TW458956B - Meta-guanidine, urea, thiourea or azacyclic amino benzoic acid compounds and derivatives thereof - Google Patents

Abstract

The present invention relates to a class of compounds represented by the Formula I or a pharmaceutically acceptable salt thereof, wherein A is pharmaceutical compositions thereof and methods of using such compounds and compositions as Αvβ3 antagonists.

Description

Printed by Zhongfu Standard Cooperative Consumer Cooperative of the Ministry of Economic Affairs ^ 59956, A 7 ___ ________B7 _ V. Description of the Invention () This case claims 35 USC § 11.9 (e) for the US patent application filed on August 30, 1995 60 / 003,277 Priority. FIELD OF THE INVENTION The present invention relates to a retarder (compound) that can be used as an integrin integrin (integrjn), and a medicine that can be used to treat the disease by inhibiting or including anti-3 integrin and avj5 3 disease. Composition and method. BACKGROUND OF THE INVENTION · Integrins are a group of cell surface glycoproteins, with the mesenchymal cells dying, so they can be used as mediators of cell adhesion and interactions that occur during various biological processes. Integrins are heterodimers that include non-covalently linked subunits of this and peptone. At present, it has been confirmed that 11 different α subunits and 6 different point subunits can be combined with various subunits to form different integrins. Integrin (also known as vitronectin receptor) has been identified as an integrin responsible for the following symptoms or disease conditions, including tumor metastasis, solid tumor growth (neoplastic formation), osteoporosis, Berger Paget's disease, malignant humoral hyperemia, angiogenesis (including tumor angiogenesis), retinopathy 'arthritis (including rheumatoid arthritis), periodontal disease, psoriasis, and smooth muscle cell migration (again, Restenosis In addition, the integrin has been found to be useful as an antiviral agent, antibacterial agent, and antimicrobial agent. Therefore, compounds that can selectively inhibit or antagonize ΛνΒ3 can be used to treat these diseases. It has been shown Λ ν / 3 3 integrin and other α V-containing integrins are bound to Arg-Gly-Asp (RGD) -containing matrix macromolecules. Containing -4- paper waves, the Chinese National Standard (CNS) A4 specification (2! 〇X297mm) ---------- install-(please read the note on the back ^^ item ^-4 to write this page) Order

V. Description of the invention (The compound of the RGD sequence mimics the extracellular matrix 'ligand and binds to the cell surface stylus. However, it is known that the peptides are generally non-selective for RGD-dependent integrins such as' bound to pentamidine'. Most rGd peptides of vA also bind to ~ Θ 5 '~ 73 1 and 戌 Π1 ^ 3. The antagonistic effect of platelet e i! BB3 (also known as fibrinogen receptor) has been known to block human platelet aggregation. In order to avoid bleeding side effects in the treatment of symptoms or disease conditions associated with integrin o? W3 3, it is advantageous to develop a selective antagonist against aIIb々3. Tumor cell invasion occurs in three steps: (丨) tumor cells attach to the extracellular matrix; (2) protein lysis of the matrix; and (3) cells move through the lysis barrier. This method can be repeated and can cause metastases to occur away from the original tumor.

Seftor et al. (Proc ’Natl. Acad. Sci. USA, Vol. 89, (1992) 155 7-1561) have revealed that a 3 integrin has biological functions in melanoma cell invasion. Montgomery et al. (Proc. Natl. Acad · Sci. USA, Vol · 91, (1994) 8856-60) have demonstrated that integrin 表现 expressed on human _ melanoma cells can promote survival signals and protect cells from death (apoptosis ). The regulation of tumor cell metastasis pathways can interfere with tumor metastasis by interfering with the vb3 integrin · cell adhesion receptor.

Brooks et al. (Cell. Vol. 79 (1994) 1157-1164) have demonstrated that the antagonist provides a medical method for the treatment of neoplasia (inhibition of the formation of solid tumors) because the systemic administration of 3 antagonists can make a variety of tissues The difference is that human tumors have largely subsided. The adhesion receptor, integrin 3, has been identified as a marker for chicken and human angiogenic blood vessels. Therefore, this receptor plays an important role in angiogenesis or neovascularization. -5-. This paper applies Chinese national standards (CNS ) Α4 specification (210 X 297 mm) {Please read the note on the back ^ '% to write this page)' Installation · Central Ministry of Economy and Trade Standards Co., Ltd. Printing Co., Ltd .: ^ Q 5 β Α7 _______ Β7_. · 5. Description of the invention f) Color. Angiogenesis is characterized by the invasion, migration, and proliferation of smooth muscle and endothelial cells. A3 antagonists inhibit this process by selectively promoting apoptosis in the neovascular distribution. The growth of new blood vessels, or angiogenesis, also causes pathological symptoms, such as diabetic retinopathy (Adonis et al., Amer. J. Ophthal, Vol. 118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp. Med., Vol, 175, (1992), 1135-113S). Therefore, 3 antagonists can be used as medical targets for the treatment of diseases related to neoangiogenesis (Brooks et al., Science, VoL 264, (1994), 569-: 571). '' It has been reported that cell surface receptor 3 is the main integrin on osteoclasts that is responsible for adhering to bone ° Erosion of osteoclasts causes bone resorption, and when bone resorption activity is greater than bone formation activity, osteoporosis (osteoporosis) occurs; causing Increased number of fractures, inability and mortality. Antagonists of Lu 3 have been shown to be effective inhibitors of osteosynthesis' in vitro [Sat. et al, j Cell. Biol., Vol. 111 (1990) 1713-1723] and in vivo [Fisher et aI · ,

Endocrinology, Vol. 132 (1993) 141 1..1413]. Antagonism of π v / 5 3. Causes reduced bone resorption, thus restoring the normal balance of skeletal formation and resorption activity. Therefore, it is advantageous to provide an antagonist of osteoclast% 3, which is an effective inhibitor of skeletal absorption, so it can be used to treat or prevent osteoporosis. The role of the integrin printed by the Ministry of Economic Affairs of the Ministry of Economic Affairs for the industrial and consumer cooperatives in the movement of smooth muscle cells also makes it possible to: as a prevention or inhibition of neovascular intimal proliferation (which is changed after the vascular growth procedure. The main cause) of the medical target (Choi et al., J. Vasc_ Surg. V01 1 (1) (1994) 125-34). Prevention or inhibition of neovascular intimal proliferation with agents can prevent or inhibit restenosis. -6-This paper music scale is applicable to Chinese National Standard (CNS) A4 specification (210X297mm) A7 B7 V. Description of invention () ’

White (Current Biology, Vol. 3 (9) (1993) 596-599) has reported that adenovirus uses or VB3 to enter host cells i. The integrin appears to be required for the saturating effect of virions, and may be required for the viral genome to penetrate into the host cell's cell mass. Therefore, compounds that inhibit .rY /? 3 can be used as antiviral agents. Summary of the Invention The present invention relates to compounds zt

X -HIR c-n NIR Y—c—z / f h c

R I o = G or a pharmaceutically acceptable salt thereof, where A is

NIR

X

R7Γ N-R Y1 is selected from the group consisting of N-R2, 0 and S: * R2 is selected from the group consisting of: alkyl: aryl: hydroxyl: alkyl: cyano: nitrate Alkyl group: Alkenyl group: Alkenyl group: Alkylamino group: Alkylcarbonyl group; Arylcarbonyl group: Alkoxycarbonyl group: Aralkylenecarbonyl group: Alkylcarbonyl group: Alkoxycarbonyl group: Alkylthiocarbonyl group;醯 oxy 曱 oxycarbonyl: alkyl select 悻 is one or more selected from the list of T. Paper size applicable to China National Standard (CNS) A4 specifications (2! 0X297 mm) 4 5 dy 5 β A7 B7 * g a ~-; ------- 5. Description of the invention (), Substituting group substitution: lower alkyl, halogen, hydroxyl, alkyl, cyano, nitro, carboxyl, amine, alkyl Oxy, aryl, aryl are optionally one or more of halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkanesulfonyl, alkylthio, nitro, carboxyl, amine, hydroxyl , Sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocyclic ring or fused monocyclic heterocyclic ring; the aryl group is optionally substituted by one or more substituents selected from the group consisting of: Alkyl, hydroxyl, low Alkyl, alkoxy, methylenedioxy, ethoxydioxy, cyano ,, nitro., Alkylthio, alkanesulfonyl, sulfonic acid, sulfonamide, carboxyl derivative, amine Group, aryl group, fused aryl group, monocyclic heterocyclic ring and fused monocyclic heterocyclic ring; monocyclic heterocyclic ring :: and monocyclic heterocyclic ring are optionally substituted with one or more substituents selected from: halogen, Alkyl, lower alkyl, alkoxy, amine, nitro, hydroxyl, carboxyl derivatives, cyano, pothio, dry alkynyl, continuous acid, continuous amine, aryl, or networked aryl ; Or R2 and R7 together form a 4 to 12-membered dinitrogen-containing heterocyclic ring, the selectivity is one or more. Multiple substituents selected from the following: lower alkyl, hydroxyl, keto, alkoxy, pixel, Phenyl, amino, carboxy or carboxy ester, and fused phenyl: or R2 and R7 together form a 5-membered heteroaromatic ring, the selectivity is one or more selected from the group consisting of lower alkyl, phenyl or hydroxyl Substituent substitution; or · R2 and R7 together form a 5-membered heteroaromatic ring fused with a phenyl group: printed by R7 (when not connected to R2) and R8 Choose each烷基; alkyl: alkenyl;; alkynyl; aralkyl; amine: alkylamino; hydroxy: alkoxy; arylamino;: amine: alkylcarbonyl: arylcarbonyl: alkoxycarbonyl: aryloxy Group; aryloxycarbonyl group: alkanecarbonyl group: fluorenyloxycarbonyl group; pit thiocarbonyl group: arylthiocarbonyl group: fluorenyl group. Fluorenyloxycarbonyl group; cycloalkyl group: bicycloalkyl group: aryl group: fluorenyl group; benzamidine group ： -8-Chinese paper standard (CNS) A4 specification (2tOX2 ~ 7mm) is applicable to this paper method 尺度 ^ 4 58 9 56 V. Description of invention (e A7 B7 Printed alkyl group by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Selectivity is substituted by one or more substituents selected from the group consisting of lower alkyl, halogen, mesityl, fluorenyl, cyano, nitro, carboxyl derivative, amine, carboxy, thio, sulfur extraction The aryl group, the aryl group, the aryl group, the aryl group, and the aryl group are optionally selected from one or more of the following substituents. Substituted by the following substituents: haloyl, hydrazone, lower alkyl, alkoxy, methylene Dioxy, ethoxydioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano'nitro, carboxy derivative, aryloxy, fluorenylamino, fluorenylamino, Amine, alkylamino, diamido, trifluoroalkoxy, trifluoromethyl, sulfo ''s sulfonyl, sulfanyl, sulfonic acid, sulfanil, aryl, fused Aryl, monocyclic heterocycle, fused monocyclic heterocycle: The aryl group is optionally substituted by one or more substituents selected from the group consisting of: halogen, commercial alkyl, lower alkyl, alkoxy-, methylene Dioxy, ethoxydioxy, alkylthio, alkylthio, thio, hydroxy, cyano, nitro, carboxy derivative, aryloxy, fluorenylamino, fluorenylamino, amine , Alkylamino, Monophosphino, Difluoroalkyloxy, Trifluoromethyl, Substituted phenyl group, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic Heterocyclic, fused monocyclic heterocycles; monocyclic heterocycles: monocyclic heterocycles are optionally substituted with one or more substituents selected from the group consisting of halide, haloalkyl, lower alkyl, alkoxy, aromatic Oxygen, amine, nitro, aryl, bis-derivative, aryl, thio, sulfanyl, amidino, aryl, or fused aryl: monocyclic and bicyclic heterocycloalkyl: _s〇2rI0 Where R 1 0 is selected from alkyl, aryl and monocyclic heterocycles, Selectively substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, cyano, nitro, amine, fluorenylamino, trifluoroalkyl, fluorene Amine, Alkylaminosulfonyl, Alkylsulfonyl, Alkylsulfonylamino, Alkylamino, Dialkylamino, Trifluoromethylthio, Trifluoroalkoxy, Trifluoromethylsulfonyl, Aromatic Base, aryloxy-9-Private paper music scale is applicable to Chinese National Standard (CNS) A4 Regulation (210X297 gram)

458 95S A7 B7 V. Description of the invention () group, thio group, thio group and monocyclic heterocyclic ring: and 0Ιί -C-RNR 7 π ΐ? 8 —, where R10 is as defined above and R — forms a 4- 12-membered monocyclic or bicyclic ring containing one nitrogen, optionally substituted with one or more substituents selected from the group consisting of a low-pitched group, a carboxyl derivative, an aryl group or a hydroxyl group, wherein the ring optionally contains a heteroatom selected from 〇, N & s R3 is selected from Η, alkyl ·, alkenyl, alkynyl, benzyl, and phenethyl; or A is -porium R5 'NR7 (please read the note on the back and then + poor (This page). Installed.-Ordered by the Ministry of Economic Affairs, the Central Government Escalator Bureau, Consumer Cooperatives. Y2 is selected from the group consisting of alkyl; cycloalkyl; dienyl; aryl; monocyclic heterocycle: Aryl substitution, aryl may optionally be one or more substituents selected from halogen, haloalkyl, alkyl, nitro, hydroxyl, alkoxy, aryl-oxy, aryl or fused aryl Substitution: aryl selectivity is one or more selected from the group consisting of halogen, haloalkyl, hydroxyl, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, and ethylidene Dioxy Or an alkyl substituent; block: alkenyl; -S-R9 and -O-R9, where R9 is selected from H: alkyl: aralkyl, aryl: alkenyl: and alkynyl; or R9 Forms two 4- to 12-membered heterocycles containing one nitrogen and one sulfur or one oxygen with R7. The selectivity is low alkyl, hydroxyl, phenyl, phenyl, poly or phenyl acetate, and slightly phenyl. Replace; or 10 * private paper size applies to China Family Standards (CNS) A4C (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy 458 956 A7 ____B7_ V. Description of the invention (8). ^ .R9 and R7 -From thiazole: humidazole: benzoxazol; or benzopyrazole: and R5 and R7 are as defined above; or Y2 (when Y2 is carbon) and R7 together form a 4-12 member containing one nitrogen or two Nitrogen, ring selectivity is substituted by alkyl, aryl, keto or hydroxy:: or ... A is N—R2-

N FR5 N-R7 R0 where R 2 and R 7 together form a 5 to 8 member diaza heterocyclic ring, the selectivity is: one or more selected from the group consisting of low alkyl, hydroxyl, keto, and phenyl Or derived from carboxyl #, the substituent is substituted: R8 is selected from alkoxycarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkanecarbonyl, alkoxycarbonyl, alkthiocarbonyl, arylthiocarbonyl, or alkoxycarbonyl : R 3 is as defined above:. Or * A is' R0 „·

—-N—C 'N-R7' 1: R8.: In the formula, R2 and R7 together form a 5-8 membered dinitrogen-containing heterocyclic ring with a selectivity of -11-The paper scale is applicable to Chinese national standards ( CNS) A4 specification (210 × 297 mm) installed-(Please read the precautions on the back ^ this page first) A 4, M ^ 45895 ^ A7 B7 _ '' V. Description of the invention (), short-based, keto-based, Phenyl or alkynyl: R8 is all selected from alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, oxyalkanoyl, self-burning > Air methoxy truncation;: Z 1 is one or more substituents selected from: Η; alkyl; hydroxy; alkoxy: aryloxy: nansin; haloalkyl: haloalkoxy: nitro ; Amine; Amido: Amidino; Dialkylamino: Cyano: Alkylthio; Alkylsulfonyl; Carboxyl Derivatives: Trihaloacetamido; Acetamido: Aryl · Condensed Aryl ·, Cycloalkyl: thio: monocyclic heterocyclic ring; fused monocyclic heterocyclic ring: and A, where A is as defined above: V is selected from -N- (R6) ·, where R6 is also Η: lower alkyl : Cycloalkyl, aryl stem; aryl: and monocyclic heterocycle: or R6 and Υ together Forming a 4--1 2-membered nitrogen-containing ring: Υ 'Υ', Z and 2 ^ are each selected from lice; .base; aryl; and cycloalkynyl; or γ and Z—to form a cycloalkyl group: Or Υ3 and Zn3 together to form a cycloalkyl group. Η is 1, 2 or 3: t is 0, 1 or 2: p is 0, 1, 2 or 3; printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs R is X-R3, where X is selected from 0, S and NR4, wherein r3 & R4 is each selected from hydrogen: alkyl: dilute: block: 1¾; alkyl: aryl; aryl; aryl; sugar; steroid; poly Rhodium ether; Brilliant amine group: Benzyl group N, N · Disylamine | trimethylamine; trimethyl ethyl oxymethyl group: in the case of free acid and its pharmaceutically acceptable salt; R 1 is selected from hydrogen ·, Alkynyl: alkenyl: alkynyl: aryl: tertyl derivative: haloalkyl; ring gauge: monocyclic. Heterocyclic: monocyclic heterocyclic ring is optionally substituted with the following groups: alkyl, functional Haloalkyl, cyano, hydroxy, aryl, fused aryl, nitrate-12- This paper ruler is applicable to China National Standard (CNS) A4 specification (210X297 mm)

TO A7 B7 Printed base, Polyoxy, Aryloxy, Persaldi, Aroyl, Dimethylamine, Sulfur, Alkylthio, Carboxyl Derivative, Amine group, amido group; therefore, the base is optionally substituted by one or more of the following groups: self-priming, self-alkyl, several groups, oxo, aryloxy, thio, thiothio, block, fluorenyl , Tiger, arylthio, sulfanyl, sulfenyl, sulfonyl, arylsulfinyl, aryl, g | yl, aryl, nitro, amine, amido, diamine, and sulfonium Amine, arylamine, fluorenylamine, carboxy derivative, sulfonamide, sulfonic acid, phosphonic acid derivative, phosphinic acid derivative, aryl, arylthio, arylsulfoxide or arylsulfonium, The selectivity on the aryl ring is the following. Substituted groups: halogen) alkynyl, sulfonyl, cyano, nitro, hydroxy 'aryl derivatives, acyloxy, aryloxy, amine, λι * amine Group, dioxin * amino group, g-amino group, aryl group, reticulated aryl group, monocyclic heterocyclic ring and monocyclic heterocyclic ring, monocyclic heterocyclic thio group, monocyclic heterocyclic ring, and monocyclic ring Heterocyclic ring Alkyl, nitro, hydroxy, -alkyloxy, fused aryl or alkyl substitution: alkylcarbonyl, substituted by alkylcarbonyl, and arylcarbonyl: aryl is substituted by one or more of the following groups for selectivity: Alkyl, alkyl, alkoxy, aryloxy, methylenedioxy, ethoxydioxy, thioalkyl, sulfanylthio, thio, hydroxy, cyano, nitro, fluorene Oxy 'carboxy derivative, carboxyalkoxy; fluorenylamino, fluorenylamino, amine, alkylamino, diamine, trifluoroalkoxy, trifluoromethanesulfonyl, alkylsulfonyl , Sulfonic acid, sulfonamide, aryl, fused aryl 'monocyclic heterocycles and fused monocyclic heterocycles: and -13- (CNS) A4 specifications (210X297 mm) ~~'.: _J I: j I .------- install ------ order ----- 1 — {Please read the note page on the back) 11 V. Description of the invention () ο IIc

N R7 R8 Α7 Β7 where R7 and R8 are as defined above, if R and R are connected together, R7 and R8 include amino acids: and R11 is selected from fluorene, the radical 'aryl gauge', alkenyl, alkynyl, and _. Or printed by the Central Bureau of the Ministry of Economic Affairs of the Shellfish Consumer Cooperatives' or R11 and Υ together to form a 4-12 member nitrogen ring. Another object of the present invention is to provide a pharmaceutical group comprising a compound of formula I. When the compound and composition can be used to selectively inhibit or antagonize & Θ S substances. Ά 3 integration + ′ Therefore, in another embodiment, the present invention relates to a method for selectively depressing antagonism of heart 3 integrin. The present invention also relates to the treatment or inhibition of pathological symptoms, such as osteoporosis, malignant body fluid hypercalcemia, Berger disease, tumor metastasis, solid tumor growth (neoplastic formation), angiogenesis, including tumor angiogenesis. ), Retinopathy (including diabetic retinopathy), arthritis (including rheumatoid arthritis), periodontal disease, psoriasis, smooth muscle cell movement and restenosis, and for mammals in need of this treatment3 In addition, the agent can be used as Antiviral and antimicrobial agents. Detailed Description The invention relates to a compound represented by the above formula (I). A preferred embodiment of the present invention is the compound 14 of the following formula 11-This paper scale is applicable to the Chinese national standard rate (coffee) Congmi (plus father's day, please read the notes on the back first *-¥ write (This page)

12 4 ‘ο A7 B7 V. Description of the invention (NR7yt ^ = (XRe N-—R5 ο

Z1

Where R 5 'R 7 and R 8 are each selected from H, alkyl, aryl, carboxyalkyl, substituted aryl, substituted arylsulfonyl, and aralkyl, or from NR7 and R8 together A 4- to 12-membered nitrogen-containing ring is formed, optionally substituted, and other variables are as described in Formula I. Another preferred embodiment of the present invention is a compound of formula III

(Please read the notes on the back A. '^ K this page first)

J Printed by the Central Consumers Bureau of the Ministry of Economic Affairs of the Consumer Cooperatives in the formula, Y1 is -NR2, forming a optionally substituted 4 1 2 member ring. The other variables are defined as above, formula i. Another preferred embodiment of the present invention is the Xiawu IVI compound. -15- The paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) 46S3S8 V. Description of the invention (13 A7 B7 -NR7

R1 0

In the formula, Y and the ruler form a 4-12 member ring, and other variables are defined as in Formula I above. Another preferred embodiment of the present invention is a compound of formula V

^ IHi ^ c ί'1 NIR RΟΛ The Ministry of Economic Affairs of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the consumer cooperation Du printed equipment: the variables in the formula as defined in the above formula I. -The present invention also relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula V. -* The present invention also relates to a method for selectively inhibiting or antagonizing integrin, more specifically,-a kind of inhibition of bone and mass absorption, periodontal disease, osteoporosis, malignant fluid surface calcium, Berger's disease , Tumor metastasis, solid tumor growth (tumor formation), angiogenesis (including tumor angiogenesis), retinopathy (:--16- This paper size applies to the Chinese national standard (CNS "八 4Touch (21〇χ: ~ A58956 V. Description of the invention (A7 B7 Printed by the Consumer Cooperative of the Central Bureau of Accreditation of the Ministry of Economic Affairs including diabetic retinopathy), arthritis (including rheumatoid arthritis), smooth muscle cell movement and restenosis methods, by application Compounds of Formulae I-V and pharmaceutically acceptable carriers are therapeutically effective to achieve this inhibition. The following are definitions of various terms used herein: The terms "alkylJ or" low-alkylJ "as used herein mean straight-chain or The branched-chain nicotyl has about 1 to about 10 carbon atoms, and more preferably 1 to about 6 moles. Examples of the tiger group are methyl'ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, first butyl ' Tributyl, pentyl, neopentyl, hexyl, isohexyl, etc. As used herein, the term "alkenyl" or "low alkenyl" refers to an unsaturated acyclic hydrocarbon containing at least one double bond and 2 to about 6 carbons Atoms in which the carbon-carbon double bond within the alkenyl group may have a cis or trans geometric form for the substituent on the double-bonded carbon. Examples of distant groups are ethenyl, propionyl, butyl, isobutyridyl, Pentenyl, hexyl, etc. As used herein, the term "alkynyl" or "lower alkyl" refers to a non-cyclic nicotyl group containing one or more triple bonds and 2 to about 6 carbon atoms. Examples of such groups Are alkynyl, propynyl, butynyl, pentyl, hexynyl, etc. The term "cycloalkyl" as used herein means a saturated or partially unsaturated cyclic carbon group containing from 3 to about 8 Carbon atoms, preferably 4 to about 6 carbon atoms. Examples of the cycloalkyl group include cyclopropyl, cyclopropenyl, cyclobutyl, cyclofluorenyl, cyclohexyl, 2-cyclohex-1-yl, and the like. The term "aryl" as used herein means that the aromatic ring system contains one or more aromatic rings. Preferred aryl groups include one, two, or three aromatic rings. The term includes aryl groups such as benzyl Pyridyl, fluorenyl, methylphene, furan, biphenyl, etc .. -17- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) Read the note on the back first, then f binding, M 458 95 & A7 B7 15 V. Description of the invention () Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The term "cyano" used in this article is represented by the formula l · c N. The term used in this article " Hydroxyl J and "hydroxyl" are synonymous, and are represented by the group of the formula OH. ^ The term "lower alkyl" or "alkylene" as used herein is a divalent divalent of about 1 to about 6 atoms. Linear or branched saturated hydrocarbon group. As used herein, "alkoxy" means a group containing -OR20 in a straight or branched chain, where R20 is an alkyl group as defined above. Examples of alkoxy include fluorenyloxy, ethoxy, n-propoxy, n-butoxy, isopropoxy 'isobutoxy, second butoxy, third butoxy, etc. as used herein The term "arylrodyl" or "aralkyl" is a radical of formula R22-R21, where R21 is an aryl group as defined above, and R22 is an alkylene group as defined above. Examples of aralkyl groups include benzyl , Pyridylmethyl, · propylpropyl, phenethyl and the like. The term "nitro-J" as used herein is represented by the group of formula 丨 -NO2. The term "halogen" or "quotient" used herein refers to bromine, gas, fluorine or the term "halogen" as used herein "Alkyl" means an alkyl group as defined above substituted with one or more hard atoms by one or more of the same or different halo groups. Examples of the halogenated group include trifluoromethyl, difluoroethyl, fluoropropyl and the like. The term "carboxy" as used in the text refers to the base of COOH. As used herein, the term "carboxy ester". A group of the formula-COOR2 3, where R23 is selected from the group consisting of amidine, alkyl 'aralkyl or aryl (as defined above). -18- Applicable to Chinese national standard (CNS) Α4 standard (21〇 > < 297). U .: --------- ":::; equipment-(Please (Read the precautions on the back (write this page)

r_.J r Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 4 5 8 9 A 'A 7 B7' Β 'V. Description of the invention () Y6 The term "complex derivative" as used in this text 丨 丨 of -C -Y7R-3 group, wherein Y 6 and Y 7 are each selected from 0, N and S, and R23 is selected from fluorene, alkyl, aryl, or aryl (as defined above). The term "amine group" as used herein is represented by a group of formula -νη2. As used herein, the term "alkylsulfonyl" or "alkyl" represents the group of Formula 0II--S-R. wherein R24 is an alkyl group as defined above. II. The term "alkylthio" as used herein The base of the formula-SR24, where R24 is the gauge base as defined above. 0 'f! · The term used in the text "The base of the formula J-S-f, where R 25 in II 0 is fluorene, alkyl or aryl (as defined above). (Please read the note on the back first Matter I is enough to write this page)-Binding · Order-19- This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm)

17 V. Description of the invention () 0 'R7 II / The term "sulfonamide" used in this text 丨 -S-N, .. 丨 I. Bu) 0 R8 where R7 and R8 are as defined above. As used herein, the term "rimary aryl J represents an aromatic ring (aryl group as defined above). It is bound to one or more stupid rings. The term" fused aryl "includes amidino. The term "monocyclic heterocycle" or "monocyclic heterocyclyl" as used herein contains 4 to about 12 atoms, preferably about 5 to about 10 atoms, of which 1 to 3 atoms are selected from If there are two or more different heteroatoms of oxygen, nitrogen and sulfur, at least one heteroatom must be nitrogen. The monocyclic heterocyclic ring is represented by mito, squeak, p ratio far away, rugged, u bottom 0 south, three jun, · σ Saifen, p ratio bite, noisy ridge, thia di " wait. As used herein, the term "fused monocyclic heterocyclic ring" refers to a monocyclic heterocyclic ring fused as defined above. Examples of the fused monocyclic heterocyclic ring include benzofuran, benzopiperan, dioxole, benzopyrimidazole, benzopyrene, benzimidazole, and the like. "The term" fluorenylenedioxy "as used herein refers to B0, and the term" oxyethylenedioxy "refers to the J group. -20- The size of this paper applies to Chinese National Standard (CNS) A4 (210X297 mm) I -------- Π installation ------ order ------ ^ extravagant Read the notes on the back again. ¾ Write this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (18 A7 B7 The term "4-12 members containing dinitrogen heterocycles" as used in this paper Table 9 Base, where m is 1 or 2, R19 is fluorene, aryl R10 aryl or aralkyl, preferably a ring of 4 to 9 members, including rings such as imidazoline, as used herein. A substituted heteroaryl ring '' includes, for example, the formula

The "5-membered heteroaryl ring condensed phenyl group" in the table of "or" is a "5-membered heteroaryl ring condensed phenyl group", and the 5-membered hetero1 aromatic ring fused phenyl group is represented by benzimidazole. : The term "bicyclyl" as used herein means that bicyclic nicotinyl contains 6 to about 12 carbon atoms and is saturated or partially unsaturated. The term used in this article "醯 基 J 式 〇 · the base, its I Kun Yi-,. (Please read the note on the back 4 '-write this page first)-Order ·: 捸 h.

J Printed by the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs, R2 6 is a aryl group, an alkenyl group, an alkynyl group, a aryl group, or an aryl dry group. Stupid formaldehyde and so on. The term "thio" as used herein refers to the base of hS Η. 21-This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 4 5 ^ QK " Α7 Β7 19 V. Description of the invention () Printed by the Central Consumers Bureau of Ministry of Economic Affairs, Consumer Cooperatives ο II Used in this paper The term "sulfonyl" is the base of formula -S-R: 7,. I! 0 where R27 is an alkyl, aryl, or aromatic group as defined above. The term "haloalkylthio" as used herein refers to a group of formula -S-R28, where: R28 is a haloalkyl group as defined above. As used herein, the term "aryloxy J phenotype?-A base of R 2 9 wherein R 29 is an aryl group as defined above. 〇 The term" SS-based amino group "as used herein. Formula F 3- & —NH— | wherein R3Q is as defined above. Aspartyl, aralkyl, or aryl. 〇 As used herein, the term "amido" represents the NH2 group of Formula M. The term "alkylamine.yl" as used herein represents a radical of the formula -NHR32, where R32 is an alkyl group as defined above. -The term "dialkylamino" as used herein represents a group of the formula -NR33R34 / wherein R33 and R34 are the same or different alkyl groups as defined above. As used herein, the term "trifluoromethyl J represents the radical of formula cf3. The term" trifluoroalkoxy "as used herein represents the radical of formula F3C-R35-0-; where R35 is a bond or An alkylene group as defined above. -22- This paper scale is applicable to China National Standards (CNS) A4 (210X297 mm) 458956 A7 B7 V. Description of the invention β) 〇 The term "alkylaminosulfonyl" used in this paper is represented by R3S-10. Base, where R36 is the gauge base as defined above. ◦ The term "alkylamine" as used herein is a group of the formula R36 _ ^ ___ NH __ |. 0, where R3 6 is an alkyl group as defined above. The term "trifluoromethylthio 'group" as used herein is a formula; ο The term "trifluoromethanesulfonyl" as used in this paper is F3C-S-II 0 (阅读 Notes on the back of the book—scratched paper 筲)-Stapled printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The term used herein Γ4-1 2-membered monocyclic or bicyclic ring containing one nitrogen "Table 4_ 12 saturated or partially unsaturated monocyclic or bicyclic with 2 atoms, preferably * _ 9 original Ring, one of which is nitrogen. The ring may optionally contain other heteroatoms selected from nitrogen, oxygen or sulfur. This group includes morpholine, hexachlorotene, diazepine, thiomorpholine, pyrrolidine, proline, aza (σ, ") cycloheptene, etc. The term" benzyl "as used herein means The term "phenethyl" used in the basic text is shown in Table 1 M-23 This paper size applies to the Chinese National Standard (CMS) A4 specification (210X297 mm) 458956

A 7 ； __ B7 21 ~ ------ Five, description of the invention () The term used in this article Γ4-12 members contain a nitrogen-containing sulfur, or a heterocyclic ring of oxygen "The table contains 4 to 12 Atom ', preferably a ring of 4 to 9 atoms, wherein at least one atom is nitrogen and at least one atom is oxygen or sulfur. This definition includes the ring. For example, the term "aryl continuation group" or "aryl hindering group" as used in this text is used in this paper. The formula 0 »1 is a base, wherein Η3 7 is an aryl group as defined above. As used herein, the term "alkylarylene J or" arylarylene J "is a group of 0-s— |, wherein R38 is an alkyl or aryl group as defined above. '〇 Terms used herein" "Phosphonic acid derivatives" Form I-? OR3e ORW n 1 HI · (Please read the precautions on the back-fill in this page first) Binding the base printed by the Bayer Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, of which R39 and R40 Is the same or different, is alkyl, aryl, or aralkyl. -0 * The term "hypotenic acid derivative" as used in this text | 丨 __-P-OR4 '*-The base of Η' where R41 is Η, present, aryl or aryl (as defined above) . As used herein, the term "arylthio group formula __SR42 group, where R42 is an aryl group as defined above" · The term "monocyclic heterocyclic thio group" used herein refers to the group of SR43_ .-24-Fit papers (CNS) A4 · (21Gx297) issued by this paper. '22 V. Description of the invention (_ A7 B7. Where R43 is a monocyclic heterocyclic group as defined above. The term used in this article " "Monocyclic heterocyclic fluorene" and "monocyclic heterocyclic fluorene" Respective formulae ο 〇 Bu S-R43 and iso-R «groups, where the rule 43 is the term" alkane " The radical J is a radical of the formula II, in which R50-C-R50 is an alkyl group as defined above.-The term "arylcarbonyl" as used herein is a radical of the formula || where R51-C-R31 is as defined above The term "alkoxycarbonyl J is used in the basic text of Zhifang". The radical R52-C-where R52 is an alkoxy group as defined above.-Equipment-Λ1 (Please read the precautions on the back and fill out this page first. } Set the basis for the expression "aryloxycarbonyl-based" used in this article by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, where R51 is as Definition of aryl group 0II R51-0-C-0 The term "sulkanyl group" as used in this text R5i-C--25- This paper is in accordance with 11 national standards (CNS) A4 specifications (210X297) Peng) 23 A7 B7 V. Description of the invention (where R33 is as defined above. The term "nanalkoxycarbonyl" is used in the basic text. 丨 丨

R55-0-C group, in which R5 3 is an i alkyl group as defined above. Please read the note on the back. The term "alkylthiocarbonyl" used in this article is Ri0-S-C,-item group of formula 0II, where R5 0 is an alkyl group as defined above. The term "arylthiocarbonyl" as used herein has the formula R51 -S -C-, wherein R31 is an aryl group as defined above. As used herein, the term "methoxymethoxycarbonyl J

1T Printed by the Central Bureau of Standards of the Ministry of Economic Affairs of the Consumer Co-operative Society II, where R54 is the base of R54-0-CH2-0-C-as defined above. As used herein, the term "arylamino group J represents a group of the formula R51-NH-, where R51 is an aryl group as defined above.-The term" polyisopropyl ether "as used herein refers to a diol generally used, such as three Ethylene glycol, tetraethylene glycol, polyethylene glycol, etc. * As used herein, the term `` alkylamino '' is shown in Formula R50

0 li C 26- This paper size is applicable to Chinese National Standard (CMS) A4 specification (2lOX: 297 mm> A7 B7

^ δδ 9 SB V. Description of the Invention (Base of 24), where R30 is a kneeling group as defined above 0 The term "N, N · dialkylamidoamine" as used herein is represented by Rs〇 \ Μ

Rso- N-C ^ —, where r. 0 is the same or different alkyl group as defined above. As used in this article, the term "trimethyl. Ethoxymethyl" is represented by the formula 〇Me, || Me 〒 _c_ ° ~ CH2 ~ Me base I-shaped coat-Λ (Please read the precautions on the back-' (Domains are written on this page) The term "fluorenyl" as used herein represents the base of the formula R55_〇_, where R is a fluorenyl group as defined above. As used herein, a "composition" refers to a product that is a mixture or combination of more than one element or ingredient. The term "pharmaceutically acceptable carrier" as used herein refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating substance, which involves carrying or transporting a chemical agent . '' The term "therapeutically effective amount" refers to the amount of a drug or agent that can trigger a biological or medical response in a tissue, system, or animal, and is sought by researchers or physicians. The following are the abbreviations and corresponding meanings that can be used interchangeably in this article:, Proton Nuclear Magnetic Resonance

AcOH = acetic acid · BHg-THF; 顿 'pit · four or bite p' south complex · benzyl group BOC = third butoxycarbonyl-27-This paper size applies to Chinese national standards (CNS > A4 specifications (2 〖 OX297 mm), -'β I. One! One printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs and printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 4 fS8 9 56 A7 B7 5. Description of the invention (25) ButLi: butyl Lithium 'Cat. = Catalytic amount CH2C12 = digas CH3 CN = acetonitrile CH3I = iodomethane CHN analysis = carbon / hydrogen / nitrogen analysis CHNCI analysis = carbon / hydrogen / nitrogen / chlorine element analysis CHNS analysis = carbon / hydrogen / Nitrogen / sulfur element analysis DCC = 1,3-dicyclohexylcarbodiimide 'DIBAL = diisobutylaluminum hydride DIEA = diisopropylethylamine DMA = N, N-dimethylacetamidamine DMAP = 4 , (N, N-Diamido) pyridine DMF = N, N -Dimethylformamide DSC = Carbo-acid disuccinate Si; EDC1 = 1- (3-Diamidoaminopropyl) -3 -Ethylcarbodiimide hydrochloride Et = Ethyl Et20 = Diethyl ether Et3N = Triethylamine EtOAc = Ethyl acetate EtOH = Ethanol FAB MS = Fast Atomic Impact Mass Spectrometry.g = gram GIHA = m-guanidine Hipuric acid-28-i, pack--, (Please read the notes on the back ^ ¾ ^ this page) The size of the paper used in this edition applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) Central Standard of the Ministry of Economy 扃 Printed by Employee Consumer Cooperatives d58 9 56 A7 B7 V. Description of the invention (26) GIHA HC 丨 = m-guanidinokiuronic acid HPLC = high performance liquid chromatography 1β〇isobutyl chloroformate i-Pr = isopropyl i-Prop = isopropyl K 2 C 0 3 = carbonic acid KOH = potassium hydroxide KSCN = potassium thiocyanate

LiOH = lithium hydroxide MCPBA = m-gas peroxybenzoic acid or m-chloroperbenzoic acid

Me = methyl

MeOH = methanol

MesCl = Medium Si base gas mg = mg

MgS04 = osmium sulfate m 1 = milliliter m L = milliliter M S = mass spectrum Ν2 = nitrogen

NaCNBH3 = sodium cyanide shed

NaH = Sodium hydride NaHC03 = Sodium hydrogen acid

NaOH = Sodium hydroxide Na2P〇4 = Sodium linoleate-29- This paper uses the Chinese National Standard (CNS) A4 size (210X297 mm) (Please read the precautions on the back # '-Fill this page first) 11 .-装--

， 1T 45B 956 A7 B7 Consumption cooperation between employees of the Central Bureau of Standards of the Ministry of Economic Affairs Du Yinzhuang 27 5. Description of the invention () Na2S〇4 = sodium sulfate NEt3 = triethylamine · NH4HC03 = sodium bicarbonate NH4 + HC02-= ammonium formate NMM = N-fluorenylmorpholine NMR = nuclear magnetic resonance RPHPLO reversed-phase high performance liquid chromatography RT = room temperature Pd / C = planed carbon Ph = phenyl P t / C = obstructed t = BOC = third Butoxycarbonyl TFA = trifluoroacetic acid THF = tetrahydrofuran TMEDA = trimethylethylenediamine TMS = trimethylsilyl △ = heated reaction mixture The compounds shown by formula I-V can exist in various isomeric forms, including All isomeric forms. Pharmaceutically acceptable salts including tautomeric forms, as well as isomers and tautomers. In the structure and chemical formula herein, a bond is pulled across one of the rings to pull out any possible atom on the ring. :, The term "pharmaceutically acceptable salt" is expressed! A salt prepared by contacting a compound with an anion that is generally considered suitable for human consumption. Medically acceptable salt of -30-This paper size is applicable to Chinese national standards | CNS) (Xunfu 297 public celebration) -______ I -------- Ί ^-(Please read the precautions on the back first ^ : Write this page) Order i.it 458 956 Printed by the Central Consumers 'Bureau of the Ministry of Economic Affairs and Consumer Cooperatives of the Ministry of Economic Affairs A7 B7 28 ~~ ------------- V. Description of Invention ()' Examples Includes hydrochloride, hydrobromide, hydroiodate, sulfate, phosphate, acetate, propionate, lactate, cis-succinate, rhodium, succinate, tartrate All 9 pharmaceutically acceptable salts can be prepared in a conventional manner 3 (See Berge et al., J. Pharm. $ Ci. 66 (1), 1-19 (1977) :, for other examples of pharmaceutically acceptable.) For It selectively inhibits or antagonizes perone 3 integrin. The compounds of the present invention may contain single-dose formulations of conventional pharmaceutically acceptable carriers, adjuvants and vehicles for oral, parenteral, inhalation or topical application. The term "parenteral" as used herein includes, for example, subcutaneous, intravenous, intramuscular, intrasternal, infusion techniques, or intraperitoneal. The compounds of the present invention are prepared by any suitable route in the form of a pharmaceutical composition suitable for that route and as desired A therapeutically effective dose is administered. Preventing or suppressing the progression of a medical symptom or the therapeutically effective dose of a compound required to treat the symptom can be easily determined by preclinical and clinical methods well known to those skilled in the art using medical techniques. Accordingly, the present invention provides a method for treating a disease by selectively inhibiting or antagonizing cell surface receptors, comprising administering a therapeutically effective amount of a compound selected from the group consisting of compounds represented by formula IV, wherein one or more compounds of formula IV and one: or more Non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to as "carriers" in the text) and other active ingredients (if required) are administered together. Specifically, the present invention provides a method for suppressing a ν / 5 3 sprint surface receptor. The present invention is best to provide a method for inhibiting bone resorption, treating osteoporosis, inhibiting malignant body fluid hypercalcemia, treating Berger's disease, inhibiting tumor metastasis, inhibiting neoplasia (solid tumor growth), and inhibiting angiogenesis. -This paper scale is applicable to Chinese National Standard (CNS) A4C ^ · (21 × 297mm) (Please read the notes on the back before filling this page). Binding ip 4δδ 956 A7 ------- B7 V. Description of the invention (29) '-· — (including M angiogenesis), treatment of diabetic retinopathy, joint suppression "fitting-(please read the precautions on the back &# · write this page) points, psoriasis and Periodontal disease 'method of inhibiting smooth muscle cell movement (including re-narrowing). Based on standard laboratory experimental techniques and preparations known and understood by those skilled in the art, and compared with known useless compounds, compounds of formula 丨It can be used to treat patients suffering from the above-mentioned pathological symptoms. Those skilled in the art should understand that the selection of the most suitable compound of the present invention is within the ability of those skilled in the art, and it depends on various factors, including evaluation criteria analysis and Results obtained in animal mode. Treating a patient suffering from a pathological condition includes administering to the patient a therapeutically effective amount of a compound of formula I that controls the symptom or prolongs the patient's survival rate beyond that expected from the treatment. "Suppression" symptoms. The expression of slowing, moderate fet, suppressing or stopping the cup does not necessarily mean that the symptoms are completely eliminated. The effect of prolonging the survival rate of patients is significantly more effective than originally or naturally, which also means that the symptoms are favorably controlled to a certain degree. As mentioned before, the compounds of the invention can be used in a variety of biological, prophylactic or therapeutic aspects. These compounds can be used for the prevention or treatment of any disease condition or symptom in which integrin is the mainstay. The dosage of the compound and / or the composition containing the compound printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs is based on various factors, including the type, age, weight, sex, and medical symptoms of the patient: Severity of the symptoms: Administration Route: and the activity of the particular compound used so the dosage can vary widely. Doses ranging from about 0 mg to about 100 mg per kg of body weight per day can be used to treat the above symptoms. The active ingredients for injection are formulated into a composition, for example, which can make -32- this paper flower again applicable to the Chinese National Standard (CMS) A4 specification (210X297 mm) printed by A7 '- ------—__- _ B7 V. Description of the invention (30) Use salt water 'dextrose or water as a suitable carrier. A typical daily dose is about 0.01 to 10 mg / kg of body weight per day, in multiple doses, depending on the above factors. For administration to mammals in need of such treatment, a therapeutically effective amount of the compound is generally combined with one or more adjuvants suitable for the above-mentioned route of administration. Compounds can be used with sugar, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, gold Albizia gum, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol are mixed and made into tablets or encapsulated for easy application. Alternatively, the compound is soluble in water, polyethylene glycol, propylene glycol, ethanol 'corn oil, whisker oil, peanut oil, sesame oil, stupid methanol, sodium chloride, and / or various buffers. Other adjuvants and methods of application are also available "Q" is widely known in medical technology. The medicinal composition that can be used in the present invention can be subjected to conventional medical operations, such as reducing bacteria, and / or can contain conventional medical adjuvants, such as preservatives, dwelling agents, and wetting agents. , Emulsifier, buffer and so on. The general synthetic sequence for preparing compounds useful in the present invention is shown in Figure J_XXI. Describe aspects of the invention and actual procedures, if applicable. The following drawings and examples are only for illustrating the present invention, but not limiting the scope or spirit. Those skilled in the art will readily recognize that known variations of the conditions and methods described in the examples and methods can be used to synthesize the compound β of the present invention. Unless otherwise stated, all starting materials and equipment used are commercially available. -33 · The scale of this paper applies to the Chinese National Standard (CNS) Α4 specification (210X297). T — \ {Please read the notes on the back first to complete this page.) Order, ρ li A58 9 56 V. Invention Description (A7 B7 31

Figure I ho2c c〇2h

'K H + nh4 + ch3co2'

A

Jr ---------- ^-(Please read the notes on the back first to fill in this page)

EtOH HCI (anhydrous) Δ

(A) Order printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. 34- The standard of this paper is applicable to the Chinese National Standard (CNS) A4 specifications (2) OX: 297 mm. Α7 __ B7 V. Description of the invention (32) Figure depicts the synthesis of pyridyl.-amino acids, which can be used to synthesize compounds of the present invention where 1 is pyridyl. This reaction can be modified using conventional methods to prepare other aromatic, subradical or heterocyclic substituted amino acids, substituted with pyridyl quinal than any other suitable aldehyde. Briefly, in Figure I, ammonium acetate is added to pyridine and isopropanol, followed by malonic acid. The reaction mixture was stirred at reflux, and the resulting precipitate was filtered, washed with hot isopropanol, and dried to obtain 3-amino-3-(3-p-pyridyl) propionic acid. Ethanol is synthesized by heating the acid in excess ethanol in the presence of excess HC 丨 gas. In addition, it can be used in the present invention; 3-amino acids can be reacted by modified Knoevenagel (Secor, HV; Edwards, WBJJ Org. Chem. 1979, 44, 3136-40; Bellasoued, M .; Arous-Chtar, R .; Gaudemar, MJ; J. Organometal. Chem. 1982, 23 1, 185-9), and Reformatski reaction with Schiff test (Furukawa, M .; Okawara, T .; Noguchi, Y .; Terawaki, Y. Chem. Pharm Bull. 1978, 26, 260), Michael addition reaction of acrylic derivatives (Davies, SG; Ichihara, 0. Tetrahedron: A symmetry 1991, 2, 183-6; Furukawa, M .; Okawara, TR .; Terawaki , Y. Chem. Pharm. Bull ,, 1977, 25, 1319-25). Recent methods include the use of organometallics such as in the coupling of Pd or Zn intermediaries (Kon op elski, J .; Chu, KS .; Negrete, GRJ Org. Chem. 1991, 56, 1355; Mokhallalati, MK; Wu, M : J .; Prigden, LN Tetrahedron Lett. 1993, 34, 47-50) to supplement more traditional reactions such as reductive amination of fluorenyl-ketoesters. The racemic alkyl /?-Amino ester can also be conveniently prepared from the corresponding lu-lactam by treatment with anhydrous HC1 gas in ethanol. /?-内 醯 胺 系 由 -35- (# 先 闻 读后 背面 NOTE #,. // Fill the kidney on this page) β- 装 — This paper size applies to China National Standards (CNS) grid (210X297) (%) • 458 956 A7 B7 V. Description of the invention () Preparation of ene and chloroisocyanate (Szabo, WA Aldrichimica Acta, 1977, 23 and references cited therein) 3 This method can be used to prepare α and 々- Substituted / 5-amino acids ° (Manhas, MS; Wagle, DR; Chong, J .; Bose, A, K. Heterocycles, 1988, 27, 1755.) Another form a · Substituted /?- The amino acid pathway is Raney nickel reduction of cyanoacetate at 20 to 8 (TC range temperature and 20 to 100 atm pressure (Testa, E .; Fontanella, L .; Fava, F. Fermaco Ed. Sci. 1958, 13, 152; Testa, E .; Fontanella, L. Annalen 1959, 625, 95). Many procedures can also be used to prepare /?-Amino acids from keto acid hydrazine (Gootijes, J. Nomte, W, Th. Rec. Trav. Chem. 1953, 72, 721) »Monthly loss (Anziegin, A .; Gulewivich, WZ Physiol. Chem., 1926, 158, 32) and nitropropionic acid reduction. Finally Compounds are usually purified by Phase High Energy Liquid Phase Analysis (RP HPLC) [High Performance Liquid Chromatography Protein and Peptide Chemistry, F. Lottspeich, A. Henscher, K, P. Hupa, (eds.) Walter DeGruyter, New York, 1 9 8 1 ] Or crystallized. I ----------- — equipment-\ (Please read the notes on the back ^ fill in this page first) * ^ τ Λ Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs- 36- The size of this paper applies to China _ housekeeping standard (CNS) Α4 size (210 × 297 mm) V. Description of invention (34 A7 B7

`` II (1) cTV is called t-BocNH C02H + CICO2- DMF (2) (A) + NMM in DMF

t-Boc-NhT

(Please read the precautions on the back of the page and fill in this page first) Binding 'Order Printed by the Central Consumers' Bureau of the Ministry of Economic Affairs, Printed by the Consumers' Cooperatives-37 This paper method applies the Chinese National Standard (CNS) A4 specification (2 lOX 297 mm) 4 6 ί: 5 9 5 6 Α7 * ------ Β7 V. Description of the invention ~~~-Figure 11 Example Tit can be used for α_amino acid coupling in the Lu_amino acid compound prepared in Figure I method. The prepared compound can be used for coupling to a substituted benzoic acid compound ' to prepare the desired compound. This method can be modified using conventional methods to couple other aminoglycolic acids to the Θ-amino esters prepared in Figure 1. Jan 1: "In Fig. II, t-Boc-glycerol was added to DMF and N · -methylmorphine 'was added followed by true butyl pivalate. In a separate flask, the substituted /?-Amino ester was mixed with N-methylmorpholine in DMF. The two mixtures are combined and stirred at room temperature to produce '(谙 read the note on the back of the page to write this page). Packing. Order printed by the Ministry of Economic Affairs, Central Standards Bureau, Consumer Products Cooperative Produced by using HC 1 / Dioxin Lu Yan deprotected and produced (B) '. -38- This paper size is applicable to China National Standards (CNS) Α4 specifications (2 〖0 × 297Xingli） V. Description of the invention ('h2n,, co2h

1) DEA two gas land ι «ι · / η2ο Δ

2) HCI A7 B7

Figure III HN ^ / NH2 (· ηνο3) Me, / Ν ,, Ν ΝΗ U Η (C) Μθ, co2h HCi (锖 Please read the notes on the back first—please fill this page) Printed by the cooperative -39 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 4 q Hong A7 B7 " 37, '~~~-V. Description of the invention () Figure 111 illustrates an example that can be used to prepare the invention The method of the guanidinobenzoic acid moiety, which can be used for coupling to glycine-fluorene-amino acid. It can also be accomplished by using other suitable guanidating reagents known to those skilled in the art, such as pbijun-jimai. HC1 (Aldrich). The method of Figure 111 can be modified using conventional techniques and methods to prepare alternative compounds that can be used for coupling to 5-amino acids. Briefly, in Fig. III ', 3-aminobenzoic acid is added to 3,5-dimethylpyrazole-1-carboxamidine nitrate-in dioxolane, water and DIEA. ; The kun compound was stirred at reflux, and the precipitate was filtered, washed and dried. The precipitate was then dissolved in water or a slurry, acidified with H C 1 and concentrated. The solvent is removed, and the residue is dried in ether or tang liquid, and dried to produce 3-guanidinobenzoate hydrochloride (0. Printed by Shellfish Consumer Cooperative, Central Standards Bureau of the Ministry of Economic Affairs -40- This paper size applies to Chinese national standards (CNS) Α4 specifications (210X297 mm) ^ 58 956 A7 B7 V. Description of the invention (38 {C) + ClC〇2 ⑴ / \ Ο N—CH3 v_ / ·-:-»-DMF (2) (Sunday) , NMM in DMF NHII H2N / ^ 'NH- 〇

, ΝΗ * ^ γ

1) Li0H / H20 2) TFA ---------- install-(please read the notes on the back first #-土 write this page) Order NH, person

NH

2TFA Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -41-This paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) ^ 4 58 9 56 at ________ Β7 V. Description of the Invention (39) Figure IV illustrates It can be used to couple the guanidinobenzoic acid (c) to the lu-amino ester (B) moiety of the desired compound of the present invention. This method can be modified using conventional methods known to those skilled in the art. Briefly, in Figure IV, 3-butylguanidobenzoic acid (C) (prepared in Figure III) was added to DMF and N-methylmorpholine, and isobutyl formate was added. The reaction mixture was stirred and a slurry of the / 5 amino ester compound (B) (prepared in Figure II) and * N-methylmorpholine was added to the reaction mixture in portions, and the mixture was filtered and washed with D M F. D M F removed. The resulting ester was dissolved in water, washed with ether, UOH was added to the aqueous layer, and stirred for hours. The solution was treated with trifluoroacetic acid to pH = 5, and the product was purified by RPHPLC to give the desired compound. Printed by the Shell Standard Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs -42- The paper scale is applicable to the Chinese national standard (CNS} A4 specification (2! 0 × 297 revolutions) 5. Description of the invention, 40 ho2c ’co2h -co2h H2N-

Ri (1) A7 B7 1__v Step A R1CHO + NH4 CH3CO2

R3〇H HCJ gas △

Step B

_ / T \ 巳 OC—N——C R6 H2N- Δ, -C02R3, ri -HCI (E) Please read the precautions on the back of this page. JJ £ -C02H + CIC02- n 〇 N—CH3 ^ == ^-BOC—N— | -CDMF ^ \ Zj l] \ 0 C—NH- -C02R3

Ri _ Order (2) (E), NMM in DMF η HCW Dioxin Land Park '/ γ \ ο ΝΝ-

Re Z (F) C—ΝΗ- -C02R3

Ri

HCI Central Standards Bureau, Ministry of Economic Affairs, Central Consumer Bureau, Consumer Cooperatives, Co., Ltd. If R1 1 is not Η 'alkylation, use the j-quasi-alkylation procedure here to form -CO ^ R3 HN ^ R' -HC! It can be used instead of (E) in the synthetic methods herein. -43- Chinese paper standard (CNS) A4 specification (210X297 mm) δβ 3 Α7 Β7 * V. Description of the invention (Figure V (continued) ^ Step C.

NH

HN

CO: H +, Ν, ΙΝΠ2

ΝΗ2 1) DEA

NH X j-HC is produced on land.

2) HCI R5

co2h * M〇l (A1 > HN. R5

Z1

CO ^ H j (\ ^ m = 1-3 + NammaNH S-Me · HI

/ · ~ · (〇 m = 1-3i) i’i§W / H2〇 HN \ ^ N

A 2) HCI

, co3h HCI (Please read the precautions on the back ^: Fill in this page) -Pack. HN R5

CO ^ H HCI 2 »

= 1-4 M 'EtQH OMe (Λ2)

A-4 HN R5

Z1

C〇2H

DEA

HCI OMe 2) HCI

>!. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -44 This paper is in accordance with the Chinese National Standard (CNS) A4 specification (210X 297 mm) .m A7 B7 V. Description of the invention Λ2 HN R5

Z1 co2h

KSCN diagram V (continued) #step (:( continued) Table solution HC ^ H2N N — R5 Δ

(A5) co2h S-R0

(A5 Bu R—I THF · △

(Please read the notes on the back before filling out this page).

(AS) + CH3I

THF

1) DIEA

S—Mo (A7) + H \ Dioxin Land_ / h2o R3 2) HCI

Order HN R5

C02H + Zi Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy

-45 This paper size applies to Chinese National Standard (CNS) Ad specifications (2 丨 OX297 mm) V. Description of the invention (43) HN. R3

CO: Me ZZ ·

HN

1) THF + rtH = C = 0 HN. R3

C02Me 1) THF 2 «A7 B7 Figure V (continued) Step C (continued)

, fVNH, N. 2) Na〇H / H2〇 / l --Lu Yuan 3) H *

co2h Z '(A11) ____ R7NH 2) NaOH / H20 / Dioxolane R5 3) H +

(A12)

COjH Z-1 ------------ install-(Please read the notes on the back # ,. Fill in this page) Order Η o = c =

Only 7, R〆

1) THF 2) NaOH / H2〇y Dioxol Rfl 3) " [§ '

C02H (A13) > i.

SHCHN Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

C〇2Me r7 1) THF + nnh a 2) NaO> VH20 /. Digas 眭 3) η * r 'm

* 46-This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) A7 B7 V. Description of the invention (44 (A1-14) + CIC02-

Figure V (continued) Step D ⑴ / 〇 N—CH3 DMF (2) (F), NMM in DMF

C〇2R3

1) Li〇H / H2Q 2) TFA (Please read the notes on the back first and fill out this page)

N- R6 \ Z M 〇 • C '〇—NH_

-go2h, R1 TFA order printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives -47- Sheet size is applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) > 4 D 〇you A7 B7 V. Description of the invention (Figure 45 illustrates methods that can be used to prepare the various compounds of the present invention. The dream method is more specifically defined in the following examples and Figure WV. This method can be modified by those skilled in the art to replace known reagents and conditions of conventional methods to produce The desired compound, in particular, in Figure V, Step C: In the synthesis of the intermediates benzyl acid (A1) to (A 14), the starting amine benzene HN, R5 formic acid 21 is commercially available Or, it can be reduced to the corresponding amino nitrobenzidine by reduction of the corresponding nitrobenzoic acid. Nitrobenzoic acid can be obtained commercially, or synthesized by suitable nitration of benzoic acid, and then reduced to the desired amino phenyl hydrazone. Acid. It is when R 3 is Η. If R 5 is not H, the alkylation of the amino group can be achieved by conventional methods. In addition, the synthesis of intermediate (A2) can also be used as us 3,202,600 In the case of i, the revealer starts with a suitable aminobenzoic acid and ends. Intermediate a (A 3) used in the synthesis of the means I - (Read precautions traffic to the write back surface of the page set by the ▲} Ml standard 5-membered cooperatives printing fee% OMe

'1-4 Ο can be synthesized from 1v and (Me) 3 OBF4 in digas methane

The intermediate (A 4) used in the synthesis of 'Y Η ΟΜβ can be -48- Λ ------------ I / I 1 copies. Paper rule and applicable national standards (CNS ) A4 specification (2) £) X297) 46 A7 B7 V. Description of the invention (Y1 2-CN and MeOH (1 equivalent) and HC1 gas (1 equivalent)) were synthesized in heptamine. All other reagents in Figure V are It is commercially available or can be easily synthesized by methods known to the artisan. ^ Intermediate [(A1) to (A14)] in Step C of Figure V and intermediate (F) (Figure 乂 Step C) can be coupled using other coupling reagents known to those skilled in the art, except in Step V of Figure V The mixed acid anhydride method is described in order to produce the final desired product.丨 ..._ I: _ 」ί I. ~ Pack. Order -------- Ί (Please read the notes on the back and fill in this page first) ..:, Consumers' Cooperatives, Central Standards Bureau, Ministry of Economic Affairs Printing 1 _____________-49-2 This paper is suitable for financial purposesϋ ϋ 家 转 (GNS) ⑽ Broadcast Q χ 297 thin) A7ά sa-g.se--V. Description of the invention (47) Staff consumption of the Central Standards Bureau of the Ministry of Economic Affairs Cooperative printed VA 0

OHO

Hq

0N vaLUmώσιιΛΗιϋLLH1ofo

XX

Jf ΛΛ

Η〇 = ΛΛ m2 〇ΗοέαοίΝΕΊΊΙηΕα 」8 = χχ ΐ Μ

(Please read the notes on the back of the paper first and write this page) -install · loH / 龀 δ- Η = ΛΛ h χ ^ οοπχχ ioo

OHO

〇Η ° 建 Β 丨 谛-5-* ?? ^ J ^ Ho = xx Η = λλ mZ

20 £ io ^ o (CNl --- τ H_1vaa U

〇iZ

ΟΜ Η Η ΛΛ flrI) NOo = χχ

AJ οΗ〇 Α— order V-OH Η3ρχ.ο0 die 50

EJCM 5vaa U 6 * Θ3

This paper size applies the Chinese National Standard (CMS) A4 specification (2I0'X297 mm) 458 956 V. Description of the invention (48 A7 B7 Figure VA illustrates a method that can be used to prepare aldehyde (Rl), which is not commercially available. ' For the preparation of amino acids, as shown in step A of FIG. V, the amino acids can be used to synthesize the compound t Mn n 7F of the present invention. FIG. Steps A to D. Other methods known to those skilled in the art are available. The aldehydes of the compound of the present invention are prepared. *, ° are used to synthesize the available standard paper for printing and printing on the paper of the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative. (Note # -fill this page)

458 9 b〇 A7 B7 49 V. Description of the invention (.)

sl > S Printed by the Central Standard of the Ministry of Economy

囫 孤 晚) 锴 ¥ Kinky- 乜 (CNOJϋ = 9είο

I -------- jf .------ IT ------; j '. / I.' .. \ (Please read the notes on the back before filling this page) '52 -This paper size is applicable to Chinese National Standard (CNS) A4 specification (2 丨 0X297mm) 5. Description of invention (50

Meal # ¥ όηο ^ ((WW ^^ A e-EIsig ^ s-sCN Α7 Β7

, < ---------— 装-/ (Please read the note on the back 1 and fill in 'write this page)

SIAHI

v (H-ovx ^^ 如 如 交 li / oleaves private Λ® (s η§ο £ § (ο (β) o / pdfa, π .ο

Of-XOBN -ο 0¾ 1. 0 & Η (5 · 7 " νΗ ζ δοοί Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ο ο

ζ .0

-53- This paper size is applicable to China National Standard (CNS) Α4 size (2 丨 0 X 297 mm)

Printed by the Central Laboratories of the Ministry of Economic Affairs, Consumer Cooperatives > ,, '...; A7 B7 V. Description of the invention (51 Figure VI (A) Alternative synthesis method of compound of formula I. All reagents are commercially available or from Manufactured by methods known to those skilled in the art. The synthesis of cold-amino esters is as described in compound (E) in step A of Figure V. Coupling, guanidination or gland and alternative methods for the formation of sulfur can be used by those skilled Figure V 1 (B) shows another alternative synthetic method of the compounds of the present invention is commercially available, or manufactured by standard and known methods. All reagents can be easily read before you read Φ 意 意 意 再-Capital Page襞 h 54- This paper size applies the Chinese National Standard (CNS) A4 specification (2 丨 〇 × 297mm) 'b U ΰ ο: Α7 Β7 — V. Description of the invention () j_ I. HSS ^ His (3 — · —

S-Gais® Sandpiper- < (CN. SSNlrsa C ^ OQU (Jo) vn o

Y 0 '' a idh (ε Nafo-VBQ ϋΓ (z xz

SU ^ [s-wv ^ i V s-caii] 镏 砩 File-^ (ζ ϋ-^ IQ ^ l [ω) ^ §ΦΝΛ ό o & S0. (Please read the notes on the back first—you write this K)-equipment. ≪ 1) 11Λ s 4ό4. .. ,, ^ Printed by the Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs

ox · — _p

9-ϊοπ (l

5 5 The size of this paper is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm)-* 'a V. Description of the invention (', 53

Hcyy

A7 B7 Central Standard of the Ministry of Economic Affairs, male workers' consumer cooperatives cracked 0 «x -rows _0

0¾ io & ΗβΛνιΗ X

£ ss w (H-l) vv < ^. ^ 如 如 交 ϋ / υ 乐 淞 λ® ((ν i HSUJIol ^ lAoiJS_ (^ Γ. ^ Α

[(3) vv yeast private Λ (please read the precautions on the back-fill in this page first) 'install. Order 0 考 0! 1 (1

ICN

This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) d ^ 〇y; A7 B7 54 5. Description of the invention () Figure VII (A) and (B) are similar to Figure VI (A) and (B) provides another method for synthesizing the compound of the present invention. (Figure VIIB is a more general method than figure νΠΑ.) As shown in Figure _ VI, the reagents and conditions are not limited to the definitions in the figure. You can be familiar with the skilled artist. Alternative reagents known to people can replace 3 ---------- -^ 1 ------ ΪΓ ------- j {Please read the precautions on the back and fill in this page first) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-57- Steering (CNS) A4 specification (210X297 mm) 458 956 at ΒΓ 5. Description of the invention ()

ΙΙΙΛ a

0 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ox-HO £ o_ o-sCNio 〇ο:

S — 1 Binding 7α.,:. \. (Please read the precautions on the back ^ :, fill in this page first) -58- This paper size is applicable to China National Standard (CN'S) A4 size (210X297 mm) k 458 9 56 at B7 V. Description of the invention (V) Fig. V111 illustrates a synthetic method for forming the A group in the general formula I to be amine oxazoline or amine group. All starting materials and reagents are commercially available or defined in the figures and examples shown. Alternative coupling methods or alternative reagents and conditions can be used as known to those skilled in the art. ’--------- install-(please read the notes on the back first and fill in this page)

， 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 59- This paper size adopts the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 45b956 A7 B7 V. Description of the invention (57 H ^ p

i ΊΙ # ^ ΰί = / 0; ^ 备 4 '-Η = α: Macro and -92 = 5: if.i > ^ ca = ££

1 one by one 1LJU = & Si-H = £ il # fe < Ds = £. 3WRcg = s:

IU 14 {^ " Md = 5: -32 = 5: 9n.is? 5: f & > tyou

H Q4te, S33

ON

Central Standards Bureau, Ministry of Economic Affairs, Shellfish Consumer Cooperatives-Sr System

Hcci sdp (> -60-

ά〇H f · VHFrHOraNd ^ xolusιι, 'ΗΙ ~ ττ > 1οα3Λ13Να: ν2α juxo > ΉοεΝο ^ ΉΟ ^' ί-α, ΗΙΪΞ- ^ ΒΉ23 · ϊ5: ~ !! υοζ-^ &-· ^^^^ Link ^^ Λ ^ Ί-ΙΝ-^^ ίι ΙΗΙ ##-Jo = tt: < os = & ow ^ fc1LU = Q:-^ ro = 5: 『l = s; 6nN-feJ = rd = s- ai = & loe: u # feGi = Q: ed = 5: ni = a: SUNt · Private / 0. = 0: -Work = & inch £ ι ^: ^ '· υα! 3 = Η · Μς = δ: Ή = δ: ίίειπ, ι in fecB Hcc-crd = & .φ · 5μ5; Σ: ε U # # crco = cc:-£ = & .c: m = £: —— • 1— t—-I-I n -1 n _ ti m I Γ IIII k ^,, 0¾ i VJ (please read the notes on the back first # Scroll this page) This paper size applies Chinese National Standard (CNS) A4 Grid (2 [0 X 297 mm) 4 BB 9 56 at B7 _ 5. Description of the invention () vii .ε icsi dsgrlHoV- · 〇

HN H x ^ oo / \ / \ z ^ Λ1 X s dwJQ ^ AJsf ^ 03 '^ f / LL.SQosa%

InHCNoc ^ o CNi ατΝΐ * — / Luseosa I (Please read the precautions on the back to complete this page) Pack-T, -'e Printed by the Central Standards Bureau, Ministry of Economic Affairs, Consumer Cooperatives

, N, H

, s,, 8S

H -61- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 5. Description of the invention ('ix 画 ioo) x200 \ / \ / ^% 00-Yn ^ loom οοωχ ^ Ηο ^^ ο

(0-9) 〇09 二 杏 驷 (ιοΐοοΗ I 杳 ‘耻 Η A—

Hoo A7 B7

S3 / HNS 2:

(ΰώ) ιοιη 二 在 # 034〇1〇 二 在 细 ο

X A. (!!!

---------- 装 — (Please read the notes on the back ^ -mark this page first) n ^ oo

Yin Zhen, a Consumer Cooperative of Employees of the Central Standards Bureau of the Ministry of Economic Affairs 〇 i HN〇D / i〇3

ο 8aHN (ID-9) 3SI- 苳 私 (19 工 EN | 4 ‘驷

o ί.

X order os-b-vil -C5XO0II _ 'ήου-^' η-: JHi -Η〇 deaf 0! Order 101. 'Q (No6H ^ LUN.u.'lMQ-.% ^ L30a-sm-lN -N (一 ϋ-9) inch Sl · Xuanzhi (loi6n i # private order. 1 -62 * This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 458956 V. Description of the invention () Figure IX , X and XI are other examples of synthesizing specific compounds of the present invention. All starting materials and reagents are commercially available or disclosed in this specification. Alternative methods, reagents and conditions can be used by those skilled in the art. (Please read the back first Please note i write this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -63 This paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) 458 956 at B7 Printed by the Consumer Cooperative V. Description of the invention (61 for compounds · where 1) R1 = COjH (E) is commercially available -C〇2Et h2n- 'HCi

Figure XII 2) Co2Et

Ο II / Ri = C—N BOCNH- R / 'Re -C02Et

1) NMM DMF (please read the precautions on the back to fill in this page) installed '+ cico2- co2h

2) HN -Rr in DMF

Re • tr (commercially available) 丨 -C〇2Et BOCNH-

Where HN -R7 'Re

Dioxolane / HCI h2n- co2ei R7 .HCI R0 CK II N 0 ((E) from Figure A Step A, O 〇 when R1 =) i; 'Re C-N' epiamino acid, the amino group The acid is protected with a suitable protecting group. For other methods based on R1, please refer to the following -64-This paper size applies Chinese National Standard (CNS) A4 specification (2 〖〇 × 297mm） 458 956 A7 B7 V. Description of the invention (62) Figure XIU continued) -COjBn co2h (Commercially available jl BOCNH-

1) b2h6, thfo.c 2) AcOH / MeOH

BOCNH

C OjSn OH (Please read the notes on the back ^ Therapy write this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs BOCNH ·

BOC-NH

C 〇2Bn O II s—If o MCPBA or H2〇2 C 〇2white Π

BOCNH

C HjC Ij O'C MesCI. Et3N COjBn

hIS—Y ^ (K7C03. OMF 70 " C DMAP

S —Girl Dou II O

MCPBA 1 or H2〇2 / H20 / CH3CN

B〇C-NH

C〇20n

-C〇2 Π HCI / l dioxin BOCNH BOCNH BOCNH

* Where: Ri = -CH2S-Y4 —-CH2S—Y name JI 〇 —CH2S〇2—P (Y " 'pit group ’aryl group, heterocyclic are optional substitutions, as defined in Formula I η2ν

C 〇 2 Β π -HCI * All of these can be used as intercalates in Fujian to illustrate the synthetic method of the compounds of the present invention, such as (E), 65- This paper is in accordance with China's national standards ( CNS) A4 specification (2.0 × 297 mm) 458956 A7 B7 V. Explanation of the invention χπ (continued). In a similar method, the compound of the present invention can be synthesized by the following method: R1 is a substituted alkyl group: ': 80CNH .

CO20n 0 Ji Ο—S-Me Μ Ο

DMF KCN-BOCNH .7CTC DMAP DMF-'70 " C DMAP MU 〇H nh3 -80CNH. 25Ό, BOCNH K2C〇3 HN --- BOC, male DMF 70 " C DMAP

Dioxol D / HCI / —COjBn

Ri -HCi I ---------- Install-(Please read the notes on the back first * Fill in this page) Ordered by the Central Consumers Bureau of the Ministry of Economic Affairs and printed by the Consumer Cooperatives -66- This paper size is applicable to China National Standard (CNS) A4M (2 〖〇: < 297 mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 4 A7 B7 V. Description of the Invention (64) Figure XΙΙΑ

〇 / ^ ΟΒπ 0. A Swem Ox. Guang \ 〇Bn k / H Η 1 OH T 〇1 nucleophile, ^ eg MgXR-j Λ〇Βη? HC1 / dioxolidine j ^^ OBn OH Boc ^ Λ . M 〇rTFA / CH2Cb fj ^ f < R) OH

orTFA / CH2Cl2

Swem Ox.

----------_ Installation-(Please read the precautions on the back and fill out this page first), -B -67- The standard of this paper is applicable to China National Standard (CNS) A4 specifications (2). X297 mm) 56 A7 B7 V. Description of the invention (65) Figure XIIA shows the protected aspartame fluorenyl aldehyde prepared from the asparagine SS-based alcohol prepared in Figure xh using the Swern oxidation procedure, and the Reagents (such as commercially available Grignard reagents or GHgnard reagents prepared by standard procedures) to produce C-4, R 1-substituted aspartame fluorenyl alcohol derivativesa. This primary amine product can use standard acidic conditions Removal of the BOC group produces an intermediate /?-Amino acid (eg, Figure I). BOC-protected C-4 substituted alcohols can be oxidatively converted to keto derivatives in a second Swern, and then BOC is removed to produce the desired intermediate amine (see Figure I). Please read the note below for printing and binding. Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Printed by the Bayer Consumer Cooperative. -68- This paper size applies to the Chinese National Standard (CNS) A4 specification (2tOX 297 mm) 5B 9 5β (A7 B7 66

Figure XIII Synthetic compound, where

Pd / C

co2h then processes h2n ^ /-X / C〇2h in the same manner as other derivative methods exemplified in the above-mentioned country. Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs.

-69 * (Please read the precautions on the back if you write this page)

This paper size applies Chinese National Standard {CNS) M specification (2 丨 〇 X 297 mm) V. Description of invention (67

7 Ξζ A7 B7 > IX painting o

4 > 4-iIAJa ^ asa ^-& -iwa ^ wwius ^ N iveIIAH-CIis

IS5V0-Z I-pack-(Please read the notes on the back first. Fill out this page) Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs o ^ ΗΊΟΗ i 彳 υ ° ο · mwl ^ MSH (ε o ° o -sz- uHLzisss.ou

N · 70 This paper size applies the Chinese National Standard (CMS) A4 specification (210X297 mm) 6 A7 B7 V. Description of the invention (68) Figure XIV Synthesis of epiaminohydrocousin (coumarins) (see J. Rico, Tett. Let., 1994, 35, 6599-6602), which can be easily opened to R 1 as an o-hydroxyphenyl group, and then substituted with Z 1. --------- Outfit-(Please read the precautions on the back ίν ^ -Write this page)-? Τ Printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs 71-This paper is for China Standard (CNS) A4 specification (210X297 mm) A7 .B7 * * 5. Description of the invention (

Figure XIV A

ROH / HC!

.HCI coupling to Fujian VU (B) (Η) to activate state DSC / NMM or IBCF / NMM in DMF

a. NaOH or LiOH in two-gas land salamander: H2 ◦ or THF: H2 0 or CH3 CN: H2 0 or b [pig liver esterase (PLE)

Printed by the Central Standards Bureau of the Ministry of Economic Affairs—Industrial and Consumer Cooperatives 衿 in buffered aqueous solution or, c. Aqueous acid solution

Z1 (J. Same definition as Z1-72- This paper size applies to Chinese National Standard (CMS) A4 specification (210 X 297 mm) A7 B7 70 V. Description of the invention (Figure XI VA epiamino hydroxanthoate ester Synthesized from Aminohydrohumorin in Figure XIV, which is then coupled with the intermediate (H) in Figure VI 1 (B), using DSC / NMM / DMF or IBCF / NMM / DMF and then with Aminohydrohumin Ester hydrochloride / NMM activation (H). It is then hydrolyzed using standard conditions to form a carboxylic acid derivative. --------- Outfit—— (Please read the notes on the back first to write this page}

-* 1T Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs-73- Good paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) _, 4 ό ϋ PLUS ^ Α7 Β7 — V. Description of the invention ( )

Figure XIV B

Coupled to (η) in graph vn (B), use DSC / NMIW or 丨 B CF / NMM to activate the DMF

(Please read the precautions on the back first to complete this page)-Installed. M. Γ Order Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

The definition of Zn- is the same as ζ1 -74- — Λ. This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) V. Description of the invention J2 A7 B7 Figure XIVB Table 4-Aminohydrothioxanthodin Synthesized from thio-vanacin. Thioflavin can be easily prepared according to JA Panetta and H. Rapoport, J. Qrg. Qhem., I982, 2626_2628 and the references cited therein, and can be converted into 4-amino group according to the general procedure of Figure XIV Hydrosulphonylhumulin derivative. Coupling of amine hydrothio humourin with intermediate (H) of Figure VII (B) can be achieved using methods similar to Figures XIV and XIVA. Hydrolysis to produce carboxylic acid The vinegar-thiol product can be easily achieved by using a base (such as LiOH or NaOH) in an organic solvent aqueous solution. * (Please read the Precautions on the back #, while writing this page).

'ST r Printed by the Central Bureau of Standards of the Ministry of Economic Affairs and Consumer Cooperatives -75- This paper size is applicable to China Standards (CNS) A4 (210X297 mm) 458956 A7 B7 _ V. Description of the invention () £ 0:

J-s.X 00 gI2 / 2 ε-νεζ; ^ _ I A,

^ υ £ υ J73N «SI ω _ IH- > ~ A ^ 00m i ^ N? E ^ I_ / ιλχ a.

v HeLJ lxo HN,

HS -nx, χ «ου / \ 5- H '/-ox ^ A_〇? Ε (ν-7 ® f lyzu ^ o (l ·

^

φνΛ®-® ^ 1— · — i ^ sc \ ig M si: Jsa

i + HCT ΝυεΗο / 9.Η / ΗοηΓ · (Please read the notes on the back first and write this page) luHf? Printed by HOE .. o ^ x ^ -ocw ao to / pd: £ a

(ν) ΙΙΛΜ? ΐΜομ 孓 〇 Corpse HN

i,-/ 'N E-ijl) /

-76- This paper is in accordance with Chinese National Standard (CNS) A4 standard (210X297 mm) A7 4 58 9 58_Έ_ V. Description of the invention (74) * Figure X Table VI Substitute for cyclic guanidine in the compound of the present invention Synthesis. Substitute reagents and substances known to those skilled in the art may be appropriately substituted and easily recognized by those skilled in the art to produce the desired compounds. ---------— Packing-- (Please read the note on the back 4-4. Write this page) Order Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Printed by the Consumers Cooperatives -77- This paper size applies to China National Standard (CMS) A4 specification (210 X 297 mm) 75 458 95 'A7 B7 V. Description of the invention () η (ν8 IIAXa 8 mm

(Please read the notes on the back # · Fill in this page first) -Install.

r T 1 *-'H Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (I)

((zv) o leave Af > draw) A—

Li-sa: S2N cvoooa WLusa si g f? H / f = r o = u /

(CN -78- Paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297mm) 76 4 5 ii 3 □ 〇A7 B7 V. Description of the invention ('ΗΝ' / ΰ Sαα 00 χεοο / ^-Α ΝΗ ¾ £ ό * ο (SIAX hinders JUJNll-sa

V LULUGQg $

(NΗ2α.α · ρο

Central Standard of Ministry of Economic Affairs 部 Printed by Employee Consumer Cooperative 隼 扃

Η (Νοαϋα MU 琴 = 3 & -Sτΐοχ, α ο & ^ 00L ΗΝ / Ν U.LL / .. A—

I or Νοχοδ ^ ί3π \ \ maHon a cu 8

(Please read the note on the back of the page to fill out this page first). Loading ... 1. Order Λ ΝΗ -79- This paper size is applicable to China National Sample (CNS) A4 specification (210 × 297 mm) 77 A7 B7 V. Description of the invention (Figure XVII illustrates A. Table 5 or 6-membered cyclic guanidine synthesis method.. AA to tF may be hydrogen or other substituents, as the above A is a diaza heterocyclic ring: meaning, if appropriate substituted diamine It is commercially available or can be easily synthesized by those skilled in the art. L Pack-(Please read the note on the back # 'play this page first) Order printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economy -80- Private paper scale Applicable to China National Standard (CNS) M specifications (210 X 297 mm) 5 ^ Invention note, 78 A7 B7 5: ¾

In X 丨 0—N 〇 IHXF " W

AJ HN, HOUJ t-lr’f IH. 8 甲 s 3WW 1—ο ^ 0 ^ X0. «ΩΝ

(Please read the precautions on the back first-f-4. Write this page)

rtHO Printed by the Consumer Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs hn > -n2, \ v / ^ E ΑΊ ^ 0 ^ X0 x «oo (xz

The scale of this paper applies the Chinese National Standard (CNS) A4 specification (2ίΟ × 297 mm) 79 4: V. Description of the invention () But κ · ^ -δο = χ W X? Y 丨 κ 丨 0 丨 ζ ^ 10—X—? ^ ° rto = A7 B7 XIX

WHO JUJIN 丨 x 丨 a—03 · + ^? Y 丨 X 丨 0 丨 N N 丨 01X—: Tto =

(Please read the note on the back first. Fill in this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

I NH to Λ

1α: ΐο3ο6Η (CN J? 3NLL-sa 82 This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) ro > b A7 B7 V. Description of the invention (8C)) xx m ηΐχ— = νΗΝ Ν— α-X-Hor ▲ -IV = οιί 〇fs- ^ l-u'iigang * ^^ " -τμι ^ ίφκ- 嘁 · 3ο = χ sr ^ CJ, lcr 士 Ν Η ΟΛ. Central Bureau of Standards, Ministry of Economic Affairs Printed by the employee consumer cooperative, ν dieN χ— = ο 丄 ◦? F Yi 〇 £ 〇Η Η〇

-7 (-ce ^ —bS05X (2 jlunu-'s. TM [>! ®ι ^ 1-^ Binding. ^ (Please read the notes on the back first to fill in this page)): -83- This paper size applies China National Standard (CNS) A4 specification (210X 297 mm) A7 B7 * 81 V. Description of invention () 〇S 〇Η H010 /, N / hr

---------- 7: -install-- (please read the note on the back first # Qin write this page) A! Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs • s mc? ON = o = s + ^ x2 / ^ \ 0, o- HN 〇

Η Η Ν / bLU order m 4

VZLUgoH (zfe 0.0jN06H ... colLUN-dsa ίίϊ-(--84- This paper size applies to China National Standard (CNS) A4 size (2I0X29? Mm) a

V. Description of the invention (Figure xvm-xx shows the synthesis of prodrugs, in which-or two guanidine nitrogens are functionalized with -financial energy. These methods are only used to illustrate the method of preparing the compounds of the present invention. Rather than limiting its scope and spirit. Other methods, reagents, and conditions known to those skilled in the art of rust can be used to synthesize the compounds of the present invention. (Please read the precautions on the back of the product ^ ¾. Write this page). Central Standard of the Ministry of Economics Printed by Bureau Shell Consumer Cooperatives -85 This paper is printed in Chinese standard (CNS) A4 gauge (210X297 mm) 458 9 56 a7 'B7 _V. Description of the invention ()-/ HN srcs ^ cr ^ & (5

^^^^^^ < ^ '^ < π: < ϊτο:

s. 〇 χζ / \ 〇

-Υ Χ2 ζ ιχχ a Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs <: -0

99 bu zssa = a) t: 钿%-呔 oiik Temporary Θ • 81 > 纥 硕 囫 This paper size applies to China National Standard (CNS) A4 (210X2? 7mm) Η ^ ίοχ

oszrowzs-(60060 ieXId. PS = s3fcik life ice's real% s > ® 458956 A7 B7 V. Description of the invention (84 Figure X Step XI-further examples of possible prodrugs or active substances of the compounds of the present invention.-Specific In other words, Figure X XI illustrates the synthesis of cyclic and acyclic guanidine compounds with N- # or N-alkyloxy analogs. The cited references provide suitable derivatization of aniline illustrated in Figure VIB Synthetic details: Example A 3- > 1-B: 500-amino-4-hydroxy .- (35) -Benzyl butyrate preparation

(Please read the precautions on the reverse page before writing this page). Packing. I. Order 41. Central Standards Bureau of the Ministry of Economic Affairs®, Industrial and Consumer Cooperation, Du Printing, Fire-fighting, N-t-Boc-L, Astronomy Benzyl amine (75 g, 2'0 mmol) was dissolved in THF (30 ml), and BH3-THF (400 ml '40 mmol) was added dropwise over 30 minutes. Under pressure. In solution at 0. (: After 2.5 hours of zen mixing, the reaction mixture was evaporated with 19% acetic acid in MeOH (50 ml) and the solvent was evaporated. The residue was dissolved in ether (200 ml) with ιΝΗα,:., And K 2 It was washed with C03 and water, and dried over MgS04. The product was separated by removal of the solvent in air (melting point 56-5 7. (:, from isopropyl ether / hexane). 19_ ^ 1 ^ 11 (d6 -DMSO) ^ 1.4 (s, 9H), 2.68 (d) 2H, J = 6 Hz), 3.82 (d, 2H, J = 5 Hz), 4.01 (m, 1H), 5.16 (s, 2H), 5.21 (bs, 1H), 7.37 (bSj 5H)., Example B -87- Kernel paper size applies Chinese National Standard (CNS) 8 4 ^^ (2ΐ〇χ297mm ^^ 4 5 8 9 56 A7 — _ B7 '85' V. Description of the invention () Preparation of 3-amino-4- (anthranilide)-(3S) -butyric acid benzyl ester

Example A of 3-N -1 _ Boc -amino-4 -k- (3 S)-phenyl butyrate (1 0 • «gram '3 2 mmoles) in dimethylformamide (50 ml) and then dissolved in triethylamine (4.4 g, 46 mmol). Add isatoic Sf and stir the solution at 25 ° C for 24 hours. After the reaction (detected by RPHPLC) was completed, water was added to the product, and the product was extracted with ethyl acetate and 1000 liters, and dried over Na2S04. On evaporation of the solvent, 12 g of a yellow oil were obtained. In this oil, dioxolane (20 ml) was added, then 4N HC1 was added to dioxolane (20 ml). The reaction was carried out for 4 hours. The acid was added, and the oily substance was separated from the solution. The ether was added to the oily substance and decanted. This procedure is repeated twice. Ether was added to the semi-solid material and stirred vigorously for 16 hours. Obtained a white solid with MS and NMR consistent with the structure shown "-Example BB. -3 -Nitrophenyl glutamyl glycine production. Preparation: (Please read the precautions on the back 1 to write this page) · J ·. Ding · τ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

17 4 5S § A7 B7, 86 V. Description of the invention () Glycine (20 g '266 mmol) is added to water (200 ml), then hydroxide (20 g' 3 5 7 Millimoles), cooled to 0 in an ice bath. Alas. To this solution was added dropwise a solution of 3-nitrobenzidine gas (2.0 g, 108 mmol) in acetonitrile (20 ml) over a period of 10 minutes. After the reaction is complete (3-4 hours), concentrated hydrochloric acid is added until p Η = 2 and then a saturated aqueous NaCl solution (75 ml) is added. The product was filtered, washed with water, and air-dried (22 g, 90% yield). iH-NMR (d6-DMSO) 3.92 (d, 2H, J = 6.1), 7'9 (t, 1H, J = 7.9), 8.3 (t, IH, J = 5.6), 8.35 (m, 2H), 8.69 (s, 1H), 9.25 (t, 1H, J = 7.2 Hz). MS (FAB) m / e 231.0 (M + Li +). Elemental analysis C9H8N205 Calculated 値: C, 45.89 Η, 4.25 N, 9_92 Measured 値: .C, 45.97 H, 4.44 N, 10.11 ·

Example C Preparation of N- [2-[[(3-Nitrophenyl) carbonyl] amino] -1-oxoethyl] -fluorenyl-alanine ethyl ester

Ί ΓΓΥ ο 'C02Et Printed N, N · -bissuccinimide carbonate (14 g, 5.5 mmol) by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Glycine (10 g, 4.5 mmol) was added to anhydrous dimethylformamide (30 ml), and then added to N, N-dimethylaminopyridine (200 mg). After 1 hour, Lu-alanine ethyl acetate hydrochloride (7g '-89-* This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) A7 B7 87 V. Description of the invention (4.6 millimoles Ear) was added in 20% potassium carbonate aqueous solution (50 ml) in one portion. The reaction was completed and the product was collected by filtration (14 g, 97% yield).! H-NMR (d6-DMSO) 6 1.18 (t, 3H, J = 7.2 Hz), 2.46 (t, 2H, J = 7.0), 3.34 (q, 2H, J1 = 6.7 Hz, J2 = 12.6 Hz), 3.87 (d, '2H, J = 5.9 Hz), 4,05 (q, 2H, J1 == 7.4 Hz, J2 = 14.2 Hz), 7.8 (t, lH, J = 8.0 Hz), 8.1 (t, lHt J = 5.6 Hz), 8.35 (m, 2H), 8.71 (s, lH), 9.22 (bs, 1H). MS (FAB) m / e 324.2 (M + H +). Elemental analysis C14H17N3 06 H20 Calculated 値: c, 49.26 Η, 4.99 N, 12.32 Measured 値: C, 4.9.42 H, 5,01 N, Γ2.21

Example D Preparation of 3-[[(cyanoimino) (methylthio) methyl] amino] phenylbenzoic acid methyl ester

C02Me Printing of 3-Aminomethylbenzyl Formate (Table 6.04, 40 mM) and N-Cyanodithioimide Dimethyl Carbonate (11.96 g, 80 mM) ) The stirred mixture in pyridine (70 milliwells) was heated at reflux under nitrogen for 2-5 hours. The reaction mixture was cooled to room temperature. After standing at room temperature overnight, + the title compound was crystallized 'from the reaction mixture to obtain 6.2 g (two harvests). The title compound was used in the following examples without further purification. 90- This paper uses the Chinese national standard (CNS > Ren 4 ^ grid (2 丨 0 × 297) v 4 5Bq A7 B7 V. Description of the invention (88 NMR is consistent with the structure shown).

Example E Preparation of 3-[[(cyanoimino) [(benzyl) amino] methyl] amino] benzyl carboxylate Η

The Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed the compound (iog) of Example D and the stirring mixture of benzylamine (440 mg) in ethanol (15 milliliters, liters). It was heated under nitrogen flow 3 hour. The hide should be cooled to room temperature. After standing at room temperature overnight, a white solid was obtained, which was isolated by filtration (720 mg). The crude filtrate was purified by chromatography on silica (eluent, ethyl acetate / hexane, 1: 1, 1) to obtain the title compound (55 mg) as a white solid. * NMR is consistent with the structure shown ''-

'Example F 3-[[(Cyanoimino) (methylamino) 基;] Amino] Preparation of methyl benzoate

0〇2 ^ 6 91-This paper size applies Chinese National Standard (CNS) A4 specification (2tOX297 mm): 9 5§ t. Description of the invention (89 A7 B7 The title compound was prepared as described in Example E, but benzyl The amine was replaced with the same amount of methylamine. The title compound was obtained as a white solid (55% yield). NMR was consistent with the structure shown, Example G [[Amine (cyanoimino) fluorenyl] amino] benzene Preparation of methyl formate

C 〇2Μθ ΝΗ, Ί — (Please read the precautions on the back to write this page) Ι Example D compound (丨 0 g) and ammonium hydroxide (2 milliliters) in ethanol (20 mL) I mixture was sealed Tube in 70%. 〇 Heating for 3.5 hours. The reaction mixture was cooled to room temperature and the volume was reduced to -half. After standing at room temperature overnight, a white solid was obtained, which was separated by filtration and washed with methanol. The title compound (389 mg) was obtained as a white solid. NMR is consistent with the structure shown. .. Example 〇-[[(Cyanoimino) (ethylamino) methyl] amino] benzoic acid methyl ester Production Order Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

The reaction was carried out as described in Example G, but ammonium hydroxide was replaced with an equivalent amount of ethylamine 92- The national paper standard (CNS) A4 specification (2〗 0 × 297 male thin) is applicable to this paper standard A7 B7 »V. Description of the invention (90) The title compound (78%) was obtained as a white solid. N M R corresponds to the structure shown. . — Preparation of j-[[(cyanoimino) (benzyl) amino]) methyl] amine · methyl] benzoate ·

In a stirred solution of the compound of Example E (250 mg) in THF (2 ml) and MeOH (2 ml), IN NaOH (2 ml) was added. The reaction mixture was stirred at room temperature for 2 hours. White solid. The residue was suspended in water and acidified by adding 1N HC1. The resulting solid was dried over 'washed with diethyl ether' to give the title compound (14 mg), which was used in the following examples without further purification. NMR is consistent with the structure shown,

Example J -3 · [[(Cyanoimino) (amido) methyl] amino] benzoic acid preparation

NC

-93-

The paper scale is applicable to the Chinese National Standard (CMS) A4 specification (210X297 public) 458 956 V. Description of the invention (91 A7 B7 The standard compound is prepared as described in Example !, but the compound of Example E is replaced by the compound of Example F. Get the title Compound (87%), with the same amount of white solid. The body NMR is consistent with the structure shown. Example K-[[Amino (cyanoimino) methyl] amino] benzoic acid Preparation NC >

C02H NH, 'The title compound was prepared as described in Example I, but the compound of Example E was replaced by the equivalent compound of Example G. The title compound (92%) was obtained as a white solid. NMR was consistent with the structure shown

Example L J-[[(Aminoimino) (ethylamino) methyl] amino]. Preparation of phenylarsinic acid -I ^ i- ^^^ 1 ^ n- * nl ^^^ 1 ^ ^^ 1 IV— * I (Please read the notes on the reverse side and fill in this page first) α Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

The title compound was prepared as described in Example I, but in Example E, the compound was replaced with an equivalent amount of the compound in Example VII. Obtained the title compound (81%) as a white solid. 94-. The standard for private paper is applicable to China National Standards (CNS > A4 is now (210X297) S)

4 58 95S V. Description of the invention (92 N M R is consistent with the structure shown. Example M Preparation of m-guanidoguanuric acid H c 1

m- ΌΟ ^ Μ Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs, step A. Glycine (200 g) and K 0 Η (200 g) in water (1000 ml). A solution of benzamidine chloride (100 g) in acetonitrile (100 ml) was treated dropwise. The reaction mixture was warmed to room temperature and stirred for 4 hours: 12N HC1 aqueous solution was added until p Η < 2. The reaction mixture was allowed to stand at room temperature overnight. The resulting solid was filtered, washed with water (2X250 pull-up), and dried at 60 ° C in a vacuum. 100 g of m-nitro-maleic acid was isolated. MS, iH-NMR and CHN analysis were consistent with the desired product. In step B ', a suspension of m-nitronuric acid (50 g) and 5% Pd / C (5 g) in methanol (200 ml)-received 50 psi H2. After 2 hours, the reaction mixture passed 遽-* \. The resulting gray solid was washed with 2% HC1 · water solution (2 X 250 ml). The yellow solution was freeze-dried to obtain m-amino-maleic acid H C1 (30 g) ° Step C 'm-amino-maleic acid HC 丨 (10 g), NMM (12 ml) and pyto-1-carboxamidine HC1 (8.3g) -95 in Dioxin's Luan (80ml) Spreading Water (20ml) This paper size applies to Chinese National Standard (CNS) A4 specification (210X297). Please read the notes on the back first Item #-·· '^. Writing Book I ·} 6 .Packing · 1T- 458 956 A7 ._: ____ B7 V. Description of the Invention (93) The mixture was refluxed for 6 hours. The heat was removed and the reaction mixture was cooled to room temperature. Saturated HC1 water (100 ml) was added and the reaction mixture was filtered. The resulting solid was washed with dioxolane (20 ml) and then with acetone (20 ml). Salmon-colored solid was dissolved in 1: 1 CH3 CN: Η 2 0 and treated with 20% H (pl aqueous solution (pH < 3). Freeze-dried solid m-guanidoguanuric acid HC1 (10 g) MS, W -NMR and CHN analysis were consistent with the desired product. Example N '' 3-[[(Cyanoimino η (2-pyridyl.methyl) amino] methyl] amino] phenylbenzoate preparation

Consumption cooperation between employees of the Central Bureau of Standards of the Ministry of Economic Affairs and the printing of the title compound was prepared according to the procedure described in Example E, but the benzylamine was substituted with the equivalent of 2- (aminomethyl) _u to obtain the title compound. White solid (75% yield). ,-· N M R is consistent with the structure shown '. Example 0 Preparation of J _ [[(cyanoimino) [(2-t »ratio. This methyl) amino] amido] amino] benzoic acid -96- This paper size applies to Chinese National Standard (CNS ) M specifications (21 × 297 mm) t— 4 5 B 9 A? B7 V. Description of the invention (94

C = N V

CO, Η

N

The title compound was prepared according to the procedure described in Example I, but the compound of Example E was replaced with the equivalent of the compound of Example N to obtain the title compound as a white solid (70% yield). N M R is consistent with the structure shown. ttiZ · 3-[[(cyanoimino) [(3-pyridylmethyl) amino] methyl] amino] phenyl benzoate (Please read the precautions on the back first. Pavilion # ,. (Write this page)-installed _

3 The title compound was prepared according to the procedure described in Example E. The title compound was obtained by substituting the same amount of 3- (aminomethyl) -pyridine for the title compound. , Solid (70% yield). '': N M R is consistent with the structure shown. -97 · Applicable to China National Standards (CNS > Α4 size (2ί297 × 297 mm) for private paper scales. 5. Description of the invention (95 A7 B7 fiiQ. 3-[[(cyanoimino) [(3-pyridyl Preparation of methyl, amino) amino] methyl] amino] benzoic acid ·

The OH / one title compound was prepared according to the procedure described in Example I, but the Example E compound was replaced with an equivalent amount of the Example P compound. The title compound was obtained as a white solid (65% yield). NMR is consistent with the structure shown. Example R ’Preparation (please read the notes on the back to write this page). Packing. Ordering I. Printed by the Consumers’ Cooperative of the Central Bureau of the Ministry of Economic Affairs

Between DL-3-amino-3-phenylpropionic acid (Γ6.5 g, 0.1.M), dioxolane (160 ml), water (40 ml) and triethylamine (25 ml) To the stirred solution was added di-tert-butyl dicarbonate (18.6 g, mol). The reaction mixture was quasi-98-centimeter 97 2 Α7 B7 in the quasi-standard countries. V. Description of the invention (Stirred at room temperature for 16 hours. The reaction mixture was concentrated in the air to obtain an oily solution, which was dissolved in ethyl acetate. The resulting solution was washed with water, osmium, NaCl and wood. The organic layer was separated and dried (Na2SO4) and offered to give the crude product (8.9 g), which was used in the next step (Example S) without further purification. NM K · and the structure shown—for 3 · preparationο

---------- Pack-(Please read the note on the back # '-write this page first) Order the compound of Example 11 (8.3 g. 30 millimoles) in a stirred solution of 0.01 milliliter (50 milliliters), K2CO3 (100 grams) and benzyl bromide (5.7 grams '30 millimoles) were added. The reaction mixture was stirred at room temperature under nitrogen pressure for 16 hours. The reaction mixture was diluted with water (400 ml) and extracted with ethyl acetate. 'The organic layer was separated, washed with water, 5% NaHC03 and water, and dried (Na2S04).' Shrinked in air.-Zhongzao to obtain the crude ester (8.5 g). The problem solving method was used in the next step (example T) without further purification. N M R is consistent with the structure shown. ,, Example T Preparation __.-99-The standard of this record is applicable to CNS) • 5 ^ 9 56 V. Description of the invention (A? B7 97

To the reaction solution of the compound of Example S (2.0 g) in methane (20 ml) was added 'trifluoroacetic acid (20 laugh)' and the reaction was stirred at room temperature for hr. The reaction mixture was concentrated in the air to obtain 2.05 g of crude product, which was used in the next step (Example U) without further purification. , N M R is consistent with the structure shown? t ηυ_preparation hn-ch2- t-Boc

C02Bn c 一 ΝΗ— (l Printed on Nt-Boc-Glycine (876 mg '5 mmol), Dichloride (20 ml), N-A To a stirred solution of morpholine (1.01 g), IBCF (690 mg) was added at 0 ° C, and the reaction mixture was stirred at 0 ° C for 1 ^ minute. The product of Example T (1.845 g) was added to the reaction mixture. The reaction mixture was heated to room temperature and stirred for another 6 hours. The mixture was water Λ and then saturated 唉 -100- This paper size applies Chinese National Standard (CNS) A4 specification (2 丨 0 > < 2 (Mm) A7 B7. 98 ------------- V. Description of the invention () · Sodium bicarbonate solution and washing with water, drying (N ^ SO4), and concentrating in the air to obtain: crude product ( 2.2 g). The crude product was purified via a flash column using 92 5: 7: 〇CHCI3 · ethanol, N Η * 〇 Η as eluent to obtain the title compound (1.8 2 g), as an oil. NMR spectrum and shown Structure is consistent * Example V Preparation ... *

c Please read the note on the back of this page. $ ^ This page >., Packing _, 1-Male Labor Consumption Cooperation Department of the Central Ladder Bureau of the Ministry of Economic Affairs, printed the compound U in the example (1.8 g) in the two gas tiger (20 ml) Add trifluoroacetic acid (12 ml) to the stirring solution in), and the mixture should be stirred at room temperature for 6 hours. The mixture was concentrated in the air to obtain the crude product (g) as an oily gum, which was used in the next step (Example 132, Example 133, Example 134) without further purification. N M R is consistent with the structure shown. •: f η 1 (±) /?-[[2-[[[3-[(Amineimine 4amido) amino]], phenyl] carbonyl] amino] ethylamido] amino] pyridine -3.- Preparation of ethyl propionate and bis (trifluoroacetic acid) salt 101 The size of the paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) r Λ Α7, Β7 Central Laboratories of the Ministry of Economic Affairs, Consumer Cooperative Azalea-99 V. Description of the invention (). NH II;; hnX, nh2 ^ C 1 / • II 0 (RS) Step A in 3-pyridinecarboxaldehyde (300 ml) in 2-propanol (3 L) was added acetic acid (297 g) 'and then malonic acid (398 g) was added. The reaction mixture was stirred at reflux for 5 hours. Shen; Dianwu trend; hot filter, wash with hot_isopropanol (2 liters). The resulting white solid was dried to obtain DL-3-amino-3- (3. ^ pyridyl) 4 acid (220 g) as a white solid. NMR and MS were consistent with the desired product "Step B f DL_3-Amino-3- (3-pyridinyl) propanoic acid (220 g) in step A was slurried in absolute EtOH (3.6 liters). HC1 gas (a lecture bottle, 1/2 pound) was bubbled into the reaction mixture and stirred for 40 minutes (slow exotherm to 61 X). The paddle: liquid is then heated at reflux for 4 hours (a solution forms after 1 to 1,5 hours). The reaction mixture was cooled to 5 ° C in an ice bath. After stirring at 5 ° C for 1.5 hours, the white precipitate formed was filtered and washed thoroughly with ether. After drying under air at 50 ° C, the yield of DL-3-amino-3- (3-pyridyl) propionic acid ethyl ester dihydrochloride was 331.3 g, as a white solid. NMR and MS were consistent with the desired product. -102-

ί: Pack-{Please read the note on the back ^^ Item #-. 4Write this page)-The size of the paper used in this edition is in accordance with the Chinese National Standard (〇Grab) 44 胡 ^ (210 father 297 public consultation ) * Jj A '.: ,,; ·' A7 B7 V. Description of the invention (1QQ) Printed on step c of DL-3 -amino-3- (3- Blofenyl) _ethyl propionate dihydrochloride; (220.6 g, 0_83 moles) in anhydrous THF (2 liters) triethylamine (167.2 g, 1.65 moles) 'Nt-Boc-glycine Acid N-hydroxysuccinimide (225 g, 0.826 mol) (Sigma) was added in several portions at 5-1 CTC (without exotherm). The reaction mixture was stirred at room temperature overnight. The resulting precipitate was filtered and washed with THF. The solvent in the filtrate was then removed under vacuum. The residue was taken up in ethyl acetate (2.3 liters). The ethyl acetate layer was washed with saturated sodium bicarbonate (2 X 900 ml) and Η20 (3 X 900 ml), dried over MgS04, and removed under air. The residue was slurried in 10% ethyl acetate / hexane (2.5 liters) overnight. The precipitate was filtered, washed with 10% ethyl acetate / hexane (1 L) and then washed with hexane, and then dried to obtain yS-[[2-[[(1,1-Difluorenylethoxy) carbonyl] Amino] ethylammonio] amino] pyridine-3-propionic acid ethyl ester (233 g) as a white solid. N M R and M S are consistent with the desired structure. Step D Lu-[[2-[[(1,1-dimethylethoxy) carbonyl] amino] ethylfluorenyl] amino;]: ethyl pyridine-3-propionate (from Step VIIC ) (232 g, 0 66 mol) dissolved in warm dioxin (1 liter). After cooling to room temperature, 4M HC1 was slowly added in dioxin (1.6 liter) (Aldrich): After a minute a white precipitate formed and then turned into a thick sticky substance. After 2 hours, the solvent was decanted. The viscous substance was slurried in ether, and the ether was decanted until a white solid was produced. Β was dried under vacuum. Ethyl propionate dihydrochloride (224.2 g) was a white hygroscopic solid. NMR and MS are consistent with the desired structure. '-103- Applicable to China National Standard (CNS) A4 size (210X297 mm) for clothing and paper size (Please read the notes on the back and write the book first) Binding and binding. Press 6 9 a? Β7 101 ~-V. Description of the invention () • »

Step E. 3,5-Dimethylpyrazole-1 -carboxamidine nitrate (6 g, 0.03 mole): (Aldrich) and diisopropylamine (3.8 g '0.03 mole) in dioxolane (20 M: L) and water (10 ml) were added with 3-aminobenzoic acid (2,7 g, 0.02 mole). The reaction mixture was stirred at reflux for 2.5 hours, and then the precipitate formed at β overnight was filtered at room temperature, washed with dioxin / Η 2 0, and dried. The precipitate was then slurried in Η20 and acidified with concentrated HC1 until a solution formed. The solvent was removed under vacuum and the residue was slurried in ether twice (ether decantation). The product was dried under vacuum to obtain 3-guanidinobenzoate (1.77 g) as a white solid. MS and NMR are consistent with the desired structure β Step F, the product of Step E (0.49 g, 0.023 mol) and N * methylmorpholine (0.23 g, 0.0023 mol) in anhydrous DM F (8 Ml) was added isobutyl formate (0.31 g, 0.0023 moles) and the temperature of the ice bath. After stirring for 5 minutes at an ice bath temperature, a slurry of the product of step D (0.73 g, 0.023 mole) and N-fluorenylmorpholine (0.46 g, 0.0045 mole) in anhydrous DMF (8 ml) Portions added. The reaction mixture was stirred at room temperature overnight. Solvent-removed on a water bath at 78 ° C under emptiness, and the product was separated by RPHPLC to obtain (±)-[[2, [[[[[[Aminoiminomethyl) amino] phenyl] phenyl ] Carbonyl] amino] ethyl] ethyl] amino] pyridine-3-propionic acid ethyl ester, bis (trifluoroacetic acid) salt (800 mg), as a wet white solid. M S and N M R are consistent with the desired structure. Example 2 '(±) fluorene-[[2-[[[[[Aminoiminomethyl) amino] benzyl] carbonyl] amino] amino] ethylfluorenyl] amino] pyridine- 3-propionic acid, bis (trifluoroacetic acid) salt system-104-This paper X Dragon is suitable for China National Standard (CNS) A4 size (210X297 mm) Packing — {Please read the notes on the back first, 4 'write this page)

Order I 458 956 V. Description of the invention (for A7 B7 102

NH

0 Ο II, c

0H .2TFA <#Notes on the back of the first reading from each page) Add the product of Example 1 (700 mg, 0.001 mol) to H2O (20 ml) with LiOH (160 mg, 0.Q038 mol ). The reaction mixture was stirred at room temperature for 1 hour. After lowering ρ Η to Ξ 5 with TFA, the product was separated by RPHPLC to obtain (±) Lu-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino ] Acetyl] amino] pyridine-3 -propionic acid, bis (trifluoroacetic acid) salt (640 mg), as a white solid. MS and NMR are consistent with the desired structure. Example '3-· Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Lu)-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amine-based ] Ethyl ethyl] amino] ethyl phenylpropionate "Preparation of trifluoroacetate

-105- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X2SI7 mm) 458966 V. Description of the invention (103 A7 B7. The above compounds were prepared according to the method of Example 1, but replaced with equivalent amount of benzyl acid 3-pyridinecarboxaldehyde. NMR and MS are consistent with the desired structure. Example 4 (Shi) /?-[[2-[[[3-[(Aminoiminomethyl) amino] phenyl] carboxyl ] Amine] Acetyl] Amine] Phenylpropionic acid, trifluoroacetate preparation — < Please read the note on the back first ^

I

(R

OH cno Printed by the Pager Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. The product of Example 3 (0.37 g, 0.0007 mol) was added to water (10 ml) with LiOH (80 mg, 0.002 mol). The reaction mixture was stirred at room temperature for one hour. pΗ was reduced to about 3 with TFA, and the product was separated by RPHPLC to obtain (±) /?-[[2-[[[3-[(aminoiminomethyl) amino] benzyl] carbonyl] amine ] Acetyl] amino] phenylpropionic acid, trifluoroacetate (280 mg), as a white solid; MS and NMR were consistent with the desired structure. '' Example j [(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] -1,3-dioxole-5 -propionic acid ethyl Preparation of esters and trifluoroacetate-106- This paper size is applicable to the Chinese National Standard (CMS) A4 (21f) X297 mm) Printed by the Bayer Consumer Cooperative of the Central Bureau of Standardization of the Ministry of Economic Affairs. Invention Description (104)

The above compound was prepared according to the method of Example 1, but the 3-pyridinecarboxaldehyde in step A was replaced with an equivalent amount of piperonal (AIdrich). · MS and NMR are consistent with the desired structure β Example 6, (±) /?-[[2-[[[3-[(Amineimine methyl) amino] phenyl] carbonyl] amino] ethyl Fluorenyl] amino] -1,3-benzodioxo-5-propionic acid, trifluoroacetate

(R and S)

To the product of Example 5 (0.35 1, 0.0006 mol) was added LiOH (70 mg, 0.0017 mol) to Ben (40 ml) and CH3CN (5 ml). The reaction mixture was stirred at room temperature for 1 hour, the pH was reduced to about 4,5 with TFA, and the product was separated by RPHPLC to obtain a (±) point-[[2-[[[3-[(aminoiminoamidoformamidine)) -107- This paper wave is again applicable to China National Standard (CNS) A4 »(2 丨 0X297mm) ............... .. _ .Γ: 1 I binding (please read the note on the back ^^ item gray ^ write this page > 5. Description of the invention (105 A7 B7 Amine] phenyl] carbonyl] amino] ethenyl] amine Base] -1,3 -benzyl dioxo-5-propanoic acid, trifluoroacetate (280 mg), as a white solid and NMR consistent with the desired structure. Example 7 (±) / 5-[[2 -[[[3-[(Aminoiminomethyl) amino] fluoren-1-1-yl] carbonyl] amino] ethylfluorenyl] amino] eridine-3-propionic acid ethyl ester, bis (tri Fluoroacetic acid) salt. Preparation :.

Ο

2TFA < Please read the notes on the back #, .. / € write this page) Order

-I Printed in step A by the Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperative, in 3-nitro-1-acetic acid ethyl ester (2.5 g, 0.011 mole) (Aidrich) in 'MeOH / H2O (40 ml) (1 : 1) LiOH (1.8 g, 4 eq) was added. The solution was stirred overnight at room temperature. The solvent was removed. The a-residue was removed under H2 vapor and the solution was dissolved in H2O 'and acidified with concentrated HC1. The resulting precipitate was filtered, washed with H2O, and dried to give 3-nitro-1-theanic acid (2.18 g) as a white solid. In step B, 3-nitro-1, hydrazone (1.77 g, 0.008 mol) was dissolved in a minimum amount of hot MeOH at 6 〇〇 / 〇pd / C (300 ml) was added, and the reaction mixture was shaken on a parr It was shaken at 50 pSi H2 for 5 hours. The catalyst was filtered by celite, 108-degrees, and the scales are common to the national standard (CNS) M specifications (strong 7 mm). 3. Printed by the Bayer Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs c B 9 56 A7 _ __ -____ B7 ", 106 ----------- 5. Description of the invention () Remove the residue under dry air, "Residue dried to obtain 3 _ amine_bucaric acid (1.43 g), pink Colored solid. : Step C. At 3,5-Dimethylpyrazole, Carboxamidine Nitrate (6 g, 0.008 moles) (Aldrich) and Diisopropylethylamine (2 g, 2 g). (0088 moles) was added to dioxolane (5 liters) and water (2 :: 5 ml) 3-amine _ _ _ formic acid (丨 grams, 0.0053 mol). The reaction mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature, and the precipitate was filtered, washed with dioxolane / H20, and dried. The precipitate was then slurried in Η20 and acidified with concentrated hci. The solvent was removed on a 70 ° C water bath under vacuum, and the residue was slurried three times in ether (ether decantation). It was then dried under vacuum to obtain 3 -guanidinothecoate hydrochloride (46 mg) as a white solid. Step D (0015 mole) and N · methylmorpholine (150 mg) were added to anhydrous DMF (8 ml), isobutyl formate (2 10 mg), and the temperature of the ice bath. After 5 minutes of incubation at the ice bath temperature, a slurry of the product of Step D (490 mg, 0.0015 mol) 'N-methylmorpholine (300 mg) and anhydrous DMF (6 ml) of Example 1 was added in one portion. The reaction mixture was stirred at room temperature overnight. The solvent was left under vacuum at 7 8. (: Removed on water bath, the product was separated by RPHPLC to obtain (±) 々-[[2-[[[[[[ ] Ethyl-8¾yl] amino] "Bis-3--3-propanoic acid ethyl ester, bis (trifluoroacetic acid) salt (410 mg) 'is a white solid.' MS and NMR are consistent with the desired structure. Example 8 -109- The size of this paper applies to the Chinese National Standard (CNS) Α4 specification (210X297 mm) (please read the note on the back ^ < 1. item *?-4'manuscript 1]-installed. 4 4.

• 2ΊΤΛ Printed A7 _._______ B7 printed by the pager consumer cooperative of the China Central Bureau of Economic Affairs 107 V. Description of the invention () (±) Lu-[[2-[[[3-[(Amineimineamino) Preparation of Amine] fluoren-1-yl] carbonyl] Amine] Ethylamido] Amino] -pyridine-3-propionic acid, · Bis (trifluoroacetic acid) salt preparation

To the compound of Example 7 Step D (280 mg, 0.0004 mol) in water (15 mL) and CH3CN (2 ml), LiOH (70 g, 0.0016 mol) was added. The reaction mixture was stirred at room temperature for 1 hour. p Η was reduced to 5 by TFA, and the product was separated by RPHPLC to obtain (±) /?-[[2-[[[l-[(aminoiminomethyl) amino] fluoren-3-yl] sulfonyl ] Amine group] Ethyl group] Amine group] Pyridine_3_propionic acid, bis (difluoroacetic acid) salt (240 mg), hygroscopic white solid a μ S and NMR are consistent with the desired structure "-Example 9 (Earth) / 5-[[2-[[[[(3- (4,5 -dihydro-1H -imidazol-2-yl) amino] fluorenyl] zoyl] amino] ethynyl] amino ] P 比 症 -3-Ethyl propionate, preparation of bis (trifluoroacrylic acid) salt-110- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) • \ le (please listen first Read the notes on the back, write this page)

Α7 Β7 V. Description of the Invention (1ί) 8)

Step A... In 2-methylthio-2-imidazolinium hydroiodide (14.6 g, 0.06 moxon) (Aldrich) and diisopropylethylamine (7.6 g, 0.06 mo Ear) To dioxolane (40 ml) and H2 0 (20 ml ') was added 3-aminobenzylcarboxylic acid (5-4 g' 0.04 mole). The reaction mixture was stirred at reflux overnight. The solution was cooled in an ice bath, and the resulting precipitate was filtered and washed with dioxin. Crude Goods • 1

Purification was performed to obtain 3- (2-aminoimidazoline) benzoic acid (800 mg). Step B Printed by the Ministry of Economic Affairs Central Bureau of Prototypes and Consumers Cooperative Production --------- Packing-... (Read the note on the back of the poem first 4.W page) The product in step A ( 400 mg, 0.00125 mol) and N-methyl? 4 (130 mg, 0.00125 mol) were added to anhydrous DMF (8 ml) with isobutyl formate (170 mg, 0.00125 mol). After stirring for 5 minutes at the temperature of the ice bath, the product of step D (4 10 mg, 0.00 125 mol) and N-methyl-morpholine (250 mg, 0.0025 mol) in Example 1 were dried in anhydrous DMF (6 ml). Join in one. The reaction mixture was stirred at room temperature overnight. The solvent was removed on a water bath at 7 9 ° C under vacuum, and the product was separated by RPHPLC to obtain (±) /?-[[2-[[[[[[3-[(4,5-dihydro-1H-imidazole-2- (Amino) amino] phenyl] carbonyl] amino] ethoxy] amino] pyridine-3-propionic acid ethyl ester, bis (trifluoroacetate) salt (600 mg), as a wet white solid. M S and N M R are consistent with the desired structure. -111-This paper size applies to China National Standards (CNS) A4 (2Ι ×× 297 mm) 4 58 9 53. Α7. Β7 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (1.9) » Real life i 1 〇 (±) /?-[[2-[[[[[[[[[[[4,5-Dihydro-1H-imidazol-2-yl) amino] phenyl] carbonyl] amino] ethyl] Of Amino] amino] -pyridine-3 -propionic acid, bis (triaminoacetic acid) salt

To the product of Example 9 Step B (450 mg., 0.00068 mol) was added LiOH (110 mg, 0.027 mol) in water (20 ml). The reaction mixture was stirred at room temperature for 1 hour. pΗ was reduced to 5 by TFA, and the product was separated by RPHPLC to obtain (±) /?-|; [2-[[|; 3-[(4,5-diargon-1 ^ imidazol-2-yl) amino group) ] Phenyl] carbonyl] amino] ethenyl] amino] -erbino-3-propionic acid, bis (trifluoroacetic acid) salt (250 mg), hygroscopic white. Solid. M S and N M R are consistent with the desired structure. _. Example 1 1 • (±) 々-[[2-[[[[[[[3,4,5,6'tetrahydro-21 {-azapyridin-7-yl] amino] benzyl] Carbonyl] amino] ethylamido] amino] pyridine-3-propanoic acid ethyl ester, bis (trifluoroacetic acid) salt -112- This paper size applies to Chinese National Standard (CN'S) A4 (210X297 mm)- -------- Equipment-(Please read the precautions on the back page first) Order 458 956 A7 A7 _ B7. 110 V. Description of the invention (

(Racemic) Η

• 2TFA Step A 'Add 3-aminobenzene to 1-aza (acryl) -2-methoxy-1-cycloheptene (3.67 g, 0.0288 mol: (Aldrich) in absolute ethanol (20 ml) The osmate salt (5 g '0.0288 moles solution formed rapidly. The reaction mixture was stirred at room temperature overnight. The resulting precipitate was filtered, washed with ether, and dried under vacuum to obtain 3- (1-aza-2 -Amino-1-. Cyclothione; ii) Benzoic acid (4.9 g) ..

Step B Printed in step A (0,5 g, 0.0019 mol) and N-methylmorpholine (0.19 g '0.0019 mol) in anhydrous DMF (8.ml) ) Isobutyl isoformate (0.25 g '0.019 mol) ^ After stirring at ice bath temperature for 5 minutes, the product of step D of Example 1 (0-6 g, 0.0019 mol) and N- A slurry of fluorenylmorpholine ('0.3S g' 0.0037 mol) in anhydrous DMF (7 ml) was added in one portion. 'The reaction mixture was stirred overnight at room temperature. The solvent was removed on a 78 water bath under vacuum and the product was separated by RPHPLC to obtain the title compound (490 mg). Β NMR and MS were consistent with the desired structure. '. Example 1.2 (±) / S-[[2-[[[[[[[[3,4,5,6-i hydrogen-2'-aza, fluorene-7-yl) amino] phenyl] phenyl ] Carbonyl] Amine] Ethylamido] Amine] pyridine-3_propionic acid, bis (trifluoroacetamidine: .-113- This paper is applicable to China National Standards (CMS > A4 size (210XW7mm) 458 95β A7 B7 V. Description of the invention (111 Preparation of salt

(Racemic) 0

ΓΓ, ΟΗ.2TFA To the product of Step 11 in Example 11 (400 mg '0.00058 mol) in water (20. ml) was added LiOH (SO mg, 0.0019 mol). The reaction mixture was stirred at room temperature for 1 hour. p Η was reduced to 4.5 with TFA and the product was separated with rphplC to obtain 320 mg (±) of cold-[[2-[[[3: [(3,4,5,6, tetrahydro-2 > 1-azapyridine] -7-yl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -pyridine, propionic acid, bis (trifluoroacetic acid) salt, as a white solid. MS and NMII are related to the structure of hearing desire. Example 1 3, (±) / 5-[[2-[[[[[[[[3,4,5,6-tetrahydro-2H-aza leather-7-yl) amino] phenyl] carbonyl] Preparation of Amine] Ethylamido] Amine] -1,3-Phenylhydrazine-5-propanoic acid ethyl ester, Preparation of TFA salt —-------- Packing-• '(Please go first Read the note on the back-write this page on ice}

Printed by 1T Central Consumers Bureau of the Ministry of Economic Affairs

ο 〆 ΠΠΟ

A -114 This paper size applies Chinese National Standard (CNS) A4 regulations (21 × 297 mm) Β09. V. Description of the invention (112 A7 B7 The above compounds were prepared according to the method of Example 11 but An equivalent amount of Aldrich was substituted for A3-pyridine in Example Bili. The MS and NMR and the desired structure in Example 11 Step b were caused.-Example 14 (Plant [[2 _ [[卜 [( 3,45,6_tetrazine · 2H, aza_7-yl) amino group] phenyl group] amino group] ethyl wall group] amino group] -1,3-benzyl dinono-5- Preparation of propionic acid, TFA salt

σ II 〇-OH .TFA Τ 'outfit-(Please read the notes on the back first to write this page) Order 4 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-the product of Example 13 (〇46 grams, 〇〇〇〇〇〇〇〇〇〇〇9191mol) in water (100ml) and dioxin (7-5ml) to LiOH (80mg, 0.0018mol). The reaction mixture was stirred at room temperature for 2 hours. ρ η was obtained from TFA # to 5 ·, and the product was separated by RPHPLC '(±-[[2-[[[3-[(3,4,5,6-tetraargon 2H-azafluorene-7-yl) amine [Benzyl] benzyl] M group] Amine group] Ethyl fluorenyl group] Amine group] -1,3-benzodioxo-5-propanoic acid (440 mg), TFA salt, white solid. MS and NMR are consistent with For consistent structure, Example 1 5 (Earth) Lu-[[2-[[[[[[[[3,4,5,6-tetrahydro-2 ^ -aza leather-7-yl) amino] phenyl] ] Carbonyl] Amino] Ethylamido] Amine] -Phenylpropionic acid, trifluoroacetate -115- Sheet size is applicable to China National Standard (CNS) A4 specification (210X297 mm)

J 459 V. Description of the invention (113 A7 B7 0

The above compound was prepared according to the method of Example 12, but the same amount of benzyl was used in place of the 3-pyridinecarboxyl 'in Step A of Example 1 and then used in Step 0 of Example 1 as described in Example 11 and Step B. M S and N M R are consistent with the desired structure. 'Example 16 · (±) 々-[[2-[[[[[[[[[3,4.-Earthine-2Η-pyrrole-5-yl] amino] .phenyl]]]] Ethyl [Amino]-Preparation of this bite-3-propionic acid ethyl vinegar, bis (tri, acetic acid) salt (please read the notes on the back first ^^ write this page) Pack.-Order by the Central Bureau of Standards of the Ministry of Economy Printed by Employee Consumer Cooperative

.OEt C-^ .2TFA The above compound was prepared according to the method of Example i 1 except that i_aza_ 2_methoxy-1 -cyclopentane * was used instead of 1-aza-2-methyl in step A. Oxy-1-cycloheptene. MS and NMR are consistent with the desired structure. Β * 1_aza · 2 · methoxy-1-cyclopentene is manufactured as follows: On 2-paper-pyrrolidinone paper, the standard is Ningguo National Standard (CNS A4 ^ 10x297). Fare-paying) 458 956 V. Description of the invention (A7 B7 114 (2.7 g, 0.033 mole)) To CH2C12 (100 mmol 4) was added tetrafluorobotrisyloxylock (Oxoniuin) salt (10 g ) (Aldrich). The reaction mixture was stirred at room temperature for 2 days. Saturated NaHC03 was added, and after shaking in a separatory funnel, CH2C12 was separated and removed by distillation. 1 g of the desired compound was separated by further distillation under atmospheric pressure and separated. Collect the part with a boiling point of about 120 ° C.-. 'Example 17. (Earth) point-[[2-[[[3-[(3,4-dihydro-2Η-pyrrole-5-yl) amine [Benzyl] benzyl] carbonyl] amino] ethenyl] amino] -pyridine-3-propionic acid, preparation of bis (trifluoroacetic acid) salt. --------- Ί 袭-! Ί h (Please read the notes on the back first ^ ckthis page)

.ΟΗ C g 2TFA Order h. Printed on the product of Example 16 (380 mg, 0.00057 mol) in water (15 liters) and added LiOH (100 mg, 0.002 mol) to the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. * The reaction mixture was stirred-stirred at room temperature for 2 hours. The pH dropped to 5 with TFA and the product was separated by RPHPLC to obtain (±) Lu-[[2-[[[3-[(3,4-dihydro-2H-pyrrole-5-yl) amino] phenyl] phenyl ] Condensyl] amino] ethoxy] amino] -r [rho] -3-propanoic acid, bis (trifluoroacetic acid) salt (150 mg), as a white solid. MS ^ NMR is consistent with the desired structure. Example 1 8 (±) Cold-[[1-[[[[[[Amineiminemethyl.amino] amino] phenyl] carbonyl] amine-117- This paper size applies to Chinese national standards (CNS ) A4 specification (210X297 mm) 458956 V. Description of the invention (A7 B7 based] -1-cyclopropyl] carbonyl] amino] pyridine-3-propanoic acid ethyl ester, bis. (Trifluoroacetic acid): Preparation of salt

The above compound was prepared according to the method of Example 1, but replaced with the same amount of 1-Boc-amino) cyclopropyl_n-hydroxysuccinimide carboxylate (Sigma) in Step 1 of Example 1 to N-1- Boc-N-hydroxysuccinimide of glycine. MS and NMR are consistent with the desired structure. Example 1 9 (±) / 5-[[1-[[[[[[[Aminoimine'methyl) amino] phenyl] carbonyl] amino]] Cyclopropyl-1yl] carbonyl] amino] pyridine · 3-propionic acid, bis (trifluoroacetic acid) salt. Preparation----------- 7 ~ skirt-- (Please read the back first Precautions ^ -¾ This page) Yeast-Order the policy of employee consumer cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

; 2TFA -118- This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 4 58 A7 B7 V. Description of the invention (116) The product of Example 18 (220 mg, p.00033 moles) To the water (15 'liter) was added LiOH (60 mg, 0.0013 moles). The reaction mixture was stirred at room temperature for 1.5 hours. The pH was reduced to 3 with TFA, and the product was subjected to RPHPLC to obtain ([[Aminoiminomethyl) amino] phenyl] carbonyl] amino] -cyclopropyl-1-yl] carbonyl] amino] -Pyridine-3-propionic acid, bis (trifluoroacetic acid) salt (no mg) 'is a white solid. MS and NMR are consistent with the desired structure. Example 2 0 (±) /?-[[2-[[[4 -Ga-3-[(3,4,5,6-tetrahydro-21azabenzene-7-yl) amino] phenyl] carbonyl] amino] ethenyl] amino] pyridine-3-propane The purpose of acid ethyl S, preparation of double TFA salt :: Packing-{Please read the precautions on the back # .. € on this page) -_j

, OEt .2TFA (racemic), printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, the above compounds were prepared according to the method of Example 1.1, but with the same amount of 3-amino group ... 4-gas. Aldrich) replaces the 3-amino-benzoate hydrochloride in Example a, step a. ] VIS and NMR are consistent with the desired structure. Example 2 1 (±) cold-[[2-[[[4- 气 -3-[(3,4,5,6-tetrahydro-2 ^ 1-argon-7-yl) amino] Table base] several bases] amine group] ethyl fluorenyl group] amine group] p than this 3-propionic acid, the preparation of double TFA salt -119 This paper size applies to Chinese national standard ((: yang) six 4 specifications (' 2! 0 \ 297 mm) ^ 4 58 9 5β Α7 Β7 V. Description of the invention () :,

.2TFA, 0Η To the product of Example 20 (150 mg, 0.0002 mol) in water (15 ml) was added LiOH (40 mg, 0.0008 mol). The reaction mixture was stirred at room temperature for 1 hour. p Η is reduced to 3 with TFA: the product is isolated by RPHPLC to obtain (Shi) Wan-[[2-[[[4- 气 -3-[(3,4,5,6-tetrahydro-211- Azapine-7-yl '). Amine] phenyl] carbonyl] amino] ethylamidine] amino] pyridine-3-propanoic acid, bis-TFA salt (100 mg), as a white solid. MS and NMR are consistent with the desired structure. · Example 2 2. (±) / 5-[[2-[[[[3,5-bis [(3,4,5,6-tetrahydro-211-aza leather-7-yl) amine]] Of phenyl] carbonyl] amino] ethynyl] amino] pyridine-3-propionic acid, tris (trifluoroacetic acid) salt—

1.1!-I-\ — 装-(Please read the precautions on the back to write this page: I order α. Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

.3TFA

NH

(Racemic) -120- The standard of this paper is applicable to China National Standard (CNS) A4 (2 OX297 mm) 118 45 [V. Description of the invention (A7 B7 The above compounds were prepared according to the method of Example '12, but Substitute 3,5, di.aminobenzoic acid dihydrochloride (0.3 equivalents) (Fluka) in the same amount as in Example 1 1 Step a. 3-Amino · benzoate. MS, NMR and desired structure Example 2 3 (Earth) cold-[[2-[[[3-[[. Imino-[(phenylamidino) amino] methyl] amino] phenyl] carbonyl] amino] ethyl Preparation of fluorenyl] amino] pyridine-3-dicarboxylic acid ethyl ester, bis (trifluoro acid) salt

Η Ο

.2TFA ---------. 1¾-- (谙 Please read the notes on the reverse side and write this page first) Print step A 1_ (3-carboxyphenyl) 2-thiourea (5 g, 0.025 mole) (TransWorld Chemicals) in THF (75 ml) and CH3I (3.62 g, 0.025 mole) was stirred at reflux for 2 hours. The solvent was removed under vacuum. The residue was slurried in ether (3X), (each time the ether was decanted), and dried under hydrazine to obtain N- (3-carboxyphenyl) -S-methyliso Thiourea hydroiodate (7.8 g) as a yellow solid. Step B To the product of Step 骒 A (1.5 g, 0.0044 moles) and diisopropylethylamine (0.57 g, 0.0044 moles) were added benzene (5 ml) and dioxin (5 ml). Methylamine (0.48 g, 0.004 (Mole). The reaction mixture is at reflux -121-this paper size applies to China National Standard (CNS) A4 (2ωχ297 mm)

W • > i ‘丨 ,,,. /1^.0 〇 A7 B7,119 V. Description of the invention Heating for 6 hours. The reaction mixture was cooled to room temperature and a splatter formed. Dioxin (6 ml) was added and the slurry was stirred at room temperature overnight. Precipitate. After being washed, it was washed with dioxolane / Η, dried, and slurried in hO, and acidified with 11 (1: 1). The solvent was removed under agitation, and the residue was slurried in ether (3χ Each time the acid is decanted). After drying, the '1-(3-methylphenyl) -2-benzylguanidine hydrochloride (800 mg) is separated as a white solid. MS and N MR are in the desired structure — □ Step C '" The title compound was prepared according to Example 1, Step F, but the equivalent of the product of B above was used to replace the product of Example 1 Step E in Step F. MS and NMR were consistent with the desired structure. ^. Example 24 · (±) / 5-[[2-[[[3-[[Iminino-[(phenylmethyl) amino] methyl] amino] phenyl] carbon] amino] ethyl Preparation] Amine] '^ Bizhen-3-propionic acid, preparation of bis (trifluoroacrylic acid) salt (Please read the precautions on the back first, then rt ·· this I) Packing--Order _ Ministry of Economic Affairs Central Printed by Shell Bureau Consumer Cooperative

Λοη

.2TFA

Nh The product of Step 23. (330 milliseconds, 0.00045 moles) in water (20 -122- This paper size applies the Chinese National Standard (CNS) A4 specification (210XW7)) '4 ρ θ Q Q, c V. Description of the invention (120 A7. B7 ml) LiOH (80 mg) was added. The reaction mixture was stirred at room temperature for 1 hour. PΗ was reduced to 3 by TFA, and the product was separated by RPHPLC to obtain (±) Lu · [[ 2-[[[3-[[Iminino-[(phenylmethyl) amino] methyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3-propionic acid 'Bis (trifluoroacetate) salt (330 mg) as a white solid. IMS and NMR are consistent with the desired structure. Example 2,5. (±) /?-[[2-[[[3-[(Imine Of benzyl) amino] phenyl] carbonyl] amino] ethynyl] amino] pyridine-3-propionic acid ethyl ester, preparation of bis (trifluoroacetic acid) salt

Η Ν, ό

, C02Et. 2TFA (I read the notes on the reverse side of this page and write down this page). Order 1 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Step A. In ethyl benzimidate hydrochloride (3 g, 0.016 mol) (Fluka) and (2.1 g, 0.016 mol) diisopropylethyl.amine to h20 (i3 ml) and dioxolane (15 ml) with 3-aminobenzylcarboxylic acid (2 22 G, 0.016 mol) (Aldrich). The reaction mixture was stirred at room temperature for 4 days. The resulting precipitate was filtered, washed with dioxolane / f ^ O, and the dry precipitate was slurried in ^ 〇 and acidified with concentrated HC1. The solvent was removed under vacuum and the residue was slurried in ether. The ether was decanted, and the residue was dried under reduced pressure to obtain ^^ carboxy phenyl) benzoate hydrochloride (70. mg) as a white solid. The structure is consistent with whatever you want. Private paper scale system 10 ® House Standard (CNS) A4 · (123-12145895ft A7 B7 V. Description of the invention (Step 骒 B The title compound was prepared according to Example 1 and Step F, but the same amount of the product of A above was used to replace Example 1 Step 骒) The product of E is in step F. MS and NMR are consistent with the desired structure. Example 26 (±) 々-[[2-, [[[3-[(Imininophenylmethyl) amino] benzene Of carbonyl] amino] amino] ethenyl] amino] pyridine-3-propionic acid, preparation of bis (trifluoroacetic acid) salt

0H • 2TFA Read First Read Read Back Note

I ί. Binding Printed by the Consumers Cooperative of the Central Government Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs. Example 25. The product of step B (240 mg, 0.0034 mol) was added to water (20 ml) with LiOH (50 mg) < reaction The mixture was stirred at room temperature for 35 minutes. The pH was reduced to 3 with TFA, and the product was separated by RPHPLC to obtain (±) Lu-[[2 · [[[[[[[[Iminophenylphenylmethyl] amino] phenyl] carbonyl] amino] ethyl] acetamidine Propyl] amine, propyl] pyridine-3-propionic acid, bis (trifluoroacetic acid) salt (120 mg), as a white solid. MS and NMR are consistent with the desired structure. , Example 2 7 (±) Lu-[[2-[[[[[[Aminoiminomethyl) amine}] phenyl] carbonyl] amino] ethyl]]]], Preparation of 5-Gas Dibenzoic Acid and Trifluoroacetate-124- M's Zhang scale Applicable to Chinese National Standard (CNS) A4 Specification (210X297 mm) 122 V. Description of the Invention () A7 B7 〇

The above compounds were prepared according to the square tone of Example 2; however, the example was replaced with an equivalent amount of 3 5_dichlorobenzaldehyde (Aldddi)! 3-Pyridinecarboxaldehyde in step eight. , (±) 々-[[2-[[[3-[(3'4'5,6-tetrahydro: 21 ^ aza_7_yl) amino] benzyl m-based] amino] ethyl Amidino.] Amine] _4_ Preparation of pentanoic acid, trifluoroacetate 'Please note on the back of the cabinet I un ^^^ 1 1 Item # -4Write this page) Order-Λ

The above compound was printed according to the method of Example 12 in the male workers' consumer cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, but with the same amount of 3_s_amino-4-pentanoic acid ethyl ester hydrochloride (j Med chem. 1995, 38, 3378-3394) Substitute dl-3 · .amino-3- (3.-pyridyl) propionate dihydrochloride 'in Step C of Example 1 and reuse it in Step D of Example 1, as in Example 1 Step 1 b. 'Example 3 4 -125- This paper size applies the Chinese National Standard (CNS) A4 specification (2.0 × 297): 458 956 Α7 Β7 123 V. Description of the invention () S-[[2-[[[3 -[[Imine (1-pyrrolidinyl) methyl] amino] phenyl] carbonylJamino] ethynyl] amino] -4-pentynyl acid, trifluoroacetate

The above compounds were prepared according to the method of Example 24, but the same amount of pyrrolidine was used to replace the benzylamine 'in step 23 of Example 23 and the equivalent of 3_s_amino-4_valeric acid ethyl ester hydrochloride to replace the step of Example 1. The DL-3-amino-3- (3-pyridyl) propanoic acid ethyl ester dihydrochloride in C was used in step D of Example 1 as described in step C of Example 23. Real Θ 3 5,-Point 5-[[2-[[[[[[Aminoiminomethyl) amino] 2,5,6-trifluorophenyl] carbonyl] amino] ethylamidine ] Amino] 4-pentynyl acid, the preparation of trifluoroacetic acid I -------- Ί .. \ 装-{Please read the note on the back ^^ Item exhibition ¥. ^ ' (This page)-, printed by ΤΓ The Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

126 'This paper scale is applicable to Chinese National Standard (CNS) A4 specification (21 × 297 mm) A7 B7 458 956s 124 ~ V. Description of the invention () The above compounds were prepared according to the method of Example 2, but the same amount of 3_s_amine Ethyl-4-pentynylacetate hydrochloride was replaced in Example i, step c. 〇 3 -amino_% (·? -Pyridyl) ethyl propionate-hydrochloride, and an equivalent amount of 3 • amino _2,5,6-trifluorobenzoic acid replaces the 3-aminobenzoic acid in step 1 of Example 1. '' Example 3 6 '(±) 々-[[2-[[[〇-[(aminoiminoamido) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -3,5 -Bis (trifluorofluorenyl). Preparation of phenylpropionic acid and trifluoroacetate 盐 ^-(Please read the note on the back first # '-4Write this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (±) / 5-[[2-[[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] Of amine] amino] -3,5-bis ('trifluorofluorenyl) phenylpropionate-the above compound was prepared according to the method of Example 1, but with an equivalent amount of 3,5-bis-trifluoromethyl Substituted phenylbenzene (AldΓicll) to replace 3-^^ in step A than bite. N M R and mass spectrum are consistent with the desired structure. Step B To 260 mg (0.00039 mol) of the product from Step A was added LiOH (41 g, 0.00098 mol) to water (25 ml) and CH3CN (10 ml). The reaction mixture was stirred at room temperature for 1 hour. The pH is reduced to 3 with TFA and the product is reversed -127-This paper size is applicable to China National Standard (CNS) A4 specifications (210X297 mm) A7 B7

95F 125 V. Description of the invention (preparation by HPLC separation to obtain (after lyophilization) 210 mg of the title compound as a white solid. NMR and mass spectrometry are consistent with the desired structure. Example 3 7. (±) / S-[[2- [[[3-[(Amineiminoamido) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] biphenyl] -4 -propionic acid, preparation of trifluoroacetate H2N . Η, C〆II ΜΗ Ο II C,

Η TFA

c-OH II Printed by the Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs The above compound was prepared according to the method of Example 2, but replaced with the equivalent of 4 · biphenylcarboxaldehyde 3.Pyridinecarboxaldehyde in step A of Example 1. -Example 3 8 _ (±) y?-[[2-[[[3-[(Amineimine-methylmethyl) amino group 5_ (trifluoromethyl) phenyl] carbonyl] amino] ethyl Fluorenyl] amino] -3,5-bis (trifluorofluorenyl) phenylpropionate, trifluoroacetate preparation 128- Sheet paper size applicable to Chinese National Standard (CNS} A4 Specification (21〇 > < 297 public works > A7 B7 doBgee —126 ~~ 5. Description of the invention ()

The above compound printed by Zhengong Consumer Cooperative of Central Bureau of Quasi-Ministry of Economics was prepared according to the method of Example I, but replaced with the equivalent of 3,5 • bistrifluoromethylbenzene 'magnetic (Aldrich) in step A. While in the same amount of 3-amino-5 -trifluoromethylbenzyl. Formic acid [which consists of 3 nitro 5-trifluorofluorenylbenzoic acid (Lancaster) in ethanol. At 10% pd / C at 50 psi It was synthesized by reduction for 4 hours] instead of 3-aminobenzoic acid in step E, and the reaction mixture generated in step e was stirred at reflux for 2.5 hours. N M R and mass spectrum are consistent with the desired structure. Example 3 9 (±); 5-[[2-[[[[[[Aminoiminomethyl) amino] -5- (trifluorofluorenyl) phenyl] carbonyl] amino] ethane] [Amino] amino] -3,5-bis (trifluoromethyl) phenylpropionic acid ,. Preparation of trifluoroacetate-'Π

In 600 mg (0,00082 moles) of the product of Example 3 in 12 ml of water and 1 2 • 129 · This paper is again applicable to the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm)

127 Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (140 milligrams (0.0033 moles) of LiOH was added to ml of CH3CN. The reaction mixture was stirred at room temperature for 1.5 hours. P Η, TFA decreased to 2.5, the product Separation by reverse phase prep HPLC to obtain (after lyophilization) 52 mg (±) points [ρ-αP · [(aminoiminomethyl) amino] -5_ (trifluoromethyl) phenyl] carbonyl ] Amine] Ethylamino] Amino] -3,5 · bis (trifluoromethyl) benzenedicarboxylic acid, trifluoroacetate 'is a white solid.' NMR and mass spectrum are consistent with the desired structure., Example 4 0 3S-[[2-[[[3-[(Aminocarbonylamino) phenyl] carbonyl] amino] ethylfluorenyl] amino] -4. Preparation of acetylenic acid H2N 'N Η

Step A 3S-amino-4-pentanoic acid ethyl ester hydrochloride was prepared by the method of j. Med. Chem. 1995, U, 3378-94. -Step B-2 g of m-aminokismic acid was treated with urea (2 g) in a 5% HC1 aqueous solution (25 ml) and the solution was refluxed for 4 hours. 1 · N-Aminomethylaminoamino, uric acid was purified by HPLC (RP-CH3CN / H2O) "ice; dried, and 1.2 g of a white solid was obtained. ^ 1 $ was consistent with the desired product.

Step C 130 This paper size applies Chinese National Standard (CNS) A4 specifications (2 丨 〇 > < 297 public directors) (Please read the precautions on the back before i / k this page)

-1Zo 5 ′, description of the invention () A suspension of m-urea uric acid (1.2 g) in DMF (5 ml) and pyridine (5 ml) was treated with DSC (1.5 g). A catalytic amount of DMAP was added and the reaction mixture was stirred for 3 hours. A solution of 3S-aminovaleric acid hydrochloride (0.8 g) and K2C03 (0.7 g) in a saturated aqueous solution of NaHC03 (5 ml) was added to the reaction mixture. The resulting mixed tablet was stirred at room temperature overnight. The reaction mixture was diluted to 45 ml with 1 _ 1 CH3CN_H20 and acidified with trifluoroacetic acid (5 ml). The ester was purified by HPLC (RP-CH3.CN/H20) and a white solid (125 mg) was recovered after lyophilization. This material was then treated with 1: 1 CH3CN: H2O (20 ml) and tested with LiOH (pH > 12). After the reaction was complete, the product was analyzed by HPLC (RP-CH3CN / H2OW4K, 60 mg). MS, 1 H-NMR and CΗN analysis were consistent with the desired product.-Example 4 1 (± ) /?-[[2-[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] fluoren-1-propionic acid, trifluoro Preparation of Acetate-I: (Please read the notes on the back # '' write this page first) Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

Step A A mixture of freshly distilled 1-teacarboxaldehyde (8.6 g), ammonium acetate (10. 6 g) and propionic acid (5.7 g) in isopropanol (50 ml) was refluxed for 4 hours. Reaction mix, co2h -k_ -131-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 Gongchu) A7 B7 458956 V. Description of the invention () (Please read the precautions on the back before ^: nest (This page)

The mixture was washed while hot, washed with hot isopropanol (2x50 ml), water (125 ml), and isopropanol (100 ml), and dried at 40 sc in the air. 4.6 gm of S-aminopyridine-1-propionic acid was isolated as a white solid. MS and 1 H-NMR were consistent with the desired product. 9 Step B. A suspension of the product of step A (4'6 g) in methanol (100 ml) was treated with 4N HC1 / dioxolane (10 ml). The reaction mixture was stirred overnight and excess solvent was removed under reduced pressure. The oil was dissolved in 1: 1 CH3 C N: Η 20 and purified by HPLC (RP-CH3CN / H20). 々S Aminopyrene-1 -propionate (4.6 g) was obtained as a white solid. M S and 1 H-NMR were consistent with the desired product.

Step C. Suspension of the Cooperative Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-Urea-Hyaluronic Acid HC1 (1.4 g) in DMF (5 ml) and pyridine (5 ml) was treated with DSC (3 g) and catalytic amount DMAP . The reaction mixture was stirred at room temperature overnight. The resulting solution was treated with a solution of the product of Step B (1.7 g) and NMM (0.6 ml) in DMF (2.5 ml) and late bite (2.5 ml). The mixture was stirred at room temperature overnight. The reaction mixture was then treated with TFA and diluted to 50 ml with 1: 1 CH3CN: H20. The solution was purified by HPLC (RP-CH3CN / H20). After freeze-drying, (±) 々S-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] carbonyl ] Amino] ethylammonium.amino] amino] fluoren-1-propionic acid methyl ester (1.3 g) as a white solid. M S and 1 H-NMR are consistent with the desired product》

Step D The product of Step C (0.5 g) in 1: 1 CH3CN: H20 (15 ml) -132- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) ^ 58958 5. Description of the invention (A7 The solution of B7 130 was treated with LiOH to pH> 12. The reaction was detected by HPLC (RP-CH3 CN / H20). When the hydrolysis was completed, the desired substance was purified by HPLC (RP-CH3CN / H20). After freeze-drying, A white solid (0.3 g) was recovered. MS, IH-NMR and CHN were consistent with the desired product 9 'Example 42 (土) 3-[[[3-[(aminoiminomethyl) amino] benzyl] Preparation of carbonyl] amino] -2-oxypyrrolidine-1-propionic acid, trifluoroacetate

.TFA, co2h (Please read the notes on the back ^., ¾¼ • This page)

;; ιιίν, · F, s. Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

Step A A solution of N- (third butoxycarbonyl) -L-methionine (6.2 g) in DMF (2 ^ mmol " 'l) and Echinococcus aureus (25 ml) was treated with DSC (9.6 g ) And catalytic amount D MAP treatment. After 4 hours, an aqueous solution of ethyl alanine HC1 (3.8 g) and K 2 C 0 3 (3.5 g) in a saturated aqueous NaHC03 solution was added. The reaction mixture was stirred at room temperature overnight. The excess solvent was removed under reduced pressure and purified by HPLC (RP-CH3CN / H20). Obtain N- [2-[[(l, l-dimethylethoxy) carbonyl] amino] · 4- (methylthio) -1-oxybutyl] alanine, ethyl ester (7.0 g) , Was colorless oil. This oil was confirmed to be the desired product by MS. It was used without further purification. Step 6.5 g of the oil in step A was dissolved in DMF (25 ml) 'with CH3I (5.0 millimeters. _ -133- This paper size applies to Chinese national standards (CNS) A4 specifications (210x297)

Iga 95β V. Invention description (A7 B7 131 liters) processing. After about 1 hour, NaH (0.50 g) was added followed by NaH (0.50 g). The reaction mixture was treated with H20 (25 mL) and EtOAc (200 mL). The organic layer was washed with H20 (3x25 ml), saturated aqueous NaCl (1x25 ml), and dried over Na2S04. Excess solvent is removed-removed under reduced pressure

N-, C02Et Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, and obtained 4 grams of tan semi-solid. MS was consistent with the desired structure, and was used without further purification. Step C. A solution of the product of Step B (4 g) in ethanol (50 'ml) was treated with 4N.HCI / dioxolane (20 ml). Excess solvent was removed under reduced pressure. The crude solid was purified by HPLC (RP-CH2CN / H20). A 20% HC1 aqueous solution (10 ml) was added, and after freeze-drying, 1 g of 3-amino-2-oxypyrrolidine-1-propionic acid ethyl ester was obtained as a white solid. MS is consistent with the desired structure. In step D *, a solution of guanidyl hippuric acid HC1 (0.7 g) in D M F (3 ml) and pyridine (3 ml) was treated with D S C (0.8 g) and catalytic 4 D M AP. After 3 hours, the product of step C (0.7 g) was added to a solution of 0 (3 ml) and an equimolar amount of K2C03. The reaction mixture was stirred at room temperature overnight. The desired ester was separated by HPLC (RP-CH3CN / H20). A white solid (100 mg) was treated with H2O (10 ml) and made basic (pH> 12) with UOH. After 2 hours ν *, the desired product is separated by hplc (rp-ch3cn / h2o), freeze-dried -134 This paper size is in accordance with Chinese Standard (CNS) A4 (210X297 mm) (Please read the back Note again (for this page) Order '• .S.

A7. B7 132 " — -------- V. Description of the invention () ° 75 mg (±) 3 _ [[[3 _ [(aminoiminomethyl) amino] phenyl] phenyl] [Amino] amino] -2-oxy tr Bihagi-i-propionic acid, trifluoroacetate, as a white solid. MS, h-NMR and CHN analysis were consistent with the desired product. Example 4 3 3 R-[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] · 4 · pentynyl acid, hydrochloride Preparation, 〇Π / C, ρ 0Η

Η Righteous CH

Step A 3- (N- (Third-butoxycarbonyl) amino) pent-4-ynoic acid ethyl ester (3. g) [Dig Med. Chem., 1995, 3 8, 3 378-94] in CH2C12 (60 mL) was treated with TFA (30 mL) at 0 ° C. The reaction mixture was stirred for 3 hours. The excess solvent was removed under reduced pressure to obtain a yellow oil (3.3 g). This oil was identified by MS as the desired product. -

Step B-1 solution of guanyl hippurate HC1 (3.3 g) in DMF (12 ml.) And pyridine (12 ml) treated with DSC (6.1 g) and the amount of DMAP was treated after 3 hours * A solution of the crude product from step A (3.3 g) in a saturated aqueous solution of NaHC03 (12 ml) was added. The reaction mixture was stirred at room temperature overnight, and excess solvent was removed under reduced pressure. The resulting solid was treated with TFA and 1: 1 CH3CN: H2O. The product was separated by HPL.C (RP-CH3CN / H20), 3R-[[2-,-* * 135- #-This paper wave standard is applicable to China National Standard (CNS) A4 specification (210X 297 mm) --- ----- 「. 装 — (Please read the note on the back # .- € Write this page first), -ιτ Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Central Standards Bureau of the Ministry of Economic Affairs Printed by A7 " B7--〒33 —-Fifteen, description of the invention () [[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] amino] pentyl Ethyl alkynate trifluoroacetate (3 g) as a white solid. MS and 1 H-NMR are consistent with the desired product

I

The product of Step C (3 g) was dissolved in 1: 1 CH3CN: H2O (50 ml) and treated with LiOH (pH> 12). After 4 hours, the reaction mixture was acidified with TFA and the TFA salt of the desired product was separated by HPLC (RP-CH3CN / H20). The lyophilized solid (2.5 g) was slurried with 1: 3 CH3CN: H2O (100 ml) and ion exchange resin AG 2-X8 gas form (0ioRad) (50 g). The mixture was filtered and filtered with 20% HC1 (5 ml )deal with. The clear solution was freeze-dried and the ion exchange method was repeated. The desired product (2.2 g) was obtained. MS,]! ! NMR and CHNC1 are consistent with the desired product. Example 4 4 '3S-[[2-[[[[[((Phenylfluorenyl) hexyl] carbonyl] amino] phenyl] carbonyl] carbonyl] amino] ethylfluorenyl] amino] -4- Preparation of valynic acid

Step A. m-Amino Huronic acid HCI (20 g) in CH3CN (100 ml) was treated with phenyl isocyanate (16 ml). The reaction mixture was treated with a 5% HC1 aqueous solution (400 ml), filtered, and washed with water (50 ml) to obtain 21 g.-(-136-) This paper is in accordance with China National Standard (CNS) A4 (210X297) (Li) I -------- 1¾ .-- (Please read the precautions on the back before writing this page) Order

^ 458956 134 V. Description of the invention () Benzyl occluded) Huronic acid ° Ms and 1 H-NMR are consistent with the desired product "No further purification. ,

Step 骒 B 3S-[[2-[[[[[(phenylmethyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ethylammonium] amino] -4-pent Ethyl alkynate was prepared using the method of Example 40, but replacing m-urea uric acid with an equimolar amount of m- (phenylamidinyl urea) hippurate. The desired ester was purified by HPLC (RP-CH3CN / H.20) to obtain 1.2 g of a white solid. MS and 1 H-NMR were consistent with the desired ester.

Step C 3S-[[2-[[[[[((Phenylmethyl) amino] carbonyl] amino] phenyl] carbonyl] 'amino] ethylfluorenyl] amino] -4-pent The solution of ethyl alkynate (1.0 g) in 1: 1 CH3CN: Η 2 0 (20 ml) was treated with K q Η (p Η > 1 2). After 4 hours, the reaction mixture was acidified with TF A / purified twice by HPLC (RP-CH3CN / H 2 0) to obtain a white solid (300 mg). MS, 1 H-NMR and C Η N were consistent with the desired product. Example 4 5 3S-[[2-[[[[[Amine-iminomethyl) amino] phenyl] carbonyl-] amino] ethenyl] amino] -4-pentynyl acid, Preparation of Hydrochloride-~ —Ί .1-I I--I f ―-I Λ # / _ 1 (Please read the notes on the back-¾.¾. Write this page) Order _ Central Bureau of Standards, Ministry of Economic Affairs Printed by Offload Consumer Cooperatives

Example 5 The product of 8 (6 g) was dissolved in 1: 1 CH3 CN: Η 2 〇 (75 ml) ^ 137- This paper size is applicable to the Chinese National Standard (CMS.) A4 specification (210X297 mm) A7! &Quot; 4 58 9 56 _ 135 5. In the description of the invention (), it is treated with KOH. The pH was maintained above 12 by the addition of KOH. After 4 hours, the reaction mixture was acidified with TFA 'and purified by HPLC (RP-CH3CN / H2O). After suitable partial lyophilization, TF A salt (4.2 g) was obtained. The solid was slurried in 1: 1 CH3CN: H2O (100 ml) and treated with ion exchange resin AG 2 x 8 chlorine (BioRad) (50 g). The mixture was quenched and treated with 20% HCI (5 mL). After the ice is dried, the ion exchange is repeated. HC1 salt (3.5 g) of the desired product was obtained. MS, iH-NMR and CHNC1 were consistent with the desired product. Example 4 6 Preparation of Lu-[[2-[[[3-[(Amine; carbonylamino) phenyl] carbonyl] amino] ethyl}] amino] pyridine-3 · propionic acid, hydrochloride ~ '--------- / install — (please read the note on the back 4-'c to write this page) k.

-Order " Indica gland (4 g) and / 5 · [[2-[[[[3-[(Aminophenyl) carbonyl] amino]]] [Amino] amino] eridine_ 3 · Ethyl propionate trifluoroacetate (4 g) was dissolved in a 20% HC1 solution (50 ml) and refluxed for 6 hours. The reaction mixture was made basic with KOH (ρ Η > 1 2). After 4 hours' the reaction mixture was acidified with τ f A and purified by HPLC (HP-CF ^ CN / H20). The white solid was dissolved in 1 · i CH3CN: H2O (100 ml), and the ion exchange as described in step 43 of Example 43 was performed. After lyophilization, the desired product (32 g) was obtained. M s, i H_ -138- Full paper measuring rule and General Ningguo National Standard (CNS) A4 specification (21 ^ 797 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 956 B7 V. Description of the invention () NMR and CHNC1 are consistent with the desired product. Example 4 7 (±) / 3-[[2-[[[[[[(phenylmethyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amine Of phenyl] pyridine-3-propionic acid, hydrochloride

The product of Example 48 (5 g) was dissolved in 1: 1 CH3CN.:H20 (75 ml) and treated with KOH. The pH was maintained above 12 by the addition of KOH. After 4 hours, the reaction mixture was acidified with TFA and purified by HPLC (RP-CH3CN / H20). After lyophilization, TFA salt (4.5 g) was obtained. The solid was slurried in 1: 1 CH3CN: H2O (100 ml) and ion exchange resin AG2-X8 gas form (BioRadM 50 g). The mixture was filtered and treated with 20% HC1 (5 ml-l). After freeze drying, the ion exchange was repeated. The desired product (4.1 g) was obtained as a white solid. MS, h-NMR and CHNC1 were consistent with the desired product. Example 4 8 (±) fluorene-[[2-[[[3-[[[(phenylmethyl > amino] carbonyl] amino] phenyl] coagulant] amino] ethylfluorenyl] amino ] Pyridine-3-propanoic acid ethyl ester, preparation of hydrochloride-139- The standard of this paper is applicable to China National Standard (CNS) A4 (210 乂 297mm) (Please read the notes on the back before writing in C Page) Γ installed., 11 458 956 b7 '--- Τ37 ~-5. Description of the invention ()

^ 〇〇〇２〇2Η5 Η I ″ Step A ′ A solution of m-nitro-maleic acid (5.6 g) in DMF (25 ml) was treated with DSC (9.6 g) and a catalytic amount of DMAP. After 5 hours, ethyl 3-amino-3- (3-pyridyl) propionate 2HC1 (8 g) and K2C03 (2 g) were saturated. '-

A solution of NaHC03 in water (25 ml) was added-the reaction mixture was stirred at room temperature overnight. Water (25 ml) was added, and the mixture was overheated. The resulting solid was washed with water (25 ml), slurried with C.H 3 C N. (25 ml), and filtered. Obtained / 5-[ί2-[[(3-nitrobenzyl) carbonyl] .amino] ethylammonio] amino] -pyridine-3 -propionic acid ethyl ester (6.5 g) as a white solid. The MS was consistent with the desired product. Step B. The suspension of the product of Step A (6.5 g) and 5% Pd / C (0-6 g) in water (500 ml) and ethanol (50 ml) received 50 psi H2 calendar. 3 hours. Mixture Printed by Zhengong Xiaobei Cooperative of the Central Bureau of Standards of the Ministry of Economics After filtration through celite, excess solvent is removed under reduced pressure. The resulting oil β C H 2 C 12 was treated and the solvent was removed under reduced pressure. Recovered /?-[[2-[[(3-Aminophenyl) alkanoyl] amino] ethylammonyl] amine'yl] · ϊγ than r3-propionate ethyl acetate (.5.8 g), yellow Brown bubbles. MS and 1 H-NMR were consistent with the desired product.

Step C A solution of the product of Step B (1.9 g) in CH3CN (5 ml) was treated with isocyanide.

I -140- ------ This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 male thin) BU 458 956 Λ7 Α7 B7 V. Description of the invention (138) Benzyl acid (0.8 ml) treatment. After 1 hour, benzyl isocyanate (· 0.05, ml) was added to complete the reaction. After 0.25 hours, the reaction mixture was treated with water (50 ml). The resulting beneficial oil was dissolved in CH3CN to TFA was acidified. The solution was purified by HPLC (RP-CH3CN / H20), freeze-dried, and the white solid was purified by HPLC (RP-qH3CN / H20) and treated with 20% HC1 (10 mL). The desired product (1.3 g) was obtained , As a white solid. MS, β-NMIL and CHNC1 are consistent with the desired product. Example 5 1 (±) Lu-[[2-[[[3-[(Amine.iminoimidomethyl) amino] benzene) Preparation of carbonyl] amino] ethyl] ethyl] amino] furan-3-propionic acid ethyl ester and trifluoroacetate (please read the precautions on the back first and then rlir this page)

0 IIc,

Ο II

.TFA-subscription

L Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A-3-furancarboxaldehyde (8.6 ml), monoethyl malonate (15.8 g) and ammonium acetate-(9.6 g) in isopropanol (200 ml) The suspension in nitrogen is heated to reflux under nitrogen— ·. After 5 hours, excess solvent was removed under reduced pressure, the semi-solid was treated with water (250 ml) and acidified to pH 2 using 12N HC1. The aqueous layer was washed with CH2C12 (2X 100 ml). The aqueous layer was neutralized with k2C03 to pH > 9. The product was extracted with CH2C12 (2 × 100 ml). The organic layer was dried over Na2S04, and the excess solvent was removed under reduced pressure to obtain -aminofuran-3 -ethyl propionate (5 g) -141-This paper uses the Chinese National Standard (CNS) A4 specification (2Ι0 × 29? (Mm) tt 6 5 9 8 54 Β ----- 139 V. Description of the invention (), it is golden oil. M S and 1 H-NMR were consistent with the desired product.

Step B-A solution of guanidyl hippuric acid HC1 (1.4 g) in DMF (5 ml) 'and pyridine (5 ml) was treated with DSC (1.9 g) and a catalytic amount of DMAP. After 5 hours, in step A To a solution of the product (1.2 g) in CH3CN (1 ml) was added a saturated aqueous solution of NaHC03 (1 ml). The reaction mixture was stirred at room temperature overnight 'and purified by HPLC (RP-CH3 C.N / H 2 0). 'Ice; MS, iH-NMR and CHN analysis of the dried solid (1.2 g) were consistent with the desired product. Example 5.2 (±) fluorene-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethynyl] amine] anan-3-propane Preparation of acid and trigas acetate ---------- ^ II (Please read the precautions on the back before < write this page >

*? τ The product of Example 51 (0.6 g) printed by the Ministry of Economic Affairs of the China National Standards and Technology Administration Bureau, was dissolved in 1: .1 CH3CN: H20 (15 ml), and treated with NaOH (p Η > 1 2 ). After 4 hours, the reaction mixture was acidified with TFA and purified by HPLC (RP-CH30N / H20). MS 'h-NMR and CHN analysis of the freeze-dried solid (0'3 g) was consistent with the desired product. Example 5 3 3-[[2-[[[3-[(Amineiminomethyl) amino) ] Benyl] carbonyl] amine] B-142- This paper size applies to Chinese national standards (CMS > A4 specification (210X297) 4 56 9 56 A7 B7-14〇- 5. Description of the invention () ] Amino] glutaric acid, the preparation of triacetate 'NH = C, N H2

CHO one

A Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A 3-Dimethyl ketoglutarate (13 ml) in methanol (50 ml) treated with ammonium formate (5 g) and NaCNBH3 (2 g) . 10 ml of water was added and excess solvent was removed under reduced pressure. The semi-solid was dissolved in 5% HC1 aqueous solution (250 ml) and washed with CH2C12 (2 × 50 0 ml). The aqueous layer # k2C03 was made alkaline (pH> 9), and the product was extracted with CH2C12 (2 × 75 ml). The organic layers were combined and dried over Na 2 S 0 4. The excess solvent was removed to obtain 2.5 g (±) of 3-dimethylaminodicarboxylic acid dimethyl ester. It was dissolved in methanol (50 ml) and treated with 4N HC1 / dioxolane (10 ml). The excess solvent was removed under reduced pressure to obtain 2'.7 g (soil) 3-aminoglutarate dimethyl hydrochloride. MS and 1 H-NMR were consistent with the desired product. Step B-The solution of m-guanidine horse urine posture 14 (1; 1 (1.5 g) in 01 ^ 1? (4.5 ml) and 1: 1 (4.5 ml) with DSC (1.8 g) and catalytic amount DMAP treatment. After 2 hours, a solution of dimethyl 3-aminoglutarate hydrochloride (1.1 g) and NMM (3 50 μl) in water (3 ml) was added to the reaction mixture. The reaction mixture was After stirring overnight at room temperature, the product was separated by HPLC. 1.5 g of 3-[[2-'[[[[[[3-[(Amineimidoamido) amino] a] benzyl] carbonyl] amino] ethylamido] Amine-143- (Please read the note on the back 4 bee " this page) Order p 4 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) £-♦ 9 5 6 Α7 _ _ Β7 ~ Τ ~~ Τ7Ϊ: ----- 5. Description of the invention () yl] glutaric acid, dimethyl, as a white solid. MS and 1 H-NMR are consistent with the desired τ product.

The product of Step C (750 mg) was dissolved in 1: 1 CH3C &: H2O (40 ml) and treated with KOH (pH> 12). After 4 hours, the reaction mixture was acidified with TFA and purified by HPLC (RP-CH3CN / H20). MS,] H-NMR and CHN analysis of the freeze-dried solid (400 mg) was consistent with the desired product. Example 5 4 · (±) 3-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethoxy] amino] glutaric acid hydrogen Preparation of methyl ester and trifluoroacetate (please read the notes on the back first # ..: €, ir page) Pack. N H2: = c

-no

onnc > HN

A Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Step A. A solution of m-guanyl hippuric acid HCU 1.5 g) in DMF (4.5 ml) and pyridine (4.5 ml) was treated with DSC (1.8 g) and a catalytic amount of DM AP. After 2 hours, a solution of dimethyl 3-aminoglutarate hydrochloride (1.1. G) and NMM (350 µl) in water (3 ml) was added to the reaction mixture. The reaction mixture should be stirred at room temperature overnight, and the product was separated by HPLC to obtain 3-[[2-[[[[ ] Amine ·] pentyl-144- This paper · size applies to Chinese National Standards (CNS) VIII (210X297 male ▲). A7 ____ 'B7 ~~ T35 ----- --- V. Description of the invention () One methyl ester of one acid (1.5 g) as a white solid. MS and 1 H-NMR were consistent with the desired product. , &Quot;. *

70.5 mg of step B The product of step A was dissolved in Na2po4 buffer (50 ml, 50 mM, pH 8.5) and treated with porcine enzyme (200 microliters). For pH, LiOH p Zhou Lang was used. After 48 hours, the solution was acidified with τ f A and purified by HPLC (RP. CH3CN / H20). The MS, iH-NMR and CHN analysis of the freeze-dried solid (175 mg) was consistent with the lean product. ---------- ^! (Please read the precautions on the back before this page) Example 5 5 (±) /?-[[2-[[[3-[(Amineimine Group) Preparation of amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] furan-2-propionic acid, trifluoroacetate

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, Step A-2-furancarboxaldehyde (4.8ml), monoethylmalonate (6.6g) and ammonium acetate (9,6g) in isopropanol ( 50 ml) of the suspension at reflux 6 <], h. The excess solvent was removed under reduced pressure, and the resulting oil was treated with ethyl acetate (100 mL) and 50/0 HCI aqueous solution (400 mL). The aqueous layer was then washed with ethyl acetate (100 mL). The aqueous layer was made alkaline (pH 9) with K2C03. The product was extracted with CH2C12 (2 × 100 ml). The organic layers were combined, dried over Na2S04, and the excess solvent was removed. Lu-aminofuran-2-ethyl propionate (2.5 g) was recovered in a dark color. -145- This paper is again suitable for national standards (CNS) ) A4 size (210X297mm) AAr > 5. Description of the invention (-) Α7 Β7 The employees of the Central Government Bureau of the Ministry of Economic Affairs consume oil printed by cooperatives. M S and 1 H-NMR were consistent with the desired product. The dark oil was treated as described in Example 5 3 Step A 'to obtain 2.7 g of cold-aminofuran-2. Ethyl propionate hydrochloride. Step B-A solution of guanidyl hippuric acid HC1 (272 mg) in DMF (1 ml) and pyridine (1 liter) was treated with DSC (450 mg) and a catalytic amount of DMAP. After 2 hours, the product of step A (221 mg) and NMM (111 µl) were added in a solution of water (1 ml) and CH3CN (1 ml). The reaction mixture was stirred at room temperature overnight. (±) /?-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] furan_2 · propionic acid ethyl The ester was purified by 1 ^ 1 ^ (1 ^ -CH3 CN / Η20), frozen and dried to obtain a white solid (200 mg). AMS was consistent with the desired product. Step C _ The product of Step B (200. mg). It was dissolved in '_1: 1 CH3 CN: H2O (20 ml) and treated with KOH (PH > 12). After 4 hours, the reaction mixture was acidified with TFA and purified by HPLC (RP-CH3CN / H20). MS, iH-NMR and CHN analysis of the freeze-dried solid (175 mg) was consistent with the desired product. -Example 5 6 (±) > (?-[[2-[[[[[[[Aminoalkylenemethyl) amino] phenyl] carbonyl] amino] ethoxy] amine] tea Preparation of -2-propionic acid and diacetate NH II H2N〆, N Η {Please read the precautions on the back before buying) -Pack. M -Order ί? · Cr II 〇

-146 This paper size is applicable to China National Broadcasting Standard (CNS) A4 (210 X 邛 7mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 4589 & 6 a? B7

—------ | · · _Μ ----- " 1 M 144 V. Description of the invention () ψ ^ Α 2-Raldehyde (7.8 ml) and ammonium acetate (9.6 g) in isopropanol ( 50 ml) of the suspension was heated at reflux for 1 hour. Add malonic acid (5 '2 g) and add' Continue refluxing for 3 hours. "The reaction mixture was filtered while hot. The solid was washed with hot isopropanol (50 ml) and then with CH3CN (100 ml). A white solid was emptied. After drying overnight, recover the aminonaphthalene-2-propionic acid (9 g) ° MS and 1 H-NMR consistent with the desired structure 3 Step B 'The product of Step A (2.5 g) in methanol (100 ml) The suspension was treated with 4N HC1 / dioxolane (10 ml). The resulting solution was stirred overnight. The excess solvent was removed under reduced pressure and the semi-solid was purified by HPLC (RP-CH3 CN / H 2 0). The solid was dissolved in CH3CN / H2O 'and treated with a 20% HCI aqueous solution (5 ml) and freeze-dried to obtain / 5-aminonaphthalene-2-dicarboxylic acid methyl ester hydrochloride (1.1 g). MS and 1 H-NMR were consistent with the desired structure.

Step C. A solution of guanidinoequuric acid HC1 (0.7 g) in D M F (4 ml) and pyridine (4 ml) was treated with D S C (1.1 g) and a catalytic amount of D M A P. After 4 hours, a solution of the product of Step B (0.9 g), NMM (0.4 ml) in DMF (2 ml), pyridine (2 ml) and water (1 ml) was added. The reaction mixture was stirred at room temperature overnight and acidified with TFA. The desired product was separated by HPLC (RP · CH3CN / H20). MS, NMR and CHN analysis of the freeze-dried solid (0.7 g) was consistent with the desired product.

Step 骒 D The product of Step C (200 mg) is dissolved in 1: 1 CH3CN: H2〇 (20 milli-147-this paper size is applicable to China National Standards (CNS) A4 specifications (2 丨 0X297 mm) κ · ί n I »nnn * _I-Ji I Λ7 (please read the notes on the back first and then this page), er line '1 · ^ 458 956 A1 A7 -------__ V. Description of the invention (145) liters) In the process, it was treated with KOH (PH> 12). After 4 hours, the reaction mixture was acidified with TFA and purified by HPLC (RP-CH3CN / H20). MS, ^ -NMR and CHN analysis of the freeze-dried solid (175 mg) was consistent with the desired compound. Example 5 7 '(Shi) point _ [[2 _ [[[3 _ [(Aminoiminomethyl) amino] phenyl] carbonyl-] amino] ethylammonium] amino] farphen-3 -Preparation of methyl propionate and trifluoroacetate

(Please read the notes on the back before this page)

Mr. Outfit | Order

Step A 3-A solution of thiophene carboxaldehyde (11.2 ml) in isopropanol (loo ml) was treated with ammonium acetate (20 g). The resulting mixture was heated and malonic acid (104 g) was added. The reaction mixture was refluxed for 4 hours' while filtering hot. The solid was washed with hot true propanol, alcohol (2 × 50 ml) and dried in the air at 40 ° C overnight. Recovered 8 g / 3.-aminofulphen-3.propionic acid. M S and 1 H-NMR were consistent with the desired product. -r step B 1

A suspension of the product from step A (5 g) in methanol (100 ml) was treated with 4N HC1 / dioxolane (10 ml). The reaction mixture was allowed to drain overnight. Excess solvent was removed under reduced pressure. /?-Aminopyrone-3 -propionic acid methyl ester hydrochloride (7.8 g) was isolated as a yellow 'colored foam. MS and 1 H-NMR are the same as the desired product. • ♦: -148- This paper is again applicable to China National Standard (CMS) A4 Zigzag (210X297 mm) line. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

I 956 V. Description of the invention () A7 B7 Consistent. Step c-A solution of guanidyl hippuric acid HC1 (2.7 g) in DMF (10 ml) and pyridine (10 mmol > liter) was treated with DSC (.4.5 g) and catalytic amount of DMAP 3 after 4 hours' The product of step B (2.2 g) and a solution of NMM (1.3 ml) in DMF (5 ml) were added. The reaction was stirred at room temperature overnight. The reaction mixture was treated with 1: 1 CH3CN: H2O (50 ml) and acidified with TFA. Jingyu compounds were separated by HPLC (RP-CH3CN / H20). MS, h-NMR and CHN analysis of the freeze-dried solid (2.2 g) was consistent with the desired product. Example 5 8 3S-[[2-[[[3-[(Amineiminoamido) amino] phenyl] carbonyl] amino] ethyl SI; yl] amino] -4, pentanoic acid ethyl Xue, _ Preparation of trifluoroacetate,

(Please read the precautions on the back of this page before this page.) Packing * 11 Printed Room-Guanyl Humaric Acid HCI (2,7 g) in DMF (10 ml) and pyridine (10 The solution in ml) was treated with DSC (4.5 g) and a catalytic amount of DMAP. After 4 hours, a solution of 3S-amino · 4-pentenoic acid ethyl ester hydrochloride (1.8 g) and NMM (1.1 ml) in DM F (5 ml) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was treated with 1: 1 CH3CN: H2O (50 ml) and acidified with TFA. The desired compound is separated by HPLC (RP-CH3CN / H20) -149- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 4 5Θ 9Β6 Α7 Β7 Τ? 7 ~ V. Description of the invention ( ). MS, W-NMR and CHN analysis of the lyophilized dried solid (2.6 g) was consistent with the desired product. Example 5 9 (Earth) /?-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] aminothiophene-3 -Preparation of propionic acid and trifluoroacetate 'Η2Ν-

ΝΗ II-(X Η cr II ο

(Please read the precautions on the back of the page before V% this page.) The product of Example 5 7 (750 mM) was dissolved in 1: 1 CH3 C Ν: Η 2 Ο (20 ml) and treated with Κ Ο Ο (Ρ Η > 1 2). After 4 hours, the reaction mixture was purified by TFA acidification & HPLC (RP.CH3 (: N / H2O). ΜS, 1 H-NMR and C Η N analysis and analysis of lyophilized solid (500 mg) The desired products are consistent. 0 · Example 6 0 · (±) 2_ [3-[[2-[[[[[[[Amine-iminoamido}) amino] phenyl] carbonyl] amino] ethoxy] Preparation of Amine] -4-carboxybutyl] sulfofluorenyl] benzoic acid, trifluoroacetate

-150- Private paper size applies to China National Standards (CNS) μ specifications (210 × 297 mm) Order 'Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 9 56 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 148- 5. Description of the invention () Step A A solution of 2-[(3-amino-4-carboxybutyl) thio] benzoic acid (1 g) (prepared according to US 5,409,939) in methanol (50 ml) 4N HC1 / dioxolane (10 ml) was treated overnight. The excess solvent was removed under reduced pressure to obtain the desired product (0.9 g). 2-[(3-amino-4- (fluorenoxycarbonyl) as a white solid The MS of the butyl] thio] benzoic acid methyl ester is consistent with the structure shown. Step B. A solution of m-guanidinoequuric acid HC1 (0-8 g) in DMF (3 ml) and pyridine (3 ml) was treated with DSC (1.2 G) and a catalytic amount of DMAP. After 2 hours, the product of step A (1 g) and a solution of NMM (0.3 ml) in DMF (3 ml) were added. The reaction mixture was stirred at room temperature overnight. KO was added until ρ Η is greater than 12. After 4 hours, the reaction mixture is acidified and purified by HPLC (RP-CHs CN / Η 2 0). Freeze-dried Body, (±) 2-[3-[[2-[[[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] _4_carboxyl Butyl] thio] benzoic acid, trifluoroacetate (750 mg) in MS, 1 H-NMR and C 及 N analysis were consistent with the desired product "Step C The product of step B (320 mg) in 1: 1 CH3CN : The solution in Η20 (50 ml) was treated with m-gas peroxybenzoic acid (340 mg). The reaction mixture was stirred at room temperature overnight and purified by HPLC (RP-CH3CN / H20). Freeze-dried solid (300 mg) The MS, iH-NMR and CHN analysis were consistent with the desired product. Example 6 1 (Earth) /?-[[2-[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] ] Amine-151-Pack-< Please read the notes on the back before this page), # τ β ^ This paper size applies to Chinese National Standard (CNS) Α4 size (210X297 mm), 149, V. Description of the invention () 7 7 Α Β group] ethyl fluorenyl] amine] thiophene-2 -propionic acid, the preparation of three gas acetate Η 2 \ Ν

\ cno

Printed by Step A '3 -Amine-3-(2 -thienyl) propionic acid (0-5 g) (replacement example 5.7 step a medium molar amount 2 -methylphenone- A solution of acetaldehyde) in methanol (50 ml) was treated with 4N HC1 / dioxolane '(10 ml). After 6 mussels, the excess solvent was removed under reduced pressure to obtain a waxy solid treated with Et20 / CH3CN to give methylamino-2-propanoate (370 ml); as a white powder. M S and 1 Η-ΝΛ / IR are consistent with the desired product. Step B-The solution of guanidinoyl uric acid HC1 (0.4 g) in DMF (1.5 ml) and bedding (1.5 ml) was treated with DSC (0.6 g) and catalytic amount £ > MAP in .3 hours The product of Step VIII (0.3 g) and a solution of NMM (220 µl) in DMF (1.5-ml) were added. The reaction mixture was stirred at room temperature overnight. Vinegar was separated by HPLC (RP-CH3CN / H20) and freeze-dried. The resulting white solid was treated with KOH (pH> 12) in 1: 4 CH3CN * · H2Q. After 4 hours, the reaction mixture was acidified with TF A and purified by HPLC (RP_CH; j C N / H 2 O). Ice; MS, 1 H-NMR and CHN analysis of the dried solid (300 mg) was consistent with the desired product. (Please read the precautions on the back before making this page) • Binding and binding -152- This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 OX297 mm) 458956 Α7 Β7 V. Description of the invention () Example 62 (±) 2 · [3-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -4-carboxybutyl Of methyl] thio] methylbenzoate, thorium trifluoroacetate ..

The cooperation of shellfish consumer cooperation between the Central Bureau of Standards of the Ministry of Economic Affairs and Imprint-Mandarin-guanyl hippurate HC1 (0,8 g) in DMF (3 ml ·) and pyridine (3 ml). DMAP processing. After 2 hours, '2 [[3-Amino-4- (methoxycarbonyl) butyl] thio] benzoic acid methyl ester (1 g) [prepared according to US 5,409,939], NMM (0.3 ml) in DMF (3 ml) of the solution was added = the reaction mixture was stirred at room temperature overnight. Κ Ο Η is added until ρ Η is too large. After 2 <!, The reaction mixture was acidified and purified by HPLC (RP-CH3CN / H20). MS, W-NMR and CHN analysis of the freeze-dried solid (250 mg) was consistent with the desired product. Example 6 3 (±) 3, [[2-[[[3-[(Aminoiminomethyl)) Preparation of Amine] Phenyl] carbonyl] Amine] Ethylamido] Amine] -5-[(4-methylphenyl) thio] valeric acid. Preparation of methyl ester and trifluoroacetate 153 Applicable to paper size China National Standard (CNS) A4 (210X297 mm) ---------- ^ ------ ir ------ m (Please read the precautions on the back before this page )

458956 A7 B7 Printed by Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs --151 V. Description of Invention ()

Step A 3-Amino-5-[(4-methylphenyl'yl) thio) valeric acid. (I.〇g) [prepared according to jU.S. 5,409,939] in methanol (50 ml) 'solution Treated with 4N HCl / dioxolane (10 mL). The reaction mixture was stirred at room temperature overnight. Excessive dissolution 1.-The agent was removed under reduced pressure to obtain 3-amino-5-[(4-methylphenyl) thio] acetic acid ethyl ester (1.1 g) as a white solid. MS and 1 H-NMR were consistent with the desired product. Step B. A solution of m-guanidinoyl uric acid HC1 (0.6 g) in DMF (2 ml) and pyridine (2 ml) was treated with DSC (0.7 g) and tritiated DMAP. After 1 hour, the product of step A (0.6 g) was added to a solution of saturated aqueous NaHC03 (1.5 ml) and acetonitrile (1.5 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with TF A, and the title compound (0,6 g) was separated by HPLC. It appeared as a white solid. MS and 1 H-NMR were consistent with the desired product. Example 6 4. (±) 3-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethoxy] amino] -4- [ Preparation of [(4 · methylphenyl) sulfofluorenyl] amino] butyric acid methyl ester and trifluoroacetate-154- The paper Λ degree is applicable to Chinese National Standard (CNS) A4 specification (2 丨 0 × 297 mm) ) (Please read the precautions on the reverse side before illuminating this page).

, ST '956 A7 B7 ~ 152 ~ Five', description of the invention ()

Step A_ Aminoacetaldehyde dimethyl acetal (15.8 g). Q-toluenesulfonyl gas (19.1 g) and £ 1 # (10.1 g) in (2): 12 (2. 〇mL) the mixture was stirred for 2 hours. The reaction mixture was treated with 5% HC1 aqueous solution (50ml) and Et20 (200ml). The layers were separated, and the organic layer was treated with 5.% HC1 aqueous solution (50ml), H2O (50+ Ml), washed with Na2S04. Excess solvent was removed under reduced pressure. 30 g of the desired ethyl ether was obtained: '

Confirm I ^ with MS and 1 H-NMR (Please read the precautions on the back of the page, and then the VvC page) Order the printing of Step B-Step A (10 grams) ), CH3CN (70 ml) and HCI aqueous solution-(15 ml) were heated to 50 ° C for 10 minutes. Diethyl ether was added and the desired aldehyde was extracted. The aldehyde was then used without further purification. Desired aldehyde

Confirm with M; S 155 This paper size applies to China National Standard (CNS) A4 (210X297 mm) 153 4 (j 9 δΰ Α7 Β7

5. Description of the invention (

Step C A mixture of ethyl diazoacetate (2.3 g) and SnCl2 (2.5 g) in CH2C12 (75 ml) was treated with the aldehyde (5 g) of step B '. After 2 hours, HC1 solution and Et20 were added, and the organic layer was separated and dried over MgS04. The solvent was removed under reduced pressure to obtain 5 g of crude ketoester. It was confirmed by MS and 1H-NMR without further advancement (锖 Please read the precautions on the back before i /-black page)-install and purify use. Step D of Step C; 5-ketoester (12 g), methanol (100 ml), pressure + HC02- (30 g) and NaCNBH3 (1.3 g) and stirred. After 24 hours, excess solvent was removed under reduced pressure. The resulting semi-solid was treated with CH2C12, and the desired product was extracted with HC1 aqueous solution. The solvent was removed to obtain 6 g of crude amine ester. M. Order J.4. Printed by the Ministry of Economic Affairs, 4-Central Bureau of Standards, Consumer Cooperatives, Confirmed by MS and 1 H-NMR

Step E-A solution of guanyl hippuric acid HC1 (337 mg) in DMF (1 ml) and pyridine (1 ml) was treated with DSC (0.4 g) and a catalytic amount of DMAP. After 2 hours, a solution of the product of Step D (322 mg) and NMM (220 µl) in DMF (1 ml) was added. The reaction mixture was stirred at room temperature overnight. Reaction Mix-156 In this paper, the national standard (CNS) μ specifications (210.'〆297 mm) 154 < 1d οΰ A7 B7 V. Description of the invention (The compound is acidified with TFA, the title compound (25 0 mg) was separated by HPLC (RP-CH3CN / H20) as 'white solid'. MS, CHN and 1 H-NMR were consistent with the desired product. Example 6 5 (±) 3-[[2 · [[[3 -[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -4-[(4-methylphenyl) sulfonamido] amino] butanoic acid Of Trifluoroacetate

.TFA (Please read the note on the back f to write this page). Pack. -M Type the product of Example 64 (180 mg) printed by the Shellfish Consumer Cooperative of the Central Bureau of Economic Affairs in I: 1 CH3CN: Η20 (4 The solution in ml) was treated with LiOH (100 mg). After 2 hours, the reaction mixture was acidified with TFA and purified by HPLC (RP-CH3CN / H20). The title compound (100 mg) was isolated as a white solid. MS, iH-NMR and CHN analysis were consistent with the desired product. Example '6 6 (±) 3-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] Ethyl] amino] -5- [ Preparation of (4-methylphenyl) thio] pentamidine, trifluoroacetate 157 The paper size is applicable to China National Standard (CNS) A4 (.2IOX297 mm)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 155, Invention Description () h2n

-TFA 180 mg of the product of Example 63 in 1: 1 CH3CN: H20 (4 ml) was treated with LiOH (100 mg). After 2 hours, the reaction mixture was acidified with TFA and HPLC (RP-CH3 CN / H20 )purification. 3-[[2- [[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl; | amino] -5-[(4-fluorenylbenzene Group) Thio] valeric acid, trifluoroacid (100 mg), isolated as a white solid. MS, 1 H-NMR and CΗN analysis were consistent with the desired product. Example 6 7 1. (Earth) 3-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethoxy] amino] -5- Preparation of [(4-methylphenyl) sulfonamido] valeric acid, trifluoroacetate-ΝΗ

H2N, C, N

.TFA shirt 63 product (200 mg) in 1: 1 CH3CN: H20 (4 ml) • 158 This paper size uses the Chinese National Standard (CNS) A4 specification (2 丨 〇 × ”7 mm> I --- ----- ^ ------ 1T ------ ^ (Please read the note on the back first, then r-, 4 'this page)

V. Description of the invention The pan solution in () was treated with m-chloroperlactylbenzoic acid (460 mg.) And the β reaction mixture was stirred at room temperature overnight. The reaction mixture was treated with LiOH (200 mg). The reaction mixture was extracted at 2 hours. The material was acidified with tf_A and purified by # HPL'C (RP-CH3CN / H20). 3-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethynyl] amino] -5-[(4-methylphenyl ) Benzyl] pentanoic acid 'trifluoroacetate (180 mg) was isolated as a white solid. Ms, 1 H-NMR and C Η N analysis were consistent with the desired product. Example 6 8 3S-[[2-[[[[[Aminoiminoamido) amino] phenyl] carbonyl] amino] ethylamido] amino] -4- (phenylthio) Preparation of butyric acid and trifluoroacetate (please read the precautions on the back before ε page)

Order hi Step A-3S-[[(1,1-Dimethylethoxy) carbonyl.] Amino] -4-[(methylsulfonyl) -oxy] benzyl butyrate (3-9 g ) [Prepared according to US Pat. No. 5,409,939], a suspension of sulfur base * (1'1 ml) and K2C03 (1.4 g) in DMF (20 ml) was stirred at room temperature overnight. The reaction mixture was treated with ethyl acetate. The organic layer was washed with water, 2 x 25 mL and saturated NaCl (25 mL). The organic layer was dried over Na 2 SO 4; excess solvent was removed under reduced pressure to obtain a golden oil (4.5 g). The oil was dissolved in CH2C12 (100 ml) and treated with T'FA (20 ml). In 4 hours -159- This paper size applies the Chinese National Standard (CNS) A4 specification (2.10XM7mm) line. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Central Laboratories of the Ministry of Economics Printed by the Bayer Consumer Cooperatives 56 a? B7 157 5. After the description of the invention (), the excess solvent was removed under reduced pressure, and the product was purified by HPLC (RP-CH3CN / H20). 3S · Amino-4- (phenylthio) butyric acid methyl ester TFA salt (1.2 g) was isolated as a white solid. MS and 1 H-NMR were consistent with the desired product.

Step B. The solution in m-guanylmauric acid HC1 (273 mg) and NMM (110 µl) and DMF (1 ml) was treated with trimethylacetamyl chloride (120 µl). After 30 minutes, a solution of the product from step A (208 mg), NMM (110 microliters), and a catalytic amount of DMAP in DMF (1 mL) was added. After 4 hours, 3S-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] ethenyl] amino] -4- (benzenesulfide Benzyl) butyrate (200 mg) was isolated by HPLC (RP-CH3CN / H20) as a white solid. MS and 1 H-NMR were consistent with the desired product.

Step C. A solution of 200 mg of the product of Step IXB in 1: 1 CH3C.N: H20 (4 ml) was treated with KO Η (p Η > 1 2). After 2+ hours, the reaction mixture was acidified with TFA and the product was isolated by HPLC (RP-CH3CN / H20). 3S-[[2-[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -4- (phenylthio) butanoic acid, Trifluoroacetate (100 mg) was isolated as a white carcass. MS, 1 H-NMR and CHN analysis and the desired product-Example 6 9 3S-[[2-[[[3-[(Aminoiminomethyl) amino] benzyl] carbonyl] amino ] Ethyl ethyl] amino] -4 -pentynylic acid, the preparation of trifluoroacetate-160- The paper scale is suitable for China National Car (CNS) Α4Ϊ1 grid (210X297 mm) 1 ·! Nnn I n seed coat Order — line ... (Please read the precautions on the back before making the factory .. consume this page) Printed by the China National Standards Bureau of the Ministry of Economic Affairs. Printed by the Industrial and Consumer Cooperative 458 9 56 5. Description of the invention ()

Step A. A solution of m-guanylmauric acid HC1 (2.7 g) in pMF (10 ml) was treated with trimethylacetamyl chloride (1.3 ml). After 30 minutes, a solution of 35-amino-4-pentynic acid, -hydrochloride (1.8 g), NMM (1.5 ml) and a catalytic amount of DMAP in DMF (10 ml) was added. The reaction mixture was stirred at room temperature overnight. 3S-[[[[[[ (L5. G) was separated by HPLC (RP-CH3CN / H20), and the white solid was the same as the desired product.

Step B A solution of the product of Step A (1.5 g) in 1: 1 H20 / CH3CN (75 ml) was treated with KOH (pH> 12). After 2 hours, the reaction mixture was acidified with TFA and the product was purified by HPLC (RP-CH3CN / H2O). The title compound was a freeze-dried solid (1.2 g). MS, h-NMR and CHN analysis were consistent with the desired product. 'Example 70. 3R-[[2-[[[[[Aminoiminomethyl) amino] benzyl,] carbonyl] amino] ethylfluorenyl] amino] -4 -carbamic acid ， 'The preparation of trifluoroacetate-161-This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) ------------ ^ ------.- IT ------ (Please K. Read the note on the back of w-rr.v 'for this page)-. Printed by the Industrial and Commercial Bureau of the Ministry of Economic Affairs for the Industrial and Consumer Cooperatives ¾ 5. Description of the Invention (159)

Step A .. A suspension of m-guanidinomaleic acid HC1 (0.8 g) and NMM (0.3 ml) in DMF (.2.5 ml) was treated with trimethylacetamidine (0.4 ml). After 30 minutes, a solution of 3R-amino-4-pentynyl ethyl ester (0.4 g), NMM (0.3 ml) and a catalytic amount of DMAP in DMF (2.5 ml) was added. The reaction mixture was stirred at room temperature overnight. .3R-[[2-[[[3-[(aminoiminomethyl)) amino] epoxy] zoyl] amino] ethynyl] amino] -4 -valeric acid ethyl acetate, Trifluoroacetate (0.5 g) was separated by HPLC (RP-CH3CN / H20) as a white solid. MS was consistent with the desired product. The solution of the product of step B (0.5 g) in 1: 1 CH3CN / H20 (75 ml) was treated with LiOH (pH> 12). After 2 hours, the reaction mixture was acidified with T TFA and the product was purified by HPLC (RP-CH3CN / H20). The title compound was a lyophilized solid (250 mg). MS, iH-NMR and CHN analysis were consistent with the desired product. .,, Example 7 1

2-[[2S-[[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -2- (carboxymethyl ) Ethyl] sulfonyl] benzoic acid, TFA -162- This paper size is applicable to the Chinese national standard (CNS> A4 now U! 0X297) 隹 Pack-(Please read the precautions on the back before 4- ¾ This page) Order 4 A7- _______ —Ίϋ〇 ~ *-V. Description of the invention () Preparation of salt

Example 7 The product of 2 (120 mg) in methanol (10 ml) was treated with glutamate *, glutamic acid (100 mg), and the reaction mixture was treated at room temperature overnight with HPLC (RP-CH3CN / H20). )purification. The title compound was isolated as a white solid. The ^ -NMR and CHN analysis are consistent with the desired product. Example 7 2 2-[[25-[[2-. [[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -2 ( Carboxyfluorenyl) ethyl] thio] benzoic acid ', the preparation of trifluoroacetate-.. 11111 * ---------';!? (Jing first read the notes on the back ¾ then r 筠This page j

• Set I-line Central Standards of the Ministry of Economy 扃 Printed by employee consumer cooperatives

-163- This paper size is applicable to National Standards (CNS) A4d§ · (21〇 乂 297 乂 · 厘) Employees 'Cooperative Standards Bureau of the Ministry of Economic Affairs · Printed by the society A7 ____ B7 " / m ~~'- ------- 5. Description of the invention () Step A · The solution of Example A (6.2g) in CH2Ci2 (40ml) at 0 ° C with triethylamine (4.25ml) and methanesulfonyl chloride ( 2.3 ml). After 3 hours, 3S-[[(1,1-dimethylethoxy) carbonyl] amino group 4-[(methylsulfonyl) -oxy] benzyl butyrate was prepared by using ethyl acetate / Diethyl ether extraction and separation. The organic layer was dried over Na 2 S 0 4 and the excess solvent was removed to obtain 3 s-[[(1,1-dimethylethoxy) carbonyl] amino] -4-[(methylsulfonyl) -oxyl. A suspension of benzyl butyrate (8.8 g of product, K2CO3 (3.0 g) and catalytic amount 18-crown-6, DMAP and tetrabutylammonium hydrogen sulfate in d MF (10 ml) was sulphur Treated with methyl salicylate (3.8 ml). After 2 hours, the product was extracted with ethyl acetate. The organic layer was dried over Na 2 S 0 4 and excess solvent was removed under reduced pressure = generated oil (10.2 g ) Dissolved in CH2C12 (50 ml), treated with TFA (20 ml) "The reaction mixture was stirred at room temperature overnight" excess solvent was removed under reduced pressure, the oil was dissolved in 1 ·· 1 CH3 CN:: 2 〇, NaOH was used to make basic (ρ Η> 12). After 2 hours, the reaction mixture was acidified with TFA and the product was purified using HPLC (RP-CH3CN / Η20). 20% HC1 (2¾ liters) was added and the product was freeze-dried. Obtained Yellow solid (0.9 g). MS is consistent with 2-[(2-amino-3-chipropyl) thio] benzoic acid. HC1 salt. Step B 3-aminobenzoic acid (41.1 g) in dioxo圜 (3 00 milli The solution in) was treated with 3,5-difluorenyl- (pyrazole-1-carboxamidine) ^ 11 ^ 03 (100 g), 01 [human (90 ml), and H20 (00 ml). The reaction mixture Reflux for 3 hours and stir at room temperature overnight. Filter the solids with dioxin (150 ml) and 1: 1 dioxane • 164- This paper is in accordance with China National Standard (CNS) A4 specifications (2 丨 OX2? 7 (Mm) (Please read the precautions on the back before r.'4 · this page) Binding line C | --TS2 ~ V. Description of the invention () A7 B7 Lu Lu, printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs: Wash with 20 (250 ml). The solid was suspended in diethyl ether (400 ml) and CH3CN (100 ml), and treated with 4N HC1 / dioxolane (100 ml) and 20% HC1 (1 ml). After 48 hours, the reaction mixture was filtered 'dried to obtain 3-[(aminoiminomethyl) amino] -phenylarsinic acid (34.1 g)' as a pale purple solid. MS was consistent with the desired product. Step骒 C 2-[(2S-Amino-4-carboxybutyl) thio] benzoic acid (09 g) and a solution of diea (1.5 ml) in DMF (5 ml) with n-[(1, Bu Dimethyl $ oxy) carbonyl] glycine, 2,5-Dioxopyrrolidin-butyl ester (1.1 g) and a catalytic amount of DMAP. After 1 hour, methanol (5 ml) and 4N HC1 / dioxolane (10 ml) were added. After 18 hours, methyl 2-[[[2S-[(2-aminoethylethyl) amino] -3-(methoxycarbonyl) propyl] benzoate was analyzed by HPLC (RP-CH3CN / H2〇) Separation. The desired product (1.0 g) was obtained as a white solid. MS was consistent with the desired product. Step D The product of Step C (200 mg) and a solution of NMM (130 µl) in DMF (1 ml) were treated with IBCF (152 µl). After 2 minutes-, the reaction mixture was treated with the product of Step B (330 mg), NMM (260 microliters) and a solution of the catalytic amount of D M A P in D M F (1 ml). After 2 hours, the reaction mixture was treated with Η20, made basic with NaOH (ρΗ> 1 2) »After 4 hours' the reaction mixture was acidified with TFA, and the product was separated by HPLC (RP-CH3CN / Η 2 0). The title compound (200 mg) was obtained as a white solid. M S '1 H-NMR and C Η N analysis were consistent with the desired product. Example 7 9 -165- This paper size applies to Chinese national standard (CNS > A4 size U 丨 0X297mm) Kind of book-(Please read the precautions on the back of Jing first, and then use this page) Order-I. 458 956 A7 B7 V. Description of the invention (163 (±) / 3-[[2-[[[3-[(Aminoiminomethyl) amino] phenyl] carbonylJ methylamino] ethylenyl] Preparation of amino] pyridine-3-propanoic acid ethyl ester, bis (trifluoroacetic acid) salt ...

C02Et Printing step A of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A 200 ml flask equipped with a Teflon-coated stir bar was charged with Nt-8〇 carbamic acid (3.80 g, 0.019 mol) and anhydrous. ^ ^ (70 ml). To this was added N-methylmorpholine (NMMj (2.1 ml, 1.92 g, 0.019 mol)) and the resulting mixture was cooled to 0. (: (salt-ice water bath). After a few minutes, isobutyl formate ( IBCF) (95%, 2.74 g, 2.6 ml, 0.019 mol) was added. After about 5 minutes, 3-amino-3-pyridin-3-ylpropyl ethyl dihydrochloride (5.0 g '0' 〇19mol) and NMM (3-84g, 0.038mol) in DMF (40ml) were added, and the resulting mixture was reacted at 0-5.0. The volatiles were on a rotary evaporator (600aC) It was removed to obtain a semi-solid. It was taken up in ethyl acetate and dilute hydrochloric acid (pH 2). EtO Ac (200 ml) was added to the aqueous layer, and the aqueous layer was added at pH 7 by adding solid sodium bicarbonate to about 7. p Η was adjusted to 8 by adding a dilute aqueous NaOH solution. The layers were separated and the aqueous layer was washed with EtO Ac. The combined organic layers were dried (Na2S〇4) and the volatiles were removed to obtain a concentrated oil. Consistent. '' Step B -166 ^ This paper size applies the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) ----------- ¾ clothing — (Please read the Note for re-purchase) Order-'458 956 A7 B7 Printed by the Central Standard of the Ministry of Economic Affairs, Printed by Consumers Cooperatives V. Description of Invention (164) Step. The product of A is dissolved in dioxolane (20 ml) , Transfer into a round flask equipped with a Teflon-covered scrambler and connect it to a mineral oil frother. Add 4N HC1 dioxin (about 30 ml) to it. In about 1 After an hour, the air was used to remove excess HC1 gas, and the reaction mixture was concentrated on a rotary evaporator. The excess HC1 was driven off by dioxolane with a second evaporation to obtain a white foam:; MS and NMR were consistent with the desired product The title compound was obtained as a dihydrochloride. Step C The title compound was obtained from the coupling of 3-guanidinobenzoic acid and the product of step b using conditions and procedures substantially the same as those used in step A. Therefore, in 3-guanidylbenzene The formate salt (15 g, 70 mmol, Aldrich) was dissolved in DMF (70 mL) and added-the equivalent of NMM (0.77 mL, 7.0 mmol) was cooled to 0 ° C. One Equivalent ibcF (0.91 ml, 7 mmol) after several minutes, equivalent to the carnitine prepared in step b Pyrimidinyl amino acid ester (2'4 g = HC1 salt) and a solution in NMM (0.78 ml) and DMF (about 50 ml) were added, and the reaction mixture was heated to room temperature overnight. The volatiles were removed and the product Preparative reverse-phase high-performance liquid chromatography (RPHPLC) using 9 9: 1 water, 0.050 / 〇TFA: acetonitrile, 0.05% TFA to a concentration gradient of 45:55 in 80 minutes at 80 ml / The fractions of the desired product separated by a at a minute flow rate were combined and lyophilized to obtain the title compound (0.96 g) as a fluffy solid whose NMR and MS were consistent with the desired product. Example 8 0 (土) y5-[[ 2-[[[3-[(feyliminomethyl) amino] phenyl] carbonyl] methylamino] ethenyl] amino] pyridine-3-propionic acid, bis (trifluoroacetic acid) salt Preparation -167- < Please read the precautions on the back before f is this page), binding. Order one. 4. This paper is compliant with Chinese national standard (CNS> A4 specification (210X297 mm) 4 58 9 56_ V. Description of the invention (A7 B7 165

The product of Example 70 (0.33 g) was dissolved in water (20 ml) and PΗ was adjusted to 11 by adding a dilute aqueous LiOH solution. After about 1 hour, the ester was substantially hydrolyzed as shown by the C-18 HPLC analysis. Desired product (±) θ-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] methylamino] ethylfluorenyl] amino] pyridine-3 -Propionic acid, bis (trifluoroacetic acid) salt was separated by preparative C-18 HPLC using essentially the same as shown in Example 7 9 Step C, freeze-dried (0.19 g) beta proton NMR, FAB MS, and elemental analysis (CHN) is consistent with the desired product 0 Example 8 1 · 々-[[2 · [[[3 _ [(aminoiminomethyl) amino] phenyl] carbonyl] amine] -1-oxypropyl] amino] pyridine-3-propanoic acid ethyl ester, preparation of bis (trifluoroacetic acid) salt '(please read the note on the back first, see this page). Printed by the Consumer Standards Cooperative of the Ministry of Standards

Step AR, SNt-Boc alanine (2.0 g, 0.0106 mol) is coupled to 3-amino-168-private paper size applies Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) Central Bureau of Standards, Ministry of Economic Affairs Printed by the employee consumer cooperative 458 9 56 a? ___. B7_ V. Description of the invention (166) '-3-Pyridyl-ethyl propionate dihydrochloride (3, 2 g). The procedure of step 79 in Example 79 is used. The obtained product (3.42 g, 88% isolated yield) and MS and NMR were consistent with the desired N-Boc product. Step B, Boc protecting group was obtained by removing the product from Step A using the procedure of Example 79, Step B ' Dihydrochloride (3.5 g) as a white solid. MS and NMR spectra are consistent with the desired amino ester. _ Step C. ^ Lu-[[2-[[[3-[(Amineimine Methylmethyl) amino] phenyl] carbonyl] amino group 1-oxypropyl] 'amino] pyridine-3-propionic acid ethyl ester, preparation of bis (trifluoroacetic acid) salt. Obtained in step B Urethane (L6 g) was coupled to 3-guanidinobenzoic acid (0.75 g, 3.5 mmol) using the procedure of Example 79 (conditions / to obtain the title compound (1.8 g, 2.7 mmol, 79% separation) Yield) double Trifluoroacetic acid) salt, as a white solid (after freeze-drying), MS and proton NiMR are consistent with the desired product. Example 8 2 U [2-[[[3-[(aminoiminoamido)) amine Benzyl] Benzyl] Carbonyl] Amine] _ 1-oxypropyl] Amine] pyridine-3-propanoic acid, the preparation of bis (trifluoroacetic acid) salt Page) • Binding. Thread

I

N Η

'-169- This paper size applies to Chinese national standard (CNS> (210X297mm) 96b Α7. ______ Β7 V. Description of the invention (167) " —- Example 8 The product (0.5 g) Use Example 8 〇 The procedure was hydrolyzed. The desired product was a di-TFA salt 'and was separated by preparative CM.8 HPLC using conditions substantially the same as those shown in Example 7 9 Step C, freeze-dried (0.45 g). Proton NMR and FAB MS was consistent with the desired product. Example 8 3 * (Earth) / 5-[[2-[[[[[[Aminoiminomethyl) aminob 4.methylphenyl] alkynyl] amine [Ethyl] ethynyl] amino] t; Preparation of Bizhen-3, propionic acid, bis (trifluoro acid) salt

Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

Step A Nt-Boc Glycine is coupled to 3-amino-3 .- (3-pyridyl) propanoic acid dihydrochloride (5.0 g '0.019 旲), using the procedure of Example 79 Step A' during processing After 'yellow oil was obtained (6.0 g, 90%) with MS consistent with the desired-compound. * • Step B

Boc, the removal of the protecting group is from the product of step A (5.9 g) dissolved in dioxin garden (about 20 ml) and TFA, the reaction is advanced, and stored for several minutes until the release of gas stops. The volatiles were removed on a rotary evaporator to obtain a brown oil. MS and NMR were consistent with the desired product.

Step C '.'. -170- 'This paper size applies Chinese National Standard (CNS) A4 specification (2 丨 0 X 297mm) .. 丨' 4 63 9 56 A7 B7 ^ gg ------ -V. Explanation of the invention () The amine ester prepared in step B is used in Example 79. The procedure of step C is coupled to 4-methyl-3-nitrobenzoic acid to obtain an oil for preparative rphPLC (C-18) After purification, the desired coupling product (1.76 g) was obtained as an amorphous solid. The NMR and MS were consistent with the desired product.

The solids present in the product of Step D were reduced using the following procedure. The product from step c (1.75 g) was transferred to a 6-pan Fischer-Porter pressure bottle equipped with a pressure gauge and inlet and outlet valves. The starting compound was dissolved in glacial acetic acid and 3% Pd / C catalyst (about 1 g ) Add and seal the bottle. After three emptying and nitrogen cycles, the bottle was pressurized with hydrogen (55 psig), and the reaction was performed at room temperature overnight. The catalyst was removed by celite filtration, and the colorless solution was concentrated to obtain a yellow viscous oil (2.0 g), the MS of which was consistent with the desired aniline.

Step E Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The aniline of Step D (1.0 g '2.12 mmol) was guanylated using the following procedure. Aniline is dissolved in acetonitrile (approximately 50 ml), 1H_pyrazole · buccal hydrochloride (0.342 g '2.3 mmol) in water and triethylamine (ο. &Quot; g, 0.92 ml, 6.4 mmol) Ear) Add 'solution to reflux. After heating overnight 'volatiles were removed on a rotary hairdresser' and the obtained semi-solid gift was purified by preparative RPHPLC 'to obtain the desired gUanidated product (0,3 g, after freeze-drying)' Its NMR and MS are consistent with the desired structure.

The guanidinium vinegar obtained in step F was hydrolyzed to an acid, and the crude (03 g) was dissolved in water (20 ml), and dilute LiOH was added to make ρ 1 11. After about 1 hour, the conversion of "Yuanquan to acid" was measured by RPHPLC. The title compound was preparative -171-This paper is in accordance with Chinese national standard (CNS > Α4 size (210X297 mm) o S 9 56 Α7 Β7 five 2. Description of the invention (169 HPLC purification 'freeze-dried to obtain the di-tfa salt as a white powder (0.19 g)' whose NMR and MS are consistent with the desired product. Example 8 4 points-[[2-[[(3-amine group -4-methylphenyl) carbonyl] amino] ethyl] ethyl] amine] Preparation of pyran-3 -propionic acid 'bis (trifluoroacetic acid) salt

Example 8 The aniline monoester obtained in step D 3 was hydrolyzed to an acid using conditions and purification methods similar to those in step 8 3 step F to obtain the desired aniline mono acid, β · [[2-[[(3-amino -4-methylbenzyl) carbonyl] amino] ethylfluorenyl] amino] pyridine-3-propionic acid, bis (trifluoroacetic acid) salt, whose NMR and MS are consistent with the desired product. Example 8 5 (±) ^-[[2-[[[[Aminoiminomethyl) amino] methyl] benzyl] carbonyl] amino] ethylfluorenyl] amino] pyridine- Preparation of 3-propionic acid and bis (trifluoroacetic acid) salt ---------- Packing-- (Please read the precautions on the back before this page) Printed by a cooperative

-172- This paper music scale is applicable to China National Standards (CNS) A4 (240X297 mm) ___B7 ___B7 Printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs ~ ΐ7ό '~~-5. Description of the invention ()

Step A 3-Cyanobenzoic acid (7.0 g, 0.0476 mol) was added to a round bottom flask (200 mL) and dissolved in DMF: pyridine (50 mL). Add disuccinium carbonate (DSC '14.6 g, 0.0571 mol) and catalytic amount of DAMP to this solution »When the gas release ceases, the third butyl glycine (9.6 g, 0.057 mol) is added and reacted overnight. Triethylamine (10 ml) was added and stirred for several minutes. The volatiles were removed on a rotary evaporator and the crude reaction mixture was dissolved in water and ethyl acetate. The aqueous layer was made acidic by adding dilute hydrochloric acid, the layers were separated, and the aqueous layer was discarded. The organic phase was washed with a saturated aqueous solution of Lonic acid Lona, dried (NaJC ^) 'and concentrated to obtain the product (11.1 g). The MS was consistent with the desired coupling product. Step B .. The cyano third butyl ester obtained in Step A was reduced to the corresponding benzylamine compound in a manner similar to that in Step D of Example 82. Therefore, cyano tert-butyl ester (10.0 g, 0.0681 mole) was dissolved in acetic acid (about 70 ml), and heated and cooled. The catalyst was added (0.5 g of 3% Pd / C), and the reaction mixture was transferred to a 6 ounce Fischer-Porter bottle 'pressurized with hydrogen (55 psig) and hydrogen was continuously added until argon absorption ceased. The catalyst was removed by filtration through celite, and the solvent was removed by evaporation to obtain a crude phenylfluorenylamino third butyl ester, which was consistent with the desired compound a.

Step C

The Boc group was removed from the product of step b in a manner similar to that of step 8.3 of Example 8.3 to obtain a benzylamino acid whose MS was consistent with the desired product. -

Step D -173- This paper size applies the Chinese national standard (CNS > Μ said grid (2 丨 0X297 public love) {Please read the note on the back before reading this page) Line-I, Central Bureau of Standards, Ministry of Economic Affairs Printed by employees' consumer cooperatives A7 B7 V. Description of the invention (171) The amino acid (9.0 g, 0.03 mole) obtained in step C is dissolved in acetonitrile:. Water (about 1: 1). Ethylamine was added. After a few minutes, the volatiles were removed and a crude triethylamine salt was obtained. It was re-dissolved in acetonitrile: water (200 ml), 1Η-pyrazole-1-carboxy vein hydrochloride (4.3 g, 0.03 mole) was added, and the reaction mixture was refluxed. After the reaction mixture was refluxed overnight, the reaction mixture was concentrated to Semi-solid 3 was dissolved in water (20 ml) and ρρ was adjusted to about 7 by adding solid sodium bicarbonate. A precipitate was formed and removed by filtration. M S and N M R are consistent with zwitterions. The product is converted into the hydrochloride, treated with zwitterions in water, and hydrochloric acid is added until ρ Η is about 2. It was freeze-dried to obtain a hydrochloric acid hood. Step E. The guanidino-acid was obtained from the product obtained in step D (0.47 g) using the procedure of Example 83, Step F, and hydrolysis. When freeze-dried, a solid was obtained (0.41 g) as a di-TFA salt, with MS and NMR consistent with the desired product.

Step F The guanidino · acid prepared in Step E is coupled to 3-amino_3_ (3-pyridyl) propanoic acid 'using the procedure of Step A. Using preparative RPHPLC, a solid (1.66 g) was obtained 'whose MS and NMR were consistent with the desired product. '' Example 8 6 -3S-[[. 2-[[[3 _ [(Amineimine'yl) amino] phenyl] carbonyl] amino] ethoxy] amino] -4 -hydroxybutane Preparation of acids

.-174-. Ning 1 [Ning 1 [National Standard Twins (CNs) 8 4 specifications (2 丨 0X297 mm)] (谙 Please read the notes on the back before ^-\ this page). Printed by the Central Standards Bureau of the Ministry of Online Economics and Labor Cooperatives A7 Β7 V. Description of Invention (172)

Step A Preparation of 3-Nt-Boc-amino-4-hydroxy-butyric acid methyl ester N-t_Boc aspartic acid, benzyl ester (10.0 mmol) is dissolved in THF (10 ml) at 30 Add BH3-THF (20 ml, 20.0 mmol) in a 0 ° C solution dropwise over N2T over a minute. After the mixture was stirred at 0 ° C for 1-2 hours, the reaction mixture was quenched with a solution of 10% AcOH in MeOH (10 ml) and the solvent was evaporated. The residue was dissolved in EtOAc and extracted with 1N HC1'0 and 1M NH4HC03. After drying over MgS04, the solvent was removed in the air and the product was recovered. M S is consistent with the desired product. Step B Preparation of Nt-Boc-3-amino-2,3-dihydro-5-oxy-35-furan 3-Nt-Boc-amino-4-hydroxy-butyric acid benzyl ester (20 g, 64 millimoles) in dichloromethane (200 ml) at 25 ° C for 16 hours in the presence of a catalytic amount of camphorsulfonic acid. The solvent was removed in the air. The crude material was purified by flash chromatography 'on a dream gel bed (22 cm X 6 cm Merck 60 Silicagel) with a concentration gradient of hexane / ethyl acetate (90/10 to 70/3 0; 200 ml / min flow rate). . Pure N-t-Boc-3-aminolactone was isolated as a white solid (5.4 g), and its M S was consistent with the desired compound.

Step C 3-Preparation of amino-2,3-dihydro-5-oxy-3S-squenan hydrochloride The 3-Nt-Boc-aminolactone (5.0 g, 25 mmol) isolated in step B Ear) Dissolved in 4N HC1 dioxan (20 ml). After stirring at 25 ° C for 45 minutes, 4N HC1 dioxolane solution (10 ml) was added. After 1 hour at 25 ° C, excess HC1 was removed in the air. The resulting solution crystallizes when left to stand "-175- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) ——. Meal-(Please read the precautions on the back before congratulating this page) Order " Ϊ 458956 Α7 Β7 Printed by the Ministry of Economic Affairs' order to the Central Bureau of quasi-bureau off-line consumer cooperatives V. Description of the invention () White crystalline material is filtered and dried (2.9 g); 1H, Jl = 18.3 Hz, J2 = 2.5 Hz), 3.0 (dd, 1H, Jl = 8.5 Hz, J2 = 18.3 Hz), 4.1 (m, 1H), 4.35 (dd, 1H, J = 10.5 Hz, J2 = 2.7 Hz), 4.5 (dd, 1H, Jl = 10.5 Hz, J2 = 6.5 Hz), MS (FAB) 102.1. (M + H +) »Step D 3 -Amino-2,3-dihydro-5- The oxy-3S-furan hydrochloride was coupled to m-guanidino · urethane hydrochloride (GIHA) using the following procedure. GIHA (1.6 g, 5.9 mmol) was added to DMF (approximately 30 ml) with one equivalent of NMM (0.59 g, 0.64 ml, 5.82 mmol), and the mixture was stirred for several minutes until a precipitate formed. The mixture was cooled to 0 SC, one equivalent of DSC (1.49 g, 5,82 mmol) and a catalytic amount of DMAP were added, and the reaction was carried out for at least 0.5 hours. When the activation was substantially completed, 3.amino-5-oxy-3S-furan hydrochloride (0.8 g, 5.82 mmol) was added to the reaction mixture, and then one equivalent of NMM (0,59 g, 0.64 Ml, 5.82 mmol), allowing the reaction to proceed to completion (1-16 hours). The volatiles were removed (rotary evaporation at 60 ° C), and the residue was dissolved in the minimum amount of water: acetonitrile (the minimum amount of ethyl acetate was used for dissolution). Pure T F A was added to bring the p of the solution to about 3, and the desired coupling product was isolated by preparative RPHPLC. After lyophilization, the TF A salt was obtained as a hygroscopic solid (0.54 g). Step E The title compound was obtained by dissolving the product of Step D (0.54 g) in water (20 ml). Dilute aqueous NaOH was added to bring the pH of the solution to about U. At the completion of the reaction, as determined by analytical RPHPLC, the solution (final ρηκ8) ____ -176- This paper size applies to China Standard (CNS) M specifications (2 丨 0 > < 297 mm) (Please read the Note (buy it from the fire)) Packing. Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, printed by 458 956 Α7 A 7 B7, V5. Description of the invention (4) Freeze drying. The product was confirmed with protons N M R and M S. Example 8 7 (±) /?-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -2 -hydroxyl Preparation of phenylpropionic acid, sodium salt, trifluoroacetate, 0

3-Amino-Hydroxyl hydrochloride (2.'0 g, 0.010 moles), prepared according to J. Rico, Tett. Let., 1994, 35, 6599-6602 Μ, coupled to GIHA (1.50 g , 0.0041 mole), essentially using the procedure of step 86D in Example. Purified by preparative RPHPLC to obtain the desired product as a mixture of lavender and hydroxy acid TFA salt. After freeze-drying, it was a pale yellow powder (1.50 g). Substantially complete conversion to the desired phenol-acid is obtained by dissolving the purified mixture 'in water, adjusting pp to 7-8 with a dilute aqueous NaOH solution, and freeze-drying-. Mass NMR and MS are consistent with the molecule- (. Acid (carboxylate) form (trifluoroacetic acid, sodium salt). ”Example 8 8. (±) /?-[[2-[[[3- [(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -2, hydroxy-5-fluorenylphenylpropionic acid, trifluoroacetate [-177 -'(Please read the note on the back before f, > ν page) • Packing. Ϊ́ ^ τ .14: The size of thread paper is applicable to Chinese National Standard (CNS) grid (210 × 297 mm) 458 956 Α7 Α7 _____ Β7 V. Description of the Invention (175) ο

3-Amino-6-methylargon humulant was prepared according to the lack of references cited in Example 87, coupled to GIHA, using a quantity, conditions, and purification similar to Example 87 to obtain a yellow-brown solid (〇 · 76 g). Its MS and NMR are consistent with the desired product (TFA, sodium salt). Example 39. (±) 3-[[2-[[[[[Aminoiminomethyl) amino] benzyl] carbonyl] amino] ethenyl] amino] -4-[( Preparation of 2-hydroxyethyl) amino] -4-oxybutyric acid, trifluoroacetate-

TFA. Step A I --------- Install-(Please read the note_item on the back before ^ '3 *, .. Benwa) Order

.1C

M Printed by the Central Laboratories of the Ministry of Economy

Boc Μ .Η

〇 C02Bn ΌΗ 178 • 178- The paper scale is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 4 58 9 56 a? B7 V. Description of the invention (176) > 1-b: 6〇 (: Tiandong Amino acid "" -benzyl methyl ester (7.7 mmol, 2.50 g) was dissolved in DMF: pyridine (1: 1, 70 ml), DSC (2.2 g, 8.5 mmol) and a catalytic amount of DMAP were added. In the gas After the release ceased (about 1 hour), ethanolamine (0.52 g, 8.3 mmol) was added to eridine (^ 0 ml) and reacted at room temperature overnight. The volatiles were removed to obtain golden tincture. The resulting product was partitioned into EtOAc And HC1 solution. The organic layer was washed with saturated aqueous sodium coagulate solution, dried (anhydrous sodium sulfate), and the volatiles were removed to obtain a golden oil (2.64 g). Its proton NMR anti-MS and the desired protection Phenamine is consistent.

Step B < Please read the note fis on the back before you go to this page) .... install ... co2h

-Order 'Central sample from the Ministry of Economic Affairs, printed by employee consumer cooperatives The crude product of step A (2.3 g) is dephenylated using standard procedures. Therefore, the product of Step A was absorbed in ethyl acetate (about 70 ml), transferred into a 'Fischer-Porter pressure bottle, and 3% red / finished (1 g) and hydrogen (54 psig) were added.混合物 The mixture should be stirred vigorously and supplemented with hydrogen (if necessary). After the argon was no longer absorbed, the catalyst was removed by celite filtration and the volatiles were removed to obtain a colorless oil (1.73 g). Gardenia NMR and MS are consistent with the desired dephenylhydrazone product.

Step C -179- This paper size applies the Chinese National Standard (CMS) A4 specification (210X297mm) 458 5. Description of the invention (1) A7 B7

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The crude product of step B is dissolved in dioxolane (20 ml), and 4N HC1 is added to the dioxolane (40 ml) and stirred vigorously. The reaction proceeds until the release of the gas stops (about 15 minutes). The volatiles are removed, and the can is golden oil. The NMR and MS were consistent with the desired deprotected amino acid product. Step D. The product of Step C (1.0 g, 4.7 mmol) was coupled to GIHA (1.5 g, 4.11 mmol) using a procedure similar to Example 8 6 Step D. The crude coupling reaction product was concentrated to Thick oil, reconstituted in water :: acetonitrile and purified by preparative RPHPLC to obtain the desired (±) 3-[[2-[[[[ [Carbonyl] amino] amino] ethylfluorenyl] amino] 4-[(2.hydroxyethyl) amino] -4-oxybutyric acid, trifluoroacetate (0.44 g, after lyophilization). Proton τ NMR and MS are consistent with the desired product. Example 9 4 '. 2-Aminophenylarsinic acid 2S-[[2-[[[[[[[Aminoiminomethyl) amino] benzyl] .carbonyl] amino] ethenyl] amine Propyl] -3 -carboxypropyl ester, preparation of bis (trifluoroacetic acid) salt, monohydrate I ^-_, · .. {Please read the note on the back ^ Η item first, then # ··-> ΐ ^ 4 pages), -ίτ 腺 -180- This paper size applies to the Chinese National Standard {CNS > Α4 size (2! 〇 乂 297 public directors) Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Lijin 4 59 f) 56 Α7 ____ Β7 V. Description of the Invention (178)

Step A Preparation of 3-Nt-Boc-L-amino-4-hydroxy- (3 ^)-butyrate benzoate N, t-Boc aspartic acid, /?-Benzyl ester (Sigma) (75 G, 20 mmol) 9 was dissolved in THF (30 mL), and BH3-THF (400 mL, 40 mmol) was added dropwise over 30 minutes at 0 ° C in N2T. After the solution was stirred at 0 ° C for 2.5 hours, the reaction was quenched with 50 ml of a 10% acetic acid in MeOH and the solvent was evaporated. The residue was dissolved in ether (200 ml), saturated K2C 0 3 with 1N HC1 ', washed with water, and dried in MgS04. Solvent in the air to remove / isolate the product (melting point 5 6-5 7 ° C ..., from isopropyl ether / hexane). 1 ^ NMR (d6-DMSO) ά 1.4 (s, 9H), 2.68 (d, 2H, J '= 6Hz), 3.82 (d, 2H, J = 5 Hz), 4.01 (m, 1H 乂 5.16 (s, 2H), 5.21 (bs, 1H), 7.37 (bs, 5H).

-Step B Preparation of 3-amino-4- (anthranilide)-(3S) -butyrate butyrate 3-N-tBoc-amino-4-hydroxy- (3S) -butyrate butyrate The ester (10 g, 32 mmol) was dissolved in 50 ml of dimethylformamide and then dissolved in triethylamine (4.4 g of '4 6 somol). Isatoic (5.0 g, 3 mmol) was added to the solution and stirred at 25 ° C for 24 hours. After the reaction is completed (by reverse-phase HPLC) -181-Private paper ruler ^ Applicable to China National Standard (CNS) Standard 8 (21 × 297 mm) _J. Λ: I ---------— ------ ir ------ line '· (Please read the notes on the back before filling in the page), printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, r 45B95S. A7 ------ B7 V. Description of the invention (179)-Detection, water was added, the product was extracted with ethyl acetate (100 ml), and dried over N ^ SO4. The solvent was evaporated to produce 12 g of yellow oil. In this oil, dioxin Lupin (20 ml) was added, followed by 4N Ηα in dioxolane (ml). The reaction was carried out for 4 hours, ether was added and the oil was separated from the solution. The ether was added to the oil and decanted. This procedure is repeated twice. Ether was added to the semi-solid and stirred vigorously for 16 hours. A white solid was collected, and its M s and H NMR were consistent with the structure shown. Step C carbon IN, N · 1 Hupper imine. Dsc (1.4 g, 0,5 mmol) was added to GIHA (1.0 g, 0.5 mmol) in anhydrous dimethylformamide (20 ml), then add dimethylamino tr specific bite (1000 mg) β after 1 hour, 3-amine -(O-aminobenzoate) _ (3S) -benzyl butyrate (0.7 g., 0.5 mmol) was added in DMF / NMM (1: 1) (5.0 ml) in one portion. The product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (10 g). M S and 1 H-NMR were consistent with the structure shown a Step D Step C The benzyl ester was hydrogenated using N 2 gas and catalyst Pd / C (500 mg, -5%) for 4 hours. After the reaction was completed, the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (1.0 g). MS and 1 H-NMR were consistent with the structures shown. Example 9 5 is _ [[2-[[[3-[(Amineiminemethyl) amino] benzyl] carbonyl] amino] ethenyl] amino] -1,4-benzodi Preparation of dioxin-6-propionic acid and trifluoroacetate-182- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the note § on the back before reading) # -Text page)

-P order line · .1 A7 B7 458 956 V. Description of the invention (18Q)

_Step A Add ammonium acetate (12.5 g) to isopropyl alcohol (205 ml) in 1,4-benzodioxan-6-acid (Aldrich) (10 g), and then add glycerin Acid (6.0 g). The reaction mixture was stirred at reflux for 5 hours. The reaction mixture was hot filtered while washing with hot isopropanol (100 mL). The resulting white solid was dried to obtain 01 ^ -3-amino-3- (1,4-benzodioxane) -propionic acid ('6.3 g)' as a white solid. MS and 1H-NMR with the structure shown Consistent.

Step B Step DL-3 -Amine · Amino-3- (1,4-phenylhydrazone dioxane) -propionic acid (6 g) in absolute EtOH (250 ml) and acetamidine (20 ml) Slurry to liquid. The slurry was then heated at reflux for 4 hours. The reaction mixture was cooled to 25 ° C, and the solvent was evaporated under reduced pressure to obtain a solid, which was washed with ethyl acetate (50 ml) to obtain DL-3-amino-3- (1,4-benzodioxane ) -Ethyl propionate (6.5 g) as a white solid. M S and 1 H-NMR are consistent with the structure shown 3.

Step C. Ν, Ν, -bissuccinimide carbonate (DSC) (1.4 g, 0.5 mmol) Add GIHA (1.0 g, 0.5 mmol) to anhydrous dimethylformamide (20 Milli-183- This paper method applies the Chinese national standard (CNS Μ4 is now (210X297 mm) (read the note on the back first and then this page) * τ Printed by the Ministry of Economic Affairs Central Standardization Bureau Staff Consumer Cooperative 458 956 A7 _____ ^ ____ B7 V. Description of the invention (181 liters), and then add dimethylaminopyridine (100 ml). After 1 hour, the product of step B (0.7 g '0.5 mmol) Add in DMF / NM (1: 1) (5.0 ml) in one portion. After the reaction and completion, the product was purified by reverse phase chromatography (water / ethyl chloride) to give a white solid (1 -1 g) MS and 1 H-NMR are consistent with the structures shown.

Step D DL-3 -Amino-3- (1,4 · phenylhydrazone dioxin) -ethyl propionate (product of step C) (500 mg) dissolved in water / acetonitrile (1: 1) The reaction mixture was then added with lithium 'lithium hydroxide (100 mg) and the reaction mixture was stirred at 25 ° C and detected by HPLC. After the hydrolysis is complete (1-2 hours), three, fluoroacetic acids are added until ρ η = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to give 255 mg of a white solid. MS and 1H-NMR are consistent with the structures shown. Example 9 6 Preparation of N-[[2-[[[[[[Amine.iminoamido) amino] phenyl] carbonyl] amino] ethylamido] -naphthalene alanine, ethyl ester ---------- ^ .-- (Please read the precautions on the back first, then the Shanghai Bird page)-Order

Printed with N, NΓ-bissuccinimide carbonate (DSC) (1.4 g, 0.5 mmol) by the Central Standards Bureau of the Ministry of Online Economics and Consumer Cooperatives. ) To anhydrous dimethylaminoglycine (2 ^) ml), then add dimethylaminopyridine (100ml). After 1 hour, Lu-alanine ethyl ester hydrochloride (0.7 g, 0.5 mmol) was added in DMF / NMM (1: 1) (5.0 ml) in one portion. The product was purified by reversed-phase chromatography (water / B-184- this paper is in accordance with China National Standard (CNS) A4 specification (210X297 mm)) 5. Description of the invention (182 nitrile) purification, yielding 1.1 grams of white consistency. A7 B7 .Solids. MS and 1 H-NMR with structure examples 9 7 N-[[[[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] acetamidine Of Alkyl] -Cold-Alanine

The compound of Example 9 (500 mg) was dissolved in water / acetic acid (1: 1) / then a bell hydroxide (200 mg) was added. Reaction mixture 衿 25. 〇 Stir and detect by HPLC. After the hydrolysis was completed (1_2 hours), trifluoroacetic acid was added until pH = 2 »The product was purified by reverse phase chromatography (water / acetonitrile), yielding 375 mg of a white solid. M S and 1 H-NMR are consistent with the structures shown. Example 9 8 (±) /?-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylcarcinyl] amine] »Le-3 -Ethyl cool propionate, the preparation of bis (trifluoroacetic acid) salt 〈Read the notes on the back of the poem first # -¾ .. Ben J. Order _ > f Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

2TFA H20 -185- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 9 56 V. Description of invention (183)

Step A To 3-quinolinecarboxaldehyde (eight 1 £ 11 ^ 11) (10 g) in isopropanol (205 ml), add ammonium acetate (12.5 g), and then add malonic acid (6 〇g). The reaction mixture was stirred at reflux for 5 hours. The reaction mixture was filtered while hot and washed with hot isopropanol (100 ml). The resulting white solid was dried to obtain DL-3-amino-3- (3-quinoline) propionic acid (6'3 g) as a white solid. MS & iH-NMR is consistent with the structure shown. .

Step B

The DL-3-amino-3- (3.quinoline) propionic acid (6 g) in step A was slurried in absolute EtOH (250 ml) and acetamidine (20 ml). The slurry was then heated under reflux for 4 hours. The reaction mixture was cooled to 2 5 ° C, and the solvent was evaporated under reduced pressure to obtain a solid, which was washed with diethyl ether (50 ml) to obtain DL-3 -amino-'3- (3-fluoroline) propionic acid ethyl ester (6 , 5 g) 'as a white solid. And ΐΗ-NMR are consistent with the structure shown.

Step C N, N · -bissuccinimide carbonate (DSC) (1.4 g, 0-5 mmol) GIHA (1.0 g, 0,5 mmol) was added to anhydrous dimethylformamide (2 0 ml), and then added dimethylaminospyridine (100 ml). After 1 hour, DL-3 -amino-3- (3- »quinine) acetic acid propionate (ι · 2 g, 0.5 mmol) in DMF / NMM (1: 1) (5.0 ml) Join in one. The product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (i 2 g). M S and 1 H-NMR are consistent with the structures shown. Example 9 9-Lu-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl-186- This paper size applies to Chinese National Standards (CNS) Α4 Specification (2t〇X297mm) --------- #-(Please read the precautions on the back before this page) Thread Printing by the Central Standards Bureau of the Ministry of Economic Affairs, printed by the cooperative 9 9 A7 B7 — 一 ._-V. Description of the invention (184) Preparation of fluorenyl] amino] pyridinoline-3 -propionic acid, bis (trifluoroacetic acid) salt

N 2 H mne

NH

Η '-Ν cno one

2TFA H20 The compound of Example 98 (600 mg) was dissolved in water / acetonitrile (1: 1), and lithium hydroxide (100 mg) was added. The reaction mixture was stirred at 25 ° C and detected by HPLC. After the hydrolysis is complete (1-2 hours), trifluoroacetic acid is added until pH = 2. The product was purified by reversed phase chromatography (water / acetonitrile) to yield 470 mg of a white solid. MS and 1H-NMR are consistent with the structures shown. Example 1 0 0 · /?-[[2-[[[[[[[[[4,5-Dihydro4azol-2-yl) amino] phenyl] carbonyl] amino] ethanyl] huayl] Preparation of pyridine-3-propionate and trifluoroacetate

N \ S 、 HN ο ^-< Please read the notes on the back before making this page \) Order 〇Economy. Printed by Deng Central Standard Bureau Staff Consumer Cooperative Ό " TFA Step A 3-Jingji Benzyl Cool Of Glycerine 'Acid ·

187-

This paper size applies to Chinese National Standard (CNS) A4 specification (21〇x ^ 7ST 458 956 A7 B7 V. Description of the invention (185)

> 'CO2H Staff of the Central Standards Bureau of the Ministry of Economic Affairs

Glycine (20 g, 266 mmol) was added to water (200 ml), then potassium hydroxide (20 g, 3 57 mmol) was added, and it was cooled to 0 in an ice bath.匸 9 Dropwise in this solution over 10 minutes. Add 3-nitrobenzylhydrazine (Aldrich). (20 g, 108 mmol) falling in acetonitrile (20 mmol) . After the reaction was completed (3-4 hours), concentrated hydrochloric acid was added until pΗ = 1, and then a saturated aqueous NaC1 solution (75 ml) was added. The product was filtered, washed with water, and air-dried (22 g, 90 ° /. Yield) "1H-NMR (d6-DMSO) β, 3.92 (d, 2H, J = 6.1), 7.9 (t, 1H, J = 7.9), 8.3 (t, 1H, J = 5.6), 8.35 (m, 2H), 8.69 (s, 1H), 9.25 (t, 1H, J = 7.2 Hz) .MS (FAB) m / e 231.0 (M + Li +) 〇c9h8n2o5 elemental analysis calculation 値: C, 45.89; H, 4.25; N, 9.92 Measured 値: C, 45.97; H, 4.44; N, 10.11 Step 骒 B. Nitropolymethylglycine (4 g) was dissolved in ethanol (60 ml) in a Parr bottle. Carbon / carbon 5% (500 ml) was added, and the mixture was hydrogenated in a Parr unit at 50 psi for 5 hours. After the reaction was completed, the palladium catalyst was removed by filtration through a celite plug. The solvent is removed under reduced pressure, and the sample is dried in the air. ”Step C -188 * The paper scale is applicable to the Chinese National Standard (CNS) A4 (210X297 mm). F Please read the precautions on the back before you go to this page. > • Packing. -1. Order _ 4 I f 4 58 9 56 A7 _____B7. V. Description of the invention (186) ^ Acetonitrile (5 ml) was added to the crude aniline in step B, then 2-(methylthio) was added. -2-thiazoline (7 g), heated to reflux for 6 hours. The solvent was removed under reduced pressure to obtain a solid. Diethyl ether was added and the solid was filtered to obtain a yellow-brown solid (4.6 g). Step D'N, N Carbonate, Disuccinimidylimide (DSC) (1.4 g, 0.5 mmol) Add 2- (methylthio) -2-pyrimazole '(1.0 g, 0.5 mmol) ) In anhydrous dimethylformamide (20 ml), then add dimethylaminopyridine (100 ml). 3 After 1 hour, 0 ethyl-.3-amino-3- (3-pyridyl) Ethyl propionate (1.2 g, 0.5 mmol) was added in DMF / NMM (1: 1) (5.0 ml) in one portion. The product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (520 g). M S and 1 H-NMR are consistent with the structures shown. Example 10-10,000-[[2-[[[[[[[3-[(4,5-Dihydrothiazol-2-yl) amino] phenyl] carbonyl] amino] ethynyl] amine]] -3 -Preparation of propionic acid and trifluoroacid I ------------ pack-(please read the precautions on the back first before t this page): Negotiate the staff consumption of the Central Standards Bureau of the Ministry of Economic Affairs Cooperation-it print

The compound of Example 100 (600 mg) was dissolved in water / acetonitrile (1: 1), and then lithium hydroxide (100 mg) was added. The reaction mixture was stirred at 25 ° C. The Chinese national standard was applied at 189-private paper scale ( CNS) A4 specification (210X 297 mm 458956 A7 B7 V. Description of the invention, 187 HPLC detection. After the hydrolysis is completed (1-2 hours), trifluoroacetic acid is added until pH = 2. The product is subjected to reverse phase chromatography (water / Acetonitrile), resulting in wo mg of a white solid. MS and 1 H-KMR are consistent with the structure shown. Example 10 2N-[[2-[[[3-[[[(Benzyl I) amino]] carbonyl ] Amine] Amidino] carbonyl] Amine] Ethylamido] Amine]-/?-Alanine: Ethyl Acetate Preparation

C〇2Et ^-... '(Please read the precautions on the back before ^-, ~ this page) Central Standards of the Ministry of Economic Affairs DL printed by employees' cooperatives DL- (3-nitrobenzylglycol glycine) Ethyl) -3-aminoamino-ethyl propionate (2 g, 0.62 mmol) (Example 100, step A) was added to absolute ethanol (60 ml) in a Parr bottle. Palladium / carbon 5% (500 ml) was added and the mixture was hydrogenated in a Parr unit at 50 psi for 5 hours. After the reaction was completed, the palladium catalyst was removed by filtration through a celite plug. The solvent was removed under reduced pressure, and the sample was dried in the air. Acetonitrile (5 liters) was added to the crude benzylamine, and then to phenylisocyanate (700 mg, 0.75 'millimoles). The solution formed a solid. Diethyl ether was added to the solid and filtered to obtain a benzyl ester as a salmon flesh-colored solid ('2.6 g, 99% yield). The product (1 g portion) was purified by reverse phase chromatography (water / acetonitrile) to obtain a white solid: iH-NMR (d6-DMSO) d 1.17 (t, 3H, J = 7.3 Hz), 2.48 (t, 2H, 1 = 7.1 Hz), 3.45 (q, 2H, 1 ^ 6.8 Hz, J2 = 13.2 Hz), 3.80 (d, 2H, J = 6.9 Hz), 4.06 (q, 2H,) ^ 7.5 Hz, J2 = 13.4 Hz ), 4.31 (d, 2H, J = 7.5 Hz), 7.2-7.4 (m, 5H), 7.8 (t, 1H, -190- Private paper sizes are applicable to China National Standard (CNS) A4 specifications (2 丨 Ox297 mm ) Order: I-Code · 188 188 Α7 Β7 58 9 56 V. Description of the invention (J = 8.0 Hz), 7.85 (bs, 1H), 8.1 (t, 1H, 3 = 5.6 Hz), 8.35 (m, 2H) , 8.71 (S? IH), 8.78 (bs, 1H), 9.22 (bs, 1H) »MS (FAB) m / e 427.3 (M + H +). Elemental analysis. · C22H26N405 1.5 H20 Calculation 値: C, 58.28 Η , 5.74 N, 12.36 Measured 値 ·· C, 58.48 H, 5.57 N, 12.25 ^ · Example 1 0 3 3 · [[2-[[[[[(Benzyl) amino] carbonyl] amine] amine []] Phenyl] carbonyl] amino] ethanyl] amino] -propionic acid ------------ ^-(please read the precautions of the ancestor first, then # -4 this page )

Co2h was prepared in Example 102; the ft compound (400 mg, 0.094 mmol) was dissolved in water / acetonitrile (1.1), and then the hydrogen peroxide (100 mg, 0.4 mmol) was added. The reaction mixture was stirred at 25 ° C and detected by HPLC. After the hydrolysis is complete (1_2-hours), trifluoroacetic acid is added until pH = 2. The product was purified by reverse phase chromatography (water & acetonitrile) to yield 265 mg of a white solid: 1 H-NMR (d6-DMSO) 忒 2.48 (t5 2H, J = 7.1 Hz), 3.45 (q, 2H, 1 ^ 6.8 Hz, J2 = 13.2 Hz), »3.80 (d, 2H, J = 6.9 Hz), 4.31 (d, 2H, J = 7.5 Hz), 7.2-7.4 (m, 5H), 7.8 (t, 1H, J = 8.0 Hz), 7.85 (bs, 1H), 8.1 (t, 1H, 1-5.6 Hz), 8.35 (m, 2H), 8.71 (s, 1H), 8.78 (bs, 1H), 9.22 (bs, 1H) -191-Private paper 'size applies to China National Standards (CNS) A4 (210X297 mm) > k · Printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 458356 Α7 Β7 5. Description of the invention () MS (FAB) m / e 405.6 (M + Li +). Elemental analysis C20H22N4Q5 0.5 H20 Calculated 値: C, 59.00 H, 5.39 N, 13.75 Measured 値: .C, 59.29 H, 5.11 N, 13.63 Example 104-[[2-[[(3-nitrophenyl) carbonyl] amine Preparation of ethyl] ethenyl] amino] pyridine propionate (please read the precautions on the back before ^^ this page) Pack. Ο

1T Λ According to the same procedure used in the preparation of Example C, but substituted with the same amount of D L-3-aminoamino-3-propionyl ethyl propionate. Dot-alanine ethyl ester hydrochloride. N, N1-bissuccinimide imide (14 g, 5.5 mmol) added 3-nitro-benzylidene glycine (10 g '4.5 mmol) to anhydrous dimethyl amidine Amidine- (30 ml), then diamidopyridine (200 ml) was added. After 1 hour, DL-3 -amino-3- (3-p-pyridyl) propionic acid ethyl g-dihydrochloride (13 g, 4.6 mmol) was at 20 ° /. Aqueous potassium carbonate (50 ml) was added in one portion. 'After the reaction was completed, the product was collected in a transition (11.5 g, 80%). μS and 1 H-NMR are consistent with the structures shown. Example \ 〇5-192 This paper size adopts Chinese national standard (CNS M4 specification (2 丨 0X29? Mm) > Printed by the Consumers ’Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Ⅴ.5 Description of the invention () Α7 Β7_ /?-[[2-[[[[[(Benzyl) amino] carbonyl] amino] phenyl] quinyl] amino] acetamidine] amino] pyridine-3-propionic acid Preparation of ethyl ester and trifluoroacetate

， C02Et Printed Example 104 of DL- (3-Nitrobenzylglycinylpyridinyl) -3 -Phenylamino l 3 · Pyridinylpropionate (2 g, 0.62 mmol) into absolute ethanol (60 ml) in a Parr bottle. Palladium / carbon 5% (500 ml) was added and the mixture was argonized at 50 psi in a Parr apparatus for 1.5 hours. After the reaction was completed, the palladium catalyst 4 was removed by filtration through a celite plug. The solvent was removed under reduced pressure, and the sample was dried in the air. Acetonitrile (5 ml) was added to the crude aniline, and then to benzyl isocyanate (700 mg '0.75 mmol). It was dissolved to form a solid β-diethyl ether, and the product was filtered. The product was purified by reverse phase chromatography (water / acetonitrile) to obtain a white solid (1.5 g). MS and 1 H-NMR are consistent with the structures shown. Example 106 '(±) /?-[[2-[[[3-[[[(Benzyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ethyldonyl] amino ] 说 Jun-3-Preparation of propionic acid

Ν Η

193 This paper size is in accordance with Chinese National Standard (CNS) A4 specification (2ι297 × 297 mm) ----------- Packing-- (Please read the precautions on the back before this page) Order A7 B7 191 V. Description of the invention (The compound of Example 105 (400 mg, 0.0094 mmol) was dissolved in water / acetonitrile U: 1), and then lithium hydroxide (100 mg, 0.4 mmol) was added. The reaction mixture was stirred at 25T. After the hydrolysis was completed (1.2 hours), difluoroacetic acid was added until ρΗ = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (200 mg). MSilH_NMR is consistent with the structure shown. · Example 10 7 point-[[2-[[[3-[[[(aniline) carbonyl] amino] benzyl] carbonyl] amino] ethylfluorenyl] amino] 11-Hyoden-3- C. Ethyl Acetate Production & (Please read the precautions on the back before #text page)-Pack ·

C02Et Ding-I. DL- (j-Chrysyl benzylglycine to prepare amine-3- (3-0 specific bite) ethyl propionate (2 g, 0.64 mmol) add absolute ethanol ( 6'0 ml), in

Parr bottle. Palladium / carbon 5. /. (500 ml) was added and the mixture was stirred at 50 pSi at

Hydrogenated in a Parr apparatus for 1.5 hours. After the reaction was completed, the fine catalyst was removed by filtration through a celite plug. The solvent was removed under reduced pressure, and the sample was dried in the air ^ ». Acetonitrile (5 ml) was added to the crude aniline and then to benzyl isophthalate (600 mg, 0.75 mmol). The solution formed a solid. Diethyl ether was added and the product was passed through. The product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (1.1 g). MS and 1 H-NMR are consistent with the structures shown. -194- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297mm). Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 4 5-9 q V. Description of the invention (192 A7 B7

co2h Example 1 0 8 (±) y5-[[2 _ [[[[[[(Anilino) carbonyl] amino] phenyl] carbonyl] amino] ethynylamino] pyridine-3-propane Acid, trifluoroacetic acid

Example of Ph-HN, the compound of 107 (500 mg, p: 095 mmol) was dissolved in water / acetonitrile (1: υ, then lithium hydroxide '(100 mg, 0.4 mmol) 》 The reaction mixture was stirred at 25. (: Stirred and detected by HPLC. After the completion of the hydrolysis (1-2 hours), trifluoroacetic acid was added until ρΗ = 2. The product was purified by reverse phase chromatography (water / acetone) to produce White solid (350 mg). MS and 1 H-NMR are consistent with the structure shown. '' 'Example 10.09-[[2-[[[3- (Aminecarbonylamino) phenyl] carbonyl] amine [Ethyl] ethylenyl] amino] pyridine-3-propanoic acid ethyl ester 'trifluoroacetate (please read the precautions on the back before filling in V? Page). Printed by Employee Consumer Cooperative

-195 This paper size is in accordance with Chinese National Standard (CNS) M specifications (2 [0X297 mm) 458 956 A7 ___B7 ______ V. Description of the invention (193) DL- (3-nitrobenzylidene glycamine) Ethyl-3-methylamino-3- (3-pyridyl) propionate (2 g, 0.62 mmol) was added to absolute ethanol (60 ml) in a Parr bottle. 5% carbon (500 ml) was added, and the mixture was hydrogenated in a Parr device at 50 psi for 1-5 hours. After completion, the fine catalyst was removed by filtration through a celite plug. The solvent was removed under reduced pressure and the sample was dried in the air. Hydrochloric acid (20%, 75 ml) • Add to the crude aniline, and then to the vein (2 g). The solution was heated to reflux for 15 'hours. After the reaction was completed (15 hours), the product was purified by reverse phase chromatography (water / .acetonitrile) and freeze-dried to obtain a white solid (1_2 g of PMS and 1 及 -NMR consistent with the structure shown. Example 1 1 0 A- [[2-[[[3- (Aminocarbonylaminofluorene) phenyl] carbonyl] amino] ethyl] ethylfluorenyl] amino] pyridine-3-propionic acid, preparation of trifluoroacetate ------- --- ^-(Please read the precautions on the back before 4 ··-this page) -s

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The compound of Example 109 (500 mg j 0.095 mmol) was dissolved in water / ethoxyl (1: 1), and lithium hydroxide (100 mg, 0.4 mmol) was added. ). Reaction; the kun compound was incubated at 25 ° C 'and measured by HPLC. After the hydrolysis was completed (12 hours), 'trifluoroacetic acid was added until pH = 2. The product was purified by reverse phase chromatography (water / acetonitrile) and freeze-dried 'to give a white solid (350 mg). Ms & 1h NMR is consistent with the structure shown. __ -196 'This paper is oriented towards the homepage of the paper glU Home Network L (CNS) A4 Brain (21 () χ297mm) ~~ -----458956- A7 -------- B7 .I 1 5 Explanation of the invention (194)-Example 1 1 1 々 _ [[2 '[[[[3 · [[[[((4 · methylphenyl) sulfonyl) amino] carbonyl] amino] phenyl] carbonyl] ] Amino] Acetyl] Amino] Pyridin-3-propionate, Preparation of trifluoroacetate ·

{Please read the precautions on the back before you read Torimoto I)

k D L- (3-Nitrobenzylideneglycinamido) _3 _amidoamino_ 3 3 _pyridyl) ethyl propylene (2 g, 0.64¾ mole) was added absolute ethanol (60 ml ), In the Parr bottle. Palladium / carbon 5% (500 ml) was added and the mixture was hydrogenated in a Parr apparatus at 50 psi for 1.5 hours. After the reaction was completed, the palladium catalyst was removed by celite plugging. The solvent was removed under reduced pressure and the sample was dried in the air. Ethyl (5 ml) was added to the crude leather amine ', and then p-toluene isocyanate, .methyl ester (600 mg, 0,75 mmol) was added. The solution formed a solid. Diethyl hydrazone was added and the product was over; The product was purified by reverse phase chromatography (water / ethoxy) and dried on ice to obtain a solid (1.1 g). MS and 1 H-NMR were consistent with the structures shown. Example 1 1 2 Lu-[[2-[[ί3-ί [[[(4 · methylphenyl) sulfonyl] amino] carbonyl] amino]]] -197-This paper size applies to Chinese National Standards (CNS ) A4 specification (210 X 297¾%), va 'is. · Member of the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperative Printing 458356 A7 _____ __ B7 ·. -1QC " ---- V. Description of the invention ()-H3 c Benzyl] Tibetan group] Amino group] Ethyl group] Ethyl group] Aminopyridine-3-propionic acid, three gas furnace acid preparation. Β 瓜

Η C batch of clothes-< Please read the notes on the back before 垆 f this page} Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

The compound of Example 111 (500 mg, 0.095 mmol) was dissolved in Lyme / Ethanol (1: 1), and then lithium hydroxide (100 mg, 0.4 mmol) was added. The reaction mixture was stirred at 25 ° C and detected by HPLC. After the hydrolysis is complete (1_2 hours), 'trifluoroacetic acid is added until p Η = 2 ·. The product was purified by reversed phase chromatography (water / Ethanol) and freeze-dried to give a white solid (350 mg) a MS & iH_NM R was consistent with the structure. Example 1 13 ′-[[2-[[[[[[Aminothiomethyl) amino] phenyl] carbonyl] amino] acetamidine.'yl] amino] pyridine-3-propionic acid Preparation of ethyl ester and trifluoroacetate

irV Ο -198- This paper size is applicable to Chinese National Standard (CNS) A4 specification (2 丨 OX 297 mm) 5. Description of the invention (196 A7 B7. DL- (3.-Nitrobenzylglycol glycinyl) ) -3 -Amido-3-(3-pyridyl) ethyl propionate (2 g, 0.64 mmol) was added to absolute ethanol (60 ml),-in a Parr bottle. Palladium / carbon 5% ( 500 ml) was added, and the mixture was hydrogenated in a Parr apparatus at 50 psi for 1.5 hours. After the reaction was completed, the palladium catalyst was removed by filtration through a celite plug. The solvent was removed under reduced pressure, and the sample was dried in the air. Acetonitrile ( 5 ml) was added to crude aniline, followed by benzoic acid isothiocyanate (600 mg, 0.75 mmol). After the reaction was completed, the solvent was removed under reduced pressure. To the resulting oil was added Methanol (50 ml), then K2C0.3 (2 g) was added, and the reaction mixture was stirred until the hydrolysis was completed. The product was purified by reverse phase chromatography (water / acetonitrile), and freeze-dried to obtain white 'color solid tincture (980 mg ). MS and 1H-NMR are consistent with the structure shown. Example 1 140,000-[[2-[[[3-[(Aminothiomethyl) amino] phenyl] carbonyl] amine ] Ethylamino] Amine] I »Bizhen-3-propionic acid, the preparation of trifluoroacetate I ---------, ^! (Please read the precautions on the back before filling ¾ .. (Ear ears) ** τ, 1 Λ Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

co2h The compound of Example 113 (500 mg '0.095 mmol) was dissolved in water / acetonitrile (1: 1) and then lithium hydroxide (.100 mg, 0.4 mmol) was added. The reaction mixture was stirred at 25 ° C and detected by HPLC. After the hydrolysis is complete (1 _ 2 ′ · !, h), trifluoroacetic acid is added until p Η = 2. The product was subjected to reversed phase chromatography (water / B 199 private paper standard applicable Chinese National Standard (CNS) a4 size (21ΐ) × 297 mm) ---- M. Α7 Β7 ^ 5 R 9 56 197 V. Description of the invention () Nitrile), purified and freeze-dried 'to give a white solid (350 mg). M S and 1 H-NMR are consistent with the structures shown. ‘Example 1 1 5 DL- (3 -Supranylbenzylglycine-glycine-glycine-phenylpropanoic acid ^ (Preparation of vinegar. 〇

Ministry of Economic Affairs, Central Bureau of Standards, Consumer Cooperatives, printed slow acid N, N_-two-breaker brewing. Amino-based brewing (14 g '5.5 mmol) with 3-nitro-benzylidene glycine (10 g , 4.5 millimolar) in anhydrous dimethylaminomethylamine (30 ml), and then into dimethylaminomethyl bite (200 ml). After 1 hour, DL-3 -amino-3-phenylpropionic acid ethyl chloride hydrochloride (12 g, 4.6 mmol) was added in 20% potassium carbonate aqueous solution (50 ml) in one portion. After completion of the reaction, the product was collected by filtration (12 g, 87% yield). M S and 1 H-NMR are consistent with the structures shown. -Example U 16 * Preparation of β-[[2-[[[[[[Aminothiomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] _ethyl propionate -200-This paper size applies Chinese National Standard (CNS) Α4 specification (210 X 297 public epidemic)

198 V. Description of Invention (

The compound of Co2Et Example 115 (2 g, 0.64 mmol) was added to absolute ethanol (60 mL) in a Parr bottle. Add 5% carbon (500 ml), and the mixture was hydrogenated in a Parr apparatus at 50 psi for 1.5 hours. After the reaction was completed, the palladium catalyst was removed by filtration through a celite plug. The solvent was removed under reduced pressure, and the sample was dried in the air. Acetonitrile (5 ml) was added to the crude aniline and then to benzyl isothiocyanate (600 mg '0.75 mmol). After the reaction was completed, the solvent was removed under reduced pressure. To this oil was added methanol (50 ml), followed by K2CO3 (2 g), and the reaction mixture was stirred until the hydrolysis was complete. The product was purified by reverse phase chromatography (water / acetonitrile) and freeze-dried to obtain a white solid (980 mg). M S and 1 H-NMR are consistent with the structures shown. Example 1 1 7 [Preparation of [(aminothiomethyl) amino] benzyl] zoyl] amino] ethoxy] amino] phenylpropionic acid, I ^-(please read the first Note 4¾ .. This page) Order m Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

co2h The compound of Example 116 (500 mg, 0.095 mmol) was dissolved in water / acetic acid (1: 1), and lithium hydroxide (100 mg, 0.4 mmol) was added. -201-This paper size is in accordance with Chinese National Standard (CNS) A4 (2I0X297). A7 B7 5. Description of the Invention (199) ”The mixture should be stirred at 25 ° C and detected by HPLC. After the hydrolysis is complete (1_2 hours), 'trifluoroacetic acid is added until p Η = 2. The product was purified by reverse phase analysis (water / acetonitrile) and freeze-dried to give a white solid (350 mg). M s and I Η NMR are consistent with the structures shown. Example 1 1 8/5 _ [[2-[[[[[[(Benzyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ethoxy] amino] phenylpropanoic acid .Preparation of ethyl ester

、 C02Et (Please read the precautions of the arm surface and then fill in this page)-Packing. Order printed by DL- (3-Benzyl-Phenyl-L-Glycine)- 3-Ethylamino-3-ethylbenzylpropionate (2 g, 0.62 mmol) was added to absolute ethanol (60 ml) and placed in a parr bottle. Fine / carbon 5% (500 ml) was added to the mixture and hydrogenated in a parr apparatus at 50 psf for 1.5 hours. After the reaction was completed, the palladium catalyst was plugged and removed by celhe. The cereal was removed under reduced pressure and the sample was dried in the air. Acetonitrile (5 ml) was added to the crude benzylamine and then added to benzyl isocyanate (mg, 0.75 mmol) to form a solid. Diethyl ether avoids the transition by adding solids. The product was purified by reverse phase chromatography (water / acetonitrile) and freeze-dried to obtain a white solid (1.5 g). MS and 1'-NMR are consistent with the structure shown. Example 1 1 9 -202- The paper size is in accordance with the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) 4 A7 B7 V. Description of the invention (200) I Point-[[2-[[[3- [ Preparation of [[(Benzyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ethanyl] amino] phenylpropionic acid

CO ^ H Example 1 18 Compound (400 mg, 0.094 mmol), dissolved in water / acetonitrile (1: 1), and then lithium hydride (100 mg, 0.4 mmol) was added at 25 ° C was stirred and detected by HPLC. After the hydrolysis was completed (1-2 hours), trifluoroacetic acid was added until p H = 2. The product was purified by reverse phase chromatography (water / acetonitrile) and freeze-dried to give a white solid (200 .Mg). MS and 1 H-NMR are consistent with the structure shown. '., Example 1 2 0' θ-[[2, [[((3-Nitrophenyl) carbonyl] amino] ethylfluorenyl] amine Based] -pyrene, 3-benzobenzopyrene-5-propionic acid vinegar (please read the precautions on the back before #free page). Binding. _J. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

-203- This paper uses China National Standard (CNS) A4 (2 丨 〇297297 mm) C; 1 A7 B7 M 201 5. Description of the invention () N, N'-bissuccinimide carbonate Esters (I4 g, 5-5 mmol) were added 3-nitro-benzylidene glycine (10 g, 4.5 mmol) to anhydrous dimethylformamide (30 ml) +, then Methylamine-pyridine (200 ml). After 1 hour, DL-3-amino.-3-piperinal ethyl propionate (7 g, 4.6 mmol) was dissolved in 20% aqueous carbonic acid solution (50 ml). Join as Fen. After the reaction was completed, the product was collected by filtration (14 g, 97% yield, yield). MS and 1 H-NMR are consistent with the structure shown. Example 1 2 1 /?-[[2-[[[3-[[[(Benzenyl) amino 1carbonyl] amino] phenyl] carbonyl] amine [Base] Ethyl]] amino] -1,3 -Benzylidenepyridino-5-propanoic acid ethyl g Preparation I f-- (Read the precautions on the back before reading this page)

Bn > HNL 乂 0

ΓΓΤΝ 0

C02Et

, 1T Member of the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperation. The compound of Example 120 (2 g, 0-62 mmol) was added to absolute ethanol (60 mmol) in a Parr bottle. 5% (500 ml) was added and the mixture was hydrogenated in a Parr unit at 50 psi for 1.5 hours. After the reaction was completed, the red catalyst was removed by filtration through a celite plug. The solvent was removed under reduced pressure, and the sample was dried in the air. Acetonitrile (5 ml) was added to the crude aniline, and then to anisole isocyanate (700 mg, 0.75 mmol). The solution formed a solid. Diethyl ether was added and the product was filtered. The product was purified by reversed-phase chromatography (water / acetonitrile), iced; Donggan 204- Private paper size General Chinese National Standard (CNS) A4 grid (210X297 mm)

202 V. Description of the invention (Dry, a white solid (1.5 g) was obtained. MS and 1 H-NMR are consistent with the structure shown. Example 1 2 2, Point _ [[2 _ [[[3-[[[(benzene Fluorenyl) amino] carbonyl] amino] phenyl] carbonyl] amino] hexyl] amino] -1,3-phenylhydrazinedioxopropanoic acid

co2h (Please read the notes on the back first, then this page)

ΓΤ Μ Ministry of Economic Affairs_Central Bureau of Prospective Workers Consumer Cooperative printed a case of a compound of 121 (400 mg, 0 094 mmol) dissolved in water / acetonitrile (1.1), and then added lithium hydroxide 'lithium (mg , 〇4mmol). The reaction mixture was stirred at 25X and detected by HPLC. After the hydrolysis is complete (1_2 hours), difluoroacetic acid is added until P H = 2. The product was purified by reverse phase chromatography (water / ethylazine) 'and lyophilized to give a white solid (200 mg). S and! Η · NMR is consistent with the structure shown. Example 1 2 3 A-[[2-[[[3-3-[[(Anilino) carbonyl] amino] phenyl] carbonyl] amino] ethylammonium] amino] -1,3-phenylhydrazone Preparation of dioxo_5 -ethyl propionate-205, the paper size is in accordance with the national standard (CNS) A4 specification (2Ι0 × 2? 7 mm) of the paper. 1T suspect I -I. 458956 A7 B7 V. Description of the invention ( 203

Η

Printed DL- (3-Nitrobenzylmethylglycinyl) -3 -donkey · amino-3-hexahydroρ-pyridine ethyl propionate ( 2 g, 0.62 mmol.) Add absolute ethanol (60 ml), in a parr bottle. Palladium / carbon 5% (500 ml) was added, and the mixture was argonized at 50 psi in a Parr apparatus for 1.5 hours. After the reaction was completed, the 'red catalyst' was removed by filtration through a celite plug. The solvent was removed under reduced pressure and the sample was dried in the air. Acetonitrile (5 ml) was added to the crude aniline, followed by benzoic isocyanate (700 mg, 0.75 mmol). The solution formed a solid. Diethyl ether was added and the product was filtered. The product was purified by reverse-phase chromatography (water / acetonitrile) and freeze-dried to obtain a white solid (1.5 g). MS and 1 H-NMR are consistent with the structure shown β-Example. 124 々 _ [[2-[[[3 · 3-[[(Anilino) thiol] amino] phenyl] carbonyl] amino] ethyl Alkyl group] Amine group] -1,3-Benzamidine dioxo-5 -propionic acid Preparation 206 Spring paper wave scale Applicable to Chinese National Standard (CNS) A4 specification (2ί〇 × 297 mm) '(Please read first Note on the back again ^-gas page) 158956 A7 B7

5. Description of the invention (204 rv- The compound of Example 123 (400 mg, 0.094 mmol) was dissolved in water / acetonitrile (1: 1), and then lithium hydroxide (100 mg, 0.4 mmol) was added. Reaction The mixture was stirred at 25eC and detected by HPLC. After the completion of the hydrolysis (1_2 hours), trifluoroacetic acid was added until p Η = 2. The ash was purified by reverse phase chromatography (water / acetonitrile), and freeze-dried to give a white solid ( 200 mg). MS and ΐΗ-NMR are consistent with the structure shown. Example 1 2 6 β · [[2 · [[[3-[[[[((4- (Aminopyridyl) benzyl) benzyl] amino] ] Carbonyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3-propionic acid, the preparation of trifluoroacetate ------------ load! F please first Read the notes on the back and reinvest this page ¾) • Order-Step. Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

-one

, C =: o \ NH

cno

TFA

-207- Thai paper size is applicable to China Gujia Standard (CNS) A4 specification (210 × 297 mm) 4 58 9 56 A7 __ B7 V. Description of the invention (2Q5)

Printed by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs on 4_ (Aminomethyl) -Tolusulfonamide Hydrochloride Hydrate (Aldrich) (6g) Add phenyl isocyanate 3-ethoxycarbonyl ester to acetonitrile (Lancaster) (5 g) and triethylamine (5 ml). The reaction mixture was stirred for 1 hour. The solvent was removed under reduced pressure to obtain a solid. Water was added and the solids were filtered (10.2 g). M S and 1 H-NMR are consistent with the structures shown. Step B. The compound of Step A (10 g) was dissolved in water / acetonitrile (1: 1), and then lithium hydroxide (4 g) was added. The reaction mixture was stirred at 25 ° C and detected by HPLC. After the hydrolysis is complete (4-6 hours), 10% aqueous HC1 solution is used until pH = 2. The product was purified by filtration to obtain a white solid (7 g). M S and I H-NMR are consistent with the structure shown *

Step C N, N'-bissuccinimide carbonate (DSC) (1.4 g, 0.5 mmol) carboxylic acid-urea and benzyl 4- (aminomethyl) benzenesulfonamide 3. Ethoxycarbonyl isocyanate (1 g, 0.5 mmol) [see Figure V (A 13)] in anhydrous dimethylamidamine (20 ml), then dimethylaminopyridine ( 100 ml After 1 hour, the compound of Step 1 (2.2 g, 0.5 mmol) from Example 1 was added in DMF / NMM (1: 1) (5.0 ml) in one portion. After the reaction was completed, the product was added in one portion. Purification by reverse phase chromatography (water / acetonitrile), lyophilization yielded a white solid (1.2 g). MS and 1 H-NMR were consistent with the structure shown.

Step 骒 D The compound from Step C (600 mg) was dissolved in water / acetonitrile (1 ·· I), and then lithium hydroxide (100 mg) was added. The reaction mixture is stirred at 2 5 X: -208- This paper size applies the Chinese National Standard (CNS) A4 specification (2I0X297 mm) (Please read the precautions on the back and fill in this page) " · * D. 458956 A7 B7 V. Description of the invention (206)) HPLC detection. After the hydrolysis was completed (2 hours), trifluoroacetic acid was added until pH = 2 = the product was purified by reverse phase chromatography (water / acetonitrile), and freeze-dried to give 500 mg of a white solid. ： MS and 1 H-NMR are consistent with the structure shown. ”Example 1 2 7 々-[[2-[[[3-[[[((3-Pyridinylfluorenyl) amino] carbonyl] carbonyl] amine [Phenyl] carbonyl] amino] ethyl] ethyl] amino] ρ than this 3-propionic acid 'bis (trifluoroacetic acid) salt,

2TFA

(#Xianmin read the notes on the back and then fill in W. this page)-Binding-Bookmarking Printing Step A__ 3_ _ Ebexamine (Aldrich) (6g) in the Central Standards Bureau of the Ministry of Economic Affairs To acetonitrile was added benzyl isogasic acid 3 · ethoxyzan · yl ester (Lacaster) ($ g) and triethylamine (5ml). The reaction mixture was stirred for 1 hour. The solvent was removed under reduced pressure to obtain a solid. Add 7k and filter the solids (12g). MSA 1 H-NMR and the structure shown-the compound of step B and step A (10 g) was dissolved in water / acetonitrile (1: 1), and then 209- the paper scale was applied to Chinese national standards (CNS > A4 ^ Grid (210x297). Add 45B y A7 ______B7_ 5. Description of the invention (2Q7) Lithium hydroxide (4 g) is added. The reaction mixture is stirred at 25 ° C and detected by HPLC. After the hydrolysis is completed (4-6 hours) ), 10% HC1 aqueous solution was added until pH = 2. The product was purified by filtration to obtain a white solid (5.6 g). MS and 1 H-NMR were consistent with the structure shown.

Step C: N, N carbonate, disuccinimidylimide (DSC) (1.4 g, 0.5 mmol), add 3-pyridylamine carboxylic acid-urea (Aidrieh) and phenyl isocyanate 3-ethoxy Carbonyl ester (1 g '0.5 mmol) [see Figure v (A 1 3)] in anhydrous dimethylformamide (20 ml), and then add diamidopyridine (100 ml). After 1 hour, the compound of Example 1 Step C (2.2 g, 0,5 mmol) was added in one portion to DMF / NMM (1 -1) (5,0 ml). After the reaction was completed, the product was purified by reverse phase chromatography (water / acetonitrile) and freeze-dried to give a white solid (L1 g). MS and 1 H-NMR are consistent with the structures shown. Step 0 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The compound in step C (500 mg) was dissolved in water / ethyl wax (1: 丨), and then lithium hydroxide (100 mg) * was added to the reaction mixture at 25. 〇 Stir and measure by HPLC. After the hydrolysis is complete (1-2 hours), trifluoroacid is added until p Η = 2. The product was purified by reverse phase chromatography (water / acetonitrile) and freeze-dried to give 430 mg of a white solid. MS and 1 H-NMR are consistent with the structures shown. Example 1 2 9 々-[[2-[[[3-[[[(2-carboxyethyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ethylammonium] amino] pyridine- Preparation of 3-propionic acid and trifluoroacetate __- 210- Liyang) People 4 specifications (210 '乂 297) ...' > 9 56 A7 B: 7 'V. Description of the invention (2Q8

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Step A The compound of Example 104 (1.5 g) was added to ethanol (60 ml) in a bottle. Carbon / palladium 5% (500 ml) was added and the mixture was hydrogenated in Parr I at 50 psi for 1.5 hours. The palladium catalyst was removed by filtration through a cdite plug. The solvent was removed under reduced pressure and the sample was dried in the air. Step B: Acetonitrile (5¾ liters) was added to the crude aniline 'of Step A, and then added to ethyl isocyanopropionate (AldriCh) (800 mg), followed by stirring for 1 hour. The solvent was removed under reduced pressure to obtain a solid. Diacetic acid was added, and the solid was filtered to obtain a tan solid. The product was purified by reverse phase chromatography (water / acetonitrile) and freeze-dried to obtain 500 mg of a white solid. Ms and 丨: ^ 1 ^ 11 is consistent with the structure shown. Step C ′ The compound of Step B (500 mg) is dissolved in water / acetyl (1:!), And then lithium hydroxide (100 mg) is added. ) The reaction mixture was stirred at 2 μc and detected by HPLC. After hydrolysis and hydration (2 · 2 hours), trifluoroacetic acid was added until p Η = 2. The product was purified by reversed-phase chromatography (water / acetonitrile), and freeze-dried to produce -211-This paper is suitable for National Standard D (CNS) A4 specifications (2 丨 0X297 mm) 11 ^-(Please read first Note on the back, please fill in this page again.) Ping Ping _____B7 V. Description of the invention (209) 220 mg white solid. : MS and JH-NMR are consistent with the structure shown. -Example ΙθΟ Preparation of phenylethyl] amino] carbonyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3 · -propionic acid, trifluoroacetate

on% Η ™

Η ο \ cno Printing step A of the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Add the phenylethylamine cyanate (Aldrich) (6 g) to acetonitrile and add phenyl isocyanate 3 -ethoxycarbonyl ester (Lancaster ) (5 g) and triethylamine (5 ml). The reaction mixture was stirred for 1 hour. The solvent was removed under reduced pressure to obtain a ballast. Water was added and the solids were filtered (11 g). MS and 1 H-NMR are consistent with the indicated structure. *

Step B The compound of Step A (10 g) was dissolved in water / acetonitrile (1: 1), and then lithium hydroxide (4 g) was added. The reaction mixture was stirred at 25 ° C and detected by HPLC. After the hydrolysis is complete (4-6 hours), 10% aqueous HC1 solution is added until pH = 2. The product was purified by filtration to obtain 6 g of white solid) and W-NMR was consistent with the structure shown. -212 * The paper size of the table applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ^ 5c ;; 9 56. A7. _B7___ _ 210 V. Description of the invention () Step C 'Carbonate N, N_-bisamber 醯Iminodiester (DSCKI. 4 g, 0.5 mErr) Carboxylic acid-urea with phenylethylamine and 3-ethoxycarbonyl phenyl isocyanate (1 g '0-5 mmol) (See Figure V (A13)] in anhydrous dimethylamidamine (20 ml), and then add the diamidine group 51 specific bite (100 ml). After 1,] hours, the compound from Step 1 of Example 1 (2.2 g, 0-5 mmol) was added in DMF / NMM (1: 1) (5.0 ml) in one portion. After the reaction was completed, the product was purified by reverse phase layering (water / acetonitrile) and freeze-dried to give a white solid (1.0 g). MS and 1H-NMR are consistent with the structures shown.

Step D The compound of Step C (800 mg) was dissolved in jujube / acetonitrile (1: 1), and then lithium hydroxide (100 mg.) Was added. The reaction mixture was stirred at 2 5 T: detected by HPLC. After the hydrolysis was completed (1-2 hours), trifluoroacetic acid was added until p Η = 2. The product was purified by reversed phase chromatography (water / acetonitrile) and freeze-dried to yield 633 mg of white solid. OMS and 1H-NMR were consistent with the structure shown. Example 1 3 1 Cold-[[2 _ [[[3-[[ [(lS-methyl] amino] carbonyl] amino] benzyl] carbonyl] amino] ethylammonium] amino] pyridine-3 -propionate trifluoroacetate preparation -------- -^ — (Please read the notes on the back before filling in: €, this page) 1. r Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

-213- China National Standard (CNS) A4 specifications are applicable to each paper size (21〇 > < 297mm) V. Description of the invention (211 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Step A in 1- 荇Methylamine (Aldrich) (5 g) was added to acetonitrile 3-ethoxycarbonyl phenyl isocyanate (Lancaster) (5 g) and triethylamine (5 ml). The reaction mixture was stirred for 1 hour. Remove under pressure to obtain a solid. Water was added and the solid was filtered (9 g). MS and 1 H-NMR were consistent with the structure shown. Step B The compound of Step A (8 g) was dissolved in water / acetonitrile (1: I), then lithium hydroxide (3 g) was added. The reaction mixture was stirred at 25 ° C and detected by HPLC. After the hydrolysis was completed (4-6 hours), a 10% aqueous solution of HC1 was used until ph = 2. Purify by filtration to obtain a white solid (5.6 g). MS and 1 H-NMR are consistent with the structure shown. Step C 'Carbonate N, N'-No. 2 Perylene imine (DSC) (1.4 g, 0.5 mmol) Ear) Carboxylic acid-urea and phenyl isocyanate 3-ethoxycarbonyl vinegar (1-g '0.5 mmol) added to 1-amidamine [see Figure V (A13)] Dimethylformamide (20 mL) in water was then added to dimethylaminopyridine (100 mL). After 1 hour, the compound of Example C, Step C (2.2 g, 0.5 mmol) was added to DMF / NMM (1: 1) (5.0 ml) was added in one portion. After the reaction was completed, the product was purified by reverse phase chromatography (water / acetonitrile) and freeze-dried to give a white solid (1.0 g). MS and 1 H-NMR Consistent with the structure shown. Step 骒 D Step C compound (600 mg) was dissolved in water / acetonitrile ([: 1]), and then lithium hydroxide (100 mg) was added. The reaction mixture was stirred at 2VC and analyzed by HPLC. Detection. After the hydrolysis is completed (1.2 hours), trifluoroacetic acid is added until -214- Private paper size applies Chinese National Standard (CNS) A4 specifications (210 × 297 male thin) (Please read the precautions on the back before copying this Page). Order r 58 58 212 Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives, printed A7 B7 V. Description of the invention (p Η = 2 ^ The product was purified by reverse phase chromatography (.water / acetonitrile), freeze-dried to produce 410 mg of white solid. MS and 1 H-NMR are consistent with the structure shown. Example 1 2 2 Cold-[[2 · [[[3-[[( Imino) amino stupid Yue-yl] methyl; | suspected yl] amino] ethyl-ylamino brewing of brewing prepared stupid Yue benzenepropanoic acid amino] phenyl]]]

, Co2Bn In a stirring solution of the product of Example I (140 mg, 0.52 mM) in Digas (25 ml), triethylamine (0.5 ml) and DMAP (0.5 ml) were added at 0 ° C. 10 mg), EDC1 (95 mg) and exemplified compound (215 mg, 0.52 mM). The reaction mixture was at 0 ° C. 〇 Stir for 5 minutes to reach room temperature 'and then stir for another 16 hours. The reaction mixture was concentrated in the air to obtain an oily gum, which was dissolved in ethyl acetate, and the resulting solution was washed with water, saturated NaHC03 solution and water. The organic layer was separated, dried (4), and evaporated to obtain a crude product. Crude _ purified on chromatographic chromatography (eluent: ethyl acetate), excess solvent was removed to obtain the title compound (88 mg) as a clear oil. MS and NMR are consistent with the structure shown. Example 1 3 3 points _ [[>-[[[[[[[Cyanoimino) methyl · amino] methyl] amino] phenyl] carbonyl-215- This paper is applicable to China Standard (CNS) Α4 specification (2 [〇Χ297 公 疫) (Please read the precautions on the back before filling in this page)

458956 Α7 Β7 Ⅴ Description of the invention Preparation of (213) yl] amino] ethylfluorenyl] amino] phenylpropionate 0

p C〇2 Economy. Printed in a stirred solution of the product of Example J (90 mg, 0.41 mM) in methane (25 ml) by the Central Standards Bureau Shellfish Consumer Cooperative. Add triethyl at 0 ° C. Amine (0.5 ml), DMAP (10 mg), feDCI (95 mg) and the compound of Example V (2 m mg, 0.52 mM). The reaction mixture was stirred at 0 C for 15 minutes to reach Darwin, and then stirred for another 16 hours. The reaction mixture was concentrated in the air to obtain 4 g of an oily gum, which was dissolved in ethyl acetate. The resulting solution was washed with water, a saturated NaHC03 aqueous solution and then with water. The organic layer was separated, dried (Na2S04), and evaporated to obtain a crude product. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate), and the excess solvent was removed to obtain the title compound I: 80 mg) as a clear oil. NMR was consistent with the structure shown. Example 1 3 4 · Lu _ [[2-[[[3-[[(Cyanoimino (amino) methyl] amino] phenyl] carbonyl] amino] ethylammonium] amino] Preparation of benzyl phenylpropionate

Η

-216- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 X297 mm) (please read the notes on the back first and then fill in the original text)-binding-order 458956 A7 B7 214 Five 'invention description ( In a stirred solution of the product of Example K (212 mg, 1.0 mM) in methane (25 ml), triethylamine (0.5 ml), DMAP (10 mg), EDC1 (95 Mg) and the compound of Example V (215 mg, 0-52 mM). The reaction mixture was stirred at 0 ° C for 15 minutes to reach the kiln temperature, and then stirred for another 16 hours. The reaction mixture was concentrated in the air to obtain an oil. Gum 'which was dissolved in ethyl acetate. The resulting solution was washed with water, saturated NaHC03 aqueous solution and then with' water. The organic layer was separated, dried (Na2 s 0 4), and steamed to obtain the crude product. The crude product was obtained in silicon Purification by chromatography (eluent: ethyl acetate) 'Excess solvent was removed to obtain the title compound (285 mg) as a clear oil. NMR was consistent with the structure shown. Example 1 3 5 Cyanoimino) (ethyl Amino) fluorenyl] amino] phenyl] carbonyl] amino] ethanyl] amino] ethyl phenylpropionate (Please read the notes on the back before this page)

Η

-秌-Printed on the product of Example L (464.mg, 2.μm), DL-Lu-[(2-amino-boxyethyl) amino] phenyl, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Ethyl-3-propionate (728 milligrams, 2.0 mM) '[prepared according to Example 1 (steps B, C and D),' equivalent to DL-3 -amino-3- (3-phenyl ) Stirring of propionic acid substituted DL-3-amino-3- (3-pyridyl) propionic acid] 'triethylamine' (2.0 ml) and DMAP (20 mg) in digas methane (5 ml) -217- ί 458956 A7 B7 V. Description of the invention (215 solution, EDC1 (191 mg) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 15 minutes to reach room temperature, and then stirred for 16 hours. Reaction The mixture was concentrated in the air to obtain an oily gum, which was dissolved in ethyl acetate. The resulting solution was washed with water, saturated NaHC03 aqueous solution and water. The organic layer was separated, dried (Na2S04), and evaporated to obtain the crude product. The crude product was at C18 Purification by reverse phase HPLC on a column (eluent: 0.5% TFA-water / acetonitrile) to obtain the title compound (280 mg) as a white solid. Analysis of C24H28N604 0J H20: Calculated 値: C, 61.34; H, 6 .13; N, 17.88. Found 値: C, 61.17; H, 6.26; N, 17.85. NMR is consistent with the structure shown. Example 136,000-[[2-[[[3-[[(cyano Preparation of imino) [(fluorenylmethyl) amino] methyl] amino] phenyl] carbonyl] amino] ethyl] amino] benzene] propionic acid, Central Standard of the Ministry of Economic Affairs Print

To a stirred solution of the compound of Example 32 (88 mg) in methanol (2 ml) and THF (2 ml) was added 1 N sodium hydroxide (2 ml). The reaction mixture was stirred at room temperature for 2 hours, evaporated, and the residue was dissolved in water. The resulting solution was adjusted to pH 4 with 1 N hydrochloric acid, and the resulting solid was separated by filtration. Filtrate -218- The national standard (CNS) A4 specification of this paper is applicable to this paper (21〇 > < 297 public epidemic J. Read the precautions on the back ¾ and then fill it with oxygen ^ 葸)

216 " 458 956 A7 B7 V. Description of the invention (washed with water and then with diethyl ether. The title compound (62 mg) was obtained as a white solid. Analysis of C27H26N6O4 0.5 H2 0 0.25 EtjO: Calculated 値: C, 63.93; Η, 5.65 ;. Ν, 15.97. Found 値: C, 63.96; Η, 5.73; Ν, 15.81. NMR is consistent with the structure shown.-.. Example 1 3 7 Points-[[2-[[[3 -[[(Cyanoimino) (methylamino) fluorenyl] amino] phenyl] carbonyl] amino] ethoxy] cavyl] phenylpropionic acid (Please read the precautions on the back first (F page again).

CO2H was printed by the Consumer Cooperatives of the Central Bureau of Quasi-Economic Bureau of the Ministry of Economic Affairs. The 1N Hydroxide was added to a stirred solution of methanol (3 ml) and THF (3 ml) in Example 133 (24.0 mg). Sodium chloride (3 milliliters). The reaction mixture was stirred at room temperature for 2 hours' and evaporated and the residue was dissolved in water. The resulting solution was adjusted to pH 4 with 1N hydrochloric acid, and extracted with acetic acid-ethyl acetate / MeOH. The organic extract was washed with water, dried (Na2S.04), and evaporated to obtain a transparent gum. The crude product was purified by reverse-phase HPLC on a C 1 8 column (eluent: 0.5% TFA-water / acetonitrile) 'freeze-dried' to obtain the title compound (8.8 mg) as a white solid. _ 心 21 心 2 ^ 〇4 0.55 Analysis of TFA: 219 This paper size is applicable to China National Standard (CNS) A4 (210x 297 mm) 408956 A7 B7 V. Description of the invention (217 Calculation 値: C, 54.71; H, 4.68; N, 17.32. Measured C: C, 54.92; H, 4.70; N, 16.93. NMR is consistent with the structure shown. Example 138,000-[[〗-[[[[[[Amine (cyano Preparation of imino) methyl] amino] phenyl] carbonyl] amino] ethylethyl] amino] phenylpropionic acid

co2h (please read the precautions on the back of this page first and then add this page). m. The compound of Example 134 (285 mg) in methanol (3 ml) and th.F (3 1N sodium hydroxide (3ml) was added to the stirred solution in the solution. The reaction mixture was stirred at room temperature for 2 hours' and evaporated, and the residue was dissolved in water. The resulting solution was adjusted to pH 4 with 1N hydrochloric acid, and extracted with ethyl acetate / MeOH. The organic extract was washed with water and dried (NajSO4) and evaporated to obtain an off-white solid. The crude I was purified by reverse-phase HPLC on a C 1 8 column (eluent: 0.50 / 0.0 .TFA · water / acetonitrile), and lyophilized to obtain the title compound (65 mg) as a white solid solution. Analysis for C20H20N604 1.25 H20, 0.3 Me0H: Calculated 値: C} 55.35; H, 5.42; N, 19.08. Found 値: ‘C, 55.70; H, 5.01; N, 18.69. NMR is consistent with the structure shown. -220- Thai paper scale is applicable to China National Sample (CNS) Α4% grid (21 〇χ 297 at public expense) 466 66 A7 B7 V. Invention of Ming (218) Example 1 3 9_ 0-[[2-[[[3 -[[(Cyanoimino) (ethylamino) methyl] amino] phenyl] carbonyl] amino] ethenyl] amino] phenylpropionic acid

Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs To a stirred solution of the compound of Example 135 (285 mg) in methanol (3 ml) and THF (3 ml) was added 1 N sodium hydroxide (3 ml). The reaction mixture was allowed to evaporate at room temperature for 2 hours, and the residue was dissolved in water. The resulting solution was adjusted to pH 4 with 1N hydrochloric acid, and extracted with ethyl acetate / MeOH. The organic extract was washed with water, dried (Na2S04), and evaporated to give an off-white solid. The crude product was purified by reverse-phase HPLC on a C 1 8 column (eluent: 0.5% TFA-water / ethionine) 'and freeze-dried to give the title compound (18 mg) as a white solid. Analysis of C22H24N6〇4 0.35 Η2 〇:-Calculation 値: C, 59.68; H, 5.62; N, 18.98. Found 値: C, 59.80; H, 5.6, 1; N, 18.59. NMR is consistent with the structure shown. Example 1 40. 3S-[[2-[[[[[[[Cyanoimino) (amido) methyl] amino] phenyl; carbonyl] Preparation of Amine] Ethylamido] Amino] -4-Methynyl Ethyl Acetate -221-This paper size is applicable to China National Standards (CNS) A4 ^ (210X297 mm) I ------- -¢ — (Please read the notes on the back * ϊ 本 育) Order) f __j V. Description of the invention (219

ΗΝΎ, Α7 Β7 Η, C02Et Employees of the Central Standards Bureau, Ministry of Economic Affairs, Consumer Consumption Cooperation Du printed the product of Example J (4) 6 mg, 2_〇ni] Vi), DL-y5-[(2-amino. Oxo Ethyl) amino] ethyl 4-pentynyl acid (624 mg, 20 mM) [prepared according to Example 1 (steps B'C and D), in equal amounts of 3S-amino-4_pentynyl acid Ethyl ester (J. Med. Chem., 1995, 3378) substituted for DL-3_amino group · (3_pyridyl) propanoic acid], triethylamine (2.0 ml) and OMAP (20 mg) in two To a stirred solution in a gas gauge (20 ml), EDC1 (382 mg, 2.0 mM) was added at 0 °. The reaction mixture was stirred for 15 minutes at TC to make Daxuan overflow, and then stirred for another 16 hours. The reaction mixture was concentrated in the air to obtain an oily gum, which was dissolved in ethyl acetate. The resulting solution was saturated with water, saturated NaHC03 aqueous solution and washed with water. The organic layer was separated, dried (Na2S0 4), and evaporated to obtain the crude product. The crude product was purified on a C 1 S column with rphplc (eluent: 0.5% TFA-water / acetonitrile) 'freeze-dried The title compound (280 mg) was obtained as a white solid. NMR was consistent with the structure shown. Analysis of Ci7HiSN604 0.45: Calculated 値: C, 50.99; H, 4.41; N, 19.93 .. Measured 値: -C, 51.28 H, 4.70; N, 19.72. Example 1 4 1 3 ^ [[2-[[[3 _ [[(cyanoimino) (: methylamino) methyl] amino] benzyl] carbonyl-222 -Applicable to Chinese national sample rate (CNs > Yao Ruge (210X297mm)) f Please fill in the vc '+ f page on the back of the book}-Binding · Order-. ^ 458 9 56 A7 B7

V. Description of the invention Preparation of (22Q group) amino group] ethyl alcohol group] amino group] valynic acid

co2h Printed in a stirred solution of the compound of Example 140 (280 mg) in methanol (3 ml) and tHF (3 ml) by the Shellfish Consumer Cooperative of the Central Bureau of quasi-Ministry of Economic Affairs, co2h. Add 1 N sodium hydroxide (3 ml) The β reaction mixture was stirred at room temperature for 2 hours. The 'Lofa' residue was dissolved in water. The resulting solution was adjusted to pH 4 with 1N hydrochloric acid, and extracted with ethyl acetate / MeOH. The organic extract was washed with water and dried (N a2 S Ο 4) 'and evaporated to obtain an off-white solid. The crude product was purified by reverse-phase HPLC on a C18 column (eluent: TFA-water / acetonitrile) and lyophilized to obtain the title compound (122 mg) as a white solid. -'C17H18N604 0.45 Analysis of TFA: Meter # 値: C, 50.99; H, 4.41; N, 19.93. -\ Measured 値: C, 51.28; H, 4.70; N, 19.72. • NMR is consistent with the structure shown. '' Example 1 4 3 million _ [[2-[[[3-[[(Cyanoimino) [2-ff than methylenemethyl] amine '] methyl]] amino] each group] condensed group] Preparation of Amine] Ethylamino] Amine] Ethyl Acetate, 3-Gas ^ -Acid Preparation -223- The paper standard is applicable to China National Standard (CNS) A4 (210X297 mm) Shen Yi-(Read first (Read the notes on the back and fill out this page)

’1T A7 B7,221 V. Description of the invention

The title compound was synthesized according to the procedure described in Example 135, but replaced the compound of Example L with the compound of Example 0 in equal amounts. The title compound was obtained. NMR is consistent with the structure shown. C2gH29N704 1 TFA 1H2 0:, Calculate 値: C, 54.63; H, 4.89; N, 14.86. Found 値: C, 54.28; H, 4.58; N, 14.63. -Example ί 4 4/5-[[2-[[[[[(cyano'imino)) [2-pyridylmethyl] amino] fluorenyl] amino] benzyl] carbonyl] amine [Acetyl] ethenyl] amino] phenylpropyl bee, the preparation of bis (trifluoroacetic acid) salt -------------- pack-). (Please read the precautions on the back first and then the soul nest book Page) Order Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

02 -224- The standard of this paper is applicable to the Chinese National Standard (CNS) 6 4 ^ (210X297 mm) 458956 V. Description of the invention (Α7 Β7 222 The title compound was prepared according to the procedure described in Example 136, but the same amount of actual The compound was substituted. The compound of Example VII was also obtained. The title compound Yang was obtained as a white solid. The NMR was consistent with the structure shown., C26H25N7〇4 2 TFA 1Η2 ο:-Deca 値 'C, 48.33; Η, 3.92; Ν , 13.15. Measured 値: C, 48.21; Η, 3.59; Ν, 13.19-Example 1 4 3 '(Please read the precautions on the back before filling this page) θ-Cyanoimine) [3-υ 比Preparation of pyridylfluorenyl] amino] methyl] amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] ethyl phenylpropionate, preparation of trifluoroacetate '

The title compound was prepared according to the procedure described in Example 135, but the equivalent compound of Example Q was used instead of the compound of Example L. The title compound was obtained as a white solid. NMR is consistent with the structure shown. '' C28H29N7〇4 1 TFA 1Η2 〇: 'Calculate 値: C, 54.63; Η, 4.89; Ν, 14.86. -225- 'The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 458956 V. Description of the invention (223) Actual measurement: C, 54.24; H, 4.85; N, 14.41. Example 1 4 6 Cold-[[2-[[[3-[[(cyanoimino)] [3-pyridylmethyl] amino] methyl]., Amino] phenyl] carbonyl] amino ] Acetyl] amino] phenylpropionic acid, preparation of bis (trifluoroacetic acid) salt

Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economics The title compound was prepared according to the procedure described in Example 136, but replaced the compound of Example 132 with the equivalent compound of Example 145. The title compound was obtained as a white solid. -NMR is consistent with the structure shown a C26H25N7O4 2 TFA 0.25H2 0: calculated 値: C, 49, 22; H, 3.79; N, 13.39. Found 値: C, 49.50; H, 4.05; N, 13.64. Example 1 4 7 Preparation of Lu-[[2-[[(3-Amino-4-Phenyl) condensyl] Amine]. Ethylamido] Amino] Ethyl Phenylpropionate Standards are applicable to China National Standard (CNS) A4 specifications (210X297 mm) · * · Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ^ 58 956 A7 —__ B7 V. Description of the invention (224)

The title compound was prepared according to the procedure described in Example 135, but replacing the compound of Example L with an equivalent amount of 3-aminoM-chlorobenzoic acid. The title compound was obtained as a brown solid (93.5% yield). NMR and the structure shown-"Example 1.4 8 Lu-[[2-[_ [[4-气 -3-[[[[((I, .l-Difluorenylethoxy) pyridyl] amine [] [[(1,1-dimethylethoxy) carbonyl] imino] fluorenyl] amine tomb] benzyl] carbonyl] amino] ethylethyl] amino] ethyl phenylpropionate

The product of Example 147 (400 mg, 1.13 mM), .N, N, -bis-Boc- 1. thiourea (311 mg, 1-13 mM) [Edwin_J. Iwanowicz et al, Synthetic Communications, 23 (10) ( 1993) 1443-1445] > Addition of DMF (6 ml) and triethylamine (0.6 ml) in a stirred solution -227- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (please listen first (Read the notes on the back again #-¾ 本 寻)

A7 B7 158956 V. Description of the invention (), add HgCl2 (360 mg). The mixture was at 0-5. 〇 Stir for 15 minutes and warm to room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 mL) and filtered through Celite under vacuum. The filtrate was concentrated in the air, and it was found that an oily gum was purified by J5 gel. The column was purified by using 100% ethyl acetate as a eluent to obtain the title compound (254 mg) as a white solid. NMR is consistent with the structure shown. ^ 31 ^ 40 ^ 5 ^ 8 1-5 H20: Calculate 値: C, 55, 31; .Η, 6_44; N, 10.40. Measured C: C, 55.17; H, 6.50; N, 10.56 »· Example 1 4 9 A-[[2-[[[[[[Amineiminomethyl) amino] _4_Gaphenyl]) Preparation of Carbonyl] Amine] Ethylamido] Amino] Ethyl Phenylpropionate, Trifluoroacetate (Please read the precautions on the back before writing 4. Ben.

B

Printed by Shelley Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs. In a stirred solution of the product of Example 148 (420 mg) in methane (5 ml), add TFA (9 ml) at 0 ° C. Warm and stir at room temperature for 1.5 hours. The mixture was concentrated in the air to obtain a crude product. The crude product was purified by reverse phase HPLC on a C18 column (eluent: 0-5%, tfa • water / acetonitrile), and freeze-dried to obtain the title compound (68 mg) as a white solid. -228- The national standard (CNS) A4 specification (210X297) for this paper standard I; t- 9 56 α7 Β7 r-^^ ------------- V. Invention Explanation () «C2iH24N3〇4C1 1.0 TFA 0.45 Η2 〇:. · ≫ Calculate 値: c, 48.63; Η, 4.60; N, 12.33. , Measured 値: C, 48.28; Η, 4.16; Ν, 12.13. Example 1 5 0 θ-[[2-[[1 >-[(Aminoiminomethyl) amino] -4 -Phenylphenyl) anyl] amino] ethyldonyl] amino] phenylpropyl Preparation of acids.

The title compound was prepared according to the procedure described in Example 136, but replacing the compound of Example 132 with the equivalent of the compound of Example 149. The title compound was obtained as a white solid. NMR is consistent with the structure shown. C19H20N504.C1 1.5 TFA:, Calculated 値: C, 44.87; H, 3.68; N, 11.89. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. Actual measurement: 'C, 44_54; H, 3.80; N, 11.43. Example 1 5 2 Preparation of cold-[[2-[[(5-amino-2-chlorophenyl) carbonyl] amino] ethenyl; methyl] benzyl propionate -229- This paper is for China National Standard (CNS) A4 Specification (210X297mm) ^ 956 V. Description of Invention (227

Α7 Β7

The title compound was prepared according to the procedure described in Example 1.35, but replacing the compound of Example L with an equivalent amount of 3-amino-6-chlorobenzoic acid to obtain the title compound as a light brown solid. -NMR with the structure shown. Example 1 5 3 Cold _ [[2-[[[2- 气-5-[[[[((l, l-dimethylethoxy) carbonyl] amino]] Preparation of [[(1,1-Difluorenylethoxy) carbonyl] imino] methyl] amino] benzyl] carbonyl] amino] ethylfluorenyl] amino] methyl phenylpropionate

〇2Μθ ----------- Shenyi— (Please read the precautions on the back before filling this page) Order h. The title compound printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy is based on examples Prepared by the procedure described in 148, but replacing the compound of Example 146 with the equivalent of the compound of Example 152. The title compound-was obtained as a white solid. .. NMR is consistent with the structure shown. Example 1 5 4 Ni-Ga- 5- [[[[((1,1-dimethylethoxy) carbonyl] amino] [[(1,1-dimethylethoxy) carbonyl] imine ] Methyl] Amine] Phenyl] carbonyl] Amine] Ethylamido] Amino] Phenylpropionic acid -230- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) l · A7 'B7 of the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs V. Invention Description (228)

The title compound was prepared according to the procedure described in Example 136, but replacing the compound of Example 132 with the equivalent of the compound of Example 153. The title compound was obtained as a white solid. NMR is consistent with the structure shown. Example 1 5 5 Point-[[2-[[[[[Aminoiminomethyl) amino] -2 -Phenylphenyl) carbonyl] Amino] Ethylamido] Amino] phenylpropanoic acid ., Preparation of trifluoroacetateΗ ΗΝ ^ 〒 / Ν, ΝΗ2

C-

II o, 0Η The title compound was prepared according to the procedure described in Example 150, but replacing the compound of Example 149 with the equivalent of the compound of Example 154. The title compound was obtained as a white solid. · NMR is consistent with the structure shown. C19H20N504.C1 1 TFA 0.25 H2 0: Calculated 値: C, 47.02; H, 4.04; N, 13.06. Measured 値 ·· C, 47, 17; Η, 3.85; N, 12.72. 231-The paper size of the table applies to the China National Standard (CNS) A4 (210X297). {Please read the notes on the back before filling it out. This page)

956 V. Description of the invention (229 A7 B7 Example 1 5 6 Using the procedures of the present disclosure and starting with the necessary reagents, the following compounds were prepared

OR3 R3 Υ1 R7 Et or · Η 0 η—Bu Et or Η 〇 i-Pr Et 1 or Η '0 t-Bu Et or Η 0 n-Pr Et or Η 0 Et or Η ο Et or Η 〇.Hexyl Et or Η ο • Cyclohexylmethyl Et or Η 0 • D is printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

Et or Η

Et or Η Et I Η S s. 232- _ This paper has a standard Chinese National Standard (CNS) A4 (2 ΙΌ X 297 mm)

Cyclohexylmethyl 3-pyridyl (Please read the precautions on the back before writing this page)

2305 cs yi β A7 B7 V. Description of the invention (R3

Yl_ R7

Et or Η Ο

Et or Η

Et or Η

(Please read the notes on the back before filling this page)

Et or Η 0

* π ''. 4.

Et or Η Ο Η

Voice, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

Et ic Η

Et or Η Ο Ο • 233 The paper scale is applicable to China National Standard (CNS) A4 specification (210 × 297 mm) Η

458956 at B7 V. Description of the invention? 31 Y '

KL

Et or Η 0

Et or Η Ο

NC

Et or Η Ο

(Please read the notes on the back before displaying this page) ο2ν

Et, or Η Ο

MeO

Et or Η Ο

Et or Η Ο

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Me

Et or Η

Et or Η Ο Ο, 234-

F3c

This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 458 956 A7 B7 V. Description of the invention (232

Et or Η

H2N〇2S Ο

Et or Μ Μθ〇23 Ο

Et or Η Ο

〇 JI H2NC

(Please read the notes on the back before filling this page)

Et or Η η2ν, Ο

Et 4 η Ο ΑοΗΝ Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

Et or Η

Et or Η 0 〇, 235 ‘This paper size applies to China National Standard (CNS) AOU (210X297 mm)

MeC ^ S '

C

458 956 A7 B7 V. Description of the invention (233 R3 Y1 Β Guang

Et or Η 0

Ο

Et or -Η Μ〇2Ν Ο

---------- Hey— (Please read the precautions on the back before filling the page)

Et A Η f3co Ο

Order

PhO

Et or Η Ο

f3cs Printed by the Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs

Et or Η

Et -ic H 0 o -236-The paper scale is applicable to the Chinese National Standard (CNS) A4 (210X297 mm)

f3co2s

Printed by the Central Government of the Ministry of Economic Affairs and printed by the Employee Consumer Cooperatives 5B956 ^ 234 ~ V. Description of the Invention ()

-237- (Please read the precautions on the back before each bird page).

, ST

槔 · I This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 458 956 A7 B7 V. Description of the invention (235 R3

Et or Η 0

MeO OMe

Et or Η Ο

Cl

Cl

Et or Η Ο f3c CF3

Et or Η Ο

F

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Et or Η Ο -238, the paper method and scale are applicable to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 5 9 56 A7 B7 V. Description of the invention (236

tnAA preparation

'OCR, the above compound was prepared according to the procedure described in Example E,' but benzylamine was replaced with p-aminomethyl benzsulfenamine. The above compound was obtained as a white solid. ------------ Installation-- (Please read the precautions on the back and then this page). Volume NMR is consistent with the structure shown. Order I: Central Ministry of Economic Affairs 橾Printed by Zhunxun Employee Cooperatives

f case AB

The above compound was prepared according to the procedure described in Example I, and the compound in place of the compound in Example E was replaced by the compound. The above compounds were obtained: -239-This paper size is in accordance with Chinese National Standard (CNS) A4 specification (21〇7 ^ 7 mm > t. V. Description of the invention (237 A7 B7 solid. NMR and structure shown-Preparation)

Example AC. 〇 ^ -Co2Et hV-ch2— (ϋ—ΝΗ— 』Η B〇c.

C !. — ^ — (Please read the precautions on the back before removing. The above-mentioned compounds are prepared according to the procedures described in Example 14. However, * 1 is called glycine instead of the compound of Example j. , And dl_3_amino (3,5, -dioxophenyl) propionic acid ethyl ester to take rdl_々 [(2_amino_ 丨 乂: yl) amino group]. 4-pentynyl ethyl ester The above compounds were obtained, and the oily NMR was consistent with the structure shown. • Greed AD Preparation β Λ Printed by i.

H2N-CH2-C-NH-CH

The above compounds were prepared according to the procedure described in Example 161. 240- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 5. The compound of the invention description (238) AC replaces Example 159. Grain ... The above compound was obtained, and the β-NMR of the oily gum was consistent with the structure shown. Example 1 5 7 3S-[[2-[[[3-[[[[[(4- (Amine-toluenesulfonyl) benzyl) benzyl (Amino) amino] (cyanoimino) fluorenyl] amino] phenyl] carbonyl] amine; i] ethynyl] amino] -4-pentynyl ethyl ester.

'VY ^ C02Et HOC

C III c IH < Please read the notes on the back before filling out this page)-Binding. Binding. 1. The title compound was prepared according to the procedure described in Example 140, but the compound of Example AA was used instead of the example Compound of J. The above compound was obtained as an oily gum = '.-NMR was consistent with the structure shown. Example 1 5 8, jS-[[2-[[[3-[[[[(((4- (Aminosulfonyl) phenylphenyl) amino) amino] (cyanoimino) methyl] amino] Private base] several bases] amines] ethyl alcohols] amines] arsenic acid 'trifluoroacetate, the preparation of monohydrate, 241-♦-The central government bureau of the Ministry of Economic Affairs, the Consumer Cooperatives Co., Ltd. Printed paper size applicable Chinese National Standard (〇1 ^) Sixty-four Rules ^ (21〇 Father 297 issued) 956 V. Invention Description (239) A7 B7

S〇2NH2 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economics. The compound was prepared according to the procedure described in Example 141 'but replaced the compound of Example 140 with the compound of Example 157. The crude product was purified by RPHPLC on a C8 column (eluent: 0,5% TFA-water / acetonitrile) and freeze-dried to obtain the title compound as a white solid. N M R is consistent with the structure shown. C23H23N70.6S. Analysis of 1.25 TFA:. Calculate 値: C, 44.64; H, 3.86; N, 14.29. Measured 値: _ C, 44.85; H, 4.00; N, 14.36. Example 1 5 9-Lu-[[2-[[[3-[[Amine (cyanoimino) methyl] amino] phenylcarbonyl]] Amine] Ethyl] Amine] -3, Preparation of 5-digas ethyl phenylpropionate-

NIH ·

HIN

---------- Installation-/ '/ (Please read the precautions on the back before filling in the page} Order. -242- As long as the paper is in the standard, the national standard (CNS) A4 specification ( 210X297 mm) 4 58 9 56. A7 The title compound was prepared according to the procedure described in Example 140, but using the example, the compound of Example J replaced the compound of Example J 丨 and using the compound of Example AD to take the cold [(2 · Amine · 1-oxyethyl) amino] Ethyl pivaloate. The title compound was obtained as an oily gum. 9 NMR was consistent with the structure shown. Example 1 6 0-[3, [[amine (Cyanoimino) methyl] amino] phenyl] carbonyl] Amine] Ethylamido] Amino] _3,5 · Dichlorophenylpropionic acid Preparation ^-< Please read the back (Notes to fill in poverty-this page)

Ordered by the Central Standards Bureau of the Ministry of Economic Affairs, printed by the male laborer's consumer cooperative. The title compound 'was prepared according to the procedure described in Example 141, but replaced the compound of Example 140 with the compound of Example 159. The crude product was purified by RPHPLC on a c 1 8 column (eluent: 0.5% TfA_water / acetonitrile),-ice * freeze-dried to obtain the title compound as a white solid. '-NMR is consistent with the structure shown. -· ≫ Example 1 6 1 Lu _ [[2-[[[[[Amine (aminocarbonyl) imino] methyl] amino] phenyl] carbonyl] amino] ethyl]] Base] -3,5 Preparation of Digas-Table Ethyl Acetate, Trigas Acetate -243-This paper size is applicable to China's National Standard (CNS) A4 specification (210X297 mm) A7 ^ A58 956_ B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs241

To a stirred solution of the product of Example 159 (.2,65 g) in dichloromethane (120 ml) was added trifluoroacetic acid (60 ml). The reaction mixture was stirred at 25 ° C for 1 hour. 3 The reaction mixture was concentrated in the air to obtain a crude product, which was crystallized from ether to obtain the title compound (2.02 g) as a white solid. -NMR is consistent with the structure shown. Analysis of C2lH22N5004Cl3 1.05 TFA: Calculated 値: C, 43.31; H, 3.79; N, 10.98. Found 値: C, 43.18; H, 3.81; N, 10.64. Example 162 Lu-[[2-[[[3-[[Amine (aminocarbonyl) imino] methyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -3,5 -Preparation of digas phenylpropionic acid, trifluoroacetic acid salt,.

cr ci < please read the notes on the back before lf this page)-Ordering-i. -244- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 242458956 B7 V. Description of the invention (Title The compound was prepared according to the procedure described in Example 141, but the compound of Example 141 was replaced with the compound of Example 161. The title compound was obtained as a white solid.. NMR was consistent with the structure shown. C20H20N605C12 1,25 TFA Analysis: Calculate 値: C, 42, 37; H, 3.36; N, 13.18. Measured 値: C, 42.48; H, 3.46; N, I2.%. Example Preparation

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

The title compound was prepared according to the procedure described in Example 141, but replacing the compound of Example 14 with the compound of Example A C. The title compound was obtained as a white solid. N M R is consistent with the structure shown < >. t n a f. Preparation ο

This paper size applies Chinese National Standard (CNS) A4 specifications (210 × 297 Public Security J 458956 A7 B7 V. Description of the invention (243 Compounds in Example AE (954 mg, 33 mmol), DMF (10 ml), K2C03 (1 g ), Nal (129 mg) was added to a stirred solution of 363 mg of 2-gas_1 ^ "_ dimethylacetamide (363 mg, 3. mmol), and the mixture was stirred at room temperature for 16 hours. Reaction The mixture was concentrated in the air to obtain an oily gum, which was crystallized from diethyl ether to obtain a white solid (AF *) (61 mg). NMR was consistent with the structure shown. '

Example A G Preparation 0

N Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The title compound was prepared according to the procedure described in Example 161, but the compound of Example A F was substituted for the compound of Example 159 to obtain the title compound, which was in the form of an oily gum. ‘. NMR is consistent with the structure shown. Example 1 6 3 Lu-[[2-[[[[[[Aminoiminomethyl) amino] phenyl}] carbonyl] amino] ethylfluorenyl] amino] -3,5-digas Preparation of phenylpropionate [(dimethylamino) carbonyl] methyl ester 246 This paper size applies to Chinese National Standard (CNS) M specifications (2 丨 0 乂 297 mm) 4 such as 9 56 Α7 ----- Β7 5 , Invention description (244 发明

The title compound was prepared according to the procedure described in Example 132, except that the compound of Example VII was replaced with m-guanidinobenzylic acid and the compound of Example V was replaced with the compound of Example A (). The title compound was obtained as a white solid NMR is consistent with the killed structure s C23H26N6〇3Cl2 1.3 Analysis of TFA: Calculated 値: C, 44.85; If, 4.01; N, 12.28. Found 値: C, 44.51; 188; N, 12.38. Example A Η Preparation (please (Please read the notes on the back before t this page)

Printed by the Consumer Consumption Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Ethyl chloroformate (8 ml) was added to a stirred solution of 2-'methyl 2-thiothiourea (1, 1: 1 g) in dichloromethane (150 ml) > and saturated Sodium bicarbonate solution (150 ml). The reaction mixture was stirred at room temperature for 18 hours. Reaction Mixing: -247- This paper size is in accordance with Chinese National Standard (CNS) A4. (210X297 mm) Φ; 5 9 245 V. Description of the invention (The material is washed with water and dried with Na 2 S 04 'in the air Concentrated to obtain a crude oily gum, which was purified by flash column chromatography to obtain the above compound (98 g) as a white solid. NMR was consistent with the structure shown. Example 164 Preparation

(#Please read the precautions on the back, and then write this page on the rabbit.) Packing. H. 4. The title compound was prepared according to the procedure described in Example 14 but with 3-amine. The compound of Example j was replaced by an acid, and tert-butyl acetic acid was substituted with 3-amino (3,5-dichlorophenyl) propionic acid + DL-Lu-[, (2-amino-1-oxy 6-yl] -4-fluorynyl ethyl ester. The title compound was obtained as an oily gum. The NMR was consistent with the structure shown. • Real f 丨 1 6 5 3'5-Digas-/?-[[2- [[[3-[[[(ethoxycarbonyl) amino]] [(ethoxycarbonyl) imine] methyl] amino] .phenyl] carbonyl] amino] ethyl ] Phenylpropanoic acid 1, dimethyl ethyl ester preparation-248 This paper scale is applicable to China National Standard (CNS) A4 specification (21 × 297 mm) Preprinted by the Consumers' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs 2464 Μ 956 Α7 Β7 Η u C02Et

5. Description of the invention (% The compound of Example A (250 mg) in DMF (2 ml) and .triethylamine (150 mg) was added to the stirred solution of the compound of Example 164 (150 mg). The mixture was cooled to 0. ° C, stirred at 0 ° C for 5 minutes. The mixture was treated with HgCl2 (50 ml) and stirred at room temperature for 1 small beer. The mixture was concentrated in the air to obtain an oily gum, which was purified by flash column chromatography to obtain Oily gum .. NMR is consistent with the structure shown. Example 1 6 6 3,5 · Dichloro-Lu-[[2-[[[3-[[[(ethoxycarbonyl) amino]] [(ethyl Preparation of oxo) imine] methyl] amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] phthalic acid---------- ^ ---- --ir ------- Step on {please note on the back, please fill out this page} Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Consumer Cooperatives, M Η C02Et

The title compound was prepared in accordance with the procedure described in Example 160, but with Example-249, this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 __ B7 V. Description of the invention (247) I65 Compound substitution Compound of Example 159. The title compound was obtained as a white solid. N M R is consistent with the structure shown. C25H27N508C12 Analysis of 0.5 Η20, 0.25 TFA: Total I 値: C, 48.31; Η, 4.49; Team 11.05. Found 値: C, 48.55; Η, 4.2 Γ; Ν, 10.84.

. 、 Example AI preparation " ---------- install-(Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs in a stirred suspension of 3 · amino-4-gas benzoic acid (25_0 g, 157 mmol) in MeOH (300 ml). Hydrogenate until methanol dissolves. The reaction mixture was stirred at 0-5 ° C for 30 minutes to room temperature and then stirred for another 4 days. The reaction mixture was concentrated in the air, and the resulting white solid was triturated with diethyl ether to obtain the above compound; 26.2 g. • NMR as a white solid was consistent with the structure shown. Example AJ. Preparation / -250- The paper K degree is applicable to China National Select Standard (CNS) A4 specification (2 丨 0X297 mm) _ —1 ---- I— I · ^ 6β966 V. Description of the invention (248) A7 B7

BOC

C02Me in bis-t-Boc-thio vein (24.8 g, 90 mmol) and 3-amino-4-chlorobenzoic acid ethyl ester (20 g, 90 mmol) in dimethylformamide (120 Ml) and triethylamine (45 ml). To this solution was added mercury chloride (11) (30.1 g, 111 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 15 minutes to reach room temperature and then stirred for another 2 hours. The reaction mixture was diluted with ethyl acetate (600 ml), and the resulting slurry was filtered under reduced pressure, and the filtrate was concentrated to obtain an oily gel, which was purified by chromatography on silica gel (eluent: ethyl acetate / heptane 2 0: ' 80) to obtain the above compound (8.6 g) as a white solid. N M R is consistent with the structure shown = 1

Example A K (Please read the precautions on the back before filling this page) 嚷 · ir 1. lr Preparation Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

The product of Step AI was dissolved in MeOH (3 ml) and 1 M NaOH (14 ml) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours and reacted; Kun compound-251-This paper size applies Chinese National Standard (CNS) A4 specification (2 丨 〇'〆297 mm) 5. Description of the invention (249) A7 B7 at The radon was concentrated in the air, and the residue was dissolved in water and washed with ether. The aqueous layer was acidified with 1NHC1 to pH = 3. A white precipitate was formed, filtered, washed with water and ether, and dried to obtain 1.2 g of a white solid. N M R is consistent with the structure shown.

AL preparation

C〇2H (Please read the precautions on the back before filling in this page) The product printed in step AJ (550 mg, 133 mmol) by CH2C12 (4 ml) TFA (1 ml) was added to the solution at 0 ° C. After the addition, the ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to obtain a colorless oil. A solution of 2N HC1 in dioxin (2 ml) 'white precipitate was added thereto to form a β solution, which was concentrated and contracted in vacuo to obtain 280 mg of the desired product as a white solid. I-NMR is consistent with the structure shown. Example 167 Dot-[[2-[[[3-[(Amineiminemethyl) amino]] 4-Aerophenyl] carbonyl] Amine] Ethyl] Amine] -3,5- Preparation of Digas Ethyl Phenylpropionate-252- This paper is suitable for the national standard (CNS) A4 (210X297 mm) ll '1T 458956 A7 B7 F. Description of the invention (25 ())

Et 02 C Printed Example of Al · Compound (500 mg) and 1-fluorenylhexapyridine (400 mg) in DMF (20 ml). Cooled to 0 ° c. Isobutyl chloroformate (274 mg) was added under nitrogen pressure. The reaction mixture was stirred for 5 minutes, and then a solution of the compound of Example A D (866 mg) in DM F (2 ml) was added. The reaction mixture was slowly warmed to room temperature and stirred for 6 hours in a chamber. The solution was quenched with water and extracted with ethyl acetate. The organic extract was washed with water, dried over Nat2S04, and concentrated in the air. The residue was purified by RPHPLC and freeze-dried to obtain the desired product as an oily gum (3.99 mg). Analysis of C2iH22N3〇4Cl3 1 TFA, 0′5 Η2 〇: Calculate 値: C, 43.31; H, 3.79; N, 10.98-, Measured 値: C, 43.18; H, 3.81; N, 10.64. _ Example I 6 8 β-[[2-[[[[[[Aminoiminomethyl) amino] -4-chlorophenyl] carbonyl] amino] ethylfluorenyl] amino]- Preparation of 3,5-dichlorophenylpropionic acid and trifluoroacetate-253- The paper size is applicable to the Chinese National Standard (CMS) A4 specification (21〇2mm) ---------- 1V4 -(Please read the notes on the back before filling this page)-Order. A7 B7 V. Description of the invention (

COjH 458 * 956

Ch v, CI The title compound was prepared according to the procedures described in the examples, but the compound of example 167 was replaced by the compound of example 167. The title compound was obtained as a white solid. NMR is consistent with the structure shown. Analysis of C19Hi8N304CI3. 1 TFA: Calculate 値: C, 41.98; H, 3.19; N, η · 66. Found 値: C, 42.14; Η, 3.30; Ν, 1U8. Example 1 Interaction Preparation — ^-(Please read the note ^^ on the back before filling this page)

The title compound was prepared in accordance with the procedure described in Example 140, but 'Korean-Korea's Ministry of Economic Affairs Central Labor Bureau Consumers' Cooperatives printed K 装 compound instead of the compound of Example J. The title compound was obtained. NMR is consistent with the structure shown. Analysis of CisHaoNA 0.6 TFA: Calculation 値: C, 50.93; H, 4.59; N, 18.56. Measured C: C, 50.69; H, 4.71; N, ‘18 .32. Example 1 7 0 254 sheets of paper in the form of an example; ^ Applicable to China's "Standard (CNS) A4 specifications (Xun 297 Gong Cheng 458956 V. Description of the invention (252) Α7 Β7 3S-[[2-[[[3 -[[Amine '[(Amino group) imine] methyl] amino] phenyl] carbonyl] amino] ethenyl] amino] __ 4-pentynyl ethyl ester

Co2Et Η The title compound was prepared according to the procedure described in Example 161, but replacing the compound of Example 159 with the compound of Example 169. The title compound was obtained as an oil. NMR is consistent with the structure shown, ν Example 1 7 1 3S-[[2-[[[[[[[[Amino [(Aminocarbonyl) imino] methyl] amino] phenyl] Zangyl] amine [Ethyl] ethenyl] amino] -4-pentynyl acid 'trifluoroacetic acid salt hydrate · (please note the f item on the back of the cabinet and fill in this page) m. Order the central standard bureau of the Ministry of Economic Affairs Printed by Consumer Cooperative Η2 Ν ο CV h

Η 02 C The title compound was prepared according to the procedure described in Bee Example 141, but replaced the compound of Example 14 with the compound of Example 170. The title compound was obtained as -255. The paper scale was applicable to the Chinese National Standards of Standards (CNS) Ba Shi ^ (2 [〇χ297 公 瘦) 956 A7 _______ 'B7 5. Description of the invention (253) White solid. NMR is consistent with the structure shown. Example 1 7 2 3 5-[[2-[[[3-[(Aminoiminomethyl) amino] -4-aminophenyl] carbonyl] amino] ethylfluorenyl] amino] -4 -Preparation of ethyl valerate.

The title compound was prepared according to the procedure described in Example 167, but k D L-

I-[(2-amino-1-oxyethyl) amino]. 4-pentynyl ethyl ester was substituted for the compound of Example AD. The title compound was obtained as an oily gum. N M R is consistent with the structure shown. Example 1 7 3 3S-[[2-[[[[[Amineiminoamido) amino] -4-aminophenyl] carbonyl] amino] ethylamido] amino] -4- Preparation of valproic acid and trifluoro'acetate (Please read the notes on the back before filling this page)

Η 02 C c 'H—N, -256- This paper size is applicable to Chinese national standard (CNS > A4 size ΰΐ〇 × 297mm) _ 49 66 A7 B7 V. Description of the invention (254) The title compound is based on an example Prepared by the procedure described in 141, but replacing the compound of Example 140 with the compound of Example 172. The title compound was obtained as a white solid. N M R is consistent with the structure shown. Analysis of C15H16N504C1, 1 TFA, 0.5 Η20: Calculate 値: C, 41,77; 3.7, 3.71; Η, 14.33. Found 値: C, 41.84; Η, 3.64; Ν, 13.94. Example 174 (±) Lu-[[2-[[[[[[Aminoimidoamido) amino] phenyl] ethanyl] amino] ethylamido] amine 蓦] -3,4 · Preparation of Digas Phenylpropionate, Ester, Trifluoroacetate

Η2 V yt NH ^ r NH. 〇

TFA

(Please read the precautions on the back before filling in this page) • Install n ^ mi ", nfft, rr Print steps A r-• DL-? -Amino group of the staff consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -(3,4-dichlorobenzene poly). Ethyl propionate hydrochloride was prepared according to steps A and B of Example 1, but replaced with equivalent 3 ', 4-dichlorobenzoic acid (Aldrich) in step A of Example 1. Medium 3-Pyridine. Step B-M-guanidyl hippurate (Example M) (400 mg, 0.0015 mol) and N-methylmorpholine (150 mg, 0.0015 mol) in anhydrous DMF ( 6ml) This paper is in accordance with Chinese national standard (CNS > A4 size (210X297mm) 40d 956. A? ____ B7 V. Description of the invention (255) * I, medium 'In the temperature of the ice bath, add chloroamidine Isobutyl acid ester (200 mg, 0.0015 moles). After stirring for 5 minutes, the product of step A, DL-3 -Amino-3- (3,4-dichlorobenzyl) propanoic acid ethyl ester hydrochloride (440 mg, 0.0015 mol) and a slurry of N-methylmorpholine (150 mg '0.015 mol) in anhydrous DMF (6 ml) was added monovalently at an ice bath temperature. The reaction mixture was Stir overnight. Solvent in air Under 7 8 X: Removed on water bath, the product was separated by rphPLC to obtain the title compound (520 mg) as a white solid. MS and NMR were consistent with the desired structure. Example 1 7 5 (±) Lu-[[2 -1 [[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethenyl] amino] -3,4-diphenylphenylpropionate, trifluoroacetate Preparation ---------- S-- (Please read the notes on the back before filling in the page) —M. Order kr. 〇

Printed on the product of Example 174 (420 mg j 0.0007 mol) in water (8 ml) and CH3CN (8 ml) with the addition of L10H (118 mg, 0.003 mol) ). The reaction mixture was stirred at room temperature for 1.5 hours. pΗ decreased to about 3 with TF A, and the product was separated by RPHPLC to obtain the title compound * (390 mg) (after lyophilization) as a white solid. , M S and NMR are consistent with the desired structure. -258-This paper size applies to China National Standards (CNS) A4 gauge (210X297 mm) 4 5. Description of the invention (256) A7 B7 Example 1 7 6 [(Aminoiminomethyl) amino] _5_ (trifluoromethyl) quinyl] amino] ethylfluorenyl] amine] _3,4_Digas ethyl phenylpropionate, trifluoroacetate preparation 〇

The above compounds were prepared according to the method of Example 38, but 3,5-bis-trifluorofluorenylanisole was replaced with an equivalent amount of 3,5-digas benzaldehyde (Aldrich). MS and NMR were consistent with the desired structure. (Please read the notes on the back before filling this page)

_ ^-Order I Example of printing by the Central Bureau of Standards of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, 1 7 7. (±) 々-[[2-[[[[[[[Amineiminoamido) amino]] · 5- (trifluoromethyl) phenyl] carbonyl] amino] ethylfluorenyl] amino] -3,5-digas phenylpropionic acid, trifluoroacetate-〇

-259- This paper size applies the Chinese National Standard (CNS) (219 × 297 mm) 4 Α7 Β7 257 V. Description of the invention (the product of Example 176 (620 mg, 0.00094. Moore) in water (1.0 ml) LiOH (157 mg, 0.0037 moles) was added to CH3CN (10 ml). The reaction mixture was stirred at room temperature for 2 hours. PΗ was reduced to about 3 by TFA, and the product was isolated by RPHPLC to obtain the title compound (56 0 mg, after freeze-drying), as a white solid. MS and NMΪ? / Consistent with the desired structure. • Example 1 7 8 (±) /?-[[2-[[[3-[(4,5 -Diargon-1H_imidazol-2-yl) amine ijphenyl] carbonyl] amine] ethyl] ethyl] amino 3,5 • bis (trifluoromethyl) phenylpropionate, trifluoroacetate Preparation beam-(Please read the notes on the back of the feed before filling this page) 〇

-Order Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -260-

I The above compounds were prepared according to the method of Example 9, but 3,5_bis · trifluoromethylbenzyl (Aldrich) was used instead of 3 in Reward A. _ Late bite is secreted in Example 9 Step B » MS and NMR are consistent with the desired structure. Example 1 7 9 Dihydroimidyl) amino] phenyl] condensate] amine] ethyl alcohol] amine]. 3,5_bis (trifluoromethyl.yl) phenylpropanoic acid. Trifluoroacetate Preparation of this paper ft scale applicable to Chinese national standard ship, two A7 B7 9 5g 5. Description of the invention (258)

To the product of Example 178 (36 mg, 0.0005 mol) in water (8 ml) and (only 3 (: 1'4 (8 ml)) was added 1 mg (88 mg, 0.005). The reaction mixture was stirred at room temperature for 3 hours. The pH was lowered to about 3 with TFA, and the product was separated by RPHPLC to obtain the title compound (300 mg, after drying with ice cream) as a white solid. MS and NMR is consistent with the desired structure. Example 1 8 0 '(±) Lu-[[2-[[[[3 · [(aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] Of amino] amino] -2,5-dimethylphenylpropionate, trifluoroacetate,

The above compound was printed according to the method of Example 174, but printed by the equivalent of 2,5_ methylbenzaldehyde (Aldnch) in Example 174. 261-Good paper killing is applicable to China National Standards (CNS) A4 (2 丨 〇XW) 5. Description of invention (259 A7 B7 MS and NMR are consistent with the desired structure. Example 1 8 1 (±) Lu-[ [2-[[[3 _ [(Amineimidoamido) amino] phenyl] carbonyl] amino] ethenyl] amino] -2,5, dimethylphenylpropionic acid, trifluoroacetic acid Preparation of salt

< Please read the notes on the back before filling in this page). Yan. The product printed by Example ΙδΟ (71〇mg, O.OOU Mor) in water (1 0 ml) and CH3CN (10 ml) was added LiOH (215 mg, 0.005 moles). The reaction mixture was stirred at room temperature for 2,5 hours * pΗ was reduced to about 3 with TF A, and the product was separated by RPHPLC to obtain the title compound (600 mg, after lyophilization) as a white solid. MS and NMR are consistent with the desired structure β Example 1 8 2 ′, (±) / 3-[[2-[[[[[[Amineimidoamido) amino] phenyl] carbonyl] amine • Of ethyl] ethenyl] amino] -3-chlorophenylpropionate, ethyl trifluoroacetate,

NH

-262- Applicable to China National Elephant Standard (CNS) M specifications (210X297 public epidemic)-Order 6g A7 B7 V. Description of the invention (2e (D) The above compounds were prepared according to the method of Example 174, but the same amount of 3 _Chlorobenzoaldehyde (Aldrich) was substituted for the 3,4-diphenylbenzyl P MS and NMR in Step A of Example 174. It was consistent with the desired structure ... Example 183 (±) β-[[2-[[[3- [ Preparation of (aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -3 -p-phenylene diacid, trifluoroacetate σ

(Please read the precautions on the back before filling this page). Packing-The product printed in Example 182 (720.m.g, 0.0013 mol) in water (15 ml) printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs. To CH3CN (10 ml) was added LiOH (880 mg, 0: 02 mole). Reaction; Kun compound was allowed to stand at room temperature for 1 hour. pΗ was reduced to about 2 with TF A, and the product was separated by RPHPLC to obtain the title compound (550 mg, · on ice; after drying) as a white solid. ‘MS and NMR are consistent with the desired structure. · '. Example 1 will be 4 (±) yS-[[2-[[[[[[Aminoamidinomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino]- Preparation of 3-bromophenylpropanoic acid ethyl ester and trifluoroacetate.

NH I. Co2Et-order 1 'line' · -263- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) '1 4 q Α7 Β7 5. Description of the invention (261 The above compounds are based on Example 174 was prepared, but the same amount of 3-bromobenzaldehyde (Aldrich) was used to replace the 3,4-dichlorobenzaldehyde in step A of Example 174. MS and NMR were consistent with the desired structure. Example 1 8 5 (±) 々-[[2-[[[3-[(Aminoiminoamido) amino] amino] phenyl] carbonyl] amino] ethylii] amino] -3 · propanoic acid, r; ξ «Preparation of Gas Acetate

ΝΗ όο2η.

Br (please read the note ^ κ on the back before filling out this page) The product printed in Example 184 (lo mg, 0.0CH65 mol) in water (15 ml) and (: 113 €> ^ (10 ml) was added 1 ^^^ 1 (210 mg, 0.0005 mole). The reaction mixture was stirred at room temperature for 1.5 hours. PΗ was reduced to about 2.5 with TFA, and the product was subjected to RPHPLC Isolation gave the title compound (460 mg, after lyophilization) as a white solid. -MS and NMR were consistent with the desired structure. 'Example 1 8 6 (±) /?-[[2-[[[3- [ (Aminoiminomethyl) Amine] Benyl] Carbonyl] Amine] Ethylamido] Amine] -4 -bromophenylpropionate, Preparation of trifluoroacetate. 264- Good paper size application Chinese National Standard (CNS> Α4 Specification (210 × 297 mm) Order-line, 458956 A7 B7 V. Description of Invention (262

The above compound was prepared according to the method of Example! 74, but replaced with 3,4-dichlorobenzidine in step 174 of Example 174 with an equivalent amount of 4K-Acetone (Bird Kh). · MS and NMR and desired structure-cause 3. Example 1 87 (士) 广 [[2-[[[3-[(Aminoiminomethyl) amino] phenylfluorenyl] pyridyl] ethyl Fermentation group] amine group] _4_bromobenzylic acid, trifluoroacetate preparation. 〇

LiOH (290 mg '0.0069 mol) was added to the depleted product of Example 186 (1.3 mg, 0.0023 mol) in water (15 ml) and CH3CN (I5 ml). The mixture was stirred at room temperature for 1 hour. The pH was reduced to about 2.5 with TF Α, and the product was separated by RPHPLC to obtain the title compound (1 "g, after freeze-drying), as a white solid = > -265- This paper is applicable to China National Standards (CNS) Α4 specifications (UOX297 mm) ^ 956956 A7 B7 V. Description of the invention (263 MS friends NMR is consistent with the desired structure. Example 1 88 (±) /?-[[2-[[[[[[3-[(3,4; 5,6-tetrahydro-2 ^ -aza-7-yl) amino] phenyl] carbonyl] amino] ethyl] ethynylamino 3,5-dichlorophenylpropionate, trifluoro Preparation of acetate. 〇α

The above-mentioned compound was prepared according to the method of Example 11, but the equivalent of 3., 5-digas benzaldehyde (Aldrich) was used to replace the 3-pyridine aldehyde in Step A of Example 1 in Step 11 of Step 11 in Example 11. M S and NMR are consistent with the desired structure. Example 1 8 9 (±) Lu _ [[2-[[[[[[[3,4,5,6-tetrahydro-21 {, aza-7-yl) amino] phenyl] carbonyl ] Amine] Acetyl] Amine] —3,5-Digas Phenylpropionic Acid, Trifluoroacetate Preparation __ I --------- ^-(Please read the note on the back first (Please fill in this page for matters) Order f, printed by the Ministry of Economic Affairs ^ Central Consumers ’Bureau Consumer Cooperatives.

266 Thai paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 458956 A7 ___ ____B7 V. Description of the invention (264) The product of Example 188 (370 mg, 0.00057 mol) in water (20 ml) and To CH3CN (15 ml) was added LiOH (192 mg, 0.0046 moles). The reaction mixture was stirred at room temperature for 3 hours. ρη was reduced to about 2.5 with TF A, and the product was separated by RPHPLC 'to obtain the title compound (280 mg, after lyophilization)' as a white solid. 'M S and NMR are consistent with the desired structure. 'Example 1 9 0 (±) y?-[[2-[[[[[[[[[4,5-Dihydro-1 ^ imidazol-2-yl) amino] phenyl] carbonyl] amino] ethyl Preparation of fluorenyl] amino] _3,5-diethyl phenylpropionate, trifluoroacetic acid 'salt. ------------ (Please read the note on the back before filling in k Ben I)

The above compound was printed according to the method of Example 9 by the Consumer Cooperatives of the Central Bureau of Standards and Quarantine of the Ministry of Economic Affairs, but the equivalent of _3,5-digas benzaldehyde (Aldrich) was used to replace the 3-bamboo in step A of Example 1. Pyridoxal was used in Example 9, Step B. M S and NMR are consistent with the desired structure. Example 1 9 1. (±) y3-[[2-[[[3-[(4,5-dihydro-1 二 · imidazol-2-yl) amino] phenyl] carbonyl] amino] ethylamidine [Amino] amino] -3,5-diphenylphenylpropanoic acid, trifluoroacetate preparation-267- This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) A7 B7 V. Description of the invention ( )

To the product of Example 190 (200 mg, 20002 mol) in water (10 ml) and CH3CN (H) ml was added LiOH (54 mg, 0.0013 mol). The reaction mixture was stirred at room temperature for 5 hours, β p H was reduced to about 2.5 by T F A, and the product was separated by RPHPLC to obtain the title compound (90 mg, after lyophilization) as a white solid. M S and NMR are consistent with the desired result. Example 1 9 2 (soil);? -[[2-[[[[[[Aminoiminoamido) amino] amino] phenyl] carbonyl] amino] ethylamido] amino] -3,5-dimethylphenylpropionate Preparation of esters and trifluoroacetates

The above compound was printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs according to the method of Example 174, but the equivalent of 3,% dimethylbenzaldehyde (Lancaster) was used instead of 3,4_dichlorobenzyl in step a ” _-268- This paper size is applicable to Chinese national standard (0can) 8 4; ^ (210 \ 297 公 楚)

9BS A7 B7 5. Description of the invention () MS and NMR are consistent with the desired structure. Example 1 9 3 (±) y5-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbon] amino] ethoxy] amino] -3, Preparation of 5-dimethylphenylpropionic acid and trifluoroacetate.

To the product of Example 192. (" 730 mg '0.0013 moles) in water (10 liters) and 0 ^ 3 匸 1 ^ (10 ml) was added 1 ^ 011 (221 mg, 0.05 Moore). The reaction mixture was stirred at room temperature for 1 hour. The pH was lowered to about 2.5 by TFA, and the product was separated by RPHPLC to obtain the title compound (570 mg, after drying on ice) as a white solid. , M S and NMR. Are consistent with the desired structure. Example 1 9 4 (±) 々-[[2-[[[[[[Aminoiminomethyl) amino] phenyl-] carbonyl] amino] ethoxy] amino] -j, 5-Preparation of Monomethyl Acetate, Acetate Triacetate (Please read the precautions on the back before filling Lin 1 page). Packing. Order. 0: Printed by the Central Consumers' Bureau of the Ministry of Economic Affairs, Consumer Consumption Cooperative System

-269- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)

^ '4 5E 9 5β Α7 B7 V. Description of the invention (267) The above compound was prepared according to the method of Example 174, but replaced with the same amount of 3,5-dioxoxybenzaldehyde (Aldrich) in Step 174 of Example 174. 4-Dichlorobenzyl. MS and NMR are consistent with the desired structure. (Please read the precautions on the back before filling the reverse page)-Installation · Example 1 9 5 (±) / 3-[[2-[[[[3 · [(Amineimidoamido) amino] benzene) benzene Of carbonyl] amino] amino] ethenyl] amino] -3, · 5-dimethoxyphenylpropionic acid, trifluoroacetate

—ΤΓ— To the product of Example 194 (800 mg, p.00014 moles) was added water (20 ml) and CH3CN (8 ml) with LiOHi 230 mg, 0.0055 moles). The reaction mixture was stirred at room temperature for 1.5 hours. ρΗ was reduced to about 3 'with TF A, and the product was separated by HPHPLC to obtain the title compound (670 mg, after freeze-drying) as a white-colored solid. . M S and NMR are consistent with the desired structure. Example Γ9 6. (±) 0-[[2-[[[3-[(Amineimidoamido) amino];] phenyl] carbonyl] amino] ethylamido] amino] -3, Preparation of 5-digas phenylpropionate (2,2-dimethyl-1-oxypropoxy) methyl ester and trifluoroacetate -270- Good paper size applicable to China National Standard (CNS) A4 size (210x297 (Mm) Wei /, Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ^ hd > 3 56 A7 B7 V. Description of Invention (268) 〇 Λη

TFA Step A. DL-3 -amino- 3- (3,5-dichlorophenyl) propionic acid was prepared according to the method of step a of Example 1 but with an equivalent amount of 3,5-dichlorophosphonium formaldehyde (Aldrich) Instead of biting the 3-p ratio several times in step A of Example 1. MS and NMR are consistent with the desired structure.

Step B The product of Step A (3.0 g, 0.0128 mmol) was added to dioxin (25 mmol, liter) and water (13 ml). NaOH (0.52 g, 0.013 mole) was added to the ice bath at In water (1 3 ml). After stirring at the ice bath temperature for 10 minutes, B 0 C anhydride (3.0 g, 0.014 mol) was added at the ice bath temperature. The reaction mixture was stirred at room temperature for 2 hours. After the dioxin was removed in the air tank, the aqueous solution was cooled in an ice bath. After covering with ethyl acetate, the pH was lowered to 2.4 with KHS04. The ethyl acetate layer was separated. The aqueous layer was extracted twice with ethyl acetate. > The combined ethyl acetate layer was washed with Η 2 Ο (3 X), and 'dried with MgS04. The solvent was moved down in the air-removed. The residue was slurried in 5% ethyl acetate / methane overnight to give a white solid. It was filtered, washed with 10% ethyl acetate / hexane, and dried to obtain? -30 (:-01 ^; 3-amino-3- (3,5-diphenylphenyl) propionic acid. (2.9 g) as a white solid. '

Step C The product from Step B (2.5 g, 0.0075 mmol) in acetone (30 ml) -271-This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the notes on the back first (Refill bird page)

Printed by Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs' 4 58 9 5S a? B7 269 V. Description of the invention () and water (5 ml) KO (87%) (0.5 g, 0.0075 mol). To this was added chloromethyl trimethyl acetate (1.3 g, 0.0084 moles) (Aldrich), and then NaI (190 mg) 3 was added to the reaction mixture and stirred overnight at reflux. The solvent was removed under air. The residue was absorbed into ether. The ether was washed with saturated NaHC03 (2X), H20 (3X), dried over MgS04, and removed under a tin pot to obtain N-BOC-DL-3-amino-3- (3,5-diphenylphenyl) propane Trimethylacetoxymethyl ester (2-92 g) as a white solid. MS and NMR_ have the desired structure.

Step D To the product of Step C (2.92 g, 0.0065 mmol) was added an excess of 4M HC1 dioxan (Aldrich). The reaction mixture was stirred at room temperature overnight. The solvent was removed under agitation and the residue was slurried 2X with petroleum ether / isopropyl ether (50:50) and 1X with petroleum ether (each solvent decantation). The resulting solid was dried under tritium air to obtain DL-3-amino-3- (3,5-diphenylphenyl) propionic acid trimethylacetoxymethyl hydrochloride (2.0 g) as a white solid. \ MS and NMR are consistent with the desired structure. Step E 'The title compound was prepared according to the method described in Example 174, Step B, but replacing the product of Step D with an equivalent amount of the product of Example A. Step 4 in Example 174. The title compound was isolated as a white solid. MS and NMR are consistent with the desired structure. Example 197. (Earth) 3,5-difluorocyanimido) (methylamino) methyl] amino] benzyl] quinyl] amino] ethyl ethyl] amino] ethyl phenylpropionate Preparation of vinegar-272- This paper size is applicable to Chinese National Standards (CNS) / \ 4 计 潘 ί 210X297 mm) ------------ (Please read the precautions on the back before filling in this page ) hj order

270458 95S A7 B7 V. Description of the invention (ch3 NH ^.

Step A / ^-[(2-Aminoethylammonium) Amine] (3,5: diphenylphenyl) · 3-propionate ethyl ester hydrochloride based on the printing of consumer cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs Example i was prepared by the method of step A_D, but the equivalent of 3,5_ digas benzyl was used to substitute the example of Qian Jun. ms & nm_ The desired structure is consistent. Step B The product of the above step A (11 g,,.. .00, 31 mol), the product of Example] (_mg, 0.0031 mol), DMAP (38 mg ', __31 mol) EDCI (600 mg, 0.00M mole) was added to diethylamine (20 mg, 0.0031 mole) and digas methane (12 ml) at an ice bath temperature. The reaction mixture was stirred at an ice bath temperature for 15 minutes and then at room temperature overnight. After the solvent was removed under agitation, the residue was taken up in ethyl acetate. The acetic acid-diethyl ether was washed with saturated NaHC03 (1X), H20 (2X), dried over MgSQ4, and then removed under vacuum. The resulting solid was slurried in ethyl acetate / isopropyl ether (1: 3) for 1 hour. The resulting solid was filtered, washed with isopropyl ether, and dried under vacuum to obtain the title compound (1.35 g) as a white solid. Example 198 (±) 3, hydrazone-yS-[[2-[[[[[3-[(cyanoimino) (methylamino) methyl] methyl] amino] phenyl] carbonyl] amino] ethyl Preparation of fluorenyl] amino] phenylpropionic acid -273- This paper size is applicable to Chinese National Standard (CNS) A4 specification (2! 0X 297mm) Packing--I {Please read the note on the back before filling (Per page). Order

I tor

458 95S A7 B7 V. Description of the invention (271

To the product of Example I97, Step B (1.18 g, 0.023 mol) in water (15 ml) and CH3CN (15 ml) was added LiOH (240 mg, 0.0057 mol). The reaction mixture was stirred at room temperature for 3 hours. pΗ was reduced to about 3 with TF A, and the product was separated by RPHPLC to obtain the title compound (1.02 g, after freeze-drying) as a white solid. MS and NMR are consistent with the desired structure. .Example 1 9 9 (±) 3,5-dichloro- / 5-[[2-[[[[[[[[1,4,5,6-tetrahydropyrimidin-2-yl) amino] phenyl] ] Carbonyl] Amine] Ethyl] -amino] ethyl phenylpropionate, trifluoroacetate preparation < Please read the w-item on the back of the note first and then fill in this page. Printed by Betty Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs, 1Τ β

To the product of Example 23, Step A (10.1 g, 0.03 mmol) was added to 0MF (15 ml) 1,3-diamino.propane (2.3 g, 0.031 mole), triethylamine 274-wood paper The scale is applicable to the Chinese National Standard (CNS) Ba Ru _ ^ grid (210X25 »/ mm) Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ^ 458 956 A / ------ B7 V. Description of the invention (272) (3.9 grams' 0.03 moles) and dmAP (420 mg). The reaction mixture was heated at 140-150 C for 4.5 hours (thick precipitate). After cooling to room temperature, water (30 ml) was added 'After stirring for 5 minutes, the precipitate was filtered and washed with water. The deposits are slurried in water and acidified with concentrated HC1. A solution was formed. After the solvent was removed by drying on ice, the residue was slurried 2x with isopropyl ether (decanted every time with isopropane). After drying in the air, 40 g of 3- (2 • amino-1,4,5,6-tetrahydropyrimidine) benzoate was obtained as a white solid. The ms and N MR are consistent with the desired structure.

Step B Add the product of Step A (884 mg, 0.0035 mol) and .NMM (350 mg '0.0035 mol) in anhydrous DMF (6 ml) to isobutyl chloroformate (470 mg' 0 , 0035 Mol). After 5 minutes of mixing, the slurry of the product of Example 197 Step A (1.07 g, 0.003 moles) and NMM (300 mg '0.003 moles) in anhydrous DMF (6 ml) was placed on an ice bath. Join. The solution was stirred at room temperature overnight. The solvent was removed under vacuum and the product was separated by RPHPLC to obtain the title compound (820 mg, after lyophilization) as a white solid. MS and NMR are consistent with the desired structure. Example 2 0 0 (±) 3,5-Digas- / 3-[[2 _ [[[[[[[[[1,4,5,6-Tetrahydrosulfan-2-yl) amino] phenyl]] Kanji] Amine] Ethylethyl] -Amino] Phenylpropionic acid, Trifluoroacetate preparation -275- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (please read the back first) (Note ^ V and fill in " page)

^ 4 53 9 58 A7 __.__ B7 V. Description of the invention (273). '·

To the product of Example 199, Step B (780 mg, 0.0012 moles) was added LiOH (830 mg, 0,005 moles) in water (10 ml) and CH3CN (10 ml). The reaction mixture was stirred at room temperature for 1.5 hours. pΗ was reduced to about 2.5 with TFA and the product was isolated by RPHPLC to obtain the title compound (560 mg, after lyophilization) 'as a white solid. M S and NMR are consistent with the desired structure. 'Example 20 1 (±) cold-[[2-[[[3-[[[(Aminocarbonyl) imine] methylamino] methyl] amino] phenyl] eumyl] amino] ethyl Fluorenyl] amino] -3,5-diphenylphenylpropionic acid for preparation Please read the notice on the back before w. Page 1 of this page

To the product of Example 198 (300 mg, 0.0006 mol) was added TFA. (6 ml) in water (25 ml) and CH3CN (10 ml). The reaction mixture was stirred at room temperature for 2 weeks. The product was isolated by RPHPLC to obtain the title compound (290 mg, after lyophilization) as a white solid. ‘-276-This paper size applies the Chinese National Standard (CNS) A4 specification UI0X297 mm) ί’. 4 53 g > 56 'Α7 _______ Β7 ____ 5. Description of the invention (274). MS and NMR are consistent with the desired structure. ί Example 202 »'>. (±) Xiu-[[2-[[[[[[[[[[[[3,4-Dihydro · 2Η · pyrrole-5-yl] amino] phenyl] thiol] amino] amino ] Ethyl ethyl] amino] -3,5-dichlorophenylpropionate ethyl trifluoroacetate

The above compound was prepared according to the method of Example '16, but the equivalent of 3,5-dichlorobenzaldehyde (Aldrich) was used to replace the 3-pyridinecarboxaldehyde in Step A of Example 1 (which was used to synthesize the product of Step D of Example 1, using Step 11 in Example 11). M S and NMR are consistent with the desired structure. Example 2 0 3 (±) Cold-[[2-[[[[[[[3,4-Dihydro-2fluorene-pyrrole-5-yl) amino] benzyl] carbonyl] amino] ethyldonyl] Amine] -3,5 -Digas phenylpropionic acid, trifluoro ig · acid salt preparation '' m-I (Please read the precautions on the back before filling the free sheet) Order the staff of the Central Standards Bureau of the Ministry of Economic Affairs Printed by a cooperative

The size of this paper applies to the Chinese National Standard (CNS > A4). (2I0X 297mm> A7 B7 V. Description of the invention (275) The product of Example 2 (1'27g, 0002 mol) in water (15 ml) and CH; 3CN (15 ml) was added LiOH (345 mg, 0.0082 mole). The reaction mixture was stirred at room temperature for 1 '5 hours., Ρ · Η was reduced to 2.7 with TFA, the product Separation by RPHPLC 'gave the title compound (80 mg,' after lyophilization) as a white solid. MS and NMR were consistent with the desired structure. Example 2 0 4 (±) j, 5-dichloro-[[2- f [[3-[(2,3,4,5-tetrahydropyridine-6-yl) amine * ', phenyl] phenyl] carbonyl] amino] ethylfluorenyl] aminetai] -ethyl phenylpropionate , Preparation of trifluoroacetate I pull clothes-(#Read the precautions on the back before filling {气 木 页)

Order _ · Printing step A of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, add 0-methylvalerolide imide (〇akw.ood) (6.9 g, 0.061 mol) to -CH3CN (75 ml) 3-Aminobenzoic acid hydrochloride (Aldrich) (10 g, 0.0576 mol). After brief heating to form a solution, the reaction mixture was stirred at room temperature. The resulting precipitate was filtered, washed with CH3CN, and dried under vacuum to obtain 3- (1-aza-2-amino-1-cyclohexene) benzoate hydrochloride «(12.2 g) 'as a white solid . MS and NMR are consistent with the desired structure.

Step B 278- The scale of the private paper wave applies the Chinese National Standard (CMS) A4 specification (210X297 mm). (≫: Issue 9 58 V. Description of the invention (276) A7 B7 The standard compound is based on the one described in Example 199 It was prepared by the method, but the product of Step A was replaced by an equivalent amount of the product of Step 199 in Example 199 and Step B. MS and NMR were consistent with the desired structure. Example 2 0 5 (±) 3,5-dichloro -/ 5-[j; 2-[[[[[[[3-[(2,3,4,5 -tetra-argonide-6-yl) amino] phenyl] carbonyl] amino] Γ.SS.] amine Of phenyl] -phenylpropionic acid, trifluoroacetate

—-------- ^! F Please read the notes on the back before filling in this page) 1 --Order— The product printed in Step B of Example 204 by the Shellfisher Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs ( 890 mg, 0.0014 moles) was added LiOH (236 mg, -0.0056 moles) to water (20 ml) and CH3CN (20 ml). The reaction mixture was stirred at room temperature for 1 hour. pΗ was reduced to about 3 with T F A, and the product was separated by RPHRLC to obtain the title compound (3 to 20 mg, after freeze-drying) 'as a white solid. MS and NMR are consistent with the desired structure. Example 206... (±) /?-[[2-[[[[[[Aminethiothio] amino] phenyl] carbonyl] amino] ethoxy] amino] -3,5 -Preparation of di-air beam propionic acid-279- The paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) B7 V. Description of the invention (277 〇 2Η

The above compound was prepared according to the method of 'Example 19δ, but the equivalent of 1_ Carboxyphenyl) -2-thiourea (Transworld) was used in place of the product of Example | in Step 197 of Example IB. MS and NMR are consistent with the desired structure. Example 2 0 7 (±) Hiko-[[2-[[[[3 _ [(Amineimineamido) amino] phenyl] quinoyl] amino] ethoxy] amino] -3,4 -Preparation of dibromophenylpropionic acid and trifluoroacetate (please read the precautions on the back before filling this page) H2

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs The above compound was prepared according to the winter method of Example 175, but the equivalent of 3,4-dibromobenzaldehyde (Lancaster) was used to replace the 3,4-digas benzaldehyde in Step 174 of Example 174. M S and NMR are consistent with the desired structure. Example 208 (±) fluorene-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino J acetamido] amino] -3-fluoro-5 -(Trifluorofluorenyl) phenylpropionic acid, trifluoroacetate-280- Private paper grade applicable to China National Standard (CNS) A4 (210X297 mm) A7 B7

The above compounds were prepared according to the method of Example I75, but with the same amount of 3 _

S qQ V. Preparation of the invention (8) _ 5. Trigas methyl benzoate (Lancaster) replaces the 3 4 _-gas benzaldehyde in step 174 of Example 174. -MS and NMR are consistent with the desired structure. .Example 2 0 9 'm! (Please read the notes on the back before filling this page) Order 0. (±) /?-[[2 · [[[3-[(Aminoimidomethyl ) Amino] phenyl] carbonyl] amino] ethoxy] amino] -3] -xi-5-fluorobenzenedicarboxylic acid, trifluoroacetate

Printed snail A by the Consumer Cooperative of the China Standards Bureau of the Ministry of Economic Development. In 1-fluoro_3,5-dibromoben (Lancastei) (10 g, 0,394 mol) in anhydrous ether (50 ml), In a flame-dried flask, under nitrogen at -78 eC, add dropwise: L6 ml of butyllithium in hexane (Aldrich). Adding -281-This paper size is in accordance with Chinese National Standard (CNS) A4 (2lOX297 male iT) '^ A7 B7 V. Description of the invention (279) The temperature during entry is kept below -7 8 ° C. After the addition was complete, the reaction mixture was stirred at -78 C for 50 minutes. The reaction mixing potential was slowly heated to -30, and then hot water DMF (3.6 g, 0.049 mol) was added dropwise at a rate that kept the temperature below -20 ° C. After the addition was completed, the temperature was slowly raised to 0 within 1 hour and then stirred at room temperature overnight. The reaction mixture was slowly poured into a cold i 0% Ηα aqueous solution (80 ml). After 15 minutes of incubation, the ether layer was detached, and the ether was washed with Η20 (· 4 ×) and 'dried with MgS04' and then removed in the air to obtain 3-bromo-5_fluorobenzene. (8 · 16 g ), Presented according to Percy liquid ·. μS and NMR are consistent with the desired structure. Step B The title compound was prepared according to the method of Example 175, but replacing the equivalent of 3,4-dichlorobenzaldehyde in step A with the same amount of 3-bromo · 5-fluorobenzaldehyde (step A above). M S and NMR are consistent with the desired structure. '' Example 2 1 0 (±) ^-[[2-[[[(Amineimine · methyl) amino] benzyl] carbonyl] amino] ethenyl] amino], 3 Preparation of 1,5-dibromophenylpropionic acid, trifluoroacetate (please read the notes on the back before filling in the private page) -Order-line m

fN Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

Step A

-282- This paper size applies to China National Standards (CNS) A4 size (210x297 mm) Printed by Zhengong Consumer Cooperative, Central Government Bureau of the Ministry of Economic Affairs 458956 A7 B7 V. Description of the invention (280)

I To 3,5--lancaster (20 g, 0.061 mole) in water (27 ml) and ice acid (27 ml), add hexamethylenetetramine (Aldrich ). The reaction mixture was heated at reflux for 2 hours, then HC1 (22 ml) was added and the reflux was continued for 30 minutes. After cooling to room temperature, the reaction mixture was poured into water (230 ml) and stirred for 10 minutes. The resulting precipitate was filtered and washed 'dried' with η 2 to obtain 3,5-dibromobenzaldehyde (il, 45 g) as a white solid. MS and NMR are consistent with the desired structure "Step B The title compound was prepared according to the method of Example 175, but replaced by the same amount of 3,5-Dimo. , 4-Dichlorobenzaldehyde »MS and NMR are consistent with the desired structure. Example 2 1 1 (±) 3,5-dibromo-fluorene-[[2-[[[[[[[[[1,4,5,6-tetrahydropyrimidin-2 -yl] amino] phenyl] phenyl ] Carbonyl] amino] ethyl]] amino] phenylpropionic acid, trifluoroacetate preparation ·

Step A Lu-[(2-aminoethylammonium) amino] (3,5-dibromophenyl) -3-propanoic acid ethyl ester hydrochloride was prepared according to the method of steps A to D of Example 1, but In the same amount 3,5--283- This paper size applies to Chinese national standards (CNS > A4 specifications (2 [0 X 297 public directors) ---------- ^ — /: / (Please First read the notes on the back and then fill in the private note) Order 4 A7 B7 V. Description of the invention (281) Dioxalaldehyde (Example 210, step a) Replace the 3-pyridine carboxyl group in Example 1 Step MS. For structure consistency.

Step B The title compound was prepared according to the method of Example 200, but replaced with the equivalent of the product of Example 211 Step A (above) in Example 199 Step b of Example 197 Step A. MS and NMR are as good as the desired structure. •. Example 2 1 j (±) / 5-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino]- Bromine_; Preparation of 5-methylphenylpropionate 'trifluoroacetate 〇

Step A Printed by the Consumer Cooperatives of the Central Bureau of Quasi-Economic Bureau of the Ministry of Economic Affairs. Add benzamyl peroxide (3 04 g '〇.〇13 mol). The reaction mixture was heated to reflux in a 250 ml round bottom flask. N-Bromosuccinimide (18.15 g '0-10 Molar) was added in 1 portion * over 15 minutes. After 2 hours, the heating was continued and the reaction mixture was cooled to room temperature. The precipitated solids were removed by filtration. The filtrate was concentrated. The residue was sucked into the tiger and the solid matter was removed by filtration. The filtrate was passed through a small pad of silica gel and the filtrate was concentrated. The resulting yellow oil was triturated on ice with MeOH to give 3-bromo-5-methylbenzyl bromide (7.34 g) as a white solid. MS and NMR are consistent with the desired structure.

Step 骒 B -284- This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210_X297 mm) 458 956 A7 B7 282 Printed by the Consumers' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs -Methylbenzyl bromide (step A above) (5.49 g, 20 mmol) in water (9 ml) and glacial acetic acid (9.0¾ liters). Add hexamethylenetetramine (4.5 0 g '3 2 The reaction mixture was removed at reflux for 2 hours. Then concentrated HCU 7.0 ml) was added and the mixture was refluxed for another 15 minutes. After cooling to room temperature, the reaction mixture was diluted with water (75 ml) and extracted with ether (150 ml). The ether layer was washed with H20 (3 × 25 ml), 10% NaHC03 (2 × 50 ml) and dried over MgSO +. The ether was transferred under a vacuum, and the residue was chromatographed on silica gel with hexane and 10% E t 2 0 / hexane to obtain 3 _ Mo_ 5 _ methyl benzoic acid (2,80 g). Yellow oil, which solidified on standing. M $ and NMR are consistent with the desired structure》

Step C The title compound was prepared according to the method of Example I75, but replacing the 3,2-diphenylbenzaldehyde in step A of Example 174 with the same amount of + 3.bromo.5-.fluorenylbenzaldehyde (the above step A). MS and NMR are consistent with the desired structure. Example 2 1 3 (±) 4-[[2-[[[[[[Amineimine fluorenylmethyl) amino] -5_ (trifluoromethyl) phenyl] carbonyl] amino] ethyl] ethyl; [Amine] _3,5 · Dibromophenylpropionic acid_, Preparation of trifluoroacetate '. 3

-285- The paper size of the dagger is applicable to China National Standards (CNS) 8-4 (21〇) < 297 Publication 458956 A7 ---- 283 --- 5. Description of the invention (). The above compounds are based on Example 39. Prepared by the method, but replacing the 3,5-bis-trifluoromethylbenzaldehyde in Example 38 with an equal amount of 3,5-dibromobenzaldehyde (Example 210, step a). MS and NMR are consistent with the desired structure. • Example 2 1 (±) β-[[2 _ [[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -3- Preparation of bromo-5-gas benzoic acid and three elephant acetate

Step A. In 1-gas-3,5-dimethoxybenzene (Esprit) (? 0 g, 0'074 mol) in absolute ethanol (150 ml), in a flame-dried flask, under argon, under 78. 〇, 1.6 ml of butyl bell was added dropwise. The temperature was kept below -7 ° C, and then heated to -301. Anhydrous DMF (6.8 g, 0.092 mol) was added dropwise, and the temperature remained below -2 0 ° C. After the addition was completed, the reaction mixture was slowly heated to 0 ° C, and then stirred at room temperature overnight. The β reaction mixture was poured slowly Cold 10% HC1 aqueous solution (160 ml). After stirring for 15 minutes, the ether layer was separated, the ether was washed with hydrazone 20 (4 ×), dried over MgS04, and then removed under vacuum to obtain 3.bromo-5-fluorobenzaldehyde (13 g) as a white solid. MS and NMR are consistent with the desired structure.

Step B -286-This paper size is in accordance with the Chinese National Standard (CNS) A4g (210X297 mm) (Please read the precautions on the back before filling in the page). Binding and printing r 4 ^ 8 956 A7 B7 V. Description of the invention (284 The title compound was prepared according to the method of Example 17 5 but replaced with fragrant 1-3-soil _ 5-fluorobenzidine (step a) above to replace the example 174 3,4 acetaldehyde in step flooding a. MS and NMR are consistent with the desired structure. Example 2 1 5 (±) 3-xi-5-qi · 々 _ [[2 _ [[[[[[[3-[(1,4, 5,6_tetrahydrobite_ Amino] phenyl] carbonyl] Amine] Ethylamido] -Amino] Phenylpropionic acid

Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

Step A-[(2-Aminoacetamido) amino] (3-Mo'-5-Gaphenyl) _Ethyl dipropionate hydrochloride was prepared according to the method of step AD in Example 1, but waited for The amount of 3, riding a 5-gas benzyl route (Example 214, step A) replaced the 3-tonne aldehyde in step a of Example 1. MS and NMR are consistent with the desired structure. a few

Step B The title compound was prepared according to the method of Example 2000, but the product of Step 8 (above) was replaced by the same amount of the product of Step 197 of Step 199 as in Example 197. MS and NMR are consistent with the desired structure a. Example 2 1 6 (±) y3-[[2-[[[3-[. (Amineiminoamido) amino] amino group) #_ (trifluoromethyl)- 287- The size of this paper is applicable to China National Standard (CNS) A4 (2ϊ〇χ 297 公 楚) 468 9 56 A7 B7 V. Description of the invention (285 Phenyl] carbonyl] amino] ethenyl] amine]- Preparation of 3_bromo-5-gas phenylpropionic acid and trifluoroacetate 〇H2

The above compounds were prepared according to the method of Example 39, but the equivalent of 3 -bromo-5 -chlorobenzaldehyde (Example 214, step A) was used to replace the 3,5-bis-trifluoromethylbenzaldehyde e MS and NMR in Example 38. Consistent with the desired structure. Example 2 1 7 (Shi) 3., 5_ Digas-[[2-[[[[[[[[[[[[1,4,5,6-Tetrahydrocyclo-2-yl) amino]]]]] [Amino] Amino] Ethyl] -Amino] Phenylpropanoic acid [2- [2- [2- (2- (Ethoxy) ethoxy] ethoxy Lethyl] ester, trifluoroacetate Preparation I --------—— Mo—— (Please read the notes on the back before filling in the page) i.

Ding, -'B Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

XT

-OH The product of Example 200 (200 mg, 0.00033 mole) was added to DMA (1.5 ml) and carbonyldiimidazole (67 mg, 0.00041 mole) was added. The reaction mixture was stirred at room temperature for 1 hour. Tetraethylene glycol (214 mg, 0.0011 mol) -288- This paper size applies to Chinese National Standard (CNS) A4 (2I0x297 mm) 286 A7 B7 V. Description of the invention (addition, the reaction mixture is stirred at 60 ° C Overnight. The reaction mixture was cooled to room temperature, and the product was separated by RPHPLC to obtain the title compound (120 mg, after lyophilization) as a wet white solid. MS and NMR were consistent with the desired structure. Example 2 1 8 ( ±) y5-[[2-[[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -3,5-digas-benzene Preparation of [2- [2- [2- [2- (2-hydroxyethoxy) ethoxy] ethoxy'ethoxy] ethyl] propionate, trifluoroacetate.

(Please read the notes on the back before filling ^ heart page)

OH The above compound was prepared according to the method of Example 2 17 but the equivalent of the product of Example 27 was used instead of the product of Example 200. μ S and NMR are consistent with the desired structure Example 2 1 9 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (±) Lu-[[2-[[[3 · [(Aminoiminomethyl) amino] Phenyl] carbonyl] amine • ^] ethynyl] amino] _3 · bromo-5-iodohexanoic acid, the preparation of trifluoroacetate 0 Η2

-289- The standard of this paper is applicable to Chinese National Standard (CNS) A4 specification (210X297mm) Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (28)

Step A Methanol (40 ml) was added to a 250 ml 囷 bottom flask, and then 60 ml of a saturated solution of anhydrous hydrochloric acid was added. Then 3-Bromo-5-iodobenzene · acetic acid (Aldrich) (5.02 g ', 0.015 mol) was added, and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into a cold saturated NaHC03 solution (700 ml). The mixture was extracted 3X with digas methane (1 （ml). The organic layers were combined, dried over MgS04, and concentrated under reduced pressure to obtain methyl 5-bromo-3-benzoate (5.08 g) as a pink solid. Melting point = 5 5-5 7, C. MS and NMR are consistent with the desired structure.

Step B: Methyl 5-bromo-3-iodobenzoate (step a) above (5.01 g, 0.015 mol) in anhydrous dichloromethane (100 ml) at -78 ec in 2 minutes Diisobutylaluminum hydride (5-50 ml, 0.03 mole) was added dropwise. The mixture was stirred for 1 hour 'and then heated to 0 ° C. The reaction solution was poured into 600 ml of cold 3 N HC1 and extracted 3X with dichloromethane (150 ml). The organic layers were combined, dried over MgS04, and concentrated under reduced pressure to give 5-bromo-3 -iodobenzyl alcohol (4.54 g) as a white solid. Melting point = 110-112 ° c. MS and NMR are consistent with the desired structure.

Step C 5-Bromo-3-iodobenzyl alcohol (3.01 g, 9.6 mmol) was magnetically stirred 'in a 50 ml round-bottomed flask and diluted with 15 ml of anhydrous digas methane to obtain a cloudy solution. The reaction beaker was then stoppered and fixed with a wire. Anhydrous monochloromethane (0.5 ml) was added to another 100 ml round bottom flask equipped with a cold finger (^ | nger). Condensation of nitrogen dioxide (1 72 g, 18.7 mmol) ___- 290-

Dimension Gutil Pipi (⑽) M secret (2IGX297 public P ^ — (Please read the precautions on the back before filling in ir.p page, ιτ P. 2 ------- B7 11, ^ ___ __ .. _ V. Description of the invention (288) The solution of dichloromethane in -2 (TC. The solution of this alcohol is cooled to 0 * C, and the solution of nitrogen dioxide / two winds • Jiapo * is under static nitrogen pressure. The tube was transferred into the reaction flask via a cannula. After the nitrogen dioxide solution was transferred in, the reaction solution was magnetically stirred at 0 ° C for 15 minutes. The reaction solution was stirred at room temperature for 18 'hours. The reaction flask was vented in a fume hood The excess nitrogen dioxide was discharged as nitrogen vapor. The reaction solution was then concentrated by rotary evaporation and resuspended in 30 ml of ether. The ether solution was washed in a 500 ml separatory funnel with 200 ml of a 10% sodium bicarbonate solution. The resulting aqueous solution Extracted three times with 150 ml of ether. The organic layers were combined, dried over Na2S04, filtered, and concentrated under vacuum to obtain 2.89 g of a yellow solid. The product was separated by flash chromatography to obtain 5-bromo-3 -benzidine It is a white liquid. MS and NMR are consistent with the desired structure.

Step D The title compound was prepared according to the method in Example 175, but replacing the same amount of 5_brook_ 3 -iodobenzaldehyde (step C above) with the 3,4_ digasbenzaldehyde in step 174 of Example 174 = MS and NMR. The desired structure is consistent. _ Example 2 2 0 Printed by the Consumer Cooperatives of the Central Bureau of Accreditation of the Ministry of Economy (±) 3,5-dichloro- /?-[[2-[[[j-{(1,4,5,6-tetrahydro Pyrimidine_2.yl) amino] phenyl] carbonyl] amino] ethynyl] -amino] benzylpropanoic acid [2- [2_ (2_yongethoxy) ethoxy] ethoxy] Ethyl] The purpose of the preparation of difluoroacetate -291-This paper size is applicable to China National Standard (CNS) A4 (2 丨 0X297 mm) A7 B7 V. Description of the invention (289

OH The above compound was prepared according to the method of Example 217, but tetraethylene glycol was replaced with an equivalent amount of triethylene glycol. MS and NMR are consistent with the desired structure. Example 2 2 2, (±) Lu-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethynyl] amino] -2- Preparation of hydroxy-4 -methoxyphenylpropionic acid

{Please read the notes on the back before filling {®; < ί pages) .Sound-Order

.1L Printed (RS) -4-Amino · 7 · Methoxygenin Hydrochloride by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs. (1.26 g, 5.5 mmol) Tett. Let., 1994, Q, 6599-6602, prepared from 7-methoxyoxyvannin (Aldrich)] Coupling to GIHA (1.50 g, 5.5 mmol), Substantially using Example 8 6. Step D of Procedures and proportions. Purified by preparative RPHPLC to obtain the desired product as a mixture of hydroxanthin (lactone) and phenoxy-acid TFA salt. After freeze-drying, it was a pale yellow powder (1.25 g). -292- This paper is universal in size Chinese National Standard (CNS) A4 specification (2! 0 × 297 mm) 458 356 A7 B7 V. Description of the invention (290. Essentially all yuan is converted into the desired age_acid, which can be dissolved in water from the purified leakage compound to Dilute NaOH solution to adjust pH to 7-8, and ice-dried (0,5 g). MS and NMR are consistent with the molecule of phenol-carboxylic acid. Example 2 2 3 (±);?-[[2- [ [[3-[(Aminoiminoamido) amino] benzyl] carbonyl] amino] ethoxy] amino] -5 -kilyl-4-methoxyphenylaranylpropanoic acid, Preparation of trifluoroacetate. '

(Please read the precautions on the back before filling this page) • Packing and printing (RS) 4-amino-8-methoxy-hydropsoralen printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ( psoralen) hydrochloride (2.2 g '8.1 mmol) [according to J. Rico, Tett. Let ·, 1994, 33, 6599-6602' prepared from 8-fluorenoxypsoralen] conjugated to 〇ΙΗΑ (2.0 g, 7.3 mmol), essentially using the procedure and ratio of Example 86, Step D, and the product was isolated by preparative RPHPLC as the desired phenol-acid. ‘M S and NMR are consistent with the desired structure. Example 224 (±) Lu-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethenyl] amino] · 9Η-No.-2 -Preparation of propionic acid and trifluoroacetate-293- Good paper · Standards applicable to Chinese National Standard (CNS) A, 4 specifications (21 × 2 2 mm) 锿 'Μ 4 58 956 Α7 Β7 V. Description of the invention ( 291)

Step A. '. (±) θ-Amino-9H-fluorene-2-propionic acid

Employees' Cooperatives of the Central Economic and Technical Bureau of the Ministry of Economic Affairs of the People's Republic of China, Yin Ju 2-Wei-Ji (5'0 g, · 26 mmol, Aldrich) combined malonic acid (3.25 g, 31 mmol), ammonium acetate (2.4 g , 31 mmol) and isopropanol (70 ml), reflux overnight. After cooling, the precipitated solid was collected by transition and dried. MS and NMR are at odds with the desired structure,-. Step B., (soil) Lu · amino-9H- 苐 -2-propanoic acid acetamidine every step _ absorbed in absolute EtOH, anhydrous HC1 gas is added to Saturated and the mixture was refluxed overnight. The volatiles were removed and the resulting solid was partitioned between ethyl acetate and water. The aqueous layer was made alkaline with 2,5 N NaOH, and extracted with pEt0Ac (2 x 200 ml). The organic layer is dried (anhydrous NaS〇4), anhydrous ^ 1 (: 1 gas is added until the precipitation stops. Volatile matter is removed until a solid residue is generated 294- This paper is Λ degree applicable to China National Standard (CNS) A4

A7 B7 292 ^ 58956 5. Description of the invention (up to now. It was milled with diethyl ether to obtain a solid, which was collected by filtration. NMR was consistent with the desired structure.

Step C The title compound was prepared in the following manner. GIHA (0.41 g, 1.5 mmol) was essentially coupled to the product of step b above (0.42 g '1.5 mmol) using the procedure of Example 86, Step D. Preparative RpHPLC was used to isolate the ethyl ester of the title compound. The product (280 mg) was hydrolyzed to-by treating the dioxolane aqueous solution (.1: 1) with excess LiOH, acidifying with TFA, and purifying the product by RPHPLC. After lyophilization, a white amorphous solid (250 mg) was obtained. MS and N.MR are consistent with the structure shown. '' Example 22 5 (±) Lu-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethynyl] amino] -3,5 -Dichloro-2-light phenylpropanoic acid, trifluoroacrylic acid salt, -Preparation of hydrates (please read the precautions on the back before filling in ^,% pages) Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economy

Step A HN h2n

Cl The above compounds are composed of 3,5-digas salicylaldehyde (10.0 grams, 52.4 millimoles-295- private paper scales applicable to Chinese National Standard {CNS) A4 specifications (2IOX297 mm) · A7 B7 · 458956 293 five 2. Description of the invention () Aldrich), malonic acid and ammonium acetate were prepared in isopropanol using substantially the same procedure and ratio reaction as in Example 224, Step A. MS $ NMR is consistent with the desired intermediate. »Step B · GIHA (1.0 g, 3.7 mmol) and the product from Step A (1.1 g, .4.4 mmol) use essentially Example 8 6 Step D The same procedures and proportions are coupled. The soft product was separated by C -18 RPHPLC, and appropriate portions were combined and lyophilized to obtain the title compound (0.42 g). MS and NMR are consistent with the structure shown. Example 2 2 6 · (±) / 5-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -2 -Preparation of acetyl-5-nitrophenylpropionate 'trifluoroacetate

< Please read the precautions on the back before this page?)

, 1T 1-Impression of Consumer Cooperatives of Employees of the Central Standards Bureau of the Ministry of Economic Affairs (RS) -4 -Amine-6-nitro-hydrochlorophyllin monoacid (1.1 g, 4,4 mmol-ear) [Based on J Rico, Tett. Let., 1994, 6599-6602, prepared from 7-Cyclofasin (Aldrich)] was coupled to 〇IHA (1.0 g., 3.7 mmol), essentially using Example 8 6 steps D procedures and ratios, for example. Purified by preparative RPHPLC to obtain the desired product, which is a mixture of hydrohumorin (lactone) and phenoxy-acid TFA salt. After freeze-drying, it was in powder form. Substantially completely converted into the desired phenol-acid, which can be dissolved in water from the purified mixture, and the size of this paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 458 95 © Α7 Β7 V. Invention Explanation (Dilute NaOH aqueous solution adjusts p H to 7-8 until the reaction is completely measured by H p L c and freeze-dried. NMR and MS are consistent with the desired phenol-carboxylic acid form of the molecule. Example 2 2 7 (±) /?-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethenyl] amino] · 3,5-dibromo Preparation of 2-Hydroxyphenylpropionic acid, trifluoroacetate, monohydrate

Br

Step A ^ — "(Please read the notes on the back before ^ r this page).

The above-mentioned hydrazone-amino acid ester hydrochloride of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Line Economy was prepared according to the method of steps A and B of Example 1, but using 3,5-dibromosalicylaldehyde (20.0). G, 0.0715 mol, Aldrich) instead of the 3-pyridine 'quinal in step A of Example 1, keeping the ratio of 3 μS and the NMR consistent with the desired structure. Step B (±) 10,000-[[2 · [[[[[[3-[(Amineimine phenylamine) amino] benzyl] carbonyl] amine] 297- This paper size applies to Chinese national standards (CNS > Α4 Specifications (210X297 mm) ^ 956 Α7 Β7 295 ------- V. Description of the invention () yl] ethylfluorenyl] amino] -3,5-dibromo-2-light phenylpropionate , Trifluoroacetate, monohydrate

GIHA (1.0 g ' 3.7 millimoles) and the product of step A (7 g grams, 4.4 millimoles) were substantially coupled using the same procedures and ratios as in Example 8, Step 6, D. The desired product was separated by C-1S RPHPLC, and the appropriate parts were combined and freeze-dried to obtain (±) / 3-[[2-[[[3 ·-[(aminoiminomethyl) amino]] Phenyl] carbonyl] 'amino] ethoxy] amino] -3,5-dihydro-2-quinylphenylpropionate ethyl acetate, trifluoroacetate' monohydrate (0.52 g). MS and NMR are consistent with the structure shown. '' .. I batch of clothes-\ 1)-(Please read the precautions on the back before ν ^ this page)-# Step C.

The product of step B was substantially converted to an acid using the procedure and conditions of Example 6, but the hydrolysis solvent was dioxolane: water. Purified by preparative C-1 8 RPHPLC 'to obtain TF A salt. (300 mg). MS and NMR are consistent with the structure shown. Example 2 2 8 -298-This paper size is in accordance with Chinese National Standard (CNS) A4 (210 × 297 mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (296) A7 B7 (±) y? -[[2, [[[[[[3-[(Amineiminoamido) amino] amino] phenyl] amido] amine.yl] ethylamido] amino]] " 5_ Acid 'trifluoroacetate' preparation of monohydrate '

Br Please read the precautions of A and then%. The title compound on this page was prepared using essentially the same procedure and ratio as in Example 224, but replaced with 5 -bromosalicylic acid 3, $-two-gas water yangjing 'to obtain the title. Ethyl compounds. After the ester hydrolysis, 'acid-fermentation' was obtained (0.3 g 'after lyophilization). MS and NMR are consistent with the structure shown. Example 2.2 9 (±) /?-[[2- [[[3-[(Amineimine'ylmethyl) amino] phenyl] carbonyl] amino ] Ethylammonium] Amine] -Cyclohexanepropionic acid, trifluoroacetate, monohydrate preparation., Co2h Order Printed by the Central Bureau of Economic Affairs, Consumer Cooperatives

Step A

h2n -299- The scale of this paper is applicable to China National Standard (CNS) A4 (21〇X: 297 mm) 458956 A7 B7, V. Description of the invention (297)

(R, S) -3-Amino-3-phenylpropanoic acid ethyl ester hydrochloride (1.7 g) was dissolved in absolute EtOH (70 ml). 5% Pt / C was added, and the reaction mixture was transferred to a pressure bottle. . After cleaning, the reaction bottle was pressurized with hydrogen (54 psig). Let the reaction go to completion. The volatiles were removed and the product was used without further purification. MS and NMR are consistent with the structure shown. " '-~' + Step B, (R, S) -3 -Amino-3-cyclohexylpropanoic acid ethyl acetate, hydrochloride and GI__H printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy Substantially used Example 8 The same procedure and ratio coupling of 6 step D. (Earth) / 5 · [[2 _ [[[[[[3-[(Aminoiminoamido)) amino] phenyl] carbonyl] amino] ethylamido] amino] -cyclohexanepropanoic acid ethyl The ester, trifluoroacetate, and monohydrate were separated using C-18 RPHPLC, iced; dried, and a white amorphous powder was obtained. (±) y? _ [[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -cyclohexylpropionate The ester, tridenyl acetate, monohydrate was hydrolyzed using the procedure of Example 224, Step C to obtain the title compound (0.5 g). MS and;. NMR are consistent with the structures shown. * Example 2 3 〇 (Earth-[[2-[[[[[[[Aminoiminomethyl) amino 1 Benzene] carbonyl] amino] ethylfluorenyl] amino] -3,5- Preparation of ethyl dichloro-2-hydroxyphenylpropionate, trifluoroacetate, and monohydrate_-300-This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 4 58 95i (298 A7 B7

CI

Step A

Cl (Please read the precautions on the back first, and then ί 'this page)-Installed · Central Ministry of Economic Affairs

(RS) -4-Amino-6,8-digassaloxin hydrochloride was prepared according to the procedures of steps A and B of Example 233, but replaced with 3,5-digassalicylaldehyde in Step 233 of Example 233. 3-Bromo-5-chlorowater was used. '' The above Θ amine ethanoic acid hydrochloride is dissolved in absolute Et by (RS) -4 · amino-6 > 8 · dichlorohumycin hydrochloride (8.0 g, 0.0007 mol). H (30 ml) was prepared by adding 4N HC1 to dioxan (10 ml), and the reaction was stirred at room temperature for 2.5 hours. The HC1 was removed by rotary evaporation (cold) and the reaction mixture was concentrated to a solid (50). The solid was treated with EtoAc (25 ml) and EhCK 10 ml), stirred, and a white solid was collected, and the impurities were separated by filtration (5.84 g). MS and NMR are consistent with the desired hydrochloride salt of ethyl y3-amino acid. Step 骒 B-301 t Paper Standard Common Chinese National Standard (CNS) A4 Specification (2I0X297 mm)-Order-One 458 956 A7 · B7 299 ---------- V. Description of Invention () GIHAHC1 (3.4 g, 0.0124 moles) was dissolved in dimethylacetamide (40 ml), N-methylmorpholine NMM (1.36 ml, 0.004 moles) was added, and the solution was cooled to 0-5 C, and mild. Isobutyric acid (61 ml, 0.0124 mol) was added to the reaction for about 10 minutes. At this time, the product of step a (3,90 g, 0, 8 nmol) and a solution of NMM (1.36 ml) in DMA (20 ml) were added to the reaction mixture. The coupling was allowed to proceed overnight. 3 Volatile matter was removed ' The reaction mixture was re-dissolved in acetonitrile: water, and TFA was added to bring pΗ to about 2. The desired product was separated by preparative C-1 8 RPHPLC and dried on ice to obtain a TFA salt (2.61 g). MS and NMR are consistent with the structure of the title compound. 〇 * ------------ install-(please read the precautions on the back before r '' write this page

n, -IT Example 23 1 11 (±) Cold-[[2 · [[[[[[[Amineimidomethyl) amino] phenyl] carbonyl] amino] ethyl alcohol] amino group] -5 -Gas-2-Pyridyl Extraction of Propylene, Trigas Acetate, —Hydrate Preparation

Can

In Printed by the Consumer Affairs Cooperative of the Central Government Bureau of the Ministry of Economic Affairs, the compounds were prepared using essentially the same procedures and proportions as in Example 224, but replaced with 3,5 -dichlorochloric salicylate in the end of 5. After fermentation, 'acid-stuffing' was obtained (0.3 g, on ice; after drying in the east). MS and NMR are consistent with the shown configuration. Example 2 3 2. -302- This paper size applies to Chinese National Standard (CNS) A4 (210X: 297 mm) 5. Description of the invention (300 A7 B7 (soil) 3,5-digas-2-hydroxy- /?-[[[[[[[[[[[3,4,5,6-Tetrahydro-azabenzene-7-yl) amino] phenyl] carbonyl] -amino] ethylfluorenyl] amine Of phenyl] phenylpropionate 'trifluoroacetate, monohydrate

--------- i-- (Please read the note on the back page first.) .1 --- Order—Meta-Aminopuric Acid printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs ( 2.0 g, 8.7 mmol) to acetonitrile (50 ml) was added 1-aza-2-methoxy-1-cycloheptane (1.2 g, 9.5 mmol) (Aldrich). The reaction was carried out at room temperature over the weekend. The solvent was removed and the residue was triturated with diethyl ether to obtain a solid (1.6 g). According to the analytical system RPHPLC 'MS- and NM.R, it was essentially pure 3- (1-aza-2-amino group. -1-cycloheptane) equuric acid. Product obtained in step B _ step A, 3- (1-.aza-2-amino-1-, cycloheptane) equuric acid (1.0 g, 3.2 mmol) Ear) Coupling with the compound prepared in Step A of Example 230 (1.0 g, 3.2: millimoles), essentially using Example 230 Step B of -303- This paper wave scale is applicable to Chinese national standards ((: see> person 4 specifications) (210 fathers and 297 males >-gland .301 .301 A7 B7.; C3 956 V. Description of the invention (procedures and conditions, but with 3-(. 1-azaamino-1-cycloheptane) maleic acid Substituted GIHA. Purified by C-18 RPHPLC to obtain the ethyl ester of the standard compound (0,5 g). MS and NMR were consistent with the structure shown.

Step C The product (0.35 g) prepared in step 骒 B is dissolved in dioxobutane: water (1: 1, 30 ml), and the pH is adjusted to about 1 l by adding LiOH (NaOH can replace LiOH freely). Upon complete hydrolysis to the acid (measured by analytical RPHPLC), the reaction mixture was acidified to about pp 2-3 with the addition of TFA, and the desired compound was isolated by preparative C-18 RPHPLC. MS and NMR are consistent with the structure of the title compound. Example 23 3 (±) y5-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carboxy] amino] ethylfluorenyl] amino] -3-bromo- Preparation of 5-Gas-2-hydroxyphenylpropionic acid, trifluoroacetate, monohydrate ινπ > -Ν

NH

Printed by Shellfish Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs

Step A

Br -304- This paper has been re-used in China National Standard (CNS) A < 4 specification (210X297 mm) 9 5S 302 V. Description of invention () A7 B7

A solution of 3-bromo-5-gas salicylaldehyde (0.00 mol, 0.407 mol) and triethylamine (56 ml) in acetic anhydride (14.0 ml) was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and the volatiles were removed under air. The resulting solid was partitioned between ethyl acetate and an aqueous sodium hydrogen carbonate solution, and the layers were separated. The aqueous layers were re-extracted with EtOAc. The organic layers were combined, dried (Na2SO4), and the volatiles were removed under 眞 2 to obtain a solid (13.5 g MS & NMR consistent with the structure shown. Step B

Br < Please read the precautions on the back before V is this page). Pack. .F Order the product obtained in step A (lo.o g '., 0.039 mole) into 4-amine 6-Ga-8-Hydroxyhumin hydrochloride (5.1 g, 185 mmol), according to J. Rico, Tett, Let., 1994, 3_5, 6599 · 6602, with the following 'revisions: by double -Lithium trimethylsilylphosphonium amine is added to the fumed 'oxacin produced in step A' before addition of one equivalent of HOAc fired at 0 ° C.

Step C The product of Step B (4.0 g '0,013 mol) was coupled to GIHAHC1 (33 g, 0.012 mol), essentially using the procedure of Shiqiu 23 °, but replacing the example with the compound obtained in step 6. 3 0 > The compound of step A, purified by c_j 8 RPHPLC and hydrolyzed according to the appropriate part according to the procedure of step 232 in Example 232 -305-Private paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) Printed by the Consumer Central Cooperative of Shenyang Bureau of Standards, Ministry of Online Economy ^

5. Description of the invention (3Q3), to obtain the desired compound (TFA salt), after freeze-drying, it is a fluffy white powder (4.8 g). MS and NMR are consistent with the structure shown. Example 2 3 4. (±) 5-Amino [(aminoiminomethyl) amino] phenyl] Alkyl] Amino] Ethyl] Amino] -2 -Arylidenephthalic acid. , Bis (trifluoroacetic acid) salt., Preparation of monohydrate 2 NA,

l · (Please read the precautions on the back of this page before quoting this page) Μ. The product of Example 226 (0.5 g) printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs was dissolved in AcOH: H20 (2: 1, 60 ml) In 3% Pd / C (0.5 g, Aldrich). The reaction mixture was pressurized with hydrogen (20 psig) and stirred vigorously for 2 hours. Reaction = catalyst was removed by filtration, and the mixture was concentrated to a thick oil. This oil was dissolved in water and the desired compound was separated by C-18 RPHPLC. MS and NMR are consistent with the structure shown. Example 2 3 5-(±) /?-[[2-[[[[[Aminoiminomethyl) fluorenyl] phenyl] carbonyl] amine: yl] ethylfluorenyl.] Amino] -5-Bromopyridine-3-propionic acid, preparation of bis (trifluoroacetic acid) salt, monohydrate

This paper size is applicable to Chinese National Standard (CNS) A4 specification (2 丨 0 X 297 mm) Binding line A7 B7 304 V. Description of the invention (

Step A N (OCH3) CH3

In 5-bromoniconic acid (20.0 g, 0.10 mole), 0, N-Difluorenylhydroxylamine (9.8 g, 0.1 mole) and 1-ethyl-3- (3-dimethylaminopropylpropane) Base) carbodiimide hydrochloride solution in DMF (200 ml) was added _ 1-kisyltribite (200 ml of 0.5M solution in DMF, 0.10 mole) and triethylamine (19.7 Ml, 0.14 mol) and the reaction mixture was stirred vigorously for 18 hours. The volatiles were removed at 60 ° C in a vacuum until porridge was formed. The reaction mixture was partitioned between ethyl acetate (300 ml) and a saturated aqueous sodium bicarbonate solution, the layers were separated, and the aqueous layer was re-extracted with EtOAc. The organic layers were combined, dried (Na2S04) and concentrated to a dark yellow oil (21.4 g). _ M S and NMR are consistent with the structure shown. Step B '

The solution of the product obtained in step A (.12.9 g, 0_053 mol) in THF (300 ml) was printed in THF (300 ml) by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, and the solution was cooled to 0 ° C in LAH in THF (53 ml of 1.0M raw material Solution, Aldrich) was added via syringe. After 0.5 hours, KHS04 (19'6 g, 0: .13 moles in 100 ml of water) was added. In the number.-307- This paper size applies the Chinese National Standard (CNS) A4 specification (2I0X297 mm.) ^ 95§ A7.-_ B7 V. Description of the invention (3ί35) ^ _ — Minutes later, the dilute α aqueous solution ( 50 ml) was added, the organic layer was separated, dried (Na2S04), the volatiles were removed, and a yellow oil was obtained, which solidified upon standing. The solid was purified by sublimation, and Jiang Fuyan embraced the servant to serve the title compound as a white solid (7,8 g). MS and NMR are consistent with the structure shown. Step C · ~: Install — (Please read the precautions on the back before ^ > this page)

The above A-amino acid ester hydrochloride was prepared in accordance with the method of steps 8 and 6 of Example 1 (6,24 g, 0.034 moles) to replace the p ratio chain in step a, and maintain the ratio. for sure. The product was separated by c · 8 rphplc as a di-TFA salt. MS and NMR are consistent with the structure shown. Step D Order m-Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs

The product of Step C is coupled to GHIA HC1 (0.5 g, 1.8 mmol), essentially using the procedure of Example 230. Step B, but replacing the product of Step c (and two equivalents of NMM) in Example 230. Step A product. Ethyl acetate of the product

308 This paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (6)-C-18 RPHPLC separation, showing two. ^^ eight salts. MS and NMR are consistent with the structure shown. ,

Step E The product of Step D1 (200 mg) was hydrolyzed to the corresponding acid, which was substantially completed using the procedure of Example 232, Step C. The product was isolated by .c_18 RPHPLC as di-TFA salt 'freeze-dried' to obtain the title compound as a white solid (j 50 mg). MS and NMR are consistent with the structures shown. Example 2 3 6 (±) 3-Bromo-5_gas-2-hydroxy-fluorene · [[2 _ [[|; 3 _ [(1,4,5,6_tetrahydropyrimidin-2-yl) amino] benzene Preparation of carbonyl] carbonyl] amino] • ethylfluorenyl] amino] phenylpropionic acid, trifluoro-acetate, monohydrate 0 Step

〇Η. Printing of 1- (3 · carboxyphenyl) · 2 · thiourea (Ά0g, 7 丨 3mmol) at £ t〇H (absolute '140.ml) Iodinoxane (102 g) was added to the solution, and the solution was recovered for 2.5 hours. The volatiles were removed at 6 CTC under emptiness to obtain a yellow oil. -309- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 458956 Λ7 I-Β7

5. Description of the invention () Treatment with the third butyl fluorenyl ether 'removes the volatiles to obtain a yellow foam, which becomes firm when cooled. MS and NMR are consistent with the structure shown. tMB

Add the catalytic amount of DMAP and 1,3-diaminopropane (1.2 g, 0.016 mol) to the product of Step A (5.0 g '0.015 mol) in DMA (50 ml), and heat the solution to 100T for 48 hours. The volatiles are removed until a thick oil is formed. This oil was treated successively with EtOAc, Et20 and MeOH (50 ml) to obtain a solid material 'which was isolated by filtration. The product was suspended in 4 N HC1 in dioxolane and stirred for several hours. The resulting solid was passed through an oven, washed with Et20, and dried (800 mg). MS and NMR are consistent with the structure shown, as HC1 salt. Step C, .ί », ----- I: I ---! 1—1--t— (Please read the notes on the back before copying this X) Set the standard in the Ministry of Economy and staff consumption Cooperative cooperative policy

To (RS) -4-amino-6 · chloro-8-bromohydrohumurin hydrochloride (2.6 g) prepared in Example 233, Step B was dissolved in THF (50 ml) and triethylamine (1.0 Ml) and Nt-Boc-Glycine-N-Hydroxysuccinimide (2.0g 'Sigma) -310- · This paper size applies to Chinese National Standards (CNS > A4 size (210X297mm) 458 956 Α7 Β7 'V. Description of the invention (), to complete the reaction ... The volatiles are removed and the residue is partitioned between Et0AC and water. The organic layer is separated' washed with dilute HC1 aqueous solution, saturated sodium bicarbonate 'and dried (Na2S〇4 ) 'Concentrated to a dark foam (3.2 g). The product was used in the next step without further purification.

Step D

Lupin (20ml), and add HCI (4N in Dioxolane, Aldrich) in a fully agitated solution »When the gas evolution stops (about 0.5 hours), the volatiles are removed ' A turbid bee was obtained, which was confirmed with diethyl ether, and then washed to obtain a yellow solid (2.46 g). M S and NMR are consistent with the structure shown, and they are salty honey. Step E-Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs ------------ ^-(Please read the precautions on the back before tiling this page).) M The product of step D (1,4 G) and the product of step B (1.0 g) were essentially coupled using the procedure of step 230 of Example 230. When the coupling reaction is complete, the volatiles are removed from the crude reaction mixture. The reaction mixture was dissolved in dioxolane: water. 'Ρ was adjusted to' about 1 1 by adding an aqueous NaOH solution. The p technique was maintained above 10 until complete hydrolysis was determined by analytical RPHPLC. At this time, the pH was adjusted to 2-3 by adding TFA, and the desired product was separated by preparative c-1 3 RPHPLC (0.35 g, after freeze-drying). MS and NMR were consistent with the structure shown. Ladder standard (CNS) A4 specification (210 × 297 mm) A7 B7 9 56 309 5. Description of the invention () It is TFA salt. Plant example 2 3 7 (±) 3,5-dichloro-2_hydroxy-lu-[[2-[[[3-[(1,4,5,6-Tetraaeroline this 2-yl) amine []] Phenyl] carbonyl] amino] ethenyl] amino] phenylpropanoic acid, 'trifluoroacid salt, preparation of monohydrate it ---------- ^-(please first Read the notes on the back again (4Γ '· this page) The central standard of the Ministry of Economic Affairs prints the above compound (350 mg) for employees' cooperatives using essentially the conditions and procedures of Example 236, but in accordance with Example 233 steps A and B Procedure (RS) -4-Amino-6,8-dihydrohydrosalantin hydrochloride prepared from the corresponding salicyl salamander was used to replace the (RS) -amino-6-bromo-8- Chlorohydrin hydrochloride. MS and NMR are in accordance with the structure shown by t, and they are T F A salts. , Example 2 3 8 (±) 3,5 -Digas- / 9-[[2-[[[3-[(4,5 -Dihydro-Harden-2-yl) amino] phenyl] carbonyl ] Amino] Acetyl] Amino group 2-Hydroxyphenylpropionic acid, trifluoroacetate, monohydrate preparation-

312- I.

1T

CI The paper scale is applicable to China National Standard (CNS) A4 (210x297 mm) 3109δ6 A7 B7 V. Description of the invention (

Step A

—N NH The above compound was prepared according to the procedures of steps 8 and 8 of Example 236, but substituted with ethylamine (1,2-diaminoethane) and 3-diaminodioxane in step ^.

Step B 〇 ^ 2

(Please read the notes on the back before irlir this page) • Binding. Order r Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

The desired end product (300 mg) was prepared by coupling the product of step a with the hydrochloride salt of the above compound (prepared in Example 237) according to the winter coupling procedure of Example 237. MS and NMR with the structure shown—Ao, as TFA salt = Example 2 3 9 '(±) 3-Bromo-5-Gas-Lu-[[2-[' [[3-[(4,5-Dihydro -1 ^ -pyrrolidin-2-yl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -2-hydroxyphenylpropionic acid, trifluoroacetate, monohydrate preparation

313- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 4 5. Description of the invention (311 A7 B7 The above compounds were prepared according to the procedure of Example 238, but the product of Step A in Example 238 was used instead of Example 237 The product of step B. MS and NMR are consistent with the structure shown, as a TFA salt. Example 2 4 0 (±) 3,5-dichloro- /?-[[2-[[[3-[[[(ζ : Preparation of oxycarbonyl) amino] thiomethyl] amino] benzyl] carbonyl] amino] ethylfluorenyl] amino] -phenylpropionic acid

Step A 3 · Amino · 3 · (3,5-dioxophenyl) propionic acid, third butyl ester

{Please read the note on the back of the page, and then this page)-Binding · Threading. • fi " hr Printed by the Consumers Cooperative of the China Standards Bureau of the Ministry of Economic Affairs 13.5 grams of 1 · bromo-3,5 -diqiben (Aldrich, I · 3.5 g), second acrylic acid ester (Alddch 'li.i ml), triethylamine (84 mmol), Pd (〇Ac) 2 (0.12 g), tri-p-toluylphosphine A mixture of (09 g of y and acetonitrile (20 ml) was prepared in a steel bomb under nitrogen. Sealed and heated to 120 »C for 16 hours. Aeroform (40 ml) was added and cooled to the reaction mixture. , The mixture is based on ether and water -314- _ scale applicable to China (2i0x297; i ¥ A7 B7 ----- 312 ---------- 5. Description of the invention () Extraction. The organic phase is washed with water, MgS04 was dried and shrunk in the air. The residue was quickly filtered through silica gel using 8% ethyl acetate in hexane as the eluent to obtain 15 grams of slightly concentrated product (12.6 grams) and tertiary butanol ( 35 ml) and ammonia (40 ml) in a steel bullet heated to 80 ° C for 25 hours (pressure 'at room temperature; at 80C' is .500 psi) = _ After cooling and outgassing 'Inside The material was concentrated under vacuum. The residue was extracted with ethyl acetate (100 milliwells) and added 'cooled' thin salt Han (1N '100 ml). The aqueous phase was tested with solid K2C03 and extracted with ether and methane. The organic phase was dried over k2C03 and concentrated under vacuum to obtain the above compound (11 g) as a thick red-brown liquid.

Step Mania B ----------_- yi 丨 I (Please read the precautions on the back before filling in this page)

Order

P-Consumers' cooperative of the Central Standards Bureau of the Ministry of Gland Economics, India. Cooperated with 3-nitrobenzene (7g, Aldrich) in CH2CI, medium. Put it in the solution-add the glycine methylate at -78 ° C. Ester hydrochloride (5 g, Aldrich), then triethylamine (20 ml) was added. The mixture was heated to room temperature for 16 hours. The volatiles were removed and the residue was extracted with ethyl acetate and wood. The organic phase was washed with water ', dried over MgS04, and concentrated under vacuum. The residue was stirred in tetra-hydrofuran (50 ml) and aqueous lithium hydroxide solution (50 ml, 1M) for 15 minutes. The volatiles were removed, and the residue was treated with hydrochloric acid (50 ml, 3M), with ethyl acetate and -315-. This paper size applies Chinese National Standard (CNS) A * specifications (21〇 > < 297 mm). Printed by the Consumer Standards Cooperative of the Ministry of Standards of the Ministry of Education 4 _ Α7 Β7 ΤΪ3 ~ ----------_______ V. Description of the invention () Water extraction. The organic phase was washed with water, dried over MgS04, and concentrated under vacuum. To a stirred solution of the residue (2.24 g) in tetrahydrofuran (15 ml) was added 4-methylmorpholine (1.1 ml, Aldrich) and isobutyl formate (1.3 ml 'Aldrich) in _78 °. After 30 minutes, 3_amino_3_ (3,5_dichlorobenzyl) propanone butyric acid (2.91 g, prepared in the above step a) was added. The mixture was heated to room temperature for 2 hours. The volatiles were removed, and the residue was extracted with ethyl acetate and water. The organic phase was washed with water, dried over MgS04, and concentrated under vacuum. A solution of the residue in tetrahydrofuran and ethanol (1:30 ml) was shaken in Parr hydrogenated with 3% Pd / C (0.5 g) for 5 hours under 5 psi argon pressure. The mixture was filtered and the filtrate was concentrated to obtain the above compound as a thick copper gum. This product was used without further purification. Step C A mixture of the compound of Step B (1.2 g) and ethoxycarbonyl isothiosulfate (Aldrich '0.3 μl) in toluene (5 ml) was heated to reflux for 30 minutes. Chromatography gave the second butyl ester of the title compound (0'78 g) as a white solid. A solution of the third butyl ester (0.3 g) in trifluoroacetic acid (4 ml) was placed at 23 ×: standing for 16 hours. The volatiles were removed and the residue was purified by HPLC to give the title compound as a white solid. C22H22N406S. G.5 H20-calculated 値: c, 48.〇1; Η, 4.21; Ν, 10 ′ 18; S, 5,83 found: C, 47.61;., 4.11; Ν, 9.94; S, 5.83 Example 2 4 1 3'5-Digas _ /?-[[2-[[[3-[[[(ethoxycarbonyl) amino] iminomethyl] amine-316- China National Standard (CNS) Μ Specifications (210 > < 297 mm) (Please read the precautions on the back before filling out this page} Installation · '11 -line os® ΤΐΤ A7 B7 V. Description of the invention (\ 基) benzene Of carbonyl] carbonyl] amino] ethylfluorenyl] amino] phenylpropanoic acid monohydrate from fluoroacetate

Step A (Please read the notes on the back before writing this page) -Install-Η Η

VVW o S o A mixture of tert-butyl aminoformate (Lancaster, 5 g) and 4oxycarbonyl isothiohydrogenate (Aldrich, 5 ml) in toluene (15 ml) was heated to reflux for 2 hours. The solution was cooled to room temperature for 16 hours. The precipitated solid was washed with hexane to obtain the above compound ($ .5 g) as a white solid.

Steps B and 1T. Employees' cooperatives in the Central Standards Bureau of the Ministry of Economic Affairs

The M's scale is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 0X297). 458956 315 V. Description of the invention () The cucurbitate (13g) produced in step B of Example 240 and step A To a stirred solution of the product (0.7 g) in DMF (7 ml), gasified spring (0.77 g) and triethylamine (0.8 ml) were added at a valence. Kun Kun was warmed to room temperature for 1 hour, and continued to stir for 1 hour. The mixture was diluted with ethyl acetate and filtered through ceUte. The filtrate was washed with water, dried over MgS04, and concentrated under vacuum. The residue was purified / obtained by chromatography as a white solid. Step C '' The solution of the product of Step B (0-5 g) in fluoroacetic acid (10 ml) was left at 23 X for 2 hours. The volatiles were removed and the residue was purified by HpLC to give the title compound as a white solid. C22H23N506C12 1.25 CF3 COOH.O.5 H20 Calculated 値: C, 42.96; Η, 3.86; N, 10.23; ci, 10.35 Measured 値: C, 43.21; H, 3.49; N, 10, 20; ci, 10.52 Example 2 4 2-[[2-[[[3-[(Amineiminoamido) amino] phenyl] carbonyl] amino] ethylamido] amino] [1,1_ -biphenyl] -3 -Preparation of Propionic Acid-Printed by Male Workers Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs

Step A

-318- This paper size is in use _ National Standard (CNS) A4 size (210X297 mm) Λ ’4 58 9 56 A7 ______B7 V. Description of the invention (316)

9.64 g (41.4 mmol) 3-bromobiphenyl, 58 ml (42 g, 4 μmol) triethylamine, 6.73 g (52. · 6 mmol) tert-butyl propionate , Mg (2,05 mmol) of tri-p-toluylphosphine and 83 mg of palladium acetate in 15 ml of dimethylformamide in a oil bath and stirred overnight. After cooling, the mixture was partitioned between Between ethyl acetate and water, the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel using a dichloromethane / hexane mixture as the eluent to obtain 10.5 g of the above compound as a very pale yellow oil. ^ -NMR (CDC13) 7.77-7.36 (m, 9H), 7.69 (d, J = 15 Hz, 1H), 6,47 (d, J = 15 Hz, 1H), 1.58 (s, 9H). ’Step B-(Please read the notes on the back before r ¥ f this page).

1T mr, cable

The Consumer Cooperative of the Central Bureau of Guidance Bureau of the Ministry of Economic Affairs printed a mixture of 10.5 g (37.5 mmol) of the product of step a, 50 ml of liquid ammonia, 5.2 g of acetic acid, and 80 ml of third butanol at 180 ° C for 18 hours. After cooling, the mixture is distributed between ethyl acetate and aqueous sodium bisulfate solution. -319- This paper is sized according to China National Standard (CNS) A4 (210x297 mm) ^ ^ 458956 A7 _____ __ B7 317 *- ------ V. Description of the invention () '... The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, evaporated, and the residue was chromatographed on silica gel. Ethyl cool acid and then 10% methanol_ 丨% ammonium hydroxide_89% ethyl acetate as the eluent to obtain 4.75 g of the above compound as a colorless oil. Analysis of C ^ HuNO2 1 / δ H2 0 (MW 299.65): Calculated 値: C, 76.16; H, 7.74; N, 4.67. Measured 値: C, 76, 29; H, 7.57; N, 4.66.

Step C Pan-[[2-[{[3-[(Aminoiminoamido) amino] amino] phenyl] • carbonyl] amino] ethylamido] amino] [1,1′-biphenyl Based] · 3 _ propionic acid 丨, i diethyl ethyl (Please read the precautions on the back before clicking this page) Pack '1

P; printed by the Ministry of Economic Affairs of the Central Ministry of Economic Affairs, Shellfish Consumer Cooperative, printed in 1.00 g (3.66 mmol) of the compound of Example M in 20 ml of anhydrous dimethyl methylamine, stirred in an ice bath under argon pressure 467 μl (3'84 mmol) of N-methylhexahydropyridine was added to the solution to give a white solid. After 15 minutes of stirring, '500 microliters (3.84 mmol) of isobutyl chloroacetate was added dropwise' and stirring was continued for about 20 minutes to produce a homogeneous solution. A solution of 109 g (3.66 mmol, ear) of the product of Step B in 5 ml of dimethylformamide was added, and the mixture was stirred at room temperature overnight. The concentrate was concentrated to obtain 2.88 g of an orange oil. 1.50 grams of crude mixture was prepared by reverse phase Ή plc, using 90% to 50% three __ -320- This paper standard system f Guan Jia Pi (CNS) Cong Mi (―Fantasy Fighting while taking advantage of)-~ Economy A7 B7 r — ''--Printed by the Central Bureau of Standards, Ministry of Standards and Industry. V. Description of the invention (), Fluoroacetic acid aqueous solution-acetonitrile concentration gradient, and then partially evaporated, to obtain 800 mg of the above compound, a white solid. ^ -NMR (CDCI3-DMSO) 8.93 (br s, 1H), 8.56 (t, 1H), 8.22 (d, 1H)) 7.81-7.12 (m, 13H, 5.46 (dd, 1H), 4.12 (t, 2H ), 2.88 (dd, 1H), 2.77 (dd, 1H), 1.31 (s, 9H).

Step D 800 mg of the product of Step C was added to 10 ml of dichloromethane in a solution of 10 ml of trifluoroacetic acid, and the mixture was stirred at room temperature overnight. After concentration, the above-mentioned compound (25 mg) was obtained as a pure white solid by reverse phase preparative ΗPLC using a mixture of trifluoroacetic acid 馥 aqueous solution-acetonitrile as the eluent. Analysis of C25H26N5 〇4 CFCOOH 1/2 Η2 0 (MW 581.53): Calculate 値: C, 55.77; Η, 4.33; Ν, 12.04. Found 値: C, 55.81; Η, 4.57; Ν, 11.68. Example 2.4 3 A-[[2-[[[3-[(Amineimidoamido) amino] phenyl] carbonyl] amino] ethyldonyl] amino]. Secret _5_ Preparation of propionic acid ’trifluoroacid salt-

Step A -321-The scales of this book are in accordance with Chinese National Standard (CNS) A4 specifications (210X297mm)

458 9Sd A7 B7 V. Description of the invention (319) OOO-t-Bu

5.00 g (S1.1 mmol) of 5-bromopyrimidine, 3.14 g (3 1.1 mmol) of triethylamine, 5.06 g (39,5 mmol) of tert-butyl propionate, 475 mg of tributyl The mixture of ortho-phenylphosphine and 63 mg of palladium acetate in acetonitrile ml was stirred under reflux for 8 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on silica gel using a concentration gradient of 30% -50% ethyl acetate to obtain 0.99 g of the above-mentioned compound 'sheep white crystalline solid. ^ -NMR (CDC13) 9.19 (S, 1H), 8.86 (s, 2H), 7.53 (d, J-15 Hz, 1H), 6.54 (d, J = 15 Hz, 1H)} 1.55 (s, 9H) 0Step B I -------- 1¾ Clothing II (Please read the notes on the back before cherishing 4 pages) 4 °-Printed by X Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs

(X

A solution of 1.28 g (6.21 mmol) of the product from step a in 12 ml of benzylamine was stirred in Youlo at 70-80 ° C overnight. After cooling, the excess benzylamine was evaporated and the residue was chromatographed on silica gel using 50% ethyl acetate-hexane as 322. This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm). Central Ministry of Economic Affairs Printed by the staff of the Bureau of Standards, Guizhou Cooperative, 458.95β Α7 Β7 320-V. Description of the invention ()... Dissolving agent, 1.33 g of the above-mentioned compound was obtained, and it was colorless oil. ^ -NMR (CDC13) 9.18 (s, 1H), 8.78 (s, 2H), 7.21 (m, 5H), 4.14 (t, 1H), 3.68 (d, 1H), 3.59 (d, 1H), 2.73 ( dd, 1H), 2.57 (dd, 1H), 1.41 (s, 9H). Step C.

To a solution of 1.33 g (4.25 mmol) of the product of step B in 50 ml of 4: 1 ethanol · cyclohexane, 10% palladium / carbon was added. The mixture was stirred under reflux overnight under argon, 35 mg of pyridine p-toluenesulfonate was added, and the mixture was refluxed for 8 hours. After cooling, the mixture was filtered and the filtrate was concentrated. The residue was filtered through silica gel using 10% methanol-ethyl acetate as a dissolving agent to obtain the above compound (852 mg) as a waxy mound. -^ -NMR (CDCI3) 9.26 (s, 1H), 8.78 (s, 2H), 4.46 (dd, 1H), 2.64 (m, 2H), 1.81 (br s, 1H), 1.43 (s, 9H) «

Step D

-323-This paper size is in accordance with Chinese National Standard (CNS) M specifications (210 X 297 mm) 1 · I In I-i ^ i —l-nnn 1-(r T In I In 1 In n 'U3. i Read ... / <. (Please read the notes on the back first and then fill in this page) The Central Government Bureau of the Ministry of Economic Affairs, the Ministry of Economic Affairs, Co-operative Society, printed A7-B7 " ^ ------ ---- V. Description of the invention () Add 1.04 g (3.82 mmol) of meta-guanidyl uric acid in 8 ml of anhydrous difluorenylhydrazine in a solution stirred under argon in an ice bath and add dropwise 398 mg (4'01 millimoles) of N-fluorenylhexahydropyridine to give a white solid. The mixture was stirred for 10 minutes, and then 1.03 g (4.0 1 millimoles) of disuccinimidyl carbonate solid was added. With stirring After 1.5 hours, a transparent homogeneous solution was obtained, and 852 mg (3.82 mmol) of the product of Step C was added. After stirring overnight at room temperature, the mixture was evaporated to dryness. The mixture was passed through the reverse phase of PLC and trifluoroacetic acid in water -A mixture of acetonitrile and then a suitable portion of evaporation to obtain the above compound (230 mg) as a white solid. ^ H-NMR (CDCI3-DMSO) 10.58 ( s, 1H), 9.09 (s, 1H), .8.76 (s, 2H); 8.57 (t, 1H), 8.49 (d, 1H), 7.79-7.11 (m, 4H), 5.36 (dd, 1H), 4.07 (ΐ, 2H), 2,90 (dd, 1H), 2.79 (dd, 1H), 1.35 (s, 9H) 0

Step E 230 mg of the product of Step D was dissolved in 20 ml of 1: 1 dichloroformamidine-trifluoroacetic acid, and the resulting mixture was stirred at room temperature overnight. After evaporation, the mixture was passed through a reverse-phase PLC, and a trifluoroacetic acid aqueous solution-acetonitrile mixture was used, and then an appropriate portion was evaporated to obtain the above compound (183 mg) as a white solid. OC17H19N704 CFCOOH 1/2 H20 (MW508 .41) Analysis: Calculate 値: C, 44.89; Η, 3.97. Found 値: C, 44.75; Η, 4.16. Example 2 4 4 Cold-[[2-[[[3 · [(Aminoiminoamido) amino] benzyl] carbonyl] amino] ethyl-324- This paper size applies to Chinese National Standards (CNS) A4 size (210X 297mm) ^ ....... Γ: _______. --------- ¾ ------ ^ ------ 0 (Please read the (Notes are written on this page again) Α7 Β7 ΐ:? 4 6S ^ ββ '32? V. Description of the invention (fluorenyl] amino] -3 -methyl phenphen-2-propionic acid 'trifluoroacetate

Step A

10.0 g (56.5 mmol) 2-bromo-3-methylbiphene, 1.5 ml (9.18 g '71 · 8 mmol) tert-butyl acrylate, 15.7 ml (11.4 g, 113 mmol) Mol) triethylamine, 857 mg of tri-o-o-phenylphosphine, and 113 mg of acetic acid. The mixture in 20 ml of acetonitrile was stirred under argon for 8 hours. After cooling. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with vinegar-ethyl acetate, and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to obtain. Crimson oil. ^ -NMR (CDClj) 7.78 (d, J = 15Hz, 1H), 7.24 (d, J = 6Hz, 1H), 6.87 (d, J = 6Hz, 1H), 6.13 (d, J = 15Hz, 1H), 2..36 (s, 3H), 1.56 (s' 9H).

Step B -325- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) " 458956 A7, _ B7 323 V. Description of the invention ()

8.00 g (35.7 mmol) of the product from step a was reacted with ammonia in the same manner as in Example 242, step B. The crude product was chromatographed on silica gel using 50% ethyl acetate-hexane as a eluent to obtain the above compound (1.78 g) as a red oil, which crystallized upon standing. 1 H NMR (CDC13) 7.11 (d, 1H) 6.78 (d, 1H)., 4.72 (m, 1H), 2.58 (m, 2H), 2.23 (br s, 2H), 2.21 (s, 3H), 1.44 (s, 9H) 〇 Step C /?-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -3 -Methylphenphen-2-propionic acid, ΐ -Dimethyl ethyl ester-\ (Please read the precautions on the back before writing this page), τ Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

530 microliters (432 mg, 432 mg, 432 mg, 432 mg, 432 mg, 4.36 mmol) N-fluorenylhexahydropyridine, yielding a white solid. To this mixture was added 1.12 g (4.36 mmol) of solid succinimide carbonate, and the resulting mixture was stirred for 3 CT minutes to give a clear solution. • 326- This paper size is in accordance with Chinese National Standard (CNS) A4 scale (210X297 mm) 458956 A7 ___ — __B? ______ 5. Description of the invention (324). 1_00 g (4.15 mmol) Step ^ The product is in 8 ml A solution in dimethylformamide was added. The mixture was stirred at room temperature overnight. The volatiles were evaporated to obtain 3.8 g of residue. 1.5 g of the mixture was subjected to reverse phase η p LC using a trifluoroacetic acid aqueous solution-acetonitrile mixture 'and then an appropriate portion was evaporated to obtain the above-mentioned compound (171 mg) as an off-white solid to be converted into an acid. It was confirmed as in step 骒 D As described. Step D. A solution of 167 mg of the product of Step C in 15 ml of 1: 1 digasmethane-trifluoroacetic acid was stirred at room temperature overnight. The residue was subjected to reverse phase PLC using a mixture of an aqueous trifluoroacetic acid solution and acetonitrile, followed by appropriate partial evaporation to obtain the above compound (103 mg) as a white solid.

Analysis of CigH2iN5 O4S CF3 COOH (MW 517.48):. Calculate 値: C, 46.42; Η, 4.29; N, 13.53. Found 値: C, 46.88; H, 4.52; N, 13.24. Example 2.4 3 (±) fluorene-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -3- (fluorene Thio)-Preparation of phenylpropionic acid and trifluoroacetate (Please read the precautions on the back before writing this page) SMe printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

.TFA -1 / 4H2〇… 327- This paper scale is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 4 58 9 56 a? Β7 Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Instructions () Step A 3- [3- (methyl'thio) phenyl] -2E-propionic acid 1,1-dimethylethyl ester 〇2-- ^ 'SMq Palladium acetate (110 mg' 0.0 ' Mol), 3-bromothioanisole (10 g, 0.05 mol), tert-butyl acrylate (7.7 g, 0.06 mol), tri-p-toluylphosphine (0.76 g, 〇′〇). Mol) and triethylamine (5.1 g, mol / mol) in 20 ml of DMF were heated to 120 ° C for 20 hours. The solid was removed by filtration and washed with CH2C12. The filtrate was concentrated to an oily solid. Ethyl acetate was added and the solids were removed by filtration. The filtrate was concentrated to an oil. The product was purified by silica gel. The structure is supported by NM R. Analysis of C I4Η1802 S (250.36): Calculate 値: C, 67,16; Η, 7.25. · Measured 値: C, 67 · 33; Η, 7.24. Step B Amino-3- [3- (methylthio) phenyl] • 1,1-dimethylethyl propionate '• »Monohydrochloride-328- This paper is applicable to Chinese national standards ( CNS > Α4 specification (210x297mm) --------- install — Λ- (Please read the notes on the back before " write this page} k Order M. '458956 ^ V. Description of the invention ( 326) NH,

The product of step A (10 g, 0,04 mol) was treated with ammonia-saturated t-BuOH and 1 ml of acetic acid at 110 ° C and 900 psi in a Parr shaker for 78 hours. The kun compound was mashed and concentrated to a dark oil. The product was purified by silica gel chromatography, and a solution of free base in 100 ml of EtOAc was treated with 7N HC1 in dioxolane. The precipitate was washed with EtOAc, and dried. The structure is supported by NM R. Analysis of C 14H22NO2SC1.0.1 Η2 〇 (303.85 + 0.1 m Η2 0): Calculate 値: C, 55.01; Η, 7.32; Ν, 4.58. ‘Measured 値: C, 54.89; Η, 7.36; Ν, 4.41. Step C (±) y?-[[2-[[[[[[Aminoiminoamido) amino] phenyl] carbonyl] amino] ethyldonyl] amino] -3- (formaldehyde Thio) -Phenylpropane. Acid 1,1-Difluorenyl-ethyl acetate, trifluoroacetate (Please read the precautions on the back before this page)-Packing. I. Order-Line-(N Central Standard of Ministry of Economy Bureau employee consumer cooperation Du printed SMe

N-Methyl Hexahydrone (0.69 g, 0.007 mol) Add the example μ of the chemical compound -329- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7,327 V. Description of the invention (0.91 g, 0.00334 moles) in 20 ml of DMF, (TC. White solid precipitated. After 10 minutes, IBCF (0.47 g, 1000 SW moles) was added. After 15 minutes (all liquid-containing) ), The product of step B (101 g, 0.00334 mole) was added to a solution in 6 ml of DMF. The ice bath was removed, and the solution was stirred at room temperature for 20 hours. The solution was concentrated to an orange slurry. The product was Purified by reverse phase HPLC [CH3CN / H2O (0.06% TFA)]. Structure supported by NMR. Analysis of C24H; iiN504S. TFA_1 / 2 H20 (60.8 · 64): Calculated 値: c, 51_31; H, 5.47 N, 11, 51 .. 1. Measured 値: C, 51'46; H, 5.67; N, 11.51.

Step D (Please read the precautions on the back before writing this page)-Pack-JE. SMe

< 1T i Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs, the product of step C (0.50 g) in 10 ml of CH2C12 / TFA (1: 1). Stir at room temperature for 2 to 4 hours. After concentrating to a pale yellow oil, the product was purified by reverse-phase HPLC [CH3CN / H2O (0.06% TFA)]. The structure is supported by NMR. C20H23N5 04S.TFA.l / 4 H20 (548.03) i Analysis: Calculated 値: C, 48.22; H, 4.51; N, 12.78. Found 値: C, 48.19; H, 4.66; N, 12,80. The size of the private paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 tolerance) ^ Ψ 4od 9S € 'A7 _____B7 328 ~ " ------------ 5. Description of the invention () Example 2 4 6 (± ) "-[[2-[[[[[[Aminoiminoamido) amino] amino] phenyl] carbonyl] amino] ethylamido] amino] -6 -methyl-pyridine-2 -Preparation of propionic acid, bis (trifluoroacetic acid) salt

-(Please read the notes on the back before writing this page)

Step A 3- (6-methyl-2-pyridyl) -2E-1,1-difluorenyl ethyl propionate

Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives to print 6-methyl-2-pyridinecarboxylic acid (9.0 g, 0.074 mole) and (third butylcarbonylamidino) triphenylphosphorane (28.0 g, 0.074 mol) in 150 ml of toluene. The solution was heated to 8 5 -9 0 ° C for 5 hours and stirred at room temperature for 20 hours. -The white solid was removed by filtration, and the filtrate was concentrated. 1: 1 toluene / hexane (100 ml) was added, and more white solid was precipitated ', which was removed by filtration. The filtrate was concentrated to an oil. The product was purified by silica gel chromatography. The structure is supported by N M R; ^. Analysis of C13H17N02 (219.29):. Calculate 値: C, 71,21; H, 7.81; N, 6.39. Measured 値: C, 70.S4; H: 7.81; N, 6.32. •-331-This paper size is in accordance with Chinese National Standard (CNS) A4 (21〇 × 297 mm) H_J 9 5 C A7 H_J 9 5 C A7 Printed by B7. 329 " ~ 5 , Description of the invention ()

Step B (±) 6-methyl- / 5-[[(phenoxycarbonyl) .methyl] amino] pyridine-2-propanoic acid 1,1-dimethylethyl ester, ΝΗ0Η20〇2φ: Talk -A solution of the product of step 骒 Α (5.0 g, 0.0228 mol) in benzylamine (4 ^ 9 g, 0.456 mol) was heated to 80 ° C for 6 hours. Then in 2001 for 20 hours. The solution was heated at 115 ° C for 3 hours, then concentrated to an oil, and the product was purified by silica gel chromatography. The structure is supported by N MR; analysis of C20H26N202 (326-44): calculation 値: C, 73.59; H, 8,03; N, .8.58. Found 値: C, 73, 12; H, 8, 14; N, 8_41.

Step C (±); 3-amino-6-methyl-rhodido-2-propanoic acid 1,1-difluorenylacetamidine |-

The product of Step B (5.7 g, 0.017 mol) was treated in 3A-EtOH (100 ml) with a catalytic amount of 4% Pd / .C at 5 psi and room temperature for 8 hours. After filtration, the filtrate was concentrated to an oil. The product was purified by gluten chromatography. .The structure is supported by Ν μ R-332- The size of the paper method is applicable to China National Standards (CMS) A4 specifications (21〇 × 297 mm) '---------- #-(Please read the back first (Notes from this page) Ding 4 ° .¼ A7 B7 rr

330 V. Description of Invention ()

c 13Η20N2 〇2.0.3 m H2 0 (242.62) Analysis: Calculate 値: C, 64.35; Η, 8.60; N, 11.55 Measured 値: C, 64.15; H, 8.38; N, 11.46 Step D

Following the reaction procedure described in Example 245, steps C and O, but replacing the point amino group with (to) / 5-amino-6-methylerbin-2-propanoic acid 1,1-di, methyl ethyl ester- 3- (methylthio) phenylpropanoic acid 1,1-difluorenylethyl ester to prepare the title compound. Structure is supported by NM R. Analysis of C23H24N608F6 (626.47): Calculate 値: C, 44.10; H, 3, 86; N, 13.4 Bu. Measured 値: C, 44.12; H, 3.70; N, 13.36 ·. · Example 2 4 7, A-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino group 3- (fluorenesulfonyl Preparation of fluorenyl) -phenylpropionic acid, bis (trifluoroacetic acid) salt. 333 This paper is sized according to China National Standard (CNS) A4 (210 X 297 mm) «I n I. J Order. N {Please first (Please read the notes on the back of this page and then irk this page) .... Printed by the Central Bureau of Standards of the Ministry of Economic Affairs and Consumer Cooperatives A7 B7. V. Description of Invention (331

Step A methyl-3 bromobenzene: cornerstone wind

Br

(Please read the notes on the back ^ this page first) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

Oxone® (90.8 g, 0.15 mol) in .250 ml of Η20 was added with 3-bromothioanisole (15 g '0.0739 mol) in 25 ml Me. H and 200 ml of acetone solution. The mixture was stirred at room temperature for 2 Q hours. The beta solution was concentrated to remove MeOH and acetone. Water (400 mL) was added and the product was extracted into EtOAc. The EtOAc was dried over sodium sulfate, filtered, and treated ... a secret, compiled, and a solid was obtained. The structure is supported by NMR.

Step B

-334- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X25 »7mm) ^ 58956 V. Description of the invention (A7 B7 332 According to the reaction procedure described in Example 245 steps A-D, but with A ' -3 -bromophenyl, substituted with 3-bromothiobenzyl 'to prepare the title compound. C 20H23N5 06S'2TFA (689.55): Analysis: Calculated: C, 41.81; H, 3.65; N, 10.16; s, 4.65. Found 値: C, 41.91; H, 3.74; N, 10.45; .S, 5.15. Example 2 4.9 θ-[[2-[[[[[Aminoiminomethyl) amino] benzene [Carbonyl] amino] ethyl] ethenyl] amino] 5-diethoxy-phenylpropionic acid, trifluoroacetate

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

Step A

Add K 2 C 0 3 (20 g) and ethyl iodide (20 g) to 3,5-dihydroxybenzaldehyde (10 g) in DMF (1 (? 0 'ml). The mixture is at 2 5 Stir at ° C for 3 days, add D water (250 ml), and extract the product into ethyl acetate. The organic layer is separated, washed with water and brine, and dried over Na 2 S 0 4 to obtain 3,5-diethoxybenzene. Base-335- private paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 458 956 A7 B7 5. Description of the invention (333) Carboxaldehyde (12 g), dark oil. This substance is used for Next step. MS & H_NMR is consistent with the structure shown. Step B-

To 3,5 · diethoxyphenylcarboxaldehyde (step A) (10 g) in ethanol (70 ml) was added ammonium acetate (12.5 g), followed by ethyl hydrogen malonate (0 g). The reaction mixture was stirred at reflux for 5 hours. The solution was cooled and the ethanol was removed under reduced pressure. HC1 solution (100 ml) was added and the mixture was partitioned between ethyl acetate. The organic layer was discarded, and the acid layer was mixed with solid 1 <: 2 <: 03 to produce basic 8. The mixture was partitioned into dichloromethane (150 ml), separated, and dried over Na2S04. The solvent was evaporated to obtain ethyl DL-3-amino-3- (3,5-diethoxyphenyl) propionate as an oil. Ether (100 ml) was added, then HC1 was added in dioxane (20 ml, 4N) and stirred vigorously for 1 hour. The HCI salt was collected by filtration (6.3 g). MS and H-NMR are consistent with the structure shown. — Step C. < Please read the notes on the back #, &#; write this page). Install. M. Order Printed by the Central Standards Bureau, Ministry of Economic Affairs, Consumer Cooperatives

-336- This paper is from the application of CNS Standard M (2 offers of 297 meetings) A7 B7 453 95 饫 5. Description of the invention (334) · N, N, -bissuccinimide carbonate ( DSC) (1.0 g, 0.4 mmol) Add the compound of Example M (1.0 g, 0.4 mmol) to anhydrous dimethylamidamine (6 ml), followed by dimethylaminopyridine (1.00 mg) . After 20 minutes, DL-3 -amino-3- (3,5-di.ethoxyphenyl) propanoic acid ethyl ester hydrochloride (1.1 g, 0.5 mmol) was added, followed by NMM ( 2.0 ml) 3 After completion of the reaction (1 to 16 hours), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (1.1 g). MS and H-NMR are consistent with the structure shown.

CON co2h The DL-3-amino-3- (3,5-diethoxyphenyl) propanyl ethyl ester adduct (500 mg) dissolved in step C printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs In water / acetonitrile (丨: medium, and then add / bell hydroxide (100 gram). The reaction mixture is stirred at 25 ° C., measured with η pl C 4-. After the hydrolysis is completed (1-2 hours) —, Trifluoroacetic acid was added until ρ η = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to yield 255 mg of the title compound as a white solid. MS and H-NMR were consistent with the structure shown. Examples 2 5 〇 (Earth) fluorene-[[2-[[[[[[Aminoiminomethyl) amino] benzyl] leanyl] kanyl] ethenyl] amino] -4- Preparation of bromophen-2-propionic acid and trifluoroacetate-337- The paper size is applicable to the Chinese national standard (〇 ^) 戍 4 ^^ (2! 0 father 297 mm) __________B7 V. Invention • Ming ( ) 〇

Step on A

The Male Cooperative Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed ammonium acetate (2.5 equivalents) in 3-bromop-sephed-5--5-acid (Aldrich) (10 g) in acetone (70 ml), and then added. Ethyl hydrogen malonate (j equivalent). The reaction mixture was stirred at reflux for 5 hours. The solution was cooled and the ethanol was removed under reduced pressure. HC1 solution (100 ml) was added and the mixture was partitioned into ethyl acetate. The organic layer was discarded, and the acid layer was made alkaline with solid κ 2 c 0 3. The resulting mixture was partitioned into dioxane (150 ml), separated, and dried over Na2S04. The solvent was evaporated 'to obtain D L -3 -amino-3-(bromophene) propionic acid ethyl ester as an oil. Ether (100 ml) was added 'and then HC1 in dioxolane' (20 ml, 4N) was added 'and stirred vigorously for 1 hour. ‘HC1 salt was collected by filtration. (6.3 g). MS and H-NMR are consistent with the structure shown. Step B -338- This paper size applies Chinese National Standard (CNS) A4 specification (2i × 297mm) • '^ a © 6' A7 B7 V. Description of the invention (33) 0

C〇2Et

N, N, -bissuccinimide carbonate (DSCMLO g, 0.4 mmol) Add compound VII (1.0 g, 0.4 mmol) in anhydrous dimethylphosphonium amine in Figure VII (6 ml) and then diaminopyridine (100 mg) was added. After 20 minutes, DL-3-amino-3- (3-bromo "thiophene) propanoic acid ethyl ester hydrochloride (1.1 g, 0.5 mmol) was added 'followed by NMM (2: 0 Ml). After completion of the reaction (1-1 to 16 hours), the product was purified by reverse phase chromatography, ((water / acetonitrile) to give a white solid (1.1 g). MS and Η-NMR were consistent with the structure shown. Procedure C h2n HNw. Equipment-{Please read the notes on the back t write this page) Order I. F = Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic AffairsΗ

2. The DL-3 -amino-3- (3-bromothiophene) propionate adduct (500 mg) produced in C02H Step B was dissolved in water / acetonitrile Π: 1), and then hydrogen was added. Lithium oxide (100 mg). The reaction mixture was mixed on a 2 5 C wall and tested with η p l C. After the hydrolysis was complete (1-2 hours), 'trifluoroacetic acid was added until ρη = 2. The product is inverse 339 ‘paper scale applied to Chinese National Standard (CMS) A4 specification (21〇χ 297 seam)

A7 BT

Purification by phase chromatography (water / acetonitrile) gave 255 mg of the title compound as a white solid. iMS and H-NMR are consistent with the structures shown.

Example 2 5 1 Cold '[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -5 -chlorothiophene- 2-Preparation of propionate and trigas acetate 'co2h s (Please read the precautions on the back ^ 碛 write this page). Pack-' Cl

Step A

Chain: |

P r Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs in 2 · thiothiophene-5-carboxaldehyde (Aldrich) (10 g) in hexanol (70 ml). • Add acetic acid. Press (2.5 equivalents), k Then add ethyl malonate (II equivalents). The reaction mixture was stirred at reflux for 5 hours. The solution was cooled and the ethanol was removed under reduced pressure. Aqueous HC1 (100 ml) was added and the mixture was partitioned between ethyl acetate. The organic layer was discarded, and the acid layer was made alkaline with solid K2C03. The resulting mixture was partitioned into Diqijiayu (150 ml), separated, and dried over Na, S04. The solvent was evaporated to obtain DL-3 -amino-3-(2-airophen) propionic acid ethyl ester as oil -340- This paper is based on Chinese National Standard (CNS) A4 (2 丨 0X297 mm) 〉

V. Description of the invention (shape. 鲢 (100 ml) is added, then ^^ 丨 added in dioxin garden (20 ml, 4N), stirred vigorously for 1 hour. HC1 salt was collected by filtration (63 grams). MS and Η- NMR is consistent with the structure shown. Step 骒 Β η2ν

N, N'-bissuccinimide carbonate (DSC) (1.0 g, 0.4 mmol) Add the compound of Example M (1.Q g, 0.4 mmol) to anhydrous dimethyl Rhenium, sulfonamide (6 ml), then dimethylaminopyridine (00 mg) was added. After 20 minutes, DL-3 -amino-3- (2-chlorophenphene) propanoic acid ethyl ester hydrochloride (1.1 g, 0.5 mmol) was added, followed by NM (2.0 ml) . After completion of the reaction (1-16 hours), the product was purified by reverse phase analysis (water / ethyl chloride) to give a white solid (1.1 g). MS and Η-NMR are consistent with the structure shown-. Step C '— ·. €-(Please read the precautions on the back before you quote this page) ^ Printed by the Central Standards Bureau, Ministry of Economic Affairs, Consumer Cooperatives

Η Η CON ^ ΧΟΝ.

'C02H

TFA

Cl-341-This paper uses China National Standard (CNS) A4 size (210X297 male thin) 4 A7 B7,339 V. DL-3-pyridine-3- (2- Phenyl) ethyl propionate adduct (500 mg) was dissolved in water / acetone (1: 1), and lithium argon oxide (100 mg) was added. The reaction mixture was stirred at 25 ° C and detected by hplc. After the solution was completed (1-2 hours), trifluoroacetic acid was added until ρ η = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to yield 255 mg of the title compound as a white solid. MS and H-NMR are consistent with the structure shown. ... Example 2 5 2 々 _ [[2-[[[[[[Amineiminoamido) amino] phenyl] carbonyl] amino] ethylamido] amino] -IΗ-said Preparation of Bite-3-propionic acid, trifluoroacetate

Step A HN ^ NH2

TFA

〇〇2H Printed by the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs

C02Et in 3 -pyridinylaldehyde (Maybridge) (10 g) in ethanol (70 ml) such as ammonium acetate (2.5 equivalents), then add propyl hydrogen diacetate (丨 "equivalents). The mixture should be stirred at reflux for 5 hours. The solution was cooled, ethanol was added under reduced pressure, and HC1 aqueous solution (100 liters) was added. The mixture was distributed to ethyl acetate 342. The paper size was in accordance with Chinese National Standard (CNS) 8.4 (2 （χ297 mm) Inverse shift '458 956 V. Description of the invention (340 A7 B7

The organic layer was discarded and the acid layer was made alkaline with solid κ 2 C 0 3. The resulting mixture was partitioned between methane (150 ml) and separated, and dried over Na2SO4. The solvent was evaporated to obtain DL-3 · amino-3- (3-1 »specific odor) ethyl propionate, which was oily. Acid (100 ml) was added, then HCI was added in dioxan (20 ml, 4N), stirred vigorously for 1 hour, and HCI · salt was collected by filtration (3 g). MS and H.NMR are consistent with the structure shown. Step B

nh ^ NH '、 C〇2Et (Please read the notes on the back to write this page) S

N / NH .JK.- Printed N, N, -Disuccinimide Carbonate (DSCK 1.0 g, 0.4 mmol) by the Central Government Bureau of Shellfish Consumer Cooperative of the Ministry of Economic Affairs Add Compound H in Figure VII (1.0 g, 0.4 mmol) in anhydrous dimethylpentamine (6 ml) and then dimethylaminopyridine (100 mg). After 20 minutes, DL-3-amino-3- (3-p-bital) propionate ethyl acetate hydrochloride. (Ι · ιg, 0.5 mmol) was added followed by nmM (2.0 ml) . After completion of the reaction-(1.66 hours) 'the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (1.1 g). MS and H-NMR are consistent with the structure shown. .

Step C -343- The paper size is in accordance with the Chinese national standard (CMS> M specification (210X297 male thin 458 g B6 A7 B7 V. Description of the invention (341)

The DL-3 -amino-$ '-(3-? Pico) propionate adduct (500 mg) produced in step B was dissolved in water / acetonitrile (1: 1), and then Into hydroxide (100 mg). Reaction mixture at 25. (: Stirring, detected by Η LC. After the hydrolysis is complete (1-2 hours), trifluoroacetic acid is added until ρ Η = 2. The product is purified by reverse phase chromatography (water / acetonitrile) to yield 255 mg The title <Dagger compound, as a white solid. MS and H-NMR are consistent with the structure shown. Example 2 5 3 * Lu-[[2-[[[3-[(aminoiminomethyl) amine []] Phenyl] carbonyl] amino] ethylfluorenyl] amino] -5 · fluorenylphene-2-propionic acid, trifluoroacetate • fc —-------- dream — ' .! (Please read the precautionary note of "#" 'WOBEN 贳) r Central Standards of the Ministry of Economic Affairs 扃 Printed by Employee Consumer Cooperatives

.Μ -344- This paper uses Chinese National Standard (CNS) A4 (2! 0 X 297 mm) ^ 58956 A7 B7- V. Description of the invention (34 2 HCl · H2N, / ^ c〇2Et ch3 in 5-Methylmethylphene-2-Lancaster (10 g) was added to ethanol (70 ml) with ammonium acetate (2.5 equivalents), and then ethyl hydrogen malonate (1.1 equivalents) was added. The reaction mixture was Stir at reflux for 5 hours. The solution was cooled and the ethanol was removed under reduced pressure. Aqueous HC1 solution (100 ml) was added and the mixture was partitioned into ethyl acetate. The organic layer was discarded and the acid layer was solid K 2.C 0 3 Made basic. The resulting mixture was partitioned into dichloromethane (1.50 ml) ', separated, and dried over Na 2 S 0 4. The solvent was evaporated to obtain DL-3-amino-3- (5-methylfluorenyl). Ethyl propionate, as an oil. Ether (100 ml) was added, then HC1 was added to diosmium glutinosa (20 ml, 4N), and stirred vigorously for 1 hour. HC1 salt was collected by filtration (6.3 g). And Η-NMR is consistent with the structure shown. Step B installation ---- f Please read the precautions on the back before reading this page).

I Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs r

N, N_-bissuccinimide carbonate (DSCK 1.0 g, 0.4 mmol) Add the compound of Example M (10 g, 0.4 mmol) to anhydrous methylformamide (6 Ml) and then dimethylaminopyridine (mg). In the 20-345-private paper standard, China National Standards (CNS) Α4 specifications (210 × 297 mm) 5 //. Η A7, B7, invention description (34 3

Η After CON minutes, 'DL-3 -Amino-3- (3-methylpheno) propanoic acid ethyl ester sulfonium salt (1.1 g, 0.5 mmol) was added' followed by NMM (2.0 ml ). After the reaction was completed (1 to 16 hours), the product was purified by reverse phase chromatography (water / ethoxy) to give a white solid (1,1 g). MS and H-NhR are consistent with the structures shown. Step C.

H2N ^ NH HN ^ 〇r

---------- ^ — (Please read the precautions on the back before v writing this page >> DL-3 -amino group produced in step B of the Consumer Cooperatives of the Central Operation Bureau of the Ministry of Economic Affairs -, 3 ^ (5-methylthiophene) ethyl propionate adduct (500 mg) was dissolved in water / acetonitrile (1: 1), and then lithium argon oxide (100 mg) was added. The reaction was mixed at 2 Stir at 5 ° C and detect with η PLC. After the hydrolysis is complete (1-2 hours), trifluoroacetic acid is added until ρΗ = 2. The product is purified by reverse phase chromatography (water / acetonitrile) to yield 255 mg of the title compound, White solid. MS and H-NMR are consistent with the structure shown. Example 254.-Pan-[[2-[[[3-[(Amineimidomethyl.) Amino] phenyl] carbonyl] Preparation of Amine] Acetyl] Amine] -2,3,5-trichloro-phenylpropionic acid, trifluoroacetate

346-ΪΤ plate ^ Paper scale is applicable to Chinese National Standard (匸 吣) 44 (210/297 mm) 9 〇6 Α7. Β7

V. Description of the invention () Step A

To 2,3,5-trigas benzyl alcohol (10 g) in ethanol (70 ml) was added ammonium acetate (2.5 equivalents), followed by ethyl hydrogen malonate (1.1 equivalents). The reaction mixture was stirred at reflux for 5 hours. The solution was cooled down, and the HC1 aqueous solution (100 ml) was removed under reduced pressure on an ethanol meter, and the mixture was partitioned into ethyl acetate. The organic layer was discarded, and the acid layer was made alkaline with solid K2C03. The resulting mixture was partitioned into dichloromethane (150¾ liters), separated and dried over Na2S04. The solvent was evaporated to obtain ethyl DL-3-amino-3- (2,3,5-trifluorophenyl) propanoate as an oil (6.3 g). MSAH_-NMR is consistent with the structure shown. Step B 4 Meal-{Please read the notes on the back to write this page), Ding., Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

N, N'-bissuccinimide carbonate (DSC) (1.0 g, 0.4 mmol) was added to the compound of Example M (1.0 g, 0.4 mmol) in anhydrous dimethylformamide ( 6 ml), then dimethylaminopyridine (100 mg). 2 0-347- This paper size applies the Chinese national standard (CNS &gt; A4 size (210X297 mm) V. Description of the invention (345 A7 B7 minutes later 'DL-3-Amine 3, 5-Digas private base) Bingxue Yixue (1.1 g '0.5' mol) was added, and then added, NM (2.0 ml). After the reaction was completed (1-16 hours), the product was subjected to reversed phase chromatography (water / acetonitrile) ) Purification yielded a white solid (1.1 g). MS and H-NMR were consistent with the structure shown. Step C '-h2n,

ΗΝ Η

---------- $ —— (Notes on the back of Qianxian Pavilion read this page) DL-3-amino-3 produced in step B of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy -(2,3,5-Tris-phenyl) propionic acid ethyl adduct (500 mg) was dissolved in water / acetonitrile (1: 1), and then lithium hydroxide (100 mg) was added. The reaction mixture was stirred at 25 * C and detected by HPLC. After the hydrolysis is complete (1-2 hours), trifluoroacetic acid is added until pH = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to yield 255 mg of the title compound as a white solid. MS and H-NMR are consistent with the structures shown. Example 25 5 — Lu-[[2 _ [[[3-[(Aminoiminomethyl ') amine}] phenyl] carbonyl] amino] ethyl] amino] -2- (carboxyfluorenyl oxide ) -Phenylpropionic acid, trifluoroacetate

-348- This paper is in the slavery county (CNS) of China (2lQx297). Γ; V. Description of the invention (346) A7 B7 Step A, H2N 'H〇2〇 ^ ^ 0., C02Et

Ammonium acetate (2.5 equivalents) was added to 2-methylamidophenoxyacetic acid (Fisher) (1 () g) in ethanol (70 mmol), and then ethyl malonate (1 ounce) was added. Reaction The mixture was stirred at reflux for 5 hours, and the solution was filtered to obtain ethyl amine-3- (2-fluorenylphenoxyacetate) propionate. The solids were g = MS and H-NMR were consistent with the structure shown Step B

f Please read the precautions on the back before you post this page]-Pack. m ^-Order 1 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-Carbonic acid N, N'-. Disuccinimidyl imide (DSC ) (1.0 g, 0.4 mmol) The compound of Example M (1.0 g, 0.4 mmol) was added to anhydrous dimethylformamide (6 ml) and then dimethyl Aminopyridine (U) (0 mg). After 20 minutes, DL-3 -amino-3- (2-methylphenoxyacetic acid) ethyl propionate (1.1 g, 0.5 mmol) was added, followed by NM (2.0 ml) . After the reaction is completed (1 to 16 hours), the product is purified by reversed-phase chromatography (water / acetonitrile) -349- This paper size applies to China National Standard (CNS) A4 (210X297 mm)

5. Description of the invention (347) * 'produces a white solid (1.1 grams). MS and H-NMR are consistent with the structure shown. Step C,

The Dl-3-amino-3- (2-formamylphenoxyacetic acid) ethyl propionate adduct (500 mg) produced in step B was dissolved in water / acetonitrile (1: 1), and then added Lithium hydroxide (100 mg) was stirred at 2.5 ° C and detected by HPLC. After the hydrolysis was completed (1-2 hours), trifluoroacetic acid was added until ρ η = 23. The product was purified by reverse phase chromatography (water / acetonitrile) to give 255 mg of the title compound as a white solid. MS and Η-NMR are consistent with the structures shown. Example 2 5 6 A-[[2-[[[[[[Aminoimidoamido) amino] phenyl] carbonyl] amino] ethylamido] amino] -4 -methoxy- Preparation of 1,3 -benzodioxo-6-propionic acid, tri-fluoroacetate '---------- ^-(Please read the notes on the back before this page) Order the Ministry of Economic Affairs Printed by the Central Standards Bureau Shellfish Consumer Cooperative

-350- This paper size is in accordance with Chinese National Standard (CN ’S) A4 (210X297 mm) 4 58 9 56 Α7 Β7 348 Printed by the Male Workers Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

5. Description of the invention (

Step A

To 2. · piperinal (FisheT) (10 g) in ethanol (70 ml) was added ammonium acetate (2.5 equivalents), and then ethyl malonate (1.1 equivalents) was added. ). The reaction mixture was stirred at reflux for 5 hours = &gt; The solution was cooled, and the ethanol was removed under reduced pressure. HC1 aqueous solution (100 ml) was added, and the mixture was partitioned into ethyl acetate. The organic layer was discarded, and the acid layer was made basic with solid k2co3. The resulting mixture was partitioned into dioxane (150 ml), separated, and dried over NayC »4. The solvent was evaporated to obtain ethyl DL-3-amino-3- (2-methoxypiperine aldehyde) propionate as an oil (6.3 g). MS and Η-NMR are consistent with the shown structure S Step B N, N, -bissuccinimide carbonate: (DSC) (1.0 g, 0.4 mmol) Add the compound of Example M (1.0 g, 0.4 millimolar) in anhydrous dimethylformamide (6 ml) and then bisaminopyridine (100 mg). At 2 〇 351 this paper size applies the Chinese National Standard (CNS) Α4 specification (2 丨 0X297) (please read the precautions on the back before ^; write this page)

|: R 458 956 A7 B7. V. Description of the invention (349) minutes, DL-3-amino-3- (2-methoxypiperine Vietnam) propionate (11 g, 0.5 mmol) Mol), followed by NM (2.0 ml). After completion of the reaction (1-16 hours), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (1.1 g). MS and H-NMR are consistent with the structure shown. Step C:

----------- (Please read the precautions on the back to write this page) The DL-3 -amino group produced in step B by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives printed 3- (2-Methoxypiperine aldehyde) acetic acid adduct (500 mg) was dissolved in water / acetonitrile 0: ", and then hydrogen emulsified 11. (100 ¾ g) was added. The reaction exhibited at 25 ° C The reaction was detected by HPLC. After the hydrolysis was completed (1-2 hours), 'trifluoroacetic acid was added until p Η = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to yield 255 mg of the title compound. 'Mainly white solid. MS and Η-NMR are consistent with the structure shown. Example 257 [[Amineimino] amino] phenyl] carbonyl] amino] ethyl.fluorenyl] amino]- Preparation of 5-odorous 2 -methoxymethoxy ^ propionic acid, .trifluoroacetate.

_______- 352- The standard of this paper applies to China National Standard (CNS> A # Specification (21〇 &gt; &lt; 297mm)

'1T 456956 350 V. Description of the invention () Ψ3Δ. A7 B7

To 3-bromo6-methoxybenzaldehyde (Aldrich) (10 g) in ethanol (70 ml) was added ammonium acetate (2.5 equivalents), followed by ethyl hydrogen malonate (1.1 equivalents). The reaction mixture was stirred at reflux for 5 hours. The solution was cooled and the ethanol was removed under reduced pressure. Aqueous HC1 (100 ml) was added and the mixture was partitioned between ethyl acetate. The organic layer was discarded, and the acid layer was made alkaline with solid K2C03. The resulting mixture was partitioned into methane (150 ml), separated, and dried over Na2S04. The solvent was evaporated to obtain ethyl DL-3-amino-3- (3-bromo-6-methoxyphenyl) propanoate as an oil (6.3 g). MS and H-NMR are consistent with the structure shown. Step B ----------- ¾-- (Please read the notes on the back 4 '· --fill this tile first) Order Η ^ Ο

TFA

The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed N, N · -bissuccinimide carbonate (D_SC) (1.9 g, 0.4 mmol) Compound added to Example M (1.0 g, 0.4 mmol) (Ear) to anhydrous dimethylformamide (6 ml), then add dimethylaminopyridine (100 mg). After 20 minutes, 'DL-3 -amino-3- (3-brook-6-methoxyphenyl) propionate g 353- This paper size applies to China National Standard (CNS) A4 specification (210X297) %) '458 956

A7 B7 5. Description of the invention (351) &quot; &quot; _ '(1' 1g '0.5 millimoles) was added, and then NMM (2.0 ml) was added. After completion of the reaction (1-16 hours), the product was purified by reverse phase chromatography (water / ethyl acetate) to give a white solid (1.1 g). MS and Η-NMR are consistent with the structure shown. Step C

The DL-3 -amino-5- (3-mo-6-methoxybenzyl) propionate ethyl adduct produced in step B (500 mg) was dissolved in water / acetonitrile (1: 1) Then add lithium hydroxide (100 mg). The reaction mixture was stirred at 25ttC and detected by HPLC. After the hydrolysis was completed (1-2 hours), trifluoroacetic acid was added until ρ η = 2 °. The product was purified by reverse phase chromatography (water / ethyl chloride) to yield 255 mg of the title compound as a white solid. MS and Η-NMR Consistent with the structure shown. '' Example 2 5 8/5 [3-[(Amineimidomethyl :: amino] phenyl] carbonyl-] amino] ethenyl] amino] -6-chloro-1,3-benzene幷 Eboxy-5-propanoic acid, 'trifluoroacetate-preparation' — 1¾-- (Please read the note on the back ^ 'quite this page first) Order. M ip Staff consumption of the Central Bureau of Standards, Ministry of Economic Affairs Printed by a cooperative

-354- This paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 458956 A7 B7 V. Description of the invention (352

Step A

C02Et 〇 In 6-Pepper Lancaster (10 g) in ethanol (70 ml) add ammonium acetate (2.5 equivalents), and then add ethyl hydrogen malonate (1.1 equivalents) a reaction mixture at reflux Stir for 5 hours. The solution was cooled and the ethanol was removed under reduced pressure. Η (: 1 aqueous solution (100 ml) was added, and the mixture was partitioned into ethyl acetate. The organic layer was discarded, and the acid layer was made alkaline with solid K 2 * C 0 3. The resulting mixture was partitioned into dichloromethane (150 ml) ), Separated and dried over Na2S04. The solvent was evaporated to obtain DL · 3-amino-3-(6-piperazine) ethyl propionate as an oil (6.3 g). MS and NMR were shown with the structure shown Consistent. Step B · · I --------- Swimsuit-&gt; τ. {Please read the precautions on the back | &quot; 'Write this page） Order _ Staff Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs Print

N, N'-bissuccinimide carbonate (DSC) (1.0 g, 0.4 mmol) was added to the compound of Example M (1.0 g, 0.4 mmol) in anhydrous dimethyl methyl-355- Applicable to China National Standard (CNS) A4 specification (210 × 297 mm) 45d 956

A7 B7. I ^ 353 ~~~ ---- V. Description of the invention () S teleamine (6 ml), and then add monomethylamino eel (1000 mg). After 20 minutes, DL-3 -amino-3- (3-piperyl) ethyl propionate (υ g, 0.5 mmol) was added, followed by NMM (2.0 ml). After completion of the reaction (1 to 16 hours), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (1.1 g). MS and H-NMR are consistent with the structure shown 3 Step C

(Please read the notes on the back to write this page first) Binding and Ordering DL-3 -Amine-3-(6 -Pepper.base ) Ethyl propionate adduct (500 mg) was dissolved in water / acetonitrile (1: 1), and then lithium hydroxide (100 mg) was added to the reaction mixture at 25 ° C. &lt;: Stir and detect with hplC. After the hydrolysate was formed (1-2 hours), 'trifluoroacetic acid was added until the product a was purified by reverse phase chromatography (water / acetonitrile) to give 255 mg of the title compound as a white solid. MS and H-NMR are consistent with the structure shown. Example 2 590,000-[[2-[[[3-[(Amineiminoamido) amino] phenyl] xiang] amino] ethyl sulfide] amino] benzofuran-2 -Preparation of propionic acid and trifluoroacetate-356- The paper size Lang Tguan S ^ TcNS) AA ^ m (210X297 ^) —— line '3 956 A7 B7 V. Description of the invention (354

C〇2H

Step A

co2et (please read the precautions on the back first from this page).

I Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

In 2-Benzosulfan Lancaster (10 g) in ethanol (70 ml / add ammonium acetate (2.5 equivalents), and then add hydrogen malonate (M 畲 amount). The reaction mixture was stirred at reflux. 5 hours. The solution was cooled and the ethanol was removed under reduced pressure. Aqueous HC1 solution (100 ml) was added and the mixture was partitioned into ethyl acetate. The organic layer was discarded and the acid layer was made alkaline with solid K2c03.-Generated The mixture was partitioned into dichloromethane (150 ml), separated, and dried over Na 2 SO 4-The mixture was heated to give DL-j-amino-3, (2-benzyl) propanoic acid ethyl ester. It is oily (6.3 g). MS and H-NMR are compared with the structure shown. Step B -357- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) Order 4 5 '丨 Record: 9¾ Berry A7 B7 Invention Description (355

N, N, -bissuccinimide carbonate (DSC) (1.0 g, 0.4 mmol) was added to the compound of Example M (1.0 g, 0.4 mmol) in anhydrous difluorenylformamide ( 6 ml) and then dimethylaminopyridine (100 mg). Add 20 oz. Fe 'DL-3 -amino-3-(2-phenylsulfanyl) propionate (11 g, 0-5 mmol) and then add NMM (2.0 ml) ^ After completion of reverse anesthesia (1-6 hours), the product was purified by reverse phase chromatography (permanent / acetonitrile) to give a white solid (1.1 g). MS and H-NMR are consistent with the structure shown. Step C. — Xiang — (Please read the note at the back of the page before filling out the purchase) Order the cooperation of employees of the Central Bureau of the Ministry of Economic Affairs.

The DL-3-amino-3- (2. Phenylsulfonyl sulfanyl) adduct (500 mg) produced in the step is dissolved in water / acetonitrile (1: 丨), and hydrogen is added after ° _ ~ The standard of oxygen-358 · paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm> A7 'B7 V. Description of the invention (356 Lithium (100 mg) 3 The reaction mixture is stirred at 25 ° C and H p Lc detection. After the hydrolysis is complete (1-2 hours), trifluoroacetic acid is added until pH = 2a. The product 'is purified by reverse phase chromatography (water / acetonitrile) to yield 255 mg of the title compound as a white solid' Structure> MS and H-NMR are the same as shown and the structure is the same. * Example 2 60. Dot-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amine [Ethyl] ethenyl] amino] -3- (carboxymethoxy) · phenylpropionic acid, trifluoroacetate

〇, C02H

Step A

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. Ammonium acetate (2.5 equivalents) was added to 3-methylmethylphenoxyacetic acid (Fisher) (10 g) in ethanol (70 ml), followed by ethyl hydrogen malonate. Ester (丨 丨 equivalent). The reaction mixture was stirred at reflux for 5 hours, and the solution was filtered to obtain Dl_3_amino-3- (3-fluorenylphenoxyacetic acid) ethyl propionate (g). MS and Η-NMR are consistent with the structures shown. -359- ·. The standard of private paper is applicable to China National Standard (CNS) Α4 specification (2ί〇 ×: 297mm) Μ B7 357 V. Description of the invention (

Step B

C02Et

C02H

N, N, -bisamber. Sensimidinyl ester (DSC) U.0.0 g '0.4 mmol.) The compound of Example M (1.0 g. 0.4 mmol) was added to anhydrous di Amidinoformamide (6 ml) was then added to dimethylaminopyridine (1 mg). After 20 minutes, DL-3-amino-3- (3-methylfluorenylphenoxyacetic acid) ethyl propionate (1.1 g, 0.5 mmol) was added 'followed by NMM (2.0 ml'). After completion of the reaction (1-16 hours), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (1.1 g). MS and H-NMR are consistent with the structures shown. Step C

H2N,, co2h Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs' co2h

The DL-3 -amino-3-(3-methylphenoxyacetic acid) ethyl propionate adduct (500 mg) produced in step B was dissolved in water / acetonitrile (1: 1), and then Add lithium hydroxide (1 mg). The reaction mixture was stirred at 2 5 ° C with Η PLC -360- This paper size is in accordance with Chinese National Standard (CNS) 8 4 specifications (2! 〇 × 297 mm) 5. Description of the invention, 358 Α7 Β7 Detection 3 in hydrolysis After completion (1-2 hours), trifluoroacetic acid was added until pH = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to give 255 mg of the title compound as a white solid. MS and H-NMR are consistent with the structures shown. Example 2 6 1 3-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethenyl] amino] -4,4,4- Preparation of trifluorobutyric acid and trifluoroacetate

co2h (Please read the notes on the back to write this page first)-equipment · 1.

Step A HCI H2N, O02Et cf3 Order 1¼ Printed by Shelley Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy Printed in j-amino-4,4,4 · trifluorobutyric acid (Lancaster) (2 g) in ethanol (70 ml) HC1 was added to dioxan (20 mL, 4 N) and stirred vigorously for 1 hour. The solvent was removed under reduced pressure. The HC1 salt was collected as a solid (2.3 g). MS and Η-NMR were consistent with the structure shown. ‘Step 骒 Β 6 -361 Standard for private paper is applicable to China National Standard (CNS) Α4 specification (2ί〇χ 297 公 楚)

Q A7 B7 V. Description of the invention (359

NH 0 F- 'C02Et

-F

F N, N_-bissuccinimide carbonate (DSC) (1.0 g, 0'4 mmol) Add the compound of Example M + (1.0 g '0_4 mmol) to anhydrous dimethyl To formamide (6 ml), then dimethylaminopyridine (100 mg) was added. After 20 minutes, 'DL-3 · amino-3- (4,4,4-trifluoro) propionic acid ethyl ester (ij g, 0.5 mmol) was added, and fresh NM (2 · 0 ml). After completion of the reaction (1 to 16 hours), the product was purified by reverse phase chromatography (water / ethyl 'guess) to give a white solid (1.1 g). MS and Η-NMR are consistent with the structures shown. Step C ‘η2ν ^^ νη 〇Κ,, 〇2h C Surprise first read the note on the back of the page.“ Write this page ”--install-m« ^^ 1 TJ — ^^ 1,-· °

TFA 〇F3 Seal of the Consumer Cooperative of Employees of the Central Standards Bureau of the Ministry of Economic Affairs-DL-3-amino-3- (4,4,4-trifluoro) acetate adduct (500 mg) dissolved in step B To water / acetonitrile (1: 1), then lithium hydroxide (1000 mg) was added. The reaction mixture was stirred at 25 ° C and detected by ΗPLC after completion of water% 1 (1-2 hours). 'Trifluoroacetic acid was added until the β product was purified by reversed phase chromatography (water / acetonitrile), yielding 255 Mg of the title compound as a white solid. MS and H-NMR are consistent with the structure shown. -362 Applicable paper size for China National Standard (CNS) A4 (210X297 mm) p 458956 F A7 * ______ B7_ «Example 2 6 2 (土) 々-[[2-[[[3-[(Amine-based Imininomethyl) amino] phenyl] carbonyl] amino] ethenyl] amino] -3-. Preparation of bromo-4,5-dimethoxyphenylpropionic acid, trifluoroacetate.

〇Me ammonium acetate (2.5 equivalents) was added to 3-bromo-4,5-dimethoxybenzaldehyde (eight 1 (^ (^) (10 g)) in ethanol (70 milliwell), and then propanedialdehyde Ethyl Hydrogen Ester * Printed by the Central Standard of the Ministry of Economic Affairs and printed by the Consumers' Cooperatives ------------ (Please read the precautions on the back first to write this page) 4

. (1.1 equivalent). The reaction mixture was stirred at reflux for 5 hours. The solution was cooled and the ethanol was removed under reduced pressure. Aqueous HC1 (100 ml) was added, and the mixture was partitioned into ethyl acetate. The organic layer was discarded, and the acid layer was made alkaline with solid k2co3. The resulting mixture was partitioned into methane (150 ml), separated, and dried over Na2S04. The solvent was evaporated to obtain ethyl Dré 3-amino-3- (3-bromo-4,5dimethoxyphenyl) propanoate as an oil (6.3 g). MS and H-NMR -363- This paper is again applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) Gal. 4 58 9 56 A7 B7 V. Description of the invention (361

Consistent with structure shown Step B

(Please read the precautions on the reverse side before writing this page) Loading · N, N carbonate, disuccinimidyl imide (DSC) (1.0, none, 0.4 mmol) Add the compound of Example M ( 1.0 g, 0.4 mmol) in anhydrous dimethylamidamine (6 ml), then dimethylaminopyridine (100 mg) was added. After 20 minutes, DL-3- Ethyl 3- (2-bromo-4,5-dimethoxyphenyl) propanoate (1.1 g, 0.5 mmol) was added, followed by NMM (2.0 ml). After completion of the reaction (1 to 16 hours), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (1.1 g). MS and H-NMR showed the same structure

Step C Order β, printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs h2n ^ nh Η Η

-364- The size of this paper is applicable to the Chinese National Standard (CNS) A4 (210 × 297 mm) 458956 A7 B7 362 V. Description of the invention (DL-3-amino-3- (3-bromo-4 produced in step B) Ethyl acetate propionate (500 mg) was dissolved in water / acetonitrile (1: 1), and then argon oxidized with bell (100 mg) was added. Stir and detect by HPLC. After the hydrolysis is complete (1-2 hours), trifluoroacetic acid is added until pH = 2. The product is purified by reverse phase chromatography (water / acetonitrile) to give 255 mg of the title compound 'as a white solid. MS and H-NMR are consistent with the structures shown. *, Example 2 6 3.

[(Aminoiminomethyl) amino] phenyl] renyl] amino] ethylfluorenyl] amino] -4 -fluorenyl valeric acid, trifluorowaxate

(Please read the Attention Master # on the back, and bend the page to install it.

ΝΗ, Ο i-Pr

'C02H-* Order: β H2N' Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Step A 'C02Et i-Pr DL-3-amino-3-(iso: two groups). Ethyl propionate was prepared in accordance with the method of Example 5 3 step A, but with ethyl acetate, isopropyl acetate. (10 g) Substituted 3-ketoglutarate for the purpose. MS and H-NMR are consistent with the structure shown. Step B. 365 The iron scale of this paper applies the Chinese National Standard (CNS) A4 specification (2〗 0 × 297 mm) ^ -458 9 56 A7 B7 V. Description of the invention (363

0 i-Pr, C02Et

N, N_-bissuccinimide carbonate (DSC) (1.0 g, 0.4 mmol) was added to the compound of Example M (0.0 g, 0.4 mmol) in anhydrous dimethylformamide ( 6 ml), then dimethylaminopyridine (100 mg) was added. After 20 minutes, DL-3-amino-3- (isopropyl) propionic acid ethyl ester (ΐ · g, 0 "mmol) was added, followed by NM (2.0 ml). After the reaction was completed (1-1 to 16 hours), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (1.1 g). MS and Η-NMR are consistent with the structures shown. Step C

F COfNk ^ C〇N Η i-Pr {Please read the notes on the back before filling in this page) DL-3 -Amine-3 produced in Step B of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Isopropyl) ethyl propionate adduct (500 mg) was dissolved in water / acetonitrile (1: 1), and then lithium hydroxide (100 mg) was added to the reaction mixture and stirred at 2 5 C, with η pl C ΊChast test. After the hydrolysis is complete (1-2 hours), trifluoroacetic acid is added until ρ η = 2. The product was purified by reversed-phase chromatography ((water / acetonitrile)) to produce 255 mg of the title compound, which was white -366-the size of this paper was in accordance with China National Standard (CNS) A4 (210 X 297 mm) 5'4 68 9 56 'A7 B7, Description of the invention (364 solid. MS and H-NMR are consistent with the structure shown. Example 264 3-[[2-[[[3-[(Amineiminomethyl) amino] benzyl] Preparation of carbonyl] amino] ethylammonyl] amino] -pentanoic acid, trifluoroacetate

丨 Ύ 叫 Η 〇 Et (Please read the precautions on the back first—like writing this page): 摅 装-

Step A H2N,, co2b β

Et. 4 〇 [-3-Amino-3- (3-ethyl) propanoic acid ethyl ester was prepared by the method of Step 53 in Example 53, but acetyl ethyl acetate (10 g) was taken as Λ "'Jiudai 3-Methyl glutaric acid. MS and H-NMR are consistent with the structure shown.

Step B

367 This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) B7 V. Description of the invention (365 N, N, -bissuccinimide (DSC) carbonate (1.0 g, 0.4 mmol) The compound of Example M (1.0 g '0.4 mmol) was added to anhydrous dimethylamidamine (6 ml), followed by dimethylaminopyridine (100 mg). After 20 minutes DL-3-Amino-3- (ethyl) acetic acid ethyl ester (1.1 g '0: 5 mmol) was added, followed by NMM (2.0 ml). After the reaction was completed (1-16 hours), The product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (1.1 g). MS and H-NMR were consistent with the structure shown. Step C_

C02H Printed 'DL-3 -Amine · 3 · (ethyl) propionate adduct (500 mg) produced by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs' Consumer Cooperatives in water / acetonitrile (1: 1), then lithium hydride (100 mg) was added. The reaction mixture was stirred at 25 ° C and detected with Η PL C. After the water solution is completed (1-2 hours), ‘trifluoroacetic acid is added until P Η == 2. -The product was purified by reverse phase chromatography ((water / acetonitrile)) to give 25,5 · mg of the title compound as white I-solid 3 M S and Η-NMR consistent with the structure shown. , 'Example 2 6 5 million-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethynyl]] group] -5- · / Stink-3: Gas-2-Preparation of base-phenyl-acrylic red 'digas vinegar fe · salt 368 This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) nn I n ^ 衣 nn I ^-! 线 \ l / (Please read the precautions on the back before writing this page) A7 B7 V. Description of the invention (366

Step A

, CI (Please read the notes on the reverse side and prepare a sample to write this page) Printed on the basis of DL-3-bromo-5-gas-2-hydroxyaminyl hydrochloride hydrochloride according to the figure by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs XIV preparation. The method of G. Casiraghi, et al. J. Chem. Soc. Perkin Trans 1 p. 3 18, 1978 was used to prepare 4-bromo-2-gas water salamander, 6-bromo-8-gas-chlorophyllin system Prepared by Vogel's The Textbook 0f Practical Organic Chemistry, fifth edition p. 1040. Aminohumulin was prepared by the method described in Example 87 using 7-gas-5-bromohumulin (7 g). MS and Y NMR are consistent with the structures shown. Step B. -369- This paper size applies Chinese National Standard (CNS) A4 specification (2 [0 × 297mm) 9 5 @ A7 B7 V. Description of the invention (367

N, N_-bissuccinimide carbonate (DSC) (1.0 g, 0.4 mmol) added to the compound (1.0 g, 0.4 "mol) in anhydrous dimethyl ammonium (6 Ml), followed by diamidopyridine (100 mg). After 20 minutes, DL-3-bromo-5-gas-2-hydroxyaminohumulin hydrochloride (g, 0.5 mmol) was added Then, NMM (2.0 ml) was added. After the reaction was completed (1 to 16 hours), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (1.1 g) ° MS and H-NMR. Consistent with the structure shown.,

Step C H2N ^^ NHHNW. Η

CON

, C0N TFA

(谙 Please read the precautions on the back *. ¥, write this page). Binding. Order 01 ^ 3- &gt; Smelt-5-Gas-2-Beiji produced in step 3 by the Consumer Cooperatives of the Central Standard Bureau of the Ministry of Economic Affairs Aminolactone adduct • (500 mg) dissolved in water / acetonitrile (1: j), slowly opened to form (2. hydroxy acid), and purified by reverse phase chromatography and freeze-dried to yield 255 mg of the title The compound was a white solid as a TFA salt. MS and H-NMR are consistent with the structure shown. Example 2 6 6 Cold-[[2-[[[3-[[[((4-pyridylmethyl) amino] carbonyl] amino] phenyl] carbonyl] carbonyl370 This paper size is in accordance with Chinese Standard (CNS) A4 (210X297 mm) 458 956 A7 B7 V. Description of the invention (368-based] amino] ethylfluorenyl] amino] pyridine-3-propionic acid, (bis) Preparation of trifluoroacetate

NH C〇2H ό .-- i I (Please read the notes on the back before writing this page loosely)

Step A Η 0Ν ~ IC〇2- | _ · Order printed by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, printed tertiary butyl glycine (20 g, 119 mmol) and added to water (200 ml), then add carbonic acid In potassium (20 g, 180 mmol), cool to CTC in an ice bath. To this solution was added dropwise a solution of 3-nitro-benzyl chloride (20 g, 108 mmol) in acetonitrile (20 ml) over 10 minutes. After the reaction was completed (3-4 hours), concentrated hydrochloric acid was added until p η = 3, and then a saturated aqueous NaCl solution (75 ml) was added. The product was filtered, washed with water, and air-dried (22 g, 90% yield). MS and H-NMR are consistent with the structure shown.

Step B -371-The paper size applies the Chinese National Standard (CNS) (2ί〇297297 mm) * 458956 at B7 V. Description of the invention (369) ◎ -Hv-resistant r '(3-nitrophenylfluorenyl) Tertiary butyl glycine (υg) was added to absolute ethanol (60 ml) in a Parr bottle. Palladium / carbon 5% (1 g) was added and the mixture was hydrogenated in a Parr unit at 50 psi for 2.5 hour. After the reaction was completed, the palladium catalyst was removed by filtration through a celite plug. The solvent was removed under reduced pressure, and the sample was dried and dried in the air. Dimethylformamide (25 ml) was added with crude aniline tert-butyl ester, followed by triethylamine (1.5 equivalents) and cooled to zero. 〇. Phenyl chloroacetate (6.5 g, 1.1 equivalents) was added and the reaction mixture was stirred for 2 hours. Water was added and the solid was filtered to obtain phenylaminocarbamate as a white solid (12.5 g '99% yield). MS and H-NMR are consistent with the structure shown.

’Step C

Dipyridylamine (25 ml) printed by Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs was added to the phenylaminocarboxylic acid in the third step of step B, and then 4-pyridylmethylamine (1.1 equivalent) was added. in. The reaction mixture was heated at 70 ° C and stirred for 2 hours, and ‘stirred at 25 ° C for 12 hours. Water was added, the mixture was partitioned into ethyl acetate, separated, washed with brine, dried with Na 2 S 〇4 -372-this paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) 458956 A7 B7 V. Invention Description (370

dry. An oil (6 g) was obtained. MS and Η-NMR are consistent with the structure shown. Step D HCI ·

CON- Butan &lt;: The compound (6 g) was dissolved in dioxolane (25 ml). ‘To this solution was added HC1 to dioxan (20 ml, 4N). The solution was stirred for 12 hours, the solvent was removed under reduced pressure, and then acid was added. The solids were dried, and dried in an empty oven for 12 hours. Step E Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

N, N · -bissuccinimide carbonate (DSC) (1.0 g, 0.4 mmol) was added to the snail D compound (1,0 g, 0.4 mmol) in anhydrous di Fluorenylformamidine (6 ml / m, then dimethylaminopyridine (100 mg) was added. After 20 minutes, DL-3 amino-3-pyridinyl propionate hydrochloride (1.1- 373- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (2) 0X297 mm. _ I. JII! I— n 1 ~ 'ni ^ n 1 (Please read the note on the back first—fill out this page) ^ 1 458956

A7 B7 V. Description of the invention (371 g, 0-5 millimoles) was added, then NMM (2.0 ml) was added. After the reaction was completed (1 to 16 hours), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (1.1 g). MS and Η-NMR are consistent with the structures shown. Step F

DL-3-Amino-3 · -pyridylpropionate ethyl adduct I (500 mg) produced in the printing step 贝 of the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs was dissolved in water / acetonitrile (1: '1 ), Then lithium hydroxide (100 mg) was added. The reaction mixture was stirred at 25 ° C and detected by HPLC. After the hydrolysis is complete (1-2 hours), trifluoroacetic acid is added until p Η = 2. 'The product was purified by reverse phase chromatography (water / acetonitrile) to yield 255 mg of the title compound as a white-solid> MS and H-NMlt were consistent with the structure shown. · 'Example 2 6 7 3,5-Dichloro-million-[[2-[[[[[[((4-Pyridylmethyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ] Ethyl ethyl] amine] -phenylpropionic acid, trifluoroacetate preparation — one ¾ 1T; 41 (please read the notes on the back of the product before 'fill' this page) __-374-This paper is applicable to the standard囷 National Standard (CNS) A4 specification (210X 297 mm) 4 9 56 A7 B7 V. Description of the invention (372

Step A

(Please read the precautions on the back before filling out this page.) Binding and ordering printed N, N, -bissuccinimide carbonate (DSC) (1.0 g, 0.4 Millimoles) The compound produced in step B of Example 208 (1.0 g, 0- · 4 millimoles) was added to dimethyl methyl amine (6 ml) and then dimethylamino group was added. This • (100 mg). After 20 minutes, DL-3-amino-3- (i, 3-diphenylphenyl) propanoic acid ethyl ester hydrochloride (1.1 g, 0.5 mmol) was added, and then NMM (2.0 ml) was added. After completion of the reaction (1-16 hours), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (1.1 g). MS and H.NMR were consistent with the structure shown.

Step B -375- The national standard (CNS) (210X297 mm) of this paper is applicable to this paper. 373 2 4589 56 A7 B7 V. Description of the invention (

Η

The DL-3 -amino-3- (1,3-dichlorophenyl) propionate adduct (500 mg) produced in Bud A is dissolved in water / acetonitrile (1: 1), and then Gas lithium oxide (100 mg) was added. The reaction mixture was stirred at 25 ° C and detected by HPLC. After the hydrolysis is complete (2 hours), trifluoroacetic acid is added until p Η = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to give 255 mg of the title compound as a white solid. MS and Η-NMR are consistent with the structures shown. Example 26 8 Lu-[[2-[[[3-[[[(2-Pyridinylmethyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine- Preparation of 3-propionic acid and (bis) trifluoroacetate

(¾Xianxian¾Notes on the back of the ear) • Shang. -A .Chain Printing policy of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy

Step A

ΎΗ ', co2h

N-376 This paper size applies to Chinese National Standard (CNS) A4 specification (2 丨 QX297 mm) N * 4 58 9 56 A7 B7 V. Description of the invention (374

Dimethylformamide (25 ml) was added to the tertiary butylaminocarbamate of Example 266, step B, and then 4-pyridylamidoamine (1.1 equivalents). The reaction mixture was heated at 70 ° F. and stirred for 2 hours, and stirred at 25 ° C for 1-2 hours. Water was added and the mixture was partitioned between ethyl acetate, separated, washed with brine and dried over Na2S04. An oil (6 g) was obtained. The ms and H-NMR are consistent with those shown in the '. Step β

HCI

co2h {Please read the precautions on the back #, fill out this page}. Pretend to be printed by a member of the Central Marking Bureau of the Ministry of Economic Affairs, printed by a consumer cooperative

The compound produced in Buman A (6 g) is contained in dioxolane (25 ml). To this solution, add HC1 to dioxan (20 ml, 4N) »solution. Incubate for 1-2 hours, remove the solvent under reduced pressure, and then add ether. Solids. Filtered and dried in an air oven for 1 2 hours \

Step C ΝΗ ,, ΝΗ Ya. 0-

C〇2Et -377- MG scale applicable to China g standard (CNS) A4 specification (210x297 mm ^ 50956 A7 -------- B7 37c ~ -_ ----____ V. Description of the invention () N, N'-bissuccinimide carbonate (DSC) (10 g, 0.04 mol) Add the compound produced in step β (L0 g, 0 4 mol) to anhydrous dimethyl Methylformamide (6 ml), then add diaminopyridine (100 mg). After 20 minutes, 'DL-3 -amino-3-pyridylpropanoic acid ethyl ester hydrochloride (1 : 1 g, 0.5 mmol) followed by NMM (2.0 ml). After the reaction was charged (1-16 hours), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (1.1 G) MS and Η-NMR are consistent with the structure shown.

Step D

'The DL-3 -amino-3-pyridyl propionate ethyl adduct produced in step C (500 mg · g) was dissolved in water / acetonitrile (1: 1), and then lithium hydroxide U was added. Mg). The reaction mixture was stirred at 25 ° C and detected by Η PI: C. After the water-decomposition (1-2 hours), 'three gas acetic acid was added until ρ η = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to give 550 mg of the title compound as a white solid. MS and H-NMR. Are consistent with the structure shown. Example 2 6 9 3,5-Dichloro-Lu-[[2-[[[[[[(Benzyl) amino] ninyl] amino] phenyl] carbonyl] amino] ethynyl ] Amine] Preparation of malic acid and monohydrate -378-This paper applies the Chinese National Standard (CNS) A4 specification (21 〇 297 Gongchu) {Please read the precautions on the back before writing the text Page) .. .1. Printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs. 5. Description of Invention (376

A7 B7

Step A Η, Ν Η (Please read the notes on the back before / fill in this page)

CON ^ j ^ COs-)-(3-nitrobenzylidene) glyceryl tert-butyl ester (10 g) was added to absolute ethanol (60 ml) and placed in a Parr bottle. Red / 5% (1 g) was added and the mixture was hydrogenated in a Parr unit at 50 psi for 2.5 hours. After the reaction was completed, the catalyst was removed. It was removed by filtration through a celite plug. Solvent_ is removed under reduced pressure—the sample is dried in the air. .Step B. Binding Chain Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy

ΝΗ ΝΗ

con ^ / C〇2-]-Acetonitrile (50 ml) was added to the crude amidine (10 g) produced in step A -379- This paper is also compatible with the Chinese National Standard (CNS) A4 specification (210X297 mm) ) Printed by the Central Standard Shellfish Consumer Cooperative. Preparation 5. Description of the invention (377 Α7 Β7) and then added to benzyl isocyanate (7.0g). The reaction mixture was heated to 70 ° C for 2 hours, and the solvent was under reduced pressure. Removed. Diethyl ether was added, and the solid was filtered to obtain benzyl methyl urea tert-butyl ester (U2.6 g as a salmon-colored solid). Step C.

NH

C02H

The compound produced in step B (6 g j is dissolved in dioxolane (25 ml). To this solution is added HC1 in dioxolane (20 ml, 4N). The solution is stirred for 1 2 hours, and the solvent Remove under sound reduction, then add ether. Filter the solids and dry in an air oven for 12 hours. Step 骒 D

V. N, N, -bissuccinimide carbonate (DSC) (1.0 g, 0.4 mmol) Add the compound produced in step C (1.0 g, 0.4 mmol. (Ear)) Packed in anhydrous &gt; II 1 (please read the notes on the back '^ write this book first') ir: win '-380-This paper size is applicable to Chinese National Standard (CNS) A4 (210X297mm) Α7 Β7 V. Description of the Invention To (378) methylamidamine (6 ml), then dimethylaminopyridine (100 mg) was added. After 20 minutes, DL-3-amino-3- (1,3-diphenylphenyl) propanoic acid ethyl ester hydrochloride (1.1 g, 0.5 mmol) was added, followed by NMM (2.0 ml). After completion of the reaction (1 to 16 hours), the product was purified by reverse phase chromatography (water / ethoxy) to give a white solid (1.2 g). MS and H-NMR are consistent with the structures shown. Step Ε (Please read the notes on the back before ^: Write this page}

co2h The DL-3-amino-3- (1,3-diphenylphenyl) propionate ethyl adduct (500 mg) produced in step D of the consumer cooperation cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs was dissolved in Water / acetonitrile (1: 1), then add hydrogen-gasification bell (100 gram). The reaction mixture was dried at 25 ° C, and was detected by Η PL LC. After the hydrolysis is complete (1-2 hours), trifluoroacetic acid is added until = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to give 250 mg of the title compound as a white solid. MS and H-NMR are consistent with the structure shown. Example 2 7 0 3-Gas-point-[[2-[[[3-[. [[(Stupid methyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ethyl] yl] amine grave ] Phenylpropionate, Monohydrate · Preparation-381-Wood paper size applies Chinese National Standard (CNS) A4 (210x297). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs * 458956 Α7 A / B7 379 V. Invention description ()

N, N.-bissuccinimide carbonate (DSC) (1.0 bird, 0.4 mmol) The compound produced in Example 269, Step C (1.0 g, σ. 4 mmol) (Ear) To anhydrous dimethylmethamphetamine (6 ml), then add diamido® specific bite-(100 mg). After 20 minutes, DL-3 · amino-3- (3-phenylphenyl) propanoic acid ethyl ester hydrochloride (1.1 g ,: 0.5 mmol, mole) was added, and then · NMM (2.0 ml) was added ° After the reaction was completed (.1-1 to 16 hours), the product was purified by reverse phase chromatography (water / ethyl acetate) to give a white solid (0.9 g). MS and Η-NMR are consistent with the structures shown. Step B -382- This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page)

A7 B7 380 * 458 956 V. Description of the invention (DL-3 -amino-3 · (3-chlorophenyl) propionate ethyl adduct produced in step A (500 gram) is dissolved in water / acetonitrile (1: 丨), and then add the bell hydroxide (100 mg). The reaction mixture was stirred at 2 5 C and detected by η PLC. After the hydrolysis was completed (1-2 hours), 'trifluoroacetic acid was added until = 2 = The product was purified by reverse phase chromatography (water / acetonitrile) to yield? 50 mg of the title compound as a white solid. MS and H-NMR were consistent with the structure shown, Example 2 7 1 Points-[[2 · [[ [3-[[[(1-phenylethyl) amino] carbonyl] amino] phenyl] carbonyl]

I Amine group] Ethyl group] Amine group] ρ than this 3-propionic acid, the preparation of trifluoroacetate (read the note on the back of the first read 4 ·· Fill in this page)

co2h Printed by the Industrial and Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs

Step A PI &gt; ^ / CH3 NH Η-COK- CO 2 -f- Dimethylformamide (25¾ liters) was added to the phenylaminocarbamic acid third butyl ester of Step 266 of Example 266, and then α-formaldehyde Benzylamine (1.1 equivalents). Anti-383 paper music scale applies Chinese National Standard (CNS) A4 specifications (210X297 mm printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 458956 A 7 _____ B7 V. Description of the invention (381) And stirred for 2 hours and 25 hours at 25 ° C. Water was added, the mixture was partitioned into ethyl acetate, separated, washed with brine, and dried over Na2S04. An oil (6 g) was obtained. MS and Η-NMR showed The structure is the same.

The compound (6 g) produced in step A was dissolved in dichloromethane (50 $ l). To this solution was added TFA (20 ml). The solution was stirred for 12 hours. The solvent was removed under reduced pressure, and then ether was added. The solids were filtered and dried in an air-drying oven for 1.2 hours. Step C

N, N carbonate, disuccinylidene amine ester (DSC) (1.0 g, 0.4 mmol) The compound produced in step B (1.0 g, 0.4 mmol) was added to anhydrous di- 384- The size of this paper is applicable to China National Standard (CNS) A4 (210X297 mm) (read the notes on the back first and write this page). Binding 1.-0T, 45ο 966 Α7 Β7 V. Description of the invention (382 Amidinoformamidine (6 ml) 'and then added dimethylamino I »Biyodo (100 mg). After 20 minutes, DL-3 -amino-3-p than bityl Hexyl propionate | hydrochloride (I '' g, 0.5 mmol) was added 'then NMM (2.0 ml) was added. After the reaction was completed (1 to 16 hours), the product was subjected to reverse phase chromatography (water / (Acetonitrile) purification to give a white solid (1.0 g). MS and H-NMR are consistent with the structure shown. Step D ^ The DL-3 -amino-3-pyridylpropionic acid ethyl ester adduct produced in step C ( 500 mg) was dissolved in water / acetonitrile (1: 1), and then hydrogen 'lithium oxide (100 mg) was added. The reaction mixture was stirred at 25 T and detected by PLC. After the hydrolysis was completed (1-2 hours) ), Trifluoroacetic acid This was purified until ρη = 2. The product was purified by reversed phase chromatography (water / acetonitrile) to give 15b mg of the title compound as a white solid. MS and H-NMR were consistent with the structure shown. Example 2 7 2 · 万-[[2_ [[[3-[[[((1Η-Benzimidazol-2-yl) methyl] amino] carbonyl] amino] phenyl] carbonyl] amino] ethyl alcohol] amine] -3,5 -Preparation of digas phenylpropionic acid and trifluoroacetate C Please read the notes on the back before filling in this page). Packing and ordering m -A. Printing by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

-385- This paper size is in accordance with Chinese National Standard (CNS) 6 and 4 (210X297) A7 B7 ', 厶 ㈢9 δ®. 5. Description of the invention (383:

Step A Η Ν- Η • N ^^ / CON ,. Cao, C02 ~ \ -dimethylformamide (25 ml) was added to the phenylaminophosphonic acid tert-butyl ester of Step 266 in Example 266, Then 2-aminomethylbenzimidazole (Aldrich) (11 eq) was added. The reaction mixture was heated to 70 ° C and stirred for 2 hours ′ stirred at 25 ° C for 1-2 hours. Water was added and the mixture was partitioned between ethyl acetate and ethyl acetate, separated, washed with brine, and dried over Na2S04. An oil was obtained (6 g). MS and H-NMR are consistent with the structure shown.

Step B

co2h The compound produced by Step A of the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (6 g) was dissolved in methane (50 ml). To this solution was added T F A (20 ml,). The mixture was stirred for 1-2 hours. The solvent was removed under reduced pressure and k was added. The solid was filtered and dried in an air oven for 1.2 hours. Step C _ -386- The paper size is applied to the Chinese National Standard (CMS) A4 (210 X 297 mm). Printed by the Bayer Consumer Cooperative of the Zhongfu Guiding Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (384)

N, N'-bisamber imidic acid ester (DSC) (1.0 g, 0.4 mmol) was added to the compound produced in step B (1.0 g, 0.4 mmol) in anhydrous dimethylformamide (6 ml), then dimethylaminopyridine (100 mg) was added. After 20 minutes, DL-3 -amino-3- (1,3-diphenylphenyl) propionic acid ethyl chloride hydrochloride (1.1 g, 0.5 mmol) was added followed by NMM (2/0 ml ). After the reaction was completed (1-16, j, h), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (0.8 g). MS and H-NMR are consistent with the structures shown.

Step D The DL-3-amino-3- (1,3-difluorobenzene.yl) _acetate propionate adduct (500 mg) was dissolved in water / acetonitrile (1: 1) Then, add oxygen and hydrogen (100 mg). The reaction mixture was stirred at 25 ° C and detected by HPLC. After the hydrolysis is complete (1-2 hours), trifluoroacetic acid is added until pH = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to give 125 mg of the title compound as a white solid. MS and H-NMR were consistent with the structure shown. Example 2 7 3 is-[U-[[[[[[[[(3,5-Diphenylphenyl) methyl] amino] carbonyl] amino]] -387- The paper size is applicable to the Chinese national standard (CNS) 210X297 public splash {Please read the notes on the back before writing this page)

A7 B7 385 V. Description of the Invention (Private group] · fel group] Amine group] Ethyl group] Amine group]? Lake -3-propionic acid, three gas acetate

CI

TFA

ΑγΝΗ 丫 ～ c〇2H Ο (Please read the notes on the back first ^-€ Write this page) -Pack-

Step A

Η Η Η

Μ I. 丁-&quot; Μ Printed dimethylformamide (25 ml) by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and added phenylamino group of step 266 in Example 266 • 1 ^ Second butyl carbamide 'and then added , 3,5 -digas benzylamine (Lancaster) (1.1 equivalents). The reaction mixture was heated and stirred at 70 ° C for 2 hours and at 25 ° C for 1-2 hours. Water was added, and the mixture was partitioned between ethyl acetate, separated, washed with brine, and dried over Na2S04. The obtained oil·like substance (6 g) e MS and H-NMR were consistent with the structure shown,

Step B 388 This paper size applies Chinese National Standard (CMS) A4 specification (2 〖0 × 297mm） 458956 A7 B7 V. Description of the invention (386

co ^ c02H The compound produced in step A (6 g ·) was dissolved in methane (50 ml). To this mixture was added T F A (20 mL, 4 n). The mixture was stirred for 1-2 hours. The solvent was removed under reduced pressure, and then ether was added. Solid matter. Filter and dry in an air oven for 1-2 hours.

Step C ---------- Ｍ 装 —— f Please read the notes on the back before writing this page)

Ci

-Order.

Li I β Printed N, N_-disuccinimide carbonate (DSC) (1.0 g, 0.4 mmol) by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs • Add the compound produced in step B (1.0 g, 0.4 mmol) in anhydrous dimethylamidamine (6 ml), and then dimethylaminopyridine (100 mg) was added. After 20 minutes, DL-3 -amino-3 +-(pyridyl) propionic acid ethyl ester hydrochloride (1.1 g, 0.5 mmol) was added, followed by NM (2.0 ml). After the reaction was completed (16 hours), the product was purified by reverse phase chromatography (water / ethyl chloride) to give a white solid (0.8 g). MS and H-NMR are consistent with the structure shown. -389 Standards for private paper waves apply to Chinese national standards (CNS &gt; Α4 specifications (2 丨 0 × 297mm) 458 956 A7. B7 I ™ 387 5. Description of the invention ()

In step D, the DL-3 -amino-3- {pyridyl) ethyl propionate adduct (500 mg) produced in step C is dissolved in water / ethoxyl (1: 1), and then lithium hydroxide is added. (100 mg). The reaction mixture was stirred at 25 ° C and detected by H p L C. After the hydrolysis is complete (1-2 hours), trifluoroacid is added until ρ η = _2. The product was purified by reverse phase chromatography (water / acetonitrile) to yield 125 mg of the title compound as a white solid. M S and Η-NMR: consistent with the affinity structure. Example 2 7 4 3-[[2 · [[[[[[[[(3.5-Di + phenyl) methyl] amino] carbonyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] Preparation of Amine] Butyric Acid I --------- ^-(Please read the notes on the back before filling this page)

Cl

NK

NH

'CO2H Order i The policy of employee consumer cooperatives of the Central Bureau of Standards of the Ministry of Economy

Step A c

Cl

NH, N methylformamide (25 ml) was added to benzylaminomethyl-390 in step 266 of Example 266- This paper size is applicable to China National Standard (CNS) A4 (210X297 public director) 4 5 8 9 5 A7 B7 V. Description of the invention (388) To the third butyl acid, and then add 3,5-dichlorobenzidine (Lancaster) (1.1 equivalents). The reaction mixture was heated and stirred at 70 ° C for 2 hours and at 251 for 1-2 hours. Water was added and the mixture was partitioned between ethyl acetate, separated, washed with brine and dried over Na2S04. An oil (6 g) was obtained. MS and H-} NMR; the structures shown are consistent. Step B-

CI

Η

con \ ^ c02H Printed by Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs The compound (6 g) produced in Step A was dissolved in methane (50 ml). To this mixture was added TFA '(20 ml). The mixture was stirred for 1-2 hours. The solvent was removed under reduced pressure, and then ether was added. The solid was filtered and dried in an air oven for 1-2 hours. MS and H-NMR are consistent with the structure shown. Step C 1

CI

N, N · -bissuccinimide carbonate (DSC) (1.0 g, 0.4 mmol) -391-Private paper size applicable to China National Standard (CNS) A4 (210X297 male feet) 4 5 d 9 56 A7 B7 V. Description of the invention () Add the compound produced in step B (1.0 g, 0.4 mmol) to anhydrous dimethyl famine (6 ml), and then add dimethylaminopyridine (100%). Mg). After 20 minutes, 'DL-3-amino-3. (Methyl) propionic acid ethyl ester (Aldrich) (1.1 g' 0.5 mmol) was added, followed by NMM (2.0 ml). After the reaction was completed (1 to 16 hours), the product was purified by reverse phase chromatography (water / ethoxy) to give a white solid (0.8 g). MS and H-NMR were consistent with the structure shown. Step D. The DL-3 -amino-3- (methyl) propionic acid ethyl acetate adduct (500 mg) produced in step C is dissolved in water / acetonitrile (1: 1), and then lithium hydroxide is added. (100 mg). The reaction mixture was stirred at 25 ° C and detected with Η PL C. After the water solution was completed (1-2 + hours), trifluoroacid was added until ρΗ = ^ 2 β product was purified by reverse phase chromatography (water / acetonitrile) to give 125 mg of the title compound as a white solid. 》 MS and H-NMR are consistent with the structures shown. Example 2 7 5 Cold-[[2- [[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] -3,5- Preparation of bis (1-methyl-ethoxy) phenylpropionic acid, trifluoroacetate. '--------- pack-\) &gt; · {Please read the precautions on the back before filling ^ This page) Order 1_k Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Step A

-392- This paper uses Chinese national standards, (0 Deng), 4 specifications (210 乂 297 mm) 4 5 〇 9 56 A7 B7 V. Description of the invention (39Q) J-Pr—〇

CHO

Ό-i-Pr To 3,5-dihydroxybenzaldehyde (10 g) in acetone (loo ml) was added K2 &lt; Γ03 (20 g) and isopropyl moth (20 g). The mixture was heated at reflux and stirred for 2 days. Water (2 ^ 0 ml) was added and the product was extracted into ethyl acetate. The organic layer was separated ', washed with water and brine, and dried over Na 2 SO 4 to obtain 3,5-diisopropoxyphenylcarboxyl (12 g) as a dark oil. This substance is used in the next step. MS and H-NMR are consistent with the structure shown "Step B

(Please read the note on the back # ... to complete this page)

懢-I I ordered Du printed by the Ministry of Economic Affairs of the Central Standards Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs in 3,5-diisopropoxyphenylcarboxaldehyde (step A) (10 grams) in ethanol (70 milligrams)

1 liter) was added ammonium acetate (12.5 g), and then ethyl malonate (6.0 g) was added. The reaction mixture was stirred at reflux for 5 small mixtures to cool, and ethanol was removed under reduced pressure. HC1 solution (100 ml) was added and the mixture · partitioned in ethyl acetate. The organic layer was discarded, and the acid layer was made alkaline with solid K2C03. The resulting mixture was partitioned into dioxane (150 ml), separated, dried with Na2S04 and the β-solvent was evaporated to obtain DL-.3-amine hydrazine-3- (3,5-diisopropylbenzyl) propionate- 393- Private paper size applies ^ National Standard (CNS) A4 specification (21όχ297 mm A7 B7 V. Description of the invention (391)

Ester, oily. Ether (100 ml) was added, then HC1 was added in dioxane (20 ml '4N), and stirred vigorously for 1 hour. HC1 salt was collected by filtration (4.3 g). MS and H-NMR are consistent with the structure shown. Step C

-----------(Please read the precautions on the back of Jing before _r write f) N, N _ -disuccinimidyl henium (* DSC) (1.0 g, 0.4 Mmol) Add the compound of Example M (1.0 g, 0.4 mmol) to anhydrous dimethylformamide (6 ml), then add dimethylaminopyridine (100 mg) a. After 20 minutes, DL-3-Amino-3- (3,5-diisopropoxyphenyl) propanoic acid ethyl ester hydrochloride (1.1 g, 0.5 mmol) was added, followed by NMM (2.0 ml). After completion of the reaction (1 to 16 hours), the compound was purified by reverse phase chromatography ('water / acetonitrile) to give a white solid (0.8 g). MS and H-NMR are consistent with the structures shown. ...

Step D The DL-3 · amino-3- (3,5-diisopropoxyphenyl) propionic acid ethyl adduct produced in step C (500 mg) was dissolved in water / acetonitrile (I: 1) Medium, then add hydroxide (100 mg). The reaction mixture was stirred at 25 ° C and detected by HPLC. After the hydrolysis is completed (1-2 hours), trifluoroacetic acid is added until, pH = 2 394- Private paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm). Printed by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs System J-^ 5β A7 A7 _B7 V. Description of the invention (392). The product was purified by reverse phase chromatography (water / acetonitrile) to give 625 mg of the title compound as a white solid. MS and Η-NMR are consistent with the structures shown. Example 2 7 6 A-[[2 · [[[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -3,5-dibromo Preparation of 4-hydroxyphenylpropionic acid, trifluoroacetate

---------- ^ I · \ · (谙 Read the precautions on the back first / fill in this page) 11

Step A

_ Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs on the addition of ammonium acetate to 4-hydroxy-3-yl-3,5-dibromobenzaldehyde (eight (: 11) (10 g) in ethanol (70 ml) (2.5 eq.), Then add ethyl malonate (1.1 eq.). The reaction mixture was stirred at reflux for 5 hours. The mixture was cooled, ethanol was removed under reduced pressure. HC1 aqueous solution (100 ml) was added, and the mixture was partitioned between acetic acid Ethyl ester. The organic layer is discarded, and the acid layer is made alkaline with solid K2C03. Raw-395- This paper size applies to Chinese national standards (CNS> A4 specifications (210 ×: 297 mm>) • 458956 A7 B7 ) * 一 &quot; &quot; &quot; '

The compound V is partitioned into dichloromethane (150 ml), separated and dried over Na2S04. The solvent was evaporated to give ethyl) 1 ^ -3- &gt; yl-3- (4-hydroxy-3,5-dibromophenyl) propanoate as a solid = collected by filtration (1.3 g) MS and H -NMR is consistent with the structure shown.

Step B

N, N · -bissuccinimide carbonate (DSC) (1.0 g, 0.4 mmol) was added to the compound of Example M (1.0 g, 0.4 mmol) in anhydrous dimethylformamide (6 ml ), And then add diamidopyridine (100 mg) β. After 20 minutes, ethyl DL-3-amino-3- (4-hydroxy-3,5-dibromophenyl) propionate Hydrochloride (1.1 g, 0.5 mmol) was added, followed by NMM (2.0 ml). After completion of the reaction (1-16 hours), the product was purified by reverse phase chromatography (water / ethyl acetate) to give a white solid (0.89 g). MS and H-NMR are consistent with the structure shown. 0 Step C "DL-3-amino-3- (4-hydroxy-3,5-dibromobenzyl) propionate adduct produced in step B (500 mg) was dissolved in water / acetic acid (1: 1), and then lithium hydroxide (100 mg) was added. The reaction mixture was stirred at 25 ° C and detected by HPLC. After the hydrolysis was completed ( 1-2. Hours), adding trifluoroacetic acid until -396-. The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ~ '' ~ M clothes — (Please read the note on the back before reading Fill out this page & order _ 1m Printed by the Central Laboratories of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives ^ 4 58 9 56 A7. B7 --294 ~ '---- V. Description of the invention (') pH = 2. Product Purification by reverse phase decantation (water / acetonitrile) gave 425 mg of the title compound as a white solid. MS and H-NMR were consistent with the structure shown. Example 277 θ-[[2-[[[3-[( Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] · 3,5-digas-4-hydroxyphenylpropionic acid, trifluoroacetate preparation

Step A (Notes on the back of Shi Xianmin reading-^ -.- Fill this page) • Binding

Central Laboratories of the Ministry of Economic Affairs, printed by the Industrial Workers Cooperative, added ammonium acetate (2.5 equivalents) to ethanol (70 ml) in 4-hydroxy-3,5-dichlorobenzaldehyde (eight 1011 ^ 11) (10 g) ) And then 'Hydroxymalonate (1.1 eq) was added. The reaction mixture was stirred at reflux for 5 hours. The mixture was cooled and the ethanol was removed under reduced pressure. Aqueous HC1 (100 ml) was added and the mixture was partitioned between ethyl acetate. The organic layer is discarded, and the acid layer is made alkaline with solid reverse 2 (: 03. Raw -397'-) This paper size applies the Chinese National Standard (CNS) A4 specification (? 10 &gt; &lt; 297 mm) 458956 A7 B7 5 , Description of invention (395

The resulting mixture was partitioned into methane (150.ml), separated, and dried over Na2S04. The solvent was evaporated to obtain ethyl DL-3-amino-3- (4-hydroxy-3,5-diphenylphenyl) propanoate as a solid (· 2.5 g) +. MS and H-NMR are consistent with the structure shown. Step B

(谙 Please read the precautions on the back before filling this page) Packing _ Printed by N.N. Carbonate, Disuccinimide (DSC) (1.0 g, 0.4 mmol) *. Add the compound of Example M (1.0 g, 0.4 mmol) to anhydrous dimethylamidamine (6 ml), and then add dimethylaminopyridine (100 mg). After 204 minutes, DL-3-amino-3- (4-hydroxy-3,5-dichlorophenyl) propanoic acid ethyl ester hydrochloride (1.1 g, 0.5 mmol) was added, Then NM · (2.0 ml) was added. After completion of the reaction (1-16 hours), the compound was purified by reverse phase chromatography (.water / acetonitrile) to give a white solid (0.9 g). MS and H-NMR are consistent with the structures shown. Step C · DL-3-amino-3- (4-hydroxy-3,5-diphenylphenyl) propionate adduct (500 mg) dissolved in water / acetonitrile (1: 1), then add lithium hydroxide (100 mg) Λ reaction mixture and stir at 25 ° C, to -398- 'this paper scale is applicable to China National Standard (CNS) A4 specifications (210X297 mm) order 4-state 966 A7 B7 5. Description of the invention (3Θ6) Η PLC detection. After the hydrolysis is complete (1-2 hours), trigas 1 acetic acid is added until ρΗ = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to give 325 mg of the title compound as a white solid. MS and H-NMR were consistent with the structure shown. Example 2 7 8 Cold-[[2-[[[[[[[[[[5,6-Dihydro-4Η-thiagen-2-yl) amino] phenyl] carbonyl] amino] acetate] amino] Preparation of υ bite-3-propionic acid, bis (tri-vanoacetic acid) salt

Step A (Please read the notes on the back before filling in this page).

H2N

C02Et The compound (2.0g) prepared in the example 104 of the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs was dissolved in absolute ethanol (60ml) in a Parr bottle. 5% / 500mg was added / finished The mixture was hydrogenated in a Parr apparatus at 50 psi for 2.5 hours. After the reaction was completed, the palladium catalyst was removed by filtration through a celit.e plug. The solvent was removed under reduced pressure, and the sample was dried in the air. -399- ^ Paper ^ degree applies Chinese National Standard (CNS &gt; A4. Specifications (210X297 mm) 49 6β Α7 Β7 V. Description of the invention (‘Step B

The compound prepared in Step A of the Consumer Cooperatives ’Printing Cooperative in the Ministry of Economic Affairs of the Ministry of Economic Affairs was added to acetonitrile (20 ml), and then 2-methylthiodihydro-13--13p well (2.0 g) [based J chem. Perkin Transaction,] 943, ρ · 243-245], and heated for 4 hours. After the reaction was completed, water was added and the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (1.3 g). MS and H-NMR were consistent with the structure shown. The DL-3 -amino-3- (p-bitenyl) propionate ethoxylate adduct (700 mg) produced in step C and step B was dissolved in water / acetonitrile (1: 1), and then hydrogen was added. Lithium oxide (100 mg). The reaction mixture was stirred at 25 ° C and measured by Η P L C debt. After the hydrolysis was completed (1-2 hours), trifluoroacetic acid was added until pf_j = 2-. The product was purified by reverse phase chromatography (water / acetonitrile) to give 520 mg of the title compound as a white solid. M.S and H-NMR are consistent with the structures shown. Example 279 β-[[2-[[[5-[(Amineylidenemethyl) yearnyl] -2-ylbenzyl] ajiyl] amino] ethylethyl] amino] -3, Preparation of 5-digas-phenylpropionic acid and trifluoroacetate-400- MM scale applicable to China National Standard (CNS) &quot; ^ Specification (210X297 mm) (Please read the precautions on the back before writing This page) Binding 4 ^ A7 B7 V. Description of the invention (398)

Step A

—--------- Installation-\ ~ .... (Please read the notes on the back before ^ ', write this page) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Aminosalicyl salicylate (10 g), K2co3 (10 g) and bis-tertiary butoxy carbonate (12 g) were placed in water / acetonitrile (100 ml '(1: in a beaker » The process of the reaction was detected by ΗPLC. After the reaction was completed, dilute HC1 aqueous solution was added (ρΗ = 4), the product was separated, and filtered to give a tan-red solid (15 g). The compound was placed in an oven at 70 ° C was dried for 16 hours. -MS and Η -NMR were consistent with the structure shown. -Step B c〇G \ ^ C02Et

OH Carbonate N, N · -bissuccinimide (DSC) (2.0 g, 0.8 mmol) -401-The paper scale is applicable to the national standard (CNS) A4; C cell (2 丨 0; &lt;; 297 mm)

V. Description of the invention (399) Add the N-Boc compound (2.0 g, 0.4 mmol) produced in step A to anhydrous diamidinofluoramide (4 ml), and then add dimethylaminopyridine. (100 mg). After 20 minutes, glycine 'acid ethyl ester hydrochloride (2.1 g, 0.9 mmol) was added, followed by DIEA (2.0 ml). After the reaction was completed (2 * hours), the product was ethyl acetate (100 Ml), extracted with HC1 solution, brine, and dried over Na2SO4 to obtain a dark oil (2.5 g). MS and H-NMR are consistent with the structure shown.

Step C I ---------- install I-(谙 first read the precautions on the back and then #; 'this page)

Ethyl glycinate N-Boc phenylamidine adduct (2 g) produced in the printing of Step B by the Consumer Cooperative of the Central Bureau of the Central Bureau of the Ministry of Economic Affairs was dissolved in water / acetonitrile (1: 1). Then add lithium hydroxide (200 mg). The reaction mixture was stirred at 25X and detected by HPLC. After the hydrolysis is complete (1-2 hours), hydrochloric acid is added until p Η = 4. The product was extracted with ethyl acetate (1000 mL), washed with aqueous HC1 solution, brine, and dried over Na2SO4 to obtain a dark oil. This oil and ether were vigorously removed, and after filtration, a solid (1.9 g) was produced, and dried in an air oven for 16 hours. MS and Η-NMR are consistent with the structures shown. Step D--402- This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm ') 4 5 ο 9 5 ο-Α7 __- .___ Β7 five' Invention description (4M)

Endoic acid N, N'-No. 2 Permimidate (DsC) (10 g, 0.4 mmol) The glycine compound (10 g, 0.4 mmol) produced in Step C was added Mol) to anhydrous dimethylaminoformamide (6 ml), then dimethylaminopyridine (100 mg) was added. After 20 minutes, DL, 3-amino-3- (3,5-diphenylphenyl) propanoic acid ethyl ester hydrochloride (1.1 g, 0.5.mmol) was added, followed by NMM (2.0 Ml). Hours after the reaction was completed), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (0.9 g). M S and Η-NMR are consistent with the structure shown. Β Step E 〈Please read the precautions on the back and then “« write this page}. _ 丨 丨 t_ n n n.

The compound produced in step D (6 g) was dissolved in dioxolane (50 ml). To this mixture was added HC1 / dioxane. Lupin (20 ml, 4 N). Mix and mix for 1-2 hours. The solvent was removed under reduced pressure, and then ether was added. Solvents • The β solids were removed under reduced pressure and purified by reversed-phase chromatography (water / acetonitrile).. T -403- This paper is sized to the Chinese National Standard (CNS) A4 (· 2ί0 × 297 mm)印 印 956 at ____B7_ V. Description of the invention (4〇1) &gt; Raw white · solid (0.8g) e MS and H-NMR are consistent with the structure shown β} Step F · _

The aniline from step E was dissolved in acetonitrile (20 ml). To this mixture was added pyrazolecarboxamidine hydrochloride (2 g), followed by DIEA »The mixture was heated back for 4 hours. After completion of the reaction (1 to 16 hours), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (0.9 g). MS and H-NMR are consistent with the structures shown.

Step G, Step F. Production of raw DL-3-amino-3- (3,5-dichlorophenyl) propionic acid ethyl adduct (500 mg) dissolved in water / acetonitrile (1: 1) Then add gas to oxidize money (100 gram). The reaction mixture was stirred at 2 5 C, and η p l C was added. 'After completion of hydrolysis (1-2 hours)' trifluoroacetic acid was added until ρΗ = 2. Product • Purified by reverse phase chromatography (permanent / acetonitrile) to yield 125 mg of the title compound as a white solid. MS and H-NMR are consistent with the structures shown. Example 2 8 0, Preparation of phenoxyamino) carbonyl] amino] benzyl] number] amine] ethyl] amino] amino] pyridine-3 -propionic acid'trifluoroacetate__ 404-本Paper size applies to Chinese National Standards (CNS) A yS · U! Ox2i »7mm) 11-I II _-I · I -------- 1 Pack-(Please read the precautions on the back first ^-^ Write this page) Printed A7 B7 &quot; 4 ^ δ9B6 by the Consumer Cooperatives of the China Standards Bureau of the Ministry of Nickel Economy V. Description of the Invention (4C12)

Step A

To o-phenylhydroxylamine hydrochloride (Fluka) (4 g), phenylisocyanate was added to acetonitrile so that 3-ethylethanyl (Lancaster) (5 g) and NMM (1 equivalent) were added. The reaction mixture was stirred at 7 CTC for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure to obtain a solid. Water was added and the tan solid was filtered (7.5 g). MS and H-NMR are consistent with the structure shown. 'Step B (please read the notes on the back #. According to this page) Binding. Order 1 — Record — Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Ph—〇 The compound (7 g) produced in step 骒 Α is dissolved in water / acetonitrile (1: 1), and the formula is -405-. This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm). Printed by the Consumer Standards Cooperative of the Central Bureau of Standards "4589S8 α" &quot;, --- ~~ ____ B7 V. Description of the invention (403) After adding lithium hydroxide (4 dragons). The reaction mixture was stirred at 25: c and detected by HPLC. After the hydrolysis is complete (4-6 hours), 10% HC · 丨 aqueous solution is added until pH = 2. The product was filtered and a bang white boudoir (7 g) was obtained 'and dried in an air oven at 70 sC for 16 hours. MS and H-NMR are consistent with the structure shown. step

N, N, -bissuccinimide carbonate (DSC) (1.4 g, 0.5 mmol) carboxylic acid-urea and benzyl isocyanate of o-phenylhydroxylamine produced in step Bf 3 Gastric ethoxycarbonyl ester ((A13) in Figure V) (10 g, 0.5 mmol) in anhydrous dimethylformamide (20 ml), and then dimethylaminocaline (100 mg). After 1 hour, 3-transyl-3- (pyridyl) propanoic acid glycine-DL-ethyl ester hydrochloride (2.2 g, 0.7 mmol) was added to DMF / NMM (1: 1) ( 5'0-ml) in one portion. After the reaction was completed, the product was purified by reverse phase chromatography (permanent / acetonitrile) to give a white solid (0.8 g). MS and H-NMR are consistent with the structure shown.

Step D The compound (300 mg) produced in Step C was dissolved in water / acetonitrile (1: 丄), and then lithium hydroxide (100 mg) was added. The reaction mixture was stirred at 2 5 ° C -406-. This paper Dimensions are applicable to China and China National Lightweight (CNS) A4 specifications (210 X 297 mm) (please read the notes on the back # .. Fill in this page)-Packing. Order ^ 58958 A7 B7 V. Description of Invention (4Q4) Stir and detect by HPLC. After the hydrolysis is complete (1-2 hours), trifluoro-acid is added until p Η = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to give 500 mg of the title compound as a white solid. MS and Η-NMR are consistent with the structures shown. Example 2 8 1 Cold-[[2-[[[[[(Anilino) amino] + carbonyl] amino] phenyl] carbonyl] amino] acetamidine] amino] pyridine-3- Preparation of propionic acid and trifluoroacetate

Step A

(Please read the notes on the back before filling in this page.) Printed by phenylhydrazine hydrochloride (3.5 g) in acetonitrile, printed by phenylhydrazine hydrochloride (3.5 g), Central Standard Laboratories of Ministry of Economic Affairs Lancaster (5 g) and NMM (1 equivalent). The reaction mixture was stirred at 70 ° C for 1 hour. After the reaction is completed, the solvent is reduced by 407- This paper size applies the Chinese National Standard (CNS) A4 specification (21 × 297 mm). 5. Description of the invention (4ί35 Α7 Β7) is removed to obtain a solid. Water is added to the yellow Brown solid was filtered (8.7 g) MS and Η-NMR were consistent with the structure shown. Step B.

HN &gt; Qrc〇2H

The compound (5 g) produced in step A was dissolved in water / acetonitrile: ^, and then lithium hydroxide (3 g) was added. The reaction mixture was stirred at 25 ° C and detected by HpLC. After the hydrolysis is complete (4-6 hours), 10% aqueous HC1 solution is added until pH = 4. The product was filtered to obtain a yellow solid (3.2 g), which was dried at 70X in an empty supply tank for 16 hours. MS and H-NMR are consistent with the structure shown. Step C (Please read the note on the back before you fill out this page)

'1T P. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

TFA

N, N'-bissuccinimide carbonate (DSC) (500 mg, 0.5 mmol) was added to the compound and compound produced in step B and phenyl isocyanate 3-ethyl gas. -408- A degree of this paper applies Chinese National Standard (CNS) A4M (210X297mm) Ί L ·

^ ^ ^ 5 D. Α7 ------- B · 7, V. Description of the invention (4Q6) · Ester (1.0 g, 0.5 mmol) in anhydrous dimethylformamide (20 ml) Then, dimethylamine pyridine (100 mg) was added. After 1 hour, h-amino-3- (pyridyl) propanoic acid, glycine-DL-ethyl hydrochloride (1 g, 0 7 mmol) was prepared in DMF / NMM (1: 1) (5. 0 ml) was added in one portion. After the reaction was completed, the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (0.8 g). MS and H-NMR are consistent with the structure shown.

The compound (300 mg) produced in step D was dissolved in water / acetonitrile: ^, and then lithium hydroxide (100 mg) was added. The reaction mixture was stirred at 251 and detected by HPLC. After the hydrolysis was completed (1-2 hours), trifluoroacetic acid was added until p Η = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to give 500 mg of the title compound as a white solid. MS and H-NMR are consistent with the structure shown. Example 2 8 2 Dot-[[2-[[[[3: [(5-Amino-1} 2,4-triazol-3-yl) amino] benzyl] carboxy] amine] ethanyl] Amine] _3,5-Digas-phenylpropionic acid, trifluoroacetate preparation innn I i Pack IIII order nn ~, chain (please read the precautions on the back # .. Fill in 'this buy):' Economy Printed by the Shell Standard Consumer Cooperative of the Ministry of Standards

Step A

-409- This paper size is applicable to China · National Standard Rate (CMS) A4 specification (210X297mm) Α7 · _ B7 407-V. Description of the invention ()

Glycine (20 g '266 mmol) was added to water (200 ml), then potassium hydroxide (20 g, 357 mmol) was added, and the mixture was cooled to 0 eC in an ice bath. To this mixture was added dropwise a solution of 3_nitrophenylhydrazine (Aldrich) (20 g '108 mmol) in acetonitrile (20 ml) over 40 minutes. After the reaction was completed (3-4 Hours). 'Concentrated hydrochloric acid was added until p Η = 1, and then a saturated aqueous NaCl solution (75 ml) was added. The product was filtered, washed with water, and air-dried (22 g, 90% yield).

Step B (Please read the notes on the back before writing this page)

-Printing of N, N'-bissuccinimide carbonate (DSC) (1.5 g, 0.7 mmol) by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, and adding the compound produced in step A (1: 0 g, 0.4 millimolar) in anhydrous dimethylformamide (6 ml), then dimethylaminopyridine (1000 mg) was added. 9 After 20 minutes, DL-3-amino-3-'(3 ', 5-Dichlorophenyl) propionic acid ethyl ester hydrochloride (1.1 g, 0.5 mmol) was added, followed by NMM (2.0 ml). After the reaction is completed (1 to 16 hours), the product is added with water / HC1 aqueous solution-410. The paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 cm) ^ ό 3 y 66. A7 '_______ B7____ 5 , Description of the invention (4 £ ϊ8) (5ml) and separation through 遽 ▲ raw white solid (0.9g). MS and H-NMR are consistent with the structure shown. ‘*

Step C

11 &quot;-I »L

The compound produced in step B is subjected to the conditions described in Tetrahedron Letters, Vol. 25, 1984, 839-842 to reduce the nitro group. This reduction was performed with 2 g of a nitro compound.

Step D (Please read the precautions on the back before you fill out this page)-Install ·

In cooperation with the shellfish consumer of the Central Standards Bureau of the Ministry of Economic Affairs, the compound printed in step C was added with isopropanol (20 ml), and then diphenoxycyanamide (1 g) (Aldrich) . The reaction mixture was stirred at 70 ° C for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure to obtain a solid. Ether was added and the tan solid was filtered (3.2 g). MS and Η-NMR are in accordance with the structure shown. 3 -41Ϊ-This paper size applies to Chinese National Standard Plum (CNS) A4 size (210X297 mm) 4 58 9 56 A7 B7 V. Description of the invention (4Q9)

Step E

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs To the compound (1 g) produced in step D, ethanol (1 () ml) was added, followed by hydrazine (1.5 ml) (Aldrich). The reaction mixture was stirred at 2 5 T for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure to obtain a solid. After completion of the reaction (1 hour), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (0.7 g). MS and H-NMR are consistent with the structure shown.

Step F The compound (300, mg) produced in Step E was dissolved in water / ethoxylate (1: 1), and then lithium hydroxide (100 mg) was added. The reaction mixture was stirred at 2 5 X. PLC detection "After the hydrolysis is completed (, 1-2 hours), trifluoroacetic acid is added until ρ Η = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to yield 430 mg of the title compound as a white solid. MS and H-NMR are consistent with the structure shown. Example 2 8 3 points-[[h [[[3-[(1,2,3,4-tetrahydro-2,4-dioxypyrimidin-6-yl) amino] benzyl] condensed group] Amine group] Ethyl alcohol group] Amine group &lt;] p ratio bite-3 · bisacid, trifluoroacetate preparation-412- This paper uses China National Standard (CNS) A4 size (210X297) ^ 956 a7 B7 &quot; 410 'V. Description of the invention ()

Step A

〇

{Please read the precautions on the back first, and then write this page) Printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs, 2-Aminobenzoic acid (4g), added to ethoxyethanol (4ml), and then add 6-chlorouracil (4 ml), heated to 125 ° C for 3-4 hours. The product was filtered, washed with ether, and air-dried (4..5 g) to obtain a tan solid. MS and H-NMR are consistent with the structure shown. Step B-〇

N, N'-bissuccinimide carbonate (DSC) (2 g, 0.7 mmol) plus -413- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 411 58 9 5 6. '7 A7 • B7 V. Description of the invention (

The compound produced in step A (2.0 g, 0.4 mmol) was added to anhydrous dimethylformamide (6 ml), and then dimethylamino 7-pyridine (100 mg) β was added. After 20 minutes, glycine dibutyl hydrochloride (1.1 g '0.5 mmol) was added, followed by D IE A (2.0 mmol). After the reaction was completed (2-3 hours), the product was separated by extraction with ethyl acetate, washed with HC1 aqueous solution, saturated K2CO3, brine, and dried over Na2SO4 to obtain a yellow oil (3 g). MS and Η-NMR are consistent with the structure shown. Step C 〇

j ^ C〇2H (Please read the precautions on the back before writing <I>)

.IT β, the compound produced in step B (2 g) was dissolved in methane (50 ml). To this mixture was added T F A (20 ml). The mixture was stirred for 12 hours. The solvent was removed under reduced pressure, and then ether was added. The solid (1.8 g) was "filtered and dried in the air for 1-2 hours. MS and H-NMR were consistent with the structure shown.

Step D i- Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

, ^ NH 〇, C02Et -4l4-This paper size is applicable to China National Standard (CNS) A4 (.210X 297 mm) Printed by the Bayer Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. '--- --- 5. Description of the invention () N, N'-disuccinium carbonate. Iminoester (0sc) (1.5 g, 0.7 mmol) was added to Example 283 in step C The resulting compound (1.0 · g, 0.4 mmol) was added to anhydrous dimethylformamide (6 mmol'l), followed by the addition of diaminopyridine (100 mg). After 20 minutes, DL-3-amino-3- (pyridyl) ethyl hexanoate hydrochloride (1.1 g &apos; 0.5 mmol) was added, followed by NMM (2.0 mL). After completion of the reaction (1 to 16 hours), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (0.9 g). MS and H-NMR are consistent with the structure shown. Step E The compound (300 mg) produced in Step 骒 D was dissolved in water / acetonitrile (1: 丄), and then lithium hydroxide (100 mg) was added. The reaction mixture was stirred at 2 5 ec and detected by HPLC. After the hydrolysis is complete (1-2 hours), trifluoroacetic acid is added until p Η = 2. The product was purified by reversed-phase chromatography (Hydroxyacetate) to give 430 mg of the title compound as a white solid. MS and H-NMR with the structure shown—Caution Example 284 3,5 · Dichloro-[[2-[[[3-[(1,2,3,4-tetrahydro-2,4'dioxane Of pyrimidine-6-yl) amino] phenyl] carbonyl] amino] ethenyl] amino] phenylpropionic acid.

-415- This paper size is in accordance with China National Standard (CNS) A4 (210X297mm) (please read the precautions on the back before filling in this page).

'^ 53 9 5ί &gt; Λ: Α7 __ Β7 Τ? 3 ~ &quot;: V. Description of the invention () Step A 〇

Printed by the Consumers Cooperative of the Central Bureau of the Ministry of Economic Affairs of the Consumer Cooperative, N, N, · disuccinimidyl carbonate (DSC) (0-6 g). Anhydrous dimethylmethasamine (6 ml) was then added to dimethylaminopyridine (100 mg). After 20 minutes, .01 &gt; -3-amino-3- (3,5--phenylphenyl) propionate acetate hydrochloride (1,1 g, 0.5 mmol) was added, followed by 1 ^] ^ River (2: 0 ml). After the reaction was completed (1 to 16 hours), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (0.9 g). MS and 11-] ^ 1 ^ 11 are consistent with the structure shown. Step B The compound (200 mg · g) produced in Step A was dissolved in water / acetonitrile (1: υ), and then lithium hydroxide (100 mg) was added. The reaction mixture was stirred at 25, and Detected by PLC. After the hydrolysis was completed (丨 -2 hours), trifluoroacetic acid was added until pH = 2. The product was purified by reversed-phase chromatography (water / acetonitrile) to yield 105 'mg of the title compound. White solid. MS and H-NMR are consistent with the structure shown. Example 2 S 5 3,5-Digas-; 9-[[2-[[[3-1 [Imine (1-.hexahydro? Ratio Syndrome) Methyl] Amine] Phenyl] Carbonyl] Amine] -Ethylamido] Amino] Phenylpropionic acid, Trifluoroacetate 416- 'This paper is applicable to the National Standard of China (CNS) A4 Specifications (210X297 mm) (Please read the precautions on the back first. Write this page) Pack. Order

m.-ML A7 B7 V. Description of the invention Preparation of H4

〇

ΝΚ

Step A

(Please read the precautions on the back before writing this page)-Loading ·-Ordering Γ The above compounds were prepared according to the method of Example 24, but with one equivalent of hexahydropyridine instead of benzylamine in step 23 of Example 23 Equal amount of DL-3-amino-3- (3,5-diphenylphenyl) propanoic acid ethyl ester hydrochloride was substituted for DL-3-, amino-3-(3-pyridyl) in step 1 of Example 1. Ethyl propionate dihydrochloride was used again in Example 1 Step D, as described in Example 2 3 Step C β .MS and Η · NMR and structure shown-* \-cause 0, Step I · The compound produced in step A (200. mg) was dissolved in water / ethoxyl (1: 1), and then lithium hydroxide (100 mg) was added. The reaction mixture was stirred at 25 ° C and detected by HPLC. After the completion of the hydrolysis (1-2 hours. Hr) 'Trifluoroacetic acid plus 417 This paper size applies to the Chinese storehouse standard (CNS) A4 specification (210X297 mm). 4 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Description of the invention / 415 A7 B7 into pH = 2. The product was purified by reversed-phase chromatography (water / acetonitrile) to give 05 mg of the title compound as a white solid. : MS and H-NMR are consistent with the structure shown. Example 286 /?-[[2-[[[[3 · [(Benzazol-2-yl) amino] phenyl] carbonyl] amino] ethyl} ] Amine] Pyridine-3-propionic acid, trifluoroacetate

TFA

C〇2H -------------- &lt; Please read the notes on the back before writing this page)

Step A The compound (20 g) prepared in Example 104 was added to absolute ethanol (60 ml) 'in Parr. Palladium / carbon 5% (500 mg) was added and the mixture was hydrogenated in a Parr apparatus at 50 ° F for 2.5 hours. After the reaction was completed, the palladium catalyst was removed by filtration through a celite plug. The solvent was removed under reduced pressure, and the samples were dried in the air. Ii Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs.

Step B 〇

-418- Thai paper prostitutes apply Chinese National Standards (CNS) Congxie (training 297 Kung Chu) V. Description of the invention (4 A7 B7 16 The Ministry of Economic Affairs Central Bureau of Standards Staff Consumption Cooperative printed the compound produced in step A In dmF (20 ml) = To this mixture was added 2-chlorobenzimazole (Alddch) (2 g) and K 2 C 0 3 (4 g). The mixture was heated to 7 ITC until the aniline was consumed and the reaction was complete After that, the product was purified by reverse phase chromatography (water / acetonitrile) to give 215 mg of the title compound as a white solid. MS and H-NMR were consistent with the structure shown..

Step C The compound (200 mg) produced in Step B was dissolved in water / acetonitrile (1: 1) and then lithium hydroxide (100 mM) was added. The reaction mixture was stirred at 2 5 ac and detected by HPLC. After the hydrolysis was complete (1-2 hours), trifluoroacetic acid was added until p H = 2. The product was purified by reverse-phase chromatography (water · / acetonitrile) to yield W5 mg of the title compound as a white solid. MS and H-NMR are consistent with the structure shown. Example 2 8 7 Cold phenyl-1H-imidazol-2-yl) amino] phenyl] carbonyl] amino] ethyl] donyl] amino] pyridine-3-propionate: Preparation of trifluoroacetate

Step A

Η HCI H2N \ / CON, / C〇2Et Taste -419 This paper size is applicable to the Chinese National Standard (CNS.M4 specification (210X297)) 458956 Α7 B7 V. Description of the invention, 417 Example M step " 5 g) was added to ethanol (100 ml), then anhydrous HC1 was added to dioxan (10 ml) β mixture and heated to reflux for 2 hours. The solvent was removed under reduced pressure to obtain ethanoate (5.5 '6g). 1 Ιί ix ί l. Known pages MS and Η-NMR are consistent with the structure shown. Step B

Η CON ^^ CC ^ Et To the product (3 g) of step A was added acetonitrile (50 ml), followed by bromoethyl (2.7 g) and D I e A (2 ml). The mixture was heated for 2 hours and the solvent was removed under reduced pressure. The product was isolated by extraction with ethyl acetate and dried over Na 2 S 04 'to obtain a dark red solid (5 g). &lt; M S and Y-NMR are consistent with the structure shown.

Step C

CON ^ COsH Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs The compound (2 g) produced in step B was dissolved in water / acetonitrile (1: 1), and then bell hydroxide (1000 mg) was added. The reaction mixture was stirred at 2 5 C and detected by HPLC. After the hydrolysis is completed (4-6 hours), HC1 aqueous solution is added -420- This paper size is applicable; National Standard (CNS) A4 specification (21〇 乂 297 mm) &quot; 458 956 A7 B7 418

V. Description of the invention (until pH = 7. The product is filtered and dried in an oven to obtain 2.6 g of a yellow-brown solid. MS and H-NMR are consistent with the structure shown. Step D 0

Printing of N, N'-bissuccinimide carbonate (DSC) (0.3 g, 0.7 mmol) by the Central Bureau of Standards and Consumer Cooperatives of the Ministry of Economic Affairs Add the compound produced in step C (0.5 g, 0.4 mmol) Mol) in anhydrous dimethylformamide (5 ml) and then octacosamidopyridine (100 mg). After 20 minutes, DL-3 -amino-3- (pyridyl) propanoic acid ethyl ester hydrochloride (0.1 g, 0.5 mmol) was added 'followed by NMM (2.0 ml). After the reaction was completed (1-16 hours), the product was purified by reverse phase chromatography (water / acetic acid) to give a white solid (0.9 g). MS and H-NMR are consistent with the structure shown. Step E '' The compound (250 · mg) produced in Step D was dissolved in water / acetonitrile (1: 丄), and then lithium hydroxide (1.00 mg) was added. The reaction mixture was stirred at 25 and detected by HP.LC. Hour after the completion of the hydrolysis), trifluoroacetic acid was added until p Η = 2. The product was purified by reverse-phase chromatography (water / acetonitrile) to give 1 () mg of the title compound as a white solid. MS and Η-NMR are consistent with the structures shown. . Example 2 8 8 3-[[2-[[[3-[[(Amineimidoamido) amino] phenyl] carbonyl] amino] ethyl-421-Applicable to Chinese national standards (CNS) Α4 ^ 格 (2⑴ × 297 public epidemic I pack-(Please read the precautions on the back before writing this page)-, 17

I l: r 4 58 9 56 'A7 B7 * -— 419 V. Description of the invention () fluorenyl] amino] -5-[(3,5-dichloro-phenyl) amino] -5_oxy Preparation of Pentaesthus trifluoroacetate

Step A

Printed by the Central Labor Bureau of the Ministry of Economic Affairs, Consumer Cooperative, a mixture of aminoglutaric acid (Sigma) (5g) and trifluoroacetic anhydride (5 丨 §1 ^) (20ml) at 2 5 eC ~ stir 2 hour. The solvent was removed under reduced pressure to obtain an oil. To this oil was added ether (50 ml) and the product was filtered (5 g). MS and H-NMR are consistent with the structure shown. Step B

-422- This paper size applies to China National Standards (CNS) A4 specification (210X297 mm) l: 468956 A7 B7 — — ~ 5. Description of the invention () Product of step A and 3,5 -dichlorobenzylamine (6 g) of a mixture of DMF (20 ml) was stirred for 16 hours. After the reaction was completed, HC1 aqueous solution (100 ml) and ethyl acetate (100 ml) were added, and the mixture was shaken and separated. The organic layer was separated, washed with brine, and dried over Na2SO4 to obtain acid amide (4 g). MS and H-NMR were consistent with the structure shown.

Step C

(Please read the note on the back # 'Fill in this page first)

^ C〇2H HCIΉ2N — The trifluoroacetyl group of the product of Step B is removed by heating the compound produced in Step B with dilute », ammonium hydroxide (10 ml in 50 ml water). After the reaction was completed, the mixture was acidified with 10% HC1, and the product (2.5 g) was filtered. MS and Η · NMR are consistent with the structures shown. Step D.

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The compound (2 g) produced in step C was added with ethanol (100 ml), and then anhydrous HC1 was added to dioxin (10 ml). The mixture was heated to reflux for 2 hours. The solvent was removed under reduced pressure to obtain ethyl ester (9, 9 g). μ S and '-423-This paper size applies to Chinese National Standards (CNs) Α4 size (210 X 297 Gongchu) ^ ^ 58956 A.7 B7 V. Description of the invention (421

H-NMR is consistent with the structure shown. Step E

Printed with N, N'-disuccinic acid carbonate, diimide (DSC) (0.6 g, 0.7 mmol) in Central Consumer Bureau of Ministry of Economic Affairs and Consumer Cooperatives (0.6 g, 0.4 mmol) in anhydrous dimethylamidamine (5 ml) and then dimethylaminopyridine (100 mg). After 20 minutes, the compound produced in step D of Example 288 (0.7 g, 0.5 mmol) was added, and then NMM (2.0 ml) was added. After the reaction was completed (1-6 hours), the product was purified by reverse phase chromatography (water / acetonitrile) to give a white solid (0.51 g). MS and H-NMR were consistent with the structure shown. Step F-· The compound (250 mg) produced in step £ was dissolved in water / acetonitrile (1: 1), and then lithium argon oxide (100 mg) was added. The reaction mixture was stirred at 25 for detection by HPLC. After the hydrolysis was completed (1.2 hours), 'trifluoroacetic acid was added until ρΗ = 2. The product was purified by reverse phase chromatography (, water / acetonitrile) to give mg of the title compound as eMS and H-NMR as a white solid in accordance with the structure shown. Example 2 8 9 424- The X degree of each paper applies the Chinese National Standard (CNS) Α4 specification (2Ι〇χ297βcenti) (please read the note 11 ^. On the back before filling in this page)

Order I 458956 A7 B7 V. Description of the invention 422 is [[2-[[[3 · [[(aminoiminomethyl) amino] -5-carboxyphenyl] carbonyl] amine] ethyl] ] Amine] Preparation of Ebit-3-propionic acid, bis (trifluoroacetic acid) salt

Step A

C〇2 ~ j— ---------- ^-(Please read the note on the back of this page to write this page first) C02Me, 1T 1! A Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed N, N'-bissuccinimide carbonate (DSC) (6.5 g) and added 5-nitroisophthalic acid methyl ester (5 g) to anhydrous dithion Methylformamide (10 ml), then add dimethylaminomethyl bite (200 mg). After 20 minutes, tert-butyl glycinate (2.6 g) was added, then NMM (2.0 ml after the reaction was completed (4 hours · hour) 'The product was extracted with ethyl acetate and separated with Na2s 〇4 Drying to produce a white solid (5.1 g). MS and Η-NMR are consistent with the structure shown. Step B '-425 Min paper size applies Chinese National Standard (CNS) 8 4 specifications (210X297 mm) Α7 Β7 Economy Ministry of Central Standards Bureau, Consumers' Cooperatives, Printing Policy V. Description of Invention (423)

The compound (5 g) produced in step A was dissolved in dioxolane (50 ml). To this mixture was added anhydrous HC1 (20 mL, 4 N). The mixture was stirred for 1-2 hours. The solvent was removed under reduced pressure, and then ether was added. The solvent was removed under reduced pressure and the solid was filtered to give a white solid (4 g). Dry in an air oven. M S and Y-NMR are consistent with the structure shown q Step C

N, N 1 -disuccinimidylimide (DSC) (2 g) plus Λ: the compound produced in step 骒 Β (2 g) in anhydrous dimethylformamide (10 ml),. Dimethylaminopyridine (200 mg) was then added. After 20 minutes, 1 ^ 3-amino-3- (pyridyl) propanoic acid ethyl ester hydrochloride (1.6 g) was added, followed by NM (2.0 mmol). After the reaction was completed (4 hours), the product was separated by extraction with ethyl acetate and dried over Na 2 SO 4 to give an oil (3 g). MS and H-NMR are consistent with the structure shown.

Step 骒 D * 426- This paper music scale is applicable to Chinese National Standard (CNS) A4 specification (2I0X297mm). S Γ ta. I ....... J ----------) 1 pack ------— Order ------- ▲ (Please read the notes on the back first ¾. ^ ¾ 'this page> .9% A7 B7 V. Description of the invention (424

The compound produced in step C is subjected to Tetrahedron, Letters, Vol. 25, 1984, 83 9-842, under the conditions to reduce the fluorenyl group. This reduction was performed with 2 g of a nitro compound to obtain i g of the product β M S and H: NMR was consistent with the structure shown. Step Ε

C〇2Et (Please read the precautionary note on the back to buy the balance book) Packing · Central Standards Bureau of the Ministry of Economic Affairs

The compound produced in TFA step D [g was guanidined according to the method of Example M and purified by reverse phase chromatography (water / acetonitrile) to give 110 mg of the title compound as a white-colored solid. MS and Η-NMR are consistent with the structures shown. Step F — The compound produced in step (00 mg) was dissolved in water / acetonitrile (丨: i), and then lithium argon oxide (100 mg) was added. The reaction mixture was stirred at 25.c and detected by HPLC. After the hydrolysis is complete (1-2 hours), trifluoroacetic acid is added until pH = 2. The product was purified by reversed-phase chromatography (water / acetonitrile) to produce u〇__. 427-This paper is suitable for standard S, ilg, home care (CMS) A (21GX297 mm) &quot; ~~~ 'l · 458 9 56 A7… B7 V. Description of the invention, 425 mg of the title compound, as a white solid, MS and H-NM.R and the structure shown "Example 2 9 0 A-[[2-[[[3-[[ (Aminoiminomethyl) amino] -5-hydroxyphenyl] carbonyl] Amino] Ethylamido] Amino] _ 3,5-trichloro-phenylpropionic acid, trifluoroacetate

{Please read the notes on the back before writing this page)

Step A

C〇2- Printing of N, N'-bisamber Silimide (DSC) (65 g) by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (5 g) ) To anhydrous methyl methyl succinylamine (10 ml), then add dimethylaminopyridine (200 mg) β. After 20 minutes, add tert-butyl / 5-glycine (2.6 g), Then NM (2.0 ml) was added. After the reaction was completed (4 hours), the product was separated by extraction with ethyl picrate and dried over Na 2 SO 4 to give a white solid (5.1 g). MS and H-NMR with the structure shown -428- This paper size is applicable to Chinese National Standard (CMS). A4 specification (210X297 mm)

Μ 4 58 9 56 Α7 Β7, ^ 2Β ~-Fifth, invention Qin Ming (). Step B

The compound (5 g) produced in step A was dissolved in dioxin (50 ml). To this mixture was added anhydrous HC1 (20 mL, 4N). The mixture was stirred for 12 hours. The solvent was removed under reduced pressure, then ether was added, and the solvent was removed under reduced pressure. The solid was filtered to give a white solid (4 g). Dry in the empty entertainment box. MS and H-NMR are consistent with the structure shown. Step C

(Please read the precautions on the back before buying the copybook) k-pack. Ordered by the staff of the Central Standards Bureau of the Ministry of Economic Affairs, printed by N, N'-bissuccinimide carbonate (DSC) (2 grams) added The compound (2 g) produced in step B was added to dimethylformamide (10 ml), and then dimethylaminopyridine (200 mg) was added. After 20 minutes, DL-3-amino-3- (3,5-difluorophenyl) propanoic acid ethyl ester hydrochloride (1.6 g) was added, followed by NM (2.0 ml). After the reaction is completed (4 hours), the product is vinegar-429- This paper is suitable for the national standard soap (CNS> A # m. (210 × 297 mm) -----—! 427 427 A7 B7 58 956 5 2. Description of the invention (Isolated by extraction with ethyl acetate, dried with _N a 2 S 04, resulting in an oil (3 g). MS and H-NMR are consistent with the structure shown.

Step D

Η 'C02Et C02Me The compounds produced in Infantry C were subjected to the conditions described in Tetrahedron Letters, Vo 1.25, 1984, 839-842 to reduce the nitro group. This reduction was performed with 2 g of a nitro compound to obtain 1 g. _ Steps £

1 g of the compound produced in step D printed by the Central Standards Bureau of the Ministry of Economic Affairs, Real Industrial Consumer Cooperative, was guanidized according to the method of Example M and purified by reverse phase chromatography (water / acetonitrile) to yield 110 mg of the title compound as a white solid. . MS and H-NMR are consistent with the structures shown.

Step F -430- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) ^ 4 58 9 56. A? ---- B7 V. Description of the invention (428), H2N ^^ NH,

The compound (mg) produced in step E) was dissolved in water / ethoxyl, (1: D, and then the reaction mixture was added with a hydroxide (100 mg) a. The reaction mixture was stirred and analyzed by HPLC. After the hydrolysis was completed ( 1_2 hours), tri-gas acetic acid was added until pH = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to produce 25 grams of the standard amidine compound as a white solid. MS | H_NMR was consistent with the structure shown. Example 29 1. / 5-[[2-[[[3,5-bis [(aminoiminomethyl) amino] benzyl] carbonyl] amino] ethylfluorenyl] amino] -3, Preparation of 5-dichloro-phenylpropionic acid, bis (trifluoroacetic acid) salt. --------- ¾-- {Please read the notes on the back before writing this page} Order _ Ministry of Economy Printing steps A- 〇 of the Consumer Standards Cooperative of the Central Bureau of Standards

-431-The size of this paper applies Chinese National Standard (CN'S) A4 specification 210X297 mm 9 56 V. Description of the invention (429) A7 B7 ^ n \ j ^ jtc〇n-^-co2h Glycine ( (20 g, 266 mmol) and water (200 ml), then potassium hydroxide (20 g? 357 mmol), and cool to 0 ° C in an ice bath. A solution of 3,5-dichlorobenzyl chloride (20 g, 108 mmol) in acetonitrile (20 ml) was dropped into this mixture dropwise over 10 minutes. After completion of the reaction (3-4 hours), concentrated hydrochloric acid was added until p Η = 1. The product was transitioned, washed with water and air-dried (20 g). MS and Η-NMR are consistent with the structures shown. Step B.

N ----- C Η〇Κ 、 、 C〇2Et c ——-------- ^ 装 ------ ίτ ------ &gt; .. (Please read first Note on the back cover this page again) Printed N, Nl-disuccinimidyl imide (DSC) (1,2 g) by adding the compound produced in step A by Shelley Consumer Cooperative of Central Bureau of Standards of the Ministry of Economic Affairs (2 g) in anhydrous dimethylamidamine (10 ml), then dimethylaminopyridine (200 mg) was added. After 20 minutes, D L -3 · amino-3- (3,5-diphenylphenyl) propan heptaate hydrochloride (1.2 g) was added, followed by NMM (2.0 ml). After the reaction is completed (4,], and hrs), the product is separated with vinegar and ethyl alcohol, dried with Na ^ SOj, and produced. Yellow; '甴 (2.1 g) -432- This paper scale applies Chinese national standard ( CNS &gt; Α4 specification (210X297 mm) 5 B 9 56 A? B7 V. Description of the invention (430

. M S and Y-NMR are consistent with the structure shown Step C

The compound produced in step B was subjected to the conditions described in tetrahedron Letters, VoI. 25: 1984, 83 9-842 to reduce the nitro group. This reduction was performed with 2.5 g of the nitro compound to obtain 2.1 g of 3,5-di Aniline derivatives. MS and Η-NMR are consistent with the structures shown. Step D 'Ο

^ γΝΗγ ^ αο2B ρλ ° rS Please ▲ Read the notice on the back and fill it in. Γ Write this page. 2 grams of the compound produced in Step C printed by the staff of the Central Government of the Ministry of Economic Affairs. Purification by reverse phase chromatography (water / acetonitrile) using 4 g of guanidating agent) gave 800 mg of the title compound as a white solid. MS and H-NMR are consistent with the structures shown. Step E. The compound (500 mg) produced in Step D is dissolved in water / acetonitrile (1: 1) -433- This paper size is applicable to China National Standard (CNS) A4 (210 X 2 to 7 mm) • U_58 A7 · 'Β7 ·' 43Ϊ ------- 5. In the description of the invention (), then add lithium hydroxide (100 mg). The reaction mixture was stirred at 2 5 X: Stir 'and detected by HPLC. After the hydrolysis is complete (1 to 2 hours), trifluoroacetic acid is added until p H = 2. The product was purified by reverse phase chromatography (water / acetonitrile) to give 450 mg of the title compound as a white solid. MS and H-NMR are consistent with the structure shown. Example 2 9 2 Therapy-[[2-[[[3-[(Aminoiminomethyl) amino] · 5 · (trifluoroacetamido) amino] phenyl] carbonyl}] amino] Preparation of acetamyl] amino] -3,5-dichlorophenylpropionic acid, trifluoroacetate

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Step A

5 ”Amino-3-nitrobenzoic acid (Lancaster) (3 g) and trifluoroacetic anhydride -434- This paper is applicable to China National Cricket (CNS) A4 specifications (21.0X297); 5. Description of the invention , 432 A7 B7 (Sigma) (20 ml) in dichloromethane and stirred at 25 »c for 2 days. The solvent was removed under reduced pressure to obtain an oil. Water (50 ml) was added to this oil. The product was filtered (4.5 g). The product was in an oven at 70. (: drying for 16 hours

MS and H-NMR are consistent with the structure shown * Step B Η

N, N · -bissuccinimide (E) 'SC) (3 g) was added to the compound (2.7 g) produced in step A in anhydrous dimethylformamide (4 ml), and then Dimethylaminopyridine (200 mg) was added. After 20 minutes, tert-butyl glycine hydrochloride (2.7 g) was added, followed by NM (2.0 ml). After the reaction was completed (4 hours), the product was separated by extraction with ethyl acetate and dried over Na2S (D4 to give a yellow oil (3.3 g). MS and H-NMR were consistent with the structure shown. Step C · ': 31. : i7, installed-(Please read the precautions on the back before filling in this page) Order -4. _ · Printed by the Central Laboratories of the Ministry of Economic Affairs and Consumer Cooperatives

C〇j ^ / C〇2H F3 435 Private paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) A7 B7. 433 V. Description of the invention () Compound produced in step B (3 g) Dissolved in dichloromethane (50 ml). To this mixture was added TFA (20 ml). The mixture was stirred for 12 hours. The solvent was removed under reduced pressure, and then ether was added. The solid (2.7 g) was washed through And dried in the air for 2 hours. MS and Η-NMR are consistent with the structure shown.

Step D

Printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs of the Consumer Cooperative, N, N, disuccinimidyl imide (DSC) (1.5 g) and added. The product of step C (1.2 g) in anhydrous dimethyl methyl. Alkali amine (10 ml), then dimethylaminopyridine (200 mg,) was added. After 20 minutes, DL-3-amino-3- (3,5-diazino) propanoic acid ethyl ester hydrochloride (1.7 g) was added, followed by NM (2.0 ml). After the reaction was completed (4 hours), the product was separated by extraction with ethyl acetate and dried over Na: 2S04 to give a yellow oil (2.1 g). MS and Η-NMR are consistent with the structures shown. Step E

CF3 -436- Chinese paper standards are applicable to China National Standard (CNS) A4 specifications (210X297 mm) 〇 A7 B7 434 V. Description of the invention ()

I The compound produced in Step D was subjected to the conditions described in Tetrahedron Letters, Vol. 25, 1984, 839-842 to reduce the nitro group. This reduction was carried out with 1.8 g of a nitro compound to obtain 1.8 g of a 3 "anilino derivative. M S and Η · NMR are consistent with the structure shown °

Step F

1.5 g of the compound produced in step E was guanidined according to the method of Example M (using 3 g of a guanidizing agent) and purified by port phase chromatography (water / acetonitrile) to give 750 mg of the title compound as a ocher solid. MS and HN.MR are consistent with the structure shown. 0 The compound produced in Step G-Step F (500 mg) was dissolved in water / acetonitrile (丨: engineering) • Medium 'and then lithium hydroxide (100 mg) was added. The mixture was searched at 25 ° C and detected by PLC. After the hydrolysis is complete (1-2 hours), trifluoroacetic acid is added until ρ Η = 2. The product was purified by reverse-phase chromatography (water / acetic acid) to give .300 mg of the title compound as a white solid. .MS and H-NMR are consistent with the structure shown 3 Example 2 9 3 -437-'This paper is again applicable to National Standards (CNS) VIII Specifications (210X29 · / mm) ~ ^-{Please first Pavilion Read the notes on the back and write 4 'on this page) 1. Order, mr. Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy 〇 A7 B7 V. Description of the Invention t35) Lu Yiku Amine Group) _5_ [(Amine Group Aminomethyl) Amine] Phenyl] carbonyl] Amine] Ethylamine] Amine] 5 · —Phenylphthalic Acid 'Difluorocarbon Salt

-------------- (Please read the precautions on the back before filling this page)

Step A

Order the printing of 5-amino-3-nitrobenzoic acid (Lancaster) (5 g) and acetic anhydride (Sigma)-(10 ml) in methane gas produced by the Central Working Bureau of the Ministry of Economic Affairs The mixture was stirred at 25 aC for 2 days. The solvent was removed under reduced pressure to obtain an oil. Water (50 ml) was added to this oil and the product was transitioned (4.5 g). The product was dried in an oven at 70 ° C for 16 hours. MS and Y · NMR are consistent with the structure shown.

Step B -438 The private paper scale is applicable to the Chinese National Standard (CNS) A4 specification. (210X297 male sauce) 458956 A7, B7 V. Description of the invention (436), ^ ^ N ^^^^ CONlN ^ CQ2--f- HN-COCH3 N, N'-bissuccinimide carbonate (DSC) (3 g) was added to the compound produced in step A (3 g) in anhydrous dimethylformamide (6 ml), then . Then add dimethylaminopyridine (200 mg). After 20 minutes, tert-butyl glycine hydrochloride (2.1 g) was added, then NMM (2.0 ml) was added. After the reaction was completed (4 hours), the product was extracted with 'ethyl acetate and Isolated and dried over Na 2 SO 4 to give a yellow oil (3.3 g). MS and H-NMR are consistent with the structure shown. 'HN-COCH3-Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The compound (3 g) produced in Step B is dissolved in dichloromethane (10 ml). To this mixture was added T F A (10 ml). Search the mixture; mix 1 2, 丨, hour. The solvent was removed under reduced pressure and 眯 was added. The solids (3 g) were filtered and dried in an air oven for 1-2 hours. MS and Η-NMR are consistent with the structures shown.

Step D -439-This paper size applies to China National Standard (CNS) Α4 size (210X29? Mm) Printed by the Male Workers Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs f * 4 58 9 56 V. Description of the invention (437)

N, N '_- bissuccinimide carbonate (DSC) (1.5 g) was added to the product of step C (1.2 g) in anhydrous dimethylformamide (10 ml), followed by dimethylamine Pyridine (200 'mg). After 20 minutes, ‘DL-3-amino-3. (3,5-dichlorophenyl) propionate I ester hydrochloride (1.7 g)? Into, then add NMM (2,0 ml) ^ After the reaction of benzene formation (4 hours), the product was separated by extraction with ethyl acetate, dried over Na2S04 · 'to produce a yellow oil (2 g) ° MS and. -NMR is consistent with the structure shown.

Step E

• The compound produced in step D is reduced under the conditions described in Tetrahedron Letters, Vol. 25, 1984, 839-842 to reduce the nitro group. This reduction was performed with 1,5 g of a nitro compound to obtain 1.5 g of a 3-aniline derivative. MS and Η-NMR are consistent with the structures shown.

Step F -440- This paper size applies Chinese National Standard (CNS) Α4 specification (210x29? Mm)

458956 A7 B7 V ’, description of the invention (438

H4 g of the compound produced in step E was guanidized (using 2 g of guanidating agent) according to the method of Example µ and purified by reverse phase chromatography (water / acetonitrile) to give 750,000 mg of the above compound as a white solid. MS and H-NMR are consistent with the structures shown. Step G The compound (300 mg) produced in Step F was dissolved in water / acetonitrile IX: j), and then lithium hydroxide (100 mg) was added. The reaction mixture was stirred and detected by HPLC. After the hydrolysis is completed (1_2, 〖'), trifluoroacetic acid is added until pH = 2. The product was purified by reverse phase chromatography (· water / acetonitrile) to give 200 mg of the title compound as a white solid. MS and H_NMR are consistent with the structure shown. I: One ---------- install-(please read the notes on the back before authoring the copy 苋) Order the Yincong of the Consumers' Cooperative of the Central Bureau of the Ministry of Economic Affairs

Step A Example 2 9 4-2 9 6

-441-Μ Min Zhang scale is applicable to Chinese National Standard (CNS) A4% grid (210X297 mm) 45〇95β · Α7 Β7 439 V. Description of invention () Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

A 2-liter three-necked round-bottomed flask equipped with a magnetic stirrer was charged with amine-3,5-digas-benzylic acid (52.78 g, 0.2255 mol). / 5-Amino-3,5_ diphenylpropionic acid was dissolved in 900 ml of acetone and 300 ml of water, and carbonic acid was added approximately (3.0 equivalents '71 .70 g, 0.6765 moles).卩 ^ 1 = 10. ? ^ 100; succin carbonate carbonate imine vinegar (Sigma Chemical Co., 1.0 equivalent, 76.06 g, 0.2255 mole) was dissolved in 600 ml of acetone, slowly added to the alkaline aqueous solution, through the addition funnel, within 4 5 minutes. The reaction mixture was stirred at room temperature for 16 hours. HPLC analysis (Waters, C18, reverse phase, 25 cm column, 50-90% acetonitrile in water, within 30 minutes) showed amine-3,5-dichlorobenzene. Propionic acid is consumed. The acetone was removed from the reaction mixture under vacuum. The basic aqueous phase was acidified to pH = 3 using 3.0N hydrochloric acid. In a 2 liter separatory funnel, the acid layer was washed with 1 liter of ethyl acetate, the water layer was removed, and the organic layer was washed (2 X 250 ml of water, 2 X 250 milliwells of saturated sodium gas) * The organic layer was dried (Magnesium sulfate), filtered, and concentrated to 300 ml in a vacuum. Petroleum ether (300 ml) was added and a white flocculent solid precipitated. After air-drying for 24 hours, 38.49 g of the first product was isolated (38% yield). The mother liquor is reserved for future use. NMR (D ^ 1S0): 2.62-2.72 (m, 2H), 4.15-4.32 (m, 1H), 7.21-7.40 (m, 5H), 7.45 (s, 1H), 7.60-7.70 (m, 2H), 7.85 (d, j = 7 Hz, 2H), 7.99 (d, j = 7 Hz, 1H). MS (FAB) m / e (relative intensity): 456.2 (20), 179 (100). Step B -442-The paper Λ degree applies to the Chinese National Standard (CNS) A4 specification (2 [0 × 2ζ &gt; 7 mm) f Please read the notes on the back before writing this page) i: 兰-装 | Order Α7 Β7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

V. Description of the invention (44Q

Wang Resin (25.0 g '28 .. 0. House Mor &gt;) was placed in a 1 liter three-necked round bottom flask equipped with a top sander and nitrogen inlet. The resin was swelled with 250 ml of dichloromethane for 5 minutes And then drained. The FMOC-protected amino acid (25.66 g '56.0 mmol) produced in Step A was activated in another 5000 ml round bottom flask by dissolving in two gases Methane / dimethylmethamine (4: 1'125'ml) 'was added via a syringe. Diisopropylcarbodiimide (djc, 8.77ml, 56.0mmol) was added, followed by dimethyl formamide Amine v ratio (DMAP, 0.342 g, 2.8 mmol). The solution was stirred at 25 eC for 15 minutes, and then added to the pre-expanded Wang resin. The slurry was stirred at 25 ° C for 2 hours. The reaction mixture was drained and methanol was used. (3 X 250 ml), two gas pits (3 X 250 ml) and diethyl ether (3 X 250 ml). Then the resin was swelled in 250 ml of two gas methane and drained. The activated product of step A. (12.83 g, 28.0 mmol, DIC, 4.36 ml., 2S.0 mmol, DMAP, 0.170 g, 1.4 mmol in 100 ml of digas methane / dimethylformaldehyde Formamidine 4: 1) was added to the expanded resin. The slurry was stirred at 25 ° C for 1 hour. The resin was drained and washed as described above. Element τ analysis of the resin-bound substance: Calculated 値 ': C, 81.31; H, 6.30 N, 1.05; C1, 5.33 〇 Measured 値: C, 79.03; H, 6.37; N, 1.16; C1, 5.74. -443- The standard of this paper applies to Chinese national standard {CNS> A4 (210X297 mm)) 1. Tsai-{Please read the notes on the back before 'fill this page) -'βτ 9 56 A7 B7 V. Description of the invention (441 step c Ο

Printed by the Central Ministry of Economic Affairs of the NH-FMOC Ministry of Economic Affairs and Consumer Cooperatives — I — I read the precautions on the back and then write this page) The product of Step B (28.0¾ Mor) is equipped with a top stirrer and 250 ml of a 1 liter three-necked round bottom flask with a nitrogen inlet was used. Digas methane was bulged for 15 minutes in advance. »The solvent was discharged, and 20% hexahydropyridine / dimethylformamide was added. The solution (125 ml) was added, and the slurry was added. Stir at 25 ° C for 2 hours. The resin was drained and washed with dimethylformamide (3x100 ml), methanol (3x100 ml), digas methane (3x100 ml) and diethyl ether (3x100 ml). The resin was dried for 1 hour using a household hollower. FMOC · Glycine activation solution (20.81 g, 70.0 mmol, DIC, 10.95 ml, 70.0 mmol, DMAP, 0.85 g, 7.0 mmol, 150 ml digasmidine 1/2 Phenylsuccinimide, 4: 1) Add to pre-expanded resin through a syringe, and stir at 2 5 eC for 2 hours. The resin was drained and washed (methane, methanol, and diethyl ether, 3 x 100 mL each). Resin was pre-expanded in 250 ml of dichloromethane for 15 minutes, drained, and activated FMOC-glycine solution (10.45 g, 35.0 mmol, DIC, 5.42 ml, 35.0 mmol, DMAP, 0.42 g, 3.5 mmol) Ear, in 100 ml of dichloromethane / dimethylformamide 4: 1) was added to the expanded resin via a syringe. The slurry was stirred at 25X: 1 hour. The resin was drained and washed (digassed rotane'methanol and diethyl ether, each 3 × 100 ml). The resin was dried in air for 1 hour. Kaisei • Test (Kaishr, E., Color Test for -444- Sheet size is applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm> 5¾ A7 B7 U2) 5. Description of the invention

Detection of Free Terminal Amino Groups in the Solid-Phase Synthesis of Peptides. Anal. Biochem. 1970, 34, 595-598) shows that the coupling is complete.

Step D C〇2Hv ^ r NH, C02H-take NHC—〇

Printed in a 500 ml round-bottomed flask equipped with a magnetic stirrer, 3 · Amino-Phenylic Acid (Aldrich, 10.0 g, 50.8 mmol) was dissolved in 50 ml Dioxolane and 133 ml of 10% sodium carbonate. The stirred solution was cooled to zero. 〇 (ice / water), vanillyl methyl gallate (13-78 g, 53.3 mmol, in 50 ml of dioxolane) was added dropwise over 15 minutes. The reaction mixture was heated to 2 5 t overnight. HP LC analysis (as described above) showed that starting material consumed 5,000 ml of water was added to the reaction mixture and a white precipitate formed immediately. The solids were collected, washed with 1000/0 citric acid, and dried under vacuum. Isolated 15.23 g (83.4% yield) of a white-floc solid. NiMR (DMSO): 4.18-4.25 (m, .3H), 7.25-7.41 (m, 6H), 7.62-7.72 (m, 3ti), 7.89-7.90 (m, 3H). MS (FAB): Product ion M + H measured at m / z 360.

Step E -445-This paper size applies Chinese National Standard (CNS) A4 specification (hox297). 458956 V. Description of the invention (443) A7 B7 〇

nhc ^ O ~, fm0c Printed by 20.0 grams of the product of Step C (22.4 millimoles) in 500ml of Erqijiadian, pre-expanded for 30 minutes. Drain the solvent, add 250 ml of 20% hexahydropyridine / dimethylformamide, and stir at 25 ° C for 40 minutes. The resin was drained and washed with dimethylformamide, methanol, dichloromethane and diethyl ether (3 x 150 ml of each solvent). Kaiser tests show that protection is intact. The resin was dried with household krypton air for 45 minutes. The resin was then pre-expanded with 250 ml of dichloromethane, drained, and the activated product of step D (13.54 g ·, 35: 5 mmol, DIC, 5.55 ml, 35.5 mmol, · OMAP, 0.88 g, 7.2 mmol Mol, in 100 ml of digasmethane / dimethylamidamine 4: 1) was added to the pre-expanded resin. The reaction mixture was stirred at 25aC for 16 hours. Drain the resin and wash as described above. Kaiser tests showed incomplete response. The coupling reaction was repeated, the resin was drained, and washed. Repeated Kaiser tests showed that the coupling reaction was complete. Small part-Resin FMOC deprotection (30 min., With 20% hexahydropyridine / dimethyl- *, formamidine), and then the resin is cleaved. (1 hour, with 9 50 / 〇trifluoroacetic acid / Water) for NMR analysis. NMR (DMSO): 2.68-2.78 (m, 2H), 3.88 (d, j = 7 Hz, 2H), 5.06-5, 20 (m, 1H), 7.32-7.69 ( m, 4H), 7.54 (t, j = 8 Hz, 1H), 7.76 (s ,. '1H), 7.83 (d, j = 8 Hz, 1H), 8.57 (d, j = 9 Hz, 1H), 8.87 (t, j = 9 Hz ·, 1H). -446- Private paper music scale is applicable to Chinese National Standard (CNS) A4 specification (2I0X297mm) (Please read the precautions on the back before coming to this page) 458 956 A7 — B7 V. Invention Description (444)

The resin of Step E (2.0 g, 2.0 mmol) was pre-expanded in 20 ml of dimethylformamide in a 100 ml round-bottomed flask and drained, and then 20% of hexahydropyridine was used in a 200 ml well. Dimethylformamide was treated at 25 ° C for 40 minutes. Resin 4 'was washed with dimethylformamide, methanol, digasmethane and diethyl ether (3x10 ml each). The Kaiser test is indeterminate, to protect the ‘protection steps to repeat the wash. Repeated KaiseT tests are still uncertain and the substance is reused. 2.0 g of resin was divided into two 1.0 g portions and placed in a 2-dram glass bottle. Dimethylformamide (4.0 ml / bottle) was added, and then methyl isothiocyanate (1.4622 g, 20 mmol) was added. The cap is tightly closed and heated to 80 ° C for 4 hours. The resin was filtered and washed with dimethylmethylamine'methanol, digasmethane and diethyl ether (3x10 ml each). The resin is dried in the air. -Step G · 7 ^ · Installation-(Please read the notes on the back 4 · Fill in this page). Order the Central Standard of the Ministry of Economic Affairs

-447- This paper size applies to the national standard (CNS) A4 specification UiOX297 mm ^ 458956 A7 B7 V. Description of the invention (445) The resin produced in step F is transferred into a 100 ml glass (fritted) reactor D The resin was swollen with dichloromethane (3 × 10 ml) and drained. In another bottle, 2-chloro-t-methylpyridine iodide (Aldrich, 0.405 g, 1.58 mmol) was dissolved in 5 liters of dimethylformamide /. Pre-swelled resin was then added to triethylamine (0,441 ml, 3.17 mmol). Reaction «The slurry was stirred at 25 ° C for 8 hours. The resin was drained and washed with dimethylamidamine and dichloromethane (3 x 10 ml each). The resin was dried in the air.

1 I--I (Please read the notes on the back before filling out this page). Equipment. Λ ^ ΗΝ—,

1 Ν Order of the resin product of step G (0.666 g, 0.7 mmol) printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs was transferred to a 15 ml glass fritted tube and suspended in 35 ml Amidine / digas methane (i: 1). Amidine (2.0 M in tetrahydrofuran, 4.4 mmol, 8: 8 mmol) was added to the resin slurry, and stirred at 251 for 16 hours. The resin was drained and washed with dimethylformamide, methanol, methane and diethyl ether (3 x 10 ml each). The resin was dried in the air for 1 hour. Step I--448-This paper applies the Chinese National Standards (CNS) standard (2 [〇χ297mm) 4 5 8 9 A7 B7 V. Description of the invention (446)

The resin product of NHT Step G (.0.666 g, 0.7 mmol) was transferred into a 15 ml glass tube and suspended in 3.5 ml. Dimethylformamide / digas methane (1: 1) 3 ethylamine (2.0M In tetrahydrofuran (44 ml, 8.8 mmol) was added to the resin slurry, and the mixture was stirred at 2 5 C for 16 hours. The resin was drained and washed with dimethylformamide, methanol, dichloromethane and diethyl ether (3 x 10 ml each). The resin was dried in the air for 1 hour.

Step J ---------- 7. '. Install-(Please read the precautions on the back before writing 4 ...)

* 1T Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

〇 '^ 0rNH The resin product of Step G (0.666 g, 0'7 mmol) was placed in a 15 ml glass breaking tube and suspended in 3.5 ml of difluorenylamine and dichloromethane (1: 1) Medium. Isopropylamine (0.749 ml, 8.8 mmol) was added to the resin slurry at 25 ° C. (: Incubate for 6 hours. Drain the resin and use dimethylformamide, methanol, and digas-methyl tiger 449-Good paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 45B 956 A7 __ _ 丨 B7 V. Description of the Invention (447)

I and diethyl ether (3x10 ml each) were washed with a resin and dried in the air for 1 hour. Example 2 9 4 (±) 3,5-Digas-[[2-[[[[[[3- [Umethylamino) (methylimino) methyl] amino] phenyl] carbonyl] amino] ethyl Preparation of fluorenyl] amino] phenylpropionic acid, trifluoroacetate (please read the note on the back before writing this page)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, the resin product of Bulu · Treat 2.5 hours with 2.5 ml of 95% trifluoroacetic acid / water for 1 hour. The filtrate was collected and the resin was collected with 2 &gt; 1 ml of 5-0% trifluoroacetic acid / methane washing 'filtrate. The resin was washed with 1 ml of methane. All the filtrates were combined in a 2-British flask and concentrated under a nitrogen stream. Toluene was added to help remove excess trifluoroacetic acid and the sample was concentrated under a nitrogen stream. The last two methane (1 ml) was added and the sample was shrunk to obtain 198.3 mg of golden oil. Η P L C (220 nM as above) shows a 91 1% pure main cooling. NMR (DMSO): 2.72 (d, j = 7Hz, 2H), 2.79 (s, 6H), 3.87 (d, j-7 Hz, 2H), 5.11-5.20 (m, 1H): 7.30-7.58 (m, 5H), 7.70-7.80 (m, 4H), 8.55 (d, j = 8 Hz, 1H), 8.76 (t, j = 3Hz, 1H), 9.39 (s, 1H). MS (ES); product ion measured at m / z 480 3 __ -450- This paper is suitable for China National Standards (CNS &gt; M size (210X297 cm) ~ '' '• f 458 9B6 A7 B7 5 Explanation of the invention (448) Example 2 9 5, (±) 3,5-dichloro- / 3-[[2-[[; [3 _ [[(ethylamino) (methylimino) fluorenyl] amine Preparation of phenyl] phenyl] carbonyl] amino] ethylfluorenyl] fluorenyl] phenylpropionic acid, trifluoroacetate: * 〇

Ο II NHC,

Take N

NI

Printed by TFA Central Bureau of Standards, Ministry of Economic Affairs, Shelley Consumer Cooperative. The resin product from Step I was treated with 2.5 ml of 95% trifluoroacetic acid / water at 25 ×: processing for 1 hour. The filtrate was collected and the resin was washed with 2 ji 1 ml of 50% trifluoroacetic acid / dichloromethane, and the filtrate was collected. The resin was washed with 1 ml of methane. All the filtrates were combined in a 2-British flask 'and concentrated under a nitrogen stream. Toluene (丨 ml) was added to assist in removing excess trifluoroacetic acid, and the sample was reflowed under nitrogen. Concentration. Finally, methane (1 ml) was added to the sample, and the product was concentrated again to obtain 261.2 mg of golden oil. Η P L C (as the aforementioned '220ηιΜ) showed a 94% pure main peak. NMR (DMSO): 1.11 (t, j = 7Hz, 3H), 2.72 (d, J = 7Hz, 2H), 2.79 (s, 3H), 3.25-3.60 (m, 2H), 3.87 (d, j = 7 Hz, 2H), '5.02-5.20 (m, 1H), 7.30-7.58 (m? 5H),-7.70-7.85' (m, 4H), 8.55 (d, j = 8 Hz, 1H), 8.76 (t , j = 3Hz, 1H), 9.40 (s, 1H). MS $ S): Product ion 451. Paper size is applicable to Chinese National Standard (CNS) A4 specification (21 OX 297 mm) (谙 Read the precautions on the back before ^ '. Write this page)

A7 B7 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

.) Ur4 58 9 5S V. Description of the invention (449) Example 2 9 6 (±) 3,5 · dichloro-cold, [[2 _ [[[3-[[[(1-methylethyl) amino ] (Methylimino) methyl] amino] benzyl] carbonyl] amino] ethylethyl] amino] phenylpropionic acid 'trifluoroacetate

The resin product of step J was treated with 2.5 ml of 95% trifluoroacetic acid / water at 25 X for 1 hour. The filtrate was collected. The 9 resin was washed with 2 x 1 ml of 50% trifluoroacetic acid / dichloromethane, and the filtrate was collected. The resin was washed with 1 ml of dichloromethane. All the filtrates were combined in a 2-British flask and shrunk under a nitrogen stream. Methylbenzyl (丨 ml.) Was added to help remove excess trifluoroacetic acid, and the sample was concentrated under nitrogen flow. Finally dichloromethane (1 ml) was added, and the sample was concentrated to obtain 330.3 mg of golden oil-. HPLC (as before, 220 nM) showed a 89% pure main peak. NMR • (DMSO): 1.15 (d, j = 7Hz, 6H), 2.72 (d, j = 7Hz, 2H) f 2.79 (ds) = 1 Hz; 3H), 3.79-3.92 (m, 3H), 5 / 05-5.20 (m, 1H), 7.30-7.50 (m, 5H), 7.60-7.78 (m, 4H), 8.55 (d, j = 8 Hz, 1H), 8.76 (t, j = 3Hz, 1H), 9.40 (s, 1H). MS (ES): Product ion measured at m / z. 508. · -452-. This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297mm) (Please read the precautions on the back before writing this page)

458966 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Α7 Β7 V. Description of Invention (45Q)

Example 2 9 7 d Q Q

Step A

A 50-ml round-bottomed flask equipped with a magnetic stirrer was charged with 3-amino-3- (4-fluorophenyl) propionic acid (0.300 g ' 1.64 mmol). The propionic acid was dissolved in 1 liter of copper propylene and 6 ml of water and added with sodium carbonate (053 g, 4.92 mmol). pH = 10. FMOC succinyl carbonate imide vinegar (Sigma Chemical Co., 0.553 g, 1.64 mmol) was dissolved in 6 ml of acetone, slowly added to the alkaline aqueous solution, and passed through the addition funnel 'within 20 minutes. The reaction mixture was stirred at room temperature for 16 hours. HPLC analysis (Waters, C18, reverse phase, 25 cm column, 50-90% acetonitrile in water, within 30 minutes) showed consumption of starting material. The acetone was removed from the reaction mixture under vacuum. Alkaline aqueous phase-acidified with 3.0N hydrochloric acid to pH = 3 = in a 50 ml separatory funnel, the acid layer was washed with 15 ml vinegar-ethyl acetate, and the water was removed to remove 'organic rabbit wash (2 x 3 0 ml of water, 2 x 30 ml of saturated sodium vapor). The organic layer was dried (magnesium sulfate), filtered, and concentrated under vacuum. Petroleum ether (1.0 ml) was added and a white flocculent solid precipitated. After 24 hours air drying / manic, 0.582 g of the first product was isolated (87 5% yield). The mother liquor is reserved for future use. 3 ^ 11 (〇 奶 〇): 2.55-2.75 (111,211), 4.10-4.30 (m, 1H), 4.85-4.95 (m, 1H); '7.12 (t, j = 8 Hz, 2H), 7.24 --453-This paper size applies to China National Standard (CNS) A4 specification (2! 0 × 2? 7 public epidemic) ί 7Τ, installed-(Please read the precautions on the back before 4 (write this page)

11T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs I r 4 ^ 8 9 〇 β.-A7 B7 · 1 i! 1 &quot; ^ &quot; V. Description of Invention ()

7.42 (m, 5H), 7.64 (d, j = 8 Hz, 2H), 7.82-7.94 (m, 3H). MS (FAB): Product ion M + Li was measured at m / z412.

Step B

Wang resin (0,60 g ' 0.36 mmol) was placed in a loo ml round bottom flask. The resin was swelled with 8 ml of two-gas methane for 15 minutes and then allowed to drain. The FMOC-protected amino acid (0,365 g, 0.9 mmol) produced in step A was activated in another 25 ml round-bottomed flask, and was dissolved in dioxane / dimethylformamide (4 : 1 '19 ml), add diisopropylcarbodiimide (DIC' 0.141 ml '0.90 mmol) through a syringe, and then add dimethylaminopyridine (DMAP, 22 mg, 0.18 Mol). The solution was stirred at 25 aC for 15 minutes and then added to the pre-expanded Wang resin. The liquid was stirred at 2 5 for 2 hours. The reaction mixture was drained and washed with methanol (3 X 100 mL), dioxane (3 X 10 mL), and diethyl ether (3 x 100 mL). To complete the reaction, the coupling procedure is repeated. After drying in the air, the resin was swelled with 8 ml of digas methane, drained, and 8 ml of 20% hexahydropyridine / dimethylamidine was added to the polymer solution and shaken for 30 minutes. Drain the resin and wash as described above. The resin was dried in the air for 1 hour. Resin bond 'Elemental analysis of matter: _ Calculation 値: c, 88’23; H, 7.36; N, 0.76; C1, 1.03. -454-. This paper size applies to Chinese National Standard Li (CNS) A4 specification (210X29? Mm) ';-(Please read the notes on the back before copying this page] &amp; Ordering

MJ 956 A7 B7 V. Description of the invention (452), found 値.: C, 87.13; H, 7’31; N, 0.79; C1 ’1.06

Step C

Printed by Shellfish Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs The product of step B is expanded with 8 ml of digas methane and then drained. FMOC-Glycine activation solution (0.267 g, 0.90 mmol, DlC '0.140 ml, 0.90 mmol, DMAP, 22 mg, 0.18 mmol' in 10 ml digas methane / dimethyl formaldehyde Methylformamide, 4: 1) added to the pre-expanded resin via the injection street, and stirred at 25 ° C for 2 hours. Β resin drained and washed (digas methane, methanol and diethyl ether, each. 3 x 1 〇mL). The resin was pre-expanded with 20 ml of digas methane for 15 minutes, drained, and the coupling reaction was repeated to complete the reaction. Kaiser test (Kaiser, E_, Color Test for Detection of Free Terminal Amino Groups in the Solid-Phase '.Synthesis of Peptides Anal. Biochem. 1970, 34, 595-598) showed that the coupling was complete. Then the resin was suspended in? • In 20 ml of hexahydropyridine / dimethylformamide for 30 minutes, drain and wash with dimethylformamide, digasmethane, methanol and diethyl ether (3x 10 ml each). Resin is dried in the air for 1 hour 〇 *

Step D __, -455- This paper size is applicable to the Chinese National Standard of China (CNS) Α4 · _ (210X297 mm) — ~ — V. Description of the invention (453) A7 B7 ε〇2ΗΊ〇Γ

Nt + FMOC In a 500 ml 'round bottom flask equipped with a magnetic stirrer, 3-amino-benzoic acid (Aldrich, 10.0 g &gt; 50.8 mmol) was dissolved in 50 ml of dioxolane and 133 ml of 10% In sodium carbonate. The stirred solution was cooled to 0 ° C (ice / water), and fluorenyl chloroformate (13.78 g, 53.3 mmol, in 50 ml of dioxolane) was added dropwise over 15 minutes. The reaction mixture was heated to 25 ° C overnight. Η P LC analysis (as described above) showed consumption of starting material. 500 ml of water was added to the reaction mixture, and a white precipitate formed immediately. The solids were collected, pickled with 10% citric acid, and dried under air. 15.23 g (83.4% yield) of a white flocculent solid. NMR (DMS0): · 4.18-4.25 (m, * 3H), 7.25-7.41 (in, 6H), 7.62-7.72 (m, 3H), 7.80-7.90 (m, 3H) ^ MS (FAB): product ion M + H is measured at in / z 3 60. Step E '(Please read the notes on the back before filling out this page) Order-. &Gt; Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

NH-FMOC 456 Private paper standard General Chinese National Standard (CNS) A4 specification (210X29? Mm) i 5 G 9 50 V. Description of invention (454) A7 B7

The resin product of step C was pre-expanded with 10 ml of dichloromethane, drained, and the activated product of step D (0.343 g, 0.90 mmol, DIC, 0.141 ml, 0.90 mmol, DMAP, 22 mg, 18 millimoles, 5 ml of monogas methyl tiger / methyl methylamine 4: 1) was added to the pre-stretched resin. The reaction mixture was dialed out at 2 5 C for 16 hours. The resin was drained and washed as before: j Kaiser test showed incomplete reaction. The coupling reaction was repeated and the resin was drained and washed. Repeated Kaiser tests showed that the coupling reaction was complete. The resin was dried in the air for 1 hour. Step F Cao A

Ο II NHC, I; -------- ί-- (Please read the notes on the back before filling in this page) Order _ I. k Resin Co., Ltd. printed by the Consumer Cooperatives of the Ministry of Economic Affairs, Central Standard Bureau The product was placed in a 100 ml round-bottomed flask, pre-expanded with 10 ml of dimethylformamide, drained, and then with 20 ml of 20% -hexahydrop-pyridine / dimethylformamide in Treat at 25 ° C for 10 minutes. Drain the resin and repeat the process. ‘Procedure. Resin after washing; wash with dimethyl 5f, amine, methanol, digas, and diethyl mystery (3x10 ml each). The Kaiser test showed that the deprotection step was complete. The resin was placed in a 2 dram glass bottle. Dimethylformamide (8.0 ml) was added, then methyl isocyanate (0.526 g, 7.2 mmol) was added to the bottle tightly and heated to 80 ° C for 4 hours. , Wash with dimethylformamide, methanol, digasmethane and diethyl ether (3x10 ml each). Resin in the air -457 This paper size applies to China National Standard (CNS) A4 (210X297 mm) 48β: -. A7 ______; _ B7 Five 'Invention (455). Dry. Elemental analysis of resin-bound substances:

Calculate 値: C, 83.56; H, 6.46; N, 2,19; F 1 03; S, 1.35. Found 値: C, 82, 32; H, 6.67; N, 2.53; F, 1.02; S, 1.44. Step G The resin product from Step F (100 ml, 0.06 mmol) was transferred into a 2-inch glass bottle. The resin was swollen with methane (3 x 1 ml) and drained. In the reed bottle, 2-chloro-1-methylpyridine (Aldrich, 18.4 mg, 0.072 mmol) is dissolved in 0 ml of dimethylformamide / dichloro. Dried 4: 1, add The pre-expanded resin was then added to triethylamine (20.1 μl, 0144 mmol). The reaction slurry was stirred at 25 ° C for 16 hours. The resin was drained and washed with dimethylformamide, methanol, dioxane and diethyl ether (3 x 4 ml each). The resin was dried in the air for 3 hours. The resin was treated with 95% trifluoroacetic acid (1.5 ml) for 1 hour. Resin filtered to 50 ° /. Wash with trifluoroacetic acid / digas methane (2 X 1.0 ml) and then digas methane (1 x 0.0 ml). The filtrates were combined and dried in a 2 British money bottle under emptying. . 'Example 2 9 7 (±) Cold-[[2-[[[[[(Ethylamino) (methylcocolyl) methyl] amine-yl] benzyl] truncated] amino] ethyl Fluorenyl] Amine] _4 · Fluorophenylpropionate 'Trifluoroacetate Preparation Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

.TFA

F 458- The size of this paper mark applies to Chinese National Standard (CNS) A4 specification (2iOX297 mm) A7 B7 V. Description of the invention (456) Separate 2S.1 mg of golden oil. NMR (DMSO): 1.13 (t, j = 7 Hz, 3H), 2.65-2.75 (m, 2H), 2.76-2,85 (m, 3H), 3.25 (t, j = 3Hz, 2H), 3.80- 3.95 (m, 2H), 5.10-5.21 (m, 1H), 7.13 (t? J = 8 Hz, 2H), 7.30-7.40 (m, 3H), 7.52 (t, j = 8 Hz, 1H), 7.65 -7.85 (m, 3H), 8.49 (d, j = 8 Hz, 1H), 8.71 (t, j = 8 Hz, 1H), 9.40 (s, 1H). HPLC (as before, 220 nM) 90.15 ° / ° pure. MS (ES): product ion at m / z 444; cut to β, example 2 9 8 (±) 4-fluoro- /?-[[2-[[[3-[[[((1-methylethyl ) Amino] (methylimino) fluorenyl] amine] phenyl] carbonyl] amine. Ethyl] ethyl fluorenyl] amine] phenylpropionic acid, trifluoroacetate preparation 〇 〇 ΝΗ—

NHC-^^ NhS 'Ί ^

'' _TFA

F t Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs • Separate 44.9 mg of golden oil. 1 '' ^^ (〇) \ / 1 $ 0): 1.16 ({1,. 』= 7 1 ^, 6H), 2.61-2.70 (m, 2H), 2.73-2.80 (m, 3H), 3.75-3.90 (m, 3H), 5.10-5.21 (m, 1H), 7.11 (t, j = 8 Hzf 2H), 7.25-7.3 7 (m, 3H), 7.49 (t, j = 8 Hz, 1H), 7.59- 7.82 (m, 3H), 8.49 (d, j = 8 Hz, IH), S.70 (t, j = 3 Hz, 1H), '9.40 (s, IH). HPLC (as before, 220 nM) 98% pure. M S (ES): The product ion was measured at P / z 45 S. -459-Standard for Chinese paper (CNS) A4 specification (2 〖〇297297mmΥ ^ * 4 V. Description of invention 457 A7 B7. Example 2 9 9 (±) 4, fluorine _ [[2- [ [[3-[[[(4-Pyridylmethyl) amino]]} imino) methyl] amino] phenyl] carbonyl] amino] ethylsulfonyl] amino] phenylpropanoic acid, Preparation of trifluoroacetate

Isolated 31.6 mg of golden oil. NMR (DMSO): 2.60-2.72 (m, 2H), 2.81-2.89 (d, j = 7Hz, 3H), 3.80-3.95 (m, 2H), 4.61-4.80 (bs, 2H), 5.10-5.21 (m , 1H), 7.01-7.22 (m, 4H), 7.29-7.44 (m, 3H), 7.50 (t, j = 8 Hz, 1H), 7.65-7.85 (.m, 3H), 8.40-8.50 (d, j = 8 Hz, 1H), 8.70-8,85 (m, 3H), 9.73 (s, 1H) e MS (ES): The product is obtained at m / z 507. The following compounds were prepared according to similar solid-phase synthesis as described in Examples 294-299. ., (Please read the precautions on the back before planting this page to write this page) Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 460 This paper is a Chinese standard for meat scales (CNS) A4 (210X297 mm) A7 B7 458 956 V. Description of Invention (458

R

R3 Η ◦ ‘

ΗΝ'hi ^-

ΝΗ I

.TFA Printed by the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs

Ο Examples Rt r2 K3 r5, 300 Cl H Cl —H 301 Cl H Cl -H .V cf3 302 * Cl H Cl h〇L _ 1 TFA 303 ^ Cl H Cl -H t .TFA 461-(Please read the back first Please pay attention to this page, please fill in this page) Order Γ-This paper size is applicable to Chinese National Standard (CNS) A4 (210X297mm) Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 458 956 A7 __B7 V. Description of Invention (459) Example Ri r2. R4 304 Cl H Cl -H .TFA 305 Cl H Cl -H t .TFA o 306 Cl II Cl -11 -cn2ciij 307 Cl H Cl -H -ch2ch2ch3 308 Cl H Cl -H kc, cf3 309 Cl H Cl -H 0 .TFA-310 Cl H Cl -H '. O 311 Cl H Cl -H kX) 312 Cl H Cl -H 1 · (Please read the notes on the back before filling this page) Order', &gt; '-462- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs * 458956 A7 _ ^ _ B7 V. Description of Invention (46Q)-Awards Ri 313 Cl H Cl yC 314 Cl H Cl -H 315 Cl H Cl --H Β〇 丨 3 ch3 316 Cl H Cl -U • h 〇y Cl / C! 317 Cl H Cl -H 0 rci 318 Cl H Cl -H , 319 Cl H Cl -H 'h 0, OMe I. ^ 1 1 -------- :. 1 (Please read the precautions on the back before filling out this page) -463- The standard of this paper is applicable to Chinese national standards ( CNS) Α4 specification (210 X 297 mm) '4〇a 956 ~ 46Ϊ 5', description of the invention () Example printed by the Central Consumers' Bureau of the Ministry of Economic Affairs and Consumer Cooperatives ^ 2 r3 &amp; r5 320 C1 Η Cl a ch3 0 321 C1 Η Cl '-ch3 0 .TFA 322 C1 Η Cl —CHj .kJ〇, fa 323 C1 Η Cl -CHj -TFA 324 C1 Η Cl -ch3 [NH 325 C1 (· Η Cl -ch3 .ΤΡΛ- ^ -NH 326 C1 Η Cl -ch3 -eH2 (CF2) 2CF3 327 C1 Η Cl -CHk k CF3 * ό -464- The standard of this paper is Chinese National Standard (CNS_) A4 (210X297 mm) (please read it first) Note on the back then fill in the page). | 衣 _ 腺 部 8596 5 4

7 7 AB 462 V. Description of the invention () Example printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy 3'28 C1 Η Cl -ch3 4 .¾. '329 C1 Η Cl -CHj 330 C1 Η Cl -CH3 331 C1 Η Cl -ch3 〇332 01 Η Cl -ch3 0 | —C Triple N 1 333 C1 Η Cl -ch3 1 ^ &gt; T ^ ν'ΝΗ2 334 C1 Η Cl _ch3 .TFA 335 C1 Η Cl -CHj. 336 C1 Η Cl -CH3 337 C1 Η Cl &quot; CH3 (Please read the precautions on the reverse side and fill in the Vr page) -465-The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 54 * Γ 'A7B7 5 、 Explanation () Example is only 2 Rj 338 C1 Η Cl -cu3 | —OH 339 C1 Η Cl -ch3 (Please read the precautions on the back before filling in the page) Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -466, this Paper size applies to Chinese National Standard (CNS), A4 size (210 X 297 mm) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs -4? ^ Α κβ at __: _______ Β7 ______ V. Description of Invention (464) Example 3 6 1 (Earth) 3,5-dichloro-; S-[[2-[[[3-[(i, 4,5,6-tetrahydro-5,5-diamidopyrimidin-2-yl) amine Yl] benzene.yl] Yl] amino] acetyl-yl] amino] propanoic acid stupid, trifluoroacetic acid salt of - Step A '·

To a suspension of 1- (3-carboxyphenyl) -2-thiourea (produced in step 236 of Example 236) (10.0 g, 0.051 mole) in ethanol (100 ml) was added iodomethol. (3.5 ml), heated at 7 ° C. under nitrogen for 2.5 hours, the reaction mixture was concentrated under reduced pressure, the residue was decanted with 10% EtOAc in ether (2 × 100 ml), and the supernatant was decanted. The solid was dried in the air for 2 hours, dissolved in DMF (75 ml), and 2,2-dimethyl-1,3-propanediamine (42 g, 0.41 mole) was added dropwise to DMF (20 ml). ) In the solution, within 1 hour. The resulting complex was heated at 80 ° C under nitrogen pressure for 16 hours, while capturing the thiol mercaptan in the 5% sodium nitrate solution. DMF in the air Medium steamed crane, »-The residue was dissolved in water (50 ml) and washed with diethyl ether (3 x 25 ml). When a white precipitate was obtained, the aqueous phase was acidified with 2 N HC1 to p Η 4.0. Filtered with water and Washed with ether and dried to obtain 8.0 g (63%) of the desired product as a white powder. MS and 1 Η-NMR are consistent with the structure shown. Step B -467- This paper applies Chinese national standard (CNS) Α4 Specifications (210_ × 297 mm) ---------- install! Fc / · f please first listen to the notes on the back ¾ then fill in ears,} 1Γ_-place · .Ml V. Description of the invention (465 A7 B7

ΤΤ &quot; N-fluorenylmorpholine (0.46 ml) was added to a suspension of HC1 salt (1.0 g, 0.0035 mol) in DMF (15 ml) and cooled to -10 ° in an ice-salt bath. C. The reaction mixture was then treated with isobutyl formate (0405 ml) and incubated at -10 ° C 'for 30 minutes. N-methylmorpholine (0.46 ml) was added with tert-butyl glycine hydrochloride ( 0.6 g) in a solution of 0X in DMF (5 ml) to produce an amine solution. The resulting reaction mixture was stirred at -10 ° C for 1 hour and at room temperature under argon pressure for 16 hours. DMF was distilled in the air, and the residue was treated with 5% sodium bicarbonate (25 ml) and EtOAc (25 ml) and stirred at room temperature for 30 minutes. A white precipitate was obtained. The precipitate was filtered, washed with water (2 x 20 mL) and EtOAc (2 x 20 mL), and dried to obtain the desired product, 0.58 g (46%). MS and 1 H-NMR are consistent with the structure shown. Step c-I install-.Γ (#Read the precautions on the back before filling this page)

* ST Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs 〇

〇

OH The product of step B (0.6g '0.0017 mole) was suspended in dioxopropane (20ml), 4N HC1 in dioxopropane (0.9ml), stirred at room temperature for paper size. China National Standard (CNS) A4 specification (210x297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 4 58 9 56 A7 _ B7 '466 -------- V. Description of the invention () Overnight = reaction mixture Dilute with diethyl ether, filter, and wash the residue with diethyl ether (3 x 20 mL). The resulting pale yellow solid was dried in a desiccator over 1 ^ & 〇1 ^ particles, and used in the next step without purification. Step D.

To a suspension of the HC1 salt prepared in step C in DMF (10 ml) was added N-methylmorphine (0.21 ml), and it was cooled to -100 in an ice-salt bath. The reaction mixture was then treated with isobutyl formate (0.24 mL), and stirred at · 10 ° C for 30 minutes. 'N-fluorenylmorpholine (0-46 mL) was added with DL-3-amino-3- ( 3,5-dichlorophenyl) propionate (as produced in steps a and b of Example 1, but replacing 3-u-pyridine with 3,5-dichloroanisole) ((χ6g, 0.002 Moore) in DMF (5 ml) at 0 ° C to produce an amine solution. The resulting reaction mixture was stirred at -10 ° C for 1 hour and at room temperature under argon pressure for 6 hours. 3 DMF was emptied in the air. Medium distillation, the residue was triturated with ether (2X25 ml), and the supernatant was liquid-liquid. The insoluble residue was purified by reverse phase H p LC using a 30-minute concentration gradient of 5-70% CH3C Ν in water. At a flow rate of 70 ml / min. Appropriate fractions were combined and dried on ice to obtain the desired TFA salt as a pale yellow powder. MS and 1H-NMR were consistent with the structure shown. * 例 3 6 2 (± ) 3,5-Digas-2-hydroxy _ /?-[[2-[[[3-[(1,, 4,5,6-tetrahydro-5,5- -469 Guan Family Standard (CNS) A4 · (2 敝 297 敝) (Please read the precautions on the back of the first cabinet and fill in this page). 458 956 467 V. Description of the invention ()-,-Preparation of dimethylpyrimidin-2-yl) amino] phenyl] carbonyl] amino] ethenyl] amino] benzylic acid, trifluoroacetate . '

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The above compound was prepared by coupling the product of Step C of Example 361 with the product of Step 440 of Example 440, as described in Example 361. The desired product was purified by reverse-phase HPLC using a 30-minute concentration gradient of 5-70% CH3CN in water at a flow rate of 70 ml / min. Appropriate portions are combined and freeze-dried to obtain the desired TFA salt. MS and 1 H-NMR are consistent with the structures shown. Example 3 6 3

I 彡-[[[[[[[[Aminoiminomethyl) amine 棊] phenyl] carbonyl] amino] ethylfluorenyl] amino] -4-fluorophenylpropionic acid, three Preparation of fluoroacetate

Step A 4 · Final phenyl bromide (10.0 g, 0.057 mol) 'tert-butyl acrylate (9.52 -470- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 cm) ) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs, printed by B. Du, r B 458 956 A7 __B7 5. Description of the invention (468 gram, 0.074 mole), palladium acetate (0, 13 grams, 0.00057 mole), three-to- A mixture of tolphosphine (0.87 g, 0.029 mol) and triethylamine (5.78 g, 0-057 mol) in 30 ml of DMF was heated at 12 CTC for 16 hours. The mixture was cooled 'and treated with 500 ml of water. The aqueous phase was extracted with ethyl acetate (3 x 200 ml) and the organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by chromatography on silica gel (ethyl acetate / hexane, 1: 9) to obtain 1.03 g of the product as a yellow oil (80%). N M R is consistent with the structure shown. Analysis and calculation of C 13H15F02 値: C, 70.25; H, 6.80. Found 値: C, 69.77; H, 7.08. Step B The product of Step A (8.7 g, 0.039 moles) was treated with ammonia-saturated third butanol and 3 ml of acetic acid at 110 ° C and 900 psi in a Parr shaker for 48 hours. The mixture was filtered; concentrated and concentrated. The residue was dissolved in 200 ml of cold in HC1 and extracted with ethyl acetate. The aqueous phase was then basified with potassium carbonate and extracted with dichloromethane (2 x 200 ml). The combined extracts were washed with brine, dried over magnesium sulfate, and filtered. The solution was concentrated 'to obtain 4.2 3 g of a yellow oil (41%). The structure is in the N M R spectrum. Support 15-Step C. To a solution of the compound of Example M (1.0 g, 0.0037 moles) in 10 ml of DMF was quickly added N-methyl (0.42 g, 0.0037 moles). The mixture was searched out at room temperature for 20 minutes' and then treated with isobutyl formate at 0 ° C. After 15 minutes, a solution of the product of step B in 3 ml of DMF was added. The reaction mixture was warmed to room temperature and stirred overnight. "Dimethylformamide was removed in the air, and the residue was purified by reverse phase. PLC [acetonitrile / water (containing 0.5% -471-This paper scale applies to Chinese national standard plum ( CNS) Α4 specification (210 × 297 mm) ί 谙 First read the notes on the back and then fill in Γ-4 pages). Binding · Order 0Γ: 4 58 3 5§ A7 ____B7_ V. Description of the invention (4S9). · TFA) ] To obtain 0.97 g of pale yellow 'solid (44%). C 23H27N5 04F. 1.0 Η2 0.1.0 Analysis of TFA: Calculate 値: C, 50,93; Η, 5.30; Ν, 11.88. Found 値: C, 50.61; Η, 4.92; Ν, 11.74.

Step D The suspension of the product from Step C in 10 ml of dioxane is at zero. 6 Add 6 ml TF A. The mixture was stirred at room temperature for 4 hours. The solvent was removed and the residue was purified by reverse-phase HPLC [acetonitrile / water (containing 0'5% TFA)] to obtain 0.75 g of the title compound as a white solid (75%). c 19H2ON5 04F 1.5 Analysis of TFA _ · Calculation 値: r C, 46.16; H, 3.79; N, 12.23. Found 値: C, 45.86; only, 3.68; N, 12.23. Example 3 6 4, (Earth-[[2 · [[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylethyl] amino] -1 -2 -Preparation of propionic acid and ginseng (trifluoroacetic acid) salt (please read the notes on the back before filling in r-page j -¾.)

Step A 2-Mimid. Also Carboxaldehyde (6.0 g, 0.063 moles.) And (Third Butylcarbonylmethylene) Triphenylphosphine (29: 4 g, 0.078 moles) in 150 ml, four -472 in argon furan The paper scale is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) A7 B7 V. Description of the invention (47Q) The solution is heated at 5 5 Torr overnight. The clear solution was cooled and concentrated in the air. The residue was purified by chromatography on silica gel (ethyl acetate / hexane, 8: 2) to obtain 9.7 g of the product (1: 1 E / Z mixture) as a white solid (79%). Analysis of C10H14N2O2: Calculate 値: C, 61.84; H, 7.27; Ν, 14.42. Measured 値: C, 61.52; Η, 7.39; Ν, 14.21 »Step B Slowly add step A to a suspension of prewashed sodium hydride (0.62 g, 0.026 mole) in 40 ml of anhydrous dimethylformamide. Product. After 30 minutes, '2- (trimethylsilyl) ethoxyfluorenyl was added, and the reaction mixture was stirred at room temperature for 2 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel (ethyl acetate / hexane, 1: 1) to obtain 3.54 g of E isomer as a colorless oil and 2.66 g of Z isomer as a white solid (73% ). Analysis of C 16H28N2 03Si: Calculate 値: C, 59.22; H, 8.70; N, 8.63. Found 値: C, 58.94; H, 9.12; N, 8.53. .

Step C Printed by the Consumers ’Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs ---------- install— (please read the precautions on the back and fill in the r- &gt; page) in the N-benzyl ( In a solution of trimethylsilyl} amine (2.16 g, 0.012 mole) in 30 ml of anhydrous tetrahydrofuran, slowly add n-butyllithium (0.012 mole) at -78 eC. After 30 minutes, step B The product (2.6 g, 0.008 moles) was added to a solution of 15 ml of tetrahydrofuran, and the reaction mixture was stirred at this temperature for 2.5 hours. The reaction mixture was then quenched with acetic acid in tetrahydrofuran; the solution was quenched, and then saturated carbonic acid was added. Sodium hydride to p Η 9 β Water phase is wrong -473- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economy printed A7, B7 V. Description of the invention (471 ) Extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel (ethyl acetate / hexane, 4: 4) to obtain 1.96 g of product, which was Analysis of transparent oil (60%) s C23H37N3〇3Si: s ten isocyanate: C, 64.00; H, 8.64; N, 9.73. Measured tritium: C, 63.72; H, 8.85; N, 9.73. Step D.. The product in step C (5.4 g '0.0125 mole) and ammonium formamide (7.89 g '0.125 mol) was added to 150 ml of methanol solution pd / C (170 mg). The kun compound was stirred at reflux for 3 hours. The catalyst was filtered through celite, and the filtrate was concentrated. The residue was dissolved in 400 ml of water, Saturated with carbonic acid, acetic acid

I ethyl acetate extraction. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated 'to obtain 3.9 g of product as a colorless oil (91%). The N M R spectrum showed that the compound was pure enough to be used in the next step. Steps

The above compounds were synthesized under the same conditions as described in Example 363, step fc. The crude product was digested with reversed-phase HPLC [acetonitrile / water (containing 0.5% TFA)] to obtain 1.5 g of the product as a yellow solid (60%): -474- This paper is in accordance with China National Standard (CNS) A4 specifications ( 210x297 male stupid) swollen clothes-. · V · I .. {please read the notes on the back and fill in this page) hi order. BA Α7 Β7 V. Description of the invention (472 c 26H41N7 05si · 2.5 TFA Analysis: Calculate 値: C, 44 · 07; Η, 5.19; Ν, 11.61. Measured 値: C, 44.24; Η, 5.14; Ν, 11.91. Step F The title compound is in accordance with the procedure described in Example 36S, Step D. Obtained from the product of step E. The crude product was purified by reverse phase [PLC] [acetonitrile / water (containing 0.5% TFA)] to obtain 0.35 g of the title compound as a yellow solid (24%) r · c 16H19N7 04.3.0 Analysis of TFA: &gt; Calculate 値: C, 36 · 93; H, 3.10; N, 13.70. Measured 値: C, 37.76; Η ·, 2.95; Ν, 14.22. Example 3.6 5 Cold-[[2- [[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] -2,3,5,6-tetrafluorobenzoic acid, trifluoro Preparation of acetate

H2V NH (Please read the notes on the back before filling this page)

F

F The above compounds are based on the reaction procedures described in Step A of Step 363 and Step 骒 C to Step F. Sequential manufacturing &gt; Structure is confirmed by NMR spectrum °-C19H17N504F4 · 1.5 Analysis of TFA: Calculate 値: C, 42 .: 18; H ,. 2.98; N, 11.18. -475- This paper size applies to Chinese national standards (CMS &gt; A4 size (210X297mm) A7 B7 V. Description of the invention (4) Measured 値: C, 42.24; H, 3.07; N, 11.12. Wide example 3 6 6 [(Aminoiminofluorenyl) amino] phenyl] carbonyl] amino] ethyl] ethenyl] amino] -5 -bromofluorene-2 -propionic acid, trifluoroacetate preparation.

Br

Product of the third butyl ester of the above compound (prepared according to a similar method described in this article) (1.0 g '1,91 mmol) and trifluoroacetic acid (14.8 g (10.0 mmol, liter, 13_0 mmol) in dioxane (25 ml) was stirred at 0x for 30 minutes. The reaction mixture was warmed to room temperature and stirred for 6 hours. The solvent was removed under reduced pressure. The crude product was purified with reverse-phase HP Lt (acetonitrile, .water, trifluoroacetic acid) to obtain the pure title compound (0.43 g, 38%) as a white solid. c 17H1SN5 04SBr · CF3 COOH Analysis of Η2 0: .- Calculation 値: C, 38'01; H, 3.53; N, 11.67; S, 5.34-• Measured 値: C, 38:07; 3.23; N, 11.48; S; 4.99 Example 3'6 7 (Shi) 3,5-Digas-; 3-[[2-[[[[3 ·, [(1,4,5,6-Tetrahydro-5,5-Di Methylpyrimidin-2-yl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] phenylpropionic acid, trifluoroacetate preparation -476- This paper is applicable to China National Standard (CNS) A4 specification (210X29 * 7mm) Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ________B7 474-V. Description of the invention ()

Example 361 The ethyl ester (022 g) prepared in step DD was hydrolyzed to acid with hM.LiOH (1.8 ml) in acetonitrile (0.2 ml 0.18 g of acid as a pale yellow powder. MS and 1η-N MR are consistent with the structures shown. '.' Example 3 6 8 (±) 3-bromo-5-dichloro-2-hydroxy _ /? _ [. [2-[[[3-[(1,4,: 5,6-tetrahydro_ 5,5 -Difluorenyl ° · Dense Syndrome-2 -yl) Amine] phenyl] carbonyl] Amine] Ethylphenyl] Amine.] Phenylpropionate, Trifluoroacetate

The above compounds are based on the procedure described in Example 361. The acid (0.6 g) prepared in Step C of Example 361 and the product of Step B (0'5 g) in Example 233 are used. -477- This paper applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling out this page)

A7 B7 Bu 458 9 56 V. Description of the invention (475 combined preparation. The desired product was separated by reverse-phase HP LC to obtain 0.38 g of the above compound as a pale yellow powder. MS and 1 H-NMR were consistent with the structure shown. 谙Read the precautions on the back first and then f. Example 3 7 0 Lu-[[2 _ [[[3 _ [(Amineimine methylamine.) Amine] phenyl] carbonyl] Amine] Ethyl] Amine ] -2-Preparation of p-phenylphenylpropionic acid, g salt,

A solution of mol) in dioxane (100 ml) was added with a solution of thiophenol (9.55 g '86.68 mmol) and pyridine (7' ml) in dichloromethane (150 ml). Inside ice and water bath. After 8 hours at room temperature, the reaction mixture was washed with dilute hydrochloric acid (100 ml, 1N), brine (100 ml), dried (MgS04), and concentrated to obtain 19.0 g (91%) of the desired thioester. Crystalline solid

Step B Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Synthesis of thio-vanacin: a mixture of thio-cinnamic acid s-phenyl ester (140 g, 58 25 mmol) and vaporized aluminum (39 g) was stirred and heated at 85 ° C for 3 hours. The hot reaction mixture was carefully poured onto ice, then extracted with ethyl acetate (3 X 300 mL), washed with brine (200 mL), dried (MgS04), and concentrated. The residue was recrystallized from hexane-ethyl acetate to obtain 5.2 g (52%) of the desired product as pale yellow crystals. '-478. This paper size applies Chinese National Standard (CNS) A4 specification (210X297 public love k 458 956 at B7 ~; _476 second ~ five, description of the invention) Step c 4-amino-3,4-dihydro Synthesis of Thiohumyrin Hydrochloride: Lithium Hexamethyldisilazane (10.22 ml of 1N, 10.22 mmol) Slowly add thiohumylide (1.41 g, 8.52 mmol) to tetrahydrofuran (20 ml ) In the solution at -78 ° C. After 45 minutes, the reaction mixture was heated to 0 ° C and then quenched with glacial acetic acid (0.5 11 g). After 10 minutes, the reaction mixture was partitioned into ethyl acetate. (100 ml) and sodium bicarbonate (1 ml). The organic layer was dried (MgS04) and concentrated. The obtained residue was dissolved in ether (100 ml), dioxolane / HC1 (20 ml, 4N). Add. The formed precipitate is filtered and the solid is dried in the air to obtain (0.50 g, 27%) of the desired product as a yellow powder.

Step D Printed by the Consumers' Cooperative of the Central Bureau of Quasi-Ministry of the Ministry of Economic Affairs (read the precautions on the back before filling this page) m-guanylmauric acid (0.506 g, 1.855 mmol) in dimethyl methylamine ( 5 ml) and N-methylmorpholine (0.187 g, 1.855 mmol) were cooled to 0 eC and stirred for 15 minutes. Isobutyl chloroformate (0.253 g, 1.855 mmol) was added in three portions. After 10 minutes, 4-amino-3,4-diargythiohumulin hydrochloride (0.404 g, 1.855 mmol) was added in one portion, then N-methylmorpholine (0.187 g, 1.855 No mol) added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and the residue was dissolved in tetrahydrofuran / water (1: 1, 5 ml) and chromatographed (reverse phase, 95: 5 water: acetonitrile in 30 minutes to 30:70 water) : Acetonitrile, containing 0.1% TFA). The solution was dissolved on ice and dried in the east to obtain 0.3 00 g of the title compound as a pale yellow powder. M S and proton NMR are consistent with the desired product. Example 3 7 1 -479 * This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 458956 A7 B7 V. Description of the invention (477). (±) /?-[[2-[[[3 -[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonyl] amino] -5-chloro-2-vinylbenzene. Preparation of acid, di-bell salt

----I Printed by Step A, Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs, Synthesis of S- (4-chlorophenyl) thiothiocinnamic acid: Cinnamon hydrazone (26,0 g '156.J mmol) Ear) To a solution of digas methylacetate (100 ml) was added thiophenol (22.6 g '156.3 mmol) and pyridine (ΐ2.6 ml) in digas carbamate (200 ml). The solution was in an ice-water bath. After 18 hours at room temperature, the reaction mixture was washed with dilute hydrochloric acid (100 mL, 1N), brine (100 mL), dried (MgS04) and concentrated to obtain 40.0 g (96%) of the desired Thioester, as a crystalline solid. 1 Step B-Synthesis of 6-Gasthiolavan: thio-cinnamic acid s_ (4-chlorobenzyl) ester- (19.4g) and powdered aluminum powder (52g) are stirred at 125 eC And heat for 3 hours. The hot reaction mixture was carefully poured onto ice / water, then extracted with ethyl acetate (3 X 300 ml) and washed with brine (200 ml), dried (MgS04) and concentrated. The residue was triturated with hexane-ethyl acetate to obtain 2.0 g (14%) of the desired product as pale yellow crystals. Step C -480-(Please read the precautions on the back before filling ^ winter page).

-1T This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm)., ¾

Q Ο Ο Α7 Β7 478 V. Description of the invention (Synthesis of 4-amino-6-chloro-3,4-dihydrothio humourin hydrochloride: Hexamethyldisarditrazine (6.4 ml, 1N) (6,4 mmol), slowly add a solution of 6-chlorothiohumulin (1.05 g, 5.345 mmol) in tetrahydrofuran (20 ml) at -78 ° C. After 4 5 minutes The reaction mixture was heated to 0 ° C and then quenched with glacial acetic acid (0.32 1 g). After 10 minutes, the reaction mixture was partitioned between ethyl acetate (100 ml) and sodium bicarbonate (100 ml). Organic layer Dry (MgS04) and concentrate. The obtained residue was dissolved in ether (100 ml), dioxolane / HC1 (20 ml, 4N) was added. The formed precipitate was filtered and the solid was dried in the air To obtain (0.80 g, 60%) of the desired product as a yellow powder.

Step D The solution of m-guanyl hippuric acid (0.548 g '2.0 mmol) in dimethylformamide (5 mL) and N-methylmorpholine (0.220 mL, 2.0 mmol) was cooled to zero. ° C, stirring for 15 minutes. Isobutyl chloroarsinate (0.260 ml, 2.0 mmol) was added in three portions. After 10 minutes, '4-Amino-6-Ga-3,4-dihydrothiohumulin hydrochloride (0.50 g, 2.0 mmol) was added in one portion, and then N-methylmorpholine ( 0.220 ml, 2.0 mmol). The reaction-mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and the residue was dissolved in tetrahydrofuran / water (1: 1, 5 ml) and chromatographed (reverse phase, 95: 5 water: acetonitrile in 60 minutes to 30:70 water: acetonitrile) containing 0.1% TFA) a eluate was basified with an aqueous lithium hydroxide solution and then freeze-dried to obtain 0,300 g of the title compound as a pale yellow powder. MS and NMR are consistent with the structure shown. Example 3 7 2 -481-Private paper size is applicable to Chinese National Standard (CNS) A4 now (210 × 297 mm) .I. IJ n · II [. ~ &Quot; Line (Please read the precautions on the back before filling W This page} 4799 5 β Α7 Β7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (The following compounds were prepared according to the methods described in Examples 370-371

Ri X = SH; X = SH; X = SH; X = SH; X = SH; X = SH; X = SH; X == SH; X = SH;

^ /-R2 = ci; rJ / R4 = h ri ^ 2 = f; r3 / Ri = h ^, η2 = μθ; r3 / R) =: h Ri / R2 = CF3; Ri, R2 = Br; Hj, Ι ^^ Η R * = H / R2 = f; R3 ^ = h Ri = H, R2 = Br; Ri / R ^ = H

R, = H, R2 = CH3; Rj, i ^ = H In the above compounds, R3 and R4—starting from (CH2) 3 or (CH2). 3 7 4 I nailing line (please read the precautions on the back first) lf. this page) &gt; 'Employees of the Central Bureau of Standards of the Ministry of Economic Affairs, Cooperatives HN,

H2N

The above compounds are the compound prepared in step 233 and 3-guanidine. -482- This paper size is applicable to Chinese National Standard (CNS) A4 (21 × 297 mm)

V. Description of the invention (48Q A7 B7-yl-5-difluoromethylequuric acid (prepared according to the procedure of Example 38)) was prepared by reaction, and the proportion and procedure of Step 3 in Example N were actually used, but with 3 · guanidyl 5_ Trifluoromethyl hippurate replaced GIHA HC1. The desired product was separated by C-18 · RPHPLC. Example 3 7 5.

The above compounds were prepared using the procedure of Example 374, but the (RS) -4-amino-6,8T dichloro-hydrohumulin hydrochloride prepared in Example 237 was used in place of the compound in Step 233 of Example 233. The product was separated by C-18 RPHPLC. Example 3 76 (Please read the precautions on the back first, fill in f. This book) Binding — r Ministry of Economic Affairs, Ministry of Education, Bureau of Accuracy, X, and Consumer Printing Du CF,

The above compound was prepared using the procedure of Example 374, but the (RS) -4-amino-6-gas-hydrohumulin hydrochloride prepared in Example 23 1 was used in place of the compound of Step 233 of Step 233. The desired product was isolated by C-18 RPHPLC. 483 This paper music scale applies the Chinese National Standard (CNS) A4 specification (2 [0 × 297 mm) A7 B7 481 V. Description of the invention (. Example 3 77 CF3

The compounds described above were prepared using the procedure of Example 374, replacing the compound of Example 233 Step B with the compound prepared in Example 227. The desired product was separated by 0-ΐ8 RPHPLC. Example 378 ^-{Please read the notes on the back first, then page 4..fl-v)

No. 02, mr The above compound was prepared using the procedure of Example 374, but the (RS) -4 -amino * 6-stilbyl-hydrovannyl hydrochloride prepared in Example 226 was used instead of Example 233 in Step B. Preparation of compounds. The desired product was isolated by C-18 RPHPLC. Example 3 7 9 Gland Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Standard General Chinese Garden Furniture Ratio (CNS) A4 Specification (210X297 mm &quot; '^ 4 A7 B7 V. Description of the Invention (482 The above compound is the product of Use Example 3 78. The product was prepared using the conditions of Example 234. The desired product was prepared in accordance with the conditions of Example 234. C-18 RPHPLC separation》 Example 3 S 〇

The above compounds were prepared using the procedure of Example 374, but the compound prepared in Example 235 and an equivalent NMM coupling step were used instead of the compound prepared in Example 233 Step a and an equivalent of NMM β. 18 RPHPLC separation. Example 3 8 1 (Xu Xianmin read the note ^ 1 ^^ on the back and refill the factory. This page). Binding Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

The above compounds were prepared using the procedure of Example 374, but the compounds prepared in Example B were replaced with (rs) _4-yl-6-methyl-hydrosalmonin hydrochloride (prepared in Example 88). The desired product is separated by C-18 Rj> HPLC Example 3 8 2 Amine, ο 勹 Ido line -485- The paper method Λ degree is applicable to the Chinese National Standard (CNS) A4 specification (2 10 × 297 mm 458956 A7 B7- V. Description of the invention ( 483

The compounds described above were prepared using the procedure of Example 374. However, the compound prepared in Step B of Example 233 was replaced with (RS) -4-amino-hydrohumulin hydrochloride (prepared in Example 87). The desired product was isolated by C-18 RPHPLC. Example 3 8 3

och3 It --- N} i {Please read the notes on the back before filling page r4) The above compounds were prepared using the procedure of Example 374, but with (RS) -4-amine * group-7-methoxy · Hydroxanthin hydrochloride (prepared in Example ·) replaces the compound prepared in Example-233 Step B. The desired product was separated by C-18 RPHPLC. Example 3 84 -486- This paper size is applicable to China · National Standards (CNS> A4 specifications (210X297mm)> Printed by A7, Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs B7

H2N

&gt; • 458966 V. Description of the Invention (484)

The above compounds were prepared using the procedure of Example 3 74, but (RS) -4-amino-8-methoxy-hydropsoralen hydrochloride (prepared in Example 223) was used instead of the compound prepared in Step 233 of Example 233. Compound. The desired product was separated by C-18 RPHPLC 〇 Example 3 8 5. (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs Step A Preparation

_- 487-, The private paper music scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 /;%) &quot; 453 966. · A7 _______________B7 V. Description of the invention (485) 'The above compounds are composed of 7; S_Asia, Methyldioxy-humulin (which can be derived from 7,8-di- light-yl-chromen-2) according to p, Castillo, j. C.

Rodriguez-Ubis, and F. Rodriguez, Synthesis, &quot; 10, 839-840 _ 1. _ (1986) Preparation Using the procedure of Example 233, step 'A and B'.

Step B The compound described above was prepared using the procedure of Example 374, but the hydrochloride salt of the product of Step A was used in place of the compound prepared in Step B of Example 233. The desired product was isolated by C-18 RPHPLC. Example 3 8 6 (Please read the note on the back first, then fill in k, ^ ·· page)-·

preparation

The above compounds are composed of 6,7-methylenedioxy-humulin [which can be obtained from 6,7-diademyl-phenylhydrazone-tetra-2-one according to Spaeth, et al., Chem. Ber., 70 , -488 r * This paper size is applicable to China National Standard (CNS) A4 specification (210 × 297 mm). &F; f The central standard of the Ministry of Economic Affairs is printed for Beige Consumer Cooperatives 5; 4; 6 9α6, invention description (486) A7 B7 = Milk) Preparation] The procedure was prepared using the actual material 'The above compound was prepared using the procedure of Example 374, but using the product of Step a (the hydrochloride replaced the compound prepared in Step 233 of Example 233. The desired product was C-18 RPHPLC separation. Example 3 8 7 CF,

---------- ^ II (Please read the note on the back and fill in f 'this note) Step A Preparation

The above-mentioned compounds are printed by 5,6-methylene-monooxy-physalin [which can be based on 5,6-dihydroxy-phenylpyran-2-one P.c &amp; sti110, J 'C. Rodriguez-Ubis, and F. Rodriguez, Synthesis, also, prepared by 8: 9-840 (1986)] were prepared using the procedure of Examples 233, steps A and B. -489-This paper size applies Chinese National Standard (CNS) A4 standard (210X297 public love) .487 A7 B7

5. Description of the invention (

Step B The above compound was prepared using the procedure of Example 374, but the hydrochloride salt of the product of Step A was used in place of the compound prepared in Step 233, Example 233B. The desired product was isolated by C-18 RPHPLC. '' Example 3 8 8

Η Step A Preparation Batch-(Please read the precautions on the back, then the soul Γ, wood page) Ding 4 ° Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

The above compounds can be obtained from horse chestnut bark Fenbu 5 (: 111 丨 11) (into 1 £ 11 ^ (: 11, which is essentially free of _ glands. ) Printed A7 _____B7 printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the Invention (488) ~-for hydration, ^ Ρζ〇5 is stored in the air dryer) in essence based on s. Kat〇, et al. 'Bull. Chem' Soc. Jap ”54, 6, 1981, 895, 895, 896, and phenyl. Λ_D-glucopyranoside is converted to phenyl-2,3'4,6-tetra- 〇-benzyl-drinking _D_ grape piperanoside, and replace the appropriate molar amount reagent to complete the conversion of horse chestnut bark glycoside to the above compounds. The desired product can be standard silica gel chromatography or preparative c_ls rphplc: Isolation. Step B, 〇

The above compound was prepared using the procedure of Example 233, Step B, but replacing the product of Example 233, Step A with the product of Step A. Step C_

.-491-The size of this paper is applicable to China National Standard (CNS) A4 (210X297mm) {Please read the notes on the back before filling in this page)-Binding-Staple .1. R A7 B7

HO · ~ ^ ΌΗ 5. Description of the Invention (489) The above compounds were prepared using the sequence of Example 3 74-4, and the hydrochloride product of Step b was used instead of the compound prepared in Step 233 of Example 233. The desired product was isolated by C-18 RPHPLC.

Step D

OHOH

〇r— ° H system— (Jing first read the precautions on the back and then fill in r. J. The above compound is prepared by dissolving the product of step C in an appropriate solvent (such as an aqueous ethanol solution), and moving it to the inlet and outlet valve, Remove the benzyl group in the Fischer-Porter pressure bottle with pressure gauge and willingness release valve, and use standard welding hydrogenolysis procedures (5% Pd / C catalyst and hydrogen pressure) until the demethylation reaction is substantially complete So far *-The desired product is separated by C -1 8 RPHPLC. Example 3 89 Order Λ Printed by the Central Laboratories of the Ministry of Economic Affairs

-492-This paper scale is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) * fer45B 956 A7 • B7 V. Description of the invention (49Q) Step A. 'Preparation Ο

The compounds described above were essentially prepared using the procedures of Example Step 235, Step A-C. Step B Above .. Example. The compound was prepared essentially using the procedures of Step 235 and Step E of Example 235, and was separated using preparative C-18 RPHPLC: 'Example 3 9 0. Tm In I---n (Please read first (Notes on the back, and then write this page on chess) Order.m 1.4. Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

4 -Chloro-2 -Preparation of OH '丨 I y Cl -493- This paper size is applicable to China National Standards (CNS) A4 specifications (2 丨 0 X 297 mm) I .r 4 5 B 9 5 6-. A7 __B7 _ V. Description of the invention (491) * ι The above compounds are prepared according to the procedures of ic. J. Edgar and SN Falling, J. Org. Chem., 55, 16, 1990, 5287-5291 ~ Step B, Preparation of 5-Gas-3_iodosalicylaldehyde

The 4 -Ga-2 -Breaking Age 'prepared in Step A was converted to salicylaldehyde using the procedure of G. Casiraghi, et al., J_C.S. Perkin I, 1978, 318-321. Step C. 6- Preparation of Qi-8-vanazone

The consumer cooperative of the Shiyang Standard Bureau of the Ministry of Economic Affairs printed 5-Gas-3-Iodine salicylaldehyde into the corresponding lavender, 6_Ga_8_Iodine, using essentially the procedure of step 233 in Example 233. Instead of 3 ▲. 5 chloro_ 水 扬 ® ^ with 5_ 气 _3_Iodine water lift chain. The desired product can be separated by standard silica chromatography or a steam room.

Step D __ 494- This paper bears the size of the country of wealth (210X297 mm) B7. A7 492 V. Description of the invention ((R, S) -4_amino-6-chloro-8-iodo-hydrohumulin Preparation

The above compound was prepared substantially using the procedure of Example 233, Step B, but the product of Step C was used instead of 3-bromo-5-gashydanal to obtain a substantially pure hydrochloride product. Step E _ ------- 1 'The above-mentioned, example compound was prepared using the procedure of Example 274, but the product prepared in Step D was used in place of the compound prepared in Example 233, Step B. The green product was separated by C-18 RPHPLC. .Example 3 9 1

(Please read the precautions on the back before filling out this page); H. Packing. H. The above compounds printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics were prepared using the procedure of Example 8 6 Step 骒 D, but with 3_guanidine The _5 · trifluoromethyl hippurate. Phosphonium salt replaces GIHA HC1. The desired product was isolated by C-18 RPHPLC. Example 3 9 2 -495-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 1 4 ίΓ ^ ^ VJ ν .. &lt;. Α7 Β7 ——; 5. Description of the invention () Steps A Preparation

--------- ^ ----;} Packing-(Please read the notes on the back before filling out this page) h. Order the printing of the above compounds by the Central Standards Bureau of the Ministry of Economic Affairs, Masonry Consumer Cooperatives Prepared above using the procedure of Example 235, Step A, but replacing 5-bromonicotinic acid with BO C-L -aspartic acid-4 -third butyl ester (Fluka).

Step B Preparation \ '0. Λοη ·' h2nt ^ y &quot; CF2CF3. 0 '.. The above compounds are essentially based on MR Angelastro, et al., J. Med. -496- The paper dimensions are subject to the Chinese National Standard (CNS ) A4 specification (210X297 mm) Central Bureau of Standards, Ministry of Economic Affairs; printed by the Industrial and Consumer Cooperatives' 4 ^ -0 Γ-Α7 I -------: ----____ 5. Explanation of the invention (494)

Chem., 1994, 37, 453 8-4554, but replace the reference compound 2 with the product of step a »{(S)-[l- (methoxymethylamino) carbonyl] -2-methyl Propyl] aminocarboxylic acid '1,1-dimethyl4-ester}' and essentially deprotected in accordance with the procedure used to obtain reference compound 3 to obtain the HCI salt of the above compound.

Step C The compound of the above example was prepared using Example 8 in the same order as in Step A. However, the product of step B was used to replace the third glycine, vinegar, and 3_guanidino_5_trifluoromethylequuric acid. The hydrochloride replaced GIHA HC1. The desired product was separated by .c-18 RPHPLC. _ .. Example 3 93

Step A Preparation of -3-Nt-Boc-amino-4-hydroxy- (3S) -benzyl butyrate Nt-Boc-L-aspartic acid, cold-phenylacetate (10.0 mmol Ear) was dissolved in 10 ml of THF, and a solution of BH3-THF (20 ml, 20.0 mmol) in 0 ° C was added dropwise over 30 minutes under argon. Stir the mixture at 0 ° C

After 2 hours, the reaction mixture was quenched by adding a solution of 10% acetic acid in methanol dropwise, and the solvent was evaporated. The oil residue is dissolved in ethyl acetate, and the scale is -497-^^, suitable for household use. (210X297'centimeter) 2 — 'S ------ iT ------ β • 1 (Please read the precautions on the back of the cabinet first and then fill out this page) Α7 · B7 '4 5-' V. Description of the invention (495 HC1, H20 and 1MNH4HC03 extraction. Ethyl acetate layer dried (Na2s〇4) 'Evaporation of volatiles 'Oil was obtained which was crystallized from isopropanol / hexane (melting point, 56-57Ό):! H NMR, CDC13, ί, 1.45 (S, 9H), 2.65 (d' 2H), 3.68 (d, 2H) , 5.12 (s, 2H), 5'25 (m, 1H), 7.35 (m, 5H).

Step B Preparation

The 3-Nt-Boc-amino-4-hydroxy- (3S) -benzyl butyrate prepared in Step A was oxidized to the corresponding aldehyde using the following Swern oxidation conditions: grass gas (6.40 g '20 .72 mmol) Ear) was dissolved in anhydrous (: 112 (: 12 (25 ml), and cooled to _63.degree. Using a dry ice / chloroform bath under argon. Anhydrous dmSO (g, 41.4 mol) was dissolved in CH2Cl2 (12 ml ), Added dropwise over 15 minutes. Alcohol (6.40 g, 20,7 mmol) was dissolved in dioxane (50 ml) and added over 10 minutes. After the reaction mixture was stirred for 10 minutes, Et3N (11.6 ml '82 .9 millimoles' 4.0 equivalents) in CH2C12 (25 ml) in 15 minutes. Stir the resulting mixture for $ 15 minutes and add water (31 ml) to sweat. Pour the resulting slurry into On hexane (25 ml), the organic layer was washed with KHSO4 aqueous solution. The aqueous layer was extracted with diethyl ether. The combined organic extracts were washed with saturated NaHC03, dried (Na2S04), and evaporated to obtain 5.S g of pale yellow oil. The above is the desired aldehyde. A small portion is purified by flash chromatography (hexane ___-498: this document is suitable for niF interpolation of scoring cnITX ^ 格 ⑺0x297 / &gt; t 4 ΑΊ B7 Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the Invention (496) / Ethyl Acetate, Merck 60 Silicone: 1H NMR (300 MHz), CDC13, d, 1.46 (s, 9H), 2,95 (m, 2H), 4.37 (m, 1H), 5.13 (s, 2H), 5.62 (m, 1H), 7.38 (m, 5H), 9.65 (s, lH) f MS (FAB +) 314.3 ( M + Li) Step C. Preparation of 3-Nt-Boc-amino · 4-fluorenyl-4-phenyl- (3S) · benzyl methyl butyrate The aldehyde prepared in step 骒 B (5.0 g , 15 mmol) in a solution of diethyl ether (150 ml) at-40 ° C (acetonitrile / dry ice bath) dropwise add a 3.0 M solution of phenyl magnesium bromide in diethyl ether (10.8 ml, 32.6 millimoles, 2 equivalents) The resulting mixture was stirred for 15 minutes and warmed to room temperature. After a few minutes, the mixture was poured into 1M K2ΗP04. The aqueous layer was extracted with ether, and the combined layers were saturated with N. aHC 0 3 was washed with water, dried (N a 2 S 0 _ |), evaporated to obtain an oil (5.66 g), which was used in the next step without further purification: 1 幵 1 ^ 1 \ / 111 (30 (3 MHz ), CDC13, ί, 1.4 (multiple singlet, 9H), 2.65 (m, 2H), 4.18 (m, 1H), 5.15 (s, 2H)} 7.4 (m, 10H); MS (FAB +) 392.4 (M + Li +) o Step D Preparation of 2-phenyl-3-Nt-Boc-amino-5-oxy-3S-furan The hydroxy-ester product of step C (5.31 g, 13.8 mmol) Mol) was absorbed into benzene (100 ml). A catalytic amount of camphor acid was added, the solution was refluxed (Dean-Stark) for 5 hours, and the solvent was removed. 50% was converted to lactone, the reaction mixture was reconstituted, and refluxed for 6 hours. The solvent was removed, and the resulting oil was absorbed into ethyl acetate. The organic was washed with saturated NaHC03, dried (Na2S04), and evaporated to obtain the desired compound. A mixture of enantiolactone (a viscous oil in a 2: 1 ratio) and benzyl alcohol -499-This paper applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm). Note: Please fill in this page again) Order β. I. a A7 B7 V. Description of the invention (497) Compound: 1H NMR (300 MHz), CDC13, d, 1'35, 1.45 (s, 2: 1: 9H) , 2.75 (m, 2H), 4,5, 4.75 (m, 2: · 1,1H), 4.7 (s, 2H), 5.1 (m, 1H), 5.7 (d, 1H), 7.35 (m, 10H ); MS (FAB +) 284,6 (M decaLi +) 〇2-phenyl-3-amino-5 · oxy-3 s-furan hydrochloride preparation.

(Please read the precautions on the back before filling in this page). Install 'Lactone (0.94 g, 3.4 mmol) prepared in step D for consumer cooperation of the Central Standards Bureau of the Ministry of Economic Affairs at 41 ^ Ηα Treat in dioxin (20 ml) at room temperature until gas evolution ceases. Excess HC1 was removed by evaporation. The desired depleted aminolactone was isolated as a crystalline solid 'dried (0:48 g, 66%): iHNMR (300 MHz), DMS, 3.05 (m, 2Η), 4.4 (m, 1Η), 5.85 (d, 1Η), 7.4 (s, 5Η), 8.2 (bs, 3H); MS (FAB +) 178 (M + H +). -Step F, preparation o.

〇AH o Order, &gt; 11 -500- Private paper size applies Chinese National Standard (CNS) (2ί〇Χ 297 公 爱) 5. Description of the invention (498) A7 B7 The above compounds were prepared using the procedure of Example 374, However, the product was used instead of the compound prepared in Step B of Example 233. C-18 RPHPLC The desired product was isolated as in Example 3 9 4 ΗΝ ^ Η2Ν

The above compound was essentially prepared according to the procedure of Example 39.3, but substituted phenylmagnesium bromide in step C with brominated * fluorophenylmagnesium. `` Example 3 95

f Please read the notes on the back before filling in _ ^ This page} -11 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

The above compound was prepared essentially according to the procedure of Example 393. Phenylmagnesium was substituted for the benzylmagnesium bromide in step C. Example 3 9 6 But brominated 4, -501-This paper size applies Chinese National Standard (CNS) A4 specification (21 × 297 mm) 45895¾ A7 B7 V. Description of the invention (499

The above compound was essentially prepared according to the procedure of Example 393., but the alb. * Bromophenylmagnesium was used in place of the phenylmagnesium bromide in step C. '' Example 3 9 7

--------- Install | _ s \ &gt;. · (Please read the notes on the back before filling in 'see this page) Ding _,-' ° Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The above compound was prepared essentially according to the procedure of Example 393, but the adenyl magnesium replaced the phenyl magnesium bromide in step C. *, Example 3 9 8

This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) '458956 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Sweat —., / (Jing first read the precautions on the back and then fill in this page) This paper size is applicable to the Chinese National Standard (CNS) A4 viewing grid (210X297 mm) 1T ·

〇

The above compound essentially follows the procedure of Example 393 in place of the phenylmagnesium hydrochloride in step Xc. Take bromide as an example 4 0 2

I ™ I 11 Zhuang Yi. Order (please read the precautions on the back before making this one. This page) The central standard of the Ministry of Economic Affairs and the Employee Consumer Cooperatives printed the above compounds according to the procedure of Example 393, but-using bromide Example: Substituting magnesium bromide in step C: phenylmagnesium halide, Example 4 · 3

504- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) .....) line 95® A7 B7 502 V. Description of the invention The above compound is essentially based on the procedure of Example 393 instead of step C Desertification of phenylhydrazone.备 ’But the difference is Australianization Example 4 0 4

--------- 1¾—— (Please read the notes on the back before filling. ¾ This page)

Step A Preparation of 4-bromomagnesium-1,2-(. Fluorenylenedioxy) benzene

BrMg

〇 / The staff of the Central Ministry of Health and Labor of the Ministry of Economic Affairs of the People's Republic of China printed the cooperative in 1'74 g (0'〇72 Mo-ear) of freshly ground crushed magnesium in 106 ml of anhydrous thF 'in a 250 ml round-bottomed flask. In 4 drops, n 1 g (Ojamor M-bromo-ι, 2 · (methylene dioxan) benzene in 50 ml of anhydrous THF was added. During the addition, the reaction mixture was sonicated. The bath maintains a low hair 50C. When the reaction is completed, the compound is overly concerned, and it is used for the next step. Step B '505 The size of the paper is applicable to the Chinese National Standard (CNS) M specifications (21〇.κ297 公 爱 503 ί.χ Α7 Β7

V. Description of the invention

The above compound was prepared essentially according to the procedure of Example 393, but the Grignard of Step VIIA was used in place of the phenylmagnesium bromide in Step 393 of Example 393. Example 4 0 5. '---------- Shen Yi-(Please read the notes on the back before filling in poverty, this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Step A Preparation

Order

M-506- This paper size is in accordance with Chinese National Standard (CNS) A4. U〗 〖0X297 mm. V. Description of the invention (504 A7 B7 The above compounds are prepared according to the procedure of Example 5 5 Step A. Methyl phenyl benzoate methyl ester Substituted .2-furancarboxaldehyde. Step B prepared but with 2-

The above compound was prepared according to the procedures of Steps B and C of Example 55, but the product of Step A of Example 55 was replaced by the product of Step A. Example 4.0 6

---------- Seed clothing — (Please read the precautions on the back before filling in the k't page) _ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Step A Preparation

Gland -507- This paper size is applicable to China National Standard (CNS) A4 (210 X 29 * 7 mm) 5. Description of the invention (505 A7 B7

Ph Example 3 The product of step 93C is oxidized to the above step using the procedure of Example 393, step B. Step B ‘Preparation 〇 Ph

I .-------- install ------ order ------ f (Please read the notes on the back before filling this page) The above is printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs The compound was prepared according to the procedure of Example 393, Step E using the product from Step A above. -__ Step C. Preparation. ′. -508 This paper scale is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 4 58 9 56 A7 B7 V. Description of the invention (506

The example compound was prepared essentially using the procedure of Example 374, and the product replaced the compound prepared in Example 233, Step B. The H π degree system was obtained by converting the benzyl ester substantially to the corresponding carboxylic acid using the procedure of Example 4, and the desired product was separated by C-18 RPHPLC. '' Example 4 0 7 4 1 4 Using the procedure of Example 406, but substituting the appropriate protected aspartamidinyl alcohol prepared in Example 3-403 for the asparagine alcohol of step A of Example 406, the following representative was prepared Sex compounds: but with step

Sao B Printed by the Consumer Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs. 509 μM standard is applicable to the Chinese National Standard (CNS) A4 specification (210XM7 mm) (Please read the note on the back and fill in the 3T page first}

4 5 8 9 56 A7 B7 V. Description of the invention (507 Example 4 07 HN ^ h2n /

cf3

Example 4 08

HN ^ ^ H2N ’’ H Example 4〇9

(Please read the notes on the back before completing this page) HN, $ H〆 cf3

Λ

T hN ~ OH 〇 Example 410 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs cf3

〇 ch3 -510- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297mm) 458956 A7 B7 V. Description of invention (508 Poor case 411

Lean example 412. HN, H2Ny

〇 Λ

Cr OH Ο (Please read the precautions on the back before filling this page) Example 413

xΛ

A H, OH 〇 Example. 414 CF printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs,

-511-This paper size is in accordance with Chinese National Standard (CMS) A4 specification (210X297mm) 4 58 95β Α7 Β7 V. Description of the invention (5Q9) Example 4 15 〇

In Example 23, the product of step A was added to DMF in excess of 1,3-diamino-2-mercaptopropane and a catalytic amount of D M A P, and the solution was heated until the initial $ _methylisothiocone salt_ was completely converted. The desired product can be precipitated with a zwitterion or separated by preparative C-U RPHPLC (see US Patent 2,899,426 for related procedures). After the water was removed by drying, the zwitterion was stirred in Aldrich in a total amount of 4n ^^, and the HCI salt was separated by vortexing, ..., and • A to form a hydrochloride salt. Step B. ---------- ^ — (Please read the notes on the back before filling in r: this page), ar gland Μ mr 1 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

CI-512- The standard of this paper is Chinese national standard (CNS &gt; A4 specification (210X297mm) 4 58 9 5g A7 B7 C-ϊΠ 5. Description of the invention (The above compounds are essentially replaced by the products prepared by the procedure of Example 233) 2S3 GHIA hydrochloride in step C. Examples 416-43 9 — I The procedure of Example 415 is essentially used, but with the appropriate base winter gas-8 hydrogen hydrochlorophyllin hydrochloride, can be prepared = Substituted (RS) · 4-amine coat 11 the following representative compounds

But with step A

CI instance

&lt; Please read the notes on the back before filling this page) Binding _ Orders and Seals Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Example 418 / ~ · N V ~ nh h

-513 The paper size of the table applies the Chinese National Standard (CNS) A4 specification (2I0X297 Gongcheng) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 4 □ 9 S ^:.. A7 B7 V. Description of Invention (511) 〇

(Please read the precautions on the back before filling ^ 'this page) Packing. H.-= 5 One-one-one spine -514- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) V. Description of the invention (512 Α7 Β7 Example 42 4

Example 425 1 NHC

/-^ 〇— ^ -NH

Η, Ν

—--------- Installation-(Please read the notes on the back before filling in 1 ¥ this page) Printed by the Consumers ’Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

-515- This paper size applies to China National Standards (CNS) A4 (210 ×: Z97mm) Order r 9 5: Α7 Β7 V. Description of Invention (513 Poor Example 429 &gt; N Ή V_NH Η

Ο · 〇 Ν Η

Example 4 3 Ο Η 丨 /-Ν ° ~ ^ y ~ ΝΗ

Η Ν ', Ν Η ΟΗ

JZ \ (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 〇Cl.

516- The size of this paper is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) Ν Order 514 V. Description of the invention (A7 B7

VJ; n example 43

Λοη (Please read the notes on the back before filling in poverty education) · $ Ν 印 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

-517- This paper size applies to China National Standard (CNS) A4 (210 X 2 to 7 mm)

IT broken 4SB 955 A7 ΒΤ 5. Invention description (515 Example 43 8 ν_ΝΗ η ο

请 (Please read the notes on the back before completing this page) Bee

'1T gland m Λ r Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -518- This paper size is applicable to the Chinese National Standard (CNS) M Appearance (2 丨 〇 &gt; &lt; 297 mm) 458956 A7 B7- * V. Description of the invention (516 Example 4 4 0

Step A

Cl (please read the notes on the reverse side and fill in this page). Pack. Order the above compounds using the procedure of Example 233, steps A and B, but replace 3 in step A with 3,5-dichlorosalicylic aldehyde. -Bromo-5-gassalicylaldehyde MS and NMR are consistent with the structure shown (HC1 salt). Step B-

The above compounds are obtained from the product of step A with anhydrous HC1 gas in formazan 丄 丄 甲 甲 in the appropriate -519- This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printed 458956 A7 B7_ V. Description of the invention (517: Preparation in the reactor while maintaining vigorous stirring. Removed after the completion of the echo, the solution is concentrated to dryness. The crude product is used in the second 2: or the product can be Separation by M.I8RPHPLC, drying on ice, obtaining substantially pure material 1. Step C. 〇

The above compound is prepared by dissolving the product of Step B in DMF. Add an equal molar amount of di-tert-butyl dicarbonate and triethylamine and a catalytic amount of DMAP to the exhaustion solution. When the reaction is completed, the volatiles are removed under the air, and the product is distributed between a dilute aqueous hydrochloric acid solution and ethyl acetate. The organic layer was washed with water, dried (Na2S04), and concentrated to obtain the above compound, which was used in the next step without further purification. Alternatively, the product can be isolated &apos; lyophilized by C-I8 RPHPLC to obtain a substantially pure material. — I Step D ί, ---------- 参-., *. (Please read the notes on the back before filling in. ^ This page &gt; 1Τ Ministry of Economic Affairs t.消 # Cooperative print 0

-520 The paper scale is applicable to the Chinese Standard of National Standard {CNS) A4 (2I0X297 mm) 1 ^ 58 9 56 A7 B7 V. Description of the invention (518 The above compounds are based on one equivalent of acetic anhydride or acetic acid and one equivalent Triethylamine is prepared by adding the product of Step C in a stirred solution of DMF in an inert atmosphere. When the reaction is completed, the volatiles are removed under agitation, and the reaction residue is partitioned between a dilute aqueous hydrochloric acid solution and ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaHC0, dried (n a2 S 0 4), and concentrated to obtain the above compound, which can be used in the next step without further purification. Alternatively, the product can be separated by C-18 RPHPLC and freeze-dried To obtain a substantially pure substance

Step E

f read the note on the back ^^^^^^ this page} order the above compounds are processed from the product of step 0 with 4N HC1 in dioxolane, and stirred vigorously to prepare 3 after the release of gas stops The excess HQ. Gas was removed under vacant air, and the reaction mixture was concentrated at less than about 40%. The product was milled with diethyl ether to essentially obtain the desired product. Alternatively, the product can be separated by c-18 RPHPLC, iced; dried, to obtain a substantially pure material.

Step F -521-This paper size applies the Chinese national standard (CNsTTi ^ (2 〖0 &gt; &lt; 297gong sauce) _ 印 Printed by the Employees' Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs 5. Description of the invention (519 Α7 Β7

The above-mentioned compound. Was prepared according to the procedure of Step 230 of Example 230, but the product of Step A of Example 230 was replaced by the product of Step E. ; Example 44 1.

CI The above compound was prepared by treating the D M F mixture of the compound of Example 225 with two equivalents of N-fluorenylmorpholine and one equivalent of acetic anhydride or ethyl chloride. At the completion of the reaction, the desired product can be separated by C -1 8 RPHPLC and freeze-dried explosion. Example 4 4 2 (Please read the precautions on the back before filling the poor page). Printed by Industrial and Consumer Cooperatives

IHI Ο ΗΝ

C | 522-This paper size applies the Chinese National Standard (CMS) A4 grid (2I0X297 mm) 4 ο 4 5 6 'Α7' -------___ Β7 _ 5. Description of the invention (52.) The above compounds are based on Example 225 The d MF mixture of the compounds is prepared by treating two equivalents of N-fluorenylmorpholine and one equivalent of benzoic anhydride or benzamidine chloride. When the reaction is complete, the desired product can be isolated by C-18 RPHPLC and lyophilization. Example 4 4 3-4 5 2 11 I. 1 ^ 1 1-II Km ii 1. ^ 1 ~ / {Please read the precautions on the back first and then fill out this page) Customize the use case 230 step B Procedure, but replacing the product of Example 230 Step A with an appropriate amine, the following representative compounds can be prepared: '〇 Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

V. Description of the invention (521 A7 B7

Example 448

HN, H2N

(Please read the precautions on the back before filling out the rr page) • Binding. Order Example

Consumers' Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs

Gland -524- This paper size is applicable to Chinese National Standard (CNS) A4 specification (2! 〇 X 297 cm) .522 .522 A7 B7 45395 · V. Description of the invention ('Example 4 50 〇

Example 〇

Example 4 52

(Please read the precautions on the back before filling in the poor page) Binding and binding. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Gland Economics -525- This paper scale is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) ) 5. Description of the invention (523 Α7 Β7 Example 4 5 3-4 6 0 Example 393 was used, but the product of step 骡 e was replaced with the appropriate amine hydrochloride in step F, and 3_guanidyl_5 was replaced with GIHAHC1 · Trifluoromethyl hippuric acid can be prepared in the following step. Representative compounds: Lean Example 4 5 3

Example 454 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

526 The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) '-^ I i ---------- ^ ------ ir ------ gland. (Please read the notes on the back before filling in this page) 458956 Α7 Β7 V. Description of the invention (524) Example 4 55

Λ OH, ΟΗ Η 6 Example 456

—--------- Installation-• N ―... {Please read the notes on the back before filling in this page) i.-&Quot; Example 4 57.

Printed by the Employees' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs-527- This paper size applies to the Chinese National Standard (CNS) A4 (2 丨 0 X 297 male; ^) ^ '^ 4 58 9 56 A7 B7 Five' invention description (525 〇 Example 458

Example 4 59 HNy-nη2ν η

ch2 i j ί binding chain (please read the precautions on the back before filling ^ 'this page &gt; example 460 printed by the staff consumer cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

, nH 〇

OH OH

H -528- This paper is also applicable to China National Standard (CNS) A4 specification (2 丨 0 X 297 mm) f · Central Standard of the Ministry of Economic Affairs 扃 Printed by Employee Consumer Cooperatives 4 ^ Β956 • Α7 —---—__— _ V. Description of the invention (). ^ \ Example 4 6 1-4 6 9-The procedure of Example 4 was used, but substituted with the assured asparagine alcohol prepared in Example 3 material 403. Example 4 Asparagine alcohol of step A and substituting 3_guanidino_5-trifluoromethylequuric acid with GIHA HC1 in Example 393, step F 'can prepare the following representative compounds: Example 4 61

-Λοη

529 The scale of this paper applies the Chinese National Standard (CNS) A4 specification (2ω × 297 mm) I --------- Shenyi— Λ--. (Please read the note on the back ^ before filling in this page) ... i. -5 涞. A7 B7 527-V. Description of the invention () Example 4 64 Ο

(Please read the precautions on the back before filling the kidney page.) Pack. Example 466 library. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

-530 This paper size is applicable to China National Standard (CNS) Α4 size (210X297mm) 9 56 Α7 Β7 V. Description of invention (528 Example 4 67

〇 Example 4

ΌΗ'.〇 (Please read the notes on the back before filling k. This page) Example 469

〇N Η 〇 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 531-This paper size applies to Chinese National Standards (CNS) A4 specifications (2! 0 × 297 mm) 5 -Γ; · ^ 5β, Description of the invention (529) A7 B7 Example 4 7 0 Preparation

Printed in Step A of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs at 3,4,5,6-tetrahydro-.2-pyrimidinthiol (Aldrich) (5.0 g, 0.043 mol) and triethylamine (8_7 g, 0.086 Mol) was added dropwise in CH2C12 (50 ml) at a temperature of ice bath [(Aldrich) 13.5 g, 0.086 mole). The reaction mixture was then shaken off at room temperature overnight. The reaction mixture was washed with (: 1 ^ 2 (: 12.) :( 112 (: 12 filtrate was washed with 1 ^ 0 (3 \), dried ton 804, Remove under vacuum .. The residue is recrystallized from 50% EtOAc / hexane to obtain 9.03 g of 3,4,5,6 tetrahydro-2-pyrimidinethione N, N, -diphenylaminocarboxylic acid 'Yellow solid =-MS and NMR are consistent with the desired structure.' Step B ', a. The product of step C (200 mg, 0.0000 mol) in Example 282, the product of step A above ( 150 mg, 0.00042 mol) and triethylamine (142 mg, 0.00OH mol) in 3 ml DMF: add wo mg (0.00046 mol) HgCh at the temperature of the ice bath. The reaction mixture is at the temperature of the ice bath. Stir 丨 / 2 hours' Stir at room temperature for 2 hours. 100 · m · g HgCl2 is added. The reaction mixture is at--532 This paper size applies Chinese National Standard (CMS) A4 specification (2 丨 0X 297 mm) ¾- -(Please read the notes on the back before filling in this page)

1-IT thorn ·

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (530) 6 ° C overnight. Excess ethyl acetate was added, and the slurry was washed with ceiite. The filtrate was washed with H2O (3X) through a silica gel pad. The product was separated by silica gel chromatography to obtain the above compound (110 mg) as a white solid. M S and N M R are consistent with the desired structure. · Example 4 7 1

'Step A To 3,4,5,6 · tetrahydro-2-pyrimidinethiol (j.Aldrich) (10 g, 0.086 mol) was added to absolute ethanol (75 ml) methyl iodide (75 ml) 12,2 g, .0086 mole) The reaction mixture was allowed to reflux for 2.5 hours. The solvent was removed under a vacuum to remove the residue and dried 'to obtain 3,4,5,6-tetrahydro-2-methylthiopyrimidine.hi (22 g) as a white solid. .MS and NMR are consistent with the desired structure. 'Step B' The product from step A above (5. 丨 6 g '), 0.02 moles and triethylamine (41 g, 0,04 moles) in C Η 2 C 12 (2 5 ml) Aldrich (3.13 g '0.02 mol) was added dropwise at the temperature of the ice bath. The reaction mixture was stirred at room temperature overnight. Shen Dianwu's thing, washed with CH2Ci2. CH2Cl2 solution is H2〇-533-This paper size applies to Chinese national standard (CNS &gt; _A4 size (210X297)) ~~ '~~ · --- (Please read the note f on the back and fill in the clothing page )-Binding bo A7 B7 V. Description of the invention (531 (3 \) Wash, dry at 1 ^ 3〇4, remove under empty space to obtain 3,4,5,6-tetrahydro-2 -methylthiopyrimidine -Nv phenylaminophosphonium · ester (4.8 g) as a white solid, and the NMR was consistent with the desired structure. Step C 'The product from step B above (2 g, 0.008 moles) in CH3CN (12 Ml) was added to the product of Example M, Step B (1.84 g, 0.008 mole). The reaction was stirred at reflux overnight. The product was isolated by RPHPLC to obtain 3,4,5, '6-tetrahydro-N-phenylamine. Methylmethylpyridyl_ 2 -pyrimidine-m-aminokineturic acid, TFA (1 g), as a white solid. Step D The above compound was prepared according to the method of Example Π4, but with an equivalent amount of 3., 5_digasbenzene Formaldehyde was substituted for 3,4-digas benzaldehyde in Example 174, step a, and the product of step C was substituted with the same amount of meta-guanidyl maleic acid · HC1 in. Example 174 Step B MS and NMR are consistent with the desired structure "Example 4 72 system ......... β ^: i exhibition ------. order ------ finally &lt; please read the notes on the back before filling in this section I) Staff of Central Bureau of Standards, Ministry of Economic Affairs Printed by Consumer Cooperatives

534 The scale of this paper applies the Chinese National Standard (CMS) A4 specification (210X297 mm) A7 B7 '4 £ 5; 1 9 8 6 532 ~ 5. Description of the invention ()

Step A: 2-methylthio-2-imidyl # .HI (Aldrich) (10 g, 0.0041 mo re) and triethylamine (4.14 g, .0.041 mo) in (: 112 (: 12 (50 ml) was added BOC Aldrich (8.94 g, 0.041 mole) at the temperature of the ice bath. The reaction mixture was stirred at room temperature overnight. The CH2CI2 filtrate was washed with H20 (3X), dried over MgS04, and H20 (3X ) Washed, dried over MgS04, and removed under airspace to obtain N-BOC-2-.methylthio-2-imidazoline (8.1 g) as a transparent liquid, which turned into a white solid upon standing. MS and NMR Consistent with the desired structure "Step B To the product of Step A above (2.7 g, 0.0124 moles) was added CH3CN (6 ml) 3-amino-5-trifluorofluorenyl-phenylarsinic acid (from 3- -5.- Trifluorobenzoic acid (Lancaster) was synthesized by catalytic hydrogenation (P d / C) and then treated with HC1) (3 g, 0.0124 mol). The reaction mixture was stirred at 3 5 · 4 〇ec After 10 days, after cooling to room temperature, the sanitary matter was filtered, washed with C η 3 CN, and dried to obtain 3- (N-BOC-4,5-diargylimidazol-2-yl) amino group- Trifluorofluorenylbenzoic acid. HC1 (3.2 g) as a white solid-MS and NM R is consistent with the desired structure.

Step 骒 C The above compound was prepared according to the method of Example 200, but the product of Step B in Example 198 was replaced with the same amount of the product of Step A in Example 198. The penta-intermediate ethyl ester 'N-B 0 C derivative was treated with TFA 1 Hours to remove the β OC protecting group. MS and NMR were consistent with the desired structure. -535- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297mm) s I. I—--I-1 · —: _-—-1 -II Clothing 1 (Please read the Note ^^ item again ^ 'This page &gt; Count _ · &quot; Printed by QF- A7 ____B7 533 printed by the Consumers ’Cooperatives of the Central Standards Bureau of the Ministry of Economics 5. Description of the invention () Example 4 7 3

Printed in Step A of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs on 3-Amino_-5-trifluorofluorenylmauric acid hydrochloride [prepared according to steps a and B, but with 3 -nitro. 5-trifluorobenzyl fermentation gas (made from 3_nitro_5_tris. · «Phenylacetic acid (Lancaster) and thionyl chloride) substitution example jv {Step pro A middle-nitrobenzyl chloride ] (3 g '' 0.01 mole) To CH3CN. (5 ml) was added the product of Example 472, Step A (2.¾ g ', 0..01 mole). The reaction mixture was stirred at 35 ° C for 3 days and then at reflux for 4 hours. After cooling, CH3CN was decanted, and the residue was slurried in ether several times (ether decantation), and then dried to obtain 3- (4,5 · dihydro-1H-imidazol-2-yl) amino-5- Trifluorofluorenyl hippuric acid, HCI (2.5 g), as a white solid. MS and NMR are consistent with the desired structure. Step B · The above compound was prepared according to the method of Example 210, but the same amount of the product of Step B as described above was used in place of the intermediate guanidinoguanine.HC1 in Step B of Example 174. MS and NMR are consistent with the desired structure. Example 4 7 4 -536- 1 (Please read the precautions on the back before filling this page) --Installation. A. | Discussion: _ This paper size applies to China National Standard (CNS) A4 specification (21〇 × 297) %)

If ^ A7 __—____ B7 1. 丨 — 534 &quot; V. Description of the invention () Preparation

Step A. At 2.methylthio-2-imidazoline Hi (Alddch) (10 g, mol) and triethylamine (8.3 g, 0: 082 mole) in Cj ^ C 丨To 2 (> 0 ml) was added dropwise ethyl formate (Aldrich) (4.5 g, mol) at an ice bath temperature. The reaction mixture was stirred at room temperature overnight. The precipitate was filtered and washed with CH. The C Η 2 C 12 filtrate was washed with Η 2 〇 ('3 phantom wash., Dried with MgS04, and removed in the air and removed' to obtain 2-methyl sulfo_2-iminoline ethylamino acetic acid (7.1 g) It is a transparent yellow tincture. MS and NMR are consistent with the desired structure. Step B-The product (5.73 g, 0.0305 mol) from the above step A was prepared on ch3CN (12 Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs). Printed, ---------- ^ —— {Please read the precautions on the back and then fill in this page)-Millifolia) Add m-amino uric acid, HC1 (Example M step B) ( 7.02 grams, 0.0305 moles). The reaction mixture was stirred at room temperature overnight, and stirred at 5 trc for 6 hours' at .8 0 * C for 2 hours. After cooling to room temperature and stirring overnight at Xuan temperature, the precipitate was filtered, washed with CH3CN, and dried to obtain 3- (4,5-dihydro-N-ethylaminoformate-imidazol-2-yl). Amino hippuric acid. HC1 (9.6 g) 1 * as a white solid. -537-This paper size applies to China National Standards (CNS) M specifications (2UJX297 mm) 535 535 A7. B7 »458956 5. Description of the invention (MS and NMR are consistent with the desired structure.

Step 骒 C The above compound was prepared according to the method of Example 174, but replaced Example 174 with the equivalent of the product of Step B in Step 174. Step B intermediate-guanidylequuric acid was replaced by the same amount ^ Example 230 The product of Step A is in Example ο Step B. . 'Almost MS and NMR are consistent with the desired structure. Preparation., _ Example 4 7 5

The compound printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs was prepared according to the method of Example 4 74, but the equivalent amount of phenyl formate (Aldrich) was used to replace the ethyl acetonate in step 474 ', and in step 474 The reaction mixture in B was heated at 70 * C for 8 hours and then at room temperature for 2 days. MS and NMR are consistent with the desired structure. '' Using the methods, reagents, and conditions exemplified in the figures and examples of this disclosure (or synthesizing reagents from readily available starting materials by methods known to those skilled in the art), the following compounds of the present invention are synthesized: -538 This paper and Applicable to the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) 4 58 9 51 A7 B7 V. Description of the invention (536 Example 4 7 6-5 1 7 Example) ί 76 # 477.

.ΓΛ% n ^ nh Example 478 γ 〇 ▽ ΗN. Example 479 'D ° HN, (Please read the notes on the back before filling out the page) Central Standards of the Ministry of Economics 扃 Printed by Employee Consumer Cooperatives

cf3 〇

539- The paper size applies to Chinese national standards (CNS &gt; A4 size (210X297 mm)) 5. Description of invention (537 A7 B7

n

η (please listen to the precautions on the back before filling this page) Pack. Ding 4 °

11L Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs

-540- This paper size applies to Chinese national standard (CNS &gt; A4 size (2 [〇297mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 4:58 9 B§ V. Description of the invention (538)

(Please read the precautions on the back of the cabinet first and then fill in 41). Binding and ordering _- 541-This paper size is applicable to the national and national standards ^ 匚 阳 丨 Six may see the grid "price 乂 ^ 了 公 牦" 4 5 Π 56 A7, · Β7 V. Description of the invention (539 —rH °

cf3

Example 489

NVNH a Regulation, 490 y ° 'HN,

F3 'Ν1-Γ ^ γ &quot;

(Please read the precautions on the back before filling in "'Private 1'") Ordering in the i · kr world 丨 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economics Example 491 ΓΛ HNL /

CF3, νη * ^ &quot; Ύ 〇

-542- This ^ paper size applies to the Chinese National Standard (CNS) A4 specification (210X297’mm) 9S6 A7 B7 V. Description of the invention (54C))

NH

---------- Equipment-(Notes on the back of Shi Xianmin, then fill in W 乂. Page) Du Yinye

-543- line. Y. This paper size applies to Chinese National Standard (CNS) A4 specification (2〗 0X297 mm) 4 S © A7 B7 V. Description of the invention (541 Example 497

HN. C02Et H.

OH Cl

Br N Example 498

ΝΗ C

Cl (please read the precautions on the back before filling this page). Equipment. ΓΛ π ~ C—OEt Poor Example 49 ^^ Q ΗΝ ‘

cf3 —rNH 〇 c 02Et

OH

Cl, V5 Example 500 O j-y o ElO—C—N N—C—OEtY 0, N, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

I

c

-544 This paper scale is applicable to China National Standard (CNS), A4 specification (210 X 297 mm)

4 D A7 B7 V. Description of the invention (542 ί

EtO—C—C—OEt Example 丨 501 1 Eight ^ 'NH- ^ V ^ NH .O

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. O. CF3 tl II EtOC- ^ NHC ~ OEt Example, 502.

HN. Poverty cases 505 -545 This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) I -------- ^ —— (Please read the precautions on the back before filling in Page) Engagement.

* ί; 4 ^ V. Description of Invention () Printed by the Consumers' Cooperative of the Central Standardization Bureau of the Ministry of Economic Affairs

〇 〇

(Please read the notes on the back of the first cabinet, and then fill in this page). The size of this paper is 1T, which is applicable to the Chinese National Standard (CNS) A4 specification (2 [OX 297mm) 458956 A7 B7 * 5. Description of the invention ( 544 instances 511

Et〇-C N N-C-OEt Example 512. Y 〇

CF3

'N

C02Et OH a

Cl

H

&lt; Notes on the back of Zhu Xianmin, then fill in this book I) Example 513 Heart / NHT 〇 hn 'eight or eight nh / ^ 7nh

Br co2h

Br Example 514 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Example 515

HN

NH / T co2h NH.

Br VH 〇

HK People / NH N

C〇2H

-547- This paper size is applicable to China National Standard (CNS) A4 (210X 297mm). A7 B7, 458 956 V. Description of the invention (545 η

Example 51

&quot; W

(Please read the precautions on the back before filling in the man page)-Pack. Order _ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-548-This paper uses the Chinese National Standard (CNS) A4 specification (2 [0X297 mm Fifth, the description of the invention ()

NH

A7 B7

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Example # a BC Ώ. £ F 518 OH Cl Cl. Br HH 519 Oil Cl Cl OH II H 520 OH Cl Cl 'no2 HH 521 OH Cl Cl Worker HH 522 OH Cl Cl Cl HH 523 OH Cl Cl Cl H Cl 524 OH Cl Cl OMe H • H 525 OH Cl Cl H cf3 H 526 OH Cl Cl H OH H 527 OH Cl Cl H OMe H 528 OH Cl Cl H Cl H 529 OH ci Cl H Cl Cl 530 OH Cl Cl H Br H 531 OH Cl Cl 'Cl OH H 532 OH pi Cl Br OH H 533 OH Cl Cl • I OH H -549- This paper size applies to the Chinese National Standard (Eagle Milk) 6 4 specifications (210 乂 29,7 mm) (please first (Read the notes on the back and fill in the special page).

45B 9BB A7 B7 V. Description of the invention (547

NH

NH &quot; Y

D

B

C Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

Example # h BC β EE 534 OH Br Cl Br HH 535 OH Br Cl OH n H 536 OH Br Cl ^ no2 HH 537 OH Br Cl IHH 538 OH * Br Cl. Cl, * HH 539 OH Br Cl Cl * H Cl 540 OH • Br .cl OMe HH 541 OH Br Cl H cf3 H 542 OH-Br Cl H OH H 543 OH Dr Cl H OMe H 544 OH Br Cl H Cl H 545 OH Br Cl H Cl Cl 546 OH Br Cl H Corpse 547 OH Br Cl Cl OH H 548 OH Br Cl 'Br OH H 549 OH Br Cl I OH H (Please read the precautions on the back before filling this page).

* 1T -550 This paper size is applicable to Chinese National Standard (CNS) Α4 specification (210X297 mm) 4 Q56 at __—_ B7, rt Λ ^, 548. 5. Description of the invention () ·

Printed by the Masonry Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Example # AB c E s F 550 OH I Cl Br HH 551 OH I Cl OH H II 552 OH I Cl no2 HH 553 OH Industrial Cl IHH 554 OH .I Cl 'Cl HH 555 OH * I Cl Cl H Cl 556 OH I Cl OMe HH 557 OH I Cl H .cf3 H 558 OH I Cl H OH H 559 OH I Cl H OMe H 560 OH I Cl H Cl H 561 OH I .Cl H Cl Cl 562 OH I Cl H Br 'H 563 OH I Cl cf3 HH 564 OH I Cl ci OH H 565 OH Industrial Cl Br OH H 566 OH I Cl I OH H (Please read the notes on the back before filling this page) Reference -551-This paper size is applicable to China Standard (CNS) A4 specification (2I0X297 mm) A7 4 c 9 i® B7 — V. Description of the invention () ·

Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

Example # h £ s B £ F 567 Η Br Cl Br HH 568 Η Br Cl on H 11 569 Η Br Cl No. 2 HH 570 Η Br Cl IHH 571 Η Br Cl Cl HH 572 Η Br Cl Cl H Cl 573 Η Br ..Cl. OMe HH 574 Η, Br Cl H cf3 H 575 Η Br .Cl H OH H 576 Η Br Cl 'H, OMe H 577 Η Br .u 1 H Cl H 578 Η Br .Cl H + Cl Cl 579 Η 'Br Cl H Br H 580 Η Br Cl Cl OH H 581 Η. Br Cl Br OH H 5B2 Η Br Cl I OH H ---------- install-(Please read the note on the back first Matters need to be filled in this page) Ding 4ff -552- 'The paper scale is applicable to the Chinese national standard (CNS) A4 specification (2 [OX 297 mm) 4SS956 A7 .B7 550 · V. Description of the invention ()

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Example # h S. £ DEP 583 Η Br Br Br HH 584 Η Br Br OH H II 585 Η Br Br no2 HH 586 Η Br Br HH 587 Η Br Br Cl HH 588 Η Br Br Cl H Cl 589 Η Br BY. OMe HH 590 Η Br Br H cf3 H 591 Η Br Br »·. H OH H S92 Η Br V .. Br, H OMe H 593 Η Br Br, H, Cl H 594 Η Br .Br H Cl Cl 1 595 • Η. Br Br H Br. H 596 Η Br Br Cl OH H 597 Η. Br pr Br OH H 598 II Br Br I OH -H I --------- ^-(Please read the back first Note for refilling this page) Order lr thorn. -553 This paper music scale is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 458956 A7 B7 V. Description of invention (551

NH

'νη &quot; Ύ D

Β C Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

Example # A Β CDET 599 Η Br I Br H .H 600 Η Br .1 OH H 'H 601 Η Br I no2 HH 602 Η Br .IIHH 603 Η Br I. Cl HH 604 Η Br I Cl H Cl 605 Η Br I OMe HH 606 Η Br IH cf3 .H 607 Η Br HH OH H 608 Η Br HH OMe H 609 Br · H Cl H 6X0 Η Br I .H Cl Cl 611 Η .Br IH Br H 612 Η Br I Cl OH H 613 Η Br I Br OH H 614 Η Dr. _ x OH II -554- This paper size is based on China. House standard rate (CNS) A4 specification (2ί〇 × 297 mm) (Please read first Note on the back, fill in this page again) Pack. Order 458956 V. Description of the invention (552 A7 B7

NH

'NR'

D

Pat

C Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy

Example # A Β QEEP 615 II II ΒΓ "II II 616, Η II Oil 11 ii 617 Η IIN〇2 HH 6X8 Η IIIH H. 619 Η II Cl HH 620 Η II Cl H Cl 621 Η I: I OMe HH 622 Η Η IIH CF3. H 623 Η IIH OH H 624 VI VIH OMe H 625 Η IIH Cl H 626 Η II, H Cl Cl 627 Η IIH Br H 628 Η I. I Cl OH H 629 Η X, I Br OH H 630 Η工 II OH H ——. Outfit-., \ (Read the precautions on the back of the first cabinet and then fill in the page) Order -555- Applicable to Chinese National Standard (CNS) A4 size (2! 0X 29 7 mm) )

A7 __ ^ _ B7 V. Description of the Invention (553)

D C

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Example # AIC Β Ε Σ 631 Η C1 C1 Br Η H 632 Η C1 C1 OH 1 Bu II 633 Η C1 C1 Ν〇2 Η H 634 Η C1 C1 I Η H 635 Η C1 .C1 Cl Η H 636 Η C1 C1 Cl Η Cl 637 Η C1 C1 OMQ Η H 638 Η C1 C1 Η cf3 H 639 Η C1 C1 *, _ Η OH H 640 11 C1 V C1 Η OMe H 641 Η C1 C1 Η C 丄 H .642 Η C1 C1 Η Cl Cl 643 Η C1 C1. 'Η Br H 644 Η -C1 C1 C1 OH H 645 Η C1 C1 Br OH H 646 Η C1 C1 I' OH H '-556-. * This paper size applies to China National Standard (CNS) A4 size (210X 297mm) (Please read the precautions on the back before filling in this purchase)

458956 A7 B7 V. Description of the invention (554

C

B DuPont Printing

Example # h B c DEF 647, 丨 OH Cl Cl 'Br HH 648 OH Cl Cl on HH 649 OH Cl Cl No. 2 HH 650 OH Cl Cl IHH 651 OH Cl Cl Cl HH 652 OH Cl Cl Cl H Cl 653 OH Cl Cl OMe HH 654 OH Cl Cl H 'CF3 .H 655 OH Cl Cl H OH H 656 OH Cl Cl H OMe H 657 OH Cl, Cl H Cl H 658 OH Cl .Cl H' Cl Cl 659 OH Cl Cl H Br H 660 OH Cl Cl. Cl OH H 661 OH · # Cl Cl Br », OH H 662 Oil Cl Cl -I OH H -557- This paper size is applicable to China National Standard (CNS.) A4 specification (210X297 mm) (Please read the precautions on the back before filling in this page) Binding. Order A7 __ * _ B7 V. Invention Description (555).

Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

Example # h Ά £ Π E z 663 OH Br Cl -Br HH 664 OH Br '-Cl OH HH 665 OH Br Cl No. 2 HH 6 6 6 OH Br Cl IHH 667 OH Br Cl .Cl HH 668 OH Br Cl Cl H Cl 669 1 OH Br Cl OMe HH 670 OH Br Cl H cf3 H ¢ 71 OH Br Cl H OH H 672 on Dr Cl IE OMe H 673 OH Br Cl H Cl H 674 OH Br Cl H Cl Cl 675 OH Br Cl H Br H 676 OH-Br Cl Cl OH H 677 OH .Br cl Br OH H 678 OH Br Cl Engineering * OH H (Please read the precautions on the back before filling &quot; this page) Binding. Thread-558- this Paper size applies Chinese National Standard (CNS). A4 specification (2! 〇 X 297 mm) A7 1 4 Jian Na __B7 556 5. Description of the invention ()

Du printed by the Central Bureau of Standards, Ministry of Economic Affairs

# H B c D Ά F 679 OH I Cl Br HH 680 OH I Cl OH HH ^ 681 OH I Cl ^ no2 HH 682 OH Industrial Cl IHH 683 OH I Cl Cl HH 684 OH I Cl Cl H Cl 685 OH I Cl OMe HH 686 OH:, Cl · Cl H cf3 H 687 OH I Cl ... H OH H 688 on I Cl H OMe H 689 OH I Cl H Cl H 690 OH I. ^ Cl H Cl Cl 691 OH I. Cl H Br H 692 OH I Cl Cl OH H 693 OH X Cl Br OH H 694 OH I. Cl OH H I ----------- --- (Please read the precautions on the back before (Fill in this page) -s # · -559- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm j V. Description of invention (557

D Α7 Β7, ΝΗ ^ γ 〇.

C Β Printed by the Male Workers Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Example # A Denc DEP 695 Η Cl Cl Br HH 696 Η Cl Cl OH HH 697 Η Cl Cl No. 2 HH 698 Η Cl Cl HHH 699 Η Cl Cl Cl HH 700 Η Cl Cl Cl H Cl 701 Η-Cl * , C1 OMe HH 702 Η Cl Cl H cf3 H 7 03 Η Cl · Cl H OH H 7 04 II Cl Cl H OMe H 705 Η Cl. Cl H Cl H 706 Η Cl ^ Cl H Cl Cl 707 Η Cl Cl H Br H 708 Η Cl Cl Cl OH H 709 Η Cl Cl Br OH H 710 Η Cl Cl I OH H -560- This paper size applies to China National Standard (CNS) Α4 size (210 X 297 mm) (Please read the back first (Please note this page before filling in this page) Binding _ 458 956 A7 _ _B7 V. Description of the invention (558)

B Printed by the Consumers' Cooperative of Zhongli Standards Bureau, Ministry of Economic Affairs

Example # h &amp; su £ F 711 Η Br ai Br HH 712 Η Br Cl OH H ΊΙ 713 Η Br Cl No 2, HH 714 Η .Br Cl IHH 715 Η Br Cl Cl HH 716 Η Br Cl Cl H Cl 717 Η Br Cl OMe H, H 718 Η Br 1 Cl H cf3 H 719 Η Br .Cl H OH H 720 Η 1 Br Cl .. H OMe H 721 11 Br. Cl H Cl H 722 * Br Br Cl H Cl Cl 723 Η Br ^ Cl H Br H 7 24 Η Br Cl Cl OH H 7 25 Η Br Cl Br OH H 726 Η Br Cl I OH H (谙 Please read the notes on the back before filling this page) -pack. 、 V5 front ， -561-This paper size applies Chinese national standard (CNS〇A4 specification (210 X 297 mm) 4 58 9 56 A7, B7 V. Description of invention (559)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Example # A Β CD 'EF 727 Η Βγ Br Br HH 728 .Η. Br Br OH H. H 729 Η Br Br' no2 HH 730 Η 'Br Br HH 731 Η Br Br Cl H • H 732 Η Br Br G1 H Cl 733 Η Br Br OMe. HH 7 34 Η Br Br H cf3 H 735 Η Br Br H OH H 7 36 Η Br Dr H OMe H 737 Η Br Br H Cl H 738 Η Br Br H Cl Cl 739 Η Br Br H Br H 7Λ0 Η Br. Dr Cl OH II 741 »Η Br Br Br OH H 742 Η Br J Br I OH H I --------- pain-{Please read the precautions on the back first (Fill in this page) Order -562- This paper size applies to China National Standard (CNS) A4 (210X297 mm). 4 5.8 9 56 A7 B7

V. Description of the invention (56Q

D

B

C Printed by the Shellfish Consumer Cooperative of the Central Guiding Bureau of the Ministry of Economy

Example # A Β c &quot; 1 DEP 743 Η, Br I Br HH 744 Η Br I OH HH 7 45 Η-Br I '-no2 KH 746 Η Br IIHH 747 Η Br X Cl HH 7 48 Η Br I' Cl H Cl 749 Η Br I OMe HH 750 Η Br IH CF3 .H 751 Η Br Engineering, H OH H 752 π IH OMe H 753 Η Br IH Cl H 754 Η Br —IH Cl Cl 755 Η Br. Engineering H Br H 756 Br Br Industrial Cl OH H 757 Η 'Br ·. I Br OH H 758' Η Br II OH H -563- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (谙 Read the back first Note for refilling the road). Assembling-ordering line A7 B7 e; Aj V. Description of the invention ()

Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

Example # a Β 5. EEF 7 59 Η: I Br HH 760 ,, I OH HH 761 Η II no2 H. H 762 Η I .. IHH 763 Η II Cl. HH 764 Η II Cl H Cl 765. Η II OMe HH 7 66 Η IIH cf3 H 767 ΗIIH OH H 768 Η IIH OMe • H 769 Η I HCl H 770 Η I, IH Cl Cl 771 Η I, H Br H 772 Η II Cl OH H 773 Η II Br OH H 774 工 工 II Oil H —— Install-\ — (Please read the precautions on the back before wall meal page) 11 · &quot; Order-564- This paper size applies to Chinese National Standard (CNS) A4 specifications (2iOXW7 mm) A7 B7 V. Description of the invention (562)

D

C Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs # h £ 775 OH Cl 77 6 OH Cl ΊΊΊ OH Cl 778 OH Cl 779 OH Cl 780 OH Cl 781 OH Cl 782 OH Cl 7S3 OH • Cl 784 OH Cl 785 OH Cl 786 OH Cl 787 OH Cl 788 OH Cl 789 OH Cl 790 OH Cl

Q £ F Cl Br HH Cl on HH Cl no2 HH Cl IHH Cl Cl HH Cl Cl H Cl Cl 1 OMe HH Cl H cf3 H Cl H OH H Cl H. OMe H Cl H Cl H Cl H Cl Cl Cl H Br H Cl Cl OH H Cl Br OH H Cl I OH H 565-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) &lt; Please read the notes on the back before filling in this year's page). Equipment. 4 D y 〇6 A7 B7 V. Description of the invention (563)

Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

Award Example #, h 'B' CDEF 791 OH Br Cl Br HH 792 OH Br. Cl OH H · H 793 OH Br Cl no2 HH 794 OH Br Cl IHH 795 OH Br Cl Cl H. H 7 96 OH Br Cl Cl H Cl 797 OH Br Cl OMe HH 798 OH Br Cl H cf3 H 799 OH Br Cl H OH H 800 OH Br Cl. H OMe H 801 Oil Br Cl H Cl H 802 OH Br Cl. H Cl Cl 803 OH Br -Cl. 'H Br H 804 OH * Br Cl Cl OH H 805 OH • Br Cl. Br OH H 806 OH Br Cl I · OH H (#Read the precautions on the back before filling in the operation page).

mIT -566- This paper music scale is applicable to Chinese National Standard (CNS) A4 specification (210 XM7 mm) A7 B7 ’V. Description of invention (564)

Printed by the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs

Case # ABCDEF 807 OH I — Cl Br HH 808 1 OH I Cl OH HH 809 OH I Cl N〇2 HH 810 OH I Cl Worker H .1 H 811 OH I Cl Cl HH 812 OH I Cl Cl H Cl 813 OH I Cl OMe HH 814 OH I Cl H CF3 H 815 OH I -Cl H OH H 816 OH I Cl,. H OMe H 817 OH C1 Cl H Cl H 818 OH I Cl H Cl Cl 819 OH I .Cl H Br H 820 OH .1 Cl Cl OH H 821 OH Industrial Cl · Br 'OH H 822 OH' · Industrial Cl Industrial OH H I --------- # ------ IT ------ Itching {Please read the precautions on the back of the book before filling in this page) ... -567- This paper size applies the Chinese National Standard (CNS.) A4 (2 丨 OX297 mm) '4 5〇i: · ) b ^ ·· A7 B7 565 V. Description of the invention (

Printed by the Shellfish Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs

Example #. A B cp EF 823 Η C1 Cl Br HH 824 Η • ci .Cl HHH 825 Η Cl Cl no2 HH 826 Η Cl Cl. IHH 827 1 Η Cl Cl. Cl HH 828 Η Cl Cl Cl H Cl 829 Η Cl .Cl OMe HH 830 Η Cl * Cl H cf3 H 831 Η Cl, Cl H OH H 832 Η Cl Cl, · H OMe H 333 Η Cl Cl H Cl H 834 Η Cl Cl H Cl .Cl 835 Η cx -Cl H Br H 836 Η Cl Cl Cl OH H 837 Η Cl Cl Br OH H 838 Η Cl Cl I OH H (please read the precautions on the back before filling in the page). Binding · Order-568- This paper is a good size paper in China National Standard (CNS) A4 specification (210 X 297 mm) 4 4 V. Description of invention (566 A7 B7

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

A .1 CDEF 839 Η Br cl Br HH 840 Η Br Cl OH II H 841 Η Br Cl NO ^ HH 842 Br Br Cl IHH 843 Η Br Cl Cl HH 845 Η Br .-. Cl Cl H Cl 8-4 6 Η Br Cl OMe HH 847 Η Br. Cl H CF3 H 848, Η Br Cl H OH H 849 Η Br Cl ·. H OMe H 850 Η Br Cl H Cl H 851 Η Br cx H Cl Cl 852 Η Br r Cl H Br H 853 Η Br Cl Cl OH H 854 Η Br Cl Br OH H 855 Η Br Cl I OH H (Please read the notes on the back before filling in ^ 4.) Disgrace -569- This paper size applies to Chinese national standards ( CNS) A4 specification (210x297 mm) Ι'.ί · 413 3 9 56 A7 B7 V. Description of the invention (567)

D

C Example of printed work cooperation between the Central Standards Bureau of the Ministry of Economic Affairs # a Β 856 Η Br 857 Η Br 858 Η Br 859 Η Br 360 Η Br 861 Η Br 862 Η Br 863 Η Br 864 Η Br 865 1 Η Br 866 Η Br 867 Η Br 868 Η Br 869 Η Br 870 Η Br 871 Η Br

c DE .F Br Br HH Br OH HH Br no2 HH Br IHH Br Cl HH Br Cl H Cl Br OMe HH Br H cf3 H Br H OH H Br-. H OMe H Br H Cl H Br H Cl Cl Br H Br 1 H Br Cl OH H Br Br OH H Br Industrial OH H .570- The paper size is applicable to the national standard (CNS) A4 specification (2 [0X297 mm) I -------- seed coat- &lt; Please read the notes on the back before filling the If 'page) Order A7 Β7 V. Description of the invention (568).

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Example # δ, SCDE z 872 Η Br Br HH 87 3 Η · Br I OH II II 87 4 η Dr I no2 II H 875 Η Br 'Gong HH 876 Η Br I Cl HH 1 877 Η Br I Cl H Cl 8 78 Br Br I OMe HH 879 Η Br IH cf3 H 880 Η Br IH OH H 881 Η Br I. V H. OMe H 882 Η Br IH Cl H 883 Η Br IH Cl Cl 884 Η Br -Ϊ H Br H * 885 Η Br I Cl OH H 886 Η Br I Br OH H 887 Η Br II OH H 1 dish-two (please read the precautions on the back first and then fill in this page) -571-This paper size applies to Chinese national standards (CNS) A4 specifications (210X297 mm) &gt; ^ 4 F c ;: '^ r ^ A7 B7 V. Description of the invention (569)

Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

Example # A Β .CDEF 888 Η II Br HH 889 Η IX OH HH 890 Η I Engineering νο 2 HH 891 Η II .IHH 892 Η I &gt; 1 Cl HH 893 Η II Cl H • Cl C94 Η II OMe HH 895 Η IIH cf3 H 896 Η I HOH 897 Η IIH Glut: 11,898 Η IIH Cl H 899 Η IIH Cl Cl 900 Η .I, IH Br H 901-Η II Cl -OH H 902 Η II Br OH H 903 ^ Η III OH H ---------- i clothing—I .f: ... (Please read the precautions on the back before filling in the i ^ clothing page) -572-This paper size applies to Chinese national standards ( CNS) A4 specification (210X297 mm) 5. Description of invention (570

NH

D A7 B7

Economy • Printed by Deng Central Standards Bureau Staff Consumer Cooperative

Example β A B c DEF 904 Η cf3 Br, Br HH 905 Η: cf3 Br OH HH 906 Η cf3 Br no2 HH 907 Η cf3 Br IHH 90S Η cf3 Br .Cl HH 909 Η-cf3 Br Cl H Cl 910 Η cf3 Br OMe HH 911 Η cf3 Br H cf3 H 912 Η cf3 Br H OH H 913 Η cf3 Br * H OMe H 914 Η cf3 Br H Cl H 915 Η cf3, Br H Cl Cl 916 Η. Cf3-Br H Br H 917 Η cf3, · Br cf3 HH 918 Η cf3 Br HHH 919 Η cf3 Br Cl OH H 920 • Η cf3 Br Br OH H 921 Η cf3 Br I OH H -573- This paper is in accordance with China National Standard (CNS) A4 specification (210X297 (Mm) (Please read the precautions on the back before filling out the wooden page). Packing. Ordering-/ 1 ^ q ^ ^ Η '' Α7 Β7 571 V. Description of the invention ()

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Example # ά £ DEF 922 Η CF] Br Br HH 923 II cf3 Br OH H. JI 924 Η cf3 Br .no2 HH 925 Η, * cf3 Br I. HH 926 Η cf3 Br Cl HH 927 Η cf3 Br Cl H. Cl 928 Η cf3 Br, OMe HH 929 Η. Cf3 Br H1 cf3 H 930 Η • cf3 Br _ H OH, H 931 Η cf3 Br H OMe H 932 Η. Cf3 Br H Cl H 933 Η cf3 .Br H Cl Cl 934 Η cf3 Br H Br H 935 Η CF3 'Br cf3 HH 936 Η .cf3 Br HH .H 937 II cf3 • Dr Cl OR H 938 Η cf3 Br Br OH H 939 Η CF, Br I OH H (Please read the back first Note for re-filling kr this page)-binding. Order ♦ -574- This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 458 956 V. Description of the invention ()

Examples of goods printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs # a 940 Η 941 Η 942 Η 943 Η 944 Η 945 Η 946 Η 947 'Η 948 Η 949 Η. 950 Η 951 Η 952 Η 953 Η 954 Η 955 Η 956 Η Η 957 Η

Once DEF cf3 Br Br HH cf3 Br OH HH cf3 Br no2 HH cf3 1 Br IHH cf3 Br Cl HH cf3 Br Cl H Cl cf3 Br OM &quot; e HH cf3 Br H * cf3 H cf3 Br &lt; &gt; H OH H V · Br H OMe H cf3 Br H Cl H cf3 Br H Cl Cl cf3 Br H Br H CFj Br CF3. HH cf3 Br HHH cf3 Br Cl OH H cf3 Br Br OH H cf3 Br .1 OH H -575-Paper Dimensions are applicable to China National Standard (CNS) A4 (2 丨 〇 X 297 mm) I pack-(Please read the precautions on the back before filling in gray pages)

m1T 458956 A7 B7 V. Description of the invention (573) ''

NH

C Employees' cooperatives in the Central Standards Bureau of the Ministry of Economy

Example # h Β c. D, EF 958 Η _cf3 I Br HH 959 Η cf3 OH HH 960 Η. Cf3 I · no2 HH 961 Η CFj 工-工 HH 962 Η cf3 I Cl HH 963 Η C.F3 I Cl H Cl 964 Η cf3, OMe HH 965 Η cf3. HH, cf3 H 966 Η cf3 H H OH H 9 67 Η cf3 IH OMe H 968 Η cf3 I, H Cl H 969 Η cf3 XH Cl Cl 970 Η cf3 ^ IH Br .H 971 Η cf3 cf3 HH 972 Η cf3 * IHHH 973 Η cf3 I Cl OH H 9 74 Η cf3 I Br OH H 975 Η 'II OH H Xiang-(Please read the notes on the back before filling tW page)

.1T -576- The standard of this paper is Chinese national standard (CNS &gt; A4 now (2Ϊ × 297mm) 458 956 V. Description of the invention (574) A7 B7

Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

Example # h Β CDEF 976 Η cf3 I Br HH 977 Η cf3 I OH 11 H 97S Η cf3 3no2 HH 979 Η cf3 IIHH 980 Η cf3 I. Cl H. H 981 Η cf3 11 Cl H Cl 982 Η · cf3 OMe HH 983 Η cf3, I .H cf3 H 984 Η cf3 I 'H' OH H 985 Η cf3 I. H OMe H 906 'Η. Ci, IH Cl * H 987 Η CF3 I.' H Cl Cl 988 Η cf3 Ί H Br H 989 Η cf3 I cf3 H 'H 990 Η cf3 IHHH 991 Η cf3 Industrial Cl OH H S92 Η cf3 I Br OH H 993 Η cf3 I — I * OH H (Please read the notes on the back before filling (See 忒 1).

、 1T _-577- This paper size adopts China National Standard (CNS) A4 specification (210X 297 mm) 4 58 yse. Λ7 Β7 V. Description of the invention ()

Printed by the Central Ministry of Economic Affairs

.Example # A Βc DEF 994 Η cf3 I Br HH 995 Η cf3 / Engineering Oil HH 996 Η cf3 I no2 HH 997 Η cf3 I Engineering HH 998 Η cf3 Engineering. Cl H. H 999 Η cf3 Engineering Cl H Cl 1000 Η cf3 I OMe HH 1001 Η CF3 IIH cf3 H 1002 Η cf3 I * · Π OH H 1003 Η cf3. 工 H OMe H 1004 11 cf3 I II Cl 11 1005 Η cf3 ^ I .H Cl Cl 1006 Η 'cf3 -I , H Br H 1007 Η cf3 I cf3 HH 1008 Η cf3 IHHH 1009 Η cf3 .'I Cl OH H 1010 Η 'cf3 .I Br OH H 1011 Η cf3 * I OH H {Please read the precautions on the back first Fill ¾, private page). Binding-578- The standard of this paper is applicable to China National Standard (CNS) A4 (210X297. Mm) A7 B7 576 5. Description of the invention (The activity of the compound of the present invention is tested in the following analysis. The test results in the analysis are listed in Table 1 6

Vitronectin withered analysis material Human Vitronectin receptor (3) was purified from human placenta, as described previously [Pytela et al., Methods in Enzymology, 144: 475-489 (1987)]. Human Vitronectin line. Purified from fresh cold plasma, as previously described [Yatohgo et al., Cell Structure and Function, 13: 281-292 (1988)]. Biotinylated human Vitronectin is prepared by coupling NHS-biotin from Pierce Chemical Company (Rockford, IL) with purified Vitronectin, as previously described [Charo et al., J. Biol. Chem. 266 (3): 1415- 1421 (1991)]. Analytical buffers, OPD matrix tablets, and RIA grade BSA were obtained from Sigma (St. Louis, MO). Anti-biotin antibodies were obtained from Calbiochem (La Jolla, CA) = Linbro microtiter plates were obtained from Flow Labs (McLean, VA). A DP reagent was obtained from Sigma (St. Louis, MD). Methods Solid-phase receptor analysis-This analysis is essentially the same as the foregoing [Niiya et al., Blood, 70: 475-483 (1987).]. The purified human Vitronectin receptor (αν /? 3) was diluted to 1.0 μg / ml from the raw material solution in Tris buffered saline pH 7.4 (TBS ++) containing 1.0 mM Ca ++, Mg ++ and Mn +. The diluted receptor was immediately transferred to a Linbro microtiter plate at 100 μl / well (100 nanograms receptor / well). Plates were sealed &apos; at 4X: incubated overnight, allowing receptors to bind to wells. The remaining steps were performed at room temperature. The analysis board is empty, 200 microliters of 1% RIA-grade BSA at -579- 矣 paper rule and applicable Chinese Standard (CNS) A4g (2 [0X297 mm) ^-(Please read the precautions on the back before filling {¾This page) Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 56 56 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 Β7 V. Invention Description (577) TBS + + + Medium (TBS + + + / BSA) Add to mask exposed plastic surface. After 2 hours of incubation, the assay plates were washed with TBS ++, using a 96-well plate washer. The logarithmic serial dilution of the test compound and the control group starts with the raw material concentration of 2 'use 2nM biotinylated Vitronectin in TBS + + + / BSA1 as the diluent 3 and add the standard ligand to the test (or control) ligand premix And then 50 microliters of part was transferred to the analysis plate using a cetus Propette robot; the final concentration of the standard ligand was 丨 nM, and the highest concentration of the test compound was 1.0 X IO-4%. The competition took place over 2 hours, then each well was washed with a plate washer 'as previously described. Affinity purified horseradish peroxidase spiked goat avidin carcass was diluted to 1: 3000 in TBS + + / BSA, and 125 microliters were added to each well. After 30 minutes, the plates were washed &apos; and incubated with Opd / h202 substrate in 100 mM / liter citrate buffer ρ η 50. The plate was read with a microtiter plate reader at a wavelength of 450 nm, and when the maximum bound control well reached an absorbance of about 1.0 ('Final Green A45C) was analyzed for analysis. Data were analyzed using a macro written and EXCELTM spreadsheet program. For the two sets of concentration determinations, the mean, standard deviation, and% CV a average A4 Μ 値 for the four largest binding controls (without competition (B_ MAX) average normalization (normaiized). Normalization is performed-a four-parameter curve fit calculation (Rodbard et al., Int. Atomic Energy Agency, Vienna, pp 469 (1977)), Plot on a semi-logarithmic table to inhibit the maximum binding of 50% biotinylated Vitronectin and the calculated concentration corresponding to R2 (IC 50). Report the inhibitory effect of the compound at the maximum concentration tested greater than 50%: otherwise IC 5 〇 Reported at concentrations greater than the maximum tested. Β-[[2-[[5-[(Aminoiminomethyl) amino] -1-oxypentyl] amino-580- This paper size Applicable to China National Standard (CNS) Α4 specification (210 × 297 mm) (谙 Read the notes on the back before filling out this page) • Chen. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Α7 Β7 578 5. Description of the invention () 1-oxyethyl] amino] -3-pyridinepropionic acid [ USSN 08 / 375,338 'Example 1] is a potent av / S3 antagonist (10; 50 in the 3-10 nM range), included on each plate as a positive control. Purified Ilb / IIIa receptor Analytical material Human fibrinogen receptor (a II5y? 3) was purified from outdated platelets (Pytela, R ', Pierschbacher, MD Argraves, S., Suzuki, S., and Rouslahti, E. &quot; Arginine- Glycine-Aspartic acid adhesion receptors &quot;, Methods in Enzymology 144 (1987): 475-489.) Human Vitronectin is purified from fresh ice bunch plasma, such as Yatohgo, T ,, Izumi, M., Kashiwagi, H., and Hayashi , M., &quot; Novel Purification of vitronectin from human plasma by heparin affinity chromatography &quot;, Cell Structure and Function 13 (1988): 281-292. Biotinylated human Vitronectin is prepared by Pierce Chemical Company (Rockford, IL) NHS-Biotin coupled with purified Vitronectin, as described above (Charo, IF, Nannizzi, L., Phillips, DR, Hsu, MA, Scarborough , RM, &quot; Inhibition of fibrinogen binding to GP Ilb / IIIa by a GP Ilia PePtide, ^ L-Biol Chem. 266 (3) (1991): 1415-1421.) Analytical buffer, OPD matrix Ingots, and RIA grade BS A were obtained from Sigma (St. Louis, MO). Anti-biotin antibodies were obtained from calbiochem (La Jolla, CA). Linbro microtiter plates were obtained from Flow Labs (McLean, VA). ADP reagent was obtained from Sigma (St. Louis, MD). Method -581-Paper scale is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)-Hello. Order 579 :! β Α7 Β7 Central Ministry of Economic Affairs Printed by the Bureau of Standards Consumer Cooperatives 5. Description of Invention (Solid Phase Receptor Analysis This analysis is essentially the same as Niiya, K., Hodson, E., Bader, R ·, Byers-Ward, V. Koziol, JA, Plow, EF, and Ruggeri, ZM, &quot; Increased surface expression of the membrane glycoprotein Ilb / IIIa complex induced by platelet activation:

Relationships to the binding of fibrinogen and platelet aggregation &quot;, Blood 70 (1987): 475-483. Purified. Human Fibrinogen Receptor (a Iib y? 3) was diluted to 1.0 μg from the raw material solution in Tris buffered saline pH 7.4 (TBS + + +) containing 1.0 Ca ++, Mg + and Mn + +. / Ml. The diluted receptor was immediately transferred to a Linbro microtiter plate at 100 μl / well (100 nanograms receptor / well). The plate was sealed and incubated overnight at 4 ° C to allow receptor binding to the wells = the remaining steps were performed at room temperature. The analysis plate was emptied. 200 μl of 1% RIA Grade B SA was added to TBS + + + (TBS + + / / BSA) to cover the exposed plastic surface. After 2 hours of incubation, the assay plates were washed with TBS + + +. Logarithmic serial dilutions of the test compound and control group using a 96-well plate washer were started with a starting material concentration of 2 mM. 2 nM biotinylated Vitronectin was used in TBS +. + + / BSA as a diluent. The standard ligand is premixed with the test (or control) ligand and then 50 microliters are transferred to the analysis plate using a CETUS Propette robot; the final concentration of the standard ligand is 1 nM. The highest concentration was 1.0 X 1 (T 4 M. Competition took place for 2 hours, and then each well was washed with a plate washer, as previously described. Affinity purified horseradish peroxidase spiked goat anti-biotin antibody in TBS + + + / BSA was diluted to 1: 3000, and 125 microliters were added to each well. After 30 minutes, the plate was washed with 0 DD / Η 2 〇2 matrix at 100 mM / liter -582- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back before filling in the private page) • Image; Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 418 9 58 A7 B7 580 5. Description of the invention () Cultivated in citrate buffer pH 5.0. The plate was read with a microtiter plate reader at a wavelength of 450 nm. When the maximum binding control well reached about 1.0 absorbance, record the final green A 4 50 for analysis. ® data using a macro written and EXCELTM extended paper program (Spreadsheet program) Analysis = average, standard deviation, and% CV for the two groups of concentrations determined. A45 ° average for the two groups. Normalization for the four largest bound controls (without competitors) (B-MAX). Normalization was performed. A four-parameter curve fit algorithm [Rodbard et al ,, Int. Atomic Energy Agency, Vienna, pp 469 (1977)] is plotted on a semi-logarithmic table to suppress the maximum 50% biotinylated Vitronectin Combining and responding. The calculated concentration of R2 (IC 50) reports that the inhibitory effect of the compound at the maximum concentration tested is greater than 50%: otherwise IC5Q is reported at a concentration greater than the maximum concentration tested "[[5-[(amino group Aminofluorenyl) amino] · 1-oxypentyl] amino] -1-oxyethyl] amino] -3-pyridinepropionic acid [USSN 08 / 375,338, Example 1] is an effective αν / 53 antagonist (1 (: 50 in the range of 3-10 nM)) was included on each plate as a positive control. Analysis of human platelet-rich plasma 'A healthy aspirin-free supplier was selected by volunteers. Platelet-rich blood purple and ADP-induced platelet aggregation analysis such as Zucker, M.B., &quot; Pl atelet Aggregation Measured by the Photometric Method &quot;, Methods in Enzymology 169 (1989): 1 17-133. Using a standard venipuncture of a butterfly, 45 ml of whole blood can be drawn into a 60 ml syringe containing 5 ml of 3.8% trisodium citrate. After being thoroughly mixed in the injection capsule, anticoagulated whole blood was transferred into a 50 ml conical polyethylene tube. 3 blood-583-This paper size applies to China National Standard (CNS) A4 (210X297 mm) —---- ---- Install, — (Please read the note on the back before filling in this page)

•• Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of IT &gt; ίΗ4 68 9 ^ β Α7 _____ Β7 V. Description of the invention (581) ^ &quot; — ~~~:-Centrifuge at 200 Xg for 12 minutes at room temperature to Deposition of non-platelet cells. Platelet-rich plasma is transferred into polyethylene tubes and stored at room temperature until use. Blood platelet-less plasma was centrifuged from the remaining blood at 2000 x g for a second 5 minutes. Platelet counts are typically between 30,000 and 50,000 per microliter. Platelet-rich plasma (0.45 ml) was placed in a siliconized cuvette (cuveUes), stirred at 37 'c (1100 Γπι) for 1 minute' and then 50 microliters of previously diluted test compound was added. After 1 minute of mixing, 'aggregated It was initiated by the addition of 50 microliters of 200 μM ADP. Agglutination was recorded for 3 minutes in a payion dual-tank agglutination meter (Scientific, Buffalo, NY). A series of test compound dilutions were used to maximize The percentage of inhibition of the response (saline control 絚) determines the dose-response curve. For all compounds compared to the two groups, the concentration of 50% maximum inhibition (IC 50) is the largest test concentration with 50% or greater inhibition. Graphical calculation of the dose-response curve of the compound; otherwise, IC50 is reported at greater than the maximum test concentration. M 2 1 melanoma cell adhesion analysis This analysis involves α ν 3 dependent adhesion of human melanoma cells to human fibers. Fibrinogen coated plastic tissue culture dish. Fibrinogen is purified from human blood. Fibronectin and plasminogen are removed from the preparation. Samples were passed through gelatin-sepharose 4B and lysine-sepharose 4B resins respectively. Fibrinogen was diluted to 10 μg / ml in coating buffer (20 mM Tris-HCl, 150 mM NaCl, pH 7.4). 10 μl of diluted Fibrinogen was added to each well of a 96 # Immulon 2 microtiter plate (Dynatech; Chantilly, Va) and allowed to coat overnight at 4 ° C. The plate was coated with 1% BSA (Miles / Pentex; -584-) National Standard (CMS.) A4 grid (210 X 297 mm) ---------- like-- \ (Please read the notes on the back before filling in ^ / ^-pages) Order 458958 A7 __ B7 V. Description of the invention (582)-Kankakee (IL) in adhesion buffer (Hank balanced salt solution, Ca or Mg-free [HBSS--], 50 mM Hepes, 1 mg / ml BSA, pH 7.4) Block at 37 ° C for 1 hour. The M2 1 human melanoma cell line was provided by Dr. j. Smith, La Jolla Cancer Research Institute. The M2 1 cell line was added to the cell dissociation solution with HBSS-wash in a tissue culture flask (sigina ), And obtained by incubating at 37 ° C for 5 minutes. The harvested cells were subjected to an adhesion analysis buffer containing 200 &quot; M Mn ++ Washed 3 times. The cells were counted and suspended in an adhesion analysis buffer containing 200 # μ Mn ++ to a density of 2 × 10 6 / ml. M 2 1 cells were pre-incubated with ~ B3 antagonists for 30 minutes at room temperature. After pre-incubation, a solution containing a mixture of cells and antagonists was added to each well of the microtiter plate and combined at 37 ° C for 30 minutes. Printed by the staff of the Central Bureau of Standards, Ministry of Economic Affairs, Cooperative. After adhesion, the plate was gently washed three times with 200 μl of washing buffer (50 nl MTΓis-HCl, 150 mM NaCl, pH 7.4) using a large hole pipette tip. The plate was quickly blotted dry and 100 μl of cell lysis buffer (50 mM sodium acetate, pH 5.0, 0.5% Triton X-100, 0.3 mg / ml p-nitrobenzoic acid [Sigma]) was added to each well. The plate was incubated at 37 ° C for 60 minutes, and microliters of 1N NaOH was added to stop the reaction. Each well was read at 412 nM using an automatic plate reader. -585- This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 〇297297mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ^ 4 5 8 9 56 A 7 B7 V. Description of the invention (583)

.Table I 1 Example · AvB3 IC50 (nM) Engineering b / IIIa IC50 (nM) M21 Smoker_, Tumor Cell IC 50 fnM) y Human PRP (/ xM) 1 76.9 8350 &gt; 200 2 0.54 51,2 0.25 200 3 498 72900 3050 4 3.17 i 473 3,3 &gt; 200 5, 22 7 3150 6 1 * 04 15 * 9 80 8 0.69 9 * 83 0 * 28 73.3 10 0.92 54.4 1,82 &gt; 200 12 1.1 595 9 : 32 &gt; 200 14 1.62 139 5,42 &gt; 200 15 10.2 3830 202 &gt; 200 17 2.66 137 3,64 &gt; 200 19 303 72000 21 2.44 1910 &gt; 200 22 1.37 280 &gt; 200 24 0.91 58.6 12.7 &gt; 200 26 14 * 2 809 \ · &gt; 200 27 1.53 178 &gt; 200 30 1.75 424 320 &gt; 200 3Λ 9Λ · 3 269 &gt; 200 35 bV. 1 6.21 69. S 36_ Fly step JB 14,6 1580 143 &gt; 200 37 0 * 88 13.9 &gt; 20.0 39 12 * 2 1540 &gt; 20-0 40 10,3 834 &gt; 200 41 12,1 830 &gt; 200 42 124 9B00 43 28.3 αβ4〇188-&gt; 200 44 0,33 998 1 »'&gt; 20-0 45 0.69 39 * 5 2 * 54 t 167 -586- (Read the precautions on the back before filling in this page) This paper size applies Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) in the Ministry of Economic Affairs Sao Falcon Bureau employees consumer cooperatives India with ύ 5 H 9 ^ ^ A7 B7 V. invention is described in (584)

AvB3 IC50 (nM) b / IIIa IC50 (nM) • .M21 black. Tumor cell IC 50 (nM) human PHP 46 5,34 1680 147 &gt; 200 47 0.86 42 7 0 1-13 &gt; 200. 51 9730 &gt; 100000 52 3 · 62 139 11,7 &gt; 200 53 54.6 930 &gt; 200 54 10.7 175 &gt; 200 55 4.77 117 &gt; 200 56 3 * 12 65.3 * 6-37 &gt; 200 57 1340 15300 58 162 5740 59 2.35 172 24 * 3 &gt; 200 60 (B) 1.21 72 * 7 &gt; 200 60 (C) 0.73 16 * 4 0.74 &gt; 200 61 1,76 192 228 &gt; 200 62 1.42 28.4 &gt; 200 65 9.7 170 13.8 &gt; 200 66 1.44 73.7 2,51 &gt; 100 67 2 * 05 92.3 4.08 &gt; 200 68 5,48 125 &gt; 200 69 0.92 33.6 0.95 &gt; 200-70 63 3240 924 &gt; 200 71 * 20 * 4 202 1040 * ^ 1 &gt; 200 72 1 * 21 152 &gt; 200 80 9.49 4 * 35 30 82 334 353 '83 3,39 97 · 7 11 &gt; 200 84 2800 246 * 85 6.65 8; 07 86 8 * 79 246 &gt; 200 87 6.35 73 2-&gt; 200 88 8-44 945. 52..31 &gt; 200, (Please read the notes on the back before filling this page) Order __- 587- This paper size applies Chinese Bacteria Standard (⑽) A4 Lai (210x297)

A: 4 5β A7 B7 V. Description of the invention (585 _ I printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5 ′ 丨 ^ AVB3 IC50 CnM) lib / engineering workers a IC50 (nM) M21 melanoma cell IC 50 (nM),-: human PRP ί'μΜ) 89 1240 9B30 94 1.16 101 i &gt; 200 95 1-43 25.4 &gt; 200 96 1810 5400 97 26 * 9 1170 163 98 146 50 0 99 0,38 1.89 '0.49 57,5 100 8360 &gt; 100000 101 1680 65700 .103 16.6 19100 &gt; 20.0 106 0.79 3140 0.8.1 &gt; 200 107 6400 13700 103 25 * 2 487 0 &gt; 200 109 575 &gt; 100000 110 4.5 I860 * 177 &gt; 200 112 284 6340 113 27 6 100000 114 3-26 2940 200 &gt; 200 116 15500 &gt; 100000 117 · 60.1 20100 &gt; 200 119 3.61 11100 9σ. 4 &gt; 20-0 121 2840 &gt; 100000 122 0.79 420. -&gt; 20.0 123 11800 85500 124 22 31,7 &gt; 20 * 0 126 2.48 2010.,, '&gt; 200 127 0.51 461 1 &gt; 200 129 68.9 9460-&gt; 200 130 4 7 2690 &gt; 200 131 3.82 1760 &gt; 20.0- 135 50700 &gt; 100000 -588 scales are applicable to Chinese National Standards (210/297 mm) (Please read the notes on the back before filling out this page) 6 5 9 8 5 Λα

7 7 AB V. Description of the invention (586) Printed / Examples by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs: AVB3 IC50 (ηM) Ilb / IIIa IC50 (nM), M2I Black 1 Tumor Cell IC 50 (nM) Human PRP (μΜ ) '136 54 * 4 14200 &gt; 20,0 137 16 2 6500 &gt; 200 138 36 * 9 5820 &gt; 200 139 23.8 16100 &gt; 200 140 4590 &gt; 100000 141' 3 * 09 125 &gt; 200 143 6700 &gt; 100000 · 144 55.3 5030 &gt; 200 145 2 7 20 &gt; 100000 146 14.3 8 79 &gt; 200 150 5_74 631 &gt; 200 155 5.05 31.1 &gt; 200 158 10 · 1 547 160 25.6 10400 • 丨 162 4.62 1340 &gt; 200 166 13000 45900 163 2.29 269 171 .0.35 83.2 .173 0.5 17 * 4 175 '2.12 205 177 0.58 137 &gt; 20.0 179 2 knives 2 927 181 132 22800-183 1,58 258 185 1.47 166 187 1 · 31 264 189 4.03 1980 J.91 0.49 70.3 .1 &gt; 20.0 193 2.56 209 &gt; 20.0 195 1.09 98 198 114 37800 200 0,48 1100 &gt; 200 -589- {谙 Read the precautions on the back before filling in "| this Page) * π This paper size applies Chinese National Standard (CNS) A4 Grid (210X 297mm) 458956 V. Description of the invention (587) Awards ΛνΒ3 IC50 (ΠΜ) Industrial engineering b / IIIa IC50 (nM) Μ2Ι melanoma fine J ^ IC 50 _Human 1 PRP (μΜΓ 201 58 * 1 10300 , * 203 3-56 650 205 1.68 1240 206 78,5 22000 207 0.9 148 208 1,15 277 209 0.83 140 210 2 * 62 343, 211 0,47 607 212. 1.93 306 213 2.93 334 214 2.35 454 215 0.41 656 '216 1 326 217 * 7 4 * 8 78900 219 2.29 253 221 70.5 hi &gt; 200 222 2.02 112. &Gt; 200 223 4.36 293 * &gt; 200 224 0,71 25.9. 225 2.76 471 &gt; 20.0 226 7.07 2910 &gt; 200 227 14.1 2640 &gt; 200 228 3 * 36 583 &gt; 200 229 39.1 10600 231 2 * 99 424 232 19.1 12100 &gt; 200 233 3.31 64 7 &gt; 200 234 89 * 3 830 235 0.54 29 * 9 236 0.53 1250 237 0.57 1950 238 0.92 646 -590- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 659 854

7 7 AB V. Description of the invention (588) Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ^ 'Example AVB3 IC50 (ΠM) lib / Gonggong aH IC50 (nM) M21 melanoma cells 1C 50 (nM)' 1 Human 1 PRP Χμ ^ ί 239 0.83 ^ 673 240 49400 76400. 241 557 17200 242 2.28 533 243 0.35 23.6 244 17,6 4560 245 0.96 134 246 7 · 24 802 247 1,24 417 „1 * 248 12300 21000 249 5.31 244 ^ ^ 251 (B) 3.49 280 251 (C) 0.76 124 252 1.52 213 253 0.34 109 254; 6.5 6910 255 28.4 6050-256 0.58 22 257 49.2 4660 ··· V 259 0.81 86.7 260 0.74 65.3-261 6.47 4 710 262 1- 24 172 263 4 * 19 2760 264 2.18 574 265 6.19 706 266 0.77 1810 267 131 43900 268 0.67 7430 269 209 25400 270 5.51 9160 271 29.9 4610 272 893 8210, -591-This paper size applies to Chinese National Standard (CNS) A4 Choice (210X 297mm) v ^ n ^^^^ 1 1-{Please read the precautions on the back before filling out this page) -3 Central Standard of the Ministry of Economy 扃 Employee Consumer Cooperatives Co., Ltd .---- '' · 'Example + &gt; νΒ3 IC50 (nM) Ilb / IIIa IC50 (ΠΜ) M21 Black pain cells 1C buckle (nM) One by one "·-^. Human &gt; PRP (μΛ) 273 12,9 * 4160 k 274 31-1 21200. 275 6.98 1200 2 76 1.25 111 277 .1.41 198 .2 78 · 0 * 45 150 279 7 * 12 637 * * 281 4.16 11500 282 864 9 770 234 195 18400 285 229 3170 286 413 8090 ^ 287 49-7 41.1 288 8.62 1060 289 0.9 621 290 1 * 62 1020 * 291 1-24 37 * 4 292 3 · 55 337 294 17 3 1990 _ · 1, * 295 144 4560 296 404 9450 297 89.8 3920 298 252 5560 299 109 927 362 0.84 7260 363 2 * 12 509 3 64 3.58 223 365 16.9 8470 366 0-44 91.3 367 0.35 1540 (please read the notes on the back before filling in this page) A7 • B7,589, * V. Description of the invention ()-592-. This Paper size applies to China National Standard (CNS) A4 (210X297 mm) I-I -------.-M In m — I n —i--'^^ um I i' IT1 .1

Claims (1)

458956 Patent Application No. 118 Amendment of Patent Scope (July 1990) ABCD Gong Heyu "Spoken Chinese Seal 1 Patent Application Scope Compound 〇 ^ II fCH2Jp-C'-R Η RP. Ri Please read the precautions above or its pharmacologically acceptable salt, where A is Υΐ. —Ν Ν—R7 R5 R0 &gt; IT Central Bureau of Standards In the seal of the male labor consumer cooperative, 合作 1 is selected from N-R2, 0 and S; R2 is selected from Η; Cu alkyl group; cyano group; amine carbonyl group; Cw alkoxy group; alkyl group is optionally substituted with amine group; or R2 and R7 together form an amine-substituted triazolyl group; or R7 (when not bonded to R2) and R8 are each selected from Η; C 丨 -8 alkyl; benzyl; aniline; Cu Alkylcarbonyl; alkoxycarbonyl; phenoxy; phenyl; alkyl is optionally substituted with a substituent selected from the group consisting of: aryl, phenyl, pyridyl, benzimidazole, and fluorenyl; A plurality of substituents selected from the group consisting of: functional groups, fluorenyl groups; -s02R 'where Ri0 is phenyl and optionally substituted with Ci-6 alkyl groups; NR7 and R8 together form a 5-membered nitrogen-containing group Single ring; This paper size is in accordance with China National Standards (CNS) A4 (210X297) 458956 A8 B8 C8 D $ 6. The scope of patent application R5 is Η; or Α is Rs'.p. ) Wherein R9 and R: or Y2 in the formula is -S-R9 and -0_R9: or 6-membered heterocyclic ring containing a nitrogen and a sulfur R9 and R7 together is oxazole; and R5 and R7 are as defined above; or .Y2 (When Y2 is carbon) with 117_ to form a 5_7 member containing a nitrogen ring; or Α to form a 5 Ν-R2 Rs. Ν-R? Re Shijia Standard Bureau of the Ministry of Economic Affairs In the formula, R2 and R7 together form 5 or 6 members. The nitrogen-containing heterocyclic ring is selected from one or more selected from hydroxyl, C6 alkyl, or phenyl; and R8 is hydrogen; R 5 It is defined as above; or -2-This paper size uses the Chinese standard (CNS) A4 format (210X297 mm)-β (Please read the precautions on the back before filling this page) 458 956 ABCD 6. Scope of Patent Application Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, where z is ^ or more than one selected from the following: H; c] -6 alkyl; hydroxyl; phenyl; halogen; halogen C i Alkyl; azepine amino; carboxy derivative; trihaloacetamide; and A, where A is as defined above; V is selected from -N- (R6)-, wherein R6 is selected from fluorene and Cu alkyl; γ and z is each selected from the group consisting of hydrogen and Cu alkyl; η is 1; t is 0; P is 1; R · is X-R3, which is again 0, where; ^ is selected from hydrogen; alkyl; benzene C alkyl; Polyalkyl ethers; in the case of free acids, and their pharmaceutically acceptable salts; selected from argon; Cu alkyl; C! .6 polyamino alcohols; (^ 2-6 block groups; phenyl groups; Ci-6 carboxylic acids; Ci-6 alkyl-Cw carboxylic acid esters; jCi6 alkyl, '»specific alkyl groups; benzodifluorenyl groups; succinyl groups; thyl groups; cyclohexyl groups; amidinyl groups; imidino groups; Dioxanyl; Junlinyl; Betayl; Benzoxanyl .; Ct_6 alkyl is substituted with the following groups: hydroxy, benzenesulfonyl, hexamethylbenzyl, thiophenylsulfonate; Or more than one positional selectivity is the following group substitution: halogen, Ci_6 gauge, Ci_6 Alkyl, C 1-6 alkoxy, Benzyl, C 6-6 thio, thio, hydroxy, nitro, C! -6 alkoxycarbonyl ', hydroxycarbonyl-Cid alkoxy, carboxyl ! -6 alkoxy; Cu amine, amine, (: 1-6 alkanesulfonyl, fused phenyl; benzodioxoyl is substituted by Ci-6 alkoxy; benzofuranyl is hydroxyl And C! .6 alkoxy substitution; and pyridyl is halogen and (^ .6 alkyl substitution; and ___- 3- This paper size applies to Chinese national standards (CMS &gt; A4 specifications (210X297 mm) ( (Please read the notes on the back before filling this page) Order 458956 Bismuth C8 D8 VI. The scope of patent application R11 is Η »2. According to the compound in the first patent application park, where A is • u · ——R7 1 1. Rs R ° .., In the policy of the Central Government Bureau of the Ministry of Economic Affairs, the Consumer Cooperatives, Y1 is selected from N-R2, 0, and S; R2 is selected from pyrene, Ci.6, and ammonium. Oxinyl, alkyl is optionally amine-substituted; or R2 and R7 together form an amine-substituted triazolyl group; or R7 (when not connected with R2) and R8 are each selected from Η; Cu gauge group;, benzyl group; aniline group; Ci · 8 antialkyl group; Cn Oxophenylphenoxy; phenyl; tigeryl optionally substituted with a substituent selected from carboxyl 'phenyl, pyridyl, benzimidazole, fluorenyl, and phenyl selectivity is one or more Substituent substitution: sulfonyl 'sulfonyl; -S02R10, where R10 is phenyl, optionally substituted by C 丨 -6 alkyl; NR7 and R8 together form a 5-membered monocyclic ring containing nitrogen; R5 is Alas. 3. The compound according to item 2 of the applied patent garden, wherein V is -N (R6)-, wherein R6 is selected from H &amp; C1_6 alkyl; η is 1; t is 0; p is 1; 4-present Paper size: Chinese National Standard (CNS) 8 43 ^ (210X297 mm) (Please read the notes on the back before filling in this tile)-Order · I f 4 fc.o 9 5S B8 C8 _ D8 The patent application scope II is 0-R3. 4. The compound according to item 3 of the scope of patent application, which is selected from: (±) dots-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amine [Ethyl] ethyl ethyl] amino] ethyl ratio of 3-propionate; (±) Lu-[[2-[[[3-[(aminoiminomethyl) amino] phenyl]] Carbonyl] amine] amine] acetamyl] amine] ρ than bite-3-propanoic acid (±)-[[2-[[[3 _ [(aminoiminomethyl) amino] benzene] benzene []] Carbonyl] amino]. Ethyl ethyl] amino] ethyl phenylpropionate; (±) Lu-[[2-[[[3-[(aminoiminomethyl) amino] Phenyl] carbonyl] amino] ethenyl] amino] phenylpropanoic acid; (±) n-[[2-[[[3 _ [(aminoiminomethyl) amino] phenyl] carbonyl] Skin group] Ethyl group] Amine group] -I, 3 · Dioxole-5-propionate ethyl ester; (±) θ-[[2-[[[3-[(Amine group Iminomethyl) amino] phenyl] carbonyl] amino] ethyl] amino] -1,3-benzodioxo-5-propionic acid; (±) point-[[2- [[[3-[(Aminoiminomethyl) amino] fluoren-1-yl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3 -propionic acid ethyl ester; (±) / 3 -[[2-[[[[[Aminoiminomethyl) amino] fluoren-1-yl] carbonyl] amino] ethylfluorenyl] amino]- Pyridin-3-propionic acid; (Earth) yS-[[l-[[[[[[Amineimine'methyl) amino] phenyl] carbonyl] · amino] -cyclopropan-1- [Carbonyl] amino] pyridine-3 -propanoic acid; _ (±) square-[[2-[[[3-[[imino-[(phenylmethyl) amino] methyl] amino] amino ] Phenyl] carbonyl] amino] ethenyl] amino] pyridine · 3-propanoic acid; (±) Ling-[[2-[[[[[Aminoiminomethyl) amino]] Phenyl] carbonyl] ___—_- 5 -___ This paper is again suitable for China National Standards of Houses (CNS) 8 (4) (210XW7 public envy) Printed by the Central Standards Bureau of the Ministry of Economics® ί Industrial Consumer Cooperatives 4 5a 956 cl D8 VI. Scope of patent application * · Amine] Ethyl} amino] -3,5-dichlorophenylpropionic acid; 々S-[[2-[[[3-[[Imine (1-pyrrole Pyridyl) formamidine] amino] phenyl] carbonyl] amino] ethenyl] amino] -4-fluorynyl acid; S- [[2-[[[3-[(aminoimino (Methyl) amino] 2,5,6-trifluorophenyl] carbonyl] amino] ethanyl] amino] -4-pentynyl acid; '(±) / S-[[2-[[[[ 3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -3,5-bis (trifluoromethyl) phenylpropanoic acid; (±) / 9-[[2-[[[3-[(aminoiminomethyl Amine] phenyl] carbonyl] amino] ethenyl] amino] biphenyl] -4-propionic acid; (±) ling-[[2-[[[[ (Amino) amino] -5- (trifluoromethyl) phenyl] carbonyl] amino] ethylfluorenyl] amino] -3,5-bis (trifluoromethyl) phenylpropanoic acid; (±) stone _ [[2-[[[[[(Phenylmethyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ethylamidine] amino] pyridine-3-propionic acid .; (±) reed-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] furan-3-propionic acid Ethyl ester; (±)-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] furan-3-propane Acid; 3-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] glutaric acid; (±) 3- [[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl]]. Amino] methyl glutarate; (±) cold- [[2-[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] furan-2-propionic acid; this paper is in Chinese National Standard (CNS) Α4 (210 × 297 mm) (Please read the notes on the back first Then fill out this page) i &gt; Printed by ABCD, Central Labor Bureau, Ministry of Economic Affairs, Machining and Consumer Cooperatives 6. Scope of Patent Application (±) θ-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] phenyl] Carbonyl group] amine group] ethyl fluorenyl group] amine group] 荇 -2 ~ propionic acid; (earth) yS-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] carbonyl ] Amine] Ethylamido] Amino] thiophene-propionic acid methyl ester; 3 5-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino ] Ethyl ethyl] amino] -4-pentynyl ethyl ester; (±) Lu-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amine []] Ethyl ethyl] amine], β thiophene 3 ** propionic acid; (earth) 2- [3-[[2 · [[[3-[(aminoiminoamido)) amine ] Phenyl] carbonyl] amino] ethylfluorenyl] amino] -4-carboxybutyl] sulfofluorenyl] benzoic acid; (Earth) / 5-[[2-[[[[3 .- [(amino Iminomethyl) amino] phenyl] carbonyl] amino] ethanoyl] amino] ρcephen-2-propionic acid; (Earth) 2- [3-[[2-[[[[3- [(Amineimine T group) amino] phenyl] carbonyl] amino] ethylethyl] amino] -4-carboxybutyl] thio] methyl benzoate; (± :) 3-[[ 2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ethenyl] amine ] -4-[(4-methylphenyl) sulfonamido] amino] butanoic acid; (±) 3-[[2-[[[3-[(aminoiminomethyl) amino]] Phenyl] carbonyl] amino] ethylfluorenyl] amino] -5-[(4-methylphenyl) thio] pentanoic acid; (±) 3-[[2-[[[3-[(amine Iminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -5-[(4-methylphenyl) sulfonamido] pentanoic acid; 3S-[[2- [[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] amino] ethenyl] amino] -4- (phenylthio) 'butyric acid; 3S-[[ 2-[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amine (Please read the precautions on the reverse side before filling out this page) Γ ί C This paper applies Chinese national standard (CNS &gt; A4 Ligue (210 × 297 mm) A8 B8 C8 D8 4 〒, patent application scope] ethyl ethyl] amino] -4-pentynyl acid; 3R-[[2-[[[[ (Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethenyl] amino] -4-pentynyl acid; 2-[[2S-[[2-[[[[[ (Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -2- (carboxymethyl) ethyl] sulfonamido] benzoic acid; 2-[[2S -[[2-[[[3-[(Aminoiminomethyl) amino] benzene [Carbonyl] amino] amino] ethenyl] amino] -2- (carboxymethyl) ethyl] thio] benzoic acid; (±)-[[2-[[[3-[( Aminomethyl) amino] phenyl] carbonyl] methylamino] ethylfluorenyl] amino] pyridine-3 -propionic acid ethyl ester; (±) / 5-[[2-[[[3-[( Aminoiminomethyl) amino] phenyl] carbonyl] methylamino] ethylammonium] amino] pyridine-3-propionic acid; ./5- [[2-[[[3-[(amine Iminomethyl) amino] phenyl] carbonyl] amino] -1-.oxypropyl] amino] pyridine-3-propanoic acid ethyl ester; reed-[[2-[[[3- [(Aminoiminomethyl) amino] phenyl] carbonyl] amino] -1 -oxypropyl] amino] pyridine-3 -propionic acid; (±); 5-[[2- [ [[3-[(Aminoimidomethyl.amino) amino] -4-methylphenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3 -propionic acid; (±) / 3 -[[2-[[[[[Aminoiminomethyl) amino] methyl] phenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3-propionic acid; 3S- [[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethenyl] amino] -4 · hydroxybutyric acid; (Earth) point-[[ 2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] -2-hydroxyphenylpropanoic acid; -8- This paper is based on the Chinese national standard (CNS> A4 size (210X297 mm) (please read the precautions on the back before filling in this page)). 9 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs Range (±) / S-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -2-hydroxy-5 -Methylphenylpropionic acid ;. (±) 3-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -4-[(2-hydroxyethyl) amino] -4-oxybutanoic acid; 2-aminobenzoic acid 2S-[[2-[[[3-[(aminoiminomethyl)) amine [Phenyl] carbonyl] amino] ethyl] ethyl] amino] -3-carboxypropyl; linger-[[2-[[[3 _ [(aminoiminomethyl) amino] phenyl] phenyl] Carbonyl] amino] ethenyl] amino] -1., 4-benzodioxin (dioxin) -6-propionic acid; N-[[2-[[[3-[(aminoimino (Methyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] -Θ-alanine; (±) n-[[2-[[[3-[(aminoiminomethyl)) amino ] Phenyl] carbonyl] amino] ethylfluorenyl] amino] -phosphono-3-propanoic acid ethyl ester;. 々-[[2-[[[3-[(4,5-dihydrothiazole-2 -Yl) amino] phenyl] carbonyl Phenyl] amino] ethyl] ethyl] amino] pyridine-3-propanoic acid ethyl ester; N-[[2-[[[3-[[[(benzyl) amino] carbonyl] amino] phenyl ] Carbonyl] amine] ethylethyl] amino] -yS-alanine; 3-[[2-[[[3-[[[(phenylhydrazone) amino] carbonyl] amino] phenyl] carbonyl ] 'Amino] Ethyl] Amine] -propionic acid; Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, Masonry Consumer Cooperative (please read the precautions on the back before filling this page) (±) yS-[[2- [[[[[(Benzyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ethenyl] amino] pyridine-3-ampric acid; ling-[[2- [ [[3-[[[(aniline) carbonyl] amino] phenyl] carbonyl] amino] ethenyl] amino]; | pyridine 3 -ethyl propionate; ling-[[2-[[[[ 3- (Aminocarbonylamino) phenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3-ethyl propionate, trifluoroacetate; __- 9J; _ This paper size applies to China Standard (CNS_) ^ i specification (210X297 mm) &quot; * 458 956 B8 D8 VI. Application for patent scope Ling-[[2-[[[3- 以 [[(4-methylphenyl) sulfonyl]] Amine] carbonyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3-propanidine; call _ [[2- [[[3-[(aminothiomethyl ) Amino] phenyl] carbonyl] amino] ethynyl] amino] pyridine-3-ethyl propionate; ling-phenylmethyl) amino] carbonyl] amino] phenyl] carbonyl] amino] Acetyl] amino] phenylpropionic acid; ling · * [[2-[[[3-[[[[[((4- (Aminosulfonyl) benzyl] amino] carbonyl] amino] benzene] benzene []] Carbonyl] amino] ethenyl] amino] pyridine-3-propanoic acid; 'n-[[2-[[[3-[[[(3-pyridinylmethyl) amino] carbonyl] Amine] phenyl] carbonyl] amino] ethenyl] amino] pyridine-3-propionic acid; linger-[[2-[[[[[(2-carboxyethyl) amino]] carbonyl group ] Amino] benzyl] carbonyl] amino] ethenyl] amino] pyridine-3 -propionic acid; ./?-[[2-[[[3-[[[(2-phenylethyl] Amine] carbonyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3-propionic acid; cold-[[2 -_ [[[[[[[(1-fluorenyl Methyl] amino] carbonyl] amino] phenyl] carbonyl] amino] ethenyl] amino] pyridine-3-propanoic acid; ling-[[2-[[[[[cyano Amine) methylamino] methyl] amino] phenyl] carbonyl] amino] ethylethyl] amino] phenylphenyl phenylpropionate; printed by Yinyang 榡 Associate Bureau of the Ministry of Economic Affairs, employee consumer cooperative (read first on the back) Note $ item is to be completed on this page) LING-[[2-[[[3-[[(cyano Amine (amino) fluorenyl] amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] benzyl phenylpropionate; Lu-[[2-[[[3-[[(cyano Imino) (ethylamino) methyl] amino] phenyl] carbonyl] amino] ethylethyl] amino] phenylpropionate; / 3-[[2-[[[[3 _ [[( Cyanoimino) [(benzidine) amino] methyl] amino] phenyl] carbonyl] amino] ethenyl] amino] phenylpropionic acid; -10-this paper uses China National Standards (CNS &gt; Λ4 see 丨 prepared (210X297)) Ministry of Health Central Bureau of Standards! Industrial and Consumer Cooperatives Cooperative Policy ^ 4 5 8 9 56 as Βδ C8 _ D8 VI. Application for Patent Range- [ί2-[[[3-[[(cyanoimino) (methylamino)) methyl; [amine [Phenyl] carbonyl] amino] ethyl] ethyl] amino] phenylpropionic acid;-[[2-[[[3-[[amino (cyanoimino) methyl] amino] benzene []] Carbonyl] amino] ethenyl] amino] phenylpropionic acid; ling _ [[2-[[[[[cyanoimino) (ethylamino) methyl] amino] benzene Phenyl] acyl] amino] ethyl] ethyl] amino] phenylpropionic acid; 3S-[[2-[[[3-[[(cyanoimino) (methylamino;) methyl] amino ] Phenyl] carbonyl] amino] ethylfluorenyl] amino] -4-pentynyl ethyl ester; -3S-[[2 _ [[[3-[[(cyanoimino)) (methylamino) Methyl] amino] benzyl] carbonyl] amino] ethenyl] amino] pentynyl acid; aminoimino) [2-pyridylmethyl] amino] methyl] amino] phenyl Carbonyl] amino] ethyl] ethyl] amino] phenylpropionate; .- [[2-[[[3-[[(cyanoimino)] [2-pyridylmethyl] amino ] Methyl] amino] phenyl] carbonyl] amino] ethenyl] amino] phenylpropionic acid;-[[2-[[[3-[[(cyanoimino)] [3-pyridine Methyl] amino] methyl] amino] benzene [] [] [Amino] ethyl] ethyl] amino] phenylpropionate ethyl acetate;-[[2-[[[3-[[(cyanoimino)] [3-pyridylmethyl] amino ] Methyl] amino] phenyl] phenyl] amine] ethyl] ethenyl] amino] benzene.propionic acid; / S-[[2-[[[4-chloro-3-[[[[(l , L-dimethylethoxy) carbonyl] amino] [[(1,1-dimethylethoxy) carbonyl] imino] methyl] amino] phenyl] carbonyl] amino] ethyl Fluorenyl] amino] ethyl phenylpropionate; ling-[[2-[[[[[amino [iminoimidomethyl] amino]]-4-chlorophenyl) carbonyl] amino] ethyl Fluorenyl] amino] phenylpropionic acid; ling-[[2-[[[[[amino] iminomethyl) amino] -2-aminophenyl) carbonyl-11-used on this paper scale China National Standards (CNS) A4 Specification (210 &gt; &lt; 297 public epidemic 7 (please read the precautions on the back before filling out this page) Order: 9 4 58 9 56 is8 C8 D8 VI. Application for Patent Scope Base] Amine] Ethylamido] amino] phenylpropionic acid; 3S-[[2-[[[3-[[[[(((4- (Aminosulfonyl) benzyl) benzyl) amino)] Amino) methyl] amino] phenyl] carbonyl] amino] ethanyl] amino] -4-pentynyl acid; call-[[2-[[[3-[[amino (aminocarbonyl) Imino] methyl] amino] phenyl] carbonyl ] Amine] ethylammonium] amino] -3,5 -dichloro-phenylpropanoic acid ethyl ester; ling- [U-[[[3-[[amino (aminocarbonyl) imino] methyl] methyl] Amine] phenyl] carbonyl] amino] ethenyl] amino] -3,5-dichlorophenylpropionic acid; 3,5-dichloro- / 5-[[2-[[[3- [ [[(Ethoxycarbonyl) amino] [(ethoxycarbonyl) imine] methyl] amino] phenyl] carbonyl] amino] ethoxy] amino] phenylpropionic acid;-[ [2-[[[[[[Aminoiminomethyl) amino] -4-aminophenyl] carbonyl, yl] amino] ethylfluorenyl] amino] -3,5-dichlorobenzene Ethyl propionate; Lu-[[2 _ [[[[[[Aminoiminomethyl) amino] -4-chlorophenyl] carbonyl] amino] ethylammonium] amino] -3, 5-dichlorophenylpropionic acid; 3S-[[2-[[[3-[[amino [(aminocarbonyl) imino] methyl] amino] phenyl] carbonyl] amino] ethyl} ] Aminyl 4-pentanoic acid ethyl ester; Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs {Please read the “Notes on the back before filling this page”) 3S-[[2-[[[[ Amino [(aminocarbonyl) imino] fluorenyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -4-pentynyl acid; 3S-[[2-[[[3 -[(Aminoiminomethyl) amino] -4 -chlorophenyl] carbonyl] amino] ethyl Acid group] amino] -4-pentanoic acid ethyl alcohol; 3S-[[[[[[3 · [(aminoiminomethyl) amino] -4-chlorophenyl] carbonyl group] Amine] Ethyl] amino] -4-pentynyl acid; (±) month-[[2-[[[3 _ [(aminoiminomethyl) amino] phenyl] carbonyl] -12] -This paper uses China National Standards (CNS &gt; A4 size (210X297mm) 6 5 9 CD 5 4 ABCD 6. Application scope of patents • Amine] Ethyl]] Amine] -3, 4_ Dichlorophenylpropionic acid; (±) / 9-[[2-[[[[[[Aminoiminomethyl) amino] -5- (trifluoromethyl) benzyl] carbonyl] amino ] Ethylammonyl] amino] -3,5-dichlorophenylpropionic acid; (±) cold-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] ] Amino] Ethyl] 'amino] -2,5-dimethylphenylpropanoic acid; (Earth) / 5-[[2-[[[3-[(Aminoiminomethyl)) amine [Phenyl] carbonyl] amino] ethyl] ethyl] amino] -3 -chlorophenylpropanoic acid ethyl ester; (±); 3-[[2-[[[3-[(aminoiminoimidomethyl) (Amino) amino] phenyl] carbonyl] amino] ethenyl] amino] -3 -bromophenylpropionate; (earth) point-[[2-[[[3-[(aminoimine Methyl) amino] phenyl] carbonyl] amino] ethyl] amino] -3-bromophenylpropanoic acid; ±) Ling-[[2-[[[[[Amineiminomethyl) amino] phenyl] carbonyl] .Amine] Ethylamido] Amino] -4-bromophenylpropanoate Esters; (±) Lu-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -4-bromophenylpropyl Acid; (±) fluorene-[[2, [[[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylethyl] amino] -3,5 -di Methionine .; Agricultural Printing Policy of Employees' Cooperative Cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Aminomethyl) amino] phenyl] carbonyl] amino] ethyl] amino] -3,5-dimethoxyphenylpropionic acid; (±) / 3-[[2-[[[3 -[(Aminoiminomethyl) amino] phenyl] carbonyl]. Amine] Ethyl] Amine] -3,5-dichlorophenylpropionic acid (2,2-dimethyl-bu Oxypropoxy) formamidine; (±) 3,5-dichloro- ling-[[2-[[[3-[(cyanoimino) (methylamino) methyl] amino] benzene Carbonyl] amino] ethyl] ethyl] amino] phenylpropanoic acid; ___ -13 -___ This paper size applies to China ’s family ladder f (CNS) A4 specification (210X297 public envy) ^ ABCD ^ 45 ^ 956 Apply for patent ) Ling-[[2-[[[[[(Aminocarbonyl) imine] methylamino] methyl]. Amine] phenyl] carbonyl] amino] ethylammonium] amino] -3,5-digas phenylpropionic acid; (±) ling-[[2-[[[[[[[Aminothiomethyl] amino] phenyl] carbonyl] amino] ethanyl] amine] amine Phenyl] -3,5-dichlorophenylpropionic acid; (±) cold-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] acetamidine [Amino] amino] -3,4-dibromophenylpropanoic acid; (±) fluorene-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino ] .Hexanoic acid] amino] -3-fluoro-5- (trifluoromethyl) benzenedicarboxylic acid; <±) / 3-[[2-[[[3-[(aminoiminomethyl ) Amine] phenyl] carbonyl] Amine] Ethyl] Amino] -3 -A-5-fluorophenylpropionic acid; (±) 々-[[2-[[[3-[(Amine group Aminomethyl) amino] phenyl] carbonyl] amino] ethoxy] amino] -3,5-dibromophenylpropanoic acid;. (±) / 5-[[2-[[[3- [(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -3-bromo-5-methylphenylpropanoic acid; (soil) Lu-[[2- [[[3-[(Aminoiminomethyl) amino] _5- (trifluoromethyl) phenyl] carbonyl] amino] ethylfluorenyl] amino] -3,5-dibromophenylpropyl Acid; (±) cold-[[2-[[[3-[( Iminomethyl) amino] phenyl] carbonyl]. Amino] ethylammonium] amino] -2 -hydroxy-4-methoxyphenylpropanoic acid; (±) point-[[2- [ [[3-[(Aminoiminomethyl) amino] phenyl] carbonyl; | Amine] Ethylamido] Amine] -5 -hydroxy-4-methoxybenzofuran-6-propyl Acid; (±) /?-[[2-[[[[[[Aminoiminomethylyamine] phenyl] carbonyl] -a; -amino] ethylammonium] amino] -9H -No. 2-propionic acid; _ (±) /?-[[2-[[[3-[(Aminoiminomethyl) amino] phenyl; | carbonyl] ___- 14-paper size CNS Standard A4 (210 father and 297) (please note the $ item on the back of Min Ji before filling out this page) Order -9. Cooperate with the shellfish consumer of the Central Government Bureau of the Ministry of Economic Affairs, approved for printing 958 958 Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperative, A8 B8 C8 D8 7. Application for patents Amino] Ethyl} Amine] _3,5-dichloro-2-hydroxyphenylpropionic acid; (± ) Lu-[[2-[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] amino] -2 -Ethyl-5-nitro Phenylpropionic acid; (±) cold-[[2-[[[[[aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl alcohol] Amine] -3,5-dibromo-2-merylphenylpropanoic acid; (±) Ling-[[2-[[[3 · [(Amineiminomethyl) amino] phenyl] carbonyl] carbonyl ] Amine] Ethylamine] Amine] -5 -Amo-2-Epiphenylphenylpropionic acid; (±) cold-[[2-[[[3-[(Aminoiminomethyl)) amino ] Phenyl] carbonyl] monoamino] ethylfluorenyl] amino] -cyclo & alkanoic acid; (±)-[[2-[[[3-[(aminoiminomethyl)) amino ] Phenyl] carbonyl] Amino] Ethyl] Amino] -3,5 -digas-2-acrylic acid ethyl acetate; (±) β-[[2-[[[3-[( Aminoiminomethyl) amino] phenyl] carbonyl] .Amine] Ethylamido] Amino] -5 · Ga-2-Hydroxyphenylpropionic acid; (±))-[[2-[[ [3-[(Aminoiminomethyl) amino] .Phenyl] carbonyl] Amine] Ethylamido] Amino] -3 -bromo-5-chloro-2-hydroxyphenylpropanoic acid .; ( ±) 5-Amino-fluorene-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethoxy] amino] -2-hydroxy Phenylpropionic acid; (±) y3-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -5 -bromo -Pyridine-3-propionic acid;. (±) 3,5-digas- / 3-[[2-[[[3-[[[((ethoxycarbonyl) amino] thiomethyl] amino]] Phenyl] carbonyl] amino] ethyl] Phenyl] -phenylpropionic acid;. 3,5-dichloro- Ling-[[2-[[[[[(ethoxycarbonyl) amino] iminomethyl] _ / amino] phenyl]] Carbonyl] amino] ethenyl] amino] phenylpropanoic acid; '--[[2-[[[[. 3 _ [(aminoiminomethyl) amino] phenyl] carbonyl] amine-15- '' The size of the paper method is applicable to the Chinese National Standard (CNS) A4 (210X297 male *) ---------— (Please read the precautions on the back before filling this page) Order 9. 8 5 9 Printed by ABiCD Ministry of Economic Affairs, Central Bureau of Standards and Quarantine, Shellfish Consumer Cooperatives 6. Scope of Patent Application] Ethyl] Amine] [1,1_ -biphenyl] -3 -propionic acid; no-[[2-[[ [3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] amino] pyrimidine-5 -propionic acid; ling-[[2-[[[3- [ (Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethoxy] amino] -3 -methylp-phene-2-propionic acid; (±) fluorene-[[2- [[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylethyl] amino] ~ 3- (methylthiophenylpropionic acid; (±) ubi-[[ 2-[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] -6-methyl-pyridine-2-propionic acid; ^- [[2-[[[3 · [(Amine Iminomethyl) amino] phenyl] carbonyl] amino] ethynyl] amino] -3-'(methylamino) -phenylpropionic acid; ling-[[2-[[[3- [(Aminoiminomethyl) amino] phenyl] carbonyl] amine, group] ethylfluorenyl] amino] -3,5-diethoxy-phenylpropionic acid; V (±) cold- [ [2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] -4-bromop-phene-2-propionic acid; cold -[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -5 -airthiophene-2 -propionic acid ;. Ling-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethynyl] amino] '-ΙΗ-ρ 比 Jun-3-two Acid; ling-[[2-[[[[[aminoiminomethyl) amino] phenyl] carbonyl] amino] ethoxy] amino] -5 -methylthiophene-2 -Adipic acid; / S-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amine mono-yl] ethenyl] amino] -2,3 , 5-trichloro-phenylpropionic acid; cold-[[2-[[[. 3-[(aminoiminomethyl) amino] phenyl] carbonyl] amine __- 16- This paper size 逋Adopt Chinese National Standard (CNS) Ad Grid (210X297 public address) (Please read the precautions on the back before filling this page ), Π Printed by the Ministry of Economic Affairs and the Central Bureau of Labor and Consumer Cooperatives &gt; · ν '_ A 〇 D8 VI. Application for patent scope «· Base] Ethyl] Amine] -2- (Carboxymethoxy)- Phenylpropanoic acid;-[[2-[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethenyl] amino group> 4-methoxy- 1,3-Benzodioxo-6-propionic acid .; Ling-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl} ] Amino] -5-bromo-2-methoxyphenylpropanoic acid; dot-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] Acetyl] amino] benzofuran-2-propionic acid; Lu-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] 'ethyl Fluorenyl] amino] -3- (carboxymethoxy) -phenylpropanoic acid; 3-[[2-[[[3-ί (aminoiminomethyl) amino] phenyl] carbonyl] amine [Ethyl] ethenyl] amino.]-4,4,4-trifluorobutanoic acid;. (±) 0-[[2-[[[3-[(aminoiminomethyl) amino] Phenyl] carbonyl] .amino] ethylammonium] amino] -3-bromo-4,5-dimethoxyphenylpropanoic acid; 3-[[2-[[[3-[(aminoimine Methyl) amino] phenyl] carbonyl] amino] ethynyl] amino] -4-methylvaleric acid; [2-[[[ 3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -pentanoic acid; stone-[[2 _ [[[3-[(aminoimine Methyl) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] -5_bromo-3-chloro-2-hydroxy-phenylpropanoic acid ·; cold-[[2-[[[3_ [[[(4-Pyridinylmethyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3-propionic acid; 3,5-dichloro-z- [[2-[[[[[[(4-Pyridinylmethyl) amino] carbonyl] -amino] phenyl] carbonyl] amino] ethenyl] amino] -phenylpropionic acid; 彡-[[2 _ [[[[[[2-Pyridylmethyl) amino] carbonyl] amino] benzene ___- 17 -___ This paper size is applicable to China National Standard (CNS) A4 specifications ( 210X297 mm) &quot; (Please read the notes on the back before filling in this S ·.) The consumption cooperation of employees of the Central Bureau of Standards of the Ministry of Economic Affairs in the printing f '' &gt; 45d 956 Shao C8 D8 VI. Patent application scope base] carbonyl] amino group] ethylfluorenyl group] amino] pyridine-3-propionic acid; 3, 5-Dichloro-Ling-[[2-[[[[[(Benzyl) amino] amido] amino] phenyl] phenyl] carbonyl] amino] ethylamido] amino] phenylpropyl Acid; 3-chloro-fluorene-[[2-[[[[[(benzyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ethylammonium] amino] phenylpropyl Acid; Lu-[[2-[[[3-[[[(phenylphenylethyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3- Propionic acid; ling-[[2-[[[3-[[[[(1Η-benzimidazol-2-yl) methyl] amino] carbonyl] amino] phenyl] carbonyl] amine}] acetamidine [Amino] amino] -3,5-digas phenylpropanoic acid; #-[[2-[[[[[[[[[(3,5-Dichlorophenyl) methyl] amino] carbonyl] amine] Phenyl] phenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3-propionic acid;: 3-[[2-[[[3-[[[[[(3.5-Dichlorophenyl)) Methyl] amino] carbonyl] amino] phenyl] carbonyl] amino] ethoxy] amino] butanoic acid; dot-[[2-[[[3-[(aminoiminomethyl)) Amine] phenyl] carbonyl] amino] ethenyl] amino] -3,5 · -bis (1-methyl-ethoxy) phenylpropyl ; Point-[[2-[[[3-[(aminoiminomethyl) amino]; | phenyl] carbonyl] amino] ethenyl] amino;! -3,5-dibromo- 4-hydroxyphenylpropionic acid; β-[[2-[[[[[Aminoiminomethyl) amino] _2-hydroxyphenyl] carbonyl] amino] ethenyl] amino]- 3,5-dichloro-phenylpropionic acid; Lu-[[2_ [[[[[[[(phenoxyamino) carbonyl] amino] phenyl] carbonyl] amino] ethoxy]] ·] 0 specific attack-3-propionic acid; lingering-[[2-[[[[(aniline) amino] carbonyl] amino] phenyl] carbonyl;] amino] ethylamyl] Amine] pyridine-3 · propionic acid; -18-This paper size is in accordance with China Standards (CNS) Α4 grid (210X297 mm) (please read the precautions on the back before filling out this page) Order economy Printed by the Consumer Affairs Cooperative of the Central Government Bureau ^ 458 95S 7T, patent application scope ling-[[2-[[[3-[(5-Amine group · 1,2,4-triazol-3-yl). Amine] phenyl] .Carbonyl] Amino] Ethylamine] Amino] -3,5-dichloro-phenylpropanoic acid; -3-[[2-[[[3-[[(Amine Aminomethyl) amino] phenyl] carbonyl] amino] ethoxy] amino] -5-[(3,5-dichloro-phenyl) amino] -5-oxypentanoic acid ;. Point _ [[2-[[[3-[[(Amineimine Aminyl) amino] -5-carboxyphenyl] carbonyl] amino] ethoxy] amino] pyridine-3-propionic acid; ling-[[2-[[[3,5-bis [(amino group Aminomethyl) amino] phenyl; Icarbonyl] Amine] Ethyl] amino] -3,5-dichloro-phenylpropanoic acid; Cold-[[2-[[[3-[(Amine Iminomethyl) amino] -5- (trifluoroethylfluorenyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -3,5-dichlorophenylpropionic acid; (±) 3,5-Dichloro-Ling-[[2-[[[[[(Methylamino) (methylimino) methyl] amino] phenyl] carbonyl] amino] hexane] [] Amino] phenylpropionic acid; (±) 3,5-dichlorochloro-[[2-[[[3-[[(ethylamino) (methylimino) methyl] amino] phenyl] phenyl ] Carbonyl] amino] ethanyl] amino] phenylpropanoic acid; (±) 3,5 · dichloro- / 5-[[2-[[[3-[[[(bumethylethyl) amino]] (Methylimino) methyl] amino] phenyl] carbonyl] amino] ethenyl] amino] phenylpropionic acid; (±) zhao-[[2-[[[3-[[(ethylamine () (Methylimino) methyl] amino] phenyl] carbonyl] amino] ethylethyl] amino] -4-fluorophenylpropanoic acid; _ (±) 4 · fluoro-point-[[2 -[[[3-[[[(1-methylethyl) amino] (methylimino) methyl] amino] phenyl] carbonyl] amino] ethenyl] amino] phenylpropyl ·;. -19- This paper is not used in a good way. 囷 ® Home Kneading Standard (CNS) Eighty-four Road (210X297 male *) (Please read the precautions on the back before filling this page) Order 0 5 9 8 5 4 ABCD points, patent application scope (±) 4-fluoro- &quot;-[[2-[[[[[((4-pyridylmethyl) amino]] (methylidene) T-based] amine [Phenyl] carbonyl] amino] ethyl] ethyl] amino] phenylpropionic acid; cold-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] Amine] Ethyl] amino] -4 -fluorophenylpropionic acid; (±) cold-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] Amine] Ethylamido] amino] -1H-imidazole-2-propanoic acid; Cold-[[2-[[[3-[(Amineimidoamido) amino] phenyl] carbonyl] min [Ethyl] ethenyl] amino] -2,3, 5,6-xifluorobenzoic acid; ling-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] phenyl] Carbonyl] amino] ethylammonyl] amino] -5 -bromothiophene-2 -propane.acid; .ling-[[2-[[[[[aminoiminomethyl) amino] benzene] benzene Phenyl] carbonyl] amine. Phenyl] ethyl] amino] -2-phenylphenylpropionic acid; (±) / 5-[[2-[[[3-[(aminoiminomethyl)) amine Phenyl] phenyl] carbonyl] amino] ethylfluorenyl] amino] -5-chloro-2-fluorenylphenylpropyl . 5. The compound according to item 3 of the scope of patent application, wherein Y1 is N-R2 and R2 is cyano. Printed by the Central Standards Bureau, Ministry of Economic Affairs, shoulder worker consumer cooperative (please read the precautions on the back before filling out this page) 6. The compound according to item 5 of the scope of patent application, wherein the compound is selected from: LING-[[2-[[ [3-[[(Cyanoimino) Tamino] methyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] benzyl phenylpropionate; / 5-[[2 -[[[[3 · [[(Cyanoimino (amino) methyl] amino] phenyl] __ carbonyl] amino] ethyl}] amino] benzyl phenylpropionate; ling- [ U-[[[[[(cyanoimino) [(benzyl) amino] methyl] amine] 20-This paper is standard for China National Standard (CNS) A4 (210X297 mm) ) Printed by the Consumers' Cooperative of the Ministry of Common Carnations, 4-Central Bureau of the Central Government, V Small 4 58 9 56 A8 B8 C8 ___D8 VI. Application for Patent Range Base] Phenyl] carbonyl] Amine] Ethylamido] Amine] Phenylpropionic ; Dot-[[2 _ [[[3-[[(Cyanoimino) (methylamino) formamidine] amino] phenyl] zoyl] amino] ethylamido] amino] phenylpropanoic acid LING-[[2-[[[[[Amine (cyanoimino) methyl] amino] phenyl] carbonyl] amino] ethylethyl] amino] phenylpropionic acid; cold- [[2-[[[3-[[(Cyanoimino) Ethylamino) methyl] amino] benzene.yl] carbonyl] amino] ethylfluorenyl] amino] phenylpropionic acid; 3S-[[2-[[[3-[[(cyanoimino)) (Methylamino) methyl] amino] phenyl], carbonyl] amino] ethylfluorenyl] -4-yl] ethyl alkynyl; 3S-[[2-[[[3-[[ (Cyanoimino) (methylamino) methyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] pentynyl acid; call-[[2-[[[3-[[ (Cyanoimino) [2-pyridylmethyl] amino] methyl.amido] amino] benzyl] carbonyl] amino] ethenyl] amino] ethyl phenylpropionate; cold- [ [2-[[[3-[[(cyanoimino)] [2-pyridylmethyl] amino] methyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] benzene Propionic acid; β _ [[2-[[[3 · [[(cyanoimino) [3-pyridylmethyl] amino] methyl] amino] phenyl] carbonyl] amino] ethyl Fluorenyl] amino] ethyl phenylpropionate; cold-[[2-[[[3-[[(cyanoimino) [3-pyridylmethyl] amino] fluorenyl] amino] benzene []] Carbonyl] amino] ethenyl] amino] phenylpropanoic acid; 3S-[[2-[[[3-[[[[((4- (aminosulfonyl) benzyl) benzyl) amino] (Cyanoimino) methyl] amino] phenyl] carbonyl] amino] ethanyl] amino] -4-pentynyl ethyl ester 3S-[[2-[[[3-[[[[((4- (Aminosulfonyl) benzyl) amino) (cyanoimino) methyl] amino] phenyl] carbonyl] amine Base] Ethyl] Amine] -4- -21-This paper size is applicable to China National Standard (CNS) A4 (2 丨 0X297) ((Please read the precautions on the back before filling this page) Order Α8 Β8 C8 D8 458356 VI. Scope of application for patents Valproic acid; • (Earth) 3,5 -dichloro-Ling-[[2-[[[3-[(cyanoimide 棊) (methylamino)) Fluorenyl] amino] phenyl] carbonyl] amino] ethenyl] amino] phenylpropionic acid. 7. The compound according to item 2 of the scope of patent application, where A is •. »Y1 'meaning——NN—R7 RS R ° L · where Y1 is N-R2; R2 and R7 form a trinity together; R5 and R8 is hydrogen. 8. The compound according to item 7 of the patent application park, wherein V is -N (R6)-, wherein R6 is selected from η and alkyl; η is 1; t is 0; p is 1 β 9. According to the application The eighth patent compound in the patent garden is 3,5-dichloro-zhao-[[2 _ [[[[[[[[[3- [1,2,3, Rintetrahydro-2,4-dioxopyrimidine-6-yl ) Amino] phenyl] -carbonyl] amine cap] ethynyl] amino] phenylpropionic acid. 10. The compound according to item 1 of the scope of the patent application, where Α is ... (Please read the notes on the back before filling in this page) Order 9. Printed by the Men's Workers Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs -----—__- ^-This paper bears the degree A for the Chinese National Winter Standard (CNS) standard (2 〖〇χ297 公 χ) 1 4 5 ^ 9 56 ll _ D8 VI. In the scope of patent application, Y2 is -S-R9 and -0-R ?, where ^^ and ruler? Together form a 5 or 6-membered heterocyclic ring containing one nitrogen and one sulfur; or R9 and R7 together as an air suffix; and R5 and R7 as defined above; or. Y2 (when Y2 is carbon) and R7 together form a 5-7 members contain a nitrogen ring. 11. The compound according to item 10 of the patent application park, wherein Y2 and R7 together form a 5-7 member ring. 12. The compound according to item 11 of the scope of patent application, wherein .. V is -N (R6)-, wherein R6 is selected from η and C 丨 alkyl; η is 1;, t is 0; p is 1. 13. The compound according to item 12 of the scope of patent application, wherein the compound is selected from (soil) /?-[[2-[[[3-[(394,5,6-tetrahydro-2 ^ azepine-7) -Amino] Amino] phenyl] carbonyl] Amine] Ethylamido] Amino] Supridin-3-propionic acid; Printed by the Central Government Bureau of the Ministry of Economic Affairs, Machining and Consumer Cooperatives (Lu)-[[2- [[[3-[(3,4,5,6'tetrahydro-2 ^ 1-azepine-7-yl) amino] phenyl] carbonyl] amino] ethenyl] amino group 1, 3-benzodioxo-5-propionic acid; (±) zhao-[[2-[[[3-[(3,4,5,6-tetrahydro-2 ^ 1-aza leather-7_ Group) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] -benzylpropanoic acid; (±) 10,000-[[2-[[[3-[(3,4-Diargon-2H- Pyrrole-5-yl) amino group] -23 -___ This paper uses the Chinese national standard ^ (CNS) A4 (2 丨 〇 &gt; &lt; 297 mm) ~ &quot; Central Ministry of Economic Affairs A8 4 5d 9 5g I ____ printed by the Industrial and Commercial Cooperatives 6. Scope of patent application Phenyl] strict group] amino group] ethoxy] amino group] Specific 3-propion, (±) Lu-[[2- [[[4-Chloro-3-[(3,4,5,6-tetrahydro-211-azepine-7-yl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] Pyridine-3-propionic acid ethyl ester; (±) / 9-[[2-[[[4-chloro-3-[(3,4,5,6-tetrahydro-2 ^ 1-azapyridine-7-yl) amino] phenyl] carbonyl] amino] ethylethyl] amino] pyridine-3 · propionic acid; (±.) Call-[[2-[[[4 -Chloro-3-[(3,4,5,6-tetrahydro-2H-azafluoren-7-yl) amino] phenyl] carbonyl] amino] ethanyl] amino] pyridine-3- Propionic acid; (±) zhao-[[2-[[[3,5-bis [(3,4,5,6-tetrahydro-211-azepine-7-yl) amino] phenyl] carbonyl ] Amine] Ethylamido] Amine] pyridine-3 -propane, acid; (±) ling-[[2-[[[[[Iminophenylphenylmethyl] amino] phenyl] carbonyl] carbonyl ] Amino] Ethyl] amino] pyridine-3-propionic acid; (±) / 3- [[2-[[[3-[(3,4,5,6-tetrahydro-2H-aza萆 -7-yl) amine] phenyl] carbonyl] amino] ethylfluorenyl] amino] -4-pentynyl acid; / 3-[[2-[[[[[[3-[(4,5 · 二Hydroxazol-2-yl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3 -propionic acid ethyl ester; (±) cold-[[2-[[[3- [ (3,4,5,6-tetrahydro-211-aza leather-7-yl) Amino] phenyl] carbonyl] amino] ethenyl] amino] -3,5-dichlorophenylpropionic acid _ (±) zhao-[[2-[[[3-[(3,4-dihydro-2H-pyrrole-5-yl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino ] -3,5-dichlorophenylpropionic acid; (±) 3,5-dichloro-cold-[[2-[[[3-[(2,3,4,5-tetrahydropyridine-6- _-24-_ The scale of this paper is applicable to China National Standard (CNS) A4 (2 丨 0X297) ^ i (please read the precautions on the back before filling this page) 11T 9., 'mss. Λβ B8 C8 D8 Patent application scope) Amino] phenyl] carbonyl] Amine] Ethylamido] Amino] -Phenylpropanoic acid; (±) 3,5-dichloro-2-hydroxy-cold-[[ 2-[[[[[[[3,4,5,6-tetrahydro-azepine-7-yl] amino] phenyl] carbonyl] -amino] ethylammonium] amino] phenylpropanoic acid Reed-[[2-[[[[[[ 3-propionic acid; 3,5-dichloro-cold-[[2-[[[3-[[imino (1-hexahydropyridyl) methyl] amino] phenyl] carbonyl] amino] -Ethenyl] amino] phenylpropanoic acid; 'n-[[2 _ [[[[[[[benzobenzozol-2-yl] amino] phenyl] carbonyl] amino] ethanyl] amine Yl] pyridine-3 -propionic acid. 14. The compound according to item 1 of the patent application park has the following formula: (Please read the precautions on the back before filling this page) _ Order. Shellfisher consumer cooperation in the Central Government Bureau of the Ministry of Economic Affairs in printing -25- The standard of this paper is the Chinese National Standard (CNS) Α4 (210 × 297 mm), λ 58 9 56 ABICD 6. Scope of Patent Application 6. The Central Bureau of Standards of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page) .IT This paper size is applicable to China National Standards (CNS &gt; (210X297 mm) Α8 Β8 C8 D8 458956 六 、 Scope of patent application 0 Η X. Ν Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs «. ο-27- (Please read the notes on the back first and then fill in, \ Xian) This paper size is applicable to China National Standards (CNS &gt; A4 now (210X297mm) 458 956 Patent Application Park A8 BS C8 DS Printed by the Employees' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs -28- _ Called C Please read the notes on the back before filling out this page) Order 9. This paper size is applicable to China National Standards (CNS) _A4 specifications (210X297 mm) 4 5 6 9 5β 6. Scope of patent application AB, CD Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy (Please read the precautions on the reverse side before filling out this page). 9. This paper size is based on China National Standard (CNS) A4 (210X297 mm) 059 d5 4 ABCD VI. Patent Application Scope (Please read the notes on the back before filling out this page) -30-.丨） This paper music scale is applicable to China National Standard (CNS) _A4 specification (210X297 mm) Order liif 4 5d 9 56 A8 BS C8 D8 Patent Application Scope (Please read the precautions on the back before filling in this page.) The standard of this paper is Chinese Standard (CNS) A4 (210 &gt; &lt; 297 mm) Order Α8 Β8 C8 D8 (Please read the precautions on the back before filling in this page) -32- This paper size adopts Chinese National Standard (CNS) A4 now (210X297) 嫠 9 cO β A 8 8 8 8 ABCD VI. Scope of patent application Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs f b 33- (Please read the notes on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specification (210X297 male) 65 9S54 ABCD 6. Scope of patent application Central Laboratories of Ministry of Economy _-34- This paper size is based on the Chinese standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page) d58956 6. Scope of patent application (Please read the notes on the back before filling out this page) -Printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of IT and Economy -35- This paper size is applicable to China National Standards (CNS) A4 (210X297 mm) 6 59 35 ABCD 々, apply for patent gas, printed by tK Industrial Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs (Please read the notes on the back of the book before you fill in this page) Order _-36- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 3 9¾6 A8 B8 C8 D8 Patent application scope The policy of employee consumer cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (Please read the notes on the back before filling this page) Patent application scope Η OO ^ Et ΗR 'C〇2H (谙 Please read the notes on the back before filling in this page) 38- This paper size is applicable to China National Standards (CNS) A4 (210X297 cm). This paper uses Chinese National Standard (CNS) A4 regulations (210X297) (please read the precautions on the back before filling out this page) Order A8 B8 CS D8 458956 6. Scope of patent application 〇 Η C II 〇, 〇Η Printed policy of Shellfish Consumer Cooperative of Central Ministry of Economic Affairs, Ministry of Economic Affairs -40- (Please read the notes on the back before filling this page) i. Order OI. This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) r. Cooperative printed ABCD This paper size applies to China National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page) 059 8 5 d ABCD patent application scope 0 NC-YS.NH 'C〇2H ό ό Ν〇 / ί ^ γ ^ ί / ΝΗ Me〆 〇〇2Η 0 Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Η Ή 42-(Please read the notes on the back before filling this page) The scale of this paper applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) ^^ 45B 9 56 Ag B8 C8 D8 6. Scope of patent application Printed by the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs -43- This paper size applies to Chinese national standard (CNS> A4 size (210X297mm) (Please read the precautions on the back before filling this page) 65985 Λ 8 88 8 ABCD 6. Scope of patent application Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs -44-The size of this paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) (Please read the notes on the back before filling this page) Printed by the Consumer Sample Cooperative of the Central Sample Rate Bureau of the Ministry of Economic Affairs Α8 Β8 C8 D8 Patent Application range Η η -45- The paper Λ degree is applicable to China National Standards Standard (CNS) 8.4 (210 X 297 mm) (Please read the precautions on the back before filling this page) 45 六 、 Scope of patent application Economic ‘Ping Central Standards Bureau, Male Workers’ Consumer Cooperatives, India 'Cl Cl sC〇2Et' C02H co2et (Please read the precautions on the back before filling out this page) Order C- ^ wl. -46-Chinese paper standard (CNS) A4 specification (21 OX297 mm) 6. Application for patent scope Ministry of Economic Affairs Central Bureau of Standards Consumer Policy Cooperative This paper size applies to China National Standard (CNS) A4 ^ (210X29? Mm) D8 of the Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperatives 6. The scope of patent application 〇 〇 -48- {Please read the precautions on the back before filling this page} This paper size is applicable to Chinese national standards &lt; CNS) A4 size (210 × 297 mm) 659 ABCD patent application scope 〇 H2N ^ NI NH Ο ΝΗ, ^ γΝΗ &gt; χ ^ α〇2Η Βγ C〇2Et Employee policy of the Central Standards Bureau of the Ministry of Economy 49- (Please read the notes on the back before filling this page) The size of this paper is in accordance with Chinese National Standard (CNS) Α4 gauge (210 × 297 mm), r η α B ^ as 8. BS C8 Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs This paper size applies to China Gujiazheng (CMS) A4 specification (210X 297 mm) A8 B8 C8 D8 Patent application scope 〇 Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs H2. &Quot; γΝNH -51-(Please note on the back of ^ before filling this page) The paper scale is applicable to China National Standards (CNS) A4 (210X 297 mm) Apply for patent ΝΗ (Please read the precautions on the back before filling out this page) * • 52- This paper size applies to China National Standard (CNS) A4 * L ^ (21〇 &gt; &lt; 297 Public Envy) Patent Application Park A8 B8 C8 D8 (Please read the notes on the reverse side before filling out this page) Order k. Printing policy of Shellfish Consumer Cooperative, Bureau of Decision, Standards Bureau, Ministry of Economic Affairs * 53- The size of this paper is applicable to China National Standard (CNS) A4 (21〇 × 297 mm) cl. R v 4 58 9 56 ABCD HN 〇 on iVrx N C〇2H Br (Please read the notes on the back before filling this page), 1T Printed by the Consumers Cooperative of the Central Standards Bureau, Ministry of Economic Affairs, CO2H- -54- This paper size applies to Chinese national standards (CNS &gt; A4 scale (210 乂 297mm *) A8 ^ 4 5'8 9 56 II D8 (Please read the precautions on the back before filling out this page) Ministry of Economy -55- The paper scale is free to use Chinese National Standards (CNS) A4 specifications (210 X 297 mm) A8, v 4-58 95 ^ cs D8 --------- 袭 — f-/, — v- (please read the notes on the back before filling out this page) Order: &gt; -9. Printed by the Ministry of Economic Affairs t Central Standards Bureau Off-line Consumer Cooperatives Policy -56- The standard of this paper is Chinese National Standard (CNS) A4 (210X297 mm). Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Consumers and Consumers Cooperatives. 45B 958 ϋ CS D8 6. Scope of patent application SMe (Please read the precautions on the reverse side before filling out this page) No. 9 -57- This paper size uses China National Standards (CNS) Μ Appearance (210X297 mm) i:-45B 956 8 88 S ABCD VI. Patent application scope 〇 (Please read the precautions on the back before filling out this page) Order &lt; &gt; Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Printed by the Consumers Cooperative -58- The scale of this paper is applicable to China National Standards (CNS) A4 (21〇297297) Application for patent scope A8 B8 C8 D8 C〇2H (Please read the precautions on the back before filling out this page) Order τ &gt; · Stamp of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs: 59- This paper size is applicable to China National Standard (CNS) Α4 size (210 × 297 mm) 6 Lf; CQ; 4 ABCD 0 (Please read the notes on the back before filling out this page) Table. Order Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -60- This paper size is applicable to China National Standards (CNS) A4 (210 &gt; &lt; 297 public director) ύ-_ Λ58 956 Α8 Β8 C8 D8 , ΝΗ ^ γ ΝΗ Ο F- F Ό〇2Η; .1 -F Printing policy of the Central Government Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 61-This paper size applies to China National Standard (CNS) Α4 size (210X297 mm) {Please read the precautions on the back before filling this page) Order 458 956 A8 B3 C8 D8 Patent Application Scope NH, C〇2H ό nn utt Tt tli JJ 1 ^ —J-1 ^ 1 ** ^^^ n i o (Please read the precautions on the back before filling in this page) Order P. r Printed by the Central Laboratories Bureau of the Ministry of Economy, printed by the Shellfish Consumer Cooperative ΝΗ &quot; ^ γΝΗγ ^ 〇〇2ΗΟ 62 -62- This paper size adopts the Chinese National Standard (CNS) A4AWM 210X297 mm). Price A R 8 9 56 6. Scope of patent application p A8 BS C8 D8 , C〇2H (Please read the notes on the back before filling this page) Cl NHνη ^ γ '' c〇2H N is called {ΰ -63- The paper scale is applicable to the Chinese Family Standards (CNS) Α4 grid (210 × 297 cm) 9 56 The scope of patent application A8 B8 C8 D8 Cl NH &quot; CO2H (Please read the precautions on the back before filling out this page) Order -64- This paper supports the Chinese National Standard (CNS) A4 specification (210X297 mm) 65 9 8 54 rrk ^ 8 88 8 ABCD patent application scope PV Ν, Υ ° 〇.U. &Quot; Λ Ό〇2Η Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 〇 (Please read the notes on the back before filling this page) This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 458956 A8 B8 C8 D8 6. Scope of patent application ό CO2H (Please read the precautions on the back before filling out this page) Printed by the Consumer Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs if cr ^^ c NH ^ People 66- This paper size is applicable to China National Standards (CNS) A4 (2 丨 0X2? 7mm) A8 B8 C8 D8 4 58 9 56 Η Printing policy of Zhengong Consumer Cooperative of Central Bureau of Accreditation of the Ministry of Economic Affairs ^ 〇 〇 〇 ⅡII π VIII JviHC ^ ^ NHC. Ho ^ v ^ hc 67 This paper size is applicable to China National Standards (CNS) A4 (2 丨 OX297) — printed by Bei Gong Xiao F Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs d 58 9 56 A8 B8 C8 D8 〇 〇 NHC Ο Hz V NH 'c〇2H (Please read the notes on the back before filling this page) F 〇 F -68 This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 4 5B 9 5β ABCD Printed by the Central Laboratories of the Ministry of Economic Affairs The size of this paper is in accordance with China National Standard (CNS) Α4 (210 × 297 mm) (注意 Please read the notes on the back before filling in this page)-^ ΓΜ. Policy of Employee Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs This paper uses Chinese National Standard (CNS) A4 specifications (21〇 &gt; &lt; 297mm) (Please read the precautions on the back before filling this page) f 'γ-λ 8 9 5 A8 B8 C8 D8 OHUC OMUC 0Η 0Η CHO (Please read the precautions on the back before filling out this page), 1T α: Central Government Bureau of the Ministry of Economic Affairs®: Printed by Industrial and Consumer Cooperatives HN c CHO Η onMC f cno Η S ο This paper size is applicable to China National Standard (CNS) Α4 size (21〇 ×; 297mm) y · 45 A8 BS C8 D8 〇IIC, (Please read the notes on the back before filling out this page) ΐτ. Printed by the Shellfish Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs -72 This paper uses China National Standard (CNS) A4 size (210 &gt; &lt; 297 public variable) 158 956 A8 BS C8 D8 Ο Ck. ^ Cl (please read the notes on the back first and fill in this page), 1T. 4 Nhi Renren / C〇2H 丨 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs σ &lt;] 〇-73- This paper size is applicable to China National Standards (CNS) A4 specifications (210X297 mm) A8 B8 C8 D8 f, 458 9 56 VI. Application for patent scope U — a kind for the treatment of mammals through ανβ3 integration A pharmaceutical composition of medicament-mediated diseases comprising a therapeutically effective amount of a compound of formula Or a pharmaceutically acceptable salt thereof, where A is RS R〇. In the formula of the Central Government Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperative, Y1 is selected from N-R2, 0 and S; R2 is selected from Η; (^ · 6 alkyl; cyano; amine carbonyl .; cU8 alkoxycarbonyl; alkyl is optionally amine-substituted; or R2 and R7 together form an amine-substituted triazolyl group; or R7 (when not connected to R2) and R8 are each selected from Η; Cu alkyl; benzyl; aniline; alkylcarbonyl; fluorene-6 alkoxycarbonyl; phenoxy; phenyl; alkyl is optionally substituted with a substituent selected from carboxy, phenyl, 11 , Benzimidyl, adenyl, .phenyl is optionally substituted with one or more substituents selected from the group consisting of halides, sulfonyl groups;-S02R10, wherein Rio is phenyl, and the selectivity is (: Alkyl alkyl substitution; -74- This paper uses the national sample rate of China (0 ^ &gt; People 4 specifications (210 &gt; &lt; 297) *) 458956 A8 B8 C8 D8 Patent application scope NR7 and R8 together form one 5-membered monocyclic ring containing nitrogen; R5 is Η; or A is Ύ2 -N ^^ NR7 Rs where Y2 is -S-R9 and _〇_R9, of which envy and Han 7 form a 5 or 6 member Heterocyclic ring containing one nitrogen and one sulfur; or R9 and R7 -Starting from n and R5 and R7 as defined above; or Y 2 (when Y 2 is carbon) and R · 7-forming a 5-7 member containing a nitrogen ring; or ./ A is (please first (Please read the notes on the back and fill in this page again.) Printed by the Ministry of Economic Affairs, Central Standards Bureau, Industrial Consumer Cooperatives, N &quot; R2—N— ^ 'R5. V'R? Where R2 and R7 together form a 5 or 6 member with A heterocyclic ring of two nitrogen, the selectivity is one or more selected from the group consisting of hydroxy, Cl.6 alkyl or phenyl; and R8 is hydrogen; and R5 is as defined above; CNS) A4 Hu Pan (2 丨 0X297 mm) s, s, printed by Zhongfu-like quasi-office industrial and consumer cooperative of the Ministry of Economic Affairs 4 58 9 56 AS B8 C8 ---------__ D8 6. Scope of patent application Or Z 1 is one or more substituents selected from the group consisting of: H; ci-alkyl; hydroxy; phenyl, halogen; haloalkyl 6 alkyl; azepine amino; carboxy derivative; trihaloacetamidine Amine; and A, wherein a is as defined above; V is selected from -N- (R6) ·, wherein R6 is selected from η and Ci-6 alkyl; Y and Z are each selected from hydrogen and (: bu 6 alkyl; η is 1 t is 0; p is 1; R ^ X-RJ 'where X is 0 and R3 Selected from hydrogen; c "6 alkyl; benzene C! -6 alkyl, polyalkyl ether; in free acid, and its pharmaceutically acceptable salts; R1 selected from hydrogen; CbS alkyl; Cu6 carbonylamine Ci8 alkanol; c2_s alkynyl; phenyl; C! · 6 carboxylic acid; C! · 6 alkyl_Cl_6 carboxylic acid ester; tCi 6 alkyl; pyridyl; benzodioxoyl; furanyl; Cyclohexyl; pyrimidinyl; imidazolyl; benzodioxanyl; fluorenyl; pyranyl; benzoanyl; C! -6 alkyl is substituted by the following groups: hydroxyl, benzenesulfonyl; Item: benzyl, benzoate; phenyl is optionally substituted at one or more positions with the following groups: halogen, haloalkyl, Ci-6 alkyl, Ct.6 alkoxy, phenyl 'CU6 alkylthio, thio, hydroxy, terminal' Cm alkoxycarbonyl 'hydroxycarbonyl-(: 1-6 alkoxy' oxy 'Cu phenyl, amine, Cis ^ alkoxy, fused phenyl ; Benzodioxoyl is substituted by Ci-6 alkoxy; benzoP Guananyl is substituted by cis and CI-6 alkoxy; and -76- This paper is used by China National Standards (CNS) M Speaking grid (210X297 mm) (谙 Read the precautions on the back first (Write this page) Order 4 5 B 9 56 Αδ 58 C8 D8 VI. Patent application scope 4 * 0 Titanium is Nansu and C 1.6 is substituted; and R1 1 is Η; and a pharmaceutically acceptable carrier Agent. 16. The pharmaceutical composition 'where A is Y' according to the scope of the patent application, where X is Y '. X.-R7 1 I · R5 R0.' In the correction formula, Y1 is selected from N-R2, 0 and S; R2 is selected Since 山 -6 alkyl group; cyano group; amine carbonyl group; Cus alkoxycarbonyl group; alkyl group is optionally substituted with amine group; or R2 and R7 together form amine substituted triazolyl group; or R7 (when not When connected with R2) and RS are each selected from Η; Cm alkyl; benzyl; aniline; Cu alkylcarbonyl; Ci-6 alkoxycarbonyl; phenoxy; phenyl; Substituents selected from the following: carboxyl, phenyl, pyridyl, benzimidazole, fluorenyl, and phenyl is optionally substituted with one or more substituents selected from the group consisting of halides, sulfonyl groups; Central Ministry of Economic Affairs印 Printed by Zhuhai Bureau Shellfish Consumer Cooperation (please read the notes on the back before filling out this page) -S02R1G, which is phenyl, optionally substituted with Ci 6 alkyl; NR7 and R8 together form a 5-member containing A monocyclic ring of nitrogen; R5 is Η = Π. The pharmaceutical composition according to item i 5 of the scope of patent application, wherein V is -N (R6)-, wherein R6 is selected from hiCi.s fluorenyl groups; η is 1; - 77- Private paper standards are applicable to China National Standards (CNS &gt; Α4 specifications (210X297 mm 6 5 ί) Θ 5 4 ABCD Central government bureau of the Ministry of Economic Affairs, shellfish consumer cooperation, printed by the agency. 6. The scope of patent application t is 0 p is 10 18. The pharmaceutical composition according to item 17 of the scope of patent application, wherein the compound is selected from: (soil); 3-[[2-[[[3-[(aminoiminomethyl ) Amino] phenyl; | carbonyl] amino] ethyl] ethyl] pyridine-3 · propionic acid ethyl ester; (±) θ-[[2-[[[3-[(aminoimino Methyl) amino] phenyl] carbonyl] amino] amino] ethyl] amino] 11 than this 3-propionic acid; ((±) cold-[[2-[[[3-[( Aminoiminomethyl) Amino] phenyl] carbonyl] Amine] Ethylamido] Amino] Ethyl phenylpropionate; (±)-[[2-[[[3-[(Amine Iminomethyl) amino] phenyl] carbonyl] amino] ethyl] ethyl] phenyl] phenylpropanoic acid; (±) zhao-[(aminoiminomethyl) amino] phenyl] carbonyl ] Amino] ethoxy] Amino group 1,3-Benzobenzoate (.dioxole}-5-propionic acid ethyl ester; (±) Lu-[[2-[[[3-[(Amine group Iminomethyl) amino] phenyl] carbonyl] amino] ethyl] amino] -1,3-benzodioxo-5-propionic acid; (±) LING-[[2-[[[3-[(Aminoiminomethyl) amino] fluoren-1-yl] condensate] amino] ethynyl] amino] ρ than this- 3-Ethyl propionate; (Shi) zhao-[[2-[[[3-[(Aminoiminomethyl) amino] fluoren-1-yl] carbonyl] amino] ethanyl] amine [] -Pyridine-3-propionic acid; (±) ling-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] -cycloprop-1-yl] carbonyl] amino] pyridine _3_propionic acid; (±) cold-[[2-[[[3, [[imino-[(phenylmethyl) amino] methyl] -78) paper ruler Ke Zhun (CNS) ΑTV ^ (21〇χ25 &gt; 7 public envy) ------- Q—I (Please read the notes on the back before filling this page) Order 9 Central Standards Bureau of the Ministry of Economic Affairs®; Industrial and consumer cooperative seal «. Hf'45P Ί56 will! C8 D8 VI. Patent application scope amine] phenyl] carbonyl] amino] ethoxy] amino] pyridine-3-propionic acid; (±) may- [ [2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] -3,5-dichlorophenylpropanoic acid; Ling S- [[2-[[[3-[[Imine (1-pyrrolidinyl) methyl] amino] phenyl] carbonyl] amino] ethenyl] amino] -4-pentynyl acid: point !! 5-[[2-[[[[[Aminoiminomethyl) amino] 2,5,6-trifluorophenyl] carbonyl] amino] ethylfluorenyl] amino] -4- Pentynyl acid; (±) Lu-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -3,5 -Bis (trifluoromethyl) phenylpropanoic acid; (±) ling-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ethyl ] Amino group [1,1'-biphenyl] -4-propionic acid; (±) y5-[[2-[[[3-[(Aminoiminomethyl) amino] -5-] (Trifluoro.methyl) phenyl] carbonyl] amino] ethenyl] amino] -3,5-bis (trifluoromethyl) phenylpropanoic acid; (±) call-[[2-[[[[ 3-[[[(phenylmethyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ethylammonium] amino] pyridine-3-propanoic acid ethyl ester; (±) Office-[[ 2-[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] furan-3-propionic acid ethyl ester; (±) Lu- [ [2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] furan-3 -propanoic acid; 3- [[2- [ [[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethanyl] amino] glutaric acid; (±) 3-[[2-[[[3- [(Aminoiminomethyl) Base] phenyl] carbonyl] amino] ethylfluorenyl] amino] hydrogen glutarate; _79- _ — This paper is applicable to China National Standard (CNS) A4 (2 丨 0X 297 mm) ) ~ (Please read the notes on the back before filling this page) 950 A8 B8 α D8 VI. Patent Application Range (±) θ- [[2-[[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amine Phenyl] furan-2-propionic acid; (±) -dot-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] ethanyl] amino ] 荇 -2-propanoic acid; (±) n-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] Thiophene-3 -propionic acid methyl ester; 3S-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -4 -Ethyl pentynyl; • (±) m-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethanyl] amino] Thiophene 3-propionic acid; (±) 2- [3-[[2-[[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amine Group] -4-carboxybutyl] sulfofluorenyl] benzoic acid; ./±)Lu-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl]; | Amine] Ethylamido] Amino] p-phenphen-2-propionic acid; (±) 2- [3-[[2-[[[3-[(Amineiminomethyl) amino] benzene) benzene Methyl] carbonyl] amino] ethyl] ethyl] amino] -4 -carboxybutyl] thio] methyl benzoate; (±) 3-[[2-[[[3-[(amino Methyl) amine] phenyl] carbonyl] amine] ethyl] amino] -4-[(4-methylphenyl) sulfonyl] amino] butanoic acid; (±) 3- [ [2-[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] 'amino] ethylfluorenyl] amino] -5-[(4-methylphenyl) sulfur Group] valeric acid; (±) 3-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -5- [(4-fluorenylphenyl) sulfonamido] pentanoic acid; 3S-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amine-80-Ben Paper size applies to China National Standard (CNS) Α4 size (210X297 mm) (Please read the notes on the back before filling in this KK) Order-Q. Printed by the Shell Standard Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 403958 A8 B8 C8 D8 Application of patent scope by the Central Bureau of Standards for Shellfish Consumer Cooperatives] Ethylamido] amino] _4_ (phenylthio) butyric acid; 3Sd [2-[[[3_ [(Amineimidomethyl) amino ] Phenyl] carbonyl] amino] ethynyl] amino] -4-pentyne: acid; 3 R-[[2-[[[3-[(aminoiminoamido) amino) amine] benzene Group] carbonyl] amino] ethenyl] amino] -4-pentynyl acid; '2-[[2S-[[2-[[[[[[[ Iminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -2- (carboxymethyl) ethyl] sulfonyl] benzoic acid; 2-[[2S- [[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -2- (carboxymethyl) ethyl] thio ] Benzoic acid; (±) n-[[2-[[[3-[(aminoiminomethyl) amino] benzyl] carbonyl] methylamino] ethylfluorenyl] amino] pyridine-3 -Ethyl propionate; (soil)-[[2-[[[[[Amineiminoamido) amino] phenyl] carbonyl] methylamino] acetamidine] amino] Pyridine-3 -propionic acid; .- [[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] -propoxypropyl; I amino ] Pyridine-3-propanoic acid ethyl ester; cold-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] -1-oxypropyl] Amino group] ** than 3-propanoic acid; (±) Ling-[[2-[[[[[[Aminoiminomethyl) amino] -4 -methylphenyl] carbonyl]] Amine] Ethylamido] Amino] pyridine-3-propanoic acid; (±) Pan .- [[2-[[[3-[(Aminoiminomethyl) amino] methyl] phenyl ] Carbonyl] amino] ethenyl] amino] pyridine-3-propionic acid; '3S-[[2-[[[3-[(aminoiminomethyl)) amine ] Phenyl] carbonyl] amino] ethynyl] amino] -4-hydroxybutyric acid; 81-This paper is suitable for Chinese national standards ^ (CNS) A4 (210X297 mm)-j ----- ---- Q! ----- IT ------ 〇Ί (please read the notes on the back before filling this page) Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 458956 il C8 D8 Patent application scope (±) 10,000-[[2-[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylethyl] amino] -2 -hydroxybenzene Propionic acid; (±) ten thousand-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] acetamidine] amino] -2 -hydroxy- 5-methylphenylpropionic acid; (±) 3-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -4-[(2-hydroxyethyl) amino] -4-oxybutyric acid; .2-aminobenzoic acid 2S-[[2-[[[3-[(aminoiminoamidofluorenyl) Amine] phenyl] carbonyl] amino] ethenyl] amino] -3-carboxypropyl; 'stone-[[2-[[[3-[(aminoiminomethyl) amino] Phenyl] carbonyl] amino] ethylfluorenyl] amino] -1,4-benzodioxin-6-propionic acid; N-[[2-[[[3-[(amino Amine f) amine] phenyl] carbonyl] [Ethyl] ethenyl] -fang-alanine; (±) Lu-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ] Amine] -pyridoline-3 -ethyl propionate;-[[2-{[[3-[(4,5-Dihydro-Sep-2-yl) amino] phenyl] + carbonyl ] Amino] Ethylamido] amino] pyridine-3 -propionic acid ethyl ester; N-[[2-[[[[[[(Benzyl) amino] carbonyl] amino] phenyl]] Carbonyl] amine] ethyl] amino] -jS-alanine; 3-[[2-[[[3-[[[(benzyl) amino] carbonyl] amino] phenyl] carbonyl] Amine] Ethylamido] Amino] -propionic acid; (±) Me-[[2-[[[3-[[[(Benzyl) amino] carbonyl] amino] phenyl] carbonyl] amine [Ethyl] ethynyl] amino] pyridine-3-propanoic acid; ling-[[2-[[[[[(aniline) carbonyl] amino] phenyl] carbonyl] amino]] ethyl alcohol ] Amine] Specific bite -3 -Ethyl propionate, -82 -_____ This paper is scaled with Chinese National Standard (CNS) A4 (21〇X; 297 mm) {Please read the notes on the back first (Fill in this page again), ΤΓ 9 4,58 9 56 A8 B8 C8 D8 Printed by Shellfish Consumer Cooperative, Central Standards Bureau of the Ministry of Economic Affairs 6. Scope of patent application · Cold-[[2-[[[3- (aminocarbonylamino ) Phenyl] carbonyl ] Amine] Ethyl]] amino] pyridine-3 -ethyl propionate, trifluoroacetate; ling _ [[2-[[[3-[[[[(4 -methylphenyl) sulfonate] Fluorenyl] amino] carbonyl] amino] phenyl] carbonyl] amino] ethenyl] amino] pyridine-3 + -propionic acid; ling-[[2-[[[[[[ Methyl) amino] phenyl] carbonyl] amino] ethynyl_] amino] pyridine-3 · propionic acid ethyl ester; not-[[2-[[[3-[[[(phenylmethyl ) Amino] carbonyl] amino] phenyl] carbonyl] amino]. Ethylammonium] amino] phenylpropionic acid; /?-[[2-[[[[[[[[(( Aminosulfonyl) benzyl] amino] carbonyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3-dicarboxylic acid; cold-[[2-[[[3 -[[[(3-Pyridylmethyl) amino] carbonyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3-propionic acid;-cold-[[2- [ [[3-[[[(2-carboxyethyl) amino] carbonyl] amino] benzyl] carbonyl] amino] ethenyl] amino] pyridine-3-propionic acid; cold-[[2 -[[[[[[(2-Phenylethyl] amino] carbonyl] amino] phenyl] carbonyl] amino] ethynyl] amino] pyridine-3-propionic acid; cold-[ [2-[[[[[[(1-1-Methylmethyl] amino] carbonyl] amino] phenyl] phenyl_amino] amino] ethynyl] amino] 1? -Therefore, -[[2-[[[[[(Cyanoimino) methylamino] methyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] phenylpropionate Ester; call-[[2-[[[3-[[(cyanoimino (amino) methyl] amino] phenyl] carbonyl] amino] ethylammonium] amino] phenylpropionate benzene Methyl ester; cold-[[2-[[[3-[[(cyanoimino) (ethylamino) methyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] benzene Ethyl propionate; -83- (Please read the notes on the back before filling in this page) Γ pii C This paper size is in Chinese National Standard (CNS) A4 size (21 OX297 mm) A8 B8 C8 D8 4 58 9 56 VI. Scope of patent application • »Ling-[[2-[[[[[cyanoimino]] [(benzyl) amino] methyl] amino] phenyl] carbonyl] amine []] Ethyl] ethyl] amino] phenylpropionic acid; stone-[[2-[[[[[(cyanoimino) (methylamino) methyl] amino] phenyl] carbonyl] amine [Ethyl] ethenyl] amino] phenylpropanoic acid Γ cold-[[2-[[[[[amino (cyanoimino) methyl] amino] phenyl] carbonyl; iamino] Acetyl] amino] phenylpropanoic acid; /?-[[2-[[[[[(cyanoimino) (ethylamino) methyl] amino] phenyl] carbonyl] amino ] Fluorenyl] amino] phenylpropanoic acid;) S-[[2-[[[[[[(cyanoimino) (methylamino) methyl] amino] phenyl] peptyl] amino] ] Ethyl ethyl] amino] -4-pentanoic acid ethyl vinegar; 3S-[[2-[[[3-[[(cyanoimino) (methylamine tomb) methyl] amino] phenyl ] Carbonyl] amino] ethenyl] amino] pentynyl acid; ling-[[2-[[[3-[[(cyanoimino)] [2-pyridyl.methyl] amino] methyl] methyl [Amino] Amino] Phenyl] Carbonyl] Amino] Ethyl} Amino] Ethyl Phenylpropionate; Call-[[2-[[[[ Methylmethyl] amino] methyl] amino] phenyl] carbonyl] amino] ethenyl] amino] phenylpropionic acid; cold-[[2-[[[3-[[(cyanoimine (Yl) [3-pyridylmethyl] amino] methyl] amino] phenyl] carbonyl] amino] ethylethyl] amino] phenylpropanoic acid ethyl ester; call-[[2-[[[3 -[[(Cyanoimido) [3-pyridylmethyl] amino] methyl] amino] phenyl] carbonyl] amino] ethenyl] amino] phenylpropionic acid; linger-[[ 2-[[[4- 气 -3-[[[((l, l-dimethylethoxy) carbonyl] amino] [[(1,1-dimethylethoxy) carbonyl] imine [Methyl] amino] phenyl] phenyl] amino] ethyl] ethynyl] amino] ethylphenylpropionate, cold-[[2-[[[3-[(amino Aminomethyl) Amino] -4-chlorophenyl) carbonyl-84- This paper size applies to the national standard of China Solids (CNS> A4 standard (2 丨 0X297 mm) (Please read the precautions on the back before filling (This page) -1 ° Printed by the Central Bureau of Economics and the Central Bureau of Standardization of the Ministry of Economic Affairs and the Central Standards Bureau of the Ministry of Economic Affairs—Industrial and Consumer Cooperatives' Printing Policy 458 9 56 i! C8 D8 6. Application for Patent Scope Base] Amine Base] Ethyl Base] Amino] phenylpropionic acid; Lu _ [[2-[[[[[Aminoiminomethyl) amino] -2-chlorophenyl) carbonyl] amino] ethylfluorenyl] amino] Phenylpropionic acid; 3S-[[2-[[[3-[[[[((4- (Aminosulfonyl) benzyl) amine) tomb] (cyanoimino) methyl] amino]] [Carbonyl] amino] amino] ethenyl] amino] -4-pentanthic acid; lu-[[2-[[[3-[[amino (aminocarbonyl) imino] methyl] amino] Phenyl] carbonyl] amino] ethenyl] amino] -3,5 -dichloro-phenylpropanoic acid ethyl ester; 'ling-[[2-[[[[[[Aminecarbonyl]). Imino] methyl] amino] phenyl] carbonyl] amino] ethenyl] amino] -3} 5-dichlorophenylpropionic acid; 3,5-dichloro-fluorene-[[2- [ [[3-[[((ethoxycarbonyl) amino]] [(ethoxycarbonyl) imine] methyl] amino] phenyl] carbonyl ] Amine] ethylammonyl] amine.phenyl] phenylpropanoic acid; ling-[[2-[[[3-[(aminoiminomethyl) amino]] 4-chlorophenyl] carbonyl] amine [Ethyl] ethenyl] amino] ethyl 3,5 -dichlorophenylpropionate; ling-[[2-[[[3-[(aminoiminomethyl) amino] -4-chloro] Phenyl] carbonyl] amino] ethynyl] amino] -3,5-diphenylphenylpropionic acid; 3S-[[2-[[[3-[[amino [[aminocarbonyl] imino) imine ] Methyl] amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] -4-pentynyl ethyl ester; 3S-[[2-[[[3-[[amino [[amino Carbonyl) imino] methyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -4-pentynyl acid; 3S-[[2-[[[3-[(amino group Aminomethyl) amino] -4-chlorophenyl] carbonyl-yl] amino] ethylfluorenyl] amino] -4-pentynyl ethyl ester; 3S- [[2-[[[3- [ (Aminoiminomethyl) amino] -4-aminophenyl] carbonyl ____ -85- This paper size is in accordance with China National Standard (CNS) A4 (210X297). (Please read the back Note for re-filling this page) Order. _ 4 6 LD Q. Printed by ABCD Printed by the Consumer Affairs Cooperative of the China Liquor Bureau of the Ministry of Economic Affairs Scope of Patent Application: Amine] Ethyl]] Amine] -4- Valproic acid; (±) point -[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -3,4-dichlorophenylpropionic acid; ( Soil) net-[[2-[[[3-[(aminoiminomethyl) amino] -5- (triaminomethyl) phenyl] carbonyl · amino] amino] ethenyl; | Amine] —3,5-dichlorophenylpropionic acid; _ (±) 10,000-[[2-[[[[[[Aminoiminomethyl) amino] benzene tomb] carbonyl] amino] Ethyl] amino] -2,5-dimethylphenylpropanoic acid; (Earth) / 3-[[2-[[[3-[(Aminoiminomethyl) amino] phenyl]] Carbonyl] amino] ethylammonium] amino] -3 -ethyl phenylpropionate; (±) point-[[2-[[[3 _ [(aminoiminomethyl) amino] phenyl] phenyl ] Carbonyl] amine] ethyl] ethyl] amino] -3-bromophenylpropanoate; (±) stone-[[2-[[[3-[(aminoiminomethyl) amino]] Phenyl] carbonyl] -amino] ethylfluorenyl] amino] -3-bromophenylpropionic acid; (±) / 3-[[2-[[[3-[(aminoiminomethyl)) amine [Phenyl] carbonyl] amino] ethyl] ethyl] amino] -4-bromophenylpropanoic acid ethyl ester; (±) yS-[[2-[[[3-[(aminoiminomethyl ) Amine] phenyl] carbonyl] Amine] Ethyl] Amino] -4 -moprofenic acid; (±) zhao-[[2-[[[3-[(Aminoiminomethyl ) Amino] phenyl] carbonyl] Amine] acetate] amino] · 3,5-dimethylphenylpropanoic acid; (±) point-[[2-[[[3-[(aminoiminoamido) amino) phenyl] phenyl ] Carbonyl] amino] ethylammonio] amino] -3,5-dimethoxyphenylpropanoic acid; (±) cold-[[2-[[[3-[(aminoiminomethyl y Amine] phenyl] carbonyl; j_amino] ethoxylamino] -3,5-dichlorobenzylic acid (2,2-dimethyl-1-oxypropoxy) methyl ester; __- 86- This &amp; Zhang Zhiping uses China National Standards (CNS) _A4 specifications (21〇2 for public directors) &quot; (Please read the _ notes on the back before filling this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Health ¾. 4 Insurance] 56 U C8 D8 VI. Patent Application Scope * «(±) 3,5- 二 气 -yS-[[2-[[[[[[ Cyanoimino) (methylamino) -methyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] phenylpropionic acid; (±) fluorene-[[2-[[[3 -[[[(Aminocarbonyl) imino] methylamino] methyl] amino] phenyl] carbonyl] amino] $ fluorenyl] amino] -3,5-dichlorophenylarsinic acid; ( Soil)-[[2-[[[3-[(Aminothiomethyl) amino] phenyl] carbonyl] amino] ethyl] amino] -3,5-dichlorophenylpropionic acid ; (±) 々-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino]. Ethoxy] amino] -3,4 -di Moprofen; • (±) cold-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl brewing tomb.] Cavity]- 3- (3-fluoromethyl) phenylpropanoic acid; (±) 10,000-[[2-[[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ] Ethylyl] amino] -3-odorant 5-like phenylpropanoic acid; (±) Lu-[[2-[[[3-[(aminoiminomethyl) amino] phenyl) phenyl ] Carbonyl] amine] ethyl ethyl] amino] -3,5-diphenylphenylpropionic acid; (±) point-[[2-[[[3-[(aminoimine (Methyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -3-bromo-5-methylbenzene'propanoic acid; (±) call-[[2-[[[3- [ (Aminoiminomethyl) amino] -5- (trifluoromethyl) phenyl] carbonyl] amino] ethylfluorenyl] amino] -3,5-dibromophthalic acid; (±) Cold-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] amine tomb] -2 -Cyclo-4-methoxy Benzoic acid; (±) stone, [[2-[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl ethyl] amine] -5- -4 * methoxybenzo p-furan-6-bis-acid; (±) β- [[2-[[[3 _ [(aminoiminoamido) amino] benzene: yl] carbonyl ] -87- This paper is free to use Chinese National Standards (CNS) Α4 wash (210X297 mm) (锖 Please read the precautions on the back before filling this page) Order: 5 6 5 α ABICD VI. Patent Application Amine [Ethyl] ethenyl] amino] -9H-fluoren-2-propionic acid; (±) fluorene-[[2-[[[3-[(aminoiminomethyl) amino] benzyl] carbonyl ] Amino] Ethylamido] Amino] -3,5-dichloro-2-hydroxyphenylpropanoic acid; (±) stone-[[2-[[[3-[(Aminoiminomethyl)) Amine] phenyl] carbonyl] amine] ethanyl] amino]- 2-hydroxy-5-nitrophenylpropionic acid; _ (±) /?-[[2-[[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl Fluorenyl] amino] -3,5-dibromo-2-hydroxyphenylpropanoic acid; (earth); S-[[2-[[[3-[(aminoiminomethyl) amino] benzene [Carbonyl] amino] amino] ethenyl] amino; 1-5 -bromo-2-hydroxyphenylpropanoic acid; V (terephthalene)-[[2-[[[3-[(aminoiminoimidomethyl) (Amino) amino] phenyl] carbonyl] amino] ethenyl] amino: I-cyclohexanepropanoic acid; (±) θ-[[2-[[[3-[(Amineimine (Methyl) amino] phenyl] carbonyl], amino] ethylfluorenyl] amino; 1-3,5-dichloro-2-hydroxybenzylic acid ethyl ester; (±) 10,000-[[2- [[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylethyl] amino] -5 -chloro-2-hydroxyphenylpropanoic acid; (±) Lu- [[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] -3-bromo-5 -chloro-2-hydroxybenzene Propionic acid; printed policy of Zhengong Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) (±) 5-amino-/?-[[2-[[[3- [ (Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethynyl] amino] -2-hydroxyphenylpropionic acid; (±) Mundane-[[2-[[[3--[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -5 -bromo-pyridine-3 -Propionic acid; (±) 3,5-dichloro-ban-[[2-[[[[[((ethoxycarbonyl) amino] thiomethyl-yl] amino] phenyl] yenyl] Amine] ethynyl] amino] -phenylpropionic acid; 3,5-dichloro-cold-[[2-[[[3-[[[(ethoxycarbonyl) amino] iminomethyl]]- 88- This paper Xj! Free use China National Kneading Rate (CNS) A4 specification (210X297 mm) CC 6 5 ABCD Central Bureau of Standards, Ministry of Economic Affairs, Shellfisher, consumer cooperation, printing 6. Application for patent scope Amine] Phenyl] Carbonyl] amino] ethylfluorenyl] amino] benzenedicarboxylic acid; fluorene-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino; [ethyl Fluorenyl] amino] [1, 丨 '-biphenyl] -3 -propionic acid; cold-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl ] Amine] Ethylamido] Amine] Pyrimidine-5 -propanoic acid; Lu-[[2-[[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] Ethyldonyl] amino] -3 -methyl p-phenen-2-acid; (earth) stone-[[2-[[[3-[(aminoiminomethyl) amino] phenyl) phenyl ] Carbonyl] amine] ethyl] ethyl] amino] · 3- (methylthio) -benzene Acid; (±) point-[[2-[[[[[Aminoiminoamido) amino] phenyl] carbonyl] amino] ethylethyl] amino] -6-methyl- Pyridine-2-propionic acid; ling-[[2-[[[[[aminoiminomethyl) amino] phenyl] carbonyl] amine.yl] ethylammonium] amino] -3- (Methanesulfonyl) -phenylpropanoic acid;-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl}]. ] _3,5 · diethoxy · phenylpropionic acid; (Shi) / 3-[[2-[[[3-[(Amineiminomethyl) amino] phenyl] carbonyl] amino] Acetyl] amino] -4-bromopyrimidine-2-propanoic acid; /?-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amine [Ethyl] ethenyl] amino] -5 -chloropyrimidin-2 -propionic acid; ling-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] carbonyl] Amine] acetamidine] amino] -1H -pyrazole-3-propionic acid;-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] Amine-yl] ethynyl] amino] -5-methylρ-phene-2-propanoic acid,-[[2 · [[[3-[(Amineimidomethyl) amino] phenyl] phenyl ] Carbonyl] Amine paper size quick use China National Standards (CNS) Α4 grid (210x297 cm) --------- JJ-- (Please read the back first Please pay attention to this page and fill in this page again) Order JH. 458956 Bismuth CS D8 VI. Application for special scope of scope] Ethyl hydrazine] Amine] -2,3,5-trigas-benzylpropionic acid; Wan-[[2- [[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino] -2- (carboxymethoxy) · phenylpropionic acid;-[ [2-[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethanyl] amino] -4-methoxy-1J-benzenedioxo- 6-propionic acid; not-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethenyl] amino] -5-bromo-2 -Methoxyphenylphenylpropionic acid; cold-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] 'ethylamidine] amino] benzo Furan-2 -gallic acid; ling-[[2-[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -3- ( Carboxymethoxy) -benzylpropanoic acid; 3-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amine.yl] ethenyl] amino] -4,4,4-trifluorobutanoic acid; (±) cold-[[2-[[[3 · [(aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl} ] Amine] -3 -bromo-4,5-dimethoxyphenylpropanoic acid 3-[[2-[[[3-[(Amineimine Methyl) amino] phenyl] carbonyl] amino] ethenyl] amino] -4-methylvaleric acid; printed by Shelley Consumer Cooperative, Central Stairs Bureau, Ministry of Economic Affairs (Fill in this page) 07. 3-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethenyl] amino] -valeric acid; Ling -[U-[[[3-[(Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylammonium] amino] -5 -bromo-3-chloro-2-hydroxy- Phenylpropanoic acid; cold-[[2-[[[3-[[[(4-pyridylmethyl) amino] carbonyl] amino] benzene_yl] carbonyl] amino] ethenyl] amino] Pyridine-3-propionic acid; 3,5-dichloro-ling-[[2-[[[[[[(4-pyridylmethyl) amino] carbonyl] carbonyl] _- 90 -___ This paper is 逋Using the Chinese standard (CNS) A4 (210 &gt; &lt; 297 public ^^ 4 ^ 58 9 56) Application scope of the patent Amino] phenyl] carbonyl] amino] ethenyl] amino] -benzene Propionic acid; (Please read the notes on the back before filling out this page) Call-[[2-[[[3-[[[(2-Pyridylmethyl) amino] carbonyl] amino] phenyl]] Carbonyl] amino] ethenyl] amino] pyridine-3-propanoic acid; 335-dichloro-; 5 · [[2-[[[3-[[[(benzylmethyl) amino]] [Amino] Amino] Phenyl] carbonyl] Amino] Ethyl} Amino] Phenylpropanoic acid; 3-chloro-cold-[[2-[[[3-[[[(phenylbenzyl) amino]] Carbonyl group] amino group] phenyl group] carbonyl group] amino group] acetamidine] amino group] phenylpropionic acid; lingering-[[2-[[[[[(1-phenylethyl) amino]] carbonyl group ] Amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] pyridine-3 -propionic acid; /?-[[2-[[[3-[[[[[(1Η-Benzimidazole-2 -Yl) methyl] amino] carbonyl] amino] phenyl] carbonyl] amino] ethylethyl] amino] -3,5-dichlorobenzylic acid;,-[[2-[[[[ 3-[[[[((3,5-Diphenylphenyl) methyl] amino] carbonyl] amino] phenyl] phenyl] carbonyl] amino] ethynyl] amino] pyridine-3-propionic acid; 3 -[[2-[[[3-[[Π (3,5, dichlorophenyl) methyl] amino] carbonyl] amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] but Acid; ling-[[2-[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] ethenyl] amino] -3,5-bis (1- Methyl-ethoxy) phenylpropanoic acid; Employees' cooperatives printed by the Central Bureau of Standards of the Ministry of Economic Affairs printed $ L Shi-[[2-[[[3-[(Aminoiminomethyl) amino] phenyl] Carbonyl] amino] ethenyl] amino] -3,5-dibromo-4-hydroxyphenylpropanoic acid; call-[[2-[[[5-[(aminoimino Aminyl) amino] -2-hydroxyphenyl] carbonylhydrazine] amino] ethenyl] amino] -3,5-dichloro-phenylpropionic acid; ling-[[2-[[[[[[[ (Phenoxyamino) carbonyl] amino] phenyl] carbonyl] amino] ethylammonyl] amino] pyridine-3 -propionic acid; ____- 91 -_ This paper is in accordance with China National Standards (CNS) A4 specification (210 × 297 mm) ABCD 458 9 56 6. The scope of patent application is not-[[2-[[[3-[[[(aniline) amino] carbonyl] amino] phenyl] carbonyl] amine] ] Ethylamido] amino] pyridine-3 -propionic acid; ling-[[2-[[[3-amino_ 基, 2,4 · triazole-3 -yl] amino]] Phenyl] carbonyl] amino] ethenyl] amino group 3,5-dichloro-phenylpropanoic acid; 3-[[2-[[[3-[[(Amine-iminomethyl)) amino ] Phenyl] carbonyl] amino] ethenyl] amino] -5 _ [(3,5-dichloro-phenyl) amino; | _5-oxypentanoic acid; ling-[[2-[[[[[[ 3-[[(Aminoiminomethyl) amino] _5_carboxyphenyl] quinyl] amino] ethylfluorenyl] amino] pyridine-3 -propionic acid; ling-[[2- [ [[3,5-bis [(aminoiminomethyl.yl;) amino; | phenyl] carbonyl] amino] ethylfluorenyl] amino] -3,5-digas · phenylpropionic acid; Cold _ [[2-[[[3-[(aminoiminomethyl) amino] _5 · (tri Fluoroacetamidine.yl) amino 1phenyl] carbonylcarbonyl] amino] ethanyl] amino] —3,5-dichlorophenylpropionic acid; (±) 3,5-dichloro-ling-[- 2-[[[3-[[(methylamino) (fluorenimine) methyl] amino] phenyl] carbonyl] amino] ethynyl] amino] phenylpropionic acid; (±) 3, 5-dichloro-zhao-[[2-[[[[[(Ethylamino) (methylimine tomb) methyl] amino] phenyl] carbonyl] amino] ethylammonium] amino] Phenylpropionic acid; (±) 3,5_ dichloro- / 5-[[2-[[[3-[[[((1-methylethyl) amino]] (methylimino) methyl] amino) ] Phenyl] carbonyl] amino] ethenyl] amino] phenylpropanoic acid; (±) m-[[2-[[[3-[[(ethylamino) (fluorenimine) methyl] Amine] -phenyl] carbonyl] amino] ethenyl] amino] -4-fluorophenylpropanoic acid; (±) 4-fluoro_ling-[[2-[[[[[[1 (1 -Methylethyl) amino] (methyl-92-)-This paper uses China National Standard (CNS) A4g (210X297) (Please read the precautions on the back before filling this page) Order Λ V Printed 458956 Α8 Β8 C8 D8 from the Central Bureau of Standards of the Ministry of Economic Affairs. 6. Scope of Patent Application &gt; * Amino) methyl] amino] phenyl] carbonyl] amino] ethoxy]. Amine ] Phenylpropanoic acid (±) 4-fluoro- / S-[[2-[[[3-[[[(4-pyridylmethyl) amino] (methylimino) methyl.amino] amino] phenyl] carbonyl ] Amino] Ethylamido] amino] phenylpropanoic acid; cold-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amino] ethyl] ] Amine] -4-fluorophenylpropionic acid; (±) -dot-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl ] Amine] -1H-imidazole-2-propanoic acid; cold-[[2-[[[[[[Aminoiminomethyl) amino] phenyl] carbonyl] amino] ethylfluorenyl] Amine] -2,3,5,6-tetrafluorobenzoic acid; ling-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amine.yl] Ethyl] amino] -5 -bromopyrimidin-2 -propionic acid; ling-[[2-[[[3-[(aminoiminomethyl) amino]] phenyl] carbonyl] amino group ] Ethylammonyl] amino] -2-fluorenylphenylpropanoic acid; (earth) dot-[[2-[[[3-[(aminoiminomethyl) amino] phenyl] carbonyl] amine [Ethyl] ethenyl] amino] -5-chloro-2-sulfophenylpropanoic acid. Printed by the Consumers' Cooperatives of the China Prospective Bureau of the Ministry of Economic Affairs 19. According to the 17th application for a patent, the pharmaceutical composition of which γΐ, Ν_R2, and R2 are cyano. 20. The pharmaceutical composition according to item 19 of the scope of patent application, wherein the compound is selected from the group consisting of:-[[2-[[[3-[[(cyanoimino) methylamino] methyl] amino] ] Phenyl] carbonyl] amino] ethenyl] amino] benzyl propionate; ling-[[2-[[[. 3-[[(cyanoimino (amino) methyl)] Amine] Phenyl] -93- This paper size uses Chinese National Standards (CNS) A4 Appearance (210X297 public envy) 4SB AS B8 C8 DS Phenyl] phenylpropanoic acid; g-[[2-[[[3 _ [[(cyanoimino)] [(benzyl) amino] methyl] amino] phenyl] condensate] Amino group] Ethyl group] Amino group] Phenylpropionic acid; Ling-[[2-[[[[[[cyanoimino) (methylamino) methyl] amino] phenyl] carbonyl] Amine] Ethylamido] Amino] phenylpropanoic acid; Dot-[[2-[[[3-[[Amine (cyanoimino) methyl] amino] phenyl] carbonyl.yl] amine [Ethyl] ethenyl] amino] phenylpropanoic acid; ling-[[2-[[[([cyanoimino) (ethylamino) methyl] amino] phenyl], carbonyl] Amine] ethenyl] biyl] phenylpropanoic acid; .. 3S-[[2-[[[3-[[(cyanoimino) (methylamino) methyl] amino] benzene ] Carbonyl] amino] ethenyl] amino] -4-pentynyl ethyl ester; .3S-[[2-[[[3-[[(cyanoimino) (methylamino) methyl ] Amino] benzene, carbonyl, carbonyl] amino] ethenyl] amino] pentanoic acid; ling-['[2-[[[3-[[(cyanoimino)] [2-pyridyl Methyl] amino] methyl] amino] phenyl] carbonyl] amino] ethenyl] amino] phenylpropionic acid · ethyl ester; LING-[[2-[[[3 _ [[cyano Amine) [2-pyridylmethyl] amino] methyl] amino] phenyl] carbonyl] amino] ethylammonyl] amino] phenylpropanoic acid; call-[[2-[[[3- [[(Cyanoimino) [3-pyridylmethyl] amino] methyl] amino] phenyl] carbonyl] amino] ethoxy] amino] ethyl phenylpropionate; call-[ [2-[[[[[(Cyanoimino)] [3-Pyridinylmethyl] amino] methyl] amino] phenyl] carbonyl] amino] ethoxy] amino] benzene Propionic acid; 3S-[[2- [J; [3-[[[[((4 · (aminosulfonyl) benzyl) amino) amino] (cyano-imino) methyl] amino] Phenyl] carbonyl] amino] ethenyl] amino] -4-pentynylacetate; -94- Chinese paper standard (CNS) A4 size (210X297 male *)-* --- --- I-, _i —Λ κ [(Please read the notes on the back first (Fill in this page) Order-Λν. A8 B8 C8 D8 卞 45 · 3 9 printed by Shellfish Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 6. Scope of patent application 3S-[[2-[[[3-[[[[[ (4- (Aminosulfonyl) benzyl) amino] (cyanoimino) methyl] amino] phenyl] carbonyl] amino] ethanyl] amino] -4-pentyne Acid; (±) 3,5-digas-methyl-[[2-[[[[[[Cyanoimino) (methylamino) methyl] amino] phenyl] carbonyl] amino] Acetyl] amino] phenylpropionic acid. 21. The pharmaceutical composition according to item 5 of the scope of the patent application, where A is N Rs N—R7 IR0 where Y1 is N-R2;. R2 and R7 together form a triazole; R5 and R8 are hydrogen The male labor consumer cooperative of the Central Central Bureau of Standards and Pharmacy printed a pharmaceutical composition according to item 21 of the scope of patent application, where V is -N (R6)-, where R6 is selected from Η and C! -6 alkyl; 1; t is 0; p is 1. 23. The pharmaceutical composition according to item 22 of the scope of patent application, wherein the compound is selected from the group consisting of: 3,5-dichloro- / 9-[[2-[[[[[[ -2,4-dioxopyrimidin-6-yl) amino] phenyl] -carbonyl] amino] ethylfluorenyl] amino] ethyl phenylpropionate. -95- This paper size applies to China National Standards (CNS) A4iJUS · (2 丨 0X297) The scope of patent application is fine. 24. According to the patent composition of the patent application Fanyuan No. A, D2, Y2, and NR7, where γ2 is _m0-R9, where envy and R7 form a 5 or 6 member. A heterocyclic ring containing one nitrogen and one sulfur; or R9 and R7 together are oxazole; and R5 and R7 are as defined above; or 'Y2 (when Y2 is carbon) together with R7 to form a 5-7 member -nitrogen ring. 25. The pharmaceutical composition according to the scope of application for patent No. 24, wherein ya 2 and trans 7 together form a 5-7 member ring. 26. The pharmaceutical composition according to item 25 of the scope of the patent application, wherein V is -N (R6)-'wherein R6 is selected from the group;' η is 1; t is 0; p is 1. 27. The pharmaceutical composition according to item 26 of the scope of application for a patent, wherein the compound is selected from: (±) points-[[2-[[[3-[(3,4,5,6-tetrahydro-21 ^ nitrogen Hexamidine_7-yl) yl] benzyl] akynyl] amino] ethynyl] amino] kappa_3-diacid; (±) zhao-[[2-[[[3-[( 3,4,5,6_tetrahydro-2H-azafluoren-7-yl) amine] phenyl] carbonyl] amino] 6 fluorenyl] amino] -1,3-benzodioxo-5 -Propionic acid; 96- This paper is a Chinese standard (CNS) Α4 size (210X297) 嫠 1 ~~ 'n · I. ~~ -1 — J—i — (谙 Please read the notes on the back first (Fill in this page again) 、 1T Printed by CCB of the Ministry of Economic Affairs of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, CC 4 ABCD, printed by the Central Standards Bureau of the Ministry of Economy, Shellfish Consumer Ik Cooperative, printed patent application scope * (±) LING, [[2-[[ [3 ”[(3,4,5,6-tetrahydro-21! -Azepine-7-yl) amine] phenyl] carbonyl] amino] ethanyl] amino] -phenylpropionic acid; (±) Not-[[2-[[[3-[(3,4-dihydro-21pyrrole-5-yl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -pyridine -3-propionic acid; (soil) Lu-[[2-[[[4-chloro-3-[(3,4,5,6-tetrahydro-2H-aza leather-7-yl) amino] Phenyl] carbonyl] amino] ethylfluorenyl] amine ] Pyridine-3 -ethyl propionate; (±) ling-[[2-[[[4-chloro-3-[(3,4,5,6-tetrahydro-2H-azale-7-yl ) Amino] phenyl] carbonyl] amino] ethenyl] amino] pyridine-3 -propanoic acid; (soil)-[[2-[[[4-chloro-3-[(3,4, 5,6-tetrahydro-2H-aza-7-yl) amino] phenyl] carbonyl] amino] ethyl] ethyl] pyridine-3 -propionic acid; (±) LING-[[ 2-[[[3,5-bis [(3,4,5,6-tetraargon-2H-azafluorene-7-yl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino ] Pyridine-3-propanoic acid; (±) fluorene-[[2 _ [[[[[[[Remoteaminophenylmethyl] amino] phenyl] carbonyl] amino] amino] ethylfluorenyl] amino] pyridine -3 -propionic acid; (±) / 3- [[2-[[[[[[3,4,5,6-tetrahydro-2H-azepine-7-yl) amino] phenyl] Carbonyl] amino] ethenyl] amino] -4-pentynyl acid; therapy-[[2-[[[3-[(4,5-diazolo-2-yl) amino] phenyl ] Carbonyl] amino] ethyl] ethyl] amino] pyridine-3 -propionic acid ethyl ester; (土) 召-[[2-[[[3-[(3,4,5,6-tetrahydro- 2H-azapyridin-7-yl) Amine] phenyl] carbonyl] Amine] Ethylamido] Amine] -3,5-dichlorophenylpropionic acid; (CNS) Μ specifications (2i〇 &lt; 297 mm) (Please read the back first Notes on filling out this page) 6 5 9 3 5 ABCD 6. Application scope (±) Cold-[[2-[[[[[[[[[3,4-Difluorene-2H-pyrrole-5-yl) amino] phenyl] carbonyl] Amine] ethylammonium] amidine] -3,5-dichlorobenzene bis.Acid; (±) 3,5-dichloro-Ling-[-[2-[[[3- [4,4] , 5-tetrahydropyridine-6-yl) amino] phenyl] carbonyl] amino] ethylfluorenyl] amino] -phenylpropionic acid; (±) 3,5-dichloro-2-hydroxy-Ling- [[2-[[[[[[[[3,4,5,6-tetrahydrazone-azafluorene, 7-yl) amino] phenyl] carbonyl] -amino] ethanyl] amine ;-[[2-[[[3-[(5,6-dihydro-4H-thienin-2-yl) amino] phenyl] carbonyl] amino] ethyl] ethyl] amino.] Pyridine -3-propanoic acid; 3,5-dichloro- / 3-[[2-[[[3-[[Imine. (1-Hexahydro? 1 specific methyl) methyl] amino] phenyl ] Carbonyl] amino] -acetamido] amino] phenylpropanoic acid; β-[[2-[[[3-[(benzoxazol-2-yl) amino] phenyl] carbonyl] amino ] .Acetyl] amino] pyridine-3 -propionic acid &quot; 28. The pharmaceutical composition according to item 15 of the scope of patent application, in which the compound is selected. From: ΝΗ (谙 Please read the precautions on the back before filling in this Page) * ir Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs -98- Chinese paper rubbing scale (CNS) A4 pit (2 丨 0X2? 7mm) Ge Yi, ". Λ | · Vi- ·,» · lj Y Staff Consumption of Central Bureau of Standards, Ministry of Economic Affairs Cooperative printed AS B8 C8 D8 patent application scope _- 99- The scale of this paper uses the Chinese National Rubbing (CNS) Α4297 21 OX297 mm ABCD t d58956 6. Scope of patent application 6. Printing policy of J Industrial Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs -100- (Please read the notes on the back before filling this page) The standard of this paper is Chinese national standard (CNS &gt; A4 now (210X297mm)?! ^ 458 9 56 AS Β8 C8 DS 6. Application scope h2n ^ .n NΗ Η Printed by the Employees' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs Λ) (谙 Please read the precautions on the back before filling in this page) -101-This paper size is applicable to China National Standards (CNS) Α4 size (2! 〇 ×: 297 mm). Printing 458956 A8 B8 CZ D8, patent application scope -102- (Please read the precautions on the back before filling this page) '^. Q. This paper uses the Chinese national standard (CNS &gt; Α4 size (2l0X; 29 &quot; 7mm) for patent application) h2n ^ c. Public-AS B8 C8 DS H, N Printed by the Men ’s Consumer Cooperatives of the Ministry of Economy, Central Standards Bureau -103- (Please read the notes on the back before filling out this page) This paper size is applicable to China National Standards (CNS) A4 (210X 297 mm)?! ^ '45B 9 56 A8 BS CS D3 VI. Scope of Patent Application II Η NH Η l! O Printed by Industrial and Consumer Cooperatives -104- The size of this paper is in accordance with China National Standard (CNS) A4 (210X2? 7mm) -s '6 LO * /' B 5 4 8 8 8 οο ABCD Application scope Η: cno ONC NHnc Η CNO one (Please read the notes on the back before filling this page) Η NM-C cno Η -Ν 印 Indian policy of the Central Laboratories of the Ministry of Economic Affairs of the Bayong Consumer Cooperative Η / NNC π 2 Η ° -105- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (2I0X297mm) 458956 6. Scope of patent application A8 BS C8 D8 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The size of this paper is in accordance with China National Standards (CNS) A4 (210X297) d58956 6. Scope of patent application Α8 Β8 CS D8 NH2II c'II ο XXj (Please read the precautions on the back before filling out this page) Printing Policy of Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs -107- This paper uses Chinese National Standard (CNS) A4 (210 × 2ί &gt; 7mm) 45895 ^ 6. Scope of patent application (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -108-This paper uses China National Standard (CNS &gt; A4 size (210X297mm)) | | r45B96 ^ A8 B8 C8 D8 ΓΗ 〇 〇 II Η, C, II 〇 I 印 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs X Consumer Cooperatives i? NH II C〆 II o -109- (Please read the notes on the back before filling this page) This paper music scale is applicable to national standards (CNS) Α4 specifications (2 丨 0X297 mm) 5 6B9 ABCD 6. Scope of patent application Q! (Please read the precautions on the back before filling out this page) _ Order. Printing policy of the Consumers ’Cooperative of the Central Government Bureau of the Ministry of Economic Affairs This paper size is applicable to China National Standard (CNS) A4 (21〇 &gt; &lt; 297mm) 54 6 5 ABCD 6. Scope of Patent Application τΤγ Η Ν, 'C.ChEt 'CO2H (Please read the notes on the back before filling out this page) Printed by the Male Workers Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs ό c〇2B -111 · This paper size is applicable to China National Standards & CNS) A4 size (210X297 mm) 458956 A8 B8 CS D8 , ΝΓ Η Ν'νγ / ^ · 〇02Είo (please read the precautions on the back of the cabinet before filling out this page) The policy of the Consumers' Cooperative of the Central Bureau of Work, Central Ministry of Economic Affairs CH3XX S〇2 H2N ^ S HN. 〇 H H ό 'C〇2Et | H H , C〇2H. O 112- This paper size is applicable to China National Standards (CNS) A4, see the grid (210X297) * Printed by the Bayou Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs 458 9 56 8 8 8 8 ABCD VI. Application Patent scope HN'C- ° HN rr Η , 〇H 、 cril ο 113 &lt; Please read the notes on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specification (210X297 cm.) Γ 4 58 9 5.6 ABCD Η Η C IIο, ΟΗ Η ο NC-V ΝΗ2 ίΓΤ 丫 ⑽. ° ό Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperatives NC * Et〆 · ^ ΝΗ Η 'C〇2Et 114 (Please read the notes on the back before filling this page) The paper size is in accordance with Chinese National Standards (CNS) A4 specifications (210 × 297 mm) A8 BS C3 D8 6. Scope of patent application (Please read the notes on the back before filling out this page), 1T Printed by tK Industrial Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs -115-This paper scale is applicable to the Chinese National Standard (CNS) A4 wash case (210X297 mm) β LQ9rD5 4 8 88 8 ABCD patent application scope 〇 .NH Me ^ Η 'C02H (Please read the notes on the back before filling this page) Ό ό. Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperatives Η Η C〇2HA ο 116- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 458956 6. Scope of patent application A8 B8 C8 D8 The paper scale is applicable to China National Standard (CNS) A4 (210X297 mm.) Δ58 956 8888 ABCD 6. Scope of Patent Application (Please read the notes on the back before filling out this page) Λ Dong-/ Order Printed by the Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs -118- This paper uses the Chinese National Standard (CNS) A4 specification (210 × 297 mm) A8 BS C8 D8 458956 Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ο Η 2 ο -119- {Please read the notes on the back before filling this page) This paper music Xj Wen Xiao uses the Chinese National Standard (CNS &gt; A4 size (210X297 mm) A 4 53 9 56 ___- 120- The size of this paper is in accordance with China National Standards (CNS) A4 (2 10 × 297 mm) p-4 5B 9 g C8 D8 6. Scope of patent application 〇 Printed by the Consumer Cooperatives of China Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page] -121-This paper music scale is applicable to China National Standards (CNS) Sixty Four Cells (210 × 297 mm) 4 β 3 9 Α8 BS C8 D8 VI. Patent Application 〇 νη &quot; Ύ NhV ^ C02H Br (Please read the precautions on the reverse side before filling out this page) Printed by the Consumers ’Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs ^ NH -122- Chinese paper standard (CNS) A4 washing standard (2I0X297 mm) of this paper standard Δ5B 9B6 ABCD VI. Patent application scope 〇 ΝΗ m nh ^ t ^ co2h o Hi 〇 t-Bu (Please read the precautions on the back of the product before filling out this page.) Printing policy of Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs CN Called 123 _ This paper size adopts China National Standard (CNS) A4 size (210X297 mm) 458956 6. Scope of patent application Printed by the Shellfish Consumer Cooperative of the Central Sample Bureau of the Ministry of Economic Affairs -124-(Please read the notes on the back before filling this page) This paper uses the Chinese National Standard (CNS) A4it grid (210X297 mm) 458 9 56 Α8 Β8 C8 D8 Patent application scope H2 ΝΗ 〇 Nl ΝΗ Printing policy of the Consumers' Cooperatives, Central Standards Bureau, Ministry of Economic Affairs F • 125 · The size of this paper is applicable to China National Standards (CNS) A4 see-through (210 × 297 mm) 6 5 9 8 54 ABCD patent application scope H2N HNV ^ -N , co2h Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs -126- (Please read the notes on the back before filling this page) This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 458 956 A 8 B8 C8 D8 Φ -127 -__ This paper size is applicable to China National Standards (CNS) Α4 size (2! 〇X297 公 Organization) (# 先 min read the notes on the back before filling this page) 6 5985 4 ABICD 6. Scope of patent application HN. HsN, Co2Et, CI Ct. CO ^ H HN \ f-bN 〇 Νύσα (Please read the notes on the reverse side before filling out this page) u. NH CQ2H. 、 1T · O -Ν ' NH. NK H2O OH o. Printed by Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economy HN \ -128-Standard for this paper: China National Standard (CNS) Α4 size (210 × 297 mm) 458 956 A8 B8 C8 D8 6. Scope of patent application Π Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs ΗΝ ^ ΝΗ ΝΚ Ph CO2H -129- (Please read the precautions on the back before filling out this page) This paper size is applicable to Chinese National Standard (CNS) M specifications (2 丨 0X297 mm) 4 kr 85 ABICD 6. Scope of patent application SMe Ministry of Economic Affairs, Central Bureau of Standardization, Cooperative, Middle East, Cooperative, Middle East (Please read the notes on the back before filling out this page) This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (210X297gong) -130-_ A8 B8 C8 D8 Printed by the Consumers' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs 458956 6. Scope of patent application ci ΰη -131 -_ Chinese paper ladder standard for paper scale (CNS &gt; A4 size (210X297)) (Please read the precautions on the back before filling in this page) s 5 9 8 5 4 ABCD patent application scope ΝΗ ^ V ^ C〇2H N / NH, NH2 ΝΗ * ^ Νγ, ΝΗν ^ ^ C〇2Hi 0 ch3 NH) O c NH Ministry of Economic Affairs, Yin Jun, Prospective Staff, Consumer Cooperatives, India HN ^ Team A Anh ^ v ^ nh,, c〇2h H02C -132 (Please read the notes on the back before filling this page) This paper size is applicable to Chinese Standard (CNS) A4 specification (210X297 mm) 0 S985 4 T IP ABCD 0 The policy of employee consumer cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs C〇2H -133- (Please read the notes on the back before filling this page) The scale of this paper is printed in accordance with Chinese National Standard (CNS) A4 (210X2? 7mm). (Please read the precautions on the back before filling in this page) The dimensions of this paper are applicable to the Chinese National Standard (CNS) A4 (210X297 mm). The Central Bureau of Standards of the Ministry of Economic Affairs, Peugeot Consumer Cooperatives, India 53 9 5β ^ C8 D8 6 Scope of patent application (Please read the precautions on the back before filling this page) -135- This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 458956 8 δ 8 8 ABCD (Please read the precautions on the back before filling out this page) Printed by CI, Employees' Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs -136- The standard of this paper is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 cm) 65985 4 ABCD VI. Patent Application Scope CI (Please read the notes on the back before filling in this tile) Printed by the Men ’s Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs _- 137-_ This paper size is applicable to the Chinese National Standard (CNS) A4 (2i × 297mm): 4589¾6 Patent Application Range A8 B8 CS D3 ο PK (Please read the precautions on the back before filling out this page) Order Λ: I Printed by the Consumer Sample Cooperatives of the Central Bureau of Procurement, Ministry of Economic Affairs -138-This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 cm) 9 5π Α8 Β8 C8 D8 Scope of patent application , C〇2H (Please read the precautions on the back before filling out this page) Printed by the Central Bureau of Standards, Ministry of Economic Affairs and Consumer Cooperatives 〇 〇 〇 丨 1_ ^ I! Hoc &gt; ^^ hc ΝΗα cr ^^ ci 139 The paper scale is applicable to Chinese national standards (CNS &gt; A4 gauge (210X297) Λ -NH 659β5 4 ABICD VI &quot; Approval of patent application Printed by the Central Government Bureau of the Ministry of Economic Affairs (Please read the note on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) i, v · Scope of patent application ο 〇 A8 B8 C8 D8 Cao NIT, Κ ^ Ν— , Ν Ο C〇2H Ό〇2Η ΝΗ (Please read the notes on the back before filling out this page) * 1Τ Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs F F! &Quot; [ΐ -141-This paper size applies to China National Sample (CNS) Α4 size (210 X 297 mm) 458 956 A8 B8 C8 DS Scope of patent application Br --------- T-/-(谙 Please read the notes on the back before filling in this page) Order Printed by J Industry Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs Cl Η Η cr II 〇 -OH 1 -142- This paper music 1 is applicable to Chinese national standard (cns) A4 specification (210 × 297 mm) * 458 9 ^ 6 ABCD (Please read the notes on the back before filling out this page) Printing policy of the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs , 17. · Γ ^ 458956 ^ D8, patent application Ganwei, printed by male workers' consumer cooperative of Central Standards Bureau of Ministry of Economic Affairs (Please read the notice on the back before filling out this page) This paper size is applicable to China National Standard (CMS) A4 scale (210X297 mm) T, τ ____I. Fry 4BS 9 56 A8 B8 C8 DS VI. Patent application scope 〇 NH ' C NH C02H! Cl Ο Alas. CO2H j Printed by the Shellfish Consumer Cooperative of the Central Sample Bureau of the Ministry of Economic Affairs 〇 H rrV &quot; c〇2H called 145- (Please read the precautions on the back before filling this page) The size of this paper is printed by China National Standard (CNS) A4 (210X2S7 public director) \ 4 65 9 A BC D This paper size applies to China National Standard (CNS) A4 (210X297mm) 458956 Patent Application No. 118 Amendment of Patent Scope (July 1990) ABCD Gong Heyu "Spoken Chinese Seal 1 Patent Application Scope Compound 〇 ^ II fCH2Jp-C'-R Η RP. Ri Please read the precautions above or its pharmacologically acceptable salt, where A is Υΐ. —Ν Ν—R7 R5 R0 &gt; IT Central Bureau of Standards In the seal of the male labor consumer cooperative, 合作 1 is selected from N-R2, 0 and S; R2 is selected from Η; Cu alkyl group; cyano group; amine carbonyl group; Cw alkoxy group; alkyl group is optionally substituted with amine group; or R2 and R7 together form an amine-substituted triazolyl group; or R7 (when not bonded to R2) and R8 are each selected from Η; C 丨 -8 alkyl; benzyl; aniline; Cu Alkylcarbonyl; alkoxycarbonyl; phenoxy; phenyl; alkyl is optionally substituted with a substituent selected from the group consisting of: aryl, phenyl, pyridyl, benzimidazole, and fluorenyl; A plurality of substituents selected from the group consisting of: functional groups, fluorenyl groups; -s02R 'where Ri0 is phenyl and optionally substituted with Ci-6 alkyl groups; NR7 and R8 together form a 5-membered nitrogen-containing group Single ring; This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297)