TW446704B - Naphtho[2,3-B]heteroar-4-yl derivatives for treating metabolic disorders related to insulin resistance or hyperglycemia - Google Patents

Abstract

This invention provides compounds of formula I having the structure, wherein R1 and R2 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or cyclopenty; R3 and R4 are alkyl of 1-6 carbon atoms; R5 is hydrogen or bromine; W is S, or O; X is O; R6 is hydrogen or alkyl of 1-6 carbon atoms; Y is methylene, carbonyl, or -SO2-; Z is phenyl, or thienyl; R7 and R8 are each, independently, hydrogen, carboxyl, hydroxyl, or -OCOR10; R10 is aryl of 6-12 carbon atoms, or alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia. Y is methylene, carbonyl, -SO2-, or-SO-; Z is phenyl, heteroaryl, or naphthyl; R7 and R8 are each, independently, hydrogen, carboxyl, acyl of 2-7 carbon atoms, hydroxyl, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkanoyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aryloxycarbonyl of 7-13 carbon atoms, heteroaryl-oxycarbonyl, heteroaryl, tetrazolyl, mercapto, alkylsulfanyl of 1-6 carbon atoms, nitrile, amino, carbamoyl, aminoalkyl of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, -NHSO2CF3, carboxyaldehyde, halogen, nitro, acylamino of 1-6 carbon atoms, 3-hydroxy-cyclobut-3-ene-4-yl-1,2-dione, or tetronic acid, -OCOR10, -OR10; R10 is aryl of 6-12 carbon atoms, aralkyl of 7-13 carbon atoms, monocyclic or bicyclic heteroaryl or a monocyclic or bicyclic heteroaralkyl, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.

Description

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 446 7 0 4 47 A7 B7 V. Description of the Invention (/) Background of the Invention It is known that glucose-resistant patients often have insulin resistance. Reaven et al. (Aaerican Journal of Medicine 1976, 60, 80) used perfusion glucose and insulin (insulin / vine grape fixation technique) and oral glucose resistance tests to indicate that insulin resistance exists in a wide range of non-fat necks. In non-ketogenic patients. The patient went from having critical glucose resistance to being markedly fasting to hyperglycemia. Diabetic patients in this study included insulin-related (IDDM) and non-insulin-related (N I D D Η) patients. Related to parenchymal insulin resistance is more tidal hyperglycemia, which can be determined by accurately measuring the circulating plasma insulin concentration in the patient's plasma. Hyperemia may occur due to insulin resistance, such as in obese and / or diabetic patients (NIDDH) and / or glucose non-resistant patients, or 1DDf • patients, due to excessive injection (more than normal physiological endocrine Secreted hormone) caused by insulin. The association between hyperglycemia and obesity and macrovascular hemorrhage (such as atherosclerosis) has been determined by mathematical experiments, clinical and epidemiological studies (reviewed by Stout, Metabolism 1985, 34,?, And by Pyoral a Et al. Diabetes / ((etab ο 1 ism Reeviews 1 9 87, 3, 4 6 3 detailed). Oral administration of S glucose 1 and 2 hours will significantly increase plasma insulin concentration, thus increasing coronary The risk of palpitations. Since most studies do not include diabetic patients, there is not enough data on the risk of atherosclerosis and diabetes, but non-diabetic patients all point in the same direction (Pyorala et al.). However, diabetes The mortality rate due to atherosclerosis in patients exceeds the non-diabetic population (Py〇 £ * aia and other paper standards apply Chinese National Standard (CNS) A4 (210 x 297 mm) --------- ------------ Order ---------- > < Please read the notes on the back before filling out this page) 5. Description of the invention (A7 B7 Gravity position, with the Portuguese Θ and vertical anti-ettoxin na cause, island di risk surgery m critical technology Γ0 pressure constant pressure f Blood solids, high blood sugar, high blood sugar, high fat, high fat, high fat, high fat, high fat, high fat, high fat, high fat, high fat, high fat, high fat, high fat, high fat, high fat, high fat, high fat, high fat, high fat, high fat, high fat and high fat. Porcine interstitial fl; Θ J 7 t resistance and 5 years of activity of humans, D1 island irrigation, etc. 1 to 2 30 0 high blood pressure and straight and muscle muscles around the perivascular group 9 II- high disease Fatty and high pressure can be made (please read the precautions on the back before filling out this page). The presupposition of the island island pancreatic fever is made by the B force of the machine. The 1E S system is limited to k & v but it is communicated. The blood numbers and heart organs often divided into different tubes were stimulated by the renin-stimulated island to stimulate the pancreas. C, the blood pressure of hemorrhin, which is often congested, is then increased to the pancreatic and renal resistance. Once the island is predominant, the island of the pancreas is resistant to the combination of the islands and the pancreas. The islets of the pancreas are the group of pancreatic tissues. If the island is pancreatic and the pancreas is eliminated, the enzymes will be activated in the early stage. Shows that the pancreas is stronger than that of fibrillin. It is obvious that according to the fat syndrome, hepatic volume in the department, tired. Meat often e D1 base of ah, 0 pass η and ri pass Ha Ha-by-line-Consumer Cooperation of Intellectual Property Bureau of the Ministry of Economic Affairs and Du The white egg making festival will call the enzyme device TP which is affected by fp and its prime island. -A? Membrane P TP activity ο P Enzyme activator amine is changed by caseinization Acid acid phosphorus phosphorus deionizer is divided into acid and amylase islands and pancreatic enzymes. In the special activity of the antisense enzymes, "pfv conjugated dll — 0 is controlled by the signal after the device is adjusted, but also enzymes ^ pli, ^ Energetic enzymes, such as 0%, and acid-phosphate-free proton-receptor-separated enzyme-excited paper X®, are applicable to the Seven Kingdoms Standard (C >: S) A1 I grid (2 buckles t) A7 446704 ______B7___ 5 The invention description ($) receptor is closely related, so it is most likely to regulate the insulin receptor kinase activity, including PTP1B, LAR, PTPor and SH-PTP2 (BJ Goldstein, (Please read the precautions on the back before filling this page) J · Cellular Biochetistry 1992, 48, 33; BJ

Goldstein, Receptor 1993, 3, 1-1 5; F. Ahtnad and B. J. Goldstein Biochem. Biophys Acta 1995, 1248, 57-69) e

McGuire et al. (Diabetes 1991, 40, 939) found that patients with non-diarrhea and glucose-resistant patients had significantly increased PTPase activity in the muscle group compared with normal people, and that insulin infusion could not inhibit insulin-sensitive patients as much as possible. PTPase activity β

Meyerovitch et al. (J. Clinical Invest. 1989, 84, 976) showed significantly increased liver PTPase activity in two IDDM mouse wedges (removal of diabetic BB mice and STZ-induced diabetic mice). Sredy et al. ( Metabolis », 44, 1G74, 1995) Observed from obesity, diabetes 〇1» / 〇1) mice (^ 0 (1 of the mouse model), their livers are similar? 1? Enzyme activity increased 〇 Ministry of Economic Affairs wisdom Printed by the Consumer Cooperative of the Property Bureau, the compound of the present invention shows inhibition of PTP_β of mouse liver withdrawal body and human recombinant PTPase MB (hPTP-lB) in vitro. It can be used to treat obesity, glutamate resistance, and sugar rat disease , Insulin resistance associated with hypertension and hemorrhagic diseases of large and small blood vessels. B.lieidl, et al. (EP 69349A1) published oxazolodinone A as an antibacterial agent. The paper standard is applicable to China National Standard (CNS) A4 specifications ( 210 X 297 mm) A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

NHAc

A △ • Bridges, et al. (EP 568289A2) published thienothioph. Eamidine B is a urea kinase inhibitor. Bu

H2N

B Η.-H Chen, et al., Indian J. C hea., Sect. B: Org C he bi. Include. Med. C he bi. 1 9 9 6, 3 5 B (1 2), 1 3 0 4-1 3 07 Published Compound C. This paper ruler 1 meets the Chinese National Standard (CNSM! Specification (2U.iv) 97g g _: > Packing -------- Order --------- Line (please first (Read the notes on the back and fill out this page) 446 704 A7 B7

N. E. Guirguis, et al., J. Prakat.

N. R, Guirguis, et al. Liebigs Ann. Ch. M. Dubroeucq et al. (EP 248734A1) also published E (Rl = Co2H) as anxiolytic. r ------------ Order --------- line., τ (Please read the notes on the back before filling this page)

This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) A7 _B7_ V. Description of the invention (6) T. Kuroda et al., J. Or g. Chem. 1 9 9 4, 59, 7 3 5 3-7 3 5 7 and J. Chem, Soc ,, Cheia, Consraun. 1991, 1635-1636.

F A.I. HaseniW A, J · Pr a k t. Che®. 1 9 7 7, 3 1 9, 6 8 9-6 9 2 Published Benzofuran G ^

MeQ ----------------------- Order --- I ----- (Please read the notes on the back before filling this page)

G Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs as an artifact (6 items received, etc.) A photo) Ao) This light Y 5 ο Electricity 3 (Professional book) Naphthyl aromatic 1 4 Son of the member Example Code y 物 ο Η Η Structure mz under 1 If L is a ring-shaped phen ring 啃

Wood paper scale applicable + national standard Ψ (CNWA1 specification mu ^ 297 mm) 446704 A7 B7 V. Description of the invention (7)

Η J. P. Konopeliski et al., Synlett 1996, 609-611, Ind. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

P, Molina et al., Tetrahedron, 1994, 50, 5027-36, and Tetrahedron Lett., 1 9 9 3, 34, 2809-2812 "Dry IJ Contains" cited in this paper. The paper standards are applicable to the Chinese National Standard (CNS) A4. (210 X 297 mm) ------------ r-i I! I — — Order · J — J — — ί γ (Please read the notes on the back before filling this page) A7 B7 V. Description of the invention (Biological J.

R = Η or Me

R Napolitano et al., Tetrahedron, 19 8.9, 45, 6749 60 published indole K. Η

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

ΗΚ G. Dryhurst et al., J. Am.

NH; ------------- install -------- order --------- line (please read the precautions on the back before filling this page) 1989, 111

L • 10 · A7 B7 446704 V. Description of the invention (9 M. d'Ischia et al., Tetrahedron, 1987, 43, 4 3 1-4 3 4 publish compound M.

< Please read the notice on the back before filling this page) Printed on the last page of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (A-M) and does not contain appropriate substituents for in vitro PTPase inhibitory activity or in vivo Anti-diabetic activity. DESCRIPTION OF THE INVENTION The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which can be used to treat metabolic abnormalities associated with insulin resistance and hyperglycemia: R7, 〆

This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) — — — — A7 B7 V. Description of the invention (Base 'cyano, alkane hydrogen is R1 per alkane and alkane in B

2 R-based amine ΠΠ- amine amine diyl amine alkyl sulfonyl 0 0 alkane gas all mono-benzene or phenyl phenyl sulfan-Shaan. 01 hydroxy phenyl hydroxy sulfonium,, the halogen halides with ring 8 to take 3- Tri-C or, radicals

R hydrogen is 4 R and 4 alkyl and alkyl alkyl fluoro per alkyl hydroxy 醯 7 I OJ C alkyl amine (Please read the precautions on the back before filling this page)

5 R for hydrogen

'S 6, I S C1 is W. Sulfinyl halooxy alkane β-based aryl aryl, hydrazone cyanosulfonate, aryl, alkyl fluoride gas peroxane 6 aryl 1-12

R is ο is

R is c R C or -N or hydrogen, hydrogen alkane or 2 Η

6 R ** = ΐί 丨 ^ ί alkane

p Y Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

R group hydroxy-; group so 醯 t or ·-? _ 2 group C 2 ο Tsai > -S or group, carboxyl group, carbonyl aromatic hydrogen, heterocyclic; group, each J ES 1 phenylene is For 8 R and alkoxy rf-based group--mine chloride 2 1 c C gas, ,, arylheterocyclopentane, sulfanyl 6-arylaryl 1-carbonyl 6 C -6 gas 1 1, C a C-based, 3, carbonyl 7-1-based gas C7 hydrogen-based carbonyl alkane_alkyl allyl square heteroamine, sulfur C fluoro ,, peraryl V 3 oxalaldehyde 1 I 2 6 tetramethyl c C, 'Amine', 'Alkyl'-based alkylaminoamine alkylalkylamines | A7 4 46 7 0 4 B7_ V. Description of the invention (d) -NHS02CF3, carboxaldehyde, halogen, nitro, ( : ^ Aldiamino, 3-hydroxy-cyclobut-3-en-4-yl-1, 2-di-, or 2,4-dioxotetrahydrofuran, -OCOR10, -OR10; R ΐσ is C 6-aryl , C 7-13 aralkyl, monocyclic or bicyclic heteroaryl, or monocyclic or bicyclic heteroaralkyl, Ci-6 alkyl, Ci-S perfluoroalkyl. Pharmaceutically acceptable salts can be made from organic and inorganic acids Formed, such as acetic acid, propionic acid, lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid Malonic acid, phenylacetic acid, hydroxysuccinic acid, phthalic acid, tritic acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid , And similar known permissible acids. When the compound of the present invention contains a carboxylate or phenol group, or can form an appropriate group of a phosphonium addition salt, salts can be formed from organic and inorganic phosphonium, preferably a phosphonium metal salt, such as sodium, lithium Or potassium. Alkyl, alkoxy, and alkanyl groups, alone or in combination with other words, are defined as branched or straight-chain optionally substituted with fluorine β cycloalkyl and optionally substituted with fluorine. Halogen is bromine, nitrogen, fluorine and Iodine. The aryl, aralkyl, aralkyl, aryl, aryl, or aryl ring substituents of the aryl carbonyl group are preferably phenyl, naphthyl, or 1,4-phenylhydrazine 5-yl, most preferably phenyl. The aryl moiety can be arbitrarily mono-, di-, or tri-substituted with a substituent selected from Ci-e alkyl, Ci-S alkylsulfonyl, Ci-e alkyl, Gas methyl, sulfonium, sulfur, C2-7 fluorocarbon, alkylamino, and dialkylamino groups where each alkyl group is Ci-6, nitro, cyano, -C02H, C2_7 alkylcarbonyloxy And C2_7 alkylcarbonyl The heteroaryl part of heteroaryl, heteroaralkyl and heteroaryloxycarbonyl is defined as -1 3- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read the back first Please fill in this page for the matters needing attention) Packing -------- Order --------- Printed by the Consumers 'Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs < A7 _B7_ V. Description of the invention (, >) Stable 5-10 membered mono- or di-heterocyclic fluorene, which contains a fluorene atom and 1-3 copper heteroatoms selected from 0 and s, a is selected from η phosphono, iso Porphyrinyl, pyridinyl, indyl, isoindolyl, pyrrolyl, bridolinyl, morphazolyl, fluorenyl, isofluorenyl, iso_azolyl, Btthenyl, daphthyl , Pyrimidinyl, sulfanyl, furanyl, benzofuranyl, benzoxazolyl, benzodiazolyl, pyrimidinyl, pyrrolidinyl, benzoxazolyl, benzopyrazolyl, Benzamidine isofluorenyl, isoxazolyl, oxadiazolyl, tris-yl, isophenylhydrazine, p-phenylene and phenylhydrazine. Heteroaryl can be mono-, di- or tri-substituted with any substituent selected from Ci-6 alkyl, alkanesulfonyl, Ci-s alkane, trifluoromethyl, halogen, sulfhydryl, C2-7 alkane Carbonyl, Ci-e alkylamino, and dialkylamino groups in which each alkyl group is Ci-e, nitro, amino, -co2H, C2-7 alkylcarbonyloxy, and C2-7 alkylcarbonyl. The compounds of the present invention may contain one asymmetric sulfonium ion and some of the compounds of the present invention may contain more than one asymmetric center, and thus may contain optical isomers and diastereomers. When stereochemistry is ignored, the present invention contains the optical isomers and diastereomers; and racemic and resolved enantiomerically pure R and S stereoisomers; and other R and S stereoisomers are mixed Chemicals and pharmaceuticals allow salt. The compounds of the present invention can also be atropisomer by limiting or slowly rotating aryl-tricyclic or aryl-bicyclic single bonds. This restricted rotation yields another pair of palm centers to give the enantiomer. When the molecule contains another pair of palm centers, diastereomers are present and can be detected by MMR and other optical techniques. Formula I When atropisomer stereochemistry is disregarded, the present invention contains the atropisomer (enantiomers and diastereomers); and racemic and resolved pure diastereomers and diastereomeric mixtures and pharmaceuticals Allow salt. The present invention is more than-] 4-------------- install -------- order --------- line (please read the precautions on the back before filling (This page) This paper is K degree suitable for two towels and S garden furniture. Specifications (210 X297 · public wear

The compound containing the chemical compound Zhongjia its salt, Xu Rong Pharma, or its compound, is hydrogen, and each compound is 2 R and the alkane gas is S. Alkyl methyl fluorotrifluoroethane is generated in 6 generations of 1 C and is based on phenyl benzene or 6 radicals. Phenylbromochlorooxymethanamine Bt R hydrogen and each alkane

X, 4. S ο is an alkane or an unsubstituted haloalkyloxyaryl alkane ^ ^ 0 ® M. Or; all 61 & oxan 6-6 oxofur 1-C1 alkane or M, ¾ group ¾ group Base Gas 0 Sulfur (Please read the notes on the back before filling out this page) or Hydrogen is based on alkane ρ Υ is printed for bases and fluorofluorosulphonyl groups for the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Zidylazole 'Carboximidine C, Pyridine, C2CE, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C. 712 pyrimidinylhydrothiolptt thiofurfuryl s Lf _ hope or π ΐ 脞 if XOR '' carboxycarbonyloxyalkane aryl 13 azole 7 tetrayl sulfonyl aryl methylamine amine amine & amp i Isocool V, full-M, 62--6-kiloyl '] C 1 oxygen, yl 1 C azole C, aryl fluorene: amine, radical su P, hydrazone * 7-' alkane C group I oxane fea Cyanide 6 hydroxy-ε, β- 1-ylpyridine '1 6 C c I gas, amine alkane 6 > ^ 0 C carboxy' 6 alkane | amine C1 6 is 1-based alkane ' Substitute pyrimidine or pyrimidine OR Basic Nitrosamidine Sulfane -------- Order --------- Line 丨 This paper size applies to China National Standard (CNS) A4 specification (2J0X297 mm)

Ketodi I 2 * radical I 4 I ene I 3 I butyl ring hydroxy aryl 12-6 C is aryl aromatic heterocyclic ring or cyclic monoalkyl aryl aryl aryl slashing ** or cyclic mono or berry alkane K The compound containing the formula is better and the alkane in the hair is better. • 'f * J · 1. 1-based C alkane 6 0-is C 1 each 2 4 RR and salt salt drug; Compound, bromine bromide ο or 0 is S ο is or (please read the notes on the back before filling out this page) install or hydrogen for berry alkyl 6 azole. Blind C1; or-plant 'S 02¾ Chuns kK I, or nt, halo, 1-6 carbonyl carbonyl hydrogen C1, carbene, methyl, phenylene, etc .: printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

, Radical R1 cyano C0 hydroxyl, -0, radical, oxazolyl 醯! f 醯 e Isosulfone 1, C-based S 'pyridine 1-r J-based alkane i is Θ a salt C Xuorong 1-6' drug C-based system to replace its heterocycle and take a cyclic monocyclic pyridine ' Pyrimido or aryl is 0:12 and fordidine is a 16- ^ mt ^ -o ^ c® alkane or or ¾benzyl alkane-line. Example base-hydrazyl base

Dii-based sulfonylbenzene I-isopropanoic acid-hydroxy-hydroxy-iso-smelling cake ί bundle-methyl I 4 " 0} fluorenyl 0 sulfo «benzene J benzoic acid benzyl _ kexiang example 0 ^ νί 骈 琴 I 蕋 甲Looking forward to ¥ C = l · This paper size is applicable to the National Corrugated Book (CNS) A4 specification GKh 297 male f) 446704 A7 _B7_ V. Description of the invention (, Γ) • Cyclopentyl-benzene gas Fluorenyl] -2-hydroxy-benzoic acid; Example 4 4- [4- (9-Bromo-2,3-dimethyl-naphthalenepyrene [2, 3-b] Blind-4- (Please read the back first Note on this page, please fill in this page) Base) -2, 6-diisopropyl-benzenesulfonyl] -2-hydroxy-benzoic acid; Example 5 2 -Ethyloxy- 4- [4- (9 -Bromo-2, 3 -dimethyl-naphthalenepyrene [2, 3-b] span-4-yl) -2, β -dimethyl-phenoxysulfonyl] -benzoic acid; Example 6 2- Acetaldehyde-4-[4-(3 -bromo-2, 3 -dimethyl-naphthalene [2,3-b] azepan-4-yl) -2-cyclopentyl-benzenesulfonaldehyde Group] -Benzyl acid; Example 7 2-Butanylamino-4- 丨 4- (9-bromo-2, 3-dimethyl-naphthalenepyrene [2, 3-b] darkphen-4-yl)- 2, δ-dimethyl-phenoxysulfinofluorenylbenzoic acid; Example 8 2-fluorenylamino- 4- [4- (9-bromo-2, 3 -dimethyl-naphthalenefluorene [2 (3 -b] phen-4-yl) -2,6-di Methyl-benzene sulfonaldehyde] -τ acid; Example 9 2-propanyloxy-4- [4- (9-bromo-2, 3-dimethyl-phyllene [2,3-b] Pan-4-yl) -2, 6-dimethyl-benzenesulfenyl] -benzoic acid; Example 1 0 5-[4-(9 -Bromo-2, 3 -dimethyl-Lyridine〗 2 , 3-b] benzophen-4-yl) -2-cyclopentyl-phenoxysulfanyl] -4-methoxy-benzophen-3-carboxylic acid; Example 11 5- [4- (9- Bromo-2,3-dimethyl-lysamidine [2,3-bI benzophene 4-yl) -2-cyclopentyl-phenoxysulfosulfanyl 4-hydroxy-blazepan-3-carboxylic acid; Example 12 4- [2-Cyclopentyl-4- (2,3-dishenyl-naphthalene [2,3-1)] | 1 phenpheny-4-yl:)-benzenesulfonyl]- 2-Hydroxy-benzoic acid; Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1 3 4-[2 -Cyclopentyl-4-(2, 3 -dimethyl-naphthalenepyrene [2, 3-b] furan -4-yl) -benzenesulfenylsulfonyl 2-hydroxy-benzoic acid; Example 1 4 4-[2 -Bromo-4-(2, 3 -dimethyl-Lyridin [2, 3-b] furan -4 -yl) -benzenesulfonyl] -6-ethyl-phenoxysulfonyl] -2-hydroxy-benzyl acid; Example 1 5 4-[4-(2, 3 -dimethyl-leaf骈 [2, 3-b] furan-4 -yl)--1 7 _ This paper size applies to China National Standard (CNS) A4 (210 X 297 (Mm) Printed A7 _B7_ by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the Invention (A) Benzenesulfonyl 2,6-diethyl-benzenesulfonyl] -2 -hydroxy-arsinic acid; Example] G 4-f_ 4-(9 -Bromo-2,3-dimethyl-naphthalenepyrene [2, 3-b] Bantan-4 -yl) -2, 6-dimethyl-phenoxsulfonium 1-2 -hydroxy-benzoic acid tert-butyl ester; Example 1 7 2-(4 -Mechloroninofluorenyl) oxy-4-[4-(9 -Bromo-2,3-dimethyl-Rylide骈 [2, 3-b] P? Pan-4-yl) -2, 6-dimethyl-benzenesulfonyl] -T acid; Example 18 5- [4- (2, 3-dimethyl -Naphthalene hydrazone i2, 3-b] benzophen-4-yl) -2, 6-diethyl-benzenesulfenylsulfanyl 4-methoxy-blazepan-3-carboxylic acid; Example 1 S 5- Pyridine-2 -yl-benzophen-2-sulfonic acid 2-cyclopentyl-4-(2,3-dimethyl-naphthalenepyrene [2, 3-b] benzophen-4-yl) -phenyl ester; Example 20 4 -Benzyloxy-5- 丨 4- (2, 3 -dimethyl-lysam [2, 3-b] iphenphen-4 -yl) -2, 6 -diethyl-phenoxy Sulfobiphenyl 4-methoxy-Pf phen-3-carboxylic acid; Example 2] 3-[2 -Chenpentyl-4-(2, 3 ~ dimethyl-Lyridin [2, 3-b Η Sepan-4-yl > -benzylsulfenylbenzylic acid; Example 22 5- (2-Methanesulfonyl-pyrimidine-4- Group) P Hanpan-2-sulfonic acid 2-cyclopentyl-4- (2,3-dimethyl-naphthalene cake [2,3-11] _powder-4-yl) -benzenecool; Example 2 3 2 -benzylamino-4-[4-(2, 3 -dimethyl-naphthalenepyrene [2, 3-b] benzophen-4-yl) -2, G -dimethyl-phenoxysulfonyl ] -Benzyl acid; Example 24 2- (4-chlorobenzylfluorenyl) oxy-4- (4- (2, 3 -dimethyl-naphthylhydrazine [2, 3-b] pyridin-4 -yl)- 2, 6 -dimethyl-phenoxysulfonyl] -benzyl acid; Example; Ϊ 5 SI alkaline acid 2-carboxy-5 ~ 丨 4-(2, 3 -dimethyl-naphthalene 骈 U, 3-b ] -1 8-The scale of this book is suitable for the country + national standard standard specifications Q1G, 2 & T public) ------------- install -------- order-- ------- line (please read the precautions on the back before filling this page) d d6 7 Ο 4 A7 _B7 V. Description of the invention (W) Look forward to 6 2 cases of basic acid 4-base 0 -b-3 6-T, 4-, 4-carboxy, carboxyl, ester, phenyl-1, hydrazone, p-oxybenzyl, methyl bromide, methane-oxo, 1-toluene, benzoyl] The table shows that it is available for sale in this city. The legalization of the material system can be obtained from the original listing. Published Articles Published Publications Presented by Relics Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and printed by Consumer Cooperatives

(VI

Rsftr, I 9 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) ------------- ¾ ---- (Please read the precautions on the back before (Fill in this page) Order --------- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Λ7 ___B7_ V. Description of the Invention (d) In the reaction scheme 1, 2, 3 -dimethylbenzophene (II: W is S) 3 -methylbenzophene-carboxaldehyde can be obtained from the market, using W ο 1 ff-Kishner conditions (well refluxed in KOH / ethylene glycol. Compound (II) can be treated with i ~ 1.3 Mo Ear-equivalent lithium alkane agents, such as N-butyl lithium, are most suitable for aprotic solvents (such as THF), at -78 ° C ~ room temperature, reaction under inert gas such as nitrogen or argon can be obtained 2-lithiated- 崦Or a furan derivative. This lithium compound is reacted with more than one molar equivalent of formaldehyde at -78 ° C to room temperature for 5 minutes to 3 hours to obtain a compound of formula (III: Q = 0 H). III) The hydroxyl group (Q = 0 Η) can be removed by reduction method, such as hydrogenation using a platinum catalyst to obtain a compound of formula (III: Q = Η), but it is easiest to use Nutiiitis et al. (Org. Prep. And Proceed. Int. 1 9 9 1, 2 3, 4 0 3-4 1 1 ) Method, wherein (III: g = H; W is S or 0), in a suitable solvent such as diethyl ether, THF or methane, and stirred at (TC ~ room temperature with 1 ~ 10 mole equivalents of borohydride Sodium, a compound of formula (III: Q = can be obtained by slowly adding 1-5D molar equivalents of trifluoroacetic acid over 15 minutes to 3 hours. In addition, the 2-lithium compound containing compound (II) is aprotic such as THF The solvent can be directly reacted with more than one molar equivalent of benzyl halide such as benzyl bromide (PhCH2 Br) at -78 ° C ~ room temperature to provide a compound of formula (III: Q = W is S or 0). Compounds of formula (III: Q = Η) can be converted to commercially available formulae with one or more molar equivalents (ΐ V: X =-0 M e) benzylhydrazine can be obtained (V: X =-0 H e) Derivatives of this kind. This brew is most easily used with 1 ~ 5 mol equivalent of Lewis acid catalyst, such as tin tetragas or ammonium chloride, such as digas methane, 1,2-digas ethane or Carbon disulfide is an inert solvent at -78 ° C to room temperature. T。 gas (醯 V: X =-0 H e) can be compared with benzyl acid in accordance with standard method -2 0-. This paper H even 珣 middle circle National Standard Feng iL'NSMl Specifications 丨 ϋ >: 1:97 mm) ------------- Installation -------- Order --------- Line (Please read the precautions on the back before filling this page) A7 446704 _B7_ Five 2. Description of the invention (θ) The raw material of benzic acid ^ T 醯 chloride (IV: X = -0Me) obtained by using grass gas and sulfonium gas is commercially available or can be prepared by known methods. For example, the acid starting material of τ 醯 gas (IV) can be prepared by the modification method of Schuster et al., J. Org. Chem. 1898, 53, 5818. Commercially available 2,6-dipropofol is brominated (bromo / acetic acid), methylated (iodomethane / potassium sulfonate / DMF) at the 4-position, and reacted with n-butyllithium to exchange lithium halides. The reaction of organolithium with disulfonated sulfonium gives 3,5-diisopropyl-4-methylbenzyl acid. In addition, 2, 6- (mono- or di-substituted) phenols are commercially available and can be methylated (iodomethane / potassium sulfonate / DHF), brominated at the 4-position with 2-chlorobenzaldehyde gas, proud of the existence of gasification Lithium in an inert solvent such as digas methane at room temperature, and react with potassium tributoxide in water / ethanol dimethyl ether at room temperature to obtain the target 2, 6- (mono- or di-substituted) benzyl acid. The cyclization of compounds of formula (V: X = -0Me) is generally suitable to use 1 to 10 mol equivalents of strong Lewis acid, such as trihaloborane, most preferably tribromoborane. The reaction is suitable at -78 ° C ~ room temperature, or heated to 5 (TC, in a halogenated hydrocarbon solvent such as digas methane, under an inert gas such as nitrogen or argon. It will not only cyclization and aromatic cyclization and loss of water at the same time And demethylation of the prominent methyl group to obtain a compound of the formula (VI: X =-0 Η). The compound of the formula (VI: χ = -0 可) can be sulfonated with phenoloxy, using more than one pseudo Ear-equivalent appropriate sulfonium elixir to obtain the formula (η sulfonate. The sulfonaldehyde is often an aryl or heteroarylsulfonium sulfonium gas. The reaction is suitable for standard methods using an appropriate age such as sodium hydride, pyrimidine or Tris sulfonium. Solvents such as methane, THF or water are carried out at room temperature. The raw materials for sulfonium are commercially available or can be prepared by known methods. For example, aryl or heteroarylsulfonium can be used -2 1 -This paper size applies to China National Standard (CNS) A4 (210x297 mm) I -------- ^ --------- (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Printed by A7 B7. 5. Description of the invention (/) Aryl or heteroarylsulfonic acid with more than one mordan Oxalamide or sulfonium gas is reacted in a suitable solvent such as digas methane, aeroform or ether to obtain an aryl or heteroarylsulfonium gas. This reaction is generally based on Shaojing (Qm-Gi Mo Er) It is catalyzed by dimethylformamide. In addition, sulfonium gas can also be prepared by the modification method of Barrac 100ugh et al., Arch. Phai'ffi. (W einheii) 19 9 0, 323, 507. It will be commercially available 4-Aminosalic acid sodium salt dihydrate can be obtained by nitriding with sodium nitrite. At HOAc / HCl and -10 ° C, the diazide salt is converted to radon gas due to the presence of gasified copper (I). The introduction of disulfide sulfur is completed. The R7 and ϋ8 groups connected to Z can be re-derivatized. For example, when R? Or E8 is a carboxylic acid ester or alcohol, this compound can be converted to a relative carboxylic acid or alcohol using standard methods. This transformed alkali-containing solution contains more than one mole equivalent of water of an alkali metal hydride such as NaO Η and water such as THF, dioxane or a lower alcohol (such as methanol), or a mixture of THF and a lower alcohol at D-40 ° The reaction is carried out under C. The acid conditions for converting the ester to an acid include the use of trifluoroacetic acid under a suitable solvent such as methane, e. ^ A vs T A 檫 7, gold is chlorine phase, gas is used, R7 is used, and S is bis, so when KR-1 is turned into gas, the product may be 〇,? 1 Use alkane ί ethyl affinity ethanol to make the boron mixture such as brominated with grade β 傜 brominated at so this lithium one lithium three times this gas, DM. Contrast, is, it is appropriate to use ester hydrogen phase hydrogen Alcohol, gold and manganese make or aluminum as the most alcoholic acid, such as oxidized and oxidized, e is also gaseous and carboxyl, but can be converted from sodium alkane U to glycol 7Γ by boron. 8 Alcohol hydrogen phase _R7 pseudo salt should be W grade boron to three when its ingot is reversed \ 1 So, turn like this. > Your Majesty R7 pair, Alcohol Acidifier _ Acidizer When the phase ketone is soluble or complex. In order to improve the acidity of the hydrocarbons, the aldehyde should be converted to aldehyde, such as strong _ Carboxylic acid inert reaction method is equivalent to this amount. Order --- it --- I t Please read the notes on the back before filling out this page): t. Paper Sense 坨 + § S Standard Leather (CNSM) Specifications (:: Ίϋ 297 male f; A7 44670 ^ B7_ V. Description of the invention (M) Fluorohexyl sulfonated diimine, acetic anhydride, trifluoroacetic anhydride, grass gas or disulfurized sulfur) and gasification. When R7 or R8 is a carboxylic acid, this compound may be Conversion to carboxylic acid amines. This transformation can use standard methods to convert carboxylic acids to carboxylic acid amines. This method involves converting an acid to an activated acid and reacting with more than one mole equivalent of the desired amine. This amine contains ammonia such as Ammonium hydride, hydroxylamine and 2-amine propionitrile. The method of activating carboxylic acid involves reacting an acid with more than one molar equivalent of grass gas or sulfonium gas to obtain carboxylic acid gas such as methane, nitrogen or ether. A suitable solvent. This reaction often catalyzes dimethylformamide in small amounts (0.01-0.1 mole equivalents). Other methods for activating carboxylic acids include sulfonating dicyclohexyl sulfide with more than one mole of acid Amine, in the presence or absence of more than one mole equivalent Hydroxybenzazole triazole, in a suitable solvent such as diaminomethane or dimethylformamide, and sleep at 0-6 (TC). When R3 or R4 is a carboxylic acid, this compound can use alkyl or triazine Aryl acetate (aryl trihelimide acetate), esterified in the presence or absence of a solvent such as BF3Et20 or methanesulfonic acid, such as methylene chloride, ethyl acetate or cyclohexane. When R7 or K8 is nitrate This compound can be reduced to the relative amine compound. It is most suitable to use fluoride, in ethyl acetate and 40-intrc, or with ethanol or montmorillonite in o-iotrc, or in the presence of Pd- The catalyst is argonized under the C catalyst. When R7 or R8 is a nitro group or an alcohol, this compound can be aminated with more than one mole equivalent of a suitable ammonium agent. The ammonium agent is generally a low alkyl or aryl carboxylic acid anhydride. Or low alkyl or aryl carboxyl gas. The reaction is performed using standard methods, such as using pyridine as a solvent with or without a co-solvent (such as digas methane), and reacting at o ° c ~ room temperature. When R7 When R8 is an alcohol, it can be fermented with low alkyl or aryl carboxylic anhydride, and its strip is reacted with iodine-manganese in ether and refluxed at room temperature. When "3 -2 3- Paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) < Please read the precautions on the back before filling this page) Loading -------- Order -------- -Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs and printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7_: _ 5. When the invention description (β) or R4 is alcohol, this compound can be reacted according to Mitsunohu reaction (for a review, see Oyo Mitsunobu Synthesis , 1981, 1-2

The co-reagents required for the Miisiinobu reaction contain more than 1 mole equivalent of low alkane azide dicarboxylic acid, such as diethyl diazepine dicarboxylate and more than 1 mole equivalent of triaryl hydrazone, such as triphenylhydrazone, such as diethyl ether, THF & gt A suitable solvent for benzene or toluene, which is reacted at -2 (TC ~ 12 (1 ° C. When R7 or R8 is a nitrile, this compound can be reduced to an amine compound, which uses gaseous tin (II) to reflux Ethyl acetate_ or catalyst hydrogenation in an inert solvent such as B_ under a catalyst containing such as Raney nickel or lithium aluminum halide. When R 7 or R 8 is nitrile, it can be converted to carboxylic acid using standard methods. Amidine, if HC1 / HC 20 is refluxed at room temperature, or a warmer method such as reacting the eye with an alkali solution of Η 202. When | {7 or 1 ^ is a halogen or triflate, it may be According to the method of Leibeskind et al. (J. Org. Chent. 1990, 55, 5359) to 3-hydroxycyclobutan-3-en-4-yl-1,2-di, when R7 or 148 is an alcohol, it can be alkane Reaction with a suitable alkylating agent, such as alkane hydrazones of more than 1 mole equivalent, in a suitable solvent such as THF, DHF or DMS0 under a base containing, for example, potassium carbonate or sodium hydroxide, at (TC ~ 6 (TC). When R 3 or R When 4 is a carboxylic acid, the compound can be used with a coupling agent such as 1- (3-dimethylaminepropyl) -3-ethylcarbodiimide in a suitable solvent such as triethylamine or DMAP and DMF. The next coupling to 2, 4-two gas tetrahydrofuran. -24- ------------- installed -------- order i ------- line (please read Note on the back, please fill out this page) 446704 V. Description of the invention (η 流 稃 2 Α7 Β7

f (VIII)

RE

Br R7 or (IX)

R8— z, OH

Printing of clothing by employees' cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Other derivatives of formula (I) compounds can be prepared according to the following law. Phenols and amines of the formula (VI: X = NH2i OH, -CH2NH2) can be alkylated to 1 mol equivalent of haloalkaryl or pinane heteroaryl of formula (VIII) and more than 1 mol equivalent. (Such as potassium sulfonate), reaction in a polar aprotic solvent such as DMF to obtain the alkylate of formula (I). A phenol of formula (VI; X = 0Η) can be reacted with a hydroxyalkaryl or hydroxyphosphonium heteroaryl of formula (IX) according to Mitsunobu reaction (for a review, refer to Oyo Mitsunobu Synthesis, 1 9 8 1, ί-2 7). (I) Alkides. Other co-reagents required for the Mitsunoobii reaction contain oligoalkyl azides of more than 1 mol equivalent, such as diethyl azide dicarboxylic acid or diisopropyl hydrazone dicarboxylic acid, and triaryl hydrazone of more than 1 mol equivalent. (Such as triphenylhydrazone), as a solvent such as diethyl ether, THF, benzene or toluene, and react at -20 ° C ~ 12 G. The hydroxyalkaryl or hydroxyalkheteroaryl starting materials are commercially available or can be prepared by known methods. For example, aryl or heteroaryl carboxylic acids or esters can use standard methods-2 5-: / 装 -------- Order ------- I »" {Please read the back of the river first Please fill in this page for the matters needing attention.) This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210x 297 mm). 5. Description of the invention (w A7 B7 reduction to a relatively first-class enzyme, such as lithium aluminum hydride in ether. Aromatic Or heteroaryl aldehydes or cyano groups can be reduced to relatively primary alcohols, using metal catalysts such as sodium ferment, sodium borohydride, and lithium aluminohydride. Formula (vm) haloalkaryl or _alkheteroaryl raw materials for the city It is commercially available or can be prepared by known methods. For example, a hydroxyalkaryl or hydroxyalkheteroaryl of formula (IX) can be reacted with sulfonium gas, three-walled P, triphenylene or triphenylsulfonium, in In the presence of tetracarbonated carbon, it is converted to halogen derivatives. In addition, haloalkaryl or alkheteroaryl raw materials can also be obtained by brominating the alkaryl or alkheteroaryl group with N-bromobutimidine. AI Β N, reacted in solvents such as benzene and with or without UV irradiation. Flow stalk 3 R7

7 0 (person T person, r8

CI

------------- Installation -------- Order --------- Line (Please read the precautions on the back before filling this page) Intellectual Property of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperative (I: X is -NH-; -CH2NH-) Reaction Scheme 3 Other derivatives can be prepared according to the following method. Compounds of formula (V I: X = Ν Η 2, Ο Η, -C Η 2 Ν Η 2) can be oxidized with phenol to obtain compounds of formula (I). The halogenating agent is generally an arylcarboxylic anhydride, or an aryl / heteroarylcarboxylic acid chloride. Use standard methods to perform the reaction, such as using pyridine as a solvent with or without a co-solvent (such as dichloromethane), and react at 0 ° C ~ room temperature. -2 6-This standard scale is suitable for the 0 family standard in the standard specifications (21 bu: 37 male f) j 4 46 7 0 4 A7 _B7 V. Description of the invention (,)

(Please read the precautions on the back before filling out this page) Packing -------- Order --------- The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs is printed in the three steps of the reaction process 4 The compound of formula (VI: X = 0 Η) can be converted into the compound of formula (VI: X = -CH2 NH2). The compound of formula (VI: χ = 0Η) is reacted with trifluoromethanesulfonic anhydride or trifluoromethanesulfonium chloride in digas methane in the presence of pyridine or triethylamine at o ° c ~ room temperature to obtain the formula (X) compounds. The formula (Γ) trif late can be reacted with potassium cyanide or zinc sulfide in the presence of tetrachrysene triphenylsulfonium (0) (which can be prepared from bistriphenylphosphonium nickel (II) bromide and Zn / PPh3) Is a nitrile of formula (XI). Nitrile (Jil) can also be converted to an amine compound (VI: X = -CH2NH2), which is formed by gasification -27- This paper size is applicable to National Standards (CNS) A4 (210 X 297 mm) A7 B7

X

V. Description of the invention (4 m (τη reflux with ethyl acetate, or catalyst hydrogenation under a catalyst containing, for example, Raney nickel or lithium aluminum hydride, under an inert solvent such as diethyl ether. The resulting compound (VI: X =- c Η 2 NH 2) can be used in reaction scheme 1 to prepare formula (1: X =-C Η 2 Ν Η-) sulfonamide, or in reaction scheme 2 to prepare amines of formula (i: X = -Cfi2NH-) Derivatives, or in reaction scheme 3 to prepare hydrazine of formula (I: X =-CH 2 N H-). Scheme i

X

I;-c N; aryl; heteroaryl; X is 0H) Other derivatives of the compound of formula (I) in the reaction stream 5 can be prepared according to the following method. Formula (Vi * · R1 and R2 are η; X is 0H) Phenol (Reaction Scheme 2) can be iodinated to the formula (VhR1 and R2 is I; Ji is 0Η) diiodophenol, which is commonly used above 2 moles Iodine, in the presence of more than 2 mol equivalents of alkali metal rhenium hydroxide such as NaOH, in alcohol solvents such as methanol, at -2 ° C to room temperature. C Similarly, monoiodophenol (VI:!? 1 or R2 is ι; χ is 0H) can be represented by the formula (VI: R 1 or R 2 is Η; X is 0 Η :) Phenol, using 1 to 1, 5 moles of iodine. In the presence of mole equivalents such as NaOH's Alkali Metal Hydrogen-2 8-Sheet & Degree Applicable Sg Home Standard Specification < 37g f) -------- Order --------- (Please read first Note on the back, please fill in this page) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 1 446704 1 446704 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 ___B7_ V. Description of the invention (β) The solvent is obtained by reacting at -2 ° C to room temperature. Monoiodophenol (VI: R2 is I; X is 0H) or diiodophenol (VI: 1 and R2 is I; X is 0H) can be converted into relative formula (VI: R2 is I; X is-OMe) or ( VliR1 and R2 are I; X is-OMe) methyl ether derivatives, which is caused by the phenol and a suitable methylating agent, such as methyl iodide or dimethyl sulfate of more than 1 mole equivalent, using an alkali metal sulfonic acid A salt or a hydride base (such as potassium sulfonate or sodium hydride) is obtained by reacting in a suitable solvent such as THF, DMF or DHS0. This reaction is generally carried out at 0 ~ 6Q ° C. The formula (VI: R1 and / or R2 is Br; X is-0Me > mono or dibromo derivatives can be prepared by replacing bromine with iodine in a similar manner. Formula (VI: R2 is I; X is-OMe) A monoiodomethyl ether derivative or a formula (VI: R1 and R2 is I; X is-OHe) can be reacted with copper (I) which is more than 1 mole equivalent (for monoiodide) Or react with copper (I) sulfide (more than 2 mol equivalents) (for diiodide) to obtain monomethyl ether of formula (VI: R2 is CN; X is -OHe) or formula (VI: R1 and R2 are CN; X is-OHe) Dimethyl ether. The tritiation reaction is generally carried out at 1 G 0 ~ 2 5 (TC, using polar aprotic solvents, such as DMF, 1-methyl-2-pyrrolidine can also be used if morpholine or pyrimidine. The formula (VI: and / or R2 is CN; X is -OMe) is converted to the relative formula (VI: R1 and / or R2 is CN; 3 [is- 0H) mono- or bisphenol compounds, which are pseudo-standard demethylation methods, including the use of digas methane containing boron tribromide or boron trichloride containing more than 1 mole, at -78 ° C ~ Reaction under temperature. Formula (VI: R1 and / or R2 is I; j [is -0He) methyl ether derivative-29- This paper size applies Chinese national standard (CN S) A4 specification (210 > < 297 mm) ------------ · ι.t --------- order --------- (please first闿 Read the back; I will fill in this page again.) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Or ϋ 2 is aryl or heteroaryl; X is -〇M e), which is based on Suzuki reaction conditions (Journal of the Cheiica 1 Society Chemical Coimunica-t, ions 1 9 7 9 886¾ Synthetic Communications 19 8 1 11 i 7) 5U) ^ Other co-reagents required for the Suzuki reaction contain more than 1 mole of metal catalysts such as tetrakistriphenyl-o-platin or platinum (II) acetate, and such as hydroxide Ι octahydrate or sulfonic acid Sodium hydroxide, in solvents such as benzene, toluene, or DHS0 / water. Raw materials for aryl or heteroarylboronic acids are commercially available or can be prepared by known methods. Formula (VI: R1 and / or R2 is aryl or Heteroaryl; X is -OMe) Mono or diaryl or mono or diheteroaryl methyl chloride can be converted to formula (VI: and / or R2 is aryl or heteroaryl; X is -0H) Relative to mono or diaryl or mono or diheteroaryl phenol, its coal use standard Demethylation method involves the use of dichloromethane containing boron tribromide or boron trioxide above mol equivalents and reacting at -78 ° C to room temperature. The compound in reaction scheme 5 (VI: R1 and / or R2 is fluorene, I, Br, arylheteroaryl, eye) can be used in other reaction schemes to prepare the compound of formula (I). For example, a compound (v I: R 1 and / or R 2 is Η, I, Br, arylheteroaryl, nitrile; X is 〇Η) can be used in Reaction Scheme 1 to prepare formula (I: E1 and / or κ2 * !!, I, Br, arylheteroaryl, sulfonyl ester, or in reaction scheme 2 to prepare formula (I: ίΐ1 and / or P is Η, I, B r, arylheteroaryl ,-)-0-alkylated derivatives, or in Reaction Scheme 3 to prepare formula (I: R 1 and / or R 2 is fluorene, I, B r, arylheteroaryl, eye) ester. Compound Γ V i: R 1 and / or in all Reaction Scheme 5? ? 2 for ", 1,61'arylheteroaryl, 3 Shaw) can be used for inversion: Ying -3 0-the paper size of the table is far away from the Shikoku Wai home label! Specifications (2) 0 >: 7 male f ; ------------- Installation -------- Order --------- Line (Please read the precautions on the back before filling this page) 446 7 04 A7 B7

V. Description of the Invention (Clever) Schemes 4, 6, 7, and 8 are modified. Flow 6

(VI: R 5 = I, alkyl group, all-air alkyl group, nitrile, alkane group, aryl group, aralkyl group, aryl sulfonaldehyde group) Other formulas in Reaction Scheme 6 (VI: X = 0H; R5 = ii) compound derivatives can be prepared according to the following method. The compound of formula (VI: X = 0 Η; R s = Η) can be deuterated with oxygen atoms on phenol, which can be obtained by using an appropriate aldehyde forming agent of more than 1 mol equivalent (VI: χ = 0- 酷 基; Rs = Ii) The compound β-chelating agent is generally a low alkyl or aryl carboxylic anhydride, or a low alkyl or aryl carboxylic acid. The reaction is performed using standard methods, such as using pyridine as a solvent with or without a co-solvent (such as digas methane), and reacting at 0 ° C ~ room temperature. Hydrated phenols of formula (VI ·· x = 0-fluorenyl; Ιί5 = H) can be formed by desertification at the 9-position on the furan [2,3-b] carpan or naphthalene [2, 3-bI furan ring] A halogenated bromophenol of formula (VI: X = 0-Coolyl; R5 = Br). The bromination reaction generally uses 1 to 1.3 mole equivalent molecular bromine, and the catalyst is used to vaporize iron (I II) in the dark, using an inert solvent such as dichloromethane or trifluoride, at -7 8 ° C. ～ Reaction at room temperature 〇-3 1-This paper size is applicable to China National Standard (CNS) A4 specification m〇X 297mm) I Packing -------- Order --------- Line ^ (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs and printed by the Consumer Cooperatives of the Ministry of Economic Affairs and the Intellectual Property Bureau of the Ministry of Economic Affairs. , Formula (VI: X = fl Η; R 5 = Η) phenol can be brominated at 9-position on hydrazine [2, 3-b] phenol or naphthalene hydrazone 1, 2, and ί-b] furan hydrazone to obtain formula ( VI: X = GΗ; R5 = Br). Bromination reaction-generally use i ~ 1.3 mole equivalent molecular bromine, and the amount of ferric chloride (Η I) under the catalyst with black, use an inert solvent, such as methane or carbon tetrachloride, at -78 ° C ~ Reaction at room temperature. The halogenated bromophenol of formula (VI: X = 0-fluorenyl group; R5 = Br) can be converted into the halogenated cyanophenol of formula (VT: X = 0-fluorenyl group; = CN). It is obtained by reacting copper (I) halide above the equivalent. Gasification reaction is generally carried out at 100 ~ 2 5 (TC, using a polar aprotic solvent, such as DMF, 1 -methyl-2 -pyrrole 聢 _ or Η Μ Ρ Α. Bf morpholine or pyridine e can also be used The VI group of the formula (VI: X = 0-fluorenyl group; Rs = Br, CN) can be removed using a standard method to obtain the formula (VI: X = Ο Η; R 5 = BI ·, CN). Use water containing more than 1 Molar equivalent, such as NaOH, rhenium metal hydride, and a co-solvent such as THF, dioxin, or a low fluorinated alcohol (such as methanol, or a mixture of THF and a low hydrocarbon alcohol) in (TC ~ 4 (TC Under acidic conditions, it is also possible to use acidic conditions, which react a compound with a mineral acid (e.g. HC1 or sulfuric acid) above 1 mole equivalent in water with a co-solvent in the presence or absence of THF, at room temperature ~ 8 (TC.) (VI: X = 0 Η; R 5 = Η > The compound can sulfonate the oxygen atom of phenol, and its sulfonium is used.] An appropriate sulfonium sulfonium above the molar equivalent can be obtained by the formula (VI: X =-0 S 0 2 R '; R 5 = Η) sulfonate. Sulfonium (R')-generally low alkyl or aryl sulfonic anhydride, or low alkyl or aryl sulfonium. Use standard methods such as pyridine as solvent. In existence or inferiority Co-solvent of dichloromethane -32 ^ Wooden body. Zhang ruler 1 uses the national standard 隹 fCNSirV 丨 Specification (2_ 丨 (;: Kg) ------------- Crack *- ------ Order .--------- line (please read the > i on the back before filling in this page) A7 1 446 7 0 4 B7_ V. Description of the invention (d) 〇 ° C ~ room temperature reaction. Formula (VI: HS02R '; Rs = i〇 sulfonate can be treated with iodinating agent, Yu Lai [2, 3-b] blind phen or 萦 骈 [2, 3 -b] Iodization of the 9-position on the furan ring to obtain an iodosulfonic acid ester of formula (VI: X = -0S02R ';. An appropriate iodinating agent contains 0.7 mol equivalent or more of iodine and 0.25 mol equivalent or more of iodic acid in 1 ^ And 8 {)% acetic acid, a small amount of concentrated sulfuric acid, reacted at room temperature to 80 °. The iodosulfonic acid ester of the formula (VI: X = -0S02R '; R5 = ϊ) can be catalyzed with the reagent (VI) The iodine atom is exchanged with a perfluoroalkyl group to obtain the formula (VI: US02R '; RS = perfluoroalkyl). The reagents and conditions for the interchange reaction include (VI: X = -0S02IT; R5 = 1) under waterless conditions. 10 moles of perfluorocarboxylic acid pin iRC02Na: R is perfluoroalkyl) and 1 ~ 5 moles of copper (I) iodide, in inert solvents with high boiling points, such as DMF, DMA or methyl-2 -Pyrrolidone, reacted at 140 ~ 200 ° C. In addition, the compound of formula (11 :: = -0302 |? '; 1? 5 = perfluoroalkyl) can also be represented by formula (VI: X =-0 S 0 2 R ′; R 5 = I) is prepared by activating the former with 1 to 10 mole equivalents of perfluoroalkane iodide and mole equivalents to activate Cii〇 in an inert solvent with a high boiling point, such as DMF, DMA or methyl- 2-Pft-pyrrolidone, retrospective at 4 0 ~ 2 0 (TC. In addition, compounds of formula t (VI: X =-0 S 0 2 R '; R5 = I) can also be treated with 0.5 to 2 mole equivalents of bis (trifluoromethyl) mercury and 2 to 4 moles of house activation. Compounds of formula (VI: X = -0S02B '; R5 = perfluoroalkyl) can be obtained by reacting in a high boiling point inert solvent, such as DHF, DHA or p-methyl-2-pyrrolidine_, at 140 ~ 200 ° C. Derivatives of alkyl compounds of formula (\ / 1: ^ = -03021 ?, 1 ^: alkyl) -3 3-This paper size applies to China National Standard (CNS) A4 specification (2) 0 X 297 mm)

It -------- Order --------- line. ≪ Please read the notes on the back before filling out this page) Intellectual Property Bureau, Ministry of Economic Affairs, Employee Consumer Cooperative, Printed by Intellectual Property Bureau, Ministry of Economic Affairs Printed by the employee consumer cooperative K ^ A7 B7_ V. Description of the invention (") The product can be represented by the formula (V M X =-0 S 0 2 R '; β 5 = T) and 3 moles of the lowest tetraalkane tin. Presence of platinum catalysts (such as 1 ~ 1 fimol% bis (triphenylene) platinum chloride), suitable solvents such as DMF, I) M A or 1-methyl-2-pyrrolidine, at 1 4 0 ~ 2 0 (prepared by reaction at TC. The sulfonyl ester group can be further removed by the formula (VI: X = -0SO 2 R '; K5 = alkyl, perfluoroalkyl) according to standard methods. The formula (VI: X =-〇 Η; R 5 = alkyl, perfluoroalkyl) phenol "containing the use of an aqueous solution in which 1 mol or more of alkali metal hydride such as NaO Η water, and a co-solvent For example, THF and lower hydrocarbon alcohol τ react at room temperature to 110 ° C. Formula (VI: X =-0 Η; R 5 = alkoxy group, aralkyl group, aryloxy group) alkoxy , Aralkyloxy and aryloxy derivatives can be represented by the formula (VI: X = 0H or-0S02 R1; Rs = 1) and 3 moles When the most low alkali metal alkane gaseous compounds, such as sodium monoxide, are in the presence of copper (I) or copper (ΪΙ) catalysts, such as 1 ~] 0% of copper (II) gasification in DMF, D M A or 1 -methyl-2 -pyrrolidine_ suitable solvent, prepared by reaction at 8 β ~ 1 8 ITC ^ This reaction can remove the sulfonic acid group. Formula iVI: X = 0H; = alkanesulfonyl group , Aromatic sulfonyl) compounds Alkylsulfonyl and aromatic compounds can be represented by the formula (VJ: X: 0 Η or -0 S 0 2 JT; R s = I) Thiol, thiopyridine or 2-N, N ~ dimethylamine ethyl sulfide, 1 mol equivalent of alkali metal hydride such as Na 0 Η,] mol equivalent of copper (I) or copper ( U) catalyst, such as gasified copper (1) in a suitable solvent such as I) MF, DM A or methyl-2-pyrrolidinone, prepared by reaction at 100 ~ 18 (TC. By This reaction can remove the sulfonic acid group. -3 4-The paper size fits the national standard (CNSM I specification (2) (ιχ37 公 f) ------------- manufactured- ------ Order --------- Line (Please read the precautions on the back before filling this page) A7 446 7 0 4 B7_ V. Description of the invention (") VI: X = f) H; RS = I) compounds can be converted to methyl ether derivatives of the relative formula (VI: X = -0Me; RS = i), which is a phenol with a suitable methylating agent, such as 1 Mo Methyl iodide or dimethyl sulfate above the ear equivalent, obtained by reacting a base such as a sulfonium metal sulfonate or a hydride (such as potassium sulfonate or sodium hydride) in an appropriate solvent such as THF, DMF or DMS0. This reaction is generally carried out at 0 ~ 6 (TC. Formula: VI: X = -OMe; R 5 = iodomethyl ether derivative can be reacted with arylboronic acid or heteroarylboronic acid to obtain formula (VI: RS is aryl or Heteroaryl; X is -0 H e), which is based on S uzuki; stress conditions (J 〇urna 1 〇fthe C he bi ioa] Society Cheraical Communications 1 9 7 9 8 8 6 and Synthetic Communications 1981 11 (7 ) 513) „

Other co-reagents required for the Suzuki reaction contain more than 1 mole of eggs such as tetrakistriphenylphosphonium platinum or platinum (II) acetate metal catalysts, and bases such as barium hydride octahydrate or sodium sulfonate, such as benzene , Toluene or DMS0 / water solvent. The aryl or heteroaryl boronic acid raw materials are commercially available or can be prepared by a known method of β. Formula (VI: is an aryl or heteroaryl group; the fork is _〇 ^) can be converted to the relative formula (VI : R 5 is aryl or heteroaryl; X is -0 Η) Phenols, 傜 uses standard demethylation method, including the use of boron tribromide or boron trichloride containing more than 1 mole equivalent Atmospheric methane, react at -78 ° C ~ room temperature. Compounds in Reaction Scheme 6 (VI: X is -0H; R5 is Br, I, alkyl, perfluoroalkyl, -CN, alkoxy, aryl, aralkyl, arylsulfonyl) can be used for In other reaction schemes, compounds of formula (I) are prepared. For example, the compound (VI: X is -0 Η; R 5 is B r, I, alkyl, perfluorinated. The size of this paper applies Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the back (Please fill in this page again)

^ .J — —---- Order ------- I I Printed by the Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs

A7 _B7_ V. Description of the Invention (X) Alkyl, -CN, alkoxy, aryloxy, aralkoxy, arylsulfonyl) can be used in the procedure 1 to prepare formula (I: R5 is Br 1, alkyl, perfluoroalkyl, -CN, alkane, aryl, aralkyl, arylsulfonyl), or sulfonyl esters in reaction scheme 2 to prepare formula (I: RS is Br , I, alkyl, perfluoroalkyl, -CN, alkoxy, aryloxy, aralkylamino, arylsulfonyl) alkylated derivatives, or in Reaction Scheme 3 to prepare formula (I: RS is Br, I, alkyl, perfluoroalkyl, -CN, alkoxy, aryloxy, aralkyloxy, arylsulfonyl) ester. All compounds in Reaction Scheme 5 (VI: RS is Br, I, alkyl, perfluoroalkyl, -CK, alkane, aryl, aralkyl, arylsulfonyl) can be used in Reaction Scheme 4, G, 7 and 8 are modified.

(VI: R 1 or R 2 Η) Alkylamino, dialkylamino, cyclic amino) Compounds of formula (VI: R 1 or R 2 = Η) can be mononitrated to formula (VI: R 1 or R 2 = ND 2) compounds, iron (III) trinitrate and low-alkanol solvents should be used. Nitro compounds of formula (V I: R 1 or R 2 = N 〇 2) can be reduced to formula -3 6-

The dimensions of this paper are Ψ 囷 National Standard Specification G] U, mm J ------------- Packing -------- Order --------- (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 446704 _B7_ V. Description of the Invention (W) VI: R 1 or R 2 = N Η 2) amine compounds, It is best to use a digas in ethyl acetate and at 40-100 ° C, or with trap or montmorillonite ethanol and at 40-10ITC, or in the presence of a catalyst such as Pd-C, in a suitable solvent Catalyst hydrogenation. Formula < VI: R 1 or R 2 = N Η 2) The amine compound may be dialkylated to 1 mol or more haloalkane and 1 mol or more alkali metal master salt, such as potassium sulfonate, in a polar non- The reaction with a protic solvent such as DHF can give an alkylate of formula (VI). Using a bidentate alkylating agent, such as commercially available 1,4-dibromobutane, a cyclic amine compound of the formula (VkR1 or R2 = cyclic amine) can be obtained. Compound (VI: R1 or R2 = N02, UH2, alkylamine, dialkylamine, cycloalkylamine) in Reaction Scheme 7 can be used in other reaction schemes to prepare compounds of formula (Π. For example, compound (IiR1 or R2 = N02 , NH2, alkylamine, dialkylamine, cycloalkylamine; X is 0H) can be used in reaction scheme 1 to prepare the formula (I: R 1 or ϋ 2 = N 0 2, N Η 2, alkylamine, dioxane Amine, ammonium amine) sulfoacetate, or in Reaction Scheme 2 to prepare alkylated derivatives of formula (I: R 1 or R 2 -NO 2, NH 2, alkylamine, dialkylamine, cycloalkylamine), or In reaction scheme 3 to prepare formula (IiR1 or R2 = N02, NH2, alkylamine, dialkylamine, cycloalkylamine) esters ^ All compounds in reaction scheme 7 (ItR1 or R2 = N〇2, 〇2, alkylamine, Dialkylamine, naphthenicamine) can be used in reaction schemes 4, 5, 6 and 8 and modified. This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) ------- ----^ ------ I --------- Line V < Please read the notes on the back before filling this page} Printed by A, Consumer Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs, (Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, V. Invention Description)

And / or R 4 is an amine alkyl) compound.

Formula 丨 v]: X is 0-ethyl group; R3 and / or R4 are amine alkyl compounds) can be decooled to obtain formula (VI: X is 0 Η; R 3 and / or R 4 is amine group ) Compound. The dehydration reaction includes the use of an aqueous solution, which uses 1 mo of water such as Na a halo alkali metal hydroxide, and a co-solvent such as THF ~ 3 8-printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs «4 46 7 0 4 a? ____B7_ V. Description of the invention (W). Dioxane or a lower hydrocarbon alcohol (such as methanol), or a mixture of TBF and a lower hydrocarbon alcohol, is reacted at 0 ° C ~ 40 ° C. Acidic conditions can also be used. The compound is reacted with 1 mol above the mineral acid (such as HC1 or sulfuric acid) in water, and co-solvent with or without THF at room temperature ~ 8 ITC. Compounds (VI: R3 and / or R4 are amine alkyl, haloalkylamine) can be used in other reaction schemes to prepare compounds of formula (I). For example, the compound (VI: R3 and / or K4 is an amine alkyl group, and haloalkylamine; X is 0%) can be used in Reaction Scheme 1 to prepare a formula (I: R3 and / or R4 is an amine alkyl group, haloalkylamine) Sulfonium esters, or in reaction scheme 2 to prepare formula (I: R3 and / or R4 is an amine alkyl, haloalkylamine) ether derivative, or in reaction scheme 3 to prepare formula (I: R3 and / or R4 is Amine alkyl, haloalkylamine) esters. All of the compounds in Anti-Scheme 8 (VI: R3 & / _ R4 are amine alkyls, butane amines) can be used in Reaction Schemes 4, 5, 6 and 7 and modified. The compounds of the present invention can be used to treat metabolic abnormalities associated with insulin resistance and hyperglycemia, typically accompanied by obesity or glucose intolerance. Therefore, the compounds of the present invention are particularly useful for treating or inhibiting type II diabetes. The compounds of the invention can also be used to regulate the amount of glucose in abnormalities such as type I diabetes. The compounds of the present invention have the ability to treat or inhibit metabolic abnormalities associated with anti-insulinism and hypertensive disease. The representative compounds of the present invention are used to measure the inhibitory effect of PTPase in the following standard pharmacological test methods. By PTP 1 B = rake. See Wuzhong et al. 5¾ + Erji Fat Bfe to make it non-sense, using this standard pharmacological test method to evaluate heavy neoprotein protein tyrosine phosphatase-39- This paper Standards are applicable to China National Standard (CNS) A4 (210 X 297 mm) ------------- I. IJ ---- II Order ----- 1 11 ^- < Please read the notes on the back before filling in this page) 5. The inhibitory activity of A7 _B7_ printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs (4) (P T P). Its use is relative to the 11 4 2-1 1 5 3 insulin receptor (I 1?) Kinase domain dodecaphosphorin peptide as a substrate, synthesized in Π 4 6, 1 1 5 G and 丨 1 5 1 Phosphotyrosine. The method used and the results obtained are summarized below. Human recombinant PTP] B (hPTPlB) was prepared according to the method of Goldstein (see Goldstein et al., Mol. Cell. Biochem. 109, 107, 1992). The enzyme preparation used was contained in a small tube containing 40 [SO- 1 0 0 0 0 g / ml protein in mM Tris-HCl, Q. 2 mM EDTA, 25 mM NaCl, 50% glycerol and 3 mM Mol DTT. P P 醏 live:-using the peacock wire-molybdenum ammonium method as described in Lanzetta ^ A (Anal. Biochem. 1 0 0, 9 5, 19 9 9) to measure the release of micromolar from recombinant PTP1B Of phosphoric acid. A 9 (5 wells plate counter was used. The test method used a ten :: phospholipid ife (TRDIpYETDYpYRK) synthesized by AnaSpec, Inc. (San Jose, CA) relative to the insulin receptor amino acid 1142-Π53 as the test method. Incorporating phosphotyrosine to 1140, 1 1 50 and 1 5 5. The recombinant r Ρ Τ Ρ 1 fi was buffered (ρ Η 7.4, containing 10 millimoles T is-HC ], I 0 millimolar-thiohydrin ethanol and 30% glycerol) diluted to 1 g / jn] to get about 1 G 0 0 0-2 0 ϋ fl 0 release phosphoric acid / min / mg protein "Add diluted enzyme (16.6.5 liters) to 6 2] Microliter should contain 8 1 .93 3 mols of EP solution p 7.4, 1.1 mols- Thiol ethanol, pre-cultured with test compound or DMS0 (control) 5 min / 37 ° C. Add pre-cultured recombinant h Ρ Τ Ρ 1 Β: inhibitor mixture to contain []. 5 ml IR triphosphate fatty peptide 96 (well-precultured to 37) wells through the plate to initiate the dephosphorylation reaction. Each well reaches a final concentration of 50 mM -40 ^ The paper is suitable for national standards 丨 Specifications) --------------------- Order "- ------- (Please read the precautions on the back before filling this page) {446 7 0 4 A7 ________B7_____; _ 5. Description of the invention (clever) HEPES, 8.46 millimolar thiohydrin and 50 micromolar IB tripeptide. After 37X15 minutes, 200 people were added to withdraw the peacock fiber-molybdenum molybdenum-Tween20 stopping agent (HG / AH / Tw) to stop the reaction. This terminating agent contains 3% 0.45% of malachite green sulphate, 1 part of 4-2% molybdenum ammonium tetrahydrate in 4 N H C 1 and 0.5% Twe’en 20. In the control group, 200 microliters of MG / AM / Tw were added to each well containing 10.5 liters of IR triphosphate, and 39.5 microliters of recombinase was added to pre-culture with DMS 0 or drug β at room temperature. 2 5 points. The tritium photometry was measured using a plate counter (Bio-Tek) at 6 50 η B. Four samples and controls were prepared and repeated. Calculated: Based on a known potassium phosphate standard curve, PTPase activity can be expressed in micromolar phosphate / min / mg protein released. The hPTPlB inhibitory effect of the test compound was calculated as a percentage compared to the control (the activity achieved by DMS0). The IC of the test compound can be determined using a four-media non-linear logistic regression of PTPase activity obtained from SAS 6.08, PROC KLIN. The results are as follows. (Please read the notes on the back before filling this page) — I! 11 Order --------- Line i Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy-4 1- This paper size applies to China Standard (CNS) A4 specification (210 X 297 public housing) 5. Description of the invention (and)

7 7 AB ICW (Chemor) example printed by the Intellectual Property Bureau of the Ministry of Economic Affairs.] 0,048 2 0.106 3 0.028 4 0.033 5 0.081 8 0.056 7 0.049 8 0.021 9 0.042 10 0,039 1. 1 0.028 12 0.080 Phenyl arsine oxidation (Reference standard) 3 9.7 Sodium o-vanadate (reference standard) 2 4 4 .8 Molybdenum ammonium tetrahydrate (Li Kao standard) 8,7 -4 -------- Order --------- line (please read the notes on the back before filling this page) 446 7 0 4 A7 _B7_ V. Description of the invention (heart) (Please read the back first Please fill in this page again on the basis of the meaning of the matter.) Based on the results obtained by standard pharmacological tests, the compounds of the present invention can inhibit the activity of PTP enzymes, so they can be used to treat metabolic disorders related to insulin resistance and hyperglycemia, especially with obesity Patients with glucose intolerance β In particular, the compounds of the present invention can be used to treat or inhibit type II diabetes, and to regulate the amount of glucose such as in type I diabetes abnormalities β The term control here means to maintain the amount of glucose in General clinical scope. The effective dose for this compound can be administered in a single daily dose of about 1 mg / kg to 250 mg / kg, and can be administered in a single dose or in two or more divided doses. This dose can be administered by a method that can guide the living compound to the patient's bloodstream, including oral administration, implantation, parenteral administration (including intravenous, intraperitoneal and subcutaneous injection), anal, vaginal and skin dermal administration. For the purposes of this publication, transdermal administration is used to include all body linings that pass through the body surface such as the epidermis and mucosal tissues. This administration administers the compound of the present invention or a pharmaceutical acceptable salt thereof as a lotion, emulsion, foam, patch, suspension, solution, and suppository (anal and vaginal). The oral formula for the active compound of the present invention printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs may contain any conventional oral administration forms, including lozenges, gums, inhalation forms, pellets, rhodoid tablets and oral administration liquids, suspensions Liquid or solution. Capsules can contain active compounds mixed with inert filters and / or diluents such as made-to-allow starches (such as corn, horseshoe or wood meal), 耱, synthetic sweeteners, powdered cellulose, such as crystalline vitamins and 檝Crystalline cellulose, powder, gelatin, glue, etc. β appropriate tablet formulations can be used in accordance with the conventional methods of rattan, wet granulation or dry granulation, using pharmaceutical acceptable diluents, binding agents, lubricants, dispersants, suspensions or stabilizers Contains but is not limited to the following, such as magnesium stearate, stearic acid, sodium lauryl sulfate, microcrystalline fiber -43- This paper size is applicable to China National Standard (CNS) A4 specifications (2) 0 × 297 mm) Economy Department of Intellectual Property Bureau's consumer cooperation Du printed A7 _B7_ V. Description of the invention) Vitamins, sodium carboxymethylcellulose, polyvinylacetone, gelatin, alginic acid, arabic_, yellow exposure, sodium citrate, Silicate complex, calcium sulfonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starch and powdered sugar. Oral administration here can use standard late or timed prescriptions to vary activation The collection of the compound. Suppositories can be formulated with conventional substances, with or without cocoa butter, with or without tincture (to change the suppository's melting point), and glycerin. Water-soluble suppository bases such as polyethylene glycols of various molecular weights can also be used. It is to be understood that the dosage, form and administration method of the compound of the present invention may depend on the disease and the patient to be treated, and on the instructions of the doctor. It is advisable to administer one or more of the compounds in small doses and increase the dose to achieve the desired result. The following production method details the method for preparing the representative compound of the present invention. Level 4-"4- (9-Zhang-2 · 3-Eshenmou-sai" "2. 3-bm Pan-4"--2-Lei Bing-Zhu Qi, 醅 Ί Ί-2 -Ci-Ben brewing step 1 4 -Break of a certain -2-Hui Zhi at Zai Wen, will be commercially available to obtain 4-ammonium salicylic acid sodium salt dihydrate (5 Q. 25 g, 0. 2 3 7 3 mole) water (1 19 ml) stirred solution was added 10% N a 〇 Η (3.4 millimoles >) and sodium nitrite (1 8 · 〇 6 g, 0 · 2 6 1 7 mol) water (4 4 ml). Add vigorously concentrated HC] (153 ml) and glacial acetic acid (7 fi ml), and maintain the temperature at-] (TC. After 5 minutes, dark orange The solution was added to 0 A f of copper (I :) (2.35 5g, Q. 0 2 3 7 9 mol) with vigorous stirring; (128 ml), which had been pre-cooled to (TC .Saturation with disulfurized sulfur-4 4-wood paper scale is suitable for the standard a.'XSM! Specifications of the garden garden; ----------; --- installation ------ --Order --------- line (please read the notes on the back before filling this page) A7 1 446704 _B7_ V. Description of the invention 0.5 hours. Remove the ice bath and stir for 18 hours. Add crushed ice (2 liters) to stop the reaction, warm to room temperature and filter. The mixture was stirred with 20% THF / ether (1 liter), dried (MgS04), filtered and concentrated to obtain 36.32 g (G 4%) of the title compound as a red solid, melting point 1 70-1 8 5 ° C; 1 H NHR (DH5 0- d6) δ 7, ll-7.16 (ffl, 2H), 7. 7 6 (d, 1 Η), 13.2-14.4 {br. S, 2 Η) 〇 Step 2? Bt hopes to obtain commercially available 3-methylbiphenecarboxaldehyde (20 g, 0.51 mol), trap hydrate (31 ml) and glycerol (72 ml) and stir under reflux for 20 minutes. Cool below 10D ° C, slowly add K0H (22.9 g, 0.408 mole),

Heat at 125-130 ° C for 1.5 hours. It was cooled to room temperature, water was added to stop the reaction, and extracted with ether. The combined ether extract was washed with 5% HC1, common salt water, dried (MgStW) and concentrated. Purification by silica gel column chromatography (pentane) gave the title compound as an oil (15.81 g, 89%): 1 HHR {COCla) δ G.97 {d, 1Η, J = 8Jz), 6.77 ( d, 1H, J = 8Hz), 2.35 {s, 3H), 2. 14 (s, 3H) 〇 Step 3 2-Section even -4.5-2-Shen hope at -7 8 ° C, will To a stirred solution of 2, 3 -dimethylbenzophene (5.0 g, 44.6 mmol) in THF (89.3 ml) was added dropwise 2.5M BuLi / hexane (17.9 ml, 44.6 mmol). Moore). After the addition was complete, the dry ice / acetone bath was replaced with an ice water bath and mixed with Q. 7 for 5 hours. At -8 ° C, add 1'〇 (44.6 ml) of benzyl bromide (5.30 ml, 44.6 mmol), its own-4 5-This paper size applies the Chinese National Standard (CNS) A4 specification (210 x 297 mm) --------- IIJ ^ · — II I --- Order If ----- II, (谙 Please read the notes on the back before filling this page) Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by Consumer Cooperatives Printed by Consumers' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Λ7 _B7_ V. Description of Invention (Section) Pre-cooled to -7 8 ° C. After the addition was complete, stir for 18 hours and warm to room temperature. Filter through a silica gel bed (1% E t 0 A c / petroleum ether) and concentrate the filtrate. Purified with B i tage KP-S i 1 (1% E t 0 A c / petroleum ether) to obtain 6.9 S 0 g (77%) of the title compound as an oil: 1 H NHR (DMS0-d6) < J 2.ΙΠ (s, 3fl), 2.Zl (s, 3H), 3.98 (s, 2H), 6.58 (s, 1H); 7.18-7.37 (1, 5H) 0 Step 4 (2-Some- 4.5 -2: Shen At P points -3--)-(4-A S-3-field Bing Cai)-marriage at room temperature, will contain 3-isopropyl-4-methyl C Η 2 C 1 2 (4 6 Gml) of acid (27.00g, 0.139 mole, 1 ^ -33537-? 8-9) and grass gas (13.3ml, 0.153mol) Add N, N-DMF (5 drops) to the stirring solution. After 2 hours, cool to -7 8. Add vaporized tin (IV) (1? .89 ml, 0.153 mole), and then add 2-nodyl-4, 5-dimethylforman (28.12 g, 0.13 9 mole) (:) 12 {: 12 (120 ml), which has been pre-chilled to -78 ° C. After the addition is complete, remove the dry ice / acrylic bath and stir] for 8 hours and warm to room temperature. Add water (2 liters) to medium Ih reaction, take acetic acid. Combine the acetic acid extract with 1 NHC 1 (3 X 500 ml), water (2 X 500 ml), NaHC03i2 x 500 ml), and saline (1 x 500 ml). Wash, dry (H g S 0 4) and concentrate. Purified by silica gel column chromatography (5% E t 0 A c / petroleum ether) to obtain 4315 g (83%) of the title compound as an oil: 111 — [{(»^ 130- (16) £ 5 1. 1 3 { s, 3Ή), 1. 15 fs, 3 Η), 1.8 1 (s, 3 Η), 2. 2 6 (s, 3 Η), 3. 2 3 (q, 1 Η), 3, 8 5 (S, 2 Η), 3. 8 8 (R, 3 Η), 7.04-7,24 -4 G-------------- * ------- ^ --------- (Please read the notes on the back before filling this page) 4 46 7 0 4 A7 _B7_ _ V. Description of the invention (#) (i, GH), 7.55 (dd, 1H), 7.63 (d, lH) 〇 Step 5 (Please read the precautions on the back before filling this page) 4- (2.Seishin-Case f2. Pan-4-yl > -2-risicol_phenol At -78 ° C, (2-benzyl-4,5-dimethylbenzophen-3-yl)-(4-methylamino-3-isopropylphenyl) methanone (6.48 g, 0.0178 Boron tribromide (9.4 ml, 0.099 mole) was added dropwise to a stirring solution of CH 2 Cl 2 (75 ml) in mol). After the addition was complete, remove the dry ice / acetone bath and wedge and stir for 2 hours. Add KH2PO4 (100 ml) was extracted with CH2CI2 and concentrated. Purified by silica gel column chromatography (5% E t0 Ac / petroleum ether) to obtain 1.67 g (27%) of the title compound as yellow Body: 1 H NMR {DMS0 -d6) d 9. 49 (s, 1 H), 8.42 (s, 1H), 7.94 (d, 1H), 7.47-7. 32 (and, 3 Η), 7.0 1 (s, 1 Η), 693 (s, 2 Η), 3. 32 (top, 1 H), 2.39 (s, 3H), 1.59 (s, 3H), 1.19 {d, 6H) „Step 6 7 . 酴 2- 里 告 甚 -4- (?.. 3-Dishenyl- 蓥 骈 [2. 3-hl favors P 分 -4- a certain) -2-Justhate at 5 ° C, will contain 4 -(2, 3 -dimethyl-fluorene [2, 3-b] printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs-4_-4) -2-Isopropyl-phenol (0,500 g, 1.44 mmoles of pyrimidine (3.5 ml) was added to the stirred solution of acetic anhydride (0.167 ml, 1.78 mmol). After 5.5 hours, water was added to stop the reaction, acidified and taken up with ether. The extract was washed with water, brine and concentrated in that order. Purified by silica-column chromatography (5 & 7% EtOAe / petroleum ether, gradient) to obtain 84 g (59%) of the title compound as a white solid: 1 HU MR {DHS 0-d 6) < 5 8. 4 9 (s, 1H), 8. 0-7.9 6 (d, 1H), 7.48--4 7 — This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Intellectual Property of the Ministry of Economic Affairs Printed clothing A7 B7_ of the Consumer Cooperatives of the Bureau V. Description of the invention (〇) 7. 31 (m, 4 Η), 7. 2 G (s, 2 H), 3.1D (septet, 1 H), 2.40 (s, 3H), 2.37 (s; 3H), K56 (S, 3H), 1.1Md, i5H). Step 7 Z 醵 2-Lipingmou-4_-fQ -Zhang-2. Ershenmou- 棻 骈 f2. 3-blfft (Pan-4-even) -Ethyl ester at -7 ire will contain acetic acid 2-Iso Propyl-4-(2, 3-dimethyl-naphthalene [2, 3-b] phen-4-yl) -2-phenyl ester (0.484 g, 1.25 mmol) and vaporized iron ( I II) (0.01 g, G_0 G6 2 mmol) in a stirred solution of CH 2 C 1 2 (1 丨 ml), and bromine (0.07 1 ml, 1 38 mmol) CH 2 C 1 2 < 2 ml) ^ 4 G points, add diluted Na HC 0 3 to react with ih, diluted with water (100 * liters) and Extraction will be combined with ether extraction, washed with water and concentrated ^ to

Biotage KP-Si] purification (5% EtOAc / Petroleum K) yielded 0.321 g (55%) of the title compound as a pale yellow solid: 1 Η NHR (DMS 0-d 6) <? 8.20 (d, 1 H ), 7.67-7.62 (m, 1 H), 7.52-7.43 (mt 2 H), 7.34 (d, 1 H), 7.22 (m, 2 H), 3.09 (septet, 1 H) f 2.43 (s, 3 H), 2.37 (s, 3 H), 1.54 (s, 3 H), 1.16 and 1.15 (two doub 丨 ets, 6H, 'optical isomers) · MS (EI). [MH! Bromine isotope pattern Anal. Calc, for Ci5H23Br02S: C, 64.24, H, 4.96, N, 0.00. Found: C, 63.84, H, 4.90, N, 0.06. Step 8 4- (9-Bromo-2. 3-dimethyl-naphthalene 骈`` 2i 3-.bl carbene.-4diyl.) = 2-.

Heterogeneous 1L will be acetic acid containing 2-isopropyl-4-(9-Mo-2, 3-dimethyl-naphthalene hydrazine [2, 3-h] blindphen-fluorene-yl) -benzene HF: H e () Η (1 0: 7, 18 ml) of the ester (G. 3] 5 g, 0 · 6 7 4 mol) was added to the stirring solution with 1 Ν Κ 0 li (0 · 8 1m-4 8-------------- install -------- order --------- line (please read the notes on the back before filling (This page) This ruler is applicable to Chinese netizens Fu a, \ S), \ 4 specifications (210 X male; I i A7 4 46 7 0 4 ____B7_ V. Description of the invention (47) liters) β 1.5 After hours, concentrate, stir with water (5 D ml), acidify with 10% HC] and lift with ether. The combined ether extract was washed with water (2 x ml), concentrated and dried to obtain 0.34 g of the title compound as a white solid: NMR (DMSO-d6) δ 9.56 (s, 1 Η), 8.17 (d, 1 Η) , 7.64-7.60 (ddd, 1 Η), 7.53-7.52 (d, 1 Η), 7.46-7.42 (ddd, 1 Η), 7.03 (d, l Η), 6.97-6.91 (m, 2 Η), 3.31 -3.28 (m, l H), 2,42 (s, 3 H), 1.58 (s, 3 H), 1.16 (d, 6 H). MS (EI), [M +], 1 bromo isotope pattern, 424/426; Anal. Calc, for C23H2iBr〇S: C, 64.94, H, 4.98, N, 0.00 · Found: C, 64:11, H, 4.99, N, 0.03. Step 9 i-``4-(9 -淖 -2. 3-二 申 申-赛 骈 「2 3-h] II Sophon-4-a) r.2-Isopropyl-Fruit At room temperature, 4- (9-bromo-2,3-dimethyl-fluorene [2, 3-b] oxaphen-4-yl) -2-propofol (0.306 g, 0.744 mmol) Ear) 0.05 mol 1: 1 buffer solution? 119: 111 ^ (10: 3, 3.56 ml, 0.2 mol) After adding 2.58 Na0H (0.2 8 5 ml, 0.713 mmol) to the solution, then A small amount of THF was added to form a solution β 0.5 hours, and then cooled to a dropwise addition of human 4-gassulfonyl-2-hydroxy-benzoic acid (0.3 38 grams, 1.43 millimoles) of THF (2.85 milliliters, 0.5 moles), maintain pHIO and add 2N NaOHe at the same time. After the addition is complete, warm to room temperature and stir for 1.5 hours. Add sulfosulfanyl-2-hydroxy: 1 * 1 ^ (2_85 ml, 0.5 mol) of benzylsulfonyl-2-hydroxy: benzoic acid (0.338 g, 1.43 mmol). Stir for 1.5 hours. Add 2 NHC The reaction was stopped by 1 (40 ml) and extracted with ethyl acetate. The combined extract was washed with 2N HC1 {3 ×), dried (M g S 0 4), and concentrated. 2% Η 3 Ρ 0 〆H e 0 Η Treatment of B i 〇tage Κ Ρ-Sil dissociation with 15 & 25% EtOAc / hexane gradient purification can get 0.294 -49- This paper size applies Chinese National Standard (CNS) A4 specification (210 x 297 mm)- ---------- L1 -------- Order ----- J — · Line 1- * 7 (Please read the note on the back first to write this page) Ministry of Economic Affairs Intellectual Property Printed by A7 Consumer Cooperatives

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the invention (w) grams (G (5%) of the title compound as a yellow solid, melting point > 2 2 5 ° C; Ή NMR (DMS0-d6): δ 0.96 ( d, 3 Η), 1.02 (d, 3 Η), 1.48 (s, 3 Η), 2.50 (s, 3 Η), 3.08 (heptet, 1 Η), 7.26-7.39 (m, 5 Η), 7.43 ( dd, 1 Η), 7.50 (t, 1 Η), 7.66 (t, 1 Η), 8.05 (d, 1 Η), 8.21 (d, 1 H). IR (KBr) 3425, 2950, 1675, 1400 and 1190 cm * 1. Mass 镨 (-ESI), m / z 623/625 (M-H). Anal. Calcd. For C30H25BrO6S2: C, 57.60; H, 4.03; N, 0.00. Found: C, 57.88; H , 4.29 N, 0.09. Example 2 4-f4- 3-Dimethylseven-stupid »" 2. S-blUS PAN-4-some) -2. Γ) -two-shen even-guan 氤 醅 1-镩芾-芾 ... steps] (2-benzyl-4. 5-two Shenshen-favor hope-?-Even,-(4-Shen Arshi-L two Shenju even)-Tian Yan Yu Han 3, 5-Dimethyl-p-da @ 香 菌 酸 (15.2 g, 84.4 mmol, R Ν-2] 5 5 3-4 6-8) anhydrous digas methane (200 ml) in the chamber Add mildew gas (9.6ml, 11 Q mmol) and Ν, Ν-dimethylmethanamine (5 drops) under mild simmering. After stirring for 2 hours Remove the solvent. Dissolve in anhydrous digas methane (200 ml) under nitrogen and add to 2,3-dimethyl-5 -benzidine (17 "g, 84.4 mmol). Tin chloride {IV) (10.8 ml, 92.8 mmol) was quickly added at -78 ° C. Remove the -8 ° C bath and stir at room temperature for 2 hours. Pour into ice water (1000 ml) and extract once with diethyl ether (700 ml), then extract with diethyl ether (400 ml). The combined ether layer was washed with ice-water (50 Q ml), dilute sodium gallate (50 Q ml), water (500 ml), brine (1000 ml), and dried (N 2 S04). The title compound was obtained as a yellow oil by concentration reduction (25.2 g, -5 0-------------- • equipment -------- order -------- ---- line (please read the notes on the back before filling this page) A7; 446 7 0 4 .__ B7__ V. Description of the Invention (49) 82%): NMR (DMSO-d6) δ 7.40 (s, 2 Η ), 7.24-7.15 (m, 3 Η), 7.06 (d, 2 Η), 3.83 (s, 2 Η), 3.70 (s, 3 Η), 2.28 (s, 3 Η), 2.26 (s, 6 Η ), 1.83 (s, 3 Η). (Please read the notes on the back before filling out this page) Step 2 a- (. Dijiashi-sai 骈 「2. 3-hl-nt m -4-¾)- 2. Fi-xylenol containing (2-fluorenyl-4, 5-dimethyl-8 $ phen-3-yl)-(4-methylamino-3, 5-xylyl) > -methyl Ketone (25.2 g, 69.2 mmol) in anhydrous dichloromethane (420 ml), cooled to -78 ° C under nitrogen. Boron tribromide (20.9 ml, 221 mmol) was added dropwise over 16 minutes, Stir at 78 ° C for 1.5 hours. Remove the -78 ° C bath and stir at room temperature for 4 hours. Pour into ice water (ml). It contains a little bisulphite pin, and lift with ether (1 〇OOmL) once, and then extracted with ethyl «(300mL). The combined ether layer was washed with water. (10t) D ml), washed twice with brine (1000 ml), and dried (Na2S04). Concentrated under reduced pressure to obtain a dark residue, and the second time with (2-fluorenyl- 4, 5-Dimethyl-benzophen-3-yl)-(4-methylamino-3,5-xylyl) -methanone (13.9 g, 38.1 mmol) and boron tribromide (11 5 ml, 122 mmol). The product was combined with silica gel and chromatographed with petroleum ether: ethyl acetate (90:10) to produce 4- (2, 3- Dimethyl-fluorene [2,3-bj Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

-Beerphen-4 -yl> -2, 6, xylenol (2 4 _ 0 g, B 7%), NMR (DMS0-d6) δ 8.41 (s, 2 Η), 7.93 (d, 1 Η ), 7.49-7.39 (m, 2 Η), 7.34-7.28 (m, Η), 6.87 (s, 2 Η), 2.38 (s, 3 Η), 2.23 (s, 6 Η), 1.62 (s, 3 H). MS (EI), [M +] 332. Step 3 7. 酴 4- (2. 3- 二 申 某-赛 骈 Γ2. 朌 -4 -even). -5 1-This paper size applies to + country National Standard (CNS) A4 Specification (210 X 297 mm) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 _B7_ V. Description of the Invention (β) fi-Dishenate will contain 4-2, 3-dimethyl -Naphthylpyrene [2, 3-b] -quinone-4 -yl) -2, (1-xylenol (24 g, 72 2 mol) pyridine (200 ml) in ammonia At 0 ° C, add acetic anhydride (8.9 ml, S3.9 mmol) dropwise within 1 G minutes. After 45 minutes at 0 ° C, place in a freezer for 18 hours and remove Stir in an ice bath for 2 hours to warm to room temperature. Pour into water (1 (300 ml), acidify with 10% HC 1 to ρ Η 1. Pick up with ether (100 ml) , Wash with 10% HC 1 (10 "I 0 ml), and wash with water (10 fl Q ml)

Wash twice and once with saline (700 ml) and dry (MgS04). Concentrated under reduced pressure and chromatographed with petroleum ether: ethyl acetate (97: 3) to prepare the title compound as a milky white solid (22.4 g, 79%): NMR (CDC13) δ 8.26 (s, 1 Η), 7.87 (d, 1 Η), 7.58 (d, 1 Η), 7.44-7.40 (m, 1 Η), 7.33-7.29 (m, 1 Η), 7.07 (s, 2 Η), 2.42 (s , 3 Η), 2.41 (s, 3 Η), 2.23 (s, 6 Η), 1.67 (sf 3 Η). MS (EI), [M + J 374. AnaJ. Calc, for C24H2202S: C, 76.97, Η, 5.92, Ν, 0.00 · Found: C, 76.17, H, 5.75, N, 0.22. Step 4 7, m &-(a--2 .__ 3- 二 申 某-蓥 _ 「? 3-dagger 1 -Mipan-4-even) -2. F >-Dishenyl ester in acetic acid containing 4-(2, 3 -dimethyl-fluorene f 2, 3-b]-»$ phen-4 -yl) -2, β ~ xylene_ (10.0 g, 26.7 mmol) and ferric chloride (0.2 3 g 4 mmol) in anhydrous dichloromethane (2 3] ml), cooled under nitrogen- 7 8 ° C. Add bromine (1.5 ml, 29.4 mmol) of anhydrous dichloromethane (38 ml) D 3 f) in the dark and within 50 minutes, then dilute the di-Asian Sodium sulfate (K reaction, diluted with water, and extracted with ethyl acetate. The ether layer -5 2----------------- ----- Order · -------- (Please read the notes on the back before filling this page) Α7 446 7 Ο 4 Β7_ 5. Description of the invention (β) Wash twice with water and wash with saline 1 It was then dried (HgS04). It was concentrated under reduced pressure and chromatographed with petroleum ether: ethyl acetate (97: 3, followed by 95: 5). (Please read the notes on the back before filling in (This page) The title compound as a white solid (6.7 g, 55%), NMR (DHS0-d6) < 5 8.27 (d, 1 Η), 7.60 (d, 1 Η), 7.56-7.52 (ddd, IH), 7.38-7.34 (ddd, 1 H), 7.06 (s, 2 H), 2.43 (s, 3 H), 2.41 (s, 3 H), 2.22 (s, 6 H), 1.64 (s, 3 H). MS (EI), [M +}, I bromine isotope pattern, 452/454. Anal. Calc, for C24H2lBr02S: C, 63.58, H, 4.67, N, 0.00. Found: C, 63.41, H, 4.45, N, 0.08 Step 5 4-(9--2. 3-Dimethyl-iso-Str? -3-bl -Fanpan-4 -Small -2. 6-Di Shenphenol will contain 4- (9-Bromo- Tetrahydrofuran (240 Employee, Intellectual Property Office, Ministry of Economic Affairs, Ministry of Economic Affairs, China) Consumption cooperative prints ml) and methanol (80 ml), dropwise at room temperature KOH (17.2 ml, 1N solution, 17.2 mmol). After 4 hours at room temperature, place in the freezer for 18 hours. Remove the freezer and stir at room temperature. Add K 0 Η (4 1.5 ml, 1 S solution, 4] · 5 mmol), tetrahydrofuran (50 ml) and methanol (10 ml diluted with water (50 Q ml >), acidified with IN HC1 and Extract with ether. Wash the ether layer twice with water (50D ml) and dry (MgS04) s. Concentrate under reduced pressure and adsorb silica gel. Chromatography with petroleum age: ethyl acetate (97: 3, then 95: 5) White foamy solid can be obtained from the title compound

(5.5 g, 93%), NMR < CDCL3) δ 8, 4 1 (s, 1 Η),. 8.1 B (d, 1 Η), 7.64-7.54 (m, 2 Η), 7.46-7.40 (m, 1 Η), 6.89 (s, 2 Η), 2.41 (s, 3 Η), 2_23 (s, 6 H), 1.60 (s, 3 H) 'MS (-ESI), [MH], 1 O isotope pattern, 409/411. Step 6 _ 4-Γ4- (9-? A-2. Two g even 茇 骈 2. Hope-A-some) -5 3-This paper size applies China National Standard (CNS) A4 specification (210 X 297 mm) A7 _____B7 _ 5. Description of the invention (β) fi-dimethyla-pyridyl-benzyl-benzylacetate method of step 9 in Example 1, Use 4-(9 -bromo-2, 3 -dimethyl-naphthalene 骈 2,3-1)] -Pphenphen-4-yl) -2,6-dimethyl-(0.302 g, 0.744 mmol Ear) and 4-sulfosulfanyl-2-hydroxy-carboxic acid (1.09 g, 4.C1 mmol) can be used to prepare the title compound. Purified with Dynanax C18 (85% C Η + ACN / Η 2 〇 ( Containing 0.1% TFA)) can be obtained as a yellow solid of the title compound (0.2 g, 44% 丨, melting point > 225 "C; 1 Η NMR (DMSO-d6) δ 1.59 (s, 3 Η), 2.16 (s, 6 Η), 2.45 (s, 3 Η), 7.19 (S, 2 Η), 7.46-7.52 (m, 4 Η), 7.65-7.69 (m, 1 ), 8.07 (d, 1 Η), 8.21 (d, 1 H). IR (KBr) 3450, 2900, 1675, 1385 and 1185 cm'1. Mass (-ESI), m / z 609/611 (M -H). Anal. Calcd. For C29HMBr06S2 0,7H2O: C, 55.81; H, 3.94 N, 0.00. Found: C, 55.93; H, 4.23 N, 0.12. ®L3— jj: —U-C9 .r_U, —3 -Dimethyl.-sai 骈 "Plant 3-h 1 P Relying -4-even) -2 -Cyclopsium-Stupid tracing group 1-2 -Xiongqi-, Section: Step 1 Erran Ji-Hou Yifen-3-even) -f 3-顼 rg even -4-Tianqi-Ji-stupid .. Ji)-A_ ------------ • equipment ------- ----- Order --------- (Please read the precautions on the back before filling out this page) Basic 1 " 0 Ϊ · 1 3 Includes 8. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Water is not acidic, mellow, melane, methylcellulose, temperature, and humidity are less than two. ≫ Fermentation 25r liters early ί amine 32 glutamate hydration methyl methylsulfide and two liters 1 mol mix 4 Stirring \ ιί · Ermo mg Ermo to 8 ° Η »7 Such as I # 于 于 5 容 {• H. Phenoconcentration, strong benzyl pressure, 5-min-post-time base, 1 Γ, Γ, Γ, V, Γ, Γ, I, I, 倒, 倒, 0, 0, 0, 化, 0, Μ, Μ, Μ, p, p, ac, 下, 下, 室, M, and 下National Standards (CNS) A 丨 邋 格 ί2ΚΡ.2ί7 public cage) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 _ Β7__ V. Description of the invention (μ) Ice water (200 ml) and ether (2Q0 ml) Take it. The ether layer was washed twice with sodium bisulfate (50 ml) and once with brine (50 ml). Concentrated under reduced pressure and chromatographed with petroleum ether: ethyl acetate (95: 5) to prepare the title compound as an amber oil (4.8 g, 52%), (DHS0-d6M 7; 61-7.54 (m, 2 Η), 7.24-7.14 (m, 3 Η), 7.08-7.02 (m, 3 Η), 3.87 (s, 3 Η), 3.84 (s, 2 Η), 3.42-3.30 (m, 1 Η), 2.26 (s, 3 Η), 2.00-1.85 (m, 2 Η), 1.81 (s, 3 Η), 1.74-1.58 (m, 4 Η), 1.48-1.36 (m, 2 H). MS (Ei) , (M + 1 404. Ann). Cnlc. For C26H2g02S: C, 77.19, H, 6.98, N, 0.00. Found: CF 76.26, H, 7.24, N, 0.04. Step 2 2- 环 戍 其 -4- (? .3-Di-Shen-Sai- "2.3-Bu1 崠 pan-4-yl): 1 in (2-benzyl-4, 5-dimethylbenzyl-3-yl)-(3 -Cyclopentyl-4-methoxy-phenyl) -methanone (4.8 g, 11.7 mmol) anhydrous digas methane (70 ml), in a tritium gas at -78 ° C, drop in 20 minutes Boron tribromide (3.6 ml, 37.6 mmol) was added, and stirred at room temperature for 22 hours. Β was poured into ice water (60 ((ml), and extracted with ethyl acetate (8fl0 ml). The ether layer was Wash twice with water (500 ml) and once with brine (5 D0 ml). Reduce the concentration and chromatograph with petroleum ether: acetic acid.酦 (97: 3) can be obtained as a white solid (3.4 g, 78%) of the title compound, mp 156-158 ° C; (DMSO-d6) δ 9.48 (s, 1 Η), 8.42 (s, 1 Η) , 7.93 (d, 1 Η), 7.46-7.41 (m, 2 Η), 7.35-7.30 (m, 1 Η), 7.00 (s, 1 Η), 6,95 * 6.90 (m, 2 Η), 3.38 -3.28 (m, 1 Η), 2.39 (s, 3 Η), 1.99-1.90 (m, 2 Η), 1.68-1.47 (m, 6 Η), 1.60 (s, 3 Η). MS (EI): [Μ +] 372. Anal. Calc, for C2; H24OS: C, 80.60, H, 6.49, N, 0.00. Found: C, 80.39, H, 6.43, N, 0.04. Step 3 酴 2-璀 ft 甚- 4- (2. Ershenji- 窠 骈 「2. 3-bl beer hope-4- -5 5-This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) ----- -------- ^-11 --- II Order ------- ^, (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 _B7_ V. Description of the Invention (M) Leather) -Benzol will contain 2-ring 丨 Goki-4- (2,3-dimethyl-lysam [2, 3-b] B-Hexyl-4-yl)- Anhydropyridine (20 ml) of phenol (2.8 g, 7, 5 mmol) was added dropwise to the acetic anhydride (0.22 ml, 9.8 mmol) under nitrogen and sludge temperature. Keep in the freezer for 4 1 hours. Dilute and acidify to 0% H C 1 to ρ Η 1. Extract with ethyl acetate (f) (0 ml), wash the ether layer with 5% HC1 (100 ml), wash twice with water (100 ml) and wash with brine (100 ml) 1 time, dried (MgS (l4). Reduced concentration to give the title compound as a white solid (3.) g, 98%): (DMSO-d6) 5 8.48 (s, 1 Η), 7.97 (d, 1 Η), 7.47-7.43 (m, 1 Η), 7.38-7.36 (m, 2 Η), 7.28 (s, 1 Η), 7.19 (d, 2 Η), 3.14 (quintet, 1 Η), 2.40 (s , 3 Η), 2.37 (s, 3 Η), 1.99-1.91 (m, 2 Η), 1.69-1.40 (m, 6 Η), 1.56 (s, 3 H). MS (EI), [M +] 414 Anal. CaJc. For C27H2602S: C, 78.23, H, 6.32, N, 0.00. Found: C, 77.68, H, 6.39, N, 0.04. Step 4 7, Case?-Support If -4-(9-淖-?. 3 -dimethylone-sai 骈 「2. 3-h USopan-4- 某） -Rongku than 2 -cyclopentyl-4-(2, 3 -dimethyl-strate骈 [2, 3-b] IIHanphen-4-yl) -benzene_ (2.9 g, 7.7 mmol) anhydrous digas methane (fi 8 ml) was added with gasified iron (0.06 g , Q. 4 1 mmol). Cool to -7 8 ° C under nitrogen. Add 0.44 ml of bromine in the dark and within 15 minutes. 8. 5 mmol丨 The anhydrous dichloromethane compound (11 ml). Stir for 4 5 minutes at -7 8 Υ to dilute the sodium bisulphite! I: React, dilute with water (2 [丨 0 ml 丨. Diethyl ether (300 ml) ) Extraction, the ether layer with water and edible water. Concentrated under reduced pressure and chromatographed with petroleum ether: acetic acid-5 6-This paper ruler is suitable for the national standard (CNSM.1 specification 297 male f) n ^ ^ 1 ^^ 1 ft n ^^ 1 nn I heart * ^^ 1-n ^^ 1 ^^ 1 1 fl ^^ 1 1 ^ 1. ^ Nm I (Please read the precautions on the back before filling this page ) A7 446704 __B7____ 5. Description of the invention (K) ethyl ester (9.5: 5) can be used to prepare the title compound as a white solid (2.7 g, 7 g%) (CDC13): S8.28 (d, lH), 7.58- 7.52 (m, 2H), 7J9- 7.34 (m, 1 H), 7,29 (d, 1 Η), 7.18 < dd, 1 Η), 7.14 and 7.13 (d, 1 Η), 3.18 (quintet, I Η), 2.44 (s, 3 Η), 2.40 (s, 3 Η), 2.06-2.02 (m, 2 Η), 1.75-1.45 (m containing a singlet at δ 1.60, 9 H). MS (EI) , [M +], 1 Bromine isotope pattern, 492/494: Anal.! Calc, for C27H25Br02S: C, 65.72, H, 5.11, N, 0.00. Found: C, 63.18, H, 4.96, N, 0.00. Step 5 4-(fl-. Second leisure-Race R- hi 植 盼 -4-ΐ 挥) ¾ some-age 'will contain 2-cyclopentyl-4- (9-bromo-2,3-dimethyl-naphthalene) acetone [2, 3-b] phenone -4-yl) -phenyl ester (2.7 g, 5.4 mmol) tetrahydrofuran (88 ml) and methanol (30 ml), KOH (6.5 ml, U solution, 6.5 mmol) was added dropwise at room temperature. ear). 1.5 hours after the reduction of concentration. Combined with water (2β〇mL) and acidified, taking 10% HC1 to ρΗ1β and taking it up with ether (300mL), washing the ether layer twice with water and drying (M gSO 4) β and concentrating under reduced pressure to obtain the title compound. White solid (2.4 g, 100%) (DMSOd6) δ 9.54 (s, 1 Η), 8.16 (d, 1 Η), 7.61 (m, 1 Η), 7.52 (s, IH), 7.43 (m, 1 H), 7.03 (s, 1 H), 6.93 (m, 2 H), 3.32 (m, 1 H) t 2.41 (S, 3 H), 1.94 (m, 2 H), 1.58 (s , 3 H), 1.72-1.42 (m, 6 H). MS (EI), [M +], l-m-isotopic pattern, 450/452. Anal. R: i] c. R () i C ^ H ^ BrOS: C. 66.52, II, 5. 丨 3, N, 〇〇〇〇, Found: C, 67.17, H, 5.25, N, 0.04. Step 6 4- [4- (9- 通 -2.3- Ershenmou-sai 骈 1 ~ 2.3-bu ~ 1 眈 pan-4 某) -2- 谞 penta-¾ 氲 氲 醅 1-2-throw-benzyl-57- This paper size applies to China Standard (CNS) A4 specification (210 X 297 mm) ------------ ------- Order --------- Cord (Please read the note on the back first Please fill in this page again) Printed by the Consumers 'Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 Printed by the Consumers' Cooperative of Intellectual Property Bureau of the Ministry of Economy Method using 4- (9-bromo-2,3-dimethyl-Ceamidine 12,3-b] pyridin-4-yl ')-2-cyclopentyl-phenol (0.289 g, mM no 丨And 4-gassulfonium-2-hydroxy-benzoic acid (0.7 g,

3.03 mmol) to obtain the title compound βC18 purified (+1 0 0% CH 3 C Ν (included. 1% TFA)) to obtain the title compound as a yellow solid (0 2 5 g, 60%), Melting point> 2 2 5 ° C; 1 Η NMR (DMSO-d6) δ 1.31-1.36 (m, 2 Η), 1.49-1.59 (m, 5 H), 1.61-1.63 (m, 3 H), 1.78- 1.82 (m, 1 H), 2.44 (s, 3 H), 3.04-3.10 (m, IH), 7.25-7.31 (m, 3 H). 7.34 -7.37 (m, 3 H), 7.50 (t, 1 H), 7.66 (t, 1 H), 8.02 (d. 1 H), 8.21 (d, 1 H). IR (KBr): 3425, 2900, 1650,】 400and l 175 cm. 1. See spectrum (- ESI), mil 649/651 (M-H). Anal. Calcd. For C3JH21Br06S2 0.6H2O: C, 58.02; H, 4.29 N, 0.00. Found: C. 57.98; H, 4.35 N, 0.10. Example 4._ 4- "4- (9-? / Fu-?-. 3-Dimethyl even 葳 骈" 2. 3-hlBt -4 -4-) -Bi Shi-¾ 酴: Step 1 f?-帑 -4-4 5-Di Shen shi-Dian Pan-3-）)-Π 5-Di Bu bing-4-Chi qi 茱-Zhu shi)-methyl ketone The method in the same way as in Example 2 uses 3,5-diisopropyl-p-anisoleic acid (5.0 g, 2 1.2 mmol, 0-1) 7 4 3 9-5 9-5), grass moth (2.2 millimeters) , 25.4 millimoles), and N, N-dimethylformamide (2 drops), 2, 3-dimethyl-5 -benzylphene U. 3 g, 21.2 millimoles) The title compound (4.1 g, 45%) can be obtained by gasifying tin (IV) (5.0 ml, 42.7 mmol) and anhydrous digas methane (82 ml). NMR (DMS 0-d 6)- 58-This paper is used in China E Home Standard (CNS) Ai specification LJ97 mm) ------------- Installation -------- Order ----- ---- Line (please read the precautions on the back before filling this page), 'i 446 7 Ο 4 Α7 Β7 V. Description of the invention (〇δ 7.47 (s, 2 Η), 7.23-7.12 (m, 3 Η), 7.02-6.99 (m, 2 Η), 3.86 (s, 2 Η), 3.73 (s, 3 3 · 31-3.20 (m, 2 Η), 2.27 (s, 3 Η), 1.82 (s, 3 Η), 1.15 (d, 12 H). MS (EI), [M +] 420. Step 2 6- m Follow the method of step 2 in Example 2 using (2-benzyl-4,5_dimethylformate) -Cipan-3-yl) _ (3 > 5-diisopropyl-4-methylamino-phenyl) -methyl- (4.3 g, i.i. Millimoire), boron tribromide ( 3 ”ml, 32.4« »ears, and digas methane (60 ml) to obtain the title compound as a yellow foam (1.2 g, 30%), NMR (DMS0-d6M8.42 ( st 1 Η), 8.24 (s, 1 Η), 7.94 (d, 1 Η), 7,48-7.32 (m, 3 Η), 6.90 (s, 2 Η), 3.45 3.35 (m, 2 Η), 2.38 (s, 3 Η), 1.57 (s, 3 Η), 1.15 (d, 12 H). MS (-ESI), [MH] 387. Step 3 Monoacetic acid 4-(2,3-dimethyl- Naphthalene fluorene [2,3-1 >] phenphen-4-yl)-?, 6-difpropylbenzene imitated ¢ 1 2 Ⅱzhonglai 骈 丨 2, step Dai 3 method, make 4-C2 , 3 -dimethyl-m-phenphen-4-yl) -2, 6-diisopropyl-phenol (5,0 g, ------------ ¾ ---- ---- Order --------- line ... \ (Please read the notes on the back before filling this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, Private 13 ·? Mole. , Acetic anhydride (1.6S ml, 17.8 mmol) and pyridine (85 ml) can be used to prepare the title compound as a white solid (5.37 g, 91%}, melting point 2 4 3-2 4 5 ° C; NHR {DMS 0-d 6) 8. 4 9 (s, 1 Η), 7. 9 8 (d, 1 Η), 7.49-7.39 (m, 3 Η), 7.16 (s, 2 Η), 3.01 (septet, 2 Η), 2.43 (s, 3 Η), 2.41 (s, 3 Η), 1.56 (s, 3 Η), 1.16 (d, 12 Η). MS (EI), [Μ +] 430; Anal. Calc, for C2gH30O2S: C, 78.10, H, 7.02, N, 0.00. Found: C, 77.95, H, 7.04, N, 0.07. Β Η PLC analysis 锝 main components (99.3%) e -59 This paper size applies the Chinese National Standard (CNS) A4 specification (21 × x297 mm) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 _B7_ V. Description of the invention) Step 4 7, Phenol 4-(9 -fluorene-2 3 -Di-Shen-Sai-"2.3-h 1 H Hanpan-4 -yl) -2.6-Dilithium-propyl The method of step 4 in Gelaiku Example 2 uses acetic acid 4-(2, 3 -dimethyl-cytar [2, 3-b] phen-4 -yl) -2, 6 'diisopropyl Phenyl ester (0.8 g, 18.5 mmol), gasified iron (0.016 g, 0.1 mmol), bromine (0.13 ml, 2.6 mmol) and methane (19 ml) ) A white solid (0.53 g, 56%) of the title compound can be obtained, NM E (DHS0-d6) (ί 8.Z 1 (d, 1Η), 7.68-7.62 (m, lH) , 7.60-7.42 (ιβ, ZΗ), 7.18 (s, 2Η), 3.00 (septet, 2H), Z.42 (s, 6H), 1.53 (s, 3H) S 1.14 (d, 12H) .Step 5 4 -f9-Chase-Ertian-Stupid "? 3- blU Gyeonggi-4-even) -2. (, ≫-Diisopropylammonium-the method of step 5 in the same example 2 using acetic acid 4-(9 -bromo-2,3-dimethyl- Naphthalenepyrene (2,3-b] pan-4-yl) -2,6-diisopropylbenzyl ester (0,52 g, 1.0 mmol), 1 0 0 H (1.64 ml, 1 N Solution, 1.6 mmol, tetrahydrofuran (18. 5 ml) and methanol U1.5 ml) to prepare the title compound as a white solid (0.45 g, 95%}, melting point 212-216 ° C; NMR (DMS0-d6) < y 8.30 (s, i

Hj, 8.17 (d, IH), 7.61 (ddd, 1 H), 7.53 (d, 1 H), 7.44 (ddd, 1 H), 6.92 (s, 2 H). 3.41 (septet, 2 H), 2.41 (s, 3 H), 1.55 (s, 3 H), 1.15 (d, 12 H). MS (E1), [M +]. 1 Isotopic pattern, · 466/468. Anal. Calc, for C26H27BrOS: C ， 66.80, H, 5.82, N, 0.00. Found: C, 66.17, H, 5.63, N, 0.06. Step 0 -6 0-This paper tile is suitable for 1 Chinese standard Fengfeng (CNSMl specification (2jG X 4 7 Company 1) n up IV ^^ 1 I ^^ 1 «n ^^ 1 1 ^ 1 Hi I In n I (Please read the precautions on the back before filling out this page) 446 7 04 A7 Staff Consumption of Intellectual Property Bureau, Ministry of Economic Affairs Cooperative printed B7 V. Description of the invention (β) in -U-f 9-Leak-?.: ¾-Dishenji-棻 骈 Γ 2. 3-b 1 -Diluprofen-pyridine, a method of step 9 in the 2-hydroxy-arthroic acid example 1, using 4-(9 -bromo-2, 3 -dimethyl-naphthalene [2, 3- b] benzophen-4-yl} -2, 6-diisopropyl-phenol (0_291

G, 0.6 2 3 millimoles) and 4-ptosulfonyl-2-hydroxy-caric acid (0.768 grams, 3.24 millimoles) can be used to prepare the title compound. Purification with 1 ^ 1 ^ 118 \ 018 (100% CH3CN (containing 0.1% TFA)) gave the title compound as a white solid (0.09 g, 22%), melting point> 225 ° C; iHNMR (DMSO-d6) δ 1.09 (t, 12 H), 1.54 (s, 3 Η), 2.45 (s, 3 H), 3.14-3.22 (m. 2 Η). 7.27 (s, 2 H), 7.41-7.46 (m, 2 H ), 7.50-7.53 (m, 2 H), 7.65-7.69 (m, 1 H), 8.09 (dT 1 H), 8.21-8.23 (m, 1 H). IR (KBr) 3400, 2950, 1700, 1375 and 1180 cm · '. m HF (-ESI), m / z 665/667 (M-H). Anal. Calcd. for C, 3HMBr06S2 1.7H, 0: C, 56.76; H, 4.97 N, 0.00. Found : C, 56.73; H, 4.81 N, 0.12. Both. 5 „2-7, 醅 某-4- Γ4- (9 -zhang-2. Dijia 某-Sai 骈" 2. 3-bl ΙΠΤΡ 分- 4-even) -2. Ft-di-shenyl-¾capryl 1-benzylphenol containing 4- [4- (9_bromo-2,3-dimethyl-naphthalenepyrene [2,3-b ] Benzene-4-yl) -2,6-dimethyl-benzenesulfenyl] -2-hydroxy-benzoic acid (0.36 g, 0.5 7 2 mmol), acetic anhydride (4.5 5 ml) and magnesium iodide (0.159 g, 0.5 7 2 mol) in anhydrous ether (10.0 ml, 0.05 mol) at reflux for 0.5 hours. Cool to room temperature and stop the reaction with water. (1 5 Q ml) to Extract with ether and concentrate β. Dissolve the crude in THF: water (1: 1, 10 ml) and reflux for 1 hour. Cool to room temperature, dilute with water (50 milldannes), and extract β with ethyl acetate and ethyl acetate. Combined with organic layer reduction, silicon passivation is treated with 2% Η 3 Ρ 0 4 / H e 0 ，, and dissociation is treated with 2 0 & 2 5% E t 0 A c. This paper size applies to China National Standard (CNS) A4 specifications. (210 X 297 mm) --- I -------- 1 * Millet .------- Order ---- I ----.- (Please read the notes on the back first (Fill in this page again) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs * '1 ^ A7 _B7_ V. Description of the invention (μ) / Petroleum fermentation gradient, a white solid (0.298 g, 76%) of the title compound can be obtained. (DMSO-d6) δ 1.58 (s, 3 Η), 2.15 (s, 6 i I), 2 JiUs, 3 Η), 2.45 (s, 3 H), 7.20 (s, 2 H), 7.46-7.54 ( m, 2 H), 7.67 (t, 1 H), 7.94 (d, 1 H), 8.05 (dd. 1 H), 8.20-8.25 (m, 2 H), 13.75-13.95 (br.s., i H). Mass spectrum (-ESI), m / z 651/653 (MH). M fi 醯 氤 ju- ¢ 9 -bromo-2. 3 -dishenyl- 基 i 2. 3-b 1 tt -4 -A >-?-Cyclobutadiene-Cyclofluorenylpyridine The method of 5 makes fluorene 4-[4-(9 -bromo-2, 3 -dimethyl-fluorene f 2, 3-b] blind 1 -yl)-2 -cyclopentyl-benzene sulfonium Gib 2-hydroxy-arsanoic acid (0.23 g, 0.45 mmol), acetic anhydride (3.6 ml, 3 δ · 2 mmol) and magnesium iodide (0.12 5 G, 0.45 mmol) to give the title compound. The silica gel was purified by treatment with 2% H ^ ρ (] 4 / M e 0 ，, and dissociated with ϋ & 3 0% E t (} A c / petroleum acid gradient, to obtain the title compound as a colorless solid (0.2 4 5 g, 79%), melting point 1 5 5-1 6 7 ° C 1 Η NMR (DMSO-d6) δ 1.32-1.38 (m, 2 Η), 1.49-1.53 (m, 5 Η), 1.58- 1.63 (m. 3 Η), 1.78-1.80 (m, 1 Η), 2.30 (s, 3 Η), 2.45 (s, 3 Η), 3.00-3.28 (m. 1 Η). 7.25-7.29 (m, 2 Η), 7.36-7.39 (m, 2 Η), 7.50 (t, 1 Η), 7.67 (t. 1 Η), 7.83 (d, I Η), 7.93 (dd, 1 Η), 8.19-8.22 ( m, 2 Η), 13.6-13.8 (br. s, 1 H). Object spectrum (-ESI), m / z 691/693 (M-H). AnaJ. Calcd. for C ^ H ^ BrOyS, 0.3H , O: C, 58.42; H, 4.27 N, 0.00. Found: C, 58.38; H, 4.55 N, 0,10. @ L1. 2_- 丁 醯 ^ -4- [4-(9 -Bromo-2, 3-Dimethyldi 1 HU— 丄 —Li U-covered ft method using 4-丨 4-f 9 -Bromo-2, 3 -dimethyl-Lydrogen-Γϊ 2-This paper is for China National Standard (CNSM! Specification f — II ----------------- I order '11! — Ill * (Please read the precautions on the back before filling this page) A7 446704 B7__ Five, Description of the Invention (W) [2,3-1)] »$ phen-4-yl) -2,6-dimethyl-benzenesulfenyl] -2-hydroxy-arthroic acid (0.32 5 g , 0. 31 mol), butyric anhydride (4.2.3 ml) and magnesium iodide (0.148 g, 0.531 mol) to prepare the title compound. 2% H3P (U /

Purified by MeflH treatment with Biotage RP-Sil, dissociated with a 2Q% EtOAc / petroleum ether gradient, to obtain the title compound as a white solid (0.164 g, 45%), melting point 110-115 ^^ 11 NMR (DHS0-d6) < 5fl.97 (t, 3, H), 1.58 (s, 3 Η), 1.66 (sextet, 2 Η), 2.15 (s, 6 Η), 2.45 (s, 3 Η), 2.60 (t, 2 Η) . 7.19 (s, 2 Η), 7.46-7.53 (m, 2 Η), 7.67 (t, 1 Η), 7.92 (d, 1 Η), 8.05 (dd, 1 Η), 8.23 (t. 2 Η) , 13.80-13.95 (br.s, 1 H). Spectrum (: ESI), m / z 679/681 (Μ-H). Anal., Calcd. For C „H39BrO, Sj: C, 58.15; H, 4.29 N, 0.00. Found: C. 57.83: H. 4.61 N. 0.04. Ms 2-section argon and even 4- "4- (9-? Fu-2. Dimethyl even-sai" "? Hi hope -4-Some 1 -2, R-dimethyla-Rhodium argon glutamate and even 1-¾ case 5 method, using 4-[4-(9 -bromo-2,3-dimethyl-naphthalene) [2, 3-b] P Hanpan-4-yl) -2,6-dimethyl-benzenesulfenylsulfanyl] -2-hydroxy-arthroic acid (0.3 g, 0.4 9 1 mmol Ear), benzyl anhydride (3.33 ml) and magnesium iodide (0.137 g, 0.4 91 mmol) were used to prepare the title compound. Purified by treatment with 2% HaPtU / MeOH, and dissolved. 10 & 15%

EtOAc / petroleum gradient to obtain the title compound as a white solid (0.144 g, 41%), melting point 172-185 °; 111 and 11 feet (0 > 180- < 16) accounted for 1.53 (s, 3 H) , 2.15 (s, 6 Η), 2.32 (s, 3 Η), 7.18 (s, 2 Η), 7.45-7.47 (m, 2 Η), 7.59 -7.66 (m, 3 Η), 7.77 (t, I Η), 8.05 (d, 1 Η), 8.10-8.13 (m, 3 Η), 8.19 (d, 1 Η), 8.28 (d, 1 H). Eaves (-ESI), m / z 713/715 (Μ-H). Anal. Calcd. For C36H27Br07S2 0.75H2O: C, 59.30; H, 3.94 N, 0.00. Found: C, 59.27; H, 3.83 N, 0.08. -63- The paper dimensions are applicable to Chinese national standards ( CNS) A4 specification (210 X 297 mm) ------------ 1 ^ · -----Order_ --- II (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs_B7_ V. Description of the invention (^) @ LS— 2-propyl alkali 颔, even- 淖-? 3-Two Shenji-sai 骈 "2. 3-h] (Please (Read the notes on the back before filling out this page)

Efpan-4 -a) -2. Ϊ́ ΐ-dimethyl a-rong argi 礓 醯 1-a method of Example 5 using 4-[4-(9 -bromo-2, 3 -dimethyl- Naphthalenepyrene [2,3-Merphene-4-yl) -2,6-dimethyl-phenoxysulfonyl] -2-hydroxy-arthroic acid (0.3 g, 0.4 9 1 mmol Ear), propionic anhydride (1.8 ml) and iodine (g, 0.4fH millimolar) to prepare the title compound. Treated with 2% Η 3 P 0 4 / M e 〇 Η Purification, dissociation with 20% E t. 0 A c / petroleum ether gradient: the title compound was obtained as a white solid (G. 2 2 8 g, 70%), melting point 1 8 2-1 8 5 ° C; 1 Μ MR (DMS 0-(Π) β 1. 1 4 (t, 3 Η), 1.58 (s, 3 Η), 2.15 (s , 6 Η), 2.45 (s, 3 Η), 2.63 (q, 2 Η), 7.20 (s, 2 Η), .7-48 (π. 2 Η), 7.67 (t, 1 Η), 7.93 ( d, 1 Η), 8.05 (dd, 1 Η), 8.20-8.25 (m, 2 Η). Mass J (+ APCI), m / z 667/669 (Μ + Η). Anal. Calcd. for C? 2H27Br07S; 0.6H: O: C, 56.65; H, 4.19 N, 0.00. Found: C, 56.67; H, 4.29 N, 0.12. 5-"4- (9 -it-? 2. 3- bl 11¾ pan-4-some) -2-ring 戍 some-Mo 氤 碏 醅 some]-4 -Shenxi shi-卩 hanpan-3-brewing step i ")-" 4-(9 -Chun-?. 3-Dijia even-葳 骈 "? 3-h 1 Favor -4-even) -2-壻 丨 Fa-Rong Qi 碏 醯 基 1-4-Interrogation-Btim -3 -Consumption cooperative of employees of the Intellectual Property Bureau of the Ministry of Economic Affairs printed at room temperature, will contain 4-(9 -bromo-2, 3 -dimethyl-naphthalene 骈 f 2, 3-b] _phen-4 -Yl) -2 -cyclopentyl-phenol (0 · 3 Q 8 mg, II. Β 8 3 mmol) S, IDMF (: i, 41 ml) was added with G 0% N a Η / oil (2 7 ″ mg, ¢). 6 8 3 millimoles) D 0. After 5 hours, add commercially available: 3 -methoxy-4-ίmethoxyphile 丨 唓 phen-2 -sulfonyl gas ί (]. 2 0 4 -G 4-The size of this paper is suitable for the national standard of Shanwei 丨 Specifications ι21ϋ > 297) 446704 A7 B7 Printing of clothing by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economy --- In — — — — — — ^ i — — — — — — — --- Read the notes on the back of the IC before filling in this page) 5. Description of the invention (W) mg, 0.751 mmol) N-DMF (1.37 ml) β 1 hour, add IN HC1 ( 50 ml) to stop the reaction, combined with another product obtained from the same reaction, and extracted with 25% CH2Cl2 / EtOAc. The combined extract was washed with water (3x) and dried (MgS04). Purification with Biotage KP-S i 1 (15% ethyl acetate / petroleum ether) gave the title compound as a colorless solid (0.593 g, 64%): 1 H NHR (DHS0-d6) < J1.2i)- J.41 (m, 2 Η), 1.43-1.83 (m, 9H), 2.44 (s, 3 H), 3.24 (quintet, 1 H), 3.85 (s, 3 H), 3.99 (s, 3 H) , 7.24-7.38 (m, 4 H), 7.50 (t, 1 H), 7.66 (t, 1 H), 8.21 (d, 1 H). 8.81 (s, 1 H). Step 2 5- 「4- {9- 春 -2,3- 二 申 申-赛 軿 「2, ;; ^ 眈 | 1 分 -4- 基） -2- 基 pentyl-Zhu hydrogen 醯 1-4-Shen Qi- I hope that at room temperature, 5-[4 (9 -bromo-2, 3 -dimethyl-fluorene

[2,3-b] fluoren-4-yl) -2-cyclopentyl-benzenesulfenyl] -4 * methylamino-benzophene-3-carboxylic acid methyl acetate (0.722 mg, 1_05 mmol Ear) THF: MeOH (3: 2, 10 ml) was added to IN KOH (5.26 ml). After 1.5 hours, the reaction was stopped by adding IN HC1 (40 ml). The combined extract was dried (HgS04) and concentrated β. Purified by treating Biotage KP-Sil with 2% H3 P04 / HeOH, and dissolved in 25% EtOAc / hexane to give the title compound as a white solid (0.5S 6 g, 85%), melting point > 2 2 5 T: NMR (DMS0-d6) δ 1.34-1.39 (m, 2 H), 1.49-1.54 (m, 5 H), 1'62 -1.73 (m , 3 H), 1.79 * 1.83 (m, 1 H), 2.43 (s, 3 H), 3.23 (quintet, 1 H), 3.97 (s, 3 H), 7.24 (dd, 1 H), 7.30 (d , IH), 7.34-7.36 (m, 2 H), 7.49 (t, 1 H), 7.64 (t. 1 H), 8.19 (d, JH), 8.72 (s, IH), 13.34 (br. S, 1 H). IR (KBr) 3400, 2950, 1690, 1375 and 860 cm, 〆 ('ESI), m / z 669/671 (M-H). Anal. Calcd. For C3lH27Br06Sj: C, 55.44 ; H, 4.05 N, 0.00. Found: C, 55.25; H, 4.11 N, 0.01. -65- This paper size applies to China National Standard (CNS) A4 (210x297 mm) Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs * · '-A7 B7_ V. Description of the Invention (κ) Example 1 1 ")-" 4-(9-ί FU-?. 3-Ershen even-policy 骈 2 3-b U hanpan-4 -ji ) -2-If pentamyl-pyridine 1-4-Huimou-Panpan-phenol at 7-8 , Will contain 5-[4-(S -bromo-2, 3 -dimethyl-naphthalenepyrene [2, 3- h] Utphen-4-yl) -2-cyclopentyl-benzenesulfonyl] -4 -Methystilbene-K-Pan-3-carboxylic acid (0.286 g, 0.42 6 mmol) in dichloromethane (2.8 G ml) stirred with 1 M boron tribromide / digas Methane (1.3 £ ml, 1.32 millimoles) ^ After the addition is complete, replace the dry ice / acrylic bath with an ice water bath and mix for 1 hour. Add crushed ice to stop the reaction, dilute with water (4 C ml), and then diethyl ether Extraction. Combining the diethyl ether layer with another reaction obtained from the same reaction and concentrating. Purify β i 〇tage KP-S i 1 with 2% H3P〇4 / MeOH, and dissolve with 35% E t 0 A c / hexane. The title compound was obtained as a pale yellow solid (0.273 g, 95%), melting point> 2 3 (TC; Ή NMR {DMSO-d6) δ 1.31-1.40 (m, 2 Η). 1.47 (s , 3 Η), 1.50-1.67 (m, 5 Η), 1.S0-1.83 (m, 1 Η), 2.42 (s, 3 Η), 3.32 (quintet, 1 Η), 7.22 (dd, i H) , 7.31-7.37 (m, 3 H), 7.48 (t, 1 H), 7.64 (t, 1 H), 8.19 (d, 1 H). 8.64 (s. 1 H). IR (KBr) 3400, 2950 , 1650, 1375 and 1150 cm. 丨. Mass spectrum (-ACPI) .m / z665 (M-HJ. Anal. Cal cd. for C30H, 5BrO6S3 0.5H2O: C, 54.05; H, 3.93 N. 0.00. Found: C. 54.09; H, 3.98 N, 0.05. a_ii 4-"? -Cyclopentam-4-(2.3-Dimethyl even-Sai 骈 "2.3-b 1 P 寒 望 -4-基" The method of step 9 in Example 1 is used, using 4-(2, 3- Dimethyl-fluorenyl U, 3-b] pentan-4 -yl) -2 -cyclopentyl--and 4-sulfamoyl-2 -hydroxy-arthroic acid can be obtained as the title compound. 2% Η-, P i) 4 / M e 0 H treatment silica gel purification, dissolve with ί! -Of,-This paper ruler. ¾ Applicable to Chinese national standard specifications (Π0 X 29? Public hair) ------ --------------- Order --------- (Please read the notes on the back before filling this page)

Claims (1)

446704 Application for patent ni__ A8 B8 C8 D8 Ύ ~ ^ -12.29 Supplement X / Y Patent Case No. 881 07606 "Naphthalene [2,3-B] heteroaryl-4-yl Derivatives for the Treatment of Metabolic Abnormalities Related to Insulin Resistance or Hyperglycemia" (Amended in Dec. 89) 6. Application Patents: 1. A compound of the following formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each hydrogen, Cualkyl, or cyclopentyl; R3 and R4 are Cualkyl; R5 is hydrogen or bromine: W X is 0; X is 0; R6 is hydrogen or Cu alkyl; Y is methylene, carbonyl * or -S02-; Z is phenyl or thienyl: R7 and R8 are each hydrogen, carboxyl, and hydroxyl , Or -CO〇RR · 1 G is a C 6.: 2 aryl group, or c 5.6 courtyard group. 2. If the compound in the first item of the patent application scope is 4- [4- (9-bromo-2,3-, this paper size applies to Chinese National Standard (CNS) A4 specification (210X297 cm)) I I1 1 «I II-^^ 1 I. ^ _1-I- I ^^ 1 ^^ 1 ^ -5 (Please read the precautions on the back before filling out this page) Staff of the Ministry of Economic Affairs, Smart Finance-4 Bureau, #Join Society Printed 1 0 Ministry of Economic Affairs 4 葸 τΗ; Printed by the 4th cooperative, bs C8 D8 6. Scope of patent application dimethyl-naphthalene [2,3-b] thiophen-4-yl) -2-isopropyl-phenoxysulfon Fluorenyl] -2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof. 3. For example, the compound in the scope of patent application No. 1 is 4- [4- (9-bromo-2,3-dimethyl-naphthalenepyrene [2, 3-b] thiophen-4-yl) -2, 6-dimethyl-phenoxysulfanyl] -2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof. 4. The compound as claimed in item 1 of the scope of patent application, which is 4- [4- (9-bromo-2,3-dimethyl · naphthalene [2,3-b] thiophen-4-yl) -2- Cyclopentyl-phenoxysulfanyl] -2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof. 5. The compound as claimed in the first item of the patent application scope, which is 4- [4- (9-bromo-2,3-dimethyl-naphthalenepyrene [2,3-b] _phen-4-yl) -2 , 6-diisopropyl-phenoxysulfanyl] -2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof. 6. The compound according to item 1 of the scope of patent application, which is 2-acetoxy-4- [4- (9-bromo-2,3-dimethyl-naphthalenepyrene [2,3-b] thiophene- 4-yl) -2,6-dimethyl-phenoxysulfanyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 7. The compound according to item 1 of the scope of patent application, which is 2-acetoxy-4- [4- (9-bromo-2,3-dimethyl-naphthalenepyrene [2,3-b] thiophene- 4-yl) -2-cyclopentyl, phenoxysulfanyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 8. The compound according to item 1 of the scope of patent application, which is 2-acetoxy-4- [4- (9-bromo-2,3-dimethyl-naphthalenepyrene [2,3-b] thiophene- 4-yl) -2,6-dimethyl-phenoxysulfanyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 9. The compound according to item 1 of the scope of patent application, which is 2-benzyloxy-4, [4- (9-bromo-2,3-dimethyl-naphthalenefluorene [2,3-b] thiophene- 4-yl) -2,6 · dimethyl-phenoxysulfanyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 10. If the compound in the scope of application for item 1 is 2-propoxyl-4----------'— ^ 1 —----, order ------- . ^ (Please read the precautions on the back before filling in this page) The water paper dagger mat uses the Chinese national standard S: CMS is a 4 rule _ grid; printed by the Consumer Finance Cooperative of the 4th Bureau of Public Welfare and Finance of the Ministry of Economic Affairs 446 7 04 C8 D8 Scope of patent application [4- (9-Bromo-2,3-dimethyl-naphthalenepyrene [2, 3-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl ] -Benzyl acid or a pharmaceutically acceptable salt thereof. 11. The compound according to item 1 of the scope of patent application, which is 5- [4- (9-bromo-2,3-dimethyl-naphthalenepyrene [2,3-b] thiophen-4-yl) -2- Cyclopentyl-phenoxysulfosulfanyl 4-methoxy-thiophene-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 12. The compound as claimed in item 1 of the scope of patent application, which is 5- [4- (9-bromo-2,3 · dimethyl-naphthalenepyrene [2,3-b] thiophen-4-yl) -2- Cyclopentyl-phenoxysulfanyl] -4-hydroxy.thiophene-3-carboxylic acid or a pharmaceutically acceptable salt thereof. Π The compound according to item 1 of the patent application scope, which is 4- [2-cyclopentyl-4- (2,3-dimethyl-naphthalenepyrene [2, 3-b] thiophen-4-yl) -benzene Oxosulfenyl] -2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof. 14. The compound according to item 1 of the scope of patent application, which is 4- [2-cyclopentyl-4- (2,3-dimethyl-naphthalenepyrene [2,3-b] furan-4-yl)- Phenoxysulfonyl] -2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof. 15. The compound according to item 1 of the scope of patent application, which is 4- [2-bromo-4- (2,3-dimethyl-naphthalenepyrene [2,3-b] furan-4-ylphenoxysulfonium []-6-ethyl-phenoxysulfanyl] -2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof. 16. If the compound of the scope of application for item 1 is 4- [4- (2,3 -Dimethyl-naphthalenepyrene [2,3-b] furan-4-yl) -phenoxysulfonyl] -2,6-diethyl-phenoxysulfonyl] -2-hydroxy-benzoic acid or Its pharmaceutically acceptable salt. 17. For example, the compound in the scope of patent application No. 1 is 4 · [4- (9-bromo-2,3-dimethyl-naphthalenepyrene [2,3-b] thiophene-4- Group) -2,6-dimethyl-phenoxysulfonyl] -2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof. 18. For example, the compound in the scope of patent application No. 1 is 2- (4-methyl Oxybenzine (please read the precautions on the back before filling this page), 1T This paper size applies the Chinese national standard {CMS) A4 specification (规格 〇 × 297mm) β—ai. Ministry of Economic Affairs " A8 BS C8 D8 printed by Consumer Cooperatives VI. Patent application scope) oxy-4- [4- (9-bromo-2,3-dimethyl-naphthalenepyrene [2, 3-b] thiophen-4-yl ) -2,6-dimethyl-phenoxysulfanyl] -benzoic acid or its preparation Allow salt. 19. The compound as claimed in item 1 of the scope of patent application, which is 5- [4- (2,3-dimethyl-naphthalenepyrene [2, 3-b] thiophen-4-yl) -2,6-diethyl -Phenoxysulfonyl] -4-methoxy-thiophene-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 20. The compound according to item 1 of the scope of patent application, which is 5-pyridin-2-yl-thiophene-2-sulfonic acid 2-cyclopentyl-4- (2,3-dimethyl-naphthalene} [2, 3-b] thiophen-4-yl) phenyl ester or a pharmaceutically acceptable salt thereof. 21. The compound according to item 1 of the scope of patent application, which is 4-benzyloxy-5- [4- (2,3-dimethyl-naphthalenepyrene [2,3-b] thiophen-4-yl) · 2,6-diethyl-phenoxysulfanyl] -4-methoxy-thiophene-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 22. The compound according to item 1 of the scope of patent application, which is 3- [2-cyclopentyl M-0, 3-dimethyl-naphthalenepyrene [2, 3-b] thiophen-4-yl) -phenoxy Sulfonyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 23. The compound according to item 1 of the scope of patent application, which is 5- (2-methanesulfonyl-pyrimidin-4-yl) thiophene-2-sulfonic acid 2-cyclopentyl 4- (2,3-di Methyl-naphthalenepyrene [2, 3-b] thiophen-4-yl) -phenyl ester or a pharmaceutically acceptable salt thereof. 2 The compound as described in the first item of the patent application scope, which is 2-benzyloxy-4- [4- (2,3-dimethyl-naphthalene [2,3-b] thiophen-4-yl)- 2,6-dimethyl-phenoxysulfonyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 25. The compound according to item 1 of the scope of patent application, which is 2- (4-chlorobenzylfluorenyl) oxy-benz (4- (2,3-dimethyl-naphthalenepyrene [2,3-b] thiophene- 4-yl) -2,6-dimethyl-phenoxysulfofluorenyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 26 The compound according to item 1 of the scope of patent application, which is nicotinic acid 2-carboxyl-coated paper伕 Conformity applies to Chinese national standards.:CNS: · A4 specifications ί. 二 'ί: · > Public f ----------- meal ------ 1T ---- --0 (Please read the notes on the back before filling this page) 446 7 0 4 Α8 Β8 C8 D8 Six 'application for patent scope 5- [4- (2,3-dimethyl-naphthalene 骈 [2, 3- b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfanyl] -benzyl ester or a pharmaceutically acceptable salt thereof. 27_ The compound as claimed in item 1 of the scope of patent application, which is nicotinic acid 2 -Carboxy · 5- [4- (9-Bromo-2,3-dimethyl-naphthalenepyrene [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl ] -Benzyl ester or a pharmaceutically acceptable salt thereof 2E—A pharmaceutical composition for treating an animal with an anti-insulin or hyperglycemia mediated metabolic abnormality, containing an effective amount of a compound of the formula I or a pharmaceutically acceptable salt thereof, (Please read the notes on the back first (Fill in this page) ^ X Ordered by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs where R1 and R2 are each hydrogen, alkyl, or cyclopentyl R3 and R4 are Ci.6 alkyl; R5 is hydrogen or bromine; W is S, or 0: X Is 0; R6 is argon or Cu alkyl: Y is methylene, carbonyl, or -S02- ί This paper size applies Chinese National Standard {CNS) A4 specification (2! 0X2W mm) When the Ministry of Economic Affairs is smart, it will print B8, C8 DS, and cooperation. 6. The scope of application for patent z is phenyl or thienyl; R7 and R8 are each hydrogen, carboxyl, hydroxyl, or -CO〇R1Q; R1Q It is C6.12 aryl, or Cy alkyl. Modified pharmaceutical composition for treating or inhibiting animal-type π diabetes mellitus 'containing an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof administered to the animal' Wherein R1 and R2 are each hydrogen 1 CV6 alkyl, or cyclopentyl; R3 and R4 are Cu alkyl; R5 is hydrogen or bromine; W is S, or 0; X is 0; R6 is hydrogen or Cu alkyl; Y is methylene, carbonyl, or -S02-; Z is phenyl or thienyl; R71RS is each hydrogen, carboxy 'hydroxyl, or -COOR1Q; is C6-12 aryl, or alkyl. Taizhilangduo GM China's palm label: (+ 'NS. Λ4 specifications,:!! / Public sincerity ------ ΪΤ ------ 0 (please read the precautions before filling out this page) 446 7 0 4 A8 B8 C8 D8 VI. Patent application scope 3D · —A kind of medicinal composition for regulating the amount of grapes in animals, including effective for the animal The amount of a compound of formula I or a pharmaceutically acceptable salt thereof, (Please read the notes on the reverse side and fill in this page first) Printed by the Consumer Cooperatives of the 4th Bureau of Finance and Economics of the Ministry of Economic Affairs, where R1 and R2 are each argon 'C i-6, or cyclopentyl; Alkyl; R5 is hydrogen or bromine: W is S, or 0; X is 0; R6 is hydrogen or Cu alkyl; Y is methylene 'group, or -S02-; Z is phenyl or thienyl; R7 and R8 are each hydrogen ', acyl, or _COOR10: R1Q is C6-12 aryl, or Cm alkyl. This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297). Ordered? 3 -4- Application date η owed // ¾ Case number ^ 118107606 Category --f f -t-- 446704 Ministry of Economic Affairs t Central Standards Bureau Staff Consumer Cooperative Cooperative Seal—Patent Specification (Amended in Dec. 89) Invention A I. New name Chinese for the treatment of metabolic abnormalities related to insulin resistance or hyperglycemia [2] , 3-B] heteroaryl-4-yl derivative English NAPHTHCH2,3-B] HETEROAR-4-YL DERIVATIVES FOR — TREATING METABOLIC DISORDERS RELATED TO INSULIN RESISTANCE OR HYPERGLYCEMIA _ Invention One 'Name of the person who created the name Nationality,--1 1. Paul Jeffrey Dollings 2. Arlene Joan Dietrich 3. Jay Edvard Wrobe1 1. United States 2. United States 3. United States Residence and Residence 1. Pennsylvania, United States No. 1012, Magic Road, Newtown, 189 40 2. 13 Connell Road, New Jersey 08075, United States 3. Beautiful paintings, New Jersey 08648 Lawrence 郷 Rose Tree Lane 15 銶 Name · (Name 4) ' American Home Products Corporation _ American Home Products Corporation III. Applicant's residence and residence (office) New Jersey 07940-0874 Mandison 5 Gillard Farm Agency Name of the person Egon E. Berg Binding Line This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (by this bureau) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Large category A6_ B6 PC classification This case has been applied for a patent to the United States (region), the date of application: a microorganism has been deposited in: Case number: ® Yes □ No claim of priority 1 May 12, 998 0S / 076, 446 Date of deposit: Deposit number: -------— F---! 1 1— ----- I ϋ -ΪΙ— I _ (Please read the notes on the back before filling in each page on this page) • 2b- 本Paper degree applicable national national standard (CNS) A4 specification (210X 297. mm) A7 B7 446704 V. Description of the invention (9 M. d'Ischia et al., Tetrahedron, 1987, 43, 4 3 1-4 3 4 Published Compound M. < Please read the notice on the back before filling this page) Printed on the last page of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (A-M) and does not contain appropriate substituents for in vitro PTPase inhibitory activity or in vivo Anti-diabetic activity. DESCRIPTION OF THE INVENTION The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which can be used to treat metabolic abnormalities associated with insulin resistance and hyperglycemia: R7, 〆 This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) I ^ — — — — ——— I,, 1 — —, [-III n — — — — — — — — — — — — — A7 B7 V. Description of the invention (groups of cyano and alkane are R1 2 R based on alkene and B in the group P1-amine amine diyl amine alkyl sulfonium 0 alkane gas Single benzene or phenyl phenyl sulfonate-Shaanxi. 01 phenyl phenoxy hydrazone,, the basic halogen halides to take the ring 8 to take 3-tri-C or, the radical oxyalkyl alkyl fluoro all or radical fluoro per R hydrogen For each 4 R and alkyl alkyl fluoro allyl alkoxy hydrazone 7 I OJ C alkaneamine (please read the precautions on the back before filling this page) hydrogen is 5 R 'S 6, IS C1 is W prime halogen Oxyalkane β-based oxyaryl, sulfonyl cyanosulfonate, aryl, alkyl fluorinated alkane 6 aryl 1-12 R is ο is R is c RC or -N or hydrogen, hydrogen alkane or 2 Η 6 R ** = ΐί 丨 ^ ί Alkyl Y Y Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs R Hydroxy-; group so 醯 t or ·-? _ 2 group C 2 ο Tsai > -S or group, carboxyl group, carbonyl aromatic hydrogen, heterocyclic; group, each J ES 1 phenylene is 8 R and alkoxy rf group _ -mine chlorine 2 1 c C gas, ,, arylheterohapin, sulfanyl 6 aryl aryl 1-carbonyl 6 C _ 6 gas 1 1, C a another C group , 3, carbonyl 7-1-based gas C7 hydrogen-based carbonyl alkane_alkanefull square heteroamine, sulfur C fluoro group, peraryl V 3 oxalaldehyde 1 I 2 6 tetramethyl c C 、 'Amine' 'Alkyl'-based alkylaminoamine alkyl alkyl groups per alkylamine line | The compound containing the chemical compound Zhongjia its salt, Xu Rong Pharma, or its compound, is hydrogen, and each compound is 2 R and the alkane gas is S. Alkyl methyl fluorotrifluoroethane is generated in 6 generations of 1 C and is based on phenyl benzene or 6 radicals Phenylbromochlorooxymethanyl Bt R hydrogen and is each alkane X, 4. S ο is an alkane or a halogen-based alkyloxyaryl alkane ^ ^ 0 ® Μ. Or; all 61 & 6-6 oxofuran 1-C1 alkane or M, ¾-based ¾-based gas-based 0 sulphur (please read the precautions on the back before filling this page) or hydrogen is alkane ρ Υ is pyridine and Ministry of Economic Affairs wisdom The property bureau employee consumer cooperative printed basic fluorofluoroyl, aziridyl, oxazolyl ', carbonyl, pyridino, C, pyridine, c2ce, aryl, carbonyl, methyl, S, hydroxy Gasyl benzoxazole β, carbonyl alkaneazole 6 full aryl 1-712 pyrimidinyl hydrosulfanyl ptt thiofurfuryl s Lf _ hope or π ΐ 脞 if XOR 'carboxycarbonyl oxoalkane aryl 13 azole 7 tetrayl sulfonyl sulfonium methylamine amine & i isocool V full M, 62-6 ] C 1 oxygen, ^ 1 oxazole C, aryl fluorene: amine, group su P, hydrazine * 7- 'alkane C group I oxane fea cyano 6 hydroxy-ε, β 1-1 pyridine' 1 6 C c I gas, amine alkane halide 6 > ^ 0 C carboxy '6 alkane | amine C1 6 is 1-based C-alkane's per amine alkane to substitute for pyrimidine or pyrimidine or nitronitro Sulfane -------- Order --------- Line 丨 This paper size is applicable to China National Standard (CNS) A4 specification (2J0X297 mm) Ketodi I 2 * radical I 4 I ene I 3 I butyl ring hydroxy aryl 12-6 C is aryl aromatic heterocyclic ring or cyclic monoalkyl aryl aryl aryl slashing ** or cyclic mono or berry alkane K The compound containing the formula is better and the alkane in the hair is better. • 'f * J · 1. 1-based C alkane 6 0-is C 1 each 2 4 RR and salt salt drug; Compound, bromine bromide ο or 0 is S ο is or (Please read the precautions on the back before filling out this page) Install or hydrogen for berry alkyl 6 azole. Blind C1; or-Plant'S 02¾ Chuns kK I, or nt, halo, 1-6 carbonyl carbonyl hydrogen C1, carbene, methyl, phenylene and phenylene are as follows: printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs, base R1 Cyano C0 hydroxyl, -0, radical, oxazolyl hydrazone! f 醯 e Isosulfone 1, C-based S 'pyridine 1-r J-based alkane i is Θ a salt C Xuorong 1-6' drug-based system based on aromatic heterocyclic and monocyclic pyridinyl ' Pyrimido or aryl is 0:12 and fordidine is a 16- ^ mt ^ -o ^ c® alkane or or ¾benzyl alkane-line. Example base-fluorene I Isopropanoic acid-Basic hydroxyl odor cake ί bundle-methyl I 4 " 0} fluorenyl 0 sulfo «benzene J benzoic acid benzyl _ kexiang example 0 ^ νί 骈 琴 I 蕋 甲 Hope ¥ C = l · 本Paper size is suitable for National Corrugated Book (CNS) A4 specification GKh 297 male f) 446704 Patent application ni__ A8 B8 C8 D8 Ύ ~ ^ -12.29 Supplement X / Y Patent Case No. 881 07606 "Naphthalene [2,3-B] heteroaryl-4-yl Derivatives for the Treatment of Metabolic Abnormalities Related to Insulin Resistance or Hyperglycemia" (Amended in Dec. 89) 6. Application Patents: 1. A compound of the following formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each hydrogen, Cualkyl, or cyclopentyl; R3 and R4 are Cualkyl; R5 is hydrogen or bromine: W X is 0; X is 0; R6 is hydrogen or Cu alkyl; Y is methylene, carbonyl * or -S02-; Z is phenyl or thienyl: R7 and R8 are each hydrogen, carboxyl, and hydroxyl , Or -CO〇RR · 1 G is a C 6.: 2 aryl group, or c 5.6 courtyard group. 2. If the compound in the first item of the patent application scope is 4- [4- (9-bromo-2,3-, this paper size applies to Chinese National Standard (CNS) A4 specification (210X297 cm)) I I1 1 «I II-^^ 1 I. ^ _1-I- I ^^ 1 ^^ 1 ^ -5 (Please read the precautions on the back before filling out this page) Ministry of Economic Affairs, Intellectual Property-4 Bureau staff Juan # Cooperative Society Printing 1 0