CN1308627A - 11-Aryl-benzo[b]naphtho[2,3-d]furans and 11-aryl-aryl-benzo[b]anphtho[2,3-d]thiophenes useful in the treatment of insulin resistance and hyperglycemia - Google Patents

11-Aryl-benzo[b]naphtho[2,3-d]furans and 11-aryl-aryl-benzo[b]anphtho[2,3-d]thiophenes useful in the treatment of insulin resistance and hyperglycemia Download PDF

Info

Publication number
CN1308627A
CN1308627A CN99808422A CN99808422A CN1308627A CN 1308627 A CN1308627 A CN 1308627A CN 99808422 A CN99808422 A CN 99808422A CN 99808422 A CN99808422 A CN 99808422A CN 1308627 A CN1308627 A CN 1308627A
Authority
CN
China
Prior art keywords
benzo
naphtho
thiophene
carbon atom
bromo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN99808422A
Other languages
Chinese (zh)
Inventor
J·E·弗罗贝尔
A·J·迪特里希
李泽南
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth LLC
Original Assignee
American Home Products Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Home Products Corp filed Critical American Home Products Corp
Publication of CN1308627A publication Critical patent/CN1308627A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/74—Naphthothiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Furan Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention provides compounds of formula (I) having a structure wherein A is hydrogen, halogen, or OH; B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, nitro, amino or OR; R is hydrogen, alkyl of 1-6 carbon atoms, -COR<1>, -CH2CO2R<1>, -CH(R<1a>)CO2R<1>, or -SO2R<1>; R<1> and R<1a> are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms or aryl; E is S, SO, SO2, O; X is hydrogen, halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy of 6-12 carbon atoms, nitro, amino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl, or -OCH2CO2R<1b>; R<1b> is hydrogen or alkyl of 1-6 carbon atoms; Y and Z are each, independently, hydrogen or OR<2>; R<2> is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or -CH2CO2R<3>; R<3> is hydrogen or alkyl of 1-6 carbon atoms; C is hydrogen, halogen or OR<4>; R<4> is hydrogen, alkyl of 1-6 carbon atoms, -CH(R<5>)W, -C(CH3)2CO2R<6>, 5-thiazolidine-2,4-dione, -CH(R<7>)CH2CO2R<6>, -COR<6>, PO3(R<6>)2, or -SO2R<6>; R<5> is hydrogen, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH2(1H-imidazol-4-yl), -CH2(3-1H-indolyl), -CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), -CH2(3-pyridyl), or -CH2CO2H; W is -CO2R<6>, -CONH2, -CONHOH, CN, -CONH(CH2)2CN, 5-tetrazole, -PO3(R<6>)2, -CH2OH, or -CH2Br, -CONR<6>CHR<7>CO2R<8>, R<6> is hydrogen, alkyl of 1-6 carbon atoms, aryl or aralkyl.

Description

Can be used for treating 11-aryl-benzo [b] naphtho-[2,3-d] furans and 11-aryl-benzo [b] naphtho-[2,3-d] thiophene of insulin resistance and hyperglycemia
Background of invention
People recognize that for a long time ubiquity insulin resistance in the patient of glucose intolerance.(American Journal of Medicine 1976 such as Reaven, 60,80) use to continue infusion glucose and Regular Insulin (Regular Insulin/glucose lock shape (clamp) technology) and oral glucose tolerance test confirmation, insulin resistance is present in not among non-obesity on the same group, the non-ketoacidosis patient.These patients' scope is from the extremely tangible fasting hyperglycemia of critical (borderline) glucose tolerance.In these researchs, diabetic groups comprises insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) two class patients.
Consistent with lasting insulin resistance is the hyperinsulinemia that is easier to measure, and this can measure by the circulation blood insulin concentration in the accurate mensuration patient blood plasma.Hyperinsulinemia can occur as the result of insulin resistance, for example, in the patient of obesity and/or diabetes (NIDDM) patient and/or glucose intolerance, perhaps in IDDM patient, occur as result with the excessive insulin injection of comparing through the hormone normal physiological release of endocrine pancreas.
(sum up by a large amount of experiments, clinical and epidemiological study by Stout, Metabolism, 1985,34,7 and by Pyorala etc., Diabetes/Metabolism Reviews1987,3,463 sum up in more detail), established well hyperinsulinemia and obesity and with the contact of the ischemic disease (for example atherosclerosis) of great vessels.In 1 to 2 hour, significance raises relevant with the risk of coronary heart disease increase on the statistics of plasma insulin after the oral glucose lifting capacity.
Because in fact most these researchs get rid of the diabetic subject, the data that the risk of atheromatosis is relevant with diabetic symptom are not a lot, but demonstrate the identical trend (Pyorala etc.) with the ND.Yet in diabetic population, the sickness rate of the atheromatosis on M ﹠ M statistics surpasses ND crowd (Pyorala etc., Jarrett Diabetes/Metabolism Reviews 1989,5,547; Harris etc., from the mortality ratio of diabetes, Diabetes in America 1985).
The independent risk factors of atheromatosis are fat also relevant with insulin resistance with hypertension.Use Regular Insulin/glucose clamp connexion method, tracer glucose infusion and indirect heat assay method, the insulin resistance that has confirmed essential hypertension is positioned at peripheral tissues's (mainly being muscle) and directly related (DeFronzo and Ferrannini with hypertensive seriousness, DiabetesCare 1991,14,173).In suffering from hypertensive obese person, insulin resistance produces hyperinsulinemia, this disease is recovered by the mechanism that thermogenesis restriction body weight further increases, and heavily absorbs and stimulates sympathetic nervous system at kidney, heart and vascular system but Regular Insulin also increases kidney sodium, thereby cause hypertension.
Have recognized that at present insulin resistance generally is the result who has defective in the insulin receptor signalling system on the site after Regular Insulin is incorporated into acceptor.The scientific evidence that confirms the accumulation of insulin resistance in responding to the main tissue of Regular Insulin (muscle, liver, fat) is pointed out strongly, commitment in this cascade, particularly when insulin receptor kinase activates, there is the defective in the insulin signaling conduction, as if it weakened (the summary of Haring, Diabetalogia 1991,34, and 848).
Protein-tyrosine phosphatase (PTP enzyme) plays an important role in the regulation and control of proteinic phosphorylation.The interaction of Regular Insulin and its acceptor causes some the tyrosine molecular phosphorus acidifying in described receptor protein, activates described receptor kinase thus.The PTP enzyme makes activated insulin receptor dephosphorylation, and tyrosine kinase activity is weakened.The PTP enzyme also can be by the catalysis insulin receptor kinase cell substrate dephosphorylation to regulate (post-receptor) signal behind the acceptor.As if probably with insulin receptor closely related and regulate and control probably thus the active enzyme of insulin receptor kinase comprise PTP1B, LAR, PTP α and SH-PTP2 (B.J.Goldstein, J.Cellular Biochemistry 1992,48,33; B.J.Goldstein, Receptor 1993,3,1-15; F.Ahmad and B.J.Goldstein, Biochim.Biophys Acta 1995,1248,57-69).
(Diabetes 1991 for McGuire etc.; 40; 939) confirm that non-diabetic glucose intolerance patient has the PTP enzyme activity level of obvious rising in muscle tissue, and infusion of insulin can not suppress the PTP enzymic activity as the patient of insulin sensitivity with respect to normal patient.
Meyerovitch etc. (J.Clinical Invest.1989,84,976) promptly observe the PTP enzymic activity of remarkable increase at the rodent model of two kinds of IDDM in the liver of heredity diabetes BioBreeding rat and STZ inductive diabetes rat.Sredy etc. (Metabolism, 44,1074,1995) observe the PTP enzymic activity of similar increase in liver obesity, diabetes ob/ob mouse (the hereditary rodent model of NIDDM).
The compounds of this invention is at external PTP enzyme and the people's derivatize reorganization PTP enzyme-1B (hPTP-1B) that suppresses to be derived from rat liver microsomes that shown.They are used for the treatment of and obesity, glucose intolerance, diabetes, the hypertension insulin resistance relevant with the big and small vessel ischemic disease.
K.Shinzo etc., Heterocycles 1982,19, and 1033-1037 discloses the synthetic of benzo [b] naphtho-[2,3-d] thiophene, and two embodiment also has the 11-phenyl substituent, shown in following structure A.None embodiment contains suitable substituents in this article, and also not having any substituting group on the 11-phenyl is that anti-diabetic activity institute is requisite in external PTP enzyme inhibition activity or the body.
Figure A9980842200241
(A),R=H,CH 3
J.Hastings etc., J.Chem.Soc., Pekin Trans.l 1975,19,1995-1998 and J.Hastings etc., J.Chem.Soc., Pekin Trans.l 1972,14,1839-1842 discloses three benzos [b] naphtho-[2,3-d] embodiment of furans, they also have the 11-phenyl substituent, shown in following structure B.At these J.Chem.Soc., in the article of Pekin Trans.l, none embodiment has the necessary suitable replacement of anti-diabetic activity in external PTP enzyme inhibition activity or the body on the 11-phenyl.
Figure A9980842200251
1) R=CH 3, the R of R ＇=H2), the R=H of R ＇=H3), R ＇=CH 3Invention is described
The invention provides chemical compounds I or its pharmacy acceptable salt with following formula structure
Figure A9980842200252
Wherein A is hydrogen, halogen or OH; B and D be independently of one another hydrogen, halogen, CN, a 1-6 carbon atom alkyl, aryl,
The aralkyl of 6-12 carbon atom, nitro, amino or OR; R be hydrogen, a 1-6 carbon atom alkyl ,-COR 1,-CH 2CO 2R 1,-CH (R 1a) CO 2R 1
Or-SO 2R 1R 1And R 1aBe the alkyl of hydrogen, a 1-6 carbon atom, the virtue of a 6-12 carbon atom independently of one another
Alkyl or aryl; E is S, SO, SO 2, O; X be alkyl, CN, a 1-6 carbon atom of hydrogen, halogen, a 1-6 carbon atom perfluoroalkyl,
The alkoxy aryl of the alkoxyl group of 1-6 carbon atom, aryloxy, a 6-12 carbon atom,
Alkyl alkylthio base, sulfur alkyl aryl, the pyridyl of nitro, amino, a 1-6 carbon atom
Sulfane base, 2-N, N-dimethylamino second sulfane base or-OCH 2CO 2R 1bR 1bAlkyl for hydrogen or 1-6 carbon atom; Y and Z are hydrogen or OR independently of one another 2R 2For the aralkyl of the alkyl of hydrogen, a 1-6 carbon atom, a 6-12 carbon atom or-
CH 2CO 2R 3R 3Alkyl for hydrogen or 1-6 carbon atom; C is hydrogen, halogen or OR 4R 4For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R 5) W ,-C (CH 3) 2CO 2R 6, the 5-thiazole
Alkane-2, the 4-diketone ,-CH (R 7) CH 2CO 2R 6,-COR 6,-PO 3(R 6) 2Or-SO 2R 6R 5Alkyl, aralkyl, aryl, CH for hydrogen, a 1-6 carbon atom 2(1H-imidazol-4 yl),
-CH 2(3-1H-indyl) ,-CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl),
-CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl) ,-CH 2(3-pyridyl) or
-CH 2CO 2H; W is-CO 2R 6,-CONH 2,-CONHOH, CN ,-CONH (CH 2) 2CN, 5-four
Azoles ,-PO 3(R 6) 2,-CH 2OH or-CH 2Br ,-CONR 6CHR 7CO 2R 8R 6Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom; R 7Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom; R 8Be alkyl, the aryl or aralkyl of hydrogen, a 1-6 carbon atom, described compound or its pharmacy acceptable salt can be used for treating the metabolism disorder relevant with insulin resistance or hyperglycemia.
When compound of the present invention contains basic moiety, as work as R 5For-CH 2(3-pyridyl) or when containing similar basic moiety, mineral acid and organic acid and similarly known acceptable acid by for example being acetate, propionic acid, lactic acid, citric acid, tartrate, succsinic acid, fumaric acid, toxilic acid, propanedioic acid, amygdalic acid, oxysuccinic acid, phthalic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methylsulfonic acid, naphthene sulfonic acid, Phenylsulfonic acid, toluenesulphonic acids, camphorsulfonic acid can form pharmacy acceptable salt.When compound of the present invention contains carboxylicesters or phenol moieties, also can form salt, preferably an alkali metal salt, for example sodium salt, lithium salts or sylvite by organic bases and mineral alkali.
Alkyl comprises a straight chain and a chain portion.Halogen is meant bromine, chlorine, fluorine and iodine.The substituent aryl moiety of described aryl or aralkyl is preferably phenyl or naphthyl; More preferably phenyl.Described aryl moiety can be randomly with the alkylamino of the carbalkoxy of the alkoxyl group of the alkyl that is selected from following substituting group one, two or three replacement: a 1-6 carbon atom, a 1-6 carbon atom, trifluoromethyl, halogen, a 2-7 carbon atom, a 1-6 carbon atom and dialkylamino (wherein each described alkyl has 1-6 carbon atom), nitro, cyano group ,-CO 2The alkyl-carbonyl oxygen base of H, a 2-7 carbon atom and the alkyl-carbonyl of 2-7 carbon atom.
Compound of the present invention can contain unsymmetrical carbon, and some The compounds of this invention may contain one or more asymmetric centers, therefore may produce optically active isomer and diastereomer.Although do not show the stereochemistry in the formula I, the present invention includes this class optically active isomer and diastereomer; And the R and the S steric isomer of the enantiomer-pure of racemic and fractionation; And other mixture and the pharmacy acceptable salt thereof of R and S steric isomer.
Compound of the present invention can be atropisomer because may be restricted or rotation is slow around the single bonded rotation of aryl three ring.This restricted rotation produces extra chirality, produces enantiomeric form.If another chiral centre is arranged in this molecule, then there is diastereomer, can in NMR and by other analytical technology, observe.Though do not show, the present invention includes this class atropisomer (enantiomorph and diastereomer corresponding to atropisomer stereochemistry in the formula I; And pure diastereomer and non-enantiomer mixture racemic, that split) and pharmacy acceptable salt.
Preferred compound of the present invention comprises formula I compound or its pharmacy acceptable salt, and wherein A and B are hydrogen or bromine independently of one another; C and D are OH; E is S or O; X be alkyl, CN, a 1-6 carbon atom of hydrogen, halogen, a 1-6 carbon atom alkoxyl group,
The aryloxy of 6-12 carbon atom; The alkoxy aryl of 6-12 carbon atom, aryl sulfane
Base or pyridyl sulfane base; Y and Z are hydrogen.
The another kind of preferred compound of the present invention comprises formula I compound or its pharmacy acceptable salt, and wherein A is a hydrogen; B and D are hydrogen, halogen, a 1-6 carbon atom alkyl, aryl or 6-12 independently of one another
The aralkyl of carbon atom; C is OR 4E is S, O; X be alkyl, a 1-6 carbon atom of hydrogen, halogen, a 1-6 carbon atom perfluoroalkyl, CN,
The alkoxy aryl of the alkoxyl group of 1-6 carbon atom, aryloxy, a 6-12 carbon atom,
Sulfur alkyl aryl, pyridyl sulfane base; Y and Z are H; R 4For the alkyl of H, a 1-6 carbon atom ,-CH (R 5) W or 5-thiazolidine-2, the 4-diketone; R 5For the aralkyl of the alkyl of H, a 1-6 carbon atom, a 6-12 carbon atom, aryl ,-
CH 2(3-1H-indyl) ,-CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl),
-CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl) or-CH 2(3-pyridyl); W is-CO 2R 6,-CONH 2,-CONHOH, 5-tetrazolium or-PO 3(R 6) 2R 6Alkyl for hydrogen or 1-6 carbon atom.
Preferred The compounds of this invention comprises: (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-phenoxy group]-3-phenyl-propionic acid; (R)-and 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid; (5 '-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-[1,1 '; 3 ' 1 "] terphenyl-2 '-Ji oxygen base)-acetate; 4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-di-isopropyl-phenoxy group]-acetate (R)-2-[2,6-two bromo-4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3--phenyl-propionic acid; 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-(4-fluorophenyl)-propionic acid; (R)-2-[2-bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-6-methoxyl group-phenoxy group]-3-phenyl-propionic acid; (R)-and 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-propionic acid; (R)-and 2-[2,6-two bromo-4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-propionic acid; 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-caproic acid; (R)-and 2-[2,6-two bromo-4-(6-methoxyl group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid; (R)-and 2-[2,6-two bromo-4-(6-chloro-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid; (R)-and 2-[2,6-two bromo-4-(6-phenyl sulfane base-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-propionic acid; (R)-and 2-[2,6-two bromo-4-(6-phenyl sulfane base-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid; 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-(1H-indol-3-yl)-propionic acid; (R)-and 2-[2,6-two iodo-(4-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid; (R)-and 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-butyric acid; (R)-and 2-[2,6-two bromo-4-(6-trifluoromethyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid; (S)-and 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-butyric acid; (R)-2-(4-benzo [b] naphtho-[2,3-d] thiophene-11-base-2,6-two bromo-phenoxy groups)-4-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-butyric acid; (R)-and 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-4-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-butyric acid; 1-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propyl group }-phosphonic acids; (R)-and 2-[2,6-two bromo-4-(6-(pyridin-4-yl sulfane base)-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid; (R)-and 2-[2,6-two bromo-4-(6-benzyloxy-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid; (S)-and 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-methyl propionate; (R)-and 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-the 2-phenyl-acetic acid; [2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-acetate; [2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxymethyl]-phosphonic acids; (S)-and 2-[2,6-two bromo-4-(6-cyano group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid; 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-(naphthalene-2-yl)-propionic acid; (R)-and 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-4-(1-oxo-1,3-dihydro-isoindole-2-yl)-butyric acid; (R)-and 2-[2,6-two bromo-4-(6-methyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid; (R)-and 5-{1-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-2-phenyl-ethyl }-the 1H-tetrazolium; (R)-and 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-N-hydroxyl-3-phenyl-propionic acid amide; 5-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-thiazolidine-2, the 4-diketone; (R)-and 2-[2,6-two iodo-4-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-propionic acid; 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-pyridin-3-yl-propionic acid; (R)-and 2-[4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-di-isopropyl-phenoxy group]-3-phenyl-propionic acid; (R)-and 2-[4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-di-isopropyl-phenoxy group]-propionic acid; 4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1, the 2-diphenol; 3-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1, the 2-diphenol; 4-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1, the 2-diphenol; [2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-phenoxy group]-acetate; 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-phenol; Or its pharmacy acceptable salt.
According to following scheme, can maybe can adopt the starting material of diplomatic method preparation to prepare compound of the present invention by commercially available starting material.These schemes show the preparation of representative compounds of the present invention.Scheme 1A
In scheme among the 1A, in-78 ℃ to the temperature range of room temperature, under inert atmosphere such as nitrogen or argon gas,, most preferably in non-protonic solvent such as THF, handle commercially available benzo-thiophene (II: Y=H with the alkyl lithium reagents (as the N-butyllithium) of 1-1.3 molar weight; E is S) or cumarone (II: Y=H; E is O), generate 2-lithiumation benzo-thiophene or benzofuran derivative.Generally in-78 ℃ to room temperature, with one or the phenyl aldehyde of many molar weights and this lithiumation analogue situ reaction 5 minutes to 3 hours, production (III: Y, Z=H; Q=OH; E is S or O) compound.Use multiple method of reducing, as using palladium catalyst hydrogenation with production (III: Q, Y, Z=H; E is S or O) compound remove the hydroxyl (Q=OH) of (III), adopt (Org.Prep.and Proceed.Int.1991 such as Nutaitis but the most conventional is, 23, method 403-411) is removed the hydroxyl (Q=OH) of (III), wherein in suitable solvent as ether, THF or methylene dichloride, in 0 ℃ to room temperature, with (III: Q, Y, Z=H; Q=OH; E is S or O) stir with the sodium borohydride of 1-10 molar weight.The trifluoroacetic acid that in 15 minutes to 3 hours, slowly adds the 1-50 molar weight, production (III: Y, Z=H; E is S or O) compound.Perhaps, in-78 ℃ to room temperature, can in non-protonic solvent such as THF, make benzo-thiophene (II: Y=H; E is S) or cumarone (II: Y=H; E is O) 2-lithiumation analogue and one or the benzyl halide such as the bromotoluene (PhCH of many molar weights 2Br) reaction is with direct production (III: Q, Y, Z=H; E is S or O) compound.
Can use 6-methoxyl group benzo-thiophene (II: Y=OMe in a similar fashion; E is S, S.L.Graham etc., and j.Med.Chem.1989,32,2548-2554) as starting material, adopt above order, production (III: Q, Z=H; Y=OMe; E is S) compound.Moreover, perhaps adopt above order, by benzo-thiophene (II: Y=H; E is S) or cumarone (II: Y=H; E is O) beginning, with 3-methoxybenzaldehyde (adjacent aubepine) substituted benzaldehyde, preparation formula (III: Q, Y=H; Z=OMe; E is S or O) compound.Back one compound (III: Q, Y=H; Z=OMe; E is S or O) also can be as mentioned above, by 3-methoxy-benzyl halogen such as 3-methoxy-benzyl bromine and benzo-thiophene (II: Y=H; E is S) or cumarone (II: Y=H; E is O) 2-lithiumation analogue preparation.
Available one or the commercially available formula of many molar weights (IV: A, B, C, D are H or OMe; A, B, the substituent combination of C, D have at least one OMe group, but no more than 3 OMe groups) Benzoyl chloride, acidylate formula (III: Q=H; Y, Z are H or OMe; E is S or O) compound, (IV: A, B, C, D are H or OMe to production; A, B, the substituent combination of C, D have at least one OMe group, but no more than 3 OMe groups; Y, Z are H or OMe; E is S or O) acylated derivatives.Generally in as-78 ℃ to the temperature of room temperature, at inert solvent such as methylene dichloride, 1, in 2-ethylene dichloride or the dithiocarbonic anhydride, the most easily finish this acylation reaction with the Lewis acid catalyst of 1-5 molar weight such as tin tetrachloride or aluminum chloride.
The general strong Lewis acid of preferably adopting the 1-10 molar weight is as three halogen borines, the most frequently used tribromo borine, and (V: A, B, C, D are H or OMe to perfect; A, B, the substituent combination of C, D have at least one OMe group, but no more than 3 OMe groups; Y, Z are H or OMe; E is S or O) cyclisation of compound.This reaction is preferably in halocarbon solvent such as the methylene dichloride, and under inert atmosphere such as nitrogen or argon gas, under-78 ℃, temperature is carried out to room temperature simultaneously.These steps not only realize cyclisation or aromizing and lose water simultaneously, and cause side chain methoxyl group part demethylation, and (I a:A, B, C, D are H or OH to cause production; A, B, the substituent combination of C, D have at least one OH group, but no more than 3 OH groups; Y, Z are H or OMe; E is S or O) compound.
At formula (III: Q, Y=H; Z=OMe; E is S or O) when a methoxyl group part is contained in the Z position of compound, do as common, realize that with Lewis acid catalyst such as tin tetrachloride (IV: A, B, D are H to formula; C is OMe; E is S or O) acidylate of compound, (V: A, B, D, Y are H to production on the spot; C, Z are OMe; E is S or O) compound.Under this acylation condition, this compound is owing to its Z=OMe part is activated, easily further cyclisation and directly production (I a:A, B, D, Y are H; C, Z are OMe; E is S or O) compound.Also can be with boron tribromide or boron trichloride with this compound demethylation, (I a:A, B, D, Y are H to production; C, Z are OH; E is S or O) compound.
To be similar to the mode of reacting among the above scheme 1A, by formula (III: Q, Y, Z=H; E is S or O) (IV: A is H for compound and suitable Benzoyl chloride; B, D are the alkyl of 1-6 carbon atom; C is OMe) beginning, can preparation formula (I a:A is H; B, D are the alkyl of 1-6 carbon atom; C is OH; Y, Z are H; E is S or O) compound.Adopt reagent as oxalyl chloride or thionyl chloride by standard method by corresponding phenylformic acid, (IV: A is H to prepare described Benzoyl chloride; B, D are the alkyl of 1-6 carbon atom; C is OMe).(IV: A is H to described Benzoyl chloride; B, D are the alkyl of 1-6 carbon atom; C is OMe) initial phenylformic acid be commercially available, maybe can easily prepare with currently known methods.For example, (IV: A is H to Benzoyl chloride; B, D are sec.-propyl; C is OMe) sour starting material can adopt Schuster etc., J.Org.Chem.1988, the preparation of the amending method of 53,5819 method.Therefore, with commercially available 2, the 6-diisopropyl phenol is in 4 brominations (bromine/acetate), methylate (methyl iodide/salt of wormwood/DMF), with the n-Butyl Lithium reaction,, make the organolithium kind and the carbon dioxide reaction of gained to realize the exchange of lithium halogen, generate 3,5-di-isopropyl, 4-methoxybenzoic acid.
Can be by formula (III: Q, Y, Z=H; E is S or O) (IV: A, C are F for compound and suitable Benzoyl chloride; D is H; B is OMe) beginning, (I a:A, C are F to preparation formula; D is H; B is OH; Y, Z are H; E is S or O) compound.Adopt reagent as oxalyl chloride or thionyl chloride by standard method by corresponding phenylformic acid, (IV: A, C are F to prepare described Benzoyl chloride; D is H; B is OMe).(IV: A, C are F to described Benzoyl chloride; D is H; B is OMe) initial phenylformic acid can be by known 4-bromo-2,6-difluoroaniline (L.I.Kruse etc., Biochemistry 1986,25,7271-7278) preparation easily, method is to make 4-bromo-2, and 6-difluoroaniline and n-Butyl Lithium reaction realize bromine and the deprotonation of fluorine atom ortho position, make the organolithium kind and the carbon dioxide reaction of gained, make carboxy moiety be positioned at the ortho position of bromine and fluorine atom, and further react, realize lithium-bromine exchange with n-Butyl Lithium, and the organolithium kind that makes last generation is when water treatment and the proton source reaction, generate 2,4-difluoro, 3-methoxybenzoic acid.At following paper F; Mongin and M.Schlosser, Tetrahedron Lett.1996,37, find among the 6551-6554 that the ortho lithiation reaction that relates to fluorine has precedence over lithium-bromine permutoid reaction.Scheme 1B
In scheme 1B, according to Syn.Comm.1987,17, the method of 341-354, in the biphasic mixture of water and methylene dichloride, under room temperature, make commercially available salicylic aldehyde (VI) and the 2-bromoacetophenone (VII) of one or more molar weight, salt of wormwood and 5% (mole) the sulfuric acid TBuA reaction of one or more molar weight, production (VIII: Q=O) compound.Adopt Wolf-Kishner condition (adopt hydrazine, use KOH then, in glycol ether, reflux), the ketone group of reducible (VIII) (Q=O), production (VIII: Q=H 2) compound.
Can (IX: A, B, C, D be H or OMe with the commercially available formula of one or more molar weight; A, B, the substituent combination of C, D have at least one OMe group, but no more than 3 OMe groups) Benzoyl chloride, acidylate formula (VIII: Q=H 2) compound, (X: A, B, C, D are H or OMe to production; A, B, the substituent combination of C, D have at least one OMe group, but no more than 3 OMe groups) acylated derivatives.Generally in as-78 ℃ to the temperature of room temperature, at inert solvent such as methylene dichloride, 1, in 2-ethylene dichloride or the dithiocarbonic anhydride, adopt the Lewis acid catalyst of 1-5 molar weight such as tin tetrachloride or aluminum chloride the most easily to finish this acylation reaction.
The general strong Lewis acid of preferably adopting 1-10 molar weight is as three halogen borines, the most frequently used tribromo borine, and (X: A, B, C, D are H or OMe to perfect; A, B, the substituent combination of C, D have at least one OMe group, but no more than 3 OMe groups) cyclisation of compound.This reaction is preferably in halocarbon solvent such as the methylene dichloride, and under inert atmosphere such as nitrogen or argon gas, under-78 ℃, temperature is carried out to room temperature simultaneously.These steps not only realize cyclisation or aromizing and lose water simultaneously, and cause any side chain methoxyl group part demethylation, cause production (I a ': A, B, C, D are H or OH; A, B, the substituent combination of C, D have at least one OH group, but no more than 3 OH groups) compound.
In the mode of reacting among the similar above scheme 1B, (VIII: Q is H by formula 2) (IX: A is H for compound and suitable Benzoyl chloride; B, D are the alkyl of 1-6 carbon atom; C is OMe) beginning, can preparation formula (I a ': A is H; B, D are the alkyl of 1-6 carbon atom; C is OH) compound.Adopt reagent as oxalyl chloride or thionyl chloride by standard method by corresponding phenylformic acid, (IX: A is H to prepare described Benzoyl chloride; B, D are the alkyl of 1-6 carbon atom; C is OMe).(IX: A is H to described Benzoyl chloride; B, D are the alkyl of 1-6 carbon atom; C is OMe) initial phenylformic acid be commercially available, maybe can easily prepare with currently known methods.For example, (IX: A is H to Benzoyl chloride; B, D are sec.-propyl; C is OMe) sour starting material can adopt Schuster etc., J.Org.Chem.1988, the preparation of the amending method of 53,5819 method.Therefore, with commercially available 2, the 6-diisopropyl phenol is in 4 brominations (bromine/acetate), methylate (methyl iodide/salt of wormwood/DMF), with the n-Butyl Lithium reaction,, make the organolithium kind and the carbon dioxide reaction of gained to realize the exchange of lithium halogen, provide 3,5-di-isopropyl, 4-methoxybenzoic acid.Scheme 2
Figure A9980842200371
Other derivative of formula I compound can adopt following method preparation in scheme 2.In suitable solvent such as acetate, (I b:B, D, X are H with formula with the molecular bromine more than 3 molar weights or 3 molar weights; C is OH; E is S, O) phenol bromination on 3 positions, (I b:B, D, X are Br to production; C is OH; E is S or O) three brominated phenol.The acetate of 1-50 molar weight (as potassium acetate or sodium acetate) also can be as the cosolvent in this reaction, although be not absolute demand.By adopting alkali such as alkaline carbonate or oxyhydroxide (as salt of wormwood or sodium hydroxide), in suitable solvent such as THF, DMF or DMSO, (I b:B, D, X are Br to make formula; C is OH; E is S, O) three bromo phenol moieties and suitable methylating agent as one or the methyl-iodide or the methyl-sulfate reaction of many molar weights, can be with described three brominated phenol demethylations, (I b:B, D, X are Br to production; C is OMe; E is S, O) methyl ether.Reaction is generally carried out in 0 ℃ to 60 ℃ temperature range.
Can be in 140-200 ℃ temperature range, in the presence of two (triphenyl phosphine) Palladous chloride II of palladium catalyst such as 1-10% (mole), in suitable solvent such as DMF, DMA or 1-methyl alcohol-3-pyrrolidone, (I b:B, D, X are Br to make formula; C is OMe; E is S, O) methyl ether and the reaction of the tetraalkyl tin of 3 or 3 above molar weights, (I b:B, D, X are the alkyl of 1-6 carbon atom to production; C is OMe; E is S, O) the tetraalkyl methoxy derivatives.Employing standard demethylation method is included in-78 ℃ to room temperature, in methylene dichloride with one or the boron tribromide or the boron trichloride of many molar weights; In 190 ℃ under 280 ℃, with excessive pure hydrochloric acid pyridine; In 0 ℃ under 50 ℃, in acetate, use Hydrogen bromide; In-78 ℃ under 50 ℃, in methylene dichloride, tetracol phenixin or acetonitrile with excessive trimethyl silyl bromine or trimethyl silyl iodine; Under 100 ℃ to 250 ℃ temperature, in pyridine or quinoline with lithium iodide and one or the Lewis of many molar weights acid as aluminum chloride or boron trifluoride in the presence of, in solvent such as methylene dichloride, in-78 ℃ to 50 ℃ temperature ranges, with ethyl, methyl or the isopropyl mercaptan of a mole or many molar weights; (I c:B, D, X are the alkyl of 1-6 carbon atom this methoxyl group analogue can be converted into formula; E is S, O) corresponding phenolic like thing.
In the presence of 2 molar weights or alkali metal hydroxide such as NaOH more than 2 molar weights, in alcoholic solvent such as methyl alcohol, in-20 ℃ to room temperature, (I b:B, D, X are H to the iodine of available at least 2 molar weights with formula; C is OH; E is S or O) phenol (scheme 2) easily iodate be that (I b:B, D are I to formula; X is H; C is OH; E is S or O) two riodoxol.Equally, in the presence of the alkali metal hydroxide such as NaOH of at least 1 molar weight, in alcoholic solvent such as methyl alcohol, in-20 ℃ to room temperature, (I b:B, D, X are H to the iodine of available 1-1.5 molar weight by formula; C is OH; E is S or O) phenol (scheme 2) preparation formula (I b:B is I; X, D are H; C is OH; E is S or O) a riodoxol.By in suitable solvent such as THF, DMF or DMSO, adopt alkali such as alkaline carbonate or oxyhydroxide (as salt of wormwood or sodium hydroxide), make phenol moieties and suitable methylating agent as one or the methyl-iodide or the methyl-sulfate reaction of many molar weights, can make or a riodoxol (I b:B is I; X, D are H; C is OH; E is S or O) or two riodoxol (I b:B, D are I; X is H; C is OH; E is S or O) (I b:B is I to be converted into corresponding formula; X, D are H; C is OMe; E is S or O) or (I b:B, D are I; X is H; C is OMe; E is S or O) the methyl ether derivative.This reaction is generally carried out in 0 ℃ to 60 ℃ temperature range.
(I b:B is I to formula; X, D are H; C is OMe; E is S or O) an iodo-methyl ether derivant or formula (I b:B, D are I; X is H; C is OMe; E is S or O) two iodo methyl ethers can be with one or the cupric cyanide (I) (for an iodo analogue) of many molar weights or 2 molar weights or above cupric cyanide (I) (for the two iodo derivatives) reaction of 2 molar weights, (I b:B is CN to production; X, D are H; C is OMe; E is S or O) a cyano methyl ether or formula (I b:B, D are CN; X is H; C is OMe; E is S or O) the dicyano methyl ether.General under 100-250 ℃ temperature range, use polar aprotic solvent such as DMF, 1-Methyl-2-Pyrrolidone or HMPA to carry out this cyanogenation.Also can use quinoline or pyridine.Employing standard demethylation method comprises and uses one or the boron tribromide or the boron trichloride of many molar weights, in methylene dichloride, in-78 ℃ to room temperature; Use excessive pure hydrochloric acid pyridine, in 190-280 ℃; Use Hydrogen bromide, in acetate, in 0 ℃ to 50 ℃; Use excessive trimethyl silyl bromine or trimethyl silyl iodine, in methylene dichloride, tetracol phenixin or acetonitrile, in-78 ℃ to 50 ℃; Use lithium iodide, in pyridine or quinoline, thiomethyl alcohol, sulfur alcohol or isopropyl mercaptan in 100-250 ℃ temperature and use one or many molar weights, one or the Lewis of many molar weights acid as aluminum chloride or boron trifluoride in the presence of, in solvent, under-78 ℃ to 50 ℃ temperature as methylene dichloride; Can (I b:B be CN with formula; D is H or CN; X is H; C is OMe; E is S or O) one or dicyano methoxyl group analogue be converted into corresponding formula (I c:B be CN; D is H or CN; X is H; E is S or O) one or dicyano phenol analogue (scheme 2).
(I b:B is I can to make formula; X, D are H; C is OMe; E is S or O) an iodo-methyl ether derivant or formula (I b:B, D are I; X is H; C is OMe; E is S or O) two iodo methyl ethers and one or the cupric bromide (I) (for an iodo analogue) of many molar weights or 2 molar weights or above cupric bromide (I) (for the two iodo derivatives) reaction of 2 molar weights, (I b:B is Br to production; X, D are H; C is OMe; E is S or O) a bromo methyl ether or formula (I b:B, D are Br; X is H; C is OMe; E is S or O) two bromo methyl ethers.General under 100-250 ℃ temperature range, use polar aprotic solvent such as DMF, 1-Methyl-2-Pyrrolidone or HMPA to carry out this bromine/iodine permutoid reaction.Also can use quinoline or pyridine.Employing standard demethylation method comprises and uses one or the boron tribromide or the boron trichloride of many molar weights, in methylene dichloride, in-78 ℃ to room temperature; Use excessive pure hydrochloric acid pyridine, in 190-280 ℃; Use Hydrogen bromide, in acetate, in 0 ℃ to 50 ℃; Use excessive trimethyl silyl bromine or trimethyl silyl iodine, in methylene dichloride, tetracol phenixin or acetonitrile, in-78 ℃ to 50 ℃; Use lithium iodide, in pyridine or quinoline, in 100-250 ℃ temperature and use one or thiomethyl alcohol, sulfur alcohol or the isopropyl mercaptan of many molar weights, one or the Lewis of many molar weights acid as aluminum chloride or boron trifluoride in the presence of, in solvent, under-78 ℃ to 50 ℃ temperature as methylene dichloride; Can (I b:B be Br with formula; D is H or Br; X is H; C is OMe; E is S or O) one or two bromo methoxyl group analogues be converted into corresponding formula (I c:B be Br; D is H or Br; X is H; E is S or O) one or two bromo phenols like thing (scheme 2).
(I b:B is Br, I can to make formula; X, D are H; C is OH, OMe; E is S or O) an iodo or a bromo methyl ether or amphyl or formula (I b:B, D are Br, I; X is H; C is OH, OMe; E is S or O) two iodos or two bromo methyl ethers or phenol (scheme 2), with one or the aryl boric acid (for an iodo or a bromo analogue) of many molar weights or 2 molar weights or above aryl boric acid (for two iodos or the two bromo derivatives) reaction of 2 molar weights, (I b:B is a phenyl to production; X, D are H; C is OH, OMe; E is S or O) a phenyl methyl ether or phenol or formula (I b:B, D are phenyl; X is H; C is OH, OMe; E is S or O) two bromo methyl ether or phenol.The most normal Suzuki reaction (N.Miyaura that is called as of this reaction, T.Yanagi, A Suzuki, Synthetic Comm.1981,11,513-319), and comprise that the palladium catalyst that uses 0.5-10% (mole) is as four (triphenyl phosphine) palladiums or palladium (II) kind such as acid chloride or [1,1 '-two (diphenylphosphino) ferrocene] palladium (II).Also need one or the alkali metal base of many molar weights, some alkali more commonly used comprises yellow soda ash, salt of wormwood or cesium carbonate; Sodium hydroxide, potassium hydroxide, hydrated barta or thallic hydroxide and potassiumphosphate.This reaction can be carried out in multiple solvent, comprises benzene, THF, diox, DME or DMF.For some solvent wherein, can be used as cosolvent such as THF and benzene, water or methyl alcohol.This reaction is generally carried out in the temperature range of room temperature to 120 ℃.
Employing standard demethylation method comprises and uses one or the boron tribromide or the boron trichloride of many molar weights, in methylene dichloride, in-78 ℃ to room temperature; Use excessive pure hydrochloric acid pyridine, in 190-280 ℃; Use Hydrogen bromide, in acetate, in 0 ℃ to 50 ℃; Use excessive trimethyl silyl bromine or trimethyl silyl iodine, in methylene dichloride, tetracol phenixin or acetonitrile, in-78 ℃ to 50 ℃; Use lithium iodide, in pyridine or quinoline, in 100-250 ℃ and use one or thiomethyl alcohol, sulfur alcohol or the isopropyl mercaptan of many molar weights, one or the Lewis acid of many molar weights as aluminum chloride or boron trifluoride in the presence of, in solvent as methylene dichloride, in-78 ℃ under 50 ℃; Can (I b:B be Br with formula; D is H or Br; X is H; C is OMe; E is S or O) one or two bromo methoxyl group analogues and formula (I b; B is Ph; D is H or Ph; X is H; C is DMe; E is S or O) one and phenylbenzene methoxy base class be converted into corresponding formula (I c:B be Br like thing; D is H or Br; X is H; E is S or O) one or two bromo phenols (I b:B is Ph like thing or formula; D is H or Ph; X is H; C is OH; E is S or O) one or phenylbenzene phenol analogue (scheme 2).Scheme 3
Figure A9980842200411
Other derivative of formula I compound can prepare by the following method in the scheme 3.With one or the suitable acylating agent of many molar weights, (I d:B, C, D are H or OH, and B, C, D combination have at least one OH group with formula; E is S or O) compound (scheme 3) acidylate on the oxygen of phenol, (I d:B, C, D are H or OCOR to production, and B, C, D combination have at least one OCOR group; R is alkyl, the aryl of 1-6 carbon atom; E is S or O) compound.Described acylating agent is generally the chloride of acid of the alkyl or aryl of the carboxylic acid anhydride of alkyl or aryl of 1-6 carbon atom or 1-6 carbon atom.Described being reflected under the standard conditions carried out, and described condition is for example for using pyridine as solvent, uses or do not use cosolvent such as methylene dichloride, carries out to room temperature in 0 ℃.(I d:B, C, D are H or OCOR, and B, C, D combination have at least one OCOR group with formula then; R is alkyl, the aryl of 1-6 carbon atom; E is S or O) acylation of phenol in 6 brominations of benzo [b] naphtho-[2,3-d] thiophene or benzo [b] naphtho-[2,3-d] furan nucleus, (I e:B, C, D are H or OCOR to production, and B, C, D combination have at least one OCOR group; R is alkyl, the aryl of 1-6 carbon atom; X is Br; E is S or O) acidylate brominated phenol (scheme 3).The general molecular bromine that adopts the 1-1.3 molar weight in inert solvent such as methylene dichloride or tetracol phenixin, is carried out this bromination reaction in-78 ℃ to room temperature.
Adopt similar bromination reaction, (I d:B, D are the alkyl of 1-6 carbon atom, and C is OH with formula; E is S or O) phenol in 6 brominations of benzo [b] naphtho-[2,3-d] thiophene or benzo [b] naphtho-[2,3-d] furan nucleus, (I e:B, D are the alkyl of 1-6 carbon atom to production, and C is OH; X is Br; E is S or O) brominated phenol (scheme 3).The general molecular bromine that adopts the 1-1.3 molar weight is carried out this bromination reaction in-78 ℃ to room temperature in inert solvent such as methylene dichloride or tetracol phenixin.
Adopt standard conditions then, (I e:B, C, D are H or OCOR to the removal formula, and B, C, D combination have at least one OCOR group; R is alkyl, the aryl of 1-6 carbon atom; X is Br; E is S or O) the acyl group of acidylate brominated phenol, (I e:B, C, D are H or OH to production, and B, C, D combination have at least one OH group; X is Br; E is S or O) brominated phenol (scheme 3).These conditions comprise aqueous bases, wherein use one or the alkali metal hydroxide (as sodium hydroxide) of many molar weights, in the mixed solution of water and cosolvent such as THF, diox or lower alcohol (as methyl alcohol) or THF and lower alcohol, and temperature range 0-40 ℃.Also can use acidic conditions, wherein in the temperature range of room temperature to 80 ℃, in water, have or do not have under the cosolvent (as THF), make this compound and one or the mineral acid (as HCl or sulfuric acid) of many molar weights react.
(I d:B, C, D are H or OCOR, and B, C, D combination have at least one OCOR with formula; R is alkyl, the aryl of 1-6 carbon atom; E is S or O) acylation of phenol nitrated, formula is provided, and (I e:B, C, D are H or OCOR, and B, C, D combination has at least one OCOR group; R is alkyl, the aryl of 1-6 carbon atom; X is NO 2E is S or O) nitro-compound (scheme 3).Rare nitric acid is suitable for realizing this conversion in 0 ℃ to the temperature range of room temperature.Adopt appropriate reductant to carry out catalytic hydrogenation as HCl or the ethyl acetate solution that uses palladium or platinum catalyst, tindichloride, can (I e:B, C, D be H or OCOR, and B, C, D combination have at least one OCOR with formula; R is alkyl, the aryl of 1-6 carbon atom; X is NO 2E is S or O) nitro-compound further be reduced to formula (I e:B, C, D be H or OCOR, and B, C, D combination has at least one OCOR; R is alkyl, the aryl of 1-6 carbon atom; X is NH 2E is S or O) primary amine.Adopt standard conditions, (I e:B, C, D are H or OCOR, and B, C, D combination have at least one OCOR can to remove formula; R is alkyl, the aryl of 1-6 carbon atom; X is NO 2And NH 2E is S or O) acyl group of compound, generate that (I e:B, C, D are H or OH, and B, C, D combination have at least one OH group; R is alkyl, the aryl of 1-6 carbon atom; X is NO 2And NH 2E is S or O) phenol.
By with one or the reaction of the cupric cyanide (I) of many molar weights, can (I e:B, C, D be H or OCOR, and B, C, D combination have at least one OCOR group with formula; R is alkyl, the aryl of 1-6 carbon atom; X is Br; E is S or O) the acidylate brominated phenol be converted into formula (I e:B, C, D be H or OCOR, and B, C, D combination has at least one OCOR group; R is alkyl, the aryl of 1-6 carbon atom; X is CN; E is S or O) acidylate cyano group phenol.General under 100-250 ℃ temperature range, use among polar aprotic solvent such as DMF, 1-Methyl-2-Pyrrolidone or the HMPA and carry out this cyanogenation.Also can use quinoline or pyridine.Usually (I e:B, C, D are H or OCOR, and B, C, D combination have at least one OCOR in release under the cyanogenation condition; R is alkyl, the aryl of 1-6 carbon atom; X is CN; E is S or O) acyl group, (I e:B, C, D are H or OH, and B, C, D combination has at least one OCOR group to obtain formula; X is CN; E is S or O) cyano group phenol.By with one or the aqueous solution of the alkali metal hydroxide of many molar weights add and contain that (I e:B, C, D are H or OCOR, and B, C, D combination have at least one OCOR group; R is alkyl, the aryl of 1-6 carbon atom; X is CN; E is S or O) reaction mixture in, handle then, can the most easily carry out thisly formula being provided (I e:B, C, D being H or OH, and B, C, D combination has at least one OH group; X is CN; E is S or O) the acyl group of cyano group phenol discharge.(I e:B, C, D are H or OCOR, and B, C, D combination have at least one OCOR group also can to adopt standard conditions to remove isolating formula; R is alkyl, the aryl of 1-6 carbon atom; X is CN; E is S or O) the acyl group of acidylate cyano group phenol, formula is provided, and (I e:B, C, D are H or OH, and B, C, D combination have at least one OH; X is CN; E is S or O) cyano group phenol.These conditions comprise aqueous bases, wherein use one or the alkali metal hydroxide (as sodium hydroxide) of many molar weights, in the mixed solution of water and cosolvent such as THF, diox or lower alcohol (as methyl alcohol) or THF and lower alcohol, and temperature range 0-40 ℃.Also can use acidic conditions, wherein in the temperature range of room temperature to 80 ℃, in water, have or do not have under the cosolvent (as THF), make this compound and one or the mineral acid (as HCl or sulfuric acid) of many molar weights react.
Available one or the suitable sulfonyl agent of many molar weights, (I d:B, C, D are H or OH with formula; B, C, D combination have at least one OH; E is S or O) compound (scheme 3) alkylsulfonylization on the oxygen of its phenol, (I d:B, C, D are H or OSO to production 2R; B, C, D combination have at least one OSO 2The R group; R is alkyl, the aryl of 1-6 carbon atom; E is S or O) sulphonate.This sulfonyl agent generally is the SULPHURYL CHLORIDE of the alkyl or aryl of the sulphonic acid anhydride of alkyl or aryl of 1-6 carbon atom or 1-6 carbon atom.This is reflected under the standard conditions and carries out, for example 0 ℃ to the temperature of room temperature, with pyridine as solvent, have or do not have the condition of cosolvent (as methylene dichloride).
(I d:B, C, D are H or OSO with formula 2R; B, C, D combination have at least one OSO 2The R group; R is alkyl, the aryl of 1-6 carbon atom; E is S or O) sulphonate handle with chlorizating agent, and on the 6-position of benzo [b] naphtho-[2,3-d] thiophene or benzo [b] naphtho-[2,3-d] furan nucleus, carry out chlorination, (I e:B, C, D are production HOr OSO 2R, B, C, D combination have at least one OSO 2The R group; R is alkyl, the aryl of 1-6 carbon atom; X is Cl; E is S or O) the chloro sulphonate.Suitable chlorizating agent is included in-78 ℃ to the 0 ℃ temperature range, in suitable halocarbon such as methylene dichloride or chloroform, and one or SULPHURYL CHLORIDE, chlorine or the N-chlorosuccinimide of many molar weights.Can adopt standard conditions then, (I e:B, C, D are H or OSO from formula 2R, B, C, D combination have at least one OSO 2R; R is alkyl, the aryl of 1-6 carbon atom; X is Cl; E is S or O) the chloro sulphonate remove sulfonate ester group, (I e:B, C, D are H or OH to production, and B, C, D combination have at least one OH group; X is Cl; E is S or O) chlorinated phenol (scheme 3).These conditions comprise aqueous bases, wherein use one or the alkali metal hydroxide (as sodium hydroxide) of many molar weights, in the mixed solution of water and cosolvent such as THF, diox or lower alcohol (as methyl alcohol) or THF and lower alcohol, and temperature range room temperature to 110 ℃.
Also (I d:B, C, D are H or OSO with formula 2R, B, C, D combination have at least one OSO 2The R group; R is alkyl, the aryl of 1-6 carbon atom; E is S or O) sulphonate handle with iodination reagent, and on the 6-position of benzo [b] naphtho-[2,3-d] thiophene or benzo [b] naphtho-[2,3-d] furan nucleus, carry out iodate, (I e:B, C, D are H or OSO to production 2R, B, C, D combination have at least one OSO 2The R group; R is alkyl, the aryl of 1-6 carbon atom; X is I; E is S or O) the iodo sulphonate.Suitable iodination reagent is included in room temperature to the 80 ℃ temperature range, in the mixed solution of THF and 80% acetic acid aqueous solution that has a small amount of vitriol oil, and the mixture of the acid iodide of the molecular iodine of 0.7 or 0.7 above molar weight and 0.25 or 0.25 above molar weight.Can adopt standard conditions then, (I e:B, C, D are H or OSO from formula 2R, B, C, D combination have at least one OSO 2R; R is alkyl, the aryl of 1-6 carbon atom; X is I; E is S or O) the iodo sulphonate remove sulfonate ester group, (I e:B, C, D are H or OH to production, and B, C, D combination have at least one OH; X is I; E is S or O) riodoxol (scheme 3).These conditions comprise aqueous bases, wherein use one or the alkali metal hydroxide (as sodium hydroxide) of many molar weights, in the mixed solution of water and cosolvent such as THF, diox or lower alcohol (as methyl alcohol) or THF and lower alcohol, and temperature range room temperature to 110 ℃.Scheme 4
Figure A9980842200451
(I f:C, D are H or OSO to formula 2R; C, D can not be H; R is alkyl, the aryl of 1-6 carbon atom; E is S or O) the iodo sulphonate be the starting point easily of other derivative of the formula I compound shown in scheme 4 or the following method.(I f:C, D are H or OSO can to make compound 2R; C, D can not be H; R is alkyl, the aryl of 1-6 carbon atom; E is S or O) but have the reagent that iodine atom exchanges among (the I f) of perfluoroalkyl of 1-6 carbon atom with catalysis and react, and (I g:C, D are H or OSO to production 2R; C, D can not be H; R is alkyl, the aryl of 1-6 carbon atom; X is the perfluoroalkyl of 1-6 carbon atom; E is S or O) compound (scheme 4).The reagent and the condition that realize this permutoid reaction comprise: in 140 ℃-200 ℃ temperature range, in high boiling inert solvent such as DMF, DMA or 1-Methyl-2-Pyrrolidone, under anhydrous condition, make the perfluorocarboxylic acid sodium (RCO of (I f) and 1-10 molar weight 2Na:R is a perfluoroalkyl) and the cupric iodide (I) of 1-5 molar weight react.Perhaps, can be in 140 ℃-200 ℃ temperature range, in high boiling inert solvent such as DMF, DMA or 1-Methyl-2-Pyrrolidone, (I f:C, D are H or OSO with formula 2R; C, D can not be H; R is alkyl, the aryl of 1-6 carbon atom; E is S or O) compound is by making itself and the perfluoroalkyl iodides of 1-10 molar weight and the activation Cu of 1-5 molar weight 0React, (I g:C, D are H or OSO to preparation formula 2R; C, D can not be H; R is alkyl, the aryl of 1-6 carbon atom; X is the perfluoroalkyl of 1-6 carbon atom; E is S or O) compound.Moreover, also can be in 140 ℃-200 ℃ temperature range, in high boiling inert solvent such as DMF, DMA or 1-Methyl-2-Pyrrolidone, (I f:C, D are H or OSO to make formula 2R; C, D can not be H; R is alkyl, the aryl of 1-6 carbon atom; E is S or O) two (trifluoromethyl mercury) and the activation Cu of 2-4 molar weight of compound and 0.5-2 molar weight 0React, (I g:C, D are H or OSO to preparation formula 2R; C, D can not be H; R is alkyl, the aryl of 1-6 carbon atom; X is CF 3E is S or O) compound.
Can be in 140 ℃-200 ℃ temperature range, in appropriate solvent such as DMF, DMA or 1-Methyl-2-Pyrrolidone, in the presence of two (triphenyl phosphine) Palladous chloride II of palladium catalyst such as 1-10% (mole), (I f:C, D are H or OSO by making 2R; C, D can not be H; R is alkyl, the aryl of 1-6 carbon atom; E is S or O) to react with the rudimentary tetraalkyl tin of 3 or 3 above molar weights, (I g:C, D are H or OSO to preparation formula 2R; C, D can not be H; R is alkyl, the aryl of 1-6 carbon atom; X is the alkyl of 1-6 carbon atom; E is S or O) 1-6 carbon atom derivative of the 6-alkyl of compound.
The available standards condition, (I g:C, D are H or OSO from formula 2R; C, D can not be H; R is alkyl, the aryl of 1-6 carbon atom; X is the alkyl of 1-6 carbon atom or the perfluoroalkyl of 1-6 carbon atom; E is S or O) sulphonate in remove this sulfonate group, (I g:C, D are H or OH and obtain formula; C, D can not be H; X is the alkyl of 1-6 carbon atom or the perfluoroalkyl of 1-6 carbon atom; E is S or O) phenol.These conditions comprise aqueous bases, wherein use one or the alkali metal hydroxide of many molar weights sodium hydroxide for example, and in the water of the mixed solution that has cosolvent such as THF, diox or lower alcohol (as methyl alcohol) or THF and lower alcohol, temperature range is a room temperature to 110 ℃.
Can be in 80 ℃-180 ℃ temperature range, in appropriate solvent such as DMF, DMA or 1-Methyl-2-Pyrrolidone, in the presence of the cupric chloride (II) of copper (I) or copper (II) catalyzer such as 1-10% (mole), (I f:C, D are H or OSO by making 2R; C, D can not be H; R is alkyl, the aryl of 1-6 carbon atom; E is S or O) to react with the elementary alkali metal alkoxide of 3 or 3 above molar weights, (I g:C, D are H, OH to preparation formula; C, D can not be H; X is the alkoxyl group of 1-6 carbon atom; E is S or O) the 6-alkoxy derivative of compound.Under described reaction conditions, (I f:C, D are H or OSO to remove formula 2R; C, D can not be H; R is alkyl, the aryl of 1-6 carbon atom; E is S or O) sulfonic group.
Can be in 100 ℃-180 ℃ temperature range, in appropriate solvent such as DMF, DMA or 1-Methyl-2-Pyrrolidone, (I f:C, D are H or OSO by making 2R; C, D can not be H; R is alkyl, the aryl of 1-6 carbon atom; E is S or O) with one or alkyl sulfhydryl, aryl thiophenol, sulfo-pyridine or the 2-N of suitable 1-6 carbon atom of many molar weights, N-dimethylamino sulfur alcohol, one or the alkali metal hydroxide (as sodium hydroxide) of many molar weights, one or the copper (I) or copper (II) catalyzer (as Red copper oxide (I)) of many molar weights react, (I g:C, D are H or OH to come preparation formula; C, D can not be H; X is alkyl alkylthio base, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of 1-6 carbon atom, N-dimethylamino second sulfane base; E is S or O) the 6-sulfanyl derivatives of compound.Under described reaction conditions, remove that (I f:C, D are H or OSO 2R; C, D can not be H; R is alkyl, the aryl of 1-6 carbon atom; E is S or O) sulfonic group.Scheme 5
Figure A9980842200471
Other derivative of formula I compound can adopt following method preparation in scheme 5.In appropriate solvent such as acetate, (I h:A is H or OH to the molecular bromine of available at least 2 molar weights with formula; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) phenol 2 position brominations, (I i:A is H or OH to obtain formula; B, D are Br; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) two brominated phenol.The acetate of 1-50 molar weight (as potassium acetate or sodium acetate) also can be as the cosolvent in this reaction, although be not absolute demand.
In suitable solvent such as lower alcohol solvent (most convenient methyl alcohol), (I h:A is H or OH with formula with the chlorine more than 2 molar weights or 2 molar weights; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) phenol 2 position chlorinations, (I i:A is H or OH to obtain formula; B, D are Cl; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) dichloro-phenol.This is reflected at-78 ℃ and carries out to the temperature range of room temperature.
In lower alcohol solvent, most convenient is with three iron nitrates (III), and (I h:A is H with formula; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) phenol one a nitrated accepted way of doing sth (I i:A is H; B is NO 2D is H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) phenol.
Under 40-100 ℃, in ethyl acetate, the easiest tindichloride of using; Perhaps under 40-100 ℃, in ethanol, with hydrazine and montmorillonitic clay; (I i:A is H with formula; B is NO 2D is H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) nitro-compound, the reduction accepted way of doing sth (I i:A is H; B is NH 2D is H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, amino, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) aminocompound.
In appropriate solvent such as acetate, (I i:A is H to the molecular bromine of available at least 2 molar weights with formula; B is NO 2D is H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) nitro-compound, bromination is that (I i:A is H to formula; B is NO 2D is Br; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) compound.Cosolvent in yet can reacting as this with the acetate (as potassium acetate or sodium acetate) of 1-50 molar weight is not although be absolute demand.Under 40-100 ℃, in ethyl acetate, the easiest tindichloride of using; Perhaps under 40-100 ℃, in ethanol, with hydrazine and montmorillonitic clay; (I i:A is H with formula; B is NO 2D is Br; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) the bromo nitryl compound, the reduction accepted way of doing sth (I i:A is H; B is NH 2D is Br; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) the bromo aminocompound.
Can be on the 6-position of benzo [b] naphtho-[2,3-b] thiphene ring, (I i:A is OH with formula; B, D are Br; X is H; E is S or O) the further bromination of two bromo bis-phenols, (I i:A is OH to production; B, D, X are Br; E is S or O) bis-phenol.Generally-78 ℃ to the temperature range of room temperature, in inert solvent such as methylene dichloride or tetracol phenixin, carry out this bromination reaction with the molecular bromine of 1-1.3 molar weight.Scheme 6
Figure A9980842200501
Other derivative that can be equipped with formula I compound in the scheme 6 in order to the below legal system.Can be in appropriate solvent such as acetate, (I j:C is H to the molecular bromine of usefulness at least 1 molar weight with formula; D is OH; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) the phenol monobromination, (I k:A, B are H to obtain formula; C is Br; D is OH; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) brominated phenol; Or in appropriate solvent such as acetate, (I j:C is H to the molecular bromine of usefulness at least 2 molar weights with formula; D is OH; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) the phenol dibrominated, (I k:B is H to obtain formula; A, C are Br; D is OH; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) brominated phenol.Similarly, in appropriate solvent such as acetate, (I j:C, D are OH with formula with the molecular bromine of 1 molar weight; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) the bis-phenol monobromo turn to formula (I k:A be H; B is Br; C, D are OH; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) and (I k:A is Br; B is H; C, D are OH; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) the mixture of bromo bis-phenol.Can be a pure bromo product with this mixture separation with ordinary method.
In polar aprotic solvent such as DMF, available one or the alkaline carbonate such as the salt of wormwood of many molar weights, (I k:A is H with formula with alkylogen, allyl halide or the benzyl halide of 1-6 carbon atom; B is Br; C, D are OH; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) the phenolic hydroxyl group that occupies in the C position of bromo bis-phenol on regioselectivity ground alkylation, (I k:A is H to obtain formula; B is Br; C is alkoxyl group, allyloxy or the benzyloxy of 1-6 carbon atom; D is OH; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) an alkylate.
In polar aprotic solvent such as DMF, with one or the alkaline carbonate such as the salt of wormwood of many molar weights, (I k:A is H to the alkylogen of an available 1-6 carbon atom with formula; B is Br; C is a benzyloxy; D is OH; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) the further alkylation of a benzyl product, (I k:A is H to obtain formula; B is Br; C is a benzyloxy; D is the alkoxyl group of 1-6 carbon atom; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) the dialkyl group product.
Can adopt standard hydrogenolysis condition, for example in lower alcohol or ethyl acetate or THF, with hydrogen and 5-10% palladium on carbon catalyst, (I k:A is H to the removal formula; B is Br; C is a benzyloxy; D is the alkoxyl group of 1-6 carbon atom; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S or O) benzyl of compound.Scheme 7
Figure A9980842200521
Other derivative that can be equipped with formula I compound in the scheme 7 in order to the below legal system.Can be in polar aprotic solvent (as DMF), (I l:Y, C are OH to make formula; Z is H; E is S) bis-phenol and one or the monobromo-acetic acid methyl esters of many molar weights and one or alkaline carbonate (as the salt of wormwood) reaction of many molar weights, (I m:Y is OCH to obtain formula 2CO 2CH 3, C is OH; Z is H; E is S) an alkylate.This product may pollute the formula that a small amount of (＜10%) is arranged, and (I m:C is OCH 2CO 2CH 3Y is OH; Z is H; E is S) regional isomer.Can adopt ordinary method to separate described regional isomer.
Perhaps, can be in polar aprotic solvent (as DMF), with 2 molar weights or the above formula (X of 2 molar weights 2CH 2CO 2R 6, X wherein 2Be Cl, Br or I, and R 6Alkyl for 1-6 carbon atom) alkaline carbonate (as salt of wormwood) that alkyl halogen acetates and 2 molar weights or 2 molar weights are above, (I l:Y, C are OH with formula; Z is H; E is S) or (I l:Z, C are OH; Y is H; E is S or O) the bis-phenol dialkyl groupization, (I m:Y, C are OCH to obtain formula 2CO 2R 6Z is H; E is S; R 6Alkyl for 1-6 carbon atom) or (I m:Z, C are OCH 2CO 2R 6Y is H; E is S or O; R 6Alkyl for 1-6 carbon atom) dialkyl group product.
Can adopt standard conditions, (I m:Y is OCH with formula 2CO 2CH 3C is OH; Z is H; E is S) an ester and formula (I m:Y, C are OCH 2CO 2R 6Z is H; E is S) or formula (I m:Z, C are OCH 2CO 2R 6Y is H; E is S or O) diester be converted into its carboxylic acid analogue, (I m:Y is OCH to obtain formula 2CO 2H; C is OH; Z is H; E is S) monocarboxylic acid and formula (I m:Y, C are OCH 2CO 2H; Z is H; E is S) or formula (I m:Z, C are OCH 2CO 2H; Y is H; E is S or O) dicarboxylic acid.The condition that realizes these conversions comprises aqueous bases, wherein use one or the alkali metal hydroxide (as sodium hydroxide) of many molar weights, in the water of the mixed solution that has cosolvent such as THF, diox or lower alcohol (as methyl alcohol) or THF and lower alcohol, temperature range 0-40 ℃.Scheme 8
Figure A9980842200531
Other derivative that can be equipped with formula I compound in the scheme 8 in order to the below legal system.Can be in polar aprotic solvent (as DMF), with one or formula (the X of many molar weights 2CHR 6 'CO 2R 6, X wherein 2Be Cl, Br or I, and R 6Be the alkyl of 1-6 carbon atom, R 6 'Be H) alkyl halogen acetates and one or the alkaline carbonate (as salt of wormwood) of many molar weights, (I n:B is H to make formula; A, C are the alkoxyl group of H, Br or 1-6 carbon atom; D is OH; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S, O) the phenol alkylation, (I o:B is H to obtain formula; A, C are the alkoxyl group of H, Br or 1-6 carbon atom; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 6Be the alkyl of 1-6 carbon atom, R 6 'Be H; E is S, O) alkylate.
Perhaps, can be in polar aprotic solvent (as DMF), with 2 molar weights or the above formula (X of 2 molar weights 2CHR 6 'CO 2R 6, X wherein 2Be Cl, Br or I, and R 6Be the alkyl of 1-6 carbon atom, R 6 'Be H) alkyl halogen acetates and the above alkaline carbonate (as salt of wormwood) of 2 molar weights or 2 molar weights, (I n:A, B are H or Br with formula; C, D are OH; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S, O) the bis-phenol dialkyl groupization, (I o:A, B are H or Br to obtain formula; C is OCHR 6 'CO 2R 6X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 6Alkyl for 1-6 carbon atom; R 6 'Be H; E is S, O) the dialkyl group ester.
Moreover, under the condition of Mitsunobu reaction (summary is seen Oyo Mitsunobu Synthesis, 1981, and 1-27), (I n:B is H or halogen to make formula; A is H or halogen; C is the alkoxyl group of H, Br or 1-6 carbon atom; D is OH; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S, O) phenol and formula CH (OH) (R 6 ') CO 2R 6(R 6, R 6 'Be the alkyl of 1-6 carbon atom, aralkyl, aryl) 2-hydroxycarboxylic acid esters reaction, (I o:B is H or halogen to obtain formula; A is H or halogen; C is the alkoxyl group of H, Br or 1-6 carbon atom; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 6, R 6 'Be the alkyl of 1-6 carbon atom, aralkyl, aryl; E is S, O) ester.Other essential coreagent of realizing this Mitsunobu reaction is included in temperature-20 under 120 ℃, in appropriate solvent such as ether, THF, benzene or toluene, one or the azodicarboxy acid diesters (as diethylazodicarboxylate or diisopropyl azo-2-carboxylic acid) of the alkyl of 1-6 carbon atom of many molar weights and one or the triaryl phosphine (as triphenyl phosphine) of many molar weights.
Adopt standard conditions, (I o:A, B are H or halogen can to make formula; C is the alkoxyl group of H, Br or 1-6 carbon atom; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 6, R 6 'Be the alkyl of 1-6 carbon atom, aralkyl, aryl; E is S, O) an ester and formula (I o:A, B are H or Br; C is OCHR 6 'CO 2R 6X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 6Alkyl for 1-6 carbon atom; R 6 'Be H; E is S, O) diester be converted into its carboxylic acid analogue, (I o:A, B are H or halogen to obtain formula; C is the alkoxyl group of H, Br or 1-6 carbon atom; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 6Be H; R 6 'Alkyl, aralkyl, aryl for 1-6 carbon atom; E is S, O) monocarboxylic acid and formula (I o:A, B are H or Br; C is OCHR 6 'CO 2R 6X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 6, R 6 'Be H; E is S, O) dicarboxylic acid.The condition that realizes these conversion reactions comprises aqueous bases, wherein use one or the alkali metal hydroxide (as sodium hydroxide) of many molar weights, in the water of the mixed solution that has cosolvent such as THF, diox or lower alcohol (as methyl alcohol) or THF and lower alcohol, temperature range 0-40 ℃.Scheme 9
Figure A9980842200561
Can utilize following method to prepare other derivative of formula I compound in the scheme 9.Can be in polar aprotic solvent such as DMF, with one or formula (the X of many molar weights 2CH 2CO 2R 6, X wherein 2Be Cl, Br or I, and R 6Alkyl for 1-6 carbon atom) alkyl halogen acetates and one or the alkaline carbonate (as salt of wormwood) of many molar weights, (I p:A is H with formula; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H or OCH 2CO 2R 6, but Y and Z are not OCH simultaneously 2CO 2R 6X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the former alkyl alkylthio base that gives of a 1-6 carbon, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 6Alkyl for 1-6 carbon atom; E is S, O) the phenol alkylation, (I q:A is H to production; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H or OCH 2CO 2R 6, but Y and Z are not OCH simultaneously 2CO 2R 6X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CO 2R 6R 5Be H; R 6Alkyl for 1-6 carbon atom; E is S, O) alkylate.
Under the condition of Mitsunobu reaction (summary is seen Oyo Mitsunobu Synthesis, 1981, and 1-27), (I p:A is H or OH to make formula; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H or OCH 2CO 2R 6, but Y and Z are not OCH simultaneously 2CO 2R 6X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 6Alkyl for 1-6 carbon atom; E is S, O) phenol and formula CH (OH) (R 5) CO 2R 6(R 5Alkyl, aralkyl, aryl, CH for H, a 1-6 carbon atom 2(1H-imidazol-4 yl), CH 2(3-1H-indyl), CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl), CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl), CH 2(3-pyridyl), CH 2CO 2R 6, R 6Alkyl for 1-6 carbon atom) 2-hydroxycarboxylic acid esters reaction, (I q:A is H or OH to production; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H or OCH 2CO 2R 6, but Y and Z are not OCH simultaneously 2CO 2R 6X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CO 2R 6R 5Alkyl, aralkyl, aryl, CH for H, a 1-6 carbon atom 2(1H-imidazol-4 yl), CH 2(3-1H-indyl), CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl), CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl), CH 2(3-pyridyl), CH 2CO 2R 6, R 6Alkyl for 1-6 carbon atom; E is S, O) ester.Other essential coreagent of realizing this Mitsunobu reaction is included in temperature-20 under 120 ℃, in appropriate solvent such as ether, THF, benzene or toluene, one or the azodicarboxy acid diesters (as diethylazodicarboxylate or diisopropyl azo-2-carboxylic acid) of the alkyl of 1-6 carbon atom of many molar weights and one or the triaryl phosphine (as triphenyl phosphine) of many molar weights.
Formula CH (OH) (R 5) CO 2R 6(R 5Alkyl, aralkyl, aryl, CH for H, a 1-6 carbon atom 2(1H-imidazol-4 yl), CH 2(3-1H-indyl), CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl), CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl), CH 2(3-pyridyl), CH 2CO 2R 6, R 6Alkyl for 1-6 carbon atom) 2-hydroxycarboxylic acid esters is commercially available, or can be by commercially available carboxylic acid precursor preparation under standard esterification reaction conditions.Can be by order with 1) sodium borohydride is in THF-water; 2) trifluoroacetic acid/chloroform; 3) triethyl-silicane/trifluoroacetic acid and 4) sodium bicarbonate aqueous solution is handled, by (S)-(+)-2-hydroxyl-1, and 3-dioxo-2-isoindole methyl-butyrate preparation (S)-(+)-2-hydroxyl-1-oxo-3-dihydro-2-isoindole methyl-butyrate.Can be according to B.A.Lefker, W.A.Hada, P.J.McGarry Tetrahedron Lett.1994,35, the two step methods of 5205-5208 prepare 3-(pyridin-3-yl)-Phenylacetic acid ethylester by commercially available 3-pyridylaldehyde and ethyl chloroacetate.
Can-78 ℃ to the temperature range of room temperature, in suitable solvent such as THF, with one or the highly basic of many molar weights such as di-isopropyl lithamide handle formula (I q:A be H; B, D are alkyl, aryl, the aralkyl of H, halogen, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom; Y, Z are H; X is alkoxyl group, the aralkoxy of perfluoroalkyl, a 1-6 carbon atom of alkyl, CN, a 1-6 carbon atom of H, halogen, a 1-6 carbon atom, alkyl alkylthio base, the sulfur alkyl aryl of a 1-6 carbon atom; W is CO 2TBu; R 5Be H; E is S, O) ester.This step produces the negatively charged ion of described ester carbonyl group α position.With one or the formula X of many molar weights 2R 5(X wherein 2Be halogen; R 5Be alkyl or aralkyl) alkylogen handle the negatively charged ion produced and temperature to room temperature, (I q:A is H to production; B, D are alkyl, aryl, the aralkyl of H, halogen, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom; Y, Z are H; X is alkoxyl group, the aralkoxy of perfluoroalkyl, a 1-6 carbon atom of alkyl, CN, a 1-6 carbon atom of H, halogen, a 1-6 carbon atom, alkyl alkylthio base, the sulfur alkyl aryl of a 1-6 carbon atom; W is CO 2TBu; R 5Be alkyl or aralkyl; E is S, O) the alkylation ester.
Under standard conditions, can (I q:A be H or OH with formula; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H or OCH 2CO 2R 6, but Y and Z are not OCH simultaneously 2CO 2R 6X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CO 2R 6R 5Alkyl, aralkyl, aryl, CH for H, a 1-6 carbon atom 2(1H-imidazol-4 yl), CH 2(3-1H-indyl), CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl), CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl), CH 2(3-pyridyl), CH 2CO 2R 6, R 6Alkyl for 1-6 carbon atom; E is S, O) ester be converted into its carboxylic acid analogue, (I q:A is H or OH to production; B, D are alkyl, aryl, the aralkyl of H, halogen, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H or OCH 2CO 2H, but Y and Z are not OCH simultaneously 2CO 2H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CO 2H; R 5Alkyl, aralkyl, aryl, CH for H, a 1-6 carbon atom 2(1H-imidazol-4 yl), CH 2(3-1H-indyl), CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl), CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl), CH 2(3-pyridyl), CH 2CO 2H; E is S, O) carboxylic acid.The condition that realizes these conversion reactions comprises aqueous bases, wherein use one or the alkali metal hydroxide (as sodium hydroxide) of many molar weights, in the water of the mixed solution that has cosolvent such as THF, diox or lower alcohol (as methyl alcohol) or THF and lower alcohol, temperature range 0-40 ℃.Perhaps, also can use acidic conditions, wherein in the temperature range of room temperature to 80 ℃, in water, have or do not have under the cosolvent (as THF), make above-mentioned formula (I q) carboxylicesters and one or the mineral acid (as HCl or sulfuric acid) of many molar weights react.Moreover, can use many other conditions and realize that above-mentioned ester is converted into acid, produce (I q).These conditions comprise makes above-mentioned formula (I q) carboxylicesters: in-78 ℃ to room temperature, in methylene dichloride with one or the boron tribromide or the boron trichloride reaction of many molar weights; In 0 ℃ under 50 ℃, in acetate with one or the reaction of the Hydrogen bromide of many molar weights; In-78 ℃ under 50 ℃, in methylene dichloride, tetracol phenixin or acetonitrile with one or the trimethyl silyl bromine or the trimethyl silyl Iod R of many molar weights; Under 100 ℃ to 250 ℃ temperature, in pyridine or quinoline with one or the reaction of the lithium iodide of many molar weights.
(I q:A is H when formula; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H; X is Br or I; W is CO 2R 6R 5Alkyl, aralkyl, aryl, CH for H, a 1-6 carbon atom 2(1H-imidazol-4 yl), CH 2(3-1H-indyl), CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl), CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl), CH 2(3-pyridyl), CH 2CO 2R 6, R 6Alkyl for 1-6 carbon atom; E is S, O) ester in 0 ℃ to the room temperature in methylene dichloride during with 2 molar weights or the trimethyl silyl Iod R more than 2 molar weights, being converted into carboxylic acid (is that W is CO 2H), but also 6-halogen (X is Br or I) is reduced, (I q:A is H to production; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H; X is H; W is CO 2H; R 5Alkyl, aralkyl, aryl, CH for H, a 1-6 carbon atom 2(1H-imidazol-4 yl), CH 2(3-1H-indyl), CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl), CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl), CH 2(3-pyridyl), CH 2CO 2H; E is S, O) carboxylic acid.
In suitable solvent such as THF or DMF, with one or trifluoromethyl sulfonyloxy methyl-phosphorous acid diethyl ester (D.P.Phillion and the S.S.Andrew Tet.Lett.1986 of many molar weights, 1477-1480) and one or the alkalimetal hydride (as sodium hydride) of many molar weights, (I p:A is H with formula; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H or OCH 2CO 2R 6, but Y and Z are not OCH simultaneously 2CO 2R 6X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 6Alkyl for 1-6 carbon atom; E is S, O) the phenol alkylation, (I q:A is H to production; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H or OCH 2CO 2R 6, but Y and Z are not OCH simultaneously 2CO 2R 6X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is PO 3Et 2R 5Be H; R 6Alkyl for 1-6 carbon atom; E is S, O) the diethyl phosphonate product.
Under the condition of Mitsunobu reaction (summary is seen Oyo Mitsunobu Synthesis, 1981, and 1-27), (I p:A is H or OH can to make formula; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H or OCH 2CO 2R 6, but Y and Z are not OCH simultaneously 2CO 2R 6X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 6Alkyl for 1-6 carbon atom; E is S, O) phenol and formula CH (OH) (R 5) PO 3(R 6) 2(R 5Alkyl, aralkyl, aryl for H, a 1-6 carbon atom; R 6Alkyl for 1-6 carbon atom) 2-hydroxyethylidene diphosphonic acid diester reaction, (I q:A is H or OH to production; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H or OCH 2CO 2R 6, but Y and Z are not OCH simultaneously 2CO 2R 6X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is PO 3(R 6) 2R 5Be alkyl, aralkyl, the aryl of H, a 1-6 carbon atom, R 6Alkyl for 1-6 carbon atom; E is S, O) phosphonic acid diester.Other essential coreagent of realizing this Mitsunobu reaction is included in temperature-20 under 120 ℃, in appropriate solvent such as ether, THF, benzene or toluene, one or the azodicarboxy acid diesters (as diethylazodicarboxylate or diisopropyl azo-2-carboxylic acid) of the alkyl of 1-6 carbon atom of many molar weights and one or the triaryl phosphine (as triphenyl phosphine) of many molar weights.Can be at through type HP (O) (OR under the standard conditions 6) 2(R 6Alkyl for 1-6 carbon atom) dialkyl phosphonate and formula R 5CHO (R 5Alkyl, aryl, aralkyl for 1-6 carbon atom) aldehyde reaction, preparation formula (CH (OH) (R 5) PO 3R 6) (R 5Be alkyl, aralkyl, the aryl of H, a 1-6 carbon atom, R 6Alkyl for 1-6 carbon atom) 2-hydroxyethylidene diphosphonic acid diester.
Adopt standard conditions, can be with (I q:A is H or OH; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H or OCH 2CO 2R 6, but Y and Z are not OCH simultaneously 2CO 2R 6X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is PO 3(R 6) 2R 5Be alkyl, aralkyl, the aryl of H, a 1-6 carbon atom, R 6Alkyl for H, a 1-6 carbon atom; E is S, O) phosphonic acid diester be converted into its phosphonate analogue, (I q:A is H or OH to production; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H or OCH 2CO 2R 6, but Y and Z are not OCH simultaneously 2CO 2R 6X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is PO 3H 2R 5Be alkyl, aralkyl, the aryl of H, a 1-6 carbon atom, R 6Alkyl for 1-6 carbon atom; E is S, O) phosphonic acids.Also the condition that can adopt is, in 40 to 100 ℃ temperature range, in water, is having or is not having under cosolvent such as the THF, makes phosphonic acid diester and 2 molar weights or above mineral acid (as HCl or the sulfuric acid) reaction of 2 molar weights of above-mentioned formula (I q).Moreover, can use many other conditions and realize that above-mentioned diester is converted into acid, produce (I q).These conditions comprise the phosphonic acid diester that makes formula (I q): in-78 ℃ to room temperature, in methylene dichloride with 2 molar weights or boron tribromide more than 2 molar weights or boron trichloride reaction; In 0 ℃ under 50 ℃, in acetate with the reaction of 2 molar weights or the Hydrogen bromide more than 2 molar weights; In-78 ℃ under 50 ℃, in methylene dichloride, tetracol phenixin or acetonitrile with 2 molar weights or trimethyl silyl bromine more than 2 molar weights or trimethyl silyl Iod R; Under 60 ℃ to 250 ℃ temperature, in pyridine or quinoline, react with 2 molar weights or the lithium iodide more than 2 molar weights.
In 0 ℃ to 100 ℃ temperature range, by with the ester starting material be dissolved in ammonia gas react in the lower alcohol solvent (as methyl alcohol or ethanol), can (I q:A be H or OH with formula; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CO 2R 6R 5Alkyl, aralkyl, aryl, CH for H, a 1-6 carbon atom 2(1H-imidazol-4 yl), CH 2(3-1H-indyl), CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl), CH 2(3-pyridyl), R 6Alkyl for 1-6 carbon atom; E is S, O) ester be converted into formula (I q:A be H or OH; B, D are alkyl, aryl, the aralkyl of H, halogen, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CONH 2R 5Alkyl, aralkyl, aryl, CH for H, a 1-6 carbon atom 2(1H-imidazol-4 yl), CH 2(3-1H-indyl), CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl), CH 2(3-pyridyl); E is S, O) its carboxylic acid primary amide analogue.
Perhaps, can (I q:A be H or OH with formula; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CO 2H; R 5Alkyl, aralkyl, aryl, CH for H, a 1-6 carbon atom 2(1H-imidazol-4 yl), CH 2(3-1H-indyl), CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl), CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl), CH 2(3-pyridyl); E is S, O) ester be converted into formula (I q:A be H or OH; B, D are alkyl, aryl, the aralkyl of H, halogen, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CONH 2, CONHOH, CON (CH 2) 2CN; R 5Alkyl, aralkyl, aryl, CH for H, a 1-6 carbon atom 2(1H-imidazol-4 yl), CH 2(3-1H-indyl), CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl), CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl), CH 2(3-pyridyl); E is S, O) its carboxylic acid amide analogue.Can adopt the realization carboxylic acid to finish this conversion to the standard method that carboxylic acid amide transforms.These methods comprise makes described acid be converted into activated acids, and make itself and one or the required amine reaction of many molar weights.Amine in such comprises ammonia, azanol and the 1-aminopropionitrile of ammonium hydroxide form.Activating carboxy acid's method be included in make in the suitable solvent (as methylene dichloride, chloroform or ether) as described in acid and one or the oxalyl chloride of many molar weights or thionyl chloride reaction, generate the carboxylic chloride of acid.This reaction comes catalysis by the dimethyl formamide that adds a small amount of (0.01-0.1 molar weight) usually.Other method that activates described carboxylic acid comprises: in 0 ℃ to 60 ℃ temperature range, in suitable solvent (as methylene dichloride or dimethyl formamide), have or the situation of the hydroxybenzotriazole of none or many molar weights under, make described acid and one or the dicyclohexylcarbodiimide reaction of many molar weights.
Can be in polar aprotic solvent such as DMF, with one or formula (the X of many molar weights 2CH 2CN, wherein X 2Be Cl, Br or I) the halo acetonitrile and one or many Ma you the amount alkaline carbonate (as salt of wormwood), (I p:A is H with formula; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S, O) the phenol alkylation, (I q:A is H to production; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CN; R 5Be H; E is S, O) nitrile.
Perhaps, be the functional reagent of nitrile with uncle's methane amide official being dewatered, (I q:A is H or OH with formula; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CONH 2R 5Alkyl, aralkyl, aryl, CH for H, a 1-6 carbon atom 2(1H-imidazol-4 yl), CH 2(3-1H-indyl), CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl), CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl), CH 2(3-pyridyl); E is S, O) the carboxylic acid amide analogue be converted into formula (I q:A be H or OH; B, D are alkyl, aryl, the aralkyl of H, halogen, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CN; R 5Alkyl, aralkyl, aryl, CH for H, a 1-6 carbon atom 2(1H-imidazol-4 yl), CH 2(3-1H-indyl), CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl), CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl), CH 2(3-pyridyl); E is S, O) its nitrile analogue.A set condition of realizing this conversion comprises: in 60 ℃ to 120 ℃ temperature range, in suitable solvent such as diox, make described carboxylic acid primary amide and one or the trifluoroacetic anhydride of many molar weights and 2 molar weights or the above pyridine reaction of 2 molar weights.
Can be by in 60 ℃ to 120 ℃ temperature range, in suitable solvent such as benzene or dimethylbenzene, (I q:A is H or OH with formula; B, D are alkyl, aryl, the aralkyl of H, halogen, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CN; R 5Alkyl, aralkyl, aryl, CH for H, a 1-6 carbon atom 2(1H-imidazol-4 yl), CH 2(3-1H-indyl), CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl), CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl), CH 2(3-pyridyl); E is S, O) the nitrile analogue by with one or the TMA (TriMethylAmine) of many molar weights and one or the trimethyl silyl trinitride reaction of many molar weights, (I q:A is H or OH to be converted into formula; B, D are alkyl, aryl, the aralkyl of H, halogen, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is the 5-tetrazolium; R 5Alkyl, aralkyl, aryl, CH for H, a 1-6 carbon atom 2(1H-imidazol-4 yl), CH 2(3-1H-indyl), CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl), CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl), CH 2(3-pyridyl); E is S, O) tetrazolium.Perhaps, can be in 60 ℃ to 160 ℃ temperature range, in suitable solvent such as dimethyl formamide, make the described nitrile official can be with one or the ammonium azide reaction of many molar weights.
Can by-78 ℃ to the temperature range of room temperature, in suitable solvent such as THF, (I q:A is H with formula; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom; Y, Z are H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CO 2R 6R 5Alkyl, aralkyl, aryl for H, a 1-6 carbon atom; R 6Alkyl for 1-6 carbon atom; E is S, O) ester by make itself and one or the lithium aluminum hydride of many molar weights and one or the ammonium chloride reaction of many molar weights, (I q:A is H to be converted into formula; B, D are alkyl, aryl, the aralkyl of H, halogen, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom; Y, Z are H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CH 2OH; R 5Alkyl, aralkyl, aryl for H, a 1-6 carbon atom; R 6Alkyl for 1-6 carbon atom; E is S, O) its primary alconol analogue.
In-20 ℃ to 120 ℃ temperature range, in suitable solvent such as ether, can (I q:A be H with formula; B, D are alkyl, aryl, the aralkyl of H, halogen, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; Y, Z are H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CH 2OH; R 5Alkyl, aralkyl, aryl for H, a 1-6 carbon atom; R 6Alkyl for 1-6 carbon atom; E is S, O) the primary alconol analogue by make itself and one or the lithiumbromide of many molar weights and one or the azodicarboxy acid diesters (as diethylazodicarboxylate or diisopropyl azo-2-carboxylic acid) of the alkyl of 1-6 carbon atom of many molar weights and one or triaryl phosphine (as the triphenyl phosphine) reaction of many molar weights, (I q:A is H to be converted into formula; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom; Y, Z are H; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of H, halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; W is CH 2Br; R 5Alkyl, aralkyl, aryl for H, a 1-6 carbon atom; R 6Alkyl for 1-6 carbon atom; E is S, O) uncle bromide.Scheme 10
Can adopt following method to prepare other derivative of formula I compound in the scheme 10.Under the condition of Mitsunobu reaction (summary is seen Oyo Mitsunobu Synthesis, 1981, and 1-27), (I r:A is H or halogen to make formula; C is halogen or methoxyl group; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S, O) phenol and formula CH (OH) (R 1a) CO 2R 1(R 1, R 1aAlkyl, aralkyl, aryl for 1-6 carbon atom) 2-hydroxycarboxylic acid esters reaction, (I s:A is H or halogen to production; C is halogen or methoxyl group; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 1Alkyl, aralkyl, aryl for 1-6 carbon atom; R 1aAlkyl, aralkyl, aryl for H or 1-6 carbon atom; E is S, O) ester.Other essential coreagent of realizing this Mitsunobu reaction is included in temperature-20 under 120 ℃, in appropriate solvent such as ether, THF, benzene or toluene, one or the azodicarboxy acid diesters (as diethylazodicarboxylate or diisopropyl azo-2-carboxylic acid) of the alkyl of 1-6 carbon atom of many molar weights and one or the triaryl phosphine (as triphenyl phosphine) of many molar weights.
Can be under the standard enzymatic synthesis condition, by commercially available carboxylic acid precursor, preparation formula CH (OH) (R 1a) CO 2R 1(R 1, R 1aAlkyl, aralkyl, aryl for 1-6 carbon atom) the 2-hydroxycarboxylic acid esters.
Can be under standard conditions, (I s:A is H or halogen with formula; C is halogen or methoxyl group; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 1Alkyl, aralkyl, aryl for 1-6 carbon atom; R 1aAlkyl, aralkyl, aryl for H or 1-6 carbon atom; E is S, O) ester be converted into its carboxylic acid analogue, (I s:A is H or halogen to production; C is halogen or methoxyl group; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 1Be H; R 1aAlkyl, aralkyl, aryl for H or 1-6 carbon atom; E is S, O) carboxylic acid.The condition that realizes these conversion reactions comprises aqueous bases, wherein use one or the alkali metal hydroxide (as sodium hydroxide) of many molar weights, in the water of the mixed solution that has cosolvent such as THF, diox or lower alcohol (as methyl alcohol) or THF and lower alcohol, temperature range 0-40 ℃.Scheme 11
Can adopt following method to prepare other derivative of formula I compound in the scheme 11.(I t:B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom to make formula; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S, O) phenol and one or (two) trimethyl silyl lithamide of many molar weights react to room temperature in-78 ℃, and at-78 ℃ to the temperature range of room temperature, in inert atmosphere,, make described lithium salts and one or the 5-bromo thiazole alkane-2 of many molar weights with suitable solvent such as THF, the 4-diketone is (according to Zask etc., J.Med Chem, 1990,33, the method of 1418-1423) further reaction, production (I u:R 4For (R, S)-the 5-thiazolidine-2, the 4-diketone; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S, O) compound.
Perhaps, according to J.W.Perich and R.B.Johns, Syntheis, 1988, the method of 142-140, under the room temperature in THF, (I t:B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom can to make formula; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S, O) phenol and one or the tetrazolium and the N of many molar weights, the reaction of the N-diethylamino di(2-ethylhexyl)phosphate tert-butyl ester, then in-40 ℃ add one or many molar weights between-chloro-benzoic acid, production (I u:R 4For P (O) (OtBu) 2B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S, O) phosphodiester.Then these phosphodiesters with one or the hydrochloric acid of many molar weights in suitable solvent such as diox, handle production (I u:R 4For P (O) (OH) 2B, D are alkyl, aryl, aralkyl, the nitro of H, halogen, CN, a 1-6 carbon atom; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S, O) phosphonic acids.
(I t:B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom by handle formula with 2 molar weights or the solid sodium hydroxide more than 2 molar weights; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S, O) phenol, then a large amount of excessive also as in the presence of the acetone of solvent, with one or many molar weights 1,1,1-three chloro-2-methyl-2-propyl alcohol tetrahydrate processing can make described phenol be converted into formula (I u:R 4Be C (CH 3) 2CO 2H; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S, O) carboxylic acid.
By with one or the β-Bing Chunsuanneizhi of many molar weights handle, and with one or the potassium tert.-butoxide of many molar weights in suitable solvent such as THF, handle, (I t:B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom can to make formula; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S, O) phenol be converted into formula (I u:R 4Be CH 2CH 2CO 2H; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S, O) carboxylic acid.
Under the condition of Mitsunobu reaction (summary is seen Oyo Mitsunobu Synthesis, 1981, and 1-27), (I t:B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom can to make formula; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; E is S, O) phenol and formula CH (OH) (R 7) CH 2CO 2R 6(R 7Alkyl for H or 1-6 carbon atom; R 6Alkyl for 1-6 carbon atom) 3-hydroxycarboxylic acid esters reaction, production (I u:R 4Be (R)-CH (R 7) CH 2CO 2R 6B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 7Alkyl for H or 1-6 carbon atom; R 6Alkyl for 1-6 carbon atom; E is S, O) ester.Other essential coreagent of realizing this Mitsunobu reaction is included in temperature-20 under 120 ℃, in appropriate solvent such as ether, THF, benzene or toluene, one or the azodicarboxy acid diesters (as diethylazodicarboxylate or diisopropyl azo-2-carboxylic acid) of the alkyl of 1-6 carbon atom of many molar weights and one or the triaryl phosphine (as triphenyl phosphine) of many molar weights.
Formula CH (OH) (R 7) CH 2CO 2R 6(R 7Alkyl for H or 1-6 carbon atom; R 6Alkyl for 1-6 carbon atom) 3-hydroxycarboxylic acid esters is commercially available, or can be by commercially available carboxylic acid precursor preparation under standard esterification reaction conditions.
Adopt several standard conditions, can make formula (I u:R 4Be (R)-CH (R 7) CH 2CO 2R 6B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 7Alkyl for H or 1-6 carbon atom; R 6Alkyl for 1-6 carbon atom; E is S, O) ester be converted into formula (I u:R 4Be (R)-CH (R 7) CH 2CO 2H; B, D are alkyl, aryl, the aralkyl of H, halogen, CN, a 1-6 carbon atom, alkoxyl group, the nitro of a 1-6 carbon atom; X is alkyl, the perfluoroalkyl of CN, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, aralkoxy, nitro, the alkyl alkylthio base of a 1-6 carbon atom, sulfur alkyl aryl, pyridyl sulfane base, the 2-N of halogen, a 1-6 carbon atom, N-dimethylaminoethyl sulfane base; R 7Alkyl for H or 1-6 carbon atom; E is S, O) acid, described standard conditions comprise: in 40 to 120 ℃ temperature range, in one or more solvents or two or more solvent (as water, THF Huo diox) combination, make ester and 2 molar weights or above mineral acid (as HCl or the sulfuric acid) reaction of 2 molar weights of formula (I u).Moreover, can realize that above-mentioned ester transforms to acid with many other conditions, produce (I u).These conditions comprise the ester that makes formula (I u): in-78 ℃ to room temperature, in methylene dichloride with 2 molar weights or boron tribromide more than 2 molar weights or boron trichloride reaction; In 0 ℃ under 50 ℃, in acetate with the reaction of 2 molar weights or the Hydrogen bromide more than 2 molar weights; In-78 ℃ under 50 ℃, in methylene dichloride, tetracol phenixin or acetonitrile with 2 molar weights or trimethyl silyl bromine more than 2 molar weights or trimethyl silyl Iod R; Under 60 ℃ to 250 ℃ temperature, in pyridine or quinoline, react with 2 molar weights or the lithium iodide more than 2 molar weights.Scheme 12
Figure A9980842200721
Can adopt following method to prepare other derivative of formula I compound in the scheme 12.Can-78 ℃ to the temperature range of room temperature, in halocarbon solvent such as methylene dichloride, (I v:B, D are the alkyl of H, halogen, a 1-6 carbon atom to make formula; R 5Alkyl, aryl or aralkyl for H, a 1-6 carbon atom; R 6Alkyl for 1-6 carbon atom; E is S, O) ester and one or the reaction of the boron tribromide of many molar weights, (I w:B, D are the alkyl of H, halogen, a 1-6 carbon atom to production; R 5Alkyl, aryl or aralkyl for H, a 1-6 carbon atom; R 6Alkyl for 1-6 carbon atom; R 8Be H; E is S, O) phenol.
Can be in polar aprotic solvent such as DMF, with one or the formula R of many molar weights 8X (R 8Be the alkyl of 1-6 carbon atom, rudimentary aralkyl and CH 2CO 2CH 3X is a halogen; E is S, O) alkylating agent and one or the basic metal carbonic acid potassium (as salt of wormwood) of many molar weights, (I w:B, D are the alkyl of H, halogen, a 1-6 carbon atom with formula; R 5Alkyl, aryl or aralkyl for H, a 1-6 carbon atom; R 6Alkyl for 1-6 carbon atom; R 8Be H; E is S, O) the phenol alkylation, (I w:B, D are the alkyl of H, halogen, a 1-6 carbon atom to production; R 5Alkyl, aryl or aralkyl for H, a 1-6 carbon atom; R 6Alkyl for 1-6 carbon atom; R 8Be the alkyl of 1-6 carbon atom, rudimentary aralkyl and CH 2CO 2CH 3E is S, O) alkylating phenol.
Adopt standard conditions, can (I w:B, D be the alkyl of H, halogen, a 1-6 carbon atom with formula; R 5Alkyl, aryl or aralkyl for H, a 1-6 carbon atom; R 6Alkyl for 1-6 carbon atom; R 8Be the alkyl of 1-6 carbon atom, rudimentary aralkyl and CH 2CO 2CH 3E is S, O) ester be converted into its carboxylic acid analogue, (I w:B, D are the alkyl of H, halogen, a 1-6 carbon atom to production; R 5Alkyl, aryl or aralkyl for H, a 1-6 carbon atom; R 6Be H; R 8Be the alkyl of 1-6 carbon atom, rudimentary aralkyl and CH 2CO 2H; E is S, O) carboxylic acid.The condition that realizes these conversion reactions comprises aqueous bases, wherein use one or the alkali metal hydroxide (as sodium hydroxide) of many molar weights, in the water of the mixed solution that has cosolvent such as THF, diox or lower alcohol (as methyl alcohol) or THF and lower alcohol, temperature range 0-40 ℃.Scheme 13
Can adopt following method to prepare other derivative of formula I compound in the scheme 13.Can be in-20 ℃ to 40 ℃ temperature range, in methylene dichloride with one or the oxygenant such as the metachloroperbenzoic acid of many molar weights; Or in the temperature range of room temperature to 100 ℃, in acetate and water, with one or the peracetic acid of many molar weights; (I x:B, D are the alkyl of H, halogen, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom to make formula; X is the alkyl of halogen, a 1-6 carbon atom, the perfluoroalkyl of CN, a 1-6 carbon atom, alkoxyl group, the aralkoxy of a 1-6 carbon atom; R 5Alkyl, aryl or aralkyl for H, a 1-6 carbon atom; R 6Alkyl for H, a 1-6 carbon atom) compound is converted into formula (I y:n is 1; B, D are the alkyl of H, halogen, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom; X is the alkyl of halogen, a 1-6 carbon atom, the perfluoroalkyl of CN, a 1-6 carbon atom, alkoxyl group, the aralkoxy of a 1-6 carbon atom; R 5Alkyl, aryl or aralkyl for H, a 1-6 carbon atom; R 6Alkyl for H, a 1-6 carbon atom) its sulfoxide derivant.
Can be in-20 ℃ to 60 ℃ temperature range, in methylene dichloride with 2 molar weights or oxygenant more than 2 molar weights such as metachloroperbenzoic acid; Or in the temperature range of room temperature to 100 ℃, in acetate and water, with 2 molar weights or the above peracetic acid of 2 molar weights; (I x:B, D are the alkyl of H, halogen, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom to make formula; X is the alkyl of halogen, a 1-6 carbon atom, the perfluoroalkyl of CN, a 1-6 carbon atom, alkoxyl group, the aralkoxy of a 1-6 carbon atom; R 5Alkyl, aryl or aralkyl for H, a 1-6 carbon atom; R 6Alkyl for H, a 1-6 carbon atom) compound is converted into formula (I y:n is 2; B, D are the alkyl of H, halogen, a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom; X is the alkyl of halogen, a 1-6 carbon atom, the perfluoroalkyl of CN, a 1-6 carbon atom, alkoxyl group, the aralkoxy of a 1-6 carbon atom; R 5Alkyl, aryl or aralkyl for H, a 1-6 carbon atom; R 6Alkyl for H, a 1-6 carbon atom) its sulfone derivatives.
The compounds of this invention can be used for treating the metabolism disorder relevant with insulin resistance or hyperglycemia, especially with obesity or the relevant metabolism disorder of the not anti-disease of glucose.Therefore, The compounds of this invention especially can be used for treatment or suppresses type II diabetes.The compounds of this invention also can be used for regulating the glucose level in disease such as the insulin-dependent diabetes mellitus (IDDM).
Can determine the ability of The compounds of this invention treatment or inhibition and insulin resistance or hyperglycemia diseases associated with representative compounds of the present invention according to the standard pharmacological test method of following mensuration to the PTP enzyme inhibition.Rats'liver albumen-tyrosine phosphorylation enzyme (PTP enzyme) is to the dephosphorylized restraining effect of insulin receptor ten bisphosphate peptides of triphosphoric acidization
This standard pharmacological test method adopts the phosphoric acid tyrosyl dodecapeptide corresponding to 1142-1153 insulin receptor kinase structural domain as substrate; they are phosphorylation on 1146,1150 and 1151 tyrosine residuess, assesses the restraining effect to rat liver microsomes PTP enzymic activity.Method that following brief description is used and the result who obtains.The preparation of microsomal fraction: by using CO 2Suffocating, (body weight 100-150g male Sprague-Dawley rat (Charles River, Kingston NY), keep with the rodent food (Purina) of standard) also carries out the wide otomy of Bilateral chest to the execution rat.Extract liver and wash and weigh with cold 0.85% salt solution (w/v).Stir evenly tissue on ice with liquid A in 10 volumes slow and as by as described in Meyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir S, the KahnCR, basically the separating particles body.In two kinds of non-insulin-dependent diabetes mellitus mouse models, make hyperglycemia normalizing .J Clin Invest 1991 with vanadate; 87:1286-1294 and Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD editor. cellular elements biology. New York: Garland publishing company, 1989 (making an amendment slightly).Through silk goods filter liver homogenate with remove any residual fragment of tissue and then under 40 ℃ in 10, under the 000xg centrifugal 20 minutes.Supernatant decanted liquid and under 40 ℃ in 100, under the 000xg centrifugal 60 minutes.To precipitate, microsome and a small amount of carrier are at 20mM TRIS-HCl (pH7.4), the 50mM 2 mercapto ethanol, 250mM sucrose, 2mM EDTA, 10mM EGTA, 2mM AEBSF, 0.1mM TLCK, 0.1mM TPCK, 0.5mM benzamidine, the 25ug/ml leupeptin, 5ug/ml pepstatin A, 5ug/ml H5B protease inhibitor, the 5ug/ml chymotrypsin inhibitor, resuspending also slightly stirs evenly up to ultimate density and reaches about 850ug protein/ml in the 10ug/ml aprotinin (buffer A).(Pierce chemical company, Rockford IL), measure protein concn through Pierce coomassie eurymeric protein test as standard substance to use the crystallization bovine serum albumin.Measure the PTP enzymic activity: adopt Victoria Green WPB-ammonium molybdate method of describing as Lanzetta PA, Alvarez LJ, Reinach PS, Candia OA to be used.Be suitable for nmole flow measurement (the Anal Biochem.1979 of inorganic phosphate; 100:95-97) the improved test of also suitable plate reader is used for measuring through the phosphatic nmole that rat liver microsomes PTP enzyme discharges.This test method use as substrate (San Jose CA) entrusts synthetic ten bisphosphate peptides by AnaSpec company.Peptide TRDIYETDYYRK corresponding to the 1142-1153 catalytic domain of insulin receptor is the tyrosine of phosphorylation on 1146,1150 and 1151 tyrosine residuess.37 the degree ℃ under, the microsomal fraction (83.25ul) that will contain or not contain the 81.83mM HEPES reaction buffer (pH7.4) of test-compound (6.25ul) and 305.5ul was hatched 10 minutes in advance.Be equipped with on the LABLINE Multi-Blok well heater of titer plate colligator, making 10.5ul peptide substrates balance to 37 degree ℃ of ultimate density 50uM.Add the microsome that contains or do not contain medicine hatch in advance and prepare liquid (39.5ul) starting the dephosphorylation reaction, under 37 degree ℃, this reaction was carried out 30 minutes.Hold back agent (MG/AM/Tw) through adding 200ul Victoria Green WPB-ammonium molybdate-polysorbas20 stops this reaction.Hold back agent contains 3 part of 0.45% Victoria Green WPB hydrochloride in 4NHCl and 0.5% polysorbas20,1 part of 4.2% ammonium molybdate tetrahydrate.Prepare the sample blank group through 200ul MG/AM/Tw being joined the film liquid that contains or do not contain medicine of hatching in advance that also adds 39.5ul in the substrate subsequently.At room temperature, make color developing 30 minutes and under 650nm, use the optical density of plate reader (Molecular Devices) working sample.The operation of preparation sample and blank group repeats four times.Its microsome of activity rating PTP enzyme inhibition of screening 50uM (finally) medicine.Calculate: the PTP enzymic activity that with the potassiumphosphate typical curve is benchmark is represented with the phosphatic nmole number that the every min of every mg protein is discharged.Test compound is calculated as the percentage ratio of Phosphoric acid esterase contrast to the restraining effect of reorganization PTP1B.Use SAS to discharge 6.08 PROC NLIN, measure the IC of test-compound with four parametrical nonlinearity logistical regressions of PTP enzymic activity 50Value.All compounds give with the concentration of 50 μ M.Use representative compounds of the present invention, obtain following result.
Embodiment Variation % with contrast
????7 ?????1.03
????14 ????-34.19
????15 ????-43.68
????18 ????-15.22
????20 ????-26.86
????21 ????-32.41
????22 ????-16.83
????23 ????-8.92
????24 ?????3.16
????25 ????-38.31
????26 ????-8.68
????27 ????-35.78
????30 ?????1.00
????32 ????-58.12
????34 ????-3.40
????37 ????-3.02
????40 ????-1.40
????41 ????-39.32
????42 ????-21.28
????43 ????-14.62
????47 ????-3.50
????58 ????-43.32
????59 ????-35.46
????60 ????-25.07
????61 ????-54.82
????62 ????-40.14
????63 ????-47.53
????64 ????-15.90
????68 ????-26.32
????70 ????-29.03
????71 ????-35.74
????74 ????-21.61
????76 ????-18.89
????79 ????-82.58
????81 ????-47.69
????82 ????-39.80
????83 ????-57.89
????84 ????-73.91
????85 ????-71.67
Embodiment Variation % with contrast
????86 ????-69.35
????87 ????-63.18
????88 ????-67.03
????89 ????-61.04
????90 ????-79.04
????91 ????-97.10
????92 ????-98.16
????93 ????-58.35
????94 ????-95.80
????95 ????-75.45
????108 ????-72.94
????109 ????-66.67
????110 ????-12.78
????111 ????-76.45
????113 ????-101.01
????114 ????-68.03
????115 ????-55.43
????116 ????-61.89
????117 ????-79.06
????118 ????-82.00
????119 ????-75.29
????120 ????-17.35
????121 ????-74.70
????122 ????-85.46??
????123 ????-87.44??
????124 ????-70.01??
????125 ????-73.96????
????126 ????-78.77??????
????127 ????-37.08??????
????128 ????-50.94????
????129 ????-59.03????
????130 ????-72.14??????
????131 ????-66.21???
????132 ????-49.27????
????133 ????-27.89????
????134 ????-69.86??
????135 ????-59.75????
????136 ????-63.42??????
Embodiment Variation % with contrast
????137 ????-64.92
????138 ????-69.13
????139 ????-64.89
????140 ????-71.19
????141 ????-76.58
????142 ????-104.68
????143 ????-76.98
????144 ????-85.24
????146 ????-71.95
????147 ????-66.60
????148 ????-82.62
????149 ?????59.82
????150 ????-92.46
????152 ????-95.22
????155 ????-82.25
????156 ????-71.12
????161 ????-8.03
????162 ????-60.67
????163 ????-38.40
????164 ????-70.32
????165 ????-3.12
????166 ????-26.86
????167 ????-16.99
????168 ????-17.85
????169 ????-9.30
????170 ????-18.79
????171 ????-71.04
????172 ????-70.95
????174 ?????0.39
????175 ????-69.20
????177 ????-69.35
????178 ????-42.41
????179 ????-66.27
????180 ????-50.64
????184 ????-46.44
????185 ????-98.45
????186 ????-74.87
????187 ????-57.64
????189 ????-89.32
Embodiment Variation % with contrast
????194 ????-79.35??
????195 ????-29.34????
????196 ????-80.08??????
????200 ????-50.62??
????201 ????-75.75
????203 ????-86.47???
????210 ????-51.55???
????211 ????-36.82??
????213 ????-54.40??
????215 ????-80.93??
????216 ????-60.67????
????217 ????-80.42???
Phenyl-arsine oxide (reference standard) ????-57.06???
Restraining effect through the triphosphoric acid insulin receptor ten bisphosphate peptide dephosphorylations of hPTP1B
This standard pharmacological experimental method uses the phosphoric acid tyrosyl dodecapeptide corresponding to the 1142-1153 insulin receptor kinase territory of phosphorylation on 1146,1150 and 1151 tyrosine residuess as substrate, estimates the active restraining effect of recombinant rat Protein Tyrosine Phosphatases PTP1B.Following Short Description the method used and the result who obtains.
As by as described in the Goldstein (referring to .Mol.Cell.Biochem.109 such as Goldstein, 107,1992), the preparation people PTP1B that recombinates.Used enzyme is prepared liquid to be placed at and to contain in 33mM Tris-HCl, 2mM EDTA, 10% glycerine and the 10mM 2 mercapto ethanol in the proteinic microtubule of 500-700 μ g/ml.The measurement of PTP enzymic activity: (Anal Biochem.100:95,1979) that adopt as Lanzetta etc. described and the Victoria Green WPB-ammonium molybdate method that the is suitable for plate reader phosphatic nmole detection that PTP1B discharges of recombinating.This test method use as substrate (San Jose CA) entrusts synthetic ten bisphosphate peptides by AnaSpec company.Peptide TRDIYETDYYRK corresponding to the 1142-1153 catalytic domain of insulin receptor is the tyrosine of phosphorylation on 1146,1150 and 1151 tyrosine residuess.With damping fluid (pH7.4 contains 33mM Tris-HCl, 2mMEDTA and 50mM b-mercaptoethanol) dilution reorganization rPTP1B, obtain activity and be approximately 1000-2000 nmoles/min/mg protein.Under 37 ℃, with the enzyme (83.25ul) that diluted with or do not hatch in advance 10 minutes with the 81.83mM HEPES reaction buffer (pH7.4) of test-compound (6.25mL) and 305.5mL, be equipped with on the LABLINEMulti-Blok well heater of titer plate colligator, making the 10.5ml peptide substrates balance to 37 ℃ under the ultimate density 50uM.Add the recombinase that contains or do not contain medicine of hatching in advance and prepare liquid (39.5ml), under 37 ℃, this reaction was carried out 30 minutes to start the dephosphorylation reaction.Through adding hold back agent (MG/AM/Tw) termination reaction of 200mL Victoria Green WPB-ammonium molybdate-polysorbas20.Hold back agent contains 3 part of 0.45% Victoria Green WPB hydrochloride in 4N HCl and 0.5% polysorbas20,1 part of 4.2% ammonium molybdate tetrahydrate.Prepare the sample blank group through 200mL MG/AM/Tw being joined in the substrate and add subsequently the recombinase that contains or do not contain medicine that 39.5ml hatches in advance.At room temperature, make color developing 30 minutes and under 650nm, use the optical density of plate reader (MolecularDevices) working sample.Each four parts of preparation sample and blank.Calculate: the PTP enzymic activity that with the potassiumphosphate typical curve is benchmark is represented with the phosphatic nmole number that the every min of every mg protein is discharged.Test-compound is calculated as the percentage ratio of Phosphoric acid esterase control group to the restraining effect of reorganization PTP1B.Use SAS to discharge 6.08 PROCNLIN, measure the IC of test-compound with four parametrical nonlinearity logistical regressions of PTP enzymic activity 50Value.Obtain following result.
Embodiment ????IC50(μM)
????18 ????0.554
????21 ????0.384
????37 ????1.18
????40 ????1.10
????41 ????1.08
????42 ????1.50
????43 ????0.189
????58 ????1.01
????59 ????0.612
????60 ????0.129
????62 ????0.654
????63 ????0.904
????64 ????0.347
????68 ????1.02
????70 ????0.074
????71 ????0.079
????79 ????0.386
????81 ????1.99
????82 ????2.00
????87 ????1.68
????89 ????0.126
????91 ????1.30
????92 ????0.644
????108 ????0.061
????109 ????0.071
????110 ????1.52
????111 ????0.062
????113 ????0.045
????114 ????0.589
????115 ????0.279
????116 ????0.765
????117 ????1.51
????118 ????0.031
????120 ????0.541
????121 ????0.184
Embodiment ????IC50(μM)
????122 ????0.036
????123 ????0.082
????124 ????0.085
????126 ????0.298
????127 ????0.064
????128 ????0.025
????129 ????0.046
????130 ????0.80
????132 ????0.311
????133 ????0.506
????134 ????0.093
????135 ????0.209
????136 ????0.050
????137 ????0.341
????138 ????0.636
????139 ????0.061
????140 ????0.204
????141 ????0.126
????142 ????0.103
????143 ????1.17
????144 ????1.13
????146 ????0.064
????148 ????1.23
????150 ????0.207
????152 ????0.994
????155 ????0.056
????156 ????0.026
????162 ????0.145
????165 ????0.665
????166 ????0.565
????168 ????0.994
????169 ????1.22
????170 ????0.607
????171 ????0.302
????172 ????0.076
????177 ????1.08
????178 ????0.480
????179 ????0.203
????180 ????0.384
????184 ????0.045
Embodiment ????IC50(μM)
????189 ????1.39
????190 ????2.00
????191 ????0.118
????194 ????0.217
????195 ????0.889
????196 ????0.174
????200 ????1.17
????203 ????0.402
????210 ????1.06
????215 ????0.49
????216 ????0.083
Phenyl-arsine oxide (reference standard) ????39.7
Sodium orthovanadate (reference standard) ????244.8
Ammonium molybdate tetrahydrate (reference standard) ????8.7
Use diabetes (ob/ob) mouse, confirm the activity of the reduction blood glucose of representative compounds of the present invention with body internal standard method.Employed method and the Short Description as a result that obtains are as follows.
Its feature of non-insulin-dependent diabetes mellitus (NIDDM) (NIDDM) syndrome is generally obesity, hyperglycemia, unusual insulin secretion, hyperinsulinemia and insulin resistance.Genetic obesity-hyperglycemia ob/ob mouse presents this type of multiple metabolic disturbance and is considered to be used to study the useful model [Coleman, D.:Diabelogia 14:141-148,1978] of the hypoglycemic drug of treatment NIDDM.
In each test method, the mouse at similar age [male or female ob/ob (C57B1/6J) and their lean litermates (ob/+ or+/+, the Jackson laboratory), the age 2 was to 5 months sizes (10-65g)] be divided into 4 groups at random according to body weight, every group of 10 mouse.Each cage is raised 5 mouse, arbitrarily drinks water, and feeds to raise with normal rodent food and keeps.Every day, mouse by gavage (being suspended in 0.5% methylcellulose gum of 0.5ml) accept to be dissolved in the tap water or with food blended test-compound.The dosage that gives compound is in 2.5 to 200mg/kg body weight/day scopes.Feed to raise based on body weight weekly and calculate dosage and be expressed as active part.Give positive control ciglitazone (5-(4-(1-methyl cyclohexane ylmethoxy) benzyl)-2 with 100mg/kg/ days dosage, the 4-diketone) (referring to Chang, A.Wyse, B., Gilchrist, B., Peterson, T. and Diani, A.Diabetes 32:830-838,1983.), this medicine produces significantly reduced plasma glucose.Control group mice is only accepted carrier.
In the 4th day, the 7th day or the 14th day morning, after tail vein or sacrificed by decapitation, two bleed (approximately 50uL) collected the test tube that contains Sodium Fluoride.For every day wherein giving these researchs of compound through gavage, give behind the compound two hours, collect blood sample.Through centrifugal separation plasma and on Abbott V.P. analyser enzyme process measure the concentration of glucose.
To every mouse, the per-cent with respect to the plasma glucose of the average blood plasma glucose of vehicle treated mouse that calculates the 4th day, the 7th day or the 14th day changes.Be used to estimate the significant difference (CMS SAS discharges 5.18) of the plasma glucose levels between control group and each the compounds for treating group according to the variable analysis of DunettShi comparative experiments (a tail method).
Result displayed shows that The compounds of this invention is the hyperglycemia medicine in following table, because they reduce the blood glucose level in the diabetic mice.
Embodiment Dosage (mg/Kg) The glucose of comparing with carrier changes % The Regular Insulin of comparing with carrier changes %
????70 ????25 ????-28.55 ?????45.68(a)
????79 ????100 ????-22.6 ????-60.9
????79 ????100 ????-22.60 ????-60.85
????87 ????100 ????-15.77(a) ????-87.97
????89 ????10 ????-24.9 ????b
????108 ????100 ????-45.83 ????-72.56
????108 ????75 ????-49.74 ????-89.61
????108 ????50 ????-34.79 ????-84.77
????108 ????25 ????-25.66 ????-71.03
????108 ????10 ????-26.09 ????-30.33(a)
????109 ????25 ????-26.31 ????-71.64
????111 ????100 ????-39.36 ????-17.85(a)
????113 ????25 ????-0.50(a) ????-55.84
????115 ????100 ????-33.9 ?????52.00
????117 ????100 ????-14.5(a) ????-83.8
Embodiment Dosage (mg/Kg) The glucose of comparing with carrier changes % The Regular Insulin of comparing with carrier changes %
????121 ????100 ????-54.57 ????-87.76
????121 ????10 ?????1.37(a) ????-41.81
????122 ????100 ????-28.13 ????-37.40
????123 ????75 ????-23.96 ????-40.94
????125 ????95 ????-27.58 ????-89.68
????126 ????25 ????-28.55?????? ????-62.39
????127 ????25 ????-18.75(a)?? ????-76,54
????128 ????25 ?????3.10(a) ????-38.83
????129 ????25 ????-14.86(a) ????-54.58
????131 ????25 ????-3.63(a)???? ????-67.55
????135 ????25 ????-15.83(a)??? ????-57.43
????136 ????25 ????-23.63 ????-52.05
????138 ????25 ????-13.84(a) ????-91.90
????139 ????25 ????-18.5(a) ????-22.00
????146 ????100 ????-45.79 ????-56.19
????155 ????25 ????-28.89 ????-63.23
????172 ????100 ?????5.62(a) ????-52.05
????189 ????100 ????-46.8 ?????11.00(a)
????191 ????25 ????-36.5 ????-64.3
????191 ????10 ????-22.8 ????b
????194 ????25 ????-32.0 ????b
????203 ????100 ????-16.1(a) ????-91.0
????215 ????100 ????-39.36 ????-4.66(a)
????216 ????25 ????-42.4 ????-85.6
????216 ????25 ????-38.7 ????-84.0
????216 ????10 ????-28.7 ????-69.4
????216 ????5 ????-14.8(a) ????-55.9
Ciglitazone (reference standard) ????100 ????-43 ????-39
A-is no remarkable activity (p＜0.05) under this dosage.The b-undetermined
Based on the result who in described standard pharmacological experimental method, obtains, representative compounds of the present invention has demonstrated in diabetic mice and has suppressed the PTP enzymic activity and reduce the blood glucose level, and be used for the treatment of the Metabolic disorder relevant thus, normally relevant Metabolic disorder with obesity or glucose intolerance with insulin resistance or hyperglycemia.More particularly, The compounds of this invention is used for the treatment of or suppresses type II diabetes, and is used for being adjusted in the glucose level as the disease of insulin-dependent diabetes mellitus (IDDM).As used herein, term is regulated to mean and is kept glucose level in clinical normal range.
To about 250mg/kg, can effectively give these compounds at the about 1mg/kg of dosage every day, and can single dose or give with twice or the dosage that repeatedly separates.That any way that can be used for directly will giving at this active compound recipient's blood flow comprises is oral, by implantation, non-enteron aisle (comprising vein, intraperitoneal and subcutaneous injection), rectum, vagina and the such dosage of transdermal administration.For the purpose of the disclosure, percutaneous dosing is understood to include the administration that all body passages that pass body surface and liner comprise epidermis and mucosal tissue.Use can be carried out such administration with the The compounds of this invention of lotion, creme, foaming agent, patch, suspensoid, solution and suppository (rectum and vagina) form existence or their pharmacy acceptable salt.
The oral preparations that contains active compound of the present invention can comprise any conventional oral form of using, and it comprises tablet, capsule, hypogloeeis form, lozenge, dragee and oral liquid, suspensoid or solution.Capsule can contain for example mixture of crystallization and Microcrystalline Cellulose, tinting material, gelatin, glue etc. of for example pharmaceutically acceptable starch of active compound and inert filler and/or thinner (for example corn, potato or tapioca (flour)), carbohydrate, artificial sweetening agent, powdered cellulose.Can be by conventional compacting; the method of wet granulation or dry granulation prepares useful tablet formulation and uses pharmaceutically acceptable thinner; tackiness agent; lubricant; disintegrating agent; suspension agent or stablizer include but is not limited to Magnesium Stearate; stearic acid; talcum powder; sodium lauryl sulphate; Microcrystalline Cellulose; calcium carboxymethylcellulose; polyvinylpyrrolidone; gelatin; alginic acid; gum arabic; xanthan gum; Sodium Citrate; composition silicate; lime carbonate; glycine; dextran; sucrose; sorbyl alcohol; Lin Suanergai; calcium sulfate; lactose; kaolin; mannitol; sodium-chlor; talcum powder; dry starch and powdered sugar.Can use standard delay or division of day and night delivery formulations at this oral preparations with the absorption that changes active compound.Can be from traditional material, comprise that the cocoa beans ester and the glycerine that add or do not add with the wax that changes the suppository fusing point prepare suppository formulations.Also can use for example polyoxyethylene glycol of various molecular weights of water soluble suppository bases.
People understand dosage, system and the mode of administration of these compounds will be according to the illness of being treated and individual and change and will determine scheme according to the judgement of the medical practitioner that participates in.Beginning gives one or more compound and increase dosage at this with low dosage and act as preferably up to meeting the requirements of.
The preparation process of following method explanation representative embodiment of the present invention.
Embodiment 1 benzo [b] thiophene-2-base-(phenyl)-methyl alcohol
Under-78 ℃, dry nitrogen atmosphere, n-Butyl Lithium (35ml, 2.5N hexane solution) is dropped to the benzo-thiophene of stirring, and (11.5g is in THF 85.6mmol) (300ml) solution.After 1 hour, add phenyl aldehyde (9.6ml, 94.4mmol) and remove cooling bath.After 30 minutes, add saturated aqueous ammonium chloride again, reaction mixture is allocated between water and the ether.Ether is mutually with salt water washing and concentrated.The solid that produces grinds and filters with sherwood oil, obtains the title compound (17.7g, 86%) of white solid: NMR (CDCl3): δ 7.78 (m, 1H, thiophene H), 7.68 (m, 1H, thiophene H), and 7.22-7.56 (m, 7H), (7.12 s, 1H, thiophene H), 6.12 (d, 1H, OH), 2.51 (d, 1H, CH).
Embodiment 2 (6-methoxyl group benzo [b] thiophene-2-base-(phenyl)-methyl alcohol
Under-78 ℃, dry nitrogen atmosphere, with n-Butyl Lithium (12.5ml, 2.5N hexane solution) drop to stirring 6-methoxyl group benzo-thiophene (5.0g, 30.4mmol, S.L.Graham etc., J.Med.Chem.1989,32, in THF 2548-2554) (70ml) solution.After 1 hour, and the adding phenyl aldehyde (3.42ml, 33.4mmol).After 45 minutes, add saturated aqueous ammonium chloride again, reaction mixture is allocated between water and the ether.Ether is mutually with the salt water washing and to wherein adding silica gel.Remove solvent, adsorptive through flash chromatography separate (elutriant: 9: 1 sherwood oils: ethyl acetate), obtain the title compound (5.5g, 66%) of white solid: mp 79-80:NMR (CDCl3): δ 7.55 (d, J=9Hz, 1H), d7.49 (ddd, J=7,1,1Hz, 2H), 7.39 (ddd, J=7,7,1Hz, 2H), 7.26 (m, 1H), 7.01 (s, 1H), 6.94 (d, J=8Hz, 1H), 6.09 (d, J=4Hz, 1H), 3.85 (s, 3H), 2.46 (d, J=4Hz, 1H); MS (EI): 270 (25%, MI).
Embodiment 3 benzos [b] thiophene-2-base-(3-methoxyl group-phenyl)-methyl alcohol
According to the method preparation of embodiment 1, use the meta-anisaldehyde 99 substituted benzaldehyde.White solid: mp 63-65 ℃; MS (+FAB): [M+] 270; The analytical calculation value of C16H14O2S: C, 71.08, H, 5.22, N, 0.00.Measured value: C, 71.07, H, 5.16, N, 0.13.
Embodiment 42-benzyl-benzo [b] thiophene
With trifluoroacetic acid (105ml) in 35 minutes, drop to stirring benzo [b] thiophene 2-base-(phenyl)-methyl alcohol (17.6g, 73.2mmol), (13.75g is 364mmol) and in the suspension of ether (1.3L) for sodium borohydride.Again after 5 minutes, add to reaction mixture in 10% aqueous sodium hydroxide solution (1.3L) and stirred 30 minutes.Separate each layer, ether is used salt solution (500ml) washing and dry (sal epsom) mutually.Concentrated ether obtains the title compound (15.2g, 92%) of white solid mutually: NMR (CDCl3): δ 7.73 (d, J=6Hz, 1, thiophene H), 7.65 (d, J=7Hz, 1H, thiophene H), 7.20-7.38 (m, 7H), 7.00 (s, 1H, thiophene H), 4.22 (s, 2H, CH2).
Embodiment 52-benzyl-6-methoxyl group-benzo [b] thiophene
According to the method for embodiment 4, by (6-methoxyl group-benzo [b] thiophene-2-base-(phenyl)-methyl alcohol (embodiment 2) preparation.White solid: mp 60-61 ℃; NMR (CDCl3): δ 7.53 (d, J=9Hz, 1H), d7.35-7.22 (m, 6H), 6.93 (dd, J=8,2Hz, 1H), 6.91 (d, J=1Hz, 1H), 4.19 (s, 2H), 3.84 (s, 3H); MS (EI): 254 (50%, MI); The analytical calculation value of C16H14OS: C, 75.56, H, 5.55, N, 0.00.Measured value: C, 75.62, H, 5.44, N, 0.02.
Embodiment 62-(3-methoxyl group-benzyl)-benzo [b] thiophene
According to the method for embodiment 4, by benzo [b] thiophene-2-base-(3-methoxyl group-phenyl)-methyl alcohol (embodiment 3) preparation.White solid: mp 74-75.5 ℃; MS (+FAB): [M+] 254; The analytical calculation value of C16H14OS: C, 75.56, H, 5.55, N, 0.00.Measured value: C, 75.85, H, 5.48, N, 0.01.
Embodiment 7 (2-benzyl-benzo [b] thiene-3-yl-)-(4-methoxyl group-phenyl)-ketone
Under dry nitrogen atmosphere; with tin tetrachloride (9.0ml; 76.91mmol) in 25 minutes, drop to 2-benzyl-benzo [b] thiophene (14.87g, 96.79mmol), (11.75g is 68.87mmol) and in the stirred solution of dithiocarbonic anhydride (75ml) to anisoyl chlorine.After 6 hours, reaction mixture is added in the water, use dichloromethane extraction.Dichloromethane extraction liquid saturated sodium bicarbonate aqueous solution and salt water washing.Remove solvent and the solid that produces is ground with sherwood oil, obtain the title compound (20.2g, 85%) of white solid: mp 135-137 ℃: NMR (CDCl3): δ 7.85 (dm, J=9Hz, 2H), 7.73 (dm, 1H), 7.42 (dm, 1H), and 7.18-7.30 (m, 7H), 6.93 (dm, J=9Hz, 2H), 4.21 (s, 2H), CH2), 3.88 (s, 3H, CH3): IR (KBr, cm-1): 1650; MS (EI): 358 (100%, MI), 343 (15%), 327 (75%); The analytical calculation value of C23H18O2S: C, 77.07, H, 5.06, N, 0.00.Measured value: C, 76.91, H, 5.02, N ,-0.12.
Embodiment 8 (2-benzyl-6-methoxyl group-benzo [b] thiene-3-yl-)-(4-methoxyl group-phenyl)-ketone
Under dry nitrogen atmosphere; with tin tetrachloride (2.0ml; 17.09mmol) in 10 minutes, drop to 2-benzyl-6-methoxyl group benzo [b] thiophene (2.71g, 10.65mmol), (1.93g is 11.29mmol) and in-78 ℃ of stirred solutions of dithiocarbonic anhydride (41ml) to anisoyl chlorine.In-78 ℃ after 1 hour, with the slow ground temperature of reaction mixture to room temperature and stirred 16 hours.Reaction mixture is added in the water, use extracted with diethyl ether.Ether is mutually with the salt water washing and to wherein adding silica gel.Remove solvent and adsorptive is separated (elutriant: 9: 1 sherwood oils: ethyl acetate), obtain the title compound (2.42g, 58%) of white solid: mp 110-112 ℃: NMR (CDCl3): δ 7.84 (d, J=9Hz through flash chromatography, 2H), and 7.31-7.18 (m, 7H), 7.92 (d, J=9Hz, 2H), 6.97 (dd, J=9,2Hz, 1H), 4.17 (s, 2H), 3.88 (s, 3H), 3.883 (s, 3H): MS (FAB+): 389 (80%, M+H); The analytical calculation value of C24H20O3S: C, 74.20, H, 5.19, N, 0.00.Measured value: C, 74.94, H, 5.10, N, 0.03.
Embodiment 94-bromo-2,6-di-isopropyl phenylmethylether
This is Schuster, Ingeborg I.; Parvez, Masood; Freyer, Alan, J.J.Org.Chem.1988, the amending method of 53,5819 method.(6.3ml, acetate 119mmol) (40ml) drips of solution adds to 2, in the stirred solution under the room temperature of the acetate (280ml) of 6-diisopropanol (20ml, 97.1mmol 90% technical grade) with bromine.After 6 hours, add entry, the mixture extracted with diethyl ether.Ether is dry mutually and concentrated, and resistates separates (sherwood oil: elutriant), obtain the 4-bromo-2 of red oil, 6-diisopropanol (16.2g, 65%) through flash chromatography.This oily matter is dissolved among the DMF (50ml), to wherein add methyl iodide (11.7ml, 189mmol) and salt of wormwood (26.3g, 117ml).Reaction mixture was stirred 5 hours and dilute with water.This mixture extracted with diethyl ether, and, concentrate and separate (sherwood oil: elutriant), obtain the title compound (15.4g of colorless oil through flash chromatography with the ether extraction liquid drying, 90%): NMR (CDCl3): δ 7.17 (s, 2H), 3.70 (s, 3H), 3.29 (septet, 1H), 1.20 (d, 12H).
Embodiment 103,5-di-isopropyl, 4-methoxybenzoic acid
This is Schuster, Ingeborg I.; Parvez, Masood; Freyer, Alan, J.J.Org.Chem.1988, the amending method of 53,5819 method.(2.5N hexane solution, 13.0ml 32.5mmol) dropped to 4-bromo-2 in 20 minutes, (8.0g is in-78 ℃ of stirred solutions of THF 29.5mmol) (185ml) for 6-di-isopropyl phenylmethylether with n-Butyl Lithium.In-78 ℃ after 2 hours, reaction mixture is added in the dry ice that grinds very carefully carefully.The suspension that produces was stirred under room temperature 20 minutes, and add in the water carefully.Water is with the 10%HCl acidified aqueous solution and use extracted with diethyl ether.Ether extraction liquid is dry and concentrated.Solidify when the oily matter that produces leaves standstill, this solid is ground with sherwood oil, obtain the title compound (5.38g, 77%) of white solid: NMR (CDCl3): δ 7.87 (s, 2H), 3.76 (s, 3H), 3.35 (septet, 1H), 1.25 (d, 12H).
Embodiment 11 (2-benzyl-benzo [b] thiene-3-yl-)-(3,5-di-isopropyl-4-methoxyl group-phenyl)-ketone
Under dry nitrogen atmosphere, 1 DMF is added to oxalyl chloride, and (1.4ml, 16.2mmol), 3, (4.0g is in dichloromethane solution 14.7mmol) for 5-di-isopropyl-4-methoxybenzoic acid.After 4 hours, remove solvent and the solid that produces is ground with sherwood oil, and vacuum-drying.In this solid, add 2-benzyl-benzo [b] thiophene (3.32g, 13.4mmol) and methylene dichloride (75ml).The solution that produces is stirred under dry nitrogen atmosphere and be cooled to-78 ℃.In 20 minutes, drip tin tetrachloride (3.44ml, 29.48mmol).Reaction mixture temperature to room temperature and stirring spent the night.Reaction mixture is added in the water, use extracted with diethyl ether.Ether phase water and salt water washing.Add silica gel and remove solvent.Adsorptive is separated (gradient, sherwood oil to 95: 5 sherwood oils: ethyl acetate) through flash chromatography.Remove solvent, solid grinds with ether, obtains the title compound (3.68g, 62%) of white solid: mp 124-125 ℃: NMR (CDCl3): δ 7.75 (ddd, J=8,2,1Hz, 1H), 7.64 (s, 2H), 7.48 (ddd, J=8,2,1,1H), 7.30-7.19 (m, 7H), 4.22 (s, 2H), 3.80 (s, 3H), 3.35 (septet, J=7Hz, 2H), 1.19 (d, J=7Hz, 12H); MS (+FAB): 443 (100%, M+H); The analytical calculation value of C29H30O2S: C, 78.69, H, 6.83, N, 0.00.Measured value: C, 78.57, H, 6.88, N, 0.14.
Embodiment 12 (2-benzyl-benzo [b] thiene-3-yl-)-(3-methoxyl group-phenyl)-ketone
According to the method for embodiment 8, by 2-benzyl-benzo [b] thiophene and an anisoyl chlorine preparation.White solid: MS (EI): [M+], 358.
Embodiment 13 (2-benzyl-benzo [b] thiene-3-yl-)-(3,4-dimethoxy-phenyl)-ketone
According to the method for embodiment 8, by 2-benzyl-benzo [b] thiophene and 3, the preparation of 4-dimethoxy-benzoyl chloride.White solid: MS (EI): [M+], 388.
Embodiment 144-benzo [b] naphtho-[2,3-d] thiophene-11-base-phenol
Under-78 ℃, dry nitrogen atmosphere, dichloromethane solution (130ml with the 1.0M boron tribromide, (14.5g is in the stirred solution of methylene dichloride 40.45mmol) (130ml) 130mmol) slowly to add to (2-benzyl-benzo [b] thiene-3-yl-)-(4-methoxyl group-phenyl)-ketone.Allow solution temperature to room temperature and stirring spend the night.The quencher of reaction mixture water, and be allocated between water and the methylene dichloride.With silica gel add methylene dichloride mutually in, and remove solvent.Adsorptive separates (elutriant: 4: 1 sherwood oils: ethyl acetate), obtain white solid (9.75g) through flash chromatography.With this solid recrystallize from acetate, obtain canescence spicule (8.78,56%): mp:112-116 ℃; NMR (CDCl3): δ 8.33 (s, 1H), 7.94 (dt, J=8Hz, 1H), 7.77 (dm, J=8Hz, 1H), 7.64 (dm, J=8Hz, 1H), 7.52 (ddd, J=8,7,1HZ, 1H), 7.37 (m, 2H), 7.29 (d, J=9Hz, 2H), 7.11 (d, J=9Hz, 2H), 7.08 (m, 1H), 6.85 (dm, J=8Hz, 1H), 2.11 (s, 3H, acetate CH3); MS (EI): 326 (100%, MI); The analytical calculation value of C22H14OSC2H4O2: C, 74.59, H, 4.69, N, 0.00.Measured value: C, 74.40, H, 4.59, N, 0.15.
Embodiment 1511-(4-hydroxyl-phenyl)-benzo [b] naphtho-[2,3-d] benzene sulphur-3-phenol
Under-78 ℃, dry nitrogen atmosphere, with boron tribromide (5ml, 52.9mmol) (2-benzyl-6-methoxyl group-benzo [b] thiene-3-yl-)-(2.30g is in the stirred solution of methylene dichloride 5.92mmol) (30ml) for (4-methoxyl group-phenyl)-ketone in slow adding.Allow the solution temperature to room temperature and stirred 4 hours.The quencher of reaction mixture water, and be allocated between water and the ether.With silica gel add ether mutually in, and remove solvent.Adsorptive separates (elutriant: 7: 3 sherwood oils: ethyl acetate), obtain white solid (2.08g, 96%): mp:197-199 ℃ through flash chromatography; NMR (CDCl 3): δ 8.28 (s, 1H), 7.92 (d, J=8Hz, 1H), 7.59 (dm, J=8Hz, 1H), 7.50 (ddd, J=8,7,1Hz, 1H), and 7.39-7.25 (m, 5H), 7.21 (d, J=2Hz, 1H), 7.11 (d, J=9Hz, 2H), 6.69 (d, J=9Hz, 1H), 6.57 (dd, J=9,2Hz, 1H), 5.03 (s, 1H), 4.94 (s, 1H); MS (FAB+): 343 (15%, M+H); The analytical calculation value of C22H14O2S: C, 77.17, H, 4.12, N, 0.00.Measured value: C, 76.74, H, 4.04, N, 0.02.
Embodiment 164-(6-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-di-isopropyl-phenol
Under-78 ℃, dry nitrogen atmosphere, with pure boron tribromide (4.3ml, 45.2mmol) drop to that (2-benzyl-benzo [b] thiene-3-yl-)-(3.57g is in the stirred suspension of methylene dichloride 8.07mmol) (30ml) for (3,5-di-isopropyl-4-methoxyl group-phenyl)-ketone.Allow the solution temperature to room temperature and stirred 1.5 hours.Reaction mixture is cooled to 0 ℃, the careful quencher of water.Reaction mixture is allocated between water and the ether.Ether phase water and salt water washing.With silica gel add ether mutually in, and remove solvent.Adsorptive separates (elutriant: 99: 1 to 97: 1 sherwood oils: ethyl acetate), obtain white solid (1.46g, 44%): NMR (CDCl through flash chromatography 3): δ 8.33 (s, 1H), 7.95 (ddd, J=8,1,1,1H), 7.77 (ddd, J=8,1,1Hz, 1H), 7.73 (ddd, J=8,1,1Hz, 1H), 7.53 (ddd, J=8,8,1,1H), 7.40 (ddd, J=8,8,1Hz, 1H), 7.34 (ddd, J=8,8,1Hz, 1H), 7.10 (s, 2H), 7.04 (ddd, J=8,8,1Hz, 1H), 6.75 (ddd, J=8,1,1Hz, 1H), 5.01 (s, 1H), 3.31 (septet, J=7Hz, 2H), 1.29 (s, J=7Hz, 6H), 1.27 (s, J=7Hz, 6H); MS (+FAB): 411 (100%, M+H); The analytical calculation value of C28H26OS: C, 81.91, H, 6.38, N, 0.00.Measured value: C, 81.10, H, 6.54, N, 0.40.
Embodiment 17 3-benzo [b] naphtho-[2,3-d] thiophene-11-base-phenol
According to the method for embodiment 15, prepare by (2-benzyl-benzo [b] thiene-3-yl-)-(3-methoxyl group-phenyl)-ketone (embodiment 12).White solid: mp 92-94 ℃: MS (EI): [M+], 326; The analytical calculation value of C22H14OS: C, 80.95, H, 4.32, N, 0.00.Measured value: C, 80.01, H, 4.18, N, 0.04.
Embodiment 184-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1, the 2-diphenol
According to the method for embodiment 15, prepare by (2-benzyl-benzo [b] thiene-3-yl-)-(3,4-dimethoxy-phenyl)-ketone (embodiment 13).White solid: mp 188-189 ℃: MS (EI): [M+], 342; The analytical calculation value of C22H14O2S: C, 77.17, H, 4.12, N, 0.00.Measured value: C, 76.47, H, 3.85, N, 0.00.
Embodiment 198-methoxyl group-11-(4-methoxyl group-phenyl)-benzo [b] naphtho-[2,3-d] thiophene
In 24 minutes; to the 2-of cold (78 ℃) (3-methoxy-benzyl)-benzo [b] thiophene (2.10g, 8.26mmol) and to anisoyl chlorine (1.48g drips tin chloride IV (2.90ml in anhydrous methylene chloride 8.67mmoL) (31ml) solution; 24.8mmol, 3eq).Stirring is spent the night and after stirring 7 hours under the room temperature, reaction mixture is inclined to water (175ml) in warm the dry ice bath, and (2 * 300ml) extract organism with ether.Extraction liquid is merged, use the salt water washing.Add silica gel and remove solvent.Adsorptive separates (97/3 petrol ether/ethyl acetate) through flash chromatography, obtains the title compound (1.92g, 63%) of white solid: mp 158-159 ℃; MS (+FAB): [M+] 370; The analytical calculation value of C24H18O2S: C, 77.81, H, 4.90, N, 0.00.Measured value: C, 78.00, H, 4.76, N, 0.03.
Embodiment 2011-(4-hydroxyl-phenyl)-benzo [b] naphtho-[2,3-d] benzene sulphur-8-phenol
In 18 minutes, to the 8-methoxyl group-11-of cold (75 ℃) (4-methoxyl group-phenyl)-benzo [b] naphtho-[2,3-d] thiophene (1.92g, 5.18mmol) anhydrous methylene chloride solution in drip boron tribromide (1M dichloromethane solution, 6.74ml, 6.74mmol, 1.3eq).Under cooling, stirred 3.5 hours and in stir about under the room temperature after 19 hours, reaction mixture water (100ml) quencher, with methylene dichloride (50ml) dilution, organism is with ether (1 * 100ml, 1 * 75ml) extraction.Extraction liquid is merged, mix with the salt water washing and with silica gel.Remove solvent, adsorptive through flash chromatography separate (74/26 petrol ether/ethyl acetate) and with 92 ℃ of dried overnight, obtain the title compound (1.07g, 91%) of pale solid: mp 233-235 ℃; NMR (DMSO-d6): δ 9.91 (wide s, 1H), 9.77 (wide s, 1H), 8.30 (s, 1H), 7.88 (d, J=8Hz, 1H), 7.40 (d, J=8Hz, 1H), 7.35 (ddd, J=8,8,1Hz, 1H), 7.23 (d, J=2Hz, 1H), 7.15 (d, J=8Hz, 2H), 7.09 (ddd, J=8,8,1Hz, 1H), 7.06-7.00 (multiplet, in 7.05 contain one bimodal, J=8Hz, 3H), 6.71 (d, J=8Hz, 1H); MS (+FAB): [M+] 343; The analytical calculation value of C22H14O2S: C, 77.17, H, 4.12, N, 0.00.Measured value: C, 76.43, H, 3.82, N, 0.01.
Embodiment 212,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
Under room temperature, (3.1ml, glacial acetic acid 60.17mmol) (30ml) solution added 4-benzo [b] naphtho-[2,3-d] thiophene-11-base-phenol (5.0g in 5 minutes with bromine, 15.32mmol) and potassium acetate (15.0g is in the stirring turbid solution of acetate 153mmol) (92ml).Notice heat release, produce yellow mercury oxide.After 45 minutes, reaction mixture is added in the water (1L), add solid sulfur sodium thiosulfate (2g), suspension was stirred 5 minutes.Leach solid and water (1L), sherwood oil (2 * 300ml), 3: 1 sherwood oils: ether (3 * 50ml) and sherwood oil (2 * 300ml) washing and vacuum-dryings obtain tawny solid (7.00g).Crystallization goes out additional quantity from mother liquor, and it is added in the total amount (tawny solid, 8.31g, 96%).Purity in this stage product is 95%, yet the product of recrystallize from acetate can be further purified, and obtains the title compound of white solid: mp 226.5-227 ℃: NMR (CDCl3): δ 8.35 (ddd, J=8,1,1Hz, 1H), 7.84 (ddd, J=8,1,1Hz, 1H), 7.67 (ddd, J=8,7,1Hz, 1H), 7.60 (ddd, J=8,1,1Hz, 1H), 7.55 (s, 2H), 7.49 (ddd, J=8,7,1Hz, 1H), 7.45 (ddd, J=8,7,1Hz, 1H), 7.21 (ddd, J=8,7,1Hz, 1H), 6.87 (ddd, J=8,1,1Hz, 1H), 6.19 (s, 1H, OH); MS (APCI): [M-H]-, 3 bromine isotope figures, 559 (25%), 561 (75%), 563 (100%), 565 (45%); The analytical calculation value of C22H11Br3OS: C, 46.92, H, 1.97, N, 0.00.Measured value: C, 46.67, H, 1.85, N, 0.03.
Embodiment 2211-(3,5-two bromo-4-methoxyl group-phenyl)-benzo [b] naphtho-[2,3-d] thiophene
Under room temperature, dry nitrogen atmosphere, (0.383ml 6.16mmol) adds to 2 with methyl iodide, 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (2.13g, 4.4mmol), (0.669g is 4.34mmol) and in the stirred suspension of DMF (15ml) for salt of wormwood.After 3 hours, the reaction mixture dilute with water leaches the solid of generation and washes with water.Be dissolved in solid in the methylene dichloride and add silica gel (40ml).Remove solvent, adsorptive separates (90: 10 sherwood oils: methylene dichloride), obtain the title compound (2.0g, 91%) of white solid: mp238.5-239.5 ℃: NMR (CDCl3): δ 8.36 (ddd, J=8 through flash chromatography, 1,1Hz, 1H), 7.84 (ddd, J=8,1,1Hz, 1H), 7.67 (ddd, J=8,7,1Hz, 1H), 7.60 (s, 2H), 7.58 (ddd, J=8,1,1Hz, 1H), 7.50 (ddd, J=8,7,1Hz, 1H), 7.45 (ddd, J=8,7,1Hz, 1H), 7.20 (ddd, J=8,7,1Hz, 1H), 6.80 (ddd, J=8,1,1Hz, 1H), 4.11 (s, 3H, CH3); MS (EI): [M+], 3 bromine isotope figures, 574 (35%), 576 (95%), 578 (100%), 580 (45%); The analytical calculation value of C23H13Br3OS: C, 47.87, H, 2.27, N, 0.00.Measured value: C, 47.73, H, 1.88, N, 0.03.
Embodiment 2311-(4-methoxyl group-phenyl)-benzo [b] naphtho-[2,3-d] thiophene
According to the method for embodiment 22, prepare by benzo [b] naphtho-[2,3-d] thiophene-11 bases-phenol (embodiment 14).White solid (0.516g, 50%): mp:220-221 ℃; NMR (DMSO-d6): δ 8.60 (s, 1H), 8.04 (d, J=8Hz, 1H), 7.96 (d, J=8Hz, 1H), 7.57 (ddd, J=8,7,1Hz, 1H), 7.50 (ddd, J=8,1,1Hz, 1H), 7.46-7.40 (m, 3H), 7.33 (d, J=9Hz, 2H), 7.24 (d, J=9Hz, 2H), 7.14 (ddd, J=8,7,1Hz, 1H), 6.75 (d, J=8Hz, 1H), 3.33 (s, 3H); MS (EI): 340 (100%, MI); The analytical calculation value of C23H16OS: C, 81.14, H, 4.74, N, 0.00.Measured value: C, 81.11, H, 4.57, N, 0.14.
Embodiment 2411-(4-methoxyl group-3,5-dimethyl-phenyl)-6-methyl-benzo [b] naphtho-[2,3-d] thiophene
Under 100 ℃, argon gas, with 6-bromo-11-(3,5-two bromo-4-methoxyl group-phenyl)-benzo [b] naphtho-[2,3-d] thiophene (1.0g, 1.733mmol), tin tetramethide (2.0ml, 14.38mmol), two (triphenylphosphine) Palladous chloride II (100mg, 8mol%) and the suspension of DMF (8ml) the sealing pressurized vessel in the heating 17 hours (dissolving after 30 minutes).Reaction mixture is added in the entry water extracted with diethyl ether.With silica gel add ether mutually in and remove ether.Adsorptive separates (96: 4 sherwood oils: ethyl acetate), obtain the title compound (0.63g, 86%) of white solid: mp154-156 ℃: NMR (CDCl3): δ 8.16 (ddd, J=8,1 through flash chromatography, 1Hz, 1H), 7.80 (dd, J=8,1Hz, 1H), 7.70 (dd, J=8,1Hz, 1H), 7.57 (ddd, J=8,7,1Hz, 1H), 7.41 (ddd, J=8,7,1Hz, 1H), 7.35 (ddd, J=8,8,1Hz, 1H), 7.07 (ddd, J=8,7,1Hz, 1H), 7.04 (s, 2H), 6.79 (dd, J=8,1Hz, 1H), 3.92 (s, 3H), 2.97 (s, 3H), 2.39 (s, 6H); MS (EI): 382 (100%, MI); The analytical calculation value of C26H22OS: C, 81.64, H, 5.80, N, 0.00.Measured value: C, 81.30, H, 5.99, N, 0.38.
Embodiment 252,6-dimethyl-4-(6-methyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
With 11-(4-methoxyl group-3,5-dimethyl-phenyl)-6-methyl-benzo [b] naphtho-[2,3-d] thiophene (0.55g, 1.44mmol) and pyridine hydrochloride (1.0g, mixture 8.64mmol) heated 1.25 hours in 240 ℃ of oil baths.During this period, and the pyridine hydrochloride of adding additional quantity (1.0g, 8.64mmol).Reaction mixture is cooled to room temperature, and is allocated between rare HCl and the ether.With silica gel add ether mutually in and remove solvent.Adsorptive separates (9: 1 sherwood oils: ethyl acetate), obtain the title compound (340mg) of yellow solid through flash chromatography.With this solid recrystallize from acetate, obtain the title compound (0.215g, 41%) of light yellow solid; Mp 147-149 ℃: NMR (CDCl3): δ 8.15 (ddd, J=8,1,1Hz, 1H), 7.80 (ddd, J=8,1,1Hz, 1H), 7.71 (ddd, J=8,1,1Hz, 1H), 7.56 (ddd, J=8,7,1Hz, 1H), 7.39 (ddd, J=8,7,1Hz, 1H), 7.35 (ddd, J=8,8,1Hz, 1H), 7.09 (ddd, J=8,7,1Hz, 1H), 7.01 (s, 2H), 6.79 (ddd, J=8,1,1Hz, 1H), 2.96 (s, 3H), 2.36 (s, 6H); MS (EI): 368 (100%, MI); The analytical calculation value of C25H20OS: C, 81.49, H, 5.47, N, 0.00.Measured value: C, 81.62, H, 5.32, N ,-0.03.
Embodiment 264-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two iodo-phenol
With iodine (4.5g, 17.6mmol) in 1 hour, drop to 0 ℃ of following 4-benzo [b] naphtho-[2,3-d] thiophene-11-base-phenol (2.3ml, 7.05mmol), sodium hydroxide (97%, 0.581g, 14.1mmol) methyl alcohol (46ml) stirred solution in, and mixture stirred 1 hour in 0 ℃, under room temperature, stirred 6 hours.Reaction mixture water (200ml) dilution, (2 * 200ml) extract aqueous mixture with ether.Ether extraction liquid is with 5% sodium bisulfite and water, with salt solution and anhydrous magnesium sulfate drying.Add silica gel (50ml).Remove solvent, adsorptive separates (elutriant: 8: 2 sherwood oils: methylene dichloride), obtain the title compound (2.2g, 54%) of white solid: mp 213-214 ℃ through flash chromatography; MS (FAB): [M-H]-, 576.8; The analytical calculation value of C22H12I2OS: C, 45.70, H, 2.09, N, 0.00.Measured value: C, 45.82, H, 2.07, N, 0.30.
Embodiment 274-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-iodo-phenol
With iodine (4.5g, 17.6mmol) in 1 hour, drop to 0 ℃ of following 4-benzo [b] naphtho-[2,3-d] thiophene-11-base-phenol (2.3ml, 7.05mmol), sodium hydroxide (97%, 0.581g, 14.1mmol) methyl alcohol (46ml) stirred solution in, and mixture stirred 1 hour in 0 ℃, under room temperature, stirred 6 hours.Reaction mixture water (200ml) dilution, (2 * 200ml) extract aqueous mixture with ether.Ether extraction liquid is with 5% sodium bisulfite and water, with salt solution and anhydrous magnesium sulfate drying.Add silica gel (50ml).Remove solvent, adsorptive separates (elutriant: 8: 2 sherwood oils: methylene dichloride), obtain the title compound (0.624g, 20%) of white solid: mp 125-128 ℃ through flash chromatography; MS (EI): [M+], 452; The analytical calculation value of C22H13IOS: C, 58.42, H, 2.90, N, 0.00.Measured value: C, 58.46, H, 3.00, N, 0.09.
Embodiment 2811-(4-methoxyl group-3,5-two iodo-phenyl)-benzo [b] naphtho-[2,3-d] thiophene
According to the method for embodiment 22, by 4-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two iodo-phenol (embodiment 26) preparation.White solid: mp 228-230 ℃: MS (EI): [M+], 592; The analytical calculation value of C23H14I2OS: C, 46.65, H, 2.38, N, 0.00.Measured value: C, 45.95, H, 2.25, N, 0.19.
Embodiment 2911-(3-iodo-4-methoxyl group-phenyl)-benzo [b] naphtho-[2,3-d] thiophene
According to the method for embodiment 22, by 4-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-iodo-phenol (embodiment 27) preparation.White solid: mp 274-275 ℃: MS (EI): [M+], 466 (100%, MI); The analytical calculation value of C23H15IOS: C, 59.24, H, 3.24, N, 0.00.Measured value: C, 58.53, H, 3.11, N, 0.11.
Embodiment 305-benzo [b] naphtho-[2,3-d] thiophene-11-base-2-methoxyl group-m-dicyanobenzene
Under the dry nitrogen atmosphere, with 11-(3,5-two iodo-4-methoxyl group-phenyl)-benzo [b] naphtho-[2,3-d] thiophene (4.55g, 7.68mmol) and cupric cyanide (I) (3.13g, 38.4mmol) suspension in 1-Methyl-2-Pyrrolidone (18ml) heats in 150 ℃ of oil baths.After 1 hour, solution is added in the entry (200ml), dilute with 10% aqueous hydrochloric acid.Leach solid and through flash chromatography (silica gel: elutriant: methylene dichloride), obtain the title compound (2.47g, 82%) of yellow solid: mp 214-215 ℃; MS (EI): [M+], 390 (100%, MI); The analytical calculation value of C25H14N2OS: C, 76.90, H, 3.61, N, 7.17.Measured value: C, 76.48, H, 3.46, N, 7.17.
Embodiment 315-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-methoxyl group-cyanobenzene
According to the method for embodiment 30, by 11-(3-iodo-4-methoxyl group-phenyl)-benzo [b] naphtho-[2,3-d] thiophene (embodiment 29) preparation.White solid: mp 230-232 ℃: MS (EI): [M+], 365 (100%, MI); The analytical calculation value of C24H15NOS: C, 78.88, H, 4.41, N, 3.83.Measured value: C, 77.61, H, 4.23, N, 4.10.
Embodiment 325-benzo [b] naphtho-[2,3-d] thiophene-11-base-2-hydroxyl-m-dicyanobenzene
According to the method for embodiment 20, by 5-benzo [b] naphtho-[2,3-d] thiophene-11-base-2-methoxyl group-m-dicyanobenzene (embodiment 30) preparation.White solid: mp 274-276 ℃: MS (EI): [M+], 376 (80%, MI); The analytical calculation value of C24H12N2OS: C, 76.58, H, 3.21, N, 7.44.Measured value: C, 76.20, H, 3.19, N, 7.35.
Embodiment 33 5-benzo [b] naphtho-[2,3-d] thiophene-11-base-2-hydroxyl-cyanobenzenes
According to the method for embodiment 20, by 5-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-methoxyl group-cyanobenzene (embodiment 31) preparation.White solid: mp 231-232 ℃: MS (EI): [M+], 351 (100%, MI); The analytical calculation value of C23H13NOS: C, 78.61, H, 3.73, N, 3.99.Measured value: C, 78.27, H, 3.59, N, 3.89.
Embodiment 344-(benzo [b] naphtho-[2,3-d] thiophene 11-base-phenol)-acetic ester
With diacetyl oxide (0.62ml, 6.57mmol) add to 0 ℃, (2.0g is 6.13mmol) in the stirred solution in pyridine (8ml) for 4-benzo [b] naphtho-[2,3-d] thiophene-11-base-phenol.After 7 hours reaction mixture is added in the water, leach the solid of generation and wash with water, vacuum-drying obtains the title compound (2.23g, 99%) of white solid: mp:160-161 ℃; NMR (CDCl3): δ 8.36 (s, 1H), 795 (d, J=8Hz, 1H), 7.78 (d, J=8Hz, 1H), 7.61 (d, J=8Hz, 1H), 7.53 (ddd, J=8,7,1Hz, 1H), 7.47-7.33 (m, 6H), 7.08 (ddd, J=8,7,1Hz, 1H), 6.76 (d, J=8Hz, 1H), 2.42 (s, 3H, CH3); MS (EI): 368 (100%, MI); The analytical calculation value of C24H16O2S: C, 78.24, H, 4.38, N, 0.00.Measured value: C, 77.99, H, 4.29, N, 0.02.
Embodiment 35 acetate 3-benzo [b] naphtho-[2,3-d] thiophene-11-base-phenyl esters
According to the method for embodiment 34, by 3-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 17) preparation.White solid: mp 122-124 ℃: MS (EI): [M+], 368; The analytical calculation value of C24H16O2S: C, 78.24, H, 4.38, N, 0.00.Measured value: C, 77.47, H, 4.19, N, 0.27.
Embodiment 36 acetate 2-acetoxyl groups-4-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester
According to the method for embodiment 34, by 4-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1,2-diphenol (embodiment 18) preparation.White solid: mp 179-180 ℃: MS (EI): [M+], 426; The analytical calculation value of C26H18O4S: C, 73.22, H, 4.25, N, 0.00.Measured value: C, 73.17, H, 4.30, N, 0.12.
Embodiment 374-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-base-phenol)-acetate (ester)
With bromine (0.35ml, 6.63mmol) methylene dichloride (10ml) solution in 15 minutes, drop to-20 ℃, 4-(benzo [b] naphtho-[2 that stirs, 3-d] thiophene-11-base-phenol) (2.22g is in methylene dichloride 6.03mmol) (45ml) solution for acetate (ester).With solution stirring 1.5 hours, use rare hypo solution quencher then.Remove organic solvent, add entry and leach the solid of generation, wash with water, grind with sherwood oil, vacuum-drying obtains the title compound (2.60,96%) of white solid: mp:204-205 ℃; NMR (CDCl3): δ 8.35 (ddd, J=8,1,1Hz, 1H), 7.81 (ddd, J=8,1,1Hz, 1H), and 7.68-7.61 (m, 2H), 7.47-7.36 (m, 6H), 7.08 (ddd, J=8,8,1Hz, 1H), 6.69 (ddd, J=8,1,1Hz, 1H), 2.42 (s, 3H, CH3); MS (EI): [M+], 1 bromine isotope figure, 446 (60%, MI), 448 (65%, MI), 404 (100%), 406 (95%); The analytical calculation value of C24H15BrO2S: C, 64.44, H, 3.38, N, 0.00.Measured value: C, 64.18, H, 3.34, N ,-0.03.
Embodiment 38 acetate 3-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester
According to the method for embodiment 37, by acetate 3-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester (embodiment 35) preparation.White solid: mp 74-76 ℃: MS (EI): [M+], 1 bromine isotope figure, 446,448; The analytical calculation value of C24H15BrO2S: C, 64.44, H, 3.38, N, 0.00.Measured value: C, 63.77, H, 3.08, N, 0.12.
Embodiment 39 acetate 2-acetoxyl group-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester
According to the method for embodiment 37, by acetate 2-acetoxyl group-4-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester (embodiment 36) preparation.White solid: mp 178-179 ℃: MS (EI): [M+], 1 bromine isotope figure, 504,506; The analytical calculation value of C26H17BrO4S: C, 61.79, H, 3.39, N, 0.00.Measured value: C, 61.37, H, 3.32, N, 0.11.
Embodiment 404-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-di-isopropyl-phenol
Under-20 ℃, dry nitrogen atmosphere, with bromine (0.185ml, 3.50mmol) methylene dichloride (7ml) solution in 40 minutes, drop to 4-(6-benzo [b] naphtho-[2 that under lucifuge, stirs, 3-d] thiophene-11-yl)-2, (1.31g is in methylene dichloride 3.18mmol) (26ml) solution for 6-di-isopropyl-phenol.After 15 minutes, add rare sodium thiosulfate solution, and reaction mixture is allocated between water and the ether.Ether obtains the title compound (1.65g, 100%) of white solid: mp:189-190 ℃ mutually with salt water washing and concentrated; NMR (CDCl3): δ 8.35 (ddd, J=8,1,1,1H), 7.80 (ddd, J=8,1,1Hz, 1H), 7.74 (ddd, J=8,1,1Hz, 1H), 7.65 (ddd, J=8,8,1,1H), 7.45 (ddd, J=8,8,1Hz, 1H), 7.37 (ddd, J=8,8,1Hz, 1H), 7.08 (s, 2H), 7.06 (ddd, J=8,8,1Hz, 1H), 6.68 (ddd, J=8,1,1Hz, 1H), 5.03 (s, 1H), 3.31 (septets, J=7Hz, 2H), 1.29 (d, J=7Hz, 6H), 1.26 (d, J=7Hz, 6H); MS (EI): 488 (90%); 490 (100); The analytical calculation value of C28H25BrOS: C, 68.71, H, 5.15, N, 0.00.Measured value: C, 67.74, H, 5.02, N, 0.07.
Embodiment 414-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
(6.0ml, (2.60g is 5.81mmol) in the suspension in THF (20ml)/methane (15ml) 6.0mmol) to add to 4-(6-bromo-benzo [b] naphtho-[2, the 3-d] thiophene-11-phenol) acetate (ester) that stirs under the room temperature with aqueous sodium hydroxide solution.Dissolve immediately, and reaction mixture becomes green.After 1 hour, remove organic solvent, add entry, reaction mixture 10%HCl acidifying washes the solid of generation with water, with sherwood oil grinding, vacuum-drying then, obtains the title compound (2.18g, 93%) of white solid.Part solid (0.5g) from acetic acid/water and hexanaphthene/acetonitrile recrystallize: mp:211-213 ℃; NMR (CDCl3): δ 8.34 (ddd, J=8,1,1Hz, 1H), 7.80 (ddd, J=8,1,1Hz, 1H), 7.67-7.62 (m, 2H), 7.43 (ddd, J=8,8,1Hz, 1H), 7.39 (ddd, J=8,8,1Hz, 1H), 7.27 (d, J=9Hz, 2H), 7.12 (d, J=9Hz, 2H), 7.11 (m, 1H), 6.78 (ddd, J=8,1,1Hz, 1H), 4.99 (s, 1H, OH); MS (EI): [M+], 1 bromine isotope figure, 404 (100%, MI), 406 (96%, MI); The analytical calculation value of C22H13BrOS: C, 65.19, H, 3.23, N, 0.00.Measured value: C, 64.87, H, 3.00, N, 0.03.
Embodiment 423-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
According to the method for embodiment 41, by acetate 3-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester (embodiment 38) preparation.White solid: mp 110-111 ℃: NMR (CDCl3): δ 8.35 (dd, J=8,1Hz, 1H), 7.81 (d, J=8Hz, 1H), 7.67-7.63 (m, 2H), 7.53 (dd, J=8,7Hz, 1H), 7.44 (ddd, J=8,7,1Hz, 1H), 7.39 (ddd, J=8,7,1Hz, 1H), 7.13-7.09 (m, 2H), 7.00 (dd, J=8,1Hz, 1H), 6.88 (dd, J=1,1Hz, 1H), 6.78 (dd, J=8,1Hz, 1H), 4.99 (s, 1H, OH); MS (EI): [M+], 1 bromine isotope figure, 404 (95%), 406 (100%); The analytical calculation value of C22H13BrOS: C, 65.19, H, 3.23, N, 0.00.Measured value: C, 64.85, H, 3.51, N, 0.43.
Embodiment 434-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1, the 2-diphenol
According to the method for embodiment 41, by acetate 2-acetoxyl group-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester (embodiment 39) preparation.White solid: mp 181-182 ℃: MS (EI): [M+], 1 bromine isotope figure, 420 (95%); The analytical calculation value of C22H13BrO2S: C, 62.72, H, 3.11, N, 0.00.Measured value: C, 62.11, H, 3.10, N, 0.13.
Embodiment 4411-(4-hydroxyl-phenyl)-benzo [b] naphtho-[2,3-d] thiophene-6-formonitrile HCN
With 4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-base-phenol) acetate (ester) (2.0g, 4.47mmol), cupric cyanide (I) (2.0g, 22.3mmol), the heating 9 hours in 150 ℃ of oil baths in the pressurized vessel of sealing of the suspension of N-Methyl pyrrolidone (10ml).Reaction mixture is cooled to room temperature, adds in the entry, use ethyl acetate extraction.Water is filtered, the solid that produces is dissolved among the THF.Merging THF also concentrates mutually with ethyl acetate mutually.(1.0N, 4.5ml 4.5mmol) add in the resistates with THF (100ml), methyl alcohol (50ml) and aqueous sodium hydroxide solution.After 5 minutes, add entry, reaction mixture 10%HCl acidifying will produce solid and leach, and wash with water and grind with ether (3 *), grind with sherwood oil then.With solid vacuum-drying, obtain tawny solid title compound (1.27g, 82%): mp:307-309 ℃: NMR (CDCl3): δ 8.35 (ddd, J=8,1,1Hz, 1H), 7.84 (ddd, J=8,1,1Hz, 1H), 7.76-7.69 (m, 2H), 7.51 (ddd, J=8,8,1Hz, 1H), 7.44 (ddd, J=8,8,1Hz, 1H), 7.27 (d, J=9Hz, 2H), 7.15 (d, J=9Hz, 2H), 7.14 (m, 1H), 6.82 (ddd, J=8,1,1Hz, 1H), 5.08 (s, 1H); IR (KBr, cm-1): 2210 (CN); MS (EI): [M+], 451 (40%, MI); The analytical calculation value of C23H13NOS: C, 78.61, H, 3.73, N, 3.99.Measured value: C, 77.84, H, 3.46, N, 3.89.
Embodiment 45 methylsulfonic acid 4-(benzo [b] naphtho-[2,3-d] thiophene-11-base-phenyl ester
With methylsulfonyl chloride (0.63ml, 8.14mmol) drop to cold (ice bath), (2.00g is 5.43mmol) in the solution in dry methylene chloride (10ml) and pyridine (2.08ml) for 4-benzo [b] naphtho-[2,3-d] thiophene-11-base-phenol., after 36 hours reaction mixture is mixed with water (100ml) in stir about under the room temperature.Organism with 10%HCl (100ml) washing and concentrated, obtains the title compound (2.51g, 100%) of white solid: mp:136-139 ℃ with ether (100ml) extraction; NMR (CDCl3): δ 8.38 (s, 1H), 7.97-7.95 (m, 1H), 7.80-7.78 (m, 1H), 7.60-7.50 (m, 6H), 7.43-7.35 (m, 2H), 7.07 (ddd, J=8,7,1Hz, 1H), 6.68 (d, J=8Hz, 1H), 3.33 (s, 3H); MS (EI): [M+] 404 (100%); The analytical calculation value of C23H16O3S2+0.07C6H14: C, 68.52, H, 4.17, N, 0.03.Measured value: C, 67.91, H, 3.85, N, 0.06.
Embodiment 46 methylsulfonic acid 4-(6-chloro-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester
Under room temperature, dry nitrogen atmosphere, (0.21ml, (1.00g is in chloroform 2.47mmol) (10ml) solution 2.60mmol) to drop to methylsulfonic acid 4-benzo [b] naphtho-[2,3-d] thiophene-11-base-phenyl ester with SULPHURYL CHLORIDE.Stir after 19 hours, reaction mixture is added in the entry (100ml), (2 * 100ml) extract organism with ether.Combining extraction liquid mixes with the salt water washing and with silica gel, removes solvent.Adsorptive separates (85/15 petrol ether/ethyl acetate) through flash chromatography, obtains the title compound (0.957g, 88%) of white solid: mp:155-158 ℃; NMR (CDCl3): δ 8.41 (ddd, J=8,1,1Hz, 1H), 7.82 (ddd, J=8,1,1Hz, 1H), 7.67 (ddd, J=8,7,1Hz, 1H), 7.61-7.56 (m, 3H), 7.51-7.45 (m, 3H), and 7.42-7.38 (ddd, J=8,7,1Hz, 1H), 7.10 (ddd, J=8,7,1Hz, 1H), 6.64 (d, J=8Hz, 1H), 3.34 (s, 3H); MS (+EI): [M+], 1 chlorine isotope figure, 438 (100%), 440 (40%); The analytical calculation value of C23H15ClO3S2: C, 62.93, H, 3.49, N, 0.00.Measured value: C, 62.72, H, 3.25, N, 0.03.
Embodiment 47 methylsulfonic acid 4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester
To methylsulfonic acid 4-benzo [b] naphtho-[2,3-d] thiophene-11-base-phenyl ester (2.24g, 5.54mmol) at tetrahydrofuran (THF) (22.4ml), 80% acetic acid aqueous solution (0.244g, 1.39mmol) and sulfuric acid (0.6ml) in solution in add iodine (0.984g, 3.87mmol) and acid iodide (0.244g, 1.39mmol).Reaction mixture was stirred under room temperature 88 hours, mix with aqueous solution of sodium bisulfite (100ml) then.Organism extracts with ether (500ml).Extraction liquid is concentrated, handle, obtain the title compound (2.75g, 94%) of yellow solid: mp:176-186 ℃ with benzene and sherwood oil; NMR (CDCl3): δ 8.24 (ddd, J=8,1,1Hz, 1H), 7.81 (ddd, J=8,1,1Hz, 1H), and 7.65-7.58 (m, 3H), 7.52-7.38 (m, 5H), 7.11-7.07 (ddd, J=8,7,1Hz, 1H), 6.57 (d, J=8,1,1Hz, 1H), 3.33 (s, 3H); MS (+FAB): [M+] m/z 530 (65%), [M+H]+m/z 531 (25%); The analytical calculation value of C23H15IO3S2: C, 52.08, H, 2.85, N, 0.00.Measured value: C, 51.75, H, 2.75, N, 0.06.
Embodiment 48 methylsulfonic acid 4-(6-trifluoromethyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester
Under agitation, with new activatory ketone (0.359g, 5.66mmol) and two (trifluoromethyl) mercury (0.993g, the 3.78mmol) heating 2 hours under 144 ℃, dry nitrogen atmosphere of the mixture in N,N-dimethylacetamide (12ml).After the cooling, (1.00g, N,N-dimethylacetamide 1.89mmol) (12ml) solution heat mixture 3 hours 20 minutes in 160-168 ℃ to add methylsulfonic acid 4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester.After the cooling, this mixture is inclined to water, (2 * 200ml) extract organism with ether.Combining extraction liquid adds silica gel (about 30ml) and removes solvent.Adsorptive separates (elutriant: 80: 20 sherwood oils: ethyl acetate), obtain the title compound (0.697g, 85%) into white solid: mp:215-216 ℃ through flash chromatography; NMR (CDCl3): δ 8.39-8.36 (m, 1H), 7.81-7.79 (m, 1H), 7.71-7.67 (m, 1H), 7.61-7.59 (m, 3H), 7.51-7.46 (m, 3H), 7.41 (ddd, J=8,7,1Hz, 1H), 7.08 (ddd, J=8,7,1Hz, 1H), 6.54 (d, J=8Hz, 1H), 3.35 (s, 3H); MS+FAB[M+H]+m/z 473 and m+472; The analytical calculation value of C24H15F3O3S20.15C6H6: C, 61.76, H, 3.31, N, 0.00.Measured value: C, 61.20, H, 3.11, N, 0.16.
Embodiment 49 methylsulfonic acid 4-(6-methyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester
Under 103 ℃, argon gas, with methylsulfonic acid 4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester (1.65g, 3.11mmol), tin tetramethide (3.58,25.8mmole) and two (triphenylphosphine) Palladous chloride II (0.218g, 0.311mmole 10mol%) at dry N, the suspension in the dinethylformamide (16ml) heated 4 hours in the pressurized vessel of sealing, placed under the room temperature and spent the night.Reaction mixture is added in the entry (200ml), use extracted with diethyl ether.Add silica gel (40ml) and remove solvent.Adsorptive separates (85: 15 sherwood oils: ethyl acetate), obtain the title compound (1.12g, 86%) of light yellow solid: mp 172-173 ℃: NMR (CDCl3): δ 8.18 (ddd, J=8,1,1Hz through flash chromatography, 1H), 7.81 (ddd, J=1,1,8Hz, 1H), and 7.62-7.55 (m, 3H), 7.50-7.48 (m, 2H), 7.44-7.34 (m, 2H), 7.06 (ddd, J=8,7,1Hz, 1H), 6.64 (ddd, J=8,1,1Hz), 3.32 (s, 3H), 2.99 (s, 3H); MS (EI) [m/z] 418 (100%); The analytical calculation value of C24H18O3S2: C, 68.87, H, 4.34, N, 0.00.Measured value: C, 68.60, H, 4.26, N, 0.02.
Embodiment 504-(6-chloro-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
With methylsulfonic acid 4-(6-chloro-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester (0.917g, 2.09mmol) Zai diox (13ml) and sodium hydroxide solution (2.5N, 6.7ml, 16.7mmol, biphasic mixture reflux 8eq) spends the night.After being cooled to room temperature, reaction mixture is mixed with water (50ml), use the concentrated hydrochloric acid acidifying, and stirred 15 minutes.Collect rough white solid product after filtration, it is dissolved in the ether, mix with silica gel and remove solvent.Adsorptive separates (85/15-80/20 petrol ether/ethyl acetate) through flash chromatography, obtains the title compound (0.705g, 94%) of white solid: mp 193-195 ℃: NMR (CDCl3): δ 8.37 (ddd, J=8,1Hz, 1H), 7.81 (ddd, J=8,1,1Hz, 1H), 7.68-7.63 (m, 2H), 7.44 (ddd, J=8,7,1Hz, 1H), 7.39 (ddd, J=8,7,1Hz, 1H), 7.29-7.26 (m, 2H), 7.14-7.09 (m, 3H), 6.81 (ddd, J=8,1,1Hz, 1H), 5.01 (d, J=4Hz, 1H); MS (+EI): [M+], 1 chlorine isotope figure, 360 (100%), 362 (45%); The analytical calculation value of C22H13ClOS: C, 73.23, H, 3.63, N, 0.00.Measured value: C, 72.86, H, 3.24, N, 0.04.
Embodiment 514-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
To methylsulfonic acid 4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester (1.0g, 1.89mmol) tetrahydrofuran (THF) (5ml) solution in add 2.5N aqueous sodium hydroxide solution (6.0ml), with biphasic reaction mixture reflux 5 hours, about 18 hours of heating under 110C in the sealing load test tube then.10% hcl acidifying is used in reaction mixture water (100ml) dilution, and (2 * 100ml) extract organism with ether.Combining extraction liquid, water (100ml) washing concentrates and handles with sherwood oil, obtains title compound (0.869g is higher than theoretical value); NMR (DMSO-d6): δ 9.85 (s, 1H, OH), 8.15 (d, J=8Hz, 1H), 8.02 (d, J=8Hz, 1H), 7.73 (ddd, J=8,7,1Hz, 1H), 7.69-7.44 (m, 3H), 7.21-7.16 (m, 3H), 7.09-7.06 (m, 2H), 6.68 (d, J=8Hz, 1H).
Embodiment 524-(6-trifluoromethyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
According to the method for embodiment 51, by methylsulfonic acid 4-(6-trifluoromethyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester (embodiment 48) preparation.White solid: mp 210-211 ℃; NMR (CDCl3): δ 8.35 (m, 1H), 7.80-7.77 (m, 1H), 7.72-7.64 (m, 2H), 7.47 (ddd, J=8,7,1Hz, 1H), 7.39 (ddd, J=8,7,1Hz, 1H), 7.28-7.24 (m, 2H), 7.16-7.08 (m, 3H), 6.75 (d, J=8Hz, 1H), 5.03 (s, 1H); MS:(+) EI (directly probe) [M+]: 394 (100%); The analytical calculation value of C23H13F3OS: C, 70.04, H, 3.32, N, 0.00.Measured value: C, 69.68,3.12, N, 0.10.
Embodiment 534-(6-methyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
According to the method for embodiment 51, by methylsulfonic acid 4-(6-methyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester (embodiment 49) preparation.White solid: mp 184-185 ℃; NMR (CDCl3): δ 8.16 (ddd, J=8,1,1Hz, 1H), 7.81 (ddd, J=8,1,1Hz, 1H), 7.67 (ddd, J=8,1,1Hz, 1H), 7.58 (ddd, J=8,7,1Hz, 1H), 7.42-7.34 (m, 2H), 7.29-7.26 (m, 3H), 7.12-7.06 (m, 3H), 6.82 (ddd, J=8,1,1Hz, 1H), 4.94 (s, 1H), 2.98 (s, 3H); MS:(EI): [M+], 340 (100%); The analytical calculation value of C23H16OS: C, 81.14, H, 4.74, N, 0.00.Measured value: C, 81.47, H, 4.59, N, 0.02.
Embodiment 544-(6-methoxyl group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
3 addings of branch sodium hydride in the anhydrous methanol (13.2ml) of cold (ice bath) (80% (weight) mineral oil suspension, 1.70g, 56.6mmol).In cooling bath, stirred 0.5 hour and after stirring 50 minutes under the room temperature, (0.251g is 1.87mmol) with methylsulfonic acid 4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester (3.00g to add the cupric chloride II, 5.66mmol) dry N, the solution of dinethylformamide (24ml).Reaction mixture refluxed was heated about 3 hours, be cooled to room temperature, water (400ml) dilution is with 10% hcl acidifying and use extracted with diethyl ether.The united extraction thing adds silica gel also except that desolvating.Adsorptive separates (40/60 sherwood oil/methylene dichloride) through flash chromatography, obtains the title compound (1.82g, 90%) of white solid: mp 218-223 ℃; NMR (CDCl3): δ 8.27 (ddd, J=8,1,1Hz, 1H), 7.80 (ddd, J=8,1,1Hz, 1H), 7.65 (ddd, J=8,1,1Hz, 1H), 7.57 (ddd, J=8,7,1Hz, 1H), 7.40 (ddd, J=8,7,1Hz, 1H), 7.36 (ddd, J=8,1,7,1Hz, 1H), and 7.30-7.26 (m, 2H), 7.13-7.07 (m, 3H), 6.85 (ddd, J=8,1,1Hz, 1H), 4.98 (s, 1H), 4.21 (s, 3H); MS:(EI): [M+], 356 (100%); The analytical calculation value of C23H16O2S: C, 77.50, H, 4.52, N, 0.00.Measured value: C, 76.79, H, 4.61, N, 0.11.
Embodiment 554-(6-phenyl sulfane base-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
With sodium hydroxide (0.183g, 4.58mmol) add methylsulfonic acid 4-(6-iodo-benzo [b] naphtho-[2 that stirs under the room temperature, 3-d] thiophene-11-yl)-phenyl ester (1.04g, 1.95mmol), thiophenol (0.47ml, 4.578mmol), Red copper oxide (I) (0.326,2.28mmol) and in the solution of dimethyl formamide (20ml).Container is heated in the oil bath under 155-160 ℃, argon atmosphere.After 7 hours, reaction mixture is cooled to room temperature, adds in the entry, with 10% hcl acidifying and use extracted with diethyl ether.Ether extraction liquid is filtered with the removal mantoquita, and add silica gel.Remove solvent, adsorptive is through flash chromatography (elutriant: gradient: 9: 1 to 85: 15 sherwood oils: ethyl acetate), obtain the title compound (0.721g, 86%) of white solid: mp 162-164 ℃; NMR (DMSO-d6): δ 9.87 (s, 1H), 8.48 (ddd, J=8,1,1Hz, 1H), 7.95 (ddd, J=8,1,1Hz, 1H), 7.66 (m, 2H), 7.52 (ddd, J=8,7,1Hz, 1H), 7.44 (ddd, J=8,7,1Hz, 1H), 7.27-7.07 (m, 10H), 6.76 (d, J=8Hz, 1H); MS (EI): 434 (M+, 100%); The analytical calculation value of C28H18OS: C, 77.39, H, 4.19, N, 0.00.Measured value: C, 76.82, H, 3.95, N, 0.16.
Embodiment 564-[6-(2-dimethylamino-ethyl sulfane base)-benzo [b] naphtho-[2,3-d] thiophene-11-yl]-phenol
In pressurized vessel, under room temperature to methylsulfonic acid 4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester (1.00g, 1.89mmol), hydrochloric acid dimethylamino sulfur alcohol (0.614g, 4.34mmol, 2.3eq) and red copper oxid I (0.316g, 8.69mmol,, add the sodium hydroxide (0.348g that grinds very carefully in the suspension in the dinethylformamide (24ml) 1.17eq) at anhydrous N, 8.69mmol, 4.6eq).Container is full of argon gas, and sealing was also under agitation heated 6 hours down in 155 ℃ (oil baths), and heating is 12 hours under room temperature.Incline reaction mixture to water (100ml) and use extracted with diethyl ether.Leach the solid that remains on aqueous phase as suspension.Filtrate is used extracted with diethyl ether 1 time again.Combining extraction liquid also adds silica gel.Remove solvent, adsorptive is through flash chromatography (gradient: 94/6-95/5 methylene dichloride: Virahol), obtain solid title compound (0.707g, 87%): NMR (DMSO-d6): δ 9.83 (s, 1H, OH), 8.65 (d, J=8Hz, 1H), 7.98 (d, J=8Hz, 1H), 7.71 (ddd, J=8,7,1Hz, 1H), 7.61 (d, J=8Hz, 1H), 7.50 (ddd, J=8,7,1Hz, 1H), 7.43 (ddd, J=8,7,1Hz, 1H), 7.21-7.05 (m, 3H), and 7.08-7.04 (m, 2H), 6.73 (d, J=8Hz, 1H), 3.35-3.27 (m) 3.10 (t, J=6Hz, 2H), 2.21-2.08 (wide unimodal, 6H); MS (EI): [M+] 429.
Embodiment 574-[6-(pyridin-4-yl sulfane base)-benzo [b] naphtho-[2,3-d] thiophene-11-yl]-phenol
To methylsulfonic acid 4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester (1.00g, 1.89mmol), 4-mercaptopyridine (0.614g, 4.34mmol, 2.3eq) and red copper oxid I (0.316g, 2.21mmol, 1.17eq) at anhydrous N, add the sodium hydroxide (0.174g that grinds very carefully in the suspension in the dinethylformamide (24ml), 4.34mmol, 2.3eq), and with mixture heating 5 hours under 157 ℃ (oil baths), argon gas in pressure bottle, and under room temperature, stir and spend the night.Reaction mixture is inclined to water (100ml), and organism extracts with ether (2.300ml).Combining extraction liquid, dry and add silica gel with salt solution.Remove solvent, adsorptive separates (97/3 methylene dichloride: Virahol), obtain solid, it is stirred spend the night and collect sintered glass funnel through flash chromatography in water (100ml), air-dry, obtain solid title compound (0.587,73%): NMR (DMSO-d6): δ 9.90 (s, 1H), 8.37 (d, J=8Hz, 1H), 8.30 (d, J=5Hz, 2H), 7.95 (d, J=8Hz, 1H), 7.70 (m, 2H), 7.57 (m, 1H), 7.45 (t, J=8Hz, 1H), 7.28 (d, J=Hz, 2H), 7.20 (t, J=8Hz, 1H), 7.11 (d, J=8Hz, 2H), 6.96 (d, J=6Hz, 2H), 6.77 (d, J=8Hz, 1H); MS (EI): [M+] 435.
Embodiment 5811-(3,5-two bromo-4-hydroxyl-phenyl)-benzo [b] naphtho-[2,3-d] thiophene-6-formonitrile HCN
With bromine (0.21ml, 4.07mmol) acetate (3ml) solution under room temperature, drop to 11-(4-hydroxyl-phenyl)-benzo [b] naphtho-[2 of stirring, 3-d] and thiophene-6-formonitrile HCN (650mg, 1.85mmol), (1.82g is 18.5mmol) and in the suspension of acetate (17ml) for potassium acetate.After 35 minutes, add entry (100ml) and small amount of solid S-WAT.With suspension filtered, solid washes with water, grinds and vacuum-drying with sherwood oil, obtains tawny solid title compound (1.04g, 96%): mp 321-323 ℃; NMR (CDCl 3): δ 8.36 (ddd, J=8,1,1Hz, 1H), 7.87 (ddd, J=8,1,1Hz, 1H), 7.76 (ddd, J=8,7,1Hz, 1H), 7.67 (ddd, J=8,1,1Hz, 1H), 7.56 (ddd, J=8,7,1Hz, 1H), 7.54 (s, 2H), 7.50 (ddd, J=8,7,1Hz, 1H), 7.27 (ddd, J=8,7,1Hz, 1H), 6.90 (ddd, J=8,1,1Hz, 1H), 6.24 (s, 1H, OH); MS (EI): [M+], 2 bromine isotope figures, 507 (55%), 509 (100%), 511 (55%); The analytical calculation value of C23H11Br2NOS0.5H2O: C, 53.31, H, 2.33, N, 2.70.Measured value: C, 53.51, H, 2.28, N, 2.70.
Adopt the method for embodiment 58 and suitable starting material, the compound among the preparation embodiment 59-66.
Embodiment 592,6-two bromo-4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
By 4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 51) preparation.White solid: mp 221-222 ℃; NMR (CDCl3): δ 8.22 (d, J=8Hz, 1H), 7.83 (d, J=8Hz, 1H), 7.63 (ddd, J=8,7,1Hz, 1H), 7.55 (d, J=8Hz, 1H), 7.54 (s, 2H), 7.50-7.43 (m, 2H), 7.20 (ddd, J=8,7,1Hz, 1H), 6.83 (d, J=8Hz, 1H); MS (+FAB): [M+], 2 bromine isotope figures, 608 (25%), 609.7 (100%), 612 (35%); The analytical calculation value of C22H11Br2IOS: C, 43.31, H, 1.82, N, 0.00.Measured value: C, 42.98, H, 1.93, N, 0.26.
Embodiment 602,6-two bromo-4-(6-chloro-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
By 4-(6-chloro-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 50) preparation.White solid: mp 222-223 ℃; NMR (CDCl3): δ 8.39 (ddd, J=8,1,1Hz, 1H), 7.84 (ddd, J=8,1,1Hz, 1H), 7.67 (ddd, J=8,7,1Hz, 1H), 7.61 (ddd, J=8,1,1Hz, 1H), 7.55 (s, 2H), 7.52-7.43 (m, 2H), 7.23 (ddd, J=8,7,1Hz, 1H), 6.89 (ddd, J=8,1,1Hz, 1H), 6.19 (s, 1H); MS (EI): [M+], 2 bromine isotope figures, 1 chlorine isotope figure, 516 (38%), 518 (100%), 520 (72%), 521 (20%); The analytical calculation value of C22H11Br2ClOS: C, 50.95, H, 2.14.Measured value: C, 51.12, H, 2.20.
Embodiment 612,6-two bromo-4-(6-trifluoromethyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
By 4-(6-trifluoromethyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 52) preparation.White solid: mp 223-225 ℃; NMR (CDCl3): δ 8.37 (ddd, J=8,1,1Hz, 1H), 7.82 (m, 2H), 7.54-7.50 (m, 2H), 7.53 (s, 2H), 7.45 (ddd, J=8,7,1Hz, 1H), 7.20 (ddd, J=8,7,1Hz, 1H), 6.83 (d, J=8Hz, 1H), 6.22 (s, 1H, OH); MS (+) EI (directly probe) [M+], 2 bromine isotope figures, 550 (52%), 552 (100%) 554 (58%); The analytical calculation value of C23H11Br2F3OS: C, 50.03, H, 2.01, N, 0.00.Measured value: C, 49.66, H, 2.07, N, 0.08.
Embodiment 622,6-two bromo-4-(6-methyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
By 4-(6-methyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 53) preparation.White solid: mp 224-226 ℃; NMR (CDCl3): δ 8.17 (ddd, J=8,1,1Hz, 1H), 7.84 (ddd, J=8,1,1Hz, 1H), 7.62-7.58 (m, 2H), 7.55 (s, 2H), 7.47-7.39 (m, 3H), 7.18 (ddd, J=8,7,1Hz, 1H), 6.89 (ddd, J=8,1,1Hz, 1H), 6.16 (s, 1H); MS (ESI): m/z 495.2 (40%), and 497.1 (100%) 499.2 (27%); The analytical calculation value of C23H14Br2OS: C, 55.45, H, 2.83, N, 0.00.Measured value: C, 56.17, H, 2.78, N, 0.13.
Embodiment 632,6-two bromo-4-(6-methoxyl group benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
By 4-(6-methoxyl group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 54) preparation.White solid: mp 233-234 ℃; NMR (DMSO-d6): δ 10.35 (wide s, 1H), 8.23 (ddd, J=8Hz, 1H), 8.03 (d, J=8Hz, 1H), 7.69-7.64 (m, 1H), 7.64 (s, 2H), 7.54 (d, J=4Hz, 2H), 7.48 (ddd, J=8,7,1Hz, 1H), 7.26 (ddd, J=8,7,1Hz, 1H), 6.84 (d, J=8Hz, 1H), 4.13 (s, 3H); MS (EI): [M+], 2 bromine isotope figures, 512 (48%), 514 (100%), 516 (54%); The analytical calculation value of C23H14Br2O2S: C, 53.72, H, 2.74, N, 0.00.Measured value: C, 53.62, H, 2.55, N, 0.18.
Embodiment 642,6-two bromo-4-(6-phenyl sulfane base-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
By 4-(6-phenyl sulfane base-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 55) preparation.White solid: mp 152-155 ℃; NMR (DMSO-d6): δ 10.42 (s, 1H), 8.49 (d, J=8Hz, 1H), 7.99 (d, J=8Hz, 1H), 7.55 (s, 2H), 7.69 (ddd, J=8,7,1Hz, 1H), 7.63 (d, J=8Hz, 1H), 7.57 (ddd, J=8,7,1Hz, 1H), 7.48 (ddd, J=8,7,1Hz, 1H), 7.28 (ddd, J=8,7,1Hz, 1H), 7.25-7.21 (m, 2H), 7.14 (ddd, J=8,7,1Hz, 1H), 7.09 (d, J=8Hz, 2H), 6.81 (d, J=8Hz, 1H), 1.90 (s, 3H, AcOH); MS (EI): [M+], 2 bromine isotope figures, 590 (50%), 592 (100%), 594 (60%); The analytical calculation value of C28H16Br2OS21.0CH3CO2H0.5H2O: C, 54.48, H, 3.20, N, 0.00.Measured value: C, 54.56, H, 2.91, N, 0.23.
Embodiment 652,6-two bromo-4-[6-(pyridin-4-yl sulfane base)-benzo [b] naphtho-[2,3-d] thiophene-11-yl]-phenol
By 4-[6-(pyridin-4-yl sulfane base)-benzo [b] naphtho-[2,3-d] thiophene-11-yl]-phenol (embodiment 57) preparation.Yellow solid: mp 225-270 ℃ (decomposition); NMR (DMSO-d6): δ 10.48 (s, 1H ,-OH), 8.40 (dd, J=8,1Hz, 2H), 8.37 (d, J=8Hz, 1H), 8.00 (d, J=8Hz, 1H), 7.76 (s, 2H), and 7.75-7.68 (m, 2H), 7.62 (ddd, J=8,7,1Hz, 1H), 7.50 (ddd, J=8,7,1Hz, 1H), 7.31 (ddd, J=8,7,1Hz, 1H), 7.20 (dd, J=6,1Hz, 2H), 6.83 (d, J=8Hz, 1H); The analytical calculation value of C27H15Br2NOS2: C, 54.65, H, 2.55, N, 2.36 measured values: C, 48.94, H, 2.46, N, 2.22.
Embodiment 662,6-two bromo-4-[6-(2-dimethylaminoethyl sulfane base)-benzo [b] naphtho-[2,3-d] thiophene-11-yl]-phenol
By 4-[6-(2-dimethylaminoethyl sulfane base)-benzo [b] naphtho-[2,3-d] thiophene-11-yl]-phenol (embodiment 56) preparation.Yellow solid: NMR (DMSO-d6): δ 8.65 (d, J=8Hz, 1H), 8.04 (d, J=8Hz, 1H), 7.77 (septet, J=3Hz, 1H), 7.65 (s, 2H), 7.60-7.58 (m, 2H), 7.50 (dd, J=8,1Hz, 1H), 7.27 (ddd, J=8,7,1Hz, 1H), 6.86 and 6.63 (s, isomer, 1H), 6.79 (d, J=8Hz, 1H), 3.24 (d, m, 2H), 2.85 (m, 2H); MS (EI): [M+], 2 bromine isotope figures, 585 (3%), 587 (7%), 589 (4%).
Embodiment 672,6-two chloro-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
In methyl alcohol (20ml), fed chlorine 2 minutes.This solution is cooled to-78 ℃, and add to-78 ℃ 4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-(0.609g is in methyl alcohol 1.50mmol) (15ml) solution for phenol.After 25 minutes, solution is added in the biphasic mixture of rare sodium thiosulfate solution of quick stirring and ether.Separate each layer, with silica gel add ether mutually in.Remove ether, adsorptive separates (gradient: 9: 1 to 1: 1 sherwood oils: ethyl acetate) through flash chromatography.Add to silica gel in the flow point that contains required product and remove solvent.Adsorptive separates (9: 1 sherwood oils: ethyl acetate) through flash chromatography.Add silica gel in the flow point contain required generation and remove solvent.Adsorptive through flash chromatography separate (7: 3 sherwood oils: ethyl acetate), obtain the title compound (0.082g, 12%) of white solid: NMR (DMSO-d6): δ 10.65 (s, 1H), 8.28 (ddd, J=8,1,1Hz, 1H), 8.07 (ddd, J=8,1,1Hz, 1H), 7.78 (ddd, J=9,5,2Hz, 1H), 7.63-7.58 (m, 2H), 7.53 (s, 2H), 7.52 (ddd, J=8,8,1Hz, 1H), 7.31 (ddd, J=8,7,1Hz, 1H), 6.69 (d, J=8Hz, 1H); MS (EI): [M+], 1 bromine isotope figure, 2 chlorine isotope figures, 472 (60%), 474 (100%), 476 (50%).
Embodiment 682-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
According to the method for embodiment 58, by 3-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 42) preparation.White solid: mp 111-112 ℃; MS (+FAB): [M+], 482; The analytical calculation value of C22H12Br2OS: C, 54.57, H, 2.50, N, 0.00.Measured value: C, 53.72, H, 2.35, N, 0.41.
Embodiment 692,4-two bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol
According to the method for embodiment 58, by 3-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 42) preparation.White solid: 269-270 ℃; MS (+FAB): [M+], 560,562,564,566; The analytical calculation value of C22H12Br3OS: C, 46.93, H, 1.97, N, 0.00.Measured value: C, 46.43, H, 2.20, N, 0.11.
Embodiment 703-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1, the 2-diphenol
According to the method for embodiment 58, by 4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1,2-diphenol (embodiment 43) preparation.White solid: mp 212-213 ℃; MS (EI): [M+], 2 bromine isotope figures, 498,500,502; The analytical calculation value of C22H12Br2O2S: C, 52.83, H, 2.42, N, 0.00.Measured value: C, 52.08, H, 2.55, N, 0.01.
Embodiment 714-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1, the 2-diphenol
According to the method for embodiment 58, by 4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1,2-diphenol (embodiment 43) preparation.White solid: mp 138-140 ℃; MS (EI): [M+], 2 bromine isotope figures, 498,500,502; The analytical calculation value of C22H12Br2O2S: C, 52.83, H, 2.42, N, 0.00.Measured value: C, 52.17, H, 2.71, N, 0.05.
Embodiment 72[11-(4-hydroxyl-phenyl)-benzo [b] naphtho-[2,3-d] thiene-3-yl-oxygen base]-methyl acetate
With 11-(4-hydroxyl-phenyl)-benzo [b] naphtho-[2,3-d] benzene sulphur-3-phenol (1.36g, 3.96mmol), methyl bromoacetate (0.38ml, 4.01mmol), salt of wormwood (0.548g, 3.97mmol) and N, dinethylformamide (21ml) mixes to be incorporated under the room temperature and stirred 2.5 hours.Reaction mixture is added in the entry also with ethyl acetate and THF extraction.Add silica gel in the organic phase and remove solvent.Adsorptive separates (elutriant: gradient methylene dichloride to 98: 2 methylene dichloride: acetonitrile), obtain the title compound (0.953g, 58%) of white solid: mp 229-231 ℃ through flash chromatography; NMR (DMSOd6): δ 9.78 (s, 1H), 8.51 (s, 1H), 8.00 (d, J=8Hz, 1H), 7.56-7.39 (m, 4H), 7.18 (d, J=9Hz, 2H), 7.05 (d, J=9Hz, 2H), 6.79 (d, J=9,2Hz, 1H), 6.66 (d, J=9Hz, 1H), 4.86 (s, 2H), 3.68 (s, 3H); MS (EI): 414 (100%, M+); The analytical calculation value of C25H18O4S: C, 72.45, H, 4.38, N, 0.00.Measured value: C, 71.78, H, 4.41, N, 0.13.
Embodiment 73[11-(4-methoxycarbonyl methoxyl group-phenyl)-benzo [b] naphtho-[2,3-d] thiene-3-yl-oxygen base]-methyl acetate
With 11-(4-hydroxyl-phenyl)-benzo [b] naphtho-[2,3-d] benzene sulphur-3-phenol (0.60g, 1.752mmol), methyl bromoacetate (0.70ml, 7.39mmol), salt of wormwood (1.2g, 8.76mmol) and N, dinethylformamide (8ml) mixes to be incorporated in to stir under the room temperature and spends the night.Add in the entry reaction mixture and filtration.Solid washes with water and vacuum-drying, obtains the title compound (0.82g, 96%) of white solid: mp 152-154 ℃; NMR (CDCl3): δ 8.27 (s, 1H), 7.91 (dt, J=8,1Hz, 1H), 7.61 (dm, J=8Hz, 1H), 7.49 (ddd, J=8,7,1Hz, 1H), 7.39-7.26 (m, 3H), 7.18 (d, J=9Hz, 2H), 6.66 (dd, J=1Hz, 2H), 4.82 (s, 2H), 4.67 (s, 2H), 3.90 (s, 3H), 3.81 (s, 3H); MS (FAB+): 487 (10%, M+H); The analytical calculation value of C28H22O6S: C, 69.12, H, 4.56, N, 0.00.Measured value: C, 67.52, H, 4.40, N, 0.07.
Embodiment 74[11-(4-carboxyl methoxyl group-phenyl)-benzo [b] naphtho-[2,3-d] thiene-3-yl-oxygen base]-acetate
With 1.0N aqueous sodium hydroxide solution (8.0ml, 8.0mmol) adding [11-(4-methoxycarbonyl methoxyl group-phenyl)-benzo [b] naphtho-[2,3-d] thiene-3-yl-oxygen base]-(0.750g is 1.54mmol) in the stirred solution in THF (20ml) and methyl alcohol (13ml) for methyl acetate.Dissolve.After following 3 hours, the reaction mixture dilute with water is also used ether (100ml) extraction in room temperature.Water also filters with 10% aqueous hydrochloric acid acidifying.Solid washes with water and grinds with sherwood oil.Solid in 70 ℃ of following vacuum-dryings, is obtained gray solid.With solid recrystallize from acetate, obtain the title compound (0.502,71%) of white solid: mp 220-222 ℃; NMR (DMSO-d6): δ 12.8 (wide s, 2H), 8.54 (s, 1H), 8.02 (s, J=8Hz, 1H), 7.56-7.409m, 4H), 7.31 (d, J=8Hz, 2H), 7.23 (d, J=8Hz, 2H), 6.73 (dd, J=9,1Hz, 1H), 6.56 (d, J=9Hz, 1H), 4.85 (s, 2H), 4.74 (s, 2H), 1.97 (s, 2.49H, 0.83mol acetate); MS (FAB+): 459 (20%, M+H); The analytical calculation value of C26H18O6S0.83CH3CO2H: C, 65.46, H, 4.24, N, 0.00.Measured value: C, 64.47, N, 4.05, N, 0.03.
Embodiment 75[11-(4-methoxycarbonyl methoxyl group-phenyl)-benzo [b] naphtho-[2,3-d] thiophene-8-base oxygen base]-methyl acetate
To 11-(4-hydroxyl-phenyl)-benzo [b] naphtho-[2,3-d] benzene sulphur-8-phenol (0.600g, 1.75mmol) and salt of wormwood (0.605g, 4.38mmol, 2.5eq) at anhydrous N, and dripping bromine methyl acetate in the suspension in the dinethylformamide (3ml) (0.50ml, 5.26mmol).Stir after 26 hours, (0.166ml 1.75mmol) also continues to stir 64 hours to add extra methyl bromoacetate.Remove solvent and add entry (100ml).Solid is dissolved in the mixture of ether and methylene dichloride and and mixes with silica gel.Remove solvent, adsorptive separates (70/30 petrol ether/ethyl acetate) through flash chromatography, obtains the title compound (0.300g, 35%) of yellow solid.
Embodiment 76[11-(4-carboxyl methoxyl group-phenyl)-benzo [b] naphtho-[2,3-d] thiophene-8-base oxygen base]-acetate
To [11-(4-methoxycarbonyl methoxyl group-phenyl)-benzo [b] naphtho-[2,3-d] thiophene-8-base oxygen base]-methyl acetate (0.268g, 0.551mmol) under room temperature, drip in the solution in tetrahydrofuran (THF) (8ml) and methyl alcohol (5ml) potassium hydroxide aqueous solution (1N, 2.2ml, 2.2mmol).Stir after 2 hours, introduce again potassium hydroxide (1N, 1ml, 1mmol).Behind the restir 14 hours, remove solvent, in resistates water-soluble (50ml),, and use the extracted with diethyl ether organism with 10% aqueous hydrochloric acid acidifying.Remove solvent and,, obtain the title compound (0.18g, 43%) of white solid: mp 245-246 ℃ in 53 ℃ of dryings with benzene and sherwood oil processing; NMR (DMSO-d6) δ 13.08 (wide s, 2H), 8.44 (s, 1H), 7.93 (d, J=8Hz, 1H), 7.45-7.35 (m, 3H), 7.31 (d, J=9Hz, 2H), 7.22 (d, J=9Hz, 2H), 7.17 (dd, J=3,9Hz, 1H), 7.10 (ddd, J=9,9,1Hz, 1H), 6.67 (d, J=8Hz, 1H), 4.84 (d, J=7Hz, 4H); MS (EI): [M+] 458; The analytical calculation value of C26H18O6S: C, 68.11, H, 3.96, N, 0.00.Measured value: C, 66.41, H, 3.95, N, 0.05.
Embodiment 77[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-methyl acetate
Mix 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (1.0g, 1.78mmol), methyl bromoacetate (0.35ml, 3.70mmol), salt of wormwood (0.50g, 3.62mmol) and N, dinethylformamide (5ml), and under room temperature, stir and spend the night.Add in the entry reaction mixture and filtration.Solid washes with water and vacuum-drying, obtains the title compound (1.11g, 98%) of white solid: mp 183-184 ℃; NMR (CDCl3): δ 8.36 (ddd, J=8,1,1Hz, 1H), 7.84 (ddd, J=8,1,1Hz, 1H), 7.68 (ddd, J=8,7,1Hz, 1H), 7.62 (s, 2H), 7.57 (ddd, J=8,1,1Hz, 1H), 7.51 (ddd, J=8,7,1Hz, 1H), 7.42 (ddd, J=8,7,1Hz, 1H), 7.18 (ddd, J=8,7,1Hz, 1H), 6.72 (ddd, J=8,1,1Hz, 1H), 4.88 (s, 2H), 3.94 (s, 3H); MS (EI): [M+], 3 bromine isotope figures, 632 (30%), 634 (90%) 636 (100%) 638 (35%); The analytical calculation value of C25H15Br3O3S: C, 47.27, H, 2.38, N, 0.00.Measured value: C, 47.17, H, 2.19, N, 0.09.
Embodiment 78[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-tert.-butyl acetate
Under room temperature, dry nitrogen atmosphere, to 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (1.5g, 2.66mmol) dry DMF (10ml) suspension in add salt of wormwood (0.496g, 3.59mmol), then the dripping bromine tert.-butyl acetate (0.79ml, 3.59mmol).Stir after 3 hours, will also filter in the reaction mixture impouring water (250ml).White solid washes with water, is dissolved in the methylene dichloride then and adds silica gel.Remove solvent, the silica gel adsorption thing through flash chromatography (96: 4 sherwood oils: ethyl acetate), obtain the title compound (1.14g, 64%) of white solid: NMR (CDCl3): δ 8.36 (d, J=8Hz, 1H, ArH), 7.85 (d, J=8Hz, 1H, ArH), 7.67 (ddd, J=8,7,1Hz, 1H, ArH), 7.60 (s, 2H, ArH), and 7.59-7.36 (m, 3H, ArH), 7.19 (t, J=7Hz, 1H, ArH), 6.75 (d, J=7Hz, 1H, ArH), 4.73 (s, 2H, CH2), 1.60 (s, 9H, 3 (CH3); MS (EI): [M+], 3 bromine isotope figures, 674 (29%), 676 (85%), 678 (85%), 680 (35%); The analytical calculation value of C28H21Br3O3S: C, 49.66, H, 3.12, N, 0.00.Measured value: C, 49.55, H, 2.84, N, 0.06.
Embodiment 79[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-acetate
With 1.0N potassium hydroxide aqueous solution (2.66ml, 2.66mmol) add [2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-(1.51g is 2.37mmol) in the stirred solution in THF (13ml) and methyl alcohol (4ml) for methyl acetate.Dissolve.After following 2.5 hours, the reaction mixture dilute with water is also used ether (100ml) extraction in room temperature.Water also filters with 10% aqueous hydrochloric acid acidifying.Solid washes with water and grinds with sherwood oil.Solid in 70 ℃ of following vacuum-dryings, is obtained the title compound (1.34g, 91%) of white solid: mp 259-261 ℃; NMR (DMSO-d6): δ 8.29 (dd, J=8,1Hz, 1H), 8.06 (dd, J=8,1Hz, 1H), 7.82 (s, 2H), 7.79 (ddd, J=8,6,2Hz, 1H), 7.61 (m, 2H), 7.52 (ddd, J=8,7,1Hz, 1H), 7.32 (ddd, J=8,7,1Hz, 1H), 6.73 (dd, J=8,1Hz, 1H), 4.78 (s, 2H); MS (EI): [M+], 3 bromine isotope figures, 618 (30%) 620 (90%) 622 (100%) 624 (50%); The analytical calculation value of C24H13Br3O3S: C, 46.41, H, 2.11, N, 0.00.Measured value: C, 46.38, H, 1.99, N, 0.01.
Embodiment 80[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-acetic acid sodium salt
With aqueous sodium hydroxide solution (1.00N, 0.315ml, 0.315mmol) add [2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-(194mg is 0.315mmol) in the stirred solution in THF (1ml)/methyl alcohol (1ml) for acetate.Reaction mixture is concentrated, add entry (2.5ml) and leach solid (101mg).Water is evaporated to ether driedly with ether (25ml) extraction mutually, obtains second solid (77mg).Combining solid grinds and vacuum-drying with toluene and benzene, obtains tawny solid title compound (152mg, 76%): mp 315-317 ℃; NMR (DMSO-d6): δ 8.28 (d, J=8.5Hz, 1H), 8.07 (d, J=8Hz, 1H), 7.79 (ddd, J=8,7,2Hz, 1H), 7.76 (s, 2H), 7.62 (m, 2H), 7.52 (ddd, J=8,8,1Hz, 1H), 7.33 (ddd, J=8,8,1Hz, 1H), 6.69 (d, J=8Hz, 1H), 4.27 (s, 2H); MS (FAB): [M-Na], 3 bromine isotope figures, 617,619,621,622; The analytical calculation value of C24H12Br3O3SNa0.75H2O: C, 43.90, H, 2.07, N, 0.00.Measured value: C, 44.09, H, 2.18, N, 0.03.
Embodiment 81[(4-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-dicyano-phenoxy group]-acetate
With 5-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-hydroxyl-m-dicyanobenzene (0.455g, 1.21mmol), methyl bromoacetate (0.351ml, 3.63mmol), salt of wormwood (0.251g, 1.81mmol) and N, dinethylformamide (5.0ml) mixes to be incorporated under the room temperature and stirred 2 days.Reaction mixture water (60ml) dilutes and is acidified to pH1 with 10% aqueous hydrochloric acid, and water is extracted with ethyl acetate (100ml).Acetic acid ethyl acetate extract washes with water, with salt solution and anhydrous magnesium sulfate drying and concentrated, obtains white solid.Be dissolved in solid in the ethyl acetate (60ml) and add silica gel.Remove solvent, adsorptive separates (elutriant: 8: 2 sherwood oils: ethyl acetate) through flash chromatography, obtain white solid methyl esters (0.370g, 83%): (170mg is dissolved in the 5ml water with wet chemical, 1.23mmol) (0.275g is 0.613mmol) in the stirred solution in THF (10ml) to add this methyl esters under room temperature.After 31 hours, reaction mixture water (100ml) dilutes and is acidified to pH1 with 10% aqueous hydrochloric acid, and water extracts with ethyl acetate (150ml).Acetic acid ethyl acetate extract washes with water, with salt solution and anhydrous magnesium sulfate drying and concentrated, obtains the title compound (0.207g, 78%) of white solid: mp 134-136 ℃; NMR (CDCl3): δ 8.43 (s, 1H), 7.98 (dd, J=8,1Hz, 1H), 7.91 (s, 2H), 7.8 (dd, J=8,1Hz, 1H), 7.58 (ddd, J=8,7,1Hz, 1H), 7.49-7.42 (m, 3H), 7.36 (dd, J=8,1Hz, 1H), 7.18 (ddd, J=8,7,1Hz, 1H), 6.70 (dd, J=8,1Hz, 1H), 4.47 (s, 2H); MS (EI): 434 (100%, MI); The calculated value of the high resolving power MS of C26H14N2O3S (EI): C, 434.072516, measured value: 434.078475.The analytical calculation value of C26H14N2O3S: C, 71.88, H, 3.25, N, 6.45.Measured value: C, 70.80, H, 3.14, N, 6.18.
Embodiment 82[(4-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-cyano group-phenoxy group]-acetate
With 5-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-hydroxyl-cyanobenzene (0.386g, 1.1mmol), methyl bromoacetate (0.266ml, 2.75mmol), salt of wormwood (0.228g, 1.65mmol) and N, dinethylformamide (5.0ml) mixes to be incorporated under the room temperature and stirred 1.5 hours.Reaction mixture water (120ml) dilutes and is acidified to pH1 with 10% aqueous hydrochloric acid, and aqueous mixture extracts with ethyl acetate (150ml).Acetic acid ethyl acetate extract washes with water, with salt solution and anhydrous magnesium sulfate drying and concentrated, obtains white solid.Be dissolved in solid in the ethyl acetate (60ml) and add silica gel.Remove solvent, adsorptive separates (elutriant: 7: 3 sherwood oils: ethyl acetate), obtain white solid methyl esters (0.195g, 42%) through flash chromatography.(124mg is dissolved in the 4ml water, and (0.190g is 0.45mmol) in the stirred solution in THF (5ml) 0.90mmol) to add this methyl esters under room temperature with wet chemical.After 23 hours, reaction mixture water (80ml) dilutes and is acidified to pH1 with 10% aqueous hydrochloric acid, and water extracts with ethyl acetate (100ml).Acetic acid ethyl acetate extract washes with water, with salt solution and anhydrous magnesium sulfate drying and concentrated, obtains the title compound (0.116g, 63%) of white solid: mp 235-236 ℃; NMR (CDCl3): δ 8.38 (s, 1H), 7.96 (d, J=8Hz, 1H), 7.81 (dd, J=8,1Hz, 1H), 7.72 (d, J=2Hz, 1H), 7.61 (dd, J=8,1Hz, 1H), 7.55 (ddd, J=8,7,1Hz, 1H), 7.45-7.38 (m, 3H), 7.19 (d, J=8Hz, 1H), 7.12 (ddd, J=8,7,1Hz, 1H), 6.73 (d, J=8Hz, 1H), 5.04 (s, 2H); MS (EI): 409 (100%, MI); The analytical calculation value of C25H15NO3S: C, 73.33, H, 3.69, N, 3.42.Measured value: C, 71.66, H, 3.33, N, 3.31.
Embodiment 83 (4-benzo [b] naphtho-[2,3-d] thiophene-11-base-2,6-two iodo-phenoxy groups]-acetate
With 4-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two iodo-phenol (0.543g, 0.94mmol), methyl bromoacetate (0.181ml, 1.88mmol), (0.141g, 1.03mmol) and N, dinethylformamide (5.4ml) mixes to be incorporated under the room temperature and stirred 1 hour salt of wormwood.Add in the entry reaction mixture and filtration.Solid washes with water and vacuum-drying, obtains (4-benzo [b] naphtho-[2,3-d] thiophene-11-base-2,6-two iodo-phenoxy groups)-methyl acetate white solid (0.537g, 88%): mp 203-205 ℃.((0.55g is in THF 0.85mmol) (5.0ml) stirred solution 1.28mmol) to add this methyl esters under room temperature for 0.5N, 2.54ml with potassium hydroxide aqueous solution.With solution concentration, water (75ml) dilutes and 10% aqueous hydrochloric acid acidifying after 1 hour.Leach solid and wash with water, obtain the title compound (0.428g, 80%) of white solid: mp 250-252 ℃; NMR (DMSO-d6): δ 8.66 (s, 1H), 8.07 (d, J=8Hz, 1H), 8.01 (d, J=8Hz, 1H), 7.93 (s, 2H), 7.61 (ddd, J=8,7,1Hz, 1H), 7.54-7.48 (m, 2H), 7.47 (ddd, J=8,7,1Hz, 1H), 7.27 (ddd, J=8,7,1Hz, 1H), 6.71 (d, J=8Hz, 1H), 4.69 (s, 2H); MS (EI): 636 (100%, MI); The analytical calculation value of C24H14I2O3S: C, 45.31, H, 2.22, N, 0.00.Measured value: C, 44.95, H, 1.99, N, 0.23.
Adopt the method for embodiment 83 and suitable starting material, the compound among the preparation embodiment 84-95.
Embodiment 84[4-benzo [b] naphtho-[2,3-d] thiophene-11-base-phenoxy group]-acetate
By 4-benzo [b] naphtho-[2,3-d] thiophene-11-base-phenol (embodiment 14) preparation.White solid: mp 221-223 ℃; NMR (DMSO-d6): δ 13.05 (wide s, 1H), 8.61 (s, 1H), 8.05 (d, J=8Hz, 1H), 7.96 (d, J=7Hz, 1H), 7.58 (ddd, J=8,7,1Hz, 1H), 7.51-7.40 (m, 3H), 7.33 (d, J=9Hz, 2H), 7.23 (d, J=9Hz, 2H), 7.12 (ddd, J=8,7,1Hz, 1H), 6.71 (ddd, J=8,1,1Hz, 1H), 4.86 (s, 2H); MS (EI): [M+], 384 (100%); The analytical calculation value of C24H16O3S: C, 74.98, H, 4.20, N, 0.00.Measured value: C, 74.62, H, 4.14, N, 0.08.
Embodiment 85 (4-benzo [b] naphtho-[2,3-d] thiophene-11-base-2-iodo-phenoxy group)-acetate
By 4-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-iodo-phenol (embodiment 27) preparation.White solid: mp 248-249 ℃; NMR (DMSO-d6): δ 8.63 (s, 1H), 8.05 (d, J=8Hz, 1H), 7.98 (d, J=7Hz, 1H), 7.81 (d, J=2Hz, 1H), 7.61-7.56 (m, 1H), 7.49-7.48 (m, 2H), 7.44 (ddd, J=8,7,1Hz, 1H), 7.41 (dd, J=8,2Hz, 1H), 7.20 (d, J=8Hz, 1H), 7.17 (ddd, J=8,7,1Hz, 1H), 6.75 (d, J=8, Hz, 1H), 4.96 (s, 2H); MS (EI): 510 (100%, MI); The analytical calculation value of C24H15IO3S: C, 56.48, H, 2.96, N, 0.00.Measured value: C, 56.35, H, 2.84, N, 0.27.
Embodiment 86{2,6-dimethyl-4-[6-methyl-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)]-phenoxy group }-acetate
By 2,6-dimethyl-4-[6-methyl-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)]-phenoxy group }-methyl acetate (embodiment 25) preparation.White solid: mp 155-181 ℃; NMR (DMSO-d6): δ 12.95 (wide s, 1H), 8.23 (d, J=8Hz, 1H), 7.97 (d, J=8Hz, 1H), 7.63 (d, J=8,7,1Hz, 1H), 7.58 (d, J=8Hz, 1H), 7.47 (ddd, J=8,7,1Hz, 1H), 7.41 (ddd, J=8,8,1Hz, 1H), 7.15 (ddd, J=8,7,1Hz, 1H), 7.05 (s, 2H), 6.67 (d, J=8Hz, 1H), 4.59 (s, 2H), 2.92 (s, 3H), 2.34 (s, 6H); MS (EI): [M+], 426 (100%); The analytical calculation value of C27H22O3S: C, 76.03, H, 5.20, N, 0.00.Measured value: C, 75.64, H, 5.31, N, 0.02.
Embodiment 87[4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-acetate
Prepare by [4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-methyl acetate (embodiment 41).White solid: mp 198-200 ℃; NMR (CDCl3): δ 8.34 (ddd, J=8,1,1Hz, 1H), 7.80 (ddd, J=8,1,1Hz, 1H), 7.66-7.61 (m, 2H), 7.45-7.38 (m, 2H), 7.36 (d, J=9Hz, 2H), 7.22 (d, J=9Hz, 2H), 7.09 (ddd, J=8,7,1Hz, 1H), 6.71 (ddd, J=8,1,1Hz, 1H), 4.89 (s, 2H); MS (EI): [M+], 1 bromine isotope figure, 462 (95%), 464 (100%); The analytical calculation value of C24H15BrO3S0.6CH3CO2H0.28H2O: C, 60.00, H, 3.37, N, 0.00.Measured value: C, 59.82, H, 3.42, N, 0.03.
Embodiment 88[2,6-dimethyl-4-(6-cyano group-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-acetate
Prepare by [2,6-dimethyl-4-(6-cyano group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-methyl acetate (embodiment 58).White solid: mp 259-261 ℃; NMR (DMSO-d6): δ 13.2 (wide s, 1H), 8.27 (d, J=8Hz, 1H), 8.16 (d, J=8,1H), 7.91 (ddd, J=8,7,1Hz, 1H), 7.89 (s, 2H), 7.74-7.65 (m, 2H), 7.59 (ddd, J=8,7,1Hz, 1H), 7.38 (ddd, J=8,7,1Hz, 1H), 6.75 (d, J=8Hz, 1H), 4.78 (s, 2H); MS (EI): [M+], 2 bromine isotope figures, 565 (45%), 567 (100%) 569 (50%); The analytical calculation value of C25H13Br32NO3S: C, 52.93, H, 2.31, N, 2.47.Measured value: C, 51.96, H, 2.07, N, 2.31.
Embodiment 89[4-(6-bromo-benzo [b1 naphtho-[2,3-d] thiophene-11-yl)-2,6-di-isopropyl-phenoxy group]-acetate
By [4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-di-isopropyl-phenol (embodiment 40) preparation.White solid: mp 220-221 ℃; NMR (CDCl3): δ 8.37 (ddd, J=8,1,1,1H), 7.81 (ddd, J=8,1,1Hz, 1H), 7.69 (ddd, J=8,1,1Hz, 1H), 7.66 (ddd, J=8,8,1,1H), 7.48 (ddd, J=8,8,1Hz, 1H), 7.38 (ddd, J=8,8,1Hz, 1H), 7.19 (s, 2H), 7.02 (ddd, J=8,8,1Hz, 1H), 6.54 (d, J=8Hz, 1H), 4.69 (s, 2H), 3.42 (septets, J=7Hz, 2H), 1.28 (d, J=7Hz, 6H), 1.23 (d, J=7Hz, 6H); MS (+FAB): 546 (90%), 548 (100); The analytical calculation value of C30H27BrO3S: C, 65.81, H, 4.97, N, 0.00.Measured value: C, 65.56, H, 4.89, N, 0.10.
Embodiment 90[3-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-acetate
By 3-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 42) preparation.White solid: mp 180-181 ℃; MS (+FAB): [M+], 462; The analytical calculation value of C24H15BrO3S: C, 62.21, H, 3.26, N, 0.00.Measured value: C, 61.90, H, 3.19, N, 0.13.
Embodiment 91[2-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-acetate
By 2-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 68) preparation.White solid: mp 174-175 ℃; MS (+FAB): [M+], 2 bromine isotope figures, 540,542,544; The analytical calculation value of C24H14Br2O3S: C, 53.16, H, 2.60, N, 0.00.Measured value: C, 52.91, H, 2.75, N, 0.48.
Embodiment 92[2,4-two bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-acetate
By 2,4-two bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 69) preparation.White solid: mp 256-258 ℃; MS (+FAB): [M+], 618; The analytical calculation value of C24H13Br3O3S: C, 46.41, H, 2.11, N, 0.00.Measured value: C, 46.26, H, 2.17, N, 0.07.
Embodiment 935-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-carboxyl methoxyl group-phenoxy group]-acetate
By 4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1,2-diphenol (embodiment 42) preparation.White solid: mp 222-224 ℃; MS (+FAB): [M+], 536; The analytical calculation value of C26H17BrO6S: C, 58.11, H, 3.19, N, 0.00.Measured value: C, 57.58, H, 3.00, N, 0.15.
Embodiment 943-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-carboxyl methoxyl group-phenoxy group]-acetate
By 3-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1,2-diphenol (embodiment 70) preparation.White solid: mp 135-137 ℃; MS (EI): [M+], 2 bromine isotope figures, 614,616,618; The analytical calculation value of C26H16Br2O6S: C, 50.67, H, 2.26, N, 0.00.Measured value: C, 49.45, H, 2.73, N, 0.11.
Embodiment 954-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-carboxyl methoxyl group-phenoxy group]-acetate
By 4-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1,2-diphenol (embodiment 71) preparation.White solid: mp 256-257 ℃; MS (EI): [M+], 2 bromine isotope figures, 614,616,618; The analytical calculation value of C26H16Br2O6S: C, 50.67, H, 2.26, N, 0.00.Measured value: C, 50.88, H, 2.96, N, 0.04.
Embodiment 96 (S)-2-hydroxyl-3-phenylpropionic acid methyl esters
With commercially available (S)-2-hydroxyl-3-phenylpropionic acid (5.0g, 30.1mmol) and methyl alcohol (125ml) solution of right-toluenesulphonic acids hydrate (1g) refluxed 17 hours, remove water with the 3A molecular sieve simultaneously.With solution concentration and be dissolved in the ether.Diethyl ether solution also concentrates with saturated sodium bicarbonate, salt water washing, obtains the title compound (5.32g, 98%) of white solid: NMR (CDCl3): and δ 7.36-7.20 (m, 5H), 4.47 (ddd, J=5,6,7Hz, 1H), 3.78 (s, 3H), 3.14 (dd, J=5,14Hz, 1H), 2.97 (dd, J=7,14Hz), 2.69 (d, J=6Hz, 1H).
Embodiment 97 (R)-2-hydroxyl-3-phenylpropionic acid methyl esters
According to the method for embodiment 96, by commercially available (R)-2-hydroxyl-3-phenylpropionic acid preparation.White solid: NMR (CDCl3): δ 7.34-7.20 (m, 5H), 4.47 (ddd, J=5,6,7Hz, 1H), 3.78 (s, 3H), 3.14 (dd, J=5,14Hz, 1H), 2.97 (dd, J=7,14Hz), 2.69 (d, J=6Hz, 1H).
Embodiment 98D, L-indoles-3-methyl lactate
According to the method for embodiment 96, by commercially available D, L-indoles-3-lactic acid preparation.White solid: mp 42-44 ℃; NMR (CDCl3): δ 8.07 (m, 1H, NH), 7.61 (d, J=8Hz, 1H), 7.34 (d, J=8Hz, 1H), 7.19-7.10 (m, 3H), 5.45 (q, J=6Hz, 1H), 3.72 (s, 3H), 3.25 (dd, J=7,6Hz, 2H), 2.75 (d, J=6Hz, 1H, OH); MS (EI): [M+], 219.
Embodiment 99 (S)-(+)-hydroxyl-1,3-dioxo-2-isoindoline methyl-butyrate
According to the method for embodiment 9, by commercially available (S)-(+)-Alpha-hydroxy-1,3-dioxo-2-isoindoline butyric acid preparation.White solid: mp 123-124.5 ℃; MS (EI): [M+], 263; The analytical calculation value of C13H13NO5: C, 59.31, H, 4.98, N, 5.32.Measured value: C, 59.04, H, 5.02, N, 5.06.
Embodiment 100L-B-imidazole lactic acid methyl ester hydrochloride
Under dry nitrogen atmosphere, in 10 minutes, (4.8ml, (1.11g is in the suspension that methyl alcohol 5.7mmol) (7ml) stirs 68.4mmol) to drop to commercially available L-β-imidazole lactic acid hydrochloride under the room temperature with thionyl chloride.Solution was heated 2 days in 60 ℃ of oil baths.After being cooled to room temperature, reaction mixture is concentrated, handle, obtain the title compound (1.07g, 90%) of heavy-gravity white solid with ethyl acetate; NMR (DMSO-d6): δ 8.63 (s, 1H), 7.23 (s, 1H), 4.35 (t, J=6Hz, 1H), 3.62 (s, 3H, OCH3), 2.90 (d, J=6Hz, 2H); MS (EI): 170 (10%, MI), 111 (40%), 81 (100%).
Embodiment 101N-t-BOC-L-β-imidazole lactic acid methyl esters
Under dry nitrogen atmosphere, (0.878ml, (0.87g is in methyl alcohol 4.2mmol) (12ml) stirred solution 6.3mmol) to drop to L-β-imidazole lactic acid methyl ester hydrochloride under the room temperature with triethylamine.Continue under the room temperature and stirred 40 minutes.After 6 hours, reaction mixture is concentrated, obtain oily matter and add methylene dichloride.Methylene dichloride water and salt water washing.Add silica gel (12ml).Remove solvent, the silica gel adsorption thing separates (elutriant: 4: 6 sherwood oils: ethyl acetate), obtain the title compound (0.86g, 75%) of oily matter through flash chromatography; MS (EI): [M+], 270.
Embodiment 102 (S)-2-[4-nitro benzoyl]-the 4-phenylbutyrate
To cold (ice bath) commercially available (R)-2-hydroxy-4-phenyl-ethyl butyrate (1.86ml, 9.60mmol), p-nitrobenzoic acid (6.42g, 38.4mmole, 4eq) and triphenylphosphine (10.07g, 38.4mmole, in 40 minutes, drip diethylazodicarboxylate (6.05ml, 38.4mmole in anhydrous tetrahydro furan 4eq.) (110ml) solution, 4eq), internal temperature is remained on 4-5 ℃ simultaneously.Behind the restir 1 hour, remove ice bath, solution was stirred under room temperature 5 days.Remove solvent, resistates is dissolved in the mixture (600ml) of ether and ethyl acetate again.Add silica gel (200ml) and remove solvent.Adsorptive separates (elutriant: 80/20-70/30 sherwood oil: ethyl acetate), obtain the title compound (4.03g) of yellow oil through flash chromatography; NMR (CDCl3): δ 8.30 (d, J=9Hz, 2H), 8.18 (d, J=9Hz, 2H), 7.38-7.18 (m, 5H), 5.28 (t, J=2Hz, 1H), 4.23 (q, J=7Hz, 2H), 2.85 (t, J=8Hz, 2H), 2.40-2.33 (m, 2H), 1.29 (t, J=7Hz, 3H); MS[(+) FAB]: [M+H] m/z=358.
Embodiment 103 (S)-2-hydroxyl-3-phenylbutyrate
In 0.5 hour, to potassium cyanide (0.176g adds (S)-2-[4-nitro benzoyl in dehydrated alcohol 2.70mmole) (43ml) suspension]-4-phenylbutyrate (3.86g, dehydrated alcohol 10.8mmol) (38ml) solution.Stir and remove solvent after 2.25 hours, residue diluted with water is also used the dilute hydrochloric acid acidifying.The organism extracted with diethyl ether.Extraction liquid is merged, add silica gel (60ml) and remove solvent.Adsorptive separates through flash chromatography, and elutriant is (a gradient 90/10-80/20 petrol ether/ethyl acetate), and solvent is handled with benzene, obtains the title compound (1.67g, 74%) of yellow oil: [a] 25D+178.23 (10.98mg/ml CHCl3); NMR (CDCl3): δ 7.38-7.16 (m, 5H), 4.30-4.10 (m, 3H), 2.9-2.6 (m, 3H), 2.2-1.9 (m, 2H), 1.15 (t, 4Hz, 3H);
Embodiment 1043-pyridin-3-yl ethyl propionate
According to B.A.Lefker, W.A.Hada, P.J.McGarry Tetrahedron Lett.1994,35, the method of 5205-5208, under nitrogen atmosphere, will two (trimethyl silyl) ammonification sodium (1.0N in THF, 44.3ml, 44.3mmol) drop to 3-pyridylaldehyde (4.41ml, 46.7mmol), (4.93ml, 46.7mmol) and in the stirred solution of THF (34ml), its drop rate makes and temperature is remained on below-50 ℃ ethyl chloroacetate.In-78 ℃ after 45 minutes, with reaction mixture temperature to 0 ℃, water quencher and concentrating then.Resistates is allocated between ether and the water.Ether is dry and concentrated with salt solution mutually.Be dissolved in resistates in the ethyl acetate and add palladium hydroxide on the carbon (wet type, the Degussa type, 20%Pd content, 1g).Mixture hydrogenation 2 hours under the 45psi hydrogen-pressure.Reaction mixture is filtered and removes solvent through thru sulka floc.Resistates separates (2: 3 sherwood oils: ethyl acetate, elutriant) through flash chromatography, obtains the title compound (3.83g, 42%) of oily matter; NMR (CDCl3); 8.24 (m, 2H), 7.60 (d, 1H), 7.22 (dd, 1H), 4.45 (t, 1H), 4.22 (q, 2H), 3.15 (dd, 1H), 2.95 (dd, 1H), 1.27 (t, 3H).
Embodiment 105 (S)-(+)-α, 3-dihydroxyl-1-oxo-2-isoindoline methyl-butyrate
(0.474g, 12.54mmol) gradation adds (s)-(+)-Alpha-hydroxy-l of-20 ℃, 3-dioxo-2-isoindoline methyl-butyrate (3.0g, in the stirred solution of THF/ water (30/1.38ml) 11.4mmol) 6 hours with sodium borohydride.After being cooled to room temperature, careful quencher reaction mixture is with 10% aqueous hydrochloric acid acidifying.Aqueous mixture extracts with ethyl acetate (300ml).Acetic acid ethyl acetate extract water and salt water washing.Add silica gel (15ml).Remove solvent, adsorptive separates (95: 5 sherwood oils of elutriant: methylene dichloride), obtain the title compound (0.96g, 32%) of oily matter: MS (EI): [M+], 265 through flash chromatography.
Embodiment 106 (S)-(+)-Alpha-hydroxy-1-oxo-2-isoindoline methyl-butyrate
Under dry nitrogen atmosphere, (1.1ml 7.66mmol) drops to (s)-(+)-α, 3-dihydroxyl-1-oxo-2-isoindoline methyl-butyrate (0.84g, in the stirred suspension of chloroform 3.19mmol) (10ml) 2 hours with trifluoroacetic anhydride.Reaction mixture concentrated obtains oily matter, under room temperature, dry nitrogen atmosphere, add trifluoroacetic acid (3.4ml) and triethyl silicane (1.1m, 3.83mmol).After 6 hours, use 10% sodium bicarbonate aqueous solution quencher reaction mixture carefully.Aqueous mixture extracts with methylene dichloride (150ml).Dichloromethane extraction liquid water and salt water washing.Add silica gel (12ml).Remove solvent, adsorptive separates (15: 85 sherwood oils of elutriant: ethyl acetate), obtain oily matter (0.50g, 63%) through flash chromatography; Mp 73.5-74.5 ℃: MS (EI): [M+], 247.
Embodiment 107 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-methyl propionate
Under nitrogen atmosphere, with diethylazodicarboxylate 0.437ml, 2-74mmol) drop to 2 under the room temperature, 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (1.00g, 1.83mmol), (S)-2-hydroxyl-3-phenylpropionic acid methyl esters (0.494g, 2.74mmol), (0.72g is 2.74mmol) and in the suspension of benzene (12ml) for triphenylphosphine.Dissolve, solution was heated 3.5 hours in 80 ℃ of oil baths.After being cooled to room temperature, reaction mixture is with the methylene dichloride dilution and add silica gel (30ml).Reaction mixture is concentrated, and the silica gel adsorption thing separates (96: 4 sherwood oils: ethyl acetate), obtain the title compound (1.20g, 90%) of white solid: mp138-139.5 ℃ through flash chromatography; NMR (CDCl3): δ 8.36 (ddd, J=8,1,1Hz, 1H), 7.83 (ddd, J=8,1,1Hz, 1H),, 7.68 (ddd, J=8,7,1Hz, 1H), 7.60 (dd, J=5,2Hz, 2H), 7.60-7.48 (m, 2H), 7.46-7.28 (m, 6H), 7.18 (ddd, J=8,7,1Hz, 1H), 6.74 (ddd, J=8,1,1Hz, 1H), 5.26 (t, J=8Hz, 1H), 3.76 (s, 3H), 3.59 (dd, J=8,5Hz, 2H); MS (FAB+): [M+], 3 bromine isotope figures, 722 (30%), 724 (70%) 726 (100%) 728 (35%); The analytical calculation value of C32H21Br3O3S: C, 52.99, H, 2.99, N, 0.00.Measured value: C, 52.60, H, 2.68, N, 0.07.
Embodiment 108 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
With potassium hydroxide aqueous solution (1N, 6.37ml, 6.37mmol) add (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-(2.31g is in THF 3.19mmol) (22ml)/methyl alcohol (15ml) solution for 3-phenyl-methyl propionate.After 2 hours with solution concentration, water (100ml) dilution and with 10% aqueous hydrochloric acid acidifying.Leach solid, wash with water and grind with sherwood oil.With its recrystallize from methyl alcohol, obtain the title compound (1.52g, 67%) of white solid: mp 140-142 ℃: [a] D25=+25.66 (10.52mg/ml CHCl3) then; NMR (DMSO-d6): δ 13.26 (wide s, 1H), 8.29 (d, J=8Hz, 1H), 8.07 (d, J=8Hz, 1H), 7.80 (m, 1H), 7.79 (dd, J=7,3Hz, 2H), 7.63 (ddd, J=8,7,1Hz, 1H), 7.55 (d, J=8Hz, 1H), 7.51 (ddd, J=8,7,1Hz, 1H), 7.41 (d, J=7Hz, 2H), and 7.38-7.32 (m, 3H), 7.31-7.22 (m, 3H), 6.64 (d, J=8Hz, 1H), 5.32 (t, J=7Hz, 1H), 3.41 (d, J=7Hz, 2H); MS (EI): [M+], 3 bromine isotope figures, 708 (35%), 710 (90%) 712 (100%) 714 (40%); The analytical calculation value of C31H19Br3O3S: C, 52.35, H, 2.69, N, 0.00.Measured value: C, 52.46, H, 2.59, N, 0.10.Chiral analysis type HPLC measures this compound and has about 100% EE[post: Chirbiotic V, 5 micron (4.6 * 250mm); Isocratic elution, 1: 1 ethanol: hexane; Flow velocity=0.80ml/min; Volume injected=0.3 μ l; Sample concentration=0.25mg/ml; Retention time, R-enantiomorph=21 minute; Retention time, s-enantiomorph=16 minute].
Embodiment 109 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid sodium salt
Under room temperature, with sodium hydroxide (1N, 0.417ml, 0.417mmol) adding (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-(0.297g is 0.418mmol) in the stirred solution in THF (1.3ml)/methyl alcohol (1.3) for 3-phenyl-propionic acid.Remove solvent after 30 minutes, solvent in 70 ℃ of following dried overnight, obtains the title compound (0.31g of white solid by rotary evaporation benzene fast processing, 100%): mp 261-265 ℃: NMR (DMSO-d6): δ 8.27 (d, J=8Hz, 1H), 8.03 (d, J=8Hz, 1H), 7.79 (ddd, J=8,8,1Hz, 1H), 7.63 (ddd, J=8,7,1Hz, 1H), 7.58-7.47 (m, 4H), 7.41 (d, J=7Hz, 2H), and 7.35-7.32 (m, 1H), 7.22 (t, J=7Hz, 1H), 6.77 (d, J=8Hz, 1H), 5.42 (dd, J=8,4Hz, 1H), 3.4 (m, 2H); MS (ESI): [M-H]-, 3 bromine isotope figures, 707,709,711,713; The analytical calculation value of C31H18Br3O3SNa: C, 50.78, H, 2.47, N, 0.00.Measured value: C, 50.82, H, 2.79, N, 0.02.
Embodiment 110 (S)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-methyl propionate
Under dry nitrogen atmosphere, with diethylazodicarboxylate (0.839ml, 5.50mmol) drop to 2 under the room temperature, 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (2.00g, 3.55mmol), (R)-2-hydroxyl-3-phenylpropionic acid methyl esters (0.96g, 5.50mmol), (1.40g is 5.50mmol) and in the stirred suspension of benzene (15ml) for triphenylphosphine.Dissolve, solution was heated 19 hours in 80 ℃ of oil baths.After being cooled to room temperature, reaction mixture is with the ether dilution and add silica gel (60ml).Reaction mixture is concentrated, and the silica gel adsorption thing separates (95: 5 sherwood oils: ethyl acetate), obtain the title compound (2.48g, 94%) of white solid: mp 140-143 ℃ through flash chromatography; [a] D25=-56.87 ° (10.02mg/ml CHCl3); NMR (CDCl3): δ 8.36 (ddd, J=8,1,1Hz, 1H), 7.83 (ddd, J=8,1,1Hz, 1H), 7.68 (ddd, J=8,7,1Hz, 1H), 7.60 (dd, J=5,2Hz, 2H), 7.60-7.49 (m, 2H), 7.46-7.27 (m, 6H), 7.18 (ddd, J=8,7,1Hz, 1H), 6.74 (ddd, J=8,1,1Hz, 1H), 5.26 (dd, J=8,6Hz, 1H), 3.76 (s, 3H), 3.59 (dd, J=8,5Hz, 2H); MS (FAB+): [M+], 3 bromine isotope figures, 722 (31%), 724 (94%) 726 (100%) 728 (40%); The analytical calculation value of C32H21Br3O3S: C, 52.99, H, 2.99, N, 0.00.Measured value: C, 52.99, H, 2.85, N, 0.03.
Embodiment 111 (S)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
With potassium hydroxide aqueous solution (1N, 2.40ml, 2.40mmol) add (S)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-(0.88g is in THF 1.21mmol) (12ml)/methyl alcohol (8ml) solution for 3-phenyl-methyl propionate.After 2 hours with solution concentration, water (50ml) dilution and with 10% aqueous hydrochloric acid acidifying.Then reaction mixture is allocated between water and the ether.Ether is concentrated mutually and grind with ether and sherwood oil.With its recrystallize from methyl alcohol, obtain the title compound (0.54g, 63%) of white solid: [a] D25=-24.81 ° (10.08mg/ml CHCl3) then; NMR (CDCl 3): δ 8.36 (d, J=8Hz, 1H), 7.81 (d, J=8Hz, 1H), 7.68 (ddd, J=8,5,3Hz, 1H), 7.58 (dd, J=10,2Hz, 2H), 7.54-7.48 (m, 2H), 7.44-7.27 (m, 6H), 7.16 (ddd, J=8,7,1), 6.72 (d, J=8Hz, 1H), 5.45 (t, J=7Hz, 1H), 3.59 (d, J=7Hz, 2H); MS (EI): [M+], 3 bromine isotope figures, 708 (24%), 710 (80%) 712 (100%) 714 (40%); The analytical calculation value of C31H19Br3O3S: C, 52.35, H, 2.69, N, 0.00.Measured value: C, 52.05, H, 2.59, N, 0.10.Chiral analysis type HPLC measures this compound and has about 100% EE[post: Chirobiotic V, 5 micron (4.6 * 250mm); Isocratic elution, 1: 1 ethanol: hexane; Flow velocity=0.80ml/min; Volume injected=0.3 μ l; Sample concentration=0.25mg/ml; Retention time, R-enantiomorph=21 minute; Retention time, s-enantiomorph=16 minute].
Embodiment 112 (R)-2-[2,6-two bromo-4-(6-methoxyl group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-methyl propionate
According to the method for embodiment 107, by 2,6-two bromo-4-(6-methoxyl group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 63) and (S)-2-hydroxyl-3-phenylpropionic acid methyl esters (embodiment 96) preparation.White solid (0.608g, 96%): NMR (THF-d8): δ 8.29-8.26 (m, 1H), 7.87 (d, J=8Hz, 1H), 7.72-7.68 (dd, 2H, J=4,2Hz), 7.60-7.56 (m, 2H), 7.48-7.37 (m, 4H), 7.32-7.28 (m, 2H), 7.25-7.23 (m, 2H), 7.20-7.15 (m, 2H), 6.85-6.82 (m, 1H), 5.22 (dd, 1H, J=14,2, Hz), 4.17 (s, 1H), 3.71 (s, 1H), 3.58 (s, 6H); MS (FAB+): [M+], 2 bromine isotope figures, 674 (40%), 676 (66), 678 (45%); The analytical calculation value of C33H24Br2O4S: C, 58.60, H, 3.58, N, 0.00.Measured value: C, 58.11, H, 3.53, N, 0.19.
Embodiment 113 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-butyric acid
Under dry nitrogen atmosphere, with diethylazodicarboxylate (EDAD, 0.210ml, 1.33mmol) add 2 under the room temperature, 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (0.500g, 0.888mmol), (S)-2-hydroxy-4-phenyl ethyl butyrate (0.277g, 1.33mmol), (0.350g is 1.33mmol) and in the stirred suspension of benzene (3.8ml) for triphenylphosphine.Dissolve, solution was heated 2 hours in 80 ℃ of oil baths.After being cooled to room temperature, reaction mixture is with the ether dilution and add silica gel.Reaction mixture is concentrated, and the silica gel adsorption thing separates (95: 5 sherwood oils: ethyl acetate), obtain white solid (0.570g, 85%) through flash chromatography.((0.562g is 0.746mmol) in the stirred solution in THF (12ml)/methyl alcohol (5ml) 1.4mmol) to add this solid for 1N, 1.4ml with potassium hydroxide aqueous solution.After 3 hours with solution concentration, dilute with water, and with 10% aqueous hydrochloric acid acidifying.Leach solid, wash with water and grind, obtain the title compound (0.526g, 97%) of white solid: mp 115-120 ℃ with sherwood oil; NMR (DMSO-d6): δ 13.3 (wide s, 1H), 8.29 (d, J=8Hz, 1H), 8.07 (d, J=8Hz, 1H), 7.83 (d, J=2Hz, 1H), 7.81 (d, J=2Hz, 1H), 7.80 (ddd, J=8,7,1Hz, 1H), 7.65-7.58 (m, 2H), 7.51 (ddd, J=8,8,1Hz, 1H), 7.33-7.20 (m, 6H), 6.67 (d, J=8Hz, 1H), 5.15 (dd, J=6Hz, 1H), 3.00 (m, 1H), 2.79 (m, 1H), 2.34 (m, 2H); MS (FAB+): [M+], 3 bromine isotope figures, 722,724,726,728; The analytical calculation value of C32H21Br3O3S: C, 52.99, H, 2.92, N, 0.00.Measured value: C, 52.49, H, 2.69, N, 0.17.
Adopt the method for embodiment 113 and suitable starting material, the compound among the preparation embodiment 114-144.
Embodiment 114 (S)-2-[4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
By 4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 41) and (R)-2-hydroxyl-3-phenylpropionic acid methyl esters (embodiment 97) preparation.White solid: [a] D25=+17.94 ° (10.30mg/ml, CHCl3): NMR (CDCl3): δ 8.31 (ddd, J=8,1,1Hz, 1H), 7.76 (ddd, J=8,1,1Hz, 1H), 7.60 (ddd, J=8,8,1Hz, 1H), 7.54 (d, J=8Hz, 1H), 7.44-7.29 (m, 6H), and 7.24-7.20 (m, 4H), 7.19=7.04 (m, 3H), 6.62 (d, J=8Hz, 1H), 5.08 (dd, J=7,5Hz, 1H), 3.44 (d, J=5Hz, 1H), 3.43 (d, J=7Hz, 1H); MS (FAB+): [M+], bromine isotope figure, 553 (11%), 569 (12%); The analytical calculation value of C31H21BrO3S: C, 67.27, H, 3.82, N, 0.00.Measured value: C, 65.17, H, 3.64, N, 0.04.It is 98.9%[post: movapak that analysis mode HPLC measures this compound purity, 5 micron (4.6 * 250mm); Isocratic elution, 7: 3 acetonitriles: 0.01M potassium primary phosphate, pH=3.5; Flow velocity=1.0ml/min].
Embodiment 115 (S)-2-[2,6-two bromo-4-(6-cyano group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
By 11-(3,5-two bromo-4-hydroxyl-phenyl)-benzo [b] naphtho-[2,3-d] thiophene-6-formonitrile HCN (embodiment 58) and (R)-2-hydroxy-4-phenyl methyl propionate (embodiment 97) preparation.White solid: mp176-178 ℃: NMR (CDCl3): δ 8.36 (ddd, J=8,1,1Hz, 1H), 7.85 (d, J=8Hz, 1H), 7.77 (ddd, J=8,8,2Hz, 1H), 7.58 (d, J=2Hz, 1H), and 7.61-7.54 (m, 2H), 7.56 (d, J=2Hz, 1H), 7.47 (ddd, J=8,8,1Hz, 1H), 7.41 (ddd, J=8,1,1,2H), and 7.36-7.26 (m, 3H), 7.20 (ddd, J=8,8,1,1H), 6.75 (ddd, J=8,1,1Hz, 1H), 5.46 (t, J=7Hz, 1H), 3.59 (d, J=7Hz, 2H); MS (FAB): [M-H], 2 bromine isotope figures, 654 (2%), 656 (4%), 658 (2%); The analytical calculation value of C32H19Br2NO3S: C, 58.47, H, 2.91, N, 2.13.Measured value: C, 58.23, H, 2.69, N, 2.03.
Embodiment 116 (R)-2-[4-(6-cyano group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
By 11-(4-hydroxyl-phenyl)-benzo [b] naphtho-[2,3-d] thiophene-6-formonitrile HCN (embodiment 44) and (S)-2-hydroxyl-3-phenylpropionic acid methyl esters (embodiment 97) preparation.White solid: mp 145-148 ℃: [a] D25=-2.03 ° (7.883mg/ml CHCl3); NMR (CDCl3): δ 8.31 (ddd, J=8,1,1Hz, 1H), 7.78 (ddd, J=8,1,1Hz, 1H), 7.70 (ddd, J=8,8,1Hz, 1H), 7.56 (ddd, J=8,1,1Hz, 1H), 7.47-7.37 (m, 6H), 7.32 (ddd, J=8,7,1Hz, 1H), 7.20 (dd, J=8,2Hz, 1H), 7.14-7.05 (m, 4H), 6.62 (ddd, J=8,1,1Hz, 1H), 5.06 (dd, J=7,5Hz, 1H), 3.44 (d, J=5Hz, 1H), 3.42 (d, J=7Hz, 1H); MS (EI): [M+], 499 (100%); The analytical calculation value of C32H21NO3S: C, 76.93, H, 4.24, N, 2.80.Measured value: C, 75.77, H, 4.22, N, 2.70.
Embodiment 117 (R)-2-[4-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
By 4-benzo [b] naphtho-[2,3-d] thiophene-11-base-phenol (embodiment 14) and (S)-2-hydroxyl-3-phenylpropionic acid methyl esters (embodiment 96) preparation.White solid: [a] 25/D=-19.09 ° (8.538mg/ml, CHCl3); NMR (CDCl3): δ 8.30 (s, 1H), 7.91 (d, J=8Hz, 1H), 7.73 (d, J=8Hz, 1H), 7.55-7.24 (m, 10H), 7.14-7.09 (m, 2H), 7.05 (ddd, J=8,7,1Hz, 1H), 6.70 (d, J=8Hz, 1H), 5.09 (dd, J=8,5Hz, 1H), 3.42 (m, 2H); MS (EI): [M+], 474 (100%); The analytical calculation value of C31H22O3S: C, 78.46, H, 4.67, N, 0.00.Measured value: C, 77.09, H, 4.60, N, 0.03.Analysis mode HPLC purity (98.5%).
Embodiment 118 (S)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-butyric acid
By 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 21) and commercially available (R)-2-hydroxy-4-phenyl ethyl butyrate preparation.White solid: mp 180-181 ℃; [a] D25=+5.83 ° (10.3mg/ml CHCl3); NMR (CDCl3): δ 8.36 (d, J=8Hz, 1H), 7.83 (d, J=8Hz, 1H), 7.67 (ddd, J=8,7,1Hz, 1H), 7.64 (dd, J=5,2Hz, 2H), and 7.63-7.49 (m, 2H), 7.42 (ddd, J=8,7,1Hz, 1H), 7.34-7.22 (m, 5H), 7.12 (ddd, J=8,7,1Hz, 1H), 6.76 (d, J=8Hz, 1H), 5.30 (t, 1H), 3.21-2.87 (m, 2H, 2.59-2.49 (m, 2H); MS (FAB-): [M-H]-, 3 bromine isotope figures, 721,723,725,727; The analytical calculation value of C32H21Br3O3S: C, 53.00, H, 2.92, N, 0.00.Measured value: C, 52.63, H, 2.68, N, 0.09.
Embodiment 119 (R)-2-[4-(3-carboxyl methoxyl group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
By [11-(4-hydroxyl-phenyl)-benzo [b] naphtho-[2,3-d] thiene-3-yl-oxygen base]-methyl acetate (embodiment 72) and (S)-2-hydroxy-4-phenyl methyl propionate (embodiment 96) preparation.White solid: mp 191-201 ℃:; NMR (DMSO-d6): δ 13.1 (wide s, 2H), 8.45 (s, 1H), 8.01 (d, J=8Hz, 1H), 7.55-7.25 (m, 11H), 7.16 (d, J=9Hz, 2H), 6.67 (dd, J=9,2Hz, 1H), 6.49 (d, J=9Hz, 1H), 5.18 (dd, J=7,4Hz, 1H), 4.74 (s, 2H), 3.28 (dd, J=7,4Hz, 1H), 3.21 (dd, J=14,7Hz, 1H); MS (EI): 458 (80%, M+); The analytical calculation value of C33H24O6S: C, 72.25, H, 4.41, N, 0.00.Measured value: C, 69.57, H, 4.15, N, 0.32; Analysis mode HPLC:92% purity.
Embodiment 120 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-(1H-imidazol-4 yl)-propionic salt hydrochlorate
By 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 21) and N-t-BOC-L-β-imidazole lactic acid methyl esters (embodiment 101) preparation.White solid: mp＞265 ℃; NMR (CDCl3): δ 9.00 (s, 1H), 8.29 (d, J=8Hz, 1H), 8.08 (d, J=8Hz, 1H), 7.84-7.78 (m, 3H), 7.65-7.51 (m, 4H), 7.28 (dd, J=8,1Hz, 1H), 6.68 (d, J=8Hz, 1H), 5.40 (t, J=7Hz, 1H), 3.49-3.47 (m, 2H); MS (+FAB): [M+H]+, 3 bromine isotope figures, 699,701,703,705; The analytical calculation value of C28H17Br3N2O3S: C, 45.59, H, 2.46, N, 3.80.Measured value: C, 45.69, H, 2.38, N, 3.76.
Embodiment 121 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-propionic acid
By 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 21) and commercially available (S)-methyl lactate preparation.White solid: mp 131-133 ℃; NMR (CDCl3): δ 8.37 (d, J=9Hz, 1H), 7.84 (d, J=8Hz, 1H), and 7.71-7.65 (m, 3H), 7.57-7.50 (m, 2H), 7.45 (ddd, J=8,7,1Hz, 1H), 7.18 (ddd, J=8,7,1Hz, 1H), 6.73 (d, J=8Hz, 1H), 5.36 (q, J=7Hz, 1H), 1.82 (d, J=7Hz, 3H); MS (EI): [M-H]+, 3 bromine isotope figures, 631 (14%), 633 (44%), 635 (42%), 637 (16%); The analytical calculation value of C25H15Br3O3S: C, 47.27, H, 2.38, N, 0.00.Measured value: C, 47.57, H, 2.33, N, 0.03.
Embodiment 122 (R, S)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-(1H-indol-3-yl)-propionic acid
By 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 21) and D, L-indoles-3-methyl lactate (embodiment 98) preparation.White solid: mp 146-147 ℃; NMR (CDCl3): δ 8.36 (d, J=9Hz, 1H), 8.04-8.03 (m, 1H, NH), 7.81 (d, J=8Hz, 1H), 7.72-7.65 (m, 2H), 7.60 (s, 2H), 7.59-7.59 (m, 2H), 7.42-7.37 (m, 2Hz), 7.28 (d, 2Hz, 1H), 7.22 (ddd, J=8,7,1Hz, 1H), 7.16 (dd, J=8,1Hz, 1H), 7.12 (dd, J=8,1Hz, 1H), 6.73 (d, J=8Hz, 1H), 5.45 (t, J=6Hz, 1H), 3.75 (d, J=7Hz, 2H); MS (FAB+): [M+], 3 bromine isotope figures, 747,749,751,753; The analytical calculation value of C33H20Br3NO3S: C, 52.83, H, 2.69, N, 1.87.Measured value: C, 53.08, H, 2.73, N, 1.19.
Embodiment 1232-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-caproic acid
By 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 21) and commercially available (R, S)-preparation of hydroxypentanoic acid methyl esters.White solid: mp 212-213 ℃; NMR (CDCl3): δ 8.36 (d, J=8Hz, 1H), 7.83 (d, J=8Hz, 1H), 7.67 (ddd, J=8,5,1Hz, 1H), 7.63 (dd, J=2,1Hz, 2H), 7.58-7.42 (m, 3H), 7.16 (t, J=8,1H), 6.75 (d, J=8Hz, 1H), 5.23 (t, J=5Hz, 1H), 2.26-2.16 (m, 2H), 1.8-1.73 (m, 1H), 1.60-1.41 (m, 3H), 0.99 (t, 3H); MS (EI): [M+], 3 bromine isotope figures, 674 (35%), 676 (90%), 678 (100%), 680 (35%); The analytical calculation value of C28H21Br3O3S: C, 49.66, H, 3.12, N, 0.00.Measured value: C, 49.28, H, 2.90, N, 0.09.
Embodiment 124 (2R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-4-(1-oxo-1,3-dihydro-isoindole-2-yl)-butyric acid
By 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 21) and (S)-(+)-Alpha-hydroxy-1-oxo-2-isoindoline methyl-butyrate (embodiment 106) preparation.White solid: mp 239-241 ℃; NMR (CDCl3): δ 8.34 (d, J=8Hz, 1H), 7.90 (d, J=8Hz, 1H), 7.80 (d, J=8Hz, 1H), 7.66 (ddd, J=8,7,1Hz, 1H), 7.62-7.58 (m, 4H), 7.52-7.47 (m, 3H), 7.39 (ddd, J=8,7,1Hz, 1H), 7.14 (ddd, J=8,7,1Hz, 1H), 6.72 (d, J=8, Hz, 1H), 5.39 (t, J=7Hz, 1H), 4.59 (m, 2H), 4.22-3.93 (m, 2H), 2.65 (t, J=6Hz, 2H); MS (+FAB): [M+H]+, 3 bromine isotope figures, 778,780,782,784; The analytical calculation value of C34H22Br3NO4S: C, 52.33, H, 2.84, N, 1.79.Measured value: C, 52.11, H, 2.73, N, 1.79.
Embodiment 125 (R)-2-[2,6-two bromo-4-(6-trifluoromethyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
By 2,6-two bromo-4-(6-trifluoromethyl-benzo [b] naphtho-[2,3-d] thiophene 11-yl)-phenol (embodiment 61) and (S)-2-hydroxyl-3-phenylpropionic acid methyl esters (embodiment 96) preparation.White solid: mp109-143 ℃; [a] D25=+47.99 ° (10.002mg/ml CH3OH); NMR (DMSO-d6): δ 13.26 (s, 1H), 8.30-8.27 (m, 1H), 8.06 (d, J=7Hz, 1H), 7.87-7.81 (m, 3H), 7.71-7.60 (m, 2H), 7.52 (dd, J=8,1Hz, 1H), and 7.43-7.24 (m, 6H), 6.60 (d, J=8Hz, 1H), 5.33 (t, J=7Hz, 1H), 3.41 (d, J=7Hz, 2H); MS (EI): [M+], 2 bromine isotope figures, 698 (8%), 700 (20%) 702 (15%); The analytical calculation value of C32H19Br2F3O3S: C, 54.88, H, 2.74, N, 0.00.Measured value: C, 55.29, H, 3.11, N, 0.10.
Embodiment 126 (R)-2-[2,6-two bromo-4-(6-methoxyl group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
By 2,6-two bromo-4-(6-methoxyl group benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 63) and (S)-2-hydroxyl-3-phenylpropionic acid methyl esters (embodiment 96) preparation.White solid: mp102-110 ℃; NMR (DMSO-d6): δ 13.2 (broad peak, 1H), 8.23 (d, J=8Hz, 1H), 8.02 (d, J=8Hz, 1H), 7.74 (dd, J=6,2Hz, 2H), 7.56 (ddd, J=8,7,1,1H), 7.56 (ddd, J=8,7,1,1H), and 7.51-7.45 (m, 2H), 7.42-7.40 (m, 2H), 7.36-7.32 (m, 4H), 7.30-7.20 (m, 2H), 6.68 (d, J=8Hz, 1H), 5.30 (t, J=7Hz, 1H), 4.13 (s, 3H), 3.41 (d, J=7Hz, 2H); MS (EI): [M+], M/z 660 (46%), and 662 (100%), 664 (54%); The high resolving power sample mass spectrum calculated value of C32H22Br2O4S: 659.960553, the actual measurement mass spectrum: 659.953875, mass deviation 6.7nam; The analytical calculation value of C32H22Br2O4S0.23C6H6: C, 58.08, H, 3.37, N, 0.00.Measured value: C, 59.34, H, 3.24, N, 0.04.
Embodiment 127 (R)-2-{2,6-two bromo-4-[6-chloro-benzo [b] naphtho-[2,3-d] thiophene-11-yls]-phenoxy group }-3-phenyl-propionic acid
By 2,6-two bromo-4-(6-chloro-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 60) and (S)-2-hydroxy-4-phenyl methyl propionate (embodiment 96) preparation.White solid: [a] 25/D=+19.63 ° (8.805mg/ml, CHCl3); NMR (DMSO-d6): δ 13.25-13.22 (wide unimodal, 1H), 8.32 (d, J=8Hz, 1H), 8.70 (d, J=8Hz, 1H), and 7.81-7.79 (ddd, J=8,7,1Hz, 1H), 7.79 (dd, J10,2Hz, 2H), 7.64 (ddd, J=8,7,1Hz, 1H), 7.58-7.49 (m, 2H), 7.42-7.32 (m, 4H), 7.29-7.24 (m, 2H), 6.66 (d, J=8Hz, 1H), 5.32 (t, J=6Hz, 1H), 3.41 (d, J=7Hz, 2H); MS (ESI): [(M-H)+], 2 bromine isotope figures, 1 chlorine isotope figure, 663 (40%), 665 (100%), 667 (60%), 669 (17%); The analytical calculation value of C31H19Br2ClO3S: C, 55.84, H, 2.87, N, 0.00.Measured value: C, 56.95, H, 3.00, N, 0.24.
Embodiment 128 (R)-2-[2,6-two bromo-4-(6-phenyl sulfane base-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
By 2,6-two bromo-4-(6-phenyl sulfane base-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 64) and (S)-2-hydroxy-4-phenyl methyl propionate (embodiment 96) preparation.White solid: NMR (DMSO-d6): δ 8.50 (d, J=8Hz, 1H), 7.98 (d, J=8Hz, 1H), 7.82 (d, J=2Hz, 1H), 7.81 (d, J=2Hz, 1H), 7.71 (ddd, J=6,5,2Hz, 2H), 7.58 (m, 2H), 7.47 (ddd, J=8,8,1Hz, 1H), 7.42 (d, J=8HZ, 2H), 7.34 (t, J=7Hz, 2H), 7.29-7.20 (m, 4H), 7.17-7.08 (m, 3H), 6.67 (d, J=8Hz, 1H), 5.35 (t, J=7Hz, 1H, CH), 3.41 (d, J=7Hz, 2H); MS (+FAB): [M+], 2 bromine isotope figures, 738 (35%), 740 (90%), 742 (60%); The analytical calculation value of C37H24Br2O3S2: C, 60.01, H, 3.27, N, 0.00.Measured value: C, 58.57, H, 3.04, N, 0.22.
Embodiment 129 (R)-2-[2,6-two bromo-4-(6-phenyl sulfane base-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-propionic acid
By 2,6-two bromo-4-(6-phenyl sulfane base-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 64) and commercially available (S)-methyl lactate preparation.White solid: mp 232-234 ℃; NMR (DMSO-d6): δ 8.51 (d, J=8Hz, 1H), 8.00 (d, J=8Hz, 1H), 7.89 (d, J=2Hz, 1H), 7.89 (d, J=2H, 1H), 7.71 (ddd, J=8,7,1Hz, 1H), 7.65 (d, J=8Hz, 1H), 7.60 (ddd, J=8,7,1Hz, 1H), 7.49 (ddd, J=8,7,1Hz, 1H), 7.28-7. (m, 4H), 7.17-7.09 (m, 4H), 6.68 (d, J=8Hz, 1H), 5.13 (dd, J=7,14Hz, 1H), 1.64 (d, J=7Hz, 2H); MS (+FAB): [M+], 2 bromine isotope figures, 662 (35%), 664 (100%), 666 (60%); The analytical calculation value of C31H20Br2O3S2: C, 56.04, H, 3.03, N, 0.00.Measured value: C, 55.53, H, 2.86, N, 0.24.
Embodiment 130 (R)-2-[2,6-two chloro-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
By 2,6-two chloro-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 67) and (S)-2-hydroxy-4-phenyl methyl propionate (embodiment 96) preparation.White solid: NMR (DMSO-d6): δ 13.25 (wide s, 1H), 8.29 (d, J=8Hz, 1H), 8.07 (d, J=8Hz, 1H), 7.80 (ddd, J=8,8,1,1H), 7.65-7.61 (m, 1H), 7.63 (d, J=2Hz, 1H), 7.61 (d, J=2Hz, 1H), 7.55 (dd, J=8,1,1H), 7.51 (dd, J=8,1,1H), 7.41 (dd, J=8,1,2H), 7.34 (ddd, J=8,8,1,2H), 7.27 (ddd, J=8,8,1,2H), 6.66 (d, J=8Hz, 1H), 5.28 (t, J=7Hz, 1H), 3.44-3.30 (m, 2H); MS (+FAB): [M+], 1 bromine isotope figure, 2 chlorine isotope figures, 620,622,624; The analytical calculation value of C31H19BRCl2O3S: C, 59.83, H, 3.08, N, 0.00.Measured value: C, 59.31, H, 2.93, N, 0.40.
Embodiment 131 (R)-benzo [b] naphtho-[2,3-d] thiophene-11-base-2,6-two iodo-phenoxy groups)-3-phenyl-propionic acid
By 4-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two iodo-phenol (embodiment 26) and (S)-2-hydroxy-4-phenyl methyl propionate (embodiment 96) preparation.White solid: mp 115-117 ℃; NMR (CDCl3): δ 8.36 (s, 1H), 7.95 (dd, J=8,1Hz, 1H), 7.87 (d, J=2Hz, 1H), 7.85 (d, J=2Hz, 1H), 7.78 (dd, J=8,1Hz, 1H), 7.58-7.27 (m, 9H), 7.12 (ddd, J=8,7,1Hz, 1H), 6.77 (d, J=8,1Hz, 1H), 5.56 (t, J=7Hz, 1H), 3.67-3.55 (m, 2H); MS (EI): [M+], 726; The analytical calculation value of C31H20I2O3S: C, 51.26, H, 2.77, N, 0.00.Measured value: C, 51.49, H, 2.87, N, 0.13.
Embodiment 132 (R)-2-(4-benzo [b] naphtho-[2,3-d] thiophene-11-base-2,6-two iodo-phenoxy groups)-propionic acid
By 4-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two iodo-phenol (embodiment 26) and commercially available (S)-methyl lactate preparation.White solid: mp 134-136:NMR (CDCl3): δ 8.38 (s, 1H), 7.95 (dd, J=8,6Hz, 1H), 7.93 (d, J=1Hz, 2H), 7.81 (d, J=8Hz, 1H), 7.58 (ddd, J=8,7,1Hz, 1H), 7.59-7.54 (m2H), 7.49-7.40 (m, 2H), 7.15 (ddd, J=8,7,1Hz, 1H), 6.77 (d, J=8,1Hz, 1H), 5.48 (q, J=7Hz, 1H), 1.82 (d, J=7Hz, 2H); MS (+FAB): [M+H]+, 651; The analytical calculation value of C26H16I2O3S: C, 46.18, H, 2.48, N, 0.00.Measured value: C, 46.60, H, 2.50, N, 0.21.
Embodiment 133 (R)-2-{2,6-two bromo-4-[6-(2-dimethylaminoethyl sulfane base)-benzo [b] naphtho-[2,3-d] thiophene-11-yl]-phenoxy group }-3-phenyl-propionic acid
By 2,6-two bromo-4-[6-(2-dimethylamino-ethyl sulfane base)-benzo [b] naphtho-[2,3-d] thiophene-11-yl]-phenol (embodiment 66) and (S)-2-hydroxyl-3-phenylpropionic acid methyl esters (embodiment 96) preparation.White solid: mp 169-174 ℃; NMR (DMSO-d6): δ 13.3 (wide s, 1H), 8.64 (d, J=8Hz, 1H), 8.04 (d, J=8Hz, 1H), 7.81 (ddd, J=8,7,1Hz, 1H), 7.76 (dd, J=16,1Hz), and 7.72-7.48 (m, 4H), 7.42-7.22 (m, 7H), 6.64 (d, J=8Hz, 1H), 5.32 (t, J=7Hz, 1H), 3.36-3.14 (m, 6H), 2.64 (s, 6H); MS (+FAB): [(M+H)+], 2 bromine isotope figures, 734 (55%), 736 (100%), 738 (70%); The analytical calculation value of C35H29Br2NO3S2: C, 54.45, H, 3.92, N, 1.81.Measured value: C, 54.46, H, 3.76, N, 1.66.
Embodiment 134 (R)-2-{2,6-two bromo-4-[6-(pyridin-4-yl sulfane base)-benzo [b] naphtho-[2,3-d] thiophene-11-yl]-phenoxy group }-3-phenyl-propionic acid
By 2,6-two bromo-4-[6-(pyridin-4-yl sulfane base)-benzo [b] naphtho-[2,3-d] thiophene-11-yl]-phenol (embodiment 65) and (S)-2-hydroxyl-3-phenylpropionic acid methyl esters (embodiment 96) preparation.White solid: NMR (DMSO-d6): δ 13.3 (wide unimodal, 1H), 8.45 (m, 2H), 8.37 (d, J=8Hz, 1H), 7.99 (d, J=8Hz, 1H), 7.85 (dd, J=7,2Hz, 2H), 7.77-7.74 (m, 1H), 7.66-7.65 (m, 2H), 7.50 (t, J7Hz, 1H), 7.43-7.25 (m, 8H), 6.68 (d, J=8Hz, 1H), 5.35 (dd, J8,2Hz, 1H), 3-43 (d, J=7Hz, 2H); MS (+FAB): [(M+H)+], 739.9 (70%), 741.9 (100%), 743.9 (90%); High resolving power (FAB)+ve, the calculated mass of C36H24Br2NO3S2: 739.95644; Actual measurement quality 739.96224, mass deviation 5.80mmu.The analytical calculation value of C36H23Br2NO3S2: C, 55.58, H, 3.11, N, 1.80.Measured value: C, 55.38, H, 3.37, N, 1.92.
Embodiment 135 (R)-2-[2,6-two bromo-4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-propionic acid
By 2,6-two bromo-4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 59) and commercially available (S)-methyl lactate preparation.White solid: mp 129-196 ℃ (decomposition); 25/D=+4.312 ° of optically-active [a] (8.812mg/ml, CHCl3); NMR (DMSO-d6): δ 13.12 (wide s, 1H), 8.12 (d, J=8,1Hz, 1H), 8.06 (d, J=7Hz, 1H), 7.82 (q, J=Hz, 2H), 7.75 (ddd, J=8,7,1Hz, 1H), 7.62-7.49 (m, 3H), 7.27 (ddd, J=8,7,1Hz, 1H), 6.61 (d, J=8Hz, 1H), 5.12 (q, J=7Hz, 1H), 1.63 (d, J=7Hz, 3H); MS (+FAB): [M+], 2 bromine isotope figures, 680 (45%), 682 (100%), 684 (60%); The analytical calculation value of C25H15Br2IO3S: C, 44.02, H, 2.22, N, 0.00.Measured value: C, 44.66, H, 2.54, N, 0.21.
Embodiment 136 (R)-2-[2,6-two bromo-4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
By 2,6-two bromo-4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 59) and (S)-2-hydroxy-4-phenyl methyl propionate (embodiment 96) preparation.White solid: [a] 25/D=+31.791 ° (9.940mg/ml, CHCl3); NMR (CDCl3): δ 8.23 (ddd, J=8,1,1Hz, 1H), 7.81 (ddd, J=8,1,1Hz, 1H), 7.64 (ddd, J=8,7,1Hz, 1H), 7.58 (dd, J=9,2Hz, 2H), and 7.52-7.39 (m, 7H), 7.37-7.28 (m, 2H), 6.68 (ddd, J=8,1,1Hz, 1H), 5.48 (t, J=7Hz, 1H ,-CH), 3.5 (d, J=7Hz, 2H); MS (+FAB): [M+], 2 bromine isotope figures, 756 (65%), 758 (100%), 760 (90%); The analytical calculation value of C31H19Br2IO3S: C, 49.10, H, 2.53, N, 0.00.Measured value: C, 50.75, H, 3.00, N, 0.09.
Embodiment 1372-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-pyridin-3-yl-propionic acid
By 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 21) and 3-pyridin-3-yl-ethyl propionate (embodiment 104) preparation.White solid: NMR (DMSO-d6): δ 8.98 (s, 1H), 8.82 (d, J=5Hz, 1H), 8.57 (d, J=8Hz, 1H), 8,28 (d, J=8Hz, 1H), 8.07 (d, J=8Hz, 1H), 7.96 (dd, J=8,6Hz, 1H), 7.82 (d, J=2Hz, 1H), 7.79 (m, 1H), 7.78 (d, J=2Hz, 1H), 7.62 (dd, J=8,1Hz, 1H), 7.57-7.50 (m, 2H), 7.27 (dd, J=8,1Hz, 1H), 6.67 (d, J=8Hz, 1H), 5.45 (dd, J=6,2,1H), 3.60 (m, 2H); MS (+FAB): [M+H]+, 3 bromine isotope figures, 710,712,714,716; The analytical calculation value of C30H18Br3NO3SHCl: C, 48.13, H, 2.56, N, 1.87.Measured value: C, 48.12, H, 2.86, N, 1.65.
Embodiment 138 (R)-2-[2,6-dimethyl-4-(6-methyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
By 2,6-dimethyl-4-(6-methyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 25) and (S)-2-hydroxyl-3-phenylpropionic acid methyl esters (embodiment 96) preparation.White solid: NMR (DMSO-d6): δ 13.0 (broadband, 1H), 8.18 (d, J=8Hz, 1H), 7.91 (d, J=8Hz, 1H), 7.61-7.53 (m, 2H), 7.43 (ddd, J=8,7,1Hz, 1H), and 7.45-7.28 (m, 5H), 7.25-7.21 (m, 1H), 7.01 (ddd, J=8,7,1Hz, 1H), 6.95 (d, J=5Hz, 2H), 6.53 (d, J=8Hz, 1H), 4.75 (t, J=7Hz, 1H), 3.32-3.24 (m, 2H), 2.87 (s, 3H), 2.56 (s, 3H), 2.18 (s, 3H): MS (EI): [M+], 516; The analytical calculation value of C34H28O3S: C, 79.04, H, 5.46, N, 0.00.Measured value: C, 79.13, H, 5.41, N, 0.11.
Embodiment 139 (2R)-2-[4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-di-isopropyl-phenoxy group)-3-phenyl-propionic acid
By 4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-di-isopropyl-phenol (embodiment 40) and (S)-2-hydroxyl-3-phenylpropionic acid methyl esters (embodiment 96) preparation.White solid: NMR (DMSO-d6): δ 13.08 (wide s, 1H), 8.27 (d, J=8Hz, 1H), 8.00 (d, J=8Hz, 1H), 7.76 (ddd, J=8,8,1,1H), and 7.66-7.58 (m, 2H), 7.43 (ddd, J=8,8,1Hz, 1H), 7.40-7.34 (m, 4H), 7.31-7.25 (m, 1H), 7.12 (s, 2H), 7.08 (ddd, J=8,8,1,1H), 6.36 (d, J=8Hz, 1H), 4.55 (t, J=7Hz, 1H), 3.45 (septet, J=7Hz, 2H), 3.32 (d, J=7Hz, 2H), 1.14 (d, J=7Hz, 3H), 1.09 (d, J=7Hz, 3H), 1.05 (d, J=7Hz, 3H), 1.03 (d, J=7Hz, 3H); MS (+FAB): [M+], 636 (95%), 638 (100%); The analytical calculation value of C37H33BrO3S: C, 69.70, H, 5.11, N, 0.00.Measured value: C, 69.48, H, 5.11, N, 0.11.
Embodiment 140 (R)-2-[4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-di-isopropyl-phenoxy group)-propionic acid
By 4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-di-isopropyl-phenol (embodiment 40) and commercially available (S)-methyl lactate preparation.White solid: mp 214-215 ℃; NMR (CDCl3): δ 8.37 (ddd, J=8,1,1,1H), 7.80 (d, J=8Hz, 1H), 7.70 (ddd, J=8,1,1Hz, 1H), 7.66 (ddd, J=8,8,1,1H), 7.48 (ddd, J=8,8,1Hz, 1H), 7.37 (ddd, J=8,8,1Hz, 1H), 7.18 (s, 2H), 7.01 (ddd, J=8,8,1Hz, 1H), 6.53 (d, J=8Hz, 1H), 4.75 (q, J=7Hz, 1H), 3.47 (septets, J=7Hz, 1H), 3.41 (septet, J=7Hz, 1H), 1.71 (d, J=7Hz, 3H), 1.25 (d, J=7Hz, 6H), 1.20 (d, J=7Hz, 3H), 1.19 (d, J=7Hz, 3H); MS (EI): 560 (90%), 562 (100%); The analytical calculation value of C31H29BrO3S: C, 66.31, H, 5.21N, 0.00.Measured value: C, 65.90, H, 5.18, N, 0.02.
Embodiment 141 (R)-2-[2,6-two bromo-4-(6-methyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
By 2,6-two bromo-4-(6-methyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 62) and (S)-2-hydroxyl-3-phenylpropionic acid methyl esters (embodiment 96) preparation.White solid: mp117-122 ℃; [a] D25=+34.13 ° (9.963mg/ml CHCl3); NMR (DMSO-d6): δ 8.17 (d, J=8Hz, 1H), 7.81 (d, J=8Hz, 1H), 7.63-7.58 (m, 1H), 7.57 (dd, J=6,2Hz, 2H), 7.52-7.46 (m, 2H), 7.42-7.38 (m, 3H), 7.37-7.28 (m, 3H), 7.16-7.10 (dt, J=1,6Hz, 1H), 6.76 (d, J=8Hz, 1H), 5.45 (t, J=7Hz, 1H, CH), 3.59 (d, J=7Hz, 2H), 2.98 (s, 3H); MS (EI): [M+], 643.6 (20%), 644.4 (50%), 645.5 (100%), 647.7 (30%); The analytical calculation value of C32H22Br2O3S: C, 59.46, H, 3.43, N, 0.00.Measured value: C, 59.34, H, 3.24, N, 0.04.
Embodiment 142 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-propionic acid
By 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 21) and commercially available (S)-(+)-methyl mandelate preparation.White solid: mp 135-137 ℃; MS (FAB-): [M-H]-, 693; The analytical calculation value of C30H17Br3O3S: C, 51.68, H, 2.46, N, 0.00.Measured value: C, 51.57, H, 2.89, N, 0.14.
Embodiment 143 (S)-2-[2-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-propionic acid
By 2-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 68) and commercially available (R)-methyl lactate preparation.White solid: mp 132-134 ℃; MS (+EI): [M+], 2 bromine isotope figures, 554,556,558; The analytical calculation value of C25H16Br2O3S: C, 53.98, H, 2.90, N, 0.00.Measured value: C, 52.97, H, 2.98, N, 0.04.
Embodiment 144 (R)-2-[2-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-propionic acid
By 2-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (embodiment 68) and commercially available (R)-methyl lactate preparation.White solid: mp 133-134.5 ℃; MS (ESI): [M-H]-, 2 bromine isotope figures, 553,555,557; The analytical calculation value of C25H16Br2O3S: C, 53.98, H, 2.90, N, 0.00.Measured value: C, 53.18, H, 2.82, N, 0.04.
Embodiment 145 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-4-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-methyl-butyrate
Under dry nitrogen atmosphere, with diethylazodicarboxylate (0.293ml, 1.86mmol) drop under the room temperature, 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (0.700g, 1.24mmol), (S)-(+)-2-hydroxyl-1,3-dioxo-2-isoindoline methyl-butyrate (0.490g, 1.86mmol), (0.488g is 1.86mmol) and in the stirred suspension of benzene (5.5ml) for triphenylphosphine.Dissolve, solution was heated 1.5 hours in 80 ℃ of oil baths.After the cooling room temperature, reaction mixture dilutes with methylene dichloride, and adds silica gel (20ml).Reaction mixture is concentrated, and adsorptive separates (83: 17 sherwood oils: ethyl acetate), obtain the title compound (0.822g, 81%) of white solid: mp 221-222 ℃ through flash chromatography; NMR (DMSO-d6): δ 8.29 (d, J=8Hz, 1), 8.08 (d, J=8Hz, 1H), 7.98 (ddd, J=8,7,1Hz, 2H), 7.87-7.83 (m, 4H), 7.80 (ddd, J=8,7,1Hz, 1H), 7.66-7.58 (m, 2H), 7.53 (ddd, J=8,7,1Hz, 1H), 7.29 (ddd, J=8,7,1Hz, 1H), 6.71 (d, J=8Hz, 1H), 5.16 (t, 1H), 3.94 (m, 2H), 3.71 (s, 3H), 2.50 (m, 2H); MS (FAB+): [M+], 3 bromine isotope figures, 805 (22%), 807 (88%), 809 (100%), 811 (42%); The analytical calculation value of C35H22Br3NO5S: C, 52.01, H, 2.74, N, 1.73.Measured value: C, 52.02, H, 2.70, N, 1.73.
Embodiment 146 (R)-2-(4-benzo [b] naphtho-[2,3-d] thiophene-11-base-2,6-two bromo-phenoxy groups)-4-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-butyric acid
Under dry nitrogen atmosphere, with iodo trimethyl silane (0.203ml, 1.43mmol) add (the R)-2-[2 under the room temperature, 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-4-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-methyl-butyrate (0.770,0.953mmol) in the stirred suspension in methylene dichloride (8ml).After 2 hours, (3 * 0.203ml 4.29mmol) added in the dark brown solution that produces under room temperature, adds 3 times with the iodo trimethyl silane every 12 hours.Solution with water (0.4ml) quencher concentrates and handles (3 * 50ml) with benzene.Be dissolved in the resistates that produces in the ethyl acetate (60ml) and add silica gel (through acid elution, 8ml).Remove solvent, adsorptive separates (7: 3 sherwood oils: ethyl acetate), obtain the title compound (0.304g, 45%) of yellow solid: mp 222-223 ℃ through flash chromatography; NMR (CDCl3): δ 8.37 (s, 1H), 7.95 (d, J=8Hz, 1H), 7.89-7.85 (m, 2H), 7.79 (dd, J=8,1Hz, 1H), 7.78-7.71 (m, 2H), 7.64 (d, J=10Hz, 1H), 7.62 (d, J=10Hz, 1H), 7.59 (dd, J=8,1Hz, 1H), 7.55 (ddd, J=8,7,1Hz, 1H), 7.46 (ddd, J=8,7,1Hz, 1H), 7.40 (ddd, J=8,7,1Hz, 1H), 7.19 (ddd, J=8,7,1Hz, 1H), 6.88 (d, J=8Hz, 1H), 5.27 (t, J=7Hz, 1H, 1H, CH), 4.12 (m, 2H), 2.65 (t, J=6Hz, 2H); MS (FAB-): [M-H]-, 2 bromine isotope figures, 713,714,716; The analytical calculation value of C34H21Br2NO5S: C, 57.08, H, 2.96, N, 1.96.Measured value: C, 56.43, H, 2.74, N, 1.90.
Embodiment 147 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-4-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-butyric acid
Under dry nitrogen atmosphere, with iodo trimethyl silane (2.8ml, the 1N dichloromethane solution) (the R)-2-[2 under dripping-10 ℃, 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-4-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-methyl-butyrate (0.770,0.953mmol) in the stirred solution in methylene dichloride (14ml).Allow the solution temperature to room temperature, stir then and spend the night.With the reaction mixture quencher, water (100ml) is dilution further, is allocated in water and methylene dichloride (between 2 * 75ml).Dichloromethane extraction liquid is concentrated and grind with sherwood oil.With its recrystallize from acetate, obtain the title compound (0.228g, 52%) of gray solid: mp215-217 ℃ then; NMR (CDCl3): δ 8.35 (d, J=8Hz, 1), and 7.89-7.86 (m, 2H), 7.82 (dd, J=8,1Hz, 1H), 7.76-7.71 (m, 2H), 7.67 (ddd, J=8,7,1Hz, 1H), 7.63-7.59 (m, 3H), 7.58 (ddd, J=8,7,1Hz, 1H), 7.42 (ddd, J=8,7,1Hz, 1H), 7.20 (ddd, J=8,7,1Hz, 1H), 6.81 (d, J=8Hz, 1H), 5.27 (t, J=7Hz, 1H, 1H), 4.12 (m, 2H), 2.65 (t, J=7Hz, 2); MS (EI): [M+], 3 bromine isotope figures, 791 (75%), 793 (98%), 795 (100%); 797 (38%); The analytical calculation value of C34H20Br3NO5S: C, 51.41, H, 2.54, N, 1.76.Measured value: C, 51.65, H, 2.37, N, 1.70.
Embodiment 148 (R)-2-(4-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group)-4-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-butyric acid
Under dry nitrogen atmosphere, with iodo trimethyl silane (1.31ml, 9.23mmol) be added drop-wise to (R)-2-(4-benzo [b] naphtho-[2 under-0 ℃, 3-d] thiophene-11-yl)-phenoxy group)-4-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-(1.17g is 2.05mmol) in the stirred suspension in methylene dichloride (15ml) for methyl-butyrate.After 1 hour, allow the solution temperature to room temperature.After 1 hour, reaction mixture further dilutes with 10% aqueous solution of sodium bisulfite quencher, water (100ml).Aqueous mixture extracts with ethyl acetate (150ml).Acetic acid ethyl acetate extract washes with water, with salt solution and anhydrous magnesium sulfate drying and concentrated, obtains white solid.With this solid recrystallize from acetic acid aqueous solution, and through HPLC (Dynamax C18 post, 90: 10 acetonitriles: purifying water (all having 0.1%TFA)) obtains the title compound (0.420g, 32%) of light yellow solid: mp 145-147 ℃; NMR (CDCl3): δ 8.31 (s, 1H), 7.92 (d, J=8Hz, 1H), 7.87-7.84 (2 kinds of diastereomers, J=8Hz, 2H), 7.75 (d, J=8Hz, 1H), 7.72-7.69 (2 kinds of diastereomers, J=8Hz, 2H), 7.59 (d, J=8Hz, 1H), 7.49 (ddd, J=8,7,1Hz, 1H), and 7.39-7.33 (m, 2H), 7.29-7.22 (m, 2H), 7.15 (ddd, J=8,7,1Hz, 1H), 7.05 (dd, J=9,8Hz, 1H), 7.01 (dd, J=9,8Hz, 1H), 6.75 (d, J=8Hz, 1H), 4.99 (t, J=6Hz, 1H), 4.09 (t, J=6Hz, 2H), 2.52 (q, J=6Hz, 2H); MS (+FAB): [M+H]+, 558; The analytical calculation value of C34H23NO5S: C, 73.23, H, 4.16, N, 2.51.Measured value: C, 71.82, H, 4.00, N, 2.61.
Embodiment 149 (R)-2-[4-(3-carboxyl methoxyl group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group-4-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-butyric acid
Under dry nitrogen atmosphere, with diethylazodicarboxylate (DEAD, 0.133ml, 0.845mmol) add to 11-(4-hydroxyl-phenyl)-benzo [b] naphtho-[2 under the room temperature, 3-d] thiophene-11-base oxygen base)-methyl acetate (0.140g, 0.338mmol), the L-3-methyl phenylacetate (0.133g, 0.845mmol), (0.222g is 0.845mmol) and in the stirred suspension of benzene (1.5ml) for triphenylphosphine.Dissolve, solution was heated 6 hours in 80 ℃ of oil baths.Add again the diethylazodicarboxylate (DEADm 0.053ml, 0.338mmol), the L-3-methyl phenylacetate (0.070g, 0.338mmol) and triphenylphosphine (0.103g, 0.338mmol).5.5 after hour reaction mixture is cooled to room temperature.Reaction mixture dilutes with ether, and adds silica gel.Reaction mixture is concentrated, and adsorptive separates (99: 1 to 98: 2 methylene dichloride of gradient: acetonitrile), obtain white solid (0.190g) through flash chromatography.With this solid recrystallize from the acetonitrile that contains 0.1% trifluoroacetic acid, obtain white solid (144mg).(1.4ml is in the stirred solution of this solid in methylene dichloride (3.0ml) that dichloromethane solution adding 1.4mmol) is-78 ℃ with the 1.0M boron tribromide.After 45 minutes, with the reaction mixture temperature to room temperature.3.5 after hour, reaction mixture is cooled to-78 ℃, and the 1.0N boron tribromide of adding additional quantity (0.8ml, 0.8mmol).With the reaction mixture temperature to room temperature.After 2 hours, add entry again, the reaction mixture ethyl acetate extraction.Ethyl acetate is concentrated and (anti-phase: 7: 3 acetonitriles with 0.1% trifluoroacetic acid: purifying water) through HPLC mutually.Compound (13mg) recrystallize from acetic acid/water that produces obtains the title compound (0.005g, 2%) of white solid: mp 259-260 ℃; NMR (DMSO-d6): δ 13.2 (wide s, 2H), 8.54 (s, 1H), 8.02 (d, J=8Hz, 1H), and 7.88-7.81 (m, 4H), 7.55-7.44 (m, 4H), 7.25 (dd, J=9,2Hz, 2H), 7.11-7.04 (m, 2H), 6.79 (dd, J=9,2Hz, 1H), 6.52 (d, J=9Hz, 1H), 5.03 (dd, J=8,2Hz, 1H), 4.75 (s, 2H), 3.92 (m, 2H), 2.32 (m, 2H); MS (FAB+): 632 (10%, M+H); Analysis mode HPLC: purity is 98.8%.
Embodiment 150 (R)-2-[4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-4-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-butyric acid
Under dry nitrogen atmosphere, with boron tribromide (1M dichloromethane solution, 10.4ml, 10.4mmol) drop to (R)-2-[4-(6-bromo-benzo [b] naphtho-[2 of-10 ℃, 3-d] thiophene-11-yl)-phenoxy group-4-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-(1.35g is 2.08mmol) in the stirred solution in methylene dichloride (35ml) for methyl-butyrate.After 1 hour, allow the solution temperature to room temperature.After 1 hour, with the reaction mixture quencher, water (100ml) is dilution further, is allocated between water and the methylene dichloride.With the concentrated mutually solid that obtains of methylene dichloride.Isolate solid, through HPLC (Dynamax C18 post, 95: 5 acetonitriles: purifying water (all having 0.1%TFA)) obtains the title compound (0.420g, 32%) of light yellow solid: mp＞69 ℃ (decomposition); NMR (CDCl3): δ 8.32 (d, J=8Hz, 1H), 7.86-7.84 (2d, J=8Hz, 2H), 7.77 (d, J=8Hz, 1H), 7.72-7.70 (d, J=8Hz, 2H), 7.64-7.59 (m, 2H), 7.43-7.36 (m, 2H), 7.25-7.16 (m, 3H), 7.05 (dd, J=9,8Hz, 1H), 7.01 (dd, J=9,8Hz, 1H), 6.68 (d, J=8Hz, 1H), 4.99 (t, J=6Hz, 1H), 4.09 (t, J=6Hz, 2H), 2.52 (q, J=6Hz, 2H); MS (EI): [M+], 1 bromine isotope figure, 635 (90%), 637 (100%); The analytical calculation value of C34H22BrNO5S: C, 64.16, H, 3.48, N, 2.20.Measured value: C, 64.19, H, 4.04, N, 2.08.
Embodiment 151 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-Succinic acid dimethylester
Under dry nitrogen atmosphere, with diethylazodicarboxylate (0.254ml, 1.61mmol) drop to 2 under the room temperature, 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (0.600g, 1.10mmol), (S)-(-)-oxysuccinic acid dimethyl ester (0.213ml, 1.61mmol) and triphenylphosphine (0.421g is 1.61mmol) in the stirred suspension in benzene (7.5ml).Solution was heated 23 hours in 79 ℃ of oil baths.Add extra (S)-(-)-oxysuccinic acid dimethyl ester (0.043g, 0.321mmol) and triphenylphosphine (0.084g, 0.321mmol) and the diethylazodicarboxylate (0.050ml, 0.321mmol), with reaction mixture reheat 10 hours.Reaction mixture is cooled to room temperature,, mixes with silica gel (20ml) and concentrated with methylene dichloride dilution.The silica gel adsorption thing separates (92: 8 sherwood oils: ethyl acetate), obtain the title compound (0.398g, 51%) of white solid: mp 118-121 ℃ through flash chromatography; NMR (CDCl3): δ 8.36 (dd, J=8,0.5Hz, 1H), 7.83 (dd, J=8,0.5Hz, 1H), 7.68 (ddd, J=8,7,1Hz, 1H), 7.61-7.59 (m, 3H), 7.55-7.43 (m, 2H), and 7.26-7.21 (m, 1H), 6.79 (d, J=8Hz, 1H), 5.46 (t, J=6Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.32-3.30 (m, 1H); MS (EI): [M+], 3 bromine isotope figures, 704 (5%), 706 (15%), 708 (15%), 710 (4%); The analytical calculation value of C28H19Br3O5S: C, 47.55, H, 2.71, N, 0.00.Measured value: C, 47.93, H, 2.65, N, 0.14.
Embodiment 152 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-succsinic acid
In the pressure bottle of sealing, with (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-(0.317g 0.448mmol) mixes with water (5ml) and concentrated hydrochloric acid (1ml) and heated 9 hours at 4M HCl De diox (5ml) solution Succinic acid dimethylester.After at room temperature keeping 14 hours again, reaction mixture is allocated between water and the ether.Separate each layer, acid-treated silica gel (7ml) is added in the ether layer.Remove solvent, adsorptive separates (acid-treated silica gel, 80: 20 sherwood oils of elutriant: ethyl acetate), obtain the title compound (0.142g, 47%) of white solid: mp 163-164 ℃ through flash chromatography; [a] D25=+14.16 ° (8.825mg/ml, methyl alcohol); NMR (DMSO-d6): δ 13.6-13.2 (wide unimodal, 1H), 12.7-12.6 (wide unimodal, 1H), 8.28 (d, J=8Hz, 1H), 8.07 (d, J=8Hz, 1H), 7.82-7.78 (m, 3H), 7.65-7.57 (m, 2H), 7.52 (dd, J=7,1Hz, 1H), 7.31 (dd, J=7,1,1H), 6.70 (d, J=8Hz, 1H), 5.32 (d, J=8Hz), 3.67 (m, 2H); MS (FAB): [M-H]-, detect 3 bromine figures, 675 (25%), 677 (10%), 679 (25%); The analytical calculation value of C26H15Br3O5S: C, 45.78, H, 2.23, N, 0.00.Measured value: C, 46.42, H, 2.40, N, 0.05.
Embodiment 1532-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-(the 4-fluoro-phenyl-propionic acid tert-butyl ester
Under the dry argon gas atmosphere, (through CaH2 distillation, 0.169ml 1.2mol) adds in the anhydrous tetrahydro furan (0.65ml) and is cooled to-74 ℃ with Diisopropylamine.(2.5M in hexane, 0.516ml 1.29mmole), with mixture temperature to 0 ℃ 10 minutes, is cooled to-74 ℃ again to drip n-Butyl Lithium.Add hexamethylphosphoramide (0.83ml), slow (0.5 hour) drips (R)-2-[2 after 5 minutes, 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-the propionic acid tert-butyl ester (0.715g, anhydrous tetrahydro furan 1.06mmole) (2.8ml) solution.After stirring 1 hour under-75 ℃, and dropping 4-fluoro benzyl bromide (0.158ml, 1.29mmol).In-80 ℃ of restir after 1 hour, with the reaction mixture temperature to ambient temperature overnight.Reaction mixture is with rare aqueous ammonium chloride solution quencher and be allocated in water (100ml) and 1: 1 methylene dichloride: between the diethyl ether solution (130ml).After extracting again 1 time and merge organic layer with methylene dichloride (50ml), add silica gel and also remove solvent.Methylene dichloride) and HPLC (post: Waters SilicaPrep Pak adsorptive is through flash chromatography (7: 3 sherwood oils of elutriant:; 99: 1 to 95: 5 sherwood oils of gradient: ethyl acetate; Flow velocity=225ml/min), obtain the title compound (0.265g, 32%) of white solid: mp 80-100 ℃; NMR (CDCl3): δ 8.35 (dd, J=8,1Hz, 1H), 7.83 (dd, J=6,1Hz, 1H), 7.66 (ddd, J=6,5,1Hz, 1H), 7.58 (dd, H=4,2Hz, 2H), 7.53-7.38 (m, J=2Hz, 5H), 7.18 (ddd, J=7,1,1,1H), 7.04 (t, J=9Hz, 2H), 6.83 (d, J=8Hz, 1H), 5.31 (t, J=6Hz, 1H), 3.49 (t, J=6Hz, 2H), 1.40 (s, 9H); MS (FAB+): [M+], 3 bromine figures, 782 (20%), 784 (70%), 786 (80%), 788 (35%); The analytical calculation value of C35H26Br3FO3S: C, 53.53, H, 3.34, N, 0.00.Measured value: C, 53.25, H, 3.21, N, 0.04.
Embodiment 154 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-naphthalene-2-base-propionic acid tert-butyl ester
Under the dry argon gas atmosphere, (through CaH2 distillation, 0.233ml 1.78mmol) adds in the anhydrous tetrahydro furan (0.91ml) and is cooled to-74 ℃ with Diisopropylamine.(2.5M in hexane, 0.71ml 1.78mmole), with mixture temperature to 0 ℃ about 20 minutes, is cooled to-75 ℃ again to drip n-Butyl Lithium.Add hexamethylphosphoramide (2ml), slow (0.5 hour) drips (R)-2-[2 after 10 minutes, 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-the propionic acid tert-butyl ester (1.004g, anhydrous tetrahydro furan 1.48mmole) (3ml) solution.After stirring 1 hour under-75 ℃, and dropping 2-brooethyl naphthalene (0.393g, 1.78mmol).In-80 ℃ of restir after 0.5 hour, with the reaction mixture temperature to ambient temperature overnight.Reaction mixture is with rare aqueous ammonium chloride solution quencher and be allocated in water (100ml) and 1: 1 methylene dichloride: between the diethyl ether solution (200ml).After extracting again 1 time and merge organic layer with methylene dichloride, ethyl acetate) and HPLC (2 times) (first post: Waters SilicaPrep Pak water (100ml) washing and through flash chromatography (7: 3 sherwood oils of elutriant:; 98: 2 hexane/acetate acetate of constant gradient; Flow velocity=225ml/min; Second post: Waters Silica Prep Pak; Gradient, 75: 25 to 60: 40 sherwood oils: methylene dichloride), obtain the title compound (0.280g, 23%) of white solid: NMR (CDCl3): δ 8.35 (d, J=8Hz, 1H), 7.88-7.80 (m, 5H), 7.66 (ddd, J=6,5,1Hz, 1H), 7.61 (d, J=2Hz, 1H), 7.60 (d, H=2Hz, 1H), 7.58-7.56 (m, 2H), 7.51-7.41 (m, 4H), 7.18 (ddd, J=7,1,1,1H), 6.83 (dd, J=7,1Hz, 1H), 5.44 (t, J=8Hz, 1H), 1.34 (s, 9H); MS (FAB+): [M+], 3 bromine figures, 814 (30%), 816 (95%) 818 (100%); The analytical calculation value of C39H296Br3O3S: C, 57.30, H, 3.58, N, 0.00.Measured value: C, 57.55, H, 3.75, N, 0.02.
Embodiment 1552-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-(4-fluoro-phenyl)-propionic acid
With 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-(0.232g, 0.295mmole) suspension in trifluoroacetic acid (5ml) was in 55 ℃ of heating 11 hours for 3-(4-fluoro-phenyl)-propionic acid tert-butyl ester.After being cooled to room temperature, inclining reaction mixture to water (60ml) and use extracted with diethyl ether.The extraction liquid water and the salt water washing that merge concentrate and in 60 ℃ of vacuum-dryings, obtain the title compound (0.187g, 98%) of pale solid: NMR (CDCl3): δ 8.36 (d, J=7Hz, 1H), 7.82 (d, J=7Hz, 1H), 7.68 (ddd, J=8,6,2Hz, 1H), 7.58 (dd, J=8,2Hz, 2H), 7.55-7.48 (m, 2H), 7.45-7.35 (m, 3H), 7.15 (dt, J=7,1,1Hz, 1H), 7.03 (ttJ=10,3,1,2H), 6.71 (d, J=8Hz, 1H), 5.44 (t, J=6Hz, 1H), 3.56 (d, J=7Hz, 2H); MS (+FAB): [M+], 3 bromine isotope figures, 726 (15%), 728 (30%), 730 (35%), 732 (15%); The analytical calculation value of C31H18Br3FO3S: C, 51.06, H, 2.49, N, 0.00.Measured value: C, 50.80, H, 2.46, N, 0.10.
Embodiment 1562-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-naphthalene-2-base-propionic acid
With 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-naphthalene-2-base-propionic acid tert-butyl ester (0.221g, trifluoroacetic acid 0.270mmole) (10ml) solution be heated to 50 ℃ 15 hours.Mixture is cooled to room temperature and mixes with water.Add ether, separate with water layer and concentrate from the organic suspension liquid that will produce.Resistates in 46 ℃ of vacuum concentration, is obtained the title compound (0.186g, 90%) of pale solid: mp 270-271 ℃; NMR (DMSO-d6): δ 13.25 (wide unimodal, 1H), 8.28 (d, J=8Hz, 1H), 8.06 (d, J=8Hz, 1H), 7.91 (m, 4H), 781 (d, J=2Hz, 1H), 7.79 (d, J=2Hz, 1H), 7.82-7.77 (m, 1H), 7.63-7.47 (m, 6H), 7.25 (dd, J=7,1Hz, 1H), 6.64 (d, J=8Hz, 1H), 5.42 (d, J=7Hz, 1H), 3.59 (d, J=7Hz, 2H); MS (FAB+): [M+], 3 bromine figures, 757.8 (21%), 759.8 (100%), 761.8 (100%) 763.8 (50%); The analytical calculation value of C31H19Br3O3S: C, 55.07, H, 3.04, N, 0.00.Measured value: C, 55.36, H, 2.89, N, 0.06.
Embodiment 157 trifluoro-methanesulfonyl oxy methyl-phosphorous acid diethyl esters
According to D.P.Phollion and S.S.Andrew Tet.Lett.1986, the preparation of the method for 1477-1480.Under nitrogen, with trifluoromethanesulfanhydride anhydride (11.6ml, 68.9mmol) methylene dichloride (45ml) solution in 20 minutes, drop to-10 ℃ the hydroxymethyl phosphonic acid diethyl ester (10.82g, 64.4mmol) and pyridine (5.76ml is in the stirred solution of methylene dichloride 68.9mmol) (170ml).Mixture was stirred 1 hour in-10 ℃, and place refrigerator (15 ℃ to-20 ℃) to spend the night.Reaction mixture washs with cold methylene dichloride dilution and with cold 1N HCl and frozen water.Separate organic layer, with salt solution, anhydrous magnesium sulfate drying and concentrate, obtain oily matter (12.58g, 65%): MS (+FAB): [M+H]+, 423.
Embodiment 158{2,6-two bromo-4-[6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yls]-phenoxymethyl }-diethyl phosphonate
Under dry nitrogen atmosphere, with 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl]-phenol (1.00g, 1.78mmol) THF (5ml) solution in 15 minutes, drop to 0 ℃ 80% sodium hydride (0.08g be in THF 2.67mmol) (10ml) stirred solution.Mixture stirred 40 minutes in 0 ℃ of oil bath after, in 15 minutes, drip trifluoro-methanesulfonyl oxy methyl-phosphorous acid diethyl ester (0.80g, 2.67mmol) solution.Then with the reaction mixture temperature to room temperature and stirred 1 hour.Reaction mixture water (80ml) quencher and dilution.Leach the solid of generation, wash with water and grind with sherwood oil.Solid in 50 ℃ of vacuum-dryings, is obtained the title compound (1.12g, 88%) of white solid: mp 178-180 ℃; NMR (CDCl3): δ 8.36 (d, J=9Hz, 1H), 7.84 (d, J=8Hz, 1H), 7.68 (ddd, J=7,6,1Hz, 1H), 7.62 (s, 2H), and 7.57-7.49 (m, 2H), 7.45 (ddd, J=8,7,1Hz, 1H), 7.18 (ddd, J=8,7,1Hz, 1H), 6.73 (d, J=8Hz, 1H), 4.61 (s, 2H), 4.41 (q, 4H), 1.49 (t, 6H, CH3); MS (EI): [M+], 3 bromine isotope figures, 710 (35%), 712 (95%), 714 (100%), 716 (40%); The analytical calculation value of C27H22Br3O4PS: C, 45.47, H, 3.11, N, 0.00.Measured value: C, 45.30, H, 2.95, N, 0.07.
Embodiment 159[4-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxymethyl]-diethyl phosphonate
Under dry nitrogen atmosphere, with 4-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-(1.00g, THF 3.06mmol) (5ml) solution dropped to 0 ℃ 80% sodium hydride in 15 minutes (0.138g is in THF 4.95mmol) (10ml) stirred solution for phenol.Mixture stirred 1 hour in 0 ℃ of oil bath after, in 15 minutes, drip trifluoro-methanesulfonyl oxy methyl-phosphorous acid diethyl ester (1.4g, 4.95mmol) solution.Then with the reaction mixture temperature to room temperature and stirred 2 hours.Reaction mixture water (150ml) quencher and dilution.(2 * 150ml) extract aqueous mixture with ethyl acetate.Acetic acid ethyl acetate extract washes with water, with salt solution and anhydrous magnesium sulfate drying and concentrated, obtains white solid.Solid separates (elutriant: 7: 3 sherwood oils: ethyl acetate), obtain the title compound (0.922g, 63%) of white solid: mp 129-130 ℃ through flash chromatography; MS (EI): [M+], 476 (100%, MI); The analytical calculation value of C27H25O4PS: C, 68.05, H, 5.29, N, 0.00.Measured value: C, 66.58, H, 5.34, N, 0.00.
Embodiment 1603-phenyl-1-hydrogen-1-propyl phosphonous acid diethyl ester
With aluminum oxide (15g) add hydrocinnamic aldehyde under the room temperature (3.93ml, 28.3mmol) and diethyl phosphite (3.72ml is in the stirred solution of methylene dichloride 28.3mmol) (30ml).Mixture was stirred under room temperature 2 days.Reaction mixture is filtered, methylene dichloride filtrate is concentrated and grind, obtain the title compound (4.10g, 53%) of white solid: mp 60-61 ℃ with sherwood oil; MS (+FAB): [M+H]+, 273 (100%, MI); The analytical calculation value of C13H31O4P: C, 57.35, H, 7.77, N, 0.00.Measured value: C, 57.48, H, 7.87, N, 0.04.
Embodiment 161{1-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propyl group }-diethyl phosphonate
Under dry nitrogen atmosphere, with diethylazodicarboxylate (0.420ml, 2.67mmol) drop to 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl]-phenol (1.00g, 1.78mmol), 3-phenyl-1-hydrogen-1-propyl phosphonous acid diethyl ester (0.730g, 2.67mmol), (0.700g is 2.67mmol) and in the stirred suspension under the room temperature of benzene (9ml) for triphenylphosphine.Solution is heated 4 minor clocks in 80 ℃ of oil baths.After being cooled to room temperature, reaction mixture is allocated between water (80ml) and the methylene dichloride (100ml).Methylene dichloride is used 10% aqueous hydrochloric acid (80ml) washing mutually and is added silica gel (20ml).Remove solvent, the silica gel adsorption thing separates (95: 5 methylene dichloride: acetonitrile), obtain the title compound (1.17g, 73%) of white solid: mp 161-162 ℃ through flash chromatography; MS (EI): [M+], 3 bromine isotope figures, 814,816,818,820; The analytical calculation value of C35H30Br3O4PS: C, 51.43, H, 3.70, N, 0.00.Measured value: C, 51.36, H, 3.67, N, 0.03.
Embodiment 162[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxymethyl]-phosphonic acids
Under dry nitrogen atmosphere, with iodo trimethyl silane (0.63ml, 4.41mmol) in 10 minutes, drop to 0 ℃ { 2,6-two bromo-4-[6-bromo-benzo [b] naphtho-s [2,3-d] thiophene-11-yl]-phenoxymethyl }-(1.05g is in methylene dichloride 1.47mmol) (29ml) stirred solution for diethyl phosphonate.In 0 ℃ after 1 hour, reaction mixture water (0.5ml) quencher was stirred 30 minutes under room temperature, water (50ml) dilution then.Leach solid, be allocated in it between ethyl acetate (100ml) and 20% aqueous hydrochloric acid (60ml) and stirred 3 hours.Leach solid, wash with water and grind with sherwood oil.Solid in 100 ℃ of vacuum-dryings, is obtained the title compound (0.428g, 44%) of pale solid: mp 334-335 ℃; NMR (DMSO-d6): δ 8.26 (d, J=9Hz, 1H), 8.07 (d, J=8Hz, 1H), 7.84 (s, 2H), 7.79 (ddd, J=8,7,1Hz, 1H), 7.65-7.57 (m, 2H), 7.52 (dd, J=7,1Hz, 1H), 7.32 (ddd, J=8,7,1Hz, 1H), 6.67 (d, J=8Hz, 1H), 4.32 (d, J=1Hz, 2H); MS (ESI): [M-H]-, 3 bromine isotope figures; The analytical calculation value of C23H14Br3O4PS: C, 42.04, H, 2.15, N, 0.00.Measured value: C, 41.26, H, 2.12, N, 0.05; Karl Fischer:0.58molH2O.
Embodiment 163[4-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxymethyl]-phosphonic acids
Under dry nitrogen atmosphere, with iodo trimethyl silane (0.78ml, 5.49mmol) in 10 minutes, drop to 0-5 ℃ [4-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxymethyl]-(0.871g is in the stirred solution of methylene dichloride 1.83mmol) (24ml) for diethyl phosphonate.After 1 hour, this solution with water (0.6ml) quencher adds 10% aqueous sodium carbonate (100ml), the mixture washed with dichloromethane.Water layer is with 10% aqueous hydrochloric acid acidifying.Leach solid, recrystallize from methyl alcohol (75ml) obtains the title compound (0.65g, 85%) of white solid: mp240-242 ℃; MS (EI): [M+], 420; The analytical calculation value of C23H17O4PS: C, 65.17, H, 4.08, N, 0.00.Measured value: C, 63.95, H, 3.89, N, 0.41.
Embodiment 164{1-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propyl group }-phosphonic acids
Under dry nitrogen atmosphere, with iodo trimethyl silane (0.56ml, 3.93mmol) in 10 minutes, drop to 0 ℃, { 1-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propyl group }-(1.07g is in methylene dichloride 1.31mmol) (26ml) stirred solution for diethyl phosphonate.In 0 ℃ after 1 hour, reaction mixture stirred 30 minutes under room temperature with 10% aqueous solution of sodium bisulfite (1ml) quencher.Mixture is allocated between methylene dichloride (100ml) and the water (100ml).Methylene dichloride is used 18% aqueous hydrochloric acid (100ml) washing mutually, concentrates, and grinds with sherwood oil, obtains rough solid (0.894g).With solid recrystallize from 85% acetic acid aqueous solution (50ml), obtain the title compound (0.466g, 47%) of pale solid: NMR (CDCl3): δ 8.33 (d, J=9Hz, 1H), 7.76 (d, J=7Hz, 1H), 7.59 (ddd, J=8,7,1Hz, 1H), 7.48-7.40 (m, 3H), and 7.36-7.28 (m, 2H), 7.06-6.98 (m, 5H), 6.91-6.83 (m, 1H), 6.77 (d, J=8Hz, 1H), and 5.47-5.42 (m, 1H), 4.50 (s, 2H), 3.05-2.85 (m, 2H), and 2.59-2.41 (m, 2H); MS (FAB-): [M-H]-, 3 bromine isotope figures, 756; The analytical calculation value of C31H22Br3O4PS: C, 48.91, H, 2.91, N, 0.00.Measured value: C, 49.29, H, 2.90, N ,-0.02.
Embodiment 1652-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-ethanamide
Purged methyl alcohol (10ml) 10 minutes with ammonia in 0 ℃.(0.50g, 0.787mmol) and sealed vessel, temperature is to room temperature and stirred 2 days to add [2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-methyl acetate.Reaction mixture is concentrated, with ether dilution and filtration.Solid is boiled in ethyl acetate (8ml), and heat filtering is also used ethyl acetate and the pentane washing, and vacuum-drying, obtains the title compound (0.22g, 45%) of white solid: mp 263-265 ℃; NMR (DMSO-d6): δ 8.29 (d, J=8Hz, 1H), 8.09 (d, J=8Hz, 1H), 7.88 (s, 2H), 7.80 (ddd, J=8,7,1Hz, 1H), 7.67-7.51 (m, 5H), 7.30 (ddd, J=8,7,1Hz, 1H), 6.71 (d, J=8Hz, 1H), 4.56 (s, 2H); MS (EI): [M+], 3 bromine isotope figures, 617 (30%), 619 (90%) 621 (100%) 623 (40%); The analytical calculation value of C24H14Br3NO2S: C, 46.48, H, 2.28, N, 2.26.Measured value: C, 45.69, H, 2.02, N, 2.14.
Embodiment 166 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid amide
Under dry nitrogen atmosphere, with (the R)-2-[2 under 3 DMF adding room temperatures, 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid (2.09g, 2.94mmol), (0.31ml is 3.53mmol) and in the stirred solution of methylene dichloride (31ml) for oxalyl chloride.2.5 add after hour oxalyl chloride (0.10ml, 1.14mmol, add again after 6 hours oxalyl chloride (0.10ml, 1.14mmol).6.5 after hour, reaction mixture is concentrated and vacuum-drying.Solid is dissolved in the methylene dichloride (25ml) and in 2 minutes adds in refrigerative (0 ℃) the dense ammonium hydroxide (50ml).Remove methylene dichloride, leach the solid of generation, wash with water and vacuum-drying, obtain the title compound (1.99g, 95%) of white solid: mp 220-222 ℃; NMR (DMSO-d6): δ 8.28 (d, J=8Hz, 1H), 8.07 (d, J=8Hz, 1H), 7.80 (ddd, 8,7,1Hz, 1H), 7.75 (d, J=2Hz, lH), 7.74 (d, J=2Hz, 1H), 7.67-7.62 (m, 2H), and 7.53-7.48 (m, 2H), 7.41-7.24 (m, 7H), 6.69 (d, J=8Hz, 1H), 5.74 (s, 1H, 0.5eq CHCl2), 5.23 (t, J=6Hz, 1H), 3.46-3.27 (m, 2H); MS (+FAB): [M+], 3 bromine isotope figures, 707 (30%), 709 (75%) 711 (100%) 713 (40%); The analytical calculation value of C31H20Br3NO2S0.56CH2Cl2: C, 50.02, H, 2.82, N, 1.85.Measured value: C, 49.67, H, 2.67, N, 1.96.
Embodiment 167 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-N-hydroxyl-3-phenyl-propionic acid amide
DMF (2) is added (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid (0.736g, 1.03mmol), (0.11ml is 1.27mmol) and in the stirred solution of methylene dichloride (11ml) for oxalyl chloride.Remove solvent after 1 hour.Resistates is dissolved in the chloroform (3.5ml), and drop to oxammonium hydrochloride under 0 ℃ of quick stirring (0.097g, 1.34mmol), yellow soda ash (0.191,1.65mmol), in the suspension of water (3.5ml) and chloroform (3.5ml).Suspension temperature to the room temperature and stirring of this stirring spent the night.Add entry, reaction mixture chloroform extraction, the silica gel that 2% phosphoric acid/methyl alcohol is handled add chloroform mutually in and remove solvent.Adsorptive separates (gradient: 4: 1 to 3: 2 sherwood oils: ethyl acetate), obtain the title compound (0.464g, 64%) of white solid: mp 143-144 ℃ through flash chromatography; NMR (DMSO-d6): δ 9.03 (d, J=2Hz, 1H), 8.29 (d, J=8Hz, 1H), 8.07 (d, J=8Hz, 1H), 7.81 (ddd, J=8,7,1Hz, 1H), 7.78 (s, 2H), 7.63 (ddd, J=8,7,1Hz, 1H), 7.56 (d, J=8Hz, 1H), 7.52 (ddd, J=8,7,1Hz, 1H), 7.36-7.25 (m, 6H), 6.71 (d, J=8Hz, 1H), 5.32 (dd, J=9,5Hz, 1H), 3.51-3.39 (m, 2H); MS (FAB+): [M+], 3 bromine isotope figures 723 (20%), 725 (55%) 727 (50%) 729 (30%); The analytical calculation value of C31H20NBr3O3S: C, 51.27, H, 2.78, N, 1.93.Measured value: C, 51.19, H, 2.69, N, 1.86.
Embodiment 168 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-N-(3-nitrilo (nitrolo)-propyl group)-3-phenyl-propionic acid amide
Under dry nitrogen atmosphere, with dicyclohexylcarbodiimide (0.605g, 2.926mmol) add (the R)-2-[2 of 0 ℃ of stirring, 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid (2.08g, 2.926mmol), the 2-aminopropionitrile (0.215ml, 2.926mmol), (0.448g is in DMF 2.926mmol) (7.2ml) solution for HOBT.16.5 after hour, add reaction mixture in the entry and be allocated in water/ethyl acetate and THF between.Add silica gel in the organic phase and remove solvent.Adsorptive through flash chromatography (7: 3, sherwood oil: ethyl acetate), obtain pale solid (2.23g).Be dissolved in this solid in the methylene dichloride and add silica gel.Remove solvent, adsorptive separates (gradient: methylene dichloride to 97.5: 2.5 methylene dichloride: acetonitrile), obtain the title compound (1.89g, 85%) of white solid: mp 194-195 ℃ through flash chromatography; NMR (DMSO-d6): δ 8.70 (t, J=6Hz, 1H), 8.28 (ddd, J=8,1,1Hz, 1H), 8.07 (dd, J=8,1Hz, 1H), 7.80 (ddd, J=8,7,1Hz, 1H), 7.76 (s, 2H), 7.63 (ddd, J=8,7,1Hz, 1H), 7.52 (ddd, J=8,7,1Hz, 1H), 7.48 (dd, J=8,1,1Hz, 1H), 7.37-7.24 (m, 6H), 6.74 (d, J=8Hz, 1H), 5.16 (t, J=6Hz, 1H), 3.51-3.26 (m, 2H), 2.62 (t, J=6Hz, 1H); MS (EI): [M+], 3 bromine isotope figures, 760 762,764,766; The analytical calculation value of C34H23Br3N2O2S: C, 53.50, H, 3.04, N, 3.67.Measured value: C, 53.24, H, 2.86, N, 4.02.
Embodiment 169[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-acetonitrile
With bromoacetonitrile (0.25ml, 3.56mmol) add stir under the room temperature 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (1.0g, 1.78mmol) and salt of wormwood (0.615g is in DMF 4.45mmol) (5ml) solution.2.5 after hour, reaction mixture is added in the entry, filter, wash with water and grind with sherwood oil.Solid in 80 ℃ of vacuum-dryings, is obtained the title compound (1.03g, 96%) of white solid: NMR (DMSO-d6): δ 8.29 (d, J=8Hz, 1H), 8.08 (d, J=8Hz, 1H), 7.92 (s, 2H), 7.80 (ddd, J=8,7,1Hz, 1H), 7.65-7.51 (m, 3H), 7.27 (ddd, J=8,7,1Hz, 1H), 6.68 (d, J=8Hz, 1H), 5.36 (s, 2H); MS (+FAB): [M+], 3 bromine isotope figures, 599,601,603,605; The analytical calculation value of C24H12Br3NOS: C, 47.87, H, 2.01, N, 2.33.Measured value: C, 47.83, H, 1.92, N, 2.32.
Embodiment 170 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionitrile
With trifluoroacetic anhydride (0.375,2.65mmol) add (the R)-2-[2 that stirs under the room temperature, 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid amide (1.68g, 2.37mmol), (0.393ml is 4.74mmol) with in the suspension of diox (5.4ml) for pyridine.Dissolve, solution was heated 2 hours in 105 ℃ of oil baths.Reaction mixture is cooled to room temperature, with the ether dilution, with 5% hydrochloric acid and salt water washing.With silica gel add ether mutually in and remove solvent.Adsorptive separates (ether is as elutriant) through flash chromatography, obtains the title compound (1.38g, 84%) of white solid: mp 160-165 ℃; NMR (DMSO-d6): δ 8.29 (d, J=8Hz, 1H), 8.07 (d, J=8Hz, 1H), 7.93 (d, J=2Hz, 1H), 7.91 (d, J=2Hz, 1H), 7.80 (ddd, 8,7,1Hz, 1H), 7.65-7.33 (m, 8H), 7.23 (ddd, 8,7,1Hz, 1H), 6.65 (d, J=8Hz, 1H), 5.87 (t, J=7Hz, 1H), 3.58 (m, 2H); MS (EI): [M+], 3 bromine isotope figures, 689 (30%), 691 (95%), 693 (100%) 695 (40%); The analytical calculation value of C31H18Br3NOS: C, 53.74, H, 2.62, N, 2.02.Measured value: C, 53.60, H, 2.60, N, 1.83.
Embodiment 1715-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxymethyl]-the 1H-tetrazolium
Under dry nitrogen atmosphere, with trimethyl aluminium (2.55ml, 3.84mmol, 2.0M toluene solution) add [2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-acetonitrile (0.615g, 1.02mmol) in.(0.510ml 3.84mmol), heats solution in 80 ℃ of oil baths to add the trimethyl silyl trinitride then.16.5 after hour reaction mixture is cooled to room temperature, adds in the entry carefully.Mixture is allocated between diluted hydrochloric acid aqueous solution and the ethyl acetate.Separate each layer, the silica gel of the methanol solution of 2% phosphoric acid washing is added in the organic phase.Remove solvent, adsorptive carries out flash chromatography separation (elutriant: gradient: 4: 1 to 7: 3 sherwood oils: ethyl acetate) with the silica gel of the methanol solution washing of 2% phosphoric acid, recrystallize from hexanaphthene obtains the title compound (0.365g, 55%) of white solid: mp 243-245 ℃; NMR (DMSO-d6): δ 8.29 (d, J=8Hz, 1H), 8.09 (d, J=8Hz, 1H), 7.89 (s, 2H), 7.80 (ddd, J=8,7,1Hz, 1H), and 7.66-7.57 (m, 2H), 7.55 (ddd, J=8,7,1Hz, 1H), 7.40 (ddd, J=8,7,1Hz, 1H), 6.71 (d, J=8Hz, 1H), 5.64 (s, 2H), 1.34 (hexanaphthene, 0.3 molar weights); MS (EI): [M+], 3 bromine isotope figures, 642,644,646,648; The analytical calculation value of C24H13Br3N4OS0.33C6H12: C, 46.39, H, 2.55, N, 8.32.Measured value: C, 46.28, H, 2.43, N, 7.90.
Embodiment 172 (R)-5-{1-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-2-phenyl-ethyl }-the 1H-tetrazolium
Under dry nitrogen atmosphere, trimethyl aluminium (7.24ml, 14.4mmol, 2.0M toluene solution) is added (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionitrile (1.33g, 1.93mmol) in.(1.92ml 14.4mmol), heats solution in 85 ℃ of oil baths to add the trimethyl silyl trinitride then.After 7 hours reaction mixture is cooled to room temperature, dilutes with ether.Add entry carefully, after stopping to bubble, mixture is allocated between diluted hydrochloric acid aqueous solution and the ether.Ether is concentrated mutually, use sherwood oil, small amount of methanol, a small amount of ether successively, grind with sherwood oil at last, obtain the title compound (0.802g, 57%) of white solid: mp 238-239 ℃; NMR (DMSO-d6): δ 8.28 (d, J=8Hz, 1H), 8.07 (d, J=8Hz, 1H), 7.81-7.74 (m, 3H), 7.62 (ddd, 8,7,1Hz, 1H), 7.57-7.53 (m, 2H), 7.44 (ddd, 8,7,1Hz, 1H), 7.38-7.22 (m, 5H), 6.60 (d, J=8Hz, 1H), 5.87 (dd, J=9,7Hz, 1H), 3.90 (dd, J=13,7,1H), 3.80 (dd, J=13,8,1H); MS (ESI): [M-H], 3 bromine isotope figures, 731 (60%), 733 (90%) 735 (100%) 737 (60%); The analytical calculation value of C31H19Br3N40S: C, 50.64, H, 2.61, N, 7.62.Measured value: C, 49.65, H, 2.434, N, 7.16.
Embodiment 173 (R)-6-bromo-11-[3,5-two bromo-4-(1-methylol-2-phenyl-oxyethyl group)-phenyl]-benzo [b] naphtho-[2,3-d] thiophene
Under dry nitrogen atmosphere, with (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-methyl propionate (0.30g, 0.414mmol) THF (4.2ml) drop to the mixed hydride of-78 ℃ of lithium aluminum hydride/aluminum chloride (1.0M THF solution) that stir down (0.435ml be in THF 0.414mmol) (3ml) solution.After 1 hour, allow the solution temperature to room temperature.After 2 hours, use methyl alcohol (3ml) quencher reaction mixture carefully, water (80ml) is dilution further.(2 * 80ml) further extract aqueous mixture with ethyl acetate.Acetic acid ethyl acetate extract washes with water, with salt solution and anhydrous magnesium sulfate drying and concentrated, obtains the title compound (0.28g, 97%) of white solid: mp 83-85 ℃; MS (EI): [M+], 3 bromine isotope figures, 694,696,698,700.
Embodiment 174 (R)-6-bromo-11-[3,5-two bromo-4-(1-brooethyl-2-phenyl-oxyethyl group)-phenyl]-benzo [b] naphtho-[2,3-d] thiophene
Under dry nitrogen atmosphere, (0.151ml, (0.257g is in THF 0.98mmol) (6ml) solution 0.96mmol) to drop to 0 ℃ of triphenylphosphine that stirs down with the diethylazodicarboxylate.After 20 minutes, lithiumbromide is added in the subdiaphanous reaction mixture, adds (R)-6-bromo-11-[3 then, 5-two bromo-4-(1-methylol-2-phenyl-oxyethyl group)-phenyl]-benzo [b] naphtho-[2,3-d] thiophene (0.273g, THF 0.392mmol) (3ml) solution.After 1 hour, allow the solution temperature to room temperature.After 2 hours, water (0.2ml) quencher reaction mixture is with further dilution of ether (50ml).Add silica gel (8ml).Remove solvent, the silica gel adsorption thing separates (98: 2 sherwood oils of elutriant: ethyl acetate), obtain the title compound (0.23g, 73%) of white solid: mp＞90 ℃ (decomposition) through flash chromatography; MS (EI): [M+], 4 bromine isotope figures, 756,758,760,762,764; The analytical calculation value of C28H17Br3N2O3S0.25 hexane: C, 49.97, H, 2.97, N, 0.00.Measured value: C, 49.97, H, 2.83, N, 0.02.
Embodiment 1755-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-thiazolidine-2, the 4-diketone
Under dry nitrogen atmosphere, with (two) trimethyl silyl lithamide (1.0M in THF, 5.32ml, 5.32mmol) in 20 minutes, drop to-78 ℃ stir down 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (1.50g, 2.66mmol), 5-bromo thiazole alkane diketone (Zask etc., J.Med Chem, 1990,33,1418-1423,0.522g, 2.66mmol) and in THF (20ml) solution.After 45 minutes, with the reaction mixture temperature to room temperature.After 2 hours, reaction mixture is added in the entry and use 10% hcl acidifying, use extracted with diethyl ether.With silica gel add ether mutually in and remove solvent.Adsorptive through flash chromatography separate (7: 3 sherwood oils: ethyl acetate), obtain the title compound (0.882g, 49%) of white solid: NMR (DMSO-d6): δ 12.75 (s, 1H), 8.30 (dd, J=8,1Hz, 1H), 8.09 (ddd, J=8,1,1Hz, 1H), 7.92 (s, 2H), 7.81 (ddd, J=8,7,1Hz, 1H), and 7.67-7.59 (m, 2H), 7.54 (ddd, J=8,7,1Hz, 1H), 7.27 (ddd, J=8,7,1Hz, 1H), 6.96 (s, 1H), 6.65 (d, J=8Hz, 1H); MS (ESI): [M-H]-, 3 bromine isotope figures, 674,676,678,680; The analytical calculation value of C25H12Br3NO3S2: C, 44.27, H, 1.78, N, 2.07.Measured value: C, 44.20, H, 1.90, N, 2.14.
The embodiment 176 di(2-ethylhexyl)phosphate tert-butyl esters 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester
Under dry nitrogen atmosphere, with tetrazolium (0.215g, 3.0mmol) in 2 of room temperature property adding next time stirring, 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (0.527g, 1.0mmol), N, the N-diethylamino di(2-ethylhexyl)phosphate tert-butyl ester (93%, 0.353ml, in the suspension of THF 1.0mmol).Dissolve.After 1 hour, solution is cooled to-40 ℃, produces suspension.Slowly add m-chlorobenzoic acid (80%, 0.26g, 1.2mmol) so that elevated temperature not.The suspension that produces is slowly to warm to room temperature, and dissolve this moment.Add 10% aqueous solution of sodium bisulfite and biphasic mixture was stirred 20 minutes.Reaction mixture is dissolved in the ether also with aqueous solution of sodium bisulfite and saturated sodium bicarbonate aqueous solution washing.Ether is concentrated mutually and filters.White solid grinds with ether, separates (gradient: methylene dichloride to 97.5: 2.5 methylene dichloride: acetonitrile), obtain the title compound (0.324g, 43%) of white solid: NMR (DMSO-d6): δ 8.25 (d through flash chromatography then, J=9Hz, 1H), 8.06 (d, J=8Hz, 1H), 7.86 (s, 2H), 7.75 (ddd, J=8,7,1Hz, 1H), 7.56 (ddd, J=8,7,1Hz, 1H), 7.50 (ddd, J=8,7,1Hz, 1H), 7.44 (d, J=8Hz, 1H), 7.14 (ddd, J=8,7,1Hz, 1H), 6.77 (d, J=8Hz, 1H), 1.51 (s, 18H); MS (+FAB): [M+], 3 bromine isotope figures, 752,754,756,758; The analytical calculation value of C30H28Br3O4PS: C, 47.71, H, 3.74, N, 0.00.Measured value: C, 47.87, H, 3.69, N, 0.10.
Embodiment 177 phosphoric acid one-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl] ester
(4N is in diox, and 1.5ml 6mmol) adds the di(2-ethylhexyl)phosphate tert-butyl ester 2 that stirs under the room temperature, and 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-(2.90g is in diox 0.384mmol) (6ml) solution for phenyl ester with HCl.4.5 after hour, remove solvent, solid grinds with ether, sherwood oil, and vacuum-drying, obtains the title compound (0.220,86%) of white solid: NMR (DMSO-d6): δ 8.29 (d, J=8Hz, 1H), 8.08 (d, J=8Hz, 1H), 7.83 (s, 2H), 7.80 (ddd, J=8,7,1Hz, 1H), 7.64 (ddd, J=8,7,1Hz, 1H), 7.56-7.51 (m, 2H), 7.26 (ddd, J=8,7,1Hz, 1H), 6.71 (d, J=8Hz, 1H); MS (+FAB): [M+], 3 bromine isotope figures, 640,642,644,646; The analytical calculation value of C22H12Br3O4PS: C, 41.09, H, 1.88, N, 0.00.Measured value: C, 41.71, H, 2.22, N, 0.07.
Embodiment 1782-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-2-methyl-propionic acid
In 3 hours, with solid sodium hydroxide (0.682g, 17.05mmol) add 2 of 0 ℃ of following stirring with 3 equal portions, 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenyl ester (0.800g, 1.421mmol), 1,1, (1.06g is in acetone 4.263mmol) (7.5ml) suspension for 1-three chloro-2-methyl-2-propyl alcohol tetrahydrate.With the suspension temperature that produces to room temperature and stirred 15 hours.Reaction mixture is added in the entry, with 10% aqueous hydrochloric acid acidifying and use extracted with diethyl ether.Add (methanol solution of the 2% phosphoric acid) silica gel of acid elution and remove solvent in mutually to ether.Adsorptive separates the (silica gel that the methanol solution of 2% phosphoric acid is handled through flash chromatography; Elutriant: gradient: 9: 1 to 8: 2 sherwood oils: ethyl acetate), obtain the title compound (0.620g, 67%) of white solid: NMR (DMSO-d6): δ 13.00 (wide s, 1H), 8.29 (d, J=8Hz, 1H), 8.09 (d, J=8Hz, 1H), 7.85 (s, 2H), 7.81 (ddd, J=7,6,1Hz, 1H), 7.67-7.60 (m, 2H), 7.52 (ddd, J=8,7,1Hz, 1H), 7.23 (ddd, J=8,7,1Hz, 1H), 6.60 (d, J=8Hz, 1H), 1.70 (s, 6H); MS (ESI): [M-H], 3 bromine isotope figures, 645 (20%), 647 (60%), 649 (1000%), 651 (30%); The analytical calculation value of C26H17Br3O3S: C, 48.10, H, 2.64, N, 0.00.Measured value: C, 47.78, H, 2.76, N, 0.31.
Embodiment 1793-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-propionic acid
Under dry nitrogen atmosphere, with β-Bing Chunsuanneizhi (0.186ml, 2.66mmol) add stir under the room temperature 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (1.5g, 2.66mmol), (0.314g is in THF 2.66mmol) (33ml) solution for potassium tert.-butoxide.After 2 days reaction mixture is added in the entry, with 10% aqueous hydrochloric acid acidifying and use ethyl acetate extraction.Add (methanol solution of the 2% phosphoric acid) silica gel of acid elution and remove solvent in mutually to ethyl acetate.Adsorptive separates the (silica gel that the methanol solution of 2% phosphoric acid is handled through flash chromatography; Elutriant: gradient: 9: 1 to 8: 2 sherwood oils: ethyl acetate), obtain the title compound (0.748g, 44%) of pale solid: mp 218-220 ℃: NMR (DMSO-d6): δ 12.48 (wide s, 1H), 8.28 (d, J=8Hz, 1H), 8.08 (d, J=8Hz, 1H), 7.83 (s, 2H), 7.79 (ddd, J=7,6,1Hz, 1H), and 7.64-7.57 (m, 2H), 7.52 (ddd, J=8,7,1Hz, 1H), 7.31 (ddd, J=8,7,1Hz, 1H), 6.69 (d, J=8Hz, 1H), 4.44 (t, J=6Hz, 2H), 2.89 (t, J=6Hz, 2H); MS (+FAB): [M+], 3 bromine isotope figures, 632 (30%), 634 (70%) 636 (80%) 638 (40%); The analytical calculation value of C25H15Br3O3S: C, 47.27, H, 2.38, N, 0.00.Measured value: C, 47.68, H, 2.36, N, 0.01.
Embodiment 180 (R)-3-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-butyric acid
Under dry nitrogen atmosphere, with diethylazodicarboxylate (0.420ml, 2.66mmol) drop to stir under the room temperature 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenol (0.50g, 0.89mmol), methyl-(S)-(+)-3-butyric ester (0.30ml, 2.66mmol), (0.70g is in the suspension of benzene 2.66mmol) (6ml) for triphenylphosphine.Dissolve, solution was heated 4 hours in 80 ℃ of oil baths.After being cooled to room temperature, reaction mixture is with the methylene dichloride dilution and add silica gel (15ml).Remove solvent, the silica gel adsorption thing separates (9: 1 sherwood oils of elutriant: ethyl acetate) through flash chromatography, obtain the methyl esters (0.345g of white solid, 52%): mp143-144 ℃: aqueous hydrochloric acid (3.0ml) is added this methyl esters that stirs under room temperature (0.308g is in 4.0M hydrogenchloride/diox (6.0ml) solution 0.464mmol).This suspension in the pressure reactor was heated 2 hours in 80 ℃ of oil baths.Add in the resistates that produces with solution concentration and with ether (40ml).Add silica gel (3ml).Remove solvent, the silica gel adsorption thing separates (elutriant: ethyl acetate), obtain the title compound (0.143g, 48%) into white solid: mp175-176 ℃: NMR (DMSO-d6): δ 8.36 (d, J=8Hz through flash chromatography, 1H), 7.83 (d, J=8Hz, 1H), 7.68 (ddd, J=8,7,1Hz, 1H), 7.61-7.58 (m, 3H), 7.52 (dd, J=8Hz, 1H), 7.43 (ddd, J=8,7,1Hz, 1H), 7.17 (ddd, J=8,7,1Hz, 1H), 6.78 (d, J=8Hz, 1H), 5.29 (q, J=7Hz, 1H), 3.20 (dd, J=6Hz, 1H), 2.91 (dd, J=6Hz, 1H), 1.62 (d, J=7Hz, 3H); MS (EI): M+, 3 bromine isotope figures, 646,648,650,652; The analytical calculation value of C26H17Br3O3S: C, 48.10, H, 2.64 N, 0.00.Measured value: C, 48.49, H, 2.63, N, 0.16.
Embodiment 181 (R)-2-[4-(6-hydroxyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two bromo-phenoxy groups]-3-phenyl-methyl propionate
Under dry nitrogen atmosphere, in 25 minutes, to cold (70 ℃ of dry ice/isopropanol are bathed) (R)-2-[4-(6-methoxyl group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two bromo-phenoxy groups]-3-phenyl-methyl propionate (1.10g, 1.63mmol) dry methylene chloride (11ml) solution in drip the 1M boron tribromide dichloromethane solution (5.20ml, 5.20mmol, 3.2eq).After-55 ℃ of standing over night, reaction mixture is kept stirring 5 hours between-20 ℃ to-30 ℃, incline then to water (50ml), organism extracts with ether (100ml).Ether phase water and salt water washing concentrate, and handle with sherwood oil, obtain the title compound (1.10,100%) of yellow solid.
Embodiment 182 (R)-2-[4-(6-benzyloxy-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two bromo-phenoxy groups]-3-phenyl-methyl propionate
Under room temperature, dry nitrogen atmosphere, to (R)-2-[4-(6-hydroxyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two bromo-phenoxy groups]-3-phenyl-methyl propionate (0.50g, 0.755mmol) dry N, drip in dinethylformamide (5ml) solution bromotoluene (0.27ml, 2.27mmol, 3eq).Behind the stir about 17 hours, reactant water (50ml) quencher, organism extracted with diethyl ether.Extraction liquid water, salt water washing also mix in silica gel.Remove solvent, the silica gel adsorption thing separates (97/3 petrol ether/ethyl acetate) through flash chromatography, and handles solvent with benzene and sherwood oil, obtains the title compound (0.572g, 84%) of light yellow solid: NMR (CDCl3): δ 8.30 (ddd, J=8,1,1Hz, 1H), 7.82 (ddd, J=8,1,1Hz, 1H), 7.68 (ddd, J=8,1,1Hz, 2H), 7.62 (dd, J=3,2Hz, 2H), 7.60-7.55 (m, 2H), 7.51-7.26 (m, 10H), 7.16 (ddd, J=8,7,1Hz, 1H), 6.81 (ddd, J=8,1Hz, 1H), 5.34 (s, 2H), 5.25 (dd, J=6,2Hz, 1H), 3.76 (s, 3H), 3.59 (septet, J=Hz, 2H); MS (EI): [M+], 2 bromine isotope figures, 750 (2%), 752 (3.5%), 754 (2.5%); The analytical calculation value of C39H28Br2O4S: C, 62.25, H, 3.75, N, 0.00; Measured value: C, 61.66, H, 3.53, N, 0.25.
Embodiment 183 (R)-2-[2,6-two bromo-4-(6-methoxycarbonyl methoxyl group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-methyl propionate
Under room temperature, dry nitrogen atmosphere, to (R)-2-[2,6-two bromo-4-(6-hydroxyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-methyl propionate (0.60g, anhydrous N 0.906mmol) adds salt of wormwood (0.376g in the dinethylformamide solution, 2.72mmol, 3eq) and methyl bromoacetate (0.26ml, 2.72mmol, 3eq).Stir after 24 hours, reaction mixture is mixed with water (60ml), (2 * 100ml) extract organism with ether.Combining extraction liquid and water (2 * 100ml) and salt solution (100ml) washing.Add silica gel and remove solvent.Adsorptive separates (elutriant 88/12 petrol ether/ethyl acetate and 85/15 ether/ethyl acetate) through 2 flash chromatographies, obtains the title compound (0.493g, 73%) of white solid: and NMR (CDCl3): δ 8.38 (d, J=8Hz, 1H), 7.81 (d, J=8Hz, 1H), 7.64-7.59 (m, 3H), 7.55 (d, J=8Hz, 1H), 7.48 (ddd, J=8,7,1Hz, 1H), and 7.43-7.26 (m, 6H), 7.16 (ddd, J=8,7,1Hz, 1H), 6.79 (d, J=8Hz, 1H), 5.25 (dd, J=8,6Hz, 1H), 4.94 (s, 2H), 3.92 (s, 3H), 3.76 (s, 3H), 3.57 (septet, J=7Hz, 2H); MS (EI): M+, 2 bromine isotope figures, 732 (1.8%), 734 (4%), 736 (0.8%); The analytical calculation value of C35H26Br2O6S: C, 57.24, H, 3.57, N, 0.00.Measured value: C, 57.01, H, 3.42, N ,-0.07.
Embodiment 184 (R)-2-[4-(6-benzyloxy-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two bromo-phenoxy groups]-3-phenyl-propionic acid
To (R)-2-[4-(6-benzyloxy-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two bromo-phenoxy groups]-3-phenyl-methyl propionate (0.484g, 0.644mmol) in the solution of tetrahydrofuran (THF) (9ml) and methyl (3ml), under room temperature, drip potassium hydroxide aqueous solution (1N, 1.29ml, 1.29mmol, 2eq).Stir and remove solvent after 2.5 hours, resistates is allocated between diluted hydrochloric acid aqueous solution and the ether.With the violent jolting of this two phase system and separate each layer.Ether layer water and salt water washing, and mix with acid-treated (methanol solution of 2% phosphoric acid) silica gel.Remove ether, adsorptive separates (acid-treated silica gel, 90/10 petrol ether/ethyl acetate) through flash chromatography, obtains the title compound (0.354g, 74.5%) of white solid: and [a] 25/D=+24.77 ° (10.091mg/ml, CHCl3); NMR (CDCl3): δ 8.29 (d, J=8Hz, 1H), 7.80 (d, J=8Hz, 1H), 7.68 (d, J=8Hz, 2H), 7.61 (dd, J=10,2Hz, 2H), and 7.59-7.56 (m, 1H), 7.51-7.47 (m, 3H), 7.46-7.27 (m, 8H), 7.15 (ddd, J=8,7,1Hz, 1H), 6.80 (d, J=Hz, 1H), 5.47 (t, J=7Hz, 1H), 5.34 (s, 2H), 3.59 (d, J=7Hz, 2H); MS (CI): [(M+H)+], 2 bromine isotope figures, 737 (6%), 739 (10%), 741 (4%); The analytical calculation value of C38H26Br2O4S: C, 61.80, H, 3.55, N, 0.00; Measured value: C, 62.15, H, 3.52, N, 0.07.
Embodiment 185 (R)-2-[2,6-two bromo-4-(6-carboxyl methoxyl group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
To (R)-2-[2,6-two bromo-4-(6-carboxyl methoxyl group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-methyl propionate (0.436g, 0.594mmol) in the solution of tetrahydrofuran (THF) (9ml) and methyl alcohol (3ml), under room temperature, drip potassium hydroxide aqueous solution (1N, 2.37ml, 2.37mmol, 4eq).Stir and remove solvent after 3.5 hours, resistates is mixed with water.This suspension is with 10% aqueous hydrochloric acid acidifying and add ether.With this biphasic mixture shake well, separate each layer then.Organism washes with water and concentrates.Resistates grinds and vacuum-drying with sherwood oil, obtains the title compound (0.366g, 87%) of white solid: mp110-120 ℃; [a] 25/D=+49.62 ° (10.076mg/ml, methyl alcohol); NMR (DMSO-d6): δ 13.21 (wide s, 2H), 8.40 (d, J=8Hz, 1H), 8.03 (d, J=8Hz, 1H), 7.74 (dd, J=2,8Hz, 2H), 7.68 (ddd, J=8,7,1Hz, 1H), 7.57 (ddd, J=8,7,1Hz, 1H), and 7.52-7.45 (m, 2H), 7.43-7.38 (m, 2H), 7.37-7.11 (m, 2H), 7.10-7.20 (m, 2H), 6.69 (d, J=8Hz, 1H), 5.30 (t, J=7Hz, 1H), 4.90 (s, 2H), 3.41 (d, J=7Hz, 2H); MS (+FAB): [M+], 2 bromine isotope figures, 704 (9%), 706 (22%), 708 (22%); The analytical calculation value of C33212Br2O6S: C, 56.11, H, 3.14, N, 0.00, measured value: C, 55.93, H, 3.28, N, 0.09.
Embodiment 186[2,6-two bromo-4-(6-bromo-5,5-dioxo-5H-6-benzo [b] naphtho-[2,3-d] thiophene-11-yl)]-phenoxy group]-acetate
Under room temperature to stir [2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-(0.050g 0.0805mmol) drips 30% aqueous hydrogen peroxide solution (0.082ml to acetate in the suspension in glacial acetic acid (2ml), 0.805mmol, 10eq).Suspension was heated 2.5 hours in 105-107 ℃.Reaction mixture is cooled to room temperature and leaches solid, use petroleum ether, obtain title compound (0.042g, 79%): mp281-282.5 ℃; NMR (DMSO-d6): δ 8.42 (d, J=8Hz, 1H), 7.66-7.61 (m, 2H), 7.50 (d, J=8Hz, 1H), 6.51-6.48 (m, 1H), 4.75 (s, 3H), 1.90 (s, 3H); MS (EI): [M+], 3 bromine isotope figures, 650 (32%), 652 (95%), 654 (100%), 656 (38%); The analytical calculation value of C24H13Br3O5SCH3COOH: C, 43.79, H, 2.40, N, 0.00; Measured value: C, 43.66, H, 2.26, N, 0.08.
Embodiment 187[2,6-two bromo-4-(6-bromo-5-oxo-5H-4-benzo [b] naphtho-[2,3-d] thiophene-11-yl)]-phenoxy group]-acetate
Under room temperature to stir [2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-(0.450g 0.725mmol) drips 30% aqueous hydrogen peroxide solution (0.75ml to acetate in the suspension in glacial acetic acid (4ml), 7.25mmol, 10eq).With suspension in 105 ℃ of heating.But when not dissolving, add 15ml acetate again.Dissolve rapidly, solution was heated 5.5 hours in 105 ℃.When being cooled to room temperature, be settled out yellow solid.Take out solid and mix with the ether extraction liquid of the filtrate of taking from dilution.Solid not exclusively is dissolved in the ether, does not also dissolve when adding ethyl acetate, takes out solid after filtration.With solid recrystallize from acetate,, obtain the title compound (0.055g, 12%) of yellow solid: mp287-289 ℃ through heat filtering; NMR (DMSO-d6): δ 13.3 (broadband, 1H), 8.39 (d, J=8,1H), 8.14 (ddd, J=8,1,1Hz, 1H), 7.91 (d, J=2Hz, 1H), 7.84 (ddd, J=8,7,1Hz, 1H), 7.77-7.72 (m, 2H), 7.60-7.50 (m, 3H), 6.45 (ddd, J=8,1,1Hz, 1H), 4.75 (s, 2H); MS (EI): [M+], 3 bromine isotope figures, 634 (25%), 636 (70%), 638 (75%), 640 (30%); The analytical calculation value of C24H13Br3O4S: C, 45.24, H, 2.06, N, 0.00; Measured value: C, 44.89, H, 1.76, N, 0.06.
Embodiment 188 (R)-2-[2,6-two bromo-4-(6-bromo-5,5-dioxo-5H-5 (λ 6)-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-methyl propionate
Under room temperature to (the R)-2-[2 that stirs, 6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-methyl propionate (0.94g, 1.30mmol) in the suspension in glacial acetic acid (38ml) and 30% aqueous hydrogen peroxide solution (1.5ml, 13mmol) in 100-110 ℃ of heating (dissolving) 5.5 hours, under room temperature, keep then spending the night.Remove solvent, be dissolved in solid residue in the methylene dichloride and add silica gel.Remove solvent, adsorptive separates (80: 20 sherwood oils: ethyl acetate), obtain the title compound (0.937g, 95%) of yellow solid: mp156-157 ℃ through flash chromatography; [a] D25=+47.92 ° (10.017mg/ml CHCl3); NMR (CDCl3): δ 8.48 (d, J=7Hz, 1H), 7.89 (d, J=6Hz, 1H), 7.74 (ddd, J=8,7,1Hz, 1H), 7.64 (ddd, J=8,7,1Hz, 1H), 7.54 (dd, J=7,4Hz, 2H), 7.50-7.27 (m, 8H), 6.44 (dd, J=7,1Hz, 1H), 5.27 (dd, J=6,8Hz, 1H), 3.75 (s, 3H), 3.56 (m, 2H); MS (+FAB): [M+H]+, 3 bromine figures, 755 (8%), 757 (20%), 759 (30%), 761 (10%); The analytical calculation value of C32H21Br3O5S: C, 50.75, H, 2.80, N, 0.00; Measured value: C, 50.75, H, 2.61, N ,-0.04.
Embodiment 189 (R)-2-[2,6-two bromo-4-(6-bromo-5,5-dioxo-5H-5 (λ 6)-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid
With potassium hydroxide aqueous solution (1N, 2.22ml, 2.22mmol) adding (R)-2-[2,6-two bromo-4-(6-bromo-5,5-dioxo-5H-5 (λ 6)-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-(0.832g is 1.11mmol) in the stirred solution in tetrahydrofuran (THF) (7.5ml)/methyl alcohol (5.5ml) for 3-phenyl-methyl propionate.With solution concentration, dilute with water is also with 10% aqueous hydrochloric acid acidifying after 1 hour.The organism extracted with diethyl ether.Remove ether, resistates is spent the night in 53 ℃ of vacuum-dryings, obtain the title compound (0.534g, 65%) of white solid: mp173-193 ℃; [a] D25=+42.73 °; NMR (CDCl3): δ 8.47 (dd, J=8,1Hz, 1H), 7.76 (dd, J=8,1Hz, 1H), 7.74 (ddd, J=7,3,1Hz, 1H), 7.64 (ddd, J=7,3,1Hz, 1H), 7.55-7.46 (m, 3H), 7.41-7.27 (m, 7H), 6.42 (d, J=8Hz, 1H), 5.44 (t, J=7Hz, 1H) 3.57 (d, J=7Hz, 2H); MS (EI): [M+], 3 bromine isotope figures, 740 (2%), 742 (8%), 744 (6%), 746 (2%); The analytical calculation value of C31H19Br3O5S: C, 50.09, H, 2.58, N, 0.00; Measured value: C, 50.18, H, 2.71, N, 0.00.
Embodiment 1905 '-benzo [b] naphtho-[2,3-d] thiophene-11-base-[1,1 '; 3 ', 1 "] terphenyl-2 '-phenol
With 4-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two iodo-phenol (1.26g, 2.18mmol), phenylo boric acid (0.584g, 4.80mmol), hydrated barta eight hydrate (2.75g, 8.72mmol), (10mg, 0.087mmol) and 6: 1 glycol dimethyl ethers: the solution of water (49ml) is heated to 80 ℃ and spends the night acid chloride.Add additional quantity phenylo boric acid (0.29g, 2.40mmol) and the acid chloride of catalytic amount, with solution reheat 4 hours.Reaction mixture is acidified to pH1 with concentrated hydrochloric acid, with ethyl acetate dilution and wash with water.Remove solvent, raw product through flash chromatography separate (99: 1 ethyl acetate: sherwood oil), obtain the title compound (0.948g, 91%) of white solid: NMR (DMSO-d6): δ 8.76 (s, 1H), 8.61 (s, 1H), 8.05 (d, J=8Hz, 1H), 7.99 (d, J=8Hz, 1H), 7.77 (d, J=9Hz, 1H), 7.63-7.30 (m, 13H), 7.25 (s, 2H), 7.22 (ddd, J=8,8,1Hz, 1H), 7.08 (d, J=9Hz, 1H); MS (EI): 492 (100%, MI); The analytical calculation value of C34H22OS1.6H2O: C, 80.48, H, 5.01, N, 0.00; Measured value: C, 80.26, H, 4.63, N, 0.05.
Embodiment 191 (5 '-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-[1,1 '; 3 ', 1 "] terphenyl-2 '-Ji oxygen base)-acetate
With 5 '-benzo [b] naphtho-[2,3-d] thiophene-11-base-[1,1 '; 3 ', 1 "] terphenyl-2 '-phenol (0.145g, 0.30mmol), methyl bromoacetate (0.057ml, 0.61mmol), (0.046g, 0.33mmol) and N, dinethylformamide (5ml) mixes to be incorporated under the room temperature and stirred 3 days salt of wormwood.Add reaction mixture in the entry and use ethyl acetate extraction.Ethyl acetate layer is also dry with 1N aqueous hydrochloric acid, saturated sodium bicarbonate washing *(sal epsom).Remove ethyl acetate, raw product separates (95: 5 ethyl acetate: sherwood oil), obtain (5 '-benzo [b] naphtho-[2,3-d] thiophene-11-base-[1,1 ' of white solid through flash chromatography; 3 ', 1 "] terphenyl-2 '-Ji oxygen base)-methyl acetate (0.177g).(1N, 1.61ml 1.61mmol) are lowered to this methyl esters at 3: 2 THF in room temperature: in the stirred solution in the methyl alcohol (5.0ml) with potassium hydroxide aqueous solution.After 2 hours with solution concentration, water (75ml) dilution and with 10% aqueous hydrochloric acid acidifying.Leach solid and wash with water, obtain the title compound (0.119g, 69%) of white solid: mp＞132 ℃ (decomposition); NMR (DMSO-d6): δ 12.60 (s, 1H), 8.63 (s, 1H), 8.07 (d, J=8Hz, 1H), 7.99 (d, J=8Hz, 1H), 7.76 (d, J=8Hz, 1H), 7.67-7.41 (m, 11H), 7.40-7.33 (m, 2H), 7.24 (ddd, J=8,8,1Hz, 1H), 6.91 (d, J=9Hz, 1H); MS (EI): 536 (100%, MI); The analytical calculation value of C36H24O3S0.5H2O: C, 79.24, H, 4.62, N, 0.00; Measured value: C, 78.80, H, 4.57, N, 0.09.
Embodiment 1923-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-benzyloxy-phenol
With 3-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-benzene-1, and the 2-diphenol (0.390g, 0.78mmol) and salt of wormwood (0.108g, the 0.78mmol) heating 20 minutes under 0 ℃, dry nitrogen atmosphere of the suspension in DMF (4ml).(0.093ml 0.78mmol) dropped in this mixture in 10 minutes with bromotoluene.With mixture in 0 ℃ stir 6.5 hours after, to pH1, water (60ml) is dilution further with the aqueous hydrochloric acid quencher for reaction mixture, aqueous mixture is with methylene dichloride (2 * 60ml) extractions.The organic extract liquid that merges washes and uses the salt solution drying with water.Add silica gel (5ml).Remove solvent, adsorptive separates through flash chromatography that (elutriant: sherwood oil: methylene dichloride 6: 4 is to sherwood oil: ethyl acetate 6: 4), obtain title compound (87%) and 2-bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-mixture (271mg, 59%) of 6-benzyloxy-phenol (13%).This mixture need not separate and be used for next reaction: and NMR (CDCl3): δ 8.35 (d, J=8Hz, 1H), 7.79 (d, J=8Hz, 1H), and 7.72-7.33 (m, 9H), 7.18 (d, J=2Hz, 1H), 7.17 (ddd, J=8,7,1Hz, 1H), 6.93 (d, J=2Hz, 1H), 6.87 (d, J=8Hz, 1H), 5.71 (s, 1H), 5.32 (t, J=7Hz, 2H).
Embodiment 1932-bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-6-methoxyl group-phenol
In 20 minutes, with methyl iodide (0.086ml, 1.38mmol) drop to [3-bromo-5-(6-bromo-benzo [b] naphtho-[2 that stirs under the room temperature, 3-d] thiophene-11-yl)-2-benzyloxy-phenol (purity 87%, pollution has 2-bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-6-benzyloxy-phenol (13%), 0.271g, 0.46mmol), (0.191g is 1.384mmol) and in the light suspension fluid of DMF (2ml) for salt of wormwood.After stirring 3 hours under the room temperature, reaction mixture uses the aqueous hydrochloric acid quencher to pH1 with mixture, and further dilution of water (40ml), aqueous mixture methylene dichloride (80ml) extraction.Organic extract liquid washes with water, with salt solution and anhydrous magnesium sulfate drying and concentrated, obtain 11-(3-methoxyl group-4-benzyloxy-5-bromo-phenyl)-6-bromo-benzo [b] naphtho-[2,3-d] thiophene (87%) and 11-(4-methoxyl group-3-benzyloxy-5-bromo-phenyl)-6-bromo-benzo [b] naphtho-[2,3-d] mixture (279mg, 100%) of thiophene (13%).This mixture need not separation and is used for next step reaction.With this mixture (279mg, 0.49mmol) and the ethyl acetate of 10% palladium on carbon (28mg): ethanol (1.5: 10,15ml) solution hydrogenation 6 hours under 51psi, room temperature in the Parr container.Reaction mixture filters and uses hot ethyl acetate by Solka Floc bed: ethanol (1.5: 10) washing.Silica gel (5ml) is added in the filtrate.Remove solvent, adsorptive separates through flash chromatography that (elutriant: sherwood oil: methylene dichloride 6: 4 is to sherwood oil: ethyl acetate 7: 3), obtain white solid (145mg), it contains the title compound of the 73%2-bromo-4-that has an appointment (benzo [b] naphtho-[2,3-d] thiophene-11-yl)-6-methoxyl group-phenol and 27%.The method of being summarized according to embodiment 34 (acidylate of phenol), embodiment 37 (6 brominations) and embodiment 41 (saponification of acyl moiety) is introduced 6 of great majority (73%) again with bromine, obtains the title compound of white solid: mp216-218 ℃: NMR (CDCl3): δ 8.36 (d, J=8Hz, 1H), 7.83 (d, J=8Hz, 1H), 7.68-7.64 (m, 2H), and 7.50-7.43 (m, 2H), 7.21 (d, J=2Hz, 1H), 7.18 (d, J=8Hz, 1H), 6.93 (d, J=8Hz, 1H), 6.87 (d, J=8Hz, 1H), 6.20 (s, 1H), 3.86 (s, 3H); MS (+FAB): [M+], 2 bromine isotope figures, 512.
Embodiment 194 (R)-2-[2-bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-6-methoxyl group-phenoxy group]-3-phenyl-propionic acid
According to the method for embodiment 113, by 2-bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-methoxyl group-phenol (embodiment 193) and (S)-2-hydroxyl-3-phenylpropionic acid methyl esters (embodiment 96) preparation.White solid: mp＞103 ℃ (decomposition); NMR (CDCl3): δ 8.36 (ddd, J=8,1,1Hz, 1H), 7.83 (ddd, J=8,7,1Hz, 1H), 7.67 (ddd, J=8,7,1Hz, 1H), and 7.57-7.26 (m, 9H), 7.18 (ddd, J=8,7,1Hz, 1H), 6.89 (ddd, J=8,1,1Hz, 1H), 6.79 (ddd, J=8,7,1Hz, 1H), 5.29 (t, 1H), 3.76,3.74 (ds, 3H), 3.39-3.46 (m, 2H); MS (EI): [M+], 2 bromine isotope figures, 660; The analytical calculation value of C32H22Br2O4S: C, 58.02, H, 3.35, N, 0.00.Measured value: C, 58.04, H, 3.73, N, 0.02.
Embodiment 1953-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-methoxyl group-phenol
With iodine methyl alcohol (0.074ml, 1.2mmol) in 5 minutes, add to 3-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-the yl)-benzene-1 that stirs under the room temperature, 2-diphenol (0.30g, 0.60mmol), (0.083g is 0.6mmol) in the light suspension fluid in DMF (1.5ml) for salt of wormwood.After stirring 1.5 hours under the room temperature, to pH1, water (80ml) is dilution further with the aqueous hydrochloric acid quencher for reaction mixture, aqueous mixture methylene dichloride (120ml) extraction with mixture.Organic extract liquid washes and uses the salt solution drying with water.Add silica gel (5ml).Remove solvent, adsorptive separates through flash chromatography that (elutriant: sherwood oil: methylene dichloride 7: 3 to 1: 1 is sherwood oil then: ethyl acetate 7: 3), obtain the title compound (85mg, 29%) of white solid: mp233-234 ℃; NMR (CDCl3): δ 8.35 (ddd, J=8,1,1Hz, 1H), 7.82 (ddd, J=8,1,1Hz, 1H), 7.66 (ddd, J=8,7,1Hz, 1H), 7.65 (dd, J=8,1Hz, 1H), 7.48 (ddd, J=8,7,1Hz, 1H), 7.43 (ddd, J=8,7,1Hz, 1H), 7.17 (ddd, J=8,7,1Hz, 1H), 7.15 (d, J=2Hz, 1H), 7.00 (d, J=2Hz, 1H), 6.87 (ddd, J=8,1,1Hz, 1H), 5.93 (s, 1H), 4.14 (s, 3); MS (EI): [M+], 2 bromine isotope figures, 512; The analytical calculation value of C23H14B2O2S: C, 53.72, H, 2.74, N, 0.00.Measured value: C, 53.85, H, 2.98, N, 0.02.
Embodiment 196 (R)-2-[3-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-methoxyl group-phenoxy group]-3-phenyl-propionic acid
According to the method for embodiment 113, by 3-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2-methoxyl group-phenol (embodiment 195) and (S)-2-hydroxyl-3-phenylpropionic acid methyl esters (embodiment 96) preparation.White solid: mp＞99 ℃ (decomposition); NMR (CDCl3): δ 8.34 (ddd, J=8,1,1Hz, 1H), 7.79 (ddd, J=8,7,1Hz, 1H), 7.64 (ddd, J=8,7,1Hz, 1H), 7.52 (dd, J=8,1Hz, 1H), 7.45 (ddd, J=8,7,1Hz, 1H), 7.39 (ddd, J=8,7,1Hz, 1H), 7.28-7.07 (m, 7H), 6.67 (ddd, J=8,1,1Hz, 1H), 6.63 (d, J=2Hz, 1H), 4.91-4.84 (m, 1H), 3.33-3.20 (m, 2H), 3.95,3.89 (ds, 3H); MS (+FAB): [M+H]+, 2 bromine isotope figures, 660,662,664; The analytical calculation value of C32H22Br2O4S: C, 58.02, H, 3.35, N, 0.00.Measured value: C, 58.37, H, 3.63, N, 0.03.
Embodiment 1972,4-two fluoro-3-methoxyl group-phenylformic acid
With 5-bromo-1, and 3-difluoro-2-methoxyl-benzene (12.35g, 55.4mmole, L-I.Kruse etc., Biochemistry 1986,25, and anhydrous tetrahydro furan 7271-7278) (350ml) solution is transferred in the flame-dried 1L flask by pipeline.Under dry nitrogen atmosphere, solution is cooled to-80 ℃, under agitation in 1 hour by syringe pump drip n-Butyl Lithium (2.5M in hexane, 24.35ml, 60.9mmol) solution.Stir after 2.5 hours, dry carbonic acid gas was fed in the refrigerative reaction mixture 0.5 hour.Incline solution to trash ice then and stirred 0.5 hour.Mixture added in the entry (600ml) carefully and use 10% hcl acidifying.The organism extracted with diethyl ether.Extraction liquid merged and use the salt water washing.Concentrate and after leaving standstill 2 days under the room temperature, resistates is dissolved in the ether and with the silica gel of acid treatment (methanol solution of 2%H3PO4) again mixes.Remove solvent, adsorptive separates through flash chromatography, obtains the title compound of pale solid: mp191-192 ℃; NMR (400MHz, DMSO-d6): δ 13.37 (wide unimodal, 1H), 7.63-7.58 (m, 1H), 7.25-7.20 (m, 1H), 3.92 (s, 3H); MS (+FAB): (M+H): 189 (12%), 154 (100%), 136 (75%); The analytical calculation value of C8H6F2O3: C, 51.08, H, 3.21.Measured value: C, 50.98, H, 3.15.The flow point that concentrated polarity is lower obtains the 6-bromo-2 of white solid, 4-two fluoro-3-methoxyl group-phenylformic acid (3.44g, 23%): mp 92-94 ℃; NMR (400MHz, DMSO-d6): δ 14.18 (wide unimodal, 1H), 7.65 (dd, J=3,1Hz, 1H), 3.94 (s, 3H); MS:(+FAB) (M+H): 267/269 (38%), 91 (100%); The analytical calculation value of C8H5BrF2O3: C, 35.98, H, 1.89, N, 0.00.Measured value: C, 36.26, H, 1.79, N, 0.03.
Embodiment 198 (2-benzyl-benzo [b] thiene-3-yl-)-(2-4-two fluoro-3-methoxyl group-phenyl)-ketone
Under dry nitrogen atmosphere, to 2,4-two fluoro-3-methoxyl group-phenylformic acid (3.55g, 18.9mmol) and N, drip in anhydrous methylene chloride (70ml) suspension of dinethylformamide (3) oxalyl chloride (2.80ml, 32.1mmol).Stir after 3 hours, add extra oxalyl chloride (1.6ml, 16.1mmol).Behind the restir 1 hour, remove solvent and excessive oxalyl chloride, obtain semi-solid residue, use it for subsequent reaction.
Under dry nitrogen atmosphere; in 55 minutes to 2-benzyl benzo [b] thiophene (3.85g that is cooled to-80 ℃; 17.2mmole) and above-mentioned chloride of acid (3.90g, and dropping tin chloride IV in the thick suspension of methylene dichloride 18.9mmole) (56ml) (4.43ml, 37.8mmol).Behind the restir 1 hour, remove ice bath.When the solution temperature is dissolved during to room temperature.Behind the stir about 15 hours, reaction mixture is added in the entry (200ml) the organism extracted with diethyl ether.Extraction liquid is merged, use the salt water washing, mix with silica gel.Remove solvent, adsorptive separates (gradient 100% sherwood oil to 97/3 petrol ether/ethyl acetate) through flash chromatography, obtains the title compound (2.19g, 34% yield) of yellow oil: NMR (400MHz, DMSO-d6): δ 7.97-7.94 (m, 1H), and 7.77-7.20 (m, 10H), 4.33 (s, 2H), 4.24 (s, 3H); MS (EI) is (M+): 394 (100%).
Embodiment 1993-(benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two fluoro-phenol
Under dry nitrogen atmosphere, to cold (78 ℃) (2-benzyl-benzo [b] thiene-3-yl-)-(2-4-two fluoro-3-methoxyl group-phenyl)-ketone (2.07g, 5.28mmole) anhydrous methylene chloride (20ml) solution in, by syringe pump in 43 minutes, drip boron tribromide (1.60ml, 16.9mmol).Restir was removed ice bath after 14 minutes, with reactant stir about 4 hours under room temperature.The garnet mixture is cooled off the careful quencher of water, organism extracted with diethyl ether in ice bath.Extraction liquid also concentrates with the salt water washing, obtains the raw product (2.2g) of yellow foam.Solid is dissolved in again in the mixture of ether, tetrahydrofuran (THF) and methylene dichloride, (60ml) mixes with silica gel.Remove solvent, adsorptive separates (90/10 petrol ether/ethyl acetate) through flash chromatography, obtains the title compound (1.4g of white solid, 74%): NMR (300MHz, DMSO-d6): δ 10.57 (s, 1H), 8.69 (s, 1H), 8.09 (d, J=8Hz, 1H), 8.02 (d, J=8Hz, 1H), 7.64-7.23 (m, 6H), and 6.94-6.83 (m, 2H).
Embodiment 2003-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two fluoro-phenol
To cold (23 ℃ of dry ice/tetracol phenixin are bathed) 3-(benzo [b] naphtho-[2; 3-d] thiophene-11-yl)-2; 6-two fluoro-phenol (1.38g; 3.81mmol) methylene dichloride (35ml) solution in; dripping bromine (0.22ml, methylene dichloride 4.19mmol) (7ml) solution very lentamente in 28 minutes.Behind the restir 1.5 hours, reactant is with rare sodium bisulfite quencher, organism extracted with diethyl ether.Extraction liquid is concentrated, obtain yellow solid (1.64g, 98% thick yield).One aliquot is dissolved in the methylene dichloride and with silica gel mixes.Remove solvent, adsorptive separates (85/15 petrol ether/ethyl acetate) through flash chromatography, obtains the title compound of pale solid: mp180-182 ℃; NMR (400MHz, DMSO-d6): δ 10.64 (s, 1H), 8.30 (d, J=9Hz, 1H), 8.09 (d, J=9Hz, 1H), 7.82-7.78 (m, 1H), 7.64-7.51 (m, 3H), 7.42-7.37 (m, 1H), and 7.33-7.29 (m, 1H), 6.96-6.91 (m, 1H), 6.81-6.78 (m, 1H); MS (FAB): (M-H): observe 1 bromine figure, 439/441 (8%); The analytical calculation value of C22H11BrF2OS: C, 59.88, H, 2.51, N, 0.00%.Measured value: C, 59.82, H, 2.59 N, 0.06.
Embodiment 201[3-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two fluoro-phenoxy groups]-acetate
Under room temperature, dry nitrogen atmosphere, to 3-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two fluoro-phenol (0.200g, 0.453mmol) and salt of wormwood (0.085,0.612mmol) N, dripping bromine methyl acetate in dinethylformamide (2ml) suspension (0.086ml, 0.906mmol).Stir after 2.5 hours, reaction mixture is mixed the organism extracted with diethyl ether with water (50ml).Extraction liquid is mixed with silica gel, remove solvent, adsorptive separates (90/10 petrol ether/ethyl acetate) through flash chromatography.Solvent is handled with benzene (2 *) and sherwood oil, obtains [3-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two fluoro-the phenoxy groups]-methyl acetate (0.198g, 85%) of white solid.To this methyl esters (0.190g, 0.370mmol) in tetrahydrofuran (THF) (3ml) and methyl alcohol (1ml) solution, under room temperature, drip the 1N potassium hydroxide aqueous solution (0.5ml, 0.55mmol).Stir and remove solvent after 1 hour, water is added in the solid residue.Aqueous mixture 10% hcl acidifying, the organism extracted with diethyl ether.Behind the violent jolting number minute, separate each layer, organic layer washes with water and is concentrated.Resistates is handled and vacuum-drying with benzene, obtains the title compound (0.177g, 95%) of white solid; Mp195-197 ℃; NMR (400MHz, DMSO-d6): δ 13.11 (wide s, 1H), 8.31 (d, J=8Hz, 1H), 8.09 (d, J=8Hz, 1H), and 7.83-7.79 (m, 1H), 7.64-7.46 (m, 4H), 7.31-7.27 (m, 1H), 7.23-7.17 (m, 1H), 6.81 (d, J=8Hz, 1H), 4.89 (s, 1H); MS (FAB): (M-H): observe 1 bromine figure: 497/499 (35%/38%); The calculated value of HRMS:C24H13BrF2O3S M+: 497.97368, the actual measurement quality: 497.97787, mass deviation 4.19mmu; Analysis mode HPLC purity 97%; The analytical calculation value of C24H13BrF2O3S: C, 57.72, H, 2.62%, N, 0.00.Measured value: C, 56.77, H, 2.79%, N, 0.00.
Embodiment 202 (R)-2-[3-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two fluoro-phenoxy groups]-propionic acid
Under room temperature, dry nitrogen atmosphere, to 3-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two fluoro-phenol (0.570g, 1.29mmol), commercially available (S)-methyl lactate (O.246ml, 2.58mmol) and triphenylphosphine (0.677g is in dry-out benzene 2.58mmol) (7ml) solution, the adding diethylazodicarboxylate (0.406ml, 2.58mmol).Be sealed in reaction mixture in the pressure bottle and immerse in 105 ℃ of oil baths of preheating.Heat after 2.5 hours, with mixture stir about 14 hours under room temperature.Reaction mixture mixes with the methylene dichloride dilution and with silica gel then.Remove solvent, adsorptive separates (90/10 petrol ether/ethyl acetate) through flash chromatography.Obtain (the R)-2-[3-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2 of white solid, 6-two fluoro-phenoxy groups]-methyl propionate (O.59g, 86%).Under room temperature to this methyl esters (0.46g, drip in tetrahydrofuran (THF) 0.929mmol) (18ml) and methyl alcohol (6ml) solution 1N potassium hydroxide aqueous solution (1.39ml, 1.39mmol).Stir and remove solvent after 2 hours, resistates is mixed with water (50ml) and use 10% hcl acidifying.With solid phase extraction in ether.With each layer shake well together, separate each layer, organic layer washes with water and concentrates, and obtains the title compound (0.396g, 88%) of white solid: [a] D25=+13.22 (9.383mg/ml methyl alcohol); NMR (400MHz, DMSO-d6): δ 13.11 (s, 1H), 8.31 (d, J=8Hz, 1H), 8.10-8.08 (m, 1H), and 7.83-7.78 (m, 1H), 7.65-7.46 (m, 4H), 7.32-7.19 (m, 2H), 6.82-6.75 (m, 1H), 4.98-4.93 (m, 1H), 1.53-1.50 (m, 3H); MS (FAB): (M-H)-: observe 1 bromine figure: 511/513 (2%); The analytical calculation value of C25H15BrF2O3S: C, 58.49, H, 2.95, N, 0.00.Measured value: C, 58.41, H, 3.44, N, 0.02.
Embodiment 203 (R)-2-[3-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two fluoro-phenoxy groups]-3-phenyl-propionic acid
Under room temperature, dry nitrogen atmosphere, to 3-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two fluoro-phenol (0.700g, 1.59mmol), (S)-2-hydroxyl-3-phenylpropionic acid methyl esters (0.572g, 3.17mmol) and triphenylphosphine (0.831g is in dry benzene 3.17mmol) (10ml) solution, the dropping diethylazodicarboxylate (0.50ml, 3.17mmol).Be sealed in reaction mixture in the pressure bottle and immerse in 105 ℃ of oil baths of preheating, heated 2.5 hours.Stir about is 14 hours under room temperature, and reaction mixture mixes with the methylene dichloride dilution and with silica gel.Remove solvent, adsorptive separates (90/10 petrol ether/ethyl acetate) through flash chromatography, obtains (the R)-2-[3-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2 of pale solid, 6-two fluoro-phenoxy groups]-3-phenyl-methyl propionate (0.73g, 76%).To this methyl esters (0.66g, drip in tetrahydrofuran (THF) 1.09mmol) (21ml) and methyl alcohol (7ml) solution 1N potassium hydroxide aqueous solution (1.64ml, 1.64mmol).Stir and remove solvent after 2 hours, resistates is mixed with water (50ml) and use 10% hcl acidifying.Solid phase extraction in ether, with each layer jolting number together minute, is separated each layer then, and organic layer washes with water and concentrates, and obtains the title compound (0.613g, 95%) of white solid: [a] D25=-13.81 (9.413mg/ml chloroform); NMR (400MHz, DMSO-d6): δ 13.21 (s, 1H), 8.30 (d, J=8Hz, 1H), 8.18 (d, J=8Hz, 1H), 7.82-7.78 (m, 1H), and 7.62-7.41 (m, 4H), 7.35-7.14 (m, 7H), 6.74 (dd, J=8,9Hz, 1H), and 5.17-5.11 (m, 1H), 3.32-3.24 (m, 1H), and 3.19-3.12 (m, 1H), NMR shows the benzene that has 0.22 molar weight; MS (+FAB): (M:+): observe 1 bromine figure: 588/590 (78%, 75%); The analytical calculation value of C31H19BrF2O3S0.22C6H6: C, 63.99, H, 3.38, N, 0.00.Measured value: C, 64.52, H, 3.48, N, 0.06.
Embodiment 2042-benzofuryl phenyl-ketone
According to Syn.Comm.1987,17, the method of 341-354, with salicylic aldehyde (21.3ml, 0.20mol), 2-bromoacetophenone (39.8g, 0.20mol), salt of wormwood (30%, 30g is in 700ml water), tetrabutyl ammonium sulfate (3.5g, 5% (mole)) and methylene dichloride (1.5L) vigorous stirring 19 hours.Separate each layer, methylene dichloride phase water and salt water washing.Then it is concentrated, resistates is recrystallize from ethanol (200ml), obtains the title compound (37.9g, 85%) of white crystal; Mp88-90 ℃; NMR (DMSO-d6): δ 8.00 (m, 2H), 7.86 (ddd, J=8,1.5,0.5Hz, 1H), 7.80 (d, J=1Hz, 1H), 7.77 (ddd, J=8,2,1Hz, 1H), 7.77 (ddd, J=8,2,1Hz, 1H), 7.72 (m, 1H), 7.63-7.55 (m, 3H), 6.73 (dd, J=8,1Hz, 1H), 7.39 (ddd, J=8,7,1Hz, 1H); MS (EI): [M+], 222 (100%); The analytical calculation value of C15H10O2: C, 81.07, H, 4.54, N, 0.00.Measured value: C, 81.05, H, 4.44, N ,-0.09.
Embodiment 2052-benzyl-cumarone
With 2-benzofuryl phenyl-ketone (34.8g, 0.157mol), the hydrazine monohydrate (31ml, 0.639mol) and the suspension of glycol ether (72ml) be heated to and refluxed 10 minutes, be cooled to room temperature.Adding potassium hydroxide (22.9g, 0.408mol).Reaction mixture was heated 1 hour in 130 ℃ of oil baths, be cooled to room temperature and add in the entry.The oily matter extracted with diethyl ether.With silica gel add ether mutually in and remove solvent.Adsorptive separates (elutriant: sherwood oil), obtain the title compound (23.9g, 90%) of oily matter through flash chromatography; NMR (CDCl3): δ 7.5-7.1 (m, 9H), 6.38 (s, 1H), 4.10 (s, 2H).
Embodiment 206 (2-benzyl-cumarone-3-yl)-(4-methoxyl group-phenyl)-ketone
Under room temperature, dry nitrogen atmosphere, with tin tetrachloride (6.5ml, 55.5mmol) in 30 minutes, add to 2-benzyl-cumarone (10.0g, 48.01mmol), (8.51g is 49.93mmol) and in the stirred solution of dithiocarbonic anhydride (53ml) for anisoyl chlorine.After 15 hours, reaction mixture is added in the entry, use dichloromethane extraction.With silica gel add methylene dichloride mutually in and remove solvent.Adsorptive separates (95: 5 sherwood oils: ethyl acetate is as eluent) through flash chromatography, obtains the title compound (13.84g, 84%) of white solid; Mp84-85 ℃; NMR (CDCl3): δ 7.87 (dm, J=9Hz, 2H), 7.46 (dm, 1H), 7.36-7.12 (m, 8H), 6.97 (dm, J=9Hz, 2H), 4.29 (s, 2H), 3.90 (s, 3H); MS (EI): 342 (100%, MI); The analytical calculation value of C23H18O3: C, 80.68, H, 5.30, N, 0.00.Measured value: C, 80.61, H, 5.25, N, 0.10.
Embodiment 207 (2-benzyl-cumarone-3-yl)-(2,4-dimethoxy-phenyl)-ketone
According to the method for embodiment 207, by 2-benzyl-cumarone and 2, the preparation of 4-dimethoxy-benzoyl chloride.White solid (6.88g): mp 74-76C; NMR (CDCl3): δ 7.47 (d, J=8Hz, 1H), 7.40 (dd, J=2.1Hz, 1H), and 7.31-7.24 (m, 5H), 7.24-7.19 (m, 2H), and 7.16-7.12 (m, 1H), 6.55 (d, J=2, Hz, 1H), 6.48 (s, 1H), 4.29 (s, 2H), 3.89 (s, 3H), 3.58 (s, 3H), MS (EI): [M *+ m/z] 372 (55%), 165 (100%), 234 (88%); The analytical calculation value of C24H20O4: C, 77.40, H, 5.41, N, 0.00.Measured value: C, 77.48, H, 5.44, N, 0.09.
Embodiment 2084-benzo [b] naphtho-[2,3-d] furans-11-yl)-phenol
Under dry nitrogen atmosphere, with boron tribromide (1.0M dichloromethane solution, 130ml, (12.0g is in methylene dichloride 35.05mmol) (140ml) solution 130mmol) to drip (2-benzyl-cumarone-3-yl)-(4-methoxyl group-phenyl)-ketone as for-78 ℃ of stirrings in 30 minutes.With the solution temperature to room temperature.After 23 hours, carefully add entry.Separate each layer, dichloromethane layer water (3 *), salt water washing are to wherein adding silica gel.Remove solvent, adsorptive separates (gradient: 9: 1 to 1: 1 sherwood oils: ethyl acetate), obtain the title compound (4.56g, 42%) of pale solid: mp137-138 ℃ through flash chromatography; NMR (CDCl3): δ 8.01 (dt, J=8Hz, 1H), 7.94 (s, 1H), 7.89 (dm, J=8Hz, 1 H), 7.53 (m, 2H), 7.44-7.36 (m, 2H), 7.38 (d, J=9Hz, 2H), 7.10 (d, J=9Hz, 2H), 7.13-7.06 (m, 1H), 7.01 (dm, J=8Hz, 1H); MS (EI): 310 (100%, MI); The calculated value of high resolving power MS (EI) C22H14O2: 310.0993803, measured value: 310.09878; The analytical calculation value of C22H14O2: C, 85.14, H, 4.55, N, 0.00.Measured value: C, 84.33, H, 4.30, N, 0.03.
Embodiment 2094-(benzo [b] naphtho-[2,3-d] furans-11-yl)-benzene-1, the 3-diphenol
Under dry nitrogen atmosphere, to cold (76 ℃ of dry ice, isopropanol bath) (2-benzyl-cumarone-3-yl)-(2,4-dimethoxy-phenyl)-ketone (6.13g, 16.5mmol) anhydrous methylene chloride (60ml) solution in, the dichloromethane solution of dropping 1M boron tribromide in 20 minutes (100ml, 100mmol, 6.06eq).Remove the dry ice bath, reaction mixture was stirred under room temperature 45 hours.After the cooling, carefully add entry in ice bath, behind the quencher reaction mixture, water (300ml) is diluted reaction mixture further.Organism ether and dichloromethane extraction.Combining extraction liquid, water and salt water washing, and mix with silica gel.Remove solvent, adsorptive separates (80/20 petrol ether/ethyl acetate) through flash chromatography, obtains the title compound (2.07g, 38%) of white solid: mp201-202 ℃; NMR (CDCl3): δ 8.03 (ddd, J=8,7,1Hz, 1H), 8.01 (s, 1H), 7.82-779 (m, 1H), 7.58-7.54 (m, 2H), 7.48-7.43 (m, 2H), 7.20 (d, J=8Hz, 1H), 7.18-7.15 (m, 2H), 6.70 (m, 2H), 5.00 (s, 1H), 4.70 (s, 1H); The sample quality calculated value of high resolving power MS C22H14O3: 326.0942951, measured value: 326.09019, mass deviation 4mmu.The analytical calculation value of C22H14O3: C, 80.97, H, 4.32, N, 0.00.Measured value: C, 79.80, H, 4.10, N, 0.07.
Embodiment 2102,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-phenol
With 4-benzo [b] naphtho-[2,3-d] furans-11-yl)-(3.0g, 9.67mmol) the stirred suspension slightly heated in acetate (85ml) and water (6ml) is to realize dissolving for phenol.Dripping bromine (1.8ml, acetate 34.01mmol) (20ml) solution in 10 minutes then.The suspension that produces was stirred under room temperature 2 hours.Add entry and solid sulfur sodium thiosulfate, and reaction mixture is filtered.Solid washes with water and grinds with sherwood oil, obtains white solid (4.37g, 83%).With 1 part of (1.0g) this solid recrystallize from acetate (45ml), recrystallize from hexane then obtains the title compound of white solid: mp175-176 ℃; NMR (CDCl3): δ 8.45 (ddd, J=8,1,1Hz, 1H), 7.74 (ddd, J=8,1,1Hz, 1H), 7.70-7.65 (m, 2H), 7.62 (s, 2H), 7.53-7.48 (m, 2H), 7.20 (ddd, J=8,7,1Hz, 1H), 7.02 (ddd, J=8,1,1Hz, 1H), 6.17 (s, 1H); MS (EI): [M+], 3 bromine isotope figures, 544 (30%), 546 (100%), 548 (100%), 550 (30%); The analytical calculation value of C22H11Br3O2: C, 48.30, H, 2.03, N, 0.00.Measured value: C, 48.22, H, 1.79, N, 0.11.
Embodiment 2112,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-3-hydroxyl-phenol
Under room temperature, in 20 minutes to 4-(benzo [b] naphtho-[2,3-d] furans-11-yl)-benzene-1, the 3-diphenol (1.48g, 4.55mmol) and potassium salt (4.46g, dripping bromine in glacial acetic acid 45.5mmole) (15ml) solution (0.75ml, 14.6mmol).Stir after 0.5 hour and mixture is concentrated resistates water (20ml) dilution.Leach the solid of generation, water and petroleum ether in 40 ℃ of vacuum-dryings, obtain raw product (2.5g).Solid is dissolved in the ethyl acetate, mixes with silica gel and remove solvent.Adsorptive separates (gradient 85/15 petrol ether/ethyl acetate) through flash chromatography, obtains yellow solid (0.990g, dibrominated and tribromide mixture of products).Under nitrogen, to this solid (0.437g, in cold (10 ℃) solution of anhydrous methylene chloride 1.11mmol) (10ml) in 30 minutes dripping bromine (0.057ml, anhydrous methylene chloride 1.11mmol) (2ml) solution.After stirring is spent the night in temperature is bathed, in this reaction mixture impouring water (80ml), use ether extraction.The united extraction thing with rare aqueous solution of sodium bisulfite and salt solution thorough washing, adds silica gel.Remove solvent, adsorptive separates (87/13 petrol ether/ethyl acetate) through flash chromatography, obtains the title compound (0.429g) of pale solid: mp226-228 ℃; NMR (CDCl3): δ 8.48 (ddd, J=8,1,1Hz, 1H), 7.73-7.69 (m, 2H), 7.66 (ddd, J=8,1,1Hz, 1H), 7.51 (ddd, J=8,1,1Hz, 2H), 7.49 (s, 1H), 7.22 (ddd, J=8,7,1Hz, 1H), 7.04 (ddd, J=8,1,1Hz, 1H), 6.18 (s, 1H), 5.47 (s, 1H); MS (EI): [M+], 3 bromine isotope figures, 560 (20%), 562 (75%), 564 (44%), 566 (25%); The analytical calculation value of C22H11Br3O3: C, 46.93, H, 1.97, N, 0.00.Measured value: C, 46.63, H, 1.93, N, 0.09.
Embodiment 2124-(benzo [b] naphtho-[2,3-d] furans-11-yl)-methyl acetate
With methyl bromoacetate (0.554ml 5.8mmol) is incorporated in 4-benzo [b] naphtho-[2, the 3-d] furans-11-yl that stirs under the room temperature)-phenol (0.90g, 2.90mmol), (0.81g is 5.8mmol) and in the suspension of dimethyl formamide (7ml) for salt of wormwood.After 20 hours, add reaction mixture in the entry and use extracted with diethyl ether.With silica gel add ether mutually in and remove solvent.Adsorptive separates (9: 1 sherwood oils: ethyl acetate is as elutriant) through flash chromatography, obtains the title compound (0.845g, 76%) of white solid; Mp146-147 ℃; NMR (DMSO-d6): δ 8.19 (s, 1H), 8.13 (d, J=8Hz, 1H), 7.69 (d, J=8Hz, 1H), 7.67 (d, J=8Hz, 1H), 7.58 (ddd, J=8,7,1Hz, 1H), 7.50 (ddd, J=8,7,1Hz, 1H), 7.47-7.43 (m, 1H), 7.43 (d, J=9Hz, 2H), 7.24 (d, J=9Hz, 2H), 7.17 (ddd, J=8,7,1Hz, 1H), 6.88 (dd, J=8,5Hz, 1H), 4.98 (s, 2H), 3.76 (s, 3H); MS (EI): 382 (100%, MI); C25H18O4 analytical calculation value: C, 78.52, H, 4.74, N, 0.00.Measured value: C, 77.88, H, 4.71, N, 0.07.
Embodiment 2134-(benzo [b] naphtho-[2,3-d] furans-11-yl)-acetate
((0.80g is 2.09mmol) in the stirred solution in THF (9ml) and methyl alcohol (9ml) 2.85mmol) to add 4-(benzo [b] naphtho-[2,3-d] furans-11-base-phenoxy group)-methyl acetate for 1.0M, 2.85ml with potassium hydroxide.After 2 hours, remove solvent, add entry, reaction mixture 10% hcl acidifying.After stirring is spent the night, leach solid and wash with water, grind and, obtain white solid (0.735g, 95%) in 100 ℃ of vacuum-dryings with hexane.This solid from acetate, recrystallize from hexane/ethyl acetate then, is obtained the title compound (0.338g, 44%) of white solid: mp205-207 ℃: NMR (CDCl3): δ 8.01 (d, J=8,1,0.5Hz, 1H), 7.95 (s, 1H), 7.76 (ddd, J=8,1,0.5Hz, 1H), and 7.55-7.36 (m, 4H), 7.47 (d, J=9Hz, 2H), 7.21 (d, J=9Hz, 2H), 7.08 (ddd, J=9,8,1Hz, 1H), 6.88 (ddd, J=8,1,5Hz, 1H), 4.89 (s, 2H); MS (EI): 368 (100%, MI); C24H16O4 analytical calculation value: C, 78.25, H, 4.38, N, 0.00.Measured value: C, 77.84, H, 4.30, N, 0.14.
Embodiment 214[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-phenoxy group]-methyl acetate
With methyl bromoacetate (.554ml, 5.8mmol) be incorporated in stir under the room temperature 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-phenol (1.6g, 2.92mmol), (0.81g is 5.8mmol) and in the suspension of dimethyl formamide (7ml) for salt of wormwood.After 21 hours, add in the entry reaction mixture and filtration.Be dissolved in solid among the THF and add silica gel.Remove solvent.Adsorptive separates (9: 1 sherwood oils: ethyl acetate is as elutriant) through flash chromatography, obtains the title compound (0.987g, 55%) of white solid; Mp188-189 ℃; NMR (DMSO-d6): δ 8.37 (d, J=8Hz, 1H), 7.91 (s, 2H), 7.84 (d, J=8Hz, 1H), 7.80 (ddd, J=8,7,1Hz, 1H), 7.70 (d, J=8Hz, 1H), and 7.64-7.58 (m, 2H), 7.31 (t, J=8Hz, 1H), 6.92 (d, J=8,1H), 4.88 (s, 2H), 3.80 (s, 3H); MS (EI): [M+], 3 bromine isotope figures, 616 (30%), 618 (100%), 620 (100%) 622 (30%); C25H15Br3O4 analytical calculation value: C, 48.50, H, 2.44, N, 0.00.Measured value: C, 48.53,, 2.29, N, 0.00.
Embodiment 215[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-phenoxy group]-acetate
(1.60mmol) [2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-phenoxy group]-(0.90g is 1.45mmol) in the stirred solution in THF (9ml) and methyl alcohol (5ml) for methyl acetate in adding for 1.0M, 1.60ml with potassium hydroxide.After 3 hours, remove solvent, add entry, reaction mixture 10% hcl acidifying.After stirring is spent the night, leach solid and wash with water, grind and, obtain the title compound (0.821g, 94%) of white solid: mp250-252 ℃: NMR (DMSO-d6): δ 8.37 (d, J=8Hz in 100 ℃ of vacuum-dryings with hexane, 1H), 7.90 (s, 2H), 7.84 (d, J=8Hz, 1H), 7.70 (ddd, J=8,6,1Hz, 1H), 7.61 (ddd, J=8,1,1Hz, 1H), 7.62-7.58 (m, 2H), 7.31 (ddd, J=8,7,1Hz, 1H), 6.92 (ddd, J=8,1,1Hz, 1H), 4.75 (s, 2H); MS (EI): [M+], 3 bromine isotope figures, 602 (40%), 604 (95%) 606 (100%) 608 (40%); C24H13Br3O4 analytical calculation value: C, 47.64, H, 2.17, N, 0.00.Measured value: C, 47.33, H, 1.95, N, 0.04.
Embodiment 216 (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-phenoxy group]-3-phenyl-propionic acid
Under dry nitrogen atmosphere, with diethylazodicarboxylate (DEAD, 0.108ml, 0.686mmol) add stir under the room temperature 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-phenol (0.250g, 0.457mmol), (S)-2-hydroxyl-3-phenylpropionic acid methyl esters (0.124g, 0.686mmol), (0.180g is 0.686mmol) and in the solution of benzene (2ml) for triphenylphosphine.Dissolve, solution was heated 4.5 hours in 80 ℃ of oil baths.After being cooled to room temperature, reaction mixture is with the ether dilution and add silica gel.Reaction mixture is concentrated, and the silica gel adsorption thing separates (95: 5 sherwood oils: ethyl acetate), obtain white solid (0.266g, 82%) through flash chromatography.(1N, 1.3ml 1.3mmol) add in the stirred solution of this oily matter in THF (3ml)/methyl alcohol (1.3ml) with potassium hydroxide aqueous solution.1.5 after hour with solution concentration, water (100ml) dilution and with 10% aqueous hydrochloric acid acidifying.Leach solid, wash with water and grind, obtain the title compound (0.256g, 98%) of white solid with sherwood oil: NMR (DMSO-d6): δ 13.25 (wide s, 1H), 8.36 (d, J=8Hz, 1H), 7.84-7.77 (m, 3H), 7.67-7.56 (m, 3H), 7.40 (d, J=8 Hz, 2H), 7.33 (d, J=8Hz, 2H), 7.27 (t, J=8Hz, 2H), 6.85 (ddd, J=8,1,1Hz, 1H), 5.31 (t, J=7Hz, 1H), 3.41 (d, J=7Hz, 2H); MS (+FAB): [M+], 3 bromine isotope figures, 692 (35%), 694 (90%), 696 (100%) 698 (50%); The analytical calculation value of C31H19Br3O4: C, 53.56, H, 2.75, N, 0.00.Measured value: C, 52.44, H, 2.82, N ,-0.13.
Embodiment 217[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-3-hydroxyl-phenoxy group]-acetate
Under room temperature, dry nitrogen atmosphere, to [2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-3-hydroxyl-phenol (1.28g, 2.27mmole) anhydrous tetrahydro furan (64ml) solution in add triphenylphosphine (1.193g, 4.55mmole), methyl glycolate (0.351ml, 4.55mmol) and the diethylazodicarboxylate (0.305ml, 4.55mmole).After stirring 8 days under the room temperature, (10ml) quencher of reactant water is also removed solvent.Yellow residual solid is dissolved in the mixture of methylene dichloride, ether and ethyl acetate, mixes with silica gel.Remove solvent, adsorptive separates (40/60 sherwood oil/methylene dichloride) through flash chromatography, obtains white solid (0.342g, 24%).Under room temperature to this solid (0.490g, drip in tetrahydrofuran (THF) 0.772mmol) (6ml) and methyl alcohol (2ml) solution 0.5M potassium hydroxide aqueous solution (3.24ml, 1.62mmol, 2.1eq).After stirring 1.5 hours under the room temperature, remove solvent, resistates is mixed with water.After removing impurity with ether (20ml), water is with 10% aqueous hydrochloric acid acidifying.The organism extracted with diethyl ether.Extraction liquid is merged, concentrates, handle several and, obtain the title compound (0.380g, 79%) of pale solid: mp194-240 ℃ in 60 ℃ of vacuum-dryings with benzene; NMR (DMSO-d6): δ 13.15 (s, 1H), 9.58 (s, 1H, OH), 8.35 (d, J=8Hz, 1H), 7.83 (d, J=8Hz, 1H), 7.78 (ddd, J=8,7,1Hz, 1H), 7.67-7.57 (m, 4H), 7.31 (t, J=8Hz, 1H), 6.94-6.92 (m, 1H), 4.70 (s, 2H); MS (+FAB): [M+], 3 bromine isotope figures, 618 (34%), 620 (100%), 622 (100%), 624 (34%); The analytical calculation value of C24H13Br3O5: C, 46.41, H, 2.11, N, 0.00.Measured value: C, 46.78, H, 2.05.

Claims (52)

1. the compound or its pharmacy acceptable salt that have following formula I structure
Figure A9980842200021
Wherein A is hydrogen, halogen or OH; B and D be independently of one another hydrogen, halogen, CN, a 1-6 carbon atom alkyl, aryl,
The aralkyl of 6-12 carbon atom, nitro, amino or OR; R be hydrogen, a 1-6 carbon atom alkyl ,-COR 1,-CH 2CO 2R 1,-CH (R 1a) CO 2R 1
Or-SO 2R 1R 1And R 1aBe the alkyl of hydrogen, a 1-6 carbon atom, the virtue of a 6-12 carbon atom independently of one another
Alkyl or aryl; E is S, SO, SO 2, O; X be alkyl, CN, a 1-6 carbon atom of hydrogen, halogen, a 1-6 carbon atom perfluoroalkyl,
The alkoxy aryl of the alkoxyl group of 1-6 carbon atom, aryloxy, a 6-12 carbon atom,
Alkyl alkylthio base, sulfur alkyl aryl, the pyridyl of nitro, amino, a 1-6 carbon atom
Sulfane base, 2-N, N-dimethylaminoethyl sulfane base or-OCH 2CO 2R 1bR 1bAlkyl for hydrogen or 1-6 carbon atom; Y and Z are hydrogen or OR independently of one another 2R 2For the aralkyl of the alkyl of hydrogen, a 1-6 carbon atom, a 6-12 carbon atom or-
CH 2CO 2R 3R 3Alkyl for hydrogen or 1-6 carbon atom; C is hydrogen, halogen or OR 4R 4For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R 5) W ,-C (CH 3) 2CO 2R 6, the 5-thiazole
Alkane-2, the 4-diketone ,-CH (R 7) CH 2CO 2R 6,-COR 6,-PO 3(R 6) 2Or-SO 2R 6R 5Alkyl, aralkyl, aryl, CH for hydrogen, a 1-6 carbon atom 2(1H-imidazol-4 yl),
-CH 2(3-1H-indyl) ,-CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl),
-CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl) ,-CH 2(3-pyridyl) or
-CH 2CO 2H; W is-CO 2R 6,-CONH 2,-CONHOH, CN ,-CONH (CH 2) 2CN, 5-four
Azoles ,-PO 3(R 6) 2,-CH 2OH or-CH 2Br ,-CONR 6CHR 7CO 2R 8R 6Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom; R 7Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom; R 8Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom.
2. according to compound or its pharmacy acceptable salt of claim 1, wherein A and B are hydrogen or bromine independently of one another; C and D are OH; E is S or O; X be alkyl, CN, a 1-6 carbon atom of hydrogen, halogen, a 1-6 carbon atom alkoxyl group,
The aryloxy of 6-12 carbon atom; The alkoxy aryl of 6-12 carbon atom, aryl sulfane
Base or pyridyl sulfane base; Y and Z are hydrogen.
3. according to compound or its pharmacy acceptable salt of claim 1, wherein A is a hydrogen; B and D are that alkyl, aryl, the 6-12 of hydrogen, halogen, a 1-6 carbon atom is individual independently of one another
The alkoxyl group of the aralkyl of a carbon atom or 1-6 carbon atom; C is OR 4E is S, O; X be alkyl, a 1-6 carbon atom of hydrogen, halogen, a 1-6 carbon atom perfluoroalkyl, CN,
The alkoxy aryl of the alkoxyl group of 1-6 carbon atom, aryloxy, a 6-12 carbon atom,
Sulfur alkyl aryl, pyridyl sulfane base; Y and Z are H; R 4For the alkyl of H, a 1-6 carbon atom ,-CH (R 5) W or 5-thiazolidine-2, the 4-diketone; R 5For the aralkyl of the alkyl of H hydrogen, a 1-6 carbon atom, a 6-12 carbon atom, aryl ,-
CH 2(3-1H-indyl) ,-CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl),
-CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl) or-CH 2(3-pyridyl); W is-CO 2R 6,-CONH 2,-CONHOH, 5-tetrazolium or-PO 3(R 6) 2R 6Alkyl for hydrogen or 1-6 carbon atom.
4. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-phenoxy group]-3-phenyl-propionic acid or its pharmacy acceptable salt.
5. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid or its pharmacy acceptable salt.
6. the compound of claim 1, it is (5 '-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-[1,1 '; 3 ' 1 "] terphenyl-2 '-Ji oxygen base)-acetate or its pharmacy acceptable salt.
7. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid or its pharmacy acceptable salt.
8. the compound of claim 1, it is 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-(4-fluorophenyl)-propionic acid or its pharmacy acceptable salt.
9. the compound of claim 1, it is (R)-2-[2-bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-6-methoxyl group-phenoxy group]-3-phenyl-propionic acid or its pharmacy acceptable salt.
10. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-propionic acid or its pharmacy acceptable salt.
11. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(6-iodo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-propionic acid or its pharmacy acceptable salt.
12. the compound of claim 1, it is 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-caproic acid or its pharmacy acceptable salt.
13. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(6-methoxyl group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid or its pharmacy acceptable salt.
14. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(6-chloro-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid or its pharmacy acceptable salt.
15. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(6-phenyl-sulfane base-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid or its pharmacy acceptable salt.
16. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(6-phenyl-sulfane base-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-propionic acid or its pharmacy acceptable salt.
17. the compound of claim 1, its be (R, S)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-(1H-indol-3-yl)-propionic acid or its pharmacy acceptable salt.
18. the compound of claim 1, it is (R)-benzo [b] naphtho-[2,3-d] thiophene-11-base-2,6-two iodo-phenoxy groups)-3-phenyl-propionic acid or its pharmacy acceptable salt.
19. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-butyric acid or its pharmacy acceptable salt.
20. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(6-trifluoromethyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid or its pharmacy acceptable salt.
21. the compound of claim 1, it is (S)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-butyric acid or its pharmacy acceptable salt.
22. the compound of claim 1, it is (R)-2-(4-benzo [b] naphtho-[2,3-d] thiophene-11-base-2,6-two bromo-phenoxy groups)-4-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-butyric acid or its pharmacy acceptable salt.
23. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-4-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-butyric acid or its pharmacy acceptable salt.
24. the compound of claim 1, it is { 1-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propyl group }-diethyl phosphonate or its pharmacy acceptable salt.
25. the compound of claim 1, it is (R)-2-{2,6-two bromo-4-[6-(pyridin-4-yl sulfane base)-benzo [b] naphtho-[2,3-d] thiophene-11-yl]-phenoxy group }-3-phenyl-propionic acid or its pharmacy acceptable salt.
26. the compound of claim 1, it is (R)-2-[4-(6-benzyloxy-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-two bromo-phenoxy groups]-3-phenyl-propionic acid or its pharmacy acceptable salt.
27. the compound of claim 1, it is (S)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-methyl propionate or its pharmacy acceptable salt.
28. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-phenyl-acetic acid or its pharmacy acceptable salt.
29. the compound of claim 1, it is [2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-acetate or its pharmacy acceptable salt.
30. the compound of claim 1, it is [2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxymethyl]-phosphonic acids or its pharmacy acceptable salt.
31. the compound of claim 1, it is [2,6-two bromo-4-(6-cyano group-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-acetate or its pharmacy acceptable salt.
32. the compound of claim 1, it is 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-naphthalene-2-base-propionic acid or its pharmacy acceptable salt.
33. the compound of claim 1, it is (2R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-4-(1-oxo-1,3-dihydro-isoindole-2-yl)-butyric acid or its pharmacy acceptable salt.
34. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(6-methyl-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-phenyl-propionic acid or its pharmacy acceptable salt.
35. the compound of claim 1, it is (R)-5-{1-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-2-phenyl-ethyl }-1H-tetrazolium or its pharmacy acceptable salt.
36. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-N-hydroxyl-3-phenyl-propionic acid amide or its pharmacy acceptable salt.
37. the compound of claim 1, it is 5-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-thiazolidine-2,4-diketone or its pharmacy acceptable salt.
38. the compound of claim 1, it is (R)-2-(4-benzo [b] naphtho-[2,3-d] thiophene-11-base-2,6-two iodo-phenoxy groups)-propionic acid or its pharmacy acceptable salt.
39. the compound of claim 1, it is 2-[2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-phenoxy group]-3-pyridin-3-yl-propionic acid.
40. the compound of claim 1, it is (2R)-2-[4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-di-isopropyl-phenoxy group]-3-phenyl-propionic acid or its pharmacy acceptable salt.
41. the compound of claim 1, it is 4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-di-isopropyl-phenol or its pharmacy acceptable salt.
42. the compound of claim 1, it is 4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1,2-diphenol or its pharmacy acceptable salt.
43. the compound of claim 1, it is 3-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1,2-diphenol or its pharmacy acceptable salt.
44. the compound of claim 1, it is 4-bromo-5-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-benzene-1,2-diphenol or its pharmacy acceptable salt.
45. the compound of claim 1, it is [2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-phenoxy group]-acetate or its pharmacy acceptable salt.
46. the compound of claim 1, it is 2,6-two bromo-4-(6-bromo-benzo [b] naphtho-[2,3-d] furans-11-yl)-phenol or its pharmacy acceptable salt.
47. the compound of claim 1, it is [4-(6-bromo-benzo [b] naphtho-[2,3-d] thiophene-11-yl)-2,6-di-isopropyl-phenoxy group]-acetate or its pharmacy acceptable salt.
48. A compound according to claim 1, which is 4 - benzo [b] naphtho [2,3-d] thiophene -11 - yl - phenol; 11 - (4 - hydroxy - phenyl) - benzo [b] naphtho [2,3-d] thiophen-3 - phenol; 4 - (6 - benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2,6 - diisopropyl - phenol; 3 - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 4 - (benzo [b] naphtho [2,3-d] thiophene -11 - yl) - benzene-1 ,2 - diol; 8 - methoxypsoralen-11 - (4 - methoxy - phenyl) - benzo [b] naphtho [2,3-d] thiophene; 11 - (4 - hydroxy - phenyl) - benzo [b] naphtho [2,3-d] thiophen -8 - phenol; 2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 11 - (3,5 - dibromo - 4 - methoxy - phenyl) - benzo [b] naphtho [2,3-d] thiophene; 11 - (4 - methoxy - phenyl) - benzo [b] naphtho [2,3-d] thiophene; 11 - (4 - methoxy-3 ,5 - dimethyl - phenyl)-6 - methyl - benzo [b] naphtho [2,3-d] thiophene; 2,6 - dimethyl-4 - (6 - methyl - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 4 - (benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2,6 - diiodo - phenol; 4 - (benzo [b] naphtho [2,3-d] thiophene -11 - yl)-2-iodo - phenol; 11 - (4 - methoxy-3 ,5 - diiodo-phenyl) - benzo [b] naphtho [2,3-d] thiophene; 11 - (3 - iodo-4 - methoxy - phenyl) - benzo [b] naphtho [2,3-d] thiophene; 5 - benzo [b] naphtho [2,3-d] thiophene -11 --2 - methoxy - isophthalonitrile; 5 - (benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2 - methoxy - benzonitrile; 5 - benzo [b] naphtho [2,3-d] thiophene -11 --2 - hydroxy - isophthalonitrile; 5 - benzo [b] naphtho [2,3-d] thiophene -11 --2 - hydroxy - benzonitrile; 4 - benzo [b] naphtho [2,3-d] thiophene -11 - yl - phenol) acetate; Acid 3 - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenyl ester; Acetic acid 2 - acetoxy-4 - (benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenyl ester; 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl - phenol) acetate; Acid 3 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenyl ester; Acetic acid 2 - acetoxy-4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenyl ester; 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 3 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 11 - (4 - hydroxy - phenyl) - benzo [b] naphtho [2,3-d] thiophene -6 - carbonitrile; Methanesulfonic acid 4 - benzo [b] naphtho [2,3-d] thiophene -11 - yl - phenyl ester; Methanesulfonic acid 4 - (6 - chloro - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenyl ester; Methanesulfonic acid 4 - (6 - iodo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenyl ester; Methanesulfonic acid 4 - (6 - (trifluoromethyl) - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenyl ester; Methanesulfonic acid 4 - (6 - methyl - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenyl ester; 4 - (6 - chloro - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 4 - (6 - iodo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 4 - (6 - (trifluoromethyl) - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 4 - (6 - methyl - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 4 - (6 - methoxy - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 4 - (6 - phenyl sulfanyl - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 4 - [6 - (2 - dimethylamino - ethyl-sulfanyl) - benzo [b] naphtho [2,3-d] thiophene -11 - yl] - phenyl Phenol; 4 - [6 - (pyridin-4 - yl sulfanyl) - benzo [b] naphtho [2,3-d] thiophene -11 - yl] - phenol; 11 - (3,5 - dibromo - 4 - hydroxy - phenyl) - benzo [b] naphtho [2,3-d] thiophene -6 - carbonitrile; 2,6 - dibromo - 4 - (6 - iodo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 2,6 - dibromo - 4 - (6 - chloro - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 2,6 - dibromo - 4 - (6 - (trifluoromethyl) - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 2,6 - dibromo - 4 - (6 - methyl - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 2,6 - dibromo - 4 - (6 - methoxy-benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 2,6 - dibromo - 4 - (6 - phenyl sulfanyl - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 2,6 - dibromo - 4 - [6 - (pyridin-4 - yl sulfanyl) - benzo [b] naphtho [2,3-d] thiophene -11 - yl] - Phenol; 2,6 - dibromo - 4 - [6 - (2 - dimethylamino - ethyl sulfanyl) - benzo [b] naphtho [2,3-d] thiophene -11 - Yl] - phenol; 2,6 - dichloro-4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 2 - bromo-4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; 2,4 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenol; [11 - (4 - hydroxy - phenyl) - benzo [b] naphtho [2,3-d] thiophen-3 - yloxy] - acetic acid methyl ester; [11 - (4 - methoxy-carbonyl-methoxy - phenyl) - benzo [b] naphtho [2,3-d] thiophen-3 - yloxy Yl] - acetic acid methyl ester; [11 - (4 - carboxy-methoxy - phenyl) - benzo [b] naphtho [2,3-d] thiophen-3-yloxy] - - B Acid; [11 - (4 - methoxy-carbonyl-methoxy - phenyl) - benzo [b] naphtho [2,3-d] thiophene -8 - yloxy Yl] - acetic acid methyl ester; [11 - (4 - carboxy-methoxy - phenyl) - benzo [b] naphtho [2,3-d] thiophene -8 - yloxy] - acetic Acid; [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - acetic acid methyl Esters; [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - acetic acid tert- Butyl; [2,6 - dichloro-4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - acetate Salts; [(4 - benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2,6 - dicyano - phenoxy] - acetic acid; [(4 - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - 2 - cyano - phenoxy] - acetic acid; (4 - benzo [b] naphtho [2,3-d] thiophene -11 - yl 2,6 - diiodo - phenoxy) - acetic acid; [4 - benzo [b] naphtho [2,3-d] thiophene -11 - yl - phenoxy] - acetic acid; (4 - benzo [b] naphtho [2,3-d] thiophene -11 --2 - iodo - phenoxy) - acetic acid; {2,6 - dichloro-4 - [6 - methyl - benzo [b] naphtho [2,3-d] thiophene -11 - yl)] - phenoxy} - acetic Acid; [4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - acetic acid; [3 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - acetic acid; [2 - bromo-5 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - acetic acid; [2,4 - dibromo-5 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - acetic acid; 5 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2 - carboxymethoxy - phenoxy] - acetic Acid; 3 - bromo -5 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2 - carboxymethoxy - phenoxy Yl] - acetic acid; 4 - bromo-5 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2 - carboxymethoxy - phenoxy Yl] - acetic acid; (R) -2 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -3 - Phenyl - methyl propionate; (R) -2 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -3 - Phenyl - propionate; (S) -2 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -3 - Phenyl - propionic acid; (R) -2 - [2,6 - dibromo - 4 - (6 - methoxy - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy Yl] -3 - phenyl - propionic acid methyl ester; (S) -2 - [4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -3 - phenyl - C Acid; (S) -2 - [2,6 - dibromo - 4 - (6 - cyano - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - 3 - phenyl - propionic acid; (R) -2 - [4 - (6 - cyano - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -3 - phenyl - Acid; (R) -2 - [4 - (benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -3 - phenyl - propionic acid; (R) -2 - [4 - (3 - carboxy-methoxy - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -3 - Phenyl - propionic acid; (R) -2 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -3 - (1H-imidazol-4 - yl) - propionic acid hydrochloride; (R) -2 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -3 - Phenyl - propionic acid; (R) -2 - {2,6 - dibromo - 4 - [6 - (2 - dimethylamino - ethyl-sulfanyl) - benzo [b] naphtho [2,3 - d] thiophene -11 - yl] - phenoxy} -3 - phenyl - propionic acid; (R) -2 - [2,6 - dimethyl-4 - (6 - methyl - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy Yl] -3 - phenyl - propionic acid; (R) -2 - [4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2,6 - diisopropyl - phenoxy Yl] - propionic acid; (S) -2 - [2 - bromo-5 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - C Acid; (R) -2 - [2 - bromo-5 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - C Acid; (R) -2 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -4 - (1,3 - dioxo-1 ,3 - dihydro - isoindol-2 - yl) - butyrate; (R) -2 - (4 - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy) -4 - (1,3 - dioxo - 1,3 - dihydro - isoindol-2 - yl) - butyric acid; (R) -2 - [4 - (3 - carboxy-methoxy - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy - (1,3 - dioxo-1 ,3 - dihydro - isoindol-2 - yl) - butyric acid; (R) -2 - [4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -4 - (1,3 - dioxo- 1 ,3 - dihydro - isoindol-2 - yl) - butyric acid; (R) -2 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - Dimethyl succinate; (R) -2 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - Succinic acid; 2 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -3 - (4 - Fluoro - phenyl - propionic acid tert-butyl ester; (R) -2 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -3 - Naphthalene-2 ​​- yl - propionic acid tert-butyl ester; {2,6 - dibromo - 4 - [6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl)] - phenoxymethyl} - Phosphonate; [4 - (benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxymethyl] - phosphonic acid diethyl ester; [4 - (benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxymethyl] - phosphonic acid; {1 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -3 - phenyl Base - propyl} - phosphonic acid; 2 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - acetyl Amines; (R) -2 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -3 - Phenyl - propanamide; (R) -2 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - N-(3 - nitro - propyl) of 3 - phenyl - propanamide; [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - acetonitrile; (R) -2 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -3 - Phenyl - propionitrile; 5 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxymethyl] - 1H-tetrazole; (R) -6 - bromo -11 - [3,5 - dibromo - 4 - (1 - (hydroxymethyl)-2 - phenyl - ethoxy) - phenyl] - benzo [b] Naphtho [2,3-d] thiophene; (R) -6 - bromo -11 - [3,5 - dibromo - 4 - (1 - bromomethyl-2 - phenyl - ethoxy) - phenyl] - benzo [b] Naphtho [2,3-d] thiophene; Acid tert-butyl 2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenyl Esters; Phosphate - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenyl] Esters; 2 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] -2 - methyl Base - propionic acid; 3 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - C Acid; (R) -3 - [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenoxy] - Butyric acid; (R) -2 - [4 - (6 - hydroxy - benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2,6 - dibromo - phenoxy Yl] -3 - phenyl - propionic acid methyl ester; (R) -2 - [4 - (6 - benzyloxy - benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2,6 - dibromo - phenoxy Yl] -3 - phenyl - propionic acid methyl ester; (R) -2 - [2,6 - dibromo - 4 - (6 - methoxy-carbonyl-methoxy - benzo [b] naphtho [2,3-d] thiophene - 11 - yl) - phenoxy] -3 - phenyl - propionic acid methyl ester; (R) -2 - [2,6 - dibromo - 4 - (6 - carboxy-methoxy - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - Phenoxy] -3 - phenyl - propionic acid; [2,6 - dibromo - 4 - (6 - bromo-5, 5 - dioxo-5H-6-benzo [b] naphtho [2,3-d] thiophene -11 - Yl) - phenoxy] - acetic acid; [2,6 - dibromo - 4 - (6 - bromo-5 - oxo-5H-4-benzo [b] naphtho [2,3-d] thiophene -11 - yl) - phenyl Oxy] - acetic acid; (R) -2 - [2,6 - dibromo - 4 - (6 - bromo-5, 5 - dioxo-5H-5 (λ6) - benzo [b] naphtho [2,3-d] Thienyl -11 - yl) - phenoxy] -3 - phenyl - propionic acid methyl ester; (R) -2 - [2,6 - dibromo - 4 - (6 - bromo-5, 5 - dioxo-5H-5 (λ6) - benzo [b] naphtho [2,3-d] Thienyl -11 - yl) - phenoxy] -3 - phenyl - propionic acid; 5'-benzo [b] naphtho [2,3-d] thiophene -11 - yl - [1,1 '; 3'1 "] terphenyl-2'-phenol 3 - bromo -5 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) - 2 - benzyloxy - phenol; 2 - bromo-4 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) -6 - methoxy - phenol; 3 - bromo -5 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2 - methoxy - phenol; (R) -2 - [3 - bromo-5 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2 - methoxy - phenoxy Yl] -3 - phenyl - propionic acid; 3 - (benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2,6 - difluoro - phenol; 3 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2,6 - difluoro - phenol; [3 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2,6 - difluoro - phenoxy] - acetic acid; (R) -2 - [3 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2,6 - difluoro - phenoxy] - Acid; (R) -2 - [3 - (6 - bromo - benzo [b] naphtho [2,3-d] thiophene -11 - yl) -2,6 - difluoro - phenoxy] -3 - Phenyl - propionic acid; 4 - benzo [b] naphtho [2,3-d] furan -11 - yl) - phenol; 4 - (benzo [b] naphtho [2,3-d] furan -11 - yl) - benzene-1 ,3 - diol; 2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] furan -11 - yl) -3 - hydroxy - phenol; 4 - (benzo [b] naphtho [2,3-d] furan -11 - yl - phenoxy) - acetic acid methyl ester; 4 - (benzo [b] naphtho [2,3-d] furan -11 - yl - phenoxy) - acetic acid; [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] furan -11 - yl) - phenoxy] - acetic acid methyl Esters; [2,6 - dibromo - 4 - (6 - bromo - benzo [b] naphtho [2,3-d] furan -11 - yl) -3 - hydroxy - phenoxy] - Acetic acid; Or a pharmaceutically acceptable salt thereof. ...
49. treatment is by the method for the metabolism disorder of insulin resistance or hyperglycemia mediation in the Mammals of needs treatments, described method comprises and gives formula I compound or its pharmacy acceptable salt that described Mammals has the following formula structure: Wherein A is hydrogen, halogen or OH; B and D be independently of one another hydrogen, halogen, CN, a 1-6 carbon atom alkyl, aryl,
The aralkyl of 6-12 carbon atom, nitro, amino or OR; R be hydrogen, a 1-6 carbon atom alkyl ,-COR 1,-CH 2CO 2R 1,-CH (R 1a) CO 2R 1
Or-SO 2R 1R 1And R 1aBe the alkyl of hydrogen, a 1-6 carbon atom, the virtue of a 6-12 carbon atom independently of one another
Alkyl or aryl; E is S, SO, SO 2, O; X be alkyl, CN, a 1-6 carbon atom of hydrogen, halogen, a 1-6 carbon atom perfluoroalkyl,
The alkoxy aryl of the alkoxyl group of 1-6 carbon atom, aryloxy, a 6-12 carbon atom,
Alkyl alkylthio base, sulfur alkyl aryl, the pyridyl of nitro, amino, a 1-6 carbon atom
Sulfane base, 2-N, N-dimethylamino second sulfane base or-OCH 2CO 2R 1bR 1bAlkyl for hydrogen or 1-6 carbon atom; Y and Z are hydrogen or OR independently of one another 2R 2For the aralkyl of the alkyl of hydrogen, a 1-6 carbon atom, a 6-12 carbon atom or-
CH 2CO 2R 3R 3Alkyl for hydrogen or 1-6 carbon atom; C is hydrogen, halogen or OR 4R 4For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R 5) W ,-C (CH 3) 2CO 2R 6, the 5-thiazole
Alkane-2, the 4-diketone ,-CH (R 7) CH 2CO 2R 6,-COR 6, PO 3(R 6) 2Or-SO 2R 6R 5Alkyl, aralkyl, aryl, CH for hydrogen, a 1-6 carbon atom 2(1H-imidazol-4 yl),
-CH 2(3-1H-indyl) ,-CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl),
-CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl) ,-CH 2(3-pyridyl) or
-CH 2CO 2H; W is-CO 2R 6,-CONH 2,-CONHOH, CN ,-CONH (CH 2) 2CN, 5-four
Azoles ,-PO 3(R 6) 2,-CH 2OH or-CH 2Br ,-CONR 6CHR 7CO 2R 8R 6Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom; R 7Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom; R 8Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom.
50. comprising, the method for treatment or inhibition type II diabetes in the Mammals of needs treatment, described method give formula I compound or its pharmacy acceptable salt that described Mammals has the following formula structure: Wherein A is hydrogen, halogen or OH; B and D be independently of one another hydrogen, halogen, CN, a 1-6 carbon atom alkyl, aryl,
The aralkyl of 6-12 carbon atom, nitro, amino or OR; R be hydrogen, a 1-6 carbon atom alkyl ,-COR 1,-CH 2CO 2R 1,-CH (R 1a) CO 2R 1
Or-SO 2R 1R 1And R 1aBe the alkyl of hydrogen, a 1-6 carbon atom, the virtue of a 6-12 carbon atom independently of one another
Alkyl or aryl; E is S, SO, SO 2, O; X be alkyl, CN, a 1-6 carbon atom of hydrogen, halogen, a 1-6 carbon atom perfluoroalkyl,
The alkoxy aryl of the alkoxyl group of 1-6 carbon atom, aryloxy, a 6-12 carbon atom,
Alkyl alkylthio base, sulfur alkyl aryl, the pyridyl of nitro, amino, a 1-6 carbon atom
Sulfane base, 2-N, N-dimethylaminoethyl sulfane base or-OCH 2CO 2R 1bR 1bAlkyl for hydrogen or 1-6 carbon atom; Y and Z are hydrogen or OR independently of one another 2R 2For the aralkyl of the alkyl of hydrogen, a 1-6 carbon atom, a 6-12 carbon atom or-
CH 2CO 2R 3R 3Alkyl for hydrogen or 1-6 carbon atom; C is hydrogen, halogen or OR 4R 4For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R 5) W ,-C (CH 3) 2CO 2R 6, the 5-thiazole
Alkane-2, the 4-diketone ,-CH (R 7) CH 2CO 2R 6,-COR 6,-PO 3(R 6) 2Or-SO 2R 6R 5Alkyl, aralkyl, aryl, CH for hydrogen, a 1-6 carbon atom 2(1H-imidazol-4 yl),
-CH 2(3-1H-indyl) ,-CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl),
-CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl) ,-CH 2(3-pyridyl) or-
CH 2CO 2H; W is-CO 2R 6,-CONH 2,-CONHOH, CN ,-CONH (CH 2) 2CN, 5-four
Azoles ,-PO 3(R 6) 2,-CH 2OH or-CH 2Br ,-CONR 6CHR 7CO 2R 8R 6Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom; R 7Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom; R 8Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom.
51. comprising, the method for adjusting glucose level in the Mammals of needs treatment, described method give formula I compound or its pharmacy acceptable salt that described Mammals has the following formula structure: Wherein A is hydrogen, halogen or OH; B and D be independently of one another hydrogen, halogen, CN, a 1-6 carbon atom alkyl, aryl,
The aralkyl of 6-12 carbon atom, nitro, amino or OR; R be hydrogen, a 1-6 carbon atom alkyl ,-COR 1,-CH 2CO 2R 1,-CH (R 1a) CO 2R 1
Or-SO 2R 1R 1And R 1aBe the alkyl of hydrogen, a 1-6 carbon atom, the virtue of a 6-12 carbon atom independently of one another
Alkyl or aryl; E is S, SO, SO 2, O; X be alkyl, CN, a 1-6 carbon atom of hydrogen, halogen, a 1-6 carbon atom perfluoroalkyl,
The alkoxy aryl of the alkoxyl group of 1-6 carbon atom, aryloxy, a 6-12 carbon atom,
Alkyl alkylthio base, sulfur alkyl aryl, the pyridyl of nitro, amino, a 1-6 carbon atom
Sulfane base, 2-N, N-dimethylaminoethyl sulfane base or-OCH 2CO 2R 1bR 1bAlkyl for hydrogen or 1-6 carbon atom; Y and Z are hydrogen or OR independently of one another 2R 2For the aralkyl of the alkyl of hydrogen, a 1-6 carbon atom, a 6-12 carbon atom or-
CH 2CO 2R 3R 3Alkyl for hydrogen or 1-6 carbon atom; C is hydrogen, halogen or OR 4R 4For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R 5) W ,-C (CH 3) 2CO 2R 6, the 5-thiazole
Alkane-2, the 4-diketone ,-CH (R 7) CH 2CO 2R 6,-COR 6, PO 3(R 6) 2Or-SO 2R 6R 5Alkyl, aralkyl, aryl, CH for hydrogen, a 1-6 carbon atom 2(1H-imidazol-4 yl),
-CH 2(3-1H-indyl) ,-CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl),
-CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl) ,-CH 2(3-pyridyl) or
-CH 2CO 2H; W is-CO 2R 6,-CONH 2,-CONHOH, CN ,-CONH (CH 2) 2CN, 5-four
Azoles ,-PO 3(R 6) 2,-CH 2OH or-CH 2Br ,-CONR 6CHR 7CO 2R 8R 6Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom; R 7Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom; R 8Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom.
52. medicinal compositions, it comprises formula I compound or its pharmacy acceptable salt and a kind of pharmaceutical carrier with following formula structure:
Figure A9980842200201
Wherein A is hydrogen, halogen or OH; B and D be independently of one another hydrogen, halogen, CN, a 1-6 carbon atom alkyl, aryl,
The aralkyl of 6-12 carbon atom, nitro, amino or OR; R be hydrogen, a 1-6 carbon atom alkyl ,-COR 1,-CH 2CO 2R 1,-CH (R 1a) CO 2R 1
Or-SO 2R 1R 1And R 1aBe the alkyl of hydrogen, a 1-6 carbon atom, the virtue of a 6-12 carbon atom independently of one another
Alkyl or aryl; E is S, SO, SO 2, O; X be alkyl, CN, a 1-6 carbon atom of hydrogen, halogen, a 1-6 carbon atom perfluoroalkyl,
The alkoxy aryl of the alkoxyl group of 1-6 carbon atom, aryloxy, a 6-12 carbon atom,
Alkyl alkylthio base, sulfur alkyl aryl, the pyridyl of nitro, amino, a 1-6 carbon atom
Sulfane base, 2-N, N-dimethylaminoethyl sulfane base or-OCH 2CO 2R 1bR 1bAlkyl for hydrogen or 1-6 carbon atom; Y and Z are hydrogen or OR independently of one another 2R 2For the aralkyl of the alkyl of hydrogen, a 1-6 carbon atom, a 6-12 carbon atom or-
CH 2CO 2R 3R 3Alkyl for hydrogen or 1-6 carbon atom; C is hydrogen, halogen or OR 4R 4For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R 5) W ,-C (CH 3) 2CO 2R 6, the 5-thiazole
Alkane-2, the 4-diketone ,-CH (R 7) CH 2CO 2R 6,-COR 6,-PO 3(R 6) 2Or-SO 2R 6R 5Alkyl, aralkyl, aryl, CH for hydrogen, a 1-6 carbon atom 2(1H-imidazol-4 yl),
-CH 2(3-1H-indyl) ,-CH 2CH 2(1,3-dioxo-1,3-dihydro-isoindole-2-yl),
-CH 2CH 2(1-oxo-1,3-dihydro-isoindole-2-yl) ,-CH 2(3-pyridyl) or-
CH 2CO 2H; W is-CO 2R 6,-CONH 2,-CONHOH, CN ,-CONH (CH 2) 2CN, 5-four
Azoles ,-PO 3(R 6) 2,-CH 2OH or-CH 2Br ,-CONR 6CHR 7CO 2R 8R 6Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom; R 7Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom; R 8Alkyl, aryl or aralkyl for hydrogen, a 1-6 carbon atom.
CN99808422A 1998-05-12 1999-05-10 11-Aryl-benzo[b]naphtho[2,3-d]furans and 11-aryl-aryl-benzo[b]anphtho[2,3-d]thiophenes useful in the treatment of insulin resistance and hyperglycemia Pending CN1308627A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7659298A 1998-05-12 1998-05-12
US09/076592 1998-05-12

Publications (1)

Publication Number Publication Date
CN1308627A true CN1308627A (en) 2001-08-15

Family

ID=22133016

Family Applications (1)

Application Number Title Priority Date Filing Date
CN99808422A Pending CN1308627A (en) 1998-05-12 1999-05-10 11-Aryl-benzo[b]naphtho[2,3-d]furans and 11-aryl-aryl-benzo[b]anphtho[2,3-d]thiophenes useful in the treatment of insulin resistance and hyperglycemia

Country Status (6)

Country Link
EP (1) EP1077970A1 (en)
JP (1) JP2002514638A (en)
CN (1) CN1308627A (en)
AU (1) AU3979199A (en)
CA (1) CA2330623A1 (en)
WO (1) WO1999058521A1 (en)

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6281238B1 (en) * 1998-05-12 2001-08-28 American Home Products Corporation 4-aryl-1-oxa-9-thia-cylopenta[B]fluorenes
US6498182B2 (en) 2000-09-26 2002-12-24 Biovitrum Ab Compounds
AU2002251978B2 (en) 2001-02-09 2007-07-19 Merck & Co., Inc. 2-aryloxy-2-arylalkanoic acids for diabetes and lipid disorders
DE10140148B4 (en) 2001-08-16 2012-07-19 Merck Patent Gmbh Fluorinated polycycles and their use in liquid crystal mixtures and in liquid crystal displays
WO2003048140A1 (en) 2001-12-03 2003-06-12 Japan Tobacco Inc. Azole compound and medicinal use thereof
JP2005520858A (en) * 2002-03-20 2005-07-14 メタボレックス， インコーポレイテッド Substituted phenylacetic acid
BR0314721A (en) 2002-10-23 2005-08-02 Glenmark Pharmaceuticals Ltd Tricyclic compounds useful for treating inflammatory and allergic disorders, processes for their preparation and pharmaceutical compositions containing them
DK1620429T3 (en) 2003-04-11 2009-05-18 Glenmark Pharmaceuticals Sa New heterocyclic compounds useful in the treatment of inflammatory and allergic diseases, methods of their preparation and pharmaceutical compositions containing them
GB0311406D0 (en) 2003-05-17 2003-06-25 Queen Mary & Westfield College Substituted phosphonate fluorescent sensors,and use thereof
JPWO2004106542A1 (en) 2003-05-29 2006-07-20 三共株式会社 Insulin resistance improving agent and screening method thereof
US7371759B2 (en) 2003-09-25 2008-05-13 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
WO2005035551A2 (en) 2003-10-08 2005-04-21 Incyte Corporation Inhibitors of proteins that bind phosphorylated molecules
US7420059B2 (en) 2003-11-20 2008-09-02 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
WO2006011024A2 (en) * 2004-07-19 2006-02-02 Glenmark Pharmaceuticals Ltd. New tricyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
DK1831227T3 (en) 2004-12-17 2013-08-19 Glenmark Pharmaceuticals Sa Hitherto unknown, heterocyclic compounds useful in the treatment of inflammatory and allergic disorders
AP2334A (en) 2004-12-17 2011-12-06 Glenmark Pharmaceuticals Sa Novel heterocyclic compounds useful for the treatment of inflamatory and allergic disorders.
GB0708507D0 (en) 2007-05-02 2007-06-13 Queen Mary & Westfield College Substituted phosphonates and their use
EP2170930B3 (en) 2007-06-04 2013-10-02 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
EP2328910B1 (en) 2008-06-04 2014-08-06 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
AU2009270833B2 (en) 2008-07-16 2015-02-19 Bausch Health Ireland Limited Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
GB0822486D0 (en) * 2008-12-10 2009-01-14 Univ Liverpool Compounds for use in the treatment of pain
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
WO2014057522A1 (en) 2012-10-12 2014-04-17 Mochida Pharmaceutical Co., Ltd. Compositions and methods for treating non-alcoholic steatohepatitis
AU2014235215A1 (en) 2013-03-15 2015-10-01 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
JP2016514670A (en) 2013-03-15 2016-05-23 シナジー ファーマシューティカルズ インコーポレイテッド Guanylate cyclase receptor agonists in combination with other drugs
SG11201507288UA (en) 2013-03-15 2015-10-29 Mochida Pharm Co Ltd Compositions and methods for treating non-alcoholic steatohepatitis
US10441560B2 (en) 2013-03-15 2019-10-15 Mochida Pharmaceutical Co., Ltd. Compositions and methods for treating non-alcoholic steatohepatitis
BR112015030326A2 (en) 2013-06-05 2017-08-29 Synergy Pharmaceuticals Inc ULTRAPURE GUANYLATE CYCLASE C AGONISTS, METHOD OF MANUFACTURING AND USING THEM

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2750426B1 (en) * 1996-06-28 1998-08-07 Cird Galderma NOVEL HETEROCYCLIC BIARYLATED COMPOUNDS AND THEIR USE IN HUMAN OR VETERINARY MEDICINE AND IN COSMETICS

Also Published As

Publication number Publication date
AU3979199A (en) 1999-11-29
CA2330623A1 (en) 1999-11-18
WO1999058521A1 (en) 1999-11-18
EP1077970A1 (en) 2001-02-28
JP2002514638A (en) 2002-05-21

Similar Documents

Publication Publication Date Title
CN1308627A (en) 11-Aryl-benzo[b]naphtho[2,3-d]furans and 11-aryl-aryl-benzo[b]anphtho[2,3-d]thiophenes useful in the treatment of insulin resistance and hyperglycemia
CN1060171C (en) Substituted biphenyl isoxazole sulfonamides
CN1046711C (en) Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists
CN1308626A (en) Benzothiophenes, benzofurans, and indoles useful in the treatment of insulin resistance and hyperglycemia
CN1045768C (en) Angiotension II antagonists
CN1263750C (en) Heterocyclic sulfonamide inhibitors of beta amyloid production
CN1221533C (en) Heterobicyclic sulfonamide derivative and sulfonic ester derivative
CN1203066C (en) (Methylsulfonyl) phenyl-2-(5H)-furanones as cox-2 inhibitors
CN1252057C (en) Thiazole derivatives for treating PPAR related disorders
CN1507442A (en) Furan and thiophene derivatives that activate human peroxisome proliferator activated receptors
CN1133040A (en) Benzothiophenes and related compounds as estrogen agonists
CN1505613A (en) Substituted indoles, pharmaceutical compositions containing such indoles and their use as ppar-gamma binding agents
CN1578659A (en) Modulators of peroxisome proliferator activated receptors (ppar)
CN1349525A (en) Di-aryl acid derivatives as PPAR receptor ligands
CN1742007A (en) Indole-derivative modulators of steroid hormone nuclear receptors
CN1160045A (en) Matrix metalloprotease inhibitors
CN1543456A (en) Substituted naphthyl benzofuran derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
CN1794989A (en) N-(((((1,3-thiazol-2-yl)amino)carbonyl)phenyl)sulfonyl)phenylalanine derivatives and related compounds for the treatment of diabetes
CN1298404A (en) Inhibitors of phospholipase A2
CN1628111A (en) 2-furancarboxylic acid hydrazides and pharmaceutical compositions containing the same
CN1812978A (en) Phenyl substituted carboxylic acids as inhibitors of protein tyrosine phosphatase-1b
CN1902171A (en) Benzylether amine compounds useful as CCR-5 antagonists
CN1812979A (en) Substituted amino carboxylic acids as inhibitors of protein tyrosine phosphatase-1b
CN1898205A (en) Indolinone derivatives and their use in treating disease-states such as cancer
CN1623537A (en) Biaryl sulfonamides and its using method

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication