TW200424175A - Inhibitors of severe acute respiratory syndrome (SARS) 3c-like proteinase - Google Patents

Abstract

The invention relates to methods of inhibiting SARS-related coronavirus viral replication activity comprising contacting a SARS-related coronavirus protease with a therapeutically effective amount of a rhinovirus protease inhibitor, and compositions comprising the same.

Description

200424175 (1) Description of the invention: [Technical field to which the invention belongs] The present invention relates to a method for inhibiting the replication activity of severe acute respiratory syndrome (SARS) virus, which comprises combining a SARS-associated coronavirus-like 3C protease and a therapeutically effective amount of rhinovirus 3C Protease inhibitor contact. The present invention further relates to a pharmaceutical composition containing a rhinovirus 3C protease (RVP) inhibitor by administering an effective amount of such rhinovirus protease inhibitor to a mammal. [Previous Technology] A worldwide outbreak of severe acute respiratory syndrome-associated virus (SARS) was associated with exposure from a single ill health worker from Guangdong Province, China. Recently, causative agents have been identified as new coronaviruses. There is a need for effective treatment of SARS-associated coronavirus in this technology. In particular, recent evidence strongly suggests that the new coronavirus is the causative agent of SARs (cdc). The function of coronavirus replication and transcription is so-called, replicase, and gene coding (Thi ^ HeroM et al. 2001). This gene contains two overlapping polyproteins that are widely treated by disease two proteases. The C-proximal region is at the junction of eleven conserved functions, and is treated by a coronavirus subject, or a class 3C, protease (Ziebuhr, Snijder et al. 2000). The ", 3C-like" protease name is derived from some similarities between coronavirus enzymes and the conventional parvovirus 3C protease (Gorbaler ^ Koomn et al. 1989). It includes qualitative preference, and cysteine is catalysing It is used as an active site nucleophile and its similarity in inferred overall peptide folding. Very recently, Hilgenfdd and colleagues published a high-resolution 1-ray structure of the major protease of porcine transportable gastroenteritis coronavirus 92051 200424175

Palm et al. 2002). Atomic coordination can be obtained through the protein data bank under the acceptance code 1LVO. For almost 10 years, research organizations such as Pfizer-La Jolla have engaged in an effort to discover and develop medicines for the treatment of common colds in a way that is a key enzyme in rhinovirus replication, meaning 3C protease Is subject (Matthews, Smith et al. 1994). Parvoviruses are a group of small unenveloped positive strand RNA viruses that infect humans and other animals. Such viruses include human rhinovirus, human poliovirus, human coxsackie disease, (1 virus, human Echo virus, human and bovine enterovirus, encephalomyocarditis virus, meningitis virus, foot and mouth virus, A Hepatitis virus and others. Parvovirus infections can be treated by inhibiting proteolytic 3C enzymes. These enzymes are required for the natural maturation of parvoviruses. They are expensive and allow large proteins with large genomes to automatically catalyze the split into An essential viral protein. The members of the 3C protease family are cysteine proteases, of which the hydrogen-sulfur group most often cleaves the bran-amidamine-glycylamine bond. It is recognized that the inhibition of 3C protease will block many The proteolytic and cleavage effect of proteins, which in turn can be produced by interfering with virions, and slow down the maturation and replication of the virus. Effective non-toxic agents with a wide range of activities against multiple rhinovirus serotypes have been identified (Patick, Binfoi * d Et al. 1999). Significant catalytic and structural similarity between rhinovirus 3C protease and coronavirus "class 3C" major protease, referring to < Selection Rhinovirus 3C protease inhibitors can be used to combat major coronavirus proteases. [Summary of the Invention] The present invention provides a method for inhibiting the activity of coronavirus 3C protease (also known as proteinase) 92051 200424175, which comprises coronavirus 3C protease and effective The amount of parvovirus inhibitor compound is preferably in contact with a rhinovirus inhibitor compound or a tinkerer. The present invention provides a new type of method that interferes with or prevents the replication activity of SARs virus. The rhinovirus protease inhibitor is contacted with an effective amount.-In a specific embodiment of the present invention, SARs coronavirus-like redundant protease inhibitors are administered orally or intravenously. * 月 也 & for-species A method of treating symptoms in a patient by activating a coronavirus-like 3C protease is to administer a pharmaceutically effective amount of a rhinovirus protease inhibitor to the patient. The present invention also provides a target for fun inhibition. This method is used as a way to treat indications caused by SARS-associated virus infection. The present invention also provides a kind of utilization Anti-SARS coronavirus-like protease nasal detoxification inhibitor identified by the virus or cell target as a standard to treat the symptoms caused by SARS-associated virus infection. / The invention also provides-a confirmation that will interfere with the expected treatment As a result of SARS infection, Stone applied for functional cellular or viral pathways of the members, the treatment is by administering rhinovirus protease inhibitors. The present invention also provides a method for using rhinovirus protease inhibitors to understand the effects of other SARS inhibitors. A method of mechanism tools. * The invention also provides a method for performing gene profiling using rhinovirus protease inhibitors to monitor the upward or downward regulation of genes to identify inhibitors used to treat indications caused by SARS_ Purpose. 92051 200424175 cv ^ (A medicinal product for the treatment of SARS in mammals-a rhinovirus protease inhibitor for the effective treatment of SARS 'and a pharmaceutically acceptable carrier. In addition, the present invention provides: A method for disturbing or preventing viral replication activity of a coronavirus associated with the s hall, comprising contacting a SARS-associated coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor:

Where M is 0 or S;

Ri is Η, F, alkyl, 0Η, SH or 0-alkyl; R2 and R5 are independently selected from Η, 々γγΒι

Di 1¾ ϊ) or an alkyl group, wherein the alkyl group is different from

The conditions are that at least one of & or must be or 1¾, and when the rule 2 or 115 is the following group ^ χ-ΥγΒι D1 X is = CH or = CF, and Υι is = CH or = CF , 92051 -9- 200424175 or X together with 1 and 7 to form a three-membered ring, where Q is 0-, X is -CH- or _CF_, and Y is -Ol ·, -CF- or -c ( Alkyl)-, where R10 and Ru are independently H, halo, or alkyl, or together with the carbon atom to which they are attached, form a cycloalkyl or heterocycloalkyl, or X is -CH2-, -CF2- , -CHF- or each, and K is · α, each, pendulum 12_, _c (r13) (r14) ·, _c (0) ... ((3) κ ((: υΐ4 >, where Ri2 is Η or alkyl And is independently η, F or alkyl with Ri4, or forms a cycloalkyl or heterocycloalkyl together with the atoms to which they are bound; s (0), Se (o), P-ORi 5 A! Is C, CH, CF, s, p, Se, N, NRI 5, or p-nr15r16, where R15 and r16 are independent domain groups, fluorenyl, heterocyclic alkyl, aryl or aryl groups or combined with them The atoms together form a heterocyclic alkynyl group; A has a group of groups that can form hydrogen bonds without shared electron pairs; and 坧 is fluorene, F, alkynyl, Alkyl, heterocyclyl, aryl, fluorenyl, _0R17, -sr17, · 17Ri8, depending on i9NR "Rh" or "R", R =, R18 and r19 are independent 4H, alkyl, and cycloalkyl Group, heterocycloalkyl group, aryl group, heteroaryl group, or fluorenyl group; with the proviso that when Di is an unshared group having a hydrogen bond capable of forming a hydrogen bond, it does not exist; and when W carbon, In Dl, n Ding Mao% sub-pairing group -NR25R2 ^ f,

1 is not -NR〗 7 Ri 8, where R, R, 25, and R26 are each independently H, alkyl, or cycloalkane "_ ¥ k group, aryl or heteroaryl group; 92051 200424175 and wherein D!- A! -Bi optionally forms a nitro group, where 丨 丨 is n; and further, when R2 or R5 is the following group: 〆 /, a f 1¾ j X is = CH or = CF, and Y2 is = C, = CH or = CF, or X forms a three-membered ring with Y2 and Q ', where Q is _c (Ri〇) (Rii) _ or -O-, X is _CH- or -CF-, and Υ2 Is -CH-, -CF- or _c (alkyl)-, where R10 and Ru are independently fluorene, halogen or alkyl, or together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl , Or X is -CH2 _, _CF2 _, _CHF- or each, and Υ2 is, each, ... C (0) _, -C (s) ·, or -c (cr, 13r, 14 >, where R12 is Hydrazone, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -0R, 13, -NR, 13r, 14, -C (0) _R, i3, -S〇2 ~ or -CXS )! ^ 3 'and% 3 and% 4 are independently η, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or together with the atom to which they are attached form a cycloalkyl group Or heterocyclic alkyl; A2 is C CH, CF, s, P, Se, N, NR15, s (0), Se (o), P0Ri5 or p-nr15r16, where Ri5 and Xin 6 are independently alkyl, cycloalkyl, heterocycloalkane Group, aryl or heteroaryl group, or together with the atom to which they are bound to form a heterocycloalkyl group; A is a partial group having an unshared electron pair capable of forming a hydrogen bond; and B2 is fluorene, F, or alkane Group, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -ORu ^ -sr17. ^ Nr17r18.-nr19nr17r18 ^ .nr17〇r18, 92051 -11-200424175 where R17, R18 and R19 are independent 4H, Alkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, or fluorenyl; and any combination of Y2, A2, b2 & d2, which may form a cyclofluorenyl, heterocycloalkyl, Aryl or heteroaryl; R3 and R6 are independently fluorene, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C (0) R17, -OR17, _SRl7, _NRi7Ri8, "19NR" ~ or -NRj η ORj gj where Ri 7, R! S and Ri9 are independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or fluorenyl; or Forms a cycloalkyl or heterocyclic ring with the carbon atoms to which they are attached Aryl group, aryl group, heteroaryl group, -〇R17 -NRj η ORj g ^ alkyl group, cycloalkyl group, heterocyclic alkyl group & is amidine, alkyl group, cycloalkyl group, heterocyclic alkyl group, -SR17,- NR17R18, -NR19NR17R184 where Ri 7, Ri 8 and Ri 9 are independently fluorene, aryl, aryl, heteroaryl or acid group; or R7, together with% or R6, and the atom to which they are attached form a heterocycloalkane R 2 0 is Η, 0 Η or any suitable organic moiety; and Z and Zi are independently Η, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -c ( o) r21, -C02R21, _CN, -C (0) NR21R22, -C (0) NR21〇r22, -c (s) r21, -c (s) nr21r22, -N02, -S0R21, -so2r21, -so2nr21r22 , -S0 (NR2 i) (0R2 2), -S0NR2 i, -S〇3 R2 i, -p〇 (〇r2 i) 2, -P〇 (r2 i) (r2 2), -PO (NR21R22) (OR23), P0 (NR21R22) (NR23R24), -C (0) NR21NR22R23 or -C (S) NR2iNR22R23, where Rn, R22, Rn and R24 are independently H, alkyl, cycloalkyl, hetero-12 -92051 200424175 cycloalkyl, aryl, heteroaryl, fluorenyl, or sulfanyl, or any two of R2i, R22, R23, and R24 together with the atoms to which they are bonded form a heterocycloalkane ; Or as defined above, Zi and Ri as defined above, and the atom bonded to Z i and the heart together to form a cycloalkyl or heterocycloalkyl group, or both Z and Zi and their combined atoms as defined above Together form a cycloalkyl or heterocyclic group: or a pharmaceutically acceptable precursor drug, M, an active metabolite, or a solvate; and wherein the compound or a pharmaceutically acceptable precursor drug, a salt, an active metabolism thereof The product or solvate, in the detection of HI_HeLa cell culture, has anti-ribonucleic acid activity and has an ECm of less than or equal to ιOM # M. In another aspect, the present invention provides a method for interfering or preventing viral replication activity of SARS-associated coronavirus, comprising contacting a SARS-associated coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula II:

Called (II), 92051 OH,

α 〇, -13- 200424175

Or, Muzi can be connected to the text < salt, solvate, prodrug or pharmacologically active metabolism product. In yet another aspect, the present invention provides a method for interfering with or preventing viral replication activity of associated coronaviruses, which comprises turning a difficult-to-associated coronavirus a into a therapeutically effective amount of a formula IIA rhinovirus protease inhibitor contact:

Prodrugs or pharmaceutical activities or their musically acceptable salts, solvates, metabolites. In yet another aspect, the present invention provides a virus that interferes with or prevents SARS-associated coronavirus, including a coronavirus protease and a therapeutically effective amount of a IIB rhinovirus 3c protease inhibitor. 92051 -14- 200424175

Where z R10 is Η or CH3; R20 is Η, OH, CH2OH, or OCH2Ph; R30 is H'OH or OCH2Ph; R4〇 is H or CN; and R50 is CH2CH3, CH3, CH2Ph, CH2CH2Ph, CH2CH2OH, or CH2 (2_p Biddenyl); or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof. In another aspect, the present invention provides a method for interfering or preventing the viral replication activity of a SARS-associated coronavirus, comprising contacting a SARS-associated coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula IIC:

-15- NH2 (IIC), 92051 200424175, where Rl00 is CH3, phenyl, phi " 4 TsiriR, Tru // i Signin (INCH3), ph (4-〇CH3), pyridyl or 2-furan Or its pharmaceutically acceptable salt, Xuannan 丨 Bayou ,, and, < He Zhaozhao compound, Keti drugs or pharmaceutical active metabolic products. In another aspect, the present invention provides a method for interfering or preventing SARS-associated corona detoxification (virus replication activity), which comprises contacting a sars-associated coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of the formula:

among them:

Ral is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, provided that Ral is not a substituted tetrahydropyrrolyl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl is Unsubstituted or substituted with one or more appropriate substituents; is a substituent having the formula:

J ^ CRfR9 where:

Rf and Rg are each independently fluorene or a lower alkyl group; m is 0 or 1; P is an integer from 0 to 5; 92051 -16- 200424175 A is CH or N; when? When 1, 2, 3, 4 or 5, 8 2 is 0 (1111) (111), > 1 (cut), 3, 3 (0), S (0) 2 or 0, and when p is 0 , A] is, N (RixRj), s (Ri)

, S (0) (R1), s (〇) 2 (Ri) or O (Ri), wherein each of Rh, Ri and Rj is independently H or lower alkyl; each existing A3 is independently C (Rh ) (Ri), N (Rj), S, S (O), s (0) 2 or 0; where each of Rh, 圮 and Rj is independently h or lower alkyl; when 卩 is 1, 2, 3 , 4 or 5, when 8 is 4) ^ (1 ^), (: (1111) (111), or 0; and when p is 0, A4 is NCRkXR1), QRhXRiXRj), and (XR1), where each of Rh, R1 and Rj are independently fluorene or lower alkyl, each Rk is fluorene, alkyl, aryl, or test group, and each R1 is fluorene, alkyl, or aryl; provided that no more than two heteroatoms are continuous Appears in the ring formed by A !, (A2) m, (Α3) ρ, A4, and 00 described above, where each dotted line in the ring, when A2 exists, depicts a single bond, When A2 does not exist, it is a hydrogen atom;

Rd is fluorene, halogen, light or alkynyl, alkynyl or thiol, wherein alkynyl, pitoxy or thiol is unsubstituted or substituted with one or more appropriate substituents;

Rb is fluorene or alkynyl, unsubstituted or substituted by one or more appropriate substituents; each of Z and Z1 is independently fluorene, F, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, Where alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is unsubstituted or substituted with one or more appropriate substituents, -C (〇) Rn-C02Rn-CN, -C (0 ) NRnR. , -C (0) NRn0R °, -C (S) Rn, -C (S) ORn-C (S) NRnR〇, -17- 92051 200424175 -C (= NRn) R0, -C (= NRn) OR 〇, -N02, -SOR °, -S02Rn, -S02NRnR〇, -S02 (NRn) (0R.), -SONRn, -S03Rn, -PO (ORn) 2, -PO (ORn) (OR〇),- PO (NRnR〇) (ORP), -PO (NRnR〇) (NRPRq), -C (0) NRnNR0RP, -C (S) NRnNR ° RP, where Rn, RQ, RP and each independently are H or alkyl , Cycloalkyl, aryl, heterocycloalkyl, fluorenyl, or sulfanyl, wherein alkyl, cycloalkyl, aryl, heterocycloalkyl, fluorenyl, or sulfanyl are unsubstituted or substituted by a Or multiple suitable substituents, or any two of Rn, R °, RP, and their combined atoms to be used together to form a heterocyclic alkyl group, which may be substituted, or Z and Rd and their The bonded atoms together form a cycloalkyl or heterocycloalkyl group, where Z and Rd are as defined above, except for some groups that cannot form a cycloalkyl or heterocycloalkyl group, or Z and Z1 and others The bonded atoms together form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above (except that some of the groups that cannot form a cycloalkyl or heterocycloalkyl group are Outside); or its prodrugs, pharmaceutically acceptable salts, pharmaceutically active metabolism products or pharmaceutically acceptable solvates. In another aspect, the present invention provides a method for interfering or preventing viral replication activity of SARS-associated coronavirus, comprising contacting a SARS-associated coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula IIIA: 〇Rc Z1

Rb

people

Rb Rd (NIA) -18- 92051 200424175 where:

Ra2 is alkyl, aryl or heteroaryl, wherein alkyl, aryl or heteroaryl is unsubstituted 'or substituted with one or more appropriate substituents; and RC is a substituent having the formula:

Wherein: 圮 and each are independently Η or lower alkyl; m is 0 or 1; P is an integer from 0 to 5; \ is CH or N; when? When 1, 2, 3, 4 or 5, person 2 is 0; jealousy) (1 ^), special]), 8, 8 (0), S (0) 2, or 0, and when p is 0, Eight 2 is c (Rh) (RixR), N (Ri) (Rj), s ^), S (0) (RJ), 8 (0) 2 (111), or 〇 (Ri), where each Rh, and Rj is independently η or a low-carbon surface group; each existing A3 is independently C (Rh) (Ri), N (Rj), S, S (O), S (0) 2, or 0; wherein each Rh, Ri and Rj are independently H or lower alkyl; when? When 1, 2, 3, 4 or 5, eight 4 is Ning 9, 0: (jealous) (to) or 0; and when P is 0, A4 is N ^ XR1), C (Rh) (Ri) (Rj) and O milk, wherein each of Rh, Ri and 拗 is independently Η or lower alkyl, each Rk is H, alkyl, aryl or 醯 'and each R1 is Η, alkyl or aryl; Eight 1 (eight 2) m, (A3) ρ, A4, and C = 0, provided that no more than two heteroatoms appear consecutively as described above by each of the rings in the ring 92051 -19- 200424175 dashed line, when a2 exists, it depicts a single bond, and when a2 does not exist, it is a hydrogen atom;

Rd is fluorene, halogen, mesyl or alkyl, alkoxy, or alkylthio, wherein alkyl, carboxy, or alkylthio is unsubstituted or substituted with one or more appropriate substituents;

Rb is fluorene or alkyl, unsubstituted or substituted with one or more appropriate substituents; each of Z and Z1 is independently fluorene, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, Where alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are unsubstituted or substituted with one or more appropriate substituents, -C (0) Rn-C02Rn-CN, -C (0 ) NRnR0, -C (0) NRn0R0, -C (S) Rn, -C (S) ORn-C (S) NRnR0, -C (= NRn) R. , -C (= NRn) OR. , -N02, -SOR °, -S02Rn, -S02NRnR〇, -S02 (NRn) (OR〇), -SONRn, -S03Rn, _PO (ORn) 2, -PO (ORn) (OR〇), -PCXNRUROXORP) , -PO (NRnR °) (NRPRq), -CCCONRnNRORP, -C (S) NRnNR ° RP, where Rn, R. , RP, and Rq are each independently H or alkyl, cycloalkyl, aryl, heterocycloalkyl, fluorenyl, or sulfanyl, among which alkyl, cycloalkyl, aryl, heterocycloalkyl, and St radical Or the sulfur group is unsubstituted, or substituted with one or more appropriate substituents, or any two of Rn, R °, RP, and F5 are used together with the atom to which they are combined to form a heterocycloalkyl group, It may be substituted, or Z may form cycloalkyl or heterocycloalkyl together with Rd and their combined atoms, where Z and Rd are as defined above, but they cannot form a cycloalkyl or heterocycloalkyl moiety Except for several groups, or Z together with Z1 and the atoms to which they are bonded form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above (but not capable of forming a cycloalkyl or heterocycloalkane-20- 92051 200424175 except for some groups); salts, pharmacologically active metabolic products or their prodrugs, pharmaceutically acceptable substances or pharmaceutically acceptable solvates. " In yet another aspect, the present invention provides a method of virus replication that interferes with or prevents SARS-associated scleroderma virus, and a complex I / tongue method, which includes a method for treating SARS-associated coronavirus protease and treating upper right poems. Close contact with K-type IIIB rhinovirus 3C protease inhibitors:

Ra3 is aryl, heterocyclic, heteroaryl or arylamino carboxyl, wherein aryl, hetero% alkyl, heteroaryl or arylamino carbonyl is unsubstituted or substituted by one or more appropriate substituents Substituted; and is a substituent having the formula:

Wherein: 圮 and each are independently Η or lower alkyl; m is 0 or 1; P is an integer from 0 to 5;

Ai is CH or N; when P is 1, 2, 3, 4 or 5, A2 is C (Rh) (Ri), N (Rj), S, S (O) -21- 92051 200424175 s (0 ) 2 or ο, and when pg0, N (Ri 欣 j), s (Ri)

, SCOXR1), SCCOdR1), or CXR1), where each of Rh, Ri, and Rj is independently H or a lower alkyl group; each existing A3 is independently C (Rh) (Ri), N (Rj), S, S (O), s (0) 2 or 0; wherein each of Rh, Ri and Ri is independently H or lower alkyl; when? When 1, 2, 3, 4 or 5, enter 4 is called 1 ^), (^ (1111) (1 ^) or 0; and when p is 0, A4 is N ^ XR1), 0: (jealous ) (1 ^) (Cut) and 〇 (Ri), wherein each of Rh, R1 and Rj is independently Η or lower alkyl, each Rk is η, alkyl, aryl or δ ^ 'and each R1 is Hydrazone, alkynyl, or aryl; provided that no more than two heteroatoms appear consecutively in the ring formed by Ai, (A2) m, (eight 3) p, A *, and C = 0 as described above Where the dashed lines in the ring 'when A: exists, it depicts a single bond, and when a2 does not exist, it is a hydrogen atom;

Rd is fluorene, halogen, hydroxy or alkyl, alkoxy or alkylthio, wherein alkyl, alkoxy or alkylthio is unsubstituted or substituted with one or more appropriate substituents;

Rb is fluorene or alkyl, unsubstituted or substituted by one or more appropriate substituents;

Re is fluorene, hydrogen, or hydroxy, or alkyl, alkoxy, or alkylthio, wherein alkyl, alkoxy, or thiothio is unsubstituted or substituted with one or more appropriate substituents;

Z and Z1 are each independently fluorenyl, F,,) yl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, in which alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl Are unsubstituted or substituted with one or more appropriate substituents, -c (0) Rn_c〇2Rn-CN -22- 92051 200424175, -C (0) NRnR °, -C (0) NRn0R °, -C (S) Rn, -C (S) ORn-C (S) NRnR0, -C (two NRn) R0, -C (= NRn) OR〇, -N02, -SOR0, -S02Rn, -S02NRnR〇, -S02 (NRn) (0R0), -SONRn, -S03Rn, -PO (ORn) 2, -PO (ORn) (OR〇), -PO (NRnR °) (ORP), -PO (NRnR °) (NRPRq), -C (0) NRnNR ° RP, _C (S) NRnNR ° RP, where Rn, R. , RP, and H are each independently H or alkyl, cycloalkyl, aryl, heterocycloalkyl, fluorenyl, or sulfanyl, wherein alkyl, cycloalkyl, aryl, heterocycloalkyl, or The thio group is unsubstituted, or substituted with one or more appropriate substituents, or any two of Rn, R °, RP, and RQ are used together with their combined atoms to form a heterocycloalkyl group, as the case may be After substitution, or Z and Rd and their combined atoms together form a cycloalkyl or heterocycloalkyl, where Z and Rd are as defined above, but cannot form part of a cycloalkyl or heterocycloalkyl Except for the group, or Z and Z1 and the atoms to which they are bound form a cycloalkyl or heterocycloalkyl, wherein Z and Z1 are as defined above (but can not form part of a cycloalkyl or heterocycloalkyl group) Except for the group); or its prodrugs, pharmaceutically acceptable salts, pharmaceutically active metabolites, or pharmaceutically acceptable solvates. In another aspect, the present invention provides a method for interfering or preventing viral replication activity of SARS-associated coronavirus, comprising contacting a SARS-associated coronavirus protease with a therapeutically effective amount of a IIIC rhinovirus 3C protease inhibitor of formula: 92051

-23- (IIIC) 200424175 where:

Ra4 is aryloxy, heteroaryloxy, alkoxy, cycloalkyloxy, heterocyclyloxy, aryl, cycloalkyl, or heteroaryl, of which aryloxy, heteroaryloxy , Alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryl, cycloalkyl, or heteroaryl, unsubstituted, or substituted with one or more appropriate substituents: and

Rc is a substituent having the formula:

Where: ^ is independently Η or a lower alkyl group; m is 0 or 1; P is an integer from 0 to 5; 8 is CH or N; when 卩 is 1, 2, 3, 4 or 5, Eight 2 is (3 (1111) (1 ^), Fengru), 8, 8 (0), s (0) 2, or 0, and when p is 0, a2 is c (Rh) (Ri) (Rj ), N (Ri) (Rj), s (Ri), S (〇) (R1), S (0) 2 (Ri) or 〇 (Ri), where each of Rh, Ri and Rj is independently Η or low Carbon-based group; each existing A3 system is independently C (Rh) (Ri), N (Rj), S, S (O), s (0) 2 or 0; where each Rh, Ri and tangent system are independently η Or lower alkyl; when? When 1, 2, 3, 4 or 5, 8 is 4), 0 (1111) (1 ^) or 0; and when P is 0, A4SN (Rk) (Ri), c (Rh) ( RixR is in the form of 0), wherein each of Rh, R1 and yang is independently fluorene or lower alkyl, each Rk is fluorene, alkyl, aryl or 92051 -24-200424175 fluorenyl, and each R1 is fluorene Radical or aryl; provided that no more than two heteroatoms appear consecutively in the ring formed by \, (A2) m, (Α3) ρ, A4, and C = 0, where the ring Each dashed line in the figure depicts a single bond when A2 exists, and a hydrogen atom when A2 does not exist;

Rd is fluorene, halogen, hydroxy or alkyl, alkoxy or alkylthio, wherein alkyl, alkoxy or alkylthio is unsubstituted or substituted with one or more appropriate substituents;

Rb is a fluorene or a radical, which is unsubstituted or substituted by one or more appropriate substituents;

Re is fluorene, sulfonin, hydroxy or alkyl, alkoxy or alkylthio, wherein alkyl, alkoxy or thiothio is unsubstituted or substituted with one or more appropriate substituents; Each independently is fluorene, F, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is unsubstituted, Or substituted with one or more appropriate substituents, -C (0) Rn-C02Rn-CN, -C (0) NRnR0, -C (0) NRn0R0, -C (S) Rn, -C (S) 〇Rn -C (S) NRnR0, -C (= NRn) R. , -C (two NRn) OR °, -NO〗, -SOR °, -S02Rn, -S02NRnR0, -S02 (NRn) (OR〇), -SONRn, -S03Rn, -PO (ORn) 2, -PO ( ORn) (OR〇), -PO (NRnR0) (ORP), -PO (NRnR0) (NRPRq), -C (0) NRnNR0RP, -C (S) NRnNR ° RP, among which Rn, R. , RP and each independently H or alkyl, cycloalkyl, aryl, heterocycloalkyl, fluorenyl, or sulfanyl, wherein alkyl, cycloalkyl, aryl, heterocycloalkyl, fluorenyl, or sulfur Amidino is unsubstituted or substituted with one or more appropriate substituents, or any two of Rn, RQ, Rp, and Rq combined with each other -25- 92051 200424175 etc. , To form a substituted, heterocycloalkyl, which may be formed through the atoms bound by the temple together to form a cycloalkyl or heterocycloalkyl, in which z and Rd are the same as those of the above-mentioned private groups. To form a fluorenyl or heterocyclic alkene: ', f they are combined "atoms-from forming a cycloalkyl or heterocycloalkyl as defined above (but not capable of forming a cyclic fluorenyl or heterocyclic alkynyl group < partial group Except the group);: its prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite or pharmaceutically acceptable solvate. In another aspect, the present invention provides a method that interferes with or prevents SARS-related coronal and maternal disease; a method of producing "methods" that includes inhibiting coronavirus related proteases and a therapeutically effective amount of rhinovirus protease inhibitors. Agent contact:

Zi where: (IV), Y is -N (Ry)-, -C (Ry) (Ry)-, or -ο-, where each Ry is independently H or lower alkyl; K is Η, F, or alkane Radical, OH, SH or O-alkyl;

(^ 4ΐ) (^ 4ΐ) 1 and & each independently is Η ^ Άη2; or 7.rR4iKR4i). ', Where n is an integer 0 to 5' \ is 0 or n, a2 is independently selected from each A3 system From qR4i) (R4i), N (R41), s, s (0), S (0) 2, and 0, and see you! Or NR41, where each of the individual 92051 -26- 200424175 is H or a low-carbon alkyl group, provided that $ ^ — can not afford more than 2 heteroatoms to appear in the series by Aι, A2, (A3) n, A4 And the ring formed by C = 0

A4 〇I (A3) n and the condition is that at least one of R2 and & is ^ r (r41) (r41) R5 and Rg are each independently Η, F, alkyl, 瑗, 11, ^% k Aryl, heterocycloalkyl, aryl or heteroaryl; each of the heart and Η is independently Η, 观, guanyl, heteroweiyl, aryl, heteroaryl, i7, -SR17, -NR17R18, i9NRi7Ri8 or See i7〇Ri8, where R17, R18 and r19 are each independently fluorene, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or fluorenyl; R9 is a five-membered heterocyclic ring with one to three options A heteroatom from 〇, N & s, ° V \., Or ~ is ^ 'and its center is 7, 〇; and z and Zi are each independently Η, F, alkyl, cycloalkyl, heterocycloalkyl, Aryl, heteroaryl, -C (0) R2 i, -C02 R2 i, -CN, -C (0) NR2 i R2 2, -C (0) NR2 1 0R2 2, -c (s) r21, -c (s) nr21r22, -N02, -sor21, -so2r21, -so2nr21r22 N -SO (NR2!) (OR2 2) > -SONR2! > -S〇3 R2!--P〇 (〇R2! ) 2 > -PO (R21) (R2 2) Λ -P〇 (NR2 ^ 22) (0 ^ 3) ^ P〇 (NR21R22) (NR23R24) ^ -C (0) NR21NR22 is also 2 3 or < ( 8 lectures 112 # 11221123, of which 1121; ^ 22, 1123 and 1124 are each independently H, Group, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fluorenyl, or sulfanyl, or any two of R2 1, r22, r23, and R24 together with the atoms to which they are bound form a heterocyclic group 'On the condition that Z and Zi are not both Η; or 21 forms a cycloalkyl or heterocycloalkyl group together with Z 1 and the atom to which they are bonded; or Z forms a naphthene together with the atom to which they are bonded by zjp 92051 -27- 200424175 or its prodrugs, salts or solvates. Pharmaceutically active metabolites, pharmaceutically acceptable, and other aspects' The present invention provides a kind of interference or prevention of SARS Method for virus replication activity of related coronavirus, which comprises associating coronavirus related protease with an effective amount] rhinovirus 3c protease inhibitor

Wherein Y is y) _, _where) is called or _0_, wherein each is independently a thief low-carbon alkyl; R1 is selected from the group consisting of optionally substituted, Lu I ^ ^ ^ eight alkyl,% Alkyl, heterocycloalkyl, aryl, heteroaryl, and -cccorm, and β16 and 8000R are selected from optionally substituted alkyl, alkynyl, heterocyclyl, and JK ^ Mantu , Squaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, and amine; R2 and R8 are each independently selected from Η, f ^, m, depending on the condition, Νι Substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R3 and R9 are each independently selected from hydrazone and optionally substituted alkyl, alkyl, heterocycloalkyl, aryl, Heteroaryl, u, _sr17, i7r18, _nr19nr17r18, and -NR%, wherein r17, r18, and r19 are each independently selected from fluorene, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and Fluorenyl; R4 is a suitable organic moiety; 92051 -28- 200424175 each R5, R6 and R7 are independently fluorene or lower alkyl; m is 0 or 1; p is 0,1,2,3,4 Or 5; \ is CH or N; when m is 1, the 8 2 series is selected from c (Ri〇xRn), N (Ri2), s, s (〇), s (〇) 2, and 0; when P is not ο, each A3 series is independently selected from C (R10) (RU), N (R12), S, s (0), 8 ( 0) 2 and 0; wherein Ri 0, R 11 and R 12 are each independently H or a lower alkyl group; when P is not 0, A4 is selected from N (R13), C (R10) (Rii), and 0, and When ρ is 0, A4 is selected from N (Ri3) (Rl4), c (r1 ()) (r11) (r12), and 〇 (r14), and the conditions are 疋, when A4 is 〇 (Ri4), A Not CH; where r10, r11, and r12 are each fluorene or lower alkyl, RU is η, alkyl, aryl, or fluorenyl, and is fluorene, alkyl, or aryl; , 疋 'Al, (A2) m, (Α3) ρ and A4 together do not contain more than two consecutive heteroatoms; or fa drugs, pharmaceutically acceptable salts, pharmaceutically active metabolites, or pharmaceutically acceptable Accepted solvates. In another aspect, the present invention provides a method for interfering or preventing SARS-related coronavirus: viral replication activity of the virus. Rhinovirus 3C protease inhibitor of Formula VI exposure:

92051 (VI) -29 200424175 of which:

Ra is alkylcarbonylalkyl, cycloalkylcarbonylalkyl, arylcarbonylalkyl, heteroarylcarbonylalkyl, alkylcarbonylaminoalkyl, cycloalkylcarbonylaminoalkyl, heterocycloalkylcarbonylamino Alkyl, arylcarbonylaminoalkyl, heteroarylcarbonylaminoalkyl, alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, heterocycloalkylaminocarbonylalkyl, arylaminocarbonylalkane And heteroarylaminocarbonylalkyl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moiety may be unsubstituted or substituted with one or more appropriately Radical substitution

Rb is fluorene or alkyl, unsubstituted or substituted with one or more suitable substituents; Rd is fluorene, halo, light or alkynyl, alkoxy or thio, wherein aryl, alkoxy or Alkylthio is unsubstituted or substituted with one or more appropriate substituents;

Re is a partial group having the formula:

Re and Rf are each independently fluorene or a low-carbon alkyl; m is 0 or 1, provided that when m is 1, Ra is not an amine-substituted alkylcarbonylalkyl or amine-substituted alkylcarbonylaminoalkane And when m is 0, Ra is selected from alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, heterocycloalkylaminocarboxyalkyl, arylaminocarbonylalkyl, heteroarylamino Carbonylalkyl and heteroarylcarbonylaminoalkyl, provided that Ra is not a substituted indolecarbonylaminoalkyl; p is an integer from 0 to 5; 92051 -30- 200424175 A is CH or N; When P is 1, 2, 3, 4, or 5, A24C (Rg) (Rh), N (Ri), s, S (O), s (o) 2, or 0, and when p is 0, ~ Is c (Rg) (Rh) (Ri), N (Rg), s⑽), S (0) (Rg), S (0) 2 (Rg), or 0 (Rg), where each of Rg, Rh and ... Is independently η or a lower alkyl group; each of the three existing 3 is independently C (Rg) (Rh), N (Ri), s, s (〇), 8 (〇) 2 or 〇 ′ Miao and 圮 are independently H or lower alkyl; when P is 1, 2, 3, 4 or 5, A4 is N (Rj), C (Rg) (Rh) or 0, and when p is 0 , A4gN (Rj) (Rk), C (Rg) (Rh) (Ri), and 〇 (Rk), each of which Rg, R, and R1 are each independently fluorene or a low retort group, each rj · is η, alkynyl, aryl, or fluorenyl, and each is 11 or alkyl or aryl; provided that it does not exceed two Heteroatoms appear continuously in the ring formed by Aι, (eight 2) rn, (Α3) ρ, eight 4 and c = 0 described above, in which the dotted lines in the ring, when eight 2 exists Is a single bond, and when a is absent, it is a hydrogen atom; and Z and Zi are each independently fluorene, F, fluorenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkane , Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are unsubstituted, or substituted with one or more appropriate substituents,-(3 (0) 111, _c〇2r1, -CN, -CCCONRiR111 , -CCCONRiOIT, -C (S) Ri, -qspRLqSjNR1! ^, -CbNR1)! ^, CbNRqOR111, -N02, -SORm, -S02R1, -SC ^ NRiR111, -SC ^ CNRyCOR111), -SONR1, -SC ^ R1, -POCOR1)], -PGKOrIxorhi), -PCXNF ^ RmXOR11), -PCKNF ^ irXNRnR. ), -QC ^ NRjNRmRn, -Q ^ NRiNRmR11, where R1, Rm, Rn, and R. Each independently is H or alkyl, cycloalkyl, aryl, heterocycloalkyl, donkey or thiomethyl, wherein alkyl, cycloalkyl-31-92051 200424175, aryl, heterocycloalkyl, or more A suitable substituent is substituted for the combined atoms, and the sulfonyl or thiol group is unsubstituted or substituted by one or two of R1, Rm, Rn, and R. And other groups to form a heterocycloalkyl group, which may optionally form a cycloalkyl group or a heterocycloalkane or Z and R with them to form a cycloalkyl group or a heterocyclic alkyl group, where Z and Rd is as defined above, except for some of the radicals, or they are bonded together to form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above; or a prodrug of the compound, It can be connected to the double salt, medicinal active new aM Gaucher product or pharmaceutically acceptable solvate. The invention provides a universal sense that interferes with or prevents the virus replication activity of SARS-associated coronavirus, which comprises connecting a SARS-associated coronavirus protease with a therapeutically effective tone, a formula VII Dan virus 3C protease inhibitor

Or its prodrug, pharmacologically acceptable. ^ Muzi sacrifice < salt or pharmaceutically acceptable solvent. The present invention provides a method for interfering or preventing the virus replication activity of sars-associated coronavirus, which comprises correlating coronavirus 92051 -32- 200424175 viral protease and a therapeutically effective amount of rhinovirus IIIC Protease inhibitor exposure: Ο Rb Z1

among them:

Ra is a substituted or unsubstituted heterocycloalkyl or heterocycloalkyl; Rb is a substituent having the formula:

, (Eight 3) | I (A2) m where: 圮 and the silicon system are independently Η or a lower alkyl group; m is 1; P is an integer from 1 to 5; \ is CH or N; A2 is C (Rh) (Ri), N (Rj), S, S (O), S (0) 2, or 0; where each of Rh, Ri, and Rj is independently H or a low-carbon academy; each existing A3 is independently C ( Rh) (Ri), N (Rj), S, S (O), S (〇) 2 or 〇; wherein each of Rh, Ri and Rj is independently H or lower alkyl; Α4 is N (Rk), C (Rh) (Ri) or 0; provided that no more than two heteroatoms appear consecutively in the ring formed by Ai, (A2) m, (A3) p, A *, and 00 described above 5 where each of the rings in the ring is 92051 200424175, the dashed line depicts a single bond;

Re is fluorene, halo, or substituted or unsubstituted low-carbon alkyl;

Rd is fluorene, halogen, ethyl, substituted or unsubstituted academic radical, alkoxy or alkylthio;

Re is Η or substituted or unsubstituted alkyl; and Z and Z1 are independently Η, F, unsubstituted or substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl , -C (0) Rn, -C02Rn, -CN, -C (0) NRnR °, -C (0) NRn0R. , -C (S) Rn, -C (S) ORn, -C (S) NRnR. , -N〇2, -SOR0, cold S02 Rn, -S〇2 NRn R. , -S02 (NRn) (OR.), -S〇NRn, -S03 Rn, -PO (〇Rn) 2, -PO (ORn) (OR0), -PO (NRnR0) (ORP), -PO (NRnR0 ) (NRPRq), -C (0) NRnNR ° RP or -C (S) NRnNR ° RP, where Rn, R. , RP, and M are independently H, substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocycloalkyl, fluorenyl, or sulfanyl, or any two of Rn, R °, Rp, and Rq and their combined atoms are used together to form a heterocycloalkyl group, which may be substituted, or Z and Rd and their combined atoms together form a cycloalkyl or heterocycloalkyl group, or Z and Z1 and The atoms to which they bind together form a cycloalkyl or heterocycloalkyl; or a prodrug, a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof. In another aspect, the present invention provides a method for interfering or preventing viral replication activity of SARS-associated coronavirus, comprising contacting a SARS-associated coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor, the agent being selected Including: -34- 92051 200424175 〇

And pharmaceutically acceptable salts, pharmaceutically active metabolites or solvates thereof. In yet another specific embodiment of the present invention, the method described above utilizes a rhinovirus inhibitor selected from the group consisting of: 2- (2-dongylethyl) benzoic acid N-acylamine; 2- ( Propylthio) -p than yodo-3-N- (acyl) methanamine; [4- (N_hydroxyamino) -2R-isobutyl-3S_ (〇thiophen-2-ylthio) (Methyl) succinyl] -L-phenylalanine methyl amine; 92051 -35-200424175 N-hydroxy-5-phenylpentanamine; 2- (phenyl-2_ethylpyridylamine ; 2- (thiothio) benzoic acid N-hydroxyamidamine; 6-biphenyl-4-yl- [2,2-dimethyl-1 heptodian-4-ylamine methyl) -propyl Aminomethyl] -hexanoic acid N-hydroxyamidoamine; 3R (6- (4-biphenyl) -3- (N-methylaminomethyl))-hexanoic acid N-methylaminoamine; 2 -Lynyl continued S Shengji-Cyclopentyl-1 · associated empirical amine; 2-Lynyl sulfenyl-cyclohexylpyridine benzyl acid amine; 6-fluorenylsulfonyl-cyclohexyl- 1-enecarboxylic acid hydroxyamidine; 1- (N-hydroxy) -3- (2-bisfluorenyl) urea; 3R- (6- (4-biphenyl) propyl) -N- (3- P-aminopyridine) -hexanoic acid] SI »# fluorenyl-fluorenylamine; 4- (2-{[5-peramino-3- (3-phenyl-propyl) -3,4- Dichloro-2-Hp bilo-3 [Methyl] • amino} · 4-methyl-pentylamino) benzoic acid methyl ester; 5- # to amino-3- (3-phenyl-propyl) -3,4-dihydro-2 -Η-ρ ratio ρ each-3-betanoic acid (2-cyclohexyl_ 1-methylamine methylamidino-ethyl) sulfonamide; 4- (2-{[5-hydroxyamino group each (3-pentyl ) -3,4-dihydro-2-H-pyrrole-3-carbonyl] -amino group} methylmethyl-pentylamino) benzoic acid methyl ester; 6-biphenyl-4-yl-3- ( 11)-(2-Cyclomethylolethylaminemethylamidino) _hexane hydroxamic acid; 6-biphenyl_4-yl_3- (R)-(l (S)-# present Methyl-2,2-dimethyl-propylcarbamate) _hexane hydroxamic acid; 2- (biphenyl-4-ylcontinyl) -cyclohexyl_1_fomerate Amine; 6- (Lianfengji Xingji) _________ 1_fine · metanoic acid benzyl amine; 92051 -36- 200424175 2-benzylthio-j hexano-1-dilute acid Acid amine; 2-methylthio-cyclohexanoic acid light acid amine; trans-2 · • benzylthio-cyclohexanecarboxylic acid hydroxylamine; trans-2- (biphenylyl) -Methylthio) -hydroxylamine of cyclohexanecarboxylic acid; 6-biphenylyl-3- (R)-(1-hydroxymethyl-2- (S)-(lH-imidazol-4-yl) -Ethylaminomethylammonium) -hexane hydroxamic acid; N-Cycloyl-2- [2-fluorenyl-3_ (3-phenyl- ) -Tetrazol-sulfan-3-yl] -ethanamine; trans-2- (4-phenoxy-methylenethio) -cyclohexylcarboxylic acid hydroxylamine; 2- (4- Indan-1-yl-N-methylthio) _cyclohexylpyrimidinamide; 2- (3-Lian-4-4-yl-propyl) yl-Nl- (2,4,5-dichloro -6-methyl-tetrazol-weiran-3-yl) -succinic acid amine; 2- (2-biphenyl-4-yl · ethylthio) -cyclohexanoic acid Amine; 2- (3-Biphenyl-4-yl-propyl) -N4-hydroxy-N1- (2-hydroxy_cyclohexyl) -succinylamine; 6-biphenyl-4-yl each (1 • hydroxy Imino · ethyl) -hexanoic acid hydroxyamidine; 3- (R)-(2-hydroxy small (S)-(1H_imidazole_4_yl) -ethylamine formamidine) -6_ (4 -(2-methyl · pyrimazol-4-yl) -phenyl) -hexane hydroxamic acid; 6-biphenyl-4-yl-3- (3-meryl-hexahydroρ ratio lake-1 -Tanyl) -Hexanoic acid-Chrysylamine; H4-methoxy-benzenesulfonyl >hexahydropyridine-2-carboxylate; 1-H4-bromo-phenoxy) -benzenesulfonate Fluorenyl) -hexahydropyridine-2-carboxylic acid hydroxyamidine; N- (l-benzyl-2-hydroxy-ethyl) -N4-hydroxyl-isobutyl-succinimidine; 6-biphenyl-4 -Yl-3 (R) -2 (S) _hydroxy- (1 (S) -hydroxymethyl-2,2-dimethyl-propylaminomethyl) -hexanoic acid Hydroxamic acid; 6-biphenyl-4-yl-3- (2-hydroxy small hydromethyl-propylaminomethyl) -hexanoic acid hydroxamic acid; 92051 -37 · 200424175 trans-2- (3 -Biphenyl-4-yl · propyl) _cyclohexanecarboxylic acid hydroxyamidine; 1_ [4_biphenyl-4-yloxy) -benzenesulfonyl hexahydropyridine asparagine hydroxylamine; 1 -(4-phenoxy-benzenesulfonyl) > hexahydropyridine asparagine hydroxyamidate; 6-biphenyl-4-yl-3- (R)-(l_ (S) -hydroxymethyl_2 -(3-pyridyl) -ethylaminofluorenyl) -hexane hydroxamic acid; 6-biphenyl-4-yl-2S_ # fluorenyl-3R- (1S-hydroxymethyl each methylthio- Propylaminomethane) -hexanoic hydroxamic acid;: 1- [_ [4- (4-bromo-phenoxy) _benzenesulfonamido] dong (third · butoxycarbonyl > hexahydro Pycnogenol || 2-Hydroxypyramine, 1- [4- (4-bromo-phenoxy) _benzenesulfonyl] _Hydroxypyroxy_2_carboxylic acid hydroxypyramine; 4-ethyl Fluorenyl small [4-phenoxy-benzenesulfonyl] -hexahydropyridine_2_carboxylic acid N-hydroxyamidamine; 1- (one " winter-based tentium fet) -hexamidine ratio-2 -Read amine acid test; 6 · biphenyl-4_yl hydrazone- (2-g isopropyl-1-tetrahydroanan-3- (S) -aminocarbamic acid group) -hexyl hydroxamic acid ; 1-[_ [4- (4-Bromo-phenoxy) -benzoic acid group] -4-methyl- Hexahydro (: _-2-metanoic acid N- # Cyclopyramine; 4- (4-methoxyphenylphenoxy) -thiomorpholine-3-metanoic acid amine; 3 -(Diphenylphosphinic acid)-hydroxyammonium propionate;-1- [4- (4-chlorophenoxy) benzenesulfonyl] -thiomorpholin-3-amine formamidine) hexa Pyridoxine-2-carboxamide; 4 [4-phenoxy-phenylanyl] -Hexane Benzosuccinyl] -thiomorpholine-3-metanoic acid N-chimonyl donutylamine; 3 [2-Lean-4-yl-ethylthio] -tetramethylene-η-citrul-4- Therefore N-Amino acid amines; 92051 -38- 200424175 1- [4-phenoxy-phenoxy acid group] -4-methyl-hexachloro-p-bihexyl-2-amino acid N-fatyl®amine; 6-biphenyl-4-yl-3- (R)-(2-keto-monoazaheptane-3- (S) -ylaminomethylmethyl) -hexane hydroxamic acid; 4- ( 111-4 丨 Hydroxy-2-continyl group) -thiomorpholine-3-polyacid amine; 1- (methyl-phenylphosphinic acid) -hexahydropyridine-2- (R) -Hydroxylamine carboxylate; 1- (1,3-dimur-iso-4 丨 Homo-2-contylyl nitrogen? Biyodo-2-metanoic acid via acid amines; 4-methyl_1- (4- (4-chlorophenyl) benzenesulfonyl) -N-hydroxy-2R-hexahydropyridoxamine hydrochloride ; 1- [4-chlorophenoxyphenoxy continuum] -N-peryl-2R-: r; nitrogen-rhodiumamine, 2- (3-phenyl-propylsulfonyl) -cyclo 1- (tetrahydropyrrole-1-sulfofluorenyl) -hexahydropyridine-2-carboxylic acid hydroxyfluorenamine; l- (s rhampidin-1 · continuing group) -Hamster p-pyridine-2-prylamido, 4-[-[4-brook_phenoxy-benzoic acid] -copper thiomorpholine-3-metanoic acid-N- Mesitylamide; 1- [4- (4-methoxy-phenylsulfanyl) -benzoic acid] -7T nitrogen p-pyridine-2-ammonium acid amidamide; 1- [4- ( 4-Gas-phenoxy) -benzoic acid] -4- (second-butoxyyl) chloropyridine-2-amino acid N-light acid amine; 6-pyridyl-3_ (4-Phenoxy-benzoic acid group) -ττNimetide-4-Ceramics, 4- (third-butoxycarbonyl) -1- (4- (pyridin-2-yl) ) Oxybenzenesulfonyl) -N-hydroxy-hexahydropyridine-2-carboxamide; 4 _ [(4-fluorophenoxy) -benzenesulfonyl] -thiomorpholine-3- Carboxylic acid N-hydroxyammonium amine; 4- [4- (fluoro-phenoxy) -benzenesulfonyl] -ketothio? Fluoroline-3-carboxylic acid N-hydroxy 92051 -39- 200424175 fluorenamine; 4- (4-butoxy-benzoylammonyl) -thiomorpholine-3 · metanoic acid Sylamine; 4- (4-butoxy-benzene continyl) 1-ketothiomorpholine p-Lin-3-amino acid amine; 1- [4- (4-fluorophenyl) benzene ] -4- (Third-butoxyalkyl) -2R-Hexahydro bp well · 2-Amino acid amines; 1-((4- (4-chlorophenyl) -hexahydro p ratio Flavor) -1-continuous acid group) _Hexahydro pbitol-2-betanoic acid # to amidine; cis-2-phenethylthio-cyclohexanecarboxylic acid hydroxyamidine; 1-[-[ 4- (4-fluorophenyl) benzenesulfonyl) -N-hydroxy-2R-hexahydropyridinecarboxamide hydrochloride; 1- (diphenylphosphinic acid) -tetrahydropyrrole-2 (R ) -Hydroxy carboxylic acid amine; trans-2-phenethylcontanoic acid-cyclohexanoic acid stilbene amine; 1- [4- (4-fluorophenyl) -hexahydropyridine [Yl] -hexahydropyridine-induced hydroxyamidine; 1-1- [4- (4-fluorophenylsulfanyl) -phenyl-continyl] -hexahydrop-pyridin-2-acrylamido; 4-1- [4- (Bromo-phenoxy) -benzenesulfonyl] -2,2_dimethyl-1-one-thiomorpholine-3-carboxylic acid hydroxyamidine; 1- ( Tetrahydropyrrole-1-carbonyl) -tetrahydropyrrole_2 (R) _carboxylic acid hydroxylamine ; Bromophenoxy) -benzenesulfonyl] -2,2-dimethyl-1-one-thiomorpholine · 3-metanosyl light amidine; 4- (ethoxycarbonyl) fluorenyl -1- (4- (4-chlorophenyl) benzenesulfonyl) -N-hydroxy_2R-hexahydropyridinecarboxamidine hydrochloride; 1-phenethylaminemethylfluorenyl-tetrahydropyrrole- 2- (R) -metanoic acid hydroxylamidine;!-(4-fluorenyl-hexahydropyridine-1-sulfonyl) -hexahydropyridine-2-carboxylic acid hydroxylamidine; 3 (S) _N- Ketyl-4- (4-Heptaline-4-yl) oxyphenylpyridyl) -2,2-dimethyl_tetrahydro--40- 92051 200424175 2H-1,4-thiagen-3- Carboxamide; 2 (R) -4-methyl-1- (4- (4-fluorophenyl) benzenesulfonamido) -N-hydroxy-hexahydropyridine_2-carboxamide; 1- ( (2-pyridyl) -4-hexahydropyridine-1_continyl) -hexahydropyridine_2_carboxylic acid hydroxylamine; 1- 1- [4- (physinol-4-ylamine) Stilbene) -phenylphenic acid] -hexahydro p-pyridine_2 · acrylamido; N- (4-phenoxy-benzenesulfonyl) -D-tertiary-leucine- N-Hydroxyamine; 2,2-Dimethyl-4- [4-Obipyridin-2-yloxy) -benzoxamidino] -thiomorpholine hydroxyamidoamine; Ν-1- [4 · (4-Fluorophenoxy) benzene and phenyl group) -D-Third-leucine light group Amine; 3 (R) -N-Hydroxy (4-heptapyridin_4_yl) oxybenzenesulfonyl) -2,2dimethyl-tetrahydro_2Η-1,4-rhohu-3 -Jun amine hydrochloride; 2- [4- (4-Rat-phenoxy) -benzyl amine; hydrazine-3,3 «· dimethyl-butylamine; 3 (R) -N-Hydroxy-4- (4- (furan-3-yl) phenoxybenzenesulfonyl) > 2 > Dimethyl · tetrafluorene-2H-1,4h ?? ; 2-1 · [4- (koubito-2-yl-oxy) -benzene stone scutellaria sylvestris] Anthyl-Cycloyl 3-dimethylbutanamine; 2- (2-biphenyl-4 -Yl-ethylsulfonyl) -cyclohex-1 · ene-carboxylic acid amine carboxylic acid; 6- (2-biphenyl-4-yl-ethylcontinyl) -cyclohex_1_ 晞Acrylic acid amines; Ν · (4-phenoxy • phenylpyridinyl) -3,3-dimethylmethylsulfanyl cysteine N_hydroxyammonium amine; 1- (4-phenoxy -Hexahydro P than Lake -1-Si group) -Hexahydrotoxin bite_ 2-hydroxy acid amine; N- (4- [4-chlorophenoxy] -phenyllyl) -3,3- Di-gamma_s_ (methyl shirt) _d · hemamidine-41-92051 200424175 acid N-mesylamidine; N- (4- [4-chlorophenoxy] -benzenesulfonyl} > 3,3 _Dimethyl_s_ (methylsulfinamilide) _d_ cysteine NM-based amine; cis-2- (2-phenyl · ethanesulfonyl) _Cyclohexanecarboxylic acid hydroxyamidine; 3 (R) -N-hydroxy-4- (4- (imidazolyl) phenoxybenzenesulfonyl) -2,2dimethyl, hydrogen-2H-1 , 4-farken-3-carboxamide; 3 (R) -N side group-4- (4-〇 Bi Lake-4-yl) oxybenzoic acid group) _2,2_dimethyl-tetra Hydrogen_ 2H-1,4-thiagen-3-carboxamidine; 4 small [2- (2-hydroxyamine methylamidomethyl net phenyl-pentamylamino) acetomethyl_pentamyl] -Methyl benzoate; trans-2- (2-phenyl-ethyl benzoate) -cyclohexanoic acid light acid amine; 3.3-dimethyl-2- (4-phenoxy-benzene Thiomethyl) -butyric acid N-hydroxyamidamine; 2- (2_biphenyl-4-yl-ethanedifluorenyl) -cyclohexane metaboic acid isobaric acid ester; 2-[_ [ 4- (4-Chlorophenyl) -hexahydropyridine small sulfonamidoamine] _3_methyl-3- (pyridin-2-ylmethylthio) -butyric acid N-hydroxyfluorenamine; 3.3-dimethyl 2- (4-phenoxy-benzenesulfonylmethyl) -butyric acid N-hydroxyfluorenamine; 2 (R)-[4- (4-fluoro-phenoxy) benzenesulfonamido] -3-methyl-3- (pyridin-2-ylthio) _hydroxyammonium butyrate; 3 (R) -N-hydroxy-4- (4-(-((pyridin-4-yl) methyl ) Oxybenzenesulfonyl) -2,2-dimethyl-tetrahydro-2H-1,4w sethen-3-betamine; 1 small [4- (4-chloro -Phenoxy) -benzenesulfonyl PK1-methyl-1H-imidazolium sulfonyl) -hexahydropyridine-2-carboxylic acid hydroxylamine; 1- [4- (pyridin-2-ylthio) ) -Hydroxypyridylsulfonyl] -Hydroxypyridinecarboxylic acid hydroxyamidine; 92051 -42- 200424175 2R- [4- (4-furan-3-yl-phenoxy) -benzenesulfonamido ] Hydroxy-3-methyl-3- (pyridine-4-ylthio) -butyric acid amine; trans-2- (2-biphenyl-4-yl-ethylthio) -cyclohexane Acid amine; N4- (2,2-dimethyl-is-hydroxymethyl-propyl) · N1_hydroxy-3R [3- (4-exo-bidine_4-yl-phenyl) ^ Bilo-1-yl] -succinimide; [4- (4-fluoro_phenoxy) -benzenesulfonyl)]-3,3-dimethyl-5-keto-hexahydropyridine Geng 1 Carboxylic acid hydroxyamidine; 2 (R)-[4- (4-Qiyl-phenoxy) benzylamine] each methyl hepta-3-yl-phenoxy) butyrate hydroxyl Hydrazine; 1-[-[2- (benzotetra-2-ylsulfanyl) -hexahydro p-pyridian acid group] • hexahydrosulfo-2-carboxylic acid hydroxyamidine; 5- [ 4- (4-fluoro-phenoxy) -benzenesulfonamido] _4,5,6,7_tetrafluorene-3H-imidazo [4,5, _c] pyridine-6-carboxylic acid hydroxyamidine; 1 -[4- (叶 匕 枝 -4-ylthio) -Hexahydropyridine-1-thio] -Hexahydrodagger_ 2-ammonium methanoate; 1- [4- (4-methoxy-phenylamine continuation group) -hexahydro p ratio acid group] Hexahydro-2-amino acid ; 2 (R)-[4- (4-methylphenoxy) benzenesulfonamido] -3-methyl-3 heptamethyl-continyl) hydroxyammonium butyrate; bu [4- (4-methyl_phenylaminesulfonyl) -hexahydropyridine-1-sulfonyl] _hexahydropyridine_ 2-carboxylic acid hydroxylamine; 4-methoxy-benzenesulfonyl) -2 , 2-Dimethyl-thiomorpholine melamine acid hydroxyamidine; 4-1- [4- (4-chloro-phenoxy) -benzenesulfonyl] -2,2-dimethyl- Thiomorph 4_3_Better > 43- 92051 200424175 Acid hydroxyamidamine; 2 (1 ^)-[4- (4- > odor-winteroxy) -benzylamine group] -3 -Methyl-3- (aceton-4-yl-sulfoxide) hydroxyammonium butyrate; '(4-methoxy-benzenesulfonyl) -2,2-dimethyl-1-one- Thiomorpholine-3-carboxylic acid hydroxyamidine; 4-4_ (4-chloro-phenoxy) -benzenesulfonyl] -2,2-dimethoxy-keto-thiomorpholin -3-ammonium hydroxyamidoamine; 3 (S) -2,2- · -methyl-4- [4_ (ρ 比 -4--4-ylthio) -benzenezol S blue group] -thiomorpho Lynn 3-carboxylic acid hydroxyamidine; 3,3-dimethyl-N-hydroxy-2R-[_ [4 (-(pyridine -4-ylthio) -hexahydropyridine small sulfofluorenylamino] -butanidine; N-hydroxy-2-[-[(4-toluenesulfonyl) amino] acetamidinium; [4 ( -(4-imidazol-1-yl-phenoxyhexahydropyridine small sulfofluorenyl] -hexahydropyridine aspartate hydroxyamidinate; H4_ (4_imidazole small group-phenylthio) -hexahydropyridine small Sulfofluorenyl] -hexahydropyridine-2-carboxylic acid hydroxyfluorenamine; 2fluorene- [4- (4-chloro-benzylfluorenyl)> cyclohexanesulfonyl] -hexahydropyridine small carboxylic acid hydroxyfluoramine ; L (R)-[4- (4-chloro-benzylidene) · hexahydropyridine_ 丨 _sulfofluorenyl] _hexahydropyridine carboxylic acid hydroxylamine; l (RH4-p 比比 -2 -Yl-hexamethylpyridine, small sulfofluorenyl hexahydropyridine, 2-carboxylic acid hydroxypyramine; l (R)-[4- (4-imidazole-l-yl_phenoxy) _hexahydropyridine small sulfonium Fluorenyl] _hexahydropyridine · 2-carboxylic acid hydroxyamidine; 92051 -44- 200424175 N-benzyl-3,3-dimethyl-2R- [4 (-(morpholin plin-4-yl) ) -Hydrogen p-pyridine-1-continyl sulfonylamino] -butyramine; N-hydroxy-3-methyl-3- (5-methyl-isopurazolyl-methylthio) -2R- [4-Opyridin-4-ylthio) -hexahydropyridine-continylamino] -butanidine; N-side group 2R- [4- (4-imid-1--1-yl -Phenoxy) -hexahydroedian-1- Acidic amino group] · 3,3-dimethyl-butanosamine; 2R- [4- (4-chloro-benzylidene) -hexahydrop-pyridine-1-contylamino]] N -Light-yl-3-methyl-3-methylthio-butydonylamine; N- hair group_3-methyl-3-methylthio-2R_ [4- (p 比 症 -4-ylthio) -Hexachloro p-pyridine-1 · sulfonylamino] -butyrylamidine; 1min 38,2,2-dimethyl-1-keto-4-[-[4 (七 比 岭 -4- Oxy) -phenylphenoxy] -thiomorpholine-3-carboxylic acid sulfonamide; 4- {2- (4-fluoromethylmethyl) -6-methyl-5-[(5-methyl Isoisopyrazol-3-fluorenyl) -amino] -4-hydrazinoheptylheptylamino} -5- (2-fluorenyltetrahydrop-pyridin-3-yl) -pentan-2-associated Acetic acid; and its pharmaceutically acceptable salts. Other specific embodiments of the present invention include U.S. patent application serial numbers 08/825331, 08/991282 (U.S. Patent 6020371), 09/421560 (U.S. Patent 6331554), 09/947381 (Gazette No. 0032237A-1), 09 / 597148 (U.S. Patent 6369226), 09/882345 (Gazette No. 0061916), 09/301977 (U.S. Patent No. 6531452), 09/647712, 10/289982, 09/631708 (U.S. Patent No. 6534530), 09/834783 (Gazette No. 0006943-A1) and 09/726376 (US Patent 6514997), all of which are incorporated herein by reference in their entirety. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS For the purposes of the present invention, as described herein and the requester, the following terms 92051-45-200424175 are defined as follows: "Included" as used herein is used in a limited sense. Dagger, is an open, non-saturated, monovalent hydrocarbon group used in this article, and the ancient soil, unless otherwise specified, includes the combination and bridging of a 4-chain, branched or cyclic moiety ( Including fused .like partial group) 'or the group of the aforementioned partial group is less than three carbon atoms:. As for the fluorenyl group of the shao group, this group must have to "hetero ::" means An alkyl having 1 to 4 carbon atoms in its chain. Chain == means a straight or branched heteroatom having 2 to 12 atoms in the chain from mi to 0 ^. Examples of < J < alkyl groups include alkyl compounds and the like. The eighth primary and secondary amines, alkyl sulfides, and the term "fluorenyl" as used herein, unless otherwise specified, include fluorenyl moieties having at least one carbon-carbon double bond. Group, wherein the alkyl group is as defined above, and includes the isomers of the alkenyl group and the 2 isomer. As used herein, " block group, " unless otherwise specified, includes an alkynyl moiety having at least one carbon-carbon parameter bond, wherein the alkynyl group is as defined above. "The term refers to a saturated, partially saturated, unsaturated, or aromatic, monocyclic or fused or non-fused cyclic ring structure with only carbocyclic atoms (a heteroatom 'means non-carbon Ring atom). Examples of carbocyclic rings include lysyl, aryl, and cycloalkyl-aryl. "Heterocycle"-a term that refers to a saturated, partially saturated, unsaturated, or aromatic, mono 92051 -46- 200424175 cyclic or fused or non-fused polycyclic ring structure having one or more selected from Heteroatoms of N, 0 and S. Exemplary heterocycles include heterocycloalkyl, heteroaryl, and heterocycloalkyl-heteroaryl. A cyclic radical means a saturated or partially saturated, monocyclic or blended or spiro polycyclic ring structure with a total of 3 to 18 carbon ring atoms (but without any heteroatoms). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, auryl and the like. `` Heteroalkylated '' means a monocyclic or fused or spiro polycyclic ring structure, which is saturated or partially saturated and has a total of 3 to 18 ring atoms, containing 1 to $ selected from nitrogen , Oxygen and sulfur heteroatoms. Illustrative examples of heterocycloalkyl include tetrahydropyrrolyl, tetrahydrofuranyl, hexahydropyridyl, hexahydropyridyl, morpholinyl, thiomorpholinyl, aziridinyl and the like. … The term "aryl" as used in this text, unless otherwise indicated, includes organic moieties such as phenyl or fluorenyl derived from aromatic hydrocarbons by removal of a hydrogen. As used in this text, the term "4-10 membered heterocyclic group" refers to both aromatic and non-aromatic heterocyclic groups, containing one to four heteroatoms each selected from each other. The cyclic group has a tetrad. Each of the two primitives is in the system, and the additional condition is that the group 基 Q 马 1 and Yihe 3 have two adjacent or s atoms. Non-aromatic heterocyclic groups include groups that have only 4 atoms in their system, but aromatic heterocyclic groups must have at least 5 ortho = ring systems. Heterocyclic groups include fused ring fluorene. 4-membered heterocyclic family

An example of a group is -nitrotetrafluorenyl (derived from -nitrotetrakisyl Z). An example is hydrasyl, and an example of a 10-membered heterocyclic group is fluorenyl. 92051 -47- 200424175 Aromatic heterocyclic Examples of groups are tetrahydropyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrofluorenyl, tetrahydropiperanyl, dihydropiperanyl, tetrahydrothiosulfanyl, hexahydroxanthene, Morpholinyl, thiomorpholinyl, thiooxolyl, hexahydropyridyl, --azatetramethyl, propylene oxide, epithiazole, sulfoxanthenyl, oxetamine Fluorenyl, thioheptamyl, oxazaheptenyl, diazaheptenyl, thiazeptadenyl, 2,3,6-tetrahydropyridyl, 2-hydropyrrolyl, 3 -Dihydropyrrolyl, dihydroindolyl, 2H_piperanyl, 4H_piperanyl, dioxolanyl, 丨, 3-dioxofluorenyl, dihydropyrazolyl, dithiolupinyl , Dithiocarbamyl, dihydropiperanyl, dihydropyrimyl, dihydrofuranyl, tetrahydropyrazolyl, dihydroimidazolyl, tetrahydroimidazolyl, 3-nitrobicyclo and [3 · 1 · 0] Hexyl, 3-nitrobicyclo [41o] heptyl, 3H, indolyl, and arylene. Examples of family heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyridyl, diazolyl, pyrenyl, tetrazolyl, furyl, fluorenyl, isoxazolyl, pyrazolyl, Oxazolyl, isopyrazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, fluorinyl, indazolyl, indyl, indyl , Dacrotyl, tricrotyl, isordinyl, pyridinyl, purinyl, pyridazolyl, pyrimidazolyl, furyl, benzofuryl, benzothiophenyl, benzopyrene Oxazolyl, benzoxazolyl, quinazolinyl, quinazolinyl, 4-pyridyl, and furanopyridyl. The aforementioned groups, if derived from the groups listed above, can be used where feasible. It is connected and connected via fluorene. For example, a group derived from pyrrole may be a pyrrole small group (N_linked) or a pyrrole 1 group (c-linked). Furthermore, a group derived from imidazole may be an imidazole small group ( ) Or imidazol-3-yl (C-linked). Heterocyclic group, in which 2 ring carbon atoms = substituted with a hydrazone (= 〇) partial group, is it UL thio? Fu 92051 -48- 200 424175 Linyl. Polycyclic aromatic ring structure with heteroatoms of nitrogen, oxygen and sulfur. M heteroaryl lf means monocyclic or fused or spiro with 4 to 18 ring atoms, containing 1 to 5 Illustrative examples selected from the group consisting of oxazolyl, pyrazolyl, 2-tetralyl, tetrafluorenyl, and heteroaryl, including pyrrolyl, thienyl, Psuccinyl, succinyl, aridyl, p-pyridine Group, oxalyl, quinolyl, quinolyl, benzoxamidine, & benzodiaxyl, benzodioxolyl, benzofluorenyl Etc. As used herein, the term "pi-oxyl" is used to refer to halo and other 4 pore soils. Unless otherwise specified, it includes O-fe radicals, where the radicals are as defined above. "Amine-pi- The word, means -NH2 group. The term "halogen" means chlorine, fluorine, bromine or iodine. As used herein, the term "commercial group", unless otherwise indicated by A, means fluoro, chloro, bromo or iodo. Preferred groups are fluoro, chloro and bromo. "Pharmaceutically acceptable salts are salts that retain the biological effectiveness of the free acids and bases of a particular compound and are not biologically or otherwise undesirable. The compounds of this invention may be sufficiently acidic, sufficient Basic or two functional groups, and therefore react with any of a variety of inorganic or organic bases, and inorganic and organic acids to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include via the compounds of the present invention and Salts made by the reaction of mineral or organic acids or inorganic bases, such as the following salts, including sulfates, pyrosulfide salts, Fei 1 fee salts, sulfites, acid sulfites, phosphates, monohydrogen Phosphate, dihydrophosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprate, caprylate, propionate, formate, isobutyl Salt, hexanoate, heptanoate, propionate 92051 -49- 200424175 salt, oxalate, malonate, succinate, suberate, sebacate, fumarate , Maleic acid salt, butyne hydrazone 4_ diacid salt, hexane AlkyneDibenzoate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate Formate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, Benzenebutyrate, lactate, 7-methylbutyrate, glycolate, tartaric acid Salt, methane sulfonate, propane sulfonate, osmium sulfonate, osmium-2-sulfonate and phenylglycolate. The term "substituted" means a specific group or part of a group With one or more substituents. &quot; Unsubstituted "means that a particular group is unsubstituted. The term" substituted, as the case may be "means that a particular group is unsubstituted or substituted with one or more substituents The term "SARS-inhibitor" means any rhinovirus protease inhibitor compound represented by formula, or a pharmaceutically acceptable salt, hydrate, precursor animal, active metabolite, or solvate thereof. Thing. Examples of rhinovirus protease inhibitors can be found in, but not limited to, U.S. Patent Application Serial Nos. 09/30/977 and 09/726376, all of which are incorporated herein by reference in their entirety. As used herein, "through rhinovirus protease-mediated processes" refers to biological, physiological, endocrinological, and other physical processes that respond to rhinovirus inhibitors described herein. Sexually mediated by limbs or stylistic combinations (such as SARS-associated viruses). The power of this process can be achieved in vitro or in vivo. In vivo modulation can be performed in a wide range of patients, such as humans, rodents , Sheep, pigs, dairy cows, etc. In a cell that interferes or prevents, 'SARS-associated coronavirus ("Sars ,,,, skeleton) virus complex 92051 -50- 200424175 system term, which means when and not ribose Enzymes or cells that temporarily or stably transduce a ribozyme-encoded vector reduce the SARS replication or production of the SARS component necessary for progeny viruses in the cell. Simple and convenient tests for determining whether SARS virus replication has been reduced include ELISA tests for the presence, absence, or reduced presence of anti-SARS antibodies in the patient's blood (Nasoff et al., PNAS 88: 5462-5466, 1991), RT-PCR (Yu et al., Viral Hepatitis and Liver Diseases 574-477, Nishioka, Suzuki, and Mishiro (eds.); Springer-Verlag, Tokyo 1994). This method is commonly known to those skilled in the art. Alternatively, all RNAs obtained from transduced and infected "control" cells can be isolated and subjected to spot or Northom analysis and assayed with SARS-specific DNA to determine if SARS replication Be lowered. Alternatively, the decrease in the expression of SARS proteins can also be used as an indicator of SARS replication inhibition. When compared to control cells, a reduction of more than fifty percent in SARS replication is typically a quantitative prevention of SARS replication. The term "pharmaceutically acceptable carrier" refers to a carrier or adjuvant that can be administered to a patient with a compound of the present invention without disrupting the pharmacological activity of the compound, and when sufficient to deliver a therapeutic amount The compounds are non-toxic when administered in a dose. The term "π prodrug" is a compound that can be decomposed under physiological conditions or by solvent into a specific compound or a pharmaceutically acceptable salt of such a compound. A prodrug may be one of the isohydroxyl groups of the present invention Derivatives of hydroxamate compounds, which contain some groups, such as -C02R, -P0 (0R) 2, or -ONR, which can be cleaved under physiological conditions or by solvolysis. Anything that provides pharmacy A suitable R-substituted -51- 92051 200424175 group is acceptable for solvolysis or cleavage products. The prodrugs containing such partial groups can be treated with appropriate reagents according to conventional procedures. The acid or hydroxyl group is an isohydroxyl ester compound. The term "π active metabolism product" refers to the pharmacological effect of a specific hydroxamate compound or its salt in the body through metabolism. The product of chemical activity. Inhibitor compounds described herein as prodrugs and active metabolites can be identified using routine techniques known in the art. See, for example, Bertolini et al., MM. 40: 2011-2016 (1997); Shan et al., 乂 / &gt; / ^ Institute · Scl, S6 (7) · 765-767 (1997); Drug Dev. Res ., 34: 220-230 (1995); 13: 224-331 (1984); Bundgaard, "Design of Prodrugs" (Elsevier Press, 1985); Larsen, # 鳢 ## 之 詨 # and genus Use, Drug Design and Development (Krogsgaard-Larsen et al., Harwood University Press, 1991); Dear et al., C / zramaiogr. 5, 748: 281-293 (2000); Spraul et al., J. PhaHnaceuticcdly &amp; Biomedical Analysis, U) (8) · 60U605 (1992) · and Prox et al. 3 (2) · 103-112 (1992). The term "solvate'f" means a pharmaceutically acceptable solvate form of a particular compound, which retains the biological effectiveness of such compounds. Examples of solvates include compounds of the invention, A combination of propanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine. If the inhibitor compound used in the method of the present invention is a base, the desired salt can be made by any suitable method known in the art, Including free bases with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, scaly acid, etc.), or organic acids (such as acetic acid, maleic acid, succinic acid, phenylglycolic acid, trans-but-52 -92051 200424175: Diacid, malonic acid, pyruvate, oxalic acid, glycolic acid, salicylic acid, piperanose: earth acid (^ such as glucuronic acid or galacturonic acid), cardiolic acid (such as citric acid or tartaric acid) ) Amino acid (such as aspartic acid or glutamic acid), aromatic acid "such as aspartic acid or cinnamic acid), continuous acid (such as p-toluene acid or ethanoic acid) treatment. # 右 用 万 ， The inhibitor compound in this Benming method is an acid, and the desired salt can be made by any method known in the art, including the free acid, and ', Organic or organic testing (such as amine (-, grade, secondary or tertiary)), metal chloride or soil metal hydroxide treatment. Illustrative examples of suitable salts include amines derived from amines (such as glycine and arginine), ammonia, primary amines, secondary amines, tertiary amines, and cyclic amines (suspected, ammonium, and ammonium) (Lu Ru acupoint pyridoxine, morpholine, and hexahydropyridine) organic salts, and inorganic salts derived from sodium, ㈡π, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. Inhibition In the case of solid compounds, precursors, precursors, and compounds, wood, salt, or solvates are solid, those skilled in the art should be aware of the differences in the methods of the present invention. Light moon depleted acid ester compounds, prodrugs, carbazepine, and / or compounds can exist in different polymorphs or crystalline forms, and all Qiu Lili + 丄 ^, p are intended to be used in the present invention and specific chemical formulas In addition, the hydroxamate compounds, salts, prodrugs, and solvent blends used in the present invention can be tautomers, all of which are intended to be used herein. The broad scope of the invention. In some cases, it is used in the present invention Agent compounds, salts, prodrugs, and solvates can have an opponent center. When the center of the palm is present, it is possible to use the compound and salt before the salt. Single stereoisomers, racemates, and / or mixtures of adducts and / 92051 -53- 200424175 or diastereomers exist. Yes, such early incorporations and their The mixtures are intended to be in the broad sense of the present invention. Racemization is as clear as the person skilled in the art, and it is clear that the character of the palm isomerization is pure, and the compound is one, which means that it contains at least enough activity. ^^ ―The same character as the pharmacologically pure compound, preferably containing at least a single amount of a single palm isomer, more preferably at least 95% (90% of the hand) structure! ), #. S I 〇〇〇 / is more preferably 97.5% (95% ee), and preferably at least 99% (98% ee). Ugly used in this article to "treat" means to reverse , 缓 #, Inhibit this unless you use the word &lt;, Therapeutic Work &quot; unless otherwise stated, unless Form 6p Taxi ... Unless otherwise specified, it means as just now, slippery and oral therapy. In a preferred embodiment of the present invention, "into the mouth," ,,,,,, or oral or therapeutic operations " It means to reduce the disease state at least in humans. Its second line is relieved by inhibiting the activity of one or more coronavirus 3C insect enzymes. It has not been limited to 3C such as SARS etiology agents. Protease. Representative disease states in the SARS condition include fever, dryness5, dyspnea, headache, blood oxygenation, / immunoglobulin reduction, leprosy (transaminase content, and viral titre initial consonance reduction A method of treating a disease state 'includes the use of one or more compounds of the invention in any conventionally acceptable manner. According to the present invention, Shizhi / J Moxibustion, some preferred embodiments 5 are one or more compounds of the present invention, which are two, two, and two, and are to be burned to mammals, such as human m. Infected by a coronavirus such as Cazhi 92051 -54- 200424175. The present invention also includes a preventive method which comprises administering an effective amount of a compound of the present invention 'or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite or Solvate. According to certain preferred embodiments, an effective amount of one or more compounds of the present invention, or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof, is administered to an agent at the etiology of sars Humans at risk of infection. The preventive method of the present invention includes using one or more compounds of the present invention in any conventionally acceptable manner. Recent evidence indicates that the new coronavirus is a causative agent for SARS. The nucleotide sequence of SARS-associated coronaviruses has also recently been measured and is publicly available. The activity of inhibitor compounds as inhibitors of SARS-associated viral activity can be measured by any suitable method available in the art, including in vivo and in vitro testing. The activity of the compounds of the present invention as inhibitors of coronavirus-like 3C protease activity (such as the 3C protease-like SARS coronavirus) can be measured by any suitable method known to those skilled in the art, including in vivo and in vitro detection. Examples of suitable tests for measurement of activity include the test of detoxification of cell cultures described herein, and the detection of anti-proteases described herein, such as the tests described in Examples 1 to 3. The administration of inhibitor compounds and their pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates can be performed according to any of the accepted modes of administration available to those skilled in the art. Illustrative examples of appropriate modes of administration include oral, nasal, pulmonary, parenteral, topical, transdermal, and rectal. Oral, 92051 -55- 200424175 intravenous and nasal delivery are preferred. S-fiber inhibitors can be a pharmaceutical composition to any suitable medicine. Zhou Dang medicine forms include temple kick L &gt; Zhu Q, semi-solid, liquid or lyophilized formula, chains / tablets, powders, capsules, suppositories, suspensions, microlipids and aerosols. SA formulations can be made into solutions using any of a variety of procedures. For example, the inhibitory inhibitor ^ is dissolved with ^ (e.g., 1MHC1) and diluted with 5% dextrose in L volume (D5W) at a sufficient volume to produce the desired final concentration of the SARS inhibitor (e.g., about 15 mM). Bite, man ancient, provide D5W solution suitable for m 3 with about 15mM HC1 can be used to be made: floating inhibitor solution. Furthermore, inhibitors can be suspended ... for example, using methylcellulose (called it.) Acceptable methods for preparing suitable pharmaceutical forms of pharmaceutical compositions are known and are routinely determined by those skilled in the art. For example, medicinal preparations can be prepared according to the customary techniques of M Pharmacists, which involve some = granulation and compression (when necessary for tablet form), or mixing: filling: the second solution ingredients are obtained 'in an appropriate manner' for oral administration , Parenteral: =, intraocular, ear ... or rectal administration of the pharmaceutical composition 2 years old can also contain appropriate excipients, diluents, vehicles, other, and other pharmaceutical active agents, according to the intended use Acceptable _, diluents, vehicles or excipients on fixed or liquid substrates can be used in such long-le composition. Illustrative solid, clever Α Α Β starch: lining, knitting two Hydrate, white clay, recommended sugar, talc, gelatin, gelatin gum, magnesium stearate and stearic acid. Illustrative liquid carrier, peanut oil m salt solution and water. Carrier or osmium 92051 -56- 200424175 Agents may include a prolonged release, such as monostearate Glycyrrhizine or Fatty Oil or Vinegar, alone or with sacrifice. When liquid carriers are used: Dose μ, emulsion, soft gelatin capsules, sterile injectable liquids | columns such as solutions) or non-aqueous or aqueous liquid suspensions Form. The dosage of the pharmaceutical composition may contain at least a therapeutically effective amount, and is preferably composed of one or more pharmaceutical dosage units. Selected = mammals that can be treated with any of the known or appropriate methods of administration of this dose and administered by a coronavirus-related agent, such as ointments or creams; Mouth: type; rectal method, such as suppositories; parenteral method, by injection. Intravenous method; or continuous intravaginal, intranasal, intratracheal, intraauricular perfusion. When the composition is administered with a cytotoxic drug, it may be administered before, and / or after the introduction of the cytotoxic drug. ^ 'When the composition is introduced with radiotherapy Jiang Yun to start the treatment. ▲, the composition is preferably the terms "therapeutic effective amount" and "effective amount" in radiation, the amount 'when administered to sprayed animals in need of treatment, is sufficient to achieve the right = replication by SARS virus The treatment of the injury or disease state that is alleviated by inhibition ^ such as enhancing anti-cancer therapy, or inhibiting neurotoxicity caused by stroke, head injury and neurodegeneration = disease. The specific circle in the method of the present invention = preparation ' &amp; The therapeutically effective amount varies depending on factors such as ARS inhibitor, disease status and its severity, which requires the mammal's body and characteristics. Its amount can be measured routinely by a technician It should be clear that the actual dosage of the proposed inhibitor of the composition «92051 -57- 200424175 in the present invention is based on the nature of the specific agent used, the specific composition formulated, the mode of administration and the specific location, and the treatment The host and symptoms are selected. The most appropriate dose for a particular set of conditions can be determined by those skilled in the art using conventional dosimetry tests. For example, for oral administration, the dose that can be used About 0.001 to about 1000 mg / kg of body weight, preferably about 0.1 to about 100 mg / kg of body weight, and more preferably about 1 to about 50 mg / kg of body weight, accompanied by repeated treatment processes at appropriate intervals. Coronary The protein functions required for viral replication and transcription are encoded by the so-called `` replicase π gene. Two overlapping polyprotein lines have been translated from this gene and are widely processed by viral proteases. The C-proximal region is in eleven The junction between the conserved functional sites is treated by a coronavirus body or a π class 3C &quot; protease. The "class 3C" protease name is derived from some similarities between the coronavirus enzyme and the conventional parvovirus 3C protease. These include qualitative preference, cysteine's use as an active site nucleophile in catalysis, and its similarity to inferred overall peptide folding. The amino acid sequence of the coronavirus-like 3C protease associated with SARS, compared with other known coronaviruses, shows that the amino acid sequence is highly conserved, especially in the catalytically important regions of the protease (Figure 1). The amino acids in the cleavage position of the protease are from N to C-terminus and are numbered as follows: -P3-P2-Pl-Pl'-P2f-P3f, where the cleavage occurs between the P1 and PΓ residues (Schechter &amp; Berger, 1967). Acceptance specificity is mainly determined by the positions of P2, P1, and PΓ. The specificity of the major protease division site of coronaviruses is highly conserved, in which glutamine is required at P1 and small amino acids are required at P1 '(General Journal of Virology 83, pp. 595-599 (2002)). After almost 10 years 5 Pfizer-La Jolla has been engaged in an effort 5 to discover and 92051-58- 200424175, treatment-general v-utility drugs, which are based on rhinovirus 1, master &lt; key enzymes (meaning 3C protease) is the target. Multi-resistance: = blood group <wide range of effective non-toxic agents have been confirmed. These compounds are described in, for example, U.S. Patent No. 6,514,997, &amp; Magic 1 shirt 2 5'962,487. This article is for reference. Recently, Jenfeld and colleagues published the analysis of X-ray and marginal structure of porcine transmissible gastroenteritis coronavirus major protease (EMB0 Journal, Volume I, Section 3.3224 (fiber)). The U department obtained it through the protein information bank under the code 1LVO. In this case, human rhinovirus 3C protease and coronavirus, similar to π &quot; main protease incubation and structural similarity observation, the conclusion was reached that the selected nasal `` protease inhibitors can be used to resist coronavirus main ( Class 3C) protease (Figure 3). : When developing strategies for therapeutically effective serine and cysteine protease suppression, several considerations came into play. For many of these proteins, the 'specific pockets' for identification of substrates (or inhibitors) are shallow, and the cassia seed system is widely dispersed over a large surface area. The inherent difficulties in finding small molecules with high affinity for this binding site are similar in many ways to those encountered in attempts to disrupt protein fB protein interactions with small effector molecules. Serine proteases, such as along factors and thrombin, are involved in the blood coagulation pathway and have a deep and well-defined phantom-specific pocket protein that has been effectively concealed by structurally different small and non-covalent inhibitors. And therefore the exception to this generalization (19). However, 搿 is known to be a virus

In the case of serine and gene deficiency, 6 A and cysteine I proteases are coded by methods, such as serine protease cancer treatment groups, and hepatitis C is responsible for λ.

汴 人 池 3 虫虫 白, parvovirus 3C 92051 -59- 200424175 protease and coronavirus-like 3C protease, qualitative discrimination is modulated by extensive protein B protein interaction, the fact that it means the design of specific inhibitors A significant hindrance. Among them, the peptide receptor that easily cuts off amidine carbonyl is replaced by Michael receptor. It was first introduced by Hanzlik and co-investigators as a unique irreversible inhibitor of cysteine protease papain (20, 21). My reasoning is that although this reaction may be aided by the particularly nucleophilic sulfonium ion pair in the papain-like cysteine protease, the appropriately activated Michael receptor may also be subjected to 3C and 3C-like proteases. It is speculated that there is no nucleophilic catalytic addition of cysteine. The covalent and irreversible inactivation of 0 3C and 3C-like proteases by the Michael receptor is based on a kinetic mechanism that can be divided into two parts. E + I El —► ΕΛ ka inhibitors first form a reversible encounter complex with 3C, and then they can undergo a chemical step (nucleophilic attack by the reactive site Cys), leading to the formation of stable covalent bonds. The second-order rate constant (k ^ s / 1) found with regard to inactivation depends on both the equilibrium binding constant and the chemical rate k3 of covalent bond formation (Meara, JP &amp; Rich, DH (1995) Bioorg Med. CheriL Lett 5, 2277-2282). We expect that Michael receptor inhibitors that are specific for 3C-like proteases, like 3C proteases, may achieve a high enzyme inactivation rate by combining a moderate rate of well-balanced binding and covalent bond formation. The rate of chemical inactivation is speculatively determined not only by the inherent electrophilic properties of the inhibitor, but also by how the 5-reactive ethylenyl group relative to Cys in the reactive position, such as -60- 92051 200424175, is targeted before nucleophilic attack And the extent to which the transition state of the reaction can be stabilized by the enzyme. The intrinsically weak Michael acceptor acts as a mechanism-based activation that increases the rate of chemical steps and is therefore a method of l ^ bs / l, conceptually trying to achieve a similar effect only by increasing intrinsic electrophilic reactivity More attractive because the latter may impart unwanted properties to such compounds. [Embodiment] Examples In the following examples, unless otherwise indicated, all temperatures are presented in degrees Celsius, and all parts and percentages are weight ratios. Reagents can be purchased from commercially available suppliers, such as Sigma Aldrich Chemical Company or Lancaster Synthesis Company, and can be used without further purification unless otherwise indicated. Tetrahydrofuran (THF) and N, N-dimethylformamide (DMF) can be purchased from Aldrich in certain sealed bottles and used as received. All solvents can be purified using standard methods known to those skilled in the art unless otherwise indicated. SARS coronavirus protease inhibitors, as used in the methods of the present invention, can be made as described in U.S. Patent Application Serial Nos. 09/301977 and 09/726376 (Dragovich et al.), Each of which is incorporated in full text This article is for reference. Preferred compounds according to the present invention can be prepared in a manner similar to that detailed below. Example 1-The ability to protect against infectious compounds The ability to protect cells from infection with SARS coronavirus is similar to that of Weislow, .S, Kiser, R, Fine, DL, Bader, J, Shoemaker, RH and Boyd , MR 1989 (A novel soluble formazan test on the effects of HIV-1 cytopathy: the application of high-throughput screening of synthetic and natural products for AIDS antiviral activity, National Cancer Institute Journal 81 (08): 577-586) described in -61- 92051 200424175 cell viability test, using neutral red staining as the endpoint for measurement. Briefly, Vero cells were resuspended in a culture medium or medium containing only the appropriate concentration of compound. Infect cells with SARS-associated viruses, or sham-infect using only media. After one to seven days, neutral red was added to the test plate and cultured at 37 ° C for one hour. The cells were lysed and the amount of neutral red produced was quantified spectrophotometrically at 540 nm. . Data are expressed as a percentage of neutral red produced in compound-treated cells compared to neutral red produced in wells of cells not infected with compounds. The fifty percent effective concentration (EC50) is calculated to increase the percentage of neutral red produced in infected compound-treated cells to 50% of those produced by uninfected cells Compound concentration. The 50% cytotoxic concentration (CC50) is calculated to reduce the percentage of neutral red produced in uninfected cells treated with the compound to a concentration of 50% of the compound produced in uninfected cells without the compound. The therapeutic index is calculated by dividing the cytotoxicity (CC50) by the antiviral activity (EC50). Example 2-Viral Yield Detecting Ability of Compounds to Protect Cells from Infection Prins? SA Fuhrman, JW Meador, LS Zalman, DA Matthews and ST Worland. 1999, In vitro antiviral activity of AG7088, an effective inhibitor of human rhinovirus 3C protease, Antimicrob · Agents and Chemo. Assessed in the virus yield test described above. In short, the 0.2 ml serial ten-fold dilution of SARS-associated virus was adsorbed on 92051 -62- 200424175

Vero cell monolayer. After one hour of adsorption, the cell monolayer was washed twice with PBS and covered with 0.5% Seaplaque agarose (FMC Bioproducts, Rockland, ME). After incubation at 34 ° C for one to seven days, the cell monolayers were fixed with EAF (65% ethanol, 22% acetic acid, and 4% formaldehyde), stained with 1% crystal violet, and virus plaques were calculated. Data are expressed in plaque forming units (PFU) per milliliter. The fifty percent EC50 was calculated to reduce the number of PFU / ml in infected infected cell-treated cells to a compound concentration of 50% of that produced by infected compound-free cells. Example 3-Detection and Analysis of Coronavirus 3C Protease FRET The proteolytic activity of Coronavirus 3C protease was measured using continuous fluorescence resonance energy transfer detection. The substrate DABCYL-GRAVFQGPVG-EDANS was prepared by modification of the core decapeptide (American Peptide System) and purified by C-18 resin (Alltech) by HPLC before use. Other peptide cores are possible and can be derived, for example, from protease cleavage sites in the published SARS coronavirus sequence. Preferred peptides retain the P1 and PΓ amino acids (QG) of the decapeptide described above (the site of proteolytic cleavage). In addition, other fluorescent probe / quencher combinations are possible. This test contains a reaction buffer (50 mM Tris, pH 7.5, 1 mM EDTA), 0.1 to 10 AM substrate, 5 to 50 nM coronavirus 3C protease, 2% DMSO, and inhibitor, as appropriate. DABCYL-EDANS is cleaved by the plasma peptide and is monitored by the appearance of fluorescent emission at 490 nm (after excitation at 336 nm). The data is analyzed by the non-linear regression analysis program Kalidagraph, using the following equation: FU = deviation + (limit) (1-dagger. 1 ^) 1) where the deviation is equal to the fluorescence signal of the undivided peptide substrate, and the limit is Equal to 92051 -63- 200424175 fluorescence of fully split peptide substrates. Kobs is the first-order rate constant of this reaction, and in the absence of any inhibitor, it indicates the utilization by mass. In the enzyme initiation reaction containing an irreversible inhibitor, and when the calculated limit is below 20% of the theoretical maximum limit, the calculated kobs indicates the rate of inactivation of the coronavirus 3C protease. The slope of the kobs to [1] graph (kobs / 1) is a measure of the antibody's antibody affinity for enzymes. For very fast and irreversible inhibitors, kobs / 1 is calculated from observations with only one or two [; 1], not as slope. Example 4-Structure-assisted selection of homosexual models of Michael receptor-based inhibitors of 3C-like protease inhibitors Generated as a template. BLAST was used to confirm the 3C-like protease from the SARS genomic RNA sequence (AY274119). Fewer adjustments to BLAST output will result in alignment with a high percentage of identity and several gaps (Figure 1), and This alignment system was used in Insight2000 (Sanchez and Sali 2000) in the MODELLER suite to generate an isomorphic model. Twelve residues with high structural conservation (Figure 2) are generated by rhinovirus 3C (1CQQ) and TGEV Visual inspection of the 3C-like protease (1LV0) structure and the SARS-like 3C protease homology model was confirmed. The structures were superimposed in a common reference skeleton by making root mean square differences (RMSD) between the atoms of these residues in the main chain ) To a minimum, of which RMSD &lt; 0.6 Angstrom 2. Examination of the structure in the shared reference framework confirms the strong conservation of the side chain configuration of the catalytic cysteine and histidine residues (Figure 3). 92051- 64- 200424175 Modeling and analysis of the electronic and three-dimensional features of the "3Cn protease" coronavirus near the active site of cysteine and adjacent S1 and sr specific pockets of coronaviruses are similar to the closely aligned corresponding features based on the above structural overlap Rhinovirus 3C protease. In Sr-specific pockets, the main chain nitrogens Glyl45 and Cysl47 activate the carbonyl oxygen in AG7088. The order and structural position of these two residues are conserved in the TGEV structure (Glyl42 and Cysl44). In the S1-specific pocket, there are three hydrogen bonds between AG7088 and rhinovirus 3C protease (Figure 4). These three hydrogen-bonding systems are preserved in the SARS model, one of which involves the corresponding His nitrogen in two proteins, while the others are replaced by substitution residues. Regardless of the substitution in the S1 pocket sequence, the solvents of rhinovirus 3C protease and SARS mode easily enter the surface and have considerable consistency in the P1 binding position (Figure 5). In addition, the review of the overlapping structure shows that an inhibitor, such as AG7088, can be all seven hydrogen bonds with the coronavirus π-type 3Cf 'protease at PI, P2, and P3 found for rhinovirus 3C protease (Fig. 4). The structural differences are most advantageous in S3 and S4 pockets, which indicates that the most suitable inhibitors of rhinovirus 3C protease and SARS will differ in this region. Furthermore, S2 specific pockets are more restricted in coronavirus protease, which indicates that inhibitors with side chains smaller than fluoroamphetamine (such as in AG7088) may be preferred. This is consistent with the popularity of Leu in the sequence of many known coronavirus division sites (Hegyi and Ziebuhr 2002). The specificity of the major protease division site of coronavirus is highly conserved, which requires glutamine at P1 and a small amino acid at P1 '(Hegyi and Ziebuhr 2002). The parvovirus 3C protease also favors split positions with pivalate at P1 and either Gly or Ala at PΓ. The above structure -65- 92051 200424175 structural overlap shows how the two proteins are constructed in their individual S4 specific pockets, which are quite different. The polypeptide chain cycle that forms S4 is also positioned differently relative to SI, S2, and S3 in the two viral proteases. Modeling analysis leads to the following suggestions for inhibitors: 1. Inhibitors based on Michael receptors with appropriate specificity should be based on compounds containing methyl and ethyl esters to covalently make coronaviruses. 3C "protease inactivation. 2. Select a compound with a donkey amine or inner donkey amine side chain at pi. 3. Select compounds with different substituents at P2, including phe, but also smaller side chains, such as leu and val. 4. Broad broad variability should be acceptable at P3, because the position of this side chain is completely accessible to the solvent. The size and elasticity of the configuration at P4 may be important. Based on model making, smaller may be larger and better. Includes analogs containing thiocarbamates. SARS protease inhibitor compounds containing Michael receptors were selected based on the above qualitative criteria. Alternatively, we can also park available compounds to an isotropic model like SARS protease. This model can be constructed using the known structure of the proteases of coronal disease and the gene sequence of the "3c" class 3 protease of SARS virus. Example 5-SARS protease Michae 丨 receptor-based inhibitors with the standard Michael receptor-based inhibitors discussed above using the protease and antiviral assays described in Examples 1-3 above Detection. The following compounds were identified as SARS-associated virus-like protease inhibitors 92051 -66- 200424175. Table 1 below provides examples of inhibitor compounds that can be used as SARS-related 3C protease inhibitors. However, the present invention is not limited to these specific examples. Table 1 No.Molecular structure

Chemical nameMolecular formula Ethyl hexano-2-hexanoate molecular weight 482.534 2

6-Aminomethyl-4--4-[[] 2- [3- (2,2-dimethylpropanyl C28 H36 N4 06 amino) -2-keto-2H-pyridin-1-yl] 3-Phenylpropionylamino} -hex-2-enoate 524.614 3

% 4- [2- (3-Fluorocarbonylamino-4-methyl-2-keto-2H- C32 H36 N4 07-based) -3 -phenylpropylaminoamino-6-aminomethylamino Ethyl hexanoate 588.657 4

4- [2- (3-benzyloxycarbonylamino-2-keto-2H-pyridine-1-C31 H40N4O7 group) -3-cyclohexyl-propanylamino] -6-aminomethylamidino-hexyl Ethyl-2-enoate 580.678 6

6-Aminomethyl-4- (2- {4-methyl-3-[(5-methyl-isofluorenyl C29 H33 N5 07 azole-3-carbonyl) -amino] -2-keto-2H -Pyridine-1-yl} -3-phenyl-propanylamino) -hexano-2-associate ethyl 4- [2- (3-fluorenyloxycarbonylamino-2-keto-2H-pyridine Bite-1-C33 H36 N4 07-yl) -3-benzylpropanylamino) -5- (2-§Isopropyltetrahydrop-pyrrol-3-yl) -pent-2-enoic acid ethyl ester 4 -(3- (4-fluorophenyl) -2- {3-[(5-methylisozazol-3- C30 H32 F N5 〇7kisyl) -amino] -2-S isopropyl tiger -1 -yl] -propanylamino) -5- (2-ketotetrahydropyrrole-3-yl) -pent-2-enoate 563.608 600.668 593.609 92051 -67- 200424175 8 9

4- (2- {3-[(5-methylisohumidazole-3-carbonyl) -amino] -2-C25 H31 N5 07 酉 isopropyl-2 Η-ρ ratio -1 -yl} -butyl Aminoamino) -5- (2-fluorenyltetramethylpyridinyl ^ -yl) -pentan-2-associate ethyl ester 4- (2- {3-[(5-methyl-isohumidazole- 3-carbonyl) -amino] -2-C29 H35 N5 〇7 isopropyl-2H-P ratio bite-1 -yl} -pent-4-blockylamino) -5- (2-keto- Tetrahydropyrrole-3-yl) -pentano-2-acid 2,2-dimethyl-propyl ester 513.548 565.623

. (E)-(S) -4-[(S) -3- (3,4-difluoro-phenyl) -2- (3-{[l- C30 H31 F2 N5 〇7 (5-methyl -Isopurazol-3-yl) -formamyl] -amino} -2-keto-2H-pyridin-1-yl) -propanylamino] -5 p-Pyrrol-3-yl) -pentan-2-associd acid g 611.599 11

(EHS) -4-[(S) -2- (3-{[H5 · methyl-isoxazole-3-C28 H37 N5 07 group) -methylamino] -amino} -2-one- 2H-pyridyl) -butynylamino] -5-((S) -2-S isopropyl-tetrachloro p ratio p each-3-yl) -pentan-2-associated acid Methyl-propanone

(E)-(S) -2-methyl-4-[(S) -2- (3-{[l- (5-methylisoC27 H31 N5 〇7 oxazol-3-yl) -formamidine Yl] -amino} -2-keto-2H-pyridine-butyl) -pent-4-alkynylamino] -5-((S) -2-ketotetrazyl) -pentan-2 -Ethyl Acetate (EHS) -4-[(S) -2- (3-{[l- (5-methyl-iso. # Azole-3-C27H31 N507 group) -formamyl] -amino group } -2-keto-2'-pyridin-1-yl) -pent-4-ynylamidoamino] -5-((S) -2-keto-tetrahydropyrrole-3-yl) penta- Isopropyl 2-enoate 537.57 537.57

(E)-(S) -4-[(S) -3- (3,4-difluorophenyl) -2- (3-{[l- C31 H33 F2 N5 〇7 (5-methylisohum Azol-3-yl) -formamyl] -amino} -2-keto-2H-pyridine-1 -yl) -propanylamino] -5-((S) -2-fluorene isopropyl tetra Nitrogen! 17 each 3-yl) -pentan-2-associate isopropyl 625.626

(E)-(S) -4-[(S) -3- (3,4-difluorophenyl) -2- (3 _ {[l- C33 H35 F2 N5 〇7 (5-methylisoxazole -3-yl) -methylamino] -amino} -2-keto-2H-pyridine-1 -yl) -propanylamino] -5-((S) -2-ketotetrahydropyrrole -3-yl) -pentyl-2-pentenoate 651.664 92051 -68- 200424175

(E)-(S; M-[(S)-: 3- (3,4-difluorophenyl) -2- (3-{[l- C34 H37 F2 N5〇7 (5-fluorenyl isoxurin Azol-3-yl) -fluorenyl] -amino} -2-keto-2H-pyridin-1-yl) -propanylamino] -5-((S) -2-fluorene (Gasyl) -Hydroxy-2-tetracarboxylic acid, hexadecanoic acid, 4- [2- (3-{[l- (5-methyl-iso ° o-ase-3-yl) -methyl C30 H35 N5. 7 fluorenyl] -amino} -2-keto-2H-pyridinyl) -pentan-4-blockylamino] -5- (2-fluorenyl-tetraazapyrrol-3-yl) _ Cyclohexylpentanoate 665.69 577.635

(E) -4- [2- (3-{[1-(5-methyl-isoxazol-3-yl) &gt; formamyl] -aminob 2-keto-2H-pyridine-1- ) -Butyridinylamino] -M2-keto-tetrahydropyrrole-3-yl) -pent-2-enoic acid cyclohexyl ester (ΕΜ- [2_ (3 _ {[1-(5_ methyl-isopurazol -3-yl) -methylamino] -amino} -2-keto-2fluorenyl-pyridyl) -butanylamino] -5- (2-keto-tetrahydro ) -Ethyl pentano-2-acetate C29 H37 N5 07 C30 H33 N5 07 567.639 575.619

(EHS) -4-[(S) -2- (3-{[l- (5-methyl-isoxazol-3-C31 H35 N5 07-yl) -methylaminol-aminopyridine 2-one -2H-pyridinyl) -3-phenyl-propanylamino] -5-((S) -2-fluorenyl-tetrahydroexo 17 each-3-yl) -pentan-2-associated Isopropyl acid 6-Aminomethyl-4- (3- (4-Gaphenyl) -2-[(4-Methoxy C28 H31 Cl N4 06 -1H-H 丨 indol-2-carbonyl) -Amine] -Propanylamino} -Hex-2-dilute acid ethyl ester 589.646 555.028 22 ^

6-Aminomethyl-4--4- (3- (4-fluorophenyl) -2-[(4-methoxyC28 H31 F N4 06-111-'^ fruit-2-kisyl)- Amine] -propylamino}}-hex-2-enoate 538.573 92051 -69- 200424175 23

6-Aminomethyl-4--4- (3- (3-fluorophenyl) -2-[(4-methoxyC28 H31 F N4 06-1H-pyridin-2-carbonyl) -amino]- Propionylamino} -hex-2-enoate ethyl 538.573 24

(E)-(S) -4-[(l-fluoren-2-yl-fluorenyl) -amino group] -5- C22 H24 N2 04 ((S) -2-fluorenyl-four-wind ρ ratio 卩(Each-3-yl) -fluoren-2-enoate 380.442 25

4- [2- (3-benzyloxycarbonylamino-2-keto-2H-pyridine small C31 H34 N4 07-yl) -3-phenylpropanylamino] -6-aminomethylaminohex-2 -Ethyl acrylate 574.631 26

4- {2- (4-fluorobenzyl) -6-methyl-5-[(5-fluorenyl isolinate C31 H39 F N4〇7 azole-3-carbonyl) -amino] -4-one Heptylaminoamino group 5-% (2-ketotetrahydropyrrole-3-yl) -pentan-2-acetic acid ethyl ester 598.668 [Simplified illustration] Figure 1 is a translation from the SARS genome (AY274119) and the like The 3C protein is aligned with the sequence of the TGEV-like 3C protease (1LVO) used for the similar model. The position of the first indel was adjusted from BLAST alignment to better reflect multiple alignments of other coronavirus-like 3C proteins (Anand, Palm et al. 2002). 43% of the residues are identical in this alignment. Figure 2 depicts the twelve residues used to overlap the structure of the 3C-like protein, which was confirmed by visual inspection. It includes regions close to catalytic cysteine, catalytic histidine, and structurally conserved broad strands. Figure 3 is a SARS-like 3C protein-70- 92051 200424175 enzyme (atomic colored wire) superimposed on the co-crystal structure of rhinovirus 3C protease (purple metal wire) bound to AG7088 (atomic colored rods). Same sex model. Figure 4 shows the hydrogen bonds between AG7088 and rhinovirus 3C protein enzyme derived from the co-crystal structure (1CQQ), and the corresponding hydrogen bonds between AG7088 and the SARS 3C protease model, when superimposed on the structure of rhinovirus 3C protease. Four of the predicted hydrogen bonds between AG7088 and the SARS 3C protease model have also been found in the co-crystal structure of TGEV (1LVO), in which water or a small molecule of 2-methyl-2,4-pentanediol are substituted Inhibitor. Figure 5 shows that the solvent at the AG7088 binding site in rhinovirus 3C protease crystal structure is easily accessible (Connolly) surface (top panel) and the corresponding surface (bottom panel) in the SARS 3C protease model. Figure 6 shows the percentage (%) identity among 3C proteases of coronavirus, including SARS (AY274119), MHV: mouse hepatitis virus (M55148), BCoV: bovine coronavirus (Q8V440), PEDV: porcine epidemic diarrhea virus (Q91AV2) , FIPV: feline infectious peritonitis virus (Q98VG9), TGEV: infectious gastroenteritis virus (Q91W05), HCoV: human coronavirus 229E (Q9DLNO), AIBV: avian infectious bronchitis virus (M95169). Figure 7 depicts a germline tree of coronavirus 3C protease. Figure 8 shows the molecular model of compound 1 in the binding site of the SARS-like 3C protease. Figure 9 shows the molecular model of compound 2 in the binding site of the SARS-like 3C protease. Figure 10 shows the molecular model of compound 3 in the binding site of the SARS-like 3C protease. Figure 11 shows the molecular model of compound 4 in the binding position of the SARS-like 3C protease 92051-71-200424175. Figure 12 shows the molecular model of compound 5 in the binding position of SARS class 3C protease. Figure 13 shows the molecular model of compound 6 in the binding position of SARS class 3C protease. Figure 14 shows the compound 7 in the binding position of SARS class 3C protease. Molecular model. Figure 15 shows the molecular model of compound 8 in the binding position of SARS class 3C protease. Figure 16 shows the molecular model of compound 9 in the binding position of SARS class 3C protease. Figure 17 shows compound 10 in the binding position of SARS class 3C protease. Molecular model. Fig. 18 is a molecular model of compound 11 in the binding position of SARS-like 3C protease. Fig. 19 is a molecular model of compound 12 in the binding position of SARS-like 3C protease. Fig. 20 is a molecular model of compound 13 in the binding position of SARS-like 3C protease. Fig. 21 is a molecular model of compound 14 in the binding position of SARS-like 3C protease. Fig. 22 is a molecular model of compound 15 in the binding position of SARS-like 3C protease. Figure 23 shows a model 92051 -72- 200424175 of the compound 16 in the binding site of the SARS-like 3C protease. Figure 24 is a molecular model of compound 17 in the binding site of the SARS-like 3C protease. Figure 25 is a molecular model of compound 18 in the binding site of the SARS-like 3C protease. Fig. 26 is a molecular model of compound 19 in the binding position of SARS-like 3C protease. Figure 27 is a molecular model of compound 20 in the binding site of the SARS-like 3C protease. Fig. 28 is a molecular model of compound 21 in the binding position of SARS-like 3C protease. Figure 29 is a molecular model of compound 22 in the binding site of the SARS-like 3C protease. Fig. 30 is a molecular model of compound 23 in the binding position of SARS-like 3C protease. Figure 31 is a molecular model of compound 24 in the binding site of the SARS-like 3C protease. Figure 32 is a molecular model of compound 25 in the binding site of the SARS-like 3C protease. Fig. 33 is a molecular model of compound 26 in the binding position of SARS-like 3C protease. Although the present invention has been described in terms of various preferred embodiments and special examples, it should be understood that the present invention is not limited by the foregoing detailed description, but is limited only by the scope of the attached patent application and its equivalent Define. -73- 92051

Claims (1)

^^ 175 Patent application park: • A method that interferes with or prevents the viral replication activity of SARS-associated coronaviruses, which includes contacting a SARS-associated coronavirus protease with a therapeutically effective amount of a rhabdovirus 3C protease inhibitor. The method according to item 1 of the scope of patent application, wherein the inhibitor is administered orally, intravenously or by inhalation. 3 • A pharmaceutical composition for treating SARS-associated coronavirus in a mammal ', comprising a quantity of rhinovirus inhibitors effective in treating SARS-associated coronavirus, and a pharmaceutically acceptable carrier. 4. The method according to item 1 of the scope of patent application, which uses an inhibitor of formula I: Where M is 0 or S; &amp; is Η, F, alkyl, Η, SH or 0 · alkyl; R2 and R5 are independently selected from Η, Or alkyl, where the alkyl is different 々ΓΒι Di with the proviso that at least one of R2 or R5 must be D, or k, 92051 200424175, and when &amp; or R5 is the following group, f, fBl D], X is = CH or = CF , And or = CF, or X forms a three-membered ring with y and 卩 ′, where Q is _C (Ri〇) (Rn)-or -Ο- 'X is -CH · or -CF-, and Yi is -CH_, -CF-, or -C (alkyl group> 'its center 0 and &amp; 1 are independently Η, ι 素 or alkyl, or together with the carbon atom to which they are attached to form a cycloalkyl group Or heterocycloalkyl, or X is -CH2-, -CF2-, · 〇 ^ or _8_, sYi.-O -'- S -'- NRu-, -c (r13) (r14)-, -c (o) ..._ qS) ^-c (CRi3Ri4) _, whose center 2 is fluorene or alkyl, and Ri3 and Ri4 are independently H, F, or alkyl, or form a cycloalkyl group together with the atoms they are combined with Or heterocycloalkyl; Ai is C, CH, CF, S, p, Se, n, NR! 5, S (0), Se (O), P-OR15aP-NR15R16, where R15 and 6 are independently Alkyl, cycloalkyl, heterocycloalkyl, square or heteroaryl, or together with the atoms to which they are bound to form a heterocycloalkyl; Di is an unshared electron having a hydrogen bond Partial groups; and Bι is Η, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -〇R17, -SR17, _nr17Ri8, -NRi9NR port Ri8, or · NRi7〇Ri8 , Wherein R17, Rls, and R19 are independently fluorene, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or fluorenyl; and with the proviso that when Di is an unsubstituted hydrogen bond When shared electricity 92051 -2- 200424175 partial group DN of the sub-pair, 3 is not present; and when ~ is 叩 3 carbon, D! Is a partial group with unshared electron pair capable of forming hydrogen bond _ NR25R26, B! Is not -NR17R18, where r25 and r26 are independently 11, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and where D! -Αι -Βι is formed as appropriate Nitro, where eight is n; and wherein, when &amp; or R5 is the following group, X is = CH or = CF, and Υ2 is, = CH or = CF, or X is formed together with Y # Q ' Three-membered ring, where Q is -c (Ri〇) (r &quot;) _ or -〇-, X is -CH- or -CF_, and y2 is _CH_, _CF_, or _c (alkyl) where Ri Q and Ri i are independently Η, 素 prime or alkynyl, or, and their The attached carbon is pre-formed to form a Wei group or a heterocyclic alkyl group, or X is -CH2-, -CF2-, -CHF- or _s, and γ2 is _〇_, _S, _N (R, 12)- , -C (〇) ·, you'13) (11'14) ... c⑻ or c (cr, i3r, ") _, where R, 12 is H, alkyl, cycloalkyl, heterocycloalkyl, aromatic Heterowanyl_〇Rl3, -NR, 13R, 14, -C (0) -R'13, _s〇2R'13 or C (S) R i3 and R13 and R '! 4 are independently H and alkane A cycloalkyl group, a cycloalkyl group, a heterocyclic alkyl group, an aryl group, or a heteroaryl group, or together with the atom to which they are attached, form a cycloalkyl group or a heterocyclic group; 2 is C CH, CF, S, P, Se, N, NR15, s (0), Se (0), P_〇Ri 5 or P-NRi 5 Ri 6, where r15 and r16 are independently alkyl, cycloalkyl, heterocycloalkyl, aryl or Heteroaryl 'or together with the atoms to which they are bound forms hetero92051 200424175 cycloalkyl; 〇2 is a partial group having an unshared electron pair capable of forming a hydrogen bond; and B2 is fluorene, F, alkyl, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR17, -SR17, -NR17r18, _1919 171118 or -NR17〇R18, where Ri7, R! 8 and Ri9 are independent Cycloalkyl , Heterocycloalkyl, aryl, heteroaryl, or fluorenyl; and further wherein any combination of A, A2, and D2, as appropriate, may form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; &amp; Independent from the heart is Η, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -c (o) r17, -Rl7, _SRi7, _NRi7Ri8, _NRl9NRi7Ri8 or _nr17or18, which Center 7, is independently fluorene, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or fluorenyl; or &amp; together with the heart and the carbon atom to which they are attached, forms a cycloalkyl or hetero Cycloalkyl; hydrazone, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -sr17, _nr17r18, as shown in 19 or 17 or i7Ri8, where R17, chi and Rule 9 is independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or fluorenyl; or%, together with I or Xin, and the atoms to which they are attached form a heterocycloalkane ^ Rm is Η, 〇Η or any suitable organic moiety; and Z and ZJ are independently Η, F, alkyl, cycloalkyl, heterocycloalkyl, aryl ^ &gt; -C (0) R2l &gt; -C02R21 ^ _CN ^ -C (〇) NR2iR 22 ^ 92051 -4- 200424175 -c (o) nr2 i or2 2, -c (s) r2 i, -c (s) nr2! R2 2, -no2, -sor2 i, -so2 r2!, -S02NR2iR22, -SO (NR21) (OR22), -SONR2i, -S03R21, -PO (OR21) 2, -PO (R21) (R22), -P0 (NR21R22) (0R23), PO (NR2iR22)-(NR23R24),- C (0) NR21NR22R24-C (S) NR21NR22R23, where R21, R22, R23, and R24 are independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fluorenyl, or sulfanyl , Or any two of R2 1, R2 2, R2 3, and R2 4 together with the atoms to which they are bonded form a heterocyclic alkyl; or Zi as defined above and &amp; as defined above, and Zι and Ri The bonded atoms' together form a cycloalkyl or heterocycloalkyl group, or Z as defined above, together with Zl and their bonded atoms together form a cycloalkyl or heterocycloalkyl group; or it is musically acceptable Prodrug, salt, active metabolite or solvate; and wherein the compound or a pharmaceutically acceptable prodrug, salt, active metabolite or solvate thereof has anti-coronal virus activity in HI_HeLa cell culture assay , With ECSG less than or equal to 10 # M. 5. According to the method of applying for a patent | item a around item i, which uses a π rhinovirus inhibitor: Its center is ... 92051 (II), 200424175 Or a pharmaceutically acceptable salt, solvate, prodrug or pharmaceutically active metabolite thereof. 6. The method according to item 1 of the scope of patent application, which uses a rhinovirus inhibitor of formula IIB: R3〇NH2 (iib) R1 () is H or CH3; R20 is Η, OH, CH2OH or OCH2Ph; -6- 92051 200424175 R30 is Η, OH or OH2Ph; R40 is Η or CN; and R50 is CH2 CH3 , CH3, CH2 Ph, CH2 CH2 Ph, CH2 CH2 OH, or CH2 (2-pyridyl); or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolism product thereof. 7. The method according to item 1 of the scope of patent application, which utilizes a He rhinovirus inhibitor: nh2 (丨 lc) where R100 is CH3, phenyl, Ph (4-NCH3), Ph (4-〇CH3), κ-pyridyl or 2-furanyl; or a musically acceptable salt, solvate , Prodrugs or pharmaceutically active metabolites. • According to the method of item 丨 of the patent application, which is based on the use of rhinovirus suppression 92051 200424175 where: Ral is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, provided that Ra 1 is not a substituted tetrahydropyhalyl, wherein cycloalkyl, heterocycloalkyl, aromatic Or aryl is unsubstituted or substituted with one or more appropriate substituents; RC is a substituent having the formula: Where: ^ and each independently represent Η or a lower alkyl group; m is 0 or 1; P is an integer from 0 to 5; and CH or N; when P is 1, 2, 3, 4, or 5, A2 C (Rh) (Ri), N (Rj), S, S (O), S (0) 2 or 0, and when p * 〇, N (Ri) (Rj), SCR1), S⑼ ( Ri), s (0) 2 (Ri), or 〇 (Ri), where each of Rh, Ri, and Rj is H or a low-carbon base; each of the existing 3 systems is independently C (Rh) (Ri ), N (Rj), S, S (O), S (0) 2 or 0; wherein each of Rh, Ri and Rj is independently H or lower alkyl; when? When 1, 2, 3, 4 or 5, enter 4 as &gt; 1 (1 ^), (: (1111) (111) or 0; and when p is 0, A4 is NCRkXR1), C (Rh) (Ri) (Rj) and 〇 (Ri), where each of Rh, Ri and Rj is independently Η or lower alkyl, each protects as! ·! , Alkyl, aryl, or fluorenyl, and each Ri is fluorene, alkyl, or aryl; 92051 200424175 provided that no more than two heteroatoms appear consecutively as described above by \, (A2) m, (A3) In the ring formed by p, A4, and 00, the dotted lines in the soil, when A is present, ^ depicts a single bond, and when eight 2 is not present, it is a hydrogen atom; Rd is Η, halogen , Hydroxy or alkyl, alkoxy or alkylthio, wherein alkyl, alkoxy or alkylthio is unsubstituted or substituted with one or more appropriate substituents; i Rb is fluorene or alkyl, unsubstituted Substituted or substituted by one or more appropriate substituents I; Z and Z1 are each independently fluorene, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl , Heterocycloalkyl, aryl or heteroaryl is unsubstituted or substituted with one or more appropriate substituents, -C (0) Rn-C02Rn-CN, -C (0) NRnR. , -C (0) NRn0R °, -C (S) Rn, -C (S) ORn_C (S) NRnR0, -C (= NRn) R0, _C (= NRn) OR0, -N02, -SOR0, -S02Rn , -S02NRnR. , -S02 (NRn) (0R.), -SONRn, -S03Rn, -PO (ORn) 2, _PO (ORn) (OR.), -P0 (NRn R.) (ORP), -PO (NRn R. ) (NRP Rq) #, -C (0) NRnNR ° RP, -Q ^ NRnNRORP, where Rn, R. , RP and Rq are each independently H or an alkyl group, a cycloalkyl group, an aryl group, a heterocycloalkyl group, a fluorenyl group, or a sulfur β fluorenyl group, wherein the alkyl group, a cycloalkyl group, an aryl group, a heterocycloalkyl group, and a fluorenyl group Or Thio is unsubstituted, or substituted with one or more appropriate substituents, or any two of Rn, RQ, RP, and R5 are used together with their combined atoms to form a heterocycloalkyl group, which can be visualized In the case of substitution, or Z and Rd and their combined atoms together form a cycloalkyl or heterocycloalkyl, where Z and Rd are as defined above, but can not form a cycloalkyl or 92051 -9-424175 heterocycle Except for some of the alkyl groups, or Z and Z1 and their combination — $ 予 together to form a cycloalkyl or heterocycloalkyl, where both Z and Z1 are as above and afflicted with me (but can not Except for some groups that form cycloalkyl or heterocycloalkyl); or its prodrugs, pharmacologically acceptable a, sapwood, etc., sparsely salt, pharmaceutically active metabolites, or pharmaceutically acceptable solvents Thing. 9. The method according to the scope of application for patent β, which is a utilization type of rhinovirus inhibitor: Where: Ra2 is alkyl, aryl or heteroaryl, wherein alkyl, aryl or heteroaryl is unsubstituted or substituted with one or more appropriate substituents; and is a substituent having the formula: Where: 圮 and silicon are each independently Η or a lower alkyl group; ηι is 0 or 1; P is an integer from 0 to 5; Ai is CH or N; when 卩 is 1, 2, 3, 4, or 5, eight 2 is 〇 (1 ^) 0 ^ 1), called 11 ″), 3 92051 • 10- 200424175 S (0) S (0) 2 or 0 'and when 卩 is ^, it is coffee) times) (such as) , N (Ri) (Rj) S (R) S (0) (R), s (〇) 2 (R1), or 〇 (Ri), where each of Rh, Ri and Rj is independently H or a low-carbon alkyl ; Each A3 is independently C (Rh) (Ri), N (Rj), S, S (O), S (0) 2 or 0; where each Rh, RtRj is independently H or lower alkyl ; _ When p is 1, 2, 3, 4 or 5, a4 is N (Rk), C (Rh) (Ri) or 0; and when ρ is 0 'A * is N (Rk) (Ri) , Q ^ XRiXRj) and 〇 (Ri), where 'each Rh, R1 and RJ are independently H or lower alkyl, each is H, alkyl, onium aryl or acid group' and each Ri is Η, alkyl Or aryl; provided that 'no more than two heteroatoms appear consecutively in the ring formed by Ai, (eight 2) m, (A;) ρ, eight 4 and C = 0, where Each dashed line in the ring depicts a single bond when A2 exists, and when a2 does not exist Is a hydrogen atom; Rd is halogen, hydroxy or alkyl, alkoxy, or alkylthio, wherein fluorenyl, alkoxy, or alkylthio is unsubstituted or substituted with one or more appropriate substituents; Rb is fluorene or alkyl, unsubstituted or substituted with one or more appropriate substituents; each of Z and Z1 is independently fluorene, F, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl , Where alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is unsubstituted or substituted with one or more appropriate substituents, • C (0) Rn-C02Rn-CN, -C ( 0) NRnR0, -C (0) NRn0R0, -C (S) Rn, -C (S) ORn-C (S) NRnR °, -C (= NRn) R0, -C (= NRn) OR〇 ' -N02, -SOR0, -S02Rn, -S02NRnR. , _S02 (NRn) (0R.), -S0NRn, -S03Rn, 92051 -11- 200424175 -PO (ORn) 2, -PO (ORn) (OR.), -P〇 (NW) (〇Rp), _p 〇 (NRn R.) (Qing Rq), -C (0) NRnNR〇Rp, -C (S) NRnNR〇RP, where Rn, ro, rp, and each JL are H or alkyl, cycloalkyl, Aryl, heterocycloalkyl, fluorenyl, or thiofluorenyl, wherein alkyl, cycloalkyl, aryl, heterocycloalkyl, fluorenyl, or thiosulfanyl are unsubstituted, or are appropriately substituted with one or more Group substitution, or any two of R, R, RP, and Rq are used together with their combined atoms to form a heterocycloalkyl group, which may be substituted, as appropriate, or Z is formed with Rd and their combined atoms Cycloalkyl or heterocycloalkyl, in which Z and Rd are as defined above, except for some groups that cannot form cycloalkyl or heterocycloalkyl, or Z is formed together with Z1 and the atoms to which they are bound Cycloalkyl or heterocycloalkyl, where Z and Z1 are as defined above (except for some groups that are not capable of forming cycloalkyl or heterocycloalkyl); Salt, medicinal active metabolite or drug The acceptable solvates. 10. The method according to item 1 of the scope of patent application, which uses SIIIB rhinovirus inhibitors: Where: Ra3 is aryl, heterocycloalkyl, heteroaryl or arylaminocarbonyl, wherein aryl, heterocycloalkyl, heteroaryl or arylaminocarbonyl is unsubstituted, or is suitably substituted by one or more Substituent substitution; and -12- 92051 200424175 Rc is a substituent having the formula: Where: Rf and sand are each independently Η or a lower alkyl group m is 0 or 1; P is an integer from 0 to 5; \ is CH or N; when P is 1, 2, 3, 4 or 5, A2 is C (Rh) (Ri), N (Rj), S, S (〇), S (0) 2 or 0, and when p is 0, a is c (Rh) (Ri) (Rj), N (Ri) (Rj), MR1), SCOXR1), s (〇) 2 (Ri), or 〇 (Ri), wherein each of Rh, 圮, and ^ is independently H or a low-carbon alkyl; each of the A3 series present Independently C (Rh) (Ri), N (Rj), S, S (O), S (0) 2 or 0; wherein each of Rh, Ri and Rj is independently H or lower alkyl; when P is When 1, 2, 3, 4 or 5, A4 is N (Rk), or 0 'and when p is 0' A4 is N (Rk) (Rl), c (Rh) (Ri) (Rj), and 〇 Milk, in which RR and RJ are independently H or low-carbon alkyl, each of which is h, alkyl, aryl, or fluorenyl, and each R1 is H, alkyl or aryl; b ... "1, &lt;% ,,, and Bema Gondu once again said that in the ring formed by \, (A2) m, (Α3) ρ, α4, and c = 0, which = each dotted line in the ring, When A2 is present, it is a single bond, and when A is present, it is a hydrogen atom; Carbooxy or alkylthio, whose Rd is fluorene and halogen Hydroxyl or fluorenyl group 92051 -13- 200424175 The middle, oxy or thiol group is unsubstituted or substituted with one or more appropriate substituents; Rb is fluorenyl or carbyl group, unsubstituted or substituted with one or more Substituted by a suitable substituent; Re is fluorene, halogen, hydroxy or alkyl, alkoxy or alkylthio, wherein alkyl, alkoxy or alkylthio is unsubstituted or substituted by one or more suitable substituents Substitution; Z and Z1 are each independently Y, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl Is unsubstituted or substituted with one or more appropriate substituents, -C (0) Rn-C02Rn-CN, -C (0) NRnR0, -C (0) NRn0R0, -C (S) Rn, _C ( S) 0Rn-C (S) NRnR0, -C (= NRn) R0, -C (= NRn) 0R0, -N02, -S0R0, -S02Rn, _S02NRnR., -S02 (NRn) (0R.), -SONRn , -S03Rn, -PO (ORn) 2, -PO (ORn) (OF °), _PO (NRnR〇) (ORP), -PO (NRnR〇) (NRPRq), -C (0) NRnNR ° RP,- C (S) NRnNR ° RP, where Rn, R., RP, and F5 are each independently H or alkyl, cycloalkyl, aryl, heterocycloalkyl, fluorenyl, or sulfanyl, wherein alkyl, Cycloalkyl, aryl, heterocycloalkyl, fluorenyl, or thiofluorenyl are unsubstituted or substituted with one or more appropriate substituents, or any two of Rn, R °, RP, and Rq, and others The combined atoms are used together to form a heterocycloalkyl, which may be substituted, or Z and Rd and their combined atoms together form a cycloalkyl or heterocycloalkyl, where both Z and Rd are as defined above, Except for those groups which are not capable of forming a cycloalkyl or heterocycloalkyl group, or Z and Z1 together with the atoms to which they are bonded form a cycloalkyl or heterocyclic ring. 14- 92051 200424175 fluorenyl, where z and z1 All are as defined above (except for some groups of heterocycloalkyl); $ can form cycloalkyl or its prodrug, pharmaceutically acceptable salt product or pharmaceutically acceptable solvate. Pharmaceutical activity Xinchen 11_ Method according to item i of the patent application Ra4 is aryloxy, heteroaryloxy, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryl, cycloalkyl or heteroaryl, of which aryloxy, heteroaryloxy , Alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryl, cycloalkyl, or heteroaryl are unsubstituted or substituted with one or more appropriate substituents; and Rc has the formula The substituent: Where: Rf and Rg are each independently fluorene or a lower alkyl group; m is 0 or 1; P is an integer from 0 to 5; A is CH or N; 92051 -15- 200424175 Tian Wei, 3, 4 or 5 hours , A2 is C (Rh) (Ri), N (Rj), S, s (0) S (〇) 2, or 0 ′, and when P is 0, A ^ QRhXRiXRj), N (Ri) (Rj), S (R1), S (〇) (R1), S (〇) 2 (Ri), or 0 times), wherein each of Rh, Ri, and Rj is independently H or a low-carbon alkyl group; each existing A3 is independently C (Rh) (Ri), N (Rj), s, S (O), S (0) 2 or 0, wherein each of Rh, 圮 and Rj is independently H or lower alkyl; when P is 1, At 2, 3, 4 or 5, A4 is N (Rk), C (Rh) (Ri) or 0 ′ and when p is 0, A4 is N ^ XR1), C (Rh) (Ri) (Rj) And 0 (111), wherein each of Rh, R1, and RJ is independently fluorene or lower alkyl, each Rk is η, alkyl, aryl, or fluorenyl, and each Ri is fluorene, alkyl, or aryl; Provided that 'no more than two heteroatoms appear consecutively in the ring formed by A !, (A2) m, (A3) ρ, α4, and c = 0, where each dotted line in the ring When A2 is present, it is a single bond, and when it is not, it is a hydrogen atom. Rd is fluorene, halogen, hydroxy or alkyl, alkoxy or alkylthio, wherein fluorenyl, alkoxy or alkylthio is unsubstituted or substituted with one or more appropriate substituents; Rb is fluorene or Alkyl, unsubstituted or substituted with one or more appropriate substituents; Re is fluorene, autogen, hydroxy or alkyl, alkoxy, or alkylthio, wherein the radical, oxy, or alkylthio is unsubstituted Substituted, or substituted by one or more appropriate substituents; Z and each independently are η, F, fluorenyl, cycloalkyl, heterocycloalkyl, aryl or androstyl 'wherein alkyl, cycloalkyl, hetero Marginal fe, aryl or hetero92051 -16- 200424175 aryl is unsubstituted or substituted with one or more appropriate substituents, -C (0) Rn-C〇2Rn-CN, -C (0) NRnR . , -C (0) NRn0R. , -C (S) Rn, -C (S) ORn-C (S) NRnR0, -C (= NRn) R0, -C (= NRn) OR0, -N02, -SOR0, -S02Rn, -S02NRnR °, -S02 (NRn) (0R °), -S0NRn, -S03Rn, P0 (0Rn) 2, -P0 (0Rn) (0R °), -P0 (NRnR °) (0RP), -P0 (NRnR °) (NRP R5), -C (0) NRnNR ° RP, -C (S) NRnNR0RP, among which Rn, R. , RP and each independently H or alkyl, cycloalkyl, aryl, heterocycloalkyl, fluorenyl, or sulfanyl, wherein alkyl, cycloalkyl, aryl, heterocycloalkyl, fluorenyl, or sulfur The fluorenyl group is unsubstituted, or substituted with one or more appropriate substituents, or any two of Rn, R °, RP, and RQ are used together with the atoms to which they are combined to form a heterocycloalkyl group, as the case may be After substitution, or Z and Rd and their combined atoms together form a cycloalkyl or heterocycloalkyl, where Z and Rd are as defined above, but cannot form part of a cycloalkyl or heterocycloalkyl Except for the group, or Z and Z1 and the atoms to which they are bound form a cycloalkyl or heterocycloalkyl, wherein Z and Z1 are as defined above (but can not form part of a cycloalkyl or heterocycloalkyl group) Except for the group); or its prodrugs, pharmaceutically acceptable salts, pharmaceutically active metabolites, or pharmaceutically acceptable solvates. 12. The method according to item 1 of the scope of patent application, which is inhibited by rhinovirus of formula IV! 1 · 92051 -17- 200424175 where: Y is Na &gt;, y) (Ry &gt; or 〇_, where each Ry is independently a lower alkyl group; Ri is Η, F, alkyl, OH, SH or 〇 _Alkyl; (Α3) η h and &amp; each independently is η; '\ ^ νη2 · formula,' (~) (~) 'where η is an integer of 0 to 5, A ^ 〇 ^ N, A2 ^ A3 „Ai ^ c (R4iXR4i), ^^, ^, ah, and ... and ~ is Yang or ~ where each heart" is independently Η or lower alkyl, provided that no more than one heteroatom appears continuously in the borrow In a ring formed by Al, α2, (α3) η, α4, and c = 0; 0 and the condition is that at least one of R2 and &amp; is \, ^ Λνη: h and% are each independently Η, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and Rs are each independently fluorene, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterosquare, -〇R17, -SR17, -NR17R18, or NR17〇R18, where r17, r18, and r19 are each independently H , Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or fluorenyl; R9 is a five-membered heterocyclic ring having one to three heteroatoms selected from 0, N &amp; S, or R9 is Where R2 is? 1) (~) and 92051 -18- 200424175 Z and Zi are each independently fluorene, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C (0) R21, -C02Rn , -CN, -c (o) nr21r22, -C (0) NR2 i OR2 2, -C (S) R2 i, -C (S) NR2 i R2 2, -N02, -SOR2 i, -S02 R2 i , -S02NR2iR22, -SO (NR21) (OR22), -SONR21, -S03Rn, -PO (OR21) 2, -PO (R21) (R22), -P〇 (NR21R22) (〇R23), p〇 (NR21r22 )-(nr23r24), -c (o) nr21nr22r23 or · c (S) NR21NR22R23, where r21, R22, R23 and R24 are each independently η, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl Group, fluorenyl or thiofluorenyl, or any two of r21, r22, R23, and R24 together with the atoms to which they are bonded form a heterocycloalkyl group, provided that Z and Z! Are not both Η; or Z! Together with R! And the atoms to which they are bound to form a cycloalkyl or heterocycloalkyl group; or Z together with the atoms to which they are bound to form a cycloalkyl or heterocycloalkyl group; or their prodrugs, pharmaceutical activities Metabolites, pharmaceutically acceptable salts or solvates. 13_ The method according to item 丨 of the patent application, which is a viral inhibitor: Where: Y is -N (Ry)-, (howl or · 〇_, where each Ry is independently H or lower 92051 -19- 200424175 carboalkyl; R1 is selected from the optionally substituted alkyl, ring Alkyl, heterocycloalkyl, aryl, heteroaryl and &lt; (〇) ί ^ 6, wherein R1 6 is selected from optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, Heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, and amine; R2 and R8 are each independently selected from Η, F, and optionally substituted alkyl, Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R3 and R9 are each independently selected from Η and optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,- ORl 7, _SR1 7, -NR1 7 R1 8, • NR19NR17R18 &amp; _NR170R18, where R &quot;, R18, and R19 are each independently selected from fluorene, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and fluorene R4 is an appropriate organic moiety; each of R5, R6 and R7 is independently a fluorene or lower alkyl; m is 0 or 1; P is 0, 1, 2, 3, 4 or 5; Aj is CH Or N; when m is 1, A2 is selected from C (R10) (RU), N (R12), S, S (O), S (0) 2, and 0; when P is not 0, each of the 8 series is independently selected from C (R1G) (Rn), N (R12), S, S (O), 8 (0) 2 and 0; where Rio, Ru, and Ri2 are each independently η or lower alkyl; when P is not 0, A4 is selected from N (R13), C (R1G) (Rn), and 0, and when ρ is At 0, A4 is selected from n (R13) (R14), C (R10) (Rn) (R12), and 0 (R14), provided that when 8 is 0, Al is not CH; where R1 〇, Rll and R12 are each independently fluorene or lower alkyl, R13 is fluorene, alkyl, aryl or fluorenyl 92051 -20- 424175 ', and R14 is fluorene, alkyl or aryl; (A2) m, (A3) P, and A4 together do not contain more than two consecutive heteroatoms; or their prodrugs, pharmaceutically acceptable salts, pharmaceutically active metabolites, or musically acceptable solvates 14. The method according to item 1 of the scope of the patent application, which uses a rhinovirus inhibitor of formula VI: Where: Ra is carbonylalkyl, cycloalkylcarbonylalkyl, arylcarbonylalkyl, heteroarylcarbonylfluorenyl, alkylcarbonylaminoalkyl, cycloalkylcarbonylaminoalkyl, heterocylic carbonyl Aminoalkyl, arylcarbonylaminoalkyl, heteroarylcarbonylaminoalkyl, alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, heterocycloalkylaminocarbonylalkyl, arylamino Carbonylalkyl, heteroarylaminocarbonylalkyl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl moiety may be unsubstituted or substituted by one or more suitable Substituent substitution; Rb is fluorene or alkyl, unsubstituted or substituted with one or more appropriate substituents; Rd is fluorene, ||, fluorenyl or alkyl, alkoxy or alkylthio, where alkyl , Alkoxy or alkylthio is unsubstituted or substituted with one or more suitable 92051 -21-200424175 substituents; Rc is a partial group having the formula: z'-CReRf Re and Rf are each independently fluorene or low-carbon alkyl; m is 0 or 1, provided that when m is 丨, Ra is not an amine-substituted alkylcarbonylalkyl or amine-substituted alkyl Carbonylaminoalkyl, and when 111 is 0, Ra is selected from alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, heterocycloalkylaminocarbonylalkyl, arylaminocarbonylalkyl, hetero Arylaminocarbonylalkyl and heteroarylcarbonylaminoalkyl, provided that Ra is not a substituted indolecarbonylaminoalkyl; P is an integer from 0 to 5; \ is CH or N; when When 卩 is 1, 2, 3, 4 or 5, eight 2 is (: (1 ^) (1111), wind 1 ^), 8, S (〇), S (〇) 2 or 〇 'and when P is When 0, A2 is C (Rg) (Rh) (Ri), N (Rg) (Ri), S (Rg), S (0) (Rg), S (0) 2 (Rg) or 0 (Rg) Where each Rg, Rh and Ri are independently H or lower alkyl; each existing A3 is independently c (Rg) (Rh), N (Ri), S, S (O), S (0) 2 Or 0 ′ wherein each of Rg, Rh and R is independently h or lower alkyl; when P is 1, 2, 3, 4 or 5, A4 is N (Rj), C (Rg) (Rh), or 0. , And when p is 0, A4 is N (Rj) (Rk), and 0 (Rk), where Rg, Rh And R1 are independently fluorene or lower alkyl, each RJ · is η, alkyl, aryl, or alkynyl, and each RkgH ^ alkyl or aryl; 92051 -22- 200424175 provided that it does not exceed two Heteroatoms appear continuously in the ring formed by A !, (A2) m, (A3) p, A4, and 00 described above, where each dotted line in the ring, when A2 exists, depicts a single bond And when a2 is absent, it is a hydrogen atom; and Z and Z1 are each independently fluorene, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl, Heterocycloalkyl, aryl or heteroaryl is unsubstituted or substituted with one or more suitable substituents, -c (〇) Ri, -C02R1, -CN, -C ^ CONRjR111, -CXCONRJOR111,-. ⑻ 圮,, -C (= NRi) Rm,-. (, 圮 辉 爪, _N ~ ^, -SC ^ R1, -SC ^ NRjR111, -SC ^ CNRiXORm), -SONR1, -SC ^ R1, -POCOR1 ^-^ 0 (0Rl) (0Rm)--PO ^ ^^ XOR11) ^ -PO ^ R1 Rm) (NRnR °), -QC ^ NRjNRmRn, -C ^ NR ^ NRmRn, where R1, RH1, Rn and R0 are each independently H or alkyl, cycloalkyl, aromatic , Heterocycloalkyl, fluorenyl, or thiofluorenyl, wherein alkyl, cycloalkyl, aryl, heterocycloalkyl, fluorenyl, or thiosulfanyl are unsubstituted or substituted with one or more appropriate substituents Replace, or any two of R1, ", 粑, and Han. Use 'to form a heterocycloalkyl with their bonded atoms, which may be substituted, or Z and Rd and their bonded atoms together form a cycloalkyl or heterocycloalkyl, where Z and Rd are as above Wen Ding 4, except for those that are not capable of forming a cyclic group or a heterocycloalkyl group, or Z together with Z1 and the atoms to which they are bonded form a cycloalkyl group or a heterocyclic alkyl group, where both Z and Z1 are As defined above; or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of the compound. 92051 -23- 200424175 It utilizes rhinovirus of formula VIIA 15. Method according to item 1 of the scope of patent application Inhibitors 〇 Rb Z1 R is a ,, di- or unsubstituted heterocycloalkyl or heterocycloalkylalkyl; Rb is a substituent having the formula: (Α3) ρ I (A2) m where: Rf and Rg are independently Η or lower alkyl; p is an integer from 1 to 5;, is CH or N; 8 is C (Rh) (Ri), N (Rj), S, S (O), S (0) 2 or 0; wherein each of Rh, Ri and Rj is independently fluorene or lower alkyl; each existing A3 is independently CXRhXR1), N (Rj ), S, S (O), s (0) 2, or 0; where each of Rh, Ri, and Rj is independently η or lower alkyl; Α4 is N (Rk), C (Rh) (Ri), or 〇 The condition is that no more than two heteroatoms appear consecutively in the ring formed by \, (A2) m, (Α3) ρ, 8 4 and 00, where the ring -24- 92051 200424175 Each dotted line in the figure depicts a single bond; Re is fluorene, halogen, or a substituted or unsubstituted low-carbon alkyl group; Rd is fluorene, halogen, light-based, substituted or unsubstituted alkyl, alkoxy, or Sulfur; Re is fluorene or substituted or unsubstituted alkyl; and Z and Z1 are independently fluorene, F, unsubstituted or substituted alkyl, cycloalkyl, heterocycloalkyl, aryl Or heteroaryl, -C (0) Rn, -C02Rn, -CN ^ -C (0) NRnR ° ^ -C (0) NRn0R ° ^ -C (S) Rn ^ -C (S) ORn ^ -C (S) NRnR ° 、 -N0 2.-SOR0, -S02Rn, -S02NRnR °, -S02 (NRn) (0R °), -SONRn, -S03Rn, _PO (ORn) 2, -PO (ORn) (OR〇), · PO (ΝΚηΕ °) (ΟΙΙΡ), PCXNRnRoXNRPRq), _C (0) NRnNR ° RP, or -C (S) NRnNRQRP, where Rn, RQ, RP, and Rq are independently H, substituted or unsubstituted alkyl, cycloalkyl, An aryl group, a heterocyclic alkyl group, an acid group or an oleic acid group, or any two of Rn, RQ, RP, and Rq together with the atoms to which they are combined to form a heterocycloalkyl group, which may be substituted as appropriate, or Z forms a cycloalkyl or heterocycloalkyl group with Rd and the atom to which they are bound, or Z forms a cycloalkyl or heterocycloalkyl group with Z1 and the atom to which they are bound; or its prodrug, pharmacy A pharmaceutically acceptable salt or a pharmaceutically acceptable solvate. -25- 92051