TW585853B - Novel tripeptide compounds as inhibitors of trypsin-like serine proteases, process for preparation and pharmaceutical composition thereof - Google Patents

Abstract

There is provided tripeptide compounds of formula I, wherein p, q, R1, R2, R3, R4, Y, n and B have meanings given in the description which are useful as competitive inhibitors of trypsin-like proteases, such as thrombin, and in particular in the treatment of conditions where inhibition of thrombin is required (e.g. thrombosis) or as anticoagulants.

Description

585853 Μ _______B7 V. Description of the invention (1) Scope of the invention The present invention relates to a novel compound that can be used in medicine, especially a trypsin-like serine protease (especially thrombin), a competitive inhibitor, which is used as a drug Uses, pharmaceutical compositions containing them, and synthetic routes to making them. Background Hemagglutination is both the key process of hemostasis (ie, preventing loss of blood from damaged blood vessels) and thrombosis (ie, forming blood clots in blood vessels or the heart, which can sometimes cause blood vessel blockages). The coagulation system is the result of a complex series of enzymatic reactions. One of the final steps in this series of reactions is the conversion of prothrombin into active thrombin. Thrombin is known to play an important role in coagulation. It activates platelets, causes platelets to aggregate, converts fibrin into fibrin monomers, spontaneously polymerizes into fibrin polymers, and activates factor ^, which sequentially crosslinks the polymers to form Insoluble Blood Fibre Economics Central Standards Bureau Staff Consumption Cooperatives% Approved Clothing II--(Please read the precautions on the back before filling this page)-Protein. In addition, thrombin activates factor V and gastric factors, and prothrombin is produced by prothrombin • 'positive and negative #'. By inhibiting platelet aggregation and fibrin formation and cross-linking, effective thrombin inhibition is predicted The agent has antithrombotic activity. Moreover, it is predicted that antithrombotic activity can be increased by effectively inhibiting the positive feedback mechanism. The previous technique B1_eQagul · Fibrmd (1994) 5'4ΐι describes the size of thrombin. The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed 585853 A7 B7 V. Description of the invention (2) Early development of low molecular weight inhibitors.

BlomMck et al. (J. Clin. Lab. Invest. 24, suppl. 107, 59, (1969)) based on the applicable amino acid sequence located near the resection site used for the supply of fibrinogen Aα chains. 1 thrombin Inhibitor. Among the amino acid sequences in question, these authors revealed that the sequence Phe-Val-Arg (P9-P2_P1, hereinafter referred to as the P3_P2_P1 sequence) is most effective (refer to Schechten and Bergen, Biophys. Res. Corrnmm. (1967) 27, 157 and (1968) 32, 898. Thrombin inhibitors based on a dipeptidyl derivative having an α, ω-amine graft guanidine at the P1 position are described in US Patent No. 4,346,078. It is also known from international patent application WO 93/11152. Similarly, structure-related dipeptidyl derivatives have also been recorded. For example, international patent application WO 94/29336 discloses a compound having, for example, amine methyl at the P1 position. Benzamidine, cyclic amine alkyl fluorene and cyclic amine alkyl guanidine; European Patent Application 0 648 780 discloses a compound having, for example, a cyclic amine alkyl guanidine at position P1. Peptidyl derivatives are used as the base Thrombin inhibitors that have amine alkylguanidine (such as 3- or 4-aminomethyl-1-methylpiperidine) in position P1 are known from European patent applications 0 468 231 or 0 641 779 With tripeptidyl derivative as substrate and arginine at position P1 Thrombin inhibitors were first disclosed in European patent application 0180 390. Recently, there have been records of modified peptide-based derivatives in the P3 position using arginine as the substrate. For example, international patents Application WO 93/18060 discloses a hydroxy acid, the European patent application 0526 877 is a deamino acid, and the European patent application 0 542 525 is a 0-methylmandelic acid at the P3-position. It is located at the P1 position The electrophilic ketone in the substrate is the serine protease (for example, the size of this paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm)) ------, order ----- (Please read the back first Note: Please fill in this page again) 585853 V. Description of invention (thrombin) inhibitors are also known. For example, European patent application 0 discloses a peptide based α-ketoester and amidine, European patent application 3 362 002 is a fluoroalkylamidone, a European patent application erucyl triketone compound, and European patent application 0 530 167 is an α-oxyoxy ketone compound of arginine located in pm. Other structures Terminal boronic acid Inhibition of trypsin-like serine proteases whose substrates are substrates and their isothioxanthine homologues are known from European patent application 0293 881. Recently, European patent application 0669 317 and international patent application 95 / 23609 and WO 94/29336 disclose thrombin inhibitors using tripeptidyl derivatives as substrates. However, there is still a need for effective inhibitors of trypsin-like serine proteases such as thrombin. There is a particular need for a compound that is both orally bioavailable and selective for other serine proteases and inhibits thrombin. Compounds predicted to have competitive inhibitory activity against thrombin are particularly useful as anticoagulants and are therefore useful in the treatment of thrombosis and related disorders. Binding Fee Disclosure of the Invention According to the present invention, a compound of formula I is provided. R4 Ο R1 丨

(CH2) p (CH2) q -6- This paper size applies to the Chinese country # ^ TcNS) Α4 size (2IGX297 male foot) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 585853 A7 B7 V. Description of the invention ()-4} Wherein P and q each represent 0, 1, 2, 3 or 4; K represents π H '2'3 # after oxypropyl or radical'-a group is optionally substituted by a group; R2 and R3 each represent H, _) 3. Trial group, catalyl group, CHRf or Q ·, alkynyl group, the latter group is optionally substituted with one or more gas or group, or CM cycloalkyl or phenyl group, the last two This group is optionally substituted with one or more Ci4 alkyl, alkoxy, halogen, hydroxy, cyano, nitro, trifluoromethyl, N (H) R23 or c (0) 0R24; R21 and R22 represents cyclohexyl or phenyl; R23 represents fluorene, CM alkyl or C (0) R25; R24 and R25 represent fluorene or Cw tiger group; E4 represents fluorene, Cw alkyl or (CH2) sC02R41; Y represents Ci_3 alkynyl 'is optionally substituted by q · 4 fluorenyl, aryl, methylene or oxy; R41 represents fluorenyl or CU4 alkynyl; s represents 0, 1, or 2; η represents 0, 1, 2, 3 or 4; and B represents a structural fragment of formula IVa, IVb or IVc

rva ^ IVc This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) ^^-Order / W (Please read the precautions on the back before filling this page] 585853

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economics, where R5 represents thorium, halogen, or CM; and X1 and X2 individually represent single bonds or ch2; the prerequisite is that when R1, R2, and R4 all represent H, p represents 0, When γ represents (CH2) 2 and η represents tf 1, and: ⑻R3 represents unsubstituted phenyl; and (1) when B represents a structural fragment of formula IVa, and R5 represents η, then q is not 0 or 1; (Η) When B represents a structural fragment of formula ivb and χι and $ both represent CIi2, then q is not 0; and ⑸R3 represents an unsubstituted cyclohexyl group, B represents a structural fragment of formula Wa, and R5 represents Η, Then q is not 0; or a pharmaceutically acceptable salt thereof (hereinafter referred to as "the compound π of the present invention"). The compound of the present invention may have tautomerism. All tautomeric forms and mixtures thereof are included in the scope of the present invention. The compounds of the present invention may also contain one or more asymmetric carbon atoms, and therefore may have optical and / or non-mirror isomerism. All non-mirror isomers can be separated using conventional techniques such as chromatography or fractional crystallization. Various stereoisomers can be used conventionally (such as fractional crystallization or sail.) To separate the racemic mixture or other mixture of compounds and separate them. Or, under conditions that do not cause racemization or epimerization, or by derivatization, appropriate optically active starting materials such as It reacts with palmitic acid, and is prepared by separating non-image isomeric vinegar by conventional methods (such as HPLC, chromatography on silica). All stereoisomers are included in the scope of the present invention. (Please read the notes on the back and fill in the tribute first)

The paper size is suitable for financial affairs (585853 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (6 R2, R3, and Y); RW can be used as a base; and R3 can be used instead. The alkoxy group can be straight or branched, saturated or unsaturated. The alkynyl group represented by Y can be saturated or unsaturated. R5 can be represented and can replace ¥ and phenyl groups, such as chlorine, molybdenum, and benzene. In the fragment of the formula IVa, IVb or IVc, the wavy line T at the carbon atom indicates the bonding position of the fragment of TF. The abbreviation series is at the end of this specification. When B represents the structure of formula IVa, IVc or In the case of fragmentation, both meanings and # are shown in Table 7F CH2, and the preferred compounds of the present invention include those in which η represents i. When B represents a fragment of formula IVb (where χι represents a single bond and $ or a form key or table CH2) Preferred compounds of the invention include those in which n represents 2. When B represents a structural fragment of formula IVa, preferred compounds of the invention include those in which R5 represents Η. Preferred compounds of formula I include in which: R1 represents fluorene or methyl; ρ means 0; R2 means fluorene, Ci-4, or optionally Phenyl; q represents 0, 1 or 2; R3 represents CM, fluorenyl, fluorenyl, fluorinyl, optionally substituted cyclohexyl or optionally substituted phenyl; Y represents CH2, (ch2) 2 (Ch2) 3 or ch2ch (ch3) ch2; and R4 represents Η. Better compounds of the present invention include: 9- Private paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) · -I — φ ^ III --- IT ----- Fees (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 585853 A7 B7 V. Description of the invention () ^ " 7 R1 means Η; R2 represents fluorene, methyl, ethyl, or optionally substituted phenyl; q represents 0; and R3 represents optionally substituted phenyl or optionally substituted cyclohexyl. When Y represents (CH2) 2 Preferred compounds of the invention include: ⑻R3 represents a substituted phenyl group; or (b) R3 represents an unsubstituted phenyl group; and R2 is not η. Particularly preferred compounds of the invention include wherein: ρ and q each represent 0; R2 represents fluorene, methyl or ethyl; R3 represents optionally substituted phenyl or optionally substituted cyclohexyl; Υ table ch2; η represents 1 1; B represents a structural fragment of formula IVa; and R1, R4, and R5 all represent Η. When R3 represents cyclohexyl or phenyl, the preferred substituents include fluoro, trifluoromethyl, Methyldioxy, ethoxy, propoxy, especially phenyl, methyl and methoxy. Among them, the fragment R4

This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) ^ 1T (Please read the notes on the back before filling in this page) 585853 A7 B7 V. Description of the invention (8) The compound of the invention in S configuration Better. In the aforementioned fragments, the wavy lines on the nitrogen and carbon atoms mean the bonding positions of the fragments. When R1 and R2 each represent Η and p represents 0, the preferred compound of the present invention is a fragment thereof.

For the R configuration. The wavy line on the carbon atom in the previous formula indicates the bonding position of the fragment. Preferred compounds of the invention include:

Ch- (R, S) CH (0H) -C (0) -Aze-Pab;

Ch (R) CH (0H) -C (0) -Aze-Pab;

Ph- (R) CH (0H) -C (0) -Aze-Pab;

Ph (3-Me)-(R, S) CH (0H) -C (0) -Aze-Pab;

Ph (3-0MeHR? S) CH (0H) -C (0) -Aze-Pab;

Ph (3,5-di0Me)-(R, S) CH (0H) -C (0) -Aze-Pab; Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page )

Ph (3-0Me? 4-0HHR? S) CH (0H) -C (0) -Aze-Pab;

Ph- (R, S) C (Et) (0H) -C (0) -Aze-Pab;

Ph- (R, S) C (Et) (OH) -C (0) -Pro-Pab; (Ph) 2C (0H) -C (0) -Aze-Pab;

Ph (3-0ME? 4-OH)-(R, S) CH (OH) -C (0) -Pro-Pab; Ph- (R) CH (0H) -C (0) -Aze-Pab;

Ph- (R) CH (0H) -C (0) -Pic (cis-4-Me) -Pab; This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 585853 A7 B7 V. Description of the invention (9) Ph- (3,4K-〇-CH2-0-))-(R, S) CH (OH) -C (0) -Aze-Pab; Ph- (3-OMe)-(R9S) CH (OH) -C (0) -Pro-Pab; Ph- (355-diOMe)-(R, S) CH (OH) -C (0) -Pro-Pab; Ph- (R, S) C (Me ) (0H) -C (0) -Aze-Pab. Preparation method The present invention also provides a method for preparing a compound of formula I, including a compound of formula V (please read the precautions on the back before filling this page)

Where p, q, R1, R2, and R3 are as defined above, coupled with a compound of formula VI, ra ra N N printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs where R4, Υ, η, and B are as defined above; Compound R4 0 R1

N Y (CH2) p (CH2) q

0 'OH -12- This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 585853 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (10) where p, q, R1 , R2, R3, r4, and Y are as defined above, and are coupled to a compound of formula vm, H2N- (CH2) nB Vm where η and B are as defined above; they are, for example, in coupling systems (such as in DMF, EDC, DCC) Or grass gas in TBTU), appropriate tests (such as p-Yodo, DMAP, or DIPEA) and appropriate organic solvents (such as dichloromethane, acetonitrile or DMF). Compounds of formula V are either commercially available or well known in the literature or are available using known techniques. For example, compounds of formula V, where R1 and R2 each represent Η, and p and q each represent. And R3 represents the one substituted by one or more Q_4 alkyl, Q_4 alkoxy, functional element, hydroxyl, cyano, nitro, trifluoromethyl, N (H) R23 or C (0) OR24 as appropriate. Phenyl or phenyl, via aldehyde of formula IX

R3aCHO IX where R3a represents optionally substituted by one or more CM alkyl, Cle4 alkoxy, halogen, hydroxy, cyano, nitro, trifluoromethyl, N (H) R23 or C (0) 0R24 Fluorenyl or phenyl, and R23 and R24 are as previously defined,

R, 'CN X __ ___- 13- This paper size applies Chinese National Standard (CNS) A4 specification (21〇1 ^ 97 ^ ¥ 1 ---- ί 111 —. ^ Wi III u V (Please read the Note: Please fill in this page again) 11. Explanation of the invention (where R, represents Η or (CH3) 3Si, for example, at room temperature (for example, higher than room temperature but lower than 丨 ⑻.c)), in an appropriate organic solvent (for Gas-formation) exists ητ, if necessary, it is reacted in the presence of a suitable catalyst system (such as gasified ammonium ammonium), and then prepared by hydrolysis in the presence of a suitable base (such as NaOH). Or is known in the literature or can be obtained by known techniques. For example, the compound of formula W can be used to formulate the compound R4 was prepared by standard peptide coupling

XI 0-where R4 and Υ are as defined above. Similarly, a compound of formula νπ can also be prepared by subjecting a compound of formula XI to standard peptide coupling under conditions such as those described for the synthesis of compound of formula I. The compounds of formula vm, IX, and alkene are either commercially available or well known in the literature, or can be obtained using known techniques. Substituents located on a phenyl group in a compound of formula can be interconverted by techniques well known to those skilled in the art. The compounds of the invention can be isolated from their reaction mixtures using conventional techniques. Those skilled in the art know that in the aforementioned method, the functional group of the intermediate compound may need to be protected by a protecting group. The functional groups to be protected are hydroxyl, amine and carboxylic acid. Suitable for protection of hydroxyl groups -14- This paper size applies to Chinese National Standard (CNS) A4 specifications (210 > < 297mm) W ---------- IT ----- (Please read first Note on the back, please fill out this page again) Printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 485853 A7 B7 V. Description of the invention (12) The group includes trialkylsilyl and diarylalkylsilyl (such as the third Butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for amine, fluorenyl and guanidino groups include a second butoxycarbonyl group or a fluorenyloxycarbonyl group. Suitable protecting groups for protecting carboxylic acids include ^ 6 alkyl or ethyl esters. The protection and deprotection of functional groups can be performed before or after coupling. The compounds of the present invention can be prepared by one method, including N-acetylated Amino acid or N-protected amino acid coupling. When using a protected amino acid, a fluorenyl group can be added after coupling and the nitrogen atom can be deprotected using standard methods described below. And guanidyl nitrogen can be protected mono- or di-protectively with amine protecting groups, such as benzyloxycarbonyl or tertiary butoxycarbonyl. The protecting groups can be removed according to the techniques well known to those skilled in the art as described below. Before the final deprotection stage Manufactured to form a specific protected intermediate that is a compound of the present invention is novel. --------- Packing -------- Order ----- m- (Please read the precautions on the back first (Fill in this page again.) Printed on the other side of the present invention is a compound of formula Ia.

Among them, B1 represents the structural fragment of formula IVd, IVe or ivf. The scale of Zhang's scale is applicable to the Chinese National Standard (CNS) A4 specification (210x1 ^ 1 ^-Da 85853 A7 B7. V. Description of the invention (13)

, Vd iVe, vf D1 and D2 represent fluorene or benzyloxy-carboxyl, respectively, are p, q-, R1, ubiquitin 2, R3, R4, Y, η, R5, X1 and X2 as defined above, the prerequisite is D1 And D2 cannot be Η at the same time. In a fragment of the formula Γ / a, IVb or IVc, a wavy line on a carbon atom indicates the bonding position of the fragment. Revised by JWF McOmie, Plenum's Protective Groups in Organic Chemistry, published by Plenum in 1973, and TW Greene & PGM Wutz, Wiley-Interscience, second edition published in 1991. Protective group * Fully describes the purpose of the protective group. Medical use The compounds of the present invention can be used, which have pharmaceutical activity. Therefore it can be used as a medicine. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) Another aspect of the present invention provides a compound of the present invention which can be used as a drug. In particular, the compounds of the present invention are potent thrombin inhibitors, as illustrated in the following tests. It is therefore predicted that the compounds of the present invention are useful in conditions where thrombin inhibition is required. Therefore, the compound of the present invention can be used for treating or preventing thrombosis and excessive blood coagulation ability in blood and tissues of animals including humans. -16- This paper size is applicable to China National Standard (CNS) A4 (210X 297mm) 585853

(14) Description of the invention (14) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Paper size Shicai Guanjia County (CNS) A4 specification (2i () X29V ^ y) The compound of the present invention can also be used to treat undesired excess thrombin Conditions without signs of excessive blood coagulation capacity, such as neurodegenerative diseases such as Alzheimer's disease. Specific conditions can be mentioned < specific conditions include treatment and / or prevention of thrombosis and pulmonary embolism, Arterial thrombosis (for example, in patients with myocardial infarction, unstable colic, stroke and predominant stroke and peripheral arterial thrombosis), and systemic embolism from the atrium during arterial fibrosis or transmural myocardium Systemic embolism from the left ventricle after infarction. Also, 'the compounds of the present invention are predicted to be useful in preventing thrombolysis, percutaneous transluminal angioplasty (PTCA), coronary bypass surgery, microsurgery, and vascular surgery. Re-occlusion (thrombosis) usually occurs afterwards. Other symptoms include the treatment and prevention of bacterial-induced disseminated intravascular coagulation and severe trauma Poisoning or any other mechanism; anticoagulant treatment when blood comes into contact with surfaces outside the body, such as vascular grafts, vascular graft molds, vascular catheters, mechanical and bioprosthetic valves, or any other medical device; And anticoagulant therapy when the blood is in contact with a medical device in vitro, such as using a heart-lung machine during cardiovascular surgery or during hemodialysis. In addition to its effect on the coagulation process, thrombin is known Can activate a large number of cells (such as neutrophils, fibroblasts, endothelial cells and smooth muscle cells). Therefore, the compounds of the present invention can also be used to treat or prevent primary adult dyspnea syndrome, lungs after radiation or chemotherapy Department of fibrosis, septic shock, sepsis, inflammation, including but not limited to -17- .---------- IT ----- ΦΜ (Please read the precautions on the back before filling this page } 585853 V. Description of the Invention (15) Edema, acute or chronic arteriosclerosis, such as coronary artery disease, cerebral artery disease, peripheral artery disease, reperfusion injury, Restenosis after percutaneous transluminal angioplasty (PTCA). The present invention shows that compounds inhibit trypsin and / or thrombin, and can also treat pancreatitis. ^ Another aspect of the present invention provides a treatment for thrombin A method of treating a disease, which method comprises administering a therapeutically effective amount of the aforementioned compound of the formula I, or a pharmaceutically acceptable salt thereof, to a patient suffering from or susceptible to the disease. The Ministry of Economic Affairs Central Standards Bureau Staff Consumer Cooperative Printed Medicine FormulationsThe compounds of the present invention are generally oral, subcutaneous, buccal, rectal, percutaneous, nasal, tracheal, bronchial, by any other parenteral route or by inhalation, which includes a free test form, or is pharmaceutically acceptable Non-toxic active or inorganic acid addition salt in the form of a pharmaceutical formulation of the active ingredient, or a pharmaceutically acceptable dosage form. Depending on the condition to be treated, the patient and the medication, the composition can be administered at varying doses. The compounds of the present invention can also be combined with any antithrombotic agent having a different mechanism of action, such as an antiplatelet agent, such as tidopKlme, clopidogr, Prostaglandin receptor and / or protease inhibitors, fibrinogen receptor antagonists, prostaglandin mimetics: and phosphodiesterase inhibitors. The compounds of the present invention may additionally be combined with thrombolytic agents, such as neoplasm plasminogen activator (natural or recombinant), streptokinase, urokinase, prokinase, toluene etherified streptokinase plasmin Source activator is used for organic coupling and stiff urine: ------------- • 』f Please read the precautions on the back before filling in this page.

585853 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (ASPAC), animal salivary plasminogen activator, etc. to treat thrombotic disorders, especially myocardial infarction Another aspect of the present invention provides a pharmaceutical formulation comprising a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, and blended with a pharmaceutically acceptable adjuvant, diluent or carrier. A suitable daily dose of the compound of the present invention in treating humans is about 0.001 to 100 mg / kg body weight when administered orally, and 0.001 to 50 mg / kg body weight when administered parenterally. Compared with the compounds known in the prior art, the compounds of the present invention have the advantages of being more effective, less toxic, and longer-lasting, having broader-acting activity, stronger effects, fewer side effects, and easier absorption, or Has other useful medical properties.

Biological test Test A Thrombin clotting time (TT) determination 100 μΐ human thrombin (T 6769, Sigma Chem Co) in a pH 7.4 buffer solution was incubated with 100 μΐ inhibitor solution for 1 minute. 100 μΐ of normal citrated human plasma collected was added and the clotting time was measured in an automatic device (KC 10, Amelung). The clotting time in seconds vs. inhibitor concentration green plot, IC50TT was determined by interpolation. IC50 TT is an inhibitor concentration that doubles the thrombin clotting time of human plasma. -19- This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) --------------- IT ----- Lu · (Please read the note on the back first Please fill in this page again for details) 585853 A7 B7 V. Description of the invention (Π) Test B The measurement of the prothrombin-stimulated salting time (Αρττ) of the activated scent of cinnabarin using the reagent ρττ Automated 5 made by Stago. APTT was measured in human citrated plasma. Add the inhibitor to the plasma (10 μΐ inhibitor solution vs. 90 μ! Plasma), then add the reagent and calcium chloride solution, and measure Αρττ in the mixture using the coagulation analyzer KC (Amelung) according to the instructions of the reagent manufacturer. . The clotting time in seconds is plotted against the concentration of the inhibitor in plasma. IC% APTT is determined by interpolation. IC50APTT is defined as the inhibition of doubling the time of activated partial thromboplastin in human plasma.剂 浓 量。 Agent concentration. (Please read the precautions on the back before filling this page)

1T printed test by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. C. Measurement of thrombin time in vitro. The inhibitory effect on thrombin after oral or parenteral administration of the compound of the present invention was measured on awake rats. A catheter was installed one or two days before the experiment to obtain a blood sample from the carotid artery. On the experimental day, after the compound was administered to a plastic tube containing i part of sodium citrate solution (0.13 mol per liter) and 9 parts of blood, blood samples were taken at a fixed time. The tube was centrifuged 'to obtain plasma with less platelets. This blood group was used to determine the thrombin time according to the following. 100 μΐ of citric acidified mouse plasma was diluted with 100 μ! 0.9% saline solution, by adding 100 μΐ of human thrombin in a buffer solution of pH 7.4 (T 6769, 20- This paper is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) line 585853 5. Description of the invention (is)

(Sigma Chem Co, USA) allowed plasma to begin to clot. Measurement of clotting time in an automatic device (Kc Amelung, Germany). When a compound of formula la was administered, a standard curve was used to estimate the appropriate concentration of an active thrombin inhibitor of formula I in rat plasma. The time of thrombin in citrated mouse plasma relative to the known concentration of the "active" thrombin inhibitor dissolved in saline.

Test D Wave of thrombin time in urine in vitro. Awake rats were orally administered the compound of the present invention, and then left in a metabolic cage for 24 hours. The thrombin time was measured on the collected urine as described below. The collected positively acidified human plasma was incubated with concentrated rat urine or its saline diluent for one minute. Human thrombin was administered in a buffer solution (pH 7.4 '100 μΐ) ( τ 6769, & c0) to cause the plasma to start clotting. The coagulation time is measured in an automatic device (KC 10 ,.) When the substitute of Formula 1a is administered, the appropriate formula I is estimated by the standard curve. Concentration of active thrombin inhibitor in rat urine, the curve is based on the collected thrombin time in normal citrated human plasma, relative to the corresponding, active, thrombin inhibitor dissolved in the concentrated mouse Known concentration in urine (or its saline diluent). The total rat urine produced within 24 hours is multiplied by the predicted average concentration of the aforementioned active inhibitor in urine to calculate the excretion of the active inhibitor The paper size ------------- " 鰊 (Please read the notes on the back before filling in this page)-Order · Line-i-111 -21-585853 Staff Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs Printing A7 B7 V. Description of Invention (19) The example illustrates the invention. Example General experimental method Recorded on a Finnigan MAT TSQ 700 triple quadrupole mass spectrometer (FAB-MS) equipped with a motorized spray interface and a VG Platform Π mass spectrometer (LC-MS) equipped with a motorized spray interface. Mass spectrogram 0NMR and 13C NMR were measured on the BRUKER ACP 300 and Varian UNITY with 400 and 500 spectrometers, each operating at a frequency of 1Η at 300.13, 399.96, and 499.82 MHz, while the 13C frequencies were 75.46, 100.58, and 125.69 MHz.实施 例 1 Example 1

Ch- < mH (OHVC (OVAze-Pab X HC1 (i) Boc-Aze-OH) Ditributyl dicarbonate (13.75g; 63 mmol) was added to 5.777 g (57 mmol) L-azetidine-2 · carboxylic acid (H-Aze_OH) and 6.04 g (57 mmol) of steel carbonate in a mixture of 50 mL of water and 100 mL of THF. After 60 h, The THF was removed in the air, and the mixture was diluted with water and acidified with 2M potassium hydrogen sulfate. After extraction with dichloromethane and drying (magnesium sulfate), the solvent was evaporated to yield a residue, where dichloromethane: sparsely crystallized to yield 10.87 g (95 %) Colorless crystal iH-NMR (300 MHz; CDC13): 5 4.85-4.7 (br s, 1), 4.0 · 3 · 75 (m, 2), 2.65-Z35 (m, 2), 1.4 ( s, 9). -22- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) --------------- IT ----- * I (Please (Please read the notes on the back before filling this page) Printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 585853 A7 ____B7 V. Invention Description (20) (ii) Boc-Aze-PabfZ ") At room temperature, apply EDC (13.5 g; 70 mmol) was added to Boc-Aze-OH (10.87 g; 54 mmol; from step (i)), H -Pab (Z) x HC1 (18.31 g; 57 mmol; prepared according to the method described in International Patent Application WO 94/29336) and a mixture of DMAP (9.9 g; 81 mmol) in acetonitrile (270 mL). After 16 h, the solvent was removed in the air and replaced with ethyl acetate. The mixture was washed with water and aqueous citric acid solution. The organic layer was dried (magnesium sulfate) and the solvent was removed in the air to produce a residue. Boc-Aze-Pab (Z) (17.83 g) is generated when a mixture of gaseous methane, toluene, diisopropyl ether and petroleum ether is crystallized. ^ -NMR (300 MHz; CDC13): 5 7.85-7.75 (d? 1) , 7.45-7.2 (m, 7% 5.2 (s? 2 \ 4.7 (t, 1), 4.6-4.4 (m, 2), 3.95-3.8 ("q ,,, 1), 3.8-3.7 (q, 1 ), 2.5-2.3 (m, 2), 1.4 (s, 9). (Iii) H-Aze-PabrZ ^

Boc-Aze_Pab (Z) (2.44 g; 5.2 mmol; from step ii) was dissolved in a mixture of 10 mL of trifluoroacetic acid and 10 mL of digas methane. After 30 minutes, the solvent and trifluoroacetic acid were removed in the air, and the residue was dissolved in dichloromethane. The organic phase was washed with a 10% sodium carbonate solution and dried (potassium carbonate). The solvent was removed in the air, resulting in a residue, which produced colorless crystalline Aze-Pab (Z) (1.095 g; 57%) when crystallized from dichloromethane. b-NMR (300 MHz; CD3OD): 3 7.85-7.75 (d, 2), 7.45 · 7 · 25 (m, 7), 5.2 (s, 2), 4.5 (s, 2), 4 3 (d, 1), 3.65 (q, 1), 3.4-3.3 (m, 1), Z7-2.5 (m, 1), 2.4-2.2 (m, 1), (IV) Ch Y S, CHr 〇HVC (OVAze-Pab (Z, according to the methods described by Kelly and LaCour (Synth. Comm. 22, 859 (l " 2)) and according to ____ ^ 23z________ This paper size applies the Chinese National Standard (CNS) A4 specification 210X297 mm) --------- install ------ order ----- 畀 i (Please read the precautions on the back before filling this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Preparation 585853 A7 __B7 V. Description of the invention (21) Prepared in the following way: (R, S) hexahydromandelic acid (0.30 g, 1.9 mmol), catalytic amount of DMAP, and pyridine (0.31 g, 3.9 mmol) In a solution of methane (5 mL), TMSC1 (0.42 g; 3.9 mmol) was added dropwise. The reaction was stirred at room temperature for 4 h. The reaction was cooled to 0 ° C, and a catalytic amount (from 2 mL syringe added drop) 'followed by grass grass gas (0.25 g; 2.0 mmol). Reaction at 0 ° C: Stir for 1 h, add H-Aze_Pab (Z) (0.67 g; 1.8 mm ol; obtained from the mixture of step (iii)) and pyridine (0.50 g; 6.3 mmol), the reaction was warmed to room temperature and stirred overnight. A 100/0 solution of citric acid in methanol was added to the reaction ( 6 mL). After 30 minutes, the reaction was poured into a separatory funnel, diluted with 30 mL of ethyl acetate, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with a saturated bicarbonate solution and then with brine. And dried (Na2S04). Evaporated, flash chromatography on chopped gum, digas methane: methanol (99: 1 to 92: 8) was used as eluent to obtain the secondary compound (60mg; 6%). ^ -NMR (300 MHz; CDC13): 6 1.0-1.9 (m? 11 H)? 2.4-2.7 (m? 2 H)? 3.80 (d, 1 H), 4.05-4.25 (m, lH), 4.3- 4.5 (m, 2H), 4.85_5.0 (m, 1H), 5.18 (s, 2H), 7.1-7 · 5 (m, 7 H), 7.65 · 7 · 8 (m, 2 H), 7.86 (bt, 1 H, minor non-mirror isomers and / or geometric isomers), 8.33 (bt, 1 H, major non-mirror isomers and / or geometric isomers) 13C_MNR (75 Mhz , CDC13) 脒 and carbonyl carbon: δ 174.8, 170.6, 168.0 and 164.5 〇 (v) Ch- ^ S ^ CHrOHVCrOVAze-Pab x HC1

Ch- (R, S) CH (OH) -C (0) -Aze-Pab (Z) (60 mg; 0.12 mmol; from the previous step (iv)) was dissolved in ethanol (5 mL) and added 5% Pd / C and HC1 (0.1 mL; concentrated). _________-24 -_____________________ This paper size applies to the Chinese National Standard (CNS) Α4 size (210X297 mm) Binding * ^ (Please read the notes on the back before filling this page) 585853 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ____ B7 __ 5. Description of the invention (22) The mixture is agitated for 2 hours at atmospheric pressure. After filtration and evaporation, the product was purified with RPLC after preparation, and (0.005 M NH4OAC, 0.005 M HOAc) was used as the eluent for CH3CN 4: 1. After lyophilization, HCl (aq) was added, and the solution was lyophilized. The yield of the main product was I5 mg (M%). b-NMR (300 MHz; D20) complicates the spectrum due to diastereomers and / or geometric isomers: δ 0.7_2.0 (m, 11 H), 2.25-2.4 (m, 1 H) , 2.65_2.9 (m, 1 H), 3.79 (d, 1 H, minor), 4.03 (d, 1 H, major), 4.05_4 · 15 (m, 2 H, Minor), 4.35_4 · 45 (m, (bt), 2 H, major), 4.5_4 · 6 (m, 2 H), 5.20 (m, 1 H, minor, main signal and HOD Signal overlap), 7.5-7.65 (m, 2 H), 7.75-7 · 85 (m, 2 Η) 13C-NMR (75 MHz; CDC13) 脒 and carbonyl carbon (non-image isomers and / or geometry Isomers): δ 176.3, 175.4, 173.7, 173.3, 167.2 and 167.0. Example 2

Ch-rR ^ CHrOHVCrOVAze-Pab x HC1 (!) Ch 彳 R, CH (OHVa〇, Aze_PabiZ, according to Example 1 (iv) (R) hexahydromandelic acid C from 0.6 g, 3 · 8 mmol) to prepare the secondary compound in a yield of 0.15 g (10%). (ii) Ch-mCHrOHVCroVAze-Pab x HC1 from Ch- (R) CH (OH) -C (0) -Aze_Pab (Z) (0.12 g; 0.24 mmol; obtained from the foregoing) according to the method described in Example 1 (v) Step (i)) prepares the main compound. Yield: 52 mg (54%) 0 iH-NMR (300 MHz; D20; complex spectrum due to geometric isomers) · δ 0 · 7-2.0 (m, 11 Η), 2.25-2.4 (m, 1 Η), 2.65-2.9 (m, 1 Η), 3.79 (d, 1 Η, minor), -25- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) --- ------ φ-pack -------- IT ----- Feng < ηκ (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 585853 A7 B7 V. Description of the invention (23) 4.02 (d, 1 H, major), 4.05-4.15 (m, 2 H, minor), 4.35 · 4 · 45 (m, (bt), 2 H, Major), 4.5-4.6 (m, 2 Η), 5.19 (m, 1 H, minor, main signal overlaps with HOD signal), 7.5-7.65 (m, 2 H), 7.75-7.85 (m, 2 Η) 13C-NMR (75 MHz; CDC13) 脒 and carbonyl carbon (geometric isomer): 171.9, 170.2, 169.8 and 163.8. Example 3 rEt ^ CrOHVCrOVAze-Pab x HC1 rnH-Aze-PabrZ ^ x 2HC1 A secondary compound was prepared by reacting Boc-Aze-Pab (Z) (see the aforementioned example (ii)) with EtOAc saturated with gas HC1. The reaction mixture was evaporated after half an hour to give H-Aze-Pab (Z) X 2HC1 in quantitative yield. (ii) nEt ^ CrOHVCrOVAze-PabrZ ^ diethyl glycolic acid (0.13 g; 0.80 mmol), H_Aze_Pab (Z) x 2HC1 (0.39 g; 0.88 mmol; from the previous step (i), TBTU (0.28 g; 0.88 mmol) in DMF (15 mL) was cooled on an ice bath. DIPEA (0.41 g; 3.2 mmol) was added and the reaction mixture was stirred at room temperature overnight. The resulting mixture was poured into 500 mL of water and It was extracted three times with ethyl acetate. The combined organic phases were washed with NaHCCVR solution and water, dried (Na2S04) and evaporated. The crude product was subjected to flash chromatography on silica gel using methane: THF as eluent. Yield: 30 mg; 8%) 0 b-NMR (400 MHz; CDC13): δ 8.04 (bt, 1Η), 7.77 (d, 2H), 7.40 (d, 2H), 7.35-7.2 (m, 5H), 5.17 (s, 2H), 4.90 (m, m), 4.46 (dd, 1 ί), 4.39 (dd, 1 H), _-26 ^ _ This paper size applies to China National Standard (CNS) A4 (210X 297) Li) Binding * J (Please read the notes on the back before filling this page) 585853 585853 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention (24) 4.3-4.2 (m, 2 H), 2.66 (m, 1 H), 2 .44 (m, 1 H), 1.8-1.5 (m, 4 H), 0.9-0.75 (m 6 H) · (iii) ffit ^ Crom-CrOVAze ^ Pab x HC1 According to the method described in Example 1 (v) The main compound was prepared from (Et) 2C (0H) _C (0) -Aze_Pab (Z) (30 mg; 0.063 mmol; obtained from the foregoing step (ii)). Yield: 19 mg (79%). IHHNMR (300 MHz; D20; complex spectrum due to geometric isomers): δ 7 · 80 (d, 2 Η), 7.65_7 · 5 (m, 2 H), 5.43 (m, 1 Η, minor geometric isomers) ) 4.90 (m, 1 Η, major geometric isomer) 4.6-4.5 (m, 3 Η), 4.11 (m, 1 Η, geometric isomer), 3.70 (m, 1 H, geometric Isomers), 2.8-2.55 (m, 1H), 2.35-2.15 (m, 1H), 1.94.6 (m, 4 H), 1.0-0.75 (m, 6 Η) 13C-NMR (75 MHz; D20 ) Hydrazone and carbonyl carbon (geometric isomers): 178.3, 177.4, 175.0, 173.5, 167.2. Example 4 m2C (QHVCrovaVAze-Pab x HC1 (ϊ) (Ph ^ CrOHVCrQVAze-PabrZ ^) According to the method described in Example 3, a diphenyl glycolic acid (0.18 g; 0.80 rmnol) was prepared as a minor Compound. Yield: 0.16 mg (35%). LH-NMR (300 MHz; D20) · δ 7.93 (bt, 1Η)? 7.71 (d? 2 Η)? 7.54-7.15 (m? 17 Η), 5.M (s, 2 Η), 4.89 (m, 1 Η), 4.57 (m, 1 Η), 4.48 (dd, 1 Η), 4.35 (dd, 1 Η), 3.60 (m, 1 Η), 3.44 (m, 1 Η), 2.44 (m, 1 Η), 2.23 (m, 1 Η). ___- 27j_ This paper size applies to Chinese National Standards (CNS) Α4 Specification (210 × 297 mm) (Please read the notes on the back before filling out this page) Equipment · Printed by the Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 585853 A7 ___B7_ V. Description of the Invention (25) (i ^ rPh ^ CrOHVCrOVAze- Pab x HC1 The main compound was prepared according to the method described in Example 1 (v) from (Ph) 2C (0H) -C (0) -Aze-Pab (Z) (0.16 g, 0.28 mmol) from the previous step ⑼. Yield : 90 mg (68%) 0 W-NMR (400 MHz; D20) Complex spectrum due to geometric isomers: δ 7.65-7.55 (m, 2 H), 7.4-7.1 (m, 12 Η), 5.13 (m , 1 Η Minor geometric isomers), 4.77 (m, 1 H, major geometric isomers), 4 · 43 (d, 1 H), 440 (d, 1 Η), 4 · 12 (m, 1 H, major Geometric isomers), 4.05-3.9 (m, 1 H, plus 1 H minor geometric isomers), 2.55 (m, 1 H, minor geometric isomers), 2.39 (m, 1 H, major Geometric isomers), 2.08 (m, 1 H). 13C_NMR (75 MHz; D20) 脒 and carbonyl carbon (geometric isomers): δ 175.7, 174.9, 174.6, 173.4, 167.1. Example 5 n-CfHiI- rR.S >) CHrOHVCrOVAze-Pab x HC1 (i) nC ^ rR.S ^ CHrOHVCrOVAze-Pab ^ According to the method described in Example 3 (1) above, g; 0.80 mmol) to prepare a secondary compound. Yield: 0.25 g (61%). iH-NMR (400 MHz; CDC13): δ 8.24 (bt, 1H, single non-image isomer), 7.89 (bt, 1H, single non-image isomer), 7.8_7.75 (111, 211), 7.4-7.45 (m, 2 H), 7.35-7.25 (m, 5 H), 5.18 (s, 2H), 4.95-4.85 (m, 1 H), 4.55-4 · 35 (m, 2H), 4.2-4.0 (m, 3H), 2 · 8 · 2 · 65 (m, 1H), 2.6-2.4 (m, 1Η), 2.0_1 · 2 (m, 10H), 0.9-0.8 (m, 3H). 28-_____ This paper size applies to China National Standard (CNS) A4 (210X297mm) " — ^ wi ^ IT (Please read the notes on the back before filling this page) 585853 Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the consumer cooperative A7 __B7_ V. Description of the invention (26) (ii) nC ^ H ^^ S ^ CHrOHVCrOVAze-Pah x HC1 According to the method described in the previous example 1 (v), * n-C6H13- (R, S) CH (0H) -C (0) -Aze-Pab (Z) (0.14 g; 0.28 mmol; from the previous step (i)) was used to prepare the main compound with a yield of 88 mg (78%). ^ -NMR (400 MHz; D20) · δ 7.7-7.6 (m9 2Η)? 7.45-7.3 (m, 2Η)? 5.03 (m? 1Η? Single non-image isomer), 4.74 (m, 1Η, single non- Image isomers overlap with water signals), 4.45-4.35 (m, 2H), 4.3-4.1 (m, 2H), 40-3.8 (m, 1H), 2.65_2 · 45 (m, 1Η), 2 · 3 · 2 · 1 (m, 1Η), 1 · 6_0 · 9 (m, 10Η), 0.75-0.65 (m, 3Η). 13C-NMR (75 MHz; D20) 脒 and carbonyl carbon (non-image isomers) And geometric isomers): δ 176.8, 176.4, 176.0 173.5, 173.3, 173.2, 167.2. Example 6 Ph ^ R ^ CHrOHVCrOVAze-Pah (Ϊ) Ph- ^ CHrom-CrOVAze-PabrZ ^ A secondary was prepared from (R) -mandelic acid (0.12 g; 0.8 mmol) according to the method described in Example 3 (ii). Compounds. The crude product (0.315 g) was purified by flash chromatography (Si-gel; THREtOAc (6: 4)). Yield 28 g (32%) of white powder, 91.2% purity (HPLC). OH-NMR (499.803 MHz; CDC13): δ 8.14 (t, 1H), 7.72 (d, 2H), 7.42 (d, 2H) , 7.33 (t, 4H), 7.28 (m, 3H), 7.22 (d, 2H), 5.18 (s, 2H), 4.92 (s, 1H), 4.79 (dd, 1H), 4.54 (wide s, 1H ), 4.39 (d, 2H), 4.00 (q, 1H), 3.53 (q, 1H), 2.48 (m, 1H), 2.24 (111, 111), 2.19 (wide 8,111) 13C-NMR (125.688 MHz; CDC13) (carboxylic acids and carbons): δ 173.1, 170.3, 168.1, 164 · 5 〇 _____- 29ζ__ This paper size applies to China National Standard (CNS) Α4 specification (210 × 297 mm) " I (Please read the back first Precautions-: Write this page), 1T Cao-S85853 A7 B7 27 V. Description of the invention ((ii) Ph-rR ^ CHrOHVCrOVAze-Pab

Ph- (R) -CH (0H) -C (0) -Aze-Pab (Z) (107 mg; 0.214 mmol; obtained from the previous step (i)) was dissolved in THF ice (2: 1), 37 was added mg Pd / C (4 mol% Pd), the resulting solution was hydrogenated for 6 hours. The solution was filtered through hyflo and evaporated to dryness. To the resulting white powder was added 20 mL of water acidified with 0.42 mL of 1M HC1 (about 2 equivalents). The resulting solution was washed with 5 mL of EtOAc and 10 mL of diethyl ether and lyophilized twice. Yield: 72 mg (84%) of white powder. Purity: 91% (HPLC). iH-NMR (399.968 MHz; D20): δ 7.57 (t, 2H), 7.36 (d, 1H), 7.32 (s, 3), 7.27 (s, 1H), 7.25 (d, 1H), 7.19 ( m, 1H), 5.Π (s, 1H, major), 5.09 (s, 1H, minor), 5.00 (dd, 1, minor), 4.38 (s, 2, major), 4.20 ( dd, 1H, major), 3.98 (dd, 2H, minor), 3.97 (m, 1H, major), 3.75 (dd, 1H), 2.68 (s, 1H, minor), 2.65 (m , 1H, minor), 2.35 (m, 1H major), 2.12 (m, 1H, major), 2.03 (m, 1H, minor) 13C-NMR (111.581 MHz; D20) (carboxylic acid and carbon ): Δ 174.5, 173.2, 172.5, 172.4. Example 7

Pha-CF ^ -rR-S ^ CHrOHVCfOVAze-Pab x HC1 Ph (4-CFiWR.S > > CH (OHVC (OVAze-Pab (Z)) According to the method described in Example 3, from (R, S) -4 -Trifluoromethylmandelic acid (0.19 g; 0.88 mmol) to prepare the secondary compound. Flash chromatography (Si-gel; CH2C12: THF (6: 4)) yielded 0.13 g (26%) of a white powder. IH-NMR (300 MHz; CDC13): δ 9.6-9.2 (b, 1H), 8.1 (bt, 1H, non-image isomer), 7.9 (bt, 1H, non-image isomer), 7.7-7.1 (m, 13H ), 5.16 (s, 2H), 5.07 (s, _-30-_ This paper size is applicable to China National Standard (CNS) A4 specifications (210X297 mm) I — Binding • • (Please read the precautions on the back first (Fill in this page again.) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, printed 585853 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, printed A7 ____B7 V. Invention Description (28) 1H, Non-Mirror Isomers), 4.98 (s , 1H, non-mirromeric isomers), 4.80 (m 1H), 4.5 · 4 · 2 (m, 2H), 4.1-3.5 (m, 2H), 2.5-2.2 (m, 2H) 13C-NMR ( 75 MHz; CDC13) hydrazone and carbonyl acids (non-image isomers): δ 173.3, 172.4, 170.3, 168.3, 164.4 〇 (ii) Ph-^-CFO-rR.S ^ CHrOHVCrOVAze-Pab x HC1 According to the method described in Example 1 (v), Ph- (4-CF3)-(R, S) CH (0H) -C (0) -Aze- Pab (Z) (133 mg; 0.23 mmol; obtained from the previous step (i)), yielding the main compound as a white crystal powder. Yield 77mg〇70%). IH-NMR (300 MHz; D20): δ 8.84 (m, 1H), non-image isomers / geometric isomers), 8.73 (m, 1H), non-image isomers / geometric isomers), 8.52 (m, 1H), non-image isomers / Geometric isomers), 7.8-7.4 (m, 8H), 5.46, 5.44, 5.30, 5.20 (single line, 1H, non-mirror isomers / geometric isomers) 4.96 (m, 1H, non-mirror isomers) Compounds / geometric isomers; other signals from the same proton overlap with HDO signals), 4.6-4.0 (m, 4H),), 2.9-2.5 (m, 1H), 2.4-2.1 (m, 1H) 13C-NMR (75 MHz; D20), fluorene and carbonyl carbon (non-mirromeric isomers and geometric isomers): δ 173.6, 173, 3, 173, 1, 173_0, 172.9, 167.0. Example 8

Pha-OMeWR.S, CH (OHVC (OVAze-Pab X HC1 (i) Ph (4-OMeWR, CH (OHVC (OVAze-Pab (Z)) According to the method described in Example 3, from (R, S) -4 -Methoxymandelic acid (0.18 g; 1.0 mmol) to prepare secondary compounds. Flash chromatography (Si-gel; EtOAc: MeOH (95: 5)) yielded 27 mg (17%) of a white powder. __-Ή -___ This paper size applies to China National Standard (CNS) Α4 size (210 X 297 mm) · II I binding. V (Please read the precautions on the back before filling this page) 585853 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 7 B7 V. Description of the invention (29) Non-image isomerism ratio 85:15; Signal of main non-image isomers: h-NMR (400 MHz; CDC13): δ 8 · 19 (m, 1H), 7.80 (d , 2H), 7.45 (d, 2H), 7.4-7.2 (m, 7H), 7.13 (d, 2H, minor geometric isomers), 6.90 (d, 2H, major geometric isomers), 6.82 (d, 2H, minor geometric isomers), 5 21 (s, 2H), 4.9-4.85 (m, 2H; its singlet is at 4.89 (1H), 4.6-4.4 (m, 2H), 4.02 ( m, 1H), 3.81 (s, 3H), 3.55 (m, 1H), 2.62 (m, 1H), 2.32 (m, 1H) 13C-NMR (100 MHz; CDC13) 脒Carbonyl acids: δ 173.6, 170.3, 167.8, 164.6. (Ii) Ph (4-OMeWR ACHiOm-CYOVAze-Pab x HC1 According to the method described in Example 1 (v), * Ph (4_0MeHR, S) CH (0H) _C (0) -Aze-Pab (Z) (27 mg; 0.05 mmol; obtained from the previous step (i)) to prepare the main compound. 15 mg (68%) of a white powder was produced. Non-mirror isomerism ratio 85:15; obtained from Signals of main non-mirror isomers: ιΗ NMR (400 MHz; D20): δ 7.7-7.6 (m, 2H), 7.5-7.3 (m, 4H), 7.18 (d, 2H, geometric isomers), 6 97 (d, 2H, geometric isomer), 6.9-6.85 (m, 2H, geometric isomer), 5.19 (s, 1H, geometric isomer), 5.14 (s, 1H, geometric isomer) Material), 5.01 (m, 1H, geometric isomers), 4.76 (m, 1H, geometric isomers), 4.48 (s, 1H), 4.3-3.7 (m, 7H; 2 singlet lines at 3.78 , 3.77 (3H)), 2.73 (m, 1H, geometric isomer), 2 46 (m, 1H, geometric isomer), 2 · 3_2 · 0 (m, 1H) 13C-NMR (75 MHz D20), hydrazone and carbonyl carbon (geometric isomers): δ 175.5, 174.1, 173.3, 173.1, 167.1, 167.0. Example 9 -32- This paper size applies the Chinese National Standard (CNS) A4 size (210X297mm). I booklet (please read the precautions on the back before filling this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 585853 A7 ______B7__ 5. Description of the invention. (3〇) £ h (4-OHWR Ari ^ nHVaOVAze-Pab X HC1 (i) Hl (4-OHVrR S ^ CHrOHVCrOVAze-PabrZ ^) According to the method described in Example 3), from (R, S) _4-The secondary compound was prepared as tauric acid (0.34 g; 2.0 mmol). Flash chromatography (si-gel; EtoAc / EtoH (9/1)) yielded 0.18 g (17%) H-NMR (400 MHz; CDC13): δ 7.70 (d, 2H, minor non-image isomers / geometric isomers), 7.64 (d, 2H, major non-image isomers / geometric isomers) , 7.5_7.0 (m, 7H), 6.82 (d, 2H, major non-mirror isomers / geometric isomers), 6.67 (d, 2H, minor non-mirror isomers / geometric isomers), 6.43 (d, 2H, major non-mirror isomers / geometric isomers), 5.30, 5.26, 5.22, 5.21 (single line, 2H, non-mirror isomers / geometric isomers), 4.95 · 4 · 8 (m, 2H), 4.15-4.05 (m, 2H), 4.0-3.7 (m, 2H), 2.7-2.5 (m, 2H) (ii) Ph- (4-OHV (R, S) CH (OHVC (OVAze-Pab x ΗΠ) According to the method described in Example 1 (v), * Ph (4_0H) _ (R, S) CH (0H) -C (0) _Aze-Pab (Z) (94 mg; 0.18 mmol; from the previous step ①) to prepare the secondary compound. Yield: 37 mg (49%) ) White powder. 1H-NMR (600 MHz; D20): δ 7.76, 7.72, 7.71, 7.68, 7.52, 7.47, 7.40, 7.35, 7.25, 7.19, 7.11, 6.97, 6.82, 6.76, 6.73, 7.71 (dual Line, 8Η, non-image isomer / geometric isomer), 5.19 (s, 1H, non-image isomer / geometric isomer), 5.17 (s, 1H, non-image isomer / geometric isomer) ), 5.14 (s, 1H non-mirror isomer / geometric isomer), 5.01 (m, 1Η, non-mirror isomer / geometric isomer), 4.88 (m, 1H, non-mirror isomer) / Geometry isomers; other signals from the same proton overlap with HDO signals), 4.6-3.8 (m, 4H), 2.77 (m, 1H, non-mirrored isomers ___- 33- _ This paper standard applies to Chinese national standards (CNS) A4 specifications (210X: 297 mm) '' --- IT (Please read the notes on the back before filling out this page) 585853 Central Bureau of Standards, Ministry of Economic Affairs Printed by the Industrial and Consumer Cooperatives A7 B7 V. Description of the invention (31) Isomers / geometric isomers), 2.62 (m, 1H, non-mirror isomers / geometric isomers), 2.49 (m, 1H, non-mirror isomers) Compounds / geometric isomers), 2 · 3 · 2 · 1 (m, 1H) 13C-NMR (75 MHz; D20), fluorene and carbonyl carbons (non-image isomers / geometric isomers): δ 175.9, 174.8, 174.3, 173.3, 173.2, 172.9, 167.1. Example 10 Ph-CHo-rR ^ CHrom-CrOVAze-Pab x HC1 (ϊ) Ph-C% rR > iCHrOHVCrVAVAze-PabrZ > > According to the method described in Example 3, from (R) -phenyl Lactic acid (0.25 g; 1.5 mmol) was used to prepare the secondary compound. Flash chromatography (Si-gel; CH2C12: THF (6: 4)) yielded 0.28 g (36%). 'H-NMR (500 MHz; CDCI3) ^ δ 8.19 (m, 1H), 7.72 (d, 2H), 7.43 (d, 2H), 7.4-7.1 (m, 10H), 5.19 (s, 2H), 4.73 (m, 1H), 4.45-4.25 (m, 2H), 4.19 (m, 1H), 3.86 (m, 1H), 3.18 (m, 1H), 3.0-2.9 (m, 2H), Z42 (m, 1H) ), 2. 14 (m, 1H) 13C-NMR (125 MHz; CDC13), fluorene and carbonyl carbon: δ 174.5, 170.2, 167.9, 164.3. (ii) Ph-CHo-rR ^ CHrOHVCrOVAze-Pab x HC1 According to the method described in Example 1 (v), * Ph-CH2- (R) CH (OH) -C (0) -Aze-Pab (Z) ( 0.22 g; 0.43 mmol; obtained from the previous step ①) yielded 10 · 5 mg (57%) of a white powder. b-NMR (600 MHz; D20): δ 7.73 (d, 2H, major geometric isomer), 7.62 (d, 2H, minor geometric isomer), 7 · 5_7 · 4 (m, 2H), 7.4 -7.2 (m, 5H), 7.10 (m, 2H, minor geometric isomers), 4.71 (m, 1H, major geometric isomers), 4.5-4.4 (m, 2H), __ _ This paper size applies China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page)

1T ▼ Line · 585853 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (32) 4.34 (m, 1H, minor geometric isomers), 4.14 (m, 1H), 4.03 (m, 1H), 3.53 (m, 1H), 3.05-2.95 (m, 2H, major geometric isomers), 2.9-2.7 (m, 2H, minor geometric isomers), 2.65_2 · 5 (m, 1H , Minor geometric isomers), 2.5-5_2 · 3 (m, 1H, major geometric isomers), 2.3-2.l (m, lH) 13C_NMR (75 MHz; D20), pyrene and carbonyl carbon (geometry Isomers): δ 175.9, 175.0, 173.7, 173.2, 167.1, 166.8. Example 11 Ch-rR, CH (OHVC (OVPic-Pab (i) Boc-Pic-OH according to M. Bodanszky and A. Bodanszky ('Peptide Synthesis Example "Springer-Verlag) uses THF instead of dihumane as solvent ^ -NMR (300 MHz; CDC13) · δ 5.0-4.8 (br d? 1H)? 4.0 (br s? 1H)? 3.0 (br s? 1H), 2.20 (d, 1H), 1.65 (m , 2H), 1.5-1.3 (s + m, 13H) (ii) Boc-Pic-PabO According to the method described in Example 1) above, Boc-Pic-OH (2.02 g; 8.8 mmol; Obtained from the previous step (i)) to prepare the secondary compound, yielding 1.59 g (44%). FAB-MS m / z 495 (M + 1) + ^ NMR (400 MHz; CDC13): δ 7.83 (d, 2H) , 7.43 (d, 2H), 7.36-7.11 (m, 5H), 6.52 (bs, NH), 5.20 (s, 2H), 4.81-4.72 (m, 1H), 4.61-4.34 (m, 2H), 4.10 -3.90 (m, 1H), 2.79-2.64 (m, 1H), 2.36-2.25 (m, 1H), 1.73-1.3 (m, 14H) (iii) H-Pic-PabOx 2HC1 _-J5J-_ This paper Standards are applicable to China National Standard (CNS) A4 specifications (210X 297 mm) (Please read the notes on the back first, and then 4 packs-: Write this page) Order 585853 A7 B7 V. Description of the invention (33)

Boc-Pic_Pab (Z) (1.59 g; 3.25 mmol; from the previous step ii) was dissolved in 100 mL EtOAc saturated with HC1. The reaction was mixed for half an hour and evaporated to produce the main compound in quantitative yield. FAB-MSm / z395 (M + 1) + iH-NMR (300 MHz; D20): δ 7.82 (d, 2H), 7.63-7.41 (m, 7H), 5.47 (s, 2H), 4.69-4.49 (AB -The system center is located at δ 4.59, 2H), 4.03 (dd, 1H), 3.52 (bd, 1H), 3.10 (dt, 1H), 2.29 (dd, 1H), 2.08-1.61 (m, 5H) (iv) HzPiczPabiZ) The dihydrochloride obtained in the previous step (iii) was dissolved in 2M NaOH and then extracted with CH2C12, and the organic solvent was evaporated to produce a secondary compound. (y) Ch-rR ^ CHrOHVCrOVPic-PabrZ ^ According to the method described in Example 3 (ii), (R) hexahydromandelic acid (0.152 g; 0.96 mmol) and H-Pic-Pab (Z) (0.417 g , 1.06 mmol; obtained from the aforementioned step (iv)) to prepare a secondary compound. Flash chromatography (Si-gel; EtOAc: toluene (3: 2), then EtOAc) produces 90 mg (18%) 〇 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling in (This page) ^ -NMR (300 MHz; CDC13): δ 7.82 (d? 2H)? 7.5-7.2 (m, 7H), 6.63 (t, ABX-X part of the system NH), 5.21 (s, 2H), 5.14 (d, 1H), 4.46 (ABX · System, 2H), 4.26 (apparent s, 1H), 3.61 (bd, 1H), 3.52 (bd, 1H), 3.06 (dt, 1H), 2.30 (Bd, 1H), 1.92-1.0 (m, 14H), 0.95-0.8 (m, 1H) 13C-NMR (75 MHz; CDC13), rhenium and carbonyl carbon: δ 174.8, 170.3, 167.8, and 164.6. _-36-_ This paper size applies to China National Standard (CNS) Α4 size (210X297 mm) Printed by the Central Consumers' Bureau of the Ministry of Economic Affairs for consumer cooperation 585853 A7 B7 V. Description of the invention (34) (νϊ) Ch-rR ^ CHrOHVCrOVPic-Pab X HC1 According to the method described in Example 1 (v), Ch- (R) CH- (0H) C (0) _Pic-Pab (Z) (59 mg; 0.11 mmol; obtained from The aforementioned step (v)) prepares the main compound. Generates 19 mg (40%) 0 FAB-MS m / z 401 (M + 1) + iHHNMR (300 MHz; D20): Due to geometric isomers, the spectrum is complex: δ 7 · 91 · 7 · 72 (m , Major and minor geometric isomers, 2Η), 7.58 (d, minor geometric isomers, 2H), 7.53 (d, major geometric isomers, 2H), 5.17 (apparent bs, major Geometric isomers, 1H), 4.66-4.28 (m, s), 3 ·% (bd, major geometric isomers, 1H), 3.26 (bt, major geometric isomers, 1H), 3.05-2.88 (m , Minor geometric isomers, 1H), 2.39-2.20 (m, 1H), 2.0 · 0.075 (m, 16H) 13C_NMR (75 MHz; MeOH) 脒 and carbonyl carbon at δ 175..86, 173.20, 168.53. Example 12

Ch-CH2-rR ^ CHr〇HVCr〇VPic-Pab x HC1 Ch-CHo-mCHrOHVCrO ^ OH solution of phenyllactic acid (2.57 g) and rhodium on aluminum (0.75 g) in MeOH (170 mL) at 3 atmospheres , Hydrogenated in H2 atmosphere for 2 days. The mixture was filtered through hyflo and evaporated to dryness to give the product in quantitative yield. ^ -NMR (400 MHz; CDC13): δ 4.23 (bdd, 1H), 3.24 (apparent s, OH), 1.68 (bd, 1Η), 1.63-1.43 (m, 6H), 1.43-1.31 (m, 1H ), 1.21-1.0 (m, 3H), 0.95-0.75 (m, 157 mg (0.91 mmol) 2H) ---- 37. The two paper sizes apply the Chinese National Standard (CNS) A4 specification (210X297 mm)- ---- · ---- 0 ^^ ------ 1T ----- (Please read the notes on the back before filling out this page) 585853 A7 B7 V. Description of the invention (35) ⑻ rh- CHo-mCHrOHVCrOVPic-Pabrz ^ According to the method described in Example 1 (iv) above, H-Pic-Pab (Z) X 2 HC1 (353 mg; 0.76 mmol; refer to step 11 (iii)) and Ch_Ch2 (R). CH- (OH) -COOH (157 mg; 0.91 mmol; from previous step (i)) to prepare the secondary compound. Product flash chromatography (Si gel, EtOAc: toluene 07: 3)) yielded 92 mg (22%). b-NMR (300 MHz; CDC13): δ 7.72 (d, 2H), 7.46 · 7.1 · (m, 7H), 6.90 (t, NH), 5.18 (s, 2H), 5.07 (d, 1H ), 4.45 (bd, 1H), 4.37 (d, 2H), 3.73-3.47 (m, 2H), 3.10 (bt, 1H), 2.24 (bd, 1H), 2.15-2.0 (m , 1H), 1.90 (bd, 1H), 1.80-1.05 (m, 12H), 1.05-0.75 (m, 3H) 13C-NMR (75 MHz; CDC13), rhenium and carbonyl carbon: δ 175.88, 170.43, 168.04 and 164.58. (iii) Ch-CHo-rR ^ CHrOHVCrOVPic-Pab x HC1 According to the method described in Example 1 (v) above, Ch-Ch2- (R) CH (OH) -C (0) _Pic_ Pab (Z) (62 mg; 0.113 mmol; from previous step ii), the main compound was prepared, yielding 47 mg (92%). FAB-MS m / z 415 (M + 1) + h-NMR (300 MHz; D20) Complex spectrum due to geometric isomers: δ 7 · 85_7 · 71 (m, major and minor geometric isomers, 2Η ), 7.56 (d, minor geometric isomer, 2H), 7.50 (d, major geometric isomer, 2H), 5.12 (apparent bs, major geometric isomer, 1H), 4.68-4.25 (m, 3H, partially hindered by HDO), 3.80 (bd, major geometric isomer, 1H), 3.24 (bt, major geometric isomer, 1H), 2.89 (bt, minor geometric isomer, 1H ), 2.25 (m, 1H), 1.92 · 0 · 82 (m, 17H), 0 · 60 · 0 · 4〇 (m, major geometric isomers, 1H) -38- This paper standard is applicable to Chinese national standards ( CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling this page) Pack. Then fill in the item too printed by the Central Consumers Bureau of the Ministry of Economic Affairs and printed by the Consumer Cooperatives 585853 A7 B7 5. Description of the invention (36) 13C-NMR (75 MHz; D20) 脒 and carbonyl carbon (geometric isomer): δ 177.10, ten 173.88, 173.07, 167.24. Example 13

Ph-rR ^ CHrOMeVCfOVAze-Pab x HC1 (Ϊ) H-Aze-OMexHCl

MeOH (200 ml) was cooled to -40 ° C under argon atmosphere, and sulfur sulfonium chloride (47.1 g; 0.396 mmol) was added dropwise, and the reaction mixture was stirred at -100 ° C for 35 minutes. H-Aze_OH (10.0 g; 0.099 mol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to give 16.1 g (100%) of the main compound. ^ -NMR (400 MHz; CDC13) · δ 5.12-5.24 (m? 1Η)? 4.08-4.29 (m? 2Η)? 3.84 (s, 3Η), 2.65 · 2 · 87 (m, 2Η). η) Ph-fR ^ CHrOMeVCrOVAze-OMe According to the method described in Example 1 前述 above, R (-)-oc-methoxyphenylacetic acid (0.60 g; 3.6 mmol) and H-Aze-OMe X HC1 (0.55 g; 3.6 mmol; from the previous step ①) to prepare the secondary compound, yielding 0.32 g (34%). Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) ^ -NMR (400 MHz; CDC13): δ 7.29-7.48 (m? 5H), 4.71-5.08 (m9 2H) ? 3.92-4.31 (m, 2H), 3.69-3.83 (m, 3H), 3.19-3.46 (m, 3H), 2.13-2.65 (m, 2H).

(iii) Ph-mCH (OMeVC (OVAze ^ OH in Ph_ (R) CH (OMe) -C (0) -Aze-OMe (0.32 g; 1.2 mmol; from step (ii) above)) in THF (10 ml A solution of lithium hydroxide monohydrate (0.071 g; 1.7 mmol) in H20 (6 ml) was added to the solution in). The reaction mixture was stirred for 3h, after which the Chinese standard (CNS) was applied to this paper size. A4 specification (210X297 mm) 585853 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 __B7_ V. Description of the invention (37) Evaporation. The residue is dissolved in H20 and extracted with toluene. The pH of the H20 layer is adjusted to HC1 3, followed by extraction with ethyl acetate (4 times). The resulting organic layer was evaporated to yield 0.28 g (92%) of the main compound. B-NMR (300 MHz; CDC13): δ 7.30-7.50 (m, 5H), 4.95 5 · 10 (m, 1H), 4.80 (s, 1H), 4.10-4.35 (m, 2H), 3.40 (s, 3H), 2.40-2.80 (m, 2H) · iivm-aOCHiOMeVaOVAze-Pab ⑺ according to The method described in Example 1 (ii) was obtained from H-Pab (Z) x HC1 (0.36 g; 1.0 mmol) and Ph-CH (0Me) _C (0) -Aze_0H (0.25 mg; 1.0 mmol; from The foregoing step (iii)) prepared the secondary compound, yielding 0.39 g (76%) of a white powder. ^ -NMR (400 MHz; CDC13): δ 8.29 (m, 1Η)? 7.77 (d? 2Η)? 7.45 (d, 2Η), 7.4-7.2 (m, 10Η), 5.22 (s, 2Η), 4.93 (m, 1Η) ), 4.69 (s, 1Η), 4.44 (m, 2Η), 4.15 (m, 2H), 3.35 (s, 3H), 2.69 (m, 1H), 2.42 (m, 1H) ( y) Ph-fR ^ CHrOMeVCrOVAze-Pab x HC1 According to the method described in Example 1 (v), Ph_ (R) CH (OMe) -C (0) _AzePab (Z) (0.15 g; 0.29 mmol; The main compound was prepared from the foregoing step (iv)), yielding 50.4 mg (41%) of a white powder. IH-NMR (400 MHz; CD3OD; alpha hydrogen of Aze and fluorenyl hydrogen from mandelate were masked by the CD3OH signal): δ 7.8-7.6 (m, 2Η), 7.6-7.4 (m, 2Η), 7 · 4_7 · 1 (m, 5H), 4 · 6_4 · 4 (m, 2H), 4.3-4.0 (m, 2H), 3.29 (s, 3H), 2.7-2.5 (m, 1H), 2: 4-2.1 (m, 1H) · Example 14 ____ -40-_ i Paper size applies to China National Standard (CNS) A4 specification (210X297) Ί (Please read the notes on the back _ 4 items and then ¾ Pack II: write this page) Order 585853 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (38) Phr3-OMeVrR.S > tCHr 〇HVCr〇VAze-Pab x HC1 ⑺ Ph (; 3-OMeW RS) CH (OHVC (OVAze-Pab (D) The secondary compound was prepared from (R, S) -3-methoxymandelic acid (270 mg; 1.5 mmol) according to the method described in Example 3⑻, yielding 340 mg (43% ); Non-mirromeric isomerism ratio 1: 0 FAS-MSm / z531 (M + 1) + iH-NMR (400 MHz; CDC13): δ 8.14 (m, 1H, non-mirro isomer), 7.87 (m, 1Η, non-image isomer), 7.8-7.0 (m, 10Η), 6.9-6.7 (m, 3Η), 5.16 (s, 2Η), 4.96 (s, 1H, non-mirro isomer) , 4.88 (s, 1H, non-mirromeric isomers), 4.85-4.7 (m, 1H), 4.4-4.2 (m, 2H), 4.05-3.9 (m, 1H), 3.71 (s, 3H, non-mirror isomeric Structure), 3.71 (m, 1H, non-image isomer), 3.66 (s, 3H, non-image isomer), 3.58 (m, 1H, non-image isomer), 2.5-2.35 (m, 1Η ), 2.32 (m, 1H, non-image isomer), 2.20 (m, 1H, non-image isomer). 13C-NMR (100 MHz; CDC13) 脒 and carbonyl carbon (non-mirromeric isomers): δ 173.9, 173.0, 170.5, 170.4, 168.3, 168.2, 164.5. (Ή) Ph (; 3-OMeWR.S) CH (OHVC (OVAze-Pab x HC1) According to the method described in Example 1 (v), * Ph (3-0Me) _ (R, S) CH (0H) _C (0) -Aze-Pab (Z) (230 mg; 0.43 mmol; obtained from the previous step (i)) to produce the main compound, yielding 126 mg (67%) of the product. Non-mirromeric isomerism ratio 1: 1. FAS-MSm / z397 (M + l) + b-NMR (400 MHz; D20; complicated by (non-mirror isomers / geometric isomers) and some impurities): δ 7 · 6_7.1 (m, 5H), 6.9 -6.6 (m, 3H), 5.2-4.7 (m, 1_2H), 4 · 4 · 3 · 7 (m, 4 · 5Η), 3.63 (s, 3H, non-image isomers / geometric isomers), 3 · 55 (m, _-41- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before filling this page))

1T ▼ Line 585853 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention Description (39) 3H, Non-Mirror Image Isomers / Geometric Isomers, 2.5_2.3 (m, 1H), 2.2- 2.0 (m, 1H) 13C-NMR (75 MHz; D20) 脒 and carbonyl carbon (non-image isomer / geometric isomer): δ 175.8, 175.4, 174.8, 174.6, 168.5. Example 15 Ph G-MeWKSICHrOHyaOVAze-Pab X HOAc (i) (R, SV3-methylmandelic acid 3.methylacetaldehyde (12.0 g; 0.1 mol) and vaporized fluorenyl triethylammonium (1.23 g; 0.005 mol ) The mixture in CHC13 (16 ml) was stirred at 56 ° C. A solution of NaOH (25 g) in H20 (25 ml) was added dropwise to the mixture. When the addition was complete, the reaction mixture was stirred for 1 h. It was diluted with H20 (400 ml produced) and extracted with diethyl ether (3x50 ml). The pH of the mixture was adjusted to 1 with H2S04 (concentrated), and then extracted with diethyl ether (6x50 ml). The combined organic layers were dried (MgS04) and evaporated The crude product (11.6 g) was recrystallized from toluene to yield 8.47 g (51%) of the main compound. LC-MS m / z 165 (M-1); 331 (2M-1) ^ -NMR (600 MHz; CD3OD) : Δ 7.10-7.28 (m, 4H)? 5.08 (s? 1H)? 2.32 (s, 3H). (Ii) Phi3-MeWR.S) CH (OHVC (OVAze-PabO According to Example 3 (ii) Method: (R, S) -3-methylmandelic acid (0.22 g; 1.3 mmol; prepared from the previous step ⑼), a minor compound, yield 0.37 g (54%). LC-MSm / z515 (M + 1) + ^ -NMR (400 MHz; CDC13) δ 8.11-8.21 (t, NH)? 6.97-7.89 (m? 13H)? 5.18-5.24 (m, 2H), 4.83-5.00 (m, 2H), 4.37-4.58 (m, 2H), 3.50-4.11 (m, 2H), 2.39- _-42- This paper size applies to the Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the 1T-line. 585853 A7 B7 V. Description of the invention (40) 2.71 (m, 2H), 2.27-2,38 (m, 3H). (Iii) Phr3-MeWR. S) CH (OHVC (OVAze-Pab x HOAc

Ph (3_Me)-(R, S) CH (0H) -C (0) -Aze-Pab (Z) (0.105 g; 0.20 mmol; from step (ii)), acetic acid (0.012 g, 0.20 mmol) And a mixture of Pd / C (5%, 0.14 g) in ethanol (12 ml) was hydrogenated at atmospheric pressure for 6 h. The reaction mixture was filtered and the filtrate was evaporated. The crude product was dissolved in H20 and dried cold to produce a sticky product. The product was dissolved in HOAc and lyophilized again without any improvement. The product was dissolved in H20, filtered through an HPLC-filter, and lyophilized. This gave 67 mg (76%) of the main compound. LC_MSm / z381 (M + l) + ^ -NMR (400 MHz; D20) δ 6.89-7.72 (m, 8H)? 4.79-5.23 (m, 2H)? 3.76-4.51 (m, 4H), 2.38-2.82 (m, 2H), 2.15-2.27 (m, 3H). 13C-NMR (75.5 MHz; D20; complex due to non-image isomers / geometric isomers) and carbonyl carbons: δ 181.21, 175.43, 174.38, 173.94, 173.23, 173.06, 172.16, 167.00. Example 16

Ph (3-OEtWR.S) CH (OHVC (OVAze-Pab X HOAc (i) (R, SV3-ethoxymandelic acid (R, S) -3-hydroxymandelic acid (0.712 g; 4.236 mmol) is dissolved in acetonitrile (15 ml). K2C03 (2.34 g; 16.94 irnnol) was added and ethyl iodide (1.03 ml, 12.71 mmol) was added dropwise. The reaction mixture was refluxed for 2 h and then evaporated. The residue was dissolved in H20 (25 ml) and acetone ( 6 ml), the mixture was stirred at room temperature for 3 hours. The reaction mixture _-43-_ This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) ---------- IT- ---- (Please read the notes on the back before filling this page) Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 585853 A7 B7 V. Description of the invention (41) The H20 layer formed by evaporation is extracted with ethyl acetate. H20 The pH of the layers was adjusted to 2 with KHS04 aqueous solution and H20 was added to dissolve the salts formed. The H20-solution was extracted with ethyl acetate (3 times). The combined organic layers were washed with H20, dried (Na2S04) and evaporated. Residual The product was prepared by HPLC (25% acetonitrile: 75% 0.1M HOAc), and the product-containing fractions were evaporated. The aqueous layer formed was extracted with ethyl acetate (3 times). The layer was washed with H20, dried (Na2S04) and evaporated. The yield was 192 mg (22%) of the secondary compound. LC-MS M / Z 195 (M-1); 391 (2M-1) \ 587 (3M -1) -h-NMR (400 MHz; CD3OD): δ 6.80-7.27 (m, 4H), 5.08 (s, 1H), 3.99-4.13 (m, 2H), 1.34-1.40 (t, 3H). (; iimf3- OEtWILS, CH (OHVaVAze-Pab (Z, according to the method described in Example 3, from (R, S) _3-ethoxymandelic acid (0.178 g; 0.907 mmol; from the previous step (i)) to prepare a secondary Compound, yield 259 mg (52%) ° LC-MSm / z545 (M + l) + ^ -NMR (400 MHz; CDC13) · δ 6.77-7.77 (m? 13H), 5.16-5.21 (d? 2H) 9 4.78-4.99 (m, 2H), 4.27-4.51 (m, 2H), 3.53-4_07 (m, 4H), 2.21-2.60 (m, 2H), 1.29-1 · 41 (m, 3H). (Iii) PhG-OEtVrRS ^ CHrOHVCrOVAze-Pabx HOAc According to the method described in Example 15 (iii), * Ph (3-0Et)-(R, S) CH (0H) -C (0) · Aze-Pab (Z) (0.182 g; 0.33 mmol; from the previous step ii) to prepare the main compound, yield 157 mg (100%). ____- 44: _ This paper size is applicable to China National Standard (CNS) A4 (210X297mm) --------------- IT ----- (Please read the note on the back first Please fill in this page again for matters) 585853 Printed by A7 _____B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (42) LC_MSm / z411 (M + l) + ^ -NMR (400 MHz; CD3OD): δ 7.71-7.79 ( m? 2H)? 7.49-7.60 (m9 2H)? 7.19-7.30 (m, m), 6.94-7.02 (m, 2H), 6.81-6.90 (m, lH), 5.09-5.18 (m, m), 4.74 -4.81 (m, lH), 4.39-4.62 (m, 2H), 3.93-4.35 (m, 4H), 2.10-2.61 (m, 2H), 1.32-1.40 (m, 3H). 13C-NMR (100.6 MHz D20; complicated by non-mirromeric isomers / geometric isomers) 脒 and carbonyl carbons: δ 180.68, 174.30, 173.50, 173.07, 172.44, 172.26. Example 17 Ph (3-QPr (n > »V ( R.S > > CHrOHVCrOVAze-Pab x HOAc (i) (R, SV3-allyloxymandelic acid (R, S) -3-mer is tauric acid (0.504 g; 3.0 mmol) in Dissolved in anhydrous acetone (25 mL) in a nitrogen atmosphere. Add allyl bromide (0.907 g; 7.5 mmol) and anhydrous K2C03 (1.037 g, 7.5 mmol). The reaction mixture was stirred in a nitrogen atmosphere for 16 h. The material was then evaporated. The residue was dissolved in H20 (25 ml) and acetone (6 ml), and the mixture was stirred for 2 h (HPLC after the reaction). After the mixture was evaporated, the aqueous layer was extracted with ethyl acetate. The pH of the aqueous layer was KHS04 aqueous solution Adjust to 2 and extract with ethyl acetate (3 times). The combined organic layers were washed with H20, dried (Na2S04) and evaporated. A secondary compound was produced with a yield of 0.175 g (28%). ^ -NMR (500 MHz; CDC13 ) Δ 6.87-7.30 (m, 4H) 5 5.97-6.10 (m, 1H)? 5.26-5.44 (m, 2H), 5.20 (s, 1H), 4.51-4.55 (d, 2H). (Ii) PhfS -OCHoCH ^ H.VrR.S ^ rHrOHVCrOVAze-PabrZ ^ According to the method described in Example 3⑻, (R, S) -3 · 晞 propoxymandelic acid (0.167 a _____ This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the precautions on the back before filling this page). Binding & Order> 585853 A7 B7 V. Description of the invention (43) g; 0.8 mmol; from the previous step (i )) Preparation of minor compound, yield 260 mg (58%) ° NMR (500 MHz; CDC13) · δ 8.09-8.17 (t, ΝΗ)? 6.79-7.87 (m? 13Η)? 5.94-6.09 (m? 1Η)? 5.20-5.44 (m, 4Η), 4.86-5.02 (m, 2H)? 4. 32-4.62 (m, 4H)? 3.54-4.15 (m, 2H), 2.30-2.74 (m, 2H). (Iii) Phr3_OPrfaYWR.S) CH (OHVa〇VAze-Pab x HOAc According to Example 15 (iii) The method described above, * Ph (3-OCH2CH = CH2)-(R, S) CH (OH) -C (O) -Aze-Pab (Z) (0.06 g; 0.1 mmol; from the previous step (ii)) The main compound was prepared with a yield of 47 mg (97%). LC-MS m / z 425 (Μ + l) \ 423 (Μ -1) '^ -NMR (500 MHz; D20): δ 6.70-7.71 (m, 8H), 4.70-5.25 (m, 2H)? 3.78 -4.53 (m, 6H), 2.05-2.80 (m, 2H), 1.56-1.75 (m, 2H), 0.82-0.95 (m, 3H). Example 18

Phr3-OPraso > > V (< RS ^ CH (; OHVCfOVAze-Pab x HOAc ω (r, sv3-isopropoxymandelic acid) according to the method described in Example 16 (i) above, from (R, S)- The secondary compound was prepared with 3-hydroxymandelic acid (0.70 g; 4.16 mmol), Cs2C03 (5.87 g; 16.65 mmol) and isopropyl iodide (1.25 ml; 12.49 mmol) with a yield of 62 mg (7%). LC-MS m / z 209 (Μ -1) _ iH-NMR (400 MHz; CD3OD): δ 6.81_7 · 25 (m, 4H), 5.08 (s, 1H), 4.53_4 · 64 (m, 1H), 1.28-1.32 (d, 6H). _-46- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back _ 4-then fill in and install — (Write this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 585853 A7 B7 V. Description of the Invention (44)

(^ PhG-OPifisolWKSICHiOHVCiOVAze-PabO According to the method described in Example 3 (ii), from (R, S) -3 · isopropoxymandelic acid (0.063 g; 0.3 mmol; from the previous step ①) to prepare a secondary compound Yield: 60 mg (34%). LC-MS m / z559 (M + 1) + 1H-NMR (400MHz; CDCl3): 3 6.75-7.79 (m, 13H), 5.18-5.24 (m, 2H), 4.81-4.99 (m, 2H), 4.31-4.58 (m, 3H), 3.97-4.15 (m, 1H), 3.55-3.77 (m, 1H), 2.24-2.64 (m, 2H), 1.23 · 1.33 (m, 6H). (Iii) PhG-OPrdsoV ^ RACHiOHVaOVAze-Pab x HOAc According to the method described in Example 15 (iii) above, * Ph (3_OPr (iso)) · (R, S) CH (OH) _C (O)- Aze-Pab (Z) (0.05 g; 0.090 mmol; from the previous step ii) The main compound was prepared with a yield of 41 mg (93%). LC-MSm / z425 (M + 1) + ^ -NMR (400 MHz; CD3OD ): Δ 6.81-7.80 (m, 8H)? 5.08-5.18 (m? 1H)? 4.74-4.80 (m, lH), 4.53-4.64 (m, 2H), 4.41-4.51 (m, lH), 3.93 4.35 (m, 2H), 2.23 · 2.60 (m, 2H), 2.23-2.60 (m, 2H), 1.25-1.32 (m, 6H). 13C-NMR (100.6 MHz; D20; due to non-image isomers / Geometric isomers and complex) 脒 and carbonyl carbon: δ 181.10, 173.60, 173.15, 172.48, 166.39. Example 19

Ph- (2-OMeWR.S > > CH (OHVC (OVAze-Pab X HOAc (i) Ph (2-OMeWR.S) CH (OHVC (OVAze-PabO according to the method described in previous example 3 (ii), Binding by (R, S) _2-methoxymandelic acid (0.18 __ This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm)) (Please read the precautions on the back before filling this page) 585853 A7 B7 Economy Printed by the Consumers' Cooperative of the Ministry of Standards of the People's Republic of China. 5. Description of the invention (45) g; 1.0 mmol) Preparation of the secondary compound, yielding 80 mg (17%). IH-NMR (500 MHz; CDC13): δ 8 · 16-8.22 , (T, NH), 6.81-7.85 (m, 13H), 5.16-5.20 (m, 2H), 4.79-4.91 (m, 1H), 4.35-4.49 (m, 2H), 3.84-4.02 (m, 2H ), 3.63-3.80 (m, 3H), 3.32-3.56 (m, 1H), 2.21-2.57 (m, 2H). (Ii) PhQ-OMeVrKS ^ CHfOHVCfOVAze-Pabx HOAc as described in Example 15 (iii) above Method, * Ph (2_OMe) _ (R, S) CH (OH) · C (0) _Aze_Pab (Z) (0.08 g; 0.15 mmol; obtained from the previous step (i)) to prepare a secondary compound with a yield of 45 mg ( 71%). FAB-MSm / z397 (M + l) + ^ -NMR (500 MHz; D20) · δ 6.83-7.70 (m? 8H)? 4.71-4.97 (m? 1H), 4.34-4.51 (m, 2H), 3.87-4.22 (m, 3H), 3.67-3.75 (m, 3H), 2.00-2.74 (m, 2H). 13C-NMR (75.5 MHz; D20; complex due to non-image isomers / geometric isomers) 脒 and carbonyl Carbon: δ 179.96, 176.28, 174.97, 174.50, 173.44, 173.39, 173.29, 173.10, 167.12. Example 20 Ph (3,5 · 20Me)-(R, S) CH (0HVC (0) -Aze-Pab X HOAc (i) Ph (3.5-Di0MeMR, S) CH (0HVC (0VAze-Pab (Z)) According to the method described in Example 3 (i) above, (R, S) -3,5-dimethoxymandelic acid (0.21 g; 1.0 mmol; prepared according to the method described in Synthesis (1974) 724) to produce a minor compound with a yield of 0.31 g (62%). ^ -NMR (500 MHz; CDC13): δ 8.11-8.16, (t? ΝΗ)? 7.17-7.86 (m? 9Η)? 6.41-6.49 (m, 3Η), 5.21-5.24 (d, 2Η), 4.84- 5.03 (m, 2Η), 4.29-4.66 (m, 2Η), 3.67- _-48 _-_ This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling (This page) Φ • Refilling, binding, and ordering 585853 A7 __B7_ printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (46) 4.17 (m, 8H), 2.32-2.72 (m, 2H). (Ii ) Ph (3,5 · 2 0MeHR, S) CH (0HVC (0VAze-Pab x HOAc According to the method described in Example 15 (iii) above, Ph (3,5-bisOMe) _ (R, S) CH (OH) -C (0) -Aze-Pab (Z) (0.15 g; 0.27 mmol; obtained from the previous step (i)) The main compound was prepared with a yield of 120 mg (100%). ^ -NMR (500 MHz; D20): δ 7.34-7.75 (m, 4H), 6.44-6.66 (m9 3H)? 4.67-5.12 (m, 1H), 3.97-4.55 (m, 5H), 3.79 (s, 3H), 3.71- 3.74 (m, 3H), 2.14-2.85 (m, 2H). 13C-NMR (75.5 MHz; D20; complicated by non-image isomers / geometric isomers) 脒 and carbonyl carbon: δ 181.17, 174.85, 173.92 , 173.53, 173.09, 172.98 , 182.90, 166.77. Example 21

PhrS-OMe ^ -OHVrRS ^ CHrOHVCrOVAze-Pab x HOAc (ϊ) Ph G-OMe ^ -OHVrR S ^ CHrOHVCrOVAze-PaKZ) According to the method described in Example 3 实例 above, (R, S) · 4 · hydroxy-3- Methoxymandelic acid (0.20 g; 1.0) was prepared as a secondary compound with a yield of 89 mg (16%). LC-MS m / z 547 (Μ + 1) +9 545 (Μ -1) '^ -NMR (400 MHz; CDC13): δ 8.07-8.15 (m, NH), 6.64-7.86 (m, 12H), 5.20-5.27 (m, 2H), 3.57-5.00 (m, 9H), 2.31-2.74 (m, 2H) · (ii) Ph (3-OMe.4-OHVrR S ^ CHrOHVCfOVAze-Pab x HOAc

According to the method described in the aforementioned Example 15 (iii), Pli (3-〇Me, 4-〇HV L ___- 49j · _ This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm)- ------------ 1T ----- • Line (Please read the precautions on the back before filling this page)

(R, S) CH (OH), C (0) -Aze-Pab (Z) (0.085 g; 0.16 mmol; from the former, only [(i)) Preparation of the main compound, yield 57 mg (78%). FAB-MS m / z 413 (M + 1) + MHz; D2〇; complicated due to non-image isomers / geometric isomers): δ 6.66 · 7 · 83 (M, 8H), 4.80-5.25 (m, 2H), 3.88-4.59 (m, 4H), 3.68-3 88 (m, 3H), 2.10-2.85 (m, 2H), 13C-NMR (75.5 MHz; D20) Structure / geometry isomers and complex) 脒 and carbonyl carbon · δ 182.01, 175.56, 174.43, 174.04, 173.20, 173 005 166.90, 166.85. Example 22

Phr2-F. 5-CF1VrR.S> > CHr〇m-Cr〇VAze-Pab x HOAc (i) Phf2-F. 5-CF1VrR.S> tCHr〇HVC (OVAze-Pab (Z) according to the previous example The method is prepared from (11,8) _2_fluoro_5 · trifluoromethylmandelic acid (0.3 g; 1.2 mmol; prepared according to the method described in Org · Synth · Col. I, 336). Compound, yield 0.32 g (51%). FAB-MS m / z 587 (M + 1) + Printed by the Consumers' Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs 1 · 0 (Please read the precautions on the back before filling in this Page} ^ -NMR (400 MHz; CDC13): δ 7.15-7.87 (m? 12H)? 5.19-5.30 (m? 2H) 5 4.87- 5.00 (m, 1H), 4.36-4.60 (m, 3H), 4.05 -4.02 (m, 1H), 3.60 · 3 · 73 (m, 1H), 2.32 · 2.72 (m, 2H). (\ ^ Ph-r2-F.5-CF2VrR.S > > CH (OHVC (OVAze-Pab x HOAc According to the method described in Example 15 (iii) above, Ph (2-F, 5-CT3 > _ (R, S) CH (OH) -C (O) -Aze-Pab (Z) (0.15 g; 0.26 mmol; from the previous step ①) -50- This paper size applies to China National Standard (CNS) A4 specifications (210 × 297 mm) Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 585853 A7 B7 Five 、 Explanation (49) 13C -NMR (75.5 MHz; D20; complex due to non-image isomers / geometric isomers) hydrazone and carbonyl carbon: δ 182.09, 175.79, 175.48, 173.53, 173.23, 167.05. Example 24

Ph-rR.S) aMeVOHVC (OVAze-Pab X HOAc ⑴ Ph- (RS) CnV [eVOHVC (OVAze-PabO) According to the method described in the previous example 3 (ii), Methyl propionic acid (0.20 g; 1.2 mmol) was prepared as a secondary compound with a yield of 0.17 g (31%). B-NMR (500 MHz; CDC13): δ 8.04-8.14 (t, NH), 7.17-7.80 (m, 14H) ), 5.20 (s, 2H), 4.76-4.86 (m, 1Η), 4.31-4.50 (m, 2H), 3.76-3.94 (m, 2H), 2.19-2.44 (m, 2H), 1.70 (s, 3H ). rii ^ Ph-rR.S ^ CrMeyOHVCrOVAze-Pab x HOAc According to the method described in Example 15 (iii) above, * Ph- (R, S) C (Me) (0H) -C (0) _ Aze_Pab ( Z) (0.08 g; 0.16 mmol; obtained from the previous step (i)) to produce the main compound, yield 48 mg (78%), non-mirror isomerism ratio: 85:15. ^ -NMR (500 MHz; D20): δ 7.30-7.79 (m? 9Η)? 3.99-4.82 (m? 5Η) 9 2.09-2.74 (m, 2Η), 1.70-1.77 (m, 3Η). 13C-NMR (75.5 MHz; D20; due to non-image isomerism Compounds / geometric isomers) and carbonyl carbons: δ 176.90, 176.34, 173.89, 173.48, 167.00. Example 25

Ph- (IOCH (OHVC (OVAze-Pab X HOAc (ϊ) H-Aze-PabfZ ^ _152-_ This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) β 摩-(please first Read the notes on the back and fill in this page), 1T engine line 585853 A7 B7 V. Description of the invention (50) According to the method described in Example 3 (i), then alkaline extraction processing, prepared by Boc-Aze-Pac (Z) Secondary compounds: ri ^ Ph-rR ^ CHrOTBDMSVCrOVAze-Pabrzl According to the method described in Example 1⑼ above, * Ph- (R) CH (OTBDMS) -C (O) OH (0-236 g; 0.889 mmol; according to Hamada et al. Prepared as described in J. Am. Chem. Soc., (1989) 111,669) and H-Aze_Pac (Z) (0.25 g; 0.53 mmol; obtained from the aforementioned step (i); by CH2C12: Trifluoroacetic acid (1: 1; 10 ml) was stirred for 30 minutes and preactivated) to prepare a secondary compound with a yield of 160 mg (48%). B-NMR (500 MHz; CDC13): δ 7.20-7.44 (m, 10 H ), 5.22 (s, 1 H), 5.06-5.16 (m, 2 H), 4.80-4.90 (m, 1 Η), 3.92-4.43 (m, 2 H), 2.88_3 · 12 (m, 2 H ), 2.35-2.60 (m, 2H), 1.25-2.10 (m, 10 H), 0.84-0.94 (m, 9 H), 0.00-0.15 (m, 6 H) riiim- (TOCH (OHV C (OVAze-Pac x HOAc According to the method described in Example 15 (iii) above, Ph- (R) CH (OTBDMS) -C (0) _Aze_Pac (Z) (0.16 g; 0.25 mmol; obtained from the previous step) (Ii) Preparation of main compounds; purification by RPLC, yield 15 mg (14%). Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) FAB-MS m / z 373 ( M + 1) + Example 26

Ph- (R) CH (OHVr / OVA7e-Pig x HOAc (i) Boc-Aze-Pig ^ Z) According to the method described in Example 1⑻, Boc-Aze-OH (1.03 g; 5.12 mmol ; Refer to the previous example 1⑼ and H-Pig (Z) χ ZHC1 (1.86 g, 5.12 mmol; according to the country ______ This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 585853 Central Standard of the Ministry of Economic Affairs Printed by the Consumer Cooperative of the Bureau A 7___B7 V. Invention Description (53) Step (ii)) and a mixture of Pd / C (10%, 0.21 g) in ethanol (80 ml) was hydrogenated at atmospheric pressure for 3 h. The reaction mixture was passed through celite Filtration and evaporation of the filtrate. The yield was 1.36 g (91%) of the main compound. LC-MS m / z 361 (Μ -1)-b-NMR (500 MHz; CD3OD): δ 7.20-7.50 (m, 5H), 5.45 (s, 1H), 4.30 · 4 · 40 (m, 1H), 3.30-3.70 (m, 2H), 1.75-2.30 (m, 4H), 0.85-1.00 (m, 9H), 0.00 -0.20 (m, 6H). ^ Ph-rR ^ CHr0TBDMSVC (QVPro-rR.SVHigrz > > According to the method described in the previous Example 25, Pro_OH (0.36 g, 1 mmd from step (iii)) and H- (R, S) Hig (Z) x 2 HC1 (0.36 g; 1 mmol; from step (i)) Turn into This compound yielded 0.63 g of crude product and was used in the next step without purification. LC-MS m / z636 (M + 1) + 13C-NMR (100.5 MHz; CDC13) 脒 and carbonyl carbon: δ 171.57, 171.20, 163.79 , 159.22. (V) Ph-rR, CH (OHVa〇VPiO, Ph- (R) CH (OTBDMS) _C (0) _Pro- (R, S) Hig (Z) (0.63 g; 1 mmol; obtained from the foregoing) The mixture of step (iv)) and TFA (10 ml, 20% in CHA1) was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 9 with an aqueous K2C03 solution, and then the reaction mixture was extracted with 0¾¾. The combined organic layers were dried (NaAO4) and evaporated. The crude product was purified by flash chromatography on a silica gel column (40 g) with CH2C12 (100 ml), CH2C12: EtOH 95: 5 (100 ml), and CH2C12 · · EtOH (9: 1; 30 ml) wash —__-56-This paper size is applicable to China National Standard (CNS) A4 specifications (210X 297 mmΊ-(Please read the precautions on the back before filling this page).

1T ▼ Line 585853 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A 7 B7 V. Description of Invention (54). The yield was 138 mg (26%) of the secondary compound. LC_MSm / z522 (M + 1) + 13C-NMR (100.5 MHz; CDC13) 脒 and carbonyl carbon: δ 172.21, 171.20, 163.64, 159.11 〇 (vi) Ph-mCHrOHVCrOVPro ^ RS ^ Hig x HOAc According to the aforementioned example 15 (iii ), * Ph- (R) CH (OH) -C (0) -Pro- (R, S) Hig (Z) (0.071 g, 0.14 mmo from the previous step (v)) The main compound was prepared, yielding 49 mg (80%). LC-MSm / z388 (M + l) + b-NMR (400 MHz; D20; complicated by non-mirror isomers / geometric isomers): δ 7.32-7.56 (m, 5H), 5.37-5.52 (m , 1H), 4.32-4.64 (m, 1H), 3.57-3.75 (m, 2H), 3.24-3.56 (m, 4H), 2.89-3.15 (m, 2H), 1.25-2.80 (m, 9H). 13C -NMR (75.5 MHz; D20; complex due to non-image isomers / geometric isomers) and carbonyl carbons: 181.92, 174.92, 173.69, 173.03. Example 28 Ph- (R) CH (OHVCrOVPro-Dig x HOAc (im-a〇CH (OTBDMSVCrOVPro-Dig (Z)) According to the method described in Example 25 (b) above, H-Dig (Z) (0.14 g; 0.507 mmol; prepared with reference to international patent application WO 94/29336 and Ph- (R) CH (OTBDMS) _C (0) -Pro-OH (0.23 g, 0.608 mmol; refer to the aforementioned example 27 (iii)) The secondary compound was obtained, yielding 316 mg of crude product, which was used in subsequent steps without purification 0 _____- 57-_ This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back first (Fill in this page again) • Packing and ordering line 585853

Printed by A7 ____B7_ of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (56) Example 29 Ph_g〇CH (OHVC (〇MR or S) Pic (cis-4-MeVPab xHOAc and Ph- (IQCH (OHVC (OMS or R) Pic (cis-4-MeVPab x HOAc (iUR, SVN-Boc-Pic (cis-4_Me) -Pab (Z)) The method described in Example 1 (ii) was the same as (R, S) -N-Boc-Pic (cis_4-Me) _OH (0_88 g; 4.1 mmol; prepared according to the method described by Shuman et al. In J. Org · Chem. (1990), 55,738) to prepare secondary compounds Yield, 405 mg (19 ° / 〇). FAB-MSm / z509 (M + 1) + b-NMR (400 MHz; CDC13): δ 7.25-7.90 (m, 9H), 5.20 (s, 2H), 4 45-4 · 50 (m, 2Η), 4.30-4.40 (m, 1Η), 3.15-3.70 (m, 2Η), 170-2.00 (m, 4Η), 1.45 (s, 9Η), 1.15-1.30 ( m, 1H), 0.90-1.05 (m, 3H). (ii) H_ (R, S) Pic (cis-4-Me) _Pab (Z) (R, S) -N_Boc-Pic (cis · 4 -M6) · P & H 3 (Z) (0.40 g; 0.79 mmol, obtained from the previous step (i)) dissolved in CH2C12 (5 ml). Trifluoroacetic acid (5 ml) was added, and the mixture was stirred for 0.5 h. The reaction mixture was evaporated and the residue was dissolved in CH2C12, washed with aqueous Na2C03 solution and dried (MgS04) and evaporated. The crude product was purified by flash chromatography on a silica gel column and eluted with CH2C12: MeOH 95: 5 and CH2C12 · · MeOH 9: 1. The yield was 300 mg (94%) of the secondary product. FAB-MSm / z409 (M + l) + ^ -NMR (500 MHz; CD3OD): δ 7.25-7.85 (m? 9H)? 5.15 (s? 2H)? 4.35-4.45 (m, 2H)? 2.55-3.60 (m, 3H) 5 1.85-2.05 (m, 1H), 1.35-1.65 (m, 2H)? 0.90-1.20 (m, 5H) · -59-_ This paper size applies to China National Standard (CNS) A4 (210X297 mm) ) (Please read the notes on the back before filling this page)

, 1T 585853

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 ___B7_ V. Invention Description (57) (iii) Ph- (R) CH (OTBDMSVC (〇MR.S) Pic (cis-4-MeVPab (Z) Same as The method described in the above Example 3⑻, from H- (R, S) Pic (cis M-ΐν ^ -ραΙ ^ ZχοαΟ g; 0.71 mmol; obtained from the foregoing step ⑻) and 卩 ^ (R) CH (OTBDMS)- C (O) -OH (0.189 g; 0.71 mmol; prepared according to the method described by Hamada et al. In Industrial Am. Chem. Soc. (1989), 111,669). The minor compound was produced in 0.40 g crude product without further purification. It is used directly in subsequent steps. (Iv) Ph- (R) CH (OH) -C (〇MR, S) Pic (cis-4-Me) -Pab (Z) Ph- (R) CH (OTBDMS) -C (0)-(R, S) Pic (cis-4-Me) -Pab (Z) 0.40 g; from previous step (iii) without processing) treated with trifluoroacetic acid (20% in CH2C12) 3h. The reaction mixture was evaporated and the residue was purified by flash chromatography on a silica gel column 'with CH2C12: MeOH (98: 2, 95: 5 and 9: 1). The yield was 45 mg (11%) of the minor compound. (V) Ph- (R) CH (OHVC (〇V (R or S) PicO Formula-4-MeVPab xHOAc (A) and Ph- (R) CH (OHVC (〇US or R) PicO tilt- 4-MeVPab xHOAc (B) Ph- (R) CH (OH) -C (0 )-(R, S) Pic (cis-4-Me) -Pab (Z) (0.045 g; 0.083 mmol; from the previous step (iv)) and Pd / C (5%; 0.06 g) The mixture in ethanol (8 mL) was hydrogenated at atmospheric pressure for 2.5 hours. The reaction mixture was filtered and the filtrate was evaporated. The crude product was prepared by RPLC (0.1 M NH4OAC; 30% acetonitrile) to separate non-mirromeric isomers. The yield was 7 mg Compound A, non-mirromeric ratio> 99: 1, and 11 mg of compound B, non-mirromeric ratio 98: 2. Compound A: ___ -60-_ This paper size applies Chinese National Standard (CNS) A4 specifications ( 210X297 mm) (Please read the precautions on the back before filling out this page) • Binding · Order_Thread 585853

Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (58) LC_MSm / z409 (M + l) +, 407 (Ml) · iH-NMR (500 MHz; D20): δ 7.20-7.80 (m , 9H), 5.65 (s, 1H), 4.65-5.35 (m, 1H), 4.40-4.55 (m, 2H), 3.85-4.00 (m, 1H), 3.65-3.75 (m, 1Η), 2.65-3.15 (m, 2H), 2.05-2.20 (m, 1H), 1.05-1.75 (m, 2H), 0.70 · 0 · 90 (m, 3H). Compound B: LC-MS m / z 409 (M + 1) +, 407 (M -1) · ^ -NMR (500 MHz; D20): δ 7.25-7.80 (m, 9H), 4.55-5.75 (m9 2H), 4.35-4.50 (m, 3H), 3.75-3.85 ( m, 1H), 2.70-2.80 (m, 1H), 1.80-2.20 (m, 1H), 0.70-1.70 (m5 6H) _ · Example 30 Ph-rCHoVrR ^ CHrQHVCrOVAze-Pab x HC1 (Ϊ) Ph-rCHoV ^ CHrOHVCrOVAze-PabrZ) The same method as described in Example 3 (ii) above was used. H-Aze-Pab (Z) x 2 HC1 (0.434 g, 0.988 mmol) and (R) -fluorene-2-hydroxy- 4. · Phenylbutyric acid (0.162 g; 0.898 mmol), TBTU (0.433 g, 1.348 mmol) and N-methylmorpholine (0.363 g; 3.59 mmol) were prepared in DMF (15ml) as a secondary compound. Yield 105 mg (22%). LC-MS m / z 529 (Μ + 1) +? 527 (Μ -1) " lH NMR (500 MHz; CDC13): δ 8.17-8.25 (m9 NH), 7.05-7.72 (m, 14 H)? 5.16-5.22 (m, 2 H), 4.71-4.88 (m, 1H), 4.32-4.41 (m, 2 H), 3.92-4 · 04 (m, 2 H), 3.79-3.88 (m, 1 H), 2.62-2.86 (m, 2 H), 2.29-2.57 (m, 2 H)? 1.80-1.98 (m, 2 H). (Ii) Ph-rCHoWrR ^ CHrOHVCrOVAze-Pab x HC1 According to the foregoing example l ( v) The method described is from PMCH2) r (R) CH (OH) -C (0)-_161_: _______ This paper size is applicable to the Chinese National Standard (CNS) A4 specification (21 0X 297 mm 1 ~ (Please Read the notes on the back before filling this page). Binding · Order 585853 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (59) Aze_Pab (Z) (0.112 g; 0.212 mmol; obtained from the previous steps) (i) Preparation of the main compound, yield 77mg (84%). LC-MSm / z395 (M + 1) +, (Ml)-^-NMR (400 MHz; CD3OD): δ 7.77-7.77 (m? 9H)? 4.73-5.19 (m, 1H)? 4.40-4.62 (m, 2H), 3.92-4.34 (m, 3H), 2.48-2.84 (m, 3H), 2.09-2.33 (m, 1H), 1.83-2.05 (m 2H). 13C-NMR (100.6 MHz; D20; complicated by geometric isomers) 脒 and carbonyl Base carbon: δ175 · 66, 174.80, 172.56, 172.49, 166.14, 165.87. Example 31 2-Stubby- (R, S) CH (OHVC (〇VAze-Pab X HOAc (i) (R, SV (2- Fluorenyl) glycolic acid According to the method described in Example 15 (i) above, a secondary compound was prepared from 2-fluorenal (15.6 g, 100 mmol) with a yield of 12.37 g (61%). LC_MSm / z201 (Ml) +, 403 (2M · ”· iH-NMR (500 MHz; CD3OD): δ 7.43-7.98 (m, 7H), 5.29-5.35 (m, 1H) · (ii) 2-stub- (R, S) CH ( OH) _C (0) -Aze_Pab (Z) was prepared from (R, S)-(2-fluorenyl) glycolic acid (0.162 g; 0.8 mmol; obtained from the previous step ⑴) according to the method described in Example 3⑻ above. Essential compounds, yield 266 mg (60%). LC-MSm / z551 (M + l) + ^ -NMR (400 MHz; CDC13) δ 7.18-7.91 (m? 16H)? 4.86-5.26 (m? 3H)? 4.05-4.60 (m, 3H), 3.52 -3.78 (m, 2H), 2.24-2.73 (m, 2H). _162: _ This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) ----------- Λ罾 (Please read the notes on the back before filling this page) 585853 Consumer Cooperation of the Central Bureau of Commerce of the Ministry of Economic Affairs 衽 Printing A7 B7 V. Description of the invention (60) (iii) 2- 荇 基-(R, S) CH (0HVC (0) -Aze-Pab X HOAc According to the method described in Example 15 (ii) above, from 2 ^ *-(R, S) CH (0H) -C (0) -Aze-Pab (Z) (0.266 g; 0.48 mmol; from the previous step ii) The main compound was prepared with a yield of 202 mg (88%). LC-MS m / z417 (M + 1) + W-NMR (500 MHz; CD3OD): δ 7.28 · 7.96 (m, 11H), 5.30-5.40 (m, 1H), 3.95-4 · 82 (m, 5H), 2.09-2.59 (m, 2H). Example 32 3-Indolyl-CHHH (OHVC (OVAze-PabxHOAc (i) 3-indolyl CHWR ^ CHiOHVaOVAze-PabO According to the method described in Example 3), from (R, S) -3_ (3 · pyridyl) lactic acid (0.21 g, 1.0 mmol ) Preparation of the secondary compound, yield 0.22 g (45%). ^ -NMR (500 MHz; CDC13) Δ 6.57-7.80 (m? 14Η), 5.24 (s, 2H), 4.59-4.83 (m, 1H), 4.19-4.51 (m, 3H), 3.69-3.99 (m, 2H), 3.03-3.36 (m (2H), 2.31 · 2 · 56 (m, 2H). (Ii) 3-Indolyl_CH is determined by RS, CH (OHVC (OVAze-PabXHOAe) according to the method of Example 15 (iii), and 3. Indolyl-O12- (11,8) <: 11 (011) -C (O) -Aze-Pab (Z) (0.11 g; 0.20 mmol; obtained from the aforementioned step (i)) to prepare the main compound, Yield 75 mg (80%). FAB-MS m / z 420 (Μ + 1) + iH-NMR (500 MHz; D20): δ 7.00-7.75 (m, 9H), 4.61-4.71 (m, 1H), 3.74- _____- 63 _-_ This paper size applies to Chinese National Standard (CNS) A4 (210X 297mm) (Please read the precautions on the back before filling out this page) • Packing. Order ▼ 585853 Central Bureau of Standards, Ministry of Economic Affairs A7B7 printed by employee consumer cooperatives V. Description of invention (61) 4.51 (m, 5H), 3.00-3.28 (m, 2H), 1.95-2.42 (m, 2H) _13C-NMR (75.5 MHz; D20; due to geometrical differences Structure and complex) 脒 and carbonyl carbon: δ 179.38, 176.19, 175.56, 173.06, 166.78. Example 33 rCH ^ CH-rR ^ CHrOHVCrOVAze-Pab x HOAc (i) rCH ^ CH-rR ^ CHrOHVCrOVAze-Pab ^ According to the method described in Example 3), (R) -2-hydroxyisovaleric acid (0 · 12 g; 1.0 mmol) to prepare a secondary compound with a yield of 68 mg (16%). iH-NMR (300 MHz; CDC13): δ 8.25-8.40 (t, NH), 7.15-7.90 (m, 9H), 5.20 (s, 2H), 4.85-4.95 (m, 1H), 4.30-4.55 (m , 2H), 4.05-4.25 (m, 2H), 3.75-3.90 (m, 1H), 1.65_2 · 75 (m, 3H), 0 · 70 · 1 · 05 (m, 6H). (Ή) ( CHACH-ilOCHiOHVCiOVAze-Pab x HOAc According to the method described in Example 15 (iii) above, (CH3) 2CH- (R) CH (OH) · C (0) _Aze-Pab (Z) (0.068 g; 0.15 mmol; Obtained from the previous step (i)) to prepare the main compound with a yield of 13 mg (23%). ^ -NMR (300 MHz; D20) · δ 7.45-7.80 (m? 4H)? 4.85-5.25 (m9 1H)? 4.45-4.65 (m, 2H), 4.30-4.40 (m, 1H), 3.8 (M.10 (m, 2H), 2.60-2.80 (m, m), 2.20-2.35 (m, m), 1.90-2.05 (m, lH), 0.70-1.00 (m, 6H) · 13C-NMR (75.5 MHz; D20; complicated by geometric isomers) 脒 and carbonyl carbon: 182.37, 176,34, 175.38, 173.84, 173.26, 167.16.- ---------V * (Please read the precautions on the back before filling out this page), 11 _-64- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) 585853 Economy Consumers' Co-operation of the Central Bureau of the Ministry of Justice of the People's Republic of China printed A7 ___B7_ V. Invention Ming (62) Example 34 (CH ^ 2CH-rCH2 ^ 2 rR.S ^ CHrOHVCrOVAze-Pab x HOAc iCH. ^ CH-rCHo ^ rR.S ^ CHrOHVCrOVAze-PabrZl. , S) -Isoleucine (0.12 g; 0.88 mmol) was prepared as a secondary compound with a yield of 0.15 g (36%). I-NMR (300 MHz; CDC13): δ 7.15-7.80 (m, 9H), 5.20 ( s, 2H), 4.85-4.95 (m, 1H), 4.35-4.55 (m, 2H), 3.85-4.20 (m, 3H), 2.40-2.80 (m, 2H), 1.75_2 · 10 (m, 1H ), 1 · 20 · 1 · 55 (m, 2H), 0 · 75-1.00 (m, 6H). (Ii) ΓΟΗ ^ ΟΗ-ΓΟΗο ^ rKS ^ CHrOHyCfOVAze-Pab x HOAc according to the foregoing example 15 (iii) The method described above was prepared from (CH3) 2CH- (CH2) 2 (R, S) CH (OH) _C (O) -Aze-Pab (Z) (0.13 g; 0.27 mmol; obtained from the previous step (i)) Main compound, yield 0.11g (100%). iH-NMR (400 MHz; D20): δ 7.63-7.69 (m, 2H), 7.37-7.46 (m, 2H), 4.72 area 5.12 (m, 1H), 4.40-4.46 (m, 2H), 4.17-4.31 (m, 2H), 3.9 (M.02 (m, 1H), 2.50 · 2.69 (m, 1H), 2.11-2.27 (m, 1H), 1.12-1.72 (m, 3H), 0.61-0.85 (m, 6H). 13C-NMR (75.5 MHz; D20; complex due to non-image isomers / geometric isomers) 脒 and carbonyl carbon δ 176.97, 176.80, 176.61, 176.19, 173.38, 173.28, 173.17, 173.10, 166.78 , 182.02. Example 35 Ph (3-OHV (R.S> lCHrOHVCrOVPro-Pab x HC1 (i) HzProdP ^ biZ) According to the method described in Example 3 (i) above, Boc-Pro-Pab (Z) Preparation of secondary ___ _ -65- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page). A7 The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs prints the B7 V. Invention Description (63) compound, and then performs the extraction processing operation. "I, Phr3-OHWR.S) CH (OHVC (OVPn) -Pab [Z, according to The method described in the above Example 3 (1) consists of (R, S) _3-hydroxymandelic acid (0.25 g; 1.5 mmol) and H-Pro- Pab (Z) (0.63 g; 1.65 mmol; obtained from the previous step (i)) to prepare the secondary compound to give 51 mg (6%) of the main compound. FAB_MSm / z531 (M + 1) + (iii) Phr3-OHVrR. S > > CHr〇HVCr〇VPro-Pab x HC1 According to the method described in the previous example 1 (v), * Ph (3-0HHR, S) CH (0H) -C (0) -Pro-Pab (Z) (0.05 g; 0.094 mmol; obtained from the previous step ⑻ to prepare the main compound, yield 30 mg (74%). FAB-MS m / z397 (M + 1) + 13C-NMR (75.5 MHz; D20; due to non-image isomers / geometry Isomers and complex) fluorene and carbonyl carbon: δ 175.36, 175.13, 172.92, 167.13. Example 36 Ph (3,5_ diOMeV (R, S) CH (OHVC (0) -Pro-Pab X HOAc (i) Ph (3,5 · DiOMeV (R, S) CH (OH) -C (〇VPro_Pab (Z)) According to the method described in Example 3 (ii) above, (R, S) -3,5_dimethoxymandelic acid (0.08 g; 0.38 mmol; prepared according to the method described in Synthesis (1974), 724) and Qin Pro-Pab (Z) (0.16 g; 0.42 mmol; refer to Example 35 (i)). 61 mg (28%). b-NMR (500 MHz; CDC13): δ 7.70-7.80 (t, NH), 7.08-7.50 (m, 9H), 6.30 · -66- (Please read the precautions on the back before filling out this page) Paper size Applicable to China National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 585853 A7 B7 V. Description of the invention (64) 6 · 50 (m, 3H), 5 · 20 (s, 2H ), 5.00-5.10 (m, 1H), 4.25-4.70 (m, 3H), 3.60 · 3.80 (m, 6H), 3.35-3.55 (m, 1H), 2.95-3.25 (m, 1H), 1 70 · 2 · 25 (m, 4H) · (ii) Ph (3,5_ diOMe)-(R, S) CH (OHVC (〇VPro-Pab x HOAc according to the method described in Example 15 (iii) above) From Ph (3,5-: OMe)-(R, S) CH (OH) -C (O) -Pro-Pab (Z) (0.06 g; 0.10 mmol; from the previous step (i)). Compound, yield 35 mg (72%). ^ -NMR (500 MHz; D20): δ 7.23-7.80 (m? 4H)? 6.41-6.65 (m, 3H)? 5.35-5.45 (m, 1H), 4.35-4.60 (m, 3H), 3.80 (s, 3H), 3.10-3.75 (m, 5H), 1.70-2.35 (m, 4H). 13C_NMR (75.5 MHz; D20; due to non-image isomers / geometric isomerism And complex) 脒 and carbonyl carbon: δ 175.28, 175.05, 174.03, 173.46, 172.80, 172.73, 167.11, 166.95. Example 37

Ph (3-OMeWR.S) CH (OHVC (OVPro-Pab X HOAc (Ϊ) Ph (3-OMeV (R.S > tCH (OHVC (OVPro-Pab (Z > t) According to the method described in Example 3) A secondary compound was prepared from (R, S) -3_methoxymandelic acid (0.27 g; 1.5 mmol) and H-Pro-Pab (Z) (0.57 g; 1.5 mmol; see Example 35 (i) above), yield 158mg (20 ° / 〇). FAB-MS m / z 545 (M + 1) + ^ -NMR (400 MHz; CDC13) · δ 7.77-7.84 (m, 2H), 7.01-7.48 (m? 8H), 6.80-6.91 (m, 3H), 5.20-5.24 (m, 2H), 5.06-5.11 (m, lH), 4.30_4.72 (m, 3H), 3.68 · 3.79 (m, 3H), 3.38-3.79 ( m, 3H), 3.38-3.57 (m, 1H), 2.91-3.17 (m, 1H), 1.68 · _-67- _ This paper size applies to China National Standard (CNS) A4 (210X 297 mm) (Please (Please read the notes on the back before filling out this page).

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 1T 585853 A7 ____B7_ V. Description of Invention (65) 2 · 31 (m, 4H).

Phi3-OMeWR.S, CH (OHVC (OVPro-Pah x HOAc According to the method described in Example 15 (iii) above, * Ph (3_OMeHR, S) CH (OH) -C (O) -Pro_Pab (Z) (0.06 g; 0.11 mmol; obtained from the previous step (i)) to prepare the main compound, yield 39 mg (75%). LC-MS m / z 411 (M + 1) +, 409 (M 1) · iH-NMR (400 MHz; D20): δ 6.81-7.84 (m, 8Η), 5.47 (s, 1Η), 4.35-4.59 (m, 3H), 3.60-3.88 (m, 4H), 3.07-3.29 (m, 1H), 1.74 -2.37 ((m, 4H). Example 38 PM3.4 彳 -O-CH ^ CMWRACHiOHVCiOVAze-Pab x HOAc riVPh (< 3.4-r-0-CH2-O ^ VrR.S > > CHr〇HVCr〇 VAze-Pabrz >) Prepared from (R, S) -3,4-methyldioxymandelic acid (0.20 g; 1.0 mmol, prepared according to the method described in Synthesis (1974) 724) according to the method described in Example 3) above. Minor compound, yield 0.22 g (44%) W-NMR (400 MHz; acetone-da): δ 6.68-8.12 (m, 12H), 5.94-6.05 (m, 2H), 5.18 (s, 2H), 3.81-5.12 (m, 6H), 2.30-2.54 (m, 2H).

Ph (3.4 彳 -0_CH2-0-) WR.S, CH (OHVC (OVAze-Pab x HOAc According to the method described in Example 15 (iii) above, Ph (3,4-(-OCH2-0-)) (R, S) CH (OH) _C (O) -Aze-Pab (Z) (0.11 g; 0.20 mmol; obtained from the previous step (i)) The main compound was prepared with a yield of 72 mg (76%). B -NMR (500 MHz; D20): δ 6.64-7.80 (m, 7H), 5.91-6.01 (m, 2H), 4.80- __- 68 -_ This paper standard applies to China National Standard (CNS) A4 Specifications (210 X 297 mm) Binding (please read the notes on the back before filling this page) Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 585853 A7 B7 V. Description of Invention (66) 5 · 24 (m, 2H) , 3.88-4.57 (m, 4H), 2.11-2.84 (m, 2H). 13C-NMR (75.5 MHz; D20; complex due to non-image isomers / geometric isomers) 脒 and carbonyl carbon: δ 176.03, 175.70, 175.07, 174.82, 168.86. Example 39

Ph (; 3-OMe.4-OHWR.S) CH (OHVa〇VPro-Pab X HOAc mPh (< 3-OMe.4-OHWR.S > tCH (OHVC (OVPro-PabrZ, as described in Example 3) The method was prepared from (R, S) -4-hydroxy · 3 · methoxymandelic acid (0.40 g; 2.0 mmol, and H_Pro-Pab (Z) (0.76 g; 2.0 mmol; see Example 35 (i)). The yield of the compound is 32 mg (12%). FAB-MS m / z 561 (M + 1) + ^ -NMR (400 MHz; CDC13): δ 6.62-7.84 (m, 12H), 5.20-5.25 (m, 2H) ), 4.15-5.08 (m, 3H), 3.42-3.84 (m, 4H), 2.91-3.25 (m, 1H), 1.66-2.37 (m, 4H) · (1Π Ph (3-OMe.4-OHWR. S) CH (OHVC (OVPro-Pab x HOAc According to the method described in Example 15 (iii) above, * Ph (3-OMe, 4-OH)-(R, S) CH (OH) -C (O)- Pro-Pab (Z) (0.048 g; 0.09 mmol; from the previous step (i)) The main compound was prepared with a yield of 23 mg (55%). FAB-MS m / z 427 (M + 1) + iH- NMR (400 MHz; D20): δ 6.72_7 · 83 (m, 7H), 5.42 (s, 1H), 4.38-4 · 68 (m, 3H), 3.55-4.10 (m, 4H), 3.09- 3.29 (m, 1H), 1.72 · 2 · 37 (m, 4H). 13C-NMR (75.5 MHz; D20) 脒 and carbonyl carbon: δ 175.12, 173.25, 167.09. _-69- This paper size is applicable to China National standard( CNS) A4 size (210X297 mm) ·, I booklet (please read the notes on the back before filling this page) R Announcement 3 Application date 85.06.24 Case No. 85107577 Category (The above sheds are filled in by this bureau)

C4 " || | Patent Specification (Revised August 88) 585 3 5 8 Invention Type Name Invention Creation / Chinese English Name Nationality Residence, Residence Name (Name) As an inhibitor of trypsin serine protease NOVEL TRIPEPTIDE COMPOUNDS AS INHIBITORS OF TRYP5 LIKE SERINE PROTEASES, PROCESS FOR PREPARATION AND PHARMACEUTICAL COMPOSITION THEREOF n_ 1. David Gostason 1. No. P1 3758, Anhegewigen Road, Kurvik, Sweden 2. Novo 36 Wigen Road, Linden City, Sweden

IN • equipment ·

、 1T Ministry of Economic Affairs Gan.! I ^ -r:?: Ιι: 工 > vj bone cooperatives Printed line Nationality Swedish applicants Residence, residence (office) Representative name Sedder, Sweden S-15185 Kvaber No. 16 Geiger Street, Chrysway Helmson This paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 585853 No. 85107577 Patent Application Chinese Version Correction Sheet (September 89) 48) A7 B7 The main compound was prepared by the consumer cooperative of the staff of the Central Bureau of Standards and Quarantine of the Ministry of Economic Affairs, with an output of 110 mg (90%) ~. ...........-- --- j lH-NMR (500 MHz; D20) · δ 7.28-7.83 (m5 7H ) 5 5.43-5.65 (m? 1H), 4.82-5.18 (m, lH), 3.97 -4.56 (m, 4H), 2.14-2.85 (m, 2H). NC-NMR (75.5 MHz; D20; non-mirrored Isomers / geometry is complicated) 脒 and carbonyl carbon: δ 173.61, 173.33, 173.06, 172.83, 172.68, 172.62, 166.86, 164.27, 161.15, 160.92. Example 23

Ph- (RS) C (EtVOH) -C (0) -Aze-Pab x HOAc (Ϊ) Ph-iR.S >) C (Et) (OHVCiOVAze-Pab (Z > > According to the foregoing example 3 (ii) According to the method, a secondary compound was prepared from (R, S) -2-hydroxy-3-phenylbutanoic acid (0.18 g; 1.0 mmol) with a yield of 79 mg (15%). LC-MS m / z 529 ( Μ + 1) +, 527 (Μ-1) 'lH-NMR (400 MHz; CDC13): δ 7.27-7.86 (m, 14Η), 5.22 (s, 2Η), 4.82-4.93 (m, 1H), 4.39 -4.57 (m, 2H), 3.84-3.98 (m, 2H), 2.02-2.64 (m, 4H), 0.86-0.93 (m, 3H). ΠΠ Ph- (R, S) aEty〇HVa〇VAze-Pab x HOAc According to the method described in Example 15 (iii) above, * Ph- (R, S) C (Et) (OH) -C (0) -Aze-Pab (Z) (0.08 g; 0.15 mmol; Obtained from the previous step (i)) to prepare the main compound, yield 62 mg (90%) of the main compound. FAB-MS m / z 395 (M + 1) + 1H-NMR (400 MHz; D20): δ 7.27-7.84 (m , 9Η)? 4.83-5.35 (m, 1Η), 3.89-4.60 (m, 4H), 2.40 -2.61 (m, 1H), 1.95-2.30 (m, 3H), 0.78-0.95 (m, 3H) ·- 51-This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page)

1T 585853 Patent Application No. 85107577 Patent Revision Sheet of Chinese Manual (September 89) V. Description of Invention (51)

In added

The inferior compound described in the patent application WO 94/29336, yields 1.24 g (51%). (Please read the notes on the back before filling this page) lH-NMR (400 MHz; CDC13): 57.27-7.43 (m, 5H)? 5.12 (s5 2H)? 4.60-4.67 (t, 1H), 4.16-4.26 (d, 2H), 3.86-3.95 (m, 1H), 3.74-3.82 (m, 1H), 3.1.1-3.30 (m, 2H), 2.78-2.89 (m, 2H), 2.33-2.52 (bs, 2H), 1.71-1.83 (m, 3H), 1.44 (s, 9H), 1.15-1.29 (m? 2H). (ID H-Aze-Pig (Z) x 2HC1

Boc-Aze-Pig (Z) (1.2 g; 2.53 mmol; obtained from the above step (i)) in ethyl acetate (75 ml) saturated with HC1, and stirred at room temperature for ih. The reaction mixture was evaporated, diluted with water, and extracted with toluene. Lyophilization of the aqueous layer yielded 1.085 g (96%) of the main compound. {U-NMR (500 MHz; CD3OD): δ 7.32-7.46 (m, 5Η)? 5.28 (s? 2Η)? 4.99-5.05 (t, 1Η), 4.08-4.16 (m, 1Η), 3.91-3.99 ( m, 3Η), 3.13-3.25 (m, 4Η), 2.79-2.88 (m, 1H), 2.47-2.57 (m, 1H), 1.82-1.96 (m, 3H), 1.26-1.40 (m, 2H) · (iii) Ph-aOCHiOTBDMSVaOVAze-Pigm Printed by the Shellfish Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs «According to the method described in Example 25 (ii) above, * Ph- (R) CH (OTBDMS) -C (0) -ΟΗ ( 0.401 g; 1.5 mmol) and H-Aze-Pig (Z) x 2 HC1 (0.672 g; 1.5 mmol; obtained from the previous step (iii) for the preparation of the secondary compound, yield 350 mg (46%). LC -MS m / z 508 (M + 1) +, 530 (M + Na) + riv ^ i Ph- ^ CHfOHVCfOVAze-Pig x HO Ac according to the method described in Example 15 (iii) above 'by Ph- (R) CH (OTBDMS) -C (0)--54- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 585853 Patent No. 85107577 Patent Application 8 7 Chinese Manual Correction Page (September 89) _B7 "..........'_ V. Description of the Invention (52) Tae Hyun: $

L …… 1 one one one—J

Aze-Pig (Z) (0.1 g; 0.197 mmol; obtained from the previous step (iii) to prepare the main compound, yielding 81 mg (95%) of the main compound. LC-MS m / z374 (M + 1) + 1H-NMR (400 MHz; CD3OD): δ 7.25-7.50 (m? 5Η), 5.15 (s? 1H)? 4.65-4.75 (m, 1H), 4.25-4.35 (m, 1H), 3.80-4.00 (m 3H), 2.95 3.50 (m, 4H), 2.05-2.50 (m, 2H), 1.75-1.90 (m, 3H), 1.15-1.30 (m, 2H). Example 27

Ph-fR) CH (OH) -C (Q) -Pro ^ R, S) Hig x HOAc (i) H- (RS) HigfZ) x2HCl According to the method described in Example 3 (i), Boc- (R , S) Hig (Z) (prepared according to the method described in International Patent Application WO 94/29336) to prepare secondary compounds. (n) Ph-rR) CH (OTBDMSVCiOVPro-OBn) According to the method described in Example 1 (ii) above, from L-prolinol x HC1 (2.0 g; 8.26 mmol); and Ph- (R) CH ( OTBDMS) -C (O) OH) (2.0 g, 7.51 mmol, prepared according to the method described by Hamada et al. In J. Am. Chem. Soc ·, (1989) 111,669). 2.0 g (59%). Printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) lH-NMR (500 MHz; CDC13) · δ 7.22-7.55 (m5 10Η), 5.45 (s, 1H)? 5.15 (s, 2H) 5 4.45-4.55 (m, 1H), 3.70-3.82 (m, 1H), 3.05-3.15 (m, 1H), 1.65-2.15 (m, 4H), 0.85-1.05 (m, 9H ), 0.00-0.22 (m, 6H) ·

(iii) Ph- (R) CH (OTBDMSVC (OVPro-OH

Ph- (R) CH (OTBDMS) -C (0) -Pro-OBn (1.9 g; 4.19 mmol; obtained from the previous step -55- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 585853 Revised Page of Chinese Specification for Patent Application No. 85107577 (September 89) V. Description of Invention (55) LC-MSm / z622 (M + 1) + Revised Supplement

In

Tin Ph- (R) CH (OHVC (OVPro-Digm adds trifluoroacetic acid (6 ml; CH2C12 in 20%) at 0 ° C) to Ph_ (R) CH (OTBDMS) -C (O) -Pro- Dig (Z) (0.315 g; 0.506 mmol, obtained from the previous step (i)), the mixture was stirred at room temperature for 2 h. The pH # K2C03 aqueous solution of the reaction mixture was adjusted to 8 and extracted with CH2C12. The organic layer was NaCl The aqueous solution was washed, dried (Na2S04) and evaporated. The crude product (250 mg) was flash-chromatographed on a silica gel column using CH2C12: MeOH (9: 1) as the eluent to produce 180 mg (70%) of the main compound. IH -NMR (400 MHz; CDC13): δ 7.25-7.39 (m, 10H), 5.32-5.37 (bs, 1H), 5.08-5.19 (m, 2H), 4.40-4.49 (m, 1H), 4.21- 4.35 (m, 2H), 3.87-4.03 (m, 2H), 3.71-3, 79 (m, 2H), 3.18 -3.32 (m, 2H), 3Ό0-3.10 (m, 1H), 2.61-2.73 (m, 1H), 2.14-2.24 (m, 1H), 1.62-2.07 (m, 8H). (iii) Ph- (R) CH (OHVC (OVPro-Dig x HOAc) Cooperative printed (please read the notes on the back before filling this page) According to the method described in Example 15 (iii) above, * PMR) CH (OH) -C (0) -Pro-Dig (Z) (0 · 14 g; 0.276 mmol; The main compound was prepared from the aforementioned step (ii)) with a yield of 112 mg (94%). LH-NMR (400 MHz; CD3OD): δ 7.27-7.44 (m, 5H), 5.34 (s? 1H), 4.29-4.35 ( m, 1H), 4.17-4.25 (m, 2H), 3.75-3 · 83 (m, 2H), 3.63-3.73 (m, 1H), 3.25-3.34 (m, 1H), 3.08-3.23 (m , 2H)? 2.79-2.90 (m5 1H), 1.71-2.10 (m, 6H). L3C-NMR (100.6 MHz; CD3OD) 脒 and carbonyl signals: δ 174.79, 173.26, 158.16. 58- This paper standard applies to China Standards (CNS> Α4 specifications (210X 297 mm) 585853 Α7 Β7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (67) Example 40 Ph_iR.S, CffitYOHVC (OVPro-Pab X HOAc /: .. L- u /: (i) Ph- (RS, CnEtYOHVC (OVPro-Pabd τ, 丨! According to the method described in Example 3⑻ above, from (R, S) -2_hydroxy_2 · phenylbutyric acid /] (0.36 g; 2.0 mmol) and H-Pro-Pab (Z) (0.76 g; 2.0 mmol; refer to Example 35 (i) above) to prepare a secondary compound with a yield of 57 mg (5%). FAB-MSm / z543 (M + 1) + iH-NMR (400 MHz; CDC13): δ 7.24-7.88 (m, 14H), 5.23 (s, 2H), 4.44-4.81 (m, 3H), 2.98-3.25 (m, 2H), 1.49-2.32 (m, 6H), 0.85-0.95 (m, 3H) · (ii) Ph-iR.S, C (EtVOHVC (OVPro-Pab x HOAc) According to the previous example 15 (iii) According to the method described above, the main compound was prepared from Ph- (R, S) C (Et) (OH) -C (0) _Pro-Pab (Z) (0.055 g; 0.1 mmol; obtained from the previous step ①), yield 34 mg (72%). FAB-MS m / z 409 (Μ + 1) + ^ -NMR (400 MHz; D20) · δ 7.33-7.82 (m? 9H)? 4.38-4.60 (m9 3H)? 3.19-3.71 (m, 2H), 1.54-2.34 (m, 6H), 0.73-0.90 (m, 3H). 13C-NMR (75.5 MHz; D20; complex due to non-image isomers / geometric isomers) 脒 and carbonyl Carbon: δ 182.05, 176.42, 175.73, 175.59, 174.70, 174.47, 167.18. Example 41 The compounds of Examples 1 to 40 were tested in the aforementioned test A, and the IC50TT 値 was found to be less than 0.3 μM. -70- ---- ------- »· (Please read the notes on the back before filling this page) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 585853 Chinese specification for patent application No. 85107577 Front page (April 89) A7 B7 V. Description of the invention (68) Revised jt Supplementary book, Magic Hong 丨 Condensation printed by the staff consumer cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs aq = Water-based Aze = Acryl 2-Bac acid Boc = Third butoxycarbonyl Bn = Benzyl Bu = Butyl Ch = Pyrohexyl DCC = Dicyclohexylcarbodiimide DIPEA = Diisopropylethylamine DMAP = N, N_dimethylaminopyridine DMF = Di Methylformamide EDC = 1- (3-Dimethylaminepropyl) -3-ethylcarbodiimide Et = Ethyl EtOH = ethanol h = hour HC1 = hydrochloric acid HOAc = acetic acid H-Dig = 1-month Micyl-3-aminoethylaza 5-Methylene butadiene H-Dig (Z) = 3-aminoethyl-1- (N-benzyloxycarbonylfluorenyl) azetidine H-Hig = 1-month Micyl-3-aminoethyl p ratio p-H-Hig (Z) = 3-aminoethyl-1- (N-fluorenyloxycarbonylfluorenyl) pyrrolidine H-Pig = 1-fluorenyl-3- Aminomethylhexahydropyridine H-Pig (Z) = 3-aminomethyl-1_ (N · benzyloxycarbonylfluorenyl) hexahydropyridine-71-(Please read the precautions on the back before filling this page) This paper Standards are applicable to Chinese National Standard (CNS) Α4 specifications (210X 297 mm) 585853 Patent Application No. 85107577 Amendment Sheet (Chinese version) (April) I amended I supplemented the year five. Description of the invention (69) Β H-Pab = 1-fluorenyl_4 · aminomethylbenzene, _ (Please read the precautions on the back before filling this page) H-Pab (Z) = 4-aminomethyl-1- (N-fluorenyloxycarbonyl) benzene HPLC = high performance liquid chromatography

Me = methyl

Ph = phenyl

Pic = pipecolinic acid RPLO reversed phase high performance liquid chromatography TBDMS = tertiary butyldimethylsilyl TBTU = [hexafluoroboric acid zeal > ^^ '-tetramethyl-0 (benzo Triazol-1-yl) aldaldehyde 镔] THF = tetrahydrofuran THP = tetrahydro p ratio TMS = trimethylsilyl WSCI = water-soluble carbodiimide z = benzyloxycarbonyl prefix η, s , I, and t have their general definitions: positive, different, second, and third. Unless otherwise stated, the stereochemistry of amino acids is represented by (S). Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 72- This paper size applies to China National Standard (CNS) A4 (210X 297 mm)

Claims (1)

585853 8 8 8 8 A B c D Patent Application No. 085107577 Chinese Patent Application Replacement (March 1993) Application Special _ Kefan Lipid A pharmaceutical composition for use as an anticoagulant, which comprises a compound of formula I Where p and q represent 0; R1 represents Η; R2 represents Η; halogen R3 represents optionally substituted by one or more CM alkyl, CM alkoxytin, hydroxyl, N (H) R23 or methylenedioxy Phenyl; R23 represents fluorene, CM alkyl, or C (〇) R25; R25 represents CM alkyl; Y represents oxyalkylene; η represents 1; and B represents a structural fragment of formula IVa • I HN This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) The fragment: xk 'τ is in the R-configuration; or a pharmaceutically acceptable salt thereof; meanwhile, a pharmaceutically acceptable adjuvant, diluent or carrier is blended. 2. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the compound of formula I is: PMA) CH (0H) -C (0 > Aze-Pab. The pharmaceutical composition according to item j or 2 of the scope of patent application It is used for treating thrombin-inhibiting disorders. 4. The pharmaceutical composition according to item 3 of the scope of patent application, wherein the disorder is thrombosis and excessive agglutination of blood and tissue. 5 · According to item 1 of scope of patent application A pharmaceutical composition in which R3 of the compound of formula I represents phenyl substituted by N (H) R23 and a halogen. 6 · A pharmaceutical composition according to item 1 of the patent application scope, wherein R3 of the compound of formula I represents N (H) R23 and chloro substituted phenyl. -2- This paper size applies to China National Standard (CMS) A4 specification (210 X 297 mm)