TW200846322A - Heteroaryl amido lower carboxylic acid derivative - Google Patents

Abstract

The invention provides a novel compound, which exhibits S1P receptor agonist activity and is excellent as an immunosuppressive agent. In addition, the compound of this invention has few side effects and may be orally administrated. The invention relates to the compound set forth in the general chemical formula (I), salts thereof, and solvates thereof. In the general chemical formula (I), A represents a single bond, -O-, or -CH.sub.2-. R.sup.1 represents a hydrogen atom or a C1-C6 alkyl group. V represents a group selected from any of (1) to (3): (1) -G.sup.1- ; (2) -G.sup.2-N(R.sup.2)-G.sup.3- ; and (3) Formula 2, where Z1 and Z2 each independently represents a hydrogen atom or C1-C6 alkyl group; Z3 represents a hydrogen atom and so on; Q represents -CH.sub.2-O-, and Y represents the following formula (III).

Description

200846322 IX. INSTRUCTIONS·· TECHNICAL FIELD OF THE INVENTION The present invention relates to one having! _ sphingosine receptor agonist activity ‘heteroaryl decylamine lower carboxylic acid derivative which can be used as an immunosuppressant and a medicine containing the same. [Prior Art] The receptor of 1-selenate sphingosine (hereinafter referred to as sip) belongs to the family of Endothelium (Dlfferentiation Gene, hereinafter referred to as EDG) as a G-protein-associated X body, including The five subtypes of S1P1, S1P2, S1P3, S1P4, and S1P5 are also referred to as ^〇0-1, EDG-5, EDG-3, EDG-6, & EDG-8, respectively. It has been previously known that FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-L3-propanediol hydrochloride) having a sphingosine-like structure has immunosuppressive effects (Patent Literature) 1). It is generally believed that FTY72 does not exhibit an inhibitory effect on the production of cellular mediators such as IL-2 in vitro, and exhibits a different mechanism of action than the existing immunosuppressive agent FK506 or eyci〇sporine. _ However, it has recently been learned that FTY72 exhibits an action of a Slp forksome agonist by phosphorylation in a living body and exhibits an immunosuppressive action (Non-Patent Document 1). It is reported that FTY720 is currently undergoing clinical trials for transplantation and multiple sclerosis, and its side effects are causing bradycardia (Non-Patent Document 2). Therefore, the industry is looking forward to the development of novel immunosuppressive agents that overcome the above problems and show high efficiency. On the other hand, a carboxylic acid derivative having a 811 > 1 (£1) (}_1) receptor agonist or a carboxylic acid having a S1P4 (EDG-6) receptor binding ability is disclosed. 121199.doc 200846322 The derivative exhibits an immunosuppressive action (Patent Documents 2, 3, and 4), but the manufacturer expects a novel low molecular S1P receptor agonist compound which exhibits excellent effects and few side effects and can be administered orally. [Patent Document 1] International Publication No. 94/008943 pamphlet [Patent Document 2] International Publication No. 2005/000833 pamphlet [Patent Document 3] International Publication No. 2005/020882 pamphlet [Patent Document 4] International Publication No. 2004/058 Booklet No. 149 [Non-Patent Document 1] Science, 296, 346 to 349 (2002) [Non-Patent Document 2] Journal of the American Society of Nephrology 5 13 (4)? 1073^1083 (2002) [Summary of the Invention] [Invention Office] Solution to Problem] An object of the present invention is to provide a novel compound which has s 1 p receptor agonist activity, exhibits an excellent effect as an immunosuppressive agent, and has few side effects and can be administered orally. [Technical means for solving the problem], the inventors of the present invention have diligently studied to solve the above problems, and as a result, have found that a heteroaryl decylamine low carbon number carboxylic acid knot novel sigma compound is different from a compound of a prior art. It has S1P receptor agonist activity and can be used as an immunosuppressant for oral administration to reduce the number of lymphocytes in the peripheral blood of mice and has less side effects such as bradycardia in a mouse model. The present invention has been completed. That is, the present invention provides a compound, a salt thereof, or a solvent compound thereof, which is represented by the following formula (1), 121199.doc 200846322 [Chemical Formula 1]

Wherein A represents a single bond, -〇·, or _Ch2_, • R1 represents a hydrogen atom or 〇1-〇:6 alkyl, and V represents any group selected from the following (丨) to (3): (1) _GL (here, Gi represents a linear extended alkyl group having a carbon number of 1 to 5 which may have a substituent), (2) -G2-N(R2)-G3- (here, G2 represents a single bond) Or a linear alkyl group having 1 to 3 carbon atoms which may have a substituent, G3 represents a linear alkyl group having 1 to 4 carbon atoms which may have a substituent, and R2 represents a hydrogen atom, a Cl_c6 alkyl group or 3 ~8 membered cycloalkyl), (3) The following group [Chemical 2].

(wherein G4 represents a single bond, or a linear alkyl group having 1 to 2 carbon atoms which may have a substituent, and m&n independently represents 1, 2 or 3, respectively), and z1 and z2 each independently represent a hydrogen atom or Cl_c6 alkyl, 12n99.d〇c 200846322 z3 represents a hydrogen atom, a halogen atom, a cyano group, a Ci_C6 alkyl group, a halogenated ?-alkylene group, a C-C6 alkoxy group, or a halogenated oxy group, Q represents a single Keys...0-, -CH2_, _CH2-CH2_, -CH2_CH2-CH2·, -ch2-ch2-ch2-ch2-, -ch2-ch2-ch2-ch2-ch2-, -ch2-〇-, -CH2-CH2 -0-, _CH2-0-CH2_, -CH2-CH2-0-CH2·, -CHrCH2-CH2-0-, -CH2-CH2-CH2-〇-CH2-, -CH2-CH2-〇-CH2-CH2 ·, -CH2-CH2-CH2-CH2, 〇-, _CH=CH- or -CH=CH-CH2_0- (here, these groups may also have 丨~2 Ci_c6 alkyl groups or halogen atoms as substituents ), Y is the following group, [Chemical 3]

(here, Ar1 and Ar2 each independently represent a benzene ring or a 5- to 6-membered aromatic heterocyclic ring, and J1, J2, J3, J4, and J5 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, and C! -C6 alkyl, halo c^C: 6 alkyl, C "C6 alkyl fluorenyl Ci-C6 substituent, Ci-C6 alkoxy, halogenated Ci-C; 6 alkoxy, amine, single C "C6 alkylamino group, di-CrC6 alkylamino group, carboxyl group, (^-(^ alkoxycarbonyl group, amine fluorenyl group, mono-CrC6 alkylamine carbaryl group, bis(^-〇: 6 alkylamine) Mercapto, sulfonyl, mono-CKC6 alkylamine sulfonyl, di-Ci-C6 alkylamine sulfonyl, phenyl which may have a substituent, a substituent which may have a substituent, may have a substituent a stupid ethyl group, a phenethyl group which may have a substituent, a strepoxy group which may have a substituent, a benzyloxy group which may have a substituent, a phenoxymethyl group which may have a substituent of 121199.doc -10·200846322, 3 to 8 membered cycloalkyl groups which may have a substituent, 3 to 8 membered cycloalkenyl groups which may have a substituent, 3 to 8 membered cycloalkylmethyl groups which may have a substituent, and 3 to 8 members which may have a substituent Cycloalkyloxy group, 3~8 member ring base group which may have a substituent An oxy group, a 5 to 6 membered aromatic heterocyclic group which may have a substituent, a 4 to 6 membered saturated heterocyclic group which may have a substituent, or a 5 to 6 membered heteroaryloxy group which may have a substituent). Further, the present invention provides a pharmaceutical, an S1P receptor agonist, an immunosuppressive preparation, a rejection reaction for transplantation, an autoimmune disease, and the like, which comprise the above-mentioned compound, a salt thereof, or a solvate thereof, as an active ingredient, and And a therapeutic agent and/or a prophylactic agent for allergic diseases. Further, the present invention provides a medicine comprising the above compound, a salt thereof, or a solvate thereof, and an immunosuppressive agent for suppressing immunity The antibody, the rejection therapeutic drug, the antibiotic, and the steroid drug are used in combination of two or more kinds. The present invention provides a use of the above compound, a salt thereof, or a solvent-solving composition thereof for pharmaceutical production. Further, the present invention provides an antibacterial and/or (7) therapeutic method for a disease of an S1P receptor, which is characterized in that an effective amount of the above compound, a salt thereof or a solvate thereof is administered. [Effect of the invention] The heteroaryl decylamine low carbon number carboxylic acid derivative, the salt thereof, and the like thereof provided by the invention have Sip receptor agonist activity, and are also in vivo in a mouse model and in a rat The model uses oral administration to reduce the number of lymphocytes in the blood of mice and rats, and thus can be used as an effective component of immunosuppressive agents such as 121199.doc -11 - 200846322, for example, for use in mammals, especially humans. Transplant rejection, autoimmune diseases, therapeutic agents for allergic diseases, and/or prophylactic agents are effective. v, (b) effective scaling, and oral administration to reduce the blood in the peripheral blood of mice and rats Because of the number of lymphocytes, it is generally believed that such medicines can be administered. Further, these medicines are less side effects such as bradycardia seen in other Slp receptor agonists. [Embodiment] Hereinafter, each group of the #曰' battle described in the present specification will be described. "CVC6 alkyl group J, system 砉+#, < ^ a linear or branched chain saturated hydrocarbon group having a number of 1 to 6 in the form of a bamboo, and examples thereof include a methyl group, an ethyl group, and a propyl group. , isopropyl, n-butyl, isobutyl, second le-butyl, n-pentyl, 1-ethylpropyl, 2,2-dimethylpropyl, etc. The table "cloth" is a linear chain-like base composed of a methylene chain, and examples of "carbon number 1 to 2 < linear chain-forming base" include -CH2-, -CH2-CH2. Shishan Ru! ^ Feng Wei number 1~3 of the linear chain alkyl group", can be cited - CH2-, -Ch2-ch2 - _CH ΓΗ LH2-CH2-CH2- ' as "Calcium 1~4 straight The chain alkyl group "J" -CH2-, -CH2_CH2-, -CH2-CH2-CH2-^-CH2-CH〇-rw r*u H2-CH2·, as a "linear number of carbon number i~5" "Stretching base", can be listed · r 』~ 举·韵2·,.ch2_CH2...·CH2_CHy CH2- ' "CH2-CH2-CH7-CH^, nu 2 LH2 -ch2-ch2-ch2-ch2- Ch2-. Examples of the "halogen atom" include a nitrogen atom, a germanium atom, a bromine atom, and a hard atom. The "halogenated Ci-C6 alkyl group, the surface is dry," has the above-mentioned C丨-C6 alkyl group having a halogen atom as a substituent, and the number of the gold atoms of the halogen atom may be one or two or more. , i21199.doc -12- 200846322 For the case of two or more, the types of atoms of each drawing can be exemplified by: chloromethyl group, gas methyl group, di-halogen methyl group: Examples Ethyl groups are n-ethyl, u, 2, 2 fluoroethyl 1, 1-difluoro-2-methylpropyl and the like. The oxime ethyl group, the "Cl-C6-homoyloxy group", and the linear or branched alkoxy group having a carbon number of 1 to 6 are exemplified by methoxy group and ethoxy group.

: propoxy, n-butoxy, isobutoxy, tert-butoxy, "yl, 1-ethylpropoxy, 2,2-dimethylpropoxy, etc." The group "' has a _ atom as a substituent. The above-mentioned C^6-yard oxy group may be one or two from the number of atoms. When two or more are used, the types of the functional atoms may be the same. Can be different. For example, fluorine beetle, Chatian #glyfluoromethoxy, trimethyl, trichloromethoxy, pentafluoroethoxy, and the like can be mentioned. = "cvc6 ethoxyl Cl: C6 alkyl", which means that the above Cl_ group having the above _ = group as a substituent, the number of the silk groups may be _ '-, and may be two or more 'for two or more In the case of the case, the types of oxygen in each hospital may be different or different. For example, a methoxymethyl group, an ethoxymethyl group, etc. are mentioned. The "single q-c: 6-alkylamino group" means an amine group having the above-mentioned c-C6 alkyl group as a substituent, and examples thereof include a methylamino group and an ethylamine group. The "di-c"-c0 alkylamino group" means an amine group having two Ci_c6 alkyl groups as a substituent, and the types of the two Ci_C6 alkyl groups may be the same or different. For example, a dimethylamino group, an N-methyl_N_ethylamine group, etc. are mentioned. The "q-C: 6 alkoxycarbonyl group" of the stomach represents a group consisting of the above-mentioned Ci_C6 alkoxy group and a carbonyl group. For example, a methoxycarbonyl group, an ethoxycarbonyl 12 U99.doc 13-200846322 group, a n-propoxy group, an isopropoxy group, a n- oxoxy group, an isobutoxycarbonyl group, a Tributoxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, and the like. The "soap c^c: 6 alkylamine fluorenyl group" means an aminomethyl fluorenyl group having one of the above Ci_q alkyl groups as a substituent. For example, (4): a methylamine (tetra) group, an ethylamine fluorenyl group or the like. —” Today, 1, 1, another 厶’1 return: ^ L】_(J6

The amine group as a substituent may be the same as the amine group, and the two groups may be the same or different. For example, a methylaminomethyl thiol group, a diethylamine methyl fluorenyl group, a N-methylethylamine carbaryl group, etc. are mentioned. The "single cvc6 alkyl sulphate base" means an amino group thiol group having the above-mentioned Ci_C6 alkyl group as a substituent, and examples thereof include a methylamine yellow alcohol ethyl amide group. Isopropylamine sulfonyl and the like. The above-mentioned CrC6 alkylamine sulfonyl group means an amino group having two C丨_c6 alkyl groups as a substituent, and the two Ci_ groups may be different or different. For example, a dimethylamine group, a diethylamine group, an N-methyl-N-ethylaminesulfonyl group, etc. are mentioned. The gram of '3 to 8 bencycloalkyl group' means a monocyclic hydrocarbon group which is 3 to 8 members saturated, and 1 is exemplified by 'cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like. Base: such as 3 to 8 members of cycloalkenyl group, which means 3 to 8 members of unsaturated monocyclic hydrocarbons. Examples thereof include a cyclopropenyl group, a cyclobutadienyl group, a cyclopentyl group, and a cyclohexane. The phrase "3 to 8 chang: ^ w 4 + cycloalkancyclopentyl group, alkylmethyl group" means having one of the above 3 Examples of the methyl group of the group of 8 members include a cyclopropylmethyl group, a cyclobutylmethyl group, and a 121199.doc-14·200846322-based methyl group and a cyclohexylmethyl group. The "3 to 8 membered cycloalkyloxy group" means an alkoxy group having the above-mentioned μ member cycloalkyl group, and examples thereof include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyl group, and a cyclohexyloxy group. base. The so-called "3 to 8 member ring stuns the gas | ......", which has one of the above 3 to 8 membered ring groups, and examples thereof include a cyclopropylmethoxy group, a cyclobutylmethyl group, and a cyclopentylmethoxy group. Base, cyclohexylmethoxy. The so-called "5 to 6 members of Fang Fang, M class, and clothing" means that it contains nitrogen atoms and oxygen; and at least the sulfur atom is selected to be a monoatomic aromatic hetero atom. 5~6 pyrrole ring, azole ring, thiazole-producing clothes, thiophene ring, ring, (four) ring, triple saliva, salivary ring, salivary ring, sputum, etc. -... than biting ring, noise ring, spray The bite ring "Biazine ring is a group consisting of 5 to 6 member aromatic heterocyclic heterocycles, and it can be exemplified: ^ σ spear is not caused by the above 5 to 6 member aromatic groups, snail base, taste sulphonyl group, The phenyl group is sold as a base, a pyridyl group, a pyridazinyl group, a di-, an isothiazolyl group, a pyrazolyl group, and a tris a pyridyl group: and at least a different one selected from the sulfur atom, and a lower one, a saturated monocyclic heterocyclic group having a nitrogen atom and an oxygen atom. /, a 4 to 6 biting base of the atom as a constituent atom of the ring, Difficult to bite small base, suck t can be / lift · · order ~ - base, 対 _ _3 · base, etc. Soil, tetrahydrofuran_2_ base, tetrahydropyridyl so-called "5 ~ 6 member heteroaryloxy and sulfur atom selected At least, the original table does not contain the self-hydrogen atom, the oxygen atom 121199.doc ', and the atom as the constituent atom of the ring 5~6 ' 15- 200846322 member monocyclic heteroaryl ring and oxy group For example, a sulfonyloxy group, a furyloxy group, a pyranyloxy group, a pyrrolyloxy group, a pyridyl group, a pyridyloxy group, a thiazolyloxy group, an isothiazolyloxy group "azozoyloxy, isoyloxy K-oxy, pain $-oxy"

Alkoxy group, pyridazinyloxy group and the like. · /A As a "substituent" in the "may have a substituent", for example, a functional atom, a thiol group, a nitro group, a cyano group, a Cl_C6 alkyl group, a 3-8 member ring group,

Tooth C: -C6 alkyl, Cl_C6 alkoxy c _c6 alkyl, hydrazine. Alkoxy, _ 匚丨-C6 alkoxy, amine, mono-Ci_C6 alkylamino, dialkylyiamine, pendant oxy, fluorenyl, Cl_C6 alkoxy 1 yl, = ^ -c: 6 alkylamine methyl sulfonyl group, diCi_Ce alkylamine carbhydryl group, amine sulfonyl group early <^-〇6 alkylamine sulfonyl group, diCi_C6 alkylamine sulfonyl group and the like. Q, Y, m, n, Ari, Ar2, ji, γ,

Z, the A, R1, R2, v, G!, G2, G3, y, z2, and the preferred formula (1) of J5 represent a single bond, _〇_, or even _, It is preferably a single bond and -0-, more preferably a single bond. R1 in the formula (I) represents a hydrogen atom or a Ci_C6 alkyl group. As in Rl

The Ci-C6 alkyl group may, for example, be a methyl group, an ethyl group, a propyl group or an isopropyl group. Preferably, R1 is a hydrogen atom. V in the formula (1) represents any one selected from the following (1) to (3). (1) _Gl- (wherein, G1 represents a linear extended alkyl group having a carbon number of 1 to 5 which may have a substituent.), ()N(R)7-(here, G2 represents a single bond, or may be a linear alkyl group having a substituent number of 1 to 3 of the substituent 121199.doc -16- 200846322, G3 represents a linear alkyl group having 1 to 4 carbon atoms which may have a substituent, and R2 represents a hydrogen atom or an alkane Base or 3 to 8 membered cycloalkyl.), (3) the following group [Chemical 4]

(p-G1—

(CH • (wherein G4 represents a single bond, or a linear alkyl group having 1 to 2 carbon atoms which may have a substituent, and m and η each independently represent 1, 2 or 3). Here, The right side of each group represented by 1), (2), and (3) indicates a bond to -COOR1 in the formula (I). Hereinafter, a preferred aspect of the above (1) will be described in detail. -Gi_ (wherein G1 represents a linear alkyl group having a carbon number of 1 to 5 which may have a substituent.) G1 represents a linear alkyl group having a carbon number of 1-5 or less having no substituent, or When the substituent has a linear alkyl group having 1 to 5 carbon atoms and a substituent, the number of the substituents may be one or plural, and in the case of plural, the types of the substituents may be The same or different. In the case of a plurality of substituents, each substituent may be substituted on the same carbon atom in the alkylene group, or may be substituted on a different carbon atom. When Gi has a substituent The number of substituents is preferably from i to 4, more preferably from 1 to 2, and even more preferably one. As a substituent in the case where Gi has a substituent Specific examples can be exemplified in the above examples, and preferred are a halogen atom, a trans group, a CpC:6 alkyl group, an amine group, a monoamino group, a dic-c6 alkylamino group to be 121199.doc -17- 200846322 And a pendant oxy group, more preferably a hydroxyl group, an amine group, a single ei-C6 alkylamino group, and

CrC: 6 dialkylamino group' is more preferably an amine group and a single Ci_c6 alkyl amine group. The linear alkyl group having 1 to 5 carbon atoms which may have a substituent in G1 may, for example, be -Ch2_ which may have a substituent, -Ch2-CHr which may have a substituent, and _CH2_CH2 which may have a substituent -CH2_, -CH2_CH2-CH2-CH2- which may have a substituent, -CH2_CH2-CH, a wide CH2.CHr which may have a substituent, etc., preferably -CH2_ch2_ which may have a substituent and which may have a substituent - CHrCH^CH2-, more preferably -Cii2_CHy which may have a substituent, and more preferably _CH2_Ch2. which has a substituent. Specific examples of G1 include a group selected from the group consisting of a free halogen atom, a hydroxyl group, a C-C6 alkyl group, an amine group, a mono-Cl_C6 alkylamine group, and a dioxime alkylamine group. 4 groups as a substituent of _Cil2_CH2_, may have a free halogen atom, a hydroxyl group, a Cl-C6 alkyl group, an amine group, a single Ci_c6 alkyl amine group, and a group of two CkC6 alkyl amine groups selected from 1 to 4 a group as a substituent -CHyCIVCH2-, which may have a group of groups consisting of a free atom, a hydroxyl group, a c"C6 alkyl group, an amine group, a mono-Ci_C6 alkylamino group, and a dialkyl group. 4 groups as a substituent of _CH2_CH2_ch2_CHr, etc. Among them, it is preferred to have a free halogen atom, a hydroxyl group, a C6 alkyl group, an amine group, a mono-Cl_C6 alkylamine group, and a Cl_C6 alkylamine group. The group selects 1 to 2 groups as the substituent cHyCHr, and more preferably has a free halogen atom, a trans group, a CfC:6 alkyl group, an amine group, a mono C6-based amine group, and a di-Ci-C6 alkane. One group selected from the group consisting of amino groups serves as a substituent of -CH^CH2-. Here, as the halogen atom, it is preferably 121199.doc -18- 200846322 A fluorine atom and a gas atom are preferably a methyl group and an ethyl group as a Ci_C6 group, a methylamino group and an ethylamine group as a monoalkylamine group, and a dialkylamine group as a preferred one. Amidino group and N-methyl-N-ethylamine group. As a more specific example of G1, 弋112_(:|12-, -(:112彳112-CH2-, -CH2-CH2- CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-, -CH(OH)-CH2-, -CH(NH2)-CH2-, -CH(NCH3)-CH2-, CH(N(CH3) 2) -CH2-, -CH(NCH3(C2H5))-CH2-, -CH2-CH(OH)-, -CH2-CH(NH2)-, _CH(NH2)-CH2-CH2-, -CH2- CH(>iH3)-CH2-specific' is a preferred example: _ch2-CH2-, -CH(OH)-CH2-, -CH(NH2)-CH2., -CH(NHCH3)-CH2., - CH2_CH(OH)- and CHrCH (Li 2), as a more preferable example, CH2-CH2-, -CH(NH2)_CH2-, and -CH(NCH3)-CH2- are further exemplified in the specific examples. The right side of each group indicates a bond to -COOR1 in the formula (1). The following is a detailed description of the preferred aspect of the above (2). v represents VII 2 N(R 2 )-G 3 · (here, G 2 represents a single bond or a linear alkyl group having a carbon number of 丨~3 having a substituent G3 represents a substituent having a carbon number of Bu 4 linear shape of the alkylene group, R2 represents a hydrogen atom, Ci_C0 3~8 membered alkyl or cycloalkyl group. ). G2 represents a single bond, a straight-chain alkyl group having a carbon number of 3 without a substituent, or a linear alkyl group having a carbon number of 丨~3 having a substituent, and the carbon number of G3 having no substituent a straight-chain extended alkyl group of the group 4 or a linear alkyl group having a carbon number of 1 to 4 having a substituent. When G2 or G3 has a substituent, the number of substituents can be! The number of the substituents may be the same or different. Further, g2 or 03 121199.doc • 19· 200846322 In the case of a plurality of substituents, each substituent may be substituted on the same carbon atom in the alkylene group or may be substituted on a different carbon atom. The number of substituents in the case where G2 or G3 has a substituent is preferably from 1 to 4, respectively. Specific examples of the substituent in the case where G2 or G3 has a substituent include the above-exemplified examples, and a halogen atom, a trans group, a CJ-alkyl group and a pendant oxy group are preferable, and as the Ci-C6 alkyl group, for example, Listed by methyl, ethyl and the like. Further, in the case where G2 is a linear alkyl group having 1 to 3 carbon atoms, it is preferred that the carbon number of the linear chain portion of the spring G2 and G3 is 4 or less in total. The linear alkyl group having 1 to 3 carbon atoms which may have a substituent in G2 may, for example, be -Ch2_ which may have a substituent, -CIi2_CH2 which may have a substituent, may have a substituent CHz-CHz-CHz-, preferably -CH2- which may have a substituent and -CH2-CH2- which may have a substituent. The linear alkyl group having 1 to 4 carbon atoms which may have a substituent in G3 may, for example, _ch2- which may have a substituent, _ch2_lu CH2- which may have a substituent, may have a substituent -CH2-CH2-CH2-, -CHa-CHrCHrCHr which may have a substituent, preferably -CH2_ which may have a substituent, and -CH2-CH2. which may have a substituent. As G2, a single bond and _Ch2- which may have a substituent are preferred, and -CH2- which has no substituent is more preferred. Specific examples of G2 include a single bond, and may have a group of 1 to 2 groups selected from a group consisting of a free halogen atom, a hydroxyl group, a Cl-c6 alkyl group, and a pendant oxy group as a substituent. _CH2_Ch2- and the like having 1 to 2 groups selected from the group consisting of a free halogen atom, a hydroxyl group, a C!-C6 alkyl group and a pendant oxy group as a substituent. Among them, more than 121199.doc -20· 200846322 is a single bond, and a group which may have a group selected from a group consisting of a free spectre atom, a hydroxyl group, a Ci_C6 alkyl group and a pendant oxy group as a substituent, _cH2_' What is ok is _CH2- which has no substituent. As G3, preferred is ChCh_ which may have a substituent, and -CHh-CH2- which may have a substituent, and more preferably, CHCH-CH2_ which has no substituent. Specific examples of G3 include -CHy which may have a group selected from a group consisting of a free halogen atom, a hydroxyl group, a CnC6 alkyl group and a pendant oxy group as a substituent, and may have a free halogen atom, a hydroxyl group, and a Ci_C6. The group in which the alkyl group and the pendant oxy group are selected, as the substituent, _Ch2_CHr or the like, wherein _CH2_CHr having no substituent, _CH2_CH2_ having j halogen atoms as a substituent, And -CH2-CH2- having i hydroxyl groups as a substituent. In G2 and G3, a fluorine atom and a chlorine atom are preferred as the halogen atom, and a methyl group and an ethyl group are preferred as the C^C:6 alkyl group. R2 represents a hydrogen atom, a Ci-C6 alkyl group or a 3-8 membered cycloalkyl group, and is preferably a hydrogen halide atom of R2 and a CVC6 alkyl group. As the (^-(6) alkyl group in R2, a methyl group, an ethyl group, a propyl group, an isopropyl group or the like may be mentioned, and a methyl group is preferable. As a 3- to 8-membered cycloalkyl group in R2, Illustrative: a cyclopropyl group, a cyclobutyl group, etc., preferably a cyclopropyl group. As a specific example of v in the case where the V system is represented by (2), it can be listed as: -NH-CH2-CH2- - -NH-CH2-CH2-CH2- -CH2-NH-CH2-, -CH2-NH-CH2-CH2-, -CH2-N(CH3)-CH2-, -CH2-N(CH3)-CH2- CH2- > -CH2-N(C2H5)-CH2tCH2- -CH2-N(i-Pr)-CH2-CH2-, _CH2-N(c-Pr)-CH2-CH2-, -CH(CH3)- NH-CH2-, stomach 21 - 121199.doc 200846322 -ch2_nh - CH2-CH(CH3)-, -CH(CH3)-NH-CH2-CH2-, -c(ch3)2-nh-ch2-ch2-, -ch(ch3)-n(ch3)-ch2-ch2-, -c(ch3)2-n(ch3)-ch2-ch2-, -ch2-ch2-nh-ch2-, -chf-nh-ch2- Ch2-, -co_nh-ch2-ch2-, -co-n(ch3)-ch2-ch2-, -ch2-nh-ch2-ch(oh)-, -ch2-nh-ch2-chf-, etc. are preferred examples , 可歹]J: -CH2-NH-CH2-, -CH2-N(CH3)-CH2-, -CH2-NH-CH2-CH2- > -CH2-N(CH3)-CH2-CH2- -CH(CH3)-NH-CH2-CH2-, -CH2-CH2-NH-CH2-, -CH2-NH-CH2-luCH(OH)-, and -CH2-NH-CH2, CHF. again The right side of each group exemplified in the specific examples indicates a bond to -COOR1 of the formula (I). Further, i-Pr represents an isopropyl group, and c-Pr represents a cyclopropyl group. 3) The preferred aspect is described in detail. V represents the following group [Chemical 5]

—G—N (wherein G4 represents a single bond or a linear alkyl group having 1 to 2 carbon atoms which may have a substituent, and m and η each independently represent 1, 2 or 3.). m represents 1, 2 or 3, and preferably m is 1. η represents 1, 2 or 3. As a preferable combination of m and η, m is preferably 1 or 2, and η is 1, 2 or 3; more preferably m is 1, η is 1, 2 or 3; and further preferably m is 1, η is 2 or 3. G4 represents a single bond, a linear alkyl group having a carbon number of 1 to 2 having a substituent, or a linear alkyl group having 1 to 2 carbon atoms which has no substituent, and G4 has 121I99.doc -22-200846322 In the case of a substituent, the number of the substituents may be one or plural, and in the case of a plurality of substituents, the types of the substituents may be the same or different. Further, when G4 has a plurality of substituents, each substituent may be substituted on the same carbon atom in the alkylene group, or may be substituted on a different carbon atom. When G4 has a substituent, the number of substituents is preferably from 1 to 2. The substituent in the case where G4 has a substituent is exemplified above, and a halogen atom is preferably a & Cl-c6 alkyl group, more preferably a ckC6 alkyl group. • As the linear alkyl group of the carbon number which may have a substituent in G4, _CH2- which may have a substituent, _ch2-CH2_ which may have a substituent, etc. -ch2- which may have a substituent, more preferably -CH2- which has no substituent. As G4', a single bond and -CH2- which may have a substituent are preferable, and a _CHr which has no substituent is more preferable. Specific examples of G4 include a single bond '-CH2- which may have a free halogen atom and a group consisting of a ci-C6 alkyl group and 1 to 2 groups as a substituent, and may have a free halogen. The atom and the group of u selected from the group consisting of C^C:6 alkyl groups are CH2CHy and the like as a substituent. Among them, preferred are: a single bond, and one group which may have a group selected by a free, ', and C1-C6 alkyl group as a substituted CHr, more preferably a single bond, and no substituent Further, -CH2-; more preferably _CH2 having no substituent. Here, examples of the alkyl group include a methyl group and an ethyl group. When v is a group represented by (3), V is Specific examples can be cited as [Chemical 6] 121199.doc -23- 200846322

Ch3 • etc. As a good example, among them, the better one is [Chem. 7]

Further, on the right side of each of the groups indicated in the specific examples, the bond to -COOR1 in the formula (1) is shown. Ζι and f in the formula (1) each independently represent a nitrogen atom or a Ci_c fluorenyl group. Here, 'as a CVC6 alkyl group, a f group, an ethyl group, a propyl group, etc. are preferable. A methyl group is preferable. As and 22, zl and a hydrogen atom are preferred. Z3 in the formula (I) represents a hydrogen atom, a quivalent atom, a cyano group, a (tetra)alkyl group, a dentate CVG alkyl group, a CVM oxy group, or a halooxy group. Here, the C]-C6 alkyl group, the chiral Ci_c6 alkyl group, the Ci_C6oxy group, and the 6-fluorene 6 alkoxy group may be exemplified by carbon number. As z3, hydrogen ^ 121199. doc - 24 - 200846322, CrC: 6 alkyl group & Cl-C6 alkoxy group, more preferably a hydrogen atom and a mercapto group are preferred. Here, Z3 is a compound of a Ci-C6 alkyl group or a CrC:6 alkoxy group, and in many cases, it is a highly qualified compound having higher activity and fewer side effects than a compound in which Z3 is a hydrogen atom. Q in the formula (I) represents a single bond, -〇_, CHr', -CH2-CH2-CH2-, _CH2-CH2-CH2-CH2., .CH2-CH2.CH2, ch2-ch2-, .ch2 -〇·, -ch2-ch2-o-, -ch2-〇-ch2·, τη2-CH2 O CH2 ^ -CH2-CH2-CH2-O- ' "CH2-CH2-CH2-O-CH2-,- CH2-CH2-〇-CH2-CH2-, _CH2-CH2-CH2-CH2-〇-, -CH=CH· or -CH=CH-CH2-〇- (here, these groups may have 2 <^-(: 6 alkyl or a halogen atom as a substituent.) These groups may be bonded to γ in the formula (1) at any of the left and right. As such groups, an alkyl group is used as a substituent. In the case of the Ci_C6 alkyl group, for example, a methyl group or an ethyl group is preferable, and a mercapto group is preferred. The _ atom is preferably a fluorine atom or a gas atom. Further, these groups have two groups. When the Ci_C6 alkyl group or the halogen atom is used as a substituent, the kinds of the substituents may be the same or different, and each substituent may be substituted on the same carbon atom of the group or may be substituted on a different carbon atom. Further, the number of Ci_C6 alkyl groups or halogen atoms in the case where the group has a Ci_C6 alkyl group or an A atom as a substituent Preferably, it is 1 or 2. As Q, a single bond, preferably 1 to 2 Ci-C: 6 alkyl or a halogen atom as a substituent -Ch2_〇·, and may have 1 to 2 a CVC6 alkyl group or a _ atom as a substituent -CH2_CH2_CH2· 〇- 'better is _CH2_〇_ which has no substituent. Here, any of the specific examples of the Q may be Γ-bonding in the formula (1) 121199.doc -25- 200846322 γ in the formula (i), which represents the following group [Chemical 8]

or

(here, Ar1 and Ar2 each independently represent a benzene ring or a 5- to 6-membered aromatic heterocyclic ring, and J1, J2, J3, J4, and J5 each independently represent a hydrogen atom or a halogen atom.

Sub, hydroxy, nitro, cyano, C "C6 alkyl, halogenated cKC6 alkyl, CV

C6 alkoxy-Ci-C6 alkyl, CVC6 alkoxy, halogenated Ci-C6 alkoxy, amine, monoamine, di-Ci-C6 alkylamino, carboxyl, oxy-wei group, amine Sulfhydryl, mono-CrC: 6-alkylaminocarbamyl, di-aminoamine, mercapto, monoalkylamine hydrazino, di-c1> ec6 alkyl sulfonyl, may have a substituent a phenyl group, a benzyl group which may have a substituent, a phenethyl group which may have a substituent, a stupid vinyl group which may have a substituent, a phenoxy group which may have a substituent, a benzyloxy group which may have a substituent, may have a substitution a phenoxymethyl group, a 3 to 8 membered cycloalkyl group which may have a substituent, a 3 to 8 membered cycloalkenyl group which may have a substituent, a 3 to 8 membered cycloalkylmethyl group which may have a substituent, a 3 to 8 membered cycloalkyloxy group having a substituent, which may have a 3 to 8 membered fluorenylmethoxy group, a 5 to 6 membered aromatic heterodiyl group which may have a substituent, and may have a substituent 4 to 6 membered saturated heterocyclic group, or 5 to 6 membered heteroaryloxy group. ). /, in order to replace Ar1 and Ar2 in γ, respectively, as a 5- to 6-membered aromatic heterocyclic ring σ ratio slightly j chen, 吟 环 ring, σ 塞 塞 环 环 环 环 环 环 环 环 环 环 环 环For example, furan ring, thiophene ring, imidazole ring, isoxazole ring, isothiazole 121199.doc -26 - 200846322

= Also sit & - saliva %, bite ring, 哒 ° Qin ring. t bite ring, anthracene ring :, preferably a furan ring, a thiophene ring, a carbazole ring, a thiazole ring, an imidazole % m trivalent κ ring, and a pyridazine ring. As w, it is a benzene ring, a furan ring, a thiophene ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, and a pyrazine ring, more preferably a benzene:, a furan ring, The thiophene ring, the imidazole ring, the pyrazole ring, the pyridine ring, and the pyridazine %' are more preferably a benzene ring, a porphin ring, and a π-pyry ring. As w, ? is preferably a carbazole ring, a thiazole ring, an isoxazole ring, an isothiazole ring, and a triazole oxime, more preferably an oxazole ring, a thiazole ring, and a triazole ring. J, J, j3, J4 and J5 in Y are each independently represented by a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a CkC6 alkyl group, or a _ generation. 1_. Alkyl 2 c^C6 alkoxy Cl_C6 alkoxy, Ci_c0 alkoxy, halogenated C1_C6 alkoxy, amine, mono-Cl-C6 alkylamino, diylamino, carboxy Ci-C6 alkoxy Carbonyl, amine methyl sulfhydryl, mono-Ci_c6 alkyl amine sulfhydryl, di-CpC6 alkyl amine fluorenyl, amine sulfonyl, mono-c-fluorenyl 6-alkylamine sulfonyl, di-C!-C6 alkylamine a sulfonyl group, a phenyl group which may have a substituent, a benzyl group which may have a substituent, a phenethyl group which may have a substituent, a stupid vinyl group which may have a substituent, a phenoxy group which may have a substituent, may have a substitution a benzyloxy group, a phenoxymethyl group which may have a substituent, a 3 to 8 membered cycloalkyl group which may have a substituent, a 3 to 8 membered cycloalkenyl group which may have a substituent, and a 3~ which may have a substituent 8-membered cycloalkylmethyl group, 3 to 8 membered cycloalkyloxy group which may have a substituent, 3 to 8 membered cycloalkylmethoxy group which may have a substituent, and 5 to 6 membered aromatic group which may have a substituent a heterocyclic group, a 4 to 6 membered saturated heterocyclic group which may have a substituent, or a 5 to 6 membered heteroaryloxy group which may have a substituent, preferably a hydrogen 121199.doc • 27-200846322 atom, a halogen atom Nitro, , CVC6 alkyl, halogenated (^-(:6 alkyl, CKC6 alkoxy Ci-C6 alkyl, Ci-C6 alkoxy, halogenated (^-(^ alkoxy, diCrC6 alkyl amine) a phenyl group which may have a substituent, a phenethyl group which may have a substituent, a phenoxy group which may have a substituent, a oxy group which may have a substituent, a 3 to 8 membered cycloalkyl group which may have a substituent, a 3 to 8 membered cycloalkenyl group which may have a substituent, a 3 to 8 membered cycloalkylmethyl group which may have a substituent, a 3 to 8 membered cycloalkylmethoxy group which may have a substituent, and may have a substituent 5 to 6 membered aromatic heterocyclic group, more preferably a hydrogen atom, a halogen atom, a nitro group, a cyano group, a CVC6 alkyl group, a functional alkyl group, a Cl_C6 alkoxy fluorene-1-〇6 alkyl group, C!- a C6 alkoxy group, a halogenated C^-C6 alkoxy group, a phenyl group which may have a substituent, and a 3 to 8 membered cycloalkyl group which may have a substituent. As Y, the following group is preferred. 9]

'Ar1 is a benzene ring, a furan ring, a thiophene ring, an imidazole ring, a pyrazole ring, a pyridinium ring, or a pyridazine ring, and ji, j2 and j3 are each independently a hydrogen atom, a halogen atom, a trans group, a nitro group, Cyano, Cl-C6 alkyl, halogenated (^-06 alkyl, CVC6 alkoxy Cl-C6 alkyl, CVC6 alkoxy, halogenated <^-(:6 alkoxy, amine, single (^-(^alkylamino, diylamino, carboxyl, CrC6 alkoxycarbonyl, aminecarbamyl, mono-Cl_c6 alkylamine sulfhydryl, di-Cl-C6 alkylamine-methyl sulfhydryl, amine sulfonate Sulfhydryl, monoalkylamine sulfonyl, di-CrC6 alkylamine sulfonyl, phenyl which may have a substituent, may be 121199.doc -28 - 200846322 benzyl having a substituent, phenylethyl which may have a substituent a styrene group which may have a substituent, a phenoxy group which may have a substituent, a benzyloxy group which may have a substituent, a phenoxymethyl group which may have a substituent, a 3 to 8 member ring which may have a substituent An alkyl group, a 3 to 8 membered cycloalkenyl group which may have a substituent, a 3 to 8 membered alkyl group which may have a substituent, a 3 to 8 membered cycloalkyloxy group which may have a substituent, may have a substitution 3 to 8 membered cycloalkyl a methoxy group, a 5 to 6 membered aromatic heterocyclic group which may have a substituent, a 4 to 6 membered saturated heterocyclic group which may have a substituent, or a 5 to 6 membered heteroaryloxy group which may have a substituent ; and • the following groups [10]

Wherein 'Ar2 is 'anthracene ring, thiazole ring or triazole ring, and y, j2 and j3 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a ^-(^ alkyl group, an i-generation CrC6 alkyl group, CVC6 alkoxyalkyl, CVC6 alkoxylate, halogenated Ci-C6 alkoxy, amine, mono(alkylamino), diCrC6, amino, carboxyl, CrQ alkoxycarbonyl, amine Mercapto, mono-CrCs alkylamine carboxylic acid, di-CpC: 6-alkylamine-methyl indenyl, amine sulfonyl, mono-Cl_C6 alkyl sulfonyl, di-CkC6 alkylamine sulfonyl, may have a substitution a phenyl group, a benzyl group which may have a substituent, a phenethyl group which may have a substituent, a styryl group which may have a substituent, a phenoxy group which may have a substituent, a benzyloxy group which may have a substituent, a phenoxymethyl group having a substituent, a 3 to 8 membered cycloalkyl group which may have a substituent, a 3 to 8 membered cycloalkenyl group which may have a substituent, and a 121199.doc -29-200846322 having a substituent 3~ 8-membered cycloalkylmethyl group, 3 to 8 membered cycloalkyloxy group which may have a substituent, 3 to 8 membered cycloalkylmethoxy group which may have a substituent, and 5 to 6 membered aromatic group which may have a substituent miscellaneous Group, 4 ~ 6-membered saturated heterocyclic ring may have a substituent group, the case may have a 5 to 6 membered or heteroaryl group of the substituent. Y is a group, [Formula 11]

When Ar is a benzene ring, a furan ring, a thiophene ring, an imidazole ring, a pyrazole ring, a pyridine ring, or a pyridazine ring, it is preferred that jl, j2, and j3 are independently a hydrogen atom, a halogen atom, and a nitro group. , cyano, Cl_c6 alkyl, halogenated CK C6 alkyl, C "C6 alkoxy Cl_c6 alkyl, (VC6 alkoxy, halogenated (V C6 alkoxy, bis(nonyl)alkylamine, a phenyl group which may have a substituent, a phenethyl group which may have a substituent, a phenoxy group which may have a substituent, a benzyloxy group which may have a substituent, a 3 to 8 membered cycloalkyl group which may have a substituent, may have a 3 to 8 membered ring fluorenyl group of the substituent, a 3 to 8 membered cycloalkyl group which may have a substituent, a 3 to 8 membered cycloalkylmethoxy group which may have a substituent, or a substituent which may have 5 a 6-membered aromatic heterocyclic group. Further, it is more preferable that y is a halogenated C6 alkyl group, and j is (^-(:6 alkyl, halogenated CVC6 alkyl, phenyl which may have a substituent, or a 3-8 membered cycloalkyl group which may have a substituent, J3 is a hydrogen atom; a nitro group, a cyano group, or a CVC6 alkoxy group C1-C6 alkyl group, and j2 is a phenyl group which may have a substituent or may have a substituent 3 ~8环环烧基, J is a hydrogen atom, J is a heart-.6 alkoxy group J2 is a C"C6 alkyl group, which may have 121199.doc -30-200846322: stupid or may have a substituent 3~8 a cycloalkyl group, j3 is a halogen atom and J is a halogenated C-C6 alkoxy group, 丨2 is a Ci-C6 alkyl group, a phenyl group which may have a substituent, or a 3 to 8 member which may have a substituent Cycloalkyl, 3 is a hydrogenogen h here 'for Yang i, preferably a benzene ring, an epoch ring and an anthracene ring. 3 More specifically, when ^1 is a benzene ring, it is preferred The ones of Jl, J2, and J3 are hydrogenogens, and the other two are independently hydrogen atoms, (tetra), nitro, cyano, cvc6 alkyl, halogenated Ci_c6 alkyl anthracene C! c6 a compound, a Ci_c6 methoxy group, a halogenated CA oxy group, a phenyl group which may have a substituent, or a 3 to 8 member cycloalkyl group which may have a substituent. Further, the oxime J is a halogenated Ci_C6 alkane. a group, j2 is a haloalkyl group, a phenyl group which may have a substituent, or a cyclized group which may have a substituent, and 3 is a hydrogen: a subgroup; 'is a thiol group, a cyano group, or a ruthenium oxy group. a phenyl group which may have a substituent or may have a 3 to 8 members of the clothing base, J is a hydrogen atom; f is a phenyl group which may have a substituent, 2 and j3 are hydrogen atoms, and the sub-d is an oxy] group, which may have a substituted phenyl group. Or a 3- to 8-membered cycloalkyl group which may have a substituent, j3 is a hydrogen atom, and J is a halogenated CrC6 alkoxy group, J2 is a Ci-C6 alkyl group, a phenyl group which may have a substituent, or may have a substituent 3 to 8 members of the ring-burning group, J3 is a gas atom. π, A 〆 is a furan ring, a thiophene ring, an imidazole ring, a pyrazole ring, a pyridine ^, or a pyridazine ring, preferably, j2 And any one of j3 is a hydrogen atom, and the other two are independently a gas atom, a picture atom, a nitrate cyano group, a Cl_C6 alkyl group, a halogenated Ci-C6 alkyl group, a Cl_c6 alkoxy group c121 121199.doc -31 - 200846322 C6 alkyl, C^C6 alkoxy, halogenated CVC6 alkoxy, phenyl which may have a substituent, or a 3-8 membered cycloalkyl group which may have a substituent. Further, a more preferable 疋J is a halogenated C-C6 alkyl group, J is a CrC; a 6-alkyl group, a phenyl group which may have a substituent or a 3 to 8 membered cycloalkyl group which may have a substituent, and J3 is a hydrogen atom. .

When Ar1 is a benzene ring, and only two of ji, j2 and j3 are hydrogen atoms, it is preferred that Q is bonded to the 1-position of the benzene ring, and the chlorine atoms of ji, j2 and j3 are bonded to each other. In the 5th position of the benzene ring, the other 2 are bonded to the 3rd position and the 4th position of the benzene ring; or, Q is bonded to the 1st position of the benzene ring, and the hydrogen atom bonds in y, j and " It is bonded to the 3rd position of the benzene ring, and the other 2 are bonded to the 2nd position and the 4th position of the benzene ring. When two of Ar, a benzene ring, ji, j, and j are hydrogen atoms, it is preferred that Q is bonded to the benzene ring, and 1, j2, and J3 are not ruthenium atoms. One is bonded to the 4-position of the benzene ring.

When Ar1 is a furan ring or a thiophene ring, it is preferred that q is bonded to the bite ring or the 2-position of the thiophene ring, and j, j2, and j3 are respectively bonded to the =^ ring or the stimuli. At the 3rd, 4th and 5th positions of the ring; in the case of 1, 1 and ρ, only one of the money atoms, it is preferred that the 3rd position of the thiophene ring is a hydrogen atom. Second

When Ar is the case of the 嗤 ring, the car is well-bonded, q is bonded to the * position of the scent ring, and Jl, J2, and J3 are respectively bonded to the taste ring (10) and the 2 position to \5. When only one of JJ and J is a hydrogen atom, the fifth position of the imidazole ring is a hydrogen atom. In the case of a wow, it is better that q is bonded to the ton, 6 is 2, and the other is bonded to the heart ring; position; in Jl, T2LV, the τ3 mountain NIL Μ In the case where only one of the hydrogen atoms is a hydrogen atom, it is preferred that I21199.doc -32 - 200846322 is a hydrogen atom at the 4-position of the pyrazole ring. Further, it is preferred that Q is bonded to the 4-position of the pyrazole ring, and J1, J2 and j3 are bonded to the 、, 3 and 5 positions of the pyrazole ring, respectively, in J1, J2 and j3. When only i of the hydrogen atoms are present, the 5th position of the pyrazole ring is a hydrogen atom.

Ar1 is a bite ring. It is preferred that Q is bonded to the 2 or 3 position of the anthracene ring, and Ji, J2 and j3 are respectively bonded to the nibble, 5 position= and 6 position of the pyridine ring. When only one of J1, J2 and J3 is a hydrogen atom, it is preferred that the 4-position of the pyridine ring is a hydrogen atom.

When Ar1 is a pyridazine ring, it is preferred that Q is bonded to the 3-position of the pyridazine ring, and J1, J2 and J3 are bonded to the 4-position, 5-position and 6-position of the pyridazine ring, respectively. When only one of j is a hydrogen atom, it is preferred that the 4-position of the pyridazine ring is a hydrogen atom. Y is the following group, [Chemical 12]

And in the case of drinking an azole ring, a thiazole ring or a tri-salt ring, the preferred "4 and J are independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C group, a halogenated cvC6 alkyl group, and a Cl_C6 group. An oxy-Ci_C6 alkyl group, a c-heart-burning group, a halogenated CVC6 alkoxy group, a phenyl group which may have a substituent, or a 3- to 8-membered fluorenyl group having a substituent. Further, more preferably; Μ ” Courtyard, J5 is a phenyl group which may have a substituent. 1<:6

When Ar2 is an oxazole ring or a thiazole ring, it is preferred that q is bonded to the 121199.doc -33 - 200846322% spiro ring or the 2-position of the thiazole ring, and J4 and J5 are bonded to the carbazole, respectively. Ring or the 4 and 5 positions of the indazole ring.

When Ar2 is a tri-salt ring, it is preferred that the triazole ring is 1,2,4-triazole ring'. It is preferred that Q is bonded to the oxime, 2, at the 3-position of the triazole ring, and j4 And j5 is bonded to the oxime, the 1st and 5th positions of the 2,4-triazole ring, respectively.

to? In the above, J1, J2, J3, J4 and J5 are each independently a hydrogen atom, a halogen atom, a trans group, a nitro group, a cyano group, a Cl_c6 alkyl group, a halogenated Ci_c6 alkyl group, a Ci_C6 alkoxy group C-C6 alkyl group, Cl_c0 alkoxy, halogenated Ci_C6 alkoxy, amine, monoterpene-(: 6 alkylamino, di-Cl-C6 alkylamino, carboxyl, Cl-c6oxycarbonyl, aminemethanyl, Mono Cl_C6 alkylamine methyl sulfonyl, bis(^_〇6 alkylaminecarbamyl, amine sulfonyl, mono-Cl_c0 alkylamine sulfonyl, dialkylamine sulfonyl, benzene which may have a substituent a benzyl group which may have a substituent, a phenethyl group which may have a substituent, a styryl group which may have a substituent, a phenoxy group which may have a substituent, a benzyloxy group which may have a substituent, may have a substituent a phenoxymethyl group, a 3 to 8 membered cycloalkyl group which may have a substituent, a 3 to 8 membered cycloalkenyl group which may have a substituent, a 3 to 8 membered cycloalkylmethyl group which may have a substituent, may have 3 to 8 membered cycloalkyloxy group of the substituent, 3 to 8 membered cycloalkylmethoxy group which may have a substituent, 5 to 6 membered aromatic heterocyclic group which may have a substituent, and 4 which may have a substituent ~6 member saturated heterocyclic group In the case of a 5- to 6-membered heteroaryloxy group which may have a substituent, specific examples of the respective substituents include those exemplified above, and a halogen atom, a Cl_C6 alkyl group, an odor, and 3 to 8 are preferred. The cycloalkyl group is preferably a methyl group as the CrC6 alkyl group, and is preferably a cyclopropyl group as a 3 to 8 member of the ring-based base. 'As a specific example of J1, J2, J3, J4, and J5, : gas atom 121199.doc -34- 200846322 fluorine atom, chlorine atom, nitro group, cyano group, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, trifluoromethyl group, anthracene,丨-difluoro-2-methylpropyl, methoxy, ethoxy, trifluoromethoxy, dimethylamino, phenyl, stupidyl, phenoxy, benzyloxy, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, 1-methyl-1-cyclopropyl, cyclohexen-1-yl, cyclopentyl fluorenyl, cyclohexylmethyl, cyclopentyl decyloxy, cyclohexyl A methoxy group or the like is preferably a hydrogen atom, a fluorine atom, a decyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a third group. Fluoromethoxy, phenyl, stupid ethyl, phenoxy Benzyloxy, cyclopentyl and cyclohexyl. Hereinafter, a preferred combination of A, R, V, ZI, Z2, Z3, Q and γ will be described. A is a single bond 'R1 is a hydrogen atom, and v is Any one selected from the following (1) to (2): (1) Here, G1 represents a linear extended alkyl group having a carbon number of 1 to 5 which may have a substituent.), (2) -G - N(R )-G3- (herein, G2 represents a single bond or a linear alkyl group having 1 to 3 carbon atoms which may have a substituent, and G3 represents a linear chain having a carbon number of 丨~4 which may have a substituent An alkyl group, R2 represents a hydrogen atom, a C-C6 alkyl group or a 3- to 8-membered cycloalkyl group. ), Z1 and Z2 are each a hydrogen atom, z3 is a hydrogen atom or a Cl-C6 alkyl group, Q is -ch2-o-, and Y is [Chem. 13] 121199.doc -35- 200846322

(wherein Ar1 represents a benzene ring, a furan ring, a thiophene ring, an imidazole ring, a pyrazole ring, an 11-bite ring, or a pyridazine ring, and j1, j2, and j3 are each independently a hydrogen atom, a functional atom, a nitro group, and a cyano group. , CVC6 alkyl, halogenated CVC6 alkyl, alkoxy CVC6 alkyl, (VC6 alkoxy, halogenated Ci-Q alkoxy, di-Ci-C6 alkylamino, phenyl which may have a substituent, A stupid ethyl group which may have a substituent, a phenoxy group which may have a substituent, a benzyloxy group which may have a substituent, a 3 to 8 membered cycloalkyl group which may have a substituent, and 3 to 8 member% which may have a substituent An alkenyl group, a 3 to 8 membered cycloalkylmethyl group which may have a substituent, a 3 to 8 membered alkyloxy group which may have a substituent, or a 5 to 6 membered aromatic heterocyclic group which may have a substituent An example of a preferred combination. When the compound of the present invention has one or more asymmetric centers in the molecule, the mirror-isomers, racemates, and the like are also included in the case where they are not specifically indicated. a non-image isomer and a compound of denier-, temple. Further, when the compound of the present invention contains a geometric isomer, t, when not specifically stated Containing cis, and oxa compound, trans-configuration date, and when the compound of the present invention contains ^ ^ e Ψ ir -1 毚 /, the structure, the % is not specifically indicated, and includes any mutual enthalpy Mixtures of M and the like. The present invention comprises a compound of the formula (1), a solvate of the compound of the formula, and the like, and a salt of the metal salt of the compound of the present invention. , Magnesium, etc.: List. Potassium 'sodium, bell and other salts of salt, tetramethylammonium salt, tetrabutyl 121199.doc -36 - 200846322 ammonium salt and other ammonium salts, triethylamine, methylamine (hydroxymethyl) An inorganic acid salt such as a salt of an organic amine such as a methylamine; an organic acid salt such as an acetate, a lactate salt, a maleate salt, a citrate salt or an acid salt; or a monoamine, a methyl glucosamine, a salt or a salt. Examples of the solvate of the compound of the present invention include an acid salt, a phosphate salt, a nitrate salt, a tartrate salt, an oxalate salt, a fumagazine salt, an ethanesulfonate salt, and a benzenesulfonate. a compound, an ethanolate or the like. The compound of the present invention, a salt thereof, or a deuterium-- For example, a compound in which the carboxyl group of the compound represented by the formula (1) is esterified or amided can be used. The method for producing the compound represented by the formula (1) will be described below. The production method is not limited to the following methods. The compound represented by the formula (I) and the intermediate for its production can be produced by various known reactions described below. In this case, it is present in the raw material or the intermediate. In the case of protecting the functional group with a suitable protecting group, examples of such a functional group include a hydroxyl group, a carboxyl group, an amine group, a carbonyl group, and the like, a kind of the protecting group, and the conditions for introduction and removal of the protecting group. For example, McCormick is revealed in protective Gr〇lips in 〇rganic Synthesis (T·w

Green and P·G· Wuts, John Wiley & Sons, lnc·, New York, 1991). 5 The compound (1) of the present invention can be produced by the following [Production Method 1]. [Production Method 14] 121199.doc -37- 200846322

Wherein Rla represents C "C6 alkyl, χ1 and χ2 represent groups which react with each other to form q" P1 represents a protecting group, A, Q, v, G1, G2, G3, G4, R2, m, η, γ And ζι, Z2 and Z3 are the same as those of the formula (1). The ester derivative (la) in the compound (1) of the present invention can be produced as follows: a compound (1) is reacted with the compound (2) to prepare a compound. (3), after removing the protecting group pi of the compound (3) to prepare the compound (4), and then producing it by the & method or the b method. Here, as the protecting group pi, it is preferably the third group. Amino formate protecting groups such as oxycarbonyl and oxycarbonyl, arylsulfonyl protecting groups such as benzenesulfonyl and p-toluenesulfonyl, and methoxyindenyl, (2-3) Particularly preferred is an alkyl group-based nitrogen atom protecting group such as an alkyl ethoxy)methyl group, particularly preferably a third butoxycarbonyl group. The carboxylic acid derivative (lb) in the compound (I) of the present invention, by ester The body (la) is produced by the test or acid hydrolysis. In the following [manufacturing method VIII_丨]~[manufacturing method A-4], in the [manufacturing method 121] 121199.doc • 38- 2008 A method for producing the compound (3) by the reaction of the compound (1) with the compound (7) shown in 46322. The base Q is -(ch2)p-CH2-〇_ or -CH2_〇_. j hunting by [Chem. 15] [Manufacturing Method A-1]

U, Q means ·_2) ρ even_〇· or even, _ means a radical or a detached base 'eight, ', ~, and 23 denote the same as the above, 'Ρ denotes 1, 2, or 3.) Manufacturing method Α-1] can be roughly divided into the following two cases (1) W1 is the base case

The compound (7) can be produced by treating a phenol derivative (10) with an alcohol derivative (2a or 2-azo reagent and a phosphine compound (gloss reaction). As an azo reagent, azobis2, Azodi-low-acid diisopropyl vinegar, U'·(Azo two county) two-bit bite and u, • azobis(10)_dimethylamylamine), etc. Use of azo reagent 4, preferably The phenol derivative (la) is in the range of from 0 to 12 moles. Examples of the phosphine compound include triphenylphosphine, tri-n-butylphosphine, and trimethylphosphine. Preferably, it is relative to the benzene derivative ((4) is a molar range of 121199.doc •39-200846322~1,3 times the molar range. As the solvent, an ether system such as tetrahydrofuran or diethyl hydrazine is preferred. a solvent, an aprotic polar solvent such as acetonitrile, a hydrocarbon solvent such as toluene or benzene, and a solvent hydrocarbon solvent such as dichloromethane or 12-diethane. The reaction temperature is in the range of 0 ° c to the boiling point of the solvent. Preferably, it is 〇8 (the range of rc. The reaction time is usually about 1 to 24 hours. (2) W1 is a compound in the case of leaving the base. 3), it can also be produced by alkylating the phenol derivative (la) with the compound (2a or 2b) in the presence of a base, and as a compound (2a) or (2b) !, preferably the tooth atom, sulfonium sulfonate

An oxy group, a p-toluene group, and a benzene phase oxy group f. Examples of the test include hydroxides of metal hydroxides such as sodium hydroxide, hydroxide, and hydroxide, sodium hydride, hydrogenated metal hydride or sodium carbonate, carbonic acid, carbonic acid, and the like. . It is preferable to use i, and it is preferable to use a compound (2a or 2b) as a dry circumference of a molar ratio of 5 to 5 times. Examples of the solvent include inert polar solvents such as N,N-dimethylamine, diphenylsulfone, N-methylpyrrolidone, and acetonitrile, and an ether solvent such as Tiannan or diethyl ether. The reaction temperature is -2 (rc ~ soluble), preferably in the range of 〜0 to 150 ° C. The reaction time is usually about 48 to 48 hours. The compound (la) may be commercially available or made. The straw is produced by the method shown below. (1) A is a compound of a single bond (ia-i). > [Chem. 16] 121199.doc •40· 200846322

(wherein, P1, z1, z2, and z3 represent the same as above.) The compound (la-i) can be applied, for example, by the method of Christian, G., et al. (〇rg· Lett. 2003, 5, 1899). -1902.), Michael, Ε·F. et al. (J, Med. Chem, 1979, 22, 63-69·), Joseph, G. C. et al. _ Method (J· Hetwocycl·Chem· 1990, 27, 2093-2095·), Troxler, F. Method of 4 people (Helv·Chim· Acta· 1968, 51, 1203-1213·),

Arnold, L. D. et al. (W0 95/23141), or

The method of Pankaj, D. Rege et al. (〇rg· Lett. 2006, 8, 3117-3120.) to produce intermediate indole derivatives, followed by Stark, L. M. et al. (J. Org, Chern. 2000, 65, 3227_3230·), Kamiya, S. et al. (Chem. Pharm· Bull. 2001, 49, 563-571.), or Igarashi, S·personal method (Chem Pharm Bull. 2000) 48,1689_ φ 1697·), which was produced by reducing an anthracene ring to a porphyrin ring. (2) The case of a compound in which A is -0- (la-ii) [Chem. 17]

(wherein, P1, Z1, Z2 and Z3 represent the same as above.) 121199.doc -41 - 200846322 The compound (la-ii) can be, for example, applied by the method of Buon L. et al. (Tetrahedron 2000, 56, 605-614·), lakovou, K. et al. (Eur·J. Med. Chem. 1999, 34, 903-917.), Ilas, J. et al. (Tetrahedron, 2005, 61, 7325- Manufactured in accordance with the method of Francois, C. et al. (£?1, 428, 514). (3) A is a compound of -CH2- (la-iii).

(In the formula, P, Z, Z2 and Z3 represent the same as above.) The compound (la-iii) can be, for example, by the method of Atkins, R. L. et al. (J. Org Chem 1978, 43 (10) ), l975_1980·), Michael, η, etc. 2S& (J.Chem.Soc., PerkinTrans l:〇rganicandBi〇_

Organic Chemistry (1972-1999), 1980, 1933_1999), and

Production by the method of Selsam, B, L., et al. (w〇 2〇〇4/〇26837) The compound (2a and 2b) can be commercially available or can be produced by the method shown below. [Chem. 19] 121199.doc -42- 200846322 Y— (CH2)

Γ—(CH2)p —c—w]i H2 (2a-2) Y —— C——OH (2H) Y — c — w h2 (2b - 2) , 1a (6b) (wherein R300 represents A hydrogen atom, an atom & a group or an alkoxy group, a 1& represents a leaving group, and p and Y represent the same as above.)

, Banhuakou () towel W is the base of the alcohol body dl) can be reduced by the ester body (four) to make l # for the reference literature 'can be cited experimental chemistry lectures (fourth edition 'Vol· 26·Japan Learned to edit "Maruzen Co., Ltd." "Organic Synthesis, Asymmetric Synthesis, Reduction, Sugar, Labeling Compound, Ρ185~P248j. In the substance (2a), W is a compound of the detachment group. It is produced from the alcohol (2a-1)' according to $, to convert the base group into a base group such as a methoxy group, an aryl sulfoxide group or an i atom. As a reference, a lecture on experimental chemistry can be cited. The first edition, v〇1. 19•Japan & Institute, Maruzen Co., Ltd., organic synthesis I · hydrocarbons _ compounds, pus ~ j > 446 and P465 ~ 470 ° ° alcohol (2b-D and The compound 2) can be produced in the same manner as the above-mentioned alcohol (2) and the compound (2a-2). The above esters (6a and 6b) can be commercially available or can be produced by the methods described below. (a) Pierre, M. Method of Personnel (Tetrahedron Letters, 1985, 26(33), 3947-3950.); (b) Illig, C. R. et al. Act (W〇99/40088); 121199.doc -43- 200846322 (c) Gattuso, Μ· et al. (Atti della Societa Peloritana di Science Fische, Matematiche Naturali, 1968, 14(4), 371-380 (d) The method of Matsuo, M. et al. (WO 91/19708); (e) Vicentini, CB et al. (Heterocycles, 2000, 53(6), 1285-1292.); f) Tensmeyer, LG et al. (J. Org, Chem., 1966, 3 1, 1 878-1 883.);

(g) Padwa, A. et al. (J. Org. Chem., 1982, 47, 786-791.); (h) Capuano, L. et al. (Liebigs Annalen der Chemie, 1985, 12, 2305-23 12.); (i) Rafferty, MF et al. (J. Med. Chem. 1982, 25, 1204-1208.); (j) Wright, SW et al. (J. Org. Chern 1994, 59, 6095-6097.); (j-1) Liselotte, 0 et al. (Synlett, 2001, 1 893-1896.); (j-2) Fletcher, S. R. et al. Method (Bioorg. MecL Chem. Lett., 1992, 2, 627-630·); or (j-3) Ana, B. Β· et al. (Tetrahedron Lett. 2005, 46, 7769-7771.) The compound (3) in the case where the base Q has 1 to 2 (^-0:6 groups or a fluorine atom as a substituent), if used, has 1 to 2 (^-0:6 alkyl or 121199. Doc -44- 200846322 A reagent for the atom of a rat as a substituent (2e or 2d) is produced by substituting the compound or (), 717, the same method. The compound... and the rush can be a commercial product = manufactured with the above compound [ 20] .12 —丨一W1 13 or •C——W1115 (2c) (2d) (where R8~R13 indicate 1 Medium; Gan, f Rensi 1~2 are G-c6 alkyl or fluorine atoms, others are hydrogen atoms; Ru and y5#_甘Λ 虱原贶 atoms' another one is hydrogen ..wl wind atom or two All of them are a burnt group or a fluorine group, and W and Y represent the same as above.) In the original compound (2d), Wi is chlorine (W is produced by the following method (four) or a combination of materials [21 ] R14

I Y — C — W2 1ΐ5

Y — CH 'is (7) (2(H) (wherein W2 represents a chlorine atom, a bromine, a genus or a moth atom, and RM, pi 5 and Y represent the same as above.) R is a compound (2d)) By making Yi-Ning, N-Button, brewing, N-bromobutadiene, butyl succinimide, N-Butira & D: Imine or Hypochlorine, third 121199.doc • 45- 200846322 Halogenating reagent such as butyl ester, which is produced by reacting compound f 7 v · (7). The halogenation reaction can be carried out under the condition of light irradiation to the presence of a catalyst such as lactide formic acid. Implementation and implementation. As a reference for the loss of halogenation reaction, lectures on experimental chemistry (fourth edition ' Vo 1 · 19. Japan Chemical Preparation Paper, u + Zihui, Maruzen Co., Ltd.) "Organic Synthesis I: Hydrocarbon·halide, P427 to P429. The above compound (7) is commercially available or can be produced by the following documents (k) to (p). (k) Gupta, AK et al. Method (Synleu, 2〇〇4, % 2227_ 2229.); (1) Method of Casalnuovo, AL et al. (J Am chem s〇e 1990, 112, 4324-4330.); (m) Schlosser. M. et al. Human method (Eur, j 〇rg Chem, 2〇〇2, 2913-2920.); (n) Kotone, A. et al. (Japanese Patent Laid-Open No. 51-〇93999); (〇) Lyga, JW et al. (jounal 〇f Heter0Cyeiie Chemistry 1990, 27(4), 9191-921·); and (p) Shridhar, D. R. et al. (Indian J〇umal Qf)

Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry 1983, 22B (12), 1187-1190). The compound (3) wherein the group Q is _CH2-0-CH2_ can be produced by the following method. [Chem. 22] [Manufacturing Method A-2] 121199.doc -46- 200846322

(wherein Q represents -CH2-〇-CH2-, w3 represents a leaving group, and A, pi Z, Z and z3 represent the same as above.) Y,

Compound (3) can be prepared by compounding compound (ib) which is alcohol derivative 3 with 4 conjugate (2e) in the presence of a base. The cleavage group W / of the hydrazine is preferably an atom, a methyl oxy group, a toluene (tetra) oxy group, and a fluorenyl oxy group. As an examination, an alkali metal hydroxide such as a hydroxide steel, a potassium oxyhydroxide or a hydrazine hydroxide, a metal hydride such as sodium hydride or hydrogenation, a sodium carbonate or a carbon, a carbonic acid sample, etc. may be mentioned. Examples of the solvent include aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfonium N-methylpyrrolidinium, and acetonitrile.

: Ether solvent such as B. The reaction temperature is a ratio of the boiling point of the iron to the solvent, preferably in the range of 〜0 to 1 GG °C. The reaction time is around ~. 48 small The compound (lb) may be commercially available or may be produced by the method shown below. (1) A is a compound of single bond (ibq). #化23] 121199.doc -47. 200846322

(wherein 'P, Z1, Z2, and Z3 represent the methods recited in the same manner as described above (Chem. compound (lbei) can be applied by the same method as the reference of the compound (la-i), or Kamiya , S· et al

Manufactured by Pharm, Bull 2001, 49(5), 5 63-5 71.).

(2) The case where A is a compound of -0- (lb_H) [Chem. 24] z3

(wherein P z, z, and z3 represent the same as above.) The compound (lb-U) can be produced by the same method as the reference of the production of the above compound (la-ii). (3) The case where A is a compound of -CH2_ (lb-iii) [Chem. 25]

(wherein p, z, z, and z3 represent the same as above.) 121199.doc -48- 200846322 The compound (ib~iii) can be produced by the same method as the above-mentioned compound (la_iH), or by Timothy. The method of G. et al. (US No. 6,362,188) and the method of Oku, T. et al. (W〇97/11〇69). The compound (2e) may be a commercially available product or may be produced by the method shown below. [Chem. 26]

(2e) (wherein W3 and γ represent the same as above.) The compound (2e) can be produced by the same method as the above-mentioned compound (2b) or (2^2).

Further, the compound (3) in the case where the group Q has 1 to 2 〇 146 alkyl groups or a fluorine atom as a substituent is used as a compound. The reagent (lb_2) and/or (10) in which the alkyl group or the fluorine atom is used as a substituent may be produced in the same manner as the compound (2e). R16a / Η0~Π-ί fVp |17a R15b Y'c-w3 R17b (1b· ~2) (2f) (wherein R 16a and R16b, Rl7a and Rm represent each CrC6 alkyl group or fluorine atom 'The other is a hydrogen atom, 121199.doc is -49- 200846322 W, Zl, Z2 and Z3 are the same as the above-mentioned alkyl or fluorine atom, A, P1.) The above compound can be obtained by the following compound (lb-2 and 2f) may be a commercially available product or may be produced by the same method as the production method of the substance (2d or 2d-1). The compound (3) wherein the group Q is -CH=CH- or -CH2-CH2- is produced by the method described. [28] [Manufacturing Method A-3]

Z3

Z3

(wherein, Q represents -CH=CH- or -CH2-CH2-, only (10) main-p K is not (^-(:6 alkyl, Α, Ρ1, γ, Ζι, Ζ2, and Ζ3 are the same as above) The compound (3) whose base Q is -CH=CH- can be reacted with the compound-treated Wadsworth-Emmons by using the complex (1c) which is obtained by oxidizing the above compound (lb) in the presence of the compound. 121199.doc •50· 200846322 As the oxidizing agent for the oxidation reaction of the above compound (lb) to the aldehyde (lc), one commercially available one can be used. The amount of the oxidizing agent can be exemplified with respect to the compound (lb). The range of the molar amount to the molar ratio of 20 to 20 moles is preferably in the range of from 0 to 1.5 moles. Examples of the reaction solvent include hydrocarbon solvents such as toluene, benzene, and hexane, and diethyl ether. An ether solvent, a halogenated hydrocarbon solvent such as chloroform or carbon tetrachloride. The reaction temperature can be carried out in the range of the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent. For 4 hours, keep it for ~48 hours. Also, when using the swern oxidation reaction, refer to Bailey, Ρ·S· People's method (〇rg · Synth.,

Implemented by Collective Volume, 1973, 5, 489.). From the acid (lc) to the Wadsw〇rth_Emm〇ns j of the compound (3), examples of the base include an alkali metal hydride such as sodium hydride or potassium hydride, and sodium bis(tridecyl decyl) decylamine. , bis(tridecyldecylalkyl) guanamine potassium, and the like. The amount of the base to be used is preferably in the range of from 0 to 12 moles per mole of the compound (2g). Examples of the solvent include an ether solvent such as tetrahydrofuran or a third butyl methyl ether, and a hydrocarbon solvent such as toluene. The reaction temperature is in the range of -20 C to 'valley' / point, and preferably 〇 8 〇. Hey. The reaction time is usually about 1 to 24 hours. Further, the compound (3) wherein the above-mentioned group Q is _CH=CH- is contacted and reduced, and the compound (3) wherein the group Q is -CHrCH2- can be produced. As the catalyst for contact reduction, palladium (Pd) / carbon, palladium hydroxide [pd(〇H) 2] / carbon, platinum (pt) or the like can be used. Examples of the solvent include an alcohol solvent such as methanol or ethanol, an aprotic polar solvent such as N,N-dimercaptocarbamide, an ester solvent such as ethyl acetate, or an ether such as tetraterpene or dioxane. Solvent, acetic acid, etc. As the reaction temperature, 121I99.doc •51 · 200846322 is 〇C~solvent boiling fjt; 夕#

Dry circumference, preferably the room temperature of ~ 80 ° C is usually about 48 ~ 48 hours. Furthermore, it is manufactured by the above-mentioned production method φ #.田>& A , . The compound used in the process (2g) can be obtained by the following method.

Y——C——W3

II

Y—C—P—〇~R 100 (2e) (wherein R, w3 and Y represent the same as above, 0-R(2g) 100 compound (2g) can be obtained by [manufacturing method A-2] The compound shown is produced by the application of Arbuzow reaction. As a reference for the Arbuz〇w reaction, for example, Gr〇nowitz, S. et al. (Heter〇cylces 1981, 15(2), 947-959· Further, the compound (3) in the case where the group Q has 1 to 2 C^C6 alkyl groups or a fluorine atom as the φ group, if one is used (^-(:6 alkyl or fluorine) The compound (le-丨) and/or (2h) in which an atom is a substituent may be produced in the same manner as the compound (lc) and/or (2g). [Chem. 30] 121199.doc -52- 0 23 200846322

(wherein, Rl8 and R19 represent any hydrogen atom, or both R1〇G, Y, Zl, Z2 and 23, and the above compound (lc-Ι) can be obtained by [Chem. 31] ν Η Η Υ —o~R100

Ri9 〇-Ri00 (2h) . The one is an alkyl group or a fluorocarbon + and another one or a fluorine atom, A, pi, and the same as above. ) 'The method described is for manufacturing.

Z3

Wacker oxidation Z3

Z2 and z3 represent the same as above. The above compound (lc-1) can be converted into an olefin by treating the above compound (in the presence of a base with a wittig reagent (8) commercially available in 121199.doc-53-200846322. After the body (ld), it is produced by Wacker oxidation. As a test used in the Wittig reaction, a metal hydride such as sodium hydride or potassium hydride, a metal alkoxide such as sodium butoxide or potassium t-butoxide may be used. (trimethyldecyl) sodium decylamine, bis(trimethyldecyl) guanamine potassium, etc. The alkali is preferably in the range of equimolar to 12-fold molar relative to compound (8). Examples of the solvent include: an aprotic polar solvent such as methyl sulfoxide, an ether solvent such as w-hydrofuran, a third butyl methyl ether, or a hydrocarbon solvent such as toluene. The range is preferably 0 to 8 (TC. As the reaction time, usually 24 hours left wacker oxidation, refer to the method of Hegedus, Ls et al. (c〇 〇rg· Syn· 1991, 4, 552· 559·), and the method of Gaunt MJ et al. (Chem·C〇mmun·2001, 18, 1844·1845). Compound (2h) can be produced by the following method. [Formula 32] 0! II door 0 -R? 18 O-R100 ★ Y a (100

Y - C - W (2,) (2h) (wherein R, R, W3, and γ represent the same as above.) Compound (2h), which can be obtained by dill. pl7b [I仏法·2] The compound (5) which is not a hydrogen atom in any of the compounds (2f), is applied in the same manner as in the production of the above compound (10), and is subjected to a reaction of 0, 121199.doc -54 - 200846322. Production of compound (3) of -ch2-ch2-ch2-. Can be carried out by the following methods

[化33]

[Manufacturing Method A-4J

(wherein Q represents -CH2-CH2-CH2_, w4 represents a leaving group, A, p

Y, Z1, Z2, and Z3 represent the same as described above. a compound (3) wherein the group Q is -CHrCHrCH2·, which can be introduced into the compound (3a) by a coupling reaction using a metal catalyst with an acetylene derivative (2j), followed by a compound (3) 3 The hook is contact-reduced and manufactured. The conditions of the contact reduction are the same as those shown in the production method A-3. The coupling reaction described above is known as the Sonogashira reaction, and K. C. Nicolaou et al. The general theory of human "Angew, Chem. Int. Ed. 2005, 44, 4442-4489." The compound (le) may be a commercially available product, or may be applied as described above [manufacturing Α-η 121199.doc -55- 200846322 Conversion method of a non-alcohol (2a-l or 2b-1) to a compound (2&_2 or 2b_2), or Thompson, L.S.A. et al., 1994, 2, 107-108. ), manufactured by the derivative (ia). The compound (2j) used in the above production method can be produced by the following method. [34]

Y — C — C — 0H H2 H2 (2a-1) • Y — CHO Η 2 (9)

卜S—C=CH (2j) (wherein Υ represents the same as above.) The compound (2j) can be produced by oxidizing the compound (2^) manganese dioxide or Swern oxidation to form the compound (9). Manufactured according to the method of K. et al. (Synlett, 1994, 2, 1 〇 7_1 〇 8) or by the method of Takrahedron Leu. 1972, 3769_3772.彳

Further, regarding the compound (3) having a base of two Ci_CW groups or a gas atom as a substituent, if a reagent (2k) having a substituent or a mouse atom as a substituent is used instead of the compound (7)) It can be manufactured in the same way. [化35] D21 f (2k)

Y_"C—C=CH R22 (wherein R21 is a hydrogen atom and R22 represents either an alkyl group or a fluorine atom and the other one, or both are an alkyl group or a fluorine atom, 丫 is represented by the above 121199.doc -56- 200846322 The same is true.) The above compound (2k) can be produced by the following method [Chemical 36]

Y — C — COR300(6a)

R21 y—c—co2r300 - (10) R21 I Y —C —C^CH * 22 R

(2k) (wherein R21, R22, R300 and γ represent the same as above.) Compound (2k)' can be converted into compound (10) after compound (4) is synthesized in the presence of the test. The metal such as lithium is reduced with the hydride to reduce the compound (10) to form the alcohol (1)), and then the alcohol (f) is produced by the production of the above compound (2j).

The above-mentioned alkylation reaction can be referred to prasacj G, ^ & Temple people's method (J 〇

Chem. 1991, 56, 7188_7190.), or Suzuki δ* ’ 5 · Finding the person, Table (Can J. Chem. 1994, 72, 357-361.). The base of the towel Q and the compound with a single bond A (3) can be dreamed. ...the method of production [Chem. 37] [Manufacturing Method A-5] 121199.doc -57- 200846322

(2Hi> Z3

Z2 and z3 represent the same as above, and k represents 2 to 3, and R R each independently represents a hydrogen atom or a Cl_C6 alkyl group. ) Υ, z1, R500 and

The compound (3) in which the group Q and the group A are a single bond can be converted into the compound (lg) by the coupling reaction using a metal catalyst with the boron compound (21-4214). The compound (3) is produced by the reduction reaction shown in the production method of the compound (Production Method A) ((4). The coupling reaction described above is, for example, a method called w, et al. (Tetrahedr〇n) 2〇02, 58, 3101-3110·) and Leb〇uvier, N et al. (Tetrahedron Lett., 2〇〇6, 6479_6483). Compound (If) may be commercially available or may be applied [ Manufacture of the compound (1 ai) in the manufacturing method, and the manufacture of the compound (le) shown in [Production Method A-4] 121199.doc -58- 200846322 The method shown in the above is manufactured. The objects (21 1 and 21-11) may be commercially available, or may be applied by, for example, the method of Μ• et al. (SynleU, 2〇〇6, ΐ86Ί87〇) and, s • The method of et al. (Tetrahedron, 20〇6, 62, 2831-2844.) is manufactured. In the following [manufacturing method, the above [manufacturing method A-1] [Production Process A-5] Compound (3) for producing the protective group P1 deprotected to produce compound (4) or a salt thereof (e.g. hydrochloride) of the method will be described. [Formula 38] [Manufacturing Method

(wherein Q represents any of the above groups, and A, pl, Q, Y, zl, z2, and Z3 represent the same as above.) The case where the protecting group pi of the compound (3) is a third butoxycarbonyl group In the case of deprotection, it is preferable to use dehydrogenation as a reaction solvent by using a specific acid of a acid or trifluoroacetic acid, and it is preferably a hydrocarbon solvent such as dichloromethane or gas-form, tetrahydrocyanate, H. An ether solvent such as a material, a brewing agent such as acetic acid, an aprotic polar solvent such as acetonitrile, and a solvent such as methanol or B: The reaction temperature is in the range of 0 ° C to the boiling point of the solvent, and preferably 121199.doc -59 to 200846322 is in the range of room temperature to 80 ° C. The reaction time is usually from about 0 hours to about 24 hours. The compound (4) can be obtained as a salt of an acid used in the above reaction, and after the completion of the reaction, an alkali metal such as sodium hydrogencarbonate or an alkali metal such as sodium carbonate is used. The hydroxide of an alkali metal such as carbonate or sodium hydroxide is adjusted to be weakly alkaline, whereby a compound (4) which is a free amine can be obtained.

For the deprotection condition in the case where the protecting group pi of the compound (3) is a protecting group other than the above, for example, refer to Protective Gr〇ups in 〇r fat ★

Synthesis (TW Green and RG. Wuts5 John Wiley & S〇ns5 Inc., New York, 1991) In the following [manufacturing method Ci] to [manufacturing method c_3], the [manufacturing method '] is exemplified as The method of producing a cool body (ia) from the compound (4) by the a method and the b method will be described in detail. The compound of the compound (la) wherein V is -Gi_ (1) can be produced by the following method (a method in [Production Method 1]) [Chem. 39] [Manufacturing Method C-1]

i^C02Rla represents any of the above groups, A'G'Rh'Y'w'z base, Q and Z3 121199.doc -60-200846322 represent the same as above. The compound (la-1) can be produced by reacting the compound (4) or a salt thereof (e.g., a hydrochloride) with the compound (5a) to form an acid amine bond. (1) When W5 is a hydroxyl group A commercially available compound (5a) can be condensed with a compound (4) or a salt thereof (e.g., a hydrochloride) in a usual condensing agent used in the production of a linear acid. As a usual condensing agent, for example, DCC (N,N•dicyclohexylcarbodiimide), N,N-carbonyldiimidazole, DCC/H〇Bt (1-hydroxyphenylhydrazine) can be cited. Water-soluble carbodiimide such as _3_(3-dimethylaminopropyl)carbodiimide hydrochloride, preferably ethyl-3-(3-dimethylaminopropyl)carbon Yttrium imide hydrochloride, hydrazine, hydrazine-dicyclohexylcarbodiimide, and the like. As the reaction solvent, a halogenated hydrocarbon solvent such as dichloromethane, a hydrocarbon solvent such as toluene, an ether solvent such as tetrahydrofuran, or an aprotic polar solvent such as hydrazine or hydrazinocarbamide may be used. Methyl chloride, tetrahydrofuran, hydrazine, hydrazine-dimethylformamide, and the like. The reaction temperature is in the range of _2 〇 ° c to the boiling point of the solvent, and is preferably in the range of 〇 c to room temperature. The reaction time is usually about 24 hours. In the above condensation reaction, it is preferred to use triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine or 4-(N,N-dimethylamino) in the range of 1 to 30 equivalents. An organic amine base such as pyridine, particularly when a salt of the compound (4) is used, is a salt thereof, and a stoichiometric equivalent or more of the above base is used. Further, it is preferred to use an active esterification reagent such as 0.2 to 1.5 equivalents of 1-hydroxybenzotriazole or the like of the carboxylic acid derivative (5a). (2) The case where W5 is a leaving group can be commercially available, or the carboxylic acid derivative 0 of the above-mentioned (1) can be converted into a ruthenium chloride or a ruthenium by a known method. A compound obtained by nitrogen or the like is produced by reacting the compound (4) or a salt thereof (for example, a hydrochloride) in the presence of a base. As the base, an organic amine base such as triethylamine, diisopropylethylamine, methylmorphine, L-butyl or 4·(Ν,Νdimethylamino)(tetra) can be used. The amount of the base to be used may, for example, be in the range of 1 to 10 equivalents. Particularly in the case of using the salt of the compound (4), in order to neutralize the salt thereof, it is necessary to use the above-mentioned test of the stoichiometric equivalent or more. As the reaction solvent, a densified hydrocarbon solvent such as dichloromethane or an L-based bath such as toluene or an ether solvent such as tetrahydrofuran can be used. As the reaction temperature, it is preferably in the range of -20 c to the boiling point of the granule. 〇 ~ room temperature range. The reaction time is usually about 1 to 24 hours. References for the condensation reaction described in the above (1) and (2) can be listed as: Bodanszky, Μ·, Klausner, γ. s and (5) Heart (1), a

Peptide Synthesisn (A Wiley^interscience publication, New York, 1976), pettitt, G. "Synthetic peptide" (Elsevh

Scientific Publication Company, New York" (1976), "The 4th Edition of Experimental Chemistry Lecture 22, Organic Synthesis IV" (Maruzen Co., Ltd., 1991) compiled by the Chemical Society of Japan, etc. The v in the compound (la) is -G2_N(R2)_G3_2 compound (Ia_2), which can be produced by the following method, b method in the q manufacturing method η. [Chemical method C-2] 121199.doc -62 - 200846322 z3

Li, R2 (wherein Q represents any of the above groups, w6 and W7 are each a chlorine atom, a bromine atom, or an iodine atom, and A, G2, G3, Ru γ, ζ, z, and z3 represent the same as above. .)

Compound (Ia-2), which can be amidated with a commercially available compound (10) in the presence of a base to give a compound _, and then a compound and a commercially available compound (5c) or a salt thereof (for example, hydrochloric acid) The salt is produced by condensation in the presence of a base. a The above-described oximation reaction can be applied to the production method described in [Manufacturing Method ^^). Further, in the condensation of the compound (12) with the compound (5c) or a salt thereof (for example, a hydrochloride), as the base, triethylamine, diisopropylethylamine, n-methylmorpholine or pyridine can be used. 4-(N,N-dimethylamino)pyridine or the like, an organic amine base, or an inorganic base such as potassium carbonate or carbonic acid planer. The amount of the base to be used is, for example, 1 to 30 equivalents, preferably in the range of (7) equivalents. In particular, in the case of using the salt of the compound (5c), in the case of using the salt of the compound (5c), it is necessary to use a stoichiometric equivalent or more of the above base. As the reaction solvent, a halogenated hydrocarbon solvent such as methylene chloride, a hydrocarbon solvent such as toluene, an ether solvent such as tetrahydrofuran, or an aprotic polar solvent such as acetonitrile or N,N-dimethylformamide can be used. The reaction temperature is in the range of -20 ° C to the boiling point of the solvent, preferably in the range of room temperature to 80 ° C. The reaction time is usually about 48 hours. For the condensation reaction, for example, the method of Zhao, η et al. (Bioorg. Med. Chem, Lett. 2002, 12, 3105_31〇9), Jiang, χ·Η· et al. (Tetrahedron· 2005, 61, 1281-1288.), Nam, J. et al. (Tetrahedron Lett. 2003, 44, 7727-7730·), and Hayashi, Κ·4 person method (j. Med·Chem. 1989, 32, 289- 297.). Further, when G2 is a single bond, the compound (1 core 2) can form a sulfhydrylamine bond by continuously performing the above-described amide amination reaction in the same vessel and subsequent condensation reaction (the urea bond at the time of the shape) In the case where G2 is a linear alkyl group having a carbon number of 2, it can be produced by the same method. The above urea bond forming reaction can be referred to, for example, the method of Bermudez, j. et al.

Chem·1990, 33, 1932-1935·). The compound (la-2) can also be produced by subjecting the compound (4) and the compound (5d) to a production method shown by (!) in the preparation of the method (!) to form a guanamine bond. The above compound (5d) can be produced, for example, by the following method. The compound (5d) can be produced by reacting the compound (12) in the [Production Process C-2] with the compound (5C) to produce the compound (1-2), and the commercially available compound (10) /, a compound (5c) The reaction is carried out as a compound (丨3), followed by deprotection of the benzyl group by contact reduction, whereby the production is carried out. The contact reduction can be carried out by the method of contact reduction shown in [Production 121199.doc-64-200846322 Method A-3]. [化41]

H0 - C0 - G2 - N - G3 - C02Rla (5d) (wherein, W7, G2, G3, Rla, and R2 represent the same as above.) The V in the compound (la) is [manufacturing method 1] The compound (Ia-3) of the group (5) shown can be produced by the following method (b method in [Production Method 1]). [化42] [Manufacturing Method C-3]

121199.doc •65- 200846322 Q represents none of the above groups, ws and w9 represent chlorine, adipose atoms or hard atoms, respectively, and A, g4, m, n, Rla, γ, and z3 represent the same as above. The compound (Ia-3) can be applied to the coating of the compound (Μ) in [Production Method c_2] by the amination reaction of the compound 4 (4) with the commercially available compound (5d), followed by the amination reaction. The condensation reaction of the compound (13) with the commercially available compound (IV) is carried out by this.

Further, as a further synthesis method of the compound (1) of the present invention, v in the carboxylic acid derivative (Ib) described in [Production Method 1] may be a CIVCHr which may have a substituent, and a _CH2CH2CH2 which may have a substituent Or the compound _) which may have a substituent evenly having a substituent, is produced by the reaction of the compound (4) and the cyclic acid anhydride (5f) without passing through the ester (Ia). [化43] " [Manufacturing Law D]

-CHrCHrCH2·, or _ch2-CH2-CH2·CH2- which may have a substituent, Q represents any of the above groups, a, Y, Z1, Z2, and Z3 Table 121199.doc -66 - 200846322 The same. The compound ((iv) can be produced by reacting the compound (4) or a salt thereof (for example, a hydrochloride) with a cyclic acid (8) to form a guanamine bond. As a counter bank, a solvent can be used, such as dichloromethyl bromide. A self-chemical solvent such as a solvent such as a hydrocarbon solvent such as toluene or an ether solvent such as tetrahydrofuran or an aprotic polar solvent such as acetonitrile or N,N-dimercaptocarbamide. The reaction temperature is 'c. The range is preferably the range of the m point. The reaction time is about 24 hours.

The reaction can be carried out in the presence of a base, as a base in this case, preferably decylamine, diisopropylethylamine, N-methylmorpholine, pyridine, heart (N,N-difluorene) An organic amine base such as arylamino)pyridine, and an alkali metal carbonate such as potassium carbonate or carbonic acid. The amount of the base to be used may, for example, be in the range of 1 to 10 equivalents. In particular, when a salt of the compound (4) (for example, a hydrochloride) is used, it is preferred to neutralize the salt thereof, and it is preferred to use a stoichiometric equivalent or more of the above base, and after the reaction is completed, a mineral acid such as hydrochloric acid is added. It is made weakly acidic, whereby the quinones (Ib-Ι) are obtained as free tick. The above reaction can be referred to the following methods (q) to (u). (q) Rajashekhar, B. et al. (j. 〇rg chem. 1985, 50, 5480-5484.); (r) Kubo, Υ· et al. (j. 0rg. chem. 1985, 50, 5485-5487,); (s) Sun, W. S. et al. (j. Med. Chem. 2003, 46, 5619-5627·); 121199.doc -67- 200846322 (t) Lherbet, C. Et al. (Bi〇org· Med. Chem. Lett. 2003, 13, 997-1000·); and (u) Shultes, C. Μ· et al. (Bioorg. Med· chem· Lett· 2004, 14. 4347-4351.) The cyclic acid anhydride (5f) described in [Production Method D] may be a commercially available product, or may be based on or based on the methods disclosed in the above documents (q) and (1). The method is manufactured. [化44]

0 (5f)

Among the compounds used in the above production method, the compounds of the compound (2a-1), the compound (2a-2), the compound (2b_1}, the compound (2b_2), and the compound (10) have a novel compound and can be used as various compounds. Intermediate for the manufacture of compounds. Among them, the alcohol of '(2b)) and the sclerosing compound of (2b-2) (Wu = halogen) and compound #6b are particularly useful. The compound (1) of the present invention produced by the above method can be subjected to separation and purification by a method known in the art, for example, extraction, precipitation, fractionation, chromatography, crystallizing, etc. by a known method.槿 槿 化 _ _ _ with asymmetric carbon exists in the light. These optical isomers can be obtained by engraving and purifying the respective isomers by a conventional method such as separation from a suitable salt by hydrazine salt or column chromatography. 121199.doc • 68 - 200846322 As mentioned above, SIP receptor agonists are useful as immunosuppressive agents. The compound of the present invention represented by the formula (I), a salt thereof, and the like thereof have a agonist action on the ^1p sense (especially the s 1 p 1 receptor), and thus can be used as The active ingredient of the immunosuppressive agent can be used as an active ingredient of a therapeutic agent and/or a prophylactic agent for rejection of a mammal, particularly a human, such as rejection, autoimmune disease, allergic disease, and the like. Further, it is considered that the oral administration 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 An effective component of medicine such as an immunosuppressive agent that can be administered orally. Moreover, these medicines are less side effects such as bradycardia seen in other Slp receptor agonists. Here, the rejection reaction to transplantation means that the liver, kidney, heart, lung, small intestine, skin, cornea, bone, embryo tissue, osteophytes, hematopoietic stem cells, peripheral blood stem cells, mesenchymal stem cells, and sputum cells, After transplantation of transplanted liver cells, nerve cells, intestinal epithelial cells, etc.

Acute rejection occurring within 3 months and subsequent chronic rejection, as well as graft versus host disease. Further, examples of the autoimmune diseases include collagen disease, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, renal syndrome, lupus nephritis, and sjogren s Syndrome), scleroderma, polymyositis, psoriasis, inflammatory bowel disease, Crohn's disease, mixed connective group, 広 広 ^ ^ and woven disease, primary mucus Edema, Edison's disease, i A Dingzhan tl; aplastic anemia, autoimmune hemolytic anemia, autoimmune thrombocytopenia, autoimmune 121199.doc -69- 200846322 Diabetes, uveitis, φ ^, anti-stody disease, myasthenia gravis, thyroid poisoning, thyroiditis, Hasliim〇t〇, s disease. Further, as an allergic disease, for example, asthma, rhinitis, and decidual inflammation, 异J, atopic dermatitis, gas X, oral membrane X, hay fever, and the like. When the compound of the present invention represented by the general formula (1) is administered to a mammal (especially a human), it is administered orally orally orally. The medicine of the present invention can be prepared by selecting the appropriate form according to the method and the method, and (4) preparing the various preparations used in the suspension. As a form of oral medicine, _ τ 夕 · 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭The preparation of the medicine of this form can be used to explode and use the excipients, binders, colloidal disintegrating agents, lubricants, swelling agents, swelling agents, covering agents, plasticizers, and antimony agents which are usually used as additives.刽^ ^ ^ ^ % tinctures, preservatives, antioxidants, colorants, solubilizers, suspending agents, rituals, sweeteners, preservative agents, buffers, buffers The appropriate selection among the agent, the wetting agent and the like is carried out according to the usual method. As a form of non-oral medicine, it can be listed as a main agent, a soft agent, a gel, an emulsion, a dressing, a patch, a sputum, an inhalant, a spray, and an eye drop. , nasal drops, expectorants, inhalants, etc. The preparation of the drug of the form can be used as a stabilizer, a preservative, a dissolution aid, a moisturizer, a preservative, an antioxidant, a flavoring agent, a gelling agent, a neutralizing agent, a dissolution aid, which are usually used as an additive, as needed. , buffer, isotonic agent, surfactant, colorant, buffer, thickener, wetting agent, filler, adsorption promoter, county 121199.doc -70- 200846322 suitable additives for floats, adhesives, etc. Prepared according to the usual method. The medicine of the present invention can be produced by the method H, hopper, / τ, and the compound represented by the formula (1), a salt thereof, or a specific solvate thereof, which is selected from the group consisting of The anti-immunization antibody and the rejection reaction are treated with a combination of two or more kinds of antibiotics and steroid drugs. A chlorpyrifos is a compound of the present invention represented by the formula (I), a hydrazine or a solvate thereof, and one or more other pharmaceutical agents, and is orally administered.乍 is the applicator of the accompanying drug; the servant of the present invention represented by the general formula (I)

The compound of the known compound, a salt thereof, or a solvate thereof and the accompanying drug of another agent may be a combination of the two components in the (6) preparation, or may be administered as a single preparation. In the case of separate administration, each preparation may be administered due to the main clothes, or may be set up with a time difference. Further, the preparation of each preparation may be the same or different. These drugs are also prepared as a compound represented by the formula (1), a salt thereof, or a solvate thereof, such as a self-immunization inhibitor, for suppressing an immunological antibody, a therapeutic drug for rejection, an antibiotic, and a steroid drug. A set of two or more selected other agents to be combined. More specifically, 'as an immunosuppressive agent, an antibody for suppressing immunity, and a therapeutic agent for rejection, for example, cyclosporin A, tacrolimus (FK506), azathioprine (azathi〇prine), mizoribine, meth〇trexate, mycophenolate mofetil, cyclophosphamide (four)-coffee (4), sirolimus, Everolimus, prednisolone methylprednisolone, Orthoclone OKT3, anti-human lymphocyte globulin (antihuman 121199.doc 200846322 lymphocyte globulin), deoxygenase Deoxyspergualin and so on.

Examples of the antibiotic include cefuroxime sodium, meropenem trihydrate, netilmicin sulfate, sisomicin sulfate, and ceftibuten ( Ceftibuten), PA_1806, IB-367, tobramycin, PA-1420, doxorubicin, astromicin sulfate, cefetamet pivoxil hydrochloride Wait. Examples of the steroid drug include clobetasol propionate, diflorasone diacetate, fluocinonide, mometasone furoate, and mometasone furoate. Betamethasone dipropionate, betamethasone butyrate, betamethasone valerate, difluprednate, budesonide, diflucortolone Valerate), amcinonide, halcinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate ), hydrocortisone butyrate, hydrocortisone butyrate, deprodone propionate, prednisolone acetate, fluocinolone acetonide, beclomethasone propionate Propionate), triamcinolone acetonide, flumetasone pivalate, alclometasone propionate, clobetasol butyrate 121199.doc • 72- 200846322

(clobetasone butyrate), prednisolone, beclomethasone propionate, fludroxycortide, cortisone acetate, hydrocortisone, hydrocortisone phosphate, hydrocortisone sodium succinate Fluocoxone acetate, prednisolone acetate, prednisolone sodium succinate, prednisolone butyl acetate, sodium sylvestre sulphonate, halopedone acetate, methyl Prednisolone, strontium acetate-based prednisolone, methyl succinate, succinic acid, triamcinolone, triamcinol acetate, dexamethasone phosphate, dexamethasone palmitate, acetate Paramethas〇ne acetate, betamethasone, fluticas〇ne propionate, fiunisoiide, ST-126P, ciclesonide, dexamethasone palomithionate, molasses It is prasterone suifonate, deflazacort, 〆 thousand small k, two y, and y only. Xicai, -b (methylprednisol〇ne sleputanate), succinic acid methylprednisolone 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 amount of administration. It is generally preferred to use the amount of the compound (〗 〖) in the range of 0.001 mg~1〇〇〇mg per adult per person, whole body or local once a day to several times orally or not. Oral administration, or continuous intravenous administration within the range of 1 hour to 24 hours per day. [Examples] Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited thereto. 121199.doc •73- 200846322 The symbols "IR", "NMR", and "MS" in the examples indicate "infrared absorption spectrum", "nuclear magnetic resonance spectrum", and "mass analysis", respectively. "IR" is measured by ATR (Attenuation Total Reflection) method or KBr tablet method using Hitachi 270-30 spectrometer or Horiba FT-720 (S.T. Japan Durascope (Diamond/KRS-5)). Elemental analysis was performed on a Perkin-Elmer CHNS/0 2400 II.

The mass analyzer uses JEOL JMS-AX505W (El, Cl), JEOL JMS-HX110 (FD, FAB) spectrometer, Thermoquest Finning AQA (ESI), Agilent Thechnologies AgilentllOO series LC/MSD and PE SCIEX API150EX (ESI), or JMS- T100LP

In the case where the "NMR" is not specifically disclosed, 1H-NMR is used, and measurement is performed using JEOL JNM-EX400, and the measurement solvent is shown in parentheses, and TMS (tetramethylnonane) is used as an internal standard substance. The multiples in iH-NMR indicate s = singlet, d = doublet, t = triplet, q = quintuple, m = multiplet and br s = broad singular. Further, "Anal. Calcd for formula" indicates the calculated value of the elemental analysis, and "Found" indicates the measured value. The silicone used in column chromatography uses Kiesel-gel 60 (particle size: 0.060 to 0.200 mm or 0.040 to 0.063 mm) from E-Merck. Further, the culture of thin layer chromatography (TLC) was performed using Kieselgel 60 F254 manufactured by E-Merck Co., Ltd. Also, the following abbreviations are used in this specification.

Asp: aspartic acid 121199.doc • 74- 200846322 BH3, THF: borane ditetrahydrofuran complex Boc or boc: third butoxycarbonyl Boc20: di-t-butyldicarbonate Bn: benzyl CDC13 : Deuterated chloroform DEAD: Diethyl azodicarboxylate DIEA: Diisopropylethylamine DMAP: 4-(N,N-dimethylamino). Bisidine_ DMF : N,N-dimercaptoamine DMS0 : Dimercaptosulfoxide EDC · 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride Salt HOAt··1_hydroxy-7-azabenzotriazole HOBt: 1-hydroxybenzotriazole Ms: methylsulfonyl Pd/C: palladium/carbon tBu: tert-butyl® TEA: triethylamine THF: tetrahydrofuran [Example 1] 4-Phenoxy-4-[5-[(4-phenyl-5-di-mercapto-2-11-thenyl)methoxy] is 1 哚(1)-tert-butoxycarbonyl-5-hydroxyporphyrin [Chem. 45] 121199.doc -75- 200846322

Boc in 5-aryloxy-1-t-butoxy-based m-mole (3.i4 Magical (10) THF/methanol (80 in solution) at room temperature by adding 〇% chlorooxidation / carbon (50 mg), stirring under a normal pressure of hydrogen for 3 minutes. After filtering the reaction mixture, the mixture was filtered, and the mixture was washed with methanol. The mash was concentrated under reduced pressure, and ethyl acetate (50 ml) was added to the residue. The precipitated solid was filtered to give the title compound (1.85 g).

NMR (DMSO-d6) δ : 1.47 (9H5 s)5 2.95 (2H, t? J = 8.4 Hz)5 3.83 (2H,t,J = 8.5 Hz),6·51 (1H,d,J = 8.5 Hz ), 6.60 (1H, s), 7·53-7·22 (1H, m), 9.00 (1H, s). (2) 4-Phenyl-5-trifluoromethyl phenoxy-2-ol (Chem. 46)

Dissolve 4-phenyl-5-trimethylthiophene-2-indole (3·52 g) in thf (6 〇ml) and add 1 h of bh^thf complex at room temperature. THF solution (26 ml). After the reaction solution was heated to reflux for 3 hours, it was cooled to water, and water was dropped to complete the reaction. The reaction solution was extracted with ethyl acetate, and the mixture was washed with brine. The extract was dried over anhydrous sodium sulfate (MgSO4) ,6·98-7·00 (1H,m),7·37·7.42 (5H,m). 121199.doc -76- 200846322 (3) 5-Methyl-3-phenyl-2-trisole Thiol-based sigma

To a solution of 4-phenyl-5-trifluoromethylthiophene-2-decanol (482 mg) in dichloromethane (7.0 ml), add sulfinium chloride (7〇8 μl) at room temperature. "It was stirred for 16 hours. After cooling the reaction solution to room temperature, the mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, hexanes & gluten. Title compound (434 mg) NMR (CDC13) δ: 4_77 (2H, d, J = 0.7 Ηζ), 7·07 (1H, br s), 7.35-7.44 (5H, m) ο (4) 1- Dibutoxymethyl·5_[(4-phenyltrifluoromethylnonphenyl)methoxy]porphyrin [Chem. 48]

DMF (1 气ml) of 2-methylmethyl-4-phenyl-5-trifluorodecyl porphin (692 mg), 1-tributoxycarbonyl-5-hydroxyindole (588 mg) In the solution, potassium carbonate (691 mg) was added at room temperature, and the mixture was stirred at 60 ° C for 3.5 hours. The reaction mixture was concentrated under reduced pressure. ethyl acetate (15 ml) and water (1? The combined extracts were dried over anhydrous sodium sulfate and then evaporated. The resulting residue was purified using EtOAc EtOAc EtOAc EtOAc (EtOAc) ,3·07 (2H,t,J=8.7 Hz), 3·97 (2H,s),5·18 (2H,s), 6.78 (1H,d,J=8.5 Hz),6.81 (1H, s ), 7.05 (1H, s), 7.43-7.39 (5H, m), 7.77 (1H, br s). (5) 5-[(4-Phenyl-5·trimethyl-2-synyl)methoxy]°bendolin hydrochloride [Chem. 49]

1-1,4-butoxycarbonyl-5-[(4-phenyl-5-trifluoromethyl-2-nonyl)methoxy] porphyrin (1.13 g) 1,4-two To a solution of decane (5 〇ml), a solution of 4N hydrochloric acid /1,4-disane (5 ml) was stirred at room temperature for 14 hours, and the solvent was concentrated under reduced pressure. Add ethyl acetate to the residue (5

The solid which precipitated was filtered, washed with diethyl ether and dried to give the title compound ( 895 mg). NMR (CD3OD) δ : 3.33 (3Η, t, J=7.8 Hz), 3.87 (2H, t, J=7.7

Hz), 5.40 (2H, s), 7.10 (1H, dd, J==8 7, 2 6 Hz), 7 217 19 (1H, m), 7.23 (1H, br s), 7.44-7.40 (6H, m). (6) 4-Alkyloxy_4_[5_[(4·Phenyl-5)trimethyl-2·thienyl)methoxy] porphyrin-1-yl]butyric acid ethyl ester ] 121199.doc -78- 200846322

ο in a suspension of 5-[(4-phenyl-5-difluoromethyl-2-thienyl)methoxy ρ porphyrin hydrochloride (148 mg) in a chloranil (3 mi) suspension , DIEA (188 μΐ) was added at room temperature. After stirring at room temperature for 30 minutes, succinic acid monoethyl hydrazine chloride (53·9 μΐ) was added and the mixture was stirred for 5 hours. The reaction mixture was concentrated to dryness crystall The compound was not isolated and purified, and was used directly in the subsequent reaction. MS (ESI) m/z: 514 (M+H), (7) 4- 4-: 5-[5-[(4-Benzyl-5-trifluoromethylsinyl) decyloxy] Porphyrin-1-yl]butyric acid [51]

4-[5-[(4-Phenyl-5-trifluoromethyl-2-nonyl) decyloxy] porphyrin small base] ethyl butyrate (221 mg) A mixed solution of 33% methanol/THF (1.5 ml) was added 1 N aqueous sodium hydroxide (0.5 ml), and stirred at room temperature for 14 hr. After adding water (2 mi) to the reaction mixture, a 1 n aqueous hydrochloric acid solution (0.6 ml) was added to make it weakly acidic. Further, the organic matter was extracted by adding a 1% methanol/chloroform mixed solution (3 ml), and the combined organic layer suspension was concentrated until the amount of the solvent became half. The precipitated solid matter was filtered, washed with chloroform, and dried under reduced pressure. The title compound (128 mg) was obtained. 121199.doc 200846322 NMR (DMSO-d6) 3 : 2.64 (2H, t, J = 6.3 Hz), 3.13 (2H, t, J = 8.4 Hz), 3·29 (2H, d, J 2 9.0 Hz ), 4.09 (2H, t, J = 8.5 Hz), 5.34 (2H, s), 6.84 (1H, dd, J = 8.8, 2·2 Hz), 6.97 (1H, d, 1 = 2.2 Hz) , 7.35 (1H, s), 7·5〇-7·41 (5H, m), 7.96 (1H, d, J = 8.8 Hz). MS (EIS) m/z ·· 476 (M+H). The equivalent value of the elemental analysis of C24H2〇04NF3S: C, 60·62; H, 4·24; F, 11.99; N, 2·95; S, 6.74. Found: C, 60.43; H, 4, 24; F, 12.07; N, 3.05; S, 6.88. [Example 2] 4-Alkyloxy-4-[7-[(4''phenyl-5-trifluoromethyl-2-thienyl)methoxy]-2,3-dihydrophenylhydrazine , 4] pyridazin-4-yl]butyric acid (1) 4-tertiaryoxy-2,3-monohydroquinone [1,4] rakistan-4-yl) decanoic acid decyl ester [52]

a solution of 3,4-dihydro-2H-benzoquinone [1,4]oxazin-7-ol [Em·· J. Med·Chem., 1999, 34, 903-917·] (151 mg) in THF Add succinic anhydride (200 mg) to (10 ml), stir at room temperature for 6 hours, dilute the reaction solution with THF (l〇mi), add decyl alcohol (405 μM) and EDOHCl (958 mg) to the chamber. Stir under temperature for 4 days. 1 N hydrochloric acid aqueous solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The extract was washed with a saturated saline solution, and then dried with a helmet and sodium chlorate. The solvent was concentrated under reduced pressure and then the mixture was dried. The residue was purified by EtOAc EtOAc EtOAc (EtOAc). 4- 4-oxo-4-[7-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]_ 2,3-dihydrophenylhydrazine [ι,4]唠Pyridyl-4-yl]butyrate decyl ester

In 4-Methoxy-4-(7-hydroxy-2,3-dihydrophenylhydrazone p'4]oxazin-4-yl)butyric acid formazan (97 mg) in DMF (5 ml) Add 55% sodium hydride (17 mg) under ice cooling, and stir for 5 hours under ice cooling, then add 5-chloromethyl_3_phenyl-2-trifluoromethylthiophene (in mg) at 55 〇. Stir under c overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentrating under reduced pressure, the obtained residue was purified by flash column chromatography (m. NMR (CDC13)3: 2.70-2.86 (4H,m), 3.68 (3H,s),3·93 (2H s),4·29 (2Η,t,J-4.3 Ηζ),5·18 (2Η, s), 6·55-6·57 (2Η, m) 7.08 (1H, s), 7.26 (1H, s), 7.43-7.40 (5H, m). MS (ESI) m/z : 506 (M+H) + 〇(3) 4- oxo-4·[7-[(4-benzyl-5-trim-yl-2-yl) Methoxy] 2,3-dihydrophenylhydrazine [M]pyridazin-4-yl]butyric acid [Chem. 54] 121199.doc -81 - 200846322

4- 4-Alkyl-4_[7_"(4棠其$-田健0^I·7 U-based Ο-dimurenyl-2-thienyl)methoxy]·2, Hong Dihydro To a solution of hydrazine [1,4]pyridazin-4-yl]butyrate (13 〇mg) in THF (1 ml), add methanol (〇·5〇(tetra)sodium oxide aqueous solution (0·51 ml) to Stir at room temperature overnight. After adding 1 n hydrochloric acid to the reaction mixture, extract twice with ethyl acetate and wash with saturated brine.

liquid. The extract was dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by flash column chromatography (Shanshan High Speed Column L). The obtained crude product was lyophilized using water and 1,4-dioxane to give the title compound (100 mg) NMR (CDC13) δ: 2·75-2·86 (4H, m), 3·94 (2H) ,s),4·27 (2H, s),5·18 (2H,s),6·55-6·58 (2H,m),7·07 (2H,s),7·37-7· 43 (5H,m) 〇IR (ATR) cm · 3 060,1710,165 4,1619,1504,13 78,1286 1164, 1110 . 5 MS (ESI) m/z: 492 (M+H)+. C24H21F3N05S (M+H) HRMS (FAB) calc.: 492.

Calculated for the elemental analysis of C24H2〇F3N〇5S*0.5H20: c, 57.60. H 4.23; F, 11·39; N, 2, 80; S, 6.41. Measured value ·· c, 57·27· H 4.09; F, 11·〇7; N, 2.76; S, 6.40. [Example 3] 4-Alkyloxy-4-[6-[(4-phenyl-5-trifluoromethylsepenyl) 121199.doc -82- 200846322 decyloxy]-1,2,3 , 4-tetrahydro-hydroxypyridin-1, yl]butyric acid (1) 4-(6-yl-1,2,3,4-tetrahydroindolyl)_4• sideoxybutyric acid ]

OH in 6-carbyl-(1) fine hydroquinone and training this solution (9)

Succinic anhydride (1.34 g) was added and stirred at room temperature for 17 hours. Under reduced pressure

Concentration of the reaction solution was carried out by dissolving the obtained residue in a two-gas mixture, followed by extraction with an aqueous solution of sodium hydroxide. After the mixed extract was adjusted to pH 2 with Q% aqueous hydrochloric acid, extraction was carried out with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After the anhydrous sodium sulfate was filtered off, the residue was evaporated.

NMR (DMSO-d6) δ : 1.81 (2Η, t, J=7.1 Hz), 2.33-2.75 (5H m)' 3.27-3.40 (1H, m)' 3.62 (1H,t,J=6.4 Hz),6.57 (3h s) • 7.12 (1H5 s)5 9.29 (1H, s)? 12.05 (1H5 s) 〇MS (ESI) m/z : 250 (M+H)+. (2) 4-(6-Hydroxy-i,2,3,4-tetrahydroquinolin-1-yl)-4-oxobutoxybutyrate [Chem. 56]

The sulfurous gas (1·〇 ml) was added dropwise to methanol 121199.doc -83-200846322 (10 ml) under a nitrogen atmosphere at 0 ° C, and stirred for 10 minutes. In the reaction solution, 4-(6-hydroxy-i,2,3,4-tetrahydroquinolin-1-yl)-4-oxobutanoic acid was added dropwise at 20 ° C over 20 min. 540 mg) in methanol (20 ml). The reaction solution was gradually returned to room temperature while stirring, and the mixture was stirred for 3 days, and then concentrated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc) NMR (CDC13) δ : 1.86-1.97 (2Η, m)5 2.58-2.82 (6H? m)5 3·65 (3H, s), 3.74 (2H, t. J=6.1 Hz), 6.58-6.68 (2H ,m), ® 7,15-6.88 (1H,m). MS (ESI) m/z: 264 (M+H). (3) 4-Alkyloxy-4-[6-[(4-phenyl-5-trifluoromethyl 2 - phenyl) methoxy 1,2,3,4-tetrahydroquinoline -1-yl]butyrate butyrate [57]

5-chloromethyl-3-phenyl-2-trifluoromethyl porphin (347) and 4_(6•yl-1,2,3,4-tetrahydro. Chalin small base)_4• Add potassium carbonate (288 mg) to the side oxybutyrate methyl vinegar (275 (4) / combined solution (5 ml), warm to the stirring and reduce the reaction solution to room temperature, then add ice water to the acetic acid Take the combined extracts in sequence with ice water, saturated saline, clear, X,,,, water, water, melon, and dried. After removing anhydrous sodium sulfate, concentrate under reduced pressure, (four) The residue obtained was purified by flash column chromatography (EtOAc) 121199.doc -84- 200846322 NMR (CDC13) δ : 1·84-2·04 (4H,m), 2.50-2.99 (6H,m), 3·65 (3H,s), 3.76 (1H,t, Bu 5·4 Hz), 5.18 (2H, s), 6.74-6.86 (2H, m), 7·06 (1H, s), 7.34-7, 43 (5H, m). MS (ESI) m/z: 504 (M+H). (4) 4-Phenoxy-4-[6-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy 1,2,3,4-tetrahydroquinoline-1 -yl]butyric acid

4-Phenoxy-4-[6-[(4-phenyl-5-trifluoromethyl-2-thienyl)decyloxy l·1,2,3,4-tetrahydroindolyl·ι To a mixed solution of methyl butyrate (479 mg) in methanol/THF (1:2, 6 ml), 1 N sodium hydroxide solution (2 ml) was added at room temperature and stirred for 17 hours. The reaction liquid was concentrated under reduced pressure to give a residue. The residue was adjusted to pH 2 with a 1 N aqueous solution of hydrochloric acid and extracted with a 1% methanol/chloroform solution. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After the anhydrous sodium sulfate was filtered off, it was concentrated under reduced pressure, and the obtained residue was purified using silica gel flash column chromatography (m.p.).

Li R (10)Cl3) δ : 1>98 (2H, U=6.4 Hz), 2 61 2 87 (6h, spider 3.81 (2H, s), 5.22 (2H, s), 6.80-6.86 (3H, m) , 7.08 (1H, s), 7·39_7·45 (6H, m). , ' 1644, 1608, 1496, IR (ATR) cm·1 : 2943,1728, nu 121199.doc -85· 200846322 1473. MS (ESI) m/z: 490 (M+H) + calcd. calcd. s. s. s. s. s. s. Phenyl-5-trifluoromethyl-2-thienyl) methoxy] porphyrin-1-yl]pentanoic acid (1) 5-sided oxy-5-[5-[(4-phenyl- 5.·Trifluoromethyl-2-thienyl)methoxy] porphyrin-1-yl] decanoic acid ethyl ester [Chem. 59]

In a solution of 5-[(4-phenyl-5-trifluoromethyl-2-thienyl) decyloxy], porphyrin hydrochloride (67.4 mg) in dichloromethane (2.0 ml) DIEA (0.0855 ml) and ethyl 4-chloromercaptobutyrate (38·5 mg) were added at a temperature and stirred for 2 hours. A saturated aqueous solution of sodium hydrogencarbonate (aqueous solution of hydrazine and chloroform (20 ml) was added to the mixture, and the aqueous layer was extracted with chloroform (10-claw). The combined extracts were dried over anhydrous sodium sulfate. The residue was purified using EtOAc (EtOAc) (EtOAc (EtOAc) (EtOAc) 2H,m), 2.43-2.53 (4H,m),3·19 (2H,t,J=8.4 Hz), 4.07 (2H,t, J-8.4 Hz),4·15 (2H,q,J= 7.1 Hz), 5.20 (2H, s) 5 6·82 (1H, 121199.doc -86 - 200846322 dd, J=8.6, 2·6 Hz), 6.84 (1H, s), 7·07 (1H, s ), 7.35-7.47 (5H, m), 8.18 (1H, d, J = 8.6 Hz) 〇MS (ESI) m/z : 517 (M+) (2) 5-sided oxy-5-[5 -[(4-phenyl-5-trifluoromethyl-2-thienyl)decyloxy] 0-lead 13-lin-1-yl]pentanoic acid [60]

Ethyl 5-(5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy] porphyrin-1-yl]pentanoate (80.0 mg) In THF (3.0 ml), decyl alcohol (1.5 ml) and 1 N aqueous sodium hydroxide (0.470 ml) were added at room temperature. After a period of 15 hours, 1 N aqueous hydrochloric acid (0.470 ml) and water (20 ml) were added to the mixture, and the mixture was concentrated to 20 ml under reduced pressure. After a 1 N aqueous solution of hydrochloric acid (1 〇mi) and ethyl acetate (20 ml) were added to the resulting mixture, the aqueous layer was extracted with ethyl acetate (20 ml). The extract was combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was slurried with hexane, and the obtained solidified product was filtered, and dried (vacuum pump, 3 hr, 40 ° C) to give the title compound (67.3 mg). NMR (CDC13) δ : 2.04-2.14 (2H? m), 2.55 (4H, t, J=7.0 Hz), 3.20 (2H,t,J=8.4 Hz),4·07 (2H,t,J=8.4 Hz),5·21 (2H,s), 6.82 (1H,dd,J=8.7,2.7 Hz),6·85 (1H,s),7·07 (1H,s), 121199.doc -87- 200846322 7.37-7.46 (5H, m), 8.18 (1H, d, J = 8.7 Hz). IR (ATR) cm·1 : 2906,1698,1652,1488,1290,1269,1099, 1014, 698. MS (ESI) m/z: 495 (M+H) + calc. calcd for C25H22F3N04S: C, 61·34; H, 4, 53; F, 11.64; N, 2.86; S, 6.55. Found: C, 61.28; H, 4.52; F, 11.28; N, 2.90; S, 6-6b [Example 5] 6-Sideoxy-6-[5-[(4-phenyl-5-trifluoro) Methyl-2-thienyl) • Methoxy]porphyrin-1-yl]hexanoic acid (1) 6-Sideoxy-6·[5·[(4·Phenyl-5·trifluoromethyl) -2-thienyl)methoxy] ° 丨 11 吓 吓 ► ► -1 - 基] hexanoic acid 酉 酉 [Chemical 61]

5·[(4-Phenyl-5-trimethylsulfonyl-2-thinyl)methoxy]σ Liaolin hydrochloride (100 mg) and monoethyl adipate (46.5 mg) In a suspension of DMF (3.0 ml), EDNHC1 (58.0 mg), HOBt (41.0 mg), and hydrazine (0.104 ml) were added at room temperature for 4 days. Concentrate the reaction solution under reduced pressure. Add the acetic acid to the obtained concentrate (30 ml), a saturated aqueous solution of sodium hydrogencarbonate (20 ml), and water (40 ml) for liquid separation (20 ml) ) Extract the aqueous layer. The combined extracts were dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc) 129 (3H, t? J=7.1 Hz 44 (2H, t, J = 6.8 Hz), 3·19 (2H, t, J = 8.4 Hz), 4.06 (2H, t, J = 8.4 Hz), 4.14 (2H, q, J = 7.1 HZ), 5·20 (2H, s), 6.78-6.86 (2H, m), 7.07 (1H, s), 7·36-7·46 (5H, m), 8·18 (1H, d, J=8.8 Hz ). MS (ESI) m/z: 532 (M+H)+. (2) 6-Phenoxy-6-[5-[(4-phenyl-S-difluoromethyl-2-°secenyl)methoxy]porphyrin-1-yl]hexanoic acid [ 62]

On the 6-side oxy-6-[5-[(4-phenyl-5-difluoromethylsepenyl)methoxy]. To a solution of THF (4. 〇ml) of 11 ml of 1-ethylidene hexanoate (115 mg), methanol (2·〇ml) and 1 N aqueous sodium hydroxide solution (〇65) were added at room temperature. 〇鲁ml). After stirring for 15 hours, 1 N aqueous hydrochloric acid (0.65 ml) and water (20 ml) were added to the mixture, and the mixture was concentrated under reduced pressure to 2 〇 ml. After the resulting precipitate was collected by filtration, dried (yield, 3h, 40°C) to give the title compound (1. NMR (CDC13) δ : 1.70-1.90 (4H, m), 2·40-2·52 (4H, m), 3.19 (2H5 J=8.4 Hz) 5 4.06 (2H5 t5 J=8.4 Hz)? 5.20 (2H s)5 6.82 (1H, dd, J=8.6, 2.6 Hz), 6.84 (1H, s), 7.07 (1H, s), 7·38_7·46 (5H, m), 8.18 (1H, d , J = 8.4 Hz). C02H was not observed. 121199.doc -89 - 200846322 IR (ATR) cm·1 : 2943, 1701, 1649, 1487, 1383, 1288, 1263, 1109, 1014, 766, 698. MS (ESI) m/z: 504 (M+H) + C26H24F3N04S calc.: C, 62.02; H, 4.80; F, 11.32; N,2·78; S, 6.37. Found: C, 61.84; H, 4.70; F, 11.40; N, 2.78; S, 6.47 〇 [Example 6] 7-Sideoxy·7-[5-[(4-phenyl-5-trifluoro) Methyl-2-thienyl) methoxy] porphyrin-1-yl]heptanoic acid (1) 7-sided oxy- 7-[5-[(4-phenyl·5-tri-indenyl) _2 嗟 ) ) ] ] I I I I I I I ° ° ° ° ° ° ° ° ° ° ° 化 化 化 化 化 化

5-[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy ρ porphyrin hydrochloride _ salt (51·9 mg) of dichloro decane (2. 〇mi) In the solution, DIEA (0.0660 ml) and ethyl 6-chloromethylhexanoic acid (36 〇mg) were added at room temperature to disturb 2 hours. A saturated aqueous solution of sodium hydrogencarbonate (1 〇 1 1) and chloroform (20 ml) were added to the mixture, and the mixture was separated, and the aqueous layer was extracted with chloroform (1 〇mi). After the combined extracts were dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (Biotage 25M) to afford compound (68.4 mg). NMR (CDC13) δ : 1.26 (3H5 t5 J=7.2 Hz), 1.38-1.50 (2H? m). 1.63-1.80 (4H5 m)5 2.32 (2H, t5 J-7.5 Hz), 2.4l (2H, t 121199.doc 200846322 J=7,5 Ηζ),3·18 (2H,t,J=8.4 Hz), 4.06 (2H,t,J=8.4 Hz), 4.12 (2H,q,"=7·2 Hz ),5·20 (2H,s),6·78-6·86 (2H,m), 7.06 (1H,s), 7.36-7.41 (5H,m),8·18 (1H,d,J= 8.8 Hz). MS (ESI) m/z: 546 (M+H), (2) 7-s-oxy-7-[5-[(4-phenyl-5-trifluoromethyl-2-thienyl) methoxy Phenyl]-7-yl]heptanoic acid

〇

OH is 7-oxooxy-7-[5-[(4-phenyl-5.trifluoromethyl-2-thienyl)methoxy] porphyrin-1-yl]heptanoic acid ethyl ester ( To a solution of 67.0 mg) in THF (3.0 ml), decyl alcohol (1.5 ml) and 1 N aqueous sodium hydroxide (0.370 ml) were added at room temperature. After stirring for 20 hours, 1 N aqueous hydrochloric acid (0.370 ml) and water (20 ml) were added to the mixture, and the mixture was concentrated to 20 ml left φ right under reduced pressure. After the precipitate formed was collected by filtration, dried (vacuum pump, 3 hr, 40 C) to give the title compound (56.7 mg). NMR (DMSO-d6) δ : 1.27-1.37 (2Η, m)? 1.47-1.61 (4H5 m)5 2·19 (2H, t, J=7.3 Hz), 3.39 (2H, t, J=7.3 Hz) ,3·10 (2H,t, J=8,4 Hz), 4·06 (2H, t, J=8.4 Hz), 5.33 (2H, s), 6.83 (1H, dd, J = 8.8, 2, 3 Hz), 6,96 (1H, d, J = 2.3 Hz), 7·35 (1H, s) 5 7.40-7.51 (5H, m), 7·99 (1H, d, J = 8.8 Hz). C02H was not observed. IR (ATR) cm·1 : 2945, 1705, 1583, 1489, 1408, 1387, 1269, 121199.doc • 91 - 200846322 1201, 1173, 1120, 1097, 1020, 768, 700. HRMS (ESI) calcd for EtOAc (m/z): Found: 518.1604. Calculated for the elemental analysis of C27H26F3N04S*0.25H20: C, 62.12; H, 5.12; F, 10.92; N, 2.68; S, 6.14. Found: C, 62.48; H, 5.08; F, 11.30; N, 2.20; S, 6.11, [Example 7] (S)-2-hydroxy-4-oxo-4-[5-[(4) -phenyl-5-trifluoromethyl-® 2-thienyl)nonyloxy]indol-1-yl]butyric acid (1) (S)-2-yl-4-yloxy-4 -[5-[(4-Phenyl-5-tri-Imethyl-sepyl)methoxy]porphyrin-1-yl]butyrate decyl ester [Chem. 65]

(SH2,5-di-oxytetrahydrofuranyl)trifluoroacetate (1 〇 6 mg) was dissolved in methanol (2 ml) and stirred at room temperature for 35 hr. The reaction mixture was concentrated, and THF (1 ml) was added to the residue, and then, and then, at room temperature, hydrazine (60 μl), ΗΟΒ (67.6 mg) and EDC.HC1 (95.9 mg) were added. After the reaction mixture was stirred for 10 minutes, 5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]indole hydrochloride (206 mg) was added at room temperature. ΤΕΑ (80·〇μΐ), DMF (1 ml) solution. After the reaction liquid was further stirred for 14 hours, the reaction liquid was concentrated under reduced pressure, and chloroform (3 m 1 ) and hydrazine were added thereto! · 11^) 121199.doc -92- 200846322 Perform liquid separation' extraction of the aqueous layer with chloroform (1 ml x 3). The combined extracts were distilled off under reduced pressure > granules. DmS(R) (3 ml) was added to the obtained residue, and the residue was removed and purified by Southern liquid chromatography (n〇MURa Develosil Combi-RP-5) to obtain the title compound (58·7 ISiMR (CDC13) δ : 2·96 (2H5 d, J=4.9 Ηζ), 3·18 (2H, t, J=8.3

Hz)? 3.82 (3H, S)5 4.05 (2H5 t, J-8.5 Hz)? 4.60 (1H5 t5 J-4.8 HZ), 5·19 (2H, S), 6·80 (1H, dd, J= 8.8, 2.4 Hz), 6.84 (1H, d, J-2.2 Hz), 7.06 (1H5 S)5 7.42-7.38 (5H, m)5 8.13 (1H? d5 J=8.8 Hz) 〇MS (EIS)m/ z : 506 (M+H)+ (2) (S)-2-hydroxy-4-yloxy_4_[5-[(4-phenyl-5-trifluoromethyl-2-phenylyl) Oxy]porphyrin-1 -yl]butyric acid [Chemical 66]

33% sterol of (S)-2-hydroxy-4-oxophenylphenyl-5-trifluoroindolyl-2-pytyl) decyloxy] porphyrinyl]butyrate To the mixed solution of thf (i 5 ml), an i N sodium hydroxide solution 〇·5 mi was added, and the mixture was stirred at room temperature for 14 hours. After adding water (2 ml) to the reaction mixture, i n hydrochloric acid water/yield (0.6 ml) was added to make it weakly acidic. Further, the organic matter was extracted by adding a 1% methanol/gas mixture (3 ml), and the combined extracts were dried over anhydrous sodium sulfate. After adding DMSO (2 ml) to the obtained residue, the insoluble matter was removed by filtration, and the purified compound (22.0 mg) was obtained by HPLC (121. ). NMR (CDC13) δ : 3.14-2.92 (2H,m), 3.24 (2H,t,J=8 1 Hz) 4, ί7-4·02 (2H,m),4·56 (1H,br s), 5·21 (2H, s), 6 95·6Ζ8ι' (2H, m), 7·07 (1H, S), 7·41 (5H, br S) 5 8·12 (1H, d, j== 8 $ Hz) 〇· MS (EIS) m/z : 491 (M+H)+. Calculated value of elemental analysis of C24H2GO5NF3S*0.25H2〇: c 58 h

• 4·17; N, 2·82; S, 6.47. Found: C, 58 · 〇 6 : H, 4.12; N 2 · 93; S, 6.58 〇 [Cheng 8] (S)-3-hydroxy-4- oxo-4-[5-[( 4-phenyltrifluoromethyl 2-thienyl)nonyloxyindol-1-yl]butyric acid [Chem. 67] *

OH

1-tert-butoxycarbonyl-5-[(4-phenyl-5-trifluoromethyl-2-nonyl) decyloxy], porphyrin (61 mg) was dissolved in dichloromethane ( In 5 ^ 1), trifluoroacetic acid (5 ml) was added and stirred for 4 hours. The reaction solution is concentrated, and the obtained 5-[(4-phenyl-5-trifluoromethyl-2-thienyl) decyloxy] porphyrin trifluoroacetate is prepared.

A solution of THF (2 ml) was added DIEA (48 μM) and (8) </RTI> <RTIgt; The reaction solution was concentrated under reduced pressure and dissolved in DMSO (1 ml) for high-performance liquid chromatography (n〇mURA)

Purification by Develosil Combi-RP_5) gave the title compound (381 12I199.doc •94 - 200846322 mg). MS (EIS) m/z: 492 (M+H) + 〇 [Example 9] (R)-2-amino-4-yloxy-4-[5-[(4-phenyl-5-) Tris-methylmethyl-2-thienyl)methoxy]porphyrin-1-yl]butyric acid, and [Example 10] (R)-3-amino-4-oxo-4-(5) -[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]porphyrin-1-yl]butyric acid (1) (R)-4-trioxy-4-[ 5-[(4-Phenyl-5-trifluoromethyl-2-nonyl)methoxy]° bow 1 13-lin-1-yl]-2-(trifluoroacetamido) Acid, and (R)-4-sidedoxy_4-[5-(4-phenyl-5-trifluoromethyl-2-nonyl)methoxy] ° 11-lead-1 -yl ]-3 -(Trifluoroethylamino)butyric acid [Chem. 68]

25% acetonitrile / 2 in 5-[(4-phenyl-5.trifluoromethyl-2-ylthio)methoxy]porphyrin hydrochloride (206 mg), hydrazine (69·7 μΐ) In a mixed solution of methane (3 ml), (R)-2·trifluoroacetamido tartaric anhydride (106 mg) was added at room temperature. The reaction mixture was stirred for 14 hr. It was used directly in the subsequent reaction without isolation and purification. MS (ESI) m / z: 587 (M+H) + 〇121199.doc -95-200846322 (2) (R)-2-amino-4-ylidene-4_[5_[(4-phenyl -5-trifluoromethyl-2-nonyl)methoxy]porphyrin-1-yl]butyric acid, and (R)-3-amino-4-oxo- 4-[5- [(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy]porphyrin-indenyl]butyric acid [Chem. 69]

Oxyloxy·4·[5-[(4·Phenyl-5-trifluoromethyl-2-thienyl)methoxy] porphyrin-1-yl]_2_(trifluoroethenylamino) Butyric acid and (11)_4•trioxy-4-[5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]porphyrin-1-yl]- 3-(trifluoroethenylamino)butyric acid (3 〇 2 mg) in a mixture of 33% methanol / THF (1,5 ml), adding 1 n sodium hydroxide solution 〇·5 ml, to the temperature Stir under 14 hours. After adding water (2 ml) to the reaction mixture, a 1 N aqueous solution of hydrochloric acid was added until it became neutral. The extract was further extracted with 1 〇〇 /0 methanol / chloroform (3 ml), and the combined extracts were concentrated under reduced pressure, and the obtained residue was added to DMSO (6 ml). Ancient μ +, ^ π π liquid chromatography (NOMURA Develosil Combi-RP-5) i# lx ,, purified per 。. The solid precipitated from the compound fraction having a long residence time is filtered, washed with water and dried in water, and then dried to obtain (R)_2_amine 121199.doc-96-200846322 base-4-sideoxy- 4-[5-[(4-Phenyl-5-tris-decyl-2-nonyl)methoxy] 吲哚f-buki]butyric acid (21.3 mg); again, collection of short residence time The fraction of the compound was freeze-dried to obtain (R)-3-amino-4-oxo-'p-oxime; "-phenyl-5-trifluoromethyl-2-thienyl)methoxy]oxime Porphyrin-1-yl]butyric acid (36·5 mg) 〇(R)-2-amino-4-oxo-4-[5·[(4-phenyl-5-trifluoromethyl)- 2·Thienyl)methoxy]/ oleopiperidin-1-yl]butyric acid: NMR (DMSO-d6) δ : 2.70 (1Η, dd, J=17.3, 9.0 Ηζ), 3.05 (1Η, dd, J=17.1,3·1 Ηζ),3·13 (2Η,t,J=8.5 Ηζ), 3.54 (1Η, dd, J=8.9, 3.1 Hz), 4.06 (2H, dt, J=ll, 2, 8·5 Hz), 5.34 (2H, s), 6·86 (1H, dd, J=8.8, 2.4 Hz), 6.99 (1H, d, J=2.4 Hz), 7.35 (1H, br s) , 7.50-7.41 (5H, m), 8.00 (1H, d, J = 8.8 Hz) MS (EIS) m/z : 491 (M+H)+ Calculation of elemental analysis of C24H2104N2F3S.1.25H20 :C,56.19; H,4·62; N5 5.46; S,6·25. Measured: C, 56·35; H,4·56; N, 5.58; S, 6.38 ° (R)-3 -amine 4-Oxyloxy-4-[5-[(4-phenyl-5-di-dunyl-2-synyl) methoxy]porphyrin-1-yl]butyric acid: NMR (DMSO-d6) δ : 2.25 (1H, dd, J 26.2, 8·7 Hz), 2.59 (1H, dd, J = 16.1, 5.6 Hz), 3.15 (2H, t5 J = 8.5 Hz), 4.00 ( 1H, dd5 J=5.9, 8.8 Hz), 4·13 (1H, dt, J=8.3, 9·3 Hz), 4·28 (1H, dt5 J=7.6, 9.3 Hz), 5·36 (2H, s), 6.88 (1H, dd, J=8.8, 2.7 Hz), 7·01 (1H, d, J=2.4 Hz), 7.37 (1H, br s), 7.51-7.42 (5H, 121199.doc -97 - 200846322 m), 8.02 (1H, d5 J=8.8 Hz). MS (EIS) m/z : 491 (M+H), C2 4H2i〇4N2F3S·1·5Η2〇 Calculated value of elemental analysis·· c 55 7〇· Η 4.67 : F,11 ·00; Ν, 5.41; S, 6.20. Found: c 55 85 · Η 4.35; F, 11.12; Ν, 5, 38; S, 6·35 ° [Example 11] (R) 3-Amino-4- oxo-4-[5- [3,5-bis-(trifluoromethyl)benzyloxy] σ-I-Phenyl-1-yl]butyrate (1) 5-[3,5-bis-(difluoromethyl) Alkoxy]-1-tert-butoxycarbonyl porphyrin [Chem. 70]

In a DMF solution (5 ml) of 3,5-bis-(trifluoromethyl)benzyl vapor (341 mg) and ι_(t-butoxycarbonyl)-5-hydroxyporphyrin (235 mg) Potassium carbonate (415 mg) was added, and the mixture was heated to 50 ° C and stirred for 14 hours. After the reaction mixture was returned to room temperature, the insoluble material was filtered, and the obtained filtrate was concentrated under reduced pressure to give the title compound (470 mg). NMR (CDCls) δ : 1.54 (9Η, s)5 3.07 (2H? t, J=8.6 Hz)? 3.93-4·04 (2H,m), 5.12 (2H,s)5 6.74-6.84 (2H,m ), 7, 31-7.21 (1H, m), 7.84 (1H, s), 7.89 (2H, s). (2) 5-[3,5-Bis(trifluoromethyl)benzyloxy]porphyrin hydrochloride [Chem. 71] 121199.doc -98- 200846322

5-[3,5-Bis-(trifluoroindolyl)benzyl (461 mg) was dissolved in 4 N hydrochloric acid / 1 and stirred for 15 hours. The reaction mixture was concentrated in EtOAc (EtOAc m. δ : 3.16 (2H, t, J=7, 4 Hz), 3.70 (2H t J=7.8 Hz), 5.33 (2H, s), 7·02 (1H, d, J=8.6 Hz), 7.16 (1H , s), 7·35-7·28 (1H, m), 8.11 (1H, s), 8.16 (2H, s). MS (ESI) m/z: 362 (M+H)+ 〇(3) (R)-3-tributoxycarbonylaminoloxy _4_[5_[3,5-bis-(trifluoro) Methyl)benzyloxy] 1 哚 lin-1 -yl]butyric acid tert-butyl ester [Chem. 72]

5-[3,5-bis-(trifluoromethyl)benzyloxy]porphyrin hydrochloride (398 mg), Boc-D-Asp(〇tBu)-OH (289 mg), EDOHCl (288 Mg(0·697 ml) was added to a DMF solution (4 ml) of HOBt (2 〇3 mg), and stirred at room temperature for 14 hr. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified using silica gel flash column chromatography (Biotage 25S) to afford the title compound (566 mg). 121199.doc -99- 200846322 NMR (CDC13) δ : 1.42 (9H, s), 1·43 (9H, s), 2·58 (1H, dd, Ι=15·7, 5·9 Hz), 2 ·83 (1H, dd5 J=15.7, 7·8 Hz), 3·20 (2H, t, J=7.8 Hz), 4.25-4.43 (2H, m), 4.92 (1H, dd, J=15.2, 6.6 Hz), 5.13 (2H, s), 5·28 (1H, d, J-9.6 Hz), 6.80 (1H, dd, J=8.8, 2.7 Hz), 6.85 (1H, d, J=2.5 Hz), 7.84 (2H, s), 7.89 (1H, s), 8.15 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 633 (M+H)+. (4) (R)-3-Amino-4-oxo-4-[5-[3,5-bis(trifluoromethyl)benzyloxy] porphyrin-1-yl]butyric acid Hydrochloride [73]

(R)-3·t-butylcarbonylamino-4-yloxy-4_[5_[3,5-bis-(trifluoromethyl)benzyloxyp-indolyl]butyric acid Butyl ester (566 of 4 N hydrochloric acid / 1,4-second burning solution (1 〇 ml) ' was thrown at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to the obtained residue. After the solid precipitated from the alkane, dry-welding was carried out under reduced pressure, and the title compound (440 mg) was obtained. NMR (DMSO-d6) δ: 2.54-2 ηττ Ζ·86 (1Η, m) 5 3· 04 (1Η, dd, J=17.8, 4·8 Hz), 3.17 (1H, t Bu 7 δ ϊτ , LJ — 7.8 Hz), 3·57 (2H, d, J=0.5 Hz)? 4.07-4, 31 (2H5 m) 441^ ^ ),4·4Κ4·47 (1H,m),5·30 (2H,s), 6.91 (1H,dd5 J=8,8,2.2 Hz) 7 h 7.04.7.07 ( 1H5 m), 8.01 (1H, d, J=8.8 Hz), 8·10 (1H, s), 8·15 (2H. I21199.doc -100· 200846322 IR (ATR)cm·1 : 2999, 2914, 2600, 2305,1732,1653,1599, 1572. MS (ESI) m/z: 477 (M+H)+. HRMS (FAB) for C21H19F6N204: 477.1249. Measured: 477.1248 ° 〇21Η48Ρ6Ν2Ο4·1·0Ηα · Calculated value of elemental analysis of 0·25ΕΐΟΗ·0,5Η2Ο C, 48.42; Η, 4·06; C1, 6.65; F, 21.37; Ν, 5·25. Measured: C, 48.63; Η, 3.87; Cl5 6.91; F, 21.11; Ν, 5.27. 12] (R)-3-Amino-4_p-oxy-4-[5-(4-biphenylyloxy)-pyridolin-1-yl]butanoic acid hydrochloride (1) 5 -(4-biphenylmethoxy)pyroline-1-decanoic acid tert-butyl ester [化74]

.Boc

To a solution of l-Boc-5-hydroxyporphyrin (150 mg) in DMF (5 ml), add 4-methylbenzene biphenyl (155 mg), potassium carbonate (132 mg) at 70 ° C . After standing to cool to room temperature, a saturated sodium hydrogencarbonate solution was added to the reaction mixture solution, and the mixture was extracted twice with ethyl acetate, and the mixture was washed with brine. The extract was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography (yield: EtOAc) to afford the title compound (240 mg). NMR (CDC13) δ : 1·56 (9H, s), 3.06 (2H, t, J = 8.6 Ηζ), 3.97 (2H, s), 5·〇6 (2H, s), 6.78-6.83 ( 2H, m), 7·26-7·76 (10H, 121199.doc -101 - 200846322 m). (2) 5-(4-biphenylmethoxy)porphyrin hydrochloride [Chem. 75]

Add 4 N hydrochloric acid / 1,4-dioxane solution to 1-(3 -butoxycarbonyl)-5-(4-biphenylmethoxy)porphyrin (23 〇• mg) (10 ml ), mixing at room temperature for 4 hours. Diethyl ether was added to the reaction mixture, and the precipitated solid was filtered, and the title compound (198 mg) was obtained. NMR (DMSO-d6) δ : 3.15-3.19 (2H, m), 3·69·3.72 (2H, m), 5·19 (2H, s), 7.01 (1H, dd, J=2.6,8·7 Hz),7·15 (1H,d, J=2.6 Hz),7·33-7·39 (2H,m),7·45-7·54 (4H,m),7,66-7.71 (4H , m), 11.06 (1H, s). MS (ESI) m/z: 302 (M+H)+. φ (3) (R)-3·t-butoxycarbonylamino-4-yloxy-4·[5-(4-biphenyloxy) 哚 哚 -1-1 -yl] Acid tert-butyl ester [Chem. 76]

To a solution of 5_(4-biphenylmethoxy) porphyrin hydrochloride (190 mg) in DMF (10 ml), Boc-D-Asp (OtBu)-OH (195 mg), HOBt 121199. Doc -102- 200846322 (114 mg), EDOHCl (161 mg), TEA (392 μΐ) were stirred overnight. A saturated sodium hydrogencarbonate solution was added to the reaction mixture solution, and the mixture was extracted twice with ethyl acetate, and the extract was washed with brine. The extract was dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by flash column chromatography (yield). NMR (CDC13) δ : 1.42 (9H5 s)5 1.43 (9H5 s)5 2.57 (1H5 dd? J-6.1, 15.7 Hz)5 2.79-2.85 (1H5 m)? 3.19 (2H5 t5 J=8.3 Hz)? 4.26 _4·40 (2H, m), 4.89-4.95 (1H, m), 5.08 (2H, s), 5.28 (1H, d, J = 9.6 Hz), 6·81-6·85 (2H, m), 7.33-7.50 (5H,m), 7.58-7.62 (4H,m), 8.12 (1H,d,J=8.6 Hz). MS (ESI) m/z ·· 573 (M+H)+. (4) (R)-3-Amino-4-oxo-4-[5-(4-biphenylmethoxy)indolyl]butanoic acid hydrochloride [Chem. 77]

The (R)-3-t-butoxycarbonylamino-4-yloxy_4_[5·(4-diphenylmethoxy) is oxime. Add a solution of 4 ν hydrochloric acid / 1,4-dioxane (3 15 mg) to the tert-butyl butyrate (315 mg) and stir at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the residue was suspended in diethyl ether. The solid tear was taken and dried to give a labeled compound (219 mg). NMR (DMSO-d6) δ ·· 2.73-2.80 (1H,m),3·01 (1H, dd. 121199.doc -103- 200846322 J=5.8, 17.3 Hz), 3.15 (2H, t5 J=8, 2 Ηζ),4·14·4·42 (3H,in), 5·12 (2H,s),6·87 (1H,dd,J=2.4,8.4 Hz), 7.00 (1H, s)5 7.34 -7.38 (1H, m), 7·44-7·52 (4H, m), 7·65-7·68 (4H, m) 5 7.99 (1H, d, J = 8.8 Hz). IR (ATR) cm·1 : 2898, 1650, 1484, 1265, 1189. MS (ESI) m/z ·· 417 (M+H)+. HRMS (FAB) for C25H25N2 〇4 (M+H)+: 417, 1814. Measurement value: 417.1819. Calculated values of elemental analysis of R. 25Η25^!1Ν2〇4·〇·5Η2〇: C, 65.00; H, 5·67; C1,7·67; Ν, 6.06. Found: C, 64.94; Η, 5.62; C1, 7·54; Ν, 5.99 〇 [Example 13] (R)-3-Amino-4-epoxy-4·[5-(2-cyanide 4--4-phenylmethoxy"pyroline-1-yl]butanoic acid hydrochloride (1) 4-chloromethylbiphenyl-2-indolecarbonitrile [78]

Add 1 drop of sulfoxide (2〇8 μ1) and dmf to a Pasteur pipette in a solution of 4-3⁄4 曱 phenyl carbonitrile (12 〇 mg) in dichloroethane (1 〇 ml). Stir at 50 ° C overnight. After standing to cool to room temperature, the reaction mixture solution was concentrated. The resulting residue was purified by flash column chromatography (m.p.). NMR (CDC13) δ : 4.63 (2H, s), 7·46-7·57 (6H, m), 7.67 (1H, 121199.doc -104- 200846322 dd, wind 1,2.0 Ηζ), 7· 79 (lH,d,J=2.〇Hz). MS (ESI) m/z: 228 (M+H) + 〇(2) 1-(2 -butoxycarbonyl)_5_(2-cyanobiphenylmethoxy). &quot;

Add 4-chloroindolylbiphenylcarbonitrile (174 mg), potassium carbonate (132 mg) to 1-(2,2-butoxycarbonyl)hydroxyporphyrin (15 ml solution (5 ml), at 7 (Stirring at TC overnight. After standing to cool to room temperature, a saturated sodium hydrogencarbonate solution was added to the reaction mixture solution, and the mixture was extracted twice with ethyl acetate, and the mixture was washed with saturated brine. The residue was purified by EtOAc EtOAc (EtOAc) (EtOAc) 2H,t,J = 8.7 Hz),3.98 (2H5 s)5 5.08 (2H5 s)5 6.76-6.82 (2H, m)5 7.43-7.83 (9H, m) 〇MS (ESI) m/z : 327 ( M-Boc) + 〇(3) 5-(2-cyano-4-biphenylmethoxy oxyporphyrin hydrochloride [Chem. 80] I21199.doc -105- 200846322

Add 4 N hydrochloric acid / 1,4-dioxane solution to 1-(2 -butoxycarbonyl)-5-(2-cyano-4-biphenylmethoxy) sulfonium (255 mg) (1 〇 ml), stir at room temperature for 4 hours. Diethyl scale was added to the reaction mixture solution, and the precipitated solid was filtered and dried to give the title compound (222 mg).

NMR (DMSO-d6) δ : 3·16-3·20 (2H, m), 3.70-3.73 (2H, m), 5.25 (2H, s), 7·05 (1H, dd, J=2.6,8 · 7 Hz), 7.18 (1H, d, J = 2.6 Hz), 7.37 (1H, d, J = 8.7 Hz), 7·48-7·61 (5H, m), 7.67 (1H, d, J= 8.1 Hz), 7.85 (1H, dd, J=2.0, 8J Hz), 8.03 (1H, d, J=1.5 Hz), 11·20 (1H, br s). MS (ESI) m/z ·· 327 (M+H)+ 〇(4) (R)-3_t-butoxycarbonylamino group _4_sideoxy_4_[5_(2_cyano) 4-biphenylmethoxy group ϋ ϋ ϋ -1 -1 - yl] butyrate tert-butyl ester [化81]

Add Boc-D-Asp(OtBu)-OH to a solution of 5-(2-cyanobiphenyl-4-ylmethoxy) porphyrin hydrochloride (215 mg) in DMF (10 ml) 205 mg), HOBt (120 mg), EDNHC1 (170 mg), and cesium (413 μΐ) were stirred overnight. A saturated sodium bicarbonate solution was added to the reaction mixture solution, and the extract was washed with a saturated saline solution under the conditions of B 121199.doc -106 - 200846322. Anhydrous sulfuric acid

The sodium dry residue is taken from the liquid, and the residue is purified by ice kiln, and the residue is purified by rapid bureaucratic chromatography (Shanshan high-speed column L) to obtain the title compound (327). Mg). Face (Caf 13) §: 1.42 (State, 8), 143 (911, 8), 2 58 (^15.7), 2.80-2.86 (1H, m), 3.21 (2Hj t? J=g&gt; 3 Hz) , 4.28-4.41 (2H, m), 4.89-4.95 (1H, m)j 5.10 (2h, s), 5.27 〇H, d, 1 = 9.8 Hz), 6.78-6.85 (2H, m), 7.43-7.58 ^6^ m), 7-69 (1H, dd, ;=!.7? 8.1Hz), 7.83(1H} d&gt; j=i 5 8 i4 (1H,d,J=8.8 Hz) 〇MS (ESI m/z : 598 (M+H)+ 0 (7) Amino-4-sided oxy group·4_[5_(2_cyano-4_biphenylmethoxy broad porphyrin-1-yl) Acidate

, ΟΗ νη2 Ο η · Cl in (R)-3-tert-butoxycarbonylamino group _4_sideoxy_4_[5_(2_cyano-4_biphenylmethoxy) ten-lined d To the base of butyric acid, butyl vinegar (32 〇 mg) was added 4 N hydrochloric acid / Mn solution (5 ml), and the mixture was stirred at room temperature for one night at 50. . The mixture was stirred for 8 hours and further stirred at room temperature overnight. After the reaction mixture solution was concentrated under reduced pressure, the residue was suspended in diethylamine. The solid was taken and dried to give the title compound (213 mg).丽R (DMS〇-d6) δ : 2·77·2.83 (1H,m), 3 grabs 3 〇7 (ih, spider 121199.doc -107- 200846322 3.18 (2H,t,J=8.2 Ηζ), 4 ·19-4·44 (3H,m),5·20 (2H,s), 6.91 (1H,d,J=8.6 Hz), 7.05 (1H,s), 7.48-7.67 (6H,m), 7 · 84 (1H, dd, J=1.5, 8.1 Hz), 8·01-8·03 (2H, m) IR (ATR) 011^: 3239, 2219, 1643, 1486, 1419, 1180. MS (ESI m/z: 442 (M+H)+. HRMS (FAB) for C26H24N304 (M+H)+: 442.1767; found: 442.1774. Calculated for elemental analysis of C26H24ClN3O4.0.25H2O: C, 64 · 73; H, Φ 5.12; C1, 7.35; Ν, 8.71. Measured value: C, 64.42; Η, 5.05; C1, 7·41; Ν, 8.72. [Example I4] (R)-3· Amino-presentyloxy-4_[5-[(2-trifluoromethyl-4-biphenyl)decyloxy]indol-1-yl]butanoic acid (1) 4-trifluoromethane Xanthateoxy-3-trifluoromethylbenzoate 曱酉 [化83]

〇 ο

〇:S ·〇 F F F

To a solution of decyl 4-hydroxy-3·trifluoromethylbenzoate (1 〇 5 g, 4 77 mmol) in dichloromethane (50 ml), triethylamine (1 〇〇ml, 715 mmol) 4-Methylamino-based bite (58 mg, 〇·48 mmol) was ice-cooled, and then added with difluoromethalin and S-anhydride (962 μΐ, 5 72 mm〇i) at room temperature. instrument. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted twice with chloroform, and then washed with saturated aqueous ammonium chloride and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography (mjjjjjjjjjjj Shape. WNMR (CDC13) δ : 3.99 (3H, s), 7.62 (1H, d, J = 8.8 Hz), 8.34 (1H, dd, J = 2.0, 8.8 Hz), 8.44 (1H, d, J=2 .〇Hz). MS (ESI) m/z: 353 (M+H)+. (2) Methyl 2-trifluorodecyl-4-biphenylcarboxylate [Chem. 84]

+ Clb.〇h Add a phenyl group at room temperature to a solution of 4-dioxaline page^&amp;oxy-3-tris-methylbenzoic acid@@ (361 mg) in toluene (10 ml) Boric acid (25 mg), cesium carbonate (1.00 g), and water (2.0 ml) were added to a mixed solution with nitrogen for 3 minutes, and then tetrakis(triphenylphosphine)palladium (236 mg) was added. The reaction mixture was stirred at 90 ° C for 90 minutes, then cooled to room temperature, and ethyl acetate (20 ml) and brine (20 ml) After the organic layer was dried over anhydrous sodium sulfate, solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (EtOAc) eluting elut elut elut elut elut elut elut elut elut elut elut elut elut (1H, dd, J=8.0, 1.4 Ηζ), 8.43 (1Η, d5 J=1.4 Hz). (3) (2-Trifluoromethyl-4-biphenyl)methanol 121199.doc -109- 200846322 [Chem. 85]

To a solution of methyl 2-trifluoromethyl-4-bibenzoate (215 mg) in THF (10 ml), lithium borohydride (50·? After the reaction mixture was heated to reflux for 15 hours, the reaction mixture was cooled to room temperature, water (3 ml) and 1 N hydrochloric acid (30 ml) were added and extracted with ethyl acetate (2x30 ml). The combined extracts were washed with saturated aqueous sodium hydrogen sulfate (30 ml) and dried over anhydrous sodium sulfate. The residue was purified using EtOAc (EtOAc) (EtOAc) (EtOAc) , 4.81 (2H, d, Bu 5·9 Hz), 7.27-7.48 (6H, m), 7.56 (1H, br d, J = 8.3 Hz), 7·76 (1H, br s) o Φ 1-( Third butoxycarbonyl)·5_[(2-trifluoromethyl-4-biphenyl)methoxy]porphyrin [Chem. 86]

Add 2-oxobutane hydrogen T alcohol (303 mg) in THF (6. 〇ml) to dibutoxide at room temperature in (2-difluoromethyl-4-biphenyl)methanol (303) Kedah)-5-based base. Duolin 121199.doc -110- 200846322 (340 mg), triphenylphosphine (380 mg), and DEAD (0.230 ml). After 2 days at room temperature, the mixture was concentrated under reduced pressure. EtOAc m. (9H, s), 3.08 (2H, t, J = 8.7 Hz), 3.99 (2H, br s), 5·11 (2H, s) 5 6·80 (1H, d, Bu 8·8 Hz), 6.84 (1H, s), 7.30-7.43 (6H, m), 7.62 (1H, d, J = 7.8 Hz), 7.70-7.86 (1H, br), 7·81 (1H, s). MS (ESI) m/z ·· 514 (m+H_isobutene)+ 0 (5) 5-[(2-Trifluoromethyl-4-indolyl)methoxy]anthracene B [化87]

Addition of 4 N at room temperature in 1-(t-butoxycarbonyl)-5-[(2-trimethyl-methyl-4-biphenyl)methoxy-yl]porphyrin (395 mg) Hydrochloric acid / M_ dioxane solution (5.0 ml). After the reaction mixture was stirred at room temperature for 2 hours, it was concentrated under reduced pressure, and the obtained residue was crystallized with hexane for 15 hr, then filtered and dried (vacuum, 4 (TC, 2 hr), The title compound (334 mg) was obtained. NMR (DMSO-d6) δ: 3.16 (2 Η, t, J = 7.8 3 &gt; 69 (2H, tj

Hz), 5.27 (2H, s), 7.01 (1H, dd, J=8 9 2 Hz), 7 16 OH, d, 2, 2 Hz), 7·28_7.35 (3H, m), 7 You 7 48 (4H, spider 7.76 (1H, d, J = 7.8 Hz), 7.89 (1H, s). 121199.doc -Ill - 200846322 MS (ESI) m/z : 370 (M+H)+. 6) (R)-3-(Tertidinoxycarbonylamino)-4_trioxy-4-[5-[(2-trifluoromethyl-4-biphenyl)methoxy]anthracene Porphyrinyl]butyric acid tert-butyl ester [Chem. 88]

5-[(2-Trifluorodecyl-4-biphenylyl)methoxy]porphyrin hydrochloride (342 mg) and Boc-D-Asp(OtBu)-OH (244 mg) in DMF ( In a suspension of 3.0 ml), EDOHCl (243 mg), HOBt (101 mg), and TEA (0.350 ml) were added at room temperature, and stirred for 3 days. The reaction mixture was concentrated under reduced pressure. ethyl acetate (30 ml), saturated aqueous sodium hydrogen carbonate (20 ml) and water (40 ml) ) Extract the aqueous layer. After the combined extracts were dried over anhydrous sodium sulfate, solvent was evaporated under reduced pressure. The resulting residue was purified using EtOAc EtOAc (EtOAc) NMR (CDC13) δ ·· 1·42 (9H, s), 1·43 (9H, s) 5 2·58 (1H, dd, J=15.6, 6·1 Hz), 2.83 (1H, dd, J =15.6, 7.6 Hz), 3·21 (2H, t, Hz), 4·26-4·42 (2H, m), 4.88-4.98 (1H, m), 5.12 (2H, s), 5.27 (1H ,d,J=10.0 Hz),6·83 (1H,dd,J=8.7, 2.7 Hz), 6·87 (1H,s),7·29-7·43 (6H,m),7·62 (1H, d, JU Hz), 7.80 (1H, s), 8.14 (1H, d, J = 8.8 Hz). MS (ESI) m/z ·· 641 (M+H)+ 〇121199.doc -112- 200846322 (7) (R)-3-Amino- 4_sideoxy_4_[5_[(2_3 Fluoromethyl_4•biphenyl)methoxy]吲°Dollin-1 -yl]butyric acid [Chemical 89]

Lu (R&gt;3-(Tertibutoxycarbonylamino)oxy-trifluoromethylbiphenyl)methoxy]indol-1-yl]butyric acid tert-butyl ester (470 mg) 4 n Hydrochloric acid n and a solution of a solution of dioxane (1 〇〇 ml) were added at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and then granulated with hexane. The solid which was collected by filtration (vacuum, EtOAc, EtOAc, EtOAc, EtOAc) , 3.02 (1H, dd5 J=17.5, 5·1 Ηζ), 3·18 (2H, t, J=8.1 Hz), 4.14-4.30 _ (2H, m)5 4.43 (1H? dd5 J=7.5? 5.1 Hz), 5.24 (2H? s), 6.92 (1H, dd, J=9.0, 1·8 Hz), 7.05 (1H, d, J=1.8 Hz), 7.29-7.34 (2H, m)5 7·42_7 · 48 (4H, m), 7.76 (1H, d, J = 8.1 Hz), 7.89 (1H, s), 8.01 (1H, d, J = 8.8 Hz). No observed CO2H and NH2(3H) 〇IR ( ATR) cnT1 : 3028, 1722, 1655, 1597, 1487, 1423, 1317, 1120, 1068, 700. MS (ESI) m/z : 485 (M+H)+. C26H24F3N204 (M+H)+HRMS ( ESI) Calculated value: 485.1688. Test 121199.doc -113 - 200846322 Setting: 48 5.1673. Calculated for elemental analysis of C26H23F3N2O4.1.0HC1.0.5H2O: c 58·93; Η, 4·75; C1,6·69; F,10·75; N, 5.29. Measured value: c 58_85; 4·65; Cl5 6.65; F, 10.75; N, 5.19. [Example 15] (R)-3-Amino-4- oxo-4·[5-[(1-phenyl-5-) Trifluoromethyl-1 H- 咐*嗤-3 -yl)nonyloxy-1 -yl]butyrate (1) 3-methyl-1-phenyl-5-trifluoromethane ki-iH·pyrazole [Chemical 90]

OH OH in a solution of phenylhydrazine (20 mmol) in tetrahydrofuran (25 mi), adding 5,5,5-trifluoro-4-(1-pyrrolidinyl)-2-pentene-2,4-diol (4·5〇g), stirred at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by chromatography. The resulting compound is dissolved in dichloromethane

Concentrated hydrochloric acid (100 μM) was added thereto, and the mixture was stirred at room temperature for 1 hour.清洗 Wash the reaction solution from a saturated aqueous solution of sodium hydrogencarbonate (50 ml), and extract the mixture with chloroform (2 〇ml×). The combined extracts are dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Column chromatography, obtained 庐 庐 侍 砀 (2.02 g). NMR (CDC13) δ : 2·36 (3H, s), 6·60 (1H 〇7 η

, S), 7·44·7.48 (5H m) ° , n, MS (ESI) m/z : 227 (M+H)+. (2) 3 - desert methyl-1 -phenyl-5 -trifluoromethyl _ 1H- ° than saliva 121199.doc -114- 200846322 [Chem. 91]

In 3-methyl-1-indolyl-5-difluoromethyl_ih_. N-bromobutaneimine (641 ml) and benzammonium peroxide (19 mg) were added to a solution of ruthenium (6,79 mg) in carbon tetrachloride (25 ml), and the mixture was 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 thus obtained was subjected to hydrazine column chromatography to give the title compound (3 i 5 mg). NMR (CDC13) δ: 4·52 (2H, s), 6·88 (1H, s) 5 7.47-7.50 (5H, m) 〇 MS (ESI) m/z: 305 (M+H)+. (3) 1-tert-butoxycarbonyl^-[(丨-phenyltrifluoromethyl)methoxy]porphyrin [Chem. 92]

Induction of noise by 3-bromomethyl-1-phenyl-5-trifluoromethyl-11--1? than saliva (3 05 1118) and 1_(dioxaoxyl)·5-radio σ Potassium carbonate (276 mg) was added to a solution of lin (141 mg) in DMF (2 ml), and the mixture was stirred at 60 ° C for 22 hours. After returning the reaction mixture to room temperature, the insoluble material was filtered, and the obtained filtrate was concentrated under reduced pressure. The obtained title compound (128 mg) was obtained by purifying the obtained product by using the succulent gel column chromatography (Bi〇tage 25S), 121199.doc-115-200846322 residue &gt; NMR (CDC13) δ ·· 1·55 (9H, s), 3·07 (2H, t, Ρ8·6Ηζ), 3·91· 4·03 (2Η, m), 5·1〇 (2Η, s ),6·81 (1Η,d,J=8.3 Ηζ), 6.84 (1H, s), 6.91 (1H, s), 7·47-7·51 (5H, m), 7·84-7.70 (1H , m) o MS (ESI) m/z : 460 (M+H) + 〇(4) 5-[(l_phenyl-5-trifluoromethyl-1H-pyrazol-3-yl)methoxy ]] 哚 哚 porphyrin hydrochloride [化93]

Dissolving 1-tert-butoxycarbonyl-5-[(1-phenyl-5-trifluoromethyl-1H-pyrazol-3-yl)decyloxy] σ 丨 丨 杀 ( (128 mg) 4 N hydrochloric acid / 1,4-di-p-burning solution (3 ml) was stirred at room temperature for 18 hours. The reaction mixture was concentrated to dryness crystals crystals crystals crystals NMR (DMSO-d6) δ : 3.17 (2H, t, J = 7.7 Ηζ), 3·71 (2H, t, J = 7.8 Hz), 5·18 (2H, s), 7·03 (1H, dd , J = 8.8, 2.5 Hz), 7·ι7 (1H, d, J=2.5 Hz), 7·26 (1H, s), 7·33 (1H, d, Hz), 7.51-7.55 (2H, m ), 7·61-7.57 (3H, m). MS (ESI) m/z: 360 (M+H)+. (5) (R)-3 -t-butoxymethylamino-4- oxo-4-[5-[(i-phenyl 121199.doc -116- 200846322 trifluoromethyl-1H- Butyr-3-yl)methoxy]indolyl]butyric acid butyrate [Chem. 94]

5-[(1-Phenyl-5-trifluoromethyl-1H-pyrazole-3-yl)methoxy]porphyrin hydrochloride (89 mg), B〇CD-Asp(〇tBu) TEA (0.157 ml) was added at room temperature for 14 hours at room temperature under a solution of EtOAc (EtOAc) (EtOAc). The reaction mixture was concentrated under reduced pressure. NMR (CDC13) δ : 1.42 (9Η, s)? 1.43 (9H, s), 2.58 (1H3 dd5 J=15.6, 5·9 Hz), 2·83 (1H, q, J=7.7 Hz), 3· 20 (2H, t, J = 8.4 Hz), 4·26-4·47 (1H, m), 4.88-4.98 (1H, m), 5.12 (3H, s), 5.28 (1H, d, J=9.0 Hz), 6.78-6.96 (3H, m), 7·47-7·51 (5H, m), 8.13 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 631 (M+H)+. (6) (R)-3-Amino-4-oxo-4-[5-[(1. phenylamino-5-trifluoromethyl-1H-indazol-3-yl)methoxy] Porphyrinyl]butyrate [Chem. 95] 121199.doc -117· 200846322

(R)-3-Tert-butoxycarbonylamino-yloxy-4-[5-[(1-phenyl-5-difluoromethyl]1Η-pyrazol-3-yl)methoxy], The porphyrin-indole base] butyrate tributyl hydrazine (85 mg) was stirred for 24 hours at room temperature with a solution of 4 hydrazine hydrochloride/1,4·bisindole (1 〇 nil). The reaction solution was concentrated under reduced pressure. Filtered in the resulting residue

The solid which precipitated with ether was dried under reduced pressure to give the title compound (74 mg). NMR (DMSO, d6) δ: 2·74 (1H, dd, J = 17.3, 7·7 Hz), 3.06 (1H, dd, J = 17.4, 4.9 Hz), 3.18 (1H, t, J = 8.3 Hz) ), 3.38 (1H, d, J = 6.6 Hz), 4.14 - 4.31 (2H, m), 4 · 46 (1H, dd, J = 7.4, 5.1 Hz), 5.13 (2H, s), 6.92 (1H, Dd, J=8.8, 2.7 Hz), 7.05 (1H, d, J=2.5 Hz), 7.25 (1H, s), 7·51-7·62 (5H, m), 8.02 (1H, d, J= 8 · 8 Hz) 0 IR (ATR) cnT1 : 2881,1724,1651,1595,1487,1429,1390, 1365, 1290. MS (ESI) m/z: 495 (M++H)+. HRMS (FAB) calculated for C23H22F3N4: 475.1593. Measured value: 475.1605 0 &quot;

Calculated for the elemental analysis of CnH21F3N4 〇*lHC1.0.75H2O: C, 52.68; H, 4.52; Cl, 6.76; F, 10.87; N, 10.68. Found: C, 52·61; H, 4.47; Cl, 7.16; F, 10.68; N, 10.70 ° [Example 16] (R)-3-Amino-4-oxo-4-[ 5-(2-Shishimyl-4-phenylene 121199.doc • 118- 200846322 oxy)porphyrin-1-yl]butyrate (1) (2-renylbiphenyl)methanol [ 96]

〇 9^

OH is added to 2-nitrobiphenyl_4_carboxylic acid (35 〇 mg) in THF (15 丨)

ΤΕΑ (3〇1 μ1) was ice-cooled. Add ethyl chloroformate (165 μΐ) and mix for 2 hours under ice cooling, (4) money, and obtain (4) liquid. (4) The nitrided surface (327 mg) was suspended in ethanol (43 ml) for ice cooling. Here, the first obtained filter solution was added dropwise in 5 minutes at room temperature for 5 minutes. To the reaction mixture, 1 N aqueous hydrochloric acid solution was added, and extracted twice with ethyl acetate, and the extract was washed with a 1 Nil oxidizing solution and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated to obtain a titled compound: (10) mg. (6H, NMR (CDC13) δ: 1.95 (1Η, s), 4.83 (2H&gt; ^ 7&gt;3〇.7.45 m), 7.60163 (1H, m), 7·87 (1H, d, J=〇7 Hz MS (ESI) m/z : 230 (M+H) + (2) 4- gas fluorenyl-2-nitrobiphenyl [Chemical 97]

Οι 121199.doc -119- 200846322 2-Nitro-4-biphenylmethanol (290 mg) in dichloroethane solution (15 ml), add chlorosulfite (458 μΐ), search at 50 ° C Mix for 3 hours and a half. After standing to cool to room temperature, the reaction mixture solution was concentrated. The residue was purified by flash column chromatography (yield: NMR (CDC13) δ : 4·66 (2H, s), 7.30-7.32 (2H, m) 5 7·41-7·46 (4Η, m), 7.64 (1Η, dd, 7.8 Ηζ), 7·89 (1Η,d,J=1.9

Hz) 〇 (3) 1-(Tertibutoxycarbonyl)-5-(2-nitrobiphenylmethoxy) gt; porphyrin [Chem. 98]

Add 4-chloromethyl-2-nitrobiphenyl (189 mg) to a DMF solution (5 ml) of 丨 二 氧基 让 _ _ 经 经 、 Potassium carbonate (132 _ m§) was stirred at 70 ° C for one night. After it was left to cool to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was extracted twice with ethyl acetate, and the mixture was washed with brine. The extract was dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by flash column chromatography (yield). NMR (CDC13) δ : 1·55 (9H, s), 3·07 (2H, t, J = 8.7 Hz), 3.98 (2H, s), 5.12 (2H, s), 6·77-6·83 (2H, m), 7·31-7·46 (7H, m), 7.65-7.93 (2H, m). (4) 5-(2-Nitrobiphenyl-4-yloxy) porphyrin hydrochloride 121199.doc -120- 200846322 [Chem. 99]

Add 4 N hydrochloric acid / 1,4-dioxane solution to 10 - 2 -butoxycarbonyl - 5 gas 2 · nitro - 4 - biphenyl oxy oxy porphyrin (280 mg) (10 ml ), stirred at room temperature for 1 hour. To the reaction mixture, diethyl ether was added, and the precipitated φ solid was filtered and dried to give the title compound (209 mg). J=7,8 Hz),3·71 (2H,t, NMR (DMSO-d6) δ : 3.18 (2H,t, J = 7.8 Ηζ), 5·30 (2H, s), 7·05 (1H , dd, 2.6, 8·7 Hz), 7.18 (1H, d, J = 2.6 Hz), 7.33-7.49 (6H, m), 7.60 (1H, d, J = 8.1 Hz), 7.83 (1H, dd , J=1.7,7·8 Hz),8·07 (1H,d,J=1.7 Hz), 11.16 (1H,s) 〇MS (ESI) m/z : 347 (M+H)+ (5 (R)-3-Tertoxycarbonylamino group·4_[5-(2-nitrobiphenylmethoxy oxy) porphyrin-buki]-4-oxobutanoic acid third Butyl ester [100]

Add Boc-D-Asp(〇tBu)-OH to a solution of 5-(2-nitro-4-biphenylmethoxy)porphyrin hydrochloride (200 mg) in DMF (10 ml) 181 mg), HOBt (106 mg), ED〇HC1 (150 mg), cesium (364 μΐ) were stirred at 121I99.doc -121 - 200846322. A saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate, and the extract was washed with brine. The extract was dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by flash column chromatography (yield: EtOAc). Employment R (CDC13) δ : 1.42 (9H, s), 1.43 (9H, s), .2.58 (1H, dd J=6.1, 15·7 Ηζ), 2·83 (1H, dd, J=7.8 , 15,7 Ηζ),3·21 (2H t

J=8.3 Hz), 4.30-4.39 (2H, m), 4·89-4·95 (1H, m), 5·ι4 (2H s), 5.27 (1H, d, J-9.3 Hz), 6.79- 6.86 (2H? m)5 7.26-7 47 (6H,m), 7.66 (1H,dd,J=1.3,8.0 Hz), 7.93 (1H,d,J=i 3

Hz), 8·14 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 618 (M+H). (6) (R)-3-Amino-4-[5-(2-nitro-4-biphenylmethoxy)porphyrin β1_yl]-4-oneoxybutyrate 101]

(R)-3-indenylbutoxyaminoamino 4-[5-(2-nitro'-biphenylj-ylmethoxy)indol-1-yl]-4-side oxygen A 3 N hydrochloric acid/1,4-disodium bromide solution (1 〇mi) was added to the third butyl butyrate (3 〇〇 mg) and stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the residue was suspended in diethyl ether. The solid was taken and dried to give the title compound ( 205 mg). (1H, dd, NMR (DMSO-d6) δ ·· 2.76-2.87 (1H, m), 3.04 121199.doc -122- 200846322 J = 5.8, 17·5 Ηζ), 3·18 (2H, t, J =8.3 Ηζ),4·17-4·45 (3H,m), 5·25 (2H,s), 6.92 (1H,dd,J=2.5,8.8 Hz),7.06 (1H,d5 J=2.5 Hz ), 7·34-7·49 (5H, m), 7.59 (1H, d, J = 7.8 Hz) 5 7·81 (1H, dd5 J=l.6, 8.0 Hz), 8.01-8.05 (2H, m), 8·52 (2H, s). IR (ATR) cm·1 : 2861, 1724, 1643, 1527, 1484, 1184. MS (ESI) m/z ·· 462 (M+H)+. HRMS (FAB) calcd for C25H24N3 〇6 (M+H)+: 462.1665; _ C25H24ClN3 〇 6.0.5H2O Elemental analysis calculated: C, 59.23; H, 4.97; C1,6·99; N, 8.29. Found: C, 59.25; H, 5.05; Cl, 7.5 5; N, 8 · 2 6 〇 [Example 1 7] (R)-3-Amino-4-[6-[2-(4-) Phenyl)ethoxy]. σ 朵 琳 小 ] -4- -4- -4- -4- -4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4-

To a solution of 6-hydroxyl-1H-«(1.00 g) in THF (5 mL), B.sub.2 C.sub.2 (1.45 g) and DMAP (5 〇 mg) were added and the mixture was shaken at room temperature. Concentrated anti-money 1 was purified by flash chromatography (Shanshan high-speed tube) to obtain the title compound (1.43 g). NMR (CDCl3) δ: l65 (9H) (H,S),6· 49 (1H, eg, J-3.8, 〇·6 Hz), 6.95 (1H, dd, J=8.7 2 3 7 w , 厶J Hz), 7.28-7.35 (1H, 121I99.doc -123 - 200846322 m),7·37-7·42 (3H,m),7.43-7.49 (4H,m) MS (ESI) m/z : 324 (M+H)+ o (2) 1-(di-butoxy基基基)-6-基。弓卜朵琳[化103]

Boc

7 eucalyptus li.43 g) was dissolved in ethanol (20 ml), and 5% Pd/C was added, and one side of the mixture was incubated with a mixture of cesium clock and burr. The catalyst was filtered, and the residue obtained by purifying the concentrated filtrate was prepared by using the silica gel rapid column screen (3) method (Shanshan high-speed pipe column L), and 一| a servant compound (1.15 g). NMR (CDC13) δ : 1.55 (9Η, s)5 2.98 (2H5 t5 J==8.8 Hz)5 3.97 (2H,t,J = 8.3 Hz),5·20-5·71 (1H,m),6 · 43 (1H, dd, J=8.i 2·2 Hz), 6.96 (1H, d, J = 8.5 Hz), 7.55-7.34 (1H, m). ' MS (ESI) m/z : 236 (M+H) + 0 (3) 6-[2-(4-biphenylyl)-2-oxooxy]ethoxyl-1 - (t-butoxy基基基) 吲哚琳[化104]

1-(Tertibutoxycarbonyl)-6-hydroxyporphyrin (400 m§), 2-bromophenylacetophenone (515 mg), potassium carbonate (47〇nig), E&gt;MF (10) Ml) mixed 121199.doc -124- 200846322, at 7 (TC), mix 12 胄. The reaction solution is brewed with acetic acid (2 稀释 called dilute, the organic layer is washed with saturated brine, dried (anhydrous sulphuric acid) After the residue, the solvent was evaporated, and the obtained residue was purified using silica gel column chromatography (yield: s) to give the title compound (487 mg). (2 Η, t, J=8, 7 Hz), 3.98 NMR (CDC13) δ ·· 1·54 (9H, s), 3.01 br s), 7, 02 (1H, d, (2H5 m)? 7.61-7.65 (2H5 t5 J-8.7 Hz) 5 5.27 (2H? s), 6.56 (2H? J-8.3 Hz), 7.38-7.43 (1H, m), 7.45-7.51

(2H,m), 7.71 (2H,d,J=8,5 Hz),8·08 (2H,d,J = 8.3 Hz) MS (ESI) m/z : 430 (M+H)+. (4) 6-[2-(4-Biphenyl)-2-hydroxy]ethoxy (Di Lin [Chem. 105]

Dissolve 6-[2-(4-biphenyl)_2_sideoxyethoxy]sodium (tert-butoxymethyl)t-lin (478 mg) in ethanol (10), add 5% Butoxy group

Γ (500 ΙΤ 授 授 授 授 授 授 授 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500邮.冋疆卿13) δ: 154(9^0 83(ih,s), 3gi ie t J=8.5 Hz), 3.93-4.20 (4H, m), 5.15 (1H, dt, 6.52 (lH, dd5J) =B.1,2.2Hz)}7〇1(1H ^j=8i^ OH, tt, 1=7.07, 1.2 Hz), 7.42-7.47 (2H, m), 7.52 (3H d 121199.doc -125- 200846322 J=8.3 Hz), 7.63-7.58 (4H, m) MS (ESI) m/z : 432 (Μ+Ή)+ o (5) 6-[2-(4-biphenyl)ethoxy ]_;[_(Tertibutoxycarbonyl)porphyrin [Chem. 106]

Dissolve 6-[2-(4-biphenyl)_2-hydroxy]ethoxy-1β(t-butoxycarbonyl) • porphyrin (402 mg) in dichloromethane (10 ml). Under stirring, simmer. (; Add ΤΕΑ (313 μΐ), then add trifluoroacetic anhydride (156, stir under the same vein for 12 hours. After concentrating the reaction solution, add ethyl acetate (2 〇 (5) 丨), 10% Pd/C (5 〇0,mg) was subjected to contact hydrogenation for 3 days. The mixture was filtered, and the filtrate was concentrated. The residue was purified using silica gel column chromatography (m. m/z : 416 (M+H) + (6) 6-[2-(4-biphenylyl)ethoxy]-carboline hydrochloride # [化1〇7]

Add 4 N hydrochloric acid n,4•diazane solution to 6-[2-(4-biphenylyl)ethoxy H (tertiary butoxy)-based tetralin (198 mg) (1〇(6)) , stir for * hours. The title compound (167 mg) was obtained. &amp; I21199.doc -126- 200846322 MS (ESI) m/z : 316 (M+H)+. (7) (R)-4-[6-[2-(4-Biphenylyl)ethoxy], porphyrin-1-yl]-3-(t-butoxycarbonylamino)-4- Tributyl butyl acetobutyrate [Chem. 108]

6-[2-(4-Biphenyl)ethoxy]• porphyrin hydrochloride (216 mg) and Boc-D_Asp(OtBu)-OH (213 mg) were dissolved in DMF (10 ml) EDC.HC1 (177 mg), HOBt (126 mg), and cesium (428 μΐ) were added and stirred for 12 hours. The reaction mixture was diluted with ethyl acetate (200 ml), and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel flash column chromatography (yield). NMR (CDC13) δ : 1.37-1.46 (18H? m)5 2.56 (1H? dd? _ 1=15.62, 6.10 Hz)? 2.82 (1H5 dd5 J=1 5.875 8.06 Hz)? 3.07- 3.17 (4H,m) , 4.15-4.42 (4H,m)5 4.92 (1H,q,J=7.3 Hz), 5·23 (1H,d,J=9,0 Hz),6·62 (1H,dd,J=8.3, 2·4 Hz), 7.05 (1H, d, Bu 8·3 Hz), 7·32-7·37 (3H, m), 7_4〇_7·46 (2H, m), 7.51-7.55 (2H, m), 7.60-7.56 (2H, m), 7.91 (1H, d, 2 2 Hz) 〇MS (ESI) m/z : 587 (M+H) + 〇W (R) 3-Amino-4 -[6-[2-(4-biphenyl)ethoxyh-porphyrin small group]_4_ 121199.doc -127- 200846322 Sideoxybutyrate hydrochloride [化109]

OH will (8)-4-[6-[2-(4-diphenyl)ethoxy] oxime (4) small base 3_(t-butoxyaminoamine oxobutyric acid third TS|( The mixture was mixed with a solution of 4 N hydrochloric acid / M-disaki (10 ml), and the mixture was stirred. NMR (CDC13) δ : 2.71-3.22 (6H, m), 3.61-4.32 (4H, m), 4·77-4·97 (1H, m), 6.40-6.53 (1H, m), 6.79- 6·93 (1H,m), 7·15-7·49 (9H,m), 7.64-7.77 (1H,m),8·45-8·11 (4H,m) MS (ESI) m/ z: 431 (M+H)+. Calculated by HRMS (ESI) for C26H27N204 M++H: 43i 197〇8. Measured value 431.19449. Calculated value of elemental analysis of C26H26N204.HCBu1·5Η20·· c,63.22 ; Η,6·12; N,5·67. Measured: C, 63.51; H, 5.86; N, 5.57. [Example 18] (11)-3-Amino-4-[4-[2- (4-biphenyl)ethoxy]-11-bambolin-1 -yl]-4-oxobutyric acid (1) 4-[2-(4-biphenyl)-2-oxo Ethyloxy-1-(tert-butoxycarbonyl) hydrazine [110] 121199.doc -128- 200846322

OH

0Q

Be 1-(Secondoxycarbonyl)_4-hydroxyporphyrin (482 mg), 2-bromo-4, phenylacetophenone (620 mg), potassium carbonate (566 mg), DMF (10) Mix with ml) and stir at 70 C for 12 hours. The reaction mixture was diluted with ethyl acetate (2 mL), and then evaporated. Purification by gelatin flash column chromatography (Shanshan high-speed column L) was carried out to obtain the title compound (621 mg). ISiMR (CDC13) δ : 1.55 (9H, s), 3·11 (2H, t, 1 = 8.8 Ηζ), 4·00 (2H, t, J = 8.8 Hz), 5·30 (2H, s), 6·42 (1H,d,J=8'5 Hz),7·09 (1H,t,J=7.9 Hz), 7.39-7.44 (1H,m), 7.45-7.51 (2H,m), 7.61- 7.65 (2H,m),7·71 (2H,d5 J=8.3 Hz), 8_07 (2H,d, J=8.3 Hz). MS (ESI) m/z: 430 (M+H)+. (2) [2-(4-Biphenylyl)ethoxy]-l-(t-butoxycarbonyl)porphyrin [Chem. 111]

Boc was dissolved in ethanol (20 ml) by 4-[2-(4.biphenyl)-2-oxooxy]ethoxytoxybutoxy) sigma 13 lin (621 nig). 5% Pd/C (620 mg) was added and contact hydrogenation was carried out for 20 hours with stirring. Filtering touches I21199.doc -129- 200846322 The media is indifferent. The residue obtained was purified by EtOAc (EtOAc) (EtOAc) ^ &amp; main 匪 (CDCl3) δ : h55 (9H, s), 2 (2H, t, J = 8.7 Hz), 3 12 (2H, t, J = 6.8 Hz), 3.97 (2H, t, J =8.5 Hz), 4.23 (2H, t, J=6.8

Hz), 6.49 (1H, d, J=8.8H, m), 7.46-7.40 (2H, m), 7.60-7.52 (4H,m) o

MS (ESI) m/z: 416 (M+H)+. (3) 4-[2-(4-Biphenyl)ethoxy]indole hydrochloride [Chem. 112]

Add 4-N-hydrochloric acid/1,4-dioxene to 4-[2-(4-phenyl)ethoxy]-1-(t-butoxymethyl), 1[1 lin (411 mg) A solution of the alkane (10 ml) was stirred for 12 hours. The reaction mixture was concentrated to dryness crystals crystals crystals NMR (DMSO-cU) δ"· 3.03 (2H, t, J = 7.8 Hz), 3.09 (2H, t, J = 6.6 Hz), 3·68 (2H, t, J = 7.9 Hz), 4·30 (2H, t, J = 6.7 Hz), 6·94 (1H, d, J = 7.8 Hz), 7.02 (1H, d, J = 8.3 Hz), 7·28-7·37 (2H, m), 7.39-7.48 (4H, m), 7.68-7.59 (4H, m). MS (ESI) m/z: 316 (M+H)+. (4) (R)-4-[4-[2-(4·Biphenyl)ethoxy]porphyrin-1-yl]-3-(t-butoxycarbonylamino)-4- Tributyl butyl acetobutanoate 121199.doc -130- 200846322 [Chem. 113]

Dissolving 4-[2-(4-biphenylyl)ethoxy]1 porphyrin hydrochloride (320 mg) and Boc-D-Asp(0-tBu)-0H (316 mg) in DMF (10) In ml), _ EDOHCl (262 mg), HOBt (184 mg), hydrazine (380 μΐ) were added and stirred for 12 hours. The reaction mixture was diluted with ethyl acetate (200 ml), and the organic layer was evaporated. The residue was purified using EtOAc (EtOAc) (EtOAc) s), 2.56 (1H, dd, J = 15.9, 5.9 Ηζ), 2·82 (1H, dd, J = 15.9, 7·6 Hz), 3.07-3.15 (4H? m)5 4.20-4.41 (4H m)3 4.87-4.97 (1H5 m)5 5.27-5.34 (1H,m),6·59 (1H,d,J=8.3 Hz),7·14 (1H,t,J=8.2 Hz), 7.31 -7.37 (3H, m), 7.43 (2H, t, J = 7.3 Hz), 7·60-7·52 (4H, m), 7.81 (1H, d, J = 8.1 Hz) MS (ESI) m /z : 587 (M+H)+ (5) (R)-3-Amino-4_[4-[2-(4-biphenyl)ethoxy]porphyrin _; μ group]· 4_ sideoxybutyrate hydrochloride [111] 121199.doc -131 - 200846322

(R)-4-[4-[2-(4-Bylphenyl)ethoxy], porphyrin+yl]_3·(t-butoxycarbonylamino)-4-oxobutanoic acid The third butyl ester (170 mg) was mixed with 4 Ν salt 酉 / / 1,4-dioxane solution (1 〇 ml) and stirred for the next day. After concentrating the reaction mixture, the solid obtained by filtration was added with chloroform and hexanes, and dried to give the title compound (18 mg). MS (ESI) m / z: 431 (M+H). 〇 [Example 19] (R)-3-Amino- 4 </ RTI> </ RTI> ethoxy-4-[5·[2-(4-phenyl- 5-trimethylmethyl-2-indolyl)ethyl]indol-1-yl]butyrate (1) 1-(t-butoxycarbonyl)-5-methoxycarbonyl- 1Η-吲哚[化115]

DMAP (140 mg) and bOC2(R) (2.74 g) were added at room temperature in a solution of 5-methoxycarbonyl-l-indole (2·〇〇g) in Thf (50 ml). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified using EtOAc EtOAc (EtOAc) (EtOAc (EtOAc) (EtOAc) (302302302302302302302302302302302302302302302302302302302302302302 3.8 Ηζ),7·64 (1Η,d,J=3.8 Ηζ),8.01 (1Η,dd,J=8.8,1.7 121199.doc -132- 200846322 Ηζ),8·18 (1H,d,J=8.8 Hz), 8.30 (1H, d, J = 1.7 Hz). MS (ESI) m/z: 276 (M+H) + 〇 (2) 1-(decandyoxy).弓卜朵琳 [化116]

Add 5〇/〇pd/ at room temperature to a solution of 1-(t-butoxycarbonyl)-5-methoxycarbonyl-1H-indole (31〇g) in ethyl alcohol (50 ml) cQ.oo g). After stirring for 15 hours at room temperature under a hydrogen atmosphere, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using EtOAc (EtOAc) elut elut elut elut elut elut elut elut elut elut elut 8.5 Hz), 3,89 (3H, s), 4.03 (2H, t, J = 8.5 Hz), 7.80-7.83 (1H, m), 7·89 (1H, d, J = 6.8 Hz). MS ( ESI) m/z : 278 (M+H)+ (3) 1-(t-butoxycarbonyl)_5-hydroxymethylporphyrin [Chemical 117]

In a solution of 1 -(t-butoxycarbonyl)-5-nonyloxycarbonyl porphyrin (627 dichloromethane (10 ml), _78. 1.0 N toluene solution) (5·65 ml). After stirring for 3 minutes on _78, add saturated gasification to the solution of the reaction solution in the counter 121199.doc -133- 200846322 (〇· 8 〇功1 The mixture was warmed to room, w ^ with diethyl ether (60 ml), and stirred for 30 minutes. After stirring for 3 minutes with anhydrous magnesium sulfate, it was filtered through celite and purified by silica gel column chromatography (Biotage 40M). The filtrate was concentrated to dryness crystals crystals crystals crystals crystalssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss 8.8 Hz), 3.98 (2H, t, J = 8.8 Hz), 4.61 (2H, d, J = 5 9 Hz), 7·14 (1H, d, J=8, 3 Hz), 7.17 (1H, s ),7·23-8·〇〇(1H, _ br) MS (ESI) m/z : 232 (M-OH), (4) 1 -(T-butoxymethyl)-5-A醯基n引0朵琳[化118]

In a solution of 1-(t-butoxycarbonyl)-5-hydroxyindenyl porphyrin (39 〇mg) in φ TMF (10 ml), add salt (360 mg) and oxidize at room temperature. (820 mg). After the reaction mixture was stirred at room temperature for 5 hours, it was added with emulsification (820 mg). After stirring for 24 hours, the reaction mixture was filtered over Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using EtOAc EtOAc (EtOAc) NMR (CDCI3) δ ·· 1.59 (9H, s), 3·15 (2H, t, J = 8.8 Hz), 4,06 (2H, t, J = 8.8 Hz), 7.60-8.10 (ih, br) , 7.68 (1H, s), 7·69 121199.doc -134- 200846322 (1H, d, J = 6.8 Ηζ), 9·86 (1H, s). MS (ESI) m/z: 248 (M+H)+. (5) 1-(Tertibutoxycarbonyl)-5-[(E)-2-(4-phenyl-5-trifluoromethyl-2-thienyl)vinyl]°哚哚琳119]

Triethyl phosphite (650 mi) was added to 150 at room temperature in 5-(chloroindolyl)-3-phenyl-2-(trifluoromethyl)thiophene (500 mg). Stir under the arm for 5 hours. After cooling the reaction mixture to room temperature, it was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (Biotage 40M) to obtain triethyl phosphite and (4-phenyl-5-trifluoro). Methyl-2-thienyl)decylphosphonic acid diethyl hydrazine 3:1 mixture (1.48 g). A solution of this mixture (545 mg) in THF (3.0 ml) was added dropwise to THF (55%) (65 mM) of thf (3. After stirring for 30 minutes under the armpit, THF (3. 〇ml) was added (3,10-butoxy)--5-mercapto-porphyrin (3 10 mg). After stirring at room temperature for 2 hours' Water (1 〇^1), a saturated aqueous solution of ammonium chloride (20 ml), and ethyl acetate (30 ml) were added to the mixture, and the aqueous layer was extracted with ethyl acetate (20 ml). After washing with a saturated aqueous solution of sodium chloride (3 ml), the solvent was evaporated to dryness eluted with anhydrous sodium sulfate. The residue was purified using purified gel column chromatography (Biotage 40M) to give the title compound. Mg) 121199.doc -135- 200846322 NMR (CDC13) δ : 1.58 (9Ή, s), 3.12 (2H, t, Hz), 4.01 (2H, t, J = 8.8 Hz), 6.97 (1H, d, J = 15.9 Hz), 6.99 (1H, s), 7.05 (1H, d, J = 15.9 Hz), 7.22 - 7.33 (2H, m), 7 · 36 - 7 · 47 (5H, m) , 7.50-8.03 (1H, br) MS (ESI) m/z: 372 (M+H-Boc) + (6) 1-(T-butoxycarbonyl)-5-[2-(4- Phenyl-5-three Methyl _2- thienyl) ethyl] indoline [Formula 120]

In the case of 1-(t-butoxycarbonyl)-5-[(E)-2-(4-phenyl-5-trifluoromethyl-2-11secenyl)vinyl]° To a solution of 103 mg) of acetic acid in ethyl acetate (3 · 〇ml), 5% Pd/C (100 mg) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere, and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (l. This compound was used in the subsequent reaction without further purification. NMR (CDC13) δ : 1.54 (9H, s), 2·94 (2H, t, J = 8.6 Hz), 3.06 (2H, t, J = 8.6 Hz), 3·10 (2H, t, J = 7.1 Hz), 3.97 (2H, br t, J = 7.1 Hz), 6.75 (1H, d, J = 1.2 Hz), 6·95-7·〇5 (2H, m), 7 33e 7· 43 (5H, m), 7·50-7·95 (1H, br). (7) 5-[2-(4-Phenyl-5-trifluoromethyl-2-thienyl)ethyl]porphyrin hydrochloride [Chem. 121] 121199.doc -136· 200846322

Add to 1-(t-butoxycarbonyl)-5-[2-(4-phenyl-5·tris-methylpyranyl)ethyl]porphyrin (106 mg) at room temperature 4 n Hydrochloric acid / l, 4 - ^ decane solution (5.0 ml). After the mixture was stirred at room temperature for 2 hr, the title compound (1 〇〇 mg) was obtained. This compound was used in the subsequent reaction without further purification of iron.

NMR (DMSO-d6) δ ·· 3·01 (2H,t,J=8.1 Ηζ), 3·14 (2 jerseys, it 'J=8.1 Hz), 3·18 (2H, t, J=7.4 Hz ),3·67 (2H,t,J=7/ Speaking)' π 0 / 7.08 (1H, s), 7·18-7·30 (2H, m), 7·30-7.51 (5H, m) ,1〇· 11·00 (1H,br) 〇MS (ESI) m/z : 374 (M+H)+. (8) (R)-3-[(Tertibutoxycarbonyl)amino]-4·Sideoxy-4_[5-[2"4-yl-5-trifluoromethyl-2-thienyl) Ethyl]porphyrin-1-yl]butyric acid 彡Ί [化122]

Add salt (100 mg) and B〇c_D-Asp(OtBu)-OH (7 (KO mg) in DMF (3.0 ml), add Ed〇HC1 (63.〇mg), HOBt at room temperature. 44.5 mg), and τεΑ (0·152 ml), stirred for 15 hours. The reaction mixture was concentrated under reduced pressure of 121199.doc -137-200846322, and ethyl acetate (30 ml) and saturated hydrogen carbonate were added to the obtained concentrate. The sodium aqueous solution (2 〇^1) and water (40 ml) were separated, and the aqueous layer was extracted with ethyl acetate (20 ml). The combined extracts were dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by silica gel chromatography eluting to afford the title compound (33.7 <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> NMR (CDC13) δ: 1·42 (9H, s ), 1.43 (9H, s), 2.58 (1H, dd, J = 15.6, 5.9 Ηζ), 2·83 (1H, dd, J = 15.6, 7·3 Ηζ), 2·97 (2H, t, J =7.6 Hz), 3.11 (2H, t, J = 7.6 Hz), 3.20 (2H, t, J = 8.3 Hz), 4.26-4.42 (2H? m)? 4.87-4.98 (1H? m)? 5.27 (1H d? J=9.5 Hz),6·67 (1H,s),7·01-7·07 (2H,m),7·30-7·42 (5H,m), 8.12 (1H,d, J = 7. 8 Hz) MS (ESI) m/z : 533 (M+H-isobutene x 2) + (9) (R)-3-Amino-4-yloxy-4-[5-[2- (4-phenyl-5-trifluoromethyl-2-thienyl)ethyl]porphyrin-1-yl]butyrate

(R)-3-[(Tertibutoxycarbonyl)amino]-4-oxo-4-[5-|&gt;(4-phenyl-5-trifluoromethyl-2-thiophene Add ethyl 4-hydrochloride / 1,4-dioxane solution (5.0 121199.doc -138-) at room temperature in the third ethyl butyrate (33.7 mg) 200846322 ml). After the mixture was stirred for 5 hours at room temperature, the title compound (20.5 mg) was obtained. NMR (DMSO-d6) δ : 2.73 (1H, dd, J = 17.6, 7·8 Hz), 2.97 (2Η, t, J=7.7 Ηζ), 3·05 (1Η, dd, J=17.6, 5· 3 Ηζ), 3·16 (4Η, t5 J=7.9 Ηζ), 4.13-4.32 (2Η, m), 4·45 (1Η, t, J=6.2 Ηζ), 7·07 (1H, s), 7.12 (1H, d, J = 7.8 Hz), 7·23 (1H, s), 7.36-7.52 (5H, m), 7·99 (1H, d, J = 8.3 Hz). _ MS (ESI) m/z : 489 (M+H)+. HRMS (FAB) for C25H22F3N203 (M+H)+: 489.1460. Found: 489.1462. [Example 20] (R)-3-(N,N-Dimethylamino)-4-o-oxy-4-[5·(2-trifluoromethyl-4-biphenyl)methoxy吲哚]吲哚琳-1 —基]丁丁酸化[化124]

(R)-3-Amino-oxyl-4-[5-(2-trifluoromethylbiphenyl)methoxy]indol-1-yl]butanoate (1〇〇 In a methanol solution of mg), a 37% aqueous solution of formalin (0.144 ml), acetic acid (〇.5 mi), and sodium cyanohydride (24·1 mg) were added at room temperature, and the mixture was stirred for 14 hours. Water was added to the reaction mixture and stirred for 30 minutes, and then extracted with a methanol/chloroform mixed (1%) solution. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate (121199). After filtering anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure. The residue obtained by thin layer chromatography and deuteration is obtained as (r)_3_(n,n-didecylamino)_4_sideoxy 4-[5-(2 difluoromethyl_4_ Biphenyl)methoxy p-porphyrin _丨_yl]butyric acid (83 mg) 〇(R)_3-(N,N-dimethylamino)_4_sideoxy·4_[5_( 2-Trifluoromethyl-4-phenyl)methoxy]porphyrin-indole-butyric acid (83 mg), 4 N hydrochloric acid / 1 〆-dioxane solution (2 ml) at room temperature After stirring for 3 minutes, concentration was carried out at minus one. Ether was added to the residue obtained, and the precipitated solid was filtered to give the title compound (78 mg). NMR (DMSO-d6) δ : 2.82 (6H, s), 3.09 (2H, d, J = 6.6 Hz), 3.19 (2H, t, J = 7.4 Hz), 4.21. (lH, dd, J = l8.0 , 9.7 Hz), 4.42-4.49 (1H, m), 4.60 (1H, t, J = 6.1 Hz), 5.23 (2H, s), 6.91 (1H, dd, J = 8.8, 2.7 Hz), 7.07-7.03 (1H,m),7·34-7·28 (2H, m), 7.39-7.46 (5H,m),7·76 (1H,d,J=7.8 Hz),7.88 (1H,d, J= 1.2 Hz), 8.03 (1H, d, J = 8.8 Hz). IR (ATR) cm 1 : 297, 2929, 2669, 2598, 1720, 1645, 1597. MS (ESI) m/z: 513 (M+H)+. Calculated for the elemental analysis of L25H1.: L5H1::::::::::::::::::::::::::::::::::::::::::::::::::::: Found: C, 57·32; H, 4·99; Cl, 7.85; F, 9.54; N, 4.99. [Example 21] (R)-3 -Amino-4.Sideoxy-4-[7-[(4-phenyl]-methyl-3-indolyl)methoxy]_2,3- Dihydrophenylhydrazine [1,4] Noise] Butyrate (1) 4-(Secondoxy-Wilyl)-7-3⁄4yl-2,3-dioxaquinone [1,4 ]^7号嗓121199.doc -140- 200846322 [化125]

1,4-, 2,3-dihydro-7-hydroxy-4H-benzoquinone [1,4]pyridazine [EUr. j. Med. Chem·, 1999, 34, 903-917·] (151 mg) Water (2.5 ml), sodium hydrogencarbonate (252 mg), and b〇c2 (327 mg) were added to a dioxane solution (25 ml), and stirred at room temperature overnight. Water was added to the reaction mixture solution, and after dilute release, the mixture was extracted twice with ethyl acetate, and the extract was washed with brine. The extract was dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by flash column chromatography elution elution elution elution elution elution elution elution elution elution elution elution elution elution elution elution elution elution -4.23 (2H, m), 4.88 (1H, s), 6·36-6·39 (2H, m), 7.58 (1H, s). MS (ESI) m/z: 252 (M+H)+. (2) 4-tert-butoxycarbonyl-7_[(4_phenyl-5·trifluoromethyl·2·thienyl)methyl oxydihydrophenylhydrazine [1,4] noisy [Chemical 126 ]

2- gassulfonylphenyl-5-trifluoromethylthiophene (129 mg) to give 4·t-butoxycarbonyl-7-trans-yl-2,3-dihydrophenylhydrazine [μ]pyridazine Potassium carbonate (i6i mg) was added to a solution of (117 mg) in dmf (5 mi) at room temperature. After stirring at 60 ° C for 6 hours, the reaction mixture was concentrated under reduced pressure. chloroform (1 mL) and water (1 〇ml) were added for liquid separation and extracted with chloroform (5 mix 2) Water layer. The combined extracts were dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified using EtOAc EtOAc (EtOAc) NMR (CDC13) δ : 1.53 (9H? s)5 3.83 (2H5 t? J=4.5 Hz)? 4.24 (2H, t, J=4.5 Hz), 5·17 (2H, s), 6·51 (1H ,d,J=2.9 Hz), 6.55 (1H, dd, J=9.3, 2.9 Hz), 7·06 (1H, br s), 7.43·7·38 (5H, m), 7·68 (1H, Br s). (3) 7-[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy]_2,3-dihydrophenylhydrazine [1,4] oxazinidine hydrochloride [Chemical 127]

4·t-butoxycarbonyl_7_[(private phenyl·5_trifluoromethyl_2_thienyl)methoxy]-2,3-dihydrophenylhydrazine, 4], azine ( 226, the present dioxane (ι〇ml), in the solution, 4 N hydrochloric acid / hydrazine, 4-dioxane solution (ml) was added at room temperature. After stirring for 14 hours, the solvent was distilled off under reduced pressure. Diethyl ether (3 ml) was added to the residue, and the obtained crystals were evaporated to dryness eluted with diethyl ether. 45 (2H, t, J = 4.64 Hz), 4.29 (2H, t, J 4.64 Hz), 5·35 (2H, s), 6·68·6·64 (2H, m) 5 7·05 (1H , d 121199.doc -142 - 200846322 J = 8.79 Ηζ), 7·36 (1H, s), 7.50-7.41 (5H, m) (4) (R)-3-(t-butoxycarbonyl) Amino-4-oxo-4-[7-[(4-phenyl-5-trimethylmethyl-2-thienyl)decyloxy]-2,3-dihydrophenylhydrazine [1,4] ]pyridazin-4-yl]butyric acid tert-butyl ester [化128]

DIEA (59 μM), HOBt (64.1 mg) and EDOHC1 (90.9 mg) were added to a solution of Boc-D-Asp(OtBu)-OH (106 mg) in DMF (2 ml). After the reaction mixture was stirred for 1 min, 7-[(4-phenyl-5-trifluoromethyl-2-phenylphenyl) decyloxy]-2,3-dihydrophenylhydrazine was added at room temperature. [1,4] A solution of oxazine hydrochloride (156 mg), DIEA (100 μM) in DMF (1 ml). After stirring for 14 hours, the reaction mixture was concentrated under reduced pressure, and then chloroform (10 ml) and water (5 ml) were added to separate the mixture, and the aqueous layer was extracted by gas (5 mix 3). The extracts were combined, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by silica gel flash column chromatography (Biotage 25S) and the title compound (73.4 mg) was obtained. NMR (CDC13) δ : 1·46,1·39 (20H,m),3·70 (1H,s),4 4〇_ 4.22 (3H? m), 5.18 (2H5 s)5 5.37 (1H, d , J = 9.02 Hz) 5 6.60 · 6·51 (2H, m), 7.07 (1H, s), 7.44 - 7.38 (6H, m). (5) (R)-3-Amino-4-oxo-4-[7-[(4-phenyl-5-trifluoromethylthiophenyl)methoxy]-2,3-dihydro Benzoquinone [1,4]oxazin-1-yl]butyrate 121199.doc -143- 200846322 [Chemical 129]

Ηη2 ο HCI in (R)_3_(2,4-butoxycarbonyl)amino-4-oxoyl-4-[7-[(4-phenyl-5-trifluoromethyl-2-thienyl)- a solution of oxy]_2,3-dihydrophenylhydrazine[14]pyridazinyl]butyric acid tert-butyl ester in 1,4-dioxane (〇·5 ^1), added 4 N at room temperature Hydrochloric acid / 1,4 · dioxane solution (2. 〇mi). After the reaction mixture was stirred for 24 hours, a 4 n hydrochloric acid / 1,4-dioxane solution (2.0 ml) was added at room temperature, and the mixture was further stirred for 24 hr. DMSO (5 ml) was added to the obtained residue, and the insoluble matter was removed, followed by purification by high performance liquid chromatography (NOMURA Develosil Combi-RP-5). The title compound (13 · 9 m g ) was obtained by collecting the collected cold liquid stems.

NMR (CD3OD) δ : 2·37 (1H, d, J=13, 2 Ηζ), 2·61 (1H, d, J = 13.2 Hz), 4·41-3·66 (5H, br m), 5.30 (2H, s), 6.57 (2H s), 7·3 1 (1H, s), 7.45-7.35 (6H, m), 7·8 1 (6H, br s). MS (ESI) m/z: 507 (M+H)+. Calculated for elemental analysis of C24H2205N2F3S.HC1: c, 53.09·h

4·08; N,5·16; S, 5.91. Found: C, 53.19; H, 4.36; N 5.01; S, 5.95 〇 [Example 22] (R)-3-(N,N-dimethylamino sideoxy_4_[5_[(4_ Phenyl-5-trifluoromethylthienyl)methoxy]-porphyrin-1-yl]butyric acid [Chem. 130] 121199.doc •144- 200846322

〇H OH will be (R)-3-amino-4-yloxy-4-[5-[(4_phenyl-5•trifluoromethyl 2 喧 phenyl)methoxy]-fluorene Porphyrin _; μ-based] butyrate (1 〇〇 mg) was dissolved in THF (10 ml), 37% aqueous formaldehyde solution (77 μM) was added with stirring, followed by the addition of sodium dihydrogenate (127 mg), continuous mixing for 6 hours. After adding water (50 ml) to the reaction mixture, it was neutralized with saturated aqueous sodium hydrogen carbonate (50 ml), and extracted with 20 〇 / 〇 methanol / chloroform (2 x 2 〇〇 ml). After the extract was dried (anhydrous sodium sulfate), the solvent was evaporated. Dichloromethane and hexane were added to the obtained residue, and the obtained solid was filtered, and dried to give the title compound (99 mg). NMR (CDC13) δ : 2·61 (6H, s), 2.75-2.84 (2H, m), 3.18 (2H, t, J = 8.3 Hz), 4.12-4.24 (2H, m), 4·29-4 ·42 (1H,m),5·19 (2H,s),6·76-6·88 (2H,m), 7·05 (1H,s),7.33-7.43 (5H,m), _ 8.12 (1H, dd, 1 = 25.9, 17.1 Hz). MS (ESI) m/z: 520 (M+l): </RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Found: 5 19.15394. Calculated value of elemental analysis of C26H25F3N204S.0.5H20 · c, 59·19; H, 4, 59; F, 10·80; N, 5.31; S, 6.08. Found: c, 59.07; H, 4·59; F, 10.70; N, 5·22; S, 6.11 〇 [Example 23] 3-[(N-ethyl-N-fluorenyl)amino]- 4-Sideoxy-4_[5_[(4-Benzene 12I199.doc -145- 200846322 yl-5-difluoromethylnonphenyl)methoxy]indolyl]butyrate (1) 3-[(N-Hydroxycarbonylmethyl)amino]-4-oxo-4-[5-[(4-phenyl-5-trifluorodecyl-2-thienyl)methoxy ] porphyrin-1-yl]butyric acid tert-butyl ester [Chem. 131]

In 5-[(4-phenyl-5-trifluoromethyl-2-phenyl)methoxy]. Bow|Nasal hydrochloride (100 mg), benzyloxycarbonyl-MeAsp (OtBu) (126 mg), EDOHC1 (70.0 mg), HOBt (49.2 mg) in DMF (3 ml) at room temperature TEA (0.169 ml) was added and stirred at room temperature for 23 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) NMR (CDC13) δ : 1·40 and 1.43 (total 9H, per s, guanamine isomer), 2·45-2·56 (1Η, m), 2.87 and 2_89 (3 Η, per s, guanamine Isomers), 2.94-3.29 (4H, m), 3.65-4.33 (2H, m), 5·02-5·53 (4H, m), 6.76_6.85 (2H, m), 7.06 (lH, s), 7.33_7.43 (10H, m), 8.17-8.08 (1H, m). MS (ESI) m/z ·· 695 (M+H)+. (2) 3-[(N-ethyl-fluorenylmethyl)amino]_4_sideoxy_4_[5_[(4_phenyltri 121199.doc -146- 200846322 fluoromethyl-2-thiophene Methoxy]porphyrin_丨_yl]butyric acid tert-butyl ester [化132] _

3-[(N-Pentyleneoxy) Ν-methyl)amino]methanol (4)phenyl-5-trifluoromethyl-2-thienyl)methoxy]porphyrin small group Add 5% ρ mountain to the solution of butyric acid tributyl sulfonate (92 mg) in ethyl acetate (5 mi)

The residue was stirred under a stream of 4 曰 mg) and stirred under a hydrogen atmosphere for 18 hours. The catalyst was filtered off, and the obtained 2 alcohol (5 ml) and 5% Pd/c (2 〇 mg) were further filtered under a reduced pressure of hydrogen and then concentrated under reduced pressure. The reaction mixture was concentrated under reduced pressure and purified mjjjjlilililililililili丽R (CDC13) δ : 1·〇6 (3H, t, J=7.6 Hz), 1.42 (9H, s), 2.25 (3H, s), 2·34-2·67 (3H, m), 2 ·89·3·21 (2H,m),3·97 (1H,dd, J=10.0, 3.7 Hz),4·05·4·19 〇H,m),4 61 (2H, q, (4)” Hz), 5·19 (2H, s), 6.79 (1H, dd, J=9.l, 2_5 Hz), 6.84 (1H, d, J=2.0 Hz) 5 7.06 (1H? s)5 7.34-7.44 (5H5 m)5 8.17 (1H5 d J=8.8 Hz). ' MS (ESI) m/z : 589 (M+H)+. (3) 3-[(N-Ethyl-N-methyl)amino] sideoxy-4-[5_[(4_ 基基·5·三121199.doc -147 - 200846322 |L methyl- 2-nonylphenyl)methoxy]porphyrin-丨-yl]butyrate [Chemical 133]

3-[(N-Ethyl-N-methyl)amino-4-bu-4.substyloxy_4_[5_[(4•phenyl_5-

Trifluoromethyl-2-thienyl)methoxy], porphyrinyl]butyric acid tert-butyl ester (26 mg) in 4 N hydrochloric acid / 1,4-dioxane solution (2 mi), in room Stir 2 liters under warmth. The reaction solution was concentrated under reduced pressure. Ethyl ether was added to the residue, and the obtained solid was filtered. NMR (DMSO-d6) 3 : 1.09 and 1.91 (3H, t and s, J = 8.3 Hz, decylamine isomer), 2.68-2.88 (2H, m), 3.01-3.27 (5H, m), 4.15 -4.67 (4H,m), 5.39 (2H,s), 6.93 (1H,dd,J=8.8,2.2 Ηζ),7·06 (1H,d,J=1.7 Hz),7·36-7·52 (7H,m), 8.04 (1H,d,J=9.1

Hz) 〇MS (ESD) m/z : 533 (M+H) + 〇 [Example 24] 3-(N-Methylamino)-4-yloxy_4_[5 —[(4_Benzene) (5-trifluoromethyl-2-thienyl) decyloxy]butyric acid (1)3-[(1^benzyloxycarbonyl-&gt;1-methyl)amino] _4-Sideoxy-4-[5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]porphyrin-丨-yl]butyric acid [Chem. 134] 121199. Doc -148- 200846322

3-[(N-Benzyloxycarbonyl-N-methyl)amino]-4-oxo-44s ^ L [(4· stupid)

4-5 Hydrochloric acid/1,4-Diazane solution (3 ml) based on 5--5-trifluoromethyl-2_thienyl)methoxy]porphyrin-1-yl]butanyl ester (92 mg) , at room temperature, sandalwood fell for 18 hours. The resulting residue was purified by EtOAc (EtOAc): NMR (CDCl3) δ: 2·482·65 (lH, m), 2.84 and 2.86 (total 3H, per s, amidine isomer), 2·95·3·27 (3H, m), 3.50 -4.29 (3H,m), 5.02-5.55 (6H,m),6.74-6.85 (2H,m),7.05(lH,s),7.28-7.47 (10H,m),8.14-8.05 (1H, m) 〇MS (ESI) m/z : 639 (M+H)+ 〇(2) 3-(N-decylamino)-4· sideoxy-4-[5-[(4·phenyl) -5-trifluoromethyl-2-thienyl)methoxy]porphyrin-1-yl]butyric acid [Chemical 135]

3-[(N-Benzyloxyphenylmethyl)aminol-oxy-4-[5-[(4-benzene 121199.doc-149-200846322-yl-5-trifluoromethyl-2-indole)吩 曱 曱 曱 吲 吲 琳 琳 琳 ( 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 hour. The catalyst was filtered off, and ethanol (3 ml) and 5% Pd/C (20 mg) were added to the residue, and the mixture was stirred for 3 days. After the catalyst was filtered off, it was concentrated under reduced pressure. To the obtained residue, hydrazine (0·169 ml) was added at room temperature, and stirred at room temperature for 23 hours. The reaction mixture was concentrated under reduced pressure. NMR (CDC13) δ : 2.37-2.73 (4H, m), 3·26 (2H, t, J = 8.3 Hz), 3.62-3.74 (lH, m), 3.99-4.23 (2H, m), 5.22 (2H ,s),6.82-6.91 (2H,m),7.07 (1H,s),7.44-7.37 (7H,m),8.16 (1H, d, J = 8.3 Hz) o MS (ESI) m/z : 505 (M+H), [Example 25] l_[5-[(4-Phenyl·5·trifluoromethyl 2-thienyl)methoxy p-pyridin-1-ylcarbonyl]azetidine 3-carboxylic acid (1) 1-[5-[(4-phenyl-5·trifluoromethyl-2-thienyl)methoxy]porphyrinylcarbonyl]azetidine-3-indole Ester

a mixed solution of 5_[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]porphyrin hydrochloride (100 mg) in a molar ratio of 10:1 2.2 ml), 121199.doc -150- 200846322

Add triphosgene (23.7 mg) under 氮气C under a nitrogen atmosphere and stir for 14 hours. In the reaction solution, azetidine-3-formic acid methyl ester hydrochloride (36.4 mg) was added and stirred for 7 hours, and then the same amount was added, and the butyl benzoate-methyl formate methyl salt (36.4 mg) was further added. Stir for 17 hours. The reaction mixture was diluted with ethyl acetate, and then stirred for 1 minute with 1 N hydrochloric acid, and extracted with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. After the anhydrous sodium sulfate was filtered, the solvent was evaporated to dryness, and the obtained residue was subjected to silica gel column chromatography (Biotage 25S) to give the title compound (1 〇 3 mg).丽R (CDC13) δ : 3.U (2H, t, J=8.8 Hz), 3 4〇_3 49 (1H, called, 3.77 (3H, s), 3.92 (2H, t, J=8.6 Hz) , 4.30 (2H, s), 4.32 (2H, s), 5.18 (2H, s), 6.77-6.83 (2H, m), 7.04-7.06 (1H, m)^ 7.35-7.44 (5H, m), 7.61 (1H,d,J=8.8 Hz). ' MS (ESI) m/z : 517 (M+H) + (2) phenyl _5_trifluoromethyl thiophenyl) methoxy p porphyrin Alkylcarbonyl]azetidine-3-carboxylic acid [Chemical 137] p^Ff

1-[5-[(4-Phenyl-5-trifluoromethyl.2_thienyl)methoxy] σ porphyrin "carbocarbonyl" azetidin-3-carboxylic acid decyl ester (1〇3 In a methanolic solution of mg) (1:2,3 mi), add Mi Ν aqueous sodium hydroxide solution (1 121199.doc -151 - 200846322 ml) at room temperature, stir for 14 hours. Concentrate the reaction solution under reduced pressure. In the obtained solution, a 1 N aqueous solution of hydrochloric acid was added to adjust the pH to 2, and the extract was extracted with a saturated aqueous solution of sodium chloride and chloroform solution, and dried with anhydrous stone ☆ I sodium. After the anhydrous sodium sulfate was filtered off, the title compound (8 ml) was obtained under reduced pressure. ???, NMR, NMR (CDC13) 8: 3.11 (2H5 t5 1 = 8.8 Hz), 3.400.49 0Η5 m)j 3·77 ( 3Η5 s),3·92 (2Η, t5 J=8.6 Ηζ), 4·30 (2Η, s), 4·32 (2Η, s), 5·18 (2Η, s), 6.77-6.83 (2Η, m), 7.04-7.06 (1Η, m), 7.35-7.44 (5Η, m), 7.61 (1Η, d, J=8.8 Hz). IR (ATR) cm1 : 2960, 2900, 2521, 1732, 1606 , 1568, 1491. MS (ESI) m/z: 503 (M+H) + NMR calcd for C25H22F3N204S: 503·1252. Measured value: 503.1250. [Example 26] 1-[5· [(4- Phenyl-5-tris-methyl-2-_2-nonyl)methoxy]-or-dosylindole-1 -yl]weilkylmethyl]-3-furan-butyric acid (1) 1-[5 -[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy]u porphyrin-1 -yl]carbonylmethyl]-3-azetidinecarboxylic acid methyl ester [Chemical 138]

Η-CI ^ [5-[(4-propenyl-5-difluoromethylsepenyl)methoxy)p XI linlin) salt • 152- 121199.doc 200846322 acid salt (100 mg) dissolved In acetonitrile (5 ml), DIEA (85 μΐ) was added with stirring at ot, followed by the addition of chlorohydrazine chloride (21 μl), while stirring was continued. To the reaction mixture were added hydrazinidine hydrochloride (73 mg) and DIEA (169 μM), and the mixture was stirred at 50 ° C for 2 hours. The reaction mixture was concentrated to give purified crystals crystals eluted eluted elution elution NMR (CDC13) δ : 3·16 (2H, t, J = 8.5 ΗΖ), 3·36 (2H, s), 3.39. 3·48 (2H, m), 3·67·3·81 (6H, m),4·01 (2H, t5 卜8·4 Hz) 5·18 (2H, s), 6.77-6.84 (2H, m), 7.05 (1H, s), 7·35_7 43 (5H, m) , 8·14 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 531 (M+H)+. (2) 1-[5·[(4-Phenyl-5-trifluoromethyl-2-thienyl) decyloxy] porphyrinyl] benzylidene]-3-indenyl carboxylic acid 139]

Methyl l-[5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy], oxaloinyl]carbonylmethyl]-3-azetidinecarboxylate ( 1 〇 9 mg) was added THF (5 ml) and 0. 25 N aqueous sodium hydroxide solution (1.64 ml), and stirred for 5 hours. The reaction solution was neutralized with a 1 hr aqueous solution of hydrochloric acid, diluted with water (50 ml), and then extracted with 10% methanol / gas (2 χ 1 〇〇 ml). After the extract was dried (anhydrous sodium sulfate), the solvent was evaporated, and methylene chloride and hexane were added to the obtained residue, and the obtained solid matter was filtered, and dried in vacuo. The title compound (1 06 mg) was obtained. NMR (CDC13) δ: 2.93-3.03 (2H5 m)5 3.53^3.64 (1H3 m) 3·81-4·31 (8H, m), 5·09 (2H , s) 5 6.67-6, 72 (2H, m), 7.01 (1H, s), 7·35-7·41 (5H, m) 5 7.98 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 517 (M+H) + ??? C26H23F3N2O4S. 0.25 H2O. Elemental analysis: C, 59 H, 4.55, F, 10.94, N, 5.38; S, 6.15. Found: c, 59 69· 4·34; F, 10.76; N, 5·34; S, 6.14. [Example 27] 4·[Ν_[5_[(4-phenyl-5-trimethylthiophenyl)methoxy]] ϋ ϋ -1 -1 -1 -yl]amino]butyric acid (1) 4-[Ν-[5-[(4-phenyl-5-trifluoromethyl)2-thienyl)methoxy] σbendolin-1-ylcarbonyl]amino]butyrate ethyl ester [ 140]

In a solution of 5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy] σ-oxaporphyrin hydrochloride (62 mg) in dichloromethane (2 ml) Hey. Add a bite (0·50 ml) and diphosgene (14.7 mg) to the side of the arm and slowly return to room temperature for 23 hours. 4-Aminobutyric acid (3 〇 3 mg) was added to the reaction mixture, followed by stirring for 23 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The combined extracts were washed successively with 1 N aqueous hydrochloric acid, sat. 121199.doc-154-200846322 sodium bicarbonate solution, saturated water, and dried over anhydrous sodium sulfate. After removing the solvent from the anhydrous sodium sulfate, the resulting residue was subjected to flash column chromatography (BiGtage 25s) to give the title compound (2 mg). NMR (CDC13) δ : 1.25 (3Η, t, J=7.2 Hz), 1.88-1.95 (2H, m), 2-42 (2H, t, J=6.9 Hz), 3.16 (2H, t, J=8.6 Hz), 3.38 (2H, q, J=6.2 Hz), 3.90 (2H, t, J=8.6 Hz), 4.13 (2H, q, J=7.2 Hz)! 4.87-4.93 (1H, m), 5.18 ( 2H, s), 6.75-6.83 (2H, m), 7.05 (1H, s), 7.37-7.44 (5H, m), 7.84 (1H, d, J=8.6 Hz) 〇' MS (ESI) m/z : 532 (M+H)+. (2) 4-[N-[5-[(4-phenyl-5-trifluoromethyl-2-yl)thio]methoxy]n porphyrin _ 1-ylcarbonyl]amino]butyric acid 141]

Fork F-^Fo&lt;x〇Γ^Υ for 4-[Ν-[5-[(4-phenyl-5_trifluoromethyl)2_thienyl)oxy]0 哚 -1- -1- A 1 N sodium hydroxide solution (0.5 ml) was added to a decyl alcohol/THF solution (1:2, 1.5 ml) of ethyl carbonyl]amino]butyrate (12 mg), and stirred for 3 Torr. The reaction mixture was concentrated under reduced pressure. EtOAc m. NMR (DMS〇-d6) δ : 1.63-1.73 (2H, m) 5 2·24 (2H, t, J = 7.4 Hz), 3.02-3.14 (4H, m), 3.84 (2H, t, J = 8.7 Hz), 5.26-5.37 121199.doc -155 - 200846322 (3H,m),6·55 (1H,t,J=5.6 Ηζ),6·77 (1H,dd,J=8.6, 2·7 Hz) , 6·89 (1H, d, J = 2.7 Hz), 731-7.51 (6H, m) 5 7·72 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 505 (M+H) + 〇 [EXAMPLE 28] 2_[N-[2- </ RTI> </ RTI> </ RTI>嗟 ) ) 甲 甲 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚 哚-°Septyl)methoxy]porphyrin [Chemical 142]

5-[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy] porphyrin hydrochloride (234 mg) and hydrazine (167 μM) of dichloromethane (3.5 ml) In solution, chlorhexidine chloride (47.6 μM) was added at room temperature. After the reaction mixture was stirred at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. ethyl acetate (15 ml) and water (1 ml) was then evaporated to ethyl acetate (1 〇mi &gt;&lt;3) Extracting the aqueous layer. The extract was combined and dried over anhydrous sodium sulfate. This compound was used in the subsequent reaction without isolation and purification. MS (ESI) m/z: 452 (M+H)+. (2) 2-[N-[2-Sideoxy-2-[5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy] porphyrin-1-yl Ethyl]amino]ethyl acetate [Chem. 143] 121199.doc -156- 200846322

1-(Chloroethyl)-5-[(4-phenyl-5-trifluoromethylthienyl) decyloxy] 11 ebodolin (120 mg) and hydrochloric acid glycine vinegar (74.3 In a suspension of mg) in acetonitrile (2 ml), dieA (232 μM) was added at room temperature to dissolve. The reaction mixture was stirred at 70 ° C for 14 hours and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and then chloroform (i················ The extract was combined, washed with brine, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified using EtOAc EtOAc (EtOAc) NMR (CDC13) δ : 1.28 (3Η, t, J=7.1 Hz), 3.20 (2H, t, J=8.1

Hz), 3.54 (2H, s), 3.56 (2H, s), 4 shoulders (10), t, (four) "Hz), * 2〇 (2H, q' J 7.1 Hz), 5.20 (2H, s), 6.86- 6,80 (2H,m),7.06

(1H, s), 7.43-7.39 (5H, m), 8.17 (lHj d, J=8&gt;8 Hz) 〇(3) 2-[N-[2-Sideoxy-o-[(4-Phenyl) _5_trioxomethyl-2·indolyl)methoxy]porphyrin-1-yl]ethyl]amino]acetic acid [Chemical 144]

2-[N-[2-Sideoxy-2-[5-[(4·phenylfluoromethyl-2-thienyl) 121199.doc -157- 200846322 曱oxy]° 弓布朵琳- 1-ethyl]ethyl]amino]ethyl acetate (9 〇·8 mg) in 33% methanol/THF (1.5 ml) in a mixed solution, adding 1% aqueous sodium hydroxide solution, stirring at room temperature 14 hours. After adding water (5 ml) to the reaction mixture, 1 N hydrochloric acid was added until it became weakly acidic (pH 4). Further, an organic matter was extracted by adding a 20% methanol/chloroform mixture (10 ml). Methanol (5 ml) was added to the combined extracts to thereby make the suspension a solution, which was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was added to EtOAc (EtOAc) (EtOAc) eluted NMR (DMSO-d6) 5 : 3.13 (2H? t5 J=8.1 Hz) 5 3.25 (2H5 s)5 3.70 (2H, s), 4.01 (2H, t, J = 8.1 Hz), 5·35 (2H, s), 6.88 (1H, dd, J-8, 8, 2·0 Hz), 6.99 (1H, s), 7.36 (1H, s), 7·5〇-7·4ΐ (5 H, m), 7 · 9 8 (1H,d,J=8 · 8 H z) 〇MS (ESI) m/z : 491 (M+H)+. [Example 29] 3-[N-[2-Sideoxy-2-[5-[(4-phenyltrifluoromethyl stilbene)methoxy] porphyrin-1-yl]ethyl Amino]ethyl propionate (1) 3-[N-[2-Sideoxy-2-[5-[(4-phenyl-5-trifluoromethyl]thienyl)methyllacyl]° Bow 1 Mulin-1 -yl]ethyl]amino]propionic acid ethyl ester [Chemical 145]

5-[(4-Phenyl-5-trifluoromethyl-2-thienyl) decyloxy] porphyrin hydrochloride 121199.doc -158- 200846322 salt (165 mg), DIEA (146 μΐ) acetonitrile (4 ml) solution was added with chloroethyl chloride (33.5 μM) at room temperature. After stirring at room temperature for 1.5 hours, DIEA (73.2 μM) and ethyl 3-aminopropionate hydrochloride (61.4 mg) were added, and the mixture was stirred at 80 ° C for 20 hours. The reaction mixture was concentrated under reduced pressure, and a mixture of 1% methanol / chloroform (10 ml) and water (5 mi) was applied, and the aqueous layer was extracted with 1% methanol/chloroform (5 ml x 3). The combined extracts were dried over anhydrous sodium sulfate and evaporated. DMSO (3 ml) was added to the residue, and the insoluble material was removed by filtration, and the filtrate was purified by high-performance liquid chromatography (NOMURA Develosil Combi-RP-5). The collected solution was lyophilized to give the title compound (37.4 mg). NMR (CDC13) δ ·· 1·25 (3H, t, J=6.8 Hz), 2.87 (2H, t, J=6.1 Hz), 3·13 (2H, t, J=7,8 Hz), 3 · 32 (2H, t, J = 6.1 Hz), 3·95 (2H, s), 3·98 (2H, t, J = 7.8 Hz), 4_15 (2H, q, J = 7.0 Hz), 5· 15 (2H, s), 6.75 (1H, d, J = 8.8 Hz), 6.81 (1H, s), 7.05 (1H, s), 7.41-7.38 (5H, br m), 8.08 (1H ,d,J=8.8 Hz),8.31 (1H,br s),8·54 (1H,br s) 〇MS (ESI) m/z : 533 (M+H)+ 〇(2) 3-[Ν [2-Sideoxy-2-[5-[(4-phenyl-5-trifluorodecyl-2-nonyl)methoxy], porphyrin-1-yl]ethyl]amino ]propionic acid [化146]

121199.doc -159- 200846322 in 3-[N-[2-Sideoxy-2-[5·[(4-phenylitrifluoroindolyl-2-yl)phenyloxy]porphyrin- Addition of in-hydrogenated sodium hydride solution (0.5 ml) in a mixture of 1-ethyl]ethyl]amino]propionic acid ethyl ester (37·4 mg) in methanol/THF (1.5 ml) Spoiled for 14 hours. Water was added to the reaction solution (5 after adding 1 N aqueous hydrochloric acid solution until it became weakly acidic (pH 4). Further, 10% sterol/chloroform mixed solution (7.5 ml) was added to extract the organic matter. After drying over sodium sulfate, the solvent was evaporated under reduced pressure. The residue obtained from the residue was purified by adding ethyl acetate (2 ml), and then washed with ethyl acetate and diethyl ether. The title compound (2j 〇mg) was obtained. NMR (DMSO-d6) δ: 2·73 (2H, t, J = 7.6 Ηζ), 3·19 (4H, t, J-7.6 Hz) , 4·06 (2H, t, J = 7.6 Hz), 4·13 (2H, s), 5.37 (2H s), 6.92 (1H, dd, J = 8.5, 2.0 Hz), 7.05 (1H, s),7·37 (1H,s) 7.51-7.40 (5H,m), 7.98 (1H,d,J=8.5 Hz) MS (El) m/z : 505 (M+H)+ C25H2404N2F3S ( HRMS (FAB) calculated for M+H)+: 505.5 378. Measured value: 505.1409. [Example 30] 3-[N-indolyl-N-[2-o-oxy-2-[5·[(4 -Phenyl-5-trifluoromethyl-2-thienyl)methoxy-p-pyridolin-1-yl]ethyl]amino]propionic acid (1) 3-[Ν-methyl-Ν_[2 -Sideoxy-2-[5-[(4-phenyl-5-trifluoromethyl_2-thienyl)anthracene Oxy] porphyrin-1-yl]ethyl]amino]propionic acid ethyl ester [Chem. 147] 121199.doc -160- 200846322

3-[N-[2-Sideoxy-7 4 Lean I &lt; Bu^U4-Benzyl-5-trifluoromethyl-2-thienyl) decyloxy]porphyrin-1-yl]B In a solution of ethyl propionate (94.i mg) in THF (5 ml), a 37% aqueous solution of furfural (32.9 μM) was added to the palace and the mixture to the west. After stirring for 1 hour, it is known that: 7 ^ — one by one gas-based gasification (56·2 mg),

Ride for 18 hours at room temperature. A gas mixture (H) ml) and a saturated sodium hydrogencarbonate solution (5 ml) were added to the mixture, and the aqueous layer was extracted with chloroform (5 ml x 3). The combined extracts were washed with EtOAc EtOAc. This compound was used in the subsequent reaction without isolation and purification.

NMR (CDC13) δ : 1·22 (3H, t, J = 7.1 Hz), 2.39 (3H, s), 2·51 (2H, t, J = 6.6 Hz), 2·89 (2H, t, J = 6.6 Hz), 3·14 (2H, t, J = 8.5 Hz), 3.30 (2H, s), 4.10 (3H, q, J = 7.1 Hz), 4.14 (1H, t, J = 8.5 Hz), 5·19 (2H, s), 6.80 (1H, dd, J=8.8, 2.0 Hz), 6.83 (1H, bi·s), 7.05 (1H, s), 7·43-7·37 (5H, m ), 8·17 (1H, d, J = 8.8 Hz). (2) 3_[N-Mercapto-oxime [2-o-oxy-2-[5-[(4-phenyl.5-trifluoromethyl-2-thienyl)] oxy]H ϋ Lin-1-yl]ethyl]amino]propionic acid hydrochloride [化148]

121199.doc -161- 200846322 in 3-[N-methyl-N-[2-o-oxy-2-[5-[(4-phenyl-5.trifluoromethylthiophenyl)methoxy]] σ 哚 哚 -1 -1 - yl] ethyl] amino] ethyl propionate 3 3 % decyl alcohol / THF (3 ml) mixed solution, add i Ν sodium hydroxide aqueous solution (1 ml), at room temperature Stir under 14 hours. After adding water (5 ml) to the reaction mixture, a 1 N aqueous solution of hydrochloric acid was added until it became weakly acidic (pH 4). Further, an organic matter was extracted by adding a 20% methanol/chloroform mixture (15 mi). The combined extracts were dissolved in decyl alcohol (10 ml), dried over anhydrous sodium sulfate and evaporated. DMS hydrazine (3 ml) was added to the obtained residue, and the insoluble matter was removed by suction, and purified by high-performance liquid chromatography (N 〇MlJRA Develosil Combi-RP-5). The collected solution was concentrated, and 4N hydrochloric acid / 1,4-dioxane solution (2 ml) was added to the residue, and the mixture was stirred for 1 hr. A 25% diethyl ether/hexane mixture (3 ml) was added, and the obtained solid was filtered, washed with 25% diethyl ether/hexane mixture and dried under reduced pressure to give the title compound (36 () mg ). NMR (DMSO-d6) δ : 2.84 (2H, t, J = 7.3 Hz), 2.87 (3H, s), 3,19 (2H, t, J = 8.2 Hz), 3·33 (2H, br s) ,4·04 (2H,t,J=8.2 Hz), 4, 36 (2H, br s), 5.37 (2H, s), 6.93 (1H, dd, J=8.8, 2.0 Hz), 7.05 ( 1H, d, J = 2.0 Hz), 7.37 (1H, s), 7.41 - 7.51 (5H, m), 7·98 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 519 (M+H), [EXAMPLE 31] 3-[N-[2- </ RTI> </ RTI> Methoxy]porphyrin-1-yl]ethyl]amino]propionic acid (1) 1-chloroethylindolyl-5-[(2-trifluoromethyl-4-phenylbiphenyl) Oxy] porphyrin [Chemical 149] 121199.doc -162- 200846322

In a solution of 5-[(2-trifluorodecyl-4-biphenyl)methoxy porphyrin hydrochloride (146 mg), hydrazine (105 μM) in dichloromethane (3 ml) Add ethane chloride (30·0 μΐ) at a temperature. After the reaction mixture was stirred at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and then chloroform (1 ml) and water (m. The combined extracts were dried over anhydrous sodium sulfate. This compound was used in the subsequent reaction without isolation and purification. NMR (CDCI3) δ : 3.23 (2H, t, J = 8.1 Hz), 4.15 (2H, s), 4.17 (2H3 t, 1 = 8.1 Hz)? 5.12 (2H? s)5 6.89-6.83 (2H? m ) 5 7.42- 7.30 (6H, m), 7.61 (1H, d, J = 7.8 Hz), 7·81 (1H, s), 8·16 (1H, d, J = 9.0 Hz). • MS (ESI) m/z: 446 (M+H)+ 〇(2) 3-[N-[2-Sideoxy-2·[5-[5_[(2-trifluoromethyl_4_) Biphenyl)methoxy] is called 1 beelin-1-yl]ethyl]amino]propionic acid third butyl hydrazine [化150]

1-chloroethenyl-5-[(2-trifluoromethyl-4-biphenyl)methoxy]porphyrin 121199.doc -163- 200846322 (154 mg), adipic acid tributyl The ester (107 mg) in acetonitrile (3 ml) was dissolved in DIEA (205 μM) at room temperature. The reaction mixture was stirred at 70 C for 11 hours and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure. chloroform (10 ml) and saturated aqueous sodium hydrogencarbonate (5 mi) were applied to separate liquids. The aqueous layer was extracted with chloroform (5 ml x 3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by celite gel column chromatography (Bi </ RTI> <RTIgt; Wake up R (CDC13) δ : 1·46 (9H, s), 2·47 (2H, t, J = 6.7 Hz), 2.93 (2H? t? J-6.7 Hz) 5 3.20 (2H; t? J= 8.4 Hz); 3.50 (2H5 s)5 4,02 (2H, t, J=8.4 Hz), 5·12 (2H, s), 6.83 (1H, dd, J=8.8, 2.7 Hz), 6·86 (1H,s),.7·42-7·31 (6H,m),7·62 (1H,d,J=7.8 Hz), 7.80 (1H,s), 8.17 (1H,d,J=8.8 Hz). MS (ESI) m/z: 555 (M+H)+. (3) 3-[N-[2-Sideoxy-2-[5-[(2-trifluoromethyl-4)biphenyl)methoxy]. Porphyrin-1-yl]ethyl]amino]propionic acid [Chemical 151]

3-[N-[2-Sideoxy-2-[5-[5-[(2-tris-decyl)-biphenyl) methoxy]c-I-l-l-yl]ethyl To the tert-butyl propionate, difluoroacetic acid (1 ml) was added at room temperature. After the reaction mixture was stirred for 1 hour, water (5 ml) was added to the reaction mixture 121199.doc-164-200846322, and then saturated aqueous sodium hydrogencarbonate was added until it became neutral. Further, the organic matter was extracted by adding a 20% methanol/chloroform mixture (15 ml). The extract was combined, and methanol (1 g ml) was added thereto to make a suspension solution, which was dried over anhydrous sodium sulfate and then evaporated under reduced pressure. Solvent. To the obtained residue, DMSO (3 ml) was added, and the insoluble material was removed by filtration, and then purified by high-performance liquid chromatography (NOMURA Develosil Combi-RP-5). The collected solution was lyophilized, and a mixture of 33% methanol / THF (1.5 ml) was obtained. After adding water (five) hydrazine to the reaction liquid, a 1 N aqueous hydrochloric acid solution was added until it became weakly acidic (pH 4). Further, the organic matter was extracted by adding a 20% methanol/gas mixture (15 ml). The extracts were combined, and a decyl alcohol (1 〇 ml) was added thereto to dissolve the suspension, which was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. A 20% acetic acid/hexane mixture (2 ml) was added to the residue, and the resulting solid was collected by filtration. /. The ethyl acetate/hexane mixture was washed and dried under reduced pressure to give the title compound (48.9 mg). NMR (DMSO-d6) δ : 2.37 (2H, t, J = 6.7 Hz), 2.83 (2H, t, J = 6.7 Hz), 3.13 (2H, t, J = 8.0 Hz), 3·56 (2H, s),4,04 (2H,t, J=8.0 Hz), 5.21 (2H, s), 6.86 (1H, dd, J=8.5, 2.0 Hz), 6.99 (1H, br s), 7·33- 7·29 (2H,m),7·45-7·41 (5H,m),7·76 (1H, d,J=8.0 Hz), 7.88 (1H,s),7.99 (1H,d,J = 8.5 Hz). MS (ESI) m/z: 499 (M+H)+. [Example 32] (3R)·Amino-4·[5-[(4-cyclohexyltrifluoromethylphenyl)methoxy]σ-indolyl-1-yl]-4-yloxy Butyrate 12I199.doc -165- 200846322 (1) (3R)-(Tertibutoxycarbonylamino)-4-[5-[(4-cyclohexyl-2-trifluoromethylphenyl) ) methoxy]porphyrin-1·yl]-4-oxobutyric acid tert-butyl ester [Chem. 152]

5-[(4-Cyclohexyl-2-difluoromethylphenyl)methoxy] leaching hydrochloride _ (〇·21 g), B〇CD-Asp(OtBii)-〇H (Taibian Chemical (〇14 g), EDC.HC1 (0.14 g), HOBt (0.10 g) in DMF solution (5 ml), ΤΕΑ(0·35 ml) was added at room temperature and stirred for 2 days. The residue was purified to give crystall crystal crystal crystal crystal crystal crystal crystal ^-NMR (CDC13) δ : 1.11-1.48 (20Η, m), 1.59-1.69 (2H? m), 1.71-1.80 (1H, m), 1.81-1.93 (5H, m), 2.47-2.67 (2H, m), φ 2·75—2·88 (1H, m), 3·10·3·26 (2H, m), 4.19-4.40 (2H, m), 4·81-4·99 (1H, m ),5·18 (2H,s),5·29 (1H,d,J==1〇〇Hz), 6.91-6.64 (2H,m),7·38 (1H,d,JU Hz),7 45.7 54 (m, m), 7·60-7·73 (1H, m), 8.11 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 647 (M+H)+.

Porphyrin-1-yl]-4-oxobutyrate hydrochloride [Chem. 153] 121199.doc -166 - 200846322

(3R)-(2,4-Butoxycarbonylamino)-4·[5_[(4-cyclohexyl-2-trifluoromethylbenzyl) decyloxy] fluorene-1 -yl] sideoxy In the third butyl butyrate (0.32 g), 4 Ν hydrochloric acid η, 4 - dioxane solution (1 〇 ml) was added at room temperature, and after stirring for 3 days, it was concentrated under reduced pressure. Diethyl ether was added to the residue, and the solid crystals were evaporated to give the title compound (0.21 g). H-NMR (DMSO-d6) δ : 1·03-1·48 (6H, m), 1.68-1·90 (4H, m), 2.52-2.93 (2H, m), 2.94-3.23 (3H , m), 3.58-3.78 (1H, m), 4.06·4·35 (1H, m), 5.08-5.21 (2H, m), 6.84 (1H, dd, J=8.8, 2.7 Hz), 6.98 (lH) ,d,J=2.5Hz),7.09(lH,s),7.51-7.61 (3H,m),7·64 (1H,d,J=7.6 Hz),7.99 (1H,d,J=8.8

Hz), 8·37 (2H, s) 〇 IR (ATR) cnT1 : 2924, 2850, 1724, 1655, 1597, 1489, 1448. _ MS (ESI) m/z ·· 491 (M+H)+. Calculated value of elemental analysis of C26H29F3N204.1_25HC1.H20·· c.56.36; H,5·87; Cl,8·00; F,10·29; N,5.06. Found: c, 56·52; H, 5·88; Cl5 8·17; F, 10.20; Ν, 4.91. [Example 33] (3R)-Amino-4-[5-(4-cyclohexyloxyphenyl)porphyrin·1-yl]-1 -oxybutyric acid (1) 5-( 4-benzyloxyphenyl)-m-oxime [Chem. 154] 167- 121199.doc 200846322

5-bromoindole·〇〇g), 4-benzyloxyphenylboronic acid (2·33 g), tetrakis(diphenylphosphine)palladium (0.290 g), 2 N sodium carbonate aqueous solution (12·8) (ml), toluene (7 ml) and ethanol (7 ml) were mixed and heated under reflux for 13 hours. After the reaction mixture was cooled, the mixture was extracted with ethyl acetate (200 m), and the mixture was washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. After the solvent was evaporated, the residue obtained was purified mjjjjjjjjjjjjjj !H-NMR (CDC13) δ ·· 5·12 (2H, s), 6.58-6.60 (1H, m), 7·03_ 7.08 (2H, m), 7·23 (1H, t, J=2.8 Hz ), 7·31-7·49 (7H, m), 7·55-7·59 (2H, m), 8·14 (1H, br s). MS (ESI) m/z: 300 (M+H)+. (2) 5-(4-Benzyloxyphenyl)-i_(t-butoxycarbonyl H-oxime #[化155]

Bog 5-(4-Benzyloxyphenyl)·ιΗ_吲哚 (1 〇 5 g) was dissolved in THF (10 ml), and Boc20 (1.15 g) and DMAP (0.040 g) were added and stirred for 17 hours. The reaction mixture was concentrated to give the title compound (y.29 g) from EtOAc EtOAc. *H.NMR(CDC13)5: 1.69 (9h, s), 5.12 (2H5^6^^J=3.7 Hz), 7.03-7.08 (2H, m), 7.30-7.42 (3H, m), 7.44-7.53 (3H, m), 7.54-7.62 (3H, m), 7.72-7.70 (1H, m), 8.15 (1H d J=8.3 Hz). ' MS ' MS (ESI) m/z : 400 (M+H)+. (3) 1-(Secondoxycarbonyl)__5_(4•hydroxyphenyl) porphyrin [Chemical 156]

HO

\ Boc Boc Dissolve 5-(4-phenoxyphenyl)_丨_(t-butoxycarbonyl)_m_吲哚g) in a mixed solvent of THF (50 ml) and ethanol (50 ml). 5% Pd/C (1.29 g) was added, and hydrogenation was carried out for 12 hours under normal pressure while stirring. After replacing the reaction liquid with nitrogen, the catalyst was filtered and the filtrate was concentrated. The residue was purified to give the title compound (925 mg). H-NMR (CDC13) δ : 1.58 (9H3 s)? 3.13 (2H5 t5 J=8.7 Hz), 3,96_4.06(2H,m), 4.93(lH,S)/6.85-6.91(2H,m) , 7.30-7·36 (2H, m), 7.45-7.40 (2H, m). Ih was not observed on the ring. MS (ESI) m/z: 312 (M+H)+. (4) 1-(Tertibutoxycarbonyl)-5-(4-cyclohexylmethoxyphenyl)porphyrin [Chem. 157] 121199.doc 169- 200846322

5-(4-Hydroxyphenyl)-1-(t-butoxycarbonyl)-1H-called oxime (500 mg), bromomethylcyclohexane (453 μΐ), K2C03 (333 mg), and DMF (16 ml) was mixed and stirred at 80 ° C for 12 hours. The reaction mixture was allowed to cool to room temperature, and then extracted with ethyl acetate (200 ml). The extract was washed with saturated brine (2×100 ml), dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by silica gel column chromatography (yield: 2L) to give the title compound (459 mg). H-NMR (CDCI3) δ : 0.93-1.37 (6H5 m)5 1.53-1.93 (13H5 m), 3.13 (2H, t, J = 8.7 Hz), 3.27 (1H, d, J = 6.4 Hz), 3.78 (2H,d,J=6.1 Hz), 3.95-4.05 (2H,m),6·91-6·95 (2H,m), 7·34 (2H,d,J = 9.3 Hz),7.43-7.48 (2H,m),7·86 (1H,br s) 0 MS (ESI) m/z: 352 (M-tBu)+. (5) (3R)-(Tertibutoxycarbonylamino)-4-[5-(4-cyclohexylmethoxyphenyl)indol-1-yl]-4-oxobutanoic acid Third butyl ester [Chem. 158] 121199.doc -170- 200846322

Add 4 n hydrochloric acid / I, 4 · dioxane solution to h (second butoxycarbonyl)-5 · (4-cyclohexylmethoxyphenyl) porphyrin (459 mg) (1 () mi ), after stirring for 3 hours, 'concentrate. Then add B〇c_D_Asp(〇Bu-t)-〇H (326 mg), EDC.HC1 (324 mg), H〇Bt (228 mg), ΤΕΑ (471 μΐ) to appeal to DMF (l〇ml), Stir for 12 hours. The reaction solution was extracted with ethyl acetate (2 〇〇m), and the mixture was washed with brine (2 χ1 〇〇 〇〇 ,), dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue obtained was purified by silica gel column chromatography (yield: 3L). H.NMR (CDC13) δ : 1·〇6 (2H,ddd,J=23.62,12.15,2.99 Hz),1·15-1·38 (4H,m),1·41·1·45 (18H, m), 1.66-1.93 (4H, m), 2·59 (1H, dd, J = 15.8, 6.0 Hz), 2·85 (1H, dd, J = 15.9, 7.6 Hz), 3.26 (2H, t, J=8.3 Hz), 3.79 (2H, d, J=6.8 Hz), 4·29- • 4.48 (2H, m), 4.95 (1H, q, J=7.6 Hz), 5.27-5.33 (1H, m), 6.92-6.96 (2H, m), 7.36-7.40 (2H, m), 7·44·7·49 (2H, m), 8 · 24- 8 · 19 (1H, m). I h was not observed in the ϋ ϋ 琳 phenyl ring. (6) (3R)-Amino-4-[5-(4-cyclohexylmethoxyphenyl) σ porphyrin "- keb-side oxybutyrate" [Chem. 159] 121199.doc -171- 200846322

(3R)-(Tertibutoxycarbonylamino)-4-[5-(4-cyclohexyloxyphenyl)pyridin-1-yl]-4-oxobutanoic acid III To the butyl ester (400 mg), a 4 N hydrochloric acid/1,4-dioxane solution (1 ml) was added, and the mixture was stirred for 3 hr. After it was slurried with diethyl ether, the precipitate was filtered, dried and evaporated to give the title compound (198 mg). W-NMR (DMSO-d6) δ : 0.98-1.33 (5H, m), 1.62-1.86 (5H m), 2·78 (1H, dd, J=17.33, 7·32 Hz), 3·07 (1H ,dd,J=i7 46 5.49 Hz)5 3.25 (2H? t, J=8.18 Hz)? 3.81 (2H? d? J=6.35 HZ) 4.18-4.37 (3H,m), 4.46-4.52 (1H,m ), 6.99 (2H, d, J &gt; 8 79 Hz), 7.47 (1H, d, J = 8.54 Hz), 7.59 - 7.54 (3H, m), 8.11 (lH d, J = 8.54 Hz). C02H and NH2HC1 were not observed. MS (ESI) m/z: 423 (M+H)+. _ C25H3GN2〇4. HC1.0.5H2O Elemental analysis calculated: C, 64.l6. H, 6·89; Cl, 7.58; N, 5.99. Found: C, 63·76; H, 7. 〇〇· 〇Ί , 匕 1, 7·38; N, 6.07. [Example 34] (3R)-Amino-4-[5-(4.benzyloxyphenyl)porphyrin-fluorenyl], 4_ fluorenylbutyric acid (1) 5-gas 4-benzyloxy Phenyl)-1-(tert-butoxycarbonyl)porphyrin [Chem. 160] 121199.doc -172- 200846322

Boc 5-(4-hydroxyphenyl) small (t-butoxycarbonyl)-1H-, hydrazine (406 mg), benzyl bromide (31 〇μΐ), κ 2 (: 〇 3 (270 mg) and DMF (16 ml) was mixed and stirred at 80 ° C for 12 hours. The reaction solution was allowed to cool to room temperature and then extracted with ethyl acetate (2 〇〇mi) and washed with saturated brine (2×100 _ml) The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated, and the residue was evaporated to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (9H5 br s)? 3.13 (2H, t? 1=8.67 Hz), 3.96-4.05 (2H, m), 5·10 (2H, s), 6.99-7.04 (2H, m) 5 7·3 0- 7·50 (9H,m)5 7.87 (0·5Η, br s). 1/2H of porphyrin benzene ring was not observed MS (ESI) m/z : 402 (M+H)+. (3R) — (t-butoxycarbonylamino)-4-[5-(4-cyclohexylmethoxyphenyl) porphyrin-1-yl]-4-oxobutanoic acid third Butyl ester [Chem. 161]

Adding 4 N Hydrochloric Acid / 1,4-Disaki Sodium Solution (1 〇 to 5-(4-benzyloxyphenyl)_1β (Third Butoxycarbonyl Polypyro Porphyrin (446 121199.doc -173-200846322) Ml), after stirring for 3 hours, add &gt; swell. Then add Boc-D-Asp (〇Bu-t)-〇H (387 mg), EDC.HC1 (319 mg), HOBt (225 mg), TEA (464 μl) and dmf (10 ml) were stirred for 12 hours. The reaction mixture was extracted with ethyl acetate (200 ml). The extract was washed with saturated brine (2×100 ml) and dried over anhydrous sodium sulfate. The resulting residue was purified by silica gel column chromatography (3L).

H-NMR (CDC13) δ : 1·41_1·45 (18H, m), 2·59 (1H, dd, Bu 16.1, 6.3 Hz), 2.85 (1H, dd, J = 15.9, 7.6 Hz), 3·26 (2H, t, JU Hz), 4.28-4.45 (2H, m), 4·90-5·00 (1H, m), 5.08-5.14 (2H, m), 5.26-5.33 (1H, m ), 7.05-7.00 (2H, m), 7.50-7.30 (9H, m), 8.22 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 573 (M+H)+. (3) (3R)-Amino-4-[5-(4-benzyloxyphenyl)porphyrin sideoxybutyrate hydrochloride [Chem. 162]

(3RH tert-butoxycarbonylamino)-4·[5_(4-cyclohexylmethoxyphenyl) fluorene 朵 朵 -1--1-yl]-4- oxobutyric acid tert-butyl ester A solution of 4 N hydrochloric acid / 1,4-dioxane (1 〇 ml) was added to (446 mg), and the mixture was stirred for 3 hr. 121199.doc -174· 200846322 After the residue was added to diethyl ether and the residue was crystallized, the precipitate was filtered and dried to give the title compound (198 mg). ^-NMR (DMSO-d6) δ : 2.47-2.54 (1H5 m), 2.72-2.85 (1H, m), 3·25 (2H, t, J = 8.3 Hz), 4.17-4.37 (1H, m), 4.49 (2H, t5 J=5.9 Hz) 3 5.15 (2H? s)5 7.09 (2H? d, J=9.3 Hz) 5 7.61-7.31 (9H, m), 8.11 (1H, d, J = 8.3 Hz) . C02H and NH2HC were not observed. MS (ESI) m/z: 417 (M+H)+. C25H24N2 〇4. Calculated for elemental analysis of HCl · · c, 66.29; H, 5.56; Cl, 7.83; N, 6.18. Found: C, 66·96; H, 5.99; Cl, 7.82; N, 5.90. [Example 35] (3R)-Amino-4-[5-[3-(2,4-diphenyl)propoxy]-l-indolyl]-4-oxobutanoic acid (1) 3-(2,4-difluorophenyl)propanol [Chem. 163]

To a solution of THF (10 ml), LiAlH4 (0.430 g) was added under stirring, and 3-(2,4-difluorophenyl)propionic acid (1.00 g) of THF was added dropwise at 0 °C. 5 ml) solution, mix for 5 hours. Water (0. 34 ml) and 4 n aqueous sodium hydroxide solution (0.34 ml) were added to the reaction mixture, followed by water (1.36 ml) and stirred for 12 hours. The title compound (9 3 8 m g) was obtained by substituting solids &apos; ^-NMR (CDC13) δ : 1.43 (1H5 br s)3 1.80-1.89 (2H3 m)5 2.71 (2H,t,J=7.7 Hz),3·67 (2H,t,J=6.3 Hz),6.83 -6.74 121199.doc .175. 200846322 (2H,m), 7.19-7.12 (1H,m). MS (ESI) m/z: 173 (M+H)+. (2) 3-(2,4-Difluorophenyl)-1-methylsulfonyloxypropane [Chem. 164]

In a solution of 3-(2,4-difluorophenyl)propanol (938 mg) in dichloromethane (10 ml), hydrazine (1·52 ml) and MsC1 (0.633) were added at 0 °C with stirring. ® ml), stirring for 2 hours. The reaction mixture was concentrated, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj m), 2.75 (2H, t, J = 7.6 Hz), 3.01 (3H, s), 4·23 (2H, t, J = 6.3 Hz), 6.76-6.85 (2H, m), 7.20-7.12 (1H , m) 〇MS (ESI) m/z : 273 (M+Na)+. 1-(Tertibutoxycarbonyl)-5-[3-(2,4-difluorophenyl)propoxy]indole gastric salt hydrochloride [Chem.

3-(2,4-difluorophenylmethanesulfonyloxypropane (119 g), i(t-butoxycarbonyl)-5-hydroxyporphyrin (1.12 g), potassium carbonate (〇·99) The mixture was mixed with DMF (20 ml) and stirred at 9 (rc) for 16 hours. The reaction mixture was placed at 121199.doc 176-200846322 and then cooled to room temperature and then extracted with ethyl acetate (200 ml). The solution was washed with saturated brine (2×100 ml), dried over anhydrous sodium sulfate, and the solvent was removed. The residue obtained was purified by silica gel column chromatography (3L of Shanshan high-speed column) to obtain an ether. The mixture was mixed with 4 N hydrochloric acid /1,4_ dioxin solution (10 ml), and stirred for 4 hours. The reaction mixture was concentrated, and the solid was filtered and dried to give the title compound (1.16 g). NMR (CDCI3) δ : 2.03-2.11 (2Η, m), 2.80 (2H? t5 J-7.6

Hz), 3.27 (2H, t, J = 7.7 Hz), 3,99-3.90 (4H,m), 6.86-6.75 (4H, m), 7.18-7.10 (1H,m),7.55·7·50 ( 1H, m), 11.59 (2H, s) 0 MS (ESI) m/z: 290 (M+H)+. (4) (3R)-(t-butoxycarbonylamino) 44543-(14-difluorophenyl)propoxy]-1-indolyl]-4-oxobutyric acid tert-butyl Ester [Chem. 166]

1-(Dibutyloxycarbonyl)-5-[3-(2,4-difluorophenyl)propoxy]u porphyrin hydrochloride (300 mg), Boc-D-Asp (0) -tert-Bu)-OH (279 mg), EDOHCl (265 mg), HOBt (187 mg), TEA (642 μM) and DMF (10 ml) were mixed and stirred for 14 hours. The reaction mixture was extracted with ethyl acetate (200 ml), and the mixture was washed with brine (2×100 ml) and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography (yield: 2L) to give the title compound (493 mg). 121I99.doc -177- 200846322 Ή-NMR (CDC13) δ : 1.41-1.46 (18H, m), 2 〇〇.2 〇9 m), 2.57 (1H, dd, J=15.6, 6.1 Hz), 2.75- 2.86 (3H,m), 318 (2H, t, 1=8.3 Hz), 3.92 (2H, t, 1=6.2 Hz), 4.25-4.40 (2H, m), 4.87-4.96 (1H, m), 5.25 -5.30 (1H, m), 6 68 6 83 zhong m) 5 7.18-7.11 (1H, m), 8·10 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 564 (M+H)+. (7) (3R) · Amine base is called 2,4-: fluorophenyl) propoxy] small Linyl] 4-sided oxybutyrate

[化 167]

(3R)-(Tertibutoxycarbonylamino)-4·[5_[3_(2,4-difluorophenyl)propoxyl·1 -indolyl]-4-oxooxy A solution of 4 N hydrochloric acid / 1,4-dioxane (10 ml) was added to the butane butyrate (493 mg), and la was stirred. The reaction mixture was concentrated to dry crystal crystal crystal crystal crystal ]H«NMR (DMSO-d6) δ : 1.93-2.03 (2H? m)? 2.71-4.48 (11H, m), 6.74-6.79 (1H, m), 6·88-6·90 (1H, m) ,6·99-7·05 (1H, m), 7.14-7.21 (1H, m), 7·32-7·39 (1H, m)5 7·98 (1H, d, • J = 8.8 Hz) , 8.52 (3H, br s). The proton peaks of NH and C02H were not observed. MS (ESI) m/z: 405 (M+H)+.

Calculated for the elemental analysis of CnHnFzl^CVO.SI^O.USHCl: C, 54·95; H, 5.33; Cl, 9.66; F, 8.28; N, 6.10. Found: C, 55.16; Η, 5·57; C1, 9·26; F, 7.69; N, 5.96. 121199.doc •178· 200846322 [Example 36] (3R)-Amino-4-[5-(4-benzyloxy-3-trifluoromethylbenzyloxy)porphyrin-1·yl]- 4-sided oxybutyrate hydrochloride (1) (4-benzyloxy-3-trifluoromethylphenyl)methanol (WO 2003045925)

Methyl 4-hydroxy-3-trifluoromethylbenzoate (Huang, WeiyUan;

Qian,Zhaohui. Huaxue Xuebao (1987), 45(12), 1175- 9.) (1.24 g) in THF (40 ml), added lithium borohydride (261 mg), and stirred for 10 hours under heating and reflux. . After the reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid was added, and the mixture was extracted twice with ethyl acetate, and the combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was evaporated to dryness crystals crystals crystals , H-NMR (CDC13) δ : 1.69 (1H, t, J = 5, 9 Ηζ), 4·66 (2H, d, J = 5.9 Hz), 5.20 (2H, s), 7.02 (1H, d, J = 8.3 Hz), 7·30-7·47 (6H, m), 7.61 (1H, d, J = 2.0 Hz). MS (ESI) m/z: 265 (M-OH) + 〇(2) 5-(4-phenoxy-3-difluoromethylbenzyloxy)+(t-butoxycarbonyl) Lin [Chem. 169] 121199.doc -179. 200846322

Add (4-benzyloxy-3_trifluoromethylphenyl)methanol (1 -benzyloxy-3-trifluoromethylphenyl)methanol in THF (20 ml) of 1-(t-butoxycarbonyl)-5-hydroxyporphyrin (725 mg) 870 mg), triphenylphosphine (8 〇 8 mg), dEad (2.2 Torr in toluene) (1.40 ml) was stirred at room temperature overnight. After concentrating the reaction solution under reduced pressure, the tube was quickly

The residue obtained was purified by column chromatography (m.p.), to afford the title compound (981 mg). H-NMR (CDC13) δ : 1.56 (9H, s), 3.0 (2H, t, J = 8.7 Hz), 3·96 (2H, s) 5 4.95 (2H, s), 5·20 (2H, s ),6·73-6·78 (2H,m), 7·〇3 (1H,d, 8.6 Hz), 7·29-7·52 (6H,m),7·65-7·75 ( 2H, m) 〇(3) 4-[5-(4-hydroxy-3-trifluoromethyl ethoxy) 丨u Duolin small base]_(3R)_ [N-(second butyl Oxycarbonyl)amino]latinyl butyrate butyrate [Chem. 170]

Add 4N Hydrochloric Acid/1,4-Dioxane (20 ml) to 5-(4-Benzyloxytrifluoromethylbenzyloxy)-1(t-butoxycarbonyl)porphyrin (970 mg) Stir at room temperature for 1 hour. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in DMF (20 ml), and (2R)-[(t-butoxycarbonyl)amino] succinic acid 121199.doc -180 - 200846322 4-third Ding Yu (674 mg), HOBt (394 mg), edc, hci (558 mg), TEA (1.35 mg) were stirred overnight. A saturated sodium hydrogencarbonate solution was added to the reaction mixture, which was extracted twice with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (yield: 2L) to give the title compound (1.22 g). ^-NMR (CDCls) δ: 1.42 (9 Η, s ) 3 1.43 (9H5 s)5 2.57 (1H, dd, J - 6.0, 15.6 Hz), 2·82 (1H, dd, J=7.5, i5 6 Hz), 3.18 (2H, t, J = 8.3 Hz) , 4·26-4·39 (2H, m), 4.90-4.97 (3fj, m), 5.20-5.28 (3H, m); 6.76-6.81 (2H5 m)5 7.03 (1H. d J=8.3

Hz),7·30-7·52 (6H,m)5 7·65 (1H,d,J=2.〇Hz),8·12 (1H,d, J = 8_8 Hz) 〇MS (ESI) m/z : 671 (M+H) + 〇(4) (3R)-amino-4-[5-(4-phenoxy-3-trifluorodecyloxy). Porphyrin _ 卜基]-4-sided oxybutyrate hydrochloride [Chem. 171]

4_[5-(4-decyloxy-3-difluoromethyl ethoxy) 巧 朵 朵 琳 ] 】 】 】 】 】 】 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4-Hydroxybutyric acid tributyl vinegar (1 mg) was added with 4 hydrazine hydrochloride / 1,4-dioxane (5.0 ml), and stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the residue was purified mjjjjjjjjj iH-NMR (DMSO-d6) δ : 2.24 (1H, dd, J=8.9, 16.3 Ηζ), 2·58 (1H, dd, J=5.6, 16·3 Hz), 3·13 (2H, t, J=8.5 Hz), 4·00 (1H, s), 4.09-4.15 (1H, m), 4.24-4.30 (1H, m), 5·05 (2H, s)5 5.29 (2H, s), 6.80 -6.83 (1H,m),6.96 (1H,s),7.31-7.46 (6H,m), 7.67-7.71 (2H,m),7·99 (1H,d,J=8.8 Hz) 〇IR (ATR ) cm·1 ·· 2913, 1594, 1488, 1257, 1120. </RTI> </RTI> </RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; [Example 37] (3R)-Amino-4-oxooxy-4-[5-(4-phenethylethyloxy)0-indolyl-1-yl]butanoic acid hydrochloride (1) (4-Phenylethylphenyl) decyl alcohol (WO9616980) [Chem. 172]

To a solution of 4-phenylethylbenzoic acid (452 mg) in 2 THF (10 ml), EtOAc (EtOAc) (EtOAc) , the filtrate was obtained. On the other hand, ferro-boron steel (454 mg) was suspended in ethanol (6.0 ml) and cooled with ice. The filtrate obtained above was added dropwise thereto over 1 Torr, and stirred at room temperature for 1 hour. 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with a 1 N aqueous solution of sodium chloride and brine. It was concentrated with anhydrous sulfur I21199.doc -182-200846322 sodium dry extract. The residue obtained was purified by flash column chromatography (m.p.) to give the title compound (m.). (------ NMR (CDCI3) δ: 7·37 (9 Η, m). 2·89-3· 〇2 (4H,m),4·64 (2H,s),7·16_ MS (ESI) m/z : 195 (M-〇H), (2) 1-(2,2-butoxycarbonyl y5&lt; 4_phenethyl ethoxy group porphyrin [Chem. 173]

Add '4-(phenylethylphenyl)methanol (271 mg), triphenylbenzene in 1-(T-butoxycarbonyl)·% hydroxyporphyrin (2 〇〇mg) in Thf solution (10 ml) Phosphine (3 34 mg), DEAD (2,2 mol/1 in toluene) (580 μΐ), and allowed to mix overnight at room temperature. Rapid column chromatography

The obtained residue was purified to give the title compound (300 mg). 1H-NMR (CDC13) δ : 1·57 (9H, s), 2·91-3·07 (6H, m), 3.97 (2H, s), 4.92 (2H, s), 6.74-6.78 ( 2H,m),7.13-7.41 (9H,m), 7·76 (1H,s) 〇(3) (3)-[1(t-butoxycarbonyl)amino]-4- oxo -4-[5-(4-Phenylethylbenzyloxy)porphyrin-1-yl]butyric acid tert-butyl ester [Chem. 174] 121199.doc -183 - 200846322

Boc is added to a solution of 1 -(t-butoxycarbonyl)-5-(4-phenylethylbenzyloxy) porphyrin (29 mg, 0.675 mmol) 4 N hydrochloric acid η,4·disalkane (15 ml) , stir for 1 hour at room temperature. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in DMF (15 ml) &lt;&quot;&quot;(2R)-[(t-butoxycarbonyl)amino] succinic acid _ 4-butyl butyl ester (194 mg) H〇Bt (137 mg), EDOHCl (194 mg), and TEA (471 μM) were stirred at room temperature overnight. A saturated sodium hydrogencarbonate solution was added to the mixture, and the mixture was extracted twice with ethyl acetate. The mixture was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentrating under reduced pressure, the obtained residue was purified by flash column chromatography (yield). 'H-NMR (CDCI3) δ : 1.42 (9Η, s) 51.43 (9H, s), 2.58 (1H, dd, J=6.1, 15.7 Hz), 2.83 (1H, dd, J=7.5, 15.7 Hz), 2.91- • 3.00 (4H, m), 3.18 (2H, t, J=8.3 Hz), 4.26-4.40 (2H, m), 4.93 (3H, s), 5.29 (1H, d, J=9, 3 hz ), 6·76·6 81 (2H, m), 7.12-7.40 (9H, m), 8.12 (1H, d, Hz). MS (ESI) m/z ·· 602 (M+2)+ 〇(4) (3R)·Amino-4-yloxy-4-[5_(4_phenylethylbenzyloxyH丨哚·卜基] Butyrate [Chemical 175] 121199.doc -184- 200846322

(3R)-[N-(Secondoxycarbonyl)amino]_4_ oxooxy-4-[5-(4-phenethylbenzyloxy)indol-1-yl]butyric acid To the third butyl ester (355 mg), 4 盐酸 hydrochloric acid / 1,4-dioxane (1 〇 ml) was added, and stirred at room temperature overnight. Reduce the reaction solution

After concentration by pressure, the title compound (205 mg) was obtained by flash column chromatography (m.p.) (H-NMR (DMSO-d6) δ: 2.43-2.49 (1H5 m), 2.78 (1H3 dd5 J=5.4, 16·7 Hz), 2.85-2.95 (4H, m), 3·15 (2H, t, J=8.3 Hz), 4.12-4.31 (3H, m), 5.03 (2H, s), 6.84 (1H, dd, J = 2.5, 8.8 Hz), 6.97 (1H, d, J = 2.5 Hz), 7.15-7.30 (8H, m), 7.41 (1H, d, J = 7.4 Hz), 8.00 (1H,d,J=8.8 Hz) IR (ATR) cm.1 : 2923, 1650, 1592, 1486, 1371, 1263. MS (ESI) m/z : 445 (M+H), C27H29N204 (M HR-MS (FAB) calcd.: 422. 127. Found: 445.2127. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Benzyl]oxy]_ 2,3-dihydro-1H-called | 13 _ 1 -yl]-4- oxobutyric acid (1) 5 - via hydrazine beeline hydrochloride ] 121199.doc -185- 200846322

Add 4 N hydrochloric acid / 1,4-dioxane solution (5.3 ml) to 3-butyl-1-pyridiniumcarboxylic acid tert-butyl ester (500 mg) at room temperature, and spoil at room temperature 3 hour. The reaction solution was concentrated under reduced pressure, and then the mixture was crystallised with hexane for 1 hour. The obtained solid was filtered and dried (vacuum pump, 40 ° C, 1 hour) to obtain 1, 2? The title compound (413 mg). H. NMR (DMSO-d6) δ : 3.12 (2Η, t, J=7.7 Hz) 5 3.67 (2H, t, J=7.7 Hz), 6·75 (1H, d, J=8.5 Hz), 6 · 82 (1H, s), 7·23 (1H, d, J = 8.5 Hz), 9·87 (1H, s), 10.84 (1H, br s). MS (ESI) m/z: 136 (M+H)+. (2) (3R)-[N·(Tertibutoxycarbonyl)amino]-4-(5-hydroxy-2,3-dihydro-1H-indol-1-yl)·4-side oxygen Tert-butyl butyl butyrate [Chem. 177]

Called on the 5-base. Dolantine hydrochloride (413 mg) and Boc_D_Asp(OBu-ten)-OH (commercially available) (616 mg) in DMF (10 ml) suspension, add EDNHC1 (490 mg) at room temperature, HOBt (345 mg) and TEA (1 · 48 ml) were stirred for 15 hours. The reaction mixture was concentrated under reduced pressure and purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , ,J=15.7,7·4 Hz), 3.11 m), 4.85-4.93 (1H,m), 】H-NMR (CDC13) δ : 1·41 (9H, s), dd, J=15.7, 6 ·1 Ηζ), 2.81 (1Η, dd (2H, t, J=8.3 Hz), 4.20-4.36 (2H, (1H, d5 J-8.5 5.04 (1H, s), 5·29 (1H, d, (d)) .3 Hz), "3 Hz", 6.66 (1H, s), 8.04 (1H, d, J = 8.5 Hz) MS (ESI) m/z: 407 (M+H)+.

(3) 4-[5·[[2,4-Bis(trifluoromethyl)oxy]_2,3-dihydro-ih-decadela 1-yl H3RHN-(t-butoxy) Amino]_4_oxetoxybutyric acid tert-butyl ester [Chemical 178]

In a solution of [2,4-bis(difluoromethyl)phenyl]methanol (commercially available) (8 〇〇 _, (10) mi), (3RHN_(T-butoxycarbonyl)amine was added at room temperature. Base]-M5-radio- 2,3-dihydro·1H_吲, a small base) acetobutyloxybutyrate, tert-butyl 6 (121 mg), diphenylphosphine (93 8 mg), &amp; dead (2 2 m toluene bath) (0.163 ml). After the reaction mixture was stirred at room temperature for 15 hr, EtOAc (m.) 121199.doc -187- 200846322

^-NMR (CDC13) δ : 1.42 (9H, s)5 1.43 (9H5 s)5 2.58 (1H dd, J=15.8, 6.1 Hz), 2·83 (1H, dd, J=15.8, 7·4 Hz ), 3 20 (2H, t, J = 8.3 Hz), 4.24 - 4.42 (2H, m), 4.86 - 4.96 (iH m) 5.23-5.33 (1H, m), 5, 29 (2H, s), 6 ·78 (1H, dd, J=8_8 24 Hz), 6·81 (1H, s), 7·83 (1H, d, J=8.0 Hz), 7.93 (1H d J=8.0 Hz), 7.94 (1H, s), 8.13 (1H, d, J = 8.8 Hz). (4) (3R)-Amino-4-[5-[[2,4·bis(trifluoromethyl)benzyl]oxy]·2,3•dihydro-1H·indol-1-yl ]-4-sided oxybutyric acid TFA salt [Chemical 179]

4-[5-[[2,4-Bis(trifluoromethyl)benzyl]oxy]-2,3-dihydro-1Η_ι13-1-yl]-(3 R)-[N- Addition of TFA (1_0 ml) at room temperature to a solution of (t-butoxy)amino]-4-tert-butoxybutyrate tert-butyl ester (47.0 mg) in dichlorohydrazine (4.0 ml) . The reaction mixture was stirred at room temperature for 4 hr and then evaporated. The obtained residue was solidified with diethyl ether-hexane, and the obtained solid was filtered, and dried (vacuum pump, room temperature, 1 hour) to give the title compound (23·0 mg) 〇^-NMR (DMSO-d6) δ : 2.68 (1H? dd, J=17.5? 7.7 Hz)? 3.01 (1H, dd, J=17.5, 5.0 Hz), 3·16 (2H, t, J=8.2 Hz), 4.12-4.28 (2H, m ), 4.44 (1H, dd, J=7.7, 5.0 Hz), 5.31 (2H, s), 6, 87 121199.doc • 188- 200846322 (1H, dd, J=8.8, 2.4 Ηζ), 7·01 ( 1H, s), 7, 96-8.04 (2H, m), 8·09 (1H, s), 8, 14 (1H, d, J = 8.3 Hz). C02H and NH2 were not observed. IR (ATR) cm -1 : 2941,1732, 1653, 1597, 1489,1346, 1273, 1176, 1119, 1084, 1043, 721 . MS (ESI) m/z: 477 (M+H)+. HR-MS (ESI) calculated for C21H19F6N204 (M+H)+ · 477.12490. Found: 477.12219. Called C21H18F6N2〇W.0TFA, calculated for elemental analysis of 0.75H2O: C, 47·74; H, 3.42; F, 28.31; N, 4.64. Found: C, 46·36; H, 3.57; F, 27·75; Ν, 4.53 ° [Example 39] (3S)-Amino-4-sideoxy_4-[5-[[4- Phenyl-3-(trifluoromethyl)phenyl]methoxy]° ϋ ϋ -1 -1 -1 -1 · · · base] butyrate

(1) (3S)-[N-(Tertibutoxycarbonyl)amino group&gt;4.Sideoxy-4-[5-[[4-phenyl-3-(trifluoromethyl)phenyl) ]Methoxy]indole porphyrin 4•yl]butyric acid tert-butyl ester [Chem. 180]

In the same manner as in the step (1) of [Example 32], 5-[(4-phenyl-3-cyclofluoromethylphenyl)methoxy]π porphyrin hydrochloride (〇i2 and B〇c_l_

Asp(OBu-tert)-OH (Watana Chemicals) (87 post), the title compound (〇·17 g) was obtained. 121199.doc 189- 200846322 ^-NMR (CDCI3) δ : 1.37-1.50 (1 8H? m)? 2.52-2.64 (1H5 m), 2.76-2.91 (1H, m)., 3.13-3.25 (2H, m) , 4.28-4.41 (2H, m), 4.86-4.97 (1H, m)5 5.10 (2H, s), 5.26-5.42 (1H, m), 6·82 (1H, dd, J=8.8, 2·5 Hz),6·87 (1H,s), 7.29-7.43 (5H, m)5 7.61 (1H,d,J=8.1 Hz), 7.80 (1H,s), 8.14 (1H,d5 J=9.3 Hz) . MS (ESI) m/z: 641 (M+H)+. (2) (3S)-Amino-4-o-oxy-4-[5-[(4-phenyl-3-di-methylphenyl)-

Oxy] 吲哚 -1 -yl]butyrate [Chem. 181]

In the same manner as in the step (2) of [Example 32], (3S)-N-(2-butoxymethyl)-N-decylamino]-4-sideoxy-4-[ 3-[4-Phenyl-3-trifluorodecylphenyl]methoxy P-piperidin-1-yl]butyric acid tert-butyl ester (0.17 g). ^-NMR (DMSO-d6) 5 : 2.74 (1H5 dd5 1 = 17.6, 7.6 Hz), 3.04 (1H, dd, J = 17.5, 5·0 Hz), 3·17 (2H, t, J = 8.2 Hz ), 4.08-4·31 (2H, m), 4, 40-4.49 (1H, m)5 5.23 (2H, s), 6.91 (1H, dd, J=8.9, 2.6 Hz), 7·05 (1H ,d,J=2.5 Hz),7·28-7·33 (2H,m), 7.48-7.39 (4H,m),7_76 (1H,d,J=8.1 Hz),7.88 (1H,s), 8.01 (1H,d,J = 8.8 Hz), 8.41 (1H, s). 121199.doc -190- 200846322 MS (ESI) m/z : 485 (M+H)+. IR (ATR) cm·1 : 2883, 1720, 1651, 1597, 1485, 1423 〇 [Example 40] (3R)-(N-methylamino)-4- oxo-4-[5-[ (4-Phenyl-3-trifluoromethylphenyl)methoxy]porphyrin-1,yl]butyrate (1) (2R)-[N-(T-butoxycarbonyl) 4-amino] succinic acid 4-methyl ester [化182] η ^ ΗΠΙ

Boc was cooled to -10 °C with methanol (10 ml) under nitrogen, and sulphur sulphur (0.62 ml) was added dropwise. D-Me-Asp(OH) monohydrate (Wabian Chemical) (1·0 g) was added to the reaction solution, and the mixture was slowly stirred to room temperature while stirring. The reaction solution was concentrated to obtain (2R)-(N-decylamino)succinic acid 4-methylhydrazine hydrochloride, which was supplied to the subsequent reaction. !H-NMR (CD3OD) δ : 2.71 (3H5 s), 3.11-3.19 (2H, m), 3.27-3.34 (1H, m), 3.76 (3H, s) 〇(2R)-(N-methyl Adding a saturated aqueous solution of sodium hydrogencarbonate (1 〇mi) to a two-burning solution (10 ml) of amino) succinic acid 4- succinate hydrochloride

Boc 2 〇 (l_6 g) was stirred for 14 hours. 1 n hydrochloric acid was poured into the reaction solution, followed by extraction with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified using a silica gel flash column chromatography (Shanshan high-speed column L) to obtain a titled person (〇·46 g). H-NMR (CD3OD) δ : 1·43 (9H,S), 1.53 (3H,S), 2.97-3 1〇121199.doc -191 - 200846322 (2H,m),3.64 (3H,s),4.86 (1H, s). (2) (3R)-[N-(Tertibutoxycarbonyl)-indole-methylamino]_4_sideoxy[5 [(4-benzyl 3 -oxymethylphenyl)methoxy] , 蜂琳-}·基] methyl butyrate [化183]

(local 1 difluoromethylphenyl) methoxy] σ bow! 13 linne hydrochloride (0.11 g), (2R)-[n-(t-butoxycarbonyl fluorenyl)amino] succinate 4-methyl ester (〇·95 mg), EDC.HC1 (80 Mg), HOBt (56 mg) in DMF solution (5 ml), add ΤΕα (〇·19 ml) at room temperature and stir for 3 days. Concentrate the reaction solution using tantalum gel column chromatography (Bi〇tage 25S) ) Residue obtained by purification> Check the title compound (Q.13 g). φ 1h-NMR (CDC13) δ : 1.49 (9H5 s), 2.41-2.60 (1H, m)5 2.73-2.85 (3H5 m)? 3.09-3.27 (3H? m)? 3.48-3.78 (3H, m)5 3.97-4.15 (2H5 m)5 4.20-4.34 (1H, m)? 5.11 (2H? s)? 5.14-5.55 (lH , m), 6.82 (lH, dd, J = 9.6, 2.2 Hz), 6.87 (lH, s), 7.30-7.43 (5H, m), 7.61 (1H, d, J = 7.1 Hz), 7.80 (1H, s),8·13 (1H,d,J=8.6 Hz) o MS (ESI) m/z : 613 (M+H)+ 〇(3) (3R)-[N-(T-butoxycarbonyl) )_N_mercaptoamino]-4_sideoxy-4_ [5-[(4.phenyl-3-trifluoromethylphenyl) decyloxy] ϋ 丨 n 琳 lin - i _ base] Butyric acid 12I199.doc -192- 200846322 [Chem. 184]

Boc

(3R)-[N-(Di-dibutoxy)-N-methylamino]-4-sideoxy·4_[5-[(4-phenyl-3-trifluoromethylphenyl) A methanol/THF mixed solution (I/2 mi) of methyl methoxy] porphyrinyl] butyrate was added, and a 1 Ν aqueous sodium hydroxide solution (1 ml) was added at room temperature for 1 hour. The reaction solution was concentrated, and 1 Ν hydrochloric acid was added thereto to obtain a ΡΗ value of 2, and then a chloroform/nonanol mixed solution (1 〇 n was used for extraction. The combined extracts were washed with saturated brine and dried with anhydrous sulfuric acid: Solvent removal to obtain (3RHN_(t-butoxycarbonylmethylamino)-4-o-oxy-4-[5-[(4-phenyl-3-dihydrocarbamate-methyl) Methoxy] 丨 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 2.88 (3H,m),3·08-3·34 (2H,m),3·94 *27 (3H5 m) 5.12 ,m), 7.27-7.47 (6H,m),7.66-7.56 (1H,m ), 7·80 (ih 、, s), 8.14 Hz) (2H, s), 5·14-5·57 (1H, m), 6·77-6·92 (2h (!H5 d5 J =8.8 MS (ESI) m/z : 599 (M+H) + (4) (3RH methylamino)-4- oxo-4-[5-"(4 v-benzyl-3-trifluoro) Methoxy], ϋ多琳-l-yl]butyrate [Chem. 185] 121199.doc -193 - 200846322

(3R) [N-(Tertibutoxycarbonyl)-N-methylamino]-'-oxyl_4_[5[(4phenyl-3-difluoromethyl]phenyl)methoxy ]] porphyrinyl]butyric acid (〇.12, 4 N hydrochloric acid / 1,4-dioxane (3 ml) was added at room temperature, and the reaction solution was stirred with diethyl ether. The resulting solid was filtered and dried to give the title compound (64 mg). ΐΗ·Ν· (Γ&gt;Μδ0〇δ: 2·49 (3H, s), 2·80, 3·57 (4H, m) , 4·09 (1H, q, J=9.〇Hz), 4·28 (1H, dd, J=18.1, 8·3 Hz), 4.41 (1H, t, J=6.3 Hz), 5.16 (2H , s), 6.83 (1H, dd, J = 8.8, 2.2 Hz), 6.96-6·98 (1H, m), 7·20-7·25 (2H, m), 7·38-7· 31 (5H, m), 7.68 (1H, d, 8.1 Hz), 7.80 (1H, s), 7.94 (1H, d, J = 8.8

Hz). MS (ESI) m/z: 499 (M+H)+. • HR-MS (FAB) for C27H26F3N204: 499.1845. Measurement value: 499.1813. IR (ATR) cnT1 : 303 1,2924,1724,1649,1597,1570. [Example 41] (3R)-(Methylamino)-4-oxooxy-4-[5-[(4-phenyl-5-trifluoromethyl-2-thienyl)decyloxy] Porphyrin-1-yl]butyrate (1) (3R)-[N-(Tertibutoxycarbonyl)·Ν-Methylamino]-4- oxo-4-[5 -[(4-Phenyl-5-trifluoromethyl-2-nonyl)methoxy]σ引乌朵琳-1-yl]butyric acid II21199.doc -194· 200846322

[化186]

5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]"51 wood was used in the same manner as in [Example 40] (〇C c ^ m ^ 丨) The phytate hydrochloride (0.13 g) gave the title compound (0.16 g). NMR (CDCl3) 3: 1.48 (9H, s), 24i_2 63 (iHm), 2 75_ 2.87 (3H, m), 3.03- 3.26 (3H, m), 3.62-3.74 (3H, m), 3.95- 4.34 (2H, m), 5.01-5.24 (2H, m), 5.38-5.52 (1H, m), 6.71- 6.91 (2H, m ), 7.07 (1H, s), 7.36-7.45 (5H, m), 8.21-8.07 (1H, m) MS (ESI) m/z : 619 (M+H) + (2) (3R)- [N·(Tertibutoxycarbonyl)-N-methylamino]-4-teroxy-4_[5-[[4-phenyl-5-(trifluoromethyl)-2-thienyl) ]methoxy]porphyrin-1-yl]butyric acid 4 [Chemical 187]

In the same manner as in the step (3) of [Example 40], (R)-3-[N·(t-butoxycarbonyl)-N-methylamino]-4-sideoxy-4 was used. -[5-[(4-Phenyl-5-121199.doc-195-200846322 tri-Imethyl-2-thienyl)methoxyH porinyl]butyrate 曱_(〇16 g), obtained The title compound (0.19 g). ^-NMR (CDC13) δ : 1.47 (9Η, s), 2.56 (1H, dd, J=15.9, 5.6 Hz), 2.77 and 2·81 (3H, per s), 3 grabs 3 28 (3h, (4) , 3 98·4 % (2H, m), 5.20 (3H, s), 5.45_5.52 (1H, m), 6 8i (ih, d, j=9 6

Hz), 6.85 (1H, s)5 7.06 (1H, s), 7.37-7.45 (5H, m), 8.13 (1H,d,J=9.8 Hz) 〇MS (ESI) m/z : 605 (M+ H) + 0 (3) (3R)_(decylamino)·'sideoxy•phenyltrifluoromethyl_2_thienyl)methoxy;H-porphyrin-1-yl]butyrate Acid salt

In the same manner as in the step (4) of [Example 40], (3RHN_(t-butoxycarbonyl)-N-decylamino]-4- oxo-4-[5-[( 4-Phenyltrifluoromethyl-2-thienyl]methoxy]indolin-1-yl]butanoic acid gave the title compound (60 mg). NMR (DMSO-d6) δ: 2·57 ( 3H, s), 2.88 (1H, dd, ρ17·4, 6.1 Ηζ), 3·06 (1Η, dd, J=17.2, 6.6 Ηζ), 3.17 (2Η, t5 J=7.6 Ηζ), 4· 17 (1Η, q, J=8.6 Ηζ), 4·34 (1Η, dd, J=18,3, 8·2 ΗΖ), 4·49 (1H, t5 J=6.0 Hz), 5,38 (2H , s), 6.92 (1H, dd, J = 8.8, 2.7 Hz), 7.05 (1H, d, J = 2.5 Hz), 7.41 - 7.51 (5H, rn), 8.02 121199.doc -196- 200846322 ( 1H, d, J = 8.8 Hz), 9_26 (1H, s) 〇MS (ESI) m/z: 505 (M+H)+. [Example 42] (3R)-(N-decylamino) _4•Sideoxy_4_[5_[[2,4_bis(trifluoromethyl)phenyl]methoxy]吲哚琳-1 _yl]butyric acid (1) 5-[2,4-double (trifluoromethyl)phenyl]methoxy porphyrin hydrochloride [Chem. 189]

A solution of 2,4-bis(difluoromethyl)heptyl bromide (Aidrich) (4.86 g), 1-(t-butoxycarbonyl)-5-hydroxyporphyrin (3.8 g) in DMF ( In 100 ml), potassium carbonate (9.0 g) was added at room temperature, and the mixture was heated to 5 {rc for 4 days. After returning the reaction solution to room temperature, the insoluble matter was filtered, and the obtained filtrate was concentrated to obtain 丨_(t-butoxycarbonyl)-5-[2,4"bis(trimethyl)phenyl]methoxyl. The base porphyrin is used in the next step. Dissolving 1-(t-butoxycarbonyl)_5-[2,4-bis(trifluoromethyl)phenyl]methoxyporphyrin in 4 N hydrochloric acid/i,4-dioxane solution (5 In 〇ml), stir at room temperature for 1 day. After the reaction mixture was concentrated, diethyl ether was evaporated toiel H-NMR (DMSO-d6) δ : 3.10-3.22 (2H, m), 3.60-3.77 (2H, m), 5.35 (2H, s), 6.99 (1H, d, J = 8.6 Hz), 7.14 (1H, s), 7·33 (1H, d5 Bu 8·3 Hz), 8·〇2 (1H, d, h8.3 hz) 5 8·ΐ〇(1H, s), 8·15 (1H , d, J = l 〇, 〇 Hz), 10.89 (1H, s). 121199.doc -197- 200846322 (2) 4-[5-[[2,4-bis(difluoromethyl)phenyl]methoxy]. Porphyrin small group]_(3RH(N-second-butoxycarbonyl_N_indenyl)amino]_4· oxobutanoic acid methyl ester [Chemical 190]

5-[2,4-bis(difluoromethyl)phenyl]methoxy porphyrin hydrochloride (〇2〇g) ^ Boc.D-Me.Asp(〇Me).〇H(〇 .l3 g) . EDC · HC1 (0.14 g), H〇Bt (〇.1〇g) in DMF solution (5 ml), DIEA (0.44 ml) was added at room temperature for 2 days. The residue obtained by concentrating the reaction mixture was purified using EtOAc (3): ^-NMR (CDC13) 6 : 4.87 (4H, m), 1·22-1·48 (9H, m), 2.45 2.88-3.25 (3H, m), 3.58-3.78 (3H, m), 3.98-4.37 (2H m) 5.29 (2H? s)5 5.44-5.55 (1H5 m)5 6.63-6.86 (2H5 m)5 7.83 (1H,d,J=7.8 Hz),7·93 (2H,d,Bu 9· 8 Hz), 8 l2 (1H d J=8_6Hz). , ' MS (ESI) m/z : 605 (M+H)+ 〇(3)叩-叩'bis(tri-f-methyl)phenyl]methoxy]d porphyrin"]] (3R) -[N-(Tertibutoxycarbonylmethylamine oxime oxomezepine [Chem. 191] 121199.doc 198- 200846322

4-[5-[[2,4-bis(trifluoromethyl)phenyl]decyloxy]porphyrin-yl]-(3R)-[(N-tert-butoxycarbonyl-N) To a methanol/THF mixed solution (m ml) of methyl oxo]methyloxybutyrate, a 1 N aqueous solution of sodium chloride (1 ml) was added at room temperature and stirred for 1 hour. The reaction solution was concentrated, and m hydrochloric acid was added to give a pH value of 2, and then extracted with a gas/methanol mixture solution (10/1, v/v). The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent, m. !H-NMR (CDCU) δ : 1·40-1·54 (9H, m), 2.48-2.62 (1H m) 2.70-2.85 (3H5 m), 3.06-3.29 (2H5 m)5 3.95-4 33 ' m)5 5.03-5.15 and 5.42-5.51 (total 1H, per m, guanamine isomer), 5.29 (2h s), 6.67-7·00 (2H, m), 7.82 (1H, d, j = 8.3 Hz), 7 85 8 〇〇• (2H, m), 8.12 (1H, d, J = 8.8 Hz). MS (ESI) m/z : 591 (M+H) + 〇(4) 44540 bis(trifluoromethyl)phenyl]methoxy] phthalocyanine·i•yl]_(3R)-(N- Mercaptoalkyl)-4-oxobutyric acid soil [Chem. 192] 121I99.doc -199- 200846322

[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy H porphyrin-bubub (3RHN-(t-butoxycarbonyl)_N-methylamino) Add mtfa (2 ml) at room temperature for 5 hours at room temperature. Concentrate the reaction solution and add the positive residue to the obtained residue. The solid was isolated by filtration and dried to give the title compound (0························· ), 3.47-3.65 (1H, m), 3.96-4.38 (2H, m), 4.51 (1H, t, J = 6.1 Hz), 5·31 (2H, s), 6·78-6·92 (1H , m), 7·01 (1H, d, J = 13.0 Hz), 8.19-7.92 (4H, m). IR (ATR) cnT1: 3079, 2875, 1641, 1579, 1491, 1435, 139〇. Example 43] 4-[5·[[4-(cyclohexyl)-2-(trifluoromethyl)phenyl]methoxy]0 ®® porphyrin-1·yl H3RH methylamino)·4 side Oxybutyric acid (1) (3R)-[N-(t-butoxycarbonyl)·Ν_methylamino]·4_[5_[(4_cyclohexyl-2-difluoromethylphenyl) Methoxy porphyrin 丨 丨 基 ] ] ] ] 甲酯 甲酯 甲酯 199 199 199 199 199 199 199 199 199 199 199 199 199 199 199 199 199 199 199 199

5-[(4-Cyclohexyl-2-trifluorodecylphenyl) decyloxyporphyrin hydrochloride (0.21 g), B〇CD-Me-ASp(〇Me)-〇H (0.13 g ), EDC.HC1 (0.14 g), HOBt (0.10 g) in DMF solution (5 ml), and added TEA (〇.35 ml) for 2 days at room temperature. Rapid gel column chromatography using gelatin

The residue obtained by concentrating the reaction mixture was purified to give the title compound (1%). 1.67-1.96 (6H, 3.01-3.27 (3H, 5·19 (2H, s), !Η-ΝΜΚ (CDCi3) δ : 1.19.1.52 (13Η5 m)5 m),2·42·2·62 (2H ,m),2·71-2·87 (3H,m) m), 3.62-3.73 (3H? m)5 3.88-4.35 (2H m) 5.39-5.55 (1H,m),6·74-6· 87 (2H,m),7·38 (1H,d,J=7 8

Hz),7·51 (1H,s), 7.60 (1H,d,J=7.8 Hz),8·1〇(1H d J=8.6 Hz) 〇' ' MS (ESI) m/z : 619 (M +H)+ 〇(2) (3RHN-(t-butoxycarbonyl)_Nmethylamino]-[7-hexacyclohexyl)-2-(trifluoromethyl)phenyl]methoxy; · Side oxybutyric acid [Chem. 194] Soil_文

(3R)-[N-(T-butoxycarbonyl 121199.doc-201 - 200846322 yl-2-trifluoromethylphenyl)methoxy]porphyrin-1-yl]-4-side oxygen To a decyl alcohol/THF mixed solution (1/2 ml) of decyl hexanoate (176 mg), 1 N aqueous sodium hydroxide solution (1 ml) was added at room temperature for 1 hour. The reaction mixture was concentrated, EtOAc EtOAcjjjjjjjj ^-NMR (CDC13) δ : 1.22-1.45 (15Η, m), 1.59-1.91 (6H? m), 2.48-2.63 (2H, m), 2·70-2·81 (3H, m), 2· 95-3·22 (2H, m), 3.81-4.31 (1H, m), 5·16 (2H, s), 5·45 (1H, d, J=9_3 Hz), 6.75-6.79 (2H, m ), 7.00 (1H, s), 7.38 (1H, d, J = 7.6 Hz), 7.51 (1H5 d5 J = 4.7 Hz); 7.59 (1H? d, J = 8.1 Hz) 5 8.09 (1H? d? J =8.8 Hz). MS (ESI) m / z: 605 (M+H) + o (3) 4-[5-[(4-cyclohexyl-2-trifluoromethylphenyl)methoxy] porphyrin-yl ]-(3R)-(decylamino)-4-oxobutyric acid [Chem. 195]

(3R)-[N_(Tertibutoxycarbonyl)·Ν-methylamino]-4·[5-[(4-cyclohexyl-2-difluorodecylphenyl)methoxy]σ To a solution of the oxo-butyric acid (190 mg) in dichloromethane (1{) ml), tfa (2 ml) was added at room temperature for 23 hours. The reaction solution was concentrated, and the obtained residue was diluted with water, and the pH was adjusted to 7 using 1 N sodium hydroxide, and then the mixture of 121199.doc-202-200846322 (10/1, v/v) was mixed with a gas/methanol mixture. extraction. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent, the obtained residue was purified by a thin layer chromatography. The obtained oil was lyophilized to give the title compound (25 mg). iH-NMR (DMSO-d6) δ : 0.82-1.27 (4H, m), 1.35_1·85 (6H, m), 2.26-2.38 (3Η, m), 2·81 (2Η, t, J=6.5 Ηζ ), 3·10 (2Η, t, J=8.3 Hz), 3.35-3.72 (2H, m), 3·96-4·07 (4H, m), 4.94 (2H, s), 6.78 (1H, dd , JU, 2·6 Hz), 6·89 (1H, s), 7·96 (1H, d, ® J = 8.8 Hz) 5 8.04 (1H5 s) 〇IR (ATR) cm-1 : 2922, 2850 , 1728, 1643, 1620, 1595, 1493. MS (ESI) m/z: 505 (M+H)+. Calculated for the elemental analysis of C26H29F3N204*1.25HC1*H20: c, 5 6·36; Η, 5·87; Cl, 8·00; F, 10.29; N, 5.06. Found: c, 56.52; Η, 5.88; C1, 8.17; F, 10.20; N, 4·91 〇

[Example 44] 4-[5-[(4-Cyclohexyl-3-trifluoromethylphenyl)methoxy]indol-1-yl]-(3R)-(N-decylamino) -4 - oxobutyric acid (1) (31 〇-[1^-(t-butoxycarbonyl)-&gt;^methylamino]-4-[5-[(4-cyclohexyl- 3-trifluorodecylphenyl)methoxy]indolyl-i-yl]·4·methyloxybutyric acid methyl ester [Chem. 196]

4-cyclohexyl-3-trifluoromethylbenzyl vapor (〇·99 g), 丨·(third 121199.doc •203 - 200846322 oxymethyl)-5•hydroxyporphyrin (0.84 g Potassium carbonate (1·48 g) was added to a DMF solution (20 ml) at room temperature, and the mixture was stirred at 6 ° C for 4 days. After returning the reaction solution to room temperature, the insoluble matter was filtered, and the obtained mother liquid was concentrated to obtain (2-butoxycarbonyl)-5-[(4-cyclohexyl-3-trifluoromethylphenyl)methoxy Porphyrin (340 mg) was used in the subsequent step. Dissolving the third butoxycarbonyl)-5-[(4-cyclohexyl-3-trifluoromethylphenyl)methoxyporphyrin (340 mg) in 4 N hydrochloric acid / 1,4-dioxane solution (2 〇 ml), stirred at room temperature for 14 hours. The reaction mixture was concentrated to give 5-[(cyclohexyl-3-trifluoromethylphenyl) decyloxy] sulfonium hydrochloride (460 mg), which was used in the next step. 5-[(4-Cyclohexyl-3-trifluoromethylphenyl)methoxy] σ 嗓 嗓 盐 hydrochloride (185 mg), Boc-D-Me-Asp(OMe)-〇H (0.24 g), EDC.HC1 (0,17 g), HOAt (0.13 g) in DMF solution (5 ml), DIE Α (0·39 ml) was added at room temperature and stirred for 18 hours. The residue was purified by EtOAc EtOAc (EtOAc) 'H-NMR (CDCis) δ : 1.19-1.54 (12H? m)5 1.73-1.89 (2H5 m), 2.45-3.36 (8H, m), 3.48-3.81 (6H, m), 3.92-4.41 (3H, m), 4.52-4.88 (1H, m), 5.01 (2H, s), 5.08-5.56 (1H, m), 6.79 (1H, d, J = 9.1 Hz), 6.84 (1H, s), 7.41 -7.59 (2H,m), 7.65 (1H,s),8·11 (1H,d,J=8.8 Hz) 〇MS (ESI) m/z : 619 (M+H) o (2) 4-[ 5-[(4-Cyclohexyl-3-trifluoromethylphenyl)methoxy]porphyrin-丨-kib (3R)-(N-decylamino)-4· oxobutanoic acid I21199.doc -204- 200846322 [Chem. 197]

(3R)H(tert-butoxycarbonyl)-N-methylamino]4-[5-[(4-ylidene-3-ylfluoromethylphenyl)methoxy]anthracene Add a 1 N aqueous solution of sodium hydroxide (1 ml) to apricot at room temperature in a methanol/THF mixed solution (1 ml / 2 ml) Stir for 14 hours. The reaction mixture was concentrated, 1 N hydrochloric acid was added, and the precipitated solid was filtered, and dried under reduced pressure to give (3RHN-(t-butoxycarbonyl) decylamino hydrazine _[5_[(4·cyclohexyl 3- Trifluoromethylphenyl)methoxy]porphyrinyl]_4_sideoxybutyric acid, which is used in the subsequent step. : (3R)_[N-(Third butoxide) Alkylcarbonyl)-anthracene methylamino]•heart [(4·cyclohexyl-3_trifluorof-phenyl)methoxy] is called podoline + keb 4_ oxobutyric acid dichloride In the smoldering solution (1 〇ml), ☆ add A (i ml) at room temperature and stir for 4 days. Add the i N sodium hydroxide solution to the residue obtained by concentrating the reaction solution to adjust the pH to 6. The gas/methanol mixed solution, v/v) was extracted. After the extract was dried over anhydrous sulphuric acid, the solvent was evaporated under reduced pressure, and the residue obtained was purified by thin layer chromatography, and then lyophilized by hexane to obtain the title. Compound (28 mg). One

H-NMR (CDC13) δ : 1.10-1.54 (6H, m), 1.68-1 93 (5H 2.48-2.80 (5H, m), 2.82-2.99 (1H, m), 3·〇6-3 • 27 ( 2H,m) 3.93-4.37 (2H,m),4·98 (2H,s),6.64-6 85 • UH,m)5 7·4ί 121199.doc -205- 200846322 (1H,d,J=7.8 Hz), 7.51 (1H, d, j = 81 Hz), 7.63 (1H, s), 8.11 (lH, d, J = 8.3 Hz). MS (ESI) m/z: 505 (M+H) </RTI> </RTI> [ </ RTI> 4-[5-(4-cyclopentyl-3-trifluoromethylphenyl)methoxy] 〇 哚 - - 1-based]-(3R)-(N-decylamino)-4_ oxoxybutyric acid (1) 1-(t-butoxycarbonyl)-5-[(4-cyclohexyl-3_) Trifluoromethylphenyl)nonyloxy]porphyrin

[化198]

a solution of 4-cyclopentyl-3-trifluorodecylbenzyl chloride (〇·72 g), 1-(2-butoxycarbonyl)-5-hydroxyporphyrin (0·78 g) in DMF ( 15 ml) f, potassium carbonate (1.14 g) was added at room temperature, and heated to 8 ° C to stir off i day. After the anti-hemp solution was returned to room temperature, the insoluble material was filtered, and the residue obtained was purified by silica gel flash column chromatography (Biotage 40M) to give the title compound (0.97 g) as a colorless solid. (2H,t,J=8.7 !H-NMR (CDC13) δ : 2·17-1·21 (20H, m), 3.06 s), 5.00 (2H, s), Hz), 7.54 (1H, d,

Hz),3·37 (1H,t,J=8.7 Hz), 3.97 (1H 6.74-6.81 (2H,m),7·47 (1H,d,J=8.3 J = 6.5 Hz), 7.64 (1H, s). (2) 5·[(4·Cyclohexyl-3-trifluoromethylphenyl)methoxy] porphyrin hydrochloride [Chem. 199] 121199.doc -206- 200846322

Dissolving hydrazine tert-butoxy)-5-[(4-cyclohexyltri-l-methylphenyl)methoxy]+dolin (0.97 g) in 4N hydrochloric acid/M oxaloxane solution (2〇mi In the middle, it was disturbed for 3 days at room temperature. The reaction mixture was concentrated, and diethyl ether was added to the residue to give the obtained solid, which was dried to give the title compound (0.76 g).

W-NMR (DMSO-d6) δ : 1·48·1·76 (4H, m), nl 89 (2H, m)5 1.89-2.09 (2H5 m)5 3.10-3.29 (2H5 m)5 3.32-3.60 (2H m)? 3.69 (2H, t5 J=7.7 Hz)? 5.17 (2H, s), 6.98 (1H) dd! J=8.7, 2.6 Hz), 7·12 (1H, d, J=2.5 Hz) , 7.31 (in,d,J=8 6

Hz), 7·55-7·75 (3H, m), 1〇·64 (1H, s). (3) (3R)-[N-(Tertibutoxycarbonyl)-N-decylamino M_[5_[(4·cyclononyl-3-difluoromethyl) methoxy]σ "Duolin-i-based"-heart side methyl oxetine acid [Chem. 200]

5-[(4-Cyclohexyl-3-trifluorodecylphenyl)methoxy]porphyrin hydrochloride (0.20 g), B〇c_D-Me-Asp(OMe)-OH (0.13 g) , EDNHC1 (0.14 g), HOAt (0.10 g) in DMF solution (5 ml), and added 121199.doc -207-200846322 and DIEA (0.87 ml) at room temperature for 14 hours. The reaction mixture was concentrated, and the obtained residue was purified using EtOAc (EtOAc)

W-NMR (CDC13) δ : 1.32-1.91 (15H, m), 2.01-2.15 (2H, m), 2·40-2·62 (1H, m), 2·66-2·85 (3H, m ) 5 3.04-3.44 (3H m), 3.60-3.78 (4H, m), 3·98-4·34 (2H, m), 5·〇2 (2H, s), 5.08-5.58 (1H, m) ,6·78 (1H,d,J=9.3 Hz), 6.83 (1H,s) 7·47 (1H,d,J=8.6 Hz),7·54 (1H,d,J=8.3 Hz), 7.65 (1H, _ s) 5 8·11 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 605 (M+H). (4) 4-[5-[(4-Cyclopentyl-3-trifluoromethylphenyl) decyloxy] porphyrin^-ylbu(3R)_(N-methylamino)-4 - side oxybutyric acid [Chem. 201]

(3R)-[N-(decidinoxy)-N-methylamino]-4-[5-[(4·cyclopentyl 3-dimethylmethyl)methoxy] 113 ϋ ϋ ϋ -1 -1 - -1 -4 -4 - oxobutyric acid methyl hydrazine (0.21 g) in methanol / THF mixed solution (1/2 ml), adding 1 N aqueous sodium hydroxide solution at room temperature (0.70 ml) was stirred for 14 hours. The reaction solution was concentrated, and after adding 1 N hydrochloric acid to pH 2, the mixture was extracted with a mixture of chloroform and decyl alcohol (10/1, v/v), and the combined extracts were washed with saturated brine. Drying with anhydrous sodium sulfate gives (3R)-[N-(t-butoxycarbonyl)-methyl 121199.doc-208 - 200846322-aminocyclopentyl-3-trifluoromethylphenyl)methoxy] Tetralin-1-yl-4-pyreneoxybutyric acid was used in the subsequent step. (()-Team (T-butoxycarbonyl)·Ν_Methylaminopurine_[5_[(4·cyclopentyltrifluoromethylphenyl)methoxy]porphyrin_丨_yl] To a solution of _4_oxetoxybutyric acid in dichloromethane (10 ml), TFA (〇5 mi) was added at room temperature and stirred for 3 hours. The reaction mixture was concentrated, and a hydrazine aqueous solution of sodium hydroxide and 1N hydrochloric acid were added to the residue to adjust the pH to 6 and extracted with a mixture of chloroform / decyl alcohol (10/1, v/v). The solvent of the extract was distilled off, and the obtained residue was purified by thin layer chromatography. Then, n-hexane was added and solidified. The resulting solid was filtered and dried to give the title compound (671 mg). !H_NMR (CDC13) δ : 1.34-2.05 (9H, m), 2·37-3·42 (8H, m), 3·77-4·31 (3Η, m), 4.92 (2Η, s) , 5·87 (1Η, br s), 6·46-6_78 (2H, m), 7.49-7.29 (2H, m), 7.57 (1H, s), 8·04 (1H, s). MS (ESI) m/z : 491 (M+H) 〇IR (ATR)cnT1 : 2954, 2871,1716,1653,1616,1593,1489, 1377 〇® C26H29F3N2〇4*〇.〇5HCb Element of H20 Calculated for C, 61, 19; H, 6.13; Cl, 0·35; F, 11.17; N, 5.49. Found: C, 60·97; H, 5.93; Cl, 0_40; F, 11.14; N, 5.45. [Example 46] (3R)-(N-decylamino)-4-[5-(3-cyano-4-cyclohexylphenyl)methoxy]-4-indenyl group.弓卜朵琳-1 -yl]-4-sided oxybutyric acid (1) 1_(t-butoxyindolyl)-5-(3-cyano-4-cyclohexylphenylmethoxyl哚琳[化202] 121199.doc -209- 200846322

To 3-cyano-4-cyclohexylbenzyl alcohol (〇·80 g), chlorine sulfite (10 ml) was added at room temperature, and the mixture was warmed to 7 〇t: stirred for 4 hours. The reaction solution was returned to warmness and concentrated, and the obtained residue was dissolved in Dmf (20 ml), and 1-(t-butoxycarbonyl)-5-hydroxy porphyrin (〇·66 g) was added at room temperature. And _ potassium carbonate (1.2 g), warmed to 7 (TC stirred for 14 hours. After the reaction solution was returned to room temperature, 'filtered insolubles. The filtrate was concentrated and purified by gel column chromatography (Biotage 40S)) The residue was obtained to give the title compound (d,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, , 3.90-4.07 (2H, m), 4.99 (2H, S), 6.73 (1H, d, J = 9.6 Hz), 6.78 (1H, s), 7·37 (1H, d, J = 8.3 Hz), 7·57 (1H, d, J = 8.1 Hz), 7.66 (1H, s) φ 5-(3-cyanocyclohexylphenyl decyloxy) porphyrin hydrochloride [ 203]

1-(Tertilybutoxycarbonyl)-5-(3-cyano-4-cyclohexylphenyl)methoxyl ° °Dollen (0.91 g) was dissolved in 4 N hydrochloric acid / 1,4-di The mixture was stirred at room temperature for 13 hours in a simmering solution (30 ml). After concentrating the reaction mixture, the precipitated solid was filtered, washed with EtOAc EtOAc EtOAc EtOAc. W-NMR (DMSO-d6) δ : 1.23-1.53 (6H,m),1·65{87 (4H m),2.74-2.88 (1H,m)5 2.97-3.17 (2H,m),3·6 (Μ·32 (1H m),3·61·3·73 (2H,m),5·12 (2H,s), 6.87-6.99 (1H,m) 7.10 (1H3 s)5 7.25 (1H5 s) 3 7.45-7.61 (1H5 m)? 7.71 (1H&gt; dd^ 1·7 Hz), 7·82 (1H, d, J=1.5 Hz) (3) (3RHN_(Tertibutoxycarbonyl)-N Methylamino]-4-[5·[(3-cyano-4-cyclohexylphenyl)methoxy]porphyrin-1-yl]-4-oxobutanoic acid methyl ester 204]

5-(3-Cyano-4-cyclohexylphenylmethoxy) porphyrin hydrochloride (〇21

g), Boc-D_Me-Asp(OMe)-OH (0.13 g), EDC.HC1 (G.19 g), HOAt (0.14 g) in DMF solution (5 ml), add DIEA at room temperature (0 · 87 ml) Stir for 14 hours. The reaction mixture was concentrated, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 12H, m),1·68-1·99 (4H,m),2·48-2·59 (1H,m),2·71·2·88 (3H, m),2·88-3· 04 (1H, m), 3.03-3.30 (3H, πι) 5 3·57-3·77 (4H m), 3.98-4.31 (2H, m), 5.〇l (2H? s)? 5.07-5.57 (1H5 m)5 121199.doc -211 . 200846322 6·76 (1H,d,J=8.8 Ηζ),6·82 (1H,s),7.37 (1H,d,Bu 8·1

Hz),7·56 (1H,dd,J=8.3, 2·4 Hz), 7.66 (1H,s),8·11 (1H,d, J=8·8 Hz) 〇(4) 4-[ 5_[(3_Cyano-4_cyclohexylphenyl)methoxy]tetradoline+yl]·(3R) (N-methylamino side oxybutyric acid [Chem. 205]

(3R)-[N-(Tertibutoxycarbonylmethylamino) bucket [5 = [Kinyl cyano-4-cyclohexylphenyl) methoxy] σ 哚 porphyrinyl 4 4 side oxygen Methyl butyl butyrate (0.22 g) in methanol / hydrazine solution (1/2) was added and stirred at room temperature for 2 hrs of aqueous sodium hydroxide (0.76 ml). The reaction solution was concentrated, and the pH was adjusted to 2 by adding 1 N hydrochloric acid, and then extracted with a mixture of chloroform/methanol (1 〇/1, v/v). The combined extracts are cleared with saturated saline

The washing was carried out with anhydrous sodium sulfate. Taking the solvent to obtain (3r)-[n_(t-butoxycarbonyl)-N-methylamino]-4_[5_(3-cyano-4-cyclohexylphenyl)methoxy P-porphyrin · Side oxybutyric acid, which is used in the subsequent step 0 to (3R)-[N-(indenyloxybutoxy)-n-methylamino]-'[5-(3-cyanide) Base _ 'cyclohexylphenyl) decyloxy], a solution of porphyrin-side oxybutyric acid in dichloromethane (10 ml), at room temperature, TFA (〇5 ml) was added and stirred (1). In the residue obtained by concentrating the reaction solution, % 〇 1 N gas oxidized sodium water solution 121199.doc -212-200846322 liquid and 1 N hydrochloric acid were adjusted to a value of 6, and the chloroform/methanol mixed solution (10) was extracted. The extract was dried over anhydrous sodium sulfate, and the residue obtained by solvent removal under reduced pressure was purified by thin layer chromatography, and diethyl ether was added thereto to be solidified. The resulting solid was taken and dried to give the title compound (39 mg) 〇咻 1 _so_d6) s: ^ 57 (6H, m), 丨63 ι 89 (10) m), 2.49 (3H, s), 2.60 ( 1H, dd, J = i6.5, 5·5 Ηζ), 2·84 (1H, t, J-11.6 Hz) 5 3.13 (2H? t? J=8.2 Hz), 3.37 (1H5 q5 J.6.9 Hz )^ 3·86 (1H,t,J=6.9 Hz), 4,00-4.38 (2H,m),5·08 (2H,s), 6.81 (1H,d5 (four)·1 Hz), 6.95 (1H , s), 7·53 (1H, d5 J=8.3 Hz), 7.70 (1H, d, J = 7.8 Hz), 7·81 (1H, s), 8.00 (1H, d, J = 8.8 Hz) 〇 , MS (ESl) m/z : 462 (M+H) 〇IR (ATR) cnT1 : 3032, 2925, 2852, 2224, 1720, 1653, 1595 1489 . ’ 5

Calculated for elemental analysis of C27H31N304.1.75H20: c, 65/77; H 7.05, N, 8.52. Found: c, 65·62; H, 6.79; N, 8.22. [Example 47] 4-[5-[(4-Cyclopropyl-3-trifluoromethylphenyl)methoxy]porphyrin-1-yl]-(3ΙΙ)-(Ν-methylamine) ))-4-oxobutyric acid (1) (3R)-[N-(Tertibutoxycarbonyl)_N-methylaminopurine·[5_[(4-cyclopropyl-3-trifluoro) Methyl phenyl) decyloxy] porphyrin-yl]-^ methyl acetobutanoate [Chem. 206] 121199.doc -213- 200846322

5-[(4-Cyclopropyl-3-trifluoromethylphenyl)methoxy]σ porphyrin hydrochloride (123 mg), B〇cD-Me-ASp(〇Me)-〇H (87 mg), EDC.HC1 (96 mg), HOAt (67 mg) in DMF (5 ml), EtOAc. The reaction solution was poured into ice water and extracted with ethyl acetate. The combined extracts were washed with ice water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue obtained was purified mjjjjjjj W-NMR (CDC13) δ : 0.68-0.81 (2H, m), 0.97-1.11 (2H, m) 1.48 (9H, s), 2.10-2.28 (lH, m), 2.47-2.59 (lH, m), 2.69- 2.87 (3H,m), 3.01-3.27 (3H,m),3·51·3·77 (3H,m),3·94. 4.36 (2H,m),5.01 (2H,s),5.04 -5.55 (1H,m)5 6·77 (1H d J=8.8 Hz),6·77 (1H,s),7.04 (1H,d,J=7.4 Hz),7.47 (iH d,J=7.8 Hz) ), 7.66 (1H, s), 8.11 (1H, d, J = 9.3 Hz). MS (ESI) m/z: 577 (M+H). (2) 4-[5-[(4-Cyclopropyl-3-trifluoromethylphenyl) decyloxy] porphyrin-^ kib (3R)-(N-methylamino)·4 ·Side oxybutyric acid [Chem. 207] 121199.doc -214- 200846322

(3R)-[N-(Tertibutoxycarbonyl)-sodium methylamino]-4-[5-[(4-cyclopropyl-3-trifluoromethylphenyl)methoxy]0 Add 1 N aqueous sodium hydroxide solution at room temperature to a mixture of porphyrin-;1_yl]_4_methyloxybutyric acid methyl ester (88 mg) in methanol/THF (〇·3 ml/〇6 ml) (0·60 ml) Stir for 3 days. The reaction solution was concentrated, and 1N hydrochloric acid was added to make pH 2, and then extracted with a mixture of chloroform/methanol (10/1, v/V). The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain (3R)-[N·(t-butoxycarbonyl)_N-methylamino]-4-[5·[(4-cyclopropyl-3-trifluoromethylphenyl)fluorene Oxy], porphyrin-1-yl]_4_ oxoxybutyric acid, which was used in the subsequent step.

In the above (3R)-[N-(2-butoxycarbonyl)-indole-methylamino]-4_[5_[(4_%propyl-3-difluoromethylphenyl)decyloxy]η To a solution of the oxo group of oxobutyric acid in 2 g of methane (5 ml), TFA (G. 5 ml) was added at room temperature for 8 hours. In the residue obtained by concentrating the reaction liquid, the aqueous solution of sodium hydride and i N hydrochloric acid were added to adjust the pH to 6, and the mixture was extracted with a chloroform/methanol mixed solution (10/1, WV). The extract was dried over anhydrous MgSO.sub.sub.sub.sub.sub. ^-NMR (CD3〇D) δ : 2.42 (2Η, t, J=7.〇Hz)&gt; 2 89 (2H} tj &gt;7.0 Hz), 3.34 (2H, s), 3 53 (2H, s ), 4 〇 7 (2h, ^, (4) 4

Hz^ 5·〇7 (2H, s)5 6.82 (1H, s), 6.92 (lH&gt; s), 6.95 (1H, d, 121199.doc -215 - 200846322 J=8.3 Ηζ), 7·02 (2H ,d,J=7.1 Ηζ),7·19 (1H,d,J=7.3 Hz), 7.39 (2H,t,J=8.0 Hz), 7.61 (1H,d,J=9.〇Hz),7.78 (1H, s), 8.05 (1H, d, J = 9.0 Hz). MS (ESI) m/z: 467 (M+H). [Example 48] (3R)-(N-Methylamino)-4-oxoyl_4·[5·[(ΐ-phenyl-5-trifluoromethylindol-3-yl)decyloxy ]-2,3-dihydro-indole-σ-bend-1-yl]butyric acid (1) (3R)-[N-(t-butoxycarbonyl)-fluorene-methylamino] side oxygen 4--4-[5-[(1-Phenyl-5-trimethylsulfanyl-1Η-° than sal-3-yl)nonyloxy]-2,3-dihydro-1Η-吲哚-1 -yl]methyl butyrate [化208]

Add b〇c_d_m&amp;Α3ρ to 5-[(1-phenyl-5-trifluoromethyl-1Η-pyrazolyl) decyloxy], porphyrin (183 mg) in DMF solution (1 〇ml) (〇Μ^_ 〇H (109 mg), EDOHCl (117 mg), HOBt (82 5 mg), and DIEA (259 μΐ) were stirred at room temperature for 2 days at room temperature. Saturated hydrogencarbonate was added to the reaction mixture. After the aqueous layer was extracted with ethyl acetate, EtOAc (EtOAc m. NMR (CDC13) δ: 1.48 (9H? s) 2 , dried over anhydrous magnesium sulfate and purified by flash chromatography on silica gel column s), 2.52-2.56 (1H, m), 2.78 121199.doc -216 - 200846322 2.81 (3H, m), 3.09-3.21 (3H, m), 3.66-3.70 (3H, m), 4.03-4·15 (2Η, πι), 4·24-4·26 (1Η, πι), 5 ·11·5·ΐ2(2Η,πι),6·83-6·86 (2H,m),6·91 (1H,s),7.48-7.49 (5H,m),8.12 (1H,d,J = 8.8 Hz). MS (ESI) m/z: 603 (M:10). (2) (3R)-[N-(2,4-Butoxycarbonylmethylamino)-4_sideoxy[5-[(l-phenyl-5-trifluoromethyl-1Η^bisazolyl)曱 ] ] ] ] ] ] σ σ σ σ σ -1 -1 -1 -1 -1 -1 -1 -1 -1 -1

(3R)-[N-(Tertilybutoxycarbonyl)_Teammethylaminopyridinium-sideoxy[5-[(1-phenyl-5-trifluoromethylpyrazole-3-yl) A Methyl oxy] 2,3 • dihydro· 1Η-indol-1-yl]butyrate (225 mg) was dissolved in 5 % methanol / THF solvent (16 ml) - 1 n aqueous sodium hydroxide solution was added ( 8 〇ml), stir at room temperature overnight. To the reaction mixture, 1 N hydrochloric acid was added to adjust the pH to about 6. After the aqueous layer was extracted with 10% methanol/chloroform solvent, the combined extracts were washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (1 52 mg). 'H-NMR (CDC13) δ : 1.47 (9Η, s)? 2.56 (1H5 d? J=16.1 Hz), 2.79 (4H5 d3 1=10.7 Hz), 3.12-3.19 (2H, m)? 3.98-4.06 ( 1H? m),4·22-4·23 (1H,m),5·12 (2H,s), 5.46-5.47 (1H,m), 121199.doc -217- 200846322 6.85-6.89 (2H,m ),6·91 (1H,s),7·48-7·49 (5H,m),8·12 (1H,d5 J=8.5 Hz) 〇MS (ESI) m/z : 589 (M+H )+. (3) (3R)-(N-Methylamino)_4_p-oxyphenyl·5-trifluoromethyl-111-pyrazolyl)nonyloxy]-2,3-dihydro-1H- Mercapto]butyric acid [Chem. 210]

(3R)-[N-(Tertidinoxycarbonyl)-indole-methylamino]_4_sideoxy_4_[5-[(1-phenyl-5-trifluoromethyl]_·ι_ .Bistazole-3_yl)methoxy]_2,3_dihydro-1Η-indol-1-yl]butyric acid (152 mg) dissolved in 1% TFA/di-gas methane solution (10 ml) Stir at room temperature for 4 hours. After distilling off the solvent, the residue was purified by reverse phase separation HPLC &gt; to afford the title compound (5 1 mg). ^-NMR (CD3OD) δ : 2.55-2.59 (1H5 m)3 2.73 (3H5 s)5 2.78-2·82 (1H,m), 3.25 (2H,t,J=8.3 Hz),4.13-4.20 (1H , m), 4.25-4.32 (lH, m), 4, 41-4.44 (lH, m), 5.14 (2H, s), 6.87-6.90 (1H, m), 6·99-7·01 (1H, m), 7.04 (1H, s), 7.48-7.50 (2H, m), 7·55-7·56 (3H, m), 8.10 (1H, d, J = 8.8 Hz). IR (ATR) cnT1 : 1655,1595,1489,1389,1290,1228,1184, 1128, 1086, 987, 690 〇 MS (ESI) m/z ·· 489 (M+H)+. HR-MS (ESI): Calcd.: 422.21.21.21.21.21.21. Calculation of the elemental analysis of C24H23F3N4〇4.〇.〇74CF3COOH.1.25H20: C, 55.84; H, 4.96; F, 11·78; N, 10.79. Found: C, 56.12; H, 4.66; F, 11.48; N, 10-67. [Example 49] 4-[5-[3-(2,4-Difluorophenyl)propoxy]-bendoline (3R)-(N-methylamino)-4- side Oxybutyric acid (1) 4-[5-[3-(2,4-difluorophenyl)propoxy]-1-indolyl]_(3R)_(Ni-amino)-4 ·Phenyloxybutyrate butyrate [Chem. 211]

1-(Tertibutoxycarbonyl)-5-[3-(2,4-difluorophenyl)propoxy]porphyrin hydrochloride (269 mg), Boc-D-Me-Asp ( OMe)-〇H (216 mg), EDOHCl (237 mg), HOBt (167 mg), TEA (575 μΐ), and DMF (10 ml) were mixed with sandalwood for 14 hours. The reaction mixture was diluted with ethyl acetate (2 mL) and washed with brine (2×1 00 ml) and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography (m. 1H-NMR (CDC13) 3 : 1.48 (9H, s), 2·00-2·09 (2H, m), 2·54 (1Η, dd, J=15.7, 5·5 Ηζ), 2.76-2.82 ( 5Η,m),3.05-3.27 (3Η, m), 3.64-3.75 (3H,m),3·92 (2H,t,J=6.1 Hz), 3.98-4.31 (2H,m),5·15 ( 0·5Η, br s), 5.50 (〇·5Η, dd, J=8.9, 5·5 Hz), 6.70 (1H, dd, J=8.9, 2.3 Hz), 6.73·6·82 (3H, m), 7.18-7.10 121199.doc -219- 200846322 (1H,m),8·〇9 (1H,d,J=8.5 Hz). MS (ESI) m/z: 533 (m+H)+. (2) 4-[5-[3-(2,4-Difluorophenyl)propoxy porphyrinyl]-(311)-(]^_methylamino)-4- oxetidine Acidate [Chem. 212]

Boc〆1^,〇

〇 4-[5·[3·(2,4-Difluorophenyl)propoxy]-:[- porphyrinyl]methylamino)-4, oxime acetobutanoate (302 THF (4,56 ml) and 0.25 N aqueous sodium hydroxide solution (4.65 ml) were added and stirred for 17 hours. 1 N hydrochloric acid was added to the reaction solution to make it acidic, and extraction was carried out with 20% methanol/chloroform (2 x 200 ml). The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. A 4 N hydrochloric acid/1,4-dioxane solution (10 ml) was added to the residue, and the mixture was dropped for 5 hours. The reaction mixture was concentrated, and then crystallised from diethyl ether.

i-NMR (DMSO-d6) δ ·· 1.93-2.02 (2H,m),2·57 (3H,s) 2·75 (2Η,t,J=7.4 Ηζ), 2.85-3.98 (6Η,m) , 4.18 (1Η GJ = 8.8 Hz), 4·35 (1H, q, J=9.3 Hz), 4.47 (1H, t, J=6.2 Hz) 6.77 (1H, dd, J=8.8, 2.7 Hz), 6 ·88-6·91 (1H,m),6,98-7·05 (1H,m)5 7.14-7.21 (1H,m),7·39-7·32 (1H,m),8.00 (iH , d J = 8.8 Hz). The proton peaks of CO 2 H and NHHC 1 were not observed. MS (ESI) m/z: 419 (M+H) + 0 121199.doc -220 - 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Cl, 9_46; F, 8·11; Ν, 5.98. Found: C, 56.04; Η, 5.48; F, 7.75; Ν, 5.83 〇 [Example 50] 3-[[2-[5-[[2,4-bis(trifluoromethyl)benzyl]oxy) ]·2,3·Dihydro-1Η-吲哚-1-yl b 2-sided oxyethyl]amino]propionic acid TFA salt (1) 3-[[2-(benzyloxy)-2- Trioxybutyl]ethyl]amino]propionic acid (Kim,

Jin Mi; Roy, Rene· Carbohydrate Research (1997), 295 (3), 173-179.) [Chem. 213]

To a solution of tert-butyl 3-aminopropionate (commercially available) (300 g) in acetonitrile (13 〇^1), add 2-bromoacetic acid benzyl ester (commercially available xl 〇 5 ml) at room temperature. Stir at 85 ° C for 15 hours. After it was allowed to cool to room temperature, the residue was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal lH-NMR (CDC13) δ : 1.45 (9H? s), 2.42 (2H? t? J=6.7 HZ) 2.86 (2H, t, J=6.7 Hz), 3·46 (2H, s), 5.17 (2H , s), 7.29-7.40 (5H, m). No NH was observed. MS (ESI) m/z: 294 (M+H)+. (2) 3-[N-[2-(Benzyloxy)-2-oxoethoxyethyl]_N_(t-butoxycarbonyl)amino]propionic acid tert-butyl ester [Chem. 214] 121199.doc -221 - 200846322

In a solution of 3_[[2-(benzyloxy)-2-oxoethyl]amino]propionic acid tert-butyl ester (1 〇〇mg) in dichloromethane (5·〇ml), in a room Saturated sodium bicarbonate/aqueous solution (5.0 ml) and Boc2O (90.0 g) were added at room temperature, and the mixture was stirred at room temperature for 5 hours. After separating the reaction mixture, the aqueous layer was extracted with chloroform (2 〇mi). The organic layer was combined and dried over anhydrous sodium sulfate. The resulting residue was purified using EtOAc EtOAc (EtOAc) (CDC13) δ : 1.34 (1/2 of s) 5 1·42 (1/2 of 9H, s), 1·43 (1/2 of 9 Η, s), 1·55 (1/2 of 9) s)5 2.50 (1/2 of 1/2, t, J = 6.7 Hz), 2·55 (2H of 1/2, t, J=6.7 Hz), 3·49 (2H of 2H, t, J =6.7 Hz),3·54 (1/2 of 2H, t, J=6.7 Hz), 4·00 (1/2 of 2H, s), 4·09 (1/2 of 2H, s), 5 · 15 (2H, s), 7.28-7.40 (5H, m). MS (ESI) m/z: 394 (M+H (3) 2-[N-(t-butoxycarbonyl)-indole-[3-(t-butoxy)-3-oxoxypropane Amino]acetic acid [Chemical 2 15]

a solution of 3-(N-[2-(benzyloxy)-2-oxoethylethyl(t-butoxycarbonyl)amino]propionic acid tert-butyl ester (125 mg) in methanol (5.0 ml) Add 5% to 121199.doc -222- 200846322

After Pd/C (90.0 mg), it was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ), 3·99 (2H, br s). COOH was not observed. HR-MS (ESI) · C6H10N 〇 6 (M+H-isobutene (57)-isobutene (57))+ Calculated: 192.05081. Found: 192.079072. (4) 3-butylbenzyl 5-(benzyloxy)-1-pyrolinecarboxylic acid • [Chem. 2 16]

Adding carbonic acid _ (6·34 g) and brominated benzylidene at room temperature in a solution of 3-hydroxy-1-pyridinium formate (3·6〇g) in acetonitrile (7〇ml) (2.73 ml). After stirring at 90 ° C for 3 hours, it was allowed to cool to room temperature and filtered. The resulting residue was purified using EtOAc (EtOAc) (EtOAc) h-NMR (CDC13) δ : 1,55 (9H, s), 3.05 (2H, t, J = 7.5 Hz), 3·96 (2H, br s), 5.02 (2H, s), 6·77 ( 1H,d,J=8.8 Hz), 6.80 (1H, s), 7.22 (1/2 of 1H, bi* s), 7.28-7.44 (5H, m), 7.74 (1/2 of 1H, br s) 〇MS (ESI) m/z : 326 (M+H)+. (5) 5_(Benzyloxy) porphyrin hydrochloride 121199.doc -223 - 200846322 [Chem. 217]

To a solution of tert-butyl 5-(benzyloxy)_1_carbolinecarboxylic acid (4·50 §), 4 N hydrochloric acid / ι, 4-dioxane (75 ml) was added at room temperature. After 30 minutes (precipitation was observed), diethyl ether (200 ml) was added and stirred at room temperature for 15 hours. The precipitated solid was collected by filtration and dried (yield, 40°C, 2 hr) to give the title compound (3.31 g). W-NMR (DMSO-d6) δ : 3.15 (2H, t, J = 7.8 Ηζ), 3·69 (2H, t, J = 7.8 Hz), 5·12 (2H, s), 6.97 (1H , dd, J = 8.8, 2.4 Hz), 7.11 (1H, d, J = 2, 4 Hz), 7.29-7.45 (6H, m). No NH was observed. MS (ESI) m/z : 226 (M+H)+ 〇

(6) 3-[N-[2-[5-(Benzyloxy)-2,3-dihydro-1H-indol-1-yl]-2-yloxyethyl]·Ν·(第Tributyloxy] benzyl]amino] propionic acid tert-butyl ester [Chem. 218]

5-(Benzyloxy) porphyrin hydrochloride (2.0 g) and 2-[&gt;^(t-butoxycarbonyl)-N-[3-(t-butoxy)- 3-D-mercaptopropyl]amino]acetic acid (2.78g) in DMF (50 ml) suspension, add EDNHC1 (2.20 g), HOBt (1.55 g), LV ^ f V from room temperature TEA (5.32 ml) was stirred for 15 hours. Concentrate the reaction solution under reduced pressure, and add ethyl 121199.doc -224-200846322 acid ethyl acetate (7〇11), saturated aqueous sodium hydrogen carbonate solution (70 ml), and water. (5 〇W) was partitioned, and the aqueous layer was extracted with ethyl acetate (5 mL). After combining organic X X &quot;, water stone IL dry, the solvent was distilled off under reduced pressure. The residue obtained was purified using silica gel flash chromatography (Biotage 4 EtOAc) to give the title compound (3-7 g). 'H-NMR (CDC13) δ : 1.38-1.57 (18Η, m), 2.54.2.64 (2H&gt; m), 3.12-3.22 (2H, m), 3.54-3.63 (2H, m), 3.96-4.14 (2H ,

m), 4.17 (2H, s), 5.03 (2H, s), 6.75-6.88 (2H, m), 7.25-7.48 (5H, m), 8.08-8.16 (1H, m). MS (ESI) m/z: 511 (M+H) + 〇(7):3_[N_(2 -butoxycarbonyl)·Ν·[2_(5-yl-dihydroindol-1-yl)-2 -Sideoxyethyl]amino]propionic acid tert-butyl ester [Chem. 219]

3-[N_[2-[5-(Hydroxy)_2,3-dihydroindolyl]yl]_2•oxyethyl]-indole·(t-butoxycarbonyl)amino] Add 5% Pd/C (1.00 g) to a mixture of tert-butyl propionate (3·54 phantom methanol (20 ml) and THF (20 ml), and then stir at room temperature under hydrogen atmosphere. After the filtrate was concentrated, the residue was evaporated to dryness crystals crystals crystals crystalsssssssssssssssssssssssss 9Η5 s)5 1.53 (9Η) s)5 2.58 (2Η 121199.doc -225 - 200846322 J=6.6 Ηζ), 2·85 (2H, t, J=8.3 Hz), 3.58 (2H, t, J=6.6 Hz), 3,68 (2H, t, J=8.3 Hz), 4.06 (2H, s)5 6.50-6.6G (2H,m), 7·44 (1H,s),8·02 (1H,d , J=8.8 Hz) 〇MS (ESI) m/z : 421 (M+H)+. (8) 3-[Ν-[2-[5·[[2,4·bis(trifluoromethyl)benzyl]oxy]-2,3-dihydro-1H-inden-1. 1-2-Sideoxyethyl]-N-(t-butoxycarbonyl)amino]propionic acid tert-butyl ester [Chem. 220]

2,4-bis(trifluoromethyl)benzyl bromide (commercially available) (〇14〇1111) and 3-[N-(t-butoxycarbonyl)-N_[2-(5-hydroxy-2) , 3-dihydro-1H-indenyl)-2. oxoethyl]amino]propionic acid tert-butyl ester (260 mg) in DMF (5.0 ml), added potassium carbonate at room temperature ( 111 mg). After the reaction mixture φ was stirred at 50 t: for 15 hours, it was cooled to room temperature, and the precipitate was removed by filtration. Water (1 ml) and a saturated aqueous ammonium chloride solution (5 ml) were extracted from ethyl acetate (50 ml). The combined extracts were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by silica gel flash column chromatography (Biotage 25M) to give the title compound (327 mg). W-NMR (CDC13) δ : 1·38-1·58 (18H, m), 2·54-2·63 (2H, m), 3.15-3.23 (2Η, m), 3.54-3.62 (2Η, m ), 3.98-4.12 (2Η m), 4·18 (2H, s), 5·28 (2H, s), 6·70-6·83 (2H, m), 7·8 (Κ8·〇0 I21199 .doc •226- 200846322 (3H,m), 8.10-8.18 (1H,m) MS (ESI) m/z : 669 (M+Na)+ o (9) 3-[N-[2-[5 -[[2,4-bis(trifluoromethyl)benzyl]oxy]-2,3-dihydroindol-1-yl]-2-yloxyethyl]amino]propionic acid TFA salt [Chem. 221]

3-[Ν·[2-[5-[[2,4-bis(trifluoromethyl)benzyl]oxy]_2,3-dihydro-1Η·吲哚 small group]-2- side oxygen Add ethyl TFA (1 · 0) at room temperature in a solution of tert-butyl propionate (848 mg) in dichloromethane (2.0 ml). Ml). After the reaction mixture was stirred at room temperature for 2 hours, it was concentrated under reduced pressure. The mixture was solidified with diethyl ether-hexane, and dried under reduced pressure to remove the mixture. (vacuum pump, room temperature, 1 hour) The title compound (77.1 mg) was thus obtained. φ ^-NMR (DMSO-d6) δ : 2.72 (2Η, t5 J=7.4 Hz) 5 3.14-3.23 (4H, m), 4.05 (2H, t, J=8.4 Hz), 4·14 (2H, s ), 5.31 (2H, s), 6.88 (1H, dd5 J = 8.8, 2.5 Hz), 7.02 (1H, d, J = 2.5 Hz), 7.97 (1H, d, J = 8.8 Hz), 8· 01 (1H, d, J = 8.2 Hz), 8.09 (1H, s), 8.14 (1H, d, J = 8.2 Hz), 8·94 (2H, br s). Not observed c〇2H. IR (ATR) cnT1 : 3163, 1720, 1674, 1491, 1348, 1279, 1173, 1161, 1113, 1043, 721. MS (ESI) m/z: 495 (M+H)+. 121199.doc 227· 200846322 C22H2〗 HR-MS (ESI) calculated value of F6N204 (M+H)+ · 491.14055 ° Measured value: 491.13682 ° C22H2 〇F6N2 (calculated value of elemental analysis of Vl.〇TFA: C, 47·69; H, 3.50; F, 28.29; N, 4.63. Measured: C, 47.42; H, 3.46; F, 27·99; N, 4.50 〇 [Example 51] 3-[N-[2- 2-oxo-2-[5-[2-[4-phenyl-5.(trifluoromethyl)-2-thienyl]ethyl]-2,3-dihydro-1H-indole-1- Tetyl]ethyl]amino]propionic acid TFA salt • (1) 3_[N-(Tertibutoxycarbonyl)-N-[2-trioxy-2-[5-[2-[4-phenyl·5 -(二鼠曱基)-2-°Cetyl]ethyl]-2,3-dihydro-1H-σ 嗓-1 _yl]ethyl]amino]propionic acid tert-butyl ester 222]

In 1-(tert-butoxycarbonyl)-5-[2_[4-phenyl-5-(trifluoromethyl)_2_σ塞 yl]ethyl]porphyrin (115 mg) at room temperature Add 4 Ν hydrochloric acid /: [ 4 · 2 4 burning solution (5 · 0 ml). After the reaction mixture was allowed to stand at room temperature for 3 hours, it was concentrated under reduced pressure to give 5-[2-[4-phenyl-5-(trifluoromethyl)- 2 s. Petrone hydrochloride. This was dissolved in DMF (5. 〇ml), and added at room temperature of 121199.doc -228 - 200846322. 2-[N-(Tertibutoxycarbonyl)_N_[3_(T-butoxy)·3_ The pendant oxypropyl]amino]acetic acid (1 〇 0), ED 〇 HC1 (70.2 mg), HOBt (49.5 mg), and TEA (017 〇 ml) were stirred for 15 hours. The reaction mixture was concentrated under reduced pressure. To the obtained concentrate was added ethyl acetate (3 〇ml), saturated aqueous sodium bicarbonate (2 〇ml), and water (50 ml). (20 ml) extract the aqueous layer. The combined extracts were dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc (EtOAc)

]H-NMR (CDC13) δ : 1.38-1.58 (18H5 m)? 2.50-2.65 (2H, m), 2.92-3.00 (2H, m), 3.05-3.25 (4H, m), 3·45-3· 80 (4H, m), 3.95-4.32 (4H, m), 6.75 (1H, s), 7.33-7.43 (5H, m), 8.08-8.17 (1H, m) 〇MS (ESI) m/z : 659 (M+H)+. (2) 3-[N-[2-Sideoxy-2-[5-[2-[4-phenyl-5.(trifluoromethyl)-2-thienyl]ethyl]·2,3 -dihydro-1H-indol-1-yl]ethyl]amino]propionic acid TFA salt [Chem. 223]

3-[Ν-(Tertibutoxycarbonyl)-indole-[2-o-oxy-2-[5-[2-[4-phenyl-5-(trifluoromethyl)-2-thiophene a solution of tert-butyl methacrylate (130 mg) in dichloromethane (2.0 ml), ethyl]ethyl]-2,3-dihydro-1Η-indol-1-yl]ethyl]amino]propionate, TFA (1.0 ml) was added at room temperature. After the reaction mixture was stirred at room temperature for 2 hr, then concentrated, evaporated, evaporated, evaporated, evaporated. . W-NMR (DMSO-d6) δ ·· 2·70 (2H, t, 拎 7.7 Hz), 2.95 (2H, t, J = 8.3 Hz), 3.10-3.23 (6H, m), 4·04 (2H ,t,J=7.7 Hz),4·14 (2H,s),7·05 (1H,s),7.09-7.15 (1H,m),7·22 (1H,s),7·34_ 7.59 ( 5H,m),7·94 (1H,d,J=8.3 Hz), 8.95 (1H, br s). C02H was not observed. MS (ESI) m/z: 503 (M+H)+. HR, MS (ESI) calculated for C26H26F3N203S (M+H)+: 503.16162. Found: 503.1600. [Example 52] 5-Bis(trifluoromethyl)benzyl]oxy]_2,3·monohydro-1H-indol-1-yl-2-enyloxyethyl]amino]propionic acid TFA Salt (1) 3-[N-[2-[5-[[3,5-bis(trifluoromethyl)] benzyl]oxy]-2,3·dichloro_m_ 吲哚-1-yl] -2-Sideoxyethyl]_N_(t-butoxycarbonyl)amino]propionic acid tert-butyl ester [Chem. 224]

3,5-bis(trifluoromethyl)benzyl bromide (commercially available) (〇〇52 ml) and 3-[N-(second butoxycarbonyl)_N-[2_(5•hydroxy-2) , 3_ dihydroindenyl)-2-oxoethyl]amino]propionic acid tert-butyl ester (1 〇〇mg) in dMF (2. 〇ml) solution, adding potassium carbonate at room temperature ( 42·8 mg). After the reaction mixture was stirred at 5 (TC for 20 hours, cooled to room temperature, the precipitate was removed by filtration. Water (30 ml) and saturated aqueous ammonium sulfate solution (2 〇 121199.doc • 230 - 200846322 ml) were added to the filtrate. The extract was extracted with ethyl acetate (2 χ 2 〇 ml), and the combined extracts were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification of the residue by the method (Bi 〇 </ RTI> 25M) to give the title compound (127 mg). H-NMR (CDC13) δ: 1.38-1.62 (18 Η, m)5 2.53-2.63 (2H?m), 3.14-3 -25 (2H,m), 3.53-3.62 (2H,m),3.98-4.22 (4H, m),5·12 (2H,s),6·73-6·90 (2H,m),7· 84 (1H, s), 7·89 (2H, s), 8.10-8.20 (1H, m) 〇MS (ESI) m/z : 647 (M+H)+ (2)3-[&gt;1 -[2-[5-[[3,5-bis(trifluoromethyl)benzyl]oxy]-2,3-dihydro-1-(indol-1-yl)-2-yloxy Ethyl]amino]propionic acid tfa salt [Chemical 225]

3-[N-[2-[5-[[3,5-bis(trifluoromethyl)benzyl); oxy 2,3-dihydro-1 Η-indol-1-yl]-2 To a solution of the side oxyethyl](t-butoxycarbonyl)amino]propionic acid tert-butyl ester (126 mg) in dichloromethane (2.0 ml), EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 2 hr and then evaporated. After adding diethyl ether to solidify, the solvent was removed under reduced pressure and dried (vacuum, room temperature, 1 hour) to give the title compound (94.2 mg) 〇^-NMR (DMSO-d6) δ: 2.72 (2 Η, T5 J=7.3 Hz)5 3.14-3.23 (4H,m),4·05 (2H,t,J=8.3 Hz),4·14 (2H,s),5 29 (2H s), 121199.doc • 231 · 200846322 6.91 (1H, dd, J=8.8, 2.2 Hz), 7.05 (1H, d, J=2.2 Ηζ), 7.97 (1H, d, J=8.8 Hz), 8·09 (1H, s ), 8.14 (2H, s), 8.94 (2H, br s), 12·63 (1H, br s). The peak of 8.94 contains CF3COOH. IR (ATR) cnT1: 3109, 1655, 1550, 1491, 1369, 1288, 1161, 1119, 885, 684 ° MS (ESI) m/z: 491 (M+H)+. HR-MS (ESI) of C22H2iF6N2〇4 (M+H)+ is calculated as 491.14055. Found: 491.1363. Calculated for elemental analysis of C22H2GF6N204.1.0TFA: c, 47.69; H, 3.50; F, 28.29; N, 4.63. Found: c, 47.48; H, 3.41; F, 28.24; Ν, 4.39 〇 [Example 53] 3-[Ν_[2-[5-[[(Ε)·3_[2,4-bis(trifluoro) Methyl)phenyl]-2-propenyl]oxy]-2,3-dihydro-1Η-indol-1-yl]_2_sideoxyethyl]amino]propionic acid (1) 2, 4-bis(trifluoromethyl)benzoic acid (W02002/096849) [Chem. 226]

Adding NaC1 (2〇〇g) at room temperature to [2,4-bis(difluoroindolyl)phenyl]nonanol (commercially available) (2〇4 magic thf (4〇ml) solution) Manganese dioxide (4.36 g). The reaction solution was stirred for 2 days. After the insoluble soil (4), the concentrate obtained by purification of the filtrate column chromatography (BiGtage) was concentrated under reduced pressure to give the title compound. 123 g). 121199.doc -232- 200846322 ^-NMR (CDC13) δ : 7.99 (1H, d, J=8.2 Hz)? 8,05 (m 8·27 (1H, d, J=8.2 Hz), Lo.43-io.46 (1H,m) (2) (E)-3-[2,4-Bis(trifluoromethyl)phenyl]-2-acetic acid ethyl ester [Chem. 227]

Add 2-(triphenylphosphoranylidene)acetate (1.93 g) to a solution of 2,4-bis(trifluoromethyl)benzaldehyde (1.22 g) in toluene (30 ml). . After the reaction solution was heated to reflux for 15 hours, it was left to cool to room temperature 5 under reduced pressure. The title compound (1.25 g) was obtained by the purification of the title compound (yield: </ RTI> </ RTI> </ RTI> <RTIgt; 'H-NMR (CDC13) δ : 1.36 (3H? t? J=7.1 Hz), 4.30 (2H5 q? J=7.1 Hz), 6.47 (1H, d, J = 15.7 Hz), 7.79-7.86 (2H, m), 7·96 (1H, s), 8.03 (1H, dd, J = 15.7, 2·2 Hz). MS (ESI) m/z: 313 (M+H). (3) (Ε)-3·[2,4-bis(trifluoromethyl)phenyl]propen-1-ol [Chem. 228]

To a solution of (Ε)-3-[2,4-bis(trifluoromethyl)phenyl]acrylate (1.25 g) in THF (20 mL). Diisobutylaluminum hydride (0,99 121199.doc -233 - 200846322 indole solution) (10.0 ml) was added under the arm. The reaction mixture was stirred at & & & c 【 【 【 【 【 【 【 【 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和hour. Anhydrous magnesium sulfate was added to the reaction mixture, and after stirring for 3 minutes, the insoluble matter was filtered. The resulting residue was purified by silica gel flash column chromatography (EtOAc) eluting to afford title compound (1 〇 6 g). H-NMR (CDC13) δ : 1·6〇 (1H, t5 J=5.9 Hz), 4.38-4.44 (2H, m), 6·44 (1H, dt, 卜15·7, 5·1 Hz), 7·02 (1H, dd, J=15.7, 2·2 _ Hz), 7·72_7·79 (2H, m), 7·89 (1H, s). (4) 3-[N-[2-[5_[[(E)-3-[2,4-bis(trifluoromethyl)phenyl)-2-propenyl]oxy]-2,3-di Hydrogen-1H_吲哚_ι_yl]-2-sided oxyethyl]_N-(t-butoxymethyl)amino]propionic acid tert-butylate [Chemical 229]

pAbt〇H +h〇^XC^t • THF (6.0 ml) in (E)-3-[2,4·bis(trifluoromethyl)phenyl]-2-propene-i•ol (146 mg) In the solution, 3_[n-(t-butoxycarbonyl)-N-[2-(5-trans-based-2,3·dihydro·1Η-indol-1-yl)- 2-Sideoxyethyl]amino]dibutyl butyl propionate (2 〇〇 mg), triphenylphosphine (155 mg), and DEAD (2.2 Torr in toluene) (0·269 ml). The reaction mixture was stirred at room temperature for 3 days and then concentrated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc) 121199.doc .234- 200846322 'H-NMR (CDCI3) δ : L33-1.60 (18H5 m), 2.54-2.63 (2H5

m)5 3·15-3·23 (2H,m), 3.55-3.62 (2H,m),3·95-4·25 (4H m)5 4.73 (2H,s),6.40-6.50 (1H, m), 6.71-6.83 (1H, m), 7·11 (1H, d, J-15·4 Hz), 7.43-7.58 (1H, m), 7.64-7.80 (2H m), 7·89 (1H ,s), 8.20-8.32 (1H,m) 〇MS (ESI) m/z : 673 (M+H)+ 〇(5)3-[1[2_[5-[[(£)-3-[ 2,4-bis(trifluoromethyl)phenyl]_2-propenyl]oxy]-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl]amino ]propionic acid [化230]

3-[N-[2-[5-[[(E)-3-[2,4-bis(trimethyl)phenyl]-2-propenyl]oxy]-2,3-di Hydrogen-1H-indol-1-yl]-2-oxoethylethyl]-N-(t-butoxycarbonyl)amino]propionic acid tert-butyl ester (215 mg) of di-methane (5) .〇ml) In the solution, add TFA (l.〇ml) at room temperature. After the reaction mixture was stirred at room temperature for 1 to 5 hours, it was concentrated under reduced pressure. After purification of the residue by reverse phase high performance liquid chromatography (column: Nomuras Cem-RP-5 (l〇cm)), the target library was cold-dried to give the title compound (116 mg). -NMR (DMSO-d6) δ : 2·41 (2H, t, J = 6.8 Ηζ), 2·88 (2H, t, J = 6.8 Hz), 3.13 (2H, t, J = 8.5 Hz), 3 · 64 (2H, s), 4.04 (2H, t, J = 8.5 Hz), 4·80 (2H, d, J = 3.7 Hz), 6·72-6·85 (2H, m) 5 6.94 (1H , s), 7·03 (1H, d, J = 15.4 Hz), 7.94 - 8.14 (4H, m). No. 121199.doc -235 - 200846322 COOH and NH were measured. IR (ATR) cnT1 : 1643, 1493, 1346, 1282, 1269, 1171, 1115. MS (ESI) m/z: 517 (M+H)+. HR-MS (ESI) calculated for C24H23F6N204 (M+H)+: 517.156. Found: 517.15459. C24H22F6N2 (calculated for the elemental analysis of V1.0H2O: c, 53.94; H, 4·53; F, 21.33; N, 5·24. Measured: C, 53·72; Η, 4.09; F, 21.92; Ν , 5"0 ° ® [Example 54] 3-[Ν-[2·[5_[3-[2,4-bis(trifluoromethyl)phenyl]propoxy]_ 2,3-dihydro -1Η-吲哚-1-yl]-2-yloxyethyl]amino]propionic acid (1) 3-[2,4-bis(trifluoromethyl)phenyl]q-propanol 231]

Add 5〇/〇Pd at room temperature in (E)-3-[2,4-bis(trifluoromethyl)phenyl]_2-propenyl-propanol-methanol (15 ml) /C (300 mg), stirred at room temperature for 2 hours under a chlorine atmosphere. After the reaction mixture was insoluble, the title compound (6 ΐι mg) 〇taR (00013) 5::.38 (1^t, 1 = 5.1 Hz), 1.86- was obtained. 1.96 (2H, m), 2.96 (2H, t, J=7.9 Hz), 3.70-3.78 (2H, m), 7.52 (1H, d, J=8.3Hz), 7.74(1H,d,J=8.3Hz ), 7.88 (1H s). (2) Bis(trifluoromethyl)phenyl]propoxy]-2,3二121199.doc • 236 - 200846322 Hydrogen-1H-indol-1-yl]-2-yloxyethyl]_N -(Tertibutoxycarbonyl)amino]propionic acid tert-butyl ester [Chem. 232]

Add 3-[N-(Third-butyl) to a solution of 3·[2,4-bis(trifluoromethyl)phenyl]-1-propanol (148 mg) in THF (6.0 ml) Oxycarbonyl)-N-[2-#(5-hydroxy-2,3-dihydro-1H_indol-1-yl)-2. oxoethyl]amino]-tert-butyl tert-butylate (200 mg), triphenylphosphine (155 mg), and DEAD (2.2 M in toluene) (0.269 ml). After the reaction mixture was stirred at room temperature for 3 days, it was concentrated under reduced pressure. The resulting residue was purified using EtOAc EtOAc EtOAc (EtOAc) H-NMR (CDC13) δ : 1.45-1.60 (18H? m)5 1.87-1.95 (2H5 m), 2·10 (2H, br s), 2.54-2.63 (2H, m), 2·96 (2H, t, J=8.2 HZ), 3·04 (2H, t, J=7·7 Hz), 3·13-3·23 (2H, m), 3.55-3.62 (2H, m), 3.95-4.20 ( 2H, m), 7·65-7·78 (2H, m), 7.43-8.15 (4H, m). MS (ESI) m/z ·· 675 (M+H)+. (3) 3-[N-[2-[5-[3-[2,4-bis(trifluoromethyl)phenyl]propoxy]_2,3·dihydro-1Η-吲哚-1· 2-yloxyethyl]amino]propionic acid [Chemical 233] 121199.doc -237- 200846322

3-[N-[2-[5-[3-[2,4-bis(trifluoromethyl)phenyl]propoxy]·2,3-dihydro-1H-inden-1-yl a solution of tert-butyloxyethyl]-indole-(t-butoxycarbonyl)amino]propionic acid tert-butyl ester (208 mg) in dichloromethane (5·0 ml) TFA (1.0 ml) was added at a temperature. The reaction mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The residue obtained was purified by reverse-phase high-performance liquid chromatography (column: Nomuras </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; lH-NMR (DMSO-d6) δ : 1.99-2.08 (2Η, m)5 2.38 (2H, t5 J=6.7 Hz), 2.85 (2H, t, J=6.7 Hz), 2·99 (2H, t, J=7.5 Hz), 3.11 (2H, t, J=8.4 Hz), 3·59 (2H, s), 2.96-3.07 (4H, m), 6·72 (1H, dd, J=8.8, 2· 5 Hz), 6·83 (1H, d, J=2.5 Hz), 7.79 (1H, t, J=8.0 Hz), 7.95 (1H, d, J=8_8 Hz), 7.96 (1H, s), 8.01 (1H, d, J = 8.0 Hz). COOH and NH were not observed. IR (ATR) cm·1 : 1645, 1493, 1348, 1279, 1113. MS (ESI) m/z: 519 (M+H)+. HR-MS (ESI) calculated for C24H25F6N204 (M+H)+: 519.17185. Found: 519.17069.

Calculated for elemental analysis of C24H24F6N2O4.0.5H2O: c, 54.65; Η 4.78; F, 21.61; Ν, 5_31. Found: C, 54.31; Η, 4·47· F ′ A y 22.12; N, 5.17. 121199.doc -238- 200846322 [Example 55] 3-[N-[2-[5-[[4-(cyclohexyl)_3_(trifluoromethyl)phenyl]methoxy], porphyrin _1 -yl]-2-oxoethyl]amino]propionic acid hydrochloride (1) 4-(cyclohexyl)-3-(trifluoromethyl)benzoic acid (w〇2〇〇6/13i336) [化234]

Under a nitrogen atmosphere, methyl trifluoromethanesulfonyloxy(trifluoromethyl)benzoate (3.0 g) and 〇·5 M cyclohexylzinc bromide (51 ^ of gastric solution ◦ (^^ ^中中匕Add another (5) at room temperature, such as (7) charge (2) 'heated under stirring for 2 hours. After returning the reaction solution to room temperature, add saturated sodium bicarbonate solution, stir for a long time, then with magnesium fluoride The insoluble material was filtered, and the obtained filtrate was extracted with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. (Bi〇tage 4〇M) The obtained residue was purified to obtain decyl 4-(cyclohexyl)-3-(trifluoromethyl)benzoate containing impurities which were difficult to separate. MS (ESI) m/z: 309 ( M+Na)+ In a mixture of sterol/THF (ίο mi/2〇ml) of the above mixture, 1 N aqueous sodium hydroxide solution (1 ml) was added to the coffee: and stirred for 20 hours. The reaction mixture was extracted with ether, and the aqueous layer was separated. The aqueous layer was partitioned with 10% hydrochloric acid, and the precipitated solid was collected by filtration. The obtained solid was dried to give the title compound π·4 g (2 step)]. [H-NMR (DMSO-d6) δ: 1.24-1.41 (3Η, m)5 1.48-1.86 (?H m), 2· 86 (1H,t,J=11.5 Hz), 3.30 (1H,s),7·77 (1H, d,i 121199.doc -239- 200846322

Hz), 8.11-8.17 (2H, m). MS (ESI) m/z : 273 (M+H) + 〇 (2) 4-(cyclohexyl)-3-(trifluoromethyl)phenyl decyl alcohol [Chem.

Add 1-oxaborane dimethyl sulfide at room temperature in a solution of 4-(cyclohexyl)-3-(difluoroindolyl)benzoic acid (12 g) in THF (2 〇•ml) (13 ml), stir for 17 hours. Saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was stirred for a long time, and then extracted with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified using silica gel elution elution elution elution iH-NMR (CDC13) δ : 1.21-1.51 (7H, m), 1.73-1·90 (4H, m), 2.83-2.99 (1Η, m), 4·71 (2Η, s), 7.45 ( 1Η, d, J=7.4 Ηζ), _ 7·5〇 (1H, d, J = 8.1 Hz), 7·60 (1H, s). (3) 4 stomach (cyclohexyl)-3-(trifluoromethyl)benzyl vapor [Chemical 236]

Add ruthenium sulfide at room temperature in 4-(3⁄4-hexyl)-3-(trifluoromethyl)benzyl alcohol (11 g), 2 • dichlorodecane &gt; trough (50 ml) Gas (丨〇迅1) is a small disturbance worker. The residue was purified by silica gel flash chromatography (EtOAc) eluting eluting !H-NMR (CDC13) δ : 1.26-1 49 i6H m, η Μ (sister, m), 1.78-1.92 (5Η, m), 4.58 (2H, s), 7.45 (1H, d, J=8 3 Ha ” , , ,,J u Hz),7·52 (1H,d,J=8.1

Hz), 7.61 (1H, s). (4) 3-[N-(Terti-butoxy County)_Ν-[2_[5·[[Μ环己基)冬(三imethyl)phenyl]methyllacyl]t朵琳+基]· 2_Sideoxyethyl]amino]propionic acid tert-butyl ester [Chem. 237]

〇 r 03⁄4 Y°y --

. I in 4-(cyclohexyl)-3-(trifluoromethyl)benzyl chloride (99 mg) and 3-[N-(t-butoxycarbonyl)_N-[[2-(5-hydroxyindole) Addition of potassium carbonate (99) at room temperature, in the DMF solution (5 ml) of tert-butyl-propionate (〇.1〇g). (mg), stirred at 50 ° C for 14 hours. After the reaction solution was returned to room temperature, the insoluble matter was filtered. The obtained filtrate was concentrated, and the obtained residue was purified to silica gel elute !H-.NMR (CDC13) δ : 1.22-1.52 (23Η, m)? 1.71-19.7 (5H, m), 2.54-2.66 (2H, m), 2·87-3·01 (1H, m), 3.17-3.21 (2H, m), 3.57-3.61 (2H, m), 3.97-4.22 (4H, m), 5.00 (2H, s), 6.77 (1H, d, J = 9.8 Hz), 6.82 ( 1H,d,J=9.3 Hz),7·47 (1H,d, J=7.4 Hz), 7·54 (1H,d,J=8.1 Hz), 7.66 (1H,s),8·13 (1H , t, J = 9.8 Hz) 〇121199.doc -241- 200846322 MS (ESI) m/z : 661 (M+H)+. (5) 3_[Ν-[2_[5·[[4-(cyclohexyl)_3_(trifluoromethyl)phenyl]methoxy] oxopiperidin-1-yl]-2_sideoxy B Amino]propionic acid hydrochloride

3-[N-(Tertidinoxycarbonyl)-oxime[2_[5·[[4_(cyclohexyl)_3_(trifluoromethyl)phenyl]methoxy]porphyrin-1-yl [2-oxoethyl]amino]propionic acid tert-butyl ester (0.16 g, 0.24 mmol), 4 Ν hydrochloric acid / 1, 4-dioxane solution (5 ml) was added at room temperature. After stirring for 23 hours, it was concentrated under reduced pressure. Diethyl ether was added to the residue, and the solid crystals were evaporated to give the title compound (93 mg). lH-NMR (DMSO-d6) δ : 1.25-1.85 (10Η, m)5 2.69-2.87 (3H5 m),3·18 (4H,q,J=7,4 Hz),4·05 (2H,t , J=8.3 Hz), 4·13 (2H, s), 5·11 (2H, s), 6.87 (1H, dd, J=8.7, 2.6 Hz), 7.01 (1H, d, J=2.5 Hz), 7.58-7.71 (3H, m), 7.95 (1H, d, J = 8.8 Hz) 〇IR (ATR)cnT1 : 2925, 2854,1720,1655,1556,1491,1419, 1375 〇MS (ESI) m/z : 505 (M+H). C27H31F3N2 (calculated for the elemental analysis of VHCW.25H20: C, 57·55; H, 6·17; Cl, 6.29; F, 10·11; N, 4.79. Measured: C, 121199.doc -242- 200846322 57.44; H,5_94; Cl,6.66; F,10·07; Ν,5·18.

[Example 56] 3-[N-[2-〇[(i-(cyclohexylmethyl)-3)(trifluoromethyl)_1H pyrazolylmethoxymethoxyindolizin-1-yl]-2 _Sideoxyethyl]amino]propionic acid (1) 1-(cyclohexyldecyl)-3-(trifluoromethyl; uh-pyrazole-4-carboxylic acid methyl ester [Chem. 239]

Add bromomethylcyclohexane (1 ml) to DMF (3 ml) of 3 ((trifluoromethyl)-1H-pyrazole-4-carboxylate (Lancaster) (1 () g) at room temperature .〇ml) 'Cool to 〇°c. 6 〇 y was added to the reaction solution. Sodium hydride (〇 42 g, 9.6 mmol) was slowly allowed to return to room temperature while stirring for 15 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue obtained was purified using silica gel flash column chromatography (EtOAc) to afford the title compound (25 g). !H-NMR (CDC13) δ : 0.76-1.05 (5H, m), 1·14-1·45 (4H, m), 1·52-1·80 (4H, m), 1·81-1· 99 (1H,m),3·97 (2H,d,J=7.4 Hz),7·92 (1H,s) 〇MS (ESI)m/z : 291 (M+H), (2) 1_( Cyclohexylmethyl)_3-(trifluoromethyl)_1H-pyrazole ice formic acid [Chem. 240] 121199.doc -243 - 200846322

Add 1 to room temperature in methanol/THF solution of 1-(cyclohexylmethyl)-3-(trifluoromethyl)-1 hydrazine-pyrazole-4-carboxylate (2 ml/4 ml) Aqueous sodium hydroxide solution (2 ml) was stirred for 21 hours. The reaction liquid was concentrated, and 1 N hydrochloric acid was added to the residue, and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (0.16 g). 'H-NMR (DMSO-d6) δ : 0.85-1.01 (2Η5 m), 1.07-1.25 (2Η5 m), 1.42-1.52 (2Η,m), 1.54-1.71 (4Η,m), 1.89-1.74 (1Η , m), 4·04 (2H, d, J-7.1 Hz), 8·45 (1H, s). MS (ESI) m/z: 277 (M+H)+. (3) 1-(Cyclohexylmethyl)-4-hydroxymethyl-3-(trifluoromethyl:biazole [Chem. 241]

Add 1 于 at room temperature to a solution of 1-(cyclohexylmethyl)-3-(trifluoromethyl)-1 Η-pyrazole-4-carboxylic acid (〇.i6g) in THF (3 ml) Borane disulfide scale complex (0. 61 ml) was stirred for 19 hours. Saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was stirred for a long time, and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified using EtOAc EtOAc (EtOAc) !H-NMR (CDCIs) δ : 0.89-1.02 (2Η, m), 1.09-1.32 (3Η5 m)5 121199.doc • 244 - 200846322 1.55-1.94 (6H,m),2.06-2.21 (1H,m) , 3.93 (2H, d, J = 6.6 Hz), 4·66 (2H, s), 7·43 (1H, s). MS (ESI) m/z: 263 (M+H) + 〇(4) 3-[N-(T-butoxycarbonyl)-N-[2-[5-[(l-(cyclohexylmethyl) -3_(trimethylsulfonyl)-1H-pyrazol-4-ylmethoxy)porphyrin-1-yl]-2-oxoethyl]amino]propionic acid tert-butyl ester 242]

In the same manner as in the steps (3) and (4) of [Example 55], 1-(cyclohexylmethyl)-4-hydroxymethyl-3-(trifluoromethylpyrazole (0.16 g), The title compound (0.37 g) was obtained.]H-NMR (CDCls) δ: 0.87-1.34 (8H5 m)5 1.40-1.91 (23H, m), 2.50-2.69 (2H, m), 3.12-3.27 (2H, m ), 3.50-3.68 (2H, m), 3.88-4.24 (4H, m), 5.00 (2H, s), 6.67-6.87 (2H, m), 7.41-7.51 (1H, m), 8·00-8 · 19 (1H, m) MS (ESI) m/z : 665 (M+H) + (5) 3·[Ν·[2-[5-[(1-(cyclohexylmethyl)-3-) (Trifluoromethyl)-1Η-oxazol-4-ylmethoxy]porphyrin-1-yl]-2-oxoethyl]amino]propanoic acid [Chem. 243] 121199.doc 245 · 200846322

3 In the same manner as in the step (5) of [Example 55], 3-[N-(t-butoxymethyl)-indole-[2-[5-(1-(cyclohexylmethyl)-)- 3-(trifluoromethyloxazol-4-ylindolyl)porphyrin-1-yl]-2-oxoethyl]amino]propionic acid tert-butyl ester (〇·37 g), obtained The title compound (53 mg).

H-NMR (DMSO-d6) δ : 0.82-1.22 (4H5 m)5 1.36-1.84 (6H • m), 2·34 (3H, t, 1 = 6.6 Hz), 2.81 (2H, t, J= 6.5 Hz), 3·10 (2H, t, J-8·3 Hz), 3·52 (2H, s), 4·08-3·95 (4H, m), 4 94 (2H, s), 6·78 (1H, dd, J=8.7, 2·6 Hz), 6.89 (1H, s), 7.96 (1H, d, J = 8.8 Hz), 8·04 (1H, s). MS (ESI) m/z: 509 (M+H)+ 〇C25H32F3N404 (M+H)+ HR_MS (AqTOF) calculated value: 509.2376 ° Measured value: 509.2350 ° IR (ATR)cnT1 : 2922, 2850,1728, 1643,1620,1595,1493

Calculated for elemental analysis of 1403 〇 C25H31F3N4 〇d25H20: c, 56.54; H, 6·36; F, 10.73; N, 10.55. Found: C, 56.42; H, 6.13; F, 10·40; N, 10.40 〇 [Example 57] 3-[N-[2-[5_[[4-(cyclopentyl)) 2)fluorobenzyl氧基 氧基 -1 -1 - - - - - - -1 2- 2- ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (Husain, Mazhar et al, Journal Of Biological Chemistry (1980), 255(9), 4.189-97.) 121199.doc -246 - 200846322 [Chem. 244]

F C〇2Me in 2_gas_4• benzoic acid (Matrix) (5 〇 ^ methanol solution (9) (four)

In the middle, strontium sulfate ml) was added and refluxed under stirring for 3 hours. After the reaction solution was returned to room temperature, it was concentrated. Water was added to the obtained residue, and the mixture was extracted with chloroform. The mixture was washed (4) with fresh brine and dried with anhydrous sulfur. The solvent was obtained to give the title compound (m. ^H-NMR (DMSO-d6) δ : 3.77 (3Η, s), 6.62 (1Η, dd, J=13&gt;1, 2,3 Hz), 6,69 (1H5 dd5 J=8,8} 2, 5 Hz), 7.75 (1H, t, J=8.8 Hz), 10.79 (1H, s) 〇MS (ESI) m/z : 171 (M+H)+. (2) 4-(Trifluoromethanesulfonyloxy)_2_fluorobenzoic acid methyl vinegar [Chemical 245]

Add trifluoromethanesulfonic anhydride (4.6 ml) at room temperature to 2-fluoro-4-hydroxybenzoate (3. 2 g) and pyridine (1 ml of dichloromethane) (50 ml). 'Stirring for 18 hours. Concentrate the reaction mixture and add Mi n hydrochloric acid to the obtained residue to extract with ethyl acetate. The combined extracts were washed successively with saturated sodium hydrogen carbonate solution and saturated brine. Drying was carried out. The solvent was evaporated, and the obtained residue was purified eluting eluting elut elut elut elut elut elut elut elut elut 3u x [Chemical 246]

^H,s),7·14 (1H,dd,J=9 6 2 5 Hz), 7.18 (1H,dd,J=8.3, 3 4 H7,.Λ Hz), 8.08 (1H5 t? J- 8.3 Hz) 〇(3) 4-(cyclopentyl)·2·fluorobenzoic acid (10) 2嶋/Q47i(9)

In the same manner as in the procedure of [Example 55] (醯), oxy)-2-(fluoromethyl)benzoic acid, methyl g (1 $ ) (〇·76 g), 4-(trifluoromethyl) Sulfonated title compound ^43'1*84 (6H5 m)? ! ^-NMR (DMSO-d6) δ : •94-2.09 (2H, 1·5 Hz), 7·17

m), 2·91-3·08 (1H, m), 7.15 (1H 仏T , 5 ad, J = 5.9, (1H, s), 7.76 (1H, t, J = 8.1 Hz) MS (ESI m/z : 209 (M+H)+ (4) 4-(cyclopentyl)-2-fluorobenzyl alcohol

[化247] F co2h

OH The title compound (0.71 g) was obtained from m.j. ^-NMR (CDCI3) δ : 1.51-1.85 (7U, 5 m), 1.99-2.14 (2Η, m), 2·89-3·05 (1H, m), 4.72 (2H, d, 1 G·4 Hz),6·94 (1H,dd, J=11.6,1.6 Hz), 7.02 (1H,dd,J”,, •S,17 Hz), 7.30 (1H,t, 121199.doc -248- 200846322 J =7.8 Hz) (5) 4-(cyclodecyl)-2-fluorobenzyl chloride [Chem. 248]

To a solution of 4-(cyclopentyl)-2-fluorobenzyl alcohol (0.71 g), sulfite (10 ml) was added at room temperature, and the mixture was warmed to 60. (The mixture was stirred for 15 hours. The residue was evaporated to purified crystals eluted elut elut elut elut elut elut elut 8H5 m)5 2.82-3.08 (1H, m), 4.62 (2H, s), 6.95 (1H, d, 1 = 12.3 Hz), 7.01 (iH, dd, J=7.8, 1.5 Hz), 7.30 (1H, t, J = 8.0 Hz) (6) 3-[N-(Tertidinoxycarbonyl)·Ν_[2·[5_[[4_(cyclopentyl)_2_fluorobenzyl]oxy]indole L-butyl-1-yl]-2-oxoethyl]amino]propionic acid tert-butyl ester [Chem. 249]

4-((cyclopentyl)-2-(trifluoromethyl)benzyl vapor (〇.1() g) and 3-[N_(t-butoxycarbonyl)-N-[2-(5-hydroxyl) Potassium carbonate (〇····························· 21 g), stirred at 60 ° C for 18 hours. After the reaction solution was returned to room temperature, the insoluble matter was filtered. The filtrate was concentrated, and the residue obtained was purified using EtOAc EtOAc EtOAc (EtOAc) !H-NMR (CDCI3) δ : 1.06-1.89 (23Η, m), 1.95-2.14 (2H m), 2.51-2.65 (2H, m), 2.89-3.25 (3H, m), 3.51-3.64 (2h! m), 3.92-4.29 (4H, m), 5.06 (2H, s), 6.74-7.05 (sh, m), 7.36 (1H, t, J = 6.8 Hz), 8.12 (1H, t, J = 9.6 Hz ). '' MS (ESI) m/z: 597 (M+H)+. (7) 3-[[2-[5-[[4-(Cyclopentyl)-2-fluorobenzyl]oxy]porphyrin _ 丨 基 卜 ethoxyethyl]amino]amino]propanoic acid [化250]

3-[N_(Tertidinoxycarbonyl)-indole_[2_[5·[[4-(cyclopentyl)_2_fluoro]yloxy]]|porphyrin-1·yl]_2_ side a solution of oxyethyl]amino]propionic acid tert-butyl ester (0.25 g) in dichloromethane (1 〇 ml)*, tfa (2 Torr, stirring for 13 hours. The reaction mixture was concentrated, and the residue obtained was used.丨N hydrochloric acid, NaOH aqueous solution of sodium hydroxide and pH value of 7 were extracted with a mixed solution of chloroform/methanol. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained was purified by reverse phase chromatography (G.sub.n., EtOAc, EtOAc, EtOAc). (DMSO-d6) δ : i.45-2.06 (8H5 m)5 2.17-2.44 (2H3 m), 2.74-3.18 (6H,m),3·62 (1H,s)5 4·〇3 (2H, t, J=8.2 Hz), 121199.doc 200846322 5.02 (2H, s), 6.82 (1H, dd, J=9.1, 3.4 Ηζ), 6.94 (1H, s) 7.02-7.15 (2H, m), 7.31·7·48 (1H, m), 7.86-8.03 (1H, m) MS (ESI) m/z: 441 (M+H)+.

[Example 58] 3-[1^[2-[5-[[4-(cyclopentyl)_3_(trifluoromethyl)benzyl]oxy; porphyrin-1-yl]-2- side Oxyethyl]amino]propionic acid (1) 4-(cyclopentyl)-3-(trifluoromethyl)benzofuran [Chem. 251]

In the same manner as in the steps (1) and (2) of [Example 55], methyl 4-(trifluoromethanesulfonyloxy)-3-(trifluoromethyl)benzoate (ug) was used. The title compound (0.29 g). H-NMR (CDCI3) δ : 1.45-1.92 (6Η, m)? 1.99-2.17 (2H, m) 3·32-3·40 (1H, m), 4·71 (2H, d, J=5.9 Hz ), 7·41·7·70 (3H, • m). (2) 3-[N-(Tertidinoxycarbonyl)_[2_[5_[[4_(cyclopentyl)_3·(trifluoromethyl)benzyl]oxy]porphyrin-1- Tertiary 2-ethyloxyethyl]amino]propionic acid tert-butyl ester [Chem. 252]

121199.doc -251 - 200846322 In the same manner as in the steps (3) and (4) of [Example 55], (cyclopentyl)-3-(trimethyl)benzhydryl alcohol (〇.29 g) was used. ), the title compound (0·47 g) was obtained. • H-NMR (CDC13) δ : i.34-1.91 (23Η, m), ^ ^ (4), 2.53_2.7G (2Η, m), 3 Miao 3.25 (2Η, m), 3.3g_3.48 (1Η 3·51_3.64 (2H, m), 3.9 (M.26 (4H, m), 5.G2 (2H, 6.70-U7 (2H, m), 7.48 (m, d, μ 8 Hz), 7 μ ([Η, seven J-8·1 Hz), 7·65 (1H, s), 8·06_8·23 (lH, m). , (3) 3 sides 2-[5-[[4_(cyclopentyl) Base)·3_(trimethyl)phenyl]oxy]tetradolin-1-yl]-2-oxoethyl]amino]propionic acid [Chemical 253]

3-[Ν·(Terti-butoxycarbonyl)_Ν·[2_[5_[[4·(cyclopentyl)) φmethyl)]]oxy-linedyl]. Ethyl]amino]propionic acid second vinegar (G.47 g) in a solution of dichloromethane (2 〇 ,, added TFa (1 〇: 1:, 2! Stirring at a temperature of 3 曰. Concentrated reaction solution The extract is added to the obtained residual fish, and the aqueous solution of the air is emulsified and extracted with a mixed solution of chloroform/methanol. The extract is washed with saturated saline and then dried over anhydrous sodium sulfate. (4) Rapid column chromatography (Shanshan high-speed tube = residue obtained after deuteration) was obtained by solidification with diethyl ether; title: compound (0.3 lg). 121199.doc -252- 200846322 !H-NMR (DMSO -d6) δ : 1·51-1·74 (4H, m), 1.77-2.02 (4H, m)5 2.31-2.43 (2Η,m), 2·75-2·92 (2Η,m),3 ·03-3·21 (2Η, m)5 3.49-3.64 (2H,m),3.95-4.09 (2H,m),5·10 (2H,s), 6.82 (1H,d,J = 8.3 Hz) , 6.95 (1H, s), 7.57-7.71 (4H, m), 7·96 (1H, d, J = 8.8 Hz). IR (ATR)cnT1 : 295 1,2870, 1658, 1595, 1491,1415, 1377 〇 [Example 59] 3_[N-[2- side Benzyl-2-[5-[[4-phenoxy-3-(trifluoromethyl)benzyl]oxy] ° 哚 I porphyrin-1-yl]ethyl]amino]propionic acid • (1 ) phenoxy)-3-(trifluoromethyl)benzaldehyde [Chem. 254]

Add potassium bromate (2) to 4-fluoro-3-(trifluoromethyl)benzaldehyde (Aldrich) (0.96 g, 5.0 mmol) and phenol (0.47 g) in DMF (15 ml) · 1 g), stir to 70 ° C and stir for 7 hours. After the reaction solution was returned to room temperature, it was poured into ice water and extracted with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel flash chromatography (Biotage 40S) to give the title compound (0.13 g). i-NMR (CDC13) δ : 6.96 (1H, d, J = 8.1 Ηζ), 7·12 (2H, d J = 8.1 Hz), 7·29 (1H, d, J = 7.4 Hz), 7.41-7.48 (2H,m), 7.94 (1H, dd5 J=8.6, 2.0 Hz), 8.21 (1H, s), 9.96 (1H, s). MS (ESI) m/z : 267 (M+H) + 〇 121199.doc -253 · 200846322 (2 ) 4-(phenoxy)_3-(trimethylmethyl)benzyl alcohol [Chem. 255]

σ

Add sodium borohydride (18 mg) at room temperature to a solution of 4_(phenoxy)-3-(trifluoromethyl)benzaldehyde (〇· 13 g) in methanol (1··ml). day. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue obtained was purified mjjjjjjjjjj iH-NMR (CDC13) δ ·· 1.74 (1H,t,J=5.5 Ηζ), 4·71 (2H,d, J=5.1Hz) 56.92 (lH,d,J=8.6Hz), 7.02-7.04 ( 2H, m), 7.21-7·08 (1H, m), 7·30-7.54 (3H, m), 7.68 (1H, d, J = 1.7 Hz). (3) 3-[&gt;1-(Tertibutoxycarbonyl)|[2-Sideoxy_2_[5_[4_phenoxy_3_(difluoromethyl)benzyl]oxy]indole Porphyrinyl]ethyl]amino]propionic acid third • τ m [化256]

In a solution of [4-phenoxy-3-(trifluoromethyl)phenyl]methanol (88 〇) in thF (4 〇ml), 3-[N-(3rd butoxide) was added at room temperature. Carboxyl)_n_[2_(5-hydroxy-2,3·dihydro-lH_,哚_〗_yl)-2_sideoxyethyl]amino]propionic acid 121199.doc -254- 200846322 third Ester (152 mg), triphenylphosphine (103 mg), and DEAD (2.2 Torr in toluene) (0.178 ml). After the reaction mixture was stirred at room temperature for 18 hrs and then concentrated under reduced pressure, the title compound (13 6 mg) was obtained. 'H-NMR (CDC13) δ : 8.10-8.17 (1Η, m)? 7.68-7.76 (1H5 m)5 7.43-7.53 (1H,m),7.33-7.41 (2H,m),7·13·7· 20 (1H,m), 7·00-7·08 (2H,m), 6.90-6.96 (1H,m)5 6.74-6.85 (2H,m), 5.00(2H,s),3.99_4.82 ( 4H, m), 3.54-3.62 (2H, m), 3.14-3.23 (2H, m), 2.54-2.63 (2H, m), 1.37-1.58 (18H, m). MS (ESI) m/z ·· 671 (M+H)+. (4) 3-[N-[2-Sideoxy-2-[5-[[4-phenoxy-3-(trifluoromethyl)benzyl]oxy]° 引σ朵琳-1 _ Alkyl]amino]propionic acid [Chemical 257]

3-[N-(Tertibutoxycarbonyl)-N-[2-o-oxy-2-[5-[4-phenoxy- •(difluoromethyl)benzyl]oxy]σ TTFA (1 ml) was added to a solution of the first vinegar (135 mg) in dioxane (10 ml), and the mixture was stirred for 6 hours. The reaction liquid was concentrated, and a saturated sodium carbonate &gt; gluten solution was added to the obtained residue to extract with a mixed solution of chloroform/methanol (3:1, v/v). After the combined extracts were dried over anhydrous sodium sulfate, the solvent was evaporated. The residue obtained was purified by EtOAc (EtOAc): 121199.doc -255 - 200846322 'H-NMR (CDC13) δ : 0.77 (2H5 s), 0.82-0.95 (1H? m)5 1.05 (3H,d,J=6.6Hz), 1.27(2H,S), 2.19-2.22(lH,m),2_37-2:71 (4H,m),3.09-3.30 (2H,m),3·57-4·27 (2H,m),5·02 (2H,s) , 6·75-6·89 (2H, m), 7.05 (1H, s), 7.41-7.53 (1H, m) 5 7.66 (1H, s). MS (ESI) m/z: 515 (M+H) + 〇 [Bei] 60] 3-[N-[2-[5-(4-isopropyl-3-trifluorodecyloxy) Synthesis of the mouth of the porphyrin-1-yl]-2-oxoethyl]amino]propionic acid TFA salt ruthenyl boronic acid (Reference: US 2007/3539 and US 2006/472845) (1 Methyl 4-isopropenyl-3-trifluorodecylbenzoate [Chemical 258]

Add isopropenyl rotten acid (us 200 7/3 5 39) to 曱 / 谷谷液(14 ml) in 4-difluoromethyl decyloxy-3-trifluoromethyl benzoate oxime ester g) Us 2006/472845) (770 mg), carbonic acid (4·4〇g), water (7 〇ml), tetrakis(diphenylphosphine) (0) (52〇mg), stirred overnight under heating and reflux . After the reaction mixture was allowed to stand to room temperature, water was added and extracted with diethyl ether three times. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained was purified by flash column chromatography (yield: 2L) to afford the title compound: 129. h-NMR (CDC13) δ : 2·09 (3H, s), 3·95 (3H, s), 4·92 (1H, s), 5·27 (1Η, t, J=1.5 Ηζ), 7.34 (1Η,d,J=7.8 Hz), 8·14 (1Η, dd, J=1.2, 7.8 Hz), 8.32 (1H,d,J=1.2 Hz)〇MS (ESI) m/z : 245 (M +H)+ 〇(2) 4-isopropyl-3,trifluoromethylbenzoic acid methyl ester [Chemical 259]

Add 5% Pd/C (aqueous) (300 mg) to a solution of methyl 4-isopropyl-3-trifluoromethylbenzoate (1.05 g) in ethyl acetate (20 ml). 1 hour at room temperature. The reaction mixture was filtered. ^-NMR (CDCI3) δ : 1.29 (6Η, d, 1=6.9 Hz), 3.37-3.44 (1H, m), 3·94 (3H, s), 7.56 (1H, d, J = 8.3 Hz), 8·16 (1H, dd, J=1.5, 8.3 Hz), 8·28 (1H, d, J=1.5 Hz). MS (ESI) m/z: 247 (M+H)+. (3) (4-Isopropyl-3-trifluoromethylphenyl)methanol [Chemical 260]

121199.doc -257- 200846322 Add lithium borohydride (177 mg) to a solution of isopropyl 4-isopropyl-3-trifluoromethylbenzoate (1 〇〇g) in tHF (30 ml). Stir under reflux overnight. After the reaction mixture was allowed to cool to room temperature, hydrazine N hydrochloric acid was added and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering the insolubles, the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (m.p.) to afford title compound (840 mg). H-NMR (CDC13) δ : 1·26 (6H, d, J=6.9 Ηζ), 1.72 (1H, s), 3·32-3·38 (1H, m), 4.71 (2H, s) , 7.46-7.52 (2H, m), 7·60 (1H, s) 〇MS (ESI) m/z : 201 (M-OH)+. (4) 4-Gasmethyl-i-isopropyltrifluoromethylbenzene [Chem. 261]

Add (9-isopropylidene chloride (138 ml), DMF ((4-isopropyl 3-trifluorodecylphenyl) methanol (83 〇 (5)) in j, 孓 dichloroethane solution (20 ml) 2 drops of the Pasteur pipette were stirred at 50 ° C for hr. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. Purified by flash column chromatography (Shanshan high-speed column L) The residue was obtained as the title compound (yield: </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -7.61 (3Ρϊ,m) 〇(5) 3-[N-Tertioxycarbonyl-Ν·[2_[5_(4-isopropyl)-trifluoromethylbenzyl 121199.doc -258 · 200846322 Oxygen Base) porphyrin-1 -yl]_2_sideoxyethyl]amino]propionic acid tert-butyl ester [Chem. 262]

Dmf of 3-[&gt;H 2 -butoxycarbonyl)-oxime-[2·(5-hydroxyphenyl)-oxyethyl]amino]propionic acid tert-butyl ester (23丨mg) To the solution (1 〇ml), 4·chloromercaptoisopropyl 2-3-trifluorodecylbenzene (118 mg) and potassium cesium carbonate (104 mg) were added, and the mixture was mixed overnight at 7 (TC). After the solution was allowed to cool to room temperature, water was added and the mixture was extracted with ethyl acetate three times. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate and filtered and evaporated. The residue obtained was purified by chromatography (m.p.) (yield::::::::::::::::::::::::::::: ,2·55-2·63 (2H,m), 3.16-3.22 (2H,m),3·33-3·39 φ (1H,m),3·56·3·61 (2H,m), 3.99-4.18 (4H,m), 5.01 (2H, s), 6.76-6.84 (2H,m), 7.49 (1H,d,J=8"Hz),7·56 (1H,d, J=8.1 Hz ), 7·65 (1H, s), 8·10·8·15 (1H, m) MS (ESI) m/z : 621 (M+H)+ (6) 3-[N-[2 -[5-(4-isopropyl-3-trifluoromethylbenzyloxy) phthalocyanine]_ 2-sided oxyethyl ] Amino] propanoic acid TFA salt [Formula 263] 121199.doc -259- 200846322

[3][Ν-(Tertibutoxycarbonyl)-indole-[2-[5-(4-isopropyl-3-trifluoromethylbenzyloxy)porphyrin-1-yl]·2 Add TF (2.0 ml) under ice-cooling, and stir at room temperature. 4 _Ethyloxyethyl]amino]propionic acid tert-butyl ester (310 mg) in dichloromethane (8 〇^1). After an hour, TFA (1.0 ml) was added, and the mixture was stirred at room temperature for one hour. After the reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the residue was evaporated to afford the title compound (271 mg) </RTI> </RTI> NMR (DMSO-d6) δ ··1·24 (6H, d, J=6 ,6 Ηζ),2·73 (2H,t, J=7.4 Hz), 3.16-3.27 (5H,m),4,04-4.14 (4H,m),5.13 (2H, s),6·88 ( 1H, dd, J = 2.7, 8·8 Hz), 7·02 (1H, d, J = 2.7 Hz), 7.66-7.71 (3H, m), 7.97 (1H, d, J = 8.8 Hz). IR (ATR) cnT1 : 2962, 1641, 1182, 1133, 1116. </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Calculated for the elemental analysis of C24H27F3N2〇4*CF3C〇2H: c, 53.98; H, 4.88; F, 19.70; Ν, 4.84. Found: c, 53·98; H, 4.96; F, 19·44; N, 4·63 ο [Example 67] 3-[Ν-[2-[5-[4·(1_methyl ring) Propyl)-3·(tris-methyl)benzyloxy]-2,3-dihydro-1indole-indol-1-yl]-2-yloxyethyl]amino]propionic acid (1) [4-isopropenyl-3-(trifluoromethyl)phenyl]methanol 121199.doc -260- 200846322 [Chem.

0

Add diisobutylaluminum hydride (〇) under 〇〇c in a solution of 4', propionyl-3-(difluoromethyl)benzoic acid in methyl vinegar (878 mg) in THF (20 ml) 99 m benzene bath) (9·1 〇mi). The reaction mixture was applied to hydrazine. After stirring for 1 hour under stirring, a saturated aqueous solution of ammonium chloride (3. 〇 ml) was added, and the mixture was warmed to room temperature, diluted with diethyl ether (1 ml), and stirred at room temperature for hr. Anhydrous magnesium sulfate was added to the reaction mixture, and after stirring for 30 minutes, the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue obtained was purified eluting eluting eluting eluting ^H-NMR (CDCI3) δ : 7.65 (1Η, d, J=〇.5 Hz), 7.49 (1H, dd, J=8.3, 0.5 Hz), 7.25 (1H, d, J=8.3 Hz), 5.22 (lH, t, J=1.5

Hz), 4.88 (1H, s), 4.75 (2H, d, J = 5.9 Hz), 2.07 (3H, s), 1.73 (1H, t, J = 5.9 Hz). (2) Ternyl butyl [[4-isopropenyl-3-(trifluoromethyl)] benzyl] oxy] diphenyl decane [Chem. 265] οο [4-isopropenyl-3-(3 Fluoromethyl) phenyl]methanol (735 mg) of two gases 121199.doc -261 - 200846322 In a solution of methane (10 ml), ΤΕΑ(〇·7η如), DMAP (42.0 mg), and Third butyl diphenyl decyl alkylate (1 〇 6 ml). After the reaction mixture was stirred at room temperature for 2 days, the reaction mixture was concentrated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc) ^-NMR (CDC13) δ : 7.65-7.70 (4Η, m)? 7.58 (1H? s)5 7.3 5- 7·47 (7H,m),7·20 (1H,d,J=7.8 Hz), 5·21 (1H, t5 J=l, 6 Hz), 4·88 (1H, s), 4·78 (2H, s), 2·07 (3H, s), 1·10 (9H, s) . ® (3) Ternrahedron [[4-(1-methyl-1·cyclopropyl)-3-(trifluoromethyl)benzyl]oxy]diphenyl zebra (Tetrahedron Lett. 1998, 39,8621) [Chem. 266]

Dichloromethane (4.0 ml) was added to diethyl ether (1·0 hexane solution) (2.23 ml). A solution of TFA (172 μM) in dichloromethane (4.0 ml) was added dropwise under the arm. After the reaction mixture was stirred for 20 minutes, a solution of dichloromethane (1. After the reaction mixture was stirred for 20 minutes, tert-butyl [(4-isopropenyl-3-(trifluoromethyl)benzyloxy]diphenyl decane (490 mg) in m. The reaction mixture was warmed to room temperature. After stirring for 15 hr, dichloromethane (15 ml) and saturated aqueous ammonium sulfate (20 ml) were evaporated. The combined extracts were dried over anhydrous sodium sulfate, and then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. 445 mg). iH-NMR (CDC13) δ : 7·64-7·70 (4H, m), 7.54 (1H, S), 7·5〇 (1Η, d, J=8.1 Ηζ), 7.34-7.46 (7Η,m),4·75 (2Η,s), ι·35

(3H, s), 1.10 (9H, s), 〇·87-0·93 (2H, m), 0.74-0.78 (2H m) ° (4) [4-(1-mercapto-l-cyclopropane Benzyl-3-(trifluoromethyl)phenyl]methanol (Tetrahedron Lett. 1998, 39, 8621) • [Chemical 267] σο to tert-butyl [[4-(1 • fluorenyl-1-cyclopropane) a solution of pyridine (4.0 ml) in a solution of -3-(trifluoromethyl)benzyl]oxy]diphenyl sulfonium (442 mg) in pyridine (5 ml) After 〇ml), the mixture was stirred at room temperature for 16 hours and the reaction solution was added to ice water (30 m 1), and extracted with ethyl acetate (2 x 20 ml). The combined extracts were washed with aq. The residue was purified using EtOAc EtOAc (EtOAc) tNMR (CDC13) δ : 7.60 (1H,d5 ]=:1·5 Ηζ),7·55 (m,d, J=7.9 Hz)5 7.46 (1H, d, J=7.9 Hz)5 4.71 (2H, s)5 1.69 (1H? br s), 1·35 (3H, s), 0·88-0·93 (2H, m), 〇·75-〇·8〇 (2H, m). 121199.doc •263 - 200846322 MS (ESI) m/z : 213 (M-OH)+. (5) 3-[N-(Tertibutoxycarbonyl)-N-[2-[5-[4-(l-methyl-)cyclopropyl)-3-(trifluoromethyl)benzyl Oxy], oxalyl-1-yl]-2-oxoethyl]amino]propionic acid ethyl ester [Chem. 268]

[4-(1-Mercapto-1-cyclopropyl)-3-(trifluoromethyl)benyl]methanol (172 mg)

In a solution of THF (8.0 ml), 3-[N-(t-butoxycarbonyl)-indole-[2-(5-hydroxy-2,3-dihydro-1H-indole-) was added at room temperature. 1-yl)-2-oxoethyl]amino]propionic acid B (301 mg), triphenylphosphine (235 mg), and DEAD (2.22 toluene solution) (0.407 ml). After the reaction mixture was stirred at room temperature for 17 hr, EtOAc EtOAc m. δ : 7.35-8.16 (4Η? m)y 6.73-6.85 (2Η, m), 5.01(2H,s), 3.97-4.30 (6H,m), 3.58-3.68 (2H,m),3.13-3· 23(2Η5ηι), 2·63·2·73(2Η,ιη),1·2(Μ·60(ΐ5Η,ιη), 0·88- 0·94 (2H,m), 0.75-0.81 (2H, m) MS (ESI) m/z: 605 (M+H) + (6) 3-[N-[2-[5-[4-(l-indolyl-1-cyclopropyl)_3_( Trifluoromethyl)benzyloxy] 2,3-dihydro-1HH1-yl]-2-oxoethyl]amino]propanoic acid 121199.doc -264- 200846322 [Chem.

[3-[N-(2,4-Butoxycarbonyl)·Ν·Methyl-indole·cyclopropyl)-3-(trifluoromethyl)benzyloxyH]indolyl]_2_sideoxyethyl A solution of ethylamine propionate (0.49 g) in THF / methanol mixture (4 ml / 2 ml) was stirred at room temperature for 1 day with 1 N aqueous sodium hydroxide (2 ml). The reaction solution was concentrated, 1N hydrochloric acid was added, and extracted with a mixture of chloroform/methanol (1 〇/1, v/v). The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent, 3-[N_(t-butoxycarbonyl)_N-[2-[5-[4-(l-methyl-1-cyclopropyltrifluoromethyl)benzyloxy]] The crude product of fluorene-1-yl]-2-oxoethyl]amino]propanoic acid was used in the subsequent reaction. 3-[N-(Tertibutoxycarbonyl)_n-[2-[5-[4-(1•methyl-1-cyclopropyl)-3-(trifluoromethyl)benzyloxy) Add a TFA (1 ml) to a dichloromethane solution (1 () ml) of thiol] “ 则 则 则 则 则 丙 丙 ' ' ' ' ' ' ' ' To the residue, a saturated sodium hydrogencarbonate solution was added, and the mixture was extracted with a chloroform/methanol (10:1, v/v) mixture. The combined extracts were dried over anhydrous sodium sulfate and evaporated · 48 g) 〇b-NMR (CD3OD) δ : 0.66-1.01 (4H, m), 1·33·1·34 (3H, m), 2·41 (2Η, t, J=7.1 Ηζ), 2.88 (2Η,t,J=7.2 Ηζ), 3.17 (1Η,d, 121199.doc -265· 200846322 J = 8.0 Ηζ),3·34 (2H,d,J=0.7 Hz),3.53 (1H,s) ,4·07 (2H,t, J=8.2 Hz),5.07 (2H,s),6,84-6.67 (1H,m),6.90 (1H,s), 7.49-7.70 (3H,m),8.04 (1H,d,J=9.0 Hz) IR (ATR)cm·1 : 2925, 2854,1720,1655,1556,1491,1419, 1375 〇MS (ESI) m/z : 477 (M+H)+ [Example 62] 3-[Ν-[2-[5·[[1_isopropyl-3-(trifluoromethyl)-1Hj-biazole-4-yl) ]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]] )·1Η-pyrazole-4-carboxylic acid ethyl ester [Chemical 270]

F

Add sodium hydride (190 mg) to 3-(trifluoromethyl)pyrazole·4·carboxylate (W093/25535; 620 mg) to DMF &gt; gluten (15 ml) at 8 °C Stir for 1.1 hours. After the reaction mixture was allowed to cool to room temperature, 2-iodopropane (440 μl) was added, and stirred at 8 (TC 10). The reaction mixture was allowed to cool to room temperature, and water was added to 75% ethyl acetate/hexane. The mixed solution was extracted, and the combined extracts were washed with saturated brine and dried over anhydrous magnesium sulfate. Mg).H-NMR (CDCI3) δ : 1.35 (3Η, t, J=7.2 Hz), 1.53 (3H5 s), 121I99.doc -266 - 200846322 1·55 (3H, s), 4·31, (2Η,q,J=7.2 Ηζ),4·50-4·60 (1H,m) 8.01 (1H,s) 〇MS (ESI)m/z ·· 251 (M+H)10. (2) [1-isopropyl-3·(trifluoromethyl)-1Η-σ than 嗤-4-yl]methanol [Chem. 271]

Add lithium aluminum hydride (112 mg) to a solution of 1-isopropyl-3-(trifluoromethyl)-1?-indazole-4-indoleate (62 mg) in THF (16 ml) Heat and reflux for 40 minutes. After the reaction mixture was allowed to stand at room temperature, water (110 μM), 1 N aqueous sodium hydroxide solution (110 μM) and water (33 〇 μΐ) were sequentially added thereto, and dried over anhydrous sulfuric acid to filter insoluble materials. The title compound (508 mg) was obtained. ]H-NMR (CDC13) δ ·· 1.51 (3H, s), 1.52 (3H, s), 4.47-4.57 • (1Η, m), 4·67 (2Η, s), 7·52 (1Η, s ). MS (ESI) m/z ·· 209 (M+H)+. (3) 3-[N-(Tertibutoxycarbonyl)-indole-[2·trioxy-2-[5-[[l-isopropyl-3-(trifluoromethyl)-1Η- Pyrazol-4-yl]methoxy]-2,3-dihydro-1H-indole-1-yl]ethyl]amino]propionic acid tert-butyl ester [Chem. 272] 121199.doc •267- 200846322

Add sulphurous acid chloride (21〇01) to [1-isopropyl-3-(3-trifluoroindolyl-4-yl)methanol (200 mg) in dichloromethane (10 ml) at 5 The mixture was stirred overnight. The reaction mixture was allowed to cool to room temperature and then concentrated. The residue was dissolved in DMF (20 ml) Carbonyl))-N-[2-o-oxy-2-(5-carbyl·2,3-dihydrol-indole-indolyl-1)ethyl]amino]propionic acid tert-butyl ester (6 〇 6 mg), stirred at room temperature for 1 day. After the reaction mixture was diluted with ethyl acetate and water, the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with saturated brine After the magnesium was dried, the insoluble material was filtered, and the filtrate was concentrated. The residue obtained was purified by flash chromatography eluting to afford the title compound (463 mg). NMR (CDCls) δ: 1.40 (3 Η 5 s) 5 1.41 (3H , s)? 1.43 (6H, s), 1.49 (6H, s), 1.52 (6H, d, J = 6.8 Hz), 2.57-2.61 (2H, m) • 3.19 (2H, q, J-8.7 Hz), 3.58 (2H, m), 4.01-4.07 (2JJ m) 4·18 (2H, s), 4·52 (1H, m), 4·98 (2H, s), 6·76·6· 80 (2H m), 7.55 (1H, m), 8.13 (1H, m) 〇MS (ESI) m/z : 611 (M+H), (4)3_[&gt;!-[2-[5-[[1 -isopropyl-3-(trifluoromethyl)_1^1^biazole-4-yl]methoxy]_2,3-dihydro-1H-indol-1-yl]-2_sideoxy Ethyl]amino]propionic acid [Chem. 273] 121199.doc -268- 200846322

3-[Ν·(Tertibutoxycarbonyl)-N-[2-trioxyisopropyl-3-(trifluoromethyl)_1Η·pyrazole-4-yl]decyloxy]-2 , 3_Dihydro-1H-indol-1-yl]ethyl]amino]propionic acid tert-butyl ester (448 mg) was dissolved in a 20% TFA/dichlorodecane mixed solution (16 ml). Stir at room temperature for 5 hours. After the solvent of the reaction mixture was evaporated, the residue was purified to purified crystals eluted eluted h-NMR (CD3OD) δ ·· 1·49 (3H, s), 1.51 (3H, s), 2.64-2.67 (4H, m), 3.24 (2H, t, J = 7.8 Hz), 4.06-4.11 ( 4H,m),4.53-4.60 (1Η,m),4·98 (2Η,s), 6.81 (1Η,d,Ηζ),6·91 (1H,s),7·89 (1H,s), 8.04 (1H, d, J = 8.8 Hz). IR (ATR) cm·1 ·· 1641,1493,1363,1325,1286,1267,1172, 1153,1122, 1068, 1012, 845, 798 〇MS (ESI) m/z : 455 (M+H)+ 〇 _ _ C21H25F3N4 (calculated for elemental analysis of V0.1CF3COOH.H2O: C, 52·62; H, 5.65; F, 12·96; N, 11.58. Measured: C, 52.56; H, 5.45; F, 12.62 N, 11.15. [Example 63] 3-[N-[2-Sideoxy-2-[5-[[l-cyclohexyl-3-(trifluoromethyl)-1H-pyrazole-4- Methoxy]-2,3-dihydro-1H-indol-1-yl]ethyl]amino]propionic acid (1) 1-cyclohexyl-3·(trifluoromethyl)-1Η- Ethyl pyrazole-4-carboxylate [Chem. 274] 121199.doc -269- 200846322

Add sodium hydride (195 mg) to DMF solution (15 ml) of oxazolidine-4-decanoate (620 mg) in ethyl acetate (620 mg), and stir for 9 hours at 8 °C. After the solution was allowed to cool to room temperature, bromocyclohexane (548^) was added and stirred at 80 C for 1 day. After the reaction mixture was allowed to cool to room temperature, water was added to 75% ethyl acetate/hexane solution. The extract was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. Purified by flash chromatography on a silica gel column to obtain the title compound (15) 0 mg). ^H-NMR (CDC13) δ : 1.23-1.28 (2H, m), !.35 (3H, t, J=7.2 Hz), 1.42-1.47 (2H, m), 1.64-1.77 (2H ,m),190 i 94 (2H, m), 2.17-2.21 (2H,m), 4.16 (1H,m),4.31 (2H,q,j=7.2

Hz), 8.00 (1H, s). ' MS (ESI) m/z: 291 (M+H)+. (2) [1-Cyclohexyl- 3-(trifluoromethylidene-4-yl)methanol [Chemical 275]

Adding hydrogenation to a solution of 1-cyclohexyl-3-(trifluoromethyl)-1Η-pyrazole-4-carboxylic acid ethyl ester (15 〇mg) 121199.doc -270· 200846322 in THF (5 · 0 ml) Ming (27.2 mg), heated under reflux for 3 5 minutes. After the reaction mixture was allowed to cool to room temperature, water (110 μM), 1 N aqueous sodium hydroxide solution (11 μM) and water (3 3 μM) were added in this order, and dried over anhydrous magnesium sulfate, and then filtered to dissolve insolubles. . The filtrate was concentrated to give the title compound (127 mg). !H-NMR (CDC13) δ : 1.20-1.30 (2Η, m)5 1.40-1.43 (2H? m), 1.65-1.71 (2H,m)5 1.89-1.92 (2H,m),2·15-2 · 17 (2H, m), 4.10-4.16 (1H, m), 4·67 (2H, s), 7·51 (1H, s). MS (ESI) m/z: 249 (M+H)+. (3) 5-[[l_Cyclohexyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]nonyloxy]porphyrin-1 -carboxylic acid tert-butyl ester [Chem. 276]

Add ruthenium chloride (11 〇) to a solution of [1-cyclohexyl-3-(trifluoromethyl)-iH-pyrazol-4-yl] decyl alcohol (125 mg) in dioxin (10 ml) Μΐ), stir at 5 ° ° C overnight. After the reaction mixture was allowed to stand to cool to room temperature, the solvent was concentrated. The residue was dissolved in DMF (20 ml), and potassium carbonate (209 mg) and &lt;RTI ID=0.0&gt;&gt; After diluting the reaction mixture with ethyl acetate and water, the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) ^-NMR (CDC13) 8:1.23-1.28 (2h, .), ^39.^43 (2H, m), 1.58 (9H, s), 1.65-1.75 (2H, m), (2H} m)? 2 16. 2.17 (2H, m), 3.06 (2H, t, J=8.7 Hz), 3.97 (2H, br s), 4.12–4-15 (1H, m), 4.97 (2H, s), 6.75- 6.77 (2H, m), 7.26 (1H, s), 7·54 (1H, s) 〇MS (ESI) m/z : 466 (M+H)+. (4) 5-[[1·Cyclohexyl_3_(trifluoromethyl)_1Η-ϋbazole_4_yl]methoxy] is called 哚 哚 [化277]

Dissolve 5-[[1-cyclohexyl-3-(dioxylmethyl)pyrazole-4-yl]methoxy]indole porphyrin-1-pyrrolic acid butyl ester (165 mg) in 4 Ν Hydrochloric acid / dioxane solution • (4.0 ml), stir at room temperature for 2.4 hours. After the solvent of the reaction mixture was concentrated, it was diluted with saturated aqueous sodium hydrogen carbonate and aqueous layer was evaporated. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate. MS (ESI) m/z: 366 (M+H)+. (5) 3-[N-(Tertibutoxycarbonyl)-indole·[2-Sideoxy_2_[5_[[ucyclohexyl] 3-(trifluoromethyl)-1Η-pyrazole-4 —基]曱oxy;|_2,3_dihydro·1H_吲哚”yl]ethyl]amino]propionic acid tert-butyl ester 121199.doc -272- 200846322 [Chem.

In a solution of crude product of 5_[[1-cyclohexyl-3-(trifluoromethyl)-indole-pyrazole-4-yl]methoxy]porphyrin (45 mg) in DMF (2.0 mi) Add 3·[Ν-(2,4-butoxycarbonyl)-indole-[2-o-oxy-2-(5-hydroxy-2,3-dihydro-1Η-吲哚-1-yl)ethyl] Amino] tert-butyl propionate (45, ed〇HC1 (28 mg), HOBt (20 mg) and DIEA (63 μl) were stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. The aqueous layer was extracted with EtOAc. EtOAc (EtOAc m. 6〇. 'H-NMR (CDC13) δ : 1.25-1.28 (2H5 m)j 1.40-1.42 (12H5 m)' 1·49 (6H,s),1.66-1.72 (4H,m),1·88- 1·91 (2H,m), 2.14-2,17(2H,m), 2.59(2H,m), 3.l7-3.19(2H,m),3.56-3.58 (2H,m),3·98 -4·06 (2H,m),4·〇9-4·17 (3H,m),4.98 (2H,s), 6.75-6.79 (2H,m),7·54 (1H,d,J= 8 3 Hz), n 8.13 (1H5 m) 〇MS (ESI) m/z : 651 (M+H)+ (6) 3-[N-[2 -Sideoxy-2·[5-[[1-cyclohexyl_3_(trifluoromethyl)_1Η-, gibberyl]methoxy^,:^^^^^^^^^^ Propionate [化279] 121199.doc 273 · 200846322

3-[N-(Tertibutoxycarbonyl)-N_[2d]oxycyclohexyl-3-(difluoroindolyl)_1H-pyrazol-4-yl]methoxy]_2,3_2 Hydrogen-1H-indole-ethyl]ethyl]amino]propionic acid tert-butyl ester (6〇mg) was dissolved in 2〇% TFA/dichlorodecane mixed solution (2.0 ml) at room temperature Stir for 6 hours. After concentrating the solvent of the reaction mixture, the residue was purified by reverse phase separation HPLC to give the title compound (22 mg). W-NMR (CD3OD) δ :1·30-1·33 (2H,m), 1.46-1.48 (2H,m), 1.73-1.82 (2H,m),1.90-1.93 (2H,m)5 2· 09-2·12 (2H,m), 2.56-2.57 (2H,m),4.08-4.10 (2H,m), 4.16-4.20 (2H,m), 4·98 (3H,m),6·80 ·6·81 (1H,m),6·90 (1H,s),7·88 (1H,s), 8·04 (1H,d,J=8.8 Hzp (4H coincides with CD3〇D peak and is not confirmed MS (ESI) m/z: 495 (M+H) + 〇 [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ ·(三说methyl)_ IH-u比峻-4-yl]decyloxy]-2,3·dihydro-1H|udolyl]ethyl]amino]propionic acid (1) 1_ring Ethyl pentyl·3-(trifluoromethyl)-1Η-pyrazole-4-carboxylate [Chem. 280] 121199.doc -274- 200846322

F

Add sodium hydride (190 mg) to a solution of 3-(trifluoromethyl)17-indol-4-pyruic acid (620 mg) in DMF (15 ml) and mix at 80 ° C. hour. After the reaction mixture was allowed to stand to room temperature, it was added to a mixture (48 〇 μΐ), and stirred at 80 ° C for 21 hours. After the reaction mixture was allowed to stand to room temperature, water was added, and the mixture was extracted with a 75% ethyl acetate/hexane mixture. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting residue was purified by flash chromatography eluting with EtOAc (EtOAc). MS (ESI) m/z: 277 (M+H)+. (2) [1-Cyclopentyl·3-(trifluoromethylbazol-4-yl)nonanol [Chemical 281]

Add hydrogenation via aluminum (140 mg) to a solution of 1-cyclopentyl-3-(3-Imethyl-methyl-4-indole-ethyl phthalate (850 mg) in THF (20 ml) The mixture was heated under reflux for 1 hour. After the reaction mixture was allowed to stand to room temperature, water (110 μM), 1 N aqueous sodium hydroxide solution (Π0 μΐ), and water (330 μl) were added, and dried over anhydrous magnesium sulfate. Filtration. Concentrate the filtrate to give the title compound (7 〇 9 mg). 121199.doc -275 - 200846322 H-NMR (CDCI3) δ: 0.85-0.88 (1H, m), 1.66-1.72 (2H?m)? 1.90 (2H, m)5 1.99 (2H3 m)5 2.13-2.19 (2H5 m)5 4.65-4.66 (3H,m), 7.50 (1H,s) 0 MS (ESI) m/z : 235 (M+H +(3) 3-[N-(Tertidinoxycarbonyl)·Ν-[2-trioxy n[[l-cyclopentyl-3-(difluoromethyl)-1Η-σ ratio嗤-4-yl]methoxy]dihydroarcho-1_yl]ethyl]amino]propionic acid tert-butyl ester [Chemical 282]

ό

Add ruthenium chloride (312) to a solution of [1. cyclopentyl-3-(trifluoromethyl)-1 Η-indol-4-yl] decyl alcohol (200 mg) in di-methane (10 ml). 11), was mixed with 仗 at 5〇〇c. After the reaction mixture was allowed to stand to cool to room temperature, the solvent was concentrated. The residue was dissolved in DMF (20 ml), potassium carbonate (59 〇mg) and MN-(t-butoxycarbonyl)-indole-[2.suppleoxy-2·(5-hydroxy-2,3) _Dihydro-1 Η-called pado-1-yl)ethyl]amino]propionic acid tert-butyl ester (395 mg) was stirred at room temperature for 2 days on weekends. The reaction mixture was diluted with ethyl acetate and water. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate.

The residue obtained was purified by flash chromatography on silica gel column to give the title compound (407 mg) 〇ln^UK (CDCI3) δ: 1.41-1.43 (12Η5 m), 1.50 (6Η5 s)5 1.70- 121199.doc • 276· 200846322 1.76 (2H? m)3 1.85-1.90 (2H? m)5 1,97-2.03 (2H5 m), 2.14-2.20 (2H? m), 2.55-2.63 (2H? m)5 3.18-3.20 (2H5 m)5 3.57- 3·59 (2H,m),3.99-4.06 (2H,m),4·09 (1H,s),4.18 (1H,s), 4_62-4·69 (1H,m ), 8.14 (1H, m) 〇MS (ESI) m/z : 637 (M+H)+ 〇(4) 3-[Ν·[2-sideoxy-:2-[5-[[i- Cyclopentyltrifluoromethyl)indolyl]methoxy]dihydro·1Η·σ 卜 」 」 基 ]]]]]]]]]]]]]]]]]

3-[Ν-(Tertilybutoxycarbonyl)-Ν[[2-o[pi]oxy-2][5_[[cyclopentyl] 3-(difluoromethyl)-1Η·σΛΛ-4-yl ]methoxy]·2,3_dihydro-1Η-purine small group]ethyl]amino]propionic acid tert-butyl ester (407 mg) dissolved in 1% TFA/dichlorohydrazine solution (15 In ml), stir at room temperature for 1 day. Further, TFA (5. 〇 ml) was added to the reaction mixture φ liquid, and the mixture was stirred at room temperature for 1.5 hours. After the solvent of the reaction mixture was distilled off, the residue was purified by reverse phase separation of HPLC to afford title compound (133 mg). iH-NMR (CD3OD) δ : 1.72-1.75 (2H, m), 1.87-1.9Ό (2H, m), 1.99-2.01 (2H, m), 2.16-2.18 (2H, m), 2.66-2.68 (2H , m), 3.23-3.26 (2H, m), 4.08-4.12 (4H, m), 4.73-4.77 (1H, m), 4·98 (2H, s), 6.81-6.83 (1H, m), 6 · 91 (1H, s) 5 7.87 (1H, s) 5 8·04-8·06 (1H, m). (2H coincides with CD3OD peak and is not confirmed.) IR (ATR) enT1 : 1643, 1493, 1363, 1286, 1269, 1167, 1122, 121199.doc .277- 200846322 1070, 1018, 845, 800 〇MS (ESI) m /z : 481 (Μ+Η)+. Calculated for the elemental analysis of C23H27F3N4 〇4.0.1CF3COOH*H2O: C, 54·65; Η, 5·75; F, 12.30; N, 10.99. Found: C, 54·54; H, 5.45; F, 12.39; Ν, 10.97. [Example 65] 3·[Ν-[2-Phenoxy-2-[5-[[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]methoxy) ]-2,3-dihydro-1H-indol-1-yl]ethyl]amino]propionic acid • (1) MN-(t-butoxycarbonyl)-N-[2- oxo- 2·[5·[[1-phenyl_5_(trifluoromethylindole-indazol-3-yl]methoxy]-2,3-dihydro-1Η·吲哚-1-yl]ethyl Amino] tert-butyl propionate [Chem. 284]

Dissolve 3-(bromomethyl)-1 phenyl 5-(trifluoromethyl)-1 Η-° 嗤 (200 mg) in DMF (20 ml), add potassium carbonate (668 mg) and 3 -[N-(Tertidinoxy-Wiki)-N-[2-Sideoxy-2-(5-carbyl-2,3·dihydro-1H-)-organo)ethyl]amine ] Tert-butyl propionate (373 mg) was stirred at room temperature overnight. Further, the reaction mixture was heated to 7 ° C and stirred for 1 day. After the reaction mixture was allowed to cool to room temperature, it was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained residue was purified by flash chromatography on silica gel to give the title compound (i 84 mg).丨H-历(CDCl3) δ : h41 (6H, s), 丨43 (6h, s), 丨5g (6h, s), 2.56-2.63 (2H, m), 3.17-3.20 (2H, m), 3.58-3.60 (2H, m), 4.03-4.15 (2H, m), 4.18 (2H, s) 55.12 (2H, s), 6.82-6.84 MS (ESI) m/z: 645 (M+H)+. (2) 3-[Ν·[2-Side oxime·[(tetra)·phenyl_5(trimethyl).n ratio _3_ 鲁基]methoxy]·2,3-dihydro- iH-,dol-1-yl]ethyl]amino]propionic acid [Chemical 285]

3-[Ν·(2,2-butoxycarbonyl)_N-[2-olyloxy-2·[5_[[Phenyl·%(difluoromethyl)-1Η-pyrazole·3_yl]曱oxy]_2,3·dihydro_1H,|哚]•基]

Ethyl]amino]propionic acid dibutyl ester (17 mg) was dissolved in 2% by weight of TFA/dioxane solution (10 ml) and stirred at room temperature for 2.5 hours. The residue of the reaction mixture was purified by reverse phase separation (HPLC) to give the title compound (98 mg). Η-NMR (CD3OD) δ : 2·57 (2H, t, J = 6.1 Hz), 3.23 - 3.26 (4H, m), 4.07-4.09 (4H, m), 5·13 (2H, s), 6.87 -6.89 (1H,m), 6·97-6·99 (1H,m),7·03-7·05 (1H,m),7·50-7·55 (5H,m), 8.05 (1H ,d,J = 8.8 Hz) 〇121199.doc -279---^一—200846322 IR (ATR) cm·1 : 1653,1597,1489,1348,1290,1265,1232, 1184, 1126, 1107, 1082 , 1039, 987, 812. MS (ESI) m/z: 489 (M+H)+. Calculated for the elemental analysis of C24H23F3N4O4, 0.1CF3COOH*H2O: C, 56.13; H, 4.89; F, 12.11; N, 10.82. Found: C, 56·08; H, 4·72; F, 12·02; N, 10.85. [Example 66] 3-[Ν-1&gt;Sideoxy-2-[5-[[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]methoxy] -2,3-dihydro-1H-indol-1-yl]ethyl]amino]propionic acid (1) [1-phenyl-5-(trifluoromethyl)_1H-indazol-4-yl Methanol [化286]

r • d

OH was added to the THF solution (16 ml) of 1-phenyl-5-(trifluoromethyl)-1 Η-pyrazole-4-furic acid (GB2149402, 500 mg) in THF (89 mg). The mixture was heated under reflux for 2 to 3 hours. After the reaction mixture was left to cool to room temperature, water (110 μΐ), 1 Ν aqueous sodium hydroxide solution (11 μM) and water (330 μΐ) were added in this order, dried over anhydrous magnesium sulfate, and filtered to remove insolubles. . The title compound (399 mg) was obtained from the concentrated solvent. H-NMR (CDC13) δ: 1.84-1.86 (1H, m), 4·78 (2H, d, J = 4, 6 Hz), 7.44-7.48 (5H, m), 7.77 (1H, s). MS (ESI) m/z: 243 (M+H)+. (2) 3·[Ν-(Tertibutoxycarbonyl)·Ν-[2-Sideoxy·2_[5-[[1·Phenyl-5- 121199.doc -280- 200846322 (Trifluoromethyl) Base) Η 吡 pyrazol-4-yl]methoxy]·2,3-dihydro-1H-inden-1-yl]ethyl]amino]propionic acid tert-butyl ester [Chem. 287]

Add sulfite chloride (226 μΐ) to [1-phenyl-5-(trifluoromethyl)-iH-pyrazol-4-yl]nonanol (150 mg) in dichloromethane (5.0 ml) And DMF (catalytic amount), stirred at 50 ° C for 2 hours. The reaction mixture was allowed to cool to room temperature and then concentrated. The residue was dissolved in DMF (5·0 ml), and potassium sulphate (514 mg) and 3-[N-(t-butoxycarbonyl)-N_[2-(5-hydroxy-2,3-di) were added. Hydrogen-1H-indol-1-yl)-2-oxoethyl]amino]propionic acid tert-butyl ester (286 mg) was stirred at 70 ° C overnight. After the reaction mixture was allowed to stand to room temperature, it was diluted with ethyl acetate and water, and then aqueous layer was extracted with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sulfuric acid &lt The residue obtained was purified by flash chromatography eluting elut elut elut elut lH-NMR (CDC13) δ : 1.41 (6H5 s)? 1.45 (6H5 d5 J-8.5 Hz) 1.50 (6H, s), 2.56-2.63 (2H, m), 3.18-3.20 (2H, m), 3· 58· 3·59 (2H,m), 4.05·4·14 (4H,m),5·08 (2H,s),6·79-6·84

(2H, m), 7.48-7.49 (5H, m), 7.81 (1H, s), 8.14 - 8.16 (1H m) 0 MS (ESI) m/z: 645 (M+H)+. 121199.doc -281- 200846322 (3) 3-[N-[2-Sideoxy_2_[5_[[1-phenyl-5-(trifluoromethylbazol-4-yl]methoxy]] _2,3-Dihydro]Hui-yl]ethyl]amino]propionic acid [Chemical 288]

3-[N-(Terti-butoxycarbonyl)_N_[2• oxy-2_[5_[[i-phenyl(trifluoromethyl)-1Η-pyrazol-4-yl]methoxy ]_2,3_Dihydro"H_indenyl] • Ethyl]amino]propionic acid tert-butyl ester (17〇mg) dissolved in 20% TFA/dichloromethane solution (10 mi), in room Stir for 25 hours at room temperature. After the solvent of the reaction mixture was evaporated. H-NMR (DMSO-d6) δ : 2.35-2.36 (2H? m)? 2.82-2.84 (2H5 m), 3·13-3·15 (4H, m), 4·04 (2H, t, J= 8.5 Hz), 5.09 (2H, s), 6.84-6.86 (lH, m), 6.98 (lH, s), 7.50-7.51 (2H, m), 7.57- 7.58 (3H? m) 5 7.99-8.01 (2H5 m) 〇 ♦ IR (ATR) cm·1 : 1643, 1595, 1493, 1363, 1313, 1267, 1223, 1184, 1111, 1063, 1022, 974, 847; 798, 764, 692, 606. MS (ESI) m/z: 489 (M+H)+. Calculation of elemental analysis of C24H23F3N4〇4*0.08CF3COOH*0.5H2〇: C, 57.28; H, 4·79; F, 12·15; N, 11·〇6. Found: c, 57.37; H, 4.67; F5 11.94; N, 11.0. [Example 67] 3-[5-[3-(2,4-difluorophenyl)-2-methylpropoxy] II 〇 〇 啉 羰 carbonylamino] propionic acid 121I99.doc -282- 200846322 (1) 3-(2,4-di-p-methylmethyl propionic acid vinegar [Chemical 289]

A solution of ethyl M2,4-difluorophenyl)propanoate (EP401166; 2_38 g) in THF (20 ml) was cooled. c, a solution of m liter of LiHMD Shi S in THF (13, 3 ml) was added dropwise with stirring. The reaction mixture was stirred at the same temperature. 1) ^• After adding the armored meat (1 · i i ml). While the reaction mixture was slowly returned to room temperature, it was stirred for 2 g, then a saturated aqueous solution of ammonium chloride was added and extracted with ethyl acetate (200 ml). The extract was dried over anhydrous sodium sulfate, and the residue was purified by silica gel column (yield: ss.) to give the title compound (414 (5) phantom. ^-NMR (CDC13) δ: 1.17 (3H d? J=6.3 Hz), 1.19 (3H5 t, Bu 7·1 Hz), 2.68-2.78 (2H, m), 2.90-2.99 (1H, m), 4.08 (2H, q, J=7.1 Hz) ,6·74-6·81 (2H,m),7.16-7.09 (1H,m) MS (ESI) m/z : 229 (M+H)+ 〇(2) 3-(2,4- Fluorophenyl)-2-methylpropanol [化290]

OH was added to a solution of ethyl 3-(2,4-difluorophenyl)-2-methylpropanoate (441 mg) in DCM (EtOAc) Under the armpit, add a solution of 〇·99 M-DIBAH in toluene (2 _90 ml). After stirring for 4 hours, 1 N hydrochloric acid (50 ml) was added and extracted with chloro s. The extract was dried over anhydrous sodium sulfate (MgSO4). (3) 1-(Tertibutoxycarbonyl)_5_[3_(2, 'difluorophenyl)_2_methylpropoxy]吲哚琳 [Chemical 291]

3-(2,4-difluorophenyl)-2-methylpropanol (25 mg), (t-butoxycarbonyl)-5-hydroxyporphyrin (318 mg) and triphenylphosphine (531 mg) was dissolved in THF (10 ml) and mDIAD (416 μl) was added with stirring. The reaction mixture was purified by silica gel column chromatography (yield:

(2H, m)? 3.96 (2H3 br s)5 6.64-6.81 (4H? m)? 7.07-7.15 (1H m),7·80-7·27 (1H,m) 〇MS (ESI) m/z : 186 (M+H)+. (4) 5·[3-(2,4-Difluorophenyl)-2-mercaptopropoxy]σ porphyrin hydrochloride [Chem. 292] 121199.doc -284« 200846322

丨HCl added 4 N hydrochloric acid to 1-(dibutyl ketocarbonyl)_5 tone 2,4-difluorophenyl)_2-mercaptopropoxy]porphyrin (105 mg) in vo a 4 g) A solution of hydrazine-dioxane (1 () ml / 40 mmol) was stirred for 2 hours. The title compound (58 mg) was obtained from the title compound (yield: 58 mg). ^-NMR (CDC13) δ : κ〇3 ί3Η , τ (3Η, d, J=6.6 Ηζ), 2.25 (1Η, td,

J=13.1, 6.4 Hz), 2.59 fm aa t (1H, dd, J==13 3, 7 7 Hz), 2 83 (ih,

Dd, J = 13.7, 6.6 Hz), 3 27 Ow ' T • (2H, t, J = 7.2 Hz), 3.77 (2H, d J = 5.9 Hz), 3.96 (2H, t, Bu 7·4 Hz) , 6 75 6 85 (4h, called, 7 teams 7.14 (1H, m), 7.52 (1H, d, 1 = 9.3 HZ), li.6G (2H, br s) MS (ESI) m/z : 304 (M+H)+ (5) 3-[N-(2nd-butoxycarbonyl; l·N_[2_[5-[3_(2,4-difluorophenyl)&gt;2-decylpropoxy L·l-carbolinyl]-2-oxoethyl]amino]propionic acid tert-butyl ester

[化293]

5-[3-(2,4-Difluorophenyl)-2-methylpropoxy]phosphonium hydrochloride (55 mg), N-(t-butoxycarbonyl)-N-(( Third butoxycarbonylethyl)aminoacetic acid (49 mg), EDOHCl (47 mg) &gt; HOBt (33 mg) and TEA (113 μM) were stirred in DMF (5 ml) for 14 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) (EtOAc) The residue was purified by EtOAc EtOAc (EtOAc) H-NMR (CDCI3) δ : i.oi oh, d? J=6.8 Hz), 1.37-1.51 (18H,m), 2.15-2.28 (1H,m),2.52-2.65 (3H,m),2.84 ( 1H, dd, J 13,4,6.6 Hz), 3.18 (2H, q, J=8.5 Hz), 3.59 (2H, q, J=6.7 Hz), 3.72-3.77 (2H, m), 3.96-4.19 ( 4H, m), 6.81·6 64 (4H, m), 7.16-7.07 (1H, m), 8.10 (1H, t, J = 9.8 Hz). MS (ESI) m/z: 589 (M+H). (6) 3 [N-(2,4-Butoxycarbonyl)-N-[2-[5_[3_(2,4-difluorophenyl))

Methylpropoxy]-l-carbolinyl]_2y oxyethyl]amino]propionic acid hydrochloride [Chem. 294] I

N-(Tertilybutoxycarbonyl)3_[5-[3_(2, phenanthrofluorophenyl)-2-methylpropoxyl·1 - porphyrinylcarbonylamino] propionate The ester (66 mg) was added to a 4 N hydrochloric acid/1,4-dioxin solution (i〇mi/4〇mmol), and stirred for 1 day. After the reaction mixture was dried with diethyl ether, the solid was filtered, and dried under reduced pressure to give the title compound (15 mg). 'H-NMR (DMSO-d6) δ : 0·94 (3H, d, J = 6.8 Hz), 2.1〇_2 21 (1H, m), 2·48-2·57 (2H, m), 2 ·73-2·85 (3H,m),3·13·3·3() (3H5 m)5 3.79 (2H5 d, J=5.9 Hz)5 4.06 (2H5 t5 J=,8.2 Hz) 4·13 (2H, s) 5 6·76 (1H, dd, J=8.7, 2.1 Hz), 6.87-6.90 (mm), 7·〇2 (1H, td, 】=8·5, 2.5 Hz), 7· 14-7·21 (1H, m), 7 36 121199.doc -286- 200846322 7.29 (1H, m), 7.95 (1H, d, J = 8.8 Hz). Unobserved (: proton peak of 0211 and NHHC1. MS (ESI) m/z: 433 (M+H) + ° [Example 68] 3-[2-[5-(3-methyl-4-trifluoro) Methylbenzyloxy)-2,3-dihydroindolyl-1-yl]-2-oxoethylamino]propionic acid (1) methyl 4-iodo-3-methylbenzoate [ 295]

Methanol (120 ml) was added to 4-iodo-3-methylbenzoic acid (3.00 g), and then sulphur chloride (4·18 ml) was added dropwise with stirring under ice. After the dropwise addition, the reaction temperature was raised to 60 ° C, and heating and stirring were carried out overnight. The reaction mixture was cooled to room temperature and concentrated to give the title compound (3·16 g). ]H-NMR (CDC13) δ : 2.48 (3H5 s)5 3.91 (3H? s)5 7.50 (1H5 dd, J=8.1, 2.2 Hz), 7.88-7.90 (2H,m) 〇MS (ESI) m/ z : 277 (M+H)+ 〇(2) methyl 3-methyl-4-trifluoromethylbenzoate [化296]

4-(3-methyl-3-benzoic acid) (3·16 g), 2,2-difluoro-2-(gassulfonate) methyl acetate (14.5 ml), copper iodide (1) DMF (110 121199.doc -287 - 200846322 ml) was added to (2.18 g), and the mixture was stirred under heating at 90 ° C for 4 hours. The reaction solution was returned to room temperature, and brine was added, and the mixture was extracted three times with ethyl acetate. The extracts were combined, washed with brine, dried over sodium sulfate and filtered and evaporated. The residue was purified by silica gel column chromatography toiel !H-NMR (CDC13) δ : 2.56 (3H? s), 3.95 (3H, s)5 7.68 (1H? d? J=8.1 Hz), 7·93 (1H, d, J=8.1 Hz), 7 ·96 (1H,s) 〇(3) (3·methyl-4·trifluorodecylphenyl)methanol [化297]

Ethyl 3-mercapto-4-trifluorodecylbenzoate (0.20 g) was dissolved in THF (10 ml) to add lithium borohydride (〇·〇6〇 g). After the reaction mixture was heated under reflux for 3 hours with stirring, it was cooled to room temperature. 1 N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The extracts were combined, washed with brine, dried over sodium sulfate and filtered and evaporated. The residue was purified by silica gel column chromatography toiel 'H-NMR (CDCI3) δ : 1.72 (1H5 t5 J=5.9 Hz) 9 2.48-2.50 (3H5 m), 4·73 (2H, d, 】=5·6 Hz), 7.26-7.26 (1H, m ), 7.29 (1H, s), 7.59 (1H, d, J = 7.8 Hz). (4) 3_[N-[2-[5-(3-Methyl-4-trifluoromethylbenzyloxy)_2,3-dihydroindole-1-yl]-2-yloxyethyl Amino]propionic acid [Chemical 298] 121199.doc »288 - 200846322

Add sulfite gas (〇·30 ml) to a solution of (3-mercapto-4-trifluoromethylphenyl)methanol (0.16 g) in 1,2-dichloroethane (8 ml). DMF (min), stir and heat for 1 hour at 6 (rc). The reaction mixture was cooled to room temperature and concentrated. Take 0.070 g of residue, add potassium carbonate (〇·12 g), 3-[N-third Oxycarbonyl-N-[2-(5-hydroxydihydroindol-1-yl)-2-oxoethyl]amino]propionic acid tert-butyl ester (0.12 g), DMF (3 ml) The mixture was suspended and stirred at 80 ° C. The reaction mixture was cooled to room temperature and concentrated, and the residue was purified to silica gel column chromatography to afford crystals (0.16 g, 0.27 mmol). 4 N Hydrochloric acid / 1,4-dicarbonate solution (3 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated and purified by reverse phase separation HPLC to give the title compound (0·041 g). (CD3OD) δ : 2.43-2.48 (3H? m), 2.53-2.56 (2H? m)5 3.21-3.23 (2H,m), 3.64-3.77 (2H,m),4.04-4.13 (4H,m), 5.11 (2H, s) 5 6·81-6·84 (1H, m), 6·94 (1H, s), 7.40-7.43 (2H, m), 7·62 (1H, d, J = 8.1 Hz ),8·01-8·06 (1H MS (ESI) m/z: 437 (M+H)+. Calculated for C22H23F3N2 〇 4.0.25H2O: C, 59.93; H, 5.37; N,6·35; F, 12.93. Found: C, 60.03; H, 5·20; N, 6.33; F, 12.63 〇IR (ATR) cm-1 ·· 493, 1362, 1115, 1045, 843, 607. 121199.doc -289- 200846322 [ Example 69] 3H (L-isobutyl-4-trimethylene),-2,3-dihydroindol-1-yl]-2-oxoethylamino]propionic acid (1) ) 3-hydroxyiodobenzoate oxime [Chemical 299]

Methanol (1 〇〇 ml) was added to 3-ethyl-4-iodobenzoic acid (5 〇〇 g), and sulphur sulphate (6.91 ml) was added dropwise with stirring under ice. After the dropwise addition, the reaction temperature was raised to 60 ° C. The reaction mixture was cooled to room temperature, and the title compound (5.27 g) was obtained. ]H-NMR (CDCI3) δ : 3.91 (3H5 s)5 7.33 (1H, dd5 J=8.3, 2.0

Hz), 7.62 (1H, d, J = 2.0 Hz), 7_75 (1H, d, J = 8.3 Hz). MS (ESI) m/z: 279 (M+H)+. (2) Methyl 3-benzyloxy-4-iodobenzoate [Chem. 300]

•

I methyl 3-hydroxy-4-iodobenzoate (5·27 g), benzyl bromide (2.70 ml) and potassium carbonate (7.85 g) in acetonitrile (200 ml), heated under reflux with stirring 1 · 5 hours. The reaction temperature was returned to room temperature and filtered to remove insolubles. The filtrate was concentrated, and the residue was purified mjjjjjjjjjj 121199.doc -290 - 200846322 ^-NMR (CDCI3) δ : 3.91 (3H? s)5 5.2i (2H5 s)5 7.34-7.43 (4H,m),7·52-7·54 (3H,m) , 7·88 (1H, d, J = 8.1 Hz). MS (ESI) m/z: 369 (M+H)+. (3) Methyl 3-benzyloxy-4-trifluoromethylbenzoate [Chemical 301]

Methyl 3-benzyloxy-4-iodobenzoate (6.97 g), 2,2-difluoro-2-(fluorosulfonyl)acetic acid methyl vinegar (23·9 ml), moth steel (1) DMF (190 ml) was added to (3.61 g), and stirred at 90 ° C for 4 hours. The reaction solution was returned to room temperature. The saturated brine was added and extracted three times with ethyl acetate. The extracts were combined, washed with saturated brine, dried over sodium sulfate, and filtered and evaporated. The residue was purified by silica gel column chromatography to afford the title compound (5.88 g) 〇H-NMR (CDC13) δ: 3.95 (3Η5 3·95 (3Η, s), 5·25 (2Η, s), 7.34 -7·35 Η,m),7·46 (2Η,d,J=7.1 Ηζ),7·66- • (1Η,m),7·38·7·42 (2Η,m),7·46 7·69 (2Η,m), 7.73 (1Η, s). (4) Methyl 3-hydroxy-4-trifluoromethylbenzoate [Chem. 302]

Methyl 3-benzyloxy-4·trifluoromethylbenzoate (5.88 g), 5% Pd/C touch 121199.doc -291 . 200846322 Adding methanol (200 g) to the medium (wet) (1 ·20 g) Ml), stir under a hydrogen atmosphere at room temperature. The reaction solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (3.94 g). &quot;H-NMR (CDC13) δ ·· 3·95 (3H,s),6·〇3 (1H,S),7·60 (1H d 5 U 5 J=8.0 Ηζ),7·66 (1Η , d, J = 8.0 Ηζ), 7·69 (1Η, s). (5) Methyl 3-trifluoromethanesulfonyloxy-4-tetrafluoromethylbenzoate [Chem. 303]

Add methylene chloride to methyl 3-hydroxy-4-trifluoromethylbenzoate (3.00 g), hydrazine (2,85 ml), DMAP (0.170 g), and add trifluoromethane with stirring under ice cooling. Sulfonic anhydride (2.68 ml). The reaction mixture was warmed to room temperature and stirred for 1 hour. A saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extracts were combined, washed with saturated brine, dried over sodium sulfate and then filtered and evaporated. The residue was purified by silica gel column chromatography toiel 1H-NMR (CDC13) δ : 4.00 (3H, S), 7·86 (1H, d, J = 8.1 Hz), 8.15-8.17 (2H, m). (6) 3-isobutyl-4-tris-methylbenzoic acid formazan [Chem. 304] 121199.doc -292- 200846322

Buy methoxy_4_trifluoromethylbenzoic acid methyl _ (ο/.g), tetrakis(triphenylphosphine)palladium (0) (0·13 g), 2-methyl To the propylboronic acid (〇·35 g) and the carbonic acid (1·9 §), water (2.5 ml) and toluene (5 ml) were added, and the mixture was stirred under a nitrogen stream at 80 C overnight. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted three times with diethylamine. The extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography chromatography eluting h-NMR (CDC13) δ ·· 0·94 (6H,d,J=6.6 Hz), 1.97-2.04 (1H, m), 2.70 (2H,d,拎6·9 Hz),3·95 (3H ,s),7·69·7·70 (1H,m), 7.93-7.94 (1H,m),7·98 (1H,s) 〇(7) (3·isobutyl-4-trifluoromethyl) Phenyl phenyl)methanol [化305]

Methyl 3-isobutyl-4-trifluorodecylbenzoate (〇·24 g) was dissolved in THF (10 ml), and a boronic acid chain (0·060 g) was added thereto, and the mixture was heated under reflux with stirring. hour. The reaction mixture was cooled to room temperature, 1N hydrochloric acid was added, and then extracted three times with ethyl acetate. The combined stroke liquid was washed with saturated saline solution and dried with sodium sulfate. After insoluble matter was filtered, the filtrate was concentrated. The residue was purified to give the title compound (0.16 g). iH-NMR (CDC13) δ : 0·93 (6H, d, J = 6.6 Hz), 1.72 (1H, t, J = 5.9 Hz), 1.92-2·02 (1H, m) 5 2·66 (2H,d,J=7.4 Hz), 4.74 (2H,d,J=5.9 Hz),7·28-7·31 (2H,m), 7.61 (1H,d,J=8.1

Hz) 〇(8) 3-[N-[2-[5-(3-isobutyl·4_trifluorodecylbenzyloxy)_2,3-dihydroindol-1-yl]·2· Side oxyethyl]amino]propionic acid [化306]

Add ruthenium chloride (0·26 ml) and DMF (micronuclear) to (3-isobutyl-4-trifluoromethylphenyl)methanol (〇16 phantom 匕^ dichloroethane solution (7 ml) The mixture was heated and stirred at 60 ° C for 1 hour. The reaction mixture was cooled to room temperature and concentrated. 0.09 g of residue was added, and potassium carbonate (012 g) and 3-[N-t-butoxy-oxocarbonyl] were added. 2-(5-Hydroxy-2,3-dihydroindole-1-yl)-2-oxoethyl]amino]propionic acid tert-butyl ester (0·12 g), DMF (3 ml) The mixture was suspended, and the mixture was incubated at 8 rc. The reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography to obtain an oily substance (〇· 18 g). To the oil was added 4N-hydrochloric acid in 1,4-di- 4 s (3 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified by reverse phase separation to give the title compound (0.040 g). H-NMR (CD3〇D) δ : 0.90 (6Η, d5 J=6.6 Hz)5 1.91-1.98 121199.doc -294- 200846322 (lH,m),2.66-2.70 (4H,m),3.21(2H ,t,J=8,3Hz),3.33-3·35 (2H,m),4·06 (2H,t,J=8.3 Hz), 4·12 (2H,s), 5.13 (2H,s) , 6.83 (1H, d, J=8.9 Hz), 6.93 (1H, s), 7.41 (1H, d, J = 8.1 Hz), 7.45 (1H, s), 7·64 (1H, d, J = 8.1 Hz), 8· 02 (1H, d, J = 8.9 Hz) MS (ESI) m/z: 479 (M+H)+. Calculated for C25H29F3N204*1.75H20: C, 58.87; H, 6.42; N,5 49. Measured value: C, 58.62; H, 6.00; N, 5.26. IR (ATR) cm'1: 2960, 1651, 1597, 1491, 1309, 1113.

[Example 70] 3-[Ν-[2_[5-(3·cyclopropyl-4-trifluoromethylbenzyloxy)-2,3-dihydroindol-1-yl]-2. Oxyethyl]amino]propionic acid (1) 3-3⁄4 propyl-4-trifluoromethylbenzoic acid formazan [Chem. 3 07]

3 - two murine stone 醯 methoxy-4-trifluoromethylbenzoic acid formazan (0.40 g), tetrakis (di-based phosphine) (〇) (〇 13 g), cyclopropyl rotten acid ( 〇·29 g) and carbonic acid|color (1·9 g) were added with water (2.5 ml) and toluene (5 ml), and the mixture was heated under stirring at 8 (rc) under nitrogen flow. The reaction solution was cooled to room temperature and added. The mixture was extracted with EtOAc (3 mL). EtOAc (EtOAc m. 121199.doc -295- 200846322 咕-NMR (CDCl3) δ : 〇.84·〇·86 (2H,m),! 〇6 iu (2H,m), 2.21-2.25 (1H,m),3.93 (3H, s), 7.67_7 69 (2H, m), 7 89 (1H, t, J = 4.4 Hz). ' (2) (3-cyclopropyl-4·trifluoromethylphenyl)methanol [ 308]

Methyl 3-% propyl-4-difluoromethylbenzoate was dissolved in THF (H) ml), and lithium borohydride (〇〇7〇g) was added thereto at 6 Torr. Stir under the armpits. Cool the reaction mixture to room temperature and add! N hydrochloric acid was extracted 3 times with ethyl acetate. The extracts were combined, washed with saturated brine, dried over sodium sulfate, and filtered and evaporated. The residue was purified by silica gel column chromatography toiel H-NMR (CDC13) δ : 0.78-0.82 (2H, m), 1.〇1丄05 (2H, m), 1·70 (1H, t, J = 5.8 Hz), 2.21-2.22 (1H, m ), 4.71 (2H, d, J-5.8 Hz), 7·04 (1H, s), 7·23 (1H, d, J = 8.0 Hz), 7.60 (1H, d, J = 8.0 Hz) 〇 ( 3) 3·[Ν-[2-[5·(3-cyclopropyl-4_trifluoromethylbenzyloxy) 2,3-dihydroindol-1-yl]-2-yloxy B Amino]propionic acid [化309] 121199.doc -296- 200846322

Add ruthenium chloride (0.37 ml), DMF to a solution of (3-cyclopropyl-4-trifluoromethylphenyl) decyl alcohol (〇.22g) in 1,2 dioxaethane (10 ml). (minor) 'heat and stir at 60 ° C for 1 hour. The reaction mixture was cooled to room temperature and concentrated. Take 0.080 g of residue, add potassium carbonate (0.12 g), third butoxycarbonyl-N-[2-(5-hydroxy-2,3-dihydroindol-1-yl)-2-oxoethoxy B Amino]tert-butyl propionate (0.12 g) and DMF (3 ml) were suspended and stirred at 80 ° C overnight. The reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography to yield oil (0.16 g). A 4 N hydrochloric acid/1,4-dioxane solution (3 ml) was added to the obtained oil, and stirred at room temperature for 3 hr. The reaction mixture was concentrated to purified crystals crystals crystals ^-NMR (CD3OD) δ : 0.66-0.70 (2H? m)5 0.92-0.97 (2H5 m)5 2·06-2·09 (1H,m),2·52 (2H,t,J=6.4 Hz ), 3·12 (2H, t, J=8.1 Hz), 3.54-3.66 (2H, m), 3.96-4.00 (4H, m), 4·99 (2H, s), 6.72 (1H, dd, J =8.8, 2·5 Hz), 6·82 (1H, d, J=2.5 Hz), 7·06 (1H, s), 7.26 (1H, d, J=8.0 Hz), 7·52 (1H, d, J = 8.0 Hz), 7.93 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 463 (M+H)+. Calculated value of elemental analysis of C24H25F3N204.1.5H20 · C, 58·89; H, 5·77; N, 5.72. Found: C, 58.92; H, 5.40; N, 6.06. IR (ATR) cm·1 : 1652, 1489, 131 1,1107, 1039, 827. 121199.doc .297- 200846322

Dihydroindol-1-yl]-2-oxoethyl]amino]propanoic acid (1) Methyl 3-isopropenyl-4-trifluoromethylbenzoate [Chemical 3 10]

Φ at 3_2 dimethylsulfonyloxy-4-trifluoromethylbenzoate (〇.4〇g), tetrakis(diphenylphosphine)palladium(〇)(〇13 g), isopropenyl Water (2.5 ml) and toluene (5 ml) were added to boric acid (〇·43 ml) and cesium carbonate (1·9 g), and the mixture was stirred and stirred at 80 ° C overnight under a nitrogen stream. The reaction solution was cooled to room temperature, and water was added thereto, and extracted with diethyl ether three times. The extracts were combined, washed with saturated brine, dried over sodium sulfate, filtered, and filtered. The residue was purified by silica gel column chromatography toiel ^-NMR (CDC13) δ : 2.09 (3H5 s)? 3.95 (3H? s)5 4.91 (1H, • s), 5·27-5·2 (1H, m), 7·72 (1H, d, J=8.2 Hz), 7.92 (1H, s), 8.01 (1H, d, J=8.2 Hz) 〇(2) 3-isopropyl-4·trifluoromethylbenzoate oxime [Chemical 3 11 ]

Add methanol to 3-isopropenyl-4-trifluoromethylbenzoate (〇·28 g), 5% Pd/C 121199.doc -298 - 200846322 catalyst (wet) (0.060 g) 〇ml), in a gas atmosphere ^ under an oxygen atmosphere, stirring at room temperature overnight. The reaction mixture was concentrated and concentrated to give the title compound (0, 28 g).

W-NMR (CDC13) δ : 1.30 (6H, d, J=6, 9 HZ), 3 35-3 42 (1H m), 3.95 (3H, S), 7.67 (1H, d, J = 8.1 Hz) , 7M (1H, d, J = 8.3' Hz), 8.14 (1H, s). (3) (3-Isopropyl-4-trifluoromethylphenyl) decyl alcohol [Chem. 312]

0H Dissolve 3-isopropyl-4-trifluoromethylbenzoic acid formamidine + T 0夂T (0·28 g) in THF (10 ml), add lithium borohydride (〇〇7〇) , g), heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, and then added with N hydrochloric acid and extracted three times with ethyl acetate. The extracts were combined, washed with saturated brine, dried over sodium sulfate, filtered, and then evaporated. The residue was purified by EtOAc EtOAc (EtOAc) 'H-NMR (CDC13) δ : 1.27-1.28 Γ6Η m, 1 ^ 5 (6H,m),1·74 (1H,t,J=5.9

Hz),3·35-3·38 (1H,m),4.76 (2H d squ, a,j — 5.9 Hz), 7.23-7.26 (lH,m), 7.46 (lH,S), 7.59 (1H , d, J = 8 lHz). (4) 3-[N-[2-[5-(3-Isopropanyl-methyl-benzylbenzyl)-2,3-dihydroindole wood-1) Ethyl]amino]propionic acid [Chem. 313] 121199.doc • 299· 200846322

Add sulphurous chlorine (W2 ml, 4.4 mm 〇1) to (3-isopropyl-4-I-based) methanol (〇·19 g) in 1,2-dichloroethane 〇〇ml) , bacteria (trace) '(four). Stir under heating for 丨 hours. The reaction mixture was cooled to room temperature and the reaction mixture was concentrated. Take 0.07 g_, add carbon (tetra) (3) η

g), 3-[Ν·Tertibutoxy-based N_[2_(5_transyl 2,3·dichloro-deca-pyl)-2-yloxyethyl]amino]propyl The acid tert-butyl ester (〇12 §), dmf (3 ml) was suspended and stirred at 8 (TC overnight). The reaction solution was cooled to room temperature and concentrated. The residue was purified by a gel column chromatography. The oil was added (0.19 g, 0.31 mmol, quant.). To the obtained oil was added #N hydrochloric acid / 1,4-dioxane (3 ml), and the mixture was stirred at room temperature for 3 hours. ' Purified by reverse phase separation HPLC to give the title compound ( 〇〇 5 〇g). W-NMR (CDC13) δ : 1.26 (6H, d, J = 6.6 Ηζ), 2·64-2·66 (2H • m ),3·12-3·19 (4H,m), 3.36-3.37 (1H,m),3·75-3·78 (2h m),3.96 (2H,t,J=8.2 Hz),5.03 ( 2H, s), 6.77-6.79 (2H m) 7.29-7.30 (1H, m), 7.49 (1H, s), 7.58 (1H, d, J = 8.2 Hz) 8.07 (1H, d, J = 8.2 Hz) 〇MS (ESI) m/z: 465 (M+H)+. Calculated for C24H27F3N204*1.5H20: C, 58, 65; H 6·15; N, 5.70. Measured: C, 5 8.41 ; H,5·79; N,5.43. IR (ATR) cnT1 ·· 2962, 1643, 1491,1309, 11 9, 829. 121199.doc -300- 200846322 [Real (10)I! 72] 3-[N-[冲_(3-cyclobutyl_4•tri-methylmethyloxy)_2,3_-hydroquinone- 1-yl]-2-oxoethyl]amino]propionic acid (1) methyl 3-cyclobutyl-4-trifluoromethylbenzoate [Chemical 3 14]

0,,,Ρ OH shouted:, [0]

Methyl 3-difluoromethanetriate -4-trifluoromethylbenzoate (〇.6〇g), tetrakis(triphenylphosphine)palladium(0)(0.20 g), cyclobutylboronic acid (〇·51 g) and carbonic acid I (2·8 g) were added with water (2.5 ml) and toluene (5 mi), and the mixture was stirred and stirred overnight at 8 ° C under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and extracted with diethyl ether three times. The combined extracts were washed with a saturated aqueous solution of sodium sulfate and dried over sodium sulfate. The filtrate was concentrated to give the title compound (0.23 g). (2) (3-Cyclobutyl-4-trifluoromethylphenyl) decyl alcohol [Chem. 315]

The above 3-cyclobutyl-4-trimethoxymethylbenzoic acid methyl ester (0.23 g) was dissolved in THF (10 ml), and lithium borohydride (〇〇6〇g) was added. It was heated to reflux for 3 hours under stirring. The reaction mixture was cooled to room temperature 121199.doc -301 - 200846322, and then cooled to 〇 ° C, then 1 N hydrochloric acid was added and extracted with ethyl acetate three times. The extracts were combined, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and filtered. The residue was purified by silica gel column chromatography toiel !H-NMR (CDC13) δ : 1.75-1.77 (1H, m), 1.85-1.89 (1H, m), 1·99, 2·09 (1H, m), 2.18-2.26 (2H, m), 2 ·34-2·36 (2H,m), 3.89-3.91 (1H,m),4·78 (2H,d,J=5.6 Hz),7·27 (1H,d, J=5.6 Hz), 7.58 -7.62 (2H,m). (3) 3-[Ν-[2·[5_(3-Cyclobutyl-4)-trifluoromethylbenzyloxy)-2,3-dihydro-n-hydroxyl-1 -yl]-2 _ side Oxyethyl]amino]propionic acid [Chemical 3 16]

Add sulfite gas (0·070 ^1) to (3-cyclobutyl-4-trifluorodecylphenyl) decyl alcohol (0.040 g) in ι,2-dichloroethane (5 ml) DMF (catalyst) was heated and mixed at 60 C for 1 hour. The reaction mixture was cooled to room temperature and concentrated. Potassium carbonate (〇〇7〇g), 3_[N_Tertictyl-N-[2-(5-hydroxy-2,3-dihydroindol-1-yl)- is added to the residue. 2-tertyloxyethyl]amino]propionic acid tert-butyl ester (0.080 g), DMF (2 ml) was suspended, and the mixture was stirred at 8 °C. The reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography to obtain an oil (〇.〇6〇 g). A 10% solution of TFA•dichloromethane (3 ml) was added to the obtained oil, and the mixture was stirred at room temperature for 12 hours at 121199.doc - 302-200846322. The reaction mixture was concentrated to crystall b-NMR (CD3OD) δ : uq 9〇(1H,(4),2 〇1-2·10 (1H,m), 2.17-2.27 (2H,m),2·32-2·34 (2H,m) , 2·83 (2H, t,

Hz), 3.23 - 3.28 (2H, m), 3 · 38 (2H, t, 1 = 6.7 Hz), 3.89 - 3.91 (1H, m), 4.08 (2H, t, Hz), 4·15 (2H, s), 5·17 (2H, s), 6·86 (1H, dd, J=8.7, 2·6 Hz), 6.97 (1H, d, J: 2.6 Hz), 7.40 (1H, d, J=8.1 Hz), 7.61 (1H, d, J=8.i Hz), 7·72 (1H, s), 8 · 0 5 (1H, d, J=8 · 7 H z) 〇MS (ESI m/z : 477 (M+H)+. Calculated for C25H27F3N2 (VCF3C02H, 0·25Η2〇: C, 54.50; H, 4.83; N, 4.71; F, 19.16. Measured: C, 54·52; H, 4.75; N, 4· 65; F, 19.47. IR (ATR) cnT1: 1725, 1655, 1496, 1423, 1182, l119. [Example 73] 3-[N-[2-[5_(3·cyclopentyl trifluoromethyl)节oxy)_2,3-dihydroindol-1-yl]-2-oxoethyl]amino]propionic acid (1) 3-cyclopentene-1-yl-4-trifluoromethyl Methyl benzoate [化317]

Methyl trifluoromethanesulfonyloxy-4-trifluoromethylbenzoate (0.40 g), tetrakis(triphenylphosphine)palladium(0)(0.13 g), cyclopentene-b-based acid (0.14 g) and cesium carbonate (1.9 g) were added with water (2.5 ml) and toluene (5 ml), and the mixture was heated to reflux overnight under a nitrogen flow of 121199.doc -303 - 200846322. The reaction solution was cooled to room temperature and extracted with diethyl ether three times. The combined extracts were washed with saturated brine: washed with sodium sulfate, filtered, and the filtrate was concentrated. The title compound (〇 23 g) was obtained after the residue was purified by chromatography. !H.NMR (CDC13) δ : 2.00-2.07 (2H? m)3 2.51.2,55 (2H, m), 2.66~2.68 (2H,m),3·94 (3H,s),5·75_5 · 78 (1H, m), 7.72 (1H, d, Hz), 7.95 (1H, s), 7.98 (1H, d, Jd Hz).

(2) Methyl 3-cyclopentyltrifluoromethylbenzoate [Chem. 318]

Add methanol to methyl 3-cyclopenten-1-yl-4-trifluoromethylbenzoate (〇·23 g), 5〇/〇Pd/C catalyst (wet) (0.040 g) 〇^1), stirred at room temperature overnight under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to give the title compound (0.20 g). ^-NMR (CDC13) δ : 1.60-1.78 (4H5 m)5 1.89-1.90 (2H, m), 2.09-2.12 (2H, m), 3.37-3.40 (1H, m), 3.95 (3H, s), 7.66 (1H,d,J=8.1 Hz), 7.89 (ih,d,J=8.1 Hz), 8·13 (1H, s). (3) (3-Cyclopentyl-4-trifluoromethylphenyl) decyl alcohol [Chem. 3 19] 121199.doc - 304- 200846322

Ethyl 3-cyclopentyl-4-trifluoromethylbenzoate (〇·2〇g) was dissolved in THF (10 ml), lithium borohydride (0.〇5〇g) was added, and heated to reflux 3 hour. The reaction mixture was cooled to 〇 ° C, 1 N hydrochloric acid was added, and extracted three times with ethyl acetate. The combined extracts were washed with saturated brine and dried over sodium sulfate

After drying, the insoluble material was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography toiel H-NMR (CDC13) δ : L60-L64 (2H3 m)3 1,67-1^8 (3H m)5 1.80-1.91 (2H, m), 2.06-2.11 (2H, m), 3.33-3.41 〇 H, m), 4·74 (2H,d,J=5,6 Hz), 7.24 (1H,d,J=8 1 u, ,Ul Hz),7·46 (1H, s), 7.58 (1H , d, J = 8.1 Hz). (4) 3-[N-[2_[5_(3-Cyclopentyltrifluoromethyloxy) 2 3 哚-1-yl]-2-yloxyethyl]amino]propanoic acid [ [ 320]

^ΛΑ/γ g) of 1,2-dichloroethyl ml)' (min), at room temperature, with a third butoxycarbonyl group (3-cyclopentyl-4-trifluoromethylphenyl) Add sulfite chloride to methanol (5 ml) (0.15 under heating at 60 ° C for 1 hour. Concentrate the reaction mixture. Add potassium carbonate (0.17 g), 3 121199. Doc -305 - 200846322 经基基-2,3·Dihydro called budo·i•yl)_2_sideoxyethyl]amino] tert-butyl propionate (0.17 g), DMF (4 ml) The mixture was suspended at 8 Torr. The mixture was stirred overnight. The reaction mixture was cooled to room temperature and then concentrated. The residue was purified by silica gel column chromatography to give an oil (0.23 g). A 10% hydrazine solution of TFA-chloromethane (3 ml) was added, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated to give the title compound ( s. 19 g). NMR (CD3OD) δ: 1.62^ 1.64 (2Η, m)5 ^73^.74 (2H? m)? 1·86-1·89 (2H,m), 2.04-2.07 (2H,m),2·83 (2H,t,J= 6 7

Hz), 3·24 (2H, t, 8.3 Hz), 3.38-3.39 (3H, m), 4.07 (2H, t, J = 8.3 Hz), 4.15 (2H5 s), 5.14 (2H, s)? 6.84 (1H5 dd5 J=8.8? 2.6 Hz), 6.95 (1H, d, J = 2.6 Hz), 7.37 (1H, d, J = 8.1 Hz), 7.60 (2H, d, J = 8.1 Hz), 8·04 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 495 (M+H)+. Calculated for elemental analysis of C26H29F3N204, CF3C02H, 0·25Η20: c, 55·22; Η, 5·05; Ν, 4·60; F, 18.72. Found: c, 55·32; H, 5.05; N, 4.53; F, 18.88 0 IR (ATR) cm·1: 1728, 1657, 1495, 1182, 1115, 1036. [Example 74] 3-[N-[2-[5-(3-Cyclobutyl.4_trifluorodecylbenzyloxy)_2,3-dihydro-1-yl]-2-oxoethyl Amino]propionic acid (1) 3,3,3-trifluoro-2-hydroxyphenylpropan-1·one (Nes, WR and Burger, Alfred. Journal of the American Chemical Society (1950), 72, 5409 -13) [Chem. 321] 121199.doc -3 06 - 0 0200846322 Add 1,2-methoxy to phenylglyoxal monohydrate (5.0 g), trifluorodecyltridecyldecane (11 g) Base Ethylene (3 is claw 1), under cooling with ice, add gasification (0·57 g) and mix for 1 hour. The reaction temperature was raised to room temperature and stirred for 55% by volume. The reaction mixture was concentrated, and then THF (20 ml) and EtOAc (EtOAc) The combined extracts were subjected to clearing with saturated brine, dried over sodium sulfate, and filtered, and filtrated. The residue was purified by column chromatography to give the title compound (1, 4 g). ^NMR (CDCI3) δ ; 4.25 (1Η? d? J = 8.3Hz)5 5.40.5.44 (1H, m)5 7.55 (2H5 t5 J-7.8 Hz)? 7.70-7.72 (1H5 m)5 7.99 (2H, Ci, J=7.6 Hz) 〇(2)acetic acid 1_ 笨甲甲基·2,2,2trifluoroethyl ester [化322]

Add dichloromethane (3〇ml) to 3,3,3-difluoro-2-hydroxy-1-phenylpropanone-ketone (7)^3), acetic anhydride (0.60 ml), TEA (1.3 ml) The mixture was stirred overnight under EtOAc, and the residue was evaporated to ethylamine. iH-NMR (CDCh) δ : 2.24 (3H, s), 6.29 (1H, q, J=6.9 Hz), 7·52 (2H, t, J-7·6 Hz), 7·66 (1H ,t,J=7 6 Hz), 7.97 (2H, Shan 121199.doc •307- 200846322 J=7.6 Hz) 〇(3) 2-methyl-4_phenyl-5-trifluoromethyl saliva [ 323]

0 F

Acetic acid (5 ml) was added to hydrazine acetate-benzylidene-2,2,2•trifluoroacetic acid (〇7 μg) and ammonium acetate (0.67 g) to reflux for 5 hours. The reaction temperature was returned to room temperature, and a saturated sodium hydrogencarbonate solution was added. The extract was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and then evaporated. ^-NMR (CDC13) δ : 2.57 (3Η, s), 7.41-7.47 (3Η, m), 7.66-7·67 (2H,m) 〇

(4) 2 -&gt;Smelly methyl-4-benzin-5-three said methyl p-portion [Chem. 324]

Addition to 2-methyl-4-phenyl-5-trifluoromethyl ruthenium (〇·25 g), benzoquinone peroxide (0.030 g), N-bromosuccinimide (0.20 g) Carbon tetrachloride (1 〇 ml) was heated to reflux overnight. Further, N-bromosuccinimide (0·40 g) was added, and the mixture was heated under reflux overnight. Further, ruthenium bromide (0.40 g) was added, and 121199.doc - 308 - 200846322 was heated under reflux for 3 days. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.14 g). (5) 3-[N-[2-Sideoxy-2-[5-[(4-phenyl I tris-methylcarbazol-2-yl)methoxy]·2,3-dihydro- 1-yl]ethyl]amino]propionic acid [化325]

To the above mixture of 2-bromomethyl-4-phenyl-5-difluoromethyl hydrazine and impurities (0.090 g), potassium carbonate (0.12 g), 3-[Ν-t-butoxy group Base-1^-[2-(5-transyl-2,3-dihydro,^1-1-yl)-2-oxoethyl]amino]-tert-butyl propionate (0.12 g ), DMF (3 ml), allowed to hang, at 8 〇. Kneeling, stirring all night. The reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography, and then purified by silica gel chromatography to afford oil (0.070 g). A 10% TFA·dichloromethane solution (3 ml) was added to the obtained oil, and stirred at room temperature overnight. The reaction mixture was concentrated to give the title compound (0.062 g). ^-NMR (CD3〇D) δ : 2.79-2.81 (2H? m), 3.24-3.28 (2H5 m)5 3·36-3·38 (2H, m), 4.09 (2H, t, J=8.3 Hz ), 4·14 (2H, s), 5·28 (2H, s), 6.93 (1H, d, J = 9.1 Hz), 7.05 (1H, s), 7·48-7·49 (3H, m ), 7.67-7.68 (2H, m), 8.08 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 490 (M+H)+. 121199.doc -309 - 200846322 Calculated for elemental analysis of C24H22F3N3CVCF3C〇2H: c, 51.75; H, 3.84; Ν, 6.96. Found: C, 51.60; H, 3.91; N, 6.74. IR (ATR) cm, 1: 1660, 1491, 1188, 1126, 977, 798. [Example 75] 3·[Ν-[2-[5-(4-cyclopropyl-5-trifluoromethylthienylmethoxy)-253-one gas, oxime-1_yl]-2· Side oxyethyl]amino]propionic acid (1) 4-cyclopropyl sinter-2 -carboxylic acid [Chemical 326]

f 丨丨0~

In 4-bromo-2-thiophenecarboxaldehyde (2_〇g), tetrakis(triphenylphosphine)palladium (ruthenium) (12 g), cyclopropylboronic acid (2.7 g) and carbonic acid planer (17 g) Water (25 ml) and toluene (5 g ml) were added, and under a nitrogen stream, it was stirred and stirred overnight under (10). The reaction solution was cooled to room temperature, water was added, and extracted with diethyl ether three times. The combined extracts were washed with saturated brine and dried over sodium sulfate. After insoluble material, the filtrate was concentrated. The residue was purified by silica gel column chromatography toiel H-NMR (CDCI3) δ : 0.66-0.68 (2H5 m)5 0.97-0.99 (2H m) 1.94 (1H, tt, J=8.4, 3.9 Hz), 7.31-7.31 (1H, m), 7,50 ( 1H, d J = 1.5 Hz), 9.85 (1H, dd, J = 1.2, 0.5 Hz). (2) 4-cyclopropyl-5-deuterophene-2-carboxylic acid [Chem. 327] 121199.doc -310- 200846322

g) Add acetic acid (3 ml) and chloroform (3 mi) and mix 4 于 at room temperature. The reaction mixture was concentrated, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 〇·8ΐ

H-NMR (CDC13) δ : 0·62-0·70 (2H, m), 0.99-1.09 (2H, m), 1·86 (1H, tt,: ί=8·5, 4·0 Hz) , 7.26 (1H, d, J = 〇.5 Hz), 9.71 (1H, d, J = 〇.5 Hz) 〇 (3) 4-cyclopropyl-5-trifluorodecyl porphincarboxylic acid [Chemical 328 ]

F F

4-cyclopropyl-5-iodothiophene-2-carbaldehyde (〇·73 g), 2,2-difluoro-2-(fluorosulfonyl)acetate methyl ester (3·3 ml), copper iodide (1) Dmf (30 ml) was added to (0.50 g) and stirred at 90 C for 4 hours. The reaction solution was returned to room temperature, and brine was added and extracted with ethyl acetate three times. The extracts were combined, washed with saturated brine, dried over sodium sulfate, filtered, and filtered. The residue was purified by silica gel column chromatography toiel -NMR (CDC13) δ ·· 0.77-0.80 (2H,m),1.10-1.15 (2H,m)5 2.11-2.13 (1H,m),7·26-7·26 (1H,m),9· 87 (1H, s). 121199.doc -311 - 200846322 (4) (4-Cyclopropyltrifluoromethylthiophene-2-yl)methanol [Chemical 329]

To a solution of 4_cyclopropyltridylmethylthiophene-2-carbaldehyde (0.57 g) in methanol (25 ml), sodium borohydride (12 g) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated, and water was added and extracted with ethyl acetate three times. The extract was combined and washed with brine, dried over sodium sulfate and filtered, and then filtered. The residue was purified by silica gel column chromatography to afford the title compound (0.56 g) 〇^-NMR (CDC13) δ: 0.70^0.72 (2H?m)5 l.〇〇.l.〇5 (2H3 m)5 1.84 (1H, t, J = 6.〇Hz), 2.09-2.09 (1H, m), 4·75-4·76 (2H, m), 6·49 (1H, s). '(5) 3-[Ν·[2-[5·(4-Cyclopropyl-5-trifluorodecylthiophen-2-ylmethoxy)_ φ 2,3_Dihydro °° 1-yl]-2-oxoethyl]amino]propionic acid [化330]

Add ruthenium chloride (〇) to a solution of (4-cyclopropyl-5-trifluorodecylthiophen-2-yl)methanol (〇·〇80 g) in 1,2-diethane (5 ml) · 13 ml), DMF (catalytic amount), and stirred under heating at 60 ° C for 1 hour. The reaction mixture was cooled to room 121199.doc -312. 200846322 / dish was added / deflated. Add potassium carbonate (〇1() g), % [N first butoxycarbonyl·Ν-[2·(5-hydroxy-2,3-dihydroindole-1) to the residue of 6 g of 〇·〇 -Based on 2-oxoethyl]amino]propionic acid tert-butyl ester (0. 丨〇g), DMF (3 ml), and the suspension was stirred at 80 ° C. The reaction solution was cooled to room temperature and concentrated. The residue was purified by chopping column chromatography to give an oil (G.14 g). A 1% by weight solution of TFA_dichloromethane (3 melon 1) was added to the known ester oil, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated and purified by reverse phase-purified HPLC to give the title compound (?? b-NMR (CD3〇D) δ ·· 0·74-0·76 (2H,m),1.02-1.05 (2H,m) 2.05-2.08 (1Η,m)5 2.57 (2Η,t5 5 Ηζ)5 320-3:22 (2ίι' m),4·06-4·08 (4Η,m),4.57-4.59 (2Η,m),5·17 (2Η / 6.73 (1H,s),6.81- 6.82 (1H,m),6·92 (1H,s), 8.03 (1 d J=8.8Hz) 5 MS (ESI) m/z : 469 (M+H)+. C22H23F3N2〇4S*0.05CF3C元素2H,0·5Η2Ο Elemental analysis of the ten values: C, 54·93; Η, 5.02; Ν, 5·80; F, 12·38; S, 6.64. Measured value: C, 54·80; Η,4·79; Ν,5·80; F,12·43; S,6.53. IR (ATR) cnT1 : 1643, 1491,1288, 1109, 1016, 845. [Example 7 6] 3 - [N - [2-Lactyl-2-[5-(4-propenyl-5-dioxylmethyl)- 2,3-dihydro-p-yl]ethyl] Amino]propionic acid (1) ethyl 5-iodo-4-phenylthiazole-2-carboxylate [Chem. 331] 121199.doc -313- 200846322

Acetic acid (3 ml) and chloroform (3 ml) were added to ethyl 4-phenylthiazole-2-carboxylate (0.50 g), N-Eudyldiimide (0·53 g '2.4 mmol). Stir at 6 ° C for 6 hours. The reaction mixture was concentrated, and then purified, mjjjjjj ]H-NMR (CDC13) δ : 1.44 (3H? t5 J=7.1 Hz) 5 4.49 (2H? q5 J=7.1 Hz), 7.42-7.48 (3H5 m), 7·86-7·87 (2H, m ). MS (ESI) m/z: 360 (M+H)+. (2) Ethyl 4-phenyl-5-trifluoromethylthiazole-2-carboxylate [Chemical 332]

Ethyl 5-iodo-4-phenylthiazole-2-carboxylate (〇·60 g), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.1 ml, 17 mmol) and iodine DMF (15 ml) was added to copper (Ι) (〇·32 g, 1.67 mmol), and stirred under stirring at 9 ° C for 4 hours. The reaction solution was returned to room temperature, and extracted with saturated aqueous sodium chloride and ethyl acetate. The extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated. Purification-residue by chopping column chromatography gave the title compound (〇·44§) °^-NMR (CDCI3) δ: 1.45-1.47 (3H5 m)5 4.52 (2H? q? 1 =7.1 Hz), 7.46 -7.47 (3H, m), 7·69-7.71 (2H, m). MS (ESI) m/z: 302 (M+H). 121199.doc -314- 200846322 (3) (4-Phenyl-5-trifluoromethylthiazol-2-yl)methanol [Chemical 333]

Add sodium borohydride (〇 16 g) to a solution of 4-n-yl-5-difluoromethyl hydrazine·2·carboxylic acid ethyl ester (ο.#* g) in decyl alcohol (15 ml) at room temperature Stir down all night. The reaction solution was concentrated, and water was added and extracted three times with ethyl acetate. The combined extracts were washed with saturated &amp; brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting elut elut elut · ~ MS (ESI) m/z : 260 (]yj+H)+. (4) Side oxy moiety _(4_phenyl_5_tris(1)ylmethoxy)-2,3-dihydro 哚 哚 small group] ethyl]amino] propionic acid [Chem.

FwF

Bor .ci

Add ruthenium chloride (5 7 ml) to ethane solution (0.17 ml g of two gas readings (catalytic amount), _ warm down for 9 hours, 2.3 _〇1), and remove the residue by layer chromatography Every time, I get an oil. ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, -Dihydroindol-1-yl)-2-oxoethyl]amino]propionic acid tert-butyl ester (0.12 g) and DMF (3 ml) were suspended and stirred at room temperature for 36 hours. . The reaction mixture was concentrated, and the residue was purified to silica gel column chromatography (yield: 13 g). A 1% by weight solution of TFA-dichloromethane (3 ml) was added to the oil, which was stirred overnight at room temperature. The reaction mixture was concentrated to purified crystalljjjjjjj 'H-NMR (CD3OD) δ : 2.57 (2Η, t5 J=6.5 Hz)? 3.26-3.27 (4H? m)5 4.09-4.10 (4H? m), 5.45 (2H5 s)5 6.94 (1H? d, 1=8.9 Hz)? 7.05 (1H, s), 7·48 (3H, t, J=3.2 Hz), 7·65 (2H, d, J=3.2 Hz), 8.10 (1H, d, J = 8.9) Hz). MS (ESI) m/z: 506 (M+H)+ 〇C24H22F3N3〇4S'0.1CF3CO2H, Calculated for elemental analysis of 1·5Η20·· C,53.44; Η,4_65; Ν,7·73; F, 11.53; s, 5.90. Found: C, 53.38; H, 4.41; N, 7. 39; F, 11.89; S, 5.81. IR (ATR) cnT1 : 1666, 1489, 1344, 1132, 1016, 704. [Example 77] 3-[N-[2-[5-(4-Isobutyl-5.trisinyl σ-septene-2-yloxy)_2,3_dihydroinsult - 1-yl]-2-oxoethyl]amino]propionic acid (1) 4-isobutylthiophene-2-carbaldehyde [Chem. 335]

4 bromothiophene formaldehyde (2.0 g), tetrakis(triphenylphosphine)palladium (ruthenium) (12 g), 121199.doc -316 · 200846322 2-methylpropyl boron M3.2 g) and carbonic acid planing ( 17 g) Water (8) ml) and toluene (5 〇ml) were added, and the mixture was heated under reflux with stirring under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and extracted with diethyl ether three times. The extracts were combined, washed with saturated brine, dried over sodium sulfate, and filtered and evaporated. The residue was purified by silica gel column chromatography to give a mixture of title compound (1·4 g). (2) 5 - moth 4-isobutyl σ phenophene 2 - formic acid; [化336]

Add acetic acid (3 ml) and chloroform (3 ml) to 4-isobutylthiophene-2-carbaldehyde (〇·5〇g), Ν-iodobutaneimine (0.74 g) at 50 ° C The mixture was stirred for 9 hr. !H-NMR (CDC13) δ : 0.96 (6H, d, J = 6.6 Hz), 1.90 - 1.97 (1H, m), 2·48 (2H, d, J = 7.1 Hz), 7·32 (1H, s),9·76 (1H,d,J = 〇.5

Hz). (3) 4-Isobutyl-5-trifluorodecylthiophene-2-alformaldehyde [Chem. 337]

121199.doc -317- 200846322 on 5-indole-4-isobutylthiophene-2-carbaryl (〇·68 g), 2,2-difluoro-2-(fluorocalcinyl)acetate (3.3 ml) DMF (20 ml) was added to copper oxide 0) (0 44 g), and the mixture was stirred under heating at 80 ° C for 4 hours. The reaction solution was returned to room temperature, and brine (3×) The extracts were combined, washed with brine, dried over sodium sulfate and filtered and evaporated. The residue was purified by silica gel column chromatography to afford titled compound (0.38 g).

W-NMR (CDC13) δ : 0.95 (6H, d, J = 6.6 Hz), 1.92-1.99 (1H

m), 2·63 (2H, d, J = 7.4 Hz), 7.58-7.58 (1H, m), 9.92 (1H s) o (4) 4-isobutyl-5-trifluorodecylthiophene-2 - sterol [Chem. 33 8]

To a solution of 4% isobutyl-5-trifluoromethylthiophene-2-furaldehyde (0·38, g) in methanol (15 ml), sodium borohydride (0-070 g) was added, Stir under the dish for 1 hour. The reaction mixture was concentrated, and water was added to extract 14 people with ethyl acetate. The extracts were combined, washed with a saturated aqueous solution of sodium chloride, and aged with sodium sulfate, and then rinsed to the island, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, and the title compound (0·36 g) was obtained. 1.84^1.94 (2H, Hz), 6.82 (1H5 lH-NMR (CDC13) δ : 0.92 (6Η, d5 J=6.6 Hz) ym), 2.54-2.56 (2H, m), 4·80 (2H, d, ; ί=5·9 121199.doc -318- 200846322

(5) 3-[N-[2-[5-(4-isobutyl·5-trifluoromethyl phenyloxy)-) 2,3-dihydroindol-1-yl]-2 -Sideoxyethyl]amino]propionic acid [Chem. 339]

Add sulfite chloride (0·090 ml), DMF to a solution of 4-isobutyl-5-trifluoromethylthiophene-2-merethanol (〇〇6〇§) in dichloroethane (5 ml). (Battery amount), the mixture was heated and stirred at 60 ° C for 1 hour. The reaction solution was cooled to room temperature and concentrated. Add potassium carbonate (〇·1〇g) and 3 _[N-(Tertibutoxy)-[2-(5-.yl-2,3-dihydro) to the residue. -1-yl)-2-oxoethyl]amino]propionic acid tert-butyl ester (0·10 g), DMF (3 ml), suspended, at 8 (Γ(:τ) The reaction solution was cooled to room temperature and concentrated. The residue was purified by glu-gel column chromatography to obtain an oily substance (〇· 13 g). 10% TFA-dichloromethane was added to the oil. The resulting solution (3 ml) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by reverse phase-purified HPLC to give the title compound ( </ </ RTI> 49 g) b-NMR (CD3OD) δ: 0·91 (6H, d , J=6.6 Ηζ), ι·9ΐ4 96 (1H, m), 2.56-2.61 (4H, m), 3·21·3·28 (4H, m), 4·〇6·4·ΐ〇 (4H , m), 5.23 (2H, s), 6.84 (1H, d, J = 8.8 Hz), 6.94 (ih, s) 7·05 (1H, s), 8.04 (1H, d, J = 8.8 Hz). MS (ESI) m/z : 485 (M+H)+. C23H27F3N2〇4S.〇.1CF3C〇2H,0·75Η2〇 Elemental Analysis of the Ten Tubes 121199.doc -319· 200846322 Value·· C,54.70 H, 5.66; Ν, 5·50; F, 12·31; S, 6.29. Measured value: C, 54.71; H , 5·44; N, 5·32; F, 12.29; S, 6.17. IR (ATR) cm·1 : 2960, 1643, 1491, 1302, 1111, 1016. [Example 78] 3·[Ν-[ 2-[5-(4-Cyclohexyl-5-trifluoromethylthiophen-2-ylindenyl)-2,3-dihydroindol-1-yl]-2-oxoethyl]amine Propionate (1) 4-(1-cyclohexenyl)thiophenecarboxaldehyde [Chem. 340]

4-bromo-2-thiophenecarboxaldehyde (0.50 g), tetrakis(triphenylphosphine)palladium (ruthenium) (〇, 3〇g), 1-cyclohexen-1-ylboronic acid pinacol ester (1.1 g Water (15 ml) and toluene (30 ml) were added to a carbonic acid planer (4.3 g), and the mixture was heated under reflux with stirring under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and extracted with diethyl ether three times. The combined extracts were washed with saturated brine and dried over sodium sulfate

After drying and filtering the insoluble matter, the filtrate was concentrated. The residue was purified by silica gel column chromatography toield (2) 4-Cyclohexylthiophene-2-furaldehyde [Chem. 341]

Add methanol (30 ml) to 4-(1-cyclohexenyl)thiophene-2-carbaldehyde (〇·56 g), 5% pd/c (〇.1〇g), under hydrogen atmosphere, room temperature Stir under night. Into 121199.doc -320 - 200846322 and after the replacement of nitrogen, the yield of glutinous rice was supplemented with 5% Pd/c (〇" 〇 g), and again at hydrogen = total room temperature for 3 days. Over-reported liquid, concentrated (four) liquid. The residue was purified by column chromatography to give the title compound g). • H-NMKCCDOa:,^,^ (3Hsm) U9-2.03 (2H,m),2·61·2·64 (1H, ton 7 '〇H,d,J=1.4Hz), 9.88(1H,dJ =14Hz). 66 (3) 4-Cyclohexyl-5_iodothiophene-2_A disk [Chem. 342]

Add acetic acid (5 ml) and chloroform (5 ml) to 4-cyclohexylthiophene-2-carbaldehyde (〇·29 g), N-iodobutanediamine (0·37 g) at 50 ° C Stir for 6 hours. The reaction mixture was concentrated to purified crystals crystals crystals

H-NMR (CDC13) δ : 1.24-1.45 (5H,m)5 1.77-1.79 (1H,m), 185-1.88 (4H,m),2.56-2.59 (1H,m),7·37 (1H ,s),9.76 (1H,s) 〇(4) 4-cyclohexyl-5-trifluoromethylthiophene-2-furaldehyde [Chem. 343]

4-cyclohexyl-5-iodothiophene-2-carbaldehyde (0.37 g), 2,2-difluoro-2-(fluorosulfonate 121199.doc •321 · 200846322 fluorenyl) acetamidine g (l5 ml) Copper iodide (1) (ml added to 〇·22) was heated and given at 8 °C. After 4 hours, the reaction solution was returned to the chamber, and saturated brine was added and extracted with ethyl acetate three times. The organic layers were combined and washed with saturated &amp; brine. It was dried over anhydrous sodium sulfate, and the filtrate was concentrated and filtered. The residue was purified by silica gel column chromatography toiel !H-NMR (CDC13) δ : 1·23-1·47 (5H,m),1·76·1·91 (5H,m), 2·86·2·93 (1H,m),7· 70 (1H, q, J = 1.5 Hz), 9.92 (1H, s). (5) 4-cyclohexyl·5·trifluoromethyl 0-thiophene-2-propanol [Chem. 344]

Adding sodium hydrogen hydride (〇·〇5〇g) to a solution of 4-ί-hexyl-5-difluoromethyl porphin-2-methyl (〇·28 g) in methanol (10 ml) Warm down for 1 hour. The reaction solution was concentrated, and water was added and extracted three times with ethyl acetate. The organic layers were combined and washed with saturated brine. It was dried over anhydrous sodium sulfate, and the filtrate was concentrated and filtered. The residue was purified by EtOAc EtOAc (EtOAc) ]H-NMR (CDC13) δ : 1.33-1.42 (4Η, m), 1.73-1.85 (6H? m), 2·82-2·88 (1H, m), 4·80 (2H, dt, J= 6.1, 〇·9 Hz), 6.94 (1H, d, J=0.7 Hz) 0 (6) 3·[Ν-[2-[5-(4-cyclohexyl-5-trifluoromethylthiophene-2- Methoxy)·121199.doc -322- 200846322 2,3-Dihydroindol-1-yl p2-sided oxyethyl]amino]propionic acid [Chem.

Add sulphurous acid chloride (0·〇9〇ml) to 4-3⁄4 hexyl-5-trifluoromethylthiophene-2-methanol (〇·060 g) in 込2• digasethane solution (5 ml) , DMF (micro), ♦ at 60. . Heat under the disturbance for 1 hour. Cool to room temperature and concentrate the reaction. Potassium carbonate (0.10 g), 3_[N_(t-butoxycarbonyl)_N-[2-indolyl 2,3·dihydroindenyl)_2_side oxyethyl]amine was added to the residue. Base] propionate tributyl (0_10 g), DMF (3 ml) was suspended. After stirring overnight, the reaction solution was cooled to room temperature and concentrated. The residue was purified by chopping column chromatography to thereby obtain an oil (〇·16 g). Add 1〇. /() TFA-digas methane solution (3 ml), stirred at room temperature overnight. The reaction mixture was concentrated and purified with EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , J=6.5 Hz), 2·83-2·86 (1H, m), 3.22-3.26 (4H, m), 4·07-4·12 (4H, m), 5.22 (2H, s), 6.84 (1H, d, J = 8.8 Hz), 6.94 (1H, s), 7.17 (1H, s), 8.05 (1H, d, J = 8.8 Hz) MS (ESI) m/z : 511 (M+H +. C2 5H29F3N2〇4S*0.1 Calculated for elemental analysis of CF3C〇2H*H2〇: c, 56.05, Η' 5.81, Ν, 5.19; F, 11.61; S, 5.94. Measured value: C, 56.14; , 5·81; Ν, 4·97; F, 11.43: S, 5.94. 121199.doc - 323 - 200846322 IR (ATR) em·1 : 2929, 1658, 1491, 1113, 1014, 841. [Example 79 3-[Ν-[2·〇(2-chlorobiphenylylmethoxy p-pyroline small group]-2-oxoethyl]amino]propionate hydrochloride (1) 3 - Methyl 4-chlorotrifluoromethylsulfonate oxybenzoate [Chem. 346]

CI ΗΟ 〇 -► , .0 ΤΓ

〇 ,

Add ΤΕΑ (837 μΐ) to a solution of 3-gas-4-benzoic acid methyl st (56 G mg) in dichlorohydrazine (10 ml ml) and ice-cool, add trimethylformamide (555 μ"' After stirring for 5 hours at room temperature, it was added to the reaction mixture solution: After saturated brine, it was extracted with chloroform for 3 times, and the organic layer was washed with hydrochloric acid and brine. The organic layer was condensed with anhydrous sodium sulfate and concentrated. The title compound (808 mg) was obtained by flash column chromatography (2L) (yield: 2L). The title compound (808 mg) was obtained by NMR (CDCI3) δ: 3.95 (3H5 s)5 7.44 ( iH d 8·03 (1H, dd, J=2.1, 8·7 Hz), 8·21 (1H, d, Bu 2 ! 2 8 7 HZ) 5 MS (ESI) m/z : 319 (M+H ) + (2) 2-gas-linked base-4-carboxylic acid formazan [化347]

121199.doc 324 - 200846322 Add phenylboric acid (367 mg), potassium carbonate to a solution of methyl 3-chloro-4-trifluoromethylsulfonyloxybenzoate (800 mg) in toluene (15 ml) (1.04 g), water (4.0 ml), tetrakis(triphenylphosphine), (〇) (ι 45 mg), and stirred under heating and reflux for 3 hours. After it was left to cool to room temperature, a saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained by purification by flash column chromatography (2 mL of Shanshan high-speed column) was used to obtain the title compound (5 52 mg). iNMR (CDC13) δ : 3·95 (3H, s), 7.41-7.46 (6H, m), 7.97 (1H, dd, J=1.7, 8·1 Hz), 8·15 (1H, d, J= 1.7 Hz). MS (ESI) m/z: 247 (M+H)+.

(3) 2-chlorobiphenyl-4-carboxylic acid [Chemical 348]

OH In a solution of dimethyl 2-methylbiphenylcarboxylate (540 mg) in THF (ίο ml), add methanol (5_0 (5)^ and !N sodium hydroxide solution (5 〇8, 5 〇8 mmol), in the room The mixture was stirred overnight, and added to the reaction mixture. After the hydrochloric acid, the organic solvent was distilled off under reduced pressure. The precipitated solid was filtered and dried to give the title compound (490 mg). D6) δ : 7.43-7.56 (6Η, m)5 8.03^7.94 (2H5 m) 〇MS (ESI) m/z : 233 (M+H)+. 121199.doc -325 - 200846322 (4) 2-Chlorine Biphenyl-4-methanol [349]

To a solution of 2-chlorobiphenyl-4-carboxylic acid (470 mg) in 2 THF (2 〇) was added ΤΕΑ(423 μΐ) and ice-cooled. Ethyl chloroformate (23 1 y) was added, and the mixture was stirred under ice cooling for 1 hour. The precipitate was removed by filtration to give a filtrate. The sodium borohydride (459 mg) was suspended in ethanol (6.0 mi) and cooled with ice. The previously obtained filtrate was added dropwise thereto at 20 minutes, and the mixture was allowed to stand at room temperature for 1 hour. To the reaction mixture was added 1 N hydrochloric acid, and extracted twice with ethyl acetate. The combined extracts were washed with a 1 N aqueous sodium hydroxide solution and brine, and dried over anhydrous sodium sulfate. The residue obtained was purified by flash column chromatography (m. ^-NMR (CDC13) δ : 1.75-1.81 (1Η, m), 4.73 (2H5 d5 J=5.9 Hz), 7.30-7.50 (8H, m). MS (ESI) m/z: 219 (M+H)+. (5) 2-Chloro-4-chloromethylbiphenyl [Chemical 3 5 0]

To a solution of 2-chlorobiphenyl_4·methanol (1 &1&gt;2_dichloroethane solution), sulfoxide gas (713 μl) was added thereto, and the mixture was stirred for 2 hours under agitation. The reaction mixture was concentrated to give the title compound (394 mg) 〇H. The residue was purified by flash column chromatography (m.p.). -NMR (CDC13) δ : 4.59 (2Η, s)5 7.52-7.25 (8H5 m) 〇(6) 3 [N-(Secondoxycarbonyl)_N_[2_[5_(2_chlorobiphenyl) Oxy) porphyrin-1-yl]-2-oxoethyl]amino]propionic acid tert-butyl ester [Chem. 351]

3-[N-(Tertibutoxycarbonyl)-[2-(5-hydroxyindolyl)_2_sideoxyethyl]amino]propionic acid tert-butyl ester (21〇mg) 2DMF To the solution (5 〇ml), 2-chloro-4-chloromethylbiphenyl (142 mg) and potassium carbonate (1 〇 4 mg) were added, and stirred at 70 C overnight. After the mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the residue was evaporated to purified crystals crystals crystals H-NMR (CDC1S) δ : 1.41-1.50 (18H5 m), 2.56-2.63 (2H? m), 3.17-3.23 (2H, m), 3.56-3.62 (2H, m), 4,00-4.18 (4H m), 5.04 (2H, s), 6.78-6.85 (2H, m), 7.26-7.55 (8H, m), 8·11-8·16 (1H, m). MS (ESI) m/z : 621 (M+H) + 〇(7)3-[N-[2-[5-(2-chlorobiphenyl-4-ylmethoxy)bone | σ porphyrin &lt;• ]·2_ side oxygen 121199.doc •327- 200846322 phenylethyl]amino]propionic acid hydrochloride [Chemical 3 52]

3-[Ν-(Tertibutoxycarbonyl)-:^[2-[5-(2-chlorobiphenylmethoxy)porphyrin-1.yl]-2-oxoethyl To the third ester of propionate (311 φ mg), 4^ hydrochloric acid/1,4-di 4 (5.1111) was added, and the sample was disturbed at room temperature for day and night. Diethyl ether was added to the reaction mixture, and the precipitated solid was filtered, and then washed with ethyl acetate to afford the title compound (210 mg). 'H-NMR (DMSO-d6) δ : 2.75-2.81 (2Η, m)5 3.17-3.22 (4H? m), 4.05-4.14 (4H, m), 5·16 (2H, s), 6.89 -7·〇4 (2H,m), 7.40-7.50 (7H,m), 7.63 (1H,s),7·98 (1H, d5 J=8,6 Hz). IR (ATR) cm·1 : 2736, 1708, 1670, 1496, 1444, 1270, 1238. MS (ESI) m/z: 465 (M+H)+. HR-MS (FAB) calcd for C26H26ClN2 〇4 (M+H)+: 465 1581; Calculated for elemental analysis of C26H25C1N204*HC1: c, 62.28; H, 5 · 2 3, C15 14 · 14; N, 5.5 9. Found: C, 6 2.0 7; Η, 5 · 16; C1, 14.03; N, 5·48 〇 [Example 80] 3-[Ν·[2-[5·(4-isobutyl-3· Tris-methylbenzyloxy) oxime.淋-l-yl]-2-oxoethyl]amino]amino]propionic acid hydrochloride (1) methyl 4-isobutyl-3-trifluoromethylbenzoate I21199.doc -328 - 200846322 [化353]

Add isobutylboric acid (1·68 g), carbonic acid to a solution of 4_trifluorosulfonyloxy-3-trifluoromethylbenzoate methyl ester (1·93 g) in benzene (30 ml) Plane (8·93 g), water (15 ml), tetrakis(triphenylphosphine), and (9) (633 °), stir under heating and reflux overnight. After it was left to cool to room temperature, the reaction solution was filtered over celite, and a saturated sodium bicarbonate solution was added to the filtrate, and the mixture was extracted twice with ethyl acetate, and the combined extracts were washed with saturated brine. Dry with anhydrous sodium sulfate. The insoluble material was filtered, and the residue was evaporated to purified crystals eluted elution elution elution elution elution elution elution elution elution elution elution 6.6 Hz), 1.93-2.03 (1H? m), 2·71 (2H, d, J=7.4 Hz), 3·93 (3H, s), 7·40 (1H, d, J=8.1 φ Hz) , 8·11 (1H, dd, J=1.6, 8.1 Hz), 8·30 (1H, d, J=1.6 Hz). MS (ESI) m/z: 261 (M+H)+. (2) (4-Isobutyl-3-trifluoromethylphenyl) decyl alcohol [Chem. 354]

Add borohydride (336 mg) to THF solution of 4-isobutyl-3-trifluorodecylbenzoate (1.34 g) in THF (40 ml), and stir on heating under reflux for 7 small 121199.doc • 329 - 200846322 t After cooling to room temperature, add n n hydrochloric acid to the reaction mixture, and extract twice with acetic acid (tetra). The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and concentrated under reduced pressure. The residue obtained was purified by rapid g column chromatography (2L of Shanshan two-speed column); and the title compound (1.13 g) was obtained. Not MR (CDC13) δ : G.93 (6H,d,Ι=6·6 Ηζ), ΐ·74-1·78 (1H, m), 1.92-1.98 (1H, m), 2.65 (2H, d , J=7.1 Hz), 4.72 (2H ά J=5.6Hz)j 7.31 (1H, d, J=8.1Hz), 7.46 (1H, d, 7-63(1H, s). ' MS (ESI) m /z : 215 (M-〇H)+ (3) 4-Chloromethylisobutyl·2_trifluorodecylbenzene [Chem. 355]

Add sulfite gas (1.75 ml) to (4-isobutyl-3-trifluoromethylphenyl)methanol (1.12 dichloroethane solution (5 〇ml), stir at 50X 2 The reaction mixture was concentrated under reduced pressure. CDC13) δ : 0.93 (6Η, d? J=6.6 Hz), 1.90-2.00 (1H? m), 2·65 (2H, d, Ι=7·1 Hz), 4·59 (2H, s), 7.31 (1H, d, J = 7.8 Hz), 7.48 (1H, dd, J = 1.7, 7.8 Hz), 7.63 (1H, d, J = 1.7 Hz) (4) 3-[N_(Third butoxide)羰carbonyl)·Ν-[2-[5_(4_isobutyl-3-trifluoromethyl 121199.doc-330- 200846322 benzyloxy)porphyrin-i-yl]-2-sideoxy B Amino]dipropionate tert-butyl ester [化356]

3-[N-(2nd butyl-based)-Ν-[2-(5-trans-base 卜bendolin_1_yl)_2· oxyethyl]amino]propanoic acid Add 4-chloromethyl-1-isobutyl-2-trifluoromethylbenzene (5〇1 mg) and potassium carbonate (359 mg) to a solution of tributyl ester (841 mg) in DMF (20 ml). Stir at 60 ° C overnight. After it was left to cool to room temperature, water was added to the reaction mixture, and extracted with ethyl acetate three times. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was partitioned, and the residue obtained was purified by flash column chromatography (yield: 2L). The title compound (1,29 g) was obtained.

^-NMR (CDCI3) δ : 0.93 (6Η, d, J==6.6 Hz), 1.40-150 (18H, m), 1.92-1.99 (1H, m), 2.55-2.67 (4H, m), 3.16- 3.22 (2H, m), 3.56-3.61 (2H, m), 3.99-4.18 (4H, m), 5.01 (2H s), 6.76-6.83 (2H, m), 7.32 (1H, d J=7 6Hz) 7 5i (m J = 7.6 HZ), 7.67 (1H, s), 8.10-8.15 (1H, m). MS (ESI) m/z: 636 (M+2)+. (5) 3-[N-[2-[5-(4-Isobutyltrifluoromethane &amp; 齓 齓 卞虱 ) ) ) ) ) ) ) -1- -1-)) Amino]propionic acid hydrochloride [Chem. 357] 121199.doc -331 - 200846322

3-[N-(Tertibutoxycarbonyl)-N-[2-[5-(4-isobutyl-3-trifluoromethylbenzyloxy)porphyrin-1-yl]-2- 4N Hydrochloric acid / 1,4-dioxane (20 ml) was added to a solution of the butyl hydroxyethyl]amino]propionic acid (1,6 g), and stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue and solidified. The residue obtained was recrystallized from acetonitrile to give the title compound (808 mg). ]H-NMR (DMS〇.d6) δ : 0.89 (6H5 d5 J=6.6 Hz), 1.90-1.96 (1H, m), 2·63 (2H, d, J=7.4 Hz), 2·77 (2H , s), 3.16-3.21 (4H5 m), 4_05_4·13 (4H, m), 5.14 (2H, s), 6.88 (1H, dd, J=2.5, 8.8 Hz), 7.02 (1H, d, J = 2.0 Hz), 7·49 (1H, d, J = 8.1 Hz), 7·65-7·74 (2H, m), 7.97 (1H, d, J = 8.8 Hz). IR (ATR) cm.1: 3332, 2958, 1722, 1646, 1492, 1319, 1272, 1108. MS (ESI) m/z: 479 (M+H)+. HR-MS (ESI) calcd for C??? Calcd for C25H29F3N2 〇4*HC1.0.5H2 〇: C, 57.31; H, 5.96; Cl, 6.77; F, 10.88; N, 5.35. Found: C, 5 7.23; H, 5.93; Cl5 6.85; F, 10.94; N, 5.24 〇 [Example 8 1 ] 3 · [N- [2 - [5 - (4 _cyclopropyl-3-III) Gas methyl oxy) 〇 朵 ,, 琳-1·yl]-2-oxoethyl]amino]propionic acid TFA salt 121199.doc • 332 - 200846322 (1) 4-cyclopropyl- 3-trifluoromethylbenzoic acid methyl ketone [?358] ϋ, 0 = 4-三 I 醯 -3- oxy-3-trimethyl benzoic acid methyl vinegar (1 gen toluene ♦ solution (15 ml) Add cyclopropylboronic acid (773 claw, carbonic acid (4.89 g), water (7.5 ml), tetrakis(triphenylphosphine)palladium (〇) (347 claws, and stir under reflux for 3 hours. After the mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography (2HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH , m), 2·23-2·30 (1H, m), 3·93 (3H, s), 7.05 (1H, d, J=8. 3 Hz), 8.07 (1H, dd, Bu 1.2, 8·3 Hz), 8·28 (1H, d, J = 1.2 Hz) MS (ESI) m/z : 245 (M+H), (2 (4-cyclopropyl-3-trifluoromethylphenyl)methanol [Chemical 3 5 9]

Add borohydride (189 mg) to THF solution (20 ml) of 4-cyclopropyl-3 -trimethylmercaptobenzoic acid methyl hydrazide (705 mg), and stir under heating and reflux for 2 small 121199 .doc 333 _ 200846322 half. After it was left to cool to room temperature, 1 N hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate three times. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the residue was purified by flash column chromatography (yield: ss.). The title compound (611 mg &gt;.) H-NMR (CDC13) δ: 0.74- 0.78 (2H? m)? 1.01-1.06 (2H3 m)3 1·73 (1H,t,J=5.9 Hz), 2.16-2.24 (1H,m), 4.70 (2H,d, J=5.9 Hz), 7.03 (1H,d,J=7.8Hz), 7.41-7.43(lH,m), 7.61- 7.62 (1H,m) 〇MS (ESI) m/z : 199 (M-〇H)+ (3) 4-chloromethyl-i-cyclopropyl_2_trifluoromethylbenzene [360]

Add (7-cyclopropyl-3-trifluorodecylphenyl)methanol (600 dichloroethane (20 ml), add sulfoxide (L〇i ml), stir at 5 ° cc 1 After the reaction was allowed to cool to room temperature, the reaction mixture was evaporated to dryness crystalljjjjjjjjjjjjjj CDCI3) δ : 0.75-0.79 (2H? m)5 1.03-1.08 (2H5 m)? 2·17-2·23 (1H,m), 4.58 (2H,s),7·02 (1H,d,J = 8.1 Hz), 7·45 (1H, dd, Bu 1.7, 8.1 Hz), 7.62 (1H, d, J = 1.7 Hz) (4) 3-[N-(Tertidinoxycarbonyl)-N -[2-|&gt;(4-cyclopropyl-3-trifluoromethyl 121199.doc -334- 200846322 benzyloxy) °pyridin-1-yl]-2-oxoethylethylamine Base] tert-butyl propionate [Chemical 361]

3-[N-(T-Butoxycarbonyl[2-(5-hydroxyindol-1-yl)-2-yloxyethyl]amino]propionic acid tert-butyl ester (252 mg) Add 4-chloromethyl-1-cyclopropyl-2-trifluoromethylbenzene (125 mg) and potassium carbonate (104 mg) in DMF solution (10 ml) and stir at 60 ° C overnight. After it was left to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography (yield: 2L) to afford the title compound ( 317 mg). H-NMR (CDC13) δ: 0.75-0.79 (2H,m),1·〇2-1 ·〇6 (2H,m), 1·40-1·50 (18Η,m), 2.17-2.24 (1Η,m),2.55-2.63 (2Η,m), 3.15-3.22 (2H,m),3.56 -3.61 (2H,m),3.99-4.18 (4H,m), 5·00 (2H,s),6.74-6.82 (2H,m),7.04 (1H,d,J=81 Hz), 7.47 (1H , d, J = 8.1 Hz), 7.66 (1H, s), 8.10-8.14 (1H, m) MS (ESI) m/z : 619 (M+H) + (5) 3-[N -[2-[5-(4·cyclopropyl_3_trifluoromethylbenzyloxyindolyl)_ 2- Oxyethyl] amino] propanoic acid tfA salt [Formula 362] 121199.doc - 335 - 200846322

3 [N-(2,4-Butoxycarbonyl)_N_[2q5_(4•cyclopropyltrifluoromethylbenzyloxy) porphyrinyl]_2-oxyethyl]amino]propanoic acid In a solution of butyl ester (3 09 mg) in chloromethane (8 〇 丨), add TFA (2.〇mi) under ice cooling. Stir at room temperature for 1 hour and a half, add tfa (i 〇 ml) And then stirred under the chamber for 2 hours. The reaction mixture was concentrated under reduced vacuo. 'H-NMR (DMSO-d6) δ : 0.78-0.82 (2H9 m)9 1.02-1.07 (2H, m), 2·08-2·15 (1H, m), 2·73 (2H, t, J =7.4 Hz),3·16-3·22 (4H,m),4·03_4·14 (4H, m), 5.12 (2H,s)5 6·87 (1H,dd, J=2.7, 8.8 Hz ), 7.0G (1H, d, J = 2.7 Hz), 7.18 (1H, d, J = 8.l Hz), 7.61 (1H, d, J = 8.1 Hz), 7·72 (1H , d, Hz), 7.96 (1H, d, J = 8.7 Hz). IR (ATR) cnT1 : 1648, 1492, 13 17, 1255, 1 180, 1130, 1112. MS (ESI) m/z: 463 (M+H)+. HR-MS (ESI) calcd for C24H26F3N (M+H)+: 463. C24H25F3N2 (calculated for the elemental analysis of VCF3CO2H*0.5H2O: c, 53·34; Η, 4·65; F, 19·47; Ν, 4·78. Measured: C, 53·76; H, 4.57; F, 19.14; N, 4. 82. [Example 82] 3-[N-[2-[5-(4-isobutyl-3.methoxybenzyloxy)porphyrin, 1-yl] -2 - oxoethyl]amino]propionic acid 121199.doc -336 - 200846322 (1) Ethyl 3-methoxy-4-trifluorosulfonyloxybenzoate (w〇95/34540) [化363]

Add τεα (1·05 ml) and DMAP (61 mg) to a solution of 4-mercapto-nonyloxybenzoic acid ethyl ester (981 mg) in dichloromethane (50 ml). Fluorine anhydride (101 ml) was stirred at room temperature for 3 hours. A saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the residue obtained was purified by purified column chromatography (yield: 2H). H.NMR (CDCI3) δ : 1.41 (3H? t, J=7.2 Hz), 3.98 (3H, s)5 4.40 (2H,q,J=7.2 Hz), 7.28 (1H,d,J=8.3 Hz) ), 7.68-7.72 (2H, m). MS (ESI) m/z: 329 (M+H), (2) 4-isobutyl-3- methoxybenzoic acid ethyl ester [ 364]

To a solution of 3-methoxy-4-trifluorosulfonyloxybenzoate (656 mg) in toluene (10 ml) was added isobutylboronic acid (6 12 mg), carbonic acid (3, 26 g), water (5.0 ml), tetrakis(triphenylphosphine)|bar (〇) (231 mg), stirred under reflux at 121199.doc -337 - 200846322. The mixture was cooled to water, and the mixture was added with acetic acid ethyl acetate (w), and the organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography (m.p. 1.39 (3H5 t5 m), 2·52 (2H, d, J=7.i Hz), 3.86 ^-NMR (CDC13) δ : 〇.89 J=7.1 Hz), 1.87-1.98 (1Η, (3H, s), 4.37 (2H, qj = 7 1 w7 /

, 4, J 7.1 Hz), 7.13 (1H, d, J = 7.8 Hz), 7.50 (lH5d5 1 = 1.5 Hz) 7sr^ixj aat 1 々, /·58 (1H, dd, J=15, 7.8 Hz) . MS (ESI) m/z: 237 (M+H)+. (3) (4-Isobutyl-3-methoxyphenyl)methanol [Chemical 365]

To a solution of ethyl 4-isobutyl-3-decyloxybenzoate (37 〇 mg) in thF (20 mL) was added lithium aluminum hydride (71·1 mg), and the mixture was stirred under reflux for 1 hour. After allowing to cool to room temperature, it was ice-cooled, and water (71 μM), 1 N aqueous sodium hydroxide solution (71 μl), and water (213 μΐ) were sequentially added to the reaction mixture, and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title compound (320 mg). ^-NMR (CDCI3) δ : 0.89 (6H5 d5 1=6.6 Hz)? 1.61 (1H? t5 J=5.9 Hz), 1.84-1.95 (1H, m), 2·47 (2H, d, Hz), 3.82 (3H, s), 4.66 (2H, d, J = 5.9 Hz), 6.84 - 6.88 (2H, m), 7.06 121199.doc • 338 - 200846322 (1H, d, J = 7.6 Hz). MS (ESI) m/z : 177 (M-OH) + 〇 (4) 4-chloromethyl-1-isobutyl-2.methoxybenzene [Chem.

Add ruthenium chloride (579 μl) to a solution of (4-isobutyl-3·decyloxyphenyl) decyl alcohol (3 1 〇mg) in 1,2-dichloroetheane (15 ml) At 50. Stir under the armpit for 3 minutes. After standing to cool to room temperature, the reaction liquid was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (m.p.) to give the title compound (307 mg). H-NMR (CDC13) δ : 0.88 (6H, d, J = 6.6 Ηζ), 1.84-1·94 (1H, m), 2.47 (2H, d, J = 7.1 Hz), 3.82 (3H, s ), 4.57 (2H, s), 6.86-6·89 (2H, m) 5 7.05 (1H, d, J = 7.6 Hz). (5) 3-[N-(Terti-butoxycarbonyl)_ν_[2·[5_(4-isobutyl-3-(indolyloxybenzyl)oxy) is 1 ϋ 琳 基 】 Amino]propionic acid tert-butyl ester [Chem. 367]

In the presence of 3_[N-(t-butoxycarbonyl)-N_[2_(5-hydroxyporphyrin)-yl)-oxyethyl]amino]propionic acid tert-butyl ester (210 mg) In the DMF solution (5. 〇ml), 4-chloromethyl-丨-isobutyl-2-methoxybenzene (117 mg), carbon 121199.doc - 339-200846322 potassium (89.8 mg) was added. (10) Under the disturbance - night. After the mixture was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The insoluble material was dissolved in vacuo and concentrated under reduced pressure. The title compound (177 mg) was obtained from the residue obtained from the purified column chromatography. WR (CDCl3) δ: 0·89 (6H, d, J=6 6 Hz), i Thai 15〇(18H5m), 1.87-1.94 (lH,m)s 2.47 (2H,d)J=7&gt;1Hz) 2

2.63 (2H, m), 3.15-3.21 (2H, m), 3.59 (2H, q, Hz) 3.81 (3H, s), 3.98-4.18 (4H, m), 4.98 (2H, s), 6.77-6.91 (4H, m), 7.08 (1H, d, J = 8.1 Hz), 8·〇9-8·14 (1H, m). MS (ESI) m/z: 597 (M+H)+.

(6) isobutyl·3_methoxy ethoxy group) decandyl small group R-side oxyethyl]amino]propionic acid [Chemical 368]

3-[N-(Third τ oxime oxime)-Ν_[2·[5_(indifferent yl-3-yloxybenzyloxy)]|porphyrin-1-yl]-2-side To a solution of oxyethyl]amino]propionic acid tert-butyl ester (240 mg) was added 4 hydrazine hydrochloride, 4-dioxane (1 〇ml), and stirred at room temperature for 4 hours. After the reaction mixture was concentrated under reduced pressure, the residue was evaporated. Ή-NMR (DMSO-d6) δ : 0.84 (6Η, d, J=6.6 Hz), 1.81-!.8g 121199.doc -340 - 200846322 (1H,m),2·42 (2H,d,J= 7.1 Ηζ), 2·96 (2H, t, J = 6.9 Hz), 3.14 (2H, t, J = 8.3 Hz), 3·76-3·77 (5H, m), 4·04 (2H, t , J = 8.3 Hz), 5·01 (2H, s), 6.82-7.08 (5H, m), 7.97 (1H, d, J = 8.8 Hz), (2H coincides with DMSO.). MS (ESI) m/z: 441 (M+H)+. [Example 83] 3-[2-[5-[4-(1,1·Difluoro-2-mercaptopropyl)benzyloxy]porphyrin-1-yl]-2-yloxy B Aminoamine]propionic acid hydrochloride (1) [4-(1,1-Difluoro-2-methylpropyl)phenyl]nonanol raw material was synthesized in accordance with the Merck patent (WO05/8848). [化369]

F F

Add lithium borohydride (159 mg) to a solution of 4-(1,1-fluoro-2-methylpropyl)benzoic acid in ethyl acetate (590 mg) (25 ml), and heat to reflux. Stir for 2 hours and a half. After it was left to cool to room temperature, 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and concentrated under reduced pressure, and then purified and purified to the title compound (159 mg). Hz)? 2.27-2.37 (1H3 tn), 4·74 (2H, s), 7·40-7·44 (4H, m) (2) 1-chloromethyl-4-(l,l-two Fluor-2-methylpropyl)benzene [Chemical 370] 121199.doc •341- 200846322

Add ruthenium sulfoxide (725 μΐ) to ['(l ^difluoro-2-methylpropyl)phenyl]methanol (400 mg) in 1,2-dichloroethane (1 〇 ml) , gave a drop of 1 hour at 50 °C. After the mixture was allowed to cool to room temperature, the residue was evaporated to dryness crystals crystals crystals H-NMR (CDC13) δ: 0.99 (6H? d? J = 6.9 Hz), 2.24-2.38 (1H, • m), 4.61 (2H, s), 7.43 (4H, s). (3) 3-[N-(2,4-Butoxycarbonyl)-indole-[2·[5·[4-(1,1-difluoro-2-mercaptopropyl)benzyloxy](5) Porphyrin Tertiary butyl 2-butyl-propionate

.π L 1 Le bis methoxycarbonyl)·Ν-[2-(5-hydroxyporphyrin·yl)々·sideoxyethyl]amino]propionic acid tert-butyl vinegar (116 mg) DMF solution (5 〇 , , , , , , , 添加 添加 添加 添加 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 D D D D D D D D D D D D D . After it was left to cool to room temperature, the residue was concentrated under reduced pressure, and the residue was purified by flash column chromatography (2L) to obtain the title compound. (169m)H-NMR (CDC13) δ · π 〇〇〇·99 (6Η, d, J=6.9 Hz) jl 4〇(18H,m), 2.25-2.39 (ih m,,..., UH, m) , 2.55.2.63 (2H, m), 3.15-3.21 121199.doc -342- 200846322

(2H, m), 3.56-3.61 (2H, m), 3.99-4.18 (4H, m)} 5 〇5 (2H s), 6.76-6.83 (2H, m)5 7.43-7.47 (4H, m), 8.1 〇.δ ]5 〇H m) o MS (ESI) m/z : 603 (M+H)+. w methyl propyl) ethoxylate h-dopyl]-2_side oxyethyl]amino]propionate [Chemical 372]

3-[N-(Tertidinoxycarbonylbubatch-7#}}difluoro-2-methylpropyl)benzyloxy], porphyrin-l-yl>2-sided oxyethyl To a solution of ethylamino]propionic acid tert-butyl ester (150 mg) in ethyl acetate (5 mL) was added 4 n hydrochloric acid / ethyl acetate (2.5 ml), and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Lu]H-NMR (DMSO-d6) δ : 0.93 (6H? d5 J=6.9 Hz) 5 2.39-2.48 (1H5 m)5 2.76 (2H? t? 1=7.4 Hz)? 3.16-3.21 (4H? m ), 4.04- 4.13 (4H,m), 5.14 (2H,s),6·88 (1H,dd,J=2.5,8.8 Hz), 7·01 (1H, d, J—2.5 Hz), 7· 48·7·56 (4H,m), 7.96 (1H,d, J=8,8 Hz). IR (ATR) cm·1 : 2935, 2601, 1702, 1646, 1371, 987, 819. MS (ESI) m/z: 447 (M+H)+. HR-MS (ESI) calcd for C24H29F2N2O4 (M+H): 447. 121199.doc -343 - 200846322 Calculated for elemental analysis of C24H28F2N2〇4*HC1i〇.25H20 · c 59.14; H,6.10; C1, 7.27; F, 7.79; N, 5.75. Found: c 59·02; H, 5.96; C1,7·24; F,7·65; Ν, 5.68. [Example 84] 3-[Ν·[2-[5_(4-propyl-3-trifluoromethyloxy). Tetlin _ 1-yl]·2-sided oxyethyl]amino]propionic acid TFA salt (1) methyl 4-propyl-3-trifluoromethylbenzoate [Chem. 3 73]

Add propylboronic acid (527 mg) to a solution of 4-difluoromethane xanyloxy 3-trifluoromethylbenzoic acid methyl ester (ι·〇6 g) in benzene (15 ml). (4.89 g), water (7.5 ml), tetrakis(triphenylphosphine)palladium(0) (347 mg), stirred under stirring overnight. After it was left to cool to room temperature, a saturated sodium hydrogencarbonate solution was added to the mixture, and the mixture was extracted three times with diethyl ether. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the residue was purified to purified crystals crystals eluted eluted eluted h-NMR (CDC13) δ ·· 1.01 (3H, t, J=7.4 Hz), 1.63-1.72 (2H, m), 2.79-2.83 (2H, m), 3·94 (3H, s), 7.42 ( 1H,d,J=8.1 Hz), 8.11 (1H5 dd5 J=1.6, 8.1 Hz), 8.29 (1H3 d5 J=1.6 Hz) 〇MS (ESI) m/z : 247 (M+H)+ 〇(2 (4-propyl-3-trifluoromethylphenyl)methanol [化374] 121199.doc -344 - 200846322

Lithium aluminum hydride (112 mg) was added to ml), and stirred under heating and reflux for 3 Torr. After it was left to cool to room temperature, water (ιι 5 μΐ), 1 Ν aqueous sodium hydroxide solution (115 μl), and water (345 called anhydrous sulfur) were sequentially added to the reaction solution.

(429 mg). ^-NMR (CDCI3) δ : 0.99 (3Η, t5 J=7.2 Hz)? 1.60-1.75 (3H, m), 2·72-2·76 (2H, m), 4.71 (2H, d, J=5.9 Hz), 7·32 (1H, d, J = 7.8 Hz), 7.46 (1H, d, J = 7.8 Hz), 7.61 (1H, s). MS (ESI) m/z: 201 (M-OH)+. (3) 4-Gasmethyl-1-propyl-2-trismethylbenzene [Chemical 375]

To a solution of (4-propyl-3-trifluoromethylphenyl) sterol (420 mg) in 1,2-dichloroethane (15 ml), add sulfoxide (698 μΐ) to Stir at 50 ° C for 2 hours and a half. After it was allowed to cool to room temperature, the reaction mixture was evaporated. !H-NMR (CDCI3) δ : 1.00 (3H? t5 J=7.4 Hz), 1.60-1.69 (2H5 121199.doc -345 - 200846322 m), 2.73-2.77 (2H, m), 4.59 (2H, s) , 7.33 (1H, d, J 2 8.1 Hz), 7.48 (1H, dd, J = 1.5, 8·1 Hz), 7.62 (1H, d, J = 1.5 Hz). (4) 3-[N-(Tertidinoxycarbonyl)-indole-[2-[5-(4-propyl-3-trifluoromethylbenzyl)

Oxytoxine h-porphyrin-1-yl]-2-oxoethyl]amino]propionic acid tert-butyl ester [Chem. 376]

To (t-butoxycarbonyl)-N-[2-(5-pyridylporphyrinyl)-2-oxoethyl]amino]propanoic acid tert-butyl ester (23 1 mg) To the DMF solution (5,0 ml), 4-chloroindolyl-1-propyl-2-trifluoromethylbenzene (118 mg) and potassium carbonate (173 mg) were added at 70. (The mixture was stirred overnight. After the mixture was cooled to room temperature, the reaction mixture was evaporated to dryness, and the residue was purified by flash column chromatography (m. NMR (CDCls) δ : !.〇〇(3H5 t5 J=7.2 Hz)5 1.40-1.50

(18H, m), 1.62-1.6 8 (2H, m), 2.56-2.63 (2H, m), 2 73-2 77

(2H, m), 3·16-3·22 (2H, m), 3.56-3.61 (2H, m), 3.99-4.18 (4H, m), 5.01 (2H, s), 6.75-6.83 (2H, m),7·34 (1H,d,J=8.1 Hz), 7.51 (1H,d,J-8·1 Hz), 7.67 (1H,s),8·10-8·15 (1H m) 0 MS (ESI) m/z ·· 621 (M+H)+. (5) 3-[N-[2-[5-(4-propyl-3-trifluoromethylbenzyloxy) σ porphyrin]•yl]_2_ oxoethyl]amino]propionic acid TFA salt [Chem. 377] 121199.doc -346- 200846322

3-[N-(Tertibutoxycarbonyl)_ν-[2-[5-(4-propyl-3-trifluoromethylethoxy)porphyrin-1 -yl]-2- side To a solution of oxyethyl]amino]propionic acid tert-butyl ester (260 mg) in dichloromethane (8 mL), EtOAc (EtOAc) After the reaction mixture was concentrated under reduced pressure, the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted (2H,m), 2.67_2·73 (4H,m), 3.15-3.20 (4H,m),4·04-4·09 (4H,m),5·13 (2H,s),6·88 (1H, dd, J=2.5, 8·8 Hz), 7·01 (1H, d, J=2.5 Hz), 7.51 (1H, d, J=8.1 Hz), 7.65-7.73 (2H, m), 7_97 (1H, d, J = 8.8 Hz), 10.06 (1H, s) 〇IR (ATR) cm-1: 2964, 1724, 1648, 1492, 1182, 1135, 1112. φ MS (ESI) m/z : 465 (M+H)+. HR_MS (ESI) calculated for C24H28F3N204 (M+H)+: 465.20012; measured value · 465.19736. [Example 85] 3-[N-[2_[5-(4-isobutyl-3-trifluoromethylbenzylbenzyloxypyridin-1-yl)-2-yloxyethyl] Amino]propionic acid TFA salt (1) 4-amino-3-trifluoromethoxybenzoic acid methyl ester [Chem. 378] 121199.doc - 347 - 200846322

To a solution of 4-amino-3-trifluorodecyloxybenzoic acid (W02002/070494, 220 mg) in methanol (10 ml), sulphur chloride (76 μM) was added, and the mixture was stirred under reflux for 2 hours. Further, sulfite gas (76 μM) was added, and the mixture was stirred under heating and reflux overnight. After it was left to cool to room temperature, the reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. Sodium is dried. The insoluble material was filtered, and concentrated under reduced pressure to give the title compound ( 224 mg) </RTI> </RTI> NMR (CDC13) δ: 3·87 (3H, s), 4·30 (2H, s), 6.77 (1H, d, J =8.6 Hz), 7.78-7.84 (2H, m) 〇MS (ESI) m/z : 236 (M+H)+. (2) Methyl 4-bromo-3-trifluoromethoxybenzoate [Chemical 379]

Adding evolutionary copper (II) (255 mg) and acidified third butyl vinegar (10) μΐ to a solution of 4-amino-3-trifluorodecyloxybenzoate (in 224 acetonitrile (1 〇 ml)) 'At the 70 C, the mixture was mixed for 1 hour and a half. After it was left to cool to room temperature, a saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate 121199.doc -348 - 200846322. The insoluble material was filtered, and subjected to reduced pressure, and then the title compound (200 mg) was obtained. &gt;Η-ΝΜΚ (CDC13) δ : 3.94 (3Η, s), 7.73 (1H, d, J=8.3 Hz), 7·84 (1H, dd, J=1.7, 8·3 Hz), 7.95 -7·96 (1H, m). MS (ESI) m/z : 299 (M+H) + 〇 (3) 4-isobutyl-3-trifluoromethoxybenzoic acid methyl hydrazine [Chem.

Add isobutylboric acid (378 mg) and carbonic acid planing (2·〇2 g) to a solution of 4-(odor-3-difluoromethoxybenzoic acid methyl ester (37 mg) in benzene (12 ml). ), water (1 〇 ml), tetrakis(diphenylphosphine)palladium (ruthenium) (143 mg), and stirred under heating overnight. After it was left to cool to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium sulfate and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the residue obtained was purified by flash column chromatography (yield: W-NMR (CDC13) δ : 0.92 (6H, d, J = 6.9 Hz), 1.89-1.99 (1H, m), 2·59 (2H, d, J = 7.1 Hz), 3.92 (3H, s ), 7·30 (1H, d, J=8.3

Hz), 7·87_7·89 (2H, m) 〇 MS (ESI) m/z ·· 277 (M+H)+. (4) (4-Isobutyl-3-trioxydecyloxyphenyl) decyl alcohol [Chem. 381] 121199.doc -349- 200846322

OH To a solution of methyl 4-isobutyl-3-trifluoromethoxybenzoate (25 mg) in thf (10 ml), lithium borohydride (591 mg) was added, and the mixture was stirred under heating and reflux for 1 hour and a half. . After it was left to cool to room temperature, citric acid was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the residue obtained was purified by flash column chromatography (yield). H-NMR (CDC13) δ : 0.91 (6H, d, J = 6.6 Ηζ), 1.73 (1H, t, J = 5.9 Hz), 1.85].96 (1H, m), 2.53 (2H, d, J = 7.4 Hz), 4.68 (2H, d, J = 5.9 Hz), 7.20-7.23 (3H, m). MS (ESI) m/z: 231 (M-OH)+. (5) 4-Chloromethyl-i-isobutyl-2-trifluoromethoxybenzene [Chemical 382]

In a solution of (4-isobutyltrifluoromethoxyphenyl)methanol (160 mg) in 1,2-dichloroethane (10 m!), add sulfoxide (234 μl), dmf ( Add 1 drop of Pasteur pipette and stir for 5 hours at 5 °r. After the mixture was cooled to room temperature, the residue was evaporated to dryness crystals crystals crystals I21199.doc -350 - 200846322 H-NMR (CDC13) δ : 〇·91 (6H,d,J=6.6 Hz),1.86-1.96 (1H, m), 2.53 (2H,d,J=7.1 Hz), 4.56 (2H, s), 7·20-7·24 (3H, m) 〇(6) 3-[N-(Secondoxycarbonyl)_N_[2_[5_(4•isobutyl·3_ Trifluoromethoxybenzyloxyporphyrin-:uyl]_2_sideoxyethyl]amino]propionic acid tert-butyl ester [Chem. 383]

a DMF solution of 3-[N-(2-butoxycarbonyl)_N_[2_(5-pyridinyloxyethyl)amino]propionic acid tert-butyl ester (21 〇mg) In 1 〇ml), 4-chloroindolylisobutylidene-2•trifluoromethoxybenzene (133 mg) and potassium carbonate (82·9 mg) were added, and the mixture was stirred at 70 ° C overnight. After cooling to room temperature, the reaction mixture was evaporated.jjjjjjjjjjjjjjjjjjjjj (6H? d5 J=6.6 Hz)5 1.40-1.5〇(18H,m),1.86-1.97 (1H,m), 2.49-2.63 (4H,m),3·15-3·22 (2H,m) ,3·56·3·61 (2H,m),3·99-4·18 (4H,m),4·99 (2H, s),6·75-6·83 (2H,m), 7.21. -7.28 (3H,m),8·10_8·14 (1H, m) 0 MS (ESI) m/z: 651 (M+H)+ (7) 3-[N-[2-〇(4_isobutyl) _3_trifluoromethoxybenzyloxy) 丨哚 小 小 ] ] -2- -2- -2- -2- | | | | | | | | | | 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121

3_[N-(Tertibutoxycarbonyl)-N-[2-[5-(4-isobutyl-3-trifluoromethoxyoximeoxy)π引U多琳-1 _ base] -2 _Sideoxyethyl]amino]propionic acid tert-butyl ester (200 mg) in dioxane solution (2·25 ml), 10 TFA (0.75 ml) was added under ice cooling at room temperature After stirring for 7 hours, the mixture was concentrated under reduced pressure. methylene chloride (.sub.2,5 ml) was added to the residue. The title compound (16 2 mg) was obtained. !H-NMR (DMSO-d6) δ : 0.87 (6H5 d5 J=6.6 Hz) 3 1.82-1.92 (lH, m), 2.73 (2H, t, J = 7.4 Hz), 3.16-3, 22 (4H, m), 4.04-4.14 (4H, m), 5.11 (2H, s), 6.87 (1H, dd, J=8.8, 2·7 Hz), Lu 7.01 (1H, d, J=2.7 Hz), 7.39 ( 3H, s), 7.96 (1H, d, J = 8.8

Hz), (2H coincides with the peak of DMSO, so it is not determined). IR (ATR) cm·1 : 2960, 1637, 1496, 1253, 1197, 1170, 1137. MS (ESI) m/z: 495 (M+H)+. HR_MS (ESI) calcd for C25H30F3N2O5 (M+H)+: 495.21. Calculated for the elemental analysis of C25H29F3N205.CF3C02H: C, 53.29; H, 4·97; F, 18.73; N, 4.60. Found: C, 53.31; Η, 4.89; F, 121199.doc - 352 - 200846322 18.94; N, 4.59 〇 [Example 86] 3-[N-[2-[5-(4-cyclopropyl-3) -trifluoromethoxybenzyloxy) ciproline-1-yl]-2-oxoethylamino]propionic acid (1) 4-cyclopropyl-3-trifluoromethoxybenzoic acid Ester

Add cyclopropylboronic acid (213 mg), carbonic acid planer (2 〇 2 g), water (6 〇 ml) to a toluene solution (12 ml) of methyl bromotrifluoromethoxybenzoate (370 mg). Tetrakis(diphenylphosphine)palladium (〇) (143 mg) was stirred overnight under reflux with heating. After the mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After insoluble matter was filtered, and concentrated under reduced pressure, the residue obtained was subjected to flash column chromatography (Shanshan Expressway column L) to obtain a mixture of the title compound and impurities (312 (7) phantom. (2) (4-cyclopropyl_3) _Trifluoromethoxyphenyl)methanol [Chemical 386] 4% cyclopropyl·3_trifluoromethoxybenzoic acid decyl ester (3 〇〇mg) in THF> gluten solution (15) In ml), add lithium borohydride (mg) and mix it under heating back/melon for 1 hour. After it was left to cool to room temperature, 1 N hydrochloric acid was added to the reaction solution 121199.doc -353 - 200846322, and the mixture was extracted with ethyl acetate three times. The extract of the company was washed with saturated brine and dried over anhydrous sodium sulfate. Add dry; wood 0 filter insoluble matter 'after decompression wave shrinkage, · quick tube (four) material u good high column tube Minghua obtained residue, after fast pipe column chromatography (Shan Shan high pipe column) Purification gave the title compound (71 mg). Ή-NMR (CDC13) δ : 0.67-0.71 (2Η, m), (2R m) 1·69 (1H, t, J=5.9 Hz), 2.10-2.17 (1H, m), 4&lt;6? ^

J=5.9 Hz), 6.90 (1H, d, J = 7.8 Hz), 7.18-7.22 (2H, m). MS (ESI) m/z: 215 (M-OH)+. (3) 4-Chloromethyl-i-cyclopropyl-2_trifluoromethoxy phenyl [, 387], (4-cyclopropyl-3-3-trimethoxyphenyl)methanol (7 〇) Add ruthenium chloride (1〇9, dmf (add 1 drop with Pasteur pipette) to u(d) in u-dichloroethane solution (10 ml). Stir at rc for half an hour. After it was allowed to cool to room temperature, the reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (m.m. -0.72 (2Η, m), 1.00-1.〇5 (2Η, m), 2.10-2.17 (1H, m), 4.54 (2h, s), 6.89 (1H, d, J=7.8 Hz), 7.21- 7.23 (2H,m) (4)+3 [N-(2nd-butoxy group)_N_[2_[5"4_cyclopropyl small trifluoromethoxy ethoxy] is called Budolin small base] -2·Sideoxyethyl]amino]propionic acid third butyl vinegar 121199.doc -354 - 200846322 [Chem. 388]

Boc

'(Secondoxycarbonyl)-N-[2-(5-)-based 吲 朵 朵 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ In the dmf solution 〇ml), 4·chloromethyl]•cyclopropyltrifluoromethyl decyl benzene (e.g., mg) and potassium carbonate (33.2 mg) were added, and the mixture was stirred at 7 Torr overnight. After standing at a temperature of 7 to room temperature, the reaction solution was concentrated under reduced pressure, and the residue obtained was purified by flash column chromatography (Shanshan high-speed column L), and then subjected to high performance liquid chromatography (NOMURA Develosil c〇mbi_RP- 5) Purification gave the title compound (73 mg). W-NMR (CDCl3) δ : 〇.68_〇.72 (2H,m), 〇99 l 〇4 (2h,(4), 1.40-1.49 (18H, m), 2.10-2.17 (1H, m), 2.55 -2.63 (2H, m), 3.15-3.21 (2H, m), 3.56-3.61 (2H, m), 3.98-4.17 (4H, 4.98 (2H, s), 6.74-6.81 (2H, m), 6.91 ( 1H,d,J=7 8 Hz) 7.22-7.26 (2H,m), 8.09-8.14 (1H,m). ' MS (ESI) m/z : 635 (M+H)+ (5) 3- [N-[2-[5-(4-Cyclopropyl-3-trifluoromethoxybenzyloxy)indolyl]-2-oxoethyl]amino]propanoic acid [化389] 121199.doc • 355· 200846322

3-[N-(Tertidinoxycarbonyl)-indole[2-[5_(4_cyclopropyl_3•trifluoromethoxybenzyloxy)π哚 porphyrin 4 _yl]_2_ Add a TFA (〇·50 ml) to a solution of triethyl sulfonate (70.0 mg) of oxyethyl]amino]propionic acid (70.0 mg), and stir at room temperature. 4 hours. The reaction mixture was concentrated under reduced pressure EtOAc (EtOAc) H-NMR (DMSO-d6) δ : 0.70-0.74 (2H5 m)5 0.98-1.03 (2H? m), 2·03-2·09 (1H, m), 2·40 (2H, t5 J=6.7 Hz), 2·87 (2H, t, J 2 6.7 Hz), 3·12 (2H, t, J=8.4 Hz), 3.62 (2H, s), 4.04 (2H, t, J=8.4 Hz) ), 5.07 (2H, s), 6.81 (1H, dd, J = 2.7, 8.8 Hz), 6.94 (1H, d, J = 2.7 Hz), 7.05 (1H, d, J = 7.8 Hz), 7.34 -7.37 (2H, m), 7·97 (1H, d, J = 8.8 Hz) 〇 MS MS (ESI) m/z : 479 (M+H)+. [Example 87] 3-[N-[2-[5-(4-Cyclobutyl-3-trifluoromethylbenzyloxy)indole-1-yl]-2-yloxyethyl] Amino]propionic acid TF A salt (1) 4_cyclobutyl-3-trifluoromethylbenzoic acid methyl ester [Chem. 390]

12I199.doc -356- 200846322 In the 4-trifluoromethanesulfonyloxy thief field * #扣一乱 methyl methyl formate (1·4ΐ in toluene solution (2Θ mi), add ',, ϋ butyl Boric acid (1.20 g), cesium carbonate (6.52 g), water (1 〇 mi), tetrakis (di-(n-ylphosphine), (0) (462 mg), stirred under reflux with stirring overnight. After the person, ..., elbow ^, placed to cool to room temperature, add saturated sodium bicarbonate solution to the reaction solution, - 乂 酉 乙酯 ethyl ester was taken 3 times, the combined extract was washed with saturated saline, silly The residue was dried over anhydrous sodium sulfate. The title compound (331 MS (ESI) m / m. z : 258 M+ 〇(2) (4-cyclobutyltrifluoromethylphenyl)methanol [Chem. 391]

Add a hydrogenated butterfly (81 〇mg) to a solution (10 ml) of a mixture of 4-% butyl-3-trifluoromethylbenzoate and a mixture of impurities (10 mg), and mix under reflux. hour. After it was left to cool to room temperature, i-acid' was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After the insoluble material was concentrated under reduced pressure, the residue obtained was purified by flash column chromatography (yield). taR (CDCI3) δ :1.72-1.90 (2H, m), !.96.2.〇8 (1^ m)j 2.13-2.24 (2H, m), 2.31-2.38 (2H, m), 3.84-3.93 (1H , m), 4.72 (2H, d, J = 5.i Hz), 7, 52-7.60 (3H, m). 121199.doc - 357 - 200846322 MS (ESI) m/z : 213 (M-OH)+. (3) 4-Chloromethyl-l-cyclobutyl-2-trifluoromethylbenzene [Chemical 392]

Add (9-cyclobutyl-3-trifluorodecylphenyl)methanol (170 mg) to 1,2-dichloroethane (20 ml), add sulphur chloride (268 μM) and DMF (Add 1 drop with a pipette) and stir at 5 °C for 1 hour. After standing to cool to room temperature, the reaction mixture was concentrated under reduced pressure. The residue obtained by purification by flash column chromatography (Shanshan Expressway L) was used to obtain the title compound (160 mg). !H-NMR (CDCI3) δ : 1.82-1.90 (1H5 m), 1.97-2.09 (1H5 m), 2.14-2.24 (2Η,m), 2·31-2·39 (2Η,m),3·84 -3·92 (1Η,m), 4.59 (2H,s),7.54-7.60 (3H,m) 〇(4) 3-[N-(Tertidinoxycarbonyl)-N-[2-[5 -(4_cyclobutyl-3-trifluoroindolyloxy) ϋ ϋ ϋ ϋ -1 -1 -1 -yl]-2-oxoethyl]amino]propionic acid tertidine φ [化393 ]

3-(Ν-(Tertibutoxycarbonyl)-indole-[2-(5-hydroxyindol-1-yl)·2-o-oxyethyl]amino]dipropionate dibutyl acrylate (210 mg) in DMF solution (1 〇ml), 4-chloromethyl-1-cyclobutyl-2-trifluoromethylbenzene (149 mg), potassium carbonate (104 mg) at 70 ° C Stir under night. After it was left to cool to room 121199.doc -358 - 200846322, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (m. 〇mg). ^-NMR (CDCI3) δ : 1.40-1.49 (18H5 m)5 1.81-1.90 (1H? m),1·96-2·08 (1H,m),2·14-2·24 (2H,m) , 2,31-2.38 (2H, m), 2.55-2.63 (2H, m), 3.15-3.22 (2H, m), 3·56-3·61 (2H, m)5 3.84-4.18 (5H5 m) 5.02 (2H5 s)? 6.75-6.83 (2H5 m)5 7·58 (2H, s), 7.64 (1H, s), 8.10-8.14 (1H, m). Lu MS (ESI) m/z : 633 (M+H)+. (5) 3-[N-[2-[5-(4-Cyclobutyltrifluoromethylbenzyloxy]pyridinyl-2-dioxyethyl]amino]propionic acid TFA salt 394]

3-[N-(Terti-butoxycarbonyl)-[2-[5-(4-cyclobutyl-3-trifluorodecyloxy)porphyrin-1-yl]-2- Add a TFA (1 · 0 ml) to the dimethyloxy]-tert-propionic acid tert-butyl ester (3 16 mg) in a two-gas ablation solution (4 〇μ) under ice cooling at room temperature Stir for 9 hours. The reaction mixture was concentrated under reduced pressure. The residue was washed with diethyl ether to afford the title compound (259 mg). iH-NMR (DMSO-d6) δ : ι·79-2·05 (2H, m), 2.15-2.31 (4H, m), 2.72 (2H, t, J = 7.4 Hz), 3·19 (4H, q, J=7,4 Hz),3.75-121199.doc • 359 · 200846322 3.83 (1H,m),4·03-4·13 (4H,m),5·15 (2H,s),6.88 ( 1H, dd, J=2.7, 8,8 Hz), 7.01 (1H, d, J = 2.7 Hz), 7.71-7.76 (3H, m), 7.96 (1H, d, J = 8.8 Hz). IR (ATR) cnT1 ·· 2944, 1722, 1664, 1490, 1187, 1133. MS (ESI) m/z: 477 (M+H)+. HR-MS (ESI) calcd for C25H28F3N (M+H)+: 477. Calculated for the elemental analysis of C25H27F3N204.CF3C02H: C, 54.92; H, 4·78; F, 19.30; N, 4.74. Found: C, 54·96; Η, 4.68; F, 19.52; Ν, 4.72. [Example 88] 3-[Ν-[2-Sideoxy-2-[5-[(3-cyano-4-cyclohexyl-phenyl) decyloxy] porphyrin-1-yl] Methyl]amino]propionic acid (1) methyl 3-cyano-4-trifluoromethanesulfonyloxybenzoate [Chem. 395]

To a solution of decyl 3-cyano-4-hydroxybenzoate (870 mg) in dichloromethane (10 ml), slowly add pyridine (860 μM) and trifluoromethanesulfonic anhydride (1) at 0 °C. 13 ml). After stirring for 16 hours at room temperature, the precipitated solid was removed by filtration, and the filtrate was concentrated under reduced pressure. Water (15 ml) and ethyl acetate (20 ml) were added to the residue. After extracting the aqueous layer with ethyl acetate (3×10 ml), the combined extracts were washed with 3% aqueous solution of copper sulphate and saturated with a mixture of 121199.doc-360-200846322 under reduced pressure. Dryness gave the title compound (1.34 g). ^-NMR (CDC13) δ : 3.99 (3H5 s)? 7 59 MR η t ,h (1H,d5 J=8.8 Ή 8.37 (1H, dd, J=8.8, 2.2 Hz), 8.44 (1H, d, J =2.2 Hz) 〇MS (ESI) m/z : 310 (M+H), (2) methyl 3-cyano-4-cyclohexyl benzoate [Chem. 396]

Add bis(tri-tert-butylphosphine) at room temperature in a solution of cyano-4-4-trifluoro-W-oxybenzoic acid W (928 mg) in THF (5. 〇ml). ) (153 mg) and 〇.5 M cyclohexylmethyl desertification /thf dissolved ^ (6.60 ml). The mixture was heated under reflux for 2 hours, and then cooled to room temperature. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was stirred at room temperature for 3 hrs, and the solid was separated by filtration. The filtrate was extracted with chloroform (3×l·ml). After washing with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the filtrate was evaporated to dryness, and the residue obtained was purified by EtOAc EtOAc (EtOAc) (CDC13) δ : 1·22·1·34 (1H,m), L40-U5 (4H,m), 1.58 (1H,d,J=8.8 Hz),1·81 (1H,d,J=i2 .9 Hz), Mo (3H, t, J=9.8 Hz), 3.00-3.06 (1H, m), 3.93 (3H, s), 7.46 (1H, d, J = 8.3 Hz), 8.17 (1H ,dd,J=8.3,1.5 Hz),8·27 (1H,d,J=1.5 121199.doc -361 - 200846322

Hz). MS (ESI) m/z: 244 (M+H) + 〇 (3) 3 - cyano-4-cyclohexyl benzoic acid [ 397 ]

Methanol (3.0 ml) and 1 N aqueous sodium hydroxide solution (3.00 ml) were added to a solution of methyl 3-cyano-4-cyclohexylbenzoate (566 mg) in THF (6.0 ml). After stirring at room temperature for 3 days, water (5 〇 ml) was added to the reaction mixture, the pH was 3 with i N hydrochloric acid, and chloroform (1 〇 ml) was added thereto to carry out liquid separation. The aqueous layer was extracted with EtOAc (EtOAc). ^H-NMR (DMS〇.d6) δ : 1.23.1.3l (1H? m)? 1.33-1.56 (4Η, m), 1.73 (1Η,d,J=12.5 Ηζ),1.82 (4Η,t,J =11 7 Ηζ), 2 86_ 2.94 (1H,m),7·65 (1H,d,J=8.3 Hz), 8 15 (1H,dd,J=8 3, 1.7 Hz), 8.20 (1H,d , J = 1.7 Hz), 13 36 (1H, s). MS (ESI) m/z: 459 (2M+H)+. (4) 3-cyano-4-cyclohexyl phenyl decyl alcohol [Chem. 398] 121199.doc 362 - 200846322 ThF (5. 〇ml) solution of 3-cyano-4_cyclohexylbenzoic acid (483 mg) In the middle, slowly add 440 (440 μΐ) and ethyl chloroacetate (242 μΐ) at 0 C. After stirring for 1 hour under the chamber k, the precipitate was removed by filtration. In a separate flask, the benzoic acid derivative filtrate was slowly added to the suspension of sodium borohydride (520 mg) in ethanol (5 ml). After stirring for 1 hour, 丨N hydrochloric acid was gradually added to bring the pH to 4. To the reaction mixture, ethyl acetate (1 ml) was added for liquid separation, and the aqueous layer was extracted with ethyl acetate (3 x 5 ml). The combined extracts were dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified using EtOAc EtOAc (EtOAc) 'H-NMR (CDC13) δ : 1.21-1.32 (1Η, m), 1.38-1.51 (4H, m)5 1.74-1.92 (6H5 m)5 2.94-3.00 (1H5 m), 4.70 (2H3 d5 J=4.9

Hz), 7·36 (1H, d, &gt; 8·3 Hz), 7.53 (1H, dd, J=8.0, 1·5 Hz), 7.61 (1H, d, J=i .5 Hz). (5) 3-[N-(Tertidinoxycarbonyl)-1[2_[5_[(3-cyano-'cyclohexylbenzene)-yloxy)]-indolizin-1 -yl] -2-oxoethyl]amino]propionic acid tert-butyl ester [Chemical 399]

Add 3-phenylphosphine (364 mg), 3-[N-(T-butoxy 121199.doc) to a solution of 3-cyanocyclohexyl benzyl alcohol (249 mg) in THF (5.0 ml) -363 - 200846322 ketone)-N-[2-(5-light-based H-indolyl-1 -yl)-2-sineoxyethyl]amino]propionic acid tert-butyl ester (486 mg) and DEAD (225 μΐ). After stirring at room temperature for 18 hours, the reaction mixture was evaporated. 'H-NMR (CDC13) δ : 1.38-1.5 1 (23Η, m), 1.76-1.93 (5H5 m), 2·55-2·63 (2H, m), 2·94-3_02 (1H, m) , 3.16-3.24 (2H, m), 3.55-3.62 (2H, m), 3.99-4.08 (2H, m), 4.18 (2H, s), 4·99 (2H, s), 6.72-6.83 (2H, m), 7.33-7.40 (1H, m), 7.57 (1H, d, J = 7.8 Hz), 7.66 (1H, br s) 5 8.11 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 618 (M+H)+. (6) 3-[N-[2-[5-[(3-Cyano-4-cyclohexylphenyl)decyloxy]indolyl]-2-oxoethyl]amino]propyl] Acid [400]

[3][Ν,(2,2-butoxy)-N-[2-[5-[(3-cyano-4-cyclohexyl-phenyl)methoxy],% linyl]-oxyl To a solution of ethyl imino]propanoic acid tributyl (mg) in methyl chloride (12.0 ml) was added TFA (3.0 ml) at room temperature. After stirring for 30 minutes at f, and w, the reaction solution was concentrated under reduced pressure / dimethyl sulfoxide (6_0 ml) was added to the residue, and the insoluble matter was removed. I. Analysis (NOMURA Develosil Combi_RP_121199.doc -364 - 200846322 5) Purification, concentration of the target fraction and lyophilization to give the title compound (357 mg) 〇]H-NMR (DMSO-d6) δ: 1.19-1.54 (5Η, m)5 1.69-1.86 (5Η, m), 2.41 (2Η,t,J=6.7 Ηζ), 2.80-2.88 (1Η,m),2·89 (2Η,t, J=6.7 Hz), 3.12 (2H ,t,J=8.4 Hz),3·65 (2H,s),4·03 (2H,t, J=8.4 Hz), 5.07 (2H,s),6·82 (1H,dd,J=8.8 , 2.7 Hz), 6.95 (1H, d, J = 2.7 Hz), 7·53 (1H, d, J = 8.1 Hz), 7·70 (1H, dd, J=8.3, 1.5 Hz), 7.81 (1H,d,J=1.5 Hz),7·96 (1H,d,J=8.8

Hz) 〇 MS (ESI) m/z: 462 (M+H) + 〇 C27H3MsOr 1 ·5Η20, Calculated for elemental analysis of 0.25CF3CO2H: C, 63.88; H, 6.68; N, 8.13. Found: C, 63.91; H, 8.09; N, 6.70. [Example 89] 3-[N-[2-Sideoxy-2-[5-[(3- gas-4.cyclohexyl-phenyl)methoxy]] porphyrin-1-yl] Methylamino]propionic acid (1) methyl 3-chloro-4-trifluoromethanesulfonyloxybenzoate (ΕΡ594022) [化401]

0 〇 In a solution of 3-chloro-4-aminobenzoic acid methyl vinegar (3.44 g) in a gas-fired (50 ml) solution. Slowly add II bite (1 · 94 ml) and trifendronic anhydride (3.41 ml). After stirring at room temperature for 16 hours, the precipitated solid was removed by filtration, and the filtrate was concentrated under reduced pressure. To the resulting residue, water (30 ml) was added and the mixture was partitioned between 121199.doc - 365 - 200846322 and chloroform (50 ml). The aqueous layer was extracted with ethyl acetate (3×3 mL). 5.02 g). ^-NMR (CDC13) δ: 3.95 (3Η, s)5 7.44 (1H?d, J=8.5 Hz) 8.03 (1H, dd, J = 8.5, 2.0 Hz), 8.21 (1H, J = 2.0 Hz). MS (ESI) m/z: 319 (M+H)+. (2) Methyl 3-chloro-4-cyclohexylbenzoate (DE2341301) [Chem. 402]

Add to a solution of methyl 3-chloro-4-trifluoromethanesulfonyloxybenzoate (112 g) in N,N-didecylacetamide (10 ml) at room temperature under nitrogen. Copper iodide (1) (66.7 mg), [1, bis-bis(diphenylphosphino)ferrocene] di-palladium-palladium dichloromethane complex (143 mg) and 0.5 Μcyclohexylzinc bromide/ THF solution (8.40 ml). After heating under reflux for 2 hours, it was left to cool to room temperature, and a saturated aqueous solution of ammonium chloride (15 ml) was added to the mixture. After stirring at room temperature for 30 minutes, the precipitated solid was removed by filtration. The aqueous layer was extracted with aq. (3×10 ml), washed with brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified using EtOAc EtOAc (EtOAc) (EtOAc) (EtOAc (EtOAc) ,m), 121199.doc -366- 200846322 1.75-1.92 (5H,m),3·02-3·08 (1H,m),3.90 (3H,s),7.33 (1H,d,J=8.3 Hz ), 7·87 (1H, dd, J=8.1, 1·7 Hz), 8.01 (1H, d, J=1.7 Hz). MS (ESI) m/z : 253 (M+H) + 〇 (3) 3-chloro-4-cyclohexyl benzoic acid [Chem. 403]

To a solution of dimethyl 3-cyclo-4-cyclohexyl benzoate (474 mg) in THF (5.0 ml), methanol (2.5 ml) and 1 N aqueous sodium hydroxide (2.50 ml). After stirring at room temperature for 15 hours, water (1 ml) was added to the reaction mixture, and the mixture was adjusted to pH 3 with 1 N hydrochloric acid, and then chloroform (15 ml) was added thereto. After the aqueous layer was extracted with EtOAc (EtOAc) (EtOAc) _ !H-NMR (DMSO-d6) δ : 1.23-1.31 (1H5 m), 1.33-1.56 (4H5 m), 1.73 (lH, d, J = 12.5 Hz), 1.82 (4H, t, J = 11.7 Hz) ), 2.86-2.92 (1H, m), 7.65 (1H, d, J = 8.3 Hz), 8.15 (1H, dd, J = 8.3, 1.7 Hz), 8.20 (1H, d, J = 1.7 Hz) , 13.36 (1H, s). MS (ESI) m/z: 477 (2M+H)+. (4) 3-Chloro-4_cyclohexylbenzyl alcohol (DE2341301) [Chem. 404] 121199.doc -367 - 200846322

In a solution of 3· chloro-4-cyclohexyl benzoic acid (213 mg) in THF (5 (), for example), hydrazine (186 μM) and ethyl chloroacetate (102 μM) were slowly added. After stirring for 1 hour under the service, the precipitate which precipitated was removed by filtration. In a separate flask, sodium borohydride (263 mg) in ethanol (5.0 ml) was suspended for 3 hours/night. The filtrate of the benzoic acid derivative was slowly added at 0 C. After stirring at 〇 ° C for 1 hour, slowly add 丨N hydrochloric acid to make? The value of 11 becomes 4. Water (5 ml) and ethyl acetate (1 〇 ml) were added to the reaction mixture for liquid separation, and the aqueous layer was extracted with ethyl acetate (3×5.0 mi). The combined extracts were dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified using EtOAc EtOAc EtOAc (EtOAc (EtOAc)

Hz),1·77 (1H,d,J=12.7 Hz),1.82-1.9Ό (4H,m),2·96-3·04 (1H,m),4.63 (2H,d,J=5.9 Hz) ), 7·21 (1H, dd, J=8.1, 1.7 Hz), 7·25 (1H, d, J=8.1 Hz), 7.36 (1H, d, J=; L7 Hz). (5) 3-[N-(Tertidinoxycarbonyl)4#-}"% gas_4_cyclohexyl-phenyl) methoxy] porphyrin-1-yl]-2-yloxy Ethyl]amino]propionic acid tert-butyl ester [Chem. 405]

Add 3-phenylphosphine (225 mg), 3-[N-(t-butoxycarbonyl) to a solution of 3-chloro-4-cyclohexylbenzyl alcohol (148 mg) in THF (3.0 ml) )·121199.doc -368 - 200846322 Ν-[2·(5-Hydroxyporphyrin-1-yl)_2·sideoxyethyl;]amino]propionic acid tert-butyl ester (305 mg) and DEAD (139 μΐ). After scrambled for 4 hours at room temperature, the reaction mixture was concentrated under reduced pressure, and purified residue was purified by column chromatography (Bi〇tage 4 s) to find the title compound (2 6 4) Mg ). !H-NMR (CDCIb) δ : 1.23-1.60 (23Η? m)5 1.74-1.91 (5Η3 m), 2·55-2·63 (2Η, m), 2.96-3.04 (1Η, m), 3.15- 3.22 (2Η, m), 3·56-3·62 (2Η, m), 3.98-4.07 (2Η, m), 4.09-4.18 (2Η, m), 4.95 (2H, s), 6·74-6 · 83 (2H, m), 7.26 (2H, s), 7·41 (1H, s), 8·15-8·09 (1H, m). (6) 3-[N-[2-[5-[(3-Chloro-4-cyclohexylphenyl)decyloxy; j-porphyrinyl 2-oxoethyl]amino]propanoic acid [ 406]

3-[N-(Tertibutoxycarbonyl)-oxime [2-[5_[(3_chloro-4-ylcyclohexyl-phenyl)methoxy]]|Porphyrin-1-yl]- To a solution of 2-oxoethyl]amino]propanoic acid tributylhydrazine (264 mg) in dichloromethane (1. 6 mi) was added TFA (0.45 ml) at room temperature. After stirring at room temperature for 16 hours, the reaction liquid was concentrated under reduced pressure, and the residue was added with dimercaptosulfoxide (3 · 〇ml) to remove insolubles and then subjected to high performance liquid chromatography (NOMURA Develosil) Combi- RP-5) Purified 'concentrated target fractions, cooled, and dried in the east to give the title compound (120 mg). 121199.doc -369 - 200846322 MS (ESI) m/z : 471 (M+H)+. . 261^31〇 is 2〇4*0.5112〇, 0.1€?3 (calculated for the elemental analysis of 3〇211: C,64·04; H,6·58; Cl,7·21; F,1.16; N , 5·70 〇 measured value: C, 64·40; H, 6·54; Cl, 6.97; F, 〇·78; N, 5, 73. [Example 90] 3-[N-[2 -[5-[(4-cyclohexyl-3-fluorophenyl)methoxy], porphyrin-1-yl]-2-oxoethyl]amino]propanoic acid (1) 3-fluoro- Methyl 4-hydroxybenzoate [化407]

In a solution of 3-fluoro-4-hydroxybenzoic acid (1.17 g) in decyl alcohol (1 〇 mi), sulfurous gas (602 μΐ) was gradually added thereto. After heating under reflux for 2 hours, the reaction mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The combined organic layers were dried with anhydrous sodium sulfate. b-NMR (CDC13) δ : 3.90 (3H, s), 5·85 (1H, s), 7.04 (1H, t, J = 8.3 Ηζ), 7·79-7·75 (2H, m) 〇 ( 2) 3 -Fluoro-4_trifluoromethane xanthanoxybenzoic acid vinegar (w〇2〇〇3〇76397) [化408]

121199.doc • 370- 200846322 In a solution of methyl 3-fluoro-4-hydroxybenzoate (1·19 g) in dichloromethane (10 ml), slowly add pyridine (735 μΐ) at 0 °C. And trifluoromethanesulfonic anhydride (1.24 ml). After stirring at room temperature for 1 hour, the precipitated solid was removed by filtration, and the filtrate was concentrated under reduced pressure. Water (20 ml) and chloroform (30 ml) were added to the residue. The aqueous layer was extracted with ethyl acetate (3×20 ml), and evaporated. ). ]H-NMR (CDC13) δ : 3.95 (3H? s), 7.43 (1H, dd, J=9.0, 7.1

Hz), 7.94 - 7.91 (1H, m), 7.94 (1H, dd, J = 9.8, 2.0 Hz). (3) Methyl 4-cyclohexyl-3-fluorobenzoate [Chem. 409]

Under a nitrogen atmosphere, in a solution of methyl 3-fluoro-4-trifluoromethanesulfonate benzoate (708 mg) in N,N-dimethylacetamide (1 〇mi) at room temperature Adding intrusive copper (1) (44.6 mg), [1,1,_bis(diphenylphosphino)ferrocene] dichlorination, dioxane complex (95.7 mg) and 〇·5 Μ ring Hexylzinc bromide/THF solution (5.62 ml). After heating to reflux for 6 hours and a half, it was left to cool to room temperature. A saturated aqueous solution of ammonium chloride (i 5 mi) was added to the mixture. After stirring at room temperature for 30 minutes, the precipitated solid was removed by filtration. The aqueous layer was extracted with chloroform (3×10 ml), and the combined extracts were washed with brine and dried over anhydrous sodium sulfate. The resulting residue was purified using EtOAc EtOAc EtOAc (EtOAc) (4) 4-Cyclohexyl-3-fluorobenzoic acid [Chem. 410]

To a solution of methyl 4-cyclohexyl-3-fluorobenzoate (306 mg) in THF (4 mL), EtOAc (2·0 ml) and 1 N aqueous sodium hydroxide (2.00) Ml). After stirring at room temperature for 1 hour, water (5 ml) was added to the reaction mixture, the pH was adjusted to 3 with 1 N hydrochloric acid, and chloroform (1 ml) was added thereto to carry out liquid separation. After extracting the aqueous layer with chloroform (3×10 ml), the combined extracts were dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc (EtOAc) • ^-NMR (CDC13) δ : 1.21-1.34 (1H5 m)? ^39-1.51 (4H5 m)5 1·78 (1H,d,J=12.7 Hz),1.82-1.91 (4H,m),2 88-2 96 (ih, br m), 7.33 (1H, dd, J=7.6, 7·6 Hz), 7 72 (iH, dd, J=i〇7 1·5 Hz), 7.84 (1H , dd, J=7, 6, 1.5 Hz). '(5) 4-Cyclohexyl-3·fluorobenzyl alcohol [Chem. 411]

0 121199.doc -372 · 200846322 In a solution of 4-cyclohexyl-3-fluorobenzoic acid (36.6 mg) in 11? (2. 1111), slowly add hydrazine (34.4 μM) at 0 °C and Ethyl chloroacetate (18_9 μΐ). After stirring at room temperature for 1 hour, the precipitate which precipitated was removed by filtration. In a separate flask, the filtrate of the benzoic acid derivative was slowly added at 0 ° C in a suspension of sodium borohydride (40.6 mg) in ethanol (3. 〇 ml). Yu Yu. After mixing for 2 hours, slowly add 1 N hydrochloric acid to bring the pH to 4. Water (3 ml) and ethyl acetate (5.0 ml) were added to the mixture, and the aqueous layer was extracted with ethyl acetate (3×5·0 ml). The combined organic layers were dried over anhydrous sodium sulfate and filtered and evaporated. The residue obtained was purified using EtOAc (EtOAc) (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH , 1.74-1.90 (5H, m), 2.80-2.88 (1H, m), 4·62 (2H, s), 7·01 (1H, d5 J=11.0 Hz), 7.05 (1H, d, J=7.8 Hz), 7.20 (1H, dd, J = 7.8, 7·8 Hz). (6) 3-[N-(Tertidinoxycarbonyl)-N-[2-[5-[(4-cyclohexylfluorophenylhydrazine) decyloxy]]#10呆琳-1 -基]- 2-oxoethylethyl]amino]propionic acid tert-butylate [化412]

To a solution of 4-3⁄4 hexyl-3-fluorobenzyl alcohol (23·8 mg) in THF (2.0 ml), triphenylphosphine (39.0 mg), 3-[N-(3 butyloxy) at room temperature Benzylcarbonyl)-N-[2-(5-hydroxyindol-1-yl)-2-oxoethyl]amino]propionic acid tert-butyl ester (52.9 mg) and DEAD (24·l μl) . Stir at room temperature for 4 hours. 121199.doc •373 · 200846322 After the concentration of the reaction solution was reduced, the obtained product was purified by a hose column chromatography (test 40S), and the target was concentrated. The obtained residue was purified by thin layer chromatography to give the title compound (the latter).丨H-NMR (CDC13) δ : m.5. _,m),m,87 ie, m), 2.55-2.63 (2H, m), 2.81-2.88 (1H, m), 3.14-3.21 (2H, m), 3.55-3.62 (2H, m), 3.97 -4.06 (2H, m), 4.08-4.19 (2H, m), 4.96 (2H, s), 6.73-6.83 (2H, m), 7.07 (1H, d, J=11.0

Hz), 7.11 (1H, d, J=7.8 Hz), 7.22 (1H, t, J=7.7 Hz), 8.10 (1H, d, J=8.8 Hz) 〇(7) 3_[N-[2-[ 5-[(4-Cyclohexyl-3.1phenyl)decyloxy(tetra)]yl-2-phenyloxyethyl]amino]propanoic acid

3-[N-(2nd-butoxymethyl)methyl [2-[5-[(4-cyclohexyl-3-phenylphenyl)methoxy]] 1 porphyrin-1-yl]_2_ To a solution of the tert-butylethylamine]propanoic acid tert-butyl ester (40.8 mg) in dichloromethane (1 mL) was added TFA (1,0 ml) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. dimethyl sulfonium (2.0 ml) was added to the residue, and after insolubles were removed, and then subjected to a liquid chromatography (N〇MURA Devel) The 〇sii c〇mbi_Rp_ 5) was purified, and the target fraction was condensed and lyophilized to give the title compound (17.7 mg). HR-MS (ESI) m/z: 455 (M+H) + 〇 C26H32FN204 (M+H)+ HR-MS (ESI) Calculated: 455·2346. Found: 455.2333 〇 [Example 91] 3-[Ν-[2-[5-[[4-cyclohexyl-3-(anthracene-dimethylamino)phenyl]methoxy]anthracene] Phenyl-1-yl]-2-oxoethyl]amino]propanoic acid (1) methyl 3-nitro-4-trifluoromethanesulfonyloxybenzoate [化414]

Add pyridine (1 · 46 ml) and trifluoroanthine yellow at 0 ° C in a solution of 3-Dishyl-4--4-benzoic acid methyl vinegar (2.96 g) in dichloromethane (50 mi). Anhydride (2.78 ml). After stirring at room temperature for 16 hours, the precipitated solid was removed by filtration, and the filtrate was concentrated under reduced pressure. Water (5 〇 mi) and ethyl acetate (70 ml) were added to the resulting residue for liquid separation. The aqueous layer was extracted with ethyl acetate (3×30 ml), and evaporated, evaporated. . ^-NMR (CDC13) δ : 4.01 (3H5 s)5 7.57 (1H, d, J=8.8 Hz), 8.40 (1H, dd, J=8.5, 2.2 Hz), 8.80 (1H,d,J=2.2 Hz ). (2) Methyl 4-cyclohexyl-3-nitrobenzoate (W09961406) [Chem. 415] 121199.doc -375 - 200846322

In a solution of 3_nitro-4-trifluoromethanesulfonyloxy benzoic acid methyl ester (1·65 g) in THF (3 〇ml) under 虱*1%, add bis at room temperature ( Tri-tert-butylphosphine) (128 mg) and 〇·5 M cyclohexylmethyl bromide/τΗρ solution (13.0 ml). After heating under reflux for 4 hours, it was left to cool to room temperature, and a saturated aqueous solution of sodium hydrogencarbonate (3 mL) was added to the mixture. After stirring at room temperature for 3 minutes, the precipitated solid was removed by filtration. The filtrate was extracted with chloroform (3 χ 25 丨 丨), and the combined extracts were washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was evaporated, evaporated, mjjjjjjj H-NMR (CDC13) δ : 1.23-1.33 (1H? m)5 1.36-1.51 (4H5 m)5 1·76_1·94 (5H,m),2·99-3·07 (1H,m),3 · 95 (3H, s), 7·54 (1H, d, J = 8.3 Hz), 8·16 (1H, dd, J=8.3, 1.7 Hz), 8.33 (1H, #d? J=1.7 Hz) 〇(3) 3-Amino-4-cyclohexylbenzoic acid formazan (Urgess, Laurence E. Synthetic Communications (1997), 27(12), 2181-2191.) [Chem. 416]

To a solution of decyl 4-cyclohexyl-3-nitrobenzoate (307 g) in decyl alcohol (20 ml) 121199.doc -376-200846322 Add 5% Pd/C (10 mg). * After stirring for 17 hours at room temperature in an oxygen atmosphere, the reaction solution was filtered using a fluorite. The filtrate was concentrated under reduced pressure afforded title crystall ^-NMR (CDC13) δ : 1.24-1.48 (5H, m), 1.76-1.93 (5H, m)) 2.49 (1H, br s), 3.87 (3H, s), 7, 17 (1H, d, J = 8.0 Hz), 7.36 (1H, d, J = 1.5 Hz), 7.44 (1H, dd, J = 8. 〇, L5 Hz). (4) Methyl 4-cyclohexyl-3_(N,N-didecylamino)benzoate [Chem. 417]

• H 0 0 in 3-amino-4-cyclohexyl benzoic acid decyl phthalate (27 〇 mg) in decyl alcohol (12 guanidine solution, 37% aqueous formaldehyde solution (548 μl) and acetic acid at room temperature (6〇〇μΐ). After stirring at room temperature for 3 hours, sodium cyanoborohydride (437 mg) was added at room temperature. After stirring for 3 hours, water (15) was added to the reaction mixture to sat. The aqueous solution of sodium hydrogenate was adjusted to pH 9. The chloroform (15 ml) was added to the reaction mixture, and the aqueous layer was extracted with methylene chloride (3×l 〇ml). The combined extracts were dried over anhydrous sodium sulfate and filtered and then filtered. The filtrate was concentrated under reduced pressure to dryness crystals crystals crystalsssssssssssssssssssssssssssssssssssssssssssssssssssssssssss s), 3.12-3.20 (1H, m), 3.89 (3H, s), 7.28 (1H, d, J = 8.0 Hz)? 7.70 (1H3 dd5 1=8.0, 1.7 Hz), 7.76 (1H, d, J = 1.7 Hz) MS (ESI) m/z: 262 (M+H) +. 121199.doc -377 - 200846322 (5) 4-cyclohexyl-3-(N,N-dimethylamino) Methanol [化418]

In a suspension of THF (5. 〇 mi) of Hydrogen Li (131 mg), 〇. A solution of methyl 4-cyclohexyl-3-(N,N-dimethylamino)benzoate (276 mg) in THF (2. EtOAc) was applied dropwise. After stirring at room temperature for 2 hours and a half, diethyl ether (5.0 ml) and ethyl acetate were gradually added until hydrogen gas was no longer produced, and then a saturated aqueous solution of sodium sulfate was gradually added until the precipitate was deposited on the bottom of the flask. After stirring at room temperature for 15 hours, the precipitate was removed by filtration using Florite, and the filtrate was concentrated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc) H-NMR (CDC13) δ : 1.22-1.50 (5H, m), 1.73-1.87 (5H, m), 2.68 (6H, s), 3·06-3·14 (1H, m), 4·64 ( 2H,d,J=5.6 Hz), 7·〇4 (1H, dd, J=7.8, 1·7 Hz), 7·11 (1H, d, J=1.7 Hz), 7·22 _ (1H, d, J = 7.8 Hz). (6) 4-Cyclohexyl_3-(N,N-dimethylamino)benzyl chloride hydrochloride [Chem. 419]

Add sulfite gas at room temperature in a solution of 4-cyclohexyl-3_(n,N-dimethylamino)benzyl alcohol (174 mg) in dichlorohydrazine (5·0 ml). ) 9 μιη). After heating and refluxing for 1 hour and a half, the reaction mixture was cooled to EtOAc. 'H-NMR (CDC13) δ : 1.21-1.35 (1H5 m)5 1.43-1.53 (2H5 m)3 1.67-1.89 (7H,m), 3.27 (6H,s),3·60 (1H,br s) , 4.60 (2H, s) 5 7.52-7.44 (3H, m). (7) 3·[Ν-(Tertibutoxycarbonyl)-N-[2_[5-[[4-cyclohexyl-3-(N,N-dimethylamino)phenyl]decyloxy) ] porphyrin-1-yl]-2-oxoethyl]amino] tert-butyl propionate [Chem. 420]

Add potassium carbonate (531 mg) at room temperature to a solution of 4-cyclohexyl-3-(N,N-dimethylamino)benzyl chloride hydrochloride (202 mg) in DMF (7.5 ml) And 3 - [N-di-dibutyloxycarboxy-2-oxo- 2-(5-trans-based 丨 琳 琳 -1, yl) ethylamino] propionic acid tert-butyl ester (294 mg). After mixing 18 small φ at 75 ° C, the reaction solution was allowed to cool to room temperature and concentrated under reduced pressure. Water (10 ml) and gas (15 ml) were added to the resulting residue for liquid separation. The aqueous layer was extracted with chloroform (2×10 ml). The residue obtained was purified using EtOAc EtOAc (EtOAc) 'H-NMR (CDC13) δ : 1.25-1.51 (23Η, m)3 1.73-1.87 (5H, m), 2·55-2·64 (2H, m), 2.68 (6H, s), 3.07 ·3·22 (3H,m), 3.56-3.62 (2H,m),3.98-4.06 (2H,m),4.08-4.18 (2H,m), 4·94 (2H,br s),6.77-6.86 (2H,m)5 7.09 (1H,d,J=7,8 Hz), 121199.doc -379- 200846322 7.14 (1H,d,J=1.7 Ηζ),7·23 (1H,d5 J=7.8 Hz ), 8.15 (IH'm). ...8.09 MS (ESI) m/z : 636 (M+H)+. (8) 3-[N-〇[5-[[4-Cyclohexyl-3-(N,N-dimethylamino)phenyl]methyl] porphyrin _:U group]-2- Oxyoxyethyl]amino]propionic acid

[421]

3-[N-(2nd-butoxycarbonyl)&gt;Ν_[2_[5·[[4_cyclohexylamino]3](team 1 decylamino)phenyl]methoxy Η 朵 朵 小 小 小]_2_Sideoxyethyl]amino] propionic acid tert-butyl S (345 mg) of dichloromethane (1.6 in solution, add TFA (0.40 ml) at room temperature. After stirring for 17 hours, the reaction solution was concentrated under reduced pressure, and dimethyl sulfoxide (4 〇mi) was added to the residue, and after insolubles were removed, and then subjected to high performance liquid chromatography (n〇mura Devel〇sil)

Combi-RP-5) was purified, and the target fraction was concentrated, filtered, and the precipitated solid was washed with water and dried to give the title compound (1) (4). ^-NMR (DMSO-d6) δ : 1.16-139 (5Η? m)? 1.55-1.75 (5Η, m), 2·33 (2Η, t, 】=6·7 ΗΖ), 2·53 (6Η, s),2·81 (2Η,t,j=6,7 Ηζ), 2.95-3.03 (1Η,m), 3.06 (2η,% J=8 4 Ηζ), 3 56 (2Η, s), 3.97 ( 2Η,t,片8·4 Ηζ),4·90 (2Η,s),6·75 (1Η,仉J=8 8, 2·4 Ηζ),6·87 (1Η,s),7·01 (1Η, d, J=81 Ηζ), 7 1〇(1Η, s), 7.15(lH,d,J = 8.1HZ), 7.90 (1H, d, J=88Hz). 121199.doc -380- 200846322 MS (ESI) m/z : 480 (Μ+Η)+ 〇C28H37N3O4· 1 ·0Η2Ο, calculated for elemental analysis of O.25CF3CO2H: C,65.06; Η,7·52; Ν , 7.99. Found: C, 64·93; Η, 7.47; N, 7.91. [Example 92] 3-[Ν-[2-[5-[(3-Cyano-4-isopropylphenyl)decyloxy], porphyrin-1-yl]·2· side oxyethyl Methyl]amino]propionic acid (1) methyl 3-cyano-4-isopropenylbenzoate [Chemical 422]

Add tetrakis(triphenylphosphine)palladium (210 mg) to a solution of 3-cyano-4-trifluoromethanesulfonyloxybenzoate (3 75 mg) in toluene at room temperature under a hydrogen atmosphere. ), water (2.5 ml), cesium carbonate (2.92 g) and isopropyl sulfonate pinacol ester (456 μΐ). After stirring at 9 ° C for 12 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate (1 ml) and ethyl acetate (1 ml) were added to the residue, and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate (3×7.5 ml), and the combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The condensed filtrate. The resulting residue was purified using EtOAc EtOAc (EtOAc) elute ^H.NMR (CDCI3) δ : 2.21 (3Η, t5 J=0.7 Hz), 3.95 (3H? s)5 5·34 (1H,d,J=l.〇Hz), 5.46 (1H,d,J =1.0 Hz),7·46 (1H,d, J-8·1 Hz),8·18 (1H,ddd,J=8.1,2.0,0.7 Hz),8·33 (1H,br 121199.doc - 381-200846322 MS (ESI) m/z : 202 (M+H)+ (2) 3-cyano-4-isopropylbenzoate oxime [Chem.

To a solution of methyl 3-cyano-4-isopropenylbenzoate (164 mg) in methanol 〇 ml) was added 5 〇 / 0 Pd / C (5 mg). After stirring at room temperature for 4 hours and a half under a hydrogen atmosphere, the reaction solution was filtered using a mixture. The title compound (126 mg) was obtained from EtOAc. 'H-NMR (CDC13) δ : 1.34 (6Η, d5 J=6.8 Hz), 3.44 (1H5 dq J = 6.8, 6·8 Hz), 3.94 (3H, s), 7·49 (1H, d, J =8.3 Hz), 8·19 (1H, dd, J=8.3, 1.7 Hz), 8.28 (1H, d, J = 1.7 Hz). MS (ESI) m/z: 204 (M+H)+. (3) 3-cyano-4-isopropylbenzoic acid [Chem. 424]

OH in a solution of methyl 3-cyano-4-isopropylbenzoate (126 mg) in τηΡ (2·〇ml), adding methanol (1·〇ml) and 〗 〖Hydroxide at room temperature Sodium aqueous solution (1 ·00 ml). After the stool was mixed for 3 days, water (5 〇 ml) was added to the reaction mixture, the pH was adjusted to 3 with i N hydrochloric acid, and chloroform (10 ml) was added thereto to carry out liquid separation. Further, the aqueous layer was extracted with 121199.doc -382 - 200846322 chloroform (2x5 ml). The combined organic layer was dried over anhydrous sodium sulfate. 'H-NMR (DMSO-d6) δ : 1.36 (6Η; d5 J=6.8 Hz)3 3.43-3.5 1 (1H,m),7·54 (1H,d,J=8.3 Hz), 8.26 (1H, Dd, J=8.3, 1.5

Hz), 8·36 (1H, d, J = 1.5 Hz). MS (ESI) m/z : 379 (2M+H) + 〇 (4) 3-cyano-4-isopropylphenyl decyl alcohol [Chem.

To a solution of 3-cyanoisopropylbenzoic acid (11 〇 mg) in τηρ(3·〇 ml), hydrazine (122 μM) and ethyl chloroacetate (66.8 μM) were slowly added at 〇 °C. After stirring for 3 minutes at a temperature, the precipitate was removed by the transition. In a separate flask, the filtrate obtained above was slowly added to a suspension of sodium borohydride (144 mg) in ethanol (2 mL). After stirring at room temperature for 2 hours, 1 N hydrochloric acid was gradually added to bring the pH to 4. Water (5 ml) and ethyl acetate (1 ml) were added to the mixture, and the aqueous layer was extracted with ethyl acetate (3×5.0 ml). The combined organic layer was dried over anhydrous sodium sulfate. H-NMR (CDC13) δ : 1.30 (6H? d5 J-6.8 Hz) 5 3.33-3.40 (1H, )' 4·69 (2H, S), 7·38 (1H, d, 8.3 Hz), 7.53 (1H, dd, H.3, 2. 〇 Hz), 7.6 〇 (1Hd J = 2 〇 Hz). 121199.doc -383 - 200846322 (5) 3-Gasyl-4-isopropylbenzyl hydride [Chem. 426]

Thionyl chloride (7 〇·7 μ!) was added to 3-cyano-4-phenylpropanol (84.9 mg) in methylene chloride (2.0 mi) &gt; After heating under reflux for 3 hours, the reaction solution was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc) H-NMR (CDCi3) δ : 1.31 (6Η, d5 J=6.8 Hz)? 3.35-3.41 (1H, m), 4·56 (2H, s), 7.40 (1H, d, J=8.3 Hz), 7 · 57 (1H, dd, J=8, 3, 2.1 Hz), 7.63 (1H, d, J = 2.1 Hz). MS (ESI) m/z: 193 (M)+. (6) 3-[N-(Tertibutoxycarbonyl)_ν·[2-[5-[(3-cyanoisopropylphenyl)decyloxyP-pyridin-1-yl]-2 - side oxyethyl]amino]propionic acid third • Ding Yu [Chem. 427]

Adding carbolic acid (2 π mg) and 3-[n_ (third) to 3-cyano-4-isopropylbenzyl chloride (84. 5 mg) in DMF (2.0 ml) at room temperature Butoxycarbonyl)-N-[2-(5-hydroxyindolyl)&gt;2-sided oxyethyl]amino] 121199.doc -384 - 200846322 Tert-butyl propionate (184 mg) After stirring at 60 ° C for 4 hours and a half, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (5 ml) and chloroform (1 〇mi) were added to the residue to carry out liquid separation. After extracting the aqueous layer with chloroform (2 &lt;1 〇ml), the combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was filtered, and the filtrate was concentrated under reduced pressure. Purified by gel column chromatography (Biotage 25S) The residue was obtained to give the title compound (2 </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 3.15-3.23 (2H,m),3·36-3·42 (1H,m),3·55-3·61 (2H, m),3·99-4.19 (4H,m),5·〇〇 (2H, s), 6.73-6.84 (2H, m), 7·40 (1H, d, J=8.0 Hz), 7·58 (7H, dd, J=8.3, 1.5 Hz), 7.67 (1H,d,J=1.5 Hz), 8·12 (1H, dd, J=8.8, 8.8 Hz) 〇MS (ESI) m/z : 578 (M+H)+ 〇(7) 3-[N-[2-[5-[(3- Cyano-4-isopropylphenyl)nonyloxy]porphyrin-i-yl]_2_sideoxyethyl]amino]propionic acid [Chem. 428]

[3][Ν-(Tertibutoxycarbonyl)-N-[2-[5-[(3-cyano-4-isopropylphenyl)decyloxy]porphyrin-1-yl] -2-oxoethyl]amino]propionic acid tert-butyl ester (202 mg) in a digastric (2. 4 ml) solution, adding 121199.doc - 385 - 200846322 TFA at room temperature After mixing for 0.6 hours at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure, and dimethyl argon (6 〇ml) was added to the residue, and the insoluble matter was removed, followed by high performance liquid chromatography ( N〇MURA Devel〇sii 5) Purified 'concentrated target fraction' was lyophilized to give the title compound (1,09 mg) 〇^-NMR (DMSO-d6) δ: 1.26 (6 Η, d5 J=7.i Hz) 2 35 f2H t 3.19-3.27 (1H, m)3 3.53 (2H, s), 4.03 (2H, t, J=8.0 Hz), 5.07 (2H, s)5 6.81 (iH, dd, J=8.8, 2.4 Hz ), 6.94 (1H, d, J = 2.4 Hz), 7.56 (1H, d5 J=8.3 Hz), 7.71 (1Η, dd, J=8.35 2.0 Hz), 7.81 (1H, d, J=2.〇Hz ), 7.97 (IH, d, J=8.8 Hz) 〇MS (ESI) m/z : 421 (M)+ 〇C24H27N3〇4.0.25H2〇, 〇.25CF3C〇2H Elemental analysis calculated value: C,64.74 ; H, 6.15; N, 9.25. Measured: c, 64 42; &amp; 6 i5; N 9.24 〇 '5 [Example 93] 3-[N_[2_[5_[(4_cyclohexyl·2|phenyl)methoxyxindolinyl]-2-oxoethyl]amino]propanoic acid (1) Methylfluoro-4-hydroxyl-formate (W09734885) [Chem. 429]

To a solution of fluoro-4-hydroxybenzoic acid (5.70 g) in decyl alcohol (6 〇 ml), sulfinium chloride (2.87 ml) was slowly added at room temperature. After heating under reflux for 3 hours, the mixture was cooled to room temperature, and the mixture was concentrated under reduced pressure to afford titled titled 129. W-NMR (CDC13) δ : 3·77 (3H, s), 6.63 (1H, dd, J = 13.1, 2·3 Hz), 6.69 (1H, dd, J = 8.8, 2.3 Hz), 7.74 (1H, t, Hz), 10·82 (1H, br s). (2) Methyl 2-fluoro-4-trifluoromethanesulfonyloxybenzoate [Chem. 430]

Add pyridine (2.31 ml) and trifluoromethanesulfonic anhydride (4.23 ml) to a solution of 2-fluoro-4-hydroxybenzoic acid decyl ester (3.89 g) in dichloromethane (7 mL). ). After stirring at room temperature for 16 hours, the precipitated solid was removed by filtration, and the filtrate was concentrated under reduced pressure. Water (50 ml) and chloroform (70 ml) were added to the residue. Furthermore, after extracting with ethyl acetate (3x30 ml), the combined organic layer was washed with a 3% aqueous copper sulfate solution and saturated brine, and dried over anhydrous sodium sulfate. After the insoluble material was filtered, the filtrate was concentrated mjjjjjjj H-NMR (CDC13) δ : 3·96 (3H, s), 7.14 (1H, dd, J = 10.0, 2·2 Hz), 7·18 (1H, ddd, J=8.5, 2.2, 1.0 Hz) ),8·08 (1H,t,J=8.5

Hz) o (3) 4-cyclohexyl-2-fluorobenzoate oxime [Chem. 431] 121199.doc -387 - 200846322

Iodide was added at room temperature under a nitrogen atmosphere in a solution of methyl 2-fluorotrifluorosulfonyloxybenzoate (Ul g) in N,N-dimethylacetamide (2 〇mi). Copper (1) (76.1 mg), (1) broad bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (163 mg) and 0.5 Μcyclohexylzinc bromide/THF solution (9 · 6 ml). After heating under reflux for 2 hours, it was left to cool to room temperature, and a saturated aqueous solution of ammonium chloride (40 ml) was added to the mixture. After stirring at room temperature for 3 minutes, the precipitated solid was removed by filtration. The combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate (5). The filtered and insoluble materials were concentrated under reduced pressure to filter. The residue was purified using EtOAc EtOAc (EtOAc) W-NMR (CDC13) δ ·· 1.19-1.45 (5H,m),1.73-1.91 (5H,m), 2.54 (1H5 br s)? 3.91 (3H, s)? 6.97 (1H5 d, J=l2. 2 Hz), 7.04 φ (1H, dd, J=7.8, 1·7 Hz), 7.85 (1H, t, J = 7.8 Hz). MS (ESI) m/z : 237 (M+H), (4) 4-3⁄4 hexyl-2-lbenzoic acid [Chem. 432]

To a solution of decyl 4-cyclohexyl-2-fluorobenzoate (713 mg) in THF (8.0 ml), MeOH (4.0 ml) and 1 N aqueous sodium hydroxide 121199.doc - 388 - 200846322 (4.00 ml). After stirring at room temperature for 15 hours, water (2 ml) was added to the reaction mixture, the pH was adjusted to 3 with 1 N hydrochloric acid, and chloroform (4 ml) was added thereto to carry out liquid separation. Furthermore, the aqueous layer was extracted with chloroform (3×20 ml). ^-NMR (CDCI3) δ : 1.21-1.46 (5H5 m)5 1.74-1.92 (5H, m)j 2·52-2·60 (1H,m),7·01 (1H, dd5 卜11·7, Κ6 Hz), 7·〇8 (1H, dd, J=8.2, 1·6 Hz), 7.94 (1H, t, J=8.2 Hz). MS (ESI) m/z: 223 (M+H)+. (5) 4-cyclohexylfluorobenzyl alcohol [Chemical 433]

ο

a€C〇H In a solution of 4-cyclohexyl-2-fluorobenzoic acid (603 mg) in THF (8.0 ml), slowly add ΤΕΑ (567 μΐ) and ethyl chloroacetate at 〇 °C . After stirring at _ room temperature for 30 minutes, the precipitate which precipitated was removed by filtration. In a separate flask, the phenyl phthalic acid derivative filtrate was slowly added to the sodium borohydride (670 mg) in ethanol (10 turbid liquid). After stirring for 1 hour at 〇〇c, slowly add 1 N hydrochloric acid was used to adjust the pH to 4. Water (20 ml) and ethyl acetate (3 〇 nil) were added to the reaction mixture for liquid separation, and the aqueous layer was extracted with ethyl acetate (3 X, ml). The organic layer was dried over anhydrous sodium sulfate (MgSO4) (mjjjjjjjjj iH-NMR (CDC13) δ : 1.18-1.30 (1H, m), 1.31-1.45 (4H, m), 1.68-1·75 (1H, m), 1.75-1.89 (4H, m), 2·45-2·53 (1H,m), 4.71 (2H,d,J=6.1 Hz), 6.90 (1H,dd,J=11.7,1·5 Hz),6·98 (1H,dd5 J= 7,8, 1.5 Hz), 7·30 (1H, t5 J=7.9 Hz) (6) 4-3⁄4 hexyl-2-fluoro-nodyl chloride [化434] • αχχ〇Η - °ΧΧ〇1 To a solution of 4-cyclohexyl-2-fluorobenzyl alcohol (478 mg) in dichloromethane (10 ml) was added sulphuric acid (33 5 μM) at ambient temperature. After 1 hour and a half of hot refluxing, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the title compound (461 mg).]H-MR (CDC13) δ: 1.19-1.42 (5Η, m)5 1.75 ( 1H5 d3 J=12.5 Hz), 1.82-1.89 (4H, m), 2·50 (1H, br s), 4·61 (2H, s), 6.92 φ (1H' dd' J=11.2, 2.0 Hz), 6.98 (1H, dd, J = 7.8, 2_0 Hz), 7·30 (1H, t, J = 7.8 Hz) (7) 3-[N-(T-butoxycarbonyl)-N- [2-[5-[(4-Cyclohexyl-2-fluoro-phenyl) decyloxy] porphyrin-1-yl]-2-oxoethyl]amino]-propionic acid tert-butyl ester [化435]

To a solution of 4-cyclohexyl-2-fluorobenzyl chloride (113 mg) in DMF (3.0 ml) lacquer 121199.doc -390 - 200846322, add potassium carbonate (242 mg) and 3-[N at room temperature -(Tertibutoxymethyl)-N-[2-(5-trans-based)[侧多琳-1 -yl)-2-oxoethyl]amino]propionic acid tert-butyl ester (210 mg). After stirring at 60 ° C for 4 hours and a half, the reaction solution was cooled to room temperature and concentrated under reduced pressure. Water (5 ml) and ethyl acetate (1 〇 ml) were added to the resulting residue for liquid separation. Further, after extracting the aqueous layer with ethyl acetate (2×10 ml), the combined organic layer was dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc (EtOAc) H-NMR (CDC13) δ : 1.23-1.58 (23Η, m)5 1.70-1.89 (5H? m), 2·40-2·63 (3H,m)5 3.14-3.22 (2H,m)5 3· 56-3·61 (2H, m), 3.97-4.18 (4H, m), 5·04 (2H, s), 6·76_6·85 (2H, m), 6·88-7·02 (2H, m), 7·37 (1H, dd, J=7.3, 7·3 Hz), 8·11 (1H, dd5 J=8, 8, 8.8 Hz).

(8) 3-[Ν·[2·[5-[(4-Cyclohexyl-2-fluoro,phenyl)methoxy]σ-pyroline small group 2-side oxyethyl]amino] Propionic acid [Chemical 43 6]

3-[Ν-(Tertibutoxycarbonyl)_Ν_[2_[5_[(4_cyclohexyltoluene-phenyl)methoxyporphyrin-i-yl]_2_sideoxyethyl]amine To a solution of triethyl hydrazine propionate (265 mg) in methyl chloride (2.4 melon 1), TFA (0.60 ml) was added at room temperature. After stirring at room temperature for 3 hours, the reaction solution 121199.doc -391 - 200846322 was concentrated under reduced pressure, and dimethyl hydrazine (3.0 ml) was added to the residue, and the insoluble matter was removed. The title compound (94 2 mg) was obtained after the title compound (94 2 mg) was purified by chromatography eluting with EtOAc. MS (ESI) m/z: 455 (M+H)+. Calculated for the elemental analysis of C26H31FN204.〇.25H2〇: c, 68.03; H, 6.92; F, 4.14; N, 6.10. Found: c, 68·15; H, 6. 84; F, 4.21; N, 6.06 〇 [Example 94] 3·[Ν-[2-[5-(4-ethyl-3-trifluoromethyl) (Benzyloxy)porphyrin-1-yl]-2-oxoethyl]amino]propanoid hydrochloride (1) 3-[indolyl-(benzyloxycarbonylmethyl)amino]propyl Acid ethyl ester

〇 ten

HCI 〇

Add β-alanine ethyl ester hydrochloride (25.0 g) and DIEA (55.3 ml) to a solution of acetaminophen (10 · 7 m 1 ) in B. (6 5 0 m 1). Stir at night at 80 °C. After it was left to cool to room temperature, the reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. Dry it. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (yield: 4L) to give the title compound (16.9 g) 〇H-NMR (CDC13) δ: 1.26 (3H) ,t,J=7.2 Ηζ),2·50 (2H,t, J=6,6 Hz), 2·91 (2H,t,J=6.6 Hz), 3.47 (2H,s),4·15 ( 2H,q, 121199.doc -392- 200846322 J=7.2 Hz), 5.17 (2H, s), 7·32_7·37 (5H, m). MS (ESI) m/z: 266 (M+H)+. (2) 3-[N-(Benzyloxycarbonylmethyl)_ν·(t-butoxycarbonyl)amino]propionic acid [Chemical 438]

Boc

• Add Boc20 (16.7 g), saturated hydrogencarbonate to a solution of 2-[N-(benzyloxycarbonylmethyl)amino]propionic acid ethyl ester (16·9 g) in dioxane (200 ml). Aqueous sodium (200 ml) was stirred at room temperature overnight. The reaction mixture was extracted with chloroform (3 mL). The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (yield: 5L) to give the title compound (23.4 g) 〇W-NMR (CDC13) δ:1·22, 1·28 (3H, m), 1.34-1.47 (9H, m), • 2·58-2·65 (2H, m), 3.51-3.59 (2H, m), 4.01-4.15 (4H, m), 5·15 (2H, s), 7.33-7.36 (5H, m). MS (ESI) m/z: 366 (M+H)+. (3) MN-(t-butoxycarbonyl(carboxymethyl)amino]propionic acid ethyl ester [Chem. 439]

Boc

〇I 〇 in 3-[N-(benzyloxycarbonylmethyl)-N-(t-butoxycarbonyl)amino]propane 121199.doc -393 - 200846322 Ethyl acetate (23·3 g) of ethanol To the solution (3 Å), 5% pd/c (aqueous) (5.00 g) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered. ]H-NMR (CDCI3) δ : 1.26 (3Η, t5 J=7.0 Hz)? 1.42-1.48 (9H, m), 2.59-2.64 (2H, m), 3·52-3·58 (2H, m) , 4.02-4.16 (4H, m) 0 MS (ESI) m/z: 276 (M+H), (4) 3·[Ν-[2-(5-benzyloxyporphyrin_丨_yl) _2•Sideoxyethyl]·N_(t-butoxycarbonyl)amino]propionic acid ethyl ester [Chem. 440]

(X.

Boc human 0 in a solution of 5-benzyloxyporphyrin hydrochloride (1·54 g) in dmf (30 ml), 3-[N-(t-butoxycarbonyl)(carboxymethyl)amine Propionate

Ethyl vinegar (2·14 g), DIEA (3. 〇〇, H〇Bt (1.03 g), EDC.HC1 (1 · 47 g) ' stirred at room temperature overnight. Add saturated hydrogen carbonate to the reaction solution. The sodium aqueous solution was extracted three times with ethyl acetate, and the combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was subjected to reduced pressure and then subjected to rapid column chromatography ( The residue obtained by purification of the Shanshan high-speed column 3L) gave the title compound (2·7 illusion. H-NMR (CDC13) δ: 1.21.1.28 (3H? m), 1.40-1.49 (9H, m), 2.64-2.71 (2H,m), 3.15-3.21 (2H,m), 3.60-3.63 (2H,m), 3.98-4.18 (6H,m),5·〇2_5·〇3 (2H,m), 6.76-6.83 ( 2H,m), 121199.doc •394- 200846322 7.30-7.43 (5H,m),8·09-8·13 (1H,m) MS (ESI) m/z : 483 (M+H)+ 〇 (5) 3-[N-(Tertibutoxycarbonylhydroxyporphyrinyl)_2_sideoxyethyl]amino]propionic acid ethyl ester [Chem. 441]

Boc 〇 I Ο

3-[N-[2-(5-Benzyloxyporphyrin-i-yl)_2-sideoxyethyl]-N- (after concentration of the pressure, the resulting residue will be burned After washing, the title compound (2,0 1 g) was obtained. Dibutyloxycarbonyl)amino]propionic acid ethyl ester (2.70 g) in ethanol (6 〇m!), 5% Pd/C (aqueous) (1.00 g), stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (3L), and then reduced by H-NMR (CDC13) δ: L23-1.28 (3H, m) , 14 (M, 53 (9H, called 2.65-3.12 (4H, m), 3.60-3.92 (4H, m), 4 〇 8_4.15 (4H' (4) 6.55-6.69 (2H, m), 7.19·7· 26 (1H,m),7 86 8 〇5 (ih, called MS (ESI) m/z : 393 (M+H) X. (6) 3-Trifluoromethyl-4·vinylbenzoic acid酉 [ [化442]

〇

〇121199.doc •395 - 200846322 Add 4 to a toluene solution (9·〇ml) of 4-trifluorosulfonyloxy-3-trifluorodecylbenzoate (1·〇6 g). 4,5,5-tetramethyl-2-vinyl-indole, 3,2] dioxaborane (601 mg), carbonic acid planer (2.93 g), water (4.5 ml), tetrakis (triphenyl) Palladium (0) (347 mg) was stirred overnight under reflux with heating. After the mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (m.p.). ^-NMR (CDC13) δ : 3.95 (3Η, s)? 5.55 (1H5 d; J=ll.〇Hz)? 5.86 (1H,d,J=17.4 Hz),7.08-7.16 (1H,m),7.74 (1H, d, J = 8.3 Hz), 8·15·8·18 (1H, m), 8·31-8·31 (1H, m). MS (ESI) m/z: 231 (M+H)+. (7) Methyl 4-ethyl-3-trifluorodecylbenzoate [Chem. 443]

Add 5% Pd/C (aqueous) (100 mg) to a solution of methyl 3-trifluoromethyl-4-vinylbenzoate (230 mg) in ethyl acetate (10 ml) Stir at room temperature for 1 hour. The reaction mixture was filtered, and the solvent was evaporated. 1H-NMR (CDC13) δ : 1.28 (3H, t, J = 7.5 Ηζ), 2·88 (2H, q, J = 7.5 Hz), 3·94 (3H, s), 7.44 (1H, d, J =8.1 Hz), 8·13 (1H, 121199.doc -396 - 200846322 d, J=8.1 Ηζ), 8·29 (1H, s). MS (ESI) m/z: 233 (M+H)+. (8) (4-Ethyl-3-trifluoromethylphenyl)methanol [Chem. 444]

Lithium borohydride (65·3 mg) was added to methyl 4-ethyl-3-trifluoromethylbenzoate (232 mg) in THF (m). After it was left to cool to room temperature, iN hydrochloric acid was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (m.p.). ^-NMR (CDC13) δ : 1.25 (3Η, t, J=7.5 Hz), 1.75 (1H, s), 2-82 (2H, q, J=7.5 Hz), 4.71 (2Η, s), 7.34 ( 1H, d, J=8.1

Hz), 7·47 (1H, d, Hz), 7.61 (1H, s). (9) 4-Gasmethyl-ethyl·2_trifluorodecylbenzene [Chem. 445]

Add ruthenium chloride (338 μl), DMF (with Bath) to a solution of (4 ethyl-3-dimethylmethyl) methanol (190 mg) in 1,2-dichloroethane (10 ml) Add 1 drop) to the pipette and stir at 50 °C overnight. It was allowed to cool to room temperature. 121199.doc -397-200846322 After the reaction solution was concentrated and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (m.p.) to give the title compound (184 s lH-NMR (CDCls) δ: 1.25 (3 Η, t, J = 7.5 Hz), 2.82 (2H q J=7.5 Hz), 4.59 (2H, s), 7.35 (1H, d, J=7.8 Hz), 7.50 d, J=7.8 Hz) 5 7.62 (1H, s). '(10) 3-[N_(Tertibutoxycarbonyl)-oxime_[2_[5_(4_ethyl_3_trifluoromethylbenzyloxy)porphyrin-1-yl]-2-side Ethoxyethyl]amino]ethyl propionate [Chemical 446]

a DMF solution of 3-[N-(t-butoxycarbonyl)-indole-[2·(5-pyridyl porphyrin+yl)-o-oxyethyl]amino]propionic acid ethyl ester (173 mg) 4-(methylmethyl-1-ethyl-2-trifluoromethylbenzene (89·1 mg) and carbon potassium (71.9 mg) were added to (5.0 ml), and the mixture was stirred at 70 ° C overnight. After the mixture was allowed to cool to room temperature, the reaction mixture was filtered, and the residue was evaporated to purified crystals crystals crystals !H-NMR (CDCI3) δ : 1.21-1.28 (6Η, m), 1.40-1.49 (9H5 m)? 2.65-2.72 (2H,m),2·83 (2H,q,j=7,4 Hz) ,3·16_3.22 (2H, m), 3.60-3.64 (2H, m), 3:99-4.19 (6H,m), 5.02 (2H,s), 6·75-6·83 (2H,m ), 7.36 (1H, d, J = 8.1 Hz), 7.52 (1H, d, J = 8.1 Hz), 7.66 (1H, s), 8·10_8.14 (1H, m) 0 MS (ESI) m/z : 579 (M+H)+ 〇121199.doc -398 - 200846322 (11) 3-[N-(Tertibutoxycarbonyl)_Ν_[2 [5·(4_ethyl_3•3 Fluoromethylbenzyloxy)porphyrin-1·yl]_2-sideoxyethyl]amino]propionic acid [Chemical Formula]

3-[ν-(Tertidinoxycarbonyl)_ν_[2_[5_(4_ethyl_3•trifluoromethyl•heptyloxy)porphyrin-1·yl]-2. To a THF solution (5. 〇ml) of ethyl]amino]propionic acid ethyl ester (210 mg), methanol (1 j), 1 Ν aqueous sodium hydroxide solution (1.09 ml), and stirred at room temperature. hour. After adding 1 N hydrochloric acid to the reaction mixture for neutralization, the mixture was extracted three times with chloroform, and the combined extracts were dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was evaporated to drynessiel tNMR (CDC13) δ : 1.26 (3H, J = 7.6 Hz), 1.39-1.48 (9H, m), 2.55-2.68 (2H, m), 2.80-2.85 (2H, m), 3.20-3.24 (2H, # m), 3.65-3.71 (2H, m), 4·01-4·2〇(4H,m), 5·03 (2H,s), 6·79-6·84 (2H,m),7· 36 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = Hz), 7.66 (1H, s), 8.13 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 551 (M+H)+. (12) 3-[N-[2-[5-(4-ethyl-3-trifluoromethylbenzyloxy). Porphyrin porphyrin 2-ethyloxyethyl]amino]propionic acid hydrochloride [Chem. 448] 121199.doc -399- 200846322

???:HN-(Tertidinoxycarbonyl)·Ν-[2-[5-(Heartoethyl-3-trifluoromethyl hydroxy) oxoindolin-1-yl]-2-oxan A solution of 4% hydrochloric acid / 1,4-dioxane (4.5 ml) was added to a solution of methyl ethyl]amino]propionic acid (185 mg) in chloroformic acid (1.5 ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced vacuo. _ H-NMR (DMSO-d6) δ : 1.20 (3H, t, J = 7.5 Hz), 2.74-2.79 (4H, m), 3.16-3.21 (4H, m), 4.05-4.13 (4H, m), 5·14 (2H, s), 6.88 (1H, dd, J=2.7, 8·8 Hz), 7·01 (1H, d, J=2.7 Hz), 7.52 (1H, d, J=7.8 Hz),7·66·7·73 (2H,m)5 7·96 (1H,d, J=8.8 Hz) 〇IR (ATR)cnT1 : 2798, 1716, 1646, 1492, 1132, 1112. MS (ESI) m/z: 451 (M+H)+. HR-MS (ESI) calculated for C23H26F3N2 〇4 (m+H): 45i 18447; • Measured: 451.18267. Calculated for elemental analysis of C23H25F3N2〇4*HCh0.25H2〇: ◦ 56·21, Η, 5.44; Cl, 7·21; F, 11·60; N, 5.70. Found: c, 56.05; Η, 5.38; C1,7·05; F, 11.59; Ν, 5.58. [Example 95] 3-[Ν-[2-[5-(3,4-bistrifluoromethylbenzyloxy)indolyl]-2-oxoethyl]amino]amino]propionic acid TFA Salt (1) 4•Nitro-3-trifluorodecylbenzoic acid methyl ester [Chem. 449] 121199.doc -400· 200846322

In 4-nitro-3-tris-methoxybenzoic acid (]. Soil + τ ^U. 〇〇 之 solution in methanol (5〇

Add concentrated sulfuric acid (2.0 ml) and mix for 2 hours and a half under heating and reflux. After it was left to cool to room temperature, the reaction liquid was concentrated under reduced pressure, and a saturated sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted twice with ethyl acetate, and the extract was washed with saturated brine and dried. Dry with sodium sulfate. Filtration of the insoluble material was concentrated under reduced pressure, and the residue was purified by flash column chromatography (yield: 2L). ° h-NMR (CDCl3) δ : 4.G2 (3H, s), 7% (ih, d, (4) 3 is 8.38 (1H, dd, 1=1.5, 8.3 Hz), 8.49 (1H, d, J= 1.5 Hz) 〇(2)4-amino-3-trifluorodecylbenzoic acid methyl ester [450]

Add 1 N hydrochloric acid (4 ^) to 4-nitro-3·trifluoromethane, #田_田^, 土本甲6夂甲酉曰(1·〇6 g) in methanol solution (4〇ml) (4.25 1^) and 5% Pd/c (5 〇〇mg), under a hydrogen atmosphere, at room temperature, n db &amp; + hour abundance. The reaction solution was filtered, concentrated under reduced pressure, The obtained residue φ, day-to-day was added saturated sodium bicarbonate solution, and taken twice with ethyl acetate soap. The combined lids were washed with saturated saline and dried with sodium sulfate in helmet. The mixture was concentrated under reduced pressure to give the title compound (948 mg). 121199.doc -401 . 200846322 W-NMR (CDC13) δ : 3·88 (3H, s), 4.59 (2H, s ), 6.73 (1H, d, J = 8.6 Hz), 7.96 (1H, d, J = 8.6 Hz), 8·15 (1H, s) MS (ESI) m/z : 220 (M+H ) + (3) 4-bromo-3-trifluoromethylbenzoic acid methyl ester [Chem. 451]

Add copper (II) bromide (1 〇 4 g), nitrite nitrite to acetonitrile solution (4 〇ml) of 4-amino-3-trifluoromethylbenzoate (85 〇mg). The ester (69 μM) was stirred under reflux with heating for 30 minutes. After it was left to cool to room temperature, a saturated sodium hydrogencarbonate solution was added to the mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After the filtrate was concentrated under reduced pressure, the obtained title compound (1·〇9 g) was obtained by the purified column column chromatography (2L).

H-NMR (CDC13) δ : 3.96 (3Η&gt; s), 7.81 (1Η, d&gt; J=8.3 Hz) ί.04(1Η5 dd, 1=2.0,8.3 Hz), 8.35 (1H, d, J=2 .〇Hz) 〇(4) 3,4·Methyl bis-trifluoromethylbenzoate [Chemical 452]

Addition of copper iodide (i) (72 〇 mg), fluorine to 4-bromo·3·trifluoromethylbenzoic acid methylate (10) 7 g) solution (10) 121199.doc -402- 200846322 melon 1) Methyl sulfonyl difluoroacetate (4'78 ml) was stirred overnight at 9 °C. After the mixture was allowed to cool to room temperature, the reaction mixture was filtered over with celite, and the filtrate was concentrated under reduced pressure, and then brine was added to the residue, and the mixture was extracted three times with ethyl acetate. After washing, it was dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to flash column chromatography (2L) to obtain a mixture of the title compound and starting material (632 mg). (5) (3, 'bis-trifluoromethylphenyl) decyl alcohol [Chemical 453]

Lithium borohydride (149 mg) was added to a THF solution (20 ml) of dimethyl bis(trifluoromethyl benzoate) (62 〇 mg), and the mixture was stirred under heating under reflux for 10 hours. After it was left to cool to room temperature, 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to flash column chromatography (2L of Shanshan, and 2 br.) to obtain a mixture of the title compound and the impurity (4 bromo) (535 mg) 〇MS (ESI) m/z : 227 (M-OH)+. (6) (3,4·Ditrifluorodecylphenyl)methanol [Chemical 454] 121199.doc -403 - 200846322

4-pyridineboronic acid was added to a toluene solution (6 〇ml) of a mixture of (4-bromo-3-difluoromethyl)methanol and (3,4-bistrifluoromethylphenyl)methanol (520 mg) (3 76 mg), sulphuric acid (199 g), water (3 〇 ml), tetrakis(triphenylphosphine), (0) (236 mg), stirred under stirring overnight. After the mixture was cooled to room temperature, a saturated sodium hydrogencarbonate solution was added to the mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by flash column chromatography (yield: 2L) to give the title compound (320 mg). 'H-NMR (CDC13) δ : 1.95 (1H? t? J=5.6 Hz), 4.85 (2H5 d5 J=5.6 Hz)? 7.67-7.69 (1H, m)3 7.84-7.86 (2H5 m) 〇MS ( ESI) m/z : 227 (M-OH)+. (7) 1,2-bistrifluoromethyl-4-chloromethylbenzene [Chemical 455]

Add sulfite gas (460 μΐ) and DMF (1 drop with a Pasteur pipette) to (3,4-bistrifluorodecylphenyl)methanol (310 diethylene ethoxide solution (20 ml), Stir at 50 ° C for 1 hour and a half. After standing to cool to room temperature, the reaction solution was concentrated under reduced pressure to fast column chromatography (Shanshan high-speed tube 121199.doc -404 · 200846322

7.92 (2H, m). (8) 5 (3,4-bisdifluoromethylbenzyloxy) porphyrin_ι_carboxylic acid tert-butyl ester [Chemical 456]

Add 1,2-bistrifluoromethyl-4-chloromethylbenzene (2〇) to 5-hydroxyporphyrin·ι·t-butyl butyrate (215 DMF solution (:&gt;·ϋ ml) 〇(5) phantom, potassium carbonate (158 mg), stirred at 7 (TC for one night. After cooling to room temperature, 'filtered, the reaction solution, and concentrated under reduced pressure for rapid column chromatography) The residue obtained by the purification of the title compound (2M) was obtained (yield: 299 NMR (CDCls) δ: 1.55 (9 Η 5 s) 5 3.07 (2H5 t5 J = 8.7 Hz) 5 _ 3.97 (2H, s), 5.12 (2H, s), 6.74-6.80 (2H, m), 7.72-7 91 (4H, m) MS (ESI) m/z : 462 (M+H)+ 〇(9) 3-[N-[2-[ 5-(3,4-bistrifluoromethylbenzyloxy)porphyrin-yl].-Sideoxyethyl]-indole-(t-butoxycarbonyl)amino]propionic acid vinegar [ 457] 121199.doc -405 - 200846322

Add 4 N hydrochloric acid n, 4 唠 唠 于 (5 , ,, in 5-(3,4-bistrifluoromethylbenzyloxy) hydrazine porphyrin + decanoic acid butyl vinegar (138 mg) The mixture was stirred at room temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMF (1 〇m ,, and added 3·[ν•(T-butoxycarbonyl)_n- s yl) Base ethyl propionate (107 mg), DIEA (153 Μ), H〇Bt (52.7 mg), EDOHCl (74.8 mg), stirred at room temperature overnight. Add saturated sodium bicarbonate solution to the reaction solution The mixture was extracted with ethyl acetate three times, and the combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insolubles were filtered, and the liquid was concentrated under reduced pressure, and then subjected to rapid column chromatography (Shanshan high-speed column L The residue obtained was purified to give the title compound (m.p.) (m.) (ESI) m/z: 619 (M+H). (10) 3-[N-[2-[5-(3) ,4-bistrifluoromethylbenzyloxy)indole porphyrinyl]_2_sideoxyethyl]-indole-(t-butoxycarbonyl)amino]propionic acid [Chemical 458]

And the above impurity and 3-[Ν-[2-[5-(3,4-bistrifluoromethylbenzyloxy),,dolyl-1-yl]-2-oxoethyl]-Ν- Addition of methanol (〇9〇ml), 1 N hydrogen emulsified sodium to a mixture of tert-butoxylamino]propionate 121199.doc -406- 200846322 (201 mg) in THF (5 ml) Water" gluten (〇.9〇〇mi), stirred at room temperature for 1 hour and a half. After adding 1 N hydrochloric acid to the reaction mixture for neutralization, it was extracted three times with chloroform. The combined extracts were dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was evaporated to dryness. • H-NMR (CDC13) δ : 1.39-1.49 (9Η, m), 2.56-2.67 (2H, m)5 3.24 (2H, t, J=8.2 Hz)? 3.70-3.73 (2H, m)? 4.03- 4.17 (4H5 m), 5·15 (2H, s), 6.79-6.85 (2H, m), 7.73-7.77 (1H, m), 7.86-7.91 (2H, m), 8.16 (1H, d, Hz) . MS (ESI) m/z: 591 (M+H) + 〇(11) 3-[2-[5-(3,4-bis-trifluoromethylbenzyloxy) porphyrin "--]. Side oxyethylamino]propionic acid TFA salt [Chemical 459]

3-[N-[2-[5-(3,4-Bis-trifluoromethylbenzyloxy)indolyl]_2_side oxyethyl]-indole·(t-butoxycarbonyl)amine Adding butyl to a solution of propionic acid (丨25 tons) in dichlorosilane (4.5 1111)? After stirring at room temperature for 3 hrs, additional TFA (0.50 ml) was added and stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure. dichloromethane (3············· After the reaction mixture was concentrated under reduced pressure of 121199. doc - 407 - s s s s s s s s s s s s s s s s s s s s s s s =7.4 Hz), 3.17-3.22 (4H, m), 4·04-4·14 (4H, m), 5.31 (2H, s), 6.91 (1H, dd, J=2.7, 8.8 Hz), 7.05 ( 1H,d,J=2.7 Hz),7·96-7·99 (2H,m), 8.09-8.11 (2H,m) ° IR (ATR)cm·1 : 1727, 1660, 1494, 1313, 1168, 1126. MS (ESI) m/z: 495 (M+H)+. HR-MS (ESI) calcd for C.sub.2.

C22H2〇F6N2 (calculated value of elemental analysis of VCF3C02H: c, 47 69·H

3·50; F, 28·29; N, 4·63. Found: c, 47·54; H, 3 34 · F 28.54; N, 4.57 ° [Example 96] cyclohexene q-yl_3_trifluoromethylbenzyloxy) ° 鸣 琳 -1· ]-2-Ethyloxyethyl]amino]propionic acid hydrochloride (1) 4 - 哀 己 -1- -1-yl-3-yltrifluoromethylbenzoic acid methyl hydrazine [Chemical 460]

Add 2-cyclohexene small group + ^ Hong tetramethyl [1,3] in 4-trimethylmethanesulfonyloxy-3-trifluoromethylbenzoic acid methyl vinegar (i4i in toluene solution (12 ml) 2] Dioxane (1.〇〇g), Carbonic acid (4)... Water (10) mlf Tetrakis(triphenylphosphine)palladium(0) (462 mg), stirred under heating and reflux for 3 hours and a half. 121199.doc - 408 - 200846322 After cooling to room temperature, a saturated sodium hydrogencarbonate solution was added and the mixture was extracted with ethyl acetate three times. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure, and then the residue was purified by rapid column chromatography (2L of Shanshan high-speed column) and further purified by rapid column chromatography (Shanshan ultra pack B). The fractions were combined to give the title compound (1.12 g). H-NMR (CDC13) δ: 1.56-2.21 (8H, m), 3.94 (3H, s), 5.60 (1 Η, s), 7.26 ·7·31 (1Η,m),8·10-8·30 (2Η,m) MS (ESI) m/z : 285 (M+H)+ (2) (4-cyclohexene-i -yl·3·trifluoromethylphenyl)methanol [Chem. 461]

Add lithium borohydride (65·3 mg) to a solution of methyl 4-cyclohexen-1-yl-3-trifluorodecylbenzoate (284 mg) (10 ml), and stir under heating and reflux 5 Half a day. After it was left to cool to room temperature, 1 n hydrochloric acid was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure, and the title compound (23 5 mg) was obtained by flash column chromatography (the residue obtained by purification of the Shanshan high-speed column). ^-NMR (CDC13) δ: 1.64 -1.78 (5Η, m), 2.12-2.22 (4H, m), 4.73 (2H, d, J=5.6 Hz), 5.57 (1H) s), 7.21 (iH, d, 1=7.8 121199.doc -409 - 200846322 Ηζ),7·46 (1H,d,J=7.8 Ηζ),7·62 (1H,s) MS (ESI) m/z : 239 (M-OH)+ (3) 3-[ N-(Tertibutoxycarbonyl)·Ν-1&gt;[5-(4-Cyclohexen-1-yl-3_trifluoromethylbenzyloxy)indol-1-yl]-2- Ethyloxyethyl]amino]propionic acid ethyl ester [Chem. 162]

Add to a solution of 3\[N-(T-butoxycarbonylhydroxyporphyrin-yl)_2_ oxoethyl]amino]propionic acid ethyl ester (173 mg) in THF (1 mL) (4·cyclohexene-1-yl-3-trifluoromethylphenyl)methanol (225 mg), diphenylphosphine (276 mg), DEAD (2.2 mol/1 in toluene) (479 μl), Stir at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by flash column chromatography (Mountain Ultra Pack) to further

The analytical method (2L of Shanshan Expressway column) was repurified and mixed with impurities to obtain the title compound (437 mg). ^ ^-NMR (CDCls) δ : 1.21-1.28 (3Η, m), I.40.1.49 (9H, m) 1.64-1.78 (4H,m), 2.13-2.21 (4H,m), 2.65_2 72 ( 2H,' 妁3.16-3.22 (2H,m), 3.60-3.64 (2H,m),3.99_419 (6H,^ 5.03 (2H,s),5.58 (1H,s),6.76-6.84 (2H,m) , 7.22 UH / J = 7.6 Hz), 7.51 (1H, d, 1 = 7.6 Hz), 7.67 (1H, s), 8.1〇.8h (1H,m) 〇MS (ESI) m/z : 631 (M +H)+. (4) 3-[N-(Tertibutoxycarbonyl)-N-[2-[5-(4-cyclohexenyl_3_III) 121199.doc -410- 200846322 A (Benzyloxy) porphyrin-1-yl]-2-yloxyethyl]amino]propionic acid [Chemical 463]

3-[N-(Tertibutoxycarbonyl)_ν_[2_[5·(4_cyclohexene.(yl)trifluoromethylbenzyloxy)porphyrin-1-yl]-2-oxyloxy Methyl ethyl]amino]propionic acid ethyl ester φ (43 〇 mg) in THF solution (10 ml), methanol (2·05 ml), 1 Ν aqueous sodium hydroxide solution (2.05 ml), at room temperature Stir for 丨 hours. After adding 1 N hydrochloric acid to the reaction mixture for neutralization, the mixture was extracted with ethyl acetate three times, and the combined extracts were dried over anhydrous sodium sulfate. Filter insolubles and reduce the filtrate? The title compound (395 mg) was obtained. H-NMR (CDC13) δ : 1.39-1.49 (9H, m), 1·64-1·78 (4H, m), 2.12-2.23 (4H, m), 2.55-2.68 (2H, m), 3.23 ( 2H, t, J = 8.2 Hz), 3.67-3.72 (3H, m), 4.06-4.16 (4H, m), 5·04 (2H, s), • 5·58 (1H, S), 6.80·6 ·85 (2H,m),7·23 (1H,d,J=7.6 Hz), 7·51 (1H,d, 7.6 Hz), 7.67 (1H,s),8·ΐ4 (1H,d, Ι=8·8

Hz) 〇 MS (ESI) m/z : 603 (M+H)+. (5) 3-[Ν-[2·[5-(4·cyclohexene-in-trifluoromethyl$oxy) 哚 哚 _ 1-yl]-2-oxoethyl]amino] Propionate hydrochloride [Chem. 464] 121199.doc -411 - 200846322

3-[N-(Tertibutoxycarbonyl)_n-[2-[5-(4-cyclohexene-i-yl-3-trifluoromethylbenzyloxy). Adding 4 N Hydrochloric Acid / 1,4-Disaki to the oxoline small group]-2-oxoethyl]amino]propionic acid (200 mg) in a gas-burning solution (2·5 ml) (7·5 ml) 'Stir at room temperature for 3 〇 minutes. After the reaction mixture was concentrated under reduced pressure, the residue was purified by chromatography and dried to afford the title compound 156 (156 mg). ^-NMR (DMSO-d6) δ : 1.59-1.74 (4H, m), 2.11-2.18 (4H, m), 2.77 (2H, t, J = 7.5 Hz), 3.16-3.21 (4H, m), 4.05 -4.13 (4H,m), 5.15 (2H,s),5·54 (1H,s), 6.89 (1H,dd,J=2.5, 8.8 Hz), 7.02 (1H,d,J=2.5 Hz), 7·34 (1H,d,J=8.1 Hz), 7,66 (1H,d,J=8.1 Hz), 7.75 (1H,d,J=1.2 Hz), 7.97 (1H,d, J=8.8 Hz) 〇IR (ATR)cnT1: 2927, 1718, 1656, 1490, 1317, 1116. _ MS (ESI) m/z : 503 (M+H)+. HR-MS (ESI) calcd for C.sub.3. Calculated for the elemental analysis of C27H29F3N2CVHC: 0,5,5 Η2 :: c, 59.18; H, 5.70; Cl, 6.47; F, 10.40; Ν, 5.11. Found: c, 59.23; H, 5·68; Cl, 6. 59; F, 10.32; N, 5.05. [Example 97] 3-[N-[2-[5-(4-isopropyl-3-trifluoromethoxybenzyloxypyridin-1-yl)-2-oxoethyl Amino]propionic acid hydrochloride 121199.doc -412- 200846322 (1) 4·Isopropenyl_3_trifluoromethoxybenzoic acid methyl ester [Chem. 465]

Br

Add 2-isopropenyl-4,4,5,5-tetramethyl β to a toluene solution of methyl 4-bromo-3-trifluoromethoxybenzoate (897 mg) (15 ml). 1,3,2]dioxaborane

(677 μΐ), strontium sulphate (4·89 g), water (7.5 ml), tetrakis(triphenylphosphine) (0) (347 mg), stirred under heating and refluxed overnight, 2_ Isopropenyl·4,4,5,5-tetramethyl-[1,3,2]dioxaborane (677) with tetrakis(triphenylphosphine)palladium(0) (347 mg), heated Stir under reflux for 4 hours and a half. Place it to cool to room temperature and then 'pass the reaction solution. Add the saturated sodium bicarbonate solution to the night and extract it with ethyl acetate three times. After the liver and mouth was washed with saturated saline, it was dried with anhydrous sodium sulfate and filtered to dissolve insoluble matter. The filtrate was concentrated under reduced pressure, and then subjected to rapid column chromatography r ^ ^ (山善向速柱柱2L) The residue obtained was purified to give the title compound (765 mg).

Hz)3 3.94 (3H5 S)5 t J=1.2 Hz), 7.30-7.39 ^-NMR (CDC13) δ : 2.11 (3H) t&gt; 5.13 (1H,d,J=0.7 Hz), 5.30 (ijj (1H) , m), 7.90-7.93 (2H, m) MS (ESI) m/z: 261 (M+H) + (2) Methyl 4-isopropyl-3-trifluorodecyloxybenzoate [ 466] 121199.doc -413 - 200846322

Add 5% Pd/C (300 mg) to a solution of methyl 4-isopropenyl-3-trifluoromethoxybenzoate (755 mg) in ethyl acetate (15 ml) under hydrogen atmosphere Stir at room temperature overnight. The reaction mixture was filtered. lH-NMR (CDC13) δ : 1.25 (6Η, d5 1=6.6 Hz), 3.31-3.41 (1H? • m), 3.92 (3H, s)5 7.41 (1H,d,J=8.1 Hz), 7.85-7.94 (2H, m) 〇MS (ESI) m/z : 263 (M+H)+. (3) (4-Isopropyl-3-trifluoromethoxyphenyl)methanol [Chemical 467]

F

F 〇F F^l

XIF In a solution of methyl 4-methyl-3-trifluoromethoxybenzoate (67 mg) in thf (30 ml), lithium hydride (167 mg) was added and stirred under reflux with stirring. Hours and a half. After it was left to cool to room temperature, i N hydrochloric acid was added to the reaction mixture, and the mixture was extracted three times with 6 EtOAc. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The title compound (561 mg) was obtained by flash column chromatography (yield of the title compound (561 mg). ^-NMR (CDCI3) δ: 1.23 (6Η, d, J=6.9 Hz), 1.71 (1H, t, 121199.doc -414- 200846322 1=5.0 Hz), 3.28-3.34 (1H, m)5 4.68 (2H? d5 J=5.6 Hz), 7.22-7.34 (3H m) 217 (M-OH) + (4) 4-Methylmethyl-1-isopropyl-2-trifluoromethoxybenzene [Chem.

• Add ruthenium chloride (852 μΐ) to a solution of (4-isopropyl-3-dihydromethane base) sterol (550 jng) in 1,2-dichloroethane (25 ml) DMF (add 2 drops with a Pasteur pipette) and stir at 50 ° C for 4 hours. After it was allowed to cool to room temperature, the residue was evaporated to dryness crystals crystals crystals lH-NMR (CDC13) δ : 0.93 (6Η5 d5 J-7.1 Hz) 5 2.96-3.06 (1H? m), 4.26 (2H, s), 6.93-7.04 (3H.m) 〇(5) (third butyl Oxycarbonyl)-N-[2-[5-(4-isopropyl-3-trifluoromethoxyl)&lt;oxy] ° 引 I -1-yl]-2- oxo Ethyl]ethyl propionate [Chemical 469]

Ethyl 3-(N-(t-butoxycarbonyl)-N-[2-(5-hydroxyindol-1-yl)-2-oxoethyl]amino]propanoate (196 mg 'Addition of 4-methylmethyl_1_isopropyl·2·trifluoromethoxybenzene (152 mg) in a DMF solution (5.0 ml), carbon 121199.doc -415- 200846322 potassium (U) 4 (m) was stirred at room temperature for 7 nights. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The extract was washed with saturated brine. The residue was purified by EtOAc (EtOAc). CDC13) δ : 1.22-1.27 (9Η, m), 1.40-1.49 (9H, m), 2.64-2.71 (2H, m), 3.16-3.35 (3H, m), 3.60-3.63 (2H, m), 3 -98-4.18 (6H, m), 4.98 (2H, s), 6.75-6.83 (2H, m), i.26- Xin 7·35 (3H,in),8·09-8·13 (1H, m) (6) 3-[N-(Secondoxycarbonyl)·ν_[2-[5·(4-isopropyltrifluorosulfonyloxybenzyloxy)indol-1-yl] -2-sided oxyethyl]amino]propionic acid [470]

3-[N-(Tertibutoxycarbonyl)-N-[2-[5-(4-isopropyl-3-trifluoromethoxybenzyloxy)porphyrin-1-yl]- To a solution of 2-ethyloxyethyl]amino]propionic acid ethyl ester (300 mg) in THF (10 ml), methanol (1·5 ml), 1 ^^ aqueous sodium hydroxide (1.48 ml) Warm up and stir for 3 hours. After adding 1 N hydrochloric acid to the reaction mixture for neutralization, the mixture was extracted three times with ethyl acetate, and the combined liquid was washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure to give the title compound ( 286 mg) 〇121199.doc -416 - 200846322 H-NMR (CDC13) δ: 1.23 (6H, d, J=7.1 Ηζ), 1.39-1 ·49 (9H, m)5 2.55-2.68 (2H? m), 3.20-3.37 (3H, m), 3.69-3.72 (2H5 m), 4.01-4.16 (4H, m), 5·00 (2H, s ),6·78_6·84 (2H,m)5 7.26-7.36 (3H,m), 8.13 (1H,d,Ju Hz). MS (ESI) m/z: 581 (M+H)+. (7) 3-[N-[2-[5-(4-isopropyl-3-trifluoromethoxyoxy) oxopiperidin-1-yl]-2-oxoethyl]amino ] propionate [Chemical 471]

3-[N-(Tertibutoxycarbonyl)_N-[2-[5-(4-isopropyl-3-trifluoromethoxybenzyloxy), Ming Lin-1 —yl]-2- To the side oxyethyl]amino]propionic acid (280 mg), 4N hydrochloric acid / 1,4-dioxane (1 〇 ml) was added and stirred at room temperature for 1%. After the reaction mixture was concentrated under reduced pressure, the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted 2H5 t5 J=7.4 Hz),3·16·3·25 (5H,m)5 4.05-4.13 (4H,m),5·10 (2H, s), 6.88 (lH,d,J=8.8Hz) , 7.01 (lH, d, J = 1.5 Hz), 7.37-7·52 (3H, m) 5 7.96 (1H, d, J = 8.8 Hz). IR (ATR) cm.1 : 2967,1720,1660, 1490, 1255, 1211, 1151. MS (ESI) m/z: 481 (M+H)+ 〇121199.doc -417-200846322 C24H28F3N2〇5 (M+H)+ HR-MS (ESI) calculated value: For the analysis of the elemental analysis of C24H27F3N2O5.HC1.0.5H2O: c, 54 81, Η, 5.56; Cl, 6.74; F, 10.84; N, 5.33. Measured: C, 54 96 · H 5.47; Cl, 6.74; F, 10.91; Ν, 5·19 〇 [Example 98] 3-[Ν-[2-[5-[[4-(cyclohexyl))-2-(trifluoromethyl) Phenyl]methoxy]indolin-1-yl]_2_sideoxyethyl]amino]propionic acid hydrochloride (1) 4_(dioxaphthyloxy)-2-( Dimethylmethyl)benzoic acid methyl hydrazine [Chemical 472] ο 4- 4- 4-hydroxy-2-(trifluoromethyl)benzoic acid (Ap〇11 (In a methanol solution of 50 00 (50 ml), concentrated sulfuric acid (claw sputum) was added at room temperature, and then the mixture was stirred under ribs. After the reaction solution was returned to room temperature, it was concentrated. The residue was diluted with acetic acid sl/water and extracted with acetic acid. The combined extracts were washed with saturated sodium bicarbonate solution and saturated brine, and dried with sodium sulphate. Obtaining (iv) benzoic acid methyl vinegar, and supplying it to the subsequent reaction. (1...) in the above 4-dimethyl sulfonate (trimethylmethyl) benzoic acid methyl ketone solution ((10) is called ^4ml) was added to the chamber, and the trifluoromethane acid (4.46 ml) was stirred for 14 hours. After the reaction was condensed, the residue was diluted with ethyl acetate/water and treated with ethyl acetate. The extracts were washed successively with 1 N hydrochloric acid, saturated mountain &amp; anaerobic steel solution, saturated saline solution, 121199.doc -418-200846322, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue obtained was purified mjjjjjjjj !H-NMR (CDC13) δ ·· 3.97 (3H, s), 7.56 (1H, dd5 J=8.8, 2.2 Ηζ), 7·65 (1Η, d, J=2.5 Ηζ), 7·94 ( 1Η5 d, J=8.6 Hz). (2) 4-(cyclohexyl)-2-(trifluoromethyl)benzoic acid [Chemical 473]

• Μ 〇

THF in 4-(trifluoromethanesulfonyloxy)_2-(trifluoromethanesulfonyl)benzoquinone (2.00 g) and 0.5 Μcyclohexylzinc bromide (45.4 ml) under nitrogen atmosphere To the solution (80 ml), Pd(tert-Bu3p)2 (〇29 g) was added at room temperature, and after degassing, it was heated under reflux for 2 hours. After the reaction solution was returned to room temperature, a saturated sodium hydrogencarbonate solution was added, and the mixture was stirred for a long period of time and then filtered over Florite. The filtrate obtained was extracted with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue obtained was purified by silica gel flash column chromatography (Biotage 40S) to obtain methyl 4-(cyclohexyl)-3-(trifluoromethyl)benzoate and difficult to separate. a mixture of impurities. To a methanol/THF mixed solution (10/20 ml) of the above mixture was added 1 N aqueous sodium hydroxide (1 mL) at room temperature and stirred for 14 hours. The concentrated reaction solution was extracted with diethyl ether and the aqueous layer portion was separated. To the obtained aqueous layer was added 1 EtOAc / EtOAc (EtOAc). !H-NMR (DMSO-d6) δ : Ml-1.52 (6H? m)5 1.68-1.90 (5Η, m),2·66 (1Η,t,J=l〇.9 Ηζ),7·60 ( 2Η,t,J=7.8 Ηζ), 7.72 (1H,d,J=7.8 Hz) 〇MS (ESI) m/z : 273 (M+H)+. (3) 4-(cyclohexyl)·2·(trifluoromethyl)benzyl alcohol [Chemical 474]

Adding a borane dimethyl sulfide complex at room temperature in a solution of 4-(cyclohexyl)-2-(trifluoromethyl)benzoic acid (Ig 39 g) in ThF (50 ml) 1.76 ml) 'Stirring for 18 hours. The reaction solution was warmed to 9 ° C and stirred for 4 hours. After returning to room temperature, 1 〇Μ borane dimethyl sulfide complex (3.62 ml) was added and further stirred at 90 ° C for 15 hours, and the reaction solution was returned to room temperature, and then saturated sodium hydrogencarbonate solution was added. After stirring for a long time, extraction was carried out with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was evaporated, mjjjjjjj ^-NMR (CDCls) δ : 0.96-0.10 (4Η, m), 1.20-1.51 (4h5 m)&gt;1·66-1.87 (2H,m),2·56 (1H,s),4·84 ( 2H,d,Hz), 7·41 (1H,d,J=8.1 Hz), 7.48 (1H,s), 7.60 (1H,d,J=7.8

Hz). Specified by the main peak. 121199.doc -420- 200846322 MS (ESI) m/z : 259. (4) 4·(cyclohexyl)-2-(trifluoromethyl) nodal group gasification [Chem. 475]

Add sulfoxide (10 ml) to 4-(cyclohexyl)-2-(trifluoromethyl)benzyl alcohol (1·28 g), warm it to 80 ° C, stir; mix for 3 hours . The residue obtained by concentrating the reaction mixture was purified by using EtOAc, EtOAc, EtOAc (EtOAc). H-NMR (CDCI3) δ : 0,88-0,94 (4H5 m)5 1*16-1,48 (4H5 m) 1·93-1·75 (2Η,m),2.55-2.57 (1Η, m), 4·72 (2Η, s), 7·40 (1H, d5 J=7.8 Hz), 7.48 (1H, s), 7·53 (1H, d, J = 7.3 Hz). (5) 1-(Tertibutoxycarbonyl)-5·[[(4-(cyclohexyl)-2-(trifluoromethyl)phenyl)methoxy]porphyrin [Chemical 476]

In 4-(cyclohexyl)-2-(trifluoromethyl)benzyl chloride (1.34 g) and 1·(2-butoxycarbonyl)porphyrin (1.48 g) in DMF (3 〇mi) Potassium carbonate (2.68 g) was added at room temperature, and stirred at 50 ° C for 7 hours. After the reaction solution was returned to room temperature, the insoluble matter was filtered. The obtained filtrate was concentrated, and the residue obtained was purified using silica gel column chromatography (Biotage 40S) to obtain the title compound (1, 129 g). iH-NMR (CDC13) δ : 0·79-1·00 (4H, m), 1.22-1.55 (11H, m) 1.66-1.87 (4H, m), 2.55-2.57 (1H, m), 3.05 (2H , t, 7 Hz), 3·96 (2H, s), 5·17 (2H, s), 6.76·6·78 (2H, m), 7.38 (1H, d, J = 7.8 Hz), 7· 51-7·54 (1H,m), 7.62 (1H,d,

Hz), 7·71 (1H, dd, J=5.8, 3.3 Hz). MS (ESI) m/z: 476 (M+H) + 〇(6) 5-[[4-(cyclohexyl)-2-(trifluoromethyl)phenyl]methoxy] σ porphyrin salt Acid salt

Dissolving 1-(t-butoxycarbonyl)-5-[[4-(cyclohexyl)-2-(trifluoromethyl)phenyl]methoxy]porphyrin in 4 N hydrochloric acid / dioxane The solution (20 mi) was stirred for 14 hours. The reaction mixture was concentrated, and diethyl ether was added to the obtained residue, and the precipitated solid was collected by filtration. The title compound (1.2 g) was obtained. iH-NMR (DMSO-d6) δ : 1·〇6-1·47 (4H,m),1·61-1·87 (6H, m), 2.55-2.73 (1Η,m),3·16 ( 2Η,t,J=7.8 Ηζ), 3.57-3.83 (2H,m),5·17 (2H,s),6·96 (1H,dd,J=8.7,2.6 Hz), 7.12 (1H,d, J=2.5 Hz), 7·34 (1H5 d, J=8.8 Hz), 7.58 (2H, t, J=7.0 Hz), 7.65 (1H, d5 J=7.8 Hz), ΐ〇·89 (1H, s ). MS (ESI) m/z ·· 376 (M+H), (7) 3-[N-(di-dibutoxy)[2-[5-[[4-(cyclohexyl)·2-( Trifluoro 121199.doc • 422· 200846322 fluorenyl) benzyl]methoxy]° porphyrin-1-yl]-2. oxoethyl]amino]propionic acid tert-butyl ester [Chemical 478]

5-[[4-(cyclohexyl)_2_(trifluoromethyl)phenyl]methoxy]phosphonium hydrochloride (0.21 g), [Ν-(t-butoxycarbonyl) Add τεΑ (0·35 ml) at room temperature to a solution of oxycarbonylethyl)amino]acetic acid (0.15 g), EDC.HC1 (0.14 g), HOBt (0.10 g) in DMF (5 ml) The mixture was stirred for 20 hours. The residue obtained was purified by EtOAc EtOAc (EtOAc) (EtOAc) , 1.16-1.53 (20H, m), 1.66-2·08 (5H, m), 2.45-2.65 (3H, m), 3·05·3·27 (2H, m), 3.58 (2H, t , J=6.9 Hz), 3·92·4·25 (4H, m), 4·82-5·02 (1H, m), 5.17 (2H, s), 6.63-6.91 (2H, m), 7.39 (1H,d,J=7.8 Hz),7·53 (1H,t,J=6.1 Hz),7·58-7·67 (1H,m),8.22-8.03 (1H3 m) 〇(8) 3_ [N-[2-[5_[[4-(cyclohexyl)_2_(trimethyl)phenyl]methoxy]]] 朵 朵 -1 -1 -1 -1 -yl]-2-yloxyethyl]amine Propionate hydrochloride [Chem. 479] 121199.doc -423 - 200846322

[Tetra(butylbutoxycarbonylcyclohexyl)_2-(trifluoromethyl)phenyl]methoxy]0 oxopipelinyl]_2_sideoxyethyl]amino]propionic acid second butyl ester (0.22 g), 4 N hydrochloric acid /; 1,4-dioxane solution (10 ml) was added at room temperature, and after stirring for 23 hours, it was concentrated under reduced pressure. Diethyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried to give the title compound (0.16 g). ]H^NMR (DMSO-d6) δ : 1.16-1.52 (3H5 m)5 1.55-1.89 (6H5 m), 2,42-2.79 (4H,m)5 3.23-3.13 (4H,m),4.05 (2H ,t, J=8.3 Hz), 4.14 (2H, s), 5·13 (2H, s), 6.85 (1H, dd, J=8.8, 2·7 Hz), 6·98 (1H, s ), 7.57 (1H, d, J = 7.8 Hz), 7·59 (1H, s), 7·64 (1H, d, J = 7.8 Hz), 7.96 (1H5 d5 J = 8.8 Hz). IR (ATR) cnT1 : 2927, 2852, 2723, 2598, 2465, 2418, 2258, 2166, 2024, 1709, 1649. Lu MS (ESI) m/z : 505 (M+H)+. HR-MS (AqTOF) calculated for C27H32F3N204: 505.2314. Found: 505.2290 〇C27H31F3N2 (calculated for elemental analysis of VHC1: c, 59.94; Η, 5.96; C1,6·55; F,10·54; Ν,5·18. Measured value: c, 59.56; 5·92; C1,6·90; F,10.39; Ν,4.97.90; F,1〇_39; Ν, 4.97. [Example 99] 3-[2-Alkoxy-2-[5- (2-Trifluorodecylbiphenyl-4-yloxy)porphyrin-1-yl]ethylamino]propionic acid hydrochloride 121199.doc -424- 200846322 (1) 2- Methyl fluoromethoxyoxybiphenylcarboxylate [480]

To a solution of methyl 4-bromo-3-trifluoromethoxybenzoate (195 mg) in toluene (4.0 ml), phenylboronic acid (119 mg), carbonic acid (ο?(5), water, water

(2.0 ml), tetrakis(triphenylphosphine)palladium (ruthenium) (75 mg), stirred under heating and reflux for 2 hours and a half, then added tetrakis(triphenylphosphine)palladium(0) (75·4 mg). Stir under heating and reflux - night. After it was left to cool to room temperature, the reaction solution was filtered using a solution of fluorite, and a saturated sodium hydrogencarbonate solution was added to the solution, and the mixture was extracted twice with acetic acid, and the combined extracts were washed with saturated brine. Dry with anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (m.). ^-NMR (CDC13) δ: 3.96 (3 Η, s), 7.41-7.53 (6H, m), 8.01 8.04 (2H, m) 0 MS (ESI) m/z: 297 (M+H)+. (2) 2-Trifluorodecyloxybiphenyl-4-methanol [Chem. 481]

F

Ο

Adding THF solution of ester (172 mg) to 2-tris-decyloxybiphenyl-4-carboxylic acid A 121199.doc -425 - 200846322 (2〇1111), adding lithium borohydride (37.911^), heating Stir under reflux for one night. After it was left to cool to room temperature, the reaction solution was added with a solution of cardioic acid τ twice with ethyl acetate, and the combined extracts were washed with saturated brine = washed and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the residue was concentrated and purified by flash column chromatography (m.p.), and the title compound (148 mg) was obtained. H-NMR (CDC13) δ : 1·81 (1Η, t, J=5.6 Ηζ), 4.77 (2Η J=5.6 Hz), 7.35-7.47 (8H5 m) 〇MS (ESI) m/z : 251 (M -OH)+. (3) 4-Chloromethyl-2-trifluoromethoxybiphenyl [Chemical 482]

In ml), sulfite gas (189 μΐ), DMF (adding i drops with a Pasteur pipette), and stirring at 50 ° C for 1 hour and a half. After it was left to cool to room temperature, the reaction mixture was evaporated to dryness crystals crystals crystals crystals crystalssssssssssssssssss : 4.63 (2Η5 s)5 7.38-7.46 (8Η? m) 〇(4) 1-(Secondoxycarbonyl)-5-(2-trifluoromethoxybiphenyl-4-ylmethoxy)吲哚淋[化483] 121199.doc -426- 200846322

Add 4-chloromercapto-2-trifluoromethoxybiphenyl to a solution of 1-(dibutyloxycarboxy)-5-3⁄4-glycol (140 mg) in DMF (5.0 ml) (π 5 mg), potassium carbonate (87. 7 mg), and stirred at 70 ° C overnight. After it was left to cool to room temperature, a saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.

The extract was washed twice with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (m. H-NMR (CDCls) δ : 1.55 (9H5 s)? 3.07 (2H? t, J-8.7 Hz), 3.97 (2H? s)? 5.07 (2H, s)? 6.78-6.83 (2H? m), 7.35 -7.47 (8H, m), 7.76 (1H, s). (5) 5-(2-Difluoromethoxybiphenyl-4-indolyloxy)$ porphyrin hydrochloride [Chem. 484]

Add 4 Νhydrochloric acid anal dioxane-) to the third butyloxy-Wilyl)·5|trimethyl methoxybiphenyl-whenyl methoxy)' morphine (185 mg), stir for 1 hour. . The reaction mixture was concentrated under reduced pressure to give the title compound s. 121199.doc 427- 200846322 iH-NMR (DMSO-d6) δ : 3.18 (2H, t, J=7.7 Ηζ), 3·72 (3H, t, J=7.7 Hz), 5·26 (2H, s) , 7.04 (1H, dd, J = 2.5, 8.8 Hz), 7.18 (1H, d, J = 2.5 Hz), 7.36-7.57 (9H, m). MS (ESI) m/z: 386 (M+H)+. (6) 3-[N-[2-Sideoxy-2-[5-(2-trifluoromethoxybiphenyl-4-ylmethoxy)porphyrin-1·yl]ethyl] Amino] tert-butyl propionate [Chemical 485]

Add DIEA (187 μΐ), chloroethyl chloroform (44 μΐ) to a solution of 5-(4-phenoxymethylbenzyloxy) porphyrin hydrochloride (155 mg) in di-methane (10 ml) , 1 hour after the temperature. To the reaction mixture, a saturated sodium hydrogencarbonate solution was added and the mixture was extracted twice with chloroform. The combined extracts were washed with saturated aqueous ammonium chloride and brine, and dried over anhydrous sodium sulfate. Filter insolubles' After the filtrate was concentrated under reduced pressure, the obtained residue was dissolved in acetonitrile (20 ml), DIEA (624 μM), β-alanine tributyl ester hydrochloride (200 mg) was added at 70° Stir overnight at C. After it was left to cool to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (yield: K46 (9H, s), 2.47 (2H} t) J=6 7 Hz)j 2.93 (2H, t, J=6.7 Hz), 3.20 (2H, t, J=8.3 Hz), 3.50 (2H, s) , 4.02 (2H, t, J=8.3 Hz), 5.08 (2H, s), 6.81-6.85 (2H, m), 121199.doc 200846322 7·38-7·48 (8H,m), 8.17 (1H, d, J = 8.6 Hz) MS (ESI) m/z : 571 (M+H) + (7) 3-[N-[2-Sideoxy-2-[5-(2-trifluoromethyl) Oxyphenylbiphenyl-4-ylmethylindenyl) porphyrin-1 -yl]ethyl]amino]propionic acid hydrochloride [Chem. 486]

3-[N-[2-Sideoxy-2-[5-(2-Trifluorodecyloxybiphenylyloxycarbonyloxycarbonyl)-]ethyl]amino]propyl To the third ester of acid (120 mg), 4 N hydrochloric acid / 1,4-dioxane (1 ml) was stirred overnight. The reaction mixture was concentrated under reduced pressure. (69 mg). !H-NMR (DMSO-d6) δ : 2.74-2.78 (2Η, m)? 3.17-3.22 (4H, m), 4.05-4.14 (4H, m), 5·20 (2H, s ),6·91 (1H,dd,J=2.6, _ 8.7 Hz), 7·04 (1H,d,J=2.6 Hz), 7·41-7·56 (8H,m), 7.98 (1H, D5 J = 8.7 Hz) IR (ATR) cnT1 : 2715, 1643, 1490, 1249, 1211, 1145. MS (ESI) m/z : 515 (M+H)+ C27H26F3N205 (M+H)·HR -MS (FAB) calcd.: 515.1794. Found: 515.1832. Calculated for C.sub.2H.sub.2H.sub.2. Found: C, 5 8.16; H, 121199.doc -429- 200846322 4.69; Cl,6·51; F,10.34; Ν,5·02. [Example 100] 3-[N-[2-[ 5-(5-Cyano-1-phenyl_ιΗ-π-pyrazole_3_ylmethoxy fluorene-based small base]-2-oxoethylethylamine ] Propanoic acid hydrochloride (1) 5-hydroxy-2-phenyl -2Η- Yue-yl-pyrazol-3-benzo [487]

The raw materials were synthesized in accordance with the literature (Heterocycles, Vol. 27, No. 12, 2857-2862, 1988.). Add a hydrogen butterfly clock (271 mg) to a solution of ethyl 5-cyano-1-phenylpyrazole-3-carboxylate (1·〇〇g) in THF (40 ml), and stir with stirring under reflux. 40 minutes. After it was left to cool to room temperature, a saturated sodium hydrogencarbonate solution was added to the mixture, and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After the filtrate was concentrated under reduced pressure, the residue obtained was purified by flash column chromatography (yield: 2L). H-NMR (CDC13) δ : 2.09 (1H, t, J = 6.0 Ηζ), 4·80 (2H, d, J = 6.0 Hz), 7·03 (1H, s), 7:44-7.55 (3H ,m),7·67-7·70 (2H, m) 〇MS (ESI) m/z : 200 (M+H)+ 〇(2) Di-butoxy-yl)-5-(5 - Gas-based-1-phenyl-1H -11 is more than 唆-3-ylmethoxy) 丨 °多琳[化488] 121199.doc -430 . 200846322

Add 5-hydroxymethyl-2-phenyl-2H-pyrazole-3- to a solution of 1-(t-butoxycarbonyl) 5 hydroxy porphyrin (235 mg) in THF (5.0 ml) Formaldehyde (299 mg), triphenylphosphine (393), DEAD (2.2 Μ toluene solution) (682 μΐ), and disturbed overnight at room temperature. The reaction solution was concentrated under reduced pressure for rapid column chromatography. The residue obtained was purified by EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 97 (2H, s), 5·14 (2H, s), 6·78_6·82 (2H, m), 7 i〇(1H, s), 7.45-7.56 (3H, m), 7·69_7·76 (3H,m) MS (ESI) m/z: 417 (M+H) + (3) 5-(5-Cyano-1-phenyl_111_»biazole_3_yloxy) P-porphyrin hydrochloride [化489]

X^n household

Adding 4 N hydrochloric acid n to M methoxybutanyl-5-(5-cyano-indole-phenyl-1H-n than sal-3-yl methoxy) porphyrin (275 mg), 4• Dioxane (5 〇 〇 i 。 。 。 。 。 。 。 i i i i 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压 减压D6) one • '丄ι3 卜 7·7 Hz), 5.23 (2H, s), 7.04 (1H, dd, J=2 5, 8 7 Hz), 7 i8 121199.doc -431 - 200846322 (1H,d , J=2.5 Hz), 7.36 (1H, d, J=8.7 Ηζ), 7·55-7·66 (4H, m), 7.73-7.76 (2H, m) o MS (ESI) m/z : 317 (M+H)+. (4) 3-[N-(Tertidinoxycarbonyl)-N-[2-[5-(5-cyano-l-phenyl-1H-port 嗤-3 _ylmethoxy) fluorene Porphyrin·ΐ-yl]·2-sided oxyethyl]amino]propionic acid third

In a solution of 5-(5-cyano-1-phenyl-1Η-pyrazol-3-ylmethoxy)porphyrin (225 mg) in DMF (1 〇mi), 3_[N-( Tributyloxycarbonyl (carboxyindenyl)amino]propionic acid tert-butyl ester (2〇3 mg), DIEA (542 μ1), HOBt (l〇3 mg), ED〇HC1 (148 mg), in room Stir in the night. Add saturated sodium bicarbonate solution to the reaction solution and extract with ethyl acetate 2

The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (m. H-NMR (CDC13) δ : 1.40-1.49 (18H, m), 2.55-2.62 (2H, m), 3.16-3.22 (2H, m), 3.56-3.61 (2H, m), 3.99-4.17 (4H, m), 5.14 (2H, s), 6.79-6.84 (2H, m), 7.09 (1H, s), 7.45-7.55 (3H, m), 7.70 (2H, d, 7.6 Hz), 8 u_8 15 ( 1H, m). 121199.doc -432 - 200846322 MS (ESI) m/z : 602 (M+H)+. (5) 3_[N-[2-[5-(5-Cyano-indole·phenyl_1h_dbiazole-3-yloxy) ortho-indolyl-1-yl]-2-yloxy Ethyl]amino]propionic acid hydrochloride [Chem. 491]

Spring in 3-[Ν-(t-butoxycarbonylcyano-1βphenylpyrazole-3*•ylmethoxy)porphyrin-indole-yloxyethyl]amino]propanoic acid To dibutyl ester (330 mg), 4 Ν hydrochloric acid / 1,4-dioxin (1 〇mi) was added and stirred overnight. The reaction mixture was concentrated under reduced vacuo. b-NMR (DMSO-d6) δ : 2·76-2·80 (2H, m), 3.17-3.21 (4H, m), 4.06-4.14 (4H, m), 5·17 (2H, s), 6.92 (1H, dd, J = 2.6, 8.9 Hz), 7.05 (1H, s), 7.55-7.75 (6H, m), 7.98 (1H, d, J = 8.6 φ Hz). IR (ATR) cm·1 : 2566, 2235, 1725, 1664, 1488, 1373. MS (ESI) m/z: 446 (M+H)+. HR-MS (FAB) calculated value of C24H24N504 (M+H)+ · 446.1828. Measured value · 446.1830 ° C24H23N5O4.1.0 HCl Elemental analysis calculated: C, 59·81; H, 5·02; Cl, 7.36; Ν, 14.53. Found: C, 59.63; Η, 4·94; Cl, 7·26; Ν, 14.54 ° 433 - 121199.doc 200846322 methylbiphenyl-4-yl-methyl [Example 101] 3-[N-[2 -Phenoxy-2-[5-(3-trioxyxylin-1-yl)ethyl]amino]propionic acid hydrochloride (1) 4-Shozoyl-2-tris-decylbenzoic acid酉 [ [化492]

〇

In a solution of 4-nitro-2-trifluoromethylbenzoic acid (1. 〇〇g) in methanol (4 〇 _ _, adding sulfoxide gas (599 μl), after heating and refluxing, stirring overnight Add sulfite chloride (898 μM), and stir for 5 hours under reflux with heating. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure. After the extraction was performed twice, the combined extracts were washed with brine, and dried over anhydrous sodium sulfate. : 4.00 (3Η5 s), 7.98 (1H5 d5 J=8.3 Hz), 8.47 (1H, dd, J-2.2, 8·3 Hz), 8.61 (1H, d, J=2.2 Hz). ® MS ( ESI) m/z : unidentified molecular ion peak. (2) Methyl 4-amino-2-trifluorodecylbenzoate (w〇2〇〇6/〇767〇6) [化493]

Add 50/〇Pd/C (aqueous) (4〇〇mg) to a solution of methyl 4-nitro-2-trifluoromethylbenzoate (82〇mg) in methanol (3〇ml), Under a hydrogen atmosphere, the mixture was stirred at room temperature for 21 hours at 121199.doc -434 200846322. The reaction mixture was filtered, and the filtrate was evaporated to dryness crystals crystals 'H-NMR (CDC13) δ : 3.87 (3H? s)5 4.18 (2H, s), 6.76 (1H? dd, J=2,3,8·5 Hz), 6.98 (1H,d,J=2.3 Hz), 7·76 (1H, d, J = 8.5 Hz) 〇MS (ESI) m/z : 220 (M+H)+. (3) Methyl 4-bromo-2·trifluoromethylbenzoate [Chem. 494]

Add copper (II) bromide (402 mg) and nitrite to the third solution of 4-amino-2-trifluoromethylbenzoic acid (328). (267 μΐ)' was stirred under heating and reflux for 1 hour and a half. Let it cool down to room temperature

After that, a saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. After the filtrate was concentrated under reduced pressure, the residue was purified by flash column chromatography (m.p.). !H-NMR (CDCI3) δ : (1Η,d,J=1.5 Hz) 〇3.94 (3H,m), 7.68-7.77 (2H,m),7·90 MS (ESI) m/z : 283 (M +H)+〇(4) 3·trifluoromethylbiphenyl-4-carboxylic acid A_121199.doc -435 - 200846322 [化495]

ο In the solution of methyl 4-bromo-2-trifluoromethylbenzoate (3 50 mg) (8. 〇ml), add phenylboric acid (302), carbonic acid planer (2·〇1) g), water (4 〇 ml), tetrakis(di-propylphosphine)|bar (〇) (143 mg), stirred under reflux with heating overnight. After it was left to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentrating under reduced pressure, the obtained residue was purified by flash column chromatography elution elution elution elution elution elution elution elution elution elution -7.63 (5H?m), 7.8〇. 7·96 (3H,m) 〇MS (ESI) m/z : Unidentified molecular ion peak. (5) 3_Trifluoromethylbiphenyl·4_sterol _ [Chem. 496]

Lithium borohydride (75·8 mg) was added to a solution of 2-difluoromethoxybiphenyl-4-methyl decanoate (325 mg) in THF (2 mmol). After it was left to cool to room temperature, 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with saturated brine, 121199.doc -436 · 200846322, and then dried over anhydrous sodium sulfate After drying, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure.

H-NMR (CDC13) δ : 1.90 (1H, s)5 4.93 (2H, s), 7.37-7 49 (3H, m), 7.58-7.61 (2H, m), 7.79 (2H, m), 7·86 (1H, s). MS (ESI) m/z : 235 (M-OH) + 〇(6) 5-(3-difluoroindenylbiphenyl_4_ylmethoxy) σ porphyrin decanoic acid tert-butyl ester 497]

Add 3-trifluorodecylbiphenyl_'methanol (275 mg), triphenylphosphine (429 mg) to 5-hydroxypyroline·1_carboxylic acid tert-butyl ester (385 mg) in 1 ml of THF , DEAD (2.2 Torr in toluene) (743 μl), stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the residue was purified to purified crystals eluted

^-NMR (CDC13) δ : 1.55 (9H) s), 3.07 (2H5 t5 J=8.7 Hz), 3·97 (2H, s), 5·07 (2H, s), 6.78-6.83 (2H, m ), 7.35-7.47 (8H, m), 7.76 (1H, s) 〇MS (ESI) m/z : 469 M+. (7) 5-(3-Bis-indolylbiphenyl-4-yloxy) sigma I beeline hydrochloride [Chem. 498] 121199.doc -437- 200846322

Add 4 N hydrochloric acid n,4_dioxane to 5-(3-trifluoromethylbiphenyl-methionylmethoxy)bendronic acid formic acid tert-butyl ester (400 mg) (1 〇 stirring 2 After the reaction mixture was concentrated under reduced pressure, EtOAcjjjjjjjjjjjjjjjjjjjjj 7.8 Ηζ) 5 3·72 (2H, t5

J=7.8 Hz)? 5.30 (2H? s), 7.02 (1H5 dd? J=2.5? 8.6 Hz), 7.17 (1H,d,J=2.5 Hz),7·36-7·54 (4H,m) , 7.75-7.86 (3H, m), 8.01-8.04 (2H, m) 〇MS (ESI) m/z : 370 (M+H)+. (8) 3-[Ν·(Dibutyloxycarboxy)·ν_[2-Sideoxy-2-[5-(3-trifluoromethylbiphenyl-4-ylmethoxy)porphyrin _1_yl]ethyl]amino]propionic acid tert-butyl ester [Chemical 499]

Add 3-[(N-tert-butoxy) to a solution of 5-(3-trifluorodecylbiphenyl-4-ylmethoxy), hydrazine hydrochloride (353 mg) in DMF (10 ml) Carbonyl)-N-(carboxymethyl)amino]propionic acid tert-butyl ester (317 mg), DIEA (740 μΐ), HOBt (141 mg), and EDOHC1 (200 mg) were stirred overnight at room temperature. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate 121199.doc. The residue was purified by flash column chromatography (Shanshan high-speed column L), and then purified by flash column chromatography (2 mL of Shanshan high-speed column) to obtain the title. Compound (42〇mg) 〇!Η-ΝΜΚ (CDC13) δ : 1.40-1.50 (18Η5 m)5 2.55^2.63 (2Η? m), 3.16-3.23 (2Η,m)5 3.56-3.61 (2Η,m) ,3·99-4·18 (4Η, m), 5.27 (2H, s), 6·78-6·84 (2H, m), 7·38-7·52 (3H, m), 7'59_7 .61(2H,m), 7.75-7.81(2H,m), 7.90 (lH,s), 8.11 - 8.1 6 (1H,m) 〇MS (ESI) m/z: 655 (M+H)+. (9) 3-[N-[2-Sideoxy-2-[5-(3·trifluoromethylbiphenylmethoxy)indole-1-yl]ethyl]amino]propyl Acidate [Chemical 500]

3-[Ν-(Third butoxycarbonyl wide ν_[2-Sideoxy-2-[5-(3-trifluoromethylbiphenyl-4-yl fluorenyloxy) porphyrin J-based Adding 4 ν hydrochloric acid / 1,4-dioxane (10 ml) to a solution of tert-butyl propionate (410 mg), and stirring at room temperature overnight. Add diethyl ether to the reaction mixture. The precipitated solid was filtered and dried to give the title compound (3 14 mg). NMR (DMSO-d6) δ: 2.78 (2 Η, t5 J = 7.5 Hz), 3.20 (4H, t5 J = 7.6 Hz ), 4.06-4.15 (4H, m), 5.25 (2H, s), 6.90 (1H, dd, 121199.doc -439- 200846322 J=2.7, 8.8 Hz), 7.03 (1H, d, J=2.7 Ηζ) ,7·43-7·54 (3H,m), 7.75-7.86 (3H,m),7.99-8.02 (3H,m) 〇IR (ATR) cm·1 : 2632,1702,1654,1494,1164, </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Calculated for elemental analysis: C, 60, 02; H, ^ 4·90; Cl·, 6, 63; F, 10·65; N, 5·24. Measured: C, 60.39; Η, 4.92; Cl , 6.70; F, 10.66; N, 4.94. [Example 102] 3-[N-[2-Sideoxy-2-[5-(4- Butyl-2-trifluoromethylbenzyloxy)porphyrin·1-yl]ethyl]amino]propionic acid hydrochloride (1) 4-isobutyl-2-trifluoromethylbenzoic acid Ester [Chem. 501]

Add isobutylboric acid (4〇7 mg), carbonic acid planer (217 g), water to a solution of methyl 4-bromo-2-trifluorodecylbenzoate (377 mg) in benzene (8 〇ml) (4 〇 ml), tetrakis(di-propylphosphine), saturated (q) (154 mg), and stirred overnight under reflux. After it was left to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (yield: s.). 'H^NMR (CDC13) δ : 0.91 (6H5 d5 J=6.6 Hz), 1.85-1.96 (1H5 m), 2·57 (2H, d, J=7.1 Hz), 3.93 (3H, s), 7· 37 (1H, d, J=7 Hz), 7.51 (1H, s), 7.72 (1H, d, J = 7.8 Hz). (2) (4-Isobutyl-2-trifluoromethylphenyl)methanol [Chemical 502]

Add a hydrogen gasification clock (8 〇·3 mg) to a solution of 4-isobutyl-2-trimercaptobenzoic acid oxime ester (32 〇mg) in thf (20 ml), and stir overnight under reflux with heating. . After the mixture was cooled to room temperature, hydrazine N hydrochloric acid was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure, and then the residue was purified by flash column chromatography (m.). ^-NMR (CDCI3) δ : 0.91 (6Η, d, J=6.6 Hz), 1.80-1.93 (2H, m), 2.52 (2H, d, J=7.1 Hz), 4.84 (2H, d, J=6.1 Hz), 7.33-7·36 (2H, m), 7·59 (1H, d, J = 7.8 Hz). MS (ESI) m/z: 215 (M-〇H) + 〇(3) 5 (4-isobutyl-2-difluoromethylbenzyloxy) σ porphyrin _ 丨 carboxylic acid tert-butyl ester [Chem. 503] 121199.doc -441 - 200846322

Add (4-isobutyl-2-trifluoromethylphenyl)methanol (2 45) to a solution of 3-hydroxyporphyrin-1-decanoic acid tert-butyl ester (372 mg) in THF (395 ml) Mg), triphenylphosphine (415 mg), DEAD (2,2 Torr in toluene) (719 μΐ), stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure,yield, m. H-NMR (CDC13) δ : 0·91 (6H, d, J = 6.6 Hz), 1.55 (9H, s), 1.83-1.93 (1H, m), 2.52 (2H, d, J = 7.4 Hz), 3.06 (2H,.t, J = 8.6 Hz), 3.96 (2H, s), 5·18 (2H, s), 6.75-6.80 (2H, m), 7·32 (1H, d, J = 7.8 Hz) ), 7·45 (1H, s), 7.61-7.75 (2H, m). MS (ESI) m/z: 449 M+. (4) 5-(4-Isobutyl-2-trifluoromethylbenzyloxy) porphyrin hydrochloride [Chem. 504]

Addition of 4 hydrazine hydrochloride / Μ 哼 dioxane to HCI in 5-(4-isobutyl-2-difluoromethylbenzyloxy) σ 哚 丨 丨 甲酸 甲酸 甲酸 carboxylic acid tert-butyl ester (290 mg) 1 〇 ml) was stirred for 2 hours. The reaction mixture was concentrated under reduced vacuo. i-NMR (DMSO_d6) δ : 0.87 (6H,d,J=6 6 is called, ^ 92 121199.doc -442- 200846322 (1H,m), 2.56 (2H,d,J=7.1 Hz), 3.18 (2H , t, J = 7.7 Hz), 3·71 (2H, t, J = 7.7 Hz), 5.20 (2H, s), 6·99 (1H, dd, J = 2.6, 8.7 Hz), 7.13 (1H, d, J = 2.6 Hz), 7.36 (1H, d, J = 8.7 Hz), 7.52 (1H, d, J = 7.8 Hz), 7.58 (1H, s), 7.66 (1H, d, J = 8.1 Hz) 〇MS (ESI) m/z : 350 (M+H)+ (5) 3-[N-(T-butoxycarbonyl)-N-[2- oxo- 2_[5-(4- Isobutyl-2-trifluoromethylbenzyloxy)porphyrin-1-yl]ethyl]amino]propionic acid tert-butyl ester [Chem. 505] Boc 0 I ο | on 5- (4-iso) Butyl-2-trifluoromethylbenzyloxy) hydrazine hydrochloride (240 1 ^) 0 汹 [solution (1〇1111) added 3-[&gt; 1-(t-butoxycarbonyl) )_;^-(sodium sulfhydryl)amino]propionic acid tert-butyl ester (226 mg), DIE A (5 29 μΐ), HOBt (l〇l mg), EDOHCl (143 mg) at room temperature Stirring was carried out overnight. A saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After the solution was concentrated under reduced pressure, the residue obtained was purified by flash column chromatography (Shanshan high-speed column L), and then purified by flash column chromatography (2 mL of Shanshan high-speed column) to obtain the title. Compound (375 mg) 〇^-NMR (CDC13) δ : 0.91 (6H? d3 J==6.6 Hz)) 1.40-1.49 (18H,m),1·83-1·93 (1H,m),2.52- 2.63 (4H,m),3·16_3 22

HCI

Boc ten ml o 1

121199.doc -443 - 200846322 (2H,m),3.56-3.61 (2H,m),3.99-4.17 (4H5 m),5·19 (2H, s),6.76-6.82 (2H,m),7.32- 7.62 (3H,m),8·09·8·14 (1H, m) 〇MS (ESI) m/z : 635 (M+H)+. (6) 3-[N-[2-Sideoxy_2_[5_(4-isobutyl-2-trifluoromethylbenzyloxy)-ethyl-1-yl]ethyl]amino]propyl Acidate [Chem. 506]

F

3-[N-(Tertibutoxycarbonyloxy-2-[5-(4-isobutyl-2-trifluoromethylbenzyloxy)indol-1-yl]ethyl] 4N hydrochloric acid / 1,4-dioxane (1 〇 ml) was added to the aminobutyl]tert-butyl propionate (3 75 mg), and stirred overnight. Diethyl ether was added to the reaction mixture, and the precipitated solid was collected by filtration. It was dried to give the title compound ( 267 mg). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 7.4 Hz), 2·79 (2H, t, J = 7.4 Hz), 3.17-3.22 (4H, m), 4.06-4.15 (4H, m), 5.16 (2H, s), 6.86 (1H, dd, J =2.3, 8.7 Hz), 7.00 (1H, J=2.3 Hz), 7.50-7.67 (3H, m), 7·98 (1H, d, J=8.6 Hz) IR (ATR) em·1 : 2867, </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 121199.doc -444 - 200846322 [Example 103] 3-[Ν-[2-[5-(1-isobutyl-3-trifluoromethyl-1H-indazole-4·ylmethoxy) is called Porphyrin-1-yl]-2-oxoethyl]amino]propionic acid TFA salt (1) 1-isobutyl-3-trifluoromethyl-1Η-pyrazole-4·carboxylate [ 507]

To a solution of 3-difluoroindolyl 1 Η σ ϋ ϋ 曱 曱 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 624 After that, iodine isobutane (5 1 8 μΐ) was added, and the mixture was stirred overnight at the same temperature. After being allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with acetic acid for 3 times. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Colorless oil. W-NMR (CDC13) δ ·· 〇·94 (6H,d,J = 6.6 Ηζ), ι·35 (3H t J=7.1 Hz), 2·20-2·30 (1H, m),3·95 (2H,d,J=7.i hz) 4 32 (2H,q,J = 7.1 Hz), 7.94 (1H, s) MS (ESI) m/z : 265 (M+ H) + (2) 1-isobutyl-3-trifluoromethyl-1 to ～ ratio. sit-4-methanol [化508]

F

121199.doc -445 - 200846322 Add lithium hydride to a solution of 1-isobutyl-3-trifluoromethyl.·1Η-pyrazole-4-carboxylic acid ethyl ester (600 mg) in THF (15 11^) 103 mg), stirred under heating and reflux for 20 minutes. After standing to cool to room temperature, it was ice-cooled, and water (105 μΐ), 1 N aqueous sodium hydroxide solution (105 μl), and water (3 1 5 μΐ) were sequentially added to the reaction solution. dry. The insoluble material was filtered, and the filtrate was evaporated. H-NMR (CDC13) δ : 0.92 (6H, d, J = 6.6 Ηζ), 1.73 (1H, t, J = 5.9 Hz), 2·17·2·27 (1H, m), 3.92 (2H,d,J=7:l Hz), 4.68 (2H,d,J=5,9 Hz), 7.45 (1H, s). MS (ESI) m/z: 223 (M+H)+. (3) 5-(1-Isobutyl-3-trifluoromethyl-ih-u than 嗤_4·ylmethoxy) 吲哚 _ 1 -carboxylic acid tert-butyl ester [Chem. 509]

Add 1 -isobutyltrifluoromethyl _ 吼 _ 曱 曱 曱 ( 〇 〇 〇 〇 〇 5 5 5 5 5 5 5 5 〇 〇 〇 〇 〇 〇 〇 〇 〇 ( 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 ), diphenylphosphine (868 mg), DEAD (2.2 Μ toluene solution) (150 ml) 'stirred at room temperature overnight. A saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (yield: 2), and the title compound (564 mg) was obtained. 121199.doc -446- 200846322 ^-NMR (CDC13) δ ·· 0·92 (6H,d,J=6.6 Hz), 1.55 (9H,s), 2.16-2.27 (1H,m),3.05 (2H, t, J=8,6 Hz), 3.91-3.97 (4H, m), 4·99 (2H, s), 6.73-6.77 (2H, m), 7·46 (1H, s), 7·75 ( 1H, s) ° MS (ESI) m/z: 440 (M+H)+. (4) 5-(1-Isobutyl-3-trifluoromethyl-sodium-4-ylmethoxy)xibendolin [Chem. 510]

Add 4 N hydrochloric acid to 5-(1-isobutyl-3-trifluoromethyl-1H-pyrazol-4-ylmethoxy) phthalocyanine 1-butylic acid tert-butyl ester (555 mg) 1,4-Dioxane (15 ml) was stirred at room temperature for 1 hour and a half. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. The insoluble material was filtered. The filtrate was concentrated under reduced pressure, and the residue obtained was purified by flash column chromatography (yield). ^-NMR (CDC13) δ : 0.91 (6Η5 d5 J=6.6 Hz)? 2.16-2.26 (1H? m)? 3.00 (2H5 t? J=8.3 Hz)5 3.54 (2H) t5 J=8.3 Hz)? 3.91 (2H5 d5 J=7.4 Hz), 4.95 (2H5 s)? 6.56-6.65 (2H? m), 6.79-6.80 (1H, m), 7.46 (1H, s). MS (ESI) m/z: 339 M+ 〇(5) 3-[N-(2 -butoxycarbonyl)isobutyl_3_trifluoromethyl-121199.doc -447- 200846322 lH-u -4-ylmethoxy)porphyrin-1-yl]-2-oxoethyl]amino]propionic acid tert-butyl ester [Chem. 511]

Add 5-(1.isobutyl-3-trifluoromethyl-1H-σ-pyridin-4-ylmethoxy) σ τ ι ι 朵 (170 mg) in DMF solution (10 ml), add 3-[Ν-(Tertilybutoxy)-indenyl-(weilkinyl)amino]propionic acid tert-butyl (182 mg), DIE A (25 5 μΐ), HOBt (81.1 mg) ), EDOHCl (115 mg), was stirred overnight at room temperature. A saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by flash column chromatography (m. φ ]H-NMR (CDCls) δ : 0.91 (6H5 d5 J=6.6 Hz)? 1.40-1.50 (18H, m), 2·18-2·25 (1H, m), 2·55-2·63 ( 2H,m),3.15-3.22 (2H,m),3.56-3.61 (2H,m),3.91-4.18 (6H,m),5·00 (2H, s),6.74-6.80 (2H,m), 7.46-7.48 (1H, m), 8.10-8.15 (1H, m) 0 MS (ESI) m/z: 625 (M+H)+. (6) 3-[N-[2-[5-(l-isobutyl-3-trimermethyl-1Η_σ than 嗤4-ylmethoxy)]|蜂琳-l-基]-2 -Side oxyethyl]amino]propionic acid TFA salt [Chem. 512] 121199.doc •448 - 200846322

F

[N (Dibutyloxy.yl)-N-[2-[5-(l-isobutyl_3_trismethyl-1H-pyrazole-4-ylmethoxy) porphyrin To a solution of the cis-ethyl hydroxyethyl]amino]propionic acid tert-butyl ester (270 mg) in dichloromethane (10 ml), hydrazine (5·0 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced vacuo. 'H-NMR (DMSO-d6) δ : 0.84 (6Η, d5 J=6.6 Hz)? 2.05-2.16 (1H,m), 2.73 (2H, t5 J = 7.4 Hz), 3.16-3.23 (4H,m) ,3·99, 4·15 (6H,m),4·98 (2H,s), 6.85 (1H,dd,J=2.5,8.8 Hz), 6.97 (1H,d,J=2.5 Hz),7.96 (1H, d, J = 8.8 Hz), 8·09 (1H, s), 8.98 (1H, s) 〇MS (ESI) m/z : 469 (M+H)+. [Example 104] 2-[N-[3-Sideoxy·3-[5-[(4-Phenyltrifluoromethyl-2, fluorenyl)methoxy]] 1 porphyrin-yl] Propyl]amino]acetic acid (1) 1-[3-(&gt;1-tert-butoxycarbonylamino)propanyl]-5-[(4-phenyl-5-trifluoromethyl- 2-thienyl)methoxy]. Porphyrin (Chemical 513)

Add diEA (316 μl) at room temperature in a solution of 3-(N-tert-butoxylamlyl)propionic acid (114 mg) 1 DMF (5·0 121199.doc -449 - 200846322 ml) H〇]Bt (1〇5 mg) and EDC.HC1 (149 mg). After stirring for 1 minute, 5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]porphyrin hydrochloride (47 mg) was added at room temperature. After stirring for 14 hours, the reaction mixture was concentrated under reduced pressure. ethyl acetate (1················ The combined organic layers were evaporated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc) H-NMR (CDC13) δ : 1.43 (9H, s), 2.61 (2H, t, ==5·4 Hz), 3.18 (2H5 t5 J=8.4 Hz)? 3.51 (2H5 dt, J=5.45 5.4 Hz)5 4.03 (2H,t,J = 8.4 Hz), 5·20 (2H, s), 6.82 (1H, dd, J=8.5, 2.4 Hz), 6.84 (1H, br s), 7.06 (1H , s), 7·42·7·39 (5H, m)5 8.15 (1H, d5 J=8.5 Hz). MS (ESI) m/z: 547 (M+H) + 〇(2) 1-(3-aminopropenyl)-5-[(4-phenyl-trifluoromethyl-2- thiophenyl) Oxy] porphyrin hydrochloride [化514]

In the presence of 1-[3-(indolyl-tert-butoxycarbonylamino)propanyl]-5-[(4-phenyloxy-trifluoromethyl-2-thienyl)methoxy]0 porphyrin ( 324 melons in dioxane (〇·5 ml) solution, add 4 Ν hydrochloric acid n, 4_m solution (2〇121199.doc -450. 200846322 ml) at room temperature. After stirring for 13 hours, under reduced pressure The reaction mixture was concentrated, EtOAc mjjjjjjjjjjjjj H) + (3) 2_[Ν·[3-Sideoxy-3·[5-[(4-Phenyl-5-trifluoromethyl-2-nonyl)methoxy], porphyrin -1·yl]propyl]amino]ethyl acetate [Chemical 5 15]

To the 1-(3-aminopropionyl)-5-[(4-phenyl-5-trifluoromethyl-2-thienyl) decyloxy]°-dolinic hydrochloride (203 mg) In a suspension of acetonitrile (3.5 ml), bromoacetic acid (68.4 μM) and DIEA (293 μM) were added at room temperature. After stirring at 80 ° C for 7 hours, the reaction liquid was concentrated under reduced pressure, and a mixture of 2% methanol/chloroform (5·0 ml) and saturated aqueous sodium hydrogencarbonate (5.0^1) was added to carry out a liquid solution. Extraction was carried out with a 20% methanol/gas mixture (3 x 5.0 ml). The extracts were combined and the solvent was concentrated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc) W-NMR (CDC13) δ : 1.47 (9H, s), 2·63 (2H, t, J = 6.3 Hz), 3.00 (2H, t, 6.3 Hz), 3·18 (2H, t, J= 8.4 Hz), 3·35 (2H, s), 4·06 (2H, t, J=8.4 Hz), 5.19 (2H, s), 6·80 (1H, dd, J=8, 8, 2.2 Hz ), 6.83 (1H, br s), 7.06 (1H, s) 5 7·38-7·43 (5H, m), 8.17 (1H, d, J = 8.8 Hz). 121199.doc -451 - 200846322 MS (ESI) m/z : 561 (M+H)+. (4) 2-[N-[3-Sideoxy-3-[5-[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy]porphyrin-1-yl] Propyl]amino]acetic acid [Chem. 516]

2-[N-[3-Sideoxy-3_[5-[(4-phenyltrifluoromethylthienyl)]oxy]indole porphyrin-1-yl]propyl]amino]acetic acid A solution of ethyl ester (129 mg) in 1,4-dioxane (1.0 ml) was added 4 N hydrochloric acid / 1,4-dioxane (2.0 ml) at room temperature. After stirring for π hours, the reaction mixture was concentrated under reduced pressure and ethyl acetate (5··················· Mg> H-NMR (DMSO-d6) δ : 2.86-2.92 (2H? br m)3 3.16 (2H5 t5 J-8·3 Hz), 3.26 (2H, t, J=6.8 Hz), 3.92 (2H, s), 4·06 (2H, t, J = 8.3 Hz), 5.35 (2H, S), 6·87 (1H, dd, J=8_8, 2·2 Hz), 7·01 (1H5) d? J=2.2 Hz)? 7.36 (1H, s)5 7.50-7.41 (5H? m)5 7.99 (1H,d,J = 8.8 Hz) 〇MS (ESI) m/z : 505 (M+H) +. Calculated for the elemental analysis of CMANAS + ohu: c, 55 5〇; &4.47;C1,6·55;F,1〇·54;N,5.18; s,5 93. Measured value: c, 55.53 ; H, 4.23; C1, 6.35; F, 10.31; N, 5.22; S, 5.98 〇 [Example H &gt; 5] 3-[N_[2_sideoxy is phenyl _5_(trimethyl) _ W phenyl] methoxy] 2 '3 · dihydro _ 4 Η _ _ _ 幷 幷 秦 _ _ 121 121 199 199 199 199 199 199 199 199 199 199 121 199 199 199 199 199 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 -(Benzyloxy)phenol Reference: Eur. J. Med. Chem. 37(2〇〇2)461468 [Chem. 517]

Add 6-(benzyloxy)-l,3-benzoxazole-2(311)-one (commercially available) (5 〇〇 曱 曱 曱 ( (70 ml) solution, add sodium hydroxide at room temperature (12·4 g) Aqueous solution (Chuanml) 'Heat and reflux for 24 hours. After allowing to cool to room temperature, 6 N hydrochloric acid (60 ml) was added to the reaction mixture to make it acidic and filtered. After adding a saturated aqueous solution of sodium hydrogencarbonate to make it alkaline, the resulting solid was taken and washed with water' and dried (vacuum line, room temperature, 10 hours). The obtained solid was ethyl acetate-hexane. The alkane was reprecipitated to give the title compound (3.00 g). H-NMR (DMSO-d^) δ ·· 4.10 (2H, br s), 4.90 (2H s) 6.24 (1H, dd, J=8.4, 2·8 Hz),6·36 (1H,d,J=2.8 Hz), 6.48 (1H, d, J=8.4 Hz), 7.37-7.41 (5Ή, m), 9.00 (1H, br s). MS ( ESI) m/z : 216 (M+H) + (2) 4·(benzyloxy)-2-hydroxyphenylcarbamic acid tert-butyl ester Reference: Tetrahedron 56 (2000) 605_614 [Chem. 5 18 ] 121199.doc •453 - 200846322

OH

To a solution of 2-amino-5-(benzyloxy)phenol (3·〇〇g) in THF (30 ml), EtOAc (3······· . The reaction mixture was concentrated under reduced pressure. EtOAc m. W-NMR (CDC13) δ : 1·53 (9H, s), 5.03 (2H, s), 6.45 (1H, br s), 6.50 (1H, dd, J = 8.8, 2·8 Hz), 6·65 (1H,d,J=2,8 Hz), 6.83 (1H,d,J=8.8 Hz), 7.29-7.45 (5H,m), 8.43 (1H,br s). MS (ESI) m/z: 316 (M+H)+. (3) 7-(Benzyloxy)-2,3-dihydro-4H-1,4-benzoxazine_4_carboxylic acid tert-butyl ester References·· Tetrahedron 56 (2000) 605_614 [Chem. 519]

In a solution of 4-(benzyloxy)-2-hydroxyphenylaminocarbamic acid tert-butyl ester (1·5 〇g) in acetone (100 ml), dimethane was added at room temperature (3 28 And potassium pyroate (13. 2 g), heating under reflux for 16 hours at room temperature. The reaction solution was placed in a cold portion to room temperature and then concentrated under reduced pressure to allow rapid gel column chromatography (Biotage) The residue obtained was purified to give the title compound (1. <RTI ID=0.0></RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; , 4,24 (2H,t,J=4,4 Hz), 5.02 (2H, s),6·51 (1H,d,J=2.9 Hz), 6.55 (1H,dd,J=9.0, 2.9 Hz ), 7.29-7.45 (5H, ni), 7·64 (1H, br s) 〇MS (ESI) m/z : 342 (M+H)+ (4) 7-Hydroxy-2,3-dihydrogen -4H-M-benzoxazine-4-carboxylic acid tert-butylate [化520]

7-(Benzyloxy)-2,3-dihydro-4H-1,4-benzoxazine-4-furic acid tert-butyl ester (1·25 g) in methanol (10 ml) and THF ( After adding 5% Pd/C (500 mg) to a mixed solution of 10 ml), the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered, and then evaporated. • ^-NMR (CDC13) δ : 1.53 (9Η, s)? 3.82 (2H5 t? J=4.5 Hz), 4·22 (2H, t, J=4.5 Hz), 4·65 (1H, s), 6.35-6.40 (2H,m), 7.59 (1H,br s). MS (ESI) m/z ·· 252 (M+H)+. (5) 7-[[4-Phenyl-5-(trifluoromethyl)-2-thienyl]methoxy]_2,3·dihydro-4Η-1,4-benzoxazine-4- T-butyl formate [Chemical 521] 121199.doc -455 - 200846322

5-(Chloromethyl)-3-phenyl-2-(trifluoromethyl)thiophene (148 mg) and 7·hydroxy·2,3-dihydro-4Η·1,4-benzoxazine- 4. To a solution of tert-butyl formate (180 mg) in DMF (4.0 ml), add potassium carbonate (148 mg) at room temperature. After stirring at 5 ° C for 16 hours, the reaction solution was cooled to room temperature, and the precipitate was removed by filtration. Water (40 ml) and saturated aqueous ammonium chloride (4 ml) (2x30 ml) for extraction. The combined extracts were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified using EtOAc EtOAc (EtOAc) 'H-NMR (CDCI3) δ : 1.53 (9Η, s), 3.83 (2H? t5 J=4.4 Hz), 4.24 (2H, t, J—4.4 Hz), 5.17 (2H, s), 6·51 ( 1H,d,J=2.8 Hz), 6.54 (1H, dd, J=9.0, 2.8 Hz), 7·〇6 (1H, s), 7.37-7.45 (5H, m), 7·69 (1H, bf s). ❿ MS (ESI) m/z: 514 (M+Na)+. (6) 7-[[4-Phenyl-5-(trifluoromethyl)-2-thiophenyl]methoxy]_3, 'dihydro-2H-1,4-benzoxazine hydrochloride 522]

7-[[4_Phenyl-5-(trifluoroindolyl)_2_thienyl]nonyloxy]_2,3_dihydro_121199.doc •456 - 200846322 4Η-1,4·Benzazine To a solution of tert-butyl formate (310 mg), a 4 N hydrochloric acid dioxane solution (5·ml) was added at room temperature, and the mixture was stirred at room temperature for 2 hr. The resulting residue was slurried with hexane, and the resulting solid was filtered and dried (vacuum, 40 ° C, 2h) to give the title compound (268 mg) 〇]H-NMR (CDC13) δ: 3.62- 3.70 (2H? m)5 4.44-4.56 (2H5 m)? 5·19 (2H, s), 6.59 (1H, d, J=2.7 Hz), 6.66 (1H, dd, J=8.8, 2.7 Hz ), 7.08 (1H, s), 7.38-7.45 (5H, m), 7.52 (1H, d, J = 8.8 _ Hz). Unobserved. MS (ESI) m/z: 391 M+ 〇(7) 3-[N-(T-butoxycarbonyloxy_2-[7_[[4-phenyl]phenyl(trifluoromethyl)-2-thiophene Methoxy]_2,3_dihydro_4Η-1,4-benzoxazin-4-yl]ethyl]amino]propionic acid tert-butylate [Chemical 523]

7-[[4-Phenyl-5-(trifluoromethyl)-2-thienyl]methoxy]-3, winter dihydro-2H-1,4-benzoxazine hydrochloride (14〇 Mg) dissolved in DMF (5.0 ml), added 2-[Ν·(Tertibutoxycarbonyl)_N-[3,3,3,3,3,oxypropyl]amino group at room temperature Acetic acid (no mg), ed〇HC1 (81.5 mg), HOBt (57.9 mg), and 1)]^8 (〇, 1711111), stirred for 12 days. Concentrate the reaction solution under reduced pressure. Add ethyl acetate (3 〇ml), 121199.doc-457-200846322 saturated aqueous sodium hydrogen carbonate (40 ml), and water (40 ml) to the obtained concentrate. The aqueous layer was extracted with ethyl acetate (20 ml). The combined extracts were dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified using EtOAc EtOAc (EtOAc) (EtOAc (EtOAc) m), 3.48-3.60 (2H, m), 3.89 (2H, br s), 4.21-4.32 (4H, m), 5·18 (1/2 of 2H, s), 5.19 (1/2 2H, s) 5 6.50-6.60 (2H, m), _ 7.08 (1H, s), 7.10 (1/2 of 1H, br* s), 7.37-7.46 (5H, m), 7·50 (1/ 2 of 1H, br s). MS (ESI) m/z: 677 (M+H), (8) 3-[N-[2-[Eta]~~~~~~~~~~~~~~ -thienyl] methoxy]·2,3-dihydro-4H-1,4-benzoquin-4-yl]ethyl]amino]propionic acid TFA salt [Chem. 524]

3-[N-(Tertibutoxycarbonyl)-N-[2-o-oxy-2-|&gt;[[4-phenyl-5-(trifluoromethyl)-2-thienyl] Methoxy]-2,3-dihydro-4H-1,4-benzoquinone keto-4-yl]ethyl]amino]propionic acid tert-butyl ester (47.0 mg) of dioxo (4.0 In a solution of ml), TFA (1.0 ml) was added at room temperature. After stirring for 4 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The title compound (153 mg) was obtained from EtOAc (EtOAc). ^-NMR (DMSO-d6) δ : 2.70 (2H5 br s)5 3.17 (2H5 br s), 3·76 (2/3 of 2H, br s), 3·89 (1/3 of 2H, br s ), 4.27 (4H, br s) 5 5·37 (2H, s), 6.60-6.70 (2H, m), 7·29 (1/3 of 1H5 br s), 7.29 (1H, s), 7.40- 7.50 (5H, m), 8.02 (2/3 of 1H, br s). COOH and NH 〇 IR (ATR) cnT1 : 3157, 2978, 1726, 1680, 1508, 1381, 1288, 1174, 1119, 1014, 791, 766, 721, 696 were not observed. MS (ESI) m/z: 521 (M+H)+. HR-MS (ESI) calculated for C25H24F3N205S (M+H)+: 521.13 580. Found: 521.13115. Calculated for the elemental analysis of C25H23F3N2O5S.1.0TFA: c, 51.11; H, 3.81; F, 17.96; N, 4.41; S, 5.05. Measured value·· C, 50.83; H, 3·73; F, 18·06; N, 4·30; S, 4.90. [Example 106] 3-[N-[2-[5-(4-Cyclohexyl-3-trifluoromethylbenzyloxy)porphyrin-1-yl]-2-yloxyethyl]· Ν-mercaptoamine]propionic acid [Chemical 525]

3-[Ν-[2-[5-(4-Cyclohexyl-3·trifluoromethylbenzyloxy)porphyrinyl]-2_sideoxyethyl]amino]propanoic acid (〇· 2〇g), 37〇/〇福马林溶液(94 121199.doc -459 - 200846322 μΐ), acetic acid (0.11 ml) in methanol solution (2 ml), adding cyanoborohydride at room temperature Sodium (75 mg), stirred for 3.5 hours. To the reaction mixture, a saturated sodium hydrogencarbonate solution was added to adjust the pH value to 8, and then extracted with a chloroform/methanol mixed solution (10/1 s v/v). The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated, the residue obtained was purified mjjjjlili ^-NMR (DMSO-d6) δ : 1.23-1.89 (12Η5 m)5 2.22-2.87 (10Η,m), 3.03-3.16 (1Η,m), 4.02-4.26 (1Η,m),5.02-5.21 (2H ,m),6.74-7.04 (2H,m),7·57·7·74 (3H,m),7.81-8.00 (1H,m) o IR (ATR) cm] : 2925,2854,1637,1589, 1489, 1408, 1379 ° MS (ESI) m/z: 519 (M+H) + 〇C28H34F3N2O4 HR-MS (AqTOF) Calculated: 519·2471. Measurement value: 519.2409. [Example 107] 3-[Ν-[2-[5·(4-Cyclohexyltrifluoromethylbenzyloxy) σbendolin-1-yl]-2-oxoethyl]-indole -ethylamino]propionic acid [Chemical 526]

3-[Ν-[2-[5-(4-cyclohexyl-3-trimethylbenzyloxy) 〇 η 朵 琳 121I99.doc -460- 200846322 base]-2-sided oxyethyl Addition of sodium cyanoborohydride (75 mg, 1.2 mmol) at room temperature to a solution of the amine]propionic acid (0.2 g), formaldehyde (67 μl), acetic acid (0.10 ml) in methanol (2 ml) ), stirring for 3 days. To the reaction mixture, a saturated sodium hydrogencarbonate solution was added to adjust the pH to 8, and then extracted with a chloroform/methanol mixed solution (10/1, v/v). The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent, the title compound (21 mg) was obtained by reverse layer chromatography (GILSON, NOMURA DEVELOSIL COMBI-RP5)|屯J匕, then diethyl ether/hexane was added, and the precipitated solid was collected by filtration and dried. . ^-NMR (DMSO-d6) δ : 0.90-1.06 (3H? m)9 1.14-1.59 (6H, m),1·61-1·86 (4H,m), 2.36 (2H,t,J=7.1 Hz), 2·58-2.70 (2H, m), 2.74-2.86 (3H, m), 3.01-3.14 (2H, m), 3·41 (2H, s), 4.12 (2H, t, J=8.3 Hz),5·09 (2H,s), 6.80 (1H,dd,J=8.8, 2·7 Hz),6·93 (1H,s), 7.61-7.69 (3H,m)5 7·96 ( 1H,d,J=8.8

Hz), 8.14 (1H, s). MS (ESI) m/z: 533 (M+H)+. HR-MS (AqTOF) for C29H36F3N2〇4 (M+H)+: 533.2627. Found: 533.2699. [Example 108] 3-[N-[2-[5-(4-Cyclopentyl-3-trifluoromethylbenzyloxy), porphyrin-1-yl]-2-oxoethyl ]-N-fluorenyl]amino]propionic acid [Chemical 527] 121199.doc -461- 200846322

3_[N-|&gt;[5-(4-Cyclopentyl-3-trifluoromethylbenzyloxy)porphyrin-i-yl]-oxyethyl]amino]propionic acid (〇· 15 g), 37% of the formalin solution (ml), acetic acid (〇·50 ml) in methanol (5 ml), and sodium cyanoborohydride (80 mg) was added at room temperature and stirred for 1 day. After adding a saturated sodium hydrogencarbonate solution to the reaction mixture to adjust the pH to 8, the mixture was extracted with a chloroform/nonanol mixed solution (10/1, v/v). The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated, the residue obtained was purified mjjjjjjjjj iH-NMR (DMSO-d6) δ : 0.77-0.88 (4H, m), 1.11-1.35 (4H, m), 1·54-1·72 (2H, m), 1·74·1·91 (2H , ιη).1·92-2.04 (1H, m), 2.29 (3H, s), 2.38 (2H, t, J=7.0 Hz), 2·74 (2H, t, J=7.〇Hz), 3.08 (2H, t, J = 8.2 Hz), 4.05-4.18 (2H, m), 5.11 (2H, s) 5 6.80 (1H, d, J = 8.8 Hz), 6.93 (1H, s), 7.54 -7.74 (2H,m), 7·96 (1H, d5 J=8.8 Hz). MS (ESI) m/z: 505 (M+H)+. [Example 109] 3-[Ν-[2-[5-[(3·Cyano-4)cyclohexylphenyl)methoxy], porphyrin-1-yl]-2-yloxyethyl ]methylamino]propionic acid [化528] 121199.doc -462- 200846322

3-[Ν-[2-[5·[(3-Cyano-4-cyclohexyl-phenyl)methoxy], porphyrin small group]-2-yloxyethyl]amino]propyl Add a 37% aqueous solution of citric acid (48.5 μM) and acetic acid (1 〇〇μΐ) at room temperature in a solution of acid (94.6 mg) in methanol (2.0 nil) at room temperature for 1 hour at room temperature. Sodium cyanoborohydride (38·6 mg) was added. After stirring for 3 hours, water (3·〇 ml) was added to the reaction mixture, and the pH was made 7 with a saturated aqueous solution of sodium hydrogencarbonate. A 20% methanol mixture of chloroform (5.0 ml) was added to the reaction mixture, and the aqueous layer was extracted with a 20% methanol/chloroform mixture (3×3, 0 ml). The combined extracts were dried over anhydrous sodium sulfate. ^-NMR (DMSO-d6) δ : 1.21-1.54 (5H5 m)5 1.69-1.85 (5H, m), 2.29 (3H, s), 2.38 (2H5 t, J=6.8 Hz), 2.74 (2H t J =6 8 Hz), 2·80-2·88 (1H, m), 3.08 (2H, t, J=8e5 Hz), 3 32 (2H, s) 5 4.10 (2H, t5 J=8.5 Hz) 5.06 (2H5 s)? 6.80 (1H, s)5 6 93 (1H, s), 7.53 (1H, d, J=8.0 Hz), 7.70 (1H, dd, J=8.〇, i 2

Hz), 7·80 (1H, s), 7.96 (1H, d, J = 8.5 Hz). MS (ESI) m/z: 476 (M+H)+. Calculated value of elemental analysis of C28H33N304.1.5H20·· c,669l·h 7·22; N,8·36. Measurement value · · C, 67.09; H, 7 · 〇 2; N, 8.15. [Example 110] 3-[N-[2-[5-(4-Isobutyl-3-(trifluoromethyl)oxy)anthracene-indolyl-1-yl]-2-oxoxy B ]]-Ν-methylamino]propionic acid 121199.doc - 463 - 200846322 (1) MN-(benzyloxycarbonylmethyl)amino]propionic acid ethyl ester [Chem. 529]

HC! Addition of bromoacetic acid to the β-alanine ethyl ester hydrochloride (5.0 g) and DIEA (4,5,26 mmol) in acetonitrile (15 mL) at room temperature (2·1) Ml, 13 mmol), warmed to 80 ° C and stirred for 14 hours. The residue was purified by EtOAc (EtOAc) (EtOAc) W-NMR (CDC13) δ : 1·26 (3H, t, J=7.1 Ηζ), 2·5〇 (2H, t J=6.6 Hz), 2·91 (2H, t, J=6, 5 Hz ), 3·47 (2H, s), 4·1 (μ·17 (2H, m), 5·17 (2H, s), 7.31-7.39 (5H, m) MS (ESI) m/z : 266 (M+H)+ (2) 3-(N-carboxyindolyl-indole-ylamino)propionic acid ethyl ester [Chem. 530]

3- 3-[Ν-(Benzyloxycarbonylmethyl)amino]propionic acid ethyl ester (24 g), formalin aqueous solution (2 ml) and 10% hydrogen peroxide Pd/C (1 ·2 g) The ethanol suspension (5 〇 ml) was stirred at room temperature for 1 day under a hydrogen atmosphere. After filtering the catalyst, the obtained filtrate was concentrated to give the title compound (1.5 g). ]H-NMR (CDC13) δ : 1.19-1.33 (3H? m), 2.53 (3H? s)5 2.54- 2·70 (2H,m),2·74-3·07 (2H,m), 3.29 (2H, s), 4·17 (2H q 121199.doc -464- 200846322 J=7.2 Hz). MS (ESI) m/z: 190 (M+H) + 〇(3) 5-(4-isobutyl-3-trifluoromethylbenzyloxy) porphyrin el-decanoic acid tert-butyl ester [ 531]

On the 5-base. Add 4-chloromethyl-1-isobutyltrifluoromethylbenzene (15 mg), carbon, to DMF solution (5.0 ml) of tert-butyl-1-decanoate (118 mg) Warm potassium (104 mg), stir at 7 〇t: overnight. After the mixture was allowed to cool to room temperature, the reaction mixture was filtered, and the filtrate was evaporated to dryness, and the residue was purified by flash column chromatography (m.). NMR (CDCI3) δ . 0·93 (6H,d,J=6.6 Ηζ),1·55 (9H s) 1.91-2.01 (1H,m), 2.66 (2H,d,J=7.4 Hz),3.06 ( 2H t J=8.7 Hz), 3.97 (2H, s), 5.01 (2H, s), 6.75-6.80 (2H, m), 7·32 (1H, d, J = 8, l Hz), 7.51 (1H , d, J = 7.8 Hz), 7·68-7·76 (2H, m). MS (ESI) m/z: 450 (M+H)+. (4) 3-[N-[2-[5-(4-Isobutyl-3-trifluoromethylbenzyloxy)porphyrin-yl]-2-yloxyethyl]-N- Methylamino]ethyl propionate [Chemical 532] 121199.doc -465 - 200846322

Add 4 N hydrochloric acid / 1,4-dioxane to tert-butyl 5-(4-isobutyl-3-trifluoromethylbenzyloxy)porphyrin-1-decanoate (200 mg) 10 ml), stir for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjjjjj ), HOBt (78, 2 mg, 0·578 mmol), ® EDC.HC1 (111 mg, 0.578 mmol), stirred at room temperature overnight. A saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. The insoluble matter was filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by NH-Shixi gum fast column chromatography (Shanshan high-speed column L), and then subjected to rapid column chromatography (Shanshan high-speed column L). Repurification gave the title compound (62 mg). • iH-NMR (CDC13) δ : 0.93 (6H, d, J=6.6 Hz), 1.23 (3H, t, J=7.1 Hz), 1.91-2.01 (1H, m), 2·39 (3H, s) , 2.51 (2H, t, J = 7.0 Hz), 2.66 (2H, d, J = 7.1 Hz), 2.88 (2H, t, j = 7 〇 Hz), 3.15 (2H, t, J 2·8) 3 Hz), 3.30 (2H, s), 4·07-4·ΐ7 (4H m), 5·02 (2H, s)5 6.78-6.83 (2H, m), 7.32 (1H, d, j> 8 l Hz), 7.51 (1H,d,J=8.1 Hz),7·67 (1H,s),8·15 (1H,d,J=8 8

Hz) 〇 , MS (ESI) m/z : 521 (M+H)+. (5) 3-[Ν·[2-[5-(4-isobutyl-3-trifluoromethyloxy)oxycarbonyl] 02199.doc -466- 200846322 2-sided oxyethyl Methylamino]propionic acid

MN-PK heart-isobutyl _3_trifluoromethylbenzyloxy H1 porphyrin + yl]-2_side oxyethyl Ν Ν methylamino] propionate ethyl ester (6 illusion In the thf solution (3.0 ml), add methanol (()_35 ml), i sodium hydride solution (0.350 ml), and stir at room temperature for 1 hour. Add i N hydrochloric acid to the reaction solution for neutralization. After diluting with water, extracting with a 17% methanol/chloroform solution for 5 times, drying the combined extracts with anhydrous sodium sulfate, filtering the insoluble matter, and concentrating the filtrate under reduced pressure to obtain a rapid column chromatography (Shanshan Expressway) The resulting residue was purified to give the title compound (53 mg). NMR (DMSO-d6) δ: 0.89 (6 Η, d5 J = 6.6 Hz), 1.89-2.05 (3H, m), 2·19 (3H, s), 2·57·2·63 (4H, m)5 3.07-3.18 (4H, m), 4.18 (2H, t, J=8.5 Hz), 5.11 (2H, s), 6·80 (1H,d,J=8.8

Hz),6_94 (1H,s),7·48 (1H,d,J=7.8 Hz), 7.66 (1H,d, 8.1 Hz), 7.73 (IH,s)5 7·97 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 493 (M+H)+. [Example 111] 3-[N-[2-[5-(4-isopropyl-3-trifluoromethylbenzyloxy) hydrazin-1-yl]-2-yloxyethyl] Mercaptoamine]propionic acid (1) 5-(4-isopropyl-3.difluoromethylbenzyloxy), σ多琳_ι_carboxylic acid tert-butylate [Chem. 534] 121199.doc -467- 200846322

Add 4-chloromethyl-1-isopropyl-2-trifluoromethyl to a solution of 5 - 0 ml of DMF solution (5·0 ml) Base benzene (142 mg), potassium carbonate (104 〇^), stirred at 70 ° (: overnight). After standing and cooling to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to a flash column chromatography. The residue obtained was purified by the method (m.p.) to give the title compound (1 89 mg) 〇]H-NMR (CDC13) δ: 1.27 (6H?d5 J=6.9 Hz)5 1.55 (9H?s), 3.06 (2H, t, J = 8.7 Hz), 3.32-3.39 (1H, m), 3.97 (2H, s), 5·00 (2H, s), 6·75_6_81 (2H, m), 7, 35-7.76 (3H,m) MS (ESI) m/z: 436 (M+H) + (2) 3-[Ν-[2·[5-(4·isopropyl-3-trifluoro) Methylbenzyloxy)porphyrinyl]-2-oxoethylethyl]decylamino]propionic acid ethyl ester [Chem. 535]

Add 4 N Hydrochloric Acid/l,4-dioxane (10 ml) to 3-(4-isopropyl-3-trifluoromethylbenzyloxy)porphyrin decanoic acid tert-butyl ester (180 mg) Stir at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjjjjjj 〇Bt (72.7 mg), EDOHC1 (1〇3 121199.doc -468 - 200846322 Add saturated sodium bicarbonate to the reaction solution. The combined extracts were dried with saturated brine. The insolubles were filtered and the filtrate was reduced by mg) The solution was stirred overnight at room temperature, extracted with ethyl acetate for 3 times, and then concentrated under a pressure of anhydrous sodium sulfate. After NH_" fast f-column chromatography (the residue from the purification of Shanshan high-speed column) was further Column chromatography (Shanshan high-speed column q was re-purified to obtain the title compound (9 i mg). lH-NMR (CDCl3): </ RTI> </ RTI> </ RTI> </ RTI> 2.9 (3H, s), 2, 51

(2H, t, J=7.0 Hz), 2.88 (2H, t, J=7.0 Hz), 3.15 (2H, t, 1=8.3 Hz), 3.30-3.39 (3H, m)s 4.04-4.17 (4H, m)5 5.02 (2H, s), 6·78-6·83 (2H, m), 7 48 7 mur, 〇v ^ /.48-7.65 (3H5 m), 8.15 (1H5 d5 J=8.6 Hz) 〇MS (ESI) m/z : 507 (M+H)+. (3) 3-[N-[2-[5-(4-Isoyl_3_triamethyl-oxy)anthracene 〇 〇 小 小 ]]] 2- 2- ethoxyethyl]-N -Methylamino]propionic acid [Chem. 536].

???:HN-[2-[5-(4-isopropyl-3-trifluoromethylbenzyloxy)porphyrin·I group]-2-oxoethyl; 1-N-methylamine Add decyl alcohol (0.53 ml), 1 N aqueous sodium hydroxide solution (0.530 ml), and stir at room temperature for 1 hour and a half in THF solution (5 mM). . 1 n hydrochloric acid was added to the reaction solution, neutralized, and diluted with water, and extracted with a 17% methanol/chloroform solution. 121199.doc - 469 - 200846322 8 times. The combined strokes were dried over anhydrous sodium sulfate. The title compound (77. ^-NMR (DMSO-d6) δ was obtained after the filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (m.p. 1.24 (6H5 d5 J=6.6 Hz) 2 11-2 21 (5H,m),2·60-2·64 (2H,m),3.07-3.26 (5H,m),4 16 (2H t J=8.3 Hz),5·10 (2H,s)5 6·80 (1H,d,J=8.8 Hz), 6.93 (1H, s), 7.65-7.70 (3H,m),7·97 (1H,d, JU Hz) MS (ESI) m/z: 479 (M+H), [Example 112] 2-hydroxy-3-[Ν·[2- ethoxy-2·[5-[(4_benzene) _5_Trifluoromethyl-2-thienyl)methoxy porphyrin-indole-yl]ethyl]amino]propionic acid (1) 3-amino-2-methylpropionic acid methyl acetate Acid salt

OH Η2Ν^ΛγΟΗ Ο

HCI is a solution of (DL)-3-amino-2-hydroxypropionic acid (ΐ·〇5 g) in methanol (6〇mi) in the middle of the process. Slowly add sulfinium chloride to the temperature (1 ·3) 1 ml). After heating under reflux for 3 hours, the reaction mixture was concentrated under reduced pressure to give the title compound 5() g). H-NMR (DMSO-d6) δ : 2·88 (1H, br s), 3·06 (1H, br s), 3·66 (3H, s), 4·3 (Μ·36 (1H, m ),8·19 (1H,br s),8·25 (2H, (2) 2-hydroxy-3-[N-[2- oxo-2-[5·[(4_phenyl-5) _Trifluoromethyl-2-thienyl)methoxy; HI porphyrin _ 丨 _ yl] ethyl] amino] methyl propionate [Chem. 53 8] I21199.doc -470- 200846322

Suspended in acetonitrile (2〇ml) of 1-(2-chloroethyl)-5-[(4-phenyl·5-trifluoromethylthienyl)methoxy]° porphyrin (346 mg) In the solution, 3-amino-2-hydroxypropionate methyl ester hydrochloride (298 mg) and diea (8〇1 μΐ) were added at room temperature. At 85. ( After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate (15 ml of M.sub. The solvent of the extract was purified by silica gel column chromatography (Bi〇tage 25M) to give the title compound (199 mg). ???H-NMR (CDC13) δ : 2.06 (1 Η, br s ), 3.07 (2H5 ddd j=:22 12.7, 4·8 Hz), 3.20 (2H, t, J=8.3 Hz), 3.55 (2H,d

Hz),3·79 (3H,s), 3.99 (2H,t,J=8.3 Hz), 4.30 (1H ? J=5.7, 4.0 Hz), 5.20 (2H, s), 6·82 (1H, dd5 J=8 5, •, 2.7 Hz) 6·84 (1H, br s), 7·06 (1H, s), 7.39-7.43 (5H, m), 8 16 sen MS (ESI) m/z : 535 (M+H)+.

(3) 2-Hydroxy-3-[N-[2- oxo-2-[5-[(4-phenyl-5-三ϋ田I - 弗u τ暴-2-) Oxy]porphyrin-1·yl]ethyl]amino]propionic acid soil [Chem. 5 39]

121199.doc -471 · 200846322 in 2-hydroxy-3·[Ν-[2-trioxy-2-[5-[(4-phenyl-5-trifluoromethyl-2-nonyl)) Oxy]. To a solution of methyl phenyl hydrazide]ethyl]amino]propanoate (199 mg) in THF (2, 〇ml), methanol (1 Torr) and 1 n aqueous sodium hydroxide solution were added at room temperature ( 1. 〇ml). After stirring at room temperature for 4 hours and a half, water (2 ml) was added to the reaction mixture, and the pH was made 4 with 1 N hydrochloric acid. A 20% methanol/chloroform mixture (5 ml) was added for liquid separation. Further, the aqueous layer was extracted with a 20% methanol/chloroform mixture (2.times.5 ml), and then the mixture of the extracts was distilled off under reduced pressure. Diethyl scales were added to the residue and the precipitated solid was filtered to give the title compound (125 mg%). ^-NMR (DMSO-d6) δ : 2.90 (2H? t5 J=6.6 Hz) 5 3.15 (2H; t J 8·4 Hz), 3.81 (2H, s), 3.92 (1H, t, J = 6.6 Hz ), 4·03 (2H t J=8.4 Hz), 5·35 (2H, s), 6.89 (1H, dd5 J=8.5, 2.4 Hz), 7·0〇 (1H, d, J=2.4 Hz), 7.36 (1H, bi* s), 7.41 - 7.51 (5H, m), 7.99 (1H, d, J = 8.5 Hz). MS (ESI) m/z: 521 (M+H)+. Calculated for elemental analysis of C25H23F3N2 〇5S*0.5H2 :: c, 56.71·h 4·57; F,10·76; N, 5.29; S, 6.06. Found: c, 56.87 · ή 4.42; F, 10.90; N, 5.38; S, 6.1b [Example 113] 3-[N.ethyl-N-l&gt; side oxy-2_[5-[(4) -phenyl·5_trimethylsulfonyl-2_nonyl)methoxy] 丨ΰ 丨ΰ -1 -1 -yl]ethyl]amino]propionic acid (1) 1-[2-(Ν- Ethylamino)ethinyl]-5-[(4-phenyl-5-trifluoromethyl-2-nonanyl) decyloxy] porphyrin [Chem. 540] 121199.doc -472- 200846322

1-(2-Chloroethyl)-5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy], porphyrin (181 mg) in acetonitrile (5.0 ml) In the solution, DIEA (348 μΐ) and 2 N ethylamine/THF solution (〇·5 ml) were added at room temperature. After stirring at 90 °C for 2 hours, the reaction mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The combined extracts were dried over anhydrous sodium sulfate and filtered and evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ]H-NMR (CDC13) δ : 1.17 (3H? t, J=7.1 Hz) 5 2.71 (2H5 q5 J=7.1 Hz), 3.20 (2H, t5 J = 8.3 Hz), 3·49 (2H, s) , 4.02 (2H, t, J = 8.3 Hz), 5.20 (2H, s), 6.82 (1H, d, J = 9.0 Hz), 6.85 (1H, br s), 7.06 (1H, s), 7.38-7.43 (5H,m), 8.17 (lH,d,J==9.〇Hz). MS (ESI) m/z: 461 (M+H), (2) 3-[N-ethyl-N-[2_ </ RTI> </ RTI> </ RTI> Ethyl-2-thienyl)methoxy] is porphyrin-i-yl]ethyl]amino]propionic acid ethyl ester [Chem. 541]

121199.doc • 473 - 200846322 Thienyl) methoxy] oleyl porphyrin (45·4 mg) in THF ((K3 ml) solution, adding 1-butyl-3-methylimidazoline at room temperature Rust hexafluoride hexafluoride (2·〇^1) and ethyl acrylate (26.7 μΐ). After stirring at 60 ° C for 4 ,, the reaction solution was concentrated under reduced pressure, and a 10% methanol/chloroform mixture was added (5· 〇ml), saturated sodium bicarbonate water &gt; trough solution (2.0 ml) and water (5.0 ml) were separated, and the aqueous layer was extracted with a 1% methanol/chloroform mixture (3 x 3.0 ml). The combined extracts were concentrated under reduced pressure and purified to purified crystals eluted eluted eluted elut elut elut elut elut elut elut elut elut elut elut t, J=7.1 Ηζ),1·21 (3H,t, J=7.2 Hz), 2·49 (2H, t, J=7.0 Hz), 2·71 (2H, q5 J=7.i Hz) , 2·98 (2H, t, J = 7.1 Hz), 3.15 (2H, t, J = 8.3 Hz), 3·39 (2H, s), 4.08 (2H, q, J = 7.2 Hz), 4.16 ( 2H,t,J=8.3 Hz),5·19 (2H,s), 6.80 (1H,dd,J=8.8, 2.2 Hz),6·84 (1H,br s),7.06 (1H,s), 7.42-7.37 (5H,m),8,16 (1H,d,J=8.8 Hz) MS (ESI) m/z: 561 (M+H) + (3) 3-[N-ethyl-indole-[2. Trifluoromethyl 2-1-thienyl)methoxy]σ porphyrin·1-yl]ethyl]amino]propionic acid [Chemical 542]

3-[Ν-ethyl·Ν·〇 side oxy-2-[5-[(4-phenylidene trifluoromethyl)] methoxy] oxime 13 13-lin-1 [Ethyl]amino]propionic acid ethyl ethane (46 · 3 mg) in THF (1.0 ml), adding methanol (〇·5 ml) and 1 N 121199.doc -474- 200846322 wind at room temperature Emulsified sodium aqueous solution (0.5 ml) e was stirred at room temperature for half hour, and then water (2 ml) was added to the reaction mixture to make the pH 4. A decyl alcohol/chloroform mixture (5 ml) was added for liquid separation. Further, after extracting the aqueous layer (4)% methanol/chloroform mixed solution (10 ml), the combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Add dimethyl sapphire to the resulting residue, remove the insoluble matter, and perform high performance liquid chromatography (ν〇μ·

Develosil Combi_RP-5) was purified and the target fraction was concentrated to give a standard compound (30.5 mg).

MS (ESI) m/z: 533 (M+H)+. Calculated for elemental analysis: c, 57 95; h, 5·4〇; F, 10.18; Ν, 5·01; S, 5.73. Found: 7 86·' ' , 5 5 5.19; F, 9.95; Ν, 4.95; S, 5.69 〇 [Example 114] 3-[Ν-曱-Ν-[2- oxy 2_[5_ [(4_phenyl_5_trifluoromethyl-2-thienyl)methoxy oxopipelinyl]ethyl]amino]acetic acid (1) 3-[N-methyl-N-[2- 2-oxo-2-[5-[(4.phenyl.5-trifluorodecyl-2·thienyl)methoxy]porphyrin-1-yl]ethyl]amino]acetic acid ethyl acetate 543]

1-(2-Chloroethyl)-5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy] 吲 朵 朵 (226 mg) acetonitrile (1 〇 In the solution, DIEA (279 μM) and N-methylglycine ethyl ester hydrochloride (115 mg) were added at room temperature. After stirring at 80 ° C for 1 hour, the reaction liquid was concentrated under reduced pressure, and water (5·〇ml) and saturated sodium hydrogencarbonate were added to the obtained residue 121199.doc •475 - 200846322. / (8 · 〇mi) and 10% methanol / chloroform mixture (10 ml) for liquid separation. In turn, the water layer was extracted with a 10% methanol/gas mixture (3 x 5.0 ml). The combined extracts were dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified using EtOAc EtOAc (EtOAc) H-NMR (CDCl3) δ : 1 &gt; 27 (3H, t, J = 7.2 Hz), 2 57 (2H, s),

2.96 (2H, s), 3.18 (2H, t, J=8.3 Hz), 3.54 (3H, d, 1=10.7 Hz), 4.16 (2H, t, J=8.3 Hz), 4.17 (2Hj q, Hz) } 5 2〇(2H? s), 6.81 (1H? dd, J=8.5, 2.4 Hz), 6.84 (1H, br s), 7.06 (1H, s), 7.43-7.39 (5H, m), 8.17 ( 1H, d, J = 8.5 Hz). MS (ESI) m/z: 533 (M+H)+. (2) 3-[N-Mercapto-N-[2-trioxy-2-[5_[(4-phenyl-5-trifluoromethyl-2-phenyl) methoxy] porphyrin -1-yl]ethyl]amino]acetic acid [Chemical 544]

3-[Ν·Methyl-N-l&gt; sideoxy-2·[5-[(4-phenyl-5·trifluoromethyl-2-thienyl)decyloxy]porphyrin-1 -ethyl]ethyl]amino]acetate (218 mg) in THF (1.0 ml), MeOH (5·1) and 1 N aqueous sodium hydroxide (〇·5 ml) ). After stirring at room temperature for 15 hours, water (2 ml) was added to the reaction mixture, and the pH was adjusted to 4 with 1 N hydrochloric acid. A 20% sterol/chloroform mixture (5 ml) was added for liquid separation. Further, the aqueous layer was extracted with a mixture of 20% methanol / chloroform 121199.doc - 476 - 200846322 (2x5 ml), and the mixture was combined and dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc (EtOAc) 'H-NMR (DMS0-d6) δ : 2.27 (2H? br s)? 2.90-3.15 (2H? m)? 3·32 (3H, br s), 3·40-3·51 (3H, br m ), 4·07 (2H, br s), 5·33 (2H, s), 6.86 (lH, brs), 6.98 (lH, s), 7, 33 (lH, s), 7.38-7·48 ( 5H, m), 8.03 (1H, d, J = 8.5 Hz). MS (ESI) m/z: 505 (M+H)+. [Example 115] 3-[N-isopropyl-N-[2-o-oxy-2_[5·[(4_phenyl·5·trifluoromethyl-2-σsecenyl)methoxy) ] 哚 --i-yl]ethyl]amino]propionic acid (1) 2·(Ν-isopropylamino)ethinyl-5-[(4-phenyl-5-trifluoro Methyl-2-nonyl) decyloxy] porphyrin [Chem. 545]

1-(2·Chloroacetoxy)-5-[(4-phenyl-5-trisinyl-2-pyranyl)methoxy]anthracene I 13-lin (262 mg) acetonitrile (5 · 0 ml) solution was added DIEA (606 μM) and isopropylamine (148 μM) at room temperature. After stirring at 85 ° C for 2 hours, the reaction mixture was concentrated under reduced pressure. Water (2 ml), saturated aqueous sodium hydrogen carbonate (1·5 ml) and 1% methanol/chloroform, p human solution (3.0 ml) was dispensed. Further, the aqueous layer was extracted with a 1% by weight methanol/chloroform mixture (3χ3〇121199.doc -477-200846322 ml), and the combined extracts were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc) H-NMR (CDC13) δ : 1·Π (6H,d,J=6.1 Ηζ), 2·85 (1H, dq, J=6.1, 6.1 Hz), 3·20 (2H, t, J=8.4 Hz ),3·49 (2H, s), 4·〇3 (2H, t, J=8.4 Hz), 5·20 (2H, s), 6·82 (1H, dd, J=8.5, 2.0 Hz) , 6.84 (1H, br s), 7.06 (1H, s), 7·43-7·38 (5H, m), 8.17 (1H, d, J=8, 5 Hz) o MS (ESI) m/z : 475 (M+H), (2) 3_[N-isopropyl-N-[2_sideoxy-2-[5-[(4-phenyl-5-trifluoromethyl-2- σ)塞 基 ) methoxy 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】

In 1-[2-(indolyl-isopropylamino)ethenylphenyl-5-trifluoromethyl-2_thienyl)nonyloxy]. To a solution of porphyrin (173 mg) in THF (〇5 ml), add 1-butyl-3-mercaptoimidazolium rust hexafluoride hexafluoride (〇·75 ml) and ethyl acrylate (0.750) at room temperature. Ml). After stirring at 60 ° C for 4 days, the reaction mixture was concentrated under reduced pressure, and a mixture of 10% methanol / chloroform (5·ml), saturated aqueous sodium hydrogen carbonate (2.0 ml) and water (5.0 ml) The aqueous layer was extracted with a 1% sterol/chloroform mixture (3 x 3.0 ml). The combined extracts were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Bi〇tage 25M) to afford the title compound (1 6 〇 m g). 121199.doc •478 - 200846322 !H-NMR (CDC13) δ ·· 1·05 (6H,d,J=6.6 Ηζ),1·19 (3H,t, J=7.2 Hz), 2.46 (2H,t , Hz), 2.89 (2H, t, p7·0 Hz)' 3·05 (1H, dq, J=6.6, 6,6 Hz), 3·15 (2H, t, J=8.4 Hz), 3· 38 (2H, s), 4.05 (2H, q, J = 7.2 Hz), 4·23 (2H, t, J = 8.4 HZ), 5·20 (2H, s), 6·81 (1H, dd, J=8.8, 2.2 Hz)5 6.85 (1H, mountain J=2·2

Hz),7·06 (1H,s),7.43-7.38 (5H,m),8·17 (1H,d,8

Hz) o

(3) 3-[N-Isopropyl-NO-oxo-2-[5-[(4-phenyl-5-trifluoromethyl I phenyl)methoxy], porphyrinyl] Amino]propionic acid

3-[N-Isopropyl-indole_[2·Sideoxy_2-[5_[(4-phenyl-5:trifluoromethyl] 2-thienyl)methoxy]porphyrin-^ To a solution of ethyl iodide]ethyl propionate (160 φ mg) in THF (2.0 ml), add methanol (1.0 ml) and 1 N aqueous sodium hydroxide (1·〇ml) at room temperature. ). After stirring for 5 hours at room temperature, water (2 ml) was added to the reaction mixture, and the pH was made 4 with 1 N hydrochloric acid. A 20% methanol/chloroform mixture (5 ml) was added for liquid separation. Furthermore, the aqueous layer was extracted with a 1% methanol/chloroform mixture (2×5 ml), and the combined extracts were dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc EtOAc (EtOAc) 121199.doc -479- 200846322 [Example 116] l-[2-Sideoxy-2_[5-[(4-phenyl-5-trifluoromethyl)2-thienyl)methoxy]° 12-lin-1-yl]ethyl] brigade-4-formic acid (1) 1-[2-o-oxy-2-[5-[(4-phenyl-5-trifluoromethyl-2-) Thienyl)methoxy]°b 1 porphyrin-1·yl]ethyl]piperidine-4-furoate ethyl ester [Chemical 548]

Acetonitrile (3 A ml) of 1-(2·chloroethyl)-5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]porphyrin (226 mg) In solution, DIEA (23 5 μM) and 4-piperidinic acid ethyl ester (100 mg) were added at room temperature. After stirring at 80 ° C for 1 hour, the reaction mixture was concentrated under reduced pressure, and water (5.0 ml), saturated aqueous sodium hydrogen carbonate (3.1111) and 1% methanol/chloroform mixture were added to the residue. (10 ml) was dispensed. Furthermore, the aqueous layer was extracted with a 1% methanol/gas mixture (3 x 5.0 ml), and the combined extract φ was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using EtOAc EtOAc EtOAc (EtOAc)

iH-NMR (CDC13) δ ·· 1·25 (3H, t, J=7.2 Ηζ), ΐ·76·1·8δ (2H m), 1.89-1·97 (2H, m), 2.24 2.37 (3H,m),2·97 (2H,d J=10.7 Hz), 3.17 (2H,t5 J=8.3 Hz),3·26 (2H,s), 4.14 (2H q,J-7.2 Hz) , 4·20 (2H, t, J=8.4 Hz), 5·20 (2H, s), 6.81 (13⁄4 dd, J=8.5, 2.2 Hz), 6.85 (1H, br s), 7·06 (1H , s), 7·39-7 43 (5H, m), 8.17 (1H, d, Hz). 121199.doc -480- 200846322 MS (ESI) m/z : 573 (M+H) + 0 (2) l-[2-Sideoxy-2-[5-[(4-phenyl-5·3) Fluorinyl-2-thienyl)methoxy]porphyrin-1-yl]ethyl]piperidine-4-carboxylic acid [Chem. 549]

M2-Phenoxy-2-[5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]-]-indolyl-1-yl]ethyl]pyridine To a solution of -4-ethyl formate (145 mg) in THF (2. EtOAc), methanol (1·········· After stirring for 15 hours at room temperature, water (2 ml) was added to the reaction mixture, and the pH was made 4 with 1 n hydrochloric acid. A 20% methanol/chloroform mixture (5 ml) was added for liquid separation. Further, the aqueous layer was extracted with a mixture of 20% methanol / chloroform (2.times.5 ml), and the combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The target fraction was concentrated under reduced pressure using a hydrazine column chromatography &amp; (Biotage 25S) pure φ. Diethyl squamous (1.0 ml) and hexane (2.0 ml) were added to the residue, and the precipitated solid was filtered and dried to give the title compound (64 5 mg). H-NMR (DMSO-d6) δ : 1.53 (2H?dtd, J=11.05 11.0, 3.4 Hz), 1·75 (2H, dd, J; 13.4, 2.7 Hz), 2.03-2.16 (3H, m), 2.81 (2H, d, J=ll.〇Hz), 3.10 (2H, t5 J=8.4 Hz)? 3.18 (2H? s)5 4.16 (2H,t,J=8.4 Hz),5·34 (2H, s),6·84 (1H, dd, J=8.8, 2·2 Hz), 6.97 (1H, d, J=2.2 Hz), 7·35 (1H, s), 7.50-7.41 (5H, m), 7·98 (1H, d, J = 8 8 Hz). </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 9·83; N, 4.83; S5 5.53. Found: C, 57.93; H, 5·16; Cl, 0.83; F, 9.66; N, 4.80; S, 5.30. [Example 11 7] 3-[N-Lactinyl-N-[2-trio-yl-2-[5-[(4-phenyl-5-trifluoromethyl-2-thienyl) anthracene) Base] 哚 哚 porphyrin-i-yl]ethyl]amino]propionic acid (1) 1-[2-(Ν·cyclopropylamino)ethenyl]·5_[(4-phenyl-5) -trifluoromethyl-2·thienyl)methoxy]porphyrin [Chem. 550]

1-(2-Chloroethyl)-5-[(4-phenyl.5·trifluoromethyl-2-thienyl)decyloxy; h porphyrin (262 mg) in acetonitrile (5· In a solution of 〇ml), DIEA (606 μM) and cyclopropylamine (148 μm) were added at room temperature. After stirring at 85 °C for 2 hours, the reaction mixture was concentrated under reduced pressure. Water (2 ml), saturated aqueous sodium hydrogen carbonate (1·5 ml) and 1% decyl alcohol/chloroform mixture were added to the residue. (3·0 ml) was dispensed. Furthermore, the aqueous layer was extracted with a 1% methanol/chloroform mixture (ml), and the combined extracts were dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using EtOAc EtOAc EtOAc (EtOAc (EtOAc) ), I21199.doc -482 - 200846322

3·20 (2H, t, J=8.4 Ηζ), 3·55 (2H, s), 4.04 (2H, t, 4 j|z) 5.20 (2H, s), 6.82 (1H, dd, J=8.5 , 2.0 Hz), 6.85 (1H &gt; or S) 5 7·06 (1H, s), 7.43 - 7.39 (5H, m), 8.18 (1H, d, J = 8.5 Hz). MS (ESI) m/z: 473 (M+H)+. (2) 3-[N-Cyclopropyl-N-[2-trioxy-2-[5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]anthracene Oleone-1·yl]ethyl]amino]propionic acid ethyl ester [Chem. 551]

1-[2-(Ν-Cyclopropylamino)ethinyl]-5-[(4-phenyl-5_trioxymethyl&amp; 2-thienyl)methoxy]porphyrin (121 To a solution of mg) in THF (0.5 ml), 1-butyl-3-mercaptoimidazolium hexafluoride hexafluoride (75 ml) and ethyl acrylate (0.750 ml) were added at room temperature. After stirring at 60 ° C for 4 hrs, the reaction mixture was concentrated under reduced pressure, and then a mixture of 10% methanol / chloroform (5.0 ml), saturated aqueous sodium hydrogen carbonate (2.0 ml) and water (5.0 ml). The aqueous layer was further extracted with a 10% methanol/chloroform mixture (3×3.0 ml). The combined extracts were concentrated under reduced pressure. ^-NMR (CDC13) δ : 0.40-0.52 (4H3 m)5 i.22 (3H5 t? J=7.l

Hz), 2·19-2·25 (1H, br m), 2.56 (2H, t, J = 7.1 Hz), 3, 14 (2H, t, Hz), 3·18 (2H, t, J= 7.3 Hz), 3.52 (2H, s), 4_09 (4H, q, 7.1 Hz), 5·19 (2Ή, s), 6.81 (1H, dd, J=8.8, 2.4 Hz), 6.84 (1H, br s), 7, 06 (1H, s), 7.43-7.37 (5H, m), 8.17 (1H, 121199.doc -483 - 200846322 d, J = 8.8 Hz). MS (ESI) m/z: 573 (M+H), (3) 3-[N-cyclopropyl-N-[2- </RTI> Trifluorof-{2-bromophenyl)methoxy] phenan-1-yl]ethyl]amino]propionic acid [化552]

3-[Ν-Cyclopropyl-fluorene-[2_sideoxy-2·[5-[(4-phenyl-5-trifluoromethyl) 2-thienyl)methoxy]%丨哚To a solution of ethyl phenyl]ethyl]amino]propanoate (848 mg) in THF (1.4 ml), MeOH (·············· ). After stirring at room temperature for 15 hours, water (2 ml) was added to the reaction mixture, and the pH was 4 with 1 N hydrochloric acid. A 20% methanol/chloroform mixture (5 ml) was added for liquid separation. Further, the aqueous layer was extracted with a 2% decyl alcohol/chloroform mixture (2×5 ml), and the combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc) MS (ESI) m/z: 545 (M+H)+. [Example 118] l-[2-Sideoxy-2-[5-[(4-phenyl-5·trifluoromethyl)2-thienyl)methoxyl p porphyrin small group]ethyl Ρ- pyridine-(38)-carboxylic acid (1) 1-(t-butoxycarbonyl)piperidine _(3S)-formic acid methyl ester [Chem. 553] 121199.doc -484- 200846322

Potassium carbonate (2·49 gy and iodonane (112 ml) was added to a solution of 1-(t-butoxycarbonylpiperidinecarboxylic acid (2.75 g) in DMF (20 ml). After stirring for 3 hours, the reaction mixture was concentrated under reduced pressure. Water (15··ml) and ethyl acetate (20 ml) were added to the residue to carry out liquid separation. 〇·〇mi) Extract the aqueous layer, dry the combined extract with anhydrous sodium sulfate, filter the insoluble matter, and concentrate the filtrate under reduced pressure. Purify the residue by using Shixi rubber column chromatography (Biotage 40M). , the title compound (2.88 g) was obtained. ^-NMR (CDC13) δ: 1,46 (9H3 s), 1.56-1,74 (3H?m)5 2.00- 2.08 (1H, m), 2.45 (1H, tdd , J = 10.2, 3·9, 3·9 Hz), 2·81 (1H, ddd, 3.2, 13.7 Hz), 2·88-3·10 (1H, br m), 3·69 (3H, s ), 3,91 (1H,d,J=13.7 Hz), 4.29-4.00 (1H,br m) 〇(2) (3S)-Petidinecarboxylic acid methyl ester [Chemical 554]

Add 4-N hydrochloric acid/1,4-dioxane solution at room temperature in 1-(t-butoxycarbonyl) 唆_(3S)_ decanoic acid decyl ester (2·88 g). 〇ml). After the reaction mixture was stirred for 16 hours, it was concentrated under reduced pressure. Water (15············ Then, after extracting with a 10.% methanol/chloroform mixture (3 X 15. 〇mi), the combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound 121199.doc • 485 · 200846322 ( 577 mg). 'H-NMR (CDC13) δ : 1.40-1.52 (1Η5 m), 1.63-1.72 (2Η5 m)? 1·95-2·02 (1Η,m), 2.46 (1Η,tt,J=9.8, 3.9 Ηζ ), 2·64 (1Η, ddd, J=9.8, 12·4, 3·2 Hz), 2·82 (1H, dd, J=12.4, 9·3 Hz), 2.93 (1H, dt, J= 12.4, 3.9 Hz), 3.16 (1H, dd, J = 12.4, 3. 2 Hz), 3·68 (3H, s) 〇 (3) l-[2-Sideoxy-2-[5-[( 4-phenyl-5-trifluoromethyl 2 -thienyl) decyloxy] σbendolin-1-yl]ethyl] brigade bite _(3S)-formic acid 曱酉 [[555]

Acetonitrile in 1-(2-chloroacetoxy)-5-[(4-phenyl-5-trifluoromethyl-2-synyl)methoxy]porphyrin (360 mg) (3.0 ml In solution, DIEA (347 μM) and (3S)-piperidinecarboxylic acid methyl ester (143 mg) were added at room temperature. At 8 〇. After the mixture was stirred for 3 minutes, the reaction liquid was concentrated under reduced pressure. Water (5.0 ml), saturated aqueous sodium hydrogen carbonate (3·〇mi) and 1% methanol/chloroform mixture were added to the residue. 10 ml) was dispensed. Further, extraction was carried out with a mixture of methanol/chloroform (3 x 5.0 ml). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc) iH-NMR (CDC13) δ : 1.47-1.69 (2H, m), ι·7 (Μ·78 (1H, m), 1·89-1·97 (1H, bi* m), 2·25 (1H ,td,J=9.8, 2.4 Hz), 2.44 (1H, t, J=9.8 Hz), 2·65 (1H, ddd, J=9.8, 13.7, 3.9 Hz), 2.79·121199.doc -486- 200846322 2·86 (1H,m), 3.03-3.08 (1H,m),3·17 (2H,t,J=8,3 Hz), 3·25 (2H,s), 3.64 (3H,s), 4.18 (2H, dt, J=3.9, 8·3 Hz), 5.20 (2H, s), 6.82 (1H, d, J=8, 8 Hz), 6.85 (1H, br s), 7·0ό (1H, s), 7.43-7.39 (5H, m), 8.18 (1H, d, J = 8.8 Hz) MS (ESI) m/z : 559 (M+H)+ 〇(4) 1·[2 _Sideoxy-2-[5-[(4-phenyl-5-trifluoromethylnonphenyl) methoxy] porphyrin-1-yl]ethyl]piperidine _(3S)-carboxylic acid [化556]

1-[2-Sideoxy-2_[5-[(4-phenyl-5-trifluoromethyl-2-yl)phenyl]methoxy]indol-1-yl]ethyl]piperidine _(3S)_methyl formate (322

In a solution of THF (2.0 ml), decyl alcohol (1. for example) and aqueous solution of sodium hydroxide (1 · 〇 ml) were added at room temperature. The reaction mixture was stirred at room temperature for 15 hours and then added. After water (2 ml) and N hydrochloric acid were allowed to have a pH of 4, a mixture of 2% by weight of sterol/chloroform (5 ml) was added for liquid separation. Further, the aqueous layer was extracted with a 2% methanol/chloroform mixture (2×5 ml), and then the combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc) H-NMR (DMSO_d6)s: 126_147 (2Hbrm) i6 () (iH, br ^ 1·75 (1H, br s), 2.15 (1H, br s), 2.32 (2H, br s), 2.65 OH, br s)5 2.88 (1H, br s), 3.08 (2H, t, J=7.8 Hz), 3.21 (2H, br s), 4.U (2H, t, j=7.8 Hz), 5·33 (2H , s), 6 84 (ih, d' 121199.doc -487 - 200846322 J=8.5 Hz), 6.96 (1H, s), 7.34 (1H, s), 7.49-7.40 (5H, m), 7·98 (1H, d, J = 8.5 Hz) 〇MS (ESI) m/z: 545 (M+H) + 〇 [Example 119] l-[2-Alkoxy-2-[5-[(4- Phenyl-5-trifluoromethyl-2-thienyl)methoxy]porphyrin-1-yl]ethyl]piperidine-(3R)-carboxylic acid (1) 1-(t-butoxycarbonyl) Piperidine_(311)-methyl formate [Chemical 557]

Add potassium carbonate (2·49 g) and methyl iodide at room temperature in a solution of 1-(t-butoxycarbonyl)piperidine-(3r-bucarboxylic acid (2,75 g) in DMF (20 ml) 1.12 ml). The reaction mixture was stirred at room temperature for 3 hours, then concentrated under reduced pressure. Water (15.0 ml) and ethyl acetate (2 〇ml) were added to the residue. The aqueous layer was extracted with ethyl acetate (3×1··················································· (Biotage 40M), the obtained residue was purified to crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ,2·45 (1H,tdd,J=l〇.5,3·9,3·9 Hz), 2.78-2.85 (1H,m),2·98 (1H,br s),3·69 (3H5 s), 3.91 (1H, d, J=13.2

Hz), 4· 11 (1H, br s) 〇 (2) (3R)-Bucking carboxylic acid oxime ester [Chemical 558] 121199.doc -488 - 200846322

Add 4 N hydrochloric acid / 1,4-dioxane solution (5·〇) at room temperature in 3')-methyl acid (2·28 g) of ι-(t-butoxycarbonyl) piperidine. Ml). After the reaction mixture was stirred for 16 hours, it was concentrated under reduced pressure. Water (15.0 ml) was added to the residue, and the mixture was stirred with saturated aqueous sodium hydrogencarbonate to give a mixture of methanol and chloroform (3XI5. 0 ml) for extraction. The combined extract was dried over anhydrous sodium sulfate and filtered and evaporated. ^-NMR (CDC13) δ : 1.46-1.53 (1Η, m)5 1.62-1.72 (2H, m)? 1·96_2·03 (1H, br m), 2·48 (1H, tt, J: 9.3, 3.9 Ηζ), 2·65 (1H, ddd, J=10.7, 12.7, 3·2 Hz), 2·82 (1H, dd5 J=12.4, 9·3 Hz), 2·95 (1H, dt, J =12.7,3·7 Hz),3·18 (1H,dd,J=12_4,3.2

Hz),3·68 (3H,s) 〇(3) 1_[2-Sideoxy-2-[5-[(4-phenyl-5-trimethyl-2-nonyl)methoxy) Pyridin-1-yl]ethyl]piperidine-(3R)-decanoic acid decyl ester

1-(2-Chloroethenyl)-5-[(4-phenyl-5-trifluoromethyl-2.thienyl)methoxy]oxiine (3 60 mg) in acetonitrile (3.0 In a solution of ml), DIEA (347 μΐ) and (3R)-piperidinecarboxylate (143 mg) were added at room temperature. After reacting the reaction wave 121199.doc -489- 200846322 at 80 ° C for 30 minutes, it was concentrated under reduced pressure, and water (5.0 ml) and a saturated aqueous solution of sodium hydrogencarbonate (3 〇) were added to the residue. And 1% methanol/chloroform mixture (ίο ml) for liquid separation. Furthermore, it is 1〇0/. The aqueous layer was extracted with a methanol/chloroform mixture (3×5.0 ml), and the combined extracts were dried over anhydrous sulfuric acid steel, and the insoluble materials were separated. The concentrated liquid was concentrated under reduced pressure. The residue obtained was purified to give the title compound (323 mg).

H-NMR (CDCl3) δ : (2H, (4), i % (1H, ZJ J-13.4, 3.9 Hz), 1.88-1.96 (1H, 2.25 (1H, dt, J=2.0, 10.0 Hz), 2.44 (1H , t, J=10.0 Hz), 2.62-2.69 (1H, m), 2.80-2.86 (1H,m), 3.03-3.08 (1H,m),3 17 (2H,t,b 8 4 Hz), 3.25 (2H, s), 3.64 (3H, s), 4·18 (2H, 扎j=3 4, 8 4 Hz), 5 2〇(2H, s), 6.81 (1H, dd5 J=8.5, 2.4 Hz ), 6.85 (1H, br s), 7.06 (1H, s), 7.39-7.43 (5H, m), 8.l8 (1H5 d, J=8.5 Hz) 〇MS (ESI) m/z : 559 (M +H)+. (4) H2-Sideoxy-2-[5·[(4_Phenyl·5_trismethyl-2-_2))methoxy]°弓卜朵琳-1 -yl]ethyl] travel--(3 anti)-formic acid [化560]

1-[2-Sideoxy-2-[5-[(4-phenyl-5-trifluoromethyl-2-yl)phenyl]methoxy]pyridin-1-yl]ethyl]piperidin Methyl pyridinecarboxylate (323 mg) in THF (2.0 ml) was added methanol (1 以及 and i 121199.doc -490 - 200846322 sodium oxide solution (1.0 ml) at room temperature and stirred at room temperature 15 Add water (2 ml) to the reaction solution, and adjust the pH to 4 with 1 N hydrochloric acid, then add 2% methanol/chloroform mixture (5 ml) for liquid separation. Further '2% methanol/chloroform The mixture was extracted with aq. 155 mg). ^-NMR (DMSO-d6) δ: 1.25-Μ8 (2Η, br m), L6〇br s), 1.75 (1H, br s), 2.10-2.38 (3H, br m), 2.65 ( 1H, br s), 2.88 (1H, br s), 3.09 (2H, t, J=7.3 Hz), 3.22 (2H, br s), 4.14 (2H, t, J=7.3 Hz), 5.33 (2H, s), 6.84 (1H, d, J=8.5 Hz)! 6.96 (1H, s), 7.34 (1H, s), 7.49-7.39 (5H, m), 7.98 (lHj d, J=8 5

Hz) 〇MS (ESI) m/z : 545 (M+H)+ 〇 [Example 12〇] W2·sideoxy group·2 cases (4·stupyl-5_trifluoromethyl such as exemplyl)曱oxy] ° cited. Dolin-1-yl]ethyl]pyrrole bite _3_decanoic acid

(1) 3 -11 Bilo sine citrate B S-hydrochloride [Chem. 561]

Boc

(1·30 g) yb (tert-butoxymethyl)-3 heart each bite formate vinegar (1·61 g) of ethanol (2 〇 (4) in 'slowly add sulfoxide at room temperature Gas (i 〇 9mi). The anti-Liquid solution was heated to reflux for 2 hours, and then concentrated under reduced concentration to obtain titled person 121199.doc-491. 200846322 W-NMR (DMSO-d6) δ: 1.19 (3H, t , J=7.2 Hz), 1.95-2,05 (2H,m), 2·15 (2H,dtt,J=14.2, 7.1,7·1 Hz), 3.19-3.29 (2H, m), 3.38-3.31 (1H,m), 4.10 (2H,q,J=7.2 Hz). (2) l-[2_Sideoxy·2-[5·[(4-Phenyl-5-trifluoromethyl thiophene) Ethyl methoxy] porphyrin-1-yl]ethyl]pyrrolidine-3-carboxylic acid ethyl ester [562]

Acetonitrile (8.0 ml) at 1_(2_glycolyl)-5-[(4-phenyl-5-dimethylmethyl-2-pyranyl)methoxy]porphyrin (350 mg) To the solution, DIEA (539 μM) and ethyl 3-pyrrolidinecarboxylate hydrochloride (209 mg) were added at room temperature, and the mixture was stirred at 80 ° C for 1 hour. The reaction liquid was concentrated under reduced pressure, and water (5·0 ml), a saturated aqueous sodium hydrogen carbonate (3············ Further, the aqueous layer was extracted with a 1% methanol / chloroform mixed solution (3 x 5.0 ml), and the combined extracts were dried over anhydrous sodium sulfate, and the mixture was insoluble. The residue was purified using EtOAc (EtOAc) (EtOAc) ^-NMR (CDCls) δ : 1.25 (3H5 t) j.7 〇0 , person 2 Hz), 2.13 (2H, dt, J=8.5, 7.1 Hz), 2·66 (1H, dt,:Γ=7 ·6 7 ,7·6 Hz), 2.79 (1H, dd, J=5.9, 8·3 Hz), 2·90 (1H, dt, JU 7 , /·1 Hz), 3.04-3.14 (2H, m ),3·17 (2H,t,J=7.8 Hz), 3·4〇y T , UW,d,J=l_7 Hz), 4.14 (4H? q? J=7.2 Hz)5 5.20 (2H5 s) 5 6 8 1 nu ^ ,· ',(1H,d5 J=8.8 Hz), 121199.doc -492- 200846322 6.84 (1H,s),7.06 (1H,s)5 7·44_7·39 (5H,m ), 8·17 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 559 (M+H)+. (3) l-[2-Sideoxy-2·[5-[(4-phenyltrifluoromethyl 2·thienyl)methoxy]] 1 11 lin-1 -yl]ethyl] Bite _3-formic acid [Chemical 563]

1-[2-Sideyl-2-[5-[(4-phenyl-5-trifluoromethyl-2-synyl)methyl)pyroline-1-yl]ethyl To a solution of ethyl pyrrolidinecarboxylate (3 π mg) in THF (3.0 ml), MeOH (EtOAc) Water (5.0 ml) was added to the reaction mixture, and the pH was adjusted to 4 with N hydrochloric acid, and then a mixture of 20% methanol/chloroform (10 ml) was added. Further, the mixture was extracted with a 2% methanol/? chloroform mixture (3×5 ml), and the combined extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue was added: hexane (5.0 ml). Unconformed H-NMR _SO-d6) δ : 1.94 (2H, br s) 2 with , · 〇br 3·09 (m, br s), 3.26-3.58 (6H, br m), 4.08 (2H, Br s) , (2H, s), 6·86 (1H, d, J = 8.5 Hz), 6.96 (lH, br s), 7 34 · 32 s), 7.43 - 7.45 (5H, m), 7· 97 (1H,d,J=8.5 Hz). 121199.doc -493 - 200846322 MS (ESI) m/z : 531 (M+H) + 〇 [Example 121] 1·[2-Sideoxy-2-[5-[('phenyl __3 Fluorinyl-2-ylthiophene)methoxy]indole bunda-1 -yl]ethyl]bite_(3R)_carboxylic acid (1) (3R)-pyrrolidine decanoate hydrochloride Salt [化564]

Boc-N-NUH — HC, Ο Ο • In a solution of 1-(dibutyloxy.yl) σ piroxib-(311)-formic acid (ι·〇〇g) in sterol (10 ml), Thionite gas (712 μl) was slowly added at room temperature, and the mixture was heated under reflux for 2 hours. After the reaction mixture was cooled to room temperature, the title compound (617 mg). 'H-NMR (DMSO-d6) δ : 1.96-2.04 (1H5 m)? 2.11-2.19 (1H, m), 3.12-3.20 (4H, m), 3·23-3·36 (4H, m), 9·37 (1H, br s). (2) l-[2-Pentylsulfonyl-2-[5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]° porphyrin-1·yl]B Pyrrolidine-(3R)-carboxylic acid 2-oxo-2-[5-[(4-φ phenyl-5-trifluoromethyl-2-thienyl)methoxy] 吲哚-1 -yl]ethyl ester [Chemical 565]

Acetonitrile (5 ml) in 1-(2-ethaneethyl)-5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]porphyrin (407 mg) In the suspension, 3-(R)-pyrrolidinecarboxylic acid methyl ester hydrochloride (164 mg) and DIEA (784 μΐ) were added at room temperature, and 121199.doc -494-200846322 was stirred at 85 ° C for 2 hours. . After the reaction solution was allowed to stand to room temperature, it was concentrated under reduced pressure, and a 10% methanol/chloroform mixture (1 ml) and a saturated aqueous solution of sodium sulfonate (1 〇 ml) were added for liquid separation. Further, extraction was carried out with a mixture of 1 sterol/chloroform (3 x 10 ml), and the combined extracts were concentrated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc) H-NMR (CDC13) δ ·· 2.17-2.33 (2H, m), 2.72 (1H, dt, J=8.0, 7.6 Hz), 2·90-3·00 (2H, m), 3·14-3 · 32 (6H, m) 5 3·42 (2H, s), 4·04 (2H, t, J = 8.3 Hz), 4.15 (2H, t, J = 8.4 Hz), 4.76 (2H, s), 5.19 (4H, s) 5 6.78-6.86 (4H, m), 7.06 (2H, br s), 7·39-7·43 (l〇H, m), 8·10 (1H, d, J=8 8 Hz), 818 (1H, d, J = 8 8 Hz). MS (ESI) m/z: 946 (M+H)+. (3) 1 [2-Alkyloxy-2-[5-[(4-phenyl-5-tris)-yl-2-pyranyl) decyloxy] porphyrin-1-yl] Ethyl] fluorenidine _(3R)_carboxylic acid [Chemical 566]

In 1-[2-o-oxy-2-[5-[(4-phenyl-5-trifluoromethyl-2-thienyl)phosphonium] hydrazine. Wood I -1-yl]ethyl]T7 piroxime _(3R)_carboxylic acid 2_sideoxy-2-[5_[(4_phenyl-5-trismethylmethyl-2-thienyl)methoxy A solution of porphyrin-1-yl]ethyl ester (244 mg) in THF (2.0 ml) was added methanol (1 mL) and 1 N aqueous sodium hydroxide (1. Ml), stirred at room temperature for 7 hours. Then, water (2 ml) and diacetyl (5 ml) were added to the reaction mixture, and stirred at room temperature for 121 minutes at 121199.doc -495 - 200846322. The reaction liquid was separated, and the obtained aqueous layer was taken to pH 4 with aqueous hydrochloric acid, and then extracted with a 20% methanol/chloroform mixture (3 χ 5 ml). The combined extracts were dried with anhydrous sulfur and dried under reduced pressure. The residue was added to the residue of the residue (3 ml), and the insoluble matter was removed. The purification was carried out (NOMURA Develosil Combi-RP5), and the title compound was lyophilized to give the title compound (67 5 mg). iH-NMR (DMSO-d6) δ : 1·89 (2H, dt, J=7.1, 7.1 Hz), 2·58 (2H, dt, J=7.9, 7.9 Hz), 2·69 (1H, dd, J=8.〇, 6·3 Hz), 2·80 (1H, t, J-8·5 Hz), 2.86 (1H5 dt, J=7.15 7.1 Hz), 3.04 (2EU t, J=8.0 Hz) ,3·31 (2H, s), 4.05 (2H, t, J=8.5 Hz), 5.28 (2H, s), 6.79 (1H, dd, J=8.8, 2.0 Hz), 6.91 (1H, s), 7.30 (1H, s), 7·44-7·35 (5H, m), 7.92 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 531 (M+H)+ 〇 C27H25F3N2 〇4S.1.0H2O Elemental analysis calculated: c, 59.12; H, 4·96; F,1〇·39; N,5· 11; S, 5.85. Found: C, 58.96; H, 4.71; F, 10.20; N, 4.98; S, 5.70. [Example 122] l-[2-[5-(4-Isopropyl-3-trifluoromethylbenzyloxyxanthion-1-yl)-2-yloxyethyl] _(3R)·formic acid (1) (3 R)-ethoxycarbonylpiperidine-1-acetic acid benzyl ester [Chemical 567] Ten HfOyOv —- 〇ο 12H99.doc 200846322 bromoacetic acid glutamate (2·38 ml In a solution of acetonitrile (3 〇ml), DIEA (3_92 ml) and ethyl 3-(R)-piperidinecarboxylate (2·36 SJ, at 8 0 C) were added under the camp and w 'main> dish. After stirring for 2 hours, the reaction mixture was allowed to cool to room temperature, and concentrated under reduced pressure. Water (20 ml) and 1% methanol/chloroform mixture (30 ml) were added to the residue, and the mixture was separated. The aqueous layer was extracted with EtOAc EtOAc (EtOAc (EtOAc) δ : 1·24 (3H, dt, J=l.〇, 7·1 Hz), 1.3m 47 (1H, m), 1·58-1·77 (2H, m), 1.97 (1H, dd , J=12.4, 3·2 2.20 (1H, dt, J=3.2, 11.0 Hz), 2·36 (1H, t5 Hz) 5 2 59 2·67 (1H, m), 2·85 (1H, d , J=ll.〇Hz), 3.09 (lH dd J=ll.〇, 2.9 Hz ), 3.29 (2H, s), 4·12 (2H, q5 J=7_2 Hz), 5 16 (2H, s), 7·32-7·36 (5H, m). (2) (3R) - Ethoxyl group slightly biting _1-acetic acid [Chemical 568]

〇0 (3R)-ethoxycarbonylpiperidine- _ benzyl acetate (4·18 g) was dissolved in methanol (70 ml), adding 5% Pd/C (20 mg) under hydrogen atmosphere. Stir at room temperature for 5 hours. After the reaction mixture was filtered over EtOAc (EtOAc m. lH-NMR (CDC13) δ : 1.26 (3H5 t5 J=7.1 Hz) 5 1.50-1.60 (iH m), 1.89 (1H, dt, J=14.6, 3·4 Hz), 2·01-2·1〇 (1H,m),2 u 121199.doc -497· 200846322 2·20 (1H,m),2.69 (1H,dt,J=2.2,11,7 Ηζ),2·85 (1H,t, J= 11.6 Hz),3·06-3.14 (1H,m),3.54 (2H,s),3.58-3.65 (1H, m), 3.74 (1H,d,J=12.4 Hz), 4.15 (2H5 q,J= 7.1 Hz). (3) l-[2-(5-Benzyloxyporphyrinoxyethyl)piperidine _(3R)-ethyl formate [Chemical 569]

Add DIEA (1.57 ml), HOBt (527 mg) and EDOHCl (748 mg) at room temperature in a solution of (3R)-ethoxylated ketone acetic acid (646 mg) in DMF (10 ml). After stirring for 1 minute, 5-benzyloxyporphyrin hydrochloride (78 5 mg) was added at room temperature. After the reaction mixture was stirred at room temperature for 3 hours, it was concentrated under reduced pressure, and water (3 ml) and water (30 ml) were added to the residue. Further, after extracting the aqueous layer with chloroform (3x2 〇 ml), the combined extracts were dried over anhydrous sodium sulfate, and then reduced under reduced pressure. The residue obtained was purified by using Shixi gum column chromatography (Biotage 40S) to obtain the title compound (9 8 〇 m g).

'H-NMR (CDC13) δ : 1·21 (3H, t, J = 7.8 Hz), 1·60-1·77 (3H, m), 1·87·2·02 (1H, m), 2.15 -2.47 (2H,m),2·59"2·67 (iH m),2·79-2·87 (1H,m),3·01-3·10 (1H,m),3·14 ( 2H, t J=8.5 Hz), 3·25 (2H, s), 4·11 (2H, q, J=7.8 Hz), 4·16 (1H, dt, J=9.0, 7·1 Hz), 5.04 (2H, s), 6.79-6.84 (2H, m), 7·44· 7·29 (6H, m), 8.14 (1H, d, J = 8.8 Hz). 121199.doc -498- 200846322 MS (ESI) m/z : 423 (M+H) + (4) 1-[2-(5_ per ̄°°ϋϋϋ-1-yl)-2-sideoxyethyl] - (3R)-ethyl decanoate [化570]

Methanol (30 mg) of 1-[2-(5-benzyloxy 1 bromo-1(yl)-2)-oxyethyl]-salt-(3R)-φ decanoate (980 mg) In a solution of ml), 5% Pd/C (15 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. After the reaction mixture was filtered over with celite, the filtrate was concentrated under reduced pressure, and the residue was purified using EtOAc (EtOAc) ^H-NMR (CDCls) δ : 1.21 (3H5 t5 J^yl Hz)? 1.45-1.68 (2H? m), 1.69-1.77 (1H, m), 1.87-1.94 (1H, m), 2_24 (1H, Dt, J=3.25 10.5 Hz), 2.43 (1H, t, Ji〇.3 Hz)&gt; 2.60-2.66 (1H5 m), Φ 2·79-2·85 (1H, m), 3·03 UH, Dd, J=u.2, 2.7 Hz), 3·09 (2H, t, J=8.3 Hz), 3·24 (2H, d, J=2.7 Hz), 4·11 (2H, q, J= 7.3 Hz), 4·14 (2H, t, J = 8.5 Hz), 6.72-6.68 (2H, m), 8.07 (1H, d, J = 8.5 Hz). (5) l-[2-[5-(4-Isopropyl-3-trifluoromethylbenzyloxy)porphyrin-oxyethyl]piperidine-(3R)·ethyl formate [Chemical 571 ] 121199.doc -499- 200846322

Add potassium carbonate (290 mg) and 1-[2-() in a solution of 4-isopropyl-3-(trifluoromethyl)benzyl chloride (166 mg) in DMF (5.0 ml). 5 - Meridian. Noise-carrying - 1 _ yl) 2_ oxyethyl] brigade _ (3r) _ ethyl acetate (233 mg). After stirring at 60 ° C for 4 hours, the reaction solution was cooled to room temperature and concentrated under reduced pressure. Water (〗 〖5 ml) and a 10% methanol/gas mixture (3 〇 ml) were added to the resulting residue for liquid separation. Further, the aqueous layer was extracted with a 1% hydrazine/chloroform mixture (2×1 5 ml), and the combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc) H-NMR (CDC13) δ : 1.21 (3Η, t5 J=7.2 Hz), 1.26 (6H5 d, J=6.6 Hz), 1.46-1.57 (1H, m), 1.60-1.67 (1H, m), 1.72 1.76 (1H, m), 1.89-1.93 (1H, m), 2.21-2.29 (1H, m), 2·45 (1H t Φ J=10·7 Hz), 2·60_2·66 (1H, m) , 2.78-2.86 (1H, m), 3·03 (1H, d, J-8.8 Hz), 3.15 (2H, t5 J = 8.4 Hz), 3.25 (2H, d, J = 3.9 Hz), 3.36 (1H, dq, J=6.6, 6.6 Hz), 4.10 (2H, t, J = 7.1 Hz), 4.17 (2H, q, J = 7.3 Hz), 5.02 (2H, s), 6.79 (1H, dd, J-8.8, 2.4 Hz), 6.83 (1H, br s), 7.48 (1H, d, J=8, 〇Πζ), 7.56 (1H, d, J-8.0 Hz), 7·65 (1H, s), 8.15 (1H, d, Hz). MS (ESI) m/z: 533 (M+H)+. (6) l-[2-[5-(4-Iso-3-difluorodecylbenzyloxy) sulfanyl] 121199.doc -500 - 200846322 Side oxyethyl]acridine- (3R)-formic acid [化572]

1-[2-[5-(4-Isopropyl-3-disorganomethylbenzyloxy)anthracene 〇 〇 -1 -1 -1 -1 -1 ] ] ] · · · · · ( ( ( ( ( ( ( ( ( ( ( To a solution of ethyl formate (324 mg) in THF (3 〇mi), methanol (1.5 ml) and 1 N aqueous sodium hydroxide (1·50 ml) were added at room temperature. After the reaction mixture was stirred at room temperature for 2 hours, water (5 ml) was added, and pH was adjusted to 4 with 1 N hydrochloric acid, and a mixture of 1% methanol/chloroform (30 ml) was added thereto to carry out liquid separation. Further, the aqueous layer was extracted with a 10% methanol/chloroform mixture (2 &lt; 15 ml), and the combined extracts were dried over anhydrous sodium sulfate. Dimethyl sapite (4.0 ml) was added to the obtained residue, and the insoluble matter was removed, and then purified by high performance liquid chromatography (n〇mura Develosil Combi-RP5), and the target fraction was cooled to dryness. The title compound (149 mg). !H-NMR (DMSO-d6) δ : 1.23 (6H5 d5 J=6.8 Hz)? 1.31-1.52 (2H,m), 1.58-1.66 (1H,m),1·72-1·80 (1H,m ), 2·21 (1H, t, Hz), 2·29, 2·37 (1H, m), 2.40-2.46 (1H, m), 2.63-2.70 (1H, m), 2·89 (1H, d, J = 8.5 Hz), 3·08 (2H, t, J = 8.4 Hz) 3.18-3.22 (1H, m), 3·24 (1H, d, J = 5.4 Hz), 3.30 (2H, br s ), 4.14 (2H, t, J-8.4 Hz), 5.10 (2H, s), 6.80 (ih, dd, J = 8 8 2.0 Hz), 6.93 (1H, br s), 7·70-7·64 (3H, m), 7.95 (1H, d, J = 8_8 Hz) 〇121199.doc -501 - 200846322 MS (ESI) m/z : 505 (M+H)+. Calcd for C27H3iF3N2O4.0.75H2O: C, 62.60; H, 6.32; F,11.00; N, 5.41. Found: C, 62·66; Η, 6·18; F, 10.81; N5 5.3 8 〇 [Example 123] 3-[N-[(lS)·Methyl-2-oxooxy-2-[ 5-[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxyp-p-oxalin-1-yl]ethyl]amino]propanoic acid (1) 1-[(2S) -[N-[(Tertibutoxycarbonyl)amino]propanyl]-5-[(4-phenyl-5-trifluoromethyl-2-thienyl) decyloxy] porphyrin [ 573]

Add DIEA (523 μΐ), HOBt (176 mg) and EDC.HC1 at room temperature in a solution of N-(t-butoxycarbonyl)-D-alanine (189 mg) in DMF (5.0 ml). 249 mg). After the reaction mixture was stirred for 10 minutes, 5-[(4-bromo-difluoroindolyl) methoxy]indole hydrochloride (412 mg) was added and stirred for 14 hr. The reaction mixture was concentrated under reduced pressure. ethyl acetate (10.0 ml) and water (7.5 ml) The combined extracts were concentrated under reduced pressure and purified to purified crystals eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted Hz), 1.44 (9H, s)5 3·17·3·25 (2H, br m), 4.04-4.14 (1H, m), 4·3〇〇H, dt, H0, 9·8 Hz), 4·58 (1H, dq, J=7.3, 7·1 Hz), 5·20 (2H, s), 121199.doc - 502 - 200846322 5.44 (1H, d, J=8.0 Hz), 6.82 (1H, d, J = 8.8 Hz), 6.85 (1H, s), 7.06 (1H, s), 7.43-7.38 (5H, m), 8.15 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 547 (M+H)+. (2) 1-[(2S)-Aminopropionyl]-5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]pyrene hydrochloride 574]

1-[(2S)-N.(Tertibutoxycarbonyl)amino]propanyl]-5-[(4-phenyl-5-trifluoromethyl-2-thienyl)decyloxy To a solution of porphyrin (324 mg) in dioxane (0.5 ml), 4N hydrochloric acid / 1,4-dis-hexane (1.0 ml) was added at room temperature and stirred for 13 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj ^H-NMR (DMSO-d6) δ : 1·43 (3H, d, J = 6.8 Hz), 3.18 (2H, t, J = 8.3 Hz), 4.08-4.27 (3H, m), 5.37 (2H, s), 6.92 (1H, dd, J = 8, 8, 2.4 Hz), 7.04 (lH, (i, J = 2.4 Hz), 7.37 (lH, s), 7.41 - 7.51 (5H, m), 8,01 (1H,d,J=8.8 Hz), 8.45-8.29 (2H,br m) o MS (ESI) m/z : 447 (M+H)+ (3) 3-[N-[( lS)-fluorenyl·2_sideoxy-2-[5-[(4-phenyl-5-trifluoromethyl-2-121199.doc-503 - 200846322 thienyl)methoxy]porphyrin -1-yl]ethyl]amino]propionic acid tert-butyl ester [Chemical 575]

In the case of 1-[(:28)-aminopropenyl]-5-[(4-phenyl-5-trifluorodecyl-2-nonyl)methoxy]° (236 mg) in THF (1.0 ml), add 1-butyl-3·methylmeridene hexafluoride (2.〇mi) and tert-butyl acrylate (116) at room temperature. The mixture was stirred at 60 ° C for 24 hours, followed by the addition of tributyl acrylate (6 μM), and stirred at 60 ° C for 2 Torr. The reaction mixture was concentrated under reduced pressure. chloroform (10.0 ml) and water (7.5 ml) were added to the mixture, and the aqueous layer was extracted with chloroform (3 x 5.0 ml), and the combined extracts were concentrated under reduced pressure. The resulting residue was purified using EtOAc EtOAc (EtOAc) elute 'H-NMR (CDC13) δ : 1.31 (3H? d? J=6.8 Hz) 5 1.44 (9H5 s) • 2·41 (2H, t, J=7.6 Hz), 2.70 (1H, dt, J=ll .7, 7_3 HZ), 2.87 (1H? dt? J=ll.?5 7.3 Hz), 3.21 (2H5 t5 J=8,5 Hz)? 3.53 (1H5 q, J—6·8 Hz), 4.06 ( 1H, dt, J=7.3, 9·8 Hz), 4·22 (1H, dt J—8·5' 9·8 Hz), 5·21 (2H, s), 6.82 (1H, dd, J= 8.8, 2·4 Hz), 6.85 (1H, br s)5 7.06 (1H5 s)3 7.43-7.38 (5H, m)5 8.22 (lH d,1=8 · 8 Hz) 〇' (4) 3_[ N-[(1S)·Methyl-2-Phenoxy-2-[5-[(4-phenyl-5-trifluoromethyl_2_ fluorenyl)methoxy H) Ethyl]amino]propionic acid 121199.doc -504- 200846322 [化576]

3-[N-[(lS)-Methyl-2-oxoyl-2_[5-[(4-phenyl-5-trifluoromethyl-2-thiophenyl) decyloxy] porphyrin- Add 4-n salt φ acid/i,4- at room temperature to a solution of 1-yl]ethyl]amino]propionic acid tert-butyl vinegar (220 mg) in 1,4-bisazide (0.3 ml) Dioxane solution (1.5 ml) was stirred for 13 hours. The reaction mixture was concentrated under reduced pressure. Water (yield: 3.0 ml) was added to the residue, and the mixture was stirred with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with 20% methanol/chloroform mixture (4×3.0 ml). The combined extracts were dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc) ^-NMR (DMS0-d6) δ : 1.17 (3Η, d, J-5.6 Hz)? 2.26 (2H, t, _ J=6.8 Hz)? 2.56-2.73 (2H? m)5 3.13 (2H5 t, J ~7.8 Hz), 3.59 (1H, d, J=5.4 Hz), 4.06 (1H, dt, J=8.5, 8.0 Hz), 4·25 (1H, dt, J=8.5,8·5 Hz), 5 · 34 (2H, s), 6.86 (1H, d, Hz), 6·98 (1H, s), 7·35 (1H, s), 7.40-7.49 (5H, m), 8·06 (1H, d, J = 8.3 Hz). MS (ESI) m/z: 519 (M+H)+. Calculated value of elemental analysis of C26H25F3N204S.1.75H20 · c, 56·77; H, 5.22; F, 10·36; N, 5·09; S, 5.83. Found: c, 56.76; H, 121199.doc - 505 - 200846322 5.07; F, 10.16; Ν, 5·09; S, 5.66. [Example 124] 3-[N-[l,l-dimethyl-2-oxoyl-2-[5-[(4-phenyl-5-trifluoromethyl-2-thienyl)) Oxy]porphyrin-1-yl]ethyl]amino]propionic acid (1) 1-indole[Ν-(t-butoxycarbonyl)amino]-2-methylpropanyl]-5 -[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]porphyrin [Chemical 577]

In a solution of N-(t-butoxycarbonyl)-2,2-dimercaptoglycine (203 mg) in DMF (5.0 ml), 〇正八(523卜1), HOBt( 176 mg) and EDOHCl (249 mg) were stirred for 1 min, then 5-[(4-phenyl·5-trifluoromethyl-2-nonyl)methoxy]porphyrin was added at room temperature. Hydrochloride (4 12 mg). After stirring for 14 hours, the reaction mixture was concentrated under reduced pressure. EtOAc (1 EtOAc··················· The combined extract was concentrated under reduced pressure. ^-NMR (CDC13) δ ·· 1·28·1·45 (9H,br m)5 158 (3H,br s), 1·65 (3H,s),3.09 (2H,t,J=8.0 Hz ), 4·21 (2H, t, J=8.0 Hz), 5.20 (2H5 s)3 6.82 (1H3 dd, J=8.5? 2.2 H2)5 6.85 (1H5 br s), 7.06 (1H, s), 7.39 -7.43 (5H,m),8.02 (iH,s),8·27·819 (1H,br m) 〇121199.doc -506- 200846322

MS (ESI) m/z: 560 (M)+. (2) 1-(2-Amino-2-mercaptopropyl)_5_[(4-phenyl-5-trifluoromethyl-2-thiophenyl)methoxy]« porphyrin [578 ]

1-[2·(Secondoxycarbonylamino)-2-methylpropenyl bromide 5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]oxime Add 4 N hydrochloric acid n,4-dioxane solution (1.5 ml) to a solution of porphyrin (561 phantom) in a solution of 561 phantoms. To the residue, water (2.0 ml), a 10% methanol/chloroform mixture (3. 〇ml), and a saturated aqueous solution of sodium hydrogencarbonate were added for liquid separation, and further, a mixture of 1% methanol/chloroform (3×3. 0 ml) extract the aqueous layer. The combined extracts were anhydrous sodium sulfate.

After drying, the insoluble material was filtered, and the filtrate was evaporated to dryness to give the title compound (3 18 mg). ^-NMR (CDC13) δ : 1.49 (6H5 s), 3.11 (2H? t5 J=8.1 Hz)? 4.48 (2H, t, J=8.1 Hz), 5,20 (2H, s), 6.81 (1H, Dd, J=9.〇, 2.2 Hz), 6.85 (1H? br s)5 7.06 (1H5 s)? 7.38-7.43 (5H5 m), 8.18 (1H, d, J=9.0 Hz). MS (ESI) m/z: 461 (M+H) + o (3) 3-[N-[l,l-dimethyl-2-oxo-2-[5-[(4-phenyl) -5-trifluoromethyl 2-thienyl)methoxy]porphyrin-1-yl]ethyl]amino]propionic acid tert-butylate [化579] 121199.doc -507- 200846322

1-(2-Amino-2-mercaptopropyl)-5-[(4-phenyl-5-trifluoromethyl-2-thinyl)methoxy]porphyrin (318 mg In a solution of THF (1.0 ml), 1-butyl-3-methylimidazolium rust hexafluoride hexafluoride (2·〇ml) and tributyl acrylate (1.50 ml) were added at room temperature. The reaction solution was stirred at 60 ° C for 24 hours, then tert-butyl acrylate (3·〇 ml) was added, and stirred at 6 ° C for 4 Torr. The reaction mixture was concentrated under reduced pressure, and then aqueous mixture was evaporated, and then water (7·5 ml) was partitioned, and the aqueous layer was extracted with chloroform (3×5.0 ml). The combined extracts were concentrated under reduced pressure. MS (ESI) m/z: 589 (M+H)+. (4) 3_[1,1-Dimercapto-2-oxo-2-[5-[(4-phenyl-5-trifluoromethyl-2-thienyl)decyloxy]. Bow 1 porphyrin-1-yl]ethylamine]propionic acid [Chemical 580]

3-[Ν-[1,1-Dimethyl_2_sideoxy-2 over 5-7 4 phenyl-trifluoromethyl-2-phenylenyl)methoxy]porphyrinyl] a solution of 4 N hydrochloric acid / 1,4-dioxane at room temperature in a solution of tert-butyl propionate (40.6 mg) in 1,4-dioxane (〇·5 ml) 1 〇 ml), stir for 1 hour. Concentrate 121199.doc • 508 - 200846322 under reduced pressure, add water (20 ml), 2% methanol/chloroform mixture (3.0 ml) and saturated sodium bicarbonate solution to pH. 7. The mixture was extracted with a 20% methanol/chloroform mixture (3×3 〇 ml), and the combined extracts were dried over anhydrous sodium sulfate, filtered, and filtered. The resulting residue was purified using EtOAc EtOAc (EtOAc) MS (ESI) m/z: 533 (M+H)+. [Example 125] 2-Fluoro 3-[Ν-[2-trioxy-2-[5-[(4-phenyltrifluoromethyl-2-thienyl)methoxy]·2,3 Monohydrogen 1H-indenyl]ethyl]amino]propionic acid (1) 3-(dibenzylamino[2-fluoropropionate Cf·) Tetrahedron Lett., 2003, 44, 2375 [Chem.

&lt;Q-N-Sr0^~ ο In THF (1.10 g), THF (10 ml) and tridecyl decane chloride (1.06 ml) were added at room temperature. After stirring at room temperature for 10 minutes, ethyl 2-bromo-2-fluoroacetate (1·〇〇 g) was added at room temperature. After stirring at room temperature for 1 minute, 1 Η·1,2,3-benzotriazol-1·yl-N,N-dibenzylmethylamine (Tetrahedron Lett., 2003, 44, 2375) was added at room temperature. (2.74 g) in THF (15 ml). After stirring at room temperature for 18 hours, a saturated aqueous solution of sodium hydrogencarbonate (50 ml) was added, and the mixture was filtered using Florite, and ethyl acetate (50 ml) was added thereto, and the mixture was separated. After the organic layer was dried over anhydrous sodium sulfate, a solvent of 121199.doc-509-200846322 was distilled off under reduced pressure. The title compound (1.15 was obtained by the purification of the residue obtained by silica gel flash column chromatography (Bi〇tage 4 〇M).

H-NMR (CDC13) δ : 1.21 (3H5 t, J=7.1 Hz)? 2.92-3.ι2 (2H m)5 3.55 (2H, d5 J=13.6 Hz), 3·83 (2H, d, J= 13.6 Hz), 4 07_ 4·29 (2H, m), 4.96-5.13 (1H, m), 7.21-7.36 (10H, m). MS (ESI) m/z: 316 (M+H)+. (2) 3-Amino-2-fluoropropionate ethyl ester trifluoroacetate [Chemical 582]

OH h2n octa(palladium hydroxide (丨2〇mg) was added to a solution of ethyl 3-(dibenzylamino)-2-fluoropropionate (115 g) in ethanol (4 〇mi) at room temperature. After the hydrogen exchange was carried out, the mixture was stirred for 18 hours with the addition of difluoroacetic acid (0.337 ml). The title compound (85 mg) was obtained. 3H,t,J=7.1 Hz), 3.25-3.48 • (2H,m), 4.21 (2H,q,J=7.1 Hz), 5.30-5.47 (1H, m),8,26 (311,1^8 Included in the peak of 8.26. MS (ESI) m/z M35 M+. (3) 2-Fluoro-3-[N-[2-Sideoxy-2-[5-[(4- Phenyl-5-trifluoromethyl-2-thienyl)methoxy]-2,3-dihydroindole-indolyl]ethyl]amino]propionic acid ethyl ester [Chem. 583] 121199.doc -51〇. 200846322

To a solution of ethyl 3-amino-2-fluoropropionate trifluoroacetate (125 mg) in acetonitrile (go ml) at room temperature, 2· bromo-l-[5-[[4-phenyl 5- 5-(trifluoromethyl)-2_thienyl]methoxy]-2,3-dihydro-1H-indol-1-yl]ethanone (1 mg) and DIEA (0.175 ml) The mixture was stirred at 8 °C for 15 hours. After it was allowed to cool to room temperature, it was concentrated under reduced pressure, and the obtained residue was purified using a silica gel rapid column chromatography method (Biota§e 25M) to obtain the title compound. (60.6 mg). !H-NMR (CDC13) δ : 1.32 (3Η, t5 J=7.1 Hz), 3.12-3.32 (4H? m), 3 · 5 6 ( 2 H, s), 4 · 01 (2 H,t,J=8 · 5 H z),4 · 2 8 (2 H,q,J=7 · 1

Hz), 4.96-5.12 (1H, m), 5.20 (2H, s), 6.82 (1H, dd, J=8.6, 2.6 Hz), 6.85 (1H, s), 7.06 (1H, s), 7 · 37-7·44 (5H, m), 8.16 (1H, d, J = 8.6 Hz). No NH was observed. MS (ESI) m/z: 551 (M+H)+. • (4) 2_Fluoro-3-[N-[2-o-oxy-2-[5-[(4-phenyl-5-trifluoromethyl-2-thienyl)decyloxy]-2 ,3-dihydro-1H-inden-1.yl]ethyl]amino]propionic acid [化584]

2-Fluoro-3-[N-[2-o-oxy-2-indole[(4-phenyl-5-trifluoromethyl)2-thienyl)methoxy]-2,3-dihydro -1Η-吲哚-l-yl]ethyl]amino]propionic acid ethyl ester 121199.doc -511 · 200846322 (60_0 mg) in THF (2.0 ml), methanol was added at room temperature (1 〇ml) ), water (〇·50 ml), and 1 N aqueous sodium hydroxide solution (〇·545 ml). After stirring at room temperature for 3 hours, iN hydrochloric acid (〇·545 ml) and water (10 ml) were added to the reaction mixture, and the organic solvent was evaporated under reduced pressure. The resulting solid was filtered and dried to give the title compound (53. H-NMR (DMSO_d6) δ : 3.00-3.20 (4H,m),3·65 (2H,s), 4·02 (2H,t,J=8.4 Hz),4·90-5·07 (1H ,m),5.35 (2H,s), 6.87 (1H,dd,J=8.8,2.7 Hz),6·99 (1H,s),7·36 (1H,s), 7.40-7.51 (5H,m ), 7·99 (1H, d, J = 8.8 Hz). C02H and NH 〇 IR (ATR) cm·1 : 3055, 1674, 1491, 1371, 1290, 1265, 1242, 1115, 1093, 1014, 808, 762, 698 were not observed. MS (ESI) m/z: 523 (M+H)+. HR-MS (ESI) for C25H23F4N204S (M+H)+: 523.15654. Found: 523.15758. Calculated for elemental analysis of C25H22F4N204S: C, 57·47; H, 4·24; F, 14·54; Ν, 5.36; S, 6.14. Measured value·· C, 57·63; Η, 4·37; F, 14.06; Ν, 4·98; S, 5.95 〇 [Example 126] 3-[Ν-[2-[4-methyl-5 -[[4-Phenyl-5-(trifluoromethyl)-2-thienyl]methoxy]-2,3-dihydro-1Η-吲哚-1_yl]-2-yloxy B (amino) propionic acid (1) 5-methoxy-4-mercapto-1H-indole-1-carboxylic acid tert-butyl ester [Chem. 585] 121199.doc -512· 200846322

Add DMAp (265 mg) at room temperature to a solution of 5-methoxy-4·methyl-1H-indole-!• formic acid (commercial) (6.99 g) in THF (50 ml) Β〇(:2〇(9·95 g). The reaction mixture was stirred at room temperature for 17 hours, then concentrated under reduced pressure. Purified by silica gel flash column chromatography (Bi〇tage 4〇M) The residue was the title compound (u.3 g).

W-NMR (CDC13) δ : 1.66 (9H, s), 2·38 (3H, s), 3·87 (3H, s), 6·55 (1Η, d, J=3.5 Ηζ), 6.92 (1Η, d, J = 8.5 Ηζ), 7.56 (1H, br d, J = 3.5 Hz), 7.90 (1H, br d, J = 8.5 Hz). MS (ESI) m/z: 262 (M+H) + (2) 3-methoxy-4-mercapto-1-pyridinic acid tert-butyl ester [Chem. 586]

Adding ethanol (200 ml) at room temperature to a solution of 5-methoxy-4-methyl-1H-indole-1-carboxylic acid tert-butyl ester (12·7 g) in THF (50 ml) 5% Pd/C (6,3 5 g), the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 15 hours, then filtered, and the filtrate was concentrated under reduced pressure, and water (3 〇〇ml) After the slurry was filtered, it was filtered and dried (vacuum pump, 50 ° C, 4h) to give the title compound (12.4 g). W-NMR (CDC13) δ : 1·54 (9H, s), 2·10 (3H, s), 2.98 (2H, t, J = 8.5 Hz) 5 3.79 (3H5 s)? 3.97 (2H5 br s) 5 6.64 (1H? d5 J-8.8 Hz), 7.22 (1/2 of 1H, bi* s), 7.61 (1/2 of 1H, br s). 121199.doc -513- 200846322 MS (ESI) m/z : 264 (Μ+Η)+ 〇(3) -4-methyl·1 ·〇弓 I 〇多琳曱酸丁丁酯 (pa( Jwa, Albert. et al., J. Org Chem, (1999) 64(10), 3595-3607·) [Chem. 587]

Adding three at -78 ° C in a solution of 3-methoxy-4-methyl-1-carbolinecarboxylic acid tert-butyl ester (1 〇〇g) in dioxin (35 ml) Desertification boron (1 μ 2 gas sputum solution) (8.30 ml). The reaction mixture was slowly warmed to room temperature and stirred for 17 hours. Add saturated aqueous sodium hydrogencarbonate solution (2 〇〇ml), water (50 ml), and di-methane (1 〇〇ml) to the reaction mixture, and stir for 1 hr, then add B〇C2〇 (870 mg). . After the reaction solution was stirred at room temperature for 1 hour, the aqueous layer was taken up in a gas-fired (1 〇〇 ml). After the combined extracts were dried over anhydrous sodium sulfate, the solvent was evaporated to dryness, and the obtained residue was purified by gel column chromatography (Biotage 40M). The obtained solid was slurried in hexanes, filtered, taken and dried to give the title compound (580 mg) 〇iH-NMR (CDC13) δ: 1.56 (9H, s) 5 2·12 (3H, s), 2.98 (2H, t, J = 8.7 Hz), 3.97 (2H, br s), 4.50 (1H, s), 6.58 (1H, d, J = 8.5

Hz), 7_14 (1/2 of 1H, br s), 7.55 (1/2 of iH, br s). MS (ESI) m/z: 250 (M+H)+. (4) 4-Methyl-5-[[4-phenyl-5-(trifluoromethyl)-2-nonyl]methoxy] porphyrincarboxylic acid tert-butyl ester 121199.doc -514- 200846322 [化588]

5-(Chloromethyl)-3-phenyl-2-(trifluoromethyl)thiophene (333 mg) and 5-butyryl-4-mercapto-1-pyridiniumcarboxylic acid tert-butyl ester (3 Potassium carbonate (mo mg) was added to the solution of methylene chloride (5·0 ml) in a solution. After stirring for 16 hours, the reaction solution was cooled to room temperature, and the precipitate was removed by filtration. Water (40 ml) and saturated aqueous ammonium chloride (4 ml) were added to the filtrate, and extracted with ethyl acetate (2×30 ml). The combined extracts were washed with saturated brine (30 ml) The title compound (547 mg) was obtained from mjjjjjjjjjjj CDC13) δ : 1.55 (9H? s)? 2.16 (3H, s)5 3.00 (2H, t5 1=8.5 Hz) 5 3.98 (2H5 br s)? 5.19 (2H5 s)? 6.73 (1H5 d3 J=8.8 Hz ), 7·04 (1H, s), 7·24 (1/2 of 1H, br s), 7.35_7·45 (5H, m), 7.63 (1/2 of 1H, br s) MS (ESI) m/z : 512 (M+Na)+ (5) 4-mercapto-5-[[4-phenyl-5-(trifluoromethyl)_2-thienyl]methoxy porphyrin salt Acid salt [Chemical 589] 121199.doc -515- 200846322

In 4-methyl-5-[[4-phenyl-5·(trifluoromethyl)_2"septenyl]methoxy]succinyl carboxylic acid tributyl vinegar (547 mg) 4% hydrochloric acid diterpene solution (commercially available) (5.0 ml) was added to the mixture for 2 hours under temperature. The reaction solution was concentrated under reduced pressure.

Thereafter, the hexane was added and the resulting solid was obtained by filtration, and dried to give the title compound (43 3 mg). ^-NMR (DMSO-d6) δ : 2.16 (3Η, s), 3.13 (2H, t, J=7.7 Hz), 3.70 (2H, t, J=7.7 Hz), 5.44 (2HS s), 7.09 (1H , d5 J=8.8

Hz), 7.23 (1H, d, J = 8.8 Hz), 7.38 (ih, s), 7.40-7.52 (5H, m), 11.00 (2H, br s). Contains 1^ in the peak of 11·〇〇. MS (ESI) m/z: 390 (M+H)+. (6) 3-[N-(Tertibutoxycarbonyl)-N_[2_[4_methyl_5_[[4-Phenyl-5(trimethyl)-2-thienyl]methoxy) ]·2,3_Dihydro_1Η_吲哚d-yl]_2_sideoxyethyl]amino]propionic acid tert-butyl ester [Chem. 590]

Yuren Methyl-5-[[4-phenyl-5-(trimethylmethyl)thienyl]methoxy]indole hydrochloride (130 mg) and 2-[N-(third butoxy Alkylcarbonyl)-N-[3_(2-butyldecyl)-3-oxopropyl]amino]acetic acid (U1 mg) of dichloromethyl 121199.doc -516- 200846322 alkane (3.0 1111) in suspension Add 〇(:&gt;11(::1€87 7 11^, HOBt(61.8 mg), and ΤΕΑ(0·213 ml) for 18 hours at room temperature. Add the acetic acid (2 〇m 1 ), a saturated aqueous solution of sodium hydrogencarbonate (40 ml), and water (40 ml), and extract with ethyl acetate (20 ml). The aqueous layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The residue was purified using silica gel chromatography (Biotage 25M) to give the title compound (178 mg). NMR (CDC13) δ : 1·35·1·62 (18H,m), 2·17 (2/3 of 3H, s), 2.19 (1/3 of 3Η, s), 2·54-2·63 (2Η,m),3β08_3 18 (2Η,m), 3.54-3.62 (2Η,m),4·00-4·20 (4Η,m),5·20 (2/3 of 2H,s), 5 ·21 (1/3 2 2 H, S) 56.70-6.78 (lH, m), 7.05 (1H, s), 7 36-7. 46 (5 Η, m) 5 7.95-8.05 (1 Η, m) MS (ESI) m/z: 675 (M+H)+ (7) 3-[N-[2-[4-Benzyl·5-[[4-phenyl-5·(trifluoromethyl)_2·thienyl]methoxy] -2,3-dihydro-1H-indol-1-yl]-2-yloxyethyl]amino]propionic acid [Chemical 591]

3-[N-(Tertibutoxycarbonylmethylphenyl-5-(tri-indolyl)-2-thienyl]nonyloxy]-2,3-dioxa·1H_indole small group] -2· oxoethyl]amino]propionic acid tert-butyl ester (176 mg), added I21199.doc -517- 200846322 at room temperature plus 4 N hydrochloric acid dioxane solution (commercially available) (5 · 〇ml), stirring for 16 hours. After concentrating the reaction solution under reduced pressure, the residue was added with diethyl hydrazine to be slurried, using reverse phase high performance liquid chromatography (manufactured by Nomura Chemicals Develosil Combi- RP-5 (10 cm) was purified by filtration. The title compound was purified to dry crystals to give the title compound (60.5 mg). H-NMR (DMSO-d6) δ: 2.11 (3Η, s)? 2.37 (2H? t ? J=6.7

Hz), 2·84 (2H, t, J=6,7 Hz), 3.07 (2H, t, J=8.1 Hz), 3·59 (2H, s), 4.05 (2H, t, J=8.1 Hz) ),5·35 (2H,s),6·91 (1H,d, J=8.7 Hz),7·35 (1H,s), 7.40-7.50 (5H,m), 7.86 (1H,d,J =8.7Hz). C02H and NH were not observed. IR (ATR) cnT1 : 2951,1641,1597,1377,1288,1257,1173, 1117, 1099, 1014, 766, 698. MS (ESI) m/z: 520 (M+H) + </ s </ br> </ br> </ br> </ br> Found: 5 19.15631. Calculated for the elemental analysis of C26H25F3N2O4S*1.0H2O: C, 58.20; H, 5·07; F, 10.62; N, 5.22; S, 5.98. Found: C, 58·07; H, 4.82; F, 10.48; N, 5·13; S, 5.92. [Example 127] (R)-3-[N-(Tertibutoxycarbonyl)-N-methylamino]-cardioxy-4-[5-[(4-phenyl-5-III) Fluoromethyl-2-nonyl)methoxy]oxime. (10-[(4-phenyl-) 5-trifluoromethyl-2-thienyl)methoxy]porphyrin-1-yl]butyrate decyl ester 121199.doc •518- 200846322 [Chemical 592]

Boc in 1-(t-butoxycarbonyl)-5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]porphyrin hydrochloride (〇.1311^) ,: 8〇〇0-]\^-8:8 (01^)-OH (78 mg), EDOHCl (86 mg), HOAt (61 mg) in DMF (5 ml) at room temperature Add hydrazine (0·26 ml) and stir for 18 hours. The residue obtained by concentrating the reaction mixture was purified by silica gel column chromatography (EtOAc) to afford the title compound (8 mg). 'H-NMR (CDC13) δ : 1.48 (9Η5 s)5 2.18 (3Η, s), 2.48-2.60 (1Η,m), 2·70-2·85 (3Η,m), 3.00-3.26 (3Η, m), 3.57-3.75 (3H, m), 3·96-4·35 (2H, m), 5.10-5.19 and 5.45-5.58 (total 1H, per m, guanamine isomer), m (2H, s), 6.75 (1H, d, J = 8_8 Hz), 7·06 (1H, s), 7·45-7·33 (5H, m), 8.00 (1H, d, J = 8.6 Hz). MS (ESI) m/z: 633 (M+H). (2) (3R)_[N-(Tertibutoxycarbonylguanidino)]oxy-4-[5-[(4-phenyl-5·trifluoromethyl-2-thienyl) Methoxy]porphyrin-1·yl]butyric acid [Chemical 593]

121199.doc -519- 200846322 pours (3R) p-butoxy)·ν_methylamino] ice-side oxy+[5[(4phenyl-5·di-methyl-2) Benzyl)methoxy]. 卜 朵 朵 小 ] ] ( ( ( ( (80 mg) in methanol / THF mixed solution (1 ml / 2 ml), 1 N aqueous sodium hydroxide solution was added at room temperature ( 0.26 ml), stirring for 14 hours. The reaction mixture was concentrated, 1 N hydrochloric acid (0·13 ml) was added, and the mixture was extracted with chloroform/methanol mixture (10/1, v/v). The combined extracts were washed with saturated brine. Drying with anhydrous sodium sulfate, distilling off the solvent to give (r)_3_[(n_ 2,2-butoxycarbonyl-methyl)amino]-4- oxo-4-[(4-phenyl-5) · Three said methyl-2-nonyl) decyloxy] porphyrin-indole-yl] methyl butyrate, which was used in the subsequent step. (R)_3_[(N_ Third butoxycarbonyl-N-methyl)amino]_4_sideoxy-4_[(4-phenyl-5-trifluoromethyl-2-thienyl) decyloxy] porphyrin q- Add a TFA (0.5 ml) at room temperature and stir for 2 days. Concentrate the reaction solution and add 1 N sodium hydroxide to the residue. water The solution was adjusted to a pH of 7, and extracted with a chloroform/nonanol mixed solution (10/1, v/v). The extract was concentrated, and the residue obtained was purified by thin layer chromatography, followed by freeze drying with dioxane. , title compound (48 mg) 〇lH-NMR (CDC13) δ: 2.17 (3H5 s)5 2.43-2.67 (5H5 m), 3.03- 3·23 (2H, m), 3.75-3.92 (1H, m) , 4.01-4.30 (2H, m), 5.20 (2H, s), 6.74 (1H, s), 7.05 (1H, s), 7·32-7·44 (5H, m) 5 8·01 (1H, s) 〇IR (ATR)cnT1 : 2929, 2848, 1647,1593,1473,1377,1317, 1288 〇121199.doc - 520- 200846322 MS (ESI) m/z : 519 (M+H). HR of C26H26F3N2O4S - MS (AqTOF) calcd.: 5191567. Measured value: 519.1574. [Comprehensive Example 128] (3R)-4-[5-[(4-cyclohexyl-3-tris-methylphenyl)methoxy] -4-methyl]°bendolin-1-yl]-3-(N-methylamino)-4-oxobutyric acid (1) 〇R)-[N-(third butoxy Carbonyl)-N-methylamino]-4_[5-(4·cyclohexyl-3-trifluorodecylphenyl)decyloxy-4-methyl]-4-methylindoline-1 -基]_ 4-tert-butyl oxanoate [Chemical 594]

5·[(4-Cyclohexyl-3-trifluoromethylphenyl)methoxy]-4-methylcarboline hydrochloride (187 mg, 0.44 mmol), Boc-D-Me-Asp ( To a solution of OMe)-(0·11 g), EDOHCl (0.13 g), HOAt (90 mg) in DMF (5 ml), DIEA (0.38 ml) was added at room temperature and stirred for 14 hours. The residue obtained by concentrating the reaction mixture was purified using EtOAc (EtOAc) 'H-NMR (CDCI3) δ : 1.11-1.54 (12H? m)? 1.67-1.93 (3H5 m)) 2.16(3H,s), 2.42_2.61(lH,m), 2.70_3.25(9H, m), 3.59- 3.75 (5H, m), 3.94-4.36 (2H, m), 5.03 (2H, s), 5.11-5.57 (1H, m), 6.72 (1H, d, J=8,8 Hz) ,7·46 (1H,d,1=8.1 Hz), 7.55 (1H,d,J=7.8 Hz),7·67 (1H,s),7·98 (1H,d5 3 121199.doc -521 - 200846322

Hz). (2) (3R)-4-[5-[(4-Cyclohexyl-3·trifluoromethylphenyl)methoxy; |_4_methyl is called podoline-1-yl]-3-( N-methylamino)_4_sideoxybutyric acid [Chemical 595]

(3R)-[N-(Tertidinoxycarbonyl)·Ν_曱-ylamino]_4_[5_[(4-cyclohexyl-3-difluoromethylphenyl)decyloxy]_4_A Methyl]_4_mercapto porphyrin_丨_ kib 4-methyl ethanobutyrate (〇·21 g) in methanol/ΤΗρ^ solution (l ml/2 ml), added at room temperature 1 N aqueous sodium hydroxide solution (1 〇 ml) was stirred for μ hours. The reaction mixture was concentrated, and 1 N hydrochloric acid was added to adjust the pH to 2, and the mixture was extracted with a chloroform/methanol mixture solution (10/1, Wv), and the combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. Solvent, obtaining (11)-3-[(1^2,2-butoxycarbonyl-&gt;-methyl)amino]_4_sideoxy_4_[5_(4-cyclohexyl-3-difluoromethyl) Phenyl)methoxy_4_methyl]_4-methylporphyrin-1-yl]butyric acid was used in the next step. (3R)-[N-(2,4-Butoxycarbonyl)methylamino]-4·[5_[(4-cyclohexyl-3-difluoromethylphenyl)methoxy]-4-methyl吲哚 基 ] 121 121 121 121121.doc - 522- 200846322 Butane acid in dichloromethane (10 ml), add mi) at room temperature and stir for 5 hours. The residue obtained by concentrating the reaction mixture was adjusted to pH 6 by adding 1 N aqueous sodium hydroxide solution and 1 N hydrochloric acid, and extracted with a mixture of chloroform/methanol (10/1, Wv). The extract was concentrated, and the residue obtained was purified by EtOAc (EtOAc). W-NMR (DMSO_d6) δ : 1·23-1·88 (11H, m), 2·09 (3H, s), 2·43-2·57 (6Η, m), 2.71-2.88 (1Η, m ), 3.00-3.13 (2Η,m) 3·78·3·87 (1H,m),4.31-4.01 (2H,m),5.11 (2H,s),6·83 (1H,d,J-8.8 Hz), 7.63 (1H, d, J = 8.1 Hz), 7.68 (1H, d J = 8.3 Hz), 7·71 (1H, s), 7.88 (1H, d, J = 8.8 Hz) 〇MS (ESI m/z : 519 (M+H)+. IR (ATR) cm·1 : 2925, 2854, 1647, 1593, 1477, 1375, 1315, 1255. Calculated for the elemental analysis of C28H33F3N2 〇v〇_〇5HCh2H20: c 60·24; H, 6.70; Cl, 0.64; F, 10.21; N, 5.02. Found: c, 60.42; H, 6.40; Cl, 0.65; F, 10.06; N, 4.83. [Example 129] 4-[5·[(4-Cyclopentyl-3-trifluorodecylphenyl)methoxymethyl °°朵朵琳-1 -yl]-(3R)-(N· Methylamino)-4-oxobutyric acid (1) (3R)-[N·(Tertibutoxycarbonyl)-N-methylamino]-4-[5_[(4-cyclopentyl) Ethyl-3-trifluoromethylphenyl)methoxy]-4-methylindol-1-yl]-4-oxobutanoic acid decyl ester [Chem. 596] 121199.doc • 523 - 200846322

5-[(4-Cyclopentyl-3-trifluoromethylphenyl) decyloxy]-4-methyl porphyrin hydrochloride (0.26 g), Boc-D-Me-Asp (〇Me - 〇H (0.17 g), EDC.HC1 (0.18 g), HOAt (0.13 g) in DMF solution (5 ml), DIEA (0.56 ml) was added at room temperature for 14 hours. The residue obtained by purifying the reaction mixture was purified by silica gel flash chromatography (Biot. 25 S) to give the title compound (174 mg). !H-NMR (CDC13) δ : 1.43-2.01 (14Η, m), 2.04-2.33 (5H3 m), 2.41-2.59 (1H, m), 2.69-2.84 (3H, m), 2.96-3.22 (3H,

Ni), 3.30-3.43 (1H, ni), 3.48-3.84 (4H, m), 3.91-4.36 (2H

m),5,02 (2H,s),5.08-5.57 (1H,m),6.72 (1H,d,J=8.6 Hz), 7.47 (1H,d,J=8.1 Hz),7_55 (1H,d , J = 8.6 Hz), 7.66 (1H s), 7·98 (1H, d, Hz). φ (2) 4-[5-[(4-Cyclopentyltrifluoromethylphenyl)methoxy]indolyl-1-yl]-(3R)-(N-decylamino) _4_Phenoxybutyric acid [Chemical 597]

(3R)-[N-(Tertibutoxycarbonylmethylamino)·4_[5-[(4-cyclopentyl-3-trifluorodecylphenyl)decyloxy]methylhydrazine Phenyl-1-yl]_4_sideoxy 121199.doc -524 - 200846322 Methyl butyrate (0.17 g) in methanol/71^ mixed solution (1/2 ml), 1 N hydroxide was added at room temperature The sodium aqueous solution (1. 〇ml) was stirred for 14 hours. The reaction mixture was concentrated, 1N hydrochloric acid was added, and the precipitated solid was collected by filtration and dried to give (3R)-[N-(2-butoxycarbonyl)&gt; Methylamino]cyclopentyl·3-trifluoromethylphenyl)methoxy]_4_methylporphyrin 4_yl]_4_ oxobutyric acid, which is used in the subsequent step (3R)_[N·(Tertibutoxycarbonyl)_N•methylamino]·4_[5_[(4-cyclopentyl-3-trifluorodecylphenyl)methoxy) -4•methyl porphyrin group]· 4- side oxybutyric acid in dichloromethane (1 〇 ml), added TFA (0.5 ml) at room temperature and stirred for 7 hours. To the obtained residue, 1 N aqueous sodium hydroxide solution and i N hydrochloric acid were added to adjust the value to 6, and the mixture was extracted with a gas/sterol mixed solution (10/1, v/v). The extract was concentrated. The obtained residue was purified by EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ·70 (5H,m), 1.73-2.06 (5H, Lum)' 2·09 (3H,s),2.42-2.63 (5H,m),3.01-3.13 (2H,m)5 3.17-3.31 (1H ,m),3.79-3.88 (1H,m)5 4.06-4.35 (2H,m), 5·11 (2H,s),6·83 (1H,d,J=8.8 Hz),7·58-7 · 74 (3H, m), 7·87 (1H, d, J = 8.8 Hz) 〇MS (ESI) m/z ·· 505 (M+H).

IR (ATR) cm: 2954, 2871, 1651, 1593, 1475, 1431, ms. Calculated for elemental analysis of 匸27^34?3仏〇4*2112〇: c 59.99; H 6·53; F,10·54; N, 5.18. Found: c, 60.32; H, 6.22; F, 10.28; N, 4.97. -525 - 121199.doc 200846322 [Example 130] 3 [2_[5-cyclopentyl)-3-(trifluoromethyl)oxy] 4-methyl.弓布朵琳-1-yl]-2-yloxyethyl]amino]propionic acid (1) 1-(t-butoxymethyl)·5 Miao (cyclodecyl)_3_(three gas (hydroxy)-4-methyl porphyrin [Chemical 598]

4-(cyclopentyl)-3-(trifluoromethyl)benzyl chloride (〇5〇g), hepoxy third butoxycarbonyl)-4-methyl-5-hydroxyporphyrin (〇 · 47 g) of DMF solution (2 〇 ml), add potassium carbonate (〇·78 g) at room temperature, warm to 7 〇 and stir for μ hours. After the reaction solution was returned to room temperature, the insoluble material was filtered, and the obtained filtrate was concentrated. The obtained solid was recrystallized from ethyl acetate /hexane to afford titled compound (0.61 g).

^-NMR (CDC13) δ : 1.43-1.93 (15Η, m), 2.02.2 &lt;21 ^ m), 2.95-3.09 (2H, m), 3.31-3.44 (1H, m), 3.87-4.08 (2H, m), 5.01 (2H, s), 6.70 (1H, d, J = 8.3 Hz), 7, 19-7.33 (1H, m)'' 7.39-7.61 (2H, m), 7·66 (1H, s ). (2) 3·[Ν-(Tertibutoxycarbonyl(cyclopentyl)_3_(trifluoromethyl)benzyloxy]-4-methylindol-1-yl]_2_sideoxy B Tert-butyl]propionic acid tert-butyl ester [Chem. 599] 121199.doc • 526 - 200846322

Io-(t-butoxycarbonyl)-5-[4.(cyclopentyl)·3_(trifluoromethyl)benzyloxymethylporphyrin (〇·61 g) was dissolved in 4 at room temperature The mixture was stirred for 15 hours with hydrazine hydrochloride / hexane solution (20 ml). The reaction mixture was concentrated to give 5-[(4-3⁄4 pentyl-3-trifluoromethylphenyl) decyloxy-p-methyl porphyrin hydrochloride ( 〇·········· In the steps. • MS (ESI) m/z: 376 (M+H) + 55-[(4-cyclopentyl-3-trifluoromethylphenyl) decyloxy]_4• decyl porphyrin Salt (0.26 g), 3·[Ν_(Tertibutoxycarbonyl)_n_(3-carboxymethyl)amino]propionic acid tert-butyl ester (0.19 g), ED〇HC1 (; 0.18 g), HOAt (0.13 g) of DMF solution (5 mi) was added with DIEA (0.56 ml) at room temperature for 18 hours. The reaction mixture was concentrated, and then purified, mjjjjjjj • 'H-NMR (CDCls) δ : 0.87-1.91 (22Η, m)5 1&gt;98.2 2g (6^ m), 2·47-2.66 (3H,m), 2.98-3.16 (2H,m),3.33 -3.42 (1H m),3·52·3·66 (2H,m),3·88-4·24 (4H,m),5 qi (2h s) 6·63·6·78 (1H,m ), 7.43 - 7.59 (1H, m), 7.67 (iH, s), 8 〇 5 - 7 · 91 (2H, m). ' MS (ESI) m/z : 661 (M+H)+. (3) Cyclodecyl-3-trifluoromethyl benzyloxy) _4•methyl 〇 akisaki-1 -yl]-2 - flavonylethyl]amino]propionic acid 121199.doc - 527 - 200846322 [Chem. 600]

3-[N-(Tertibutoxycarbonyl)-N-[2-[5-[4-(cyclopentyl)-3-(trifluoromethyl)benzyloxymethylporphyrin-1 -Based on 2-oxoethyl]amino]propionic acid tert-butyl ester (0β20 g) in dichloromethane (10 ml) at room temperature # Add TFA (0.5 ml), stir 20 hours. Further, TFA ((K5 ml) was added to the reaction liquid, and the mixture was stirred for 4 hours. After concentrating the reaction liquid, the pH was adjusted to 7 using a 1 N aqueous sodium hydroxide solution, and then gas/methanol (10/1, v). /v) The mixed solution is subjected to extraction, and the combined extracts are washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated, and the obtained solid is filtered, washed with hexane and dried to give the title compound. .2〇g). H-NMR (DMS〇-d6) δ : 1.50-1.73 (4H? m)? 1.73-2.00 (4H5 m), 2·11 (3H, s), 2·67 (2H, t , J=7.0 Hz), 3.04-3.18 (4H, m), Lu 3.17-3.40 (2H, m)5 4.00-4.11 (4H? m)5 5.13 (2H? s)5 6.88 (1H,d,J= 8.8 Hz), 7.61-7.73 (3H, m), 7·82 (1H, d, J=8.8

Hz). IR (ATR) cm&quot; : 3〇555 2925, 2852, 2224, 1732, 1631? 1604. MS (ESI) m/z: 505 (M+H)+. [Example 131] 4-[5-(4-cyclopropyl-3-trifluoromethylbenzyloxymethyl-2,3-dichloro-1H-° fluorenyl H3RH methylamino)·4 - oxobutyric acid I21199.doc - 528 - 200846322 (1) 5-(4-3⁄4propyl-3-trifluoromethyloxy)-4-mercapto-2,3-dihydro-1H-吲哚-1-carboxylic acid tert-butyl ester [Chemical 601]

Add 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-methylase tert-butyl ester # (0·69 mm〇l), potassium carbonate (0.29 g), 4·gas Methyl-bucyclopropyl-2-trifluoromethylbenzene (0.16 g) and dichloromethane (7 ml) were suspended. After the reaction mixture was stirred overnight at 8 ° C, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography to give the title compound g). H-NMR (CDC13) δ : 0.75-0.79 (2Η, m), l.〇3-i.〇5 (2h, m) 1-54 (9H, s), 2.14 (3H, s), 2.18 -2.21 (lHj m), 2.99 (2H, J=8.5 Hz), 3.96-3.99 (2H, m), 5.00 (2H, s)s 6.68 (1H ? ^ J=8.3 Hz), 7.04 (1H, d, J=8.1 Hz), 7.48 (1H, d, J=g.3 Hz: 7_53·7·66 (1H, m), 7.68 (1H, s). '(7)5-(Cyclopropyltrifluoromethyl oxyl Base)_4_methyl·2,3_n 哚 hydrochloride [化602]

200846322 on 5-(4-cyclopropyl-3-trifluoromethylbenzyloxy)_4·methyl-2,3_dihydro-ίΗ_ 引味-1-甲酉夂弟二丁g曰(〇· 21 g) was added 4 ν hydrochloric acid / ι, 4- No. 2 (5 ml), and stirred at room temperature for 4 hours. The reaction mixture was concentrated to give the title compound (0.20 g). (3) (3RHN-(Tertibutoxycarbonyl)_N_methylamino]-4·[5-(4_cyclopropyl-3-difluoromethylbenzyloxy)·4_methyl-2 , 3_dihydroindolyl]_4_ methyl acetobutanoate [Chem. 603]

5-(%propyl-3-trifluoromethylbenzyloxy)-4.methyl-2,3-dihydro-1H-indole hydrochloride (0.20 g), H〇At ((M0 g) , eD〇HC1((M5 g), DIEA((M4 ml), (2R)_[N-(Tertibutoxycarbonyl)-N-methylamino]succinic acid 4·methyl S|( G·13 g) was added with dichlorohydrazine (5 ml), and stirred overnight. The reaction mixture was concentrated, saturated sodium bicarbonate solution was added, and ethyl acetate was extracted with ethyl acetate. The combined extracts were washed with saturated brine. After drying over sodium sulfate, the insoluble material was filtered, and the filtrate was concentrated. Purified residue was purified by column chromatography to give the title compound (0.23 g). H-NMR (CDC13) δ: 0·75-0· 80 (2H,m),1·02,1·〇7 (2H,m), 1.47 (9H5 s)5 2.16-2.23 (4H3 m)5 2.52-2.56 (1H5 m)5 2.76- 2.79 (3H,m ), 3.07-3.18 (3H,m)5 3.66·3·73 (4H,m),411_ 121199.doc - 530 - 200846322 4·20 (2H,m),5·03 (2H,s),6.71 ( 1H,d,J=8.6 Ηζ),7·〇5 (1H,d,Hz), 7.47-7.48 (ih,m), 7.68 (1H,s),7·97 (1H,d,Hz). MS (ESI) m/z : 591 (M+H)+ 〇(4) (3R)-[N-(T-butoxycarbonyl)_N• fluorenyl Base]_4-[5_(4_cyclopropyl-3-trifluorodecylbenzyloxy)_4-mercapto-2,3-dihydro-; 111_吲哚"· kib 4-tertiary butyl Acid [化604]

(3RMN-(Tertibutoxycarbonyl)_N-methylaminodibu-4_[5_(inhibited cyclopropyl-3-trifluoromethylbenzyloxy)_4_methyl·2,3·dihydro- 1H-indolyl 4-methyloxybutyric acid methyl ester (〇·23 g), lithium hydroxide (〇〇3〇g) was added with thf (3 ml) and water (3 ml) at room temperature Stirring overnight. The reaction mixture was concentrated, and water was added to the residue, and the mixture was extracted with a mixture of chloroform and decyl alcohol (methanol / chloroform = 1%). The combined extracts were washed with saturated brine and dried with sodium sate. After the insoluble material I was concentrated, the filtrate was concentrated, and the obtained residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted elution (2H, m), 1.33-1.47 (9H, m), 2.04-2.23 (4H, m), 2.55-2.58 (1H, m), 2.73-2.78 (3H, m), 3.02-3.21 (3H, m) 5 3.99-4.24 (2H, m), 121199.doc -531 - 200846322 4.98-5.01 (2H,m), 5.46-5.47 (1H,m),6·7〇·6·73 (1H, called, 7.04-7.05 (1H,m), 7.48 (1H,d,JU Hz), 7.68 (1H,s): 7·97 (1H,d,J = 8.6 Hz). MS (ESI) m/z : 577 (M+H)+ (5) 4-[5-(4-cyclopropyl-3-trifluoromethyl) Benzyloxy)- 4-mercapto-2,3•dichloro- 1 Η-, °-l-yl]-(3R)-(methylamino)-4- oxobutyric acid 605]

(3R)-[N_(Tertibutoxycarbonyl)_N-methylamino]-4_[5,(in Cardinal propyl-3-dimethylhydrazinyloxy)_4-methyl-2, 3 -Diazin-1-yl]_4· Side oxybutyric acid (〇·20 g) was added with a 10% TFA/dichloromethane solution (3 ml:), and stirred at room temperature overnight. The reaction mixture was concentrated to give the title compound ( 〇 _14 g) 〇lH-NMR (CD3OD) δ: 0.78-0.79 (2Η, m)? 1.03-1.05 (2H5 m)5 2·17 (4H, s), 2·75 (3H, s), 2.85-2.92 (1H, m), 3·09-3·22 (3H, m), 4.20-4.33 (2H, m), 4·57 (1H, dd, J = 8.0, 4.6 Hz), 5.09 (2H, s), 6·83 (1H, d, J = 8.9 Hz), 7·13 (1H, d, J = 7.9 Hz), 7, 56 (1H, d, J =7.9 Hz), 7.70 (1H, s), 7.95 (1H, d, J = 8.9 Hz). MS (ESI) m/z: 477 (M+H)+. 121199.doc - 532- 200846322 C25H27F3N2〇4·CF3CO2H, 0·25H2O το 素 calc calc calc calc calc calc s s s s s s s s s s s s s s s s s s. Measured value · · C, 54 · 44; H, 4.70; Ν, 4.66; F, 19.48 〇IR (ATFOcm^MSS, 1479, 1182, 1120, 823, 717. [Example 132] (3R)-(N- Mercaptoamino)-4-oxo-4-[5-[(l-phenyl-5-trifluoromethyl-1H-pyrazol-3-yl)nonyloxy]-4-methyl- 2,3-Dihydro-1H-indol-1-yl]butyric acid (1) 4-methyl- 5·[(1-phenyl-gastric 5-trifluoromethyl_111-0 than 嗤-3- Methoxy] porphyrin-1 -carboxylic acid tert-butyl ester [Chemical 606]

In the 3-bromomethyl-1-phenyl-5-trimethyl-111-11 ratio. Add potassium carbonate (181 mg) and 5-hydroxy-4-methylindole #1 -1 -carboxylic acid tert-butyl ester (90 mg) in a solution of 〇1^1卩 (60 ml) (10〇111§) ), stirring at 70 ° C for 3 days. The reaction solution was allowed to stand to cool to room temperature, and then diluted with water. The aqueous layer was extracted with EtOAc. EtOAc was evaporated. The residue obtained by flash chromatography on a silica gel column was used to afford the title compound (8 1 mg). 'H-NMR (CDC13) δ : 1.26 (9H, s), 2.16 (3H, s), 3.00 (2H, t, J = 8.5 Hz), 3.96-3.98 (2H, m), 5·11 (2H, s),6·78 (1H,d, J=8.5 Hz), 6.90 (1H, s), 7·46-7·57 (6H, m). 121199.doc -533 - 200846322 (2) 4-Methyl-5-[(ι_phenyl·5_三吲哚琳[化607] like methyl-1H"pyrazol-3-yl)decyloxy ] 4-methyl_5-[(i-phenyl_5·di

^Boc

a mouse methyl-1 Η-pyrazol-3-yl) decyloxy] porphyrin-1-carboxylic acid tert- _ (79, a solution in 4 Ν hydrochloric acid / dioxane solution (4.) in /JZL, the mixture was mixed for 2 hours. After removing the solvent, it was diluted with a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with chloroform. The combined extracts were washed with saturated brine, and the mixture was dried. After drying with anhydrous magnesium sulfate, the filtrate was filtered, and the filtrate was evaporated to give the title compound (64. MS (ESI) m/z: 374 (M+H) + (3) (3R)-[N-( Tributoxymethyl) thiomethylamino] winterside oxy-heart [5-[(1-phenyl-5-trimethylmethyl-1Η&gt;β, azole-3-yl) methoxyl ]_4•曱基_2,3_Dihydro-1H-indenyl]butyric acid decyl ester [Chem. 608]

a 5-D ((l-styl-trimethyl-methyl-pyrid-3-yl)-methoxy]-4-methyl------------ Add Ν-(third 121199.doc - 534 - 200846322 butoxycarbonyl)-N-methyl-D-aspartate 4-decyl ester (52 mg), EDOHCl (38 mg), HOBt (27 Mg) and DIEA (85 μΐ) were stirred overnight at room temperature. After a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and ethyl acetate was evaporated, and the mixture was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) (4) (3R)-[N-(Tertibutoxycarbonyl)-N-methylamino sideoxy_4_[5-[(1-styl-5-trifluoromethyl-1Η-pyridyl) Zyrid-3-yl)methoxy]-4-methyl-2,3-dihydro-1Η-indenyl]butyric acid [Chem. 609]

(3R)-[N-(Tertidinoxycarbonyl)-indole-methylamino]-'sideoxy[5-[(1-phenyl-5-trifluoromethyl-1Η-carbazole) -3-yl)methoxy]_4_methyl_2 3-monohydro-1Η-indol-1-yl]butyric acid methyl ester (5 [mg) dissolved in methanol / THF solvent (4.0 ml To the solution, 1 n aqueous sodium hydroxide solution (2 〇ml) was added, and stirred at room temperature overnight. The reaction mixture was adjusted to a pH of about 6 by adding 1 N hydrochloric acid, water was added, and the aqueous layer was extracted with a 10% methanol / chloroform solvent, and the combined extracts were washed with saturated brine and dried over anhydrous magnesium sulfate. It was filtered and the filtrate was concentrated. The residue obtained was purified by EtOAc EtOAc (EtOAc) 121199.doc - 535 - 200846322 ^-NMR (CDC13) δ : 1.48 (9H, s)? 2.18 (3H, s), 2.60-2.62 (1H, m), 2.78-2.81 (3H, m), 3.14-3.16 (3H,m),4·08-4·19 (2H,m), 5·03-5·50 (1H,m)5 5·14 (2H,s)5 6·82 (1H,d,J =8.8 Hz), 6.89 (1H, s), 7.49 (5H, s), 7.99 (1H, d, J = 8.8 Hz). (5) (3RMN-decylamino)_4·Sideoxy-4-[5-[(l-phenyl-5-trifluoromethyl-1H.pyrazol-3-yl)methoxy b 4 -methyl-2,3-dihydro-1H-indol-1-yl]butyric acid [Chem. 610]

(3RMN-(Tertibutoxycarbonyl)methylaminol-oxy-4_[5-[(1-phenyl-5-trifluoromethyl-1H-pyrazol-3-yl)methoxy) ]-4-methyl-2,3·dihydro-1Η-indenyl]butyric acid (41 mg) was dissolved in 1 〇〇/〇tfa/dichloromethane solution (5.0 ml) at room temperature After stirring for 1 hour, the solvent of the reaction mixture was evaporated, and the residue was purified to purified crystals crystals crystals crystalsssssssssssssssssssssss ? J=16.95 10·2 Hz), 2·72 (3H, s), 2·78 (1H, dd, J=16.9, 3·6 Hz), 3·19 (2H, t, Bu 8·9 HZ ), 4·18 (1H, q, J=8.9 HZ), 4·3〇 (1H, q, J=8.9 Hz), 4.41 (ih, dd, J=10.2, 3·6 Hz), 5.15 (2H, s), 6.91 (1H? d, J = 8.9 Hz) 3 7.04 (1H? s)? 7.49-7.51 (2H5 m)? 7.55. 7·56 (3H, m), 7·97 ( 1H,d,J=8.9 Hz). 121199.doc - 536- 200846322 IR (ATR) cm·1 : 1649,1597,1473,1392,1261,1225, 1182, 1124, 1099, 1084, 823, 690. MS (ESI) m/z : 503 (M+H)+ HR-MS (ESI) : C25H26F3N404 (M+H)+ Calculated value: 503,19061 〇Measured value·· 5 03.18967 ° C25H25F3N4〇4*H2 The calculated value of the elemental analysis of 0: c, 57.69; H, 5·23; F, 10.95; N, 10.76. Measured: C, 57.81; H, 5.10; F, 10.74; N, 10.50 ° [Example 133] 4-[5-(4-Cyclobutyl-3-trifluorodecylbenzyloxy)_4_methylindolin-1·yl]-(3R)-(N-methylamino)-4- Side oxybutyric acid TFA salt (1) 5-(4-cyclobutyl-3-trifluoromethylbenzyloxy)_4-methylporphyrin-; 1-carboxylic acid tert-butyl ester [Chem. 611]

Boc was added to a solution of 5-hydroxy-4-methylporphyrin-carboxylic acid tert-butyl ester (125 mg) in dichloromethane (5.0 ml) with 4_g-decylcyclobutyl-2-trifluoromethyl Benzene (162 mg) and potassium carbonate (1 〇 4 mg) were stirred at 70 ° C overnight. After it was left to cool to room temperature, a saturated sodium hydrogencarbonate solution was added to the mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the residue obtained by purifying the filtrate under reduced pressure was purified by flash column chromatography (yield: ss.). The title compound (195 mg) was obtained from 121199.doc - 537 - 200846322. W-NMR (CDC13) δ : 1·55 (9H, s), 1·82-2·39 (9H, m), 2 99 (2Η, t, J=8.5 Ηζ), 3.85-3.98 (3Η, m ), 5·〇2 (2Η, s) 6 69 (1H, d, J = 8.5 Hz), 7·58-7·66 (4H, m). (2) (3R)-[N-(Tertibutoxycarbonyl)-N-methylamino]_4&lt;5_(4_cyclobutyl-3-difluoromethylbenzyloxy)-benzol Methyl fluorene-1-yl]-4_ oxobutyl butyrate [Chem. 612]

Add 4 N hydrochloric acid / 1,4-two to 5-(4-cyclobutyl-3-trifluoromethylbenzyloxy)_4-methyl porphyrin·i•carboxylic acid tert-butyl ester (190 mg) Centane (1 〇 ml) was stirred at room temperature for 3 hours and a half. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in dichloromethane (10 ml), and (R)-2-[N-(t-butoxycarbonyl)methylamino] succinic acid 4 was added. - Methyl ester (136 mg), DIEA (350 μl), HOBt (83.5 mg), EDC.HC1 (118 mg), stirred at room temperature overnight. A saturated acid-desulfurized steel solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the title compound (235 mg) was obtained. ), 183.2.39 (9Hj m)? 2·51-2.57 (1H,m),2·77_3.18 (6H,m),3 66_4 27 (6H, ton 121199.doc - 538 - 200846322 5.04 (2H, s)? 5.16-5.52 (1H5 m)5 6.72 (1H? d5 j, gg 7·59 (2H, s), 7·66 (1H, s), 7:97 (1H, d, Bu 8·8 HZ , (3) (3R)-[N_(Tertibutoxycarbonyl)-sodium methylamino]_4_[5_(4·cyclobutyl-3-difluoromethylbenzyloxy)_4_fluorenyl吲哚琳土J 虱 虱 虱 丁

(3RHN·(Tertidinoxy-Wiki) good methylamino hydrazine _[5♦cyclobutyl_3_difluoromethylbenzyloxy&gt;4_methylporphyrin_丨_基卜' Add methanol to the oxybutyric acid (230 mg) in THF (5·〇ml).

1 N aqueous sodium hydroxide solution (114 ml) was stirred at room temperature for a few hours. 1 N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the residue obtained from the filtrated residue was purified by purified column chromatography (yield). !H-NMR (CDCls) δ : 1.47 (9H5 s), 1.82-2.38 (9H? m), 2.55- 2·60 (1Η, πι), 2.77-2·80 (3Η, πι), 3·06- 3·24(3Η,πι),3·85, 4.23 (3H,m),5.04-5.07 (2H,m),5·45-5·48 (1H,m),6·72 (1H,d, J=8.8 Hz), 7·58-7·66 (3H, m), 7.97 (1H, d, J=8.8

Hz) 〇(sentence heart ^ heart bad butyl - ^ trifluoromethyl benzyloxy ^ - ren methyl porphyrin " · base H3RHN-methyl amine) · 4_ oxo butyric acid TFA salt 121199 .doc - 539 - 200846322

[化614]

(3R)-[N-(Tertibutoxycarbonyl)-N•methylamino]_4_[5-(a)·cyclobutyl-3-trifluoromethylbenzyloxy)methyl porphyrinyl]_4_ To a solution of oxetoxybutyric acid (2 〇 0 mg) in dichloromethane (5 ml), TFA (5.0 ml) was added and stirred at room temperature for half an hour. After the reaction mixture was concentrated under reduced pressure, a mixture of diethyl ether and diisopropyl ether was added to the residue, and the resulting crystals were filtered and dried to give the title compound (147 mg). 'H-NMR (DMSO-d6) δ : 1.80-1.87 (1Η, m)? 1.94-2.31 (8H5 m), 2.49 (3H, s), 2·63 (1H, dd, J=7.3, 17.1 Hz) , 2·89 (1H, dd, J=5.6, 17·1 Hz), 3·11 (2H, t, J=8.2 Hz), 3.75-3.83 (1H,

m), 4.3-4.35 (3H, m), 5.16 (2H, s), 6.88 (1H, d, J = 9.0 Hz), 7·75 (3H, t, J = 7.9 Hz), 7.88 (1H , d, J = 9.0 Hz). IR (ATR) cnT1 : 2944, 1652, 1475, 1315, 1255, 1197, 1162, 1116, 1056 〇 MS (ESI) m/z ·· 491 (M+H)+. HR-MS (ESI) calculated for C26H3 〇F3N204 (M+H)+: 491.21.577. Found: 491.2212. [Example 134] 4-[5·(4·isopropyl-3-trifluoromethoxybenzyloxy)-4-methylindol-1-yl]-(3R)-(N-A Amino)-4-oxobutyric acid TFA salt (1) 5-(4-isopropyl-3.trifluoromethoxybenzyloxy)-4-methylporphyrin_1_1曱121199 .doc -540- 200846322 Tert-butyl acid ester [Chem. 615]

F

Add 4-chloromethyl-1-isopropyl-2-triazole to a solution of 5- mercapto-4-methyl π-pyrenecarboxylic acid tert-butyl ester (125 mg) in chlorodecane (5.0 ml) Fluorine benzene (I52 mg) and potassium carbonate (1 〇 4 mg) were stirred at 7 ° C overnight. After the reaction solution was allowed to stand to room temperature, a saturated sodium hydrogen carbonate solution was added, and the mixture was extracted three times with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The title compound (1 96 mg) was obtained by a flash column chromatography (m.p.).

H-NMR (CDCi3) s: 1.24 (6HcW = 68 Hz), 155 (9h, s), 2.15 (3H, S), 3.00 (2H, t, J = 8.5 Hz), 3.27-3.37 (1H m) 3.98 ( 2H, s), 4.99 (2H, s) 6 7〇 (iH dj=8 5Hz), w (4H,m) 〇(2) (3RHN-(Third Butoxy)_N•Methylamino] I Bu (heart propyl-...methoxy ethoxy group)&quot;

Acid methyl ester

[Chem. 616] I21199.doc 541 - 200846322

Add 4 N hydrochloric acid / 1,4- to 5-(4-isopropyl-3-trifluorodecyloxybenzyloxy)·4-methyl-butylindolinic acid tert-butyl ester (190 mg) Dioxane (10 ml), stir at room temperature: mix for 3 hours and a half. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in di-methane (10 ml), and (2R)-[N-(t-butoxycarbonyl] Methyl ester (135 mg), DIEA (347 μΐ), HOBt (82.7 mg), EDOHCl (117 mg) were stirred overnight at room temperature. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. 'Filtered, not> cereals. The filtrate was concentrated under reduced pressure. Purified by rapid column column analysis (Shanshan high-speed column L). Residue, the title compound was obtained (248 mg) 〇

lH-NMR (CDC13) δ : 1.24 (6H? d5 J=7.1 Hz), 1.43-1.53 (9H • m), 2·17 (3H, s), 2.51-2.57 (1H, m), 2.77-3.35 ( 7H,m), 3.66-3.74 (3H,m),4.03-4.31 (2H,m),5·01 (2H,s),5 14. 5.52 (1H,m),6·72 (1H,d, J = 8.8 Hz), 7, 29-7, 35 (3h m) 7.97 (1H, d5 J = 8.8 Hz). (3) (3R)-[N·(Tertibutoxycarbonyl)_N_methylamino]&gt;4_[5_(4·isopropyl-3-difluorodecyloxybenzyloxy)-4-曱基吲ΰ朵琳-基] oxomebutyric acid [Chem. 617] 121199.doc -542 - 200846322

(3R)-[N-(Tertibutoxycarbonylmethylamino)-4-[5-(4-isopropyl-3-trifluoromethoxybenzyloxy)_4_methylindole Methanol (118 ml), 1 N aqueous sodium hydroxide solution (118 ml), at room temperature, was added to a solution of methyl 4-methyl-4-butoxybutyrate (240 mg) in THF (5.0 ml). The mixture was stirred for 1 hour, and 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography (yield: 2L) to afford the title compound (2 </ s> 9 mg). W-NMR (CDC13) δ: 1·24 (6H, d, J= 7.1 Ηζ),1·47 (9H,s), 2.17(3H,s),2.55-2.60 (lH,m),2.77-2.80(3H,m),3.06-3.35 (4H,m),3 ·99-4·27 (2H,m),5·01 (2H,s), 5.45-5.49 (1H,m),6·72 (1H,d,J=8.8 Hz),7·30-7· 35 (3H,m), 7.98 # (1H,d,J=8.8 Hz) (4) 4-[5-(4-Iso,yl-3·trifluoromethoxybenzyloxy)methylhydrazine Porphyrin-^-yl]-(3R)-(N-decylamino-based oxybutyric acid tfa salt [Chem. 618]

F

Boc

121199.doc • 543 - 200846322 at (3R)-[N_(Tertibutoxycarbonyl&gt;Ν·Methylamino)·4·[5々·Isopropyl-3-difluoromethoxybenzyloxy In the methylene chloride solution (5 mg) of 4-oxybenzoic acid (200 mg), add TFA^〇ml) to stir at room temperature! Hours and a half. After the reaction mixture was concentrated under reduced pressure, the mixture was evaporated. !H-NMR (DMSO-d6) δ : 1·19 (6H, d, J = 6.8 Hz), 2.11 (3H, s), 2.50 (3H, s), 2·66 (1H, dd, J=7.1 , 17·1 Hz), 2.92 (1H, dd, J = 5.6, 17·3 Hz), 3·10 (2H, t, J=8.2 Hz), 3.17-3.24 (1H, m), 4.11 4.18 (1H, m), 4·27-4·35 (2H, m), 5.10 (2H, s), 6·87 (1H, d, J = 8.8 Hz), 7.37-7.51 (3H, m)5 7·87 (1H, d, J = 8.8 Hz) 〇IR (ATR) cm·1 ·· 2967, 1654, 1477, 1245, 1201, 1151, 1087. MS (ESI) m/z ··495 (M+H)+. HR-MS (ESI) calcd for C??? [Example 135] 4-[5-[[4-Cyclohexyl-3-(N,N-dimethylamino)phenyl]decyloxy]-4-indolyl porphyrin-1-yl] -(3RHN-methylamino)-4-oxobutyric acid (1) 1-(t-butoxycarbonyl)-5-[[4-cyclohexyl-3-(N,N-dimethyl Amino) phenyl] decyloxy]-4-methyl porphyrin [Chem. 619] 121199.doc - 544- 200846322

To a solution of 4-3⁄4-hexyl-3-(N,N-dimethylamino)benzyl chloride hydrochloride (518 mg) in dichloromethane (20 ml), 124 g) and 1-(2,2,4-butoxy)-5-pyridyl-4-methyl-H-π-lin (448 mg). The reaction solution was stirred at 60 C for 6 hr, then cooled to room temperature and concentrated under reduced pressure. Water (2 〇 ml) and an imitation (30 ml) were added to the resulting residue for liquid separation. The aqueous layer was extracted with chloroform (2×2·········· The resulting residue was purified using EtOAc EtOAc (EtOAc) H-NMR (CDC13) δ : 1.24-1.48 (5H5 m), 1.55 (9H, s), 1.74- 1·86 (5H, m), 2·16 (3H, s), 2·68 (6H, s ), 2·99 (2H, t, JT=8.7 Hz), 3.07-3.15 (1H, m), 3.97 (2H, br s), 4·96 (2H, s), 6.74 (1H, d, J = 8.5 Hz), 7.11 (ih, dd, J=7.8, 1·7 Hz), 7·17 (1H, br s), 7·23 (1H, d, J=7 8 Hz), 7.61 (1H, br s). (2) 5_[[4-Cyclohexyl-3-(N,N-didecylamino)phenyl]decyloxy]I methyl porphyrin hydrochloride [Chem. 620]

1-(Tertidinoxycarbonyl)_5-[[4-cyclohexyl-3-(N,N-didecylamine 121199.doc -545 - 200846322)phenyl]methoxy]-4- To a solution of methyl phthalocyanine (397 mg) in 1,4-second (2 〇 ml), 1 N hydrochloric acid / 1,4-dioxane (2 〇 ml) was added at room temperature. After the reaction mixture was stirred for 3 hours, it was concentrated under reduced pressure. Diethyl ether (2.0 ml) was added to the obtained residue, and the precipitated solid was collected by filtration to give the title compound (4 〇 1 mg). b-NMR (DMSO-d6) δ : 1.21-1.54 (5H, m), 1.67-1·79 (5H, m), 2·49 (3H, br s), 3·00-3·25 ( 7H, m), 3.13 (3H, t, J = 7.8 HZ), 3.70 (2H, t, J = 7.8 Hz), 5.13 (2H, S), 7.05 (lH, d, J = 8.8 Hz), 7· 22 (1H,d,J = 8.3 Hz), 7.48 (2H, br s), 7·78 (1H, br s) o MS (ESI) m/z : 365 (M+H)+ 〇(3) 4 -[5-[[4_cyclohexyldimethylamino)phenyl]methoxy]·4_methyl porphyrin-1-yl]-4-yloxy_(3RHN_(third butoxy Alkylcarbonylmethylamino]butyrate decanoate [Chem. 621]

Add DIEA at room temperature in a solution of (2R) [Ν-(2-butoxycarbonyl)•methylamino] succinate (112 mg) in a chloramphenicol (3 〇ml) solution. 372 μΐ), HOBt (75 〇mg) and edc.hci (i〇6 (4), after stirring for 10 minutes, add 5_[[4•cyclohexyl_3_(N,l-didecylamino)benzene at room temperature曱 曱 卜 甲基 甲基 & 弓 弓 弓 弓 弓 弓 弓 弓 弓 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 (5 ml) and air-mesh (10 ml) were separated. After extracting the aqueous layer with chloroform (2×l 〇ml), the combined organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue obtained was purified by EtOAc (EtOAc) (EtOAc) (EtOAc) (3H, s), 2.68 (6H, s), 2.77-2.81 (3H, m), 3·04-3·22 (3H, m), 3.65-3.74 (4H, m), 4.01-4.32 ( 2H,m),4_98 (2H, s)' 6·76 (1H,d,J=8.8 Hz), 7·11 (ih,d,J=7.8 Hz), 7.17 〇H' s),7·23 (1 H, d, J = 7.8 Hz), 7·98 (1H, d, J = 8.8 Hz). MS (ESI) m/z ·· 608 (M+H)+. (4) (3R)-[N-(Secondoxycarbonyl)methylamino]]_4_[5_[[4_cyclohexylβ3-(Ν,Ν-dimethylamino)phenyl]methoxy] 4-methyl porphyrin _; μ group]_ 4-sided oxybutyric acid [Chem. 622]

(3R) [N-(Secondoxy-Wiki)methylamino]cyclohexyl-3-(N,N-dimethylamino)phenyl]methoxy]_4_methylindole To a solution of methyl oxo-methyl acetobutanoate (243 mg) in THF (2.0 ml), methanol (1·0 ml) and 1 N aqueous sodium hydroxide (1·〇() ml) . After stirring at room temperature for 3 days, water (5 ml) was added to the reaction mixture, and the pH was adjusted to 4 with 丨N hydrochloric acid 121199.doc - 547 - 200846322. A 20% sterol/chloroform mixture (丨〇 ml) was added for liquid separation. After extracting with a mixture of 20% methanol / chloroform (2.times.s.), ^-NMR (DMSO-d6) δ : 1.27-1.49 (17Η, m), 1.74-1.87 (5H, m), 2.17 (3H, s), 2.55-2.94 (8H, m)j 3.04-3.25 (4H, m), 3.98-4.27 (2H, m)5 4.99 (2H, s), 6.76 (1H, d, J=8.5 Hz), 7·14·7·25 (3H,m), 7.98 (1H,d, J = 8.5 Hz). MS (ESI) m/z: 594 (M+H)+. (5) 4-[5-[[4-Cyclohexyl-3_(N,N_:decylamino)phenyl]decyloxy]_4_methylporphyrin· i yl H3RMN•Methylamino )_4•Sideoxybutyric acid [Chemical 623]

(3R)-[N-(Secondoxycarbonyl)-sodium methylamino]cyclohexyl-3-(N,N-didecylamino)phenyl]decyloxy]_4_fluorenylindole To a solution of porphyrinyl] 4-oxobutanoic acid (247 mg) in dioxane (2.4 mi), add TFA (0.60 ml) at room temperature, stir for 3 hours, then under reduced pressure The reaction solution was concentrated. Dimethyl sulfoxide (5 〇 ml) was added to the obtained residue, and after insoluble matter was removed, high performance liquid chromatography (N〇MURA Devel〇sil c〇mbi_Rp 5), 屯化'辰目目The fraction was lyophilized to give the title compound (91·4 mg) 〇121I99.doc 200846322

H-NMR (DMSO-d6) δ : 1.17-1.39 (5H, m)5 1.56^1.75 (5H m)5 2.03 (3H, s), 2.23 (3H, s), 2.24 (1H, dd, j= 16 2 7 9 Hz), 2.51-2.57 (1H, m), 2·54 (6H, s), 3.01 (2H, t, J=8.4

Hz),3·23 (1H,br s),3·80 (1H,t,J=7.1 Hz), 4 〇7 (1H dt J=9.8, 8_5 Hz), 4.23 (1H, dt5 J=8.1, 10.0 Hz), 4 92 (2H s) 6.78 (lH,d,J=8.8 Hz), 7.02 (lH,d,J=7.8 Hz;) 7 13 (1H s),7·15 (1H,d,J =8.1 Hz), 7.81 (1H, d, J = 8.8 Hz). MS (ESI) m/z: 494 (M+H), C29H39N3 〇4, 1.75H20 Elemental analysis: C, 6632. l·! 8.16; N, 8.00. Found: C, 66.28; H, 7.88; N, 7.86. [Example 1; 36] (3S)-(N-decylamino)-4-[7-methyl-5-[(4-phenyl·5-trifluorodecyl-2-nonyl) Methoxy]-i-indolyl]-4. oxobutyric acid lysate (1) 1·(t-butoxycarbonyl)-7-methyl-1Η-吲哚[化624]

Boc dissolved 7-mercapto-1H-indole (ι·00 g) in THF (10 ml), added

Boc2O (2.50 g) and DMAP (90.0 mg) were stirred for 20 hours. The reaction mixture was concentrated, and the residue obtained was purified by silica gel flash column chromatography (m.p., 4L). , 6.53 (1Hjd J=3.7 HZ), 7.17·7·08 (2H, called, 7.38 (1H, d, J=7.3 Hz), 7·51 121199.doc - 549 - 200846322 (1H, d5 J=3.7 Hz (2) 1-(di-dibutoxy-Weiyl)-7-methyl-inducing σ Duo Lin [Chem. 625]

Boc

Boc dissolves 1-(second butoxycarbonyl)_7_methyl_1H•吲哚 (2·5 〇 曱 in sterol (100 ml) and adds 5 〇/〇Pd/c (2.〇〇 g), under stirring, often underneath • Conduct hydrogenation for 1 day. After replacing the reaction mixture with hydrogen, filter the catalyst and concentrate the filtrate. Use gelatin fast column chromatography f, w sound to the column 3L) The residue obtained was purified to give the title compound (yield: 17 illus. W-NMR (CDC13) δ: 1·53 (9 Ή, s), 2·30 (3H, s), 2 96 (2H t J = 7.7 Hz) , 4·06 (2H, t, J = 7.3 Hz), 7·04-6·93 (3H m). ' 5 MS (ESI) m/z : 256 (M+Na)+ (3) 7- Methyl porphyrin [Chem. 626]

Add *N hydrochloric acid / dioxane solution (10 ml) to 1-(t-butoxycarbonyl)_7-methyl porphyrin (10 ml), stir for 18 hours. After concentrating the reaction solution, add the residue to the residue. The aqueous solution of sodium hydrogencarbonate was extracted with di-methane (2×100 ml). The combined extracts were dried over anhydrous sodium sulfate and evaporated to give the title compound (1 g). 129. doc 550 - 200846322 ]H -NMR (CDC13) δ : 2.13 (3H, s)5 3.05 (2H5 t, J=8.1 Hz)5 3.54·3·59 (3H,m), 6.65 (1H,t,J=7.3 Hz),6· 86 (1H,d5 J=7.3 Hz),6·98 (1H5 d, J=7.6 Hz) MS (ESI) m/z : 134 (M+H)+ (4) 5-hydroxy-7-A基-1H-吲哚(W09523141) [化627]

In a solution of 7-methyl 0 卜 系 琳 (5 00 mg) in _ (25 ml), add 0·1 Μ acid buffer (pH 7.0) (10 0 ml) after stirring off Then, (KS 〇 3) 2NO (2.22 g) was added. After the reaction mixture was stirred for 1 hour, it was extracted with ethyl acetate (500 ml). The extract was washed with saturated brine (2×200 ml), dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified using hydrazine column chromatography (2L of Shanshan high-speed column) to give the title compound (276 mg) 〇# ]Η.ΝΜΚ (DMSO-d6) δ : 2.36 (3H5 d5 J=0.5 Hz), 6.20 (1H5 t? J=2.3 Hz), 6.41-6.39 (1H, m), 6.65 (1H, d, J = 1.7 Hz), 7.17 (1H, t, J = 2.7 Hz), 8.44 (1H, s ), 10.68 (1H, s). MS (ESI) m/z : 148 (M+H) + 〇(5) 5-hydroxyl_7-methyl-1H- ° 引 ( Buchheit, Κ·-Η· et al. Bioorganic &amp; Medicinal Chemistry Letters (1995), 5(21), 2495-500) [Chem. 628] 121199.doc 551 - 200846322

5-Hydroxy-7-methyl-1H-indole (640 mg), benzyl bromide (776, potassium carbonate (902 mg), and DMF (10 ml) were mixed and allowed to stand at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (200 ml), and washed with brine (2×100 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue obtained was purified to give the title compound (763 mg). </RTI> NMR (CDC13) δ ·· 2.46 (3H, s), 5.09 (2H, s), 6.48 (1H, dd, J=3.2, 2·0 Ηζ),6·77-6·79 (1Η,m), 7.01-7.06 (1Η,m), 7·18 (1H,t,J=2.9 Hz), 7.28-7.49 (5H,m) , 7·96 (1H, br s) MS (ESI) m/z : 238 (M+H) + (6) 5-benzyloxy·!_(t-butoxycarbonyl)methyl-1H •吲哚[化629]

Dissolve 5-hydroxyl_7_mercapto]H_吲哚 (763 mg) in ΤΗ]ρ(1〇)] Add Boc2O (1.05 g) and DMAP (39.3 mg) with stirring, stir 14 hours. The residue was purified by EtOAc EtOAc (EtOAc) H. NMR (CDC13) δ : 1.62 (9Η3 s) 5 2.61 (3H, s)? 5.09 (2H, s), 6.43 (1H, d, J=4.2 Hz), 6·82 (1H, d, J =2.4 Hz),6·91 121199.doc -552 - 200846322 (1H,d,J=2.7 Hz), 7.50-7.28 (6H,m). MS (ESI) m/z: 338 (M+H)+. (7) 1-(Tertibutoxycarbonyl)-5-hydroxy-7-methylporphyrin [Chem. 630]

Dissolve 5-benzyloxy-1-(t-butoxycarbonyl)-7-methyl-1H-indole (1.18 g) in ethanol (20 ml), add 5% Pd/C (lg), The mixture was stirred under normal pressure for 2 hours, and the reaction mixture was replaced with nitrogen. The catalyst was filtered and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography (2L) to give the title compound: H-NMR (CDC13) δ: 1.52 (9H, s) 2 23 s, § ^ 2·23 OH, S ) 5 2.89 (2H, J = 7.8 Hz), 4_04 (2H, t, J = 7.8 HZ), 5 08 , T , 8 (1H, s), 6.44 (1H, J = 2.0Hz), 6.52 ( lH5d, J = 2.0 Hz). MS (ESI) m/z ·· 272 (M+Na)+. Difluoromethyl-2-thienyl) (8) 1-(Tertibutoxycarbonyl)-5-[(4-phenyloxy)-7-methylporphyrin [Chem. 631]

Boo 121199.doc -553 200846322 1-(Sexybutoxy)-5-yl-7-methyl-3-budolin (613 mg), 4-n--5-difluoromethyl- 2-°Cenylmethyl chloride (1.02 g), potassium carbonate (510 mg) and DMF (10 ml) were mixed and stirred at 85 ° C for 20 hours. After it was left to cool to room temperature, the reaction mixture was diluted with ethyl acetate (2 EtOAc) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (m.) (yield: 2L) to afford the title compound (1.07 g) 〇W-NMR (CDC13) δ: 1.52 (9H, S), 2·29 (3H, s), 2·94 (2H, t, J = 7.6 Ηζ), 4.06 (2Η, t, J=8.1 Ηζ), 5·17 (2Η, s), 6·62-6·65 (1H, m) ,6·69-6·71 (1H,m)5 7.06-7.04 (1H,m)5 7.35-7.44 (5H,m) 〇(9) 7-Methyl-5-[(4-phenyl-5) -trifluoromethylthienyl)nonyloxy]σ-initial porphyrin [Chemical 632] 丫N -^

• , (10) — XpQ in 1-(t-butoxycarbonyl)-5-[(4-phenyl-5-trifluoroindolyl-2-ylthiophenyl)methoxy]-7-methylporphyrin A solution of 4 N hydrochloric acid / dioxane (10 ml) was added to (1.07 g), and stirred for 3 hours. The reaction mixture was concentrated, and a saturated aqueous solution of argon carbonate (50 ml) was added to the residue to make a mixture, and the mixture was extracted with ethyl acetate (2 〇〇 ml). The extract was dried over anhydrous sodium sulfate and evaporatediel ^H-NMR (CDC13) δ : 2.14 (3Η, s)5 3.04 (2H, t, J=8.4 Hz), 121I99.doc - 554- 200846322 3.57 (3H,t,J=8.8 Ηζ),5·13 (2H, s), 6·55-6·57 (1H, m), 6·69-6·72 (1H, m), 7.02-7.05 (1H, m), 7·35-7·44 (5H , m). MS (ESI) m/z: 390 (M+H)+. (10) (311)-[&gt;1-(Tertibutoxycarbonyl)_:^-methylamino]-4-1&gt; Mercapto-5-[(4-phenyl-5-trifluoro) Methylthienyl)methoxy]-1-indolyl]-4-oxooxybutyric acid methyl ester [Chem. 633]

Boc added 7-methyl-5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]porphyrin (166 mg), B〇c_D-Me-Asp (OMe) -OH (lll mg), EDC.HC1 (123 mg), :HOBt (80 mg), hydrazine (59 μM), and DMF (10 ml) were scrambled for 19 hours. The reaction mixture was extracted with ethyl acetate (200 ml), and the mixture was washed with saturated aqueous sodium chloride (2 EtOAc) and dried over anhydrous sodium sulfate. The obtained residue was purified using silica gel flash column chromatography (yield: 2L) to give the title compound (98 mg). tNMR (CDC13) δ ·· 1.45-1.54 (9H,m),2·21 (3H,s),2.54 (1H,dd,J=15.5, 5.7 Hz), 2.80-2.94 (4H,m)5 3· 08-3·24 (2H, m), 3·64-3·71 (3H, m), 3.83-4.00 (1H, m), 4·20·4·35 (1H, m), 5.18 (2H, s),5·42,5·69 (1H,m),6.66 (1H,s),6·73 (1H, s),7.07-7.04 (1H,m),7·44-7·37 (5H , m). 121199.doc - 555 - 200846322 MS (ESI) m/z : 655 (M+Na)+ 〇(11) (3R)-(N-methylamino)-4·[7-fluorenyl-5-[ (4_Phenyltrimethylmethyl- 2-indolyl)decyloxy]-1-, indolinyl-4-pyreneoxybutyrate [Chem. 634]

(3R)-[N-(Tertibutoxycarbonyl)-N-decylamino]indolyl_5_[(4-phenyl-5-trifluoromethyl-2-thienyl)anthracene To a solution of methyloxyl-butyric acid methyl ester (90 mg) in THF (5 ml), aq. Neutralization was carried out by adding 丨ν hydrochloric acid to the reaction mixture, followed by extraction with 20% methanol / chloroform (2 x 100 ml). The extract was dried over anhydrous sodium sulfate and the solvent was evaporated. Then, a 4 N hydrochloric acid/1,4-dioxane solution (1 ml) was added to the residue, followed by stirring for 3 hours. The reaction mixture was concentrated, EtOAcjjjjjjjj 'H-NMR (DMSO-d6) δ : 2.04 (1.5H? s)5 2.24 (1.5H? s), 2.40- 2.43 (2H, m), 2.80-3.09 (5H, m), 3.53 (1H, t , J=8.3 HZ), 3.90-4.01 (1H, m), 4.21-4.30 (0.5H, m), 4·54·4·60 (0·5Η, m), 5·28 (2H, s)5 6.66-6.68 (0.5H, m), 6.73-6.76 (0·5Η, m), 6.80-6.85 (1H, m), 7.28-7.30 (1H, m), 7.43-7.33 (5H, m). The proton peaks of NH2C1 and CO2H were not observed. MS (ESI) m/z: 519 (M+H)+. [Example 137] 3-[N_[2-[4-methoxy-5-[[4.phenyl.5-(trifluoromethyl)] 121199.doc - 556 - 200846322 2-thienyl] oxime Oxy]-2,3-dihydro-m_吲哚_1-yl]_2_sideoxyethyl]amino]propionic acid (1) 2,3-bis(benzyloxy)benzylidene 635]

Potassium carbonate (40.0 g) and benzyl bromide (25.8) were added to a solution of 2,3-dihydroxybenzaldehyde (commercially available) (1 〇〇g) in acetonitrile (2 〇〇mi) at room temperature. Ml), stirred at 90 ° C for 4 hours. After the reaction mixture was allowed to stand to cool to room temperature, the insoluble material was filtered. After the filtrate was concentrated under reduced pressure, the obtained mixture was evaporated to methylene chloride. 'H-NMR (CDC13) δ : 5.19 (2Η, s), 5.20 (2H5 s)5 7.11 (1H, t, J=7.9 Hz), 7.25-7.50 (12H, m), 10.26 (1H, s). MS (ESI) m/z: 319 (M+H)+. (2) 2,3·bis(benzyloxy)-6-nitrobenzaldehyde and 2,3-bis(benzyloxy)-5-nitrobenzaldehyde [Chem. 636]

No2 was added to a solution of 2,3-bis(benzyloxy)benzaldehyde (20·9 g) in glacial acetic acid (400 ml). Under ice cooling, fuming nitric acid (95 ml) was added. The reaction solution was stirred at room temperature 121199.doc -557 - 200846322 for 4 hours, then added to ice (丨kg), and the resulting precipitate was collected by filtration and dried (reduced line, 50 ° C, 15 hours) , obtained a solid. It was purified by silica gel flash column chromatography (Biotage 65ix2) to obtain 2,3-bis(benzyloxy)-6-nitrobenzaldehyde (6.93 g) to obtain 2,3-bis(benzyloxy). -5-Nitrobenzaldehyde (u, 3 g). 6- Exact matrix.: W-NMR (CDC13) δ : 5·08 (2H, s), 5.26 (2H, s), 7.13 (1H, d, J = 9.2 Hz), 7.29-7.35 (5H, m) , 7.38-7.46 (5H, m), 7.93 (1H, d, J = 9.2 Hz), 10.21 (1H, s). MS (ESI) m/z: 364 (M+H)+. 5-nitrososome: 】H-NMR (CDC13) δ : 5·28 (2H, s), 5·35 (2H, s), 7·25-7·53 (10H, m), 8·08 (1H , d, J = 2.7 Hz), 8·28 (1H, d, J = 2, 7 Hz), 10.19 (1H, s) 〇 MS (ESI) m/z : 386 (M+Na)+. (3) 6-(Benzyloxy)-2-carboxylidene-3-nitrophenyl acetate [Chem. 637]

Add benzene (34 〇ml) and diethyl ether (54 ml) to 2,3-bis(benzyloxy)-6-nitrobenzaldehyde (6·90 g), and heat it to 75 ° C to prepare a solution. . A small amount of magnesium bromide-diethyl ether complex (5·4 〇 (2) was gradually added thereto. After stirring at 75 C for 15 hours, the reaction solution was left to cool to the palace, and stirred at 121199.doc - 585 - 200846322 was poured into 2 N hydrochloric acid (2 〇〇ml) and ice (200 g). Diethyl ether (200 ml) was added, and after separation, the aqueous layer was extracted with diethyl ether (200 ml). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue obtained was purified using EtOAc (Biotage 40M) to afford 3-(benzyloxy)-2-hydroxy-6 nitrobenzene. Formaldehyde (5·90 g). Dissolve the aldehyde in acetic anhydride (3 5 ml). Add sodium acetate (35 〇 mg) at room temperature and dissipate for 1 hour at 6 ° C. Place it to cool. After the temperature was reached, the mixture was poured into ice (4 〇〇g), and the mixture was stirred for 2 hours. The solid formed was collected by filtration, washed with water and dried (vacuum line, 5 〇t:, 2 曰) to give the title compound. (5.2〇g) ^-NMR (CDC13) δ : 2.29 (3Η5 s)5 5.24 (2H? s)? 7.13 (1H3 d5 J=9.3 Hz)? 7.33-7.45 (5H5 m)? 8.11 (1H) d5 J = 9.3 Hz), 10.23 (1H, s). MS (ESI) m/z: 316 (M+H)+. (4) 3-(Benzyloxy)-2-alkyl-6-nitrobenzoic acid and heart (benzyloxy)_2_(dimethoxymethyl)_3_nitrophenol [Chem. 638]

Add methanol (15 ml) and 1 at room temperature to a solution of 6-(benzyloxy)-2-methylindolyl-3-nitrophenyl acetate (2,6 μg) in THF (30 ml) N aqueous sodium hydroxide solution (25 · 0 ml). After stirring at room temperature for 1 hour, 1 N hydrochloric acid (25.0 ml) and ethyl acetate mi) were added to the reaction mixture, and the aqueous solution was taken to obtain an aqueous layer of ethyl acetate (50 ml). The organic layer was combined and dried over anhydrous sodium sulfate 127. The resulting concentrate was purified using silica gel fast column chromatography (Biotage 40M) to give 3-(p-oxy)-2-trans-based -6-propenylbenzidine (_mg). Further, as a highly polar substance, 6-(hydroxy)-2-(dimethoxymethyl)_3_stone-base benzene (149 g) furfural was obtained: • H-NMR (CDC13) δ: 5.28 (2Η , s), 7.06 (1H, d, J=8.9 Hz), 7.33-7.46 (5H, m), 7.67 (1H, d, J=g.9 Hz), 10.49 (1H, d, Pan J=2.4 Hz ), 12.57 (1H, s). MS (ESI) m/z : 272 (Μ·Η)+. Acetal: ^-NMR (CDC13) δ : 3.51 (6H, s)} 5.22 (2H, s), 6.13 (1H, s), 6.88 (1H, d, J=8.8 Hz), 7.30-7.48 (6H, m), 9.21 (1H, s) 0 MS (ESI) m/z ·· 288 (M-OMe (31))+. φ (5) 3-(Benzyloxy)-2_hydroxynitrobenzaldehyde [Chem. 639]

To a solution of 6-(hydroxyl)-2 aryloxy fluorenyl) nitrosobenzene (1·49 g) in 2-propanol (10 ml), concentrated hydrochloric acid (〇6) at room temperature 〇瓜丨). After being scrambled for 1 hour at 8 ° C, it was left to cool to m, and the resulting body was filtered by water to dry (vacuum pump, 40 ° C, 1 hour) to obtain the title 121199.doc 200846322. (1.24 g). (6) 3-(hydroxyl)-2·methoxy-6·nitrobenzoquinone [Chem. 640]

Add 3-potassium carbonate at room temperature to 3-(hydroxyl)-2, via benzyl-6 nitrobenzone (1·93 g) in methylene chloride (30 ml) &gt; After 293 w and iodomethane (0.660 ml), water (4 (10 ml)) was added to the reaction mixture, and the resulting solid was filtered and dried to give the title compound (199 g). CDC13) δ : 3.93 (3H, s) 5 5.25 (2H, s), 7·09 (1H, d, J = 9.0 Hz) 5 7.33-7.50 (5H5 m), 7.91 (1H? d5 J=9.0 Hz) 5 10.37 (1H, s) 〇MS (ESI) m/z: 288 (M+H)+ (7) 1-(benzyloxy)-2_methoxy-4-nitro-3-[( E)-2-nitrovinyl]benzene [Chem. 641]

Vn〇2~^,. H0 no2 N-(3-hydroxy)-2-methoxy-6-nitrobenzoic acid (1·99 g), fluorinated unloaded (173 mg) and crown ether (55·0 mg) In a solution of methylmorphine (35 ml), nitromethane (1.88 ml) was added at 10 °C. The reaction solution was stirred at 5 ° C. 2 121199.doc -561 - 200846322 曰, added to water (200 ml), and extracted with chloroform (2×200 ml). The combined extracts were dried over anhydrous sodium sulfate and evaporated. The resulting concentrate was purified using silica gel flash column chromatography (Biotage 40M) to give 1-[3-(benzyloxy)-2-decyloxy-6-nitrophenyl]-2-nitro-1 - Ethanol (2·08 g). This was dissolved in acetic anhydride (i 8 ml), sodium acetate (400 mg) was added at room temperature, and stirred at 6 (rc for 1 hour). The reaction mixture was allowed to cool to temperature and then poured into ice water ( The title compound (1.88 g) was obtained by EtOAc (EtOAc: EtOAc (EtOAc). 5·25 (2H, s), 7.09 (1H, d, J = 9.2 Hz), 7.36-7.45 (5H, m), 7·71 (1H, d, J = 13.6 Hz), 7.92 (1H, d, J = 9.2 Hz), 8.22 (1H, d, J = 13.6 Hz) (8) 5-(Benzyloxy)_4_methoxy" oxime (Ep343574)

[642]

Add a silicone gel to a solution of 1 (benzyloxy)-2-methoxynitro-3_[(e)_2-nitrovinyl]benzene (1.88 g) in toluene (60 ml) (14. Reduced iron (5·40 g) and glacial acetic acid (3 〇 ml) at 9 Torr. Mix with 〇 for 1 min. The reaction mixture was allowed to cool to room temperature and then filtered with ethyl acetate. The filtrate was concentrated, and chloroform (m.sub.5), water (30 ml), and saturated aqueous sodium hydrogencarbonate (i?) was added to the residue. After the mixture was filtered, the filtrate was separated. 〇ml) Extract the aqueous layer, combine the organic layers, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure. Use Tehjung 121199.doc •562-200846322 Purified column chromatography (Biotage 40M) The title compound (1.25 g) was obtained. ^-NMR (CDCI3) δ: 4.08 (3 Η, s)5 5.I3 (2H, s), 6.64-6.68 (1H, m), 6.93 (1H, d, J =8.8 Hz), 7.01 (1H, d, J==8.8 Hz), 7.15 (1H, t5 J=2.8 Hz), 7.25-7.52 (5H, m), 8·〇6 (1H, br s). (ESI) m/z : 254 (M+H) + (9) 5-(benzyloxy)-4-methoxy-1H-吲哚-1-carboxylic acid tert-butyl ester [Chem. 643]

Add DMAP (30.0 mg) and Boe2(R) (1_12) to a solution of 5-(benzyloxy)-4-methoxy-1H-oxime (1.24 g) in THF (10 ml). g). After stirring at room temperature for 15 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc) h-NMR (CDC13) δ : 1.65 (9H, s), 4·02 (3H, s), 5.16 (2H, s), 6.67 (lH, d, J = 3.7 Hz), 7.00 (lH, d, J) =8.9Hz), 7.28-7.50 (5H,m), 7.51 (1H,d,J=3.7 Ηζ),7·75 (1H,br d,J=8.9 Hz) 〇MS (ESI) m/z ·· 354 (M+H)+. (1 0) 5-Phenyl-4·methoxy-1Η·吲士琳carboxylic acid third butyl vinegar [Chem. 644] 121199.doc •563 - 200846322

Add 5% Pd/C at room temperature to a solution of 3-(benzyloxy)-4-methoxy-1H-indole-1-carboxylic acid tert-butyl ester (1.70 g) in ethanol (40 ml) (1.30 g). After stirring for 2 days at room temperature under a hydrogen atmosphere, the mixture was filtered, and the filtrate was concentrated under reduced pressure, and the mixture was crystallized with a small amount of hexane, and the resulting solid was collected by filtration and dried to give the title compound (9 8 6 Mg). 'H-NMR (CDC13) δ : 1.56 (9Η, s), 3.15 (2H? t5 J=8.7 Hz), 3·87 (3H, s)5 3_99 (2H, br t, J=7.7 Hz), 5.32 (1H, s), 6.75 (1H, d, J = 8.5 Hz), 7.09 (1/2 of 1H, br s), 7.48 (1/2 of 1H, br s) o MS (ESI) m/ z : 266 (M+H)+. (11) 4-Methoxy-5-[[4-phenyl-5-(trifluoromethyl)-2-(septyl)]decyloxy]- 1 吲哚 甲酸 carboxylic acid tert-butyl ester [ 645]

5-(Methylmethyl)-3•phenyl-2_(trimethylene) porphin (333 mg) and 5-butyl-4-methoxy-1H-carbolinecarboxylic acid tert-butyl ester (31 To a solution of 8 mg) in dichloromethane (5.0 ml), potassium carbonate (250 mg) was added at room temperature. At 5〇. After 16 hours of mixing under the armpits, the reaction solution was cooled to room temperature, and the precipitate was removed by filtration. Water (40 ml) and saturated aqueous ammonium chloride (4 mL) were added to the filtrate to ethyl acetate (2×30) Ml) for extraction. The combined extracts were washed with a saturated aqueous solution of sodium chloride (30 ml), and dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc (EtOAc) 1H-NMR (CDC13) δ : 1,55 (9H, s), 3·09 (2H, t, J=: 8.5 Hz), 3.91 (3H, s), 3·99 (2H, br s), 5.21. (2H, s) 5 6·81 (1H, d, J = 8.8 Hz), 7·05 (1H, d, J=l.〇Hz), 7.06 (1/2 of 1H, br s) 7·35 -7·45 (5H,m), 7.48 (1/2 of 1H, br s) 〇MS (ESI) m/z : 506 (M+H)+ 〇(12) 4-methoxy-5-[ [4-Phenyl-5-(trifluoromethyl)_2-thienyl]methoxy] ϋ多琳 hydrochloride [化646]

4-3-decyloxy-5-[[4-phenyl-5-(trifluoromethyl)-2-thienyl]nonyloxy]_ φ 丨-porphyrincarboxylic acid tert-butyl ester (550 mg) The 4 N hydrochloric acid/-1,4-dithionate solution (5.0 ml) was added at room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. W-NMR (DMSO-d6) δ : 3.19 (2H, t, J = 7.8 Ηζ), 3·68 (2H, t, J = 7.8 Hz), 3·86 (3H, s), 5·43 (2H , s), 7.05 (1H, d, J = 8.5 Hz), 7.16 (1H, d, J-8.5Hz), 7.38 (lH, d, J = l_5Hz), 7.40_ 7·51 (5H, m), 10.87 (1H, br s) 〇MS (ESI) m/z : 406 (M+H) + 〇121199.doc -565 - 200846322 (13) 3-[N-(T-butoxycarbonyl)-N- [2-[4-Methoxy-5-[[4-phenyl-5-(difluoroindolyl)-2-nonyl)]methoxy]-2,3-dihydro·1Η-, ϋ -1-1·yl]-2_ oxoethyl]amino]propionic acid tert-butyl ester [Chem. 647]

0 to 4-methoxy-5-[[4-phenyl-5-(trifluoromethyl)-2-thienyl] decyloxy] oxalate hydrochloride (135 mg) and 2-[N a suspension of -(t-butoxycarbonyl)-N-[3-(dibutyloxy)-3-oxopropyl]amino]acetic acid (ill mg) in dichloromethane (3.0 ml) EDOHCl (87.7 mg), HOBt (61.8 mg), and hydrazine (0. 213 ml, 1.53 mmol) were added for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure. ethyl acetate (20 ml), saturated aqueous sodium hydrogen carbonate (40 ml) and water (40 ml) ) Extract the aqueous layer. The combined extracts were dried over anhydrous sodium sulfate (MgSO4) and evaporated. The residue obtained was purified using EtOAc (EtOAc) (EtOAc) (EtOAc (EtOAc). 3·18-3·26 (2H,m),3·54-3·62 (2H,m),3·91 (2/3 of 3H, s),3·93 (1/3 of 3H,s ), 4.00-4.20 (4H, m), 5.22 (2/3 of 2H, s), 5.23 (1/32 2H, s), 6.79-6.86 (lH, m), 7.06 (lH, s), 7.35· 7.45 (5H,m),7·84-7·90 (1H,m) 〇MS (ESI) m/z : 691 (M+H)+ 〇121199.doc - 566 - 200846322 (14) 3-[N -[2-[4-methoxy-5-[[4-phenyl-5-(trifluoromethyl)-2-thienyl]]methoxy]-2,3-monohydro-indole-13引乌朵_ι_基]·2_Sideoxyethyl]amino]propionic acid [Chemical 648]

于3·[Ν-(Dibutyloxy)-Ν-[2·[4-methoxy-5-[[4_phenyl-5] •(trifluoromethyl)-2-thiophene Methoxy]_2,3_dihydro-1Η-吲哚_:μ group&gt;2_sideoxyethyl]amino]propionic acid dibutyl I (1 80 mg) at room temperature A 4 N hydrochloric acid / 1,4-dioxane solution (5 · 〇 ml) was added thereto and stirred for 16 hours. After concentrating the reaction mixture under reduced pressure, the mixture was slurried with diethyl ether, and purified by reverse phase high performance liquid chromatography (Develusil Combi-RP-5, 1 〇cm). 'The target fraction was lyophilized to give the title compound (22.3 mg) 〇h-NMR (DMSO-d6) δ: 2.37 (2H, t, J = 6.6 Hz), 2.83 (2H t

_ J=6·6 Hz), 3·13 (2H, t, J=8.3 Hz), 3·57 (2H, s), 3 81 (3H s), 4.05 (2H, t, J=8.3 Hz) ,5·36 (2H, s), 7.00 (1H, d, J=8 7 Hz), 7.37 (1H, s), 7.40-7.52 (5H, m), 7·74 (1H, d, J=8.7 Hz). C02H and NH were not observed. MS (ESI) m/z: 495 (M+H) + </ s </ s> </ br> </ br> </ br> Found: 535.14835. [Example 138] 3-[N-[2-[4-Fluoro-5·[(4·phenyl-5_trifluoromethyl 2 〇 〇 121 121 121199.doc - 567- 200846322 yl) methoxy 1,1-Phenyloxy]-2-oxoethyl]amino]propionic acid (1) 4-benzyloxy-3-fluoro-1-nitrobenzene [Chem. 649]

OH

F Ο

2-Fluoro-4-nitrobenzene (5.00 g), benzyl bromide (3.97 ml), potassium carbonate (6·6 〇g) and DMF (50 ml) were stirred at 80 ° C for 20 hours. . After the reaction mixture was allowed to cool to room temperature, water (200 ml) was added, and the residue was filtered and dried to give the title compound (7.75 g). !H-NMR (CDC13) δ : 5.25 (2H? s), 7.10-7.04 (1H, m)? 7.46-7·34 (5H, m), 8.04-7.97 (2H, m). MS (ESI) m/z: 248 (M+H)+. (2) 3-N-oxy-2-oxo-6-nitrophenylacetonitrile and 5-benzyloxy-4-fluoro-2_succinyl phenylacetonitrile (W02000047212) ^ [Chem. 650]

4_Benzyloxy-3-fluoro-1-nitrobenzene (3·〇〇g), 4-chlorophenoxyacetonitrile (2.28 g) was dissolved in dmF (50 ml) with stirring, -1 Hey. (: Add a solution of potassium butoxide (3·00 g) in DMF (10 ml), and continue to give 121199.doc -568 - 200846322 for 30 minutes at the same temperature. Add ice to the reaction solution. The extract was washed with a saturated aqueous solution of sodium chloride (2 NMR), and dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by chopping gel column chromatography (2L of Shanshan Expressway column) to obtain 3 • hydroxy-2, fluoro·6-nitrophenylacetonitrile (high polarity, ι·83 g) and % Benzyloxy-4·fluoro-2-nitrophenylacetonitrile (low polarity fraction, i.〇9 g). 'H-NMR (CDC13) δ : 4.16 (2H? d, J=2.0 Hz)? 5.27 (2H3 s)5 7·1() (1H,t,J=8.8 Hz), 7.45-7.35 (5H,m),8·07 (1H,dd, ringing J=9.4, 1.8 Hz). (3) 5- Benzyloxyfluoro-1H-吲哚[化651]

3-Benzyloxy-2-fluoro-6-nitrophenylacetonitrile (500 mg) was dissolved in a mixed solvent of 95% ethanol (10 ml) and THF (2 ml), and pt 〇 2 (5 〇 mg) was added. The contact hydrogenation was carried out at 10 atmospheres for 15 hours under stirring. After replacing with nitrogen, the catalyst was filtered and the filtrate was concentrated. The title compound (1 5 〇 m g) was obtained by purifying the residue obtained by silica gel column chromatography (Shanshan high-speed column 2 L). !H-NMR (CDC13) δ : 5.15 (2H,S), 6.60-6.63 (1H,m), 6.94 (1H,dd,J=8.5, 7.6 Hz),7·02 (1H,d,J=8.5 Hz), 7·15-7·17 (1H, m), 7·28-7·50 (5H, m), 8·1〇 (1H, br s). MS (ESI) m/z: 242 (M+H) + 〇121199.doc - 569 - 200846322 (4) 5 benzyloxy-1-(t-butoxycarbonyl)_4_fluoro·1H_吲哚[化652]

Boc Dissolve 5-benzyloxy-4-fluoro-1H-indole (244 mg) in dichloromethane (1 〇ml), add Boc2 〇 (331 mg) and DMAP (12.4 mg), stir 2 〇 • Time. The residue was purified by silica gel column chromatography (m. W-NMR (CDC13) δ : 1.65 (9H, s), 5.18 (2H, s), 6·64 (1H, d, J = 3.7 Hz), 7.01 (1H, t, 8.4 Hz), 7 ·29·7.40 (3H,m),7·48_ 7·44 (2H,m),7·53 (1H,d,J=3.4 Hz), 7.77 (1H, d, J=7.8

Hz) 〇 (5) 1-(Tertibutoxycarbonyl)_4_fluorohydroxyporphyrin [Chem. 653]

5-Benzyloxy-1-(tert-butoxycarbonyl)-4-fluoro-1 η-indole (225 mg) was dissolved in ethanol (200 ml), and 5 〇 / was added. ? (1/(:, 15 hours of contact hydrogenation under constant pressure and under normal pressure. After the reaction mixture was replaced with nitrogen, the filter was filtered and concentrated. The liquid was cut by a chopping column chromatography. Columns 2L) 121199.doc .570 - 200846322 The residue obtained was purified to give the title compound (1 68 mg). ???H-NMR (CDCls) δ: 1.54 (9 Η, s), 3.10 (2H, t, J = 8.7 Hz)? 3.96-4.06 (2H,m), 4.72 (1H,d,J=3.4 Hz), 6.79 (1H,t, J=8.8 Hz), 7.49 (1H,br s) 〇MS (ESI) m/ z : 254 (M+H)+ (6) 1-(Tertibutoxycarbonyl)_4_fluoro·5_[(4-phenyl-5-trifluoromethylthienyl)methoxy]anthracene Porphyrin

1-(Secondoxybutylidene)_4_fluoro-5-yl via phenylindole (74 mg), 4-phenyl-5-difluoromethyl-2-indoleylmethyl fluoride The compound (97 mg), carbonic acid oblique (61 mg) and DMF (5 ml) were mixed and stirred at 80 ° C for 5 hours. The reaction solution was allowed to stand to cool to room temperature and then extracted with ethyl acetate (200 ml). The extract was extracted with saturated brine (2 x 100 ml), and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography (yield: s) to give the title compound (143 mgj. NMR (CDCI3) δ: 1.55 (9H5 s) 5 3.11 (2H3 t5 J-8.5 Hz)? 4.01 (2H, t, J = 8.1 Hz), 5.22 (2H, s), 6.85 (1H, t, J = 8.5 Hz), 7.07-7.04 (1H, m), 7.63-7.33 (6H, m) 〇MS (ESI) m/z : 394 (M-99)+ (7) 3-[N-(T-butoxycarbonyl)-Ν·[2-[4·Fluoro-5_[(4·benzene) Keith trifluoromethyl-2-nonyl)methoxy]-1-indolyl]-2-oxoethyl]amino] 121199.doc -571 - 200846322 tert-butyl propionate [化655]

Add 4 ν to the third butyloxycarbonyl)-4-fluoro-5·[(4-phenylidene-5-trifluoromethyl_2-thienyl)methoxy]porphyrin (143 mg) Hydrochloric acid / 1 4- _, in liquid (10 ml), stirred for 3 hours. The reaction solution was concentrated, and 2_[N•(2nd-butoxy)-N-(t-butoxyethylethyl)amino]acetic acid (88 ^ EDOHCl (83 mg), HOBt (59 mg) was added. The mixture was stirred for 14 hours with τ (202 μl) and DMF (10 ml). The mixture was extracted with ethyl acetate (200 ml). The extract was washed with saturated brine (2×100 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 2.64 (2H3

m), 3.21-3.30 (2H, m), 3·46·=3·65 (2H, m), 3·7 (Κ3·77 (2H, m), 3.99-4.30 (2H, m) 5 5· 24 (2H, s), 6·87 (1H, dd, Bu 18 9.5 Hz)? 7.07 (1H, s)5 7.39-7.43 (5H5 m)5 7.93-7.86 (1H5 m) 0 MS (ESI) m/ z : 679 (M+H), (8) 3-[N-[2-[4-fluoro-5-[(4-phenyl-5-difluoromethyl-2_thienyl)methoxy] -1 - porphyrinyl]-2-yloxyethyl]amino]propionic acid hydrochloride [Chem. 656] 121199.doc •572- 200846322

3-[N-(Tertidinoxycarbonyl)_Ν·[2_[Heart Fluorine 5_[(4_Phenyl-5-trifluoromethyl-2-thienyl)methoxy]·吲哚Addition of 4 hydrazine hydrochloride / ι, 4 · dioxane solution (10 ml) was added to the tert-butyl ethyl propionate (196 mg) and stirred for 1 day. The reaction mixture was concentrated and purified by a reverse phase HPLc apparatus. The title compound was lyophilized to give the title compound (yield 9 mg). ^-NMR (DMSO-d6) δ : 2.35 (2H5 t, J = 6.6 Hz) 5 2.82 (2H3 t, J = 6.7 Hz), 3.14 - 3.25 (2H, m), 3.56 (2H, s), 4· 11 (2H,t, J = 8.4 Hz), 5.42 (2H, s), 7·15 (1H, t, J=8.7 Hz), 7·39 (1H, s), 7.42-7.52 (5H, m) , 7.80 (1H, d5 J = 8.5 Hz), 8.31 (1H, br s). Protons of CO 2H were not observed. MS (ESI) m/z: 523 (M+H)+. Calculated for elemental analysis of C25H22F4N2〇4S.〇.75H2〇: c, 56.02; H,4·42; F, 14.18; N,5·23; S,5·98. Found: c, 5 5.96; Η 4.15; F, 13.84; N, 5·11; S, 5, 88. [Example 139] 3-[Ν-[2-[6·Fluoro-5-[(4-phenyl-5-trifluoromethyl)-yloxy]-1-ylylene] side Oxyethyl]amino]propionic acid hydrochloride (1) 5-benzyloxy-6-fluoro-1H-indole (EP505322) [Chem. 657] 121199.doc -573 - 200846322

Dissolve 5-benzyloxy-4-fluoro-2-nitrophenylacetonitrile (1·83 g) in 95% ethanol (30 ml), add Pt〇2 (500 mg), and stir with stirring Contact hydrogenation was carried out for 15 hours. After the reaction mixture was replaced with nitrogen, the catalyst was filtered and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography (yield: 2L). H-NMR (CDC13) δ : 5.15 (2H5 s), 6.43-6.45 (1H, m), 7.11- 7.17 (2H, m), 7.21 (1H, d, J = 8.3 Hz), 7·28-7· 41 (3H,m), 7.46-7.51 (2H,m), 8.04 (1H,br s). MS (ESI) m/z: 242 (M+H)+. (2) 5-Benzyloxy-1-(t-butoxycarbonyl)-bufluoro-1Η_σ-derived bee [Chem. 658]

Boc 5-benzyloxy-6-fluoro-1H-indole (140 mg) was dissolved in dioxane (1 ml), and Boc20 (189 mg) and DMAP (7.09 mg) were added and stirred for 20 hours. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc). 2H, s) 5 6.44 (1H, d, J=3,7 Ηζ), 7·10 (1Η, d, J=8.0 Ηζ), 7.28·7·40 (3Η, m), 7·44_ I21199.doc -574 - 200846322 7·48 (2H,m), 7.52 (1H,m),7·96-7·86 (1H,m) MS (ESI) m/z : 342 (M+H)+. 3) 1-(Tertibutoxycarbonyl)-6-fluoro-5-hydroxyindole [Chem. 659]

Boc

Dissolve 5-benzyloxy-1-(t-butoxycarbonyl)_6-fluoro· m_吲哚 (185 mg) in ethanol (15 ml), add 5% Pd/C (185 mg), Contact hydrogenation was carried out for 15 hours under a mixture of stirring and pressing. After replacing with nitrogen, the catalyst was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (m. ΐΗTM δ : 1.54 (9Η5 s) 53.01(2H, t? 1=8.3 Ηζ)5 3 grab 4.01 (2Η,m)5 4·79-4·83 (1Η,(4),6·78 (ιη,d, (iv) 5 Ηζ), 7.71-7.57 (1Η, m) MS (ESI) m/z : 254 (Μ+Η)+ (4) 1-(2nd butoxymethyl)&gt;6_Fluor_5_ [(4_Phenyltrimethylmethylbutenyl) methoxy]porphyrin [Chem. 660]

Io-(t-butoxycarbonyl; fluoro-5-hydroxyporphyrin (114 mg), 4_121199.doc - 575 - 200846322 benzyl-5-difluoromethyl-2-σ-sepenomethyl The mixture was mixed with EtOAc (2 mL). The mixture was diluted with a saturated aqueous solution of sodium chloride (2×100 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue obtained was purified by silica gel column chromatography (2L). b-NMR (CDC13) δ : 1.55 (9H, s), 3·03 (2H, t, J = 8.7 Hz), 3·93·4·03 (2H, m), 5.21 (2H, s) , 6.85 (1H, d, J = 8.1 Hz), 7·05 (1H, s), 7.43-7.36 (6H, m) MS (ESI) m/z : 494 (M+H)+ (5) 3_[N-(Tertibutoxycarbonyl)_Ν_2_[6·Fluoro-5-[(4_phenyl_5·trifluoromethyl-2-phenylphenyl)methoxy]porphyrinyloxy Ethyl]amino]propionic acid tert-butyl ester [Chem. 661]

In 1-(tert-butoxycarbonyl)-6-fluoro-5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy] porphyrin (228 mg) A solution of 4 N hydrochloric acid / 1,4-dioxane (10 ml) was added and the mixture was stirred for 3 hours. The reaction solution was concentrated, and mixed with 2-[N_(t-butoxy)-N-(t-butoxycarbonylethyl)amino]acetic acid (14 mg), ED HCl (133 mg), HOBt (94 mg), TEA (234 μΐ) and DMF (10 ml) were stirred for 14 hours. The reaction solution 121199.doc - 576 - 200846322 was extracted with ethyl acetate (200 ml), and the extract was washed with saturated brine (2 mL) and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography (m.p.). !H-NMR (CDC13) δ : 1.38-1.51 (18Η, m)5 2.54-2.63 (2H, m), 3.12-3.21 (2H, m), 3·54-3·79 (4H, m), 4 ·0 (Μ·19 (2H, m), 5.23 (2H, s), 6.88 (lH, t, J = 8.4 Hz), 7.05 (lH, s), 7.38- 7.43 (5H, m), 8.10-8.01 (1H,m) MS (ESI) m/z: 679 (M+H) + (6) 3-[N-(2 -butoxycarbonyl) Ν-[2-[6·Fluor·5· [(4_Phenyl-trifluoromethyl-2-thienyl)methoxy]β1_indolyl]_2_sideoxyethyl]amino]propionic acid hydrochloride [Chemical 662]

HCI

〇

3-[1 gas second butoxycarbonyl)-6-fluoro-5.[(4-phenyl.5-trifluoromethyl-2-phenylthio) oxime; porphyrinylcarbonyl hydrazine To the tert-butyl propionate (280 mg), 4 Ν hydrochloric acid was added to dioxane solution 〇〇^), and i 曰 was stirred. The reaction mixture was concentrated, chloroform / hexane was added to solidified, and the solid was filtered, and dried to give the title compound ( 155. H-NMR (DMSO-d6) δ: 2·77 (2H, t, J = 7.4 Ηζ) ,3·16-3·25 (4H, m)5 4.11 (2H5 t) J==8.4 Hz)5 4.16 (2H, s)5 5.45 (2H? s)? 7.36 (1H? d5 J=8.5 Hz) 5 7.41-7.38 (1H, m)? 7.52-7.42 (5H? 121199.doc -5T7- 200846322 m), 7.88 (1H,d, J=12.2 Hz). The protons of COOH and NH2C1 were not observed. MS (ESI) m/z: 523 (M+H)+. Calculated for the elemental analysis of C25H22F4N2〇4S'0.75H2〇HC1: c, 52.45; H, 4.31; F, 13·27; N, 4·89; S, 5.60. Found: C, 52.40; H, 4.27; F, 12.90; N, 4.89., S, 5.38. [Example 140] 4-[5-(4-Cyclohexyl-3-trifluoromethylbenzyloxy)-4-methyl-1-indoleyl]-(3S)-(N-methyl Amino)-4-oxooxybutyrate (1) (3S)-(N-Tertioxycarbonyldecylamino)-4-[5-(4-cyclohexyl· 3-III Fluoromethylbenzyloxy)-4-mercapto-1-indolyl]-4·t-butylbutyrate butyrate [Chem. 663]

Mix (250 mg), B〇c-Me-ASp(OtBu)-〇H (153 mg), EDOHC1 (169 mg), HOBt (119 mg), ΤΕΑ (409 μΐ) and DMF (10 ml), stir 22 hours. The reaction solution was extracted with ethyl acetate (2 mL), and the mixture was washed with brine (2×100 m) and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel flash column chromatography (yield: 2L) to give the title compound (31 mg). (2) 4 [5-(4-3⁄4-Hexyl-3-difluoromethylbenzyloxy)_4-methylporphyrin 5-(4-cyclohexyl-3-trifluoromethylbenzyloxy)_4 -Methyl-1-pyroline hydrochloride 121199.doc -578 · 200846322 base H3SHN-methylamino)·4· sideoxybutyrate hydrochloride [Chem. 664]

T^l 0 HCI

UnJW0H ^νη ο (3SMN-Tertioxycarbonyl- glacial methylamino)_4_[5_(4·cyclohexyl-3-trifluoromethylbenzyloxy)-4-methylberberinyl To the second butyl acetobutyrate (310 mg), a solution of 4 Ν hydrochloric acid η,4·dioxane (1 Torr) was added, and the mixture was stirred for 1 day. The reaction mixture was concentrated, and the obtained solid was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ), 2.70-3.08 (5H, m), 4.07-4.16 (lH, m), 4.26-4.35 (1H, m), 4.40 (1H, t, J = 6.2 Hz), 5·07 (2H, s ), 6,82 (1H,d,J=8.8 Hz), 7.66-7.55 (3H,m), 7.81 (1H, d, J=8.8

Hz). The proton peaks of NHAl and C02H were not observed. MS (ESI) m/z: 519 (M+H)+ 〇 C28H33F3N2 〇4' 〇.5H2OHC1 Elemental analysis calculated: c, 59.62; H,6·25; Cl5 6.29; F,10·10; , 4.97. Found: C, 59.29; H, 6.37; Cl, 6.45; F, 1.10; N, 4.92. [Experimental method] 1 · In vivo evaluation of the substance to be tested · (1) Selection of HA-Gqi5 DNA

Chromosomal DN A was extracted from HA-Gqi5 expressing CHO 121199.doc - 579 - 200846322 cells (purchased from Molecular Devices, Inc.) using the DNeasy Tissue Kit (QIAGEN). Using the extract as a template, KOD plus DNA polymerase (TO YOB Ο) for polymerase chain reaction (polymerase chain reaction, hereinafter referred to as PCR) 〇 Purification of target PCR products and blunting kination treatment (BKL Kit : TAKARA BIO INC .), the connection to pUC118/HincII-BAP (TAKARA BIO INC.). The Ligation mix was introduced into Escherichia coli DH5a (TOYOBO), and a positive clone was selected by PCR 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 then ligated to the expression plastid pcDNA3 · lHygro (+) (Invitrogen). Then, it was introduced into Escherichia coli DH5a, and after selecting a positive clone, HA-Gqi5 expression plastid was obtained. (3) Production of HA-Gqi5-expressing CHO cells The HA-Gqi5-expressing plastid obtained in (2) was introduced into CHO-K1 cells using Fugene 6 (Roche Diagnostics Co., Ltd.) reagent, and hygromycin was used. (hygromycin) for cell selection. The cells were subjected to 2 colonizations, and HA_Gqi5 was expressed to express CHO cells by using a Western blotting method using an anti-HA antibody. (4) Selection of human SlPl (EDG-1) cDNA clonal propagation line (open biosystems, cDNA collection # 4071217) of human S1P1 (EDG·1) was used as a template to obtain human S1P1 (EDG-1) by PCR. DNA. The PCR product was inserted into PUC118 and then by site-directed mutagenesis kit (121199.doc - 580 - 200846322)

The plastid of the DNA inserted into the target sequence (The Journal of Biological Chemistry Vol. 265, No. 16, 9308~9313, 1990) was obtained. (5) Construction of human SlPl (EDG-1) expression plastids to restriction enzyme digestion of human S1P1 (EDG-1) gene inserted into PUC118 (The Journal of Biological Chemistry, Vol. 265, No. 165 9308-93 13, 1990), after purification, ligation with the expression plasmid pcDNA3.1/mycHisA (Invitrogen). Then, after introduction into Escherichia coli DH5a and selection of positive clones, human sipi (edG-1) expression plastids were obtained. (6) Human 81?1 kg00-1) expression (: 110 cells were produced using Fugene 6 (Roche Diagnostics Co., Ltd.) reagent, and the SlPl (EDG-1) expression plasmid was introduced into (3). In HA-Gqi5-expressing CHO cells, cell selection was performed using G418. Cells were selected twice, and cells stimulated by S1P to cause intracellular calcium elevation were selected. (7) Intracellular flow assay (caieiurn flux assay) The Cqi cells derived from the Gqi5 protein obtained by (S) and introduced into siPl (EDG-1) were seeded on a black bottom transparent 96-well plate at 2·5 χ 104 cell/well, and cultured overnight to be serum-free. After the medium was washed once, 2·5 mM probenicid (Promethoprim) and 1% of the buffer containing 0.25% fatty acid-free BSA (|Bow Detection Kit, Molecular Devices) were added at 37°. C and 5% C02 were allowed to react for 1 hour. Add 25 μΐ of the test compound to dilute the solution to give a final test concentration of 0 times the rolling degree 'measured by FLEXstation II (Molecular Devices). 121199.doc -581 - 200846322 Intracellular calcium concentration change 'determine intracellular calcium concentration The difference between the minimum value and the maximum peak value. Based on the s-shaped curve prepared from the measured value, £(:5〇 value is calculated as the agonist activity to the SlPl(EDG-1) receptor. In vivo evaluation (measurement of lymphocyte count reduction in blood of peripheral blood of small white blood after administration of compound): Reported that lymphocyte reduction in peripheral blood of mice after administration of S1P receptor agonist [SCIENCE, 296, 346 -349 (2002)]. Using this evaluation method, the evaluation of the test compound is carried out. After the test substance is suspended or dissolved in the MC (methylcellulose) solution according to the surface, the body weight of the mouse is 2 〇g. Oral administration of 0.2 ml. [Table 1] Administration amount of MC solution 3 mg/kg 0.6 mg 2 ml 0.3 mg/ml 10 mg/kg 2 mg 2 ml 1 mg/ml After oral administration for 4 hours, EDTA was used as an anticoagulant under ether anesthesia, and blood was collected from the posterior great vein (〇·5 mi). The number of lymphocytes in the peripheral blood was measured by a comprehensive hematology device ADVIA120 (Bayer Medical). The effect is the average number of peripheral hemolymphocytes of the test drug-administered group relative to the control (solvent administration) The ratio of the number of groups is T/c(%) to determine the effect. The calculation formula of T/C(%): T/C(%)=(the average peripheral hemolymph sphere of the drug-administered group The average number of peripheral hemolymphocytes of the group) χ丨〇〇 [test result] 121199.doc 200846322 The results of tests on the compounds of the examples are disclosed in Table 2 according to the above test methods. [Table 2] Compound S1P1 EC50 (nM) T/C (%) (3 mg/kg) T/C (%) (10 mg/kg) Compound of Example 10 1.3 21.6 16.3 Compound of Example 14 4.4 17.0 11.1 Compound of Example 29 2.4 15.5 13.9 Compound of Example 30 2.9 21.7 11.1 Compound of Example 31 6.3 30.8 19.8 3. In vivo evaluation of the test substance (test of lymphocyte count in the peripheral blood of the rat after administration of the compound) : The reduction in the number of lymphocytes in the peripheral blood of the S1P receptor agonist after administration was evaluated in rats (female Lewis). The test substance was suspended or dissolved according to Table 3. After 0.5% MC (mercaptocellulose) solution, 1 ml was orally administered to the rat body weight per 200 g. [Table 3] Amount of compound 5% of MC solution 3 mg/kg 3 mg 5 ml 0.6 mg/ml 10 mg/kg 10 mg 5 ml 2 mg/ml EDTA as an anticoagulant, orally administered 4 After an hour, blood was collected from the jugular vein under ether anesthesia (0.5 ml). The number of lymphocytes in the peripheral blood was measured by a comprehensive hematology device ADVIA120 (Bayer Medical). For the reduction of the number of lymphocytes in the peripheral blood of the test drug, the average peripheral hemolymph number of the test drug administration group at each blood collection time point is compared with the 121199.doc - 583 - 200846322 control (solvent administration) group. The ratio of the number is expressed as t/c (%). T/C (%) calculation formula: T/C (%) = (the average peripheral hemolymph number of the drug-administered group) / (the average peripheral hemolymph number of the solvent-administered group) x 100 [test Results] The results of tests on the compounds of the examples are shown in Table 4 according to the above test methods. After 4 hours of oral administration, the reduction in the number of lymphocytes in the peripheral blood after oral administration for 24 hours was also good. • [Table 4] Compound S1P1 EC50 (nM) T/C (°/〇) (3 mg/kg) T/C (%) (10 mg/kg) Compound of Example 43 8.7 34.9 25.7 Compound of Example 97 4.7 22.2 17.9 Compound of Example 119 6.2 28.7 20.7 Compound of Example 129 4.5 18.2 17.7 The compound of the present invention has agonist activity against the S1P1 receptor and is effective in reducing the number of lymphocytes in the peripheral blood by oral administration. Sex. 121199.doc - 584 -

Claims (1)

200846322 X. Patent application scope: ι_ A compound, a salt thereof, or a solvate thereof, which is represented by the formula (I). A represents a single bond, or, R1 represents a hydrogen atom or a fluorene alkyl group, and V is a group selected from the following (1) to (3): (1) -G1^ Here, Gi represents that it may have a straight-chain alkyl group having a carbon number of 取代~5), (2) -G -N(R )-G (wherein G2 represents a single bond, or a carbon number which may have a substituent of 1 to 3) a linear alkyl group, G3 represents a linear alkyl group which may have a substituent, R2 represents a hydrogen atom, a Ci_C6 alkyl group or a 3-8 membered cycloalkyl group, (3) Group —φ—铋 (here, G4 represents a single bond, or a linear alkyl group which may have a carbon number of a substituent, and m and η each independently represent 1, 2 or 3), and Ζ1 and Ζ2 are independently represented. A hydrogen atom or a Ci-C6 alkyl group, 121199.doc 200846322 z3 represents a hydrogen atom, a halogen atom, a cyano group, a (VC6 alkyl group, a halogenated Ci. c6 alkyl group, an alkoxy group, or a halogenated (^-decaneoxy group). Base, Q represents 単 bond, -0-, -CH2-, ·〇Ή2-ΟΗ2-, _(ΙΙΉ2-(ΙΉ2-(^Ή2-, -CH2-CH2-CH2-Cn2-, -CH2.CH2.CH2 .CH2.CH2., -CH2-O-^-CH2-CH2-O-x-CH2-O-CH2- &gt; -CH2-CH2-O-ch2-, -ch2_ch2-ch2-o-, -ch2- Ch2-ch2-o-ch2-, -ch2 - ch2_o-ch2-ch2·, -CH2-CH2-CH2-CH2-〇-, -CH=CH- or -CH=CH-CH2-0- (here, These groups may also have 1 to 2 CrCe alkyl groups or a halogen atom as a substituent), and Y is a group described below. (here, Ar1 and Ar2 each independently represent a benzene ring or a 5- to 6-membered aromatic heterocyclic ring, and J1, J2, J3, J4 and J5 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, and a CVC6 alkane. , halogenated CVCe alkyl, C "C6 alkoxy C!-C6 alkyl, Ci-C^ alkoxy, halogenated C1-C6 alkoxy, amine, mono CVC6 alkylamino, diCrG Alkylamino group, carboxyl group, CVC6 alkoxycarbonyl group, amine mercapto group, mono-Crh alkylamine-methyl fluorenyl group, di-Cr C6 alkylamine fluorenyl group, amine sulfonyl group, mono-Cl-C6 alkylamine sulfonate A mercapto group, a di-CrC6 alkylamine sulfonyl group, a phenyl group which may have a substituent, a benzyl group which may have a substituent, a phenethyl group which may have a substituent, a styryl group which may have a substituent, may have a substituent a phenoxy group, a benzyloxy group which may have a substituent, a phenoxyfluorenyl group which may have a substituent, and a 3 to 8 121199.doc -2- 200846322 member which may have a substituent, may have a substituent 3 to 8 membered cycloalkyl, a 38-membered cycloalkylmethyl group which may have a substituent, a 3 to 8 membered cycloalkyloxy group which may have a substituent, and a 3 to 8 membered cycloalkyl group which may have a substituent Oxygen, may have a 6-membered aromatic heterocyclic group having a substituent, a 4 to 6 membered saturated heteroaryl group which may have a substituent, or a 5 to 6 membered heteroaryloxy group which may have a substituent)]. Or a solvate of the compound of claim 1, a salt thereof, or a solvate thereof, etc., wherein the compound of claim 1, the salt thereof, or a solvate thereof, A compound of the formula (I), which is a compound of any one of the above items 1 to 3, a salt thereof, or a solvate thereof, wherein the γ group in the formula (1) is the following group (Here, J1, J2, and J3 are the same as in the claims), and Arl is a benzoin ring, a thiophene ring, an imidazole ring, a pyrazole ring, a pyridine ring, or a pyridazine ring. 5. The compound of claim 4, a salt thereof, or a solvate thereof, wherein J1, J2 and J3 are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a CKC6 alkyl group, a _rCi_C6 alkyl group, Ci-C6 alkoxyfluorenyl-fluorenyl, Crc6 alkoxy, halogenated Ci_C6 alkoxy, di-c"c6 alkylamino, phenyl which may have a substituent, phenethyl which may have a substituent, a phenoxy group which may have a substituent, a benzyloxy group which may have a substituent, a 3 to 8 membered cycloalkyl group which may have a substituent, a 3 to 8 membered cycloalkenyl group which may have a substituent, 121199.doc 200846322 may have a cycloalkyl methoxy ring group of a substituent: a decylalkyl group of 3, 8 or 8 which may have a substituent, or a 5 to 6 member aromatic impurity which may have a substituent. 6. To a pharmaceutically acceptable compound, wherein the compound of the formula (j), a salt thereof, or the like thereof is dissolved in the following group: (here, 'J and J5 are the same as those in the J5, and the same one in the Xing Xingming No. I), Ar2 is a carbazole ring, a thiazole ring, or a triazole ring. &lt; 7. The compound of claim 6, a salt thereof, or a solvate thereof, wherein J and each are independently a hydrogen atom, a _ atom, a nitro group, a cyano group, an anthracene group, a C1-C6 alkyl group ,. - Duck base, Ci C6 alkoxy, halogen Ci. An alkoxy group, a phenyl group which may have a substituent, or a 3 to 8 membered cycloalkyl group which may have a substituent. 8. The compound according to any one of items 1 to 7, the salt thereof, or the solvate thereof, wherein the V system in the formula (1) is 4- (here, the Gi system is the same as in the claim I) ). 9. The compound of claim 8, a salt thereof, or a solvate thereof, wherein the G system may have a free halogen atom, a hydroxyl group, a Ci-q alkyl group, an amine group, a mono-Ci-C6 alkyl amine group, and _CH2_Ch2_ which is a substituent of 1 to 2 groups selected from the group consisting of two Ci_C6 alkylamine groups. 10. The compound of claim 9, a salt thereof, or a solvate thereof, wherein the G system has a mono-(-- 6-alkylamino group as a substituent -CH2_CH2_. I2ll99.doc 200846322 η. The compound of any one of the items (1), the salt thereof, or the solvate thereof, wherein the V system in the formula (1) is -G2-N(R2)-G3_ (here, G2, G and R systems and the request The same in item J). 13. The compound of the East 1st 1st, the salt thereof, or a solvate thereof, wherein the G system may have a free halogenogen? , hydroxyl, Cl·. The group consisting of an alkyl group and a pendant oxy group is selected from the group consisting of 1 to 2 groups, as a substituent, and the G3 system may be composed of free atoms, (tetra), cvc^ groups and pendant oxy groups. 1 to 2 groups as a substituent of _CH2_c out-, r2 is a hydrogen atom or an alkyl group. The compound of any one of claims 1 to 7, a salt thereof, or a solvate thereof, wherein v in the formula (1) is the following group, (Here, G4, m, and n are the same as the request item). 14. The compound of claim 13, the salt thereof, or a solvate thereof, wherein G4 is _CH2-, m is 1, η is 1, 2 or 3. 15. The compound of any one of the claims n4, a salt thereof, or a solvate thereof, wherein Q^CH2_〇_ in the formula (1) (wherein the group may have 1 to 2 C) - a C6 alkyl group or a halogen atom as a substituent). 16. The compound of any one of claims 15 to 15, a salt thereof, or a solvate thereof, wherein z1 and z2 in the formula (1) are both a gas atom: 17. as in claim 丨16 Any one of a compound, a salt thereof, or a solvate thereof, wherein the Z3 in the formula (1) is a hydrogen atom. The compound of any one of claims 1 to 16, a salt thereof, or a solvate thereof, wherein Z3 is a methyl group in the formula (I). A pharmaceutical composition comprising a compound according to any one of claims 18 to 18, a salt thereof, or a solvate thereof, as an active ingredient. An S1P receptor agonist comprising the compound according to any one of claims 1 to 18, a salt thereof, or a solvate thereof as an active ingredient. An S1P1 receptor agonist comprising the compound according to any one of claims 1 to 18, a salt thereof, or a solvate thereof as an active ingredient. An immunosuppressant comprising the compound of any one of claims 1 to 8, a salt thereof, or a solvate thereof as an active ingredient. A therapeutic agent and/or a prophylactic agent for a rejection reaction, an autoimmune disease, and/or an allergic disease, which comprises a compound according to any one of claims 1 to 18, a salt thereof, or a A solvate or the like is used as an active ingredient. A pharmaceutical composition according to any one of claims 1 to 8, a salt thereof, or a solvate thereof, and an antibody selected from the group consisting of an immunosuppressive agent for suppressing immunity, and a rejection reaction. One or a combination of a therapeutic drug, an antibiotic, and a steroid drug. 121199.doc 200846322 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 121199.doc