TW200400187A - Peptidic thrombin inhibitor compound - Google Patents

Abstract

The present invention relates to a novel thrombin inhibitor compound which has a good inhibitory effect against thrombosis and can be orally administered, a process for preparing the same, and to a composition for the therapeutic and/or prophylactic treatment of various diseases associated with thrombin inhibition mechanism, which comprises the same as an active ingredient.

Description

2 * 00400187 Body *, description of the invention: [Technical field to which the invention belongs] The present invention relates to a new type of thrombin inhibitory thrombin shown in the following formula n. Solvents and 1-structures, the compound has a good inhibitory effect on blood formation and can be administered orally to blood circulation # and different administration:

，, where 'A represents-CHCOP1 -μ., 2co2R, where R1 represents hydrogen, κ c3 CrW carboxyl group, (^ c "aryl group, or aryl group B Table" H, OH, R2, 0R2 〇C (0) H2, 〇 (:( 〇) ΝΗιιΓ, 〇C (〇) 〇R / C (°) 〇R2 ^ C (〇) R2, C (0) NHR2. C (〇) NR2 .〇 P (〇) (〇R.2, or C (0) 〇 (CHR, mOC (0) R5, where • R] & B are not hydrogen at the same time, and $ R independently represent nitro; or Represents an unsubstituted or substituted C: -C6_alkyl group substituted by a group consisting of a sulfonyl group and a methoxy group; or (cHdrC ^ Cr cycloalkyl, (CH2 v heteroaryl) Or (CH2) n-heterocyclic (n = 0,1,2,3) (heteroaromatic or heterocyclic in 苴 means having one or two members selected from the group consisting of nitrogen, oxygen and sulfur Atomic 5 or 6 Lu: rs, · _4 ·, Shi Yizheng-Beizhan), or it is unsubstituted or substituted by a group selected from halogen, radical and C] -C6-alkoxy Group is substituted by benzene group which is substituted by at most; or table * c5-c, j group must be '_alkyl group, C5_Ci0_aryl group, or 92374 6 200400187 alkyl-n (r4) 2, m represents 1, 2, 3 Or an integer of 4, R. Non-hydrogen or C] -C6-alkyl, and R4 represents hydrogen or C] -C3-alkyl. The present invention also relates to a composition for the preparation of a compound as defined in the formula (1) previously containing formula ( 1) The compound is used as an active ingredient for the treatment and / or prevention of various diseases related to the mechanism of thrombin inhibition, and a method of treatment of the compound of formula G). [Prior art] Only known / a series of complex enzymatic reactions The final step in this series of reactions is the conversion of prothrombin to active thrombin. So produced; spinal blood glutamidine, and non 1 \ / », vitamin egg-,: small plate, and fibrin The conversion of protofibrin into fibrin also spontaneously polymerizes into fibrin polymerization ", and the thrombin can activate factor XIII, which results in the crosslinking of the factor factor into insoluble fibrin. In addition, thrombin can Activation should be advanced. Factor ν and factor Xm to promote anticoagulant anticoagulants ::: Thrombin inhibitors can be expected to be effective anticoagulant release 5 S by inhibiting clusters of platelets and fibrin Formation and prevention of ... Yue Yusu is currently the most commonly used sex system 钬 ^ The anti-hemolytic agent used in the above, the activity of heparin is determined by people with antithrombin. B § 之 、、、 ° 5 And the mechanism that indirectly inhibits thrombin has a low effect on the inhibition of arterial thrombosis, and it has some points. In addition, the low stability requires careful observation during the treatment of patients. The lack of resistance is the most commonly used oral preparation. Coagulant 92374 7 200400187 Coumarin is an antagonist of vitamin κ-dependent serine proteases. However, the 'fragrant ingredient' has the disadvantages that it becomes effective within a specific period (from 6 hours to, hours) from the start of administration, and it also requires careful observation due to undesired < rq blood. Those who do not care, generally emphasize the use of low molecular weight thrombin inhibitors as therapeutic agents to inhibit thrombosis, and many studies have been conducted (US Patent No. 4 / 58,192 ^; US Patent No. 4; Bi⑽emistryl984 23 pp. 85-90; J. Med. Chem. 1990, 33, p. 1 729 'Ch.CUlatión 1994' 90, p. Plus-page; WO 93/11152, WO 94 / 29336; J. Med. Chem. 1997, 40, p. 1565). In addition, WO / 3/3124 has disclosed a thrombin inhibitor for a new investigator. The thrombin inhibitor can be administered orally, and when administered orally, it will be absorbed into the blood at a conventional concentration. During the continuous study of the thrombin inhibitors disclosed in WO 00/39124, however, the inventors found that when the drug was administered orally, the inhibitors showed high absorption and therapeutic effects before food intake, But in the photo: After that, the bioavailability is greatly reduced. Therefore, the present inventors have conducted a rigorous research to improve and improve Pw v. This question has been asked, and Asia has developed an effective prodrug that is not disclosed in WO 00/39124, and then completed the present invention. & • It has also been confirmed today that the prodrug of the present invention contributes to the increase in bioavailability described in US Patent No. :: 965,692. That is to say, in the experiments on the dog's physical dynamics V and trypsin inhibition, when the parent drug of 2000/39 j was lucky, the prodrug of the present invention showed a similar biological benefit 92374 8 200400187, However, trypsin inhibitory activity is low and pancreatic enzyme I is inhibited. Because of the effect of the present invention, the enzyme a shows the effect of Xiudongbai enzyme, so it is oralized. Degradation of the substance can reduce the possible side-sense leukoenzyme caused by the inhibition of gastric and active thrombin inhibition, including π leukase or other serine acids. The prodrug form, the prodrug itself and : 2: The compound of Ming is active in the body after the administration of the anterior vein, but it is administered orally or as a tranquilizer. Therefore, the formation of active thrombin inhibition can reduce the difference between individuals or within individuals, in order to solve the difficulty in determining the plasma concentration from too high (bleeding) to too: the interval between physical time, and reduce side effects. ::: "Treatment of blood", "Inventive content" " Zha $. The purpose of the present invention is to provide a pharmacologically acceptable practice, water infusion, compounds not shown in the following formula, and its medicine. ,, , ° / cereal compound, and isomers, the compound 'branch formation has a good inhibition 纟 w 丨 Shuangduai and can be administered orally ...

In the formula, ^ represents -CH2C〇2R], where】] represents hydrogen, CV (V alkyl c3-cv phosphinyl, aryl · CrC6_alkyl, or C5_c "aryl B represents Η, 〇H, R2 , 0R2, 0c (〇) R2, 0 (: ⑼nhr2, 0C (〇) 〇R, C (0) 0R2, c (0) R2, C (0) NHR2, C (0) NR22, 0P ( 〇) (〇R:) 2, or C (0) 〇 (CHR4) mOC (〇) R5, wherein R1 and B are not hydrogen at the same time, and R and R5 independently represent nitro; or represent unsubstituted Or the substituents of the group formed by the hydroxyl group and κγ alkoxy group of the 9 92374 200400187 plant & this > ^ ^ From the stone group 11 1, the substituents of the group formed by the pore hole m are taken as a! 〇 > rp ^ (CH, ^ r 6 ^ member group; or (CH2) n-C3-CV cycloalkyl group, or a heterocyclic ^ group, or (CH2) n · heterocycle (n = G, 1 , 2, 3) (where the heteroaryl atom di 糸 refers to a hetero and c Γ5 & 6 shells having one or two groups selected from t, oxygen, and sulfur); or unsubstituted or selected Mono-to-mostly substituted benzene lanes from halogen, substituents of the group formed by the group λ · alkoxy, or C r alkynyl-N (R4) 2: square 1 aryl, aryl, or C Plant C6- m indicates 1 Integer of 2, 3 or 4, ^ represents hydrogen or alkyl, and R4 represents hydrogen or cvcv alkyl. Used in the definition of Γ !? Where is the definition of the substituent of a compound, when it is alone, such as alkoxy? " The "alkyl" together in the compound word refers to a straight or branched chain of isobutyl, and the ^^ group contains, for example, fluorenyl, ethyl, isopropyl, " " butyl and carbon number may be To the extent that anyone skilled in the art related to the present invention can expect.

′ in σ preferably includes A in the formula.-CH2C〇? R], R1 in J1 — One of R represents mouse or c, -c6_alkyl. In the chemical formula ^ ^ ^ of the formula (1) of the present invention, it is also preferable that the formula B includes H, OH, C (0) 〇r2, 〇c (〇) r2, c (〇) r2 r2 ′: Howling: 〇P (Q) (⑽) 2, or c (〇) 〇 (cHR4) m〇c (〇) R5, where R2 and R5 are independent from each other + go to the surface Substituted or substituted by a substituent selected from the group consisting of halogen, hydroxyl, and cvclenyloxy group, mono-substituted at most 3,7-membered group, (cha · heteroaryl, 92374) 0 200400187 or (CH2) n-heterocycle (n20,!, 2, 3) (where heteroaryl or heterocycle refers to a 6-membered ring with one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur ); Or represents unsubstituted or mono-substituted polyphenyl groups substituted by a substituent selected from the group consisting of halogen and alkoxy; or represents c ^ c] G_aryl-CVCV alkyl or C "C6- Alkyl · N (R4) 2, m represents an integer of i, 2, 3, or 4, R3 represents a C] -CV alkyl group, and R4 represents hydrogen or a ^ ... alkyl group. Particularly preferred include A in the formula Represents -CH / O #], where R] represents hydrogen, ethyl, or third butyl, and B represents H, oH, c (〇) 〇R2, oc (⑺r2, _ C (〇) R2, C ( ) NHR2, C (〇) NR22, OP (〇) (〇R3) 2, or c (〇) c) (CHR4) m0C (0) R5, wherein R2 and R5 independently represent fluorenyl, ethyl, iso Propyl, isobutyl, third butyl, or neopentyl, each of which is unsubstituted or substituted with a single substituent or multiple substituents selected from the group consisting of fluoro, chloro, hydroxy, and methoxy; Or represents (CH2) n-CVcv cycloalkyl (n = 〇, 1, 2, 3), imidazole, ((^^ morpholine, or cH2 • pyridine); or represents unsubstituted or selected from fluoro and The substituents of the group formed by methoxy are single substituted to most substituted phenyl groups; or phenylfluorenyl or-(ChVN (CHA, ⑴ represents an integer of 1, 2, 3, or 4, R3 represents an ethyl group, and R4 Representing hydrogen or a fluorenyl group. Typical examples of the compound represented by formula (1) of the present invention include the following formulas:

Et〇2CCH ^ D ^ pa-Pr〇-NH-CH2> 5 ^ (2-amd) -thioph. OH; H02CCH2 ^. Dpa.Pr〇.NH.CH ^ 5 ^ (2 amd) thi〇ph 〇H ; Et02CCH2 t) -Dpa-Pro-NH-CH2-5- (2-amd) -thioph; π 92374 200400187

Et02CCH2> D-Dpa-Pro-NH-CH2-5 ^ (2-amd) -thioph-C (0) 〇CH2CC13; H02CCH2-D-Dpa-Pro-NH-CH2-5 ~ (2-amd) -thioph -C (0) 〇CH2CC] 3; / Bu02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2CC13; / Bu02CCH2-D-Dpa-Pro-NH -CH2-5- (2-amd) > thioph-C (0) 〇CH2CH3;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2CH3; H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph -C (0) 〇CH2CH3; H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCH2Ph;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCH2Ph; H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph- C (0) OCH2 / Pr;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCH2 / Pr; / Bu02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCH2 / Pr; H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph ~ C (0) 0CH (CH3) 0C (0) CH3;] 2 92374 200400187

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 0CH (CH3) 0C (0) CH3; iBu02CCH2 ^ D-Dpa-Pro-NH-CH2-5 > (2-amd) -thioph-C (0) 0CH (CH3) 0C (0) CH3; H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCH2CH2OCH3;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCH2CH2OCH3; (H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph -C (0) OPh-4-F;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OPh-4-F;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-OC (〇) CH3; H02CCH2-D-Dpa-Pro-NH-CH2-5- (2 > amd) -thioph- C (0) 〇CH2CF3;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2CF3;

Et02CCH2-D-Dpa-Pro-NH-CH2-5 ~ (2-amd) -thioph-C (0) OPh-4-OCH3; H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd ) -thioph-C (0) 〇CH2CH2F;

Et02CCH2 > D > Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2CH2F;] 3 92374 200400187

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2〇C (〇) CH3; H02CCH2-D-Dpa-Pro-NH-CH2-5- ( 2-amd) -thioph-C (0) 〇CH2Cyh;

Et02CCH2-D-Dpa-Pro-NH-CH2-5 ~ (2-amd) -thioph-C (0) 〇CH2Cyh; H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph -C (0) OCH2CH2Cyh;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCH2CH2Cyh;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) -1 m i d e;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCH2CH2-Mor;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2-3-Pyr;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) NHCH2CH2OH;

Et〇2CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (〇) N (CH2CH2OH) 2;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2CH2N (CH3) 2;

Et02CCH2-D-Dpa-Pro-NH ^ CH2-5- (2-amd) -thioph-C (0) OCH2Cypr;] 4 92374 200400187

Et02CCH2-D-Dpa-Pro-NH-CH2 > 5- (2-amd) -thioph-C (0) OCH2Cypen;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) CH2iBu;

Et〇2CCH2_D-Dpa-Pi, o-NH-CH2,5- (2-amd) -thioph-C (〇) OCyh;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2Cyb;

Et02CCH2-D-Dpa-Pro-NH > CH2-5- (2-amd) -thioph-C (0) CH3;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) CH2CH3;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) / Pr;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-OC (O) zPr;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-OC (0) CH2CH3;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph > OC (Ο) ίΒυ;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-OP (0) (〇CH2CH3) 2; and

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2 * -amd) -thioph-C (0) NHCH2 / Pr. ] 5 92374 200400187 The particularly preferred compounds in the above typical examples include the following formulas: Et02CCH2-D-Dpa-Pro-NH-CH2-5 ^ (2-amd) -thioph-OH;

Et02CCH2-D ^ Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCH2 / Pr;

Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) ^ thioph-OC (〇) CH3;

Et02CCH2 »D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCH2Cyh;

Et02CCH2-D ^ pa-Pr〇.NH.CH2.5- (2 ^ amd) ^ thioph.C (0) 〇CH2CH2Cyh;

Et02CCH2-D-Dpa-Pr0.NH-CH2-5- (2-amd) .thioph-C (0) 0CH2-3-Pyr; and

Et02CCH2-D-Dpa-PrO-NH-CH2-5- (2-amd) -thioph-C (0) CH3. The compound represented by the formula (1) of the present invention may also form a pharmaceutically acceptable salt. The salts include non-toxic acid addition salts containing pharmaceutically acceptable anions, such as salts of inorganic acids (such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydroxamic acid, hydroiodic acid, etc.); organic carboxylic acids (such as tartaric acid, Formic acid, citric acid, acetic acid, chloroethyimonofluoroacetic acid, gluconic acid, phenylacetic acid, lactic acid, fumaric acid, jlaic acid) salts, or sulfonic acids (such as sulfonic acid, benzenesulfonic acid, p-toluene) Sulfonic acid, cylic acid, etc.) salt. In addition, the compound represented by the formula (1) can also be prepared, and its characteristics are: 92374 16 200400187 (a) the compound represented by the following formula (2):

(2) (In the formula, B has the same definition as above, and P represents an amine protecting group, preferably a third butoxycarbonyl group (boc)) is reacted with HC1 gas in a solvent to obtain the following formula (3) Shown compounds:

(Wherein B is as defined above), and then the compound represented by the formula (3) thus obtained is reacted with the compound represented by the following formula (4) in a solvent in the presence of a base and a catalyst: AL (4 ) (Wherein A is as defined above, and L represents a leaving group, preferably halogen) to obtain a compound represented by formula (1), or a compound represented by the following formula (la) or (lb):

(In the formula, the definition of A is the same as the foregoing). It is reacted with a carbonate, an acid in the presence of a base, 7 92374 200400187 anhydride, or a halide in a solvent to obtain a compound represented by the following formula (〗 c):

, N—B * 0 U ^ do) In the formula, 'B' represents B other than Η and OH, and B has an alkyl group or an alcohol group. Therefore, another object of the present invention is to provide a method for preparing a compound represented by the above formula (丨). As for preferable examples of the base and the catalyst in the above-mentioned (a) method, diisopropylethylamine (DIPEA) and sodium iodide (Nal) can be listed, respectively, and dichloromethane can be cited as a solvent. After the reaction is completed, a quencher, such as hexamine, which is preferably hexamine, may be added to the reaction solution to remove unreacted reactants, thereby suppressing the introduction of two A groups into the amine. Side reaction. The carbonate, anhydride, or halide in which the B 'group is introduced into the compound of formula (la) or not may be in the form of XB, ^., V ± B, RoCoB', or XCOB '(where X Represents halogen, after the formation of the halogen group, § cross gf A ^ element group), and the substitution reaction completes the anhydride or ester group removal. A specific example of the above method is shown in the following reaction schemes 1 and 2 of which are used in the following reaction schemes and fields: TEA: Triethylamine. MDC: Dichloromethane DIPEA · Diisopropylethylamine hexamine: Hexafluoride f 92374 18 200400187 [Preparation method 1] Compound (9) and compound (10) can be described in accordance with WO 00/391 24 Method to prepare. Next, the compound (1G) may be N-alkylated with various reactants and then reacted with hydroxylamine to obtain, for example, an amidoxime compound of the compound (12). The compound (1 2) itself can be a prodrug, and can also be used as a raw material for preparing other thirsts. That is, the compound (1) can be subjected to various alkylation or deuteration reactions to obtain the compound (13). In another case, the amidoxime of the compound (12) can be converted into arsine, and the arsine can be alkylated or tritiated to obtain the compound (15). In addition, the protecting group of the compound (14) can be removed by using HC1 gas, and the obtained compound (6) can be alkylated or tritiated to obtain the compound (17). The alkyl (R) and B,), carbonates, acid anhydrides (mixed acid anhydrides) and the like described herein will be more specifically described in the following examples. In the following reaction scheme, 'B' X refers to an alkyl group or a donyl halide ', and an alkyl group refers to a fluorenyl, ethyl, isopropyl, isobutyl, And the third butyl. ] 9 92374 200400187 Reaction Flowchart 1

phyplV ^

l-ch3-co2-r 'diisodiylethylamine in R, 〇2C CN hexamethylenetetramine * 3 monodansidine-], 5-fluorenediamine (monodansvl cadaverive ^

14 6Ν · enamel

[Preparation method 2] The compound (9) obtained by the production method 1 is reacted with hydroxylamine to obtain an amidoxime compound, the compound (18), and then the compound is alkylated or halogenated by various methods to obtain the compound ( 1 9). Then, remove the protective group (Boc) of the amine group (the protective group can be removed by conventional methods, such as reaction with HC1 gas, hydrogenation reaction, or reaction using trifluoroacetic acid (TFA)), and then This amine compound can be alkylated or tritiated to obtain compound (1 3). 20 92374 200400187 Reaction Scheme_Figure 2-Ethylamine / ethanol

Hydroxylamine 1 鲅 9 ~ ΓΓ ~~~ ^^ -N-〇H Carbonate, acid anhydride or halide etc. Organic; Capacitor / Alkali

1. Hydrochloric acid in monodansamidine 1,5-pentanediamine 13 Zaoran brewing 1,5-ammonium diamine The compound represented by formula (I) obtained by the method of the present invention can be converted into a salt thereof. After completion of the reaction ', the product can be isolated and purified using a work-up method such as chromatography, recrystallization and the like. :, "The compound system of the present invention" A & clothing method is not limited to the above, but can be easily combined with various synthetic methods described in this article For 屮 g., Out & select. Those skilled in the art can easily make this combination. In the above-mentioned wound of the present invention. However, it should be understood that these are more specifically described in the following examples [Medicine use] e 1 is not intended to limit the scope of the present invention. Since the compound of the present invention can be replaced by a pharmacologically active personal towel, it can be formed with the compound of the present invention. The compound of the present invention is not very useful for coagulation. It is formed by metabolism. However, the examples can be carried out in the body. ° ... Helicase inhibitors' such as the following experimentally demonstrated that the compounds of the present invention have no activity on 4-body, but show the following 92374 2] 200400187 Assayed in Scenario 1 ^ > > 7, 疋 1 β m or the coagulation time of the ancient enzyme (TJ1.4 L river spoon I (^ 50 (50% inhibitory concentration) coagulation v)) Thus, the compound of the invention becomes useful in two φ 4 ...: : It is necessary to inhibit the side effects such as glutamate in the state of thrombin. And this inhibition is related to the inhibitory mechanism of gastrointestinal bleeding, digestive diseases, and other active ingredients, and the composition includes

Compounds not included in the knife formula (). More specifically, the present invention of Sun Guhan 41 shows "'Related-a kind of treatment and / or preventive treatment package 3 human gravity matter blood and slaughter dagger composition.' a π ”drink your thromboembolic disease ... resistance phenomena, such as factor v_ mutations, and congenital or antithrombin II, protein C 'protein S, heparin cofactor„ No :: other known and hypercoagulable Symptoms related to thromboembolic disease, including circulating antiphospholipid antibodies (lupus anticoagulation factor), homocysteineemia, heparin-induced thrombocytopenia, and defects in fibrinolysis. Therefore, the compounds of the present invention are useful for treating and / or preventing these symptoms. The compounds of the present invention can be further used to treat symptoms such as an undesired excess of thrombin without symptoms of southern coagulation status, such as neurodegenerative diseases (e.g., Alzheimer's disease). Specific diseases that can be mentioned include venous thrombosis, pulmonary embolism, arterial thrombosis (such as myocardial infarction, unstable angina, stroke-based stroke, and peripheral arterial embolism), and usually arterial fibrosis Systemic examination of the left ventricle after atrial or transmural myocardial infarction 92374 22 200400187

In addition, the present invention can be expected to undergo surgery, thrombolysis, and coronary arteries and prevent general microsurgery and blood. The compound has the function of preventing reocclusion after vasodilator bypass surgery; the use / reuse of rethrombosis after tube surgery II includes treatment and / or preventive treatment of dissemination caused by bacterial trauma, poisoning or other mechanisms Sexual blood coagulation / Anticoagulation when blood comes in contact with foreign objects in the body (such as vascular grafts, vascular drainage, "catheters, mechanical and biological people.", 卞 八 工 局 Ｍ, or any other medical device surface Treatments ^ I, and § Anticoagulant therapy when blood is in contact with a medical device outside the body (for example, using a cardiopulmonary machine 4 ^ Russian: ¾ during cardiovascular surgery of a hemodialysis machine). In addition to the effects on coagulation, In addition to k, b Wenguo U, it is known that hemolytic enzymes can activate a large number of cells, such as neutrophils, retinal cells, endothelial cells, and smooth muscle cells. Therefore, the foreigner + ¾ month compound of the present invention can also be used for treatment And / or preventive treatment of primary and adult respiratory distress chickens, total tablets. Δu dyspnea syndrome, pulmonary fibrosis after radiation or chemotherapy treatment, septic shock, sepsis, inflammation In response, inflammatory reactions include, but are not limited to, acute or chronic atherosclerosis (such as coronary artery disease, arteriolar disease, peripheral arterial disease, reperfusion injury, and arterial restenosis after percutaneous transluminal angioplasty). The compounds of the present invention which can inhibit the protease and / or thrombin can also be used for the treatment of pancreatitis. In consideration of the relationship between the thrombin inhibition mechanism and the above-mentioned various diseases, the compounds of the present invention can be particularly used with large α prescriptions-and / Or preventive treatment of antiphospholipids and antibodies 92374 23 200400187 body, cysteine female gmanemia, heparin-induced thrombocytopenia, venous blood test formation, lung talent, arterial blood test formation, myocardial infarction, unstable heart, 、 人 痛 # ^ Become the main cause of stroke, peripheral arterial embolism, systemic detection, septic shock, and pancreatitis; and prevent reocclusion; and prevent rethrombosis. In another aspect, the present invention provides a need to inhibit thrombin Method for treating the symptoms of the disease, which method comprises treating a therapeutically effective amount of a compound Dosage compounds and compounds are administered to patients suffering from or affected by the symptoms. The compounds of the present invention are generally orally, buccal, rectal, transdermal, nasal, menstrual, and lactating. Administered by injection, or by inhalation. ▲ The compounds of the present invention can also be co-administered with any anticoagulant with a different mechanism of action, such as an antiplatelet agent (acetosalic acid, ticlopidine (Tlcioppne, clopidogrei)), thromboxane receptors and / or, enzyme inhibitors, fibrinogen receptor antagonists, prostacyclin Mirti tablets J (piostacyclln minetlcs, bupropionate hydrolase inhibitors, adp_receptor antagonists, and thrombin receptor antagonists. The compounds of the present invention can further be used with thrombolytic agents (such as tissue plasma f leukogen activators (natural or synthetic) )), Streptokinase, urokinase, urokinase, heterostreptokinase, hemagglutinin activator complex (AspA0, animal salivary plasma protein activator, etc.)-combined / or co-administered for treatment Blood tests, especially myocardial infarction. In another aspect, the present invention provides a pharmaceutical formula comprising a compound represented by the formula 923 described in combination with 92314 24 200400187, which is mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier. , Or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof. The active compound can be administered at the same dose depending on the condition and the route of administration of patients with amnesia and oral cavity. The dose of the compound of the present invention is about 0.001 to 100 when administered orally and the mother is not a master of the field] 0.00 g / kg of body weight, and about 0.001 to 50 mg / kg of body weight when administered by: . The compound of the present invention is excellent in pharmacokinetic properties after oral administration in China and is not good ... = injection or oily ... Injections, such as sterile aqueous solution for injection, can be used according to known steps,-, ... … And prepared with a knife, wetting or detergent. It can be used for the preparation of the solvent, such as water, aseptic solvent, etc., and can also contain a single 1 × ΐ% 〇ΐΙ) conveniently. Used as a solvent or suspension medium. Either. : Non-irritating fixed oils of glycerol and vinegar can be used for this purpose. For example, fatty acids of oleic acid can also be used for injection. 5 ^ It is suitable for use < For oral administration of tincture, etc. = = = _ 、 ㈣, ", powder, granules

Better. The solid preparation can be prepared by heart pill: W at least-selected from the group consisting of inactive diluents (:: ... compounds and ^ nw such as carbohydrate, milk bran lubricant (such as magnesium stearate), disintegrants, and: ... , 4 σ d is a fresh group containing the value of the compound represented by the formula (]) of the present invention, and then displayed ii; & i 4 4 ' Utilization rate. Compounds of the present invention show that ~ 4 can be seen, '3 offenders and 4 of them] 00 times ... Bioavailability reached about 50000 /

9221A 25 200400187 [b] The compound of the present invention has the characteristics of its own jujube body pair, hematoplegia, trypsin, and other serine proteins _ Gan and θ, Gong & Zhao, Shi Bai_ Ya have no activity. The compound still remains inactive in the stomach (Inflammation and isomerism (° Yue Cang Jian Bei Ma 1 and Guan 2). Therefore, the compound of the present invention can be used to combine # ay,, t ”1 more It may be caused by inhibition of trypsinemia and indigestion, which may be caused by an active anticoagulant. This ^ 'juice is used in the present invention to avoid human thrombin inhibitors and avoid thrombin inhibitors. It is not your field. Can | City J d Non-I ~ Yuetou Le related to this, the compounds of the present invention may also have useful pharmacological knowledge of the eight things more Λ You Qi ^ shell 'for example compared to other Baixiuhua mouth More effective, less toxic, longer action, less active, less side effects, more absorption-delay test 3). Market properties (see [Embodiment] The present invention = the following examples, examples and experimental progress —The steps are specifically explained as follows. It should be understood that these consistent examples and tests are used to explain how to limit the scope of the present invention. The abbreviations and terms used in the naming of any of the following examples are:

Boc: tert-butoxycarbonyl

Br: bromo

Bu: butyl iBu · tertiary butyl C1: chloro Cyb: cyclobutyl Cyh · cyclohexyl Cypr: cyclopropyl 92374 26 200400187

Cypen: Cyclopentyl Dpa: Diphenylalanine Et: Ethyl F: Fluoro

Imid: 口 米 口 口 / Pr: Isopropyl Mοι · · morpholine Ph: Phenyl Pro: Proline Pyi ·: Pyridine thioph: Synthesis of thiophene starting compounds The following starting compounds are referred to IPA WO 00/39124 And the method disclosed in Korean Patent Application No. 10-2001-001 7840. Boc-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph? Boc-D-Dpa-Pro-NH-CH2-5- (2-CN) -thioph ^ H02CCH2-D-Dpa- Pro-NH-CH2-5- (2-amd) -thi〇ph ^ iBu02CCH2-D-Dpa-Pro-NH-CH2-5- (2-CN) -thioph ^ / Bu02CCH2-D-Dpa-Pro-NH -CH2-5- (2 ^ amd) -thioph ^ Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-CN) -thioph, and 5-aminofluorenylthiophene-2-nitrile hydrochloride. Example 1

Preparation of Et〇2CCH2-D-Dpa-Pro-NH-CH2-5-(2-amd) -thioph-OH 27 92374 200400187 0 ο νη2 a) Et〇2CCHrD-Dpa-Pr〇-NH-CH2-5- Preparation of (2-CN) -thioph D Dpa-PrO-NH-CH2-5- (2-CN) -thioph (20 g, 40.4 mmol) was dissolved in dichloromethane (60 ml) In addition, Lu Shidian copper (0.21 g, 8.08 mmol) and ethyl acetate (927 g, 161.6 mmol) were added to it at 5r. Diisopropylethylamine (13.05 g, 101.0 mol) was then added dropwise while maintaining a temperature of 1 (rc or lower. The reaction solution was stirred for about 9 hours, followed by addition of hexamethylenetetramine ( 16.99 g, 1 2 1.2 Emole), and the mixture was stirred for about 10 hours. The reaction solution was washed with water (60 ml), 2% aqueous hydrochloric acid solution, and 5% aqueous sodium hydrogen carbonate solution (30 liters). The solvent was distilled off to obtain the title compound as a residue.

# b) Preparation of Et02CCH2-D-Dpa-Pr. NH-CH2-5- (2-amd) -thioph-OH The compound obtained in step a) was dissolved in ethanol (180 ml), and 5 ° (3 to 10 ° (: hydroxylamine hydrochloride (10.39 g, 149.5 mmol) was added to it. Then triethylamine (13.90 g, 1 3 7 · 4 mmol Mol) and at the same time maintained at 1 CTC or lower. After confirming the completion of the reaction by HPLC, the reaction solvent (ethanol) was evaporated and removed, and the residue was extracted with dichloromethane / water. The organic layer was degassed with gas. The sodium sulfide aqueous solution was washed, dried over anhydrous sodium sulfate, and then filtered to obtain the title compound as a residue. The compound obtained in 28 92374 200400187 was dissolved in ethanol (180 ml) and refluxed. The obtained solid was then filtered. And the pure title compound (16.2 mmol, 9.33 g) was obtained in 40% yield. H-NMR (400 MHz, CDCb) δ 8.65 (broad, 1H), 8.22 (t, 1H), 7.43 (d, 2H), 7.36 (t, 2H), 7.30 to 7.08 (m, 6H), 7.01 (d, 1H) 5 6.83 (d5 1H), 4.90 (s, 2H), 4.59 (dd, 1H ), 4.52 (dd5 1H), 4.36 (d, 1H) 4.28 (m5 2H), 4.08 (m, 2H), 3.35 (m, 3H), 2.74 (dd, 1H), 1.98 (m, 2H), 1.81 (m, 1H), 1.36 (m5 2H), 1.22 (t3 3H) LC-MS; [M + H] = 578 Example 2 Preparation of H〇2CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-OH

The compound obtained in step b) of Example] (1 g, 1.73 mmol) was dissolved in acetonitrile (10 ml) and stirred at room temperature. Then, a 1N aqueous sodium hydroxide solution (10 ml) was added dropwise thereto at room temperature. After 30 minutes, the completion of the reaction was confirmed by HPLC, and the reaction was terminated. Acetonitrile was distilled off under reduced pressure, and the reaction solution was adjusted to pH 6 with a 1 N aqueous hydrochloric acid solution. The solid obtained was then filtered to obtain the title compound (900 mg, 1.64 mmol) in a yield of 94%. 'H ^ NMR (400MHz, DMSO-4) δ 9.57 (%, 1H), 8 41 (t, 1H), 7.49 ~ 7.05 (m5 11H), 6.84 (d, 1H), 5.84 (s, 2H), 4.41 (m5 2H), 4.26 (dd, 1H), 4.12 (d, 1H), 3.93 (m, 1H), 3.00 (η, 1H), 1.73 (m, 1H), 1.58 (m, 2H), 1.35 (m5 1H) LOMS; [M + H] = 550 29 92374 200400187 Example 3

Et〇2CCH2-D-DPa-Pr0-NH-CH2-5- (Preparation of 2-amd: Mhiopa, 〇ο νη2 The compound (4.26 g, 7 37 _) prepared by step b) of Example 1 Mol) was dissolved in methanol (21 g), and the temperature of the reaction solution was reduced to 5 ° C. Acetic anhydride (0.75 g, 7.38 mmol) was then added dropwise thereto. After 30 minutes, the completion of the reaction was confirmed by HPLC. The reaction solution was warmed to room temperature, and 5% palladium / carbon (0.89 g) was added. The reaction / valley was stirred for about 18 hours under hydrogen bubbling to complete the reaction. The reaction solution was filtered and distilled to remove the solvent, and the residue was purified by column chromatography (50% ethyl acetate / hexane) to obtain the title compound (6.26 mmol, 3.52 g) in a yield of 85.0%. . • lH-NMR (500MHz, CDCh) δ 8.12 (broad, 1Η), 7.43 (d, 2H), r36 (t, 2Η), 730-7.12 (m, 6H), 7.01 (d, 1H), 6.83 (d3 1H), 4.85 (s, 2H), 4.52 (dd5 1H) 5 4.50 (dd, 1H)! 4 32 (d, 1H), 4 25 (m, 2H), 4.08 (m, 2H), 3 31 (m , 3H), 2.72 (dd, 1H), 2 01 (m, 2H), 1.78 (m, 1H), 1.35 (m, 2H), 1.22 (t, 3H) LC-MS; [M + H] = 562 Example 4

Preparation of Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2CC] 3 92374 30 200400187

a) Preparation of 2,2,2-dichloroethyl carbonate nifedipine trichloroethyl chloroacetate (3.2 g, 5.0 mmol) and 4-nitrophenol (2 g , 14.4 millimoles) were dissolved in dichloromethane (20 ml), and the mixture was stirred under ye 'and triethylamine (丨 · 6g, 15 · $ mmol) was slowly added dropwise. ). The mixture was stirred at 0 ° C and washed sequentially with water (5.0 ml), 1N aqueous sodium hydroxide solution (5.0 ml), and aqueous sodium chloride solution (50 ml). After drying over anhydrous sodium sulfate, it was filtered and distilled under reduced pressure. The residue was purified by column chromatography (100% chloroform) to obtain the title compound (3.4 g, 10.8 mmol) in a yield of 75%.

b) Preparation of Et〇2CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (〇) 〇CH2CC13 The compound (500 mg, 7 3 4 mol) was dissolved in diammonium phosphonium amine (10 ml), and the compound obtained in step a) (230 g, 0.734 mol) was added. Potassium carbonate (224 mg, 1.69 mmol) was then added thereto, and the mixture was stirred at 0 ° C for 10 minutes and then warmed to room temperature. After confirming the completion of the reaction by HPLC, the reaction solution was sequentially washed with a saturated aqueous sodium hydrogen carbonate solution (20 ml), water (20 ml), and a saturated aqueous sodium chloride solution (20 ml), and dried over anhydrous sodium sulfate After that, it was filtered and distilled under reduced pressure. The residue was purified by column chromatography (50% ethyl acetate / hexane) to obtain the title compound (492 mg, 0.668 mmol) in a yield of 75.0%. 92374 3] 200400187] H-NMR (400 MHz, DMS) S 9 · 15 (width, 1H), 8 37 (t, 1H), 7.85 (d, 1H), 7.43 (d, 2H), 7.27 (t, 2H), 7.25 to 7.08 (m, 6H), 6.98 (d, 1H), 4.S5 (s, 2H), 4.42 (ddd, 2H), 4.36 (m, 1H), 4.13 (d, 1H), 4.03 (q, 2H), 3.97 (dd, 1H), 3.51 (m, 1H), 3.02 (q, 1H), 1.83 (m, 1H), 1-61 (m, 2H), 1.35 (m5 1H) LC-MS; [M + H] = 736 Example 5 Preparation of H02CCH2-D-Dpa-PrO-NH-CH2 " 5- (2-amd) -thioph-C (0) 〇CH2CC13

(500 g, 0.73 mol) and potassium carbonate (120 mg, 0.87 mol) were added to a mixture of tetrahydrofuran (2.5 ml) / water (2.5 ml), and . (: The compound prepared in step a) of Example 4 (230 g, 0.73 mol) was slowly added thereto in 10 minutes. The mixture was stirred at 0 ° C for 15 minutes and warmed to room temperature and then stirred for 4 hours to complete the reaction. The solvent in the reaction solution was completely removed by evaporation, and the residue was diluted with -random pen liters). The pH value σ of the mixture was adjusted to 4 to 5 with a Q 5N hydrochloric acid aqueous solution to transfer the reactant to the organic layer. The reactant in the organic layer was maintained in a solid state and then filtered to obtain the title compound (14 mg, 0.20 mmol) in a yield of 27.7%. 92374 32 200400187! H NMR (400MHz, CDCI3) δ 9 23 (bs, 2H), 8 06 (t, 1H), 7.99 (d? 1H), 7.47-7.18 (m, 12H), 6 78 (d, 1H ), 4.77 (s5 2H), 4 60 (m, 1H), 4 39 (m, 1H), 4.32 (m, 2H)? 4.16 (m, 1H), 3.45 (m, 2H), 3.28 (s, 2H ), 2.63 (m, 1H), 1.98 (m5 1H), 1.73 (m5 1H), 1.32 (m, 1H) LC-MS; [M + H] = 710 Example 6 / tBu〇2CCH2 * " D- Preparation of Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 0CH2CC13

/ Bu〇2CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph (3 60 mg, 0.554 mmol) was added to diamidinylamine (7.2 ml) 'Add the compound prepared in step a) of Example 4 (74 mg, 0.55 4 mol) to it. After adding carbonic acid (11 $ mg, 0.831 mmol), the resulting mixture was stirred at 0 ° C for 15 minutes, and then stirred at room temperature for 5 hours. After confirming the completion of the reaction by HPLC, the solvent was completely removed by evaporation, and the residue was purified by column chromatography (50% ethyl acetate / hexane) to obtain the title compound (33 1 mg, 78.0% yield). 0.432 millimoles). 4-NMR (400MHz, CDC13) δ 9.31 (W, H), 8 04 (m, 1H), 7.60 ~ 7.] 0 (m, 10H), 6 94 (d, 1H), 4.81 (dd7 2H) , 4 55 (qd, 2H), 4.26 (m, 2H), 4.10 (m, 1H); 3.25 (m5 3H), 2 66 (m, lH), 2 07 (m, 1H), 1 67 (m, 2H)?]. 40 (s5 9H), 1.25 (m5 2H) LC-MS; [M + H] = 764 Example 7 92374 200400187 iBu02CCH2-D.Dpa.pr〇.NH.CH2.5. (^ Amd ) Preparation of thi〇ph C (〇) 〇CH2CH3

1 3 · 7 9 mol) according to the a) 4-Shi Xiao Phenyl Ethyl Carbonate prepared in Example 4 the reaction of ethyl chloroacetate (1.33 ml, 1: • step a) The title compound (1.97 g, 9.34 mmol) was obtained in a yield of 67%.

b) iBu02CCH2-D-Dpa.Pro-NH-CH2-5. (2-amd) -thioph-C (0) 0CH2CH3 was prepared according to the compound obtained in step a) (i43 mg, 0.678 mmol). The reaction was carried out in the same manner as in Example 6 to obtain the title compound (178 mg, 0.269 mmol) in a yield of 40%. iNMR (400MHz, CDC13) δ 7.75 (t, 1H), 7.44 (d, 1H), 7.15 to 7.41 (m, 10H), 6.92 (d, 1H), 4.57 (d, 2H), 4.29 (m, 2H)? 4.20 (m, 3H)? 3 25 (m, 3H); 2.68 (m, 1H), 2.14 (m, _ 1H), 1.75 (m, 1H), 1.34 ~ Ml (m, 12H) LC >MS; [M + H] = 662 Example 8

Preparation of Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCH2CH3

The compound prepared in step a) of Example 7 was reacted according to the same steps as in step 34 92374 200400187 step b) in Example 4 to obtain the title compound in a yield of 60%. iH-NMR (400MHz, CDC13) δ 7.95 (t, 1H), 7.47 (d, 1H), 7.13 to 7.41 (m, 10H), 6.95 (d, 1H), 4,55 (ddd, 2H), 4.24 ( m, 4H), 4.05 (m, 2H), 3.77 (m5 1H), 3.32 (m, 3H), 2.75 (m, 1H), 2.12 (m, 1H), 1.87 (m, 1H), 1.75 ( m, 1H), 1.41 (m, 2H), 1.35 (t, 3H), 1.23 (t, 3H) LC ^ MS; [M + H] = 634 Example 9 H02CCH2-D-Dpa-Pro-NH-CH2 Preparation of -5- (2-amd) -thioph-C (0) OCH2CH3

The compound prepared in step a) of Example 7 (62 mg, 0.294 mmol) was reacted in the same manner as in Example 5 to obtain the title compound (108 mg, 0.17 mmol) in a yield of 60%. 'H-NMR (400MHz, DMSO-r / c) δ 9.0 (br, 1H), 8.47 (t? 1H), 7.78 (d, 1H), 6 97 to 7.46 (m, 10H), 6.76 (d, 1H ), 4.30 to 4.46 (m, 3H), 3.91 to 4.10 (m, 5H), 1.71 (m, 1H), 1 59 (m, 2H), 1.31 (m, 1H), 1.18 (t, 3H) LC- MS; [M + H] = 607 Example 1 0 Preparation of H02CCH2-D-Dpa-Pro «NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2Ph

a) Preparation of 4-nitrobenzyl phenylphosphonate carbonate 35 92374 200400187 The phenylphosphonium chloroacetate (1.99 ml, 13.97 mmol) was reacted according to the same steps as in step a) in Example 4 to obtain a yield It was 60% of the title compound (2.3 g, 8.42 mmol). b) Preparation of H02CCH2 ~ D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (〇) OCH2Ph. The compound obtained in step a) (248 mg, 0.906 mmol) is implemented The reaction was carried out in the same manner as in Example 5 to obtain the title compound (459 mg) in a yield of 76%. -NMR (400MHz, DMSO-) S 8.S5 (width, 1H), 8.27 (t, 1H), 7.60 (d, 1H), 7.40 ~ 6.90 (m, 15H), 6.76 (d, 1H) , 4.85 (s, 2H), 4.21 (ddd5 2H), 4.19 (m, IH), 3.90 (d, 1H), 3 71 (dd, 1H), 2.78 (m, 1H), 1.50 (m, 1H)? 1.38 (m, 2H)? 1.08 (m, 1H) LC-MS; [M + H] = 668 Example 1 1

Preparation of Et〇2CCH2 ~ D-Dps-Pro ~ NH-CH2 ~ 5- (2-anici) -thioph-C (0) 〇CH2Ph

Ph, ^ Ph

The compound (80.2 mg, 0.294 mmol) obtained in step a) of Example 10 was reacted in the same manner as in step b) in Example 4 to obtain the title compound (121 mg, 0.174) in a yield of 59%. Mol). W-NMR (400MHz, CDC13) S 7.91 (m, 1H), 7.13 to 7.46 (m5 16H), 6.93 (d, 1H), 5.17 (s, 2H), 4.55 (ddd, 2H), 4.21 (m, 3H ), 4.00 (m5 2H), 3.29 (m, 3H)} 2.67 (m, 1H), 2.10 (m, 1H), 1.87 (m, 1H), 1.70 (m, 2H), 1.39 (m9 1H) , U8 (t, 3H) LC-MS; [M + H] = 696 36 92374 200400187 Example 1 2 H02CCH2-D-Dpa-PrO.NH-CH2-5. (2 ^ amd) .thioph-C ( 0) Preparation of OCH2 / Pr

a) Preparation of 4-nitrophenyl isobutyl carbonate. Isobutyl chloroacetate (2.0 ml, 15.42 mmol) was reacted according to the same steps as in step a) in Example 4 to obtain a yield. It was 60% of the title compound (2.21 g, 9.25 mmol).

b) Preparation of H02CCH2-D.Dpa ^ Pr0-NH-CH2-5- (2.amd) -thioph-C (〇) OCH2 / Pr The compound prepared in step a) (220 mg, 0.937 mmol) ) The reaction was carried out in the same manner as in Example 5 to obtain the title compound (400 mg, 0.580 mmol) in a yield of 67%. ! H-NMR (400MHz5 DMSO-r / 6) δ 9 010 (br, 2Η), 8.479 (t, 1H, J = 6 0Hz)? 7.806 φ (d, 1H, J = 4Hz), 7 473 (d, 2H, 7 = 7 · 6Ηζ), 7.298 (t, 2H, > 7 · 2Ηζ), 7.226 to 7.124 (m, 6H), 6 985 (d, 1H, J = 3 6Hz), 4.485 to 4.299 ( m, 3H), 4.125 (d, 1H5 J = 10 4Hz), 3 942 (dd, 1H, > 5 6Hz, 6.8Hz), 3.781 (d, 1H, J = 6.8Hz), 3.559 to 3.503 (m, 1H), 3.045 ~ 2.986 (m, 1H), 1.930 ~ 1.846 (m, 1H) 5 1.749 ~ 1.703 (m, 1H),] · 632 ~ 1.578 (m, 2H), 1.365 ~ 1.307 (m, 1H), 0.900 (d, 6H, J = 6.8Hz) LOMS; [M + H] = 634 Example 13

Et02CCH2-D-Dpa-Pro ~ NH-CH2-5 ^ (2-amd) -thioph ^ C (0) 〇CH2 / P! • Preparation 37 92374 200400187

The compound prepared in step a) of Example 12 (96 mg, 0.401 mmol) was reacted in the same manner as in step b) in Example 4 to obtain the title compound (100 mg in 47% yield). , 0.151 millimoles). 'H ^ NMR (400MHz, DMSO-r / d) δ 9.010 (br, 2Η), 8.448 (t5 1H), 7.805 (d, 1H), 7 458 (d, 2H), 7,291 (t, 2H), 7 221 to 7.131 (m, 6H), 6.980 (d,] H), 4.479 to 4.314 (m, 3H), 4.]] 4 (d, 1H), 3.935 (d, 2H), 3.995 to 3.924 ( m, 1H), 3.779 (d, 2H), 3.523 ~ 3.469 (m, 1H), 3.035 ~ 2 · 945 (η '1H), 2.095 ~ 2.102 (m, 1H), 1.934 ~ 1.876 (η' 1H), 1.798 ~ 1.689 (m, out), 1.621 ~ 1.534 (m, 2H), 1.395 ~ 1 · 295 (m, 1H), 1.151 (t, 3H), 0.S98 (d, 6H) LC-MS; [M + H] = 662 Example 1 4 Preparation of iBu02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thi〇ph-C (0) 〇CH2 / Pr

The compound prepared in step a) of Example 12 (360 mg, 1.5; 1 mmol) was reacted in the same manner as in Example 6 to obtain the title compound (250 mg, Mol) in a yield of 24%. . 38 92374 200400187 'H-NMR (400MHz, DMS0 ^ 6) δ 9.012 (br, 2H)? 8.449 (t, 1H, 7 = 5.2Hz), 7.806 (d, 1H, J = 3.2Hz), 7.456 (d, 2H, J = 7.6Hz), 7.295 (t, 2H, J = 7.4Hz), 7.217 to 7.132 (m, 6H), 6.989 (d,] H, J = 2.8Hz), 4.468 to 4.329 (m, 3H) 5 4.103 (d, 1H, /=10.4Hz), 4.035 (q, 1H, > 3.6 Ηζ), 3 779 (d, 2H, J = 6 4Hz), 3.532 ~ 3.477 (m, 1H), 3.229 ( s, 2H), 3.021 to 2.954 (m,) H), 1.984 (b, 1H), 1.926 to 1.862 (m, 1H), 1.752 to 1.669 (m5 1H), 1.638 to 1.502 (m, 2H), 1 366 (m? 10H), 0.898 (d, 6H, J = 6.4Hz) LC-MS; [M + H] = 690 Example 1 5 H02CCH2-D-Dpa-Pro-NH > CH2-5- (2-amd ) -thioph-C (O) 〇CH (CH3) oc (o) ch3

a) Yield of 1-{[(4-nitrophenoxy) carbonyl] oxy} ethyl acetate was obtained in the same steps as described in JMC, 1999, 42 (19), page 3994 90% of the title compound (1.05 g, 3.90 mmol). b) Preparation of H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (〇) 〇CH (CH3) 〇C (〇) CH3 The compound obtained in step a) ( (116 mg, 0.37 mmol) was reacted in the same manner as in Example 5 to obtain the title compound (180 mg) in a yield of 69%. 39 92374 200400187! H NMR (400MHz, CDC13) δ 9 .16 (bs, 2H), 8.59 (t, 1H, J = 5.8Hz), 7.86 (d, 1H, J = 4, 0Hz), 7.47 (d, 2H, J = 7.6Hz), 7.30 (t, 2H, J = 7.6Hz), 7.22 ~ 7.13 (m, 8H), 7.00 (d, 1H, J = 3.6Hz), 6.72 (q, 1H, J = 5.2Hz), 4.38 (m, 3H), 4.12 (d, 1H, J = 10.4Hz), 3.93 (dd, 1H, Jl = 7.6Hz, J2 = 4.4Hz), 3.53 (m, 1H), 3.11 ( s5 2H), 3.00 (m9 1H), 2.02 (s? 3H), 1.70 (m, 1H)? 1.61 (m, 2H), 1.42 (d, 3H, J = 5.2Hz), 1.34 (m, 1H) LC -MS; [M + H] = 664 Example 1 6

Preparation of Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCH (CH3) OC (〇) CH3

The compound obtained in step a) of Example 15 (230 mg, 0.85 mmol) was reacted in the same manner as in step b) in Example 4 to obtain the title compound (140 mg in a yield of 28%). ). W-NIMR (400MHz, DMS0-A) δ 9.169 (b, 2H), 8.464 (t? 1H), 7.861 (d, 1H), 7.461 (d, 2H), 7.294 (t, 2H), 7.223 to 7.134 ( m, 6H), 6.997 (d, 1H), 6.717 (q, 1H), 4 481 to 4.326 (m, 3H), 4-117 (d, 1H), 4.038 (q, 2H), 3.930 (q, 1H ), 3.529 to 3.475 (m, 1H), 3.033 to 2 975 (m,] H), 2.021 (s, 4H), factory 749 to 1.588 (m, 3H), 1.420 (d, 3H), 1.364 to 1.276 (m, 1H), 1.152 (1, 3H) LC-MS, [M + H] = 692 Example 1 7 / Bu02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph -C (0) 0CH (CH3) 0C (0) CH3 Preparation

The compound obtained in step a) of Example 15 (380 mg '1.52 92374 40 200400187 mmol) was reacted in the same manner as in Example 6 to obtain the title compound (180 mg, 0.73 mmol) in a yield of 48%. ear). iH-NMR (400MHz, DMSO-⑹δ 9.182 (b, 2H), 8.467 (t, 1H), 7.8.8 (d, 1H), 7.463 (d, 2H), 7.301 (t, 2H), 7.225 to 7.137 (m , 6H), 7.000 (d, 1H), 6.723 (q, 1H), 4.483 to 4.336 (m, 3H), 4.110 (d, 1H), 3.924 (q, IH) 5 3.559 to 3.483 (m, 1H), 3.233 (t, 2H) 3.028 ~ 2.968 (in, 1H), 2.025 (s, 4H), 1.747 ~ 1.518 (m3 3H), 1.425 (d, 3H), 1.370 (m, 10H) 'TOF MS ES +: [M + H] = 742 Example 1 8 Preparation of H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2CH2〇CH3

a) Preparation of 4-nitrophenylcarbonate 2-methoxyethoxyacetate 4-nitrophenyl chloroacetate (4.03 g, 20.0 mmol) was dissolved in dichloromethane (20 ml), Then, 2-methoxyethanol (1.52 g, 20.0 mmol) dissolved in dichloromethane (0.5 ml) and triethylamine (202 g, 2 0.0 mmol) were slowly dripped. Add to it. After completion of the reaction, the reaction mixture was sequentially washed with water (20 ml), aqueous sodium chloride solution (0 ml), and 5% aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and then steamed to obtain a yield. 37% of the title compound. H NMR (400MHz, CDCI3) δ 8.29 (m, 2H), 7.40 (m, 2H), 4.44 (td, 2H) 3 7] (td, 2H), 3.45 (s5 3H) b) H02CCH2 > D ^ Dpa- Pr〇-NH-CH2 ^ 5 ~ (2-amd) -thioph > 92374 41 200400187 Preparation of C (〇) OCH2CH2OCH3 The compound obtained in step a) (219 mg, 0.906 mmol) was the same as in Example 5. This step was carried out to obtain the title compound (376 mg) in a yield of 65%. ] H-NMR (400MHz, DMSO- ^) δ 9.03 (s5 2Η)? 8.52 (t, 1Η), 7.82 (d5 1H), 7.50 ~ 7.10 (m, 10H), 6.99 (d, 1H), 4.43 (m , 2H), 4.34 (dd, 1H), 4.11 (m, 3H), 3.94 (t, 1H), 3.26 (d, 6H), 3.01 (q,) H), 1.73 (m, 1H), 1.60 (m , 2H), 1.35 (m, 1H) LOMS; [M + H] = 636 Example 1 9

Preparation of Et02CCH2-D-Dpa-PrO-NH-CH2-5- (2-amd) -thioph- C (O) 〇CH2CH2〇CH3

The compound obtained in step a) of Example 18 (177 mg, 0.734 mmol) was reacted in the same manner as in step b) in Example 4 to obtain the title compound (242 mg) in a yield of 50%. 'H-NMR (400MHz, DMSO-rfd) δ 9.03 (s5 2H), 8.47 (t, 1H), 7.82 (d, 1H)? 7.50 to 7.00 (m, 10H), 6.98 (d5 1H), 4.45 (dd , 1H), 4.38 (m, 2H), 4.11 (m, 3H), 4.04 (q, 2H), 3.95 (m, 1H), 3.54 (m, 3H), 3.27 (s, 3H), 3.00 (m, 1H), 2.05 (m5 1H), 1.73 (m, 1H) 3 1.58 (m, 2H)} 1.35 (m, 1H), 1.15 (1, 3H) LC-MS; [M + H] -664 Example 20 H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 〇 Preparation of Ph-4-F 42 92374 200400187

a) Preparation of bis (4-fluorophenyl) carbonate. 4-Fluorine (4.0 g, 35.68 mmol) and triphosgene (1.77 g, 5.95 mmol) are simmered in a single gas (4 Triethylamine (3.61 g, 35.68 mmol) was slowly added dropwise thereto at 0 ° C. After 10 minutes, it was confirmed that the reaction was completed. The reaction mixture was then washed sequentially with water (40 ml), aqueous sodium chloride solution (20 ml). After drying over anhydrous sodium sulfate, the title compound (4.24 g, 16.9 mmol) was obtained in a yield of 95% by evaporation. 1H NMR (400MHz, CDC13) δ 7.24 (m, 4Η), 7.10 (t, 4H) b) H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph.C (0) 〇 Preparation of Ph-4-F The compound obtained in step a) (240 mg, 0.937 mmol) was reacted in the same manner as in Example 5 to obtain the title compound (3 80 mg, 0.565) in a yield of 60%. Mol). _ 'H-NMR (400MHz, DMSO- ^) δ 9.161 (d5 2H)? 8.513 (t, 1H, J = 5.8Hz), 7.883 (d,) H, J = 4Hz), 7.474 (d, 2H5 J = 7.6Hz), 7 316 (t5 2H, J = 7.0Hz), 7.298 ~ 7.140 (m, 10HX 7.019 (d, 1H, > 4.0Hz), 4.504 ~ 4.316 (m, 3H), 4.128 (d, IH, J = 10.4 Hz), 3.944 (t, 1H, J = 6.4Hz), 3.580 ~ 3.509 (m, 1Η), 3.0023 (dd, lH, J = 7.2Hz, 16.8Hz), 1.774 ~ 1.707 (m, 1H), 1.612 (q, 2H, J = 6.4Hz), 1.377 to 1.399 (m, 1H) LC / MS; [M + HH72 Example 2 1

Et02CCH2-D-Dpa-PrO-NH-CH2-5- (2-amd) -thioph- C (O) 〇Ph-4-F Preparation 43 92374 200400187

The compound prepared in step a) of Example 20 (96 mg, 0.401 mmol) was reacted in the same manner as in step b) in Example 4 to obtain the title compound (100 mg, 0.151) in a yield of 47%. Mol). ^^ NMR (400MHz, DMSO-r / 6) δ 9.010 (br, 2Η), 8.476 (t, 1H, 7 = 6.0Hz), 7.881 (d, 1 H, > 3 6Hz), 7.459 (d, 2H , J = 6.SHz), 7.293 (t, 2H, J = 7.6Hz), 7.224 ~ 7 ·] 47 (m, 10H), 7014 (d,) H, > 3.6 × Η), 4.493 ~ 4 332 (m, 3H), 4.117 (d, 1H, J =) 0.4Hz), 4.035 (m, 2H), 3 943 (dd,] H, > 5.2Hz, 7.8Hz), 3.509 ~ 3.438 (m, 1H ), 3.042 to 2.984 (m, 1H), 2.071 to 2.016 (m, 1H), 1.750 to 1.704 (m, 1H), 1.623 to 1 567 (m, 2H), 1.361 to 1.305 (m, 1H), 1.152 (t, 3H, J = 6.8Hz) LC-MS; [M + H] = 700 Example 22

Preparation of Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-〇C (o) ch3

The compound obtained in step b) of Example 1 (200 mg, 0.346 mmol) was dissolved in methanol (2.2 ml) and stirred at 0 ° C. Acetic anhydride (38. 5 mg, 0.377 mmol) was added thereto, and the resulting mixture was stirred at 0 t for 10 minutes. The solvent was distilled off under reduced pressure. The residue was diluted with dichloromethane (50 ml) and washed sequentially with a saturated aqueous solution of sodium bicarbonate (20 liters), water (20 ml), and aqueous sodium chloride solution (20 ml). 92374 44 200400187 After drying with sodium sulfate, filtration and distillation under reduced pressure, the title compound (210 mg, 0.339 mmol) was obtained in a yield of 97%. ! H NMR (400MHz, CDC13) δ 7.88 (t, 1H), 7 "5 to 7.40 (m, I1H), 6.S9 (d, 1H), 5.13 (br, 2H), 4.52 (ddd, 2H), 4.24 (m, 3H), 4.04 (m5 2H), 3.31 (m, 3H), 2.69 (m, 1H), 2 22 (s, 3H), 2 09 (m, 1H), 1.74 (m, 2H), 1.45 (m5 1H), 1 22 (t, 3H) LC-MS; [M + H] = 620 Example 23 H〇2CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) *- Preparation of thioph-C (0) OCH2CF3

a) 4-Nitrophenyl 2,2,2-trifluoroethyl carbonate was prepared using 2,2,2-trifluoroethanol (2.0 g, 20.0 mmol) according to step a in Example 18 ) Was reacted in the same step to obtain the title compound (2.0 g) in a yield of 38%. 1H NMR (400MHz, CDC13) δ 8.28 (m5 2Η), 7.41 (m, 2H), 4.63 (m, 2H) b) H02CCH2 ^ D-DPa-pi * 〇 ^ NH-CH2-5- (2-amd) Preparation of -thioph-C (0) 〇CH2CF3 The compound obtained in step a) (240 mg, 0.906 mmol) was reacted in the same manner as in Example 5 to obtain the title compound (330% in yield) (330 Mg). 45 92374 200400187 'H-NMR (400MHz, DMS〇〇δ 9.38 (wide, 1H), 9.12 (broad, 1H), 8.57 (t5 1H), 7.91 (ci, 1H), 7.50 ~ 7.05 (m, 10H ), 7.02 (d, 1H), 4.67 (q, 3H), 4.50 (dd, 1H), 4.41 (d, 3H), 4 34 (dd, 1H), 4 13 (d? 2H), 3.93 ( m, 2H), 3.00 (m5 2H)? 2.09 (s5 1H), 1.85 (m, 1H) 5 1 73 (m, 2H), 1.33 (m, 1H) LC-MS; [M + H] = 660 Implementation Example 2 4

Preparation of Et〇2CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (〇) OCH2CF3

The compound (i 9 5 mg, ο 7 3 4 pen moles) obtained in step a) of Example 2 3 was reacted according to the same steps of step b) in Example 4 to obtain a yield of 4 0% of the title compound (200 mg). Ah. IH-NMR (400MHz, DMS〇〇δ 9.H (Wide, 1H), 8 87 yoke m) 5 8 26 (s, 1H), 7.68 (s, 1H), 7.40 ^ 6.90 (m, 9H) , 6.78 (s, 1H), 4.44 (d, 2H), 4.18 (m, 3H), 3.88 (d5

1H), 3.80 (d, 2H), 3.71 (s, 1H), 2.78 (m, 1H), 1.82 (m, 1H), 149 (m, m), 13S ㈣ 2H), 1.10 (m, 1H), 0.95 (t, 3H) LC-MS; [M + H] = 688 Example 25, (2-amd)-thioph-C (O)

Preparation of Et02CCH2-D-Dpa-Pr〇.NH-CH2 OPh-4-OCH3

OMe a) Preparation of bis (4-methoxyoxybenzyl) carbonate 92374 46 200400187 4-Methoxyphenol (1.0 g, 4.96 mmol) was used according to step a) in Example 2 The reaction was carried out in the same procedure to obtain the title compound (500 mg, 1.82 mmol) in a yield of 37%. iH NMR (400MHz, CDC13) δ 6.99 (d, 4H), 6.70 (d5 4H), 3.60 (s, 6H) b) Et〇2CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) Preparation of -thioph- C (〇) OPh-4-〇CH3 The compound obtained in step a) (80.5 mg, 0.294 mmol) was reacted according to the same step as step b) in Example 4 to obtain a yield. It is 38% of the title compound (80 mg, 0.112 mmol). ! H NMR (400MHz, CDCb) δ 7.98 (t, 1Η), 7.52 (d, 1Η), 7.18 to 7.27 (m, 10Η), 7.] 0 (d, 2H), 6.98 (d, IH), 6.91 (d, 2H), 4.61 (ddd, 2H), 4.27 (m, 3H), 4.07 (m, 2H), 3.81 (s, 3H), 3.34 (m, 3H) , 2.72 (m, 1H), 2.08 (m, 1H), 1.71 (m, 2H), 1.35 (m, 1H), 1.25 (t, 3H) LC-MS; [M + H] = 712 Example 2 6 Preparation of H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCH2CH2F

a) Preparation of 4-fluoroshophenyl phenyl carbonate 2-fluoroethyl SI The 2-fluoroethanol (4.0 g, 19.84 mmol) was reacted according to the same steps as in step a) in Example 18 to obtain a yield of 46.9% of the title compound (2.13 g, 9.3 mmol). ! HNMR (400MHz, CDC13) δ 8 30 (d, 2Η), 7.41 (d, 2H), 4.78 (m, 1H), 4.66 (m5) H), 4 58 (m, IH), 4.51 (m, IH 47 92374 200400187 b) H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2CH2F Preparation of the compound obtained in step a) (208 mg, 0.906 mmol) Mol) was reacted in the same manner as in Example 5 to obtain the title compound (371 mg) in a 66% yield. ] H-NMR (400MHz, DMSO ^ / 6) δ 9.08 (s, 2Η), 8 55 (t, 1H), 7.85 (d, 1H), 7 50 ~ 7 · 10 (m, 10H), 7.00 (d , 1H), 4 67 (d, IH), 4 57 (d, 1H), 4 48 to 4.02 (m, 6H), 3 93 (m, 1H), 3.00 (m, 1H), 1.72 (m , 1H), 1.62 (m, 2H), 1.34 (m, 1H), 1.08 (q, 1H) LC-MS; [M + H] = 624 Example 27

Preparation of Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2CH2F

The compound (i 2 3 mg, 0.5 5 7 7 mol) obtained in step a) of Example 2 was reacted according to the same steps as in step b) in Example 4 to obtain a yield of 60.2%. The title compound (2 10 mg, 0.322 mmol). ] H NMR (400MHz, CDC13) δ 7.92 (t, 1H), 7.44 (d, 1H), 7.20 to 7.39 (m, 10H), 6.94 (d, 1H), 4.73 (m, 1H), 4 60 to 4 70 (m, 2H), 4.44 ~ 4.5〇 (m, 1H), 4 38 (di52H), 4 24 (m, 3H), 4.04 (m, 2H), 3.31 (m, 3H), 2.70 (m, 1H ), 2.〇7 (m? Ih), 1.69 (m? 2H), 1.35 (m, 1H), 1 22 (t, 3H) LOMS, [M + H] = 652 Example 2 8

Et02CCH2-D-Dpa-Pio-NH-CH2-5- (2-amd) -thioph-C (0) 〇CH20C (0) CH3 Preparation 92374 48 200400187

a) Preparation of {[(4-nitrophenoxy) carbonyl] oxy} fluorenyl acetate makes ethylacetoxymethyl chloroacetate (500 mg, 3.28 mmol) according to Example 1 5 The same step as in step a) was carried out to obtain the title compound (720 mg, 2.82 mmol) in a yield of 86%. b) Preparation of Et02CCH2-D-Dpa> pr0-NH-CH2-5- (2-amd) .thioph-C (〇) OCH2OC (〇) CH3 The compound obtained in step a) (200 mg, 0-78 mmol) Mol) was reacted in the same manner as in step b) in Example 4 to obtain the title compound (3 76 mg, 0.52 mmol) in a yield of 67/0. W-NMR (400MHz, DMS 0 ′) δ 9,20 (b, 2H), 8.46 (t, 1H), 7.85 (d, 1H), 7.46 (d, 2H), 7.29 (t, 2H), 7.20 ( m, 6H), 6.99 (d, 1H), 6.72 (s, 2H), 4.40 (m, 3H), 4.12 (d, 1H), 4.04 (q5 2H), 3.93 (q, 1H), 3.50 ( m, 1H), 3.00 (m, 1H), 2.02 (s, 4H), 1.60 (m, 3H), 1.32 (m, 1H), 1.15 (t, 3H) LC-MS; [M + H] = 678 Example 29 Preparation of H02CCH2-D-Dpa-Pr0-NH-CH2-5- (2-amd) ^ thioph-C (0) 0CH2Cyh

a) Preparation of 4-nitrophenylcyclohexylfluorene carbonate. Cyclohexylfluorenol (2.28 g, 20.0 mmol) was reacted according to the same steps as in step a) in Example 18 to obtain the product. The title compound with a rate of 89% was 49 92374 200400187 (4.97 g). ! H NMR (400MHz, CDC13) δ 8.27 (m) 2Η), 7.38 (m5 2H), 4.10 (d, 2H), 1.79 (m, 6H), 1.25 (m, 3H), 1.06 (m, 2H) b ) H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2Cyh Preparation of the compound obtained in step a) (262 mg, 0.937 mmol) The reaction was carried out in the same manner as in Example 5 to obtain the title compound (476 mg) in a yield of 75%. ! H-NMR (400MHz5 DMSO- ^) δ 8.36 (t, 1Η), 7.61 (d, 1Η), 7.29 (d, 2Η), 7.11 (t, 2H), 7.02 ~ 6.85 (m, 6H), 4.50 (m, 1H), 4.15 (ddd, 2H), 4.02 (d, 1H), 3.70 (t, 1H), 3.58 (d, 2H), 2.79 (m, 1H), 1.47 '(m, 5H ), 1.40 (m, 4H), 1.08 (m, 1HX 0.95 (m, 3H), 0.73 (m, 2H) LC-MS; [M + H] = 674 Example 30 0

Preparation of Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2Cyh

Ph, / Ph The compound (293 mg, 1.05 mmol) obtained in step a) of Example 29 was reacted according to the same steps as in step b) in Example 4 to obtain the title compound in a yield of 41% ( 300 mg). ^ l-NMR (400MHz, DMSO-r / 6) δ 9.04 (s, 2Η), 8.48 (t, 1H)? 7.83 (d, 1H), 7.46 (d, 2H), 7.30 (U 2H), 7.23 ~ 7 11 (m, 6H), 6.98 (d, 1H), 4.41 (ddd, 2H), 4 37 (m, 1H), 4.12 ((UH), 4 04 (m, 3H), 3.94 (dd, 1H) , 3 8] (d, 2H), 3.34 (d, 1H), 3.00 (c), 1H), 1.68 (m, 6H), 1 6] (m, 3H),] 34 (m, 1H), 1 17 (m, 7H), 0.96 (m, 2H) LC-MS; [M + H] = 702 50 92374 200400187 Example 3 1 H02CCH2-D-Dpa-PrO. NH-CH2-5. (2 > amd ). Preparation of thioph-C (0) 〇CH2CH2Cyh

a) Preparation of 4-pot phenylcyclohexylethyl carbonate. 2-¾hexylethanol (2 56 g, 2000 mmol) was reacted according to the same steps as in step a) in Example 18 to obtain the product. 88% of the title compound (5.17 g). NMR (400MHz5 CDC13) 8.27 (m, 2H), 7.38 (m > 2H) 5 4.33 (t5 2H), 1.69 (m? 7H),] .45 (m, 1H), 1.20 (m, 3H), 0.99 ( m, 2H) b) H02CCH2-D-Dpa-Pro-NH ^ CH2-5 ^ (2 ^ amd) -thioph.C (0) 〇CH2CH2Cyh Preparation of the compound obtained in step a) (275 mg, 〇 · 937 μmol) was reacted in the same manner as in Example 5 to obtain the title compound (540 mg) in a yield of 84%. h-NMR (400MHz, DMS〇- " 6) δ 8 86 (wide ,; (Η), 8.43 (t 1Η) 7 61 (d 1Η) 7.32 (d, 2H), 7.16 (t, 2H), 7.07 to 6.93 (m, 6H), 6.76 (d, 1H), 4.60 (m, 1H), 4.19 (m, 3H), 4.] 1 (m, 1H), 3 79 (t, 3H), 3.69 (t, 2H), 2.79 (m, 1H) 5 1.42 (m, 8H)? 1.25 (q? 2H), 1 08 (m5 2H), 0 94 (m, 3H), 0.66 (q, 2H). LC-MS, [M + H] = 688 Example 32

Et02CCH2-D-Dpa-Pro-NH-CH2-5 ~ (2 > amd) -thi〇ph.C (0) 〇CH2CH2Cyh Preparation 92374 51 200400187

The compound prepared in step a) of Example 31 (308 mg, 1.05 mmol) was reacted in the same manner as in step b) in Example 4 to obtain the title compound (362 in a yield of 48%) Mg). ] H-NMR (400MHz, DMSO- ^) δ 9.04 (s, 2Η), 8.47 (t, 1Η), 7.82 (d, 1Η), 7.45 (d, 2H) 5 7 · 29 ( t, 2H), 7.25 to 7.08 (m5 6H), 4.40 (ddd, 2H), 4.38 (m, 1H), 4.11 (d, 1H), 4.02 (m, 4H) 5 3.94 (dd, 1H), 3.00 (m, 1H), 1_65 (m, 8H), 1.48 machine 2H), 1.33 (m, 2H), 1.15 (m, 6H), 0.90 (m, 2H) LC-MS; [M + H] = 716 Example 3 3

Preparation of Et02CCH2-D-Dpa ^ Pr0-NH-CH2-5- (2-amd) -thioph-C (0) -Imid

Carbonyl diimidazole (290 mg, 1.79 mmol) was reacted in the same manner as in step b) in Example 4 to obtain the title compound (713 mg, 1.09 mmol) in a yield of 6%. ] H NMR (400MHz5 CDC13) δ 9 74 (br, 1Η), 8.38 (s5 1H), 8.03 (t, 1H), 7.60 (d,

Call, 7.58 (d, 1H), 7.17 ~ 7.40 (m, 10H), 7.03 (s, 1H), 6.96 (d, 1H), 4.53 (ddd, 2H), 4 25 (m, 3H), 4.0 (3 (m, 2H), 3.35 (m, 3H), 2.73 (m, 1H), 2.11 (m, 1H), 1.78 (ni, 2H), 1.32 (m, 1HX 1.20 (t, 3H ) LC-MS; [M + H] = 656 Example 3 4

Et02CCH2-D-Dpa-Pr0. NH-CH2-5- (2-amd) -thioph-C (0) 52 92374 200400187 OCH2CH2-Mor

a) Preparation of 4-stone phenyl carbonate 2-morin-4 _yl ethyl alcohol 4- (2-hydroxyethyl) morpholine (65 1 mg, 4.96 mmol) as described in Example 18 The same step of step a) was performed to obtain the title compound (1.43 g) in a yield of 97%. Lu! Η NMR (400MHz, CDCI3) δ 8.32 (m, 2Η) 5 7.56 (m5 2Η), 4 35 (t, 2Η)? 3.58 (m, 4H), 2.64 (t, 2H), 2 47 (m5 4H b) Preparation of Et〇2CCH2-D-Dpa-Pr0 ~ NH-CH2 * -5- (2-amd) -thioph-C (〇) 〇CH2CH2-M0r The compound obtained in step a) ( 586 mg, 1.98 mmol) was reacted in the same manner as in step b) in Example 4 to obtain the title compound (7 67 mg) in a yield of 54%. W-NMR (400MHz, DMSO-A) δ 8.99 (width, 2H), 8.45 (t, 1H), 7.81 (d, 1H), 7.46 (d, 2H), 7.29 (t, 2H), 7 21 ( d, 4H), 7.17 (m, 4H), 6.98 (d, 1H), 4.41 (ddd, 2H), 4.11 (t, 2H), 4 07 (d, 1H), 4Ό3 (m, 2H), 3.94 (dd, 1H), 3 57 (ί, 4H), 3.50 (m, 1H), 3 31 (m, 1H), 3.00 (m, 1H), 2.41 (m, 4H), 2.05 (m, 1H) , 1.74 (m, 1H), 1.60 (m5 2H), 1.34 (m, 1H) 5 1.15 (t5 3H), 1.10 (m, 1H) LC-MS; [M + Na] = 741 Example 3 5

Et02CCH2 »D-Dpa-Pro ^ NH-CH2-5- (2-amd) -thioph-C (0) 〇 Preparation of 3-Pyr from CH Factory 53 92374 200400187

a) Preparation of 1H-imidazole-1-carboxylic acid 3-pyridyl methyl ester

M bite methanol (4 g, 36.65 mol) was added to tetrahydrofuran (40 ml) and stirred at 0 t. Weiji Diweiwa (5.941, 36.65 mmol) dissolved in tetrahydrofuran㈣ml) was slowly added dropwise to the above mixture while stirring. After the solvent was distilled off under reduced pressure, the residue was stirred in diethyl ether to obtain the title compound (2.5 g, 12.02 mmol) in a yield of 32.8%. ] H NMR (400MHz, CDC13) δ 8.72 (s5 1Η)? 8.65 (d5 1Η), 8.13 (s, 1H)? 7.78 (d5 1 H), 7.41 (s, 1H), 7.36 (m5 1H), 7.06 ( d, 1H), 5.42 (s, 2H) b) Et02CCH2 ^ D.Dpa-Pro-.NH-CH2-5- (2-amd) -thi〇ph · C (〇) OCH2-3-Pyr The compound obtained in step a) (370 mg, 1.78 mmol) was reacted in the same manner as in step b) in Example 4 to obtain the title compound (780 mg, 1.11 mmol) in a yield of 63%. ! H NMR (400MHz, CDC13) δ 8.69 (s, 1Η), 8.54 (d, 1H), 7.93 (t, 1H), 7.77 (d? LH), 7.45 (d, lH), 7.20 ~ 7.39 (m, U) H), 6.94 (d, 1H), 5.19 (s, 2H), 4.54 (ddd52H), 4 25 (m5 3H), 4.02 (m, 2H), 3.29 (m? 3H), 2.71 (m? 1H )? 2.12 (m? 1H), 1.72 (m, 2H), 1.41 (m, 1H), 1.19 (t, 3H) LOMS; [M + H] = 697 Example 3 6

Et02CCH2-D-Dpa> Preparation of Pro-NH «CH2-5- (2-amd) -thioph-C (0) NHCH2CH2OH 54 92374 200400187

n-v ^ 〇h The compound obtained in Example 33 (200 mg, 0.31 mmol) was dissolved in dichloromethane (3 ml) and stirred. Ethanolamine (15 μl, 0.46 mmol) was added, and the mixture was stirred at reflux for about 12 hours. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (10% methanol / dichlorofluorene) to obtain a 4-6 compound (11 4 mg, 0.18 mmol) in a yield of 56.7%. ear). JH NMR (400MHz, CDC13) δ 7 93 (d, 1Η), 7.15 to 7.41 (m, 10Η), 6.89 (d, 1Η), 4.51 (ddd, 2H), 4.27 (m, 3H ), 4.05 (m, 2H), 3.69 (m, 4H), 3.34 (m, 4H), 2.73 (m, 1H), 2.08] 75 (m, 1H), 1 35 (m, 1H), 1.23 (t 3H) LC >MS; [M + H] = 649 Example 3 7

Preparation of Et02CCH2-D-Dpa-Pr0.NH-CH2-5- (2-amd) -thioph-C (0) N (CH2CH2OH) 2

The compound (196 mg, 0.30 millimoles) obtained from Bebismuth Example 33 was dissolved in chloroform (1 ml) and stirred. Tianzhai grams, 0.60 mmol, and triethylamine (60 microliters, the mixture was stirred under reflux overnight. The residue under reduced pressure was subjected to column chromatography (Shi Xijiao, Me :. Add 2,2- Diethanolamine (6060 microliters, 0.36 mmol), and chloroform was distilled off under reduced pressure, and the residual MeOH = 10: 1) was purified to obtain 92374 55 200400187 yield of 5 9% The title compound (〖23 mg, 0 · 18 mmol).] H-NMR (400MHz, DMSO 0δ 8.43 (t, 1H), 7.67 (d, 1H), 7.13 ~ 7.34 (m, 1 OH ), 6.93 (d,) H), 4.69 (m, 2H), 4.35 (m, 3H), 4.10 (m, 1H), 4.01 (m, 2H), 3.93 (m, 1H) , 3.50 (m, 6H), 2 95 (m, 1H), 2.05 (m, 1H), 1.61 (m, 3H), 1.29 (m, 1H), 1.14 (t, 3H) LC-MS; [M + H] = 693 Example 3 8

Et02CCH2-D-Dpa> Preparation of PrO-NH-CH2-5- (2-amd) -thioph- C (0) 〇CH2CH2N (CH3) 2

a) Preparation of 1H-imidazol-3-carboxylic acid 2-gas diamidoamino) ethyl ester N, N-dimethylethanolamine (2.0 g, 22.44 mmol) according to Example 35 The same steps as in step a) were carried out to obtain the title compound, which was then used to prepare the following compounds without further purification. _ b) Preparation of Et02CCH2-D-Dpa.Pr.NH-CH2-5- (2-amd) -thioph-C (〇) OCH2CH2N (CH3) 2 The compound (3) obtained in step a). (Mg, mixture, excess) was reacted in the same manner as in step b) in Example 4 to obtain the title compound (239 mg, 0.354 mmol) in a yield of 40%. NMR (400MHz, CDC13) δ 7.90 (t, 1H), 7.44 (d, 1H), 7.15 to 7.41 (m, 10H), 6.94 (d5 1H), 4.50 (ddd, 2H), 4.24 (m, 4H), 4.04 (m, 2H), 3.31 (m, 3H), 2.64 (m, 1H), 2.29 (s., 6H), 2.10 (m, 1H), 1.74 (m, 1H), 1.42 (m, 1H), 1.21 (t, 3H) LC-MS; [M + H] = 677 Example 39 92374 56 200400187

Et02CCH2 ~ D.Dpa-Pr〇 ^ NH-CH2.5- (2-amd) -thioph-C (0) 〇CH2Cypr

a) Preparation of 4-Shishophenylcyclopropylphosphonium carbonate Bis (4-Shishaobenzyl) carbonate (3.1 g, 10.19 mmol) and cyclopropyl methanol (2.0 g '27.7 mmol) ) Was dissolved in dichloromethane and triethylamine (1.5 g '10.19 mmol) was added dropwise. After the reaction was confirmed to be complete, the mixture was purified by Shixi gel column chromatography (eluent: ethyl acetate / n-hexane = 丨 / 9) to obtain the title compound (124 g, 5.23 mmol) in a yield of 51%. Moore). b) Preparation of Et02CCH2-D-Dpa-Pr0-NH-CH2-5- (2-amd) -thioph-C (0) 0CH2Cypr so that the compound pi obtained in step a) is 1 mg, 0.891 millimoles ) The reaction was carried out in the same manner as in step b) in Example 4 to obtain the title compound (328 mg, 0.497 mmol) in a yield of 56%. ! H NMR (400MHz, CDC13) δ 7.93 (t, 1Η), 7.47 (d, 1Η), 7.16 to 7.42 (m, 10Η), 6.96 (d, 1H), 4.50 (ddd, 2H), 4.25 ( m, 3H), 4.06 (m, 2H), 3.97 (d, 2H), 3.32 (m, 3H), 2.71 (m, 1H), 2.11 (m, 1H), 1.74 (ni, 2H), 1.44 (m , 1H), 1.23 (t, 3H), 0.57 (m, 2H), 0.33 (m, 1H) LOMS; [M + H] = 660 Example 40

Preparation of Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCH2Cypen

57 92374 200400187 a) Preparation of 4-nitrophenylcyclopentylfluorene carbonate (4-nitrobenzyl) carbonate (4.0 g, 3 · 4 millimoles) and cyclopentylfluorene (2.80 g, 27.96 mmol) was reacted in the same manner as in step a) in Example 39 to obtain the title compound (156 g, 5.89 mmol) in 45% yield. b) Preparation of Et02CCH2-D-Dpa ^ Pr.NH-CH2-5- (2-amd) -thioph-C (〇) 〇CH2Cypen compound (23 4 mg, 0 89.1 mmol) was reacted in the same manner as in step b) in Example 4 to obtain the title compound (379 mg, 0.55 mmol) in a yield of 62/0. ] H NMR (400MHz, CDC13) δ 7.93 (t, 1Η), 7.46 (d, 1H), 7.17 ^ 7.42 (m, 10H), 6.95 (d, 1H), 4.55 (ddd, 2H), 4.26 (m5 3H ), 4.05 (m5 4H), 3.32 (m, 3H), 2.71 (m, 1H), 2.31 (m, 1H), 2.12 (m, 1H), 1.21 ~]. 82 (m, 14H) LC-MS; [M + H] = 688 Example 4 1 • Preparation of Et〇2CCH2-D-Dpa.pr〇.NH ^ CH2-5- (2-amd) -thioph.C (0) CH2rBu

a) Preparation of tertiary acid 4-stilbene phenyl ester Dissolve the second butyl acetamidine chloride (1 ml, 7.20 mmol) and 4-nitropyrene (1 g, 6.99 mmol) in two In chloromethane (20 ml) and administrated at 0 ° C. Diethylamine (1 ml, 7, 21 mmol) was slowly added dropwise thereto, and stirred for 2 hours. The reaction mixture was washed with water (5 ml), n 58 92374 200400187 aqueous sodium hydroxide solution (5 ml), and sodium chloride aqueous solution (5 ml), and then water; after drying with sodium sulfate, filtering and decompressing under reduced pressure. The crane was steamed to obtain the title compound (1 · 2 g, 4.98 mmol) in a yield of 69.2%. ! H NMR (400MHz, CDCI3) δ 8 28 (d5 2Η) 5 7.28 (d5 2Η), 2.49 (s, 2H) 5 U6 (s, b) Et02CCH2-D-Dpa-Pro-NH-CH2-5- ( Preparation of 2-amd) -thioph-C (〇) CH2? Bia The same steps as in step b) in Example 4 of the compound obtained in step a) (215 mg, 0.891 mmol) were carried out. The reaction gave the title compound (237 mg, 0.359 mmol) in a yield of 400/0. 'H NMR (400MHz5 CDC13) δ 7.92 (t, 1H), 7.20 ^ 7.39 (m, 11H)? 6.95 (d3 1H), 4.55 (ddd, 2H), 4.25 (m, 3H), 4.04 (m, 2H) , 3.30 (m, 3H), 2.67 (m, 1H), 2.35 (s, 2H), 2.08 (m, 1H), 1.74 (m, 2H), 1.41 (m, 1H), 1.21 (t, 3H)? 1.06 (s5 9H) LC-MS; [M + H] = 660 Example 4 2

Preparation of Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCyh _

a) The preparation of 4-nitrophenylcyclohexyl carbonate enables bis (4-nitrophenyl) carbonate (1.57 g, 5.15 mmol) and cyclohexanol (1 g, 9.98 mmol) The same procedure as in step a) in Example 39 was carried out to obtain the title compound (1.24 g, 4.34 mmol) in a yield of 84%. b) Preparation of Et02CCH2-D-Dpa-PrO-NH> CH2> 5- (2-am d) -thioph- 59 92374 200400187 C (0) 0Cyh Preparation of the compound obtained in step a) (234 mg, • 891 millimoles) was reacted according to the same procedure as in step b) in Example 4 to obtain a compound (375 g, 0.545 millimoles) with a yield of 61%. 'H NMR (400MHz, CDC13) δ 7.91 (t5 1H), 7.48 (d, 1H), 7.16-7.42 (m5 l〇H), 6.92 (cl, IH), 4.64 (m, 2H), 4.52 (ddd5 2H ), 4.25 (m, 3H), 4 05 (m, 2H), 3.32 (m, 3H), 2.71 (m, 1 H), 2.10 (m, 1H), 1.98 (m, 2H), 1.25 ~ 1 · 81 (m, 8H), 1.24 (t, 3H) LC-MS; [M + H] = 688 Example 4 3

Preparation of Et02CCH2-D.Dpa-Pr0.NH-CH2-5- (2-amd) -thioph-C (0) 0CH2Cyb

a) Preparation of 4-nitrophenylcyclobutylphosphonium carbonate # Make cyclobutylfluorenol (1.63 g, 18.9 mmol) and 4-nitrophenyl chloroformate (3.80 g, 18.9 mmol) The reaction was carried out in the same manner as in step a) in Example 4 to obtain the title compound (3.51 g) in a yield of 74%. ] H NMR (400MHz, CDC13) δ 8.27 (m, 2H), 7.39 (m, 2H), 4.27 (d, 2H), 2.75 (hep5) Η), 2.13 (m, 2Η ), 1.95 (id, 2Η), 1.87 (m, 2Η) b) Et02CCH2-D.Dpa-Pro ^ NH-CH2-5- (2-amd) -thioph-C (0) 〇CH2Cyb was prepared in step a ) The obtained compound (143 mg, 0.569 mmol) was reacted according to the procedure of step b) in Example 4 to obtain the title compound (282 g) in a yield of 73% 92374 60 200400187. 'H-NMR (400MHz, DMSO · ⑹ δ 9.01 (broad, 2H), 8.49 (t, 1H), 7.80 (d, 1H), 7.29 (t, 2H), 7 18 (m, 8H), 6.98 (d, 1H), 4 39 (dd, dd, dd, 3H), 4 11 (d5 2H), 4 05 (q, 2H), 3.97 (d, 2H), 3.95 (dd, 1H), 3.50 (m , 1H), 3.31 (m, 2H), 3.00 (dd, 1H), 2.58 (hep5 1H), 2.01 (m, 3H), 1 84 (m, 2H), L73 (m, 3H), 1.60 (m? 2H), 1.33 (m, 1H), 1.15 (t, 3H) LC-MS; [M + H] = 674 Example 44

Et02CCH2-D-Dpa-Pr〇-NH-CH2-5- (2-amd) -thioph-C (0)

Preparation of CH3

a) Preparation of 4-nitrophenyl acetate Acetic anhydride (1.0 g, 16.65 mmol) was dissolved in dichloromethane (30 ml), and triethylamine (2.03 g, 20.06 mmol) was added to Here, the mixture was cooled to zero. 〇. 1-Ethyl 3- (3-diamidoaminopropyl) carbodiimide (3.84 g, 20.06 mmol) was added and stirred for 10 minutes. After stirring, add 4-nitrophenol (2.32 g, 16.68 mmol) to 0. (: The mixture was stirred for 2 hours at 10 C. After the reaction was confirmed to be complete, the reaction mixture was sequentially with water (30 ml), a saturated aqueous sodium hydrogen carbonate solution (20 ml), and an aqueous sodium chloride solution ( 15 ml) was washed and dried over anhydrous sodium sulfate. The solvent was removed by evaporation, and the residue was purified by column chromatography (ethyl acetate / hexane / dichloromethane = 1/9/1) to obtain The title compound was obtained in a yield of 50% (1.5 g, 8.3 mmol). Η NMR (400 MHz, CDCI3) δ 8 30 (m, 2H) 5 7 44 (m5 2H), 2.33 (s5 3H) 61 92374 200400187 b) Preparation of Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) > thioph-C (〇) CH3 The compound obtained in step a) (129 mg, 0.712 mmol) Ear) The reaction was carried out in the same manner as in step b) in Example 4 to obtain the title compound (190 mg) in a yield of 44%. iH-NMR (400MHz, DMSOv /,) δ 8 45 (t5 1H), 7.81 (d, 1H), 7.46 (d, 2H), 7.30 (t, 2H), 7.25 to 7.08 (m, όΗ), 6.99 ( d, 1H), 4.40 (ddd, 2H), 4.38 (m, 1H), 4 12 (d,) H), 4.04 (m, 2H), 3.94 (dd, 1H), 3.51 (m, 1H), 3.00 (dd, 1H), 2.04 (s, 3H), 1.74 (m5 1H), 1.60 (m, 2H), 1.35 (m, 1H), 1.16 (t, 3H) LC-MS; (M + H) = 604 Example 4 5

Preparation of Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) CH2CH3

a) Preparation of 4-nitrophenyl propionate Propionic anhydride (2 g, 15.37 mmol) was dissolved in dichloromethane (50 ml) and stirred at (TC. Cardionitrophenol (2 2 g, 15.37 mol) was added thereto and stirred. Triethylamine (2.2 ml, 15.86 mmol) was slowly added dropwise to the above mixture, and the mixture was stirred at 0 ° C for 3 hours. The reaction mixture was washed with water (20 ml), 1N aqueous sodium hydroxide solution (20 ml), and sodium chloride aqueous solution (20 ml). After drying over anhydrous stone and acid steel, it was filtered to obtain the yield. The title compound is 5 5 · 6 ° / 〇 (.7 g, 8.54 mmol). 92374 62 200400187 b) Et02CCH2-D-Dpa-PrO-NH-CH2-5- (2-amd) -thioph -Preparation of C (〇) CH2CH3 The compound obtained in step a) (710 mg, 3.57 mmol) was reacted according to the same steps as in step b) in Example 4 to obtain a yield of 65% *. The title compound (1.43 g, 2.32 mmol). .] H NMR (400MHz, CDC13) δ 7.93 (t, 1Η), 7.15 ^ 7.44 (m, 11H); 6 92 (d, 1H), 4 51 (ddd, 2H), 4.25 (m, 3H), 4.05 (m, 2H), 3.31 (m, 3H), 2.71 (m, 1H), 2.49 (q, 2H), 2.10 (m, 1H), 1 74 (m, 2H), 1 41 (m, 1H), 1.22 (t, 3H), l,] 5 (t, 3H) φ LC-MS; [M + H] = 618 Example 46

Preparation of Et02CCH2.D-Dpa-Pr0.NH-CH2-5- (2 ^ amd) -thioph-C (0) 7 · Ργ

a) Preparation of n-butyric acid isobutyrate Isobutyryl chloride (2 g, 15.37 mmol) was dissolved in dichloromethane (501 liters) and mixed at 0 ° C. After adding 4-nitropyrene (2.7 g, 1 8 · 6 1 8.7 millimolar) slowly and dropwise to the house, add triethylamine (2.6ml, to it, and then add this under Ot: The mixture was stirred for 3 hours. The reaction mixture was washed with water (20 ml), 1N aqueous sodium hydroxide solution (20 ml), and aqueous sodium chloride solution (20 ml). After drying over anhydrous sodium sulfate, filtering and reducing work The title compound was obtained by steaming the crane at a yield of 58% (9 · 9 g, 89 mmol). 92374 63 200400187 b) Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph- C (〇) / Pr Preparation The compound obtained in step a) (760 mg, 3.57 mmol) was reacted according to the same step as in step b) in Example 4 to obtain the product. The title compound was 50% (1.12 g, 1.77 mmol). ! H NMR (400MHz, CDC13) δ 7.99 (t, 1Η), 7.50 (d, 1Η), 7.16 ~ 7.39 (m, 10Η), 6% (cUH), 4 59 (ddd, 2H), 4.26 ( m, 3H), 3.% to 4.11 (m, 2H), 3.57 (m, 1H), 3.30 (m, 3H), 2 72 (m, 1 H), 2.12 (m,] H), 1.74 (m , 2H), 1.43 (m, 1H), 1.22 (m, 9H) LC-MS, [M + H] = 632 Example 47

Preparation of Et02CCH2-D-Dpa-Pro-NH-CH2-5> (2-amd) -thioph-OC (〇VPr

The compound obtained in step a) (732 mg, 3.50 mmol) in Example 46 was reacted in the same manner as in Example 22 to obtain the title compound (1.9 7 g) in a yield of 87.7%. Α-ΝΜΡ ^ ΟΟΜΗζ, DMS〇-rf0) δ 8.42 (t, 1H), 7.49 ~ 7.10 (m, 11H), 6.92 (d, Ιχχ 6.77 (s, 2H), 4.43 (dd, 1H) , 4.38 (d, 1H), 4.32 (dd, 1H), 4.11 (d, 1H), 4.03 (m, 2H), 3.94 (q, 1H), 3.50 (m5 1H) 5 3.00 (m, 1H), 2.72 (m, 1H), 2.05 (m5 1H), 1.72 (m, 1H)? 1 60 (m, 2H), 1.34 (m5 1H), 1.14 (m5 9H) LC-MS; [M + H] = 648 Example 48

Preparation of Et02CCH2-D ^ Dpa-Pro-NH-CH2-5- (2-amd) -thioph-OC (〇) CH2CH3 64 92374 200400187

Propionic anhydride (547 mg, 3.50 mmol) was reacted in the same manner as in Example 22 to obtain the title compound (884 mg) in a yield of 40%. 'H-NMR (400MHz, DMSO-A) δ 8.40 (t, 1H), 7,50 ~ 7 · 10 (m, 11H), 6 91 (d, 1 Η), 6.78 (s, 1H), 4 · 42 (dd, 1H), 4.37 (m, 1H), 4.32 (dd, 1H), 4.11 (d, 1H), 4.03 (m, 2H), 3.94 (q, 1H), 3.49 (m? 1H), 3.00 (m, 1H), 2.42 (m, 2H), 2.05 (m? 1H), 1.72 (m, 1H), 1.60 (m, 2H), 1.34 (m5 1H), 1.16 (t, 3H), 1.07 (t , 3H) LC-MS; [M + H] = 634 Example 4 9

Preparation of Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-OC (O) iBu

Pivalic anhydride (338 mg, 1.51 mmol) was reacted in the same manner as in Example 22 to obtain the title compound (891 mg) in a yield of 89%. tNMR (400MHz, DMS〇 ^ 5) δ 8.43 (t, 1H), 7.50 ~ 7.10 (m, 11H), 6.92 (d, 1H), 6.62 (s, 1H), 4.35 (m, 3H), 4.12 (d, 1H), 4.05 (m, 2H), 3.94 (q, 1H), 3.50 (m5 1H), 3.00 (m, 1H), 2.05 (m, 1H), 1.75 (m, 1H) 3 1.60 (m, 2H), 1.34 (m, 1H), 1.23 (s, 9H),] .16 (t, 3H) LC-MS; [M + H] = 662 Example 50 0

Preparation of Et02CCH2-D-Dpa-Pr0-NH-CH2-5- (2-amd) -thioph-OP 65 92374 200400187 (〇) (OCH2CH3) 2

Diethyl chlorophosphonate (1.1 ml, 7.85 mmol) was reacted in the same manner as in Example 22 to obtain the title compound (3.6 g, 5.04 mmol) in a yield of 71%. ear).

NMR (400MHz, CDC13) δ 7.90 (t, 1H), 7.15 to 7.41 (m, 11H), 6.90 (d, 1H), 5.14 (s, 2H), 4 52 (ddd, 2H), 4.25 (m, 7H ), 4.03 (m, 2H), 3.30 (m, 3H), 2.69 (m, 1H), 2.05 (m, 1H), 1 72 (m, 2H), 1.40 (m, 1H), 1.36 (t, 3H), 1.21 (t5 6H) LC-MS; [M + H] = 714 Example 5 1

Preparation of Et02CCH2-D-Dpa-Pro-NH-CH2 ~ 5- (2-amd) -thioph-C (0) NHCHy.Pr

Isobutylamine (100 µl, 0.99 mmol) was reacted in the same manner as in Example 36 to obtain the title compound (475 mg, 0.69 mmol) in a yield of 69%. 'H NMR (400MHz, CDC13) δ 7.88 (t, 1Η), 7.15 to 7.41 (m, 11Η), 6.90 (d, 1Η), 5.55 (t, 2H), 4.51 (ddd, 2H), 4.28 (m, 3H), 4 03 (m, 2H), 3-27 (m, 3H), 3.03 (rn, .2H), 2.72 (m, 1H), 2.15 (m, 1 Η), 1.74 (m , 3H), 1.45 (m, 1 Η), 1.24 (t, 3H), 0.93 (d, 6H) LC-MS, [M + H] = 661 Experiment 1 66 92374 200400187 Determination of thrombin clotting time Solution () 〇676〇Αliter was added to the human coagulation_ (Τ

6769, Slgma, concentration @ § (T and then the obtained lysing and nourishing ml) in the solution, the salt of human blood ⑸_ microliter), and use the automatic lifting force ~ home; 7: START'4) ^^ : Preparation concentration axis, and then use interpolation method to measure IC concentration of two domains = inhibitory concentration of doubled coagulation time of thrombin of blood polymer; Compounds and chemical compounds all show 1 〇

value. That is, ... "The IC5 ° TT D substance of degree has no activity on hematoenzyme itself. Please refer to, '2-D-Dpa'Pr0-NH-CH2-5- (2-amd), thi〇Ph The IC50TT value is 0.02 micromolar concentration. Experiment 2 Measurement of the biological activity of the hematase inhibitor and the inhibitory effect of the compound not represented by the formula (1) were confirmed by the measurement of the dissociation constant represented by the following equation 1. :

Ki [Ε] χ [I] [El] where [E] refers to the concentration of free enzymes, and 41 to [I] refers to the concentration of an unbound inhibitor, and [EI] refers to an enzyme-inhibition The concentration of the agent complex, and according to the reference in the literature; see, Methods in Enzymology, 80, younger-92374 67 200400187 361 pp. · "Biochemistry 27, pp. 2144 to 2i5i, i 988). The dissociation constant Ki represents the degree of dissociation of the __thrombin inhibitor complex. Therefore, a low dissociation constant means that the thrombin inhibitor has a high binding activity to the enzyme ', and thus it is estimated that the thrombin inhibitor has a high inhibitory activity on thrombin. The dissociation constant can be measured by reacting thrombin with a specific matrix. When the specific matrix is hydrolyzed by the action of thrombin, a color is produced, and then the color produced as a function of time is measured using a spectrophotometer instrument. degree.

Arg-4-nitroaniline acetate) is used as a substrate for thrombin, and Chromom Zym TH is used to produce color by the action of thrombin. chrozym ™ is hydrolyzed by thrombin to produce yellow paranitrate basic amines. Therefore, when the absorption of snoring, Zuo Yishi ^ and ^ between the passage of day and time changes, you can measure the so-produced puertosine and its poor b ^ ㈤ basic month female I to determine the compounds of the present invention Second enzyme inhibitory activity. That is, the activity of the enzyme can be determined by the change in absorbance, and can be directly related to the ability of the thrombin inhibitor to inhibit the enzyme activity. The inhibitory activity of serum enzymes on trypsin can be measured by one micromolar according to the same method as the above-mentioned determination of coagulability] liter) is used as a solution of p-nitrobenzamine hydrochloride (20 microdegrees ": "" Use a variety of Zhang experimental reagents between 0 and 100 micromolar concentration. Dissolve the protease in 0. 1N ， α, and then dilute to a solution of 1 microgram / ml with 'DiTr buffer. The total volume of the reaction solution is 200 microliters, which is the same as that used in the coagulation test of 92374 68 200400187. It is used to calculate 玟 · house with other procedures and thrombin. 1 60 micromolar: Km value is according to the same method of thrombin as in thrombin 1. The inhibitory activity of white enzyme: the tested compound of the present invention has a value of Γ1Kil for all compounds of thrombin and pancreatic egg. Results As for thrombin, Λ is 50 nanomolar concentration (ηM) or higher for trypsin, and Paleoclinic's is 1 micromolar or higher. Specifically, 'A e Example 22 The Ki i value of trypsin measured by the compounds of 30 and 30 is not in Table 1 below. Table

Compound M Example 22 (Example 3 0 0.30 21333 21019 Trypsin Inhibition Constant (nM) H〇2CCH2-D-Dpa-Pr〇-NH-CH2-5- (2-amd) -thioph Test 3 Pharmacokinetics Test_ The absorption rate when the compound of the present invention is administered orally will be measured by measuring the concentration of the drug in the blood according to the following procedure. The male dog is fasted for 18 hours and then consumed. The drug is taken orally 1 hour after ingestion In this article, the drug is an example of using HPCD (hydroxypropyl- / 3-cyclodextrin; hydroxypropyl- / 3-cyclodextrin) as a dissolution aid to prepare 1% (10 mg / ml) of the example The compound solution was prepared. Blood of dogs was collected at certain intervals, then extracted with dichloromethane, and then back extracted with dilute hydrochloric acid solution. HPLC content 69 92374 200400187 was used to measure the drug of the compound of the present invention in blood ^动力 The dynamic parameters are nasally measured from the above-mentioned blood concentration in the blood, and are shown in τ Shiba F Table 2 〇 Table 2 Oral injection-kg, solution, feeding) 眚 你 你 1 ^ --- ------ max (mg 3 liters) ma] (min AUC (μg • min / ml) 1 22 30

----— ^ ^ -— Examples Original compounds Note) ": CH ^ 5- (2-amd) .thioph In Table 2 above,

Cmax is the highest blood concentration,

Tmax refers to the AUC required to reach the highest blood concentration. It refers to the curve of time vs. blood concentration. 2. Convert the results of shell & j into bioavailability 3. . ), And shown in the table below 923¾ 70 200400187 Table 3 Bioavailability (%) original compound "Example 13 Example 22 Example 30 When administered after fasting (A) 42 7.1 28 0.4 When administered after ingestion (B) 4.4 3.4 9 4 Bioavailability ratio (B / A) 10 48 32 1000 Note) * 1: H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph As shown in Table 3, this The compound of Inventive Example 22 showed higher bioavailability and higher absolute bioavailability after ingestion than the original compound. In the case of the compound of Example 30, the absolute bioavailability after fasting The utilization rate is not high. However, after ingestion, the absolute bioavailability of the compound of Example 30 is increased to the same level as the original compound, and the bioavailability ratio of the compound of Example 30 is also improved to that of the original compound. 1 00 times 0 92374

Claims (1)

200400187 The scope of patent application: 1 · A compound represented by the following formula (1), a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof: ⑴, where, A represents -CH2c〇2ri, where R 丨 represents hydrogen, c] _Cf alkyl, f oligo C5-C] 0 -aryl-C] -C6 :): end group, or C5-C] 0- Aryl, B represents Η, 〇H, R2, 〇R2, 〇c (〇) r2, 〇c (〇) nhr2, 〇C (〇) 011, C (〇) or2, C (0) R2, C (〇) NHR2, C (〇) NR22, ◦P (〇) (〇R °) 2, or C (〇) 〇 (CHR4) m〇C (〇) R5, wherein 八 and B are not hydrogen at the same time, : R independently of each other represents a nitro group; or an unsubstituted or unsubstituted or substituted group of the I group selected by the mono-to-most substituted cc group, which is called V heteroaryl 6 group, Or represents (CHH-C factory ring-burnt earth or (CH2) n-heterocyclic ring (n = 〇, J, 2, middle, heteroaryl or heterocyclic ring)) (which .. ,,, # Each day has one or two nitrogens selected from the group consisting of nitrogen. A heteroatom of the mutual group-selected from the group consisting of a function, a group, and c Γ °° or a table that is unsubstituted or-substituted with at most substituents. The substituents of the group formed by the oxygen group, cc ^^^ or aryl group cvq-alkane ~ 5 "group, or ... alkynyl-fluorene, claws indicate integers of 2, 3 or 4, _ 92374 72 2004 00187 R3 represents hydrogen or c] _c6_alkyl, and R4 represents hydrogen or c] -c3-alkyl. 2. If the compound of formula 7 in the scope of the patent application / / not the compound, X can be connected to the medical stand. Salt, hydrate, solvent, ..., or isomer, wherein A represents -CH2CO2R], where Ri represents # 3. Eight represents lice or cvcv alkyl. A compound represented by formula (I), a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof. In beans, B represents H, OH, C (Q) QR2, qc (〇) r2, c ( q) r2, c (〇) nhr2, c (〇mv 〇P⑼ (ork c (Q) G (CHR4) mQc (〇) R5, wherein, R2 & R5 independently of each other are unsubstituted or selected from Halogen, via group and C] _C6_ alkoxy group consisting of a single substitution to the substituted cvcv alkyl; or represents a cycloalkyl, (CH2) n-heteroaryl, or (CH2) n_ Heterocyclic ring (n = 0, i2, 3) (wherein a heterosquaryl or heterocyclic ring refers to a 5- or 6-membered ring having one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur) ; Or represents unsubstituted or selected from halogen, and C rc 6 -alkoxy Groups of substituents are single-substituted to substituted benzoyl, or C / Cu-aryl-CVC6-alkyl or (^-(: 6-alkynyl-N (R4) 2, where m represents Bu 2 An integer of 3, 4 or 4, r3 represents c] _C6 monoalkyl 'and R4 represents hydrogen or C] -C3-alkyl. 4. The compound represented by formula (1) in item 1 of the scope of patent application, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof, wherein A represents -CH ^ CC ^ R1 'Where R] represents hydrogen, ethyl, or third butyl, and B represents H, OH, C (〇) OR2, OC (〇) R2, C (〇) R2, C (〇) NHR2, C (〇) NR22, OP (〇) (OR3) 2, or c (〇) 〇 (CHR4) mOC (0) R5, 73 92374 200400187, where 'R2 and R5 independently represent each other. Group, x-butyl group, tertiary butyl group, or neopentyl group, A group is substituted or selected from the group consisting of methyl group, chloro group, chloro group, methyl group, and methylamino group. Substituted for a single substitution at most; or represents (CHH 々 ring alkynyl (㈣ ㈣ i 2 ㈠, imidazole, (CH2) 2-morpholine, or CM pyridine); or represents unsubstituted or selected from ortho and methoxy The substituents of the group formed by the radical are mono-substituted ^ poly-substituted phenyl; or benzyl or _ (ch2) 2_n (CH3) 2, m is 1, 2, 3, or 4 substitutes, r3; 7 points <Number of kings, R represents ethyl, and R4 represents oxygen or fluorenyl. The compound represented by formula (1) in the range of interest, the pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof is selected from the group consisting of the following compounds: Et02CCH2- D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph- OH; H02CCH2-D.Dpa-Pr〇.NH.CH2-5 ^ (2-amd) -thioph- OH; Et02CCH2 ^ D-Dpa.Pr〇.NH-CH2-5- (2-amd) -thioph; Et02CCH2-D ~ Dpa-Pro-NH-CH2 ^ 5 ^ (2.amd) -thioph- C (0) 0CH2CC13; H02CCH2 -D-Dpa-Pr〇-NH> CH2-5- (2-amd) -thioph-C (0) 0CH2CC13; / Bu02CCH2-D ^ Dpa-Pr〇-NH-CH2-5- (2-amd)- thioph- C (0) 〇CH2CC13; / Bu02CCH2 ^ D ~ Dpa-Pro-NH-CH2-5- (2-amd) -thioph- 74 92374 200400187 C (0) 0CH2CH3; Et02CCH2-D »Dpa-Pro-NH -CH2-5- (2-amd) -thioph-C (0) 0CH2CH3; H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 0CH2CH3; H02CCH2 ^ D -Dpa-Pro-NH ~ CH2 ^ 5- (2-amd) -thioph-C (0) 0CH2Ph; Et02CCH2-D-Dpa-Pro-NH-CH2-5 &gt; (2-amd) -thioph-C (0 ) 0CH2Ph; H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 0CH2 / Pr; Et02CCH2-D-Dpa &gt; Pro-NH-CH2-5- (2- amd) -thioph-C (0) OCH2 / Pr; iBu02CCH2-D-Dpa-Pro-NH-CH2-5 -(2-amd) -thioph-C (0) OCH2 / Pr; H02CCH2-D-Dpa-Pro &gt; NH-CH2-5- (2-amd) -thioph-C (0) 0CH (CH3) 0C (0 ) CH3; Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2 ~ amd) -thioph-C (0) 0CH (CH3) 0C (0) CH3; / Bu02CCH2-D-Dpa-Pro-NH- CH2 &gt; 5- (2-amd) -thioph-C (0) 0CH (CH3) 0C (0) CH3; H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C ( 0) 0CH2CH20CH3; Et02CCH2-D-Dpa-Pro-NH ^ CH2-5- (2-amd) -thioph- 75 92374 C (0) 0CH2CH20CH3; H02CCH2-D-Dpa-Pro-NH-CH2-5- (2 -amd) -thioph-C (0) 0Ph-4-F; Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (〇) 〇Ph-4-F; Et02CCH2 -D-Dpa &gt; Pro-NH-CH2-5- (2-amd) -thioph-0C (0) CH3; H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 0CH2CF3; Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (〇) 〇CH2CF3; Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2 -amd) -thioph-C (0) 0Ph-4-0CH3; H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 0CH2CH2F; Et02CCH2-D-Dpa- Pro-NH-CH2-5- (2-amd) -thioph-C (0) 0CH2CH2F; Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2 ~ amd) -thioph-C (0) 0CH20C ( 0) CH3; H02CCH2 ^ D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 0CH2Cyh; E t02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) &gt; thioph-C (0) 〇CH2Cyh; H02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd)- thioph- 76 92374 C (0) 0CH2CH2Cyh; Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 0CH2CH2Cyh; Et02CCH2-D-Dpa-Pro-NH-CH2- 5- (2-amd) -thioph-C (0) -Imide; Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) OCH2CH2-Mor; Et02CCH2-D -Dpa-Pro-NH ~ CH2 ^ 5- (2-amd) -thioph-C (0) 0CH2-3-Pyr; Et02CCH2- * D-Dpa-Pro-NH-CH2-5- (2-amd)- thioph-C (0) NHCH2CH20H; Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) ^ thioph-C (0) N (CH2CH20H) 2; Et02CCH2-D-Dpa-Pro-NH- CH2-5- (2-amd) -thioph-C (0) 0CH2CH2N (CH3) 2; Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 0CH2Cypr; Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) 0CH2Cypen; Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph- C (0) CH2rBu; Et02CCH2-D-Dpa-Pi-〇- NH-CH2-5- (2-amd) -thioph-C (〇) 〇Cyh; Et02CCH2-D-Dpa-Pro-NH-CH2 ^ 5 -(2-amd) -thioph- 77 92374 200400187 C (〇) OCH2Cyb; Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (〇) CH3; Et02CCH2-D- Dpa-Pro-NH-CH2-5 -(2-amd) -thioph-C (0) CH2CH3; Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-C (0) / Pr; Lu Et02CCH2-D-Dpa -Pro-NH-CH2-5- (2-amd) -thioph- 0C (0) zPr; Et02CCH2 ~ D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-0C (0) CH2CH3 ; Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph-OC (〇), Bu; Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd)- thioph ~ 〇P (〇) (〇CH2CH3) 2; and • Et02CCH2-D-Dpa-Pro-NH-CH2-5- (2-amd) -thioph- C (〇) NHCH2zTi- 〇6. As the scope of the patent application The compound represented by formula (1) in item 1, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof, is Et〇2CCH2-D-Dpa-Pro-NH-CH2- 5- (2-amd) -thioph-OH. 7. The compound represented by formula (1) in item 1 of the scope of patent application, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof, the compound is EtC ^ CCH ^ D-Dpa- Pi-o-NH-CHrS-P-arndpthioph- 78 92374 200400187 C (〇) CH2zPr. 8. The compound represented by formula (1) in item 1 of the scope of patent application, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof, the compound is Et〇2CCH2-D-Dpa- Pro-NH-CH2-5- (2-amd) -thioph-OC (〇) CH3. 9. The compound represented by formula (1) in item 1 of the scope of patent application, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof is Et〇2CCH2-D-Dpa- Pro-NH-CH2-5- (2-amd) -thioph-C (〇) 〇CH2Cyh. 10. The compound represented by formula (1) in item 1 of the scope of patent application, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof is Et〇2CCH2-D-Dpa- Pro_NH-CH2-5- (2-amd) -thioph-C (〇) 〇CH2CH2Cyh. 11. The compound represented by formula (1) in item 1 of the scope of patent application, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof, is Et〇2CCH2-D-Dpa- Pro-NH-CH2_5- (2-amd) -thioph-C (〇) 〇CH2-3-Pyr. 12. As the compound represented by formula (1) in the first patent application scope, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof, the compound is Et〇2CCH2-D-Dpa- Pi-O-NH-CH2'5- (2-amd) -thioph-C (〇) CH3. 1 3 · A method for preparing a compound represented by formula (1) in item 1 of the scope of patent application, a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof, characterized in that: 79 92374 200400187 (a) A compound represented by the following formula (2): (In the formula, B is as defined in item 1 of the scope of the patent application, and P represents a protective group of an amine group), and is reacted with HC1 gas in a solvent to obtain a compound represented by the following formula (3): (In the formula, B is as defined in item 1 of the scope of patent application), and then in the presence of a catalyst, the compound represented by the formula (3) thus obtained and the compound represented by the following formula (4) are Reactions in Solvents · A—L (4) (Where A is as defined in item 1 of the scope of patent application, and L represents a leaving group) to obtain a compound represented by formula (1), or (b) the formula (la) or (lb) below Shown compounds: (la) (lb) (where A is as defined in the scope of the patent application), which is reacted with carbonic acid in the presence of a base 80 92374 400187 to obtain a synonym anhydride or a halide in a solvent. Compounds shown in (lc) · Ph \ 0 ^, ,, 〇c) 工 ′ B ′ represents B, β—a kind of composition other than Η and 0H, which are /, have ^ or fe groups. % 14 Homocysteine, or preventive treatment of anti-diplipid antibodies, formation, pulmonary embolism, arterial thrombocytopenia, venous thrombosis, thrombosis, AA, cardiac embolism, septic Pu Guzhi, Zhi Tong, Ke, and pancreatitis; and the prevention of re-closing and re-thrombosis, Zhishizha ^ Danji, and the pre-composition 4 include the following formula (1) Shown as a private person. Γη 乐 1 Item mouthpiece, the salt acceptable on the sauce, the solvate of the compound, the compound, the structure, and the pharmaceutically acceptable carrier. 92374 8] 200400187 柒. Designated representative map: (1) The designated representative map in this case is: (). (2) Brief description of the component representative symbols in this representative diagram: There is no scheme in this case. 捌 If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 92374