MXPA06006597A

MXPA06006597A - 3-(4-benzyloxyphenyl)propanoic acid derivatives

Info

Publication number: MXPA06006597A
Application number: MXPA/A/2006/006597A
Authority: MX
Inventors: Yasuma Tsuneo; Kitamura Shuji; Negoro Nobuyuki
Original assignee: Kitamura Shuji; Negoro Nobuyuki; Takeda Pharmaceutical Company Limited; Yasuma Tsuneo
Priority date: 2003-12-25
Filing date: 2006-06-09
Publication date: 2006-10-17

Abstract

The present invention provides a novel compound represented by the formula (I) wherein each symbol is as defined in the specification, a salt thereof and a prodrug thereof having a superior GPR40 receptor function modulating action, which can be used as an insulin secretagogue, anagent for the prophylaxis or treatment of diabetes and the like. They unexpectedly show superior GPR40 receptor agonist activity, and also show superior properties as a pharmaceutical product, such as stability and the like. Thus, they can be safe and useful pharmaceutical agents for the prophylaxis or treatment of GPR40 receptor related diseases in mammals.

Description

ACID DERIVATIVES 3- (4-BENCILOXIFENIL) PROPANOICO FIELD OF THE INVENTION The present invention relates to a novel compound having a modifying action of GPR40 receptor function and which is useful as an agent for the prophylaxis or treatment of diabetes.

Background of the Invention It has been reported in recent years that a ligand of GPR40, which is one of the receptors coupled to protein G (GPCR, for its acronym in English), is a fatty acid and GPR40 in pancreatic ß cells it is highly involved in the action of insulin secretion (Nature, 2003, vol 422, pages 173-176). In this way, a GPR40 agonist promotes insulin secretion, a GPR40 antagonist inhibits insulin secretion and the agonist and antagonist are useful as agents for the prophylaxis or treatment of type 2 diabetes, obesity, impaired tolerance to glucose, insulin resistance, neurodegenerative diseases (Alzheimer's disease) and the like (WO03 / 068959 and WO02 / 057783). On the other hand, many useful compounds have been reported as agents for the prophylaxis or treatment of diabetes. REP: 172484 For example, document O02 / 092590 describes that a peroxisome proliferator activated receptor (PPAR) modulator represented by. the formula : wherein X1: an alkyl group of 1 to 3 carbon atoms and the like; R1, R2: H and the like; R3, R4, R5: H, CH3 and the like, R26, R27: H and the like; m: 0-3; X2: O and the like, -R6, R7: H and the like; And, Z: one is CH and the other is S or O; R8: a phenyl group and the like; R9: an alkyl group of 1 to 6 carbon atoms and the like, is useful as an agent for the prophylaxis or treatment of a disease mediated by PPAR (eg, diabetes). The document O02 / 053547 discloses that an alkanoic acid derivative represented by the formula: wherein R1: a heterocyclic, 5-membered aromatic group optionally substituted; X: a bond, O, S, -NR6- (Rs: H, an optionally substituted hydrocarbon group and the like) and the like; Q: a hydrocarbon group of 1 to 20 divalent carbon atoms; Y: a bond, 0, S, -NR7- (R7: H, an optionally substituted hydrocarbon group and the like) and the like; Ring A: a ring. aromatic optionally having in addition 1 to 3 substituents; Z: - (CH2) n-Z1- (n: 1-8, Z1: 0 and the like) and the like; ring B: a benzene ring optionally having in addition 1 to 3 substituents and the like; U: a link and the like; : a hydrocarbon group of 1 to 20 divalent carbon atoms; R3: -OR8- (R8: H, an optionally substituted hydrocarbon group) or -NR9R10- (R9, R10: H, an optionally substituted hydrocarbon group and the like) and the like; provided that when ring B is a benzene ring optionally having in addition to 1 to 3 substituents, then U is a bond, it is useful as an agent for the prophylaxis or treatment of diabetes, hyperlipidemia, impaired tolerance to the glucose and the like. Document 099/11255 discloses that a compound represented by the formula: wherein R1: an alkyl group of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, a halogen atom, a trifluoromethyl group and the like; R2: -COOR3 (R3: H, an alkyl group of 1 to 4 carbon atoms) and the like; A: an alkylene group of 1 to 8 carbon atoms and the like; G: a carbon ring optionally substituted by an alkyl group of 1 to 8 carbon atoms, 'alkoxy of 1 to 8 carbon atoms, a halogen atom, a trifluoromethyl or nitro group and the like; E1: an alkylene group of 1 to 8 carbon atoms and the like, E2: -O- and the like; E3: an individual link and the like, n: 0, 1; Cycl ring; absent and the like, has a regulatory action of the PPAR receptor and is useful as an agent for the prophylaxis or treatment of metabolic abnormality diseases such as diabetes, obesity, syndrome X, hypercholesterolemia, hyperlipoproteinemia and the like. The document O00 / 64876 describes a compound represented by the formula: wherein the Arl ring, the Arll ring, the ArlII ring: an optionally substituted aryl group and the like; A: -0-, -S-, a bond, -NR13- (R_3: H, an alkyl group and the like) and the like; B: -0- and the like; D: a bond, an ethylene group; E: a bond, an ethylene group; Z: R? 02C-, (R2i) 2NCO- (R21: H, an alkyl group and the like) and the like; a, b, c, e: 0-4; d: 0-5; f: 0-6; R __-R? 2: H and the like, is useful as a ligand of the PPAR ligand receptor, a PPAR receptor agonist or a PPAR receptor antagonist and can be used as an agent for the treatment of diabetes. The document O01 / 00603 describes a compound represented by the formula: wherein X: COOH (containing ester) and the like; X1: CH2 / etcetera; the dotted line shows a double bond only when X1 is CH; X2: O and the like; R1, R2: H, Me and the like; n: 1, 2; And, Z: one is N and the other is S or O; y: an integer of 0-5; R3: CF3 and the like, can be used as a PPARd agonist and is useful as an agent for the prophylaxis or treatment of a disease mediated by PPARd (eg, hyperlipidemia, arteriosclerosis, type I or II diabetes and the like). Document O97 / 31907 discloses that a compound represented by the formula: wherein A: a phenyl group optionally substituted by halogen and the like; B: an alkylene group of 1 to 6 carbon atoms and the like; ALK: an alkylene group of 1 to 3 carbon atoms; R1: H, an alkyl group of 1 to 3 carbon atoms; Z: - (alkylene) phenyl of 1 to 3 carbon atoms optionally substituted by a halogen atom and the like, is useful as a PPARα agonist, can be used as an agent for the prophylaxis or treatment of hyperglycemia, type diabetes I or II, hyperlipidemia and the like. WO02 / 083616 describes a compound represented by the formula: wherein Ar: a phenyl group substituted by 1 to 5 same or different halogen atoms and the like; R1: a halogen atom and the like; R2: H and the like; R3, R: H, a halogen atom; m: 1, 2; n: 2-7, has a superior action of insulin sensitization, hypoglycemic action, hypolipidemic action, anti-inflammatory action, immunomodulatory action, suppressive action of lipoperoxide production and activating action of PPAR and is useful as an agent for the treatment of diabetes WOOl / 55085 discloses a compound represented by the formula: wherein A: an aryl group optionally substituted by OH and the like; X1, X2: H and the like; Y, Z: H and the like; n: 0-3; m: 0, 1; Q: O and similar; Ar: an arylene group and the like; R1-R4: H and the like, is useful as an agent for the treatment of diseases related to PPAR and is useful as an agent for the treatment of, for example, type 2 diabetes, impaired glucose tolerance, insulin resistance, hypertriglyceridemia and the like. However, it has not been fully described that these therapeutic drugs known for diabetes have a modifying action on the function of the GPR40 receptor and there is no report on a compound that has a modifying action on the function of the GPR40 receptor (useful compound as an agonist of GPR40 or an antagonist of GPR40). Under these circumstances, the development of a compound having an action modifying the function of the GPR40 receptor has been desired.

Brief Description of the Invention The present invention is directed to the provision of a novel compound having a modifying action on the function of the GPR40 receptor, which is useful as an insulin secretagogue or an agent for the prophylaxis or treatment of diabetes and similar. The present inventors have conducted several studies intensively and have discovered that the compound represented by the following formula (I) unexpectedly has a higher agonist activity of the GPR40 receptor, shows superior properties as a pharmaceutical product, such as stability and the like and can be a safe or useful pharmaceutical agent for the prophylaxis or treatment of a disease state or diseases related to the GPR40 receptor in a mammal and completed the present invention. Accordingly, the present invention provides the following. (1) A compound represented by the formula (I): wherein R1, R3, R4 and R5 are the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or a hydroxy group optionally substituted; R2 is a halogen atom, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted mercapto group, an optionally substituted acyl group or an optionally substituted heterocyclic group; R10 and R11 are the same or different and each is a hydrogen atom, a halogen atom or an alkoxy group of 1 to 6 carbon atoms; E is a bond, an alkylene group of 1 to 4 carbon atoms optionally substituted, - 1-0-W2-, -Wx-S-W2- or - 1-N (R6) -W2- (wherein W1 and 2 they are the same or different and each is a bond or an alkylene group of 1 to 3 carbon atoms optionally substituted and Re is a hydrogen atom, an optionally substituted acyl group or an optionally substituted hydrocarbon group); Ring S1 is a benzene ring optionally further having substituents selected from a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group and an optionally substituted amino group; and R is an optionally substituted hydroxy group or an optionally substituted amino group; with the proviso that R1 and R3 are not simultaneously a hydrogen atom or a salt thereof. (2) The compound according to item (1) above, wherein R2 is a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted mercapto group or a group optionally substituted heterocyclic and R10 and R11 are both hydrogen atoms or a salt thereof. (3) A prodrug of a compound according to item (1) above or a salt thereof. (4) The compound according to item (1) above, wherein R 4 and R 5 are the same or different and each is a hydrogen atom or a halogen atom or a salt thereof. (5) The compound according to item (1) above, wherein E is a bond or a salt thereof. (6) The compound according to item (1) above, wherein R is a hydroxy group or a salt thereof. (7) The compound according to item (1) above, wherein R1 and R3 are the same or different and each is an alkyl group of 1 to 6 carbon atoms or a salt thereof. (8) The compound according to item (1) above, wherein R2 is an optionally substituted hydroxy group or a salt thereof. (9) The compound according to item (1) above, wherein R10 and R11 are both hydrogen atoms or a salt thereof. (10) The compound according to item (1) above, wherein the Sa ring is a benzene ring optionally further having an alkoxy group of 1 to 6 carbon atoms or a salt thereof. (11) 3- [4- [[4'- (Benzyloxy) -2 ', 6'-dimethylbiphenyl-3-yl] methoxy] phenyl] propanoic acid; 3- (4 { [4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy, phenyl) -2, 2-difluoropropanoic acid; 3- [4- ( { 4'- [2- (Ethylsulfonyl) ethoxy] -2 ', 6'-dimethylbiphenyl-3-yl} methoxy) -2-fluorophenyl] propanoic acid; 3- [4- (. {2 ', 6' -dimethyl-4 '- [3- (2-oxopyrrolidin-1-yl) propoxy] -ifenyl-3-yl] methoxy) -2-fluorophenyl] propanoic; 3- [4- (. {2 ', 6' -dimethyl-4 '- [(6-methylpyridin-2-yl) methoxy] -biphenyl-3-yl} methoxy) -2-fluorophenyl] propanoic acid; 3- [2-fluoro-4- ( {4 '- [(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl) methoxy] -2', 6'-dimethylbiphenyl-3-acid il.}. methoxy) phenyl] propanoic; 3- [4- ({2 ', 6' -dimethyl-4 '- [(methylsulfonyl) oxy] biphenyl-3-yl} methoxy) -2-fluorophenyl] propanoic acid; 3- [4- (. {4 '- [(1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) oxy] -2', 6'-dimethylbiphenyl-3-yl} methoxy) -2 -fluorophenyl] propanoic; 3- [4- (. {2 ', 6' -dimethyl-4 '- [(3-methyloxetan-3-yl) methoxy] -biphenyl-3-yl} methoxy) -2-fluorophenyl] propanoic acid; 3- (4. {[2 ', 6'-dimethyl-4' - (tetrahydro-2 H -pyran-4-yloxy) biphenyl-3-yl] methoxy] -2-fluorophenyl) propanoic acid; 3- [4- ( {4 '- [3- (diethoxyphosphoryl) propoxy] -2', 6'-dimethylbiphenyl-3-yl} methoxy) -2-fluorophenyl] propanoic acid; 3- [2-fluoro-4- (. {6-isopropoxy-2 ', 6'-dimethyl-4' - [(3-methyloxetan-3-yl) methoxy] biphenyl-3-yl} methoxy acid ) phenyl] propanoic; or a salt of them. (12) A modulator of the function of the GPR40 receptor comprising a compound according to item (1) above or a salt thereof or a prodrug thereof. (13) A pharmaceutical agent comprising a compound according to item (1) above or a salt thereof or a prodrug thereof. (14) The pharmaceutical agent according to item (13) above, which is an agent for the prophylaxis or treatment of diabetes. (15) The use of a compound according to item (1) above or a salt thereof or a prodrug thereof for the production of a GPR40 receptor function modulator. (16) The use of a compound according to item (1) above or a salt thereof or a prodrug thereof for the production of an agent for the prophylaxis or treatment of diabetes. (17) A method for modifying a function of the GPR40 receptor in a mammal, which comprises administering an effective amount of a compound according to item (1) above or a salt thereof or a prodrug thereof to the mammal. (18) A method for the prophylaxis or treatment of diabetes in a mammal, which comprises administering an effective amount of a compound according to item (1) above or a salt thereof or a prodrug thereof to the mammal. (19) A method of producing a compound represented by the formula (Ib): ("= 1 wherein R1, R2, R3, R4, R5, R10, R11, E and the ring S1 are as defined in (1) above, or a salt thereof, which comprises reacting a compound represented by the formula (X): wherein each symbol is as defined above, or a salt thereof and a compound represented by the formula (II): wherein R4, R5, R10 and R11 are as defined above and R 'is an alkoxy group of 1 to 6 carbon atoms optionally substituted, or a salt thereof, to provide a compound represented by the formula (Ib'): wherein each symbol is as defined above, or a salt thereof and subjecting the compound or a salt thereof to a hydrolysis reaction. (20) A method of producing a compound represented by the formula (Id): wherein R1, R3, R4, R5, R10, R11, E and the ring S1 are as defined in point (1) above, Y is -O- or -S- and R2 'is a substituent, or a salt of the same, which comprises reacting a compound represented by the formula (le '): wherein R1, R3, R4, R5, R10, R11, E, Y and ring S1 are as defined above, R 'is as defined in point (19) above, or a salt thereof and a compound represented by the formula: R2'-OH wherein R2 'is as defined above, or a salt thereof, to provide a compound represented by the formula (If): wherein each symbol is as defined above, or a salt of the same and subjecting the compound or a salt thereof to a hydrolysis reaction. The compound of the present invention has a superior modifying action on the function of the GPR40 receptor and can be used as an agent for the prophylaxis or treatment of diabetes and the like.

BEST MODE FOR CARRYING OUT THE INVENTION Unless otherwise specified, such as the "halogen atom" in the present specification, there may be mentioned a fluorine atom, a chlorine atom, a bromine atom, an iodine atom. Unless otherwise specified, as the "optionally substituted hydrocarbon group" in the present specification, there may be mentioned, for example, an "optionally substituted 1 to 6 carbon alkyl group", "2 to 6 alkenyl group". optionally substituted carbon atoms "," optionally substituted C 2-6 alkynyl group "," optionally substituted C 3 -C 8 cycloalkyl group "," optionally substituted C 6 -C 14 aryl group "," aralkyl group of 7 to 16 carbon atoms optionally substituted "and the like. Unless otherwise specified, as the "alkyl group of 1 to 6 carbon atoms" in the present specification there may be mentioned, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl group , tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like. Unless otherwise specified, such as "alkenyl group of 2 to 6 carbon atoms" in the present specification can be mentioned, for example, vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1 ilo and similar. Unless otherwise specified, such as "C2-C6 alkynyl group" in the present specification can be mentioned, for example, 2-butin-1-yl, 4-pentyin-1-yl, 5-hexin-1-yl and the like. Unless otherwise specified, such as the "cycloalkyl group of 3 to 8 carbon atoms" in the present specification may be mentioned, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Unless otherwise specified, such as the "aryl group of 6 to 14 carbon atoms" in the present specification can be mentioned, for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl , 4-biphenylyl, 2-anthryl and the like. Optionally, the aryl group of 6 to 14 carbon atoms can be partially saturated and as the aryl group of 6 to 14 carbon atoms partially saturated there can be mentioned, for example, tetrahydronaphthyl and the like. Unless otherwise specified, as the "aralkyl group of 7 to 16 carbon atoms" in the present specification may be mentioned, for example, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2, 2 -diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl, 4-biphenylylmethyl and the like. Unless otherwise specified, such as "hydroxy group optionally substituted" in the present specification can be mentioned. , for example, a "hydroxy group", "optionally substituted alkoxy group of 1 to 10 carbon atoms", "optionally substituted heterocyclyloxy group", "optionally substituted aryloxy group of 6 to 14 carbon atoms", "aralkyloxy group of at 16 carbon atoms optionally substituted "," tri-alkyl-silyloxy group of 1 to 6 carbon atoms "," optionally substituted alkylsulfonyloxy group of 1 to 6 carbon atoms "," optionally substituted heterocyclylsulfonyloxy group "and the like. Unless otherwise specified, as the "alkoxy group of 1 to 6 carbon atoms" in the present specification is. it may mention, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like. As the "alkoxy group of 1 to 10 carbon atoms" in the present specification can be mentioned heptyloxy, octyloxy, nonyloxy, decyloxy and the like in addition to the alkoxy group of 1 to 6 carbon atoms mentioned above. As the "heterocyclyloxy group" in the present specification may be mentioned a hydroxy group substituted by a later "heterocyclic group". As preferable examples of the heterocyclyloxy group there may be mentioned tetrahydropyranyloxy, thiazolyloxy, pyridyloxy, pyrazolyloxy, oxazolyloxy, thienyloxy, furyloxy, tetrahydrothiopyranyloxy, 1-oxidotetrahydrothiopyranyloxy, 1,1-dioxidotetrahydrothio-pyranyloxy and the like. Unless otherwise specified, as the "aryloxy group of 6 to 14 carbon atoms" in the present specification there can be mentioned, for example, phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like. Unless otherwise specified, such as the "aralkyloxy group of 7 to 16 carbon atoms" in the present specification may be mentioned, for example, benzyloxy, phenethyloxy and the like. Unless otherwise specified, such as the "tri-alkyl-silyloxy group of 1 to 6 carbon atoms" in the present specification may be mentioned, for example, trimethylsilyloxy, tert-butyl (dimethyl) silyloxy and the like. As the "alkylsulfonyloxy group of 1 to 6 carbon atoms" in the present specification there can be mentioned, for example, methylsulfonyloxy, ethylsulfonyloxy and the like. As the "heterocyclylsulfonyloxy group" in the present specification there can be mentioned a sulfonyloxy group substituted by a later "heterocyclic group". Preferable examples of the heterocyclylsulfonyloxy group may be thienylsulfonyloxy, furylsulfonyloxy and the like. Unless otherwise specified, such as "mercapto group optionally substituted" in the present specification can be mentioned, for example, a "mercapto group", "alkylthio group of 1 to 10 carbon atoms optionally substituted", "optionally substituted heterocyclylthio group", "arylthio group of 6 to 14 optionally substituted carbon atoms "," optionally substituted aralkylthio group of 7 to 16 carbon atoms "and the like. Unless otherwise specified, such as the "alkylthio group of 1 to 6 carbon atoms" in the present specification may be mentioned, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio and similar. As the "alkylthio group of 1 to 10 carbon atoms" in the present specification may be mentioned heptylthio, octylthio, nonylthio, decylthio and the like in addition to the alkylthio group of 1 to 6 carbon atoms mentioned above. Unless otherwise specified, as the "heterocyclicthio group" in the present specification, a mercapto group substituted by a later "heterocyclic group" may be mentioned. As preferable examples of the heterocyclicthio group may be mentioned tetrahydropyranylthio, thiazolylthio, pyridylthio, pyrazolylthio, oxazolylthio, thienylthio, furylthio, tetrahydrothiopyranylthio, 1-oxidotetrahydrothiopyranylthio, 1,1-dioxidotetrahydrothiopyranylthio and the like. Unless otherwise specified as the "arylthio group of 6 to 14 carbon atoms" in the present specification there can be mentioned, for example, phenylthio, 1-naphthylthio, 2-naphthylthio and the like. Unless otherwise specified, such as "aralkylthio group of 7 to 16 carbon atoms" in the present specification can be mentioned, for example, benzylthio, phenethylthio and the like. Unless otherwise specified, as the "heterocyclic group" in the present specification there can be mentioned, for example, a heterocyclic group (monocyclic, bicyclic or tricyclic) of 4 to 14 members containing one or two classes of 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as a ring building atom, in addition to carbon atoms, preferably (i) a heterocyclic, aromatic group of 5 to 14 members (preferably 5) to 10 members), (ii) a heterocyclic, non-aromatic group of 4 to 10 members and the like. Of these, a heterocyclic, aromatic 5- or 6-membered group is preferable. Specifically, a heterocyclic, aromatic group such as thienyl (e.g., 2-thienyl, 3-thienyl), furyl (e.g., 2-furyl, 3-furyl), pyridyl (e.g. 2-pyridyl, -pyridyl, 4-pyridyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), quinolyl (e.g. -quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), isoquinolyl (for example, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl), pyrazinyl, pyrimidinyl (for example, pyrimidinyl, 4-pyrimidinyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g. -pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), isoxazolyl (e.g. -isoxazo lilo, 4-isoxazolyl, 5-isoxazolyl), indolyl (for example, 1-indolyl, 2-indolyl, 3-indolyl), 2-benzothiazolyl, 2-benzoxazolyl, benzimidazolyl (for example, 1-benzimidazolyl, 2-benzimidazolyl) , benzo [b] thienyl (e.g., 2-benzo [b] thienyl, 3-benzo [b] thienyl), benzo [b] furanyl (e.g., 2-benzo [b] furanyl, 3-benzo [b] furanyl) and the like; a heterocyclic, non-aromatic group such as pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), oxazolidinyl (e.g., 2-oxazolidinyl), imidazolinyl (e.g., 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl), morpholinyl (e.g., 2-morpholinyl, 3-morpholinyl, 4-morpholinyl), thiomorpholinyl (e.g., 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl), tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl, oxopyrrolidinyl, oxetanyl (for example, 2-oxetanyl, 3-oxetanyl) and the like. Unless otherwise specified, the "alkylsulfonyl group of 1 to 6 carbon atoms" in the present specification may be mentioned, for example, methanesulfonyl, ethylsulfonyl and the like.

Unless otherwise specified, such as the "alkylsulfinyl group of 1 to 6 carbon atoms" in the present specification can be mentioned, for example, methylsulfinyl, ethylsulfinyl and the like. Unless otherwise specified, such as "arylsulfonyl group of 6 to 14 carbon atoms" in the present specification can be mentioned, for example, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like. Unless otherwise specified, such as "arylsulfinyl group of 6 to 14 carbon atoms" in the present specification can be mentioned, for example, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and the like. Unless otherwise specified, such as "optionally esterified carboxyl group" in the present specification can be mentioned, for example, a carboxyl group, alkoxycarbonyl group of 1 to 6 carbon atoms (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), group aryloxycarbonyl of 6 to 14 carbon atoms (eg, phenoxycarbonyl etc.), aralkoxycarbonyl group of 7 to 16 carbon atoms (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.) and the like. Unless otherwise specified, as the "alkyl group of 1 to 6 carbon atoms optionally halogenated" in the present specification there may be mentioned the "alkyl group of 1 to 6 carbon atoms" mentioned above which is optionally substituted by 1 to 5"halogen atoms" mentioned above. For example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, trifluoromethyl, and the like may be mentioned. Unless otherwise specified, such as the "optionally halogenated C 1 -C 6 alkoxy group" in the present specification may be mentioned the "C 1 -C 6 alkoxy group" referred to above which is optionally substituted by 1 to 5"halogen atoms" mentioned above. For example, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy and the like may be mentioned. Unless otherwise specified, such as the "mono- or di-alkyl-amino group of 1 to 6 'carbon atoms" in the present specification may be mentioned an amino group mono- or di-substituted by the "group". alkyl of 1 to 6 carbon atoms "mentioned above. For example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like can be mentioned. Unless otherwise specified, such as the "mono- or di-aryl-amino group of 6 to 14 carbon atoms" in the present specification may be mentioned an amino group mono- or di-substituted by the "aryl group" of 6 to 14 carbon atoms "mentioned above. For example, phenylamino, diphenylamino, 1-naphthylamino, 2-naphthylamino and the like can be mentioned. Unless otherwise specified, such as the "mono- or di-aralkylamino group of 7 to 16 carbon atoms" in the present specification may be mentioned an amino group mono- or di-substituted by the "aralkyl group" of 7 to 16 carbon atoms "mentioned above. For example, benzylamino, phenethylamino and the like may be mentioned. Unless otherwise specified, as the "N-alkyl (C _, -C5) -N-aryl (C6-C? 4) -amino group" in the present specification may be mentioned an amino group substituted by the " alkyl group of 1 to 6 carbon atoms "mentioned above and the" aryl group of 6 to 14 carbon atoms "mentioned above. For example, there can be mentioned N-methyl-N-phenylamino, N-ethyl-N-phenylamino and the like. Unless otherwise specified, such as the "N-alkyl (C __-C6) -N-aralkyl (C7-C? 6) -amino" group in the present specification may be mentioned an amino group substituted by the "group C 1-6 alkyl "mentioned above and the" aralkyl group of 7 to 16 carbon atoms "mentioned above. For example, N-methyl-N-benzylamino, N-ethyl-N-benzylamino and the like can be mentioned. Unless otherwise specified, as the "mono- or di-alkyl-carbamoyl group of 1 to 6 carbon atoms" in the present specification, a carbamoyl group mono- or di-substituted by the "alkyl group" may be mentioned. of 1 to 6 carbon atoms "mentioned above. For example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like may be mentioned. Unless otherwise specified, such as "N-alkyl group (Cx-Cs) -N-alkyl (C? -C6) -carbonyl-amino" in the present specification can be mentioned an amino group substituted by the "alkyl group of 1 to 6 carbon atoms" mentioned above and an alkyl carbonyl group of 1 to 6 carbon atoms (eg, acetyl, isobutanoyl, isopentanoyl). For example, there can be mentioned N-methyl-N-acetylamino, N-ethyl-N-acetylamino and the like. Unless otherwise specified, as the "mono- or di-aryl carbamoyl group of 6 to 14 carbon atoms" in the present specification, a carbamoyl group mono- or di-substituted by the "aryl group" may be mentioned. of 6 to 14 carbon atoms "mentioned above. For example, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl and the like can be mentioned. Unless otherwise specified, such as the "5- to 7-membered mono- or di-heterocyclic carbamoyl group" in the present specification may be mentioned a carbamoyl group mono- or di-substituted by a heterocyclic group of 5 to 7 members As the 5- to 7-membered heterocyclic group there can be mentioned a heterocyclic group containing one or two classes of 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as a ring building atom, in addition to the carbon atoms. As preferable examples of the "mono- or di-heterocyclic-carbamoyl 5- to 7-membered group" may be mentioned 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and the like. Unless otherwise specified, as the "mono- or di-alkyl-sulfamoyl group of 1 to 6 carbon atoms" in the present specification, a sulfamoyl group mono- or di-substituted by the "alkyl group" may be used. from 1 to 6 carbon atoms "mentioned above, for example, methylsulfamoyl, ethylsulphamoyl, dimethylsulphamoyl, diethylsulphamoyl and the like may be mentioned. Unless otherwise specified, as the "mono- or di-aryl-sulfamoyl group of 6 to 14 carbon atoms" in the present specification, a sulfamoyl group mono- or di-substituted by the "aryl group" may be used. from 6 to 14 carbon atoms "mentioned above, for example, phenylsulfamoyl, diphenylsulphamoyl, 1-naphthylsulphamoyl, 2-naphthylsulphamoyl and the like may be mentioned. As the "mono- or di-alkyl-phosphono group of 1 to 6 carbon atoms" in the present specification there may be mentioned a phosphono group mono- or di-substituted by the "alkyl group of 1 to 6 carbon atoms" mentioned previously. For example, dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono, and the like can be mentioned. Unless otherwise specified, such as the "C 1 -C 6 optionally substituted alkyl group", "C 2 -C 6 optionally substituted alkenyl group", "substituted alkynyl group of 2 to 6 carbon atoms optionally "," alkoxy group of 1 to 10 carbon atoms optionally substituted (containing an alkoxy group of 1 to 6 carbon atoms optionally substituted) "," alkylsulfonyloxy group of 1 to 6 carbon atoms optionally substituted "and" alkylthio group " from 1 to 10 carbon atoms optionally substituted (containing an alkylthio group of 1 to 6 carbon atoms optionally substituted) "in the present specification there may be mentioned, for example, an" alkyl group of 1 to 6 carbon atoms ", "alkenyl group of 2 to 6 carbon atoms", "alkynyl group of 2 to 6 carbon atoms", "alkoxy group of 1 to 10 carbon atoms (containing an alkoxy group of 1 to 6 carbon atoms)", "alkylsulfonyl group xi of 1 to 6 carbon atoms "and" alkylthio group of 1 to 10 carbon atoms (containing an alkylthio group of 1 to 6 carbon atoms) ", each of which optionally has from 1 to 5 substituents in positions substitutable selected from (1) a halogen atom; (2) a hydroxy group; (3) an amino group; (4) a nitro group; (5) a cyano group; (6) a heterocyclic group (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, pyrrolidinyl, oxopyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl, oxetanyl) optionally substituted by 1 to 3 substituents selected from halogen atom, hydroxy group, amino group, nitro group, cyano group, optionally halogenated alkyl group of 1 to 6 carbon atoms, mono- or di-alkyl-amino group of 1 to 6 carbon atoms, aryl group of 6 to 14 carbon atoms, a mono- or di-aryl-amino group of 6 to 14 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, an alkylthio group of 1 to 6 carbon atoms carbon, alkylsulfinyl group of 1 to 6 carbon atoms, alkylsulfonyl group of 1 to 6 carbon atoms, optionally esterified carboxyl group, carbamoyl group, thiocarbamoyl group, mono- or di-alkyl-carbamoyl group of 1 to 6 atom carbon, mono- or di-aryl carbamoyl group of 6 to 14 carbon atoms, sulfamoyl group, mono- or di-alkyl-sulfamoyl group of 1 to 6 carbon atoms and mono- or di-aryl-sulfamoyl group from 6 to 14 carbon atoms; (7) a mono- or di-alkyl-amino group of 1 to 6 carbon atoms; (8) a mono- or di-aryl-amino group of 6 to 14 carbon atoms; (9) a mono- or di-aralkylamino group of 7 to 16 carbon atoms; (10) an N-alkyl (C_-C6) -N-aryl (C6-C1) -amino group; (11) an N-alkyl (C _-C6) -N-aralkyl (C7-C_6) -amino group; (12) a cycloalkyl group of 3 to 8 carbon atoms; (13) an optionally halogenated alkoxy group of 1 to 6 carbon atoms; (14) an alkylthio group of 1 to 6 carbon atoms; (15) an alkylsulfinyl group of 1 to 6 carbon atoms; (16) an alkylsulfonyl group of 1 to 6 carbon atoms; (17) an optionally esterified carboxyl group, - (18) a carbamoyl group; (19) a thiocarbamoyl group; (20) a mono- or di-alkyl-carbamoyl group of 1 to 6 carbon atoms; (21) a mono- or di-aryl carbamoyl group of 6 to 14 carbon atoms; (22) a mono- or di-heterocyclyl-carbamoyl group of 5 to 7 members; (23) an alkyl-carbonylamino group of 1 to 6 carbon atoms (eg, acetylamino, propionylamino) optionally substituted by a carboxyl group; (24) an aryloxy group of 6 to 14 carbon atoms optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy group, amino group, nitro group, cyano group, alkyl group of 1 to 6 carbon atoms optionally halogenated , mono- or di-alkyl-amino group of 1 to 6 carbon atoms, aryl group of 6 to 14 carbon atoms, mono- or di-aryl-amino group of 6 to 14 carbon atoms, cycloalkyl group of 3 to 8 carbon atoms, alkoxy group of 1 to 6 carbon atoms, alkylthio group of 1 to 6 carbon atoms, alkylsulfinyl group of 1 to 6 carbon atoms, alkylsulfonyl group of 1 to 6 carbon atoms, carboxyl group optionally esterified, carbamoyl group, thiocarbamoyl group, mono- or di-alkyl-carbamoyl group of 1 to 6 carbon atoms, mono- or di-aryl carbamoyl group of 6 to 14 carbon atoms, sulfamoyl group, mono- or dialkyl-sulfamoyl group from 1 to 6 carbon atoms and mono- or di-aryl-sulfamoyl group of 6 to 14 atom s carbon; (25) an aryl group of 6 to 14 carbon atoms optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy group, amino group, nitro group, cyano group, alkyl group of 1 to 6 carbon atoms optionally halogenated , mono- or di-alkyl-amino group of 1 to 6 carbon atoms, aryl group of 6 to 14 carbon atoms, mono- or di-aryl-amino group of 6 to 14 carbon atoms, cycloalkyl group of 3 at 8 carbon atoms, alkoxy group of 1 to 6 carbon atoms, alkylthio group of 1 to 6 carbon atoms, alkylsulfinyl group of 1 to 6 carbon atoms, alkylsulfonyl group of 1 to 6 carbon atoms, carboxyl group optionally esterified , carbamoyl group, thiocarbamoyl group, mono- or di-alkyl-carbamoyl group of 1 to 6 carbon atoms, mono- or di-aryl carbamoyl group of 6 to 14 carbon atoms, sulfamoyl group, mono- or dialkyl group sulfamoyl of 1 to 6 carbon atoms and mono- or di-aryl-sulfamoyl group of 6 to 14 atoms of carbon, - (26) a heterocyclyloxy group optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy group, amino group, nitro group, cyano group, alkyl group of 1 to 6 carbon atoms optionally halogenated, mono group - or di-alkyl-amino of 1 to 6 carbon atoms, aryl group of 6 to 14 carbon atoms, mono- or di-aryl-amino group of 6 to 14 carbon atoms, cycloalkyl group of 3 to 8 carbon atoms carbon, alkoxy group of 1 to 6 carbon atoms, alkylthio group of 1 to 6 carbon atoms, alkylsulfinyl group of 1 to 6 carbon atoms, alkylsulfonyl group of 1 to 6 carbon atoms, optionally esterified carboxyl group, carbamoyl group, thiocarbamoyl group, mono- or di-alkyl-carbamoyl group of 1 to 6 carbon atoms, mono- or di-aryl carbamoyl group of 6 to 14 carbon atoms, sulfamoyl group, mono- or di-alkyl-sulphamoyl group of 1 to 6 carbon atoms and mono- or di-aryl-sulfamoyl group of 6 to 14 carbon atoms arbono (27) a sulfamoyl group; (28) a mono- or di-alkyl-sulfamoyl group of 1 to 6 carbon atoms; (29) a mono- or di-aryl-sulfamoyl group of 6 to 14 carbon atoms; (30) an aralkyloxy group of 7 to 16 carbon atoms optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy group, amino group, nitro group, cyano group, alkyl group of 1 to 6 carbon atoms optionally halogenated , mono- or di-alkyl-amino group of 1 to 6 carbon atoms, aryl group of 6 to 14 carbon atoms, mono- or di-aryl-amino group of 6 to 14 carbon atoms, cycloalkyl group of 3 to 8 carbon atoms, alkoxy group of 1 to 6 carbon atoms, alkylthio group of 1 to 6 carbon atoms, alkylsulfinyl group of 1 to 6 carbon atoms, alkylsulfonyl group of 1 to 6 carbon atoms, carboxyl group optionally esterified, carbamoyl group, thiocarbamoyl group, mono- or di-alkyl-carbamoyl group of 1 to 6 carbon atoms, mono- or di-aryl carbamoyl group of 6 to 14 carbon atoms, sulfamoyl group, mono- or di-alkyl group -sulfamoyl of 1 to 6 carbon atoms and mono- or di-aryl-sulfamoyl group of 6 to 14 carbon volumes; (31) N-alkyl (C _-C3) -N-alkyl (C? -C6) -carbonyl-amino group; (32) a mono- or di-alkyl-phosphono group of 1 to 6 carbon atoms; and similar. As the "optionally substituted cycloalkyl group of 3 to 8 carbon atoms", "optionally substituted aryl group of 6 to 14 carbon atoms", "optionally substituted aralkyl group of 7 to 16 carbon atoms", "optionally substituted heterocyclic group" , "optionally substituted heterocyclyloxy group", "optionally substituted aryloxy group of 6 to 14 carbon atoms", "optionally substituted aralkyloxy group of 7 to 16 carbon atoms", "optionally substituted heterocyclylsulfonyloxy group", "optionally substituted heterocyclicthio group", "optionally substituted arylthio group of 6 to 14 carbon atoms" and "optionally substituted aralkylthio group of 7 to 16 carbon atoms" in the present specification may be mentioned, for example, a "cycloalkyl group of 3 to 8 carbon atoms", "aryl group of 6 to 14 carbon atoms", "aralkyl group of 7 to 16 carbon atoms", "heterocyclic group", "heterocyclyloxy group" , "aryloxy group of 6 to 14 carbon atoms", "aralkyloxy group of 7 to 16 carbon atoms", "heterocyclylsulfonyloxy group", "heterocyclylthio group", "arylthio group of 6 to 14 carbon atoms", and "group aralkylthio of 7 to 16 carbon atoms ", each of which optionally has from 1 to 5 substituents in substitutable positions selected from (1) a halogen atom; (2) a hydroxy group; (3) an amino group; (4) a nitro group; (5) a cyano group; (6) an optionally substituted alkyl group of 1 to 6 carbon atoms; (7) an alkenyl group of 2 to 6 carbon atoms optionally substituted; (8) an alkynyl group of 2 to 6 carbon atoms optionally substituted; (9) an aryl group of 6 to 14 carbon atoms optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy group, amino group, nitro group, cyano group, alkyl group of 1 to 6 carbon atoms optionally halogenated , mono- or di-alkyl-amino group of 1 to 6 carbon atoms, aryl group of 6 to 14 carbon atoms, mono- or di-aryl-amino group of 6 to 14 carbon atoms, cycloalkyl group of 3 to 8 carbon atoms, alkoxy group of 1 to 6 carbon atoms, alkylthio group of 1 to 6 carbon atoms, alkylsulfinyl group of 1 to 6 carbon atoms, alkylsulfonyl group of 1 to 6 carbon atoms, carboxyl group optionally esterified, carbamoyl group, thiocarbamoyl group, mono- or di-alkyl-carbamoyl group of 1 to 6 carbon atoms, mono- or di-aryl carbamoyl group of 6 to 14 carbon atoms, sulfamoyl group, mono- or di-alkyl group -sulfamoyl of 1 to 6 carbon atoms and mono- or di-aryl-sulfamoyl group of 6 to 14 atoms of carbon; (10) an aryloxy group of 6 to 14 carbon atoms optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy group, amino group, nitro group, cyano group, alkyl group of 1 to 6 carbon atoms optionally halogenated , mono- or di-alkyl-amino group of 1 to 6 carbon atoms, aryl group of 6 to 14 carbon atoms, mono- or di-aryl-amino group of 6 to 14 carbon atoms, cycloalkyl group of 3 to 8 carbon atoms, alkoxy group of 1 to 6 carbon atoms, alkylthio group of 1 to 6 carbon atoms, alkylsulfinyl group of 1 to 6 carbon atoms, alkylsulfonyl group of 1 to 6 carbon atoms, carboxyl group optionally esterified, carbamoyl group, thiocarbamoyl group, mono- or di-alkyl-carbamoyl group of 1 to 6 carbon atoms, mono- or di-aryl carbamoyl group of 6 to 14 carbon atoms, sulfamoyl group, mono- or di-alkyl group -sulfamoyl of 1 to 6 carbon atoms and mono- or di-aryl-sulfamoyl group of 6 to 14 ato carbon (11) an aralkyloxy group of 7 to 16 carbon atoms optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy group, amino group, nitro group, cyano group, alkyl group of 1 to 6 carbon atoms optionally halogenated , mono- or dialkylamino group of 1 to 6 carbon atoms, aryl group of 6 to 14 carbon atoms, mono- or di-aryl-amino group of 6 to 14 carbon atoms, cycloalkyl group of 3 to 8 carbon atoms , alkoxy group of 1 to 6 carbon atoms, alkylthio group of 1 to 6 carbon atoms, alkylsulfinyl group of 1 to 6 carbon atoms, alkylsulfonyl group of 1 to 6 carbon atoms, optionally esterified carboxy group, carbamoyl group, group thiocarbamoyl, mono- or di-alkyl-carbamoyl group of 1 to 6 carbon atoms, mono- or di-aryl carbamoyl group of 6 to 14 carbon atoms, sulfamoyl group, mono- or di-alkyl-sulfamoyl group of 1 to 6 carbon atoms and mono- or di-aryl-sulfamoyl group of 6 to 14 atoms carbon atoms; (12) a heterocyclic group (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, pyrrolidinyl, oxopyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl, oxetanyl) optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy group, amino group, nitro group, cyano group, optionally halogenated alkyl group of 1 to 6 carbon atoms, mono- or di-alkyl-amino group of 1 to 6 carbon atoms, aryl group of 6 to 14 carbon atoms, mono- or di-aryl-amino group of 6 to 14 carbon atoms, cycloalkyl group of 3 to 8 carbon atoms, alkoxy group of 1 to 6 carbon atoms, alkylthio group of 1 to 6 carbon atoms, alkylsulfinyl group of 1 to 6 carbon atoms, alkylsulfonyl group of 1 to 6 carbon atoms, optionally esterified carboxyl group, carbamoyl group, thiocarbamoyl group, mono- or di-alkyl group -Carbamoyl of 1 to 6 carbon atoms, mono- or di-aryl carbamoyl group of 6 to 14 carbon atoms, sulfamoyl group, mono- or di-alkyl-sulfamoyl group of 1 to 6 carbon atoms, mono- or di-aryl-sulfamoyl of 6 to 14 carbon atoms; (13) a mono- or di-alkyl-amino group of 1 to 6 carbon atoms; (14) a mono- or di-aryl-amino group of 6 to 14 carbon atoms; (15) a mono- or di-aralkyl-amino group of 7 to 16 carbon atoms; (16) N-alkyl (C _-C6) -N-aryl (C6-C__) -amino group; (17) an N-alkyl (C__-CS) -N-aralkyl (C7-C_6) -amino group; (18) a cycloalkyl group of 3 to 8 carbon atoms; (19) an alkoxy group of 1 to 6 carbon atoms optionally substituted; (20) an alkylthio group of 1 to 6 carbon atoms; (21) an alkylsulfinyl group of 1 to 6 carbon atoms; (22) an alkylsulfonyl group of 1 to 6 carbon atoms; (23) an optionally esterified carboxyl group; (24) a carbamoyl group; (25) a thiocarbamoyl group; (26) a mono- or di-alkyl carbamoyl group of 1 to 6 carbon atoms; (27) a mono- or di-aryl carbamoyl group of 6 to 14 carbon atoms; (28) a mono- or di-heterocyclyl-carbamoyl group of 5 to 7 members; (29) a sulfamoyl group; (30) a mono- or di-alkyl-sulfamoyl group of 1 to 6 carbon atoms; (31) a mono- or di-aryl-sulfamoyl group of 6 to 14 carbon atoms; (32) an N-alkyl (Q _.- C6) -N-alkyl (C __-C3) carbonyl-amino group; (33) a heterocyclyloxy group optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy group, amino group, nitro group, cyano group, alkyl group of 1 to 6 carbon atoms optionally halogenated, mono- or di- alkyl-amino of 1 to 6 carbon atoms, aryl group of 6 to 14 carbon atoms, mono- or di-aryl-amino group of 6 to 14 carbon atoms, cycloalkyl group of 3 to 8 carbon atoms, alkoxy group from 1 to 6 carbon atoms, alkylthio group of 1 to 6 carbon atoms, alkylsulfinyl group of 1 to 6 carbon atoms, alkylsulfonyl group of 1 to 6 carbon atoms, optionally esterified carboxyl group, carbamoyl group, thiocarbamoyl group, group mono- or di-alkyl-carbamoyl of 1 to 6 carbon atoms, mono- or di-aryl-carbamoyl group of 6 to 14 carbon atoms, sulfamoyl group, mono- or di-alkyl-sulfamoyl group of 1 to 6 atoms carbon and mono- or di-aryl-sulfamoyl group of 6 to 14 carbon atoms; (34) a mono- or di-alkyl-phosphono group of 1 to 6 carbon atoms; and similar. Unless otherwise specified, as the "optionally substituted amino group" in the present specification, an amino group optionally substituted by 1 or 2 substituents selected from (1) an alkyl group of 1 to 6 carbon atoms substituted may be mentioned. optionally; (2) an alkenyl group of 2 to 6 carbon atoms optionally substituted; (3) an alkynyl group of 2 to 6 carbon atoms optionally substituted; (4) a cycloalkyl group of 3 to 8 carbon atoms optionally substituted; (5) an aryl group of 6 to 14 carbon atoms optionally substituted; (6) an alkoxy group of 1 to 6 carbon atoms optionally substituted; (7) an optionally substituted acyl group; (8) an optionally substituted heterocyclic group (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, oxazolyl); (9) a sulfamoyl group; (10) a mono- or di-alkyl-sulfamoyl group of 1 to 6 carbon atoms; (11) a mono- or di-aryl-sulfamoyl group of 6 to 14 carbon atoms; and similar. When the "optionally substituted amino group" is an amino group substituted by 2 substituents, these substituents can form a nitrogen-containing heterocycle together with the adjacent nitrogen atom. As the "nitrogen-containing heterocycle" there may be mentioned, for example, a 5- to 7-membered nitrogen-containing heterocycle containing at least one nitrogen atom and optionally also containing 1 or 2 heteroatoms selected from an oxygen atom, an sulfur atom and a nitrogen atom as a ring building atom, carbon atoms can also be mentioned. Preferable examples of the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazolidine, oxazolidine, and the like. Unless otherwise specified, such as "acyl group optionally substituted" in the present specification can be mentioned the groups represented by the formula: -COR8, -CO-OR8, -S02R8, -SOR8, -PO (OR8) (OR9), -CO-NR8aR9a and -CS-NR8aR9a, wherein R8 and R9 are the same or different and each is a hydrogen atom, a hydrocarbon group optionally substituted or an optionally substituted heterocyclic group and R8a and R9a are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group or R8a and R9a can form a nitrogen-containing heterocycle optionally substituted together with the adjacent nitrogen atom and the like. As the "nitrogen-containing heterocycle" of the "optionally substituted nitrogen-containing heterocycle" of which R8a and R9a together with the adjacent nitrogen atom form, for example, a 5- to 7-membered nitrogen containing heterocycle containing at least one atom of nitrogen and optionally containing in addition to 1 to 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as a ring building atom, may be mentioned in addition to the carbon atoms. As preferable examples of the "nitrogen-containing heterocycle" can be mentioned pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazolidine, oxazolidine and the like. The nitrogen-containing heterocycle optionally has 1 to 2 substituents in substitutable positions. As these substituents may be mentioned a hydroxy group, an optionally halogenated alkyl group of 1 to 6 carbon atoms, an aryl group of 6 to 14 carbon atoms, an aralkyl group of 7 to 16 carbon atoms and the like. As preferable examples of the "optionally substituted acyl group" may be mentioned a formyl group, carboxyl group, carbamoyl group, alkylcarbonyl group of 1 to 6 carbon atoms (eg, acetyl, isobutanoyl, isopentanoyl), alkoxycarbonyl group of 1 to 6 carbon atoms (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl), cycloalkyl-carbonyl group of 3 to 8 carbon atoms (for example, cyclopentylcarbonyl, cyclohexylcarbonyl), aryl-carbonyl group of 6 to 14 carbon atoms carbon (eg, benzoyl, 1-naphthoyl, 2-naphthoyl), aralkyl-carbonyl group of 7 to 16 carbon atoms (eg, phenylacetyl, 2-phenylpropanoyl), aryloxy-carbonyl group of 6 to 14 carbon atoms ( for example, phenyloxycarbonyl, naphthyloxycarbonyl), aralkyloxycarbonyl group of 7 to 16 carbon atoms (for example, benzyloxycarbonyl, phenethyloxycarbonyl), mono- or di-alkylcarbamoyl group of 1 to 6 carbon atoms, group mono- or di-aryl carbamoyl of 6 to 14 carbon atoms, cycloalkyl-carbamoyl group of 3 to 8 carbon atoms (for example, cyclopropylcarbamoyl), aralkyl-carbamoyl group of 7 to 16 carbon atoms (for example, benzylcarbamoyl) ), alkylsulfonyl group of 1 to 6 carbon atoms, arylsulfonyl group of 6 to 14 carbon atoms, heterocyclyl carbonyl group containing nitrogen (for example, pyrrolidinylcarbonyl, piperidinylcarbonyl), alkylsulfinyl group of 1 to 6 carbon atoms, arylsulfinyl group from 6 to 14 carbon atoms, thiocarbamoyl group, mono- or di-alkyl-phosphono group of 1 to 6 carbon atoms (for example, dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono) and the like. The "alkylene group of 1 to 4 carbon atoms" of "C 1 -C 4 -alkyl group optionally substituted" in the present specification is straight or branched chain and there may be mentioned, for example, methylene, ethylene, 1-methylethylene, propylene, 1-ethylethylene, 1-methylpropylene, 2 -methylpropylene, butylene and the like. The alkylene group of 1 to 4 carbon atoms optionally has 1 to 3 substituents in the substitutable positions. As these substituents, there can be mentioned, for example, a halogen atom, hydroxy group, amino group, mono- or di-alkyl-amino group of 1 to 6 carbon atoms, mono- or di-aryl-amino group of 6 to 14 carbon atoms, mono- or di-aralkyl-amino group of 7 to 16 carbon atoms, nitro group, cyano group, alkoxy group of 1 to 6 carbon atoms, alkylthio group of 1 to 6 carbon atoms and the like . As the "alkylene group of 1 to 3 carbon atoms" of the "alkylene group of 1 to 3 carbon atoms optionally substituted" in the present specification of the "alkylene groups of 1 to 4 carbon atoms" mentioned above, can be mentioned those that have 1 to 3 carbon atoms. The alkylene group of 1 to 3 carbon atoms optionally has 1 to 3 substituents in substitutable positions. As these substituents may be mentioned those exemplified as the substituent of the aforementioned alkylene group of 1 to 4 carbon atoms. The compound represented by the formula (I) of the present invention (which is sometimes abbreviated as the compound (I) later in this document) and a salt thereof are explained below.

R 2 in formula (I) is a halogen atom, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted mercapto group, an optionally substituted acyl group or a heterocyclic group optionally substituted, preferably a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted mercapto group or an optionally substituted heterocyclic group, more preferably an optionally substituted hydrocarbon group or a hydroxy group optionally substituted. Of these, an optionally substituted hydroxy group is preferable. As specific, preferable examples of the optionally substituted hydroxy group may be mentioned (1) a hydroxy group, (2) an alkoxy group of 1 to 10 carbon atoms optionally substituted by 1 to 3 substituents selected from (a) a heterocyclic group of 4 to 7 members containing one or two classes of 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as a ring building atom, in addition to carbon atoms (preferably, pyridyl, thiazolyl, pyrrolidinyl, oxopyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl, oxetanyl), optionally substituted by 1 to 3 substituents selected from an optionally halogenated alkyl group of 1 to 6 carbon atoms, a hydroxy group and an alkoxy group -carbonyl of 1 to 6 carbon atoms, - (b) a cycloalkyl group of 3 to 8 carbon atoms, (c) a hydroxy group, (d) a group optionally halogenated carbon atom of 1 to 6 carbon atoms, (e) an amino group, (f) a mono- or di-alkyl-amino group of 1 to 6 carbon atoms, (g) an N-alkyl group (C) -C6) -N-alkyl (C _-C6) -carboni1-amino, (h) an aralkyloxy group of 7 to 16 carbon atoms, (i) an alkylthio group of 1 to 6 carbon atoms, (j) a alkylsulphinyl group of 1 to 6 carbon atoms, (k) an alkylsulfonyl group of 1 to 6 carbon atoms, and (1) a mono- or di-alkyl-phosphono group of 1 to 6 carbon atoms, (3) an heterocyclyloxy group (preferably tetrahydropyranyloxy, pyridyloxy, tetrahydrothiopyranyloxy, 1-oxidotetrahydrothiopyranyloxy), 1, 1-dioxidotetrahydrothio-pyranyloxy) optionally substituted by an optionally halogenated alkyl group of 1 to 6 carbon atoms, (4) an aralkyloxy group of 7 to 16 carbon atoms, (5) a silyloxy group optionally substituted by 1 to 3 alkyl groups of 1 to 6 carbon atoms, (6) an alkylsulfonyloxy group of 1 to 6 carbon atoms, and (7) a heterocyclylsulfonyloxy group (preferably thienylsulfonyloxy, furylsulfonyloxy). R1 and R3 in the formula (I) are the same (except when R1 and R3 are both hydrogen atoms) or different and each is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or a substituted hydroxy group optionally, preferably a hydrogen atom, a halogen atom or an alkyl group of 1 to 6 carbon atoms, more preferably a halogen atom or an alkyl group of 1 to 6 carbon atoms. Of these, an alkyl group of 1 to 6 carbon atoms (preferably methyl) is preferable. R4 and R5 in formula (I) are the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an optionally substituted hydroxy group, preferably a hydrogen atom or a halogen atom (preferably a fluorine atom). R10 and R11 in the formula (I) are the same or different and each is a hydrogen atom, a halogen atom or an alkoxy group of 1 to 6 carbon atoms, preferably both are hydrogen atoms. E in formula (I) is a bond, an alkylene group of 1 to 4 carbon atoms optionally substituted, -V ^ -O-W2- -W1-S- 2- or-1-N (R6) -W2- (1 and 2 are the same or different and each is a bond or an alkylene group of 1 to 3 carbon atoms optionally substituted and Rs is a hydrogen atom, an optionally substituted acyl group or an optionally substituted hydrocarbon group), preferably a link. The ring S1 in the formula (I) is a benzene ring optionally further having substituents selected from a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group and an optionally substituted amino group, preferably a benzene ring which also optionally has an alkoxy group of 1 to 6 carbon atoms. The number of substituents is, for example, 1 or 2. R in formula (I) is an optionally substituted hydroxy group or an optionally substituted amino group, preferably an optionally substituted hydroxy group, more preferably a hydroxy group or an alkoxy group of 1 to 6 carbon atoms. Of these, a hydroxy group is preferable. As the "preferable examples of compound (I)", the following compounds may be mentioned. [Compound A] A compound wherein R 2 is (1) a halogen atom, (2) an alkyl group of 1 to 6 carbon atoms optionally substituted by an aryloxy group of 6 to 14 carbon atoms optionally substituted by a carbon atom. halogen, (3) a hydroxy group, (4) an alkoxy group of 1 to 10 carbon atoms optionally substituted by 1 to 3 substituents selected from (a) a 5-7 membered heterocyclic group containing one or two classes from 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as a ring building atom, in addition to a carbon atom (preferably, pyridyl, thiazolyl), optionally substituted by an alkyl group of 1 to 6 atoms optionally halogenated carbon, (b) a cycloalkyl group of 3 to 8 carbon atoms, (c) a hydroxy group, (d) an optionally halogenated alkoxy group of 1 to 6 carbon atoms, (e) an amino group, and (f) a mono- or di-alkyl-amino group of 1 to 6 carbon atoms, (5) a heterocyclyloxy group (preferably tetrahydropyranyloxy), or (6) an aralkyloxy group of 7 to 16 carbon atoms; R1 and R3 are the same (except when R1 and R3 are both hydrogen atoms) or different and each is a hydrogen atom, a halogen atom or an alkyl group of 1 to 6 carbon atoms; R4 and R5 are the same or different and each is a hydrogen atom or a halogen atom; R10 and R11 are both hydrogen atoms; E is a link; ring S1 is a benzene ring optionally having also an alkoxy group of 1 to 6 carbon atoms; and R is a hydroxy group or an alkoxy group of 1 to 6 carbon atoms (preferably a hydroxy group). [Compound B] A compound wherein R 2 is (1) a halogen atom, (2) an alkyl group of 1 to 6 carbon atoms optionally substituted by an aryloxy group of 6 to 14 carbon atoms optionally substituted by a carbon atom. halogen, (3) a hydroxy group, (4) an alkoxy group of 1 to 10 carbon atoms optionally substituted by 1 to 3 substituents selected from (a) a 5-7 membered heterocyclic group containing one or two classes from 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as a ring-building atom, in addition to a carbon atom (preferably, pyridyl, thiazolyl, pyrrolidinyl, oxopyrrolidinyl, tetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl) , optionally substituted by 1 to 3 substituents selected from an optionally halogenated alkyl group of 1 to 6 carbon atoms, a hydroxy group and an alkoxycarbonyl group of 1 to 6 carbon atoms, (b) a cycloalkyl group of 3 to 8 carbon atoms, (c) a hydroxy group, (d) an optionally halogenated alkoxy group of 1 to 6 carbon atoms, (e) an amino group (f) a mono- or di-alkyl-amino group of 1 to 6 carbon atoms, (g) a Na group alkyl (C_-C3) -N-alkyl (C_-C6) -carbonyl-amino, (h) an aralkyloxy group of 7 to 16 carbon atoms, (i) an alkylthio group of 1 to 6 carbon atoms, Y (j) an alkylsulfonyl group of 1 to 6 carbon atoms, (5) a heterocyclyloxy group (preferably tetrahydropyranyloxy, pyridyloxy, tetrahydrothiopyranyloxy, 1,1-dioxidotetrahydrothiopyranyloxy), optionally substituted by an alkyl group of 1 to 6 carbon atoms halogenated optionally, (6) an aralkyloxy group of 7 to 16 carbon atoms, (7) a silyloxy group optionally substituted by 1 to 3 alkyl groups of 1 to 6 carbon atoms, (8) an alkylsulfonyloxy group of 1 to 6 carbon atoms, carbon, or (9) a 'heterocyclylsulfonyloxy group (preferably thienylsulfonyloxy, furylsulfonyloxy); R1, R3, R4, R5, R10, R11, E, the ring S1 and R are as defined for the [compound A] mentioned above. [Compound C] A compound wherein R 2 is (1) a halogen atom, (2) an alkyl group of 1 to 6 carbon atoms optionally substituted by an aryloxy group of 6 to 14 carbon atoms optionally substituted by a carbon atom. halogen, (3) a hydroxy group, (4) an alkoxy group of 1 to 10 carbon atoms optionally substituted by 1 to 3 substituents selected from (a) a 4 to 7 membered heterocyclic group containing one or two kinds of 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as a ring-building atom, in addition to a carbon atom (preferably, pyridyl, thiazolyl, pyrrolidinyl, oxopyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl, oxetanyl ), optionally substituted by 1 to 3 substituents selected from an optionally halogenated alkyl group of 1 to 6 carbon atoms, a hydroxy group and an alkoxycarbonyl group of 1 to 6 carbon atoms, (b) a cycloalkyl group of 3 to 8 carbon atoms, (c) a hydroxy group, (d) an optionally halogenated alkoxy group of 1 to 6 carbon atoms, (e) an amino group (f) a mono- or di-alkyl-amino group of 1 to 6 carbon atoms, (g) an N-alkyl (C_-C6) -N-alkyl (C? -C6) -carbonyl-amino group, (h) an aralkyloxy group of 7 to 16 carbon atoms, (i) an alkylthio group of 1 to 6 carbon atoms, (j) an alkylsulfinyl group of 1 to 6 carbon atoms, (k) an alkylsulfonyl group of 1 to 6 carbon atoms, and (1) a mono- or di-alkyl-phosphono group of 1 to 6 carbon atoms, (5) a heterocyclyloxy group (preferably tetrahydropyranyloxy, pyridyloxy, tetrahydrothiopyranyloxy, 1-oxidotetrahydrothiopyranyloxy, 1, 1-dioxidotetrahydrothio-pyranyloxy), optionally substituted by an optionally halogenated alkyl group of 1 to 6 carbon atoms, (6) an aralkyloxy group of 7 to 16 carbon atoms, (7) a substituted silyloxy group optionally from 1 to 3 alkyl groups of 1 to 6 carbon atoms, (8) an alkylsulfonyloxy group of 1 to 6 carbon atoms, or (9) a heterocyclylsulfonyloxy group (preferably thienylsulfonyloxy, furylsulfonyloxy); R1, R3, R4, R5, R10, R11, E, ring S1 and R are as defined for [Compound A] mentioned above. In the present compound, R1 and R3 are preferably the same or different and each is an alkyl group of 1 to 6 carbon atoms.

[Compound D] 3- [4- [[4 '- (benzyloxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy] phenyl] propanoic acid (Example 39); 3- (4 { [4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy} phenyl) -2,2-difluoropropanoic acid (Example 75); 3- [4- ( {4 '- [2- (Ethylsulfonyl) ethoxy] -2', 6'-dimethylbiphenyl-3-yl}. methoxy) -2-fluorophenyl] -hinolenic acid (Example 86); 3- [4- (. {2 ', 6' -dimethyl-4 '- [3- (2-oxopyrrolidin-1-yl) propoxy] biphenyl-3-yl} methoxy) -2-fluorophenyl] propanoic (Example 90); 3- [4- (. {2 ', 6' -dimethyl-4 '- [(6-methylpyridin-2-yl) methoxy] -biphenyl-3-yl) methoxy) -2-fluorophenyl] propanoic acid (Example 97); 3- [2-fluoro-4- ( {4'- [(4-hydroxy-l, 1-dioxidotetrahydro-2H-thiopyran-4-yl) methoxy] -2 ', 6'-dimethylbiphenyl-3- acid il.}. methoxy) -phenyl] propanoic acid (Example 100); 3- [4- (. {2 ', 6' -dimethyl-4 '- [(ethylsulfonyl) oxy] biphenyl-3-11) methoxy) -2-fluorophenyl] propanoic acid (Example 102); 3- [4- (. {4 '- [(1, l-dioxidotetrahydro-2H-thiopyran-4-yl) -oxy] -2'6' -dimethylbiphenyl-3-yl.} methoxy) -2 acid -fluorophenyl] -propanoic acid (Example 114); 3- [4- (. {2 ', 6' -dimethyl-4 '- [(3-methyloxetan-3-yl) methoxy] -biphenyl-3-yl} methoxy) -2-fluorophenyl] propanoic acid (Example 116); 3- (4 { [2 ', 6' -dimethyl-4 '- (tetrahydro-2 H -pyran-4-yloxy) -biphenyl-3-yl) methoxy acid} -2-fluorophenyl) propanoic (Example 118); 3- [4- ( {4 '- [3- (diethoxyphosphoryl) propoxy] -2', 6'-dimethyl-biphenyl-3-yl}. methoxy) -2-fluorophenyl] propanoic acid (Example 121); 3- [2-fluoro-4- (. {6-isopropoxy-2 ', 6'-dimethyl-4' - [(3-methyloxetan-3-yl) methoxy] biphenyl-3-yl} methoxy acid ) phenyl] propanoic (Example 125); or a salt thereof (preferably hydrochloride, etc.). As a salt of a compound used in the present invention there may be mentioned, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like. Preferable examples of the metal salts include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like. Preferable examples of the salt with an organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like. Preferable examples of the salt with an inorganic acid include a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with an organic acid include a salt with formic acid, acetic acid, trifluoroacetic acid, italic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Preferable examples of the salt with a basic amino acid include a salt with arginine, lysine, ornithine and the like. Preferable examples of the salt with an acidic amino acid include a salt with aspartic acid, glutamic acid and the like. Of these, a pharmacologically acceptable salt is preferable. For example, when the compound has an acidic functional group, metal salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt) are preferable. , magnesium salt, barium salt, etc.) and the like, ammonium salt and the like are preferable and when the compound has a basic functional group, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, acid phosphoric and the like; or salts with organic acids such as acetic acid, italic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like. A prodrug of compound (I) and a salt thereof is a compound that is converted to compound (I) due to the reaction by an enzyme, gastric acid and the like under physiological conditions in the body; that is, a compound that is converted to compound (I) by means of enzymatic oxidation, reduction, hydrolysis and the like and a compound that is converted to compound (I) by means of hydrolysis and the like by gastric acid and the like. Examples of a prodrug of compound (I) include a compound wherein an amino group of compound (I) is acylated, alkylated or phosphorylated (e.g., a compound wherein an amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-l, 3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated and the like); a compound wherein a hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated (e.g., a compound wherein a hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumedylated, alanylated, dimethylaminomethylcarbonylated and the like); a compound wherein a carboxyl group of compound (I) is esterified or amidated (for example, a compound wherein a carboxyl group of compound (I) is esterified with alkyl of 1 to 6 carbon atoms, esterified with phenyl, esterified with carboxymethyl , esterified with dimethylaminomethyl, esterified with pivaloyloxymethyl, esterified with ethoxycarbonyloxyethyl, esterified with phthalidyl, esterified with (5-methyl-2-oxo-l, 3-dioxolen-4-yl) ethyl, esterified with cyclohexyloxycarbonylethyl, methylamide and the like) and the like . Of these, a compound is preferable wherein a carboxyl group of compound (I) is esterified by an alkyl group of 1 to 6 carbon atoms such as methyl, ethyl, tert-butyl and the like. These compounds can be produced from the compound (I) by means of a method known per se. A prodrug of compound (I) can be a compound that is converted to compound (I) under physiological conditions as described in Development of Pharmaceutical Products, vol. 7, Molecule Design, 163-198, Hirokawa Shoten (1990). Later in this document, the production methods of the compound (I) or a salt thereof of the present invention are explained. Each symbol of the "following reaction schemes is as defined above unless specifically described." Each compound described in the reaction schemes can form a salt as long as it does not inhibit the reaction and, like this salt, can be mention those salts similar to the salts of the compound (I).

The compound (I) can be produced, for example, according to the method shown by the following reaction schemes 1-4. The compound (I) wherein E is E1 (E1 is a bond, an alkylene group of 1 to 4 carbon atoms optionally substituted, -W1-N (RS) - (1 and R6 are as defined above) or -0 -) (the compounds represented by the formulas (la ') and (la) (which are abbreviated as the compound (la ') and compound (la), respectively)) can be produced, for example, according to the method shown by the following Reaction Scheme 1 or a method analogous thereto.

Reaction Scheme 1 (V-1) (V-2) (V-3) wherein R 'is an alkoxy group of 1 to 6 carbon atoms optionally substituted, L is a leaving group or a hydroxy group, L' is a leaving group, M is a metal (for example, potassium, sodium, lithium, magnesium, copper, mercury, zinc, thallium, boron, tin and the like, which can be formed in a complex), Ga is a bond or an alkylene group of 1 to 4 carbon atoms optionally substituted (as the alkylene group of 1 to 4 carbon atoms optionally substituted for E) and the other symbols are as defined above. As the "leaving group" for L and L 'there may be mentioned, for example, a halogen atom (for example, fluorine, chlorine, bromine, iodine), an optionally halogenated alkylsulfonyloxy group of 1 to 6 carbon atoms (for example , methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy), an arylsulfonyloxy group of 6 to 10 carbon atoms optionally having substituents (for example, an arylsulfonyloxy group of 6 to 10 carbon atoms (eg, phenylsulfonyloxy, naphthylsulfonyloxy) optionally having 1 to 3 substituents selected from an alkyl group of 1 to 6 carbon atoms (for example, methyl, ethyl), an alkoxy group of 1 to 6 carbon atoms (for example, methoxy, ethoxy) and nitro, and the like; as specific examples may be mentioned a phenylsulfonyloxy group, a m-nitrophenylsulfonyloxy group, a p-toluenesulfonyloxy group and the like) and the like. The compounds represented by the formulas (II), (III), (Vl), (V-2) and (V-3) (which are abbreviated as compounds (II), (III), (Vl), (V-2) and (V-3), respectively) are commercially available and can also be produced according to a method known per se or a method analogous thereto. A compound represented by the formula (IV) (which is abbreviated as the compound (IV)) can be produced by reacting the compound (II) with the compound (III). (i). When L is a hydroxy group, the compound (IV) can be produced by subjecting the compound (II) and the compound (III) to the Mitsunobu reaction (Synthesis, "1981, pages 1-27). , compound (II) and the compound (III) are reacted in the presence of azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1, 1 '- (azodicarbonyl) dipiperidino and the like and phosphines such as triphenylphosphine, tributylphosphine and the like. the reaction is advantageously carried out using a solvent inert to the reaction. While the solvent is not particularly limited as long as the reaction to proceed, are preferable, for example, solvents such as ethers (e.g. diethyl ether, diisopropyl ether , 2-dimethoxyethane and the like) diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1, aromatic hydrocarbons (eg benzene, toluene and the like), saturated hydrocarbons (eg ciciohex anus, hexane and the like); the amides (for example, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide and the like); halogenated hydrocarbons (for example, dichloromethane chloroform, carbon tetrachloride, 1,2-dichloroethane and the like); the nitriles (for example, acetonitrile, propionitrile and the like); the ketones (for example, acetone, ethyl methyl ketone and the like); sulfoxides (for example, dimethyl sulfoxide and the like) and the like or a mixed solvent thereof and the like. The reaction time is generally from about 5 minutes to about 48 hours, preferably from about 10 minutes to about 24 hours. The reaction temperature is generally from about -20 to about 200 ° C, preferably from about 0 to about 100 ° C. The amount of the compound (III) to be used is from about 1 to about 5 mol, preferably from about 1 to about 2 mol relative to 1 mol of the compound (II). The amount of the "azodicarboxylate" and the "phosphine" to be used is respectively from about 1 to about 5 mol, preferably from about 1 to about 2 mol, relative to 1 mol of the compound (II) • (ii) When L is a leaving group, the compound (IV) can be produced by reacting the compound (II) with the compound (III) in the presence of a base. As the base there may be mentioned, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; the alkaline earth metal hydroxides such as barium hydroxide and the like; the alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; the alkali metal acid carbonates such as sodium acid carbonate and the like; acetates such as sodium acetate, ammonium acetate and the like, aromatic amines such as pyridine, lutidine and the like; tertiary amines - such as triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like; the alkali metal hydrides such as sodium hydride, potassium hydride and the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like; the alkali metal alkoxides having from 1 to 6 carbon atoms such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like, and the like. The reaction is advantageously carried out using a solvent inert to the reaction. While the solvent is not particularly limited as long as the reaction is preferable, for example, solvents such as ethers (e.g., diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1-2) dimethoxyethane and the like); aromatic hydrocarbons (for example, benzene, toluene and the like); saturated hydrocarbons (e.g., cyclohexane, hexane and the like); the amides (for example, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide and the like); halogenated hydrocarbons (for example, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like); the nitriles (for example, acetonitrile, propionitrile and the like); the esters (for example, methyl acetate, ethyl acetate, butyl acetate and the like); the sulfoxides (for example, dimethyl sulfoxide and the like); water and the like or a mixed solvent thereof and the like. The amount of the compound (III) to be used is from about 0.8 to 10 mol, preferably from about 0.9 to 2 mol, relative to 1 mol of the compound (II). The amount of the base to be used is about 1 to 10 mol, preferably about 1 to 3 mol, relative to 1 mol of the compound (II). The reaction time is generally from about 10 minutes to about 12 hours, preferably from about 20 minutes to about 6 hours. The reaction temperature is generally from about -50 to about 150 ° C, preferably from about -20 to about 100 ° C. The compound (la ') can be produced by reacting the compound (IV) with the compound (Vl) or the compound (V-2) or the compound (V-3) (unless otherwise specified, these compounds are collectively referred to as the compound (V)). The reaction of the compound (IV) with the compound (V) is generally carried out in the presence of a base. As the base, there may be mentioned alkali metal hydrides (eg, sodium hydride, potassium hydride and the like); the alkali metal hydroxides (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like); the alkaline earth metal hydroxides (eg, magnesium hydroxide, calcium hydroxide and the like); the alkali metal carbonates (e.g., sodium carbonate, potassium carbonate and the like); acid carbonates of alkali metals (eg, sodium hydrogen carbonate, potassium hydrogen carbonate and the like); the alkali metal alkoxides having from 1 to 6 carbon atoms (for example, sodium methoxide, sodium ethoxide, sodium tert-butoxide and the like); organic bases (for example, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene and the like); organic lithiums (for example, methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium and the like); lithium amides (eg, lithium diisopropylamide and the like) and the like. The reaction of the compound (IV) with the compound (V) is advantageously carried out using a solvent inert to the reaction. While the solvent is not particularly limited as long as the reaction proceeds, solvents such as alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, and the like) are preferable; the ethers (for example, 1,4-dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether and the like); the esters (for example, ethyl formate, ethyl acetate, n-butyl acetate and the like); halogenated hydrocarbons (for example, dichloromethane, chloroform, carbon tetrachloride, trichlorethylene and the like); the hydrocarbons (for example, n-hexane, benzene, toluene, xylene and the like); the amides (for example, formamide, N, N-dimethylformamide, N, N-dimethylacetamide and the like); the nitriles (for example, acetonitrile, propionitrile and the like); the sulfoxides (for example, dimethyl sulfoxide and the like); sulfolane; hexamethylphosphoric triamide; water and the like, a mixed solvent thereof and the like. The reaction of the compound (IV) with the compound (V) can generally be promoted by the use of a metal catalyst. As the metal catalyst metal complexes having several ligands may be used and there may be mentioned, for example, the palladium compounds [e.g., palladium (II) acetate, tetracis (triphenylphosphine) -palladium (O), bis (triphenylphosphine) palladium (II), dichlorobis (triethylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium-2, 2'-bis (diphenylphosphino) -1,1'-aminonaphthyl, a complex of palladium acetate ( II) and 1,1'-bis (diphenylphosphino) ferrocene and the like], nickel compounds [for example, tetracis (triphenylphosphine) nickel (0), bis (triethylphosphine) nickel (II) chloride, bis (triphenylphosphine) chloride nickel (II) and the like], rhodium compounds [eg, tris (triphenylphosphine) -rodio (III) chloride and the like], cobalt compounds, copper compounds [e.g., copper oxide, chloride] copper (II) and the like], platinum compounds and the like. Of these, palladium compounds, nickel compounds and copper compounds are preferable. The amount of the metal catalyst to be used is from about 0.000001 to 5 mol, preferably from about 0.0001 to 1 mol, relative to 1 mol of the compound (IV). When a metal catalyst which is unstable towards oxygen is used in this reaction, the reaction is preferably carried out in an inactive gas stream (for example, argon gas or nitrogen gas). The amount of the compound (V) to be used is from about 0.8 to 10 mol, preferably from about 0.9 to 2 mol, relative to 1 mol of the compound (IV). The amount of the base to be used is from about 1 to about 20 mol, preferably from about 1 to about 5 mol, relative to 1 mol of the compound (IV). The reaction temperature is from about -10 ° C to about 250 ° C, preferably from about 0 ° C to about 150 ° C. While the reaction time varies depending on the classes of the compound (IV), compound (V), metal catalyst, base and solvent, reaction temperature and the like, it is generally from about 1 minute to about 200 hours, preferably from about 5 minutes to about 100 hours.

The compound (la) can be produced by subjecting the compound (la ') to the hydrolysis reaction. The hydrolysis reaction is carried out using an acid or a base according to a conventional method. As the acid, there can be mentioned, for example, mineral acids (for example, hydrochloric acid, sulfuric acid and the like); Lewis acids (for example, boron trichloride, boron tribromide and the like); organic acids (for example, trifluoroacetic acid, p-toluenesulfonic acid and the like) and the like. A Lewis acid can be used concurrently with thiol or sulfur. As the base there may be mentioned, for example, the alkali metal hydroxides (for example, sodium hydroxide, potassium hydroxide, barium hydroxide and the like); the alkali metal carbonates (e.g., sodium carbonate, potassium carbonate and the like); the alkali metal alkoxides having from 1 to 6 carbon atoms (for example, sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like); organic bases (e.g., triethylamine, imidazole, formamidine and the like) and the like. The amount of acid and base to be used is about 0.5 to 10 mol, preferably about 0.5 to 6 mol, relative to 1 mol of the compound (la7). The hydrolysis reaction is carried out without solvent, or using a solvent inert to the reaction. While the solvent is not particularly limited as long as the reaction proceeds, for example, solvents such as alcohols (for example, methanol, ethanol, propanol and the like) are preferable; aromatic hydrocarbons (for example, benzene, toluene and the like); saturated hydrocarbons (e.g., cyclohexane, hexane and the like); organic acids (for example, formic acid, acetic acid and the like); the ethers (for example, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like); the amides (for example, N, N-dimethylformamide, N, N-dimethylacetamide and the like); halogenated hydrocarbons (for example, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like); the nitriles (for example, acetonitrile, propionitrile and the like); the ketones (for example, acetone, ethyl-methyl-ketone and the like); the sulfoxides (for example, dimethyl sulfoxide and the like); water and the like, a mixed solvent thereof and the like. The reaction time is generally 10 minutes to 60 hours, preferably 10 minutes to 12 hours. The reaction temperature is in general from -10 to 200 ° C, preferably from 0 to 120 ° C. The compound (I) wherein R is an alkoxy group of 1 to 6 carbon atoms optionally substituted or a hydroxy group (compound represented by the formula (Ib ') or (Ib) (which are abbreviated as the compound (Ib ') or the compound (Ib), respectively)), can be produced, for example, according to the method shown by the following Reaction Scheme 2 or a method analogous thereto.

Reaction Scheme 2 wherein R7 is an optionally substituted alkoxycarbonyl group of 1 to 4 carbon atoms or a formyl group, the other symbols are as defined above. As the "alkoxycarbonyl group of 1 to 4 carbon atoms optionally substituted" for R7, there may be mentioned an alkoxycarbonyl group of 1 to 4 carbon atoms optionally having 1 to 3 substituents such as a phenyl group, an halogen, an alkoxy group of 1 to 6 carbon atoms and the like (for example, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 2- (ethoxy) ethoxycarbonyl) and the like. A compound represented by the formula (X) (which is abbreviated as the compound (X)) can be produced by subjecting a compound represented by the formula (IX) (which is abbreviated as the compound (IX)) to the reduction reaction . The reduction reaction is carried out using a reducing agent according to a conventional method. As the reducing agent, there may be mentioned, for example, the hydrides of metals (for example, aluminum hydride, diisobutylaluminum hydride, tributyltin hydride and the like); metal hydride complexes (e.g., lim aluminum hydride, sodium borohydride and the like); borane complexes (eg, borane-tetrahydrofuran complex, borane-dimethylsulfide complex and the like); alkyl boranes (for example, texilborane, disiamylborane and the like); diborane; metals (for example, zinc, aluminum, tin, iron and the like); alkali metals (eg, sodium, lim and the like) / liquid ammonia (Birch reduction) and the like. The amount of the reducing agent to be used is determined appropriately according to the class of the reducing agent. For example, the amount of the metal hydride or the metal hydride complex to be used is from about 0.25 to about 10 mole, preferably from about 0.5 to about 5 mole, relative to 1 mole of the compound (IX), the amount of the borane complex, alkyl borane or diborane to be used is from about 1 to about 10 mole, preferably from about 1 to about 5 mole, relative to 1 mole of the compound (IX) and the amount of the metal (containing metal alkaline used for the Birch reduction) to be used is from about 1 to about 20 equivalents, preferably from about 1 to about 5 equivalents, relative to one equivalent of the compound (IX). The reduction reaction is advantageously carried out using a solvent inert to the reaction. While the solvent is not particularly limited as long as the reaction proceeds, for example, solvents such as alcohols (for example, methanol, ethanol, propanol, tert-butanol and the like) are preferable; the ethers (for example, diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like); aromatic hydrocarbons (for example, benzene, toluene and the like); saturated hydrocarbons (e.g., cyclohexane, hexane and the like); the amides (for example, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide and the like); organic acids (for example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid and the like) and the like, a mixed solvent thereof and the like. While the reaction time varies depending on the kind and amount of the reducing agent or the activity and amount of the catalyst, it is generally from about 1 hour to about 100 hours, preferably from about 1 hour to about 50 hours. The reaction temperature is generally from about -20 to about 120 ° C, preferably from about 0 to about 80 ° C. The compound (Ib ') can be produced by reacting the compound (II) and the compound (X) according to a method similar to the Mitsunobu reaction of the compound (II) with the compound (III) in the Reaction Scheme 1. The compound (Ib) can be produced from the compound (Ib ') according to a method similar to the hydrolysis reaction of the compound (la') in Reaction Scheme 1. The compound (IX) wherein E is E2 (E2 is G1 (Gx is as defined above), -N (R6) -W2- (R6 and 2 are as defined above) or -0-), (which is abbreviated as the compound (IX ') ) can be produced, for example, according to the method shown by the following Reaction Scheme 2 'or a method analogous thereto.

The compounds represented by the formulas (VII), (VIII-1), (VIII-2) and (VIII-3) (which are abbreviated as the compound (VII), the compound (VIII-1), the compound (VIII-2) and the compound (VIII-3), respectively) are readily available in the market and can also be produced according to a method known per se or a method analogous thereto.

Reaction Scheme 2 ' (VII) (IX ') The compound (IX ') can be produced by reacting the compound (VII) with the compound (VIII-1), the compound (VIII-2) or the compound (VIII-3) (unless otherwise specified) , these compounds are collectively referred to as the compound (VIII)) according to a method similar to the reaction of the compound (IV) with the compound (V) in Reaction Scheme 1. The compound (I) wherein E is E3 (E3 is - x-0-W2-, -Í ^ -S-W2- or -WX-N (R6) -W2- (W1, W2 and R6 are as defined above)), (the compounds represented by the formula (le ') and (le) (which are abbreviated as the compound (le') and the compound (le), respectively)), can be produced, for example, according to the method shown by the following Reaction Scheme 3 or a method analogous to it.

Reaction Scheme 3 where PG is a protecting group, X is -O-, -S- or - (R6) - (R6 is as defined above) and the other symbols are as defined above. As the protecting group for PG, the hydroxy protecting group, amino protecting group and mercapto protecting group which are mentioned below can be used.

The compounds represented by the formulas (XI), (XIV-1) and (XI -2) (which are abbreviated as the compound (XI), the compound (XIV-1) and the compound (XIV-2), respectively) are readily available in the market and can also be produce according to a method known per se or a method analogous thereto. A compound represented by the formula (XII) (which is abbreviated as the compound (XII)) can be produced by reacting the compound (II) with the compound (XI) according to a method similar to the reaction of the compound (II) with the compound (III) in the Reaction Scheme 1. A compound represented by the formula (XIII) (which is abbreviated as the compound (XIII)) can be produced by deprotecting the compound (XII) according to a deprotection reaction known per se or a method analogous thereto. The compound (IC) wherein E3 is -Wx-0-W2-, -Wx-S- 2- or -IR6) -W2-, 2 and R6 are as defined above and 1 is an alkylene group of 1 to 3 carbon atoms optionally substituted can be produced by reacting the compound (XIII) with the compound (XIV-1) according to a method similar to the reaction of the compound (II) with the compound (III) wherein L is a leaving group in the Reaction Scheme 1. The compound (le ') where E3 is - 1-0- 2- or -W1-S-W2- and at least one of 1 and W2 is a bond can also occur at reacting the compound (XIII) wherein X is -0- or -S- with the compound (XIV-2) according to a method similar to the Mitsunobu reaction of the compound (II) with the compound (III) in the Reaction Scheme 1. The compound (le) can be produced from the compound (IC) according to a method similar to the hydrolysis reaction of the compound (la ') in Reaction Scheme 1. The compound (I) in where R2 is a hydr group substituted oxy, a substituted amino group or a substituted mercapto group, specifically the compound (I) wherein R2 is R2'-Y- [Y is -0-, -S- or -N (RA) - (RA is an atom of hydrogen or a substituent possessed by an amino group (specifically, a substituent possessed by the amino group of the "amino group optionally substituted" for R2) and R2 'is a substituent (specifically, when Y is -0-, a substituent possessed by the hydroxy group of the "optionally substituted hydroxy group" for R2, when Y is -S-, a substituent possessed by the mercapto group of the "optionally substituted mercapto group" for R2 , when Y is -N (RA) -, a substituent possessed by the amino group of the "amino group optionally substituted" for R2)], (the compounds represented by the formulas (If) and (Id) (which are abbreviated as compound (If ') and compound (Id), respectively)), can be produced, for example, according to the method shown by the following Reaction Scheme 4 or a method analogous thereto.

Reaction Scheme 4 (Id) where each symbol is as defined above. A compound represented by the formula (Id ') (which is abbreviated as the compound (Id')) can be produced according to a method similar to the compound (a '), compound (Ib') or compound (le ') mentioned previously. A compound represented by the formula (le ') (which is abbreviated as the compound (le')) can be produced by subjecting the compound (Id ') to a deprotection reaction known per se. The compound (If) can be produced by reacting the compound (le ') with a compound represented by the formula: R2-L', according to a method similar to the reaction of the compound (II) with the compound (III) where L is a leaving group in Reaction Scheme 1. The compound (If) where Y is -O- or -S- can also be produced by reacting the compound (le ') where Y is -0- or -S- with a compound represented by the formula: R2'-0H according to a method similar to the Mitsunobu reaction of the compound (II) with the compound (III) in the Reaction Scheme 1. The compound (Id) can be produced from the compound (If) according to a method similar to the hydrolysis reaction of the compound (la ') in Reaction Scheme 1. In each of the reactions mentioned above, when the starting compound has a amino group, carboxyl group, hydroxy group or mercapto group as a substituent, a protective group generally used In the chemistry of peptides and the like can be introduced into these groups. By removing the protecting group as necessary after the reaction, the objective compound can be obtained. As the amino protecting group, there may be mentioned, for example, a formyl group; alkylcarbonyl group of 1 to 6 carbon atoms (for example acetyl, ethylcarbonyl and the like), phenylcarbonyl group, alkoxycarbonyl group of 1 to 6 carbon atoms (for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc) and the like ), allyloxycarbonyl group (Alloc), phenyloxycarbonyl group, fluorenylmethoxycarbonyl group (Fmoc), aralkylcarbonyl group of 7 to 10 carbon atoms (for example benzylcarbonyl and the like), aralkyloxycarbonyl group of 7 to 10 carbon atoms (per example, benzyloxycarbonyl (Z) and the like), aralkyl group of 7 to 10 carbon atoms (for example, benzyl and the like), trityl group, phthaloyl group, dithiasuccinoyl group or N, N-dimethylaminomethylene group, each of which has optionally substituents. As the substituent there can be used a phenyl group, halogen atom, alkylcarbonyl group of 1 to 6 carbon atoms (for example, acetyl, ethylcarbonyl, butylcarbonyl and the like), alkoxy group of 1 to 6 carbon atoms optionally substituted by one atom of halogen (for example, methoxy, ethoxy, trifluoromethoxy and the like), nitro group and the like. The number of substituents is from about 1 to 3. As the carboxy protecting group there can be mentioned, for example, an alkyl group of 1 to 6 carbon atoms, allyl group, benzyl group, phenyl group, trityl group or trialkylsilyl group and similar, each of which optionally has substituents. As the substituent there can be used a halogen atom, formyl group, alkyl carbonyl group of 1 to 6 carbon atoms (for example, acetyl, ethylcarbonyl, butylcarbonyl and the like), alkoxy group of 1 to 6 carbon atoms optionally substituted by a halogen atom (for example, methoxy, ethoxy, trifluoromethoxy and the like), nitro group and the like. The number of substituents is from 1 to 3. As the hydroxy protecting group there can be mentioned, for example, an alkyl group of 1 to 6 carbon atoms, aralkyl group of 7 to 20 carbon atoms (for example, benzyl, trityl and the like), formyl group, alkylcarbonyl group of 1 to 6 carbon atoms (eg, acetyl, ethylcarbonyl and the like), benzoyl group, aralkylcarbonyl group of 7 to 10 carbon atoms (e.g., benzylcarbonyl and the like), 2-tetrahydropyranyl group, tetrahydrofuranyl group or trialkylsilyl group (for example, trimethylsilyl, tert-butyldimethylsilyl, diisopropylethylsilyl and the like), and the like, each of which optionally has substituents. As the substituent there can be used a halogen atom, alkyl group of 1 to 6 carbon atoms, phenyl group, aralkyl group of 7 to 10 carbon atoms (for example, benzyl and the like), alkoxy group of 1 to 6 carbon atoms. carbon, nitro group and the like. The number of substituents is from about 1 to 4. As the mercapto protecting group there may be mentioned, for example, an alkyl group of 1 to 6 carbon atoms, alkyl-carbonyl group of 1 to 6 carbon atoms (for example, acetyl, ethylcarbonyl and the like), aralkyl group of 7 to 20 carbon atoms (for example, benzyl, trityl and the like) and the like, each of which optionally has substituents. As the substituent there can be used a halogen atom, alkyl group of 1 to 6 carbon atoms, phenyl group, aralkyl group of 7 to 10 carbon atoms (for example, benzyl and the like), alkoxy group of 1 to 6 carbon atoms. carbon, nitro group and the like. The number of substituents is from about 1 to 4. For the removal of the protecting group, a method known per se or a method analogous thereto is used. For example, a treatment with acid, base, reduction, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate and the like is used. The compound (I) obtained in this manner, other reaction intermediates and starting material compounds thereof can be isolated or purified from the reaction mixture by means of a method known per se, such as extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin layer chromatography, preparative high pressure liquid chromatography (preparative CLAP), liquid chromatography, intermediate pressure preparative (intermediate pressure preparative CL) and the like. The salt of the compound (I) can be produced according to a method known per se. For example, when the compound (I) is a basic compound, the salt can be produced by adding an inorganic acid or an organic acid or when the compound (I) is an acidic compound, by adding an organic base or an inorganic base. When the compound (I) has optical isomers, these respective optical isomers and mixtures thereof are naturally included within the scope of the present invention and, where desired, these isomers can also be subjected to optical resolution or can be produced individually according to a method known per se. When the compound (I) is present as a configurational isomer (stereoisomer), diastereomer, conformer or the like, each can be isolated by means of the above separation and purification methods upon request. In addition, when the compound (I) is in the form of racemates, they can also be separated into S and R forms by any conventional optical resolution. When the compound (I) includes stereoisomers, both isomers alone or mixtures of each of the isomers are included in the scope of the present invention. In addition, the compound (I) may be a hydrate or may not be a hydrate. The compound (I) can be labeled with an isotope (e.g., 3 H, 14 C, 35 S and the like) or the like. The compound (I), or a salt thereof and a prodrug thereof (which are sometimes abbreviated as the compound of the present invention later in this document) show a modulating action of the GPR40 receptor function (GPR40 receptor agonist activity and GPR40 receptor antagonist activity), particularly an agonist activity of the GPR40 receptor, show low toxicity and very few side effects (e.g., acute toxicity, chronic toxicity, genotoxicity, developmental toxicity, cardiac toxicity, drug interaction, carcinogenesis). Therefore, they are useful as a safe modulator of the function of the GPR40 receptor, preferably an agonist of the GPR40. A pharmaceutical agent containing the compound of the present invention exhibits a superior action of modifying the function of the GPR40 receptor in a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human, et cetera) and is useful as a modulator of physiological function in which the GPR40 receptor is involved or an agent for the prophylaxis or treatment of a disease state or disease in which the GPR40 receptor is involved. To be specific, the pharmaceutical agent containing the compound of the present invention is useful as a modulator of insulin secretion (preferably an insulin secretagogue), hypoglycemic drug and pancreatic β-cell protector. In addition, the pharmaceutical agent containing the compound of the present invention is useful as an agent for the prophylaxis or treatment of diseases such as diabetes, impaired glucose tolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema macular, hyperlipidemia, genital disorder, skin disease, arthropathy, osteopenia, arteriosclerosis, thrombotic disease, dyspepsia, memory and learning disorder, depression, depression and mania, schizophrenia, attention deficit hyperactivity disorder, visual impairment, "appestat" disorder (eg, hyperorexia), obesity, hypoglycemia, hypertension, edema, insulin resistance, unstable diabetes, adipose atrophy, insulin allergy, insulinoma, lipotoxicity, pancreatic fatigue, hyperinsulinemia ,, cancers. (eg breast cancer), metabolic syndrome, immune diseases (eg, immunodeficiency), inflammatory disease (eg, enteritis, arthritis, allergy), multiple sclerosis, chronic kidney failure and the like; particularly, diseases such as diabetes, impaired glucose tolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macular edema, hyperlipidemia, genital disorder, skin disease, arthropathy, osteopenia, arteriosclerosis, thrombotic disease, dyspepsia, memory and learning disorder and the like. At this point, diabetes can be mentioned that includes type 1 diabetes, type 2 diabetes and gestational diabetes. In addition, hyperlipidemia includes hypertriglyceridemia, hypercholesterolemia, hypoHD-emia, post-prandial hyperlipidemia and the like. For diagnostic criteria for diabetes, the Japanese Diabetes Society reported new diagnostic criteria in 1999. According to this report, diabetes is a condition that shows either a fasting blood glucose level (concentration of intravenous plasma glucose) not less than 126 mg / dl, a 2-hour level of the tolerance test to 75 g of oral glucose (75 g of OGTT) (intravenous plasma glucose concentration) not less than 200 mg / dl and a blood glucose level after breakfast (intravenous plasma glucose concentration) not less than 200 mg / dl. A condition that is not found under the diabetes mentioned above and that is different from "a condition that shows a fasting blood glucose level (intravenous plasma glucose concentration) less than 110 mg / dl or a 2-hour level of the tolerance test to 75 g of oral glucose (75 g of OGTT) (intravenous plasma glucose concentration) less than 140 mg / dl "(normal type) is called a" boundary type ". In addition, the ADA (American Diabetes Association) reported new diagnostic criteria for diabetes in 1997 and the WHO in 1998. According to these reports, diabetes is a condition that shows a fasting blood glucose level ( intravenous plasma glucose concentration) not less than 126 mg / dl and a 2-hour tolerance level at 75 g oral glucose (intravenous plasma glucose concentration) not less than 200 mg / dl. According to the reports mentioned above, impaired glucose tolerance is a condition that shows a fasting blood glucose level (intravenous plasma glucose concentration) of less than 126 mg / ml and a 2-hour level of glucose. tolerance test at 75 g of oral glucose (intravenous plasma glucose concentration) not lower than 140 mg / dl and lower than 200 mg / dl. According to the ADA report, a condition that shows a fasting blood glucose level (intravenous plasma glucose concentration) of not less than 110 mg / dL and less than 126 mg / dL is called impaired fasting glucose. (IFG, for its acronym in English). According to the WHO report, between the IFG (Glucose Deteriorated in Fasting), a condition that shows a 2-hour level of the tolerance test at 75 g oral glucose (intravenous plasma glucose concentration) less than 140 mg / dl is called impaired glycemia in fasting (IFG, for its acronym in English). The compound of the present invention can also be used as an agent for the prophylaxis or treatment of diabetes, borderline type, impaired glucose tolerance, IFG (Fasting Deteriorated Glucose) and IFG (Glucose Deteriorated in Fasting), as determined in accordance with the 'new diagnostic criteria mentioned above. In addition, the compound of the present invention can prevent. the progress of the borderline type, impaired tolerance to glucose, IFG (Glucose Deteriorated in Fasting) or IFG (Glucose Deteriorated in Fasting) in diabetes. The compound of the present invention is also useful as a therapeutic agent for diabetes with secondary sulfonylurea failure and provides a superior insulin secretion effect- and a hypoglycemic effect for diabetic patients for whom the sulfonylurea compounds and insulin secretagogues they act on an empty stomach they stop providing an effect of insulin secretion and, therefore, fail to provide a sufficient hypoglycemic effect. As the sulfonylurea compound, there may be mentioned at this point a compound having a sulfonylurea structure or a derivative thereof (eg, tolbutamide, glibenclamide, glilcazide, chlorpropamide, tolazamide, acetohexamide, glycpypyramide, glimepiride, glipizide, glibuzole and Similar) . As the fasting insulin secretagogue, a compound that promotes insulin secretion from pancreatic ß cells can be mentioned in the same way as a sulfonylurea compound, although it does not have a sulfonylurea structure, compounds such as glinide ( example, repaglinide, senaglinide, nateglinide, mitiglinide, a calcium salt hydrate thereof, etc.) and the like. The pharmaceutical agent comprising the compound of the present invention shows low toxicity and can be administered safely by the oral or parenteral route (eg, by means of topical, rectal, intravenous, etc.) administration in the form of the compound of the present invention as being or after mixing with a pharmaceutically acceptable carrier to provide a pharmaceutical preparation according to a method known per se that is used for the general production method for pharmaceutical preparations. The dosage form of the aforementioned pharmaceutical preparation is, for example, an oral agent such as tablets (including sublingual tablets and oral tablets, disintegrables), capsules (including soft capsules and microcapsules), granules, powders, troches, syrups, emulsions, suspensions and the like; or a parenteral agent such as injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions, etc.), external agents (eg, transdermal preparations, ointments, etc.), suppositories (eg, rectal suppositories, vaginal suppositories, etc.) ), granules, nasal preparations, pulmonary preparations (inhalations), ophthalmic preparations and the like. These agents can be controlled release preparations such as rapid release preparations and sustained release preparations (e.g., sustained release microcapsules). The content of the compound of the present invention in a pharmaceutical preparation of the present invention is from about 0.01 to about 100% by weight relative to the entire preparation. The dose of the compound of the present invention varies depending on the subjects of administration, the route of administration, the diseases, the condition and the like. When the compound is administered by the oral route to an adult patient with diabetes (body weight of approximately 60 kg), it can be administered from about 0.01 to about 30 mg / kg of body weight per day, preferably from about 0.1 to about 20 mg / kg of body weight per day, more preferably from about 1 to about 20 mg / kg of body weight per day, once a day or in several portions per day. Various organic or inorganic carriers conventionally used as materials for pharmaceutical preparations are used as pharmacologically acceptable carriers, which are added as excipients, lubricants, binding substances and disintegrants for the solid preparations; and solvents, dissolution aids, suspending agents, isotonicity agents, buffers and sedatives and the like for liquid preparations. When necessary, an additive such as a preservative, antioxidant, coloring agent, sweetening agent, adsorbing agent, wetting agent and the like can be used. As the excipient may be mentioned / for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light silicic anhydride and the like. As the lubricant may be mentioned, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. As the binder there may be mentioned, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. As the disintegrant there may be mentioned, for example, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like. As the solvent, there can be mentioned, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. As the dissolution aids, there may be mentioned, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

As the suspending agent there can be mentioned, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like. As the isotonicity agent there can be mentioned, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. As the buffer may be mentioned, for example, buffers such as phosphate, acetate, carbonate, citrate and the like. As the sedative agent there can be mentioned, for example, benzyl alcohol and the like. As the preservative, there can be mentioned, for example, p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. As the antioxidant there may be mentioned, for example, sulfite, ascorbic acid, α-tocopherol and the like. As the coloring agent there may be mentioned, for example, edible tar pigments which are soluble in water (for example, food dyes such as Red Food Dyes Nos. 2 and 3, Yellow Food Dyes Nos. 4 and 5, Blue Food Dyes Nos. 1 and 2 and the like), water-insoluble lacquer pigments (for example, aluminum salt of the edible tar pigment which is soluble in water mentioned above and the like), natural pigments (for example, β-carotene, chlorophyll, red iron oxide, etc.) and the like. As the sweetening agent there may be mentioned, for example, sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia and the like. The compound of the present invention can be used in combination with drugs such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an anti-obesity agent, a diuretic, a chemotherapeutic agent, an immunotherapeutic agent, an anti-inflammatory drug, an antithrombotic agent, a therapeutic agent for osteoporosis, a vitamin, an antidementia agent, a therapeutic agent for incontinence or pollakiuria, a therapeutic agent for dysuria and the like (which are hereinafter referred to as the drug X). As the therapeutic agent for diabetes, insulin preparations (eg, insulin preparations of animal origin extracted from the pancreas of a bovine animal and a pig) can be mentioned.; insulin preparations of human origin genetically synthesized using Escherichia coli, yeast; zinc insulin; Protamine-zinc insulin; an insulin fragment or derivative (eg, INS-1 etc.), an oral insulin preparation and the like), insulin synthesizers (eg, Pioglitazone or a salt thereof (preferably a hydrochloride), Rosiglitazone or a salt Of the same (preferably a maleate), Reglixan (JTT-501), Netoglitazone (MCC-555), GI-262570, FK-614, Rivoglitazone (CS-011), Muraglitazar (BMS-298585), the compounds described in WO99 / 58510 (for example, (E) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy)] benzyloxyimino] -4-phenylbutyric), the compounds described in WO01 / 38325, Tesaglitazar (AZ-242), BM-13-1258, LM-4156, MBX-102, LY-519818, MX-6054, LY-510929 , Belaglitazone (NN-2344), T-131 or a salt thereof, THR-0921, etc.), α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (e.g., phenformin , metformin, buformin or salts thereof (for example a hydrochloride, fumarate, succinate) and so on), insulin secretagogues [sulfonylurea (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glycolpyramide, glimepiride, etc.), repaglinide, senaglinide, mitiglinide or a calcium salt hydrate thereof, nateglinide, etc.], GLP-1 receptor agonists [eg, GLP-1, GL agent] P-1MR, NN-2211, AC-2993 (exendin-4), BIM-51077, Aib (8, 35) hGLP-1 (7, 37) NH2, CJC-1131 etc.], inhibitor of dipeptidyl-peptidase IV ( for example, NVP-DPP-278, PT-100, P32 / 98, P93 / 01, NVP-DPP-728, LAF273, TS-021 etc.), a β3 agonist (e.g., CL-316243, SR-58611 -A, UL-TG-307, AJ-9677, AZ40140, etc.), amylin agonists (e.g., pramlintide, etc.), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, etc.), gluconeogenesis inhibitors ( for example, glycogen-phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist, etc.), inhibitors of SGLT (sodium-glucose cotransporter) (e.g., T-1095, etc.), llß-hydroxysteroid inhibitors -dehydrogenase (eg, BVT-3498 et cetera), adiponectin or an agonist thereof, IKK inhibitors (eg, AS-2868, etc.), leptin resistance enhancing drugs, somatostatin receptor agonists (eg. omitted as described in WOOl / 25228, WO03 / 42204, W098 / 44921, W098 / 45285, W099 / 22735, etc.), glucokinase activators (e.g., Ro-28-1675) and the like. Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, Tolrestat, Epalrestat, Zenarestat, Zopolrestat, Fidarestat (SNK-860), AS-3201, Minalrestat (ARI-509), CT-112, etc.) , neurotrophic factors and drug-enhancing drugs (eg, NGF, NT-3, BDNF, neurotrophin production-secretion promoters described in WOOl / 14372 (eg, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- (2-methylphenoxy) -propyl] oxazole, etc.), inhibitors of protein kinase C (PKC) (eg, ruboxistaurin mesylate; 333531 etcetera), AGE inhibitors (eg, ALT-945, pimagedine, piratoxanthin, N-phenacylthiazolium bromide (ALT-766), EXO-226, ALT-711, Piridorin, Pyridoxamine, etc.), active oxygen scavengers ( for example, thioctic acid, etc.), brain vasodilators (eg, thiapride, etc.), receptor agonists of somatostatin (BIM23190) and inhibitors of the regulatory kinase-1 signaling apoptosis (ASK-1). Examples of the hyperlipidemic therapeutic agent include an HMG-CoA reductase inhibitor (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin and salts thereof (e.g., sodium salt, calcium salt) et cetera), squalene synthase inhibitors (e.g., the compounds described in WO97 / 10224, such as N- [[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl)] - 7-chloro-5- (2,3-dimethoxyphenyl) -2 -oxo-1, 2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidin-4-acetic, etc.), compounds of fibrate (for example, benzafibrate, clofibrate, simfibrate, clinofibrate, etc.), an antioxidant (e.g., lipoic acid, probucol) and the like. Examples of the antihypertensive agent include inhibitors of angiotensin-converting enzymes (e.g., captopril, enalapril, delapril, etc.), angiotensin II receptor antagonists (e.g., losartan, candesartan cilexetil, eprosartan, valsartan, telmisartan, irbesartan, olmesartan medoxomil). , tasosartan, 1- [[2 '- (2,5-dihydro-5-oxo-4H-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxy-lH acid -benzimidazole-7-carboxylic acid, etc.), calcium channel blockers (for example, manidipine, nifedipine, amlodipine, efonidipine, nicardipine, etc.), Clonidine and the like. Examples of the anti-obesity agent include antiobesity agents that act on the central nervous system (e.g., Dexfenfluramine, fenfluramine, phentermine, Sibutramine, amfepramone, dexamfetamine, Mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists (e.g., SB-568849; SNAP-7941; compounds included in WO01 / 82925 and WO01 / 87834 etc.); neuropeptide Y antagonists (e.g., CP-422935 et cetera); cannabinoid receptor antagonists (e.g., SR-141716, SR-147778, et cetera); ghrelin antagonist; llβ-hydroxysteroid dehydrogenase inhibitors (e.g., BVT-3498, etc.) and the like), pancreatic lipase inhibitors (e.g., orlistat, ATL-962, etc.), β3 agonists (e.g., CL-316243, SR -58611-A, UL-TG-307, AJ-9677, AZ40140, etc.), peptidogenic anorectics (e.g., leptin, CNTF (Ciliary Neurotropic Factor), etc.), cholecystokinin agonists (e.g., lintitript, FPL-15849 etcetera), food repressor (for example, P-57, etc.) and the like. Examples of the diuretic include xanthine derivatives (e.g., sodium salicylate and theobromine, calcium salicylate and theobromine, etc.), thiazide preparations (e.g., etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, methicylthiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonate-dehydratase inhibitors (eg, acetazolamide and the like), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefruside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.

Examples of the chemotherapeutic agent include alkylating agents (e.g., cyclophosphamide, ifosfamide, etc.), metabolic antagonists (e.g., methotrexate, 5-fluorouracil or its derivative, etc.), anti-cancer antibiotics (e.g., mitomycin, adriamycin, et cetera), anticancer agents derived from plants (for example, vincristine, vindisin, taxol, etc.), cisplatin, carboplatin, etoposide and the like. Of these, furtulon and neofurtulon, which are 5-fluorouracil derivatives and the like, are preferable. Examples of the immunotherapeutic agent include components of microorganisms or bacteria (e.g., a muramyl dipeptide derivative, picibanil, etc.), polysaccharides having immunity potency enhancing activity (e.g., lentinan, sizofiran, crestin, etc.) , cytokines obtained by means of genetic engineering techniques (e.g., interferon, interleukin (IL), etc.), colony stimulating factors (e.g., granulocyte colony stimulation factor, erythropoietin, etc.) and the like, being preferred interleukins such as IL-1, IL-2, IL-12 and the like. As the anti-inflammatory drug may be mentioned, for example, non-spheroidal anti-inflammatory agents such as aspirin, acetoaminofen, indomethacin and the like. Examples of the antithrombotic agent include heparin (e.g., sodium heparin, calcium heparin, sodium dialteparin, etc.), warfarin (e.g., potassium warfarin, etc.), antithrombin drugs (e.g., aragatroban, etc.), agents thrombolytics (e.g., urokinase, tisocinase, alteplase, nateplase, monteplasa, pamiteplase, etc.), platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, cilostasol, ethyl icosapentate, sodium boraprost, sarpogrelate hydrochloride, etc.) and similar. Examples of the osteoporosis therapeutic agent include alfacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavone, disodium risedronate, disodium pamidronate, alendronate sodium hydrate, disodium incadronate and the like. As the vitamin can be mentioned, for example, vitamin Bx, vitamin B12 and the like. Examples of the antidementia agent include tacrine, donepezil, rivastigmine, galantamine and the like. Examples of the therapeutic agent for incontinence or pollakiuria include flavoxate hydrochloride, oxybutyn hydrochloride, propiverine hydrochloride, and the like. Examples of the therapeutic agent for dysuria include acetylcholine esterase inhibitors (e.g., distigmine) and the like. In addition, drugs that have a better cachexia action established "in animal models and clinical situations, such as cyclooxygenase inhibitors (e.g. Indomethacin, etc.), Progesterone derivatives (e.g., Megesterol acetate), glycosteroid ( for example, dexamethasone, etc.), metoclopramide agents, tetrahydrocannabinol agents, fat metabolism enhancing agents (e.g., eicosapentaenoic acid, etc.), growth hormones, IGF-1 or antibodies to a cachexia inducing factor such as TNF a, LIF, IL-6, Oncostatin M and the like, can be used in combination with the compound of the present invention In addition, glycosylation inhibitors (eg, ALT-711, etc.), regeneration-promoting drugs of nerves (eg, Y-128, VX853, prosaptide, etc.), antidepressants (eg, desipramine, amitriptyline, imipramine, etc.), anticonvulsants (eg, example, lamotrigine, Trileptal, Keppra, Zonegran, Pregabalin, Harkoseride, carbamazepine), antiarrhythmic drugs (e.g., mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT- 627), inhibitors of monoamine uptake (for example, tramadol), narcotic analgesics (eg, morphine), GABA receptor agonists (eg, gabapentin, gabapentin agent MR), agonists of a2 receptors (eg, clonidine), local analgesics (eg, capsaicin) , antianxiety drugs (eg, benzothiazepines), phosphodiesterase inhibitors (eg, sildenafil), dopamine receptor agonists (eg, apomorphine) and the like can also be used in combination with the compound of the present invention. Two or more classes of the drug X mentioned above can be used in an appropriate combination. By combining the compound of the present invention and a drug X, a superior effect such as (1) the dose of the compound of the present invention or a drug X can be reduced compared to the individual administration of the compound of the present invention or a drug X, (2) the treatment period can be longer when selecting a drug X having different action and mechanism from those of the compound of the present invention, (3) A sustained treatment effect can be designed by selecting a drug X having different action and mechanism from those of the compound of the present invention, (4) a synergistic effect can be provided by a combined use of the compound of the invention. present invention and a drug X and the like. When the compound of the present invention and a drug X are used in combination, the time of administration of the compound of the present invention and the drug X is not restricted and the compound of the present invention and the drug X can be administered to a subject of administration simultaneously or may be administered at alternate times. The dosage of the drug X can be determined -according to the dose used clinically and can be appropriately selected depending on a subject of administration, route of administration, disease, combination and the like. The mode of administration of the compound of the present invention and the drug X is not particularly restricted, as long as the compound of the present invention and the drug X are combined in the administration. Examples of this mode of administration include the following methods: (1) The compound of the present invention and the drug X are formulated simultaneously to provide an individual preparation which is administered. (2) The compound of the present invention and the drug X are formulated separately to provide two classes of preparations which are administered simultaneously by means of the same route of administration. (3) The compound of the present invention and the drug X are formulated separately to provide two classes of preparations which are administered via the same route of administration at alternate times. (4) The compound of the present invention and the drug X are formulated separately to provide two classes of preparations which are administered simultaneously by means of different routes of administration. (5) The compound of the present invention and the drug X are formulated separately to provide two classes of preparations which are administered via different administration routes at alternate times (eg, the compound of the present invention and the drug). X are administered in this order or in the reverse order) and the like.

Examples The present invention is further explained in detail by reference to the following Reference Examples, Examples, Formulation Examples and Example Experimental, which are only examples of work that should not be considered as limiting and that can be changed without departing from the scope of the present invention. The term "room temperature" in the following Reference Examples and the Examples indicates the range that is in general from about 10 ° C to about 35 ° C. As "%", the yield is in mol /% mol, the solvent used for the chromatography is in% by volume and another "%" is in% by weight. The proton OH, the proton NH, etc., which could not be confirmed due to the broad peak by the NMR spectrum of protons are not included in the data. The other symbols used in this document mean the following: s: singlet d: doublet t: triplet q: quartet m: multiplet br: broad J: coupling constant Hz: Hertz CDC13: deuterated chloroform 1H NMR: proton nuclear magnetic resonance. In the following Reference Examples and the Examples, the mass spectrum (MS) and the nuclear magnetic resonance spectrum (NMR) were measured according to the following conditions. ME measuring tools: Waters Corporation ZMD, Waters Corporation ZQ2000 or Micromass Ltd., platform II.

Ionization method: Electro-Spray Ionization (ESI) or Chemical Ionization at Atmospheric Pressure (APCl). Unless otherwise specified, the ESI was used. NMR measurement tools: Varian Gemini 200 (200 MHz), Varies Gemini 300 (300 MHz), Varies, AVANCE 300, Bruker BioSpin Corp. In Reference Examples and Examples, purification by means of preparative HPLC was performed according to the following conditions. Tools of the Preparative HPLC: high flow purification system Gilson, Inc. column: YMC Combiprep ODS-A S-5 μm, 20 x 50 mm solvent: Solution A; water containing 0.1% trifluoroacetic acid, Solution B; acetonitrile containing 0.1% trifluoroacetic acid. gradient cycle A: 0.00 minutes (Solution A / Solution B = 90/10), 1.20 minutes (Solution A / Solution B = 90/10), 4.75 minutes (Solution A / Solution B = 0/100), 7.30 minutes ( Solution A / Solution B = 0/100), 7.40 minutes (Solution A / Solution B = 90/10), 7.50 minutes (Solution A / Solution B = 90/10). gradient cycle B: 0.00 minutes (Solution A / Solution B = 95/5), 1.00 minutes (Solution A / Solution B = 95/5), 5.20 minutes (Solution A / Solution B = 5/95), 6.40 minutes ( Solution A / Solution B = 5/95), 6.50 minutes (Solution A / Solution B = 95/5), 6.60 minutes (Solution A / Solution B = 95/5). flow rate: 25 ml / minute, detection method: UV 220 nm In the present specification, the melting point (mp) refers to that measured using, for example, a microfusion point measurement apparatus (Büchi, B -545) and the like. In general, the melting points vary depending on the measuring apparatus, the measurement conditions and the like. The crystal in the present specification may show a melting point different from that described in the present specification, as long as it is within the general error range.

Reference Example 1 2- (4-bromo-3-methylphenoxy) tetrahydro-2H-pyran A solution of 4-bromo-3-methylphenol (4.72 g, 25.2 mmol), 3,4-dihydro-2H-pyran (3.18 g, 37.8 mmol) and pyridinium p-toluenesulfonate (0.628 g, 2.50 mmol) in dichloromethane ( 100 L) was stirred at room temperature for 24 hours. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (7.11 g, including unreacted 3,4-dihydro-2H-pyran) as a yellow oil. XH NMR (CDC13) d: 1.58-2.06 (6H, m), 2.35 (3H, s), 3.56-3.63 (1H, m), 3.83-3.91 (HH, m), 5.37 (HH, t, J = 3.1 Hz), 6.77 (HH, dd, J = 8.8, 3.0Hz), 6.95 (HH, d, J = 3.0Hz), 7.39 (HH, d, J = 8.8Hz).

Reference Example 2 2'-methyl-4 '- (tetrahydro-2H-pyran-2-yloxy) biphenyl-3-carbaldehyde 2- (4-Bromo-3-methylphenoxy) tetrahydro-2H-pyran (7.11 g, 25.2 mmol, including 3,4-dihydro-2H-pyran) and (3-formylphenyl) boronic acid (4.50 g, 30.0 mmol) were dissolved in a mixture of an aqueous solution of 1 M sodium carbonate (60 mL), ethanol (30 mL) and toluene (60 mL) and after the argon substitution was added tetracis (triphenylphosphine) palladium (0). ) (1.73 g, 1.50 mmol). The reaction mixture was stirred under an argon atmosphere at 80 ° C for 15 hours. The reaction mixture was cooled, water and ethyl acetate were added and the insoluble material was filtered through celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (5% -30% ethyl acetate / hexane) to give the title compound (6.16 g, 82% yield, 2 steps) as a color oil pale yellow. XH NMR (CDC13) d: 1.53-1.77 (3H, m), 1.86-1.91 (2H, m), 1.98-2.09 (HH, m), 2.25 (3H, s), 3.61-3.68 (HH, m), 3.91-3.99 (HH, m), 5.48 (HH, t, J = 3.2Hz), 6.95-7.00 (2H, m), 7.15 (HH, d, J = 8.3Hz), 7.53-7.60 (2H, m) , 7.82-7.86 (2H, m), 10.06 (ÍH, s).

Reference Example 3 [2'-methyl-4 '- (tetrahydro-2H-pyran-2-yloxy) biphenyl-3-yl] methanol The 2'-methyl-4 '- (tetrahydro-2H-pyran-2-yloxy) -biphenyl-3-carbaldehyde (13.6 g, 45.9 mmol) was dissolved in a mixture of 1,2-dimethoxyethane (70 mL) and tetrahydrofuran. (70 mL) and sodium borohydride (0.870 g, 23.0 mmol) was added under cooling with ice. The mixture was stirred at the same temperature for 3 hours. To the reaction mixture was added an aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (15% -50% ethyl acetate / hexane) to provide the title compound (12.2 g, 89% yield) as a colorless oil. NMR aH (CDC13) d: 1.59-1.76 (4H, m), 1.85-1.90 (2H, m), 1.97-2.11 (1H, m), 2.25 (3H, s), 3.60-3.67 (1H, m), 3.91-3.99 (HH, m), 4.73 (2H, d, J = 5.8Hz), 5.46 (HH, t, J = 3.1Hz), 6.92-6.97 (2H, m), 7.14 (HH, d, J = 8.1Hz), 7.22-7.41 (4H, m).

Reference Example 4 2- (4-bromo-3,5-dimethylphenoxy) tetrahydro-2H-pyran A solution of 4-bromo-3,5-dimethylphenol (10.5 g, 52. 2 mmol), 3,4-dihydro-2H-pyran (8.83 g, 105 mmol) and pyridinium p-toluenesulfonate (2.64 g, 10.5 mmol) in dichloromethane (160 mL) was stirred at room temperature for 80 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-20% ethyl acetate / hexane) to give the title compound (11.5 g, 77% yield) as a colorless oil. XH NMR (CDC13) d: 1.56-1.75 (3H, m), 1.80-2.07 (3H, m), 2.37 (6H, s), 3.55-3.64 (HH, m), 3.83-3.93 (1H, m), 5.37 (1H, t, J = 3.1Hz), 6.80 (2H, s).

Reference Example 5 2 ', 6' -dimethyl-4 '- (tetrahydro-2H-pyran-2-yloxy) biphenyl-3-carbaldehyde The title compound was obtained as a yellow oil to give off 2- (4-bromo-3,5-dimethylphenoxy) tetrahydro-3H-pyran and (3-formylphenyl) boronic acid according to a method similar to the method of the example of reference 2 (83% yield). X H NMR (CDCl 3) d: 1.57-1.78 (3H, m). 1.82-1.93 (2H, m), 1.99 (6H, s), 2.04 (HH, m), 3.65 (HH, m), 3.97 (HH, m), 5.47 (1H, t, J = 3.0Hz), 6.84 (2H, s), 7.42 (HH, m), 7.58 (HH, t, J = 7.5Hz), 7.67 (HH, s), 7.86 (1H, m), 10.05 (HH, s).

Reference Example 6 [2 ', 6' -dimethyl-4 '- (tetrahydro-2H-pyran-2-yloxy) biphenyl-3-yl] methanol The title compound was obtained as a colorless oil from 2 ', 6'-dimethyl-4' - (tetrahydro-2H-pyran-2-yloxy) biphenyl-3-carbaldehyde according to a method similar to the method of Example of Reference 3 (83% yield). 2 H NMR (CDC13) d: 1.55-1.79 (4H, m), 1.80-1.93 (2H, m), 2.00 (6H, s), 2.03 (HH, m), 3.64 (HH, m), 3.97 (HH, m), 4.73 (2H, d, J = 5.7Hz), 5.45 (HH, t, J = 3.0Hz) , 6.81 (2H, s), 7.07 (HH, d, J = 7.5Hz), 7.13 (HH, s), 7.33 (1H, d, J = 7.5Hz), 7.40 (1H, t, J = 7.8Hz) .

Reference Example 7 2, 6-dimethyl-3 '- [(tetrahydro-2H-pyran-2-yloxy) methyl] biphenyl-4-ol The 2 ', 6'-dimethyl-4' - (tetrahydro-2H-pyran-2-yloxy) -biphenyl-3-carbaldehyde (9.05 g, 29.2 mmol) was dissolved in a mixture of 1,2-dimethoxyethane (50 mL ) and tetrahydrofuran (50 mL) and sodium borohydride (0.567 g, 15.0 mmol) was added under cooling with ice. The mixture was stirred at the same temperature for 3 hours. An aqueous solution of 10% citric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (15% -50% ethyl acetate / hexane) to give the title compound (3.24 g, 36% yield) as colorless crystals. XH NMR (CDC13) d: 1.47-1.93 (6H, m), 1.98 (3H, s), 1.99 (3H, s), '3.50-3.58 (HH,), 3.88-3.96 (HH, m), 4.54 ( 1H, d, J = 12.1Hz), 4.68 (HH, s), 4.73 (HH, t, J = 3.4Hz), 4.83 (1H, d, J = 12.1Hz), 6.59 (2H, s), 7.04 ( HH, d, J = 7.3Hz), 7.13 (HH, s), 7.30-7.34 (HH, m), 7.38 (HH, t, J = 7.3Hz).

Reference Example 8 2-. { [4 '- (benzyloxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy} tetrahydro-2H-pyran A solution of 2,6-dimethyl-3 '- [(tetrahydro-2H-pyran-2-yloxy) methyl] biphenyl-4-ol (1.78 g, 5.70 mmol), benzyl alcohol (0.885 mL, 8.55 mmol) and tributylphosphine (2.13 mL, 8.55 mmol) in toluene (80 mL) was stirred under ice-cooling and 1.1 '- (azodicarbonyl) dipiperidine (2.16 g, 8.55 mmol) was added in small portions. The mixture was warmed to room temperature and stirred for 24 hours. Hexane (40 mL) was added to the reaction mixture and the insoluble material, precipitate was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (hexane-10% ethyl acetate / hexane) to give the title compound as a colorless oil (1.71 g, yield). 75%). XH NMR (CDC13) d: 1.47-1.93 (6H, m), 2.01 (3H, s), 2.02 (3H, s), 3.50-3.57 (HH, m), 3.88-3.96 (HH, m), 4.54 ( 1H, d, J = 12.2Hz), 4.73 (HH, t, J = 3.5Hz), 4.83 (HH, d, J = 12.2Hz), 5.07 (2H, s), 6.75 (2H, s), 7.05 ( ÍH, d, J = 7.2Hz), 7.14 (1H, s), 7.30-7.48 (7H, m).

Reference Example 9 [4 '- (benzyloxy) -2', 6'-dimethylbiphenyl-3-yl] methanol A solution of 2-. { [4 '- (benzyloxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy} Tetrahydro-2H-pyran (1.71 g, 4.25 mmol) and p-toluenesulfonic acid monohydrate (80.8 mg, 0.425 mmol) in methanol (15 mL) was stirred at room temperature for 20 hours. The reaction solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% -50% ethyl acetate / hexane) to provide the title compound (1.13 g, 84% yield) as a colorless oil. XH NMR (CDC13) d: 1.65 (ΔH, t, J = 5.9Hz), 2.01 (6H, s), 4.73 (2H, d, J = 5.9Hz), 5.07 (2H, s), 6.75 (2H, s) ), 7.07 (HH, d, J = 7.3Hz), 7.13 (HH, s), 7.30-7.48 (7H, m).

Reference Example 10 2-. { [4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy} -tetrahydro-2H-pyran The title compound was obtained as a colorless oil from 2,6-dimethyl-3 '- [(tetrahydro-2 H -pyran-2-yloxy) methyl] biphenyl-4-ol and 2-ethoxyethanol according to a method similar to the method of Reference Example 8 (74% yield). XH NMR (CDC13) d: 1.25 (3H, t, J = 7.1Hz), 1.48-1.94 (6H, m), 2.00 (3H, s), 2.01 (3H, s), 3.50-3.57 (ÍH, m) , 3.62 (2H, q, J = 7.1Hz), 3.80 (2H, t, J = 5.0Hz), 3.88-3.96 (ÍH, m), 4.14 (2H, t, J = 5.0Hz), 4.54 (ÍH, d, J = 12.1Hz), 4.72 (HH, t, J = 3.5Hz), 4.82 (HH, d, J = 12.1Hz), 6.69 (2H, s), 7.04 (HH, d, J = 7.3Hz) , 7.13 (1H, s), 7.32 (ÍH, d, J = 7.3Hz), 7.38 (1H, t, J = 7.3Hz).

Reference Example 11 [4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methanol The title compound was obtained as a colorless oil from 2-. { [4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy} tetrahydro-2H-pyran according to a method similar to the method of Reference Example 9 (82% yield). MS m / z 301 (MH +) Reference Example 12 (2E) -3- (2-fluoro-4-methoxyphenyl) ethyl acrylate To an ice-cold solution of ethyl diethylphosphonoacetate (9.45 g, 42.1 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (suspension of 60% oil, 1.54 g, 38.5 mmol) and the mixture was stirred for 15 minutes. A solution of 2-fluoro-4-methoxybenzaldehyde (5.00 g, 32.4 mmol) in tetrahydrofuran (30 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours and water was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20% ethyl acetate / hexane) to provide the compound of the title (7.07 g, 97% yield) as a colorless oil. RMN ^? (CDC13) d: 1.33 (3H, t, J = 7.1Hz), 3.83 (3H, s), 4.26 (2H, q, J = 7.1Hz), 6.41 (1H, d, J = 16.2Hz), 6.61- 6.73 (2H, m), 7.45 (ÍH, t, J = 8.6Hz), 7.75 (1H, d, J = 16.2Hz).

Reference Example 13 Ethyl 3- (2-fluoro-4-methoxyphenyl) propanoate A mixture of ethyl (2E) -3- (2-fluoro-4-methoxyphenyl) acrylate (7.07 g, 31.5 mmol), tetrahydrofuran (50 mL), ethanol (5 mL) and platinum oxide (300 mg) was stirred overnight under an atmosphere of hydrogen at room temperature. The catalyst was filtered and the filtrate was concentrated. The residue was purified by means of silica gel column chromatography (20% ethyl acetate / hexane) to provide the title compound (5.97 g, 84% yield) as a colorless oil. XH NMR (CDC13) d: 1.23 (3H, t, J = 7.2Hz), 2.58 (2H, t, J = 7.6Hz), 2.90 (2H, t, J = 7.6Hz), 3.77 (3H, s), 4.12 (2H, q, J = 7.2Hz), 6.57-6.63 (2H,), 7.07-7.13 (ÍH, m).

Reference Example 14 Ethyl 3- (2-fluoro-4-hydroxyphenyl) propanoate To a solution of ethyl 3- (2-fluoro-4-methoxyphenyl) propanoate (57.4 g, 254 mmol) and aluminum chloride (101 g, 761 mmol) in dichloromethane (250 L) was added dropwise. Octanethiol (74.3 g, 508 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and the mixture was stirred for 30 minutes. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20% ethyl acetate / hexane) to give the title compound (44.6 g, 83% yield) as a colorless oil. XH NMR (CDC13) d: 1.23 (3H, t, J = 7.2Hz), 2.58 (2H, t, J = 8.1Hz), 2.89 (2H, t, J = 8.1Hz), 4.12 (2H, q, J = 7.2Hz), 6.51-6.56 (2H, m), 7.01-7.06 (ÍH, m).

Reference Example 15 2 ', 4' -dimethylbiphenyl-3-carboxylate ethyl The (2,4-dimethylphenyl) boronic acid (3.0 g, 20.0 mmol), ethyl 3-bromobenzoate (4.3 g, 18.8 mmol) and cesium carbonate (9.8 g, 30.0 mmol) were added to an ethanol mixture (20 g). mL) and toluene (80 mL) and after the argon substitution, tetracis (triphenylphosphine) palladium (0) (0.30 g, 0.26 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 70 ° C for 18 hours. The reaction mixture was cooled and the insoluble material was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by means of silica gel column chromatography (ethyl acetate: hexane = 1: 10) to give the title compound (5.0 g, 100% yield) as a colorless oil. XH NMR (CDC13) d: 1.39 (3H, t, J = 7.0Hz), 2.23 (3H, s), 2.37 (3H, s), 4.38 (2H, q, J = 7.0Hz), 7.02-7.54 (5H , m), 8.00-8.05 (2H, m).

Reference Example 16 (2 ', 4' -dimethylbiphenyl-3-yl) methanol To a solution of ethyl '2', 4 '-dimethylbiphenyl-3-carboxylate (5.0 g, 19.7 mmol) in anhydrous tetrahydrofuran (50 mL) was added lithium-aluminum hydride (0.91 g, 24.0 mmol) under ice cooling and the mixture was stirred at room temperature for 3 hours. The reaction solution was ice-cooled and sodium sulfate hydrate 10 (8.0 g, 24.8 mmol) was added. The mixture was stirred at room temperature for 1 hour. The insoluble, precipitated material was filtered through celite and the filtrate was concentrated under reduced pressure to provide the title compound as a colorless oil (96% yield). XH NMR (CDC13) d: 2.24 (3H, s), 2.36 (3H, s), 4.73 (2H, d, J = 6.0Hz), 7.00-7.45 (7H, m).

Reference Example 17 2 ', 4', 6 '-trimethylbiphenyl-3-carbaldehyde The title compound was obtained as a colorless oil from (2, 4, 6-trimethylphenyl) boronic acid and 3-bromobenzaldehyde according to a method similar to the method of Reference Example 15 (76% yield). MS m / z 225 (MH +) Reference Example 18 (2 ', 4', 6 '-trimethylbiphenyl-3-yl) methanol The 2 ', 4', 6 ', -trimethylbiphenyl-3-carbaldehyde (2.36 g, 10.5 mmol) was dissolved in ethanol (20 mL) and sodium borohydride (0.40 g) was added to the solution., 10.6 mmol). After stirring under ice-cooling for 3 hours, an aqueous solution of citric acid was added to the reaction solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by means of silica gel column chromatography (ethyl acetate: hexane = 1: 5-1: 2) to give the title compound (1.66 g, 70% yield) as a colorless oil. . XH NMR (CDC13) d: 2.00 (6H, s), 2.33 (3H, s), 4.73 (2H, d_J = 6.2Hz), 6.94 (2H, s), 7.00-7.42 (4H, m).

Reference Example 19 6-methoxy-2 ', 4'-dimethylbiphenyl-3-carbaldehyde The title compound was obtained as a colorless oil from l-bromo-2,4-dimethylbenzene and (5-formyl-2-methoxyphenyl) boronic acid according to a method similar to the method of Reference Example 15 (yield 87%). MS m / z 241 (MH +) Reference Example 20 (6-methoxy-2 ', 4'-dimethylbiphenyl-3-yl) methanol The title compound was obtained as a colorless oil from 6-methoxy-2 ', 4'-dimethylbiphenyl-3-carbaldehyde according to a method similar to the method of Reference Example 18 (88% yield). XH NMR (CDC13) d: 2.01 (6H, s), 3.74 (3H, s), 4.65 (2H, d, J = 5.2Hz), 6.97 (1H, d, J = 8.4Hz), 7.03 (1H, d , J = 2.2Hz), 7.06- 7.24 (3H, m), 7.35 (HH, dd, J = 2.6, 8.4Hz).

Reference Example 21 2 ', 4', 6 '-trimethylbiphenyl-3-ethylcarboxylate The title compound was obtained as a colorless oil from (2,4-, 6-trimethylphenyl) boronic acid and ethyl 3-bromobenzoate according to a method similar to the method of Reference Example 15 (80% yield). MS m / z 269 (MH +) Reference Example 22 4'-bromomethyl-2 ', 6'-dimethylbiphenyl-3-carboxylic acid ethyl ester and 2'-bromomethyl-4', 6'-dimethylbiphenyl-3-carboxylate Mixture of A solution of ethyl 2 ', 4', 6 '-trimethylbiphenyl-3-carboxylate (1.0 g, 3.73 mmol), N-bromosuccinimide (0.70 g, 3.93 mmol) and 2, 2'-azobis (isobutyronitrile) ( 65 g, 0.40 mmol) in carbon tetrachloride (30 mL) was stirred at 80 ° C for 5 hours. The reaction solution was cooled to room temperature and the insoluble material, precipitate was filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by means of silica gel column chromatography (ethyl acetate: hexane = 1: 10-1: 5) to give a mixture (0.82 g, 64%) of the title compounds as a colorless oil. The mixture was used for the next reaction without separation. MS m / z 348 (MH +) Reference Example 23 [4 '- [(4-fluorophenoxy) methyl] -2', 6 '-dimethylbiphenyl-3-yl] methanol and [2' - [(4-fluorophenoxy) methyl] -4 ', 6' - dimethylbiphenyl-3-yl] -methanol Mixture of A mixed solution of p-fluorophenol (0.32 g, 2. 85 mmol) and sodium hydride (89 mg, 2.60 mmol) in anhydrous tetrahydrofuran (20 mL) -N, N-dimethylformamide (10 mL) was stirred under ice-cooling for 20 minutes. To the solution was added the mixture (0.82 g, 2.36 mmol) obtained in Reference Example 22 and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate, washed successively with an aqueous solution of citric acid, water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The pale yellow oil obtained was dissolved in anhydrous tetrahydrofuran (20 mL) and the mixture was cooled with ice. To the solution was added dropwise 1.5 mol / l of a toluene solution of diisobutylaluminum hydride (5.0 mL, 7.5 mmol). The solution was stirred under ice cooling for 5 hours and dilute hydrochloric acid was added to the reaction solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified by means of silica gel column chromatography (ethyl acetate: hexane = 1: 10-1: 5-l: 3-l: 1) to give a mixture (0.74 g, yield of 93%). %) of the title compounds as a colorless oil. The mixture was used for the next reaction without separation. MS m / z 319 (M-OH) Reference Example 24 3- [4- [(3-bromobenzyl) oxy] phenyl] propanoate methyl To a solution of methyl 3- (4-hydroxyphenyl) propanoate (0.3 g, 1.67 mmol) in N, N-dimethylformamide (4.0 mL) was added 60% sodium hydride (0.073 g, 1.83 mmol) at 0 ° C with stirring and the mixture was stirred at the same temperature for 15 minutes. So, 3-bromobenzylbromide (0.44 g, 1.75 mmol) was added to the mixture at 0 ° C with stirring and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of 5% potassium hydrogen sulfate and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound (0.84 g, 72% yield) as a colorless powder.

XH NMR (CDCI3) d: 2.60 (2H, t, J = 7.8Hz), 2.90 (2H, t, J = 7.8Hz), 3.67 (3H, s), 5.01 (2H, s), 6.88 (2H, d , J = 8.4Hz), 7.12 (2H, d, J = 8.4Hz), 7.25 (1H, m), 7.35 (IH, d, J = 7.5Hz), 7.45 (IH, d, J = 7.5Hz), 7.59 (1H, s).

Reference Example 25 4 '- (methoxymethoxy) -2', 6'-dimethylbiphenyl-3-carbaldehyde A mixture of 4 '-hydroxy-2', 6'-dimethylbiphenyl-3-carbaldehyde (4.5 g, 19.9 mmol), chloromethyl methyl ether (2.3 mL, 30.3 mmol), potassium carbonate (5.5 g, 39.8 mmol) and potassium iodide (0.66 g, 3.98 mmol) in N, N-dimethylformamide (50 mL) was stirred at 70 ° C for 20 hours. The reaction solution was diluted with ethyl acetate, washed successively with an aqueous solution of citric acid, water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by means of silica gel column chromatography (ethyl acetate: hexane = 3: 97-1: 9) to give the title compound (1.7 g, 32% yield) as a colorless oil. . MS m / z 271 (MH +) Reference Example 26 [4'- (methoxymethoxy) -2 ', 6'-dimethylbiphenyl-3-yl] methanol The title compound was obtained as a colorless oil from 4 '- (methoxymethoxy) -2', 6'-dimethylbiphenyl-3-carbaldehyde according to a method similar to the method of Reference Example 3 (89% yield) . MS m / z 255 (MH +) Reference Example 27 Ethyl 2, 2-difluoro-3- (4-hydroxyphenyl) propanoate To a solution of ethyl 2, 2-difluoro-3- (4-methoxyphenyl) propanoate (1.72 g, 7.05 mmol) synthesized according to the method described in Synthesis, vol. 13, pages 1917-1924 (2000) and aluminum chloride (2.82 g, 21.2 mmol) in dichloromethane (50 mL) was added dropwise 1-octanotiol (2.06 g, 14.1 mmol) and the mixture was stirred at room temperature for 2 hours . The reaction mixture was poured into ice water and the mixture was stirred for 30 minutes. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (8-60% ethyl acetate / hexane) to give the title compound (0.90 g, 56% yield) as a colorless oil. XH NMR (CDC13) d: 1.26 (3H, t, J = 7.1Hz), 3.30 (2H, t, J = 16.3Hz), 4.25 (2H, q, J = 7.2Hz), 4.84 (ÍH, s), 6.74-6.82 (2H, m), 7.13 (2H, d, J = 8.3Hz).

Reference Example 28 2- (4-bromo-3,5-dimethylphenoxy) -6-methylpyridine To a solution of sodium hydroxide (0.23 g, 5.81 mmol) in methanol (50 mL) was added 4-bromo-3,5-dimethylphenol. (1.17 g, 5.81 mmol) and the mixture was allowed to stand at room temperature for 10 minutes and concentrated to dryness to give the sodium salt of 4-bromo-3,5-dimethylphenol (1.30 g). Then, a mixture of the sodium salt obtained from 4-bromo-3,5-dimethylphenol (1.30 g), 2-bromo-6-methylpyridine (1.0 g, 5.81 mmol) and copper powder (11 mg, 0.17 mmol) were added. stirred at 185 ° C for 1 hour. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane / ethyl acetate = 5 μl) to give the title compound (1.25 g, 74% yield) as a pale yellow powder . MS (ESI +): 292 (M + H), 294 Reference Example 29 2 ', 6' -dimethyl-4 '- [(6-methylpyridin-2-yl) oxy] biphenyl-3-carbaldehyde The title compound was obtained as a colorless oil from 2- (4-bromo-3,5-dimethylphenoxy) -6-methylpyridine and (3-formylphenyl) boronic acid according to a method similar to the method of Example of Reference 2 (94% yield). MS (ESI +): 318 (M + H) Reference Example 30. { 2 ', 6'-dimethyl-4' - [(6-methylpyridin-2-yl) oxy] biphenyl-3-yl} methanol The title compound was obtained as a colorless oil from the 2 ', 6'-dimethyl-4' - [(6-methylpyridin-2-yl) oxy] biphenyl-3-carbaldehyde according to a method similar to the method of Reference Example 3 (98% yield). MS (ESI +): 320 (M + H) Reference Example 31 2-bromo-5- (2-ethoxyethoxy) -1,3-dimethylbenzene To a solution of 4-bromo-3,5-dimethylphenol (12 g, 59.7 mmol), potassium iodide (1.5 g, 9.0 mmol) and potassium carbonate (9.9 g, 71.6 mmol) in N, N-dimethylformamide (80 mL) was added 2-chloroethyl ethyl ether (9.7 g, 89.3 mmol) at room temperature with stirring and the mixture was stirred at 70 ° C for 2 days. The reaction mixture was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 19 / L) to provide the title compound (15.9 g, 98% yield) as a yellow oil. MS (ESI +): 274 (M + H) Reference Example 32 [4- (2-ethoxyethoxy) -2,6-dimethylphenyl] boronic acid To a solution of 2-bromo-5- (2-ethoxyethoxy) -1,3-dimethylbenzene (10.0 g, 36.6 mmol) in tetrahydrofuran (100 mL) was added a hexane solution of n-butyllithium (1.6 M, 25.1 mL, 40.2 mmol) at -78 ° C with stirring. The reaction mixture was stirred at the same temperature for 30 minutes and triisopropyl borate (10.5 mL, 45.5 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 3 hours. 5 N Hydrochloric acid (20 mL) was added to the reaction mixture and the mixture was partitioned between ethyl acetate and water. The organic layer was dried over magnesium suífato and concentrated under reduced pressure. The residue was washed with hexane / diethyl ether and dried to give the title compound (5.9 g, 68% yield) as pale yellow crystals. XH NMR (CDC13) d: 1.24 (3H, t, J = 7.0 Hz), 2.36 (6H, S), 3.60 (2H, q, J = 7.0 Hz), 3.77 (2H, t, J = 5.0 Hz), 4.09 (2H, t, J = 5.0 Hz), 4.52 (2H, s), 6.58 (2H, S). Reference Example 33 4 '- (2-ethoxyethoxy) -6-methoxy-2', 6'-dimethylbiphenyl-3-carboxylic acid methyl ester A mixture of methyl 3-bromo-4-methoxybenzoate (0.90 g, 3.67 mmol), [4- (2-ethoxyethoxy) -2,6-dimethylphenyl] boronic acid (0.87 g, 3.67 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.13 g, 0.15 mmol) , 2- (dicyclohexylphosphino) biphenyl (79 mg, 0.22 mmol), tripotassium phosphate (1.56 g, 7.34 mmol) and toluene (20 mL) was stirred under a nitrogen atmosphere at 90 ° C for 18 hours. The reaction mixture was cooled and the insoluble material was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 9: 1-hexane / ethyl acetate = 1/1) to give the title compound. title (0.71 g, 54% yield) as a yellow oil. MS (ESI +): 359 (M + H) Reference Example 34 [4 '- (2-ethoxyethoxy) -6-methoxy-2', 6'-dimethylbiphenyl-3-yl] methanol The title compound was obtained as a colorless oil from methyl 4 '- (2-ethoxyethoxy) -6-methoxy-2', 6'-dimethylbiphenyl-3-carboxylate according to a method similar to the method of Example Reference 16 (100% yield). MS (ESI +): 331 (M + H) Reference Example 35 4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-carbaldehyde The title compound was obtained as pale yellow crystals to be derived from 4-bromo-3,5-dimethylphenol and (3-formylphenyl) boronic acid according to a method similar to the method of Reference Example 2 (yield 83 %). MS (ESI +): 227 (M + H) Reference Example 36 4 '-. { [tert -butyl (dimethyl) silyl] oxy} -2 ', 6' -dimethylbiphenyl-3-carbaldehyde To a solution of the 4 '-hydroxy-2', 6'-dimethylbiphenyl-3-carbaldehyde (9.0 g, 39.8 mmol) and imidazole (2.98 g, 43.8 mmol) in N, N-dimethylformamide (100 mL) was added tert. butyldimethylchlorosilane (6.6 g, 43.8 mmol) at room temperature with stirring and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = 4/1) to give the title compound (10.5 g, 77% yield). ) as a yellow oil. XH NMR (CDC13) d: 0.25 (6H, s), 1.02 (9H, s), 1.97 (6H, s), 6.62 (2H, s), 7.44 (HI, dt, J = 1.5, 7.5 Hz), 7.59 (1H, t, J = 7.5 Hz), 7.68 (HH, t, J = 1.5 Hz), 7.86 (HH, dt, J = 1.5, 7.5 Hz), 10.06 (HH, S).

Reference Example 37 (4 '- { [Tert -butyl (dimethyl) silyl] oxy] -2', 6'-dimethylbiphenyl-3-yl) ethanol The title compound was obtained as colorless crystals from 4 '-. { [tert -butyl (dimethyl) silyl] oxy} - 2 ', 6' -dimethylbiphenyl-3-carbaldehyde according to a method similar to the method of Reference Example 3 (89% yield). XH NMR (CDCl3) d: 0.23 (6H, s), 1.00 (9H, s), 1.96 (6H, s), 4.73 (2H, s), 6.58 (2H, s), 7.07 (1H, d, J = 7.5 Hz), 7.13 (1H, s), 7.32 (HH, d, J = 7.5 Hz), 7.40 (HH, t, J = 7.5 Hz).

Reference Example 38 (2E) -3- [4- (benzyloxy) phenyl] tert-butyl acrylate The title compound was obtained as colorless crystals from 4- (benzyloxy) benzaldehyde and tert-butyl diethyl phosphonoacetate according to a method similar to the method of Reference Example 12 (94% yield). XH NMR (CDCl3) d: 1.53 (9H, s), 5.09 (2H, s), 6.24 (1H, d, J = 15.9 Hz), 6.96 (2H, d, J = 9.0 Hz), 7.32-7.49 (7H , m), 7.54 (ÍH, d, J = 15.9 Hz).

Reference Example 39 3- (4-hydroxyphenyl) propane tert-butyl ester A mixture of tert-butyl (2E) -3- [4- (benzyloxy) phenyl] acrylate (13.3 g, 42.8 mmol), 10% palladium-carbon (1.3 g), ethanol (100 mL) and ethyl acetate ( 30 mL) was stirred under a hydrogen atmosphere at room temperature for 19 hours. The catalyst was filtered and the filtrate was concentrated under reduced pressure to provide the title compound (7.5 g, 79% yield) as colorless crystals. XH NMR (CDCl3) d: 1.41 (9H, s), 2.50 (2H, t, J = 7.8 Hz), 2.83 (2H, t, J = 7.8 Hz), 6.74 (2H, d, J = 8.7 Hz), 7.06 (2H, d, J = 8.7 Hz).

Reference Example 40 2,6-dimethyl-4-nitrophenyl trifluoromethanesulfonate To a solution of 2,6-dimethyl-4-nitrophenol (5.0 g, 29. 9 mmol) in N, N-dimethylformamide (50 mL) was added sodium hydride (60%, 1.44 g, 35.9 mmol) at 0 ° C with stirring and the mixture was stirred for 10 minutes. N-Phenylbis (trifluoromethanesulfonimide) (12.8 g, 35.9 mmol) was added and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = 5 / l) to give the title compound (9.2 g, 100% yield ) as a yellow oil. XH NMR (CDC13) d: 2.50 (6H, s), 8.03 (2H, s).

Reference Example 41 (2 ', 6' -dimethyl-4 '-nitrobiphenyl-3-yl) methanol A mixture of 2,6-dimethyl-4-nitrophenyltrifluoromethanesulfonate (9.2 g, 29.9 mmol), 3- (formylphenyl) boronic acid (4.7 g, 31.4 mmol), tris (dibenzylidene ketone) dipalladium (0) (1.10 g, 1.20 mmol ), rac-2, 2'-bis (diphenylphosphino) -1,2'-binaphthyl (1.12 g, 1.80 mmol), cesium carbonate (14.6 g, 44.9 mmol) and toluene (150 mL) was stirred under an atmosphere of nitrogen at 90 ° C for 18 hours. The reaction mixture was cooled and the insoluble material was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 9 / l-hexane / ethyl acetate = 2 / l) to give an yellow color (1.0 g). To a mixture of the yellow oil obtained (1.0 g), methanol (10 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (74 mg, 1.96 mmol) at 0 ° C with stirring and the mixture was stirred at Same temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture to divide the mixture. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 4/1-hexane / ethyl acetate = 1/1) to give the title compound (0.44 g, 6% yield). ) as pale yellow crystals. XH NMR (CDC13) d: 1.74 (1H, t, J = 5.7 Hz), 2.11 (6H, s), 4.77 (2H, d, J = 5.7 Hz), 7.04 (H, m), 7.12 (H, s) ), 7.41 (ÍH, d, J = 7.8 Hz), 7.48 (1H, t, J = 7.5 Hz), 7.97 (2H, s).

Reference Example 42 l-oxa-6-thia-spiro [2.5] octane To a suspension of trimethylsulfoxonium iodide (37.1 g, 165.1 mmol) in dimethyl sulfoxide (120 mL) was slowly added sodium hydride (6.10 g, 152.4 mmol) under an atmosphere of nitrogen at room temperature and, after stirring 1 hour, a solution of tetrahydro-4H-thiopyran-4-one (14.8 g, 127.0 mmol) in dimethyl sulfoxide (60 mL) was added dropwise over 20 minutes. The reaction solution was further stirred at room temperature for 14 hours, diluted with water and extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was allowed to stand at room temperature and the obtained crystals were washed with a small amount of hexane and dried to give the title compound (8.22 g, 50% yield) as colorless crystals in the form of needles. XH NMR (CDC13) d: 1.69-1.82 (2H, m), 1.93-2.09 (2H, m), 2.56-2.73 (4H, m), 2.85-3.01 (2H, m).

Reference Example 43 4 '- [(4-hydroxytetrahydro-2H-thiopyran-4-yl) "methoxy] -2', 6 'dimethylbiphenyl-3-carbaldehyde To a solution of l-oxa-6-thia-spiro [2.5] octane (6.33 g, 48.6 mmol) and 4 '-hydroxy-2', 6 '-dimethylbiphenyl-3-carbaldehyde (10.0 g, 44.2 mmol) in N, N-dimethylformamide (150 mL) was added potassium carbonate (6.11 g, 44.2 mmol) at room temperature with stirring and the mixture was stirred at 100 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. To the residue, 1 M hydrochloric acid was added to neutralize the solution and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure and crystallized by adding diisopropyl ether to the oil obtained. The crystals were collected by filtration to provide the title compound (12.3 g, 78% yield) as colorless crystals. XH NMR (CDC13) d: 1.76-1.91 (2H, m), 2.00 (6H, s), 2.06-2.17 (2H, m), 2.19 (1H, s), 2.41-2.55 (2H, m), 3.03- 3.19 (2H, m), 3.81 (2H, s), 6.69 (2H, s), 7.37-7.46 (HH, m), 7.55-7.71 (2H, m), 7.83-7.92 (HH, m), 10.05 ( 1H, s).

Reference Example 44 4- ( { [3 '- (hydroxymethyl) -2,6-dimethylbiphenyl-4-yl] oxy} methyl) tetrahydro-2H-thiopyran-4-ol The title compound was obtained as colorless crystals from 4 '- [(4-hydroxytetrahydro-2H-thiopyran-4-yl) methoxy] -2', 6'-dimethylbiphenyl-3-carbaldehyde according to a method similar to method of Reference Example 3 (100% yield). XH NMR (CDC13) d: 1.70 (ΔH, t, J = 5.8 Hz), 1.76-1.90 (2H, m), 2. 01 (6H, s), 2.05-2.16 (2H, m), 2.20 (ÍH, s), 2.40-2.53 (2H, m), 3.03-3.18 (2H, m), 3.80 (2H, s), 4.73 ( 2H, d, J = 5.8 Hz), 6. 67 (2H, s), 7.02-7.09 (HH, m), 7.12 (1H, s), 7.31-7.37 (HH, m), 7.41 (1H, t, J = 7.4 Hz).

Reference Example 45 methyl 3-bromo-4-hydroxybenzoate A solution of 3-bromo-4-hydroxybenzoic acid (50.4 g, 232 mmol) and the concentrated sulfuric acid (17 mL) in methanol (330 mL) was heated under reflux for 24 hours. The reaction mixture was neutralized with an aqueous solution of sodium hydroxide. The methanol was removed under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crystals obtained were washed with diethyl ether / hexane to give the title compound (45.5 g, 85% yield) as pale pink crystals. MS m / z 231 (MH +) Reference Example 46 Methyl 3-bromo-4-isopropoxybenzoate To a solution of methyl 3-bromo-4-hydroxybenzoate (15.0 g, 64.9 mmol), 2-bromopropanoate (7.68 mL, 77.9 mmol) and potassium iodide (1.0 g, 6.49 mmol) in N, N-dimethylformamide (200 mL) was added potassium carbonate (13.5 g, 97.4 mmol) and the mixture was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. Brine was added to the obtained residue and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-hexane / ethyl acetate = 9/1) to give the title compound (14.6 g, 83% yield) as a colorless oil. XH NMR (CDC13) d: 1.41 (6H, d, J = 6.0Hz), 3.89 (3H, s), 4.59-4.75 (1H, m), 6.90 (H, d, J = 8.9Hz), 7.94 (H) , dd, J = 8.7, 2.1Hz), 8.23 (ÍH, d, J = 2.1Hz).

Reference Example 47 (4-bromo-3,5-dimethylphenoxy) (tert-butyl) dimethylsilane The title compound was obtained as a colorless oil from 4-bromo-3,5-dimethylphenol according to a method similar to the method of Reference Example 36 (97% yield). X H NMR (CDCl 3) d: 0.18 (6H, s), 0.97 (9H, s), 2.34 (6H, s), 6.57 (2H, s).

Reference Example 48 (4- {[[tert-butyl (dimethyl) silyl] oxy} -2-6-dimethylphenyl) -boronic acid The title compound was obtained as pale yellow crystals in the form of prisms from (4-bromo-3,5-dimethylphenoxy) (tert-butyl) dimethylsilane according to a method similar to the method of Reference Example 32 (53% yield). XH NMR (CDC13) d: 0.19 (6H, s), 0.98 (9H, s), 2.32 (6H, s), 4.58 (2H, s), 6.47 (2H, s).

Reference Example 49 4 '-. { [tert -butyl (dimethyl) silyl] oxy} -6-isopropoxy-2 ', 6'-dimethylbiphenyl-3-carboxylate methyl a mixture of (4- {[[tert-butyl (dimethyl) silyl] oxy} -2,6-dimethylphenyl) boronic acid (500 mg, 1.83 mmol) and methyl 3-bromo-4-isopropoxybenzoate (667) mg, 2.38 mmol) was dissolved in a mixture of an aqueous solution of 2 M sodium carbonate (2.38 mL) and toluene (20 mL) and, after the argon substitution, 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (118 mg, 0.29 mmol) and the tris (dibenzylidene ketone) dipalladium (0) (67.0 mg, 0.07 mmol) were added. The reaction mixture was heated under reflux under an argon atmosphere for 1 day. The reaction mixture was cooled and brine was added. The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-hexane / ethyl acetate = 10 μl) to give the title compound (642 mg, 82% yield) as a yellow oil.

XH NMR (CDC13) d: 0.19-0.26 (6H, m), 1.00 (9H, s), 1.17 (6H, d, J = 6.0Hz), 1.92 (6H, s), 3..87 (3H, s) ), 4.42-4.57 (HH, m), 6.57 (2H, s), 6.95 (HH, d, J = 8.7Hz), 7.74 (1H, d, J = 2.3Hz), 7.99 (1H, dd, J = 8.7, 2.4Hz).

Reference Example 50 (4 '- { [Tert -butyl (dimethyl) silyl] oxy} .6-isopropoxy-2', 6'-dimethylbiphenyl-3-yl) methanol The title compound was obtained as an oil colorless from 4 '-. { [tert -butyl (dimethyl) silyl] oxy} -6-isopropoxy-2 ', 6'-dimethylbiphenyl-3-carboxylic acid methyl ester according to a method similar to the method of Reference Example 16 (85% yield). XH NMR (CDC13) d: 0.22 (6H, s), 1.00 (9H, s), 1.10 (6H, d, J = 6.2Hz), 1.94-1.98 (6H, m), 4.16-4.31 (H, m) , 4.64 (2H, d, J = 3.6Hz), 6.57 (2H, s), 6.94 (1H, d, J = 8.5Hz), 7.04 (IH, d, J = 2.1Hz), 7.24-7.31 (IH, m).

EXAMPLE 1 3- (4- {[2 '-methyl-4' - (tetrahydro-2H-pyran-2-yloxy) biphenyl-3-yl] methoxy} phenyl) propanoate methyl A solution of methyl 3- (4-hydroxyphenyl) propanoate (1.43 g, 7.94 mmol), [2'-methyl-4 '- (tetrahydro-2 H -pyran-2-yloxy) biphenyl-3-yl] methanol (2.37 g, 7.94 mmol) and tributylphosphine (2.97 mL, 11.9 mmol) in toluene (120 mL) was stirred under ice-cooling and 1,1'- (azodicarbonyl) dipiperidine (3.00 g, 11.9 mmol) was added in small portions. The mixture was warmed to room temperature and stirred for 24 hours. Hexane (60 mL) was added to the reaction mixture and the insoluble material, precipitate was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by means of silica gel column chromatography (hexane-20% ethyl acetate / hexane) to give the title compound as a colorless oil (3.05 g, yield). 83%). XH NMR (CDC13) d: 1.58-1.75 (3H, m), 1.85-1.90 (2H, m), 1.97-2.08 (HH, m), 2.23 (3H, s), 2.60 (2H, t, J = 7.8 Hz), 2.89 (2H, t, J = 7.8Hz), 3.61-3.66 (4H, m), 3.91-3.99 (1H, m), 5.07 (2H, s), 5.46 (ÍH, t, J = 3.1Hz ), 6.88-6.97 (4H, m), 7.08-7.16 (3H, m), 7.24-7.27 (1H, m), 7.35-7.43 (3H, m).

Example 2 3- (4- {[2 '-methyl-4' - (tetrahydro-2H-pyran-2-yloxy) -biphenyl-3-yl] methoxy} phenyl) propanoic acid To a solution of methyl 3- (4-. {[2'-methyl-4 '- (tetrahydro-2H-pyran-2-yloxy) biphenyl-3-yl] methoxy} phenyl) propanoate (0.599 g, 1.30 mmol) in methanol (6 mL) and tetrahydrofuran (6 mL) was added to an aqueous solution of 2 M sodium hydroxide. (2 mL) and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture and the mixture was neutralized with an aqueous solution of citric acid 10% and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to provide the title compound (0.436 g, 75% yield) as colorless, needle-like crystals. XH NMR (CDC13) d: 1.58-1.76 (3H, m), 1.85-1.90 (2H, m), 1.97-2.10 (HH, m), 2.23 (3H, s), 2.65 (2H, t, J = 7.6 Hz), 2.91 (2H, t, J = 7.6Hz), 3.60-3.66 (ÍH, m). 3.91-3.99 (HH, m), 5.08 (2H, s), 5.46 (HH, t, J = 3.1Hz), 6.89-6.97 (4H, m), 7.11-7.16 (3H, m), 7.24-7.27 ( 1H, m), 7.35-7.43 (3H, m).

Example 3 3 -. { 4- [(4 '-hydroxy-2' -methylbiphenyl-3-yl) methoxy] phenyl} -methylpropanoate A solution of methyl 3- (4-. {[2'-methyl-4 '- (tetrahydro-2H-pyran-2-yloxy) biphenyl-3-yl] methoxy} phenyl) propanoate (3.78 g, 8.21 mmol) and p-toluenesulfonic acid monohydrate (0.156 g, 0.821 mmol) in methanol (60 mL) was stirred at room temperature for 2 hours. The reaction solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by means of column chromatography on silica gel (ethyl acetate -60% / hexane) to provide the title compound (3.04 g, 98% yield) as a viscous, colorless oil. MS m / z 377 (MH +) Example 4 3- acid. { 4- [(4 '-hydroxy-2' -methylbiphenyl-3-yl) ethoxy] phenyl} -propanoic The title compound was obtained as colorless crystals in the form of prisms from 3-. { 4- [(4 '-hydroxy-2' -methylbiphenyl-3-yl) methoxy] phenyl} methyl propanoate according to a method similar to the method of Example 2 (31% yield, recrystallized from hexane-ethyl acetate). XH NMR (CDC13) d: 2.21 (3H, s), 2.65 (2H, t, J = 7.7Hz), 2.91 (2H, t, J = 7.7Hz), 5.07 (2H, s), 6.69-6.75 (2H, m), 6.92 (2H, d, J = 8.7Hz), 7.09-7.15 (3H, m), 7.23- 7.26 (1H, m), 7.35-7.43 (3H, m).

Example 5 3-. { 4 - [(4'-methoxy-2 '-methylbiphenyl-3-yl) methoxy] phenyl} methyl propanoate The title compound was obtained as a pale yellow oil from 3- (4- [(4'-hydroxy-2'-methyl-biphenyl-3-yl) methoxy] phenyl} methyl propanoate and methanol in accordance with a method similar to the method of Example 1 (92% yield) XH NMR (CDCl 3) d: 2.24 (3H, s), 2.60 (2H, t, J = 7.8Hz), 2.89 (2H, t, J = 7.8Hz), 3.66 (3H, s), 3.83 (3H, s), 5.07 (2H, s), 6.77-6.82 (2H, m), 6.91 (2H, d, J = 8.7Hz), 7.10-7.17 ( 3H,), 7.24-7.27 (ÍH, m), 7.35-7.43 (3H, m).

Example 6 3- acid. { 4- [(4'-methoxy-2 '-methylbiphenyl-3-yl) methoxy] phenyl} -propanoic The title compound was obtained as colorless crystals in the form of needles from 3-. { 4- [(4'-methoxy-2 '-methylbiphenyl-3-yl) methoxy] phenyl} methyl propanoate according to a method similar to the method of Example 2 (56% yield, recrystallized from hexane-ethyl acetate). XH NMR (CDC13) d: 2.24 (3H, s), 2.65 (2H, t, J = 7.7Hz), 2.91 (2H, t, J = 7.7Hz), 3.83 (3H, s), 5.08 (2H, s) ), 6.77-6.81 (2H,), 6.92 (2H, d, J = 8.7Hz), 7.11-7.18 (3H, m), 7.24-7.27 (HH, m), 7.36-7.44 (3H, m).

EXAMPLE 7 Methyl 3- (4-. {[4 '- (cyclopropylmethoxy) -2'-methylbiphenyl-3-yl] methoxy} phenyl) propanoate The title compound was obtained as a colorless oil from 3-. { 4- [(4 '-hydroxy-2' -methylbiphenyl-3-yl) methoxy] phenyl} methyl propanoate and cyclopropylmethanol according to a method similar to the method of Example 1 (85% yield). MS m / z 431 (MH +) Example 8 3- (4 { [4 '- (Cyclopropylmethoxy) -2' -methylbiphenyl-3-yl] methoxy.} Phenyl) propanoic acid The title compound was obtained as colorless crystals in the form of needles from methyl 3- (4- { [4'- (cyclopropylmethoxy) -2'-methyl-biphenyl-3-yl] methoxy} phenyl) propanoate. according to a method similar to the method of Example 2 (43% yield, recrystallized from hexane-ethyl acetate). MS m / z 417 (MH +) Example 9 3-. { 4- [(4'-isopropoxy-2'-methylbiphenyl-3-yl) methoxy] phenyl} -methylpropanoate The title compound was obtained as a colorless oil from 3-. { 4- [(4 '-hydroxy-2' -methylbiphenyl-3-yl) methoxy] phenyl} methyl propanoate and 2-propanol according to a method similar to the method of Example 1 (78% yield). MS m / z 419 (MH +) Example 10 3- acid. { 4- [(4'-isopropoxy-2 '-methylbiphenyl-3-yl) methoxy] phenyl} propanoic The title compound was obtained as colorless crystals in the form of needles from 3-. { 4 - [(4'-isopropoxy-2 '-methylbiphenyl-3-yl) methoxy] phenyl} Methyl propanoate according to a method similar to the method of Example 2 (56% yield, recrystallized from hexane-ethyl acetate). MS m / z 405 (MH +) EXAMPLE 11 3- (4- ({. [4 '- (benzyloxy) -2'-methyl-biphenyl-3-yl] methoxy} phenyl) propanoate methyl The title compound was obtained as a colorless oil from 3-. { 4- [(4 '-hydroxy-2' -methylbiphenyl-3-yl) methoxy] phenyl} Methyl propanoate and benzyl alcohol according to a method similar to the method of Example 1 (79% yield). MS m / z 467 (MH +) Example 12 3 - (4 { [4 '- (Benzyloxy) -2' -methylbifenil-3-yl] methoxy.} Phenyl) propanoic acid The title compound was obtained as colorless crystals in the form of needles from methyl 3- (4- { [4'- (benzyloxy) -2'-methyl-biphenyl-3-yl] methoxy} phenyl) propanoate. according to a method similar to the method of Example 2 (45% yield, recrystallized from hexane-ethyl acetate). MS m / z 453 (MH +) EXAMPLE 13 3- [4- (. {2 '- Methyl-4' - [2- (4-methyl-1,3-thiazol-5-yl) ethoxy] biphenyl-3-yl} methoxy) phenyl ] methyl propanoate The title compound was obtained as a brown oil from 3-. { 4- [(4 '-hydroxy-2' -methylbiphenyl-3-yl) ethoxy] phenyl} Methyl propanoate and 2- (4-methyl-1,3-thiazol-5-yl) ethanol according to a method similar to the method of Example 1 (62% yield). MS m / z 502 (MH +) EXAMPLE 14 3- [4- (. {2'-methyl-4 '- [2- (4-methyl-1, 3-thiazol-5-yl) ethoxy; biphenyl-3-yl-methoxy) phenyl] propanoic acid The title compound was obtained as colorless crystals in the form of plates from 3- [4- (. {2'-methyl-4 '- [2- (4-methyl-1,3-thiazol-5-yl. ) ethoxy] biphenyl-3-yl.} methoxy) phenyl] -propanoate according to a method similar to the method of Example 2 (77% yield, recrystallized from hexane-ethyl acetate). MS m / z 488 (MH +) Example 15 3- (4- {[2'-methyl-4 '- (3- (pyridin-2-yl) propoxy) biphenyl-3-yl] methoxy} phenyl) propanoate methyl A solution of 3-. { 4- [(4 '-hydroxy-2' -methylbiphenyl-3-yl) methoxy] phenyl} Methyl propanoate (0.602 g, 1.60 mmol), 3- (pyridin-2-yl) propan-l-ol (0.822 g, 6.00 mmol) and triphenylphosphine (1.57 g, 6.00 mmol) in tetrahydrofuran (20 mL) under cooling with The ice was stirred and diethyl azodicarboxylate (40% toluene solution, 2.72 mL, 6.00 mmol) was added. The mixture was warmed to room temperature and stirred for 42 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by means of silica gel column chromatography (20% -60% ethyl acetate / hexane) and preparative HPLC to provide the title compound as an oil. viscous yellow (0.446 g, 56% yield). MS m / z 496 (MH +) Example 16 3- (4. {[2 '-methyl-4' - (3- (pyridin-2-yl) propoxy) biphenyl-3-yl] methoxy} phenyl) propanoic acid A solution of methyl 3- (4-. {[2'-methyl-4 '- (3- (pyridin-2-yl) propoxy) biphenyl-3-yl] methoxy} phenyl) propanoate (0.401 g, 0.809 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added to a 2M aqueous sodium hydroxide solution (1.5 L) and the mixture was stirred at room temperature for 75 hours. Water was added to the reaction mixture and the mixture was neutralized with an aqueous solution of citric acid 10% and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (50% ethyl acetate / hexane-ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (0.186 g, yield 48 g). %) as colorless crystals in the form of prisms. MS m / z 482 (MH +) EXAMPLE 17 Methyl 3- (4-. {[2'-methyl-4 '- (1-propyl-butoxy) biphenyl-3-yl] methoxy) -phenyl) propanoate The title compound was obtained as a colorless oil from 3-. { 4- [(4 '-hydroxy-2' -methylbiphenyl-3-yl) methoxy] phenyl} methyl propanoate and 4-heptanol according to a method similar to the method of Example 1 (65% yield). XH NMR (CDC13) d: 0.94 (6H, t, J = 7.2Hz), 1.31-1.81 (8H, m), 2.22 (3H, s), 2.60 (2H, t, J = 7.8Hz), 2.89 (2H) , t, J = 7.8Hz), 3.66 (3H, s) 4.23-4.31 (1H, m), 5.07 (2H, s), 6.74-6.80 (2H, m), 6.88-6.93 (2H, m), 7.10 -7.16 (3H, m), 7.25-7.28 (1H, m), 7.36-7.43 (3H, m).

Example 18 3- (4. {[2 '-methyl-4' - (1-propyl-butoxy) -biphenyl-3-yl] methoxy} phenyl) propanoic acid The title compound was obtained as colorless crystals in the form of needles from methyl 3- (4- { [2'-methyl-4 '- (1-propylbutoxy) biphenyl-3-yl] methoxy} phenyl) propanoate according to a method similar to the method of Example 2 (77% yield, recrystallized from hexane-ethyl acetate). XH NMR (CDC13) d: 0.94 (6H, t, J = 7.3Hz), 1.33-1.76 (8H, m), 2.22 (3H, s), 2.65 (2H, t, J = 7.7Hz), 2.91 (2H) , t, J = 7.7Hz), 4.23-4.31 (ÍH, m), 5.07 (2H, s), 6.73-6.80 (2H, m), 6.92 (2H, d, J = 8.6Hz), 7.13 (3H, d, J = 8.6Hz), 7.24-7.28 (HH, m), 7.35-7.43 (3H, m).

Example 19 Ethyl 3- (4-. {[4 '- (benzyloxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy} -2-fluorophenyl) propanoate The title compound was obtained as a colorless oil from ethyl 3- (2-fluoro-4-hydroxyphenyl) propanoate and [4 '- (benzyloxy) -2', 6'-dimethylbiphenyl-3-yl] methanol according to a method similar to the method of Example 1 (76% yield). MS m / z 513 (MH +) EXAMPLE 20 3- (4 { [4 '- (Benzyloxy) -2', 6'-dimethylbifenyl-3-yl] methoxy.} -2-f-luo-phenyl) propanoic acid The title compound was obtained as colorless crystals in the form of prisms from 3- (4 { [4 '- (benzyloxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy. -fluorophenyl) -ethylpropanoate according to a method similar to the method of Example 2 (57% yield, recrystallized from heptane-ethyl acetate). MS m / z 485 (MH +) EXAMPLE 21 Ethyl 3- (4-. {[[4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy} -2-fluorophenyl) propanoate The title compound was obtained as a colorless oil from ethyl 3- (2-f-uoro-4-hydroxyphenyl) propanoate and [4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] ethanol in accordance with a method similar to the method of Example 1 (93% yield). MS m / z 495 (MH +) Example 22 3- (4- { [4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy.] -2-fluorophenyl) ropanoic acid The title compound was obtained as colorless crystals in the form of prisms from 3- (4 { [4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy. -2-fluorophenyl) ethyl propanoate according to a method similar to the method of Example 2 (77% yield, recrystallized from hexane-ethyl acetate). MS m / z 467 (MH +) EXAMPLE 23 3- (4-. {[2 ', 6' -dimethyl-4 '- (tetrahydro-2 H -pyran-2-yloxy) biphenyl-3-yl] methoxy. -2-fluorophenyl) ethyl propanoate The title compound was obtained as a colorless oil from ethyl 3- (2-fluoro-4-hydroxyphenyl) propanoate and [2 ', 6'-dimethyl-4' - (tetrahydro-2H-pyran-2- iloxy) biphenyl-3-yl] methanol according to a method similar to the method of Example 1 (89% yield). MS m / z 507 (MH +) Example 24 3-. { 2-fluoro-4- [(4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] -phenyl} ethyl propanoate The title compound was obtained as a colorless oil from 3- (4- { [2 ', 6'-dimethyl-4' - (tetrahydro-2H-pyran-2-yloxy) biphenyl-3-yl] ethyl methoxy.] -2-fluorophenyl) propanoate according to a method similar to the method of Example 3 (97% yield). MS m / z 423 (MH +) Example 25 3- acid. { 2-fluoro-4- [(4 '-hydroxy-2', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} propanoic The title compound was obtained as colorless crystals in the form of prisms from 3-. { 2-fluoro-4- [(4 '-hydroxy-2', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate according to a method similar to the method of Example 2 (82% yield, recrystallized from hexane-ethyl acetate). MS m / z 395 (MH +) EXAMPLE 26 Ethyl 3- (4-. {[2 ', 6'-dimethyl-4' - (1-propyl-butoxy) biphenyl-3-yl] methoxy} -2-fluorophenyl) propanoate The title compound was obtained as a colorless oil from 3-. { 2-fluoro-4- [(4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate and 4-heptanol according to a method similar to the method of Example 1 (88% yield). XH NMR (CDC13) d: 0.94 (6H, t, J = 7.2Hz), 1.23 (3H, t, J = 7.2Hz), 1.33-1.76 (8H, m), 1.98 (6H, s), 2.57 (2H , t, J = 7.6Hz), 2.89 (2H, t, J = 7.6Hz), 4.12 (2H, q, J = 7.2Hz), 4.21-4.29 (ÍH, m), 5.06 (2H, s), 6.62 -6.70 (4H, m), 7.05-7.12 (2H, m), 7.18 (H, s), 7.33-7.38 (1H,), 7.42 (1H, t, J = 7.5Hz).

EXAMPLE 27 3- (4. {[2 ', 6'-Dimethyl-4' - (1-propyl-butoxy) -biphenyl-3-yl] -methoxy} -2-fluorophenyl) propanoic acid The title compound was obtained as colorless crystals in the form of needles from 3- (4. {[2 ', 6' -dimethyl-4 '- (1-propylbuoxy) biphenyl-3-yl] ethoxy} -2-fluorophenyl.} Ethyl propanoate according to a method similar to the method of Example 2 (62% yield, recrystallized from heptane-ethyl acetate). XH NMR (CDCl 3) d: 0..94 ( 6H, t, J = 7.3Hz), 1.33-1.76 (8H, m), 1.97 (6H, s), 2.64 (2H, t, J = 7.6Hz), 2.91 (2H, t, J = 7.6Hz), 4. 21-4.29 (ÍH, m), 5.06 (2H, s), 6.63-6.71 (4H, m), 7.06-7.13 (2H, m), 7.18 (HH, s), 7.33-7.38 (HH, m), 7.42 (1H, t, J = 7.4Hz).

EXAMPLE 28 3- [4- [[Methyl 2 ', 6' -dimethyl-4 '- (tetrahydro-2 H -pyran-2-yloxy) biphenyl-3-yl] methoxy] phenyl] propanoate To a solution of methyl 3- (4-hydroxyphenyl) propanoate (3.28 g, 18.2 mmol), [2 ', 6' -dimethyl-4 '- (tetrahydro-2 H -pyran-2-yloxy) biphenyl-3-yl. ] methanol (5.15 g, 16.5 mmol) and triphenylphosphine (5.63 g, 21.5 mmol) in tetrahydrofuran (100 mL) was added dropwise diethyl azodicarboxylate. (solution in toluene 40%, 9.7 mL) at 0 ° C with stirring and the mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = 3 / l) to give the compound of the title (2.92 g, 37% yield) as a yellow oil. XH NMR (CDC13) d: 1.57-1.78 (3H, m), 1.82-1.90 (2H, m), 1.98 (6H, s), 2.02 (1H, m), 2.59 (2H, t, J = 7.8Hz) , 2.89 (2H, t, J = 7.8Hz), 3.62 (1H, m), 3.66 (3H, s), 3.97 (HH, m), 5.08 (2H, s), 5.45 (HH, t, J = 3.0Hz), 6.81 (2H, s), 6.89 (2H, d, J = 8.4Hz), 7.05-7.14 (3H, m), 7.18 (H, s), 7.34-7.47 (2H, m).

EXAMPLE 29 3- [4- [(4'-Hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) ethoxy] phenyl] -propanoic acid methyl ester A mixture of methyl 3- [4- [[2 ', 6' -dimethyl-4 '- (tetrahydro-2H-pyran-2-yloxy) biphenyl-3-yl] methoxy] phenyl] propanoate (2.92 g, 6.15 mmol), p-toluenesulfonic acid monohydrate (0.12 g, 0.62 mmol) and methanol (60 mL) was stirred at room temperature for 2 hours and the mixture was concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = l / 2) to give the title compound (2.12 g, 88% yield). ) as a red oil. XH NMR (CDC13) d: 1.96 (6H, s), 2.59 (2H, t, J = 7.8Hz), 2.89 (2H, t, J = 7.8Hz), 3.66 (3H, s), 4.63 (ÍH, s), 5.08 (2H, s), 6.59 (2H, s), 6.89 (2H, d, J = 8.7Hz) , 7.05-7.13 (3H, m), 7.17 (1H, s), 7.35-7.45 (2H, m).

EXAMPLE 30 3- [4- [(4'-Methoxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl] propanoic acid To a solution of methyl 3- [4- [(4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl] propanoate (0.20 g, 0.51 mmol), methane (0.041 mL, 1.02 mmol ) and triphenylphosphine (0.18 g, 0.67 mmol) in tetrahydrofuran (4.0 mL) was added dropwise the diethyl azodicarboxylate (40% toluene solution, 0.30 mL) at 0 ° C with stirring and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by means of column chromatography on silica gel (hexane / ethyl acetate = l? / L-hexane / ethyl acetate = 3 / l) to give a yellow oil (0.13 g, 65% yield). To a mixture of the obtained product, methanol (2 mL) and tetrahydrofuran (4 mL) was added to a 1N aqueous solution of sodium hydroxide (0.66 mL) at room temperature with stirring and the mixture was stirred at the same temperature for 1 hour. hour. The reaction mixture was adjusted to pH3 with 1 N hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 4 / l-hexane / ethyl acetate = l / 2) to give the title compound (0.12 g, 89% yield ) as colorless crystals. MS (APCI-): 389 (M-H) Example 31 3- [4- [(4'-Hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] -phenyl] propanoic acid To a solution of methyl 3- [4- [(4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) ethoxy] phenyl] propanoate (0.18 g, 0.46 mmol) in methanol (2 mL) and tetrahydrofuran (4 mL) was added an aqueous solution of 1 N sodium hydroxide (0.91 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was diluted with ethyl acetate, washed with 1 N hydrochloric acid and saturated brine, dried and concentrated under reduced pressure. The residue was crystallized from hexane / ethyl acetate = 4 μl to give the title compound (0.13 g, 74% yield) as colorless crystals. MS (APCI-): 375 (M-H) Example 32 3- [4- [(4'-Chloro-2'-methyl-biphenyl-3-yl) methoxy] phenyl] propanoate methyl A mixture of methyl 3- [4- [(3-bromobenzyl) oxy] -phenyl] propanoate (0.5 g, 1.43 mmol), 4-chloro-2-methylphenylboronic acid (0.30 g, 1.72 mmol), tetracis (triphenylphosphine) ) palladium (0) (0.083 g, 0.072 mmol), sodium carbonate (0.46 g, 4.29 mmol), water (5 mL), ethanol (5 mL) and toluene (25 mL) was stirred under an argon atmosphere at 90 ° C for 16 hours. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 10 / l-4 / l to give the title compound (0.50 g, 88% yield) as a colorless oil.

XH NMR (CDCl3) d: 2.22 (3H, s), 2.60 (2H, t, J = 7.8Hz), 2.90 (2H, t, -J = 7.8Hz), 3.66 (3H, s), 5.08 (2H, s), 6.91 (2H, d, J = 8.7Hz), 7.08-7.28 (6H, m), 7.34 (ÍH, broad), 7.38-7.46 (2H, m).

EXAMPLE 33 3- [4- [(4'-Chloro-2 '-methylbiphenyl-3-yl) methoxy] phenyl] - The title compound was obtained as colorless crystals from methyl 3- [4- [(4'-chloro-2'-methyl-biphenyl-3-yl) methoxy] phenyl] propanoate according to a method similar to the method of Example 31 (73% yield). MS (APCI-): 379 (M-H), 381 Example 34 3- [4- [(4'-Fluoro-2'-methylbiphenyl-3-yl) methoxy] phenyl] propanoate methyl The title compound was obtained as colorless crystals from methyl 3- [4- [(3-bromobenzyl) oxy] phenyl] -propanoate and 4-fluoro-2-methylphenylboronic acid according to a method similar to the method of Example 32 (94% yield). XH NMR (CDC13) d: 2.23 (3H, s), 2.60 (2H, t, J = 7.8Hz), 2.90 (2H, t, J = 7.8Hz), 3.66 (3H, s), 5.08 (2H, s) ), 6.86-7.00 (4H, m), 7.07-7.28 (4H, m), 7.31-7.46 (3H, m).

Example 35 3- [4- [(4'-Fluoro-2'-methyl-biphenyl-3-yl) methoxy] phenyl] -propanoic acid The title compound was obtained as colorless crystals from methyl 3- [4- [(4'-fluoro-2'-methyl-biphenyl-3-yl) methoxy] phenyl] propanoate according to a method similar to the method of Example 31 (81% yield). MS (APCI-): 363 (M-H) Example 36 3- [4- [[4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy] -phenyl] propanoate methyl To a solution of methyl 3- [4- [(4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl] propanoate (0.20 g, 0.51 mmol), 2-ethoxyethanol (0.099 mL, 1.02 mmol) and triphenylphosphine (0.18 g, 0.67 mmol) in tetrahydrofuran (4.0 mL) was added dropwise diethyl azodicarboxylate (solution in toluene 40%, 0.30 mL) at 0 ° C with stirring and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = 3 / l) to give the compound of the title (0.12 g, 51% yield) as a colorless oil. XH NMR (CDC13) d: 1.25 (3H, t, J = 6.9Hz), 1.98 (6H, s), 2.59 (2H, t, J = 7.8Hz), 2.89 (2H, t, J = 7.8Hz), 3.62 (2H, q, J = 6.9Hz), 3.66 (3H, s), 3.80 (2H, t, J = 5.1Hz), 4.14 (2H, t, J = 5.1Hz), 5.08 (2H, s), 6.68 (2H, s), 6.89 (2H, d, J = 8.4Hz), 7.04-7.14 (3H, m), 7.17 (IH, s), 7.35-7.45 (2H, m).

Example 37 3- [4- [[4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy] phenyl] propanoic acid The methyl 3- [4- [[4 '- (ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy] phenyl] propanoate (0.12 g, 0.26 mmol) was dissolved in a mixed solution of methanol ( 2 mL) and tetrahydrofuran (4 mL) and an aqueous solution of 1 N sodium hydroxide (0.52 mL) was added at room temperature with stirring. The mixture was stirred at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid, water and saturated brine, dried and concentrated under reduced pressure. The residue was crystallized from hexane / ethyl acetate = 4 μl to give the title compound (0.087 g, 75% yield) as colorless crystals. MS (APCI-): 447 (M-H) Example 38 3- [4- [[4 '- (Benzyloxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy] -phenyl] propanoate methyl The title compound was obtained as a colorless oil from methyl 3- [4- [(4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl] propanoate and benzyl alcohol in accordance with a method similar to the method of Example 36 (63% yield). XH NMR (CDC13) d: 1.99 (6H, s), 2.59 (2H, t, J = 7.8Hz), 2.89 (2H, t, J = 7.8Hz), 3.66 (3H, s), 5.07 (2H, s) ), 5.08 (2H, s), 6.75 (2H, s), 6.89 (2H, d, J = 8.7Hz), 7.05-7.13 (3H, ra), 7.18 (IH, s), 7.30-7.49 (7H, m).

Example 39 3- [4- [[4 '- (Benzyloxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy] phenyl] propanoic acid The title compound was obtained as colorless crystals from methyl 3- [4- [[4 '- (benzyloxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy] phenyl] propanoate according to a method similar to the method of Example 37 (91% yield). MS (APCI-): 465 (M-H). p.f. : 123 ° C Example 40 3- [4- [[4 '- (Cyclopropylmethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy] phenyl] propanoate methyl The title compound was obtained as a colorless oil from methyl 3- [4- [(4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl] propanoate and cyclopropylmethanol in accordance with method similar to the method of Example 36 (69% yield). XH NMR (CDC13) d: 0.31-0.39 (2H, m), 0.60-0.69 (2H, m), 1.27 (1H, m), 1.98 (6H, s), 2.59 (2H, t, J = 7.8Hz), 2.89 (2H, t, J = 7.8Hz), 3.66 (3H, s), 3.81 (2H, d, J = 6.9Hz), 5.08 (2H, s), 6. 66 (2H, s), 6.89 (2H, d, J = 8.7Hz), 7.05-7.13 (3H, m), 7.18 (1H, s), 7.35-7.45 (2H, m).

Example 41 3- [4- [[4 '- (Cyclopropylmethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy] phenyl] propanoic acid The title compound was obtained as colorless crystals from methyl 3- [4- [[4 '- (cyclopropylmethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy] phenyl] propanoate according to a method similar to the method of Example 37 (76% yield). MS (APCI-): 429 (M-H) Example 42 3- [4- [[4 '- [2- (dimethylamino) ethoxy] -2', 6'-dimethylbiphenyl-3-yl] methoxy] phenyl] propanoate methyl The title compound was obtained as a colorless oil from methyl 3- [4- [(4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl] propanoate and N, N-dimethylethanolamine according to a method similar to the method of Example 36 (38% yield). XH NMR (CDC13) d: 1.98 (6H, s), 2.35 (6H, s), 2.59 (2H, t, J = 7.8Hz), 2.75 (2H, t, J = 5.7Hz), 2.89 (2H, t , J = 7.8Hz), 3.66 (3H, s), 4.09 (2H, t, J = 5.7Hz), 5.08 (2H, s), 6.68 (2H, s), 6.89 (2H, d, J = 8.7Hz ), 7.05-7.13 (3H, m), 7.18 (HH, s), 7.35-7.45 (2H, m).

Example 43 3- [4- [[4 '- [2- (dimethylamino) ethoxy] -2', 6'-dimethylbiphenyl-3-yl] methoxy] phenyl] propanoic acid trifluoroacetate The title compound was obtained as colorless crystals from 3- [4- [[4 '- [2- (dimethylamino) ethoxy] -2', 6'-dimethylbiphenyl-3-yl] methoxy] phenyl] propanoate of. methyl according to a method similar to the method of Example 37 (87% yield). This compound was purified by preparative HPLC. MS (APCI-): 446 (M-H, as a free form) Example 44 3-. { 4- [(2 ', 4'-dimethylbiphenyl-3-yl) methoxy] phenyl} methyl propanoate The title compound was obtained from methyl 3- (4-hydroxyphenyl) propanoate and (2 ', 4'-dimethylbiphenyl-3-yl) methanol according to a method similar to the method of Example 1 (yield 83 %). MS m / z 375 (MH +) Example 45 3- acid. { 4- [(2 ', 4'-dimethylbiphenyl-3-yl) methoxy] phenyl} -propanoic The title compound was obtained from 3-. { 4- [(2 ', 4'-dimethylbiphenyl-3-yl) methoxy] phenyl} Methyl propanoate according to a method similar to the method of Example 2 (91% yield). XH NMR (CDC13) d: 2.22 (3H, s), 2.36 (3H, s), 2.65 (2H, t, J = 7.6Hz), 2.91 (2H, t, J = 7.6Hz), 5.08 (2H, s), 6.91 (2H, d, J = 8.4Hz), 7.00-7.46 (9H, m).

Example 46 3-. { 4- [(2 ', 4', 6 '-trimethylbiphenyl-3-yl) methoxy] phenyl} methyl propanoate The title compound was obtained from methyl 3- (4-hydroxyphenyl) propanoate and (2 ', 4', 6'-trimethylbiphenyl-3-yl) methanol according to a method similar to the method of Example 1 ( 71% yield).

XH NMR (CDCl3) d: 1.98 (6H, s), 2.32 (3H, s), 2.59 (2H, t, J = 7.6Hz), 2.89 (2H, t, J = 7.6Hz), 3.66 (3H, s) ), 5.08 (2H, s), 6.88 (2H, d, J = 8.8Hz), 6.93 (2H, s), 7.05-7.48 (6H, m).

EXAMPLE 47 3- acid. { 4 - [(2 ', 4', 6 '-trimethylbiphenyl-3-yl) methoxy] phenyl} -propanoic The title compound was obtained from 3-. { 4 - [(2 ', 4', 6 '-trimethylbiphenyl -3-yl) methoxy] phenyl} methyl propanoate according to a method similar to the method of Example 2 (88% yield). XH NMR (CDCl 3) d: 1.98 (6H, s), 2.32 (3H, s), 2.64 (2H, t, J = 7.4Hz), 2.90 (2H, t, J = 7.4Hz), 5.08 (2H, s), 6.89 (2H, d, J = 8.8Hz), 6.93 (2H, s), 7.04-7.48 (6H, m).

EXAMPLE 48 Methyl 3- (4- ((6-methoxy-2 ', 4'-dimethylbiphenyl-3-yl) methoxy) phenyl) propanoate The title compound was obtained from methyl 3- (4-hydroxyphenyl) propanoate and (6-methoxy-2 ', 4'-dimethylbiphenyl-3-yl) methanol according to a method similar to the method of Example 1 (68% yield). XH NMR (CDC13) d: 2.10 (3H, s), 2.36 (3H, s), 2.59 (2H, t, J = 7.6Hz), _ 2.90 (2H, t, J = 7.6Hz), 3.66 (3H, s), 3.77 (3H, s), 4.98 (2H, s), 6.90 (2H, d, J = 8.8Hz), 6.95 (1H, d, J = 8.4Hz), 7.00-7.17 (5H, m), 7.20 (ÍH, d, J = 2.2Hz), 7.39 (ÍH, dd, J = 2.2, 8.4Hz).

Example 49 3 - (4- ((6-methoxy-2 ', 4'-dimethylbifenyl-3-yl) methoxy) phenyl) propanoic acid The title compound was obtained from methyl 3- (4- ((6-methoxy-2 ', 4'-dimethylbiphenyl-3-yl) methoxy) phenyl) -propanoate according to a method similar to the method of Example 2 (100% yield). XH NMR (CDCl3) d: 2.10 (3H, s), 2.36 (3H, s), 2.65 (2H, t, J = 7.6Hz), 2.91 (2H, t, J = 7.6Hz), 3.77 (3H, s ), 4.99 (2H, s), 6.84-7.18 (8H, m), 7.20 (HH, d, J = 2.2Hz), 7.39 (HH, dd, J = 2.6, 8.4Hz).

Example 50 3-. { 2-fluoro-4- [(2 ', 4', 6 '-trimethylbiphenyl-3-yl) methoxy] phenyl} -ethyl propionate The title compound was obtained from ethyl 3- (2-fluoro-4-hydroxyphenyl) propanoate and (2 ', 4'6'-trimethylbiphenyl-3-yl) methanol according to a method similar to the method of Example 1 (74% yield). MS m / z 421 (MH +) Example 51 3- acid. { 2-fluoro-4- [(2 ', 4', 6 '-trimethylbiphenyl-3-yl) methoxy] phenyl} propanoic The title compound was obtained from 3-. { 2-fluoro-4- [(2 ', 4', 6 '-trimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate according to a method similar to the method of Example 2 (77% yield). APCI (-) 391 (M-H) Examples 52 and 53 3-. { 2-fluoro-4- [(2 '- (4-fluorophenoxymethyl) -4', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate (Example 52) and 3-. { 2-fluoro-4 ~ [(4 '- (4-fluorophenoxymethyl) -2', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate (Example 53) Mix of To a solution of the mixture (0.74 g, 2.20 mmol) obtained in Reference Example 23, ethyl 3- (2-fluoro-4-hydroxyphenyl) propanoate (0.47 g, 2.21 mmol) and tributylphosphine (0.71 mL, 2.85 mmol) ) in anhydrous tetrahydrofuran (40 mL) was added, 1 '- (azodicarbonyl) dipiperidine (0.72 g, 2.85 mmol) in small portions and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with diethyl ether (40 mL) and the precipitated product was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by means of silica gel column chromatography (ethyl acetate: hexane = 1: 10-1: 5) to give a mixture (1.08 g, 93% yield) of the title compounds as a pale yellow oil. The mixture was used for the next reaction without separation.

MS m / z 531 (MH +) Examples 54 and 55 3- acid. { 2-fluoro-4- [(2 '- (4-fluorophenoxymethyl) -4', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} propanoic (Example 54) and 3- acid. { 2-fluoro-4- [(4 '- (4-fluorophenoxymethyl) -2', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} propane (Example 55) A mixture (1.08 g, 2.04 mmol) of 3-. { 2-fluoro-4- [(2 '- (4-fluorophenoxymethyl) -4', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate and 3-. { Ethyl 2-fluoro-4- [(4 '- (4-fluorophenoxymethyl) -2', 6 '-dimethylbiphenyl-3-yl) methoxy] -phenyl] propanoate obtained in Examples 52 and 53 was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and ethanol (10 mL). To the solution was added an aqueous solution (5 mL) of 85% potassium hydroxide (0.34 g, 5.15 mmol) and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate, washed successively with an aqueous solution of citric acid, water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to chiral column chromatography (CHIRALPAK) (hexane: 2-propanol: acetic acid = 94: 6: 0.1) to purify each steric isomer. The acid 2-. { 3-fluoro-4- [(2 '- (4-fluorophenoxymethyl) -4', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} Propanoic (657 mg, 64% yield) was obtained as a pale yellow oil. XH NMR (CDCI3) d: 2.03 (3H, s), 2.38 (3H, s), 2.63 (2H, t, J = 7.4Hz), 2.90 (2H, t, J = 7.4Hz), 4.59 (2H, s) ), 5.00 (2H, s), 6.57-7.18 (9H, m), 7.23 (2H, broad s), 7.30-7.44 (2H, m).

The acid 3-. { 2-fluoro-4- [(4 '- (4-fluorophenoxymethyl) -2', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} Propanoic acid (141 mg, 14% yield) was obtained as colorless crystals in the form of prisms. XH NMR (CDCl3) d: 2.02 (6H, s), 2.05-3.00 (4H, m), 4.97 (2H, s), 5.07 (2H, s), 6.62-6.72 (2H, m), 6.90-7.14 ( 7H, m), .7.16 (2H, s), 7.36-7.50 (2H, m).

Example 56 3-. { 4- [(4'-. {[[Tert -butyl (dimethyl) silyl] oxy} -2 ', 6'-dimethyl-biphenyl-3-yl) methoxy] phenyl} tert-butyl propanoate The title compound was obtained as a pale yellow oil from (4'-. {[[Tert-butyl (dimethyl) silyl] oxy] -2. ', 6'-dimethylbiphenyl-3-yl) methanol. and tert-butyl 3- (4-hydroxyphenyl) propanoate according to a method similar to the method of Example 1 (87% yield). XH NMR (CDC13) d: 0.23 (6H, s), 1.00 (9H, s), 1.41 (9H, s), 1.95 (6H, s), 2.49 (2H, t, J = 7.8 Hz), 2.84 (2H , t, J = 7.8 Hz), 5.07 (2H, s), 6.58 (2H, s), 6.89 (2H, d, J = 8.4 Hz), 7.01-7.14 (3H, m), 7.18 (1H, s) , 7.33-7.46 (2H, m).

Example 57 3-. { 4- [(4'-Hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} tert-butyl propanoate To a solution of 3-. { 4- [(4 '- { [Tert -butyl (dimethyl) silyl] oxy} -2', 6'-dimethylbiphenyl-3-yl) methoxy] -phenyl} tert-butyl propanoate (3.28 g, 4.35 mmol) in tetrahydrofuran (24 mL) was added tetrabutylammonium fluoride (solution in 1 M tetrahydrofuran, 4.79 mmol, 4.79 mL) at room temperature with stirring and the mixture was stirred at room temperature during 2 hours . The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = 3/1) to give the title compound (1.69 g, 90% yield). ) as a colorless oil. XH NMR (CDC13) d: 1.41 (9H, s), 1.96 (6H, s), 2.50 (2H, t, J = 7.8 Hz), 2.84 (2H, t, J = 7.8 Hz), 5.08 (2H, s ), 6.59 (2H, s), 6.89 (2H, d, J = 8.7 Hz), 7.04-7.14 (3H, m), 7.18 (H, s), 7.35-7.45 (2H, m).

Example 58 3- [4- ( {4 '- [2-Ethoxy-l- (ethoxymethyl) ethoxy] -2', 6'-dimethylbiphenyl-3-yl.} Methoxy) -2-fluorophenyl] propanoate ethyl The title compound was obtained as a colorless oil from 3-. { Ethyl 2-fluoro-4- [(4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl Jpropanoate and 1,3-diethoxypropan-2-ol according to a method similar to the method of Example 1 (65% yield). MS m / z 553 (MH +) Example 59 3- [4- ( { '- [2-Ethoxy-1- (ethoxymethyl) ethoxy] -2', 6'-dimethylbiphenyl-3-yl} methoxy) -2-fluorophenyl] propanoic acid To a mixed solution of 3- [4- (. {4 '- [2-ethoxy-1- (ethoxymethyl) ethoxy] -2', 6'-dimethylbiphenyl-3-yl} methoxy) -2-fluorophenyl ] ethyl propanoate (0.665 g, 1.20 mmol) in ethanol (6 mL) and tetrahydrofuran (6 L) were added a 2M aqueous sodium hydroxide solution (2 L) and the mixture was stirred at room temperature for 72 hours. Water was added to the reaction mixture and the mixture was neutralized with an aqueous solution of 10% citric acid and extracted with ethyl acetate.

The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% -80% ethyl acetate / hexane) to give the title compound (0.588 g, 93% yield) as a viscous, colorless oil. MS m / z 525 (MH +) Example 60 3- (4- { [4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy.} -2-fluorophenyl) propanamide A mixture of 3- (4. {[4- (2-ethoxyethoxy) -2 ', 6'-dimethylbiphenyl-3-yl] methoxy} -2-fluorophenyl) propanoic acid (0.233 g, 0.500 mmol) , a solution of 7 M ammonia / methanol (0.4 mL, 280 mmol), l-ethyl-3- (3-aminopropyl) -carbodiimide hydrochloride (2.88 g, 1.50 mmol), 1-hydroxybenzotriazole (0.230 g, 1.50 mmol) , 1,8-diazabicyclo [5.4.0] -7-undecene (0.448 mL, 3.00 mmol), triethylamine (0.502 mL, 3.60 mmol) and acetonitrile (3 mL) was stirred at room temperature for 27 hours. The reaction mixture was poured into an aqueous, saturated sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by means of basic silica gel column chromatography (50% ethyl acetate / hexane-ethyl acetate) to give the title compound (0.186 g, 80% yield) as a colorless oil. MS m / z 446 (MH +) Example 61 1- [3- (4- { [4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy} -2-fluorophenyl) propanoyl] pyrrolidine The title compound was obtained as a yellow oil from 3- (4 { [4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy. -2-fluorophenyl) propanoic and pyrrolidine according to a method similar to the method of Example 60 (95% yield). MS m / z 520 (MH +) EXAMPLE 62 3- (4- { [4 '- (methoxymethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy.} Phenyl) propanoic acid To a solution of 3-. { 4- [(4'-Hydroxy-2 ', 6'-dimethylbiphenyl-3-yl.} Methoxy] phenyl] methyl propanoate (0.50 g, 1.28 mmol) potassium carbonate (0.35 g, 2.56 mmol) and iodide Sodium (0.19 g, 1.28 mmol) in N, N-dimethylformamide (5.0 mL) was added chloromethyl-methyl ether (0.13 mL, 1.66 mmol) at room temperature with stirring and the mixture was stirred at 50 ° C for 24 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure.The residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = 3 / l) to give a colorless oil, then a 1N sodium hydroxide aqueous solution was added to a mixture of the oil, methanol (4 mL) and tetrahydrofuran (8 mL). (2.6 mL) at room temperature with stirring and the mixture was stirred at the same temperature for 2 hours.The reaction mixture was adjusted to pH3 with hydrochloric acid. 1N, was diluted with ethyl acetate, washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate = 4 / l-hexane / ethyl acetate = l / 2) to give the title compound (0.12 g, 22% yield ) as colorless crystals. MS (APCI-): 419 (M-H) Example 63: 3- acid. { 4- [(4'-ethoxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] -phenyl} -propanoic The title compound was obtained as colorless crystals from 3-. { 4- [(4'-Hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} Methyl propanoate and iodoethane according to a method similar to the method of Example 62 (14% yield). MS (APCI-): 403 (M-H) EXAMPLE 64 3- (4- { [4 '- (2-Butoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy.} Phenyl) propanoic acid The title compound was obtained as colorless crystals from 3-. { 4- [(4'-Hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} methyl propanoate and 2-chloroethyl-n-butyl ether according to a method similar to the method of Example 62 (66% yield) MS (APCI-): 475 (M-H) EXAMPLE 65 3- [4- (. {4 '- [2- (Benzyloxy) ethoxy] -2', 6'-dimethylbiphenyl-3-yl} methoxy) phenyl] propanoic acid To a solution of 3-. { 4- [(4'-Hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} Methyl propanoate (0.50 g, 1.28 mmol), 2- (benzyloxy) ethanol (0.20 mL, 1.41 mmol) and tributylphosphine (0.48 mL, 1.92 mmol) in tetrahydrofuran (10 mL) were added 1.1 '- (azodicarbonyl) dipiperidine. (0.48 g, 1.92 mmol) at 0 ° C with stirring. The reaction mixture was stirred at room temperature for 18 hours and an equivalent amount of the reagents mentioned above (2- (benzyloxy) ethanol, tributylphosphine and 1,1 '- (azodicarbonyl) dipiperidine) and the mixture were added at the same temperature. it was further stirred for 18 hours. Diethyl ether was added to the reaction mixture and the insoluble material was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = 2/1) to give a colorless oil. . Then, to a mixture of the oil, methanol (4 mL) and tetrahydrofuran (8 mL) was added an aqueous solution of 1 N sodium hydroxide (2.6 mL) at room temperature with stirring and the mixture was stirred at the same temperature for 2 hours. hours. The reaction mixture was neutralized with 1N hydrochloric acid, diluted with ethyl acetate, washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4 / l-hexane / ethyl acetate = l / 2) to give the title compound (0.26 g, yield 39% ) as colorless crystals. MS (APCI-): 509 (M-H) EXAMPLE 66 3- (4. {[[2 ', 6' -dimethyl-4 '- (3-pyridin-2-ylpropoxy) biphenyl-3-yl] methoxy} phenyl) propanoic acid The title compound was obtained as a colorless oil from 3-. { 4- [(4'-Hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} methyl propanoate and 3- (pyridin-2-yl) propan-1-ol according to a method similar to the method of Example 65 (28% yield). MS (APCI-): 494 (M-H) Example 67 3- acid. { 4- [(4 '-butoxy-2', 6 '-dimethylbiphenyl-3-yl) methoxy] -phenyl} propanoic The title compound was obtained as colorless crystals from 3-. { - [(4 '-hydroxy-2', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} methyl propanoate and 1-butanol according to a method similar to the method of Example 65 (45% yield). MS (APCI-): 431 (M-H) Example 68 3- [4- (. {4 '- [2- (ethylthio) ethoxy] -2', 6'-dimethylbiphenyl-3-yl} methoxy) phenyl] propanoate methyl The title compound was obtained as a pale yellow oil from 3-. { 4- [(4'-Hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} Methyl propanoate and 2- (ethylthio) ethanol according to a method similar to the method of Example 1 (64% yield). XH NMR (CDC13) d: 1.31 (3H, t, J = 7.2 Hz), 1.98 (6H, s), 2.59 (2H, t, J = 7.8 Hz), 2.67 (2H, q, J = 7.2 Hz), 2.85-2.97 (4H, m), 3.66 (3H, s), 4.15 (2H, t, J = 6.9 Hz) , 5.08 (2H, s), 6 66 (2H, s), 6.89 (2H, d, J = 8.7 Hz), 7.04-7.14 (3H, m), 7.17 (H, s), 7.35-7.47 (2H, m).

Example 69 3- [4- ( {4'- [2- (ethylthio) ethoxy] -2 ', 6'-dimethylbiphenyl-3-yl} methoxy) phenyl] propanoic acid The title compound was obtained as colorless crystals from 3- [4- (. {4 '- [2- (ethylthio) ethoxy] -2', 6'-dimethylbiphenyl-3-yl.} Methoxy) phenyl ] methyl propanoate according to a method similar to the method of Example 37 (47% yield). MS (APCI-): 463 (M-H).

EXAMPLE 70 3- [4- ( { 4'- [2- (ethylthio) ethoxy] -2 ', 6'-dimethylbiphenyl-3-yl.} - methoxy) phenyl] tert-butyl propanoate To a solution of 3-. { 4- [(4'-Hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} tert-butyl propanoate (1.69 g, 3.91 mmol), 2- (ethylthio) ethanol (0.46 mL, 4.30 mmol) and tributylphosphine (1.46 mL, 5.86 mmol) in tetrahydrofuran (33 mL) was added 1.1% - (azodicarbonyl) ) dipiperidine (1.48 g, 5.86 mmol) at room temperature with stirring. The reaction mixture was stirred at room temperature for 16 hours and an equivalent amount of the reagents mentioned above (2- (ethylthio) ethanol, tributylphosphine and 1,1'- (azodicarbonyl) dipiperidine) and the mixture were added at the same temperature. it was further stirred for 16 hours. Diethyl ether was added to the reaction mixture and the insoluble material was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = 4/1) to give the title compound. title (1.40 g, 69% yield) as a colorless oil.

XH NMR (CDCl3) d: 1.31 (3H, t, J = 7.2 Hz), 1.41 (9H, s), 1.99 (6H, s), 2.49 (2H, t, J = 7.8 Hz), 2.67 (2H, q, J = 7.2 Hz), 2. 84 (2H, t, J = 7.8 Hz), 2.92 (2H, t, J = 6.9 Hz), 4.15 (2H, t, J = 6.9 Hz), 5.08 (2H, s), 6. 66 (2H, s), 6.89 (2H, d, J = 8.7 Hz), 7.05-7.14 (3H, m), 7.18 (H, s), 7.35-7.45 (2H, m).

Example 71 3- [4- ( { 4'- [2- (Ethylsulfonyl) ethoxy] -2 ', 6'-dimethylbiphenyl-3-yl.} - methoxy) phenyl] propane tert-butyl ester To a solution of tert-butyl 3- [4- (. {4 '- [2- (ethylthio) ethoxy] -2', 6'-dimethylbiphenyl-3-yl.} Methoxy) phenyl] propanoate (0.70) g, 1.34 mmol) in dichloromethane (14 mL) was added m-chloroperbenzoic acid (0.73 g, 2.96 mmol) at 0 ° C with stirring and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was washed with a 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = 1 / L) to give the title compound (0.67 g, 74% yield). ) as a pale yellow oil. XH NMR (CDC13) d: 1.41 (9H, s), 1.47 (3H, t, J = 7.5 Hz), 1.99 (6H, s), 2.49 (2H, t, J = 7.8 Hz), 2.84 (2H, t , J = 7.8 Hz), 3.19 (2H, q, J = 7.5 Hz), 3.42 (2H, t, J = 5.1 Hz), 4.44 (2H, t, J = 5.1 Hz), 5.08 (2H, s), 6.64 (2H, s), 6.88 (2H, d, J = 8.7 Hz), 7.03-7.14 (3H, m), 7.17 (IH, s), 7.36-7.48 (2H, m).

EXAMPLE 72 3- [4- (. {4 '- [2- (Ethylsulfonyl) ethoxy] -2', 6'-dimethyl-biphenyl-3-yl}. Methoxy) phenyl] propanoic acid To a solution of tert-butyl 3- [4- (. {4 '- [2- (ethylsulfonyl) ethoxy] -2'- 6'-dimethylbiphenyl-3-yl.] Methoxy) -phenyl] propanoate (0.37 g, 0.67 mmol) in toluene (3.7 mL) was added trifluoroacetic acid (3.7 mL) at room temperature with stirring and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the crystals obtained were collected by means of filtration, washed and dried to give the title compound (0.24 g, yield 72%) as colorless crystals. MS (APCI-): 495 (MH) Example 73: 3- [4- (. {2 ', 6' -dimethyl-4 '- [3- (6-methylpyridin-2-yl) propoxy] biphenyl-3 acid -yl.}. methoxy) phenyl] propanoic The title compound was obtained as a pale yellow oil from 3-. { 4- [(4'-Hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) ethoxy] phenyl} methyl propanoate and 3- (6-methylpyridin-2-yl) propan-1-ol according to a method similar to the method of Example 65 (17% yield). MS (APCI-): 508 (M-H) Example 74 3- (4-. {[[4'- (2-ethoxyethoxy) -2 ', 6'-dimethylbiphenyl-3-yl] ethoxy.}. Phenyl) -2,2-di? Uoropropanoate ethyl The title compound was obtained as a colorless oil from ethyl 2, 2-difluoro-3- (4-hydroxyphenyl) -propanoate and [4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl- 3-yl] methanol according to a method similar to the method of Example 1 (51% yield). MS m / z (MH +) EXAMPLE 75 3- (4 { [4 '- (2-Ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy, phenyl) -2,2-difluoropropanoic acid The title compound was obtained as a colorless oil from 3- (4 { [4 '- (2-ethoxyethoxy) -2', 6 '-dimethylbiphenyl-3-yl] methoxy.} Phenyl) - Ethyl 2, 2-difluoropropanoate according to a method similar to the method of Example 2 (79% yield). MS m / z 485 (MH +). XH NMR (CDC13) d: 1.21-1.30 (3H, m), 1.95 (6H, s), 3.25 (2H, t, J = 16.7 Hz), 3.63 (2H, q, J = 7.0 Hz), 3.77-3.85 (2H, m), 4.07-4.19 (2H, m), 5.02 (2H, s), 6.66 (2H, s), 6.87 (2H, d, J = 8.5 Hz), 7.02-7.20 (4H, m), 7.30-7.43 (2H, m).

Example 76 3- (4- {[2 ', 6'-dimethyl-4' - (tetrahydro-2H-thiopyran-4-yloxy) -biphenyl-3-yl] methoxy} phenyl) propanoate methyl The title compound was obtained as a colorless oil from 3-. { 4- [(4'-Hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} Methyl propanoate and tetrahydro-2H-thiopyran-4-ol according to a method similar to the method of Example 1 (12% yield). XH NMR (CDC13) d: 1.98 (6H, s), 1.99-2.11 (2H, m), 2.15-2.27 (2H, m), 2.53-2.65 (4H, m), 2.84-3.01 (4H, m), 3.66 (3H, s), 4.37 (HH, m), 5.08 (2H, s), 6.65 (2H, s), 6.89 (2H, d, J = 8.7 Hz), 7.05-7.14 (3H, m), 7.18 (ÍH, s), 7.35-7.46 (2H, m).

Example 77 3- (4. {[2 ', 6'-dimethyl-4' - (tetrahydro-2H-thiopyran-4-yloxy) biphenyl-3-yl] methoxy} phenyl) propanoic acid The title compound was obtained as colorless crystals from 3- (4. {[2 ', 6'-dimethyl-4' - (tetrahydro-2H-thiopyran-4-yloxy) biphenyl-3-yl] methoxy .) phenyl) methyl propanoate according to a method similar to the method of Example 37 (55% yield). MS (ESI +): 477 (M + H) EXAMPLE 78 3- [4- (. {4 '- [(1, 1-Dioxidotetrahydro-2H-thiopyran-4-yl) oxy] -2', 6'-dimethylbiphenyl-3-yl} methoxy) acid phenyl] propanoic To a solution of 3- (4- { [2 ', 6'-dimethyl-4' - (tetrahydro-2H-thiopyran-4-yloxy) biphenyl-3-yl] methoxy.} Phenyl) -propanoate of methyl (0.11 g, 0.22 mmol) in dichloromethane (2.2 mL) was added m-chloroperbenzoic acid (0.12 g, 0.49 mmol) at 0 ° C with stirring and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was washed with a 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue, methanol (2 L) and tetrahydrofuran (4 mL) was added to an aqueous solution of 1 N sodium hydroxide (0.44 mL) at room temperature with stirring and the mixture was stirred at the same temperature for 2 hours. . The reaction mixture was diluted with ethyl acetate, washed with IN hydrochloric acid and saturated brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = 1 / L) to give the title compound (43 mg, 38% yield ) as colorless crystals. MS (ESI +): 509 (M + H).

Example 79 3- [4- (. {2 ', 6' -dimethyl-4 '- [3- (6-methylpyridin-2-yl) propoxy] biphenyl-3-yl} methoxy) phenyl hydrochloride ] -propanoic acid To a solution of 3- [4- (. {2 ', 6' -dimethyl-4 '- [3- (6-methylpyridin-2-yl) propoxy] biphenyl-3-yl} methoxy) phenyl ] -propanoic acid (55 mg, 0.11 mmol) in ethyl acetate (2.2 mL) was added a solution of 4 N hydrogen chloride-ethyl acetate (81 μL, 0.32 mmol) and the mixture was concentrated under reduced pressure. The obtained crystals were collected by filtration, washed and dried to give the title compound (42 mg, 71% yield) as colorless crystals. MS (ESI +): 510 (M + H, as a free form) Example 80 3- [4- (. {2 ', 6' -dimethyl-4 '- [(6-methylpyridin-2-yl) hydrochloride ) methoxy] biphenyl-3-yl.} methoxy) phenyl] propanoic To a solution of 3-. { 4- [(4'-Hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} Methyl propanoate (0.40 g, 1.03 mmol), (6-methylpyridin-2-yl) methanol (0.14 g, 1.13 mmol) and triphenylphosphine (0.34 g, 1.31 mmol) in tetrahydrofuran (8.0 mL) were added di-diisopropyl azodicarboxylate ( solution in toluene 40%, 0.59 mL, 1.13 mmol) at room temperature with stirring. The reaction mixture was stirred at room temperature for 12 hours and an equivalent amount of the reagents mentioned above ((6-methylpiperidin-2-yl) methanol, triphenylphosphine and diisopropyl azodicarboxylate) was added and the mixture was further stirred thereto. temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = 1 / l) to give an oil colorless. Then, to a mixture of the oil, methanol (4 mL) and tetrahydrofuran (8 mL) was added an aqueous solution of 1 N sodium hydroxide (2.1 mL) at room temperature with stirring and the mixture was stirred at the same temperature for 2 hours. hours. The reaction mixture was neutralized with 2 N hydrochloric acid, diluted with ethyl acetate, washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = 1/4) -to give a colorless oil. The oil was dissolved in ethyl acetate and a solution of 4 N hydrogen chloride-ethyl acetate was added. The mixture was concentrated under reduced pressure. The obtained crystals were collected by filtration, washed and dried to give the title compound (0.24 g, 44% yield) as colorless crystals. MS (APCI-): 480 (M-H, as a free form) Example 81 3- [4- (. {2 ', 6'-dimethyl-4' - [2- (6-methylpyridin-2-yl) ethoxy] biphenyl-3-yl} methoxy) phenyl hydrochloride propanoic The title compound was obtained as colorless crystals from methyl 3- [4- [(4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) ethoxy]] phenyl] propanoate and 2- (6 -methylpyridin-2-yl) ethanol according to a method similar to the method of Example 80 (26% yield). MS (APCI-): 494 (M-H, as a free form) Example 82 3-. { 4 - [(2 ', 6'-dimethyl-4'-nitrobiphenyl-3-yl) methoxy] -2-fluorophenyl} ethyl propanoate The title compound was obtained as a pale yellow oil from (2 ', 6'-dimethyl-4'-nitrophenyl-3-yl) methanol and the 3- (2-fluoro-4-hydroxyphenyl) propanoate of ethyl according to a method similar to the method of Example 1 (97% yield). MS (ESI +): 452 (M + H) Example 83 3- acid. { 4- [(2 ', 6'-dimethyl-4'-nitrobiphenyl-3-yl) methoxy] -2-fluorophenyl} propanoic The title compound was obtained as colorless crystals from 3-. { 4- [(2 ', 6'-dimethyl-4'-nitrobiphenyl-3-yl) methoxy] -2-fluorophenyl} ethyl propanoate according to a method similar to the method of Example 37 (yield 84). EM (APCI-) 422 (M-H) EXAMPLE 84 Ethyl 3- [4- ( { 4'- [2- (ethylthio) ethoxy] -2 ', 6'-dimethylbiphenyl-3-yl.} Methoxy) -2-fluorophenyl] propanoate The title compound was obtained as a colorless oil from 3-. { 2-fluoro-4- [(4 '-hydroxy-2', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate and 2- (ethylthio) ethanol according to a method similar to the method of Example 70 (79% yield). XH NMR (CDC13) d: 1.23 (3H, t, J = 7.2 Hz), 1.31 (3H, t, J = 7.5 Hz), 1.98 (6H, s), 2.57 (2H, t, J = 7.8 Hz), 2.67 (2H, q, J = 7.5 Hz), 2.86-2.96 (4H, m), 4.07-4.19 (4H, m), 5.06 (2H, s), 6. 62-6.71 (4H, m), 7.04-7.13 (2H, m), 7.16 (ÍH, s), 7.33-7.47 (2H, m).

EXAMPLE 85 Ethyl 3- [4- (. {4 '- [2- (ethylsulfonyl) ethoxy] -2', 6'-dimethylbiphenyl-3-yl.} Methoxy) -2-fluorophenyl] propanoate The title compound was obtained as a colorless oil from 3- [4- (. {4 '- [2- (ethylthio) ethoxy] -2', 6'-dimethylbiphenyl-3-yl.} Methoxy) Ethyl 2-fluorophenyl] propanoate according to a method similar to the method of Example 71 (89% yield). MS (ESI +): 543 (M + H) EXAMPLE 86 3- [4- (. {4 '- [2- (Ethylsulfonyl) ethoxy] -2', 6'-dimethylbiphenyl-3-yl}. Methoxy) -2-fluorophenyl] propanoic acid A mixture of ethyl 3- [4- (. {4 '- [2- (ethylsulfonyl) ethoxy] -2', 6'-dimethylphenyl-3-yl.} Methoxy) -2-fluorophenyl] propanoate (0.19) g, 0.35 mmol), acetic acid (4.5 mL), water (4.0 mL) and concentrated sulfuric acid (0.65 mL) was stirred at 90 ° C for 4 hours. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 4 / l-ethyl acetate) to give the title compound (0.12 g, 61% yield) as colorless crystals. MS (APCI-): 513 (M-H). p.f. : 126-127 ° C.

EXAMPLE 87 Ethyl 3- [4- (. {4 '- [2- (diethylamino) ethoxy] -2', 6'-dimethylbiphenyl-3-yl.} Methoxy) -2-fluorophenyl] propanoate The title compound was obtained as a colorless oil from 3-. { 2-fluoro-4- [(4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate and 2- (diethylamino) ethanol according to a method similar to the method of Example 70 (100% yield). MS (ESI +): 522 (M + H) Example 88 3- [4- (. {4 '- [2 - (diethylamino) ethoxy] -2', 6'-dimethylbifenyl-3-yl hydrochloride .}. methoxy) -2 -f luorofenyl] propanoic TO . a solution of 3- [4- [. { 4 '- [2- (diethylamino) ethoxy] -2', 6'-dimethylbiphenyl-3-yl) methoxy) -2-fluorophenyl] propanoate ethyl (0.62 g, 1.18 mmol), methanol (5 mL) and tetrahydrofuran ( 10 mL) was added an aqueous solution of 1 N sodium hydroxide (2.4 mL) at room temperature with stirring and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was neutralized with 1N hydrochloric acid, diluted with ethyl acetate, washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to provide a colorless oil. The oil was dissolved in ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and a solution of 4 N hydrogen chloride-ethyl acetate was added. The precipitated crystals were collected by filtration, washed and dried to give the title compound (0.20 g, 32%) as colorless crystals. MS (ESI +): 494 (M + H, as a free form) EXAMPLE 89 3- [4- ( {2 ', 6'-dimethyl-4'- [3- (2-oxopyrrolidin-1-yl) propoxy] -biphenyl-3-yl.} Methoxy) -2- fluorophenyl] ethyl propanoate The title compound was obtained as a colorless oil from 3-. { 2-fluoro-4- [(4 '-hydroxy-2', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate and 1- (3-hydroxypropyl) pyrrolidin-2 -one according to a method similar to the method of Example 1 (67% yield). MS (ESI +): 548 (M + H) Example 90: 3- [4- (. {2 ', 6'-dimethyl-4' - [3- (2-oxopyrrolidin-1-yl) propoxy] biphenyl-3-yl} methoxy) -2- fluorophenyl] propanoic The title compound was obtained as colorless crystals from 3- [4- (. {2 ', 6' -dimethyl-4 '- [3- (2-oxopyrrolidin-1-yl) propoxy] biphenyl -3- ethyl .alpha.-methoxy) -2-fluorophenyl] propanoate according to a method similar to the method of Example 37 (64% yield). This compound was purified by means of preparative HPLC (gradient cycle A). MS (ESI +): 520 (M + H) m.p .: 139 ~ 140 ° C.

EXAMPLE 91 Ethyl 3- (2-fluoro-4-. {[4 '- (methoxymethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy} phenyl) propanoate The title compound was obtained as a colorless oil from [4 '- (methoxymethoxy) -2', 6'-dimethylbiphenyl-3-yl] methanol and ethyl 3- (2-fluoro-4-hydroxyphenyl) propanoate according to a method similar to the method of Example 1 (82% yield). XH NMR (CDC13) d: 1.23 (3H, t, J = 7.2Hz), 1.99 (6H, s), 2.57 (2H, t, J = 7.6Hz), 2.90 (2H, t, J = 7.6Hz), 3.51 (3H, s), 4.12 (2H, q, J = 7.2Hz), 5.06 (2H, s), 5.19 (2H, s), 6.60-6.75 (2H, m), 6.80 (2H, s), 7.02 -7.50 (5H, m).

EXAMPLE 92 3- (2-Fluoro-4- { [4 '- (methoxymethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy.} Phenyl) propanoic acid The title compound was obtained as colorless, needle-like crystals from 3- (2-fluoro-4- { [4 '- (methoxymethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy] phenyl) -propanoate according to a method similar to the method of Example 2 (88% yield). MS m / z 437 (MH +) EXAMPLE 93 Ethyl 3- [4- (. {4 '- [2- (ethylamino) ethoxy] -2', 6'-dimethylbiphenyl-3-yl} methoxy) -2-fluorophenyl] propanoate To a solution of 3-. { 2-fluoro-4 '- [(4' -hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} Ethyl propanoate (0.50 g, 1.18 mmol), 2-ethylaminoethanol (0.10 mL, 1.30 mmol) and tributylphosphine (0.44 mL, 1.78 mmol) in tetrahydrofuran (10 mL) were added with 1,1 '- (azodicarbonyl) dipiperidine (0.45 g). g, 1.78 mmol) at room temperature with stirring. The reaction mixture was stirred at room temperature for 16 hours. An equivalent amount of the reagents mentioned above (2-ethylaminoethanol, tributylphosphine and 1,1 '- (azodicarbonyl) dipiperidine) was added and the mixture was further stirred at the same temperature for 16 hours. Diethyl ether was added to the reaction mixture and the insoluble material was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (gradient cycle A) to provide a colorless oil. The obtained oil was dissolved in ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate, washed with water and saturated brine, dried and concentrated under reduced pressure to give the title compound (0.52 g, yield 58 g. %) as a colorless oil. MS (ESI +): 494 (M + H) Example 94 3-. { 4 - [(4'-. {2- [acetyl (ethyl) amino] ethoxy] -2 ', 6'-dimethylbiphenyl-3-yl) methoxy] -2-fluorophenyl} ethyl propanoate A mixture of 3- [4- (. {4 '- [2- (ethylamino) ethoxy] -2', 6'-dimethylbiphenyl-3-yl)} ethyl methoxy) -2-fluorophenyl] propanoate (0.27 g, 0.55 mmol), 4-dimethylaminopyridine (7 m, 55 μmol), acetic anhydride (0.10 mL, 1.09 mmol) and pyridine (5.4 L) was stirred at room temperature 62 hours The reaction mixture was concentrated and the residue was purified by means of silica gel column chromatography. (hexane / ethyl acetate = 9 μl-ethyl acetate) to give the title compound (0.25 g, yield of 85%) as a colorless oil. MS (ESI +): 536 (M + H) EXAMPLE 95 3- acid. { 4- [(4'-. {2- [acetyl (ethyl) amino] ethoxy] -2 ', 6'-dimethylbiphenyl-3-yl) ethoxy] -2-fluorophenyl} propanoic The title compound was obtained as colorless crystals from 3-. { 4- [(4 '-. {2- [acetyl (ethyl) amino] -ethoxy} -2', 6'-dimethylbiphenyl-3-yl) methoxy] -2-fluorophenyl} ethylpropanoate according to a method similar to the method of Example 37 (51% yield). MS (ESI +): 508 (M + H) Example 96 3- [4- (. {2 ', 6' -dimethyl-4 '- [(6-methylpyridin-2-yl) methoxy] biphenyl-3-yl} methoxy) -2-fluorophenyl] propanoate of ethyl To a solution of 3-. { 2-fluoro-4- [(4 '-hydroxy-2', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} Ethyl propanoate (1.2 g, 2.84 mmol), (6-methylpyridin-2-yl) methanol (0.39 g, 3.12 mmol) and triphenylphosphine (0.95 g, 3.61 mmol) in tetrahydrofuran (24 mL) were added diisopropyl azodicarboxylate (solution in toluene 40%, 1.54 mL, 3.12 mmol) at room temperature with stirring. The reaction mixture was stirred at room temperature for 12 hours and an equivalent amount of the reagents mentioned above ((6-methylpyridin-2-yl) methanol, triphenylphosphine and diisopropyl azodicarboxylate) was added. The mixture was further stirred at the same temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = 1 / l) to provide the compound of the title (1.3 g, 87% yield) as a colorless oil. MS (ESI +): 528 (M + H) Example 97 3- [4- (. {2 ', 6' -dimethyl-4 '- [(6-methylpyridin-2-yl) methoxy] biphenyl-3-yl} methoxy acid hydrochloride) -2- fluorophenyl] -propanoic acid To a mixture of 3- [4- (. {2 ', 6' -dimethyl-4 '- [(6-methylpyridin-2-yl) methoxy] biphenyl-3-yl} methoxy) -2-fluorophenyl ] -propanoate ethyl (1.30 g, 2.46 mmol), methanol (6 mL) and tetrahydrofuran (10 mL) was added an aqueous solution of 1 N sodium hydroxide (4.9 mL) at room temperature with stirring and the mixture was stirred at room temperature. the same temperature for 2 hours. The reaction mixture was neutralized with 1N hydrochloric acid, diluted with ethyl acetate, washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 4 / l-hexane / ethyl acetate) to give an oil. The oil was dissolved in ethyl acetate and a solution of 4 N hydrogen chloride-ethyl acetate was added. The precipitated crystals were collected by filtration, washed and dried to provide the title compound (1.14 g, 86% yield) as colorless crystals. MS (ESI +): 500 (M + H, as a free form), m.p .: 55-56 ° C.

EXAMPLE 98 3- [2-Fluoro-4- ( { 4 '- [(4-hydroxytetrahydro-2H-thiopyran-4-yl) methoxy] -2', 6'-dimethylbiphenyl-3-yl.} Methoxy ethyl phenyl] propanoate To a solution of 4- ( { [3 '- (hydroxymethyl) -2,6-dimethylbiphenyl-4-yl] oxy} methyl) tetrahydro-2H-thiopyran-4-ol (0.90 g, 2.51 mmol) , Ethyl 3- (2-fluoro-4-hydroxyphenyl) propanoate (0.56 g, 2.64 mmol) and tributylphosphine (0.86 mL, 3.26 mmol) in tetrahydrofuran (20 mL) were added. 1,1 '- (azodicarbonyl) dipiperidine (0.85 g.) g, 3.26 mmol) at room temperature with stirring and the mixture was stirred for 10 hours. The resulting precipitated product was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = 2/1) to give the title compound (1.24 g, 89% yield ) as a colorless oil. XH NMR (CDC13) d: 1.23 (3H, t, J = 7.2 Hz), 1.75-1.90 (2H, m), 1.99 (6H, s), 2.05-2.16 (2H, m, J = 13.9 Hz), 2.19 (ÍH, s), 2.39-2.52 (2H, m), 2.57 (2H, t, J = 7.6 Hz), 2.89 (2H, t, J = 7.6 Hz), 3.03-3.19 (2H, m), 3.79 ( 2H, s), 4.12 (2H, q, J = 7.2 Hz), 5.06 (2H, s), 6.60-6.73 (4H, m), 7.01-7.19 (3H, m), 7.33-7.48 (2H, m) .

Example 99 3- [2-fluoro-4- (. {4 '- [(4-hydroxy-l, l-dioxidotetrahydro-2H-thiopyran-4-yl) methoxy] -2', 6'-dimethylbiphenyl-3 ethyl) ethyl] propane (ethyl) -yl) -methoxy) -phenyl] propanoate The title compound was obtained as colorless crystals from 3- [2-fluoro-4- (. {4 '- [(4-hydroxytetrahydro-2H-thiopyran-4-yl) methoxy] -2', 6 ' ethyl -dimethylbiphenyl-3-yl.} methoxy) phenyl] propanoate according to a method similar to the method of Example 71 (72% yield). MS m / z 585 (MH +) EXAMPLE 100 3- [2-Fluoro-4- (. {4 '- [(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl) methoxy] -2', 6'-dimethylbiphenyl- acid 3-yl.}. Methoxy) -phenyl] propanoic The title compound was obtained as colorless crystals from 3- [2-fluoro-4- (. {4 '- [(4-hydroxy-1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) methoxy] Ethyl 2 ', 6' -dimethylbiphenyl-3-yl.}. Methoxy) phenyl] propanoate according to a method similar to the method of Example 37 (78% yield). MS m / z 557 (MH +). p.f. : 198-199 ° C.

EXAMPLE 101 Ethyl 3- [4- (. {2 ', 6' -dimethyl-4 '- [(methylsulfonyl) oxy] biphenyl-3-yl} methoxy) -2-fluorophenyl] propanoate To an iced solution of 3-. { 2-fluoro-4- [(4 '-hydroxy-2', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} Ethyl propanoate (310 mg, 0.736 mmol) in pyridine (8 mL) was added dropwise to methanesulfonyl chloride (168 mg, 1.47 mmol). The mixture was stirred at room temperature for 2 days. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate = 10 / l-l / l) to give the title compound (320 mg, 87% yield) as a colorless oil. MS m / z 501 (MH +) Example 102 3- [4- (. {2 ', 6' -dimethyl-4 '- [(methylsulfonyl) oxy] biphenyl-3-yl.} Methoxy) -2-fluorophenyl] propanoic acid The title compound was obtained as a colorless oil from 3- [4- (. {2 ', 6' -dimethyl-4 '- [(methylsulfonyl) oxy] biphenyl-3-yl} methoxy) - Ethyl 2-fluorophenyl] -propanoate according to a method similar to the method of Example 2 (61% yield). MS m / z 473 (MH +). p.f. : 124-125 ° C.

EXAMPLE 103 Ethyl 3- [4- (. {2 ', 6' -dimethyl-4 '- [(3-thienylsulfonyl) oxy] biphenyl-3-yl} methoxy) -2-fluorophenyl] propanoate The title compound was obtained as a colorless oil from 3-. { 2-fluoro-4- [(4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate and 3-thiophenesulfonyl chloride according to a method similar to the method of Example 101 (57% yield). MS m / z 569 (MH +) EXAMPLE 104 3- [4- (. {2 ', 6'-dimethyl-4' - [(3-thienylsulfonyl) oxy] biphenyl-3-yl.} Methoxy) -2-fluorophenyl] propanoic acid The title compound was obtained as colorless crystals from 3- [4- (. {2 ', 6' -dimethyl-4 '- [(3-thienylsulfonyl) oxy] biphenyl-3-yl} methoxy) -2-fluorophenyl] ethyl propanoate according to a method similar to the method of Example 2 (44% yield). MS m / z 541 (MH +) EXAMPLE 105 Ethyl 3- (4-. {[4 '- (2-ethoxyethoxy) -6-methoxy-2', 6'-dimethylbiphenyl-3-yl] methoxy} -2-fluorophenyl) propanoate The title compound was obtained as a pale yellow oil from ethyl 3- (2-fluoro-4-hydroxyphenyl) propanoate and [4 '- (2-ethoxyethoxy) -6-methoxy-2', 6 '-dimethylbiphenyl-3-yl] methanol according to a method similar to the method of Example 1 (88% yield). MS (ESI +): 525 (M + H) Example 106 3- (4 { [4 '- (2-ethoxyethoxy) -6-methoxy-2', 6'-dimethylbiphenyl-3-yl] methoxy acid} -2-fluorophenyl) propanoic To a mixture of ethyl 3- (4-. {[4 '- (2-ethoxyethoxy) -6-methoxy-2', 6'-dimethylbiphenyl-3-yl] methoxy] -2-fluorophenyl) propanoate (0.45 g, 0.86 mmol), methanol (4.5 mL) and tetrahydrofuran (9 mL) were added an aqueous solution of 1 N sodium hydroxide (1.7 mL) at room temperature with stirring and the mixture was stirred at the same temperature for 2 hours. hours. The reaction mixture was neutralized with 1 N hydrochloric acid and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate = 2/1-hexane / ethyl acetate = 1/2) to give the title compound (85 mg, 20% yield). ) as a colorless oil. MS (ESI +): 497 (M + H) Example 107 (2S) -2-. { [(3 '- { [4- (3-ethoxy-3-oxopropyl) -3-fluorophenoxy] methyl] -2-, 6-dimethylbiphenyl-4-yl) oxy] methyl} tert-butyl pyrrolidin-l-carboxylate The title compound was obtained as a colorless oil from 3-. { 2-fluoro-4- [(4 '-hydroxy-2', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate and (2S) -2- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester according to a method similar to the method of Example 1 (8.6% yield). XH NMR (CDC13) d: 1.23 (3H, t, J = 7.4Hz), 1.48 (9H, s), 1.70-2.10 (4H, m), 1.98 (6H, s), 2.57 (2H, t, J = 7.6Hz), 2.90 (2H, t, J = 7.6Hz), 3.30-3.50 (3H, m), 4.11 (2H, q, J = 7.4Hz), 4.00-4.24 (2H, m), 5.06 (2H, s), 6.60-6.72 (4H, m ), 7.04-7.48 (5H, m).

Example 108 3- acid. { 4- [(4 '- { [(2S) -1- (tert-butoxycarbonyl) pyrrolidin-2-yl] methoxy] -2', 6 '-dimethylbiphenyl-3-yl) methoxy] -2- fluorophenyl} -propanoic The title compound was obtained as a colorless solid from (2S) -2-. { [(3 '- { [4- (3-ethoxy-3-oxopropyl) -3-fluorophenoxy] methyl] -2-, 6-dimethylbiphenyl-4-yl) oxy] methyl} pyrrolidin-1-tert-butyl carboxylate according to a method similar to the method of Example 2 (61% yield). ? M (APCI-): 576 (M-H) Example 109 3- [4- (. {2 ', 6' -dimethyl-4 '- [(6-methylpyridin-2-yl) oxy] biphenyl-3-yl} methoxy) -2-fluorophenyl] propanoate of ethyl The title compound was obtained as a colorless oil from ethyl 3- (2-fluoro-4-hydroxyphenyl) propanoate and. { 2 ', 6'-dimethyl-4' - [(6-methylpyridin-2-yl) oxy] biphenyl-3-yl} methanol according to a method similar to the method of Example 1 (94% yield). MS (ESI +): 514 (M + H) EXAMPLE 110 3- [4- (. {2 ', 6' -dimethyl-4 '- [(6-methylpyridin-2-yl) oxy] biphenyl-3-yl.} Methoxy) -2-fluorophenyl] acid] propanoic The title compound was obtained as a colorless oil from 3- [4- (. {2 ', 6' -dimethyl-4 '- [(6-methylpyridin-2-yl) oxy] biphenyl-3-yl. .) ethyl methoxy) -2-fluorophenyl] propanoate according to a method similar to the method of Example 106 (62% yield). MS (ESI +): 486 (M + H) Example 111 3- [4- (. {2 ', 6' -dimethyl-4 '- [(6-methylpyridin-2-yl) oxy] biphenyl-3-yl.} Methoxy) hydrochloride) -2- fluorophenyl] -propanoic acid The title compound was obtained as colorless crystals from 3- [4- (. {2 ', 6' -dimethyl-4 '- [(6-methylpyridin-2-yl) oxy] biphenyl-3-yl} .) methoxy) -2-fluorophenyl] propanoic according to a method similar to the method of Example 79 (83% yield). MS (ESI +): 486 (M + H, as a free form) EXAMPLE 112 Ethyl 3- (4-. {[2 X 6 '-dimethyl-4'- (tetrahydro-2H-thiopyran-4-yloxy) biphenyl-3-yl] methoxy) -2-fluorophenyl) propanoate To a solution of 3-. { Ethyl 2-fluoro-4- [(4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenylpropanoate (0.50 g, 1.18 mmol), tetrahydro-2H-thiopyran-4-ol (0.15 g) , 1.30 mmol) and triphenylphosphine (0.31 g, 1.30 mmol) in tetrahydrofuran (10 mL) was added diethyl azodicarboxylate (40% toluene solution, 0.70 mL, 1.53 mmol) at room temperature with stirring. The reaction mixture was stirred at room temperature for 19 hours and an equivalent amount of the reagents mentioned above (tetrahydro-2H-thiopyran-4-ol, triphenylphosphine and diethylazodicarboxylate) was added. The mixture was further stirred at the same temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by means of silica gel column chromatography (hexane / ethyl acetate = 10 / l-hexane / ethyl acetate = 3 / l) to give the compound of the title (0.53 g, 91% yield) as a yellow oil. XH NMR (CDC13) d: 1.23 (3H, t, J = 7.1 Hz), 1.98 (6H, s), 1.99-2.11 (2H, m), 2.16-2.27 (2H, m), 2.53-2.64 (4H, m), 2.85-3.01 (4H, m), 4.07-4.17 (2H, m), 4.32-4.42 (1H, m), 5.06 (2H, s), 6.62-6.71 (4H, m), 7.05-7.12 ( 2H, m), 7.17 (1H, s), 7.34-7.46 (2H, m).

Example 113 3- [4- (. {4 '- [(1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) oxy] -2', 6'-dimethylbiphenyl-3-yl} methoxy) - Ethyl 2-fluorophenyl] propanoate The title compound was obtained as a pale yellow oil from 3- (4 { [2 ', 6'-dimethyl-4' - (tetrahydro-2H-thiopyran-4-yloxy) biphenyl-3 ethyl] -methoxy] -2-fluorophenyl) propanoate according to a method similar to the method of Example 71, except for the use of ethyl acetate in place of dichloromethane (45% yield). MS (ESI +): 555 (M + H) EXAMPLE 114 3- [4- (. {4'- [(1, 1-Dioxidotetrahydro-2H-thiopyran-4-yl) oxy] 2 ', 6'-dimethylbiphenyl-3-yl.} Methoxy) acid 2-fluorophenyl] -propanoic acid The title compound was obtained as colorless crystals from 3- [4- (. {4 '- [(1, l-dioxidotetrahydro-2H-thiopyran-4-yl) oxy] -2', 6'-dimethylbiphenyl -3-yl.}. Methoxy) -2-fluorophenyl] propanoate according to a method similar to the method of Example 37 (68% yield). MS (ESI +): 527 (M + H). p.f. : 148-149 ° C.

Example 115 3- [4 - (. {2 ', 6' -dimethyl-4 '- [(3-methyl-oethan-3-yl) methoxy] biphenyl-3-yl} methoxy) -2-fluorophenyl] propanoate of ethyl The title compound was obtained as a colorless oil from 3-. { 2-fluoro-4- [(4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate and 3-methyl-3-oxetanemethanol according to a method similar to the method of Example 70 (92% yield). MS (ESI +): 507 (M + H) Example 116 3- [4- (. {2 ', 6' -dimethyl-4 '- [(3-methyloxetan-3-yl) methoxy] -biphenyl-3-yl} methoxy) -2-fluorophenyl acid propanoic The title compound was obtained as colorless crystals from 3- [4- (. {2 ', 6' -dimethyl-4 '- [(3-methyloxetan-3-yl) methoxy] biphenyl-3-ylmethoxy) -2-fluorophenyl] ethyl propanoate according to a method similar to the method of Example 37 (67% yield). MS (ESI +): 479 (M + H). p.f. : 112-113 ° C.

EXAMPLE 117 3- (4- { [2 ', 6'-dimethyl-4' - (tetrahydro-2H-pyran-4-yloxy) biphenyl-3-yl] methoxy} -2-fluorophenyl) propanoate ethyl The title compound was obtained as a colorless oil from 3-. { 2-fluoro-4- [(4 '-hydroxy-2', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate and tetrahydro-2H-pyran-4-ol according to a method similar to the method of Example 112 (97% yield). MS (ESI +): 507 (M + H).

EXAMPLE 118 3- (4. {[2 ', 6'-dimethyl-4' - (tetrahydro-2H-pyran-4-yloxy) biphenyl-3-yl] methoxy} -2-fluorophenyl) propanoic acid The title compound was obtained as colorless crystals from 3- (4 { [2 ', 6'-dimethyl-4' - (tetrahydro-2H-pyran-4-yloxy) biphenyl-3-yl] methoxy .) -2. Fluorophenyl) -propanoate according to a method similar to the method of Example 37 (47% yield). MS (ESI +): 479 (M + H). p.f .: 123 ° C.

EXAMPLE 119 3- (4. {[2 ', 6'-dimethyl-4' - (tetrahydro-2H-thiopyran-4-yloxy) biphenyl-3-yl] methoxy} -2-fluorophenyl) propanoic acid The title compound was obtained as colorless crystals from 3- (4- {[2 ', 6' -dimethyl-4 '- (tetra idro-2H-thiopyran-4-yloxy) biphenyl-3-yl] ethyl methoxy.] -2-fluorophenyl) -propanoate according to a method similar to the method of Example 37 (49% yield). MS m / z 495 (MH +) EXAMPLE 120 Ethyl 3- [4- (. {4 '- [3- (diethoxyphosphoryl) propoxy] -2', 6'-dimethylbiphenyl-3-yl}. Methoxy) -2-fluorophenyl] propanoate To a solution of 3-. { 2-fluoro-4- [(4'-hydroxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate (315 mg, 0.74 mmol) in N, N-dimethylformamide (4 mL) was added sodium hydride (60%, 31 mg, 0.78 mmol) at 0 ° C with stirring and the mixture was stirred at room temperature for 30 minutes. Diethyl (3-bromopropyl) phosphonate (578 mg, 2.23 mmol) and potassium iodide (37 mg, 0. 22 mmol) and the mixture was further stirred overnight at 60 ° C. The reaction mixture was concentrated under reduced pressure. Brine was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by means of column chromatography on silica gel (hexane / ethyl acetate = 10 / l-l / 4) and then by means of preparative HPLC (gradient cycle A) to provide the title compound (0.22 g, 50% yield) as a colorless oil.

MS m / z 601 (MH +) Example 121 3- [4- (. {4 '- [3- (diethoxyphosphoryl) propoxy] -2', 6'-dimethylbiphenyl-3-yl} methoxy) -2-fluorophenyl] propanoic acid The title compound was obtained as a colorless oil from 3- [4- (. {4 '- [3- (diethoxyphosphoryl) propoxy] -2', 6'-dimethylbiphenyl-3-yl.} Methoxy) -2-fluorophenyl] ethyl propanoate according to a method similar to the method of Example 37 (64% yield). MS m / z 573 (MH +). XH NMR (CDC13) d: 1.33 (6H, t, J = 7.1Hz), 1.85-2.19 (10H, m), 2.62 (2H, t, J = 7.6Hz), 2.90 (2H, t, J = 7.6Hz) ), 4.03 (2H, t, J = 6.1Hz), 4.06-4.22 (4H,), 5.06 (2H, s), 6.60-6.72 (4H,), 7.03-7.18 (3H, m), 7.32-7.47 ( 2H,).

Example 122 3-. { 4 - [(4'-. {[[Tert -butyl (dimethyl) silyl] oxy} - 6-isopropoxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] -2-fluorophenyl} ethyl propanoate The title compound was obtained as a colorless oil from (4 '- { [Tert -butyl (dimethyl) silyl] oxy] -6-isopropoxy-2', 6'-dimethylbif nil-3-yl. ) methanol and ethyl 3- (2-fluoro-4-hydroxyphenyl) propanoate according to a method similar to the method of Example 1 (87% yield). XH NMR (CDCl3) d: 0.22 (6H, s), 1.00 (9H, s), 1.11 (6H, .d, J = 6.0Hz), 1.23 (3H, t, J = 7.2Hz), 1.94 (6H, s), 2.57 (2H, t, J = 7.6Hz), 2.89 (2H, t, J = 7.6Hz), 4.12 (2H, q, J = 7.2Hz), 4.21-4.34 (ÍH, m), 4.96 ( 2H, s), 6.56 (2H, s), 6.61-6.72 (2H, m), 6. 96 (1H, d, J = 8.5Hz), 7.04-7.13 (2H, m), 7.31 (1H, dd, J = 8.4, 2.4Hz).Example 123 3-. { 2 ~ fluoro-4- [(4'-hydroxy-6-isopropoxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate The title compound was obtained as a colorless oil from 3-. { 4- [(4 '-. {[[Tert -butyl (dimethyl) -silyl] oxy} - 6-isopropoxy-2', 6'-dimethylbiphenyl-3-yl) methoxy] -2-fluorophenyl} ethyl propanoate according to a method similar to the method of Example 57 (80% yield). MS m / z 481 (MH +) Example 124 3- [2-Fluoro-4- (. {6-isopropoxy-2 ', 6'-dimethyl-4' - [(3-methyloxetan-3-yl) methoxy] biphenyl-3-yl}. ethyl methoxy) phenyl] propanoate The title compound was obtained as a colorless oil from 3-. { 2-fluoro-4- [(4'-hydroxy-6-isopropoxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] phenyl} ethyl propanoate and 3-methyl-3-oxetanemethanol according to a method similar to the method of Example 70 (72% yield). MS m / z 565 (MH +) EXAMPLE 125 3- [2-Fluoro-4- (. {6-isopropoxy-2 ', 6'-dimethyl-4' - [(3-methyloxetan-3-yl) methoxy] biphenyl-3-yl} acid. methoxy) phenyl] propanoic The title compound was obtained as an amorphous, colorless powder from 3- [2-fluoro-4- (. {6-isopropoxy-2 ', 6'-dimethyl-4' - [(3-methyl-oethane-3) ethyl ethyl-methoxy] biphenyl-3-yl} methoxy) phenyl] propanoate according to a method similar to the method of Example 37 (87% yield). MS m / z 537 (MH +). XH NMR (CDC13) d: 1.15 (6H, d, J = 6.0Hz), 1.45 (3H, s), 1.98 (6H, s), 2.64 (2H, t, J = 7.7Hz), 2.90 (2H, t , J = 7.6Hz), 4.04 (2H, s), 4.31-4.41 (HH, m), 4.47 (2H, d, J = 5.8Hz), 4.66 (2H, d, J = 5.8Hz), 4.96 (2H) , s), 6.61-6.72 (4H, m), 6. 96 (HH, d, J = 8.5Hz), 7.03-7.14 (2H, m), 7.32 (HH, dd, J = 8.5, 2.3Hz).

Formulation Example 1 (production of a capsule) 1) the compound of Example 1 30 mg 2) microcrystalline cellulose 10 mg 3) lactose 19 mg 4) magnesium stearate 1 mg total 60 mg Elements 1), 2), 3) and 4) mentioned above are mixed and poured into a gelatin capsule.

Formulation Example 2 (production of a tablet) 1) the compound of Example 1 30 g 2) lactose 50 g 3) corn starch 15 g 4) calcium carboxymethyl cellulose 44 g 5) magnesium stearate 1 g For a total of 1000 tablets 140 g The total amount of elements 1), 2) and 3) mentioned above and 30 g of element 4) are kneaded with water, dried under vacuum and granules. The granulated powder is mixed with 14 g of the element 4) and 1 g of the element 5) and tablets are formed with a machine for making tablets. In this way, 1000 tablets containing 30 mg of the compound of Example 1 are obtained per tablet.

EXPERIMENTAL EXAMPLE 1 Determination of the EC50 value of the compound of the present invention against human GPR40 For the determination of the EC50 value, the CHO cell line stably expressing human GPR40 was used. Unless indicated otherwise, the CHO cell line was cultured using a-MEM medium (Invitrogen) containing 10% fetal bovine serum (Invitrogen). Cells grown near confluence were rinsed with PBS (Invitrogen) the day before the assay, detached with 0.05% Trypsin solution - EDTA (Invitrogen) and recovered by means of centrifugation.

The number of cells obtained was counted and the cells were diluted in such a way that 1 mL of the medium contained 3xl05 cells, were supplied to a 96-well plate of black walls (coster) at 100 μL per well and were cultured throughout the night in a C02 incubator. Several test compounds were added to the CHO cells prepared in this manner and changes in intracellular calcium concentration were measured using a FLIPR (Molecular Device) device. The aforementioned pre-treatment was applied to measure changes in intracellular calcium concentration by means of the FLIPR device. A test buffer was prepared to add a Fluo3-AM fluorescent dye (DOJIN) to the cells or to wash the cells immediately before the FLIPR assay. To a solution of 1 M HEPES (pH 7.4, DOJIN, 20 mL) added to HBSS (Invitrogen, 1000 mL) (later the HBSS / HEPES solution) was added a solution (10 mL) obtained by dissolving probenecid1 (Sigma, 710 mg) in 1 N NaOH (5 mL ) and add and mix a solution of HBSS / HEPES (5 mL) and the resulting solution was used as a test buffer. The Fluo3-AM dye (50 μg) was dissolved in dimethyl sulfoxide (Wako, 21 μL) and an equivalent amount of 20% pluronic acid (Molecular Probes) was added and mixed. The solution was added to the assay buffer (10.6 mL) supplemented with fetal bovine serum (105 μL) to provide a fluorescent dye solution. On the day prior to the assay, the medium from the CHO cells recently inoculated to the 96-well black-walled plate was removed, the fluorescent dye solution was immediately delivered at 100 μL per well and the cells were cultured in a C02 for 1 hour to allow uptake of the fluorescent dye by the cells. The cells after the culture were washed with the assay buffer mentioned above and settled on the FLIPR. The test compound was diluted with dimethyl sulfoxide in advance, supplied to the 96-well plate of polypropylene (sample plate) for 2 μL and cooled to -20 ° C. To the thawed sample plate was added an assay buffer containing 0.015% CHAPS (DOJIN) per 198 μL and was simultaneously established on the FLIPR together with the cell plate. After the pre-treatment mentioned above, changes in intracellular calcium concentration with the addition of several test compounds were measured by means of FLIPR. Based on the results, a dose response curve was formed for each test compound and the EC50 value was calculated. The results are shown in Table 1.

Table 1 Industrial Applicability The compound (I), a salt thereof and a prodrug thereof have a modulating action, superior to the function of the GPR40 receptor and can be used as agents for the prophylaxis or treatment of diabetes and the like. This application is based on patent applications Nos. 431629/2003 and 241484/2004 filed in Japan, the content of which is incorporated by this act as a reference.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound represented by the formula (I): characterized in that: Rx, R3, R4 and R5 are the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an optionally substituted hydroxy group; R2 is a halogen atom, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted mercapto group, an optionally substituted acyl group or an optionally substituted heterocyclic group; Rxo and Rxx are the same or different and each is E is a bond, an alkylene group of 1 to 4 carbon atoms optionally substituted, -Wx-0-W2-, -Wx-S-W2- or -Wx-N (R6) -W2- (wherein Wx and W2 are the same or different and each is a bond or an alkylene group of 1 to 3 carbon atoms optionally substituted and R6 is a hydrogen atom, an acyl group optionally substituted or an optionally substituted hydrocarbon group); the Sx ring is a benzene ring optionally further having substituents selected from a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group and an optionally substituted amino group; and R is an optionally substituted hydroxy group or an optionally substituted amino group; with the proviso that Rx and R3 are not simultaneously a hydrogen atom or a salt thereof.

2. The compound according to claim 1, characterized in that R2 is a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted mercapto group or an optionally substituted heterocyclic group, and Rxo and RX1 are both hydrogen atoms or a salt thereof.

3. A prodrug characterized in that it is a compound according to claim 1 or a salt thereof.

4. The compound according to claim 1, characterized in that R4 and R5 are the same or different and each is a hydrogen atom or a halogen atom or a salt thereof.

5. The compound according to claim 1, characterized in that E is a bond or a salt thereof.

6. The compound according to claim 1, characterized in that R is a hydroxy group or a salt thereof.

7. The compound according to claim 1, characterized in that Rx and R3 are the same or different and each is an alkyl group of 1 to 6 carbon atoms or a salt thereof.

8. The compound according to claim 1, characterized in that R2 is an optionally substituted hydroxy group or a salt thereof.

9. The compound according to claim 1, characterized in that Rxo and Rxx are both hydrogen atoms or a salt thereof.

10. The compound according to claim 1, characterized in that the Sx ring is a benzene ring optionally further having an alkoxy group of 1 to 6 carbon atoms or a salt thereof.

11. 3- [4- [[4'- (Benzyloxy) -2 ', 6'-dimethylbiphenyl-3-yl] methoxy] phenyl] propanoic acid; 3- (4 { [4 '- (2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy, phenyl) -2,2-difluoropropanoic acid; 3- [4- ( { 4'- [2- (Ethylsulfonyl) ethoxy] -2 ', 6'-dimethylbiphenyl-3-yl} methoxy) -2-fluorophenyl] propanoic acid; 3- [4- (. {2 ', 6' -dimethyl-4 '- [3- (2-oxopyrrolidin-1-yl) propoxy] biphenyl-3-yl} methoxy) -2-fluorophenyl] propanoic; 3- [4- (. {2 ', 6' -dimethyl-4 '- [(6-methylpyridin-2-yl) methoxy] -biphenyl-3-yl} methoxy) -2-fluorophenyl] propanoic acid; 3- [2-fluoro-4- ( {4'- [(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl) methoxy] -2 ', 6'-dimethylbiphenyl-3- acid il.}. methoxy) -phenyl] propanoic; 3- [4- (. {2 ', 6' -dimethyl-4 '- [(methylsulfonyl) oxy] biphenyl-3-yl} ethoxy) -2-fluoro-phenyl] -propanoic acid; 3- [4- (. {4 '- [(1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) oxy] -2', 6'-dimethylbiphenyl-3-yl}. methoxy) -2 -fluorophenyl] propanoic; 3- [4- (. {2 ', 6' -dimethyl-4 '- [(3-methyl-oethan-3-yl) methoxy] -biphenyl-3-i1.} methoxy) -2-fluorophenyl] propanoic acid; 3- (4. {[2 ', 6'-dimethyl-4' - (tetrahydro-2 H -pyran-4-yloxy) biphenyl-3-yl] methoxy] -2-fluorophenyl) propanoic acid; 3- [4- ( {4 '- [3- (diethoxyphosphoryl) propoxy] -2', 6'-dimethylbifenyl-3-yl} methoxy) -2-f luorofenyl] propanoic acid; 3 - [2-Fluoro-4- (. {6-isopropoxy-2 ', 6'-dimethyl-4' - [(3-methyloxetan-3-yl) methoxy] -ifenyl-3-yl}. ) phenyl] propanoic; or a salt of them. 12 A modulator of receiver function GPR40, characterized in that it comprises a compound according to claim 1 or a salt thereof or a pro-drug of the same. 13 A pharmaceutical agent, characterized in that it comprises a compound according to claim 1 or a salt thereof or a prodrug thereof. 14. The pharmaceutical agent according to claim 13, characterized in that it is an agent for the prophylaxis or treatment of diabetes. 15. The use of a compound according to claim 1 or a salt thereof or a prodrug thereof for the production of a GPR40 receptor function modulator. 16. The use of a compound according to claim 1 or a salt thereof or a prodrug thereof for the production of an agent for the prophylaxis or treatment of diabetes. 17. A method of producing a compound represented by the formula (Ib) wherein Rx, R2, R3, R4, Rs, Rxo, Rxx, E and the Sx ring are as defined in claim 1, or a salt thereof, characterized in that it comprises reacting a compound represented by the formula (X) : * -CHS OH (X) wherein each symbol is as defined above, or a salt thereof and a compound represented by the formula (II): wherein R4, R5, Rx0 and Rxx are as defined above and R 'is an alkoxy group of 1 to 6 carbon atoms optionally substituted, or a salt thereof, to provide a compound represented by the formula (Ib'): wherein each symbol is as defined above, or a salt thereof and subjecting the compound or a salt thereof to a hydrolysis reaction. 18. A method of producing a compound represented by the formula (Id): wherein Rx, R3, R4, R5, Rxo, Rxx, E and the Sx ring are as defined in claim 1, Y is -0- or -S- and R2 'is a substituent, or a salt thereof, characterized in that it comprises reacting a compound represented by the formula (le '): wherein Rx, R3, R4, R5, Rxo, R1X, E, Y and the Sx ring are as defined above, R 'is as defined in claim 17, or a salt thereof and a compound represented by the formula : R2'-OH wherein R2 'is as defined above, or a salt thereof, to provide a compound represented by the formula (If): wherein each symbol is as defined above, or a salt thereof and subjecting the compound or a salt thereof to a hydrolysis reaction.