TW442489B - Compounds useful as antiproliferative agents and GARFT inhibitors - Google Patents

Abstract

The invention generally relates to compounds of the formula I, which are in equilibrium with their 4-hydroxy tautomers, and their pharmaceutically acceptable salts: where n is 0 to 2; A is S, CH2, O, NH or Se, and when n is 0, A is not CH2, and when n is 1, A is not CH2 or NH; X is a substituted or unsubstituted C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or amino, or sulfur or oxygen; Ar is a substituted or unsubstituted monocyclic carbocycle or heterocycle, or fused or nonfused polycyclic carbocycle or heterocycle; and R1 and R2 are hydrogen or a moiety that forms together with attached CO2 a readily hydrolyzable ester group. These compounds and their salts are useful as inhibitors of GARFT or as antiproliferative agents. The invention also pertains to pharmaceutical compositions and methods employing such compounds as GARFT inhibitors or antiproliferative agents. The invention also relates to compounds useful as intermediates for preparing such compounds, and to their synthesis.

Description

44248 9 Α7 A 7 B7 V. Description of the Invention () This case is a pseudo-partial application of US Patent Application No. 03/010861 filed on January 29, 1993. BACKGROUND OF THE INVENTION The present invention does not include a compound as defined below, which inhibits the enzyme glycamine amide nucleotide formaldehyde transferase (GARFT). The present invention also relates to intermediates used to prepare these compounds *, pharmaceutical compositions containing these compounds, and their use for inhibiting GARFT and for inhibiting higher organisms or emblem organisms such as bacteria, yeasts, and fungi Cell growth or proliferation. This compound has bloated, anti-inflammatory, curable, and / or immunosuppressive activity. The invention also relates to the preparation of these compounds. The Ministry of Economic Affairs 4-Central Government Bureau, Shellfish Consumer Cooperative Du Printing Pack (Please read the precautions on the back before filling out this page) The larger class of anti-proliferative drugs contains anti-metabolic compounds. One of the anti-metabolites holds another class of compounds, such as known antifolates or antifoles, which are antagonists of the biotin folic acid. Generally speaking, antifolates are more compatible with pharmacologically active structures and incorporate the P-benzylglutamic acid moiety of osmic acid. The fumaric acid's linamic acid portion is double negatively charged at physiological pH. Therefore, this compound and its analogs have an active energy, which pseudo-drives the transmission system to pass through the cell membrane and gains thanksgiving. Glycine sleep nucleotide N-methyltransferase (GARFT) is presumed to be a folic acid-dependent enzyme in a biosynthetic pathway of 嗦 昤 resynthesis. This pathway is important for cell division and proliferation. It is known that closing this pathway has an anti-proliferative effect and, more particularly, an anti-tumor effect. Therefore * many folates are synthesized and studied for their ability to inhibit GARFT. This paper uses China National Standard Vehicle (CNS) A4 (210X297 mm) 442489 A7 B7 5. Description of the invention () A prototype of GARFT, a tightly bound inhibitor 5, 10-diazepine tetrazolic acid It is reported to show antitumor activity. FM Muss iat # fFoIate ant iaetabo 1 i te inhibitor to de novo purine synthesis, New Drugs t Concepts and Result in Cancer Chemotherapy, K1uver Acaden ic Publishers, Boston (1992), 65-87 ° Compound * which contains a glutamic acid or ester moiety. This compound is effective in inhibiting the growth or proliferation of cells of higher organisms or stimulating organisms such as bacteria, yeasts, and fungi on the enzyme glycinolamine nucleotide formaldehyde transferase (GARFT). The present invention further pertains to pharmaceutical compositions containing these compounds or their suitable hydrochloric acid | and the use of these compounds for GARFT inhibition. Du Yinzhuang, responsible for labor and consumer cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs (锖 Please read the notes on the back before filling in this 苋) As mentioned before, the compounds of the present invention have antiproliferative effects, a form of antitumor activity To perform. The compounds of the present invention are either active by themselves or pre-empted before being converted into an active compound in a living skull. The preferred compounds of this invention are particularly active on GARFT. The to-be-compared compound 傜 is active against the growth inhibition of L1020 cell lines and mouse leukemia cell lines that can grow in tissue culture media. The compounds of the present invention inhibit the growth of bacteria, such as E. coli, a Grignard-negative bacterium that can grow in culture medium. The compounds according to the invention and their pharmaceutically acceptable salts can be added to traditional dosage forms, such as capsules, lozenges or injectable preparations. National or national standards (CNS) A4 (210X297 mm) 44248 9 Consumption Cooperation of Employees of the Central Bureau of Standards of the Ministry of Economic Affairs 枉 India policy A7 B7_5. Description of the invention (.) Liquid pharmaceutical acceptable Carriers, diluents or excipients can also be used. Solid carriers include splash powder, lactose, calcium sulfate dihydrate, stone powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate Salt and stearic acid. The liquid certificate contains syrup, peanut oil, olive oil, saline, and water. The carrier or diluent contains any substance that can be prolonged, such as glyceryl monostearate or distearate alone. Glyceryl fatty acid or its combination with tincture. When a liquid carrier is used | The preparation is a syrup, elixir, emulsion, soft gelatin, capsule, sterile injectable liquid (such as a solution) or a non-aqueous or aqueous solution The pharmaceutical preparation is prepared in accordance with the traditional techniques of pharmaceutical chemistry. When it is necessary to form a lozenge, it involves step I or mixing such as mixing, granulation, and waist shrinking. This ingredient is suitable for producing desired products for oral administration, parenteral administration, topical administration, intrauterine administration, intraburial administration, intratracheal administration, intraocular administration, intraaural administration, and rectal administration. The composition of the invention further comprises one or more other pharmaceutically active compounds. For example, one of the following antitumor agents may be included in the composition; a cleavage inhibitor (e.g., pentobarbital); an alkylating agent ; Dihydrofolate transportase inhibitor or TS inhibitor; antimetabolites (for example, 5-air uracil I cytosine arabinoside); embedded antibiotics (for example, adriaticin, bleomycin): enzymes (E.g., asparaginase); topoisomerase (e.g., etoposide); biological response modifiers (e.g., interferon). The compounds of the present invention may also contain < read first For the matters needing attention, please fill in this S) The paper scale is remotely used Chinese National Standard (CNS) Α4 size (210X297 mm) Printed by the Central Government Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperation Du printed 44248 9 A7 B7 V. Description of the invention ) GARFT inhibitory or anti-proliferative agents, such as the compound shown in International Application No. PCT / US93 / 11795 filed on December 10, 1993, or the compound of International Publication No. W092 / 05153 published on April 2, 1992 The disclosures of these two applications are listed here as reference materials. The compounds of the present invention may also contain one or more antibacterial, antifungal, antiparasitic, antiviral, anti-ringworm or anticoccidial agents. Exemplary antibacterial agents include amines, such as sulfamethoxazole, sulfadiazine, sulfaparamethoxine, or glutamine o-dimethoxypyrimidine; dihydrofolate reductase inhibitors, such as Trimethylwuqi Yuan Beer Lake, B r ο η 〇diaprim or trimetre X ate; penicillin egg; vanguard emblem; and quinol-carboxylic acid and its fusion isothiazole analogues. Another aspect of the present invention is a method for inhibiting the growth and proliferation of cells of higher animals or microorganisms, which comprises administering an effective amount of a compound of the present invention to a host. The compounds of the invention are particularly useful for treating mammalian hosts (e.g., human hosts) and for treating bird hosts. An excellent treatment method involves administering to a host an effective amount of a compound of the invention that inhibits GARFT. Many of the anti-proliferative compounds described herein, as well as their pharmaceutically acceptable salts, are useful in the methods of treatment of the present invention. The compound may be administered in the form of a pack containing a diluent or a pharmaceutically acceptable composition as described above. -The dose of the compound contains at least one effective amount of the active compound, and is preferably made into one or more pharmaceutical dosage units. An "effective S" means an amount that is sufficient to inhibit the folic acid metabolic pathway and can benefit from it, for example, via administration of one or more drug dosage units. The size of the paper method applies to the Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling out this page) Order 442 48 9 A? B7 V. Description of the invention () Illustrated by the vertebrate host The daily cut amount includes an amount of up to 1 gram of active substance per kilogram of host * preferably half a gram per kilogram of host weight, more preferably 100 gram, and most preferably about 50 gram or less. The selected dose can be administered to a warm-blooded or breast-feeding pupa (for example, a human patient to be treated by the folate metabolic pathway tune). This can be done by any known method of administering the dose, It includes: topical administration, such as a soft palate or an emulsion; oral administration; direct administration, such as a pillar; parenteral administration for injection; or "intrauterine, #internal, intratracheal, ear Intravenous or intraocular administration to administer mosaic. The compounds according to the present invention can produce anti-proliferative effects, anti-bacterial effects, anti-parasite effects, anti-viral effects, anti-ringworm effects, antiprotozoal effects, anti-coccidial effects, anti-inflammatory effects, an immunosuppressive effect, and an One or more antifungal effects. The compounds of the present invention are particularly useful for producing an antitumor effect in a tumor-bearing vertebrate host.发 明诺诺 _ Ruiming The present invention is pseudo-antiproliferative compound capable of inhibiting GARFT and having the following general formula I: ...------I----I ^ i- HI ^ nn HI n (Please read the precautions on the back before filling out this page) Printed by the Consumers' Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs 0

Of which -9-This paper size applies to China's national kneading rate (CNS M4 specification (2 丨 0X297 mm) Printed by the Central Consumers' Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 44243 9 Λ7 Α7 Β7 V. Description of the invention () η is one in An integer between 0 and 2; Α is sulfur, CH2, oxygen, NΗ, or selenium, but it is specified that when η is 0, A is not CHz, and when η is 1, A is not CH2 or NH; X is at least once Substituted or unsubstituted Ci-Ca alkyl, substituted or unsubstituted C2-C3 alkenyl, substituted or unsubstituted (; 5-(: 3 alkynyl, substituted or unsubstituted Amine, sulfur or chlorine; A "is a mono- or mono-substituted or unsubstituted monocyclic or heterocyclic ring, or a fused or unfused polycyclic sulfonyl or heterocyclic ring system; and 1 ^ And 82 are respectively nitrogen or a moiety which is combined with the linked C02 to form a hydrolyzable ester group. The present invention is based on a pharmaceutically acceptable salt of a compound having the general formula I. ^ and The preferred parts of 1 to 2 are hydrogen, Ci-Cs alkyl, hydroxyalkyl, and aralkyl. Other preferred parts are hydrogen and cz alkyl. When X or Ar is substituted, right) ί Best with Ar * The group contains Ci-Cs alkyl, Cz-Cc alkenyl, C2-Cs alkynyl, fluorenyl, halogen, amine, hydroxy, nitro, hoop, monocyclic sulfo or heterocyclic, fused or Unfused polycyclic master or heterocyclic ring system, hydroxy Ci-U alkyl group, oxy Ci-Cs alkyl group. In other cases, A is 碕 and Ar is phenyl. Preferred compounds include subordinate compounds with the general formula] I 〇- This paper is still suitable for China National Standards (CNS) A4 specifications (2Ϊ0 × 297 male iT " (please read the precautions on the back before filling in the book) Page) Order 442489 A7 B7 V. Description of the invention ()

0

(Please read the notes on the back before filling out this page) where A 'is sulfur or ® 5 (_ is CHZ, sulfur, chlorine or HH;

Ar 傜 is as defined in Formula I; and 1 ^ and 1? 2 are as defined in Formula I; and a pharmaceutically acceptable salt thereof. The preferred parts of 1 and 3 are hydrogen, Ci-Cs alkyl, hydroxyalkyl, and aralkyl. Other preferred parts are hydrogen and h alkyl. A is preferably fluorene, 5T is preferably CH2, and A "is a phenyl group. Although the compounds represented by the general formula Ϊ and the general formula I are 4-chloro groups, and the compounds are used throughout the description of the present application. Alleged by this, but there is an interconversion equilibrium between the gas-based hydrazone and the corresponding 4-hydroxy group, and in the first case, the form of hydroxy groups that can be exchanged with each other is also indicated in this case * pseudo-glassy. The quasi-station employee consumer cooperative printed compounds with the general formula I and] Σ (where d and ^ are hydrogen) as an active antitumor and antiproliferative compound. Compounds with the general formula I and E (where Ri and 傜 are joined Co (3) easily forms an ester group, preferably ethyl) is a novel intermediate that forms the free glutamic acid form of the compound, and can also be hydrolyzed in vivo. Therefore, it can be used as a prodrug. Also contains pharmaceutically acceptable salts • Contains such as the present invention -11-This paper size applies to Chinese national standards (CNS > A4% grid (210 × 297 mm) 442489 A7 B7 V. Description of the invention (Imino acid implementation Examples of gold test salts, soil test salts, other non-toxic salts, ammonium And substituted salts such as, but not limited to, the following salts: sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethylammonium , Pyridinium salts and substituted pyridine anchors. The compounds of general formula I can be prepared by reacting the following compounds of general formula I [with a compound of general formula IV ... 0-

(III) (Please read the precautions on the reverse side before filling out this page) Policy_ [wherein B is halogen, preferably bromine]

ORj (IV) Order 0 M Printed by the Central Ministry of Economics and Labor Cooperatives of the Ministry of Economic Affairs [wherein 5Γ, A ', and Ar are as defined by general formula] I, and are hydrogen, straight bonds, or branched or ring-shaped One or more cyclins, hydroxyls or amines (^ to Ce alkyl), the reaction is in the presence of a base other than a compound of the general formula and in which at least one of the reactants is at least partially Dissolved in a suitable solvent, and under sufficient conditions to obtain a compound of general formula V: -12-This paper size is applicable to the country's national standard (CMS) A4 (2 丨 0297 g) 44248 9 〇

A7 B7 V. Description of the invention ()

(V) I

[Where X ', A', and A "are as defined by the general formula] I, and h is as defined by the general formula IV]. The inverse of the compound of the general formula ί and the compound of the general formula IV is preferred. A suitable solvent is used in which at least one or two of the reactants are soluble at the corresponding temperature. The solvent and the reaction environment are preferably prepared by passing a passivated gas (such as neon gas) before the reactants are introduced. Or nitrogen) to bubble through the solvent to remove gas. The bubbling of the inert gas is preferably flail until the reaction is complete and quenched, such as pouring into water. The preferred solvent is bipolar and aprotic. Solvents such as dimethylarylene, Ν, Ν-dimethylformamide, Ν, Ν-dimethylethylamine, or N-methyl-2-pyrrolidone. Compounds of general formula IV The neutral medium in the reaction provides a non-nucleophilic auxiliary. It is defined as a test that can neutralize the hydrogen halide generated by replacing the reaction. The sulfonic acid age or alkaline earth Or a trialkylamine, such as trimethylamine, triethylamine, or diisopropylethylamine. It is preferred to perform the reaction of a compound of general formula II and IV Method 僳 Suspend a compound of formula I, preferably 5-bromo-2,6-diamine-4 (3H) -S-pyrimidine * in a solvent. Then add the compound of formula IV and Auxiliary bases 0 -13-and paper size standards (CNS) A4 specifications (210X297 public director " 1 (please read the precautions on the back before filling this page) Order

According to the Ministry of Education, stamping the car calendar, Zhenggong Consumers' Cooperatives Co., Ltd. A 442489 A7 B7 5. Description of the invention (The reaction tank is immersed in an oil bath that has been heated to a suitable temperature (20-200¾, preferably 70-1200). The reaction The mixture can be stirred at this temperature for a necessary length of time (typically 30-330 minutes) * and then cooled to room temperature and poured into water. The product, a compound of general formula V, in a suitable solvent and in It is sufficient to obtain a compound with the general formula VI (preferably cross flow conditions), and react with an acid (preferably hydrogen acid):

H2N

(VI) where / Γ and Ar · are as defined by the general formula E, and R3 is as defined by the general formula IV. Then the compound with the general formula W is reduced, preferably "Hydride Reduction * to obtain a compound with the general formula W: I --------- # —— (Please read the notes on the back first (Fill in this question again), tr Central government Ministry of Economics sample printed for Zhengong Cooperative Cooperative

(VII) where A ', X' and Ar are as defined by the general formula E * and R3 is as defined by the general formula w. Compounds of general formula V5 are hydrolyzed under alkaline conditions to form general formula 14-The paper ruler A (Chinese national standard (CNS) A4 washer (210X297 mm) 44248 9 Α7 Β7 V. Description of the invention ( ) Compound of VI:

HN

, 0 (vm)

HjN wherein A ', X' and Ar are as defined in Formula 2. When R3 on a compound of the general formula υΐ is hydrogen, this reaction step is unnecessary, and the compound of the general formula can be combined as described below. The compound of general formula VI (or a compound of general formula, where h is hydrogen) is a free carboxylic acid form, which can be modified by an amino acid diester in a manner known to those skilled in the art. Hydrogen hydride peptide coupling • to form compounds of general formula IX: 0

C〇! «T (IX) {Please read the note on the back first, and then fill out this page) Order the Ministry of Economic Affairs t folder 棣 Receiving Bureau Shellfish Consumer Cooperatives printed A ', X' and Ar ·, 1 ^ and 1 ~ 2 is defined by the general formula I, but Ri and R 2 are not 氲. Finally, if desired, the compound of formula IX can be hydrolyzed to the free amino acid form as shown by the general formula υπ (! ^! &Amp; 3 = 1 {). Preferred compounds of the general formula IX include: (2- [4- [2-ί2-amino-4-4 -15 This paper is based on Chinese National Standards (Liyang), 4 rules per cell (210 Father 297 mm) 442489 A7 B7 V. Description of the invention (), 6,7,8-Air trioxide-3 [1-pyrimido [5,4,6] [1,4] thiazin-6-yl)- Ethyl] -benzylidene glutaric acid diethyl ester; and (2- [4- [2- (2-Amino-4-4,6,7,3-Gas-3H-pyrimido [ 5,4-6] [1,4] thiazin-6-yl) -ethyl] -benzaldehyde] -glutaric acid. The L form of these compounds is preferred. The present invention relates to a compound having the general formula XI Antiproliferative compounds: 0

B C

Men ’s Consumer Cooperatives of Central Bureau of Standards, Ministry of Economic Affairs, printed A is 0, S or Se X is a substituted or unsubstituted Ci-C3 alkyl group, a substituted or unsubstituted C2-C3 alkylene group, a substituted one Or unsubstituted (: 2-(: 3 alkynyl, substituted or unsubstituted amine, sulfur or gas; Y is 0, S or NH; B is gas or tooth element (F, Ci, Br Or I); C is hydrogen, halogen, or a substituted or unsubstituted Ct-Cs alkyl group; and d and. Are respectively hydrogen or a moiety that combines with the attached Coz to form a hydrolyzable ester group. For example, Ci-Cs alkyl. The present invention further relates to a pharmaceutically acceptable salt of a compound having the general formula XI. The present invention also relates to an intermediate product for producing the compound. Although the compound system of the general formula XI shows 4- "Air-based form" and this compound is referred to in this case's rectification description, but the air-based image is related to -16-^^^ 1 ^^^ 1 ^^^ 1 n-II i--—LE ^ mfl ^^^ 1 ml κϋ one raJ (Please read the notes on the back before filling this page) The paper method scale uses the Chinese National Standard (CNS) Μ specification (2 [0 × Μ7 mm) 442 48 9 Α7 Β7 5 ,hair Explanation (Economic beep prints that the 4-hydroxy group printed by the Jeonggong Consumer Cooperative Co., Ltd. has an interconversion equilibrium. Therefore, the compound of the present invention contains the structure 4-gas and the 4-hydroxy form of the interconversion equilibrium. It is understood that, according to the present invention, there is also a pharmaceutically acceptable salt of a 4-hydroxyisomorph of a compound of formula XI. When X or C is substituted, the preferred substituents include Ci- "Alkyl, C2-CB alkenyl, Ca-Cs alkynyl, fluorenyl, halogen, amine, hydroxy, nitro, fluorenyl, monocyclic master, monocyclic heterocycle, fused or unfused Polycyclic sulfo ring or fused or unfused heterocyclic ring system, hydroxyl Ci-Cs group, Ci-Ce group, Ci-Cs group. Preferably, X is CH2, CHiCH2, NH, gas, sulfur, CH (CHdH) or NH. Y is preferably S or 0. More preferably * B is hydrogen. C is preferably hydrogen or CH3. More preferably, each of * 1 ^ and 1? 3 G is self-hydrogen, alkyl, hydroxyalkyl, alkaryl, and aralkyl *. It is preferably selected from hydrogen and Ct-G alkyl. Those who are better are A and Y are both sulfur. X is CHZ. Compounds having the general formula XI are inhibited by using GARFT. Compounds of general formula XI (where ^ and ^ are all hydrogen) 葆 particularly have antitumor and anti-proliferative agents. Compounds of general formula XI (where 1 ^ and 1 ^ are combined with CO; forming an easily hydrolyzed An ester group, preferably an ethyl group, is a useful intermediate that forms the free glutamic acid form of the compound, and can be hydrolyzed in the living body, so it can be used as a pioneer drug. The pharmaceutically acceptable salts of the present invention Contains * for example alkali gold salts, alkaline earth salts, other non-toxic salts, ammonium salts and substituted ammonium salts of the compounds of the invention. Exemplary salts include the sodium, potassium, lithium, calcium, magnesium, anchor, and substituted anchor salts of the free acid compound. 17-Standards of this paper: National Standards of China (CNS) Μ Wash grid (2ίΟχ2? 7mm) (Please read the precautions on the back before filling this page), τ Γ 44248 9 A7 B7 V. Description of the invention ( ) A compound having the general formula XI is prepared as shown below. A starting material used to prepare a compound of general formula XI (where X is Cih) is a compound of general formula XII:

0¾ (XII) wherein B, C, and Y are as defined by formula XI; C is Cl, Br, or I; Rs is hydrogen or a moiety that combines with the attached C02 to form a hydrolyzable ester group. Preferably, D is bromine or iodine. Preferably, Re is M, (^-"alkyl, hydroxyalkyl, alkaryl, or aralkyl, and hydrogen and (^-(: 2 alkyl are more preferred. Compounds having general formula XII Pseudo-reaction with a compound of general formula απ:-·-.........-... (XIII) (Please read the notes on the back before filling this page) Exaggerate the central rubbing rate of the Ministry of Economic Affairs扃 Consumer Cooperative Cooperative Seal «. Where R3 is a substituted or unsubstituted {^-(: 6 alkyl or tris-substituted silyl group. Preferably R3 is CHaOH or trimethylsilyl group. The reaction of a compound of the general formula XII with a compound of the general formula XIII is in the presence of a suitable transition metal catalyst (preferably pseudo-rake or nickel), a non-nucleophilic auxiliary plutonium (preferably a substituted amine) • In a solvent in which at least one of the reactants can be at least partially dissolved, and in a sufficient amount to obtain a paper with a standard of -18 paper, applicable Chinese National Standard (CMS) M specification (2IOXM7 mm) 442489 A7 B7 V. Description of the invention () Kxiv's reaction under the chopsticks:

Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, where b, c and γ are defined by the general formula π above; ^ is defined by the general formula XΠ; ϋ3 傜 is defined by the general formula XIII above. When r3 is a tri-substituted silyl group * The silyl group is preferably pseudo-nucleophilic base, such as methanolic or ethanolic potassium gallate, or such as potassium gasification, gasification, or tetrabutylammonium The gasified salt is removed in a suitable solvent (such as formazan, dimethylformamide, or isopropanol) in which at least one of the reactants is at least partially soluble to produce a compound having the general formula XV: ac (XV): I where B, C, and Y are defined by the general formula π; and 傜 are defined by the general formula 3 (11. With the general formula xv compound tree and an electrophile (preferably aN-to- Butanylcarbonyl anhydride) reaction, or di-H-butanylcarbonylglycolic acid condensation anhydride) reaction * It is pseudo-low temperature (preferably about -90 to 251) * and at least one of the reactants may be A suitable solvent which is at least partially soluble (preferably tetrahydrofuran, -19-

This paper is a standard f country S family standard rate (CMS) A4 * t grid (2I0X297 mm) (Please read the precautions on the back before filling this page)

/ i AO A ^ Q A7 B7 V. Description of the invention (diethyl ether or dioxane), and the use of non-nucleophilic base test papers to reverse S • to produce a compound of the general formula XVI:

(m) wherein B, C, and Y are as defined by the general formula XI; and R6 ^ is as defined by the general formula XII; and R * and RS are each hydrogen or an easily removable nitrogen protecting group. R4 and RS are preferably hydrogen, fluorene-butoxycarbonyl, benzylmethyl or phenylmethyl 0 and then the compound of general formula XVI is reduced, preferably in the presence of a suitable gold sulfonium catalyst and reduced with 1 gas * to produce A compound of general formula XV II: The real sample consumer cooperation of the Central Sample Rate Bureau of the Ministry of Economic Affairs

(XVII) where B, C, and Y are as defined by the formula XI; and Rs nickel is as defined by the general formula χπ; and R «and R5 are as defined by the general formula XVI. Then the compound of the general formula XV II is present in the presence of a non-nucleophilic (preferably diethylamine or diisopropylethylamine), and reacts with at least one of -20 (please read the note on the back first) (Fill in this page again)

This paper size is applicable to China National Standards (CMS) A4 specification (210X 297 mm) 44248 9 A7 B7 V. Description of the invention () In a suitable solvent in which the substance can be at least partially dissolved * With an ammonium or sulfonating agent ( (Methylsulfonaldehyde or P-toluenesulfonaldehyde) is preferred to produce an active hydroxyl group. The active hydroxy group is pseudo-compatible with a suitable nucleophile *, preferably a thio acid *, more preferably potassium thioacetate, and reacted to produce a compound having the general formula XV ill:

COjR «(Please read the notes on the back before filling out this page) (XVIII) where A, B, C and Ym are as defined by general formula XI; and as defined by general formula XII; and h and Rs are like As defined by the general formula XVI; and Ac is an aldehyde group, preferably an ethyl truncation group. The Ministry of Economic Affairs, China ’s Bureau of Economics and Industry has cooperated with the Ministry of Industry and Energy to make the system, or, in a suitable solvent, use triphenyl, diethyl or dimethyl nitrogen-dicarboxylic acid and an acidic nucleophile (compared with It is preferably thioacetic acid) that can convert a compound of general formula XVII into a compound of general formula XV III. In a fermentation solvent, preferably methanol, ethanol or isopropanol, and in the presence of an alkylating agent (preferably dimethyl malonate or diethyl ester), the compound of general formula XV II is Affinity treatment, preferably pseudo-treatment with potassium sulfonate, sodium strontium, sodium hydride or potassium argon, to obtain a compound having the general formula XIX: -21 ) A4 size (210_X 297 mm) 44248 9 A7 B7

5. Description of the invention ((XIX) where A, B, C and Y 傜 are as defined by the general formula XI; and as defined by the general formula XΠ; and R * and Rs are pseudo as defined by the general formula XVI. The compound of formula XIX is processed under conditions suitable for the removal of either or both of the R4 # RS protecting groups to produce a compound of the general formula XX: (Please read the "Notes on the back side before filling out this page")

(XX) Order the consumer cooperation order of the Central Procurement Bureau of the Ministry of Economic Affairs, where A, 8, C, and Y are defined by the general formula XI; and ε? ^ Are defined by the general formula XII. When t-BOC is a protecting group, the conditions for removing the group are treated with acetic acid and then neutralized to produce a compound having the general formula XX. In a suitable solvent, preferably dioxane, the compound 傜 of the general formula XX is reacted with an alkylating agent, preferably with trimethyl or triethyloxyphilic tetrafluoroboric acid to form an intermediate aldehyde Imine ether ° This intermediate is an internal aldehyde 22-This paper uses the standard of China National Liang Zhun (CNS) A4 (210X297 mm) 44248 9 V. Description of the invention () Imine ether in a fermentation solvent (compared with Preferably methanol, ethanol or isopropanol) to react with a guanidine to form a compound having the general formula XXI:

_ COjfl · (XXI) (Please read the notes on the back * before writing this page) where A, B, C and Y are as defined by the general formula XI; and Rs is as defined by the general formula XII. Alternatively, the compound having the general formula XX is reacted with a monosulfurizing agent, preferably with PiSs or 2,4-bis (4-methylaminophenyl) -1,3-dithio-2,4-di Phosphetane (~ 2,4-disulfide) is converted into a compound having the general formula XX I to form a monoaldol compound. Then it is in a suitable alcoholic solvent (preferably methanol, ethanol or Isopropyl alcohol), alkylation with an alkylating agent, preferably alkylation with methyl iodide or trimethyl or triethyl air anchor tetrafluoroacetic acid, and then alkylation with guanidine to obtain the formula XXI The compound of the general sample XXI printed by the Ministry of Economic Affairs of the Central Bureau of Work and Consumer Cooperatives is hydrolyzed under alkaline conditions to form a compound of the general formula XXII: CNS) A4 specifications (2 丨 OX297 mm) 44248 9 A7 B7 Five invention descriptions ()

(XXII)! Ί Among them A, B, C and Υ are as defined by the general formula XI. When Rs of the compound of the general formula χχί is hydrogen, the hydrolysis reaction is unnecessary, and the compound of the general formula XIX is a coupled peptide as described below. The compound of the general formula XXII (or a compound of formula XXI ' And among them, RS argonine) free carboxylic acid form, a method known to those skilled in the art can be used to form a diester with the general formula XXIII: (Please read the precautions on the back before filling out this page)

a c

Among them, A,. B, C, and Y are as defined by the general formula XI; and Ri is a portion that is bonded to C02 to form an easily hydrolyzed ester base, such as Ci-Cs alkyl, Hydroxyl, fluorenyl or aralkyl. Finally, if desired, the compound with the general formula XXIII is hydrolyzed to -24-This paper uses the Chinese National Standard (CNS) A4 specification (210X297 mm) 442 48 9 A7 B7 V. Description of the invention () has Free lysine forms of the general formula XI (Ri and R3 are hydrogen respectively). Compounds having the general formula XI (wherein X is not CH2) can be prepared using olefins having the general formula XXIV: a

(XXIV) where B, C, and Υ are as defined by the general formula XI; except that X is not CHZ, the X is as defined by the general formula XI, and Rs is as defined by the general formula XII. When X is fluorene, oxygen, or a substituted or unsubstituted amine group * The compound of general formula XXIV is alkylated by the compound of general formula XXV shown below:

(Please read the precautions on the back before filling this page) (XXV) Printed by the Ministry of Economic Affairs, the Bureau of Work and Consumer Cooperatives, where B, C and Y are as defined by the general formula XI; X is 碕, "or A substituted or unsubstituted amine group, and h is as defined by the general formula XII. The alkylation reaction uses a propenyl halide, preferably a propenyl desert, and is completed in the presence of a non-nucleophilic age (preferably triethylamine or diisopropylethylamine). To obtain a compound having the general formula XX IV. When X—substituted or unsubstituted is not (: ^ .-. Alkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted -25-this paper size Applicable to the Chinese national standard {CMS) M wash grid (210X297 mm) 442489 A7 B7 V. Description of the invention () C2-C3 alkynyl group, the compound with the general formula XXIV can be Aldehydes of formula XXVI are prepared by olefination:

C

COA-(XXVI) Printed by the Central Procurement Bureau of the Ministry of Economic Affairs of the Industrial Consumer Cooperative XV 0 where B, C and Y are as defined by the general formula XI; X is a substituted or unsubstituted non- (: heart of ^ -Alkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted cz-c3 alkynyl. Xue with the general formula X XVI is available similar to the Journal of Chuan shih of Medicinal Cheaistry v〇 丨 .35 (1992), 1109-1116. The olefination of the aldehyde can be carried out using a methyl group transfer group, preferably methylidene-triphenyl ortho knee. Done. A compound having the general formula XXIV is reacted with a dihydroxy agent in the presence of a suitable oxidant, preferably pseudomethyl-N-gas, preferably pseudo-quaternary reaction * To obtain a compound having the formula XXVII: C0 »R · (XXVII)

HO-^ * __- The standard of this paper is easy to use in a country (CNS) A4 Zigzag U10X297 mm) — ^^ 1- ^^^ 1 tn n nn n · — In n In nn In I < Please First read the notes on the back and then fill out this page) 4 4 2 4 8 9 A7 B7_V. Description of the invention () Where B, C and Y are as defined by the general formula XI; except that X is CH2, X is false As defined by the general formula XI, and Rs is as defined by the general formula XII. A compound having the general formula XXVII is reacted with monosulfofluorene in the presence of a non-nucleophilic age, preferably triethylamine or diisopropylethylamine. Reaction to form an intermediate monosulfonylated compound. This intermediate is reacted with a strong age, preferably with sodium argon, to produce a compound of the general formula χχνίϋ: '8. C — COjR * (XX7III)

X

Jn- ml # I flu I mf i ^ n ^^^^ 1 ^^^^ 1 ^^^^ 1 ^^^^ 1 ^ (please read the precautions on the back before filling this page) Central Ministry of Economic Affairs Standard Bureau employee consumer cooperatives printed ^ (:, 乂,? And 1 ^ 傜 as defined by the general formula) (¥¥ 11. In the presence of a weaker Lewis acid catalyst, it is preferable to use aerobic acid In the presence of lithium or magnesium | react a ring gaseous compound hydrazone of the general formula XXVIII with a nitrogen-containing nucleophile, preferably with sodium azide | to obtain an intermediate product alcohol azide. This intermediate product is Lotus, preferably reduced with hydrogen in the presence of a gold catalyst, and then protected with a suitable nitrogen protecting group > preferably, protected by butoxy, benzoyl or benzyl Zhi | in order to produce a compound having the general formula XVII ': -27-This paper is applicable to the national standard (CNS) A4 (2 丨 0X297 mm) of the paper size 5. Description of the invention () A7 B7

COafl, (XVII,) where B, C, X, Y and 傜 are as defined by the general formula XXVII;] {4 and 1 ^ 傜 are as defined by the general formula XVI above. In a suitable solvent that at least partially dissolves at least one of the reactants * and in the presence of a non-nucleophilic amidine, preferably in the presence of diethylamine or diisopropylethylamine, the The compound of formula XVIL is reacted with a sulfonating agent or a sulfonating agent, and is preferably reacted with methylsulfonyl ammonia or p-toluenesulfonic acid to obtain an active hydroxyl group. The active hydroxyl group is replaced with a suitable nucleophilic amidine, preferably a thio acid salt, more preferably potassium thioacetate to produce a compound having the general formula xv III '-------- --This-(Please read the notes on the back before filling out this page) DuPont Packing

(XVIIX,) where A is defined by the general formula XI; B, C, X, Y, and Rs are defined by the general formula -28-China Paper Standard (CNS) A4 (4) 〇x297 mm) 44248 9 A7 B7 V. Description of the invention (as defined by XXVII; 1-4 and 1 ^ are as defined by the above general formula XVI; and Ac is a fluorenyl group * preferably an acetamyl group. Or, in A chemical operation using triphenylphosphonium, diethyl or dimethyl nitrogen-dicarboxylic acid, and an acidic nucleophile (preferably thioacetic acid) can convert a compound of the general formula XVII 'into Compounds of general formula XV III. In an alcoholic solvent * preferably in a solvent of methanol, ethanol or isopropanol, and in the presence of an alkylating agent, preferably dimethyl malonate or In the presence of ethyl esters | The compound having the general formula XVII 'is treated with a nucleophilic base. Preferably it is treated with potassium sulfonate, sodium sulfonate, hydrazone or hydrazone hydroxide to obtain a formula Compounds: C Please read the notes on the back before filling in this page)

< = 〇Λ (XIX,) Ordered by the Central Government Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives, where A 傜 is defined by the general formula XI; β, c, X, γ and 僳 are defined by the general formula 5 (5 (VII R * and Rs are as defined by the general formula XVI above. Compounds having the general formula XIX 'are processed under chopsticks suitable for removing either or both of R4 and Rs protecting groups to produce a Compounds with general formula XX ': -29 This paper uses Chinese National Standards (CNS) A4 (2Ι0χ 297) and 4 42 4S 3 A7 B7 V. Description of the invention ()

B: C

C02fl. Ί '(XX,) 丨

Among them, A 傜 is defined by formula XI; B, C, X, Υ, and Rs are defined by general formula XXVII. When a butoxycarbonyl group (t-BOC) is a sulphonyl group * The conditions for removing the group are assumed to be treated with difluoroacetic acid and then neutralized * to produce a compound having the general formula XX '. In a suitable solvent, preferably digas methane, the compound 逋 of the formula XX 'is reacted with an alkylated hydrazone, preferably with trimethyl or triethyloxatetramorubic acid | to form an intermediate product Aldehyde ether. The intermediate aldimine is reacted with a guanidine in an alcohol-soluble solvent (preferably methanol, ethanol, or isopropionate) to form a compound having the general formula XY; (Please read the note on the back first (Fill in this to buy)

, TT Central Government Ministry of Economic Affairs, Industry, Cooperation and Printing

(XXI,) where A is defined by the general formula XI; B, C, X, Y, and Re ^ are defined by the general formula XXVII. Or * Compounds with the general formula XX '"from reaction with a vulcanizing agent, -30-This paper size applies to Chinese standards · (CNS) A4 wash grid (2 丨 0X297 mm) 4 4248 9 A7 B7 V. DESCRIPTION OF THE INVENTION () Preference is given to PzSs or 2,4-bis (4-methoxyphenyl) -1,3-disulfide-2,4-disphetane-2,4-disulfide The reaction is transformed into a compound having the general formula XXΓ to form a monothiolide compound. It is then alkylated with an alkylating agent in a suitable alcoholic solvent (preferably methanol, ethanol, or isopropanol). Preferably it is methyl iodide or trimethyl or triethyl oxytetrazol. Boric acid alkylation and then guanidine alkylation to obtain compounds having the general formula XX Γ. Compounds with the formula XXI ′ are hydrolyzed in a neutral vehicle to form _ compounds with the general formula ΧΧΙΓ: (Please read the notes on the back * before filling this page) 0

The seal of male workers' consumer cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, where A is defined by general formula XI; B, C, X and Y are defined by general formula XXVII. When Rs of the compound of the general formula XXI is hydrogen, the hydrolysis reaction is unnecessary1 and the compound of the general formula XXI 'is a compounded compound of the following: 3 A compound having the formula XXΙΓ (or a formula) UP compounds, and Rs) are in the form of free carboxylic acid, which can be peptide-coupled with a glutamate diester by a method known to those skilled in the art to form a peptide with Diester of the formula ΧΧΙΙΓ: -31-The size of the paper method applies to the ten national standards (CNS) A4 specifications (2tOX297 mm) 44248 9 A7 B7 V. Description of the invention (

C03fl2 r

Among them, A is as defined by the general formula XI (please read the precautions on the back and then fill out this page) (XXIII, C, X and Y are as defined by the general formula XXVII; and dagger and! ^ Are one and C0 2 joins to form an easily hydrolyzed ester moiety, such as Ci-C ·; alkyl, hydroxyalkyl, alkaryl, or aralkyl. Finally, if desired > Compounds of XXIII 'can be hydrolyzed into compounds of general formula XI (among them. The preferred compound of general formula XI is (4- (2- (2-amino) 4-oxo-4,6,7,8-tetra 1 -3H-pyrimido [5,4-6]-[1,4] pyrazine-6-ylbuthyl) -2,5-sleepamine -L-glutamate) diethyl ester; 4- (2- (2-amino-4-amino-4,6,7,3-tetrahydro-3H-pyrimido [5,4-6]- [1,4] thiazin-6 * yl) -ethyl) -2,5-thienamido-L-glutamine: 4- (3- (2-amino-4-azol-4, 6,7, 8-tetrahydro-3H-pyrimido [5,4-6]-[1,4] sleepazin-6-yl) -propyl) -2,5-thiapyridinylamino-L- Iminic acid; 4- (2- (2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido [5,4-6] ~ [lt41siarazin-6-yl ) -Ethyl) -3-methyl-2,5-thiazone-amino-L-amino acid: and 4- (2- (2-amino-4-Ga-4,6,7,8-tetrahydro-3H-pyrimido [5,4-6]-[1,4] thiazin-6-yl) _ethyl)- 2.5-Amino-amino-amino-L-amino acid; The details of the compounds of the present invention are described in the following examples. 32-This paper is mounted on a scale suitable for China National Standards (CNS) A4 (2 丨 〇 X 297 (Mm) ^ 42489 A7 ___B7_ V. Description of the invention () Example 1 2- [4- [2- (2-Amine 4-gas-4,6,7,3-tetrahydro-3H-pyrimido [ 5,4-6]-[1,4] Salazine-6-ylbuthyl] benzylamido] glutaric acid Preparation of (1) (Id-dimethylchloro-but-3-yn-2-ol ):

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs at -73 ° C and under argon * 6.6 «1 of 1.6H n-butyllithium was added dropwise to 50 ml of dry tetrahydrofuran (THF) 1.037 g (10.55 «1! 11〇1) of trimethylsilylacetylene in a stirred solution. After 10 minutes at -7310, glyoxal dimethyl acetal (1.2 UU 0.46 μm β [beta]) in 5 ml of dry tetrahydrofuran (THF) was added dropwise. After 1 hour at -78T :, the reaction was quenched with about 1 ml of HaO and allowed to warm to room temperature * diluted with ethyl acetate and washed with saturated NaCl solution. The aqueous solution was extracted again with ethyl acetate, and the combined organic layer was dried over KgSO2 and concentrated under reduced pressure. To a yellow oil obtained at 785 ns in tetrahydrofuran (THF) was added 5.8 ml of 1H tetrabutylammonium gas in tetrahydrofuran. After heating at 5 ° C for 1 hour, the volatiles were evaporated * and the residue was subjected to flash chromatography on silica gel using dioxane / ethyl acetate (9: 1) for elution. In this way, the 412 ng of alkyne-alcohol was obtained as a colorless oil, compound ⑴. ^ IR (neat) 3441 (broad), 3277, 2944, 2839, 1636, 1450, 1196 / 1084011-1. XH NMR (CDC13) i: 2.42 (bsflH), 2.49 (3, ^), 3.51 (s, 3H), 3.53 (st3K), 4.36 (bs, 2H). -33-(Please read the precautions on the back before filling this page) And applicable Chinese National Standard (CNS) A4 specification (210X297 mm) v ·· 1-

4 β Q ~ τ · A7 _ _B7 V. Description of the invention () The calculated value is CsHid〇3i〇.36HzO; C, 52.81: H., 7.90. Actual value: C, 52.87; H, 7.86. (Please read the precautions on the reverse side before filling out this page) Crack Preparation (2) (4- (3-hydroxy4,4-dimethylamino-but-1-ynyl) -methylbenzoate):

Add 13ng (0.18maol) of a mashed solution of 232nl (1.78mn0l) of alkane compound 0) and 467ag (178mmo) in 5b 丨 diethylamine to methyl-4-iodobenzoate. Di (triphenyl knee) was mixed with (I) and 7 mg (0.036 miD0l) of copper iodide. After 15 minutes at room temperature, the volatiles were removed under reduced pressure, and the residue was subjected to flash chromatography on silica gel using dichloromethane / ethyl acetate (12: 1) to perform flash chromatography. Orange oily compound ⑵. IR (neat) 3451 (b3: oadh 2353, 2838, 1717, 1607, 1437, 1310, 1283, 1120, 1082αΒ′χ. XH NMR (CDC13) ί: 2.46 (bs, lH), 3.55 3.5S (3 , 3Η), 3.32 (s, 3H), 4.45 (d, lH, J · 5.4 Hz), 4.S0 »5.3 Hz), 7.52 (d, 2H, J 1 8.3 Consumer cooperative printing

Hz) '7.98 (d, 2H, J 8.3 Hzl. Analytical value is C14Hls〇5; C, 63J2: H, 6.10. Actual values: C, 62.14; H, 6. 14. 1 34-this paper wave Standards apply to 0-country standards (CNS) Α4 specifications (210X297 mm)

Er 43 3 A7 B7

ocu, V. Description of the invention (Preparation of ⑶ (4- (3-hydroxy4,4-dimethylamino-butyl) -methyl benzoate)

C〇tC > S

H, CO in a Parr device-A solution containing 14.37 g (54.38 nmol) of compound (2) in 175 ml of 'ethanol and 1.40 s of Pd on 5¾ nitrate, hydrogenated under 40 psi hydrogen chopsticks. After 2.5 hours, the reaction mixture was filtered and the catalyst was washed with acetic acid and methanol. After concentration under reduced pressure, the residue was dissolved in digas methane and filtered through a plug of silica gel, and then eluted with digas methane and then dichloromethane / ethyl acetate (1: 1) to remove residual residue. In this method * 14.34s (98¾) of benzyl alcohol and alcohol compounds Ο IH (neat) are obtained as a yellow oil. 3495 (broad), 2953, 1721, 1611, 1437, 1283, 1109,

1080 ca ~ l. XH NMR (CDC13) S 1.72-1.93 (m, 2H), 2.75-2.93 (m, 2H), 3.33 (3,3H), 3.44 (e, 3H), 3.58 3.90 (s, 3H), 4.13 (d, lH, J 6.1 Hz), 7.29 (d, 2H, J »8.1 Hz), 7.95 (df2H, J-8.2 Hz). The calculated value is CuH ^ nOsOJOHaO; C, 61.84: H, 7.56. Actual values: C, 61.83; H, 7.57. -35-This paper size applies to Chinese national standards (〇 ^ > 戍 4 see the standard (2 丨 0 > < 297mm). {Please read the notes on the back before filling in this page) Printed by the Central Ministry of Economic Affairs, the Zhuhai Cooperative Consumer Cooperative, and printed by the Central Ministry of Economic Affairs, the Central Counseling Bureau, the Shell Cooperative Consumer Cooperative, 442 48 9 A7 _B7_ V. Description of the invention () Preparation Samarium (4- (3-methylsulfonylamino-4,4-dimethylamino-butyl) -methyl benzoate):

Under Ot, in a mixed solution of 206ias (0.77iniiiol) in digas methane with 5b1 and ③ and 16 · ηι (1.1 5βιπο1) triethylamine in a stirred solution, 0.07ml (0.35amol ·) of Methanesulfonium. After 20 minutes at 0 ° C, methanesulfonyl chloride was added thereto. After 30 minutes or more * the reaction mixture was poured into a saturated NaHC03 solution and extracted twice with digas methane. The combined organic layers were dried over MgSO * and the solvent was removed under reduced pressure. The substance is very pure for future use. The reaction mixture was filtered and the catalyzed sample was eluted on silica gel with dichloromethane / ethyl acetate (20: 1) * for flash chromatography. This method can be obtained as a colorless oily methanesulfonate, compound hydrazone. IR (neat) / 2949, 2839, 17X9, 1611, 1437, 1352, 1283, 1177, 1109, 1078 an " 1. XH HMR (CDClj) S t 2.04 (m, 2H) ', 3,09 (e, 3H ), 3.41 (Γ3Η), 3.45 (3,3H), 3.90 (s, 3H), 4.38 »5.5 Hz), 4.64 ^ 7 ^ 1 ^) 7 7.29 id, 2H ^ J * 8.2 H2J; 7.96 (d, 2H #J-8.2Hz) '. Analytical calculated values are ClsH22〇vS; C, 52.01; H, 6.40; S, 9.26. Actual values: C, 52.08; H, 6.44; S, 9.25. -36-This paper standard is in accordance with the Chinese National Standard (CNS) A4 grid (210X297 male *) ------ r ---------- ^ ------ 1T {Please first M Read the notes on the back and fill in this page again) 44248 9 Preparation © (4- (3-methylsulfonyl-4-g-butyl) -methyl benzoate)

A7 B7 V. Description of the invention () Under Ot :, add 600ing (1.73 inmol) of dimethyl acetal (methanesulfonate) (compound 4) in 5 ml of methyl nitrogen to the stirring solution * Add 1 | »1 of the three gas acetic acid of 112 and 111. The reaction was warmed to room temperature and then refluxed for 24 hours. The cooled reaction mixture was diluted with ethyl acetate and sequentially washed with a saturated NaCl solution, saturated NaHCiL, and then dried again with a saturated NaCl solution (MgS0 «), and the volatiles were removed under reduced pressure. In this manner, a mesylate compound (5) can be obtained, which can be used without purification. NMR (CDCi3). Si 2.20 2.85 (ffl, 2H), 3.17 {8 ^ 77 / 3.31 (s, 3H), 4.95 (this, ^ 『β 4 · 2 8.4 H *), 7.29 '-8.1 Hz), ^ .99-8.2 Si), 9.597 «; lH). Preparation of Jun (4- (3-methoxy-benzylsulfane-4-oxobutyl) -benzoic acid

In I ^^^ 1 I 1— ^^^ 1 ^^^ 1 1 ^^^ 1 1 '艿 i (please read the precautions on the back before filling out this page) The Ministry of Economic Affairs, the Prospective Bureau of the Ministry of Economic Affairs, Consumer Affairs and Cooperation Du Yinhe

68S (2.28nnnol) mesylate-37 in dimethylformamide (DMF)-This paper size applies to China National Standard (CNS) A4 grid (210X 297 mm) 4M2 4 8 A7 B7 V. Description of the invention () compound, compound (5) and 0.4〇1111 (2.29〇 ^ 〇1)} ^ Diisopropylethylamine, add 4-methylamino-α-toluene disulfide room After 3 hours at room temperature, the reaction mixture was poured into 0.5N HC1 and extracted twice with ethyl acetate. The combined organic layers were washed twice with NaCl and dried (MgSO *), and decompressed under reduced pressure. The resulting aldehyde compound, compound 6, is very pure and can be used in the next step without further purification. IR (KBr) 2930 # 1715, 1703, L611, 1512, 1282, 1244, 1107 cm * 1. NMR (CDC13) 5: 1.80-2.IS (m, 2H), 2.75 2.99 3.53 (AB, 2H, J- 13.4 Hz), 3.81 (3,3η), 3.90 (3,3HJ; 6.33 (d, 2H, J = 8.5 Hz), 7.12 (d, 2H, J-8.2 Hz), 7.13 (d, 2H, J »8.6 Hz), 7.90 * 8.2 Hz) r 9.27 (d, lH, J-4.2 Hz). J ——— —— ... «— — · Preparation of ⑺ (4- (3- [1,3] dioxane 2-yl-3- (methoxybenzylsulfonyl) -propyl) -methyl benzoate):

The Ministry of Economic Affairs of the Ministry of Economic Affairs of the Taiwan Bureau of Shellfish Consumer Cooperatives (please read the precautions on the back before filling out this page)-containing 301mg ((K34mmoI) aldehyde compound ⑹, 94ui (1.68 maol) glycol and 42ms (0.17mniol) of pyridyl p-toluenesulfonate and 30mi of toluene in a Erlenmeyer flask were heated back to two 'and the water produced was removed with a Dean-Stark trap. After 3 hours, the reaction mixture was poured into This paper applies the national standard (CNS) A4 scale (210X297 mm) 4 4248 9 A7 _B7_ V. Description of the invention () Saturated NaC 1 solution > and extracted twice with ethyl acetate. After combining The organic layer was dried (MgSCK) and concentrated under reduced pressure. The resulting residue was eluted on silica digas with hexane-ethyl acetate (5: 1) and subjected to flash chromatography. The title compound ⑺ obtained by the method is obtained in a total yield of 8 «from methanesulfonated dimethyl beta compound. IR (neat) r, 2949, 2886 ^, 1721, 1611, 1510, 1435, 1279, '1248, 1177 , 1111, 1034 Cm " 1. ΧΗ NMR (CDC13) St 1.67 (m, lH), 1'39 (mrlH), 2.57 (a, 2H), 2.84 3.72-4.03— (m, 5H), — 3.81 (s, 3H), 3.90 (a, 3H), 4.97 (d, lH, J— 4.S Hz), 6.83 (d, 2H, J 8.6 Hz), 7.09 (d, '2H, J · 8.1 Hz ), 7.23 (d, 2H, J · 8.5 Hz), 7.88 (d, 2H, J-8.1 Hz). The calculated value is CuHwOsS; C, 65.65: H, 6.51; S, 7.97. Actual values: C, 65.72 H, 6.50; S, 8.07. Preparation of hydrazone (4- (3- [1,3] dioxane-2-yl-3-hexylpropyl) -methyl benzoate): u ^ i '^^ ^ 1 In-I l ^^^ 1 1 HI (Please read the precautions on the back before filling this page)

The Ministry of Economic Affairs, the Central Government Bureau of Work and Consumer Cooperatives, printed a cold section of a 5.70 (14.16mno 丨) compound (7) and 5.42s (17.0〇 [iimol) of mercury acetate in a dichloromethane. To OTC, and 5 ml of digas acetic acid was added in a dropwise manner. After 3 hours, a saturated solution of hydrogen sulfide was added thereto, and stirring was continued for 20 minutes at 0.7. The reaction mixture was poured into a saturated NaCl solution * and extracted twice with dioxane. Jingjie-39-This paper is in accordance with China National Standards (CNS) A4 (2I0X 297 mm) 44248 9 A7 B7 V. Description of the invention () The organic layer is dried (MgSh). Shrunk. The resulting residue was eluted with hexane-ethyl acetate (4: 1) on silicon dioxide, and subjected to flash chromatography. In this way, 1.99 (50¾) was obtained as a light buttery yeast, namely compound ⑻. IR (neat), 2951, 2886, 1719/1611/1435, 1281, 1179/1144/1111 cm-1. 1H NMR (CDCI3) 5s 1.S4 (d, lH, J-7.8 Hz), 1.74 ( πι, ΙΗ), 2.15 2.30 (a, 2H), 3.00 (η, ΙΗ), 3.90 (s, 3H), 3.37 4.91 (ά, ΙΗ, ί »4.0 Hz), 7.23 (d ^ HJ-8.1 Hz), 7.95 (d, 2H, J »3,1 Hz) · The calculated value is C14H18〇4S; C, 59.55: H, 6.14. Actual value: C '59-42; H' 6.41〇 ---------- ^-(Please read the precautions on the back before filling this page) Γ Preparation (s) (4- (3 -(2,4-diamine-6-gas-1,6-diargon-pyrimidin-5-ylsulfanyl) -3- [1,3] dioxane-2-yl-3-propylbutadiene Methyl benzoate):

1.9U (6.76imol) of thiol compound ⑻ in printed amines and 1.39s (6.78 mmoi) of 5-bromo-2,4-diamine-plchloropyrimidine in the printed amines of the Central Samples Cooperative Bureau of the Ministry of Economic Affairs To the stirred solution, 1.18ail (6.7 7iainol) of N, N-diisopropylethylamine was added. The reaction mixture was heated at 90 TC for 3 hours. The cold-headed reaction mixture was poured into an absolute NaCl solution, and the precipitate formed was collected by filtration, washed with water and -40-the paper standard GM China® Home Standard {CNS) A4 (210 X 29) (Mm) Duty-packed A7 B7 for male workers' consumption cooperation with the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention () Dry. The filter cake was slurried in methane, and hexane was slowly added thereto, and the precipitate was collected again by filtration, washed with hexane and dried. In this way, 1.91 (69¾) of dioxane * is obtained as an off-white solid, that is, compound (9) (ιη.ρ. 206-208 ^: and decomposed). IR (KBr) 3439, 3341, 31S4f 1701, 1636, 1591,} 1470, 1447, 1287 cm-1. NMR (DHSO) «: 1.64 (ιβ, ΙΗ), 1.84 2.58 (m, lH), 2.79 3.19 3.82 (3,3H), 3.85 4.83 (d, lH, J »4,3 H *), 6.33 (broad e, 4H) # 7.33 (d, 2H, J» 8.1 Hz), 7.83 (d, 2H # J * 8.1 Hz, 10.03 (s, lH). The calculated value is CieHZ2N4〇sS; C, 53.19; H, 5.46; H, 13.78; S, 7.39; Actual values: C, 52.98; H, 5.53; H, 13, 60; S, 7.76

O Preparation (") (4- (2- (2-amine_7-hydroxy-4-oxo-4,6,7,8-tetrahydro-311-pyrimido [5,4-6] [1,4 ] Sleep-6-yl-3-ethyl) -methyl benzoate):

A stirred suspension of 1.2s (2.85ai! B0l) of dioxane compound 20 in 20 ml of tetrahydrofuran and 4 ml of 2N HC1 was heated under reflux for 2.5 hours. The homogeneous solution was slowly poured into a saturated HaCO3 solution, and the precipitate was collected, and the filtrate was extracted with ethyl acetate. Collect the precipitate (58jns) formed between the two layers and combine it with the first Shen Dianwu. The ethyl acetate layer is based on -41-the paper standard (CNS) Α4 grid (210 × 297 mm) I -------- XII (please read the precautions on the back first) Fill out this page again), ν * 442489 A7 _B7_ V. Description of the invention ()

HgSO * was dried and its solvent was removed under reduced pressure. The residue (42rag) was also combined with the precipitate. In this way, 984 ^ (98¾) methanol amine compound 酦 (m.P. 213-216 VII), which is an orange solid 酦, can be obtained. IR (KBr) 3351, 3441, 1705, 163¾ 1609, 1557/1470, 1289, 1113, 1020 cm-1. NMR as a single pair of diaatereomera (DMSO) Si 1.39 and 1.96 (λ, λ, ΙΕ), 1.70 ( m, lH), 2.56-2.Θ9 (m, 3H), 3.82 (a ^ H), 4.71 and 4.84 (m, n, lH), 5.37 and 5.40 (d, d, lH, J SS Hz), 6 , 06 (s, 2H), 7.20 (d, lH, J, 4.5 Hz), 7.31 and 7.3S (d, d, 2H, J * 8.1 Hz) r 7.86 and 7.88-8.0

Hz), 10.IS and 10.19 (s, s, 1H). Analytical calculated values are: (16Ι11βM4 ** 1.7 · 20; C, 48.89; H, 5.49; N ,: 14.26; S, 8-16; actual Value: C, 48.73, 5.13, H, 14.00; S, δ · 03 ° Preparation of (11) U- (2 (2-amine-4-aero-4,6,7,8-tetrahydro-3H- Pyrimido [5,4-6] [1,4] thiazin-6-yl-3-ethyl) -methyl benzoate):

Printed by the Central Government Standards Bureau of the Ministry of Economic Affairs of the Beigong Consumer Cooperatives ^ I i II In (^ 1 ^ 1 ^^^ 1 1 ^^^ 1 ^^^ 1 ^^^ 1 ^^^ 1 ^^^ 1 (Please First read the precautions on the back and then fill in this page) In a suspension of 1-126g (3.1mmol) of methanolamine compound 0Φ in tetrahydrofuran (THF), add 2 · 3ι »1 (18.64βπιοΙ) tri-gasification Boric acid. When the addition is complete, add 0-586s (9.32amol) of sodium cyanoborohydride in portions over 5 minutes to 7 in another 30 minutes after '5.1 in methanol. Saturated ammonia was added to it. 'The reaction was diluted with ethyl acetate and -42 ~ this paper size. General Chinese national kneading rate (CNS) A4% «· (21〇x ^ 7 public shame) 44248 9 A7 B7 V. Invention Instructions () Saturated HaCI solution to wash. The organic layer was dried over MgSO * and the solvent was removed under reduced pressure. The residue was eluted on silica gel with dichloromethane / methanol (9: 1) and subjected to flash affinity chromatography. In this way, 542ing (50¾) UP 245-246t as an orange solid dehydrated ester compound can be obtained and decomposed). IR (KBr) 3358, 2936, 1721, 1644, 1595, 1537, 1447, 1346, 1281 cm · 1. XH NMR (DKSO) Si 1.72 1.90 (m, 1H), 2.80 (m, 3H), 3, 22 (m, lH), 3.52 < m, lH), 3.82 (s, 3H), 5.00 (s, 2H), 6.65 (a, lH), 7.37 (d, 2H, J »8.1 Hz >, 7.37 ( d, 2H, J * 8 ·! «r * '* I-· — _ ·· *--— — — HZ), 10.05 (3,1H). The calculated value is Cl sHiefU〇3S; C' 55.47; H, 5.24; N, 16.17; S, 9.26; actual values: C, 55.31; H, 5.29, N, 16.09; S, 9.17. Preparation of (12) (4- (2-2-amine-4-oxo-4) , 6,7,8-tetrahydro-3H-pyrimido [5,4-6] [1,4] _azin-6-yl-3-ethyl) -benzoic acid): — Binding (please read the back first) (Notes for filling in this page)

Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs. The solution of the ester compound (11) with 53.0 (1.53 yuan) and 10 ml of INNaCi was stirred at room temperature for 30 minutes. This homogeneous solution was slightly acidified with HC1 (pH 4) > After cooling in an ice bath, the slightly orange precipitate was collected by filtration and air-dried. It was then suspended in ethanol and the ethanol was removed under reduced pressure. In this way, an acid compound (12) (decomposition > 3101) of 468nis (913;) can be obtained. IR (KBr) 3285, 3086, 2923, 1S98, 1642, 1611, 1576, 1449, -43-Standard Chinese paper standard ((: Post) 8 4 ^ (210 > < 297 mm) 44248 9 Printed by the Pager Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs *. A7 B7 V. Description of the invention (1348 cm-1. ΧΗ (DMSO) ί * 1.72 (ιη, ΙΗ),

1.39 (ια, ΙΗ), 2.78 (m; 3H), 3.20 3.43 (πι, ΙΗ), 07 (3,2HV, S.S8 (3,1Η), 7.33 (d, 2H, J 8.1 Ηζ), 7.85 ( d, 2H, J »8.1 Hz), 10.11 (s.lH), 12.77 (broad β, ΙΗ) .__ ----- -------- · " _ Analytical calculation value is CisHisN * 〇3S * 1.2H2〇; C, 50 · 89; Η, 5_24; N, 15.83; S, 9.06; actual value: C, 50.70; H, 4.92, N, 15.58; S, 8.87 ° Preparation (13) (4 -(2-2-amine-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido [5,4-6] Π, 4] pyrazin-6-yl-3-ethyl) -Benaldamine) -Diethyl glutarate

Q

397 »g (1.19 lamol) of acidic compound (12), 169mg (1.25mmol) of 1-acylbenzotriazole (BOTH) in 15ml of N, N-dimethylformamide solution, 0.221 ^ (1.251111〇1) ^-diisopropylethylamine and 300ms (1.25ininol) L-glutamate diethyl hydrogenated gaseous stirring solution, 240mg (1.25Bmol) of 1- (3 -dimethyl Aminoaminopropyl) -3-ethyl-carbodiimide hafnium nitride (EDC). After 18 hours at room temperature, the reaction mixture was poured into an ice-cold saturated NaCl solution. The precipitate formed was collected. The precipitate was eluted on silica gel with diaminomethane / methanol (9: 1) and subjected to flash chromatography. In this way, 357 ng (53¾) of the desired compound (13) (ra.p. 132-136¾) can be obtained. -44 'This paper size is applicable to China National Standards (C »S) Α4 size (210X297mm) IK in * H) nm ^^^ 1 ί ^ 8ί (Please read the notes on the back before filling in this I · ) 44248 3 A7 B7 V. Description of the invention () IR (KBr) 3333 ,. 1732, 1645, 1572, 1535, 1449, 1343, ---- — 1 — ---. _ —-— — ______ 1203, 1020 cm1 'XH NKR (DMSO) Si 1.15 * 7.3 Hz), 1.17 (t, 3H, J »7.3 Hz), 1.72 (m / lH), 1.88-2.10 (m, 3H), 2.42 (t, 2H, J = 7.4 Hz), 2.79 3-22 3.50 4,02 (q, 2H, J = 7.3, 14.5 Hz), 4.09 (q, 2H, J a 7.2, jade 4.3 H2), 4.41 (π, ΙΗ), 6.21 (3.2H), 6.74 (3 / 1H), 7.32 (d / 2H, J-8.0 Hz) / 7.80 (d, 2H, J = · 8.0 H2), 8.64 (d, lH, J »7.41 Hz), 10.24 (3,1H). Analytical calculated value is C24H31N50sS; C, 55 · 69; Η, 6.04; N, 13.53; S, 6.19; Actual value: C, 55.41; H, 6. U, H, 13.48; S , 6. 12. Preparation of (14) (2- (4- (2-2-amine- * 4-oxo-4,6,7,8-tetrahydro-3H-pyridino [5,4-6] [1,4] N-SQ-6-yl) _ethyl) -benzylamine glutaric acid: -I----1-i--d I--nm (Please read the notes on the back before filling in this page)

CO | H Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China with 32〇1118 (0.618 | 11111〇1) glutamic acid compounds (13) and 611111 ^

The mixture of NaOH was stirred at room temperature for 3 hours to neutralize it with concentrated HC1 and then slightly acidified with 2NHCI. The yellowish precipitate was collected and air-dried. The filter cake was dissolved in ethanol / ethyl «and any residual water was boiled off. In this way, 220 ing (77¾) of the diacid compound (14) (tii. P. 188-190 ° C) IR (KBr) 3348 (broad), 2930, 1717, 1642, 1S39, 1505, 1348 cm " -45-This paper scale is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 44248 9 A7 B7 V. Description of the invention () 1H NMR (DMSO) 5: 1.71 1.92 (m, 2H), 2.08 2.34

(t, 2H, J-7.4 Hz}, 2.73 (m, 3H), 3.20 (m, lH), 3755 (ιηΓίΗ), T.38 (πΓ, ϊό), 6'07 (s, —2H | Factory 6.68 (3: 1H), 7.31 (d, 2H, J [1 Hz), 7.80 Tdr2H, J 8.2 Hz), 8.53 (d, lHrJ-7.7 Hz), 10. ίϊ 7s, 1H), Γ2.40 '(broad s, 2H) T analysis calculation value is: (: 3 () [123} ^ 0 * $ _ 1.5} ^ 0; (:, 49.17;) 1, 5.36; pull '14-34; S, 6.56; Actual values: C, 48.77; H, 4.97, H, 14.07; S, 6.54 ° halves and evaluation of bovine in vitro testing using L1210 mammalian white blood cancer cell line UTCC CCL219) to evaluate the presence of the compounds of the present invention Cell growth. The cell line was held in 1640 medium containing 5% heat-inactivated fetal bovine serum without evidence of anti-inflammatory activity. 160 complete titration cultures containing 150 (L1210) cells to determine * the growth medium of this culture is supplemented with 50 IU / ml penicillin and 50111 / βΙ hormone. The growth is pseudo-entangled The test compound was tested by exposure to various levels of the test compound for 3 days. The compound was prepared by the Ministry of Economic Affairs (Mosnann, Inmunol. Met.) Fei Cooperative Press — (please read the precautions on the back before filling this page) 65 (1983), 55-53) M ITT tetrazole anchor analysis method was added 4 hours after pouring into a flat plate, this modified The method is based on Cancer Res. 4δ (1988), 589-601. The water-insoluble derivative is dissolved in DMS0, diluted and diluted to a final concentration of 0.5¾ solvent in the culture. e 1 and, B i 〇che π. B i 〇phys.

Acta 67 (1963). 173-187. Divide under 221C-46-This paper size is applicable to the national kneading rate of the country (CNS) Α4 grid (210X297 mm) 44248 Γ A7 B7 5. Analysis of the invention () Analysis and make Young etal., Biochemistry 23 (1934 ), A spectroscopic method of 3979-3986, the enzyme was initially added and the reaction was monitored at 295 nm. The variable matrix is 10-methyl-5-8-dideazafolate at 0.83uM, 1.25uM, 2.5uM, and 5uMS, while the other matrix GAR (Glycosamine Nucleotide) remains fixed at 20W. The analytical mixture contained 20bM Hepes (pH 7.5), 20uM GAR, and a variable amount of 10-methylamidino-5-8-dideazafolate and the test compound (14). For this test compound • Use five concentrations ranging from 0 to about 3K. The data are plotted as a function of reaction rate versus the concentration of 10-formamyl-5-S-diazefolic acid. The inhibition constant image is then measured by plotting the slope of the curve to obtain the inhibitor concentration versus inhibition. ---------- Clothing,-< Please read "Notes on the back before filling out this page) -5 Printed by the Central Laboratories of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, 1 Printed by Heyang 14 GARFT inhibition Data and cell culture data Compound GARFT K. ICso (uM) L1210 (uM) 14 0.035 0.05 for cell culture Example 2 (4- (2-2-amine-4-oxo-4,6,7,8- Preparation of tetrahydro-3H-pyrimido [5,4-6] [1,4] thiazin-6-yl-3-ethyl) -2,5-thiabenzamide-L-glutamine (22) (Methyl-5-bromo-2-thiophene carboxylic acid ester): This paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 442489 A7 B7 V. Description of the invention ()

Compound (22) (CAS Reg. Mo. [62224-19-5]) S. G r ο η 〇witz, Ar * k · K emi 8, 19 5 5, 8 7 and S. 0 · awess ο η, Ark. Keini 11, 1955, 337 Preparation (2.3) (5-ethynyl-2-carbonylmethoxythipan): COaCHj

5s (22,7mntol) bromide (23.) in 75ml of diethylamine, (please read the precautions on the reverse side before filling out this page) -pack. 160 ml (0.23mmoi) of palladium (Π) tri- (diphenylphosphine gaseous) and a stirred solution of 65ms (0.34mmo 1) of iodide were added to 50ml of dimethylformamide Trimethylsilane acetylene. The resulting solution was stirred at 25 ° C. After 18 hours | the solvent was removed under reduced pressure, and the crude product was dissolved in 300 ml of £ 1; 20 (acetic acid), and 100 ml Extracted with IN HCI and 100ni saturated bicarbonate. The organic layer was dried over MgS (U, and the solvent was removed under reduced pressure. The residue was eluted on a silica gel with WEt 20 / hexane. Flash chromatography | to give 4.4 g (81¾ yield) of a yellow silane-protected product. This material can be used directly in the next step. 4.48 (18.5111111. 0) in 510111 dimethylformamide. 1) 3.3g (: 35.6niinol) of potassium carbide monohydrate was added to the above silane-protected acetylene. After 15 minutes at 25 ° C, the mixture was poured into 500ml of Et20 (ethyl ), And extracted four times (4X100ml) with 100m 丨 of water. The organic layer was used in _ 48 _ paper size standard (CNS) A4 specification (210X297 male I>, 11 / 11- Ministry of Economic Affairs) The Central Government Bureau of Justice, Zhenggong Consumer Cooperative Co., Ltd. 4 AQ c \ ί * ^ A7 _B7_ V. Description of the Invention ()

Ha2S0 * was dried on and the solvent was removed under reduced pressure. This crude residue was eluted on silica gel with 10S: Et3O / hexane and flash chromatography was performed to obtain the desired product (23) as orange solids with a yield of 2.65S (86iK yield). NMRtCDCl ^) 5: 3.45 (s, 1H), 3.88 (ar 3H), 7.22 (d, 1H, J = * 3.SHz), 7.65 (d, 1H, J-3.5HZ). The calculated value is C8HeS. 2; C, 57.81; H, 6.64; S, 19.29; inter-spring value: C, 57.91; H, 3.71; S, 19.13. Alternatively, another method for removing silyl groups is as follows: In a 3.7 g (0.02 mol) anhydrous K3C03 solution of methanol in 700 ml of methanol, add the above-mentioned 9.7s silane as a solid proof- Acetylene. The suspension was stirred at 35 = downstairs for 2 hours, and then the formazan was evaporated. The residue was added to 50 ml of water, which was extracted with 3 × 150 1 of EtiO, dried (MgS04) through the combined organic hydrazones and evaporated. The crude residue was subjected to rapid dissolution analysis on silica gel with 10; «Et20 / hexane to obtain the desired product (23) (38.72 g) in a yield of 98¾. Preparation of (24) (H- (Butylcarbonyl) -glycinal):

To a soaking solution of 2s N- (butoxycarbonyl) -2-hydroxy-ethylamine (obtained from Signa Chemicals) in 80ml CH2CU was added 1.3πΙ (118,6ntmOI) of dimethyl Subchloride and 1.2bI (13.7mmol) of grass dipped in chlorine. After 5 minutes, 5.4inl (38.4m * ol) of triethylamine was added to it, and the solvent was -49-this paper size is applicable to China National Standard (CNS) A4 (210X297 mm) ^ i ^ i · Ϋϋν ϋ In n ^ i € Jcx US— ml I m · n ϋ ^ ι (Please read the notes on the back before filling in this page) 442 48 3 A7 _B7_ V. Description of the invention () The liquid temperature is warmed to 25t. This mixture was mixed into 200 ml of Et20 and extracted with 100 l of water, 100 ml of 0.5 N HC 1 and 100 is of a saturated hydrogen nitrate solution. The organic layer was dried over (Na 2SCh), and the solvent was removed under reduced pressure. The crude aldehydes were dissolved in 100 m of benzene | and the solvent was removed under reduced pressure again. This crude material which was found to be unstable was used immediately in the next step. Preparation of (25.) 4-N- (butoxycarbonyl) -3-hydroxy-1- (2-carbonylmethoxy-5-thipan) -butyne

At -78 ° C, 14.3101 (14-01 ^ 01) was added to a stirred solution of 1.7s (10.2ππαο1) alkyne (23) in Ontl dry tetrahydrofuran (THF). Printed by Bei Gong Consumer Cooperative. N. L! -I —I i I ·----. 1-^^ 1 n ^^ 1 ^^ 1 X ·. (Please read the precautions on the back before filling this page ) 1M bis-trimethylsilylamine in THF. The solution was stirred at -7810 for 10 minutes and warmed to 0C for a period of 20 minutes: 5 ml of a saturated ammonium nitride solution was added to it. The mixture was poured to 200 ml of Et20, and washed with 100 811 [1:! 〇 and then saturated with 501 (3 :: 1 solution. The organic layer was dried with (<32 $ 〇4), and the solvent was depressurized. The crude residue was eluted on silica gel with 10% -40EtAc / hexane and flash chromatography was performed to obtain 0.96 g (29¾ yield) of the desired product (25) as a pale yellow oil. NMR (CDClj) St 1.46 (βΛ 9Η), 3,38 and 3.58 (ΑΒ, 2Η # J-3, 7Η2), 3.88 (sf 3Η), 4.71 (dt, 1Η, J-2.9, 5.2Hz), 3.05 ( bre, 1H), 7.15 (d, IH, J-3.9HZ), 7.64 (d, 1H, J-3.9H2). IR (naat) t 2978.3 / 1729.5 / 1685, 1523, 1452, 1368, 128S, 1167, 1098, 959, 822, 750 This paper scale is applicable to the Chinese Family Standard (CNS) A4 specification (210x29? Public jf) The Central Samples Bureau of the Ministry of Economic Affairs, Male Workers Consumer Cooperatives Co., Ltd. 44248 9 A7 ________ B7 &quot; X, Invention Description ( ) Mass spectrometry analysis with high resolution, calculated value ct sH19N03s; M + Cs ,, 45δ. 0038; actual value: 458.0051.:. Preparation of (26) (methyl-5 (4-N- (butanecarbonylcarbonyl) Amino-3-hydroxy-bubutyl-)-hexyl-2-carboxylic acid ester:

COjCHj To a stirred solution of 940 mg (2.89 nm) of the alkyne (25) in ethyl acetate (EtOAc) of 50iti 1 was added 320 mg of 5% Pd / C. The mixture was placed under 40 psi H2 gas and stirred at 253C for 17 hours. The mixture was filtered through celite (diatomaceous earth), and the solvent was removed under reduced pressure. The crude residue was eluted on silica gel with 2 (nEtOAc / CH2Cl2 and subjected to rapid decantation * to give 800ing (84¾ yield) of the desired alcohol as a yellow oil. NMR (CDCI3) ft 1.44 (a, 9H), 1.81 (m, 2H), 2.28 __ — · ·-· · · · ·----·---—. (hr »/ 1H), 2.99 (m, 2H), 3.10 and 3.29 (AB, 2H, | je3,1.3Hz), 3.74 (m, S.82 (d, 1H, J * 3.7H2), 7.S3 (d, 1H, «J * 3.7Hz). Anal. Calcd for C, 54.S9; R, 7.04; N, 4.25; S, 9.73. Found * C, 54.79? H, 7.02; jj / 4 * 29 / S / 9.63 · Another preparation alcohol (26) The method is prepared using di-to-butylcarbonylallylamine (34) (di-to-butoxycarboxyallylamine (34)): 1-This paper is applicable to the Chinese national standard (C &gt; iS) A4 specifications (;: 10 X 297 mm) --------. ¾ clothing ------ TT ------ ice (please read the precautions on the back before filling in this page) 442489 Printed by the Consumer Cooperative of the Central Bureau of Probability of the Ministry of Economic Affairs A7 B7 V. Description of the Invention () (Day. 〇3) In the configuration of 500ml ethoxylate, 57. lOg (1.0 mole) allylamine and 1.2g &lt; 0. Olaio 1) of methylaminopyridine (DMAP) To the stirring solution *, 220 g of UaON (t-B0C) E0 in 100 mi of acetonitrile was added, and the resulting mixture was stirred for 6 hours. The reaction mixture was diluted with toluene (100 μm), and the solvent was under reduced pressure of 60 ¾. • Evaporation. The resulting oil was redissolved in acetonitrile (400m 1), and • Another 1.2 g (0.01 mol) of (t-BOC) 2 in 100 acetonitrile was slowly added thereto. The reaction mixture Stir for 12 hours at 60. The solvent is evaporated under reduced pressure at 60t, diluted, and NaHC〇3 (100 atU. Is added. This is taken as 3X150jnlCH2C] 2 莩, and the combined organic layers are washed with brine, dried ( Na2S04) and evaporated: the crude residue was eluted on a silica gel with a gradient of 5-20% Et0Ac / hexane and flash chromatography was performed to obtain 156.9 mS (63¾ yield) as a transparent crystalline solid The desired product (34) U. p. 43-44 Ϊ :). {〇irJ (CDC1 ^) S (ppm) i 1.5 (3 '18H), 4.18 (dd, 2H, J * 15 Hz, J = · 1 Hz) ^ 5.14 (ddd, 2H, J »l5 Hz, J-10 Hz, Jl Hz) r 5.85 (ddt, 2H, J» i〇Hz, J = 5 Hz, J «1 Hz) IR (KBr ): 2978, 2935, 2360, 1724, 1689 I .., 1342, u3cm &quot; 1. Analysis and calculation Ci] H23N〇 *; c, 60 · 68; Η, 9.01; N, 5.44; actual value: C, 60.78; H, 9.04, H, 5.50 Preparation (35) ¢ 1- (two -Teroxybutyral amine) _Ethylene: 0 Η ~ 52 'This paper supports the Chinese national standard (CNS Μ4 standard (21〇χ29' public cage) --------- i-- ---- ίτ ------ ^ (Please read the notes on the back first and fill in this education)

4424S A7 B7 V. Description of the invention () A solution of 0.60 g (2.34 mmol 1 of di-tert-butylcarbonylallylamine (34) in 20id1 CHsCl z), which is ozonated at -78t: (40 Voltam, 500 amps, 1.0 1 / minute, 02 3 psh, until a blue color is held, and then add 10 m of dimethyl sulfide, the mixture is stirred at 25 ° C for 14 hours: the solution is added with brine to Diluted and extracted with □ 2 (: 12 (3 / 5〇1111). The organic fraction was dried (Na 2 SO 0 and evaporated: · using flash silica _ chromatography can produce 6.3nig 99% yield) as Desired product of transparent crystalline solid '(35) (mp37-39¾ J &quot; lH NMR: (CDC13) S (ppa) J 1.50 (a, 18H), 4.38 (a, 2H), 9.55 (β, 1H) _1 XR ^ fKBr): 2984, 2935, 2724, 1792, 1734, 1699, 1362, 1153 αα. The calculated values are CuHhNOsC, 55.58; Η, 8.16; N, 5.40; actual values: C, 55.20; H , 8.19, N, 5.19. Preparation of (26) (methyl-5- (4-N- (tert-butoxycarbonyl) -amino-3-hydroxy.)-Butylthiazine-2-carboxylic acid: economical Printed by the Central Bureau of Standards and Symbols, Shellfish Consumer Cooperatives -------- T Pack -------- Order (please first Read the notes on the back of the page and fill in this page again.) At -7fC, add 6.5.6ml (60mmol, 0.9) to a stirred solution of 9.64g (59mmoU5-ethynyl-2-methylthiothiophene (23) in TFHi250ntI). M) of hexamethyldisilazide lithium (Li HMDS), the mixture was stirred at -78 C for 2 hours, and a (1- (di-an-butylcarbonyl) group in TFH (40m 1.) was stirred. Amine) -acetaldehyde (35) solution was inserted into the reaction mixture by means of a cannula, and stirred at -78 ° F for 6 hours. 3.4 ml of acetic acid in methanol was added to quench the mixture. Stir for another 0 minutes, warm to Ot, add water (60ml): | It is extracted with Et0AC (3X100ml), the organic extract is washed with diluted NaCO3, and dried (Na2SO Remove to 50ml by pressure: Add the residue to StOAc (125ml-53-The paper scale is applicable to Chinese National Standards (CNS) Λ4 now U10X 297mm) Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5. Description of the invention ()), this solution was added to a Parr bottle containing 5¾ of Pd on sulfon at a psi »2 of hydrogenation for 24 hours. The crude hydrogenated material was filtered through celite and its filter cake was washed with methanol (100 ml, EtOAc OO ml). The solvent was evaporated under reduced pressure to elute 'with SOiSEtOAc in hexane' and filtered through a silica gel. The residue was solvated in 20 ml of methanol (MeOH) azeotroped with benzene (50ral) and redissolved in dry MeOH. To this mixture was added freshly prepared sodium methoxide 60m 1 (2M) in methanol: the reaction mixture was stirred for another 45 minutes, diluted HCI (0. Μ, 50nl) was added, and once the reaction mixture was EtOAc (3X75ml &gt; To extract it. The organic fractions were combined and washed with pH 7 buffer, dried (Na 2 SO 4) and evaporated. The crude residue was eluted on silica gel with 40% EtOAc / hexane, and subjected to flash chromatography, To give 9.32 g (48¾ yield) of the desired product (26). Preparation of (27) (methyl-5- (4-N- (tert-butylcarbonyl) -amino-3-acetamidine) ) -Butyl) -2- «Phosphonic acid:

At 0 ° C, to a stirred solution of 9.26s (28.1mmol) of alcohol (26) in 100ral TFH, 5.9ml (42isniol) of diethylamine and 2.4ral (31mmol) of methylamine were added. Sour gas. After 20 minutes, IOObi DMF and 12.8 g (110 mm) of thioacetic acid were added, and the resulting solution was allowed to warm to 25 ° C. After 3 days, the mixture was poured into 500 ml of water and extracted with 800 ml of Etd. The organic layer is made of 200mi of water, 200nd N HC1, and 200ml of '-54- paper scale, common Chinese National Standard (CNS) six 4 specifications (210X297 mm) --------- ¾ clothing- ---- IT ------ ί (Please read the notes on the back before filling out this page) 44248 Printing bag A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () The solution and saturated M 9 c 1 were dissolved and washed overnight. The organic layer was dried (MgS (U), and the solvent was removed under reduced pressure: the crude residue was eluted on silica with 25% EtOAc / hexane and flash chromatography was performed to give (95% yield) It is the desired thioacetic acid (27) as yellow oil. NHR (CDC13) ί 1.44 (s, 9H) # 1.91 and 2.04 (ABm, 2H), 2.37 (er 3H), 2.96 (m, 2H ), 3.36 (m, 2H), 3.SI (m, 1H), 3.85 (3, 3H), 4.74 (bra, 1H), S.79 (d, 1H, J-3.6HZ), 7.S2 ( d, 1H, J »3.6Hz). XR (neat): 3366, 2976.4, 1713, 1520, 1462.1, 1366, 1290.5, 1267.3, 1169/1098, 752, 631 cm'1. High-resolution mass spectrometry analysis, calculation Value C17H2SN〇sS2; M + Cs +, 520.0229; actual value: 520.0240: Preparation of (28) (methyl-5- (4-N- (butoxyferenyl) -amino-3- (dimethylpropyl) Difluorenyl) thiob-butyl) -®phenocarboxylic acid: 〇

C〇2CH3 In ου, to a stirred solution of 10.2 g (26 fflm0l) of the above thioacetic acid (27) in 200 ml of dry methanol was added 7.2s (52ϋππο 1) of K2C0 3-based amine and 3 · 7m I (29πηηο 1) dimethylchloromalonic acid. After 3 hours, the mixture was poured into 500ml of water, and extracted with Et20 (500ml X3). IK Stomach® with 500 m 1 @ 7f &lt;, ffjj &amp; Utg 6 spoon HaC 1 Liquid washing and drying (MgSO4 丨, and the solvent is removed under reduced pressure: the thickness of this paper is -5 5 the size of the paper is suitable for the Chinese national standard Xin (CNS M4 specification (210X297 mm) nnr binding 丨 ice (please read first) Note on the back page please fill in this page} ./tJ- Printed by the Central Standards Bureau of the Ministry of Economic Affairs-Industrial Cooperatives 4 A7 _B7__ V. Description of the invention Flash chromatography was performed to obtain 11.46 g (96% yield) of the desired thio-brewing (23) as a yellow oil. NMR (CDC13) ί: 1.44 (s, 9H), 1.85 and 2.00

fABm, 2H), 3.03 (m, 3H) r 3.30 (m, 2H), 3.30 (β, SH), 3.8S (s, 3H), 5.10 (brs, 1H), S.82 (d, 1H , J = 3.3Hz), 7.S3 (d, 1H, J-3_8Hz). IR (neat): 3442, 2974, 2955, 1734, 1713, 1512, 1460, 1435, 1366, 1291, 1267, 1167, 1098 , 1022, 732 cm * 1. High-resolution mass spectrometry analysis. The calculated value is C2 DH a S NO BS 2; M + Cs ft 608.0389; actual value: 608.0370. Preparation of (29) (6- (5-Carboxymethoxy_fluoren-2-yl) _ethyl) -2-carbonylmethylamino-3-oxy-3, 4,5,6-tetrahydro [1 4 pyrazine

At 0T: 4m 1 trifluoroacetic acid (TFA &gt;) was added to a solution of 470 mg (0.99 nifflOl) of thioether (28) in 12 ml of CHaCU. 1.5 hours later, The mixture was poured into a saturated bicarbonate solution of SOIiii 1 and extracted with CHsCU (4X 00ml). The solvent was removed under reduced pressure, and it was redissolved in 10ml of methanol: stirred at 25 ° C for 1.5 hours. The solvent was removed under reduced pressure, and the crude residue was eluted on silica gel with 4 (UEtOAc / CH2Cl2) and flash chromatography was performed to obtain 298m (88¾ yield) as the desired colorless oil. Inner _ amine (29): This paper method is applicable to Chinese Standards (CNS) A4 (2I0X 29? Public housing) n I ^ 1 nnn! Order ~~ II ^ (Please read the precautions on the back before filling this page ) 87____ 44248 9 A7 V. Description of the invention () NKR (CDC13) Si 1.94 (m, 2H), 3.01 (m, 2H), 3.4-3.7 (m, 4H), 3.80 and 3:82 (3, 3H), 3.87 (s' 3H) / S.25 (bra, 1H,), S.83 (d, 1H, J = 3-7Hz), 7.S4 (d, lH, J = * 3.7Hz). IR (KBr ): 2951, 1732, 1SS9 ~ 1462, 1294, 1267, 1194r 1137/1098, 1005, 752 cm-1. 丨 The calculated value is CHHu MOsOe; C, 48.96; H, 4.99; N, 4.08; S, 1δ. 67; actual value: C, 49.06; H, 4.93, N, 4.09; S, 18.06: Preparation of (30) methyl- ( 2- (2-Amino-4-amino-4,6,7,8-tetrahydro-3v-pyrimido [5,4-6] [1,4] _- 6-yl,)- Ethyl)]-2,5-_arsenic acid esters: 0

Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -------- install -------- Order (please read the precautions on the back before filling this page) 1.9 in 150ml CH2C 丨 2 g (5.5 tnm0l) of the above-mentioned lactamamine (29) was stirred, and 1.06 g of [7.2nwnon] dimethyloxyatrakiborate was added to the gold portion at a time. The solution was stirred at 25 ° C for 16 hours: the resulting mixture was poured into 50 inl of a 10K2CO3 solution, and extracted with CHaCU (3 × 200). The combined organic layers were dried (MgSOd, the solvent was removed under reduced pressure, and the resulting product was used directly in the next step: in another triangular flask, 1.56 g (16.6 mm) of dry guanidine was placed in the atmosphere Hydrogen: 600 ml of dry methanol was added thereto, and dry neon gas was bubbled from the solution for 10 minutes and then 926 mg of U 7.2 mmo of dry methoxy sodium was added. Via -57-This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 44248 b A7 B7 V. Description of the invention ()-Catheter • Add the crude endoaldimine prepared in 20ml MeGH to the In the resulting mixture, the solution was refluxed under neon pressure for 20 minutes. Its pH was adjusted to 4 with HCI, and the solvent was removed under reduced pressure. The crude residue was dissolved in 500raiCHCl3 | and washed with 2 × 200ml of ice. The organic layer was dried (MgSO4) * and the solvent was removed under reduced pressure. The crude residue was eluted on silica gel with 5, l (nMeOH / CH2C 丨 2 | and flash chromatography was performed to give 298 mg (33¾ yield) as an off-white solid. This material was then dissolved in 25a 1 hot MeOH And slowly cooled to 4X over a period of about 18 hours: The solid was collected by filtration to produce 180 mg (93;) of the desired pyrimidinone (30) as a yellow solid. NMR (dg-DMSO) ί : 1.72 (m, 1H), 1.88 (ra, 1H), 2.8-3.22 (m, 4H), 3.S0 (dt, 1H, J-2, 8Hz), 5.99 (brs, 2H), 6.64 (brs, 1H), 6.98 (d, 1H, J = 3.8Hz), 7.62 (d, 1H, j = 3.8H2), 10.02 (brs, 1H). Mass spectrometry analysis with high resolution, calculated C14HlsN4〇3S2; JTCs, 375.0562 Actual value: 375.0550. Another kind of pseudo-one that can be used to prepare pyrimidone (30) is described below. Printed by the Shellfish Consumer Cooperative of Central Bureau of Standards of the Ministry of Economic Affairs. ^^ 1- ^^^ 1 im · * n n &lt; Please read the precautions on the back before filling this page) In the SOOnigUMemntol) Endozyme (29) in 20b1 THF, add 648 | 118 (1.6〇1111〇〇1) Luo Weisen ([3 Generation 33〇11'5) reagent (2,4- (4-methylaminophenyl) -1,3-dithia-2,4-dihorsphenanthin } ^ 3 ^ 131 ^) -? 2, 4-disulfide). The mixture was stirred at 25 ° C for 20 hours1 and then poured into 50®1 saturated hydrogen sulfonate and extracted with 2X200ral EtOAc. The combined organic layers were washed with 50mi saturated NaCl solution, and dried (MgSOW, the solvent was removed under reduced pressure. The crude thiolactam was applied on silica gel at 83! EtOAc -58 ~ this paper, using Chinese national standards (〇?) Eight-four-gauge &lt; lattice (210 '; &lt; 297 mm)' P ¾ '4 S 2 A7 _B7_ V. Description of the invention () / CtUCh to eluate • and perform flash chromatography * to obtain Corresponding to 525nig sulfonamide (31): h3co This material is used immediately in the next step. In a mixture of 10 ml of dry THF and 10βΙ dry methanol, 525 * g of thiolactam (31) is added to 1.6b1 1H NaOH. This added 0.1 ml (1.6aiol) of methyl iodide to produce monomethylated thiolactamamine which was used in the following steps without purification.

Central Sample Rate Bureau of the Ministry of Economic Affairs

-»—» ·--^^^ 1 1 HI (n ^^^ 1 ^^^ 1 ^^^ 1 ^ 9J (Please read the notes on the back before filling this page) In another flask, Place 1.36g (14.6maml) of dry hydrogenated atmosphere. Add 300ail of dry methanol * dry neon to bubble through the solution for 10 minutes, and then add 796ais (14.7miol) of dry sodium methoxide. Via a tube The crude methylated endoaldamine prepared above was added to the resulting mixture | The solution was refluxed under neon pressure for 48 hours. Its pH was adjusted to 1 with 1NHC1 and the solvent was removed under reduced pressure. The crude residue The material was dissolved in 500 ml of CHCla * and washed with 2 × 200 ml of water. The organic layer was dried (MgS04) and the solvent was removed under reduced pressure. The crude residue was dissolved in silicone with 5-10¾ MeOH / CH2Cl2 Analyze and perform an expedient [chromatography to give 298ng (88¾ yield) as an off-white solid. This material was then dissolved in 20 ml of hot MeOH and slowly cooled to 41C over a period of about 13 hours. The solid 1 was collected to produce l80ng (9aO of the desired yellow pyrimidone (30).) ^ 59 This paper uses Chinese National Standard (CNS) A4. (2 丨 0X 297mm) 〇

4y 9 A7 B7 V. Description of the invention () Preparation (32) [(2- (2-Amino-4-amino-4,6,7,8-tetrahydro-3H-pyrimido {5,4-6 ] [1,4] Sorbenyl) -ethyl)]-2,5-Norbinic acid:

To 180 mg (0.51 nB01) of pyrimidinone (30) was added 5 ml of 1N NaOH in water. The resulting solution was stirred at 251 ° C for 20 hours. After cooling to 0, the pH was adjusted to 2 with IN HC1. The brown solid was filtered off, washed with water and dried under vacuum to give llling (64; S yield) as a brownish acid (32). NMR (ds-DKS〇): 1.72 (channel, 1H), 1.92 (m, 1H), 2.78-3.68 (m), 6.07 (brs # 2H) # S.68 (brs, 1H), 6.92 (d, ZH, J-3.7HZ), 7.52 (d, 1H, J-3.7H *), X0.12 (bre, 1H), 12.89 (brs, 1H). Mass spectrometry analysis with high resolution, calculated value; tTCV, 338.0507 ; Actual value: 338.0517. Preparation of (33) (4- (2- (2-Amino-4-oxy-4,6,7,8-tetrahydro-3H-pyrimido (5.4-6) [1,4] thiopyh-6 -Yl) -ethyl)]-2,5-thiazanamido-L-diaminoacetate: η

COgt 60 This paper is again suitable for China National Car (CNS) A4 specification (210X297 mm)

(Please read the precautions on the back before filling out this page) «V Printed by the Shellfish Consumer Cooperative of the Central Rubbing Bureau of the Ministry of Economic Affairs-Printed by the Shellfish Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs A7 B7 5. Description of the invention () 110 mg (0.33ni! B0) of 5 ml of dry THF was added to a solution of the above acid. 48 mg (0.36 mmol) of 1-isopropyl-benzotriazole hydrate, 62 ul (0.36iainol) diisopropyl Ethylethyl, 36ibs (0-36ibiii〇1) of glutamic acid diacetic acid hydrogenation, and 106ιag (0.36Bπolol) l- (3-dimethylamino-propyl) -3-ethylcarbonylation Diimide methyl iodide. The resulting solution was at 25. C. Stir for 20 hours under neon pressure, then pour into 50 ml of water. The water was extracted with 2X 150 ml EtOAc. The combined organic hydrazones were back-extracted with 3 × 50 · 1 water, then with a saturated solution of 10β1 in NaCl, and then dried (MgSO *). Then the solvent was removed under reduced pressure. The crude residue was eluted on silica gel with O-lOXMeOH / CHzClz and flash chromatography was performed to obtain 120 mg (713! Yield) of the desired yellow solid shape. Aldehyde (33). HMR (ds-propyl 1.20 (m, SK), 2.2 (a, 1H), 2 * 46 (t, lHf J = «7.6Hz), 2.78 (s, 1H), 2.82 (s, lH) f 2.92-3.1 (m, 2H), 3.41 (m, 1H) / 3.72 (dt, 1H, J-3.0, 12.7Hz), 4.02-4.2 (m, 4H), 4.58 (a, lH) r 5.90 (bra, lH) f S.05 (brs, 1H), 6.90 (d, J-3.8H *), 7.58 (d, 1H, J-3.8HZ), 7.78 (d, 1H, J »8Ha). High-resolution spectral analysis , Calculated value C ^ HnNsfLrSa; iTCs' 524.1635; actual value: 524.1650. Preparation of (21) (4- (2- (2-Amino-4-oxy-4,6,7,8-tetrahydro-3H-pyrimido (5,4-6) [1,4] thizone -6-yl) -ethyl)]-2,5-Leptamine-L-glutamine:

Add 3ml of water to 115ms (0.22nimol) of the above diethyl ester (33). The paper size meets the Chinese National Standard (CNS) A4 specification (2 丨 Ox297 mm) \ --------- ------- Install ------- Order (please read the notes on the back before filling in this I) ___ I :: 4 Λ Ο.-. Ο ^ Α7 _Β7_ V. Description of the invention ( ). Binding (please fill in this page first before filling in this page) IN NaOH solution. The resulting mixture is stirred at 25 ° C for 14 hours. After cooling to Ot, it is adjusted to pH 3.5 with IN HC1. .The solid was filtered, washed with water and dried under vacuum> to produce 82ms (30¾ yield) of the desired acid (21) as an off-white solid plaque. * 0® (dfDMSO) i: 1.S2-2.02 ( a, 4H), 2.27-(π, 2H) '2,78-3' (J0 (πι # 3H), 4.27 (dd, 1H ,. Je6, 6.8Hz), 6.00 (birs, i 2H) f 6.63 ( bre, 1H), 6.88 (d, 1H, J-3.7HZ), 7.63 (dr 1H, — J-3.7H2), 8.37 (d, 1H, J-7.4HZ) / 10.05 Cbrs ^ lH), 12.85 (br3f 2H). IR (KBr): 3371, 1700, 1643, 1543, 1345 cm-1. Mass spectrometry analysis with high resolution, calculated value Cl8H21H5〇8Sz; M * Cs ·, 468.1012; actual value: 468.1025. Analysis calculated value C1 &amp; fUi Ns〇3SrH2〇; C, 43.71; H, 4.89; N, 14.16; S, 12.97; Yellow value: C, 43.50; H, 4.67, N, 14.07, S, 12.72 Cattle Φ 彳 bubble. Evaluate GAR Determination of Inhibition Constants of Formamyl Transference: Printed by the Central Ministry of Economic Affairs

Young etal., Boichemistry 23 (1984), 3979-3986's GAR formyltransferase (GARFT) analysis method is modified and applied as follows. The reaction mixture contains the catalytic region of human 馑 GARFT, 0-250 nH test compound, 20 uM glycamine M amine nucleotide (GAR), 10 or 20 υ Ναα-methylfluorenyl-5,8-diazepine folate 00! ), 5〇111 »卩 卩 $ -1 (〇 {1 and 50 ^^ 1 ([: 1. The reaction started by adding human enzymes to a final concentration of 11 ηM, and then monitored at 294nra at 2 ° C The increase in its light absorption c in '1) 0 -62-This paper is applicable to the national standard (CNS) of the country (4) 4 (210 &gt; &lt; 297 mm) 44248 9 Consumption cooperative printing A7 B7 V. Description of the invention () The GARFT inhibition constant U,) is determined by the dependence of the inhibitor and the stable state of the substrate concentration. The observed inhibition image is determined by its effect on the FDDF concentration. Obviously LUi.app) depends on the key to determine its competitiveness against FDDF, and the inhibitory pseudo-picture is described as Ki.app:!^ + (K · / K ·) [FDDF]. Michaels of FDDF (

Michael is) constant (U, 傜 is determined separately by the dependence of catalyst rate on FDDF concentration. The measured values of L and K »are in a non-linear manner consistent with the Michaels equation, or, if applicable * Comply with the competitive inhibitory Michaelis equation. The data obtained from the tight binding inhibition are analyzed and determined in a non-linear way, and the data are consistent with the tight binding equation of Morrison (Biochem. Biophys Acta 185, 269-286). Cell lines: The cell lines used and their sources are listed in Table 2. 毎 The growth conditions and media requirements of a cell line are summarized in Table 3. All cultures are 371 :, 5¾ C0 2 in air and cultured under a moisturizing culture vessel. In vitro growth inhibition: The stock solution of the inhibitor is prepared in a sodium sulfide solution of 1 OmK in water. Stored at -20t: The inhibitory effect of this cell was modified by M, J. I jn in u η 〇. M eth 〇ds 6 5 (19 8 3), 5 5-6 3) Method to determine. _ When each cell is a pair of mesophase cells, it is added with dialyzed fetal bovine serum (Hyclone Laboratories. Inc.,

Logan, UT) Fresh RPMI growth medium (Med ίatecll, Washing- -63- Chinese paper kneading standard (CNS) A4 size (2t〇X 297 mm) II ^^^ 1 ^^^ 1 ^^ ^ 1 i ^ i ^ i ^^^ 1 ^^^ 1 (Please read the notes on the back before filling out this page) 4fg48 9 A7 B7 V. Description of the invention (Please read the precautions on the back before filling in this page) ton, DC), dilute to 18500 cells / ml * and divide into 2 to 12 columns in a 96-well flat plate. Volume (135π »1) of fresh medium was filled to use as a blank M. The plate was then placed in a 371, 5¾C02 incubator in air. After 1 to 4 hours, the plate was removed from the incubator *, and the compound (21) at a final concentration of 10X was diluted twice. Release mode | and 15ml per well * was added to the column 12-4. In reverse experiments, hypoxanthin (1.75 mM) or AICA (1.75 mM) were included in all drugs (final 潺 175 M). Wells containing each concentration of compound (21) were prepared in quadruplicate on each plate. = In the plate of the first column, 15 ml of medium without compound (21) was added. These cells were then sent to the incubator and remained undispersed during the whole cultivation period. On day 3 of L1210 and L1210 / CI920 cells * and on day 5 of CCFR-CEH cells, 50nl0,8iag / ffl of ΠΠ ((4,5-dimethyl-¾azole-2) -)-2,5-Dimethyltetrazole anchor bromide; Sigiia Catalog no. M2128) was added to all wells of the pan, and then the cells were transferred back to the culture vessel. After 4 hours, all pans were removed from the incubator and centrifuged at 1200 rpm for 7 minutes. Aspirate its medium and add 150 ml of DMS0 to each well of the plate. The mixture was mixed on a vortex mixer for 1 hour at room temperature in a dark room at room temperature. The molecular device VBaxta was used to load a flat-panel reader, and the metabolized MTT halo was determined at 540mi. The drug concentration required to reduce the cell 50¾ * is determined by MTT metabolism using interpolation between positive OD (minus the blank group) and 50¾ below the controlled OD (minus the blank group) * and is determined by interpolation . -64-The scale of this paper is in Chinese National Standard (CNS) A4 Washing (210X297 mm) A7 B7 Printed by the Industrial and Consumer Cooperatives of the Central Government Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (Table 2) The tissue source and cell line source are used in the cell line source: L1210 ATCCtf mouse, lymphocytic leukocyte cancer cell, CCRF-CEH ATCCtt human, acute lymphoblast leukocyte cancer cell ATCC = Aiaerican Type Culture Col lection Table 3 Culture conditions Pour the plate density into the incubation time for the microtiter cell line culture medium DFCS * concentration U) Pour the plate density (cells / ni) Incubation time (days) L1210 RPMI-1640 5 2500 3 CCRF-CEM RPMI-1640 10 2500 5 DFCS concentration = dialysis of fetal bovine blood sacral irrigation Table 4 Growth inhibition data using exposure entanglement (72 hours) Compound 21 Compound GARFT Ki Cell culture ICSD Cell culture IC3 0 (ηΗ) L1210 (nM) a CCRF-CEHnM) a 21 4.5 16 4.3 a: average ICsn soil standard deviation -65-This paper size is applicable to China National Standard (CNS) A4 wash (2 丨 0X297 mm) I. i- i --Shed- n ^ i In · n n I -: j (w Please please fill out the back of the Notes then this page)

Jit Α7 Β7 V. Description of the invention () Antitumor activity in vivo On day 0, 2mm3 6C3HED lymphosarcoma in an auxiliary area will be used to induce K-segmentation and subcutaneously implanted into a group of 6 female C3H / He mice. Beginning on the first day * Intraperitoneal administration of the test compound at 40XEncapsin once daily for nine days. The control group received the same treatment * but without the test compound. The percentage inhibition * shown in Table 5 below is calculated by comparing the weight of the tumor in the control group (only the diluent was obtained) and the person who obtained the test compound on day 11. (Please read the precautions on the back before filling this page) Pack. Table 5 Compound dosage (ag / kg)% inhibition. Survivor 21 12.5 100 6/6 21 25 100 3/6 21 50 Toxicity 0/6 Order economy The male labor consumer cooperative of the Ministry of Health and Human Services of the Central People's Republic of China printed in 0 days, and will pull 2mma 6C3 / BA mammalian gland tumors in an auxiliary area * and subcutaneously implant them into a group of 6 C3H / He female mice. Starting on the first day, the test compound at 40SSEnCapsiri was administered intraperitoneally once a day for nine days. The control group 僳 received the same treatment, but without the test compound. The percent inhibition shown in Table 5 below was calculated by comparing the reduction of tumors in the control group (when only the diluent was obtained) and those who obtained the test compound on day 11. -66-This paper is in ft scale and uses the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 ____ Β7 V. Description of the invention () Table 6 Compound agent child (ng / lcg &gt; Inhibition% Survivor 21 5 16 5 / 6 21 10 84 6/6 21 20 100 3/6 The chemical test of the present invention and its intermediate products contain one or more peptone compounds. The present invention includes a racemic mixture, diastereoisomeric compounds and optically active compounds For example, compounds without other optical isomers, this optically active compound can be obtained by a method known to those skilled in the art. It will be apparent to those skilled in the art that it can be performed in the method and intermediate product of the present invention. Various modifications and changes. For example, if it may be a chemical substance • The chemical group identified by it may be appropriately substituted. In some examples, the possible substituents have been noticed clearly. If more than one Re When pseudo is included in the formula, 毎 一 値 Re 傺 can be selected from various possibilities. ^^ 1 · 1. nn ^^ 1 mim I ^^ 1 ^^ 1 ^^ 1 1. ^ 1 -¾, T (Please read "Notes on the back before filling this page") Ministry of Economic Affairs Central Bureau of Consumer Cooperatives prospective employees Indian Buddhist monk's robe -67-- this paper Xiao Lang scale ladder with China National Associate (CNS) A4 size (210X297 mm)

Claims (1)

14248 9 Amendment of the scope of patent application for the application Date of amendment: April 1990 1. A compound having the following general formula I: Among them \ M .. .. C9] A, (1) printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 2. 3. 4. A is sulfur, X is an unsubstituted Cl, c3 alkyl, Substituted c2_c3 alkenyl, unsubstituted C2_C3 alkynyl, unsubstituted amine, sulfur or oxygen; Y is oxygen, sulfur or NH; B is argon or halogen; C is hydrogen, halogen or monounsaturated A substituted alkyl group; and each of the core and h is argon or a co2-connected thereto to form an easily hydrolyzable part of the ester group: or a pharmaceutically acceptable salt thereof. The compound of the above item or its salt CH2, CH2CH2, NH, oxygen, sulfur or NCH3. For example, the compound of the first item of the application scope or its salt of sulfur or oxygen, B is hydrogen, and c is hydrogen or CH3. The compound in the third item or its salt sulfur, Y is sulfur, and 1 ^ and 2 are argon, respectively, where X is where Y is where A is illlllllltn pieces -------- Order-I! — — — — · <锖 First read the notes on the back before filling in this 6 9 A8 B8 C8 D8 Compound or its salts in the range of Qiaohuan Where X is CR 6. The consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs has printed the compound or its salts such as the first item in the scope of patent application, where 1 and \ are each selected from hydrogen and (^-(: 6 alkyl. Such as The compound or a salt thereof in the sixth item of the patent application, wherein ^ and R2 are each hydrogen or a c, -c2 alkyl group. For the compound or the salt thereof in the seventh item of the patent application, wherein A is sulfur and Y is sulfur And X is CH2. For example, the compound or the salts thereof in the scope of the patent application No. 8 in which B is a gas, C is hydrogen, and each of the two is hydrogen. 10. Such as the compound in the scope of the patent application or Its salts are selected from (4- (2- (2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido [5,4-6], [1, 4] Thien-6-yl: μethyl) -2,5-thienylamino-L-glutamic acid) diethyl alcohol; 4- (2- (2-amino-4-oxo-4 , 6,7,8-tetrahydro-3fluorene-pyrimido [5,4-6]-[1,4] thiazin-6-yl) -ethyl) -2,5-thienamido-1 ^ Glutamine ; 4- (3- (2-Amino-4-oxo-4,6,7,8-tetrahydro-cris-pyrimido [5,4-6]-[1,4] fluorene-6-yl ) -Propyl) -2,5-thienamido-L-glutamine; 4- (2- (2-amino-4-oxo-4,6,7,8-tetraargon-3H- Pyrimidin [5,4-6]-[1,4] pyrazin-6-yl) -ethyl) -3-methyl-2,5 · thienylamino-L-phosphonic acid; and 4 -(2- (2-Amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido [5,4-6]-[1,4] ) -Ethyl) -2,5- ° Four amino-L-glutamine. 11. A pharmaceutical composition for the treatment of inhibiting the growth or proliferation of microbial cells or higher animal cells, comprising: ( i) An effective amount of one of the compounds having the following general formula I: 8. 9. 19 This paper size is applicable to China Solid Standard (CNS) A4 (210 X 297 g) --------- -, ^. 111 I 丨 — · Order 111 丨 llt_ (Please read the notes on the back before filling this page) a〇AS B8 CS D8 co ^ · (I). C, please read the notes on the back first. Fill out this purchase &gt; where A is sulfur; X is an unsubstituted CrC3 alkyl, unsubstituted c2_c3 alkenyl, unsubstituted C2-c3 alkynyl, unsubstituted amine, sulfur or oxygen; Y is oxygen, sulfur or NH; B is argon or dentition; C is hydrogen, dentin or an unsubstituted 2CrC6 alkyl; and Each of which is hydrogen or a C02 attached to it to form an easily hydrolyzable ester moiety; or a pharmaceutically acceptable salt of the compound, and (ii) a pharmaceutically acceptable An attached carrier, preparation or diluent. 12. For example, the pharmaceutical composition according to the scope of the application for patent application, which is 0, CH2CH2, NH, oxygen, sulfur or NCH3. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 13. For example, the pharmaceutical composition of claim 11 of the patent scope ‘where γ is sulfur or oxygen’ B is hydrogen and C is hydrogen or CH3. 14. The pharmaceutical composition of claim 13 in which a is sulfur, Y is sulfur, and X is CH2. For example, in the pharmaceutical composition under the scope of application for patent No. 14, wherein c is hydrogen, and the heart and the ruler 2 are hydrogen, respectively. 20 national standards (CNS) A4 specifications (21Q X 297) = A8 B8 C8 Scope of patent (锖 Please read the unintentional matter on the back before filling in this page} where Y is oxygen, sulfur or NH; B is argon or dentin; C is hydrogen, halogen or an unsubstituted 〇1 _ (: 6 alkyl; R6 It is hydrogen or C02 connected to it to form an easily hydrolyzable part of the base; each of the core and 115 is hydrogen or a nitrogen protecting group that can be easily removed. Compounds of which: γ is sulfur; B is hydrogen; C is hydrogen; Re is hydrogen, CVC, courtyard, hydroxyalkyl, alkaryl or aralkyl: and R4 and Rs are each hydrogen and t-butoxy Carbonyl, benzyloxycarbonyl, or benzyl. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs as the 16th scope of the patent application, which is 4_n- (tert-butoxymethylene) -3-meryl- 1- (2-methylsyl-5-11 thiophene) · butyne. I9.—A compound with the general formula VT: This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) • 42 48 9 A8 BS C8 Patent application scope (VII-) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs where X 'is an unsubstituted tCrC3 alkyl group, unsubstituted CrC; j alkylene group, unsubstituted crc3 alkynyl group, unsubstituted Amine group, sulfur or oxygen; Y is oxygen, sulfur or NH; B is hydrogen or halogen; c is hydrogen, edge or an unsubstituted alkyl group; the heart is argon or a C02 connected to it Forms an easily hydrolyzable portion of the ester group; I and R5 are each hydrogen or a nitrogen protecting group that can be easily removed. 20. For example, the compound in the 9th item of the patent application, where χι is ch2; γ is sulfur; B is hydrogen; C is hydrogen; r6 is hydrogen or Ci_C6 alkyl; and hydrazone and each are hydrogen and t-butoxycarbonyl 'Stupid methoxycarbonyl or benzyl. 21, such as the 19th compound in the scope of patent application, which is fluorenyl-5 (4 · N_ (tert-butoxycarbonyl) -amino-3-hydroxy) -butyl,), thienyl-2-carboxylic acid ester. 22, a compound with the general formula "VI": 22 This paper f family standard (CNS) A4 specification (21Q χ Norwegian Gongchu) (Please read the precautions on the back before filling this page) ^ ------ --- Order --- III ---- line 442489 A8 B8 C8 D8 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, the scope of patent application Where X 'is an unsubstituted heart-daggeryl' unsubstituted c2-c3 alkyl, unsubstituted C2-C3 alkynyl, unsubstituted amine, sulfur or oxygen; Y is Oxygen, sulfur, or NH: A is sulfur; B is hydrogen or dentin; c is hydrogen, halogen, or an unsubstituted crc6 alkyl group; 1 is hydrogen or a co2 to which it is attached-which can be easily hydrolyzed Part of the ester group; each of Han 4 and 115 is argon or a nitrogen protecting group that can be easily removed; and Ac is an alcohol group. 23. For example, the compound in the 22nd claim, wherein X is CH2; Y is sulfur; B is hydrogen; C is hydrogen; R6 is hydrogen or alkyl; and feet 4 and R5 are each hydrogen and t-butoxy Carbonyl, benzyloxycarbonyl, or benzyl. 24. For example, the 19th compound in the scope of patent application, which is methyl-5 (4-N- (tert-butoxycarbonyl) -amino-3-acetamidothio) · butyl + 2-thienylcarboxylic acid ester. 23 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) III ϊ ---- IIII clothing I1J1 — — — Order ----- i (II (please read the precautions on the back first) Fill out this page again> M2 48 A8 BS C8 D8 VI. Application for patent scope 25 · —A compound with general formula] χ〃 n * 〇jC IX &quot;) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs where A is sulfur, X 'is an unsubstituted 2CrC3 alkyl, unsubstituted c2_c3 alkenyl, unsubstituted ere; alkynyl, unsubstituted Substituted amine, sulfur or oxygen; Y is oxygen, sulfur or NH; B is hydrogen or halogen; C is hydrogen, halogen or an unsubstituted ^ -alkyl group; &amp; each is hydrogen or The linked C02_ forms an easily hydrolyzable ester moiety; R * and R · 5 are each hydrogen or a nitrogen protecting group that can be easily removed. 26. For example, the compound in the scope of application for patent No. 25, wherein A is sulfur; χ is CH2; Y is sulfur: B is hydrogen; c is hydrogen; R6 is hydrogen or C, -C6 alkyl: and ^ and Xin are each It is argon, t-butoxycarbonyl, benzylmethoxycarbonyl or phenylfluorenyl. 27. For example, the 25th compound in the scope of the patent application, which is methyl-5 (4-N butoxycarbonyl) -amino-3- (dimethylpropanefluorenyl) thiobutyl (te) -f Please read the items on the back before filling in this page) l--I ----- Order --- lit --- 24 Home reading materials in this paper (CNG A4 Secret (21Q x 297 A8 B8 C8 D8 6. The scope of patent application: thienyl carboxylic acid esters 28.-A compound having the general formula X &quot; The consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed A as sulfur; X 'is an unsubstituted &lt; ^-&lt;: 3 alkyl, unsubstituted C2-C3 alkenyl' unsubstituted C2- C3 alkynyl, unsubstituted amine, oxo or oxygen; Y is oxygen, sulfur or NH; B is hydrogen or halo; C is hydrogen, halogen or an unsubstituted (^-(: 6 alkyl And κ · 6 are each argon or a co2 connected thereto to form an easily hydrolyzable ester group portion a. 29. For example, the compound in the scope of patent application No. 28, wherein a is sulfur; X is CH2, rhenium is sulfur, B is wind, C is nitrogen, and each R6 is nitrogen or &lt; 3,-(1: 6 alkyl). 30_ As the 28th compound in the scope of patent application, which is 6-[( 5-fluorenyl ester fluoren-2-yl) -ethyl) -2-fluorenyl ester 3-fluorenyl-3,4,5,6-tetraargon [1,4]-»plug a 桊 0 25 This paper size applies the Chinese National Standard (CNS) A4 specification (210 * 297 mm) {Guess the notes on the back of the results before filling out this page} Clothing --- I ------------ -Line economy is the consumer cooperation of Intellectual Property Bureau Du printed 442 4 8 9 A8 B8 C8 D8 Where A is sulfur and X1 is an unsubstituted (^-(: 3 alkyl 'unsubstituted c2-C3 alkenyl group, unsubstituted C2-C3 alkynyl group, unsubstituted amine group, Sulfur or oxygen: Y is oxygen, sulfur, or NH; B is hydrogen or halogen; C is hydrogen, halogen, or an unsubstituted CrC6 alkyl; and R6 is each argon or a C02 connected to it Easily hydrolyzed part of the ester group. 32. For example, the compound in the scope of patent application No. 31, wherein a is sulfur; X is CH2; Y is sulfur; B is hydrogen; C is argon; and R6 is hydrogen or CVQ Alkyl. 33. The compound as claimed in item 3 of the scope of patent application, which is methyl_ [2_ (2_amino-4-oxy_4,6,7,8-tetrahydro-3H-pyrimidine 5 , 4-6] [1,4] thien-6-yl) -ethyl)]-2,5-thionate. 34 · A compound having the general formula XΙΓ: 26 paper rule &amp; f National Standard (CNS) A4 (210 x 297 mm) (Please read the precautions on the back before filling out this page) Agriculture ·-Order -------- Line 44248 Scope of patent application Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs where A is sulfur; X 'is an unsubstituted Crc3 alkyl, unsubstituted &amp; ^ alkenyl, unsubstituted h-c3 alkynyl, unsubstituted Substituted amine, sulfur or oxygen; γ is oxygen, sulfur or NH; B is hydrogen or halogen; and c is argon 'halogen or an unsubstituted Ci_C (i alkyl group. Compound of the above item, wherein A is sulfur; X is CH2; Y is sulfur "36 'As the 34th compound in the patent application scope, it is (2- (2-amino-4-oxy-4,6,7 , 8-tetrahydro-3H-pyrimido5,4,6] [1,4] thien-6-yl) -ethyl)]-2,5-pyronic acid. 37, One has the following general formula Compounds: This paper size applies to China National Standard (CNS) A4 specification (21 × 297 mm) (Please read the precautions on the back before filling this page) ^ -------- Order --ml --- 442489 A8 B8 C3 D8 Six 3 Shen 8 · • As the 37th compound in the claim range, it is optically active. 39. The compound according to item 37 of the scope of patent application, which has the following structure 40. The compound according to item 37 of the scope of patent application, which has the following structure: I iinm 1 »I ft f # n I n. N I It n 1 · n ^ -rSJJ i—-) KI— · 1 t— ft (Please read the notes on the back first # Fill in this &gt; Printed by Employee Consumer Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs 28 This paper size applies to China National Standard (CNS) A4 (210 X 297 cm) Application date 7 'Case No. S' Category C ^^ / οψ. FsLW- ^ X ^ (The above blocks are filled by the Bureau) Public% Μ Φ- · C4 i 442489 Off-line Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs Printed «. No. 84107733 ^ ^ Patent Specification-Chinese compounds that can be used as antiproliferative and GARFT inhibitor compounds in English COMPOUNDS USEFUL AS ANTIPROLIFERATIVE AGENTS AND GARFT INHIBETORS Name ⑴ Mike D. Vane ⑵ William H. Romis ⑶ 莘 Haya L. Palmer Nationality USA_Invention of residence, residence 7 7236 Mimosa Road, Carlos Bede, California, United States 12 12665 Futuola Street, San Diego, California, United States No. 8654, Bard Street American Name • Yagulong S Pharmaceutical Co., Ltd. (Name) National Box · United States. III. Applicant's Residence and Residence (Office) 10350 North Torrey Needle Pine Road, La Chora, California, USA Name of the representative: Ge Lan • Ren Se's custom-made clothes are applicable to the country of China M: M CNS) AJ Xiluo (2! 0X297 mm) loaded 14248 9 Amendment of the scope of patent application for the application Date of amendment: April 1990 1. A compound having the following general formula I: Among them \ M .. .. C9] A, (1) printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 2. 3. 4. A is sulfur, X is an unsubstituted Cl, c3 alkyl, Substituted c2_c3 alkenyl, unsubstituted C2_C3 alkynyl, unsubstituted amine, sulfur or oxygen; Y is oxygen, sulfur or NH; B is argon or halogen; C is hydrogen, halogen or monounsaturated A substituted alkyl group; and each of the core and h is argon or a co2-connected thereto to form an easily hydrolyzable part of the ester group: or a pharmaceutically acceptable salt thereof. The compound of the above item or its salt CH2, CH2CH2, NH, oxygen, sulfur or NCH3. For example, the compound of the first item of the application scope or its salt of sulfur or oxygen, B is hydrogen, and c is hydrogen or CH3. The compound in the third item or its salt sulfur, Y is sulfur, and 1 ^ and 2 are argon, respectively, where X is where Y is where A is illlllllltn pieces -------- Order-I! — — — — • &lt; 锖 Read the notes on the back before filling in this