TW201745B - - Google Patents

Description

soil45 A6 B6 V. Description of the invention (1) The present invention relates to a benzofuran derivative, its preparation method and its pharmaceutical compound. According to the first aspect of the present invention, we provide the general formula (I):

A compound, or a physiologically acceptable salt, a solvate (such as a hydrate), or a metabolically unstable ester in which R1 represents a hydrogen atom or a halogen atom or a group selected from Ge alkyl, : 2-β alkenyl, fluoroalkyl * Ci-e alkoxy, -CHO-, -C〇2H, or -COR2; Ar represents this group R3.

(Please read the precautions on the back before writing this page) • 5t · • Hit ... Green · The Ministry of Economic Affairs Central Bureau of Precinct Printing 11 R2 represents a group selected from Ci-e Yuanji 'Cz-e dilute group 'Ci-e or oxy group or -ΝΙΠ1 1 this group; R3 represents a group selected from -C02H, -NHS〇2CF3 or a C-linked -7- A 4 (210X hair) y〇1145 A6 B6 five 2. Description of the invention (..2) Tetrazolyl; R4 and Re, which can be phased by an atom or a C. Same or different. Each stand represents a hydrogen atom or a .-β group; 1 Het Represents an Ν-linked imidazolyl group at 2 Cl-β-alkenyl groups. Cz-e groups at 4- and 5-positions. One group is buried in the cyano Ci-e group.-(CHz)-( CHdpHI ^ COm position selectivity is replaced by a group. In the imidazole 1? 3 represents a session R7 represents a Ci-e alkoxy Ra represents a session 1? ° represents one, phenyl, benzene R1. And R11, son or one C 1 6 ring atoms m represents a η represents a hydroxyl group or hydrogen atom, phenyl hydrogen atom hydrogen atom oxy group or it can be -4 alkyl and the ring integer from an integer from an alkenyl group or a (^ -β alkylthio group Selectively one or two molds from one Li halogen atom or, nitro, Ci-e alkyl, C2-e alkenyl * fluoro. Re,-(CHZ) "C0R7 * or substituent substitution; C 1-β 焼 oxy; or a group selected from Hydroxy, Ci-e alkyl, phenoxy or -NR 1 ° R 11 this group; or one Ci-e burn group; or one group selected from Cpe alkyl, Ci-β alkoxy-ΗΡΙ11 this The base circle; is the same or different, each independently represents a hydrogen source or -NR1.!? 11 to generate a cell can be M selectively contains an oxygen 1 to 4, K 1 or 2 is better 0 to 4, with 0, 1 or 2 and heterocycles have 5 or atoms;, especially 1; preferably | especially 0 ί Please read the precautions on the back and then fill out this page) or; Autostructures can be enantiomers. Optically active isomers, other than 1 to 4, M 1 or 2 are preferred. The formula (I) is intended to cover all enantiomers and their mixtures including racemates when they can exist. .Compound A 4 (210Χ 297 public) 201745 A6 B6

3. Description of the invention (3)-'< «. ≪.'-* '---..- _-Contains one or two double« may exist in this cis or trans configuration. Benqingming also includes solvates within its scope, especially hydrates of compounds of general formula (I). Within the definition of W, the term 'alkyl' or Ί gas group 'as a group or one of a group means that the group is straight or branched. The term "alkenyl" as a part of a base group or a group means that the group is straight or. S, branch: bond and contains at least one carbon-carbon double bond. The term 'halo' means a fluorine, gas, halogen or iodine atom. The first Cl-β burning group This term means a wine Ci-e burning group in which one or more hydrogen atoms are replaced by two filling fluorine atoms, such as -CH2CF3. Particularly preferred is 'perfluoro-Ci-3 alkyl' which means that Ci-3alkyl is completely substituted with fluorine. It is tricyanomethyl, pentafluoroethyl, heptafluoropropyl or heptafluoroisopropyl. The definition on M when it represents a saturated heterocycle contains 5 or 6 ring atoms, one of which may be an oxygen atom. The heterocyclic group of Dangdang is a pyrrolidine • hexahydropyridine or morpholine group. A preferred class of compounds of general formula (I) is that in which the Het group is at its 2-position by a radium atom or a ds alkyl group, especially a C3-s alkyl group or a (: 3_5 alkenyl substitution. Particularly preferred are those compounds in which the 2-position substituent is monoethyl. N-propyl or n-butyl, especially a n-butyl. The Ca_5 alkenyl can also be suitable -A but-1-ene group. Another preferred class of compounds of general formula (I) is the one in which the Het group is more selected from a halogen atom or a substituent by one or two substituents- The base groups are selected from Ci-e alkyl groups, substituted by-(CH2) eRe or-((^ 2) " (: 0! ^ 7. Special 201745 λ6 Β6 V. Description of the invention (4) Yes, “represents a hydroxyl group Or Ci-e alkoxy; and preferably a hydroxy • methoxy, ethoxy • propoxy or butoxy, and especially a hydroxy or methoxy. R7 * especially represents a hydrogen source f or A hydroxy group, Ci-e alkoxy group or -ΝΙΠ11 (especially in which R1. And R11 each independently represents a hydrogen atom or a Ci-4 alkyl group) and is preferably a radium atom or a hydroxy · methoxy group • Oxy •• propoxy or butoxy • and especially a hydrogen atom or a radical or methoxy group, and m is 1 or 2 and η is 0, 1 or 2. In the particularly preferred embodiment of the present invention In the embodiment, the substituent is buried from an allergen, an atom and a group selected from -CH2〇H, -CHO, -CH2〇CH3, -C〇2H, -C02CH3, -C〇2CH2CH3, -COHHa And -CONHCHs. Compounds of general formula (I) still have a preferred p-category in which R1 represents a hydrogen atom or a halogen atom or a group selected from Ci-e alkyl groups' Ci-e alkoxy groups Group or fluoro Ci-e alkyl group, and especially a hydrogen atom or a halogen atom or a d-alkyl group. Particularly preferred are compounds in which R1 is an o atom. In compounds of general formula (I), this Het- The CH2- group is bonded to the 5- or 6-position of the benzofuran ring, and especially the 5-position. In compounds of the general formula (I), R3 can also be -C02H group or a Li C-linked tetrazolium. In compounds of general formula (I), it is also suitable that R4 and R5 can each independently represent a hydrogen atom or a halogen atom. In particular, R4 and R5 each represent a hydrogen atom. Ministry of Economy Please read the precautions on the back before filling in this page. • Order. -Line. The special compounds of the present invention include: 5_ [2- [3-Bromo-5 · [[2-butyl- 4-chloro-5- (hydroxymethyl) -1Η-imidazole-buki-10-f 4 (210X 297 ^ '^) £ 01745 A 6 B6 Printed by the Central Kneading Bureau of the Ministry of Economy V. Description of the invention (5) ] Methyl] -2 -benzofuranyl] phenyl] tetrazole; Bu [[3 -bromo-2- [2- (1Η -tetrazol-5-yl) benzyl] -5 -benzofuranyl ] Methyl] -2-butyl-4-chloro-1H-imidazole-5-fusylaldehyde; 1-[[3 -bromo-2- [2- (1Η-tetrazol-5-yl) benzyl] -5 -benzofuranyl] methyl] -2-butyl-4-chloro-1H-imidazole-5-carboxylic acid; 5- [2- [3-bromo-5-[[(2-butyl-1H -Pyrazol-bromo), methyl] -2-benzofuranyl] phenyl] -1H-tetrazole; 2- [3-bromo-5- [2-butyl-4-chloro-5- ( Hydroxymethyl) -1 {1-imidazole-: 1-yl] -2-benzofuranyl] benzoic acid; 5- [2- [5-[[2-butyl-4-chloro-5- (hydroxyl Methyl) -1Η-imidazole-butyl] methyl] -3 -methyl-2-benzofuranyl] phenyl] -1Η-tetrazole; [[3-bromo-2- [2- (1Η -Tetrazol-5-yl) stupid apple] -5 -benzofuranyl] methyl] -2 -butyl-4-chloro-1H -imidazole-5-carboxylic acid ethyl ester; Bu [[3- Bromo-2- [2- (1Η-tetrazol-5-yl) benzyl] -5-benzofuranyl] methyl] -2-butyl-1 (E) -alkenyl-4-chloro-1Η -Imidazole-5-carboxylic acid; Bu [[3-bromo-2- [2- (1Η-tetrazol-5-yl) benzyl] -5-benzylfuranyl] methyl] -4-ambient-2- Propyl-1H-imidazole-5-carboxylic acid; Bu [[3-Bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2- Butyl-1Η-imidazole-4,5-dicarboxylic acid; 5- [2- [3_ bromo-5-[(2-butyl-4-chloro-5- (methoxymethyl) -1H-imidazole-1 -Yl] methyl] -2-benzofuranyl] benzyl] -1H-tetrazole; 2-butyl-4-chloro-bu [[2-[((1Η -tetrazol-5-yl) benzene Yl] -3- (trifluoromethyl) -5-benzylfuranyl] -1H-imidazole-5-carboxylic acid; 1-[[3 -moor 2- 2- [2- (1Η- 四 伏 -5-yl ) Benzy] Benzoyl-5-yl "A (please read the precautions on the back before filling in this page) * so ·, hit · • line. -1 1-A 4 (210X 297 伂 发) A 6 B6 ^ 01745 V. Description of the invention (6) group] 2- (4-Butyl-4-chloro-1H) -triazole-5-carboxylic acid 1- (acetoxy) methyl ester; Bu [[3-Bromo-2- [ 2- (1Η -tetrazol-5-yl) benzyl] benzofuran-5-yl] methyl] -2 -butyl-4-chloro-1H -imidazole-5-methyl.acid 1- (acetyl Oxygen) ethyl ester; Bu [[3-Bromo -2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2-butyl-4-hydrogen-1H-quinazol-5-carboxylic acid 1- (Ethoxycarbonyloxy) ethyl ester; 1-[[3 -bromo-2-[2-(1 Η -tetrazol-5-yl) phenyl] -5: benzofuranyl] methyl] -2- Butyl-4- 氱 -1Η-diazole-5-carboxylic acid 2-methoxyethyl; 1-[[3_bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5 -Benzofuranyl] methyl *]-2-butyl-4-hydrogen-1H-imidazole-5-carboxamide; [U-[[3-bromo-2- [2- (1Η-tetrazole- 5-yl) phenyl] -5-benzofuranyl] methyl] -2-butyl-4-chloro-1H-imidazol-5-yl] carbonyl] pyrrolidinium; [[3-bromo-2 -[2- (1Η-tetrazol-5-yl) benzine] benzofuranyl] methyl] -2-butyl-4-chloro-N-methyl-1H-imidazole-5-carboxamide; Bu [[3-Bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzylfuranyl] methyl] -2-butyl-4-chloro-Η, Ν- Dimethyl-1H-quinazol-5-methyl ether; 1-[[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl Yl] -2-butyl-4-chloro-Ν-ethyl-1H-imidazole-5-carboxamide; Bu [[3-bromo-2- [2-UH-tetrazol-5-yl) phenyl ] -5-benzofuranyl] methyl] -4-chloro-2-ethyl-1H-imidazole-5-carboxylic acid; 1-[[3-bromo-2- [2- (1Η -Tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl .................................... ..... f ............. ¾ ...................................... .. order .......................... line (please read the notes on the back of K1 first, then fill out this page) Standard printing base ¢ 1 2 2 2 base t _ _ butyl bromochloroformate-5 I salivary beer four I four H-NH- ii f 1X / \ / IV-base- [2propyl [2 base基基基 04 ^ + 才 WF + 才) ^)) ylylfuran, benzodiazepine I _ 5 甲 5 甲 甲 甲 4 (210X 297S ^) A 6 B6 a〇i? 45 five 2. Description of the invention (7) (Please read the note on the back of the first page before filling in the hundred) yl] -2-butyl-4-chloro-N-isopropyl-1H-imidazole-5-methyl sugaramine; Bu [ [3 -Bromo-2- [2- (1Η -tetrazol-5-yl) phenyl] -5 -benzofuranyl] methyl] -2-butyl-4-iodo-1H-quinazol-5 -Carboxylic acid; [[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2-butyl-4-trifluoromethyl Yl-1H-imidazole-5-carboxylic acid; Bu [[3-bromo-2- [2- · (1Η-tetrazol-5-yl) phenyl] -5-benzylfuranyl] methyl] -2- Butyl-4-methyl-1H-imidazole-5-carboxylic acid, hydrogen chloride 1: 1); Bu [[3-Bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2-butyl-4-atmosphere -1Η-imidazole-5-acetic acid; Bu [[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2-butyl -4-chloro-1Η-quinazol-5-ethylacetate; 1-[[3-mo-2- (2- (ethoxycarbonyl) phenyl] -5-benzofuranyl] -2-butyl -4-chloro-1Η-imidazole-5-carboxylic acid; ΛΪΤ. Bu [[3 -bromo-2- (2-carboxyphenyl) -5 -benzofuranyl] methyl] -2 -butyl-4- Chloro-1H-imidazole-5-carboxylic acid; .Line [[1-[[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzylfuranyl] methyl Yl] -2 -butyl-4-chloro-1H -quinazol-5-yl] methyl] carbamic acid methyl ester; 1- [5-3 -chloro-2- [2- (1Η -tetrazole- 5-yl) benzyl] benzylfuranyl] methyl] -2-butyl-4-hydrogen-1H-imidazole-5-carboxylic acid; 1-[[3 -methoxy-2- [2- (1Η- Tetrazole-5-yl) phenyl] -5 -benzylfuranyl] methyl] -2 -butyl-4-chloro-1H -imidazole-5-carboxylic acid; printed and printed by the Central Bureau of Standards of the Ministry of Economic Affairs [[3 -Bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2-butyl-4-chloro-1H-imidazole-5-carboxylic acid 2 -Methoxy-1-methyl ethyl; 1-[[3-bromo- 2- [2-[[trifluoromethyl] sulfonyl] amino] phenyl] -5-benz-13-methyl 4 (210Χ 297Ί) A 6 Β6 5. Description of the invention (8) furanyl] methyl Yl] -2 -butyl-4-chloro-1H-imidazole-5-carboxylic acid; and its physiologically acceptable formulas, solvates, and metabolically unstable esters. According to this first aspect of the invention, there is also provided a compound of the general formula (I) above M or a physiologically acceptable cosmetic, solvate or metabolically unstable ester in which R 1 represents a hydrogen atom or a halogen The atom or a group or group is selected from C α -β alkyl 1 Cz-e alkyloxy or oxygen Cl-e alkyl;

Ar stands for this group (please read the notes on the back before filling this page)

R5 R3 represents a radical group selected from -C02H, -NHS02CF3 or a C-linked tetrazole group; R4 and R5 each independently represent an argon atom or a halogen atom;

Het represents an N-linked imidazole group which is selectively substituted by a Ci-e alkyl group and a C2-e alkenyl group at the 2-position. This azole group is selectively selected by one or two at the 4- and 5- positions Substituents (selected from a halogen atom or a group selected from C: -a alkyl,-(CH 2) »R s,-(CH 2) n C 0 R 7 or-(CH2) PHRaCOR °) substitution ; 1 to 3 represents a hydroxyl group or Ci-e alkoxy group; R7 represents a hydrogen atom or a group selected from the group consisting of hydroxyl group, alkoxy group, or. 4 (210X 297 public) 20174¾_ V. Description of the invention (9) -NRUR11 this group; R 8 represents a hydrogen atom; R9 represents a hydrogen atom or a group selected from Ci-e alkyl, Ci-e alkoxy Radical or -Nin11 this group; R1. R11 and R11 each independently represent a hydrogen atom or a D-4 alkyl group or -NRUR11 to generate a pyrrolidinyl heterocyclic ring; 'm represents an integer from 1 to 4; η represents an integer from 0 to 4; Ρ represents a The integer is from 1 to 4. The physiologically acceptable acid addition salts of the compounds of formula (I) can be derived from inorganic or organic acids. Examples of such salts include hydrochloride, hydrobromide, sulfate, phosphate, benzoate, methanesulfonate or trifluoroacetate. These compounds can also form salts with appropriate bases. Examples of such salts are alkali alkaloids (eg sodium or potassium), alkaline earth alfalfa (eg calcium or magnesium), ammonium and substituted ammonium (eg dimethylammonium, trimethylammonium, 2-hydroxyethylenedimethylammonium , Hexahydropyridine,-dimethyl hexachloropyridine mine, tetraalkylammonium, hexahydropyridine_, ethylenediammonium and gallbladder). It can be seen that for pharmaceutical use, the salts indicated above will be physiologically acceptable, but other salts may have their uses, for example, in the preparation of compounds of formula (I) and their physiologically acceptable addition salts. Printed by the Central Bureau of Standards of the Ministry of Economic Affairs ^ {Please read the precautions on the back and then fill out this page) K can also know that compounds of general formula (I) can be chemically modified in the form of MK compounds in vivo (eg Function) will provide the parent compound of general formula (I). Such prodrugs can be, for example, physiologically acceptable metabolically unstable ester derivatives. These prodrugs can be produced by esterification ’such as the general formula -15-A 4 (210X 29 * 7 g; November revised page

A 6 B6 III. Quan Ming explanation ι 10; (I) any of the mother and son includes lower alkene propylene esters) such as methoxy esters) • Halo alkane oxalane ethoxylate oxyethyl benzoyl oxa Alkyl substituted amines) or hydroxy

Si compound and other transyl esters (for example, alkynyl ester methyl ester or 2 alkyl ester · (yl ester (for example oxymethyl ester) or 1-methyl methyl ester or 1 (for example, phenylalkyl ester alkyl alkyl ester Any group should be as methyl or ethyl (such as ethyl-methoxyethyl such as 2-such as acetyl gas • alkoxycarbonyloxycarbonyloxy-benzoyl methyl ester or 4 (such as amine (such as 2 carboxylic acid group in advance Protected ester). · Enyne or propynyl ester) Alkyl sulfide for ethyl acetate or methyl ester, 1-oxoalkyl ethyl ether) · Oxyethyl ester) -aminophenyl ethyl ester or -hydroxyl ethyl ester • Conditions For coexistence. Ester compounds based esters (for example, ethyl g purpose), alkoxyalkyl alkyl esters (for example, 2, 2, 2-trichloroethane-acetoxy G ester esters (for example, 1-aryl oxyalkyl esters , Substituted or unsubstituted 2-H, H-dimethyl or 2,3-dihydroxy is exemplified by enyl esters or base esters (methyl thiomethyl)-or trimethylethoxycarbonyl (such as substituted or Non-amino ethyl propyl ester (please first hear ^ 讦 ^ 之 ： Two meanings and then go to this page) k. In addition to the above derivatives, the present invention includes compounds of the general formula (I) within its scope With other physiologically acceptable equivalence The state of things is a physiologically acceptable compound, like this metabolic instability is converted into the mother of the general formula (I) in vivo: a compound 3 According to the second aspect of the present invention, we provide the formula A compound of (I) or a physiologically acceptable warp solvate or an indefinitely metabolized ester is used for treatment.-It is stated that the compound of the present invention can be used for the treatment or prevention of hypertension. They It may also be used for IS abnormalities such as dementia (scrape like Kuzheimer's disease) and other conditions such as kidney failure, high lipid levels §1 ϋ polysymbols of 'heart failure. Order'-Ministry of Economic Affairs Central Administration '-*' Bureau Indian father · 16- A6 B6 V. Description of the invention (11) Foot print by the Central Bureau of the Ministry of Economic Affairs • Congestive heart exhaustion • Posterior myocardial infarction, brain abnormalities * Treatment of glaucoma and abnormally stable intracellular conditions. According to the invention In still another aspect, we provide a compound of formula (I) or a physiologically acceptable spice * solvate or metabolically unstable ester for use in the treatment of the above-mentioned disorders, especially hypertension. On the one hand, we provide the formula (, 1) A compound or its physiologically acceptable salt, solvate or metabolic ester is used to manufacture a therapeutic agent for the treatment of the above-mentioned conditions, especially hypertension. According to another aspect of the present invention, we provide treatment Disorders | particularly hypertension, a method that includes administering to a patient in need of such treatment a compound of formula (I) or a physiologically acceptable salt, solvate or metabolically unstable ester thereof in an effective amount ., Can be known as a compound of formula (I) or its physiologically acceptable salt, solvate or metabolically unstable ester can be K and one or more other therapeutic agents, such as M diuretics and / or different anti- Hypertension agents such as -blockers, calcium channel blockers or ACE inhibitors have their stupidity as examples. Please understand that such combined treatment constitutes another aspect of the present invention. Please note again that the treatment cited here extends to the prevention and treatment of M and established symptoms. Although it is possible to administer a compound K of the general formula (I) as the original chemical, it is best to formulate this active ingredient into a pharmaceutical formulation. The compound of formula (I) and its physiologically acceptable salts, solvates, and metabolism are optional The defined ester can be formulated and applied in any suitable way. The invention also includes within its scope, the compound of at least one compound of formula (I) or its {please read the precautions on the back of the technology before filling this page ) • Playing ·. Line · -17- A 4 (210Χ 201? 45_ Be V. Description of the invention (12) Physiologically acceptable polysaccharides, solvates or metabolically unstable esters are commonly used as medicine for humans or animals. This The sister compound can be mixed with one or more physiologically acceptable carriers or excipients in a conventional manner & used. This carrier must be acceptable in the sense that it is compatible with and compatible with other ingredients of this formula It is not harmful to the person taking it. Therefore, the compound according to the present invention can be formulated into mouth, eyes, mouth, parenteral or rectal administration or M-type suitable for administration by inhalation or insufflation. Oral is preferred. Axillary tablets and capsules can contain customary forms Such as binders, such as starch glue or polyvinylpyrrolidone: fillers, for example, lactose, microcrystalline cellulose or corn starch; lubricants * such as magnesium stearate or stearic acid; disintegrants, for example • Potato wine powder, Crdsearmellose sodium or Yi powder sodium glycolate; or a wetting agent such as sodium dodecyl sulfate. The flakes can be applied according to well-known methods. The oral liquid formulation can be, for example, water Or in the form of an oil suspension, solution, emulsion, syrup, or elixir, or it can be prepared as a dry product for mixing with water or other suitable medium before use. Such liquid formulations may contain conventional additives such as 恝Floating agent, such as glucose (please first «1 read the notes on the back and then fill in this page)

The Central Bureau of Standards of the Ministry of Economic Affairs has printed the U-peptide for the maintenance of the ester, or the fiber can be prepared as a salt-fat type, for example, it can be used, or it can be used as a habit or a mixture of slurry and water. The sugar-retaining base is not as good as sugar-collecting agents; this is linked to sucrose fermentation. The acid can be used in acetic acid, sugar oil, or vinegar alcohol, and it contains glucose two or so. Propyl is used as an example. Suhua, C, Shiweiwei, such as or in the shape of the fiber, such as the base case of nail embolism, the acid is for the nail,} nail system, sugar. Agent oil benzene with ester or pulping base with oil tablets sugar Rolled food hydroxycoconuts leaven., Including-Ye Hezhi -18- A 6 B6 ^ Qi? 45 V. Description of the invention (13) (please read the precautions on the back before filling in this page) You can find tablets and capsules Both can be made into long-lasting release formulations, and they provide controlled, continuous release of the compounds according to the invention over a period of hours. The compound of formula (I) and its physiologically acceptable salts, solvates and metabolically unstable esters can be formulated for parenteral administration by pellet injection or continuous infusion and can be in the form of M · unit dose in ampoule or with One release of the added preservative is in a multi-dose container. These complexes can be in the form of suspensions • solutions or emulsions in oil or water media, and can contain formulators such as suspending, selecting and / or dispersing agents. Another way is that the active ingredient can be in powder form, before use with a suitable vehicle • for example sterile | pyrogen-free water sister. The compound according to the present invention administered by inhalation is suitable to be provided as an aerosol , From a pressurized package or a sprayer, use a proper propellant, such as difluorodifluoromethane, trichlorofluoromethane, difluorotetrafluoroethane or other suitable gas. In the case of a heated S spray, the dose can be determined by installing a sister valve to deliver the metered dose. Alternatively, by inhalation or continuous blowing, the compound according to the invention can be in the form of a dry powder compound, for example, a powder mixture of this compound and a suitable powder base such as lactose or starch. This powder compound can be provided in the form of a molar amount. For example, the rib powder of an animal inhaler or blister pack in the form of an inhaler or insufflator can be marinated from it. Printed by the Central Kneading Bureau of the Ministry of Economic Affairs. The formula according to the invention may also contain other active ingredients such as antimicrobial agents, or preservatives. -19- T4 (210X 291 ^ Μ) 201745 V. Description of the invention (14) It can be known that the amount of a compound of the general formula (I) required for treatment not only varies according to the selected specific compound but also Means. The sex conditions of the treatment conditions and the patient ’s age and circumstances change and must be decided by the doctor or veterinarian who is responsible for the treatment. However, in general when the sister compound contains unit doses • Each unit should preferably contain 5 mg to 500 ag * When this compound is to be administered orally, the effective compound 25 mg to 400 mg is preferred. One day for the treatment of adults. 3g is preferred, K from 251 ^ to 1 〖The best it can be Μ Μ-once to 4 times. The compounds of the present invention can be prepared by various methods as described below, where each group is as defined by the general formula (i) unless otherwise specified. Therefore, according to yet another aspect of the present invention, we provide a method (A) for the preparation of compounds of general formula (I), which includes Tan formula (II) t, please read the notes on the back before filling this page). ¾.

Printed by the Central Bureau of Economic Development of the Ministry of Economy (where L is a leaving group, such as a halogen atom such as atmosphere, molybdenum or iodine, or a hydrocarbon sulfonyloxy group such as methanesulfonyloxy 'or P-toluenesulfonyloxy and R1 and Ar are as defined in the general formula (I) a compound K general formula (II I) -20- A 4 (210X 297 'two' hair) £ 01 ^ 45 A 6 B6 V. Description of the invention (15)

Printed by the Central Bureau of Economic Development of the Ministry of Economic Affairs (where R12 represents a sister g atom or a group selected from Ci-e alkyl groups * Cz-e dilute groups or Ci-e burned sulfur groups; R13 and R14 may be the same Or different each independently represents a krypton or halogen atom, or a group buried in cyano • nitro * "-4 alkyl, c2-e alkenyl, fluoroCl_e alkyl,-(CH2)« Re,-( C Η 2) n C 0 R 7,-(c Η 2) p HR e C 0 R β; and R β, R 7, R 8, R β, m, η, and ρ are as in the general formula (ι) Treatment as defined in), followed by the removal of any protective group if M is present, as described later. This reaction is performed under test conditions, for example, in sodium hydride, potassium carbonate or methanol It is preferably carried out in the presence of this reaction. This reaction is suitable for use in a solvent such as acetonitrile or an ether such as tetrahydrofuran or dihalane, a ketone such as methyl ethyl ketone or isobutyl ethyl ether 'or a substituted amide such as dimethylformamide. , At a temperature between 0 ^ 0 and the reflux heating temperature of this solvent. This general formula: (11) The intermediate compound and its acid addition is a novel compound and forms another aspect of the invention. In another pass In the method (B), a compound of the general formula (I) can be selected from the general formula (IV) (please read the precautions on the back side before filling out this page) _ _ -21-甲 4 (21〇Χ 297 伂 发) A6 B6 5. Description of the invention (16)

1 R

Printed and printed by an intermediate of the Central Office of the Ministry of Economic Affairs (where iP, Ar and Het are different as defined in the general formula (I), at least one reactive group is protected by a protecting group) . The protecting group can be any conventional protecting group, such as described by Theodora Greene in " Protective Groups in Organic Synthesis " (John Wiley and Sons Inc. 1981). Examples of the latter group protecting group include alkyl groups such as methyl or tert-butyl, or C7-10 aralkyl groups such as benzyl. When R3 is a tetrazole group, this may be protected by K. For example, -C (benzyl) 3 is trityl or a p-nitrobenzyl or 1-ethoxyethyl. Removal and protection of compounds of general formula (I) can be done using conventional techniques. Thus, for example, the aralkyl group can be K in a suitable solvent such as an alcohol such as ethyl alcohol, in the presence of a precious gold catalyst such as palladium or platinum or an oxide thereof on a support such as carbon, and Suitable for dissociation by hydrogen dissociation at room temperature and pressure. Carboxylic protecting groups such as alkyl can be used in a suitable solvent (such as an aqueous alcohol such as methanol or ethanol) in any suitable (Please Read the precautions on the back first and then fill out this page). ¾. • hit... Line -22- A 4 (210X 297 public) A 6 B6 .. V. Description of the invention (17) The temperature reaches the reflux heating by Hydrolysis dissociation. When the tetrazole group is M protected by a trityl group, it can be removed by trifluoroethyl acetate or an inorganic acid such as hydrochloric acid in a suitable solvent such as ethyl alcohol at room temperature, preferably by acid hydrolysis. Alternatively, if possible, the removal of the tetrazole group can be performed by the catalytic hydrogenation described above. In another general method (C), a compound of the general formula (I) in which the substitution of R3 in the group A represents a C-linked tetrazole group (and the group represented by Het without a When replacing the cyano group), K can be derived from the general formula Ua). Please read the precautions on the back of the technology before filling this page).

1 R

, Set * a compound printed by the Central Bureau of Economic Development of the Ministry of Economic Affairs (where R1, Ar and Het are as defined in the general formula (I) * the difference is in the base Ar, R3 represents a nitrile group) With an appropriate azide compound such as sodium azide * ammonium azide (preferred in situ from sodium azide and ammonium chloride is preferred), trialkyl azide (eg triethyl) ammonium ( K is prepared in situ from sodium azide and a trialkylammonium (such as triethylamine) or tributyltin azide reaction. The reaction is preferably carried out in a solvent such as xylene at an elevated temperature such as the reflux temperature of this solvent, which lasts between 1 and 10 days. When the azide compound is tributyltin azide, the reaction mixture can be used in the absence of a solvent at a temperature between room temperature and temperature--23-A 4 (210X 297 public) A 6 B6 5. Invention It is agreed (18) and 180TC. If it is a kind of anti-condensation, it can be removed by the use of alkali or acid solution. When the protective solution K is used to remove this protection, the compound M can be treated with an acid solution to release the free acid. The compound of general formula (la) can be prepared from a compound of formula (VIII) and a corresponding benzofuran intermediate by a method similar to that described herein. The intermediate compound of general formula (la) and its acid Addition salts are novel compounds and form yet another aspect of the invention. In another general method (D), a compound of the general formula (I) in which R3 in the base Ar represents -NHS〇2CF3, can also be from the general formula (lb) {please read the notes on the back first Rewrite this page) 乂 * 装-

. Order · The Ministry of Economic Affairs Central Kneading Bureau Printing (where R1, Ar and Het are as defined in the general formula (I) * The difference is that in the Ar group R3 represents an amine group) a compound and Trifluoromethanesulfonic anhydride is prepared by reaction in a suitable solvent such as dichloromethane. The compound of general formula (lb) can be prepared from a compound of formula (IX) and a corresponding benzofuran intermediate by a method similar to that described here. Thread · -24- A 4 (210X 297 Public Issue) A 6 B6 V. Description of the invention (19) Another way is that the compound of general formula (lb) can be K from a compound of formula (I) in which the group fflAr is -CO2H (with the proviso that it is the only linker in this molecule ) Prepared by Curt is rearrangement, using, for example, azide of diphenyl azide in the presence of a triethylamine and in a solvent such as an enzyme (e.g. tert-butanol) to produce an Carbamate males deprotect the amine in a customary manner, for example by acidolysis (using hydrochloric acid in a lyophilic enzyme). The intermediate compound of general formula (lb) and its acid addition salt are novel compounds and forms of yet another aspect of the invention. In the methods (A), (B), (C), and (D) described above, the compound of (I) can be obtained in the form of an S, obtained in the form of a physiologically acceptable salt . If necessary, you can use the method g to convert this type of nitrogen into the corresponding free acid or free state test. 〆The physiologically acceptable salt of the compound of general formula (I) can be selected from the group of general formula (I) —a compound with a common acid or sickle in a common solvent such as acetonitrile, acetone, chloroform, acid Ethyl acetate or an enzyme, such as formazan, ethylenzyme or isopropylenzyme, is prepared in reverse. Physiologically acceptable salts can also be prepared from other moles of compounds of general formula (I), including other physiologically acceptable salts, using conventional methods. The intermediate compound of general formula (II) can be read from formula (V) f, please read the precautions of the plan before writing this page) • Pack. • Order. Printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs ¾.

-25- A 4 (210X297 X hair)

A6 B6 V. Description of Invention (20) One of the thumping compounds uses this technique. The methyl group on the six-atom ring is defined as.). ‘Then, for example, a compound can be converted into an amine of the formula, tert-butyl-hypochlorite or M is photocatalyzed, so this anti-M is in a free radical initiator (the presence of azobi lsobutyronitri acetyl group> is preferred). Compounds of formula (V) at their atoms can be prepared from halogenated formula 1 hydrogen atoms>, such as a halogenated hydrocarbon, for example, compounds of formula (V) can be transported by any well-known method. The group -CHzL (when L is a halogen atom (II), a compound of N-bromobutadiene imide. 懕; W 個 当 .People, workers such as diazodiisobutylamine ( K after 0 is called AIBH) The conversion of the reactant in L is as in the above * (V) One of the halogenated light sources using N-gas sugar side light can be illuminated * and R1 is a halogen atom in benzyl peroxide • For example • A bromine -___ r- (V) one of the compounds (used for example • bromine · in an oxidized carbon. From formula (VI) where R1 represents an appropriate solvent. Please read the precautions on the back of the moraine before filling in this Page) R1 *

A compound of the formula (VII) of the Ministry of Economic Affairs Central Bureau of Preservation (VI) (where R1 · represents a hydrogen atom or a S group is selected from Ci-e alkyl or C2-〇alkenyl). 26- A · 4 (210Χ 297 2, ¾) V. Invention description? 1

(VII) (where Z represents a bromine or iodine atom or this group-OS02CF3, R4 and R5 are as defined in formula (I) and R3 ** is as defined in formula (I) for R3 Or a protected derivative) of a compound prepared by reaction. The compound of formula (VI) is first treated with an alkyl lithium compound such as n-butyl lithium at a low temperature, for example, between -1001 and Ot: in a solvent such as a chain (e.g. tetrahydrofuran). The M-boric acid trialkyl ester compound such as triisopropyl borate then treats the mixture and raises the temperature to room temperature. Then add water and Μ-anhydrous acid such as sulfuric acid to treat this mixture. Then the formula (Via) is printed by the Central Bureau of Standards of the Ministry of Economy. The formula CH will be obtained after the C is converted.

Compound 〇Palladium species 1 ⑻ in (V, in the compound -27- ...-................................................ ...... f .............. ¾ ............................... ..ίτ ......... {................. sf (please read the back page first; ± Yi Shishuo then fill out this page) A 4 (210X 297 public) 201 ^ 45 Α6 _Β6 5. Description of the invention (22) In the presence of tetrakis (triphenylphosphine) palladium (0) in the presence of a solvent such as an ether (eg dimethoxyethane), And reacting with a compound of formula (VII) in the presence of sodium carbonate or thallium hydroxide. This reaction is suitable to be carried out at elevated temperature, such as the reflux heating temperature of this solvent. The substitution of the compound of formula (V) in the group Ar where R3 represents a C-linked tetrazolyl molybdenum can be obtained from the precursor of a compound of formula (V) where this substitution is R3 represents a nitrile Group preparation, use the reagents and conditions described in method (C). In a similar situation, the intermediate of formula (VII) where R3 · represents a c-linked tetrazolyl ring can be derived from formula (VIII) ..................... .................. {.............. installation (please read the notes on the back before filling this page)

Preparation of a compound printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs ii (following the need to preserve any reactive groups) * Use methods known in this technique such as those described in method (C). The substitution of the compound of formula (V) in the group Ar in which R3 is -NHS02CF3 can be prepared from the precursor of a compound of formula (V) in which the substitution of R3 is an amine group, using method Reagents and conditions described in (D). In a similar situation, the intermediate of formula (VII) in which R3 · Table -HHS02CF3 can be obtained from formula (IX) -28-A 4 (210X 297 Yunfa); 〇1745 A6 B6 V. Description of the invention (23)

Preparation of a compound of (IX) (following the protection of any reactive groups if necessary) * Use this technique to know methods such as those described in method (D). The compound of formula (V) can also be derived from formula (X) 〇 (please read the notes on the back before filling this page). ¾. CH,

OH (X) • Ordered (where R1 is as defined before Μ) a formula (X I) which is suitably substituted with a compound

(XI). Green. Printed by the Central Bureau of Standards of the Ministry of Economic Affairs (where L is as previously defined and R3b is as in formula (VII) as R3a-29 A 4 (210X 297 Public Issue) 201745 A 6 B6 Ministry of Economic Affairs The Central Bureau of Rectification printed the five 'invention description (24) for the purpose of defining either a nitrile group for later conversion to a tetrazole group or an amine group for conversion to -NHS〇2CF3) compound Prepared by an intramolecular cyclization reaction in the presence of a sodium hydroxide or potassium carbonate. This cyclization is a two-step reaction requiring one equivalent for each step. However, it can be seen that it is possible to carry out inversion in the presence of the two best practices to avoid the need to separate the intermediates. This reaction is preferably carried out in a solvent such as an ether such as tetrahydrofuran, an enzyme such as ethyl yeast or a substituted sugar amine such as dimethylformamide • at a temperature between room temperature and the reflux heating temperature of the solvent. It can be known that the compound of formula (V) where R1 represents a hydrogen or halogen atom can also be converted to the compound of formula (V) where R1 represents this group methyl (via hydrogenolysis of Mannich «{group),- CH0 or -C0R2 (where R2 is as defined in the general formula (I)), use this technology to know the technology • such as J. A. J 〇u 1 e and G. F · S π ith in " H eter 〇cyc 1 ic Chemistry " (Van Nostrand Reinhold Company, London (1972)), A. Albert in “Heterocyclic Chemistry”, 2nd Edition (The Athlone Press, London (1968)). A. Mustafa in “Heterocylic Conpounds”, Vol. 2 (John Wileg and Sons Inc. New York (1974)), RC Elder field in "Heterocyclic Compounds ", Vol. 2 (John Viley and Sons Inc., New York (1951)) and AR Katrisky and AJ Boulton in " Advances in Heterocyclic Chemistry ", V〇1.29 (Academic Press, New York (1981)). -30- A 4 (issued by 210X 297W) (please read the precautions on the back before filling this page) • Installed, ordered. • Line. A6 B6 201745 5. Description of the invention (25) { Read the precautions on the back first and then fill out this page.) The azole of formula (III) can be prepared according to Huanzhou Patent Specification No. 02 53310A and US Painting Patent No. 4355040 or by a method similar to that described therein. The contents of some reference materials are attached for reference. Formulas (VI), (VII), (VIII) * (IX) * (X) and (XI) are known compounds or can be used for the preparation of Known compounds are prepared in a similar manner. The following example illustrates the invention. The temperature is t. "G 干 堍" refers to the use of sulfur-ordered-magnesium acid, and a thin calendar analysis (M later refers to Tlc as Thin layer chromatography) It was carried out on sand glue and column analysis was carried out on sand rattan (Merck 9385 unless otherwise stated), using one of the W times solvent system: A for ether: hexane, B for ethyl methylene chloride, C for two Methyl chloride: ethyl yeast: aqueous ammonia solution, D stands for dichloromethane: ethyl acetate, or E stands for dichloromethane: ether: acetic acid. Use the abbreviation of K times: THF stands for tetrafluorofuran; DME stands for dimethoxyethane; AIBN stands for diazobisisobutyronitrile; DMF stands for dimethylformamide; TMEDA stands for tetramethylene ethylenediamine; HBS stands for N-bromobutadiene imine; DMAP stands for 4-dimethylaminopyridine; DEAD stands for diethyl azodicarboxylate. Intermediate 1 5-申某荣 # eptimum-2-arsenic acid • Shen · Printed by the Central Kneading Bureau of the Ministry of Economic Affairs, add n-butyllithium (35.16 βΠ- dropwise to TMEDA (9.58 ml) and stir A solution of 5-methylbenzofuran (8.22g) in diethyl ether (250 ml), maintain the temperature below _60t during the addition process: warm the solution to about -101C and stir at this temperature during 45 minutes It takes 30 minutes. A precipitate is formed during the heating. The slurry is cooled and triisopropyl borate (43ml) is added to maintain the temperature below -60 ° C. After quenching with 2H HCl (70ml)- 31- A4 (210X 297%) A 6 B6 * 601745 V. Description of the invention (26) Before slowly heating this solution to room temperature. Extract the mixture with M2N HC1 (3 x 50ml) and M2N HC1 (4 x 30ml) · water ( 2 x30b1) Wash the combined organic extracts and evaporate after drying to obtain the title compound, an orange solid (12.75 g). Tlc ^ System A (1: 1>, Rf 0.3. Note: Rf = Rate of flow, ratio shift value.

Intermediate P 2-(5-A certain-2- ¾ and a certain 1¾ Tian Pian Tian Kujiang 2-bromobenzoic acid methyl ester (11.70g), intermediate 1 (12.75g) and tetra (tribenzyl K ) Palladium (0> (0.5g> solution in DME (300nl> and 2N Na2C03 (60ml) was heated at reflux with nitrogen and vigorous stirring. After 1 hour and a half, 500 mg of catalyst was added and refluxed under nitrogen Continue stirring. After about 5 hours, cool the reaction to room temperature and dilute with diethyl ether (300Bl). Separate the organic layer and wash and dry with water. After filtration and evaporation, a yellow oil bark floating liquid is obtained (19.27g), which was purified by analysing and dissociated> System A (1: 9) to obtain a yellow oil (11.06 s). The Kugelroh "steamed to obtain this title compound (4.31g) Tlc system A (1: 9), Rf 0 · 5〇 Intermediate 2 2-Γ5- (Hai Shenmou) -2-¾ and a certain amount of 1¾ methyl alcohol methyl ester intermediate 2 (0.20g) and A solution of NBS (0.098g) in carbon tetrachloride (8 ml) was heated to reflux and irradiated with K-200 tungsten filament bulbs for 1 hour. AIBN (10s) was added. After another 30 minutes, the solvent was distilled off A yellow crystalline solid was obtained and purified by chromatography Ito A (1: 9) -32- A4 (210X297 public issue) (Please read the precautions on the back before filling this page) • Pan · • Green · Printed by the Central Bureau of Economic Affairs of the Ministry of Economy ^ ^ 01745 V. Description of the invention (27) A6 B6 kk obtained this title compound (0.118 8) 0 T. 1. C. It is A (1: 9) * Rf 〇 · 42 0 Intermediate 4 2--Γ 5-Γ ( 2- T M.) -1 Η-眯 DS P _ 1-基） 甲某 1-2-cage # 裀 見 even 1 芾 甲 称 甲 JS_ The intermediate 3 (0 • 118 s) and DMF (3 B 1) Test solution treatment 2-Butyl squint (0 • 06g) and formazan (0 • 02 8 :) solution in DMF (3 ml) 0 Stir continuously at room temperature for 72 hours. Put in vacuum The solution was concentrated and the residue was dissolved in ether. 1 Washed with water (3 X 2 0 m 1) and back-extracted the combined aqueous phase with ethyl acrylate (20d 1). The combined organic phase was dried and passed m And evaporation > λ to obtain an orange oil which was purified by chromatography with system C (300: 1) dissociation > Λ to obtain this 抷 慝 compound »— · kind of light yellow ψ (0.2 4 4 g) 0 T. 1. C. System B (1: 1), Rf 0. 2 〇 Intermediate 5?, _ (3-Mo-Jiahua-2-¾ 眹 _ very) benzoic acid methyl ester Μ 1M bromine in carbon tetrachloride (0.7 ml)-• drop--drop treatment intermediate 2 (0.25 g) was cooled to a 20 t solution in carbon tetrachloride (5 ml). m Continued at -20 t: Stir for 1 hour and then slowly heat to room temperature. Continue to stir at room temperature-0 overnight-* drop-add cyclohexene (0.1 ml) dropwise and evaporate the solvent in vacuum to get this compound,-orange oil (0.26 g) 0 T 1. C. System A (1: 9) 1 'Rf 0. 45 0 Intermediate 6 2-"3-Sea_ (Bian Shenshi) -2-¾ Jing Shuanan 1¾ Tian Mu methyl ester-according to the middle Method 3 for MMHBS (0.134g) and AIBN (lOms) (please read the precautions of the plan first and then fill in this page). Printed by the Central Bureau of Economic Development of the Ministry of Economic Affairs -33- A4 (210X 297H) 201745 A6 B6 V. Description of the invention (28) Jingdi _ Niu Jujuan quasi-bureau printing ^ Intermediate 5 (0.26g) in carbon tetrachloride (8 ml) solution to obtain this title compound * A light yellow oil (0.19g ). T. lc Mito A (1: 9), Rf 0.4 .. Intermediate 7 7 2 _- "3 -Submerged- 5-" (2-Butyl-1H -Mi Beer-1-some) 1-? -Acquisition: ^^ »_ Accepting the treatment of 2-methylbutyrazolate according to the method of Intermediate 4M Intermediate 6 (0.197g) in DMF (3ml) and 2-Butylenazole (0.078g) and formazan Sodium (〇.〇25g) in DMF (3 ml) solution, Μ to get this title compound, a yellow Color oil. Tlc · Bronze B (l: l), Rf 0.2. Intermediate R 2-(5-Tian Shi-2- ¾ #P 去 晡 Very) ¾ Shen Macaque Intermediate 1 (20 g) was added to 2-nitrobenzylcarbonitrile (10.34g) and tetrakis (triphenylphosphine) palladium (〇) (1.5g) in DME (200nl) and 8% NaHC03 (50ml) with stirring under reflux under nitrogen The solution was added with a catalyst (1.5g) and the reaction was continued overnight. The reaction mixture was cooled to room temperature and diluted with ether (200 ml). After drying and evaporation, a white solid was obtained which was purified by chromatography. K System A (1: 9) dissociated M to obtain the title compound (10.58g), a white solid S. Tlc system A (1: 9), Rf 0.45. Intermediate 8 was also prepared by another method in two steps. ： AJL 2-Limou-5-Memouxu Road, add p-cresol (10〇S) in anhydrous THF (100ml) drop by drop to -34- (please read the notes on the back side first and then slap (Drive this page) .fat..order..line. F 4 (210X 291 ^^) 201745 A6 B6 V. Description of the invention (29) The Central Bureau of Economic Affairs of the Ministry of Economic Affairs prints the bromination of new worms prepared by armed stirring Butyl magnesium [magnesium (25.Og) and bromoethane (75b1)] in THF (500B1) under nitrogen addition rate of M Buried maintain slow reflux (about 30 minutes). Toluene (1.21) was added after another 30 minutes • Following M1 · 3-dimethyl-3,4,5,6-tetrahydro-2 (1Η) _pyrimidinone (125ml) 'and paraformaldehyde (70g) . The mixture was then heated at reflux for 16 hours. This concentrated compound was condensed by steaming and then added with an aqueous solution of human acid (2M, 600ml). Water (600 ml) was added and the mixture was filtered through " hyflo. &Quot; The organic phase was separated, the hydrocarbons were dried, filtered and concentrated in vacuo to obtain a brown oil. The oil was steamed and K ether (1 1 ) Extract the product from the extract. The extract is dried, filtered and concentrated in vacuo to obtain a light yellow mud and cool it to -10 ether, K ether (pre-cooled to -78C, 100ml) Developed, filtered rapidly and washed K with ether (pre-cooled to -78t) to obtain the title compound as a colorless needle-like solid (131.4s). Tlc System A (1: 5), Rf 0.5. H_L 2- (5-Shenmou -?-罙 # 〇 # Miaoshi 1 cage wall was added dropwise to the solution of the product of step (a) (130s) in anhydrous DMF (400ml) under nitrogen and stirrer stirring to formazan (56.2 g) In a solution of ethyl yeast (400ml), after another 20 minutes, add a solution of 2- (bromomethyl) benzonitrile (182.2s) in anhydrous DMF (400ιπ 丨) drop by drop. Then heat the mixture to 75 t for 30 minutes. Let this solution cool for 1 hour. Add the slurry of formazan (56.2g) in anhydrous DMF (100ml) and heat the mixture to reflux It took 1 hour and a half. The mixture was condensed in vacuo and then poured into ice water. The solid was collected and then developed with formazan to obtain the title compound (intermediate 8)-a gray-brown solid (149.4g) 3- 35- (please read the precautions of the plan first and then fill out this page) • Install _ Order. -Green. 201745 A6 ___ B6 V. Description of invention (30) Printed and printed Tlc system A (1) : 9), Rf 0.40. Intermediate 9 2-(3-zhang-5-Tianmou-2- ¾ and dizzy) a cage of M1M bromine in carbon tetrachloride (32 ml) drop by drop treatment of intermediate A solution of 8 (5.0g) in dichloromethane (80ml) (after 20 to 20t :). At -20 = stir the mixture for 1 hour and then warm to room temperature. After 1 hour at room temperature, filter The reaction mixture was evaporated. The residue was triturated with ether and the resulting solid M was collected to give the title compound, an orange solid (3.54 g) ° T · 1. C. System A (1: 9), Rf 0.40 . Intermediate 1 0?-"?-海-5- (海 田某) -2-Cage # [| Sui Nan 1 cage applied for intermediate 9 (1.70g) and MBS (0.76g) in four atmospheres of carbon (30m 丨) solution and benzoyl peroxide Acyl (0.08s) was heated to reflux under nitrogen. After 18 hours the reaction was cooled to room temperature. Filtered and concentrated in vacuo. Triturate the residue K with ether to give the title compound. A colorless solid (0 . 58 g). T.l.c. System A (1: 6) · Rf 0.25. Intermediate 1 1?-".?-张 -5-" "?-Ding-4-radon-5-(waving a certain) -1 Η-咪 呻-： ί-基 甲某 1-?-Cage # 咕 目 某 1¾ Purify according to the method of Intermediate 4 with Intermediate 10 (1.7g) to treat 2-butyl-4-chloro-1H-quinazol-5-methanol (1.23g) and methanol sodium (〇.24g (Please read the notes on the back before filling in this page) k., Order · line · -36- A 4 (210X 297S issued) 201 ^ 45 A 6 B6 V. Description of the invention (31)) in DMF (lOml ) In the solution. Purification of K series D (4: 1) by calendar analysis and dissolution to obtain this title compound (0.57 g). Tlc system D (4: 1), Rf 0.45., Intermediate 1 2 5 -Γ2-(R-A certain Zan Xian) cage 1-1H- Si Ying Intermediate 8 (94 &) in azide tri-n-Dincotin (268 s) suspension was added under nitrogen. Heat to 100-125 for 1 hour and 15 minutes. Then heat the resulting solution under nitrogen at 155-1601C for 2 hours, then pour it into an aqueous solution of sodium hydroxide (0.8H, 3070ml). Ether extraction This solution was acidified with 5N hydrochloric acid to pH 1 and the resulting precipitate was filtered, washed with water and dried under vacuum. The solid was dissolved in cool The ethyl ester was washed with water and dried. The solvent was evaporated to obtain the title compound, a pale yellow solid (100.3s). Tlc system A (1: 1), Rf 0.2. Intermediate 1 3 5- "2- (3- 海 -5- 甲某-?-茉 # 卩" Miaomou) Mined even 1-1H-Sibei Ministry of Economic Affairs Central Bureau of Rectification Printed (Please read the precautions before you fill in This page} A solution of bromine (58g) in carbon tetrachloride (140 ml) was added drop by drop over 35 minutes to intermediate 12 (50 g) in a mechanical agitator under nitrogen at room temperature in anhydrous di Solution in alkane (2090b1). The resulting solution was stirred at room temperature for 3 hours, and then cyclohexene (63ml) was added. Another preparation of this product was made in the same amount as above, and it was added at this stage Combine. Evaporate the solvent and disperse the residual brown oil (260g) between diethyl ether and aqueous sodium hydroxide. Acidify the test solution to pH 1 with hydrochloric acid, and then take Methyl Acetate. Wash the cake with ethyl acetate. Ester extract, dried and evaporated -37- A 4 (210Χ 297 g, ¾) < ^ 01745 A6 B6 V. Description of the invention (32 j K is a light yellow solid SS (125g) A thermal stupid developed under cooling, and "go to this liquid to obtain the title compound Li, a cream-colored solid (1018 g) 0 T.I.c. Zhao acetate / petroleum chain / cool acid (50: 50: 1), Rf 0.27. Intermediate 1 4 5- "2-. (. 3-Ao-5-methyl-2-benzopyridine) Rong Shi 1-2-(=: Rong Jiamou 1 -2H-Si Ying Jiang San Yi Amine (57.4g) was added to the suspension of intermediate 13 (101g) in anhydrous dichloromethane (2.91) under mechanical stirring at room temperature under nitrogen. Gaseous triphenylmethane (79.3g) was added at room temperature Following MDHAP (1.0g) and stirring the mixture under nitrogen for 3 hours. The reaction mixture was washed with water, then water and dried. The solvent was filtered off and concentrated to a volume of about 1.2 1 then «via silicone ( Merck 9385, 14 cm diameter column). Dissolve in dichloromethane to obtain a colorless solid (158.4g) which was triturated with ether and filtered to obtain the title compound, a colorless solid (147.9g) ° Tlc (dichloromethane / hexane) Alkanes 1: 1), Rf 0.28.

Intermediate 1 S 5- 「2-m 寒-r- (下田 很） -2-Cage # 眹 晡 荜 1Benzene 1-2-(Some) -2H-Four Posts Dissolve the intermediate 14 (74g) After heating the suspension to reflux, the four-carbonized carbon (2050π1) is allowed to cool the resulting colorless solution to 5〇1 and then add it (please read the precautions on the back before filling in this page) . The Ministry of Economic Affairs Central Kneading and Preservation Bureau · MBS (22.1g), "l The reaction mixture was heated to reflux with benzoyl peroxide (1.18) ° in a gas atmosphere for 3 hours and 15 minutes, and then allowed to It was cooled to room temperature. The mixture was washed with water and brine. As described above

A 4 (210X 297 public) A6 B6 ^ 01745 5. Description of the invention (33) At the same time as another preparation of this product, and at this stage it is combined and dried. The solvent K was evaporated to obtain a colorless solid H (168 g) and its M ether / formaldehyde (1: 1) was developed and then obtained to obtain the title compound, a colorless solid (160.8 g). T.l.c. (two gas methane / hexane 1: 1), Rf 0.15.

Intermediate 1 R 2-Dingmou-4 ·-tf-1H-Suiyi-5-Tianlu M manganese dioxide (63.15g) treated with 2-butyl-4 -atmosphere-1H-imidazole-5-formazan (22.0 g) Suspension in dichloromethane: 1,4-dibromoethane (2: 1) (690ml) and this inverted mixture was heated to reflux under nitrogen for 3 and a half hours. Cool the reaction mixture, filter and evaporate the filtrate to leave a slightly yellowish white solid. K Petroleum Ether developed this residue. Filter and dry K to obtain this title compound, a white solid "1 (17.9g) melting point 98-99C ° intermediate 1 7 1-" ΓΡΙΙ-;!-"?-"; >-( Two cages) -2H -Tetrale-5 -yl 1 茏 基 1-5-y # Peptide 1 certain 1 even 1-? -Butyl 4- 4-g-: lH -Slender beer- 5-Formaldehyde heats the mixture of intermediate 16 (500 mg), intermediate 15 (2.73s) and potassium carbonate (407ng) in anhydrous DMF (20ml) at 80¾ for 24 hours. Add intermediate 15 (500 mg) It was heated for 18 hours. The reaction mixture was cooled, poured into water (200 ml) and extracted with ethyl acetate K. Combined with organic extracts, dried hydrocarbons and concentrated in vacuo to a yellow foam (3.6g). Purified by chromatography, dissolved in petroleum ether / ether 3: 1, 1: 1 and then ether to obtain the title compound (1.78S), a light yellow foam. -39- A 4 (210X297 ^ no). ................................. {.............. it ........................ ^ ......... {......... ........ ^ f Please «Read the notes on the back and then write this page) Printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs A 6 Β6 2〇t? 45 V. Inventions Ming (34) (Please read the notes on the back before writing this page) Tlc System A (1: 3), Rf 0.28. Intermediate 1 8 1-““ 3- 通 -2- “2-“ 2- (Sanlong Tianshi)-? Bu flash nap-5-some 1 off even 1_ 卜 籣 # 0 矣 nanmou> Methyl 1-2 -Dingmou-4-氲 -1H -Squinted candle-R -Tian Xiang added a solution of sodium oxyhalite (3.39S) and "{acid dihydrogen sodium (3.39g) in water (4〇Β1) to intermediate 17 (2.93g) in tert-butyrate (5 〇ml) and 2-methyl-2-butene (2M in THF · 22.5nl) and THF (50 Bl) mixture. The mixture was stirred at room temperature overnight, after this time the large vacuum was removed Part of the solvent and this residue are distributed between water (containing 2N sodium hydroxide solution to about pH 2) and diethyl ether. The aqueous layer is neutralized with saturated gasified ammonium solution and extracted with ethyl acetate. Combined with this extract * Μ water and salt backwash • After drying and concentrating in vacuum, the title compound *-a white solid S3 (2.95 g). Tlc dichloromethane / formazan (10: 1), Rf 0.58 Φ 间 物 1 9 5- "2-": ^-濂 -5-"(;? -Dingmou-1 »-眯 _-1- 荜) Methyl even 1--2-cranofuran and even 1¾ Methyl) -2H-tetrazole_ Adding methylphenidate (400 mg) to 2-butyl- 1H-imidazole (400 o «g) in a solution of anhydrous DMF (40b1) and the mixture was stirred for 30 minutes. Then add Intermediate 15 (2.2g) and the reaction is carried out according to Intermediate 4 ° Purification by chromatography (ethyl acetate) to obtain the title compound 'white solid 81 (printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs f R Acetate acetate C. Matter 1. Between T. Zhongjia 4 (210X 4297 乂) 201 ^ 45 A6 B6, _-, V. Description of the invention (35) 2 _- 「5- (通 田某) -2- 3 £ # Ρ 韣 晡 某 田 _ This is obtained by treating the solution K of intermediate 8 (1.0 g) in carbon tetrachloride (40id1) with HBS (0.771g) and AIBN (0.14g) according to the method of intermediate 3 The title compound, a yellowish white crystalline solid (1.20g). T. I.c. 糸 铳 A (1: 9), Rf 0.35. Intermediate 9 1 2 ^ "5-" "2 -Dingmou-4-aza-5- (hydroxymethyl) -1 幵-眯 post-1- 其 1 田 很 L-2- cage # 眹. 然 某 1 茏 申 糖 According to the method of intermediate 4 to 2 -Butyl-4-atmosphere-1H-imidazole-5-formazan (1.15s) in DMF (5ml) solution treatment. Interst 20 (〇.70g) in anhydrous DMF (5ml) and formazan ( 0.17g) solution. Purified by chromatography, dissolving this compound as a D (2: 1), a yellowish white solid (0.272g). Tlc system D (2: 1), Rf 0.5. Intermediate 2 2 m 痗-5-"?-T -4- radon-5- (筠 甲某) -1H- 眯 盹 -1- 某 1¾ # 11 right [118 certain 1 cage Tianlu methyl ester according to the method of intermediate 4 K Intermediate 6 (1.0 g) treated a solution of formazan (113 mg) in 2-butyl-4-amino-1H-benzyl-5-methanol (358 mg) in anhydrous DMF (10 ml). The title compound, a pale yellow solid Η (3 0 6 ng), was purified by ether followed by ether / ethyl yeast (10: 1) dissolution. After Tlc ether, Rf〇.55 ° Ji 5 Intermediate 21. Printed by the Central Bureau of Accuracy-41-A4 (210X297 public) Please read the precautions on the back before you read this page). Apparel · · · · · Green · Ministry of Economy Central Bureau of Accreditation and Imprint. Α6 Β6 V. Description of the invention (36) Ertian Mou-2- cage # 眹 晡 某) Rongtian Zuojing 1- (2-hydroxy-5-methylphenyl) ethyl Si (1 g) in DMF (7 ml) The solution was added to a solution of formazan (0.39g) in ethyl yeast (7 ml). After about 10 minutes, add 2- (bromomethyl) benzophenone (1.3g) in DMF (7 ml) Solution and heat this solution to 1101C. After 2 hours, add formazan (0.39g) and follow-up at 110t: heat. After another 30 minutes, cool the reaction to room temperature and evaporate. Ethanol. Pour this solution into water / ice (200 ml) and extract with ethyl acetate (4 X 30nl). K water (4 X 20b1) was used to wash the combined organic extracts and dried bittern. Upon filtration and evaporation, a yellow oil was obtained and dissolved in dichloromethane (2 ml) and formazan (30nl). After concentration, a solid waist was collected and washed with K formazan to obtain the title compound, a white solid (0.53 g). Verification results: C, 82.3; H, 5.1; N, 5.4 C 7 H: 3 H 0 3 Calculation: C, 8 2.6; Η, 5.3; H, 5.6% intermediate; Μ 5- "( 3.5- 二甲 某 -2- cage # 0 go to beer) cage 1-1> ^ 四 _ Add the intermediate 2 3 (0 · 2 7 g) to the stack under nitrogen at 1 6 0 t stirring Tri-n-butyltin nitride (3 g) and K according to the method of intermediate 12 to obtain this standard compound • A white foam (〇.315g). Test results: C, 70.5; H, 4.9; 19.55 C 1 7 Η α 4 N 4 0 Calculation: C, 7 0. 3; Η, 4.9; N, 1 9. 3% intermediate? 5 5 _- “(3.5- 二 申 某) -2- 茉 # 11 矣 照 某) Cage 1-2- (二 _ 呆 田 很) -2H- 四 盹 -42- A 4 (210X 297W hair) ........................... ............. {.............. ¾ ........................ ......... order ......... f ................. grade (please read the precautions on the back before filling in this Page) 201745 V. Description of the invention (37 Α6 Β6 aminoethanetrioxane methyl stupene gas and

ο 1X in the middle of the world. Dispose of the dichloromethane in the presence of dichloromethane and dilute water, and release the dilute extract through this substance.夜 η over om mix! Stir with water temperature M room and its contents ο mixed solution should be dissolved X 3

Analysis, the history of the matter by its combination) 0 S 8 混 7 this (0 get '5 ° 0 M.2 solid ionization 0 color solution Rf cl \ 1 / yellow 1, shallow: 1) > la 1 species {-alkane . (1 Hexane) ° Alkane M: 3g hexane. 4: Steamed r (0 alkane and chlorinated formaldehyde solid difi fi «M color two. White white C material Dai pure pure l.Ja dry method IT.AJ氲-4- a certain basic theory f squint a Jiamou (please read the precautions on the back before driving this page). Outfit · Ministry of Economic Affairs Central Bureau of Preservation and Printing] -3- 珥 某 -2- cage # 〇 矣"6,1,2,1-2- (three cages)-? H-tetrazole treated with NBS (2,14g) and AIBH (0.35g) intermediate 25 (6.10g) in carbon tetrachloride (175 ml ) And then heated to reflux while irradiating a 250 W dysprosium bulb. After half an hour, the mixture was filtered and washed with water (3 X 100 ml). After drying, filtering and evaporating K gave a white foam. M A Enzyme (0.93g) treatment of 2-butyl-4-chloro-1H-imidazole-5-methylenzyme (3.24 S) in anhydrous DMF (30 ml) was stirred under nitrogen for about 15 minutes. Then add this A solution of the brominated material in anhydrous DMF (80 ml) and stirring at room temperature for 16 hours. Evaporate the solvent and M ethyl acetate (250 ml) to dissolve the residue and M water (3 X 10〇b1) Washed, dried, dried and evaporated to obtain an orange oil, which was purified by chromatography, Μ 糸 系 C (300 : 8: 1) The dissolving layer bubble is formed by the yellow color after the color change and the pure material method is combined to analyze the layer problem. This ether is obtained by extracting the ether from the barium and dissolves again.) Mo: 1 bubble (2 color A yellow system) Germline-得 得法. Segregating foam-43- A4 (210X 297 public) 5. Description of the invention (38) Please read the precautions on the back and then fill out this page) Tlc ether · Rf 0.45 ° Intermediate 27 Shen Argon-Fi-Tianxi-Xiemou) ¾ Shenhe added 2- (bromomethyl) benzophenone (17.6g) to methyl 2-hydroxy-5-methylbenzoate (15s) and sodium hydride ( 2.7g, 80% dispersion in oil) in a mixture of anhydrous THF (150ml) and the resulting mixture was heated to reflux for 5 hours. Then add Nahuana (2.7g, 80% dispersion in oil) and continue heating overnight. Cool this mixture to ου. Add Nahua (2.7g, 80% dispersion in oil) and dimethylsulfate (17nl) * and stir the resulting solution at room temperature for 4 hours. Remove the solvent in vacuum * ket dichloromethane (200 ml) to dissolve the residue and carefully add concentrated ammonia solution (200 ml). Remove the organic solution and extract the aqueous solution with dichloromethane (2 x 200 ml). Evaporate this merger in the dark sky * The dried phase and the residue are purified by chromatography. M Dichloromethane: hexane (1: 1) dissolves to obtain the title compound, a white solid (17 g) . T.l.c. methylene chloride: hexane (1: 1), Rf 0.3. Intermediate 28 2-"5- (Substituted methyl) -3 -methylchloro-2-cage # 11» 晡 某 1¾ Tian Lajiang intermediate 27 (0.39g), MBS (〇.33s) and AIBNU00 mg) The mixture in carbon tetrachloride (15 ml) was heated to reflux for 4 hours. The mixture was filtered and the solvent was removed in vacuo to give the title compound • A yellow oil (0.52g). Tlc dichloromethane: Hexane (1: 1), Rf 0.35. Intermediate 29 -4 4 -A4 (210Χ 297Ά *) A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 51 51. Description of invention (39 2- "5" "2-Dingmou -4-Ga-5- (珲 甲某) -1 > ^-眯 Beer-1-some 1 Jiamou-jiaguannan 1 Fushen blind Add intermediate 28 (0.52g) to 2-butyl- 4-chloro-1H-imidazole-5-methanol (0.29g) and formazan (81mg) in a mixture of DMF (10 ml) and treated according to the method of intermediate 4 The resulting mixture was purified by chromatography with ether This title compound was dissolved, and a yellowish white g solid (0.25 g), melting point 164 ~ 168. Intermediate 30 痗-?-"2-" 2- (Three cage Shenmou)-? H-四 0Φ-5 -Certain 1 stay certain 1- B-cage and squint 1 a certain 1-2-Ding certain-4-M-1H- 眯 田 雔 申 ester put azomethane in B (0.7 ml) was added to a solution of intermediate 18 (500ing) in THF (5 ml). The excess azomethane was destroyed with acetic acid and the remaining solution was concentrated to dryness. It was purified by dichloromethane K dichloromethane Methane / formaldehyde (500: 1) dissociates to give the title compound (357 mg), a white foam Ο Tlc dichloromethane / formase (50: 1), Rf 0.72. Intermediate: n 1-""% blight- ?-"2-" 2-(Sanfushen) -2 Η -Tetrazole-5 -Some 1 MoShou 1-5 -Cage Well Ρ »隉 某) Jiamou 1-2-Dingmou-4- 氤-11 < -Pan Favour-5-Methyl ethyl ester The mixture of intermediate 18 (0.5s) and 1.1'-carbonyl dipendazole (112 mg) in anhydrous TH F (1 0 m 1) was stirred at room temperature 3 hours. Add ethanol (0.36 ml) to the reaction mixture and then heat it at 70 C for 24 hours. Add ethanol (3.6 ml) and heat for 6 hours. Let the reaction mixture cool to room temperature in vacuo Concentrate and then purify by chromatographic method. Please read the precautions on the back before filling in this hundred.) Pack · • Order · _Line · -45- A 4 (210X 297 '/: hair) V. Description of the invention (40) A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs Chloromethane / methanol (500: 1) dissociated to obtain the compound in question •-A white foam (508 DS) ° T.1. C. Dichloromethane / methanol (50: 1) ', Rf 0. 86 〇 intermediate 1- Γ Γ3- m -2-"2-" 2- (Sanfutianshi) -2H -Siyouyou f)-Hua 1 cage very Ί 芾 bifuran even) Jiamou 1--丁某-4 * Radon-1 H-Mi 哗 -B -m Add a solution of DEAD (1 20 ng) in anhydrous THF (5 m 1) drop by drop to the intermediate. 18 (0 • 5g), triphenylbenzene (181 mg) And n-butanol (0. 09 Ώ 1) in a solution in anhydrous THF (5 m 1) 0 The mixture was stirred at room temperature for 3 hours, after which n-butanol (0.09 ml) was added ) And continue stirring for 1 hour. Triphenylphosphine (82 m δ) was added until the reaction mixture was followed by a drop-wise addition of DEAD (0.05m 1) in anhydrous THF (3 1) followed by overnight mixing and then the reaction mixture was concentrated in vacuo 0 Purify the residue by chromatography, Μ dichloromethane / methanol (500: 1) dissociated to obtain this title compound (484 ng) a white foam > Τ. 1 · C. Dichloromethane / methanol (500: 1) Rf 0 • 49) Medium M. Matter 33 -9- F9-f 2-(-cage cage even)-2W -Sparkle beer- 5-Hua 1 茏 某 1-5 benzanthrene »1 田 很 1- 2-(1-Haidinghua)-4- Radon-1 H-imid ΦΦS-Jiagongdi intermediate 31 (500 mg) and NBS (107 ag) in carbon tetrachloride (200 m 1) The mixture was irradiated at room temperature (UV lamp 125W, Pyrex glass m light) for 1 hour and then the solution was removed in vacuum. This product was purified by chromatography. K petroleum s: Yi Zhao (3 • 1) This title compound »{Please read the back side first Matters needing attention again on this page) -46- A4 (210Χ 297Π A6 B6 V. Description of the invention (41) A yellowish white powder. T. 1 .C. Petroleum ether: Ether (1: 1), Rf 0.67. Intermediate 34 1-"" 3-Zun-2-"? .-" 2- (Tripyridinol) -2 Butetrazole-5-some 1 Peony certain 1- 5 -Cage certain) Shenmou 1 -? -Butan-1 (F) -ene-4-gas-1H-犯 映 -B-hexaethyl ethyl ester 1,8 -diazabicyclo [5. 4 .0] undec-7- En (7 3 w 1) was added to a solution of intermediate 33 (220 mg) in THF (5 ml) and the resulting solution was stirred at room temperature for 72 hours. The mixture was condensed in vacuo and subjected to chromatography. Purify Μ petroleum ether by method: diethyl ether (3: 1) and dissociate to give the title compound (115 mg) *-a white solid. Tlc petroleum ether: diethyl ether (3: 1), Rf 0.33. Intermediate 35 1- "".? -Zhang-?-"?-" 2- (Three cages Shenmou)-; ^-四 Beer-5-some 1 茏 某 1-5-^ # P 关 安 某) Jiashi 1-4 -Radon-2 -Propyl-1H-quinazol-5-methoxol Intermediate 15 (3.1g) was treated according to the method of intermediate 17, 4-chloro-2-propyl-1 Η-imidazole-5 -carbaldehyde (6 6 0 πι g) and potassium carbonate (70 0 in g > in DMF (60ml)K ether was developed to obtain a creamy solid which was recrystallized from ethyl acetate to obtain the title compound, as a white powder (1.36 g) ° T.I.c. (Ether), Rf 0.74. Zhongwenwu 36 1-“「-淖 -2-「2-」?-(= _ 鐏 頀 某)-? Η-四 Beer-5 -base] 茏 基 1-5 -ranyl) Shenmou]- 4-Gas-?-Bingshi-1Η-imibe-5-carboxylic acid-47- A4 (210Χ 29Π) (Please read the precautions on the back before filling this page) • ^. .Subscribe. .Line. Economy Printed by the Central Bureau of the Ministry of Education 01145 A6 B6 V. Description of the invention (42) By: 'Printed by the Central Standard Bureau of the Ministry of Thailand

Add a solution of sodium nitrite (565 ig) and dihydraphosphate (593 mg) in water (10 ml) to intermediate 35 (500 mg) in tert-butanol (8 ml) and 2-methyl- 2-a mixture of butene (2M in THF, 4 ml) and TEFUO ml). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between ether and 0.25M sodium oxyhydroxide solution. Separate the ether layer and discard it. The sodium hydroxide aqueous phase was neutralized with saturated ammonium nitride solution and then extracted with K ethyl acetate. The combined ethyl acetate extract was washed with water and H water, dried and concentrated to obtain the title compound, a white solid (472 mg). T.1.c. (ether), Rf 0.67. Intermediate 37 2-Ding Mouzheng jfe-A..R-dimethystine added fuming nitric acid (32.4ml) to tartaric acid (15g) in a floating solution of concentrated nitric acid (32.4ml) and stirred at room temperature The resulting floating liquid was 30 minutes. Concentrated sulfuric acid was added to maintain the temperature at about 40t at a rate. Cool the precipitate to 10 = and allow it to stand for 30 minutes. Collect this solid • Transfer it into finely crushed ice (300g) after dry refining and dividing into several parts. Then pour the resulting mixture into a bottle at -12C and add concentrated ammonium oxide (approximately 40 nl) drop by drop until the neutral addition does not exceed a temperature of 5¾. Then add ammonium hydroxide (30 ml) and valeraldehyde (8.61 g). The solution was stirred at 01C for 5 1/2 hours and then allowed to stand at room temperature for 30 minutes. Cool the reaction mixture to ◦ and add concentrated HC1 to PH5 and separate the solid by filtration. The title compound (12.2g) was dried to a pale yellow solid. nmr δ (250 MHz, DMSO) 0.88 (H, t), 1.27 (2H -48- (Please read the precautions on the back of the Kl before filling in this page) _Green · A 4 (210X 297 伂 发) A 6 B6 5. Description of the invention (sex), 1.61 (2H, quin), 2.6 (2H, t), 7.4 (3H, br.). Intermediate 3 «2-Ding Miao Ying-diethyl dicarboxylate Add acetochloride (20.lml) drop by drop to the mixture of intermediate 37 (10.0g) in ethyl yeast (200 ml) over 10 minutes $ Heat the resulting mixture at reflux for 23 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved. The pH was adjusted to 7.5 (W8% Na2C〇3) in water (100 ml). Ethyl acetate (3 X 100 nl) was used to extract the aqueous phase and dry-refine the combined biphasic phase in vacuo to obtain the title compound 'a yellow solid (7.81 g).

n.m.r. δ (250 MHz, CDCla) 0.90 (3H.t), 1.31 (2H sex), 1.38 (6H. t), 2.79 (2H, t), 4.4 (4H, q), 10.7 (1H, br.). Intermediate 2.2.? -Tricyano-1- (2- 譠 某 -S- 田某 茏 基) ZJ- Printed by the Central Business Administration of the Ministry of Economy A solution of 2-bromo-4-methylphenol (35 g) in anhydrous diethyl ether (300 nil) was cooled in an ice bath and treated with n-butyllithium (227 ml) drop by drop under nitrogen. After the addition is complete, warm the mixture to room temperature 'and continue stirring at this temperature for 2 hours. This solution was cooled to about 60¾ and M fresh steamed trifluoroacetic anhydride was treated drop by drop. The resulting solution was stirred at low temperature for another hour and then heated to room temperature. Stir overnight at this temperature. Wash the resulting decanted mixture with chlorinated relatively saturated aqueous solution (3 X 150 ml) and dry the gambling phase. In a rotary evaporator, the remaining B key is removed by evaporation under normal pressure '____- 4 9 _ A 4 (210X 297 public) A6 B6

5. Description of the invention (44) Purify the resulting solution by column analysis to dissolve the title compound with hexane to obtain a yellow / orange crystalline solid (13.12S). 1'.1 .: Hexane, 1 ^ 〇.5. Intermediate 40 -Dilu-1-M ethyl) -4-methyl 1 cage .-?-Jiamou cage I was stirred under nitrogen. Intermediate 39 (2.23g) without $ DMF (20ml) The mixture is treated with sodium hydride (0.36 lg). The solution was stirred at room temperature for about 15 minutes. Then 2- (bromomethyl) benzonitrile (2.14g) was added and the mixture was stirred at room temperature for 1 hour. This material was poured into water (100 ml) and extracted with κ ether (3 x 50 ml). The combined phases were washed with water (3 x 30nl), dried, and evaporated to a yellow oil (3.22g). Purified by column chromatography. The title compound was dissolved by System A (1: 9). A white solid hip (1.84 g). T.l.c. System A (l: 9), Rf 0.3. Intermediate IA 1 2 _- "5-Tianshi-.?-(=argon methyl) -cage and squirm 1 cage of sperm under nitrogen stirring intermediate 40 (0.157 g) in anhydrous DMF (6 ml) The solution was treated with hydrogenated K (80% in oil; 0.015g). It was stirred overnight at about 90 ° C. The reaction mixture was cooled to room temperature and poured into water (70 ml). With ethyl acetate (4 X 20ml) and dichloromethane (20nl). Extraction .......................................... f .............. it ........................ tr .... ..... {................ Practice (surprise first!? ^ Back < Notes and then fill out this page) X 3 Printed by the Central Bureau of Economic Development of the Ministry of Economic Affairs The steaming and water filtration and the liquid drying and floating suspension can all be taken. The camera has .2 in (0 and oil and this color is washed with polyester and orange g A (c system solidification The layered yellow column of the white analysis by the powder solid color method is marked by the combination of the species and the title is dissociated. A (1: 9), Rf 0.45. Intermediate 42 5- "2-" 5-A certain 3- (triargon a certain) -2-cage # 0 矣 _ 某 1 cage 1-1 »-Four_ Heat the suspension of intermediate 41 (0.548g) in tri-n-butyltin azide (1.5g) to ~ 150TC. Bake and cool the solution to room temperature and leave the residue in 1 hour Dissolved in 2N NaOH. The resulting solution was washed with acetic acid (4 x 20 ml) and then acidified to about pH 2. The resulting suspension was extracted with ethyl acetate (4 χ25ι »1) and the combined organic phase was dried, filtered and evaporated The title compound was obtained as a yellowish white foam (0.635 g). Nmr 5 (CDC13 + DMS0 + base) 8.01 (1H, wide d), 7.6-7.55 (3H, m), 7.45 (1H, d), 7.3 (1H, d), 7.2 (1H, d), 2.45 (3H, s) ° Intermediate 4 3-Shenmou-f three articles Jiamou)-2-¾ Jinghuan 1¾ certain 1-2- ( Three cages for a solution of a four beer in chlorotrimethane (1.058), triethylamine (10.861111) and 01 ^? (~ 250es) treatment intermediate 42 (1.17s) in anhydrous dichloromethane (50ml). The resulting solution was stirred overnight at room temperature under nitrogen. The solution was diluted with dichloromethane (50 ml) and then washed with M water (3 X 25 ml). The organic phase was dried, filtered and evaporated to obtain a pale yellow solid. • Purified by column chromatography. M dichloromethane: hexane U: 1) Dissolve to obtain the title compound, a pale yellow solid (1.63 g). T.1 · C · dichloromethane: hexane (1: 1), R f 〇 · 45. -5 1- A 4 (210X 297 gong) (please read the precautions before writing this page). Order · r ^ 01745 Ministry of Economic Affairs Central Bureau of Printing and Printing. A 6 B6 .- V. Inventions Explanation i4 6) Intermediate 44 5- "2-" 5- (Haijiamou) -3- (Trivalent A) -2-Stay and murmur 1¾mou 1 -2- (Three cages Jiamou)- 2H-Four prefer treatment of intermediate 43 (0.963g) * solution in carbon tetrachloride (30 ml) according to the method of intermediate 3 MNBS (0.325g) and AIBN (~ 100mg) * This is the title compound, an orange / Yellow solid (1.13 g). Tlc dichloromethane: hexane (1: 1), Rf 0.45. Intermediate 45 · 2-Dingmou-4- radon (Sanyingshen)-?-""?- (Sanrong Shenmou) -PH- 四喜 -5-even 1¾ certain 1-5-¾ and squinting_ certain 1-1Η- 眯 _-5-A knee according to the method of the intermediate 1 7 to process the intermediate 1 6 ( 0.18 g), a mixture of intermediate 44 (0.665 g) and potassium carbonate (0.145 g) in DMF. Purification by column chromatography with system A (1: 1) dissociation gave the title compound, a white Foam (0.48 g). Tlc Mito A (1: 1), Rf 0.3. Intermediate? -Dingmou-4-radon-i-m- (Triargon) = Cage Jiamou)-? · Η-tetrazole-5-some1 -Fujing Quanan 1 Jiamou 1-1H- 眯 Beer-5-methyl bismuth added a solution of sodium chlorite (0.552 g) and sodium dihydrogen phosphate (0.552 g) in water (5 ml) To intermediate 45 (0.47 g) in a mixture of tert-butanol (10 ml), 2-methyl-2-butene (2M in THF; 3.66 ml) and THF (10 ml) and according to intermediate 36 Method to process the reaction mixture to obtain the title compound, a white foam (0.504g). Tlc ether, streak Rf 0.5. (Observe the precautions before you fill in this page) · «-· • 打 · .Line * -52- A4 (210X 297 male, ¾) A6 B6 201 ^ 45 5. Description of the invention (47) (please read the note on the back first and then fill in this page) Question 47 47 Thin-2 -(¾ 申 某) ¾Shen Tong heated MBS (3.45g) under nitrogen, dibenzyl peroxide (100 mg) and 3-bromo-2-methylbenzylmethine (3.47g) in carbon tetrachloride The mixture (40nl) was refluxed for 48 hours. The mixture was then cooled to room temperature * and decanted and concentrated in vacuo to obtain a pale yellow solid. Chromatography M; Chloromethane dissolved to obtain the title compound, a white H (4.23g), melting point 90 ~ 93 spoons. Intermediate 48 · Hai- 2- (5-甲某 -2- 茏 #peptide 陡 晡 Very) Rongjia blinding 2-hydroxy-5-methylbenzaldehyde (2.00s) and sodium formazan (0.885 g ) A solution in anhydrous DMF (20 ml) was added to the dissolving sound of intermediate 47 (.4.17g) in anhydrous DMF (10 ml), and the mixture was broadcast at room temperature for 1 hour. The solution was concentrated in vacuo and washed with ethyl acetate (50 nl) and K water (2x 100 ml). The organic phase is not dried. Filtration and concentration in vacuo yields an oil. Chromatography K System A (1:10) dissociated to give the title compound, a pale yellow oil (1.18g) T. 1 · c. System A (1: 9), Rf 0.35. Intermediate 49 • Line -9-Γ5- "" 2-Butan-4- 氲 -5-argon methyl even) -1H- 眯 azole-1- 什 1-9- 呆 # 眹 某 1¾Meal economy The Ministry of Central Rectification Bureau cracked and heated the mixture of intermediate 48 (1.16g), NBS (0.727g) and AIBK (200 ng) in carbon tetrachloride (20 ml) under reflux at the same time M—a 150W lamp The irradiation lasted 2 hours. The mixture was cooled to room temperature, filtered and concentrated in vacuo to obtain a yellow oil with dichloromethane (100 ml) and water

-53- 甲 4 (210X 201 ^ 45 A6 B6 Fifth, the description of the invention (48) (10ml) Wash the solution, dry it, filter and concentrate in vacuo to obtain a yellow oil. Heat the oil under nitrogen, A mixture of intermediate 16 (0.700g) and potassium carbonate (0.70g) in anhydrous DMF (20ml) at 80 = 16 hours. The mixture was concentrated in vacuo, ethyl acetate (40ml) and then water (2x50 ml) washing, followed by washing with saturated ammonium chloride (10 ml), drying, filtering and concentrating in vacuo to obtain a brown oil. 'Chromatography was dissolve away by the system A (2: 3). Compound, a light yellow oil (1.07g). Tlc is blunt A (1: 1), Rf 0.4. Intermediate! 1-"" 2- (2- 通 -6-cyan 某 茏 某) -5-AGE # 0 韣 照 淚 1 Tianshi 1-2-Dingmou-4-g -1H- 眯 映 -5- 甲 Credit the sodium sulfamic acid (1.51g) and the two g 'sodium sulfonate (1.55s) in water ( 15 π 1) The mixture was added to vigorously save the intermediate 49 (1.06 g) and 2-methyl-but-2-ene (2M in THF; 9.5 ml) THF (20nl) and The mixture of tert-butan (20 ml) and the reaction mixture according to the method of intermediate 36 to obtain the title compound A light yellow foam (1.08 g Tlc ether, Rf 0.3. Intermediate 51 51-Γ ".υ 草 -9- (Erage Tianshi)-? H-ggp $-5-some 1-¾ Kib 5- Beni H Fuzhenshi 1 Tianshi 1-9-Dingmou-4-Radon-1H-Shen-Tianwu 1- (Beta) Methyl Ester (Please read the precautions on the back before filling this page) -¾. • Line · The Central Bureau of Standards of the Ministry of Economic Affairs prints and mixes intermediate 18 (2.14g) and carbonic acid (370 mg) in DMF (30ml) for 20 minutes. Add methyl bromoacetate (410 mg) and broadcast the reaction -54 · A4 (210X 297 异 发) £ 01745 A 6 B6 V. Description of the invention (49) The mixture should be taken for 20 hours 0. The mixture was poured into water and extracted with ethyl acetate. This was washed with water and brine. The combined organic extracts * were dried and m was reduced to the title compound »-a white foam (2.3 S) 〇T. 1. C. ether« Rf 0 .5 ° middle 5 2 1-Γ r 3- m -?,-"Z:" 2-tri-cage leather j- 2H -tetrazole _ 5- Hua 1-Benhua 1 benzofuran certain f)-Hua 1 methyl 1 -2-butyl-4 -Radon-1 Η- 呻-Formic acid (7 丨 acrylic oxygen). B. Xing_ · A white foam (2.1 g) ° T. 1. C · Ethylene 9 Rf 0. 8 〇 White was added ethyl bromoacetate (433 η g) To intermediate 18 (2.07 g) and potassium carbonate (358 mg) in DMF (30 m 1) for 3 hours 0 Intermediate 53 1-"" 3-Bromo-2-f (three cages) -2H- Tetra-5 -Hua 1 -¾ Ί -5 -Benzofuran 1 Methyl 1 -2 -Butyl-4- radon-1 H- Mimi-5-Methoxybenzyloxymethyl A white foam (2 • 07 g) ^ Test results: C, 65.3; Η * 4.3; N, 8.6 C 5 〇H 4 2 BrC 1 Ηβ 0 5 Calculation: C, 65.1; Η >4.6; N, 9. \ ° / 〇 from the addition of methyl chloroformate (0.43 g) to intermediate 18 (2 g) in DMF (25m 1) and potassium carbonate (0 • 35 s ); Reaction time 20 hours. Purify by column chromatography and dissolve with ethyl acetate to obtain the title compound. In the middle of the room (please read the precautions on the back before writing this page) • ^. • Order. -Printed by the Central Standards Bureau of the Ministry of Economic Affairs · 5 I base of a certain yam-5 I base Parallel 0 Department 4 i Basel A 4 (210X 297 ^ :, ¾) -55-^ 01745 A 6 B6 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs Fifth, Invention Description (50) ethyl argon gas) ethyl ester White foam (1.87 g). Verification results: C, 62.9; H, 4.7; N, 8.9 Br, 8.7; C1, 3.9 C4eH42BrClNeNee Calculation: C, 63.1; Η, 4.6; N, 9.2; Br, 8.7; Cl, 3.8% -Ethyl chloride, ethyl ester (0.38g) to intermediate 18 (2g) in DMF (25ml> and potassium carbonate (0.35g); inversion time 3 days (addition of potassium carbonate (0.19g)). This title compound was obtained by chromatographic purification and dissolution with ether. Intermediate! ^ 1-““ 3-Sea-2- “2-“ 2- (San Mo Jia Mou) -2H -Tetra beer-5-some 1-¾ A certain 1-5-cage and squint 1 A even 1-2-Ding -4- Radon -1H-眯 映-5-雔 雔 "4 ·-(Anti-carbonyl) Mo 1 methyl ester-white Solid (300 mg), melting point 105-107C. From intermediate 18 (2 g) in DMF (20 ml) g: potassium carbonate (0.35 g). Add 4-bromomethylbenzamide (0.38 g) ; Inversion time of 60 hours. Purification of M system C by chromatography (2 0 0: 8: 1) dissolves the title compound. Intermediate 5B Zhang II. Dengjiamou) -2Η-四 _-5- 某 1- ¾ certain F5-cage # 11 Guan Nan certain 1 Jia certain 1-2-Ding certain -4- Radon -1H-眯 Favour -5- Jia Pi 2-ί N. H-Dimethyl anti-some) 7, ester added DEAD (0.75ml) in anhydrous THF (5ml) solution to the middle 18 (2.02g) -triphenylphosphine (1.30g) and 2-dimethylaminoethanol (0 · 40πι1) (please read the precautions on the back before filling out this page) -3 ^ · . -56- A4 (210X 297 public) A6 B6 Printed by the Central Bureau of the Ministry of Economic Affairs 201 ^ 45 5. Description of the invention (51) The solution in anhydrous THF (20ml) was stirred at room temperature under nitrogen. After 3 hours, the solution was shrunk in vacuo and the remaining gum was purified by chromatography. The ethyl acetate was dissolved to give the title compound. ~~ White foam (〇.97g). T. 1 .c. (Acetic acid Ethyl ester), Rf 0. 15. Prepared in the same way: -Intermediate S7 1- "Γ3-Mo-2-" 2-Γ2- (trityl) -2H-W _-ς- Very even 1-5 2. Benzoyranyl 1 methyl ~~ -2-Butyl-4- 気-〗 [^ -thief_-5-Tianlu 2-ll ·, 3 -di (Sanlongtian) Argon 1 propanol -A light yellow bubble bed (2.00g) Tlc (dichloromethane), Rf 0.7 from DEAD (0.75ml) in anhydrous THF (5ral), intermediate 18 (2.〇〇g), triphenylphosphine (1.30 g) and 1,3-bis (tribenzylmethoxy) propan-2-ylase (2.3〇g) in anhydrous THF (20al); reaction time 16 hours. Purify M dichloromethane: hexane (1: 1) by chromatography to obtain the title compound. Space! ^

Uil "3-bromo-2-" 2- "2- (triazine)-? Η-tetrazole-5-its Ι-y fluorene 1-5 two well D folderan 1 Tianji 1-2 -butane A certain 4-short-1H-weiying-R-A scale 2-5L. Argon 7, brewed—a colorless foam (2.61ng) Tlc dichloromethane / methanol (500: 1) * Rf 0.2 ° from DEAD ( 0.65ml) in the intermediate 18 (2g), triphenylphosphine (0.98g) and 2-methoxyethanol (〇.57s) in anhydrous THF (50nil); inversion time -57-A 4 (2l〇χ 297 伂 发) (please first «1 read the notes on the face before filling this page)

201745 V. Description of the invention (52) A 6 B6 Printed by the Central Bureau of Economics of the Ministry of Economics for 12 hours. Purified by chromatography. M. Dichloromethane / Hexane (500: 1) Dissolve to obtain the title compound. Intermediate 59 1-"" 3-Pu- "2-" 2- (Dibenzylmethyl) -2Η_tetrazole · 5 _ Hua 1-Benhua 1-Benzofuran Hua 1 Tianmou 1 -2 -7 -Long- 4- radon -1 H * imi beer _ c known as 1 a certain 7 丨 1 'a yellow glue (781 H g) Τ .1 .C. Stone phase & m / ether (1: 1), Rf 0. 5 ° from DEAD (0 • 33 g) in anhydrous THF (10 ml), intermediate 18 (1 g) > tribenzine (49 3 mg) and propan-2-ol (0.14 m 1) The reaction time is 3 days in anhydrous THF (10ml). Purification by chromatography> λ petroleum ether / ethyl chain (3: 1) dissolves away to obtain the title compound 0 * Intermediate 60 1-"" 3_ 渖-"methyl ) -2Η-四 WJ5-fj- 华 1-Benzhua1-芣 不 眹 眹 菹 華 1 申 某 1 _ 丁-4- radon-1 H-imibe-R-methylmamine solution of intermediate 18 (lg) in anhydrous THF (10 m 1) was added 1, 1,-carbonyldiimidazole (244 mg) 0 in After stirring at room temperature for 1 hour, add 1, 1 '-carbonyl dibenzosalicylate (163 mg) and continue stirring overnight 0 Add ammonia (2 1 1) until the reaction mixture is stirred for 3 hours > and then concentrate in vacuo. The C30 residue was purified by chromatography and dissolved in petroleum ether / ether (1: 2) to give the title compound (254 IQ g) (D T. 1.. · Ether 1 Rf 0.52 = intermediate 61 1-m- Γ "3-bromo-2-" 2-• [2 (dibenzomethanone)--four beer-^ * Cao-benhua (please read the precautions before you fill in this page) f 4 (210X 297 ^ '^) _-58- £ 01 ^ 45 A 6 B6 V. Description of invention (5 彡 部 部 輕 辕 訊 印 1-R-荣 # 〇 矣 晡 某 1 甲某 1-?-丁某- 4- 氲 -1H-Fuzole-FS-X1] Pyrrazole added 1,1'- to a solution of intermediate 18 (1.45g) in anhydrous THF (10 ml) Mi yl group two (44 2 mg), and the mixture was stirred overnight. Add 1,1'-carbonyl diazole (442 mg). After stirring for 2 hours, pyrrolidine (0.3 m 1) was added to the reaction mixture and after another 2 hours, pyrrolidine (0.3 ml) was added. After stirring for 2 hours, the reaction mixture was concentrated in vacuo and the residue was purified by layer method. The title compound and a white foam (1.23s) were dissolved in ether. Τ · 1 * c. Ether, Rf 0.53. Prepared in the same way:-^^ Xi 3-chasing-9- "2-" 2- (Sanguotianmou)-? H-Four beer-5-an Bufujibu 5 2 ~ 1 £ # 时 然 很1 Jiashi 1-2-Dingmou-AMN-Shenmou-1H-_5 ~ ~ white foam (1.37g) Tlc ether, Rf 0.62. From the intermediate 18 (1.45g) in anhydrous THF (l〇ml ), 1,1'-carbonyldiimidazole (442 mg) and 1,1 · -carbonyldiimidazole (442 mg) were added. Methylamine (0.31 m 1) was added to the reaction mixture and after 2 hours , After 18 hours and 26 hours, add one more time. Purify by chromatography and dissolve the ether in M ether to obtain the title compound. ^ -Μ_ ^ ι_β_2_ ^ 113- 海 -2-"?-" 2- (三Cage Tianshi 1-9-four beer-5-some 1-benzyl 1-_5_ dioxin peptide leather] Jiamou, -2-Dingshi-4-qi-Ν.Ν '-甲某 -1Η_- Fenzodi 59 (Please read the precautions on the back before filling out this page) k. _Λ · 'Line Armor 4 (2 〇〇 297 乂, hair) 01? 45 V. Description of the invention (54) A 6 B6 B- White sugar anti-white foam (1.19 g) T .1 .C. B bond, Rf 0.61 〇 from intermediate 18 (1-45 8;) in anhydrous THF (10 m 1)% 1, 1 ,-Carbonyl squint and plus 1. 1'-carbonyldiimidazole 0 Add dimethylamine (0.45 ml > 40¾ aqueous solution to this reaction mixture and add it again after 2 hours. 〇Purification by chromatography> Dissolve with ether to obtain this compound 0 intermediate物 64 1-Γ Γ 3- Pu · ?,-"2-[2- (di · benzophenanthrene) -2Η-四 Βψ _ 5- Hua 1-Benz Hua 1-5 and furfural Huayi 1 -2 _ 丁某-4- Atmosphere-N-Jiahua-1 Η-imipo-5 -7, glycosamine added 1, 1 '-carbonyldiimidazole (1 48 mg) to the stirring intermediate 18 ( 2 50 mg) solution in THF (5 ml) and the resulting solution was stirred at room temperature for 4 hours. 0 Add methylamine hydrochloride (249 .5 mg) and then triethylamine (546 U 1) and The mixture was stirred at room temperature for 16 hours. 0 Methylhydrochloride (249.5 mg) and triethylamine (546 U 1) were added and after 6 hours the solid was removed by filtration and concentrated in vacuo This filtrate was obtained by chromatography with ether dissolution. Title Compound (1 11 mg) »A white solid. T. 1. C. Ether »Rf 0. 21: Intermediate Λ3 1-1 [3- ~?-「 2-丨 2-(-Ｍ 甲 箪)-2H-四 ικϋ-5 " 华]-Benzhua 1-Pyfuran hua 1 methyl 1-2-butyl-4- and -Ν-'乙 华 -1 Η-. Imi-5 ....................... .................. f ......... ¾ ..................... ............... hit ......... {'................. line (please read first (Notes on the back will be written on this page again.) The Printing Office of the Central Bureau of Economic Development of the Ministry of Economic Affairs. 15 ml) solution and stir the resulting solution at room temperature -6 0 ~ A 4 (210X 297 public)

%: 道 Λβ. Dagger -------------------- B6 _., V. Description of invention (ce)-55:-…, Ί '-·: ·'. *… { Please read the precautions on the back of the moraine before filling in this π) 5 hours. Add edible salt (70% aqueous solution, 968 mg) and remix the resulting solution for 16 hours. The JFC mixture was concentrated in vacuo and the residue was deactivated by column chromatography. The title compound (_1.80 g) was dissolved in petroleum ether (5: Γ) as a white solid.

RfZ_ = 0.78. -Intermediate 66

... V 1: 7, a certain -1 H-Mimail Tianzui will slowly add dihydroxyacetone (65g) to liquid ammonia (250 ~ 300nl), can hydrogenate propanium imine ethyl ester (65 g). Transfer the buoyant liquid to a pressure autoclave and heat it at 90 C for 16 hours. Allow the ammonia to evaporate and then shrink the reaction mixture in vacuo. The residue was dissolved in methyl alcohol, washed with charcoal and then purified by chromatography. A gradient of M system C (300: 8: 1 to 50: 8: 1) was dissolved. This title compound was developed with copper propyl, a white solid. T.l.c. System C (50: 8: 1), Rf 0.21. Intermediate R7 Helmet-S-2 -Ethyl-1H -Squint-Electric 8 $ Intermediate 66 (19.66s) in 2-Methoxyethane §1 (175 m 丨) and 1.4-Dimorphane N-chlorobutadiene imide (21.23s) was reported to be mixed in the dark at room temperature for 18 hours. Remove the dissolved lycium in the air and the residue is partitioned between water, brine and ethyl acetate. Combine the gambling extracts, backwash with Μ water and brine. The Ministry of Economic Affairs Central Kneading and Preservation Bureau prints ii · 0 S solid 49 color 1 yellow (1 曰 物 1 combined into a reduction contract 51 mark this empty is really true in order And the two solid bodies are dried and solidified by this tanane methylene chloride with _a 5 fixing white II II-6-6: f 4 (210X297 ^^} 〇1 ^ 4δ Μ A 6 B6 V. Description of the invention (56)--> _ ++-. * _ * -T. 1. C. System C (5 0 ': 8: 1), Rf 0.55. Interrogation · Matter 6 8-4 ·-Si-2-Yimou- 1 Η-眯 映 申 路 'The intermediate 67 (11.35g) was treated according to the method of Intermediate 16 Κ of Meng dioxide (3 0. 59 g) to obtain the title compound (6.41g) ·-a white solid- Ο--'v T · — IC system C (50: 8: 1), Rf 0.73. Intermediate 6 9 ·

1- "" 3- "Cao- <-" 2- "2- (Three cages Shenmou) a 2H-Si Yingshi 1-¾ a certain 1-B-stay # QI'_ Very 1 Shenmou 1-4 -Radon-ethyl -1H-quinazole-B-methyl smoke----_ · Intermediate 6 8 (2 g), intermediate 15 (12.8 g) and potassium carbonate ( 2.61g) in anhydrous DMF (150ml) ». One * one compound. K ether and ethyl acetate developed a light-colored solid (1.08g). This is another from the mother liquid crystallizer (3.46s) The title compound (2.68g) was obtained by merging and recrystallization from ethyl acetate. Tlc petroleum mystery: diethyl ether (1: 1), Rf 0.24. Intermediate 70: forced-(three cages) -2H-tetrazole-5-罙 罙 基卜 5 Printed by the Central Bureau of Economic Development of the Ministry of Economic Affairs, please read the precautions before filling out this page)-呆 # 0 矣 喵 很 1 甲某 1-4-radon- 乙 某 -IH-眯Ying-FS-A solution of sodium chlorite (3.18g) and sodium dihydrogen phosphate (3.18g) in water (40 ml) was added to the intermediate 69 (2.65s) in tert-butyrase (40 ml) ) And 2-methyl-2-butene (2H in THF, 21.6 ml) and THF (40 ml) and treated according to the method of intermediate 18. Purified by chromatography Dichloromethane / A 3? (2 0: 1) dissociated to give this title compound-62-A · 4 (210Χ 297KS) 2 Dim_ Be V. Description of the invention (57) (2.17 g) ° Tlc dichloromethane / Methanol (10: 1), Rf 0.48. Interrogation 7 1 1-““?-海 -2-“?-“ 2-(= cage Ermou)-; ^ -tetrazole-; ^ -some 1- Stay 1-5-cage well 0 _ some 1 Shen certain 1-2-ethyl certain -4- 氲 -N-Jia certain -1H-眯 Beer-5-Shen Ji anti-dissolution intermediate 70 (503 mg) Add 1,1'-carbonyldiimidazole (33 8g) to THF (5 ml), and stir the solution at room temperature for 48 hours. The mixture was concentrated in vacuo and purified by column chromatography. K ether was dissolved The title compound (445 mg). Tlc diethyl ether, Rf 0.30. Intermediate 72-Dingmou-1H- 眯 皞 -5-Shenyan p-butyl-2H-1H-diazole-5 -methanase (2.02g ) Manganese dioxide (7.05s) was added to the suspension in anhydrous dichloromethane (40 ml) and anhydrous dimorphane (60 ml). The reaction mixture was heated at reflux for 3 and a half hours, then decanted and placed under vacuum Concentrate this quencher in the middle to obtain the title compound (U.69s), a white solid. T. 1 · c. System C (100: 16: 1), R f 0.38. Intermediate 7 3 and 7 4 1-"" 3-bromo-2-"2-" 2-(trimaranth) -2H-four beer-Fi-based] fused 1-5 (please read "Read Bamboo first" The face-to-face competition matters will be rewritten on this page) • Order........... J Some merging ¾ cover 0 A 4-beer squash f 4 (2I0X 297 ^, ¾) -63- A6 B6 £ 01745 V. Description of the invention (58) According to the method of intermediate 17 intermediate 72 (1 g) , A mixture of intermediate 15 (6.14g) and potassium carbonate (〇.98g) in anhydrous DMF (160ial). Purified by chromatography with ethyl acetate / hexane (1: 1) to dissociate and reuse dichloromethane : Intermediate yeast (70: 1) yields intermediates 73 and 74 (556 mg and 640 mg, respectively) 0 T. lc dichloromethane / methanol (70: 1), intermediate 7, 3 Rf = 0.31. Intermediate 74 Rf = 0.24. Intermediate 7_5_ _ -Tong-?-"2-" 2- (Sanrong Tianshi-Tetrazole-5-Kibufu 1-p; -y Bingran 1 Tian Tian 1- 2-Ding Shi-ΊΗ-Shuibei-5-formic acid Add a solution of sodium chlorite (665 mg) and sodium dihydrogen phosphate (665 mg) in water (10 ml) to intermediate 73 (55 The mixture of tert-butanol Π〇ml} and 2-methyl-2-butene (2M in THF, 4.4 ml) and THF (10 ml), and treated according to the method of intermediate 18 ' Compound (44mg), a white solid. Tlc dichloromethane / methanol (10: l), Rf 0.47 ° from intermediary I 75 1- "Gate-Tong-?-" 9- "9- )-: ^-Tea-.5 diyl 1-phenyl hua-1-5-nodopeptide Zingshi 1 Tian Shibu 2 -Butyl-UL-Mibi-4 -JL. (762mg) and sodium dihydrogen phosphate (762ng) in water (10ml) were added to the intermediate 74 (630ng) in tert-butanol (10 ^ 1) and 2-methyl-2-butene ( 2M in THF, 5 al) and THF (10 ml) and treated according to the method of intermediate 18 to give the title compound (443 ng), a pale yellow solid. -6 4 _ A 4 (210X 297 Gongfa) ............................. {........... ... pretend ........................ to fight ......... (... ............ Line (please read the back of the first:; i and then fill in this page) Printed by the Central Bureau of Economic Development of the Ministry of Economic Affairs £ 01745 A6 B6 • δ ·, invention description y jT .IC dichloromethane / A (10: 1), Rf 0.51. Intermediate 77 L two "" 3-bromo-2- "2-" 2- (three cages a certain) -2H-four beer 5-some burong a 1-R two _ benzochroman aiming even 1 Tian -Propion-4-radon-N -Shenmou-1H -Suiyi-FS -Shenmaoxian added 1,1'-carbonyldiimidazole (1.0s) to the middle @ 36 (1.9s) in anhydrous THF (30 ml ) And broadcast the mixture under nitrogen overnight. Add methylamine (2 ml; 40% aqueous solution) and stir the reaction mixture for 6 hours. Remove the solvent in vacuo and remove the chromatographic residue by ether. The title compound (1.56 g). Tlc ethyl chain, Rf = 〇.5. 7 intermediates Ιτ ί "3-bromo-2 _ ί 2-i 2L- (_E. A certain,--men Ying-5 -A certain 1-cage a 1-5 dibenzyl furan hua methyl 1. 2 two workers-a- m- m -Li propion -1H-眯 皡 z-5 _-_ a ISLK Dissolved intermediate 18 (1.5g ) In anhydrous THp (1 () ^ 1), add ι, ι.-Aromatic Diweiwei (0.93g) 'and stir the resulting solution at room temperature for 16 hours. Add isopropylamine (1.29 b 丨) and This solution was stirred for 2 hours. The mixture was concentrated in vacuo and purified by column chromatography, and the title compound (1.17g) was dissolved in System A (5: 丨). Tlc ether, R f = 0.70. (Please read the precautions on the back before filling in this page). ¾ .. Order .. The Central Bureau of Economics of the Ministry of Economic Affairs printed '85 -A4 (210X297 2 ') 201745 A6 B6 5 3. Description of the invention (60) Intermediate 79 2-butan-4-cab-5-pyridine-1H-quinazole added N-iodobutanediimide (15.95) to the 2-butyl group in the stir 1H-imidazole-5-methanol (10.) solution in dipyridane and the mixture was stirred at room temperature in the dark for 16 hours. The solvent and ethyl acetate (50 ml) and water (50 ml) were evaporated to remove the residue Filter out the cream-colored precipitate and wash it properly with water and dry K in the air to obtain a cream-colored powder (14.lg). Extract the aqueous mother liquor with ethyl acetate (X3). Wash this with Μ water (X2) and brine The combined extract of 榇 揇 extracts, after drying and condensing M, gave the title compound (2.8S), a cream-colored powder. Tlc series C (100: 8: 1), Rf = 0.7. Intermediate 80 2- Ding Shi-4- S &-ΙΗ- 眯 _-5-Shen Lu According to the method of Intermediate 16, M manganese dioxide (30g) treatment of intermediate 79 (16.9s) to obtain the title compound (15.lg), a shallow Yellow solid. Tlc (diethyl ether), Rf = 0.8. Middle Things 1 1- ""-chasing-?-"2-" 2- (three cages Shenmou)-? H-four favors 5-some 1¾ some]-latch- 荣 # | 1 右脑 某) Jiamou] -2-Butan-Intermediate 15 (16.6s), intermediate 50 (5 g) and potassium carbonate (3.4 g) in DMF (200 ml) > Ether: ethyl acetate (5: 1; 150ml) was developed as a light yellow splatter which was filtered and dried in vacuo to obtain the title compound (9.25g)-a light yellow powder. -66- A4 (210X 297 乂 不) (Please read the precautions on the back before writing this page). ¾. • Order. * Line · A 6 B6 £ 01745 Five'invention description (61) (please read first Note on the back and then fill in this page) T. 1 .C. Petroleum ether: Ether (1: 1), Rf = 0.4. Intermediate 1-““ 2-Sea-2- “2-“ 2- (Sanhuajia) r2H -tetrazole-5-some 1¾ certain 1- 5 -class hem) Shen certain 1-2-Ding certain -4-pump-1H-眯 喜 -5 -methyl addition A solution of sodium nitrite (7.45g) and sodium dihydrogen phosphate (9.7g) in water (50ml) was added to intermediate 81 (9.0g) in The mixture of tert-J alcohol (100 ml), 2-methyl-2-butene (13 ml) and THF (160 ml) and the treatment according to intermediate 13 gave the title compound (9.3 g), a white bubble bed. Tlc petroleum ether: diethyl ether (1: 1), Rf = 〇.l. Intermediate 8 3 _order · 1-““.?-Zhang-2- “2-“?-(Sanfu Shenmou) -21 ^ Tetra-bromo-5-yl, 1-pyridyl, 1-5-like lam) Tianmou 1-?-Dingmou-4-selenium-1H-Miao Shen, the emperor will DEAD (1.79g) in THF (50 ml) The solution was added to a solution of intermediate 82 (8.3g) tribenzylphosphine (2.69g) and ethanol (1.4g) in THF (100ml) and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and The chromatographic residue was dissolved in dichloromethane: diethyl ether (98: 2) to give the title compound (6.5g), a white foam. • Green. Tlc dichloromethane: diethyl ether (98: 2), Rf = 0_3. Things 84 Printed by the Central Bureau of Standards of the Ministry 1-"" 2-Zhang-2-"?-"?-(Three cages a certain) -2 only-Four beer-5-some 1 茏 基 1-5-罙 # 盹 照 基) Tianmou 1-2 -butmou-4-three gas methyl -1H-眯 呻 -5-methyl ethyl ester dibromodifluoromethane (1 0. 5 g) was added to the nitrogen in 40 minutes Lower-6 7 ~ ^ 4 (210X 297 ^, ¾) £ 01745 A 6 B6 V. Description of the invention (62) Suspension of cadmium gold koji (11.2g) in anhydrous DEAD (25ml) while stirring. (Note : A very exothermic reaction is required, which requires external cooling.) The reaction mixture is stirred at room temperature for 2 hours and ^ and then the dark brown solution is passed through a "filter rod" under nitrogen to a clean dry bottle This solution is about CF3Cd 1M. Add human copper bromide (l) (1.15s) to 8 ml (about 8 ramol) of the above three gas methyl cadmium reagent Relay K. Add hexamethylphosphoramide (Sul) and The mixture was broadcast at room temperature for 10 minutes. A solution of Intermediate 83 (2.1 g) in DMF (5 ml) was added and the reaction mixture was heated at 70 t: for 2 hours. The dark reaction mixture was poured into Extract in water and ethyl acetate. K water and brine wash this combined organic The extract 'was then dried and evaporated to a dark brown oil. Chromatography of this oil gave the title compound (220 mg), a pale yellow foam. ‘T.l.c. methylene chloride: diethyl ether (98: 2), Rf = 0.7. A certain carbonic acid ester of ethyl acetate butoxy 1 3 I amino amine-2 and the ethyl liquid in the floating 0. 1 to get (5 esters filter peracetic acid. The amine night vinegar over the pentane mixture continued Stir. The liquid nitrogen dissolved in the middle to the} into the 丨 add om 3) (g alcohol g oil color orange coloring problem 1 marked this Μ get hair K steamed and dissolve B to oily orange this pure The white layer is fixed by the method ........................................ (..... ......... pretend ........................ fight ... f ................. Please read the precautions on the back before filling in this page) f R m Printed by the Central Standards Bureau of the Ministry of Economic Affairs ¾ Gaijiafuyiyi 5- JI Fu *-A certain I 5 Μ 0 5 Kiran squirrel armor-4 1 Μ 7 Bribery armor-6 8-armor 4 (210Χ 297 Yunfa) A 6 B6 £ 01745 V. Invention description (6 3) f Please flash first Broken surface ν ·. '/ £ Issue matter and then fill out this page) ΙΜ_ΚIntermediate 85 (0.15 g) and sodium hydride (0.22 g) treatment intermediate ι5 (0.65 g) > in DMF (10 ml) The solution was stirred overnight. The solvent and residue are evaporated to partition between water and ethyl acetate. Then extract the aqueous phase with K ethyl acetate and the combined organic extracts Xuan Ganfeng and evaporate. The resulting coloring oil was purified by column chromatography and dissolved in System A (9: 1) to give the title compound as a yellow solid (0.25 s). T. 1 .c. Ether., Rf 0.6. Intermediate 8 7 2 -Dingmou- 4.5-Nigaki- lH- 眯 _ * ordered, MN-dichlorodiimide (28.6g) treated with 2-butyl-1H-imidazole-5-methanol (30g) in 2-The solution in methoxyethyl yeast (250 ml) and stir in the dark for 18 hours. The solvent was removed in vacuo to obtain a pale yellow solid which was separated between water: brine (1: 1) (3x100iDl) and ethyl acetate (300 ml). The aqueous phase was saturated with sodium nitrate and extracted with M ethyl acetate (3 X 50 ml). After evaporating this mixture and the combined extract and lotion in the mist, M was evaporated in the dark air to obtain a brown solid. K two gas ethane (75ml) developed this color solid and concentrated this product in vacuo and purified K system C (100: δ: 1) by chromatography to dissolve to obtain the title compound (4.8g).-Kind of shallow Orange solid. T.l.c. System C (100: 8: 1), Rf 0.71. Intermediate 88

The Ministry of Economic Affairs, Central Accreditation Bureau printed U 3-Sea- 5- ΓΓ2-Τ-4.5- 二 m-ΙΗ- Sui Du-1- very 1 Tian _ "2 (trityl) -2H-Tetra- 5-even 1 stupid 'cage-carrying pyranyl added intermediate 15 (1.0g) to intermediate 87 (0.28g) and methanol sodium 4 (210X 297, two per) 201 Post A6 ~~ ------ _56 -_ :: Fifth, the description of the invention (64) (0.078 g) in anhydrous DMF (25 ml) and treated according to the method of intermediate 4. Purified by chromatography to dissolve it in Ito A (1: 2) Obtain this stack of compounds (0.53g), a pale yellow solid Zhao ... η · m. R. (CDC 1 3) 8.2 δ (m, 1 Η), 7.6 5 S (η, 3 Η ), 6.7 5 to 7.32δ (丨 18H), 5.18δ (m, 2Η), 2.585 (t, 2Η), 1.68S (η, 2Η), 1.32δ (m, 2Η), 0.88δ ( t, 3Η). Intermediate 8¾ 2-Yunmou-4 ·-Jiamou-Rongtian Fangyi Bronze (13.8 ml) solution in THF (100 ml) was added drop by drop to the magnesium agitator under stirring under nitrogen A mixture of crumbs (4.44g) in anhydrous THF (50 ml). After the addition is complete, add Grignard reagent [solution of o-cresol (20s) in THF (100 ml)] drop by drop. Income 15 minutes later, a solution of 1,3-dimethyl-3,4,5,6-tetrahydropyrimidin-2-one (23.7g) in anhydrous formaldehyde (300 nl) was added drop by drop. To add polyoxymethylene (13.85g). Heat the resulting floating solution overnight at reflux. After cooling, treat the suspension with M10% HC1 (200 ml) and filter and then separate the organic phase. Wash the organic extracts with K water (4x100 ml) The hydrocarbons were dried and evaporated to a yellow crystalline solid (11 g). The title compound, a white crystalline solid (5.3 lg), was obtained by low-temperature crystallization from the ethyl bond. A second harvest (0.695 g) was also obtained. Please read the back < note the competition and fill in this page). Order · • Line 11 / IV A system

f R In the world, the Central Bureau of Economic Affairs of the Ministry of Economic Affairs printed a certain target and 0 Tian 0 even A Na alcohol A general

Stir in the middle of the room until add S in g A4 (210X297i) A 6 B6 5. Description of the invention (65, ι DMF (30 Bl) solution and generate phenate in the form of precipitation. Can be used at room temperature Stir continuously for ~ 15 minutes and then add α-bromo-o-methantonitrile (8.43 g). After 2 hours, add formazan (2.55 g) and heat the reaction mixture to 80¾ °. After 30 minutes, pour the reaction. Enter water (200 ml) and collect the solid by filtration to obtain a light orange solid "S (7.54g). Crystallize it from formazan to obtain the title compound, a yellowish white crystalline solid (5.04s).". Tlc system A (1: 9), Rf 0.45. Medium P side object 9 1 2-(2-罙 # 咕 咭 某 -3 -Pu-6-A certain cage A dark with bromine in the four atmosphere carbon 1 Η solution (23 ml) —A solution of intermediate 90 (4.142 g) in carbon tetrachloride (100 πΙ) under nitrogen at -10 ° C. was treated dropwise. The mixture was stirred at room temperature overnight. Additional bromine solution (12.6 ml) was added. After another 3 hours, the reaction mixture was diluted with dichloromethane (100 ml) and washed with thiosulfate (3 x 50 ml) * and water (50 ml). Dry castellation, filtration and evaporation This title compound, a yellow solid (6.65 g), is a 1: 1 mixture of 2- [3-bromo-6- (bromomethyl) -2-benzofuranyl] benzylazole Ding. 丨.: System. (1: 9), 1 ^ 〇.3, 0.50 (two points). Intermediate 92 丨-晡 基 -3 -bromo-6- (痗 田 很 Π -benzene Printed by the Central Kneading Bureau of the Ministry of Food Economy, please read the precautions on the back and fill in this page) If intermediate 9 1 is treated with bromine in 1 M solution 9 1 in carbon tetrachloride (1 0 0 m 1) The solution in. Purified by chromatography, M system AU: 1) Dissolved to obtain the title compound, a pale yellow solid (0.41g). T. 1. c. System A (1: 1) 'R f 〇 · 8: f 4 (210X297 ^^) Α6 Β6 V. Description of the invention (66) Youmao 93?-"2-Fujian Furan-'US-fi-r" 2-Dingmou- A-y- Tian Lian _ΊΗ-Fazole-1-some 1 Shenmou 1 cage Tian_ Intermediate 16 (0.20g) and intermediate 92 (0.4lg) in DMF containing potassium carbonate (0.17g > mixture in nitrogen Under heating at 80t: for 16 hours. After cooling, the yellow solution was poured into water (60ml) t and extracted with ethyl acetate (3 X 7 Ο π 1). K water (4 X 7 5 m 1) Wash the combined organic extracts * after drying. Concentrate in vacuo to obtain a yellow oil which is purified by chromatography. System A (1: 1) dissolves to give the title compound, a light Yellow foam (0.32 s). T.I.c. System A (2: 1), Rf 0.4. Intermediate 94 Slim cage (cage) cage # 阽 晡 某 1 A certain 1--2-butyl-4-radon -1H-benzozole-5-carboxylic acid will be sulfinic acid sodium (80% industrial grade, 1.51g) A solution of sodium dihydrogen orthophosphate (1.55g) in water (15 ml) was added to the stirring intermediate 93 (〇_8s) and 2-methylbut-2-ene (9.5 ml) in THF 2M solution) in THF (20 ml) and tert-butanol (20 ml). The mixture was stirred vigorously at room temperature for 16 hours, and then it was partitioned between ammonium chloride (60 ml) and ethyl acetate (100 ml). Wash the separated organic phase with water (100 ill), dry it and evaporate in vacuo to obtain the title compound 'a white color (please read the precautions on the back before reading this page) • Install · ΛΤΤ... Green · Foam δ The Central Standards Bureau of the Ministry of Economic Affairs

fo R 物 间 中 甲 4 (210Χ 297Π) A6 B6 201745 5. Description of the invention (67) (please read the precautions on the back before filling in this page) Tetrazole-5-yl 1¾ a certain 1-B-Yunlong and a certain) Tian Shi 1-? -Dingmou-4- 氲 -1H-眯 氯 -5 -Formylase will add triethylamine (182 «1) To the suspension of the product of Example 3 (700 mg) in dichloromethane (2.5 ml) and then add chlorotriphenylmethane (3 52 mg) and stir the resulting solution at room temperature for 2 hours. Then this The inverse mixture was partitioned between water (20βΠ) and dichloromethane. The separated phase was washed with% water (20ml), dried and concentrated in vacuo to obtain the title compound, a white solid (571 mg). T.1.c. Ether, Rf = 0.77 ° Intermediate 96_ 1-““?-痗 -2-“?-“?-(=. Cage Shenmou) -2 [{-tetrazole-5-some 1 Cage certain bu 5-glucofuranyl group) methyl Ί-? -Butyl s-4- radon- 5- (chloromethyl) -1H-squint add dimethyl sulfide (1 1 4 w 1) to the stirring The solution of N-chlorobutadiene imine (190 mg) in dichloromethane and the resulting white floating liquid was cooled to 20t, and then at 30 A solution of the intermediate (1 g) in dichloromethane (70nl) was added drop by drop during the clock. The suspension was warmed to 0 t: and at Ot: stirred for 4 hours and then stirred at room temperature for 48 hours. In vacuum The reaction mixture was concentrated and purified by column analysis with ether: petroleum ether (2: 1) to obtain the title compound (301 mg) as a white solid. Tlc ether: petroleum ether (2: 1), Rf = 〇.? 2. Intermediate 97 The Ministry of Economic Affairs Central Bureau of Preservation and Printing * 1 "" "2-Xia grass staying in the field) -2H-four _-5-some 1¾ a 1-S-node and peptide (hetero) field Very-Dingshi-4-aza-5-"_ 簠 里 基） -1 Η-眯 Beer Add a solution of intermediate 96 (300 mg) in DMS0 (3 ml) to Soso-73- A4 (210X 297, two shots) i A6 B6 Central Government Bureau of the Ministry of Economic Affairs printed only five, invention description (68)-__ '.…' ·, *. —-..: ·. In the sodium cyanide (109 b's ) The solution in DMS0 (7.5 Bg>) and each solution was stirred at room temperature for 24 hours. Add water (30 incense 1) and the resulting mixture K ethyl acetate-(3 X 30ml) extraction. K water (2 · -Χ 30ml) Wash the resulting organic-extract and shrink it in vacuum to obtain crude product The product was purified by column chromatography with petroleum ether: diethyl ether to dissociate to obtain this compound (57 mg)-a white solid. 1. ". (Liquid fi stone hammer) 2210, 170.9, .1 253, .146 $, 1450, 1 252, 761. 748,698 ° φquestion 98 j," Μ- 通 -2'-1 ~ 2-1 ~ 2- (三 g 申 某)-? Η-四 哞 -5- 某 1¾ Very U-y and peptide sighting) Jiamou 1-?-丁某 -d-垣 -1H- 眯 映 -5-Λ58 --—.—. Add triethylamine (82wl) to the mixture of the product of Example 48 (100 ng) in dichloromethane (10 ml) and add chlorotriphenylmethane (9 4.51 ^) At this point, the resulting solution was relayed to add 0 «4 (2 1 ^) and stir the solution at room temperature for 5 hours. Add water (1 0 π 1) and stir the mixture vigorously at room temperature for 5 minutes 。 Extracted with dichloromethane (10ml), the separated water and the combined extract of 楗 are dried and condensed in the sky to obtain the product. Column chromatography M dichloromethane / acetic acid / methanol 2: 2) The title compound, a white solid salt (60 ng), was dissolved out. Tlc dichloromethane / acetic acid / formaldehyde (96: 2: 2), Rf = 0.45. History jat 99 t;-Erzhuang -?-Cage and gourd) Datian Fang 55 Add sodium carbonate (1 Μ. 6 0 π 丨) to the intermediate 1 (4.7g), 2-bromobenzyl formate (5.89s) and tetra- (Triphenyl ) A mixture of palladium (0) (0.38g) in DME. Heat this mixture at reflux for 18 hours * Cooling -74- (please read the notes on the back and fill in the tc page). Order. * 竦 · 4 (2i〇 >-291Ά3Α. ^ £ 〇W45 A6 B6 V. Description of the invention (69) to room temperature and then concentrated in vacuo. K ether (3 x 100 Bl) extraction residue and the combined extract It was washed with brine (1 X 100ml) and dried. The solvent was evaporated to obtain a brown oil (more than 5) which was purified by column chromatography and the system A (1:20) was dissolved to obtain the title compound, a pale yellow oil ( 2.89g) 〇Tlc system A (1:20) · Rf = 0.2. Intermediate 1 0 0 2-(... 3-desert ...: ££ ..- τ .. 甲 盖 -2-benzo眹 Miao Shi) daotianchao 7, cool bromine (1.05ml) in carbon tetrachloride (5 Bl) drop by drop was added to the intermediate 99 (2.88S) in nitrogen at 251C The mixture was stirred for 1 hour, and then cyclohexene (2 ml) was added. The solvent was evaporated and the residue was purified by column chromatography. The title compound was obtained by dissolving it with a stone bond / ether (20: 1). Colorless oil (3.57g). Tlc petroleum ether / _ (2〇: 1), Rf = 25 billion. Intermediate 1 ft 1 2_- (3-if stinky -5 -floor β-?-Cangjing Xuanan) daotianchao 7, 8¾ Add NBS (1.94g) to intermediate 100 (3.56g) in four Solution in carbon chloride (80ml). Add dibenzoyl peroxide and heat under reflux Jfc · Mix more! 3 hours. The cooled mixture was decanted and the filtrate was evaporated. The residue was purified by column chromatography. The title compound was dissolved in system A (1:30), which was a colorless oil (3 66 g); Central Bureau of Economic Affairs of the Ministry of Economic Affairs Printed {Please first please the back of the page: ^ Issues and then fill out this page) Tlc Petroleum Inspection / Yishang (2〇: 1), Rf = 〇2c Intermediate 1 9 2_ 二 [_m 臭 二 5-"( 2 Er J Jin-4-Qi-5-Tian Teng Shi 1-1H -Zhang Fa-1-Ling _________ -75-f 4 (210X 297 ^, ¾) A6 B6 £ 01745 V. Description of invention (7〇 ) A 1-?-Cage and murmur a 1 ketone ethyl acetate according to the method of intermediate 1 7 Intermediate 1 6 (1.43 g) Intermediate 101 (3.66g) and potassium carbonate (1.17g) in anhydrous A mixture in DMF (60 ml) gave the title compound, a colorless gum (3.67g). Tlc ether / petroleum ether (1: 1), Rf 0.4. Intermediate 1 0 3 f >-"?-" 5- " 「5- (β Μ 甲某） -2 -Dingmou-4- m -1 H- 咪 呻 -1-华 1 甲 华 1-3- Chun-2-¾ # 喵 某 1 笨 华 1-2- (Three cages of a certain) -2H-tetrakis was added mesyl chloride (0.10 m 1) dropwise dropwise to the intermediate 95 (1.02 g) and three A mixture of ethylamine (0.13 g) in anhydrous dichloromethane (15m 1) and after stirring under nitrogen at room temperature for 1 hour, lithium azide (200 mg) and 12-crown (ether) were added- 4 (50mg) up to this solution. Concentrate the mixture in vacuo, add DMF (15ml) and heat the mixture at 60 for 2 hours. 0 Concentrate the mixture in vacuo to obtain a colorless gum. 0 Purify by chromatography This title compound (213 g) was dissolved in ethyl m / dichloromethane / hexane (0: 1: B 1: 10: 5) t a colorless gum. T · 1. C. Ether, Rf 0.85 ° middle物 1 04 1-'"" 3-Bromo-2- [2- [2-(--- 二 本 甲 筚) -2H-四 呻-5- 華 1 茏 某 1 -5-呆 # 11guanan Very 1 Tian 1_2_Ding Shi-4- ramen scorpion anti-intermediate 102 (516 mg) and tribenzine (200 rag) in anhydrous dichloromethane (10 ml) solution at room temperature under nitrogen 15 hours. The solution was concentrated in vacuo, M concentrated ammonia solution (2 ml), methanol (10 ml) and dichloromethane (2 ml) to dissolve the residue and left at room temperature for 16 hours. Concentrate in vacuum ................................. / ......... .... ^ .............................. Order ......... (.... ............ Line (Please read the notes on the back of KI before filling in this page) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs -76-A 4 (210X 2971 ') A 6 B6 V. Description of the invention (71) This solution and the product isolated by chromatography, M ethyl acetate was dissolved to give a pale yellow oil (438 mg) Purified by chromatography K system C (300: 8: 1) The title compound ( 352 mg), a light-colored oil. Tlc ethyl acetate printed by the Central Standards Bureau of the Ministry of Economic Affairs, Rf 0.2. Intermediate 1 0 5 H-1-"Γ3- Mo-2-(Sanbenjiamou) -2H-4 0Φ _ 5-Hua 1 Fu 1-5--benzofuranyl 1 methyl even 1 -2- Ding Hua-Am.- 1 Η-眯 皞 _ S- certain 1 A certain λ 7, mm Intermediate 104 (409 mg) · A solution of diethylpyridine (150 a 1) and acetic anhydride (100 U 1 in anhydrous dichloromethane (10 m 1) at room temperature for 3 hours. Separate the product by chromatography * System Β Dissolve to give the title compound, a white foam (405 mg) 0 τ. 1. C · System B (1: 1), Rf 0. 3 =! Prepared in the same way * An intermediate 1 06 "" 1-"" 3- -Γ2--(三 笨 甲某) -2H- Four beer _ 5- Hua 1-Benhua 1-f; _ Fufuro furyl methyl 1 -2-Dingmou-4- -1H- imi-FS-Hua 1 Jiamou 1 Chen Tianwu Sheng§ a kind of white Foam (434 mg) 0 T · 1.. C. System B (4: 1) -R f = 0 • 4 5 3 from intermediate 1 0 4 (5 0 0 ag) * triethylamine (200 U 1) and Chloroformic acid methyl m (100 u 1) in anhydrous dichloromethane (1 0 m 1) only solution 0 Intermediate 1 07 N-. "! Bu" "3- bromine" 2- (-stupid methyl)-_2J- Four beer-5-even 1 cage (please read the back of tellurium first; please fill out this page after the intention) • ^.. 定 '. 线. -77-A4 (210Χ 297Ί) A6 B6 201 ^ 45 5. Description of the invention (72) (please read the precautions of the plan first and then fill in this page) 1-5- 茏 # 11 # 晡 某 1 string Ί-2-丁某-4- ^ -1Η- 眯 某 1 A Even 1 globamine dissolves the intermediate 104 (398 mg) in ethyl formate (10 ml) It was heated at reflux under nitrogen for 3 hours for. The solution was condensed in vacuo and the product was separated by chromatography. The dissolution of Μ 鳸 系 B (1: 4) gave the title compound, a colorless gum. T.l.c. System B (1: 4), Rf 0.2. Intermediate 1 0 8 · "" 1-"" 3-Bromo-2- "2-" 2- (three cages of a certain) -2 ^ Four favors-5-some 1-Mo certain 1-5-Fu and squint鄄 某 1 甲 certain1-2-T certain- 4- M-1H-Penazole-5-some 1 Shen certain 1 urea Add the silicon tetraisocyanate (35ag) to the middle of stirring at room temperature under nitrogen 1 04 (505 mg) in anhydrous toluene. After 10 minutes, heat the solution to 100 liters. After 30 minutes, cool the solution and remove the solvent in vacuo. Add isopropanol (9 ml) This solution was heated with water (1 ml) and heated at reflux for 30 minutes. The solution was cooled to room temperature and concentrated in vacuo. Chromatography * M ethyl acetate was dissolved to give a white foam and its ether was prepared to obtain the title compound. · A white powder (171 nig).. Green. Tlc ethyl acetate, Rf = 0.2. Intermediate 1 0 9?.? -Dimethylpropanol 1-(2 -Sea-4-Jiamou) cage g purpose Printed by the Central Bureau of the Ministry of Economic Affairs

A solution of 2-bromo-4-methylphenol (9.14g) in anhydrous dichloromethane was cooled in an ice bath under nitrogen and chlorinated with 2,2-dimethylpropionyl (1 2.08 m 1) and DMAP (17.8 g). Continue stirring at room temperature overnight. Μ 2 N -78- A 4 (21Ό 297 public) A 6 B6 V. Description of the invention (73) HC1, 8% NaHC03 aqueous solution, water washing the reactants and Jingganfeng. Filtration and evaporation gave a pale yellow oil (17.19g). Purified by column chromatography to dissolve it with Shitong A (1:20) to obtain the title compound, a colorless oil (8.07g). T. 1. c. System A (1: 2), i? F 0.8. Intermediate 11.0.1- (2-selective-4-methyl) benzene-2.2-Nitada even propyl-1-cat will intermediate 1〇9 (18.38) in anhydrous 1 'to (54〇1 | 11) And the solution in anhydrous ether (96 ml) is cooled to -100 and it is treated with M-butyl lithium (90 ml)-drop by drop. Warm to -78 t after ~ 30 minutes: and continue stirring at this temperature overnight. The reaction was quenched with saturated aqueous MNH4C1 and warmed to room temperature. The organic phase was separated and the aqueous phase was extracted with silver carp. The combined extract of the barberry was washed with K water, dried, decanted and evaporated to obtain a yellow / orange oil (14.4g). Purification of M system A (1:20) by column chromatography dissociated to give the title compound, a yellow oil (10.32g). Tlc has been synthesized, Rf 〇.35〇 Intermediate η 1 2- (3-tert-butyl-Η-Tian Shi-?-Fu Pinghuan even) ¾ A meal intermediate 110 (9,22) in anhydrous 0 The solution in ^^ (200 pieces) is printed by the Central Bureau of Hydrogenation and Economics of the Ministry of Economy (please read the precautions before completing the page) (1.59g) and stir under nitrogen for 30 minutes. Additional DMF (75 ml) was added following Μα-Br-methyl-methyl formazan (9 · 41 g). Continue to store at room temperature for 1 hour and a half. Then add the same amount of sodium hydride (1.59g) and heat the solution to 80C: continue to mix at this temperature overnight. The volume of the solvent was reduced by evaporation and the residue was poured into water and extracted with M ethyl acetate. The combined organic extracts were washed with water and brine. After drying, decaying and evaporating, a blessing oil (19.76s) -79- A4 (210X 297 ^: ^) 201745 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs A 6 B6., 5. Description of the invention (74. By the column layer The analytical method was purified by system A (1: 9) to dissociate to obtain the title compound (3.09g). TIc System A (1: 9), Rf 0.45. Intermediate substance 1 1 2-"5- (Zhang Jiamou) -3- "1.1- (Dimethylethylacetate) 1-2-¾ Jinghuanan 1¾ Jia I 'According to the method of intermediate 3 KHBS (1.35g) treatment of intermediate 111 (1.98g) in tetrachloride The solution in carbon (40ml) used benzoyl peroxide as the base elicitor to obtain the title compound, a white foam (0.96 g) Ο T. 1 · c · System A (1: 9), R f 0 · 3 5. Intermediate 11 3: ::!-"5-" 2-butmou-4-gas-5 (argon methyl)-〗 [|-眯 Beer-1-some 1 a very poor "" 1.1- (two Shen 7, certain) 1-2-¾ and murmured 1¾ Jia blind according to the method of intermediate 17 with potassium carbonate (0.373g) to treat intermediate 112 (0.95g) and intermediate 16 (0.479g) in anhydrous DMF ( lOml) solution. Purified by column chromatography to dissolve the system A (1: 1) to give a yellowish white foam (0.86 g). Then from the layer Purification and system B (1:10) dissociated to obtain the title compound, a yellowish white foam (〇.731g). TIc system A (1: 9), Rf 0.3. Intermediate Ή 4 1- "". Ί -Μ.1-dimethylamino) -2- (¾¾mou) -5-cannabipyranyl] methyl 1-?-Butmou-4-rad-1H 1 1 3 (0. 8 g) in THF (1 0 m 1), Uncle-Ding § Xiang (1 0 m 1) and (please read the precautions on the back and then fill in this page) • Cricket · Order * • Line _ 8 0 _ A 4 (210X 297 佂 没) A 6 B6 Printed by the Central Standards Bureau of the Ministry of Economics and Development 5 'Description of the invention ί 75) 2-Methylbut-2-ene in a solution M sodium chlorite ( 1.52g) and sodium dihydrogen phosphate (1.52g) in water (10ml). Stir at room temperature and continue stirring overnight. Reduce the volume of the solvent by evaporation and the residue between IN HC1 and ethyl acetate Partition. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were dried, filtered and evaporated to give the title compound, a yellow solid (0.68 s). T.1.c. ether, R f 0 · 5. Intermediate 11 5. 2- "5-"?-Ding Shi-4-Qi-5- (Jun Jiamou) -1 »-Penazole-1-some 1 Jiamou-2-" Π · 1- (two Shen Λ) 1-2-¾ Jinghuan 1 cage wall under nitrogen under stirring K sodium borohydride (〇.〇25g) treatment intermediate 1 1 4 (0.29 g) in methanol (8 The solution y in m 1) was evaporated after 1 hour and the residue was purified by column chromatography. System K (1: 2) was dissolved to obtain the title compound, a white crystalline solid (0.256g). Ding 1 .c · System B (1 ·· 1 0), R f 0 · 2 5 · · Intermediate 1 1 fi: =!-radon-5-examining-2- "2-" 2- (Sanhuajia )-? H- 四喜 -5-some 1¾some 1 cage well _some will add n-butyl lithium (1.6TM hexane solution, 1.5 ml)-drop by drop to the intermediate 14 (0.98) under stirring under nitrogen g) A solution of -7 in THF (35 ml). After 5 minutes, add a solution of hexachloroethane (1.15 g) in THF (10 mL) drop by drop. After 10 minutes before removing the cooling bath Brine (1 m 1) was added. After warming to room temperature · This mixture was partitioned between ethyl acetate (4 0 m I) and water (4 0 m 1). The organic phase was dried and under vacuum {please first Read Note on the back and then fill out this page) • Tobacco · Order · Green. -81-A4 (210X 297 Public Issue) 201745 A 6 B6 Printed by the Central Bureau of Standards of the Ministry of Economy V. Invention Instructions (76, Medium Concentrated A white solid (1.23g). Purification of Μ 糸 System A (1: 4) by chromatography dissolves to give the title compound (0.9g), a white solid. Tlc System A (1: 9) (1: 3), Rf 0.7. Intermediate 1 1 7 1- "5-" 3-Radon- 2- "2-" 2- (three cages) -2H-tetrazole-5- 某 1 茏 某 1 呆 #H 炣 然Some Ί 申 某!-; ≫ -Dingmou-4 -Gas-1 only-squint_-5 ~ Jialu Add NBS (0.35g) to the intermediate 116 (0.9g) in carbon tetrachloride (30ml) Medium temperature (65t :) solution, followed by adding dimethylformyl peroxide (0.05g) after K. Then, the suspension was heated at reflux for 4 hours while irradiated with 250 V lamps. Filter the yellow suspension And the filtrate was concentrated in vacuo to obtain an orange solid (0.99 g) which was treated with intermediate 116 (0.27 g) and potassium carbonate (0.32 g) in DMF (30 ml) according to the method of intermediate 36. By chromatography Purified M system A (1: 7) was increased to (1: 1) to dissolve to give a yellow semi-solid (0.325g). Repurification by chromatography using System C (300: 8: 1) dissociated to give the title compound (0.107S), a nearly colorless oil. T.l.c. System A (1: 1), Rf 0.3. Intermediate 1 1 8 1- "5-".?-Radon-? .- "?-"?-(Two-cage armor)-: ^-四 映 -5- 某 1 茏 某 1 cage # P 关_ Some) a certain 1-2-butyl-4- radon -1H-眯 Beer-5-methyl nitrate sodium chlorite (80%, 0.49g) and sodium dihydrogen orthophosphate (0_51g) in water (10 The solution in ml) was added to the stirring intermediate U7 (0.46 g) in tert-butanol (10 ml) STHF (10 ml) containing 2-methylbut-2-ene (2M solution in THF, 3 ral ). Mix this mixture vigorously for 16 hours, then remove most of the solvent in a vacuum and leave the residue in vinegar. Please read the precautions on the back before filling this page)-¾. .Line · _ 8 2 _ A 4 (210X 297 ^: ^) 201745 A6 B6 Printed by the Central Standards Bureau of the Ministry of Economic Affairs V. Description of invention (77) Distribute between ethyl acetate (50ml) and water (50ml). The organic phase was dried and concentrated in vacuo to give the title compound (0.3 Sg), a yellow viscous oil Ο Tlc System A (1: 1), Rf 0.15. Intermediate 1 1 9 1- “m2-rm (三 蓏Jiamou-four beer-5-mou 1¾mou Ί -R-cage # 11 韣 NANmou) Tian Shi 1-4 -Qi-2 -methyl sugar -1H -Sui Fa-B-Tian credit 7, cool will Hungry tetraoxide ( lOmg) was added to a solution of intermediate 34 (780 mg) and sodium periodate (819 ng) in 10% water dimorphane and the resulting mixture was stirred at room temperature for 2 hours. Sodium metabisulfite was added until The mixture became colorless. K ethyl acetate (3 x 50ml) extracted the resulting compound, and the extract was dried and concentrated in vacuo to obtain the standard S compound (697 ms), a cream colored solid. T. lc petroleum Ether / ether, Rf 0.55. Intermediate substance 1 2 0 1-““ 3-zhang-2- “2-“?-(Sanhongjiamou) -2 [|-四 鹿 -5- 某 1 茏 基 1 -5 晡 某) methyl even 1-2-butene ワ beer-5- methyl ethyl ethyl tert-butoxide (64rag) was added to the n-propyl bromide tribenzyl bromide (2325mg ) A suspension of Ot in THF (3 ml) and the resulting orange mixture were stirred at 0 t for 20 minutes and then a solution of intermediate 119 (235 mg) in THF (5 al) was added during 30 seconds. Stir the resulting white suspension in OC for 30 minutes and let the temperature reach room temperature and stir the anti-83- at room temperature (please read the precautions on the back before filling out this page) A 4 (210X 297C no) A 6 B6 201745 V. Description of the invention (78) {Please read the precautions on the back before filling in " this page> The mixture should be used for 1 hour. Then, n-propyltriphenylyuan bromide (100 ng) and tert-butyryl potassium (30 mg) were added and the resulting mixture was stirred for 4 hours and a half. Add a saturated aqueous solution of ammonium nitride and acetic acid ethyl; ester 2 X 5ml extract the separated aqueous phase. The combined organic extracts were dried and concentrated in vacuo. The residue was purified by column chromatography and dissolved with petroleum ether / ether (4: 1) to give the title compound (100 ng). T.I.c. petroleum ether / ether (1: 1), Rf 0.57. Intermediate 1 2 1 1-"" 3- 濩 -2-J2-"2- (trityl) -2H-W ΒΦ-5-some Ί cage certain 1-

--Cage # 眹 照 某) Shenmou Ί-2 -pentane, 1 (Z)-锸 很--眯 Favour-R --Methyl ethyl ester according to the method of intermediate 120 Kter-butyryl potassium (196 ng ) And bromobutyltriphenylpyridinium (682 mg) in THF (10 ml). Intermediate 119 (455 mg) in THF (10 ml) gave the title compound (10 mg), a white solid . T.l.c. petroleum ether / ether (1: 1), Rf 0.57. Intermediate 1 2 2? -Door-"(? .- Dingmou-4- 氲 -5- 甲 醯 某 -11Miduo-1- 葚 1-3-methoxy:-?-Cage # 眹 咭 某 1¾ A blind blind added active manganese dioxide (1.2s) to the stirring intermediate 29 (1 printed by the Central Bureau of Economic Development of the Ministry of Economic Affairs) in dichloromethane (10ml) and 1,4-dioxane (5 ^ 丨) solution, and heating the resulting mixture at reflux for an hour. The reaction was filtered, the filtrate was evaporated in vacuo and the residual oil was purified by chromatography to dissolve the ether. A precipitated from the yellow solution White solid and re-developed and filtered to obtain this -84- A 4 (21〇X 297S;% *) 2〇i ^ 45 A6 B6 Printed by the Central Bureau of Economic Development of the Ministry of Economic Affairs 5. Description of the invention (79) Title compound (〇.46g), melting point 118 ~ 120 =. Intermediate matter 1 2 3 p-Ding Shi-4- radon outline cage 2-field M Mou-5-^ # P sodium chlorite ( 〇.8g, 80%) and dihydrogen phosphate (0.8g> in water (5 b1) solution was added to the intermediate 122 (0.4g) in tert-butyrase (10 Bl), 2-methyl-. 2-a mixture of butene (5.4nl, 2M in THF) and THF (10 ml), and the mixture is treated according to the method of intermediate 18 to obtain this standard The title compound, a white solid (0.4 g), melting point 158 ~ 160C ° φ interbody 12 4】-“「 3- 逋 -2- 「2-「 2 (三 蓏 甲某)-2Η-四 首- 5-mou 1 罙 mou BU 5- 臏 bi peptide aiming at a Jia 1-2 1-2 ding -4- radon -1Η-眯 Djfe-R-Tian Chujia Ji 簠 certain 1-uryl ethyl cool will DEAD (0.75 nl)-dropwise add a solution of I8 (2.00g), triphenylphosphine (1.30g) and (±) -1-methoxy-2-propanase (360 mg) at room temperature under nitrogen Stirring. After 16 hours, the solution was constricted in vacuo. The title compound was isolated by dissolution of K chloroform and a white foam (2.02g). T. lc chloroform, Rf 0.2. History ;! .. [· "?-海-? _-"?-(-Cyano 茏 基) -5- 茏 # 11 本 照 葚 · '田 基 1-2-丁 _ y-"radon-1H-眯 邮Ethyl-4-carboxylate 2-ethyl-5-chloro-1H-imidazole-4-carboxylic acid ethyl ester (494 mg), intermediate -85- (please read the precautions on the back before writing this page) • Packed • -ordered • • Green. A 4 (21〇X 297 II ') 201745 A6 B6 V. Description of the invention (80) 10 (838 mg) and potassium carbonate (326 mg) in anhydrous DMF (20 ml) The mixture in is heated at 70 * 0 for 3 hoursAfter cooling, the mixture was partitioned between ethyl acetate (50 ml) and brine / water (1: 1) (3 x 2g ml). The organic extract was dried and evaporated to remove the solvent. The residue was purified by column chromatography K ether / petroleum ether (1: 1) to obtain the title compound (151ng). T. 1. C. Etsune / Petroleum Ether (1: 1), Rf 0.15. Intermediate 1 2fi i-rm Fu-X2 -cyanophenyl) -5 -benzoxanan 1 Shenshi 1-2-T even 5- 氤 -1H -Zhongyou-4 -A service in the room Warmly stir the mixture of intermediate 125, ethyl yeast (1.10ml), potassium hydroxide (312 mg) and water (0.247ml) for 24 hours. After this time, add ethanol (1.10ml), potassium oxyhydroxide (31.2mg) g water (0.247ml). After 4 hours, add two equal portions of all reagents and stir the reaction mixture at room temperature for 6 hours. The reaction mixture was condensed in vacuo and the residue was diluted with water (5 ml) and then acidified to pH 3 (2N HC1). Ethyl acetate was used to extract the aqueous phase and the combined hydroxyaqueene extract and concentrated in vacuo to obtain the title compound (91 ms), a white solid. nar5 (250MHz), 0.88 (3H, t), 1.30 (2H, sex), 1.80 (2H, pent), 2.80 (2H. t), 5.35 (2H, s), 7.1 (1H, d). 7.26 ( 1H, s), 7.5 (2H, a), 7.65 (1H, t). 7.8 (1H, d), 8.0 (1H, d) = intermediate 127

The Central Bureau of Standards of the Ministry of Economic Affairs prints $ L. Please read the precautions on the back first and then fill out this page. Zhang-5- Jiamou-?-Cage and Goumou) A solution of 5 (2.20g) in methanol (20 86 A6 B6 printed by the Central Kneading Bureau of the Ministry of Economic Affairs V. Invention Description (81) ml). Heat this solution to reflux and continue heating for 3 hours. Remove the solvent in vacuo and dilute the residue with water. Methyl ether (3 X 30 ml) was used to wash this alkaline aqueous solution and then acidified to pH ~ 2 with 2N HC !. A white suspension is formed. The suspension and the combined extract of aralia were extracted with ethyl chain (4x20n 丨), dried, decanted and evaporated to obtain the title compound. A light yellow solid (1.93). , T.l.c. ether, Rf 0.7. Intermediate 1 2 8 · "2- (3-薄 -5- 甲某 -2- 荣 # 眹 某某) ¾ certain 1 brachial service 1.1-two Shen B | g_ Put the intermediate 127 (1 g) in anhydrous The solution MU in dihalane (25ml) was treated with diphenylphosphononitrile (0.65ml), triethylamine 42ml) and tert-butyrylase (0.5ml) and then heated to reflux under nitrogen. After 6 hours, cool Reaction and evaporation of the solvent M gave an orange oil. Purification by column chromatography * M system A (1:10) dissociated to give the title compound, a cream solid (0.67 g) 0 Tlc system A (1: 1), Rf 0.8. Intermediate 1 2 9 1-m Zhang-2- "2-" "Π.1- 二甲 某 ΛM even 1 锸 even 1 陵 -R-緀 # 蛀 見 這 1 Tian Shi 1-2-Ding Shi -4-M-1H -glyphine. MNBS (1.02g) and dibenzoyl peroxide (230ng) treatment + 128 (2.20g) solution in carbon tetrachloride (50nl) and heated to Irradiate it with a 250W town bulb. Cool this reaction after 2 hours g I $ -87- A4 (210Χ 297K no). Please read the precautions on the back before filling this page) k.. Order · 201745 V. Description of the invention (82) and filtration. This organic phase is washed with K water, dried and evaporated to obtain an orange oil. This orange oil is dissolved In DMF and in Ot: —Add one drop to 2-butyl-4 -ambient-1H -imidazole-5 -ethyl formate [imidazole (1.26g) + sodium hydride (60%, 0.218g) in DMF] Neutralize and stir at room temperature overnight under nitrogen. Remove the solvent and residue under reduced pressure and partition between ethyl acetate and water. This organic phase is washed with M water, dried, filtered and evaporated to give a color oil. (3.90g). The brown oil was purified by column chromatography to dissociate Ao A (1: 2) to obtain the title compound, a yellow foam (〇.832g). Intermediate substance 1 3 0 1- "" 2- (2-Amine oxazolyl) -3 -Tong- Meow 1 Joel 1-? -Ding Mou-4-1 Η-眯 Beer-5 -Department of 7, ester Κ2Ν HCl (2ml)-drop a drop Bury the solution of intermediate 129 (0.124s) in ethanol (6 ml). Stir at room temperature continuously for 1 hour and a half. Heat the reaction to reflux and stir for 1 hour following the anchovy. Cool this solution to room temperature and use 2N NaOH was neutralized to pH 7. The solvent was evaporated and the residue was partitioned between water (30 nl) and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2 X 15 ml) and the combined organic extracts were dried Combi, filtration and evaporation to give the title compound, a Tawny brown oil (0.089g). T.l.c. system A (1: 1), Rf 0.30. Intermediate 1: n

2- (Hydroxyimino) -3-Argon P. Ji 7. SS Add a solution of sodium nitrite (2.94g) in water (7 ml) at 20 ~ 30t: Add it to the stirring during 1 hour and a half A solution of ethyl 3-oxohexanoate (5.0 g) in glacial acetic acid (6 ml): stir this orange mixture for half an hour at 251C —____ _88 — A4 (210X 297 'two' no) (please first Read the precautions on the back and fill in this page). ¾... · Line. A6 B6 Printed by the Central Bureau of Economic Development of the Ministry of Economic Affairs ^ V. Invention Instructions (83) Dilute this solution with water (21ml) and save at 201C Mix for 15 hours and a half. This mixture was extracted with diethyl ether (2x20ml) and the combined extracts were washed with K water (20ml), 8% sodium bicarbonate (2x20ml) and saturated sodium saturated solution (2.0ml). This yellow solution was then dried by hydrocarbons and evaporated in the air to obtain a fluid yellow oil (4.95 s). nmrS (CDCl3) 94 (lH, brs), 4.30 ~ 4.44 (2H, 2xq), 2.68 ~ 2.82 (2H. 2xt), 1.6 ~ 1.78 (2H, 2xm), 1.3 ~ 1.4 (3 Η , 2 xt). 0 · 9 ~ 1.1 (3 Η, 2 xt). From Intermediate 1 3? 値 g 僤 2- 防 某-g-R ethyl ether add intermediate 131 (55.0g) in ethanol (600 ml) containing concentrated hydrochloric acid (30 ml) solution to the pre-reduced 5 % Platinum oxide on carbon catalyst (4.0 g). This mixture was broadcast under hydrogen for 20 hours. The catalyst is removed from the diatomaceous earth washed with acid (H C 1) and evaporated to an oil. The M is azeotropically dried by yeast fermentation. The resulting solid was washed with 10% ethanol in diethyl ether, and then collected and dried in vacuo to obtain the title compound, a white solid (43.75 g). η.Β.Γ.δ (CDCU DMSOde 250MHz) 9.18 (3H_, brs), 5.08 (1H_, s), 4.33 (2iL, O, 2.82 (2H_, t), 1.6 ~ 1.75 (2H_, π), 1. 3δ (3L, t). 0.95 (3K_, t). Intermediate Ί 3 3? -Butan-4-propan-1H-quinazol-5-tianfang B 5S Add anhydrous potassium carbonate (13.8s) to A solution of intermediate 132 (10.5g) and methyl glutamate U.2g) in ethanol (250 ml) during sowing. At -89- (please read the precautions on the back before filling in this page). ¾.

A 甲 4 (2) .0X 2W 二 Ά 01745 a6 _____ B6 V. Description of the invention (84) The mixture was stirred at room temperature for 16 hours and then evaporated to dryness. The residue was purified by column chromatography and the title was obtained by dissolving in ether Compound, a clear viscous yellow oil (3.0 g). N.ni.rS (CDCU 250MHz) 10.1 and 10.8 (1H_, 2xvbrs), 4.32 (2L, q), 2.87 (2H_, brt). 2.7 ( 2H_, t), 1.6 ~ 1.8 (4H_, m), 1.3 ~ 1.45 (5L, m + t), 0,. 82 ~ 1.0 (6U_, 2 xt) ° Intermediate 1 34 1- "" Dg -2- "?-" 2- (Ξ cage Shenmou) -2H-Tetra beer-5-mou 1¾ 1-5-cage right aiming even 1 Shenmou 1- 2 -Tmou-4 -Promou-1H -Zidazole -5-Ethyl ethyl ester was added anhydrous potassium carbonate (0.4g) to a mixture of intermediate 1 3 3 (0.71 g) and intermediate 15 (2.86 g) in anhydrous DMF at room temperature. The mixture was stirred warmly for 16 hours and then heated at 80 C for 24 hours. The reaction was cooled and concentrated in vacuo to obtain an oily solid which was poured into water. M dichloromethane and diethyl ether (2 X 100 ml each) extracted the mixture The combined extracts were dried, evaporated and evaporated to obtain a viscous oil (2.9g) which was separated from the column layer The title compound is a viscous, clear, and immobile oil (0 · 93g). It is printed by the Central Mobilization Bureau of the Ministry of Economic Affairs (please read the precautions on the back and fill out this page). Nmr5 (CDCl3 250MHz) 8.18 ~ 8.22 (lL, ni), 7.66 ~ 7.71 (1H, η), 7.3 ~ 7.62 (2L. Ra), 7.22 ~ 7.32, 7.1 ~ 7.18,6.82 ~ 6.98 (15H_, 3xin) , 7.06 (llL, br, s), 6.93 (11L. D), 6.77 (11L, dd), 5.63 (2H_, s), 4.18 (2H, q), 2.9 (2H, br t), 2.61 (2H, br t), 1 · δ2 ~ _-90-_ A 4 (210X 297 public issue) Printed by the Central Approval Bureau of the Ministry of Economic Affairs 01745 a6 B6 V. Description of the invention (85) 1.78 (4H, m). 1.3-1.4 (2H, m). 1.27 (3H, t), lo (3H, t), 0 · 87 (3H, t). Intermediate 1 Μ 2-"3-Sea-5-" "? -T certain-4-radon-5- (argon methyl) 1 H- 眯 Favour-l- even 1 a even 2- 茏 井 眹 Sight 1 1 Shen Shen 腠 According to the method of intermediate 17, the intermediate l is processed. (9.8g), intermediate 16 (4.8g) and potassium carbonate. (5 s) in DMF (250 ml). The title compound (6.2g), a white solid, was purified by chromatographic purification of M · petroleum ether / acebill (1: 1) to dissociate K. T.l.c · petroleum ether / ether (1: 1), Rf = 0.35. Intermediate 1.36 1- "" 3-Bromo-2- (2- 簠 very cage) -5-¾ and Qiqi certain) Tianmou 1-? -Butadiene-4-g -1H-squinting-5- Tian Yi added a solution of sodium chlorite (8.7g) and sodium dihydrogen phosphate (8.8g) in water (50nl) to the intermediate 135 (4.8s) in tert-butyrate (100 ml), 2-A A mixture of 2-butene (2M in THF, 60 ml) and THF (100 ml). The mixture was treated according to the method of intermediate 36 to obtain a white foam which was triturated with ether and filtered to obtain the title compound (3.75 g ), A white powder. Tlc ethyl chain, Rf = 0.30o Example 1 2- "5-" (2-Buthe-1 ^ Penazole-1-some) Jiamou 1-?-Stupid 0 炣 湳 什 1 Guijia

I Treat the intermediate 4 (0.236g) in methanol (3 ml) with 2 丨 丨 HaOH (l ml) -9 1 _ A 4 (210X 297 ^ :, ¾) (Please read the precautions on the back before filling this page ) k. • Line · 201745 A 6 B6 5. The solution in the description of invention (86) During this period, the solution became turbid. Then add formazan (~ 1 ml) to the solution until the solution is cleared and heated to reflux for 2 hours. Cool the reaction to room temperature and remove the methanol in vacuo. The residue was diluted in water (~ 5 ml) and added drop by drop to 2H HC1 to neutralize to pH7. The mixture and the combined extracts were extracted with ethyl acetate (3 x 20 ml), dried, and evaporated and evaporated to obtain the title compound * — pale yellow powder (0.085 g), melting point 153 ~ 157Ό. hplc, (conditions such as Example 7) residence time = 16.37 minutes. 2- "3-Sea-5-" (2-Butyl-1 burzozole-:!-Yl) A certain 1-9-section and kou meo very 1 cage Tianlu M2H NaOH (lial) treatment intermediate 7 ( 0.135g) The solution in formazan (3b1) becomes turbid during this period. Then add formazan (~ 1 π) until the solution becomes clear. Heat the solution at reflux for about 3 hours. The reaction was cooled and methanol was evaporated. The residue was diluted in water (~ 5 ml) and added dropwise to 2NHC1 to neutralize to pH 7. The resulting suspension was extracted with ethyl acetate (3} f2〇inl). The combined extract of 楗 楗 was dried and evaporated to obtain the title compound, a yellowish white powder (0076g), melting point 138 ~ 145Ό. Test result: C. 61.05; Η, 4.9; N, 6.2% C23H2iB "M2 〇3 Calculation: C, 60.9; Η, 4: 6; Ν, 6.9% Example (please read the precautions on the back and then fill out this page) 乂. 装 ·. 打 ·. 线 · Ministry of Economic Affairs Central Seal 5 -"?-".?-Zhang-5-"" 2-Dingmou-4-radon- ?; (Hua Shenshen) Jia Shijian whispering 1-4--92 cover armor 4 (210Χ 297 伂 发: 01745 A6 B6 V. Description of the invention (87) Add intermediate 11 (0.5g) under nitrogen 16〇υ β-tri-n-butyltin (3s) with stirring ° This mixture was stirred at 1601C for 1 hour. The resulting solution was cooled to room temperature and then made alkaline with W5N NaOH. The resulting solid was dissolved in methanol Neutralize and use acid HC 丨 to acidify to PH2. Extract the aqueous layer with ethyl oxalate (3 x 20nl). The combined organic phases are dried and evaporated to give an orange solid which is reversed-phase hPl, c. (High efficiency liquid layer Analytical method) purification (acetonitrile / water / TFA) to obtain the title compound (0.125s), a white powder, melting point 1 9 3 ~ 1 9 7 TC. Verification results: C, 52.2; H, 3.9; N, 15.0% Calculated for C24H22BrClNe〇2. 〇.1C2HF3〇2: C, 52.5; Η, 4.0; Η, 15.2¾ Example 4 t 1- "" 3-sea-2- "2- (1Η-tetrazol-5-yl) ¾ Certain 1-5-¾-furanyl 1A (please read the notes on the back of the moraine first and then fill out this page) The Ministry of Economic Affairs Central Bureau of Precinct Printing Base 1-? -Ding Qi- / t- 氡 -1H- 眯-5-Shen Xue stirred the mixture of intermediate 17 (180iag), water (5ml), THF (10ml) and concentrated hydrochloric acid (0.1ml) overnight, after which concentrated hydrochloric acid (0.2ml) was added. Continue to mix 3 Days, add concentrated strong acid (0,2ml) and dry for another 2 days , Addition of sodium hydroxide solution (2 N) K to become the pH of the solution was approximately 12 ° removed most of the solvent in vacuo and the residue was diluted with water and extracted with ethyl Μ silver carp. Then, dilute hydrochloric acid (2N) acidified the aqueous phase to about pH 3 and extracted with ethyl acetate. The organic extracts were combined, backwashed with water and brine, dried and concentrated in vacuum to obtain a white foam (121mg). 100 mg was purified by preparative HPLC (high performance liquid chromatography) to obtain the title compound 'as a white solid (1.2 2 S), melting point 1 8 3 ~ 1 8 5 t. -93- • Line. A 4 (210X 297 issued by the Ministry of Economic Affairs of the Ministry of Economic Affairs of the Central Government ¾ 201 ^ 45 a6 B6-· »·· '_. + · +. · ▲ ··. I III. 一 —, -----.m. -R, --- V. Interpretation (88 / Ir (crushed stone, cb-1) 1709, 1529, 1464, 1420, 1377, 1364, 1265, 1142. 1069, 1059, 1043, 780. Ir Infrared uses the title compound as a column chromatography M series cyno-E (75: 25: 1) to provide this non-soluble compound compound, a white solid. ^ Ir (Shipan paste, cnr1 ) 1709, 1520, 1466 ', 1452, 1370, 1 359, 1 28 1, 1261, 1248, 1 222, 1 1 45, 1 0 9 0, 1 072,

999, 985, 775, 767, 748 ° m R Ρ ·-"?-Γ3- 海-丁某 -1H-眯 Beer-1-yl) Jiamou m # gu11 since very 1¾ certain M concentrated hydrochloric acid (0.8 ml ) Treat the suspension of Intermediate 19 (1.4s) in methanol (80ml) and stir the mixture for 18 hours. Μ 2N NaOH solution adjust the pH of the anticondensate to about 10 and then remove the formazan in vacuum The residue was diluted with water and washed with ethyl ether. The aqueous phase was neutralized with a saturated solution of vaporized ammonium and then extracted with ethyl acetate. The combined ethyl acetate extract was washed with brine and dried and concentrated to obtain this The title compound *-a white solid (322ml) ° Tlc system C (3: 2), Rf = 〇. 1. Verification results: C, 56.4; H, 4.3; N. 16.85% C23H24BrK ^ 0.7H20 calculation: C , 56.4; Η, 4.6; N, 1 7. 15% Μ 7 5- 「2-「 5-」「 2-Butsh-zai-bu-5 (methyl) -1 ^^ 眯 Favour -1 -Some) Jiamou 94- A4 (210X297y no) f (.................................. <; ............... it .............................. order ... ...... f ................. color {please «1 read the notes on the back and then fill this page} 201745 B6…: γ. · ** · · ··-_ ,， · ·-_ I | · —W · |, II .. ·. ^, ^. · »--» ·. _ ≪ ΜΒΜΜ—— _. 丨 丨 " 丨 _ ™ 丨"丨 丨» __ 'Five' Description of the invention (89) 1-2- 呆 #Guozi 1 cage 1-1Η- 四 Beer will intermediate 21 (0.27g) in tri-n-butyltin azide (2.5 g) The suspension in was heated to ~ 1501. After one and a half hours, the resulting dark solution was cooled to room temperature and diluted with an aqueous solution of MNaOH (1M, 5Qml) and then diluted with water to obtain an orange solution. 5 x50inl) this solution was washed and then use 2 (< 11 (: 丨 to acidify it to about?} 12. 12. The resulting suspension was extracted with dichloromethane (4 x 5〇1111> and the combined extract of 楗 擗After drying * and evaporating to give an orange gum (0.38g). Purified by reverse phase hplc to obtain the title compound, a light light color solid (0.117s) * melting point 220 ~ 225 it. Hp 1 c, D yna丨 a XC 1 β 6 0 A 8 w 2 5 cm X 4 1.4 i. D. Column * Mobile phase: acetonitrile / water (containing .1% / TFA), 9 to 81% acetonitrile for 25 minutes to detect human 230na. Detention time = 17.8 minutes. Example 8-?-"3-Sea-Only-Γ? -Dingmou-4- 氤 -5 (Hydroxymethine-Cyrazole-1-Very) -P-Cage # P 关 然 什 1 cage field except the room Warm sowing the intermediate 22 (270®g) in NaOH solution (2N, 2η1) and methanol (10η 丨) for 42 hours. The reaction mixture was diluted with Μ water, acidified with dilute hydrochloric acid to about ί> Η7 and the precipitate was collected And dried overnight in a vacuum oven at 501C. Obtained this title compound | a creamy solid (210 mg). Melting point 145t :. Tlc ether / acetic acid (100: 1), Rf = 0.59. Central Ministry of Economic Affairs Board printing (please read the notes on the back and then fill in this page) Example 9 5-"; >-" 5-""?-Dingmou-4-Radon-5- (hydroxymethyl) -11 ^ Sui Ying-1-Shi 1 Tian Shi-95- Jia 4 (210X 297S) ^ 01745 A6 B6 V. Description of invention (90) Printed by the Ministry of Economic Affairs of the Ministry of Economic Affairs-Jiamou-Jiahan 1 Honghong M2N HC1J8 A solution of the intermediate 26 (0.63g) in formazan (10 ml) and broadcast at room temperature for ~ 60 hours. The reaction mixture was neutralized with 2N Na 0 H to pH and ethyl acetate (4 X 15ml) ) Extracted. The combined organic extracts are dried, filtered and evaporated to an orange color This was purified by hplc to obtain the title compound (0.02 g) ·-a white powder. Hplc, (conditions such as Example 7) residence time = 18.1 minutes. NurS (D.MS0) 7.8 (liL, b "d), 7.7 ~ 7.8 (2H, m), 7.7 (1H_, ddd), 7.3 ~ 7.4 (2H_, 2xd), 7.0 (UL, brd), 5.3 (2IL, s), 4.35 (21L, s), 2.5 (2L. t) · 1.9 (3L, s), 1.45 (21, n), 1.2 (2HL, m), 0.88 (3L. t). Example 1 0 5-"?-" 5-"" 2-Ding Mou-4 -f [-5-(譠 g 某) -1 H-眯 邮 -1 -yl 1 methyl 1-2-tian argon-2- ¾ and 霹 晡 1 1 certain 1-1H- flash will azide A mixture of tri-n-butyltin (0.37 g) and intermediate 29 (0.23 s) was heated at 100 ° C. for 1 hour. The residue was treated with M methanol (4 ml) and then added to the HaOH solution (2N, 20 ml). The aqueous phase was washed with diethyl ether (2x 20 ml) and then acidified with concentrated hydrochloric acid to pH 1. This mixture was extracted with methane dichloride (3 x 20 ml) and the combined extracts were dried and evaporated to give a brown solid. This solid was purified by hplc to give a yellowish white solid (30mg), melting point 179 ° ~ 181 decomposition ° 11.111. ".5 (00 (: 13 + 1 drop 0» ^ 0) 7.9 (111,1) "() ), 7.7 ~ 7.8 (2H, a), 7.65 (1L, brt), 7.6 ΠΗ, brs), 7.4 (1H, d), 7.1 (1H_. Brd), 5.4 (2E_, s), 4.4 (2H, s ), 3.7 -96- (please read the precautions on the back and then huihui this page) • Install · * Order · _color · f 41210X297 ^^) A6 ___ B6 5. Description of the invention (91) (3H, s), 2.55 (21L, t), 1.48 (3H_, m), 1.3 (21L, m), 0.8 (3H., T) 〇Example 1 1 1-````3-Sea-2-``2- (111-Tetra beer -5- 某） 經 長 1-5- 荣 # 0 矣 _ 某 1 田 基 1-2-T 某 -4- 簠 -1H- 眯 映 -fi- 申定田 ester intermediate 30 (350 ng) Add to formazan (lOmUg concentrated HCl (0.1ml) and store this mixture at room temperature for 3 hours. Add concentrated CH1 and follow the mine for 1 hour. Add HaOH solution (2N) to about pH2 Most of the solvent was evaporated. The residue was partitioned between water and ether and the aqueous layer was extracted with ether. Acidified with HC1 (2Ν) to about pH3 and extracted with ethyl acetate. The organic extracts were combined, combined with water and brine Backwashed, dried and concentrated in vacuum This is a white foam. It is purified by chromatography to dissolve the system E (100: 5: 1) to give the title compound (204 mg), a white foam, melting point 110 ° ~ 1121 ° Tlc system E (100: 5: 1) · Rf 〇.31. Μ ...... 12, 1 「「 3-海 -9-r〇_ π hQ 秘 -5- 某 1¾ 某 1-5-呆 # 11 炣 晡 某 1 A Base 1-2 -Ding pen--1H- · Zhu-5-Methyl ethyl ester Central Economic Bureau of the Ministry of Economics, please read the precautions on the back before filling in this page) Order · Set the intermediate 3l (〇 .5g), a mixture of ethanol (15ml) and concentrated HCl (0.15ml) was broadcast at room temperature for 2 hours. 3 After this time, NaOH solution (2N) was added to adjust the pH of the mixture to about 9, and removed in vacuo Most of the solvents and residues were diluted with water and extracted with ether. K diluted HCl (2N) acidified the aqueous phase to about PH3 'and extracted with ethyl acetate. Combined with these organic extracts, K water and brine were washed back, After drying and concentration in vacuo, a white foam was obtained (A4 (210X297 g; A6 B6, V. Description of the invention (92) 272mg). It was purified by chromatography and dissolved in System E (100: 5: 1) to give the title compound as a white foam (181 mg). Melting point 99 ° ~ 101 1C. T. 1. C. System Ε (100: 5: 1) Rf 0.32. Example 1 3 1- "" 3-Zhang-2-"?-(1»-四 哞 -5-even 1 mining even 1--5-cafurofuryl 1 methyl even 1-2 -dingmou- 4- g-1H-眯 Wfe-Fi- 田 丁 酷 Add intermediate .3 2 (470 ms) to n-butan (10 ml) and concentrated HC1 (0.2 nl) and stir the mixture at room temperature for 3 days. Add sodium carbonate solution (1N) to about pHIO, and remove most of the solvent in vacuum. The residue is partitioned between water and ether. Add HC1 (2N) K to make the water layer about pH2, and separate the layer And add it to the water containing 1N carbonic acid 0 solution to about pH 12. M HC1 (2N) acidified this aqueous layer to about pH 3 and ethyl acetate extraction. Combine these extracts with 楗 extracts | dried Feng and in a vacuum The title compound was reduced to a white foam (263mg). Melting point 88 ° ~ 90t. Tlc system E (100: 5: 1), Rf 0.48. Example " 2-T -4- radon-1- " "2-ΠΗ- 四 Beer-5-a) ¾ a cage Long Lu @ 什 1 甲某 1-1H- 眯 映 -S-Shenlu solution of intermediate 18 (0.517g) in anhydrous THF (20nl) Cool to -70 = and use n-butan (0.86ml; 1.51M)-drop by drop. (Please read the notes on the back side before filling this page) • it. • Hit ... Printed by the Central Kneading Bureau of the Ministry of Economic Affairs (7 ammonium ester alcoholized acetochloric acid after the vinegar addition and the remaining portion of the bell. Dissolve in 20 doses 1) broadcast 5ΙΠ P hair (2 70 steam gg I and B Dissolve the vinegar and water in the warm acid room. Solution 1) This solution ΟΠ1 takes this (5 extraction temperature solution 1) solubilized om ί 2 -98- A 4 (210X 297 public hair) £ 01 * 745 A 6 B6-5 2. Description of the invention (93) Liquid. The combined phases are dried, dried and evaporated to obtain a foam (0.46 g). Dissolve it in formazan (10ml) and HC1 (0.25ml). The resulting solution was stored and stirred at room temperature for 3 hours and then adjusted to be alkaline to pH ~ 12 and the solvent was evaporated. The resulting aqueous phase was washed with ethyl zirconium (3 x 20ml) and then acidified to pH ~ 2 by M2N HC1. The liquid was extracted with ethyl acetate (3x 20ml) and the combined organic phase was dried, and evaporated to obtain a white powder. Crystallization from ethyl yeast yielded the title compound. A white powder (0.14 g ) »Melting point 2 0 9 ° ~ 21 0 1C ° Verification results: C, 60.4; Η, 4.4; H, 17.6 C24H21ClNe〇3 Calculation: C, 60.45; Η, 4.45; H, 17,4% Example 1 5 1- "" 3- 道-?-"2- (1> ^- Post-5-some) cage certain 1- 円-cage: ^^ »aiming for a Jiamou certain -4- radon-1H-imidazole-5-skewer 7, brewing intermediate 34 in ethyl yeast (10ml) and To the solution in THF (5.0 ml) was added concentrated HC1 (0.1 ml) and the resulting solution was stirred at room temperature for 1 hour. Sodium bicarbonate solution (1% aqueous solution) was added to pH 8.5 and the mixture was extracted with ether (35 ml) and the hungry layer was dried and concentrated in vacuo. The residue was purified by chromatography to extract E (100 : 10: 1) Dissolved to obtain the title compound (45.5ng), a white solid. T.l.c. System E (100: 10: 1), Rf 0.72. η.π.Γ.δ (250MHz, CDC13) 0.92 (3H, t), 2.0 (2H. quin), 4.2 (2H, q), 5.57 (2H. s), 5.91 (1H. d), 6.68 (1H , dt), 7.0 (1H, dd), 7.08 (1H. s), 7.2 (1H, d), 7.62 (2H, m), 7.88 (1H, dd), 8.0 (1H, -99 * A4 (210X 297 ^: ^) {Please read the precautions on the back and then fill out this page) • Install ·, type .. line. Printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs 2〇5 5 Α6 __ Β6., V. Description of invention ( 94) dd) 0 Example 1 fi 1-““ 3-Sea-2- “2- (1 幵-四 _-5- 某) Cage base 1-; 5- 芏 䜹 眹 某 1 申 某 卜 2- Butan-1 (F) ene-4-gas-1H-Zanyi-5-methyl ether A solution of potassium hydroxide (8.7 mg) in ethanol (310 Wl) was added to the product of Example 15 (45.0 mg ) Stir the resulting solution in water (69 / i 1) and at a pen temperature for 18 hours. Add HC1 (2H aqueous solution) to pH 2.5 and then add water (2 π Π and the resulting mixture K ethyl acetate (2 X 3ml) extraction. The combined phase was dried and concentrated in vacuo to give the title compound, a pale yellow solid (16.6 mg). Tlc system E (100: 10: 1), Rf 0.5 3 η. π.Γ.δ (250MHz, MeOD) 0.95 (3H, t), 2.18 (2H. dquin), 5. 70 (2H, s), 6.35 (1H, dt), 6.79 (1H, dt), 7.05 (1H, dd), 7.11 (1H, s), 7.25 (1H, d), 7.6 2 (1 H, m), 7.8 (2 Η, π). Example 1 7 l- "f3-bromazole-5-sm) phenyl 1- 5-¾ and a certain 1 a certain] -4-radon-2- Propyl-1H-methyl ether was treated with a suspension of intermediate 36 (380 mg) in methanol (40 inl) with concentrated HCl (0.3 ml) and the mixture was stirred for 4 hours. The M 2 NH a ΟΗ solution adjusted the mixture. To about Ρ Η 1 0 and then remove the methanol in a vacuum. Dilute with water (please read the precautions on the back before filling in this page) • ^. Printed by the Central Bureau of Standards of the Ministry of Economy ¾ Foam with thin vinegar foam. The material is extracted in vain. One-time extraction extracts ethyl ester to condense the ethyl acid and discards the acid. II castellate is dissolved in water and dried, and then washed with 1 washed PH water ether to salt B phase M with water and This extracts the phytochemical extract of the remaining acid residue 1 B this HC acid-100-A 4 (210X 2971 'hair) 201745 A6 B6

V. Description of the invention (9S white powders (163mg. This title compound is obtained from the recrystallization and crystallization of the yeast), melting point 167β ~ 17110. Tlc ether / acetic acid (100: 1), Rf = 0.5 ° MJLS. 1- "" 3- 璁-?-"?.-f1H-Siying-5-some) benzene.f-friend, and P Fuanhua 1 Jiamou 1-?-Ding Shi-1H- 眯 ΡΦ-4.5- Dimethyl sodium hydride 60%. Dispersion, 140 mg) was added to a solution of intermediate 38 (951 mg) in DMF (40 ml) and the resulting mixture was stirred at room temperature for 15 minutes and then the intermediate was added during 20 minutes 15 (3 g) was added in three portions, and the resulting mixture was stirred at room temperature for 72 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 ml) and water (30 ml). Ethyl acetate (2 x 20 inl) extracted the separated aqueous phase and then the combined organic phases were dried and concentrated in vacuo. By chromatography with petroleum bond / ether (9: 1) followed by 10% methanol dissolved in ether The crude adduct was recrystallized from a 15% aqueous solution of ethyl yeast and chromatographed to dissolve the title compound (137 mg). T.1.c. System E, Rf 0.51. Η.π .Γ.δ (250MHz, CDCU) 0.82 (3 H, t), 1.20 (6H. T), 1.27 (2H, sex), 1.52 (2H, quin), 2.3 (2H, t), 4.09 (2H, q), 4.19 (2H, q), 5.4 (2H .s), 6.93 (1H, dd), 7.13 (1H, s), 7.30 (1H, d), 7.65 (2H, m), 7.82 (1H, dd), 8.1 (2H, dd) 〇it A 咡 撡 咴 井 ¾- 5 (please fill in this page first «Notes on the moraine surface> ¾ .. • Line · Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 20ΓΜ5 a6 ______B6, five months issued B month Instructions (96j Stir the product of Example 18 (117 ms), potassium hydroxide (31.6 mg), ethyl yeast (1.14ml) and water (253w 1) at room temperature for 18 hours and then acidify it to PH4 with M2N HC1. Acetic acid Ethyl acetate (3 x 10 nl) extracted the resulting mixture and the combined organic phases were dried and condensed in vacuo to give the title compound (37 mg).-A white solid. Tlc is cyno-E (100: 10 : 1), Rf 0.05. Nmr5 (250MHz, MeOD) 0.80 (3H, t), 1.35 (4H, m), 3.0 (2H, m), 6.1 (2H, s), 7.25 (1H, q), 7.4 (2H. M). 7.71 (2H. M), 7.85 (1H, m), 7.92 (1H, dd) ® Example 20 5- "2-" 3-Pu-5-"" 2-Butyl-4- Nitrogen-5 (Methargonine, Very Bu, 1 Bu Thief __1_ Base 1 Tianmou 1-?-Cage # 0 # nanmou 1¾-yl 1-1H-Siyou The mixture of the product of Example 3 (780 mg) 'concentrated sulfuric acid (1.5 ml) and methanol (2 0 π 1) was heated to reflux overnight. Cool the reaction mixture and remove the solvent from the stomach. Dilute the residue with K water, add HaOH solution (2N) gpH3, and extract with ethyl acetate. Combine the extracts of 楗 楗 _W 发水 @ 洗, dried and concentrated in vacuo to obtain a pale yellow solid, which was recrystallized from ethyl alcohol, and recrystallized from ethanol to give the title compound, a yellow white solid ( 2 1 7 mg), melting point 2 1 3. ~ 2 1 5 t :. Tlc dichloromethane / methanol (l〇: l), Rf 0.47: (Please read the precautions on the back before filling this page) Niaojia 4 (210X 297 qiao) 01745 A6 B6 V. Description of the invention (97) Treat the solution in the intermediate (ml) with concentrated HC1 (0.25 ml) and stir at room temperature to pH ~ 12 and evaporate the solvent . Residue |) Partition K and re-M ethyl chain (4 X 25ml) 2N HC1 acidified pH ~ 2. Ethyl acetate floating liquid and the combined organic phase are dried and white foam. From the system A (l: l) and then steamed white powder (0.32 g) melt-adhesive 149 ° ~ hp 1 .c. (Conditions such as Example 53) residence time 122 46 (0.5 g) in formic acid (15 liquid 48 Hours. Add 2N NaOH in water (50ml) and ether (50 »1 to wash this aqueous solution and then use (3 X 3 0 b 1) to extract the milk. Suspend, filter and evaporate to obtain a yellowish title compound, a 1511: (decomposition). = 23.83 minutes. 1- "" 2- "〆 two pheasants four favors -5-)) 韣 韡 晡 certain 1 Jia certain 1-2-Ding certain -4- radon -1H-眯 _ -5-Tianlu stirred the mixture of intermediate 50 (426 mg) and tri-n-butyltin azide (500 mg) at 1601C under nitrogen for 24 hours. Allow the color solution to cool to 60t and then add aqueous sodium oxide solution (0.5M, 30il). Stir the mixture until the brown gum-like solid has dissolved and then wash with ethyl acetate (2x 50 ml). After passing through the turbid solution and then acidifying with dilute HC1 (to PHI; 2M, 10 inl) . The product is collected by filtration and dried in vacuum to obtain the title compound, a white powder (213mg), melting point 150 ~ 1601 (decomposition {please read the precautions of the counter before filling this page). nmr5 (De-DMS0) 8.07 (1H, dd), 7.91 (1H, dd), 7.69 (1H, t), 7.50 (1H, t), 7.23 (1H, t), 7.05 (1H, dd), 6.92 (1H, s), 5.69 (2H, s), 2.66 (2H, t), 1.55 (2H, m), 1.29 (2H, m). 0.80 (3H, t) = -103- f 4 (21〇X 297 Public notice) 101745 A6 __ B6 V. Description of invention (98) Printed by the Central Bureau of Economic Development of the Ministry of Economic Affairs 1-"" · Ί- 海 -2- "2- (1H- 四 Beer-5-some) cage 1 Fujing Suian-5-an 1-?-Butan-4-gas-1H-Xianyou-5-an 1 methyl alkali (ethyl meth) methyl ester intermediate 51 (400 mg) in ethanol (30 Concentrate HC1 (0.1 ml) was added to the suspension in ml) and the mixture was stored at room temperature for 3 hours. M dilute argon carbonate made the reaction mixture viscous and then taken with ether. Discard these ethers for extraction The saturated aqueous solution of M ammonium chloride was neutralized with the aqueous phase and then extracted with ethyl acetate. M. The combined organic extracts were washed with brine, dried and concentrated to obtain a colorless oil. The oil was developed by M ether and filtered. The title compound, a white powder (72mg), melting point 136 ° ~ 140t :. T.l.c. ether, Rf 0.4. Prepared in the same way: one case 24 1- "" 3-zhang-2- "2- (1 ^ 四 皞 -5- 某) 茏 某 1 cage well _-5-some 1 Jiamou 1-2-ding- 4-Radon-1H-Pyrazole-5-Methyl 1- (Ethylene argon) 7, 8¾, a colorless foam (2 3 3 mg). Tlc ethyl silver carp, Rf = 0.5 ° from intermediate 52 ( 0.484g) Concentrated HC1 (0.1 D1 1) in ethanol (30 ml). Example 2 5 1-"" _?-Compliance-?-"?-(1 Η-四喜 -5-基) 臏 Very 1 -5-caged pyranyl 1 methyl 1-?-Butan-4- radon-1Η- 眯 呻 -5-methyl in addition to caged methyl argon methyl ester dissolve the intermediate 51 (l.Og) in In the 1M HC1 solution of formazan and put the resulting solution at room temperature for 2 2 minutes. Then pour it into carbonic acid (please read the precautions of the noodles before filling this page). ¾. • J · • Line. A 4 (210X 297 ^ :, ¾) • A 6 B6 I: 0i745 5. Description of the invention (99; Hydrogen sodium (8%, 20ml), with ether (1 x 50ml, 2 x 25ml) and this aqueous phase It was then acidified to pH 3 using 2N HC1. The mixture was extracted with ethyl acetate (1 X 50nl, 2 X 25ml). The combined extracts were dried, filtered and evaporated to give the title compound, a white foam (488 mg ). Ir32 00 ~ 2300cm-1 UH, wide), 1737 cm-1 (ggCO) nmraCCDCU) 8.07 (1H, m), 7.94 (1H, dd), 7.84 (1H, m), 7.67 (2H, m), 7.55 ( 1H, t), 7.39 (2H, t), 7.23 (1H, d), 6.99 (2H, m), 6.03 (2H, s), (please read the notes on the back before writing this page) Ministry of Economic Affairs Central Standards Bureau printed 51 5.54 (2Η 9 S), 2.26 (2H, t), 1.48 (2H, m). 1.20 (2H, m). 0.80 (3H, t) ° Prepared in the same way: One MJIL · 1-"" '? -Chun-?-"2- (1Η- Four beer-5-某) 茏 华] -corpse-dubenfuran even] even 1-丁蒂 -4- 鰡 -1Η- Siao-5 -methylpyridine 1-(oxygen) 7. 3 mg 1 a white solid (450 mg) c I. R. 3200 2 400 cm-1 (NH), 1758 cm " 1 (carbonate c 0) , 1717 cm " 1 (ester C 0) n. A. R • δ (CDC 1 a) 8. 06 (1 Η, dd), 7.87 (1 Η 1 dd), 7.66 (2Η > m), 7.30 (1H. D), 7.06 (1H, d), 6.96 (1Η, dd) I 6.80 (1H, q), 5.63 and 5.50 (2Η »AB system) 4.14 (2Η» q) »2.34 (2H, t), 1 · 54 (3H, d), 1 • 52 (2Η. m), 1 .25 (3H, t), 1.24 (2H, m), 0.82 (3H, t from intermediate 54 (1 .0 s), and 1 M HC 1 solution in methanol (10ml -105- k. * Order ... line.

A 4 (21 OX A 6 B6 V. Description of the invention (100) t Please read the notes on the back first and then fill in this page) Example 27 1-[[3 -Bromo-2- [2- (1Η -tetrazole -5-yl.) Benyl] -5-benzofuranyl] methyl] -2-butyl-4-chloro-1H-quinazol-5-carboxylic acid [4- (aminocarbonyl) benzyl] methyl Vinegar, a yellowish white solid (70mg), melting point 152 ° ~ 156t !. Test results: C, 54.22; H, 3.90; H, 13.44% (: 3 "278" (: 1 «7〇4 calculation: C, 55 · 70; Η, 3.95; N, 14.20% from intermediate 55, and 1M HC1 in methanol dissolves fatigue (5 ml). Example 28 1 "" 3-zhang-2- "2- (1 ^ 四 鹿 -5- 某) 茏 某 1-5-cage and sullen 1 application A certain 1-2-Ding -4- Radon -1H-Shui Beer-5-Shen Jie 2- (Ν · Μ-dimethylamine acetone). Order,. 竦, the intermediate 56 (904 mg) in The solution in 1M HC1 solution (10m 丨) in methanol was left at room temperature for 30 minutes. Add water (50ml) and ethyl acetate (50ml) and extract the aqueous phase. Wash with ethyl acetate (50m1) and Saturated ammonium chloride (70 ml) was added. Aqueous NAOH (2M, ~ 5nl) was added to make the pH of this solution 6 and then extracted with ethyl acetate gg (50: nl). The organic extract was dried, filtered and Concentrated in vacuo to obtain a hammer foam of its ether (UOinl)) developed the title compound, a white powder (115 mg) · melting point 65 ° ~ 70¾ (decomposition). T. 1. c. Ethyl acetate, R f 0. 0 5 marks. The same way to control the dive: Once Μ 2 9 济 F 1-「U 草 -2-「 2-Μ Η-四 Beer-5 -Very) Raspberry] -F S-Fujing Xuanmu: Φ \ --- one · _ Central Accreditation Bureau printing -106- A · 4 (21〇Χ 297 ^ :, ¾ A 6 B6 ^ 01745 Fifth, the invention said in March (1〇 1) Base_1-?-Dingshi- / 1-mu-1 [眯 _-5-methan 2.3-dihydroxypropyl ester, a light yellow foam (457mg). Tlc ethyl chain / trifluoroacetic acid (100 : l) ,, Rf 0.1. II-. 3600 ~ 2600 (: 111-1 ^. 0H), 1707 cm-1 (ester C0) from intermediate 57 (1.98g) and HC1 1M solution in formazan ( 20ml). Example 3 0 [[3-Bromo-2- [2-(^ Η-tetrazol-5-yl) phenyl] -5-benzylfuranyl] methyl] -2-butyl-4 -Atmosphere-1H-triazole-5-carboxylic acid 2-methoxyethyl ester was added concentrated HC1 (0.1ml) to a solution of intermediate 58 (25 1 mg) in 2-methoxyethyl yeast (4ml) and in the room The mixture was stirred overnight at a warm temperature. The solution was purified by chromatography on silica gel (Sorbsil 60) and dissolved in dichloromethane / methanol (30: 1) to obtain the title compound * a colorless foam (〇.12g). Verification result: C , 52.4; H, 4.3; N, 13.1 C27H25BrClNe〇4 calculation: C, 52.9; H. 4.1; N. 13.7% Tlc dichloromethane / methanol (30: 1), Rf = 0.2. Example: η 海 -2-Γ?-(ΊΗ-azirazole-5-some) ¾some 1- 5 -cage pyranyl ~! Jiashi 1-?-丁某 -4-tent-1H-imibe -5-Methyl ether 1-Tian Shi ethyl. To intermediate 59 (770 Bg) was added human propan-2-ol (15 ml) and concentrated HC1 (0.3 ml). After stirring for 3 hours, isopropanol (5 ml) and concentrated HC1 (0.1 ml) were added and stirred overnight. Add sodium carbonate (IN) to about pH11 and remove most of the solvent in vacuum. The residue was partitioned between water and diethyl ether. 3 This aqueous layer was extracted with diethyl ether, acidified with dilute HC1 (2N) to about PHI * and then extracted with ethyl acetate. Combine this hungry extract and wash it back with brine • After drying -107- f 4 (210X 297 ^, ¾) (please read the precautions on the back before filling this page) -¾. • Green. Ministry of Economic Affairs Preparing for printing A6 ______ V. Description of invention α〇2) Dry and concentrate in vacuum to obtain a light yellow glue. This gel was purified by chromatography and dissolved by System E (100: 5: 1) to give the title compound as a white foam (273 ° C), melting point 105 ~ 106 ° (decomposition). T.l.c. System E (100: 5: 1), Rf 0.24. m 12- "" 3-Mo-2- "2-ΠΗ-四 Beer-5-some) cage certain 1-5-¾ Pinggu Nao] Tian Shi 1-2-Dingmou-4- 镢 -1H- Zidazole-S-methyl formate intermediate 60 (240 mg) was added with human formazan (l〇nl) and HCI (〇2 u). After stirring at room temperature for 3 hours, Na 0 Η (2 N ) To about ρ Η 1 2 and then most of the solvent is removed in vacuo. This residue is partitioned between water and ether < > this aqueous layer is extracted with ether and acidified with dilute HC1 (2Ν) to about PH2 and then extracted with ethyl acetate. The organic extracts were combined, backwashed with brine, dried and concentrated in vacuo to obtain a white foam. The foam was purified by chromatography using system E (75: 25: 1) This compound was dissolved, a white foam (131 mg), melting point 131 ° ~ 133C. Tlc system Ε (75: 25: 1), Rf 0.26. Example 1- "" 1-"[^-Bromo-2- "2- (1 卜 四 映 -5- 某) Stay a certain 1-^-cage wells and even 1 Tian mou 2-butyl-4-radon-1Η- 眯 azole-5-certain 1 雔 某 1DH · Dizzy pair intermediate 61 (1.25) was added formazan (4〇! 111) and concentrated 1101 (〇.11111). After stirring at room temperature for 4 hours. Add NaOH (2N) to about PH11 and then in the true Most of the solvent was removed in the process. The residue was partitioned between water and ether. The aqueous layer was re-extracted with ketene, acidified to approximately pH 1 with dilute HC1 (2Ν) and then extracted with ethyl acetate. The extract is backwashed with water, dried and concentrated in vacuo to obtain the title compound, a white foam bed (834-108- (please read the precautions on the back before filling in this page). A4 (210X 297W) A6 B6 ^ 01745 5. Description of the invention (103) f Please read the precautions on the back before filling in this page) in g), melting point 1 2 0 ° ～ 1 2 2 1C. T. 1 . c. It is E (75: 25: 1), Rf 0.25.

Prepared in the same way: an example: U 1-m- 海 -2--四 Beer-5-some) ¾ 某 1-5- ¾ # P 关 然 某 1 甲某 Ί-?-丁某 -4- 氪 -N -A certain -1H-squinting -5- A conversion, a white foam (915 mg), melting point 218 ° ~ 2201C. T.l.c. System E (75: 25: 1), Rf 0.34. From intermediate 62 (1.32g) and a solution of HCl (lml) in methanol (40ml) 0 Μ. 3-5. -Subscribe. Zhang-2- "2- (1Η- 四喜 -5- based well 眹Nangshi 1 Jiamou 1-2 -butmou-4-gas-NN-dimethylform-1H-imidazole-5-metenamide, a white foam (754 mg), melting point 216 ° ~ 218 ° C. T. 1. c. System E (7 5 ·· 2 5 ·· 1), R f 0. 2 8. From the solution of intermediate 63 (1.15g) in HC1 in methanol (40ml). Example J. 1- " ".?-海-?-" 2- (1 »-Tetraber-5-yl) 茏 even 1-5- 茏 眏 眹 基基基 1 1- even 1-? -Butyl- 4- M-H-A -1H- 眯 _-5-methyl methamine, a white foam (70.7 mg). Tlc ether / methanol (98: 2), Rf = 0.10: η.πι.Γ.δ (2 50 MHz, CDCU). 0.85 (3H, t), 1.20 (2H, printed by the Central Standards Bureau of the Ministry of Economic Affairs), 1.50 (2H, t), 2.4 (2H, t), 2.55 (3H, d), 3.28 (2H, s ), 5.20 (2H, s), 5.75 (1H, q), 6.90 (1H, -10 9- T4 (210X 297 ^, ¾) 01 * 745 A 6 B6 V. Description of the invention (i〇4) Central Ministry of Economic Affairs Standard Bureau printing dd), 7.02 (1H, s), 7.25 (1H, m), 7.65 (1H, m), 7.85 (1H, m), 8.10 (1H, m). From the intermediate 64 (lllg) in HC1 (0.1 ml) in methanol (5 ml) Solution. M 2 7 1- "" 3-chun-2- "2- (1H-four _-5-some) ¾ kib 5 '-¾ and 眹 晡] Jiamou 1-2-Dingmou-4 -Gas-N -Ethyl-1H -Small beer -F5 -Metal reduction »-A white solid (655mg). Τ · 1.c. Ether, Rf = 0 · 17 ° Verification results: C, 53.4; Η, 4.5; Ν, 16.95 (: 2eH25N7〇2ClBr calculation: C, 53.6; Η, 4.3; Ν, 16.95% from intermediate 65 (1.0g) in HC1 (0.5 ηιΠ in methanol (30ml) solution 0 Example 38 1- "" 3-zhang-?-"2-("-四 Beer-5-yl) 茏 某 1-5- cage # 眹 某 1 甲某] -4-radon-2-ethane -1H-slender beer -5-Jiawu, a white solid (5'0 7 rag), melting point 158 ° ~ 160 ° C. T. 1 · c. System E (7 5: 2 5: 1), R f = 0 · 25. From a solution of intermediate 70 (1.0 mg) in HC1 (0.6 nil) in methanol (30ral). m 3 9 1-「） 3_? 臭 _2-.2- (1 [{-四 鹿 -5_ 基） Cage base ~ ~ 5 -¾ and Ying Nangshijiamou '-4 -Ga-2- Yishi-N- Jiamou-1 Η-眯 Beer-5-Chuan Pengchen (2 5 5 mg) = T. 1. C. Yi Mi -R f = 0. 1 3: (Please read the notes on the back first Please fill out this page again.) • Insects * * Order ... Line · A 4 (210X 297 male; __- 110-_ A 6 B6 V. Description of invention i〇5) Ir · (liquid stone press) 3200 ~ 2730, 1 652, 1546 and 1462 cm · 1. From the solution of intermediate 71 (440 mg) in HC1 (0.4 m 丨) in methanol (20 ml). Example 40 Bu "" 3-Sea-2- "2- (1 ^ 4 Favour -S-certain) ¾ 1-5 1- 茏 # 眹 某 1 Shenmou 1- 2-Ding -1H-眯 _-5-甲 _ (1 RQjng), melting point 1 δ 2. ~ 1 8 4 t. '[• 1. (:. dichloro'methane / methanol / acetic acid (10: 1: 1), 1 ^ 0.33. From the intermediate 75 (430ms) in HC1 (0.4 ml) in methanol (15ml) Solution. M 41 1-"".?-张-?-"?-(^-四 Beer-5- 某) 茏 某] -5-cage and whisper a certain 1 a certain 1 -2-butyl-1 H-slender beer-4-carbohydrate, a light yellow solid (186rag), melting point 1 7 0 ~ 1 7 2 3C: Ding. 1. (: dichloromethane / methanol / acetic acid (10: 1: 1), ^ 0.31. From the intermediate 7 6 (420mg) in HC1 (0.4ml) in methanol (15ml). Example 42-Hai- 2- "2- (1H-four beer-fi-a certain) ¾ base] -5-cage # 1! Nang 1 1 even 1-4-gas prophyl -H-1 certain 1H-squint beer 5-methyl pseudomethamine, a white solid U80mg), melting point 109 ° ~ 116_ €. T. 1. C. B @ / §1 Acid (1 0 0: 1), R f 0 · 3 6. Printed by the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back side before filling in this page) from intermediate 77 (1.4g) in HC1 (1 ml) in formazan (60 ml). -1 1 1-• f 4 (210X 297 A, ¾) 201745 A 6 B6 V. Description of invention (106) Printed example of the Central Bureau of Economic Development of the Ministry of Economic Affairs 43 1-「「 Π2- 「2- (1Η-四 _-5-some) ¾ certain-¾ and 霹 晡 certain 1 甲某 1--Ding certain-4-gas-N-S Bing certain -1H-squint Beer-methyl acetamide (0.74 g). T.l.c. Ether · Rf = 0.7. Verification results: C, 54.3; H, 4.6; N, '16 .4 C27H27N7〇2BrCl calculation: C, 54.3; Η, 4.5; 16.1% from intermediate 78 (1.15g) in HC1 (0.5 ml) in methanol (35ml) Of solution. Example 44 1- "" 3-zhang-2-1 ~ 2- (~ ^ -tetrabromo-5-yl) yoke 11-! 5-cage and yawn a certain 1 methyl 1-2-butan-4 -Iodine-1H -Pan Fang-5-Mg pound ', a white powder (350 mg), melting point 184 ° ~ 1891C. Tlc ether, Rf = 0.1. From intermediate 82 (1.0 mg) in HC1 (0.1 ml) A solution in formazan (30ml). Example 45 Hai- -tetrabromo-5-yl) ¾ certain 1-5-thiopyranyl 1 methyl certain 1-2-butan-4-trifluoromethyl-1H -眯 ΡΦ-5 -Methylene, a white solid (12mg), melting point 144 ° ~ 149t. T. 1 · c · petroleum ether / ether (1: 1), R f = 0 · 1. From the intermediate 84 ( 210mg) in HC1 (0.1 ml) in A§1 (20: al): Example 4B -112- f 4 (210X 297 ^ '^) tPlease read the notes on the back before filling this page) • Wo _, order. -Green · A 6 _ B6 l., V. Description of the invention (107, 1-““ 3- 海-?-“2- (11 ^ -tetrazole-5-some) cage certain 1- ! ^-茏 和 眡 晡 某 1 Shenmou 1-2 -Dingmou-4- Jiamou-1H-Pan Favor -5-Shen Peng • Gasification g (1: 1) .— a light yellow powder (0.119g ), Melting point 179 ° ~ 181 it. H.p.1.c. (conditions such as Example 5 3) residence time 16.8 minutes from intermediate 86 (0.25mg) in HC1 in methanol (l Oml). Example 47 '痗--Dingmou-4.5-two radon-1H-squinting -1-some 1 Shenmou 1- ?.-four very) ¾ certain 1 well 0 燣 三 三乙 乙The antimony lick was used to treat the intermediate 8 8 (0.85 g) suspension in methanol (2 5 m 1) and M 2 NHC 1 (5 m 1). Add THF (1 0 m 1) and at room temperature Stir the moist liquid for 6 2 hours. Remove the solvent in vacuo to obtain a white solid and partition it between water (25ml) and dichloromethane (4xl5! Nl). @ 合 的 湯湯 Extract was dried and In vacuo, a white solid was obtained * dissolve it in acetonitrile (10 ml) and add trifluoroacetic acid (two drops). The precipitate obtained from the "over" obtained the title compound (0.256g), a white solid, melting point 1973 ~ 1991C. N. U. ". Δ (DMS 0 d β), 7 _ 7 5 ~ 8. 0 (m, 4 Η), 7.5 8 (d, 1 Η), 7.27 (d, 1Η), 7.13 (dd, 1H), 5.42 (brs, 2H), 2.69 (t, 2H), i.55 (m, 2H), 1.3 (m, 2H), 0.85 (t, 3H). Example 48 1-````2 -Zhang-?-"2- (1 ^ 四 Beer-5- very) cage base 1-5--cage and squint even 1 Jiashi i-2-Ding Shi-4-Qi-1 Η-眯 Beer-5 -Printed by the Central Bureau of the Ministry of Economic Affairs Please fill in this page if you want to fill in the details) -Order the intermediate 9 7 (1 3 0 mg) and glacial acetic acid / concentrated HC 1 Π: 1) (5 m 1) at reflux for 2.5 hours = adding 5 NN a 0 Η makes the solution alkaline to p Η 1 0 and then extracts with a second puzzle (3 χ 1 5 ml) this aqueous phase it ft to ρ Η 5 (-113- A · 4 (210Χ 297Ί) ^ 〇Γ / 45 A 6 _Β6 Fifth, the invention description Ci〇8) 2H HC1) and then extracted with ethyl acetate and combined with the extract of the barberry dried and concentrated in vacuo to give the title compound (83mg), a shallow Creamy body. T.l.c. petroleum ether / ether / acetic acid / formaldehyde (50: 50: 1: 1), Rf = 0.07. η.πι.Γ.δ (250MHz, DHS〇-de), 0.85 (3H, t), 1.25 (2H, quin), 1.51 (2H, sex), 2.55 (2H, t) ', 3.55 (2H, s ), 5.35 (2H, s), 7.07 (2H. Dd), 7.2 (1H, d), 7.5 (1H, d), 7.78 (2H, m), 7.9 (1H, dd), 7.98 (1H, m) ° Example 49-Siyi-5-some) ¾ 某 1-5- 茏 # 11 尖 晡 某 1 甲某 Ί-2-丁某 -4- 气 -1H- 眯 映 -5-ethetyl ethyl ester will be 洌A solution of 48 product (100 mg) in ethanol (10 ml) and concentrated HC1 U drops) was heated at reflux for 2 hours. After this time, anhydrous magnesium sulfate (200 mg) was added and the reaction mixture was heated at reflux for 7 hours. By (please read the precautions on the back before filling this page) Printed by the Central Standards Bureau of the Ministry of Economic Affairs m Remove the solids and the filtrate is concentrated in vacuo c The residue is purified by column chromatography methylene chloride / ethanol / acetic acid ( 96: 2: 2) Dissociated to give this title compound »A colorless glass (14η g) 0 τ. 1. C. Dichloromethane / methanol (98: 2) · R f =: 0.55 ° η. M. R .δ (CDC 1 3 250MHz), 0.78 (3H »t), 1.12 (3H» t) * 1.3 (4Η, c), 2.0 (2Η, t), 3.33 (2H, s), 4. 0 (2H, q), 5.15 (2H, s), 6.95 (2H, m), 7.30 (1H, m), 7.65 (2H, t), 7.88 (1H, dd), 8. 0 ( 1 H, dd). Example 5 0 1-Γ6 -r 3- / S-?-Γ?-(1 Η-四 呻 -5-基) Benhua

6 6 A B

V. Description of the invention ατ〇9) 1-? -Dingmou-4-radon-1H -Zanyi-5-jialu Stir the intermediate 94 (0.58) at 16〇10〇and! 1 Nitrid; 1 £ ~ (0.7 g) mixture for 1.5 hours. After cooling, the viscosity was partitioned between sodium chloride (20ml) and ether (15ml). The separated water (& 20ial) was washed again and then acidified to pHI with 2N HC1. The resulting compound was dried to obtain the title compound, a solid (38, 3mgP ~ 140Ό nmrSUMSO), 7.95 (π, 1H), 7.88 (m, 1H), (m, 2H), 7.52 (d, 1H), 7.23 (brs, 1H). 7.03 1H), 5.72 (brs, 2H), 2.64 (t, 2H), 1.55 (m, 1.3 (π, 2H), 0.82 (t, 3H).

St.51. 1-"" 3-Sea-; >-"2- (Dihydroglucose even) 茏 某] -5-Cage # 〇 鎊 然 某 1Methyl 12_1 丁什 -4- 气 -1H-眯 _-5-Jiapei Ministry of Economic Affairs, printing butyl tin 1NS oxyethyl ether (solid dot 132. 7.75 (dd, 2H), (please read the note on the back of the leap first and then write the book) Λπ. Sodium sulfite (5.6g) and sodium dihydrogen phosphate (5.6s) in water (30inl) were added to intermediate 102 (3.364g), 2-methyl-2-butene (2N; 37ml) and tert-butanol (40m 丨) in HTFUOml) at room temperature under nitrogen mixture. The mixture was stirred for 2.5 hours • Then the organic solvent was evaporated. The residue was extracted with ethyl acetate (3 x 50ral), and the combined extract K brine ( lx 100ml) washed and dried. Evaporated to remove the solvent and the residue was purified by column chromatography to dissolve the system E (2 0 0: 2 5: 1) to obtain a foam, which was dissolved in ethanol (ΙΟπιΙ). Crystallized This title compound M is a colorless crystallite form (2.7g), melting point 148 ° ~ 150t. T.1.c. It is E (2 0 0: 2 5: 1), R f = 0.5 0. -1 1 5 * ^ 4 (210X 297 ^: ^) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs A 6 B6 Fifth, the invention description (iio) MJlL sea-carboxy cage certain) -5-¾ and the eye of a certain 1 Shenmoubu 2-Dingmou-4-gas _1H_ 味 Beer ~ 5_ Jiadijiang sodium hydroxide (89ms ) Add to the suspension of the product of Example 51 (0.5g) in ethyl yeast (5ml) in water (0.2ml). Heat the solution under reflux for 16 hours * cold, then evaporate in vacuum. The material was dissolved in water (5 m 1), and HC1 (2N; 1 ml) was added drop by drop to produce a precipitate of the title compound. It was filtered out of Μ water (2x5ml), washed and dried to obtain the title compound, a colorless solid (391mg), melting point 148 ° ~ 152Ό. Tlc system E (25: 5: 0.2), Rf = 0.45. Example 53 N- "" 1-m -chun- -four Kit-y)隹 安 某 1 田某 1-? -Butmou-4-gas-1H-眯 益 -5- 某 1 甲某] 醻 胺 Place a solution of the intermediate 105 (375mg) in methanolic hydrochloric acid (1M, 10ml) in Room temperature for 3 hours. Sodium hydroxide aqueous solution (2M, 6ml) and water (20ml) were added. The mixture was washed with diethyl ether (2x50ml), and then acidified with aqueous hydrochloric acid (2M, 10ml). Methyl ethyl acetate (20 m 1) extracted the turbid solution and the extract was dried, filtered and evaporated in vacuo to prepare a white powder (218 mg) with ether, melting point 1483 ~ 150t: (decomposition). h.p.I.c. Dynaniax-60A / solvent A: water (0.05TFA), solvent B: acetonitrile: water (9: 1 + 0.05% TFA) Gradient: 10 ~ 90% in 25 minutes residence time = 18.65 minutes. Prepare food in the same way: _t Please read the precautions on the back before writing this page). Install ·-Order. • Green. -116- A 4 (210X 297S issued) 201 Material 5 A 6 _ B6 V. Description of the invention (111) Example 54 "" 1-"3-Zhang-2-" 2-"(1 Η-四 Beer-5-) cage 5-stay and murmur 1 1 Jia 1-2-Ding -4-radon-1Η- 皯 皞 -5-some 1 a certain] methyl ester of anti-application. A white powder (275 mg), melting point 183 ° ~ 185 ΤΜ decomposition). ^! ^. 1. <:. ( Conditions such as Example 53) Retention time = 21.72 minutes. From the solution of the intermediate 10 6 (40 3rag) in methanolic hydrochloric acid UM, '10 ml). Μ_ϋ -Mo_2_ "2 _" (1Η " * 四 Beer-5-基基]-5- ¾ Pycnogenyl thiophene 1-2-butan-4- 4-M-1H-squinted beer -5- 1 jia 1 yu amine, a yellowish white solid (91 mg ), Melting point 148 ° ~ 152¾. H.p.1.c. (conditions such as Example 5 3) residence time = 19.0 2 minutes. From the intermediate 107 (397mg) in methanolic hydrochloric acid (1M, 10ml) Solution. Example 56 "" 1-"" 3-Nao-2- "2-" (1 [| -Tetramer-5-yl 1 Mo certain 1-5-dibenzopyridine even 1 Methyl 1-2- Ding Mou-4-qi-1H-Shui Beer-5-Very 1 Jiamou 1 hospital, a yellowish white Powder (91 mg), melting point 2063 ~ 210t: h.p.1.c. (conditions such as Xuan 5 3) residence time = 17.0 minutes. From intermediate 108 (154mg) in methanolic hydrochloric acid (1M, 6ml) Example 57 1-"" 3- (1 "-Dimethylethyl Berry) -2-"?-"(1 only-tetrabromo-5-yl) azulyl 1--5-¾ Very] Jiamou] -2-Butyl-4- 4-M -1H-Shuibe-5-jiapi The intermediate was processed according to the method of Example 3 1 1 4 (0.68 s) in the azide-Ministry of Economic Affairs Printed by the Central Kneading Bureau (please read the precautions on the back before filling in this page). The floating compound in butyl tin (4 g) gives this title compound, a light yellow powder (0.24 s), point 1 2 9 3 ～ 1 3 2 t: -11 · 7-A4 (210X 297 ^: ^) ^ 01745 A6 B6 V. Description of the invention (112) hplc (conditions such as example 53) Retention time = 25.39 minutes.

Example W 5- "2-" Only- "2-Dingmou-5-Gas-4- (Hua with base) -1 Bu Xiaomo-1-an"-? 1 I. 1- (二甲 乃 很) 1-2-¾ Do not disturb a solution of 1-4, prefer the treatment of the suspension of intermediate 115 (0.25g) in n-butyl tin azide (3g) according to the method of Example 3. Developed with hexane This title compound, a light yellow powder (0.087 mg), melting point 1243 ~ 127C. II. 9.1. ≪: (Condition as in Example 53) Retention time = 21.10 minutes. Example 1- "5-" 3-gas- ?-"2- (1 []-四 _-5- 基） Cage 1 茏 井 眹 某 1 A certain 1-2 -Ding certain -4- radon-1Η-眯 Beer-5 -formic acid will be concentrated hydrochloric acid (1.5ml)-Add dropwise a solution of intermediate 118 (0.76 g) in methanol (40 m 1) under stirring. After stirring for 4 hours, make this solution with 2 N sodium hydroxide Alkaline to PH12 · Then Methyl acetate (2 X 80 πι 1 wash). The separated aqueous layer was carefully acidified with hydrochloric acid and then extracted with Methyl acetate (2 X80nl). The combined organic extracts were dried and in vacuum Concentrate to obtain a yellow oil which is azeotroped with toluene (3 x 50ml) and dried under vacuum at 55 for 6 hours to obtain the title compound (0.265 g), a Yellow solid, melting point 1 1 7 = ~ 1 2 1 SC. (Please read the precautions on the back before filling in this page). Xiang ·, order-line · Printed by the Central Bureau of Standards of the Ministry of Economy · Ｍ beer four Inei I 5-very basic m. R •. Δ (DMSO), 7., 78 ~ 7.98 (m, 3H),, 7.55 (d, 1H 08 ~ 7.3 (m, 3H),, 5 '74 (br 's, 2H), 2.68 (t, 2H) 55 (m. 2H), 1.3 (m, 2H), 0.83 (t,, 3H) 〇 A 4 (210Χ 297 伂 发) 01745 A6 B6 V. Description of the invention (113) The Central Business Administration of the Ministry of Economic Affairs printed 1i Hua l-2-butan-1 (7.)-IEHUA ~ 4 ~ S-Ιϋ_imidazole_ 5 _ It is said to be stirred at room temperature Intermediate 1 2 0 (100 mg) and concentrated hydrochloric acid (0 • 05m 1) in ethyl alcohol (5 ml) and THF (2ml) solution for 3 hours. Add sodium bicarbonate 1% aqueous solution to pH 9 and The solvent was removed in vacuo. This crude separation was purified by column chromatography Μ 糸 Line E (100: 10: 1) dissolved to give the title compound (25mg), a white solid 0 ·, T · 1. C. Petroleum Ether / ether / acetic acid / methanol (100: 100: 1: 1) f Rf = 0.59 η . IQ. Γ. Δ (CDC 1 3 t 250HHz) 0.90 (3Η, t) »1.21 (3H, t), 2.0 (2H, qu 1 η), 4.2 (2Η, q), 5.57 (2H, d, J = 16Hz), 6.68 (1Η, dt, J = 16.7Hz), 7.0 (1Η, dd), 7.09 (1Η, S), 7.25 (1H, m), 7.62 (2H t C) »7.85 (1H, dd), 8.0 (1H, dd) c Make the face in the same way: — Example fil 1-" "3-Clear-P- Γ2- (1 Η- Four beer-a) Hongmou 1_ 5 -¾ and murmured a Jiahua 1-?-Pent-1 (Z)-enehua-4-M-1 Η-眯 Κϋ-5-A name, 丨 醅, A white solid (37 mg) 0 η. M. Γ. Δ (CDC 1 3 * 250MHz) 0.90 (3 Η, t) t 1. 30 (3Η, t) 1 1. 42 (2H, se X), 2.59 (2Η, dq), 4.27 (2Η, q), 5.7 (2H, s), 6.1 1 (1 H, dt, J = 12.?H z) * 6.3 (1 Η , Dt, J = 12.1 Η z), 7 .0 ~ 8 .0 (c, 7H Bu T. 1. C. Petroleum Mystery / B Mystery / Acetic Acid / A §1 (1 0 0: 1 0 0: 1 * · 1) 1 Rf = 0. 61 -119- t, please read the precautions on the back first and then fill out this page) .¾. • Hit. Line. A 4 ( 210X_ 297 Public) £, 01745 A 6 B6 V. Description of the invention αl4) From the intermediate 121 (100 mg) and concentrated HC1 (0.05 ml) in ethanol (5 ml) and T H F (2 m 1). Example 62 1-"" 3-Methyl-2- "2-Gate ^ Four beer-?;-某） 經 某 1-5- 線 # 眹 _ 某 1 甲某] -2- 丁某 -4- Qi-1H- 眯 _-5-Tanya treated the mixture of intermediate 123 (380 mg) and tri-n-butyltin azide (0.6 g) according to the method of Example 3 to obtain the title compound, a white powder (1 8 0 mg) * Melting point 1 4 0 ~ 1 4 4 t :. Verification results: C 57.23; Η, 4.56; N, 15.83% C25Hz3NeO < iCl. O.84H2O calculation: C, 57.51; Η, 4 · 7δ; N, 16.10% water test result 2.91% H2〇s〇.84 mole H20 Example 63 "2-" (1Η-tetrazol-5-yl) ¾, ^-cage well 眹 某] A 2-Dingmou-4-qi-1H-Shuibei-5-Jiawu (+)-Chuan M-1- < Please read the notes on the back before filling this page) • 汊 ·. 定 * Ministry of Economic Affairs X Central Authority's Indica Lime-Ester ... The solution of intermediate 124 (761mg) in (±) -propoxy-2-propanol (10ml) and concentrated hydrochloric acid (5 drops) was left at room temperature 2 hours. Add aqueous sodium bicarbonate solution (1%, 50ml) and M ether (2 x 30ml) to wash the mixture, then M hydrochloric acid (2M) is re-acidified to pHI. The turbidity is extracted with ethyl acetate (20m 丨) Solution, and the organic extract was washed with hydrochloric acid (2M, 3 x50ml), dried with hydroxy, filtered and concentrated in vacuo. A yellowish white foam (4 4 1 π g) ° η was contracted. "· Δ ( de DMS0), 7.77 ～ 8.0 (4H, 2xm), 7.55 (1H, -120--绛. A 4 (210X 297 public) 01745 A6 B6 5. Description of the invention (115) d), 7.20 (1H, d) , 7.10 (1H, dd), 5.71 (2H, s), 5.15 (1H, m), 3.4 (2H + HZ0, d), 3.22 (3H, s), 2.7 (2H, t), 1.58 (2H, i ), 1.31 (2H, m), 1.18 (3H, d), 0.85 (3H). Hplc Dynaiax-60A Solvent A: H20 (0.0 5 ^ TFA), Solvent B: CH3C, N: H20 (9: 1 + 0.05% TFA) 10 to 90% B-2 0 minutes; 90 to 100% B 2 minutes; 100 to 10% B 4 minutes residence time = 28.95 minutes. Example B4 Zhang--4 0Φ-5-yl) 茏 # 1- 5-¾ and squint] Jiamou,:-2-butmou-5-gas-anizole-4 -methylpyridine according to the method of Example 3 Treatment of a mixture of intermediate 126 (91: ng) and tri-n-butyltin gave the title compound (42mg) as a white solid. (Please read the precautions on the back before filling in this page) • Order · Economics Printed by the Central Standards Bureau $ l I. 1. C. Dichloromethane / ethanol / acetic acid (96: 2: 2), R f = 0.08c η. Ώ. Γ. δ (250MH Z CDC 1 3 + MDS0de) 0. 88 (3H, t), 1. .32 (2Η, S ex), 1.75 (2H), 2.75 (2H 1 t), 5. 28 (2H »S) > 6 · 8 ~ 8 · 0 (7H, m) ° Example 65 1-Γ Γ 3-bromo-2 -Γ2- Γ [ί 三 气 甲 很） 碏 见 华 1 m & ] Cage even 1-f) * -study and squeeze 1 methyl] -2 -butyl g -1H-sui-5- Jiafang 7, the intermediate 1 30 (0.15 g) and triethyl A solution of amine (0.082 ml) in anhydrous dichloromethane (10m 1) was cooled in an ice bath ^ ll to -8 0 3C and K trifluorocarboxylic acid (-121- 'f 4 (210X 297 ^' ^) five 1. Description of the invention (116) A 6 Β6 The solution of the triflic anhydride in trihydromethane 1M solution (0.42ml) is treated drop by drop. After 1 hour, add triethylamine (0.082ml) and trifluoroformic acid (tr if 1 ic) anhydride (0.42 ml) and mix in a 70C mixture. The reaction is complete in another half hour. K water (3 ml) extinguishes the mixture at 70 1C and warms to room temperature. The organic phase was separated, dried, filtered and evaporated to give an orange gum (0.22 g). The purified ketone'A (1: 2) was purified by column chromatography to obtain the title compound, a cream solid (0.153g), melting point 158 ° ~ 159T :. Τ · 1 · c · System A (1: 1), R f 0 · 4 0. Example Rfi 1-"" 2-Sea-?-"? .-" "(Sanqijiamou) 碏 醯 某 1 defense: cage base 1-5-- 苤 乹 _ 某 1 申 某 1-?-Ding A-gas-1H-imidazole d-methoxel K2H NaOH treatment solution of the product of Example 65 in formazan and heated to reflux. Continue heating for 2 hours and then cool to room temperature. Use 2H HC 丨 to acidify the reaction to p Η ~ 2 and extracted with ethyl acetate. The combined organic extracts were dried, washed and evaporated to give a yellowish white solid (0.098g). It was recrystallized from methanol aqueous solution to obtain the title compound, a cream Color solid (5 1 in g), melting point 1 6 1 ~ 1 6 2. Verification results: C, 45.4; H, 3.2; N, 6.4 C24H2〇B "C1F3N3〇5S calculation: C, 45.4; Η, 3.2; N , 6.6% Example 6 7 1-"" .Ί-海-?-"?-" Π Η-四 邮 -S-某） 沄 什 1-5-粄 井 眹 某 'Jiashi 1-?-Ding A certain 4-propyl-1Η- 眯 Beer-5-methylaureonine hydrochloric acid (1M in methanol) was added to the intermediate 134 (0.85s) in ethanol (please read the precautions on the back before filling this page ) .Ordered • 蟓-A 4 (210X 297 异 发; __- 122- ^ 01 ^ 45 Ministry of Economic Affairs Central Bureau of Preservation and Printing A 6 B6 5. The solution in the description of invention (117) (3 ml). Stir the solution at room temperature for 30 minutes and then pour it into a saturated aqueous solution of sodium bicarbonate. After washing the mixture for 15 minutes with ethyl ether (3 X 30 ml) It was acidified to pH 4 ~ 5 by adding 2N hydrochloric acid. Then the mixture was extracted with ethyl acetate (3 x 30 inl). The combined extract was dried, filtered and evaporated to obtain the title compound (0.30 8) ° hplc column Dynamax / 60A Cis Solvent A: H20 + 0.05% TFA Solvent B: Acetonitrile + H20 (9: 1) + 0.05% TFA Gradient hybridization 10 ~ 90% B 25 dwell time = 2 1.1 minutes. 7.93 (1H, m), 7.66 ~ 7.73 (2 H_, m). 7.3 (111, d), 6.89 ~ 6.95 (2 [L, a), 5.49 (2 L, s), 4.12 (2 l ·, Q), 2.38 ～ 2.4δ (2IL. N), 1.83 ～ 1.92 (21L m), 1.0 ～ 1.42 (9 H_, m), 0.7 5 (3 L, t), 0. 6 (3 Lt). Example fi only _ -5- very) 罙 Very ,: -5-stupid furanyl longi 1-?-Ding Shi-4-propy-iH-succinyl beer-5-carboxylic acid will be Example 67 The product (220mg) was dissolved in formazan (1 ^ 1). Add a 2N aqueous solution of sodium oxynitride (1 0 m U followed by methanol (~ 1 ® 1) to completely dissolve: stir this mixture at room temperature for 2 4 hours' and release with water (2 0 π 1), take B Zhao (3 X 2 0 m 1) was washed and then acidified by adding 2 NHC 1 drop by drop to P Η 4 °. The resulting precipitate was collected, washed with water on the filter pad, and dried in vacuum to get -123- < please first Read the precautions on the back and then fill out this page). Installed • • Ordered. • Color. A 4 (210Χ 297 public) 201745 A 6 B6 5. Description of the invention (118) The title compound, a white amorphous solid (0.16 g). } 1.?. 1. £: (conditions such as example 67) residence time = 17.82 minutes. n. m. r. δ (DMS 0 d β 2 5 0 Μ Η z) 7.8 L 7.9 (1 H, m), 7.7 ~ 7.48 ~ 7.6 (2Η, m), 7.19 (1Η, d), 7.0 (1Η, brs), 6.88 (lH, dd), 5.58 (2H, s), 2.76 ~ 2.87 (2H, U, 2.6 ~ 2.7 (2H, t). 1.5 ~ 1.7 (4H, m), 、 1.2〜1.34 (2H, m), 0.72〜0.9 (6H, 2xt) ° Example 1-““ 3-thin-2- “2- (1 pc-four beer-5-some) cage certain 1--5- Cage and squeeze the furanyl group 1 a certain 1-2-butyl certain -4- radon -1H-眯 Beer-5-a more than 130t stirring intermediate 136 (6 S), sodium azide (4.5s), and hydrogen A mixture of triethylamine chloride (8 g) in DMF (50 ml) for 30 hours. The mixture was cooled and diluted with water (100 ral) and the solution was washed with ethyl acetate (50 ml). The aqueous extract was acidified with 4M HC1. Extract to pH 3.5 and M ethyl acetate (75ral). Extract the organic layer with saturated sodium bicarbonate solution (60ml). Wash the alkali extract with ethyl acetate (3x30ml) and then smell with 4M HC1. Please pay attention to the back of the page and fill in the Hundred.). Ordered · The Ministry of Economic Affairs Central Kneading Bureau printed it to acidify it to pH 3.2 and extracted with Μ ethyl acetate (75 m 1). Μ water (2 X 30 m 1) Wash this organic extract And solvent removal-a solid residue was recrystallized from methanol / water (3: 2) to give the title compound (5.13 g) as a monohydrate, melting point 182 ° C. Η. M. R .δ (DMS 0-de) 0 · 82 (t, J = 7Hz f 3H), 1.29 (m, 2Η), 1.58 (η, 2H), 2. 6 5 (t 1 J = 7H ζ, 2H ), 5.71 (s, 2Η), 7.08 (dd, J = 8 2 HZ, 2H), 7.2 (d, J = 2 Η ζ, 1H), 7.4 (dt J = 8Hz, 1 Η ), 7.70 8. 0 0 (m, compound-4H): _-174- A4 (210X 297H1) -124- £ 01745 A6 B6 V. Description of the invention ¢ .119) The compound of the present invention acts against vasoconstriction in vitro U II test. Obtain aortic slivers from male New Zealand mice and equip them for recording the enamel contraction of the cumulative addition of vasoconstrictor peptide II. The effectiveness of the tested antagonist is evaluated by measuring its ability to shift the corresponding curve of the cumulative concentration of vasoconstrictor peptide II. The method used is Ackerly et al., Pr〇c. NaH Aead. Sci.,

The method of Ll (12) p. 5725 ~ 28 (1977), the one that does not contain the physiological saline solution is listed in the table below. Form (Please read the precautions on the back of the moraine before filling this page)

Ingredients Na * K * Mg2 * Caz * C 1-hpo4-so42- hc〇3- Glucose indomethacin Vitamin C Amount (mM) 14 3.4 5.9 124. 25.011.1 0.005 0.1 • Order. • Green. Central Ministry of Economic Affairs After printing this woven fabric, first bury it at MK- (80mM) and the corresponding point of γ has reached the highest point, then wash it at 0 1 5, 10 0 and 15 minutes: after another 4 5 minutes, build A 125 A 4 (210X 297S issued) 201745 A6 B6 V. Description of the invention (120 Cumulative Correspondence Curve of Vasoconstrictor Peptide II Printed by the Central Kneading Bureau of the Ministry of Economic Affairs (O.lnM to Ol / iMMlO times increase) and this organization Wash as before. Then build a second, third, and fourth vasoconstrictor peptide II cumulative curves at hourly intervals (15 minutes after each curve followed by 45 minutes of equilibration). The compounds of the present invention are tested against vasoconstriction Peptide II was administered 45 minutes before the construction of the fourth vasoconstrictor II curve. The third and fourth vasoconstrictor peptide lines are indicated by the M solution and the presence of the test antagonist (that is, the fourth curve) The EC50 value of the obtained vasoconstrictor peptide II is divided by K. In the absence of the test antagonist Three curves) obtained vasoconstrictor peptide II ECS. The value of the calculated concentration ratio (CR (C〇ncentration Ratio)). The effectiveness of the test antagonist is expressed by MpKb, which is from this equation / CR-1, PK b = -Log- ^ [Antagonist]) Calculate 'It is a rearrangement of Equation 4 described by Furchgott in Handbook of Exp. Pharmacol · »ϋ Ρ · 29〇 (1972) (eds. Blaschkott and Muscholl): The compound of the present invention will It is appropriate to show that the pKb value is in the range of 5 and 12. Therefore, we have discovered that the compound of the present invention inhibits the action of this hormone vasoconstrictor peptide II and can be used to treat conditions that require inhibition of the activity of vasoconstrictor peptide II. In particular, the compounds of these examples have been tested and found to be effective. Therefore, as yet another aspect of the present invention, a compound fel of the general formula (I) or a physiologically acceptable M, a solvate or a metabolic metabolism is provided for ________- 126 -____ A4 (210X 297 No, no: {Please read the precautions on the back before filling out this page) 丄. Buttercup., Order * £ 01745 A 6 B6 V. Description of the invention (121)

Printed by the Central Administration of the Ministry of Economic Affairs for the treatment of conditions associated with excessive or irregular vasoconstrictor peptide II activity. In another or other aspect of the present invention, a compound of formula (I) or its physiologically acceptable Salt 1 solvates or metabolically unstable esters for manufacturing-Tillering agents for the treatment of cases linked to encounter or irregular vasoconstrictor peptide II activity ° In another or another aspect of the present invention, a method is also provided For treatment in a mammal, including a human, with excessive or irregular vasoconstrictor II activity, including the administration of a compound of the general formula (D—a compound or its physiologically acceptable salt) to a mammal in need of such treatment, dissolved Substances or — esters of metabolically indefinite __. An example of an effective amount of 〇K times illustrates the pharmaceutical formulation according to the present invention 0 is used here H active ingredient ft This term represents the formula (] [)-虫。 Drug Example 1 p eye Η A active ingredient 7 0 0 mg starch glycolate 10 mg microcrystalline cellulose 5 0 mg stearic acid m 4 π g g sieve this active ingredient and microcrystalline m vitamins through one-by-four 40-memory and Mix in 1 1 «with a suitable mixer: The Ί3 powder sodium glycolate and stearic acid m are added to this powder m compound and m through a 60 mesh m 1 to be uniform in the ~ seat white dynamic press H Μ Appropriate punch pressure m C is the film can be K. __. Thin polymer coating y by thermal II The film coating m technology known to those skilled in the art is performed by Yanke (please read the back side first; i Yi Shishuo Zai Qi wrote this page) * Tap. .. mic. -127- A 4 (210X 297 public issue) 201745 A 6 B6 V. Description of invention (122) Can be combined in this film coating. 2 □ Fat tablet B Active ingredient 500 mg Lactose 100 mg Corn starch 50 mg Polyvinylpyrrolidone 3 mg Sodium starch glycolate 4 mg Measured weight tablet tablet Sidi Zhongtong tablet is divided into tablets . And the powder is in the art of sieve pyrene in the self-technical layer mesh and the rest of this coating 40 B mixed with one of its various membranes this poly mesh sieve in the heat from this to 12 :. It is made by mixing the particles in the prepared liquid and combining them to make a mixed powder. After these particles coated with M deposits pass through this layer of rice flour. The dry paint is a bit dry. It is dry and condensed. The sugar is mixed with this dry and pressed and mixed with milk. 10 will be applied to the first layer, medium ~; bed and thinning machine extension (5 grains and a combined liquid sieve, when the mulching effect is mixed to the target It is suitable for the coated water straight box 60 with the film 3. This is an example of a combination of hydrating tablets. It is suitable for mixing a machine with an ingot, and it is used as an overpressure hot medicine. 0 Inhalation (please read KI first Note please fill out this page). Insects. Hit. Printing and distribution of the Central Rubbing and Accreditation Bureau of the Ministry of Economic Affairs has only milk 4 2 A 4 (210X 297; * |) £ 01745 A 6 B6 V. Description of the invention (123) (Please read the precautions on the back before filling in this page) Mix the active ingredients in a suitable powder mixer, the granules are ground to very fine (average diameter is about 5 / im),., And lactose and fill this Powder mixture into No. 3 hard animal gelatin capsules. The contents of this chrysanthemum can be used with a powder inhaler. Drug Example 4, Yangshe BP side% w / v effective composition · 1.00 water injection back to B.P. Up to 100.00-order. Sodium chloride can be added to adjust the tonicity and pH of this solution can be adjusted to the highest stability and / or dilute acids or bases can be used or appropriate buffer salts can be added To facilitate the dissolution of this organic component. It may also include antioxidants and gold-toothed saline. To prepare food, clean and fill this solution into ampoules of appropriate size, sealed by fusion glass. This injection is made under a pressure Use one of the acceptable cycles for heat sterilization in the kettle. Another way is that this solution can be sterilized by Guoao and filled into sterile Anou under aseptic conditions. This solution can be packaged under a blunt fire gas of nitrogen. Other preferred compounds include:-Bu [[3-bromo-2-[2-(1 Η -tetrazol-5-yl) phenyl] -5 -benzylfuranyl: methyl] -2 -butane Yl-4 -chloro-1 Η -quinazol-5 -carboxylic acid, dipotassium salt; Bu [[3 -bromo-2-[2-(1 Η -tetrazol-5-yl) benzyl] -5 -benzene Benzofuranyl] methyl] -4_chloro-2-ethyl-1H-globazole-5 -ethyl formate; -129- A4 (210X 297 g; 201745 A6 B6 Printed by the Central Bureau of Economic Development of the Ministry of Economic Affairs V. Description of the invention (124) Bu [[3-Bromo-2- [2-UH-tetrazol-5-yl] phenyl: -5-benzofuranyl] methyl] -4-chloro-2-ethyl -N-isopropyl-1H-quinazol-5-carboxamide; 1-[[3 -mo- 2- [2- (1Η -tetrazol-5-yl) phenyl] -5 -benzo Furanyl] Yl] -4 -chloro-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester; 1-[[3-bromo-2- [2- (1Η-tetrazol-5-yl) benzyl] -5 -Benzofuranyl] methyl] -4 -methyl-2-propyl-1H -quinazol-5 -ethyl formate continue; 1-[[3-Methyl-2- [2- (1Η-tetrazole -5-yl) phenyl] -5-benzofuranyl] methyl] -4-methyl-1H-imidazole-5-carboxylic acid ethyl ester; 1-[[3-bromo-2- [2- (1Η -Tetrazol-5-yl) benzyl] -5 -benzylfuranyl] methyl] -5-methyl-1H-quinazol-5-carboxylic acid ethyl ester; 1-[[3 -bromo-2- 2- [ 2- (1Η -tetrazol-5-yl) benzyl] -5 -benzofuranyl] methyl] -4 -chloro-2-methyl-1H -imidazole-5-carboxylic acid ethyl ester; Bu [[3 -Bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuryl] methyl] -2-ethyl-4-methyl-1H-imidazole-5- Ethyl formate; 1-[[3 -Bromo-2-[2-(1 Η -tetrazol-5-yl) phenyl] -5-] benzofuranyl] methyl] -2-ethyl hydrochloride -4-methyl-Ν-methyl-1Η-quinazol-5-carboxamide; Bu [[3-bromo-2- [2- (1Η-tetrazol-5-yl) benzyl] -5- Benzofuranyl] methyl] -4 -chloro-2 -ethyl-1 Η -penazole-5 -butyl carboxylate; 1-[[3-mo-2-[2- (1Η-tetrazole-5 -Yl) benzyl: -5-benzylfuranyl] methyl] -4-methyl-2-propyl-1H-domain -5-formic acid; Bu [[3-bromo-2-[2-Π Η -tetrazol-5-yl) phenyl: -5-benzofuranyl: methyl] -4-methyl-1 Η- Imidazole-5-carboxylic acid; Bu [5- [3-bromo-2-: 2- (1Η-tetrazol-5-yl) benzyl: benzofuranyl] methyl] -2-butyl-4-methyl基 -1 Η-氯 azole-5 -ethyl formate; (please read the precautions on the back before filling out this page) _wo · -order · .line. -13 0- 甲 4 (210Χ 297 伂 发; 201745 A 6 B6 V. Description of the invention (125) (please listen to the precautions on the back and then fill in this page) BU [[3-Bromo-2- [2- (1H-tetrazol-5-yl) benzyl] -5 -Benzofuranyl] methyl] -4-chloro-2-methyl-1H-quinazol-5-carboxylic acid; hydrochloride 1-[[3 -bromo-2-[2-(1 Η -tetrazole -5 -yl) benzyl] -5 -benzofuranyl] methyl] -2-ethyl-4-methyl-1H-imidazole-5-carboxylic acid; 1-[[3-bromo-2- [2 -(1Η -tetrazol-5-yl) benzyl] -5 -benzofuranyl] methyl] -4 -methyl-2-pentyl-lh'-imidazole-δ-formate ethylase; 1- [ [3_Bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -4-methyl-2-pentyl-1Η-imidazole-5 -Formic acid; [[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofur Yl] methyl] -2,4-dimethyl-1H-imidazole-5-carboxylic acid ethyl ester; 1-[[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5 -benzylfuranyl] methyl] -2,4-dimethyl-1H -imidazole-5-carboxylic acid; -ding · 1-[[3-bromo-2- [2-[[(trifluoromethyl Group) sulfonyl] amino] phenyl] -5-benzofuranyl] methyl] -4 -methyl-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester; 1-[[3_ Bromo-2- [2-[[(trifluoromethyl) sulfonyl] amino] phenyl] -5-benzofuranyl] methyl] -4 -methyl-2 -propyl-1 Η- Imidazole-5 -carboxylic acid; 1-[[3-bromo-2- [2-[, :( trifluoromethyl) sulfonyl] amino] benzyl] -5 -benzofuranyl] methyl]- 2-Butyl-4-chloro-H-methyl-1H-imidazole-5-carboxamide; and its physiologically acceptable salts, solvates and metabolic esters: these compounds can be as Questions in cooking 1 3 7 1-"" · Ί -chun-2-"2-Γ?-(三 蓏 甲某) -2 Η-四 Beer-5 -even 1 茏 基 ： -5-玏 # Technical base Ί 申 even 1-4- radon-2-ethyl-1Η- 眯 Beer-Η- 申 务 乙 5 is designed to mix 7 C (0.50 g) and 1, 1 'at room temperature -Carbonyldiimidazole (-1 3 1-A 4 (210X 297 异 发) A 6 B6 Printed by the Central Bureau of Economic Development of the Ministry of Economic Affairs 3. Description of the invention (126) 0.31g) in THF (12.5nl) for 16 hours, then add ethanol (0.38 m 1) and stir the resulting solution at room temperature for 6 hours, then add ethanol after this time (760 ml) and the reaction mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue purified by column chromatography was dissolved in ether / petroleum ether (1: 1) to obtain the title compound (283 mg), a white foam. T. lc diethyl ether, Rf = 0.90 ° Prepared in the same way: -Intermediate 1 3 8 1- "".?-Chun-2- "2-" 2- (Tripyridyl)-; ^ -tetrazole-5 -Some 1 罙 some 1-5-Cage well 0 Yuran 1 Suan 1-4-気 -2- 乙 某 -N-Rongbing certain -1H-眯 Beer- 5-Metenamine, a light pink solid (3 1 6 ag). Tlc ether, Rf = 0.77. _ From the solution of intermediate 70 (0.58) and 1,1′-11 carbonyldiimidazole (0.318) in THF (12.5g), isopropylamine (〇 .551g). Intermediate 1 3 9 1-““ 3- 痗 -2- “2-“ 2- (Three cages Shenmou)-; ^-四 鹿 -5- 某 1 cage 某 1-5- cage # 0 clamped] A certain 1-4- radon-2-propyl-1H- slender beer-5- A fang Fang-a white solid (8 1 0 in g). Tlc ethyl chain / petroleum ether (1: 1), Rf = 0.71. From the solution of intermediate 36 (1.0g> and 1,1 · -carbonyldiimidazole (610 mg) in THF (25ml), add ethanol (720w 1): intermediate 1 4 0 1 -"Γ- 张 -2-Γ 2-" 2-(tris methyl) -2 Η-四 Beer-5 -yl] 茏 基] -5 _ -Cage and squint 1 Shen 1 1-4-气 -2 -ethyl-1 Η-Ｍ 米 Beer-5 -methylpyridine, -1 32- 甲 4 (210Χ 297 伂 发) (please read the precautions on the back before filling in this Page) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 201 * 745 A 6 ___ B6 V. Description of the invention (127 j a white foam (349mg). Tlc ether, Rf = 〇.93 ° from the intermediate 70 (0.5g) and 1, 1'-carbonyldiimidazole (〇.31s) in THF was added two parts of n-butanol (〇.592ml and 1.00m 丨). Intermediate 1 4 1 d-Tianshi-2-propen-1H- Suiying-5-methylpyrrolidine added hydrochloride ethyl 2-amino-3-oxobutanoate (10s) to the stirring ethyl butyric acid (83.5g) in ethanol (SOOinl ' The solution was distilled from magnesium ethoxide) and triethylamine (85ml) and the resulting mixture was stirred at room temperature for 48 hours. The solvent was removed in vacuo and the residue was diluted with water (500ml) and extracted To ethyl acetate (3x 200ml). Wash the combined organic extracts with water (2x 110ml), dry and concentrate in vacuo. Residue K Yimo (5x50ml) was developed, purified and dried. This residual light yellow solid The title compound (1 4 · 0 5 g) was obtained. Tlc B mystery, Rf = 〇.31 Question 1 4 2 1- "".? -〉 草-?-"2-"?-(Tripyridyl) -2} ^-Tetraberan-5-yl〗 -Phenyl BU 5. -Cage and not even 1 Shen Shen 1-4-Shen A certain 2-propyl-1H-squinted beer-methoxine I heated the mixture of intermediate 141 (1.5g), intermediate 15 (6.4s) and potassium carbonate (1.458) in 04 "(15〇1111) At 7011 for 6.5 hours. Allow the reaction mixture to cool to room temperature overnight and then between water (500 ai 1), ammonium chloride solution (saturated aqueous solution, 5000 m 1) and ethyl acetate ( 5 0 0 m 1) Partition: the separated tart extract with water (2 X 2 0 0 m 1) '-1 33-A 4 (210X 297 Torr) ί Please read the notes on the back first (Fill in this page again) £ 01745 A 6 _ B6 V. Description of the invention (128) Washed with brine (100 ml), dried and concentrated in vacuo to obtain the crude product. This crude product is purified by column chromatography with methylene chloride / Hexane / acetic acid (50: 50: 1) and then methanol to dissolve to obtain a concentrated product. This concentrated product was purified by chromatography with dichloromethane / ethyl bond / ethanol / acetic acid (95: 5: 2: 1) Dissolve K to get a more concentrated sample of this product and make the final purification of Ether / Petroleum ether by chromatography (3: 1 ) The title compound, a white turtle solid (350mg) = Tlc ether / petroleum puzzle (3: 1), Rf = 0.31. Prepared in the same way:-Intermediate 143 and 1 4 4 Zhang-2- "2-Γ2 -(Tripyridine) -2H-tetrazole-H-some 1 cage certain 1 -R-cage and squint) methyl even Ί-4 -methyl-1H-zine beer-5-methyl ethyl acetate ( 375 mg) _ Tlc petroleum ether / ether (1: 1) + 4% methanol + 2% acetic acid Rf = 0. 30 〇1- "" 3-zhang-2- "2-" 2- (trisylmethyl) -21 Four beer-5-some 1 cage base '-5-cage # 眹 晡 某) Shenmou 1-F; -methyl-2 Η-眯 Beer-5-ethyl methyl ethyl (lOOnig) Ding. 1. (:. Petroleum ether / ethyl mystery (1: 1) + 4% methanol + 2% acetic acid Rf = 0.20 ° from the intermediate 15 (1.47g), 4-methyl-1H-imidazole-5-carboxylic acid ethyl ester (320mg ) And potassium carbonate (350mg) in anhydrous DMF (40ml). Purified by column chromatography using petroleum § 1 / ethyl mystery (1: 1) + 4% methanol + 2% gg to dissolve the title compound. The father of the Central Bureau of Standards of the Ministry of Economic Affairs. Please read the precautions on the back and then fill out this page) • Order, -Line · Intermediate 1 4 5? -7: 這 -4- 甲某-ΙΗ-Ιί ^ Ρ ^- 5-A 5 $ -13 4- A 4 (210Χ 297, 2 'no) £ 01 * 745 a 6 B6 Five'Description of Invention (329) Add concentrated HC1 (75ml) to 2-ethyl-4-methyl-1H-imidazole (21g) and formaldehyde aqueous solution (37%, 14ml) in water (100ml ) And heated the mixture under reflux for 48 hours. After the mixture was cooled, Μ NaOH (5N) was basified to pHIO and extracted with K / N-form / isopropanol (4: 1) (3x 100ml). The combined extract of the barberry was washed with brine (1 x 200 ml) and dried. Filter and evaporate this solution K to obtain a light yellow per gum (18g) which was purified by column chromatography M chloroform / methanol / ammonia (90: 10: 1) to dissociate to obtain the title compound, a light yellow foam (12.6s) . 1.1. (; Chloroform / methanol / ammonia (90: 10: 2), 1 ^ 0.3. Intermediate 146 2 -Ethyl-4 -Shenmou-1H-Zidazole-5 -Methyl smoke will activate manganese dioxide ( 20g) was added to the medium 145 (7.0g) in a suspension of dichloromethane / dioxane (2: 1) (200ml) and the mixture was treated according to the method of intermediate 16. The M was purified by column chromatography The title compound (4 · 0 g) was obtained by dissolving it. Tlc diethyl ether Rf 0.2. Intermediate 1 4 7 Bu ""?-张-?-"?-" 2-(二 _ 呆 申 基) -2 5- ¾ And murmured) A certain-B certain 4-A even 4-H even -1H- Shui beer-5- A cigarette smoke intermediate 1 4 6 (2 · 0 g), intermediate 1 5 (1 1 · 2 4 g ) And potassium carbonate (2.4 s) in anhydrous DMF (100 0 ra 1) heated at 80 3C for 5 hours, the mixture after cooling is between water (300 m 1) and acetic acid Yi Yi (3 .............................- f .......... ..... ^ ........................ ^ (Please read the precautions on t before filling this page ) Printed by the Central Bureau of Standardization of the Ministry of Water (Laminated water column \ Mixed by water and its M glue to take a light extracting machine with a yellow agent to get the solution and go here. Steaming- Intermediate division η after ΟΠΙ and 30 tasks X wash

-135- A 4 (210X 297 d, A 6 B6 201 material 5

V. Description of the invention (13Q {Please read the precautions on the back before filling in this page) Purified K ether dissolves to obtain the title compound, a colorless foam (4.15g). T.l.c. ether, Rf 0.25. Intermediate 1 4 8 Sea-Some)-? H-Si Fang-5-some 1¾ Some 1- 5 -Cage # Pjian Xuan) Shen Mou 1-2-Yi Mou-4- Jia Mou-1H-Squinting -; S-Shen Shen added sodium chlorite (80%; 4.86g) and sodium dihydrogen phosphate (4.86g) in water (20ml) to intermediate 147 (3.94g) * 2-methyl- 2-A mixture of butene (2M; 26ml) and tert-butanol (40ml) in THF (40ml). The mixture was stirred vigorously for 24 hours and then the organic solvent was evaporated. The residue was filtered to give the title compound as a colorless solid (3.3g). T.l.c. ethyl acetate Rf0.2. Intermediate 1 4 9 • Order.? -Shenmou-1H-眯 _ -FS-Tian Di. Green. Printed by the Central Standards Bureau of the Ministry of Economic Affairs, condensing ammonia into a three-neck liter liter bottle, M gets about 250 ml Of liquid. Dihydroxyacetone (966.7g) was added in portions, and methine hydrochloride ethylimidate (66.7g) was added. This suspension was transferred to an autoclave, cooled in a propylene / dry ice bath under nitrogen, and then the autoclave was sealed and heated to 90 3C under sowing. After 18 hours, cool the autoclave to room temperature and then to 50t :. Remove the lid of the autoclave and pour the contents into 300ml of cold (501C) methanol. Allow the dark solution to warm to room temperature and then evaporate to obtain a red oil (140.2s). During the standing period, a crow was formed, which was washed with dichloromethane (2 x 300 ml), and the filtrate was concentrated in vacuo to obtain a brown oil (5 δ. 7 g). Purified by chromatographic method to dissolve (5 0: 8: 1) with Ito system C. This title is -136-, A 4 (210X 297S). Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 201745 A 6 B6 V. Description of invention (Work 3 (Technology) Compound> Yellow solid (32.5 g) 〇T. 1. C. System C dissociation (25: 8: 1) Rf 0.46 0 Intermediate 1 5 0 4- Radon-2 _ 甲 什 -1 H -Fuzole- 5-mm N-chlorobutadiene imide (28.04 g) was added to the intermediate 1 4 9 (18.2 7 g) in anhydrous dioxane (230ml) and anhydrous ¥ oxyethanol (230 ml ) In a solution at 20 ° C and processed according to the method of intermediate 67 C Purification by chromatography K system C. (100: 8: 1) The title compound f is dissolved off to obtain a yellow solid (4.9 g) () T · 1 · C. System C (100: 8: 1) Rf 0. 23 0 Intermediate 15 1 4- Radon • ethyl _ 1 Η- 眯 Beer-A release of manganese dioxide (1.89 g) To intermediate 15 0 (5 7 9 mg) in dichloromethane / diammonium (1: 2) (30 in 1) The solution in 0. The suspension was heated at reflux for 5 hours »After cooling and over-concentrating this solution in vacuo, a yellow solid (538 mg) was purified by chromatography using System C (150: 8 1) Dissolve to give the title compound, a pale yellow solid (449 mg):) T. 1. C. System C (100: 8: 1) 丨 Rf 0. 38. ≫ Intermediate 1 5 2 1- Γ: Chun-? T -Γ?-"?-(Triphenylmethyl)-? H-四 0 $ _ 5- 华 1 茏 什 1 _ fS benzofuranhua 1 Shenshi 1- 4 -Μ-2 -Methyl-1 Η- Beer-5-Tian Yanjiang intermediate 15 1 (2.09 g) • Intermediate 15 (14.17 g) and potassium carbonate (2.990 S) in anhydrous DMF (150 The mixture in ml) is heated to reflux for 4 hours. 0 Cool and pour the reaction mixture into water (600 m 1): §1 {Please read the precautions on the back before filling this page) A4 (210X 297 Issued) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs ^ 01745 A 6 _ B6 V. Description of the invention (132) Ethyl acetate (3 x60nil) extracts this aqueous phase This combined extracts were dried and concentrated to dryness to give one kind of Ti Feng in vacuo to a colorless oil (25.40g). Purification by column chromatography K ethyl bond / petroleum ether (5: 1) dissociated to give the title compound • a pale yellow solid (9.8 g). T.1.c. Ether / petroleum ether (5: 1) Rf 0.48. Intermediate 1 5 3, 1-Γ 「3- 海 -2-」 2- 「2- (三 蓏 甲某) -2H -Tetra beer-5-some 1¾ base Ί -R -Cage and murmur '1 Shen Shi 1-4-Qijiamou-1H-Sui Yi -5- Shen Peng added a solution of potassium permanganate (1.14g) in water (60ml) to the stirring intermediate 152 (4.00) in 5 minutes g) A solution of copper propyl (100ml) in 70¾. Stir the suspension at 701C for 1.5 hours, then add a solution of potassium permanganate (550mg) in water (30ml) and at 70t: continue Stir for 3 hours. Add sodium metabisulfite solution (5%, 100 ral), and extract the mixture with ethyl acetate gg (3 x 40 ml). The combined extracts were dried and compressed in vacuo to a pale yellow foam ( 2. 2 3 7 s). Purification of M dichloromethane / methanol (10: 1) by chromatography to obtain the title fc compound (500 mg). Tlc dichloromethane / methanol (10: 1) Rf 0.50. Intermediate IS 4 1-""?-海-?-2-"2-(three cages a certain)-2 Η-四 Beer-5-base 1 苤 基]-5-罙 井 眹 然 even 1- 5 -Shenmou 4-radon-2-Jiamou-1Η-眯 Beer-5-methyl add 1, 1 '-carbonyldiimidazole (2 7 2 π \ g) to the intermediate in the visual partner 1 5 3 ( 4 9 0 ms) in anhydrous THF (5 in 1) 5 $ 2 0 X: a solution. Stir this solution for 8 hours and then add sodium ethoxide (2 65 mg) and continue stirring for 1 2 hours add -1 3 8-A 4 (210X 297 异 发) t Please read the notes on the back first and then fill out this page) _Fan_ • Order. ^ 01745 A 6 __ B6 5. Description of the invention (13¾ water (20ml) and ethyl acetate (3 X 30ml) The mixture was extracted. The combined extracts were dried and concentrated in vacuo to obtain a yellow gum (777ing), which was purified by chromatography. The ethyl acetate / petroleum ether (5: 1) was dissolved to give the title compound, a White powder (117 mg). T · 1.. C. Ether / Petroleum ether (5: 1) Rf = 0.47. (Please read the precautions on the back before filling in this page) 'tap *. Thread · Intermediate 1 W "3- Chunben and Hua) -2H-Sibeihua Ί cage even 1 -R-Benzofuran. Hua 'Jiamou 1?--Ethyl-4 -methyl- 1 Η-眯 Beer_ 5- Formic acid_acetaldehyde… Add 1,1 · -carbonyldiimidazole (0.232g) to intermediate 148 (0.5s) in anhydrous THF (15ml) at room temperature under nitrogen . Search and mix the mixture for 1 hour | then add ethyl alcohol (30 mg) and stir the mixture for 43 hours. Evaporate to the solvent and residue. Purify K m ethyl acetate by chromatography. The title compound, a colorless foam (2 4 2 ώ g)) T. 1. C · ethyl acetate IS Rf 0 .75 intermediate 1 5 R 1-r Γ 3-r # _ Γ 7-12- (dibenzomethrin)-?. Η-四 Beer-5-Hua 'cage even' -η -benzoxananhua 1 Jiashi 1 -2 -7, m-4-Tianmou-Ν-ra Hua-1 H- 睬 Beer-5-methylpyramine Central Standards Bureau of the Ministry of Economic Affairs, printing and burning will add 1,1 '-base base 2 Qiming (3 24mg) to A solution of intermediate 148 (0.5g) in anhydrous THF (15ml) at room temperature under nitrogen. Mix this mixture for 1 hour, then add an aqueous solution of methylamine (40%; 0.3 m 1) and stir the mixture for 16 hours = evaporate the solvent and residues and purify by column analysis to §1 acid acetolysis Obtained the title compound, a colorless bubble bed (0.3 g): -13 9- A · 1 (210Χ 297 ^: ^ '201745 A 6 B6 V. Description of the invention (134) Tlc ethyl acetate / formazan (5 : 1) Intermediate 1 R 7 gas radon Yh P, oxychloride bubbling hydrogen chloride through bubbling through stirring) cooled in a solution of-ίου for -51C for 7 days, then in a vacuum ether (8 0 0 π 1) Neutralize and cool this solution to degassing the resulting solid under air and in true U1 s), a white solid. Intermediate 1 5 S 5 -Methyl-2-pentyl-1H -Small beer-4-methyl base B

Rf 0.85 hexanonitrile (50g) in ethyl yeast (35.9ml for 3 hours. Let this solution be placed in Zhongmei shrink. Pour the resulting oil into B-40¾ and stir for 10 minutes. The title compound is dried in nitrogen air { Please read the precautions for the noodles before filling out this page) • Install · -butyric acid Z (3 · 0 g) in portions (26m 丨) in the yeast (500ral) and place it in the solution at 2 2 t 7 2 Hour = The material is dissolved in ethyl acetate (200 m 1) and the aqueous phase is extracted with ethyl acetate. The combined concentration and residue were purified by chromatography. 2-Amino-3-oxohydrochloride was hydrolyzed to a solution of intermediate 157 (30g) and triethylamine under nitrogen. Allow the solvent to be removed in vacuo, and then wash the residue with water (200 mi). The organic extract was then dried with vinegar and dissolved in a vacuum with M system A (8: 2) to give the title solid, melting point ~ 90¾. Intermediate 1 5 9 1- ~ "3-Bromo-2-" 2- "2- (trisyl)-; ^ -tetrabromo-5-some] cage compound (3 · 0 5 g) shallow Yellow 5 • Ordered. Central Ministry of Economic Affairs-¾ Printed version of Ben Yingranji Shen Shenji: -4-Jia Shiji-] H ~~ 味 Beer-B Nail lick 7, sweet will intermediate 1 5 (3 1 s), intermediate 1 5 8 (C. 5 s) and potassium carbonate-1 il 0-A 4 (210X 297 ^: ^) 201745 A6 B6. 5. Description of the invention (135 〇.367g) in DMF ( The mixture in 50ml) was stirred at 22t for 16 hours. The mixture was diluted with diethyl ether (50m!) And washed with K water (50ml). The two phases were separated and the aqueous layer was extracted with K ethyl acetate (50al). The extract was dried and concentrated in vacuo to obtain a yellow oil, which was purified by chromatography. Mito A (6: 4) dissociated to give the title compound (0.8s), a white solid, melting point 8 9 ° ~ 9 0 1C Interrogation 1 ft 0

2.4- 二甲 很 .-1 Η-眯 Beer-5-methyl alcohol, SS Add 2-amino-3-oxybutyric acid ethyl hydrochloride (5 s) in portions to ethyl imidate ( 34.0g) and triethylamine (42αι1) in ethanol (500ml), and the resulting yellow solution was stirred overnight, the solvent and residue were removed in vacuo between water (200nii) and ether (200m丨) Distribution. The organic layer and MYB (2x200ml) were separated and the aqueous layer was extracted. The organic extract was dried and evaporated in vacuo, and the residue was washed with Methyl ethyl acetate and decanted to obtain the title compound, a white solid (1.1 g), melting point 165 ° ~ 1665C. Intermediate 1 6 1 "" 3-Chun-2-"2-" 2-(two. Cage Shenshi)-? Η-四 Beer-Fi-very Ί-cage even 1-R-茏 不 眹 某A certain 1 4 -Dimethyl even -1 Η-眯 Εφ-5 -Tianfang B 5¾ Add the intermediate 1 5 (7.6 g) to the intermediate 1 6 0 (0 · 9 g), and potassium carbonate ( 0. 9 s) solution in DMF (1 0 0 a 1) and stir the resulting solution for 3 days. Pour this mixture into water (3 0 0 m 1) δ to diethyl ether (5 X 1 5 0 ra 1) extraction: The preserved extract was washed with water (1 5 0 οι 1), brine (1 5 0 m 1), 2% lithium chloride in water (1 0 0 m 1) and then dried. Remove the solvent and residues in vacuum. Purify ib by chromatography and dissociate it with ethyl mystery / B § $ (3%) to get -1 4 1-f 4 (210X 297 ^ '^). Please read the notes on the back first (Fill in this page) Xiang. Order · -Line · Printed by the Central Bureau of Standards of the Ministry of Economic Affairs A 6 B6 ^ 01745 5. Description of the invention (136)

The title compound, a white solid (2.lg), melting point 9V ~ 100C 0 Intermediate 1 fi 2 "2-" 3-chun- 5- (bromomethyl certain) -2-Fujing suizhen 1¾ certain 1 Amine alkaloid 1.1-dimethyl ethyl ester Intermediate 1 28 (4. 29 g) and benzoyl peroxide, base (3Omg) in anhydrous carbon tetrachloride (100 m 1) The solution was heated to reflux while irradiating 1.5 cm with a 200 W lamp. The mixture was filtered and the filtrate was washed with water (2 X 100ml). The title solution was dried, washed and evaporated to obtain the title compound (5 g) 0 Intermediate 1 6 3 1-““ 3-Sea-2- “2-“ “(1.1-Dimethylethyl _) carbonyl certain 1 amine certain 1 certain 1-5 -Strange well _ Very 1 Shenmou 1- 4-A certain-propyl-1H-Shui beer-5-A jg 7, m Intermediate i 4 1 (0.5 1 g) and hydrogenated sodium (0.1 1 s; 60% dispersion in oil) in anhydrous DMF (6 m 1) was stored at room temperature and stirred for 2 hours. Cool this mixture to 0 ~ 5 t and add intermediate 16 2 (1.2 5 g ): The mixture was stirred at 0 t and the temperature was raised to room temperature for 20 hours. The solvent was evaporated in vacuo and the residue was dissolved in Yimiao (100 m 1). This solution of ethylg Water (100ml) · Sodium bicarbonate aqueous solution (8%: 100ml), lithium chloride aqueous solution U 0%; 50 m 1) Washing, drying and evaporation: The residue was purified by column analysis to obtain the title compound, A yellowish white foam (0.2 s). T · 1. c · Shitong B (2: 2 5), R f = 0.65, intermediate 1 6 4 -1 4 2-f 4 ( 210X 297 ^, ¾} tPlease read the notes on the back before writing this page) • Install, • Order. Printed and printed by the Central Business Administration of the Ministry of Economic Affairs 201745 A 6 B6 5. Description of the invention (13 " ^ The quasi-prepared seal 1- "" 2- (2-Amine, a certain)-·?-海-荣 # 0 夹 然 某] Jiamou 1-4-Tian Shi-2 -S group-1 Η -imidazole- 5-Methyl 7; the intermediate 1 6 3 (0.19 g) in a mixture of dichloromethane (3 ml) and trifluoroacetic acid (1 m 1) at 0 ° C to room temperature is 4 Hours. Remove the solvent in vacuo and add ethanol (5m 1) and ammonia (1 m 1) and re-evaporate the solution. The residue is purified by column chromatography by dichloromethane / methanol (20: 1). This title compound (0 · 136 g)> — m. Color Foam »Melting point 135 ° 136TC [7 cases 70 1-" "3-Pu-2 -Γ 2- Π H-tetrazole-5-a) dull Ί--benzofuranyl 1 Jiahua; 2-butane棊 -4 -1 Η- 眯 ΒΦ-5-serial conversion * Monopotassium added ethanolic potassium hydroxide (1.0 Μ) to the product of Example 3 (1.23 g) in ethanol (3 4 in 1) The solution in r. Concentrate this solution to 5 in 1 and then slowly add anhydrous ether (40m 1) and precipitation occurs 0 Let the precipitation settle and decanted to remove the floating liquid 0 Μ anhydrous ethyl m Stir this sink and pour Analyze (2 X 10ml) the dissolved solid in ethanol (8 Ε 1), and then kill and dry the demon Μ ethane (2 X 2 0 m 1) to obtain a white solid (1.445 S) and dissolve ϋ 5S. ~ 6 2 = C (softening) 0 Test result C, 40.8: Η, 2.3 = N, 11.9; K, 10.9 C 2 4 Η 1 S Br 2 C 1 Κ 2ν β 〇3 calculation: C, 40 .5 Η, 2.55; Η, 11.8; K, 11. 0% Example 71 1-"" 3- m _ Γ 2- (Ί Η-四 映 -5-棊) Benzene-5 _ 雜 不 眹Nang Shi: A 4-Chlorine-2 -7. Very-1 Η-Shui Beer-5-A green 7 m -143- Please read the precautions on the back first and then fill out this page) • Smoke, • Hit. • Green. A · ί (21〇Χ 297S; *!) £ 01745 A6 ______ B6 V. Description of the invention (138.i The solution of intermediate 137 (283mg) in ethanol (10ml) and concentrated HC1 (0.2ml) in Stir at room temperature for 2.5 hours and then adjust to pH 9 (2N aqueous sodium bicarbonate). Remove the solvent in vacuo and dissolve the residue in water (80ml) and extract into ether (3x30ml). Acidify the aqueous phase to pH5 (2 N HCI) and then extracted into ethyl acetate (3x30ml). The combined ethyl acetate extract was dried and concentrated in vacuo to give the title compound, a glassy solid (141 mg) * melting point 106 = ~ 108C. TIc diethyl ether R f = 0.1 2 〇 Prepared in the same way:-Example 72 Zhang-? -Γ?-(1Η-Siyou-5-some) ¾ group-¾ and even 1 a certain 1-4-radon -2-Ethyl-N-Junbingmou-1H-Zhongjiazhangfang a white solid (184mg), melting point 108 ° ~ 110t: Tlc ether R f = 0.16-'from intermediate 138 (310rag) A solution in ethanol (ΙΟπιΙ) and concentrated HCl (0.2ml). Example 73 1-Γ Γ 3-?!-2-"?-(1 ^ 四 鹿 -5- 某) 呆 很 1-5- 呆 #隹 安 1 A t please read the notes on the back before filling in this book)-order · base 1 gas-?-Propyl one 1 Η-眯 Beer-5-A lick B 5¾ light yellow solid line Ministry of Economic Affairs Printed by the Central Bureau of Standards (1 8 0 ag) 0 Tlc Ethereum / Petroleum Ether Rf = 0.09: η.ιη.Γ.δ (250MHz, CDCU) 0.79 (3H, t), 1.22 (3H, t), 1.45 ( 2H, sex), 2.22 (2H, ti, 4.2 (2H, q), 5.58 (2H, s), 7.0 (2H, d + s), 7.27 (1H, m), 7.65 44-A4 (210X 297 male ; 201745 A6 _____ B6 V. Description of the invention (139.) (2 H, m), 7.8 9 (1 Η, m), 8.0 (1 Η, π). From a solution of Intermediate 139 (460 mg) in THF (20 ml), ethanol (30 ml), and Hc 1 (0.3 ml). Example 74 1- "" 2- ^ Cao Siying -5- XY:-Β sharp whispering, free base 4-A certain propyl certain -1H-眯 azole-Fi- use credit Zgi, a white solid ( 1 8 0 ag) ° Tlc B-bond / petroleum puzzle Rf = 0.05. Η.πι.Γ.δ (250MHz, CDCU) 0.6 (3H, t), 1.2 (2H, t), 1.31 (2H, sex), 2.0 (5H, s + t), 4.1 (2H, q), 5.5 (2H, s), 6.9 (1H, s), 7.0 (1H, dd), 7.28 (1H, m), 7.68 (2H, m), 7.90 (1H, m), 8.i UH, m): a solution of intermediate 142 (350ug) in B§1 (10: 〇1) and concentrated ^ 1 (0.21111). Example 75 1- "" 3 -痗 -2-"?-(ΊΗ- 四 targeted beer-5-some) ¾ even]-茏 井 眹 某 7 Shenji 1-4 -methyl-1 Η-眯 Beer-5 -A pound of benzene 葩 ί 1 0 0 ag) '瑢 point 1 θ 2 t di Tlc ethylene glycol / petroleum / ethanol / acetic acid (80: 20: 2: 2) R f = 0.16. From the intermediate 143 (200mg) in ethanol (10m 丨) And concentrated HCl (0.2 ni〗). Printed by the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page)

Example 7R 1-".Ί-痗 -2-— 2-Η Η-四 Beer-5-Very) 歄 筚, F5-cage and 眹 晡 Very 'A certain Ί-5-A certain -1 Η-眯 映-4-Shenyue Yiyi (30mg), melting point ~ _-145-_

A 4 (210X 297D £ 01745 A 6 _ B6 V. Description of the invention (140) 185t: Tlc B mystery / petroleum mystery / ethanol / acetic acid (80: 20: 2: 2) Rf = 0.09 ° from the intermediate 144 (50ms ) In ethanol (5ml) and concentrated HCl (O.lml) solution. Li 77 '1- "" 3-chun-? .- "?-(11 ^-四 Beer-5-some) cage certain 1- Has-cage well 0 Guanranji 1 A certain Ί-4 gas-?-Shen Shi-1 Η-眯 Beer-5-A bladder B (7 4 mg), melting point 2 0 δ " * ~ 2 0 8 t. Tlc dichloromethane / methanol (10: 1) Rf = 0.42: From a solution of intermediate 154 (110 mg) in ethanol (2 ml), THF (0.5ral) and concentrated HCl (0.1 ml). W 78 M gas Chemical 1-"ί 3-Nao-2-" 2-Μ Η-Four beer-5-very) cage 1 5-愉 井 眹 晡 Ί 甲 even 1-2 -ethyl-4-methyl-1Η -Small beer-5-carbamide (01 mg)> melting point 1 6 (Γ ~ 1 6 5 t. Tlc dichloromethane / methanol (10: 1) Rf = 0.45: from the intermediate 1 5 5 (2 3 0 in g) in ethyl yeast (15 m 1) and HC 1 (0.1 m 1) solution. Example 79 g 氤 fr. 1-"「 .Ί-张 -2--Μ Η-四Beer-5 -Very) 7- 5 -Cage and Eyes_Printed by the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling in Page) a certain 1 a certain 1-? -Ethyl-4-tankyl-Ν- 甲 even-1Η- 眯 sister-5-a roller protection, a colorless solid (8 4 ai g), point 1 9 0 3 ~ 1 9 5 t: T. 1 · c · Ethyl acetate / methanol (5: 1) RfC.2: -14 6- 'f 4 (210X 297 ^' ^) 201745 A 6 B6 V. Description of the invention (141 ) From the solution of intermediate 156 (0.38) in methanol (151! 11) and concentrated 1 ^ 1 (0.21111). Example 80 lf "3-bromo-2-" 2- (1Η- 四 映 -5- 某) Cage 1-S-Fu and squint 1 Jiamou 1-4-Qimou-1H-Sui Jiaji Dingku white solid Ministry of Economy ▲ Standard Μ printing (62mg), melting point 1S7 ° ~ 199 ° C .From intermediate 140 (349mg) in n-butanol (10ml) and concentrated HC1 (0.25ml) solution. Further purification is by dissolving this product in sodium bicarbonate solution (1% aqueous solution, 80 m 1 ) And extract into Yimian (3x30ml). example? η 1-"" 3-Bromo-'2- "2- (1! ^-四 Beer-5-some) cage certain 1-5- cage # 眹 某 1 Tian certain 1-4 -uryl-2- Bingshi-1H-Shuibei-5-Tian Fang The solution of the product of Example 74 (140 mg) and potassium hydroxide (71 mg) in ethanol (1.92 m 1) and water (0.48 m 1) at room temperature Stir for 6 hours and add potassium hydroxide (120 mg) and stir the resulting solution for 16 hours at room temperature. The reaction mixture is acidified to pH 5 and extracted into ethyl acetate g | (3x10ml). The ethyl acetate phase was dried and concentrated in vacuo. The residue was recrystallized from 10% methanol / ethyl acetate to obtain the title compound (llmg) * — a white solid. Tlc · dichloromethane / ether / ethanol / §Good Acid (95: 5: 5: 1) Rf: 0.29 = nmrS (250MHz, MeOD) 0.9 (3H, t), 1.20 (2H, sex), 2.5 (3H, s), 5.92 (3H, s), 7.1 ~ 7.4 (5H, m), 7.68 (1 H, m), 7.88 (1H, m)--147 (please read the notes on the back before writing this page). Order .. line. A M210X 297 public 1 20ΓΜ5 A6 B6 Fifth, the description of the invention (142) 1-"".?-海 -2-F 2-(1 Η-四 映 -5-某) cage some FS-stay #. P 韣 然 某 1 methyl 1-5-Jiamou-1H -Small beer-4-methyl ether The solution of the product of Example 75 (60rag), potassium hydroxide (15.1mg), ethanol (0.54ml) and water (0.12ml) was stirred at room temperature for 16 hours. Remove in vacuo The dissolved and residue were diluted with water (15ml). After acidification to pH4 (2N HC1 aqueous solution), the aqueous layer was extracted into ethyl acetate (3x'15nl). The combined organic extracts were dried and in vacuum Remove the solvent to obtain the title compound (40 mg), melting point 2 4 8 t: 3 Tlc dichloromethane / ethyl alcohol / ethanol / acetic acid (95: 5: 2: 1) Rf = 0.58 .. Example 83 Bu "" 3-chun-2- 「2-ί〗 Η -Si 呻 -5-some) ¾ case 1- 5-cage and squint 1 甲某 1-2- 丁某 -4- 甲某 -1H -Mi Beer -5- 甲 it 7. 5¾ A solution of intermediate 86 (200 mg) in methanol (4 ml) and concentrated HC1 (2 ml) was stirred at room temperature overnight. Carefully add sodium bicarbonate (10 ml) until the solution became Basic. The mixture was extracted with ethyl acetate (3x 15ml) and the combined extracts were dried and evaporated in vacuo. The residue was purified by chromatography with ether, then ethyl acetate / 10% acetic acid was dissolved to obtain the title compound , A white foam (130 mg), melting point 10 1 3 ～ 1 0 5 ° C, TIc · diethyl ether / acetic acid (10: 1) R f 0.4 'Example 84 (Please read the notes on the back before filling in this hundred) • ^ _ .Subscribe · Ministry of Economic Affairs Printing cracked base Μ beer four very ¾ some very whisper and ¾ a certain-2 I 0 beer squinting 4 (210X 297 public) printed by the Central Standards Bureau of the Ministry of Economic Affairs 201 ^ 45 A 6 B6 .. V. Description of invention ( 143 .., add a solution of flounder (57 mg) in water (3 ml) to the stirring intermediate 152 (20〇! 1 ^) in copper propyl (5 1! | 1) in 70 scoops Solution. This solution was stirred at 70t for 1 hour, then potassium permanganate (57ing in 3ml of water) was added and at 70t: stirring was continued for 2 hours. Sodium metabisulfite solution (5%, 15ml) was added, and ethyl acetate M (3 x 30ml) was used to extract the aqueous phase. The combined organic phases were dried and concentrated in vacuo to give a white foam (200mg). Purification by chromatography using dichloromethane / methanol (10: 1) dissociated to give the title compound, a white 'powder (84mg), melting point 263t. Tlc dichloromethane / methanol (10: 1) Rf 0. 16 〇 cases R5 argon gas 1-"".?-Zhang-2-"2-Μ Η-Siying-F) -based) Rongshi 1 -5-荣 # 0 Guan Nan 1 methyl] -2 -7: certain 4-methyl-1Η-眯 Beer-5-Shen Si added concentrated HC 1 (0.2ml) to the intermediate 148 (1 g) Suspension in methanol (30ml) at room temperature under nitrogen: this mixture was stirred for 4 hours | Then M2N NaOH was basified to PH12. Evaporation of defermentation and residues were between water (75 ml) and Partitioned between the three puzzles (3 X 5 0 m 1.). This aqueous phase was acidified with 2 NHC 1 to P H 1. As a result, a colorless solid precipitated: the precipitate was precipitated out, M water (2 > c 1 0 m 1) and then washed with ether (2 X 1 0 in 1) to obtain the title compound, a colorless solid (0.4g), melting point 18 (T ~) 85 death: Ir (liquid stone) 3650 ~ 2200. 1717, 1250 , 761 cm-1: Μ 8 6 1-“「 3-Nao-?-」2- (1 pc-four beer-5-very) cage base 1-5-Tuijing Xianmu = 甲某 Ί-4 -Ash-2 -pentyl-1 Η-眯 呻 -5 -Shen shouyi intermediate intermediate 1 5 9 (0 _ 3 g) in methanol (6 πι I) and concentrated HC 1 (3 πι 1) Zhi-149- A 4 (210Χ 297 g; ............ ...................... ^ ............... ^ ........... ................... Order ........ f .................. itch it please K1 read the notes on the back first and then fill in this page) 201 ^ 45 A 6 B6 V. Description of the invention (1.44) The solution was stirred at 2 2 t for 1 δ hours. This suspension was alkalized to 2 NN a 0 Η to p Η = 8 and then extracted with ethyl acetate (2x30nl). The combined extracts were dried and concentrated in vacuo to obtain a yellow oil which was purified by chromatography. Methyl acetate / acetic acid (95: 5) was dissolved to give the title compound ( 〇. 1 2 g), a light yellow foam, melting point 10 3. ~ 1 0 4 t: T. 1 · c. Ether / acetic acid (9: 1) R f = 0.68 脷 87 T-Γ Γ 2- Chunyi?-"" 2-Μ Η-four beer one 5-a) cage even 1-5-cage and P-Crananyl-Tian Ji 1-4-Tian Shi-?-Rg certain -1Η-imidazole-5 -Applying a solution of the product of Example 86 (0.2g) and sodium hydroxide (2M; 2ml) in ethanol (10 ra 1) under reflux and stirring for 1 hour. The solution was concentrated in vacuo, then diluted with K water (UOml) and extracted with K ethyl acetate (10 Oal): the phases were separated and the aqueous phase was acidified with 2H HC1 to pHI, and the resulting solid was filtered off with water (10 m 1 ) Washing and drying in vacuum to obtain the title compound. (〇. 1 8 s), a white solid, melting point 1 8 ΓΓ ~ 1 9 0t (decomposition) = Tlc ether / acetic acid (9: 1) Rf = 0.34 Μ 8 8 1 _ nut-?-R 2-π Η-四 Beer-5-very) cage 1-5-fulofuranyl ..: Tian Shi 1 4-Ershen -1 Η-眯 Beer A solution of intermediate 161 (500 mg) in methanol (10 mL) and concentrated HC1 (5 ml) was stirred overnight at room temperature μ. After the reaction, the solid crystallized from this reaction is cautious. 8 Add carbonic acid hydrogen to the first. Read the precautions on the back and then fill the dome page) < •: R ft and pure combination method this prayer layer is taken from the extract) leave ml residue 5 2: XII (3 steamed embankment in the empty space really true § | two in the W and \ material dry m mixed dry B mixed Jing this thing y Take 'Zhong Cui S! Liquid machine Yiji Youyi 4 (210X 297' second 'floor) £ 01745 A 6 B6 Ministry of Economic Affairs Central Central Bureau of Privilege J > L · Fifth, the invention says' Ming (145) (10 : 1) Then the ethyl acetate / ethanol / §§ acid (10: 1: 1) was dissolved to obtain a dark solid (200mg). K chloroform was used to wash the solid and remove the insoluble matter. The title compound, a light-colored solid (130 mg), melting point 116 ° ~ 1201. T. lc ethanol / ether / acetic acid (1: 10: 1) Rf 0.5. M sa’s-cage well Suan 1 Shen 1 -2.4-Nitian-1H -Shuibei-5-jia bladder The intermediate 161 (200g) in methanol (4 ml) and concentrated HC1 (2 ml) was stored and stirred at room temperature overnight. Water (2ia) was added ]) And then M2N NaOH makes this solution alkaline. This alkaline mixture The compound was extracted with §§Acetyl Acetate (2 X 1 0 m 1) and evaporated in vacuo, and the residue was heated at reflux with a solution of ethyl P (6ml) and 2N Na0H (4 m 1) for 3 hours. Dilute with water This mixture was concentrated in vacuo and then acidified with 2 M HC. The resulting insoluble solid was filtered off and washed with diethyl ether to give the title compound, a yellowish white solid (60% ng). Melting point 1 8 5 ° ~ 1 9 0 Ό (decomposition). H. P. 丨 .c. (Conditions such as 洌 5 3) Retention time 1 4 .3 0 minutes. Example do 1-"".?-张 -2-f 2-"" fSanzang Ermou) 碏 licking even] Fangji ΊCage even 1-5-茏 井 Ρ 開 鐘] Methyl] -4-methylpropan-1H -imibe-5-methyl alcohol 1 6 3 (0.13 3 s) and anhydrous triethylamine (3 3 g) in anhydrous dichloromethane (5ml) in a 85: C with trifluoromethanesulfonamide anhydride in anhydrous dichloromethane The solution (0.33 m 1; 1 Μ) treatment: mixing this mixture at -8 5 3 ~ -7 5 t for 3 hours and adding water (5 mi: Κ 二 g 甲 垸 (2 0 ® 1) -1 5 1-(Please read the precautions on the back and then fill out this page) k. Order ·. Line A 4 (21〇X 7 Public) 201745 A 6 B6 5. Description of the invention (14 © Extract this product. The organic extract was washed with hydrochloric acid (2M; 20ml), dried * filtered and evaporated in vacuo. The residue was purified by column chromatography and dissolved with dichloromethane / methanol (50: 1) to give the title compound, a white solid (0.135 g), melting point 123 ° ~ 125C. T. 1. c. Dichloromethane / methanol (35: 1) Rf = 0.45. m 9 1, Zhang -2-"2-" Π 三 Μ Jiamou) 碏 醗 mou 1 defending 1¾mou 1-5--¾ and P »aiming 1 Shenmou 1-4-Jiamou-2-propan -1H-眯 _-5-Dimethylbenzene The solution of the product of Example 90 (〇.13g) in a mixture of formazan (6ml) and sodium hydroxide aqueous solution (2M; 2nil) was heated at reflux for 3 hours. After cooling, hydrochloric acid was added (2M; 2ml) The resulting precipitate was collected by filtration. The solid was crystallized from methanol and water to give the title compound, a colored solid (0.06g), melting point 1 6 δ ° ~ 1 7 0. Verification results: C, 47.3; H, 3.5; N, 6.6

Cz ^ HziBrFaNaOsS · 0.5H20: C, 47.3; Η, 3.6; N, 6.9¾ Example 92 Printed by the Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back and then fill out this page)!-"".?- Nao-?-"2-," Π 二 气 φsome) 砏 藤 基 1amino 荜] Cagel 1-5 -Benzogu 咭 ult 1 Tian certain 1-2 -Ding certain- 4- ^-Ν-甲A solution of -1Η- 篯 azole-5-formamide was heated at 50 t for 18 hours in a solution of the product of Example 65 (0.17s) in methylamine (10ml). Let the solvent evaporate. Dissolve the residue in Dichloromethane (50 m 丨) and M hydrochloric acid (2 M; 50 m 1) were washed. This organic solution was purified by column chromatography. M dichloromethane / methanol (20: 1) was dissolved to give the title compound 'A white foam (〇.136g), melting point 89 ° ~ 92C. Verification results: C, 46.1; Η, 3.6; N, 8.3 5 C25H23BrClF3H4〇4 calculation: C, 46.35; Η, 3.6 ; Η, 8.65% -152- A4 (210Χ 297 public)

Claims (1)

AT B7 CT D7 R1 Heti—CH2 Six 'patent application 1. A compound of general formula (I) (I). Or its physiologically acceptable salt, hydrate, Ci-4 alcohol solvate or metabolically unstable lower alkyl ester, alkoxyalkyl Alkyl ester, alkoxyalkyl alkyl ester, alkoxycarbonyloxyalkyl ester, aryloxyalkyl alkyl ester, aralkyl ester, aminoalkyl ester or hydroxyalkyl ester where R1 represents an argon atom Or a flat atom or a group is selected from Ci-e comprehensive group, fluoro Ci-e alkyl group or C: Le alkoxy group; A "represents this group (please read the precautions on the back first and then drive this page ) R3 ½ Central Ministry of Economics and Trademark of the Ministry of Economy ¾ R3 represents a base selected from -c〇2h, -HHS02CF3 or a C-connected tetrazole ring; R 4 and R s may be the same or different, each independently represents One hydrogen atom T4 (210X 297 g) 01745 A7 B7 · »i D7 VI. Patent application Fan Yaji Central Office of the Central Bureau of Quarry or a halogen atom; Het represents a N-linked imidazole group selectivity It is substituted by a Ci-e alkyl group or C2-e alkenyl group at the 2-position, and is optionally substituted at the 4: and 5-positions of the imidazolyl plaque by one or two positions and is selected from a halogen atom or a group Selected from "-β alkyl, fluoro Ci-e alkyl,-(CH2)" Re,-(CH 2) n C 0 R 7 or-(C Η 2) »» HR 8 C 0 R 9 substitution; Re Represents a hydroxy group or Ci-e alkoxy ring; R7 represents a hydrogen atom or a group selected from hydroxyl, Ue alkyl, "-β alkoxy or -NRUR11 group; R a represents a hydrogen atom; Re represents a halo atom or a group selected from "-β alkyl," _β alkoxy or -NR 1 ° R 11 radical; R1C> and R11, which may be the same-or different, each independently represents One hydrogen atom or one Ca-4 Alkyl or -Hin11 generates a pyrrolidine heterocycle »m represents an integer from 1 to 4, such as 1 or 2, preferably 1; η represents an integer from 0 to 4, such as 0, 1 or 2, M0 Or 1 is preferred; P represents an integer from 1 to 4, preferably 1 or 2. 2. According to the patent application, item 1 $ compound, where Het represents an N-linked imidazole group at the 2-position by a M atom or a Ci-6 alkyl group, K an ethyl group is preferred, or a "-5 alkenyl group, with a but-1-alkenyl group is preferred, substituted 3 3. According to the scope of application of the second item Compounds, of which H et stands for one (please read the precautions on the back before filling in the Luan page) • Install. • Play. _LINE · -Μ- TM (210X 297 Public Broadcasting) ^ 01745 B7 C7 —___ D7 VI. The patented N-linked imidazolyl ring of Shen's patent is replaced by a ®C3-S alkyl group at the 2-position, such as a s-n-propyl or M-n-butyl group *. 4. The compound according to item 2 of the application standard, where the N-linked imidialyl group is further substituted by one or two nicks from a halogen atom or a group selected from Ci-e alkyl groups *- (01 {2) »1 ^ or-((^ 2)„ (: 01 ^. 5. The compound according to patent application No. 1, wherein the N-linked imidazolyl group is composed of a halogen atom * The gas atom is preferred. 6. The compound according to item 1 of the patent application, where the N-linked azole ring is selected from a group-(CH2) eRe (where it is, such as, a Ci-e alkoxy group • For example, a methoxy, ethoxy, propoxy or butoxy group • M — a methoxy group is preferred, or Rei — a hydroxyl group is preferred, and m represents 1 or 2 Preferably) or-(CH2) nC0R7 (wherein R7 is, for example, a halo atom or a group selected from hydroxyl, Ci-β alkyl, such as a methoxy, ethoxy, propoxy or butoxy group , Or this group -NR10 !? 11 where R10 and R11 each, for example, independently represent a · M atom or an alkyl group, represents a hydrogen atom, a hydroxyl group or a methoxy group * and 11 to 〇 '1 or 2 Good) Substitution. 7. The compound according to item 6 of the Shenfan Fanyuan, wherein-(CH2) mRe is a-radical group selected from -CH20H. Or -C_H2〇CH3; or-(CH2) nC0R7 is a group The group is buried from -CH0 · -C02H, -C02CH2CH3 or -conh2; or-(C 丨 UUC0R7 is a group selected from-(: 〇2 (: 丨 13 or 4〇 随 (^ 3. 雅 洚 #Central Standards Bureau Printed (please read the precautions on the back before filling in this page) 8. According to the application, the compound of item 1 in this case, where this group Het-CH2-is the 5th-or 6 -Position * -Μ-Τ4 (210Χ 297 公 广) A7 [01745 g ____D7. 6. Patent application. Printed by the Central Department of Economic Affairs of the Ministry of Economic Affairs to be connected to the 5-position on the benzofuran ring. 9. The compound according to item 1 of the patent application, where R1 represents a hydrogen atom or a halogen atom or a radical selected from Ci-e alkyl, "-β alkenyl, (: ie alkoxy or fluorine Ci-e alkyl groups, such as a hydrogen atom or a halogen atom or a Ci-e comprehensive group, preferably a tooth atom, and a bromine atom is more preferred. 10. According to the compound of item 1 of the patent application, its R3 represents a -C〇2H group * or R3 represents a C-linked tetrazole group; 11. The compound according to item 1 of the scope of the patent application, where !? 4 and 1 ^ 5 each independently represent one A hydrogen atom or a halogen atom, M R4 and R5 each represents a hydrogen atom. 12. The compound according to item 1 of the patent application is selected from: 5- [2- [3-bromo-5- [[2-Butyl-4-chloro-5- (hydroxymethyl) -1H-imidazol-1-yl] methyl] -2-benzofuranyl] phenyl] tetrazole; Bu [[3-Bromo -2- [2- (1Η-tetrazol-5-yl) benzyl] -5-benzofuranyl] methyl] -2-butyl-4-chloro-1Η-imidazole-5-carboxyaldehyde; 1 -[[3 -Bromo-2- [2- (1Η -tetrazol-5-yl) phenyl] -5 -benzofuranyl] methyl] -2-butyl-4-hydrogen-1Η -quinazole -5-carboxylic acid; 5- [2- [3-bromo-5-[(2-butyl-1Η-imidazol-butyl) methyl] -2-benzofuranyl] phenyl] -1 Η-tetra Azole; 2- [3-bromo-5- [2-butyl-4-pyridine-5- (hydroxymethyl ϋ) -1H-imidazole-buyl: -2-benzofuranyl] succinic acid · 5- [2- [5-[[2-butyl-4-chloro-5- (hydroxymethyl Ιί) -1H-quinazol-1-yl] methyl] -3-methyl-2-benzylfuran S] Benben] -1 Η -tetrazole; (Please read first (Please fill out this page for more details). Packing .. Playing green.-T 4 (210X 297 public broadcasting) £ 01 ^ 45 B; C7 ____D7 6. Applying for a patent. [[3 -Bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2-butyl-4-amino-1H-imidazole-5 -1 ethyl formic acid; Bu [[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2-butyl-1 ( E) -Alkenyl-4-chloro-1H-imidazole-5-carboxylic acid; Bu [[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl ] Methyl] -4-Amino-2-propyl-1H-imidazole-5-carboxylic acid; 1-[[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5 -Benzofuranyl] methyl] -2-butyl-1H-imidazole-4,5-dicarboxylic acid; 5- [2- [3-bromo-5-[(2-butyl-4-chloro-5 -(Methoxymethyl) -111-imidazole-butyl] methyl] -2-benzofuranyl] phenyl] -1H-tetrazole; 2-butyl-4-gas-: 1-[[2 -[((1Η-tetrazol-5-yl) phenyl] -3- (trifluoromethyl) -5-benzofuranyl] -1H-imidazole-5-carboxylic acid; [[3-bromo-2 -[2- (1Η -tetrazol-5-yl) phenyl] benzofuran-5-yl] methyl] -2 -butyl-4-hydrogen-1H-imidazole-5-carboxylic acid 1- (ethylpyridine oxygen) Ester 9 Bu [[3-Bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] benzofuran-5-yl] methyl] -2-butyl-4-chloro-1H- Imidazole-5 -carboxylic acid 1- (acetoxy) ethyl ester> Bu [[3 -Bromo-2- [2- (1Η -tetrazol-5-yl) phenyl] -5 -benzofuranyl] methyl Yl] -2 -butyl-4-chloro-1H-imidazole-5-carboxylic acid 1- (ethylpyridine) ethyl ester; Bu [[3-bromo-2- [2- (1Η-tetrazole-5- Group) phenyl] -5-benzylfuranyl] methyl] -2-butyl-4-chloro-1H-quinazol-5-carboxylic acid 2-methoxyethyl ester; 1-[[3 -bromo-2 -[2-(1 Η -tetrazol-5-yl) benzyl] -5 -benzofuranyl] (Please read the precautions on the back before filling out this page). Install ·, hit.-Green.- Μ-= _ 5 ^. Τ 4 (210X 297 ^ 'AT B7 C7 D7 六 、 Patent application Methyl] -2-butyl-4-atmosphere-1Η- 眯 azole-5-methanamine; 1- [ [1-[[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2-butyl-4-chloro-1Η- Imidazol-5-yl] carbonyl] pyrrolidine; Bu [[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2- Butyl-4-chloro-Ν-methyl-1H-imidazole-5-methylacetamide; 1-[[3 -bromo-2- [2- (1Η-tetrawa-5-yl) phenyl] -5 -Stupid Furanyl] methyl] -2-butyl-4-pyridine-H, N-dimethyl-1H-quinazol-5-methyl sugaramine; Bu [[3-Bromo-2- [2- (1Η- Tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2-butyl-4-chloro-N-ethyl-1H-imidazole-5-methylacetamide; Bu [[3 -Bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -4-chloro-2-ethyl-1H-imidazole-5-carboxylic acid; 1-[[3-Bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2-butyl-1H-quinazol-5- Formic acid; 1-[[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -4-chloro-2-propyl-N -Methyl-1H-imidazole-5-methylacetamide; Bu [[3-bromo-2- [2-UH-tetrazol-5-yl) phenyl "-5-benzylfuranyl] methyl]- 2-Butyl-4-chloro-N-isopropyl-1H-imidazole-5-methylacetamide; Bu [[3-bromo-2- [2- (lH-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2-butyl-4-iodo-1H-imidazole-5-carboxylic acid; [[3-bromo-2-[2-(1 Η -tetrazole-5- Radical) stupyl] -5 -benzofuranyl] methyl] -2 -butyl-4-trifluoromethyl-1H -imidazole-5-carboxylic acid; standard stamp of the Ministry of Economic Affairs (please read the notes on the back first (Fill in this page again) 1-([3_ Bromo-2- [2- (1Η-tetrazole-5-5-¾) benzene H] -5-benzofuranyl] methyl] -2-butyl-4methyl-1H-imidazole-5-carboxylic acid, Chlorinated basket (1: 1); T 4 (210X 297 male) A7 _ ^ _ D7 Sixth, the patent application model [[3 -bromo-2- [2- (1Η -tetrazol-5-yl) benzene Group] -5 -benzofuranyl] methyl] -2-butyl-4-chloro-1H-quinazol-5-acetic acid; 1-[[3-bromo-2- [2- (1Η -tetrazole -5-yl) phenyl] -5 -benzofuranyl] methyl] -2-butyl-4-chloro-1H-imidazole-5-ethyl acetate; 1-[[3-bromo-2- [ 2- (ethoxycarbonyl) benzyl] -5 -benzofuranyl] -2-butyl-4-chloro-1H-imidazole-5-carboxylic acid; 1-[[3_bromo-2- (2-carboxyl Phenyl) -5 -benzofuranyl] methyl] -2 -butyl-4 -gas-1H-quinazol-5-carboxylic acid; [U-[[3-bromo-2- [2- (1Η- Tetrazol-5-yl) benzyl] -5-benzofuranyl]] methyl] -2-butyl-4-chloro-1H-quinazol-5-yl] methyl] carbamic acid methyl ester; 1-C5-3-chloro-2- [2- (1Η-tetrazol-5-yl) phenyl] benzofuranyl] methyl] -2-butyl-4-hydrogen-1H-imidazole-5- Formic acid; 1-[[3-methane-2- (2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2-butyl-4-atmosphere- 1H-imidazole-5-carboxylic acid; 1-[[3-bromo-2- [2-ΠΗ -Tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2-butyl-4-amino-1H-imidazole-5-carboxylic acid-2-methoxy-1-methylethyl Ester; Bu [[3 -Huan-2- [2-[[Trifluoromethyl] sulfonyl] phenyl] -5-benzofuranyl] methyl] -2-butyl-4-nitrogen-1H -Pyrazole-5-carboxylic acid; Bu [[3 -Ao-2- [2- (1Η -tetrazol-5-yl) benzene S] -5-benzofuranyl] methyl] -2 -butyl- 4-Nitro-1H-imidazole-5-carboxylic acid, dipotassium salt; printed by Yaji Central Standards Bureau 1-[[3 -Bromo-2-[2-(1 Η -tetrazol-5-yl) benzyl ] -5 -benzylfuranyl] methyl] -4 -chloro-2-ethyl-1H -quinazol-5-carboxylic acid ethyl ester; -Α-Θ- 甲 4 (210X 297 公 广) (Please read first (Notes on the back and then fill in this page) VI. Patent Application Area A7 B7 C7 D7 Partial Standard Print 1-[[3 -Bromo- 2- [2- (1Η -Tetrazol-5-yl) phenyl]- 5-benzofuranyl] methyl] -4-chloro-2-ethyl-N-isopropyl-1H-quinazol-5-carboxamide; 1-[[3 -bromo-2- [2- (1Η -tetrazol-5-yl) phenyl] -5 -benzofuranyl] methyl] -4-amino-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester; [[3-bromo -2- [2- (1Η -tetrazol-5-yl) phenyl] -5 -benzofuranyl] methyl] -4 -methyl-2-propan Yl-1H-imidazole-5-carboxylic acid ethyl ester; 1-[[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl]- 4-methyl-1H-imidazole-5-carboxylic acid ethyl ester; Bu [[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzylfuranyl] methyl ] -5 -Methyl-1H -imidazole-5-carboxylic acid ethyl ester; Bu [[3 -Bromo-2- [2- (1Η -tetrazol-5-yl) phenyl] -5 -benzofuranyl] Methyl] -4 -Amino-2-methyl-1H-imidazole-5-ethyl formate; Bu [[3-Bromo-2- [2- (1Η-tetrazol-5-yl) benzyl] -5 -Benzofuranyl] methyl] -2-ethyl-4-methyl-1H-imidazole-5-carboxylic acid ethyl acetate; hydrochloride 1-[[3-bromo-2- [2- (1Η-tetra Azol-5-yl) phenyl] -5 -benzofuranyl] methyl] -2-ethyl-4 -methyl-N -methyl-1H-imidazole-5-methylacetamide; Bu [[3 -Bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -4-nitro-2-ethyl-1H-imidazole-5-carboxylic acid butyl Ester; Bu [[3- 涣-2- [2- (1Η-tetrazol-5-yl) benzyl] -5-benzylfuranyl] methyl] -4 -methyl-2-propyl-1H -Imidazole-5-carboxylic acid; Bu [[3-bromo-2-[2-(1 Η -tetrazole-5 -S) phenyl] -5 -benzofuranyl] methyl] -4 -methyl- 1Η-imidazole-5-carboxylic acid; 1-[5-[ 3 -Bromo-2-[2-U Η -tetrazol-5-yl) benzyl] benzofuranyl "" (please read the precautions on the back before filling this page) • Install ·. Dozen · . Line. -Μ-Τ 4 (210X 297 public) Sixth, apply for a patent scope A7 B7 C7 D7 Yabu Department ZTE-like quasi-bureau printing base] -2 -butyl-4-methyl-1H -imidazole- 5-ethyl formate; 1-[[3-bromo-2- [2- (1Η-tetrazol-5-yl) benzyl] -5-benzofuranyl] methyl] -4-ambient-2- Methyl-1H-imidazole-5-carboxylic acid; Hydrogenated [[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2-ethyl-4-methyl-1H-quinazol-5-carboxylic acid; Bu [[3-bromo-2- [2- (1Η-tetrazol-5-yl) benzyl] -5-benzo Furanyl] methyl] -4-'methyl-2-pentyl-1H-imidazole-5-carboxylic acid ethyl ester; 1-[[3-bromo-2- [2- (1Η-tetrazole-5-yl ) Phenyl] -5 -benzofuranyl] methyl] -4-methyl-2-pentyl-1H-quinazol-5-carboxylic acid; [[3-Bromo-2- [2- (1Η- Tetrakis-5-yl) phenyl] -5-benzofuranyl] methyl] -2,4-dimethyl-1H-quinazol-5-carboxylic acid ethyl ester; Bu [[3 -Bromo-2- [2- (1Η -tetrazol-5-yl) phenyl] -5-benzylfuranyl] methyl] -2,4-dimethyl-1H-imidazole-5-carboxylic acid; Bu [[3-bromo-2- [2-[[(trifluoromethyl) sulfonyl] amino] amino] phenyl ^ -5-benzofuranyl] methyl] -4-methyl-2-propanyl Yl-1H-imidazole-5-ethyl formate; Bu [[3-bromo-2- [2-[[(trifluoromethyl) sulfonyl] amino] amino] phenyl] -5-benzylfuranyl] Methyl] -4-methyl-2-propyl-1H-imidazole-5-carboxylic acid; Bu [[3-bromo_2- [2-[[(trifluoromethyl) sulfonyl] amino] amino] benzene Group] -5 -benzofuranyl] methyl] -2 -butyl-4-aminomethyl-1H -imidazole-5-carboxamide; and its physiologically acceptable formulas, hydrates, and metabolic non-sulfur Fixed ester. 13. Preparation of compounds such as any one of items 1 to 12 in the application range or their physiologically acceptable salts, hydrates, Ci-i enzyme solvates and metabolism (please read the precautions on the back before filling (Supper page). Installed. Line. Connected to 4 (210X 297 gong) -Q-547 MX ο 7 7 7 «AB c D VI. Patent application unstable low alkyl ester, alkoxyalkyl A method of ester, alkyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, aryloxyalkyl ester, aralkyl ester, aminoalkyl ester or hydroxyalkyl ester, which includes: (A ) General formula (II) -R- A kind of benzofuran in which L represents a leaving group, and the general formula (III) (III) Printed by the Central Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling the vault page) One of the imidazole (where R12 represents a hydrogen atom or a base ring is selected from Ci-e alkane The radical or C2-e alkenyl and R13 and R14 each independently represent a hydrogen atom or a halogen atom or one selected from Ci-e alkyl, fluoro Ci-e alkyl,-(CH2) mR °,-(CH2) "COR7 ·-(CH2)" NReC0Ro reaction, following -ϋΛ- Τ 4 (210X 297 public) ;; 〇1745 Six, apply for patent Fan ® AT B7 C7 D7 K, if necessary, remove any existing protecting group Group; or (B) general formula (IV). R1 Het-CH (IV) (Please read the notes on the back before writing this page) E 1 -Ar a protected intermediate printed by the Central Department of the Ministry of Economic Affairs (at least one of the reactive groups is protected by a protective group); (C) remove the general formula (la) (la) A compound (where R3 in the group Ar represents a umbilical group) reacts with an azide followed by M, if necessary, removing any protective groups present; or (D) the conversion formula (I b) 〒M210X 297 Koji) 01745 A7 B7 C7 D7 Six 'patent application R1 Het-CH2- a compound (in the general formula (I) and / become Xiebu alkoxy group 14.-species Learn about the sister C 1-4, alkyl ester-species 15. According to high blood loss, myocardial infarction 16-species or, if necessary, its physiologically acceptable stable low alkyl ester carbonyloxyalkyl ester or The hydroxyalkane can be used as a vascular complex, which includes a compound of formula (I) as a solvate or an oxyalkyl ester, an aralkyl ester, a physiologically acceptable prevention of patent application, or an aldosteronism syndrome , Cerebrovascular heterogeneous formula (II) compound -Ar (lb) where the base A "in which R3 represents Amine groups) into a compound where R3 represents -NHS02CF3),, the salt of the compound obtained by converting the general formula (I) or its salt, hydrate, alcohol solvate or substitution, alkoxy alkyl ester, alkoxy alkoxy Alkyl esters, esters, aryl alkoxy alkyl esters, aralkyl esters, amine vinegars. Angiotensin H (angiotensin H) includes any one of the patent application scopes of items 1 to 12 or its physiology Acceptable salts, hydrates, metabolically unstable lower alkyl esters, alkoxyalkyl esters, alkoxycarbonyloxyalkyl amides, aryl oxylamine alkyl esters, hydroxyalkyl esters, and at least Agents or excipients. The pharmaceutical composition of item 14, which is (丨) used for (ii) for the treatment or prevention of cognitive abnormalities, renal failure, heart failure, congestive heart failure, posterior heart failure and glaucoma. , (Please read the precautions on the back before filling in this page) Y4 (210X297 Public Broadcasting) 01745 A7 B7 C7 D7 VI. Applying for the patent scope R1 Ar (ID or its acid addition salt where R1 and Ar are as defined in item 1 of the patent application; and L represents a leaving group. 17. A compound of general formula (la), RJ Het-CH2 Ar (la: (please read the precautions on the back before filling in this page) Printed by the Central Operations Bureau of the Ministry of Economic Affairs or its acid addition salts-R1 * Ar and Het are as described in item 1 The difference is defined by this group Ar, R3 represents a si group. 18, a compound of general formula (lb), A 4 (210X 297 Gongguang) ^ τπττ Shan VV45 A? B7 C7 D7 Six, apply for a patent R1 Ket-CH -Ar (lb) compounds or their acid addition salts where R1, Ar and Het are as defined in item 1 of the patent application. The difference is this group Ar, R3 represents an amine group. 19. A compound selected from the group consisting of: 1-[[3-Bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2- Butyl-4-gas-1H-imidazole-5-carboxylic acid; [[3-bromo-2- [2- (1Η-tetrazol-5-yl) benzyl] -5-benzofuranyl] methyl ] -2 -Butyl-4-chloro-1H -imidazole-5-carboxylic acid ethyl ester; 1-[[3_Bromo-2- [2- (1Η -tetrazol-5.yl) phenyl] -5- Benzofuranyl] methyl] -4-chloro-2-propyl-1H-imidazole-5-carboxylic acid; [[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl ] -5-Benzofuranyl] base (please read the precautions on the back before filling in this page). Packing .. playing. Bromomethyl M. Central Ministry of Economic Affairs, Central Bureau of Printing and Printing 2 R 2 ί Leaf 1 Bromo 4-Bromo Ν 四 Ν 四 四 II--nitrogen 1Η nitrogen 1Η 乙 乙 四 ^ δ ^ ^ ^ this f 本本 ί 本 Η) Η) *) -1 yl -1 yl -5-yl yl 5-yl 5-azole 5--φ ^ -ζ, ^ αyl radical., Lan, furan amine furfuro furo benzo benzo toluene toluene benzene. Thread * A 4 (210 297 KO) A7 ^ 〇 i7 45 ο? _ __〇2 6. Patent application a methyl] -2 -butyl-4-methyl-1H -imidazole-5-carboxylic acid, hydrogen chloride (1: 1); 1-[[3- Bromo-2- (2-Carboxybenzene ) -5 -benzofuranyl] methyl] -2 -butyl-4-chloro-1H-imidazole-5-carboxylic acid; Bu [5- [3_Gas-2- [2- (1Η-Tetrazole- 5-yl) phenyl] benzofuranyl] methyl] -2-butyl-4-gas-1H-imidazole-5-carboxylic acid; [[3-bromo-2- [2-[[(trifluoro Methyl) sulfonyl] amino] phenyl] -5-benzofuranyl] methyl] -2 -butyl-4-chloro-1H-imidazole-5-carboxylic acid; [[3-bromo-2 -U- (1H-tetrazol-5-yl) phenyl] -5-benzylfuranyl] methyl] -4-chloro-2-ethyl-1H-imidazole-5-carboxylic acid ethyl ester; 1- [ [3_Bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -4 -chloro-2-propyl-1H -imidazole-5- Ethyl formate; 1-[[3-bromo-2- [2- (1Η-tetrazol-5-yl) benzyl] -5-benzofuranyl] methyl] -4-methyl-2-propane Yl-1H-imidazole-5-carboxylic acid ethyl ester; Bu [[3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] -5-benzylfuranyl] methyl] -2 -Butyl-4-methyl-1H-imidazole-5-carboxylic acid ethyl ester; hydrochloride 1-[[3-bromo-2- [2- (1Η-tetrazol-5-yl) benzyl] -5 -Benzofuranyl] methyl] -2-ethyl-4-methyl-1H-quinazol-5-carboxylic acid ethyl ester; Bu [[3 -bromo-2-C2-UH-tetrazol-5-yl ) Phenyl] -5 -benzofuranyl] methyl] -4- Yl-2-propyl-1H-imidazole-5-carboxylic acid; [5- [3-bromo-2- [2- (1Η-tetrazol-5-yl) phenyl] benzofuranyl] methyl] -2 -Butyl-4 -methyl-1H -quinazol-5-carboxylic acid ethyl ketone; Printed by the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling in the " this page) «Nitride 1 -[[3-Bromo-2- [2- (1H-tetrazol-5-yl) phenyl] -5-benzofuranyl] methyl] -2 -ethyl-4-methyl-1 Η- Imidazole-5-carboxylic acid; Τ 4 (210Χ 297 ^ 4?) A7 B7 ^ 01 ^ 45_ ρ; 6. Patent application a l-[[3-bromo-2- [2-[[(trifluoromethyl) Sulfosyl] amino] benzene S] -5-benzofuranyl] methyl] -4-methyl-2-propyl-1H-quinazol-5-carboxylic acid; [[3-Bromo-2- [2-[[(trifluoromethyl) sulfonyl] amino] phenyl] -5-benzofuranyl] methyl] -2-butyl-4-gas-N-methyl-1H-imidazole -5-Methoxylamine; and its physiologically acceptable salts, hydrates, 4 yeast solvates, and metabolically unstable lower alkyl esters, alkoxyalkyl esters, alkyloxyalkyl esters, alkoxycarbonyl Oxyalkyl, aryloxyalkyl, aralkyl, aminoalkyl or hydroxyalkyl esters. (Please read the precautions on the back before filling in this page) • Installed • • Played • • Line, printed by the Central Bureau of Standards of the Ministry of Mosquitoes 4 (210X297 public) \ + \ ⑽_ 丨 倾 第 79110222 Patent application谪 案 .— 一 ,, Chinese supplement ¥ Description (August 80) The angiotensin I receptor affinity of the compounds of the present invention can be demonstrated by the following receptor binding assay: from 150-250 g males 丨ista "The crested mouse obtains the old liver. Place the male liver group in 20 volumes of U / v) in ice-cold homogenized Yejie fluid (50 mM trishydroxymethylaminomethane; 5 mM EDTA; ρΗ7.4 4t: bottom) Mpolytron P10 homogenizer homogenization (set at 8, secondary explosion, for 10 seconds each time). The homogenized substance is filtered through a 300-micron nylon mesh, and then centrifuged at 48 t at 4 t 12 minutes, the upper layer of decanted liquid was poured out * The remaining flakes were resuspended in the homogenization buffer and washed, and homogenized using polytron Π0 (set at 5, a 5 second burst) * homogenized at 48,000 grams-heart 12 Min- ^ The final tablet was floated again in 50BM TrisHCl buffer solution (pH7.4, 25υ), and the concentration was 400 μg / μm. , Store it at -70 * 0 until needed. The film is stored for up to four months before use. 々Receptor binding assay The binding assay is conventionally based on 50ηΜ trimethylolamine with a final volume of 500 μl Carboxymethane, 100 mM NaCl, 10 mM MgCU, and lnM EDTA were measured in a buffer solution supplemented with 0.1% protease-free BSA and lmM (peptide 7.4, room temperature). The reaction was carried out in the room. Carry out 90 minutes at temperature, using 0.1% polyethylene imine (PEI) treated GF / B glass fiber filter (using B "andell cell collector) vacuum filtration to separate the combined and free ligand. The filter M was washed with ice-distilled water containing 100 mM NaCl and 5raM MgCU for 7 seconds. Move the filter to a plastic mini-tube, add 5 liters of P i co-F 1 uor 30 flashing agent, and shake the bottle vigorously 2 Hours. Determine the radioactivity maintained on the filter with a liquid scintillation counter. Lvw \ 0079. G 1 -I No. 1: Nine-Ο 二二二 専 利 Application Chinese Supplementary Note (May 81) Analysis data 1 * A compound of the present invention prepared according to the method of Example 69 was analyzed by X-ray scan . On the Siemens R2n / V encoder, using monochromatic Cu-Kα rays and 20 / w scanning, a total of 3329 reflections (〇 < 20 < 115 °) can be measured. The structure is analyzed in a direct manner, and the non-hydrogen atoms are refined anisotropically. All hydrogen atoms are located on the continuous difference map and refined by anisotropy. The unit lattice generation is shown in Garden 1A, and its filling diagram is shown in Figure 1B. The water molecule is attached to the carboxylic acid group (at the 5-position of the imidazole ring, which is Het in the definition of the compound). 2. Three forms of the compound of the following formula are prepared: Form I is recrystallized from the yeast and exists in the form of ethanol solvate. It is determined by NMR that it contains 5 to 6¾ ethyl yeast, which is equivalent to 3/4 molar yeast (ie 4 molar drugs: 3 molar yeast). It is also slightly moistened by water. Form E is prepared from Form I by column chromatography with dichloromethane: diethyl ether: acetic acid (200: 50: 1), which contains no measurable amount of solvent. \ EH \ 0068.G ^ 01745 The compound is evaluated and estimated in the liJS range of 10_4M to 10_12M, the concentration of the compound when it produces a 50% specific inhibitory effect, that is, IC50, K Η solution calculation, and inhibition Constant »-*--. ·--Ki value makes Nan Cheng-Pr.u9〇ff approximation-(Ling Y_C Cheng & WH Prusoff, Biochem. Pharmacol., (1973), 22., pp3099-3108) Measure IC 5 〇ki-1 + L / kd where L is the concentration of radioligand · kd is the separation constant of radioligand. The value of MpKi under K indicates that the pKi value is the negative logarithmic value of Ki. The preferred pKi value of the compounds of the present invention is between 4 and 12. The pU values of the compounds of Examples 1 to 92 range from 5.3 to 9.7; the pKi values of the compounds of Example 3, Name, 25, 44, 45, 59 and 66 are 9.2-9.7, 8.8, 8.9, 9.1, 8.75, 9.1 and 8.8. h »\ 0079.g 201745 Form III is prepared according to the method of Example 69, which contains 1 mole of tightly bound water, and is an X-ray structure as described in point 1. Different types of the most well-known test method / familiar test method (nSC / TG), prepared three kinds of test compounds of the above three forms of graphics, Figure 2. Form I (ethanol solvate) between 2010 and 801C, M10 ° / min, clock speed, loss of 1.8¾ non-tightly bound water. 1231 on the DSC chart: One of the sharp internal heat peaks is equivalent to the weight loss of 6.4¾ loss of bound yeast solvate on the TG chart. Form I [No weight loss until it melts and decomposes at 2141C. Form m (monohydrate) has a sharp internal heat peak at 1371 on the DSC chart, which is equivalent to a weight loss of 3.34¾ on the TG chart (theoretically 1 mole is 3.14! «). Loss of water at a fairly high temperature means that the water system is tightly bound. The crystal melted at 1861C. a The truth of form m is carried out with a vacuum microbalance. Drying 20 gram samples is quite difficult. Under the compressive force of O-4 OlPa, the sample must be heated to 55 " C for 2 days to cause heavy losses. Knot! The weight loss is 2.9¾, at this time the sample may not be completely dry. ~ Moisture is obtained at 251C by increasing the relative humidity (RH) in stages, and the weight is plotted against RH (Figure 3). When it is greater than about 5¾ RH, monohydrate is formed (3.24% dry weight) Then it absorbs a little more water (total 3.550 at 90¾ RH. K samples of the unsolvated form I repeat this experiment, the weight loss caused by drying the castellations overnight at 10-4 懄 ba compressive force is 1.02 ! e. When exposed to water vapor, only a relatively small amount of water is absorbed, gaining 0.8¾ at 42¾ RH, and 1.2% at 94¾ RH. Infrared spectrum of the sample after water absorption (Nujo 1) It shows that it has not changed ^ and has not been converted into a monohydrate. \ EN \ 0068.G ®〇〇ί 27 04 92 15:33 ¥ λ1 4051505 ELKIXGT0N & FIFE • V Figure IA: X-ray crystal structure 27-04 * 92 15:33 F. \ l 4051503. ELKINGTON & FIFE ®〇l (^ 〇1! Ϊ45. *. 圊 m: paint filling diagram 27/04 '92. · 13:39 FAX 4051.50S ELKINGTON S; FIFE Figure 2: DSC / TG chart / >-N £ t ZSCH 5 (i tLe / SeOwio · t Γν & ^ ικο I · 3 «-* α ty zc * ^ STR CS5 253 ®01 153 ^ 53 3-53 Tong type I rosMTirr. · ≪ < .. M273 9.3J ΟΛΤ £ 3S Fea \ 95 \ R £ p £ R € .scz Ct I92 / S-5 / 2 0.2S Ci »SKATCf? < £ S ATftas? 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