knowledge of HCV has not produced any satisfactory anti-HCV agents or therapies. Until recently, the only established therapy for HCV disease was interferon therapy. However, there are significant side effects of interferon [MA Wlaker et al., NCS Hepatitis virus: Hepatitis C Virus: An Overview of Current Approaches and Progress] 1 'DDT, 4, pp. 518-29 (1999); D. Moradpour et al., Current and Evolving Therapies for Hepatitis C, Eur. J. Gastroenterol. Hepatol., 11, pp. 1 199-1202 (1999); HLA Janssen et al.n and Suicide Associated with Alfa-Interferon Therapy for Chronic Viral Hepatitis in chronic viral hepatitis '' J. Hepatol., 21, pp. 241-243 (1994); PF Renault et al. ,,,, a _ Side Effects of Alpha Interferon 1 'Seminars in Liver Disease, 9, pp. 273-277 (1989)] and can induce long-term remission in only some cases (~ 25%) [0 · Weiland , ', Interferon Therapy in Chronic Hepatitis C Virus Infection " 5 F ^ MS Microbiol. Rev., 14, pp. 279-288 (1994)]. Recently introduced polyethylene92593.doc -11- 200427684 Ethylene glycol interferon (PEG-Intron® and Pegasys®) and combination therapy with ribavirin and polyethylene glycol interferon (Rebetrol®) are also available. Only a modest improvement in the response rate and only a partial reduction in side effects. In addition, the prospects for effective anti-HCV vaccines remain uncertain. Therefore, there is a need for a more effective anti-HCV therapy. These inhibitors should have medical potential as protease inhibitors, specifically as serine protease inhibitors, and more specifically as HCV NS3 protease inhibitors. In particular, these compounds are suitable as antiviral agents, in particular anti-HCV agents. [Summary] The present invention provides a compound of formula I:

I or a pharmaceutically acceptable salt or mixture thereof, wherein: W is: 0 〇ο ο

Or ο

Each r6 is: 92593.doc -12- 200427684

(C1_C12) -lipids, (C6-C10) -aryl_, (^-(^ (^ • aryl ^^ is called -lipids-, (C3-C10) -cycloalkyl_ or cycloalkenyl _, [(C3-C1〇) _cycloalkyl- or cycloalkenyl]-(C1-C12) -lipid-, (C3_C10) -heterocyclyl_, (c3-ci〇) _heterocyclyl cl_cl2) m, (C5-C10) -heteroaryl_ or (C5-C10) -heteroaryl_ (C1_C12) -lipids_, or up to 3 lipid carbon atoms in each R6 of the eight, depending on the needs of chemistry The above stable arrangement method is replaced by 8, _8 (0) _, _8 (0) 2_, _〇 一 _ 氺, or 4 lures) _; where R6 can be substituted by up to 3 j substituents as required; or 2 The I group and the nitrogen atom to which it is bonded can be combined to form a 5- to 6-membered aromatic system or a 3- to 7-membered saturated or partially unsaturated ring system, where at most 3 ring atoms can be optionally N, NH, 〇 Heteroatom substitution of s, s, 80 and 80, wherein the ring system may be optionally substituted with (C6-C10) aryl, (C5_cl〇) heteroaryl, (C3_Cl〇) cycloalkyl or (C3_cl〇) Heterocyclic groups are fused, in which any ring has up to 3 substituents selected from j; each R8 in eight is _〇R, respectively; or Rs group and boron atom can be formed together as required (C3-C 10)- Heterocyclic In addition to boron, up to 3 ring atoms may be replaced by N, NH, 〇, S, SO, and S02 if necessary; is halogen, -OR, -N02, -CN, -CF3, -0CF3, -R ,, oxo-methionyl, = N (R,), = N (OR,), 1,2-fluorenedioxy, i, fluorene ^ 92593.doc -13- 200427684 oxygen, -N (R ') 2, -SRf, -SOR', -S02R ', -S02N (R') 2, -S03R ,, C (0) IT, -C (0) C (0) R ,, -C ( 0) C (0) 0R ,, -C (0) C (0) NR ', -C (0) CH2C (0) R', -C (S) R ,, -C (S) OR ',- C (0) 0R ,, -0C (0) R ,, -C (0) N (R ') 2, _0C (0) N (R,) 2, -C (S) N (Rf) 2,- (CH2) 0_2NHC (O) Rf, -N (R,) N (R ') COR ,, -N (Rf) N (R,) C (0) 0R', -N (R,) N (R ' ) CON (Rf) 2, -N (R,) S02R ', -N (R 丨) S02N (R,) 2, -N (Rf) C (0) 0R', -N (R?) C (0 ) Rf, _N (R ') C (S) Rf, -N (R') C (0) N (R,) 2, -N (R,) C (S) N (R,) 2, -N (COR ') COR, -N (ORf) R 丨, -C (= NH) N (R,) 2, -C (0) N (0R') R ,, -C (= NOR,) R ' , -0P (0) (0R ') 2, -P (0) (R') 2, -P (0) (0R ') 2S-P (0) (H) (0R'); where R 'are respectively Selected from: hydrogen-, (C1-C12) -lipid-, (C3-C10) -cycloalkyl -Or-cycloalkenyl-, [(C3-C10) -cycloalkyl or -cycloalkenyl]-(C1-C12) -lipid-, (C6-C10) -aryl-, (〇6- ( : 10) _aryl-((: 1- € 12) -lipid-, (C3_C10) _heterocyclyl_, (〇3-(: 10) -heterocyclyl-((: 1-〇12) _Lipids-, (C5-C10) -heteroaryl- and (05-010) -heteroaryl _ ((31-0: 12) -lipids-; where up to 5 atoms in R 'may be required and Substituted by J respectively; where two R's bonded to the same atom can form 5- to 6-membered aromatic 92589.doc -14-200427684 or 3- to 7-membered saturated or partially unsaturated ring systems, where Up to 3 ring atoms may optionally be substituted with heteroatoms selected from the group consisting of N, NH, 0, s, 30, and 802, where the ring system may be optionally substituted with (C6_cl〇) aryl, (C5_ci〇) Heteroaryl, (C3-C10) cycloalkyl or (C3-C1〇) heterocyclyl are fused, where any ring has up to 3 substituents each selected from j; r5 and r5. Hydrogen or (c丨 < 12) _ Lipid system, in which any hydrogen may be optionally substituted with halogen, and any terminal carbon atom of R5 may be substituted with chlorothio or L group as required, or R_5 is Ph or _CH2Ph, and is Η, where The ph or -Ci ^ Ph group may optionally be substituted with up to 3 substituents selected from]; or R5 and R5. It may form a 3- to 6-membered saturated or partially unsaturated ring system together with the atom to which it is bonded, as required. , Where at most 2 ring atoms can be replaced with N, NH, 0, S0 or S02 if necessary; wherein the ring system has at most 2 substituents selected from J; R2, R4 and R7 are: hydrogen-, (Cl-C12) _lipid-, (C3-C10) -cycloalkyl- (C1-C12) -lipid · or (〇6- € 10) -aryl- (〇1 _ (: 12) _lipid --Where each R2, R4 # R7t up to two lipid carbon atoms can be chemically stabilized by S, -S (0) _, _S (0) 2_, 〇, _n or -n ( h) _ substitution; up to 3 are selected from j each of which R2, R4 and R7 are respectively and optionally substituted with substituents;

I 92593.doc -15- 200427684

R1 and R3 are: (C1-C12) -lipid-, (C3-C10) -cycloalkyl- or -cyclodiyl-, [(C3-C10) -cycloalkyl- or -cycloalkenyl] -(C1-C12) -lipid-, (C6-C10) -aryl- (C1-C12) -lipid- or (〇5-(: 10) -heteroaryl-((: 1 < 12) -lipid -; Where up to 3 lipid carbon atoms in each of R! And R3 can be s, -s (o)-, -s (o) 2-, -〇, _ or 4 (11) _ substitution; selected from J in which each heart and chemistry 3 are separately and optionally substituted by up to 3 separate substituents; R9, R9 ,, 1 ^ 10 and 111 (), respectively -XYZ; X is a bond, -C (H) (R6)-, -〇- ,; Ri 1 is: hydrogen-, (C1-C12) -lipid-, (C6-C10) -aryl_, (06 -010) -aryl_ (〇: 1-(: 12) -lipid-, (C3-C10) -cycloalkyl- or cycloalkenyl-, [(〇3_〇10) -cycloalkyl- Or cycloalkenyl ((;: 1 弋 12) _lipid (C3-C10) -heterocyclyl-, (C3-C10) -heterocyclyl- (C1-C12) -lipid-,-(C5- C10) -heteroaryl- or (C5-C10) -heteroaryl_ (C1-C12) _lipid_, 92593.doc -16- 200427684 Among them, up to 3 lipid carbon atoms in each Ri i can be determined according to need The chemically stable arrangement method is S, _S (0)-, _S (0) 2_ -〇-, _N • or -N (H)-substitution; where R " can be substituted with up to 3 J substituents as needed; or where Rii and Z and the atom to which they are bonded can be combined to form a nitrogen-containing 5-7 -Membered monocyclic or 6-11-membered bicyclic ring systems, which may be substituted with up to 3 j substituents as required, wherein up to 3 ring atoms of the ring system may be chemically stabilized by 0, NH, S , SO or S02 substitution; Y is a bond, -ch2 ·, -c (o) ·, -c (0) c (0)-, _s (0) ·, s (〇v or -s (o) (nr12) one;

Ri 2 is: hydrogen-, (C1-C12) -lipid-, (C6_C10) -aryl_, (€ 6 < 10) -aryl _ ((:: 1_〇: 12) _lipid-, (C3-C10) -cycloalkyl- or cycloalkenyl-, [(〇3- < :: 10) -cycloalkyl- or cycloalkenyl]-(0: 1_〇12) -lipid , (C3-C10) -heterocyclyl-, (C3-C10) -heterocyclyl_ (C1-C12) _lipid, (C5-C10) -heteroaryl- or (C5_C10) -heteroaryl- (C1-C12) -lipids, where up to 3 lipid carbon atoms in each R! 2 can be s, -s (0) _, _s (0) 2_, _〇 according to a chemically stable arrangement as required. _N or _n (h) substitution, where Rk can be optionally substituted with up to 3 j substituents; 92593.doc -17- 200427684 hydrogen-, (C1_C12) _lipid-, (C3_C10) _cycloalkyl -Or-cycloalkenyl_, [(.3-(^ 10) _cycloalkenyl or -cycloalkenyl]-((^ 1-(^ 12) -aliphatic_, (C6-C10) -aryl -, (〇6-(: 10) -aryl-((: 1- (312) -lipid-, (C3-C10) -heterocyclyl-'(〇3-(: 10) -heterocyclyl -((: 1-(: 12) -lipids-, (C5-C10) -heteroaryl- or (05-010) -heteroaryl-((: 1-0: 12) -lipids-; Among them, up to 3 lipid carbon atoms in Z may be S, -S (0) _, _S (0) 2_, -0, _N-or-substitution; where any ring can be fused with (C6-C10) aryl, (C5_C10) heteroaryl, (C3-C10) cycloalkyl or (C3-C10) heterocyclyl, if necessary; where Z is respectively And optionally substituted with at most 3 substituents selected from J; V is -C (O) ·, -s (0)-or -s (0) 2-; R is -C (O)-,- s (0)-, -s (0) 2-, -N (R12) ·, -0-, or a bond; T is: (C1-C12) -lipid-; (C6-C10) -aryl -, (06- < 310) _aryl- (〇: 1- € 12) -lipid-, (C3-C10) _i-alanyl or -cyclodiyl-, [(C3-C10) · ring Alkyl or -cycloalkenyl;] _ (C1_ci2) -lipid-, 92593.doc -18- 200427684 (C3-C10) -heterocyclyl-, (C3-C10) -heterocyclyl- (Cl-Cl2 ) -Lipid-, (C5-C10) · heteroaryl- or (C5-C10) _heteroaryl_ (C1_C12) _lipid_; where up to 3 lipid-based carbon atoms in T can be chemically stable The arrangement method is replaced by s, -S (0 >, _S (0) 2-, -0-, or -N (Η)-; where each T can be substituted with up to 3 j substituents as required; or T is optional From -N (R6) (r6,); and R6, is hydrogen-, (C1-C12) -lipid-, (C6-C10) -aryl-, (匸 6-〇10) -aryl- ( 〇1-(: 12) -lipid-, (C3-C10) -cycloalkyl- or cycloolefin _, [(C3-cio) -cycloalkyl- or cycloalkenyl hC1_c12), system one, (C3-C10) -heterocyclyl-, (C3-C10) · heterocyclyl- (C1-C12)- Lipid ·, (C5-C10) · heteroaryl- or (C5-C10) -heteroaryl- (C1-C12) -lipid-, or up to 3 lipid carbon atoms in each R6 'may be required Substituted by S, -S (0)-, _S (〇) 2_, _〇, _N_ or · n (h) _ according to a chemically stable arrangement method; wherein R6 'may optionally be substituted with up to 3 J substituents · , Or R6 and R6 'can be bonded together to form a nitrogen atom (C3-C10) -heterocyclic system', where the $ chen system can be selected from up to 3, respectively, selected from 92593.doc -19- 200427684 J Substituted with a substituent. The present invention also relates to a method for preparing the above-mentioned compound, and a composition comprising the above-mentioned characterized person, and the usage thereof. These compositions can be inserted into a patient's body as an invasive device before treatment, used to treat biological specimens such as blood, and administered directly to the patient before administration to the patient. In each case, the composition will be used to inhibit HCV replication and reduce the risk and severity of HCV infection. [Embodiment] The present invention provides a compound of formula I:

Or a pharmaceutically acceptable salt or mixture thereof, wherein: W is:

Among them, each RG is 92593.doc -20-200427684 (C6-C10) -aryl-, (C6-C10) -aryl- (C1-C12) -lipid, _ (C3-C10)-% Alkyl- or cyclodiphenyl-, [(C3-C10) -cycloalkyl or cycloalkenyl HC1_C12) _lipid (C3-C10) -heterocyclyl-, (C3-C10) -heterocyclyl- ( C1-C12) -lipid (C5_C10) _heteroaryl- or (匸 5- (1; 10) -heteroaryl-((^ 1-(^ 12) -lipid-, or each of them & Up to 3 lipid carbon atoms can be set by S, -S (0)-, -S⑼2_, 0-, · N_ or · N (H) _ according to the arrangement method of chemical safety * if necessary. Substitute up to 3 J substituents; or, 'P I groups and the nitrogen atom to which they are bonded may jointly form a 5_ to 6_ shell aromatic system or a 3- to 7-membered saturated or partially unsaturated ring system , Where up to 3 ring atoms can be replaced with N, NH, 0, s, 30 and 30 as required, and the ring system can be optionally substituted with (C6-C10) aryl and (C5_cl〇) heteroaryl. (C3-C10) cycloalkyl4 (C3-C10) heterocyclyl is fused, where any ring has up to 3 substituents selected from j; where each Rs is -OR '; or the group and side atoms are visible Need to form together (C3-C10 ) -Membered heterocyclic ring, in which, in addition to boron, up to 3 ring atoms may be replaced by N, NH, 〇, S, SO, and SO 2 as necessary; J is i prime, -OR ,, -N〇2, -CN , _Cf3-0Cf3, _R,, oxo, thioxo, = N (R '), = N (0R,), i, 2-fluorenylenedioxy, 1,2-ethylenedioxy, -N (R,) 2, -SR ,, -SOR ,, -S02R ,, -S02N (R,) 2, -S03Rf > -C (0) R '. -C (0) C (0) Rf --C (0) C (0) 0Rf > 92593.doc -21-200427684 -C (0) C (0) NR ', -C (0) CH2C (0) R, -C (S) R ', -C (S) OR', -C (0) 0R ', -0C (0) Rf, -C (0) N (R,) 2, -0C (0) N (R') 2,- C (S) N (R ') 2 >-(CH2) 〇.2NHC (0) Ri > -NCR ^ NCR ^ COR1 ^ -N (R') N (R ') C (0) 0R', -N (R ') N (R') CON (R ') 2, _N (R') S02R ', -N (R') S02N (R,) 2, -N (R ') C (0) 0R , -N (R ') C (0) R', -N (Rf) C (S) R ', -N (R') C (0) N (R ') 2, -N (R') C (S) N (R ') 2, -N (COR,) COR ,, -N (OR,) R', -C (= NH) N (R,) 2, -C (0) N (0R ,) R ,, -C (= NOR ') R ,, -P (0) (0R') 2, -P (〇) (R,) 2, -P (〇) (〇R 丨) 2 or P (0) (H) (0R,); wherein R ′ is selected from: hydrogen-, (C1_ C12) · lipid ·, (C3-C10) -cycloalkyl- or -cycloalkenyl-, [(C3-C10) · cycloalkyl or · cycloalkenyl]-(Cl_C12) -lipid-, ( C6-C10) -aryl-, (06-0: 10) -aryl-((: 1-0: 12) -lipid-, (C3-C10) -heterocyclyl-, (03-010) -Heterocyclyl- (0: 1-(: 12) -lipid-, (C5-C10) -heteroaryl-and (05-010) -heteroaryl- (0: 1- €: 12)- Lipid-; where R; at most 5 atoms may be substituted with J if necessary; where two R 'bonded to the same atom may form 5- to 6-membered aromatic or 3- to 7-membered saturated or Partially unsaturated ring systems, where up to 3 ring atoms can be optionally substituted with heteroatoms selected from: N, NH, Ο, S, SO, and S02 respectively. 92589.doc -22- 200427684, where the ring system can be replaced with (C6-C10) aryl, (C5-Cl0) heteroaryl, (C3-C10) cycloalkyl or (C3-C10) heterocyclyl fused, wherein any ring has up to 3 substituents each selected from J ; R5 and R5, respectively, hydrogen or (C 1-C12) -lipid, wherein any hydrogen may be substituted with halogen as required; wherein any terminal carbon atom of R5 may be substituted with hydrogen sulfide or group as required; or R5 is Ph Or -CHJh, and I is η, wherein the ph or -CHeh group may be optionally substituted by up to 3 substituents selected from j; or I and Rr and the atom to which they are bonded may form a 3_ to 6_ member saturated or Partially unsaturated ring system, where up to 2 ring atoms can be replaced by N, NH, 0, SO, or S0 2 as required; wherein the ring system has up to 2 substituents each selected from J; R2 and R7 respectively Is: chloro-, (C1-C12) -lipid-, (C3-C10) -cycloalkyl_ (C1_C12) • lipid-or (〇6-(^ 10) -aryl _ ((31- ( ^ 12) -lipid-; where up to two lipid carbon atoms in each of R2, R4 and r7 can be chemically stabilized by S, -S (O) ·, -S (0) 2-, -0-, -N- or _N (H)-substitution; wherein each of R2, I and r7 are respectively and optionally substituted with at most 3 substituents each selected from j;

Ri and R3 are: (C1-C12) -lipid-, 92593.doc -23- 200427684 (C3-C10) -cycloalkenyl- or -cycloalkenyl-, [(03-(: 10) -ring Alkyl- or -cycloalkenyl]-((: 1-0: 12) -lipid-, (C6-C10) · aryl- (C1-C12) -lipid- or (〇5-〇10) -hetero Aryl-((: 1-(: 12) -lipid-; where up to 3 lipid carbon atoms in each of Ri and R3 can be replaced by S, -S (O)-, -S (0) 2-, -0-,-substitution; wherein each heart is substituted with 1 ^ and optionally substituted with up to 3 substituents selected from j; R9, R9 ', Rio and Rio, respectively- XYZ; X is a bond, _C (H) (R6)-, -ο-, -s_, or -N (Rn)-; R11 is: hydrogen-, (C1-C12) -lipid-, (C6 -C10) -aryl-, (C6-C10) -aryl_ (C1_C12) -lipid-, (C3_C10) _cycloalkyl- or cyclodialkyl-, [(C3-C10) _cycloalkyl- or Cycloalkenyl] _ (ci_c 12) -lipid-, (C3-C10) -heterocyclyl-, (C3-C10) -heterocyclyl- (C1-C12) -lipid-, (C5-C10 ) -Heteroaryl- or (〇5-(!: 10) -heteroaryl-((^ 1-(: 12) _lipid-), where up to 3 lipid-based carbon atoms in each Ru may be chemically dependent on need. The above stable arrangement method is S, -S (O)-, -S (〇) 2_, _〇_ , -Qin or-is called ⑴ · replacement; 92593.doc -24- 200427684 where Rn can optionally be substituted by up to 3 j substituents; or where R " and Z and the atom to which it is bonded together can form a nitrogen-containing 5_7 if necessary. -Member monocyclic or 6-n • membered bicyclic ring systems, which may be substituted with at most 取代 substituents, where up to 3 ring atoms of the ring system may be replaced by 0, NH, S, SO or S〇2 substitution; Y is one-bond, -CH2-, _c (0)-, < (〇) (:: (〇)-, _s (0), s (〇) 2 ·, or -S (0) (NR12)-;

Rl 2 is: hydrogen-, (C1-C12) -lipid-, (C6-C10) -aryl-, (〇6-(: 10) -aryl-((: 1-(: 12) -lipid- , (C3-C10) -cycloalkyl- or cyclofluorenyl-1, [(C3-C10) · cycloalkyl · or cycloalkenyl] _ (C1_C12) _lipid_, (C3-C10) -heterocyclic -((3-(: 10) -heterocyclyl- (〇1-(: 12) -lipid-, (C5-C10) -heteroaryl- or (05-0: 10) -heteroaryl -((: 1- € 12) -lipid-, where up to 3 lipid carbon atoms in each Rk can be chemically stabilized by S, _S (〇)-, -S (0) 2 -, -〇-, · N- or -N (H)-substitution; where R12 can be substituted with up to 3 J substituents as required; Z is: nitrogen-5 (C1-C12) -lipid one, 92593.doc -25- 200427684 (C3-C10) -cycloalkyl- or -cyclofluorenyl_, [(〇3-(: 10) -cycloalkyl or -cycloalkenyl] _ ((^ 1-(^ 12) -Lipid-, (C6-C10) -aryl-, (〇6- (310) -aryl-((: 1-(: 12) -lipid-,-(C3-C10) -heterocyclyl- , (03-(: 10) -heterocyclyl-((31-0: 12) -lipid-, (C5-C10) -heteroaryl- or (〇5- (310) -heteroaryl- ( (: 1- (312) _lipid-; where up to 3 lipid-based carbon atoms in Z can be S, -S (〇)-, -S (0) 2_, -O, -N_ or -N (H) _; any ring may be optionally substituted with (C6-C10) aryl, (C5_cl〇) heteroaryl, (C3-C10) A cycloalkyl or (C3-C10) heterocyclyl is fused; wherein Z is substituted separately and optionally with up to 3 substituents selected from ^; V is -C (O)-, -s (0)-or -s (0) 2-; R is -C (O)-, -S (O)-, -S (0) 2-, -N (R12)-, -O-, or a bond; T is: (C1-C12) -lipid-; (C6-C10) -aryl_, (06-(: 10) -aryl- (〇: 1-0: 12) _lipid-, (C3-C10) -Cycloalkyl or -cycloalkenyl, [(〇3 < 10) -cycloalkyl or -cycloalkenyl] _ ((:: 1_〇12) _lipids_, (C3-C10) -hetero Cyclo-, (C3-C10) -heterocyclyl_ (c, C12) -lipid-, 92593.doc -26- 200427684 (C5-C10) -heteroaryl- or (C5-C10) _heteroaryl The radical # 1 {12) _fat is in the middle of T in the middle of 3 months, and the carbon atoms can be s -S (O)-, -s (0) 2-, -〇_ according to a chemically stable arrangement method. , Or -N (H) _ substitution; wherein each T may be substituted with up to 3] substituents as required; or T is selected from -N (R6) (R6.); And R6 'is hydrogen-, (C1_C12)- Lipid-, (C6-C10) -aryl-5 (C6-C10) -aryl_ (Ci-Cl2) _lipid, (C3-C10) -cycloalkyl_ or Cycloalkenyl, [(C3-cio) -cycloalkyl- or cycloalkenyl hC1_c12) _lipid, (C3-C10) -heterocyclyl, (03 < 10) -heterocyclyl- (〇 : 1- (312) -lipid-, (C5-C10) -heteroaryl- or (C5-C10) -heteroaryl_ (ci-ci2) -lipid ·, or each of them R6, medium up to 3 Each lipid-based carbon atom can be replaced by S, _s (〇) _, -S (〇) 2_, -〇-, or -N (H) _ according to the chemically stable arrangement; 3 J substituents are substituted; or R6 and R6, and the nitrogen atom to which they are bonded may be combined to form a (C3-C10) -heterocyclic ring system, wherein the ring system may be optionally substituted with at most 3 substituents selected from J To replace. Definition 92589.doc -27- / () ^ 4 术 # naryl "is used for the phenyl group as a monocyclic aromatic ring quaternary = refers to a monocyclic or bicyclic carbocyclic aromatic ring system. All are aromatic rings Example Γ ring aromatic ring system includes two ring aromatic ring systems, ，, @ _ci〇) n ^ π / Gao Xian Understand, used in this article term or bicyclic two — — ° 6, ... ,,, And. 10 monocyclic, 4 and anointed, aromatic ring systems. The term `` heterocyclic ring '' is used herein to refer to a monocyclic or bicyclic non-aromatic ring system, each of which is dependent on the cyclization and XT to the son-in-law. The arrangement method has 1 to 3 heteroatom or heteroatom groups selected from ο, N, # ^ 〇 and 802. "Heterocyclyl, the bicyclic non-fragrant ring system is I # In-, or two rings may contain the heteroatom or heteroatom group. Knowing the terminology used in this article, (C5-C10) -heterocyclyl t which one of C5, C6, C7, C8, fluorene and fluorene is monocyclic or bicyclic: square ring b. The arrangement method of An ^ has a hetero atom or hetero atom group of N N, NH and S.

_ "Heteroaryl" is used herein to refer to a monocyclic or bicyclic aromatic ring system, in which a chemically stable arrangement has 1 to 3 heteroatoms or heteroatoms selected from 0, n, NH " S. Atomic group. " Heteroaryl " These bicyclic aromatic ring systems In specific embodiments:-One or two rings may be aromatic; and • One or two rings may contain the heteroatom or heteroatom group. It is understood that the term "(C5_C10) _heteroaryl" as used herein includes any one of C5, c6, 〇, C8, C9 and CIO monocyclic or bicyclic aromatic ring systems, and each ring of which is chemically stable The permutation method has 1 to 3 heteroatom or heteroatom groups selected from 0, N, NH and S. 92593.doc -28-200427684 The term "lipid π" is used for the # group in this article. 戍 Understand, use π too "or branched alkyl, fluorenyl, or alkynyl, for the term ㈣, C2, C3, C4, C5, C6 c;-^ C12 straight or branched carbon atom 垸 = C1 () C11 and each ^, to understand, the specific conjugates of alkenyl or alkynyl need to be at least. ^ Original term ,, cycloalkyl or ring ::: early soil or bicyclic carbocyclic or non-aromatic ring system. Cyclically dilute radicals have one or more unsaturated units. 4 Understand that the terms C6, C7, C8, C9 and C1G are monocyclic or fused or bridged bicyclic carbocyclic rings used herein. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, cycloheptyl, cycloheptyl, pro-ice, amidino and naphthyl. The phrase " chemically stable arrangement " is used herein to refer to the structure of the compound as to make the compound sufficiently stable. It is manufactured and administered to mammals by any method known in the relevant art. Typically, these compounds can be at a temperature of 4 (rc or below (C3-C10) -cycloalkenyl_ or _cycloalkenyl_), including any one, in the absence of moisture or other chemical reaction conditions. ,, and remain stable for at least one week. Preferred embodiments According to specific embodiments of the compound of formula I,

Group is

Among them; 92593.doc -29- 200427684 R9, rulers 10 and 1110, in which χ and γ are one-bonded and z is hydrogen; and ruler 9, medium; X is one-bonded; Y is one-bonded,- CH2- or -C (O)-; and z is (C1-C12) -lipid-, (C3-C10) -cycloalkyl- or -cycloalkyl-, [(€ 3-(^ 10)- Cycloalkyl or -cycloalkenyl] _ ((^ 1 _ (^ 12) -lipid-, (C6-C10) -aryl- '(〇6_〇10) -aryl- (〇1- € 12 ) -Lipid-, (C3-C10) -heterocyclyl-, (C3-C10) · heterocyclyl- (Cl-C12) _lipid-, (C5-C10) -heteroaryl- or (C5 -C10) -heteroaryl- (C1-C12) -lipid-; where up to 3 aliphatic carbon atoms in Z can be replaced by S, -S (O)-, -S ( 0) 2-, -〇-, or -N (H)-substitution; wherein any ring may be optionally substituted with (C6-C10) aryl, (C5-CIO) heteroaryl, (C3-C10) cycloalkyl or (C3_C10) heterocyclic group is fused; wherein Z is respectively and optionally substituted with up to 3 substituents selected from each other. According to another specific embodiment, r9, middle; X is a bond; Y is a bond And Z is (C1-C12) -lipid-, (C3-C10) -cycloalkyl- or cycloalkenyl-, [(C3-C10) -cycloalkyl or -cycloalkenyl]-( 〇1 < 12) _ Department "92593.doc -30- 200427684 (C6-C10) -aryl-, (€ 6 < 10) _aryl-((: 1 _ (: 12) _lipid-, (C5-C10) -heteroaryl Or (05-(^ 10) -heteroaryl- (0: 1-(: 12) -lipids; where up to 3 lipid-based carbon atoms in Z can be replaced by S according to chemically stable arrangement according to need) , -S (0) _, _S (0) 2_, -〇, or -N (H)-; any ring may be optionally substituted with (C6-C10) aryl, (C5-C10) heteroaryl, ( C3-C10) cycloalkyl or (C3-C10) heterocyclic group is fused; wherein Z is respectively and optionally substituted with up to 3 substituents each selected from j. According to another specific embodiment, R9, in; X is a single bond; Y is a single bond; and Z is (C1-C12) -lipid-, (C3_C10) _cycloalkyl- or -cyclodiyl-'[(C3-C10) -cycloalkyl Or -cycloalkenyl]-(Cl-C12) -lipid-, or (〇6 < 10) -aryl- (〇1-(: 12) -lipid-, with up to 3 aliphatic carbons in Z Atoms can be replaced by S, -S (O)-, -S (0) 2-, -〇-, _1 or _called 11) _ according to the chemically stable arrangement method; where Z is up to 3 respectively and if necessary Each is substituted with a substituent selected from J. According to another specific embodiment, I ’is 92593.doc -31-200427684

According to another

A specific embodiment

According to another specific embodiment, according to another aspect of the compound of formula I, the terms X and Y are both a bond and z is a gas X is a bond; 'R9, is a specific embodiment of ethyl; and 119, medium;, r9 R10 and R10, in which Y is _C (0)-; and z is (C1-C12) · lipid- or (C3-C1G) _heterocyclyl-hungry_lipid_; eight in 2: moderate to ^ 3 lipid-based carbon atoms can be replaced by S, -S (〇) _, -S (cn ^, son-in-law's row) 2, -〇-, _n-, or -N (Η)-according to the column method; Any ring may be fused with (C6_C10) aryl group, (C5_ci〇) heteroaryl group, (C3-C10) cycloalkyl group or (C3_C10) heterocyclic group as required; where Z is selected separately and up to 3 may be selected as required Self-substituent substituted 0 according to another specific embodiment, Z is 92589.doc -32- 200427684-0- (cl_C6) _lipid or _N (R,) 2, two of which are bonded to a nitrogen atom R, the group may form a 3- to 7-membered saturated or partially unsaturated ring system as required, wherein up to 3 ring atoms may be selected from the group consisting of · n, ΝΙί, 〇, 8, SO, and s〇2 Heteroatom replacement, where the ring system can be optionally substituted with (C6_cl〇) aryl, (C5-C10) heteroaryl, (C3-C 10) A cycloalkyl or (C3-C10) heterocyclyl is fused, wherein any ring has up to 3 substituents each selected from j. According to another specific embodiment of the compound of formula I, z is · N (R,) 2, in which two R bonded to a nitrogen atom, the group may form a 3- to 7-membered saturated or partially unsaturated as required. A ring system in which up to 3 ring atoms can be optionally replaced with heteroatoms selected from N, NH, 0, S, S0, and s02, wherein the ring system can be optionally replaced with (C6_C10) aryl group, (C5-C1 O) Heteroaryl, (c3-ci0) cyclohexyl or (C3-C10) heterocyclyl are fused, where any ring has up to 3 substituents each selected from j. According to another specific embodiment of the compound of formula I, in 1 and 10, both 乂 and ¥ are one-bonded and Z is hydrogen; and each 9 and 1 (), X is a bond Y is a single bond; and Z is (C1-C12) -lipid-, (C3-C10) -cycloalkyl- or -cycloalkenyl-, [(C3-C10) -cycloalkyl or -cyclo Alkenyl Hci_ci2 > lipid-based, (C6-C10) -aryl-, 9 '' (06-0: 10) -aryl-((^ 1_〇: 12) -lipid- (C3-C10)- Heterocyclyl_, (〇3_ < :: 10) -heterocyclyl- (0: 1- (312) -monthly system_, 92593.doc -33-200427684 (C5-C10) -heteroaryl- or (C5-C10) -heteroaryl_ (C1-C12) _lipid-; where up to 3 lipid-based carbon atoms in Z can be chemically stabilized by S, -S (O )-, _S (0) 2-, -0-, _N-, or -N (Η) _ Substitutions where any ring can be (C6-C10) aryl, j 丞 (L5-C10) heteroaryl, (C3-C10) cycloalkyl or (C3-C10) heterocyclyl is fused; wherein Z is respectively and optionally substituted with up to 3 substituents selected from each other. According to another specific embodiment, each R9, And Z is (C1-C12) · lipid-, (C3-C10) -cycloalkyl- or -cyclofluorenyl_ or [(C 3-C10) -cycloalkenyl or -cycloalkenyl] _ (c κ 12) -lipid__ where up to 3 aliphatic carbon atoms in Z can be replaced by s, -s ( o)-, _s (0) r, 〇_, _N or _N (H) _ substitution; wherein Z is respectively and optionally substituted with at most 3 substituents selected from J. According to another specific embodiment, Each I, and Riq, z are (ci_c6) _lipid-. According to another specific embodiment of the compound of formula I, Riq and RiG, wherein 乂 and 丫 are both bonded and Z is hydrogen; and Each with anti 9, middle; X is a bond, Y is a bond, and Z is (C1-C6) -lipid-, where Z is separately and optionally taken through up to 3 substituents each selected from J 92593.doc -34- 200427684 Generation 0 According to another specific embodiment of the compound of formula i, w is 0 Rfi 〇 Wherein, NR6R6 is selected from: -NH- (C1-C6 lipid), -NH_ (C3 -C6 cycloalkyl), -NH-CH (CH3) _aryl or -NH_CH (CH3) -heteroaryl, wherein the aryl or the heteroaryl can be optionally substituted with up to 3 halogens. According to another item In a specific embodiment, NR6R6 in W is:

According to another specific embodiment, NR6R6 in W is:

According to another specific embodiment, NR6R6 in W is: 92593.doc -35-

200427684 According to another specific embodiment, NR6R6 in W is: V. According to another specific embodiment of the compound of formula I, NR6R6 in the W group is:

According to another specific embodiment, NR6R6 in the W group is:

According to another specific embodiment, NR6R6 in W is:

According to another specific embodiment, W in the compound of the formula I is: 92593.doc -36- 200427684, where is as defined above. According to another specific embodiment, each Rs and a boron atom together form a (C5-C10) -membered heterocyclic ring, in which there are no other heteroatoms except boron and two oxygens. 'In another specific embodiment, W is:

Where R 'is (C1-C6) -lipid. In another embodiment, methyl. According to another specific embodiment of the compound of formula I, R5 is hydrogen and R5 is:

According to another specific embodiment, R5 is hydrogen and R5 is:

92593.doc -37- 200427684 According to another specific embodiment, r5 · and r5 in the compound of formula i are:

According to another specific embodiment of the compound of formula I, R2, R4 and R7 are respectively fluorene, methyl, ethyl or propyl. According to another specific embodiment, R2, R4 and R7 are each hydrogen. According to another specific embodiment of the compound of formula I, R3 is:

According to another specific embodiment, R3 is:

According to another specific embodiment, R3 is: L ± I I 〇 According to another specific embodiment of the compound of formula I, I is:

Or According to another specific embodiment, K is: 92593.doc -38- 200427684

According to another specific embodiment, wherein I is isopropyl or cyclohexyl. According to another specific embodiment of the compound of formula I, the R7 and n4 rv groups are: ^ 12 Rl2 R7 Rl2 R7 〇R6, I ^ TN, f R6, fjTN, 歹 Ά〆, R6, 〒 人 if, R6f 〇, R6 ′ 〇〇, heart o or heart, 0 where: R6, R6, R7 and R12 are as defined in any specific embodiments herein. According to another specific embodiment, ^ 12 Rl2 R7 Rl2 ^ 7 〇 ^ 7

Re " N " N " S " ^ R6 " N " N " S " ^ / R0 " N " N R6, N people

I II I // n I II i II R6 · 〇, R6, 〇〇, R6 · 〇 or FV 0 group: and R7 are hydrogen; R6 is · (C1-C12) -lipid-; (C6-C10) -aryl-, (06-0: 10) -aryl-((: 1-0: 12) -lipid-, (C3-C10) -cycloalkyl or -cycloalkenyl- , 92593.doc -39- 200427684 [(C3-C10) -cycloalkyl or -cycloalkenyl]-(C1_ci2) · lipid-, (C3-C10) -heterocyclyl-, (C3-C10)- Heterocyclyl- (C1-C12) -lipid-, (C5-C10) -heteroaryl-, or (〇5-〇10) -heteroaryl-((: 1 _ (: 12) _lipid- ; Wherein up to 3 lipid carbon atoms in R6 may be replaced by S, -S (〇)-, _S (0) 2_, _〇_, or -N (H)-according to a chemically stable arrangement method; and Wherein R6 is optionally substituted with at most 3 substituents selected from j; and Ri2 is as defined in any specific embodiment herein. According to another specific embodiment, R6 is: (C1-C12) -lipid-; (C6-C10) -aryl · ((: 1 < 12) aliphatic- or (C3-C10) -cycloalkyl or -cycloalkenyl_; where up to 3 aliphatic carbon atoms in R6 can be optionally determined by chemistry The above stable arrangement method is replaced by S, -S (〇) ·, -S (0) 2_, _〇_, -N-, or -N (H)- Three more substituents selected from j respectively; and Ri2 is as defined in any specific embodiment herein. According to another specific embodiment, the group is: 0 r7 r6, ο ο according to another specific implementation For example, 92593.doc -40- 200427684 o r7 R12 * 〇 group:

According to another specific embodiment of the compound of formula I, V is -C (O)-and R is a bond. According to another specific embodiment of the compound of formula I, V is -C (0)-, R is a bond, and T is: (C3-C10) -heterocyclyl- or (C5-C10) heteroaryl -; Wherein each T may be optionally substituted with up to 3 J substituents. According to another specific embodiment, T is (C5-C6) heterocyclyl- or (C5-C6) heteroaryl-; wherein each T can be optionally substituted with up to 3 J substituents. According to another specific embodiment, T is: 92593.doc -41-200427684

ci ην- ^ Λ

Cl

Η or Η where: Z is 0, S, NR ’or C (Rf) 2 According to another embodiment, T is or

Q According to another specific embodiment, the present invention does not include the following compounds: 1- 3-ethylfluorenyl-4,5-dimethyl-1fluorene-tonrole-2-carboxylic acid (cyclohexyl- {1- [3. Langhexyl-2-(1 -Badylaminoamino-butylaminomethyl) -0 Bihedron-1 _ Warmyl] -2,2-dimethyl-propylaminomethyl } -Methyl) -fluorenamine; 92593.doc -42- 200427684 2. 3-ethylfluorenyl-4,5-dimethyl-1H-pyrrole-2-carboxylic acid (cyclohexyl- {1- [2- (1-Badylaminoamino-butylaminomethyl) -3-isopropyl-.pyrrolidine-1-carbonyl] -2,2-dimethyl-propylaminomethyl } -Methyl) -fluorenamine; 3,3-ethylfluorenyl-4,5-dimethyl-1H-pyrrole-2-carboxylic acid (cyclohexyl- {1- [2- (1-cyclopropylamine) Sulfenyl-butylaminomethylmethyl) -4-oquinazolin-4-yloxy) -pyrrolidine-1-carbonyl] -2,2-dimethyl-propylaminomethylmethylmethyl ) -Amine; and 4 · 3-Ethylamido-4,5-dimethyl-1H-methylpyrrol-2-carboxylic acid ({1- [4- (5-chloro-ratio-2-yl) Milk) -2- (1-Badylaminoamino-butylaminocarbamate) -0 Bisigmadin-1-greenyl] -2,2-dimethyl-propylaminocarbamate } -ίhexyl-methyl) -guineadamine (for example: WO 03/087092 compounds 63, 64, 66, and 67). According to another specific embodiment, the present invention does not include the following compounds, wherein: V is -C (O)-, R is a bond, and T is (C5-C10) · heteroaryl 3-ethylfluorenyl-4 , 5-dimethyl-1H-pyrrole and

92593.doc -43- 200427684

(E.g. · Base in WO 03/087092).

Substituted Proline on pages 56 and 57

According to another specific embodiment, V is -c (0)-; R is a bond; and the present invention does not include the following compounds: Dimethyl-1H-. Comparison (for example: compound of formula II " on page 85 of WO 03/087092). According to another specific embodiment, the present invention does not include the following compounds: wherein T is a C5-heteroaryl group (for example: compound of formula II on page 22 in WO 03/087092). According to another specific embodiment, the present invention does not include the following compounds: wherein T is a pyrrolyl group optionally substituted (for example, a compound of formula II on page 22 in WO 03/087092). According to another specific embodiment, the present invention does not include the following compounds: wherein: V is -c (o)-, -s (o)-, or -s (o) 2-; R is a bond; and T is :

R14 is -H, -S (0) R, -S (0) 2R ', -C (0) R ,, -C (0) 0R ,, -C (0) N (Rf) 2 ^ -N (Rf) C (0) Rf > -NCCOR ^ COR1 > -S02N (R!) 2 ^ -S03R ', -C (0) C (0) R', -C (0) CH2C (0) R ', -C (S) R', -C (S) N (R,) 2,-(CH2) 0_2NHC (O) R ', -N (R,) N (R,) COR ,, -N ( R ') N (R,) C (0) 0R', 92593.doc -45- 200427684 -n (r ') n (r') con (r ') 2, -n (r') so2r ',- n (r ') so2n (r') 2, -N (R ') C (0) 0R', -N (R ') C (0) R /, -N (R') C (S) R; , -N (R >> C (0) N (R ') 2, -N (Rf) C (S) N (R') 2, -N (CORf) CORf, -N (ORf) Rf, -C ( = NH) N (R >> 2, -C (0) N (0Rf) R ', -C (= NOR') R ', -0P (0) (0R') 2, -P (0) (R ' ) 2, -P (0) (0R,) ^-P (0) (H) (0R ');

Ri5 and Ri6 are halogen, -OR ', -〇C (0) N (R') 2, -N〇2, _CN, CF3, -OCF3, -R ', oxo group, and 1,2 Methyldioxy, 1,2-ethylenedioxy, -N (Rf) 2, -SR ,, -SOR ', -S02R', -S02N (R,) 2, _S03R ,,-C (0 ) R ',-(:( 0) 0 (0) 1 ^, -C (0) CH2C (0) Rf, -C (S) R, -C (0) 0R 丨, _〇C (0) Rf, -C (0) N (Rf) 2, -0C (0) N (R 丨) 2, -C (S) N (R ') 2,-(CH2) G_2NHC (0) R ·, -N (R,) N (R,) COR ,, -N (R ') N (R') C (0) 0R ', -N (R') N (R,) CON (R,) 2, -N (R,) S02R ,, -N (R,) S02N (Rf) 2 > -N (Rf) C (0) 0Rf ^ -N (Rf) C (0) Rf > -N (R?) C (S) Rf > -N (R ') C (〇) N (R') 2, -N (R ') C (S) N (R') 2, -N (COR ') COR',- N (OR ') R', -CN, -C (= NH) N (R ') 2, -C (0) N (0R') R ', -C (= NOR') R ', -P ( 〇) (OR ') 2, -P (〇) (r') 2, -P (〇) (〇R,) 24_p (〇) (h) (or,); Z2 == 0,, = NORf4 = C (Rf) 2; R19 is -OR ', -CF3, -OCF3, -R ,, -N (R,) 2, -SR1, -C (0) R ,, -COOR ,, _c〇N (R ') 2, -N (R') COR 'or _N (COR') COR '; where two R' groups are common to the atom to which they are bonded Into a 3- to 10-membered aromatic or non-aromatic ring having at most 3 heteroatoms selected from: N, NH, 0, s, SO or S02, respectively, wherein the ring may be optionally associated with (C6_C10) aryl, ((: 5- < :: 10) heteroaryl, (匚 3-0: 10) cycloalkyl or (〇3- € 10) heterocyclyl are fused, and any ring has at most 3 separately selected A substituent from J2; or 92589.doc -46- 200427684 each R 'is selected from: hydrogen-, (C1-C12) -lipid-, (C3-C10) -cycloalkyl or -cycloalkenyl-, [(〇3-(: 10) -cycloalkyl or -cycloalkenyl]-((: 1- (312) -lipid-, (C6-C10) -aryl-, (€ 6 < 10) _ Aryl-((: 1-〇12) -lipid-, (C3-C10) -heterocyclyl-, (€ 6 < 10) -heterocyclyl- (〇1-_12) lipid-, (C5 -C10) -heteroaryl- or (C5-C10) -heteroaryl- (C1-C12) -lipid-, wherein R 'has up to 3 substituents each selected from J2; and J2 is an i element, -OR ', -0C (0) N (R') 2, -N02, -CN, -CF3, -OCF3, -R /, oxo, thio, 1,2-methylenedioxy, -N (R ') 2, -SR', -SOR ,, -S02R ,, -S02N (R ') 2, -S03Rf, -C (0) R ,, -C (0) C (0) Rf, -C (0) CH2C (0) R, -C (S) Rf -C (0) 0R ', -0C (0) R, -C (0) N (R,) 2,-0C (0) N (R') 2, -C (S) N (R ') 2,-(CH2) 〇_2NHC (0) R ,, _N (R,) N (R,) COR ,, -N (Rf) N (R,) C (0) 0R ,, -N (R, ) N (R,) CON (Rf) 2, -N (Rf) S02Rf ^ -N (R,) S02N (Rf) 2 > ^ (^) 0 (0) 0 ^ > -N (Rf) C (0) Rf > -N (Rf) C (S) R ', -N (Rf) C (0) N (Rf) 2 ^ -N (Rf) C (S) N (Rf) 2 ^ -N (CORf) CORf, -N (OR 丨) Rf, -CN, -C (= NH) N (R,) 2, -C (0) N (0Rf) Rf, -CpNOR1)! ^, -0P (0 ) (0Rf) 2, -P (0) (R >> 2, -P (0) (0R,) 2 or -P (0) (H) (0R ') (for example: page 22 in WO 03/087092 Formula II). 92593.doc -47- 200427684 According to another preferred embodiment of the compound of formula i, the compound is:

92593.doc -48- 200427684 7 8 9 10 11 12 〔: All / data 13 92593.doc -49- 200427684

92593.doc -50- 200427684 21 22 〔:, secret 対 23 24 〔/ ίΗΝΨΡ々κν 25 26 0 0 0 0 ο 27 0 〇0 〇〇) 0 92593.doc -51-200427684 28 0 〇〇ο ο 29 0 〇0 0 〇3 0 0 〇〇ο ο 31 ί ^ Ν ο + 广 〆 一. / 0 0 0 〇 〇 32 0 〇0 〇 〇 33 0 〇0 ο ο 34 Guang N. ΥΓν, '' person / Γ々 彳 梁 Λνί 〇〇〇〇〇92593.doc -52- 200427684 35 0 0 ο 0 ο 36 0 0 0 0 〇37 38 0 (/ ¾ 39 40 41 广 N 0 i (" V, / person doc 200427684

92593.doc -55- 200427684

92593.doc -56- 200427684

92593.doc -57-

Ming compounds may contain one or more asymmetric carbon atoms, so it may be possible: racemates and racemic mixtures, single enantiomers, diastereomer mixtures and individual diastereomers. The isomeric 92593.doc -58- 200427684 form of all these compounds is included in the present invention. Each of the three-dimensional carbons may have a configuration. In another specific implementation, the structure and stereochemistry of the compounds of the present invention are described in Compounds 1-77. Any preferred specific embodiments shown herein, including the above-mentioned specific embodiments, can be defined as "the preferred specific embodiment of the present invention formed by the combination of individual and georges. Those skilled in the art will understand the synthetic route shown" It also includes a comprehensive list of all the descriptions that can be synthesized in this application and the scope of the patent application. It can also be understood by those who are familiar with this technology: Reaction diagrams are used to synthesize the different parts of the month illustrated in the general reaction diagram In addition, the above-mentioned various synthetic pathways can be carried out in an alternating sequence or order, ~. To produce the desired compound. Those who are familiar with organic chemistry will do it, ~ ~ Ba Shicheng understand, other equivalent ways to synthesize the following-general reaction diagrams and preparations Various molecular parts are used. ≪% t The abbreviations used in the following reaction diagrams, preparation methods and examples are: DCM: dichloromethane THF: tetrahydrofuran DMF: N, N, -dimethylformamide EtOAc: Ethyl acetate

AcOH: Acetic acid NMM: N-methylmorpholine NMP: N-methylpyrrolidone EtOH ····················································································· OH · DCCA: dichloroacetic acid DIEA: diisopropylethylamine MeCN ·· acetonitrile TFA: trifluoroacetic acid 〇; 611: 1, 8-diazobicyclo [5.4.0] undec-7-ene DEAD: azobis Diethyl carboxylate HOBt: 1-hydroxybenzotriazole hydrate HOAt: 1-hydroxy-7-azabenzotriazole EDC: 1- (3-dimethylaminopropyl) -3-ethyl Carbodiimide hydrochloride

Boc: tertiary butyloxy

Boc20: di-tert-butyl dicarbonate

Cbz: benzyloxycarbonyl

Cbz-Cl: benzyl chloroformate

Fmoc: 9-fluorenylmethyloxyweilyl SEM: silylethoxymethyl TBAF: tetrabutylammonium fluoride

Chg: cyclohexylglycine t-BG: tert-butylglycine mCBPA: 3'-air peroxybenzoic acid DAST: (diethylamino) sulfur trifluoride TEMPO: 2,2,6,6- Tetrafluorenyl-1-hexahydrofluoride, free radical 92591.doc -60- 200427684

PyBOP: reference (pyrrolidinyl) bromide hexafluorophosphate TBTU or HATU: 2- (1 fluorene-benzotrisialyl-1-yl) · 1,1,3,3-tetramethyl sugar acid tetrafluoroborate Salt DMAP: 4 · dimethylamino. Hidayodo ΑΙΒΝ: 2,2'-azabisisobutyronitrile rt or RT · Room temperature ON: -night ND: not determined MS: mass spectrometry LC: liquid chromatography general synthesis method: The compound of the present invention can be used in accordance with related techniques It is prepared by the general method known above. These compounds should preferably be synthesized from readily available starting materials. The following reaction schemes 1-6 illustrate the synthetic routes of the compounds of the present invention. Those who are familiar with organic chemistry understand that various other molecular parts described in the general reaction diagrams and preparation examples below can be synthesized by other equivalent methods. 92593.doc -61-200427684 Reaction Figure 1:

Boc Boc

6a; R " = t-Bu 7a 6b; R " = cyclofluorenyl 6c; R " = 3-pentyl r-Vr · 〇 ^ 〇ΤΒΟΜ3

Boc 5a; R = H; R '= H 5b; R = H; R' = Me 5c; R = Me; R '= Me Scheme 1 · (a) 2-vinyl, 2-propenyl or 2- Butenyl-MgBr, CuBr.DMS, ether, -20 ° C then TMSC1, -78 ° C (65%, 73%, 84%); (b) 10% Pd-C5 H2, 1 atm, EtOH (90 %, 92%, 89%) (c) R ', ZnBr, THF, -30 ° C, BF30Et2 and TMSC1 (64%, 40%, 37%); (d) PhCH (Li) SPh5 BuLi, TMEDA,- 78 ° C (45%); (e) Acetone / water (1 ·· 1), reflux, 12h (83%) · Reaction Figure 2: RR e

5a; Et 8a; Et 9a; Et 5b; i-Pr 8b; i-Pr 9b; i-Pr 5c; s-Bu 8c; s-Bu 9c; s-Bu 6a; t-Bu 8d; t-Bu 9d t-Bu 6b; cyclofluorenyl 8e; cyclofluorenyl 9e; cyclofluorenyl 9f; 3-pentyl 6c; 3- | pentyl 8f; 3-pentyl 7a; CH2Ph 8g; CH2Ph 9g; CH2Ph reaction Figure 2 ⑻ HC] gas, EtOAc, -20 ° C (80% -90%); (b) LAH, THF, reflux (85 ° / 〇-90% Mc) Cbz-Cl, K2C03, THRH20 (1: 1) ( 60% -85%); (d) Strong's reagent acetone, (70 〇 less 0-80 〇 / 〇); (e) isobutylene, H2S04 cat ·, DCM (67% -85 ° / 0); ( f) 10% Pd-C, H2, 1 atm, EtOAc (90% -95%) · 92593.doc -62- 200427684 Reaction Figure 3:

OtBu CH2CHC = H2 ch2ch2ch3 co2ch3 Reaction Figure 3. (a) Pt02, Et0H / Ac0H / H20 (7/2/1), H2, 50 psi; (b) CbzCl, Na2C03, acetone ugly 20 (1: 1) (90) %, Two steps); (c) isobutane, H2S04 cat., CH2C12; (d) 10% Pd-C, H2, 1 atm, EtOH (84%, two) solid step #). Reaction Figure 4:

1) CICH2l / ZnEt:

DCE / 0 ° C to rt 2) NH4CI

92593.doc -63- 200427684 Reaction Figure 5:

56 Response Figure 6:

UOH

Me〇H H20, co2h

HOBt / HBTU DIEA / NMP

The above reaction schemes 1 to 6 provide synthetic routes for preparing the compounds of the present invention. Many starting proline derivatives are available from chemical suppliers known in the relevant art. Intermediate ... can be prepared according to the method described in j 39, P. 2367 (1996). Although some specific examples are described below, it is understood that the present invention can be prepared according to the above-described method 'using appropriate starting materials known to those skilled in the art. 92593.doc -64- 200427684 Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the content of the compound of formula I can effectively reduce the amount of virus in the specimen or the patient, wherein the virus encodes a serine protease necessary for the viral life cycle and also contains a pharmaceutically acceptable carrier . When pharmaceutically acceptable salts of the compounds of the present invention are used in these compositions, these salts are preferably derived from inorganic or organic acids and bases. These include the following acid salts: acetate, adipate, alginate, aspartate, benzoate, besylate, bisulfate, butyrate, citrate, camphor, Camphor sulfonate, cyclopentane-propionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptate, glycerol phosphate, hemisulfate, Heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodate, 2-hydroxyethanesulfonate, lactate, maleate, mesylate, 2-naphthalenesulfonate, Nicotinate, oxalate, paranaphthate, fruit salt, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate , Thiocyanate, tosylate, and undecanoate. Alkali salts include ammonium salts, metal test salts, such as sodium and potassium salts, soil test metal salts, such as calcium and magnesium salts, and salts with organic bases, such as dicyclohexylamine salts, N-methyl- D-glucosamine and salts with amino acids, such as: arginine, lysine, etc. In addition, basic nitrogen-containing groups can also be quaternized by the following reagents, such as: low-carbon alkyl iiides, such as: methyl, ethyl, propyl and butyl chloride, bromide and broken compounds; sulfuric acid Dialkyl esters, such as: dimethylsulfate, diethylsulfate, dibutyl, and dipentyl; long-chain halides, such as: decyl, lauryl, and nutmeg 92591.doc -65- 200427684 ^ and hard Aliphatic compounds, chemical compounds, aromatic compounds, such as: methyl and ethyl ethylate desertification materials. The result is water or loose products. The mixture is homogenized using the human bases used in the compositions and methods of the present invention to enhance selective biological growth and can also be attached with appropriate functional properties. These revision methods are related and include their ability to increase the biological permeability of the biological system (such as: blood, lymphatic system, central nervous system), improve oral utilization, improve the solubility of Tinam injection, and change the metabolism Pharmaceutically acceptable carriers that can be used to alter the excretion rate of these compositions include, but are not limited to, ion exchange agents, protoplasts, stearic acid salts, imprinting lipids, serum proteins, such as human serum albumin Buffer substances such as: phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, salt, or electrolyte such as: protamine sulfate, disodium hydrogen phosphate, hydrogen phosphate Potassium, sodium chloride, zinc tincture, colloidal "stone, Sanliuzhen, polyethylene 0, slightly sold, cellulose-based substances, polyethylene glycol m cellulose sodium, water acrylic, wax, polyethylene _Polyoxypropylene-block polymer, polyethylene glycol and lanolin. According to a preferred embodiment, the composition of the present invention is formulated for administration to a mammal, and in another embodiment, the composition of the present invention is Dispense for people These pharmaceutical compositions of the present invention can be administered orally, parenterally, by spray inhalation, topically, rectally, intranasally, intrabuccally, intravaginally or via an implanted reservoir. The term "parenteral" "Used in this article includes subcutaneous, intravenous, intramuscular, intramuscular, intra-sacral joint, intra-synovial, intra-sternal, intra-juan, trans-liver 92589.doc -66- 427684 Intra- and intracranial injection or infusion techniques. In the examples, the composition is administered orally or intravenously .... The aseptic injection form of this material can be an aqueous or oily suspension. Geer ' : Er U is formulated with a suitable suspending agent based on known techniques in the related art. Her sterile liquid injection can also be a parenterally acceptable parenteral f w, ..., mother ... * In addition, a sterile injection in diluent or solvent or a solution of buprene. The acceptable vehicle can be fixed with the second bacteria 1 and is made of mr isotonic sodium chloride solution. In addition, non-solid Use solid oils as solvents or suspension media. For this purpose, use: Class' includes synthetic mono- or diglycerols. Fatty acids °. Oil I and its glyceride derivatives are suitable for use in residual medically acceptable oils, such as: olive oil or M oil. 4Ethylated type. These oil solutions or suspensions can also contain long-bond alcohol diluents or powders such as slow methylcellulose or pharmaceutically acceptable dosage forms (including emulsions and suspensions). Commonly used similar dispersing agents. Other commonly used surfactants such as: T-ns, Spans and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms can also be used for the purpose of formulation. The daily dose of one of the protease inhibitor compounds described herein is between about 0 to about 100 mg / kg body weight, preferably between about 0.5 to about 75 mg / kg body weight per day, and is suitable for use in antiviral Prophylactic and therapeutic methods, specifically monotherapy for anti-HCV-mediated diseases. Typically, the pharmaceutical group of the present invention can be administered in about one to five times a day, or in continuous infusion. These dosing methods can be used for chronic or acute therapy. The amount of active ingredient that can be combined with a carrier substance to form a single-agent 92593.doc -67- 200427684 depends on the host being treated and the specific mode of administration. A typical formulation will contain from about 5% to about 95% active compound (w / w). In another specific yoke example, these formulations preferably contain about 20% to about 80 ° / 0 active compound. & When the composition of the present invention comprises a compound of formula I and one or more other medical treatments or prophylaxis, the dosage of this compound and the preparations used additionally should be in the range of about 1 (^%) of the normal administration dose in the early-treatment course. , Preferably between about ^ and 80%. The uw pharmaceutically acceptable composition can be any oral acceptable type for oral administration, including (but not limited to) capsules, lozenges, and aqueous suspensions ^ = In the case of tablets for oral use, the commonly used carriers include lactose and cornstarch. Typical lubricants are also added such as: magnesium stearate. Suitable for oral use: = release lactose and dried corn flour. When oral water-based cardiac solution k 'is required, it is composed of active ingredients combined with emulsifiers and suspending agents. Certain sweeteners, flavoring agents or coloring agents can also be added if they are available. It can be presented as the king of transrectal administration. It is prepared by mixing the medicament with a suitable non-irritating excipient that is liquid at room temperature "::: but is liquid at this temperature. Bee * The pharmaceutical composition of the present invention can also be administered topically, especially when treated Bianhe Yizheng is prepared by applying two organs to the area or organ when it is applied topically. Ten pairs of regions or 92693.doc -68- 200427684 The lower intestine can be applied topically using rectal suppositories (such as the above) ) Or a suitable enema formulation. It can also be used in a transdermal topical administration when used topically. The pharmaceutical composition can be formulated into the appropriate oil f, suspended or dissolved in the active ingredient in the active ingredient. Topical administration of the compound of the present invention Carriers include (but are not limited to) mineral oil, liquid paraffin, white petroleum jelly, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified wax and water. Or the C pharmaceutical composition can be formulated into a suitable lotion or cream, # Contains active ingredients in suspension or soluble-or in a variety of pharmaceutically acceptable carriers. Suitable carriers include (but are not limited to) mineral oil, sorbitan monostearic acid, polysorbate 60, whale Wax-based ester wax, cetyl stearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. ^ 'Ophthalmic pharmaceutical composition can be formulated in adjusted isotonic sterile physiological saline Micronized m or preferably ❹ Or use no preservatives (such as ammonium chlorobenzyl ammonium) and prepare a solution in pH-adjusted isotonic sterile physiological saline solution. Or, ophthalmic pharmaceutical compositions can be used in ointments (such as stone butterflies) Formulation. The pharmaceutical composition of the present invention can also be administered in the form of a nasal spray or inhalant. These compositions are prepared according to techniques known in the related art of pharmaceutical formulations, and can be used in physiological saline with benzophenone or other suitable preservatives 2. Enhance the bioavailability to promote absorption, I carbide and / or other commonly used dissolving agents or powders, etc., to make a solution. Another-item specific implementation of the 'The pharmaceutical composition is formulated into oral administration 0 specific In the examples, the composition of the present invention contains another pharmaceutical agent, 92593.doc -69- 200427684, and preferably contains a cytochrome P-450 inhibitor. These cytochrome P-450 inhibitors include, but are not limited to, ritonavir. Another specific embodiment ' The composition of the present invention comprises another antiviral agent, preferably an anti-HCV agent. These anti-viral agents include (but are not limited to): immunomodulators such as: α-, β-, and γ-interferons, polyethylene glycol-derived interferon-α compounds and thymosins; other anti-viral agents , Such as: ribavirin, amantadine and teibivudine; other inhibitors of hepatitis c protease (NS2-NS3 inhibitors and NS3-NS4A inhibitors); HCV life cycle Inhibitors of other targets, including (but not limited to): helicase and polymerase inhibitors; ribosome entry inhibitors; broad-spectrum viral inhibitors, such as: IMpDH inhibitors (eg, US patents

VX_497 and other IMPDH inhibitors, mycophenolic acid and its derivatives disclosed in the case 5,807,876 and 6,498,178; inhibitors of cytochrome P-450, such as: ritonavir or Any combination of the above. When the patient's condition improves, a maintenance dose of a compound, composition or combination of the invention may be administered if necessary. Later, you can reduce the dosage of the drug Le or $ or the frequency or both as the symptoms change, until m_ and the symptoms are alleviated to the required level and maintained to improve, you can stop the +, Λ, and J 扦 to stop e therapy. However, when any recurrence of disease symptoms occurs, intermittent treatment over a long period of time is required. It is understood that the exact dose and course of treatment for any particular oxygen-dissipating person will depend on a number of factors, including the specific compounds used, including occupancy, age, weight, general health, gender, diet, and administration. City 4, excretion rate, drug combination, and the judgment of the treating physician and the severity of the disease were treated in Tiandan + points Z. The use of active knives also varies depending on whether the compound specified in the composition contains other anti-disease 92593.doc -70- 200427684 poisons and their properties. According to another specific embodiment, the present invention provides a method for treating a patient infected with a virus. The virus is characterized by "a serine protease necessary for encoding a virus's life cycle, and the treatment method is _ ^ Tested for the W acceptable composition of the present invention. The better method is to treat patients with string and HCV infection. These treatments can completely eliminate virus infection or reduce its severity. In another specific embodiment, the fly-down Shikiyue method is used to treat patients with iiCV infection, wherein the patient is a human. In another embodiment, the method of the present invention further comprises the step of administering an antiviral agent, preferably an anti-HCV agent, to the patient. These antiviral agents include ... are not limited to): immunomodulators, such as: α_, β, γ_ interferon, polyethylene glycol-derived interferon_α compounds and thymosin; other anti_viral agents' such as: Ribavirin, amantadine and biVudine; other inhibitors of hepatitis C protease (then 2-post inhibitors and NS3-NS4A inhibitors); inhibition of other targets in the HCV life cycle Agents, including heliease and polymerase inhibitors; ribosome entry inhibitors' broad-spectrum virus inhibitors, such as: IMpDH inhibitors (eg, disclosed in US Patent Nos. 5,8G7,876 and 6,498,178 Νχ_497 and other IMPDH inhibitors, mycophenol uric acid and its derivatives); inhibitors of cytochrome P-450, such as: ritonavir or any combination thereof. These other agents may be administered as part of a single dosage form, including the osmium compound and additional antiviral agents. Alternatively, the additionally used medicine can be used as a part of the heavy dosage form and administered separately from the compound of the present invention, 92593.doc -71-200427684, wherein the additionally used medicine can be administered when it contains the compound of the present invention. The composition is administered before, together or after. Another embodiment of the present invention provides a method for pretreatment of a biological substance administered to a patient daily, which comprises contacting the biological substance with a pharmaceutically acceptable composition of a compound of the present invention. step. Biological materials in this temple include (but are not limited to): blood and its components such as: plasma, platelets: subgroups of blood cells, etc .; organs such as kidney, liver, lungs, etc .; sperm and Putian cells; bone marrow and its components and Other fluids that can be taken into the patient's body, such as physiological saline, dextrose, etc. According to another embodiment of the present invention, there is provided a method for processing material which may come into contact with a virus, which is characterized by encoding a serine protease necessary for the life cycle of the virus. This method includes the step of contacting the material with a compound according to the invention. These materials include (but are not limited to) surgical instruments = outer clothing (eg: clothing, gloves, gowns, gowns, masks, glasses, foot covers, etc.); experimental instruments and outer clothing (eg, clothing, gloves, girdles) , Gowns, masks, glasses, foot covers, etc.); devices and materials for collecting blood; and invasive devices such as shunts, stents, etc., In another specific embodiment, the compounds of the present invention can be used for experiments Tool 'to help isolate the serine protease encoded by the virus. This method includes the steps of providing the compound of the present invention to be attached to a solid support; Contacting the protease with the M body; and dissolving the amino acid protease from the solid support. In another specific embodiment, the widely isolated, serine protease in this way is HCV NS3 -NS4A protease. C 92593.doc -72- 200427684 In order to better understand the present invention, the following preparation and test examples are shown. These examples are for illustration only, and do not limit the present invention in any way. Example 1H_NMR Spectra were recorded at 500 MHz using a Bruker AMX 500 instrument. Samples were analyzed on a MicroMassZQ or QuattroII mass spectrometer using electrospray ionization analysis in a single MS mode. Samples were added to the mass spectrum using flow injection (FIA) or chromatography The mobile phase used in all mass spectrometry methods consists of an acetonitrile-water mixture (containing 0.2% osmic acid as a modifier). The term "Rt (minutes)" as used herein refers to the retention time associated with the compound ( In minutes). HPLC retention time is obtained from mass spectrometry data or using the following methods: Instrument: Hewlett Packard HP-1050; Column: YMC C18 (Cat. No. 326289C46); Gradient / gradient time: 10- 90% CH3CN / H20, then 100% CH3CN for 2 minutes; flow rate: 0.8 ml / min. Detector wavelength: 215 nM and 245 nM. The chemical name of the chemical substance selected in this paper is CambddgeSoft Corporations ChemDraw Ultra®, 7.0. Named program provided in version 1. Example 1 Pycnogenol-2-carboxylic acid (cyclohexyl- {1- [2- (1-cyclopropylaminopyridyl-butylaminopyridyl) -3 -iso Propyl-fluorene Loridine -1-_Carbonyl] -2,2-Dimethyl-propylcarbamate (methyl) _amidoamine (56) 92593.doc -73- 200427684 at -20 ° C in bromine To 100 ml of anhydrous ether, copper chloride-dimethylsulfide (9.1 g, 44.28 mmol) was added 0.99 M isopropenylmagnesium bromide (100 ml). After stirring for 15 minutes, the temperature dropped to -78. 〇, sequentially add 50 ml of ether solution of ketene hydrazone (40 g, 8.86 mmol, prepared according to the method of 117, ρ · 10775, (1995)) and TMSC1 (2 25 ml, 18 mmol) ear). The reaction mixture was stirred at -78 ° C for 1 hour, and 100 ml of ammonium hydroxide-ammonium chloride solution (1: 4) was added to stop the reaction. Extract with ether and wash the organic phase to remove all copper salts. The layer was dehydrated with sodium sulfate, concentrated in vacuo to an oil, and processed by flash chromatography (ether-hexane (2: 3) to give 3.5 g (73%) of the desired olefin intermediate.! H NMR (CDC13 ) δ 4.8 (d52H); 3.8 (m5 2H); 3.7 (d5 1H); 2.8 (m5 2H); 2.2 (d? 1H); 1.7 (s5 3H); 1.5 (s? 9H); 0.8 (s5 9H) .1 (s, 3H); .08 (s, 3H) ppm. Hydrogenated with 10% Pd-C under 1 atmosphere of hydrogen to produce 3.5 g (100%) of the desired proline 5b. HC1 gas was passed into 50 ml of ethyl acetate solution containing 5b (3.5 g, 6.47 mmol) for 5 minutes at ° C. After stirring at -20 ° C for 30 minutes, the temperature was returned to room temperature. , Stir for 1 hour. Concentrate in vacuo to 1.71 g (100%) of oil, use 2.5 equivalents of 1 M LAH in THF, reduce under reflux for 4 hours. Cool and perform Fieser operation to produce 1.35 g (85%) of Requires compound 8b. 4 NMR (CDC13) δ 4.0 (dd, 1H); 3.6 (m, 1H); 3.4 (m, 1H); 3.3 (m, 1H); 3.2 (m, 1H); 2.2 (m, 1H) ); 1.8 (m, 3H); 1.0 (d, 3H); 0.9 (d, 3H) ppm. At room temperature, in a solution containing potassium carbonate (190 mg, 1.38 mmol) 4 ml of water Add 8b (357 mg, 2.5 mmol) of 5 ml of THF dissolved 92591.doc -74- 200427684. Cool the bath to -2 ° C and add Cbz chloride (0.447 ml, 3.13 mmol) dropwise. At the same time keep the temperature at 0 to below. Stir for another 15 minutes and pour into water-ice. The aqueous phase is saturated with salt and the organic phase is separated. Then all compounds are extracted with ethyl acetate. The combined organic phases are HC1 5%, water and Washed with brine, dehydrated with sodium sulfate and concentrated in vacuo to yield 416 mg (60%) of benzamidine methylated intermediates. Take 328 mg of this product by oxidation with jones reagent to produce 260 Mg (75%) of proline intermediates. The above-mentioned proline (260¾ g '0.889 mmol) was used at room temperature in a sealed bottle using isobutylene' in a catalyst containing concentrated sulfuric acid in methylene chloride For 48 hours, 289 mg (96%) of the ester intermediate was produced. 1H NMR (CDC13) δ 7.5 (m, 5H); 5.1 (m, 2H); 4.1 (dd, 1H); 3.6 (m, 1H); 3.5 (m, 1H); 2.1 (m, 2H); 1.7 (m, 2H); 1.5 (s, 9H); 1.1 (d, 3H); 1.0 (d, 3H) ppm. Hydrogenation in ethyl acetate using 10% Pd / C yielded 290 mg (100%) of the desired compound 9b. Under Ot :, EDC (235 mg, 1.23 mmol), HOBt (203 mg, 1. ·) were added to a 2 ml solution of DCM containing Cbz-third butylglycine (271 mg, 1.02 mmol). 33 millimoles) and DIEA (0.534 milliliters, 3.07 millimoles). The resulting mixture was stirred at 0 ° C for 15 minutes. Then the above amine ester 9b was slowly added to 2 ml of DCM. The resulting reaction mixture was stirred at room temperature for 16 hours. After concentration to a residue, it was redissolved in EtOAc. It was washed sequentially with 0.5 N HCL, saturated NaHC03 aqueous solution and brine, dehydrated (Na2SO4) and concentrated in vacuo to produce the desired product, which was processed by flash chromatography (20% EtOAc / 80% hexane) to produce 480 mg (100%) pure dipeptide. NMR (CDC13) δ 4.2 (d, 2H); 4.0 (t, 1H); 3.5 (m, 1H); 2.0 (m, 3H); 2.8 (m, 2H); 1.5 92593.doc -75 -200427684 (s, 9H); 1.1 (s, 9H); lo (d, 3H); 0.9 (d, 3H) ppm. The Cbz group of the dipeptide was excluded as described above, and the coupling of the resulting amine ester dipeptide with Cbz-badhexyl glycine was shown in the next step. To a solution of Cbz-cyclohexylglycine (289 mg, 1 mmol) in 2 ml of DCM at 0 ° C was added EDC (228 mg, 1.19 mmol), HOBt (190 mg, 1.29 mmol) Ear) with DIEA (0,517 ml, 2.97 mmol). The resulting mixture was stirred at 0 ° C for 15 minutes. After that, 2 ml of a DCM solution containing the above amine ester was slowly added. The resulting reaction mixture was stirred at room temperature for 16 hours. Concentrated to a residue and redissolved in EtOAc. Sequentially washed with 0.5 N HCL, saturated NaHC03 aqueous solution and brine, dehydrated (Na2S04) and concentrated in vacuo to produce the desired product, which was processed by flash chromatography (20% EtOAc / 80% hexane) to yield 556 mg (90%) pure tripeptide. The Cbz group of the tripeptide was excluded as described above, and the coupling of the resulting amino ester tripeptide and 1,4-pyraconic acid was shown in the next step. PyBrOP (457 mg, 0.98 mmol) and DIEA (0.465 ml, 2.67 mmol) were added to a 2 ml solution of DCM containing 1,4-ammonium carboxylic acid (110 mg, 0.891 mmol). The resulting mixture was stirred at room temperature for 15 minutes. After that, 2 ml of a DCM solution containing the above amino ester was slowly added. The resulting reaction mixture was stirred at room temperature for 16 hours. Concentrated to a residue and redissolved in EtOAc. It was washed sequentially with 0.5 N HCL, saturated NaHC03 aqueous solution and brine, dehydrated (Na2S04) and concentrated in vacuo to produce the desired product. After flash chromatography (50% EtOAc / 5 0% hexane), 410 mg ( 79%) of pure tripeptide with end caps, consistent with 1H NMR (CDC13). The tertiary butyl ester of the capped tripeptide (410 mg, 0.688 mmol) was cleaved using 92593.doc -76- 200427684 1: 1 mixed TFA-DCM mixture at room temperature for 45 minutes and concentrated in vacuo. The coupling reaction between the obtained amino ester tripeptide and hydroxyamidin is explained in detail in the next step. After adding PyBOP (376 mg, 0.722 mmol) to 6 ml of an anhydrous DMF solution containing the above-terminated tripeptide at 0 ° C, NMM (0-226 mL, 2.06 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and then hydroxylamine (168 mg, 0.758 mmol) and 226 ml of NMM were slowly added. The coupling reaction was stirred for 16 hours, diluted with ethyl acetate, and washed sequentially with water (3X), 10% citric acid, water and brine. The organic layer was dehydrated (Na2S04) and concentrated in vacuo. After flash chromatography (2.5% MeOH / 97.5% ethyl acetate), 362 mg of hydroxyamidamine tetrapeptide was produced. At room temperature, it was treated with Dess-Martin periinodane reagent (650 (Mg, 1.53 mmol) with a solution of tertiary butanol (0.55 ml) in 5 ml of DCM for 3 hours. The reaction mixture was quenched with a 1 M solution of sodium thiosulfate (2 ml) and stirred until it separated into two phases. The organic layer was diluted with 5 ml of DCM, washed with 10% potassium carbonate solution (5 ml) (3 ×), dehydrated (Na2S04) and concentrated in vacuo. Flash chromatography (2.5% MeOH / 97.5% ethyl acetate) yielded 270 mg of ketamine tetrapeptide 56. LCMS M + H = 706.42, M · Η = 704.42. Dwell time (10-90% MeCN-H20 (with 0.1% TFA), within 9 minutes) = 7.73-8.81 minutes. LCMS M + H = 682.2. Example 2 3-Third-butyl-2- (third-butyl · dimethyl-silyloxymethyl) -5-oxo-pyrrolidine-1 -carboxylic acid third butyl ester (6a) in Add 0.5 M tert-butyl zinc bromide at -30 ° C over 5 minutes 92591.doc -77- 200427684

Butyl 1 ^ solution (3.7 ml, 1.83 mmol) to enone 4 & (280 mg, 0.85 mmol) in BF3OEt2 containing THF (350 μl, 2.75 mmol) and TMSC1 ( 465 μl) solution. After the heterogeneous mixture was stirred at -300c for 3.5 hours, the reaction was stopped with a saturated NHW1 solution. It was extracted with ether (3x), and the combined extracts were washed with brine 'and dried over sodium sulfate and concentrated in vacuo. Flash chromatography (10% ethyl acetate-hexane) gave 21 mg (64%) 6a. 1H NMR (CDC13) δ 3.9 (S, 1H); 3.8 (dd, 1H); 3.5 (d, 1H); 2.8 (dd, 1H); 2.3 (d? 1H); 1.9 (d? 1H) ); 1.4 (s3 9H); 0.9 (s? 18H); 0.1 (s? 3H); 0.05 (s, 3H) ppm. Example 3 3-benzyl-2- (third butyl-dimethyl_silyloxymethyl) _5_oxo_aramididine_1-carboxylic acid third butyl ester (7a) at- At 78 ° C, add TMEDA and benzylphenyl sulfide (1.99 g, 0.0095 moles) to a mixture containing n-butyllithium (5.5 ml, 0.0086 moles) and thf. ). The colorless solution turned pale yellow. After stirring at -78 ° C for 15 minutes, 10 ml of a THF solution containing u-pyrrolidone 4 (2.4 g, 0.0073 mole) was added dropwise. After the addition was complete, the reaction mixture was stirred at -78 ° C for 1 hour. The mixture was quenched with saturated 4 c 1 'valley solution' and the mixture was warmed to room temperature and poured into water. The ether mixture was extracted with ether, and the organic layer was washed with brine, dried and concentrated in vacuo. After flash chromatography (20% ethyl acetate-hexane), 69 g (45%) of the intermediate was produced. Using 16.9 grams of Raney Ni (Ra_Ni) and refluxing in acetone-water (1: 1) for 12 hours. After chromatography (2% propane), 1.2.9 g (83%) of the desired compound was produced. 7. lH nmr (CDCl3) δ 73 (m, 5 takes 3 · 8 ㈣ 2Η) 5 3.7 (d? 1H); 2.7-2.9 (m5 3H); 2.1 (m5 2H); 1.5 (s5 9H); 92593.doc- 78- 200427684 1 · 7 (s, 9H); 0.1 (s, 6H) ppm. Example 4 Roaring 2-carboxylic acid (U- [3-benzyl-2- (1-cyclopropylaminocarbamoyl-butylcarbamic acid) -nopyridine-1-carbonyl] _2, 2-Dimethyl-propylamine methylcyclohexyl-methyl) -acid amine (65) Prepared according to the method of the above reaction Figure 1 using the intermediate 7a as the starting material, yielding 65, consistent with its analytical data . Retention time (10-90 / 100 MeCN_H20 (with 0.001% TFA), within 6 minutes) = 8.0-9.2 minutes. LCMS Μ Η = 730.2. Example 5 3-cyclohexyl-pyrrolidine_2-carboxylic acid third butyl ester (i2a). Take 3-phenylproline 10a using a catalytic amount of platinum oxide in ethanol / acetic acid / water (7/2 / In 1), hydrogenation was performed under 50 pSi of hydrogen for 18 hours to produce a full amount of 3-cyclohexylproline. Compound 12a was prepared according to Example 1; the benzamidine method and the amidine method of step 3. Example 6 3-¼propylmethyl-pyrrolidine-; 1,2-dicarboxylic acid 丨 _third butyl ester 2-methyl ester (a) In a round bottom flask, allylproline (358 mg, 133 mmol) of an anhydrous DCE solution was cooled to zero. 〇 Using a syringe, slowly add diethyl hexane 15/0 / valley solution (55 liters, 6.63 mmol). To this solution was added dropwise chrysanthemum (967¼ liters, a solution of 13.3 millimolars was stirred at 0 ° C for 20 minutes, allowed to rise to temperature and stirred for 1 hour. The reaction mixture was cooled to彳 4C1 'The mixture was quenched and stirred vigorously for 10 minutes. The sodium disulfide was extracted with dichloromethane and dehydrated and concentrated in vacuo. Chromatography (200/0 ethyl acetate_hexane) yielded 65¾ g (17 〇 / 〇) Desired product A. 1h nmr (cDCi3) δ 3 8 (s, 92593.doc -79- 1H); 3.7 (S, 3H); 3.6-3.4 (m? 2H); 2.4 (m? 1H ); 2.3 (m5 1H); 13 (m, 3H); 0 · 8 (m, 1H); 0.5 (m, 2H); 0.2 (m, 2H) ppm. Example 7 3-cyclopropylmethyl-fluorene · (3-Methyl_2- {3-Methyl-2-[(Pyridin-2-carbonyl) _Amine] -Butylamido} -Butyryl) _Methyl pyrrolidine-2-carboxylic acid ( 〇Dipeptide C is prepared by coupling cyclopropylmethylproline a (41 mg, 0.16 mmol) with capped dipeptide B (52 mg, 0.16 mmol) using EDC / HOAt. After analysis (1: 1 ethyl acetate-hexane), 60 mg (77%) of the desired tripeptide C was produced. 4 NMR (CDC13) δ 9.4 (s, 1H); 8.8 (s, 1H); 8.5 ( s, 1H); 8.2 (d, 1H); 6.5 (d, 1H); 4.6 (t, 1H); 4.5 (t, 1H); 4.2 (m, 1H); 3.8 (s, 3H); 3.7 (m, 2H); 2.3 (m, 4H); 2 · 2 (m, 2H); 1.5 (s, 12H); 1.3 (m, 2H); 1.0 (m, 2H); 0 · 5 (m, 2H) ppm. Example 8 2- (3-{[3 -Cyclopropylmethyl-1- (3-methyl-2 · {3 -fluorenyl-2-[(fluorene-2-carbonyl) -amino] -butanylaminobutyridinyl) -rotidine _2_carbonyl] _amino group 2_oxo-hexylamino group) -3-phenyl-propionic acid (d) Prepared according to Example 1. Retention time (10-90% MeCN-H20 (including 0.1% TFA) 'in 6 minutes) = 7.55-7.78 minutes. LCMS M + H = 748.3. Example 9 HCV replicon cell analysis method: Take cells containing Hepatitis C disease (HCV) replicons and maintain 1 0% fetal bovine serum (FBS), 0.25 mg per milliliter of 0418 and DMEM (medium A) with appropriate supplements. On the first day, replicon monolayer cells were taken in trypsin ·· EDTA mixture at 92593.doc -80 -200427684, drain, and then dilute Medium A to a final volume of 100,000 cells per ml. 100 microliters each containing 10,000 cells was added to each well of a 96-well tissue culture plate, and cultured overnight in a tissue culture incubator at 37 ° C. On day 2, the compound (contained in 100% DMSO) was serially diluted with 2% FBS, 0.5% DMSO, and appropriate supplement DMEM (medium B). The final concentration of DMSO in a series of dilutions was maintained at 0.5%. The medium on the replicon monolayer cells was eliminated, and then medium B containing different compound concentrations was added. As a non-compound control group, a culture medium B containing no compound was added to other wells. Cells and compounds or 0.5% DMSO were grown in Medium B in a tissue incubator at 37 ° C for 48 hours. After 48 hours of incubation, the medium was removed, and the replicon monolayer cells were washed once with PBS and stored at -80 QC before RNA extraction. Thaw the culture plate containing the treated replicon monolayer cells, and add the specified amount of another RNA virus to the cells in each well, such as: bovine viral prion virus (BVDV). Add RNA extraction reagents (such as those from the RNeasy kit) to the cells immediately to avoid RNA breakdown. Follow the manufacturer's instructions, with minor modifications to improve extraction efficiency and consistency, and extract total RNA. Finally, total cellular RNA, including HCV replicon RNA, was lysed and stored at -80 ° C until further processing.

Two sets of specific primers and probes were used for Taqman real-time RT-PCR quantitative analysis. One group detects HCV and the other detects BVDV. Total RNA extracted from the treated HCV replicon cells was added to the PCR reaction, and HCV and BVDV were quantified in the same PCR well 92593.doc -81-200427684 RNA. Depending on the BVDV RNA concentration in each well, failed experiments can be ignored and discarded. The HCV RNA content in each well was in the same PCR plate and was calculated according to a standard curve. DMSO or a compound-free control group was used as 0% inhibition, and the percentage of inhibition or reduction of HCV RNA content obtained by compound treatment was calculated. IC50 (concentration at 50% inhibition of HCV RNA content) was calculated from the titration curve of any compound. Example 10 HCV Ki analysis method: HPLC Microbore method to separate 5AB substrates and products Substrate: NH2-Glu-Asp-Val-Val- (a) Abu-Cys-Ser-Met-Ser-Tyr -COOH Prepare 20 mM 5AB stock solution (or selected concentration) in DMSO w / 0 · 2 M DTT. Fractional aliquots were stored at -20 ° C. Buffer: 50 mM HEPES, pH 7.8; 20% glycerol; 100 mM NaCl Total analysis volume is 100 μl XI (microl) Analytical concentration buffer 86.5 As above 5 mM KK4A 0.5 25 μM 1 M DTT 0.5 5 mM DMSO or inhibitor 2.5 2.5% v / v 50 μM tNS3 0.05 25 nM 250 μM 5AB (starter) 20 25 μM 92593.doc -82- 200427684 Combine buffer, KK4A, DTT and tNS3; take 78 μl each Into each well of a 96-well plate. Incubate at 30 ° C for about 5-10 minutes. Take 2.5 microliters of the appropriate concentration of the test compound in DMSO (using DMS0 only as a control group) and add to each well. Incubate at room temperature for 15 minutes. The reaction was started by adding 20 μl of 250 μM 5AB substrate (equal to a concentration of 25 μM or a Km slightly below 5 ΑΒ). Incubate at 30 ° C for 20 minutes. The reaction was stopped by adding 25 μl of 10% TFA. Add 120 μl to the HPLC vial. Separate the SMS Y product from the substrate and KK4A according to the following methods: Microcolumn separation method · Instrument: Agilent 1100 degasser G1322A double pump G1312A automatic sampler G1313A column thermostat G1316A diode array detector G1315A column:

Phenomenex Jupiter; 5 microns C18; 300 angstroms; 150x2 mm; P / 0 00F-4053-B0

Column constant temperature: 40 ° C Injection volume: 100 μl

Solvent A = HPLC-grade water + 0.1% TFA

Solvent B = acetonitrile for HPLC grade + 0.1% TFA 92593.doc -83- 200427684 Time (minutes)% B Flow rate (ml / min) Maximum pressure 0 5 0.2 400 12 60 0.2 400 13 100 0.2 400 16 100 0.2 400 17 5 0.2 400 Stop time: 17 minutes Post-operation time: 10 minutes. Table 1 below shows IC5G data for certain compounds of the invention.

Compounds with Ki in the range of 0.5 μM to> 1 μM are indicated as A. Compounds with Ki in the range of 0.5 μM to 0.1 μM are indicated as B. Compounds with Ki below 0.1 μM are represented by C. Compounds with IC50 ranging from 1 μM to > 10 μM are indicated as A. Compounds with IC50 ranging from 1 μM to 0.5 μM are indicated as B. Compounds with IC50 below 0-5 μM are indicated as C. ND means no data. Table 1:

Compound Ki IC50 5 C ND 15 B ND 16 B ND 19 B ND 20 B ND 22 B ND 25 B ND 92593.doc -84- 200427684

26 C ND 27 C ND 28 c ND 29 c ND 30 B ND 31 C ND 32 B ND 33 B ND 35 A ND 36 B ND 39 CB 41 AC 42 C ND 43 B ND 44 BB 45 A ND 46 B ND 50 B ND 51 B ND 52 CC 53 B ND 54 BA 55 CB 92593.doc -85 200427684

56 B ND 57 C ND 60 ND A 62 C B 63 C B 64 B A 65 C B 66 B B 67 A A 68 C C 69 C C 71 C A 72 C B 73 B A 74 B A 75 B A 76 B A 77 B A 92593.doc 86

Claims (1)

200427684 Patent application scope: 1. A compound of formula I, I or a pharmaceutically acceptable salt or mixture thereof, wherein: W is: 〇 ^ Sr ^ R6 0 wherein each R6 is: hydrogen-, (C1-C12) -lipid-, (C6-C10) -aryl-, (06-010) -aryl-((31-012) Lipid-, (C3-C10) -cycloalkyl- or cycloalkenyl-, [(C3-C10) -cycloalkyl- or cycloalkenyl; KC1-C12) • lipid-, (C3-C10) Heterocyclyl-, (03-0: 10) -heterocyclyl- (01-0: 12) -lipid-, 92593-1.doc-1-200427684 (C5-C10) _heteroaryl-or (C5-C10) -heteroaryl- (C1-C12) -lipid-, or up to 3 aliphatic carbon atoms in each Re, may be selected by S, -S (O) · , -S (0) 2-, -0-, -N- or _n (h) substitution where R6 can be optionally substituted with up to 3 J substituents; or two R0 groups and the nitrogen atom to which they are bonded are visible Need common shape & 5_ to 6-membered aromatic system or 3- to 7-membered saturated or partially unsaturated ring system, whose _ j 3 more ring atoms can be optionally N, NH, 〇, S, SO and s 〇 里 & 2 罝, where the ring system can be fused with (C6-C10) aryl, (C5-C10) heteroaryl, (C3-C10) cycloalkyl or (C3-C10) heterocyclyl, if necessary Where any ring has up to 3 substituents each selected from J; wherein each Rs is Is -OR /; or the Rs group and the paste atom can be formed together as required (C3-C10) -Beza's 'where each Rg is -OR'; or the group and the boron atom can be formed together as required (C3- C10) -membered heterocyclic ring, in which, in addition to boron, up to 3 ring atoms may be replaced by N, NH, 〇, S, SO, and S〇2 as necessary; j is halogen, -OR1, -N02, -CN, -CF3, -OCF3, -R ,, oxo, thio, diN (R,), = N (OR '), 1,2-methylenedioxy, 1,2-ethylenedioxy Base, -N (R,) 2, -SR ', -SOR ,, -S02R', -S02N (R ') 2, -S03Rf, -C (0) R ,, -C (0) C (0) R ,, -C (0) C (0) 0R 丨, face C (0) C (0) NR,, -C (0) CH2C (0) R ,, -C (S) R ,, -C ( S) OR ', -C (0) 0R', -0C (0) R ', -C (0) N (R,) 2, -0C (0) N (R,) 2, -C (S) N (R,) 2,-(CH2) 0-2NHC (O) R ', -N (R,) N (R,) COR ,, 92593-1.doc -2- 200427684 -N (R') N (R ') C (0) 0R', -N (R ') N (R') CON (R ') 2, -N (R') S02R ', -N (R,) S02N (R,) 2 -N (Rf) C (0) 0R, -N (R,) C (0) R, -N (R,) C (S) R 丨, -N (R,) C (0) N (R,) 2, _N (R,) C (S) N (R ') 2, -N (COR,) COR, -N (OR,) Rf, -C (= NH) N (Rf) 2, -C (0) N (0R,) R ', -C (= NOR,) R, -OP (〇) ( 〇R,) 2, -P (〇) (R,) 2, -P (〇) (〇R,) 2 or -P (0) (H) (0R '); wherein R / is selected from: hydrogen -, (C1-C12) -lipid-, (C3-C10) -cycloalkyl- or -cycloalkenyl-, [(C3-Cl〇) _cycloalkyl or -cycloalkenyl]-(ci_C12) -Lipid-, (C6-C10) -aryl-, (€ 641〇) -aryl _ ((^ 1_ ^ 12) lipid-, (C3-C10) · heterocyclyl_, (〇3_ € 1〇) _heterocyclyl _ ((:: 1-〇: 12) lipid-, (C5-C10) -heteroaryl- and (〇5-〇1〇) _heteroaryl gas cl_cl2) ^ t · In which up to 5 atoms in R 'can be replaced by J if necessary, and two of them are bonded to the same atom, R can form 5_ to 6_ trigonal aromatic system or to 7-membered saturated or partially unnecessarily. Saturated ring system, where up to 3 atoms can optionally be substituted with heteroatoms selected from: N, NH, 0, S, S0 and s02, wherein the ring system can be optionally substituted with (C6-Cl0) aryl, (C5-C10) heteroaryl, (C3_C10) cycloalkyl, or (C3-C10) human bean saccharidone a ', which ring has at most 3 substituents selected from J, respectively. 92593-l.doc 200427684 5 舁 R · 5 'knife is hydrogen or (C1-C12) -lipid, in which any hydrogen may be substituted by halogen if necessary; wherein any terminal carbon atom of R5 may be substituted by sulfanyl or Hydroxy substitution; or & is ammonium or R ^, and R5 ^ h, wherein the Ph or -CHjh group may be optionally substituted by up to 3 substituents; or R5 and RSi with which they are bonded Atoms can form 3 • to 6-membered saturated or partially unsaturated ring systems together as required, where up to 2 ring atoms can be replaced with N NH 〇, S0 or S〇2 as required; where the ring system has at most 2 separately selected Substituents from J; R2, R4 and R7 are: hydrogen-, (C1-C12) -lipid-, (C3-C10) -cycloalkyl_ (C1_C12 > lipid- or-(〇6- (: 10) _Aryl-((^ 1-(^ 12) _lipids-; where up to two aliphatic carbon atoms in each of R2, R4 and R? Can be replaced by S, _s ( 〇) ...- s (〇) r, 〇_, -N or -N (H)-substitution; wherein each R2, R4 and RT are respectively and optionally substituted with at most 3 substituents selected from J; Ri and R3 is: (C1_C12) -lipid-, (C3-C10)- Alkyl_ or _cycloalkenyl_, [(C3-C10) -cycloalkyl_ or _cycloalkenyl] _ (C1_C12) _lipid-, (C6-C10) -aryl- (C1_C12) lipid Or 92591-l.doc 200427684 (C5_C10) -heteroaryl_ (C1_C12) _lipids_; as required, depending on the chemical 0-, _n_4_n (h)-where each 1 and 1 have up to 3 aliphatic carbon atoms The arrangement method of the son-in-law is replaced by S, _S (〇) _, -S (〇) 2_, where each R # R3 is substituted with up to 3 substituents, if necessary; 'R9, R9', & 1 〇 and R10, respectively -X-Y_Z; X is a bond, -C (H) (R6)-, _〇, _S _ * _ n (Ru) _; R11 is: hydrogen, (C1_C12) -lipid System-, (C6-C10) -aryl-, (〇6-〇10) _aryl-((: 1-(^ 12) lipid-, (C3-C10) _cycloalkyl- or cycloolefin -, [(€ 3- < ^ 10) -cycloalkyl- or cycloalkenyl] _ (0: 1-0: 12) -lipid-, (C3-C10) -heterocyclyl- '( 03-0: 10) -heterocyclyl- (〇1-(: 12) -lipid-, (C5-C10) · heteroaryl-, or (C5-C10) -heterocyclyl- (C1-C12 ) -Lipid- 'where up to 3 lipid carbon atoms in each Rn can be chemically stabilized by S, -S (O)-, -S (0) 2_, _〇-, -N- Or -N (H) substitution; where Ru Substituted by up to 3 J substituents as required; or where Ru and Z and the atom to which they are bonded can jointly form a 5-7-membered monocyclic ring or 6-11_membered bicyclic ring containing nitrogen 925913-1.doc 200427684 as required , Which may be substituted by up to 3] substituents, wherein up to 3 ring atoms of the ring system may be replaced by 0, NH, s, s0 or s02 according to a chemically stable arrangement; Y is a Bonding, -CH2-, -c (0) ..._ c (〇) c (〇) ...- S (〇) ... s (〇) 2_ or -S (0) (NR12) one; R1 2 is ... -, (C1-C12) -lipid-based, (C6-C10) -aryl-, (〇6-(^ 10) -aryl-((: 1- (312) lipid-, (C3-C10)- Cycloalkyl- or cycloalkenyl_, [(C3-C10) -cycloalkyl- or cycloalkenyl] _ (C1_C12) _lipid-, (C3-C10) -heterocyclyl-, (C3-C10 ) _Heterocyclyl- (C1-C12) · lipid-, (C5-C10) -heteroaryl- or (〇5- €: 10) -heteroaryl-((: 1-(: 12) _ Lipid-, where up to 3 lipid carbon atoms in each Ru can be chemically stabilized by S, -S (O)-, _S (0) 2_, -〇-, _N_ or -N (H ) _ ^; Where Ru can be substituted by up to 3 J substituents as required; Z is: hydrogen-, (C1_C12 ) -Lipid-, (C3-C10) -cycloalkyl- or -cycloalkenyl_, 92593-1.doc -6-200427684 [(C3-C10) -cycloalkenyl or -cycloalkenyl] _ ( ci_ci2) -lipid-, (C6-C10) · aryl-, (06-(: 10) -aryl- (〇: 1-(: 12) lipid-, (C3-C10) -heterocyclyl -'(€ 3-〇10) -heterocyclyl-((: 1-0: 12) aliphatic-, (C5-C10) -heteroaryl- or (〇5 < 10) _heteroaryl- ( 〇1- € 12) -lipids-; where up to 3 lipid-based carbon atoms in Z can be chemically stabilized by S'_s (0) _, 4 (0) 2-, _〇-, -N- or -N (Η) -substitution; wherein any ring may be optionally with (C6-C10) aryl, (C5-C10) heteroaryl, (C3-C10) cycloalkyl or (C3-C10) hetero The ring group is fused; wherein Z is respectively and optionally substituted with at most 3 substituents selected from J; V is —C (O)-, -S (O) · or -S (0) 2 ·; R is -C (O) ·, -s (0)-, -S (〇) 2-, -N (R12)-, -0-, or a bond; T is: (C1-C12) -lipid one; (C6-C10) -aryl, (〇6-(: 10) -aryl-((31-(: 12) lipid-, (C3-C10) -cycloalkyl or -cycloalkenyl-, (€ 3-〇10) -cycloalkyl or -cycloalkenyl]-(〇1-〇12) -lipid-, (C3-C10) -hetero -(C3-C10) -heterocyclyl- (C1-C12) lipid "'(C5-C10) -heteroaryl- or 925893-1.doc 200000427684 (〇5-(: 10 ) -Heteroaryl-((: 1-(: 12) _lipids-; where up to 3 lipophilic carbon atoms in T can be chemically stabilized by S, -S (O), -S (0) 2-, _〇-, _N- or -N (Η)-substitution; wherein each T is optionally substituted with up to 3 J substituents; or T is selected from: -N (R6) (R6.) And 1 ^ 6 'is hydrogen-, (C1-C12) -lipid-, (C6-C10) -aryl-, (C6-C10) · aryl- (C1-C12) lipid-, (C3 -C10) -cycloalkyl- or cycloalkenyl-, [(C3-C10) -cycloalkyl- or cycloalkenyl HC1-C12) · lipid-, (C3-C10) -heterocyclyl-, ( € 3- < 310) -heterocyclyl-((: 1- € 12) -lipid-, (C5-C10) -heteroaryl- or (C5-C10) · heteroaryl- (C1-C12 ) -Lipids, or each of R6, up to 3 lipid carbon atoms can be S, _S (0) _, _S (0) 2_, _〇_, or- n (H) -substitution; where R6 · may optionally be substituted by up to 3 J substituents; or I and I and the nitrogen atom to which they are bonded may form a (C3-C10) -heterocyclic ring system, where the ring system can Required by up to three substituents independently selected from J of substituents. 2. Compound according to item 1 of the scope of patent application, of which 92593-l.doc 200427684 Group is Γζ X where; in R9, Rl0, and Rl0., XM is -bonded and ζ is hydrogen; and H, in; X is a bond; Υ is a bond, _CH2_ or -C (〇)-; And Z is (C1_C12) -lipid-, (C3-C10) -cycloalkyl- or -cycloalkenyl_, [(C3-C10) · cycloalkyl or -cyclo # & Hci_ci2) _lipid · , (C6_C10) -aryl-, (06-0: 10) -aryl- (〇: 1-(: 12) aliphatic-, (C3-C10) -heterocyclyl-, (03-0: 10 ) -Heterocyclyl _ ((: 1-0: 12) lipid-, (C5-C10) · heteroaryl- or (< ^ 5 _ (^ 10) -heteroaryl _ ((^ 1- ( ^ 12) -lipid-; where up to 3 lipid-based carbon atoms in Z can be chemically stabilized by S, -S (O)-, _S (0) 2-, -〇-, -N _ Or -N (H)-substitution; wherein any ring may be fused with (C6_C10) aryl, (C5_cl〇) heteroaryl, (C3-C10) cycloalkyl or (C3-C10) heterocyclyl, if necessary; Among them, Z can be replaced by up to 3 substituted beauty groups selected from j, respectively, as required. 33 · Compound according to item 2 of Shenyan's patent scope, where r9, middle; 92593-l.doc 200427684 X is a bond; Y is a bond; and Z is (C1-C12) -lipid-, (C3-C10) -i ^ alkyl- or -Cycloalkenyl_, [(C3-C10) -cycloalkyl or -cycloalkenyl] _ (C1_C12) _lipid ·, (C6-C10) · aryl-, (€ 6- (310) -aryl -((31-〇12) lipid-, (C5-C10) -heteroaryl · or (€ 5 < 10) -heteroaryl- (〇: 1 _ (: 12) _lipid_); where Z Up to 3 lipid carbon atoms can be replaced by S, -S (0)-, -S (0) 2_, _〇_, _N_, or 氺 (H) _ according to the chemically stable arrangement method; Condensation with (C6-C10) aryl, (C5_ci〇) heteroaryl, (C3-C10) cycloalkyl or (C3-C10) heterocyclyl, if necessary; where Z is separately and if necessary, up to 3 separate Substituted by a substituent selected from 7. 4. The compound according to item 3 of the scope of the patent application, wherein R9, middle; X is a single bond; Y is a single bond; and Z is (C1-C12) · lipid-, (C3-C10) -i ^ alkyl- or -cyclodilyl- '[(C3-C10) -cycloalkyl or -cycloalkenyl] _ (c 1-c 12) -lipid- or (€ 6 < 10) -aryl- (〇1-0: 12) lipid-, where up to 3 aliphatic carbon atoms in Z may be selected by S, -S (0) _, _S ( 0) 2 ·, _〇_, #_ or 卞 (11) _ substitution ^ 92593-l.doc -10- 200427684 where 2 Do and optionally substituted with up 3 substituents independently selected from the group substituted j. Compound, where R9 is ^ rk xj \ f \ r vA / xp 'I I 5 · The compound according to item 4 of the patent application scope, wherein Rs 6. x. The compound according to item 5 of the scope of patent application, wherein the ruler 9 is 7. The compound according to item 6 of the scope of patent application, wherein it is ethyl. 8. The compound according to item 丨 in the scope of the patent application, in which the ruler and ruler are in one bond and x and γ are one bond and z is hydrogen; and r9, in the middle; X is one bond; Y is- C (O)-; and Z are (C1-C12) -lipid- or (C3-C10) -heterodecyl- (C1-C12) lipid; where up to 3 lipid-based carbon atoms in Z are visible It needs to be replaced by S, -S (O) ·, -S (0) 2-, 〇_, _ν_, or -N (Η)-according to the chemically stable arrangement method; where any ring can be replaced with (C6_C10) aryl group as required , (C5-C1〇) heteroaryl, (C3-C10) cycloalkyl or (C3-C10) heterocyclyl fused; 92593-l.doc -11- 200427684 where Z is separately and if necessary, up to 3 Respectively selected from; the substituents are substituted. 9. The compound according to item 8 of the scope of the patent application, wherein z * _〇_ (ci_c6) _ month system or -N (R ') 2, of which two R bonded to a nitrogen atom, the group can be formed as required 3- to 7-membered saturated or partially unsaturated ring systems, where up to 3 ring atoms may be replaced by heteroatoms selected from N, NH, 0, S, S0, and s02, respectively, where the ring system is visible Need to be fused with (C6_cl〇) aryl, ⑷5_ci〇) heteroaryl, (C3-CH)) cycloalkyl or (C3_cl〇) heterocyclyl, where any ring has up to 3 substituents each selected from J . ίο. The compound according to item 8 of the scope of patent application, in which 2 is 卞 (11,) 2, of which two R bonded to a nitrogen atom, the group may form 3 • to 7_ member saturated or partially unsaturated as required Ring system, where up to 3 ring atoms can be replaced by heteroatoms selected from N, NH, 0, s, so, and S02, respectively, where the ring system can be optionally replaced with (c6-C10) aryl, 〇) Heteroaryl 7 (C3-C1-0) cycloalkyl or (C3-C10) heterocyclyl is fused, where any ring has up to 3 substituents each selected from J. · 11. According to the compound in the scope of patent application No. 1, X and Y are one-bonded and Z is hydrogen in Fudanjia and R10, and each of R9, and R i G is X-bond; Y is a single bond; and Z is (C1-C12) -lipid-, (C3-C10) -cycloalkyl- or -cycloalkenyl-, [(C3-C10) -cycloalkyl or -cycloolefin Group] _ (C1_C12) _lipids_, (C6-C10) -aryl-, 92593-l.doc -12- 200427684 (€ 6- < :: 10) -aryl_ (€ 1-0: 12) Lipid-, (C3-C10) · heterocyclyl-, (C3-C10) -heterocyclyl-ci-Cl2) Lipid ... (C5-C10) -heteroaryl- or depending on chemistry Stable or -n (H)-substitution; ⑹- 匸 ⑼-heteroaryl-⑼ / ⑺-lipid-; where up to 3 lipid-based carbon atoms in Z can be substituted by S, _s (〇) _ , -S (0) 2_, -〇-, where any ring may be fused with (C6-C10) aryl, C10) heteroaryl, (C3-C10) cycloalkyl or (C3_C10) heterocyclyl, if necessary; Wherein Z is respectively and optionally substituted with at most 3 substituents each selected from j. Among them, each of R9 · and R10, 12. According to the compound of the scope of application for patent application, z is (C1-C12) -lipid-, (C3-C10) -cycloalkyl- or -cycloalkenyl -Or [(C3_C10) · cycloalkyl or -cycloalkenyl] _ ((:: 1-(: 12) -lipids_; where up to 3 lipid-based carbon atoms in Z may be arranged in a chemically stable manner as required) The method is replaced by S, _S (0)-, _S (0) 2 ·, _0_, _N-, or _N (H)-; wherein Z is substituted separately and optionally with at most 3 substituents selected from j. 13 · The compound according to item 12 of the scope of patent application, among which each Zhan 9, and Ri0, Z is (C1-C6) -lipid-. 14. The compound according to item 1 of the scope of patent application, among which X and Y are one-bonded and Z is hydrogen; and each of 119 and ruler 9, middle; 92593-l.doc -13- 200427684 X is one-bonded, Y is one-bonded and Z is (C1-C6 ) · Lipid-, where Z is respectively and optionally substituted with up to 3 substituents each selected from J. 15. The compound according to any one of claims 1-4, wherein w Wherein 'nr6r6 in w is selected from _NH_ (C1-C6 lipid), _nh_ (C3_C6 sulfanyl), _nh_ch (ch3) _aryl, or -NH-CH (CH3) _heteroaryl, which is 16. The middle reading aryl or the heteroaryl may be optionally substituted with up to 3 halogens. The compound according to item 15 of the scope of patent application, wherein NR6R6 in w is: 17. The compound according to item 16 of the scope of patent application, wherein NR6R6 in W is: 92593-l.doc -14- 200427684 F 18. The compound according to item 17 of the scope of patent application, wherein NR6R6 in w is: Ortho-locked yCT 〇 19. The compound according to claim 18 in the scope of patent application, among which: 20. The compound according to any of the is19 scope in application for patent, wherein is hydrogen and R5 is: 21 · The compound according to item 20 of the scope of patent application, wherein r5 is hydrogen and 仏 is: 22. The compound according to any one of the items 1 to 21 of the scope of the applied patent, wherein 92593-l.doc -15-200427684 R2, R4 and R7 are respectively fluorene, methyl, ethyl or propyl. 23. The compound according to item 22 of the scope of application, wherein &, h and heart are each hydrogen. 24. According to the scope of patent application! A compound according to any one of 33 to 33, wherein r is: 25. The compound according to item 24 of Shen Qing's patent scope, wherein r3 is: 26. The compound according to the scope of application for item 25, wherein & 3 is: 27. The compound according to any one of the is% of the scope of patent application, wherein r 28. The compound according to item 27 of the scope of patent application, wherein & is: 92593-l.doc -16- 200427684 29. The compound according to item 18 of the application, wherein I is isopropyl or cyclohexyl. 30. The compound according to item 1 of the scope of patent application, wherein N-t R-V Among them, Z R6, R_6, R7 and Rl2 are as defined in item 1 of the scope of patent application. 3 L The compound according to item 30 of the scope of the patent application, in which ^ 12 Rl2 ^ 7 ^ 12 ^ 7 〇R6 " NxNv ^ V R6, human] f V r6 '0, R6' 〇N〇, (V 0 or Xin 0 In the group: R6I and R7 are both hydrogen; R6 is · (C1-C12) -lipid; (C6-C10) -aryl-, (€ 6-010) -aryl- (01-012) System-, (C3-C10) -cycloalkyl or -cycloalkenyl-, [(03- € 10) -cycloalkyl or -cycloalkenyl]-(01-0: 12) -lipid-, 92593 -l.doc -17-200427684 (C3-C10) · heterocyclyl ·, (C3-C10) _heterocyclyl_ (ci-C12) -lipid-, (C5_C10) -heteroaryl or (〇5-(: 10) -heteroaryl gas (:: 1-(: 12) -lipid-; where up to 3 lipid carbon atoms in R6 can be replaced by S, 4 according to a chemically stable arrangement according to need) (0)-, _S (0) 2-, _〇-, _N-, or -N (H) _ substitution; and R6 can be optionally substituted with up to 3 substituents each selected from J; and Ru as claimed in the patent Definition of item 1 of the scope. 32. The compound according to item 31 of the scope of patent application, wherein R6 is: (C1-C12) -lipid (〇6-(^ 10) -aryl-((: 1-0: 12) Lipid- or (C3-C10) -cycloalkyl or -cycloalkenyl-; wherein R6 has at most 3 aliphatic carbons Atoms can be replaced by S, _S (0) ·, _S (0) 2_, _〇-, _1, or _called 11) _ according to the chemically stable arrangement; R6 can be selected from J at most 3 respectively. Substituent substitution; and Ru as defined in the scope of patent application item 1. 33. The compound according to the scope of patent application item 32, wherein the group is: 34. The compound according to item 33 of the scope of patent application, of which 92593-l.doc -18- 200427684 35 36. 37. 38. A compound according to any one of items 1 to 29 of the scope of the patent application, wherein V is -c (0)-; and R is a bond. A compound according to any one of claims 1 to 29, wherein V is -c (0)-; R is a single bond; and T is: (C3-C10) -heterocyclyl · or (C5_C10) Heteroaryl groups in which each T can be optionally substituted with up to 3 J substituents. The compound according to item 36 of the application, wherein τ is (C5-C6) heterocyclyl- or (C5-C6) heteroaryl-; wherein each T is optionally substituted with up to 3 J substituents. The compound according to item 37 of the application, wherein τ is: 92593-l.doc 19- 200427684 ci Cl H or pQ-H where Z Z 'is O, S, NR' or C (R,) 2, respectively. 39. The compound according to item 38 of the scope of patent application, wherein T is , N, 40. The compound according to item 1 of the scope of patent application, wherein the compound is: 92593-l.doc -20- 200427684 2 3 ° into H. . Outside q \ O 〇H 4 0 o ° Y ^ ° 〇 ^ rNH 5 CnW ^^ o ° Y ^ ° 6 [: / Li Liu 5 7 [: / ίγ. . Six δ 8 C / ^ 'a ^ xV ^: 9, one. Into. S. -χ (^) 92593-1.doc -21-200427684 10 11 12 13 P 14 15 16 17 18 ¢ / ¾ ^^ ¾ 92593-1.doc -22- 200427684 19 〇〇〇ο 〇20 21 22 23 Cn \ " a ^ 24 25 26 0 0 0 0 〇27 〇0 0 0 〇28 0 0 〇92593-1.doc -23- 200427684 29 0 〇〇o 〇30 ν ^^ λν > ^ Λ〇η 0 0 0 〇〇31 people. H 0 0 0 o 〇32 Guang N ◦ QO ,, ',' / J 0 〇0 0 〇33 0 〇0 0 〇34 0 〇〇o 〇35 0 〇0 0 ο 36 Guang N 〇) (^ V, '/ Person 0 0 0 ο ο 37 38 q ¢ / ¾ ^ ¾ 92593-1.doc -24- 200427684 39 40 41, ^ Ν 0 J ^ τ ^ ΛN > «νΛ〇Η 0 〇〇〇〇42 0 0 〇0 ο 43 44 45 46 47 cw Taihuazhong '0 〇0 0 48 0 〇0 0 92593-1.doc -25- 200427684 49 0 0 0 〇50 51 52 F 53 54 c: W Lo Or. 55 56 57 [:, read% 92593-1.doc -26- 200427684 92593-1.doc -27- 200427684 67 68 69 iW »¥ raxVB > 70 71 72 〇0 0 〇73 01 Test 6, 74 75 92593-1.doc -28- 200427684 76 N_______ 77 ------ 41 · ~ A pharmaceutical composition comprising the compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt or mixture thereof in an amount effective to inhibit serine protease; and an acceptable carrier , Adjuvant or vehicle. 42. A composition according to item 41 of the application, wherein the composition is formulated for administration to a patient. 4 3 · The composition according to item 42 of the scope of patent application, wherein the composition further comprises an agent selected from the group consisting of: an immunomodulator; an antiviral agent; a second Hcv protease inhibitor; another in the HCV life cycle Target inhibitors; and cytochrome P_450 inhibitors; or a combination thereof. The composition of item 41 in the scope of patent application from ^ Kang, wherein the immunomodulator is called tadlne) or teverase II CV bio-shield shield ring. Another target inhibitor is HCV spiral_ * ase), an inhibitor of polymerase or metalloproteinase. 45. According to the scope of the patent application, the 4th P-Through inhibitor is Littenacide). Wherein the cytochrome 46. An inhibitor of serine protease activity comprises contacting the serine 92591-l.doc -29- 200427684 protease with a compound according to any one of claims i to 40 of the scope of the patent application step. ° 47. The method according to item 46 of the claims, wherein the serine protease is HCV NS3 protease. 48. A method of treating a patient infected with HCV, comprising the step of administering to the patient a composition according to item 42 of the scope of the patent application. 49. The method according to item 48 of the scope of patent application, which further comprises re-administering to the patient an agent selected from the group consisting of: an immunomodulator; an antiviral agent; a second HCV protease inhibitor; another target of the HCV life cycle Inhibitor; or a combination thereof; wherein the additionally used agent is administered as a part of the composition according to the scope of application for patent No. 42 or in a separate dosage form. 50. The method according to item 49 of the scope of application for a patent, wherein the immunomodulator is α-, cardiac or r_ interferon or thymosin; the antiviral agent is ribavirin (ribavmn) or antatin (amantadine); Or another target inhibitor in the HCV life cycle is an inhibitor of HCV helicase, polymerase or metalloproteinase. 52. A method for eliminating or reducing contamination in a biological specimen or medical or experimental equipment, comprising the step of contacting the biological specimen or medical or experimental equipment with a composition according to item 41 of the scope of patent application. 53. The method according to item 52 of the application, wherein the specimen or device is selected from the group consisting of blood, other body fluids, biological tissues, surgical instruments, surgical gowns, conventional instruments, experimental gowns, collecting blood or body fluids Devices used; materials for storing blood or other body fluids. 54. The method according to item 53 of the application, wherein the body fluid is blood. 92593-l.doc -30- 200427684 柒. Designated representative map: (I) The designated representative map in this case is: (none) (II) The representative symbols of the component map are simply explained: 捌, if there is a chemical formula in this case, please disclose The chemical formula that best characterizes the invention: 92593.doc