TW200806611A - Novel amidopropionic acid derivatives and medicine containing the same - Google Patents

Abstract

To provide novel compound having S1P recepter agonist activation, having a beneficial effect as immune suppressor, having few side-effects and being orally-bioavailable, and medicine containing of the same. A compound represented by general formula (I) [In this formula, V represents-NH-CO-or-CO-NH-, A represents -COOR7 (R7 represents hydrogen atom or alkyl group.) and the like; R1, R2, R3 and R4 represent hydrogen atom, hydroxyl group, amino group or alkyl group, respectively; R5 and R6 represent hydrogen atom, halogen atom, alkyl group or alkoxy group, respectively; Q represents -CH2O-, -CH2-CH2-, -CH=CH-, -CH2-O-N=CR8-, -CONR9-, -NR10CO-, -CH2NR11CO- or -CH2CH2NR12CO-; Y and Z represent group constituting benzene or aromatic heterocycle], salt thereof or solvate thereof and medicine containing the same.

Description

200806611 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD The present invention relates to a compound and a medicament containing the same, which has a novel guanamine propionic acid derivative, especially having sphingosine Ι-phosphate Receptor agonist activity, useful as an immunosuppressive agent. [Prior Art] 1 _Sphingosine phosphate (hereinafter referred to as S1P) is synthesized by sphingomyelin of a cell membrane in response to stimulation in eukaryotic cells. S1P is released into the bloodstream as a result of agglutination of the platelets. The S1P receptor belongs to the family of Endothelial Differentiation Genes (hereinafter referred to as EDG) as G-protein-associated receptors, including five subtypes of S1P1, S1P2, S1P3, S1P4, and S1P5, which are also referred to as EDG-, respectively. 1. EDG-5, EDG-3, EDG-6, and EDG-8. It is known that S1P has physiological activity such as about ion influx, chemotaxis, and induction of apoptosis in various cells. It has been previously known that FTY720 (2-amino-2-[2-(4-octylphenyl)ethylidene, % propylene glycol hydrochloride) having a sphingosine-like structure has immunosuppressive effects (Patent Literature) 1). It is generally believed that FTY72 does not inhibit the production of cellular mediators such as IL-2 in vitro, and has a different mechanism of action than the existing immunosuppressant FK506 or cyci〇sporine, but recently learned that 'FTY720 Phosphorylation in the living body acts as an S1P receptor agonist and exhibits an immunosuppressive effect (Non-Patent Document 1). It is reported that FTY720 is currently undergoing clinical trials for transplantation and multiple sclerosis. The incision acts to cause a bradycardia (Non-Patent Document 2). Therefore, the manufacturer 118505.doc 200806611 expects to develop a novel immunosuppressant that overcomes the above problems and shows high efficiency. On the other hand, it is revealed that there is S1P1 (EDG-l) a phosphonic acid aminoalkyl derivative derivative compound having a receptor agonist or a carboxylic acid derivative compound having a S1P4 (EDG-6) receptor binding ability, exhibiting an immunosuppressive action (Patent Documents 2 and 3) However, the company is expected to have a novel low-molecular S1P receptor agonist compound which exhibits excellent effects and has few side effects and can be administered orally. [Patent Document 1] International Publication No. 94/008943 [Patent Document 2] Japanese Patent Publication No. 03/062248 [Patent Document 3] International Publication No. 2005/020882 [Non-Patent Document 1] Science, 296, pp. 346-349 (2002) [Non-Patent Document 2] Journal of the American Society [Problems to be Solved by the Invention] It is an object of the present invention to provide a novel compound having S1P receptor agonist activity and acting as The inventors have made diligent efforts to solve the above problems, and have found that the indoleamine has a different effect from the conventional compound. A novel compound of propionic acid structure with S1P receptor agonist activity, which can be used as a model in mice to reduce the number of lymphocytes in the peripheral blood of mice and the side effects such as bradycardia. The active ingredient of the immunosuppressive agent, and finally the present invention is completed. 118505.doc 200806611 That is, the present invention provides a solvate of the following salt or the like, which is represented by the formula (1) Compound, its

(I) Keys to the left of each group

Wherein V represents -lSiH-CO- or _CO-NH- (wherein represents a phenyl group bonded to the formula (I)), and A represents _CO〇R7 (wherein r7 represents hydrogen eyebrow virgin And a linear or branched alkyl group of C1 to C5 which may have a substituent, or a tetrazole-5, wherein R1, R2, R3 and R4 each independently represent a hydrogen atom, a group, an amine group, or a straight or branched chain group of C1 to C5, and R5 and R6 each independently represent a hydrogen atom, a _ atom, a linear or branched alkyl group of C1 to C5 which may have a substituent, or a C1~ which may have a substituent Straight or branched alkoxy groups of C5, Q is not -CH20-, -CH2-CH2-, -CH=CH-, -CH2-〇-N=CR8-, -CONR9-, -NR-CO-^ -CH2NRHC〇. , .CH2CH2NR12CO- (wherein the bond on the left side of each group is bonded to the γ bond in the formula (1), and R8, R9, R1G, R11, and R12 each independently represent a hydrogen atom, or a 〇~〇 straight a chain or a branched alkyl group, and Y represents a divalent group formed by one selected from the group consisting of an aromatic heterocyclic ring of the present and a 5- to 6-membered ring (these groups may have a substituent). Z represents a phenyl group which may have a substituent, or may have a substituent of 5 118505.doc -9- 200806611 6-membered ring of an aromatic heterocyclic group]. Further, the present invention provides a pharmaceutical comprising the above compound, a salt thereof, or a solvate thereof, as an active ingredient; an S1P receptor agonist, an S1P1 receptor agonist, an immunosuppressive agent, a rejection reaction to transplantation, A therapeutic agent and/or a prophylactic agent for an autoimmune disease and/or an allergic disease; and a solvate of the above compound, a salt thereof, or the like, and an antibody selected from the group consisting of an immunosuppressive agent for immunosuppression A medicine obtained by displacing one or more of a therapeutic drug, an antibiotic, and a steroid drug.

Further, the present invention provides a use of the above-mentioned compound, a salt thereof or the (iv) solvate. Furthermore, the present invention provides a method for treating and/or preventing an S1p receptor-associated disease such as a solvate or a solvate of the above compound, a salt thereof, or the like, an S1P1 receptor, or the like, and an immunosuppressive method. And methods of treating and/or preventing rejection of transplants, autoimmune diseases, and/or allergic diseases. Furthermore, the present invention provides a method for treating and/or preventing an S1P receptor-associated disease, which comprises the above compound, a salt thereof, or a solvate thereof, and an antibody selected from the group consisting of an immunosuppressive agent and used for immunosuppression One or a combination of one or more of a rejection therapeutic drug, an antibiotic, and a steroid drug is used in combination. Effective effect of the invention [Inventive effect] The novel guanamine propionic acid derivative, the salt thereof and the solvate thereof provided by the present invention have S1P receptor agonist activity, and The model uses oral administration to reduce the number of lymphocytes in the peripheral blood of mice, and thus can be used as an effective component of medicines such as immunosuppressive agents, for example, as a rejection reaction to a mammal in a mammal, especially a human body, especially in a human body. An active ingredient of a therapeutic agent and/or a prophylactic agent for autoimmune diseases, allergic diseases. Moreover, in terms of oral administration and reduction in the number of lymphocytes in the peripheral blood of mice, it is generally considered that such medicines can be administered orally. Further, these medicines are those having less side effects such as bradycardia seen in other Slp receptor agonists. [Embodiment] Hereinafter, the substituents described in the present specification will be described. The "linear or branched alkyl group of C1 to C5" means a linear or branched saturated hydrocarbon group having a carbon number of 5, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a positive group. Butyl, isobutyl, tert-butyl, n-pentyl, ethylidenepropyl, and 2,2-dimethylpropyl, and the like. The "linear or branched alkoxy group of C1 to C5" means a linear or branched alkoxy group having a carbon number of 丨5, and examples thereof include a methoxy group, an ethoxy group, and a propoxy group. Isopropoxy, n-butoxy, isobutyloxy, tert-butoxy, n-pentyloxy,! _Ethylpropyloxy, and 2,2-dimethylpropyloxy and the like. The "5- to 6-membered aromatic heterocyclic ring" means a 5-member or 6-membered monocyclic aromatic pathogen containing a oxynium: aryl L original I: and 1 to 3 hetero atoms in the sulfur atom. For example, furan, thiophene, pyrrole mouth, sitting mouth, mouth rice squat, sip mouth, 'gui, isothiazole, pyrazole, triazole, pyridine, pyridazine, pyrimidine, and pyridinium Azine, etc. Nai 5~6 member ring of aromatic miscellaneous class | _ ❿ clothing base, the table does not contain 5 or 6 of 6 to 6 heteroatoms selected from oxygen atoms, ruthenium atoms, and sulfur atoms φ A member of the scent of scented scented scented scented bases, such as ke···································· Thiazolyl, pyrazolyl, trisal, 17-bite, pyridazinyl, guanidino, n-methyl and the like. The "dentin atom" means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The substituents which may have a substituent in RR 11 and 2 are not particularly limited, and examples thereof include a dentate atom, a silk, an amine group, and the like; and the number of the substituents may be one or more. In the case of having a plurality of substituents, the respective substituents may be the same or different. The substituent of the kiss Y "the group may have i substituents", and there is no particular limitation of 'a phenyl group, a linear or branched alkyl group of C1 to C5, and a C1 to C5 substituted by a halogen atom. A linear or branched alkyl group. The "linear or branched alkyl group of C1 to C5" represents a linear or branched saturated hydrocarbon group having a carbon number of 丨5, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a positive group. Butyl, isobutyl, tert-butyl, n-pentyl, oxime-ethylpropyl, and 2,2-monopropyl. Further, the number of halogen atoms in the "straight chain or branched bond group of C1 to C5 substituted by a halogen atom" may be one or more, and may be substituted when a plurality of _ prime atoms are substituted. The types of atoms can be the same or different. The "cl~C5i linear or branched alkyl group substituted by a halogen atom" is exemplified by a chloromethyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-chloroethyl group, and 2,2. , 2_trifluoroethyl, ^^^tetrafluoroethyl, pentafluoroethyl, 1,1,2-trifluoro-2-chloroethyl, 3,3,3-trifluoropropyl, 2,3 - Dichloropropyl, 2-oxyethyl, and 3-propylpropyl. Hereinafter, preferred embodiments of V, A, R1 to R6, Q, γ & 118505.doc -12 - 200806611 V of the formula (I) represents -NH-CO- or -CO-nh- (wherein the bond to the left of the oxime group is represented by a phenyl group in the formula (1)) Ok, _NH_c〇.

A in the formula (1) represents -COOR7 (R7 represents a hydrogen atom or a linear or branched alkyl group of C1-C5 which may have a substituent), or a tetrazole-5-based group, preferably -COOR7. Wherein, R7 is preferably a chlorine atom > "J ethyl group, particularly preferably a hydrogen atom. The core of the formula (1) and the group independently represent a hydrogen atom, a # group, an amine group, or a C1~ a straight chain or a branched chain base of C5, wherein preferably, each is independently a hydrogen atom, a meridine, or a cl~Ck straight chain or a branch cadaveric group. ^心^ and ^(4) are linear or branched. Base: is a methyl group. Among them, both R1 and R2 are the base group, and both of them are amines, one of which is recorded and the other is an amine group, and there is a possibility that (4) 疋 exists. Both the ruler 3 and the r4 are those of the base group, the Han 3 and the oxime are both amine groups, and one of the RW is a base group and the other is an amine group. Further, in the case where V4-C〇_nh_ (wherein the bond on the left 4 side of the group represents a phenyl group bond in the formula (1)), at least one of them is via the base, R3 and R4 At least one of them is an amine soil, and there is a possibility of instability. And any one or two of R4 are independently R: Preferably, R1 and Han2 are a radical, an amine group, or a C1 to C5. Straight chain or branch (tetra), while the remaining R and R groups are argon And W, R2, R3, and both are hydrogen atoms. Straight to eight is a linear or branched alkyl group of C1 to C5, preferably a methyl group. τ H8505.doc -13- 200806611 More specifically More preferably, R1 is a hydroxyl group, an amine group, or a linear or branched alkyl group of C1 to C5, and R2, R3, and Han 4 are hydrogen atoms; R1, R2, and R are hydrogen atoms, and r4 is a hydroxyl group. , an amine group, or a linear or branched alkyl group of C1 to C5; R1 and R4 are a hydroxyl group, R2&R3 is a hydrogen atom; R1, r2, r3, and R4 are a hydrogen atom; and R1 and R4 are a methyl group. R2&R3 is a hydrogen atom. Among them, it is particularly preferable that R1 is a hydroxyl group or an amine group, R2, R3 and R4 are a hydrogen atom; R1, R2 and R3 are a hydrogen atom, and R4 is a hydroxyl group or an amine group; And R is a mouse atom, R is a fluorenyl group; and R1 and R4 are a radical, and r2 and R3 are a hydrogen atom. R5 and R6 in the formula (I) each independently represent a hydrogen atom, a _ atom, and may have a substituent. a linear or branched alkyl group of C1 to C5, or a linear or branched alkoxy group of Cl C5 which may have a substituent. Preferably, R5 and 6 are each a nitrogen atom. In the formula (1) Q represents -CH20- -CH2-〇.N= CR8-. -CONR9- > -NR10CO-, -CH^R^CO- or -C^CHar^cq- (wherein the bond to the left of each group represents a Y bond with the formula (1) '", ..., and ... each independently represent a hydrogen atom or a linear or branched alkyl group of C1 to C5). R8 is preferably a methyl group; R9, R1G, R11 and R12 are preferably a hydrogen atom. Q, preferably = is -CH2〇-, -ch2_CH2_, _CH=CH_, and _CH2 〇n=cr8 is more preferably -CH2〇- and, in the case of _CH=CH_i, preferably trans structure.

^ The quaternary group formed by i of the group consisting of the Y-form of the UT and the aromatic heterocyclic ring of the secondary ring (the groups may also have J 118505.doc -14-200806611 substituents) Among them, as for the aromatic heterocyclic ring of 5 to 6 member rings, it can be listed, 吱 嗟, 嗟, D, 洛, ten sit... Sitting, taste wow, different ten sitting... V is more than saliva, three wow, ... health, biting, and. Bisin. Y, compared to: a quinone selected from the group consisting of furan, thiophene, sulphide, thiazole, imidazole, pyrazole, trisap, benzene, and sputum: a divalent group (this The group may have a substituent, and more preferably a divalent group formed from i selected from the group consisting of thiophene, thiazole, and pyrazole (the groups may also have a substituent), More preferred is a divalent group formed by n-phene (this group may also have a (10) substituent). Preferably, it has a (10) substituent ' as the substituent, preferably a phenyl group, a straight or branched chain group, and a linear or branched alkyl group substituted by a dentate atom. More preferably, it is a phenyl group, and a linear or branched thio group of ci~C5 substituted by a halogen atom. The group to be substituted in γ is specifically a phenyl group, a methyl group, a tert-butyl group, and a trifluoromethyl group. In the case where the Y is a divalent group formed by furan, it is preferred that q is bonded to the 2-position of the furan, and Z is bonded to any of the 4- or 5-position of the furan, wherein the furan has In the case of one substituent, it is preferred that the substituent is bonded to the remaining one of the 4-position and the 5-position of the furan in which Z is not bonded. In the case where the Y is a divalent group formed by thiophene, it is preferred that Q is bonded to the 2-position of the thiophene and Z is bonded to any of the 4- or 5-position of the thiophene, wherein the thiophene is present. In the case of having one substituent, it is preferred that the substituent is bonded to the remaining one of the 4-position and the 5-position of the thiophene in which Z is not bonded. In the case where the Y system is a divalent group formed by sputum saliva, it is preferred that q is bonded to the 2-position of the azole, and the Z bond is bonded to any of the 4 and 5 positions of the carbazole. In the case where the drink has a substituent, it is preferred that the substituent is bonded to the remaining one of the 4-position and the 5-position of the 4-salt Z. In the case where Y is a divalent group formed by thiophene, it is preferred that Q is bonded to the 2-position of the thiazole, and Z is bonded to any of the 4- or 5-position of the thiazole, wherein . Plug. In the case where a substituent is present, it is preferred that the substituent is bonded to the remaining one of the 4-position and the 5-position of the thiazole in which Z is not bonded. In the case where the Y group is a divalent group formed of imidazole, it is preferred that (the bond is bonded to the 4-position of the imidazole, and the Z bond is bonded to the niobium of the imidazole and any of the two positions, wherein In the case where the oxime has a substituent, it is preferred that the substituent is bonded to the remaining one of the unbonded z in the 1-position and the 2-position of the oxime. The valence of the Y-form formed by the pyrazole In the case of a base, it is preferred that q is bonded to the 3-position of the pyrazole, and the Z bond is bonded to any one of the pi-position or the 5-position of the pyrazole, wherein when the pyrazole has i substituents Preferably, the substituent is bonded to the remaining one of the unbonded Z in the 1st and 5th positions of η. In the case where the Y is a divalent group formed by a triazole, as the third The azole, preferably ruthenium, 2,4-trimium is preferably bonded to the 3-position of the tri-salt, and is ligated to the 1-position of the triazole and the any-position of the 5-position, wherein the triazole has In the case of a "solid substituent", it is preferred that the substituent is bonded to the triazole oxime and the remaining one of the 5-position z is not bonded. In the case where the Y is a divalent group formed of benzene Preferably, the q bond is bonded to the 1 position of the benzene, and the Z bond is attached to the 3, 4 and 5 positions of the benzene. In any of the positions, wherein in the case where the benzene has one substituent, it is preferred that the substituent is bonded to any of the remaining positions in the 3-position, 4-position and 5-position of benzene where z is not bonded. In the case where the ¥ is a 2-valent base formed by a bite ratio, it is preferable that the Q bond 118505.doc • 16 _ 200806611 is at the 2 or 3 position of the ratio σ, and the Z bond is tied to the bite. Any one of the 5 and 6 positions, wherein in the case where the pyridine has 1 substituent, it is preferred that the 5 meta-substituent is bonded to the 5th and 6th positions of the σ ratio and the Z is not The remaining one of the bond. When the oxime is a divalent group formed by oxazine, it is preferred that the oxime is bonded to the 3-position of the oxazine and the oxime is bonded to the 5-position and the 6-position of the azine. In any of the positions, wherein in the case where the pyridazine has 1 substituent, it is preferred that the substituent is bonded to the remaining one of the 5-position and the 6-position of the pyridazine which is not bonded. When Υ is a divalent group formed by pyrimidine, it is preferred that q is bonded to the kiss. The fixed 2-position 'ζ' is bonded to any of the 4 and 5 positions of the mouth bite. When the mouth bite has one substituent, it is preferred that the substituent The remaining one of the unbonded ruthenium in the 4-position and the 5-position of the pyrimidine. Ζ represents a phenyl group which may have a substituent, or an aromatic heterocyclic group which may have a substituent of 5 to 6 membered rings, preferably It is a phenyl group which may have a substituent, and more preferably a phenyl group which has no substituent. As a specific example of the compound of the present invention, (s)_3_hydroxy_4_oxoyl-4-{4- [(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid, (R)-3-methyl-4-oxoyl-4-{4 -[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid, (R)_3_hydroxyoxyalkyl-4-{4·[(4 -phenyl-5-trifluoromethyl 2·thienyl)methoxy]phenylamino}butyric acid, 4-oxo-4-{4-[(4-phenyl-5-trifluoro) Methyl-2-thienyl)methoxy]phenylamino}butyric acid, (R)-2-hydroxy-4-oxoyl_4-{4-[(4-phenyl-5-trifluoro) Methyl-2-thienyl)methoxy]phenylamino)butyric acid, (s)-2-hydroxyoxyxo-4-{4-[(4-phenyl-5-trifluoromethyl) 2_thienyl)nonyloxy]phenylamino}butyric acid, 3,3-dimethyl-4-oxo-4-{4-[(4-phenyl-5-trifluoromethyl 118505. Doc -17- 200806611 -2-thienyl)nonyloxy]phenylamino}butyric acid, (S)-3-indolyl-4-oxoyl-4-{4-[(4-phenyl-5-di-a) Benzyl-2-11-thenyl)methoxy]phenylamino}butyric acid, (2S,3R)-2,3-dimethyl-4-oxoyl-4-{4-[(4- Phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid, (2R,3R)-2,3-dihydroxy-4-oxoyl-4-{4 -[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid, (2S,3S)-2,3-dihydroxy-4-oxo -4·{4-[(4-Phenyl-5-trifluoromethyl-2-thienyl) decyloxy]phenylamino}butyric acid, (R)-3-amino-4-oxo 4-(4-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid, (S)-3.amino-4-oxo Benzyl-4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid, (S)-2-amino-4- Oxo--4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid, (R)-2-amino-4 -Oxo--4-{4-[(4-phenyl-5.trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid, (S)-3-hydroxy-4 -oxoyl-4-{4-[(4-phenyl-5-trifluoromethyl-2-thiophene) (ethyl)phenylamino}butyric acid, (S)-3-hydroxy-4-oxoyl-4-{4-[(E)-2-(4-phenyl-5-trifluoromethyl) Benzyl-2-thienyl)vinyl]phenylamino}butyric acid, 4-oxo-4-{4-[(5-fluorenyl-4-phenyl-2-thiazolyl)methoxy] Phenylamino}butyric acid, 4-oxoyl-4_{4-[(5-phenyl-4-trifluoromethyl-2-thiazolyl)methoxy]phenylamino}butyric acid, 4 -Oxo--4-{[4-(1,5-diphenyl-1Η-η-pyrazol-3-yl)methoxy]phenylamino}butyric acid, 4·oxo-4- {[4-(l-Tertibutyl-5-phenyl-1H-. Bisazo-3-yl)methoxy]phenylamino}butyric acid, 4-oxo-4-{[4-(1-phenyl-5-trifluoromethyl-1Η^bazole-3) -yl)methoxy]phenylamino}butyric acid, 4-oxo-4-(4-{1-[(E)-4-biphenylmethoxyimino]ethyl}benzene Amino acid) butyric acid, (R)-3-hydroxy-4-oxoyl_4-{4-[(4,5-diphenyl-2-thienyl)-methyl 118505.doc -18- 200806611 (n)]benylamino}butyric acid, (S)-3-transyl-4-oxo-4-{4-[(4,5-diphenyl-2-thienyl)methoxy]benzene Amino acid, butyric acid, 4-oxo-4-{4-[(4,5-diphenyl-2-thienyl)methoxy]phenylamino}butyric acid, (R)-2 -hydroxy-4-oxoyl-4-{4-[(4,5-diphenyl-2-thienyl)methoxy]phenylamino}butyric acid, (S)-2-hydroxy-4 -oxoyl-4-{4-[(4,5·diphenyl-2-thienyl)methoxy]phenylamino}butyric acid, 3·{4-[(4-phenyl-5) -trifluoromethylthiophen-2-yl)methoxy]phenylhydrazinyl}propionic acid, 2-hydroxy-3-{4-[(4-phenyl-5-trifluoromethylthiophene-2- Methoxy]benzhydryl}propionic acid, and 3-mercapto_3_{4-[(4-phenyl-5-trifluoromethylthien-2-yl)methoxy]benzamide Amidino-propionic acid, preferably ··4-Oxo--4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid, (R)-2- Hydroxy-4-oxoyl-4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl)nonyloxy]phenylamino}butyric acid, (S)-2- Hydroxy-4-oxoyl-4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid, (S)-3- Methyl-4-oxoyl-4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid, (2R, 3R) -2,3-dihydroxy-4-oxoyl-4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid, (S)-2-Amino-4-oxoyl-4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid (S)-3-Hydroxy-4-oxoyl-4-{4-[(E)-2-(4-phenyl-5-trifluoromethyl-2-thienyl)vinyl]phenyl Amino}butyric acid, and 3-{4-[(4-phenyl-5-trifluoromethylthien-2-yl)methoxy]phenylhydrazinyl}propionic acid, especially good: ( S)-2-hydroxy-4-oxoyl·4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid, ( S)-3-methyl-4-oxoyl-4-{4-[(4_phenyl-5-three) Methyl-2-thienyl)methoxy]phenylamino}butyric acid, 118505.doc -19- 200806611 and (S)-3-ylamino-4-yl-oxo-4-{4_[(Ε _2·(4_Phenyl-·trismethylmethyl·2_°secenyl)vinyl]phenylamino}butyric acid. When there are one or more asymmetric ambiguities in the molecule, 'the image isomer, the racemate, the non-image isomer, and a mixture of these. Further, the 'compound of the present invention', when it contains a geometric isomer, includes a cis-configuration compound, a trans-configuration compound, and a mixture thereof, unless otherwise specified, and further, the compound of the present invention Where tautomers are included, the tautomers and mixtures thereof are included where not specifically stated. The present invention includes the compounds represented by the formula (1), salts thereof, and the solvates thereof. The salt of the compound of the present invention may, for example, be a metal salt, a metal salt such as a lock, a tetramethylammonium salt or a tetrabutylammonium salt, a triethylamine, a methylamine, a dimethylamine or a hydroxy-reductive amine. A salt of an organic amine such as tris(polymethyl)methylamine, a mineral acid salt such as a hydrochloride, a phosphate or a nitrate, an acetate, a lactate, a tartrate, an oxalic acid, a butyl succinate, a butadiene Diacid salt, citric acid salt, and acid; acid acid salt, organic acid salt such as benzenesulfonate. Examples of the solvate of the compound of the present invention include a hydrate, a methanolate, and an ethanolate. The compound of the present invention, a salt thereof, or the glutamic acid compound of the present invention may exist as a form of prodmg. The .φ 勹 勹 柰 柰 柰 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 118505.doc -20 - 200806611 The following is a description of the production method of the compound (i) of the present invention. The method for producing the compound (1) of the present invention can be roughly distinguished from the two methods of the A method and the B method described below. [Chemical 2]

(wherein R to R ^, (^) and the same as the above, '^ and X2 represent a group which mutually reacts to provide γ, and the furnace and the parent 4 represent a group which reacts with each other to provide Q.) First, The above A method will be described in detail. [Method A-1-1]

The compound of the present invention represented by the formula (1), which is a compound of _ΝΗ <〇, can be produced by the following method. [Chemical 3]

-Υ一Q

(la)

(wherein R to R, A, Q, 丫 and 2 represent the same as above, and V represents 118505.doc -21 - 200806611 -NH-CO-, and W1 represents a hydroxyl group or a leaving group). The compound (?) of the present invention can be produced by the compound (la) and the compound (2 phantom reaction to form a stilbene bond (-NH-CO-). In this production, if it is used in the manufacture of the peptide For the general method used in the production of the peptide, for example, an azide method, a ruthenium chloride method, an acid anhydride method, a Dcc (dicyclohexylcarbodiimide) method, an active ester method, N, N, _ carbonyl diimidazole method, DCC / H BT (1-hydroxyphenyl hydrazine one sitting) method, method using water-soluble carbodiimide, method using cyano acid filling _ _ Yu: M·BGdanszky,

γ· s. Klausner and A· Ondetti "Peptide Synthesis1 丨(A

Wiley-interscience pubHcati〇n, Y〇rk, Μ%年卜 g R· Pettit with "Synthetic Peptides,, (Eisevier

Publication Company, New Y〇rk, i976), Sakamoto Chemical Society, 14th edition, Experimental Chemistry Lecture, Vol. 22, Organic Synthesis (Maruzen Co., Ltd., 1991). Specifically, when the compound (4) is a thiol group, the compound (la) is condensed with the compound (2a) by using a common condensing agent used in the production of the peptide, or the W1 as a trans group is converted into The azide, chlorine atom or the like is desorbed from the group, and then reacted with the compound (10) in the presence of (d). To the ordinary condensing agent, for example, DCC (dicyclohexylcarbodiimide), water-soluble carbodiimide, DCC/H0BT (1-hydroxybenzoquinone), N, N'-yl group Two meters sit. As for the dissolution! For example, if tetrahydrofuran, sulphur, acetonitrile, toluene, methylene chloride or N is used, dimethyl melamine may be used. The reaction temperature may be, for example, _2 〇 1 to death. 118505.doc -22- 200806611 Further, when W1 of the compound (2a) is a leaving group, it can be produced by reacting the compound (2a) with the compound (la) in an aprotic solvent in the presence of a base. The compound (1) of the present invention. Among them, examples of the leaving group include a gas atom, an azide group, a p-nitrophenoxy group and the like. Examples of the aprotic 糸/谷知彳 include tetrahydrofuran, acetam, acetonitrile, toluene, dimercaptomethane, and N,N-dimercaptocarbamide. The reaction temperature may be, for example, _2 〇 to 100 ° C. As the base to be used in the reaction, for example, an inorganic base such as an alkali metal such as sodium carbonate, potassium carbonate or cesium carbonate or a carbonate of an alkaline earth metal such as pyridine, 2,6-dimethylpyridine or trimethylpyridine may be mentioned. An organic base of 4-dimethylaminopyridine, triethylamine N-methylmorphine, monoisopropylethylamine, di-σ丫bicyclo[HQ]undec-7-ene (DBU). In the case of the above reaction, when the compound (I) has a hydroxyl group or a functional group such as an amino group, a carboxyl group or a triazolyl group, the functional group is protected with a suitable protecting group as needed, and is removed after forming a guanamine bond. Protection base. Here, as the protective group, a tributyl group, a methyl group, an ethyl group, a benzyl group, a p-methoxybenzyl group, a trimethyl decyl group, an ethyl fluorenyl group, a trifluoroethyl fluorenyl group, and a benzamidine can be mentioned. Alkyl, lower alkoxycarbonyl, benzyloxycarbonyl. The protecting group is not particularly limited as long as it is a group which can be easily and selectively removed. [Production Process A_l-2] Further, the compound of the present invention (I) wherein V is -NH-CO- can also be produced by the following method. [Chemical 4] 118505.doc -23- 200806611

(The symbol of the formula indicates the same as above). The compound (I)' in the present month can be produced by reacting the compound (la) with the compound (2b) to form a guanamine bond (-NH-CO-). Specifically, the compound (1) can be produced by adding a base and reacting the compound (la) and the compound (2b) in an aprotic solvent, if necessary, and then reacting the mixture. As the aprotic solvent to be used in the reaction, there may be mentioned tetrahydrofuran, diethyl ether, acetonitrile, methylidene gas, and N,N-dimercaptocarboxamide. As the test, diethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, sodium carbonate, potassium carbonate, carbonic acid planing, etc. may be mentioned. The reaction temperature may be, for example, 〇1 to 1〇〇〇c. In the reaction, a functional group such as a hydroxyl group or an amine group is protected with a suitable protecting group as needed, and the protecting group is removed after the formation of a guanamine bond. Here, as for the protective group, those enumerated in the above Process A-1 -1 can be used. Further, the compound (2b) can be synthesized by a known method such as the method described in the following literature or by a method based thereon: J〇urnal 〇f 〇rganic

Chemistry, 1985 ’ 50 (26), p. 5480; Journal of 〇rganie Chemistry ’ 1990 ‘ 55(15) ’, p. 4763; Eur〇pean journai of Medicinal Chemistry, 2002, 37(6), p. 469;

Canadian Journal of Chemistry, 1986, 64(1), p. 104. [Production Process A-2] The compound of the present invention represented by the formula (I) wherein V is -CO-NH-, 118505.doc -24-200806611, can be produced by the following method. [Chemical 5]

Z-Y-Q

(lb)

Z-Y——Q

(wherein R1 to R6, A, q(1)'' roxm "Q Y&z is not the same as the above, and V represents -, w represents a hydroxyl group or a leaving group.) The compound (1) of the present invention can be represented by a compound (lb) is produced by forming a guanamine bond (-CO-NH-) with a compound. W2 of the compound (lb) is a hydroxy group, and the ruthenium is used for the production of a peptide. Ordinary condensing agent can be used as a fine mouth reaction. As for the ordinary condensing, for example, DCC (dicyclohexylcarbodiimide), n, n, alkaloid, and water-soluble carbodiimide For example, as the solvent, for example, tetrahydrofuran, acenaphthene, acetonitrile, toluene, dioxin, and N,N-dimethylformamide can be used. The reaction temperature is set to, for example, 2 〇. Further, when W2 of the compound (lb) is a leaving group, the present invention can be produced by reacting the compound (10) with the compound (5) in a non-f-substrate in the presence of a test. The compound (1). Examples of the leaving group include a chlorine atom, an azide group, a p-nitrophenoxy group, etc. As for the apron The solvent may, for example, be tetrahydrogen chelate, kiwi, acetonitrile, toluene, dichloromethane, hydrazine, hydrazine dimethylformamide. As the base, triethylamine or diisopropyl Amine, N-methyl morphine " than bite, sodium carbonate, carbonic acid unloading, carbonic acid planing, etc. The reaction temperature is set to, for example, _2〇~1〇〇. 〇. 118505.doc -25- 200806611 In these reactions, a functional group such as a hydroxyl group, an amine group, a carboxyl group or a diazolyl group is protected with an appropriate protecting group as necessary, and a sulfhydryl group is removed after forming a guanamine bond. As for the protecting group, a third group can be cited. Base, methyl, ethyl, benzyl, p-methoxyl group, trimethyldecyl, ethyl fluorenyl, trifluoroethenyl, benzhydryl, lower alkoxy, oxymethane Further, the protecting group is not particularly limited as long as it is a group which can be easily and selectively removed. Next, the above B method will be described in detail. [The method can be produced by the following method. ]

Wherein R to R, A, Y and Z represent the same as above, v represents -νη·C〇- or -CO-NH_, Q represents _CH2〇_, and w3 represents a secret or a leaving group). In the compound of the present invention represented by the formula (I), Q is a compound of _CH2〇, and the 'X-detail compound (I)' can be reacted with the compound (4) to form a Q-CH2〇- It is produced by a bond (hereinafter referred to as an ether bond). Specifically, in the case where the compound (4) is a thiol group, the compound (1) of the present invention can be produced by reacting the oxime (4a) with the compound (3a) to form an ether bond. The stretching reaction is carried out, for example, by an operation in an organic solvent (tetrahydrofuran, diethyl ether, ethyl hydrazine, toluene, dioxane H8505.doc -26 - 200806611 methane, etc.) in an azo compound (azodicarboxylic acid). Diethyl ester, azodicarboxylate V, propional 1,1 _(azodiyl)dipyridinium, 131,_azobis(n,n-dimethylformamide), and phosphine In the presence of a compound (triphenylphosphine, tributylphosphine, trimethylphosphine, etc.), it is from 0 to 80. The reaction is carried out under the armpits. Further, in the case of the chemical substance (W3 of 44 is a leaving group), the compound (1) of the present invention can be produced by alkylating the compound (3a) to form an ether bond with the compound (4a) in the presence of a base. Examples of the leaving group W3 include a halogen atom, a methanesulfonyloxy group, a toluenesulfonyloxy group, and a benzenesulfonyloxy group. Examples of the base include alkali metal hydroxides (sodium hydroxide, potassium hydroxide, and the like). Lithium hydroxide or the like, a hydride of an alkali metal (sodium hydride, potassium hydride, etc.) or a carbonate (sodium carbonate, potassium carbonate, carbonic acid planing, etc.). As the solvent used in the reaction, N, N- Dimethylmethaneamine, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, gas, di-methane, diethyl ether, acetonitrile. The reaction temperature is set to, for example, 〇~15 〇 °C. In these reactions, a functional group such as a hydroxyl group, an amine group, a carboxyl group or a diazolyl group is protected with an appropriate protecting group as needed, and the protecting group is removed after the ether bond is formed. As the protecting group, a third butyl group is exemplified. Methyl, ethyl, benzyl, p-methoxyl, trimethyl shi a group, an ethyl fluorenyl group, a trifluoroethenyl group, a benzamidine group, a lower alkoxycarbonyl group, or a benzyloxycarbonyl group. As a protective group, if it is a group which can be easily and selectively removed, other than the above, there is no [Production Process B-2] The compound of the present invention represented by the formula (I) wherein Q is _CH=CH_ can be produced by the following method. 118505.doc -27- 200806611 [Chem. 7]

(wherein R1 to R6, A, V, Y and Z represent the same as defined above, Q represents -CH=CH-, and R13 represents a lower alkyl group). Namely, the compound (I) of the present invention can be produced by reacting the compound (3b) with the compound (4b) in the presence of a base to form a -CH=CH- bond. As the lower alkyl group of Ri3, a linear saturated hydrocarbon group of C1 to C4 may be mentioned, and examples thereof include a methyl group, an ethyl group, a propyl group and a butyl group. As the base, there may be mentioned sodium hydride, potassium hydride, sodium methoxide, potassium ethoxide, potassium t-butoxide, sodium t-butoxide, sodium bis(dimethyl decyl) decylamine, bis(trimethyldecyl) Potassium amide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, and the like. Examples of the solvent used in the reaction include tetrahydrofuran, tert-butyl methyl ether, toluene, methanol, ethanol, and third butanol. The reaction temperature may be, for example, 0 to 150 °C. In the reaction, a functional group such as a hydroxyl group, an amine carboxyl group, or a ketone group is protected with an appropriate protecting group as necessary, and a protective group is removed after forming a CH CH. bond corresponding to Q. As the protecting group, there may be mentioned a third butyl group, a methyl group, an ethyl group, a benzyl group, a p-methoxybenzyl group, a trimethyl decyl group, an ethyl ketone group, and a triterpenoid. Alkyl, lower alkoxycarbonyl, alkoxy group. The group which is easily and selectively removed in addition to the above is not particularly limited. 118505.doc -28- 200806611 In addition, if the compound (m) in which Q is -ch=ch- is transferred by the above-mentioned manufacturing method m, the substance is contacted and reduced, and the mouth is contacted with #, lkQ4-CHrCH2. - the compound (1). The main π contact reduction catalyst, Shiyan use free carbon, turn, etc. As for the six doses, methanol, 7^1 J to dissolve ^ TO - i . /, N, N-dimethylformamide, acetic acid ethyl acetate, four wind cough, and acetic acid can be mentioned.制B [Production Process B-3] The present invention, which is represented by the formula (I), wherein Q is -ch2-o-n=cr8-, can be produced by the following method. [化8]

(3c)

(wherein R1 to R6, R8, A'V vfen 7 main - λ 丄, V 丫 and 2 are not the same as above, and Q represents -CHyO-NsCR8·), that is, by making the compound (3c The compound (I) of the present invention is produced by reacting the compound (4c) with a base in the presence of a base to form a -CH2_0-N=CR8- bond. As the solvent to be used in the reaction, there may be mentioned tetrahydrofuran, tert-butyl methyl ether, toluene, methanol, ethanol, tert-butanol, hydrazine, hydrazine-dimethylformamide #. As for the test, there may be mentioned sodium hydride, potassium hydride, sodium methoxide, potassium ethoxide, potassium t-butoxide, sodium t-butoxide, sodium bis(trimethyldecyl) decylamine, bis(trimethyldecyl) Potassiumamine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, barium carbonate, and the like. The reaction temperature may be, for example, 0 to 150 °C. In the reaction, a functional group such as a hydroxyl group, an amine 118505.doc -29-200806611 group, a carboxyl group or a triazolyl group is protected with an appropriate protecting group as needed, and a -CH2-0-n-cr corresponding to Q is formed. The protecting group is removed after the bond. As the protecting group, there may be mentioned a third butyl group, a methyl group, an ethyl group, a benzyl group, a p-methoxybenzyl group, a trimethyl decyl group, an ethyl fluorenyl group, a difluoroacetinyl group, a benzamidine group, and a lower stage. The alkoxycarbonyl group and the benzyloxy group are not particularly limited as the protecting group 'except for the group which can be easily and selectively removed except for the above. Further, in the compound (1) of the present invention, Q is a compound of _CH2_〇_N = CR8_, which can also be produced by the following method. [Chemistry 9]

R

HO-N 3 L

V-C- Ϊ I (3d) Z-—γ—C~W4 H2 (4d)

-A

~Υ-Q

v-UU (I) (wherein R1 to R6, R8, A, V, Y and Z represent the same as above, Q represents -ch2-o_n = cr8_, and W4 represents a leaving group). That is, the compound can be made to form the compound of the present invention by the compound in the presence of a base (the three sentences and the compound state ruthenium form a bond equivalent to Q-CH2.0 to raise the cr8_ bond: (1). As for the w4' in the compound (4d) Listed: spectroscopy atom, a phenolic oxy group, toluene oxy group, benzene ethoxy group, etc. As for the test, exemplified by: sodium hydride, potassium hydride, sodium methoxide, potassium ethoxide, potassium butoxide, first: Nitrogen, bis (trimethyl sulphate), bis (trimethyl sulphate), amine slag, sodium hydroxide, hydroxide, unloading, carbonic acid, carbonic acid, etc. Examples of the solvent include tetrahydrofuran, third butyl y ether, toluene, methanol, ethanol, tert-butanol, N,N-dimethylform:, etc. The reaction temperature is, for example, 〇 15 15 〇〇. 118505.doc -30- 200806611 Further, a compound (3 may be used; a reaction condition, etc.) may be produced by using a base amine and a compound (9)).

In this reaction, a trans group, an amine group, a slow group, and a third are protected with an appropriate protecting group as needed. A functional group such as a sitting group, and the protecting group is removed after forming a _called N=CR8- bond corresponding to q. As the protecting group, there may be mentioned a third butyl group, a methyl group, an ethyl group, a sulfhydryl group, a p-methoxyl group, a trimethyl sulfonyl group, an ethyl fluorenyl group, a tri-I acetyl group, a benzamidine group, and a lower stage. Alkoxy groups, alkoxy groups. The protecting group is not particularly limited as long as it is a group which can be removed (4) and selectively removed. [Production Process Β-4] The compound of (4)_c〇nr9- in the compound of the present invention represented by the formula (I) can be produced by the following method. [化10]

(3e)

Z-Y-Q

1

(wherein R1 to R6, R9, A, V, Y and Z represent the same as defined above, and q represents -CONR9-, and W5 represents a hydroxyl group or a leaving group). The compound (1) of the present invention can be produced by reacting the compound (3e) with the compound (4e) to form a guanamine bond (CONR -). When w5 of the 5 (4e) is a hydroxyl group, the compound (1) can be produced under the same reaction conditions as in the above Process A-1. X, examples of the leaving group of w5 include a chlorine atom, a p-nitrophenoxy group, an azide group, etc., and the conditions of the reaction carried out at this time are the same as those of the above-mentioned process A-Κ. For the solvent, the protecting group, and the base, the user of the above Process A-1 -1 can also be used. [Production Process Β-5] The compound of the present invention represented by the formula (1) (^ is a compound of _NR1Gc〇_, which can be produced by the following method. [Chem. 11] w--C0

(3f) L-Y——NHR (4f)

Z-Y-Q

(wherein '", ~, ", ... denotes the same as above, 'Q denotes -NR1QC0_, W6 represents a transrading or a leaving group.) The compound (I) of the present invention can be reacted with the compound (4f) by the compound (10) It is produced by forming a guanamine bond (-NR1GCO-). When W6 of the compound (3f) is a hydroxyl group, it is the same as the above-mentioned process A-1 -1. In addition, as an example of the leaving group of w6, a gas atom, a sulfonium A wm, a succinyl group, a hydrazine group, and the like are mentioned, and the reaction conditions are also The above fj method Δ ! π Jiang I is the same as 11·1. The solvent, the protecting group, and the base may be used as described in the above-mentioned Process A-1 _1. [Process B-6] Formula (I) The compound of the present invention, which is represented by the present inventors, can be produced by the following method. [Chemical 12] 118505.doc -32 - 200806611

(wherein R1 to R6, R11, A, V, ¥ and 2 represent the same as described above, q represents -CH2NRnCO-, and W6 represents a radical or a leaving group). Namely, the compound (1) of the present invention can be produced by reacting the compound (3f) with the compound (4g) to form a guanamine bond (-CH2NR "CO-). In the case where W6 of the compound (3f) is a hydroxyl group, the compound (1) can be produced by the same reaction conditions as in the above Process A-1. Further, examples in which w6 is a leaving group include a chlorine atom, a p-nitrophenoxy group, an azide group, etc., and the reaction conditions are also the same as in the above-mentioned production method Aqq. The solvent, the protecting group, and the test can also be used in the above-mentioned Process A-1 -1. [Production Process B-7] In the compound of the present invention represented by the formula (I), Q is a compound which is called a postal compound, and can be produced by the following method. [Chem. 13]

(wherein n~, v, uz represents the same as the above, and represents a _CH2CH2NRl2cmw group or a leaving group). The compound (1)' of the present invention can be produced by compounding (3f) with a compound to form a guanamine bond (-CH2CH2NR12CO-).

Q (1) The compound (1) should be produced in the same reaction conditions as in the above-mentioned Process A-W in the case where the compound (3f) is a hydroxyl group, when W6 is a hydroxyl group, 118505.doc • 33-200806611 1-1. Examples of x include a chlorine atom, a p-methoxy group, a gas group, and the like. The reaction conditions are also the same as those in the above-mentioned process A-Μ. For the solvent, the protecting group, and the test, the user of the above Process A-1 -1 can also be used. As described above, the S1P receptor agonist can be used as an immunosuppressive agent. The compound of the present invention represented by the formula (I), a salt thereof, and the like, have a agonist effect on the s1P receptor (especially the 811 > 1 receptor), and are used as an immunogen The active ingredient of the inhibitor can be used as an active ingredient of a therapeutic agent and/or a prophylactic agent for rejection of a mammal, especially a human transplant, an autoimmune disease, an allergic disease, and the like. Further, it is considered that the compound of the present invention, a salt thereof, and the like thereof are administered orally in a mouse model to reduce the number of lymphocytes in the peripheral blood of the mouse, and thus can be used as a Oral active ingredients such as immunosuppressive agents. Further, these medicines have fewer side effects such as bradycardia seen in other Slp receptor agonists. Among them, the rejection reaction to transplantation means liver, kidney, heart, viscera, lung, small intestine, skin, cornea, bone, embryo tissue, bone charm cell, hematopoietic stem cell, peripheral blood stem cell, cord blood stem cell, islet cell, Transplantation of hepatocytes, nerve cells, intestinal epithelial cells, etc., after transplantation, • Acute rejection within 3 months and subsequent chronic rejection, and graft versus host disease. Further, examples of the autoimmune diseases include collagen disease, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, renal disease syndrome, lupus nephritis, and Sj0gren syndrome. 118505.doc -34- 200806611 Scleroderma, polymyositis, psoriasis, inflammatory bowel disease, Crohn's disease, mixed connective tissue disease, primary mucinous edema, Addison's disease ), aplastic anemia, autoimmune hemolytic anemia, autoimmune thrombocytopenia, autoimmune diabetes, uveitis, anti-receptor disease, myasthenia gravis, sputum gland poisoning, Thyroiditis, Hashim〇t〇, s disease, etc. Further, as for the allergic disease, for example, atopic dermatitis 'asthma, rhinitis, conjunctivitis, hay fever, and the like can be cited. When a compound of the present invention represented by the formula (I), a salt thereof, or a solvate thereof is administered to a mammal (especially a human), it may be administered systemically or locally, orally or Donate in a non-oral manner. The medicine of the present invention can be selected according to the administration method, and is prepared according to the preparation method of various preparations which are usually employed. As for the dosage form of oral medicine, it can be exemplified by tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, syrups, and ugly agents: the preparation of the medicine of the dosage form can be as needed Use self-pass =: shape:, adhesive, disintegrant, lubricant, swelling agent, swelling: ^ clothing μ, plasticizer, stabilizer, preservative, antioxidant toner, dissolution aid, suspending agent , (RVative), buffer_porogen, sweetener, preservative, and then prepared according to the usual method. Choose a non-orally used medicine to climb over the gel, (4): injection, ointment, eye drops, nasal drops, suppositories, inhalation = inhalation, inhalation, spray, drop ^ 4 ° the dosage form Preparation of Medicine, 118505.doc -35- 200806611 It can be used as a stabilizer, preservative, dissolution aid, preservative, preservative, antioxidant, flavoring agent, gelatinization which is usually used as an additive. Agent, neutralizer, dissolution aid, buffer, isotonic agent, surfactant, colorant, buffering agent, thickener, wetting agent, filling enthalpy, adsorption promoter, suspending agent, binder, etc. Appropriate selection, and then according to the usual method of preparation. The pharmaceutical of the present invention can be prepared by using a compound represented by the formula (1), a salt thereof, or a solvate thereof, and an antibody selected from the group consisting of an immunosuppressive agent, an antibody for immunosuppression, a therapeutic agent for rejection, and an antibiotic. A type of work in a steroid drug or a combination of two or more drugs. This medicine is a compound of the present invention represented by the formula (1), a salt thereof, or a solvate thereof, and a combination of one or two or more other agents, and is administered as a concomitant medicine. The compound of the present invention, a salt thereof, or a solvate thereof, which is represented by the above, may be added to the medicinal preparation as a mixture of the two components, or may be administered as a single preparation. By. In the case of separate administration, each preparation may be administered at the same time, and the time difference may be set before and after, and the administration methods of the preparations may be the same or different. The medicines are also prepared as a compound represented by the formula (1), a salt thereof, or a solvate thereof, and a therapeutic agent selected from the group consisting of an immunosuppressive agent, an antibody for immunosuppression, an antibiotic, and a steroid drug. A kit in which one or two or more other drugs are combined. More specifically, as the immunosuppressant, the antibody for immunosuppression, and the therapeutic agent for rejection, for example, cyclosporin A (cyci〇-heart A), tacrolimus (ta_imus, FK5G6), sulfur μ can be cited.呤(四), 118505.doc -36- 200806611 Mizoribine, methotrexate, mycophenolate mofetil, cyclophosphamide, sirolimus , everolimus, prednisolone, methylprednisolone, Orthoclone OKT3, antihuman lymphocyte globulin, deoxyspergualin Wait. As the antibiotic, for example, cefuroxime sodium, meropenem trihydrate, netilmicin sulfate, sisomicin sulfate, ceftibuten (ceftibuten), PA_ 1806, IB-367, tobramycin, PA-1420, doxorubicin, astromicin sulfate, cefetamet pivoxil hydrochloride As for steroid drugs, for example, clobetasol propionate, diflorasone diacetate, fluocinonide, and mometasone decanoate (mometasone furoate), betamethasone dipropionate, beta-propionate betamethasone, betamethasone valerate, difluprednate, budesonide, difluoro-cortisol Diflucortolone valerate, amcinonide, halcionide, dexamethasone, dexamethasone propionate, valerate Pine, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrogenation of butyrate propionate 118505.doc -37- 200806611 cortisone, deprodone propionate, Prednisolone acetate, fluocinolone acetonide, beclomethasone propionate, triamcinolone acetonide, flumesone pivalate, alclometasone propionate ), clobetasone butyrate, prednisolone, beclomethasone dipropionate, fludroxycortide, cortisone acetate, hydrocortisone, hydrocortisone sodium , sodium succinate hydrocortisone, flucorconazole acetate, prednisolone acetate, prednisolone succinate, prednisolone butyl acetate, sodium prednisolone phosphate, brine prednisolone Halopredone acetate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone citrate, dexamethasone Naphtha Dexamethasone, paramethasone acetate, betamethasone, fluticasone propionate, flunisolide, ST-126P, ciclesonide, dexamethasone palomithionate, mometa Pine vinegar, prasterone sulfonate, deflazacort, methylprednisolone only k7. Xi Xiao Yi Bu, succinic acid methyl prednisolone sodium and so on. The amount of the compound of the present invention represented by the formula (I), a salt thereof, or a solvate thereof, varies depending on the symptoms, age, body weight, type and amount of the administered pharmaceutical agent, and the like. It is generally preferred that the amount of the compound (I) is administered in an amount ranging from 1 ng to 1000 mg per adult per person, or once or several times per day, orally or several times. Or continue intravenous administration within the range of 1 hour to 24 hours per 118505.doc -38 - 200806611. [Examples] Hereinafter, the test methods and test results of the compounds of the present invention will be specifically and specifically described to explain the pharmacological effects of the compounds of the present invention. [Example 1] (s)_3-hydroxy-4' oxo-4-{4-[(4-phenyl-5-trifluoromethyl-' 2 -thienyl)methoxy]phenylamine Butyl acid (1) (4-phenyl-5-trifluoromethyl-2-nonyl)methanol [14]

4-Phenyl-5-trifluoromethylthiophene-2-carboxylic acid (3.52 g) was dissolved in tetrahydrofuran (60 Π11), and the mixture of sinter-tetrachlorotr-furan was added dropwise to the temperature. A solution of tetrahydrofuran (26 ml). After the reaction solution was heated to reflux for 3 hours, it was cooled to 0 ° C, and water was added dropwise to terminate the reaction. The reaction solution was extracted with ethyl acetate, and the obtained organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate and evaporated toiel NMR (CDC13) δ: 1·99 (1H, t, J=6.0 Ηζ), 4·87 (2H, d, J=5.6 Hz), 6·98-7·00 (1H, m), 7.37-7.42 (5H, m). (2) 2-Trifluoromethyl-5-(4-nitrophenoxymethyl)_3-phenylthiophene [Chemical 15]

A solution of (4-phenyl-5-difluoromethylthienyl)methanol (185 g) in dry tetrahydrofuran (70 ml) The azodicarboxylic acid diiso is added under the armpit: 酽 (1.51111) and triphenylphosphine (2.0 §), _3 〇 minutes. Following the addition of phenol (996 mg), it was stirred at room temperature for 2 hours. After adding water to the reaction mixture, the mixture was extracted with ethyl acetate, and the layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by silica gel chromatography (hexane: ethyl acetate = 20:1) to afford the title compound (2.02 g) as an oil. NMR (CDC13) δ: 5·33 (2H, d, J = 0.7 Hz), 7.05-7.09 (2H, m) 7.12-7.13 (1H, m), 7.41-7.43 (5H, m), 8.23-8.27 ( 2H, m). '(3) 4-[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamine [Chemical 16]

2 -Difluoromethyl-5-(4-nitrophenoxymethyl)-3-phenyloxime (2.02 g) and 10% palladium hydroxide (2.0 g) were suspended in ethanol (50 ml) In the chlorine environment, it is good to mix: 17 hours. After the reaction mixture was filtered, the obtained filtrate was concentrated. The residue obtained was eluted with hexane: ethyl acetate (5: EtOAc) to give the title compound (1. 2 g) as an oil. NMR (CDC13) δ: 5.13-5.15 (2H, m), 6·64_6·68 (2H, m) 6.81-6.85 (2Η, m), 7·04-7·05 (1Η, m), 7.38-7.43 (5Η, m). MS (ESI) m/z: 350 (M+H). (4) (S)_3-hydroxy-4-oxoyl·4-{4-[(4-phenyl-5·trifluoromethyl_2_嚷118505.doc -40- 200806611 phenyl) anthracene Phenylamino}butyric acid [Chemical 17], i>°

Add (s)-2,5-dioxotetrahydrofuran to a solution of 4-[(4-phenyl-5-trifluoromethyl-2-phenyl)methoxy]phenylamine (150 mg) in dry tetrahydrofuran 3. Trifluoroacetate (273 mg), stirred for 18 hours. After the reaction mixture was concentrated under reduced pressure, the obtained residue was purified by high-performance liquid chromatography (hereinafter referred to as HPLC). Hexane was added to the obtained oil, and crystals were precipitated by filtration to obtain a labeled compound (115.2 mg) as a solid. NMR (DMSO-d6) δ: 2.43-2.48 (1H, m), 2.71 (1H, dd, J = 15.6, 4.2 Hz), 4.37 (lH, q, J = 4.2 Hz), 5.36 (2H, s), 7.00-7.03 (2H,m),7·37 (1H,d,J=1.2 Hz),7.43-7.55 (5H,m), 7.62-7.66 (2H5 m)? 9.67 (1H5 s) MS (ESI) m /z: 466 (M+H) 〇 [Example 2] (R)-3-methyl-4-oxoyl-4-{4-[(4-phenyl-5-trifluorodecyl-2 -thienyl)methoxy]phenylamino}butyric acid [Chemical 18]

Add to ([(4-phenyl-5-trifluorodecyl-2-)thienyl)methoxy]phenylamine (3() mg) 118505.doc -41 - 200806611 ) _2_methyl succinate-methyl ester (22 μΐ), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (16 mg), 1- Hydroxybenzotriazole (5 mg), stirred for 18 hours. The mixture was distilled off and the residue obtained was dissolved in dimethyl sulfoxide (1 ml), and then aqueous sodium hydroxide (1 〇〇 μl) was added and stirred for 21 hours. Hydrochloric acid (50 μM) was added to the reaction solution to carry out _ and the reverse phase separation of HpLC was carried out to obtain a labeled compound (16.1 mg) as a solid.

NMR (DMS〇-d6) δ: 1.12 (3H? d5 J=7.3 Hz)5 2.25-2.39 (1H5 m), 2.76-2.84 (1H, m), 5.35 (2H, s), 6.98-7.02 (2H, m), 7.36-7.38 (1H, m), 7·43·7·54 (7H, m), 9.84 (1H, s) MS (ESI) m/z: 464 (M+H). [Solution Example 3] (R)_3_hydroxy_4_oxoyl_4 gas 4_[(4-phenyl·5-trifluoromethyl-2-thienyl)methoxy]phenylamino} Butyric acid [Chemical 19]

4-[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamine (1〇5 mg), trifluoroacetic acid (R)-2,5-dioxotetrahydrofuran_3 • Base oxime 31 mg), dry tetrahydrofuran (1.5 ml), and mix at room temperature overnight. After concentrating the reaction mixture, it was purified by reverse phase separation HPLC to obtain a labeled compound (39 mg). δ R (DMS 〇-d6) δ: 2.43-2.47 (1H, m), 27i (ih, machine 1 = 15.6, 4.3 Hz), 4.34-4.40 (1H, m), 5.36 (2H, s), 5.98 (1H, 118505.doc • 42- 200806611 d, J=6.1 Hz), 7.01 (2H, dt, J=10.0, 2.8 Hz); 7·37 (1H, d, J=1.2 Hz), 7.42-7.53 (5H, m), 7.62-7.66 (2H, m), 9.67 (1H, s), 12.24 (1H, br s). MS (ESI) m/z: 466 (M+H) 〇 [Example 4] 4-oxoyl-4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl) Methoxy]phenylamino}butyric acid [Chemical 20]

4-[(4-Phenyl-5-tris-methyl-2-oxanyl)methoxy]phenylamine (105 mg), succinic anhydride (60 mg), dry tetrahydrofuran (1.5 ml) ), mixed and stirred at room temperature overnight. After concentrating the reaction mixture, the residue was purified by reverse phase separation HPLC to give the title compound (71 mg). NMR (DMSO-d6) δ: 2.49-2.53 (4H? m)5 5.35 (2H3 s)5 7.00 (2H, dt, J = 10.0, 2.8 Hz), 7.37 (lH, d, J = 1.2 Hz), 7.42 -7.54 (7H, m), 9.86 (1H, s). MS (ESI) m/z: 450 (M+H). [Example 5] (R)-2-Hydroxy-4-oxoyl-4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamine Butyl acid

118505.doc -43- 200806611 Methanol/liquid (1·5 ml) of (R)-2,5-dioxotetrahydrofuran-3-yl ester (218 mg) was shaken at room temperature After 5 hours, concentration was carried out. 4-[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamine (349 mg), 1-ethyl_3_(3-dimethylaminopropyl) was added to the residue. Carbide diimine hydrochloride (192 mg), 1-hydroxybenzotriazole (catalyst amount) and triethylamine (139 μM) in tetrahydrofuran (2 ml), shaken overnight at room temperature . After concentrating the reaction mixture, tetrahydrofuran (丨 ml), methanol (2 ml) and 1N aqueous sodium hydroxide solution (1.5 ml) were added, and the mixture was shaken at room temperature for 3 hours. After adding 1 equivalent of hydrochloric acid (1.5 ml) to the reaction mixture, the residue obtained by concentration was purified by reverse phase separation HPLC to give the title compound (48 mg). NMR (DMSO-d6) δ: 2.44-2.46 (1H, m), 2.55-2.56 (1H, m), 2.66-2.70 (1H, m), 4.34-4.38 (1H, m), 5.35 (2H, s) ,7_〇ι (2H,d,J=9.1 Hz),7·37 (1H,s),7.42-7.52 (6H,m), 7.64 (1H,d,J=9.1 Hz),9.67 (1H, s), 9·89 (1H, s). MS (ESI) m/z: 466 (M+H) 〇 [Example 6] (S)-2-hydroxy-4-oxoyl-4_{4-[(4·phenyl-5-trifluoromethyl) Base 2- 2-thienyl)methoxy]phenylamino}butyric acid [Chemical 22]

A (M) solution of (S)-2,5-dioxotetrakis-zircon-3-yltriacetic acid vinegar (218 mg) (1.5 ml) was stirred at room temperature for 5 hr and then concentrated. 4-[(4-Phenyl-5-trifluoromethyl-2·thienyl)decyloxy]aniline was added to the residue 118505.doc -44- 200806611 (349 mg), 1-ethyl-3_(3 - dimethylaminopropyl)carbonated triterpene imide hydrochloride (192 mg), 1-hydroxybenzotriazole (catalytic amount) and triethylamine (139 μM) in tetrahydrofuran (2 ml), Shake overnight at room temperature. After concentrating the reaction mixture, tetrahydrofuran (丨 ml), methanol (2 ml), and i aqueous sodium hydroxide (1.5 ml) were added to the residue, and the mixture was shaken at room temperature for 3 hours. To the reaction mixture was added 1 as hydrazine hydrochloride (1.5 mi), followed by concentration, and the residue obtained by reverse phase separation was purified by HPLC to obtain a labeled compound (63 mg). NMR (DMSO-d6) δ: 2.44-2.46 (1H, m), 2.54-2.57 (1H, m), 2.62-2.74 (1H, m), 4·34-4·39 (1H, m), 5· 35 (2H, s), 7·01 (2H, d, J = 9.0 Hz), 7.37 (1H, s), 7.42-7.55 (6H, m), 7.64 (1H, d, 9.0 Hz), 9.67 ( 1H, s), 9.90 (1H, s). MS (ESI) m/z: 466 (M+H). [Example 7] 3,3-dimethyl-4-oxoyl_4-{4_[(4-phenyl-5-trifluoromethyl-2-phenylthio)methoxy]phenylamino }butyric acid [Chemical 23]

4-[(4-Phenyl-5-trifluoromethyl_2-thienyl)decyloxy]aniline (24 1^), 3,3-methyltetrahydrocarbamate_2,5_2 The dry tetrahydrofuran solution (0.5 ml) of the ketone (97111 §) was shaken overnight at room temperature. After concentrating the reaction mixture, the obtained residue was purified by reverse phase separation HPLC to give the title compound (j 2 mg). NMR (DMSO-d6) δ: 1.19 (6H, s), 2.53 (2H, s), 5.35 (2H, s), 118505.doc -45-200806611 6·99 (2H,d,J=9.1 Ηζ), 7·37 (1H, s), 7.42-7.51 (7H, m), 9·79 (1H, s), 12.03 (1H, br s). MS (ESI) m/z: 478 (M+H) 〇 [EXAMPLE 8] (S) _ 3-methyl-4-oxoyl-4-{4-[(4-phenyl-5-trifluoro) Methyl-2-thienyl)nonyloxy]phenylamino}butyric acid [Chemical 24]

4-[(4-Phenyl-5-trifluoromethyl-2-thienyl) decyloxy]aniline (105 mg), (S)-3-methyl-tetrahydrofuran-2,5- A solution of diketone (60 mg) in dry tetrahydrofuran (1.5 ml) was stirred at room temperature overnight. After concentrating the reaction mixture, the residue obtained was purified by reverse phase separation HPLC to give the title compound (71 mg). NMR (DMSO-d6) δ·· 1·12 (3H,d,J=7.1 Ηζ), 2·24-2·39 (1H, m), 2.54-2.66 (1H, m), 2·75-2 · 86 (1H, m), 5.35 (2H, s), 7.00 (2H, d, J = 9.1 Hz), 7.37 (1H, s), 7.42 - 7.55 (7H, m), 9·83 (1H, s ), 12.11 (1H, br s). MS (ESI) m/z: 464 (M+H). [Example 9] (2S,3R)-2,3-dimethyl-4-oxoyl-4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl) A Oxy]phenylamino}butyric acid (1) (3R,4S)-3,4_:methyltetrahydrofuran-2,5-dione [Chem. 25] 118505.doc -46- 200806611

Trifluoroacetic anhydride (1·8 1 ml) was added to (2S,3R)-2,3-dimercaptosuccinic acid (73 1 mg) for 3 hours at 0 C. The reaction solution was concentrated to give the title compound (650 mg). (2) (2S,3R)_2,3·Dimethyl-4-oxoyl-4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]benzene Amino acid}butyric acid [Chemical 26]

Add 4-[(4-phenyl-5-trifluoromethyl-2-thienyl) to (3R,4S)-3,4-dimethyltetrahydrofuran-2,5-dione (1 mg) Methoxy]aniline (28 mg) of four murine cum/cold (1 ml) was stirred at room temperature overnight. After concentrating the reaction mixture, the residue obtained by reverse phase separation HPLC was purified to give the title compound (6.5 mg) NMR (DMSO-d6) δ · 1.06 (3H, d, J = 7.0 Hz), 1.07 (3H, d J=6.8 Hz), 2·44-2·67 (2H, m), 5·36 (2H, s) 5 6.99-7.03 (2H, m), 7·37 (1H, s), 7.42-7.56 ( 7H, m), 9.99 (lH, br s). MS (ESI) m/z: 478 (M+H) 〇 [Example 10] (2R,3R)-2,3-dihydroxy-4.oxoyl ice {heart [(4_phenyltrifluoro) Benzyl-2-fluorenyl)methoxy]phenylaminoindolic acid [Chem. 27] 118505.doc -47- 200806611 CF,

Add (+)-diethylindenyl-L-tartaric anhydride (17 mg) and dehydrogenated [(phenylphenyl-5-trifluoromethylthienyl)methoxy]phenylamine (28 mg) in tetrahydrofuran (1 ml ), stirring at room temperature overnight. After concentrating the reaction mixture, 1N aqueous sodium hydroxide solution (250 μM), tetrahydrofuran (250 μM), and methanol (250 μM) were added to the residue and shaken at room temperature for 2 hours. 1N hydrochloric acid (25 〇, μ1) was added thereto, concentrated, and purified by reverse phase separation HPLC to obtain a labeled compound (9.1 mg). NMR (DMSO-d6) δ: 4.36 (1Η, br s)5 4.40 (1H? br s), 5.36 (2H, s), 7.02 (2H, dt, J=9.8, 2.8 Hz), 7·38 (1H , d, J = 1.2 Hz), 7.42 - 7.51 (5H, m), 7.64 - 7.68 (2H, m), 9.91 (1H, s). MS (ESI) m/z: 482 (M+H). [Example 11] (2S,3S)-2,3-di-diyl-4-oxo-4-{4-[(4-phenyl.5-trifluoromethyl-2-thienyl) anthracene Phenylamino-based indolebutyric acid η [28]

Add (-)-diethylindenyl-L-tartaric anhydride (17 mg) and 4-[(4-phenyl-5-trifluoromethyl-2-synyl)methoxy]phenylamine (28 mg The tetrahydrofuran solution (1 ml) was stirred at room temperature overnight. After concentrating the reaction mixture, i-q. sodium hydroxide aqueous solution (250 μM), tetrahydrofuran (250 μM), methanol -48-118505.doc 200806611 (25 〇μ1) was added to the residue, and the mixture was shaken at room temperature for 2 hours. The residue obtained by the purification of the reverse phase separation HPLC was added to the residue obtained by the mixture of <RTI ID=0.0>> NMR (DMSO-d6) δ: 4.36 (1Η, d5 J=2.2 Hz), 4.39 (1H, d, J=2.2 Hz), 5.36 (2H, s), 6.99-7.04 (2H, m), 7.38 (1H , d, J=1.2 Hz), 7.42-7.51 (5H, m), 7.66 (2H, d, J=8.8 Hz), 9 51 (1H, s) 〇MS (ESI) m/z: 482 (M+ H).

[Example 12] (R)-3-Amino-4-oxoyl_4_{4_[(4-phenyl·5•trifluoromethyl-2-thienyl)methoxy]phenylamino }丁酸[化29]

4.[(4.Phenyl-5·trifluoromethyl-2-phenyl)phenyl]aniline _mg) was dissolved in dichloromethane (ml)-acetonitrile (1), added (8) trifluoro Ethylamine succinic anhydride (64.2 mg). After stirring at room temperature for 15 minutes, the solvent was distilled off to obtain a solid (17 〇mg) e. The solid was dissolved in methanol (1 〇ml), and 1 eq. The sodium aqueous solution (3 〇ml) was heated and stirred for 8 hours. The reaction solution was neutralized with hydrochloric acid. The residue obtained by reverse phase separation HPLC was purified (4) to obtain the labeled compound (34.2 mg). NMR (DMSO-d6) δ: 2.33 (1H, dd, J=16, 9.2 Hz), 2.55 (1H, dd, J=16, 5.2 Hz), 3.76 (1H, dd, 1=9.2, 5.2 Hz) , 5.36 (2h! 118505.doc -49- 200806611 br s),7.03 (2H,m),7·37 (1H,m),7.43-7.50 (5H,m),7.55 (2H,m) 〇MS ( ESI) m/z: 465 (M+H). [Example 13] (S)-3-amino-4-oxoyl-4_{4-[(4-phenyl-5·trifluoromethyl) -2-thienyl)methoxy]phenylamino}butyric acid [Chemical 30]

H2n-^-c Fc 4-[(4-Phenyl-5-trifluoromethyl-2-thienyl) decyloxy]aniline (1 〇〇mg) was dissolved in di-methane (5 ml) and acetonitrile (1 ml) of the mixture was then added (S)-2-trifluoroacetamide succinic anhydride (64·2 mg). After stirring for 15 minutes at room temperature, the solvent was evaporated to give a solid (17 mg). The solid was dissolved in methanol (10 ml), and then 1N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred under heating at 60 ° C for 8 hours. The reaction liquid was neutralized with 1 N hydrochloric acid, and then the solvent was evaporated under reduced pressure. The residue obtained was purified by reverse phase separation HPLC to give the title compound (26.1 mg) as a solid. NMR (DMSO-d6) δ: 2.34 (1H, dd, J=16, 9·2 Ηζ), 2·56 (1H, dd, J=16, 5.2 Hz), 3.77 (1H, dd, J=9.2, 5·2 Hz), 5.36 (2H, br s), 7.03 (2H, m), 7.37 (1H, m), 7.43-7.49 (5H, m), 7.55 (2H, m). MS (ESI) m/z: 465 (M+H) 〇 [Example 14] (S)-2-amino-4-oxoyl-4-{4-[(4-phenyl-5_3 Fluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid 118505.doc -50- 200806611 [Chem. 31]

4-[(心心基-5_Trifluoromethyl 2,thienyl)methoxy]phenylamine (12〇mg) and (S)-2-trifluoroacetamide succinic acid 1-methyl ester (84.1 mg) dissolved in a mixture of methylene chloride (5 ml) and dimethylformamide 〇^1), with 1-ethyl-3-(3-dimethylaminopropyl) carbonation Diimine imine hydrochloride (72.3, ^ benzotriazole (55.7 mg), stirred at room temperature for 12 hours. The residue obtained by distilling solvent was dissolved in ethyl acetate (30 ml). The obtained solution was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (5 ml), 10% aqueous citric acid (5 ml), water (5 ml) and brine (5 mi), and dried over anhydrous sodium sulfate. Hexane/ether (1··1) (5 ml) The solid obtained by distilling off the solvent was washed twice, and then dried under reduced pressure to obtain a powder (142 mg). The powder was dissolved in methanol (1) 〇ml), then 1 equivalent of aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred under heating for 12 hours. The reaction mixture was neutralized with i-eq. hydrochloric acid, and the solvent was evaporated under reduced pressure. Refining the residue obtained As a solid (21 · 3 mg) of the labeled compound.

NMR (DMSO-d6) δ: 2·93 (1H, dd, J=l7, 5] Hz), 3.52 (1H dd, J=7.3, 5.1 Hz), 5.35 (2H, br s), 7·〇2 (2H,m),7 37 (out m),7.43-7.54 (8H,m),10·6 (1H,br s) 〇MS (ESI) m/z: 465 (M+H) o [Examples 1 5] (R)-2-amino-4-oxoyl-4-{'[(heart phenyl_5_di 118505.doc -51- 200806611 yl-2-thienyl)methoxy]benzene Aminobutyric acid [32]

4-[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamine (160 mg) and (R)-2-trimethylacetamide succinic acid 1-methyl vinegar (134 mg) dissolved in a mixture of dichloromethane (5 ml) and dimethylformamide (1 mi), added with 丨_ethyl_3-(3-dimethylaminopropyl) carbonized The quinone imine hydrochloride (114 mg), 1-hydroxybenzotriazole (80.4 mg) was stirred at room temperature for 12 hours. The solvent was evaporated, and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The obtained solution was washed (5 ml) and dried over anhydrous sodium sulfate. The solid obtained by distilling off the solvent with hexane/ether (1:1) (5 ml) was washed twice, then dried under reduced pressure to give a powder (179 mg). This powder was dissolved in methanol (1 ml), and then 1N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred under heating at 70 ° C for 12 hours. After neutralizing the reaction liquid with i equivalent of the salt, the solvent was removed under reduced pressure. The residue obtained was purified by reverse phase separation of Hplc to give the title compound (29 5 mg) as a solid. NMR (DMSO-d6) δ: 2.93 (1H, dd, J=16, 4.8 Hz), 3.52 (1H, t, J = 4.8 Hz), 5·35 (2H, br s), 7·01 (2H, m), 7.37 (ih, m), 7.43-7·54 (8H, m), 10.6 (1H, br s) 〇MS (ESI) m/z: 465 (M+H). 118505.doc -52- 200806611 [Example 16] (S)-3-hydroxy-4-oxoyl-4_{4-[(4-phenyl-5-trifluoromethyl-2-septenyl) Ethyl]phenylamino}butyric acid (1)5-gasmethyl-3-phenyl_2-trisinoinyl π-septene [33]

To a solution of (4-phenyltrifluoromethyl-2-thienyl)methanol (482 mg) in dioxane (7.0 ml) was added sulphur chloride (708 μl) at room temperature. After stirring at 50 ° C for 16 hours, it was concentrated under reduced pressure, and the obtained oily residue was eluted with hexane to obtain the title compound (434 mg) as oily substance. . NMR (CDC13) δ: 4.77 (2H, d, J = 〇.7 Hz), 7.07 (1H, br s), 7.35-7.44 (5H, m). (2) 5-[(E)-2-(4-Nitrophenyl)ethenyldiphenyl-3-phenyl-2-trifluoromethyl phenanthrene

To 5-methoxymethyl-3-phenyl-2-trifluoromethylthiophene (4 mg), triethyl phosphite (520 μM) was added at room temperature at 15 Torr. Stir under the arm for 5 hours. The reaction liquid was concentrated under reduced pressure, and then the obtained oily residue was eluted with hexane/ethyl acetate (75:25 - 0: 100) to obtain triethyl phosphite. (4-Phenyl-5·trifluoromethyl-2·nonyl)-methyl 118505.doc -53- 200806611 Diethyl phosphinate (480 mg). This was dissolved in tetrahydrofuran (3. 〇 mi), sodium hydride (5 5% oil suspension) (60.0 mg) was added at 〇 ° C, and stirred at room temperature for 30 minutes. To the reaction mixture was added 4-nitrobenzaldehyde (19 〇 mg) in tetrahydro urethane (5·0 ml). After stirring at room temperature for 1 hour, water (30 ml) and ethyl acetate (2 ml) were added to the reaction mixture, and the mixture was separated, and the aqueous layer was extracted with ethyl acetate (2 ml). The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was eluted with hexane/ethyl acetate (100: 0 - 90: 1 Torr) using EtOAc (t. NMR (CDC13) δ: 7.06 (1H, d, J = 16.1 Hz), 7.15 (1H, br s) 7.32 (1H, d, J = 16.1 Hz), 7.37-7.47 (5H, m), 7·62 ( 2H,d, J=8.9 Hz), 8·24 (2H, d, J=8.9 Hz). (3) 4·[2-(4-Phenyl-5·trifluoromethyl-2-thienyl)ethyl]aniline [Chem. 35]

In a solution of 5-[(E)-2-(4-nitrophenyl)vinyl)-3-phenyl-2-trifluoromethylthiophene (95.0 mg) in tetrahydrofuran (5·〇ml) Methanol (10 ml) and 20% palladium hydroxide (47·5 mg) were added at room temperature, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure, and the obtained residue was eluted with hexane/diethyl ether (2:1) to obtain the title compound as an oil. NMR (DMSO-d6) δ: 2.90 (2H5 t? J=8.3 Hz), 3.08 118505.doc -54- 200806611 J=8.3 Ηζ), 3·59 (2H, br s), 6.64 (2H, d, J = 8.2 Ηζ), 6.75 (1H, br s), 6.99 (2H, d, J = 8.2 Hz), 7.33 - 7.43 (5H, m) MS (ESI) m/z: 348 (M +H) (4) (S)-3-Hydroxy-4-oxoyl_4j4-[('phenyl-4-trifluoromethyl-2-thiophenethyl)ethyl]phenylamino}butyric acid [化36]

Add (S)- at room temperature to a solution of 4-[2-(4-phenyl-5-trifluoromethyl-2-thiophenyl)ethyl]phenylamine (85 mg) in tetrahydrofuran (3.0 ml) 2,5-Dioxytetrahydrofuran-3-yltrifluoroacetate (156 mg) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was evaporated to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj NMR (CDC13) δ: 2.45 (1H5 dd, J=15.65 8.3 Hz), 2.68 (1H5 dd, J=15.6, 4.2 Hz), 2·93 (2H, t, J=7.6 Hz), 3.16 (2H, t , J=7.6 Hz), 4.36 (1H, dd, J=8.3, 4.2 Hz), 7.04 (1H, s), 7.19 (2H, d, J=8.5 Hz), 7.36-7.50 (5H, m), 7 · 62 (2H, d, J = 8.5 Hz), 9.7 (1H, s). MS (ESI) m/z: 464 (M+H) 〇 [Example 17] (S)-3-hydroxy-4-oxoyl-4-{4-[(E)-2-(4-benzene 5--5-trifluoromethyl-2-thienyl)vinyl]phenylamino}butyric acid (1) 4-[(E)-2-(4-phenyl-5-trifluoromethyl-2 -thienyl)vinyl]benzamide 118505.doc -55- 200806611 Methyl ester [Chem. 37]

Trimethyl phosphite (650 μM) was added to a solution of 5% methyl 3-phenyl-2-trimethylmethyl sigma (500 mg) at room temperature and stirred at 150 ° C for 5 hours. After concentrating under reduced enthalpy, the oily residue obtained by dissolving the obtained oil-like residue was prepared by using the Shihua gum fast column chromatography method, and the obtained oily residue was obtained as an oil. A 3:1 mixture of the labeled compound and triethyl phosphite (703 mS). A solution of the mixture in tetrahydrofuran (5.0 ml) was obtained. The mixture was added dropwise to a suspension of sodium hydride (55% oil) (84.3 mg) in tetrahydro-fusane suspension (3.0 ml). After stirring for 30 minutes at 〇cc, it was simmered. A solution of decyl 4-methylmercaptobenzoate (264 mg) in tetrahydrofuran (3 〇 (5) 丨) was added dropwise to the reaction mixture. After stirring at room temperature for 13 hours, water (1 () ml), a saturated aqueous solution of ammonium chloride (20 ml), and diethyl ether (20 ml) were added dropwise to the mixture. Water layer. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated. The obtained residue was eluted by a flash-column column chromatography using hexane/methanol (100··0 - 0 : 1 〇〇) to obtain a labeled compound (3 67 mg) as a solid. NMR (CDCls) δ: 3.93 (3Η, s)5 7.05 (1H5 d5 J=i6.l Hz)5 7.i〇(1H,br s),7·26 (1H,d,J=16.1 Hz), 7.39-7.47 (5H,m), 7 54 (2H,d,J=8.4 Hz), 8·04 (2H,d,J=8.9 Hz). (2) 4-[(E)-2-(4•Phenyl-5-trifluoromethyl-2-thienyl)vinyl]benzene 118505.doc -56- 200806611 Formic acid [Chem. 38]

In a solution of 4-[(E)-2-(4-phenyl-5-trifluorodecyl-2-thienyl)vinyl]benzoate oxime (3 65 mg) in tetrahydrofuran (4. 〇ml) Methanol (2.0 ml) and 1 equivalent of aqueous sodium hydroxide (188 mi) were added at room temperature. After stirring for 18 hours at room temperature, the methanol and tetrahydrofuran in the reaction mixture were distilled off under reduced pressure. Water (10 ml) and 1N hydrochloric acid (1.88 ml) were added to the residue, and the resulting precipitate was filtered. Drying, thereby obtaining a labeled compound (250 mg) as a solid. NMR (DMSO-d6) δ: 7.33 (1Η, d, J=16.1 Hz), 7.42-7.52 (6H3 m), 7.62 (1H, d, J = 16.1 Hz), 7·72 (2H, d, J = 7.8 Hz), 7.94 (2H, d, J = 7.8 Hz). (3) 4-[(E)-2-(4-Phenyl-5-trimethylmethyl-2-σsepenyl)ethenyl]phenyl butyl carbamic acid tert-butyl ester [Chem. 39]

In a solution of 4-[(E)-2-(4-phenyl-5·trifluoromethyl-2-thienyl)vinyl]benzoic acid (100 mg) in hexanes (4.0 ml) Diphenylphosphonium azide (74.8 μM) and triethylamine (48.4 μM) were added at room temperature. The mixture was stirred at 80 ° C for 118 hours, and then the reaction mixture was concentrated under reduced pressure. (85.0 mg). NMR (CDC13) δ: 1·53 (9H, s), 6.52 (1H, br s), 6_97 (1H, d, J = 16.1 Hz), 7.01 (1H, d, J = 1.2 Hz), 7.06 (1H ,d,J=16.1

Hz), 7.33-7.48 (9H, m). MS (ESI) m/z: 390 (M+H-isobutylene). (4) 4-[(Ε)·2_(4_Phenyl-5-difluoromethyl-2·nonyl)vinyl] strepamine [Chemical 40]

In 4·[(Ε)·2-(4-phenyl-5-trifluoromethyl-2-thienyl)vinyl]phenylcarbamic acid tert-butyl ester (82.0 mg) at room temperature 4 equivalents of a solution of hydrochloric acid di 4 was added (4.0 ml). After stirring at room temperature for 2 hours, the reaction mixture was evaporated under reduced pressure. diethyl ether (2 ml) and saturated aqueous sodium hydrogen carbonate (20 ml) ) Extract the aqueous layer. The organic layers were combined, dried over anhydrous sodium sulfate and then evaporated. The residue obtained as a caramel-like substance (5〇3 mg) 〇 NMR (CDC13) δ was obtained by the separation of the residue obtained by hexane/ethyl acetate (3: hydrazine). : 3.81 (2Η, s), 6.67 (2H, d, 1=8.5 Hz), 6.9〇7.00 (3H,m), 7.30 (2H,d,J=8.5 Hz), 7.35_7 5〇(5H, called. MS (ESI) m/z: 346 (M+H) 〇118505.doc -58- 200806611 (5) (S)-3_^yl-4-oxoyl_4·{4·[(Ε)_2- (4-Phenyl-5·trifluoromethyl-2-thienyl)vinyl]phenylamino}butyric acid [Chemical 41]

In a solution of 4-[(Ε)-2-(4-phenyl-5-trifluoromethyl-2-thienyl)vinyl] phenylamine (48.7 mg) in tetrahydrofuran (3.0 ml) at room temperature (S)-2,5-Dioxytetrahydrofuran-3-yl ester (90 mg) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified from methylene chloride/methanol (10:1). 8·1 Hz), 2.72 4·4 Hz), 7.20 NMR (DMSO-d6) δ: 2.50 (1H, dd, J=15 6 (1H, dd, J=15.6, 4·4 Hz), 4·40 (1H, dd, J=8.1, 丄n, d,

Hz)5 7.43-7.44 (5H, m)? 7.57 (2H5 d5 J==8.6 Hz) 5 7.77 (2H J=8.6 Hz), 9·92 (1H, s). MS (ESI) m/z·· 346 (M+H). [Example (8) 4-oxo-M4-[(5-methyl-4-phenyl-synthesis) methyl & phenyl]phenylamino}butyric acid (1) 5-methyl-4-benzene Thiazole [2] formic acid ethyl ester [Chem. 42] H8505.doc -59- 200806611

2-Bromo-1-phenylpropan-1-one (1.59 g) was dissolved in ethanol (2 〇 mi), and ethyl thioketoacetate (1. oo g) was added at 70 °C. The reaction solution was heated to reflux for 19 hours and cooled to room temperature. The precipitate which precipitated was removed by filtration, and the obtained liquid was concentrated under reduced pressure. The obtained residue was eluted with hexanes/acetic acid ethyl acetate (95:5~>90:10) to obtain a labeled compound (1.29 g) as a powder. NMR (CDC13) δ: 1·44 (3H, t, J=7_l Ηζ), 2·63 (3H, s), 4.48 (2H, q, J=7.2 Hz), 7·35-7·40 (1H , m) 5 7.42-7.47 (2H, m), 7·64-7_68 (2H, m). MS (ESI) m/z: 248 (M+H). (2) (5-Methyl-4-phenyl-2-mercapto) methanol [Chem. 43]

Ethyl 5-methyl-4-phenylthiazole-2-carboxylate (〇.4〇g) was dissolved in tetrahydrofuran (10 ml), and lithium aluminum hydride (614) was stirred under ice-cooling and stirred for 15 min. Add acetone (five) hydrazine to the reaction solution and stir, add ιο% (+)-potassium potassium tartrate aqueous solution (5. Concentrate the reaction solution under reduced pressure, and extract the residue obtained by two-gas-burning. Combine the organic layer. After washing with saturated brine, it was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to dissolve 118505.doc 200806611 by column chromatography using medium pressure separation with hexane/ethyl acetate (57: 43 —40 : 60) The residue obtained was dissolved to give the title compound (250 mg) as an oil. NMR (CDC13) δ: 2·56 (3H, s), 2·66 (1H, br s) ,4·91 (2H,d, J=6.1 Hz), 7.32-7.37 (1H,m), 7.41-7.46 (2H,m)5 7.60-7.64 (2H,m) 〇MS (ESI) m/z: 206 (M+H). (3) l-{4-[(5-Methyl-4-phenyl-2-thiazolyl)methoxy]phenyl} π 比 咯 定 -2 -2,5 _酉同[化44]

(5-Methyl-4-phenyl-2-thiazolyl)methanol (50.0 mg) was dissolved in methylene chloride (5 ml), and sulphur sulphur (21.2 μM) was added under ice-cooling. The reaction mixture was stirred at 50 ° C for 1.5 hr, then stirred at room temperature for 16 hr. Dioxane was added to the residue, concentrated, and then toluene was added, and the solvent was evaporated to give 2-chloromethyl-5-methyl-4-phenylthiazole. Methyl 4-oxoyl-4-(4-hydroxyphenylamino)butanoate (53.6 mg) and sodium hydride (11.5 mg) were suspended in tetrahydrofuran (5 ml) and stirred at room temperature for 15 min. Then, it is disturbed for 15 minutes at 50 C. The tetranitronethane was concentrated under reduced pressure, and N,N-dimethylformamide (5 ml) was added to the residue, and the mixture was stirred at 60 ° C for 5 minutes and then cooled in an ice bath. A solution of 2-chloromethyl-5-methyl-4-phenylthiazole in N,N-dimethylformamide (5 ml) was added to the reaction mixture at room temperature 118505.doc -61 - 200806611 Mix 3 · 5 hours 'add sodium hydride (11 · 5 mg) and mix for 3 days at room temperature. The reaction mixture was concentrated under reduced pressure and the residue obtained was partitioned from ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate, and the organic layer was combined and washed with brine. Drying with anhydrous sodium sulfate, distilling off the solvent, and using a column chromatography by medium pressure separation, hexane/ethyl acetate (25:75 - 0: the residue obtained is eluted to obtain a mark as an oil. Compound (82·1 mg) 〇NMR (CDC13) δ: 2·57 (3H, s), 2.89 (4H, s), 5·37 (2H, s) 7.09-7.13 (2Η, m), 7.20-7.24 (2Η,m),7·34_7.38 (1Η m) 7.42-7.47 (2H, m), 7.61-7.65 (2H,m) MS (ESI) m/z: 379 (M+H) 〇(4) 4-oxoyl-4-{4-[(5-methyl-4-phenyl-2-indolyl)methoxy]phenylamino}butyric acid [45]

Dissolve 1-{4-[(5-methyl-4-phenyl-2-thiazolyl)methoxy]phenylpyrrolidine·2,5-dione (45 mg) in tetrahydrofuran (5 ml) An aqueous solution (1 ml) of lithium hydroxide (5.70 mg) was added and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was neutralized with aq. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a labeled compound (32, 5 mg) as a powder of <RTI ID=0.0>> NMR (CDC13) δ: 2·47·2·50 (4H, m), 2.52 (3H, s), 5.33 (2H, s), 6.99 (2H, d, J = 9.3 Hz), 7.35-7.37 (1H , m), 7·42-7·50 (4H, m), 7.62-7.66 (2H, m), 9.91 (1H, s). MS (ESI) m/z: 397 (M+H). [Example 19] 4-oxoyl-4-{4-[(5-phenyl-4-trifluoromethyl-2-indenyl)^methoxy]phenylamino}butyric acid (1) ) 5-phenyl-4-trifluoromethylthiazole-2-carboxylic acid ethyl ester [^t46]

Dissolve 1,1,1-trifluoro-3-phenylpropan-2-one (1·〇〇g) in dioxane (50 ml) and add bromine (0.270 ml) under ice cooling. Stir at room temperature for 2 hours. The reaction solution was stirred at 4 Torr for 3 hours, and further stirred at room temperature for 20 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the aqueous layer was extracted three times with dichloromethane. The organic layer was combined, washed with saturated brine and dried over anhydrous sodium sulfate. This was dissolved in ethanol (20 ml), and then added with ethyl thioketoacetate (〇. 4 g) was stirred at room temperature for 1 hour, and then heated to reflux for 4 hours. After concentrating the reaction mixture, the obtained residue was eluted with hexane/ethyl acetate (85: 15 - 50: 50) by column chromatography to obtain a labeled compound as an oil. 0.423 g). NMR (CDCla) δ: 1.46 (3Η, t, J=7.1 Hz), 4.52 (2H, q, J=7.l 118505.doc • 63 - 200806611

Hz), 7.46-7.50 (5H, m). MS (ESI) m/z: 302 (M+H) 〇 (2) (5 - benzyl· 4 -dimethylmethyl-2 - hydrazino)methanol [Chem. 47]

Ethyl 5-phenyl-4-trifluoromethylthiazole-2.carboxylate (0.2 g) was dissolved in tetrahydrofuran (10 ml), and lithium borohydride (14.5 mg) was added under ice-cooling. Stir at room temperature for 3 hours. After water was added to the reaction mixture, the mixture was subjected to a wave under reduced pressure, and the residue obtained was extracted with trichloromethane. The organic layer was combined, washed with brine and dried over anhydrous sodium sulfate. The residue was distilled off under reduced pressure, and the obtained residue was added to a column chromatography apparatus for medium pressure separation, and dissolved in hexane/ethyl acetate (H50: 50) to obtain a labeled compound as a powder ( 172 mg). NMR (CDC13) δ: 2.51 (1H, t, Ηζ), 7.45 (5H, s). 6·1 Hz),4·99 (2H,d,J=6.1 MS (ESI) m/z: 260 (M+H) 〇(3)b(tetra)-phenyl·4·trifluoromethyl thiophene _ 2-yl)methoxy]phenyl"pyrrolidine-2,5-dione [48] 118505.doc -64- 200806611

(5-Phenyl-4-trifluoromethyl-2- sigma sigma) decyl alcohol (50·〇mg) was dissolved in dichloromethane (5 ml), and sulfuric acid was added under ice cooling. Chlorine (141 μΐ). The reaction mixture was stirred at 70 ° C for 19 hr and concentrated under reduced pressure. Dichlorohydrazine was added to the residue obtained, and the mixture was concentrated, and toluene was added thereto, and concentrated under reduced pressure to obtain 2-chloromethyl-5-phenyl-4-difluoromethyl. Then, a solution of cardiomethoxy-4-(4-phenylphenylamino)butyric acid methyl vinegar (4 2.4 mg) and potassium carbonate (28.9 mg) was suspended in N,N-dimethylformamide ( 5 ml), at 70. Stir under nip for 19 hours. The reaction liquid was concentrated under reduced pressure, and the obtained residue was partitioned between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate. The organic layer was combined and washed with brine. Drying with anhydrous sodium sulfate, distilling off the solvent, and adding the obtained residue to a column chromatography, and eluting with hexane / ethyl acetate (40: 60 - 10: 90) to obtain an oily substance. Labeled compound (42.0 mg). NMR (CDCI3) δ: 2·90 (4H, s), 5.39 (2H, s), 7.08-7.13 (2H, m), 7·23_7·27 (2Η, m), 7.41-7.49 (5Η, m) 〇MS (ESI) m/z: 433 (M+H). (4) 4_Oxo--4_{4-[(5-phenyl-4-trifluoromethyl-2-thiazolyl)methoxy]phenylamino}butyric acid [Chem. 49] 118505.doc -65 - 200806611

Dissolve l-{4-[(5-phenyl-4-trifluoromethyl-2-thiazolyl)methoxy]phenyl}pyrrolidine-2,5-dione (42.0 mg) in tetrahydrofuran (5 To a solution of lithium hydroxide (8.15 mg) (1 ml), and stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was neutralized with aq. The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was suspended in an ether-hexane mixture and stirred, and then the precipitated solid was collected by filtration to obtain a labeled compound (28.0 mg) as a powder. NMR (DMSO-d6) δ: 2.49-2.52 (4 Η, m) 5 5.46 (2H, s) 5 7.03-7.06 (2H, m), 7.51-7.55 (7H, m), 9.89 (1H, s). MS (ESI) m/z: 451 (M+H). [Example 20] 4-oxo-4-{[4-(1,5-diphenyl-1H-pyrazol-3-yl)methoxy]phenylamino}butyric acid (1) 1 ,5-diphenyl-1H-pyrazole_3_carboxylic acid oxime ester [Chem. 50] 〇

Add phenylhydrazine (108 mg) and concentrated hydrochloric acid (88 μM) to a solution of methyl 2,4-dioxo-4-phenylbutanoate (206 mg) in methanol (1 mL). 1.5 hours. The reaction solution was left to cool, then saturated sodium bicarbonate water 118505.doc -66-200806611 solution (20 ml) and ethyl acetate (25 ml) were added for partitioning. After separating the organic layer, it was washed with saturated brine (20 ml). . The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and the obtained residue was applied to a gel column chromatography and eluted with hexane / ethyl acetate (100: 0 - 40 · · 60) to obtain As a solid labeled compound (224 mg). NMR (CDC13) δ: 3.98 (3H5 s)5 7.06 (1H, s)5 7.20-7.37 (l〇H? m) 〇MS (ESI) m/z: 279 (M+H) 〇(2) (1 ,5-diphenyl-1H"pyrazol-3-yl)methanol [51]

Adding methanol (38 μm) to a solution of 1,5-diphenyl-1!1-1 [1 to 四-3-曱酸甲6 (218 111§) in tetrahydrofuran (5 ml) Lithium borohydride (21 mg) was heated to reflux for 1 hour. The reaction solution was left to cool, then water (1 mL) was added and stirred, and then extracted with chloroform (15 ml x 2). The organic layer was dried over anhydrous sulphuric acid and concentrated under reduced pressure to afford titled compound (196 mg). NMR (CDC13) δ·· 2·20 (1H, t, J=6.0 Hz), 4.80 (2H, d, J=5.9 Hz), 6.52 (1H, s), 7.20-7.36 (10H, m) . MS (ESI) m/z: 251 (M+H). (3) 3-Chloromethyl-1,5-diphenyl_1Η-indoleazole [Chem. 52] 118505.doc -67- 200806611

Add ruthenium chloride (ι1〇μι) to (1,5-diphenyl-1H-pyrazol-3-yl)methanol (189 mg) in dichloromethane (3 ml) at room temperature Stir for 21 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) The organic layer was dried over anhydrous magnesium sulfate (MgSO4). NMR (CDC13) δ: 4·71 (2H, s), 6·59 (1H, s), 7.21-7.36 (10H, m) 〇 MS (ESI) m/z: 269 (M+H). (4) 4-oxoyl-4-{[4·(1,5-diphenyl·ιη-.bazole-3·yl)methoxy]-based amine group} Butyric acid [Chem. 53]

4-oxoyl-4 was added to a solution of 3-methylmethyl-1,5-diphenyl-1Η-pyrazole (5 〇mg) in a solution of hydrazine-dihydrazinamide (3 ml). Methyl (4-hydroxyphenylamino)butanoate (42 mg) and potassium carbonate (39 mg) were stirred and stirred at 80 ° C for 18 hours. After the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was dissolved in methylene chloride (2 ml), and then 1N aqueous sodium hydroxide (372 m) was added and the mixture was stirred at room temperature for 24 hours. After adding 1 equivalent of hydrochloric acid (1 ml) to 118505.doc -68-200806611, the mixture was extracted with chloroform (10 ml) and washed with saturated brine (2 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue obtained was applied to a gel column chromatography to give a gas / methanol (50: 1 - > 3 0 : 1 - 10 : 1) It was eluted to obtain a labeled compound (41 mg) as a solid. NMR (DMSO-d6) δ: 2.43-2.55 (4H5 m)? 5.08 (2H5 s)5 6.74 (1H, s), 7·01 (2H, d, J=9.0 Hz), 7·21-7·44 (10H, m), 7.51 (2H, d, J = 9.0 Hz), 9.95 (1H, s). MS (ESI) m/z: 443 (M+H). [Example 21] 4-oxoyl-4·{[4·(1-tert-butyl-5-phenyl-1Η-β-pyrazol-3-yl)methoxy]phenylamino} Acid (1) 1 · Dibutyl-5-phenylformate formazan [Chem. 54]

To a solution of methyl 2,4-dioxo-4-phenylbutanoate (206 mg) in methanol (5 ml), add tert-butyl hydrazine hydrochloride (125 mg) and triethylamine (139 ml) and heat. Reflux for 2 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was applied to a sepering layer chromatography apparatus for separation, and hexane/acetic acid Jman ethyl ester (8··1) was obtained as Solid Labeled Compound (149 mg) 〇118505.doc -69- 200806611 NMR (CDC13) δ: 1.50 (9H, s), 3.92 (3H, s), 6.69 (1H, s), 7.32-7.46 (5H, m ). MS (ESI) m/z: 259 (M+H) 〇 (2) (1-tert-butyl-5-phenylpyrimidin-3-yl)methanol [Chem. 55]

Add 1-methylbutyric acid (54 μM) and lithium borohydride to a solution of 1-t-butyl-5-phenyl-1 Η-n in THF (148 mg) in tetrahydrofuran (5 ml). (29 mg), heated to reflux for 3 hours. After standing to cool, water (15 ml) was added to the reaction mixture, and after stirring for a while, extraction was carried out with chloroform (15 ml χ2). The organic layer was dried over anhydrous magnesium sulfate (MgSO4). NMR (CDC13) δ: 1·44 (9H, s), 2·16 (1H, t, J = 5.7 Hz), 4.70 (2H, d, J = 5.6 Hz), 6.12 (1K{,s), 7.31 -7.41 (5H, m). MS (ESI) m/z: 231 (M+H) 〇 (3) 1-tert-butyl-3-pyrene--5-phenyl-1Η_π-biazole [Chem. 56]

Add sulfite gas (79 μM) to a solution of (1-di-dibutyl-5-phenyl-l-yl)methanol (124 mg) in dioxane (3 ml) and stir at room temperature. 118505.doc -70- 200806611 Mix for 17 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The organic layer was dried over anhydrous magnesium sulfate and evaporated. NMR (CDC13) δ: 1·44 (9H, s) 5 4.64 (2H, s), 6·20 (1H, s), 7.32-7.43 (5 Η, m). MS (ESI) m/z: 495 (M+H). (4) 4-oxoyl-4-{[4_(l-t-butyl-5-phenylpyrazole-3-yl) decyloxy]phenylamino}butyric acid [Chem. 57]

Adding 'oxo' to N-N-dimethylformamide solution (3 ml) in 1-di-dibutyl-3-oxomethyl-5-phenyl-ΐΗ-σΛ°^ (50 mg) Methyl 4-(4-hydroxyphenylamino)butanoate (45 mg) and potassium carbonate (ο mg) were stirred at 8 ° C for 16 hours. After the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was dissolved in methanol (3 ml), and then 1N aqueous sodium hydroxide solution (4 〇 2 μ ΐ) was added and stirred at room temperature for 29 hours to further add i equivalent. Aqueous sodium hydroxide (402 μM) was stirred at 50 ° C for 4 hours. After adding 1 equivalent of hydrochloric acid (10 ml) and saturated saline (10 ml) to the reaction mixture to make it acidic, extraction was carried out with chloroform (10 ml x 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure of 118505. doc - 71 · 200806611. The obtained residue was applied to a stone chromatography column and dissolved in a gas / decyl alcohol (20: 1). The labeled compound (59 mg) was obtained as a solid. NMR (DMSO-d6) δ: 1·39 (9H, s), 2.48-2.54 (4H, m), 4·95 (2Η, s), 6·24 (1Η, s), 6.98 (2Η, d, J=9.0 Ηζ), 7.36-7.52 (7Η m), 9·83 (1H, s). MS (ESI) m/z: 422 (M+H). [Example 22] 4-oxoyl-4-{[4-(l-phenyl-5-trifluoromethyl-1H-indazole-3-yl)methoxy]phenylamino}butyric acid (1) 5,5,5-Trifluoro-4-(1-pyrrolidinyl)-2-pentene-2,4-diol [Chem. 58]

〇〇c ?H 9H in a 1,1,1-difluoropentane-2,4-dione (3·85 g) in hexane solution (40 ml) was added dropwise to pyrrolidine under ice-cooling ( 2·〇9 ml), stir for 30 minutes at the same temperature. The precipitated solid was collected by filtration and washed with hexane to give the title compound (4.66 g) as a solid. NMR (CDC13) δ: 1.89-1.95 (4H, m), 1.99 (3H, s), 3.20-3.25 (4H, m), 5.47 (1H, s) 〇(2) 3_methyl-1-phenyl -5-trifluoromethyl_ιη·pyrazole [Chemical 59]

OH OH was added to a solution of phenylhydrazine (20 mmol) in tetrahydrofuran (25 ml) 5,5,5 118505.doc -72-200806611 trifluoro-4-(1-pyrrolidinyl)-2-pentene-2, The diol (4·5() was stirred at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was applied to a silica gel column chromatography to hexane/ethyl acetate (100: 〇—7〇: 3{^ iced out. The obtained compound was dissolved in dichloromethane (5 〇ml), concentrated hydrochloric acid (1 〇〇μ1) was added, and stirred at room temperature for 1 hour. The reaction mixture was washed with chloroform (50 ml), and the aqueous layer was extracted with chloroform (20 ml×2). The combined organic layer was dried over anhydrous magnesium sulfate. The title compound (2.02 g) was obtained as an oily substance. NMR (CDC13) δ: 2·36 (3H, s), 6 · 60 (1H, s), 7.44-7.48 (5H, m) MS (ESI) m/z: 227 (M+H) (3) 3-ylidene-1-phenyltrifluoromethyl Tr sitting [60]

Add bromobutaneimide (641) to a four-gas fossil solution (25 ml) of 3-methyl-1-n-yl-5·trifluoromethyl-1 Η-π 嗤 (6 79 mg) Mg) and benzoyl peroxide (19 mg), heated to reflux for 21 hours. After the reaction solution was left to cool to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue obtained was taken up in a column chromatography apparatus and eluted with hexane/ethyl acetate (30:1) to obtain a labeled compound (315 mg) as an oil. NMR (CDC13) δ: 4.52 (2H, s), 6. 88 (1H, s), 7.47-7.50 (5H, 118505.doc -73 - 200806611 m). MS (ESI) m/z: 305 (M+H) 〇(4) 1_{4-[(1 phenyl-5-trifluoromethyl.nmj) methoxy]phenyl} 17 2,5 - two @同[化61]

Add 4-oxo group to n,n_dimethylformamide solution (5 ml) in 3-m-f-l-l-phenyl-5-trimethylmethyl"H" than 嗤〇22) _4_(4-hydroxyphenylamino)butyrate (89 mg) and potassium carbonate (0_6〇mm〇1) were stirred at 6 (rc for 14 hours). The reaction solution was allowed to cool to room temperature and then added. Saturated aqueous sodium hydrogencarbonate (15 ml) and ethyl acetate (30 ml), and then the organic layer was separated. The obtained organic layer was washed with saturated brine (20^1×3) and dried over anhydrous magnesium sulfate. The residue was added to a column chromatography apparatus and eluted with hexane/ethyl acetate (90:10~>3〇: 70) to obtain a labeled compound as an amorphous solid (140 mg). NMR (CDC13) δ: 2.88-2.90 (4H, m), 5.18 (2H, s), 6.93 (1H, s), 7.11 (2H, d, J = 8.8 Hz), 7.22 (2H, d, J = 8.8 Hz), 7.48-7·5 1 (5H, m) MS (ESI) m/z: 416 (M+H) (5) 4-oxoyl-4-{[4-(l- Phenyl-5-trifluoromethyl·1Η〆bazole·3-yl) methoxy]phenylamino}butyric acid [Chem. 62] A 118505.doc -74- 200806611

To 1-{4-[(1-Phenyl·5·trifluoromethyl-1H-indazol-3-yl)methoxy]phenyl}pyrrolidin-2,5-dione (133 mg) A 1 N aqueous solution of sodium hydroxide (480 μM) was added to a methanol solution (5 ml) at 50. (: stirring for 30 minutes. After the reaction solution was allowed to cool to room temperature, 1 equivalent of hydrochloric acid (1 ml) was added to make it acidic, and then extracted with chloroform (20 ml). Further, saturated salt was added to the aqueous layer. Water (2 〇 ml) was extracted with tetrahydrofuran (2 〇mi χ 2). The combined extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase separation HPLC to give the title compound as solid (95). NMR (DMSO-d6) δ: 2.47-2.52 (4H, m), 5·09 (2H, s), 6.98 (2H, d, J = 9.0 Ηζ), 7·23 (1H, s), 7.50-7.56 (7H,m),9·84 (1H,s) 〇U_[(E)_4_biphenylmethoxyimino] MS (ESI) m/z: 434 (M+H) 〇 [Example 23] 4-oxo-4-(4-ethyl}phenylamino)butyric acid (1) 4-oxoyl_4_(4·ethyl-bromoamino)butyric acid vinegar 63]

Nh2

0"X will be the amino-acetophenone (2.70 solution in di-methane (100 ml), add 118505.doc -75. 200806611 plus triethylamine (8.4 ml). Add 4- at 0 °C Chloro-4-I-oxooxybutyrate (4·3 ml), stirred for 5 minutes. Add ice to the reaction solution, mix for 15 minutes, then distribute the reaction solution to ether (50 ml) and saturated hydrogen carbonate. The organic layer was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and evaporated. Recrystallization from hexane-ethyl acetate gave the title compound (3.50 g) as needle crystals. NMR (CDC13) δ: 1·28 (3H, t, J = 7.2 Ηζ), 2·57 (3H) ,s),2_69 (2H,m),2·77 (2H,m),4·18 (2H,q,J=7.2 Hz),7·61 (2H, m),7·93 (2H,m ), 7·96 (1H, br) MS (ESI) m/z: 264 (M+H) (2) 4-oxoyl-4-[4-(1-hydroxyiminoethyl) Phenylamino]butyric acid ethyl ester [Chem. 64]

Ethyl 4-oxoyl-4-(4-ethinylphenylamino)butanoate (1·〇5 g), hydroxylamine hydrochloride (387 mg), and sodium acetate (492 mg) were dissolved in ethanol. (10 ml) and water (5 ml) were heated and refluxed for 4 hours. The reaction mixture was cooled to room temperature, ethyl acetate (20 ml) and 0.5?? Further, the aqueous layer was extracted with ethyl acetate (100 ml), and the organic layer was combined, and then washed sequentially with water (20 ml), saturated brine (20 118505.doc -76-200806611 ml) to anhydrous sodium sulfate After drying, the solvent was removed under reduced pressure. The obtained solid was recrystallized from hexane-ethyl acetate to obtain a labeled compound (857 mg) as a needle crystal (mixture of E/Z isomer 4:1). <E-isomer> NMR (CDC13) δ: 1.27 (3H? t5 J = 7.2 Hz) 5 2.25 (3H, s) 5 2.67-2.77 (4H, m), 3.34 (lH, br), 4.16 (2H, q, J = 7.2 Hz), 7.55-7.59 (4H, m). (3) 1-(4-{1-[(Ε)-4-biphenylmethoxyimino]ethyl}phenyl)pyrrole σ定-2,5 -二嗣 [Chem. 65]

Ethyl 4-oxoyl-4-[4-(1-hydroxyiminoethyl)phenylamino]butanoate (139 mg) was dissolved in hydrazine, hydrazine-dimethylformamide (5.0 ml) Among them, 4-chloromethylbiphenyl (111 mg) and carbonic acid planer (163 mg) were added at 0 ° C, and stirred at room temperature for 12 hours. The reaction mixture was poured into a mixture of ethyl acetate (10 ml) and water (10 ml), and ethyl acetate (30 ml). The organic layer was washed with brine (10 ml) and dried over anhydrous sodium sulfate. The obtained residue was added to a ruthenium column chromatography to obtain a solid as a solid by hexane/ethyl acetate (3:2)~2|methane/ethyl acetate (4:1). Compound (117 mg). 118505.doc -77- 200806611 NMR (CDC13) δ: 2.28 (3H, s), 2.90 (4H, s), 5·28 (2H, s), 7·30-7·36 (3H, m), 7.42 -7.50 (4H, m), 7.59-7.61 (4H, m), 7·78 (2H, m) 〇MS (ESI) m/z: 399 (M+H). (4) 4-oxoyl-4-(4-{l-[(E)-4-biphenylmethoxyimino]ethyl}phenylamino)butyric acid [Chem. 66]

1-(4-{l-[(E)-4-biphenylmethoxyimino]ethyl}phenyl)indolepyridine 2,5-dione (II 7 mg) was suspended in tetrahydrofuran Lithium hydroxide monohydrate (49 mg) was added to a mixture of (8 ml) and water (4 ml), and stirred for 15 minutes. Add 1 equivalent of hydrochloric acid (5 ml) to make the reaction acidic, with ethyl acetate (3 〇 ml)

Mg).

7.66-7.68 (4H, m), 10.1 (1H, br). MS (ESI) m/z: 417 (M+H) 〇

Methoxy]phenylamino}butyric acid 118505.doc -78- 200806611 (1)(£,2)-3-chloro-2,3-^-" 本基乙妇骏 [化67]

To the N,N-dimethylformamide (14 ml), phosphorus oxychloride (7.4 ml) was added dropwise under ice-cooling, and then stirred at room temperature for 30 min. Bismuth, 2_diphenylene ketone (5.21 g) was added, and stirred at 65 ° C for 20 hours. The reaction solution was poured into ice (25 ml), and a saturated aqueous solution of sodium acetate (15 〇mi) was added and then applied. The mixture was extracted with chloroform (3 XI 50 ml). The solvent was evaporated, and the residue was applied to EtOAc EtOAc EtOAc (EtOAc) NMR (CDC13) δ: 6.97-7.00 (1H, m), 7.18-7.34 (3H m) 7.36-7.64 (4H, m), 8.09-8.13 (2H, m), 9.67, 10.60 (each 5H: (2 4,5-Phenylphenophene-2-carboxylic acid ethyl hydrazine [Chem. 68]

Sodium hydride (55% oil suspension) (117 g) was suspended in tetrahydrofuran (50 ml), and ethyl thioacetate (3.24 g) was added dropwise. A solution of (E,Z)_3_chloro-2,3-diphenylpropenal (5.69 g) in tetrahydrofuran (50 ml) was added dropwise to the obtained mixture, and the mixture was stirred at room temperature for 3 days. Additional hydrogen supplementation 118505.doc -79- 200806611 Sodium (5 5% oil suspension) (0.234 g) was further stirred at room temperature for 4 hours. To the reaction mixture was added ethyl acetate (200 ml), and the obtained solution was washed with water (3×150 ml), then dried over anhydrous sodium sulfate ). NMR (CDC13) δ: 1.39 (3H5 t, J=7.1 Hz), 4.38 (2H? q5 J=7.1

Hz), 7.24-7.40 (10H, m), 7.90 (1H, s). MS (ESI) m/z: 309 (M+H). (3) (4,5-diphenyl-2-indolyl)methanol [Chem. 69]

Ethyl 4,5-monophenylthiophene-2-carboxylate (4.33 g) was dissolved in tetrahydrofuran (80 ml), and lithium borohydride (765 mg) was added, and the mixture was refluxed for 16 hours. The reaction solution was cooled in an ice bath, water (5 ml) was added, and hydrazine hydrochloride was added until it was not foamed. The extract was extracted with ethyl acetate (300 ml), dried over anhydrous sodium sulfate and evaporated. The residue was added to a ruthenium column chromatography and eluted with hexane/ethyl acetate (100·····: υ to give the title compound (3.30 g) as a waxy substance. NMR (CDC13) δ: 4.85 (2Η m) 〇s),7·07 (1H,s), 7.22-7.30 (10H, (4) 5-(4-nitrophenoxymethyl)-2,3-diphenylthiophene 70] 118505.doc 200806611

S8 (JS 〇HQ-N〇2 (4,5-diphenyl-2-thienyl)methanol (266 mg) was dissolved in methylene chloride (30 ml), and sulphur sulphide (109) was added. (μΐ), heated to reflux for 18 hours. Additional sulfite chloride (1 · 〇ml), and then heated to reflux for 6 hours, concentrated to dryness. Dissolve the residue in N, N-dimethylformamide (1 To 〇ml), p-nitrophenol (139 mg) and potassium carbonate (159 mg) were added, and the mixture was stirred at 70 ° C for 12 hours. The solvent was evaporated, and ethyl acetate (100 ml) was added to the residue. The solution was washed with water (3×50 ml), dried over anhydrous sodium sulfate, and evaporated to dryness to dryness to give the title compound (367.4 mg) as an oil. NMR (CDC13) δ: 5.33 (2H, s), 7.09 (2H,d,J=9-3 Hz), 7.20 (1H, s), 7.24-7.31 (10H, m), 8.24 (2H, d, J=9.3 Hz) (5) 4-[(4 ,5-diphenyl-2-thienyl)methoxy]phenylamine [71]

Q^^〇hQkno: Dissolve 5-(4-nitrophenoxymethyl)_2,3-diphenylthiophene (369 mg) in tetrahydrofuran (30 ml) and add methanol (lo ^1) Lithium borohydride (125 mg) 'heated back overnight. Further, hydrogen chlorination (208 mg) was added to the reaction liquid and the mixture was heated under reflux for 4 hours. Then, lithium borohydride (415 mg) was added, and then a mixture of methyl leaven (2 ml) and tetrahydrofuran (8 guanidine) was added dropwise, followed by heating under reflux for 14 hours. The reaction solution was cooled in an ice bath, water (5 〇 118505. doc 200806611 ml) was added, and then 1 eq of hydrochloric acid was added until the foaming was stopped. The mixture was neutralized with a hydrazine aqueous sodium hydroxide solution, and extracted with dichloromethane (3 EtOAc). The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was added to a medium pressure silicone gel column chromatography eluting with hexane/ethyl acetate (75:25-6:40) to give the title compound (217 mg) as an oil. NMR (DMSO-d6) δ·· 5.15 (2H,d,J=〇.7 Ηζ),6·66 (2H,d, J=8.8 Hz)5 6.87 (2H5 d3 J=8.8 Hz)5 7.13 (1H5 t? J=0.7 Hz) 5 7.21-7.30 (10H, m). (6) (R)-3-Hydroxy_4-oxoyl_4_{4_[(4,5-diphenyl_2-thienyl)oximeoxy]phenylamino}butyric acid [Chem. 72]

Add 4-[(4,5-diphenyl-2-thienyl)methoxy]aniline (35) to trifluoroacetic acid (R)-2,5-dioxotetrahydrofuran-3-yl ester (218 mg) A solution of 7 mg) in tetrahydrofuran (1.0 ml) was stirred at room temperature overnight. After concentrating the reaction mixture, it was purified by reverse phase separation HPLC to obtain a labeled compound (20.6 mg) as an amorphous material. NMR (DMSO-d6) δ: 2.46 (1 Η, dd, 1 = 15.7, 8.6 Hz), 2.71 (1H) , dd, J=15.7, 4.2 Hz), 4.37 (1H, dd, J=8.6, 4.2 Hz), 5.29 (2H, s), 7.01 (2H, d, J=9.1 Hz), 7.22-7.34 (1 1H , m), 7.64 (2H, d, J = 9.1 Hz), 9_66 (1H, s) 0 [Example 25] (S)-3-Hydroxy_4-oxoyl-4-{4-[(4 ,5-diphenyl-2-thiophene 118505.doc -82- 200806611 yl)methoxy]phenylamino}butyric acid [73]

Add 4-[(4,5-diphenyl-2-thienyl)methoxy]aniline to (S)-2,5-dioxytetrahydrofuran-3-yl ester (21·8 mg) (35. 7 THF). The reaction solution was concentrated to obtain a non-crystalline standard furan solution (1.0 ml), which was stirred at room temperature overnight, and then purified by reverse phase separation HPLC. (20.2 mg) NMR (DMSO-d6) δ: 2.46 (1 Η, dd, J = 15.9, 8.6 Hz), 2.71 (1H, dd, 1 = 15.9, 4.2 Hz), 4.37 (1H, dd, J=8.6 , 4.2 Hz), 5.29 (2H, s), 7.01 (2H, d, J=9.1 Hz), 7.23-7.34 (llH, m), 7.63 (2H,d,J=9.1 Hz),9.66 (1H,s [Example 26] 4-oxo-4-{4-[(4,5-diphenyl-2-thienyl)methoxy]phenylamino}butyric acid [Chemical 74]

Add 4_[(4,5-diphenyl_2-thienyl)methoxy]phenylamine (35_7 mg) in tetrahydrofuran solution 〇〇ml) to succinic anhydride (1〇.〇mg) at room temperature Mix together for one night. After concentrating the reaction mixture, it was purified by reverse phase separation of HpLC to obtain an amorphous compound (3 〇 9 mg). 118505.doc -83 - 200806611 NMR (CDC13) δ: 2·69 (2H, t, J=6.6 Ηζ), 28·〇 (2H, t, J=6.6

Hz), 5.21 (2H, s), 6·98 (2H, d, J = 8.8 Hz), 7.15 (1H, s), 7.24-7.29 (10H, m), 7·37 (1H, br s), 7.43 (2H,d,J=8 8

Hz). [Example 27] (R)-2-Hydroxy-4-oxoyl-4-{4-[(4,5-diphenyl_2_σsenoyl)methoxy]phenylamino}butyric acid [化75]

A solution of (R)-2,5-dioxotetrahydrofuran-3-yl trifluoroacetate (218 mg) in methanol (0.5 ml) was shaken at room temperature for 16 hr then concentrated. Add 4-[(4,5-a-based-2-yl-synyl)methoxy]phenylamine (μ 7 mg) in tetrahydrofuran (1·〇ml), 丨_ethyl_ 3_(3-dimethylaminopropyl)carbodiimide hydrochloride (19. 2 mg), 1-hydroxybenzotriazole (6. 8 mg) and triethylamine (14 μM) tetrahydrofuran The solution (2 ml) was stirred at room temperature for 24 hours. N, n-dimethylformamide 〇 ml) was added to the reaction mixture, and the mixture was mixed for 3 days. Then, a reaction solution of hydrazine was added to a reaction solution of sodium hydroxide (25 〇μ〇' for 2 days. 1 equivalent of hydrochloric acid (250 μM) was added, and after stirring for 1 hour, the solvent was removed by steaming. The obtained residue was obtained as an amorphous compound (6.6 mg). Awakened R (DMSO-d6) δ: 2.65 (1H, dd, J=15 〇, 4 4 Ηζ), 4·37 (1Η, dd, J=8.6, 4.4 Hz), 5.28 (2H, s)5 ?.〇l (2H, d, J=9.1 Hz), 7.20-7.37 (11H,m), 7.53 (2H,d,b 9 i Hz) , 9 (ih, 118505.doc -84- 200806611 [Example 28] (S)-2-Hydroxy-4-oxoyl-4-{4-[(4,5-diphenyl_2-thiophene) Methoxy]phenylamino}butyric acid [Chemical 76]

A solution of (S)-2,5-dioxotetrahydrofuran-3-yl trifluoroacetate (218 mg) in methanol (0.5 ml) was shaken at room temperature for 16 hr then concentrated. Add 4-[(4,5-diphenyl-2-thienyl)methoxy]phenylamine (35 7 mg) in tetrahydrofuran (1.0 ml), 1-ethyl·3_(3) · Dimethylaminopropyl) carbodiimide hydrochloride (19. 2 mg), 1-aminopyridinium (6 8 mg) and triethylamine (14 μM) in tetrahydrofuran (2 Ml), disturbed for 24 hours at room temperature. N,N-dimethylformamide (1 guanidine) was added to the reaction solution, and the mixture was mixed for 3 days. Then, i equivalent of an aqueous sodium hydroxide solution (25 μM) was added to the reaction mixture, followed by stirring for 2 days. After adding 1 equivalent of hydrochloric acid (250 μM), the mixture was stirred for 1 hour, and the solvent was evaporated. The residue was purified by reverse phase separation of HPLC to give the title compound (6.6 mg) as an amorphous material. NMR (DMSO-d6) 5 : 2·65 (1H, dd, Bu 14.6, 4·4 Hz), 4 37 (1H, dd, J = 7.8, 4.4 Hz), 5.28 (2H, s), 7·〇 ΐ (2H,d,J==9 j

Hz), 7.20-7.34 (1 1H, m), 7.53 (2H, d, J = 9.1 Hz), 9·86 (1H s) 〇 [Example 29] 3-{4-[ (4-Phenyl- 5-trimethylsulfonyl)methoxyx]benzhydrylamino}propionic acid 118505.doc -85- 200806611 (1) 4-[(4-phenyl-5-trifluoromethyl-sigh Phenyl-2-yl)methoxy]benzoate oxime [Chem. 77]

In the same manner as in Example ,6, 5-methoxymethyl-2-bromo-2-thiophene was synthesized from (4-phenyl-tris-tris-methyl-2-thienyl)methanol (293 mg). 4-Hydroxybenzoic acid methyl vinegar (172 mg), potassium carbonate (i72 mg), N,N-dimethylformamide (15 ml) were mixed at 7 Torr. Stir under the arm for 16 hours. The solvent was evaporated, and ethyl acetate (5 ml) was added to the residue and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was added to a medium pressure (iv) column chromatography apparatus and dissolved in hexane/acetic acid ethyl acetate (80:20 - 60:40) to obtain a labeled compound (5.79 g) as an oil.丽R (CDCl3) δ: 3.90 (3H, s), 5.28 (2H, s), 7 〇ι (2h,^ J=8.6 Hz), 7.26 (1H, d, J=0.5 Hz), 7.43-7.40 ( l〇H, m)j 8.〇3 (2H,d,J=8.6 Hz). '(2) 4-[(4-Phenyl-5_trimethyl)-indol-2-yl)methoxy]benzoic acid [Chemical 78]

4·[(4-Phenyl-5-trifluoromethyl-thiophene-(402.5 mg) was dissolved in methanol (30 ml), decyl)methoxy]benzoic acid oxime ester was added with 1 equivalent of sodium hydroxide in water. 118505.doc -86- 200806611 Liquid (2·06 ml), heated to reflux for 4 hours. An additional 1 equivalent of sodium hydroxide aqueous solution (3 · 0 ml) was added, and the mixture was further heated under reflux for 18 hours. Methanol was distilled off, water (50 ml) was added, the pH was adjusted to 2 with 1N hydrochloric acid, and extracted with ethyl acetate (1 〇〇 ml). The organic layer was washed with saturated brine (3×3 〇 ml). After drying over anhydrous sodium sulfate, the solvent was evaporated to give the title compound (38 1 mg) as a powder. NMR (CDC13) δ: 5.31 (2H, s), 7.05 (2H, d, J = 8.8 Hz), 7.11 (1H, s), 7.29-7.39 (10H, m), 8.09 (2H, d, J = 8.8 Hz). (3) 3-{4·[(4-Phenyl-5-trifluoromethylthiophen-2-yl)methoxy]benzimidamide Amino}propionic acid [Chem. 79]

4-[(4-Phenyl-5-trifluoromethylthiophen-2-yl)methoxy]benzoic acid (37.8 mg), 1-ethyl-3-(3-dimethylaminopropyl) Mixing carbodiimide hydrochloride (19.2 mg), N-hydroxybutylimine (π·5 mg), N,N•dimethylformamide (1·〇ml) at room temperature Stir under 24 hours. After adding alanine (17.8 mg) and diisopropylethylamine (35 μl), the mixture was stirred for 24 hours, and then further supplemented with diisopropylethylamine (70 μM), followed by stirring for 24 hours. The reaction solution was stirred at 80 ° C for 3 days. The solvent was distilled off, and the reverse phase was separated by reverse phase 11]?1^(::purified residue ✓) was obtained as an amorphous compound (6.8 mg). NMR (CDC13) δ: 2.74 (2H, t, J = 5.9 Hz ), 3.74 (2H, q, J=5.9 Hz), 5·27 (2H, s), 6.69 (1H, br s), 7·02 (2H, d, J = 8.8 Hz), 118505.doc -87 - 200806611 7.10 (1H, s), 7.40-7.43 (5H, m), 7·76 (2H, d, J = 8.8 Hz) MS (ESI) m/z: 450 (M+H). 30] 2 -trans-yl-3-(4-[(4-phenyl-5-trifluoromethylnonin-2-yl)methoxy]benzylideneamino}propionic acid [80]

Carbonation of 4-[(4-phenyl-5-trifluoromethyl-thiophen-2-yl)methoxy]benzoic acid (37.8 mg), puethyl-3-(3·didecylaminopropyl) Diimine hydrochloride (19.2 mg), N-hydroxybutylimine (11.5 mg), N,N-dimethylformamide (1.0 ml) were mixed and stirred at room temperature 24 hour. D-Isole acid (21.0 mg) and diisopropylethylamine (35 μM) were added, and the mixture was stirred for 24 hours, and then diisopropylethylamine (70 μM) was additionally added thereto, followed by stirring for 24 hours. The reaction solution was stirred at 80 ° C for 3 days. The solvent was distilled off, and the residue was purified by reverse phase separation of HPLC to obtain a compound (15.3 mg) as an amorphous material. NMR (DMSO-d6) δ: 3.41-3.34 (1H? m), 3.55 (1H, dt? J=13.0, 4.9 Hz), 4.15 (1H, dd, J=7.4, 4.9 Hz), 5·47 (2H , s), 7.13 (2H, d, J = 8.8 Hz), 7.41 - 7.51 (6H, m), 7.85 (2H, d, J = 8.8 Hz), 8.38 (1H, t, J = 5.6 Hz) . MS (ESI) m/z: 466 (M+H). [Example 31] 3·indolyl-3·{4-[(4-phenyl-5-trifluoromethylthiophen-2-yl)nonyloxy]benzhydrylamino}propionic acid ] 118505.doc -88- 200806611

4-[(4-Phenyl-5-difluoromethylthiophene-2-yl)methoxy]benzoic acid (37 · 8 mg), ethyl ethyl-3-(3-didecylaminopropyl) Dimethylimine hydrochloride (19.2 mg), N-pyridinium diimide (ι 5·5 mg), n,N-dimercaptocaramine (1.0 ml), mixed at room temperature Stir for 24 hours. After adding bupresamine butyric acid (20.6 mg) and diisopropylethylamine (35 μM), the mixture was stirred for 24 hours, and additional diisopropylethylamine (70 μM) was added thereto, followed by sandalwood mixing for 24 hours. The reaction solution was heated to 80 ° C and stirred for 3 days. The solvent was distilled off, and the residue was purified by reverse phase separation (HPLC) to give the title compound as an amorphous material (26 3 mg) NMR (CDC13) δ: 1·38 (3H, d, J = 6.9 Hz), 2.70 (2H, Ddd, J=23.6, 16.0, 5.1 Hz), 4·52·4·61 (1H, m), 5.27 (2H, s), 6.70 (1H, d, J = 8.3 Hz), 7.01 (2H, d, J = 8.8 Hz), 7.09 (1H, s), 7.39-7.44 (5H, m), 7·76 (2H, d, J = 8.8 Hz). MS (ESI) m/z: 464 (M+H). [Test method] l In vivo evaluation of the test substance: (1) Selection of HA-Gqi5 DNA Extraction of chromosomal DNA from HA-Gqi5-expressing CHO cells (purchased from Molecular Devices, Inc.) using DNeasy Tissue Kit (QIAGEN) The extract was used as a template, and a polymerase chain reaction (hereinafter referred to as 118505.doc-89-200806611 PCR) was carried out using KOD plus DNA polymerase (TOYOBO). The target PCR product was purified and blunting kination (BKL Kit: TAKARA BIO INC.), and ligated with pUC118/Hinc n-BAP (TAKARA BIO INC.). The Ligation mix was introduced into E. coli (TOYOBO), and a positive pure strain was selected by a PCR method to obtain a plastid into which HA-Gqi5 DNA was inserted. (2) Construction of HA-Gqi5 expression plastid The HA-Gqi5 gene inserted into PUC118 was excised by restriction enzyme digestion, and purified, and ligated to the expression plasmid pcDNA3.1Hygro(+) (Invitrogen). Then, it was introduced into Escherichia coli DH5a, and after selecting a positive pure strain, HA-Gqi5 expression plastid was obtained. (3) Preparation of HA-Gqi5-expressing CHO cells Using Fugene 6 (Roche Diagnostics Co., Ltd.) reagent, the HA-Gqi5 expression plastid obtained in (2) was introduced into CHO-K1 cells using hygromycin ( Hygromycin) for cell selection. The cells were subjected to 2 selections, and HA-Gqi5-expressing CHO cells were selected by Western blotting using an anti-HA antibody. (4) Selection of human SlPl (EDG-1) Human S1P1 (EDG-1) DNA was obtained by PCR using human S1P1 (EDG_1) cDNA clonal propagation line (open biosystems, cDNA collection #4071217) as a template. The PCR product was inserted into pUC18, and then the insertion target sequence was obtained by site-directed mutagenesis kit (Stratagene) (The Journal of Biological Chemistry Vol. 265 5 No. 16 - pages 9308 to 9313, 1990) The plastid of DNA. 118505.doc -90- 200806611 (5) Construction of human SlPl (EDG-1) expression plastids by restriction enzyme digestion of human SlPl (EDG-1) gene inserted into PUC118 (The Journal of Biological Chemistry, Vol. 265, No. 16, pp. 9308~9313, 1990), after purification, ligation with the expression plasmid pcDNA3.1/mycHisA (Invitrogen). Then, after introducing a positive pure strain into Escherichia coli DH5a, a human S1P1 (EDG-1) expression plastid was obtained. (6) Human 81?1 kg〇〇-1) Expression of 011〇 cells was prepared using Fugene 6 (Roche Diagnostics Co., Ltd.) reagent, and the SlPl (EDG-1) expression plastid was introduced into HA_Gqi5 obtained in (7). In CHO cells, cell selection was performed using G418. The cells were subjected to two colonizations, and cells which were stimulated by S1P to cause an increase in intracellular calcium were selected. (7) Caiciuni flux assay CHO cells expressing Gqi5 protein introduced with human siPl (EDG-1) obtained in (6) were seeded at 2.5x104 cell/well on black underside transparent 96 After culturing on a thin plate for one night, after washing once with serum-free medium, add 100 μL of BSA-containing buffer solution containing 2·5 mM probenecid and 0.25% fatty acid-free BSA (|bow detection kit) ,] yjolecular Devices, Inc., reacted at 37 ° C and 5% C 〇 2 for 1 hour. In order to produce a concentration of 5 times the final test concentration, 25 μΐ of the test compound diluted solution was added, and the change in intracellular mom concentration was measured by FLEXstation® (Molecular Devices) to determine the difference between the minimum and maximum peaks of intracellular calcium concentration. . Based on the S-shaped curve prepared from the measured values, the EC50 value was calculated as an agonist activity against the S1P1 (EDG_1) receptor. 118505.doc -91 - 200806611 2. In vivo evaluation of the substance to be tested (test of lymphocyte count in the peripheral blood of mice after administration of the compound): Reported that the mouse was administered with the S 1P receptor agonist Lymphocytopenia in peripheral blood (SCIENCE, 296, pp. 346-349 (2002)). The evaluation of the test compound was carried out by this evaluation method. After suspending or dissolving 6 mg of the test substance (concentration: 3 mg/ml) in 2 ml of MC (methylcellulose) solution, the mice were orally administered with 〇·2 ml (20 g per mouse body weight). The amount of the solution was 3 〇 mg/kg). Four hours after oral administration, EDTA was used as an anticoagulant under ether anesthesia, and blood was collected from the posterior great vein (0.5 ml). The number of lymphocytes in the peripheral blood was measured by an integrated hematology apparatus ADVIA120 (Bayer Healthcare). The pharmacological action of the test drug is determined by the ratio T/c (%) of the average number of peripheral hemolymph spheres of the test drug administration group to the number of control (solvent administration) groups. T/C (%) calculation formula: T/C (%) = (the average peripheral hemolymph sphere of the drug-administered group, the average peripheral hemolymph sphere of the solvent-administered group) xl〇〇 [test Results] The results of tests on the compounds of the examples are shown in Table 1 according to the above test methods. 118505.doc -92-200806611 [Table i] Compound S1P1 EC50(nM) T/C (%) Compound of Example 6 5.3 19.8 Compound of Example 8 6.6 15.9 Compound of Example 17 46.0 13.5 The compound of the present invention has a pair The agonist activity of the S1P1 receptor, and oral administration to reduce the number of lymphocytes in the peripheral blood, shows effectiveness. 118505.doc -93 -

Claims (1)

200806611 X. Patent application scope: 1. A compound, a salt thereof, or a solvate thereof, which is represented by the formula (1): [wherein, the bond table V on the left side of each group represents -NH-CO- or -CO-NH- (wherein the phenyl group is bonded to the formula (I)), and A represents -C〇〇R7 ( Wherein R7 represents a hydrogen atom or a linear or branched alkyl group of C1 to C5 which may have a substituent; or a tetrazole-5-based group, and R1, R2, R3 and R4 each independently represent a hydrogen atom, a hydroxyl group or an amine. a straight or branched alkyl group of a C1 or C5 group, R5 and R6 (4) a stand-up atom, a _ atom, and a substituent a linear or branched alkyl group of C1 to C5, or a linear or branched alkoxy group of C1 to C5 which may have a substituent, y represents -CH20-, -CH2-CH", 2 lh-ch-, -ch2-on=cr8- -CONR9- > -NR10CO- > -CH〇NRnrn -V' 2NR C0- or -ch2ch2nr12co- (where 'the key on the left side of each group J is hard-wearing in the general formula (1) Y bond, R, R10, rU and Rl2 are respectively π 表 表 、 、, or a linear or branched alkyl group of Cl 〜 C5), the group consisting of heterocycles may have 1 substitution Y Selecting a divalent group formed by one of benzene and one of the aromatics of a 5- to 6-membered ring (the groups are also a group), 118505.doc 200806611 Z represents a phenyl group which may have a substituent, or may have a substitution The aromatic heterocyclic group of the 5- to 6-membered ring of the group. The compound of claim 1, the salt thereof, or a solvate thereof, wherein z is a phenyl group which may have a substituent. The compound of Item 1 or 2, a salt thereof, or a solvate thereof, wherein Y is selected from the group consisting of furan, thiophene, oxazole, thiazole, imidazole, pyridinium, triazole, benzene, pyridine, azine, and pyrimidine. a divalent group formed by one of the groups (the groups may have one substituent). The compound of any one of claims 1 to 3, a salt thereof, or the like a solvate wherein Y is a divalent group formed from one selected from the group consisting of thiophene, thiazole and pyrazole (the groups may also have one substituent). The compound of any one of 1 to 4, a salt thereof, or a solvate thereof, wherein Y is a divalent group formed of thiophene (the group may have one substituent). The compound of any one of items 1 to 5, a salt thereof, or a solvate thereof, wherein γ is selected from a group selected from a phenyl group, a linear or branched alkyl group of C1 to C5, and a halogen substituted with a halogen atom. a group substituted with one of the group consisting of a straight chain or a branched alkyl group of C5. 7. A compound according to any one of claims 1 to 6, a salt thereof, or a solvent thereof A compound in which γ is substituted by a phenyl group. The compound of any one of claims 1 to 6, a salt thereof, or a solvate thereof, wherein Y is halogenated Substituting a group of a C1 to C5i linear or branched alkyl group substituted by a subunit. 118505.doc 200806611 9. A compound according to any one of items 1 to 8, a salt thereof, or a solvent thereof The compound, the salt thereof, or a solvate thereof, wherein any one of R1, R2, and Rw, is any one of R1, R2, and Rw. Or two linear or branched counties each independently a radical, an amine group, or a C1 to C5 group, and the remaining R1, R2, R3 and R4 groups are a hydrogen atom. U. The compound of any one of claims 1 to 10, a salt thereof, or a solvent thereof, wherein R1 is a trans group, an amine group, or a linear or branched alkyl group of C1 to C5, r2 And R3 and R4 are a hydrogen atom. The salt of R4, R2 and R3 is a hydrogen atom of the compound of any one of claims 1 to 10, wherein R4, R2 and R3 are a hydrogen atom, or a salt thereof, or a salt thereof, is a hydroxyl group, an amine group, a salt thereof, or the like. Or a linear or branched alkyl group of C1 to C5. 13. If the compound is a compound of any one of the formulas, the compound is a compound of R1 β D 4 &々# Ί , 八甲 R and R are hydroxyl groups, and R2&R3 is a ruthenium atom. And a solvate of the compound according to any one of items 1 to 9, wherein R1, R2, R3 and R4 are each a hydrogen atom. 15. The salt of any one of claims 1 to 14, or a solvent thereof, wherein R5 and R6 are each a hydrogen atom. 16. A compound according to any one of the preceding claims, wherein Q is a -CH2 couple, -CH2-〇_n=crs. 〇CHCH- or 17. Or a compound of any one of items 1 to 16, a salt thereof, or a solvent thereof, wherein the compound is a compound of any one of items 1 to 16, a salt thereof, or the like thereof. Object, where Qg_Cil:=cH-. 19. The compound of claim 18, a salt thereof, or a solvate thereof, wherein -CH=CH_ is in the trans configuration. 20. As requested! The compound of any one of 19, a salt thereof, or a solvate thereof, wherein A is -COOR7. The compound of any one of claims 1 to 20, a salt thereof, or a solvate thereof, wherein A is -COOR7 and R7 is a hydrogen atom. A solvate of a compound, a salt thereof, or the like, wherein the compound is selected from any one of the following compounds: via a oxycarbonyl group 4-{'[('phenyl_5_trifluoro Methyl 2-thienyl)methoxy]phenylamino}butyric acid, (R)_3_fluorenyl_4_oxoyl_4_{4-[(4_phenyl_5_trifluoromethyl) (2-Thienyl)methoxy]phenylamino}butyric acid, (R)_3_hydroxyoxy} 4-{4-[(4-phenyl-5-trifluoromethyl-2- Thienyl)methoxy]phenylamino}butyric acid, 4-oxo-4-{4-[(4-phenyl-5-trisylmethyl-2-nonyl)methoxy] Phenylamino}butyric acid, (R)-2-hydroxy-4-oxoyl-4-{4-[(4-indolyl-5-trifluoromethyl-2-thienyl)methoxy] Phenylamino}butyric acid, (s)_2_hydroxy-4-oxo-4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl)decyloxy]phenyl Amino} Butyric acid, 3,3-dimercapto-4-oxo-4-{4-[(4-phenyl-5-trifluoromethyl-2-syryl)methoxy] Phenylamino}butyric acid, (S)-3-methyl-4-milyl-4-{4-[(4-phenyl-5-trismethyl-2-synyl) A Phenyl]phenylamino}butyric acid, (2S,3R)-2,3-dimethyl-4-oxoyl [(4 - -5-5-di-gasmethyl-2- σ sylphenyl)methyllacyl] benzylamino}butyric acid, (2R,3R)-2,3-dihydroxy-4-oxoyl-4-{ 4-[(4-Phenyl-5-trifluoromethyl, 2-thienyl)methoxy]phenylamino}butyric acid, (2S,3S)-2,3-dihydroxy_118505.doc 200806611 4-oxoyl-4-{4-[(4-phenyl-5-trifluoromethyl-2-°secenyl)methoxy]phenylamino}butyric acid, (R)_3_amine 4--4-oxo-4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid, (S)-3- Amino oxo-4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl) decyloxy]phenylamino}butyric acid, (S)-2-amino group 4-oxoyl-4_{4_[(4-phenyl-5-trifluoromethyl-2-thienyl)decyloxy]phenylamino}butyric acid, (R)-2-amino- 4-oxoyl-4-{4-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]phenylamino}butyric acid, (S)-3-hydroxy- 4-oxoyl-4-{4-[(4-phenylpyr-5-trifluoromethyl-2-thienyl)ethyl]phenylamino}butyric acid, (S)-3-hydroxy-4 -Oxo-_4-{4-[(Ε)-2·(4-phenyl-5-trifluoromethyl-2-thienyl)vinyl]phenylamino}butyric acid, 4-oxo Base-4-{4-[(5-methyl-4) -Phenyl-2-thiazolyl) methoxy]phenylamino}butyric acid, 4-oxo-4-{4-[(5-phenyl-4-trimethyl-2-thiazolyl) Methoxy]phenylamino}butyric acid, 4-oxo-4-{[4-(1,5-diphenyl-1Η--pyrazol-3-yl)methoxy]phenyl Amino}butyric acid, 4-oxoyl-4-{[4-(1-tert-butyl-5-phenyl-1indole-indazol-3-yl)methoxy]phenylamino} Acid, 4-oxoyl-4-{[4-(1-phenyl-5-trifluoromethyl-111-mouth-bisazol-3-yl)methoxy]phenylamino}butyric acid, 4 -Oxo--4-(4-{1·[(E)-4-biphenyloximeoxyimino]ethyl}phenylamino)butyric acid, (R)-3-hydroxy-4 -Oxo--4-{4-[(4,5-diphenyl_2-thienyl)methoxy]phenylamino}butyric acid, (S)-3-yl-4-yl 4- 4-(4-[(4,5-diphenylthienyl)methoxy]phenylamino}butyric acid, 4-oxoyl-4-{4·[(4,5-diphenyl) (meth)phenylamino}butyric acid, (R)-2-yl-4-oxoyl-4-{4-[(4,5-diphenyl-2-thiophene) Methoxy]phenylamino}butyric acid, (S)_2-hydroxy-4-oxoyl-4-{4-[(4,5-diphenyl-2-thienyl)-methyl 118505. Doc 200806611 oxy]phenylamino}butyric acid, 3-丨4 m — * Η-[(4:phenyl_5_trifluoromethylthiophene-2-yl) decyloxy]benzhydrylamino-propionic acid, 2-hydroxyl_3_{4_[( 4_phenyl_ 5-trifluoromethylthiophen-2-yl)methyllacyl]benylmethylamino}propionic acid, and 3-methyl-3-3_{4-[(4_phenyl-5-)二麄田甘办, —either methylthiophen-2-yl) decyloxy]benzhydrylamino}propionic acid. 23. 24. 25. 26. 27. 28. A medicine comprising the compound of any one of claims 1 to 22, a salt thereof, or a solvate thereof, as an active ingredient. An s1P receptor agonist comprising the compound of any one of the above items, the salt thereof, or a solvate thereof, as an active ingredient. An S1P1 receptor agonist comprising the compound of any one of Claims 22 to 22, a salt thereof, or a solvate thereof, as an active ingredient. An immunosuppressive agent comprising, as an active ingredient, a compound, a salt thereof, or a solvate thereof, according to any one of the above items, for rejection, autoimmune disease, and/or allergy to transplantation. A therapeutic agent and/or a prophylactic agent for a sexually transmitted disease, which comprises the compound of any one of claims 1 to 22, a salt thereof, or a solvate thereof, as an active ingredient. A medicine, which is as claimed in claim 1 a compound according to any one of 22, a salt thereof, or a solvate thereof, and one selected from the group consisting of an immunosuppressive agent, an antibody for immunosuppression, a therapeutic drug for rejection, an antibiotic, and a steroid 118505.doc 200806611 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please Reveal the chemical formula that best shows the characteristics of the invention: 118505.doc