TW470750B - Reversible cysteine protease inhibitors - Google Patents

Abstract

A compound which is a cysteine protease inhibitor of formula 1, in which: n is 0 to 2; A-B represents a linkage of -C(O)NH-; X represents a bond, methylene or the linkage -CH2CH(R4)-, wherein R4 is hydrogen or C1-4 alkyl; Y is -NH-; Z is -C(R6)(R7)- wherein R6 is hydrogen or methyl and R7 is as defined below; Z1 is -C(R5)(R8)-, wherein R6 is hydrogen or methyl and R8 is as defined below; R1 is morpholinecarbonyl, phenyl-C1-6 alkyl-carbonyl, or C1-6 alkyl-carbonyl wherein the C1-6 alkyl is optionally substituted with carboxyl group or C1-4 alkyl ester of the carboxyl group; R7 is hydrogen, C1-6 alkyl or phenyl- or napthyl-C1-6-alkyl optionally substituted with hydroxyl on the phenyl or rapthyl moiety, R8 is hydrogen, phenyl-C1-6 alkyl, or carboxy-C1-6 alkyl; and R2 is hydrogen, C1-6 alkyl optionally substituted with one or more radicals selected from halo, phenyl, napthyl, phenyl-C1-6 alkyl, or napthyl-C1-6-alkyl; and the pharmaceutically acceptable salts, individual isomers and mixtures of isomers thereof.

Description

470750 Consumption Cooperation by Employees of the Central Procurement Bureau of the Ministry of Economic Affairs, Du printed A7 B7 V. Invention Description (1) Scope of the Invention The present invention relates to a novel reversible protease inhibitor. This inhibitor is selective for cysteine proteases. BACKGROUND OF THE INVENTION Cysteine or thiol proteases contain cysteine residues at the active site responsible for proteolysis. Because cysteine protease is associated with several diseases, including arthritis, muscular dystrophy, inflammation, tumor attack, filamentous nephritis, malaria, and other parasitic infections, it selectively and reversibly disables it This approach provides opportunities for new drug candidates. Refer to, for example, Esser, RE et a 1., Arthritis & Rheumatism (1 9 9 4) 37, 236; Meijers, M.Η.M. et a 1., Agents Actions (1993), 39 (Special Conference Issue), C219; Machleidt, W. et al. MJ, Clin. Exp. Metastasis (1992), 10, 145; Rosenthal, PJ, Wollish, li.S., Palmer, JT, Rasnick, D., J. Clin. I nvestigations (1 99 1), 88, 1467; Baricos, WH et al., Arch. Biochem. Biophys. (1991), 288,468; Thornberry, NA et al., Nature (1992), 356, 768. Rich, Protease Inhibitors (Chapter 4, " Inhibitors of Cysteine Enzymes〃) Elsevier Science Publishers (1986) has described low molecular weight inhibitors of cysteine proteases. These inhibitors include peptide aldehydes, which form hemithioacetic acid with the hemiamidic acid of the protease active site. Refer to, for example, Cheng, H., Keitz, P., and Jones, J. This paper size applies the Chinese National Standard (CNS) A4 specification (21 OX297 mm) — • In I --------- * Order (Please read the precautions on the back before filling this page) -4-470750 A7 B7 V. Description of the Invention (2) B., J. Org .. Chem. (1994), 59,7671. The disadvantage of acids is their in vivo and chemical instability. Aldehydes have been converted to 2, by the Wadsworth-Emmons-Horner modification of the Wit t ig reaction described below, unsaturated esters and < Wadsworth, W. S. Emmous, W. D. (J. Am. Chem.

Soc. (196 1), 83, 1 733) 〇II 4. · EtO-P,

, EWG base

EWG

R

EtO (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs where R = alkyl, aryl, etc. EWG = C00Et, S02Me, etc. α, a mono-unsaturated ester (Hanzlik et al., J. Med. Chem., 27 (6): 7 1 1-7 1 2 (1 984), Thompsοn et al., J. Med. Chem. 29: 104-111 (1986), Liu et al., J. Med. Chem., 35 (6): 1067 (1992) and a '/ S-unsaturated europium (Ding 110111 ~ 8 0 11 et al., The former, 11 \ 1 et al., The former) were tested as inhibitors of two cysteine proteases (xyloprotease and dipeptidylamino-peptidase I (also known as cathepsin C)). However, Thus, a, y3 —unsaturated compounds exhibit poor inhibitory properties when inhibiting papain, which ranges from less than 1M -1 se c-1 to less than γOM- ^ e c- Proof of the secondary rate constant of 1 and · below 2 OM-h e c-1 to below 60 M-1 se c-1. In addition, these chemistries are 2-amine groups other than those corresponding to glycine The size of the acid paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) -5-470750 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (3) Derivatives, or esters, phenyl Alanine has not been confirmed. Therefore, these compounds It does not exist for normal glycine derivatives, but it is not clear for phenylalanine derivatives. This is important because inhibition of enzymes usually requires palm compounds. It has been suggested that 2-amines Sulfosulfonic acid is a potential inhibitory compound. Although its inhibitory effect has not been recorded, several kinds have been prepared (Me 1 1 wa i η et al., J. Chem. Soc. 75 (1941)). In addition, it has been recorded that Mannieh condensation of sulfinic acid, aldehyde, and urethane to form urethane (Engberts Recueil 84: 942 (1965). Other methods that selectively and reversibly inhibit cysteine proteases are peptides 2 —Fluoromethyl ketone (Rasnick, D. Anal. Biochem (1985), 149,416), diazomethyl ketone (Kirschke, Η., Shaw, E. Biochem. Biphys. Tes. Commun (1 98 1), 1 0 1, 454), oxymethyl ketone (Krantz, A. et al., Biochemistry (1991), 30, 4678; Krontz, A. et al., U.S. Patent 5, 0 5 5, 4 5 1, 1 9 9 Proposed on October 8, 2011) and Ketone Tweezer Salts (Walker, B., Shaw, E., Fed. Proc. Fed. Am. Soc. Exp. Biol., (1 985), 44, 1 433 )Alkylation. Other types of cysteine protease inhibitors include epoxy succinic peptides, including £ -6 4 and its homologs (1 ^ 113 (13, 1 (.6 ± & 1., Agric. Biol. Chem ( (1978), 42, 523; Sumiya, S. et al., Chem. Pharnt. Bull. (199.2), 40, 29.9 Gour-Salin, BJ et al., J. Med. Chem., ( 1993), 36, 720), 2-. Order (please read the notes on the back before filling in this page) This paper size applies to China National Standard (CNS) A4 (21 OX 297 mm)-6-470750 Ministry of Economic Affairs Printed by A7 B7, Consumer Cooperatives of the Central Bureau of Standards 5. Description of the Invention (4) Dicarbonyl compounds (Mehdi, S., Bioorganic Chemistry (1993), 21, 249 reviewers) and N-peptidyl 0-fluorenyl Oxo fatty acid esters (B r 0mme, D., N euma η η, U., Kirschke, Η ·, Demuth, H-U ·, B iochi m. B iophys · A cta, (1 9 9 3 ), 1 2 0 2, 2 7 1. Others have recently edited other abstracts of methods for reversibly and irreversibly inhibiting cysteine proteases; see Shaw, E., Advances in Enzymology and Related Categories of Molecular Biology ( 199 0), 63, 271. SUMMARY OF THE INVENTION One aspect of the present invention is a protease inhibitor comprising a target group bonded to an electron withdrawing group via a chain of two carbon atoms, wherein the inhibitor inhibits the dissociation constant of the protease. (K i) is not more than about 100. Another aspect of the present invention is a protease inhibitor, which comprises a target group bonded to a fluorenyl group directly or via a bonding group, the bonding group being selected from intermediate carbon atoms Or two carbon atom chains, wherein the inhibitor inhibits the dissociation constant (K i) of the protease by not more than about 100. Another aspect of the present invention is a compound of formula I, preferably a protease inhibitor: \ a ^ \ s (0); R2 I where: n is 0 to 1 3; A-B represents a bond selected from —C (Ο) NR3, —CH2NR3, _C (0) CH2—and one NR3C (Ο) — , 'Among which the paper size applies the Zhongguanjia Standard (CNS) Α4 specification (21GX297 mm) ~' (Please read the precautions on the back before filling out this page) 470750 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (5) R 3 is hydrogen or as defined below; X represents bonding, methyl extension Or bonding—CH2CH (R4) —, where R4 is hydrogen, alkyl or aralkyl; Y is a CH (R5) —or —NR5—, where R5 is hydrogen or as defined below; Z is (CH2). 2 — 、 — C (R 6) (R 7) — or _N (R7) — 'where R β is hydrogen or methyl, and R 7 is as defined below; Z1 —— (CH2) 2—, a C (R6) (R8)-or —N (R8) —, where R 8 is hydrogen or methyl, and R 8 is as defined below; R 1 is hydrogen, alkoxycarbonylalkylfluorenyl, alkoxycarbonyl, photofluorenyl (Optionally substituted with a group selected from the group consisting of carbonyl, alkoxycarbonyl, and heterocycloalkylalkylamino), cycloalkylcarbonyl, and heterocycloalkylhydroxy (optionally selected from hydroxy, alkyl, and alkyl (Replaced by groups in fluorenyl, alkoxyhydroxy, aralkyloxy, and heterocycloalkylcarbonyl), aralkyloxycarbonyl, carbamoyl, alkylaminomethyl, dialkylaminomethyl, aryl R amidinomethylamidino, aralkylaminomethylamidino, aralkylamidino, arylamidino, alkanesulfinomethyl, dialkylaminosulfinomethyl, arylsulfinomethyl or heteroarylsulfinomethyl; R 7 And R 8 are each hydrogen, alkyl (optionally selected from the group consisting of hydroxyl, amine, and alkylamino) , Dialkylamino, ureido, fluorenyl, alkylthio, hydroxy, carbamoyl, alkylaminomethyl, dialkylaminomethyl, alkylsulfonyl and guanidino, or protected Substituted by groups in its derivatives), cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, groups selected from aryl and aralkyl (the dimensions of this paper are applicable to the country of China Standard (CNS) A4 specification (210 X 297 mm) ------------- Attack ---- ^ --- 1T ------ 〆 (Please read the note on the back first Please fill in this page again) 470750 Printed by A7 __B7___ of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (6) The aryl ring of the group is optionally passed through one to three selected from hydroxyl, amine, and guanidino , _, Optionally substituted with a halogen-substituted alkyl, alkoxy, and aryl group (or a group in a protected derivative thereof), or together with adjacent R3 or R5 to form a selected group (C3-C4) a divalent group in methyl and 1,2-phenylenediyl (this group is optionally substituted with a hydroxyl group or a protected derivative thereof, or a oxy group): and R 2 is hydrogen, alkyl (optionally Or more selected from the group consisting of amine, guanidino, halo, hydroxy, alkoxy, nitro, alkanesulfonyl, and arylsulfonyl, or substituted groups thereof), naphthenes Group, cycloalkylalkyl, or a group selected from aryl and aralkyl (the group's aryl ring is optionally passed through one or two selected from amine, halo, hydroxyl, and optionally Halo-substituted alkyl, alkoxy, nitro, alkanesulfonyl, arylsulfonyl, or protected compounds thereof): and pharmaceutically acceptable salts thereof, individual isomers or isomeric The structure mixture preferably has a dissociation constant (K i) when the protease is inhibited by the inhibitor is not more than about 1000 am. Another aspect of the present invention is a compound of formula II, preferably a protease inhibitor: 丨 〆 \ ζ / Α (β / Z, ^ Β \ ζ 丨 ^ II where: the group is as defined above and R9 is a cyano group,- C (0) OR1., — P (〇) (OR1.) 2 '-S (◦) (NR10) R10, C (0) R11, -S (0) R11,-C (〇) NR12R13, this paper Standards are applicable to China National Standard (CNS) A4 specifications (210X297 mm) (Please read the precautions on the back before filling out this page) 47G750 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 _V. Invention Description (7)- S (0) 2NR12R13, -C (0) NHR14 or -S (02) NHR14 'each Ri. Individual hydrogen, alkyl (optionally via one or more selected from amine, halo, hydroxyl, alkane Oxy, nitro, alkanesulfonyl and arylenesulfonyl, or substituted with a group in a protected derivative thereof), cycloalkyl, cycloalkylalkyl, or a group selected from aryl and aralkyl Group (the aryl ring system of this group is optionally substituted by one or two selected from amine, halo, hydroxyl, alkyl substituted with halo, alkoxy, nitro, alkanesulfonyl And aromatic sulfonyl, or Substituted by a group in a protected derivative) 'R11 is hydrogen, alkyl, perfluoroalkyl, cycloalkyl, cycloalkylalkyl, perfluoroaryl, perfluoroaralkyl, or selected from aryl and A group in an aralkyl group (the aryl ring of this group is optionally substituted by one or two selected from the group consisting of amine, _, hydroxy, and optionally substituted by halogen, alkyl, alkoxy, nitro , Alkylsulfonyl or arylsulfonyl, or a protected derivative thereof), R12 and R13 are each hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl or Aralkyl, and R 14 is C (0) 0 R 10, wherein R 1G is as defined above, or is a group selected from the group consisting of formulas (a) and (b): 0 person 〇R- ο (a) (b) (wherein n, A, B, Y, Z, R1, and R1. Each is as defined above, and a pharmaceutically acceptable salt; its individual isomers and mixtures of isomers, preferably those in which The inhibitors inhibit the dissociation constant (K i) of the protease not more than about 100 jc / m. Another aspect of the present invention is a compound of formula III, and the preferred protein is a Chinese paper standard applicable to China National Standard (CNS) 8-4 (2 丨〇 '乂 297 mm) (Please Note the back surface of the page read and re-fill) 470750 A7 B7 V. Description of the Invention (8) inhibitor

III Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs: The group is as defined above and R15 is hydrogen, methyl, fluorine or a group selected from the formulas (a) and (b) defined above, and R16 is Selected from phenyl or (5-6) heteroaryl (this group is optionally via at least one selected from alkylaminomethylsulfanyl, dialkylaminomethylsulfanyl, alkoxyhydroxyl, alkylaminosulfinyl Fluorenyl, dialkylaminosulfinyl, alkylsulfonyl, carboxyl, nitro, aminesulfinyl, sulfo, carbamoyl, phosphorous carboxyl, alkoxyphosphino, dialkoxy Phosphino, alkylsulfonyl, cyano, alkylsulfinyl, sulfanyl, alkylaminesulfonyl, dialkylaminosulfonyl, alkoxysulfonyl, aryl, heteroaryl, hydroxyl , Alkoxy, optionally substituted with halo, alkyl, aralkyl, halo, _ + N (R17) 3 or -N (R18) 2 groups, each of which is an alkyl group, Aryl or aralkyl, wherein each of R18 is hydrogen, alkyl, aryl, or aralkyl): and pharmaceutically acceptable salts; individual isomers or mixtures of isomers thereof, preferably the Inhibitor inhibits the protein The dissociation constant (K i) is no greater than about 100 // m. Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a cysteine protease inhibitor of the present invention, or an individual isomer, a mixture of isomers, or a pharmaceutically acceptable salt or salt thereof. And one or more (please read the notes on the back before filling this page) The paper size of this paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 470750 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (9) Combination of pharmaceutically acceptable adjuvants Another aspect of the present invention is the treatment of ameli or at ion by cystine cysteine protease in an animal with the same needs. A method of treating a condition comprising administering to the animal a therapeutically effective amount of a cysteine protease inhibitor of the invention, or an individual isomer, mixture of isomers, or a pharmaceutically acceptable salt or salt thereof. Another aspect of the present invention is a method for detecting a cysteine protease in a sample, the method comprising: (a) using a protease to test the protease activity of a sample; (b) a half of the present invention at a known concentration Detecting protease activity in the presence of a cysteine protease inhibitor; and (c) calculating the difference between items a) and b) to determine the protease activity produced by the cysteine protease. One aspect of the present invention is a method for preparing a cysteine protease inhibitor of the present invention. Brief Description of the Drawings Figure 1 is a schematic diagram of Table 1, the synthesis of a compound of formula I when X is bonded. The synthetic steps are as follows: a) HC02H, H20; b) HB r / acetic acid; c) 4-methyl codeline, isobutyl chloroformate, Mu-ROH; and 4) chromatographic purification. Group is as defined in the present invention. Fig. 2 is a schematic diagram showing the synthesis of a compound of formula I when X is a methyl group. The synthesis steps are as follows: a) 4-Methylmorpholine and isobutyl chloroformate, which are then reduced with Na BH4 in water / THF; b) This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) -12-470750 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (ίο) CH3S02Cj ?, triethylamine, CH2c 芡 2; c) RiSH , NaH, CH3OH, THF, heat; d) 4-chloroperacetic acid, CH2Cj? 2; e) HC / dioxane or p-CH3CeH4S03H / ether ·, and f) Mu_r0h, 4 Monomethylmorpholine, isobutyl chloroformate β Figure 3 shows the meaning of circle 3, the synthesis of a compound of formula I when the X is methyl. The synthesis steps are as follows: a) (CH3) 3CH2CH2SH 'NaH, MeOH, THF, heat; b) 4-chloroperbenzoic acid; c) (n — CaHjj) 4N + F-, THF, followed by BrCH2Cj ?, heat D) He / dioxane or 4-CH3CeH4S03H / ether, and; e) 4-methylmorpholine'isobutyl chloroformate, Mu-PheOH. Figure 4 is a schematic diagram of the synthesis of compounds of formula II. The synthesis steps are as follows: a) Cj? H2H + (CH3) OCH3, dicyclohexylcarbodiimide, E t3N / CH2Ci2; b) L i Aj2H4 / THF; c) NaH / THF; d) HC ^ / dioxane / CH2Cj? 2; e) 4-methylmorpholine, isobutyl chloroformate / THF: and f) H2, 5% Pd / c. Fig. 5 is a schematic diagram 5 'of the synthesis of a compound of formula I when X is ethylene. The synthesis steps are as follows: a) (CH20) n, HCj ?, dioxane, for example, when Ar = 2-a certain group; b) (E t 0) 3P; c) C Η 3 C Ο 3 H 'C Η 2 C β 2 'd) NaH' THF '< e) P ~ CH3C6H4S03H' E t 2 0; f) 4 -methyl codeline, isobutyl chloroformate; and g) H2, Pd / C. (Please read the precautions on the back before filling out this page). 11 Paper sizes are applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) -13-470750 Printed by A7, Consumers Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs B7 _V. Description of the invention (11) Figure 6 shows the synthesis of a compound of formula II in which R8 is a COOH. Figure 7 shows the synthesis of a compound of formula II in which R 9 is a P (0) (R1Q) 2. The synthesis scheme is as follows: a) NaH / THF; b) anhydrous P-CH3CeH4S03H / ether; c) 4-methylmorpholine, isobutyl chloroformate / THF, and; d) H2, pd / C. Figure 8 shows the synthesis of compounds of formula I I where R9 is -C (0) NHR14. The synthesis scheme is as follows: a) NaOH / EtOH, followed by HCj? / H20; b) sulfonamide, dicyclohexylcarbodiimide, CH2Cj? 2; c) NaH / THF, benzyl sulfonamide and methylphosphonic acid diethyl ester D) HCj? / Dioxane; e) 4-methyl codeline, isobutyl chloroformate, THF; f) H2, Pd / C, prepared by substitution starting from the carboxylate synthesized by the aforementioned scheme 6 Method; and g) aniline, dicyclohexylcarbodiimide, CH2cp2. Fig. 9 shows a general method for synthesizing a compound of formula II. Figure 10 shows the synthesis of compounds of formula I I I. The synthesis steps are as follows: a) CH3CN or its appropriate solvent, reflux; b) H20, NaOH, followed by extraction in an organic medium; c) phosphane 'THF (Wi ttig reaction); d) P — CH3CeH4S03H' ether; e) Mu — PheOH, 4-methyl codeline, isobutyl chloroformate, THF; and f) H2, Pd / C. Definition Unless otherwise stated, the paper size used in the specification and patent application scope is applicable to the Chinese National Standard (〇 阳) 8 4 specifications (210 father 297 mm) _1 / (_ (Please read the precautions on the back before filling (This page) 470750 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (12) 1 1 The following words are all based on the definition of the invention > and have the following meanings 1 1 Oxy, alkylthio, alkane Off / if fluorenyl, alkylaminomethyl 1 1, dialkylaminomethyl > heteroaryl, aralkyl and other groups in the group ft 1 I Please 1 | Think of a straight chain with 1 to 10 carbon atoms or the number of carbon atoms shown II Read 1 or branched, saturated or unsaturated hydrocarbon group (such as methyl, ethyl, propyl, isomeric 1 to 1 propylbutyl, second butyl, isobutyl , 3rd butyl vinyl, alkenes Note 1 1 propyl 1 —propenyl> isopropenyl \ 1 —butenyl 2 — butenyl matters again 1 1, 3 — butenyl, 2 — methyl Allyl, ethynyl, 1-propynyl > fill in 2-propynyl, etc.) 0 pages' «W〆1 1 alkoxyphosphino and dihodophosphino rf individually mean the group 1 I — P (0) (0 Η) 0 R and a P (0) (0 R) 2 where 1 IR is an alkyl group as defined above. VV 1 1 in an amino group and the like »means a group — C (0) R where R is the aforementioned group having a total of 1 to 1 1 1 1 carbon atoms or the number of carbon atoms shown (eg (1 1 C 1-Alkyl)> includes methyl, ethyl, propyl, propyl, isopropyl, butyl, butyl, isobutyl, crotonyl, isocrotonyl, etc.) 0 1 1 I Aryl means an aromatic mono- or multi-bad hydrocarbon group containing 6 to 14 carbon atoms or the number of carbon atoms shown 1 1 and its carbocyclic ketone or thioketone derivative > wherein 1 has a Valence carbon atom is a member of the aromatic ring—for example,> aryl includes 1 phenyl, phenyl, methyl, phenanthryl, 1 9 2 > 3 4 — tetrahydro — 5 — 1 I amidino, 1 — Hexyloxy — 1 y 2 —dihydro — 5 —fluorenyl, 1 monothio 1 I — 1 > 2 —dihydro 5 — certain group, etc.) 0 1 1 1 A Arylfluorenyl means group — C (0) A r where A r is the first 1 1 I This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) ---- 1 470750 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Description of the invention (l3) The aryl group defined in the text has a total of 7 to 15 carbon atoms or the number of carbon atoms shown (for example, (C ^ n) arylfluorenyl includes benzylfluorenyl and perylene Wait). "Cycloalkyl" in cycloalkyl and cycloalkylalkyl means a saturated or unsaturated, monocyclic or polycyclic hydrocarbon group containing 3 to 20 carbon atoms or the number of carbon atoms shown, wherein A free-valent carbon atom is a member of a non-aromatic ring 'and any of its carbocyclic ketone and thioketone derivatives (for example, the term cycloalkyl is used to include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Cyclohexenyl, bicyclo [2,2,2] octyl, 1,2,3,4 tetrahydro-1-fruityl, dioxycyclohexyl, thiocyclohexyl, 9-fluorenyl, etc.) . a Halofluorene means fluorine, chlorine, bromine or iodine. "Heterocycloalkyl" in heterocycloalkyl, heterocycloalkylalkylamino, heterocycloalkylcarbonyl, heterocyclocarbonyl and the like means that one to five of the carbon atoms shown in A heteroatom selected from N, 0, S, P or As is substituted for a cycloalkyl group as previously defined, in which the free-valent atom is a member of a non-aromatic ring, and any of its heterocyclic ketones , Thioketones, sulfones, or bis-derivatives (e.g., heterocycloalkyls include piperidinyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, earthworm, quinuclidinyl, morpholinyl, piperazine , N-methylpiperazinyl, piperazine (P i pe ad ad ny 1), 4, 4-dioxy-4 monothiapiperidinyl, 1,2, 3, 4-tetra Hydrogen—3-isodolinolinyl, 2,4-diaza-3—oxy-7-thia-6—bicyclo [3,3,0] octyl, etc.). Thus, hetero (C6) cycloalkyl includes the groups morpholinyl'piperazinyl, piperidinyl and the like. " heteroaryl " means that the original paper contains a total of 5 to 14 atoms or is shown in the original paper size ^ Chinese National Standard (CNsTa4 specification (210X297 mm) (please read the notes on the back before filling in this education) Binding · 470750 A7 B7 ___ V. Description of the invention (14) Aromatic monocyclic or polycyclic hydrocarbon group with a number of members, in which 1 to 5 carbon atoms are selected from N, 0, S, P or As A heteroatom is substituted, in which the atom having a free valence is a member of the aromatic ring, and any of its heterocyclic ketones and thioketone derivatives (for example, the heteroaryl group includes threonyl, furyl, pyrrolyl, pyrimidinyl, Isoxazolyl, oxazolyl, vermicarbyl, benzo [b] -umyl, isobenzofuranyl, purinyl, isoquinolinyl, pteridinyl, pyrimidinyl, imidazolyl, pyridyl, pyridine Oxazolyl, pyridyl, 4 ~ oxy-1,2-dichloro-1-yl, 4-thio-1'2-digas-1-yl, etc.). Therefore, hetero (C β) Aryl includes groups such as pyridyl, pyrimidinyl, etc. " 1,2-phenylenedimethyl " means a divalent radical having the formula -CH2C6H4CH2_. For example, where the fluorene is -N ( R 5), Z is a group CH (R 7) —, A is a carbonyl group and R 7 and R 5 together form a 1,2-phenylenedimethyl group RiY — Z — A — 〃 means having the formula Group: (Please read the notes on the back before filling out this page)

The central standard of the Ministry of Economic Affairs is printed by employee consumer cooperatives and their substituted derivatives and individual stereoisomers and mixtures of stereoisomers. Substituted derivatives of 1,2-benzenedienemethyl divalent groups may contain a hydroxyl group on any carbon in the ring system or on the oxygen group of any unsaturated ring carbon atom. ^ Phosphorous carboxyl refers to the group 圑 —P (〇) (OH) 2. In (C3_4) methylamine and a (C3_7) methylamine, "a methyl" means a straight-chain saturated divalent group with the number of carbon atoms shown; this paper standard applies to Chinese national standards (CNS) A4 specification (210X297 mm) ~ ~ 470750 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____B7___ V. Description of the invention (15) a (C3_4) Methylmethyl, including trimethylol ) 3_) and tetramethyl (_ (ch2) 4—). For example, the preferred embodiment of the present invention utilizes a proline residue as the A_B-Z group, where A-B represents CH2-NR3, and R3 and R7 or R8 together form a C3 methyl group. Therefore, where Y is a (NR5) —, Z is a CH (R7) — 'A is a carbonyl group and R 7 and R 5 — form a trimethyl group — R1 — Y — Z_A means having the formula Group:

And its individual stereoisomers and mixtures of stereoisomers. The substituted derivatives of tris-methyl and tetras-methyl groups may contain a hydroxyl group, or a protected derivative thereof, or an oxy group on any one ring carbon atom. Suitable hydroxy protecting groups are as defined below. " Oxa (c3_7) methyl and " aza (c3_7) methyl " mean the aforementioned methyl group in which each of the carbon atoms represented is replaced with an oxygen or nitrogen atom. For example, " oxa (C 5) m " includes 3-oxapentamethyl (1-CHsCHsOCHsC ^ z-) and 2-oxapentamethyl (1-CH2OCH2CH2CH2—). Therefore, when R21 and R 22- together form 3 _ In the case of oxapentamethyl, —C (0) NR21R22 means the group 4 —morpholine carbonyl. When R21 and R 22 together form a 3 —azatetramethyl, it is a group 1 to piperazinecarbonyl. 〇Used in the terms “R7 and adjacent R3—from” “Adjacent” means that the paper size applies the Chinese National Standard (CNS) A4 specification (2 丨 OX297 mm) — In III, K " ^ 衣 — IIIIIII —- ^ (Please read the notes on the back before filling out this page) 470750 A7 B7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (16) Individually attached to R 7 and R 3 The atoms are sequentially attached to each other. Animals include humans, non-human mammals (such as dogs, , Free of cattle, horses, sheep, goats, pigs, deer, etc.) and non-mammalian species (such as islands, etc.) 0, the disease particularly includes any unhealthy condition of the animal or part thereof and includes medical or veterinary treatment applied to the animal Unhealthy conditions caused or prone to occur, that is, side effects of their treatment 0 Λ electron-withdrawing group (E WG) means that the functional group under the broadest definition can be between itself and the carbon to which it is attached On the bond between them, a polarizing force is generated to make the electron conform to the group polarized by the electron-withdrawing base. Although not limited to any particular theory, it is believed that the polarization property can allow the electron-withdrawing group to participate in cysteine Hydrophobic or oxygen-bonding interactions at the active site of a protease inhibit the enzyme. Usually when a part is present in the 2 -position of the phosphonium compound of the general structure Ph 3P = c (R) EWG, if it has Enough to acetylate Confrontation with the decomposition of the oxygen feed line, hydrohalic acid, water, alcohol or the like to be given the safety of the polarization is adapted to be charged electron withdrawing group. A better electron-acceptor group is one which stabilizes an alkynide of the general formula (〇 R) 2 P (〇) C (R) E W G in the same way. Suitable electron withdrawing groups include a gas group, -S (〇) 2 R 2, -C (0) 〇R 10-P (0) (0 R 10) 2 »-S (〇) (NR 1 0) R 1 0 C (〇) R 1 1 — — S (0) R 1 1, — C (0) NR 1 2 R 13, —S (〇) 2N R 1 2 R 1 3, — -C (〇) NHR 1 A -S (0) 2N R 1 4, phenyl and (: 5 -6) heteroaryl, wherein R 2 R 1 〇, R 1 1 XR 1 2, R 13 and R 1 4 are as described in the brief description of the invention In the broadest sense, the paper size applies to the Chinese National Standard (CNS) A4 specification (21〇 × 29ί7mm). Please read the notes on ft before filling in I. Page 19-470750 Α7 Β7 Staff Consumption of the Central Standards Bureau of the Ministry of Economic Affairs Cooperative prints 5. As defined in the definition of invention description (17). When the electron withdrawing group is phenyl or (c5-e) heteroaryl, the ring may be substituted by one or more meta-oriented substituents (for example, Alkylcarbonyl, alkylaminosulfinyl, dialkylaminosulfinyl, alkylsulfinyl, carboxyl, nitro, aminosulfinyl, sulfo, phosphorous carboxyl, alkoxyphosphine Dialkoxy Alkyl, alkylsulfonyl, cyano, alkylsulfinyl, sulfamoyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkoxysulfinyl, disubstituted amine, tris Substituted amm ο ni 0, etc.), in situ and para-oriented substituents (such as hydroxyl, alkoxy, optionally substituted alkyl, aryl, aralkyl, halo, etc.) and electron withdrawing moieties (E.g. alkylaminomethylsulfanyl, dialkylaminomethylsulfanyl, alkoxycarbonyl, alkylaminosulfinylsulfanyl, dialkylaminosulfinylsulfanyl, alkylsulfanyl, carboxyl, nitro, Aminosulfinyl, sulfo, carbamoyl, phosphorous carboxyl, alkoxyphosphino, dialkoxyphosphino, alkylsulfo, cyano, alkylsulfinamido, aminosulfo Group, alkylaminesulfonyl, dialkylaminosulfonyl, alkoxysulfanyl, aryl, heteroaryl, etc.) 4Leaving group A has the definition commonly used in synthetic chemistry, and can be used in Atoms or groups substituted under alkylation conditions, including radicals and alkanyl or alkenesulfonyloxy groups, such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy and tosylsulfonyloxy, Alkanes Amine group, alkylcarbonylamino group, sulfamoylamino group, aminocarbonylamino group, etc. 'Isomerization is where the compounds have the same molecular formula, but the nature or sequence of atomic bonding or the arrangement of their atoms in space are different. Phenomenon, the isomers with different arrangement of atoms in space are called "stereoisomers". The stereoisomers that are not mirror images of each other are called A non-mirror isomers ", but not mirrors that can be overlapped (please read the precautions on the back before filling this page). Meal meal) 470750 A7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ______B7__ V. Description of the invention (18) The stereoscopic foreign body of the image is called " mirror isomer " or sometimes " optical alien Structure ". A carbon atom bonded to four different substituents is called a palmar center. "A compound having a palmar center with two mirror-isomeric forms of opposite palmarity is called an A racemic mixture. It has more than one The compound of the palm center has 2 " -1 mirror image isomer pairs, where η is the number of palm center. The compounds of formula I, II, III can be in the form of individual stereoisomers or stereoisomer mixtures. For example, compounds of formulae I, II, and III contain a palm center on the carbon to which the substituent R 8 is attached. In addition, compounds of formulae I, II, and III of the Z series-C (Re) (R7) are attached with R The carbon of the 7 substituent has a palm center. Therefore, for example, a compound of formulas I, II, and III in which η is 0 and Z is —C (Re) (R7) has two palm centers, and may have four types. Individual stereoisomers or any one of their mixtures. Individual stereoisomers can be defined by their absolute structure in the center of the palm. Absolute structure means that the substitution attached to the center of the palm is based on the arrangement in space. Attached to the discussion of 1 The substituent of the center of the palm is according to Cahn, The sequence of Ingold and Pre 1 og is regularly arranged. If the three highest order substitutions are arranged in space in a clockwise order based on the highest to low polarity in the space (the fourth lowest order basis is oriented away from the observer), then Is the absolute descriptor R, and the absolute descriptor S is set counterclockwise. When describing the individual stereoisomers that contain a pair of palm centers, list the absolute descriptor R or S in parentheses, followed by the hyphen and Chemical name of the compound. In the present invention, the paper size is described in accordance with the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) —ί II * n II Order — — II ^, (Please read the precautions on the back before (Fill in this page) 470750 A7 _B7___ V. Description of the invention (19) When the individual stereoisomers or mixtures of stereoisomers containing two or more palm atoms are listed, the absolute descriptors are listed immediately after the appropriate position ^ Or 5. The fluorenyl group derived from a natural amino acid means an amino acid group (such as L-phenylalanine) preceded by the descriptor L. An unnatural mirror image isomer of an amino fluorenyl group Is preceded by descriptor D. Because The stereoselectivity of the enzyme is therefore preferred for the amino acid side chain (S) or L-type, but in some cases D-type can be used. When absolute descriptors are not listed in the center of the palm, the description is simultaneously * Including two structures and their mixtures, racemates, etc. Therefore, for example, 'compounds with the formula (please read the precautions on the back before filling this page)

The printed name of the Consumer Work Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs is: when R 1 is a 4-morpholine carbonyl group, R 8 is a 2-phenethyl group and is located on the same side of the reference plane as the R 7 substituent, and R 7 is a fluorenyl group When R 19 is benzenesulfonyl, it is called N2— (4-morpholinyl) —N1— [3-phenyl-1S— (2-phenylsulfonylethyl) propyl] —L-benzene R1 is 4-morpholine carbonyl, R8 is 2-phenethyl and is located on either or both sides of the reference plane, R 7 is fluorenyl and R1 9 is phenylsulfonyl -4 -morpholine carbonyl—N1— [3-phenyl-1— (2-phenylsulfonylethyl) propyl] -L-phenylpropylamine amide; when R1 is 4-morpholine carbonyl and R8 is 2- Phenethyl and the reference plane are on the same side as the R 7 substituent. When R 7 is a 2-fluorenylmethyl group and R 19 is a phenylsulfonyl group, it is called N 2-4_morpholinecarbonyl group -N-[3 — Phenyl — 1 S is in accordance with Chinese National Standard (cns) A4 specifications (21 OX 297 mm) 470750 Printed by A7 __B7___, Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (20)-(2 —Benzene Sulfoethyl) propyl] —Shiyi (2 — (Fructyl) -L-propylamine amide; and when R 1 is 4-morpholinecarbonyl 'R 8 is 2-phenethyl and is located on the same side of the reference plane as the R7 substituent' R7 is benzyl and R19 is ethoxy When it is mineral-based, it is 4 S — (N — 4 —morpholine iron group — L —phenylpropylamine amine group) — 6 —phenylacetate. In a preferred embodiment, the composition of the present invention is a pure non-mirror structure. Alternatively, the composition contains a mixture of non-mirror isomers. Preferred specific examples have a single non-mirromeric isomer that is higher than about 70%, and at least about 90% is particularly preferred. "* Protective group 〃 has the meaning commonly used in synthetic organic chemistry, that is, to block the reactive site of a compound Of groups. Reference is made to the protecting group in organic synthesis of ‘Gre e η et al., 2nd edition, John Wiley & Sons, 1991, which is hereby incorporated by reference. Examples of the hydroxy protecting group include aryloxycarbonyl 'such as benzyloxycarbonyl and the like, arylfluorenyl such as fluorenyl and the like, and oxyhydroxy such as ethoxyhydroxy and 9-fluorenylmethoxycarbonyl and the like. Examples of the guanidino protecting group include sulfonyl groups such as 2,3,5-trimethyl-4 monomethoxyphenylsulfonyl and the like. Examples of carboxy protecting groups suitable for forming the ester moiety are alkoxycarbonyl groups having a total of 4 to 8 carbon atoms, especially a third butoxycarbonyl group (B0C) or a benzyloxycarbonyl group (CBZ, Z), especially the total number of 4 in the ring Cycloalkylamine or oxyretidinylamine to 8 atoms, especially 4-morpholinecarbonyl (Mu) and the like. ^ Protected 'in a compound group means a compound or a derivative of a group in which a reactive site is blocked by a protecting group. , Selective 〃 or '^ optionally " means the conditions or conditions described later _ This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) ~~~ ^ -23----- --------- < equipment ---- ^ ---- 1T ------ # (Please read the precautions on the back before filling out this page) 470750 Staff Consumption of Central Bureau of Standards, Ministry of Economic Affairs Cooperatives print A7 B7 V. Invention description (21) The item may or may not occur, and the narrative includes the situation or condition that occurred or the situation that did not occur. For example, " optionally further substituted by one or more functional groups " means that the substituent may be present or absent, and the compound described still falls within the scope of the present invention, and the present invention includes Or more functional compounds and compounds without functional groups. In the present invention, "disease complicated by cysteine protease" means a pathological condition complicated by cysteine protease. In some diseases, this condition is accompanied by an increase in the concentration of cysteine protease; for example, arthritis, muscle itching, inflammation, tumor attacks, and filamentous nephritis are all accompanied by increased cysteine protease concentrations. In other disorders or diseases, the condition is accompanied by the appearance of extracellular cysteine protease activity that is not present in normal tissues. In other specific examples, the ability of cysteine protease-associated pathogens (such as viruses) to infect or replicate in host organs. Specific examples of diseases complicated by cysteine protease include (but are not limited to) arthritis, itching muscles, inflammation, tumor attacks, filamentous nephritis, malaria, Alzheimer's disease, cancer metastasis, trauma, Inflammation, gingivitis, Leishmaniasis, filariasis, and other infections caused by bacteria and parasites. In particular, diseases that are complicated by melanin 1 Θ converting enzyme (I CE) are included. $ Pharmaceutically acceptable means that it can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and neither biologically nor otherwise undesirable, including those acceptable for veterinary and human pharmaceutical use. a A pharmaceutically acceptable salt means a salt that is pharmaceutically acceptable and has the desired pharmacological activity as defined above. These salts include the size of the paper formed by using inorganic acids. Applicable to China National Standard (CNS) A4 specifications (210X297 mm) -------------- ¾ clothing ------- II ------ # (Please read the precautions on the back before filling this page) -24-470750 A7 B7 printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs _V. Description of the invention (22) Sulfuric acid addition salt , Such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or those using organic acids, such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvate, lactic acid, malonic acid Acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzyl acid, o- (4-hydroxyammonium) arsinic acid, cinnamic acid, made lie acid, methanesulfonic acid Acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-sulfonic acid, p-toluenesulfonic acid, 'camphorsulfonic acid, 4_formaldehyde Bicyclo [2,2,2] octyl-2-ene-1 monocarboxylic acid, glucoheptanoic acid, 4,4 < -methylenebis (3-hydroxy-2-2-ene-1carboxylic acid), 3 —Phenylpropionic acid, trimethylacetic acid, tert-butyl Glycolic acid, lauryl sulfuric acid, gluconic acid, ammonium acid, hydroxyammonium acid, salicylic acid, stearic acid, muconic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which can be formed when an acidic proton is present which can react with an inorganic or organic base. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and sodium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, and the like. " Therapeutically effective amount Λ means an amount administered to an animal to treat a disease ', including: (1) preventing the occurrence of a disease in an animal that may be sick, but does not show or show symptoms of the disease. (2) Inhibit the disease, that is, stop its development, or (please read the precautions on the back before filling this page) This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 470750 A7 B7 V. Description of the invention (23) (3) Ameliorating the disease, that is, causing deterioration of the disease. Detailed description of the invention The present invention relates to a novel cysteine protease inhibitor. Without being bound by theory, it is believed that the inhibitor is bound to a cysteine protease according to the following schematic.

Enz

Enzyme inhibitor complex (please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. The interaction between this and the selective non-inhibitor instance is more active than this. The enzymes in the interbasin production can inhibit the reversible inhibition of species by reversing. Generally, serine, tianzhong, the present invention, such as seramine, is low. In addition, the electron polarization of formula I, hydrogen generation The mechanism of the hydrogen bond between the R, Y, and Z parts of the agent and the binding part of the enzyme and the side bond of the amino acid side of the active site is made by the enzyme inhibitor to the cysteine protease. With the inhibitors of the present invention inhibiting cysteine proteases, and asparagine and zinc protease " However, in some certain protease inhibitors can be acidic, aspartyl or other metalloproteinases for other kinds of proteases, However, the electron-withdrawing property of Shuoji is that the carbon and the carbon attached to it make it itself and the active site of serine protease, leaving a tight bond between the inhibitor and hemi-amino acid, such as the sulfur and oxygen atoms. Large There are additional paper sizes applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) -26-470750 Staff consumption cooperation of the Central Standards Bureau of the Ministry of Economic Affairs, printed A7 B7 V. Description of invention (24) Electronic or electronic pole The oxygen atom participates in the hydrogen bonding of the residues in the active site of the protease, and further inhibits the enzyme. The present invention generally provides a novel peptide-based substrate and peptidyl cysteine protease inhibitor, which has As a reversible cysteine protease inhibitor. In the present invention, a cysteine protease inhibitor 〃 means an inhibitor that inhibits a protease inhibitor. In a preferred embodiment, a cysteine protease inhibitor is a cysteamine inhibitor. Acid proteases are specific; that is, they do not inhibit other kinds of proteases, such as serine, asparagine, or other metalloproteinases. However, in alternative specific examples, the cysteine protease inhibitors of the present invention It can also inhibit other kinds of proteases. The present invention " reversibly " means that the inhibitor is non-covalently bonded to the enzyme, and is significantly different from irreversible inhibition. Wa 1sh, an enzymatic reaction mechanism, Freeman & Co., NY, 1 979. "Reversible" in the present invention is a word known to those skilled in the art. In addition, a reversible cysteine protease inhibitor It is a competitive inhibitor, that is, when it reversibly binds to an enzyme, it competes with the substrate, and the inhibitor and the substrate are mutually exclusive. In addition, the amount of inhibition is 1: 1; that is, a single inhibitor is Enough to inhibit a single enzyme molecule. The cysteine protease inhibitor system of the present invention is designed to reversibly bind to a cysteine protease. This type of binding system uses a peptide as a base or a peptidomimetic structure as a target base. This is achieved by simulating natural substrates and / or inhibitors. A peptidomimetic of the present invention means an amino peptide-like structure, but one or more of the peptides are bonded (ie, -C (0 ) NR —) is replaced by an isocratic form, ie —CH2NR —, — C (0) CH2- or this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ---------. Xiang ------ 1T ------ # (Please read the notes on the back before filling this page) -27-Member of the Central Standards Bureau of the Ministry of Economic Affairs Co-op printed 470750 A7 ___B7 _ V. invention is described in (25) a NRC (◦) - and / or non-natural amino acid in which there substituents. The "targeting group" of the present invention means a peptide or peptidomimetic residue on a cysteine protease inhibitor which binds the inhibitor to cysteine protease. In a preferred embodiment, the targeting group of the cysteine protease inhibitor comprises at least two amino acid side chains or side chain homogens which are bonded via peptide bonds or isosteres. Targeting groups may contain up to about 15 amino acids or homogeneous species, but inhibitors are typically about 1 to 7 amino acids or homogeneous species, as smaller inhibitors are often desired in therapeutic applications. Therefore, in the formulae I, II and III, η is preferably from 0 to 13 and more preferably from 0 to 5 and particularly preferably from 0 to 3. As shown in formulas I, II and III, the targeting group can be represented by natural or unnatural peptide residues of the formula: R7 R, R / R R8 where R 8 and R 7 components represent natural or unnatural amino acids Homologs or substituents, as detailed below. The target group of the inhibitor also contains other functional groups, such as R1 and those described herein. Although not limited to any particular theory, it is believed that the targeted amino group substituents interact with the surface bond sites of the protease to promote bonding. Also believe in approaching. The amino group substituent of the electron group (such as R8 in the above formula) will occupy the S 1 position of the mass-bonding site, and is therefore called the P i residue of the inhibitor. Similarly, amino acid substituents adjacent to the second position (for example, R 7 of the foregoing formula) occupy the S 2 position of the mass-bonding site and are referred to as the P 2 residue of the inhibitor. If there are additional amino acid substituents, the paper size is subject to Chinese National Standard (CNS) A4 (210 X 297 mm). • Binding ice (please read the precautions on the back before filling this page) ) 470750 A7 __B7_ printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (26) S, S 4 and other positions of the bonding site, and are called residues P 3 and P 4 of the inhibitor. Other target groups can be attached to the electron withdrawing group. If there is an amino acid substituent, they occupy positions S i > and S 2 > of the bonding site of the mass, and are individually referred to as P of the inhibitor. 3 β, P 4 > and other residues. In general, the targeting of selective enzymes is determined by the rules governing the selectivity of substrates in cysteine proteases (for example, see "Protease in Barret et al.'S Monograph on Cell and Tissue Physiology Research" Inhibitors ", Volume 12, Chapter 4: Inhibitors of Cysteine Proteases, Daniel Rich, Elsevier, New York; and the aforementioned author by Thornberry et al., Hereby incorporated by reference). For example, melanin-1 converting enzyme (ICE) accepts each amino acid substituent (ie, 2-carboxyethyl) at the Pi position, while alanine (methyl), valine ( Isopropyl) or histidine (4-imidazolylmethyl) substituents. Papain accepts spermine, lysine, N-fluorenyloxycarbonyl lysine (ie, 4-benzyloxycarbonylaminobutyl), and homophenylalanine (ie, 2-phenethyl) at the Pi position. , Guanidinophenylalanine (ie, 4-guanidinobenzyl) or n-leucine (ie, butyl) substituents, and the P 2 position is phenylalanine, tyrosine, point one (2_some Group) alanine (ie, a certain group), leucine, n-leucine, isoleucine or alanine substituents. Cathepsin B accepts spermine, lysine, N-benzyloxycarbonyl lysine, guanidylphenylalanine, homophenylalanine or n-leucine substituents at the P i position, while the P 2 position Are phenylalanine, tyrosine, 3,5-diiodotyrosine (ie, 3,5_diiodo_4 monohydroxyfluorenyl), / 3- (2_some) alanine, Crude amino acid, guanyl phenylalanine or citrulline (that is, '3 -ureidopropyl) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ^ ~~ -29---- ---------- i ---- ^ ---- 1T ------ ^ (Please read the notes on the back before filling out this page} 470750 Staff Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs Print A7 _____B7 V. Description of the invention (27) Substituents. Cathepsin L and cruzai η accept spermine, lysine, homophenylalanine, guanylphenylalanine at the position p i , Citrullic acid or n-leucine substitution, and the P 2 position is a phenylalanine, tyrosine or (2-base) alanine substituent. The systemic protease SM Pi accepts arginine , Lysine, homophenylalanine, guanidine Phenylalanine, citrulline or n-leucine substituents, and p2-position is phenylalanine, tyrosine, (2-fluorenyl) alanine, valine, leucine, n-leucine Acid, isoleucine, or alanine substituents. DPP — 1 accepts phenylalanine or tyrosine substituents at the Pi position, while P 2 has no substituents or alanine. Calpain Accepts phenylalanine, tyrosine, methionine, Θ-methanesulfonylmethylalanine (ie, 2-methanesulfonylethyl) or valine acid substituents at the P1 position, and P 2 In the position, it is a valine, leucine, n-leucine or isovaleric acid substituent. Therefore, each of R 7 and R 8 is a hydrogen or an alkyl group (optionally selected from a hydroxyl group, an amine group, and an alkane group). Amino group, dialkylamino group, urea group, fluorenyl group, alkylthio group, carboxyl group, carbamoyl group, alkylaminomethyl group, dialkylaminomethyl group, alkylsulfonyl group, or arcyl group Group, or a protected derivative thereof), cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, a group selected from aryl and arylalkyl Aryl ring selection With one to three groups selected from the group consisting of hydroxyl, amine, guanidino, halo, optionally substituted halo-substituted alkyl, alkoxy, and aryl, or protected derivatives thereof) Or together with adjacent R3 or R5 to form a group selected from (C3-4) dimethyl and 1,2 phenylphenyl dimethyl (this group is optionally substituted with a hydroxyl group, or its ------- 'Pack ------- Order ------ Ball (Please read the notes on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specifications (21〇 × 297mm) -〇0-470750 A7 B7 V. Description of the invention (28) Protected derivatives) Divalent group. Therefore, preferred R 7 and R 8 groups are natural amino acid side chains and homogeneous derivatives. This includes (but is not limited to) diamine (methyl), arginine (3-guanidinopropyl), asparagine (carbamidine methyl), citrulline (3-monouretyl), Asparagine (carboxymethyl), cysteine (fluorenylmethyl), chitosan (2-carboxyethyl), chitosan (2-aminomethylethyl), glycine (hydrogen ), Histamine (4-imidazolylmethyl), Homophenylalanine (2-phenethyl), Homoserine (2-hydroxyethyl), Isoglutamine (1-methylpropyl), L-amino acid (isobutyl), lysine (4-monoaminobutyl), methionine (2-methylthioethyl), y3 — (1-fructyl) alanine (1-methyl) , Stone mono (2-methyl) alanine (2-methyl), n-glutamic acid (butyl), n-valine (propyl), ornithine (3-aminopropyl), phenyl Alanine (fluorenyl), proline (the one described in the present invention), sarcosine (methylamine methyl), serine (hydroxymethyl), threonine (1-hydroxyethyl), tryptamine Acid (3-D), tyrosine (4-hydroxybenzyl), and valine (isopropyl). Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page). Although the broadest definition of the invention is listed in the brief description of the invention, certain compounds of the invention are preferred. For example, compounds of formulae I, II and III are generally preferred wherein η is 0 to 5; A — B represents a hydrogen atom selected from the group consisting of —C (0) NR3 — or R3 is hydrogen or as defined below; N (R5)-'wherein R5 is hydrogen or as defined below; ζ is-(CH2) 2-or -C (R 6) (R 7) —; Z1 is -CH (R 8)-; R 1 is Hydrogen's total number of alkoxycarbonylalkanoyl groups of 3 to 10 carbon atoms, (C9) alkoxycarbonyl groups, (C alkanoyl groups (optionally selected from the paper standard applicable Chinese National Standard (CNS) A4 Specifications (210X297 mm) -31-470750 A7 B7 Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China. 5. Description of the Invention (29) Hydroxyl, (c ^ q) alkoxycarbon and hetero (c4_s) cycloalkyl (c2 —10) substituted by a group in an alkylamino group, (c4-9) cycloalkylcarbon group, hetero (C4_8) cycloalkylcarbon group (optionally selected from hydroxyl group, (Ci-s) alkyl group, (C 1_5) alkyl, (C 1_5) alkyl, (c_5) alkoxycarbonyl, (ce_10) aryl (Cn) alkoxycarbonyl and hetero (c4_8) cycloalkylcarbonyl substituted with groups), ( Ce ^ y) aryl (Ci-5) alkoxycarbonyl, carbamoyl, (Ci-5) alkylamine Fluorenyl, bis (Ci-5) alkylaminomethane, (c6_10) arylaminomethane, (Ce-10) aryl (Ci_5) alkylaminomethane, and (ce-10) aryl (Ci-5) alkylfluorenyl, (Cm) arylsulfonyl, ((^ _5) alkylsulfonyl, bis (Ci_5) alkylaminesulfonyl, (ce_10) arylsulfonyl or hetero (C 5_8) aryl Sulfofluorenyl; and R 7 and R 8 are each (C 1_5) alkyl (optionally selected from the group consisting of hydroxyl, amine, alkylamino, dialkylamino, urea, fluorenyl, alkylthio, and carboxyl , Substituted with amine formamidine, alkyl amine formamyl, dialkyl amine formamyl, alkanesulfonyl and guanidino groups, or protected derivatives thereof), (c3_7) cycloalkyl (C3_7) cycloalkyl (Cb5) alkyl, pyridyl, fluorenyl, furanyl, imidazolyl, indinoyl, pyridyl (c1-6) alkyl, fluorenyl (C 1_6) alkyl, furanyl (Ci_e) alkyl, imidazolyl (Ci-6) alkyl, vermido (Cp) alkyl, selected from phenyl, fluorenyl, and phenyl (cH) alkyl , Fluorenyl (C n) alkyl (this group is optionally on the aryl ring through one to three selected from hydroxyl, amine, chloro-bromo, iodine, fluorine Methyl, trifluoromethyl, methoxy, and phenyl groups, or their protected derivatives) or together with adjacent R 3 or R 4 to form a group selected from (C 3-4) Methyl and 1 (please read the note ^ | ^ on the back before filling this page) -pack., Π I ice _ This paper size applies to Chinese national standard (匚 飑) 8 4 specifications (2 丨 0 parent 297 mm ) —UU _ 470750 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (30) '2 -Phenyldimethyl (This group is selectively derived from a hydroxyl group or a protected derivative thereof Or oxygen). More preferred compounds of formulae I, II and III are those wherein η is 0 to 2; A-B represents a bond selected from the group consisting of -C (0) NR3-, wherein R3 is hydrogen or as defined below; Υ-N (R5) —, Where R5 is hydrogen or as defined below; Z is — (CH2) 2 — or —C (R6) (R 7) — (Prerequisite is when η is 0, Z is not-(C Η 2) 2- ); Z 1 is a CH (R "-; R1 is hydrogen, (c4_8) alkoxycarbon, (C 2-6) alkanoyl (selectively selected from carboxyl, (C > 5) alkoxy) Excimer and hetero (C 4_8) cycloalkyl (C 4_6) alkylamino group substituted), —C (0) NR21R22, where R21 and R22 together form aza (C2_e) methyl, Oxa (C2_e) methyl or (C3_7) methyl, (C4_8) cycloalkylcarbonyl, benzyloxycarbonyl, ethylfluorenyl, fluorenyl, or dimethylaminesulfonyl; and R8 and R7 individually (C 5_6) cycloalkyl, (C 5_ β) cycloalkylmethyl, 3-pyridyl, 2-H singyl, 2-furanyl, 4-imidazolyl, 3-D fluorenyl, 3-Pyridylmethyl, 2-Psynmethyl, 2-furanmethyl, 4-imidazolylmethyl, 3-methylamine, (Ci-5) alkane (Selectively via a group selected from the group consisting of fluorenyl, carboxyl, amine, methylthio, mesylsulfonyl, carbamoyl, dimethylaminocarbamyl, guanidino, and hydroxyl or a protected derivative Substituted by a group), a group selected from phenyl, 1-a certain group, 1-a certain group, fluorenyl group, 1-a certain methyl group, 2 a certain methyl group, and 2 phenethyl group (the group is selective Is substituted on the aromatic ring by a group selected from the group consisting of hydroxyl, amine, chlorine, bromine and fluorine, or a protected derivative thereof) or together with adjacent R 3 or R 5 to form a member selected from ( C This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling this page) -33-470750 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Explanation (31)) The groups in dimethyl and 1,2-phenylene dimethyl (this group is optionally substituted by a hydroxyl group or a protected derivative thereof). Particularly preferred formulae I, II And III compounds wherein η is 0 to 1; A-B represents a bond selected from-(0) NR3-; γ-N (R5)-, wherein R5 is hydrogen or as defined below; ζ is a C ( R6) (R7) —; ZO1 —CH (R8) —; Ri is hydrogen, tertiary butoxyhydroxy group, fluorenyl hydroxy group, ethenyl group, 3-carboxypropionyl group, 3-methoxycarbonylpropionyl group, biotin Amine ethyl fluorenyl, phenethyl fluorenyl, fluorenyl, dimethylamine sulfonyl, sulfonyl sulfonyl, 1-piperazine-hydroxyl, 4-methylpiperazine- 1-ylhydroxyl or 4-morpholinehydroxyl ; R 7 is 3-pyridylmethyl, 2-Hsammonyl, 2-furanmethyl, 4-imidazolylmethyl, 3-fluorenylmethyl, (Ci_5) alkyl (optionally selected from Fluorenyl, carboxyl, amine, methylthio, methanesulfonyl, carbamoyl, dimethylaminoformamyl, guanidino, and hydroxy, or a group derived from a protected derivative thereof), A group selected from the group consisting of fluorenyl, bismethyl, 2-fluoromethyl, and 2-phenethyl (the aryl ring of this group is optionally substituted by a group selected from hydroxyl, amine, chlorine, bromine, and fluorine , Or substituted by a group in a protected form) or together with adjacent R 3 or R 5 to form a divalent group selected from (C3_4) methyl and 1,2-phenylene dimethyl This group is optionally hydroxy or its protected derivative or oxy (Replaced): and 8-series butyl, 2-phenethyl, 2-methanesulfonylethyl, 2-third-butoxycarbonylethyl, 2-third-butoxycarbonylmethyl, 4-third-butoxy Carboxamide, 4-benzylamine butyl or benzyloxymethyl. Particularly preferred compounds of the formulae I, II and III are those in which η is 0; A-B represents a bond selected from -C (Ο) ΝΗ-; γ〇- ΝΗ-; Z This paper size applies Chinese National Standard (CNS) Α4 Specifications (210X297 mm) — -34-II '^ * 衣 I n Order II n I ball (Please read the precautions on the back before filling this page) 470750 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7_F Description of the invention (32) system —CH (R7) —; Z1 system —CH (R8) —; R1 system hydrogen, third butoxycarbonyl, benzyloxycarbonyl, biotinaminohexyl, benzamidine, piperazine Azine-1-ylcarbonyl, 4-methylpiperazine-1 monohydroxy or 4-codeolinyl; R 7 is (C i-5) alkyl, optionally substituted benzyl, 1-methyl Group, 2-fluorenylmethyl, 3-pyridylmethyl or 2-methanesulfanylethyl: and R8 is butyl, 2-phenethyl or 2-methanesulfanylethyl. The most preferred compounds of formula I, II and III are wherein η is 0; A-B represents a bond selected from _C (Ο) NH-; Y is -NH-; Z is -CH (R 7)-; Z 1 -C H (R 8)-; R 1 is 1-piperazinyl, 4-methyl-1 -piperazine hydroxyl or 4-morpholine hydroxyl; R 7 is a selectively substituted book base, 1- Fruit methyl or 2-methylmethyl; and R 8 is phenethyl. -Generally preferred compounds of formula I wherein each R2 is (Ci_5) alkyl (optionally via one or two selected from amine, chlorine, bromine, fluorine, hydroxyl and methoxy, or protected derivatives thereof) Substituted by its group), perhalo (Ci-5) alkyl, (C3_7) cycloalkyl, (c3-7) cycloalkyl (Ci-5) alkyl or selected from phenyl 'pentafluorophenyl , Fluorenyl, and phenyl () alkyl groups (the aryl ring of this group is optionally selected from one to two selected from amino, chlorine, bromine, fluorine, hydroxyl, methoxy, and optionally halogen Methyl substituted with a methyl group or a protected derivative thereof) and R 4 is hydrogen, (-5) alkyl or (Ce ^.) Aryl (Ci_5) alkyl. More preferred compounds of formula I are those wherein R 2 is (C 1 -5) alkyl (optionally via one or two groups selected from the group consisting of amine, chlorine, bromine, fluorine and hydroxyl or protected derivatives thereof). Substitute), perfluoro (Ci_5) alkyl, (C5 —β) cycloalkyl This paper size applies the Chinese national standard (Europe) 8 4 specifications (210 parent 297 mm) _ nn 'IIII Order-^ (please first Please read the notes on the back of the page and fill in this page) 470750 A7 B7___ printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (33), (C5_6) cycloalkylmethyl or selected from phenyl, a certain group and A group in benzyl (this group is optionally substituted with a group selected from amine, hydroxyl, chlorine, bromine or fluorine, or a protected derivative thereof) and R4 is hydrogen or methyl . Particularly preferred compounds of formula I are those in which R2 is methyl, diaminomethyl, optionally substituted phenyl, 2-fluorenyl or 2-phenethyl. The most preferred compounds of formula I are those in which R 2 is phenyl, 2-fruit or 2-phenethyl, especially phenyl or 2-fluorenyl, and R 4 is hydrogen. In general, R 9 is a C (0) OR1. , —P (O) (0 R 10) 2, -S (0) (NR10) R 10 > -C (0) NHC (0) R10 or —S (0) 2NHC (0) R1. Preferred compounds of the formula II are wherein each R1D is a (Ci_5) alkyl group (optionally via one or two selected from the group consisting of amine, chlorine, bromine, fluorine, hydroxyl, and methoxy, or protected derivatives thereof). (C3_7) cycloalkyl, (C3_7) cycloalkyl (Ci-5) alkyl, or a group selected from phenyl or phenyl (Ci-e) alkyl (this The benzene ring of the group is optionally substituted by one or two groups selected from the group consisting of amine, chlorine, bromine, fluorine, hydroxyl, methoxy, and methyl substituted with a halogen group, or a protected derivative thereof. Instead). Where R 9 is -C (0) 〇R10, -P (0) (OR10) 2 '-S (0) (NR10) R10, -C (0) NHC (0) R 10 or -S (0) 2NHC (0) R1Q is more preferably a compound of formula II wherein R1. Ethyl, (C5_6) cycloalkyl, (C5_6) cycloalkylmethyl, or a group selected from phenyl and fluorenyl (the benzene ring of this group is selectively passed through a paper & standard for China National Standard (" 0NS) A4 specification (210X297 mm) ~ '(Please read the precautions on the back before filling this page) 470750 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of inventions (34) Selected from the group consisting of amine hydroxyl, chlorine, bromine or fluorine, or a protected derivative thereof). Among them, R9 is C (0) R11 or one S (0) R11. Generally, the compound of formula 1 is I. Among them, R11 is (Ci-5) alkyl, (C3-7) ring fee group, (C3_7) ring compound group. (C: i_5) a radical or a group selected from phenyl and phenyl (Ci-e) alkyl (the aryl ring of this group is optionally Fluorine, hydroxy, methyl, trifluoromethyl, and methoxy groups are substituted), wherein R11 is more preferably C (0) R11 or —S (0) RU. Compounds of formula II are ethyl, Ring (C5_e) alkyl, ring (C5_e) alkylmethyl or a group from phenyl and fluorenyl (the benzene ring of this group is Group, or a protected derivative thereof). Wherein R9 is -C (0) NR12R13 or -S (COsNRuru is generally preferred compound of formula I j wherein R12 and R13 are each (Ci-5) alkyl, (C3_7) cycloalkyl, (C3_7) cycloalkyl (Alkyl or a group selected from phenyl and phenyl (Cp6) alkyl (the benzene ring of this group is optionally selected from 1 to 2 selected from amine, chlorine, fluorine, hydroxyl, methoxy And optionally substituted by a group in a methyl group which is substituted with a halogen group. Among them, R9 is a more preferred C (0) NR12Ru or S (0) 2NRi2R13 compound of formula II wherein R12 and R13 are each ethyl, (C5-e) cycloalkyl, (C5_e) cycloalkylmethyl or a group selected from phenyl and benzyl (the benzene ring system of this group is optionally , Bromine or fluorine, or their protected derivatives). (Please read the notes on the back before filling out this page)-装-

、 1T 丨 The size of this paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297mm) -37-470750 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 __B7_ V. Description of the invention (35) where R9 is a C (0) NHR 14 or -S (0) 2NHR14 (where R14 is a group selected from the group consisting of formulae (a) and (b)), wherein each compound η, A, B, Y ′ Z, R1 and 111 (> are as defined in the aforementioned preferred compounds of formulae I, II and III ". Generally preferred compounds of formula III are those in which R15 is selected from 2-furanyl, 2-pyrenyl, 2-pyrrolyl, A group in 2-phosphopentyl ring, 2-arsenyl, 3-pyridyl, or 3-phosphoalkynyl (this group is optionally via at least one member selected from (C i -5) alkylamine formamidine , Di (C i-5) alkylaminomethylsulfenyl, (Ci_5) alkoxycarbonyl, (c ^ 5) alkylaminosulfinyl sulfenyl, di (Ci-5) alkylaminosulfinyl sulfenyl (Ci-5) alkylsulfonyl, carboxyl, nitro, aminosulfinyl, sulfo, carbamoyl, phosphorous carboxyl, (C) alkoxyphosphino, di (C ^ 5) Alkoxyphosphino, (Ci-5) alkanoyl, cyano, (Ci 5) Alkylenesulfinyl, sulfamoyl, (Ci-s) alkylaminosulfonyl, di (Cn) alkylaminosulfonyl, (Ci_5) alkoxysulfanyl, (Cl-5) Phenyl, fluorenyl, pyridyl, blindyl, furanyl, imidazolyl, arsenyl, hydroxyl, (ci_5) oxy, (C 1_5) alkyl optionally substituted with halo, Weiben , Halo, — + n (rm) 3 (wherein each R17 is (Ci-5) alkyl, phenyl or benzyl), or N (R18) 2 (wherein each r18 is hydrogen, (C1- 5) an alkyl group, a phenyl group or a benzyl group). More preferably, the compound of the formula III is wherein R 1 0 is selected from 2-furanyl, 2-uthenyl, 2-pinthenyl , 2-pyrrolyl, 2-phosphapentyl, 2-arsenyl, 3-pyridyl, or 3-phosphoalkynyl groups (this group selectively applies the Chinese National Standard (CNS) A4 via this paper standard) Specifications (210X297mm) ~ · ~~ —— ---------- install ------ order ------ ^ (Please read the precautions on the back before filling this page) . 470750 Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs print A7 ___ —_ B7 V. Description of the invention (36) At least one selected from A Aminomethylsulfonyl, dimethylaminomethylsulfanyl, methoxycarbonyl, methylaminesulfinyl, dimethylaminesulfinyl, methylsulfinyl, carboxyl, nitro, aminesulfinyl, Sulfo, amidino, phosphorous carboxyl, methoxyphosphonyl, dimethoxyphosphonyl, methylamidino, cyano, methylsulfinyl, sulfamoyl, methylaminosulfonyl , Dimethylaminosulfonyl, methoxysulfinyl, methylsulfinamido, phenyl, fluorenyl'pyridyl, fluorenyl'furanyl, imidazolyl, fluorenyl, hydroxyl, Methoxy, methyl, trifluoromethyl, benzyl halide,-+ N (R17) 3 (where each is methyl, phenyl or benzyl), or -N (R18) 2 (where each R18 Hydrogen, methyl, phenyl or benzyl). Generally preferred compounds of formula III (wherein R16 is selected from the group of formulae (a) and (b)) are those in which η, A, B, Y, Z, R1 and Ri ° are each as described in formulae I, II and III compounds. Generally, it is preferred that the cysteine protease inhibitor of the present invention is the absolute configuration (S) -configuration of each palm center. However, the preferred compound of formula I in which η is 0 is the absolute configuration of the center of the palm where the R 7 substituent is attached. For example, preferred compounds of formula I include: N 2-(4 —Morpholinecarbonyl) —N1— (3-phenyl—1R—benzenesulfonylpropyl) —L—phenylpropylamine amine (Compound 1), N2— (4-morpholinecarbonyl) —N1— (3_ Phenyl_1 S —benzenesulfonylpropyl) —L monophenylpropylamine (compound 2), N2_ (4_morpholinecarbonyl) —N1 — (3_phenyl_1_benzenesulfonylpropyl) —L — Phenylpropylamine (Compound 3), Ν2 -— (4-morpholinecarbonyl) — Ν1— (3-Phenyl_1_sulfonamidinopropyl) -L_leukoamine (this paper is standard Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the notes on the back before filling out this page} 470750 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (37) Compounds 4), N2- (4-morpholine carbonyl) -N1- (3-phenyl-1, trifluorosulfonylpropyl) -L-phenylpropylamine amide (compound 5), N2- (4-morpholine A few bases)-N1 (3-Phenyl-1-monophenylpropanyl) -L-phenylpropylamine sulfonamide (Compound 6), N2- (4-morpholinecarbonyl) —N1- (3-phenyl-1-benzenesulfonyl) Propyl) -L-leukoamine (compound 7), N 2-(4-morpholinecarbonyl) -N1- (3-phenyl-1-fluoromethanesulfonylpropyl) -L-phenylpropylamine Amine (compound 8), N2- (4-morpholinecarbonyl) -N1- (3-phenyl-1S-benzenesulfonylmethylpropyl) -L-phenylpropylamine sulfonamide (compound 9); N2— (4 -morpholinecarbonyl) -N1— {3-phenyl-1S— [2-((2-phenylethylsulfonium) ethyl] propyl) _L_phenylpropylamine amide (compound 1); N 2 — (4-Morpholinecarbonyl) _N1- {3-phenyl_1S- [2- (2-Sulfosulfonyl) ethyl] propyl (2-Syl) _L-propylamine sulfonamide (compound 11) N2 —phenethylhydrazine-N1— {3_phenyl-1 S — (2_benzenesulfonylethyl) propyl} —L —phenylpropylamine amidamine (compound 1 2), N2-(N-ye Oxoyl — Θ -propylaminofluorenyl) — N1 — [— phenyl-1S — (2-phenylsulfonylethyl) propyl] -L-phenylpropylaminofluorene (Compound 13) 3, {2-phenyl-1S- [3-phenyl-1S- (2-benzenesulfonylethyl) propylaminomethylamidino] ethylaminomethylamido} dicarboxylic acid (compound 14); 3— {2-phenyl-1S— [3-phenyl-1S— (2-benzenesulfonylethyl) propylaminoformamidine] ethylamineformamidine} propionic acid (Compound 1 5); N2- (4_morpholinecarbonyl) -N1-丨 3-phenyl-1S-[2- (2—a sulfofluorenyl) ethyl] propyl This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm)- -------- 'Binding (please read the precautions on the back before filling out this page) -40-470750 A7 _______ B7 V. Description of the invention (38)} — L-Tyramine (Compound 16 ); 3- {2-phenyl-1 S — [3-phenyl-1 S — (2-benzenesulfonylethyl) propylamine formamidine] ethylamine formamidine 丨 propionic acid methyl ester (Compound 1 7); N2— (4-Morinite-based) —N1— [3-Phenyl-1 S— (2-Benzylbenzene ethyl) propyl] -L-phenylpropylamine (Compound 1 8) ; N 2 (stone-propylamine hydrazone)

N-phenyl-1S- (2-benzenesulfonylethyl) propyl] -L-phenylpropylamine sulfonamide (compound 1 9); and 5-phenylbenzenesulfonium—3S— {N — [N— ( N—Ethylamine—L—Tyramine 醯) —L—Guamine 醢] —L—Alanine amidinamide} to form an acid (Compound 20). Preferred compounds of formula II include: 4S— (N —; sulfonyl—stilbene— (2—fluorenyl) —L—propylamine sulfonamide) —6—phenylhexanoic acid ethyl ester (compound 2 1) (2 _ some group) -L -propylamine amide) -6-phenylhexanoic acid ethyl ester (compound 22); 4S — [N — (4-morpholine carbon group) —stone—2— (fruit group—L Monopropylammonium amine] -6-phenylhexanoic acid ethyl acetate (compound 2 3); 4S_ (N —benzylamine formamidine-L —phenylpropylamine amine) — 6_

Ethyl phenylhexanoate (compound 24); 4 SN — (4 —morpholine — I · K ^^^ 1 ^^^^ 1 m — ^^ 1 I In 1 ^ 1 ^ 1 ^^ — ^ 1 nn , 5 ^ -I i (Please read the precautions on the back before filling out this page) Carbonyl printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs) -L_phenylpropylamine hydrazine) _6-phenylphenylhexanoate Compound 25); N2- (4-morpholinehydroxyl) -Nl-rOL d-nayl-IS- (2-phenylamine formamidineethyl) propyl] ^^^^ L ~ phenylpropylamine amidamine (Compound 2 6); and N2- (4-morpholinehydroxyl) —νι_ [3 —fructyl-1 S— (2-benzylamine formamidineethyl) propyl] -1 —phenylpropanamine (compound 27). Better Wu] τ τ /, eight ~ 1 1 I compounds include: Ν2--(4-morpholino)-Ν1-{3-_ difficult Ganbenji ~ 1 s This paper size applies Chinese National Standard (CNS) Α4 specifications (210 × 297 mm) ^ ~ 41 470750 A7 ____B7 _V. Description of the invention (39) (2- (4-monomethoxyphenyl) ethyl] propyl 丨 L-phenylpropylamine amide (compound 28): and N2- (4-morpholinehydroxyl) -Ni-i3-phenyl-IS- [2- (4-aminophenyl) ethyl] propyl-L-phenylpropylamine amide (compound 2 9). As is well known in the art world, Formula I includes the structure represented by the preferred category IV shown below. R7 0

Printed by the Central Standards Bureau of the Ministry of Economy—Industrial and Consumer Cooperatives where M is zero, one or two carbon atoms, A-B is as defined above, R1, R2, R7 and R8 are as previously defined, and Q is ΝΗ or CH2. A preferred specific example uses an A-B bond containing nitrogen at the B position. In this specific example, the number of carbon atoms between the carbon to which the R 8 group is attached and the sulfur atom of the base group determines whether the compound is a-amino group, / 3-amino group, or 7-amino group. As discussed in the examples below, the compounds may be referred to as aminophosphonium by the name of the amino acid or by the chemical name. So, for example, the class V is α_amino group:

Type VI is a monoamine-based master: This paper size is applicable to China National Standard (CNS) 8 4 specifications (210X297 mm) _ μ '-------- install ------- 1T --- --- ^ (Please read the notes on the back before filling this page) 470750 A7 B7 V. Description of the invention (4〇) R7 R, \

, Q A meter type νι ι r-amine based R1

Formula I I includes the structure of type VI I I, which is called amine group. Especially when R9 is an electron withdrawing group:

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. In a preferred embodiment, the inhibitor of the present invention is used to inhibit the dissociation constant of the protease. Generally, WKi in the art world indicates ‘highest ι 0 〇. In the present invention, "bond constant" or "" dissociation constant" or grammatical equivalent means the equilibrium dissociation constant of the reversible contract between the inhibitor and the enzyme. The dissociation constant is defined and measured as follows. The measurement of the dissociation constant is known in the art. For example, in the case of; _ Μ Ϋ # 月 月 者 的 逆 回流。 The schematic diagram of the reaction is as follows: Formula 3 Ε + Ι ~ ^ Ε < _-1¾ This paper size applies the Chinese National Standard (CNS) A4 specification (210X297) (Li) --------- • Equipment ------- Order ------ 4 (Please read the notes on the back before filling out this page) -43 470750 Employees of the Central Standards Bureau of the Ministry of Economic Affairs Consumption cooperatives Yinli A7 B7 V. Description of the invention (41) The enzyme and inhibitor combine to produce an enzyme-inhibitor complex E.I. It is speculated that this step is rapid and reversible without any chemical changes; the enzyme and inhibitor are held together by non-covalent forces. In this reaction, k i is a quadratic rate constant that forms an EI · I reversible complex. 1 ^ 2 is a reshaping constant of E · I complex dissociation. In this reaction, the determination of the equilibrium constant ki is performed according to techniques well known in the art, as described in the examples. For example, tests often use synthetic hair colors or fluorescent-generating substrates. For individual k 2 values, use lrwin Segel in enzyme kinetics: fast-balanced and steady-state enzyme system behavior and analysis, 1 9 7 5, 1 丨 16-Imterscience Publication, John Wiley & Sons, New York, or just For competitive bond inhibitors, it is calculated based on: Formula 4 l-CVi / V. ), &Quot;] /! ::! &Quot; KI (1+ (CS) / KM))) where V. It is the rate of mass hydrolysis when there is no inhibitor, and Vi is the rate when competitive inhibitors are present. Known dissociation constants are a method that is particularly useful for assessing the efficiency of enzymes and specific substrates or inhibitors and is often used in the art world in this way. If the inhibitor has a very low K I, it is an effective inhibitor. Therefore, 'The paper size of the present invention is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ~~~~~~ -44----------------- A-- ------ ΐτ ------ t (Please read the notes on the back before filling in this page) 470750 Duty printing of employee cooperation of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____B7 ___ V. Description of Invention (42) The dissociation constant Kz of the cystine protease inhibitor is up to about 100βM. The dissociation constant of the inhibitor of the preferred embodiment is up to about 10 'and the dissociation constant of the preferred embodiment is up to about 1 // M. Chemistry The synthesis of the inhibitors of the present invention proceeds as follows. Compounds of formula I in which X represents a bond can be prepared by the method shown in Scheme 1 in FIG. Treat the third butyl carbamate or benzyl carbamate with an appropriate aldehyde such as isobutyraldehyde or hydrocinnamaldehyde and a suitable sodium salt such as benzenesulfinic acid (Aldrich Chemical Co.) in the presence of an aqueous formic acid solution ' A corresponding N-protected amine methyl amidine is produced. The amine methyl group protected with reed oxo was deprotected in acetic acid with hydrogen bromide. Coupling with a suitable N-protected amino acid or peptide or its peptidomimetic derivative yields a compound of formula I where X represents a bond. Alternatively, a suitable N-terminal protected amino acid or a peptide derivative of a peptidomimetic derivative thereof, such as N_ (4-morpholinecarbonyl) phenylpropylamine, in an aqueous formic acid solution with a suitable aldehyde and a suitable sulfinic acid The sodium salt reacts to produce a compound of formula I where X represents a bond. Compounds of formula 1 in which X represents a methyl group bond can be prepared by methods shown individually in Figures 2 and 3 in Schemes 2 and 3. Appropriate N-protected amino acids or peptidomimetic derivatives are treated with sodium borohydride to produce the corresponding Θ-aminoethanol. Treatment of the alcohol with methanesulfonium chloride in the presence of triethylamine yields the corresponding mesylate. According to the method of Spaltenstein, A ·, Carpion, P., Miyalce, F ·, and Hopkings, PB, J. Org. Chem (1 987) 52,3759, the thiol anion is used. ^ The paper standard is applicable to the Chinese National Standard (CNS ) A4 specification (210X297 mm) A " '_ 45 A ---------- install ------- order ------ ^ (Please read the precautions on the back before (Fill in this page) 470750 Printed by A7 _B7__ of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the Invention (43) Nucleophilic substitution such as thiophenols will produce the corresponding / 3-aminosulfur. The sulfide is oxidized with 4-chloroperacetic acid to produce the corresponding N-protected yS-aminoethylphosphonium. In particular cases, the mesylate is thiolate ion derived from, for example, 2- (trimethylsilyl) ethyl mercaptan (synthesis is such as Anderson, M.B., Ranasinghe, M.B. , Palmer, JT, Fuchs, P.L_, J. Org. Chem. (1 988) 53, 3 1 25)) treatment to produce the corresponding -amine ethyl 2-trimethylsilyl ethyl sulfur. 2 Trimethylsilylethylsulfur is reduced to the corresponding Θ_aminoethyl 2-trimethylsilylethyl group, which is subjected to removal by fluoride adjustment to produce trimethylsilyl fluoride and ethylene gas vice Products, and intermediate sulfinates, which are alkylated in situ with a suitable halogen-containing species (such as methyl bromide) to produce the corresponding N_protected / 5-aminoethylhalomethyl large. This N-protected; 5-aminoethylamidine is deprotected and then coupled with the appropriate N-protected amino acid or peptide or peptidomimetic derivative to produce a compound of formula I in which the X is methyl. . Compounds of formula I I and formula I in which X is ethylene, can be prepared by the methods represented by formulae 5, 6 and 7. Formula 5 (Please read the precautions on the back before filling this page) 〇 〇

OH a)

Boc

N

Boc-b) R8

H wherein a) Cj ^ —H2N + (Me) OMe diimine, triethylamine; and b) lithium aluminum hydride. Formula 6 Dicyclohexyl carbonization The paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) -46-470750 A7 B7 V. Description of Invention (44)

ΟΗ II Boc—N, II

0 R’O 丨 丨 / P, RO

, EWG R8

Boc—i8

.EWG 7 R8 EWG H2 / Pd Boc R8 (Please read the precautions on the back before filling out this page) The Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs printed the appropriate N-tert-butycarbonylamino acid or its peptidomimetic derivative The product is converted into the corresponding amine methylaldehyde (for example, refer to the method of Fehrentz, JA and Castro, Beta) (Synthesis, (1 9 8 3) '6 7 6; Formula 5). The aldehyde is subjected to the Wittig reaction or the WittU reaction ( For example, refer to Wadsworth et al., J. Amer. Chem. Sec. 8 3: 1 7 3 3 (19 9 1); Formula 6) modified Wadsworth-Emmons-Horner conversion method to corresponding vinyl-containing compounds. Vinyl compounds are reduced by catalytic hydrogenation (see, for example, Formula 7) and deprotected, and coupled with the appropriate N-protected amino acid or peptide or peptidomimetic derivative, to produce corresponding compounds of Formula I or II. Alternatively, the vinyl-containing compound is deprotected and coupled using N-protected amino acid or peptide or peptidomimetic derivative to produce the corresponding vinyl-containing condensation product, which is subsequently reduced to produce the corresponding formula I Or II compounds. Compounds of formula II can be prepared by the method shown in Figure 4 and Scheme 4. Thai Paper size applies Chinese National Standard (CNS) A4 (210X297 mm)-Λ7 470750 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _B7 _ V. Description of the invention (45) 'Better, by N-three-butoxy The conversion of carbonylamino acid or its pseudo-derivative to the corresponding amine methylaldehyde is in methylene chloride in the presence of triethylamine and dicyclohexylcarbodiimide using N, 0-dimethylhydroxylamine salt Alternatively, the conversion system is treated with triethylamine and coupling agent benzotriazole hexafluorophosphate-1 1-oxytris (dimethylamino) scale (BOP) to treat the amino acid or its peptidomimetic derivative And use lithium aluminum hydride reduction to produce the corresponding aldehyde (for example, refer to the method of Fehrentz Castro, B .; Synthesis, (1983), 676-678). The conversion from aldehyde to the corresponding vinyl-containing ester can be It is carried out using the sodium anion of triethyl phosphorous carboxyacetate. The deprotection of vinyl-containing esters can be carried out in dioxane using hydrogen chloride. The hydrogenation is generally carried out in the presence of palladium. Among them, X is an ethylidene compound of formula I It can be easily prepared by the method shown in Figure 5 and Figure 5. A suitable N-tert-butoxycarbonyl-α-amino aldehyde prepared as described in Formula 5 with a suitable sodium anion (SMP) of —Diethyl sulfomethylmethonate, diethyl methanesulfonate methylphosphonate, etc.) treatment to produce the corresponding ethylene-containing masterbatch. The masterbatch was deprotected with anhydrous p-toluenesulfonium in ether, and then treated with N- The protected amino acid or peptide or its peptidomimetic derivative is coupled to produce the corresponding ethylene-containing condensation product, which is subsequently reduced to produce the corresponding compound of formula I. Appropriate sulfonium methylphosphonate can be used to treat aryl mercaptan with formaldehyde in the presence of hydrogen chloride, and react with triethyl phosphite to produce the corresponding diethylphosphocarboxymethylaryl sulfide, and then oxidize the sulfur Thing. Alternatively, suitable thioethers can be obtained industrially (for example, the diethyl phosphorous carboxymethyl sold by Aldrich Chemical Co. _ this paper size applies to Chinese national standards (CNS > A4 size (210X297 mm) '~~ —_ 48-(Please read the precautions on the back before filling this page)-Binding · 470750 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (46) Methyl sulfide, diethylphosphine Carboxymethyl phenyl sulfide, etc.), and oxidize the corresponding boron. Among them, R9 is a formula of COOH I; [Compounds can be prepared by the methods listed in the schematic diagram of Figure 6. Generally, R9 is a COORi. Formula 丨丨 The saponification of the compound produces the corresponding carboxylic acid ester, which results in the corresponding carboxylic acid when treated with an acid. Among them, R9 is the formula of p (〇) (r1〇) 2! J Compounds can be processed by schematic circle 6 as τκ intention 7 (Figure 7), and replace the SMP with an appropriate sodium anion of methyl bisphosphonate (such as benzylamidine and methyl diethyl phosphate). Among them, Rule 9-C (0) Compounds of the formula NHR " can be prepared as shown in Scheme 5 (Figure 8) by processing as shown in Scheme 5, Replace SMP with an appropriate diethylammonium methylphosphonate (eg diethylammonium methylphosphonate, etc.). An appropriate diammonium methylphosphonate can be triethyl phosphonocarboxacetate. The chemical product is prepared by reacting an appropriate amine. Alternatively, a compound of formula II in which the 9-series (C) NHR14 is prepared can be prepared by reacting a compound of formula I in which r9 is a COOH with an appropriate amine. For example, in methyl chloride The reaction is carried out in the presence of a cyclohexylcarbodiimide, or by any other peptide coupling reaction known to those skilled in the art. Generally, the compound of formula I1 can be obtained by the method shown in Figure 9 (Figure 9). Prepare and replace the starting materials shown in structures I-VII.

Structure I This paper size applies the Chinese National Standard (CNS) Α4 specification (210X297 mm) ------------- ά ------, 1Τ ----- ^ (please first Read the notes on the back and fill out this page} -49 470750 Α7 Β7 V. Description of the invention (47)

QHsO ^ H

Ketone synthesis is carried out by reaction of Boc-?-Amino acid with a suitable Wadsworth-Emmons' followed by reduction. Generally, the aldehyde moiety is synthesized as described above. Then the phosphonate is treated with diethyl chlorophosphonate or treated with enolate anion such as acetone or benzophenone). The alkoxide anion is treated with diisopropylamine solution by Lithium diisopropylamidamine (LDA) solution 0. House, Modern Synthetic React ions, Benjamin, Inc., Menlo Park, CA, Chapter 9 After the salt, diethyl chlorophosphonate was added. Enolate and chlorophosphoric acid As a result, a Wadsworth-Emmons reagent is formed. When synthesizing cysteine protease inhibitors, use E W G ·· Structure I I

In the presence of phosphonates, hydrogen is used to urge non-marketers to replace methyl ketones. The ketone (Η. 2nd Ed. (Ff.)) Is added to the tetrahydrofuran solution of the olefin. Diethyl enol is formed Coupling is used as structure II (please read the notes on the back before filling this page) -β Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. The Wadsworth-Emmons reaction between the aldehyde and the appropriate phosphonate is carried out, followed by hydrogenation in the presence of a suitable catalyst. Usually, the aldehyde moiety is synthesized as described above. The phosphonate is commercially available. This paper is scaled to China National Standard (CNS) A4 specification (21 ×: 297 mm) -50-470750 A7 B7

V. Description of the invention (48) EWG III when synthesizing cysteine protease inhibitors: Structure III uses ASUS as the structure ο ο cmj II XR 'sulfonium is synthesized by B oc — α —amino aldehyde and appropriate phosphine The Wadsworth-Emmous reaction between the acid esters was initiated, followed by hydrogenation in the presence of a suitable catalyst. Generally, the aldehyde moiety is synthesized as described above. Phosphonates are synthesized by treating methyl anion with chlorodiethyl phosphate. An anion is generated by the addition of Bu Li to diisopropylamine, followed by the addition of methylasyl. When synthesizing cysteine protease inhibitors, 'sulfamethoxamine was used as the EWG of structure IV: Structure IV 0 0 c2h50, || c2h5o / P " ^ | Γνηκ'4 ο IIIII. I n ^ IIIII 丨 ball (please First read the notes on the back and then fill out this page.) The synthesis of sulfonamide produced by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs is based on the Wadsworth-Emmous reaction between β ο c — α-amino aldehyde and the appropriate phosphonate. This is followed by hydrogenation in the presence of a suitable catalyst. Generally, the aldehyde moiety is synthesized as described above. Phosphonates are, for example, converted to diethylphosphonium methoate prepared by a method such as the following a) Lett., 28: 1 1 04- 1 1 08 (1 987)) by phosphorus pentachloride treatment Sulfonium chloride (^ 91 ^ & (^ 1 卜 eg, ^ Methoden der Organische Chemic (Houben-Ulieyl) This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 470750 Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Print A7 B7 _V. Description of the Invention (49)) ^, ed.E. Muller. Thieme Verlag, Stuttgart, 4th Ed., 1955, Vol IX, Chapter 14); or b) For example, ammonia, primary amine ( Including amine derivatives) or secondary amines, sulfonium chloride is treated to form sulfonamide (Quaedvlieg, aforementioned, Chapter 19). Sulfonamidophosphonate is then reacted with Boc-α-aminoaldehyde according to the Wadsworth-Emmous reaction to form the target compound. When synthesizing cysteine protease inhibitors, sulfinamide is used as the EWG of structure V: Structure V 0 0 Ming \ 11 II / P \ ΧΝΗΐί 2 The synthesis of boron is based on β ο c _ α -amino aldehyde and The Wadsworth-Emmous reaction between the appropriate phosphonates proceeds, followed by hydrogenation in the presence of a suitable catalyst. Generally, the aldehyde moiety is synthesized as described above. The phosphonate can be synthesized using one of the following methods. Treatment of dialkyl phosphonic acid dialkyl esters (such as methyl ethyl diphosphonate (Aldrich) ', which is not sold, with a thionyl chloride in the presence of aluminum chloride) to produce a dibasic phosphonium phosphine subbasic chloride (Vennstra et al ., Synthesis (1975) 519. See also Anderson, Compre-hensive Organic Chemistry (Pergamon Press), Vol. 3, Chapter 11.18, (1979). , Internat. Sulfur Chem. (B) 6: 277 (1971)) produces dialkylphosphonium sulfenamidine. This paper size applies the Chinese National Standard (CNS) A4 size (210X297 mm) (Please read the back Note: Please fill in this page again) -52-470750 A7 B7___ printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (50) When synthesizing cysteine protease inhibitors, use boronimine as the structure The EWG of VI: Structure VI 0 0 Ming 0 \ 丨 丨 II 10 / S-R10 Nv xr '° The synthesis of iminoimine is by B ο c-α -amino aldehyde and the appropriate phosphonate between Wadsworth-Emmous The reaction proceeds, followed by hydrogenation in the presence of a suitable catalyst. Generally, the aldehyde moiety is combined as previously described. The phosphonate can be synthesized according to various methods. For example, N-alkyl or N-arylphenylmethylimineimide is based on Johnson's A Comprehensive Organic C hemistry (Pergam ο η P ress), the former, Manufactured by the method described in Chapter 11.1.1. Alternatively, the lithium anion of the compound, such as N-alkylphenylmethylimide, is prepared by treating a neutral compound with butyl lithium in THF (Cram Et al., J. Amer. Chem. Soc. 9 2: 736 9 (1970)). The lithium anion is reacted with a dialkyl chlorophosphate, such as a commercially available diethyl chlorophosphate (Aldrich), to produce a synthetic boroxamine. Wadsworth-Emmous reagents necessary for compounds. When synthesizing cysteine protease inhibitors, the sulfonate is used as the EWG of structure VII: Structure V. II 0cwxjl / S〇3-M + This paper standard applies to Chinese national standards (CNS ) A4 size (210X297mm) _ 53 _! | Approval—II order (please read the precautions on the back before writing this page) 470750 Printed by A7 B7, Cooperative of Staff of Central Standards Bureau of Ministry of Economic Affairs DESCRIPTION OF THE INVENTION (51) The synthesis of sulfonate ASSO was borrowed from B. The Wadsworth-Emmous reaction between c-α-amino aldehyde and a suitable phosphonate (for example, diethylphosphonium mesylate) proceeds, followed by hydrogenation in the presence of a suitable catalyst such as Raney nickel. The phosphonate was synthesized as follows. The anion of methyl phosphonate dialkyl, such as commercially available methyl phosphonate diethyl (Aldrich), is generated by treating the phosphonate with a strong base such as L D A. The anion formed is acidified with sulfur trioxide / trimethylamine complex (Carreto et al., Tetrahedron Lett., 28: 110 4 — 1108 (1987) to form diethylphosphonium mesylate, which can be used in the Wadsworth-Emmous method In the reaction, a, yS—unsaturated sulfonate is used. Compounds of formula II can be prepared by the method shown in Figure 10 (Figure 10). Chloride compounds containing r8 and r9 are usually used commercially available reagents and products and used Familiar with the techniques of this artist. The reaction usually produces a mixture of cis and trans configurations, and the trans isomers dominate. "When the cost of a cysteine protease inhibitor is a specific example, cis-trans The disappearance of isomerization is defined as the formation of a single compound. In a specific example, the cysteine protease inhibitor of the present invention is purified as needed after synthesis, for example, to remove unreacted substances. For example, the cysteine protease of the present invention The inhibitor can be crystallized, or the solvent mixture can be passed through a silica chromatography column to purify the inhibitor. In short, the method for preparing the compound of the present invention is as follows: -IIIIIIIII —-Order— Preparation (Please read the precautions on the back before writing this page) This paper size applies to Chinese national standards (CNS > A4 size (210XW7 mm) -54-470750 A7 B7 V. Description of the invention (52 ) (A) When formula IV is prepared: 0 R8

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs where η is 0 to 1 2 »R 2 0 is cyano, —s (0) 2R 2) — C Η 2S (c 丨) 2 R 2, — C Η 2 CH (; R 4) S (0) 2R 2, — (CH 2) 2 C (0) 0 R 10, — (CH 2) 2 P (0) (0 R 10) 2, — (CH 2) 2 s (0) (NR 1 0) R 11 0, — CH 2) 2 C (0) R 11 > One (CH 2) 2 S (0) R 11 9 — (CH 2) 2 c (0) NR 1 2 R 1 3, — (CH 2) 2 s (0) 2N R 12R 13, — (CH 2) 2 c (0) NHR 14, — (CH 2) 2 s (0) 2 NHR 14 or — C Η 2 CHR 1 5 R 16 and each of A, B, X, Y, Z, R 1, R 8, R 1, • R 8, R 2, R 10, R 11, R 12, R 13, R 14, R 15 and R 1 e are as defined in the brief description of the compounds of formulae I, II and III and their pharmaceutically acceptable salts, individual isomers and mixtures of isomers thereof 9 amines of formula v:

Reaction with the compound of formula VI: ------------ install ------ order ------ line (please read the precautions on the back first, write this page) Paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) # 2 '55-470750 A7 —____ B7 5. Description of the invention (& 3)

VI wherein η, A, B, X, Y, Z, R 1, R 8 and R 2 ° are as defined above (B) to prepare a compound of formula IV (where R 2 is a S (0) 2R 2) and its pharmacy Acceptable salts, individual isomers and mixtures of isomers: Compounds of formula VIII: o Human NH2

VII reacts with an aldehyde of the formula R8CH0 and sodium sulfenylsulfonate of the formula R2S (〇) 〇Na, wherein η, A, B, X, Y, Z, R1 and R8 are as defined above; (C) preparing a compound of formula IV (where R 2. It is printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the note on the back f ... 舄 this page)-S (0) 2R2) and its pharmaceutically acceptable salts and individual isomers When it is a mixture of isomers, (1) a compound of formula NH2P (wherein P is a protecting group) is reacted with an aldehyde of formula R8CH0 and sodium sulfenylsulfonate of formula R2S (0) ONa, followed by deprotection to produce a compound of formula VIII :

This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 470750 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _______ B7_ V. Description of the invention (54) where R 2 and R 8 are as specified in the brief description of the invention And (2) reacting a compound of formula VI1I with a compound of formula ¥ 1, wherein η ′ A, B, X, γ, Z, and R 1 are each as defined above; Wherein 2 ° is a CH2S (0) 2R2 and its pharmaceutically acceptable salts, individual isomers and mixtures of isomers, (1) a compound of formula X

Reacting with a thiolate anion of formula R2S-, where L is a leaving group · R and R 8 is as previously defined, yielding a compound of formula X:

Ks

(2) oxidizing a compound of formula X to produce a compound of formula X I:

(3) reacting a compound of formula XI with a compound of formula VI 'wherein η, A, B, X, Y, Z and P1 are each as defined above; (E) preparing a compound of formula IV (where R 2 ° is cyano- ( CH 2) 2 S (0) 2R2, I: i.. This paper size applies to China National Standard (CNS) A4 (210X297 mm) -57 一

It ------- install ------ order ------ 涑 (Please read the notes on the back before writing this page) 470750 A7 __B7___ V. Description of the invention (55)-(CH2 ) 2C (0) OR10--(C Η 2) 2 P (0) (OR10) 2 '-(CH 2) 2 S (0) (NR10) R 10 >-(CH2) 2C (0) R11, -(CH2) 2S (0) R1, — (CH 2) 2 C 0) NR 12R 13--(CH2) 2S (0) 2NR12R13,-(CH2) 2C (0) NHR 14 or — (CH2) 2S ( 0) 2NHR14) and pharmaceutically acceptable salts, individual isomers and mixtures of isomers thereof, (1) an aldehyde of formula XII

PHN

CHO reacts with compounds selected from formulas XIII and XIV R2io, 〇R2 ', R21 \ 丨 丨 R2 丨 R2 | / P, 520, 20 -------- install ------ order ---- --Line (please read the notes on the back to write this page first) XIII xiv printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economics where R 8 and R 2 ° are as defined previously, and then deprotected to produce the compound of formula XV

XV (2) The compound of formula XV reacts with the compound of formula VI 'where η, A, B, X, Y, Z, and R1 are each as defined previously' and the Chinese standard (CNS) A4 specification (210X297) for this paper size (Mm) -58-470750 A7 ____B7___ V. Description of the invention (56) (3) Reduction; (F) Preparation of compound of formula IV (where R 2 ° -C H2C HR15R16) and pharmaceutically acceptable salts, individual differences When the structure and the mixture of isomers are reacted, (1) the aldehyde of formula XI I reacts with the compound of formula XVI: V = P (Ph) 3 R16 XVI where R8, R1 5 and R1 6 are defined as before, and then deprotected to produce the formula XVII compounds: (Please read the precautions on the back before writing this page) R8 R15

XVII Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (2) The compound of formula XVI I reacts with the compound of formula VI, where η, A, B, X, Y, Z, and R1 are each as defined above, and (3) reduction (G) Selectively convert the non-salt form of the compound of Formula IV into a pharmaceutically acceptable salt; This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -59-470750 Central Standard of the Ministry of Economic Affairs A7 __B7 printed by the Bureau ’s Consumer Cooperatives V. Description of the invention (q (Η) selectively converts the non-salt form of the compound of formula IV into a non-salt form; and (ii) selectively separates the compound of formula IV further into individual Stereoisomers. In one specific example, the cysteine protease inhibitor of the present invention is labeled. The "labeled cysteine protease inhibitor" of the present invention means a cysteine protease inhibitor, which Attach at least one element, isotope or chemical compound to detect cysteine protease inhibitors or cysteine protease inhibitors bound to cysteine proteases. Generally, labels are divided into three categories: a ) Isotope labeling, which may be radioactive or heavy isotope; b) immunolabeling, which may be an antibody or antigen; and c) colored or fluorescent dyes. The label can be incorporated at any position of the cysteine protease inhibitor. For example, the label may be attached to the "R1" group in Formula 1, or a radioisotope incorporated in any position. Examples of usable labels include 14C, 3H, biotin, and fluorescent labels. Pharmacology and use Once the cysteine protease inhibitor of the present invention is made, its inhibitory effect can be easily screened. The inhibitor was first tested for cysteine protease, and the target group of the inhibitor was selected as before. Alternatively, many cysteine protease enzymes and their corresponding hair color receptors are commercially available. Therefore, in the presence or absence of a cysteine protease inhibitor, synthetic hair color and texture are used to periodically test various cysteine proteases using techniques well-known in the art to confirm the transformation -------- --- Packing ------ Order ------ Brigade (Please read the notes on the back before filling out this page) This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm)-60- 470750 A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs V. Description of Invention (58) The inhibitory effect of the compound. The effective protease was then subjected to a kinetic analysis' to calculate the κt value and the dissociation constant was determined. If the compound inhibits at least one cysteine protease ', it is a cysteine protease inhibitor for the purposes of the present invention. A preferred embodiment is an inhibitor having the correct kinetic parameters for at least one target cysteine protease. In some cases, cysteine proteases are sold in pure form. The cysteine protease inhibitors of the present invention can also be tested for efficacy using a bioassay. For example, the inhibitor can be added to a cell or tissue containing a cysteine protease and the biological effect can be measured. In one specific example, the cysteine protease inhibitor of the present invention is synthesized or decorated to reduce or prevent proteolytic degradation of the inhibitor in vivo and in vitro. Generally, this is accomplished by incorporating synthetic amino acids, derivatives or substitutions into cysteine-based protease inhibitors. Rarely, an unnatural amino acid or amino acid side chain is incorporated into the cysteine protease inhibitor only, so that the inhibitor does not have a significant impact on the targeting of the enzyme. However, using this specific example of a longer chain cysteine protease inhibitor containing several targeted residues may allow for more than one synthetic derivative. In addition, unnatural amino acid substitutions can be designed to mimic the binding of natural side chains to the enzyme, while allowing more than one synthetic substituent. Alternatively, winches and the like are used to reduce or prevent inhibitor degradation. In this specific example, a modified cysteine protease inhibitor can be tested for its in vitro positive resistance to various known commercially available proteases to determine its proteolytic stability. Prospective candidates can be regularly screened in animal models, such as making _ this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ~~~ ~ -〇1;-1 ._ ^ --- ----- ^ ------ 1T ------ # (Please read the notes on the back to write this page first) 470750 Printed by the Consumers' Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs A 7 · __B7 ______ V. Description of the invention (59) Use labeled inhibitors to determine stability and efficacy in the body. The selective cysteine protease which can be inhibited by the inhibitor of the present invention is a cysteine protease having a thiol group at the active site. Such proteases are found in bacteria, viruses, eukaryotic microorganisms, plants, and animals. Hemiprotease can be roughly separated into one of four or more different subfamilies. Examples of cysteine proteases that can be inhibited by the novel cysteine protease inhibitors of the present invention include, but are not limited to, plant cysteine proteases such as papain, fig protease, tung protease, rice protease, and kiwifruit. Proteases: mammalian cysteine proteases, such as cathepsins B, H, J, L, N, S, T, 0, and C (cathepsin C is also known as dipeptidyl peptidase I), melanin converting enzyme ( ICE), calcium-activated neutral proteases, ca 1 pai η I and II; brussels hydrolyzing enzymes, viral cysteine proteases, such as picornavirus proteases 2 A and 3 C, Aphthous virus endonucleases, cardiovirus endonucleases, cowpea mosaic virus endonucleases, potato y virus peptide endonucleases I and II, adenovirus peptide endonucleases, chestnut wilt Viruses, mantle virus cysteine endopeptidases, and cysteine proteases of polio and rhinoviruses; and cysteine proteases necessary for the life cycle of known parasites, such as from malaria Worms, ajuba, Onchocerca, Trypanosoma, Leishmania, Reverse Nematode, Dietos-telium, Therileria and Schistosoma, such as concurrent malaria (P. falciparium), trypanosoma (T. cruzi, this enzyme is also known as Cruzain or cruzipain), mouse P. vinckei and c. El egans cysteine proteases. Can be borrowed cysteine protease inhibitors This paper size applies to China National Standard (CNS) 8 4 specifications (210X297 male thin) --------- Attack -------- Order ---- --Bing (please read the notes on the back before filling this page) -62-470750 Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs printed A7 B7__ V. Description of the invention (60) Complete list of inhibited cysteine proteases See Rawlings et al. 'Biche in. J. 290.205-218 (1993)' for reference. Therefore, inhibitors of cysteine proteases have a wide range of uses. For example, the inhibitors of the present invention are used to quantify the content of cysteine protease in a sample, and are therefore used in blood, lymph, saliva, or other tissue samples' and bacteria, molds, plants, yeast, viruses, or mammalian cells Assay and diagnostic kit for quantification of cysteine protease in culture. In a preferred embodiment, a standard protease test sample is used. A known concentration of a cysteine protease inhibitor is added to bind to a specific cysteine protease. Protease assays are performed, and loss of activity is corrected or cysteine protease activity using techniques known to those skilled in the art. Cysteine inhibitors can also be used to remove or inhibit contaminating cysteine proteases from samples. For example, the cysteine protease inhibitor of the present invention is added to a sample which is not expected to be hydrolyzed and degraded by a contaminating cysteine protease. Alternatively, the cysteine protease inhibitor of the present invention may be bonded to a chromatographic support using a technique known in the art to form an affinity chromatography column. Samples containing undesired cysteine proteases were passed through the column to remove proteases. In a preferred embodiment, a cysteine protease inhibitor can be used to inhibit cysteine protease involved in several diseases. In particular, it inhibits cathepsins B, L, and S, cruzain, chuckase I and I I, and melanin 1 yS converting enzyme. This enzyme is an example of lysosomal cysteine protease in various diseases with tissue degradation characteristics. This disease includes the Chinese paper standard (CNS) A4 specification (210: ^ 97 mm) of this paper standard (please read the precautions on the back before filling this page) Pack-470750 Printed by the Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs A7 B7 5. Description of the invention (61) (but not limited to) arthritis, itching of muscles, inflammation, tumor attack, filamentous nephritis, infections caused by parasites, Alzheimer's disease, gum disease, and cancer Transfer. For example, mammalian lysosomal thiol proteases play an important role in the intracellular degradation of proteins and the processing of certain peptide hormones. Enzymes like cathepsins B and L are released by tumors and may affect tumor metastasis. Cathepsin L is found in synovial fluid and transformed tissues of patients. Similarly, cathepsin B and other lysosomal proteases are released by polymorphonuclear granulocytes and macrophages during trauma and inflammation. Cysteine inhibitors can also be used in a variety of other diseases, including (but not limited to) gingivitis, malaria, Leishmaniasis, filariasis, and other bacterial and parasitic infections. The compounds can also be used in viral diseases, which are mainly based on the research of protease inhibitors required for viral replication. For example, many parvoviruses include polioviruses, foot and mouth disease viruses, and rhinoviruses that encode the cysteine protease enzymes required to cut viral polyproteins. In addition, these compounds can be used in diseases including melatonin-1 cold invertase (ICE), cysteine proteases that can treat melanin 1/5; for example, the treatment of lung, trachea, central nervous system and Peripheral membranes, eyes, ears, joints, bones, connected tissues, cardiovascular system (including the heart capsule, gastrointestinal and urogenital systems), skin and mucosal inflammation and immune diseases. Such diseases include infectious diseases of active infections in any part of the body, such as meningitis and salpingitis; concurrent infections include septic shock, multiple intravenous coagulation, and / or symptoms of dyspnea in adults; due to antigens Acute or chronic inflammation caused by the deposition of antibodies, antibodies and / or complements; the size of the paper is applicable to the Chinese National Standard (〇 呢) 6 4 specifications (210 father 297 mm) _from ---------- t .— (Please read the notes on the back before filling out this page) Order-Line. 470750 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (62) Inflammatory conditions including arthritis, Chalangitis, colitis , Encephalitis, endocarditis, filamentous nephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis. Immune-based diseases include, but are not limited to, conditions involving T-cell N and / or macrophages, such as acute and prolonged allergies, transplant rejection, and graft-to-host disease; autoimmune diseases, Includes type I diabetes and multiple sclerosis. Bone and cartilage resorption and diseases causing excessive deposition of extracellular matrix, such as interstitial lung fibrosis, liver changes, systemic sclerosis, and keloid formation can also be treated with the inhibitors of the present invention. The inhibitor can also be used to treat specific tumors that produce 1 L 1 as an autocrine growth factor, and to prevent cachexia produced by specific tumors. Apoptosis and cell death also have I C.E and I C E-like activities, which can be treated with the inhibitors of the present invention. In addition, the cysteine protease inhibitor of the present invention is applicable to pharmaceutical applications. For example, therapeutic agents such as antibiotics or antineoplastic agents can be rendered ineffective or inactivated by the endogenous cysteine protease through proteolytic breakdown. For example, it has been found that bleomycin and antineoplastic drugs can be hydrolyzed by bleomycin hydrolase and cysteine protease (see Sebti et al. Cancer Res. January 1991, pp. 227-232). Therefore, the cysteine protease inhibitor of the present invention can be administered to a patient together with a therapeutic agent to increase or increase drug activity. Such co-administration may be administered simultaneously, such as a mixture of a cysteine protease inhibitor and a drug, or they may be administered simultaneously or sequentially. In addition, cysteine protease inhibitors have been found to inhibit bacterial growth, especially human pathogenic bacteria (see Bjorck et al., Nature U3 (please read the precautions on the back before filling out this page),-^ Paper size Applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) cc -00 470750 Employees' cooperation cooperation with the Central Standards Bureau of the Ministry of Economic Affairs Du printed A7 B7 5. Invention Description (6 $ 337 ·· 385 (1989)) »Therefore The cysteine protease inhibitor of the present invention can be used as an antibacterial agent to retard or inhibit the growth of specific bacteria. The cysteine protease inhibitor of the present invention can also be used to reduce the effect of bacterial cysteine protease on host organisms. Harmful agents. For example, staphylococci produce extremely active extracellular cysteine proteases that degrade insoluble elastin, which may be due to associations in bacterial infections such as sepsis, septic arthritis, and otitis Tissue destruction. See Potempa et al., J. Biol. Chem. 263 (6): 2664-2667 (19 8 8). Therefore, the cysteine protease inhibitors of the present invention can be used to treat bacterial infections, to The cysteine protease inhibitor of the present invention is usually administered in a therapeutically effective amount via any one of the generally accepted modes known in the art, and can be used alone or in combination with another half of the present invention. Cysteine protease inhibitors may be administered in combination with another therapeutic agent. A therapeutically effective amount may vary greatly depending on the severity of the patient's disease, age and relative health, the effectiveness of the compound used, and other factors. The cysteine protease inhibition of the present invention The effective amount of the agent ranges from 10 micrograms (Mg / kg) per kilogram of body weight to 10 milligrams (mg / kg) per kilogram of body weight per day, and generally ranges from 100 Aig / kg / day to 1 mg / kg / day. Therefore, For humans of 80 kg, the therapeutically effective amount ranges from 1 mg / day to 100 mg / day, and generally ranges from 10 mg / day to 100 mg / day. This paper standard applies Chinese National Standard (CNS) A4 Specifications (210X297 mm) ---------- install ------ order ------ ice (please read the precautions on the back before filling this page) 470750 C7 D7 printed by the Bureau ’s Consumer Cooperatives V. Creation Instructions (64) General familiarity with treating the disease The skilled artisan can determine the therapeutically effective amount of the cysteine protease inhibitor of the present invention for a specific disease based on personal knowledge and the discovery of the present invention without undue experimentation. Generally, the cysteine protease inhibitor of the present invention is Administration is in the form of a pharmaceutical composition by one of the following routes: oral, systemic (eg, percutaneous, intranasal, pulmonary, or suppository) or parenteral (eg, intramuscular, intravenous, intrapulmonary, or subcutaneous). The composition may be in the form of a tablet, pill, capsule, semi-solid, powder, sustained release formulation, solution, suspension, elixir, aerosol or any other suitable composition, which usually contains the cysteine protease of the present invention Inhibitor, combined with at least one pharmaceutically acceptable adjuvant. Acceptable adjuvants are non-toxic, adjuvant and do not adversely affect the therapeutic advantages of the cysteine protease inhibitors of the present invention. The adjuvant can be any solid, liquid, semi-solid or (if aerosol composition) gas adjuvant generally available to those skilled in the art. Solid pharmaceutical adjuvants include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, maltose, rice, flour, paeony, silicone, magnesium stearate, sodium stearate, glycerol monostearate, chlorinated Sodium, dry skimmed milk powder, etc. Liquid and semi-solid adjuvants can be selected from water, ethanol, glycerol, glycerol and various oils, including petroleum, animal, vegetable or synthetic sources (such as flower oil, soybean oil, mineral oil, sesame oil, etc.). Preferred liquid carriers, especially injectable solutions, include water, salts, aqueous dextrose and glycols. Compressed gas can be used to disperse the cysteine protease inhibitor of the present invention into an aerosol. Inert gas systems suitable for this purpose include nitrogen, carbon dioxide, nitrous oxide, and the like. Description of Other Suitable Pharmaceutical Carriers and Their Formulations The paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) C7

-DI (Please read the notes on the back before ¥ for this page) r 470750 C7 D7 Printed by the Central Consumers ’Association of the Ministry of Economic Affairs and Consumer Cooperatives. V. Creative Instructions (65) In AR Alfonso Reminton's Pharmacent i ca 1 Sciences 1985, 17th edition, Easton, Pa.: Mack Publishing Compang, here for reference. The dosage of the cysteine protease inhibitor of the present invention may vary greatly depending on the type of formulation, the size of the unit dosage form, the type of adjuvant, and other factors known to those skilled in the pharmaceutical sciences. Generally, the final composition contains 0.1 to 10% W cysteine protease inhibitors, preferably 1% to 10% w, and the rest are adjuvants and auxiliary groups. Preferably, the pharmaceutical composition is administered in a unit dosage form for continuous treatment, or when the symptoms are particularly required to be relieved, it is optionally administered in a unit dosage form. A representative pharmaceutical formulation containing a cysteine protease inhibitor of the present invention is described in Example 20 below. The following examples are provided to fully describe the manner in which the foregoing invention is used, and to list the largest modes for carrying out various aspects of the invention. It is known that this example does not limit the practical scope of the present invention in any way, but is only used for illustration. All references listed in this article are here for reference. Examples Use the following abbreviation conventions to simplify the examples. Mu = Morpholine urea X aa! = Amino acid X aa 2 located at Pi position relative to the active site of the enzyme X = aa 2 = P i position relative to the active site of the enzyme The Chinese paper standard (CNS) ) A4 size (210X297mm) _ 68 _ (please read the precautions on the back before V bird page) • Install. Order i-line 470750 C7 V. Creation instructions (66) Amino acid r--c 0 2 E t = r _aminoethyl hydrazone--s 0 2 P h = r -amino group with phenyl terminal r--c 0 2h = r -aminocarboxylate r ~ -PE t = r. -amine Phosphonate r--AM = r -aminoaminoamine r--A r (Sub) γ--amino aromatic compound (appropriately substituted) β — s 0 2 P h = with phenyl substituent Β-amino group a-s 0 2 P h-a with phenyl substituent a —amino group P h homophenylalanine P SMP = benzenesulfonyl methylphosphonic acid diethyl ester NP 2 = 2 — some aniline S 〇2 2! N p = boron with 2 —m terminal P hac = phenethylfluorenyl β — A 1 a β — alanine M e 〇S 1 1 c = Methoxymethane, for example, 1 \ / 111- -P he--Η ph--β--S 0 2 in X aa 2 = P he (phenylalanine) and X aa 1 = economic Printed by the Ministry of Standards and Staff ’s Consumer Cooperatives (please read the precautions on the back, and write this page). Phenylalanine)) is converted into amine benzene stone according to the method described in the example. Example 1 This paper containing r-amino ester as an EWG is suitable for the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 69 _ 470750 Central Office of the Ministry of Economic Affairs®; printed by the Industrial and Consumer Cooperative

Cl D7 V. Creative Instructions (67) Synthesis of Cysteine Protease Inhibitors Unless otherwise stated, all reactions are performed at room temperature under an inert atmosphere of argon or nitrogen. THF was distilled from benzophenone · sodium K ety 1. All other solvents and commercially available reagents were used without purification. (S) — 4 — (4 —morpholinecarbonylphenylpropylamine hydrazone) —amino — 6 —phenylhexanoic acid ethyl ester—Mu — P he — H ph — r — C Ο 2 E t _ is synthesized as follows . Unless otherwise stated, all reagents were obtained from Aldrich, Inc. A solution of phosphorous carboxytriethyl acetate (2.20g, 9.82mmoi?) In THF (50mi?) At a temperature of 10 ° C was added with 0.39 3g of sodium hydride 60% mineral oil dispersion (9 8 2mm〇P). The mixture was stirred for 15 minutes. Boc-HphH (2. 3 5 g) 9. 82mmo 芡 was added there.

A Fehrentz method was used to convert a solution of Boc_-homophenylalanine (Synthetech) to its N, 0-dimethylhydroxylamine, followed by reduction with lithium aluminum hydride, in THF (20 m $). The mixture was stirred for 45 minutes. Add IMHCj? (30mJ?). The product was extracted with ethyl acetate (50m5), washed with a saturated NaHC03 aqueous solution (30mj?), Dried over MgS◦4, filtered, and evaporated to dryness. The dried material was dissolved in CH2CJ? 2 (10m $), and a 4.0M solution (20mJ?) Of HCj? In dioxane was added. The mixture was stirred for 30 minutes. The solvent 'was removed under reduced pressure and the residue (S) —4-amino-6-phenyl-.2-hexanoic acid ethyl ester hydrochloride was pump-dried. This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ _ _ 1 ~~~~ Thread setting (please read the precautions on the back first, then this page). 470750 A7 B7 Central Bureau of Standards, Ministry of Economic Affairs Printed by the Consumers ’Cooperative Cooperative V. Description of the invention (68) 1 1 4 —Morpholine carbonylphenylalanine (M U — P he 0 Η 1 1 2 7 4 g 9 8 2 mm 0 Meaning according to Esser, R., etc. Human 1 1, Ar th riti S & Pheumat i sm (1 9 4 I— [), 37, / —ν 1 I 2 3 6) Prepared in τ HF (-10 ° C) ( Please kj read 1 1 5 0 m Si) and add 4 — methyl codeline (1 0 8 m meaning, back 1 I 9 8 2 mm 0) followed by isobutyl chloroformate (note 1 1 1 1 2 7 m) 9 8 2 mm 0 i?) 0 mixed with anhydride, stirred for 10 minutes, and then added 1 where (-) W- 刖 step (S) — 4 -amino — 6 — filled in 1 pack Phenyl-2-hexenoate ethyl hydrochloride η · Λ * salt in D MF (10 mi?) Page 1 solution followed by 4-Methylmorpholine (108 m and 1 I 9 8 2 mm 0). The mixture was stirred for 1 hour. 1 I 1 M Η C (50 m) was added. The product was ethyl acetate (1 0 0 m 芡). 1 order 1) Extraction was washed with saturated N a Η C 0 3 aqueous solution (E) 0 m ^), 1 1 1 was dried with Mg S 0 4 and decolorized with charcoal (DARC 0), filtered and steamed 1 1 dried to produce 3 80 g of intermediate (80% yield starting from B 0 C-homophenylalanine 1) 0, silver 1 The intermediate (1 4 5 m il 3 0 9 mm ο) in ethanol 1 I alcohol To the solution in (25 m) was added 5% palladium (1 105 g) on activated carbon. The mixture was reduced on a Parr hydrogenator for 36 hours. 1 1 'm filtered the solution under reduced pressure to remove the solvent to produce 191 g (1182%) of the product. 0 1 1 TLC was performed on each sample. 2 5 4 η UV light of τη 1 I > is then developed by the second ketone, bromocresol green, or p-anisaldehyde dye 1 I U M — P he — Η P h — r — C 0 2e t of 1 1 1 Non-paper Fandu Tongzhou T hoarding standard (CMS J A4 is now available (210 X297 mm J-71-470750 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (69) 1 | Stay The factor (R f) is 0.3 5 (5% Me 0 Η / 1 1 C Η 2 C ^ 1 2) 0 1 1 Record the NMR S 1 1 on a Var i an Gem ini 300MHZ device. The spectrum please 1 0 this All 1 Η NMR data of the examples and subsequent examples are recorded as 1 1 δ value of 1 part of 1 fraction per million read back relative to the internal tetramethylsilane (the peaks marked in bold type) 0 Use The following shrink Write: S, single line; d, double attention 1 line matter 1 t, double line q quartet line; br, wide peak. An asterisk (*) term followed by 1 indicates that the message is blurred or hidden under another resonance. Fill in the writing page____ »1 | Example 2 1 1 1 containing r —aminoboron to act as EWG's cysteine protease inhibitor 1 1 Synthesis (S) — 3 — third butoxycarbonylamino group — Synthesis of 5 -phenyl-1 -benzenesulfonidine 1 pentane (B 0 C — Η 0 h — r —S 0 2 P h) 1 IPS Μ Ρ (8 8 7 mj ?, 3 0 3 4m m 〇 芡) Sodium hydride (1 I 1 2 1 g 60 0% mineral oil dispersion) was added to the solution in 1 1 1 T Η F (150 m) at 0 ° C. The mixture was stirred for 2 0 minutes 1 1 * Add 1 1 B 0 C —Homophenylalanine (7.99 g, 1 1 3 0 • 3 4 mm 0 Si) synthesized by Fe • Hentz and Costro method to T Η Solution in F (20 m5). 1 1 Stir the solution at 0 ° C for 30 minutes. 1 M HC 9. (1 I 100 m 9.) was added. The product was extracted in ethyl acetate (100 mi), 1 I was a saturated sodium carbonate aqueous solution (100 m), and brine (50 m 9). 1 1 I) Wash and dry with MG S 0 4, filter, and remove the solvent under reduced pressure. 1 1 This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) -72-470750 Central Standard of the Ministry of Economic Affairs Bureau ωκ; Printing by Industrial and Consumer Cooperatives f. A7 B7 V. Description of Invention (70). The residue was dissolved in ethanol (100 mj?) And transferred to a Parr bottle containing 5% palladium (0.92 g) on activated carbon. The mixture was reduced on a Parr device for 24 hours. The solution was filtered through Ce 1 ite and the solvent was removed under reduced pressure. The product's T L C showed a single product in quantitative yield, Rf = 0.29 (30% ethyl acetate / hexane), and was dyed white with p-anisaldehyde. Example 3 Synthesis of a Cysteine Protease Inhibitor Containing r-Amine Boron as EWG (S) — 3 —Amine — 5 —Phenyl — 1 —Benzene Expansion — Ethyl Hydrochloride (HCi? .Hph-r_S02Ph) Synthesis. To a solution of Boc-Hph-r-S02Ph ((12. 24mj ?, 30. 34mmoj?) In dichloromethane (20m), was added hydrogen chloride in dioxane (5.0Mm? Of 4.0M solution). The mixture was stirred for 90 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in CH 2 C 5 2 (50 m). The solution was carefully added to the stirred ether (500mj?). The solid was filtered off, Wash with ether (50mj?) And dry in vacuum. Example 4 Synthetic I 11 n 1 n 111 11 thread containing ramine group cysteine protease inhibitor EWG (please read the back first) Please pay attention to this page and write this page again.) This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm)-(〇470750 printed by the Central Ministry of Economic Affairs of the People's Republic of China and the Consumer Consumption Cooperative A7 __ B7 _V. Description of the invention (71) Synthesis of (S)-3 ™ (4-morpholine carbonylphenylpropylamine hydrazone) -amino-S-phenyl-1 -benzenesulfonylpentane (Mu_Ph e—Hph — r — S02Ph). Mu — A solution of PheOH (2.94g '10 .56mm〇5) in THF (75m 芡) was added with 4 -methyl codeline (1-16m] ?, 10-56mmoe) and chloroformic acid under 10 different Butyl ester (1.37mi2 '10. 56mm〇i2). The mixture was stirred for 5 minutes. Addition Wasworth-Emmous condensation of B oc-homophenylalanine and deprotection of p-toluenesulfonic acid (S) — (E)-3 -amino- 5 -phenyl-1 -benzenesulfenamidine-1 -pentene p-toluenesulfonate (500 g > 1 0.56 mm 〇 ^), followed by 4 -Methylcodeline (1-16mj ?, 10.56mm〇i?) »The mixture was stirred for 45 minutes. The solution was diluted with ethyl acetate (100mj), and 1MHCj? (2x50m $), saturated bicarbonate Aqueous sodium solution (50 mj?), Brine (50 mi2), washed with MgS04, filtered, and the solvent was removed under reduced pressure. The residue was crystallized from CH2C and 2 / ether to produce 4.27g / (72%) intermediate 1.17g This material (2.08mm〇i2) was dissolved in ethanol (25m ^). The solution was transferred to a Parr bottle filled with 5% palladium (0.30g) on activated carbon. The mixture was at room temperature Hydrogenated overnight on a Parr shaker. Ethyl acetate was added to a suspension of the product, which was crystallized from the reaction mixture. The solution was filtered and concentrated in vacuo, followed by recrystallization from CH 2 Cj 2 / hexane. Μ_Ρ · = 176—178 ° C «TLC (50% ethyl acetate / CH2Cj? 2) Rf = 0.24. -η-This paper size applies Chinese National Standard (CNS) Α4 specification (210X297 mm) ί -------- Meals ---------, 1Τ ------- ^ ( Please read the precautions on the back first-write this page on T4) 470750 A7 B7 Printed by the Central Standard of the Ministry of Economy for Employees' Cooperatives V. Description of the Invention (72) Example 5 Containing r-Aminosulfone as EWG Cysteine Synthesis of Protease Inhibitors (S) — 3- (4-morpholinecarbonyltyrosine hydrazone) —amino-5 —phenyl-1 —benzenesulfonylpentane (Mu — Ty r — Hph — r_ S〇2Ph) Of synthesis. 4-Morpholine carbonyl tyrosine (Mu — Ty r OH 'was synthesized according to the method of Esser, R. et al., Arthritis & Rheumatism (1994), 37, 236, 0 0 0 g-1. 70 mmoj?) MTHF ( 10mj?) Was added at a temperature of 10 ° C 4 monomethylmorpholine (〇_ 187mj ?, 1. 70mmoj?) And isobutyl chloroformate (0.22 m > 1. 70mm〇i2 ). After 5 minutes, HCI? · Hph-r-S02Ph (0.57 7 g '1 · 70mm〇i ?, described in Example 3) was added, followed by 4-methyl codeline (0. 187mj ?, 1. 70mmo again). The mixture was stirred for 45 minutes. Ethyl acetate (50 mj2) was added. The solution was washed with INHCj ?, a saturated aqueous solution of sodium bicarbonate, and a salt (30 ηβ each), dried over Mg S 04, filtered, and the solvent was removed under reduced pressure. The residue was precipitated from CH2C52 / ether to give 0.58 g (59%) of Mu-Tyr-Hph-r_S02Ph. MP104-107 ° C TLC: (10% MeOH / CH2Cj? 2) Rf = 0.59. 1._〆 -------- t .------- IT ------. ^ (Please read the notes on the back before writing this page) This paper size is applicable to China Standard (CNS) A4 specification (21 OX297 mm) _ 75 470750 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 ________ B7 V. Description of the invention (Example 6 Contains r-aminoamidine to be used as cysteamine of EWG Synthesis of Acid Protease Inhibitors (S) — 3- (4-morpholinecarbonyl-2—fluorenylpropylamine 醯) -amino-5-phenyl—1— (2 —sulfonylsulfonium) pentane (Mu — Np2 — Synthesis of Hph — r — S02Np). Dissolve 2-mercaptan mercaptan (9. 64g / 60. 16mmoj?) In toluene (75m). Add para-formaldehyde (3.97 g > 132mmo Ai) and HCj / Dioxane (33m ^ 4. OM solution). The mixture was stirred at room temperature for several days. The solvent was removed under reduced pressure, and the residue was suspended in hexane (200mj?) And dried on Mg S 04. Filtered and evaporated to dryness. This material-crude chloromethyl 2-a certain sulfide-was combined with triethyl phosphite (19.9 g, 65 mmo again) and heated at reflux for 4 hours. The mixture was cooled to room temperature, and ether ( 200mj?) Diluted to IMHCj ?, Saturated aqueous sodium bicarbonate solution and brine (150mj each) were washed, dried over MgS04, filtered ', and concentrated in vacuo to yield 17.35g (93% crude yield) 2-a thiothiomethylphosphine Diethyl acid. This material was dissolved in CH 2 C 2 (300 mi?) And cooled to 0 ° C. Peracetic acid (23. 5mj? 3 2% dilute acetic acid solution, Aldrich Chemical Co.) was carefully added. Mixture Residues are allowed to flow at room temperature to room temperature. The solution is washed with an initial, saturated aqueous solution of sodium hydrogen sulfite (100 m ί). Please read the notes at the back and fill in the following: Write this page This paper is for China National Standard (CNS) A4 specification (210X297 mm) 76-470750 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (74) Wash with several saturated aqueous sodium bicarbonate solution until the water phase becomes alkaline The organic phase was dried over M g S 0 4, filtered and the solvent was removed under reduced pressure. Chromatography on a 60-200 mesh silica gel (0-10% ethyl acetate / CH2C j? 2) yielded 6 5 g (34%) pure Wadsworth-Emmons reagent 2-a diethyl sulfonylidene methylphosphonic acid, and an impurity of about equal quality TLC (20% ethyl acetate / CH2Ci? 2) Rf = 0.37. A solution of diethylsulfonium methylphosphonic acid diethyl ester (3.91 g, 11.42 mmo) in THF (60 mj?) Was added at 0 ° C, sodium hydride (0.4 5 7 g 6 0% Mineral oil dispersion). The mixture was stirred for 15 minutes, and a solution of Boc-homophenylalanine (3.0 g, 11.42 mmo) in THF (5 mj) was added thereto. The mixture was stirred for 30 minutes. Add IMHCj? (100m and up). The product was extracted with ethyl acetate (100 m $), washed with a saturated aqueous sodium bicarbonate solution (75 m), brine (50 mj?), Dried over MgS04, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (10m sense), and HCj? / Dioxane (25mj? 4.0M solution) was added thereto. The mixture was stirred at room temperature for 1 hour, poured into diethyl ether (300 m), and filtered. The solid was washed with diethyl ether (2x5 Omj) and dried in vacuo to give 3.30 g (from Boc-homophenylalanine, 74%) (S)-(E) _3-Amino-5 —Phenyl-1 1- (2-sulfosulfuronium) _1-pentene. Boc-2 —Alanine (2.68g, -77-This paper size is applicable to China National Standard (CNS) A4 specification (2 丨 0 '乂 297mm) -----.--- Package ---- --ΐτ ------- m (Please read the precautions on the back before writing this page) 470750 Printed by Zhengong Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs, A7 B7__ _V. Description of the invention (μ) 8. 51mm 〇P (S y η ΐ hetech, 0 reg ο η) in THF (50mj?) Solution at -10 ° C was added 4-methyl codeline (0. 936mi ?, 8. 51mmoj?) And chlorine Isobutyl formate (1.13 m »8. 51mmoj?). The mixture was stirred for 5 minutes, and (S)-(E)-3-amino_5 —phenyl — 1 — (2 — a sulfonic acid) was added to the mixture. Ii) 1-pentene (3.30 g '8. 5 1 mm 〇j?), Followed by 4-methyl codeline (0.936 mj ?, 8. 5 1 mm 0). The mixture was stirred for 45 minutes, Diluted with ethyl acetate (100m?), Washed with IMHCj? (50m £), saturated aqueous sodium bicarbonate solution (50mj?), And brine (50m), dried over Mg S04, filtered, and under reduced pressure Remove the solvent. Intermediate (S)-(E) —3- (Third-butoxycarbonyl-2—fructylpropylamino) amino-5 Phenyl-1— (2-sulfenamidine)-1-pentene was crystallized from a suitable mixture of CH2C j? 2 / ether / hexane with a yield of 69% (3. 83g, 5.90mmoJ2). In CH2Ci? 2 (5mi2) and treated with HC ^ / dioxane (15 m 4.0 solution). The mixture was stirred at room temperature for 1 hour. The solution was poured into ether (500 m with stirring). ) And filtered. The solid was washed with diethyl ether (2 X 50 mP) and dried in vacuo to produce the intermediate (S) — (E) — 3 — (2-¾diaminase)., Monoamine — 5-benzene The base 1_ (2—a certain fluorene) —1—pentanthene, 3.41g, 99% yield. 2. 00g of this material (3.42mm) is dissolved in THF (1 5 m)?), And cooled to 0 ° C. The size of the basic paper added with 4-methylmorpholine carbonyl is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ~~~~ IK -------- installation ---- --- Order -------- line (please read the note on the back WV4 first to write this page) 470750 The central standard of the Ministry of Economic Affairs is the printing bag A7 B7 of the consumer consumer cooperative V. Description of the invention (76> Chlorine (0 · 40πιβ, 3.42mmo) and triethylamine (0.953 mm). The mixture was stirred at 0 ° C for 1 hour 'and then at room temperature for 2 hours, and ethyl acetate (50 m j?) Was added. The solution was washed with IMHCj? (30mj?), Saturated aqueous sodium bicarbonate solution (30m), brine (30m) 2), dried over MgS04, filtered and evaporated to dryness, yielding 1.58 (69%) of intermediate (S ) — (E) — 3_ (4 —morpholinecarbonyl — 2 —propylpropylamine 醯) amino — 5 —phenyl — 1 — (2 —sulfonylsulfonium) — 1-pentene. TLC: (50% ethyl acetate / hexane) Rf = 0.37. 0.73 g (1.0 mmoi?) Of this material was dissolved in ethanol (20 m) and transferred to a Parr bottle containing 5% palladium on carbon (0.30 g). The mixture was reduced on a Parr hydrogenator for 36 hours. The solution was filtered and the solvent was removed under reduced pressure. The product was purified by column chromatography on 60—200 mesh silica gel (50% ethyl acetate / CH2C $ 2 as eluent) to yield 0.14 g (19%) of pure product, Mu-

Np2 — Hph—r — S022 Np ′ and impurities. TLC = (50% ethyl acetate / CH2Cj? 2) Rf = 0.34. Example 7 Synthesis of Cysteine Protease Inhibitor Containing r-Amine Boron as EWG Ac— Tyr— Va 1— A1 a—Asp The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 79 (Please read the precautions on the back first-write this page on T4)

、 1T 470750 A7 ____________ B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. V. Synthesis of the invention (77) —T — SOsPh). Sodium hydride (.489s 60% mineral oil dispersion, i2_23mmoj?) Was added to benzylsulfonium methylphosphonic acid diethyl ester (3.58g, 12_23mmoi?) In 50mJ? THF 0 ° C solution. The mixture was stirred for 15 minutes. Add B〇c-AsPH (iS_Ot—Bu) (3.04g'll. 12mmo 爻, by converting B〇c-Asp (石 一 0 — t ~ B u) to its N, ◦ dimethyl hydroxyl Prepare ammonium amine and reduce it with lithium aluminum hydride) in THF (10 mj?). The mixture was stirred for 1 hour. Add 1MHC々 (30mj?) To him. The product was extracted with ethyl acetate (100 mj?), Saturated with a saturated aqueous solution of NaHC03 (30 mj?), Brine (30 m ^), dried over MgS04, dried over water, and evaporated to give an intermediate. Chromatography on silica gel (20-30% ethyl acetate / hexane, gradient elution) yielded 2.07g 45%) intermediate (S) _ (E) — 3 — second butoxyferoxamine — 4 — The third butyloxy-1,1-benzene fluorene, 1-butene. This material was dissolved in ether (2mj?) And treated with a solution of anhydrous p-toluenesulfonic acid (1.0 g, 5.87mmoj2) in ether (2mj?). The mixture was stirred at room temperature overnight and then diluted with diethyl ether (2.5 m β). The precipitate was filtered off, washed with ether and dried in vacuo to yield 0_80g (95%) of the subsequent intermediate (s) — (E) — 3 —amino — 4 — butoxycarbonyl — 1 benzenesulfonium _1- Butene p-toluenesulfonate. Using mixed anhydride chemistry, this substance is coupled to A c — T yr — V a 1 — A 1 a OH (prepared by standard chemistry) to produce subsequent intermediates I _-" 丨 This paper size applies Chinese national standards (CNS ) A4 specification (210X 297 mm) ---------- install ------ order ------ line (Please read the precautions on the back before filling this page) 470750 Ministry of Economic Affairs Printed by the Consumer Standards of the Central Standards Bureau A7 ______B7_ V. Description of the invention (78) (S) — (E) —3 — Ethyl tyramine, valamine, propylamine, amine — 4 — Second butoxymine-based — 1 Benzene base 1 1 suspicion. The material was treated with trifluoroacetic acid to remove the third butyl ester of the aspartic acid side chain to produce (E) _. 3 —Ethylacetamide, valamine, propylamine, amine-1, 4—via carbonyl—1—benzenesulfonium —1— Butene. 0.28 g (0.444 mmoj?) Of this material was dissolved in ethanol (10 mj?). The solution was transferred to a Parr bottle (filled with 5% palladium on carbon 0 · lg). The solution was reduced on a Parr hydrogenator overnight. The solution was filtered and the solvent was removed under reduced pressure. The residue was dissolved in methanol (5m $) and diluted with 40 × l: 1 C H2C j? 2 / ether to form a gelatinous precipitate, which was collected on a Buchner funnel to yield 0.18 (64%) yield. The ratio of the S to R isomers relative to the As p residue is approximately 3: 1 based on the integral of the double line of the aromatic region of the Ty r residue in NMR. Example 8 Synthesis of Cysteine Protease Inhibitor Using E-amino Carboxylate as EWG (S)-4- (4-morpholinecarbonylphenylpropylamine fluorene) amino-6-phenylhexanoic acid Mu — Ph e — Hph — r — C02H Synthesis. To a solution of Mu_P he — Hp h — r -C 0 2 E t (0.5 g'l · 06 mm), prepared according to the method described in Example 1, was added a Na 0 H aqueous solution (1 m 2 M solution) . The reaction was complete after 4 hours. Simultaneously add 1MHC) 2 (4mi2) and water (l0mi?) _ _ 1 I '. — -......... This paper size applies Chinese National Standard (CNS) A4 specification (2 丨 OX 297 Mm) -81 _ (Please read the notes on the back before filling out this page) 470750 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () 1 I 〇 The product is C Η 2 C j? 2 (2 X 1 0 m) > T Η F (15) 1 1 Extraction was dried with MG S 0 4 and the solvent was removed under reduced pressure. The residue 1 1 Μ U — P he — Η Ρ h — r — c 0 2h pump into solid • Yield = ί | please 1 0 3 0 (60%) 0 Hu 1 1 back 1 | example 1 implementation 9 meaning 1 1 r-aminophosphonate is cysteine of EWG Protease inhibitors β 1 1 transcripts 1 Sheet '— ^ 1 I (S) — 4 — (morpholine carbonyl phenylpropyl Amine 醯) Amino-6-phenyl 1 1 1 Diethyl hexaphosphonate is synthesized as follows: Tetraethyl methyldiphosphonate (1 I 2 0 0 g 6 9 4 mm 0) at T Η F (3 0 mj?) Add sodium hydride (0 2 7 8 g 6 0% mineral oil dispersion 1 1 | liquid »6 9 4 mm 0) in the solution of the formula I. The mixture foams quickly and then clarifies 1 1 I 0 After 5 minutes, add a solution of Β 0 C — Η P h Η (1 8 3 g 5 1 1 thread 1 6 9 4 mm 0) in T Η F (5 m parent). The mixture was stirred for 1 hour. 0 Μ Η C Si (2 0 m) was added. The product was extracted 1 1 in ethyl acetate (5 0 m) with saturated Na Η C 0 3 aqueous solution 1 | (2 0 mi?) Brine. (10 m il) washed on MG S04, 1 I dried, filtered and evaporated to yield 2 4.6 g (89%) intermediate (1 1 IS) ~ < E)-4-third butoxy Carboxamido — 6 monophenyl — 2 -hexyl 1 1 diethylenephosphonate. 0 m il 4 0 was added to a solution of this material in C Η 2C] 1 2 (3 m 9. 1 1). M Η C dioxane solution. Mix 1 1 Stir at room temperature for 15 hours 0 Remove solvent residues under reduced pressure 1 1 This paper size applies to Chinese national standards (CNSM4 specifications (plus millimeters) _ 82 470750 A7 B7 Central Bureau of Standards, Ministry of Economic Affairs Printed by the employee consumer cooperative V. Description of the invention (80) 1 Dissolved in methanol (10 m) 0 The solution was poured into ether (400 m il) 1 1 in 0 The precipitate was collected on a Buc hn er funnel with ether (2 X 1 1 2 0 m 2) Wash and pump dry to produce 1 2 5 g (60 0%) Intermediate 1 1 please \ 1 (S) a (E) — 4 — amino — 6 — phenyl — 2 — Hexenephosphonic acid I | Ester 1 Monoethyl hydrochloride 0 Μ U — P he 0 Η (1 0 4 S back 1 1 3 7 1 4 mm 0 2) at T Η F (1 5 m it The solution in) is added with 1-4-methylmorpholine (0 4 1 2 m matter 1 1 I 3 7 4 mm 0 Si) at 1 I — 10 ° C, followed by isobutyl chloroformate (% 1 0 4 8 6 m il 3 7 4 mm 0) 〇 mixed anhydride and stir for 5 pages 1 1 min. (S) — (E) — 4 —amino — 6 —phenyl — 2 1 1 monohexenephosphonic acid Ester hydrochloride (1 2 5 g 3 7 4 mm 0 again) 1 1 The solution in D MF (5 m) is then 4-methylmorpholine (order I 0 4 1 2 m il 3 7 4 mm 0) 0 The mixture was stirred for 1 h 1 1 1 h 0 ethyl acetate (50 m) was added 0 The solution was 1 M C (1 1 1 2 5 m), saturated Na a Η C 0 3 aqueous solution (Σ) 1) m \ 1) and water 1 1 line 1 (1 0 m) washed with MG g 0 4 dried, filtered, and evaporated to dryness> C 以 2 C 2 / ether / hexane (3 1 5 m 5 1 5 2 0 0 1 1 ·· 1 0 0 ratio) The product forms an oil when treated> It solidifies to 1 | 1 4 4 g (6 9%) (S) — (E) — 4 — (4 — Morpholine 1 I carbonylphenylpropylamine 醯) amino-6 monophenyl-2-diethylhexenephosphonic acid 〇1 i I 0 8 5 g This material is dissolved in ethanol (1 0 m) and Into a Parr bottle containing 1 15% palladium on activated carbon. The solution was reduced on a Parr hydrogenator for 36 hours. 0 The solution was filtered through Celite under reduced pressure. 1 1 Solvent removal yielded 0 6 6 g (76%) Oily final product 0 1 1 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 470750 A7 B7 V. Description of the invention (81) TLC: (5% MeOH / CH2CJ? 2) Rf = 0. 27 Example 1 0 ′ Synthesis of Cysteine Protease Inhibitor with r-Amineamine as ewg (S) — 3-(4 —morpholinecarbonylphenylpropylamine 醯) —amine Synthesis of phenyl-6-phenylhexylamine (Mu — Ph e — Hp h — r — AMB z 1). The Wadsworth-Emmons reagent octylamine-based methylenediphosphonic acid diethyl ester is synthesized in two stages. First, triethylphosphorocarboxacetate is saponified into diethylphosphorocarboxacetate, and then dissolved in ethyl acetate to become 0 ·. 2M concentration, treated with 1 equivalent of amidine, 0.1 equivalent of 4-dimethylaminopyridine, and 1 equivalent of dicyclohexylcarbodiimide. A solution of this Wadsworth-Emmons reagent (2.59g'9.08mm〇i?) In THF (400m) was added with sodium hydride (0.36 3g 6 0% mineral oil dispersion) at 0 ° C. , 9. 08mmoj?). The mixture was stirred at room temperature for 15 minutes, and B oc-homophenylalanine was added to it (printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back, and then click this page) 2. 39g, 9.08mmo) in THF (10m). The mixture was stirred for 1 hour. 1 M H C j? (30 mj?) Was added. The product was extracted in ethyl acetate (100mj?), Washed with a saturated aqueous sodium bicarbonate solution (50mP), brine (30mj), dried over MgSO4, filtered, and concentrated. Crystallization from ether / hexane yielded 1.81g (51% ) (S) — (E) -3 —Third-butoxycarbonylamino-6-phenyl-2 -hexenamidamine benzyl ester. This material is soluble in _____ I________ This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X_297mm_) " — '~~~ 4707 ^ ° Printed by A7 __ B7, a consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 7, Description of the invention (82 plant CH2Ci? 2 (5mj2). HCI? / Dioxane (1 0 m 5 4. 0 M solution) was added to the solution. The mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in methanol (5 mi?) And listed in diethyl ether (300 m 又), and the oily intermediate (S)-(E) -3-amino-6-phenyl-2 was separated therefrom. —Hexenamidamine hydrochloride forging, yield 82% (1.25g) »Mu-PheOH (1.05g, 3.78mmoj ^) in butyl HF (15m5) solution was added at a temperature of 10 ° C 4 —Methyl codeline (〇_ 416 mi ?, 3.78mmoi?) And isobutyl chloroformate (0.49mj ?, 3.78mmoJ?). The mixture was stirred for 10 minutes, and (S)-(E ) -3-Amino-6-phenyl-2 2-hexenamidamine hydrochloride (1-25 g, 3.78mm ··) in THF (3mJ2), followed by 4-methylmorpholine (0 4 1 6 mj? »3. 7 8 mmo). The mixture was stirred for 45 minutes. 'Ethyl acetate (40m) was added. The solution was washed with iMHCj? (10mj?), Saturated aqueous sodium bicarbonate solution (iomp), brine (5mi), dried over MgS04, filtered and evaporated to dryness. (S) — (E) — 3 — (4-morpholinecarbonylphenylpropylamine hydrazone) Amino-6-phenyl-2-hexenamidamine was precipitated from CH2C and 2 / ethyl ether with a yield of 56%. 48g (0.865mmoj?) Of this material was dissolved in ethanol (10mj) and transferred to a parr bottle containing 5% palladium on activated carbon. The mixture was reduced on a Parr hydrogenator for 4 hours. The solution was passed through C e 1 ite is filtered under reduced pressure and the remaining solvent is removed. The final product (Mu-Phe—Hph — r— AMBz 1) is made of ether / this' 4-sheet scale applies Chinese National Standard (CNS) A4 ^ (21GX297 mm) I ---------- install ------ order ------ line (please read and read the notes on the back one by one ::, write this page) 470750 A7 B7 Central Standard of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperatives V. Description of the Invention (83 1 | Owned by the hospital to get 0 2 5 (5 2%). Τ LC-(50% ethyl 1 1 ethyl acetate / hexane) R f = = (). 4 £) > 1 1 | / —n Please 1! Example 1 1 Explanation | Monoamine amine is a synthesis of cysteine protease inhibitor of EWG 1 | -1 Note 1 | (S) — 3 — (4 — morpholine carbonylphenylpropylamine hydrazone) Amine — 6 — Item 1 1 I Synthesis of Phenylhexamidine Phenyl Ester (Μ U — P he — Η ρ h — r-A Μ P h% of this product) 1 Μ U-P he-Η P h -r — C 0 2h (Page • s' 1 1 0 3 0 S was prepared as in Example 8) Triethylamine (9 0 β 1 eq) was added to the 1 1 solution in T F (5 m Ai) at -10 ° C, with 1 1 Then add isobutyl chloroformate (0 • 0 8 3 m J? 1 eq) »5 min order | Add aniline (0 0 5 8 m) after 15 minutes. Remove the cooling bath, react 1 I stir at room temperature for 2 hours 0 Add C Η 2 C 芡 2 (30 m 9.). The 1 1 I solution was washed with 1 MΗC and a saturated sodium bicarbonate water solution (each 10 m β), washed with 1 1 and dried on M g S 0 4, and the solvent was removed under reduced pressure. The residue line 1 was milled with E t 2 ◦, filtered and dried in vacuum to produce < 3.2 9 g 1 I (85%) product MU — Phe — e ph — r — AM Ph. 1 I Τ LC (1 0% Μ e 0 Η / c Η 2 1: again 2) R f = 0 · 7 0 (1 I 0 absorbs UV (2 5 4 nm) in a large amount, I 2 > 1 1 Example 1 2 1 1 1 Synthesis of Cysteine Protease Inhibitors with R — Aromatics as EWG 1 1 (S) — 4 — Aminophenyl — 3 j-(4 —Morpholinecarbonylphenylpropylamine amidino ) 1 1 This paper size applies to Chinese national standards (CMS> A4 size (210X297 mm) -86-470750 Printed by the Industrial and Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 -____ B7_ V. Description of the invention (84) Amine-based -5- Synthesis of diphenylphosphine (38. 17g'〇.i46moj?) And 4-nitronitrochloro (2 5g '〇_) from phenylpentane hydrochloride (Mu — P he — hPhe-r — C6H4NHZ · HCe) 146m〇e) was dissolved in CH3CN (100mj?) And heated at reflux for 2 hours, allowed to cool to room temperature. The reaction mixture was diluted with Et20 (300m) again, and the white solid was filtered off as Et20 (200m $) Washed and dried in vacuo on TLC to produce 53.3 g (84%) of benzene scale of 4 ~ nitro 3 fluorenyl chloride single point: (Rf = 0.71, 4: 1: 1 butanol; acetic acid : Water) elH — NMR (de-DMSO): 5. 4 0-5. 50 (2H, d, CH2P, J = 2 0 Hz); 7. 20 — 7. 40 (2H, dd, aromatics) ; 7. 40-7. 80 (12H, m, aromatics); 7. 9 0-8. 0 0 (311, 111, aromatics); 8_ 10 — 8.20 (211, (1, aromatics) 4) Nitrosyltriphenyl chloride (10. 02g, 23. lmmoi) in a stirred suspension in CH2Cj? 2 (100mj?) Was added with 4-methylmorpholine (2.5 5 m ^ & gt 23. Ιηιηοβ). When all solids are dissolved, add Boc — H ph Η (4.04 g, 15.4 mmoj?). After 24 hours, the reaction mixture was diluted with CH2C j? 2 (20) and filtered. The filtrate was filtered with 1MHCJ? (200mS) saturated sodium bicarbonate aqueous solution (200mV) was washed; dried in MgS04, filtered and concentrated under reduced pressure to produce 4.00g of crude intermediate 'part of which was purified by chromatography (this paper scale applies to Chinese national standards (CNS) A4 specifications (2! 〇X297mm> _ f ~ II II! III n ^ II I — ^ cable (please read the precautions on the back before clicking this page) 470750 V. Description of the invention (85) A7 B7 Gradient elution printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs * 1 0 — 30% ethyl acetate / hexane) for N MR analysis of intermediates> (S) ~~ Second butoxy condensing group 3 —amino group 1 — (4 — nitrophenyl) — 5-Phenyl-1-pentene. Τ LC: (30% E t 0 A c / 院 院) R f ~~ 1 0. 4 ί) ° | This substance 1 2 * 7 6 S 9 7 2 mm 0 9.) in E t 2 0 丨〔2 5 m 芡) was added to the solution in /fm*.m water p-toluenic acid (27 g 1 60 mm 0) in E t 2〇 (10 mj?). 1 Reaction stirred for 16 hours > filtered to wash the solid with E t 2 1 0 (2 5 m) and dried in vacuum to produce 2 S (6 1%) (S)-3 monoamine — 1 — (4 — Nitrophenyl) — 5 —phenyl — 1 —pentene, single point on TLC (R f == 0. 4 9 > 10% MeOH / C Η 2c j? 2) 〇Μ U — P he 0 Η (1 2 9 g 1 4. 6 3 mm 〇%) was added to the solution in Τ Η F (2 0 m parent) 4-methyl codeline (0 5 1 m parent> 4 6 3 mm 0 cross ) And isobutyl chloroformate (0 6 1 m 9 4 6 3 mm 0 again) After 3 minutes, (S) — 3 —amino — 1 — (4 mononitrophenyl)-5 -phenyl-1 -Pentene salt tm. Acid salt (borrowed by (S) — 3 — third butoxy iron amine — 1 — (4-nitrophenyl) — 5 — phenyl — 1 — pentene precursor. By HC / Dioxane-regulated deprotection to prepare »1 3 4 g, 4-20 mm 〇j?) In C Η 2 C j? 2 (20 m), followed by 4-monomethyl Morpholine (0 5 1 m > 4 6 3 m m 〇 and). The mixture was stirred while warming to room temperature. The solution mixture was diluted with C Η 2 C to 2 (100 m) again > with 1 M Η c 9. (2 1 0 0 m), saturated carbonic acid Sodium hydride water-soluble paper size applicable to Chinese National Standard (CNS) A4 specifications (2IOX297 g) 88-I ---------- installation ------ order ------ line ( Please read the precautions on the back-", write this page) 470750 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economy Dry'filtered and concentrated under reduced pressure to give a yellow oil. This product was crystallized from CH2C $ 2 / ether (2: 100, 20mj?) To produce 1. 00g (40%) (S) — 3 — (4 —morpholinecarbonylphenylpropylamine hydrazone) amino — 1 — (4 — nitrate Phenyl) -5_phenyl-1_pentene in an approximately 4: 1 E / Z mixture. 0.27g (0.49mmoj?) This material was dissolved in ethanol (50m5), transferred to a Parr bottle filled with 5% palladium on carbon (0.10g), and the original 8 above in a Parr hydrogenator. hour. The mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in 4: 1 ether / CH2Cj? 2 (100mj?), And HCj? / Dioxin (0.136m ^ 4.0M solution) was added thereto. The product was filtered off] \ 411 — Ph e-Hph-r-C6H4NH2. HCj? And dried under vacuum. Yield = 0.15 g (54%) ° TLC: (10% methanol / CH2CJ? 2) Rf = 0.31. Example 1 3 Synthesis of Cysteine Protease Inhibitor Using β-Aminosulfone as EWG (S) — 2 — (4-morpholinecarbonylphenylpropylamine 醯) Amine — 4 —Phenyl — 1 —Benzene Synthesis of sulfobutane (Mu_Ph e_Hph_ / S — S 02P h). According to the schematic diagrams recorded by the aforementioned Spaltenstein, Carpino, Miyake, and Hopkins, B oc -Homo-phenylalanine (Bo c-Hph-iS — OH) and (S)-2-third butoxycarbonylamino-1 Methanesulfonyloxy-1 monophenylbutane ((Please read the precautions on the back / '.Write this page)-Install.-Order-thread _ This paper size applies to China National Standard (CNS) A4 specifications (21 〇X297mm) -89 ~ 470750 A7 B7 V. Description of the invention (87) (Please read the precautions on the back and write this page)

Bo c-Hph — 10,000-OMs or Bo c-homophenylalanine mesylate) "Boc-homophenylalanine (10. 29g, 36. 84mmoj2) in THFClOOmj?) In a 10 Add 4-methylmorpholine (4.05m, 3 6 84mmoj?) And isobutyl chloroformate (4_7 8 m. 3 6.84mmoj?) At ° C »The solution was stirred for 10 minutes, and then filtered. The filtrate was carefully added to a 0 ° C agitated solution of sodium borohydride (2.77 g, 73.67 mm) in water (100 mj ·). The mixture was stirred for 30 minutes. Add a saturated aqueous sodium bicarbonate solution (200m). The product was extracted with CH2Cj? 2 (2xl00mj2), dried over MgS04, filtered, and the solvent was removed under reduced pressure, yielding 9.78g (100%) of Boc-homophenylalaninol. TLC: (30% ethyl acetate / hexane) Rf = 0.15. 5.83g (21. 97mmoj?) This material was dissolved in CH2C52 (150mj?), Cooled to 0 ° C, and treated with methanesulfonyl chloride (4.15m, 53.71mm05) and triethylamine (9 24mj ?, 66.3mmoj?). Mixing and mixing 30 minutes printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Water (100 m 3?) Was added; the mixture was stirred vigorously. The organic phase was separated, dried over MgS04, filtered, and the solvent was removed under reduced pressure, yielding 7.31 g (97%). TLC: (30% ethyl acetate / hexane) Rf = 0.21. A similar method was used to prepare the corresponding Boc-Hph-A-OH benzenesulfonate. Add thiophenol (0. 653m, 6_ 36mmoJ?) To THF (5mJ?) In a solution of sodium hydride (0. 254g _. I_—. — _ This paper size applies Chinese National Standard (CNS) A4 specification (210X297 Mm) 470 750 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs _____ V. Invention Description (⑽) '6. 36mmoj ?, 60% mineral oil dispersion). The mixture was stirred for 10 minutes. A solution of Boc-homophenylalanine benzene sulfonate (2.58 g, 6.36 mmo 芡) in THF (5 mj?) Was added. The solution was stirred at room temperature for 10 minutes. Methanol (2 mj?) 'Was then added and the mixture was heated at reflux for 1 hour. The solution was cooled, diluted with 1M NaOH (25nlj ^), extracted with CH2C2 (100mJ?) ', Dried over MgS04, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in CH2C $ 2 (35mi?) And cooled to 0 ° C. Add 4 monochloroperacetic acid (3.71 g 1 13.99mmo $, estimated peracid content 65%) to the solution. The mixture was stirred for 1 hour, and 10% NaOH (35 m) was added and a saturated aqueous NaHS03 solution (35 mj?) Was added. The mixture was extracted with CH2Cj? 2 (3x50mj? Part), dried over MgS04, filtered, and the solvent was removed under reduced pressure to give a waxy solid (S)-2-tert-butoxycarbonylamino-4 -phenyl-1- Toluene butane. TLC: (30% ethyl acetate / hexane) Rf = 0. 32. 1. 25g This material was dissolved in CH2C ^ 2 (5mJ2) and treated with HCi? / Dioxane (5mj? 4.0M solution). The mixture was stirred at room temperature for 2 hours. The solution was poured into ether (200mj?) To form an oily residue. Discard the supernatant. The residue was redissolved in CH2C $ 2 (1 Omj?) And poured into diethyl ether (200m). The intermediate (S) is precipitated as 2-amino-4-phenyl- 1-benzenesulfobutane hydrochloride. The solid was filtered off and dried in a vacuum to produce 0.40 g of material (38% yield, starting from B oc — homophenylalanine benzyl sulfonate. This paper is dimensioned to the Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) --------- t -------- IT ------ i (Please read the notes on the back first. Write this page)

I 470750 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs _______ V. Description of the invention (89) Mu-PheOH (0.32 2 g * 1. 23mmoJ2) in THF (10mj?) At -10 ° C, 4-methylmorpholine (0.135 mi? '1. 23 mmoj2) and isobutyl chloroformate (0.159 m' 1.23 mm 0.32) were added. The mixture was stirred for 10 minutes, and (S) 2-amino-4, 4-phenyl, 1-benzenesulfobutane hydrochloride (40 g > 1.23 mm2) was added, followed by 4-methyl. Porphyrin (0.135 mi2, 1.23 mmoj?). The mixture was stirred for 45 minutes. Add lMHCj? (15mi?). The product was extracted with ethyl acetate (30 mi?), Washed with a saturated aqueous sodium bicarbonate solution (15 m?), Brine (15 mi?), Dried over MgS04, filtered, and the solvent was removed under reduced pressure. The final product Mu — P’h e-Hph — Xiyi S02Ph weighed 0.68 g (100% yield). Example 14 Synthesis of a Cysteine Protease Inhibitor Filled with Stone-Amine Boron as EWG (S) _2 -Third-Butoxycarbonylamino- 4 -phenyl-1 1-(1 Trimethylsilane Ethyl) Monosulfobutane (Boc — Hph — Synthesize 2-Trimethylsilylethanethiol (0.86g, 6.41mmoj?) As described in Anderson, Ranasinghe, Palmer, Synthesized as described by Fachs) Sodium hydride (0_256g, 6.41mm〇i, 60% mineral oil dispersion) was added to the solution in THF (10mj?). The paper size is applicable to Chinese National Standard (CNS) A4 specification (210x ^ 97mm Ding-Q2-: -------- 1 ------- IT ------ ▲ (Please read the precautions on the back first page) 470750 A7 B7.-II-'-'-. —.I-Printing of the Consumer Work Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (90). Stir the mixture for 10 minutes. Add B oc-homophenylalanine Alcohol methyl ester (2.00 g, 5.82 mmo, synthesized as described in Example 13 above). The solution was stirred for 2 hours. Ethyl acetate (50 m $) was added. The solution was 1 MHCP at 30 m $ each. Water-soluble saturated sodium bicarbonate , And washed with brine, dried with M g S 0 4, filtered, and the solvent was removed under reduced pressure to produce an intermediate (S) _2 — tertiary butyloxy amine amino 4-benzyl butyl trimethylsilane Ethyl sulfide. TLC: (5% ethyl acetate / hexane) Rf = 0.22. This material was dissolved in CH2Cj? 2 (50mj2), cooled to a temperature of 10 ° C, and treated with 4-chloroperacetic acid (3 24g, 12.22mmo, estimated 65% peracid content) treatment. The mixture was stirred overnight. The suspension was filtered and the saturated NaHS03 aqueous solution (40mj?) And saturated sodium bicarbonate aqueous solution (50mj) were carefully added. In the filtrate. The organic phase was separated, dried over Mg SO 4, filtered, and the solvent was removed under reduced pressure. The product B was quantitatively recovered from the mesylate to produce 〇c_Hp h —Chilled S02CH2CH2TMS. TLC: (30% acetic acid Ethyl ester / hexane) Rf = 0.49. Example 1 5 Synthesis of Cysteine Protease Inhibitor with E-amino group as EWG (S)-2-(4-morpholinecarbonylphenylpropylamine hydrazone) Synthesis of Amine 1-chloromethanesulfonium-4-phenylbutane (Mu-Ph e — Hp h —Zhaoyi S02CH2Ci2). Boc — Hph- / 3 — This paper standard is applicable to Chinese national standards (C NS) A4 specification (210 XM7 mm) (please read the precautions on the back 7. Write this page).-Thread 470750 A7 B7 Printed by the consumer cooperation department of the Central Bureau of Correction of the Ministry of Economic Affairs. 5. Description of the invention () 1 1 1 S 0 2 C Η 2 C Η 2 ΤΜS (0.9 () g 1 1 2 1 8 mm 0 > as described in Example 1 4) in T Τ F (2 Ι 1 1 1) Add tetrabutyl fluoride Jbh m (8. 7 m β 1 0 M ✓-NI please 1 T Η F solution) and several molecular sieves to the solution. The mixture was stirred at room temperature for iSSL overnight. 0 Read I Read 1 Add bromo group Chloromethane (5 m ίί). The mixture is refluxed and heated for 1 hour > the back 1 to 1 is cooled and the volatile components are removed under reduced pressure. The residue was dissolved in ethyl acetate. Note 1 Ψ 1 (7.5 m) was washed with 1 M Η C 5 (50 0 Ι Ϊ 1 9.) was washed with the term ι ε Μ g S 0 4 • filtered, and removed under reduced pressure. Solvent residues rough nest 1 Loading sheet 1 (S) — 2 — third butoxycarbonylamino-1 _chloromethanesulfonium 4 —phenyl 1 butane dissolved in ether (3 m 9.) 0 added anhydrous 4 — Toluenesulfonic acid (1 0 0 0 0 g 4 7 0 mm 0 H) in diethyl ether (3 m) in 1 1 solution. The mixture was stirred at room temperature overnight. Add diethyl ether (100 m order 1) 0 Filter out the carbohydrate intermediate (S) — 2-amino — 1 — chloromethyl — sulfo 1 1 醯 — 4 — phenylbutane — 4 — tosylate (TS 〇Η Η P h 1 | — β — S 〇 2 C Η 2 C) The solid was washed with ether (2 X 2 0 mi?)] Line, and dried in vacuum to produce 0.1 9 3 substance (by β 0 C 1 I Η ρ h — β — S 0 2 C Η 2 C Η 2 TMS starting system 2 4%) 0 1 1 I Μ U — Ρ he 0 Η (0 * 10 9 g 1 1 0 3 9 2 mm 0 ) The solution in T Η F (3 m) was added at 1 1-10 ° C with 4-methylmorpholine (4 3 β L 1 0 3 9 2 mm 0 9.) and isobutyl chloroformate. (5 1 β L 1 I 0 3 9 2 τη m 0) 0 Stir the mixture for 10 minutes and add 1 I Τ S 〇Η Ρ ρ h — β — S 0 2 CH 2 C il (0 * 1 7 g > 1 1 1 0 3 9 2 mm 0) followed by 4 monomethylmorpholine (4 3 β L 1 1 This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -94-Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 —__ B7 V. Description of Invention (92) 0 392mmoj2). The mixture was stirred for 45 minutes. Ethyl acetate (20mj?) Was added, and the solution was washed with IMHCj ?, saturated sodium bicarbonate aqueous solution and brine (2m $ each), dried over MgS04, filtered, and the solvent was removed under reduced pressure to produce the final product Mu_Ph e-Hph -/ S — S.02CH2C 芡 (90mg, 48% yield) ο Example 16 Synthesis of 1- (Third Butoxycarbonyl) amino Group Using α-Aminopyrene as EWG's Cysteine Protease Inhibitor —2 —Methyl- 1-benzenesulfonylpropane (Boc-Val-α-S02Ph) Synthesis. A third suspension of butyl carbamate (2.34g, 20mmoj?) And sodium benzenesulfinate (3.28g, 20mm05) in water (20m5) was added to an isobutyraldehyde (2.00m5, 22mmo) And) a solution in formic acid (5m {). The mixture was stirred at room temperature overnight. The precipitate was filtered off, washed with water (2 X 5 Omj?) And crystallized from isopropanol / water to give 4.72 g (7 5%) of the product. Mixture 17 Synthesis of Cysteine Protease Inhibitor with α-Aminopyrene as EWG 1—Benzyloxycarbonylamino-3—phenyl-1—benzenesulfonylpropane (Z-Hph — a — S02Ph) synthesis. Sodium benzene sulfinate (10 g) This paper size is applicable to China National Standard (CNS) A4 specification (X 297 mm) Order ------- line (please read the note on the back first '. Write this page) 470750 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (93) 1 I 6 0 9 mm 0 and) and benzyl carbamate (9 2 1 g > 1 16 0 9 mm 0 9.) To a suspension in water (40 m 9.) was added 1 1 to formic acid (1 0 m ί) Hydrogen cinnamaldehyde (8 8 mj? ≫ I please 6 7 mm 0 parent) 0 The mixture was heated at 7 0 0C for 1 hour 9 cooled to room temperature | overnight at room temperature 0 product crystals precipitated out »filtered by the other Isopropanol recrystallization reads back 1 I produces 2 3 g (100%) yield 0 TLC (30% ethyl acetate Note 1 1 I ester / hexahedron) R f = C) r 5 7 Matters 1 1 | k Benbai 1 Λ I Example 1 8 Bay 1 1 with a —amino group as Ε WG Synthesis of Cysteine Protease Inhibitors 1 1 1 (R) — 1 — (4 —morpholinecarbonylphenylpropylamine fluorene) amino — 3 — 1 Order I phenyl — 1 monobenzenesulfonylpropane and (S) -1 — (4 -morpholinecarbonylphenyl 1 1 I propylamine hydrazone) amino — 3 — phenyl — 1 — benzene salt salt (M U — 1 1 IP he Η P h — a — S 0 2ph, separated epimer) 1 Synthesis of ti line 〇Method AZ — Η P h — a — S 0 2Ϊ 3 h (1 1 0 g, 2 4 4 mm 0 9.) in acetic acid (1 5 m)) treated with 1 130% hydrogen bromide for 0 3 0 minutes, the mixture was diluted with diethyl ether (13 0 0 m), and filtered with ether (2 X 3 0 m β) and washed 1 I » And dried in vacuum to produce 0 7 4 g (86%) 1 —amino — I 3 — phenyl — 1 — benzene dihydrogen bromide (Η Β r · Η Ρ h — 1 1 I a — S 0 2 P h) »Μ 1--] P he 0 Η (D. 6 4 g > 1 1 2 3 ΤΠ ΤΠ 0) at τ Η F ( 1 5 m) and 1 1 4 —methylmorpholine (0 3 0 2 m, 2 3 mmo J2) and chlorine 1 are added to the solution. The paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 470750 Α7 Β7 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the invention (94) Isobutyl formate (0.312mi2, 2.3mm). The mixture was stirred for 10 minutes. HBr .Hph — α-S02Ph (0.74 g, 2.1 m m o j?) Was added, followed by 4-methylmorpholine (0.3 2 m »2.3 m m o). After 45 minutes, the mixture was diluted with ethyl acetate (30mj?), Washed with 15mj? 1M HC5, saturated aqueous sodium bicarbonate solution, and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. 0.75 g (65%) of the product Mu — Phe — Hph — α — S Ο 2 Ρ h was produced. Method B: Triethylamine (13.9mj? '100mmo again) was added to a solution of phenylalanine ammonium hydrochloride (10g, 50mmoi2) in DMF (50mi) and CH2C ^ 2 (50moi). And 4-morpholine carbonyl chloride (5.9 mi2, 50 mm). The mixture was stirred overnight. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 μηβ) and filtered. Diethyl ether was added to the filtrate until the solution became cloudy. 7.2 g (80% yield) Intermediate 4 Monomorpholine phenylalanine amidoamine (Mu — Ph e-NH2) crystallized from the solution after 3 days. A solution of Mu-Ph eNH2 (2.2 4 g * 8. lmmoi?) In formic acid (5m 芡) was added with stirring to add cinnamaldehyde (1.17mj ?, 8.9mmop). The mixture was stirred for 5 hours, and sodium phenylsulfinate (1.33m ^, 8. lmmoj?) Was added thereto. The mixture was quickly heated to reflux in 5 minutes and allowed to cool to room temperature. The solution was stirred for 3 days. Add an equal volume of water. The product is based on CH2CP2 (3xi〇〇mj?) (Please read the notes on the back Η, and write this page) • Binding. Binding-line paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm> -yr -470750 Printing of A7 B7 printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (95) Extraction, drying with M g S 0 4, filtration, and removal of the solvent under reduced pressure. Product non-mirror (R) _ and The yield of (S) — 1 — (4-morpholinecarbonylphenylpropylamine hydrazone) amine — 3 —benzenesulfonium — 1 monophenylpropane is 3-9 g (90%) ° TLC (50% ethyl acetate / CH2Cj ^ 2) Rf = 0.27, 0.34. Non-mirror isomers were separated by flash chromatography on 230-400 mesh silica gel (20-50% ethyl acetate / C H2C j? 2, gradient elution). Example 19 Cathepsin B inhibitor using cysteine protease inhibitor of the present invention Conditions for use: 50 m Μ phosphate, pH 6.0, 2.5 EDTA > 2.5 mM DTT. Substrate : [Z — Arg-Arg-AMC] = 50 mM (Km = 190 mM). The test at 25 ° C was started by adding cat L (final concentration of about InM) and traced to 4 under excitation at 380 nm. 5 0 nm fluorescence increment 2 minutes. Note the inhibitor of the hydrolysis rate of the substrate after adding different concentrations of inhibitors. Within the overall range observed, the assay is linear. Two measurements were performed. Conditions for cathepsin S: 50 mM phosphate, p Η 6.5, 2.5 η M EDTA'2_ 5 m N DTT, substrate: [Z-Va l-Va 1 — Arg-AMC] = 10 mM (Km = 18 mM). At 2 5 ° The verification under C is based on the Chinese standard (CNS) A4 size UlOXW7 mm for this paper size_ 98 = II n I n ϋ Order — n line (Please read the precautions on the back / write this page first) 470750 A7 B7 V. Description of the invention (96) Started by adding cat S (final concentration of about 30 pM), the 450 nm fluorescence increment under excitation at 3800 nm was tracked for 2 minutes. Note the inhibitors on the rate of hydrolysis of the substrate after adding various concentrations of inhibitors. The test is linear over all observed ranges. A double determination was performed. The conditions for calenzyme are the same as those for cathepsin L, except that the Km of the substrate is 1 mM. Dixon plots were used to estimate each K i value as described in Irwin Segel in Enzyme Kinetics: Rapid Equilibrium and Steady-State System Behavior and Analysis, 195 5 'Wiley-Interscience Publication, John Wiley & Sons, Nwe York 》 The results are listed in Table 2. I. nn II 1 (please read the note on the back first, write this page) The paper printed by the Central Consumers' Bureau of the Ministry of Economic Affairs, the Consumer Cooperatives, applies the Chinese National Standard (CNS) A4 specification (21 〇X 297 mm) -99-471 ^ 750

A V. Description of Invention (97) Table 2 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

Inhibitor · Histone B (K · μΜ) Tissue White Pickled L Coarse Egg 3 Enzymes Carmen Mu-Phe- (DL) HphaS02Ph 3,000 13 5 15 Mu-Phe-HphaS02Ph-2.6 _ Mu-Phe- (DL) HphaS02Ph,--3.7-Mu-Leu-HphaS02Ph 16 1,3 1.6 0.27 Mu-Leu-HphaS02Bzl 54 0.60 4.2 076 Mu-Phe-HphaS02CH2F 170 1.5 2.8 2,0 Mu-Phe-HphaS02Bzl 77 1.2 5.2 0.92 Mu -Phe-HphaS02CR3 50 0.18 2.2 0.23 Mu-Phe-HphpS02Ph 1,100 29 0.94 5.7 Mu-Phe-HphYS02Ph 48 10 0.16 4.3 Phac-Phe-HphYS02Ph »10 0.41 12.5 1.8 Mu-Np2-HphvS022Np 20 0.26 0.53 0.10 Mu-PheE-HP 190 0.17 0.082 5.9 Suc-Phe-HphYS02Ph > 1000 1.0 0.07 1.5 Me0Suc-Phe-HphYS02Ph 81 3.2 1.2 4.7 Suc-Np2-HphvS02Ph > 1000 2,3 0.50 0.78 Suc-Np2-HphvSOp2Np > 1000 1 .1 0.24 0.23 ............. 1 _, Zp-Ala-Phe-HphYS02Ph 52 079 3.0 0.54 1 p-Ala-Phe-HphyS02Ph »50 14 11 14 Mu-Tyr-HphYS02Ph 2.3 9.5 20 Mu- Phe-HphYCO? Et 1.6 0.48 0.19 0.91 Mu-Phe-HphYCONHPh 2.6 2.0 1.3 0.13 Mu-Phe-HphYCONHBzl »50 19 30 7.7 Mu-Phe-HphYP0 (0? Et) 2 17 3.0 1.4 15 Mu-Phe-Hph-YPh -OMe 4 .8 0.94 0.37 0.89 Mu-Phe-Hph-vPh-NH? »50 2.9 9,1 3,0 (Please read the precautions on the back J; '舄 This page) _1 一 > ~ -a Γ ^^ t ^ W (CNS) A ^ (21〇X297 ^! Ι〇〇_470750 A7 B7 V. Description of the Invention (98) The following are representative pharmaceutical formulations containing the cysteine protease inhibitor of the present invention. Oral formulations Representative solutions for oral administration contain: Cysteine protease inhibitor 100 to 1000 citric acid monohydrate 105mg

S Sodium hydroxide flavoring water 18 mg appropriate amount to make it a 100% intravenous formulation. Representative solutions for intravenous administration contain: (Please read the notes on the back first and dictate this page) Central Bureau of Standards, Ministry of Economic Affairs Employee Consumer Cooperative printed cysteine protease inhibitor glucose monohydrate citrate monohydrate sodium hydroxide injection saline lozenge formulations for injection. Representative lozenges may contain: Cysteine protease inhibitor microcrystalline cellulose 10 to 100 0 in the right amount makes it equal to 1.0 0.5 mg 0. 1 8 mg in the right amount makes it 11% 7 3% This paper size applies the Chinese National Standard (CNS) A4 size (210X2.97 mm) g 101 470750 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention " Stearic acid 2 5% Colloidal silica 1% (Please read the precautions on the back before filling this page) -This paper size applies to China National Standard (CNS) A4 (210 × 297 mm)

Claims (1)

、 Appendix I to the appendix ~ A: Patent Application No. 8 5 1 0 4 3 9 2 Chinese Patent Application Amendment Revision of the Republic of China in October 2010 Amends a compound which is a cysteine protease inhibitor of Formula I Agent (please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs: η Department 0 to 2; Α — Β means -C (0) ΝΗ —; χ means _ knot, extension Methyl, or bonded to a C Η 2 CH (R 4), R 4 is hydrogen or C ρ 4 alkyl; γ is ~ N Η-;. Zn is ~ C (R ”(R 7)) as defined below Z 1 is wherein R 0 is hydrogen or methyl, and R 7 C (R 6) (R 8) — wherein R β is hydrogen or methyl, and R 8 is as defined below; R 1 is morpholine Carbonyl, phenyl-C i_β alkyl-carbonyl or C i_β alkyl (where the C i_β alkyl is substituted by a carboxyl group or C with a carboxyl group); Alkyl esters are applicable to Chinese paper standards (CNS) A4 specification (2! 〇 × 297mm) -1 470750 A8 B8 C8 D8, patent application scope R7 series hydrogen, 〇ϊ_β radical, or any phenyl group on a phenyl or some group Substituted phenyl-Che alkyl or fruit-Ci-β alkyl; R8 is hydrogen, phenyl-Ci-β alkyl, or carboxyl ~ Ci_e alkyl; R 2 is hydrogen, via one or more Ci-e alkyl, phenyl, fluorenyl, phenyl-Ci_e alkyl, or fruit-Ci-6 alkyl optionally substituted with a group selected from halo; and pharmaceutically acceptable salts thereof, Individual isomers or mixtures of isomers. 2. The compound according to item 1 of the scope of patent application, wherein R 1 is fluorenylcarbonyl, benzyloxycarbonyl, fluorenylcarbonyl, t-butoxycarbonyl, ethenyl, amber Fluorenyl, or methoxysuccinyl " 3. The compound according to item 1 of the scope of patent application, wherein the dissociation constant (K i) when the protease is inhibited by the inhibitor is not more than about 100 β Μ ο 4. For example, the compound in the scope of patent application No. 1 in which R 1 is a 4-morpholine carbonyl group; R 8 is a 2-phenethyl group; R 2 is a phenyl group or a 2-group; and R 7 is an arbitrarily substituted hydroxy group. Benzyl, 1-Fructyl or 2-Methyl (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A compound as claimed in item 4 of the patent application, wherein X represents a bond, R 1 is a 4-morpholinecarbonyl group, R 8 is a 2-phenethyl group, R 2 is a phenyl group and R 7 is a benzyl group, that is, N 2 -(4-morpholinecarbonyl) -N 1-(3 -phenyl 1R -benzenesulfonylpropyl) -L-phenylpropylamine sulfonamide "6. For the compound in the scope of patent application item 4, where X represents Methyl, R 1 is 4-morpholine carbonyl, R 8 is 2-phenethyl, R 2 is phenyl and R 7 is benzyl, that is, the compound is N 2 ~ (4-morpholine carbonyl). Paper size: China National Standard (CNS) A4 specification (2 丨 0X297 mm)-2 470750 A8 B8 C8 D8 6. Application scope of patents-N1-'(3 -phenyl 1 s -benzenesulfonyl propyl) 1 L monophenylpropylamine. (Please read the notes on the back before filling out this page) 7. If the compound in the scope of patent application is item 4, where X represents a c H 2 CH (R '), where R 4 is hydrogen and r 1 is 4 1 Phenylcarbonyl 'R 8 is 2-phenethyl, r 2 is 2-fluorenyl and R 7 is 2-methyl, which means' the compound is N 2 — (4 -morpholinecarbonyl) —N 1 — (3 —Phenyl ~ 1 —benzenesulfonylpropyl] -L —phenylpropylamine. 8. The compound according to item 4 in the scope of patent application, wherein X represents —CH 2 CH (R 4), wherein R 4 is hydrogen, R * is 4 monomorpholine carbonyl, R 8 is 2-phenethyl, r 2 Is phenyl and R 7 is 4-hydroxybenzyl, gp, and the compound is N 2-(4 -morpholinecarbonyl) -N 1-{3 -phenyl- 1 S — [2-(2-sulfonylsulfonium ) Ethyl] propyl} —L-tyramine sulfonamide ”9. The compound as claimed in item 4 of the patent application, in which X represents CH2CH (R4), where R4 is hydrogen, and R is morpholine carbonyl, R 8 is 2 to phenethyl, R 2 is phenyl and R 7 is benzyl, that is, the compound is N 2-(4-morpholinecarbonyl) -N 1- [3 -phenyl-1 S (Ministry of Economy Printed by the Intellectual Property Bureau's Consumer Cooperatives (2-Benzenesulfonylethyl)]-L-Phenylpropylamine. 10. A compound which is a cysteine protease inhibitor of formula I I: II Among which the paper size applies to Chinese National Standard (CNS) A4 specification U10X297 Gong)-3-470750 Printed by the Consumers' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Λ8 B8 C8 D8 6. The scope of patent application η system; Α — Β means —C (〇) NH—; Y is —N Η —; Z is a C (R 6) (R 7) —, where R 6 is hydrogen or methyl ′ and R 7 is as defined below; Z 1 is a C (Re) (R8)-, wherein RB is hydrogen or methyl, and R 8 is as defined below; R 1 is morpholinecarbonyl; R7 and R8 are each hydrogen, or phenyl-alkyl; R9 is -C ( 0) OR10, one P (0) (〇R10) 2, or ~ C (◦) NHR12, each of which is R1. Individually hydrogen, or (^^ alkyl, R12-based hydrogen, phenyl, or phenyl-C:! _ 6 courtyard group; and pharmaceutically acceptable salts thereof; individual isomers and mixtures of isomers thereof. 1 1. A compound as claimed in item 10 of the scope of patent application, wherein R 6 is hydrogen; R 8 is 2-phenethyl; and R 7 is benzyl. 1 2. As a compound for scope 11 of the patent application, Where R1 is 4 monomorpholine carbonyl, R 8 is 2-phenethyl, R 7 is benzyl and R 9 is ethoxycarbonyl, that is, the compound is 4 S — (N (4 -morpholinecarbonyl) -L —Phenylpropylamine, amine] -6-phenylhexanoic acid ethyl ester 13. The compound according to item 11 of the scope of patent application, wherein R1 is 4-morpholinecarbonyl, R8 is 2-phenethyl, and R7 is Benzyl and R 9 is phenyltomethylamidino, that is, the compound is N 2 — (4 —morpholinecarbonyl) —N1— [3 —phenyl)-1 S— (2-phenylaminomethylethyl) Base) This paper uses China National Standard (CNS) A4 (210X297 mm)-4-II Pack I-Staple-IIII! Line (Please read the precautions on the back before filling this page) 470750 A8 B8 C8 D8 VI, Patent scope: propyl] -L-phenylpropylamine amidamine. 1 4. The compound according to item 11 of the scope of patent application, wherein R 1 is 4-morpholine carbonyl, R 8 is 2-phenethyl, R 7 Is a fluorenyl group and R 0 is a fluorenylaminocarbamyl group, that is, the compound is N 2-4 mono (morpholinecarbonyl) -N 1-[3 -phenyl-1 S-(2 -benzylamine formamidine ethyl Propyl] propyl] -L-phenylpropylamine amide. 1 5. — A compound that is a cysteine protease inhibitor of formula III: (Please read the precautions on the back before filling this page} III Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs: η is 0; A — Β represents a C (〇) ΝΗ—; 系 is —N Η —; ZO is a C (R0) (R7) —, where R0 Is hydrogen or methyl, and is as defined below; Z1 is a C (Re) (R8) —, wherein Re is hydrogen or methyl, and R 3 is as defined below; R 1 is morpholine carbonyl; R7 and R8 Various series of hydrogen, or phenyl-alkyl; R 1 5 series of hydrogen; This paper uses China National Standard (CNS) A4 (2 × 〇W7 公 嫠)-5-470750 Employees of Intellectual Property Bureau, Ministry of Economic Affairs Cooperative printed A8 B8 C8 D8 VI. Patent application scope R 16 is selected from phenyl (optionally substituted with a group selected from Cie alkoxy or -N (R 18) 2 where R "each Hydrogen or C alkyl; and pharmaceutically acceptable salts thereof; individual isomers or mixtures of isomers thereof. 16. The compound according to item 15 of the scope of patent application, wherein R 0 is hydrogen; R 8 System 2 —phenethyl; R 7 is fluorenyl. 1 7. The compound according to item 16 of the scope of patent application, wherein R 1 is 4-morpholinecarbonyl, R 8 is 2-phenethyl, and R 7 is benzyl Base, R 1 s is hydrogen and R 1 6 is methoxyphenyl, that is, the compound is N 2-4 —morpholinecarbonyl — N1 — {3-phenyl — 1-1 S [2 — (4-monomethoxyphenyl) Ethyl] propyl 丨 L-phenylpropylamine sulfonamide. 18. The compound according to item 16 of the scope of patent application, wherein R 1 is 4 monomorpholine carbonyl, R 8 is 2-phenethyl, R 7 Is benzyl, R 15 is hydrogen and R 18 is a 4-aminophenyl ', that is, the compound is N2— (4-morpholinecarbonyl) —N1— {3-phenyl-1S— [2 — (4-amine Phenyl) ethyl] propyl 丨 L-phenylpropylamine amide. 19. A method for inhibiting a cysteine protease in vitro, comprising reversibly bonding a cysteine protease inhibitor to cysteamine Acid protease, wherein the inhibitor comprises a cysteine protease inhibitor as described in claim 1 in the scope of patent application. 20. A method for inhibiting a cysteine protease in vitro 'includes a cysteine protease inhibitor Reversibly bonded to a cysteine protease, wherein the inhibitor comprises a cysteine protease inhibitor as described in item 10 of the patent application scope. I— nn ϋ I Order Line 1111 (please read the precautions on the back before filling this page) This paper uses the Chinese National Standard (CNS) Λ * »Specifications (21〇 > < 297mm) -6 470750 A8 B8 C8 D8 Six Scope of patent application (please read the precautions on the back before filling this page) 2 1. — A method for inhibiting cysteine protease in vitro, including reversibly bonding cysteine protease inhibitor to cysteamine On an acid protease, the inhibitor comprises a cysteine protease inhibitor as described in item 15 of the patent application. 2 2. A pharmaceutical composition for inhibiting a cysteine protease, which comprises a therapeutically effective amount of a cysteine protease inhibitor such as the item 1 of the scope of patent application, or an individual isomer, isomer thereof Mixtures or pharmaceutically acceptable salts or salts, in combination with one or more pharmaceutically acceptable adjuvants. 2 3. A pharmaceutical composition for inhibiting a cysteine protease, which comprises a therapeutically effective amount of a cysteine protease inhibitor such as the item 10 of the patent application scope, or an individual isomer thereof, isomerism Or a pharmaceutically acceptable salt or salt, in combination with one or more pharmaceutically acceptable adjuvants. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 2 4. A pharmaceutical composition for inhibiting cysteine protease, which contains a therapeutically effective amount of cysteine protease inhibitor such as the scope of patent application No. 15 Agents, or individual isomers, mixtures of isomers, or pharmaceutically acceptable salts or salts thereof, in combination with one or more pharmaceutically acceptable adjuvants. 25. A method for preparing a compound of formula IV: IV Among them, R1 'Y' Z, A 'B, 11 and ruler 8 are the same as the scope of patent application. The first paper size is in accordance with Chinese National Standard (CNS) A4 (2 丨 〇 > < 297). 7 _ 470750 A8 B8 C8 D8 6. Definition of the scope of patent application, R 2 ° is a S (0 2) R 2, where R 2 is the definition of the first scope of the patent application, and its pharmaceutically acceptable salt, its individual Isomers or mixtures of isomers; the method includes: (A) (1) a compound of formula NΗ2P (wherein P is a protecting group) and an aldehyde of formula R8CH0 and a sodium sulfinate of formula R2S (0) 0Na Reaction followed by deprotection to produce a compound of formula VIII: wherein R 2 and R 8 are as previously defined; and (2) a compound of formula VI II reacts with a compound of formula VI R 1 VI Ζ ΌΗ (Please read the notes on the back before filling out this page) The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed η, A, B, X, Υ (B) to selectively convert the formula into a pharmaceutically acceptable salt (C) Selectively convert the formula into a pharmaceutically acceptable salt; and (D) Selectively formulae Z, and R 1 as previously defined; the non-salt form of the V compound is further converted to the non-salt form of the V compound; The trans-V compounds were further separated into individual volumes of paper, using the Chinese National Standard (CNS) A4 specification (2 〇 parent 297 mm) _ 8 470750 A8 B8 C8 D8 VI. Patented isomers. 2 6. —Methods for preparing compounds of formula II • R9 II z 1 and R β are as defined in the patent application, where RhY'Z'A'Bn is around the 10th definition, and its pharmaceutically acceptable salts are different. Structure or isomer mixture This method includes: (A) (1) a compound of formula IX; PHM reacts with the appropriate formula R2S-thiolate anion, where l is a leaving group and R2 and R8 are as previously defined, Generate compound JR * PHN 2 of formula X) oxidize compound of formula X or compound of formula XI --------- 1 ------ 1T ------ line (please read the back first Please fill in this page for the note items) Intellectual Property Bureau, Ministry of Economic Affairs, Consumer Consumption Cooperation S (〇) 2R2 (3) The compound of formula XI reacts with the compound of formula v I. 0 VI where η 'A, B, X', Z, and R1 are each as defined above; the East paper scale is based on the Chinese national standard ( CNS〉 A4 Specification-9 470750 Printed by Consumer Consumption Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs XIV A8 B8 C8 ____ D8 6. The scope of patent application (B) selectively converts the non-salt form of the compound of formula IV into a pharmaceutically acceptable salt; (C) selectively converts the salt form of the compound of formula IV into Non-salt form; and (D) selectively further separating compounds of formula IV into individual stereoisomers. 2 7. A method for preparing the compound of formula III: R16 III wherein R 1, Y, Z, A, B 'η, Z 1, R 15 and R 1 β are as defined in item 15 of the scope of patent application, and pharmacologically Acceptable salts; their individual isomers and mixtures of isomers; this method includes: (A) (1) an aldehyde of formula XII: Reaction with compounds of optional formulas XI II and XIV: r2, 〇 \ || R2, 〇 / P '\ / XIII where R 8 and R 2 u are as defined above, and then deprotected to produce compounds of formula XV:逋 Using the national beam of China (CNS > Α4 grid (2Ϊ〇 × 297mm) -10-II n (Please read the notes on the back before writing this page on paper) 470750 A8 B8 C8 D8 (Please read the note on the back and then f on this page) XV 2) Reaction of compound of formula XV with compound of formula VI where η, A, B, X, Υ, ζ and R1 are as defined above, and (3) Reduction; (B) selectively further converting a non-salt form of a compound of Formula I v into a pharmaceutically acceptable salt; (C) selectively further converting a salt form of a compound of Formula I v into a non-salt form; and ( D) The compound of formula I v is further separated into individual stereoisomers selectively. 2 8. — Method for preparing compound of Formula IV: Printed by the consumer cooperation of Intellectual Property Bureau of the Ministry of Economic Affairs ο β IV Among which R1 'Y, Z, A, B, n and R8 are defined as the first item in the scope of patent application' R20 series—C H2C HR15Rie, where R15 and Rie are defined as the 15th in the scope of patent application, the paper size is used China National Standard for Ladder (CNS) A4 (2 丨 0X297gong) -11-470750 A8 B8 C8 D8 6. Scope of patent application and its pharmaceutically acceptable salts; individual isomers or mixtures of isomers, The method includes: (A) (1) an aldehyde of formula XII: R · ⑽ reacts with a compound of formula XV〗: R15> = P (Ph) 3 R16 XVI where R 8, R 15 and R 16 are each as defined above , Followed by deprotection to produce a compound of formula XVII: R8 R15 --------- ^ ------ ir ------ ^ (Please read the notes on the back before continuing this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (2 ) The compound of formula XVI I reacts with the compound of formula VI: 0 VI where η, A, B, X, Y, Z, and R 1 are as defined previously, and (3) reduction: (B) selectively reacting formula IV The compound is further transformed into a pharmaceutically acceptable salt; (C) The salt form of the compound of formula IV is selectively further transformed to this paper. Standard Chinese Standard (CNS) A4 (210X297 mm) -12-470750 A8 B8 C8 D8 6. The scope of patent application is non-salt form; and (D) the compound of formula IV is further separated into individual stereoisomers selectively. (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -13-