KR20010043539A - Benzothiophenes, benzofurans, and indoles useful in the treatment of insulin resistance and hyperglycemia - Google Patents

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof useful for the treatment of metabolic diseases associated with insulin resistance or hyperglycemia.

Formula I

In the above formula (I)

Ar (a), (b) or (c), and

A, B, C, D, E, X, Y, Z ¹ and Z ² are as defined in the specification.

Description

Benzothiophenes, benzofurans, and indoles useful in the treatment of insulin resistance and hyperglycemia. ≪ RTI ID = 0.0 >

BACKGROUND OF THE INVENTION

Glucose intolerance It has long been recognized that the subject's insulin resistance is predominant. Reaven et al. (American Journal of Medicine 1976, 60, 80) injected glucose and insulin consecutively and used an oral glucose test to determine whether insulin resistance is present in various groups of non-obese, . The range of these subjects ranges from the glucose tolerance boundary to the apparent singlet hyperglycemia. The diabetic group of this study includes both insulin-dependent (IDDM) and insulin-independent (NIDDM) subjects.

The phenomenon that occurs simultaneously with persistent insulin resistance is the more easily measured insulin hypertrophy, which can be measured by an accurate measurement that circulates the plasma insulin concentration in the subject's plasma. Insulin hyperproliferation is an insulin resistance syndrome, as in the case of obesity and / or diabetes (NIDDM) subjects and / or glucose tolerance subjects, or IDDM subjects, as a result of insulin infusion exceeding the abnormal physiological release of hormones by the endocrine pancreas ≪ / RTI >

The association of hyperinsulinemia with obesity and macrovascular aetiology (eg, atherosclerosis) has been well established by a number of experimental, clinical and genetic studies (see Stout, Metabolism 1985, 34, 7; More specifically, Pyorala et al., Diabetes / Metabolism Reviews 1987, 3, 463]. Statistically significant plasma insulin elevation at 1 and 2 hours after glucose loading correlates with an increased risk of coronary heart disease.

Since most of these studies have in fact excluded diabetics, the risk-atherosclerotic risk data for diabetic conditions are not as diverse, but they provide the same direction for non-diabetic subjects (Pyorala et al). However, the incidence of atherosclerosis in the incidence and mortality statistics of diabetic populations exceeds the incidence of non-diabetic populations (see Pyorala et al .; Jarrett Diabetes / Metabolism Reviews 1989, 5, 547; Harris et al., Mortality from diabetics, in Diabetes in America 1985].

Obesity and hypertension risk factors for atherosclerosis are also associated with insulin resistance. Using insulin / glucose clamp combinations, trace glucose infusion and direct calorimetry, the insulin resistance of intrinsic hypertension is located in the peripheral tissues (usually the muscle) and directly correlated with the severity of hypertension (DeFronzo and Ferrannini, Diabetes Care 1991 , 14, 173]. In hypertension of obesity, insulin resistance causes hyperinsulinemia, which is supplemented as a mechanism to limit further weight gain through heat generation, but insulin also increases the sodium reabsorption of the kidneys, It stimulates the nervous system and causes hypertension.

It is now appreciated that insulin resistance is typically due to defects in the insulin receptor delivery system at the post-binding site of insulin to the receptor. From the accumulated scientific evidence of insulin resistance in the major tissues (muscle, liver, fat) that respond to insulin, the fact that insulin-induced transduction defects are in the insulin receptor kinase activity, which appears to be in early stages, It is strongly implicated (cf. Haring, Diabetalogia, 1991, 34, 848).

Protein-tyrosine phosphatase (PTPase) plays an important role in the regulation of the phosphorylation of proteins. The interaction of insulin and its receptor induces phosphorylation of specific tyrosine molecules in the receptor protein, activating the receptor kinase. PTPase dephosphorylates the activated insulin receptor to weaken tyrosine kinase activity. PTPases can also modulate post-receptor release by catalyzing the dephosphorylation of cellular substrates of insulin receptor kinase. Enzymes that are most closely associated with insulin receptors and appear to modulate insulin receptor kinase include PTP1B, LAR, PTPa 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].

McGuire et al. (Diabetes 1991, 40, 939) reported that non-diabetic glucose intolerant subjects had significantly elevated PTPase activity in muscle tissue compared to normal subjects and that insulin was injected as insulin-sensitized subjects Was reported to be unsuccessful.

Meyerovitch et al. (J. Clinical Invest. 1989, 84, 976] observed significantly elevated PTPase activity in the two rodent models of IDDM, the genetically diabetic BB rats and the STZ-induced diabetic rats. Sredy et al. (Metabolism, 44, 1074, 1995) observed similarly elevated PTPase activity in the liver of a hereditary rodent model of obesity, diabetic ob / ob mouse NIDDM.

The compounds of the present invention were found to inhibit PTPase derived from rat liver microsomes and human induced recombinant PTPase-1B (hPTP-1B) in vivo. It is useful for the treatment of insulin resistance associated with obesity, glucose intolerance, diabetes, hypertension, and small anemia of small blood vessels.

ratio. B. Reidl et al. (EP-A-69349A1) describe oxazololidinone of formula A as an antimicrobial agent.

a. In A. Bridges et al. (EP 56289 A2), thienothiophenamidines of formula (B) are described as urokinase inhibitors.

H.-M. Chen Chen et al., Indian J. Chem., Sect. B: Org. Chem. Include. Med. Chem. 1996, 35B (12), 1304-1307 describes the compounds of formula (C).

yen. egg. N. R. Guirguis et al., J. Prakt. Chem. 1990, 332 (3), 414-418 describes compounds of formula D.

In the above formula (D)

E is O or S.

yen. egg. Guigues et al. (Liebigs Ann. Chem. 1986, 1003-1011 discloses benzothiophenes of formula (E).

In the above formula (E)

R ₁ and R ₂ are each CO ₂ R ₃ , wherein R ₃ is H or alkyl, or H;

Also, M. Seed. In MC Dubroeucq et al. (EP 248734A1), a compound of formula E (wherein R ₁ is CO ₂ H) is described as an anti-anxiety agent.

tea. Kuroda et al., J. Org. Chem. 1994, 59, 7353-7357; and J. Chem. Soc., Chem. Commun. 1991, 1653-1636) discloses benzothiophenes of formula (F).

a. children. A. I. Hashem, J. Prakt. Chem. 1977, 319, 689-692 describe benzofuran of formula G.

Why. Y. Akao et al., Jpn. Kokai Tokkyo Koho 04016854 A2 describes six compounds containing a 4-aryl-naphtho [2,3-b] thiophene ring system. These compounds are cyclobutenediol dimers of ring systems prepared as electrophotographic photoreceptors. One typical example is represented by the structure of the following formula (H).

second. blood. J. P. Knonpelski et al. (Synlett 1996, 609-611) describe the indole of formula (I).

blood. Molina, et al. (Tetrahedron, 1994, 50, 5027-36; and Tetrahedron Lett., 1993, 34, 2809-2812 describe indole derivatives of formula (J).

In the above formula (J)

R is H or Me.

a. A. Napolitano et al. (Tetrahedron 1989, 45, 6749-60) describe the indole of formula (K).

G. G. Dryhurst et al., J. Am. Chem. Soc. 1989, 111. 719-726 describes compounds of formula L.

M. M. D'Ischia et al. (Tetrahedron 1987, 43, 431-434) describes the formula M.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, useful for the treatment of metabolic disorders associated with insulin resistance or hyperglycemia,

In the above formula (I)

Ar , or ego,

A is hydrogen, halogen or OH,

B and D are each independently hydrogen, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, hydroxyaralkyl of 6 to 12 carbon atoms, 3 to 8 cycloalkyl, nitro, amino, -NR ¹ R ^1a , -NR ¹ COR ^1a , -NR ¹ CO ₂ R ^1a , cycloalkylamino having 3 to 8 carbon atoms, morpholino, furan- Thiophen-2-yl, thiophen-3-yl, -COR ^1b or OR,

R is hydrogen, alkyl, -OCR ^1, C 1 -C _{6 - (CH 2) n CO} 2 R 1, -CH (R 1a) CO 2 R 1, -SO 2 R 1, - (CH 2) m CH ^{_{(OH) CO 2 R 1,}} - a _{(CH 2) m O (CH} 2) o CO 2 R 1, - (CH 2) m COCO 2 R 1, - (CH 2) m CH = CHCO 2 R 1 , or

R ¹ is hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl having 6 to 12 carbon atoms, aryl or CH ₂ CO ₂ R ^{1 '}

R ^{1 '} is hydrogen or alkyl having 1 to 6 carbon atoms,

E is S, SO, SO ₂ , O or NR ^1c ,

X is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, CN, aryl, aralkyl of 6 to 12 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, hydroxyaryl of 6 to 12 carbon atoms Alkyl, perfluoroalkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, aryloxy, arylalkoxy, nitro, amino, NR ² R ^2a , NR ² COR ^2a , cycloalkylamino having 3 to 8 carbon atoms, 2-N, N-dimethylaminoethylsulfanyl, -OCH ₂ CO ₂ R ^2b or -COR ^2c , wherein the alkyl, alkenyl, alkynyl,

Y is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, hydroxyaralkyl of 6 to 12 carbon atoms, -OR ³ , SR ³ , NR ³ R ^3a , -COR ^3b , morpholine or piperidine,

R ^1a , R ^1c , R ² , R ^2a , R ³ and R ^3a are each independently hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl or aryl having 6 to 12 carbon atoms,

R ^1b is alkyl or aryl having 1 to 6 carbon atoms,

R ^2b is hydrogen or alkyl having 1 to 6 carbon atoms,

R ^2c and R ^3b are each independently alkyl having 1 to 6 carbon atoms, aryl or aralkyl having 6 to 12 carbon atoms,

C is hydrogen, halogen or OR < ⁴ >

R ⁴ is hydrogen, alkyl having 1 to _{6, -CH (R 5) W} , -C (CH 3) 2 CO 2 R 6, 5- thiazolidine-2,4-dione, -CH (R ⁷⁾ _{(CH 2) m CO 2 R} 6, -COR 6, -PO 3 (R 6) 2, -SO 2 R 6, - (CH 2) p CH (OH) CO 2 R 6, - (CH 2) p and _{(CH 2) p O (CH} 2) q CO 2 R 6, - COCO 2 R 6, - (CH 2) p CH = CHCO 2 R 6 or

R ⁵ is hydrogen, aralkyl, aryl, C 1 -C 6 alkyl group having 6 to 12 carbon atoms in the -CH ₂ (1H- imidazol -4-), -CH ₂ (3-1H- indolyl), -CH ₂ CH ₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH ₂ CH ₂ (1-oxo- , -CH ₂ (3-pyridyl), -CH ₂ CO ₂ H or - (CH ₂ ) _n G,

G is NR ^6a R ^7a , NR ^6a COR ^7a , , or ego,

W is ^{_{CO 2 R 6, CONH 2,}} CONHOH, CN, CONH (CH 2) 2 CN, 5- ^{_{tetrazole, -PO 3 (R 6) 2}} , -CH 2 OH, -CONR 6b CHR 7b, -CH 2 NR ^6b CHR ^7b CO ₂ R ⁶ , -CH ₂ OCHR ^7b CO ₂ R ⁶ -CH ₂ Br or -CONR ^6b CHR ^7b CO ₂ R ⁶ ,

R ⁶ , R ^6a , R ⁷ and R ^7a are each independently hydrogen, alkyl having 1 to 6 carbon atoms or aryl,

R ^6b is hydrogen or -COR ^6c ,

R ^6c is alkyl or aryl having 1 to 6 carbon atoms,

R ^7b is hydrogen, alkyl having 1 to 6 carbon atoms or hydroxyalkyl having 1 to 6 carbon atoms,

Z ¹ and Z ² are each independently hydrogen, halogen, CN, C 1 -C 6 alkyl, aryl, aralkyl having 6 to 12 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, nitro, amino, -NR ¹ R ^1a of a, -NR ¹ COR ^1a , cycloalkylamino having 3 to 8 carbon atoms, morpholino or OR ^8, or Z ¹ and Z ² together can form a diene unit of the formula -CH = CR ⁹ -CR ¹⁰ = CR ¹¹ - However,

R < ⁸ > is hydrogen, alkyl having 1 to 6 carbon atoms or aryl,

R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, alkyl having 1 to 6 carbon atoms, aryl, halogen, hydroxy or alkoxy having 1 to 6 carbon atoms,

m is from 1 to 4,

n is 1 or 2,

p is 1 to 4,

q is 1 to 4;

Or a pharmaceutically acceptable salt is the R ⁵ CH ₂ (3- pyridyl), Y is morpholine or as in the case of containing a similar basic residue, when a basic moiety containing compound of the present invention, inorganic and organic acids Such as, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, Naphthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid and analogously known acceptable salts. Salts may also be formed from organic and inorganic acids, preferably alkali metal salts, such as sodium, lithium or potassium, if the compounds of the invention contain carboxylate or phenolic residues.

Alkyl includes both straight chain as well as side chain moieties. Halogen means bromine, chlorine, fluorine and iodine. The aryl moiety of the aryl or aralkyl substituent is preferably phenyl or naphthyl, with phenyl being most preferred. The aryl moiety is selected from the group consisting of alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl having 2 to 7 carbon atoms, alkylamino having 1 to 6 carbon atoms and alkyl group each having 1 to 6 carbon atoms Di-alkylamino, nitro, cyano, -CO ₂ H, alkylcarbonyloxy having 2 to 7 carbon atoms and alkylcarbonyl having 2 to 7 carbon atoms.

The compounds of the present invention may contain symmetrical carbon atoms and some of the compounds of the present invention may contain one or more asymmetric centers to generate optical isomers and diastereomers. Although not shown in stereochemistry in Formula I, the present invention encompasses both such optical isomers and diastereomers, as well as racemic and resolved, enantiomerically pure R and S stereoisomers and pharmaceutically acceptable ≪ / RTI >

The compounds of the present invention may be atropisomers with possible limited or slow rotation to aryl-tricyclic or aryl-acyclic single bonds. This limited rotation generates additional chirality and leads to enanthiomeric forms. If additional chirality centers are present in the molecule, the diastereomer may be present and visible through NMR or other analytical techniques. Although not shown in the context of Formula I in view of the degenerative isomeric stereochemistry, the present invention includes these art loops isomers (enantiomers and diastereomers as well as mixtures of racemic deacetylated and diastereomers) Pharmaceutically acceptable salts thereof.

Preferred compounds of the present invention include a compound of formula I 'or a pharmaceutically acceptable salt thereof.

In the above formula (I '),

A is hydrogen or halogen,

B and D are each independently selected from the group consisting of hydrogen, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, side chain alkyl, cycloalkyl of 3 to 8 carbon atoms,

R is hydrogen or alkyl of 1 to 6 carbon atoms,

E is S or O,

X is hydrogen, halogen, alkyl having 1 to 6 carbon atoms, CN, perfluoroalkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, aryloxy, arylalkoxy, nitro, amino, NR ² R ^2a , NR ² COR ² , N, N-dimethylaminoethylsulfanyl, arylsulfanyl, arylsulfanyl, pyridylsulfanyl or 2-N, N- dimethylaminoethylsulfanyl,

R ¹ , R ^1a , R ² , R ^2a , R ³ and R ^3a are each independently hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl or aryl having 6 to 12 carbon atoms,

Y is hydrogen, halogen, OR ³ , SR ³ , NR ³ R ^3a or morpholine,

C is hydrogen, halogen or OR < ⁴ >

R ⁴ is hydrogen, alkyl having 1 to ^{6, -CH (R 5) W} , -C (CH 3) 2 CO 2 R 6, 5- thiazolidine-2,4-dione, -CH (R ⁷⁾ _{(CH 2) m CO 2 R} 6, -COR 6, -PO 3 (R 6) 2, -SO 2 R 6, - (CH 2) p CH (OH) CO 2 R 6, - (CH 2) p and _{(CH 2) p O (CH} 2) q CO 2 R 6, - COCO 2 R 6, - (CH 2) p CH = CHCO 2 R 6 or

R ⁵ is hydrogen, aralkyl, aryl, C 1 -C 6 alkyl group having 6 to 12 carbon atoms in the -CH ₂ (1H- imidazol -4-), -CH ₂ (3-1H- indolyl), -CH ₂ CH ₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH ₂ CH ₂ (1-oxo- or a -CH ₂ (3- pyridyl),

W is CO ₂ R ⁶ , -CONH ₂ , -CONHOH, 5-tetrazole or -CONR ^6b CHR ^7b CO ₂ R ⁶ ,

R ⁶ , R ^6a , R ^6b , R ⁷ , R ^7a and R ^7b are each independently hydrogen, alkyl having 1 to 6 carbon atoms or aryl,

Z ¹ and Z ² are each independently hydrogen, halogen, CN, C 1 -C 6 alkyl, aryl, aralkyl having 6 to 12 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, nitro, amino, -NR ¹ R ^1a of a, -NR ¹ COR ^1a , cycloalkylamino having 3 to 8 carbon atoms, morpholino or OR ^8, or Z ¹ and Z ² together can form a diene unit of the formula -CH = CR ⁹ -CR ¹⁰ = CH- ,

R ⁹ and R ¹⁰ are each independently hydrogen or alkyl having 1 to 6 carbon atoms,

p is 1 to 4,

q is 1 to 4;

A more preferred compound of the present invention includes a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In the above formula (I)

A is hydrogen,

B and D are each independently selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms or cycloalkyl of 3 to 8 carbon atoms,

E is S or O,

X is hydrogen, halogen, alkyl having 1 to 6 carbon atoms, perfluoroalkyl having 1 to 6 carbon atoms, CN, alkoxy having 1 to 6 carbon atoms, aryloxy, arylalkoxy or arylsulfanyl having 6 to 12 carbon atoms,

Y is hydrogen, -NR < ¹ > R < ² > or morpholine,

R ¹ and R ² are each independently hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl or aryl having 6 to 12 carbon atoms,

C is OR < ⁴ >

R ⁴ is hydrogen, alkyl having 1 to 6 carbon atoms, -CH (R ⁵ ) W or 5-thiazolidin-2,4-

R ⁵ is hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl having 6 to 12 carbon atoms, aryl, -CH ₂ (3-1H-indolyl), -CH ₂ CH ₂ (1,3- Dihydro-isoindol-2-yl) or -CH ₂ CH ₂ (1-oxo-1,3-dihydro-

W is -CO ₂ R ⁶ , -CONH ₂ , -CONHOH, 5-tetrazole, -PO ₃ (R ⁶ ) ₂ or -CONR ⁶ CHR ⁶ CO ₂ R ⁶ ,

R ⁶ is hydrogen or alkyl of 1 to 6 carbon atoms,

Z ¹ and Z ² together form a diene unit of the formula -CH = CH-H = CH-.

Even more preferred compounds of the present invention include,

(R) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [ 3-phenyl-propionic acid,

(R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [ -3-phenyl-propionic acid,

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Phenyl-propionic acid,

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -2-fluoro-phenoxy] - propionic acid,

2, 6-diisopropyl-phenoxy] -acetic acid, < RTI ID = 0.0 &

(R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Yl] -3-phenyl-propionic acid,

(R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- ] -3-phenyl-propionic acid,

(R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- ] -3-phenyl-propionic acid,

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- - propionic acid,

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -2- cyclopentyl- - propionic acid,

(2,3-b] thiophen-4-yl) -phenoxy] - < / RTI > -3-phenyl-propionic acid,

(R) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [ 4-phenyl-butyric acid,

(S) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- 4-phenyl-butyric acid,

2-morpholin-4-ylmethyl-naphtho [2,3-b] thiophen-4-yl) - Phenoxy] -3-phenyl-propionic acid,

(2,3-b] thiophen-4-yl) -phenoxy] - < / RTI > - propionic acid,

2-Nitro-phenoxy] -3-phenyl-propionic acid (2-bromo-4- ,

Dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-

2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-

(R) -2- [2,6-dibromo-4- (9-bromo-2-diethylaminomethyl- -Phenoxy] -3-phenyl-propionic acid,

(2,3-b] furan-4-yl) -phenoxy] -3-phenyl-propionic acid,

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -2,6- diisopropyl-phenoxy] 3-phenyl] -propionic acid,

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -Phenyl-propionic acid,

3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3 -Phenyl-propionylamino} -acetic < / RTI > acid,

[(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- 3-phenyl-propionylamino} -acetic acid, or a pharmaceutically acceptable salt thereof.

The compounds of the present invention can be prepared from commercially available starting materials or starting materials which can be prepared using literature procedures according to the following scheme: These reaction schemes represent the preparation of representative compounds of the present invention.

In the above scheme, 1,2,3-dimethylthiophene (II) (wherein E is S) is reacted with commercially available 2,2-dimethylthiophene (II) using Wolff-Kishner conditions (hydrazine followed by KOH / ethylene glycol reflux) Lt; RTI ID = 0.0 > 3-methyl-thiophene-carboxaldehyde. ≪ / RTI > (E.g., THF) in the temperature range of -78 < 0 > C to room temperature under an inert atmosphere such as nitrogen or argon, most preferably in the presence of N-butyl 1 to 1.3 molar equivalents of an alkyl lithium reagent such as lithium to provide a 2-lithiated thiophene or furan derivative. This lithiated analog is itself reacted with at least one mole equivalent of benzaldehyde, generally at -78 占 폚 to room temperature for 5 minutes to 3 hours to give compound (III) wherein Q is OH and E is S or O. to provide. The hydroxy group of compound (III) wherein Q is OH is removed by a number of reduction processes such as hydrogenation using a palladium catalyst to give compound (III) wherein Q is H and E is S or O (III) wherein Q is OH and E is S or O is reacted in a suitable solvent such as ether, THF or dichloromethane at 0 < 0 > C to room temperature with 1 to 10 moles of sodium borohydride And then slowly adding 1 to 50 molar equivalents of trifluoroacetic acid over 15 minutes to 3 hours to yield compound (III) (where Q is H and E is S or 0) Nutaitis) (see Org. Prep. and Proceed. Int. 1991, 23, 403-411). Alternatively, the 2-lithiated analog of compound (II) (where E is S or O) in an aprotic solvent such as THF is reacted with a benzyl halide such as benzyl bromide (PhCH ₂ Br) 1 molar equivalent or more to provide compound (III) (wherein Q is H and E is S or O).

Compounds of formula (III) wherein Q is H and E is S or O are commercially available benzoic acid (IV) chloride, wherein A, B, C and D are H or OMe and substituents A, B, C (A), B, C and D are H or OMe, and the substituents A, B and C (where D, A, B and C have 1 to 3 OMe groups) And D combinations have from 1 to 3 OMe groups and E is S or O). Such acylation is generally carried out in an inert solvent (e.g. dichloromethane, 1,2-dichloroethane or carbon disulfide) using 1 to 5 molar equivalents of a Lewis acid catalyst (such as tin tetrachloride or aluminum chloride) In order to achieve the fastest.

The ring closure of compound (V) wherein A, B, C and D are H or OMe, and the A, B, C and D combinations of substituents have 1 to 3 OMe groups are trihaloboran, Is best achieved using from 1 to 10 molar equivalents of a strong Lewis acid (e.g., tribromoboran). The reaction is best carried out under heating in a halocarbon solvent (e.g. dichloromethane) at -78 < 0 > C to room temperature or at 50 < 0 > C under an inert atmosphere such as nitrogen or argon. This process not only affects the aromatization due to the ring closure and incidental water losses but also causes the dimetization of any pendant methoxy moieties and leads to the formation of compounds Ia where A, B, C and D are H, A, B, C and D combinations of substituents have 1 to 3 OMe groups and E is S or O).

In a reaction analogous to the reaction of Scheme 1 above, the compound (Ia) wherein A is H, B. D is alkyl or fluoro of 1 to 6 carbon atoms, C is OH and E is S or O, (III) wherein Q is H, E is S or O and a suitable chlorobenzoic acid (IV) wherein A is H, B and D are alkyl or fluoro of 1 to 6 carbon atoms, C is OMe. ≪ / RTI > (IV) chloride, where A is H and B and D are alkyl or fluoro of 1 to 6 carbon atoms and C is OMe, is reacted with standard reagents, such as oxalyl chloride and thionyl chloride, ≪ / RTI > is prepared from the corresponding benzoic acid. The starting benzoic acid of the benzoic acid (IV) chloride, where A is H, B and D are alkyl of 1 to 6 carbon atoms or fluoro, and C is OMe, is commercially available or can be readily prepared by known processes have. For example, the acid starting material for the benzoic acid (IV) chloride (where A is H, B and D are isopropyl, and C is OMe) can be prepared according to the method of Schuster et al., J. Org. Chem. 1988, 53, 5819]. Thus, commercially available 2,6-diisopropylphenol is brominated (bromine / acetic acid) at the 4-position, methylated (iodomethane / potassium carbonate / DMF) and reacted with n-butyllithium to carry out lithium halogen exchange And the resulting organolithium species is reacted with carbon dioxide to provide 3,5-diisopropyl-4-methoxybenzoic acid.

Further derivatives of compounds of formula (I) in Scheme 2 may be prepared by the following method. (Scheme 2) with phenol Ib in which B, D and X are H, C is OH, and E is S or O is reacted in the presence of an alcohol metal hydroxide (e.g. NaOH) Diiodophenol Ib wherein B and D are I, X is H, C is OH, and E is selected from the group consisting of: S or O). ≪ / RTI > Similarly, monoiodophenol Ib (where B is I, X and D are H, C is OH, and E is S or O) with at least one equivalent of an alkali metal hydroxide (e.g., NaOH) B, D and X are H, C is OH, E is S or N, or a salt thereof, in an alcohol solvent such as methanol at -20 < 0 > C to room temperature, O) (Scheme 2). Monoiodophenol Ib wherein B is I and X and D are H and C is OH and E is S or O or diiodophenol Ib wherein B and D are I , X is H, C is OMe, and E is S or O, can be reacted with a suitable base such as an alkali metal carbonate or a hydroxide (e.g., potassium carbonate or sodium hydroxide) in a suitable solvent such as THF, DMF or DMSO The base can be converted to the respective methyl ether derivative (Ib) by reacting the phenol moiety with a suitable methylating agent (e.g., 1 mole equivalent or more of methyl iodide or dimethyl sulfite). This reaction is generally carried out in a temperature range of 0 to 60 占 폚.

(Ib), wherein B is I, X and D are H, C is OMe and E is S or O, or diiodomethyl ether (Ib), wherein B and D is I, X is H, C is OMe, and E is S or O with respect to monoiodo analogs, copper manganese (I) cyanide copper (I) (Ib) wherein B is CN, X and D are H, C is OMe, E is S or O, or dicyanomethyl ether (Ib) (Wherein B and D are CN, X is H, C is OMe, and E is S or O). The cyanation reaction is generally carried out using a polar protic solvent (e.g., DMF, 1-methyl-2-pyrrolidone or HMPA) at a temperature range of 100 to 250 ° C. Quinoline or pyridine may also be used. Mono or dicyanomethoxy analogue Ib wherein B is CN, D is H or CN, X is H, C is OMe, and E is S or O, is reacted with dichloro At least one molar equivalent of boron tribromide or boron trichloride in methane, an excess of pure pyridinium hydrochloride at 190 to 280 ° C, bromic acid in acetic acid at 0 to 50 ° C, an excess of dichloromethane, carbon tetrachloride or Trimethylsilyl bromide or trimethylsilyl iodide in acetonitrile, lithium in pyridine or quinoline at 100-250 < 0 > C and Lewis acid in a solvent such as dichloromethane in the temperature range of -78 to 50 [ Methyl or isopropylmercaptan in the presence of at least one molar equivalent of boron (e. G., Boron) in the presence of a corresponding mono or dicyano Play analogs (Ib) can be converted to (wherein, B is CN, D is H or CN, X is H, and C is OMe, E is S or O) (Scheme 2).

(Ib), wherein B is I, X and D are H, C is OMe and E is S or O, or diiodomethyl ether (Ib), wherein B and D is I, X is H, C is OMe, and E is S or O can be prepared by reacting 1 mole equivalent or more of copper (I) bromide to monoiodo analogs or bromination (Ib) wherein B is Br, X and D are H, C is OMe, and E is S or O by reaction with at least two molar equivalents of copper (I), or monobromoether -Methyl ether (Ib), wherein B and D are Br, X is H, C is OMe, and E is S or O. The bromine / iodine exchange reaction is generally carried out using a polar aprotic solvent such as DMF, 1-methyl-2-pyrrolidinone or HMPA in the temperature range of 100 to 250 ° C. Quinoline or pyridine may also be used. Mono or dibromomethoxy analogue Ib wherein B is Br, D is H or Br, X is H, C is OMe, and E is S or O, Dichloromethane in an excess of 1 molar equivalent or more of boron tribromide or boron trichloride in excess of pure pyridinium hydrochloride at 190 to 280 DEG C, bromic acid in acetic acid at 0 to 50 DEG C, dichloromethane, carbon tetrachloride or acetonitrile In the presence of an excess of trimethylsilyl bromide or trimethylsilyl iodide, lithium iodide in pyridine or quinoline at 100-250 < 0 > C and a Lewis acid such as dichloromethane in a temperature range of -78 to 50 [ Methyl or isopropylmercaptan in the presence of at least one molar equivalent of boron trifluoride (boron fluoride)), the corresponding mono Is-dibromo-phenol analogs (Ic) can be converted to (and where, B is Br, D is H or Br, X is H, E is S or O) (Scheme 2).

Additional derivatives of compound (I) in Scheme 3 may be prepared by the following method. (Scheme 3) is reacted with 1 molar equivalents of a suitable acylating agent, such as dichloromethane, dichloromethane, dichloromethane, dichloromethane, dichloromethane, (I) wherein B, C and D are H or OCOR and the combination of B, C, and D has at least one OCOR group and R is a divalent group containing from 1 to 6 carbon atoms Alkyl, and aryl, and E is S or O. The acylating agent is generally an alkyl or aryl carboxylic acid anhydride having 1 to 6 carbon atoms or an alkyl or aryl carboxylic acid chloride having 1 to 6 carbon atoms. The reaction is carried out under standard conditions, for example with or without the use of a co-solvent (such as dichloromethane) at 0 < 0 > C to room temperature using pyridine as solvent. (I) wherein B, C and D are H or OCOR, the combination of B, C and D has at least one OCOR group, R is alkyl of 1 to 6 carbon atoms, E is S or O) is brominated at the 9-position of the naphtho [2,3-b] -thiophene or the naphtho [2,3-b] furan ring to form acylated bromophenol (Ie) Is H or OCOR, the combination of B, C and D has at least one OCOR group, R is alkyl or aryl of 1 to 6 carbon atoms, X is Br and E is S or O) (Scheme 3 ). This bromination reaction is generally carried out using a catalytic amount of iron chloride (III) in an inert solvent (e.g., dichloromethane or carbon tetrachloride) at a temperature ranging from -78 ° C to room temperature using from 1 to 1.3 molar equivalents of molecular bromine in a darkroom.

Using similar bromination reactions, the phenol (Id), wherein B and D are alkyl of 1 to 6 carbon atoms, C is OH and E is S or O, is reacted with naphtho [2,3-b] (Ie), wherein B and D are alkyl of 1 to 6 carbon atoms, C is OH, X is Br, and R < 3 > , E is S or O) (Scheme 3). This bromination reaction is generally carried out using a catalytic amount of iron chloride (III) in an inert solvent (e.g., dichloromethane or carbon tetrachloride) at a temperature ranging from -78 ° C to room temperature using from 1 to 1.3 molar equivalents of molecular bromine in a darkroom.

The acyl group is then reacted with acylated bromophenol (Ie), wherein B, C and D are H or OCOR and the combination of B, C and D has at least one OCOR group and R is alkyl of 1 to 6 carbon atoms or (Ie) wherein B, C and D are H or OH, and the combination of B, C and D is selected from the group consisting of < RTI ID = 0.0 & Having at least one OH group, X is Br, and E is S or O (Scheme 3). Such conditions include the use of a co-solvent (such as THF or dioxane) or an alcohol (such as methanol) in an amount of at least 1 molar equivalent of an alkali metal hydroxide such as sodium hydroxide at a temperature ranging from 0 to 40 DEG C, Or a mixture of THF and an alcohol having 1 to 6 carbon atoms. An acid donor can also be used in which the compound is reacted with at least one mole equivalent of an inorganic acid such as HCl or sulfuric acid in water with or without a co-solvent such as THF at a temperature ranging from room temperature to 80 < 0 > C.

Acylated phenol (Id) wherein B, C and D are H or OCOR, the combination of B, C and D has at least one OCOR group, R is alkyl or aryl of 1 to 6 carbon atoms, E is S or (Ie) wherein B, C and D are H or OCOR, the combination of B, C and D has at least one OCOR group, R is alkyl having 1 to 6 carbon atoms or aryl , X is NO ₂ , and E is S or O (Scheme 3). Dilute nitric acid in the temperature range from 0 째 C to room temperature is suitable for carrying out such conversion. (Ie) wherein B, C and D are H or COCR, C and D are both not H, R is alkyl or aryl of 1 to 6 carbon atoms, X is NO ₂ , E is S or O) is reacted with a primary amine (Ie), wherein B, C and D are H or COCR, using a suitable reducing agent such as catalytic hydrogenation with a palladium or platinum catalyst, aqueous HCl or tin dichloride in ethyl acetate , B, C and D have one or more CO groups, R is alkyl or aryl having 1 to 6 carbon atoms, X is NH ₂ , and E is S or O). (Ie) wherein B, C and D are H or OCOR, the combination of B, C and D has at least one OCOR group, R is alkyl or aryl of 1 to 6 carbon atoms, X is NO ₂ or NH ₂ and E is S or O) can be removed using standard conditions.

Acylated bromophenol (Ie) wherein B, C and D are H or COCR, B, C and D have one or more OCOR groups, R is alkyl having 1 to 6 carbon atoms or aryl, X is Br (Ie) (wherein B, C and D are H or OCOR and B, B, C and D are H or OCOR) by reaction with at least one molar equivalent of copper (I) cyanide (Scheme 3) C and D combinations have at least one OCOR group, R is alkyl or aryl having from 1 to 6 carbon atoms, X is CN and E is S or O). The cyanation reaction is generally carried out using a polar aprotic solvent such as DMF, 1-methyl-2-pyrrolidone or HMPA at a temperature range of 100 to 250 ° C. Quinoline or pyridine may also be used. (Ie), wherein B, C and D are H or OCOR, the combination of B, C and D has at least one OCOR group, R is alkyl or aryl of 1 to 6 carbon atoms, X is CN, (Ie) wherein B, C and D are H or OH and the combination of B, C and D have at least one OH group, , X is CN and E is S or O. (Ie), wherein B, C and D are H or OH, the combination of B, C and D has at least one OH group, X is CN and E is S or O, (Ie) wherein B, C and D are H or OCOR, the combination of B, C and D has at least one OCOR group, and R is a number of carbon atoms 1 to 6 alkyl or aryl, X is CN, and E is S or O). The acyl group may also be a disubstituted acylated cyanophenol (Ie) wherein B, C and D are H or OCOR, the combination of B, C and D has at least one OCOR group, and R is alkyl of 1 to 6 carbons (Ie), wherein B, C and D are HE or OH, and the combination of B, C, and D is selected from the group consisting of: R is an alkyl or aryl having 1 to 6 carbon atoms, X is CN, and E is S or O. In one embodiment, Such conditions include, but are not limited to, the addition of one molar equivalent of an alkali metal hydroxide (such as sodium hydroxide), including aqueous bases, to THF, dioxane or lower alcohols such as methanol or THF and lower alcohols Lt; / RTI > with a cosolvent such as a mixture of < RTI ID = 0.0 > Acidic conditions are also used in which the compound reacts with at least one mole equivalent of an inorganic acid such as HCl or sulfuric acid in water, with or without a co-solvent such as THF at a temperature ranging from room temperature to 80 캜.

Compound (Id) wherein B, C and D are H or OH, B, C and D combinations have at least one OH group and E is S or O (Scheme 3) is prepared by reacting 1 molar equivalent of a suitable sulfonating agent (I), wherein B, C and D are H or OSO ₂ R, the combination of B, C and D is at least one OSO ₂ R group, and R is a number of carbon atoms of 1 Lt; / RTI > is an alkyl or aryl of 1 to 6 carbon atoms and E is S or O. The sulfonating agent is generally an alkyl or aryl sulfonic acid anhydride having 1 to 6 carbon atoms or an alkyl or aryl sulfonic acid chloride having 1 to 6 carbon atoms. The reaction is carried out under standard conditions such as using pyridine as a solvent with or without a co-solvent such as dichloromethane at 0 < 0 > C to room temperature.

(I) wherein B, C and D are H or OSO ₂ R, the combination of B, C and D is at least one OSO ₂ R, R is alkyl having 1 to 6 carbon atoms or aryl, E is S or O is treated with an iodide which performs iodination at the 9-position of the naphtho [2,3-d] thiophene or the naphtho [2,3-d] furan ring to give the iodosulfonic ester (Ie) Wherein B, C and D are H or OSO ₂ R, the combination of B, C and D has at least one OSO ₂ R, R is alkyl having 1 to 6 carbon atoms or aryl, X is I, E is S Or O) can be obtained. Suitable iodinating agents include a mixture of at least 0.07 mole equivalents of molecular iodine and at least 0.025 equivalents of iodoacid in a mixture of THF and 80% aqueous acetic acid and a small amount of concentrated sulfuric acid at a temperature ranging from room temperature to 80 占 폚. (Ie) wherein B, C and D are H or ODO ₂ R, the combination of B, C and D have at least one OSO ₂ R group, R is a (Ie) wherein B, C and D are H or OH, and R < 3 > is hydrogen or an alkyl group having from 1 to 6 carbon atoms or aryl, X is I and E is S or O, B, C and D combinations have at least one OH group, X is I, and E is S or O). Such conditions include the addition of one molar equivalent of an alkali metal hydroxide (such as sodium hydroxide), including aqueous bases, in THF, dioxane or lower alcohols (such as methanol) or a mixture of THF and lower alcohols It is used in water with a co-solvent such as a mixture.

(I) wherein C and D are H or OSO ₂ R, C and D are both not H, R is alkyl having 1 to 5 carbon atoms or aryl, E is S or O Is a convenient starting point for further derivatives of compounds of formula I as shown in Scheme 4 and the methods below. Compounds (If) wherein C and D are H or OSO ₂ R, C and D are both not H, R is alkyl or aryl having 1 to 6 carbon atoms and E is S or O (Ig), wherein C and D are H or OSO ₂ R, and C and D are both H, are reacted with a reagent which catalyzes the reaction of the iodine atom of If with a lower perfluoroalkyl group, R is alkyl having 1 to 6 carbon atoms, X is lower perfluoroalkyl, and E is S or O (Scheme 4). The reagents and conditions to effect this change are those in which (If) is reacted under anhydrous conditions with 1 to 10 molar equivalents of sodium perfluorocarboxylate [RCO ₂ Na (where R is perfluoroalkyl)] and copper iodide To 5 equivalents and a high boiling point inert solvent such as DMF, DMA or 1-methyl-2-pyrrolidone at a temperature ranging from 140 to 200 < 0 > C. Alternatively, a compound (If), wherein C and D are H or OSO ₂ R, C and D both can not be H, R is alkyl or aryl having 1 to 6 carbon atoms, E is S or O is a) a perfluoroalkyl of 1 to 10 molar equivalents of activated Cu ⁰ and 1 to 5 molar equivalents in an inert solvent with a high boiling point (for example, in DMF, DMA, or 1-methyl-2-pyrrolidone) from 140 to 200 ℃ (Ig) wherein C and D are H or OSO ₂ R, C and D are both not H, R is alkyl of 1 to 6 carbon atoms, X is a lower purple Lt; / RTI > is S or O, can be prepared. Alternatively, the compound (If) wherein C and D are H or OSO ₂ R, C and D are both not H, R is alkyl having 1 to 6 carbon atoms or aryl, E is methyl a is S or O) to a bis (trifluoromethyl) mercury, and from 0.5 to 2 molar equivalents to 4 molar equivalents of activated Cu 2 ⁰ and high-boiling inert solvent (for example: DMF, DMA, or 1-methyl-2-pyrrolidone ) In a temperature range of 140 to 200 캜 to obtain a compound (Ig), wherein C and D are H or OSO ₂ R, C and D are both not H, and R is an alkyl having 1 to 6 carbon atoms and, X is CF _3, E may produce an S or O).

(Ig) wherein C and D are H or OSO ₂ R, C and D are both not H, R is alkyl having 1 to 6 carbon atoms, and X is an alkyl group having 1 to 6 carbon atoms (Wherein, C and D are H or OSO ₂ R, C and D are both not H, and R is a carbon number < RTI ID = 0.0 > 1 to 6 alkyl or aryl and E is S or O in the presence of a palladium catalyst such as 1 to 10 mol% bis (triphenylphosphine) palladium II chloride in an amount of at least 3 molar equivalents of lower tetra- In a suitable solvent such as DMA or 1-methyl-2-pyrrolidone at a temperature ranging from 140 to 200 < 0 > C.

Subsequently, the sulfone ester group is a sulfonic acid ester (Ig), wherein C and D are H or OSO ₂ R, C and D are both not H, R is alkyl of 1 to 6 carbon atoms, X is (I) wherein C and D are H or OH and C and D are both the same or different and are selected from the group consisting of Can not be H, R is alkyl having 1 to 6 carbon atoms or lower perfluoroalkyl and E is S or O. Such conditions include, but are not limited to, the addition of one mole equivalent or more of an alkali metal hydroxide (such as sodium hydroxide), including aqueous bases, with a co-solvent such as HF, dioxane or a lower alcohol such as methanol or a mixture of THF and a lower alcohol It is used in the temperature range of room temperature to 110 ° C in water.

(I) wherein C and D are H or OH, C and D are both not H, X is an alkoxy of 1 to 6 carbon atoms, and E is S or O. The 9-alkoxy derivative (Ig) (1f) wherein C and D are H or OSO ₂ R, C and D are both not H, R is alkyl or aryl of 1 to 6 carbon atoms and E is S or O (Such as sodium methoxide) in the presence of a copper (I) or copper (II) catalyst such as 1 to 10 mol% of copper (II) chloride and at least 3 molar equivalents of a lower alkali metal alkoxide In a suitable solvent such as pyrrolidone at a temperature ranging from 80 to 180 < 0 > C. (If) wherein C and D are H or OSO ₂ R, C and D are both not H, R is alkyl or aryl having 1 to 6 carbon atoms, E is S or O ≪ / RTI > is removed.

(Ig), wherein C and D are H or OH, C and D are both not H, and X is a C 1-6 alkylsulfanyl, arylsulfanyl, pyrimidinyl, (I) wherein C and D are H or OSO ₂ R, C and D are both H, and R < ₂ > R is an alkyl or aryl having 1 to 6 carbon atoms and E is S or O. Examples of suitable alkylthio, arylthiol, thiopyridine or 2-N, N-dimethylaminoethyl- (I) or copper (II) catalyst, such as copper oxide (I), in an amount of at least 1 molar equivalent of mercaptan, at least 1 molar equivalent of an alkali metal hydroxide such as sodium hydroxide, -Methyl-2-pyrrolidone in a temperature range of 100-180 < 0 > C. (If), wherein C and D are H or OSO ₂ R, C and D are both not H, R is alkyl or aryl having 1 to 6 carbon atoms, E is S or O Lt; / RTI > is removed.

Further derivatives of the compounds of formula (I) in Scheme 5 can be prepared by the following method. Phenol (Ih) wherein A is H or OH and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, 2, N, N-dimethylaminoethylsulfanyl and E is S or O) in a suitable solvent such as acetic acid in an amount of at least 2 molar equivalents of molecular bromine, such as dichloromethane, dichloromethane, Bromine at two positions to give dibromophenol (Ii), wherein A is H or OH, B and D are Br and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl , Alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl and E is S or O ) Can be obtained. Although not absolutely necessary, 1 to 50 molar equivalents of a salt of acetic acid (e.g., potassium acetate or sodium acetate) may also be used as a diluent in the reaction.

Phenol Ih wherein A is H and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, (I), wherein R < 1 > is alkyl, lower alkyl, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2-N, N- dimethylaminoethylsulfanyl and E is S or O, Phenol (Ii) wherein A is H, B is NO ₂ , D is H and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms N, N-dimethylaminoethylsulfanyl, and E is S or O) in the presence of a base such as triethylamine, triethylamine, triethylamine, triethylamine, triethylamine, .

(I) wherein A is H, B is NO ₂ , D is H and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, N, N-dimethylaminoethylsulfanyl, and E is S or O, with the proviso that at least one of R < 1 >, R < 2 >, R & use dichloride in ethyl acetate of from 40 to 100 ℃ with hydrazine in ethanol from 40 to 100 ℃ and Mont parent lily nitro clay amino compound (Ii) (wherein, a is H, and B is NH _2, D is X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, Di-sulfanyl, 2-N, N-dimethylaminoethylsulfanyl, and E is S or O.

(I) wherein A is H, B is NO ₂ , D is H and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, N, N-dimethylaminoethylsulfanyl, and E is S or O, in the presence of a base such as triethylamine, triethylamine, triethylamine, (Ii) wherein A is H, B is NO ₂ , D is Br and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, N, N-dimethylaminoethylsulfanyl, E (lower alkyl) carbonyl, lower alkoxy, aralkoxy, nitro, alkylsulfanyl having 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- Lt; / RTI > is S or O). Though not absolutely necessary, 1 to 50 molar equivalents of acetate salts (such as potassium acetate and sodium acetate) may also be used as the diluent in the reaction. (I) wherein A is H, B is NO ₂ , D is Br and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, N, N-dimethylaminoethylsulfanyl, and E is S or O, with the proviso that the compound of formula (I) is the most convenient (Ii), wherein A is H, and B is bromine, using hydrazine and montmorillinite clay in ethyl acetate at 40-100 ° C or in ethanol at 40-100 ° C, NH ₂ and D is Br and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms , Arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl, and E is S or O) You can.

The amino compound (Ii) (wherein, A is H, B is NH _2, and, D is H or Br, X is H, halogen, alkyl, CN, lower perfluoroalkyl C 1 -C 6 alkyl, C 1 -C N, N-dimethylaminoethylsulfanyl, and E is S or O can be prepared by reacting a compound of the formula (1) (wherein R < 1 > LG) COR ^1a or (LG) CO ₂ R ^1a wherein LG is Cl for an acyl halide or chloroformate, or a leaving group such as OCOR ^1a or OCO ₂ R ^1a for an anhydride or mixed anhydride, and R ^1a is (Ii), wherein A is H, B is NHCOR ^1a or NHCO ₂ R ^1a , and D is selected from the group consisting of alkyl, alkenyl, alkynyl, H or Br and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy , Nitro, carbonyl, and sulfamic alkylsulfanyl, aryl sulfanyl, sulfanyl-pyridyl, 2-N, N- dimethylaminoethyl group having 1 to 6 carbon atoms, and E is S or O, R ^1a is alkyl having 1 to 6 carbon atoms , Aralkyl, and aryl. Such acylation may be carried out in the presence of at least one equivalent of an appropriate base such as an alkali metal hydroxide, carbonate or bicarbonate or an organic amine base such as triethylamine or pyridine, in chloroform, dichloromethane, THF, dioxane and water, In the presence or absence of a catalyst such as 4-N, N-dimethylpyridine, with or without a suitable solvent such as a mixture of < RTI ID = 0.0 >

Dibromo-bisphenol (Ii) wherein A is OH, B and D are Br, X is H and E is S or O can be prepared by reacting naphtho [2,3-b] thiophene or naphtho Is further brominated at the 9-position of the [2,3-b] furan ring to form bisphenol (Ii) wherein A is OH, B, D and X are Br and E is S or O . The bromination reaction is generally carried out in an inert solvent such as dichloromethane or carbon tetrachloride with a catalytic amount of iron (III) chloride in an amount ranging from 1 to 1.3 molar equivalents of molecular bromine in a dark room at temperatures ranging from -78 ° C to room temperature.

Further derivatives of the compounds of formula (I) in scheme 6 can be prepared by the following process. Phenol Ij wherein C is H and D is OH and X is selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, N, N-dimethylaminoethylsulfanyl, and E is S or O) with at least one molar equivalent of molecular bromine in a suitable solvent such as acetic acid (Ik) wherein A and B are H, C is Br and D is OH and X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, lower alkoxy, N, N-dimethylaminoethylsulfanyl, and E is S or O. The compound of formula (I) wherein R < 1 > Or by dibromination using more than 2 molar equivalents of molecular bromine in a suitable solvent such as acetic acid to give bromophenol Ik, B is H, A and C are Br, D is OH and X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, N, N-dimethylaminoethylsulfanyl, and E is S or O. In another embodiment of the present invention, Similarly, bisphenol (Ij), wherein C and D are OH and X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, N-dimethylaminoethylsulfanyl; and E is S or O) with at least one mole of molecular bromine in a suitable solvent, such as acetic acid, (Ik) wherein A is H, B is Br, C and D are OH and X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, lower alkoxy, N, N-dimethylaminoethylsulfanyl, and E is S or O. The compound of formula (I) wherein R < 1 > (Ik) wherein A is Br, B is H, C and D are OH, D is OH and X is halogen, alkyl of 1 to 6 carbon atoms, CN, N, N-dimethylaminoethylsulfanyl, E is S, N, N-dimethylaminoethylsulfanyl, N, N-dimethylaminoethylsulfanyl, Or O). ≪ / RTI > The mixture can be separated into the pure niobium product by conventional means.

Further derivatives of the compounds of formula (I) in Scheme 7 can be prepared by the following method. Phenol (II) wherein B is H, A and C are H or Br, D is OH and X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, N, N-dimethylaminoethylsulfanyl and E is S or O, with a compound of formula X ² CHR < RTI ID = 0.0 > ^6a CO ₂ R ⁶ alkyl haloacetate wherein X ² is Cl, Br or I, R ⁶ is alkyl having 1 to 6 carbon atoms and R ^6a is H, Alkylation product (Im) wherein B is H, A and C are H or Br, D is OH, X is a halogen, a carbon number < RTI ID = 0.0 > Alkyl having 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy having 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl having 1 to 6 carbon atoms, , A pyridyl sulfanyl, 2-N, N- dimethylaminoethyl sulfanyl, R ⁶ is an alkyl group having 1 to 6 carbon atoms, and R ^6a is H, E is to obtain a is S or O).

Alternatively, bisphenol (II) wherein A and B are H or Br, C and D are OH and X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, N, N-dimethylaminoethylsulfanyl, and E is S or O) in the presence of a base such as N, N-dimethylacetamide, 2 mol of alkyl haloacetate of formula X ² CHR ^6a CO ₂ R ⁶ , wherein X ² is Cl, Br or I, R ⁶ is alkyl of 1 to 6 carbon atoms and R ^6a is H, in a polar aprotic solvent, the equivalent weight or more, and an alkali metal carbonate: alkylated D above (for example, potassium carbonate), 2 molar equivalents of di-alkylated ester (Im) (wherein, A and B is H or Br, C is OCH ₂ CO ₂ R ⁶ is, X Is selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, Six and the alkylsulfanyl, aryl sulfanyl, sulfanyl-pyridyl, 2-N, N- dimethylaminoethyl sulfanyl, R ⁶ is an alkyl group having 1 to 6 carbon atoms, and R ^6a is H, E is S or O) can be obtained.

Alternatively, phenol Il (wherein B is H or halogen, A is H or halogen, C is H, Br or alkoxy of 1 to 6 carbon atoms, D is OH, X is halogen, 2-N, N-dibenzylidene, N, N-diethylaniline, N, N-diethylaniline, (R ^6a ) CO ₂ R ⁶ of formula CH (OH) (R ^6a ) CO ₂ R ⁶ under the conditions of a Mitsunobu reaction (Oyo Mitsunobu Synthesis, 1981, 1-27) hydroxy carboxylic acid ester (wherein, R ⁶ and R ^6a is alkyl, aralkyl or aryl group having 1 to 6 carbon atoms) to give ester (Im) reacting (where, B is H or halogen, a is H or halogen, C is H, Br or alkoxy of 1 to 6 carbon atoms, X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, N, N-dimethylaminoethylsulfanyl, and R ⁶ and R ^6a are each independently selected from the group consisting of alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, nitro, alkylsulfanyl having 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, Alkyl, aralkyl or aryl, and E is S or O. Other necessary dissociation reagents to perform the Mitsunobu reaction are alkyl azodicarboxylate diesters of 1 to 6 carbon atoms in a temperature range of -20 to 120 < 0 > C in a suitable solvent such as diethyl ether, THF, benzene or toluene Ethyl azodicarboxylate or diisopropyl azodicarboxylate) and at least one mole equivalent of triarylphosphine (e.g. triphenylphosphine).

Monoester (Im) wherein A and B are H or halogen, C is H, Br or alkoxy of 1 to 6 carbon atoms and X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, N, N-dimethylaminoethylsulfanyl, and R ⁶ and R ^6a are independently selected from the group consisting of a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, an aralkoxy group, a nitro group, an alkylsulfanyl group having 1 to 6 carbon atoms, an arylsulfanyl group, a pyridylsulfanyl group, 1 to 6 alkyl, aralkyl, alkyl or aryl, E is S or O) as well as the diester (Im) (wherein, a and B is H or Br, C is a OCH ₂ CO ₂ R ^6, X is Halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N , and N- dimethylaminoethyl sulfanyl, R ⁶ is an alkyl group having 1 to 6 carbon atoms, and R ^6a is H, E is S or O) using standard conditions and the (I) wherein A and B are H or halogen, C is H, Br or alkoxy of 1 to 6 carbon atoms and X is halogen, alkyl of 1 to 6 carbon atoms, CN, alkoxy of 1 to 6 carbon atoms, N, N-dimethylaminoethylsulfanyl, R < 6 > is lower alkyl, lower alkoxy, alkoxy having 1 to 6 carbon atoms, nitro, alkylsulfanyl having 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, ⁶ is H, R ^6a is alkyl, aralkyl or aryl having 1 to 6 carbon atoms and E is S or O) and dicarboxylic acid (Im) wherein A and B are H or Br and C is OCH ₂ CO ₂ H and X is selected from the group consisting of halogen, alkyl having 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy having 1 to 6 carbon atoms, nitro, alkylsulfanyl having 1 to 6 carbon atoms, arylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl, R ⁶ and R ^6a are H, and E is S or O. Conditions to effect this conversion include the use of an alkali metal hydroxide such as sodium hydroxide in combination with a co-solvent such as THF, dioxane or a lower alcohol such as methanol, or a mixture of THF and a lower alcohol, 0 > C to 40 < 0 > C.

Further derivatives of the compounds of formula I in scheme 8 can be prepared by the following process. Acetate (In) wherein X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl , Pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl, Y is H and E is S or O with halogenating agents, in particular benzylic bromination or chlorination, , N-bromosuccinimide, N-chlorosuccinimide or sulfuryl chloride to produce a halocarboxylate (In) wherein X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoro R is alkyl, alkoxy, aralkoxy, nitro, alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl having 1 to 6 carbon atoms, Y is Cl or Br < / RTI > and E is S or O). The reaction is conveniently carried out in a suitable solvent such as dichloromethane or carbon tetrachloride at a temperature ranging from 0 < 0 > C to room temperature.

Wherein X is selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl Wherein Y is Cl or Br and E is S or O, in an appropriate solvent such as THF, DMF or dichloromethane, in the presence of an alkoxide (MOR < ^{1 >} ), Sulfide (MSR ¹ ) or amide (NHR ¹ R ² ) wherein M is an alkali metal such as Na, Li or K and R ¹ and R ² are H, alkyl, aryl or (I) wherein X is selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbons, nitro , Alkylsulfanyl having 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl, Y May be OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl, aryl or aralkyl having 1 to 6 carbon atoms, and E is S or O. The compound (In) wherein X is halogen, alkyl having 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy having 1 to 6 carbon atoms, nitro, alkylsulfanyl having 1 to 6 carbon atoms, arylsulfanyl Y is Cl or Br, and E is S or O, with the nucleophile, the acetyl group is lost incidentally to form the compound (Io (R < 2 > Wherein B and D are H and X is selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, alkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms Y is OR ¹ , SR ¹ or NR ¹ R ² , wherein R ¹ and R ² are independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, Aryl, or aralkyl), and E is S or O. < / RTI >

(In) wherein X is selected from the group consisting of halogen, alkyl having 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy having 1 to 6 carbon atoms, nitro, alkylsulfanyl having 1 to 6 carbon atoms, arylsulfanyl Y is OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl having 1 to 6 carbon atoms, aryl (Io), wherein B and D are H and X is selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl , Alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl, Y is OR ¹ , SR It is ¹ or NR ¹ R ² (wherein, R ¹ and R ² are H, alkyl having 1 to 6 carbon atoms, aryl or aralkyl), E is able to generate a S or O]. Deacidifying conditions include aqueous bases such as mixtures of THF, dioxane or lower alcohols (such as methanol), or mixtures of THF and lower alcohols in water with at least 1 molar equivalent of an alkali metal hydroxide (such as sodium hydroxide) It is used in a temperature range of 0 to 40 ° C together with a co-solvent. An acidic condition may be used in which the compound is reacted with at least one molar equivalent of an inorganic salt (HCl or sulfuric acid) and a co-solvent such as THF in water and in the absence of a co-solvent at a temperature ranging from room temperature to 80 ° C.

Compounds of formula Io wherein B and D are H and X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl, aryl sulfanyl, sulfanyl-pyridyl, 2-N, N- dimethylaminoethyl and sulfanyl, Y is Cl, Br, oR ^1, SR ¹ or NR ¹ R ² (wherein, R ¹ and R ² Is H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl) and E is S or O can be brominated at two positions using a 2 molar equivalent or more of molecular bromine in a suitable solvent such as acetic acid to give dibromophenol (Io) wherein B and D are Br and X is halogen, alkyl having 1 to 6 carbons, CN, lower perfluoroalkyl, alkoxy having 1 to 6 carbons, nitro, alkyl having 1 to 6 carbons sulfanyl, aryl sulfanyl, sulfanyl-pyridyl, 2-N, N- dimethyl amino ethyl sulfanyl, Y is Cl, Br, oR ^1, SR ¹ or NR ¹ R ² (wherein, R ¹ R ² is H, alkyl, aryl or aralkyl is a) C 1 -C 6, E may be obtained for an S or O]. Although not absolutely necessary, 1 to 50 molar equivalents of a salt of acetic acid (e.g., potassium acetate or sodium acetate) may also be used as a diluent in the reaction.

In Scheme 9, further derivatives of the formula I can be prepared by the following process. Phenol (Ip) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, N, N-dimethylamino-ethylsulfanyl, Y is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, , Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl, aryl or aralkyl having 1 to 6 carbon atoms, and E is S or O, In a polar aprotic solvent such as tetrahydrofuran, at least one mole equivalent of an alkyl haloacetate of the formula X ² CH ₂ CO ₂ R ⁶ , wherein X ² is Cl, Br or I and R ⁶ is an alkyl of 1 to 6 carbon atoms, (Iq) wherein B and D are independently selected from the group consisting of H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, Alkyl or nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² , wherein R ¹ and R ² are H, and the number of carbon atoms is ¹ , ² , a = 1-6 alkyl, aryl or aralkyl), W is CO ₂ R ⁶ (wherein, R ⁶ is an alkyl group having 1 to 6 carbon atoms) and, R ⁵ is H, E is S or O] a .

Phenol (Ip) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, N, N-dimethylamino-ethylsulfanyl, Y is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, , Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl, and E is S or O, Hydroxycarboxylic acid ester of the formula CH (OH) (R ⁵ ) CO ₂ R ⁶ , wherein R ⁵ is H, the number of carbon atoms is 1 or 2, of 1 to 6 alkyl, aralkyl, aryl, CH ₂ (1H- imidazol-4-yl), CH ₃ (3-1H- indolyl), CH ₂ CH ₂ (1,3- dioxo-l, 3 Dihydro-isoindol-2-yl), CH ₂ CH ₂ (1-oxo-1,3-dihydro- Yl), CH ₂ (3- pyridyl) or CH ₂ CO ₂ R ⁶ (wherein, R ⁶ is an alkyl group having 1 to 6 carbon atoms)] and the reaction of ester (Iq) [wherein, B and D are H, halogen , CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, carbon atoms, alkyl of 1 to 6 sulfamic carbonyl, aryl sulfanyl, sulfanyl-pyridyl, 2-N, N- dimethylamino-ethyl sulfanyl and, Y is H, Cl, Br, oR ^1, SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl, aryl or aralkyl of 1 to 6 carbon atoms, W is CO ₂ R ⁶ wherein R ⁶ is alkyl of 1 to 6 carbon atoms, R ⁵ is H, C 1 -C 6 alkyl, aralkyl, aryl, CH ₂ (1H- imidazol-4-yl), CH ₃ (3-1H- indolyl), CH ₂ CH ₂ (1,3- di Dihydro-isoindol-2-yl), CH ₂ CH ₂ (1-oxo-1,3-dihydro- CH ₂ (3-pyridyl) or CH ₂ CO ₂ R ⁶ , wherein R ⁶ is alkyl of 1 to 6 carbon atoms, and E is S or O. Other analytical reagents required to carry out the Mitsunobu reaction are alkyl azodicarboxylate diesters of 1 to 6 carbon atoms in a suitable solvent such as diethyl ether, THF, benzene or toluene at -20 to 120 < 0 > C, Dicarboxylate or diisopropyl azodicarboxylate) and at least one mole equivalent of triarylphosphine (e.g. triphenylphosphine).

Formula ^{CH (OH) (R 5)} 2- hydroxy carboxylic acid ester of a CO ₂ R ⁶ (wherein, R ⁵ is H, aralkyl, aryl, CH ₂ alkyl, C 1 -C 6 (1H- imidazol-4-yl yl), CH ₂ (3-1H- indolyl), CH ₂ CH ₂ (1,3- dioxo-1,3-dihydro-isoindol-2-yl), CH ₂ CH ₂ (1- oxo- Dihydro-isoindol-2-yl), CH ₂ (3-pyridyl) or CH ₂ COR ⁶ and R ⁶ is alkyl of 1 to 6 carbon atoms, ≪ / RTI > can be prepared from commercially available carboxylic acid precursors. (S) - (+) - 2-hydroxy-1, 3-dihydro-2-isoindolinebutyric acid, (2) trifluoroacetic acid / chloroform, (3) methylsilane / trifluoroacetic acid, and (4) aqueous sodium bicarbonate In the presence of a base. 3- (Pyridin-3-yl) -phenylacetic acid; BA Lefker) (WA Hada, PJ McGarry Tetrahedron Lett. 1994, 35, 5205-5208] and ethyl chloroacetate.

(Iq) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, N, N-dimethylamino-ethylsulfanyl, Y is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, , Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl having 1 to 6 carbon atoms, aryl or aralkyl, W is CO ₂ tBu, R ⁵ Is H and E is S or O can be treated with one mole equivalent of a strong base such as lithium diisopropylamide in a suitable solvent such as THF at -78 [deg.] C to room temperature. This process produces the anion alpha to the ester carbonyl. Treating the resulting anion with at least one molar equivalent of an alkyl halide of the formula X ² R ⁵ wherein X ² is halogen and R ⁵ is alkyl and aralkyl and heating to room temperature to give the alkylated ester Iq, B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, N, N-dimethylamino-ethylsulfanyl, Y is H, Cl, Br, OR < ^{1 &} gt ;, R & , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl, W is CO ₂ tBu, R ⁵ is alkyl and aralkyl, E is S or O. < / RTI >

(Iq) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, N, N-dimethylamino-ethylsulfanyl, Y is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, , Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl, W is CO ₂ R ⁶ , R ⁵ represents H, alkyl having 1 to 6 carbon atoms, aralkyl, aryl, CH ₂ (1H-imidazol-4-yl), CH ₂ (3-1H-indolyl), CH ₂ CH ₂ oxo-1,3-dihydro-isoindol-2-yl), CH ₂ CH ₂ (1- oxo-1,3 dihydro-isoindol-2-yl), CH ₂ (3- pyridyl), CH ₂ CO ₂ R ⁶ (wherein, R ⁶ is an alkyl group having 1 to 6), E is selected from carboxylic acids thereof using standard conditions for an S or O] cognate (Iq) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, Lower alkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylamino-ethylsulfanyl, Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl, W is CO ₂ R ⁶ R ⁵ is H, alkyl, aralkyl, aryl, CH ₂ (1H-imidazol-4-yl), CH ₂ (3-1H-indolyl), CH ₂ CH ₂ 3-dioxo-1,3-dihydro-isoindol-2-yl), CH ₂ CH ₂ (1- oxo-1,3 dihydro-isoindol-2-yl), CH ₂ (3-pyrimidin Dl), CH ₂ CO ₂ H, and E is S or O. Conditions for effecting such a conversion include the use of one or more equivalents of an alkali metal hydroxide (such as sodium hydroxide), including aqueous bases, in the presence of a base such as THF, dioxane or lower alcohols such as methanol or a mixture of THF and lower alcohols (Iq) with 1 mole equivalent of an inorganic acid such as HCl or sulfuric acid in water and a co-solvent such as THF, or in the presence of a base such as < RTI ID = 0.0 > In the absence of a co-solvent, acid conditions may also be used which react at temperatures ranging from room temperature to 80 ° C. Alternatively, a variety of other conditions can be used to effect the conversion of esters to acids leading to (Iq) By reacting the carboxylic acid ester (Iq) with 1 molar equivalent of boron tribromide or boron trichloride in dichloromethane at -78 ° C to room temperature, With bromine in an amount of 1 molar equivalent or more and 0 to 50 DEG C or by reacting with 1 mol equivalent or more of trimethylsilyl bromide or trimethylsilyl iodide in dichloromethane, carbon tetrachloride or acetonitrile at -78 to 50 DEG C, Lt; RTI ID = 0.0 > 250 C < / RTI > with lithium iodide in pyridine or quinoline.

Phenol (Ip) is reacted with 1 mole equivalent or more of diethyltrifluoromethylsulfonyloxymethylphosphonate (DP Phillion and SS Andrew Tet. Lett., 1986, 1477-1480) and in a suitable solvent such as THF and DMF (Iq), wherein B and D are independently selected from the group consisting of H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, and at least one alkali metal hydride such as sodium to yield a diethylphosphonate product , X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, C 1-6 alkyl, Alkyl, aryl or aralkyl), W is PO ₃ Et ₂ , R ⁵ is H, R ⁶ is alkyl having 1 to 6 carbon atoms, E is S or Is O. < / RTI >

Phenol (Ip) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, N, N-dimethylamino-ethylsulfanyl, Y is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, , Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl, aryl or aralkyl having 1 to 6 carbon atoms, and E is S or O, ^{CH (OH) (R 5)} PO 3 (R 6) 2- hydroxy phosphonic acid diester of ₂ (wherein, R ⁵ is an alkyl or aryl group of H, 1-6 carbon atoms, R ⁶ is a group having 1 to 6 carbon atoms Alkyl) and a Mitsunobu reaction (Oyo Mitsunobu Synthesis 1981, 1-27) to obtain a phosphonic acid diester (Iq) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms , Aryl, aral X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² , wherein R ¹ and R ² are H, and the number of carbon atoms is ¹ , ² , of 1 to 6 alkyl, aryl or aralkyl a), W is a PO ₃ (R ⁶⁾ ₂ (wherein, R ⁶ is an alkyl group having 1 to 6 carbon atoms) and, R ⁵ is alkyl of H, C 1 -C 6 , Aralkyl or aryl, and E is S or O. Other analytical reagents required to carry out the Mitsunobu reaction are alkyl azodicarboxylate diesters of 1 to 6 carbon atoms in a suitable solvent such as diethyl ether, THF, benzene or toluene at -20 to 120 < 0 > C, Dicarboxylate or diisopropyl azodicarboxylate) and at least one mole equivalent of triarylphosphine (e.g. triphenylphosphine).

Formula ^{CH (OH) (R 5)} 2- hydroxy phosphonic acid diester of the PO ₃ R ⁶ (wherein, R ⁵ is H, an alkyl, aralkyl or aryl group of 1 to 6 carbon atoms, R ⁶ is 1 to 6 carbon atoms Is an alkyl aldehyde of the formula R ⁵ CHO wherein R ⁵ is alkyl of 1 to 6 carbon atoms, under standard conditions, a dialkyl phosphonate of the formula HP (O) (OR ⁶ ) ₂ wherein R ⁶ is an alkyl of 1 to 6 carbon atoms, Alkyl, aryl or aralkyl of 1 to 6 carbon atoms).

(Iq) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, Lower alkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylamino-ethylsulfanyl, Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl having 1 to 6 carbon atoms, aryl or aralkyl, W is PO ₃ (R ⁶ ) ₂ wherein R ⁶ is alkyl having 1 to 6 carbon atoms, R ⁵ is H, alkyl, aralkyl or aryl having 1 to 6 carbon atoms, and E is S or O, (Iq) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, Alkoxy, aralkoxy, nitro, alkylsulfanyl having 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethyl Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl, aryl or aralkyl of 1 to 6 carbon atoms, , W is PO ₃ H ₂ , R ⁵ is H, alkyl having 1 to 6 carbon atoms, aralkyl or aryl, R ⁶ is H or alkyl having 1 to 6 carbon atoms, and E is S or O . Conditions for reacting the above-mentioned phosphonic acid diester (Iq) with at least one molar equivalent of an inorganic acid such as HCl or sulfuric acid in water and a co-solvent such as THF or in the absence of a co-solvent at a temperature ranging from 40 to 100 DEG C have. Alternatively, a number of different conditions can be used to acidify (dq) the above-mentioned diesters. This is achieved by reacting the phosphonic acid diester (Iq) with boron tribromide or dichloromethane in dichloromethane in dichloromethane at a molar equivalent of at least 2 molar equivalents of boron trichloride, triethylsilyl bromide or trimethylsilyl iodide in carbon tetrachloride or acetonitrile at -78 to 50 < At least 2 molar equivalents of lithium iodide in pyridine or quinoline at 60 to 250 < 0 > C.

(Iq) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, N, N-dimethylamino-ethylsulfanyl, Y is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, , Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl, W is CO ₂ R ⁶ , R ⁶ is H or alkyl having 1 to 6 carbon atoms), R ⁵ is H, alkyl having 1 to 6 carbon atoms, and E is S or O, with the starting material in a lower alcohol such as methanol or ethanol (Iq), wherein B and D are independently selected from the group consisting of H, halogen, CN, alkyl of 1 to 6 carbons X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms Y is H, Cl, Br, OR ¹ , SR ^1, or NR ¹ R ² , wherein R ¹ and R ^2, is H, alkyl, aryl or aralkyl is an alkyl) having 1 to 6, W is a CONH _2, R ⁵ is H, aralkyl, aryl, alkyl, having 1 to 6 CH ₂ (1H- imidazol -4 -yl), CH ₂ (3-1H- indolyl), CH ₂ CH ₂ (1- oxo-1,3-dihydro-and iso-indol-2-yl) or CH ₂ (3- pyridyl), E Is S or O].

Alternatively, the carboxylic acid Iq, wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylamino-ethylsulfanyl And Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl having 1 to 6 carbon atoms, aryl or aralkyl, W is CO ₂ H, and R ⁵ is H, alkyl, aralkyl, aryl, CH ₂ (1 H-imidazol-4-yl), CH ₂ (3-1H-indolyl), CH ₂ CH ₂ , 3-oxo-1,3-dihydro-isoindol-2-yl), CH ₂ CH ₂ (1- oxo-1,3 dihydro-isoindol-2-yl) or CH ₂ (3- (Iq), wherein B and D are independently selected from the group consisting of H, halogen, CN, Aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² , wherein R is selected from the group consisting of hydrogen, ¹ and R ² are H, alkyl having 1 to 6 carbon atoms, aryl or aralkyl), W is CONH ₂ , CONHOH or CONH (CH ₂ ) ₂ CN and R ⁵ is H, alkyl having 1 to 6 carbon atoms, Aryl, CH ₂ (1 H-imidazol-4-yl), CH ₂ (3-1H-indolyl), CH ₂ CH ₂ (1,3-dioxo-1,3-dihydro- 2-yl), CH ₂ CH ₂ (1-oxo-1,3-dihydro-isoindol-2-yl) or CH ₂ (3-pyridyl) and E is S or O . This conversion can be accomplished using a conversion starting material that performs the conversion of the carboxylic acid to the carboxylic acid amide. Such methods include converting the acid to an activated acid and reacting with one mole equivalent or more of the desired amine. Amines of this category include ammonia in the form of ammonium hydroxide, hydroxylamine and 2-aminopropionitrile. The method of activating the carboxylic acid comprises reacting the acid with oxalyl chloride or thionyl chloride in an amount greater than or equal to 1 molar equivalent to obtain the carboxylic acid chloride in a suitable solvent such as dichloromethane, chloroform or diethyl ether. This process is often catalyzed by a small amount (0.01 to 0.1 molar equivalents) of dimethylformamide. Other methods of activating the carboxylic acid include reacting the acid with a carboxylic acid in the presence of at least one mole equivalent of dicyclohexylcarbodiimide and at least one mole equivalent of hydroxybenzotriazole in a suitable solvent such as dichloromethane or dimethylformamide at a temperature ranging from 0 to 60 ≪ / RTI >

Phenol (Ip) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, N, N-dimethylamino-ethylsulfanyl, Y is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, , Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl, aryl or aralkyl having 1 to 6 carbon atoms, and E is S or O, Is alkylated in a polar aprotic solvent such as DMF with at least 1 mole equivalents of halo acetonitrile of X ² CH ₂ CN (where X ² is Cl, Br or I) and 1 molar equivalent of an alkali metal carbonate (such as potassium carbonate) (Iq) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, Alkyl, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl, W is CN, R < ⁵ > is H and E is S or O.

Alternatively, the carboxylic acid amide analog (Iq), wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, Alkyl, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl, W is CONH ₂ and R ⁵ is H, an alkyl, aralkyl, aryl, CH ₂ (1 H-imidazol-4-yl), CH ₂ (3-1H-indolyl), CH ₂ CH ₂ 1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH ₂ CH ₂ (1- oxo-1,3 dihydro-isoindol-2-yl) or CH ₂ (3 - pyridyl) and E is S or O, with dehydrating the primary carboxamide functional group with a nitrile functional group (Iq) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbons , CN, lower perfluoroalkyl, alkoxy having 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl having 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl, W is CN R ⁵ is H, alkyl, aralkyl, aryl, CH ₂ (1H-imidazol-4-yl), CH ₂ (3-1H-indolyl), CH ₂ CH ₂ 3-dioxo-1,3-dihydro-isoindol-2-yl), CH ₂ CH ₂ (1- oxo-1,3 dihydro-isoindol-2-yl) or CH ₂ (3-pyrimidin Dl) and E is S or O. One set of conditions for carrying out such a transformation is that the primary carboxylic acid amide in a suitable solvent such as dioxane is reacted with at least 1 mole equivalent of trifluoroacetic anhydride and at least 2 mole equivalents of pyridine with a temperature range of 60 to 120 & .

(Iq) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower purple N, N-dimethylamino-ethylsulfanyl, Y is an alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, H, Cl, Br, oR ^1, SR ¹ or NR ¹ R ² (wherein, R ¹ and R ² is H, alkyl, aryl or aralkyl group having 1 to 6 carbon atoms alkyl), W is CN, R ⁵ is H, aralkyl, aryl, CH ₂ alkyl, C 1 -C 6 (1H- imidazol -4-), CH ₂ (3-1H- indolyl), CH ₂ CH ₂ (1,3- dioxo- 1,3-dihydro-isoindol-2-yl), CH ₂ CH ₂ (1- oxo-1,3-dihydro-and iso-indol-2-yl) or CH ₂ (3- pyridyl), E Is S or O, with a nitrile functionality in a suitable solvent such as benzene or toluene at a temperature ranging from 60 to 120 < RTI ID = 0.0 > (Iq), wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, and X is an alkyl group having 1 to 6 carbon atoms, by reacting 1 mole equivalent of trimethyl aluminum with 1 mole equivalent of trimethylsilylazide, Is selected from the group consisting of H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, an aryl or aralkyl is an alkyl), W is _5-tetrahydro jolyigo, R ⁵ is H, aralkyl, aryl, CH ₂ (1H- imidazol-4-yl), alkyl having 1 to 6 CH ₂ (3- 1H- indolyl), CH ₂ CH ₂ (1,3- dioxo-1,3-dihydro-isoindol-2-yl), CH ₂ CH ₂ (1- oxo-1,3-dihydro-iso indol-2-yl) or CH ₂ (3- pyridyl) and, E is S or O] i Can. Alternatively, the nitrile functionality can be reacted with at least one mole equivalent of ammonium azide in a suitable solvent such as dimethylformamide at a temperature ranging from 60 to 160 < 0 > C.

Further derivatives of the compounds of formula (I) in Scheme 10 may be prepared by the following method. Phenol (Ir) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, N, N-dimethylamino-ethylsulfanyl, Y is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, , Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl, and E is S or O, (Bis) trimethylsilylamide in a temperature range of 78 ° C to room temperature and reacting the lithium salt with an appropriate solvent such as THF in an inert atmosphere at a temperature ranging from -78 ° C to room temperature, 1 molar equivalent or more and a half or more of the aziridine-2,4-dione (prepared according to the method described in Zask, et al., J. Med Chem., 1990, 33, 1418-1423) (I) wherein R ⁴ is (R, S) -5-thiazolidin-2,4-dione and B and D are independently selected from the group consisting of H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, Aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are independently selected from the group consisting of H, Aryl, or aralkyl), and E is S or O. < / RTI >

Alternatively, phenol (Ir) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylamino-ethylsulfanyl And Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl having 1 to 6 carbon atoms, aryl or aralkyl, E is S or O] is reacted with a 1 molar equivalent of a tetrazole in THF and di-tert-butyl N, N-diethylphosphoramidate at room temperature and then reacted in the presence of a base such as that described in JW Perich and RB Johns, (O) (OtBu) ₂ , and B and D are H, halogen (R < ⁴ > , CN, carbon Aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1-6, aryl sulfanyl, sulfanyl-pyridyl, 2-N, N- dimethylamino-ethyl and sulfanyl, Y is H, Cl, Br, oR ^1, SR ¹ or NR ¹ R ² (wherein , R ¹ and R ² are H, alkyl having 1 to 6 carbon atoms, aryl or aralkyl) and E is S or O. This phosphate diester is then treated with at least one molar equivalent of hydrochloric acid in a suitable solvent such as dioxane to form the phosphonic acid Is where R ⁴ is P (O) (OH) ₂ , B and D are H, halogen , CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, carbon atoms, alkyl of 1 to 6 sulfamic carbonyl, aryl sulfanyl, sulfanyl-pyridyl, 2-N, N- dimethylamino-ethyl sulfanyl and, Y is H, Cl, Br, oR ^1, SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl having 1 to 6 carbon atoms, aryl or aralkyl, and E is S or O.

Phenol (Ir) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, N, N-dimethylamino-ethylsulfanyl, Y is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, , Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl, aryl or aralkyl having 1 to 6 carbon atoms and E is S or O, Treated with at least 2 molar equivalents of sodium hydroxide and then treated with at least 1 molar equivalent of 1,1,1-trichloro-2-methyl-2-propanol in the presence of excess acetone, which also acts as a solvent, Wherein R ⁴ is C (CH ₃ ) ₂ CO ₂ H and B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, Alkyl having 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy having 1 to 6 carbon atoms, nitro, alkylsulfanyl having 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl, aryl or aralkyl of 1 to 6 carbon atoms, ) And E is S or O].

Phenol (Ir) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, N, N-dimethylamino-ethylsulfanyl, Y is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, , Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl, aryl or aralkyl having 1 to 6 carbon atoms, and E is S or O, treated with β- propiolactone at least one molar equivalent of a suitable solvent, such as and, by treatment with potassium tertiary butoxide to 1 mole equivalent of a carboxylic acid (is) [wherein, R ⁴ is _{CH 2 CH 2 CO 2 H,} B and D is H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, carbon N, N-dimethylamino-ethylsulfanyl, Y is H, Cl, Br, or a salt thereof, wherein R < 1 > , OR ¹ , SR ¹ or NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl, and E is S or O.

Phenol (Ir) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, N, N-dimethylamino-ethylsulfanyl, Y is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, , Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl, aryl or aralkyl having 1 to 6 carbon atoms, and E is S or O, ^{CH (OH) (R 7)} 3- hydroxy carboxylic acid ester of CH ₂ CO ₂ R ⁶ (wherein, R ⁷ is H or alkyl of 1 to 6 carbon atoms, R ⁶ is an alkyl group having 1 to 6 carbon atoms) and a Mitutoyo (Is) wherein B and D are independently selected from the group consisting of H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, and R < , X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms , Aryl or aralkyl) and E is S or O. Other disclosures needed to perform the Mitsunobu reaction include alkyl azodicarboxylate diesters (e.g., 1 to 6 carbon atoms) in a suitable solvent such as diethyl ether, THF, benzene or toluene at a temperature ranging from -20 to 120 & Diethyl azodicarboxylate or diisopropyl azodicarboxylate) and at least 1 molar equivalent of a trityl arylphosphine (such as triphenylphosphine).

Formula ^{CH (OH) (R 7)} 3- hydroxy carboxylic acid ester of CH ₂ CO ₂ R ⁶ (wherein, R ⁷ is H or alkyl of 1 to 6 carbon atoms, R ⁶ is an alkyl group having 1 to 6 carbon atoms) is Either commercially available or can be prepared from commercially available carboxylic acid precursors under standard esterification conditions.

(I) wherein B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl of 1 to 6 carbon atoms, N, N-dimethylamino-ethylsulfanyl, Y is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, , Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl, and E is S or O, (Is) by at least one solvent or at least two equivalents of an inorganic acid such as HCl or sulfuric acid in a mixture of two or more solvents such as water, THF or dioxane, Wherein R ⁴ is (R) CH (R ⁷ ) CH ₂ CO ₂ H, B and D are H, halogen, CN, alkyl, aryl, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl Y is H, Cl, Br, OR ¹ , SR ¹ or NR ¹ R ² , wherein R ¹ and R ² are H, and the number of carbon atoms is ¹ , ² , 1 to 6 alkyl, aryl or aralkyl) and E is S or O. Alternatively, a number of different conditions can be used to effect acid conversion of the above-mentioned esters (Is). This may be accomplished by reacting the ester Is with 2 molar equivalents or more of boron tribromide or boron trichloride in dichloromethane at-78 C to room temperature or with 2 molar equivalents of bromic acid in acetic acid at 0 to 50 C, With trimethylsilyl bromide or trimethylsilyl iodide in dichloromethane, carbon tetrachloride or acetonitrile at 50 ° C or with 2 mol equivalents or more of lithium iodide in pyridine or quinoline at 60 to 250 ° C do.

Nitrophenol (Ir) [wherein, B is NO _2, D is H or Br, X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy, aralkyl having from 1 to 6 carbon atoms alkoxy, nitro, an alkyl sulfamoyl group having 1 to 6 carbonyl, aryl sulfanyl, sulfanyl-pyridyl, 2-N, N- dimethylamino-ethyl and sulfanyl, Y is H, oR ^1, SR ¹ or NR ¹ R ² (wherein, R ¹ and R ² is H, having a carbon number of 1 to 6 alkyl, aryl or aralkyl), and, E is S or O is - an alkyl or aralkyl halide of formula XR ⁴ in a polar solvent such as DMF ( (Is) is alkylated with 1 mole equivalent or more of an alkali metal carbonate (e.g., potassium carbonate) and 1 mole equivalent of an alkali metal carbonate (e.g., potassium carbonate), wherein X is Cl, Br, or I and R ⁴ is alkyl or aralkyl having 1 to 6 carbon atoms. [wherein, B is NO _2, D is H or Br, X is H, halogen, alkyl having 1 to 6 carbon atoms, CN, lower perfluoroalkyl, having 1 in 6 alkoxy, aralkoxy, nitro, alkylsulfanyl, aryl sulfanyl, sulfanyl-pyridyl, 2-N, N- dimethyl amino group having 1 to 6 carbon atoms-and ethyl sulfanyl, Y is H, OR ^1, SR ^1, Or NR ¹ R ² wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl, E is S or O, and R ⁴ is alkyl or aralkyl of 1 to 6 carbon atoms ] Can be obtained.

A nitro compound (Is) wherein B is NO ₂ , D is H or Br and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms alkoxy, nitro, an alkyl sulfamoyl group having 1 to 6 carbonyl, aryl sulfanyl, sulfanyl-pyridyl, 2-N, N- dimethylamino-ethyl and sulfanyl, Y is H, oR ^1, SR ¹ or NR ¹ R ² (Wherein R ¹ and R ² are H, alkyl, aryl or aralkyl having 1 to 6 carbon atoms) and E is S or O, most rapidly at 40 to 100 ° C in the presence of tin dichloride in ethyl acetate (I) wherein B is NH ₂ , D is H or Br, and X is H, halogen, an alkyl group having from 1 to 6 carbon atoms, or an amino compound (Is), using hydrazine and montmorillinite clay in ethanol at 40 to 100 & Alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, alkylsulfone of 1 to 6 carbon atoms Y is H, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are independently selected from the group consisting of H, Aryl, or aralkyl), E is S or O, and R < ⁴ > is alkyl or aralkyl having 1 to 6 carbon atoms.

(I) wherein B is NH ₂ , D is H or Br and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms alkoxy, nitro, an alkyl sulfamoyl group having 1 to 6 carbonyl, aryl sulfanyl, sulfanyl-pyridyl, 2-N, N- dimethylamino-ethyl and sulfanyl, Y is H, oR ^1, SR ¹ or NR ¹ R ² (Wherein R ¹ and R ² are H, alkyl having 1 to 6 carbon atoms, aryl or aralkyl), E is S or O, and R ⁴ is alkyl or aralkyl having 1 to 6 carbon atoms. ² CHR ^6a CO ₂ R ⁶ alkyl haloacetate wherein X ² is Cl, Br or I, R ⁶ is alkyl having 1 to 6 carbon atoms and R ^6a is alkyl having 1 to 6 carbon atoms And alkylated product Is (where B is NCHR ^6a CO ₂ R ^{6 (} alkylene oxide)) at a molar equivalent of at least 1 molar equivalent of an alkali metal carbonate such as potassium carbonate in a polar aprotic solvent such as DMF (R ⁶ is alkyl having 1 to 6 carbon atoms, R ^6a is H or alkyl having 1 to 6 carbon atoms, and R ^6a is H), D is H or Br, X is H, halogen, Alkyl, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, Y is H, OR ¹ , SR ¹ or NR ¹ R ² wherein R ¹ and R ² are H, alkyl having 1 to 6 carbon atoms, aryl or aralkyl, E is S or O And R < ⁴ > is alkyl or aralkyl having 1 to 6 carbon atoms. Such esters can be converted to their carboxylic acid analogs using standard conditions to give the carboxylic acids Is where B is NCHR ^6a CO ₂ H where R ⁶ is alkyl of 1 to 6 carbon atoms and R ^6a is H or 1 to 6 carbon atoms Alkyl, ^R6a is H), D is H or Br and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, , alkylsulfanyl, aryl sulfanyl, sulfanyl-pyridyl, 2-N, N- dimethyl amino group having 1 to 6 carbon atoms-and ethyl sulfanyl, Y is H, oR ^1, SR ¹ or NR ¹ R ² (wherein, R ¹ and R ² are H, alkyl having 1 to 6 carbon atoms, aryl or aralkyl), E is S or O and R ⁴ is alkyl or aralkyl having 1 to 6 carbon atoms. The conditions for effecting such a conversion include, by including an aqueous base, at least 1 molar equivalent of alkali metal hydroxide (e.g., sodium hydroxide) in THF, dioxane or lower alcohols such as methanol at a temperature ranging from 0 to 40 & It is used in water with a co-solvent such as a mixture of THF and lower alcohol.

Further derivatives of the compounds of formula (I) in Scheme 11 can be prepared by the following method. The compound (It), wherein B and D are H, halogen, CN, alkyl having 1 to 6 carbon atoms, aryl, aralkyl or nitro, X is H, halogen, alkyl having 1 to 6 carbon atoms, Y is Cl, Br or OR ¹ , R ¹ and R ² are H, alkyl, aryl or aralkyl having 1 to 6 carbon atoms, and R ⁵ is an alkyl group having 1 to 6 carbon atoms, H, alkyl having 1 to 6 carbon atoms, aryl or aralkyl, and R ⁶ is H or alkyl having 1 to 6 carbon atoms) with an oxidizing agent 2 such as m-chloroperbenzoic acid in dichloromethane at a temperature ranging from -20 to 60 & (Iu), wherein n is 2, B and D are H, halogen, CN, carbon number (s), and the like, using peracetic acid in an acetic acid and water solution at room temperature to 100 & Alkyl, aryl, aralkyl or nitro, X is H, halogen, C 1-6 Alkyl, CN, and lower perfluoroalkyl, alkoxy, aralkoxy having 1 to 6 carbon atoms, nitro, Y is Cl, Br or a OR ^1, R ¹ and R ² of H. C 1 -C 6 alkyl, aryl or R ⁵ is H, alkyl having 1 to 6 carbon atoms, aryl or aralkyl, and R ⁶ is H or alkyl having 1 to 6 carbon atoms.

The compounds of the present invention are useful for treating metabolic diseases associated with insulin resistance or hyperglycemia, particularly those associated with obesity or glucose tolerance. Thus, the compounds of the present invention are particularly useful for the treatment or inhibition of type II diabetes. The compounds of the present invention are also useful for controlling glucose concentration in diseases such as type I diabetes.

The ability of the compounds of the invention to treat or inhibit insulin resistance or hyperglycemia-related disorders is achieved using representative compounds of the invention in two standard pharmacological test procedures that measure inhibition of PTPase.

Inhibition of triphosphorylated insulin receptor dodecapoepeptope dephosphorylation by rat liver protein-tyrosine phosphatase (PTPase)

Using the standard pharmacological test process, phosphotyrosyl dodecapeptide corresponding to the 1143-1153 insulin receptor kinase domain phosphorylated on the 1146, 1150 and 1151 tyrosine residues as substrates, the PTPase of rat liver microgrosome Assay inhibition of activity. The processes used and the results obtained are briefly disclosed below.

Preparation of MyogloSom Fraction: Rat (Sprague-Dawley rat, Charles River, Kingston, NY), body weight 100-150 g, maintained with standard rodent feed (Purina)] was choked with CO ₂ Sacrifice and bilateral cataracts. The liver is removed and washed with cold 0.85% (w / v) brine and weighed. The tissue was homogenized with ice to 10 volumes of Buffer A and the microsomes were prepared essentially as described in the literature by Meijerovich, Rothenberh P, Shechter Y, Bonner-Weir S ), Kahramanian (Kahn CR). Normalizes hyperglycemia in two mouse models of non-insulin dependent diabetes mellitus with vanadate. J Clin Invest 1991; 87: 1286-1294 and Albert B, Bray D, Lewis J, Raff M, Roberts K, Watson JD, editors. Molecular Biology of the cell. New York: Garland Publishing, Inc., 1989], with minimal modification. The liver homogenate is filtered through silk to remove any remaining tissue debris and then centrifuged at 10,000 xg at 40 ° C for 60 minutes. The supernatant is removed and centrifuged at 100,000 x g for 60 minutes at 40 < 0 > C. The pellet, microsomes and small vehicle were resuspended and resuspended in 20 mM TRIS-HCl (pH 7.4), 50 mM 2-mercaptoethanol, 250 mM sucrose, 2 mM EDTA, 10 mM EGTA, 2 mM AEBSF, 0.1 mM TPCK, Mu] g / mu l (buffer A) was mixed with about 850 [mu] g protein / ml protein, 5 [mu] g / mu l HbB antipain, 5 mu g / mu l chymostatin, / Ml. ≪ / RTI > Protein concentration is determined by Pierce Coomassie Plus Protein Assay (Pierce Chemical Co., Rockford, Ill.) Using crystalline bovine serum albumin as standard.

Measurement of PTPase activity: A malachite green-ammonium molybdate method as described in Lanzetta PA, Alvarez LJ, Reinach PS, Candia OA is used. An assay adapted to the platereader, improved for the nanomolar amount of inorganic phosphate (Anal. Biochem. 1979; 100: 95-97] is used for the detection of the nanomoles of phosphate liberated by the PTPase of rat liver microsomes. The test procedure uses a dodeca phosphopeptide, which is typically synthesized by AnaSpec, Inc., San Jose, Calif., As a substrate. A peptide, TRDIYETDYYRK, corresponding to the catalytic domain of the 1142-1153 insulin receptor is tyrosine phosphorylated at residues 1146, 1150 and 1151 of tyrosine. The microsomal fraction (83.25 μl) is pre-incubated for 10 min at 37 ° C with or without the use of the test compound (6.25 μl) and 305.5 μl of 83.83 mM HEPES reaction buffer, pH 7.4. At a final concentration of 50 μM, 10.5 μl of the peptide substrate is equilibrated to 37 ° C. in a LABLINE multi-block heater with a titerplate adapter. The preparation of the pre-incubated microsomes (39.5 ㎕) with or without the drug was added to initiate the diphospholylation reaction and proceeded at 37 캜 for 30 minutes. The reaction is terminated by a malachite green-molybdate ammonium-tween 20 stopping reagent (NG / AM / Tw). The stopping reagent consists of 3 parts of 0.45% malachite green hydrochloride, 1 part of 4.2% ammonium molybdate tetrahydrate in 4N HCl and 0.5% Tween 20. The sample blank is prepared by adding 200 [mu] l of MG / AM / Tw to the substrate followed by the addition of 39.5 [mu] l of pre-cultured membrane with or without drug. Color is developed at room temperature for 30 minutes, and sample absorbance is measured at 650 nm using a plate reader (Molecular Device). Four samples and blank are prepared. The screening activity of 50 μM (final) drug is assayed for inhibition of PTPase in microsomes.

Calculation: PTPase activity based on the potassium phosphate standard curve is expressed as released phosphate (nmol) / min / protein (mg). PTPase inhibition of the test compound is calculated as a percentage (%) of the control. SAS Release 6.08, four parameters of PTPase activity using PROC NLIN. Nonlinear sign logical regression is used to calculate the IC ₅₀ value of the test compound. All compounds are administered at a concentration of 50 [mu] M. The following results were obtained using representative compounds of the present invention.

Inhibition of triphosphorylated insulin receptor dodecapoepeptope dephosphorylation by hPTP1B

Using the standard pharmacological test process, phosphotyrosyldodecapeptide corresponding to the 1142-1153 insulin receptor kinase domain phosphorylated on the 1146, 1150 and 1151 tyrosine residues as substrates, the recombinant rat protein tyrosine phosphatase, PTP1B activity . ≪ / RTI > The processes used and the results obtained are briefly described below.

Human recombinant PTP1B was purchased from Goldstein et al. (Goldstein et al. Mol. Cell. Biochem. 109, 107, 1992). The enzyme preparation used is in a microtube containing 500 to 700 占 퐂 / ml of protein in 33 mM Tris-HCl, 2 mM EDTA, 10% glycerol and 10 mM 2-mercaptoethanol.

Measurement of PTPase activity: Lanzetta et al. Anl. Biochem. 100, 95, 1979, is used for the detection of the nanomoles of the liberated phosphate by recombinant PTP1B. The test procedure uses as a substrate a dodeca phosphopeptide that is typically synthesized by AnaSpec, Inc. (San Jose, Calif.). A peptide, TRDIYETDYYRK, corresponding to the catalytic domain of the 1142-1153 insulin receptor is tyrosine phosphorylated at residues 1146, 1150 and 1151 of tyrosine. Recombinant rPTP1B is diluted with buffer (pH 7.4, containing 33 mM Tris-HCl, 2 mM EDTA and 50 mM b-mercaptoethanol) to obtain an approximate activity of protein 1000-2000 nmol / min / mg. The diluted enzyme (83.25 ml) is pre-incubated for 10 min at 37 [deg.] C with or without the test compound (6.25 ml) and 305.5 ml of 81.83 mM HEPES reaction buffer, pH 7.4. At a final concentration of 50 mM, 10.5 mL of the peptide substrate is equilibrated to 37 DEG C in a LABLINE multi-block heater with a titer plate adapter. A pre-culture recombinant enzyme preparation (39.5 ml) with or without the drug was added to initiate the diphosphoylation reaction, which was allowed to proceed for 30 minutes at 37 ° C. The reaction is terminated by 200 ml of malachite green-molybdate ammonium-tween 20 stopping reagent (NG / AM / Tw). The stopping reagent consists of 3 parts of 0.45% malachite green hydrochloride, 1 part of 4.2% ammonium molybdate tetrahydrate in 4N HCl and 0.5% Tween 20. The sample blank is prepared by adding 200 [mu] l of MG / AM / Tw to the substrate and then adding 39.5 ml of pre-cultured recombinant enzyme with or without the drug. Color is developed at room temperature for 30 minutes, and sample absorbance is measured at 650 nm using a plate reader (Molecular Device). Four samples and blank are prepared.

Calculation: PTPase activity based on the potassium phosphate standard curve is expressed as released phosphate (nmol) / min / protein (mg). PTPase inhibition of the test compound is calculated as a percentage (%) of the control. SAS Release 6.08, four parameters of PTPase activity using PROC NLIN. Nonlinear sign logical regression is used to calculate the IC ₅₀ value of the test compound. The following results were obtained.

Blood glucose, which decreases the activity of representative compounds of the present invention, is demonstrated in standard in vivo procedures using diabetic (ob / ob) mice. The processes used and the results obtained are briefly described below.

Non-insulin dependent diabetes mellitus (NIDDM) is typically characterized by obesity, hyperglycemia, abnormal insulin secretion, hyperinsulinemia and insulin resistance. Genetically obese-hyperglycemic ob / ob mice exhibit a number of these metabolic abnormalities and are considered to be a useful model for finding hyperglycemic agents to treat NIDDM (Coleman, D .: Diabetologia 14: 141-148, 1978) .

In each test procedure, mice of similar age (2-5 months old male or female ob / ob (C57Bl / 6J) and its litermate (ob / + or + / +, Jackson Laboratories) 65g) is randomized into four groups of 10 mice according to body weight. Mice are housed at 5 cages per cage and maintained with water and libitum with normal rodent feed. Mice are dosed daily with test compound either by using gibbous (suspended in 0.5 ml of 0.5% methylcellulose), by dissolving in drinking water, or by mixing with food. The dose of the compound ranges from 2.5 to 200 mg per kilogram of body weight (kg). The dose is calculated on the basis of the weekly weight supplied and is expressed as the active residue. A positive regulator, cigalitazone (5- (4- (1-methylcyclohexylmethoxy) benzyl) -2,4-dione) (Chang, A., Wyse, B., Gilchrist, B., Peterson , T. and Diani, A. Diabetes 32: 830-838, 1983] at a dose of 100 mg / kg / day, which significantly reduces plasma glucose. Control mice receive only the vehicle.

On the morning of the 4th, 7th or 14th day, two drops of blood (about 50μl) are collected from the tail vein or discarded and collected into sodium fluoride containing tubes. For studies where compounds are administered daily by gavage, blood samples are collected 0-4 hours after compound administration. The parasma was separated by centrifugation and the concentration of glucose was measured by Abbott V. P. Enzymatically measured in an analyzer (Abbott V. P. Analyzer).

For each mouse, the percent change (%) of plasma glucose on days 4, 7 or 14 is calculated with respect to the mean plasma glucose of vehicle-treated mice. After analyzing the changes, the Dunett's Comparison Test (one-tailed) is used to further assess the significant difference between the plasma glucose values from the control and the individual compound treated groups (CMS SAS Release 5.18).

The results shown in the table below indicate that the compounds of the present invention lower blood glucose levels in diabetic mice, and thus exhibit anti-glycemic activity.

a - No significant activity (p <0.05) at all in this dose.

b - Not measured.

c - Measured at 0 hours.

Based on the results obtained in a standard pharmacological test process, representative compounds of the present invention inhibit PTPase activity, decrease blood glucose levels in diabetic mice, and thus are associated with obesity or insulin resistance, Or metabolic diseases associated with hyperglycemia. More particularly, the compounds of the present invention are useful for the treatment or inhibition of type II diabetes, and for the regulation of glucose levels in diseases such as type I diabetes. As used herein, the term " modulation " means maintaining the glucose concentration within a clinically normal range.

Effective administration of such compounds may be provided in a daily dose of about 1 to 250 mg / kg, and may be provided in a single dose or in divided doses of two or more. Such dosages may be achieved by any of the methods useful for inducing the active compounds of the present invention to the bloodstream of the recipient, including oral, parenteral (including intravenous, intraperitoneal and subcutaneous injection), rectal, vaginal and transdermal administration via transplantation . &Lt; / RTI &gt; For these techniques, transdermal administration includes all administration across the internal lining of the body passageway, including the surface of the body and epithelial and mucosal tissues. Such administration can be carried out in the form of lotions, creams, foams, patches, suspensions, solutions and suppositories (intestines and vaginal) using the present invention or pharmaceutically acceptable salts thereof.

Oral formulations containing the active compounds of the present invention may include any conventionally used oral form, including tablets, capsules, mouthwashes, troches, rosins, and oral solutions, suspensions or solvents . Capsules are prepared by mixing the active compound (s) with pharmaceutically acceptable starches such as corn, potato or tapioca starch, sugars, artificial sweeteners, powdered celluloses such as crystalline and microcrystalline cellulose, flour, gelatin, Gums, and the like, and / or a mixture of diluents. Useful tablet formulations may be prepared by conventional compression, wet granulation or dry granulation processes and may be in the form of granules, such as magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, Gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, silicate complex, calcium carbonate, glycine, texturin, sucrose, sorbitol, calcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, A pharmaceutically acceptable diluent, binder, lubricant, disintegrant, suspending agent or stabilizing agent may be used including but not limited to sugar powder. Oral formulations herein may employ standard delay or time delay formulations that alter the absorption of the active compound (s). The suppository formulations may be prepared from conventional materials, including waxes that modify the melting point of the suppository, and cocoa butter, with or without glycerin. Water-soluble suppository bases such as polyethylene glycols of various molecular weights may also be used.

The dosage, regimen and mode of administration of these compounds can vary depending on the disease and the subject being treated, and will depend on the judgment of the practitioner concerned. Administration of one or more compounds herein is preferably initiated at low doses and increased until the desired effect is obtained.

The following process describes the manufacture of representative embodiments of the present invention.

Example 1

2,3-dimethyl-thiophene

3-Methyl-thiophene-carboxaldehyde (20 g, 0.159 mol), hydrazine hydrate (31 mL) and diethylene glycol (72 mL) are heated to reflux for 20 minutes. After cooling to below 100 ° C, potassium hydroxide (22.9 g, 0.408 mol) is added and the reaction mixture is heated at 125-130 ° C for 1.5 h. The reaction mixture is cooled to room temperature and added to water. The aqueous mixture is extracted with ether, and the ether phase is washed with 5% aqueous HCl and brine. Removing the dried (magnesium sulphate) and the solvent, the oil was purified by flash chromatography (eluant: pentane) to provide the title compound as an oil (15.81g, 89%): NMR (CDCl 3): δ 6.97 (d, 1H, J = 8 Hz), 6.77 (d, 1H, J = 8 Hz), 2.35 (s, 3H), 2.14 (s, 3H).

Example 2

4,5-dimethylthiophen-2-yl- (phenyl) -methanol

n-Butyl lithium (19.6 mL, 49.1 mmol, 2.5 N in hexane) was added to a stirred solution of 2,3-dimethyl-thiophene (5.0 g, 44.6 mmol) in THF (100 mL) Drop it. The solution is warmed to 0 &lt; 0 &gt; C for 30 min and benzaldehyde (5.0 ml, 49.1 mmol) is added while cooling to -78 [deg.] C. After a further 45 minutes, saturated aqueous ammonium chloride is added and the reaction mixture is partitioned between water and ether. The ether phase is washed with brine and concentrated. The resulting oil was triturated with petroleum ether to provide the title compound as a white solid (7.77g, 80%): mp 80 to _{81 ℃: NMR (CDCl 3)} : δ 7.45 (ddd, J = 8, 1, 1Hz, 1H), 6.93 (s, 1H, OH), 2.29 (s, 3H), 2.05 (m, 2H), 7.37 (ddd, J = s, 3H); MS (EI) (M &lt; ^{+ &} gt ^; ) 218 (45%, MI):

Elemental analysis for C ₁₃ H ₁₄ OS:

Calculated: C, 71.52, H, 6.46, N, 0.00.

Found: C, 71.41, H, 6.42, N, 0.09.

Example 3

2-benzyl-4,5-dimethylthiophene

Trifluoroacetic acid (50 ml) was added to a solution of 4,5-dimethylthiophen-2-yl- (phenyl) -methanol (7.7 g, 35.3 mmol), sodium borohydride (6.67 g, 177 mmol) Dropwise to the suspension over 60 minutes. After an additional 1.5 hours, the reaction mixture is added to 10% aqueous sodium hydroxide (600 ml) and stirred for 30 minutes. The layers are separated and the ether phase is washed with 10% aqueous sodium hydroxide and brine and dried (magnesium sulphate). The ether phase was concentrated to provide the title compound as an oil (6.73g, 94%): NMR (CDCl 3): δ 7.33-7.19 (m, 5H), 6.47 (s, 1H), 4.03 (s, 2H), 2.27 (s, 3 H), 2.06 (m, 2 H); MS (EI) (M &lt; ^{+ &} gt ^; ) 202 (45%, MI).

Example 4

(2-benzyl-3,4-dimethyl-thiophen-3-yl) - (4- methoxy- phenyl)

Benzyl-4,5-dimethylthiophene (6.6 g, 32.62 mmol), anisole chloride (5.90 g, 34.6 mmol) and dichloromethane (120 mL) under dry nitrogen atmosphere, At -78 [deg.] C solution over 10 minutes. After 5 h at -78 [deg.] C, the reaction mixture is added to water and extracted with ether. The ether extract is washed with saturated aqueous sodium bicarbonate and brine. The solvent was removed and the resulting solid was triturated with ether to give the title compound as an off-white solid (9.62 g, 88%): mp. 85 to 86 占 폚; NMR (CDCl ₃ ):? 7.80 (ddd, J = 8, 8, 1 Hz, 2H), 7.24-7.10 (m, 5H), 7.92 (ddd, J = 2H), 3.88 (s, 3H), 2.28 (s, 3H), 1.90 (s, 3H); MS (EI): 336 (100%, MI):

Elemental analysis for C ₂₁ H ₂₀ O ₂ S:

Calculated: C, 74.97, H, 5.99, N, 0.00.

Found: C, 75.11, H, 6.02, N, 0.05.

Example 5

4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl)

Pure boron tribromide (20 mL, 212 mmol) was added to a solution of (2-benzyl-4,5-dimethyl-thiophen-3-yl) - -Phenyl) -methanone &lt; / RTI &gt; (9.40 g, 27.9 mmol). The solution is warmed to ambient temperature and stirred for 4 hours. The reaction mixture is cooled to 0 &lt; 0 &gt; C, carefully quenched with water, and the solvent is removed. Additional water was added and the resulting solid was filtered, washed with water and triturated with petroleum ether to give the title compound as a pale brown solid (8.23 g, 97%): mp. 165 to 168 占 폚; _{NMR (DMSO-d 6):} δ 9.62 (s, 1H), 8.43 (s, 1H), 7.94 (d, J = 8Hz, 1H), 7.43 (m, 2H), 7.32 (ddd, J = 8, 1 (D, J = 8 Hz, 2H), 6.90 (d, J = 9 Hz, 2H), 2.39 (s, 3H), 1.61 MS (EI): 304 (100%, MI).

Example 6

Acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester

Acetic anhydride (0.68 ml, 7.20 mmol) was added to a solution of 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (2.0 g, 6.57 mmol) in pyridine (8.6 ml) Lt; RTI ID = 0.0 &gt; 0 C. &lt; / RTI &gt; After 17 hours, the reaction mixture is added to 5% aqueous HCl and the resulting solid is filtered, washed with 5% aqueous HCl and water, and triturated with petroleum ether. This was then dried in vacuo to afford the title compound as a white solid (1.99 g, 88%): mp. 147 to 150 캜; _{NMR (DMSO-d 6):} δ 8.49 (s, 1H), 7.94 (d, J = 8Hz, 1H), 7.46 (ddd, J = 8, 6, 2, 1H), 7.38 (ddd, J = 8, (D, J = 9 Hz, 2H), 2.40 (d, J = 1 Hz, 3H), 2.34 (s, 3H), 1.57 (d, J = 1 Hz, 3H); MS (EI): 346 (90%, MI), 304 (90%, MI), 304 (100%);

Elemental analysis for C ₂₂ H ₁₈ O ₂ S:

Calculated: C, 76.27, H, 5.34, N, 0.00.

Found: C, 75.88, H, 5.04, N, 0.28.

Example 7

Acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-

A solution of bromine (0.326 ml, 6.15 mmol) in dichloromethane (9 ml) was added dropwise to a solution of acetic acid 4- (2,3-dimethyl-naphthol) in dichloromethane (47 ml) Is added dropwise over 15 minutes to a solution of 2-chloro-2,3-b] thiophen-4-yl) -phenyl ester (1.87 g, 5.41 mmol) and iron chloride (III) (50 mg, 0.31 mmol). After 10 minutes, dilute aqueous sodium bisulfite is added and the reaction mixture is partitioned between water and ether. The ether phase was washed with brine and concentrated to give the title compound as a white solid (2.09 g, 91%): mp. 190-191 占 폚; _{NMR (DMSO-d 6):} δ 8.20 (d, J = 8Hz, 1H), 7.65 (ddd, J = 8, 7, 1, 1H), 7.49 (ddd, J = 8, 7, 1Hz, 1H), 3H), 2.33 (s, 3H), 1.55 (d, J = 9 Hz, 2H), 7.43-7.38 (d, J = 1 Hz, 3H); MS (EI): 1 bromine isotope pattern 424 (95%, MI), 426 (100%);

Elemental analysis for C ₂₂ H ₁₇ BrO ₂ S:

Calculated: C, 62.12, H, 4.03, N, 0.00.

Found: C, 62.46, H, 4.05, N, 0.09.

Example 8

Dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol

Aqueous potassium hydroxide (6.0 ml, 6.0 mmol) was added to a solution of acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophene- 4-yl) -phenyl ester (0.48 g, 1.14 mmol). After 1 hour, the organic solvent was removed, water was added, the solution mixture was acidified with 10% HCl, the solid obtained was washed with water, triturated with petroleum ether and dried in vacuo to give the title compound as a white solid 0.32 g, 73%)): mp. 165 to 168 占 폚; _{NMR (DMSO-d 6):} δ 9.68 (s, 1H), 8.17 (d, J = 8Hz, 1H), 7.62 (ddd, J = 8, 6, 1Hz, 1H), 7.50 (d, J = 8Hz, J = 9 Hz, 2H), 6.91 (d, J = 9 Hz, 2H), 2.42 (d, J = 1 Hz, 3H), 7.44 (ddd, J = , 1.59 (d, J = 1 Hz, 3 H); MS (EI): 1 bromine isotope pattern 382 (95%, MI), 384 (100%);

Elemental analysis for C ₂₀ H ₁₅ BrOS:

Calculated: C, 62.67, H, 3.95, N, 0.00.

Found: C, 62.40, H, 3.91, N, 0.09.

Example 9

Dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-

A solution of bromine (0.34 ml, 5.74 mmol) in acetic acid (5 ml) was added to a solution of 4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- g, 2.87 mmol), potassium acetate (2.82 g, 28.7 mmol) and acetic acid (31 ml) at room temperature. After 1.5 hours, water (200 ml) and a small amount of solid sodium sulfite are added. The suspension was filtered and the solid was washed with water, triturated with petroleum ether and dried in vacuo to afford the title compound as a white solid (1.52 g, 88%): mp. 172-174 占 폚; _{NMR (DMSO-d 6):} 11.95 (broad s, 1H), 10.20 (broad s, 1H), 8.19 (ddd, J = 8, 1, 1Hz, 1H), 7.65 (ddd, J = 8, 6, 1Hz , 7.59 (s, 2H), 7.51-7.49 (m, 2H), 2.44 (d, J = lHz, 3H), 1.90 (s, 3H), 1.64 (d, J = lHz, 3H); MS (+ FAB): 3 bromine isotope pattern 538 (40%), 540 (100%), 542 (90%), 544 (50%);

Elemental analysis for C ₂₂ H ₁₃ Br ₃ OS · C ₂ H ₄ O ₂ :

Calculated: C, 43.95, H, 2.85, N, 0.00.

Found: C, 44.13, H, 2.66, N, 0.12.

Example 10

Methanesulfonic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester

To a solution of 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl-phenol (3.00 g, 9.86 mmol) and pyridine (4.0 ml, 49.3 mmol, 5 mmol) in methylene chloride Methylsulfonyl chloride (1.14 mL, 14.8 mmol, 1.5 eq.) Is added dropwise to a cold (ice bath) solution of the compound of formula ), Acidified with 10% hydrochloric acid and extracted with ether. The combined extracts were washed with brine, silica gel was added and the solution was removed. The adsorbates were purified by flash chromatography (45/55 petroleum ether / ethyl acetate acetate) to give the title compound as a white solid (30.2g, 80%): NMR (CDCl 3): δ 8.30 (s, 1H), 7.90 (d, J = 8Hz, 1H), 7.50-7.40 (m, 5H), 7.38-7.28 (m, IH), 3.26 (s, 3H), 2.50 (s, 3H), 1.61 (s, 3H).

Example 11

Methanesulfonic acid 4- (9-iodo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester

A solution of methanesulfonic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophene-4-carbaldehyde in 31.5 ml of tetrahydrofuran, 80% aqueous acetic acid (16 ml) and concentrated sulfuric acid (0.87 ml) Iodide (1.59 g, 6.27 mmol, 0.8 eq.) And iodic acid (0.414 g, 2.35 mmol, 0.9 eq.) Were added at room temperature to a solution of the title compound (3.00 g, 7.84 mmol) The mixture is stirred at room temperature for 12 days. The reaction mixture is poured into a dilute aqueous solution of sodium sulfite (200 ml) and the organic is extracted with ether (2 x 200 ml). The extracts are combined and silica gel is added. The solvent is removed and the adsorbed conjugate is subjected to flash chromatography (90/10 petroleum ether / ethyl acetate) without purification. The recovered material was purified by high pressure liquid chromatography to give the recovered starting material (30.5%) and a white solid (0.835 g, 30%) as the title compound: mp. 212 to 213 占 폚; _{NMR (DMSO-d 6):} δ 8.09 (d, J = 8Hz, 1H), 7.64-7.58 (m, 1H), 7.54-7.42 (m, 5H), 7.43 (d, J = 8Hz, 1H), 3.47 _{(s, 3H, SO 3 CH} 3), 2.42 (s, 3H), 1.50 (s, 3H); MS (EI): [M ^&lt; ⁺ &^gt;] 508 (100%);

Elemental analysis for C ₂₁ H ₁₇ IO ₃ S ₂ :

Calculated: C, 49.61, H, 3.37, N, 0.00.

Found: C, 49.44, H, 3.52, N, 0.03.

Example 12

4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-

To a solution of methanesulfonic acid 4- (9-iodo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester (0.620 g) in N, N- dimethylformamide (0.270 ml, 2.68 mmol) and sodium hydroxide (0.107 g, 2.68 mmol) were added to a stirred suspension of copper (I) (0.192 g, 1.34 mmol) in dry argon atmosphere. The vessel is sealed and heated at 155 ° C for 9.5 hours. After stirring at ambient temperature for about 8 hours, the reaction mixture is poured into water, acidified with hydrochloric acid, and the organic is extracted with ether. The extracts are combined, filtered, washed with water and concentrated. The yellow solid residue was dissolved in dioxane (8 ml) and 2.5N sodium hydroxide solution (4.5 ml) was added. The vial is sealed and heated at 102 ° C. When the reaction is complete (as confirmed by thin layer chromatography), the mixture is cooled to room temperature, diluted with water, and acidified with hydrochloric acid. The organics are extracted with ether, combined with silica gel, and the solvent is removed. The adsorbent was flash chromatographed (gradient 90/10-85/15 petroleum ether / ethyl acetate) and the solvent was chased with benzene and petroleum ether to give the title compound as a white solid (0.426 g, 85%) is _{obtained: NMR (DMSO-d 6)} : δ 9.70 (s, 1H, OH), 8.40 (d, J = 8Hz, 1H), 7.56-7.51 (m, 2H), 7.44-7.40 (m, 1H), 3H), 1.62 (s, 3H); 7.25-7.12 (m, 5H), 7.02 (d, J = 7 Hz, 2H), 6.93 (d, J = 9 Hz, 2H). MS (EI): [M ^&lt; ⁺ &^gt;] 412 (100%);

Elemental analysis for C ₂₆ H ₂₀ OS ₂ :

Calculated: C, 75.69, H, 4.89, N, 0.00.

Found: C, 74.98, H, 4.86, N, 0.13

Example 13

(2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) -phenol

A solution of 4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) -phenol (0.414 g, 1.00 mmol) and potassium acetate 0.982 g, 10.0 mmol) was added dropwise a solution of bromine (0.114 ml, 2.21 mmol) in glacial acetic acid (2.50 ml) over 10 minutes at room temperature. When completely dissolved, precipitates appear. After stirring for 2 hours, the reaction is quenched with dilute aqueous sodium sulphate, added to water (100 mL), acidified with 10% hydrochloric acid and extracted with ether. The extract is washed with water, the layers are separated, allowed to stand overnight, then mixed with silica gel, and the solvent is removed. The adsorption binding was purified by flash chromatography (90/10 petroleum ether / ethyl acetate) to give the title compound as an off-white solid (0.391g, 58%): NMR (DMSO-d 6): δ 10.25 (s, 1H, OH ), 8.42 (d, J = 8 Hz, 1H), 7.65 (s, 2H), 7.60-7.47 (m, 3H), 7.24-7.19 (m, 3H), 7.15-7.00 , &Lt; / RTI &gt; 3H), 1.62 (s, 3H).

Example 14

Acetic acid 4- (9-Bromo-2-chloromethyl-3-methyl-naphtho [2,3- b] thiophen-

To a solution of the acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester (4.00 g, 9.4 mmol) in anhydrous methylene chloride Sulfuryl chloride (0.76 mL, 10.3 mmol) is added dropwise over 10 minutes to the cold (ice bath) solution. After stirring in an ice bath for 1 hour, the reaction was quenched with water (100 mL) and diluted with diethyl ether. After filtration, the layers are separated. The silica gel is added to the organic layer, and the solvent is separated. The adsorption binding was purified by flash chromatography to (gradient 90 / 10-80 / 20 petroleum ether / ethyl acetate) to give the title compound as a white solid (2.57g, 59%): NMR (DMSO-d 6): δ 8.23 ( (m, 2H), 5.09 (s, 2H), 2.34 (s, 2H), 7.71 (dd, J = 8.1 Hz, 1H), 7.55-7.43 3H), 1.66 (s, 3H).

Example 15

Methyl-naphtho [2,3-b] thiophen-4-yl) -phenol

(9-bromo-2-chloromethyl-3-methyl-naphtho [2,3-b] thiophen-4- yl) - Potassium carbonate (1.08 g, 7.83 mmol, 3 eq.) And morpholine (0.683 ml, 7.83 mmol, 3 eq.) Are added to a solution of phenyl ether (1.20 g, 2.61 mmol) at room temperature under a dry nitrogen atmosphere. After 1.75 hours additional morpholine (0.227 ml) is added and after 0.5 hours 2 equivalents (0.50 ml) of morpholine is added. After stirring for an additional hour, the reaction mixture is diluted with water (125 mL) and the organics are extracted with diethyl ether (400 mL). The layers are separated and the silica gel is added to the organic phase. The solvent was removed and the adsorbed conjugate was flash chromatographed (gradient 75 / 25-70 / 30 petroleum ether / ethyl acetate) to yield the title compound as a white solid (1.00 g, 82%): mp. 250 to 251 占 폚; _{NMR (DMSO-d 6):} δ 9.69 (s, 1H), 8.18 (d, J = 8Hz, 1H), 7.63 (ddd, J = 8, 7, 1Hz, 1H), 7.51-7.42 (m, 2H) 2H), 3.71 (s, 2H), 3.60 (t, J = 5 Hz, 4H), 2.50-2.48 (m, 4H) 1.65 (s, 3 H); MS (EI): [M ^&lt; ⁺ &^gt;], 1 bromine isotope pattern 467 (10%), 469 (10%);

Elemental analysis for C ₂₄ H ₂₂ BrNO ₂ S:

Calculated: C, 61.53, H, 4.73, N, 2.99.

Found: C, 61.53, H, 4.88, N, 3.01.

Example 16

Diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -acetate

To a solution of 4- (9-bromo-2-chloromethyl-3-methyl-naphtho [2,3- b] thiophen-4-yl) -acetate (1.27 g, 2.76 mmol) and potassium carbonate (1.146 g, 8.29 mmol) was added dimethyl amine (0.86 ml, 8.29 mmol) at room temperature under a dry nitrogen atmosphere. After stirring for 3 hours, additional dimethylamine (0.50 mL, 4.83 mmol) is added and the reaction mixture is stirred at room temperature for 3 hours and then stored cold (-14 &lt; 0 &gt; C) overnight. After further stirring at room temperature for 5 hours, the reaction mixture is diluted with water (100 mL). The organics are stirred with ether. The extracts are combined, silica gel is added and the solvent is removed. The absorption of water coupled to flash chromatography (gradient 85 / 15-80 / 20 petroleum ether / ethyl acetate) to give the title compound as a yellow solid (0.332g, 26%): NMR (CHCl 3): δ 8.29 (d, J = 8 Hz, 1H), 7.54-7.51 (m, 2H), 7.36-7.30 (m, 1H), 7.20 2H), 2.80-2.45 (broad s, 4H), 1.69 (s, 3H), 1.26-1.00 (broad s, 6H); MS (EI): M + M / Z 453 One bromine present, 301 (58%), 302 (16%), 303 (7%), 382 (100%), 383 (54% , 453 (30%), 455 (30%); MS [(+) ESI]: [M + H] = 496 (65%), 1 bromine isotope pattern; High resolution MS: Mass of sample for C ₂₅ H ₃₁ N ₃ O ₃ Cl [M + H], calculated 496.09459, found 496.09407, mass deviation 0.52 mmu;

Elemental analysis for C ₂₄ H ₂₄ BrNOS:

Calcd: C, 63.43, H, 5.32, N, 3.08.

Found: C, 62.33, H, 5.11, N, 2.75.

Example 17

Methyl-naphtho [2,3-b] thiophen-4-yl) -phenol

To a solution of 4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -acetate in 18 ml ofhydrofuran and methanol (0.676 g, 1.36 mmol) was added dropwise at room temperature an aqueous solution of potassium hydroxide (1N, 1.63 ml). After stirring for 1 hour, the solvent is removed. The residue is combined with water (50 ml) and acidified with 10% hydrochloric acid. The organic impurities are extracted with ether and released as a white solid at the two-phase interface. The sticky solid is filtered off, triturated with acetic acid and concentrated. This salt of the title compound is dissolved in tetrahydrofuran and methanol and combined with saturated aqueous sodium bicarbonate. After stirring for 20 minutes, the mixture is diluted with water and stirred for an additional 10 minutes. The organic material is extracted with ether. Wash the ether layer with brine and concentrated to give the title compound as a yellow solid (0.490g, 79%): NMR (DMSO-d 6): δ 9.69 (s, 1H, OH), 8.18 (d, J = 8Hz (D, J = 8 Hz, 2H), 7.91-7.59 (m, , 2.58-2.50 (m, 4H), 1.63 (s, 3H), 1.01 (t, J = 7 Hz, 6H).

Example 18

Methyl-naphtho [2, 3-b] thiophen-4-yl) -phenol &lt; / RTI &gt;

A solution of 4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -phenol (0.462 g) in glacial acetic acid / g, 1.07 mmol) in dichloromethane (5 mL) was added a solution of bromine (0.115 mL, 2.24 mmol, 2.2 eq.) in 9/1 acetic acid / water (4 mL). After stirring for 1.5 hours, the reaction mixture is quenched with dilute aqueous sodium sulphate, further diluted with water, and the organics are extracted with ether. The insoluble solid is taken up in the flask and stirred in ether overnight. The ether was removed and the solid (0.162 g, 0.265 mmol) was dissolved in tetrahydrofuran (100 mL) and 1 N aqueous sodium hydroxide solution (0.265 mL, 0.265 mmol). After stirring for 20 minutes, the solvent is removed and the residue is stirred in water (100 mL). Water is removed and the residue is stirred in petroleum ether overnight. The solvent is removed. The residue is dissolved in tetrahydrofuran / ether and silica gel is added. The solvent was removed and the adsorbed compound was flash chromatographed (75/25 petroleum ether / ethyl acetate) to give the desired compound as a white solid (0.113 g, 17%): (DMSO-d ₆ ) 2H), 7.50-7.48 (m, 2H), 3.76 (s, 2H), 7.20 (s, 2H), 3.28-2.60 (m, 4H), 1.02 (t, J = 7 Hz, 5H); (22%), 538 (68%), 540 (80%), 541 (52%), 611 (22%). , 613 (22%);

Elemental analysis for C ₂₄ H ₂₂ Br ₃ NOS:

Calculated: C, 47.08, H, 3.62, N, 2.29.

Found: C, 47.21, H, 3.69, N, 2.21.

Example 19

Methyl-2-morpholin-4-ylmethyl-naphtho [2,3-b] thiophen-4- yl) -phenol

Methyl-2-morpholin-4-ylmethyl-naphtho [2,3-b] thiophen-4-yl) - (4- Phenol (0.854 g, 1.82 mmol) is added to a solution of bromine (0.207 ml, 4.01 mmol) in 9/1 acetic acid / water (1 ml). After stirring for 3 hours, the reaction was diluted with water (200 mL) and the organics were extracted several times with diethyl ether. The extracts were combined, concentrated and chased with benzene to give the title compound as a yellow solid (1.18 g) in quantitative yield: mp. 237 to 240 캜; NMR (pyridine _{-d 5): δ 8.43 (dd} , J = 8, 1Hz, 1H), 7.81 (s, 2H), 7.71 (d, J = 8Hz, 1H), 7.62 (m, 1H), 7.50 (m 2H), 2.55 (t, J = 4 Hz, 4H), 1.78 (s, 3H); MS (EI): [M ⁺ ], 3 bromine isotope pattern, 622 (8%), 624 (18%), 626 (19%), 628 (8%);

Elemental analysis for C ₂₄ H ₂₀ Br ₃ NO ₂ S:

Calcd: C, 46.03, H, 3.22, N, 2.24.

Found: C, 45.07, H, 3.31, N, 2.05.

Example 20

Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-nitro-phenol

Ethanol (40 ml) was added to a solution of 4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- 4-yl) phenol (1.98 g, 5.17 mmol) 2.09 g, 5.17 mmol), and the resulting dark blue solution is heated in an oil bath at 45 DEG C for 14 hours. The reaction mixture is added to dilute HCl and extracted with ether. The silica gel is added to the ether phase and the solvent is removed. Flash column (95: 5 petroleum ether: ethyl acetate) gave the title compound as an orange solid (1.63 g, 74%): mp. 183 to 185 캜; _{NMR (DMSO-d 6):} δ 11.31 (s, 1H), 8.21 (d, J = 8Hz, 1H), 7.85 (d, J = 2Hz, 1H), 7.66 (ddd, J = 8, 6, 1Hz, J = 8 Hz, 1H), 7.59 (dd, J = 8, 2 Hz, 1H), 7.48 (dd, J = , 2.44 (d, J = 1 Hz, 3 H), 1.61 (d, J = 1 H, 3 H); MS (EI): 1 bromine isotope pattern 427 (95%, MI), 429 (100%);

Elemental analysis for C ₂₀ H ₁₄ BrNO ₃ S:

Calculated: C, 56.09, H, 3.29, N, 3.27.

Found: C, 55.55, H, 3.15, N, 3.23.

Example 21

2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-

A solution of bromine (0.040 ml, 0.756 mmol) in acetic acid (0.5 nL) was added to a solution of 4- (9-bromo-2,3-dimethyl- 2-nitro-phenol (0.20 g, 0.467 mmol) and potassium acetate (0.228 g, 2.335 mmol). After 10 minutes, water is added and the reaction mixture is extracted with ether. The silica gel is added to the ether phase and the solvent is removed. Flash column (gradient: 95: 5 to 85: 5) affords the title compound as a yellow solid (0.141 g, 60%): mp. 128 to 130 캜; _{NMR (DMSO-d 6):} δ 11.30 (s, 1H), 8.22 (d, J = 8Hz, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.67 (quintuplet, J = 4Hz, 1H ), 7.51 (d, J = 4 Hz, 2H), 2.45 (s, 3H), 1.65 (s, 3H); MS (EI): 2 bromine isotope pattern 505 (40%), 507 (100%), 509 (50%);

Elemental analysis for C ₂₀ H ₁₃ Br ₂ NO ₃ S:

Calcd: C, 47.36, H, 2.58, N, 2.76.

Found: C, 47.18, H, 2.55, N, 2.63.

Example 22

Amino-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-

See Tet Lett. Montmorillinite K10 clay (425 mg) was reacted with 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophene- -2-nitro-phenol (0.608 g, 1.42 mmol), anhydrous hydrazine (0.276 L, 8.95 mmol) and ethanol (4.2 mL) and the suspension is heated at 85 <0> C for 30 min. The reaction mixture is cooled to room temperature, added to water and extracted with ether. The ether was dried and concentrated to give the title compound as a white solid (0.576 g, 100%): mp. 173-175 占 폚; _{NMR (DMSO-d 6):} δ 9.26 (s, 1H), 8.14 (dd, J = 8, 1Hz, 1H), 7.63-7.58 (m, 2H), 7.42 (ddd, J = 8, 6, 1Hz, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H), 6.54 (d, J = 2 Hz, 1H) 3H), 1.69 (s, 3H); MS (+ FAB): 1 bromine isotope pattern 398 (30%, M + H), 400 (30%, M + H);

Elemental analysis for C ₂₀ H ₁₆ BrNOS:

Calculated: C, 60.31, H, 4.05, N, 3.52.

Found: C, 61.36, H, 4.08, N, 3.25.

Example 23

2-Amino-6-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-

See Tet Lett. Bromo-2, 3-dimethyl-naphtho [2,3-d] pyrimidin- 2-nitro-phenol (1.2 g, 2.37 mmol), anhydrous hydrazine (1 ml) and ethanol (7.2 ml) and the suspension is heated at 85 ° C for 1 hour . The reaction mixture is cooled to room temperature and concentrated. The title compound is obtained as a white solid (0.741 g, 66%), by flash chromatography twice (eluent: ether, twice, eluent: 4: 1 petroleum ether: ethyl acetate) _{DMSO-d 6): δ 8.16} (ddd, J = 8, 1, 1Hz, 1H), 7.65-7.50 (m, 2H), 7.47 (ddd, J = 8, 6, 1Hz, 1H), 6.65 (d, J = 2 Hz, H), 6.57 (d, J = 2 Hz, 1H), 2.43 (d, J = 1 Hz, 3H), 1.73 (d, J = 1 Hz, 3H); MS (EI): 2 bromine isotopic pattern 475 (50%, M + H), 477 (100%, M + H), 479 (50%, M + H);

Elemental analysis for C ₂₀ H ₁₅ Br ₂ NOS:

Calcd: C, 50.34, H, 3.17, N, 2.94.

Found: C, 51.35, H, 3.35, N, 2.72.

Example 24

2-Nitro-phenoxy] -acetic acid &lt; RTI ID = 0.0 &gt;

Methyl bromoacetate (0.150 ml, 1.58 mmol) was added to a solution of potassium carbonate (0.223 g, 1.61 mmol) and 2-bromo-4- (9-bromo-2,3- dimethyl-naphtho [ 2,3-b] thiophen-4-yl) -2-nitro-phenol (0.400 g, 0.789 mmol). After 15 h, the reaction mixture is added to water and extracted with ethyl acetate. The silica gel is added to ethyl acetate and the solvent is removed. Flash adsorbed (9: 1 petroleum ether: ethyl acetate) gave the title compound as a yellow solid (0.305 g, 67%). The solid (0.050 g, 0.086 mmol) was dissolved in 1: 1 THF: methanol (2 mL) and treated with aqueous potassium hydroxide (1.0 N, 0.30 mL, 0.30 mmol). After 25 minutes, the reaction mixture is diluted with water, acidified with 10% aqueous HCl and extracted with ether. The ether phase was dried (sodium sulfate), concentrated and recrystallized from petroleum ether: ether to give the title compound as a white solid (0.025 g, 51%): mp. 228 to 229 ℃: NMR (DMSO-d 6): δ 8.23 (d, J = 9Hz, 1H), 8.14 (d, J = 2Hz, 1H), 8.04 (d, J = 2Hz, 1H), 7.69 (ddd J = 8 Hz, 1H), 4.87 (d, J = 6 Hz, 1H), 4.82 (d, J = (d, J = 6 Hz, 1 H), 2.46 (s, 3 H), 1.62 (s, 3 H); MS (+ FAB): 2 bromine isotope pattern 563 (40%), 565 (100%), 567 (50%);

Elemental analysis for C ₂₂ H ₁₅ Br ₂ NO ₅ S:

Calcd: C, 46.75, H, 2.68, N, 2.48.

Found: C, 45.18, H, 2.66, N, 2.38.

Example 25

(S) -2-hydroxy-3-phenylpropionic acid, methyl ester

A solution of commercially available (S) -2-hydroxy-3-phenylpropionic acid (5.0 g, 30.1 mmol) and p-toluenesulfonic acid hydrate (1 g) in methanol (125 mL) was treated with 4A molecular sieves Reflux while removing water. The solution is concentrated and dissolved in ether. Wash the ether solution with saturated sodium bicarbonate, brine, and concentrated to give the title compound as a white solid (5.32g, 98%): NMR (CDCl 3): δ 73.6-7.20 (m, 5H), 4.47 (ddd, J = 5, 14 Hz, 1H), 2.97 (dd, J = 7, 14 Hz), 2.69 (d, J = 6 Hz, 1H) 1H).

Example 26

(S) -2- [4-nitrobenzoyl] -4-phenylbutyric acid, ethyl ester

(1.86 ml, 9.60 mmol), p-nitrobenzoic acid (6.42 g, 38.4 mmol, 4 eq.) In anhydrous tetrahydrofuran (110 ml) (6.05 mL, 38.4 mmol, 4 eq.) Was added dropwise over 40 minutes to a cold (ice bath) solution of triphenylphosphine (10.07 g, 38.4 mmol, 4 eq) Gt; 5 C. &lt; / RTI &gt; After stirring for an additional hour at 4 to 5 &lt; 0 &gt; C, the ice bath is removed and the solution is stirred at ambient temperature for 5 days. The solvent is removed and the residue is redissolved in a mixture of ether and ethyl acetate (600 mL). Silica gel (200 ml) was added and the solvent was removed. The absorption of water coupled by flash chromatography to (gradient 80/20 70/30 petroleum ether / ethyl acetate) to give the title compound as a yellow oil _{(4.03g): NMR (CDCl 3} ): δ 8.30 (d, J = 9Hz , 2H), 8.18 (d, J = 9 Hz, 2H), 7.38-7.18 (m, 5H), 5.28 (t, J = 2 Hz, J = 8 Hz, 2H), 2.40-2.33 (m, 2H), 1.29 (t, J = 7H, 3H); MS [(+) FAB]: [M + H] m / z = 358.

Example 27

(S) -2-hydroxy-4-phenylbutyric acid, ethyl ester

To a suspension of potassium cyanide (0.176 g, 2.70 mmol) in pure ethanol (43 ml) was added (S) -2- [4-nitrobenzoyl] -4-phenylbutyric acid, ethyl ester (3.86 g, 10.8 mmol) is added dropwise over 0.5 hours. After stirring for 2.25 hours, the solvent is removed, the residue is diluted with water and acidified with dilute hydrochloric acid. The organic material is extracted with ether. The extracts are combined, silica gel (60 ml) is added and the solvent is removed. The adsorbate was flash chromatographed and the eluent (gradient 90/10- 80/20 petroleum ether / ethyl acetate) and the solvent was quenched with benzene to give the title compound as a yellow oil (1.67 g, 74%): NMR _{(CDCl 3): 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) ; _{^{[a] 25 D +178.23 at 10.98mg}} / mL CHCl 3.

Example 28

(R) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [ 3-phenyl-propionic acid methyl ester

Diethylazodicarboxylate (0.262 ml, 1.67 mmol) was added to a solution of 2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [ (0.60 g, 1.11 mmol), (S) -2-hydroxy-3-phenylpropionic acid, methyl ester (0.300 g, 1.67 mmol), triphenylphosphine (0.437 g, 1.67 mmol) 5 ml) at room temperature, and the solution is heated in an 80 占 폚 oil bath for 6 hours. Upon cooling to room temperature, the reaction mixture is diluted with ether and silica gel (30 mL) is added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (95: 5 petroleum ether: ethyl acetate) to yield the title compound as a white solid (0.76 g, 97%): mp. 174-175 占 폚; _{NMR (DMSO-d 6):} δ 8.21 (ddd, J = 8, 1, 1Hz, 1H), 7.74 (d, J = 2Hz, 1H), 7.73 (d, J = 2Hz, 1H), 7.67 (ddd, J = 8, 6, 1 Hz, 1H), 7.53 (ddd, J = 8,7,1 Hz, 1H), 7.43 (d, J = 8 Hz, 1H), 7.35-7.24 J = 7, 6 Hz, 1H), 3.61 (s, 3H), 3.43 (dd, 13, 6 Hz, 1H), 3.40 (d, J = 1 Hz, 3H); MS (+ FAB): 3 bromine isotope pattern 700 (20%), 702 (70%), 704 (75%), 706 (25%);

Elemental analysis for C ₃₀ H ₂₃ Br ₃ O ₃ S:

Calculated: C, 51.23, H, 3.30, N, 0.00.

Found: C, 51.52, H, 3.36, N, 0.12.

Example 29

(R) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [ 3-phenyl-propionic acid

Aqueous potassium hydroxide (1N, 2.00 ml, 2.00 mmol) was added to a solution of (R) -2- [2,6-dibromo-4- (9- 3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3-phenylpropionic acid methyl ester (0.699 g, 0.99 mmol). After 3 h, the solution is concentrated, diluted with water (100 mL) and acidified with 10% aq. HCl. The solid was filtered, washed with water, triturated with petroleum ether and dried under vacuum to give the title compound as a white solid (0.645 g, 94%): [a] D ²⁵ = + 14.29. ₃ ); _{NMR (DMSO-d 6):} δ 8.19 (d, J = 8H, 1H), 7.66 (ddd, J = 8, 7, 1Hz, 1H), 7.61 (s, 2H), 7.52 (ddd, J = 8, 7, 1 Hz, 1H), 7.41 (d, J = 8 Hz, 1H), 7.38-7.20 (m, 5H), 5.27 (dd, 14, 7 Hz, 1 H), 2.43 (s, 3H), 1.59 (s, 3H); MS (+ FAB): 3 bromine isotope pattern 686 (20%), 688 (75%), 690 (75%), 692 (25%);

Elemental analysis for C ₂₉ H ₂₁ Br ₃ O ₃ S:

Calculated: C, 50.53, H, 3.07, N, 0.00.

Found: C, 50.04, H, 3.11, N, 0.05.

Example 30

(R) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethylnaphtho [2,3- b] thien-4- yl) -phenoxy]

To a solution of 2,6-dibromo-4- (9-bromo-2,3-dimethylnaphtho [2,3-b] thien-4-yl) -phenol (0.300 g, 0.554 (0.131 ml, 0.831 mmol) was added to a solution of commercially available methyl (S) - (-) - lactate (0.079 ml, 0.831 mmol) and triphenylphosphine (0.218 g, 0.831 mmol) ) Is added dropwise at room temperature for 10 minutes under a dry nitrogen atmosphere. The reaction mixture is heated at reflux temperature for 4 hours and left stirring for 24 hours at ambient temperature. The reaction mixture is diluted with diethyl ether and combined with silica gel. The solvent was removed and the adsorbate was flash chromatographed (75/25 petroleum ether / methylene chloride) to give a white solid (0.283 g, 81%). Potassium hydroxide (1 N, 0.498 ml, 0.498 mmol) was added dropwise to a solution of the solid (0.260 g, 0.415 mmol) in tetrahydrofuran (9 ml) and methanol (3 ml) at room temperature. After stirring for 1.5 hours, the solvent is removed. The residue is combined with water and acidified with 10% aqueous hydrochloric acid. Add diethyl ether and stir for 10 minutes, then shake well and separate the two phases. The organic phase was washed with brine, concentrated and chased with petroleum ether to give the title compound as a white solid (0.257 g, 99%): mp. 224-225 占 폚; _{NMR (DMSO-d 6):} δ 13.09-13.06 (borad s, 1H, COOH), 8.20 (d, J = 8Hz, 1H), 7.75 (s, 2H), 7.67 (ddd, J = 8, 7, 1Hz 2H), 5.02 (q, J = 7 Hz, 1H), 2.44 (s, 3H), 1.62 (s, 3H), 1.56 (d, J = 6 Hz, 3H); 7.55-7.47 (m, 2H). MS (+ FAB): [M ⁺ ], 3 bromine isotope pattern 609.7 (30%), 611.8 (75%), 613.8 (100%), 615.7 (35%); And decomposition MS [(FAB) + ve] C 23 H 17 Br 3 O 3 S samples for mass, calculated: 609.84485, measured value: 609.85789, mass deviation 13.04 mmu.

Elemental analysis for C ₂₃ H ₁₇ Br ₃ O ₃ S:

Calcd: C, 45.05, H, 2.79, N, 0.00.

Found: C, 44.30, H, 2.69, N, 0.38.

Example 31

(S) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- 4-phenyl-butyric acid

(9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol 9) and commercially available (R) -2-hydroxy-4-phenyl-butyrate, ethyl ester. White solid: mp. 176-177 占 폚; _{^{[a] 25 /D=+7.58.(10.692mg/mL, CHCl 3}} ); _{NMR (DMSO-d 6):} δ 13.0 (broad s, 1H, COOH), 8.21 (ddd, J = 8, 7, 1Hz, 1H), 7.73 (s, 2H), 7.67 (ddd, J = 8, 7 2H), 7.24-7.18 (m, 3H), 5.03 (t, 2H), 7.52 (ddd, J = 8,7,1 Hz, 1H), 7.46 J = 6 Hz, 1H), 2.95 (m, 1H), 2.72 (m, 1H), 2.44 (s, 3H), 2.28 (m, 2H), 1.61 MS (+ FAB): [M +], 3 bromine isotope pattern 700 (30%), 702 (100%), 704 (75%), 706 706 (40%);

Elemental analysis for C ₃₀ H ₂₃ Br ₃ O ₃ S:

Calculated: C, 51.23, H, 3.30, N, 0.00.

Found: C, 51.15, H, 3.13, N, 0.00.

Example 32

(R) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -Phenyl-butyric acid

(9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol 9) and (S) -2-hydroxy-4-phenyl-butyrate, ethyl ester (example 27). White ^{solid:. [A] 25 /D=-12.187 (} 9.929mg / mL, CHCl 3); _{NMR (DMSO-d 6):} δ 13.24 (s, 1H), 8.21 (d, J = 8Hz, 1H), 7.73 (s, 2H), 7.67 (ddd, J = 8, 7, 1Hz, 1H), 7.52 2H), 7.24-7.20 (m, 3H), 5.02 (d, J = 6 Hz, 1H), 2.99-2.86 (m, 1H), 2.75-2.65 m, 1 H), 2.45 (s, 3 H), 2.30 - 2.20 (m, 2 H), 1.61 (s, 3 H); MS (+ FAB): [M +], 3 bromine isotope pattern 700 (30%), 702 (100%), 704 (90%), 706 (55%);

Elemental analysis for C ₃₀ H ₂₃ Br ₃ O ₃ S:

Calculated: C, 51.23, H, 3.30, N, 0.00.

Found: C, 51.33, H, 3.33, N, 0.29.

Example 33

(2,3-b] thiophen-4-yl) -phenoxy] - &lt; / RTI &gt; -3-phenyl-propionic acid

(2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) -phenol was prepared according to the procedure of Example 30 Example 13) and (S) -2-hydroxy-3-phenylpropionic acid, methyl ester. White solid: optical rotation _{[α] 25 / D = +22.84} (10.068mg / ㎖, CHCl 3) NMR (DMSO-d 6):. Δ 13.13 (broad s, 1H), 8.42 (d, J = 8Hz, 1H (Ddd, J = 8, 7, 1 Hz, 1H), 7.50 (ddd, J = 8, 7, 1 Hz, 1H), 7.44 2H), 5.22 (t, J = 7 Hz, 1H), 3.37-3.28 (m, 2H), 7.33-7.19 (m, 7H), 7.15-7. , 2.39 (s, 3 H), 1.62 (s, 3 H); MS (EI): [M ⁺ ], 2 bromine isotope pattern 716 (10%), 718 (20%), 720 (10%);

Elemental analysis for C ₃₅ H ₂₆ Br ₂ O ₃ S ₂ :

Calculated: C, 58.50, H, 3.65, N, 0.00.

Found: C, 58.77, H, 3.94, N, 0.16.

Example 34

(2,3-b] thiophen-4-yl) -phenoxy] - &lt; / RTI &gt; - propionic acid

(2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) -phenol was prepared according to the procedure of Example 30 Example 13) and commercially available methyl (S) - (-) - lactate. White solid: mp. 237 to 239 캜; _{^{[a] 25 /D=-1.99.(10.051mg/mL, CHCl 3}} ); _{NMR (DMSO-d 6):} δ 13.2 (broad s, 1H, COOH), 8.43 (d, J = 8Hz, 1H), 7.80 (s, 2H), 7.62-7.58 (m, 1H), 7.56-7.50 ( 3H), 1.63 (s, 3H), 1.57 (m, 2H), 7.23-7.13 (m, 3H), 7.04-7.01 (m, 2H), 5.03 (quartet, d, J = 8 Hz, 3H); MS (EI): [M @ ⁺ ], 2 bromine isotopic pattern 640 (47%), 642 (100%), 644 (56%);

Elemental analysis for C ₂₉ H ₂₂ Br ₂ O ₃ S ₂ :

Calculated: C, 54.22, H, 3.45, N, 0.00.

Found: C, 53.64, H, 3.33, N, 0.05.

Example 35

2-morpholin-4-ylmethyl-naphtho [2,3-b] thiophen-4-yl) - Phenoxy] -3-phenyl-propionic acid

Methyl-2-morpholin-4-yl-methyl-naphtho [2,3-b] thiophen-4- ) -Phenol (example 19) and commercially available methyl (S) - (-) - lactate. Yellow solid: Optical rotation, [[alpha]] = +26.512. (10.184 mg / ml), DMSO); NMR (pyridine _{-d 5): δ 8.41 (d} , J = 9Hz, 1H), 7.84 (dd, J = 3, 1Hz, 2H), 7.70 (d, J = 7Hz, 2H), 7.43-7.32 (m, 4H), 3.66 (s, 2H), 2.53 (s, 4H), 1.70 (s, 2H) 3H); MS (+ FAB): [(M + H) ⁺ ], 3 bromine isotopes 772 (20%), 774 (35%), 776 (45%);

HRMS, [M + H], mass calculated for the formula C ₃₃ H ₂₉ NO ₄ SBr ₃ , calculated: 771.93674; Found: 771.93954, mass deviation 2.80 mmu.

Elemental analysis for C ₃₃ H ₂₈ Br ₃ NO ₄ S:

Calculated: C, 51.18, H, 3.64, N, 1.81.

Found: C, 51.57, H, 3.86, N, 1.73.

Example 36

2-morpholin-4-ylmethyl-naphtho [2,3-b] thiophen-4-yl) - Phenoxy-propionic acid

Methyl-2-morpholin-4-yl-methyl-naphtho [2,3-b] thiophen-4- yl) -Phenol (example 19) and (S) -2-hydroxy-3-phenyl-propionic acid, methyl ester (example 25). Yellow solid: [a] ₂₅ / D = +13.84. (10.043 mg / ml, DMSO); NMR (pyridine _{-d 5): δ 8.42 (d} , J = 8Hz, 1H), 7.88 (s, 2H), 7.63 (m, 2H), 7.41 (m, 1H), 5.61 (q, J = 4Hz, 1H ), 3.78 (t, J = 4 Hz, 4H), 3.70-3.63 (m, 3H), 2.56 (s, 4H), 1.97 (d, J = 7 Hz, 3H), 1.71 MS (+ FAB): [(M + H) ⁺ ], 3 bromine isotope pattern 696 (35%), 698 (100%), 700 (80%), 702 (40%);

Elemental analysis for C ₂₇ H ₂₄ Br ₃ NO ₄ S HCl:

Calculated: C, 44.14, H, 3.43, N, 1.91.

Found: C, 44.94, H, 3.85, N, 1.83.

Example 37

(R) -2- [2,6-dibromo-4- (9-bromo-2-diethylaminomethyl- -Phenoxy] -3-phenyl-propionic acid

(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4- yl) -Phenol (example 18) and (S) -2-hydroxy-3-phenyl-propionic acid, methyl ester (example 25). White _{solid: NMR (DMSO-d 6)} : δ 13.3 (broad band, 1H), 8.20 (d, J = 8Hz, 1H), 7.70 (s, 2H), 7.66 (ddd, J = 8, 7, 1Hz, 1H), 7.51 (ddd, J = 8, 7, 1 Hz, 1H), 7.40-7.25 (m, 6H), 5.21 (t, J = 7 Hz, 1H) = 4, 3 Hz, 2H), 2.55 (q, J = 7 Hz, 4H), 1.63 (s, 3H), 1.02 (t, J = 7 Hz, 6H); 758 (25%), 760 (80%), 762 (75%), 764 (35%), 689 &lt; RTI ID = 0.0 &gt;(100%); HPLC analysis, Primesphere 5C-18 column, eluant 62% acetonitrile for 15 minutes with a purity of 97.8%; High resolution MS (FAB) + ve: Mass of sample for formula C ₃₃ H ₃₁ NO ₃ Br ₃ as [M + H], calculated: 759.95556, found: 759.97370 Mass deviation: 18.14 mmu.

Example 38

2-Nitro-phenoxy] -3-phenyl-propionic acid (2-bromo-4-

(9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-nitro-phenol (prepared according to the procedure of Example 30 Example 21) and (S) -2-hydroxy-3-phenyl-propionic acid, methyl ester (example 25). White solid: mp. 243 to 245 占 폚; _{NMR (DMSO-d 6):} δ 11.30 (broad s, 1H), 8.23, 8.22 (2d, J = 3Hz, 1H), 8.06, 8.04 (2d, J = 3Hz, 1H), 7.95 (t, J = 2 1H), 7.68 (m, 1H), 7.56-7.50 (m, 1H), 7.45 (d J = 8 Hz, 1H), 7.34-7.24 (m, 6H), 5.28, 5.22 ), 3.40-3.23 (m, 2H), 4.82 (d, J = 6 Hz, 1H), 2.46 (s, 3H), 1.59, 1.57 (2s, 3H); MS (+ FAB): 2 bromine isotope pattern 653, 655, 657;

Elemental analysis for C ₂₉ H ₂₁ Br ₂ NO ₅ S:

Calculated: C, 53.15, H, 3.23, N, 2.14.

Found: C, 53.77, H, 3.73, N, 2.04.

Example 39

Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl)

Step 1 2-Isopropyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-

Propyl-p-anisic acid (3.0 g, 16.5 mmol, RN-33537-78-9), oxalyl chloride (1.7 mL, 19.5 mmol), N, (IV) (2.1 ml, 18.2 mmol) and anhydrous methylene chloride (65 ml) were added to a solution of 2-amino-2- , The title compound is obtained as a dark red oil (6.5 g) which is used without further purification.

In analogy to the procedure of example 49, step 2, from (2-benzyl-4,5-dimethyl-thiophen-3-yl) - , 17.8mmol), to give the title compound from boron tribromide (9.4㎖, 99mmol) and methylene chloride (75㎖) as a yellow solid (1.7g, 27%): NMR (DMSO-d 6): δ 9.49 (s 2H), 3.32 (m, 1H), 2.39 (s, 2H), 8.42 (s, 1H), 7.94 (d, 1H), 7.47-7.32 s, 3H), 1.59 (s, 3H), 1.19 (d, 6H).

Step 2 A mixture of 2-isopropyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-

(2,3-b] thiophen-4-yl) -phenol (0.5 g, 1.4%) was obtained in a manner similar to the step of Example 49, mmol), to give the title compound was prepared from acetic anhydride (0.17㎖, 1.8mmol) and pyridine (3.5㎖) as a white solid (0.48g, 86%): NMR (DMSO-d 6): δ 8.49 (s, 1H) 3H), 2.37 (s, 3H), 1.56 (s, 3H), 8.00-7.96 (d, 1H), 7.48-7.31 , &Lt; / RTI &gt; 3H), 1.16 (d, 6H).

Step 3 Acetic acid 2-isopropyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-

(2,3-b] thiophen-4-yl) -phenyl ester (0.38 g, 0.20 mmol) was reacted in analogy to the procedure described in example 49, step 4, The title compound is obtained as a white solid (0.40 g, 88%): (DMSO-d6) from the ferric chloride (8 mg, 0.51 mmol), bromine (0.055 ml, 1.1 mmol) and methylene chloride _{d 6): δ 8.20 (d} , 1H), 7.67-7.62 (m, 1H), 7.52-7.43 (m, 2H), 7.34 (d, 1H), 7.22 (m, 2H), 3.09 (septet, 1H) , 2.43 (s, 3H), 2.37 (s, 3H), 1.54 (s, 3H), 1.16 and 1.15 (2 doublets, 6H, rotamers); MS (EI): [M ^&lt; ⁺ &^gt;], 1 bromine isotope pattern 466/468;

Elemental analysis for C ₂₅ H ₂₃ BrO ₂ S:

Calculated: C, 64.24, H, 4.96, N, 0.00.

Found: C, 63.84, H, 4.90, N, 0.06.

Step 4 2-Isopropyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-

(9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl The title compound was obtained as a cream solid (0.35 g, 99%) from the ester (0.39 g, 0.83 mmol), aqueous potassium hydroxide (1.0 mL of a 1N solution, 1.0 mmol), tetrahydrofuran (14 mL) and methanol do. _{NMR (DMSO-d 6):} δ 9.56 (s, 1H), 8,17 (d, 1H), 7.64-7.60 (ddd, 1H), 7.53-7.52 (d, 1H), 7.46-7.42 (ddd, 1H ), 7.03 (d, IH), 6.97-6.91 (m, 2H), 3.31-3.28 (m, IH), 2.42 (s, 3H), 1.58 (s, 3H), 1.16 (d, 6H); MS (EI): [M ^&lt; ⁺ &^gt;], 1 bromine isotope pattern 424/426;

Elemental analysis for C ₂₃ H ₂₁ BrOS:

Calculated: C, 64.94, H, 4.98, N, 0.00.

Found: C, 64.11, H, 4.99, N, 0.03

Step 5 2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-

To a solution of 2-isopropyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4-yl) -phenol (0.35 g, 0.81 mmol) in glacial acetic acid (11 ml) To a suspension of potassium acetate and potassium acetate (0.80 g, 8.11 mmol) was added dropwise a solution of bromine (0.05 ml, 0.97 mmol) in glacial acetic acid (1.5 ml) at room temperature. Rinse the pipette and flask with 1 ml of additional acetic acid. After stirring at room temperature for 4 hours, quench the reaction with a small amount of dilute sodium sulphate and dilute with water (100 mL). The white solid was collected on a sintered glass funnel, washed well with water, and dried (NaSO ₄ ) to give the title compound as a white solid (0.40 g, 98%): mp. 157 to 162 占 폚; _{(DMSO-d 6): δ} 9.20 (s, 1H), 8.19 (d, 1H), 7.66-7.61 (m, 1H), 7.49-7.48 (m, 2H), 7.35 (d, 1H), 7.13 (d , 1H), 3.40 (septet, 1H), 2.42 (s, 3H), 1.60 (s, 3H), 1.16 (d, 6H); MS (+ FAB): [M + H], 2 bromine isotope pattern 502 (12%), 504 (30%), 506 (18%);

Elemental analysis for C ₂₃ H ₂₀ Br ₂ O ₄ S:

Calculated: C, 54.78, H, 4.00, N, 0.00.

Found: C, 53.67, H, 3.84, N, 0.03.

Example 40

(R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- ] -3-phenyl-propionic acid

Step 1 Synthesis of (2R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Phenoxy] -3-phenylpropionic acid methyl ester

Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-d] pyrimidin- 2-hydroxy-3-phenylpropionic acid, methyl ester (0.19 g, 1.1 mmol), triphenyl (triphenylphosphine) Obtained the title compound as a white solid (0.27 g, 56%), MS: (M + H) +. _{-d 6): δ 8.20 (d} , 1H), 7.70-7.60 (m, 1H), 7.60-7.40 (m, 2H), 7.40-7.20 (m, 7H), 5.07 and 4.95 (2 triplets, 1H, rotation (2 s, 3H, rotamer), 3.40-3.20 (m, 3H), 2.45 and 2.43 (2 singlets, 3H, rotamer), 1.59 and 1.53 , 1.20-1.00 (m, 6H).

Step 2 (2R) -2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Phenoxy] -3-phenyl-propionic acid

In a manner similar to that of Example 49, Step 7, (2R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl- (0.26 g, 0.52 mmol), aqueous potassium hydroxide (1.1 mL of a 1N solution, 1.1 mmol), tetrahydrofuran (6 mL), and tetrahydrofuran And methanol (2 ml), the title compound was obtained as a white solid (0.23 g, 68%): Rot. [a] 25 / D = + 38.9 (9.970mg / mL, CHCl 3).; _{(DMSO-d 6): δ} 13.1 (broad s, 1H); (M, 2H), 7.40-7.38 (m, 1H), 7.35-7.30 (m, 4H), 7.29-7.23 ), 5.00 (m, 1H), 3.55 (septet, 1H), 3.35 (m, 2H), 2.42 and 2.43 (2 singlets, 3H, rotamer), 1.57 and 1.52 -1.03 (m, 6H); MS (+ FAB): [M +], 2Bromine isotope pattern 650 (15%), 652 (30%), 654 (21%);

Elemental analysis for C ₃₂ H ₂₈ Br ₂ O ₃ S:

Calculated: C, 58.91, H, 4.33, N, 0.00.

Found: C, 58.72, H, 4.45, N, 0.10.

Example 41

(R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4- yl) -2-isopropyl- phenoxy]

Step 1 A solution of (R) -2- [4- (2,3-dimethyl-naphtho [2,3- b] thiophen- 4- yl) -2-isopropyl-phenoxy] ester

(2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2 (tert-butoxycarbonyl) amide in a similar manner to Example 49, Step 6, 3-phenylpropionic acid, methyl ester (0.62 g, 3.5 mmol), triphenylphosphine (0.91 g, 3.5 mmol), di (tert-butyldimethylsilyl) ethyl azodicarboxylate (0.54㎖, 3.5mmol) and yields the title compound from anhydrous benzene (7.0㎖) as a yellow oil (0.18g, 41%): NMR (DMSO-d 6): δ 8.40 (s, 1H ), 7.90 (d, 1H), 7.50-7. 20 (m, 6H), 7.20-7.00 (m, 3H), 7.00-6.80 (2 doublets, 3H, rotamer), 3.30-3.20 (m, 3H), 2.40 (s, 3H), 1.50 .

Step 2 A mixture of (R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4- yl) -2-isopropyl- phenoxy]

In a manner similar to that of Example 49, Step 7, (R) -2- [4- (2,3-dimethyl-naphtho [2,3- b] thiophen- -Phenoxy] -3-phenyl-propionic acid methyl ester (0.18 g, 0.35 mmol), aqueous potassium hydroxide (0.71 ml of a 1N solution, 0.71 mmol), tetrahydrofuran (6 ml) and methanol (2 ml) was obtained as a white solid (0.072g, 41%): NMR (DMSO-d 6): δ 13.10 (broad s, 1H), 8.43 (d, 1H), 7.49 (dd, 1H), 7.46-7.29 (m, (M, 3H), 2.38 and 2.37 (m, 2H), 7.28-7.22 (m, 1H), 7.10-7.03 2 singlets, 3H, rotamer), 1.53 and 1.51 (2 singlets, 3H, rotamer), 1.15 and 1.14 (2 doublets, 3H, rotamer), 1.03 (d, 3H); MS (EI): [M &lt; + &gt;]494;

Elemental analysis for C ₃₂ H ₃₀ O ₃ S:

Calculated: C, 77.70, H, 6.11, N, 0.00.

Found: C, 75.71, H, 6.29, N, 0.03.

Example 42

(R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Yl] -3-phenyl-propionic acid

Step 1 2-sec-Butyl-4- (2,3-dimethyl-naphtho [2,3- b] thiophen-

(3.0 g, 14.4 mmol, M. Derenberg and P. Hodge, Tetrahedron Lett. 1971, 3825-3828 (Prepared by the method of DG Davies, et al., J. Chem. Soc. (C) 1971, 455-460), oxalyl chloride (1.4 ml, 15.8 mmol), N, N-dimethylformamide The title compound was prepared from oil (6.2 g, 16.6 mmol), 2,3-dimethyl-5-benzylthiophene (3.5 g, 16.6 mmol), tin (IV) chloride (1.5 ml, 15.8 mmol) and anhydrous methylene chloride ), Which is used without further purification.

(3-sec-butyl-4-methoxy-phenyl) -methanone (6.2 g, , MS (EI): [M ^&lt; ⁺ &^gt;] 360.

Step 2 2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-

In a manner similar to that of Example 39, Step 6, by reacting 2-sec-butyl-4- (2,3-dimethyl-naphtho [2,3- b] thiophen- MS [EI]: [M ⁺ H] &lt; ^{+ &} gt ;, was obtained as a solid from the title compound as a solid (0.63 g, 19%), Bromine (0.69 ml, 13 mmol), potassium acetate (6.4 g, 65 mmol) and glacial acetic acid ], 2 bromine isotope patterns, 516 (50%), 518 (100%), 520 (55%

Step 3 Preparation of (R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -Phenoxy] -3-phenyl-propionic acid

Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophene-2-carbonitrile was obtained in a manner similar to that of Example 49, Step 6, (0.63 g, 1.2 mmol), (S) -2-hydroxy-3-phenylpropionic acid, methyl ester (0.44 g, 2.4 mmol), triphenylphosphine The title compound is obtained as an oil (0.60 g, 72%) from diethyl azodicarboxylate (0.38 ml, 2.4 mmol) and anhydrous benzene (2.4 ml) which is used without further purification .

In a manner similar to that of Example 49, Step 7, (R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl- (0.55 g, 0.73 mmol), aqueous potassium hydroxide (1.6 mL of a 1N solution, 1.6 mmol), and tetrahydrofuran (7.5 mL) were added to a solution of 4- MS (EI): [M +], 2 bromine isotopic pattern 664 (14%), 666 (26%), 668 (26%) as a foam (0.26 g, 48% (14%);

Elemental analysis for C ₃₃ H ₃₀ Br ₂ O ₃ S:

Calculated: C, 59.47, H, 4.54, N, 0.00.

Found: C, 59.44, H, 4.81, N, 0.03.

Example 43

(R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [ -3-phenyl-propionic acid

Step 1 A mixture of (2-benzyl-4,5-dimethyl-thiophen-3-yl) -

(5.0 g, 27.7 mmol, RN-22934-35-6), oxalyl chloride (2.7 mL, 30.5 mmol), N, N-dimethylformamide (6.7 g, 33.2 mmol), tin chloride (IV) (3.6 mL, 30.5 mmol) and anhydrous methylene chloride (177 mL) was added dropwise to a solution of 2- to give the title compound as an oil (5.2g, 51%): NMR (DMSO-d 6): δ 7.59-7.54 (m, 2H), 7.25-7.11 (m, 3H), 7.09-7.04 (m, 3H) , 3.87 (s, 3H), 3.84 (s, 2H), 2.57 (q, 2H), 2.26 (s, 3H), 1.82 (d, 3H), 1.10 MS (+ FAB): [M + H] 365;

Elemental analysis for C ₂₃ H ₂₄ O ₂ S:

Calculated: C, 75.79, H, 6.64, N, 0.00.

Found: C, 75.34, H, 6.72, N, 0.00.

Step 2 2-Ethyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-

(3-Ethyl-4-methoxy-phenyl) -methanone (6.1 g, 0.20 mmol) was obtained in a manner similar to the step of Example 49, , 16.7mmol), to give the title compound from boron tribromide (7.1㎖, 75.4mmol) and methylene chloride (58㎖) as a solid (2.6g, 46%): ( DMSO-d 6): δ 9.49 (s, 1H), 7.32 (m, 1H), 7.02-6.90 (m, [delta] 6.94 (d, 1H), 7.43 , 3H), 2.73-2.52 (complex m, ABX pattern, 2H, rotamer), 2.40 (s, 3H), 1.62 (s, 3H), 1.15 (t, 3H); MS (EI): [M &lt; + &gt;] 332.

Step 3 A mixture of (R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Yl] -3-phenyl-propionic acid methyl ester

(2.6 g, 7.8 mmol), 2-ethyl-4- (2,3-dimethyl-naphtho [2,3b] thiophen-4-yl) -phenol in a manner analogous to the procedure of example 39, The title compound is obtained as a solid (0.73 g) from bromine (0.83 ml, 15.7 mmol), potassium acetate (7.7 g, 78.5 mmol) and glacial acetic acid (78 ml) which is used without further purification.

In a manner similar to that of Example 49, Step 6, by reacting 2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophene- 3-phenylpropionic acid, methyl ester (0.54 g, 3.0 mmol), triphenylphosphine (0.78 g, 1.5 mmol), 4- mmol), diethyl azo Taki carboxylate (0.47㎖, 3.0mmol) and to give an oil (0.58g, 60%) from anhydrous benzene (3.0㎖): (DMSO-d 6): δ 8.19 (d, 1H) , 7.65 (m, 1H), 7.54-7.22 (m, containing one single line at? 7.32,9H, 9), 5.09 and 5.01 (2, rotamer), 3.60 and 3.56 ), 3.45-3.25 (compound m, 2H, rotamer), 2.78-2.50 (compound m, ABX pattern 2H), 2.42 and 2.43 (2s, 3H, rotamer), 1.59 and 1.54 Isomer), 1.09 and 1.07 (2 t, 3H, rotamer).

Step 4 To a solution of (R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Yl] -3-phenyl-propionic acid

In analogy to the procedure of example 49, step 7, (R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- (0.41 g, 0.63 mmol), aqueous potassium hydroxide (1.3 mL of a 1N solution, 1.3 mmol), tetrahydrofuran (4.5 mL) and methanol to give the title compound attached to (1.5㎖) as a pale yellow solid (0.38g, 95%): ( DMSO-d 6): δ 13.05 (br s, 1H), 8.20 (d, 1H), 7.65 (m, 1H ), 7.54-7.18 (m, 9H), 5.05 (m, 1H), 3.33 (m, 2H), 2.90-2.50 (compound m, ABX pattern, 2H), 2.43 and 2.41 , 1.58 and 1.53 (2 s, 3H, rotamer), 1.10 and 1.09 (2 t, 3H, rotamer); MS (-ESI): [MH], 2 bromine isotope pattern 635 (44%), 637 (100%), 639 (62%);

Elemental analysis for C ₃₁ H ₂₆ Br ₂ O ₃ S:

Calculated: C, 58.32, H, 4.11, N, 0.00.

Found: C, 58.11, H, 4.32, N, 0.18.

Example 44

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- - propionic acid

Step 1 Synthesis of (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -Phenyl-propionic acid methyl ester

(9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) (S) -2-hydroxy-3-phenylpropionic acid, methyl ester (0.32 g, 1.8 mmol), triphenylphosphine (0.46 g, , 1.8mmol), O-diethyl-ji-carboxylate (to obtain the title compound from 0.28㎖, 1.8mmol) and anhydrous benzene (7.0㎖) as a white solid (0.15g, 38%): ( DMSO-d 6): δ 2H), 7.40-7.30 (m, 4H), 7.30-7.20 (m, 1H), 7.14-7.04 (m, 2H), 8.18 (m, 1H), 7.66-7.58 ), 6.92-6.87 (m, 1H), 5.27 (t, 1H), 3.70 and 3.65 (2 singlets, 3H, rotamers), 3.40-3.20 (m, 3H) , 3H), 1.15 and 1.13 (2 doublets, 3H, rotamer), 1.06 and 1.04 (2 doublets, 3H, rotamer).

Step 2 Synthesis of (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -Phenyl-propionic acid

2,3-b] thiophen-4-yl) -2,3-dimethyl-naphtho [2,3- b] thiophene-4-carboxylate was obtained in a manner similar to the step of Example 49, 2-isopropyl-phenoxy] -3-phenyl-propionic acid methyl ester (0.15 g, 0.25 mmol), aqueous potassium hydroxide (0.5 mL of a 1N solution), tetrahydrofuran (6 mL) to give the compound as a white solid (0.14g, 95%): NMR (DMSO-d 6): δ 13.14 (broad s, 1H), 8.18-8.15 (m, 1H), 7.64-7.58 (m, 1H), 2H), 6.90-6.85 (m, IH), 5.07 (m, IH), 3.39-3.18 (m, 3H), 7.48-7.31 (m, 6H), 7.30-7.22 ), 2.41 and 2.40 (2 singlets, 3H, rotamer), 1.51 and 1.49 (2 singlets, 3H, rotamer), 1.15 and 1.14 (2 doublets, 3H, rotamer), 1.04 and 1.03 Rotational isomers); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 572/574;

Elemental analysis for C ₃₂ H ₂₉ BrO ₃ S:

Calculated: C, 67.01, H, 5.10, N, 0.00.

Found: C, 67.19, H, 5.47, N, 0.03.

Example 45

(R) -2- [2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -phenoxy]

Step 1 (2-Benzyl-4,5-dimethyl-thiophen-3-yl) - (3- cyclopentyl-

To a slurry of 3-cyclopentyl-p-anisic acid (5.0 g, 22.7 mmol, RN-59216-82-9) in anhydrous methylene chloride (60 mL) was added oxalyl chloride (2.4 mL, 27.2 mmol) N, N-dimethylformamide (2 drops) is added. After stirring for 1.5 hours, the reaction mixture is concentrated under reduced pressure. The residue was dissolved in carbon disulfide (32 ml), and the resulting solution was added to 2,3-dimethyl-5-benzylthiophene (5.1 g, 25.0 mmol). Tin (IV) chloride (2.9 mL, 25.0 mmol) was added under nitrogen at -78 ° C, and the reaction mixture was stirred at room temperature for 4 hours. The solution is poured into a mixture of ice and water (200 ml) and extracted with diethyl ether (200 ml). The diethyl ether layer is washed twice with sodium bicarbonate (50 ml) and once with brine (50 ml). Concentrated under reduced pressure, and petroleum ether: ethyl acetate (95: 5) as to chromatography to give the title compound as an amber oil (4.8g, 52%): NMR (DMSO-d 6): δ 7.61-7.54 (m, 2H), 7.24-7.14 (m, 3H), 7.08-7.02 (m, 3H), 3.87 (s, 3H), 3.84 , 2.00 - 1.85 (m, 2H), 1.81 (s, 3H), 1.74 - 1.58 (m, 4H), 1.48 - 1.36 (m, 2H); MS (EI): [M &lt; + &gt;]404;

Elemental analysis for C ₂₆ H ₂₈ O ₂ S:

Calculated: C, 77.19, H, 6.98, N, 0.00.

Found: C, 76.26, H, 7.24, N, 0.04.

Step 2 2-Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-

To a solution of (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (3- cyclopentyl-4- methoxy- phenyl) -methanone (4.8 g, 11.7 mmol ) Was added dropwise boron tribromide (3.6 mL, 37.6 mmol) under nitrogen at -78 &lt; 0 &gt; C for 20 min. The reaction mixture is then stirred at room temperature for 22 hours. The solution is poured into a mixture of ice and water (600 ml) and extracted with diethyl ether (800 ml). The diethyl ether layer is washed twice with water (500 mL) and once with brine (500 mL). Concentration under reduced pressure and chromatography with petroleum ether: ethyl acetate (97: 3) gave the title compound as a white solid (3.4 g, 78%): mp. 156 to 158 占 폚; _{(DMSO-d 6): δ} 9.48 (s, 1H), 8.42 (s, 1H), 7.93 (d, 1H), 7.46-7.41 (m, 2H), 7.35-7.30 (m, 1H), 7.00 (s (M, 2H), 1.98-1.47 (m, 6H), 1.60 (s, 3H) , 3H); MS (EI): [M &lt; + &gt;]372;

Elemental analysis for C ₂₅ H ₂₄ O ₄ S:

Calculated: C, 80.60, H, 6.49, N, 0.00.

Found: C, 80.39, H, 6.43, N, 0.04.

Step 3 A solution of (R) -2- [2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -phenoxy] ester

Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) thiophene hydrochloride in a similar manner to Example 49f, -Phenol (0.40 g, 1,1 mmol), (S) -2-hydroxy-3-phenylpropionic acid, methyl ester (0.29 g, 1.6 mmol), triphenylphosphine (0.42 g, 1.6 mmol) dicarboxylate (0.25㎖, 1.6mmol) and the title compound from anhydrous benzene (6.0㎖) to give a white solid (0.26g, 46%): ( DMSO-d 6): δ 8.44 (s, 1H), 7.94 (d, 1H), 7.43-7.26 (m, 8H), 7.08-7.01 (m, 2H), 6.88-6.85 ), 3.42-3.20 (m, 3H), 2.38 (s, 3H), 2.02-1.30 (m, 11H containing single line at? 1.52).

Step 4 To a solution of (R) -2- [2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3- b] thiophen-

2,3-b] thiophen-4-yl) -2-methylpropionic acid was prepared by a method similar to the process of Example 49, Step 7, using (R) -Phenoxy] -3-phenyl-propionic acid methyl ester (0.22 g, 0.41 mmol), aqueous potassium hydroxide (0.82 ml of a 1N solution, 0.82 mmol), tetrahydrofuran (12 ml) and methanol (4 ml) Obtained as a white solid (0.21 g, 95%): Opt. Rot. [a] 25 / D = -8.19 (8.549mg / mL, CHCl 3).;

_{NMR (DMSO-d 6):} δ 13.10 (broad s, 1H), 8.43 (d, 1H), 7.93 (m, 1H), 7.43-7.20 (m, 8H), 7.07-7.02 (m, 2H), 6.88 1H), 3.90-3.17 (m, 3H), 2.38 and 2.37 (2 singlets, 3H, rotamers), 1.90 (m, 1.76 (m, 1H), 1.70-1.32 (m containing 2 singlets at? 1.54 and 1.52 (rotamer), 9H); MS (EI): [M &lt; + &gt;]520;

Elemental analysis for C ₃₄ H ₃₂ O ₃ S:

Calculated: C, 78.43, H, 6.19, N, 0.00.

Found: C, 77.96, H, 6.40, N, 0.02.

Example 46

(R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4- yl) -2,6- dimethyl- phenoxy]

Step 1 A mixture of (R) -2- [4- (2,3-dimethyl-naphtho [2,3- b] thiophen-4-yl) -2,6- dimethyl- phenoxy] Methyl ester

2,3-b] thiophen-4-yl) - (tert-butoxycarbonyl) thiophene was obtained in the same manner as in Example 49, Step 6, Methyl ester (0.49 g, 2.7 mmol), triphenylphosphine (0.71 g, 2.7 mmol), di (tert-butyldimethylsilyl) ethyl azodicarboxylate (0.36㎖, 2.7mmol) and yields the title compound from anhydrous benzene (13㎖) as a white solid (0.24g, 40%): ( DMSO-d 6): δ 8.44 (s, 1H) , 7.94 (d, 1H), 7.45-7.39 (m, 2H), 7.35-7.30 (m, 5H), 7.28-7.24 (s, 3H), 3.34-3.25 (m, 2H), 2.39 (s, 3H), 2.22 (s, 3H), 2.17 (s, 3H), 1.56 MS (EI): [M &lt; + &gt;]494;

Elemental analysis for C ₂₃ H ₃₀ O ₃ S:

Calculated: C, 77.70, H, 6.11, N, 0.00.

Found: C, 76.53, H, 5.85, N, 0.08.

Step 2 A mixture of (R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6- dimethyl- phenoxy]

(R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) (0.31 ml, 0.91 mmol), aqueous tetrahydrofuran (12 ml) and methanol (4 ml), the title compound (0.19 g, 86%) as a white solid: &lt; RTI ID = 0.0 &gt; Opt. Rot. [a] 25 / D = + 33.04 (10.170 mg / mL, MeOH);

_{NMR (DMSO-d 6):} δ 12.9 (broad s, 1H), 8.44 (s, 1H), 7.94 (d, 1H), 7.45-7.40 (m, 2H), 7.35-7.22 (m, 6H), 6.95 (s, 3H), 2.32 (s, 3H), 2.65 (s, 3H); MS (EI): [M &lt; + &gt;]480;

Elemental analysis for C ₃₁ H ₂₈ O ₃ S:

Calculated: C, 77.47, H, 5.87, N, 0.00.

Found: C, 76.23, H, 5.77, N, 0.03.

Example 47

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -2- cyclopentyl- - propionic acid

Step 1 A mixture of acetic acid 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-

To a solution of 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (2.8 g, 7.5 mmol) in anhydrous pyridine (20 ml) Acetic anhydride (0.92 ml, 9.8 mmol) was added dropwise. The reaction mixture is placed in a refrigerator. After 41 hours, the reaction is diluted and acidified to pH 1 with 10% aqueous hydrochloric acid. The mixture was extracted with diethyl ether (500 mL) and the diethyl ether layer was washed with 5% aqueous hydrochloric acid (100 mL), twice with water (100 mL), washed with brine (100 mL) , dried (MgSO _4). And concentrated under reduced pressure to obtain the title compound as a white solid (3.1g, 98%): ( DMSO-d 6): δ 8.48 (s, 1H), 7.97 (d, 1H), 7.47-7.43 (m, 1H) 3H), 2.37 (s, 3H), 1.99-1.91 (m, 2H), 7.38-7.36 , 2H), 1.69-1.40 (m, 6H), 1.56 (s, 3H); MS (EI): [M &lt; + &gt;]414;

Elemental analysis for C ₂₇ H ₂₆ O ₂ S:

Calculated: C, 78.23, H, 6.32, N, 0.00.

Found: C, 77.68, H, 6.39, N, 0.04.

Step 2 A mixture of acetic acid 2-cyclopentyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-

To a solution of 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester (2.9 g, 7.7 mmol) in anhydrous methylene chloride (68 ml) Ferric chloride (66 mg, 0.41 mmol) is added. The reaction mixture is placed under nitrogen and cooled to -78 &lt; 0 &gt; C. The reaction mixture is protected from light and a solution of bromine (0.44 mL, 8.5 mmol) in anhydrous methylene chloride (11 mL) is added dropwise over 15 minutes. After dropwise addition at -78 ° C for 45 minutes, the reaction was quenched with dilute sodium bisulfate and then poured into water (200 mL). The resulting mixture is extracted with diethyl ether (300 ml) and the diethyl ether layer is washed with water followed by brine. Concentrated under reduced pressure, petroleum ether: ethyl acetate (95: 5) to chromatography to obtain the title compound as a white solid (2.7g, 79%): ( CDCl 3): δ 8.28 (d, 1H), 7.58- (D, 1H), 7.14 (d, 1H), 3.18 (quintet, 1H), 2.44 (s, 3H), 2.40 (s, 3H), 2.06-2.02 (m, 2H), 1.75-1.45 (single line containing m, 9H at delta 1.60); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 492/494;

Elemental analysis for C ₂₇ H ₂₅ Br ₂ O ₂ S:

Calcd: C, 65.72, H, 5.11, N, 0.00.

Found: C, 63.18, H, 4.96, N, 0.00.

Step 3 2-Cyclopentyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-

To a solution of 2-cyclopentyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen- To the phenyl ester (2.7 g, 5.4 mmol) was added aqueous potassium hydroxide (6.5 mL of a 1N solution, 6.5 mmol) dropwise at room temperature. After 1.5 h, the reaction mixture is concentrated under reduced pressure. The residue obtained is combined with water (200 ml) and acidified to pH 1 with 10% aqueous hydrochloric acid. Then the solution was extracted with diethyl ether (300㎖), and washed twice with water and diethyl ether layer, dried (Na ₂ SO _4). And concentrated under reduced pressure to give the title compound as a white solid (2.4g, 100%): ( DMSO-d 6): δ 9.54 (s, 1H), 8.16 (d, 1H), 7.61 (m, 1H), 7.52 (s, 1H), 7.43 (m, 1H), 7.03 (s, 1H), 6.93 (m, 2H), 3.32 s, 3H), 1.72-1.42 (m, 6H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 450/452;

Elemental analysis for C ₂₅ H ₂₃ BrOS:

Calcd: C, 66.52, H, 5.13, N, 0.00.

Found: C, 67.17, H, 5.25, N, 0.04.

Step 4 Preparation of (R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -Phenyl-propionic acid methyl ester

(9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) (0.40 g, 0.89 mmol), (S) -2-hydroxy-3-phenylpropionic acid, methyl ester (0.48 g, 2.7 mmol), triphenylphosphine mmol), diethyl azodicarboxylate (0.42㎖, 2.7mmol) and yields the title compound from anhydrous benzene (6㎖) as a white solid (0.19g, 34%): NMR (DMSO-d 6): δ 8.17 (m, 1H), 7.64-7.59 (m, 1H), 7.45-7.40 (m, 2H), 7.38-7.24 3H), 2.40 (s, 3H), 1.95-1.30 (m, 8H), 1.49 (m, s, 3H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 612/614.

Step 5 Preparation of (R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4-yl) -2-cyclopentyl- -Phenyl-propionic acid

(R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) (0.18 g, 0.30 mmol), aqueous potassium hydroxide (0.39 mL, 0.39 mmol of 1N solution), tetrahydrofuran (6 mL) and methanol (2 mL) were added to a solution of 2- ) to give the title compound as a white solid (0.15g, 84%) _{from: NMR (DMSO-d 6)} : δ 13.12 (broad s, 1H), 8.18-8.15 (m, 1H), 7.64-7.58 (m, 1H), 7.47-7.22 (m, 7H), 7.10-7.04 (m, 2H), 6.89-6.86 s, 3H), 1.90 (m, 1H), 1.76 (m, 1H), 1.70-1.30 (m containing 2 singlets at? 1.51 and 1.50 (rotamer), 9H); MS (-ESI): [MH], 1 bromine isotope pattern 597/599;

Elemental analysis for C ₃₄ H ₃₁ BrO ₃ S:

Calculated: C, 68.11, H, 5.21, N, 0.00.

Found: C, 68.10, H, 5.31, N, 0.01.

Example 48

(R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- ] -3-phenyl-propionic acid

Step 1 2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4-yl)

A solution of 2-cyclopentyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) g, 4.4 mmol) and potassium acetate (4.4 g, 44.3 mmol) was added dropwise over 17 minutes to a suspension of bromine (0.27 ml, 5.3 mmol). Dilute the thick reaction mixture with glacial acetic acid (20 mL). After stirring at room temperature for 2 hours, the reaction mixture is poured into water (500 mL). The solution is extracted once with diethyl ether (250 ml) and then with diethyl ether (100 ml). The combined extracts are washed twice with water (100 ml). Concentration under reduced pressure and chromatography with petroleum ether: ethyl acetate (98: 2) followed by trituration with petroleum ether afforded the title compound as a white solid (1.2 g, 52%): mp. 189.5-191 占 폚; mp 189.5-191 [deg.] C; _{(DMSO-d 6): δ} 9.19 (s, 1H), 8.18 (d, 1H), 7.65-7.61 (m, 1H), 7.50-7.47 (m, 2H), 7.33 (d, 1H), 7.11 (d 2H), 1.69-1. 46 (m, 6H), 1.60 (s, 3H); MS (EI): [M +], 2 bromine isotope pattern 528 (46%), 530 (100%), 532 (52%);

Elemental analysis for C ₂₅ H ₂₂ Br ₂ O ₂ S:

Calculated: C, 56.62, H, 4.18, N, 0.00.

Found: C, 55.78, H, 4.12, N, 0.05.

Step 2 Preparation of (2R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Phenoxy] -3-phenyl-propionic acid methyl ester

To a solution of 2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6- cyclopentyl-phenol To a solution of (S) -2-hydroxy-3-phenylpropionic acid, methyl ester (0.60 g, 3.3 mmol) and triphenylphosphine (0.87 g, 3.3 mmol) in dioxane Azodicarboxylate (0.52 ml, 3.3 mmol) is added dropwise. After 5 h at room temperature the reaction mixture was adsorbed onto silica gel and chromatographed with petroleum ether: ethyl acetate (95: 5) to give the title compound as a white solid (1.2 g, 86%): mp. 167 to 168.5 DEG C; _{NMR (CDCl 3): δ 8.28} (m, 1H), 7.58-7.47 (m, 2H), 7.41-7.36 (m, 2H), 7.34-7.25 (m, 5H), 7.18 (m, 1H), 5.11 and (M, 3H), 2.44 and 2.43 (2 s, 3H, rotamer), 2.20 (m, 3H), 5.02 (2 dd, 1H, rotamer), 3.66 and 3.63 1H), 1.95 (m, 1H), 1.75-1.32 (m containing 2 singlets at? 1.63 and 1.69 (rotamer), 9H); MS (EI): [M @ +], 2 bromine isotopic pattern 690 (46%), 692 (100%), 694 (54%);

Elemental analysis for C ₃₅ H ₃₂ Br ₂ O ₃ S:

Calculated: C, 60.70, H, 4.66, N, 0.00.

Found: C, 60.31, H, 4.64, N, 0.01.

Step 3 (2R) -2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Phenoxy] -3-phenyl-propionic acid

To a solution of (2R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophene- 3-phenyl-propionic acid methyl ester (1.0 g, 1.5 mmol) in methylene chloride (10 mL) at room temperature was added dropwise aqueous potassium hydroxide (3.0 mL of a 1N solution, 3.0 mmol). After 4 hours the mixture is concentrated under reduced pressure. The residue is taken up in water (100 ml) and acidified with aqueous 10% hydrochloric acid. Stir for 15 minutes then filter the solid and wash with water: methanol (95: 5). The solid was dried under vacuum at 50 &lt; 0 &gt; C for 18 hours to give the title compound as a white solid (0.99 g, 100%): Rot. [a] 25 / D = + 38.44. (9.624 mg / mL, MeOH);

_{NMR (DMSO-d 6):} δ 13.01 (broad s, 1H), 8.19 (d, 1H), 7.67-7.62 (m, 1H), 7.54-7.22 (m, 9H), 4.92 (m, 1H), 3.46 (m, 1H), 3.34 (m, 2H), 2.42 and 2.41 (2 singlets, 3H, rotamer), 1.99 Containing m (rotamer), 6H); MS (-ESI): [MH], 2 bromine isotope pattern 675 (72%), 677 (100%), 679 (66%);

Elemental analysis for C ₃₄ H ₃₀ Br ₂ O ₃ S:

Calculated: C, 60.19, H, 4.46, N, 0.00.

Found: C, 59.53, H, 4.35, N, -0.04.

Example 49

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Phenyl-propionic acid

Step 1 (2-Benzyl-4,5-dimethyl-thiophen-3-yl) - (4- methoxy-

To a suspension of 3,5-dimethyl-anisic acid (15.2 g, 84.4 mmol, RN-21553-46-8) in anhydrous methylene chloride (200 mL) was added oxalyl chloride (9.6 mL, 110 mmol) and N, N -Dimethylformamide (5 drops) is added. After 2 hours, the solvent is removed. The obtained residue was dissolved in anhydrous methylene chloride (200 ml) and added to 2,3-dimethyl-5-benzylthiophene (17.1 g, 84.4 mmol) under nitrogen. The resulting mixture is cooled to -78 ° C and tin (IV) chloride (10.8 ml, 92.8 mmol) is added rapidly. The -78 [deg.] C bath is removed and the mixture is stirred at room temperature for 2 hours. The reaction mixture is then poured into ice water (1 L) and the resulting mixture is extracted once with diethyl ether (700 mL) and the second is extracted with diethyl ether (400 mL). The combined diethyl ether extracts are washed with ice water, dilute sodium bicarbonate (500 mL), water (500 mL), brine (1 L) (500 mL) and dried (Na ₂ SO ₄ ). Concentration under reduced pressure gave the title compound as a yellow oil (25.2 g, 82%). _{NMR (DMSO-d 6):} δ 7.40 (s, 2H), 7.24-7.15 (m, 3H), 7.06 (d, 2H), 3.83 (s, 2H), 3.70 (s, 3H), 2.28 (s, 3H), 2.26 (s, 6H), 1.83 (s, 3H).

Step 2 4- (2,3-Dimethyl-naphtho [2,3-b] thiophene-2,6-dimethyl-phenol

To a solution of (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (4- methoxy-3,5- dimethyl- phenyl) -methanone (25.2g, 69.2mmol) in anhydrous methylene chloride ) Is placed under nitrogen and cooled to -78 ° C. Boron tribromide (20.9 ml, 221 mmol) is added dropwise over 16 minutes and the resulting mixture is stirred at -78 &lt; 0 &gt; C for 1.5 hours. The bath at -78 ° C is removed and the reaction mixture is stirred at room temperature for 4 hours. The reaction mixture is then poured into ice water (1 L) containing some sodium bisulfate and the mixture is extracted once with diethyl ether (1 L) and extracted with diethyl ether (300 mL) a second time. The combined diethyl ether extracts are washed twice with water (1 L), brine (1 L) and dried (Na ₂ SO ₄ ). Concentration under reduced pressure gave a black residue which was purified by flash chromatography to give (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (4-methoxy-3,5-dimethyl- , 38.1 mmol) and boron tribromide (11.5 mL, 122 mmol). The residue was subjected to adsorption bonding with silica gel and chromatography with petroleum ether: ethyl acetate (90:10) to obtain 2,6-dimethyl-4- (2,3-dimethyl-naphtho [2,3- b] thiophen- ) to afford the amber residue (24.0g, 67%) identified by _{phenol: NMR (DMSO-d 6)} : δ 8.41 (s, 2H), 7.93 (d, 1H), 7.49-7.39 (m, 2H) , 7.34-7.28 (m, IH), 6.87 (s, 2H), 2.38 (s, 3H), 2.23 (s, 6H), 1.62 (s, 3H); MS (EI): [M &lt; + &gt;] 332.

Step 3 Acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-

To a solution of 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl- phenol (24.0 g, 72.2 mmol) in pyridine (200 ml) Acetic anhydride (8.9 ml, 93.9 mmol) was added dropwise over 10 minutes under nitrogen. After 45 min at 0 &lt; 0 &gt; C, the reaction mixture is placed in a freezer for 18 h, then transferred and stirred in an ice bath for 2 h and allowed to warm to room temperature. The reaction mixture is poured into water (1 L) and acidified to pH 1 with 10% hydrochloric acid. The resulting mixture was extracted with diethyl ether (1 L), washed with 10% hydrochloric acid (1 L), washed twice with water (1 L), washed with brine (700 mL) and dried (MgSO ₄ ) . Concentrated under reduced pressure, and petroleum ether: ethyl acetate (97: 3) to chromatography to obtain the title compound as a cream solid (22.4g, 79%): NMR (CDCl 3): δ 8.26 (s, 1H), 7.87 ( 2H), 2.42 (s, 3H), 2.41 (s, 3H), 3.40 (s, , 2.23 (s, 6 H), 1.67 (s, 3 H); MS (EI): [M &lt; + &gt;]374;

Elemental analysis for C ₂₄ H ₂₂ O ₂ S:

Calculated: C, 76.97, H, 5.92, N, 0.00.

Found: C, 76.17, H, 5.75, N, 0.22.

Step 4 A mixture of acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-

To a solution of 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl- phenyl ester (10.0 g, 26.7 mmol) in anhydrous methylene chloride (231 ml) A solution of ferric chloride (0.23 g, 1.4 mmol) is placed under nitrogen at -78 &lt; 0 &gt; C. The reaction mixture is protected from light and a solution of bromine (1.5 mL, 29.4 mmol) in anhydrous methylene chloride (38 mL) is added dropwise over 50 min. After 30 minutes, the reaction is quenched with dilute sodium bisulfite, diluted with water, and the resulting mixture is extracted with ethyl ether. It was washed twice with diethyl ether layer with water, washed with brine and dried (MgSO _4). Concentration under reduced pressure and chromatography with petroleum ether: acetate (97: 3, then 95: 5) gave the title compound as a white solid (6.7 g, 55%). _{NMR (DMSO-d 6):} δ 8.27 (d, 1H), 7.60 (d, 1H), 7.56-7.52 (ddd, 1H), 7.38-7.34 (ddd, 1H), 7.06 (s, 2H), 2.43 ( s, 3H), 2.41 (s, 3H), 2.22 (s, 6H), 1.64 (s, 3H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 452/454;

Elemental analysis for C ₂₄ H ₂₁ BrO ₂ S:

Calculated: C, 63.58, H, 4.67, N, 0.00.

Found: C, 63.41, H, 4.45, N, 0.08.

Step 5 4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-

To a solution of 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethylpyridine in 240 ml of tetrahydrofuran and methanol -Phenyl ester (6.5 g, 14.3 mmol) in anhydrous THF at room temperature is added dropwise aqueous potassium hydroxide (17.2 mL of a 1N solution, 17.2 mmol). After 4 hours, the reaction mixture is left in the freezer for 18 hours at room temperature. The reaction is transferred from the freezer and stirred at room temperature. Additional aqueous potassium hydroxide (41.5 ml of a 1N solution, 41.5 mmol), tetrahydrofuran (50 ml) and methanol (10 ml) are added. The mixture is diluted with water (500 mL), acidified with a IN aqueous hydrochloric acid solution and extracted with diethyl ether. Then washed twice with diethyl ether layer with water (500㎖), and dried (MgSO _4). Concentrate under reduced pressure to obtain a residue, which is adsorbed onto silica gel. Petroleum ether: ethyl acetate (97: 3, then 95: 5) to give the title compound by chromatography as a white foam solid (5.5g, 93%): NMR (CDCl 3): δ 8.41 (s, 1H), (S, 2H), 2.26 (s, 3H), 1.60 (s, 2H), 8.16 (d, 1H), 7.64-7.54 (m, 2H), 7.46-7.40 3H); MS (-ESI): [MH], 1 bromine isotope pattern 409/411.

Step 6 (2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -Phenyl-propionic acid methyl ester

To a solution of 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6- dimethyl-phenol (5.0 g, 12.1 was added dropwise to a solution of (S) -2-hydroxy-3-phenylpropionic acid, methyl ester (3.3 g, 18.3 mmol) and triphenylphosphine (4.8 g, 18.3 mmol) Add azodicarboxylate (2.6 mL, 18.3 mmol) dropwise. The reaction mixture is heated for 2 hours and then stirred at room temperature for 3 days. The crude reaction mixture was adsorbed on silica gel and petroleum ether: ethyl acetate (95: 5) to be twice chromatography to give the title compound as a white foam solid (4.5g, 65%): NMR (DMSO-d 6) : d 8.18 (d, 1 H), 7.64 (ddd, 1 H), 7.53-7.43 (m, 2H), 7.38-7.24 s, 3H), 3.31 (m, 2H), 2.42 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.55 MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 572/574;

Elemental analysis for C ₃₂ H ₂₉ BrO ₃ S:

Calculated: C, 67.01, H, 5.10, N, 0.00.

Found: C, 66.33, H, 5.09, N, 0.09.

HPLC analysis shows the major component (94.39%).

Step 7 (2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- 3-phenyl-propionic acid

To a solution of (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- ) -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid methyl ester (3.1 g, 5.4 mmol) at room temperature is added dropwise with aqueous potassium hydroxide (6.5 mL of a 1N solution, 6.5 mmol). After 1.5 hours at room temperature, the reaction mixture is placed in the freezer for 18 hours. The reaction is transferred from the freezer and stirred at room temperature. Additional aqueous potassium hydroxide (19.5 ml of a 1N solution, 19.5 mmol) is added and the reaction mixture is stirred at room temperature for 9.5 hours. Concentrate under reduced pressure to give a residue which is diluted with water (1 L). The aqueous layer is acidified to pH 1 using concentrated hydrochloric acid and extracted with diethyl ether (700 mL). Diethyl the ether layer washed twice with water (500㎖) and dried (Na ₂ SO _4). Concentration under reduced pressure and chromatography on silica gel (treated with 2% phosphoric acid in methanol) gave the title compound as a white solid foam (1.9 g, 64%): Rot. [a] 25 / D = + 33.38 (10.035 mg / mL, MeOH); _{NMR (DMSO-d 6):} δ 12.90 (braod singlet, 1H), 8.17 (d, 1H), 7.63 (ddd, 1H), 7.50-7.43 (m, 2H), 7.36-7.23 (m, 5H), 6.97 (s, 3H), 2.21 (s, 3H), 1.54 (s, 3H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 558/560;

Example 50

(R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4- yl) -2,6-diisopropyl- phenoxy]

Step 1 (2-Benzyl-4,5-dimethyl-thiophen-3-yl) - (3,5- diisopropyl-

(5.0 g, 21.2 mmol, RN-117439-59-5), oxalyl chloride (2.2 mL, 25.4 mmol) in a manner analogous to that of Example 49, ), N, N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylthiophene (4.3 g, 21.2 mmol), tin chloride (IV) (5.0 ml, 42.7 mmol) and anhydrous methylene chloride to give the title compound from 82㎖) as a yellow oil (4.1g, 45%): NMR (DMSO-d 6): δ 7.47 (s, 2H), 7.23-7.12 (m, 3H), 7.02-6.99 (m 2H), 3.86 (s, 2H), 3.73 (s, 3H), 3.31-3.20 (m, 2H), 2.27 (s, 3H), 1.82 MS (EI): [M &lt; + &gt;] 420.

Step 2 2,6-Diisopropyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-

In a manner similar to that of Example 49, Step 2, (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (3,5- diisopropyl- one was obtained as (4.3g, 10.0mmol), boron tribromide (3.1㎖, 32.4mmol) and methylene chloride yellow foam (1.2g, 30%) of the title compound from (60㎖): NMR (DMSO- d 6) : [delta] 8.42 (s, IH), 8.24 (s, IH), 7.94 (d, IH), 7.48-7.32 s, 3H), 1.57 (s, 3H), 1.15 (d, 12H); MS (-ESI): [MH] 387.

Step 3 Preparation of (2R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6- diisopropyl- phenoxy] -Propionic acid methyl ester

(2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenol (0.33 g, (1.5 g, 8.3 mmol), triphenylphosphine (2.2 g, 8.3 mmol), diethyl azodicarboxylate (1.3 mL, 0.84 mmol), (S) -2-hydroxy- 8.3mmol) and yields the title compound from anhydrous benzene (9.0㎖) as an oil (0.11g, 24%): NMR (DMSO-d 6): δ 8.45 (s, 1H), 7.96 (d, 1H), 7.50 3H), 3.40-3.18 (m, 4H), 2.38 (s, 3H), 1.51 (s, 3H) ), 1.14 and 1.13 (2 doublets, 6H, rotamers), 1.07 and 1.04 (2 doublets, 6H, rotamers); MS (EI): [M &lt; + &gt;] 550.

Step 4 Synthesis of (2R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6- diisopropyl- phenoxy] - propionic acid

(2R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4- yl) -2,6-diisopropyl- phenoxy] (0.10 g, 98%) from the title compound as a white solid (0.10 g, 0.20 mmol), aqueous potassium hydroxide (0.39 mL, 0.39 mmol of a 1N solution), tetrahydrofuran (3 mL) and methanol is _{obtained: NMR (DMSO-d 6)} : δ 12.97 (broad s, 1H), 8.46 (s, 1H), 7.96 (d, 1H), 7.47-7.25 (m, 8H), 7.04 (s, 2H), (S, 3H), 1.15 (d, 6H), 1.08 (d, 2H) 6H); MS (EI): [M &lt; + &gt;]536;

Elemental analysis for C ₃₅ H ₃₆ O ₃ S:

Calculated: C, 78.32, H, 6.76, N, 0.00.

Found: C, 77.12, H, 6.86, N, -0.11.

HPLC analysis shows the main component (93.2%).

Example 51

(R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4- yl) -2-fluoro-phenoxy]

Step 1 A mixture of (2-benzyl-4,5-dimethyl-thiophen-3-yl) -

Fluoro-p-anisic acid (10.0 g, 58.8 mmol), oxalyl chloride (6.2 mL, 71.0 mmol), N, N-dimethylformamide (12 mL) was added in a similar manner to the step of Example 49, The title compound was prepared from 3-dimethyl-5-benzylthiophene (11.9 g, 58.8 mmol), tin (IV) chloride (10.3 ml, 88.0 mmol) and anhydrous methylene chloride (130 ml) g, 68%): MS (+ ESI): [M + H] 355;

Elemental analysis for C ₂₁ H ₁₈ FO ₂ S:

Calculated: C, 71.16, H, 5.40, N, 0.00.

Found: C, 70.01, H, 5.43, N, -0.06.

Step 2 2-Fluoro-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-

(2-benzyl-4,5-dimethyl-thiophen-3-yl) - (3-fluoro-4-methoxy- phenyl) -methanone (prepared according to the procedure of Example 49, step MS (EI): [M +] 322; &lt; RTI ID = 0.0 &gt;

Elemental analysis for C ₂₀ H ₁₅ FOS:

Calcd: C, 74.51, H, 4.69, N, 0.00.

Found: C, 73.96, H, 4.94, N, -0.08.

Step 3 (2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -Phenyl-propionic acid

(2,3-b] thiophen-4-yl) -phenol (1.0 g, 3.1 mmol), ( Methyl ester (0.67 g, 3.7 mmol), triphenylphosphine (0.98 g, 3.7 mmol), diethyl azodicarboxylate (0.59 ml, 3.7 mmol) and anhydrous Benzene &lt; / RTI &gt; (20 ml), the title compound is obtained as a white solid (0.86 g) which is used without further purification.

2,3-b] thiophen-4-yl) -2,3-dimethyl-naphtho [2,3- b] thiophene-4-carboxylate was obtained in a manner similar to the step of Example 49, (0.86 g, 1.8 mmol), aqueous potassium hydroxide (3.6 mL of a 1N solution, 3.6 mmol), tetrahydrofuran (12 mL) and methanol (4 mL ), The title compound is obtained as a white solid (0.41 g, 63%): Rot. [a] 25 / D = +0.87 (11.473 mg / mL, MeOH);

MS (EI): [M &lt; + &gt;]470;

Elemental analysis for C ₂₉ H ₂₃ FO ₃ S:

Calcd: C, 74.20, H, 4.39, N, 0.00.

Found: C, 73.95, H, 5.22, N, 0.12.

Example 52

2-fluoro-phenoxy-3-phenyl-isoxazole-4-carboxylic acid (2- Propionic acid

Step 1 Acetic acid 2-fluoro-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-

In a manner similar to that of Example 49, Step 3, by reacting 2-fluoro-4- (2,3-dimethyl-naphtho [2,3-b] yellow solid (1.1 g) was obtained from acetic anhydride (0.36 ml, 3.8 mmol) and pyridine (7.5 ml) which was used without further purification.

Fluoro-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester (1.1 g, The title compound is obtained as a yellow oil (0.86 g, 67%), MS (EI (ESI), 254 mg, ): [M &lt; + &gt;], 1 bromine isomeric pattern, 442/444.

Step 2 2-Fluoro-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-

(0.29 g, 0.65 mmol), aqueous potassium hydroxide &lt; RTI ID = 0.0 &gt; MS (EI): [M +], 1 &lt; RTI ID = 0.0 &gt; Bromine isomeric pattern, 400/402.

Step 3 Preparation of (R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -Phenyl-propionic acid methyl ester

2-fluoro-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4-yl) -phenol (0.29 g, 0.72 mmol) (0.19 g, 1.1 mmol), triphenylphosphine (0.28 g, 1.1 mmol), diethyl azodicarboxylate (0.17 ml, 1.1 mmol) and anhydrous benzene ), The title compound is obtained as a white solid (0.23 g, 58%): MS (EI): [M +], 1 bromine isomeric pattern, 562/564.

Step 4 Preparation of (R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -Phenyl-propionic acid

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -2-fluoro-phenoxy] (0.17 g, 74%) from the title compound as a white solid (0.23 g, 0.41 mmol), aqueous potassium hydroxide (0.50 ml, 0.50 mmol of 1N solution), tetrahydrofuran (6 ml) and methanol ). HPLC analysis shows the main component (82.5%).

Example 53

[9- Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4- yl) -2,6-diisopropyl-phenoxy]

Step 1 A mixture of acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-

(2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenol (5.0 g) was obtained in a manner similar to the step of Example 49, g, 13.7 mmol), acetic anhydride (1.68 mL, 17.8 mmol) and pyridine (85 mL) as a white solid (5.37 g, 91%): mp. 243 to 245 占 폚; _{NMR (DMSO-d 6):} δ 8.49 (s, 1H), 7.98 (d, 1H), 7.49-7.39 (m, 3H), 7.16 (s, 2H), 3.01 (septet, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 1.56 (s, 3H), 1.16 (d, 12H); MS (EI): [M &lt; + &gt;]430;

Elemental analysis for C ₂₈ H ₃₀ O ₂ S:

Calculated: C, 78.10, H, 7.02, N, 0.00.

Found: C, 77.95, H, 7.04, N, 0.07;

HPLC analysis shows the main component (99.3%).

Step 2 A mixture of acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-

In a manner similar to the steps of Example 49, Step 4, acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) The title compound is obtained as a white solid (0.53 g, 56%): NMR (CDCl3) (0.80 g, 18.5 mmol), ferric chloride (16 mg, 0.1 mmol), bromine (0.13 mL, 2.6 mmol) and methylene chloride _{(DMSO-d 6): δ} 8.21 (d, 1H), 7.68-7.62 (m, 1H), 7.60-7.42 (m, 2H), 7.18 (s, 2H), 3.00 (septet, 2H), 2.42 (s , 6H), 1.53 (s, 3H), 1.14 (d, 12H).

Step 3 4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-

In a manner similar to that of Example 49, Step 5, the title compound was obtained from acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- The title compound was prepared as a cream colored solid (0.45 g, 95 mmol) from isopropyl-phenyl ester (0.52 g, 1.0 mmol), aqueous potassium hydroxide (1.64 mL of a 1N solution, 1.6 mmol), tetrahydrofuran (18.5 mL) %): Mp. 212 to 216 占 폚; _{NMR (DMSO-d 6):} δ 8.30 (s, 1H), 8.17 (d, 1H), 7.61 (ddd, 1H), 7.53 (d, 1H), 7.44 (ddd, 1H), 6.92 (s, 2H) , 3.41 (septet, 2H), 2.41 (s, 3H), 1.55 (s, 3H), 1.15 (d, 12H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 466/468;

Elemental analysis for C ₂₆ H ₂₇ BrOS:

Calculated: C, 66.80, H, 5.82, N, 0.00.

Found: C, 66.17, H, 5.63, N, 0.06.

Step 4 A mixture of [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6- diisopropyl-phenoxy]

To a solution of 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) A solution of 6-diisopropyl-phenol (0.42 g, 0.89 mmol), methyl bromoacetate (0.36 ml, 3.8 mmol) and potassium carbonate (0.42 g, 3.0 mmol) was stirred for 2 days. The reaction mixture is diluted with water and extracted with diethyl ether. Concentrated under reduced pressure, petroleum ether: ethyl acetate (95: 5) to chromatography to obtain the title compound as a white solid (0.42g, 87%): NMR (DMSO-d 6): δ 8.20 (d, 1H) 2H), 7.66-7.61 (m, 1H), 7.48 (d, 2H), 7.11 (s, 2H), 4.56 (s, , 3H), 1.51 (s, 3H), 1.18 and 1.16 (2 doublets, 12H).

Step 5 To a solution of [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6- diisopropyl-phenoxy]

2,3-b] thiophen-4-yl) -2,6-dimethyl-naphthoquinone was prepared by a method similar to the process of Example 49, (0.40 g, 0.74 mmol), aqueous potassium hydroxide (0.89 ml of a 1N solution, 0.89 mmol), tetrahydrofuran (6 ml) and methanol (2 ml) was obtained as a solid (0.37g, 95%):. mp 228 to 231 ℃; NMR (DMSO-d 6): δ 12.98 (broad s, 1H), 8.19 (d, 1H), 7.65-7.61 (m, 1H ), 7.47 (d, 2H), 7.10 (s, 2H), 4.44 (s, 2H), 3.40 (s, 3H) , 12H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 524/526;

Elemental analysis for C ₂₈ H ₂₉ BrO ₃ S:

Calculated: C, 64.00, H, 5.56, N, 0.00.

Found: C, 63.32, H, 5.39, N, 0.01.

HPLC analysis shows the main component (96%).

Example 54

(2R) -2- [2,6-dibromo-4- (2,3-dimethyl-naphtho [2,3- b] furan-4-yl) -phenoxy]

Step 1 (2-Benzyl-4,5-dimethyl-furan-3-yl) - (4- methoxy- 3,5- dibromo-phenyl)

Dibromo-p-anisic acid (8.0 g, 25.8 mmol), oxalyl chloride (2.48 mL, 28.4 mmol), N, N-dimethylform The title compound was prepared as a solid from (2 drops), 2,3-dimethyl-5-benzylfuran (5.77 g, 31.0 mmol), tin (IV) chloride (3.30 mL, 28.4 mmol) and anhydrous methylene chloride 2.92g, was obtained as 24%): NMR (DMSO- d 6): δ 7.81 (s, 2H), 7.28-7.14 (m, 3H), 7.04 (d, 2H), 3.86 (s, 3H), 3.84 (s, 2 H), 2.19 (s, 3 H), 1.81 (s, 3 H); MS (EI): [M @ +], 2 bromine isotopic pattern 476 (25%), 478 (50%), 480 (25%).

Step 2 4- (2,3-Dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-dibromo-phenol

(2-benzyl-4,5-dimethyl-furan-3-yl) - (4-methoxy-3,5- dibromo-phenyl) -methanone was prepared by a method similar to the step of Example 49, (0.93 g) from the title compound (2.52 g, 5.30 mmol), boron tribromide (3.79 mL, 40.0 mmol) and methylene chloride (18 mL) which was used without further purification: NMR _{6): δ 10.19 (br s} , 1H), 8.01 (d, 1H), 7.98 (s, 1H), 7.56 (s, 2H), 7.51 (d, 1H), 7.44 (ddd, 1H), 7.36 (ddd , &Lt; / RTI &gt; 1H), 2.39 (s, 3H), 1.62 (s, 3H); MS (-ESI): [MH], 2 bromine isotope pattern 443 (63%), 445 (100%), 447 (63%).

Step 3 Preparation of (2R) -2- [2,6-dibromo-4- (2,3-dimethyl-naphtho [2,3- b] Propionic acid methyl ester

In a manner similar to that of Example 49, Step 6, by reacting 4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] (0.71 g, 3.94 mmol), triphenylphosphine (1.03 g, 3.94 mmol), diethyl (3-methylphenyl) azodicarboxylate (0.62㎖, 3.94mmol) and to give the title compound from anhydrous benzene (3.9㎖) as a solid (1.15g, 96%): NMR (DMSO-d 6): δ 8.04 (d, 1H), 2H), 7.51-7.24 (m, 8H), 5.11 (dd, 1H), 3.63 (s, 3H), 3.53-3.35 (overlapping quartets, ABX pattern, 2H) , 2.41 (s, 3 H), 1.60 (s, 3 H); MS (EI): [M @ +], 2 bromine isotope pattern 606 (52%), 608 (100%), 610 (52%);

Step 4 Preparation of (2R) -2- [2,6-dibromo-4- (2,3-dimethyl-naphtho [ Propionic acid

In a manner similar to that of Example 49, Step 7, 2R) -2- [2,6-dibromo-4- (2,3-dimethyl-naphtho [2,3- b] (0.25 g, 0.41 mmol), aqueous potassium hydroxide (0.82 ml of a 1N solution, 0.82 mmol), tetrahydrofuran (3.0 ml) and tetrahydrofuran from methanol to give the title compound (1.0㎖) as a white solid (0.24g, 100%): NMR (DMSO-d 6): δ 13.11 (br s, 1H), 8.02 (d, 1H), 8.01 (s, 1H), 7.66 (s, 2H), 7.49-7.21 (m, 8H), 5.19 (t, 1H), 3.36 (d, 2H), 2.39 (s, 3H), 1.58 MS (EI): [M @ +], 2 bromine isotope pattern 592 (50%), 594 (100%), 596 (50%);

Elemental analysis for C ₂₉ H ₂₂ Br ₂ O ₄ :

Calculated: C, 58.61, H, 3.73, N, 0.00.

Found: C, 58.52, H, 4.01, N, 0.05.

Example 55

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -2,6- diisopropyl-phenoxy] 3-phenyl-propionic acid

Step 1 (2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4-yl) -2,6-diisopropyl-phenoxy ] -3-phenyl-propionic acid methyl ester

(9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) (0.46 g, 0.98 mmol), (S) -2-hydroxy-3-phenylpropionic acid, methyl ester (0.70 g, 3.9 mmol), triphenylphosphine g, 3.9mmol), diethyl azodicarboxylate (to obtain the title compound from 0.62㎖, 3.9mmol) and anhydrous benzene (1.0㎖) as a white solid (0.20g, 32%): NMR (DMSO-d 6) 2H), 7.35-7.27 (m, 5H), 7.06 (s, 2H), 4.55 (t, 3.55 (s, 3H), 3.35-3.19 (m, 4H), 2.41 (s, 3H), 1.49 (s, 3H), 1.13 (d, 6H), 1.06 and 1.04 (2 doublets, 6H, rotamer).

Step 2 (2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- ] -3-phenyl-propionic acid

2,3-b] thiophen-4-yl) -2,3-dimethyl-naphtho [2,3- b] thiophene-4-carboxylate was obtained in a manner similar to the step of Example 49, (0.20 g, 0.31 mmol), aqueous potassium hydroxide (1.2 mL of a 1N solution, 1.2 mmol), tetrahydrofuran (3 mL) and methanol (1 ml), the title compound is obtained as a white solid (0.18 g, 93%): mp. 222-226 占 폚; _{NMR (DMSO-d 6):} δ 13.0 (broad s, 1H), 8.20 (d, 1H), 7.64 (ddd, 1H), 7.48-7.46 (m, 2H), 7.38-7.27 (m, 5H), 7.06 (s, 2H), 4.48 (t, 1H), 3.40-3.26 (m, 4H), 2.42 (s, 3H), 1.50 (s, 3H), 1.14 (d, 6H), 1.07 (d, 6H); MS (-ESI): [MH], 1 bromine isotope pattern 558/560;

Elemental analysis for C ₃₅ H ₃₅ BrO ₃ S:

Calculated: C, 68.28, H, 5.73, N, 0.00.

Found: C, 68.15, H, 5.83, N, 0.03.

HPLC analysis shows the main component (100%).

Example 56

3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-hydroxy-phenyl] -carbamic acid tert- Butyl ester

To a solution of 2-amide-6-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] -thiophen-4-yl) -phenol (0.382 g, 0.801 mmol) and di-t-butyl dicarbonate (0.191 g, 0.875 mmol) was heated at 70 for 15 hours. The reaction mixture is diluted with ether and silica gel is added. The ether was removed and the adsorbed compound was flash chromatographed (9: 1, petroleum ether: ethyl acetate) to give the title compound as a white solid (0.447 g, 97%): mp. 205 to 207 ℃: NMR (DMSO-d 6): δ 9.61 (s, 1H), 8.55 (2, 1H), 8.19 (d, J = 8Hz, 1H), 7.65 (ddd, J = 8, 6, 2Hz (D, J = 1 Hz, 3H), 1.47 (d, J = 1 Hz, 3H), 7.52-7.46 9H); MS (EI): 2 bromine isotopic pattern 575 (20%, M +), 577 (50%, M +), 579 (20%, M +), 519 (50% , M + H-tBu), 523 (55%, M + H-tBu);

Elemental analysis for C ₂₅ H ₂₃ Br ₂ O ₃ S:

Calculated: C, 52.01, H, 4.02, N, 2.43.

Found: C, 51.09, H, 3.84, N, 2.28.

Example 57

Bromo-methoxy-5-nitro-phenyl) -2,3-dimethyl-naphtho [2,3- b] thiophene

(0.22 ml, 3.55 mmol) and potassium carbonate (0.490 g, 3.55 mmol) were added to a solution of 9-bromo-4- (3-bromo-methoxy- To a stirred solution of 2,3-dimethyl-naphtho [2,3-b] thiophene (0.600 g, 1.183 mmol) at room temperature. After 7 h, additional iodomethane (0.1 ml, 1.51 mmol) is added and the suspension is stirred for a further 17 h. The reaction mixture is added to water and extracted with ether. Silica gel is added. The ether was removed and the adsorbate was flash chromatographed (95: 5 petroleum ether: ethyl acetate) to yield the title compound as a yellow solid (0.416 g, 67%): mp. 204 to 205 占 폚; _{NMR (DMSO-d 6):} δ 8.23 (d, J = 8Hz, 1H), 8.33 (d, J = 2Hz, 1H), 8.04 (d, J = 2Hz, 1H), 7.69 (ddd, J = 8, (D, J = 1 Hz, 1H), 7.47 (d, J = 8 Hz, 1H), 4.05 , 1.62 (d, J = 1 Hz, 3H); MS (FAB +): 2 bromine isotope pattern 519, 521, 523;

Elemental analysis for C ₂₁ H ₁₅ Br ₂ NO ₃ S:

Calculated: C, 48.39, H, 2.90, N, 2.69.

Found: C, 48.16, H, 2.69, N, 2.58.

Example 58

3-Bromo-5- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4-yl) -2- methoxy-

2,3-b] thiophene (0.372, 0.714 mmol), tin dichloride &lt; RTI ID = 0.0 & (805 mg, 3.57 mmol) and ethyl acetate (4 mL) is heated to 70 &lt; 0 &gt; C to dissolve. After 30 minutes, the reaction mixture is cooled to room temperature, diluted with ethyl acetate, and silica gel is added. The ethyl acetate was removed and the adsorbed conjugate was flash chromatographed (4: 1 petroleum ether: ethyl acetate) to yield the title compound as a white solid (0.324 g, 92%): mp. 198 to 200 ℃: NMR (DMSO-d 6): δ 8.18 (d, J = 8Hz, 1H), 7.64 (ddd, J = 8, 6, 1Hz, 1H), 7.58 (d, J = 8Hz, 1H) , 7.50 (ddd, J = 8, 6, 1 Hz, 1H), 6.70 (d, J = 2 Hz, 1H), 6.64 ), 2.44 (d, J = 1 Hz, 3H), 1.73 (d, J = 1 Hz, 3H); MS (EI): 2 bromine isotope pattern 489 (50%, M +), 491 (100%, M +), 493 (60%, M +);

Elemental analysis for C ₂₁ H ₁₇ Br ₂ NOS:

Calculated: C, 51.34, H, 3.49, N, 2.85.

Found: C, 51.00, H, 3.43, N, 2.71.

Example 59

2-methoxy-phenylamino] -acetic acid methyl ester &lt; RTI ID = 0.0 &gt; (3-bromo-5-

Methyl bromoacetate (0.285 ml, 3.01 mmol) in DMF (1.7 ml) was added dropwise to a solution of 3-bromo-5- (9-bromo-2,3-dimethyl- (0.260 g, 0.529 mmol) and potassium carbonate (0.411 g, 3.00 mmol) in anhydrous tetrahydrofuran (10 mL) at room temperature. After 2 days, additional methyl bromoacetate (0.135 ml, 1.5 mmol) and the reaction mixture are stirred for an additional day. The reaction mixture is added to water, the solid is filtered off and washed with water. The solid was triturated with petroleum ether and dried under vacuum at 60 &lt; 0 &gt; C to yield the title compound as a white solid (0.212 g, 71%): mp. 194 to 198 ℃: NMR (DMSO-d 6): δ 8.17 (dd, J = 8, 1Hz, 1H), 7.63 (ddd, J = 8, 6, 1Hz, 1H), 7.53-7.45 (m, 2H) , 6.77 (d, J = 2 Hz, 1H), 6.54 (d, J = 2 Hz, 1H), 6.10 , 3H), 3.52 (s, 3H), 2.43 (s, 3H), 1.69 (s, 3H); MS (FAB +): 2 bromine isotope pattern 561, 563, 565;

Elemental analysis for C ₂₄ H ₂₁ Br ₂ NO ₃ S:

Calculated: C, 51.17, H, 3.76, N, 2.49.

Found: C, 50.43, H, 3.63, N, 2.53.

Example 60

Yl) -2-methoxy-phenylamino] acetic acid &lt; RTI ID = 0.0 &gt; (3-Bromo-

Aqueous potassium hydroxide (1N, 0.64 ml, 0.64 mmol) was added to a solution of [3-bromo-5- (9-bromo-2,3-dimethyl- , 3-b] thiophen-4-yl) -2-methoxy-phenylamino] acetic acid methyl ester (0.180 g, 0.320 mmol) at room temperature. After 4 hours, the solvent is removed and water is added. The suspension is acidified and extracted with ether. Silica gel is added. The ether was removed and the adsorbed compound was purified by flash chromatography (gradient: 7: 3 petroleum ether: ethyl acetate, 9: 1 ethyl acetate: methanol) to yield the title compound as a white solid (0.112 g, 64% . > 190 ℃ _{(decomposition): NMR (DMSO-d 6} ): δ 8.16 (d, J = 8Hz, 1H), 7.63 (ddd, J = 8, 6, 1Hz, 1H), 7.56 (d, J = 8Hz, 1H), 7.48 (ddd, J = 8, 6,1 Hz, 1H), 6.72 (d, J = 2 Hz, 1H), 6.43 s, 3H), 3.46 (s, 2H), 2.42 (s, 3H), 1.71 (s, 3H); MS (FAB +): 2 bromine isotope pattern 547, 549, 551;

Elemental analysis for C ₂₃ H ₁₉ Br ₂ NO ₃ S:

Calcd: C, 50.29, H, 3.49, N, 2.55.

Found: C, 49.54, H, 3.73, N, 2.26.

Example 61

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -Phenyl-propionic acid

Step 1 (2-Benzyl-4,5-dimethyl-thiophen-3-yl) - (4- methoxy-

In a manner similar to that of Example 49, Step 1, 3,5-diethyl-p-anisic acid (9.45 g, 45.4 mmol, J. Lipowitz and T. Cohen, J. Org. Chem. 1986, 18, 2213-2215; CK Bradsher et al; J. Am. Chem. Soc. 1954, 76, 2357-2362; N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylthiophene (11.0 g, 54.5 mmol), chloride tin (IV) (5.8㎖, 49.9mmol) and the title compound was obtained from a dry methylene chloride (291㎖) as an oil (17.7g, 99%): NMR (DMSO-d 6): δ 7.43 (s, 2H) 3H), 2.26 (s, 3H), 1.83 (s, 3H), 7.24-7.11 (m, 3H), 7.07-7.01 , &Lt; / RTI &gt; 3H), 1.14 (t, 6H).

Step 2 4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl)

In a manner similar to that of Example 49, Step 2, (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (4-methoxy- (16.6 g) from the title compound (17.67 g, 45.0 mmol), boron tribromide (12.8 mL, 135.4 mmol) and methylene chloride (90 mL) which was used without further purification: NMR (DMSOd _{6): δ 8.41 (s,} 1H), 8.31 (s, 1H), 7.93 (d, 1H), 7.47 (d, 1H), 7.42 (ddd, 1H), 7.32 (ddd, 1H), 6.86 (s, 2H), 2.76-2.56 (complex m, ABX pattern, 4H), 2.39 (s, 3H), 1.60 (s, 3H), 1.14 (t, 6H); MS (+ ESI): [M] &lt; + &gt; 360.

Step 3 Acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-

In a manner similar to that of Example 49, Step 3, by reacting 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl- , 46.0 mmol), acetic anhydride (5.66 mL, 59.9 mmol), pyridine (92 mL) and methylene chloride (92 mL) and triturated with acetone: hexane (1: 1) is obtained as (6.58g, 37%): NMR (DMSO-d 6): δ 8.47 (s, 1H), 7.97 (d, 1H), 7.49-7.34 (m, 3H), 7.11 (s, 2H), 2.60-2.46 (m, 4H), 2.40 (doublet s, 6H), 1.59 (s, 3H), 1.13 (t, 6H); MS (+ ESI): [M + H] &lt; + &gt;403;

Elemental analysis for C ₂₆ H ₂₆ O ₂ S:

Calcd: C, 77.57, H, 6.51, N, 0.00.

Found: C, 76.46, H, 6.60, N, 0.19.

Step 4 A mixture of acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-

In a similar manner to the procedures of Example 49, Step 4, acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl- The title compound is obtained as a solid (1.2 g, 100%): NMR (DMSO (CDCl3, 300 MHz, DMSO _{-d 6): δ 8.20 (d} , 1H), 7.68-7.61 (m, 1H), 7.49 (d, 2H), 7.13 (s, 2H), 2.60-2.47 (m, 4H), 2.42 (s, 3H ), 2.40 (s, 3H), 1.56 (s, 3H), 1.13 (t, 6H); MS (+ APCI): [M + H], 1 bromine isotope pattern 481/483;

Elemental analysis for C ₂₆ H ₂₅ BrO ₂ S:

Calculated: C, 64.86, H, 5.23, N, 0.00.

Found: C, 63.06, H, 5.13, N, 0.03.

Step 5 4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl)

(9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6- The title compound was prepared as a solid (0.83 &lt; RTI ID = 0.0 &gt; mmol) &lt; / RTI &gt; from methanol enough to afford diethyl- phenyl ester (1.0 g, 2.1 mmol), aqueous potassium hydroxide (2.5 mL of a 1N solution, 2.5 mmol), tetrahydrofuran g, was obtained as 91%): NMR (DMSO- d 6): δ 8.36 (s, 1H), 8.16 (d, 1H), 7.61 (ddd, 1H), 7.55 (d, 1H), 7.44 (ddd, 1H), 6.88 (s, 2H), 2.76-2.56 (complex m, ABX pattern, 4H), 2.41 (s, 3H), 1.58 (s, 3H), 1.14 (t, 6H); MS (+ APCI): [M + H], 1 bromine isotope pattern 439/441.

Step 6 (2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -3-phenyl-propionic acid methyl ester

(9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6- Diethyl-phenol (0.83 g, 1.89 mmol), (S) -2-hydroxy-3-phenylpropionic acid, methyl ester (2.72 g, 15.0 mmol), triphenylphosphine (3.96 g, 15.0 mmol) azodicarboxylate (2.36㎖, 15.0mmol) and the title compound was obtained from the anhydrous benzene (40㎖) as a solid (0.74g, 65%): NMR (DMSO-d 6): δ 8.18 (d, 1H), (M, 2H), 7.37-7.23 (m, 5H), 7.01 (s, 2H), 4.69 m, 2H), 2.74-2.45 (m, 4H), 2.41 (s, 3H), 1.53 (s, 3H), 1.09 and 1.08 (2 t, 6H); MS (+ APCI): [M + H], 1 bromine isotope pattern 601/603.

Step 7 (2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -3-phenyl-propionic acid

2,3-b] thiophen-4-yl) -2,3-dimethyl-naphtho [2,3- b] thiophene-4-carboxylate was obtained in a manner similar to the step of Example 49, (0.70 g, 1.16 mmol), aqueous potassium hydroxide (2.3 mL of a 1 N solution, 2.3 mmol), tetrahydrofuran (11.6 mL) and homogenous A solid is obtained from methanol which is sufficient to produce a solution. Recrystallized from hexane / acetone to give the title compound as a white solid (0.15g, 22%): NMR (DMSO-d 6): δ 12.91 (br s, 1H), 8.18 (d, 1H), 7.63 (ddd (M, 2H), 7.51-7.42 (m, 2H), 7.36-7.22 (m, 5H), 7.00 (s, 2H), 4.62 (S, 3H), 1.45 (t, 2H); MS (-ESI): [MH], 1 bromine isotope pattern 585/587;

Elemental analysis for C ₃₃ H ₃₁ BrO ₃ S:

Calcd: C, 67.46, H, 5.32, N, 0.00.

Found: C, 66.84, H, 5.24, N, 0.03.

Example 62

3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3 -Phenyl-propionylamino} -acetic acid &lt; / RTI &gt;

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- (0.34g, 1.77mmol), glycine ethyl ester hydrochloride (0.24g, 1.72mmol), phenyl- propionic acid (0.5g, 0.89mmol), 1- (3- dimethyl- aminopropyl) -3- ethylcarbodiimide hydrochloride , Potassium carbonate (0.50 g, 3.62 mmol) and methylene chloride (6 ml) was stirred at room temperature. After 3 days the reaction was diluted with methylene chloride, washed twice with water, washed once with brine and dried (Na ₂ SO _4). Adsorbed onto silica gel and chromatographed with hexane: ethyl acetate (75:25) to give a solid (0.4 g) which was partitioned between potassium hydroxide (1.11 ml, 1.11 mmol), tetrahydrofuran (8.9 ml) It is treated with sufficient methanol to produce one solution. 24 hours at room temperature after the reaction mixture was diluted with diethyl ether, once with 1N aqueous hydrochloric acid, washed twice with water, once with brine and dried (Na ₂ SO _4). The screen was concentrated under reduced pressure and recrystallized from hexane / ethyl acetate to give a white solid (0.20g, 36%): NMR (DMSO-d 6): δ 12.58 (br s, 1H), 8.53 (t, 1H), 8.18 (d, 1H), 7.64 (ddd, 1H), 7.52-7.43 (m, 2H), 7.34-7.19 (m, 5H) 3H), 2.29 (s, 3H), 2.19 (s, 3H), 1.56 (s, 3H) ; MS (+ APCI): [M + H], 1 bromine isotope pattern 616/618;

Elemental analysis for C ₃₃ H ₃₀ BrO ₄ S:

Calculated: C, 64.29, H, 4.90, N, 2.27.

Found: C, 63.97, H, 4.48, N, 2.03.

Example 63

[(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- 3-phenyl-propionylamino} -acetic acid

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- (0.48 g, 0.82 mmol), oxalyl chloride (0.071 ml, 0.81 mmol) and benzene (16.3 ml) was stirred at room temperature for 40 minutes. Glycine ethyl ester hydrochloride (0.14 g, 1.0 mmol) and potassium carbonate (0.36 g, 2.6 mmol) were added and the resulting slurry was stirred overnight at room temperature. The reaction mixture was adsorbed onto silica gel and chromatographed with hexane: ethyl acetate (90:10) to give a solid (0.17 g) which was dissolved in a mixture of potassium hydroxide (1.32 ml of a 1N solution, 1.32 mmol), tetrahydrofuran ) And sufficient methanol to produce a homogeneous solution. After stirring for 30 minutes at room temperature, the reaction mixture was diluted with diethyl ether, once with 1N aqueous hydrochloric acid, washed once with once with water, brine and dried (Na ₂ SO _4). The solution is concentrated under reduced pressure, dissolved in methylene chloride, dried (Na ₂ SO _4). And concentrated under reduced pressure to give a white solid (0.14g, 26%): NMR (DMSO-d 6): δ 12.51 (br s, 1H), 8.49 (t, 1H), 8.17 (d, 1H), 7.62 ( 1H), 7.46 (d, 2H), 7.32-7.17 (m, 5H), 6.95 (s, ABX pattern, 2H), 3.30-3.10 (overlapping quartets, ABX pattern, 2H), 2.80-2.50 (compound m, ABX pattern, 4H), 2.41 (s, 3H), 1.54 , 6H); MS (-ESI): [MH], 1 bromine isotope pattern 642/644;

Elemental analysis for C ₃₅ H ₃₄ BrNO ₄ S:

Calcd: C, 65.21, H, 5.32, N, 2.17.

Found: C, 65.03, H, 5.36, N, 2.07.

Example 64

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -phenoxy]

Step 1 A solution of (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- ester

In a manner similar to that of Example 49, Step 6, starting from 4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- , Methyl ester (4.8 g, 26.6 mmol), triphenylphosphine (7.0 g, 26.7 mmol), diethyl azodicarboxylate (4.2 mL, 13.4 mmol), (S) -2-hydroxy- , 26.7mmol) and the title compound was obtained from the anhydrous benzene (74㎖) as a solid (4.8g, 66%): NMR (DMSO-d 6): δ 8.17 (d, J = 8Hz, 1H), 7.62 (ddd J = 8 Hz, 2H), 5.25 (dd, J = 5 Hz), 7.51-7.20 (m, 2H), 2.41 (s, 3H), 1.51 (s, 3H); 3.67 (s, 3H), 3.25 (complex m, ABX pattern, 2H). MS (+ APCI): [M + H] &lt; ⁺ &gt;, 1 bromine isotope pattern 545/547;

Elemental analysis for C ₃₀ H ₂₅ BrO ₃ S:

Calculated: C, 66.06, H, 4.62, N, 0.00.

Found: C, 66.15, H, 4.83, N, -0.11.

Step 2: (2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -phenoxy]

2,3-b] thiophen-4-yl) -2,3-dimethyl-naphtho [2,3- b] thiophene-4-carboxylate was obtained in a manner similar to the step of Example 49, 3-phenyl-propionic acid methyl ester (0.6 g, 1.10 mmol), aqueous potassium hydroxide (1.3 mL of a 1N solution, 1.3 mmol), tetrahydrofuran (15.7 mL) and methanol from to obtain the title compound as a solid (0.58g, 99%): NMR (DMSO-d 6): δ 13.14 (br s, 1H), 8.17 (d, J = 8Hz, 1H), 7.62 (ddd, J = J = 8 Hz, 2H), 5.08 (dd, J = 5, 8 Hz, 1H), 7.48-7.20 (m, ), 3.32-3.15 (overlapping 2 quartets, ABX pattern, 2H), 2.41 (s, 3H), 1.53 (s, 3H); MS (+ APCI): [M + H] &lt; ⁺ &gt;, 1 bromine isotope pattern 531/533;

Elemental analysis for C ₂₉ H ₂₃ BrO ₃ S:

Calcd: C, 65.54, H, 4.36, N, 0.00.

Found: C, 65.51, H, 4.61, N, 0.09.

Example 65

(2S) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Phenyl-propionic acid

Step 1 (2S) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- 3-phenyl-propionic acid methyl ester

(9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6- (20.0 g, 76.3 mmol), diethyl azo (10.4 g, 25.4 mmol), (S) -2-hydroxy-3-phenylpropionic acid, methyl ester The title compound is obtained as a sticky solid (8.66 g, 59%) from dicarboxylate (12.0 ml, 76.2 mmol) and anhydrous THF (139 ml): Opt. Rot. [a] 25 / D = -44.19 (9.188 mg / mL, MeOH); _{NMR (DMSO-d 6):} δ 8.18 (d, J = 8Hz, 1H), 7.62 (ddd, J = 2, 6, 8Hz, 1H), 7.51-7.42 (m, 2H), 7.36-7.23 (m, (S, 3H), 2.22 (s, 3H), 2.17 (s, 3H) (s, 3 H), 1.54 (s, 3 H); MS (+ APCI): [M + H], 1 bromine isotope pattern 537/575;

Elemental analysis for C ₃₂ H ₂₉ BrO ₃ S:

Calculated: C, 67.01, H, 5.10, N, 0.00.

Found: C, 66.72, H, 4.86, N, 0.12.

Step 2 (2S) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- 3-phenyl-propionic acid

2,3-b] thiophen-4-yl) -2,3-dimethyl-naphthoquinone The title compound was prepared from (2S) -2- [4- (9- (4.0 g, 6.97 mmol), aqueous potassium hydroxide (8.4 mL of a 1N solution, 8.4 mmol), tetrahydrofuran (99.6 mL) and a homogeneous solution The title compound is obtained as a white solid (1.45 g, 37%): mp. 134 to 139 占 폚; Opt. Rot. [?] 25 / D = -35.86 (10.040 mg / mL, MeOH);

_{NMR (DMSO-d 6):} δ 12.92 (br s, 1H), 8.17 (d, J = 8Hz, 1H), 7.63 (ddd, J = 2, 6, 8Hz, 1H), 7.52-7.42 (m, 2H ), 7.37-7.21 (m, 5H), 6.97 (s, 2H), 4.72 (t, J = 7 Hz, 1H), 3.25 , &Lt; / RTI &gt; 3H), 2.22 (s, 3H), 1.54 (s, 3H); MS (-ESI): [MH], 1 bromine isotope pattern 557/559;

Elemental analysis for C ₃₁ H ₂₇ BrO ₃ S:

Calcd: C, 66.55, H, 4.86, N, 0.00.

Found: C, 66.17, H, 4.87, N, 0.01.

HPLC analysis shows the main component (98.1%).

Example 66

(2R) -2- [4- (9-bromo-2,3-dimethyl-1-oxo-1H-naphtho [2,3- b] thiophen- Phenoxy] -3-phenyl-propionic acid

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho 92,3-bthiophen-4-yl) -2,6- dimethyl-phenoxy] -Propionic acid (0.5 g, 0.89 mmol), glacial acetic acid (6.6 ml) and 30% aqueous hydrogen peroxide solution (1.0 ml, 9.8 mmol) which is immediately diluted with water and extracted with diethyl ether. Purification by chromatography using methanol / methylene chloride gave the title compound as a pale yellow solid (0.12 g, 23%): Rot. [a] 25 / D = + 29.57 (7.88 mg / mL, MeOH); _{NMR (DMSO-d 6):} δ 13.10 (br s, 1H), 8.28 (d, J = 8Hz, 1H), 7.74 (ddd, J = 1, 7, 8Hz, 1H), 7.63 (ddd, J = 1 1H), 7.39 (d, J = 8 Hz, 1H), 7.36-7.18 (m, 5H), 7.01 (s, 1H), 3.23 (m, 2H), 2.24, 2.21, 2.20, 2.18 (4s, mixture of sulfoxide diastereomers, 6H), 2.17 (s, 3H), 1.42 (s, 3H); MS (-APCI): [MH] ^- , 1 bromine isotope pattern 573/575;

Elemental analysis for C ₃₁ H ₂₇ BrO ₄ S:

Calcd: C, 64.70, H, 4.73, N, 0.00.

Found: C, 64.18, H, 4.44, N, -0.03.

HPLC analysis shows a mixture of two main peaks (45.16%, 47.72%), sulfoxide diastereomer.

Example 67

(R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4- yl) -2,6-diethyl- phenoxy]

Step 1 Synthesis of (2R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen- Propionic acid methyl ester

In a manner similar to that of Example 49, Step 6, by reacting 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl- (3.36 g, 18.6 mmol), triphenylphosphine (4.8 g, 18.3 mmol), diethyl azodicarboxylate (0.48 g, 2.33 mmol) and (S) -2-hydroxy- 2.92㎖, 18.5mmol) and the title compound was obtained from the anhydrous benzene (75㎖) as a solid (0.50g, 42%): NMR (DMSO-d 6): δ 8.44 (s, 1H), 7.94 (d, J J = 7 Hz, 2H), 3.55 (s, 3H), 3.27 and 3.22 (overlapping 2 dd, J = 8 Hz, 1H), 7.48-7.22 6, 13 Hz, 2H), 2.70-2.40 (complex m, ABX pattern 4H), 2.38 (s, 3H), 1.53 (s, 3H), 1.10 and 1.09 (overlapping 2 triplets, J = 8 Hz, 6H); MS (+ APCI): [M + H] &lt; ⁺ &gt;, 523.

Step 2 Synthesis of (2R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen- Propionic acid

In a manner similar to that of Example 49, Step 7, (2R) -2- [4- (2,3-dimethyl-naphtho [2,3- b] thiophen- (0.46 g, 0.88 mmol), aqueous potassium hydroxide (1.1 mL of a 1N solution, 1.1 mmol), tetrahydrofuran (12.6 mL) and a homogeneous solution to give the title compound as a white solid (0.43g, 89%) from sufficient _{methanol: NMR (DMSO-d 6)} : δ 12.91 (br s, 1H), 8.44 (s, 1H), 7.94 (d, J = 8Hz (M, 8H), 6.98 (s, 2H), 4.61 (t, J = 7 Hz, 1H), 3.25 2H), 2.55 (s, 3H), 1.55 (s, 3H), 1.10 and 1.09 (overlapping 2 triplets, J = 8Hz, 6H); MS (-ESI): [MH] ^- , 507;

Elemental analysis for C ₃₃ H ₃₂ O ₃ S 0.6H ₂ O:

Calculated: C, 76.30, H, 6.44, N, 0.00.

Found: C, 76.44, H, 6.49, N, 0.04.

Example 68

3-phenyl-propyl) -2, &lt; / RTI &gt; &Lt; RTI ID = 0.0 &gt;

(2R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl (2 drops), benzene (9 ml), glycine ethyl ester (0.27 g, 0.53 mmol), oxalyl chloride (0.046 ml, 0.53 mmol), N, N-dimethylformamide A solid is obtained from hydrochloride (0.18 g, 1.29 mmol) and calcium carbonate (0.46 g, 3.33 mmol) which is adsorbed onto silica gel and chromatographed with hexane: ethyl acetate (90:10). The resulting solid (0.18 g) is treated with sufficient methanol to produce potassium hydroxide (2.34 ml of a 1N solution, 2.34 mmol), tetrahydrofuran (10 ml) and homogeneous solution. Is obtained from which the title compound as a pale yellow solid (0.10g, 33%): NMR (DMSO-d 6): δ 12.52 (br s, 1H), 8.48 (t, J = 6Hz, 1H), 8.43 (s, 1H), 7.94 (d, J = 8 Hz, 1H), 7.48-7.16 (m, 8H), 6.93 (s, 2H), 4.73 (t, J = 7 Hz, 1H), 3.79 and 3.73 (Dd, J = 7, 14 Hz, 1H), 3.15 (dd, J = 7, 14 Hz, 1H), 2.80-2.50 (compound m, ABX pattern, 4H), 2.39 , 3H), 1.56 (s, 3H), 1.07 (t, J = 8 Hz, 6H); MS (+ APCI): [M + H] &lt; ⁺ &gt;,566;

Elemental analysis for C ₃₅ H ₃₅ NO ₄ S:

Calcd: C, 74.31, H, 6.24, N, 2.48.

Found: C, 74.11, H, 6.69, N, 2.24.

Example 69

4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl)

Step 1 (2-Benzyl-4,5-dimethyl-furan-3-yl) - (4- methoxy-

In analogy to the procedure of example 49, step 1, 3,5-diethyl-p-anisic acid (10.66 g, 51.2 mmol; J. Lipowitz and T. Cohen, J. Org. J. Alexander, Org. Prep. Proced. Int., 1986, 18, 2213-2215), &lt; RTI ID = 0.0 &gt; (2 drops), 2,3-dichloroaniline (4.9 ml, 56.2 mmol), 4-bromo-2,6-diethylaniline The title compound is obtained as an oil (22 g, &gt; 100%) from dimethyl-5-benzylfuran (11.4 g, 61.2 mmol), tin (IV) chloride (6.6 mL, 56.4 mmol) and anhydrous methylene chloride (198 mL) _{NMR (DMSO-d 6):} δ 7.42 (s, 2H), 7.29-7.21 (m, 3H), 7.04 (d, J = 7Hz, 2H), 3.82 (s, 2H), 3.74 (s, 3H), 2.61 (quartet, J = 8 Hz, 4H), 2.19 (s, 3H), 1.83 (s, 3H), 1.13 (t, J = 8 Hz, 6H).

Step 2 4- (2,3-Dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-diethyl-

(4-methoxy-3,5-diethyl-phenyl) - (4-methoxy-benzyl) The title compound was obtained as an off-white solid (3.09 g, 17.5%) after refluxing for 4 hours: methanone (22 g), boron tribromide (36.8 ml, 389 mmol) and methylene chloride (180 ml) _{DMSO-d 6): δ 8.29} (s, 1H), 7.96 (d, J = 8Hz, 1H), 7.90 (s, 1H), 7.57 (d, J = 8Hz, 1H), 7.39 (ddd, J = 1 , 7.8 (s, 1H), 7.29 (ddd, J = 1, 7, 8 Hz, 1H), 6.89 (s, 1H), 2.75-2.55 (compound m, ABX pattern 4H) (s, 3H), 1.15 (t, J = 8 Hz, 6H); MS (EI): [M &lt; + &gt;]344;

Elemental analysis for C ₂₄ H ₂₄ O ₂ :

Calculated: C, 83.69, H, 7.02, N, 0.00.

Found: C, 82.53, H, 7.11, N, 0.05.

Example 70

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] Phenyl-propionic acid

Step 1 A mixture of acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] furan-

In a manner similar to that of Example 49, Step 3, by reacting 4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-diethyl- A solid (2.23 g) was obtained from acetic anhydride (0.62 ml, 6.6 mmol) and pyridine (10.2 ml) which was used without further purification.

In a manner similar to that of Example 49, Step 4, acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) The title compound is obtained as a solid (0.29 g, 10%): NMR (DMSO-d6, _{d 6): δ 8.26 (d} , J = 8Hz, 1H), 7.64 (ddd, J = 1, 7, 8Hz, 1H), 7.59 (d, J = 9Hz, 1H), 7.48 (ddd, J = 1, 3H), 2.42 (s, 3H), 1.54 (s, 3H), 2.54 (s, 2H), 2.54 and 2.53 (overlapping quartets, J = 1.14 (t, J = 7 Hz, 6 H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 464/466.

Step 2 4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] furan-4-yl)

In a manner similar to that of Example 49, Step 5, acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] (0.29 g, 0.62 mmol), from aqueous methanol (0.75 ml, 0.75 mmol), aqueous tetrahydrofuran (8.9 ml) and methanol sufficient to give a homogeneous solution, was obtained as 100%): NMR (DMSO- d 6): δ 8.36 (s, 1H), 8.21 (d, J = 8Hz, 1H), 7.63 (d, J = 8Hz, 1H), 7.59 (ddd, J (Ddd, J = 1, 7, 8 Hz, 1H), 6.91 (s, 2H), 2.69 and 2.62 (overlapping quartets, J = 7 Hz, 4H), 2.41 , 3H), 1.55 (s, 3H), 1.14 (t, J = 7 Hz, 6H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 442/424.

Step 3 (2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] 3-phenyl-propionic acid

2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -2 (3H) -quinolinone was prepared in a manner similar to that of Example 49, Step 6, , Methyl ester (1.38 g, 7.66 mmol), triphenylphosphine (1.98 g, 7.55 mmol), 2-hydroxy- , The title compound was obtained as a solid (0.15 g, 39%) from diethylazodicarboxylate (1.2 mL, 7.62 mmol) and anhydrous benzene (0.85 mL) and used without further purification.

2,3-b] furan-4-yl) - (4-fluoro-phenyl) (0.15 g, 0.25 mmol), aqueous potassium hydroxide (0.98 ml of a 1N solution, 0.98 mmol), tetrahydrofuran (2.5 ml) and a homogeneous solution to give the title compound from sufficient methanol to produce a white solid (0.1g, 71%): NMR (DMSO-d 6): δ 12.95 (br s, 1H), 8.23 (d, J = 8Hz, 1H) J = 7 Hz, 1 H), 3.25 (d, J = 8 Hz), 7.66 (m, 1H), 7.64-7.53 (m, 2H), 7.43-7.30 7Hz, 2H), 2.82-2.52 (complex m, ABX pattern, 4H), 2.41 (s, 3H), 1.49 (s, 3H), 1.11 and 1.10 (overlapping 2 triplets, J = 7 Hz, 6H); MS (-ESI): [MH], 1 bromine isotope pattern 569/571;

Elemental analysis for C ₃₃ H ₃₁ BrO ₄ :

Calcd: C, 69.35, H, 5.47, N, 0.00.

Found: C, 69.93, H, 5.84, N, 0.19.

HPLC analysis shows the main component (98.3%).

Example 71

(R) -2- [2-Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -phenoxy]

Step 1 (2R) -2- [2-Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -phenoxy]

Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (0.80 g) was obtained in a manner similar to that of Example 49, 3.2 mmol), methyl (S) - (-) - lactate (0.24 ml, 3.3 mmol), triphenylphosphine (g 0.84, 3.2 mmol), diethyl azodicarboxylate ) And anhydrous benzene (5 ml), the title compound was obtained as a white solid (0.67 g, 68%): mp. 65 to 66 占 폚; _{NMR (DMSO-d 6):} δ 8.46 (s, 1H), 7.96 (d, J = 8Hz, 1H), 7.50-7.30 (m, 3H), 7.14 (m, 1H), 7.09 and 7.08 (2 dd, J = 8 Hz, Atrop isomer, 1H), 6.95 and 6.92 (2 d, J = 8 Hz, Atrop isomer, 1H), 5.14 and 5.11 (2 quartets, J = 7 Hz, Atrop isomer, (J = 7 Hz) at 3.61 (s, 3H), 2.00 (m, 2H), 1.77-1.50 δ 1.57 with single line, 12H); MS (EI): [M &lt; + &gt;],458;

Elemental analysis for C ₂₉ H ₃₀ O ₃ S:

Calculated: C, 75.95, H, 6.59, N, 0.00.

Found: C, 74.93, H, 6.55, N, -0.09.

Step 2 (2R) -2- [2-Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -phenoxy]

2,3-b] thiophen-4-yl) -2,3-dimethyl-naphthoquinone The title compound was prepared from (2R) -2- [ (0.55 &lt; RTI ID = 0.0 &gt; (0.55 g, &lt; / RTI &gt; 1.3 mmol), from aqueous methanolic potassium hydroxide (1.98 mL, 1.98 mmol), tetrahydrofuran (9 mL) g, 95%): &lt; RTI ID = 0.0 &gt; Opt. Rot. [a] 25 / D = + 7.95 (10.068 mg / mL, MeOH);

_{NMR (DMSO-d 6):} δ 13.02 (br s, 1H), 8.46 (s, 1H), 7.96 (d, J = 8Hz, 1H), 7.50-7.30 (m, 3H), 7.13 and 7.12 (2 doublets (2 doublets, J = 8 Hz, atropisomer, 1 H), 7.11 and 7.09 (2 dd, J = 2, 8 Hz, atropisomer, 1H), 6.93 and 6.91 (J = 7 Hz) at and δ at m δ 1.60 (q, J = 7 Hz, 1H), 3.44 (m, 1H), 2.41 Single line at 1.58, 12H); MS (EI): [M &lt; + &gt;],444;

Elemental analysis for C ₂₈ H ₂₈ O ₃ S:

Calculated: C, 75.64, H, 6.35, N, 0.00.

Found: C, 74.10, H, 6.32, N, -0.09.

HPLC analysis shows the main component (99.99%).

Example 72

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -2- cyclopentyl-

Cyclopentyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophene-2- carboxylate was obtained in a manner similar to that of Example 49, Step 6, (0.37 g, 0.99 mmol), methyl (S) - (-) - lactate (0.75 g, 7.9 mmol), triphenylphosphine (2.1 g, 8.0 mmol), diethyl azodicarboxylate (1.23 ml, 7.8 mmol) and anhydrous benzene (1.0 ml), the title compound was obtained as a solid (0.20 g, 28%) which was used without further purification.

2,3-b] thiophen-4-yl) -2,3-dimethyl-naphtho [2,3- b] thiophene-4-carboxylate was obtained in a manner similar to the step of Example 49, -Phenoxy] -propionic acid methyl ester (0.20 g, 0.37 mmol), aqueous potassium hydroxide (0.74 ml of a 1N solution, 0.74 mmol), tetrahydrofuran (3.7 ml) and a homogeneous solvent from methanol to give the title compound as an off-white solid (0.18g, 95%): NMR (DMSO-d 6): δ 13.00 (br s, 1H), 8.18 (d, J = 8Hz, 1H), 7.63 (m, 1H), 7.50-7.40 (m, 2H), 7.14 and 7.13 (2 doublets, J = 2 Hz, atropisomer, 1H), 7.10 and 7.09 (2 dd, J = 2, 8 Hz, atropisomer, (M, 2H), 2.94 (s, 3H), 2.94 (s, 3H) 1.78-1.46 (containing a single line at 12.5 and at 1.58 (j = 7 Hz, atrop isomer) delta 1.54 containing m 2 doublets, 12H); MS (-ESI): [MH], 1 bromine isotope pattern 521/523;

Elemental analysis for C ₂₈ H ₂₇ BrO ₃ S:

Calculated: C, 64.24, H, 5.20, N, 0.00.

Found: C, 64.11, H, 5.52, N, 0.10.

Example 73

3-dimethyl-naphtho [2,3-d] thiophen-4-yl) -2-cyclopentyl-phenoxy] -butyric acid

Step 1 4- [9- Bromo-2,3-dimethyl-naphtho [2,3-d] thiophen-4- yl) -2-cyclopentyl-phenoxy] -butyric acid methyl ester

2-cyclopentyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4-yl) -phenol (0.30 g, 0.81 mmol) , Methyl ester (1.5 ml, 13.0 mmol), 60% sodium hydride (0.09 g, 2.3 mmol), potassium carbonate (1.0 g, 7.2 mmol) and anhydrous benzene (2 ml) was heated at 100 ° C for 36 hours. By using a hexane / ethyl acetate is purified by chromatography to give the title compound as a solid (0.23g, 52%): NMR (DMSO-d 6): δ 8.18 (d, J = 8Hz, 1H), 7.62 (ddd 3H), 3.31 (s, 3H), 3.31 (quintet, J = 8.4 Hz, 1H), 7.50-7.41 (m, 2H), 7.16-7.04 (M, 2H), 1.74 (m, 2H), 1.74-1.45 (m, 1.56, 2H), 2.57 9H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 550/552.

Step 2 4- [9- Bromo-2,3-dimethyl-naphtho [2,3-d] thiophen-4- yl) -2-cyclopentyl-phenoxy]

2,3-d] thiophen-4-yl) -2-cyclohexane The title compound was obtained from 4- [4- (9- (1.33 mmol, 1.66 mmol) and aqueous methanol (9.2 ml) and methanol to give a homogeneous solution of the title compound an off-white solid (0.22g, 100%) was obtained _{as: NMR (DMSO-d 6)} : δ 12.15 (br s, 1H), 8.18 (d, J = 8Hz, 1H), 7.62 (ddd, J = 2, 1H), 2.48 (t, J = 7 Hz, 1 H), 3.45 (m, 2.41 (s, 3H), 2.04 (doublet, J = 7 Hz, 2H), 1.96 (m, 2H), 1.72-1.44 (single line inclusion at 9? MS (-ESI): [MH] ⁺ , 1 bromine isotope pattern 535/537;

Elemental analysis for C ₂₉ H ₂₉ BrO ₃ S:

Calculated: C, 64.80, H, 5.44, N, 0.00.

Found: C, 64.20, H, 5.50, N, 0.03.

Example 74

Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-d] furan-4-yl)

(10g, 45.4mmol, RN-59216-82-9), oxalyl chloride (4.4ml, 50.4mmol), N, N-dimethylformamide in a manner analogous to that of Example 49, (2 drops), 2,3-dimethyl-5-benzylfuran (10.1 g, 54.2 mmol), tin (IV) chloride (5.8 ml, 49.6 mmol) and anhydrous methylene chloride (18.8 g) which is used without further purification.

(2-benzyl-4,5-dimethyl-furan-3-yl) - (3-cyclopentyl-4-methoxy-benzyl) -pyrrolidine in analogy to the procedure described in example 49, step 2, The title compound is obtained as a light tan solid (1.56 g, 9.6%), from (18.8 g, 48.4 mmol), boron tribromide (34.8 ml, 368 mmol) and methylene chloride (167 ml) _{-d 6): δ 9.46 (s} , 1H), 7.96 (d, J = 8Hz, 1H), 7.90 (s, 1H), 7.54 (d, J = 8Hz, 1H), 7.39 (ddd, J = 1, (Dd, J = 1, 7, 8 Hz, 1H), 7.04 (d, J = 2 Hz, 1H), 6.97 J = 8 Hz, 1H), 3.38-3.26 (m, 1H), 2.36 (s, 3H), 1.96 (m, 2H), 1.74-1.44 (single line inclusion at m? 1.55, 9H); MS (EI): [M &lt; + &gt;]356;

Elemental analysis for C ₂₅ H ₂₄ O ₂ :

Calcd: C, 84.24, H, 6.798 N, 0.00.

Found: C, 83.48, H, 6.71, N, 0.04.

Example 75

Acetic acid 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] furan-

In a manner similar to that of Example 49, Step 3, by reacting 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -phenol (4.81 g, 13.5 mmol (0.92 g, 17%) which was obtained as a light yellow solid, (1.60 g, 17.0 mmol), acetic anhydride (1.60 ml, 17.0 mmol), pyridine (27 ml) and methylene chloride (27 ml), which was chromatographed with hexane / ethyl acetate. is obtained _{as: NMR (DMSO-d 6)} : δ 8.00 (d, J = 8Hz, 1H), 7.97 (s, 1H), 7.42 (ddd, J = 1, 7, 8Hz, 1H), 7.34 (ddd, J = 8 Hz, 1H), 7.14 (d, J = 2 Hz, 1H), 7.22 (dd, J = 1H), 2.37 (s, 3H), 2.36 (s, 3H), 1.96 (m, 2H), 1.74-1.44 (single line inclusion at 9? MS (+ ESI): [M + H] &lt; ⁺ &gt;,399;

Elemental analysis for C ₂₇ H ₂₆ O ₃ :

Calcd: C, 81.38, H, 6.58, N, 0.00.

Found: C, 80.76, H, 6.65, N, 0.05.

Example 76

(R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4- yl) -2-ethyl- phenoxy]

In a manner similar to that of Example 49, Step 6, by reacting 2-ethyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen- (4.78 g, 26.5 mmol), triphenylphosphine (6.96 g, 26.5 mmol), diethyl azodicarboxylate (4.18 ml, 26.5 mmol, ) And anhydrous benzene (8.8 ml), which is used without further purification.

In a manner similar to that of Example 49, Step 7, (R) -2- [4- (2,3-dimethyl-naphtho [2,3- b] thiophen- (0.65 g, 0.65 mmol) in aqueous potassium hydroxide (3.2 mL) and methanol sufficient to yield a homogeneous solution to obtain the title compound as a yellow foam (0.10g, 63%): NMR (DMSO-d 6): δ 13.11 (br s, 1H), 8.43 (d, J = 2Hz, 1H), 7.93 (dd, J = J = 4.8 Hz, 1H), 7.48-7.20 (m, 8H), 7.10-7.00 (m, 2H), 6.86 (dd, J = 2H), 2.38 (s, 3H), 1.56 and 1.54 (2 s, art), 3.42 (m, ABX pattern, 2H), 2.75-2.52 (complex m, ABX pattern, atropisomer, 2H) Rope isomer, 3H), 1.08 and 1.06 (2 t, J = 7 Hz, 3H); MS (EI): [M &lt; + &gt;],480;

Elemental analysis for C ₃₁ H ₂₈ O ₃ S:

Calculated: C, 77.47, H, 5.87, N, 0.00.

Found: C, 74.55, H, 5.87, N, 0.20

Example 77

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Propionic acid

Step 1 A mixture of acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl)

In a manner similar to that of Example 49, Step 3, by reacting 2-ethyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen- ), Acetic anhydride (0.52 mL, 5.5 mmol) and pyridine (8.4 mL) which was chromatographed with hexane / ethyl acetate to afford the title compound as a solid (1.62 g,> 100% _{DMSO-d 6): δ 8.49} (s, 1H), 7.97 (d, J = 9Hz, 1H), 7.50-7.43 (m, 1H), 7.40-7.35 (m, 2H), 7.27 (s, 1H), 3H), 1.58 (s, 3H), 1.13 (t, J = 8 Hz, 3H), 7.21 (s, 2H), 2.57 (doublet of quartets, J = 8 Hz, 2H) ); MS (EI): [M &lt; + &gt;]374;

Elemental analysis for C ₂₄ H ₂₂ O ₂ S:

Calculated: C, 76.97, H, 5.92, N, 0.00.

Found: C, 75.72, H, 5.92, N, 0.03.

Step 2 A solution of acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-

In a manner similar to that of Example 49, Step 4, acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) The title compound is obtained as a solid (0.48 g, 26%): NMR (DMSO-d6, _t, ): 隆 8.21 (d, J = 9 Hz, 1H), 7.65 (ddd, J = 2.6 Hz, 1H), 7.57-7.40 ), 2.56 (doublet of quartets, J = 8 Hz, 2H), 2.43 (s, 3H), 2.37 (s, 3H), 1.56 (s, 3H), 1.13 (t, J = 8 Hz, 3H).

Step 3 4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-

In a manner similar to that of Example 49, Step 5, acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- (1.4 g, &gt; 100%) from the ester (1.5 g, 3.3 mmol), aqueous potassium hydroxide (4.0 mL of a 1N solution, 4.0 mmol), tetrahydrofuran (55 mL) and methanol is _{obtained: NMR (DMSO-d 6)} : δ 9.55 (s, 1H), 8.16 (d, J = 9Hz, 1H), 7.62 (ddd, J = 1, 7, 8Hz, 1H), 7.54 (d, J 2H), 2.41 (s, 3H), 1.59 (m, 2H), 7.44 (ddd, J = s, 3H), 1.13 (t, J = 8 Hz, 3H).

Step 4 Synthesis of (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Phenyl-propionic acid methyl ester

(9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) - Phenyl) propionic acid, methyl ester (0.31 g, 1.72 mmol), triphenylphosphine (0.45 g, 1.72 mmol), di (tert-butyldimethylsilyl) ethyl azodicarboxylate (0.27㎖, 1.71mmol) and to give the title compound from anhydrous benzene (5㎖) as a glassy residue (0.22g, 33%): NMR (DMSO-d 6): δ 8.22 (d, J 2H), 6.92 (dd, J = 2.8 Hz, 1H), 7.66 (ddd, J = 3,6,8Hz, 1H), 7.59-7.22 3H), 3.32 (m, 2H), 2.64 (complex, 2H), 2.45 (s, 3H), 1.55 (s, 3H) ), 1.12 and 1.10 (2 t, J = 7 Hz, atropisomer, 3H).

Step 5 Synthesis of (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Phenyl-propionic acid

2,3-b] thiophen-4-yl) -2,3-dimethyl-naphtho [2,3- b] thiophene-4-carboxylate was obtained in a manner similar to the step of Example 49, (1N solution, 0.46 mL, 0.46 mmol), tetrahydrofuran (15 mL) and methanol (5 mL) were added to a solution of 2- The title compound is obtained as a white solid (0.19 g, 90%): Rot. [a] 25 / D = + 1.55 (8.396 mg / mL, MeOH);

_{NMR (DMSO-d 6):} δ 13,15 (br s, 1H), 8.17 (dd, J = 4, 9Hz, 1H), 7.66-7.58 (m, 1H), 7.50-7.21 (m, 7H), (M, 2H), 6.88 (dd, J = 4, 9 Hz, 1H), 5.09 and 5.06 (2 dd, J = 4.8 Hz, atropisomer, 1H) 2H), 2.66 and 2.56 (2 doublets, doubled doublet, ABX pattern, atropisomer, 2H), 2.42 and 2.40 (2s, atropisomers, 3H), 1.53 and 1.52 (2s, atropisomers, 3H) , 1.08 and 1.06 (2 t, J = 8 Hz, atropisomer, 3H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 558/560;

Elemental analysis for C ₃₁ H ₂₇ BrO ₃ S:

Calcd: C, 66.54, H, 4.86, N, 0.00.

Found: C, 66.91, H, 5.28, N, -0.07.

Example 78

2-Bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl)

Ethyl-p-anisic acid (4.95 g, 19.1 mmol), oxalyl chloride (1.8 mL, 20.6 mmol), N, N-dimethyl (7.85 &lt; RTI ID = 0.0 &gt; (g, &lt; / RTI &gt; 2) from formamide (2 drops), 2,3- dimethyl- 5- benzylthiophene (4.3 g, 23.1 mmol), tin (IV) chloride (2.5 mL, 21.4 mmol) and anhydrous methylene chloride g,%), which is used without further purification.

(2-benzyl-4,5-dimethyl-furan-3-yl) - (3-bromo-5-ethyl-4-methoxy-benzenesulfonyl chloride) was prepared in analogy to the procedure described in example 49, step 2, The title compound is obtained as a white solid (0.85 g, 12%): NMR (CDCl3, 300 MHz, CDCl3) .depsilon.-methoxy- phenyl) -methanone (7.85 g, 18.4 mmol), boron tribromide (13.2 ml, 14.0 mmol) and methylene chloride _{(DMSO-d 6): δ} 9.17 (s, 1H), 7.99 (d, J = 8Hz, 1H), 7.95 (s, 1H), 7.52 (d, J = 8Hz, 1H), 7.42 (ddd, J = (Complex, ABX pattern, 2H), 2.37 (s, 3H), 1.59 (d, J = 2 Hz, 1H), 7.37-7.30 (s, 3H), 1.15 (t, J = 8 Hz, 3H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 394/396;

Elemental analysis for C ₂₂ H ₁₉ BrO ₂ :

Calcd: C, 66.85, H, 4.84, N, 0.00.

Found: C, 67.07, H, 4.85, N, 0.05.

Example 79

(2-bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6-ethyl- phenoxy]

Step 1 Synthesis of (2R) -2- [2-bromo-4- (2,3-dimethyl-naphtho [2,3- b] -Propionic acid methyl ester

Bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6 3-phenylpropionic acid, methyl ester (0.54 g, 3.0 mmol), triphenylphosphine (0.80 g, 3.1 mmol), diethyl azodicarboxylate (0.48㎖, 3.0mmol) and yields the title compound from anhydrous benzene (1.0㎖) as a solid (0.37g, 88%): NMR (DMSO-d 6): δ 8.02 (d, J = 8Hz (2 dd, J = 6, 8 Hz, atropisomer, 3H), 3.60 and 3.57 (2 s), atropine , 2.40 and 2.39 (2 s, atropisomers, 3H), 1.58 and 1.53 (2 s, 3H), 3.47-3.30 (m, 2H), 2.80-2.52 , Art rope isomer, 3H), 1.12 and 1.10 (2 t, J = 8 Hz, atrop isomer, 3H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 556/558.

Step 2 Preparation of (2R) -2- [2-bromo-4- (2,3-dimethyl-naphtho [ - propionic acid

(2R) -2- [2-bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) - (0.34 g, 0.61 mmol), aqueous potassium hydroxide (1.2 mL of a 1N solution, 1.2 mmol), tetrahydrofuran (6.0 mL) and a homogeneous solution the title compound was prepared from sufficient methanol to give a white foam (0.31g, 94%): NMR (DMSO-d 6): δ 8.01 (d, J = 8Hz, 1H), 7.97 (d, J = 2Hz, 1H) , 7.48 (d, J = 9 Hz, 2H), 7.46-7.22 (m, 9H), 7.20 (dd, J = 2.6 Hz, 1H) (2 t, J = 7 Hz, 3 H), 2.55 (composite m, ABX pattern, 2H), 2.38 and 2.36 (2 s, atropisomers, 3H), 1.56 and 1.51 Art rope isomer, 3H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 542/544;

Elemental analysis for C ₃₁ H ₂₇ BrO ₄ :

Calculated: C, 68.51, H, 5.01, N, 0.00.

Found: C, 68.22, H, 5.42, N, 0.10.

Example 80

4- [2,3-b] furan-4-yl) -6-ethyl-phenoxy]

Step 1 4- [2-Bromo-4- (2,3-dimethyl-naphtho [2,3- b] furan-4-yl) -6-ethyl- phenoxy] -butyric acid methyl ester

4-yl) -6-ethyl-phenol (0.30 g, 0.76 mmol), 60% sodium hydride (33 mg, 0.83 mmol), 4-bromobutyric acid, methyl ester (0.44 ml, 3.82 mmol) and anhydrous benzene (1.0 ml) was heated at 100 ° C for 6 hours. A second portion of the 4-bromobutyric acid methyl ester (0.45 mL, 3.91 mmol) and potassium carbonate (0.5 g, 3.62 mmol) were added and the reaction mixture was heated at 100 &lt; 0 &gt; C for 6 h. The crude reaction mixture was chromatographed with hexane / ethyl acetate to give the title compound as a solid (0.31g, 82%): NMR (DMSO-d 6): δ 8.00 (d, J = 8Hz, 1H), 7.98 (s , 7.48 (ddd, J = 8 Hz, 1H), 7.46 (d, J = (Dd, J = 6.9 Hz, 1H), 3.63 (s, 3H), 4.06 (T, J = 7 Hz, 2H), 2.38 (s, 3H), 2.09 (quint. D, J = 7, 15 Hz, 1H) J = 7 Hz, 2H), 1.56 (s, 3H), 1.18 (t, J = 7 Hz, 3H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 494/496.

Step 2 4- [2-Bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6-ethyl-phenoxy] -butyric acid

In a manner similar to that of Example 49, Step 7, 4- [2-bromo-4- (2,3-dimethyl-naphtho [2,3- b] Phenoxy] -butyric acid methyl ester (0.31 g, 0.63 mmol), aqueous potassium hydroxide (1.25 mL of a 1N solution, 1.25 mmol), and tetrahydrofuran (6.3 mL) It was obtained as a solid (0.26g, 87%): NMR (DMSO-d 6): δ 12.15 (br s, 1H), 8.01 (d, J = 8Hz, 1H), 7.98 (s, 1H), 7.48 (d J = 8 Hz, 1H), 7.46 (d, J = 2 Hz, 1H), 7.42 (ddd, J = (dd, J = 6 Hz, 1H), 4.04 (dd, J = 6, 9 Hz, 1H), 3.98 (T, J = 7 Hz, 2H), 2.38 (s, 3H), 2.06 (quintet, J = 7 Hz, 2H), 1.46 1.19 (t, J = 7 Hz, 3 H); MS (-ESI): [MH] ^- , 1 bromine isotope pattern 479/481;

Elemental analysis for C ₂₃₆ H ₂₅ BrO ₄ :

Calculated: C, 64.87, H, 5.23, N, 0.00.

Found: C, 64.94, H, 5.34, N, 0.08.

Example 81

4- [2-bromo-4- (2,3-dimethyl-naphtho [2,3- b] furan-4-yl) -6-ethyl- phenoxy] -butylamide 0.4 hydrate

Phenoxy] -butyric acid (60 mg, 0.12 mmol), &lt; RTI ID = 0.0 &gt; A solution of salicyl chloride (10.8 L, 0.12 mmol), N, N-dimethylformamide (2.0 L) and methylene chloride (1.0 mL) was stirred at room temperature. After 2.5 h, a saturated solution of ammonia in acetonitrile (5 ml) was added and the resulting mixture was stirred at room temperature for 2 days. Concentrate under reduced pressure to obtain a residue which is suspended in 3% ethanol (31 ml) in water and stirred at room temperature for 18 hours. The slurry was filtered, and washed well with water and air dried to give the title compound as an off-white solid (52.6mg, 88%): NMR (DMSO-d 6): δ 8.00 (d, J = 8Hz, 1H), 7.98 (s, 1H), 7.49 (d, J = 8 Hz, 1H), 7.45 (d, J = 2 Hz, 1H), 7.43 (ddd, J = J = 6.8 Hz, 2H), 7.25 (d, J = 2 Hz, 1H), 6.79 (br s, 1H), 4.01 J = 7, 15 Hz, 1H), 2.38 (s, 3H), 23.5 (t, J = 7 Hz, 2H), 2.04 (triplet, J = 7 Hz, 2H), 1.56 (s, 3H), 1.19 (t, J = 7 Hz, 3H); MS (+ ESI): [M + H] &lt; ⁺ &gt;, 1 bromine isotope pattern 480/482;

Elemental analysis for C ₂₅ H ₂₆ BrNO ₃ ¥ 0.4H ₂ O:

Calculated: C, 64.04, H, 5.54, N, 2.87.

Found: C, 64.01, H, 5.43, N, 2.89.

Example 82

4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl)

Step 1 (2-Benzyl-4,5-dimethyl-furan-3-yl) - (4- methoxy-

(5.0 g, 27.7 mmol), oxalyl chloride (2.7 mL, 31.0 mmol), N, N-dimethylformamide (2 drops The title compound was prepared from oil (7.24 g, 75%) from 2,3-dimethyl-5-benzylfuran (6.2 g, 33.3 mmol), tin (IV) chloride (3.6 mL, 30.8 mmol) and anhydrous methylene chloride was obtained as a%): NMR (DMSO-d 6): δ 7.61 (dd, J = 2, 8Hz, 1H), 7.54 (d, J = 2Hz, 1H), 7.28-7.13 (m, 3H), 7.09- 2H), 2.16 (s, 3H), 1.78 (s, 3H), 1.08 (t, 2H) J = 7 Hz, 3H).

Step 2 4- (2,3-Dimethyl-naphtho [2,3-b] furan-4-yl)

(2-benzyl-4,5-dimethyl-thiophen-3-yl) - (4-methoxy-3-ethyl- phenyl) -methanone (7.0 g, , 10.1mmol), three to give a boron tribromide (14.4㎖, 152.3mmol) and methylene chloride (off-white solid (0.61g, 9.6%) of the title compound from 69㎖): NMR (DMSO-d 6): δ 9.45 ( J = 8 Hz, 1H), 7.97 (d, J = 8 Hz, 1H), 7.90 (ddd, J = 1, 7, 8 Hz, 1H), 7.02 (d, J = 2 Hz, 1H), 6.98 (S, 3H), 1.56 (s, 3H), 1.14 (t, J = 7 Hz, 3H), 2.58 (quartet d, J = 7, 14 Hz, 1H) ); MS (EI): [M &lt; + &gt;] 316.

Example 83

2-propyl-phenoxy] -3-phenyl-isoxazole-2-carboxylic acid methyl ester was prepared from (R) -2- [4- (9- Propionic acid

Step 1 (2-Benzyl-4,5-dimethyl-thiophen-3-yl) - (4- methoxy-

In a manner similar to that of Example 49, Step 1, 3-propyl-p-anisic acid (3.0 g, 15.4 mmol), oxalyl chloride (1.48 mL, 17.0 mmol), N, N- dimethylformamide ), 2,3-dimethyl-5-benzylthiophene (3.75 g, 18.5 mmol), tin (IV) chloride (1.99 ml, 17.0 mmol) and anhydrous methylene chloride (99 ml) was obtained as 38%): NMR (DMSO- d 6): δ 7.58 (dd, J = 2, 8hz, 1H), 7.53 (d, J = 2hz, 1H), 7.25-7.11 (m, 3H), 7.10 2H), 2.26 (s, 3H), 1.81 (s, 3H), 1.51 (sextet) , J = 7 Hz, 2H), 0.87 (t, J = 7 Hz, 3H); MS (EI): [M &lt; + &gt;] 378 ,.

Step 2 4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl)

(2-benzyl-4,5-dimethyl-thiophen-3-yl) - (4- methoxy-3- propyl- phenyl) -methanone (2.70 g, , 7.1mmol), to give the title compound from boron tribromide (5.12㎖, 54.2mmol) and methylene chloride (24.5㎖) as a solid (1.77g, 71%): NMR (DMSO-d 6): δ 9.44 (s (M, 3H), 2.61 (m, IH), 2.52 (m, IH), 8.42 , 1H), 2.39 (s, 3H), 1.70-1.50 (singleton containing m, 5H at delta 1.63), 0.88 (t, J = 7 Hz, 3H); MS (EI): [M &lt; + &gt;] 346.

Step 3 A mixture of acetic acid 4- (2,3-dimethylnaphtho [2,3-b] thiophen-4-yl)

In a manner similar to that of Example 49, Step 3, 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) ), Acetic anhydride (0.46 ml, 4.9 mmol) and pyridine (7.5 ml) which was chromatographed with hexane / ethyl acetate to give the title compound as a solid (0.81 g, 56%): NMR _{-d 6): δ 8.50 (s} , 1H), 7.98 (d, J = 9Hz, 1H), 7.51-7.44 (m, 1H), 7.40-7.36 (m, 2H), 7.26 (s, 1H), 7.23 (m, 2H), 2.55 (m, 2H), 2.42 (s, 3H), 2.38 (s, 3H), 1.64-1.53 3H); MS (EI): [M &lt; + &gt;] 388.

Step 4 A mixture of acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-

In a manner similar to that of Example 49, Step 4, acetic acid 4- (2,3-dimethylnaphtho [2,3-b] thiophen-4-yl) mmol), to obtain a ferric chloride (16.7mg, 0.10mmol), bromine (0.12㎖, 2.3mmol) and methylene chloride (solid (0.38g, 39%) of the title compound from 21㎖): NMR (DMSO-d 6 (ddd, J = 1, 6, 8 Hz, 1H), 7.48 (ddd, J = 1, 6, 8 Hz, 1H), 7.43 (M, 2H), 2.43 (s, 3H), 2.36 (s, 3H), 1.63-1.50 , 5H), 0.86 (t, J = 7 Hz, 3H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 466/468.

Step 5 Synthesis of (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Phenyl-propionic acid

In a manner similar to that of Example 49, Step 5, the title compound was obtained from acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- 4- (9-bromo-2,3-dihydro-benzoic acid), which is a solid from ester (0.36 g, 0.77 mmol), aqueous potassium hydroxide (0.92 ml of a 1N solution, 0.92 mmol), tetrahydrofuran (11.4 ml) -Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-propyl-phenol (0.62 g) which is used without further purification.

2,3-b] thiophen-4-yl) - (2-methylthiazol-2-yl) (1.12 g, 6.2 mmol), triphenylphosphine (1.60 g, 6.1 mmol), and diethyl azodicarboxylic acid (0.77 mmol) were added to a solution of 2-hydroxy-3-phenylpropionic acid 2- (4- (9-bromo-2,3-dimethyl-naphtho [2,3 &lt; RTI ID = 0.0 &gt; -b] thiophen-4-yl) -2-propyl-phenoxy] -3-phenyl-propionic acid methyl ester (0.23 g).

2,3-b] thiophen-4-yl) -2,3-dimethyl-naphtho [2,3- b] thiophene-4-carboxylate was obtained in a manner similar to the step of Example 49, (0.23 g, 0.39 mmol), aqueous potassium hydroxide (0.93 ml of a 1N solution, 0.93 mmol), tetrahydrofuran (4.6 ml) and a homogeneous solution to give the title compound from methanol sufficient to as a yellow foam (0.17g, 74%): NMR (DMSO-d 6): δ 13.15 (br s, 1H), 8.18 (d, J = 3, 9Hz, 1H) 1H), 7.67-7.59 (m, 1H), 7.50-7.23 (m, 7H), 7.52-7.40 (m, 2H), 6.88 (dd, J = (M, 2H), 2.73-2.53 (m, 2H), 2.42 (s, 3H), 1.60-1.40 (m singlet isomers containing 2 singlets at? 1.56 and 1.54, 5H), 0.87 and 0.85 J = 7 Hz, atrop isomer, 3H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 572/574.

Example 84

[9-bromo-4- (4-methoxy-3,5-dimethylphenyl) -3-methylnaphtho [2,3- b] thien-

A mixture of 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl- anisole (2.0 g, 4.7 mmol), sulfuryl chloride (0.42 ml, 5.3 mmol), diisopropylethylamine (0.90 ml, 5.2 mmol) and anhydrous methylene chloride (24 ml) was stirred at 0 ° C for about 2 hours. Subsequently, the crude The reaction mixture was diluted with diethyl ether, washed twice with water, once with brine and dried (Na ₂ SO _4). Concentration under reduced pressure gave a residue that was immediately treated with sodium acetate (1.2 g, 14.6 mmol) and N, N-dimethylformamide (16.8 mmol). After 24 h, the reaction mixture is diluted with diethyl ether, washed three times with water, once with brine, and then dried (Na ₂ SO ₄ ). Concentrated under reduced pressure to give the residue, and this provides the title compound by chromatography with hexanes / ethyl acetate as a yellow foam (0.36g, 27%): NMR (DMSO-d 6): δ 8.41 (s, 1H), 2H), 7.05 (s, 2H), 3.78 (s, 3H), 2.30 (d, J = (s, 6H), 2.08 (s, 3H), 1.68 (s, 3H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 482/484;

Elemental analysis for C ₂₅ H ₂₃ BrO ₃ S:

Calculated: C, 62.11, H, 4.80, N, 0.00.

Found: C, 61.86, H, 4.75, N, 0.04.

Example 85

Dimethyl-naphtho [2,3-b] thien-4-yl) -2-methyl-phenylacetate

Step 1 A mixture of acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl)

(10 g, 60.2 mmol), oxalyl chloride (5.77 mL, 66.1 mmol), N, N-dimethylformamide (2 drops) (24.4 g) from 2,3-dimethyl-5-benzylthiophene (14.6 g, 72.2 mmol), tin chloride (IV) (7.75 mL, 66.2 mmol) and anhydrous methylene chloride (300 mL) It is used without further purification.

In a manner similar to that of Example 49, Step 2, by reacting (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (4- methoxy- ), Boron tribromide (17.1 ml, 180.9 mmol) and methylene chloride (120 ml). This residue is treated with acetic anhydride (7.4 ml, 78.4 mmol), pyridine (58 ml) and methylene chloride (400 ml) in a similar manner to that of Example 49, Step 3. By conventional post-treatment to obtain the title compound as a solid (9.83g, 45.5%): NMR (DMSO-d 6): δ 8.48 (s, 1H), 7.97 (d, J = 8Hz, 1H), 7.50-7.33 (m, 3H), 7.27 (s, 1H), 7.21 (s, 2H), 2.40 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H), 1.58 MS (+ APCI): [M + H] &lt; + &gt; 361.

Step 2 4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thien-

In a manner similar to that of Example 49, Step 4, acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen- The title compound is obtained as a solid (5.44 g, 90.7%) from ferrous chloride (0.11 g, 0.68 mmol), bromine (14.3 ml of a 1.07 M solution in carbon tetrachloride, 15.3 mmol) and methylene chloride (63 ml) _{NMR (DMSO-d 6):} δ 8.20 (d, J = 9Hz, 1H), 7.65 (ddd, J = 2, 6, 8Hz, 1H), 7.52-7.42 (m, 2H), 7.30 (s, 1H) , 7.23 (s, 2H), 2.43 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H), 1.56 (s, 3H); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 438/440;

Elemental analysis for C ₂₃ H ₁₉ BrO ₂ S:

Calculated: C, 62.87, H, 4.36, N, 0.00.

Found: C, 62.27, H, 3.99, N, 0.10.

Example 86

Diethylaminoethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenyl ester

Step 1 A mixture of acetic acid 4- (9-bromo-2-bromomethyl-3-methyl-naphtho [2,3- b] thiophen-

In a similar manner to that of Example 49, Step 4, the title compound was obtained from acetic acid 4- (2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen- (9-bromo-phenyl) -acetic acid was obtained in the form of a white solid from acetic acid 4- (9-bromo-phenyl) -phenyl ester (10.0 g, 26.7 mmol), ferric chloride (0.23 g, 1.42 mmol), bromine (1.51 ml in 38 ml of carbon tetrachloride, 29.4 mmol) (6.68 g, 55%) and the title compound as a yellow solid (1.60 g) in tetrahydrofuran is obtained _{as: NMR (DMSO-d 6)} : δ 8.28 (m, 1H), 7.62-7.56 (m, 2H), 7.41-7.37 (m, 1H), 7.06 (s, 2H), 4.70 (s, 2H ), 2.42 (s, 3H), 2.24 (s, 6H), 1.72 (s, 3H); MS (EI): [M &lt; + &gt;], 2 bromine isotope pattern 530/532/534;

Elemental analysis for C ₂₄ H ₂₀ Br ₂ O ₂ S:

Calculated: C, 54.15, H, 3.79, N, 0.00.

Found: C, 53.81, H, 3.61, N, 0.10.

Step 2 A solution of acetic acid 4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3- b] thiophen-

A solution of acetic acid 4- (9-bromo-2-bromomethyl-3-methyl-naphtho [2,3-b] thiophen- ) Is treated with diethylamine (0.71 ml, 6.82 mmol), potassium carbonate (0.94 g, 6.82 mmol) and N, N-dimethylformamide (12.1 ml). After 1 hour at room temperature, the reaction mixture is poured into water (250 mL), filtered and rinsed well with water. Is obtained by air-drying the title compound as a yellow solid (1.13g, 94.5%): NMR (DMSO-d 6): δ 8.19 (d, 1H), 7.66-7.61 (m, 1H), 7.47 (d, 2H) 3H), 1.61 (s, 3H), 1.02 (t, 6H), 7.13 (s, 2H) ); MS (EI): [M &lt; + &gt;], 1 bromine isotope pattern 523/525;

Elemental analysis for C ₂₈ H ₃₀ BrNO ₂ S:

Calculated: C, 64.12, H, 5.77, N, 2.67.

Found: C, 63.30, H, 5.67, N, 2.55.

Example 87

2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl- -Phenyl-propionic acid

Step 1 4- (9-Bromo-2-diethylaminoethyl-3-methyl-naphtho [2,3- b] thiophen-

In a manner similar to that of Example 49, Step 5, acetic acid 4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3- b] thiophen- The title compound was prepared from the title compound as a yellow solid (1.0 g, 2.15 mmol), 2,6-dimethyl-phenyl ester (1.13 g, 2.15 mmol), aqueous potassium hydroxide (2.58 mL of a 1N solution, 2.58 mmol), tetrahydrofuran (28 mL) g, was obtained as 96%): NMR (DMSO- d 6): δ 8.47 (s, 1H), 8.17 (d, 1H), 7.64-7.59 (m, 1H), 7.55-7.45 (m, 1H), 3H), 1.01 (m, &lt; RTI ID = 0.0 &gt; 1H), &lt; 6H).

Step 2 Preparation of (2R) -2- [4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3- b] thiophen- -Phenoxy] -3-phenyl-propionic acid methyl ester

Methyl-naphtho [2,3-b] thiophen-4-yl) -2 (1 H) -quinolinone , Methyl ester (0.67 g, 3.73 mmol), triphenylphosphine (0.98 g, 3.73 mmol), 2-hydroxy-3-phenylpropionic acid, diethyl azodicarboxylate (0.59㎖, 3.73mmol) and to give the title compound from anhydrous benzene (10㎖) as a solid (0.46g, 38%): NMR (DMSO-d 6): δ 8.19 (d, 1H 1H), 7.66-7.61 (m, 1H), 7.47-7.45 (m, 2H), 7.34 (d, 4H), 7.32-7.26 3H), 2.19 (s, 3H), 1.59 (s, 3H), 3.74 (s, 2H) , 1.03 (t, 6 H); MS (+ ESI): [M + H] &lt; ⁺ &gt;, 1 bromine isotope pattern 644/646;

Elemental analysis for C ₃₆ H ₃₈ BrNO ₃ S:

Calculated: C, 67.07, H, 5.94, N, 2.17.

Found: C, 66.73, H, 5.93, N, 2.15.

Step 3 (2R) -2- [4- (9-Bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3- b] thiophen- -Phenoxy] -3-phenyl-propionic acid

In a manner similar to that of Example 49, Step 7, (2R) -2- [4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [ 3-phenyl-propionic acid methyl ester (0.35 g, 0.98 mmol), aqueous potassium hydroxide (1.95 mL of a 1N solution, 1.95 mmol), tetrahydrofuran ) and methanol (solid of the title compound from 3㎖) (0.35g,> was obtained as 100%): NMR (DMSO- d 6): δ 12.90 (br s, 1H), 8.19 (d, 1H), 7.66- 1H), 7.72 (t, 1H), 3.74 (m, 2H), 7.50-7.43 (m, 2H), 7.37-7. 31 (m, 4H), 7.28-7.24 3H), 1.60 (s, 3H), 1.02 (t, 6H), 2.23 (s, 2H) ; MS (-ESI): [MH] ⁺ , 1 bromine isotope pattern 628/630;

Elemental analysis for C ₃₅ H ₃₆ BrNO ₃ S:

Calcd: C, 66.66, H, 5.75, N, 2.22.

Found: C, 66.95, H, 5.99, N, 2.26.

Example 88

(2R) -2- [4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [ -Phenoxy] -3-phenyl-propionic acid

This compound is the title compound as a yellow solid using the appropriate starting materials by prepared in analogy to Example _{87: NMR (DMSO-d 6} ): δ 13.00 (br s, 1H), 8.18 (d, 1H) 2H), 7.63-7.60 (m, 1H), 7.46-7.44 (m, 2H), 7.36-7.24 2H), 3.25 (d, 2H), 2.54 (q, 4H), 1.52 (s, 3H), 1.13 (d, 6H), 1.06 (d, 6H), 1.00 (t, 6H); MS (-ESI): [MH] ⁺ , 1 bromine isotope pattern 684/686;

Elemental analysis for C ₃₉ H ₄₄ BrNO ₃ S:

Calculated: C, 68.21, H, 6.46, N, 2.04.

Found: C, 68.04, H, 6.52, N, 1.92.

HPLC analysis indicates the major component (97.4%).

Claims (44)

A compound of formula (I) or a pharmaceutically acceptable salt thereof. Formula I In the above formula (I) Ar , or ego, A is hydrogen, halogen or OH, B and D are each independently hydrogen, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, hydroxyaralkyl of 6 to 12 carbon atoms, 3 to 8 cycloalkyl, nitro, amino, -NR ¹ R ^1a , -NR ¹ COR ^1a , -NR ¹ CO ₂ R ^1a , cycloalkylamino having 3 to 8 carbon atoms, morpholino, furan- Thiophen-2-yl, thiophen-3-yl, -COR ^1b or OR, R is hydrogen, alkyl, -OCR ^1, C 1 -C _{6 - (CH 2) n CO} 2 R 1, -CH (R 1a) CO 2 R 1, -SO 2 R 1, - (CH 2) m CH ^{_{(OH) CO 2 R 1,}} - (CH 2) m COCO 2 R 1, - (CH 2) m CH = CHCO 2 R 1 or _{- (CH 2) m o (} CH 2) o CO 2 R 1 ' is , R ¹ is hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl having 6 to 12 carbon atoms, aryl or CH ₂ CO ₂ R ^{1 '} R ^{1 '} is hydrogen or alkyl having 1 to 6 carbon atoms, E is S, SO, SO ₂ , O or NR ^1c , X is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, CN, aryl, aralkyl of 6 to 12 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, hydroxyaryl of 6 to 12 carbon atoms Alkyl, perfluoroalkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, aryloxy, arylalkoxy, nitro, amino, NR ² R ^2a , NR ² COR ^2a , cycloalkylamino having 3 to 8 carbon atoms, 2-N, N-dimethylaminoethylsulfanyl, -OCH ₂ CO ₂ R ^2b or -COR ^2c , wherein the alkyl, alkenyl, alkynyl, Y is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, hydroxyaralkyl of 6 to 12 carbon atoms, -OR ³ , SR ³ , NR ³ R ^3a , -COR ^3b , morpholine or piperidine, R ^1a , R ^1c , R ² , R ^2a , R ³ and R ^3a are each independently hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl or aryl having 6 to 12 carbon atoms, R ^1b is alkyl or aryl having 1 to 6 carbon atoms, R ^2b is hydrogen or alkyl having 1 to 6 carbon atoms, R ^2c and R ^3b are each independently alkyl having 1 to 6 carbon atoms, aryl or aralkyl having 6 to 12 carbon atoms, C is hydrogen, halogen or OR &lt; ⁴ &gt; R ⁴ is hydrogen, alkyl having 1 to _{6, -CH (R 5) W} , -C (CH 3) 2 CO 2 R 6, 5- thiazolidine-2,4-dione, -CH (R ⁷⁾ _{(CH 2) m CO 2 R} 6, -COR 6, -PO 3 (R 6) 2, -SO 2 R 6, - (CH 2) p CH (OH) CO 2 R 6, - (CH 2) p and _{(CH 2) p O (CH} 2) q CO 2 R 6, - COCO 2 R 6, - (CH 2) p CH = CHCO 2 R 6 or R ⁵ is hydrogen, aralkyl, aryl, C 1 -C 6 alkyl group having 6 to 12 carbon atoms in the -CH ₂ (1H- imidazol -4-), -CH ₂ (3-1H- indolyl), -CH ₂ CH ₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH ₂ CH ₂ (1-oxo- , -CH ₂ (3-pyridyl), -CH ₂ CO ₂ H or - (CH ₂ ) _n G, G is NR ^6a R ^7a , NR ^6a COR ^7a , , or ego, W is _{^{CO 2 R 6, CONH 2,}} CONHOH, CN, CONH (CH 2) 2 CN, 5- _{^{tetrazole, -PO 3 (R 6) 2}} , -CH 2 OH, -CONR 6b CHR 7b, -CH 2 NR ^6b CHR ^7b CO ₂ R ⁶ , -CH ₂ OCHR ^7b CO ₂ R ⁶ -CH ₂ Br or -CONR ^6b CHR ^7b CO ₂ R ⁶ , R ⁶ , R ^6a , R ⁷ and R ^7a are each independently hydrogen, alkyl having 1 to 6 carbon atoms or aryl, R ^6b is hydrogen or -COR ^6c , R ^6c is alkyl or aryl having 1 to 6 carbon atoms, R ^7b is hydrogen or -COR ^6c , R ^6c is hydrogen, alkyl having 1 to 6 carbon atoms or hydroxyalkyl having 1 to 6 carbon atoms, Z ¹ and Z ² are each independently hydrogen, halogen, CN, C 1 -C 6 alkyl, aryl, aralkyl having 6 to 12 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, nitro, amino, -NR ¹ R ^1a of a, -NR ¹ COR ^1a , cycloalkylamino having 3 to 8 carbon atoms, morpholino or OR ^8, or Z ¹ and Z ² together can form a diene unit of the formula -CH = CR ⁹ -CR ¹⁰ = CR ¹¹ - However, R &lt; ⁸ &gt; is hydrogen, alkyl having 1 to 6 carbon atoms or aryl, R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, alkyl having 1 to 6 carbon atoms, aryl, halogen, hydroxy or alkoxy having 1 to 6 carbon atoms, m is from 1 to 4, n is 1 or 2, p is 1 to 4, q is 1 to 4; The method according to claim 1, Ar ego, A is hydrogen or halogen, B and D are each independently selected from the group consisting of hydrogen, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, branched alkyl, cycloalkyl of 3 to 8 carbon atoms, R is hydrogen or alkyl having 1 to 6 carbon atoms, E is S or O, Of X is hydrogen, halogen, C1 to 6 alkyl, CN, having a carbon number of 1 to 6 perfluoroalkyl, C 1 -C 6 alkoxy, aryloxy, arylalkoxy, nitro, amino, NR ² R ^2a of a, NR ² COR ² , N, N-dimethylaminoethylsulfanyl, arylsulfanyl, arylsulfanyl, pyridylsulfanyl or 2-N, N- dimethylaminoethylsulfanyl, R ¹ , R ^1a , R ² , R ^2a , R ³ and R ^3a are each independently hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl or aryl having 6 to 12 carbon atoms, Y is hydrogen, halogen, OR ³ , SR ³ , NR ³ R ^3a or morpholine, C is hydrogen, halogen or OR &lt; ⁴ &gt; R ⁴ is hydrogen, alkyl having 1 to ^{6, -CH (R 5) W} , -C (CH 3) 2 CO 2 R 6, 5- thiazolidine-2,4-dione, -CH (R ⁷⁾ _{(CH 2) m CO 2 R} 6, -COR 6, -PO 3 (R 6) 2, -SO 2 R 6, - (CH 2) p CH (OH) CO 2 R 6, - (CH 2) p and _{(CH 2) p O (CH} 2) q CO 2 R 6, - COCO 2 R 6, - (CH 2) p CH = CHCO 2 R 6 or R ⁵ is hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl having 6 to 12 carbon atoms, aryl, -CH ₂ (1H-imidazol-4-yl), -CH ₂ (3-1H- ₂ CH ₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH ₂ CH ₂ (1-oxo- or a -CH ₂ (3- pyridyl), W is CO ₂ R ⁶ , -CONH ₂ , -CONHOH, 5-tetrazole or -CONR ^6b CHR ^7b CO ₂ R ⁶ , R ⁶ , R ^6a , R ^6b , R ⁷ , R ^7a and R ^7b are each independently hydrogen, alkyl of 1 to 6 carbon atoms or aryl, Z ¹ and Z ² are each independently hydrogen, halogen, CN, C 1 -C 6 alkyl, aryl, aralkyl having 6 to 12 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, nitro, amino, -NR ¹ R ^1a of a, -NR ¹ COR ^1a , cycloalkylamino having 3 to 8 carbon atoms, morpholino or OR _8, or Z ¹ and Z ² together can form a diene unit of the formula -CH = CR ⁹ -CR ¹⁰ = CH- , R ⁹ and R ¹⁰ are each independently hydrogen or alkyl having 1 to 6 carbon atoms, p is from 1 to 4, a compound wherein q is 1 to 4, or a pharmaceutically acceptable salt thereof. 3. The method of claim 2, A is hydrogen, B and D are each independently halogen, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms or cycloalkyl of 3 to 8 carbon atoms, E is S or O, X is hydrogen, halogen, alkyl having 1 to 6 carbon atoms, perfluoroalkyl having 1 to 6 carbon atoms, CN, alkoxy having 1 to 6 carbon atoms, aryloxy, arylalkoxy or arylsulfanyl having 6 to 12 carbon atoms, Y is hydrogen, -NR &lt; ¹ &gt; R &lt; ² &gt; or morpholine, R ¹ and R ² are each independently hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl or aryl having 6 to 12 carbon atoms, C is OR ⁴ , R ⁴ is hydrogen, alkyl having 1 to 6 carbon atoms, -CH (R ⁵ ) W or 5-thiazolidin-2,4- R ⁵ is hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl having 6 to 12 carbon atoms, aryl, -CH ₂ (3-1H-indolyl), -CH ₂ CH ₂ (1,3- Dihydro-isoindol-2-yl) or -CH ₂ CH ₂ (1-oxo-1,3-dihydro- W is _{^{-CO 2 R 6, -CONH 2,}} -CONHOH, 5- tetrazole, -PO ₃ (R ⁶⁾ _2, or _{^{-CONR 6 CHR 6 CO 2 R 6}} , R ⁶ is hydrogen or alkyl of 1 to 6 carbon atoms, Z ¹ and Z ² together form a diene unit of the formula -CH = CH-H = CH-, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (R) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethyl- ) -Phenoxy] -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [ -Ethyl-phenoxy] -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which is (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Phenoxy] -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Yl] -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which is [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Acetic acid or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [ -sec-butyl-phenoxy] -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [ -Isopropyl-phenoxy] -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [ -Cyclopentyl-phenoxy] -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Yl] -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Yl] -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which is (R) -2- [2,6-dibromo-4- (2,3-dimethyl- Yl) -phenoxy] -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (R) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethyl- ) -Phenoxy] -4-phenyl-butyric acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (S) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethyl- ) -Phenoxy] -4-phenyl-butyric acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is 2- [2,6-dibromo-4- (9-bromo-3-methyl-2-morpholin- -4-yl) -phenoxy] -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which is (R) -2- [2,6-dibromo-4- (2,3-dimethyl- Yl) -phenoxy] -propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which is selected from the group consisting of [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. The compound according to claim 1, which is 2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- A pharmaceutically acceptable salt thereof. The compound according to claim 1, which is 2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4-yl) A pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which is (R) -2- [2,6-dibromo-4- (9-bromo-2-diethylaminomethyl- 4-yl) -phenoxy] -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (R) -2- [2,6-dibromo-4- (2,3-dimethyl-naphtho [ 3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (2R) -2- [4-9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -Phenoxy] -3-phenyl-propionic acid. 2. The compound of claim 1 which is (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -Phenoxy] -3-phenyl-propionic acid. 2. The compound of claim 1 which is {(2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -Phenoxy] -3-phenyl-propionylamino} -acetic acid. 2. The compound of claim 1 which is {(2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Ethyl-phenoxy] -3-phenyl-propionylamino} -acetic acid. 2. The compound of claim 1 which is (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (2S) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Phenoxy] -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which is {(2R) -2- [4- (2,3-dimethyl-naphtho [2,3- b] thiophen- -3-phenyl-propionylamino} -acetic acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] Phenoxy] -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (R) -2- [2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -phenoxy] Or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Yl] -propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen- -Propionic &lt; / RTI &gt; acid or a pharmaceutically acceptable salt thereof. The compound according to claim 1 which is 2-bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) salt. 2. The compound according to claim 1, which is (R) -2- [2-bromo-4- (2,3-dimethyl- -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- ] -3-phenyl-propionic acid, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is (2R) -2- [4- (9-bromo-2-diethyl-aminomethyl- 2,6-diisopropyl-phenoxy] -3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 which is 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl- 2,3-b] thiophen-4-yl) -phenol, 4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [ 4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4- yl) -phenol, 4- (9- Methyl-naphtho [2,3-b] thiophen-4-yl) -phenol, 4- (9- -Methyl-naphtho [2,3-b] thiophen-4-yl) -acetic acid, 4- (9- 4-yl) -phenol, 2,6-dibromo-4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3- b] thiophene- Yl) -phenol, 2,6-dibromo-4- (9-bromo-3-methyl- 2-amino-4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- -Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol, (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol, 2-nitro-phenoxy] -acetic acid, (R) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethylnaphtho [2,3-b] thien-4-yl) -phenoxy] Methyl-2-morpholin-4-ylmethyl-naphtho [2,3-b] thiophen-4- yl) -phenoxy] 2,3-b] thiophen-4-yl) -6-isopropyl-phenol, (R) -2- [4- (2,3-dimethyl-naphtho [2,3- b] thiophen-4- yl) -2-isopropyl-phenoxy] ) - 2- [2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3- b] thiophen-4-yl) -phenoxy] 3-phenyl-propionic acid, (R) -2 &lt; RTI ID = 0.0 &gt; (R) - [4- (2,3-dimethyl-naphtho [2,3- b] thiophen-4-yl) -2,6- diisopropyl- phenoxy] Phenoxy] -3-phenyl-propionic acid, (R) -2- (4-fluoro- 2-ethyl-phenoxy] -3-phenyl-propionic acid, 3-bromo-2,3-dimethyl-naphtho [ Methoxy-phenylamine or [3-bromo-5- (9-bromo-2,3-dimethyl-naphtho [ Amino] -acetic acid, (2R) -2- [4- (9- (3-methyl- -Bromo-2,3-dimethyl-1-oxo-1H-naphtho [2,3-b] (R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-diethyl-phenoxy ] -3-phenyl-propionic acid, 4- (2,3-dimethyl-naphtho [2,3- b] 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3- b] thiophen-4-yl) -2-cyclopentyl- Yl) -phenol, acetic acid 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3- b] thiophen- Ester, (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen- Phenyl-propionic acid, 4- [2-bromo-4- (2,3-dimethyl-naphtho [2,3- b] (2,3-b] furan-4-yl) -6-ethyl-phenoxy] -butyramide, 4- (2,3- -Naphtho [2,3-b] furan-4-yl) -2-ethyl-phenol, [9- 2,3-b] thien-2-yl] methyl acetate, 4- (9- 2-methyl-phenylacetate, acetic acid 4- (9-bromo-2-diethylaminomethyl-3-methyl -Naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenyl ester or 2- [4- (9- 2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof. The process according to claim 1, which comprises reacting acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen- -Naphtho [2,3- b] thiophen-4-yl) -phenyl ester, methanesulfonic acid 4- (2,3-dimethyl-naphtho [ Phenyl ester, methanesulfonic acid 4- (9-iodo-2,3-dimethyl-naphtho [2,3- b] thiophen- Yl) -phenyl ester, (R) -2- [2,6-dibromo-4- (9-bromo-thiophen- 3-phenylpropionic acid methyl ester, [3-bromo-5- (9-bromo-2-methyl- 3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-hydroxy-phenyl] -carbamic acid tert- butyl ester, 9- Methoxy-5-nitrophenyl) -2,3-dimethyl-naphtho [2,3-b] thiophene or [3-bromo-5- (9- 2,3-b] thiophen-4-yl) -2-methoxy-phenylamino] Ester compounds. A method for the treatment of metabolic disease mediated by insulin resistance or hyperglycemia in a mammal comprising administering a compound of formula I of claim 1 to a mammal in need thereof for the treatment of metabolic disease mediated by insulin resistance or hyperglycemia. A method of treating or inhibiting type II diabetes in a mammal, comprising administering a compound of formula I according to claim 1 to a mammal in need of such treatment or inhibition of type II diabetes. A method of modulating the glucose concentration in a mammal comprising administering a compound of formula I according to claim 1 to a mammal in need of modulation of glucose concentration. A pharmaceutical composition comprising a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.