SA96170499B1 - Prodrugs of thrombine inhibitors - Google Patents

Abstract

Abstract: The present invention relates to providing compounds of formula I,R 1O(O)C-CH2-(R)Cgl-Aze-Pab-R2 I wherein R1 and r2 have meanings given in the description, which are useful as prodrugs for inhibitors of para-proteases trypsin, like thrombin, particularly in the treatment of conditions where thrombin suppression is required (eg thrombosis) or as anticoagulants.

Description

Y — — prodrugs of thrombine inhibitors Full description

1. * 4 except * BA: This invention relates to pharmaceutically useful prodrugs of pharmaceutically active compounds; Where the effective compounds are; particulary; adequate inhibitors of serine proteases similar to trypsin ¢ and thrombin in particular; using prodrugs as therapeutics; And pharmaceutical formulations

° It contains it and the industrial methods for its production.

Blood clotting is the important process involved in both stopping bleeding (i.e. preventing blood loss from a damaged blood vessel) and thrombosis (i.e. forming a blood clot in a blood vessel” which sometimes leads to

vessel obstruction). Coagulation is the result of a series of enzymatic reactions. One of the final steps in this series of reactions is the conversion of the thrombin proenzyme of the proenzyme into the active enzyme thrombin. It is known that thrombin plays a central role in clotting. It activates the platelets; Which leads to platelet aggregation and converts the fibrin generator into fibrin monomers, which polymerize at the same time into fibrin polymers, and activates factor 1011, which in turn crosslinks the polymers to form insoluble fibrin. Furthermore it; The thrombin activates factor V1 and factor VII which leads to the generation of a 'positive feedback' of the thrombin pro

.thrombin TYA

_- B -

by inhibiting platelet aggregation and fibrin formation and crosslinking; It will thus be expected to be shown

Inhibitors of thrombin lead to anti-inflammatory activity. in addition to; will be expected

The anti-AM activity is enhanced by effective inhibition of the positive feedback mechanism.

The development of low-molecular-weight thrombin-inhibitors was then explained by Claesson in Blood Coagul 5411 (1994).

Fibrin

Blomback and others mentioned (107.59) (1969) (J.

Clin-Lab.

Invest 24 Suppl. Inhibitors

thrombin is based on an amino acid sequence located around the H-chain cleavage site of an antigen

fibrin. of the amino acid sequences annotated; These authors suggested that sequencing

The tripeptide Phe - Val -Arg would be the most effective inhibitor.

0 a Jul has been exposed as thrombin inhibitors based on a low weight Bd peptide in eg; US Patent No. EY ET VA and International Patent Applications; International Application No. 1117/9, International Application No. 789977/49, International Application No. 1805660, International Application No. 5/01, European Patent Applications No. 654780 and YY) m and 46 4p for you and 0 mi tYoYo oYTAVY 2 and 071 Or 11 h and 86 oY.) VY

STATELY YAVAAY\o recently reported daa then disclosed thrombin inhibitors based on peptide derivatives in European Patent Application No. 74917. and international patent applications; International Application No. 56/176045, Application No. do vera, International Application No. 96/754776, and International Application No. 15/717

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—-— $ _ Specifically, the last request reveals the 'peptide' derivative R*00C - CH; - (R) Cgl - Aze - Pab - H R® Cua represents the hydrogen R-benzyl Crs alkyl sf although it is known that these active compounds exhibit significant anti-thrombin activity; ° It will be beneficial to improve their pharmacokinetic properties after each of the administration

Oral route and non-enteric administration. Examples of pharmacokinetic properties to be improved include: (a) providing improved absorption from the gastrointestinal tract with a view to minimizing the potential for endogenous and/or interoceptive change in the bioavailability of the active compounds; and

0 (b) normalization of the plasma composition time frame (i.e., reduction of the ratio of maximum value/minimum value in plasma concentration over the dosing period); With a view to reducing the risk of overdose and side effects caused by a maximum concentration value that is too high (eg bleeding); and those caused by one of which is very low (eg thrombin formation); and

ve (c) increase the duration of action of the active compounds. Furthermore it; Oral and non-intestinal administration of active thrombin inhibitors may cause unwanted local bleeding (eg in the intestinal cavity or subcutaneously) as a result of a high topical concentration.

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QO —_— _ at the end; Potent thrombin inhibitors given by ALLL that also inhibit trypsin and other serine proteases may exhibit additional gastrointestinal side effects; Including dyspepsia (eg, if trypsin is inhibited in the intestinal lumen). Although certain N-benzyloxycarbonyl derivatives are also disclosed as thrombin inhibitors in IPO A E/YAYY, it is not indicated that these derivatives may be useful as prodrugs. In reality; International Application No. 799277/95 did not provide an indication of suitable prodrugs for the active compounds. We have found that the foregoing problems can be solved by administering compounds according to the present invention which are; While inactive by itself, upon oral and/or non-enteric ye administration they are metabolized in the body to form effective thrombin inhibitors; which includes those referred to above. hag is common to invention 2 according to the invention; Provide a compound of formula (1) R'O (0(6- CH, - (R) Cgl - Aze — Pab — R? \o where -R*JsR! Ar N (RY) R® (e) because AC (0) OR and T represent Cs alkylene ¢ and R? (which replaces one of the hydrogen atoms in the amidino unit of (Pab- H) TYA

__ 4m_ represents OH R R® (E) OC R C (0) OR' R OC (0) R® (Dc) “C (0) OCH and C alkyl 0 hydrogen Jia from or alkylphenyl ben Cua) the last group having optionally substituted by a cis alkyl or alkoxy from or nitro or “(halogen and R*) or represented as independent hydrogen or Cys alkyl or phenyl, 2-naphthyl or represent; when R!N (RY) R® iss 0 (0) on together with an ll nitrogen atom is attached to it pyrrolidinyl pyrrolidinyl or piperidinyl + and C representing an alkyl Pd or phenyl, 2-naphthyl (all of which have an optionally substituted by an alkyl MH (halogen) and R representing -2 naphthyl, phenyl a (Gua) © alkylphenyl the last three groups have 0 optionally substituted by an alkyl mr sinitro sf Cig alkoxy sl d) or Crp alkyl (where the last group is optionally substituted by M alkoxy or C16 acyloxy or “(halogen) and R® stands for Ar oleate hydrogen hydrogen ben + and R® stands for 2-naphthyl, phenyl or M alkoxy or © alkyl (where the last group has 1 optionally substituted by halogen, Cy alkoxy, or “(Cy acyloxy) and provided that when it does not represent the base of Jia R2sn-hexyl of n-butyl sf ethyl of methyl of “C(O)OR] then RY is not benzyl ; or their pharmaceutically acceptable salts (hereinafter referred to as the “compounds of the invention”). TYA

A- The compounds of the invention may exhibit cyclic properties. All tautomeric forms and their mixtures fall within the scope of the invention. The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereomeric properties. All © enisomers can be separated using conventional techniques; For example chromatographic separation or partial crystallization. The isolation of the different stereoisomers can be done by separating racemic or other mixtures of compounds using conventional techniques; For example; Partial Crystallization or HPLC Alternatively, the desired optical isomers can be made by reacting suitable photoactive starting materials under conditions that will not cause racemisation or 0 to result in glycosylation or by (BEE). For example, by homochiral acid followed by separation of the dimeric derivatives by conventional means (eg HPLC and silica chromatography) All Jala stereoisomers are included within the scope of the invention. Additional to the invention, a compound of formula (1) as specified herein is provided by 1 by but without the requirement that it be a prodrug The alkyl groups which may be represented by RY may be 357, 25, 28 and 20 straight or be when there are a sufficient number of carbon atoms; branched, cyclic or partially cyclic, saturated or unsaturated, interrupted by oxygen and/or substituted or terminated by 011, provided that the OH group is not connected to carbon atoms) SP? carbon atom which is 0 adjacent to the .oxygen atom TYA

A — — we mean by the expression “partially cyclic alkyl groups” groups such as .CH,Ch may be alkyl groups that can represent substituent groups in 183 and 85 straight or be; When there are enough carbon atoms; branched or be saturated or unsaturated and be © discontinuous by .oxygen The alkyl part of the alkylphenyl groups represented by 8 may be straight or be; when there is enough sie of carbon atoms; branched and/or be saturated or unsaturated. The alkylene Ole gana which is represented by Al may be straight or be ¢ Laie there are sufficient number of branched carbon atoms and/or it is saturated or unsaturated. b The alkoxy groups which may be represented by 3 and can be substituted by Rr? and Rg are straight or be; When a sufficient number of carbon atoms are branched and/or saturated or not, the list of abbreviations is given at the end of this specification. Pursuant to an additional feature of the invention a compound of formula (1) as specified herein is provided by \o before with the following additional terms: (a) 30 does not represent AC (0) OR * (b) and 2 independently does not represents hydrogen and (c) R® does not represent alkyl .p; Where R? is .0C (0) R® TYA

q — — according to an additional feature of the invention a compound of formula (I) is provided wherein: R! (7) OR* (0) and (b) represent RY and a independently represents hydrogen “and (c) R® represents alkyl b” when R? is 0C. (0) R® © when JSR! nt A'C (0) N (RY) = compounds of choice of the invention include those where: A' represents the alkylene of ¢ Cy alkyl of hydrogen Ji <R* “alkyl JiR' from or Cag cycloalkyl” or such groups where 13 and 85 together transport pyrrolidinyl ~~ 0 when RY is AC (0)0 RY Preferred compounds of the invention include such compounds where A represents Cus alkylene R* represents Cp alkyl .w when RY represents 83 The preferred compounds of the invention include those where hydrogen J—iai R? The last group is straight or formed; when there are a sufficient number of carbon atoms » branched Ss (partially cyclic or cyclic) or bitter alkylphenyl (where TYA is

- .and 1 - the last group has an optional substitution; It may or may not be straight. When there are enough carbon atoms (branched). The preferred compounds of the invention include those where 82 OH (ii or us) OC (O)R® in Alla) is the last; © represents phenyl with an optional substitution or Cun) ©, alkyl The latter group a may be straight or it may be; When there are enough carbon atoms; branched It is cyclic or partially cyclic and/or is saturated or unsaturated)). The most preferred compounds of the invention include those where: R!represents h ¢ or alkyl rect; or alkyl resounding clattering; or a partially cycloalkyl Cao ¢ or a cycloalkyl d© or an optionally substituted straight alkylphenyl”; or Cs alkylphenyl branched 1. It has an optional substituent “phenyl - alkyl of” or LAC (0) 7 RHR (where; in the latter case Al represents alkylene times Rs less than Cys alkyl of hydrogen is a Cas alkyl or cycloalkyl from or representing R* and together with (A'C ©) 0 8 3 (pyrrolidinyl) (where ¢ in the latter case; alkyl fii from and you represent Tola outside ); R stands for OH or 0(8) OC (where, in the latter case, R® stands for an optionally substituted phenyl, a straight 0©, or a branched alkyl mono) latter The preferred compounds of the invention include in particular those compounds where: L represents Cog alkyl straight i.e. cycloalkyl 0m or alkylphenyl straight and optionally substituted 3 YA

- 11 -

Cs alkyl bitter straight or alkyl representing R® (where, in the latter case, OC (O) R° or OH representing R? branched). z has an optional substituent» includes the optional substituent © alkylphenyl representing RP RY representing R! (when, in particular). The preferred compounds of the invention include the compounds mentioned in the examples. - (R) Cgl - Aze - Pab — OOCPh 116, OOCCH; - (R) Cgl - Aze — Pab - OH and EtOOCCH; - (R) Cgl - OAM — Pab - OH 3BnOOCCH; - (R) Cgl - Aze —Pab - OH ve 3nPrOOCCH; - (R) Cgl - Aze — Pab ~OH and 1PrOOCCH; - (R) Cgl } Aze - Pab - OH and tBuOOCCH; - (R) Cgl - Aze - Pab - OH(nPr); NCOCH, OOCCH; - (R) Cgl - Aze - Pab — OH

ChNHCOCH, - (R) Cgl - Aze —Pab— OH 0 f EtOOCCH;, - (R) Cgl - Aze - Pab = OAC

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3HOOCCH; - (R) Cgl - Aze - T - OH 3sHOOCCH; - (R) Cgl - Aze — Pab - 0 - cis — Oleyl Particularly preferred compounds of the invention include: and Me OOCCH; - (R) Cgl - Aze - Pab - OH I and OOCCH; - (R) or - Aze — Pab - OH ° 9nPr OOCCH; - (R) Cgl - OAM - Pab - OH 31 Pr OOCCH; - (R) Cgl - Aze - Pab - OH 3Bn OOCCH; - B Cgl - Aze — Pab—- OH and Et OOCCH; - (R) Cgl - Aze — Pab — OAc: preparation \ and nuclei including (I) of the invention A process is also provided for the preparation of compounds of the formula lids by the reaction of a corresponding compound of the formula OH representing R? where (I) is a preparation of a compound of formula (0) (on an alkoxide base as specified herein before” with OC (0) R® representing R? where (I) For example at room temperature in the presence of a solvent “(eg alkali metal alkoxide) THF (eg aka (5 pac \o b) (where alkylphenyl sf ¢ phenyl sf « 2 - naphthyl TYA represents C(O) OR” represents R? where TYA

These last ternary groups can have an optionally substituted by alkyl yen , cis alkoxy , (halogen | nitro , or alkyl yen (where in this last group can have an optionally substituted with Crs + Crs an ethoxy alkoxy or halogen with hydroxylamine or an adieu salt, for example, at room temperature in the presence of a suitable base (for example, potassium carbonate or triethylamine) and a suitable organic solvent ( For example, THF R (EtOH H- (R) Cgl - Aze — Pab-R®

wherein it is 82 as specified herein with a compound having the formula (ITD).

C-CH*-L' 1 ramh l where SSL! left set; eg halide jill (eg Jp (bromide) or atamqastamanabuala (eg trifluoromethylsulphonate) and the WER is specified in this parameter be by ¢ eg between room temperature and room temperature high (eg 0 5”) in the presence of a suitable base (eg potassium carbonate) and solvent

,. (acetonitrile, DMF, or appropriate organic THF (eg Ne

(D) Preparation of a compound of formula (1) RY Cua representing 11 and 82 representing OH by the reaction of a corresponding compound of formula (I) where C represents an alkyl free that alkylphenyl :© + and 8 represents OH or C(0)OR7 with a suitable base (eg hydroxide alkali metal alkoxide) at room temperature in the presence of a bound organic solvent (eg water or MeOH).

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_ p \ — (e) preparation of a compound of formula (I) where R? is OC (0) R® and RE is as specified herein above; By reacting a corresponding compound of formula (1) where 82 is OH with a compound of formula (IV) (Iv) RC (R)-O-CR® 0 or a compound of formula Hal (V) Hal Cua is © or Br ¢ and in either case it is 187 as defined herein by eg at room temperature in the presence of a suitable base (eg Jal) triethylamine or pyridine or (DMAP) and an appropriate organic substitute (on the article methylene chloride 0 or (THF) and prepare a compound with the formula (I) where R' represents H and 82 represents "OC (0)R® and 8 as defined herein is accepted by the reaction of a corresponding compound of formula (VI) (VI) P'0 (0)C CH, - (R)Cgl - Aze - Pab - R ? where PU stands for a variable ester protective group of an acid (eg tBu or (Bn 82) stands for “OC(0)R® \o where RS is as specified herein by 6+ with a suitable acid (eg TFA eg at room temperature in the presence of a suitable organic solvent Jo) eg methylene chloride TYA

Oo — \ _ (g) preparation of a compound of formula (1) where Jia is a 5 mm alkylphenyl alkyl from an OH or OR' (0) 0” and R7 as specified herein by ib ule is an esterification of a corresponding compound of formula (VID) (VII) R™0(0)C - CH; - (R) Cgl - Aze - Pab - R® 0 where R™® represents a Crp alkyl or a Cys alkylphenyl group other than that which is formed and is as defined herein Bs by 0 Substituting alkyl Variable Substitute Cando Circumstances well known to those persons skilled in the art Compounds of formula (11) may be prepared by deprotection of a compound of formula VIII) (« ve p - (VIII) Boc - (R) Cgl - Aze - Pab wherein 82 being as specified herein above; under conditions well known to those persons skilled in the art. Compounds of formula (VII) 5 (VI) may be prepared similarly to those methods described herein. BS was previously used to prepare compounds of formula rR} — 5 “(I) of which SR represents 3c representing m alkyl mm alkylphenyl of . Compounds of formula (VII) can be prepared by the reaction A compound of formula (IX) (IX) H -Pab - R? TYA

where R? is as specified herein before with “Boc- Cgl - Azc - OH eg JA) at room temperature in the presence of a suitable coupling system le) eg EDC Compounds of formula R? Cua ¢ (v1) representing OH can be prepared by a corresponding compound reaction It has the formula (VII) where R? is C(O)OR or (00010702)0).; Cua 87 as previously defined 5 R® is 11 or atoles of and is naphthyl - 2, phenyl, Cue alkoxy, or Crs alkyl (where in the latter group may be optionally substituted for a halogen, Cis alkoxy, or (Cis acyloxy) with hydroxylamine 0 salt added dia acid, for example, at room temperature and in the presence of an appropriate base (eg potassium carbonate or triethylamine) and a suitable organic solvent (eg THF or EtOH). Compounds of formula (VIII) can be prepared in which R? C(0)O RT decreases, i.e. “C(O)OCH(R®) OC(O)R by the Boc - (R) reaction Cgl - Aze - Pab - H with a compound of formula «(X) (x) L'C (0) OR* Vo where LP is a leaving group (eg halogen or (phenolate The mode of reducing the effect of OC(O)(L8)CH - being 87 and PH 7 as specified herein by eg at or below room temperature and in the presence of a suitable base (eg JU 3) and a suitable organic solvent (eg (THF) TYA

VY — \ _— compounds of formula (VIII) where 2 Jig kJ (0) OC can be alternatively prepared by the reaction of a corresponding compound of formula (7111); Cua “8 represents OH with a compound of formula (IV) as specified herein before; For example at room temperature and in the presence of a suitable base (for example pyridine triethylamine or (DMAP) and a suitable organic solvent AS for example methylene chloride or (THF) and it can be done with dL patience, Preparation of compounds of formula (v1) where Jia R? OC(O)R® by the reaction of 11 - Boc - (R)Cgl - Aze - Pab with a compound of formula (XI) ct (x1) R® CO(0) -0 -0 - C(O) R® Cus is as specified herein by for example at a temperature of 45 yo. yall and in the presence of a solvent soluble organics (eg (THF). Compounds of formula (VIII) where 82 represents OH can be prepared by reacting a corresponding compound of formula (VIII) where R? represents 8 (00)0 R® as defined herein shall be with a suitable base (eg Je) “(eg alkali metal alkoxide) at room temperature and in the presence of a binding solvent (eg THF. vo compounds of formula (IX) are well known in the literature or may be prepared using methods similar to those described in this patent before.11-(R)Cgl-Aze-Pab-302 can be prepared by reaction H-Pab-H or a derivative thereof protected with Boe - (R)Cgl - Aze - Pab - OH eg as described herein before for compounds of formula (17111). TYA

Alternatively, 11 - Boe - (R)Cgl - Aze - Pab can be prepared by deprotecting a compound of formula “(X1I) (x11) Boc - (R)Cgl - Aze - Pab - P? where P? has a protective group perpendicular to Boe under conditions well known to those persons skilled in the art.

Compounds of formulas (I), (17), (7), (XT) (X)5, and (07) are either commercially available or well known

referenced or available using known techniques (eg as described in this article).

acquittal later).

The compounds of the invention can be isolated from their reaction mixtures using conventional Cli 0.

Those skilled in the art may realize that in the process described by Jf the groups need

Functionality of the intermediates until they are protected by protective groups.

Jails functional groups that are desirable for protection on amino hydroxy, amidino, and

carboxylic acid Suitable hydroxy protecting groups include trialkylsilyl and 0d-diarylsilyl groups (eg t-butyldiphenylsilyl sl t-butyldimethylsilyl or (trimethylsilyl and

Ibda “Rum 0: Lot 60. Jain i Protective groups suitable for carboxylic acid on

Cy alkyl esters or benzyl amino and amidino protecting groups include

benzoyloxy carbonyl i t-butyloxycarbonyl compounds may be monomeric amidino nitrogens or

Double protection.

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q _ \ — protection groups may be removed according to techniques which are well known to those persons skilled in the art; Such techniques are described herein below. The use of protective groups is further explained in "Protective Groups in Organic Chemistry", edited by JWF McOmie, Plenum Press "Protective Groups in Organic Synthesis" 2nd edition, TW Greene & PGM Wutz, © Wiley (1973), (1973) Interscience (1991). Medical and Pharmaceutical Use: The compounds of the invention are considered useful because they are metabolized in the body to form compounds with pharmacological activity that are therefore referred to as drugs and specifically as prodrugs. The invention; although it is not 0 as shown in the test (JB) for example ¢ thrombin in the body to form strong inhibitors of the following. It shows the same thrombin value for da we mean The compounds of the invention are considered ineffective in

MY micromo 1 as determined in the following A test is more than TT vo. Thus, the compounds of the invention are expected to be useful in those cases where inhibition of the coagulation process is required. References are made to the compounds of the invention for both the pharmacological and/or prophylactic treatment of thrombinogenesis and hypercoagulability in the blood and tissues of animals, including humans. TYA

IV

It is known that the potential for hypercoagulability may lead to thrombin obstructive diseases. Obstructive thrombin diseases, which may be indicated, include resistance to activator p protein (Jie) converting factor (V dale) and genetic or acquired antibody defects. thrombin 1, protein ©, protein S and factor IT heparin Other conditions known to be associated with the possibility of hypercoagulability and occlusive disease include thrombin; Circulation of antiphospholipid antibodies (anticoagulant lupus), homocysteinemia, thrombocytopenia, aul gy, heparin, and defects in fibrinolysis. Thus, reference is made to the compounds of the invention in the pharmacological and preventive treatment of these cases. The compounds of the invention are furthermore indicated in the treatment of conditions where there is an undesirable excess of 0 thrombin without evidence of the possibility of thrombosis; For example, in diseases of nerve damage such as Alzheimer's disease. Includes limited disease states that may be indicated for pharmacological and/or prophylactic treatment of venous thromboembolism, pulmonary embolism, and arterial thromboembolism (eg myocardial infarction, unstable angina, and ischemic stroke caused by thromboembolism ey 1 Peripheral arterial embolism) and systemic embolism, usually from the atria during arterial fibrosis or from the left ventricle after complete infarction of the myocardial wall. moreover; It is expected that the compounds of the invention will have a general utility in preventing recurrence of occlusion (i.e., thrombosis) after thrombosis, percutaneous transcutaneous angioplasty (PTA) and Aad bypass operations) and in preventing clot re-formation after microsurgery and vascular surgery. 0 in general. TYA

1- Additional drug and/or prophylactic treatment of disseminated intravascular coagulation caused by lily, including anti-clotting treatment of spat by bacteria, multiple wounds, poisoning, or any mechanism when blood is in contact with foreign surfaces in the body. Such as vascular grafts, vascular stents, vascular catheters, alternative mechanical or biological valves. Or any medical device. And anti-clot treatment when blood is in contact with medical devices outside the body. Alo during cardiovascular surgery using a heart-lung machine or in Hemodialysis. Jia sae suctions thrombin in addition to its effects on the coagulation process, as it is known that white neutrophils, endothelial cells, and smooth muscle cells). For the pharmacological and/or prophylactic treatment of spontaneous respiratory distress syndrome in adults, rheumatoid fibrosis following radiation or chemotherapy, septic shock, bacterial septicemia, and inflammatory responses, including, but not limited to, arterial disease (A). Acute or chronic cerebral edema, peripheral artery disease, revascularization damage, and restenosis after percutaneous percutaneous angioplasty (PTA) is also useful in treating thrombin and/or trypsin. The compounds of the invention that suppress L1 may be pancreatitis. According to an additional feature of the present invention; There is provided a method for treating a condition requiring inhibition of thrombin wherein the method involves administering a therapeutically effective amount of a compound of formula (1) as determined from this thrombin. Je to a person suffering from; or exposing it to the state of (liana before; or its acceptable salt

a

The compounds of the invention would normally be administered orally, buccally, or by intravenous route

rectally, or through the skin, or through the nose, or through the trachea (trachea), or by

By bronchial route or by any non-intestinal route (AT) or by inhalation; In the form of.

Pharmaceutical preparations which include a prodrug either as a free base; Or the salt of adding an organic acid

0 or inorganic, non-toxic, pharmaceutically acceptable formulation in a pharmaceutically acceptable dosage form. depending on

the disorder, the patient to be treated, and the route of administration; Formulas may be given in

Variable doses.

The compounds of the invention may also be combined and/or co-administered with any antiangiogenic agent

thrombosis by a different mechanism of action; Acetylsalicylic acid binder of the antiplatelet agents, ticlopidine 0, clopidogrel, thromboxane metabolite, and/or phosphodiesterase inhibitors

and ADP receptor cofactors (0:1). In addition, compounds of the invention may be combined and/or co-administered with buffering agents

clot such as tissue activator (*=b) plasminogen or product of genetic recombination) and streptokinase and

Anisolated streptokinase plasminogen and an active prourckinase and urokinase complex in the treatment of animal salivary gland diseases; and similar plasminogen and activators (ASPAC) ve

clot formation; Specifically, myocardial infarction.

According to an additional feature of the invention, a pharmaceutical composition is provided that includes a compound of formula (1) as

He is specified in this patent before; or a pharmaceutically acceptable dale in mixture with an adjuvant or substance

diluent or carrier; Pharmacologically acceptable.

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The appropriate daily doses of the compounds of the invention in the pharmaceutical treatment of humans are approx

0 to 001 mg/kg body weight for oral administration and 0.001 to ou

mg/kg body weight in non-enteric administration.

The compounds of the invention have the advantage that they may have improved pharmacokinetic properties; Such compounds o are specified in this patent from Jad in both cases after oral and non-administrative administration.

intestinal When compared with compounds of the formula:

120 (0)C - CH; - (R) Cgl - Aze - Pab - H

Where they are as specified in this patent of “Jad” and specifically the compound “Rr? Cua stands for H

The compounds of the invention are ineffective for thrombin, trypsin and serine proteases.

0 - the other. The compounds thus remain inactive in the gastrointestinal tract and possible complications can be avoided suffering by oral anticoagulants which are effective by themselves i.e. bleeding and dyspepsia resulting from trypsin inhibition moreover; Local bleeding associated with and after administration can be avoided by an effective non-intestinal thrombin-jaded by using the compounds of the invention.

1. The compounds of the invention may also have the advantage that they may be more efficient than compounds known in prior art; They are less toxic than cle, are longer acting than cle, have a wider range of activity than cle, and produce side effects than cle, and are more easily absorbed than cle, or may have other beneficial pharmaceutical properties than them.

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Biological tests: test 0 (determination of the clotting time of T) thrombin 1). Then incubate human thrombin (T6769, Sigma Chem Co) final concentration Cla ag), Ee data NIH °/ml) in pH buffer solution “pH hydr number Y, ¢ pH 001 (µL) and inhibitor solution 001 (µL) for 1 min. Normal citrated pooled human plasma was then added; 001 microliters of elution and measurement of clotting time in an automated device (KC 10 Amelung). The clotting time in seconds was plotted against the inhibitor concentration and the IC TT was determined by interpolation. 0 is 10.77 is the LID concentration which doubles the clotting time of human plasma. Test B Determination of thrombin time in ex vivo plasma: The thrombin expression after oral or non-intestinal administration of the compounds of the invention was examined in conscious rats that had been catheterized for blood sampling; One day before the experiment or Vo two days; from the carotid artery. on the experimental day; then give the compound; Dissolved in 'ethanol Solutol™: water) 0:0 +4 L and then draw blood samples at fixed times in plastic tubes containing one part (YY) citrate solution (+ one part per liter) and 9 parts blood . TYA has been fired

po Y oS — central tubes for platelet-poor plasma. Plasma was used to determine the thrombin time as described below. then dilute the citrate-treated mouse plasma; 0 μl “by saline solution yoo μl ¢ and eA was coagulated by the addition of human thrombin 5 (T6769, Sigma Chem CO, USA) 0 in a pH buffer pH (YE pH 100 μL). The clotting time was measured in an automated device (KC10, Amelung, Germany). The concentrations of the active thrombin inhibitor HO(O)C-CH; (R)Cgl- were determined. Aze - Pab - H (refer to ISPC No. 19775/14) in mouse plasma to known concentrations of the aforementioned active thrombin inhibitor dissolved in brine. 0 Based on estimated plasma concentrations of active Jadial thrombin HO(0)C- CH; (R)Cgl- Aze - Pab - H (which is assumed to be thrombin time prolongation induced by the aforementioned compound) in Ql, the area under the curve was calculated after administration by Oral or non-intestinal administration of the first drug (AUCPA), using the trapezoidal rule and extrapolating the data to infinity. - Pab - H after oral or non-enteric administration of the first drug in the following: (AUC active, iv / dose((CAUCpd / dose ] X100 / ] 1YA

where »1 is AUCactive, the area under the curve obtained after intravenous administration of 11-HO(O)C-CH,Cgl-Aze-Pab® to conscious rats as described above. Jab test: Determination of urine thrombin time outside the organism 0 “The amount of active thrombin acceptor 11 - HO(O)C- CH; (R) Cgl-Aze-Pab, which is excreted in the urine after oral or non-intestinal administration of the compounds of the invention; And dissolved in Solutol™: ethanol: water (10 0 30) by determining the urine thrombin time outside the organism (assuming that prolongation of thrombin time is induced by the aforementioned compound). Conscious rats were placed in cages its metabolites, which allow separate gan for urine and feces YE saad 0 hours following oral administration of the compounds of the invention The thrombin time on pooled urine was determined as described below. citrated (100 microliters) with rat urine Sal or diluted with saline for 1 min. Plasma coagulation was then initiated by administration of human thrombin (Sigma Chem Company, 16769, 16769) in buffer number 0. pH (pH 7.4 100 microliters). The clotting time was measured in a device (KC10, Amelung). Concentrations of the active thrombin recombinant 11 - HO(O)C- CH were estimated; (R) Cgl-Aze-Pab in mouse urine using standard curves related to the thrombin time in pooled normal human plasma treated by citrated to known concentrations of the indicated active thrombin inhibitor TYA.

YX Y _ — pre-dissolved in concentrated rat urine (or saline diluents thereof). The amount of active recombinant excreted in the urine (AMOUNT) can be calculated by multiplying the rate of mouse kidney urine production over the YE-hour period by the estimated mean concentration of the previously indicated active recombinant Ad in the urine. The bioavailability of the active thrombin inhibitor CH; (R)Cgl-Aze - Pab - H -110(0)0 after 0 oral or non-enteric administration of the first drug as follows: (AMOUNT pd / dose) / (AMOUNT active , iv / dose) [0] where AUCactive, iv is the area under the curve obtained after intravenous administration of 11-HO(O)C-CH,(R)Cgl-Aze-Pab to conscious rats as is Annotated by D. Test:

LC-MS was detected in urine by HO(O)C- CH, (R)Cgl- Aze - Pab - 11 identification 0 which was elicited by HO(O)C- CH, (R)Cgl- Aze - Pab-11 active thrombin inhibitor was quantified in urine following oral or non-intestinal administration of the compounds of the invention; And the solute, as explained in MS - 1.0, is water (0:10:91) by means of Solutol™ analysis:

Yali. Vo, then conducting animal studies as described in the previous method C. Then the gel samples were collected and frozen at -1°C before being analyzed. Urine samples were analyzed for their content of CH, (R)Cgl-Aze - Pab - H -©(110)0 according to the following method: TY A

YA - - : thawed urine samples were mixed; as required; administered in a centrifuge. Solid phase extraction tubes (2059 - 1210) (Analytichem Bond Elut) were activated.

No. by methanol (Ja 1) and prepared by (1 ml) acetonitrile water (00:04) followed by (1 ml) 01 fomic acid and (00 μL) aged the internal standard (Yo) was added. 0 µmol/L) to each extraction tube. For urine standards; (1*μl) standard solution was added. (107 µl) sample added or; For urine standards, a drained urine sample was added to each tube and then drawn through it by gravity or a light vacuum. The remaining urine was cleaned with 1 (ml) Y) ammonium acetate mmol/L); Prior to elutriation by Y) ammonium acetate : acetonitrile (Jeo 1(mmol/l) (©*: 15). The pooled eluate was transferred into autosampler vials and (107 µL) of extract was injected onto a column Liquid Chromatography Hypersil BDS - C18; 3um,) (75mm x4.0mm i.d.; Hewlett Pakard No.79926 03 - 354 elution by VY) mmol/L) ammonium acetate pH regulator With acetonitrile +¢/7 and fomic acid 1 at VO 0 ml/min. The flow was divided so that jy Su entered l/min ve electronic scattering source fons of a P-E Sciex API - 3 AS spectrometer. Each notch has HO(0)C- CH; HO(O) C-CH; (R)Cgl-Aze - Pab - Hy (R)Cgl-Aze - Pab - H (internal standard) retention times close to 1.0 min. Its molecular ions () + (MH) were tracked at 2 EEX, 7 m/, respectively; When distinguishing a block unit. Paul's criteria were used at two levels; One of them is at the limit of quantification; To calibrate a foundation on area ratios a maximum value of: : a

YX 4 —_ _ HO(O)C- CH, (R)Cgl- Aze - Pab - H over the inner led range. The integrity of the method was checked over the range v = v2 On μmol/L. The coefficient of variation was 1 - 7 at )= 7 μmol/L Ys at 166 μmol/L. The quantification limit for Use Workim0150©6 was 0 litres. By multiplying the total urine output over a sae period of YE h by the measured concentration of: HO(O)C- CH, (8(081- Aze - Pab-H 0) in the urine; the amount of active recombinant excreted can be calculated. In urine (AMOUNT) the bioavailability of the active thrombin inhibitor was then calculated as described in the preceding method C. Detailed description of the invention is illustrated by the following examples. Triple block quadrupole 700 Finnigan MAT TSQ BCNMR 5 "HNMR measurements were performed on BRUKER ACP 300 spectrometers and 5300 Vorian UNITY, plus 400 Å which operate at 17 frequencies, Foo NY £99,AY 5,749,974 MHz on All cas and at BC frequencies of Vo, 48 1010 and 4 µH respectively. Chemical displacements are notated in units of 5. TYA -

- Y. = Prepare starting materials “H-(R)Aze-PabZxHcl 5 “Boc-(R)Cgl-Aze-PabxHcl 5 “Boc-(R)Cgl-Aze-Pab-H” then prepare “Boc -Aze-OHs and 7-Boc(R)Cgl-5 «Bn-OOCCH,(R)Cgl-Aze-Pab-Z

AE YATE according to the methods described in the international patent application PabZxHl and “Reference Example No. 0

EtOOCCH,; (R)Cgl-Aze - PabCOOC H, CH = CH,

Boc(R)Cgl-Aze - PabCOOH, CH= CH, (1)

TY) dropwise to a solution of allyl chloroformate (mmol) 1 gram; VY) was added

THF (1"01) in 306 (R)Cgl-Aze - Pab - H mmol) 17 grams; mol) 146 da Al 1) and 0 water, and the aqueous phase (do 001) was extracted one; the reaction mixture was concentrated and dela was added. The concentration of the combined organic phases was methylene chloride (Jo 001 XY) produced by To give (1.8 grams) of the crude product, which was purified by alumine chromatography, by: (JAY GUAM “0A) as a rinse liquid. The concentration was given (Y4: Y TA) EN THF using p5:0: of the subtitle compound as a white solid. 5.32 (d, J=17 Hz, 1H), 5.18 (d, J=10 Hz, 1H), 5.06 (d, 7 Hz, 1H), 4.82 (bs, 1H), 4.61 (d, J=6 Hz, 2H), 4.58-4.48 (mn, 1H), 4.38-4.27 (m, 2H), 4.14-4.03 (m, 1H), 3.77- 3.68 (m, 1H), 2.60-0.90 (m, 24H).

TYA:

11 - (R) Cgl-Aze - Pab - COO CH, CH = CH2 x 2TFA (Y) (previous) (V) from step cy m Yo Gl a YY) to a solution of in methylene chloride (01 ml) in Boc - (R) Cgl- Aze - Pab - COO CH, CH = CH', then the reaction mixture was stirred at ambient temperature TFA (Je 11) zero degrees; it was done. Addition (grams) of the compound of the subtitle as Article 7 A) Ht for a period of? hours followed by concentration to give solid clay 'H NMR (500 MHz, MeOH (d4)): 5.7.80 (d, 2H), 7.57 (d, 2H), 6.02 (m, 1H), 5.45 (d , 1-17 Hz, 1H), 5.33 (d, 1-10 Hz, 1H), 5.91-4.80 (m, 3H), 4.56 (s, 2H), 4.38 (bq, 1-8 Hz, 1H), 3.71 (d, J=7 Hz, 1H), 2.76-2.60 (m, 1H), 2.35-2.20 (m, 1H), 1.9-1.0 (m, 11H).

EtOOCC H2 - (R) Cgl- Aze - Pab - COO CH, CH=CH, (¥) 0 < (from the previous step) J sa, then stir a mixture of (4 mg 20 mmol) Lot A 15 mg )s H-(R) Cgl-Aze - Pab - COO CH, CH = CH2 x 2TFA m for 2 hours followed by addition of 500° THF (ml) water and (10 ml) +1) 5 KoCOs: 6 after stirring at 1117 degrees. (Je 1 (in ethyl bromoacetate mmol) 1.04 mg; 144 hours, then filtering the reaction mixture and concentrating it at 164 ambient for gall time; hours and at a temperature of yo (¥ at 1A) EN (THF EtOAc) and purified it by flash chromatography by using . of the aforementioned compound as a white solid (7 Ly mg; Yet) as a separating liquid to give! 11 NMR (400 MHz, 5.8.46 (bt, 1H), 7.81 (d, 2H), 7.35 (d, 2H), 6.08-5.94 (m, 1H), 5.35 (d, J=18) Hz, 1H), 5.23 (d, J=11 Hz, 1H), 4.93 (dd, J=6 and 9 Hz, 1H), 4.66 (d,

TYA

-— and WS 2H), 462-438 (AB part of an ABX-spectrum), 4.16-4.04) (m, 4H), 3.20 (d, 2H), 2.86 (d, 1H), 2.64-2.45 ( m, 2H), 2.0-1.0 (m 17H). NMR (100 MHz, CDCl) carbonyl and amidine signals: . § 175.33, 172.24, 170.72, p. 168.19, 164.35 0 Example Reference No. ?. nPr0000H; - (R) Cgl- Aze - Pab - COO CH, CH = CH2 Then prepare lik oS yall for the procedure & explained in Example 1) 9 from ¥ On mg; ¢ for 0 mmol ¢ See Example (Y) above) H-(R)Cgl-Aze-Pab-COOCH,CH=CH2 x 2TFA, (10 mg) n-propyl bromoacetate (Use Lar AA to give YVYV) mg sales (41 A white solid." H-NMR (400 MHz, CDCl): & 8.48 (bt, 1H), 7.83 (d, 2H), 7.35 (d, 2H) ), 6.76 (broad, Ve 1H), 6.02 (m, 1H), 5.37 (dd, 1H), 5.24 (dd, 1H), 4.94 (t, 1H), 4.67 (dd, 2H), 4.49 (AB part of an ABX-spectrum, 2H), 4.12 (m, 2H), 3.98 (t, 2H), 3.24 (AB-system, 2H), 2.87 (d, 1H), 2.52 (m, 2H) , 1.99 (bd, 2H), 1.80-1.50 (m, 7H), 1.61 (q, 2H), 1.30-1.10 (m, 2H), 1.00 (qd, 2H), 0.90 (t, 3H). C-NMR (100 MHz, CDCI3) amidine and carbonyl signals: 8.175.4, 172.3, 170.7, Vo no 164.5, 167.9 TYA

Reference example number? tBu 0000 112 - (R) Cgl- Aze - Pab - COO CH, CH = 2 The said compound was prepared according to the procedure described in Example 1 (©) from 1.47 cana YAS) mmol; Refer to Example No. 1 (¥) above) Cgl- Aze - Pab- COO CH, CH= 012 x 2TFA - 11 © and (46 mg; 156 mmol) t-butyl bromoacetate to give (9 came 779) as a white solid. ), 5.36 (d, J=16 Hz, 1H), 5.22 (d, J=10 Hz, 1H), 4.93 (dd, J=9 and 6 Hz, 1H), 4.76 (d, Hz, 2H) , 4.57-4.46 (m, 2H), 4.18-4.04 (m, 2H), 3.19-3.08 (AB-spectrum, JAB =20 1-6 Hz, 2H), 2.86 (d, J=8 Hz, 1H ), 2.72-2.53 (m, 2H), 2.0-0.9 (m, 23H). ,167.81 Reference Example No. ?Et 0OCC H2 - (R) Cgl- Aze - Pab - COO Et Boc - (R) Cgl- Aze -Pab- COOEt (V) 0 Then prepare the subtitle compound according to the procedure described in Mithqal No. (1) (1) of Tee (mg ra mmol) Boc - R) Cgl- Aze-Pab-H and (You mg + BA mmol) ethyl chloroformate which yields 0 mg; 0) as a white solid. TYA

I H-NMR (300 MHz, 85): 9.37 (bs, 1H), 8.16 (bs, 1H), 7.72 (d, 2H), 7.18 (d, 2H), 5.17 (d, 1H), 4.73 ) 1H), 4.47 (dd, 1H), 4.27 (m, 2H), 4.06 (q, 2H), 3.66 (1, 1H), 2.48 (m, 1H), 2.37 (m, 1H), 1.4-1.8 ( m, 7H), 1.22 (s, 9H), 1.34-0.8 (m 7H). Ta C-NMR (75 MHz, CDCls) carbonyl and amidine signals: . 5.172.6, 170.7, 1 67.9, 164.8, 156.0 °

H - (R) Cgl - Aze - Pab - COOEt x 2110 (¥) at zero degrees over 0 minutes to a solution of hydrogen chloride added in Boc - (R) Cgl - Aze - Pab - COO Et (previous) (1) from step “de mL 145 mg; YE) the reaction mixture was reacted at zero degrees for one hour followed by ld and then EtOAc mL”9). white ila as substance Yeo 0 mg; YYo) concentration to give "

I H-NMR (300 MHz, D2 0(: .8.7.85 (d, 2H), 7.61 (d, 2H), 4.98 (dd, 1H), 4.60 (s, 1H), 4.44 (p, SH), 3.90 (d, 1H), 2.73 (m, 1H), 2.37 (m, 1H), 2.0-1.65 (m, 9H), 1.39 (t, 3H), 1.4-1.1 (m, 7H), 0.98 (m, 1H).3 C-NMR (75 MHz, D2 O) amidine and carbonyl signals: 5.1727, 169.4, 166.8, 154.3.

Et OOCCH, - (R)Cgl - Aze - Pab - COOEt (¥) 0m “1 of (110 mg) (©) 1 The said compound was prepared according to the procedure described in Example No.

H - (R) Cgl - Aze - Pab - COOEt x 40 (previous) (Y) mmol from step as yellow powder (/71 mg; 0 ) yield ethyl bromoacetate mmol) 171 mg; 0, ©) Fatih. TY A

—_ 7 m — “H-NMR (300 MHz, CDCl): 6 5 8.48 (bt, 1H), 7.81 (d, 2H), 7.38 (d, 2H), 4.51 (AB part of an ABX-spectrum) , 2H), 4.21 (q, 2H), 4.15-4.05 (m, 4H), 3.21 (AB-spectrum, 2H), 2.86 (d, 1H), 2.68 (m, 1H), 2.53 (m, 1H), 1.96 (bd, 2H), 1.90-1.70 (m, 12H), 1.35 (t, 3H), 1.22 (t, 6H), 1.30-0.95 (m, 2H).

B® C-NMR (75 MHz, CDCI3) carbonyl! and amidine signals: . 5.175.5, 172.2, 170.7, ° 167.6, 164.9 © Reference Example No.

And OOCCH; - (R) Cgl - Aze - Pab - COO-nPr

Boc - (R) Cgl - Aze - Pab - COO -nPr (01) The sub-annone compound was prepared according to the procedure described in Example No. 1 (1) above, with 0 mmol (VE “Ja 0597) and 306 - (8) Cgl - Aze - Pab - H (mmol) 11 pla 7) using (7Y1) yield of 5.4 mg n-propyl chloroformate "H-NMR (400 MHz,): ‎ 8 8.25 (bt, 1H), 7.82 (d, 2H), 7.31 (d, 2H), 5.09 (bd, 1H), 4.87 (dd, 1H), 4.58 (dd, 1H), 4.39 (dd, 2H) , 4.14 (q, 1H), 4.10 (t, 2H), 3.79 (t, 1H), 2.54 (dm, 2H), 2.21 (s, 1H), 1.87-1.55 (m, 8H), 1.33 (s, 9H ), 1.45-1.0 (m, 4H), 0.99 (t, 3H).Vo no C-NMR (100 MHz, CDCI3) amidine and carbonyl signals: § 172.7, 170.6, 167.8, 165.0, 155.9.

TYA

11 - (R) Cgl - Aze - Pab - COO - nPr x 2FTA (7) (?) using 1 The subtitle compound was prepared according to the procedure described in the previous example. (1) ( From step Boc - (R) Cgl - Aze - Pab - COO - mmol) so YY (1.? gram; yield in y mg. 1 H-NMR (400 MHz, MeOH-d4) : 587.77 (d, 2H), 7.60 (d, 1H), 4.86 (dd, 1H), 4.56 (AB © part of an ABX-spectrum, 2H), 4.33 (m, 4H), 3.72 (d, 1H), 3.30 (m, 1H), 2.68 (m, 1H), 228 (m, 1H), 1.9-1.7 (m, 9H), 1.4-1.1 (m, 6H), 1.02 (t, 3H).3 C-NMR (100 MHz, MeOH-d4) carbonyl and amidine signals: 6.172.7, 169.3, 168.0, 161.4.

Et 0OCCH, - (R) le - Aze - Pab - COO - it (¥) 0 14 (ada 7) of (7) 1 digit JE of the procedure described in lh and then prepare the compound mentioned

H-(R)Cgl-Aze-Pab-COO-nPr x 2FTA (previous) (Y) from step (J ga) was filled as a solid (70A cana +, YY) to give ethyl bromoacetate mmol) 187 aaa) YA)s white. } H-NMR (400 MHz, CDCly): 5 8.46 (bt, 1H), 7.82 (d, 2H), 7.32 (d, 2H), 4.92 ( dd, 1H), m 4.49 (AB part of an ABX-spectrum, 2H), 4.10 (m, 6H), 3.23 (AB-spectrum, 2H), 2.80 (dm, 2H), 1.98 (bd, 2H) ), 1.74 (q, 2H), 1.63 (dd, 2H), 1.52 (m, 1), 1.21 (t, 3H), 1.20-1.10 (m, 2H), 0.98 (t, 3H).

TYA

— vv —_0*3 C-NMR (100 MHz, CDCls) carbonyl and amidine signals: . § 175.3, 172.2, 170.7, 167.6, 164.8. 1 Reference No. JB

Me OOCCH, - (R) Cgl - Aze - Pab - COO - nPr

H - (R) preceding (¥) 1 M The said compound was prepared according to the procedure described in Example No. (Y) © mmol; Refer to Example No. 1.57 p (¥10 mg; - Aze - Pab - COO - nPr x 2FTA as a substance (751 mg; 11 £) to give methyl bromoacetate mmol) (174 previous f (14 mg; 1H), 4.49 (AB part of an ABX spectrum), 4.12 (m, 2H), 4.10 (t, 2H), 3.63 \ (s, 3H), 3.24 (s, 2H), 2.87 (d, 1H), 2.65 (m, 1H), 2.52 (m, 1H), 2.01 (broad, 1H), 1.96 (bd, 2H), 1.75 (q, 4H), 1.63 (bdd, 1H), 1.53 (m, 1H), 1.3- 1.1 (m, 5H), 0.99 (t, 3H).

B® C-NMR (100 MHz, CDCI3) carbonyl and amidine signals: . 8.175.3, 172.5, 170.7, 167.7, 165.0. 7 Reference example no. 1

Et OOCCH, - (R) Cgl - Aze - Pab - COOCH, CH, OMe

Boc - (R) Cgl - Aze - Pab - COOCH, CH; ome()

Ty A

- M - The subtitle compound (lida) was prepared for the procedure described in Example No. (1) (1) above, using (>” grams; 7 1 mmol) of Boge - (R) Cgl- Aze - Pab - H f ( y q¢ \g ¢ \mmol) chloroformate given ©2-20600<7. Yield 7.9 mg (767). H-NMR (400 MHz, CDCl): & 8.24 (bt, 1H), 7.83 (d, 2H), 7.31 (d, 2H), 5.08 (bd, 1H) ), a 4.87 (dd, 1H), 4.58 (dd, 1H), 4.39 (dd, 2H), 4.30 (t, 2H), 4.15 (m, 1H), 3.79 (bt, 1H), 3.68° (t, 2H), 3.40 (s, 3H), 2.65-2.45 (m, 2H), 2.20 (broad, 1H), 1.9-1.55 (m, 6H), 1 34 (s, 9H), 1.3-0.95 (m, 6H). C-NMR (100 MHz, CDCl) carbonyl and amidine signals: 8.1727, 170.7, 167.8, 164.6, 155.9. H - (R) Cgl- Aze - Pab - COOCH, CH, OMe x2FTA (Y) 0 above and that (Y) 1 The subtitle compound was prepared according to the procedure described in Example No. (1) (from step Boc - (R) Cgl- Aze - Pab - COOCH, CH; OMe grams (V,V)) using H-NMR (400 MHz, MeOH-d4): 8 7.77 (d, 2H), 7.59 (d, 2H), 4.85 (dd, 1H), 4.56 ( d, 2H), 4.49 (m, 2H), 4.37 (m, 1H), 4.28 (m, 1H), 3.70 (m, 3H), 3.37 (s, 3H), 2.68 (m, 1H), m 2.28 (m, 1H), 1.9-1.7 (m, 7H), 1.4-1.1 (m, 6H). 3 C-NMR (100 MHz, MeOH-d4) carbonyl and amidine signals: . 8.172.7, 169.3, 168.0, 154.6.

TYA

-Ya-

Et OOCC H, - (R) or - Aze - Pab - COO H, CH, OMe (7) from Gall) (*) \ for the procedure discussed in Mithqal No. Wada and then prepare the aforementioned compound ' ex) (Y ) (/89? mg 1 35 mmol; from step mmol) +, AY mg; YYA) 5 11 - (R) Cgl- Aze - Pab - COOCH, CH; OMe x2FTA to give a crude product which was purified by alumina chromatography (ethyl bromoacetate 0 mg FY) as a rinse fluid. The production was (7:1) methylene chloride (THF) using a white solid. (0 4'

H-NMR (400 MHz, CDCls): § 8.46 (bt, 1H), 7.83 (d, 2H), 7.32 (4 2H), 7.21 (broad, 1H), 4.92 (dd, 1H), 4.49 (AB part of an ABX spectrum, 2H), 4.30 (t, 2H), 4.12 (q, 2H), 4.07 (q, 2H), 3.68 ( 1H), 3.40 (s, 3H), 3.24 (s, 2H), 2.62 (m , 1H), 2.52 (m, 1H), 2.07 1 (broad, 1H), 1.97 (bd, 1H), 1.8-1.5 (m, SH), 1.3-1.1 (m, 6H), 1.05-0.95 (m, 2H). 13 C-NMR (100 MHz, CDCI3) carbonyl and amidine signals: . 8.175.3, 172.2, 170.7, 167.8, 164.6. 4 Reference example no

Me 0000 H; - (R) Cgl - Aze - Pab- COOH, CH, OMe 0 ¢ mmol oY from) 86 mg; (9) 1 Then prepare the compound according to the procedure described in Example No.

VYA)s 11 - Bug Cgl- Aze - Pab - COOCH, CH, OMe (prev) 2118*« 1 (refer to Example No. to give a crude product which has been purified by methyl bromoacetate mmol) 1.84 mg;

To produce J ahd as a liquid 1: ¥) methylene chloride :THF flash chromatography using . mg 1 7 ( as a white solid Yoo ) is

H-NMR (400 MHz, CDCl;): 56 8.44 (t, 1H), 7.83 (d, 2H), 731 (d, 2H), 4.92 (dd, 1H), 4.49 (AB part of an ABX spectrum, 2H) ), 4.30 (t, 2H), 4.13 (m, 2H), 3.68 ) 2H), 3.63 (s, 3H), 3.39 (5, 3H), 3.25 (s, 2H), 2.87 (d, 1H), 2.62 (m, 1H), 2.52 (m, 1H), 1.96 (bd, o 1H), 1.8-1.5 (m, 6H), 1.3-1.1 (m, SH), 1.00 (q, 2H). * C-NMR (100 MHz, CDCI3) carbonyl and amidine signals: . § 175.2, 172.6, 170.7, 167.8, 164.5. 1 Reference No. Jha

Et 00001 - dd - um - on b - 000 -nBu 0

Boc - (R) Cgl - Aze - Pab - COO - NH (1) from (1) 1 Then prepare the subtitle compound according to the procedure explained in Article No. Milli Yo ala and (306 - (R) Cgl - Aze - Pab - COO - H (Use 7.1 mL ala 1.01) h.m. 1.5 mol) « - B-chloroformate after stirring at ambient temperature for a period Then, the methylene chloride concentrate was washed and the reaction mixture extracted by three parts of vo (787) mg 1 and concentrated to give (NapSO), and dried by cole the organic phase incorporated by 1 of the title compound The subarray is a white solid

TYA

! H-NMR (300 MHz, CDCl): §9.81-9.31 (bs, 1H), 8.36-8.20 (m, 1H), 7.35 (d, 2H), 7.84 (d, 2H), 6.78-6.43 (bs, 1H) ), 5.054.82 (m, 2H), 4.69-4.15 (m, 3H), 4.15-4.08 (m, 3H), 3.86-3.70 (m, 1H), 2.68-2.42 (m, 2H), 1.92-0.88 (m, 25H).

B C-NMR (125 MHz, CDCl;) amidine and carbonyl signals: . § 172.5, 170.7, 167.9, 164.9, 156.0. ° 11 - (R) Cgl - Aze - Pab - COO - nBu x 2HCI (Y)

Boc - sell Cgl-Aze -Pab- 000 nBu ex) (1 (g; 0.4 mmol) from step ¥,0) as a white solid. (7 001 9) To give d mg "H-NMR (300 MHz, MeOH-d4): 5 7.78-7.60 (m, 2H), 4.66-4.49 (m, 2H), 0.98 (2H), 01 4.49-4.35 (m, 3H) , 4.35-4.22 (m, 1H), 3.75 (d, 1H), 1.92-1.67 (m, 8H), 1.56-1.07 (m, 8H).The signal of one of the protons is partially obscured by the CD3 OH- signal

B® C-NMR (100 MHz, MeOH-d4) amidine and carbonyl signals: . § 172.7, 169.3, 167.9, 154.7

And OOCCH; - (R) A - Aze - Pab - COO - nBu (¥) Vo

Ye from) q mg; (1) (9) and then prepare the said compound according to the procedure described in Example No. (mmol) +, AA stereo; VEY) 5H - (R) Cgl - Aze - Pab - COO nBu x 2301 mmol) using a gradient of ate ddl 448 produced by ethyl bromoacetate chromatography

TYA

(770) 900 mg as separating fluid to give 7 1.8 to 001 EtOH 5 methylene chloride white. Alia as H-NMR (300 MHz, CDCl3): 8 9.70-9.36 (bs , 1H), 8.47 (t, 1H), 7.81 (d, 2H), 7.32 (d, 2H), 7.07-6.73 (bs, 1H), 4.97-4.87 (dd, 1H), 4.62-4.35 (m, 2H ), 4.20-3.98 (m, 6H), 3.27-3.12 (m, 2H), 2.84 (s, 1H), 2.70-2.40 (m, 2H), 2.03-0.85 (m, 22H) °

B® C-NMR (75 MHz, CDCl;) amidine and carbonyl signals: . § 175.3, 172.3, 170.8, 167.9, 165.0

FAB-MS: (m+1)=558 (m/z) : 01 Reference No. Jha 1i C(O) OOCCH; -(R)Cgl-Aze-Pab-Z©.

Prl C(O) CH,C H,CH, OH )( mm AYA g; 1 and butyrolactone - mmol) 576.5 al a 8 ) a mixture of was stirred at a temperature room for 7,5 hours. The product was concentrated in a vacuum to give pyrrolidine (mol) of the product as a yellow oil. (70) mg 15

I H-NMR (300 MHz, MeOH-d4): 583.58 (t, 2H), 3.50 (t, 2H), 3.40 (t, 2H), 2.42 (t, 2H), 2.06-1.75 m (m , 6H)

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OOCCH, Br (7) meta-Prl C(O) CH,C HyC (?; ml; 55.8 mmol) bromoacetyl bromide was added dropwise to a mixture of VY) g ; 45.48 mmol; From the previous (1) step, Hy OH depended on Pr C(O) CHC £0,A cal ja 0.7 mmol) DMAP in methylene chloride at zero degrees. After M was stirred at room temperature for 1.8 hours, another portion of 1 (mL; 11.4 mmol) bromoacetyl bromide 5)€ g was added; 11.4 mmol) DMAP and the reaction was retarded for 1.0 h. Water was added and methylene chloride was extracted 7 times. The organic phase was dried with 0.50 Nay and concentrated to give 0.17” mg (FAV) of the product as a yellow oil. H-NMR (400 MHz, CDCL): 8 4.15 (t, 2H), 3.75 (6, 2H), 3.40-3.31 (m, 4H), 230 2H), 1.98-1.83 (m, 4H) , 1.81-1.73 (m, 2H) 1 Prl C(0) CH,C H,C 1110000 - (R)Cgl - Aze - Pab (2) (01) The aforementioned compound was prepared according to the procedure described in Example No. 1 (©) of z (7 grams” Aze - Pab - Z (Use Lo 00.4 - 081) - 11 and (9, grams” Vif milli musul; from previous step (7) (C) O) CH,C 11:0 H,O0CCH, Br 0:1. The crude product was techniced by 1 flash chromatography using (Y:7:1) isopropanol:EtOAC 'heptane' as a separating liquid to give (7, ;g) which was then purified using a preparative RPLC using acetonitrile 44 in NH, OAc) + M as the sequencing liquid to give 7.14 mg (777) of the product as a white solid. (b's, 1H), 8.36 (t, 1H), 7.96-7.58 (m, 3H), 9.80-9.22 6 H-NMR (500 MHz, CDCl;) ' a (d, 2H), 7.37-7.22 (m, SH ), 5.20 (s, 2H), 4.95-4.88 (dd, 1H), 4.72-4.29 (m, 2H), 7.45 (m, 2H), 4.04-3.88 (m, 2H), 3.40 (t, 2H) ), 3.34 (t, 2H), 3.28-3.17 (m, 2H), 2.85 4.15-4.04 A

(d, 1H), 2.67-2.48 (m, 1H), 2.23 (t, 2H), 2.14-0.93 (m, 18H). 3 C-NMR (125 MHz, CDCl;) amidine and carbonyl signals: . 5.175.3, 172.4, 170.9, 170.4, 168.2, 164.6

FAB-MS: (m+1)=703 (m/z) 1 Reference Example No. °

ChNHC(O)CH,OOCCH; - (R) Cgl - Aze - Pab Z

Ch NHC rum CH, OH (1) gram » 097.9 mmol (1 mmol) Astambu Otamadin and 55.48 Gla 4) then stirred a mixture of

AY hour. The product was concentrated to give Y.0 m for 001 at a temperature of 2.5-dioxol,4-dioxane mol) of the product as a brown solid. (7000) mg 0

I H-NMR (500 MHz, MeOH-d4): . § 3.92 (s, 2H), 3.75-3.65 (m, 1H), .1.90-1.58 (m, 5H), 1.43-1.07 (m, SH). The signal of two of the protons are obscured by the CD3 OH- signal.

B C-NMR (125 MHz, MeOH-d4) amidine and carbonyl! signals: . 5.174.0, 62.5, 33.7, 26.5, 26.1, 26.0 The signal of one of the carbons is obscured by the CD3 OD-signal. Vo

Ch NHC (0) CH, OOCCH;Br (Y ) was added dropwise to a mixture of bromoacetyl bromide (mmol) 55.8 (Ja §) g; 17) and Ch NHC (0 (previous 011.01) (1) g; 50.9 mmol; from step A) at zero degrees after stirring in methylene chloride (Jo Av) in DMAP (mmol) 4

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- brighten (11.4 mmol) (da 1 h; additional 0.5 portions were added at room temperature and the reaction mixture was returned for DMAP (DMAP) VV, 8 mmol) a) ja 0 §) 5 bromoacetyl bromide h. Water was added and the phase was extracted by three parts of 5 > 5S yi 9Na, SO, and dried by cela the organic phase by Jue methylene chloride of the product was obtained as a brown solid. (VF) mg 017 to give 0 Hz NMR (400 MHz, CDCL): § 6.12-6.00 (bs, 1H), 4.62 (s, 2H), 3.90 (s, 2H), 3.84-3.76 (m, 1H), 1.95 -1.86 (m, 2H), 1.75-1.65 (m, 2H), 1.65-1.56 (m, 1H), 1.43-1.29 (m, 2H), 1.24-1.10 (m, 3H).

Ch NHC(0) © H, 00CCH, - (R)Cgl - Aze - Pab (2) (¥) with the beginning (©) 1 The said compound was prepared in a manner similar to the procedure described in Example No. 0 mmol ; from 1,6 al ja and (*, 11 - (R)Cgl-Aze -Pab Z mmol) 01.4 cal al) from (05:1070)0.Product purified Raw by © Hy OOCCH, Br step (¥( previous).

Jad as liquid (1)?::0) isopropanol EtOAc theptane flash chromatography using V70 + acetonitrile preparative using sequential RPLC followed by concentration and then by elution. Concentration and freeze-drying of 7.76 mg (777) of SM Molar 11 NEL OAc 0 gave the product as a white solid. H-NMR (500 MHz, CDCl): . 5.9.78-9.25 (bs, 1H ), 7.90 (t, 1H), 7.78 (d, 2H), 7.44 (d, 2H), 7.38-7.24 (m, SH), 6.66 (¢, 1H), 5.20 ( s, 2H), 4.90-4.83 (dd, 1H), 4.60-4 45 (m, 2H), 4.18-3.93 (m, 4H), 3.73-3.62 (m, 1H), (d, 1H), 3.23, 3.44 (AB, 2H), 2.87, 2.65- 2.08 (m, 3H), 1.98-0.93 (m, 22H) | 0

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_ $1 = 3 C-NMR (125 MHz, CDCl;) amidine and carbonyl signals: . § 175.1, 171.7, 170.7, 168.8, 166.1, 164.4

FAB-MS: (m+1)=703 (m/z)

VY Example reference number (aPr) ;NC(O) CH; OOCCH, - (R)Cgl - Aze - Pab - COOCH, 0000 (CH); 0 (nPr); NC (0) 0111.011 (1) ¥1.0 mL (©) 52,5-dioxo-1,4-dioxane mmol) 117.4 mole; 7.0 7) A mixture of ,

TV for -0 for one hour and at a0 degree 0 in degree di-n-propylamine (mmol) the -di-n-propylamine was subsequently removed in a vacuum with an excess amount of toluene ddl ) hour. The remaining 7) + methanol was purified by aluminescence chromatography using (111) mg of the desired compound. 5.08 as a sequencing liquid to give methylene chloride !H NMR (300 MHz, CDCL): 8.4. 1 (d, 2H), 3.65 (t, 1H), 3.25-3.35 (m, 2H), 29-0 (m, 2H), 1.45-1.6 (m, 4H), 0.8-0.95 (m, 6H) ( nPr), NC(O)CH, OOCCH, Br (Y) (1) from step 0 (Pr):NC(0) CHo OH (g; ,7 mmol) + VEY) mixture was stirred of 1 mmol) acid 801 1 col a f (p or dcc g; 4 1 4 mmol) 0 01 ) preceding) and h. TAMM V,0; At room temperature for methylene chloride (Je 00) in bromoacetic

Kugelorhr The precipitate was removed by filtration and the solvent was removed from the filtrate under vacuum. Distillation gave mg (704) of the desired compound. +N to remain

TYA

HNMR (300 MHz, CDCl): 5.4.8 (s, 2H), 4.0 (s, 2H), 3.2-3.3 (m, 2H), 3.05-3.15 (m, 2H), 1.5-1.7 ( m, 4H), 0.8-1.0 (dt, 6H)

Pivaloyloxymethyl 4-nitrophenyl carbonate (1) mM YO g; V,49) silver pivalate mmol) YO g g; V,0) returned mixture from Alexander et al. JMed chem ( (1988) 31.318) iodomethyl 4-nitrophenyl carbonate mol) in (84 mL) 8 for 2 hours; Then the 0206 was removed under vacuum and the residue was dissolved in toluene, filtered through Heflo and purified by flash chromatography using shell.toluene. = Al as separator fluid ¢ mg (¢ 10) of title compound M ! 11 NMR (300 MHz; CDCl): .8.8.25 (d, 2H), 7.40 (d, 2H), 5.85 (s) , 2H), 12 (s, 2H) no C NMR (75 MHz, CDCl;) amidine and carbonyl signals: .6.176.777, 6 'Boc-(R)Cgl-Aze-Pab-COOCH, OOCC(CHs) ); )4( pivalyloxymethyl 4-nitrophenyl carbonate mmol)£ala V,VA) A solution of 10 at room temperature was added to a solution of methylene chloride (Ja Y +) (from step (©) the former) in mmol (£,V0 «Jo +,11) and 08-300 (Cgl-Aze-Pab-H) g; ; mmol (VAR) of da) after one hour the methylene chloride (ml) 01 was dissolved in triethylamine and the mixture was purified by flash chromatography EtOAc with methylene chloride from the subtitle compound. (v0 0) 1 mg, XY as sequencing liquid to give to EtOAc using XY.

TYA

—_3 A _ 7 NMR (300 MHz, CDCl): 89.5 (bs, 1H), 8.25 (t, 1H), 7.8 (d, 2H), 7.3 ) 2H, 7.0 (bs, 1H), 5.0-4.8 (m, 2H), 4.65-4.5 (m, 1H), 4.5-4.3 (m, 2H), 4.2-4.05 (m, 1H), 3.75 (t, 1H), 2.7-2.4 (m, 2H), 1.9 -1.45 (m, 5H), 1.45-0.8 (m, 24H)

H--(R)Cgl-Aze-Pab-COOCH,O0CC(CHz)s (°) (from Boc-(R)Cgl-Aze-Pab-COOCH,00CC(CHs)s mg; +10 mM 0 mol) YYV) was dissolved after 1178.1178 (J— VY) methylene chloride (ml) Y¢) step (4) previous) in a mixture of acetonitrile 2 hours was removed again. concentration of the reaction mixture in a vacuum; The solvent was added in vacuo to give a crude sub-heading product which was used without further purification in the next step. Cgl-Aze-Pab-COOCH;00CC(CHs)s((nPr), NC(O)CH;00CCH,-(R (1) 0) The remainder from step (0) was mixed with aaa 0501( 57 mM Pr) (aPr),NC(O)CH,00CCH,Br (from previous (Y) step) (480; cama #5 mmol) and 1600 in (©mL) THF and heat it up for? hours at 40 °C. The reaction mixture was filtered and concentrated into a crude product which was purified by preparative RPLC to give YA (mg) 271 of the said compound 0 HNMR (300 MHz, CDCl): § 9.3-9.6 (bs, 1H), 8.5 (m, 1H), 7.95-8.15 (bs, 1H), 7.85- (d, 2H), 7.2-7.3 (d, 2H), 5.8 (s, 2H), 4.8-4.9 (dd, 1H), 4.5-4.7 (m, 3H), 4.0-4.4 (m, 7.95 3H), 2.8-3.4 (m, 5H), 2.2-2.7 ( m, 3H), 1.75-1.3 (m, 9H), 1.3-1.0 (m, 14H), 1.0-0.7 (m, TH).

— 9 ¢ — NMR (75 MHz, CDCI3) amidine and carbonyl signals: . §.177.24, 175.30, 171 85, 6H 03 .163.14 , 165.82 , 168.78 , 170.79 Reference Example No. (17): EtOOCCH;-(R) Cgl-Aze-Pab-COOCH,00CC(CH;) s ° Then prepare the aforementioned compound in a manner similar to the procedure described in Example No. VY ) (previously from al ya +, £1) 16 mMol) Boc-(R) Boc-(R) )Cgl-Aze- Crude Pab-COOCH;00CC(CHs)s (see JE No. (former ENVY) using acetonitrile as solvent. After stirring overnight at yal temperature) 43 the solvent was removed in broilers and the residue was divided between EtOAc and water. The aqueous phase was extracted three times with 6/20 and the combined organic phases were dried 0 (80 pH) and the solvent was removed in broilers. Then expose the remainder to a flash chromatogram with methanol | methylene chloride as a rinse fluid. hel Freeze drying of acetic acid (771 cama A) of the said compound. (bs, 1H), 8.5 (t, 1H), 7.35 (d, 2H), 5.85 (s, 2H), 8.9.9 . LUT: HNMR (300 MHz, s (dd, 2H), 4.6-4.35 (m, 2H), 4.15-4.0 (m, 4), 3.2 (s, 2H), 2.85 (d, 1H), 2.7-2.45 (m, 5.90 (m, 2H), 1.8-1.45 (m, SH), 1.3-0.9 (m, 18H). Vo 2.0-1.9,2 C NMR (75 MHz, CDCI3) amidine and carbonyl signals: 5.177.23, 175.48, 172.29, 13.163.14, 168.85, 170.80 TYA

_ m 0 _- dl Ve) Cumulative reference example

EtOOCCH,-(R)Cgl-Aze-Pab-COOCH, O0CC(CHs);

Boc-(R) Cgl-Aze-Pab-COOCH(CH;)OOCCH; (1)

Boc-(R)Cgl-Aze-Pab-H mmol 1,6 al) 2 YA) a solution of l-acetoxyethyl 4-nitrophenyl carbonate g was stirred; mmol) #0 f (5° triethylamine mmol) 04 filling V,90) 5 (Alexander et al, J. Med. Chem. (1988) 31, 318) by Lc sie 116 hours at room temperature for methylene chloride (do £4) in aqueous (+ (1) and its concentration is NayCOs. The resulting solution was slightly concentrated and washed with EtOAc (aka LG) EtOAc was liquified into a crude product which was then purified by flash chromatography to give 0.09 mg (7/7) of the subtitle compound. 0 A H NMR (300 MHz, CDCl): 8.9.5. (bs, 1H), 8.25 ( ) 1H), 7.85 (d, 2H), 7.35 (d, 2H), 6.95 (q, 1H), 6.7 (bs, 1H), 5.0-4.85 (m, 2H), -4.65 4.5 (m, 1H), 4.5-4.25 (m, 2H), 4.2- 4.05 (m, 1H)3.75 (t, 1H), 2.65-2.45 (m, 2H)2.05 (s, 3H), 1.9-1.45 ( m, 11H), 1.45-0 8 (m, 12H). No NMR (75 MHz, CDCl3) amidine and carbonyl signals: . § 172.61, 170.80, 169.54, Vo 168.91, 162.50, 156.02. Ta

1 _ © - Cgl-Aze-Pab-COOCH(CH;)OOCCH;(H-(R (Y)) The crude subtitle compound was prepared according to the procedure described in Example VY (0) above from YY) grams; TA mmol; º Boc-(R)Cgl-Aze-Pab-COOCH(CH;)OOCCHs; (from step (1)(previous). EtOOCCH,(R) Cgl-Aze-Pab-COOCH(CH;)OOCCH;(¥) H-(R)Cgl-Aze-Pab-COOCH(CH:)OOCCH; from the previous (Y) step was dissolved in ( de Vor) methylene chloride, then the mixture was washed with a solution of 118:00 700 and the organic phase was dried by KpCO; and filtered. VO) mg was added; 0,© mmol) :16:00 f (0 mg 7.7 memone) ethyl (O-trifluoromethanesulphonyl)-glycolate FC methylene chloride (Joo) 0 The reaction mixture was stirred for 0 - 10 minutes at: room temperature and then concentrated in a vacuum. The residue was dissolved in 6/20 and the resulting mixture was filtered through a cellite. The filtrate was subjected to flash chromatography using EtOAc as separating liquid followed by HPLC to give (mg; Y is the name of the said compound. (bs, 1H), 8.3 (t, 1H), 7.7 (d, 2H), 7.2 (d, 2H), 6.85 5.9.5 . Speed: 1111/1 (300 MHz, m0 -2.5 1H), 4.8 (t, 1H), 4.45-4.25 (m, 2H), 4.1-3.85 (m, 4H), 3.1 (s, 2H) , 2.75 ) 1H), ) (m, 2H),1.95 (s, 3H), 1.9-1.8 (m, 1H), 1.7-1.25 (m, 8H), 1.25-1.75 (m, 8H). 2.3 C NMR (75.5 MHz, CDCI3) amidine and carbonyl signals: . 8.175.26, 172.34, 170.81, 3 : 169.49 , 168.80 , 162.43 .

—- M Y —_— :) Vo ) Example No

MeOOCCH,-(R)Cgl-Aze-Pab-OCCPh

Boc-(R)Cgl-Aze-Pab-OCCPh ()) A drop of THF (J 01 (dissolved in dibenzoyl peroxide mmol) ¥,F cane 007) 00 mmol added 1 gm) per minute to a solution of ½ to a drop over a range of 0 in THF (mmol) 11,801,1100 in (£0 ml) V+ © pla YAY) 5 Boc-(R)Cgl-Aze- Pab-H Hour; The reaction mixture was concentrated and YE was subjected to 17 °C. After stirring at 10°C for a period of the title compound (10 7 mg; 14) preparation. This RPLC gave the resulting raw product to the by-product as a white solid.

I H-NMR (500 MHz, CDCL): . § 8.26 (m, 1H), 8.09 (m, 2H), 7.72 (m, 2H), 7.59 (m, ve 1H), 7.48 (m, 2H), 7.36 (d, 2H), 5.13 (s, 2H) , 4.87-4.98 (m, 2H), 4.54-4.61 (m, 1H), 4.33-4.47 (m, 2H), 4.13-4.19 (m, 1H), 3.81 ( 1H), 2.53-2.63 (m, 2H) , 1.73-1.86 (m, 3H), 1.66-1.72 (m, 2H), 1.36 (s, 9H), 0.968-1.28 (m, 6H). 3 C-NMR (100 MHz, CDCl;) amidine and carbonyl signals: . 8.6 172.7, 170.6, 163.9, 157.0, 155.9. Vo

LC-MS: nv/z 592 (M+H"); m/z 614 (M+Na"). : Boc-(R) Cgl-Aze-Pab-OCCPh (Y) mmol) 0.10 mg; (001) solution of M270 in grade TFA (de 1) was added. methylene chloride (J—s YA) (prev) in (1) (from step Boc-(R)Cgl-Aze-Pab-OOCPh

TYA

- ov - after stirring for 1 hour; The reaction mixture was concentrated and the resulting crude product was divided among 11 NaOH 5 M EtOAc. The phases were separated and the organic layer (504:10) was dried and evaporated. Yield (cane $A 797) as a white solid. “H-NMR (400 MHz, MeOH-d4): .8.8.18 (m, 2H), 7.77 (m, 2H), 7.64 (m, 1H), 7.52 (m, 2H), 7.43 (d, 2H), 4.75-4.81 (m, 1H), 4.50 (s, 2H), 4.18-4.34 (m, 2H), 3.12 (d, 1H), o 2.57-2.68 (m, 1H), 2.23-2 33 (m, 1H), 1.88-1.96 (m, 1H), 1.73-1.84 (m, 2H), 1.59-1.71 (m, 2H), 1.45-1.57 (m, 1H), 0.80-1.34 (m, SH ) LC-MS: m/z 492 (M+H"); m/z 514 (M+Na") MeOOCCH,-(R)Cgl-Aze-Pab-OOCPh( v ) 0 /1/97 (mg; 1.16 mmol) added methyl bromoacetate to a solution of z (4850 mg 9597 mmol) H-(R) Cgl-Aze-Pab-OOCPh (from previous (Y) step cane YY) ? mmol) KaCOs in (©) acetonitrile (de) at 01 °C. The reaction mixture was stirred at 07 °C for VE h. The reaction mixture was filtered and concentrated to give a crude product, which was purified by a preparative RPLC to give (7719 cana 749) of the compound reported as a 01 white solid.171-1017 (500 MHz, CDCl): 9 (m, 1H), 7.47 (m, 2H), 7.34 (m, 2H), 5.27 (s, 2H), 4.93 (dd, 1H), 4.59 (dd, 1H), 4.40 (dd, 1H) , 4.12 (m, 2H), 3.65 (s, 3H), 2.87 (d, 1H), 2.72-2.63 (m, 1H), 2.55-2.48 (m, 1H), 1.96 (m, 1H), 1.74 ( m, 2H), 1.67 (d, 1H), 1.59 (d, 1H), 1.56-1.50 (m, 1H), 1.29- 1.08 (m, 4H), 1.04-0.94 (m, 1H) Y.

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C-NMR (100 MHz, CDCl) amidine and carbonyl signals: . 8.175.1, 172.5, 170.6, for 164.0 , 157.1 LC-MS: m/z 564 (M+H") ' Example No. (uh): MeOOCCH,-(R)Cgl-Aze-Pab-CH Then add (Ra 0 5 (Ja mol £1 0 mmol) KOMe at .5 XY degree to a solution of 1475 ane YT (mmol) MeOOCCH,-(R) Cgl-Aze-Pab-OC(O)Ph (see Mal No. )(0 above) in (6,; THF (Je) after 11 minutes of stirring the mixture was concentrated and subjected to a preparative RPLC. This gave cada 101 7 M0 of the said compound as a white solid.H-NMR (500 MHz, MeOH-d4): & 7.59 (d, 2H), 7.34 (d, 2H), 4.83 (s, 2H) , 4.82-4.76 \' (m, 1H), 4.48 (d, 1H), 4.33 (d, 1H), 4.15-4.30 (m,2H), 3.64 (s, 3H), 3.04 (d, 1H) , 2.57 (m, 1H), 2.26 (m, 1H), 1.95 (m, 1H), 1.75 (m, 2H), 1.58-1.70 (m, 2H), 1.53 (m, 1H), ( m, 4H), 1.04 (m, 1H) 1.31-1.10 C-NMR (100 MHz, MeOH-d4): amidine and carbonyl! signals: § 175.9, 174.3, 172.7, the Vo 155.2 LC-MS: m/z 460 (M+H"), m/z 482 (M+Na") Na

- Duh (VV) Example No

EtOOCCH,-(R)Cgl-Aze-Pab-OH mmol); R)Cgl-Aze-Pab-C(0)OCH(CH;)OOCCH,;©,V mL +,A) 5 hydroxylamine hydrochloride (Js— mM 177 mg VY) m added And the mixture was stirred at room temperature 495 EtOH in (; ml) triethylamine mmol) preparation. This gave the RPLC for the duration of; days. The reaction mixture was concentrated and the crude product was exposed to i"( of the said compound. A (pda Ao)" H-NMR (300 MHz, CD; OD): .87.6 (d, 2H), 7.35 (d, 2H) ), 4.75-4.85 m, 1H), 445 (m, 2H), 4.0-4.35 (m, 4H), 3.35 (d, 2H), 3.05 (d, 1H), 2.5-2.65 (m, 1H), 2 2-2.35 (m, 1 1H), 1.9-2.05 (m, 1H), 1.4-1.85 (m, SH), 0.85-1.35 (m, 8H)

B C-NMR (75.5 MHz, CD; OD): amidine and carbonyl signals: . § 175.97, 173.91, 172.72, 155.23

LC-MS: (m+1)=474 (m/z) : ( 1 A) Example number ho

BnOOCCH,-(R)Cgl-Aze-Pab-OH to a solution of BnOOCCH,-(R)Cgl-Aze-Pab-Z mmol) 0.97 g; 1) added mmol) 1.7 4 “Ja 017 (and hydroxylamine hydrochloride mg; ,99 mmol) YY)

TYA

-J-triethylamine in EtOH The reaction mixture was stirred at room temperature for fe hour and then concentrated. The crude product was purified by a preparative RPLC using acetonitrile © 7 in 10 70.06 M as the sequencing liquid to give YE + mg (757) of said compound. LC-MS: (m+1) = 536 (m/z)0 Example No. (14): nPrOOCCH,-(R)Cgl-Aze-Pab-Z The said compound was prepared similarly to the procedure described in Example No. (9) above from Vor) mg; 01 mmol) H-(R)Cgl-Aze-Pab-Z x 2 HCI Rho(4 7 mg; 0116© mmol) n-propyl bromoacetate Yield tana You *# 7/). 0 (/r) 606 = FAB-MS: (m+1) Ex. 0 "): nPrOOCCH,-(R)Cgl-Aze-Pab-OH Said compound was prepared similarly For the procedure described in example YA above of 17 cana VAY (mmol) nPrOOCCH,-(R)Cgl-Aze-Pab-Z (see example 19 above). Crude product by RPLC preparative using acetonitrile 40 in 1 mol NH4OAc as sequencing liquid to give 751 mg VE of the desired compound. LC-MS: (m+1) = 488 (m /z) TYA

B_ 7 o — Example No. (Rk : ) YA iPrOOCCH,-(R)Cgl-Aze-Pab-OH Said compound was prepared similarly to the procedure described in Example No. VA above from (0414 mg ; 17 mmol) 8(081-426-020-2)-70000117 (see example va below). o Yield (ada 10 77 LC-MS: (m+1) = 488 (m/z) Example 7): tBuOOCCH,-(R)Cgl-Aze-Pab-OH Then, the aforementioned compound was prepared in a manner similar to the procedure described in Example No. (Gall) \ A from 011 cane VFA (0 mmol) tBuOOCCH-(R)Cgl-Aze-Pab-Z (see Example No. YY the next). Output Yield EA (ada Ya.7): LC-MS: (m+1) = 502 (m/z) Example No. (¥)(Y (nPr),NCOCH,00CCH,-) R)Cgl-Aze-Pab-(OH)DHOOCCH,-(R)Cgl (Boc)-Aze-Pab-Boc(}) A solution of (+ cane TV 1.0 mmol) was stirred HOOCCH,-(R)Cgl-Aze-Pab-OH (see example number XY A below) o ¢ s 1 mg 7 mmol) 0d(300) and 7 3 0 Y o poms mmol) TYA

A — 0 — DMAP in sTHF water (1:01) at room temperature for 2 hours. The sub-reaction mixture was concentrated as a white solid. LC-MS: (m+1) = 643 ( m/z).

(nPr),NCOCH,O0CCH,-(R)Cgl-Aze-Pab-O-Boc(Y) 0 (from HOOCCH,-(R)Cgl-Aze-Pab-O-Boc mmol) (+.) 0 cana 001) A solution of (NY (see Example No. (nPr);NCOCH,0H mmol) 117 cana YV) was stirred (previous 5) (1) step in DMAP (mg x mmol) Ye (former EDC) and 2 mg; mmol) at room temperature for € days. The reaction mixture was concentrated and purified with acetonitrile (Ja©)

RPLC yo was prepared and lyophilized to give (pYA)ada 0 from the subtitle compound. LC-MS: (m+1) = 787 (m/z) (nPr),NCOCH,00CCH,-) R)Cgl-Aze-Pab-OH(Y') [VAY] A solution of ) + Y mg was stirred; ¥0 ,+ mmol) (nPr),NCOCH,;00CCH;- (R)Cgl(Boc)-Aze-Pab-O-Boc in (1:1) methylene chloride: TFA at ° Room temperature s.d.ve. 0 min. The reaction mixture was concentrated and lyophilized from acetonitrile and water to give © mg (?7/) of said compound. LC-MS: (m+1) = 587 (m/z) TYA

_ 5 © Example No. (9): ChNHCOCH;O0CCH,-(R)Cgl-Aze-Pab-OH Then prepare the aforementioned compound in a manner similar to the procedure described in the previous example No. YA from 117 cama (11) mM mol) ChHNHCOCH,00CCH,-(R)Cgl-Aze-Pab-Z (see example 11° (9) above). Output yield mg. LC-MS: (m+1) = 585 (m/z) [+ V4 0] Example #2 (Y): MeNHCOCH,OO0CCH,-(R)Cgl-Aze-Pab-OH Then prepare the said compound in a manner similar to the procedure described in the previous YA example from 0 (1 mg VY + mmol) MeNHCOCH,00CCH,-(R)Cgl-Aze-Pab-Z (see example Next number). OAc m H-(R)Cgl-Aze-Pab-OAc (1) TYA

. = - The subtitle compound was prepared similarly to the procedure described in JE No. combat YY (steps db 1345 ((¥) 5 (Y)s (1) using acetic acid anhydride instead of -propanoic acid anhydride LC-MS: (m+1) = 430 (m/z) EtOOCCH,-(R)Cgl-Aze-Pab-OAc (Y) 0 Then prepare the said compound similarly to the procedure described in Example No. 1 9 (prev of YY) mg 0.1 mmol) cana V+ 0) 3 H-(R)Cgl-Aze-Pab-OAc 17 mM ethyl (Js—e .bromoacetate) Yield TY mg YY LC-MS: (m+1) = 516 (m/z) a Example (l7): EtOOCCH,-(R)Cgl-Aze-Pab-OC( O)Et Boc-(R)Cgl-Aze-Pab-OH (V) added 1 g; 0.7 mmol) Boc-(R)Cgl-Aze-Pab-Z to a solution of triethylamine 5 hydroxylamine hydrochloride in EtOH The reaction mixture was stirred at \o room temperature for £ v an hour and its concentration, Laie, then the crude product was purified by a preparatory RPLC. LC-MS: (m+1) = 488 (m/z) TYA

Boc-(R)Cgl-Aze-Pab-OC(0) Et (7) A solution of (011 cameme (+9, mmol) Boc-(R)Cgl-Aze-Pab-OH) was stirred From step (1) above) 5 (0,¥ propanoic acid anhydride (J) at room temperature for £0 min and then concentrated. The crude product was purified by preparative RPLC using 0 acetonitrile © 7 in NH OAc , 8 l molar as sequential separation fluid to give ) 17 mg 0 0 of the subtitle compound.

LC-MS: (m+1) = 544 (m/z).

H-(R)Cgl-Aze-Pab-OC(0) Et (7) Then prepare the subtitle compound similarly to the procedure described in article #1 (1”) (0 above from cama YYA) ££ ,+mmol) Boc-(R)Cgl-Aze-Pab-OC(O)Et (from previous step 7 Yao {ada Ya.).

LC-MS: (m+1) = 444 (m/z) EtOOCCH,-(R)Cgl-Aze-Pab-OC(0) Et (¢) added ( aaa) wo £0 mmol ) EtOOCCH,080,CF; (an aged preparation (triflic anhydride and ethyl glycolate) was added dropwise to a solution of (0101) mg 80 mM H-(R)Cgl-Aze-Pab-OOCEt (Js) From step (previous) Y YY (ada Ye As mmol) K,CO; in 1) methylene chloride (Js) at 0 °A Ja after the reaction mixture was stirred at room temperature for 1 hour Then the reaction mixture was washed with water, citric acid, and ¢ TYA water

And dry it (NaSO.) and concentrate it. Then, the crude product was purified by a preparative RPLC using acetonitrile 750 in NHLOAC (+ M) as a separating liquid to give “+ mg (77/) of the said compound. : LC-MS: (m+1) = 530 ( m/z)° Example A) g): HOOCCH;-(R)Cgl-Aze-Pab-OH tBuOOCCH,-(R)Cgl-Aze-Pab-OOCPh (V) was prepared The subtitle compound similarly Jal - explained in Example No. \ (7) above from You) Combined; 159 mmol) H-(R)Cgl-Aze-Pab-OOCPh (See Example No. (Yo 0 ex) and (911 mg; , + mmol) 00171000002681816 - .yield 711 mg; (R)Cgl-Aze-Pab-OOC Ph(Y) and then prepare the subtitle compound similarly to the al e described in Example No. \(Y) 10 above from (777 mg; 1.7 mmol) ) tBuOOCCH,-(R)Cgl-Aze-Pab-OOCPh (from ghd 3 ) \ ( preceding) . Yield of product lo mg; YY º LC-MS: (m+1) = 550 (m/z).

__yi_ HOOCCH,-(R)Cgl-Aze-Pab-OH (¥) A solution of (60 mg;+ mmol) HOOCCH,-(R)Cgl-Aze-Pab-O0CPh was stirred (from the previous (Y) step) and (71 mol; 17 mmol) 160146 in (10 mL) THF (1.0 mL) methanol at room temperature for © minutes. The reaction mixture was concentrated and lyophilized from 0 water acetonitrile s to give cana YA (777) of the said compound. LC-MS: (m+1) = 446 (m/z) (¥ 3 ) Example No.

HOOCCH:-(R)Cgl-Aze-Pab-O-cis-Oleyl tBuOOCCH,-(R)Cgl-Aze-Pab-Z (1) 0 “a solution of VY)g stirred” 7, 8 mMol) tBuOOCCH,-(R)Cgl-Aze-Pab-Z (see example 7 below) and (677 Vir A cana mmol) 30020 5 cana TA) 0.573 mmol) DMAP in THF (Je *1) at room temperature for YE hr. Additional 300:0 (0 mg 4 mmol) V1 at #°C was added after another YE hr. The reaction mixture was concentrated and purified by a preparative RPLC to give ah mg (A 0 ) of the desired compound. LC-MS: (m+1) = 720 (m/z) Ve TYA tBuOOCCH,-(R)Cgl (Bco) (-Aze-Pab-OH (Y) former YA) and then prepare the subtitle compound similar to the procedure described in Example No. (1) (step tBUOOCCH-(R)Cgl (Beo)-Aze-Pab-) Z (Use m +,A cane 0 ( from previous 711). Yield 7 mg; -LC-MS: (m+1) = 602 (m/z) © tBuOOCCH;-(R (Cgl (Bco)-Aze-Pab-O-cis-Oley! (1) ~~ tBuOOCCH-(R)Cgl (Bco)-Aze-Pab-OH (Usa m +,07 came 7 40) Done A solution of 0.11 mg (and cis-oleylchloride 17 mmol) ©0975 aaa YY) (ex) (Y) (from step ©) was stirred for 1 min. The reaction mixture was concentrated and purified. methylene chloride in triethylamine mmol).

LC-MS: (m+1) = 867 (m/z)

HOOCCH-(R)Cgl -Aze-Pab-cis-Oleyl (¢) prior to (Y)1 Said compound was prepared similarly to the procedure described in Example (from step tBuOOCCH,-(R)Cgl (Bco)-Aze-Pab-O-cis-Oleyl mmol) 175 (aaa YYY) . preceding) 9) 0

LC-MS: (m+1) < 710 (m/z)

TYA

DZD4 _— Reference Example No. (0 ): Cyclooctyl-OOCCH,-(R)Cgl-Aze-Pab-Z Cyclooctyl-bromoacetate() dissolved (01 (ala) TV) mmol) cyclooctyl 5 (¥,+ g) DMAP in M methylene chloride followed by addition of (1 ml; VY mmol) .bromacetyl chloride after stirring for VA h; The reaction mixture was washed with aqueous Na,CO5 (¥ M) HCl (1 M), dried, concentrated, and purified by flash chromatography with PAREN methylene chloride: petroleum ether (+10©) to give 0.8 “mg (777) of the compound of the subtitle. Similar to the procedure described in mmol) 1.17 mg YY) 5 H-(R)Cgl-Aze-Pab-Z x 21101 mmol) 017 mg; VY) (181) mg YY ex). Product yield (1) (from step cyclooctyl bromoacetate

LC-MS: (m+1) = 674 (m/2)

TYA

Reference example (HT) tBuCH,O00CCH;-(R)Cgl-Aze-Pab-Z-Aze-Pab-Z Then prepare said compound similar to the procedure described in the previous example \(*) of cal ja Y,0) 7,; mmol) 21101 H-(R)Cgl-Aze-Pab-Z x f (01 g” 5.7 mmol) tertbutylmetyl bromoacetate © yield of product VAY (773) mg FAB-MS : (m+1) = 634 (m/z) Reference Example #77: Me)BnOOCCH,-(R)Cgl-Aze-Pab-Z -2( Methylbenzyl bromoacetate())b Then prepare the subtitle compound in a manner similar to the procedure described in the previous article (1) Ya (from © gram; £1 mmol) A al ja 1,1) Y 5 2-methylbenzylalcohol (mM-bromacetyl chloride). Yield AY mg (/AY) Me)BnOOCCH,-(R)Cgl-Aze-Pab-Z (Y)-2) Then prepare the said compound in a manner similar to the procedure described in Example 1 (9) precursor of 0A (0 mg; 1 mmol) H-(R)Cgl-Aze-Pab-Z x 2HCI f (190,011 cane mmol); 2-methylbenzyl bromoacetate (from step 1(previous)). Yield 1 mg 18.0 LC-MS: (m+1) = 668 (m/z)

Reference Example #77: ChCH,00CCH,-(R)Cgl-Aze-Pab-Z solution returned from )1.81 g; 117 mmol) BhOOCCH,-(R)Cgl-Aze-Pab-Z and (mL) cyclohexyl methylalcohol in (4 57 µL) triethylamine and (mL) methylene chloride 0 Duration ; days. The reaction mixture was blended to give a crude product which was purified by flash chromatography using methanol:methylene chloride (5:0) as the separating liquid to give 8.11 mg (LY 1) of the said compound. FAB-MS: m+1) = 660 (m/z) Reference Example No. (TE) ChOOCCH-(R)Cgl-Aze-Pab-Z 0 Cyclohexyl bromoacetate()) and then prepare the subtitle compound similarly to the procedure annotated in JE no. -Aze-Pab-Z (Y) \o and then prepare the said compound in a manner similar to the procedure described in Example No. \ (v) above from ala Y,0) 77,? mmol) 21101 s H-(R)Cgl-Aze-Pab-Z x (1.0 g” 5.7 mmol) cyclohexyl bromoacetate yield 117 mg (V0)7 (TYA) |

- A - Reference Example No. (75):

PhC(Me),O0CCH;-(R)Cgl-Aze-Pab-Z 2-Phenyl-2-propyl bromoacetate ( 1 ) and then prepare the said sub-title compound similarly to the procedure described in Example No. Yo 1 ) ° (prev of) 9 YY ol mM 2-phenyl-2-propanol (Js f) 77 g; 7 mmol) (744) mg 0.1 yield bromacetylchloride

PhC(Me),00CCH,-(R)Cgl-Aze-Pab-Z (1) The aforementioned compound was prepared similarly to the procedure described in Example 1 (©) above from (017 grams) 7.7 mL mol) 21101 H-(R)Cgl-Aze-Pab-Z x f (140 mg; Y,0 mmol) (7 AN) mg VY ex). Product yield (1) (from step 2-phenyl-2-propyl bromoacetate 10" H-NMR (500 MHz; CDCL). 8 9.3 (brs, 1H), 8.35 (t, 1H), 7.75 (d, 2H), 7.45 (d, 2H), 7.30-7.05 (m, 10H or 11H), 5.15 (s, 2H), 4.78 (t, 1H), 4.40-4.30(AB part of ABX spectrum, 2H), 3.95 ( q, 1H), 3.74 (q, 1H), 3.27-3.19 (AB-spectrum, 2H), 2.72 (d, 1H), 2.43 (q, 2H), 1.93 (br d, 1H), 1.75-1.60 ( m, 9H or 10H), 1.54 (d, 1H), 1.49-1.40 (m, 1H), 1.25-1.0 (m, 4H), 0.92 (q, 1H) \o

Ya

Reference Example No. (7?): MeNHCOCH,00CCH,-(R)Cgl-Aze-Pab-Z Said compound was prepared similarly to the procedure described in JE No. 1C0 preceding from 1)g ; lamma mmol) 2110 H-(R)Cgl-Aze-Pab-Z x f ) 4 vc; Y mmol (e) MeNHCOCH,O0CCH,Br (prepared similarly to the procedures described in Example No. VY in the previous steps (1), (7), and () using methylamine instead. cyclohexylamine Yield Yield YA. mg VAL) FAB-MS: (m+1) = 635 (m/z) Reference Example No. (FY) {BuOOCCH,-(R)Cgl-Aze- Pab-Z 0 preceding from 1) 9 and then prepare the said compound in a manner similar to the procedure described in Example No. (mmol VY mg YY) and H-(R)Cgl-Aze-Pab-Z x 2110 mmol) (1 cane 0144) (7179). 471 mg yield t-butyl bromoacetate

LC-MS: (m+1) = 620 (m/z)

TYA

- A. Reference Example No. (): (Me);CHC(Me);00CCH,-(R)Cgl-Aze-Pab-Z Said compound was prepared similarly to the procedure described in Example No. 1)0 ex from YAY (mg 0.4 mmol) 21101 H-(R)Cgl-Aze-Pab-Z x f (5 1 cama 1.17 mmol) 3-dimethyl-2 -butyl bromoacetate 0,12 Yield +09 cana (71) FAB-MS: (m+1) = 648 (m/z) Reference Example # (v9) iPrOOCCH,-(R) Cgl-Aze-Pab-Z Said compound was prepared similarly to the procedure described in Example (Y) 1 above from Ver) 0 0 mg; VY mM H-(R)Cgl-Aze-Pab-Z x 2110 (Uso f (7 mg 1.0 mmol) isopropyl bromoacetate yield YYo mg (1?/). FAB-MS: (m+1) = 606 (m/z) Example Reference No. CHE) BnOOCCH,-(R)Cgl-Aze-Pab-COOPh (4-OMe) d (1) Boc -(R)Cgl-Aze-Pab-COOPh (4-OMe) TYA

Then prepare the aforementioned subtitle compound in a manner similar to the procedure described in Example No. 790 (1) above from .4-methoxyphenyl chloroformate 5 Boc-(R)Cgl-Aze-Pab-H FAB-MS: (m +1) = 622 (m/z) H-(R)Cgl-Aze-Pab-COOPh (4-OMe) x 210 (Y) 0 Then prepare said sub-title compound similarly to the procedure described in Example ¢ (Y) of Boc-(R)Cgl-Aze-Pab-COOPh (4 -OMe) (from step 1(previous). BnOOCCHS,-(R)Cgl-Aze-Pab-COOPh (4-OMe) (¥) and then prepare the said compound in a manner similar to the procedure described in example #1 (9) above from (85/mg) 21101 H -(R)Cgl-Aze-Pab-COOPh (4-OMe) x (from previous (Y) step) 5 (40 0 eg 1.7 mmol) benzyl bromoacetate yield 10 mg (7 07) FAB-MS: (m+1) = 670 (m/z) Reference Example #59: ChCOCH,00CCH,-(R)Cgl-Aze-Pab-COOPh (). 4-OMe) and then prepare the said compound in a manner similar to the procedure described in Example 1 9 (previously from aan 00€) 0 34 mmol) 21101 H-(R)Cgl-Aze-Pab-COOPh (4 -OMe) x (see example t+ ) ¥ (previous) and (1 5 mg 7 mmol) cyclohexylmethyl bromoacetate yield ve mg A) 1 { TYA

FAB-MS: (m+1) = 676 (m/z)

HEY) Reference Example No. : (2-Me)BnOOCCH,-(R)Cgl-Aze-Pab-COOPh (4-OMe) preceding (¥)1 Said compound was prepared similarly to the procedure described in the example No. (refer to Example 50 (7) above) H-(R)Cgl-Aze-Pab-COOPh mmol)(4-0148) 1 came 0YY) mg 1098 product yield 2. (methyl)benzyl bromoacetate (mmol) 0.5 cane YN 0) 4 (7 YY)

LC-MS: (m+1) = 684 (m/z)

HEY) Reference Example No

EtOOCCH,-(R)Cgl-Aze-Pab-COOPh (4-Me) 0

Boc-(R)Cgl-Aze-Pab-COOPh (4-Me) (V) \ said subtitle compound was prepared similarly to the procedure described in Example 18 mg AO + and (Boc-(R) Cgl-Aze-Pab (prev) 7 g; 707 mmol) ( \ ) (700) mg 0.74 yield 4-tolyl-chloroformate mmol)

FAB-MS: (m+1) = 606 (m/z) Vo

TYA

yr - ْ - H-(R)Cgl-Aze-Pab-COOPh (4-Me) (Y) The said sub-title compound was prepared similarly to the procedure described in example ¢ (7) above from 164 ane (YAA) mmol) Boc-(R)Cgl-Aze-Pab -COOPh (4- Me) (Step 1 (previous)). The yield of the product is mg (/79). Said compound was prepared similarly to the procedure described in Example 1 (©) above from YAA) mg; 6 mmol) H-(R)Cgl-Aze-Pab-COOPh (4-Me) (previous (Y) step aged) and (117,4 cane 11 mmol) ethyl bromoacetate yield product AV mg (YE) 0 7 {FAB-MS: (m+1) = 592 (m/z) Reference Example #88 BnOOCCH,-(R)Cgl-Aze-Pab-COOPh ( 4-Me) and then prepare the said compound in a manner similar to the procedure described in example 1 (7) above from 0 (77? mg; 154 mmol) H-(R)Cgl-Aze-Pab- COOPh (4-Me) (see Example No. ?; (Y) above) and (no mg; 1 mmol) benzyl bromoacetate yield no mg (0 7) FAB-MS: (m +1) = 654 (m/z) TYA

Reference Example No. (20) BnOOCCH,-(R)Cgl-Aze-Pab-COO-nBu Said compound was prepared similarly to the procedure described in Example No. (V)1 above from 175 cana £00) mmol) H-(R)Cgl-Aze-Pab-COO-nBu x 2HCI (see example 1 (1)(0 above) and (0? AA cane, + mmol) benzyl bromoacetate Yield output YY stereo (A) ¢ 7). FAB-MS: (m+1) = 620 (m/z) Reference Example No. (£7) 1iPrOOCCH,-(R)Cgl-Aze -Pab-COOCH,CH=CH, ye and then prepare the said compound in a manner similar to the procedure described in example 1 9 (previous from +,1V (ane £01) mmol) H-(R) Cgl-Aze-Pab-COOCH,CH=CH, x 2TFA (see Example No. (Y) 1 above) 4 (0 18 cane V mmol £0) isopropyl bromoacetate yield 7954" mg ) va 7( FAB-MS: (m+1) = 556 (m/z) : a

: - and for (:)£v) reference example no

EtOOCCH;-(R)Cgl-Aze-Pab-COO-iBu

Boc-Pab-COO-Bu (1) in i-butyl chloroformate mg ¥.¥ mmol (TV) added (B0c),0 3 Pab-Z (prepared from Boc-Pab -H (Use to a solution of (000 mg; After stirring for a period of hours, water was added. Then drying of the organic sub-phase. 1 5.0 (bs, 1H), 4.33 (bd, 2H), 3.93 (d, 2H), 2.04 (m, 1H), 1.45 (s, 9H), 0.97 (d, 6H)

H-Pab-COO-iBux 2HCI (Y)

Eady The mentioned sub-title compound was prepared similarly to the procedure described in the previous example. (Y) (/AN) mg ty. output result yo

I H-NMR (500 MHz, MeOD). 5.7.89 (d, 2H), 7.75 (d, 2H), 4.30 (s, 2H), 4.17 (d, 2H), 211-2.05 (m, 1H), 1.02 (d, 6H)

TYA

Y 2 — _ Boc-(R)Cgl-Aze-Pab-COO-iBu (¥) TV added) mg; 0.4 mmol EDC to a solution of cane EA (1.4 mmol) Boc-(R)Cgl-Aze-OH and (07 cane 0 mmol) H-Pab- COO-Bux2 HCl (from previous (Y) step) 5 To) mg; 5.7 mmol) DMAP in 10 (mL) acetonitrile after stirring for ? © days at room temperature; The reaction mixture was concentrated and then dissolved in aqueous EtOAc the organic phase Jt was quenched with NaHCO; (aqueous) dried (Naz2S04) concentrated and purified by flash chromatography using EtOAc as sequencing liquid to give oY (mg) Y 70) of the sub-title compound. H-(R)Cgl-Aze-Pab-COO-iB, x 2110 (¢) 0 Said sub-title compound was prepared similarly to the procedure described in example No. ( 7) ex from (500 mg; 15848 mmol) Boc-(R)Cgl-Aze-Pab-COO-iBu (from step )*(previous). Yield yield yi.mg (7AY) EtOOCCH,-(R)Cgl-Aze-Pab-COO-iBu 0 and then prepare said compound similarly to the procedure described in Example 1 (9) above from 0 (190 mg; 57 mmol) H-(R)Cgl-Aze-Pab-COO-iBu x 2HCI (from step £(previous) f (0 mg; VE mmol) ethyl bromoacetate. Yield Yeo mg (No ¢ 7) { .FAB-MS: (m+1) = 558 (m/z) TYA

Reference Example (tA): BnOOCCH,-(R)Cgl-Aze-Pab-COO-nPr Then prepare said compound similar to the procedure described in Example No. 1 090 (previously from 017 cana 07) mmol) 21101 H-(R)Cgl-Aze-Pab-COO-nPr x (see Example #© (7) ° above) and YAY (0.1 mmol) .benzyl yield bromoacetate 4 mg yield (Yo 7). “H-NMR: (400 MHz, CDCl). 5.8.43 (bs, 1H), 7.78 (d, 2H), 7.38-7.27 (m, 7H) , 5.05 (s, 2H), 4.90 (dd, 1H), 4.56-4 39 (AB part of ABX spectrum, 2H), 4.12-4.03 (m, 3H), 3.98- (q, 1H), 3.33-3.22 (AB-spectrum, 2H), 2.85 (d, 1H), 2.65-0.94 (m, 19H) 3.91 Reference Example No. (89) 0 ton 00-0m00-ta-a-1,0(-510020077 0) EtSCOOCH,00C Ch (} ) 1 0 Ja molan TA mmol) NaOH at 0 °C was added to a solution of (16.7 g; 45.3 mmol) tetrabutylammonium . hydrogensulphate and (8 gr £1 mmol) cyclohexane carboxylic acid in chloride 016071606. After yo stirred for 0 min, the reaction mixture was filtered, washed with methylene chloride, dissolved in toluene, concentrated, and dissolved in THE to give [00©001]+30,20]. (g ¢ 5.4? mmol) added EtSCOOCHCI (see 1990), 1159 (Folkmann and Lund, J.

Synthesis to a THF solution of [BugNJHOOCCh] at room temperature. After stirring at TYA temperature

except -: the room for 71 hours; The reaction mixture was concentrated and purified by flash chromatography to give 1.00 mg (780) of the subtitle compound. H-NMR (400 MHz, CDCl;) diagnostic peaks .8.5.80 (s, 2H, O--CH, --0), 2.85 (q, 2H, ' CH; --S) CICOOCH,00CCh (Y)° A (5 g 1 mmol) SO,Cl, added at zero degrees m drop by drop to (y.9) grams; 11.8 mmol) EtSCOOCH,00CCh (from step 1(previous). After stirring for ½ min the reaction mixture was concentrated to give VAY 770 mg of the desired compound. H-NMR (500 MHz, CDCls) diagnostic peaks . 8.5.82 (s, 211, O--CH, --0) ' Boc-(R)Cgl-Aze-Pab-COOCH,O00CCh (¥)0 Said subtitle compound was prepared similarly to the procedure described in Example 1 (1) above from YOu) mg; 0.99 mmol) Boc-(R)Cgl-Aze-Pab-H 5 (£10 mg); 7.1 mmol) CICOOCH,00CCh (from step (Y) above). The crude product was purified by preparative RPLC. Yield Yoo mg (7.4) FAB-MS: (m+1) = 656 (m/z) 0 H-(R)Cgl-Aze-Pab-COOCH,00CCh x 2 TFA (5) Said sub-title compound was prepared similarly to the procedure described in Example 1 TYA

(7) the previous one from Boc-(R)Cgl-Aze-Pab-COOCH,00CCh (from the previous () step). EtOOCCH;-(R)Cgl-Aze-Pab-COOCH,O0CCh ( ) The said compound was prepared similarly to the procedure described in Example 1 (7) above from 1¥4 mg 1.75 mmol ) H-(R)Cgl-Aze-Pab-COOCH;00CCh x 2 TFA (from step 0)¢ (previous) 178 cane AT) mmol) ethyl trifluoroacetate yield AV mg (779) (t br, 1H), 7.83 (d, 2H), 7.37 (d, 2H), 5.86 (s, 250), 8.48 8. H-NMR giver (400 MHz, ' (dd) , 1H), 4.15-4.39 (AB part of ABX spectrum, 2H), 4.18-4.05 (m, 5H), 3.26-3.17 4.95 (AB-spectrum, 2H), 2.87 (d, 1H), 2.75-0.95 (m, 29H) die 1, reference No. (0) EtOOCCH,-(R)Cgl-Aze-Pab-COOCH,00CCh Then prepare the aforementioned compound in a manner similar to the procedure described in the previous example No. 4, which begins with cyclohexyl acetic acid instead of cyclohexane carboxylic acid Product yield VE mg (VY) FAB-MS: (m+1) = 656 (m/z) . \o TYA

- M (01) Reference No. Je

EtOOCCH,-(R)Cgl-Aze-Pab-COOCH (Me) OOCPh No. £9 preceding Jel and then prepare said compound in a manner similar to the procedure described in (reported from 0100011)01:(0 and 20811 using the procedure EtSCOOCH(CH;)Cl initiated by .5:50000:01 from Yau (Folkmann et al, in J. Synthesis, (1990), 1159 m annotated by {7YY) yield and no mg

FAB-MS: (m+1) = 650 (m/z) (2%) Reference Example No.

EtOOCCH,-(R)Cgl-Aze-Pab-COOCH,00CPh Then prepare the aforementioned compound in a manner similar to the procedure explained in the previous article No. 9 £1 yield of product +0 mg cyclohexane carboxylic acid instead of benzoic acid using (7 v9) } H-NMR (300 MHz, CDCls) . 8.9.73-9.25 (s br, 1H), 8.45 (t, 1H), 8.05 (d, 2H), 7.83 (d, 2H), 7.60-7.10 (m, 6H), 6.10 (s, 2H), 4.96 -4.84 (dd, 1H), 4.62-4.30 (ABX, 2H), 4.20- 3.93 (m, 4H), 3.25 (s, 2H), 2.84 (d, 1H), 2.73-2.41 (m, 2H), 2.41 -0.87 (m, 15H) yo no C-NMR (300 MHz, CDCI3, amidine and carbonyl carbons) . § 163.1, 165.3, 169.0, 170.8, 172.3, 175.5

TYA

Reference Example No. HOF) BnOOCCH,-(R)Cgl-Aze-Pab-COOCH (Me)OAc Then prepare the said compound in a manner similar to the procedure described in Example No. 1 (7) above from 171 cana 018) mH-(R)Cgl-Aze-Pab-COOCH(CH;)OC(O)CH; mmol).yield product \¢ mg) (ry 0 FAB-MS: (m+1) = 650 (m/z) Reference Example No. Hof) EtOCCH,-(R)Cgl- Aze-Pab-COOCH,0Ac H-(R)Cgl-Aze-Pab-COOCH,0Ac x 2TFA ()) \ Then prepare said subtitle compound similar to the procedure described in Example 1 above (step (1) and (7)) using ana)acetoxymethyl 4-nitrophenylcarbonate similar to the method described in JEL No. VY (*) using silver acetate instead of silver pivalate. The mixing gave The subtitle compound was used in the next step without further purification.

EtOOCCH,-(R)Cgl-Aze-Pab-COOCH,0Ac (Y) 0 Preceding (1) (7) The aforementioned compound was prepared in a manner similar to the procedure described in Example No. (1) preceding (from Step H-(R)Cgl-Aze-Pab-COOCH (CH;)OAc x 2TFA (mmol) +,AY) and (0.0 mmol) ethyl bromoacetate yielding 145 mg. TYA

FAB-MS: (m+1) = 574 (m/z) (00) Reference Example No.

EtOOCCH,-(R)Cgl-Aze-Pab-COOCH,0Ac Previous from (©) 1 The said compound was prepared similarly to the procedure described in Example No. of Example No. aa) H-(R)Cgl- Aze-Pab-COOCH (CH;)OAc x 2TFA (Use mM + YT) 0 Yield 107 mg . t-butyl bromoacetate (mmol) 76/177 mg; VT) 5 (prev) (1) (27).

FAB-MS: (1g) = 602 (m/z) (57): (Reference Example No.

BnOOCCH,-(R)Cgl-Aze-Pab-COOCH,00C-tBu 0 from (TF) 1 Said compound was prepared similarly to the procedure described in Example No.

VY (see Example No. H-(R)Cgl-Aze-Pab-COOCH,OOC-tBa mmol) 101 mg 4 ) 10476 yield benzyl bromoacetate mmol) + AC μl 01 prev) and ( )©( . 0" 0 mg FAB-MS: (m+1) = 678 (m/z) Vo

TYA

AY — _ Reference Example No. (eV) EtOCCH;-(R)Cgl-Aze-Pab-COOCH,CCls Boc-(R)Cgl-Aze-Pab-COOCH,CCl (1) ~ Then prepare the aforementioned subtitle compound similarly to the procedure described in Example No. 3 GL (1) 0 of 1 (g 7.11 mmol) Boc-(R)Cgl-Aze-Pab-H and (71 mL) Y NaOH and (554 cana 7.77 mmol) trichloroethyl chloroformate yielding 0.1 mg (74 7( Ha-(R)Cgl-Aze-Pab- COOCH,CCl; (7) The aforementioned sub-title compound was prepared similarly to the procedure described in JE No. 1 (1 (0) above from (8 0.097 cal a 0.1 mmol) Boc-(R)Cgl-Aze-Pab-COOCH,CCl (step cog) 1 (previous). 2H), 7.61 (d, 2H), 5.10 (s, 2H), 4.87-4 81 (m, 2H), 4.63-4.52 (q, 2H), 4.41-4.34 (m, 1H), 4.30-4.24 (m, 1H), 3.72 (d, 1H), 2.72 - (m, 1H), 2.32-2.25 (m, 1H), 1.88-1.10 (m, 14H) 2.63 EtOOCCH,-(R)Cgl -Aze-Pab-COOCH,CCl; (¥) Vo and then prepare the said compound in a manner similar to the procedure described in Example 1 (*) above from (£11 mg +,0Y mmol) H-(R)Cgl-Aze-Pab-COOCH, CCly (TYA

- only mg A yield yield (1.517 mM ethyl bromoacetate) (previous) (40 mg; (Y)/77) ' H-NMR (500 MHz; CDC) . 8.8 .47 (bt, 1H), 7.83 (d, 2H), 7.48 (bs, 1H), 7.31 (4 2H), 4.92 (dd, 1H), 4.85 (s, 2H), 4.58-4.39 (AB part of ABX spectrum, 2H), 4.16-4.06 (m, 4H), 3.24 (s, 2H), 4.87 (d, 1H), 2.65-2.59 (m, 1H), 2.56-2.48 (m, 1H), 2.10-0.95 ( m, 8 16H) Reference Example No. (4H):

MeOOC-C(=CEt)CH,00CCH,-(R)Cgl-Aze-Pab-Z

MeOOC-C(=CH)C(OH)E (1)

Vo) drop by drop to a solution of propionaldehyde mol) + WWE Gla 011 (0 g; 600176 mol) 0 was added and (methyl acrylate mol) IN al a

Lag VE The reaction mixture was stirred at room temperature for 55.1 4-diazobicyclo[2,2,2]octane The organic phase was washed with water and brine. ethyl acetate (a Yoo) 102 mg was added, filtered and concentrated to give the desired compound. Product yield (Na2SO4) and drying: (7 5 9 Vo "H-NMR: (400 MHz, CDCl) 8.6.24 (s, 1H), 5.81 (s, 1H), 4.34 (t, 1H), 3.78 (s, 3H), 2.82 (bs, 1H), 1.69 (m, 2H), 0.95 (t, 3H)

TYA

Ao — (?) MeOOC-C(=CEt) CH,Br aad add ) © y 1 mL; A (approximately 7) HBr drop by drop to 9 grams A and mmol) MeOOC-C(=CH)C(OH)Et (from step (1) above) at zero degree a after © Minutes (+ml) were added by 1]1.50 drop by drop. The reaction mixture was stirred for 1 hour at room temperature. Then two phases were separated and the upper phase, ether aul, was diluted. Then the ether phase NaHCO was washed; Aqueous cle dail, its drying (B011 and vegetable charcoal) and its concentration. The residue was purified by flash chromatography. Yield and mg (2 7) I H-NMR: (400 MHz, CDCI3). 8.6.97 (3H), 4.23 (s, 2H), 3.8 (s, 3H), 2.32 (m, 2H), (t, 3H) 1.13 BuOOCCH,-(R)Cgl-Aze-Pab-Z (¥) 0 The said sub-title compound was prepared similarly to the procedure described in Example 1 (7) above from ( 1 g; HOOCCH,-(R)Cgl-Aze-Pab-Z (£).

A A solution of tBuOOCCH,-(R)Cgl-Aze-Pab-Z (from previous step 0) TFA in methylene chloride was stirred at room temperature for ¥ hours. The reaction mixture was concentrated and lyophilized with HCl (01 eq.

TYA

MeOOC-C(=CEt)CH,00CCH,-(R)Cgl-Aze-Pab-Z (°) lyophilized solution of YT) mg; (+8 mmol) HOOCCH,-(R)Cgl-Aze-Pab-Z (from the previous (?) step) 0.779 eda YA) mmol) 1 M NaOH f (? (Jo water.) 2 DMF (Se) was added followed by the dropwise addition of L (1 0 mg. 9 J 0, mmol) 0 14”000-0602001108:7 (of Previous (Y) step) in zero degrees. The reaction mixture was stirred for 4 ? 1 hour at room temperature, diluted with (© toluene (Ja), washed with water, dried (118:50 M), and concentrated. The residue was purified by flash chromatography using ace:8:methanol (140 M) as a rinse liquid. Yield 0 mg (77/).FAB-MS: (m+1) = 690 (m/z) 1 Reference Example No. (09) MenOOCCH,-(R)Cgl-Aze-Pab-COOPh(4-OMe) MenOOCH,Br (V) and then prepare the aforementioned subtitle compound in a manner similar to the procedure described in Example No. 7 (1) above from (01 mmol) (VY)s Men OH mmol) bromoacetyl chloride Yield yo Yield 0 mg (70%) MenOOCCH,-(R)Cgl-Aze-Pab-COOPh(4-OMe) (Y) Said compound was prepared similarly to the procedure described in Example (F) 1 prev of YY) mg; 1 mM H-(R)Cgl-Aze-Pab-COO-Ph(4-OMe) (Use (see Example No. (Y)t+TYA)

AY —_ _ previous) 5 (£17 mg; 1.0 mM Men OOCCH:Br (Use (from step (1) above). Yield as 7 mg (72) FAB-MS: (m+1) - 718 (m/z) Reference Example No. ) 0 1( tBuOOCCH;-(R)Cgl-Aze-Pab-COOnPr 0 from (9) 1 and then prepare the said compound in a manner similar to the procedure described in Example No. (Y) © (see Example No. H-(R)Cgl-Aze-Pab-COO-nPr (mmol) + AVY (mg OVO) 011 mg yield. t-butyl bromoacetate{Js— 0.10 ms (prev) 5 (VAT) came (YY) FAB-MS: (m+1) = 572 (m/z) 11(:0) reference example No

MenOOCCH,-(R)Cgl-Aze-Pab-Z Then prepare the aforementioned compound in a manner similar to the procedure described in Example No. (*) from

Men mmol) 0.46 and (4, “g” H-(R)Cgl-Aze-Pab-Z mmol) 0.71 al a +)

AYA) (previous 177 mg). The outcome of the output (1) 09 (see Example No. 00001139 Vo

FAB-MS: (m+1) = 702 (m/z)

TYA

- YM - Reference Example No. (617): BnOOCCH-(R)Cgl-Aze-Pab-COO-Bn(4-NOy) Boc-(R)Cgl-Aze-Pab-CO0-Bn(4-NO) >) (1) Then prepare the aforementioned sub-title compound in a manner similar to the procedure described in Example No. (1) (1) above from (1.0 grams” YA mmol) (Boc-(R)Cgl- Aze-Pab-H t(? Y ml) NaOH ¥ M 5 0A (mg 1.4 mmol) -benzyl chloroformate 4-3102. Yield 0.1 FAB-MS: (m+1) = 651 (m/z) H-(R)Cgl-Aze-Pab-COO-Bn(4-NO,) (7) \Then prepare the said sub-title compound similarly to the procedure described in JE No. ¢(Y) above from (0.7 g; 7.17 mM H-(R)Cgl-Aze-Pab- COO-Bn(4-NOy) (Use (step notch) \ (previous). Yield 1 mg ( 9 7) FAB-MS: (m+1) = 551 (w/z) BnOOCCH ,-(R)Cgl-Aze-Pab-COO-Bn(4-NO,) (¥) \o Then prepare the said compound in a manner similar to the procedure described in example #1 (9) above from v0) g; 1868 mmol) H-(R)Cgl-Aze-Pab-COO-Bn(4-NOy) from the previous (Y) step and (10 mg d+ mmol) 'benzyl bromoacetate FAB-MS: (m+1) = 699 (m/z) TYA

(17): Reference Example No

EtOOCCH,-(R)Cgl-Aze-Pab-COO-Bn(4-NO,) preceded by (7) 1 of the compound mentioned in a manner similar to the procedure described in Example No. , then TY (mol) ( 52-000-3:)4-102-”g-a0 (11-08 (refer to example number hor +, VA mg YY) yield of product ;; mg ethyl bromoacetate mmol) 147 “lg Se £V) 5 ex) (1( 0 (1) A) 'H-NMR: (300 MHz; CDCl) . 5.9.55 (bs, 1H), 8.50 (bt, 1H), 8.20 (d, 2H), 7.80 (d, 2H), 7.60 (d, 2H), 7.35 (d, 2H), 6.87 (bs, 1H) , 4.95 (dd, 1H), 4.65-4.40 (AB part of

ABX spectrum, 2H), 4.18-4.04 (m, 5H), 3.27-3.15 (AB-spectrum, 2H), 2.87 (d, 1H), 2.75-2.60 (m, 1H), 2.57-2.45 (m, 1H) , 2.00-0.95 (m, 16H). 1 7 (Reference Example No

PrIC(0O)CH,O00CCH,-(R)Cgl-Aze-Pab-Z

PrIC(O)CH,OH (1( mM AY «J A) 52,5-dioxo-1,4-dioxane mM) 117 A mixture of (? g; excess lias) was returned by evaporation. pyrrolidine 1 h removed sad pyrrolidine mol) Veo (799) Yield;.? mg

FAB-MS: (m+1) = 130 (m/z) aka

—- a. - PrlC(O)CH,00CCH,Br (7) added (+17g); (YY mmol) bromoacetyl bromide dropwise at zero degrees to a solution of (0% 7.1 plo) PriC(O)CH,0H (previous step (1) in ) 0 DMF (Je) The reaction mixture was stirred for 0.1 h at zero degrees and for °?* h at Aa room temperature. Canal add) 9 grams; mmol) additional bromoacetyl bromide and the reaction mixture was heated to a Avda and stirred at . (7 1) mg YY. hour and focus. The yield of the product is 11 room temperature for a period of time

FAB-MS: (m+1) = 252 (/2)

PriC(0)CH,O0CCH,-(R)Cgl-Aze-Pab-Z (previous 9 of (No. 1 9 JE) and then prepare the said compound similarly to the procedure described in 0.mMol) 117 cana V+ +) 5 H-(R)Cgl-Aze-Pab-Z mol) la V mg; OAL) (71 0 ) ) 1i (from step ( ) ( previous). Output yield in mg 0 (0211:0007

H-NMR. (500MHz; CDCI3). 8.9.66-9.42 (bs, 1H), 8.64-8.56 (m, 1H), 8.03-7.93 (d, 2H), 7.89-7.66 (bs, 1H), 7.45 (d, 2H), 7.45-7.25 (m , SH), 5.20 (s, 2H), 4.98-4.92 (dd, 1H), 4.82-4.74 (m, 1H), 4.62, 4.58 (AB spectrum, 2H), 4.26-4.05 (m, 3H), -3.47 3.16 (m, Vo 6H), 2.95 (d, 1H), 2.78-2.68 (m, 1H), 2.54-2.42 (m, 1H), 2.03-1.95 (m, 16H)

TYA

(16): Reference No. Jie (2-Me)BnOOCCH,-(R)Cgl-Aze-Pab-COO-Bn(4-NOy)

Oe prior (©) 1 The said compound was prepared similarly to the procedure described in Example 1” (see Example H-(R)Cgl-Aze-Pab-COO-Bn(4-NO,) mmol) +, A+ mg 001) (see previous example 2-(methyl)benzyl bromoacetate) and (; 77 mg; 373 mmol) (Y) © (73%) mg OYA ex). Result of Output (1) ©"

I H-NMR (400MHz, CDCI3) . 5.9.34 (bs, 1H), 8.38 (t, 1H), 8.09 (d, 2H), 7.72 (d, 0 748 (d, 2H), 7.37 (bs, 1H), 7.23 (d, 2H), 7.17 -7.05 (m, 4H), 5.18 (s, 2H), 5.00 (s, 25D), 4.81 (dd, 1H), 4.45-4.34 (AB part of ABX spectrum, 2H), 4.04-3.97 (q, 1H) , 3.93-3.86 (q, 1H), 3.27-3.17 (AB spectrum, 2H), 2.79 (d, 1H), 2.54-2.35 (m, 2H), 2.22 (s, 3H), \ 1.91-1.84 (bd, 1H),1.71-1.39 (m, SH),1.19-0.84 (m, 4H).(1) Reference Example No.

MeOOCCH;-(R)Cgl-Aze-Pab-COO-Et Preceding (9) 1 shown in Example J 3 The said compound was prepared in a manner similar to the procedure

(VY) (Y) 4 (see example Hy-(R)Cgl-Aze-Pab-COO-Et mmol) 14 (aaa Yeo) 0 (457) 0 mg 1848 yield methyl bromoacetate (mmol) VAY cana

LC-MS: (m+1) = 516 (m/z)

TYA

Y _ 9 _ Example Reference No. (TV) (nPr),NC(0)CH,00CCH,-(R)Cgl-Aze-Pab-COO-Bn(4-NO,) (nPr ),NC(O)CH,00CCH,C! (1) A mixture of YEE) combined with 0.97 mM (0Pr)NC(O)CHOH (J se) was stirred (see Example No. VY (1) (oo above) and (177) (1.77 cane mmol) bromacetyl chloride at room temperature for VY h. The mixture was poured into aqueous NaHCO and extracted by -methylene chloride. The organic phase was washed with Y,121150. ,+m) aqueous, brine, and drying vo pS fis FAB-MS: (m+1)=237(m/z) H-NMR: (400 MHz, CDCL;) 584.82 (s, 2H), 4.22 (s, 2H), 3.31-3.26 (t, 2H), 3.10-3.15 ' (t, 2H), 1.68-1.52 (m, 2H), 1.97-0.86 (m, 6H) 1 (nPr );NC(O)CH,O00CCH,~(R)Cgl-Aze-Pab-COO-Bn(4-NO,) (¥) The said compound was prepared similarly to the procedure described in Example 1 (1) prev of 1317 cane YET (mmol) H-(R)Cgl-Aze-Pab-COO-Bn(4-NOy) (see Ex. 11 (Y) prev) 111) 5 gama 148 mmol) (MPr)NC(O)CH00CCHCL (from step (1(\o) above). Yield as mg 7 FAB-MS: (m+1) = 750 (n/z)a

ay - - Reference Example No. (TA) (2-Me)BnOOCCH,-(R)Cgl-Aze-Pab-COOCH;00C tBu Said compound was prepared similarly to the procedure described in Example 1 (©) from PAV) mg; 1/17 mmol) H-(R)Cgl-Aze-Pab-COOCH,00CtBu (see alt. VY (0(0) above) YV0)5 mg; AN + mmol) 2-(methyl)benzyl bromoacetate (see JU) No. 1 (?) (previous). Yield YY mg (77.5). FAB-MS: (m+1) = 692 (m/z) Example No. ) 3 3 All compounds of Examples 1 to TA were tested in the previous A test and all of them showed a TCsoTT value of 0 more than 1 micromolar uM (meaning it was ineffective by itself for thrombin by comparison with the active inhibitor HOOC-CH,-(R)Cgl-Aze-Pab-H which showed ICsTT of 0.00 μM (muM JY se Example No. ((v 0): Compounds of Examples 1 to 68 were tested in one, two, or all of the previous b-ve and/or d tests; all showed bioavailability by Oral and/or non-intestinal route in mouse when the active inhibitor (HOOC-CH,-Cgl-Aze-Pab-H) was either as free acid and/or as one or more more ester Based on the fact that HOOC-CH,-(R)Cgl-Aze-Pab-H is formed in Ql the bioavailability was calculated according to the formula described in b-test and/or h-test according to mode.

C4 - List of abbreviations: [weit] um hams aaa butyl = Bu cyclohexylglycine = color aaa er ©

DCC

DMAP ae ban | mon]

IE ka I 4-aminomethyl-1-(N-benzyloxycarbonylamidino) = me Me (amino-hydroxyiminomethyl) benzene meee ka

The prefixes Sgn and 1 have their usual meanings: normal, iso, binary, and thirty. The prefixes in the dss NMR spectrum mean and; and by singular; binary; trio; quadruple; and wide, respectively. The spatial distribution of amino acids is (S) if not otherwise stated. TYA

Claims (1)

an — - claims 1 - 1 is a compound of the formula ([); Y m R'O(0)C-CHy-(R)Cgl-Aze-Pab-R> 7 where: ¢ N —A'C(O)OR* J —A'C(ONRHR ® J — R® La © Akh representing an alkylene of R?4 (which replaces (saa) hydrogen atoms in the amidino unit of Pab-H (Pab-H) representing JOH 7 As a square. A ¢ (halogen 4R* 11) let each separately represent alkyl J H M A phenyl » that is, naphthyl - 2; VY or where it stands for a group —A'C(ONRYHR ® with the nitrogen atom to which their VY bonds ¢piperdi 0 pyrrolidinyl (Maw 0 kJ represents alkyl d', phenyl ¢, or naphthyl-2 (can be in any of these Yo optionally substituted by (halogen Cr alkyl ¢ 1 : or an acceptable salt thereof; where Aze «cyclohexyglycine Cgl Jad is represented .1-amidino-4-aminomethylbenzene Ji Pab 5 S-azetidine-2-carboxylic acid VY 1 7- Compound of formula (); Pursuant to claim (1), where Cis did not represent alkylene Y when H represented A'C(ONRHR® - TYA). _av — \ ¥ - is a compound of formula (1) lig of claims No. (1) or (7); where lig is Y representing H, i.e. Crgalkyl, when for A'CONRHR® Jac -. 1; - A compound of formula (I) according to any of the claims from No. (1) to No. (Y)” where th is an alkyl of any Cy cycloalkyl where v is a form of no cycloalkyl -. 1 0 is a compound of formula (I) according to any of the claims number (1) through number Y (7) where RY and p are both pyrrolidinyl where R' is A'COINRHR® 1 1 - a compound of formula (1); According to any of the claims from No. (7) to No. Y (6) where AM represents alkylene once and RY represents H r alkyl of Crs Cs cycloalkyl of alkyl v or sR?na both represent pyrrolidinyl \" - a compound of formula (1); according to claim (1); where Ay is a cis alkylene Y and R! is A'C(O)OR* -. RY where oY) or number (1) is a compound of formula (1); according to the two claims - A 1 - A'C(0)OR* is R' when Cig alkyl stands for Y A where oA) or a composite number (Y) of formula (1); According to claim No. 4 1 Craalkyl is R* when Cys alkylene is Y TYA ap - - 1 01 - is a compound of formula (1); Uy of claim (1); where 83 represents 11 and Cry alkyl Y | (this last group can be straight; or where there are a sufficient number of carbon atoms; it can be branched and/ or partially cyclic or cyclic) ¢ or Cis alkylphenyl (the latter group may have an optional substitution; 2 may be straight; or - where there are sufficient numbers of carbon atoms 1 - may be branched); Whereas for RJ 1 \ - compound according to Claims No. (1) or No. (10) where JH Jar! Cryo alkyl 7 is a straight alkyl of . and branched; or Cup alkyl Partially cyclic or Cypalkyl v cyclic; that is, straight Cs alkylphenyl optionally substituted; or a branched alkylphenyl ¢ optionally substituted. straight; Y or alkylphenyl 5) » Coo cycloalkyl © straight has an optional substitution. 1 1 - compound of formula oT) according to any of the claims No. (1) through No. Y (9) where 182 represents OH 1100 1 - compound of formula (); in accordance with For any of the claims No. (1) through No. R® dus (VY) Y denotes phenyl has an optional substitution or an alkyl © (and this last group Y can be straight or - where there is Sufficient number of carbon atoms - can be branched, cyclic or partially cyclic Sai a 050 fs ° unsaturated) when R? represents 00220(87 .YA 1 1 - Compound according to Claim No. (R® Cua ¢ ) 0 represents phenyl with “Ah the Y optional” or straight Cpqalkyl; i.e. branched Cig alkyl or cis-oleyl 1 1 - Compound according to claim No. (Yo) ', where R® represents straight Cia alkyl or branched Cy alkyl Y. 117 1 - Compound according to any of the claims of No. (1) to No. (11) or from No. (1) 7 to No. (V7) where when c represents and 3 Cis alkylphenyl Ji has Jan v optional, the optional substituent group is alkyl ring VA \ - compound according to claim number (VY) where the substituent group is a placebo .methyl Y 1 4 - compound according to claim (1), wherein it is Me OOCCH; - (R) Cgl - Aze - Pab - OOCPh Y and (nPr); NCO CH, OOCCH, ~ (R) Cgl - Aze — Pab - OH v and ChN HCOCH,00CCH, — (R ) Cgl - Aze — Pab — OH ¢ and (R) Cgl - Aze — Pab — OAc © - 210000 and HOOCCH; —(R) Cgl - Aze — Pab — O — cis ~ Oleyl 1 and 1 0 - compound according to claim (1), where EtOOCCH; — (R) Cgl - Aze — Pab - OAc TYA — a “1 \ - is a composite of formula (1) pursuant to claim (1) taking into account Y the additional conditions that AICOOR! Jaa YR and SRY is not an id separately — 'H' and that mg does not represent C 1-17 alkyl ¢ when R? represents .OC(O)R® ¢ YY \ = Composite of formula (1) according to protection radius 1 where RY is —A'C(O)OR Y and 8 and p are - all over Acuity - ¢H and Crp alkyl Jaa RS v when .OC(OR® R? YY 1 - Pharmaceutical formulation comprising a compound of 3-terminated fish in an adjuvant mixture Pharmaceutically acceptable ¢ carrier, adjuvant, diluent, TE 1 - compound of formula (1) according to any of Claims No. (1) to (TY) 7 or A pharmaceutically acceptable salt thereof for use as a fishing compound. Ala treatment requiring a thrombin inhibition 1\- compound of Formula (I) as defined in any of Claims No. (1) Y through (77); or a pharmaceutically acceptable salt thereof for use in YA treatment — \ 0 \ —_— v coagulation. YY 1 - A compound of formula (1) according to any of Claims No. (1) to (YY)Y or a pharmaceutically acceptable die salt for use as an anticoagulant. TA 1 - Use of a compound of formula (1) Ts of any of the claims No. (1) l to (77); or a pharmaceutically acceptable salt thereof for use as an active ingredient in the manufacture of drug 7 for the treatment of a condition requiring thrombin skimming 1 4 - Said use according to claim No. (A) ¥ (¢ wherein the condition is Y coagulation. 1 © - Compound use of formula (1) according to any of claims No. (1) ¥ to (Y Y) ( ¢ or a fishable salt thereof for use as an active ingredient in the manufacture of v anti-coagulant. ©1 1 - the use mentioned in claim no. (TA) where the case is Y highly coagulable Hypercoagulability in blood and tissues TY 1 - use of the compound of formula (1) according to any of Claims No. Y (1) as a prodrug. YY 1 — process for preparing the compound of formula (I) comprising on the following: ENE Y (a) for compounds of formula (1) in which R? is 011; the reaction of the corresponding compound ¥ of formula (I) where R? is R® 5 OC(OR®) as defined in claim ¢ no. (1) with alkoxide base ¢© (b) for compounds of formula (I) in which R? is 011; a compound reaction corresponds to , compound of formula (1) where R? is C(O)OR" 5 is for naphthyl - 2 ", phenyl " 7 and Cys alkylphenyl (these last three groups can have an optionally substituted A for the alkoxy ¢ Crs alkyl of Any nitro a (halogen) ie Crp alkyl q (and this last group can have an optional substitution with Crs alkoxy 5 ¢ acyloxy Ve rin) halogen with hydroxylamine or salt Addition of an acid therefrom. 1) with a compound of formula (TIT) Ve whose formula is R'O(0)C-CH,-L!Vo where GL! is a leaving group and RY of claim No. (1 ); alkylphenyl § from and R? YA stands for 011 with base; 4 | (e) For compounds of formula (1) in which ©! is OCO(R®) and WSR' is Yo defined in claim (1); corresponding compound reaction of formula (1) where 82 1 represents OH with a compound of formula (IV) R°C (0) - 0 ~C(O) R® (Iv) YY YY or a compound of formula (V) R ® C (0) Hal 7) Y¢ TYA - tuberculosis - Yo where Bro Cl Ji Hal and in both cases; RE is pursuant to claim 0 (1); oo TV (and) for compounds of Formula 1 where Lee Jad C Rath R 5 OCOR' Jaa YA pursuant to claim No. (1); reaction of a corresponding compound of Formula (VI) (0)CCH; - (R)Cgl - Aze - Pab - R* (V1) Yq 210 Ye, where A is a protective group that is an unstable acid ester; and RY is © 00088 where “20 of claim (1); with acid; YY (g) for compounds of formula (1) where RY is RP and alkyl BR?, d or YY is very high:© and 82 “OH” represents transesterification of the corresponding compound of formula (VID ) Y¢ R'*0(0)C-CH,-(R)Cgl-Aze-Pab-R> (VID) ve n where R™ is an alkyl group and d is Ci alkylphenyl other than that b formed or a substituent group is a non-localized alkyl and R? represents . Oh