TW200403244A - 1β-Methylcarbapenem derivatives for oral use - Google Patents

Abstract

The present invention relates to a compound of the following formula (I), [wherein, R1 and R9: each independently representing H or a C1-C6 alkyl group, R2: a C1-C15 alkyl group, a C3-C7 cycloalkyl group or C6-C10 aryl group, n is an integer of 1' 2 or 3. X: sulfur atom or oxygen atom, R3, R4 and R5: each independently representing H, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C7-C12 aralkyl group, or a C6-C10 aryl group, Alk: an C2-C10 alkylene group optionally substituted with hydroxy group, a C3-C7 cycloalkyl group, an optionally substituted carbamoyl or a C6-C10 aryl group, p' q' r and s: each independently representing an integer of 1' 2 or 3,] or the pharmaceutically acceptable salt, ester derivative thereof.

Description

200403244 发明, Description of the invention: [Technical Field] The present invention relates to a 1 Θ-methyl carbon complex compound (I) having excellent antibacterial activity, and its music allowable salt or an ester derivative thereof, containing the compound as an active ingredient. A pharmaceutical composition (especially an antibacterial agent), using a compound for manufacturing the pharmaceutical composition or a pharmacologically acceptable salt or an ester derivative thereof, or administering a pharmacologically effective amount of the compound or its Pharmacology allows the prevention or treatment of diseases (especially bacterial infections) of alkaloid derivatives. [Prior art] _ There is an urgent need to develop carbamate derivatives with antibacterial activity that have a strong balance against a wide range of pathogenic bacteria. Japanese Patent Application Laid-Open No. 8-5 3 4 5 3 discloses a 1 A-methyl carbon complex compound having a structure similar to the present invention. [Summary of the Invention] As a result of the inventor's development of 1 A-methyl carbon complex compounds over the years, it was found that the compound (I) of the present invention has stronger antibacterial power than the previous 1-methyl carbon complex compounds The present invention has been completed as an antibacterial agent for treating or preventing (especially treatment) bacterial infections, and particularly for respiratory system infections. ® The present invention relates to a compound of the general formula or a pharmacologically acceptable salt or an ester derivative thereof:

[Wherein R1 and R9 are each hydrogen or Ci-Cs alkyl, R2 is Ci-C15 alkyl, C3-C7 cycloalkyl, or C6-C] G aryl, -6- 200403244 η is 1, 2 or 3 , X is a sulfur atom or an oxygen atom, and A is a formula

N- (a-1)

—N Μ— Vs or (a-2)

N—R5 (a-3) {wherein R3, R4 and R5 are each hydrogen, CrQ alkyl, hydroxyalkyl, C3-C6 cycloalkyl, C7-C12 aralkyl or C6-C1G aryl ’

Aik is a C2-C1G alkyl group which may be substituted {the substituent is a hydroxyl group, a C3_C0 cycloalkyl group, and a carbamoyl group may be substituted (the substituent is a C 1 -C 6 alkyl group) 2 of the alkyl group It can be combined with a nitrogen atom to form a 3 to 7 member nitrogen-containing heterocyclic ring which can be substituted.) Or C 6-C!. Aryl}, each of 1, 9, 1 * and 5 is 1, 2 or 3}. The "C] -C6 alkyl" in R1, R3, R4, R5 and R9 mentioned above and the "alkyl" part in "C7-C12 # alkyl" in R3, R4 and R5 are straight or branched alkyl , Such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, third butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl , 2,2-dimethylbutyl, 1,2-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, Buethylbutyl, 1-methyl-2-methylpropyl and the like. It is preferably C ^ C3 alkyl, and particularly preferably methyl. The "C 丨 -C 1 5 alkyl" in R2 is a straight or branched c 丨 -C 丨 5 alkyl, such as the "q-C6 alkyl" mentioned above, and such as heptyl, isoheptyl, octyl, nonyl Base, decyl, 200403244 11-base, 12-base, 13-base, 14-base, 15-base, etc. It is preferably an alkyl group, preferably a C! -C3 alkyl group, and particularly preferably a methyl group. The "C3-C7 cycloalkyl" in R2, R3, R4 and R5, and the "C 3-C 7 cycloalkyl" in the substituent of Aik "substitutable C 2 -C! 〇 alkylene" are C 3-C 7 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. It is preferably a C 5 -C 6 cycloalkyl group, and also preferably a cyclohexyl group. "〇6-01〇aryl" in 112, 113, 114, and 115, "aryl" in "C7-C12 aralkyl" in 113, 114, and 115, and "acceptable C2-C10" in Aik The "C6-C! G square group" in the substituent of "Shenyuanji" is, for example, phenyl, benzyl, naphthyl, etc., preferably phenyl. The "〇7-0: 12 aralkyl" in R3, R4, and R5 is the "C6-C1 () aryl" described above, and one "Ci_C6 courtyard" is preferably a cardyl. Straight or branched C 2 -C! 0 hydroxyl group of "C 2-C! 〇 alkylene" in A 1 k, such as ethylene, propyl, trimethylene, 1-ethyl-1,2- Ethyl, 1-propyl-1,2-ethyl, 1-isopropyl-1,2, 2-ethyl, 1-butyl-1,2, 2-ethyl, U2-dimethyl- 1,2-Ethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene and the like. It should be C 2-C 6 ’院 基’, more preferably the following formula

(Wherein R is C 2 -C 4 alkyl). A 1 k "C 2 -C! O alkylene" substituent "Substitutable carbamoyl group" of the "Substitutable 3 to 7-membered heterocyclic group" among the substituents "3 to 7-membered heterocyclic group" is a group containing 1 to 2 nitrogen atoms and may contain oxygen or sulfur atoms

Saturated heterocyclic groups of I 200403244, such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperidinyl, thiomorpholinyl, etc., are preferably 4- to 7-membered heterocyclic rings containing nitrogen More preferably, it is azetidinyl, piperidinyl, morpholinyl or thiomorpholinyl.

Aik's "C2-ClG extended alkyl" substituent "Substitutable amine formamyl" Substituents of "substitutable 3- to 7-membered heterocyclic group" are hydroxyalkyl, amine Cl-C6 alkyl (the amine group can be replaced with 1 ~ 2 Ci-h alkyl groups), carbamoyl group (the amine group can be replaced with 丨 ~ 2 Cl_C6 alkyl groups), carboxyl group, hydroxyl group, amine (Can be substituted with 1 ~ 2 C! -C6 alkyl groups), or may have 1 ~ 2 substituted with the same or different groups selected from C〗 -C 6 alkoxy and C] -C 6 alkyl groups The aforementioned "3 to 7-membered heterocyclic group" is preferably aziridinyl, azetidinyl, piperinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, or 1,1_monooxomorphin base.

R3, R4 and R5 or A 1 k "Substitutable C 2 -C] 0 alkyl" Substituent "Substitutable Aminomethyl" Substituent "Substitutable 3 ~ 7 The hydroxyCrh alkyl group in the substituent of "membered heterocyclic group" is the above-mentioned "alkyl group" substituted with 1 to 2 hydroxyl groups, and preferably a Cl-C4 alkyl group substituted with 1 hydroxyl group.

Aik's "C2-C1G alkylene" substituent "Aminomethylamido" which can be substituted Substitutes "3-7-membered heterocyclic group which can be substituted" "Amine" "C I-C 6 alkyl (the amine group can be substituted with 1 ~ 2. C!-C 6 courtyard)" "amine C 1 -c 6 courtyard" is the one with 1 ~ 2 amino groups substituted The "C! -C6 alkyl group" mentioned above is preferably a C! -C4 alkyl group substituted with one amine group. "Protection by biological methods such as hydrolysis in vivo-9-200403244" of compound (I) refers to the protective group in human body that can be cleaved by biological methods such as hydrolysis to generate compound (I) or its salt, (I) The carboxyl or hydroxy group is protected to obtain an ester derivative. Whether it is such a derivative, firstly, after oral administration or intravenous injection in experimental animals such as rats and mice, the body fluids of the animals are investigated, and the original compound (I) Whether or not its salt can be detected. The protective group forming a carboxy ester derivative is, for example, Ci-C ^ o alkyl, c3-c6 cycloalkyl, c 3-C 6 cycloalkyl C]-C 4 alkyl, c 2-C Ϊ 0 alkoxy Group c! -C4 alkyl, alkoxycarbonyl CKC4 alkyl, phenyl which may be substituted (the substituent is selected from halogen, C1-C4 alkyl, C1-C4 alkyloxy, methylene monooxy, C] 1 or 2 radicals of -C6 alkylalkoxy.), Ci-Cio alkyloxoxybenzyl, phthaloyl, 5-methyl-2-oxo-1,3-dioxanyl-4-yl Methyl, etc. The protective group forming the hydroxyester derivative is, for example, a C! -C! O alkylfluorenyl group, a C6-C1G arylcarbonyl group, a Ci-C1G alkoxycarbonyl group, an aminofluorenyl group, and the like. The "C ^ Cio alkyl" is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, third butyl, pentyl, 2-pentyl, 3-pentyl Base, isopentyl, hexyl, 2-hexyl, 3-hexyl, isohexyl, heptyl, octyl, nonyl, decyl, etc., preferably Ci_C6 alkyl, more preferably C2-C4 alkyl 'most preferably Ethyl. "C3-C6 cycloalkyl" is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and preferably cyclopentyl or cyclohexyl. "C 3-C 6 cycloalkyl C!-C 4 alkyl" is, for example, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl, cyclobutyl Ethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl and the like are preferably cyclopropylmethyl. -10- 200403244 "c2-c1 () alkoxyoxy K4 alkyl" is, for example, ethoxymethyl, 1- (ethoxy) ethyl, 1- (ethoxy) propyl, 1- (Ethyloxy) butyl, propoxymethyl, 1- (propyloxy) ethyl, isopropyloxymethyl, 1- (isopropyloxy) ethyl, butoxymethyl , 1- (butylammonyloxy) ethyl, isobutylammonyloxymethyl, 1- (butylammonyloxy) ethyl, pentamyloxymethyl, 1- (tamopenthyloxy) ethyl, pentyl Fluorenylmethyl, 1- (pentamyloxy) ethyl, isoamyloxymethyl, 1- (isopentyloxy) ethyl, hexamethyleneoxymethyl, 1- (hexamethyleneoxy) ethyl Methyl, octyloxymethyl, 1- (octyloxy) ethyl, decyloxymethyl, cyclopentylcarbonyloxymethyl, 1-methylcyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1 -Methylcyclohexylcarbonyloxymethyl and the like, preferably c2-c6 alkanoyloxymethyl or 1- (C2-C6 alkanoyloxy) ethyl. "Ci-Cio alkoxycarbonyloxy C ^ -Ci alkyl" is, for example, methoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyl (Oxy) ethyl, 1- (ethoxyferoxy) propyl, 1- (ethanegas group) butyl, propoxy gas group methyl, 1- (propoxycarbonyloxy) ethyl, iso Propoxycarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl, butoxycarbonyloxymethyl, 1- (butoxycarbonyloxy) ethyl, isobutoxycarbonyloxymethyl, 1- ( Isobutoxycarbonyloxy) ethyl, second butoxycarbonyloxymethyl, 1- (second butoxycarbonyloxy) ethyl, third butoxycarbonyloxymethyl, 1- (third butoxycarbonyloxy) (Oxy) ethyl, pentoxycarbonyloxymethyl, 1- (pentoxycarbonyloxy) ethyl, (bumethylbutoxycarbonyloxy) methyl, 1- (methylbutoxycarbonyloxy) ethyl, (2-methylbutoxycarbonyloxy) methyl, 1- (2-methylbutoxycarbonyloxy) ethyl, (3-methylbutoxycarbonyloxy) methyl, 1- (3-methyl Butoxycarbonyloxy) ethyl, (1-ethylpropoxycarbonyloxy) methyl, 1- (buethylpropoxycarbonyloxy) ethyl, hexyloxycarbonyloxymethyl, 1- (hexaneoxycarbonyl (Oxy) ethyl, (1-methylpentoxycarbonyloxy) Base, 1- (bumethylpentyloxy) ethyl, mesooxycarbonyloxymethyl, 1- (noon curtain oxygen) ethene-11- 200403244 Group) ethyl, cyclopentyloxycarbonyloxymethylpentoxyquinoxy) ethyl, cyclohexyloxycarbonyloxymethyl, b (cyclohexyloxycarbonyloxy) ethyl, etc., preferably Ci_C6 alkoxycarbonyloxymethyl Or alkoxycarbonyloxy) ethyl. A phenyl group which may be substituted (when the substituent is 1 or 2 groups selected from a halogen atom, a C! -C4 alkyl group, a Cl-C4 alkyloxy group, a methylenedioxy group, and a Cl-c6 alkyloxy group. ”” Is, for example, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-tolyl, tolyl 'methoxyphenyl, 4-methoxyphenyl, 3 4′-monomethoxyphenyl, 3,4-methylenedioxyphenyl, 3-acetamidophenyl, 4-acetoxyphenyl, etc. are preferably unsubstituted phenyl groups. "Alkyloxybenzyl" is, for example, 2-ethoxybenzyl, 3-ethoxybenzyl, 4-ethoxybenzyl, 3-propoxybenzyl, 4-propoxybenzyl, 4- Butanyloxybenzyl, 4-pentanoxyloxybenzyl, 4-hexamethyleneoxybenzyl, 4-octyloxybenzyl, 4-decyloxybenzyl, etc., preferably 3_ or 4_ (c2-C4 alkyl (Methoxy) benzyl. "Alkyl" is, for example, methylamyl, ethylamyl, propylamyl, butylamyl, butylamyl, hexyl, octyl, decyl, and the like, and is preferably a C2-C6 alkylamyl. The "C6-C1G arylcarbonyl group" is, for example, benzylfluorenyl, p-naphthyl '2-naphthoic acid, and the like, and preferably benzylfluorenyl. "C ^ Cio alkoxycarbonyl" is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl, etc., and is preferably a C2_C6 alkoxycarbonyl . "Amine group" is, for example, glycine group, propylamine group, A-propylamine group, leucine, isoleucine, amphetamine group, histamine, aspartate, -12-200403244 Amino acids such as patamic acid and lysine are preferably glycine groups. The compound (1) and its pharmacologically acceptable ester of the present invention can form a "pharmacologically acceptable salt" when necessary. "The pharmacologically acceptable salt" is a salt formed by the compound (I) of the present invention, and is preferably a salt, potassium salt, lithium salt, etc. Alkaline earth metal salts such as alkali metal salts, calcium salts, magnesium salts, etc., metal salts such as iron salts, zinc salts, copper salts, nickel salts, and cobalt salts, inorganic salts such as ammonium salts, third octylamine salts, and dibenzyl Amine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methyl glutamine salt, guanidine salt 'diethylamine salt, triethylamine salt, dicyclohexylamine salt , N, N, -dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenylethylamine salt, piperon salt, tetramethylammonium salt, ginseng (hydroxyl Amine salts, such as organic salts, such as methyl) aminomethane, hydrohalides, hydrochlorides, hydrobromides, and hydroiodates; nitrates, perchlorates, sulfates, and phosphoric acid Inorganic acid salts such as salts, such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; low-alkane sulfonates; aromatic sulfonates such as benzenesulfonate and p-toluenesulfonate; acetates and malic acid salt Organic acid salts such as fumarate, succinate, citrate, ascorbate, tartrate, oxalate, and maleate, and ornithine, glutamate, aspartate, etc. Amino acid salts. In the compound (I) of the present invention, the pharmacologically acceptable salts and esters thereof include their solvates (preferably, hydrates). When the compound (I) of the present invention has asymmetric carbon atoms, each asymmetric carbon The atoms may have any coordination independently, and there is no particular limitation. The present invention includes each stereoisomer, or a mixture of two or more stereoisomers in any proportion. The compound of the general formula (I) is preferably a compound of the following formula. 13- 200403244 (1) (1-1) A in which A is a compound of the formula / Ik, —ΝΝ— R4 R5 (a-3)

N— (a-1) eight Γ -Ν Ν—

Vs or (a-2) {wherein R3, R4 and R5 are each hydrogen, K3 alkyl, C5-C6 cycloalkyl, benzyl or phenyl,

Aik is a C2-C6 alkylene group which can be substituted (when the substituent is a C5-C6 cycloalkyl group or a phenyl group), each of 1, 2, 1 'and 3 is 1 or 2. } (1-2-1) A is a compound of the formula —N— (a-1) NWq (wherein R3 is hydrogen, and P and q are each 1 or 2). (1-2-2) A is a compound of the formula

(Wherein R3 is hydrogen, p is 1, and q is 2). (1-3-1) A is a compound of the formula

—N N— Vs (a-2) (where r and s are both 2). (1-4-1) A is a compound of the formula (a-3) R4 R5 (where R4 and R5 are both hydrogen,-14-200403244 A 1 k is C 2 -C 6 alkylene). (1-4-2) A is a compound of the formula

(Wherein R is C 2 -C 4 alkyl). (2) As for compounds in which R1 (2-1) R1 is hydrogen or C] -C3 alkyl. (2-2) A compound in which R1 is hydrogen. (3) As for R2 · (3-1) Compounds in which R2 is an alkyl group, a C5-C6 cycloalkyl group, or a phenyl group. (3-2) A compound in which R2 is methyl, cyclohexyl or phenyl. (4) As for η (4-1) η is 1 compound. (4-2) A compound in which η is 1, and the substitution position of the sulfur atom is at the 3-position of the azetidine ring. (5) (5-1) X is a sulfur atom. (6-1) R9 in φ (6) R9 is hydrogen or a Ci-Cs alkyl compound. (6-2) A compound in which R9 is a methyl group. Among the above, preferred substituents are compounds obtained by arbitrarily combining two or more substituents, and more preferably the following compounds. (7) R1 and R9 are each chlorine or C1-C3 radical 'R ~ is C1-C3 radical, C5-C6 ring radical or phenyl, η is 1, X is a sulfur atom, and A is a radical of the formula Compound, ·: Ό

(a -1) -15- 200403244 (wherein R3 is hydrogen, and p and q are each 1 or 2). (8) R1 and R9 are each hydrogen or Ci-C3 alkyl, R2 is Ci-C3 alkyl, C5-C6 cycloalkyl or phenyl, η is 1, X is a sulfur atom, and A is a compound of the formula jWr • —N yN — (a ~ 2)

Vs (where 1 and S are both 2). (9) R1 and R9 are each hydrogen or C "C3 alkyl 'R2-Cl-C3 alkyl, C5-C6 cycloalkyl or phenyl ^ η is a sulfur atom, and A is a compound of the formula N- R5

> lk \

——N 14 R4 (where R4 and R5 are both hydrogen,

Aik is C2-C6 alkylene). (lO) A compound in which R1 is hydrogen, R9 is methyl, methyl, cyclohexyl or phenyl, 11 is 1, the substitution position of the sulfur atom is at position 3 of the butyridine ring, and A is a compound of the formula

(a-1)

(Wherein R3 is hydrogen, P is 1, and q is 2). (11) A compound in which R is hydrogen, R9 is methyl, R2 is methyl, cyclohexyl or phenyl, η is a compound having a substitution position of 1 ′ sulfur atom at position 3 of the azetidine ring, χ is a sulfur atom, and A is the following formula Compound (a-2) 「—NN— V; (where both r and s are 2). (12) R is hydrogen, R9 is methyl, R2 is methyl, cyclohexyl or phenyl, n It is a compound in which the substitution position of 1 'k-orthofluorene is at the 3rd position of the azetidine ring, χ is a sulfur-16-200403244 atom, and A is a compound of the formula —N Η (where R is a C2-C4 compound). Specific examples of the compound (I) of the present invention are listed in Tables 1 to 8. However, the compounds of the present invention are not limited thereto. In the following tables, Me is methyl, Et is ethyl, Pr is propyl, iPr is isopropyl, and Bu Is butyl, tBu is third butyl, Pent is pentyl, Hex is hexyl, cPr is cyclopropyl, cBu is cyclobutyl, cPent is cyclopentyl, cHex is cyclohexyl, Ph is phenyl, and Bn is Benzyl, Q is 5-methyl-2-oxo-1,3-difluorenylalkylene, and the position is the bonding position of the sulfur atom. (Table 1)

Compound number X η position R1 R2 p q R3

Η Η 1 1 Me Η Η 1 1 Et Η Η 1 1 Pr Η Η 1 1 iPr Η Η 1 1 cPr Η Η 1 1 Bu Η Η 1 1 Ph Η Η 2 1 Me Η Η 2 1 Et Η Η 2 1 Pr Η Η 2 1 iPr -17- 1 1 S 1 3 2 1- 3 S 1 3 1- 4 S 1 3 1- 5 S 1 3 1- 6 S 1 3 1- 7 S 1 3 1- 8 S 1 3 1- 9 S 1 3 1-10 S 1 3 1- 11 S 1 3 3 1- 2 S 1 3 200403244 Bu 12 S 1 3 1-13 S 1 3 1- 14 SI 3 1 ~ 15 S 1 3 1- 16 S 1 3 1- 17 S 1 3 1- 18 SI 3 1- 19 SI 3 1- 20 SI 3 1-21 S 1 3 1-22 SI 3 1- 23 S 1 3 1- 24 SI 3 1- 25 S 1 3 1-26 S 1 3 1-27 SI 3 1- 28 SI 3 1- 29 S 1 3 Ί- 30 SI 3 1- 31 S 1 3 1- 32 SI 3 1- 33 SI 3 1- 34 S 1 3 1- 35 SI 3 1-36 SI 3 1-37 SI 3 1- 38 S 1 3 1 ~ 39 SI 3 1 ~ 40 S 1 3 HH 2 1 cPr HH 2 1 Bu HH 2 1 Ph HH 2 2 Me HH 2 2 Et HH 2 2 Pr HH 2 2 iPr HH 2 2 cPr HH 2 2 Bu HH 2 2 Ph H Me 1 1 Me H Me 1 1 Et H Me 1 1 Pr H Me 1 1 iPr H Me 1 1 cPr H Me 1 1 Bu H Me 1 1 Ph H Me 2 1 Me H Me 2 1 Et H Me 2 1 Pr H Me 2 1 iPr H Me 2 1 cPr H Me 2 1 Bu H Me 2 1 Ph H Me 2 1 Me H Me 2 1 Et H Me 2 2 Pr H Me 2 2 iPr H Me 2 2 cP r -18- 200403244 1- 41 BU 42 1-43 1- 44 1- 45 1-46 1-47 1- 48 BU 49 1- 50 1-51 1- 52 1- 53 1- 54 1- 55 BU 56 1- 57 1- 58 1- 59 1- 60 1-61 BU 62 1- 63 1-64 1- 65 1 ~ 66 1- 67 1- 68 1- 69 Η Η Η Η Η Η Η Η Η Η Η Η Me Η Η Η Η Η Η Η Η Me Me Me Me • Me Me Me Me Me

Me Me Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn H H H H H H

Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu

-19- 200403244 1- 70 S 1 3 1- 71 SI 3 Bu 72 SI 3 1- 73 SI 3 1- 74 SI 3 Bu 75 SI 3 1- 76 SI 3 1- 77 S 1 3 1- 78 SI 3 1 -79 S 1 3 1- 80 SI 3 1- 81 SI 3 Bu 82 SI 3 1- 83 S 1 3 1- 84 S 1 3 1- 85 SI 3 1- 86 S 1 3 1- 87 S 1 3 1- 88 S 1 3 1- 89 SI 3 1- 90 S 1 3 Bu 91 SI 3 1- 92 SI 3 1- 93 S 1 3 1- 94 SI 3 1- 95 SI 3 1- 96 SI 3 1- 97 SI 3 1- 98 SI 3

Me H 1 1 Ph Me H 2 1 Me Me H 2 1 Et Me H 2 1 Pr Me H 2 1 iPr Me H 2 1 cPr Me H 2 1 Bu Me H 2 1 Ph Me H 2 2 Me Me H 2 2 Et Me H 2 2 Pr Me H 2 2 iPr Me H 2 2 cPr Me H 2 2 Bu Me H 2 2 Ph Me Me 1 1 Me Me Me 1 1 Et Me Me 1 1 Pr Me Me 1 1 iPr Me Me 1 1 cPr Me Me 1 1 Bu Me Me 1 1 Ph Me Me 2 1 Me Me Me 2 1 Et Me Me 2 1 Pr Me Me 2 1 iPr Me Me 2 1 cPr Me Me 2 1 Bu Me Me 2 1 Ph -20- 200403244 1 -99 S 1 3 1-100 S 1 3 1-101 S 1 3 1-102 S 1 3 1-103 S 1 3 1-104 S 1 3 1-105 S 1 3 1-106 S 1 3 1-107 S 1 3 1-108 S 1 3 1-109 S 13 1-110 S 1 3 1-Chuan S 1 3 H12 S 1 3 1-113 S 1 3 H14 S 1 3 1-Π5 S 1 3 1-Π6 SI 3 1 -117 S 1 3 1-118 S 1 3 1-119 S 1 3 1-120 S 1 3 1-121 S 1 3 1-122 S 1 3 1-123 S 1 3 1-124 S 1 3 1 -125 S 1 3 1-126 SI 3 1-127 S 2 3

Me Me 2 2 Me Me Me 2 2 Et Me Me 2 2 Pr Me Me 2 2 iPr Me Me 2 2 cPr Me Me 2 2 Bu Me Me 2 2 Ph Me Bn 1 1 Me Me Bn 1 1 Et Me Bn 1 1 Pr Me Bn 1 1 iPr Me Bn 1 1 cPr Me Bn 1 1 Bu Me Bn 1 1 Ph Me Bn 2 1 Me Me Bn 2 1 Et Me Bn 2 1 Pr Me Bn 2 1 iPr Me Bn 2 1 cPr Me Bn 2 1 Bu Me Bn 2 1 Ph Me Bn 2 2 Me Me Bn 2 2 Et Me Bn 2 2 Pr Me Bn 2 2 iPr Me Bn 1 2 cPr Me Bn 2 2 Bu Me Bn 2 2 Ph HH 1 1 Me -21- 200403244 1- 128 1-129 1-130 1-131 1-132 1-133 Bu 134 1-135 1-136 1-137 1-138 1-139 1-140 1-141 1-142 H43 1-144 1-145 1 -146 1-147 1-148 1-149 1-150 H51 1-152 1-153 1-154 1-155 1-156 S 2 S 2 S 2 S 2 S 2 S 2 S HH 3 HH. 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 1 1 Et 1 1 Pr 1 1 iPr 1 1 cPr 1 1 Bu 1 1 Ph 2 1 Me 2 1 Et 2 1 Pr 2 1 iPr 2 1 cPr 2 1 Bu 2 1 Ph 2 2 Me 2 2 Et 2 2 Pr 2 2 iPr 2 2 cPr 2 2 Bu 2 2 Ph 1 1 Me 1 1 Et 1 1 Pr 1 1 iPr 1 1 cPr 1 1 Bu 1 1 Ph 2 1 Me 2 1 Et

-22-200403244 1-157 1-158 1-159 1-160 1-161 1-162 1-163 1 -164 1-165 1-166 1-167 1-168 1-170 1-171 1 -172 Bu 173 1-174 1-175 1-176 1-177 1-178 1 -179 1-180 1-181 1-182 1-183 H84 H85

3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 2 1 Pr 2 1 iPr 2 1 cPr 2 1 Bu 2 1 Ph 2 2 Me 2 2 Et 2 2 Pr 2 2 iPr 2 2 cPr 2 2 Bu 2 2 Ph 1 1 Me 1 1 Et 1 1 Pr 1 1 iPr 1 1 cPr 1 1 Bu 1 1 Ph 2 1 Me 2 1 Et 2 1 Pr 2 1 iPr 2 1 cPr 2 1 Bu 2 1 Ph 2 2 Me 2 2 Et 2 2 Pr

-23- 200403244 1-186 1-187 1-188 1-189 1-190 1-191 1-192 1-193 1-194 1-195 1-196 1-197 1-198 K199 1-200 1-201 1-202 1-203 1-204 1-205 Bu 206 1-207 1-208 1-209 1-210 1-211 1-212 1-213 Bu 214 Η Bn 2 2 iPr Η Bn 1 2 cPr Η Bn 2 2 Bu Η Bn 2 2 Ph Me H 1 1 Me Me H 1 1 Et Me H 1 1 Pr Me H 1 1 iPr Me H 1 1 cPr Me H 1 1 Bu Me H 1 1 Ph Me H 2 1 Me Me · H 2 1 Et Me H 2 1 Pr Me H 2 1 iPr Me H 2 1 cPr Me H 2 1 Bu Me H 2 1 Ph Me H 2 2 Me Me H 2 2 Et Me H 2 2 Pr Me H 2 2 iPr Me H 2 2 cPr Me H 2 2 Bu Me H 2 2 Ph Me Me 1 1 Me Me Me 1 1 Et Me Me 1 1 Pr Me Me 1 1 iPr -24- 200403244 1-215 S 2 3 1-216 S 2 3 1 -217 S 2 3 1-218 S 2 3 1-219 S 2 3 1-220 S 2 3 221 S 2 3 1-222 S 2 3 1-223 S 2 3 1-224 S 2 3 1-225 S .2 3 1-226 S 2 3 1-227 S 2 3 1-228 S 2 3 1-229 S 2 3 1-230 S 2 3 1-231 S 2 3 1-232 S 2 3 1-233 S 2 3 1-234 S 2 3 1-235 S 2 3 1-236 S 2 3 1-237 S 2 3 238 S 2 3 1-239 S 2 3 1-240 S 2 3 1-241 S 2 3 1- 242 S 2 3 1-243 S 2 3

Me Me 1 1 cPr Me Me 1 1 Bu Me Me 1 1 Ph Me Me 2 1 Me Me Me 1 1 Et Me Me 2 1 Pr Me Me 2 1 iPr Me Me 2 1 cPr Me Me 2 1 Bu Me Me 2 1 Ph Me Me 2 2 Me Me Me 2 1 Et Me Me 2 2 Pr Me Me 2 1 iPr Me Me 1 2 cPr Me Me 2 2 Bu Me Me 2 2 Ph Me Bn 1 1 Me Me Bn 1 1 Et Me Bn 1 1 Pr Me Bn 1 1 iPr Me Bn 1 1 cPr Me Bn 1 1 Bu Me Bn 1 1 Ph Me Bn 2 1 Me Me Bn 2 1 Et Me Bn. 2 1 Pr Me Bn 2 1 iPr Me Bn 2 1 cPr -25- 200403244 1-244 BU 245 1-246 1-247 1-248 1-249 1-250 1-251 1-252 1-253 1-254 1-255 1-256 BU 257 1-258 BU 259 1-260 1- 261 1-262 1-263 1-264 BU 265 BU 266 BU 267 1-268 BU 269 BU 270 1-271 BU 272

3 Me Bn 3 Me Bn 3 Me Bn 3 Me Bn 3 Me Bn 3 Me Bn 3 Me Bn 3 Me Bn 3 Me Bn 4 HH 4 HH 4 HH 4 HH 4 HH 4 HH 4 HH 4 HH 4 HH 4 HH 4 HH 4 HH 4 HH 4 HH 4 HH 4 HH 4 HH 4 HH 4 HH 2 1 Bu 2 1 Ph 2 2 Me 2 2 Et 2 2 Pr 2 2 iPr 2 2 cPr 2 2 Bu 2 2 Ph 1 1 Me 1 1 Et 1 1 Pr 1 1 iPr 1 1 cPr 1 1 Bu 1 1 Ph 2 1 Me 2 1 Et 2 1 Pr 2 1 iPr 2 1 cPr 2 1 Bu 2 1 Ph 2 2 Me 2 2 Et 2 2, Pr 2 2 iPr 2 2 cPr

4 Η H 2 2 Bu

-26- 200403244 BU 273 BU 274 BU 275 1-276 1-277 1-278 1-279 1-280 1-281 BU 282 BU 283 1-284 BU 285 BU 286 1-287 1-288 1-289 1- 290 1-291 BU 292 1-293 1-294 1-295 BU 296 1-297 1-298 BU 299 1-300 1-301 S 3 S 3 S 3 4 Η Η 2 2 Ph 4 Η Me 1 1 Me 4 Η Me 1 1 Et 4 Η Me 1 1 Pr 4 Η Me 1 1 iPr 4 Η Me 1 1 cPr 4 Η Me 1 1 Bu 4 Η Me 1 1 Ph 4 Η Me 2 1 Me 4 Η Me 2 1 Et 4 Η Me 2 1 Pr 4 Η Me 2 1 iPr 4 Η Me 2 1 cPr 4 Η Me 2 1 Bu 4 Η Me 2 1 Ph 4 Η Me 2 2 Me 4 Η Me 2 2 Et 4 Η Me 2 2 Pr 4 Η Me 2 2 iPr 4 Η Me 2 2 cPr 4 Η Me 2 2 Bu 4 Η Me 2 2 Ph 4 Η Bn 1 1 Me 4 Η Bn 1 1 Et 4 Η Bn 1 1 Pr 4 · Η Bn 1 1 iPr 4 Η Bn 1 1 cPr 4 Η Bn 1 1 Bu 4 Η Bn 1 1 Ph

-27- 200403244 1-302 BU 303 BU 304 1-305 1-306 1-307 BU 308 1-309 1-310 1-311 1-312 1-313 1-314 1-315 1-316 1-317 1 -318 1-319 1-320 1-321 1-322 BU 323 BU 324 1-325 1-326 1-327 1-328 1-329 BU 330 4 Η Bn 2 1 Me 4 Η Bn 2 1 Et 4 Η Bn 2 1 Pr 4 Η • Bn 2 1 iPr 4 Η Bn 2 1 cPr 4 Η Bn 2 1 Bu 4 Η Bn 1 1 Ph 4 Η Bn 2 2 -Me 4 Η Bn 2 2 Et 4 Η Bn 2 2 Pr 4 Η Bn 2 2 iPr 4 Η Bn 2 2 cPr 4 Η Bn 2 2 Bu 4 Η Bn 2 2 Ph 4 Me H 1 1 .Me 4 Me H 1 1 Et 4 Me H 1 1 Pr 4 Me H 1 1 iPr 4 Me H 1 1 cPr 4 Me H 1 1 Bu 4 Me H 1 1 Ph 4 Me H 2 1 Me 4 Me H 2 1 Et 4 Me H 2 1 Pr 4 Me H 2 1 iPr 4 Me H 2 1 cPr 4 Me H 2 1 Bu 4 Me H 2 1 Ph 4 Me H 2 2 Me

-28- 200403244 BU 331 1-332 BU 333 1-334 1-335 1-336 1-337 1-338 1-339 BU 340 1-341 1-342 1-343 BU 344 BU 345 1-346 BU 347 BU 348 BU 349 BU 350 BU 351 1-352 1-353 BU 354 1-355 1-356 1-357 1-358 BU 359 S 3 4 Me H 2 2 Et 4 Me H 2 2 Pr 4 Me H 2 2 iPr 4 Me H 2 2 cPr 4 Me H 2 2 Bu 4 Me H 2 2 Ph 4 Me Me 1 1 Me 4 Me Me 1 1 Et 4 Me Me * 1 1 Pr 4 Me Me 1 1 iPr 4 Me Me 1 1 cPr 4 Me Me 1 1 Bu 4 Me Me 1 1 Ph 4 Me Me 2 1 Me 4 Me Me 2 1 Et 4 Me Me 2 1 Pr 4 Me Me 2 1 iPr 4 Me Me 2 1 cPr 4 Me Me 2 1 Bu 4 Me Me 2 1 Ph 4 Me Me 2 2 Me 4 Me Me 2 2 Et 4 Me Me 2 2 Pr 4 Me Me 2 2 iPr 4 Me Me 2 2 cPr 4 Me Me 2 2 Bu 4 Me Me 2 2 Ph 4 Me Bn 1 1 Me 4 Me Bn 1 1 Et

-29- 200403244 1-360 1-361 1-362 1-363 1-364 BU 365 1-366 1-367 1-368 1-369 1-370 1-371 1-372 BU 373 1-374 BU 375 1 -376 1-377 BU 378 BU 379 BU 380 1-381 1-382 1-383 BU 384 BU 385 BU 386 1-387 BU 388

4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 4 Me Bn 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 3 HH 1 1 Pr 1 1 iPr 1 1 cPr 1 1 Bu 11 Ph 2 1 Me 2 1 Et 2 1 Pr 2 1 iPr 2 1 cPr 2 1 Bu 2 1 Ph 2 2 Me 2 2 Et 2 2 Pr 2 2 iPr 2 2 cPr 2 2 Bu 2 2 Ph 1 1 Me 1 1 Et 1 1 Pr 1 1 iPr 1 1 cPr 1 1 Bu 1 1 Ph 2 1 Me 2 1 Et 2 1 Pr

-30- 200403244 389 0 1 3 Η Η 2 1 iPr 1-390 0 1 3 Η Η 2 1 cPr 1-391 0 1 3 Η Η 2 1 Bu 1-392 0 1 3 Η Η 2 1 Ph 1-393 0 1 3 Η Η 2 2 Me 1-394 0 1 3 Η Η 2 2 Et 1-395 0 1 3 Η Η 2 2 Pr 1-396 0 1 3 Η Η 2 2 iPr

1-397 0 1 3 Η Η 2 2 cPr 1-398 0 1 3 Η Η 2 2 Bu BU 399 0 1 3 Η Η 2 2 Ph 1-400 0 1 3 Η Me 1 1 Me 1-401 0 1 3 Η Me 1 1 Et 1-402 0 1 3 Η Me 1 1 Pr 1-403 01 3 H Me 1 1 iPr 1-404 01 3 H Me 1 1 cPr 1-405 0 1 3 H Me 1 1 Bu 1-406 0 1 3 H Me 1 1 Ph

Bu 407 0 1 3 H Me 2 1 Me 1-408 0 1 3 H Me 2 1 Et 1-409 0 1 3 H Me 2 1 Pr 1-410 01 3 H Me 2 1 iPr Bu 411 01 3 H Me 2 1 cPr 1-412 0 1 3 H Me 2 1 Bu 413 0 1 3 H Me 2 1 Ph 1-414 0 1 3 H Me 2 2 Me 1-415 0 1 3 H Me 2 2 Et 416 0 1 3 H Me 2 2 Pr BU 417 0 1 3 H Me 2 2 iPr -31- 200403244 1-418 1-419 1-420 1-421 1-422 1-423 1-424 BU 425 1-426 BU 427 1-428 1 -429 1-430 1-431 1-432 1-433 1-434 BU 435 1-436 1-437 1-438 1-439 1-440 BU 441 BU 442 BU 443 BU 444 BU 445 BU 446 200403244 1-447 0 1 3 BU 448 0 1 3 1-449 0 1 3 BU 450 0 1 3 1-451 0 1 3 1-452 0 1 3 1-453 01 3 1-454 0 1 3 1 ~ 455 0 1 3 1- 456 01 3 BU 457 0 1 3 BU 458 0 1 3 1-459 0 1 3 BU 460 01 3 1-461 0 1 3 1-462 0 1 3 1-463 0 1 3 BU 464 0 1 3 1-465 0 1 3 1-466 0 1 3 1-467 0 1 3 1-468 0 1 3 1-469 0 1 3 BU 470 0 1 3 1-471 0 1 3 BU 472 0 1 3 1-473 0 1 3 BU 474 01 3 1-475 0 1 3

Me H 1 1 Bu Me H 1 1 Ph Me H 2 1 Me Me H 2 1 Et Me H 2 1 Pr Me H 2 1 iPr Me H 2 1 cPr Me H 2 1 Bu Me H 2 1 Ph Me H 2 2 Me Me H 2 2 Et Me H 2 2 Pr Me H 2 2 iPr Me H 2 2 cPr Me H 2 2 Bu Me H 2 2 Ph Me Me 1 1 Me Me Me 1 1 Et Me Me 1 1 Pr Me Me 1 1 iPr Me Me 1 1 cPr Me Me 1 1 Bu Me Me 1 1 Ph Me Me 2 1 Me Me Me 2 1 Et Me Me 2 1 Pr Me Me 2 1 iPr Me Me 1 1 cPr Me Me 2 1 Bu -33- 200403244 1 -476 0 1 3 477 0 1 3 1-478 0 1 3 1-479 0 1 3 1-480 0 1 3 1-481 0 1 3 1-482 0 1 3 1-483 0 1 3 1-484 0 1 3 1-485 0 1 3 1-486 0 1 3 1-487 0 1 3 1-488 0 1 3 1-489 0 1 3 490 0] 3 1-491 0 1 3 1-492 0 1 3 1 -493 〇1 3 1-494 01 3 1-495 0 1 3 1-496 0 1 3 1-497 0 1 3 1-498 0 1 3 1-499 0 1 3 1-500 0 1 3 1-501 〇 1 3 BU 502 0 1 3 1-503 0] 3 BU 504 0 1 3

Me Me 2 1 Ph Me Me 2 2 Me Me Me 2 2 Et Me Me 2 2 Pr Me Me 2 2 iPr Me Me 2 2 cPr Me Me 2 2 Bu Me Me 2 2 Ph Me .Bn 1 1 Me Me Bn 1 1 Et Me Bn 1 1 Pr Me Bn 1 1 iPr Me Bn 1 1 cPr Me Bn 1 1 Bu Me Bn 1 1 Ph Me Bn 2 1 Me Me Bn 2 1 Et Me Bn 2 1 Pr Me Bn 2 1 iPr Me Bn 2 1 cPr Me Bn 2 1 Bu Me Bn 2 1 Ph Me Bn 2 2 Me Me Bn 2 2 Et Me Bn 2 2 Pr Me Bn 2 2 iPr Me Bn 2 2 cPr Me Bn 2 2 Bu Me Bn 2 2 Ph -34- 200403244 1-505 0 2 3 1-506 0 2 3 1-507 0 2 3 1-508 0 2 3 509 0 1 3 1-510 0 2 3 511 0 2 3 1-512 0 1 3 1-513 02 3 1-514 0 2 3 1-515 0 2 3 1-516 0 2 3 1-517 0 2 3 1-518 0 2 3 1-519 0 2 3 1-520 0 2 3 1-521 0 2 3 1 -522 0 2 3 1-523 02 3 1-524 0 2 3 1-525 0 2 3 1-526 0 2 3 1-527 0 2 3 1-528 0 2 3 1-529 0 2 3 1-530 0 2 3 1-531 02 3 1-532 0 2 3 1-533 0 2 3

Η Η 1 1 Me Η Η 1 1 Et Η Η 1 1 Pr Η Η 1 1 iPr Η Η 1 1 cPr Η Η. 1 1 Bu Η Η 1 1 Ph Η Η 2 1 Me Η Η 2 1 Et Η Η 2 1 Pr Η Η 2 1 iPr Η Η 2 1 cPr Η Η 2 1 Bu Η Η 2 1 Ph Η Η 2 2 Me Η Η 2 2 Et Η Η 2 2 Pr Η Η 2 2 iPr Η Η 2 2 cPr Η Η 2 2 Bu Η Η 2 2 Ph Η Me 1 1 Me Η Me 1 1 Et Η Me 1 1 Pr Η Me 1 1 iPr Η Me 1 1 cPr Η Me 1 1 Bu Η Me 1 1 Ph Η Me 2 1 Me -35- 200403244 534 0 2 3 1-535 0 2 3 1-536 0 2 3 1-537 0 2 3 1-538 0 2 3 1-539 0 2 3 1-540 0 2 3 1-541 0 2 3 1-542 0 2 3 1-543 02 3 1-544 0 2 3 1-545 0 2 3 1-546 0 2 3 547 0 2 3 1-548 0 2 3 1-549 0 2 3 1-550 0 2 3 1 -551 0 2 3 1-552 0 2 3 1-553 0 2 3 1-554 0 2 3 1-555 0 2 3 1-556 0 2 3 1-557 0 2 3 558 0 2 3 1-559 0 2 3 1-560 0 2 3 1-561 0 2 3 1-562 0 2 3 Η Me 2 1 Et Η Me 2 1 Pr Η Me 2 1 iPr Η Me 2 1 cPr Η Me 2 1 Bu Η Me 2 1 Ph Η Me 2 2 Me Η Me 2 2 Et Η Me 2 2 Pr Η Me 2 2 iPr Η Me 2 2 cPr Η Me 2 2 Bu Η Me 2 2 Ph Η Bn 1 1 Me Η Bn 1 1 Et Η Bn 1 1 Pr Η Bn 1 1 iPr Η Bn 1 1 cPr Η Bn 1 1 Bu Η Bn 1 1 Ph Η Bn 2 1 Me Η Bn 2 1 Et Η Bn 2 1 Pr Η Bn 2 1 iPr Η Bn 2 1 cPr Η Bn 2 1 Bu Η Bn 2 1 Ph Η Bn 1 2 Me Η Bn 2 2 Et

-36- 4 200403244 1-563 1-564 1-565 1-566 1-567 1-568 1-569 BU 570 BU 571 1-572 1-573 BU 574 1-575 1-576 1-577 1-578 BU 579 1-580 BU 581 BU 582 BU 583 1-584 BU 585 BU 586 1-587 1-588 BU 589 1-590 1-591

3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me H 3 Me Me 3 Me Me 3 Me Me 2 2 Pr 2 2 iPr 2 2 cPr 2 2 Bu 2 2 Ph 1 1 Me 1 1 Et 1 1 Pr 1 1 iPr 1 1 cPr 1 1 Bu 1 1 Ph 2 1 Me 2 1 Et 2 1 Pr 2 1 iPr 2 1 cPr 2 1 Bu 2 1 Ph 2 2 Me 2 2 Et 2 2 Pr 2 2 iPr 2 2 cPr 2 2 Bu 2 2 Ph 1 1 Me 1 1 Et 1 1 Pr

-37- 200403244 BU 592 1-593 1-594 1-595 1-596 BU 597 1-598 1-599 1-600 1-601 BU 602 1-603 1-604 BU 605 1-606 1-607 BU 608 1-609 1-610 1-611 1-612 1-613 1-614 Bu 615 1-616 1-617 1-618 1-619 1-620

0 2

0 2 3 Me Me 1 1 iPr 3 Me Me 1 1 cPr 3 Me Me 1 1 Bu 3 Me Me 1 1 Ph 3 Me Me 2 1 Me 3 Me Me 2 1 Et 3 Me Me 2 1 Pr 3 Me Me 2 1 iPr 3 Me Me 2 1 cPr 3 Me Me 2 1 Bu 3 Me Me 2 1 Ph 3 Me Me 2 2 Me 3 Me Me 2 2 Et 3 Me Me 2 2 Pr 3 Me Me 2 1 iPr 3 Me Me 2 2 cPr 3 Me Me 2 2 Bu 3 Me Me 2 2 Ph 3 Me Bn 1 1 Me 3 Me Bn 1 1 Et 3 Me Bn 1 1 Pr 3 Me Bn 1 1 iPr 3 Me Bn 1 1 cPr 3 Me Bn 1 1 Bu 3 Me Bn 1 1 Ph 3 Me Bn 2 1 Me 3 Me Bn 2} Et 3 Me Bn 2 1 Pr 3 Me Bn 2 1 iPr

»38- 200403244 BU 621 BU 622 1-623 BU 624 1-625 BU 626 BU 627 1-628 1-629 1-630 1-631 1-632 1-633 1-634 1-635 1-636 1-637 1-638 1-639 1-640 1-641 1-642 Bu 643 1-644 1-645 1-646 1-647 1-648 Bu 649 3 Me Bn 2 1 cPr 3 Me Bn 2 1 Bu 3 Me Bn 2 1 Ph 3 Me Bn 2 2 Me 3 Me Bn 2 2 Et 3 Me Bn 2 2 Pr 3 Me Bn 2 2 iPr 3 Me Bn 2 2 cPr 3 Me Bn 2 2 Bu 3 Me Bn 2 1 Ph 4 HH 1 1 Me 4 HH 1 1 Et 4 HH 1 1 Pr 4 HH 1 1 iPr 4 HH 1 1 cPr 4 HH 1 1 Bu 4 HH 1 1 Ph 4 HH 2 1 Me 4 HH 2 1 Et 4 HH 2 1 Pr 4 HH 2 1 iPr 4 HH 2 1 cPr 4 HH 2 1 Bu 4 HH 2 1 Ph 4 HH 2 2 Me 4 HH 2 2 Et 4 HH 2 2 Pr 4 HH 2 2 iPr 4 HH 2 2 cPr

-39- 200403244 1-650 BU 651 BU 652 1-653 1-654 1-655 1-656 1-657 1-658 BU 659 1-660 1-661 BU 662 1-663 1-664 1 -665 1- 666 BU 667 1-668 1-669 1-670 1-671 1-672 1-673 1-674 BU 675 BU 676 1-677 BU 678

4 Η Η 2 2 Bu 4 Η Η 2 2 Ph 4 Η Me 1 1 Me 4 Η Me 1 1 Et 4 Η Me 1 1 Pr 4 Η Me 1 1 iPr 4 Η Me 1 1 cPr 4 Η Me 1 1 Bu 4 Η Me 1 1 Ph 4 Η Me 2 1 Me 4 Η Me 2 1 Et 4 Η Me 2 1 Pr 4 Η Me 2 1 iPr 4 Η Me 2 1 cPr 4 Η Me 2 1 Bu 4 Η Me 2 1 Ph 4 Η. Me 2 2 Me 4 Η Me 2 2 Et 4 Η Me 2 2 Pr 4 Η Me 2 2 iPr 4 Η Me 2 2 cPr 4 Η Me 2 2 Bu 4 Η Me 2 2 Ph 4 Η Bn 1 1 Me 4 Η Bn 1 1 Et 4 Η Bn 1 1 Pr 4 Η Bn 1 1 iPr 4 Η Bn 1 1. cPr 4 Η Bn 1 1 Bu

-40- 200403244 1-679 BU 680 1-681 1-682 1-683 BU 684 1-685 1-686 1-687 1-688 BU 689 1-690 1-691 BU 692 1-693 1-694 BU 695 1-696 1-697 1-698 1-699 BU 700 1-701 1-702 BU 703 1-704 1-705 BU 706 1-707 4 Η Bn 1 1 Ph 4 Η. Bn 2 1 Me 4 Η Bn 2 1 Et 4 Η Bn 2 1 Pr 4 Η Bn 2 1 iPr 4 Η Bn 2 1 cPr 4 Η Bn 2 1 Bu 4 Η Bn 2 1 Ph 4 Η Bn 2 2 Me 4 Η Bn 2 2 Et 4 Η Bn 2 2 Pr 4 Η Bn 2 2 iPr 4 Η Bn 2 2 cPr 4 Η Bn 2 2 Bu 4 Η Bn 2 2 Ph 4 Me H 1 1 Me 4 Me H 1 1 Et 4 Me H 1 1 Pr 4 Me H 1 1 iPr 4 Me H 1 1 cPr 4 Me H 1 1 Bu 4 Me H 1 1 Ph 4 Me H 2 1 Me 4 Me H 2 1 Et 4 Me H 2 1 Pr 4 Me H 2 1 iPr 4 Me H 2 1 cPr 4 Me H 2 1 Bu 4 Me H 2 1 Ph

-41- 200403244 1-708 1-709 1-710 1-711 1-712 1-713 1-714 1-715 1-716 1-717 1-718 1-719 1-720 1-721 BU 722 BU 723 1-724 1-725 1-726 1-727 1-728 1-729 1-730 1-731 1-732 1-733 1-734 BU 735 BU 736 4 Me H 2 2 Me 4 Me H 2 2 Et 4 Me H 2 2 Pr 4 Me H 2 2 iPr 4 Me H 2 2 cPr 4 Me H 2 2 Bu 4 Me H 2 2 Ph 4 Me Me 1 1 Me 4 Me Me 1 1 Et 4 Me Me 1 1 Pr 4 Me Me 1 1 iPr 4 Me Me 1 1 cPr 4 Me Me 1 1 Bu 4 Me Me 1 1 Ph 4 Me Me 2 1 Me 4 Me Me 2 1 Et 4 Me Me 2 1 Pr 4 Me Me 2 1 iPr 4 Me Me 2 1 cPr 4 Me Me 2 1 Bu 4 Me Me 2 1 Ph 4 Me Me 2 2 Me 4 Me Me 2 2 Et 4 Me Me 2 2 Pr 4 Me Me 2 2 iPr 4 Me Me 2 2 cPr 4 Me Me 2 2 Bu 4 Me Me 1 2 Ph 4 Me Bn 1 1 Me

-42- 200403244 1-737 1-738 1-739 1-740 Bu 741 1-742 1-743 1-744 1-745 1-746 1-747 1-748 1-749 1-750 1-751 1- 752 BU 753 BU 754 1-755 1-756 BU 757 1-758 BU 759 BU 760 1-761 1-762 BU 763 1-764 BU 765 S 2 4 Me Bn 1 1 Et 4 Me Bn 1 1 Pr 4 Me Bn 1 1 iPr 4 Me Bn 1 1 cPr 4 Me Bn 1 1 Bu 4 Me Bn 1 1 Ph 4 Me Bn 2 1 Me 4 Me Bn 2 1 Et 4 Me Bn 2 1 Pr 4 Me Bn 2 1 iPr 4 Me Bn 2 1 cPr 4 Me Bn 2 1 Bu 4 Me Bn 2 1 Ph 4 Me Bn 2 2 Me 4 Me Bn 2 2 Et 4 Me Bn 2 2 Pr 4 Me Bn 2 2 iPr 4 Me Bn 2 2 cPr 4 Me. Bn 2 2 Bu 4 Me Bn 2 2 Ph 3 HH 1 1 cHex 3 HH 2 1 cHex 3 HH 2 2 cHex 3 HH 1 1 cHex 3 HH 2 1 cHex 3 HH 2 2 cHex 4 HH 1 1 cHex 4 HH 2 1 cHex 4 HH 2 2 cHex

-43- 200403244 1-766 0 1 3 HH 1 1 cHex 1-767 0 1 3 HH 2 1 cHex 1-768 0 1 3 HH 2 2 cHex 1-769 0 2 3 HH 1 1 cHex 1-770 0 2 3 HH 2 1 cHex 1-771 0 2 3 HH 2 2 cHex 1-772 0 3 4 HH 1 1 cHex 1-773 0 3 4 HH 2 1 cHex 1-774 0 3 4 HH 2 2 cHex

(Table 2)

(Ha)

Compound number X gate position R1 R3 P q R2 R9 la- 1 S 1 3 HH 1 1 Me H la- 2 s 1 3 HH 1 1 Et H 1a- 3 s 1 3 HH 1 1 Pr H 1 a- 4 s 1 3 HH 1 1 iPr H 1 a- 5 s 1 3 HH 1 1 cPr H 1a- 6 s 1 3 HH 1 1 Bu H 1 a- 7 s 1 3 HH 1 Ί Ph H 1 a- 8 s 1 3 HH 1 1 cHex H 1 a- 9 s 1 3 HH 2 1 Me H 1 a- 10 s 1 3 HH 2 1 Et H

-44- 200403244 la- 11 1a- 12 la- 13 la- 14 la- 15 la- 16 la- 17 1a- 18 la- 19 la- 20 la- 21 la- 22 la- 23 la- 24 la- 25 la -26 la- 27 la- 28 la- 29 la- 30 1a- 31 la- 32 1 a- 33 la- 34 la- 35 la- 36 1a- 37 la- 38 1a- 39 S 2 S 2 S 2

H H H H H H H H H H H H H H H H H H H H H H H H

H H H H 2 1

Pr iPr cPr H Bu H Ph H cHex H

HHH 1 2 Me HH 1 2 Et HH 1 2 Pr HH 2 2 iPr HH 2 2 cPr HH 2 2 Bu HH 2 2 Ph HH 2 2 cHex HH 1 1 Me HH 1 1 Et HH 1 1 Pr HH 1 1 iPr H 1 1

H H H H H H H H H cPr Bu Ph

H H H

cHex H Me H Et H Pr H iPr H cPr H Bu H Ph H -45- 200403244 1a_ 40 la- 41 la- 42 la- 43 la- 44 la- 45 la- 46 la- 47 la- 48 la- 49 1a -50 1a- 51 la- 52 la- 53 la- 54 la- 55 la- 56 la- 57 la- 58 la- 59 la- 60 la- 61 la- 62 la- 63 la- 64 1a- 65 la- 66 la- 67 la- 68 S 2 S 2 S 2 S 2 S 2 S 2 S 3 S 3

3 HH 2 1 cHex H 3 HH 2 2 Me H 3 HH 2 2 Et H 3 HH 2 2 Pr H 3 HH 2 2 iPr H 3 HH 2 2 cPr H 3 HH 2 2 Bu H 3 HH 2 2 Ph H 3 HH 2 2 cHex H 4 HH 1 1 Me H 4 HH 1 1 Et H 4 HH 1 1 Pr H 4 HH 1 1 iPr H 4 HH 1 1 cPr H 4 HH 1 1 Bu H 4 HH 1 1 Ph H 4 HH 1 1 cHex H 4 HH 2 1 Me H 4 HH 2 1 Et H 4 HH 2 1 Pr H 4 HH 2 1 iPr H 4 HH 2 1 cPr H 4 HH 2 1 Bu H 4 HH 2 1 Ph H 4 HH 2 1 cHex H 4 HH 2 2 Me H 4 HH 2 2 Et H 4 HH 2 2 Pr H 4 HH 2 2 iPr H

-46- 200403244 la- 69 S3 4 Η la- 70 S3 4 Η la- 71 S3 4 Η la- 72 S3 4 Η la- 73 SI 3 Η la- 74 SI 3 Η la- 75 S 1 3 Η la- 76 SI 3 Η la- 77 SI 3 Η 1a- 78 SI 3 Η

la- 79 S 1 3 H

la- 80 SI 3 H

la- 81 S 1 3 H

la- 82 SI 3 H

1a- 83 S 1 3 H

la- 84 SI 3 H

la- 85 S 1 3 H

la- 86 S 1 3 H

la- 87 SI 3 H

la- 88 SI 3 H

la- 89 S 1 3 H

la- 90 S 1 3 H

la- 91 SI 3 H

la- 92 S 1 3 H

la- 93 S 1 3 H

la- 94 SI 3 H

la- 95 SI 3 H

la- 96 SI 3 H

la- 97 SI 3 HH 2 2 cPr HH 2 2 Bu HH 2 2 Ph HH 2 2 cHex HH 1 1 Me Et H 1 1 Me Pr H 1 1 Me iPr H 1 1 Me Bu H 2 1 Me Et H 2 1 Me Pr H 2 1 Me iPr H 2 1 Me Bu H 2 2 Me Et H 2 2 Me Pr H 2 2 Me iPr H 2 2 Me Bu H 1 1 Ph Et H 1 1 Ph Pr H 1 1 Ph iPr H 1 1 Ph Bu H 2 1 Ph Et H 2 1 Ph Pr H 2 1 Ph iPr H 2 1 Ph Bu H 2 2 Ph Et H 2 2 Ph Pr H 2 2 Ph iPr H 2 2 Ph Bu H 1 1 cHex Et

-47- 200403244 la- 98 S 1 3 HH 1 1 cHex Pr la- 99 S 1 3 HH 1 1 cHex iPr la-100 S 1 3 HH 1 1 cHex Bu la-101 S 1 3 HH 2 1 cHex Et la- 102 S 1 3 HH 2 1 cHex Pr la-103 S 1 3 HH 2 1 cHex iPr la-104 S 1 3 HH 2 1 cHex Bu 1a-105 S 1 3 HH 2 2 cHex Et la-106 S 1 3 HH, 2 2 cHex Pr la-107 S 1 3 HH 2 2 cHex iPr la-108 S 1 3 HH 1 2 cHex Bu

(table 3 )

_ ^ _ · Compound number X η Position R1 R3 pq R2 2-〗 S 1 3 2-2 S 1 3 2-3 S 1 3 2- 4 S 1 3 2- 5 S 1 3 2- 6 S 1 3 2 -7 S 1 3 2- 8 S 1 3 HH 1 1 Me HH 1 1 Et HH 1 1 Pr HH 1 1 iPr HH 1 1 cPr HH 1 1 Bu HH 1 1 Ph HH 2 1 Me -48- 200403244 2- 9 2- 10 2- 11 2- 12 2- 13 2-14 2- 15 2- 16 2- 17 1- 18 2-19 2-20 2- 21 2-22 2- 23 2- 24 2- 25 2- 26 2- 27 2- 28 2- 29 2- 30 2- 31 2- 32 2- 33 2- 34 2- 35 2- 36 2- 37

3 Η Η 2 1 Et 3-Η Η 2 1 Pr 3 Η Η 2 1 iPr 3 Η Η 2 1 cPr 3 Η Η 2 1 Bu 3 Η Η 2 1 Ph 3 Η Η 2 2 Me 3 Η Η 2 2 Et 3 Η Η 2 2 Pr 3 Η Η 2 2 iPr 3 Η Η 2 2 cPr 3 Η Η 2 2 Bu 3 Η Η 2 2 Ph 3 Η Me 1 1 Me 3 Η Me 1 1 Et 3 Η Me 1 1 Pr 3 Η Me 1 1 iPr 3 Η Me 1 1 cPr 3 ΗMe 1 1 Bu 3 Η Me 1 1 Ph 3 Η Me 2 1 Me 3 Η Me 2 1 Et 3 Η Me 2 1 Pr 3 Η Me 2 1 iPr 3 Η Me 2 1 cPr 3 Η Me 2 1 Bu 3 Η Me 2 1 Ph 3 Η Me 2 2 Me 3 Η Me 2 2 Et

-49- 200403244 2-38 2- 39 2- 40 2- 41 2-42 2-43 2- 44 2-45 1- 46 2- 47 2-48 2- 49 2- 50 2-51 2- 52 2 -53 2- 54 2-55 2- 56 2- 57 2- 58 2- 59 2-60 2-61 2- 62 2-63 2- 64 2-65 2- 66 Η Me 2 2 Pr Η Me 2 2 iPr Η Me 2 2 cPr Η Me 2 2 Bu Η Me 2 2 Ph Η Bn 1 1 Me Η Bn 1 1 Et Η Bn 1 1 Pr Η Bn 1 1 iPr Η Bn 1 1 cPr Η Bn 1 1 Bu Η Bn 1 1 Ph Η Bn 2 1 Me Η Bn 2 1 Et Η Bn 2 1 Pr Η Bn 2 1 iPr Η Bn 2 1 cPr Η Bn 2 1 Bu Η Bn 2 1 Ph Η Bn 2 2 Me Η Bn 1 2 Et Η Bn 2 2 Pr Η Bn 2 2 iPr Η Bn 2 2 cPr Η Bn 2 2 Bu Η Bn 2 2 Ph Me H 1 1 Me Me H 1 1 Et Me H 1 1 Pr -50- 200403244 2- 67 SI 3 2- 68 S 1 3 2- 69 SI 3 2- 70 SI 3 2- 71 S 1 3 2- 72 S 1 3 2- 73 S 1 3 2- 74 S 1 3 2- 75 S 1 3 2- 76 SI 3 2- 77 S 1 3 2- 78 S 1 3 2- 79 S 1 3 2- 80 S 1 3 2- 81 SI 3 2- 82 S 1 3 2- 83 SI 3 2- 84 SI 3 2- 85 S 1 3 2- 86 S 1 3 2- 87 SI 3 2-88 SI 3 2-89 SI 3 2- 90 S 1 3 2- 91 S 1 3 2-92 SI 3 2- 93 SI 3 2-94 SI 3 2- 95 SI 3

Me H 1 1 iPr Me H 1 1 cPr Me H 1 1 Bu Me H 1 1 Ph Me H 2 1 Me Me H 2 1 Et Me H 2 1 Pr Me H 2 1 iPr Me H 2 1 cPr Me H 2 1 Bu Me H 2 1 Ph Me H 2 2 Me Me H 2 2 Et Me H 2 2 Pr Me H 2 2 iPr Me H 2 2 cPr Me H 2 1 Bu Me H 2 2 Ph Me Me 1 1 Me Me Me 1 1 Et Me Me 1 1 Pr Me Me 1 1 iPr Me Me 1 1 cPr Me Me 1 1 Bu Me Me 1 1 Ph Me Me 2 * 1 Me Me Me 2 1 Et Me Me 2 1 Pr Me Me 2 1 iPr-51- 200403244 2- 96 2-97 2- 98 2-99 2-100 2-101 2-102 2-103 2-104 2-105 2-106 2-107 2-108 2-109 2-110 2-111 2- Π2 2-113 2-114 2-115 2-Π6 2-117 2-118 2 -119 2-120 2-121 2-122 2-123 2-124

Me Me 2 1 cPr Me Me 2 1 Bu Me Me 2 1 Ph Me Me 1 2 Me Me Me 2 2 Et Me Me 2 2 Pr Me Me 2 2 iPr Me Me 2 2 cPr Me Me 2 2 Bu Me Me 2 2 Ph Me Bn 1 1 Me Me Bn 1 1 Et Me Bn 1 1 Pr Me Bn 1 1 iPr Me Bn 1 1 cPr Me Bn 1 1 Bu Me- Bn 1 1 Ph Me Bn 2 1 Me Me. Bn 2 1 Et Me Bn 2 1 Pr Me Bn 2 1 iPr Me Bn 2 1 cPr Me Bn 2 1 Bu Me Bn 2 1 Ph Me Bn 2 2 Me Me Bn 2 2 Et Me Bn 2 2 Pr Me Bn 2 2 iPr Me Bn 2 2 cPr

-52- 200403244 2-125 S 1 3 2-126 S 1 3 2-127 S 2 3 2-128 S 2 3 2-129 S 2 3 2-130 S 2 3 2-131 S 2 3 2-132 S 2 3 2-133 S 2 3 2-134 S 2 3 2-135 S 2 3 2-136 S 2 3 2-137 S 2 3 2-138 S 2 3 2-139 S 2 3 2-140 S 2 3 2-141 S 1 3 2-142 S 2 3 2-143 S 2 3 2-144 S 2 3 2-145 S 2 3 2-146 S 2 3 2-147 S 2 3 2-148 S 2 3 2- 149 S 2 3 2-150 S 2 3 2-151 S 2 3 2-152 S 2 3 2-153 S 2 3

Me Bn 2 2 Bu Me Bn 2 2 Ph HH 1 1 Me HH 1 1 Et HH 1 1 Pr HH 1 1 iPr HH 1 1 cPr HH 1 1 Bu HH 1 1 Ph HH 2 1 Me HH 1 1 Et HH 1 1 Pr HH 2 1 iPr HH 2 1 cPr HH 2 1 Bu HH 2 1 Ph HH 2 2 Me HH 2 2 Et H. H 2 2 Pr HH 2 2 iPr HH 2 2 cPr HH 2 2 Bu HH 2 2 Ph H Me 1 1 Me H Me 1 1 Et H Me 1 1 Pr H Me 1 1 iPr H Me 1 1 cPr H Me 1 1 Bu-53- 200403244 2-154 2-155 2-156 2-157 2-158 2-159 2- 160 2-161 2-162 2-163 2-164 2-165 2-166 2-167 2-168 2-169 2-170 2-171 2-172 2-173 2-174 2-175 2-176 2 -177 2-178 2-179 2-180 2-181 2-182 200403244 2-183 S 2 3 2-184, S 2 3 2-185 S 2 3 2-186 S 2 3 2-187 S 2 3 2 -188 S 2 3 2-189 S 2 3 2-190 S 2 3 2-191 S 2 3 2-192 S 2 3 2-193 S 2 3 2-194 S 2 3 2-195 S 2 3 2-196 S 2 3 2-197 S 2 3 2-198 S 2 3 2-199 S 2 3 2-200 S 2 3 2-201 S 2 3 2-202 S 2 3 2-203 S 2 3 2-204 S 2 3 2-205 S 2 3 2-206 S 2 3 2-207 S 2 3 2-208 S 2 3 2-209 S 2 3 2-210 S 2 3 2-211 S 2 3

H Bn 2 2 Me H Bn 2 2 Et H Bn 2 2 Pr H Bn 2 2 iPr H Bn 2 2 cPr H Bn 2 2 Bu H Bn 2 2 Ph Me H 1 1 Me Me H 1 1 Et Me H 1 1 Pr Me H 1 1 iPr Me H 1 1 cPr Me H 1 1 Bu Me H 1 1 Ph Me H 2 1 Me Me H 2 1 Et Me H 2 1 Pr Me H 2 1 iPr Me. H 2 1 cPr Me H 2 1 Bu Me H 2 1 Ph Me H 2 2 Me Me H 2 2 Et Me H 2 2 Pr Me H 2 2 iPr Me H 2 2 cPr Me H 2 2 Bu Me H 2 2 Ph Me Me 1 1 Me -55- 200403244 2-212 S 2 3 2-213 S 2 3 2-214 S 2 3 2-215 S 2 3 2-216 S 2 3 2-217 S 2 3 2-218 S 2 3 2-219 S 2 3 2- 220 S 2 3 2-221 S 2 3 2-222 S 2 3 2-223 S 2 3 2-224 S 2 3 2-225 S 2 3 2-226 S 2 3 2-227 S 2 3 2-228 S 2 3 2-229 S 2 3 2-230 S 2 3 2-231 S 2 3 2-232 S 2 3 2-233 S 2 3 2-234 S 2 3 2-235 S 2 3 2-236 S 2 3 2-237 S 2 3 2-238 S 2 3 2-239 S 2 3 2-240 S 2 3

Me Me 1 1 Et Me Me 1 1 Pr Me Me 1 1 iPr Me Me 1 1 cPr Me Me 1 1 Bu Me Me 1 1 Ph Me Me 2 1 Me Me Me 2 1 Et Me Me 2 1 Pr Me Me 1 1 iPr Me Me 2 1 cPr Me Me 2 1 Bu Me Me 2 1 Ph Me Me 2 2 Me Me Me 2 2 Et Me Me 2 2 Pr Me Me 2 2 iPr Me Me 2 2 cPr Me Me 2 2 Bu Me Me 2 2 Ph Me Bn 1 1 Me Me Bn 1 1 Et Me Bn 1 1 Pr Me Bn 1 1 iPr Me Bn 1 1 cPr Me Bn 1 1 Bu Me Bn 1 1 Ph Me Bn 2 1 Me Me Bn 2 1 Et -56- 200403244 2 -241 2-242 2-243 2-244 2-245 2-246 2-247 2-248 2-249 2-250 2-251 2-252 2-253 2-254 2-255 2-256 2-257 2-258 2-259 2-260 2-261 2-262 2-263 2-264 2-265 2-265 2-267 2-268 2-269

δ 3 S 3 S 3 3 Me Bn 2 1 Pr 3 Me Bn 2 1 iPr 3 Me Bn 2 1 cPr 3 Me Bn 2 1 Bu 3 Me Bn 2 1 Ph 3 Me Bn 2 2 Me 3 Me Bn 2 2 Et 3 Me Bn 2 2 Pr 3 Me Bn 2 2 iPr 3 Me Bn 2 2 cPr 3 Me Bn 2 2 Bu 3 Me Bn 2 2 Ph 4 HH 1 1 Me 4 HH 1 1 Et 4 HH 1 1 Pr 4 HH 1 1 iPr 4 HH 1 1 cPr 4 HH 1 1 Bu 4 HH 1 1 Ph 4 HH 2 1 Me 4 HH 2 1 Et 4 HH 2 1 Pr 4 HH 2 1 iPr 4 HH 2 1 cPr 4 HH 2 1 Bu 4 HH 2 1 Ph 4 HH 2 2 Me 4 HH 2 2 Et 4 HH 1 2 Pr

-57- 200403244 2-270 S3 4 Η Η 2 2 iPr 2-271 S3 4 Η Η 2 2 cPr 2-272 S3 4 Η Η 2 2 Bu 2-273 S3 4 Η Η 2 2 Ph 2-274 S3 4 Η Me 1 1 Me 2-275 S3 4 Η Me 1 1 Et 2-276 S3 4 Η Me 1 1 Pr 2-277 S3 4 H Me 1 1 iPr

2-278 S3 4 H Me 1 1 cPr 2-279 S3 4 H Me 1 1 Bu 2-280 S3 4 H Me 1 1 Ph 2-281 S3 4 H Me 2 1 Me 2-282 S3 4 H Me 2 1 Et 2-283 S3 4 H Me 2 1 Pr 2-284 S3 4 H Me 2 1 iPr 2-285 S3 4 H Me 2 1 cPr 2-286 S 3 4 H Me 2 1 Bu

2-287 S3 4 H Me 2 1 Ph 2-288 S3 4 H Me 2 2 Me 2-289 S3 4 H Me 2 2 Et 2-290 S3 4 H Me 2 2 Pr 2-291 S3 4 H Me 2 2 iPr 2-292 S3 4 H Me 2 2 cPr 2-293 S 3 4 H Me 2 2 Bu 2-294 S3 4 H Me 2 2 Ph 2-295 S3 4 Η Bn 1 1 Me 2-296 S3 4 H Bn 1 1 Et 2-297 S3 4 Η Bn 1 1 Pr 2-298 S3 4 H Bn 1 1 iPr -58- 200403244 2-299 2-300 2-301 2-302 2-303 2-304 2-305 2-306 2 -307 2-308 2-309 2-310 2-311 2-312 2-313 2-314 2-315 2-316 2-317 2-318 2-319 2-320 2-321 2-322 2-323 2-324 2-325 2-326 2-327

S 3 S 3 S 3 S 3 4 H Bn 1 1 cPr 4 H Bn 1 1 Bu 4 H Bn 1 1 Ph 4 H Bn 2 1 Me 4 H Bn 2 1 Et 4 H Bn 2 1 Pr 4 H Bn 2 1 iPr 4 H Bn 2 1 cPr 4 H Bn 2 1 Bu 4 H Bn 2 1 Ph 4 H Bn 2 2 Me 4 H Bn 2 2 Et 4 H Bn 2 2 Pr 4 H Bn 2 2 iPr 4 H Bn 2 2 cPr 4 H Bn 2 2 Bu 4 H Bn 2 2 Ph 4 Me H 1 1 Me 4 Me. H 1 1 Et 4 Me H 1 1 Pr 4 Me H 1 1 iPr 4 Me H 1 1 cPr 4 Me H 1 1 Bu 4 Me H 1 1 Ph 4 Me H 2 1 Me 4 Me H 2 1 Et 4 Me H 2 1 Pr 4 Me H 2 1 iPr 4 Me H 2 1 cPr

-59- 200403244 2-3.28 2-329 2-330 2-331 2-332 2-333 2-334 2-335 2-336 2-337 2-338 2-339 2-340 2-341 2-342 2 -343 2-344 2-345 2-346 2-347 2-348 2-349 2-350 2-351 2-352 2-353 2-354 2-355 2-356

S 3 4 Me H 2 1 Bu 4 Me H 2 1 Ph 4 Me H 2 1 Me 4 Me H 2 2 Et 4 Me H 2 2 Pr 4 Me H 2 2 iPr 4 Me H 2 2 cPr 4 Me H 2 2 Bu 4 Me H 2 2 Ph 4 Me Me 1 1 Me 4 Me Me 1 1 Et 4 Me Me 1 1 Pr 4 Me Me 1 1 iPr 4 Me Me 1 1 cPr 4 Me Me 1 1 Bu 4 Me Me 1 1 Ph 4 Me Me 2 1 Me 4 Me Me 2 1 Et 4 Me Me 2 1 Pr 4 Me Me 2 1 iPr 4 Me Me 2 1 cPr 4 Me Me 2 1 Bu 4 Me Me 2 1 Ph 4 Me Me 2 2 Me 4 Me Me 2 2 Et 4 Me Me 2 2 Pr 4 Me Me 2 2 iPr 4 Me Me 2 2 cPr 4 Me Me 2 2 Bu

-60- 200403244 2-357 2-358 2-359 2-360 2-361 2-362 2-363 2-364 2-365 2-366 2-367 2-368 2-369 2-370 2-371 2 -372 2-373 2-374 2-375 2-376 2-377 2-378 2-379 2-380 2-381 2-382 2-383 2-384 2-385

4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 3 H 3 H 3 H 3 H

3

Me Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn HHHHHHH 2 2 Ph 1 1 Me 1 1 Et 1 1 Pr 1 1 iPr 1 1 cPr 1 1 Bu 1 1 Ph 2 1 Me 2 1 Et 2 1 Pr 2. 1 iPr 2 1 cPr 2 1 Bu 2 1 Ph 2 2 Me 2 2 Et 2 2 Pr 2 2 iPr 2 2 cPr 2 2 Bu 2 2 Ph 1 1 Me 1 1 Et 1 1 Pr 1 1 iPr 1 1 cPr 1 1 Bu 1 1 Ph

-61- 200403244 2-386 2-387 2-388 2-389 2-390 2-391 2-392 2-393 2-394 2-395 2-396 2-397 2-398 2-399 2-400 2 -401 2-402 2-403 2-404 2-405 2-406 2-407 2-408 2-409 2-410 2-411 2-412 2-413 2-414 200403244 2-415 2-416 2- 417 2-418 2-419 2-420 2-421 2-422 2-423 2-424 2-425 2-426 2-427 2-428 2-429 2-430 2-431 2-432 2-433 2 -434 2-435 2-436 2-437 2-438 2-439 2-440 2-441 2-442 2-443

0 1 0 1

3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H. Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 H Bn 3 Me H 3 Me H 2 2 Et 2 2 Pr 2 2 iPr 2 2 cPr 2 2 Bu 2 2 Ph 1 1 Me 1 1 Et 1 1 Pr 1 1 iPr 1 1 cPr 1 1 Bu 1 1 Ph 2 1 Me 2 1 Et 2 1 Pr 2 1 iPr 2 1 cPr 2 1 Bu 2 1 Ph 2 2 Me 2 2 Et 2 2 Pr 2 1 iPr 2 2 cPr 2 2 Bu 2 2 Ph 1 1 Me 1 1 Et

-63- 200403244 2-444 2-445 2-446 2-447 2-448 2-449 2-450 2-451 2-452 2-453 2-454 2-455 2-456 2-457 2-458 2 -459 2-460 2-461 2-462 2-463 2-464 2-465 2-466 2-467 2-468 2-469 2-470 2-471 2-472 3 Me H 1 1 Pr 3 Me H 1 1 iPr 3 Me H 1 1 cPr 3 Me H 1 1 Bu 3 Me H 1 1 Ph 3 Me H 2 1 Me 3 Me H 2 1 Et 3 Me H 2 1 Pr 3 Me H 2 1 iPr 3 Me H 2 1 cPr 3 Me H 2 1 Bu 3 Me H 2 1 Ph 3 Me H 2 2 Me 3 Me H 2 2 Et 3 Me H 2 2 Pr 3 Me H 2 2 iPr 3 Me H 2 2 cPr 3 Me H 2 2 Bu 3 Me. H 2 2 Ph 3 Me Me 1 1 Me 3 Me Me 1 1 Et 3 Me Me 1 1 Pr 3 Me Me 1 1 iPr 3 Me Me 1 1 cPr 3 Me Me 1 1 Bu 3 Me Me 1 1 Ph 3 Me Me 2 1 Me 3 Me Me 2 1 Et 3 Me Me 2 1 Pr

• 64-200403244 2-473 0 1 3 Me Me 2 1 iPr 2-474 0 1 3 Me Me 2 1 cPr 2-475 0 1 3 Me Me 2 1 Bu 2-476 0 1 3 Me Me 2, 1 Ph 2 -477 0 1 3 Me Me 2 2 Me 2-478 0 1 3 Me Me 2 2 Et 2-479 0 1 3 Me Me 2 2 Pr 2-480 0 1 3 Me Me 2 2 iPr 2-481 0 1 3 Me Me 2 2 cPr 2-482 0 1 3 Me Me 2 2 Bu 2-483 0 1 3 Me Me 2 2 Ph 2-484 0 1 3 Me Bn 1 1 Me 2-485 0 1 3 Me Bn 1 1 Et 2- 486 0 1 3 Me Bn 1 1 Pr 2-487 0 1 3 Me Bn 1 1 iPr 2-488 0 1 3 Me Bn 1 1 cPr 2-489 0 1 3 Me Bn 1 1 Bu 2-490 0 1 3 Me Bn 1 1 Ph 2-491 0 1 3 Me Bn 2 1 Me 2-492 0 1 3 Me Bn 2 1 Et 2-493 0 1 3 Me Bn 2 1 Pr 2-494 0 1 3 Me Bn 1 1 iPr 2-495 0 1 3 Me Bn 2 1 cPr 2-496 0 1 3 Me Bn 2 1 Bu 2-497 0 1 3 Me Bn 2 1 Ph 2-498 0 1 3 Me Bn 2 2 Me 2-499 0 1 3 Me Bn 1 2 Et 2-500 0 1 3 Me Bn 2 2 Pr 2-501 0 1 3 Me Bn 2 2 iPr

-65- 200403244 2-502 2-503 2-504 2-505 2-506 2-507 2-508 2-509 2-510 2-5Π 2-512 2-513 2-514 2-515 2-516 2 -517 2-518 2-519 2-520 2-521 2-522 2-523 2-524 2-525 2-526 2-527 2-528 2-529 2-530 200403244 2-53 1 0 2 3 H Me 1 1 Bu 2-532 0 2 3 H Me 1 1 Ph 2-533 0 2 3 H Me 2 1 Me 2-534 0 2 3 H Me 2 1 Et 2-535 0 2 3 H Me 2 1 Pr 2- 536 02 3 H Me 2 1 iPr 2-537 02 3 H Me 2 1 cPr 2-538 0 2 3 H Me 2 1 Bu 2-539 0 2 3 H Me 2 1 Ph 2-540 0 2 3 H Me 2 2 Me 2-541 0 2 3 H Me 2 2 Et 2-542 0 2 3 H Me 2 2 Pr 2-543 02 3 H Me 2 2 iPr 2-544 0 2 3 H Me 2 2 cPr 2-545 0 2 3 H Me 2 2 Bu 2-546 0 2 3 H Me 2 2 Ph 2-547 0 2 3 H Bn 1 1 Me 2-548 0 2 3 Η Bn 1 1 Et 2-549 0 2 3 H Bn 1 1 Pr 2 -550 02 3 H Bn 1 1 iPr 2-551 02 3 Η Bn 1 1 cPr 2-552 0 2 3 Η Bn 1 1 Bu 2-553 0 2 3 Η Bn 1 1 Ph 2-554 0 2 3 H Bn 2 1 Me 2-555 0 2 3 H Bn 2 1 Et 2-556 0 2 3 H Bn 2 1 Pr 2-557 02 3 H Bn 2 1 iPr 2-558 02 3 H Bn 2 1 cPr 2-559 0 2 3 H Bn 2 1 Bu

-67- 200403244 2-560 2-561 2-562 2-563 2-564 2-565 2-566 2-567 2-568 2-569 2-570 2-571 2-572 2-573 2-574 2 -575 2-576 2-577 2-578 2-579 2-580 2-581 2-582 2-583 2-584 2-585 2-586 2-587 2-588 3 Η Bn 2 1 Ph 3 Η Bn 2 2 Me 3 Η Bn 2 2 Et 3 Η Bn 2 2 Pr 3 Η Bn 2 2 iPr 3 Η Bn 2 2 cPr 3 Η Bn 2 2 Bu 3 Η Bn 2 2 Ph 3 Me H 1 1 Me 3 Me H 1 1 Et 3 Me H 1 1 Pr 3 Me H 1 1 iPr 3 Me H 1 1 cPr 3 Me H 1 1 Bu 3 Me H 1 1 Ph 3 Me H 2 1 Me 3 Me H 2 1 Et 3 Me H 2 1 Pr 3 Me. H 2 1 iPr 3 Me H 2 1 cPr 3 Me H 2 1 Bu 3 Me H 2 1 Ph 3 Me H 2 2 Me 3 Me H 2 2 Et 3 Me H 2 2 Pr 3 Me H 2 2 iPr 3 Me H 2 2 cPr 3 Me H 2 2 Bu 3 Me H 2 2 Ph -68- 200403244 2-589 0 2 3 2-590 0 2 3 2-591 02 3 2-592 0 2 3 2-593 0 2 3 2 -594 02 3 2-595 0 2 3 2-596 0 2 3 2-597 0 2 3 2-598 0 2 3 2-599 0 2 3 2-600 0 2 3 2-601 0 2 3 2-602 02 3 2-603 0 2 3 2-604 0 2 3 2-605 0 2 3 2-606 0 2 3 2-607 0 2 3 2-608 0 2 3 2-609 0 2 3 2-610 0 2 3 2 -611 0 2 3 2-612 0 2 3 2-613 0 2 3 2-614 02 3 2-615 02 3 2-616 0 2 3 2-617 0 2 3

Me Me 1 1 Me Me Me 1 1 Et Me Me 1 1 Pr Me Me 1 1 iPr Me Me 1 1 cPr Me Me 1 1 Bu Me Me 1 1 Ph Me Me 2 1 Me Me Me 2 1 Et Me Me 1 1 Pr Me Me 2 1 iPr Me Me 2 1 cPr Me Me 2 1 Bu Me Me 2 1 Ph Me Me 2 2 Me Me Me 2 2 Et Me Me 2 2 Pr Me Me 2 2 iPr Me Me 2 2 cPr Me Me 2 2 Bu Me Me 2 2 Ph Me Bn 1 1 Me Me Bn 1 1 Et Me Bn 1 1 Pr Me Bn 1 1 iPr Me Bn 1 1 cPr Me Bn 1 1 Bu Me Bn 1 1 Ph Me Bn 2 1 Me -69- 200403244 2 -618 2-619 2-620 2-621 2-622 2-623 2-624 2-625 2-626 2-627 2-628 2-629 2-630 2-631 2-632 2-633 2-634 2-635 2-636 2-637 2-638 2-639 2-640 2-641 2-642 2-643 2-644 2-645 2-646 3 Me Bn 2 1 Et 3 Me Bn 2 1 Pr 3 Me Bn 2 1 iPr 3 Me Bn 2 1 cPr 3 Me Bn 2 1 Bu 3 Me Bn 2 1 Ph 3 Me Bn 2 2 Me 3 Me Bn 2 2 Et 3 Me Bn 2 2 Pr 3 Me Bn 2 2 iPr 3 Me Bn 2 2 cPr 3 Me Bn 2 2 Bu 3 Me Bn 2 2 Ph 4 HH 1 1 Me 4 HH 1 1 Et 4 HH 1 1 Pr 4 HH 1 1 iPr 4 HH 1 1 cPr 4 HH 1 1 Bu 4 HH 1 1 Ph 4 HH 2 1 Me 4 HH 2 1 Et 4 HH 2 1 Pr 4 HH 2 1 iPr 4 HH 2 1 cPr 4 HH 2 1 Bu 4 H H 2 1 Ph 4 H H 2 2 Me 4 H H 2 2 Et

-70- 200403244 2-647 0 3 4 Η Η 2 2 Pr 2-648 0 3 4 Η Η 2 2 iPr 2-649 0 3 4 Η Η 2 2 cPr 2-650 0 3 4 Η Η 2 2 Bu 2- 651 0 3 4 Η Η 2 2 Ph 2-652 0 3 4 Η Me 1 1 Me 2-653 0 3 4 Η Me 1 1 Et

2-654 0 3 4 Η Me 1 1 Pr 2-655 0 3 4 H Me 1 1 i Pr 2-656 03 4 H Me 1 1 cPr 2-657 0 3 4 H Me 1 1 Bu 2-658 0 3 4 H Me 1 1 Ph 2-659 0 3 4 H Me 2 1 Me 2-660 0 3 4 H Me 2 1 Et 2-661 0 3 4 H Me 2 1 Pr 2-662 03 4 H Me 2 1 iPr 2- 663 0 3 4 H Me 2 1 cPr

2-664 0 3 4 H Me 2 1 Bu 2-665 0 3 4 H Me 2 1 Ph 2-666 0 3 4 H Me 2 2 Me 2-667 0 3 4 H Me 2 2 Et 2-668 0 3 4 H Me 2 2 Pr 2-669 0 3 4 H Me 2 2 i Pr 2-670 0 3 4 H Me 2 2 cPr 2-671 0 3 4 H Me 2 2 Bu 2-672 0 3 4 H Me 2 2 Ph 2-673 0 3 4 Η Bn 1 1 Me 2-674 0 3 4 H Bn 1 1 Et 2-675 0 3 4 H Bn 1 1 Pr -71-200403244 2-676 03 4 Η Bn 1 1 iPr 2-677 03 4 H Bn 1 1 cPr 2-678 0 3 4 H Bn 1 1 Bu 2-679 0 3 4 H Bn 1 1 Ph 2-680 0 3 4 H Bn 2 1 Me 2-681 0 3 4 H Bn 2 1 Et 2-682 0 3 4 H Bn 2 1 Pr

2-683 03 4 H Bn 2 1 iPr 2-684 03 4 H Bn 2 1 cPr 2-685 0 3 4 H Bn 2 1 Bu 2-686 0 3 4 H Bn 2 1 Ph 2-687 0 3 4 H Bn 2 2 Me 2-688 0 3 4 H Bn 2 2 Et 2-689 0 3 4 H Bn 2 2 Pr 2-690 03 4 H Bn 2 2 iPr 2-691 03 4 H Bn 2 2 cPr 2-692 0 3 4 H Bn 2 2 Bu

2-693 0 3 4 H Bn 2 2 Ph 2-694 0 3 4 Me Η 1 1 Me 2-695 0 3 4 Me Η 1 1 Et 2-696 0 3 4 Me Η 1 1 Pr 2-697 03 4 Me H 1 1 iPr 2-698 03 4 Me Η 1 1 cPr 2-699 0 3 4 Me H 1 1 Bu 2-700 0 3 4 Me Η 1 1 Ph 2-701 0 3 4 Me H 2 1 Me 2-702 0 3 4 Me H 2 1 Et 2-703 0 3 4 Me H 2 1 Pr 2-704 0 3 4 Me H 1 1 i Pr-72- 200403244 2-705 2-706 2-707 2-708 2-709 2-709 2-710 2-711 2-712 2-713 2-714 2-715 2-716 2-717 2-718 2-719 2-720 2-721 2-722 2-723 2-724 2-725 2- 726 2-727 2-728 2-729 2-730 2-731 2-732 2-733 0 3 0 3 4 Me H 2 1 cPr 4 Me H 2 1 Bu 4 Me H 2 1 Ph 4 Me H 2 2 Me 4 Me H 2 2 Et 4 Me H 2 2 Pr 4 Me H 2 2 iPr 4 Me H 2 2 cPr 4 Me H 2 2 Bu 4 Me H 2 2 Ph 4 Me Me 1 1 Me 4 Me Me 1 1 Et 4 Me Me 1 1 Pr 4 Me Me 1 1 i'Pr 4 Me Me 1 1 cPr 4 Me Me 1 1 Bu 4 Me Me 1 1 Ph 4 Me Me 2 1 Me 4 Me Me 2 1 Et 4 Me Me 2 1 Pr 4 Me Me 2 1 iPr 4 Me Me 2 1 cPr 4 Me Me 2 1 Bu 4 Me Me 2 1 Ph 4 Me Me 2 2 Me 4 Me Me 2 2 Et 4 Me Me 2 2 Pr 4 Me Me 2 2 iPr 4 Me Me 2 2 cPr

-73- 200403244 2-734 2-735 2-736 2-737 2-738 2-739 2-740 2-741 2-742 2-743 2-744 2-745 2-746 2-747 2-748 2 -749 2-750 2-751 2-752 2-753 2-754 2-755 2-756 2-757 2-758 2-759 2-760 2-761 2-762 0 3 4 Me Me 2 2 Bu 4 Me Me 2 2 Ph 4 Me Bn 1 1 Me 4 Me Bn 1 1 Et 4 Me Bn 1 1 Pr 4 Me Bn 1 1 iPr 4 Me Bn 1 1 cPr 4 Me Bn 1 1 Bu 4 Me Bn 1 1 Ph 4 Me Bn 1 1 Me 4 Me Bn 1 1 Et 4 Me Bn 2 1 Pr 4 Me Bn 2 1 iPr 4 Me Bn 2 1 cPr 4 Me Bn 2 1 Bu 4 Me Bn 2 1 Ph 4 Me Bn 2 2 Me 4 Me Bn 2 2 Et 4 Me Bn 1 2 Pr 4 Me Bn 2 2 iPr 4 Me Bn 2 2 cPr 4 Me Bn 2 2 Bu 4 Me Bn 2 2 Ph 3 HH 1 1 .cHex 3 HH 2 1 cHex 3 HH 2 2 cHex 3 HH 1 1 cHex 3 HH 2 1 cHex 3 HH 2 2 cHex

-74 200403244 HH 1 1 cHex HH 2 1 cHex HH 2 2 cHex HH 1 1 cHex HH 2 1 cHex HH 2 2 cHex HH 1 1 cHex HH 2 1 cHex HH 2 2 cHex HH 1 1 cHex HH 2 1 cHex HH 2 2 cHex

2-763 S 3 4 2-764 S 3 4 2-765 S 3 4 2-766 0 1 3 2-767 0 1 3 2-768 0 1 3 2-769 0 2 3 2-770 0 2 3 2- 771 0 2 3 2-772 0 3 4 2-773 0 34 2-774 0 3 4 (Table 4)

(Bu 2a)

Compound number X η position R1 2 R3 p q R2 R9

3 Η H 3 Η H 3 Η H 3 Η H 3 Η H 3 Η H 3 Η H 2a- 1 2a-2 2 a- 3 2a- 4 2a- 5 2a-6 2a- 7 1

1 1 Me H

1 1 Et H

1 1 Pr H

1 1 iPr H

1 1 cPr H

1 1 Bu H 2

1 Ph H 200403244 2a- 8 S 1 3 Η Η 2a- 9 S 1 3 Η Η 2a- 10 SI 3 Η Η 2a- 11 SI 3 Η Η 2a- 12 SI 3 Η Η 2a- 13 SI 3 Η Η 2a- 14 SI 3 Η Η 2a- 15 SI 3 Η Η 2a- 16 SI 3 Η Η 2a- 17 SI 3 Η Η 2a- 18 S 1 3 Η Η 2a- 19 SI 3 Η Η 2a- 20 SI 3 Η 2a- 21 SI 3 Η Η 2a- 22 SI 3 Η Η 2a- 23 SI 3 Η Η 2a- 24 S 1, 3 Η Η 2a- 25 S 2 3 Η Η 2a- 26 S 2 3 Η Η 2a- 27 S 2 3 Η a 2a- 28 S 2 3 Η Η 2a- 29 S 2 3 Η Η 2a- 30 S 2 3 Η Η 2a- 31 S 2 3 Η Η 2a- 32 S 2 3 Η Η 2a- 33 S 2 3 Η Η 2a- 34 S 2 3 Η Η 2a- 35 S 2 3 Η Η 2a- 36 S 2 3 Η Η 1 1 cHex Η 2 1 Me Η 2 1 Et Η 2 1 Pr Η 2 1 iPr Η 2 1 cPr Η 2 1 Bu Η 2 1 Ph Η 2 1 cHex Η 2 2 Me Η 2 2 Et Η 2 2 Pr Η 2 2 iPr Η 2 2 cPr Η 2 2 Bu Η 2 2 Ph Η 2 2 cHex Η 1 1 Me Η 1 1 Et Η 1 1 Pr Η 1 1 iPr Η 1 1 cPr Η 1 1 Bu Η 1 1 Ph Η 1 1 cHex Η 2 1 Me Η 2 1 Et Η 2 1 Pr Η 21 iPr Η

-76- 200403244 2a- 37 2a- 38 2a- 39 2a- 40 2a- 41 2a- 42 2a- 43 2a- 44 2a- 45 2a- 46 2a- 47 2a- 48 2a- 49 2a- 50 2a- 51 2a -52 2a- 53 2a- 54 2a- 55 2a- 56 2a- 57 2a- 58 2a- 59 2a- 60 2a- 61 2a- 62 2a- 63 2a- 64 2a- 65

3 H 3 H 3 H 3 H 3 H 3 H 3 H 3 H 3 H 3 H 3 H 3 H 4 H 4 H 4 H 4 H 4 H 4 H 4 H 4 H 4 H

H H H H H H H H H H H H H H H H H H H H H H H H H H

2 1 cPr H 2 1 Bu H 2 1 Ph H 2 1 cHex H 2 2 Me H 2 2 Et H 2 2 Pr H 2 2 iPr H 2 2 cPr H 2 2 Bu H 2 2 Ph H 2 2 cHex H 1 1 Me H 1 1 Et H 1 1 Pr H 1 1 iPr H 1 1 cPr H 1 1 Bu H 1 1 Ph H 1 1 cHex H 2 1 Me H 2 1 Et H 2 1 Pr H 2 1 iPr H 2 1 cPr H 2 1 Bu H 2 1 Ph H 2 1 cHex H 2 2 Me H

-77- 200403244 2a- 66 2a- 67 2a- 68 2a- 69 2a- 70 2a- 71 2a- 72 2a- 73 2a- 74 2a- 75 2a- 76 2a- 77 2a- 78 2a- 79 2a- 80 2a -81 2a- 82 2a- 83 2a- 84 2a- 85 2a- 86 2a- 87 2a- 88 2a- 89 2a- 90 2a- 91 2a- 92 2a- 93 2a- 94 4 HH 2 2 Et H 4 HH 2 2 Pr H 4 HH 2 2 iPr H 4 HH 2 2 cPr H 4 HH 2 2 Bu H 4 HH 2 2 Ph H 4 HH 2 2 cHex H 3 HH 1 1 Me Et 3 HH 1 1 Me Pr 3 HH 1 1 Me iPr 3 HH 1 1 Me Bu 3 HH 2 1 Me Et 3 HH 2 1 Me Pr 3 HH 2 1 Me iPr 3 HH 2 1 Me Bu 3 HH 2 2 Me Et 3 HH 2 2 Me Pr 3 HH 2 2 Me iPr 3 HH 2 2 Me Bu 3 HH 1 1 Ph Et 3 HH 1 1 Ph Pr 3 HH 1 1 Ph iPr 3 HH 1 1 Ph Bu 3 HH 2 1 Ph Et 3 HH 2 1 Ph Pr 3 HH 2 1 Ph iPr 3 HH 2 1 Ph Bu 3 HH 2 2 Ph Et 3 HH 2 2 Ph Pr

-78- 200403244 2a- 95 SI 3 Η

2a- 96 SI 3 H

2a- 97 S 1 3 H

2a- 98 SI 3 H

2a- 99 SI 3 H

2a-100 S 1 3 H

2a-l01 S 1 3 H

2aH02 SI 3 H

2a-103 S 1 3 H

2a_104 S】 3 H

2a-105 S 1 3 H

2a-106 S 1 3 H

2aH07 S 1 3 H

2a-108 SI 3 H

H 2 2 Ph iPr H 2 2 Ph Bu H 1 1 cHex Et H 1 1 cHex Pr H 1 1 cHex iPr H 1 1 cHex Bu H 2 1 cHex Et H 1 1 cHex Pr H 2 1 cHex iPr H 2 1 cHex Bu H 2 2 cHex Et H 2 2 cHex Pr H 2 2 cHex iPr H 2 2 cHex Bu (Table 5)

Compound number X n Position R1 rs R2 3-1 SI 3 H 2 2 Me 3- 2 S 1 3 H 2 2 Et 3- 3 S 1 3 H 2 2 Pr 3-4 SI 3 H 2 2 iPr 3- 5 SI 3 H 2 2 cPr -79- 200403244 3-6 3-7 3- 8 3- 9 3 -10 3-11 3-12 3-13 3 -14 3-15 3-16 3-17 3 -18 3- 19 3-20 3-21 3-22 3-23 3-24 3-25 3-26 3-27 3-28 3-29 3-30 3-31 3-32 3-33 3-34 200403244 3-35 3-36 3-37 3-38 3-39 3-40 3-41 3-42 3-43 3-44 3-45 3-46 3-47 3-48 3-49 3-50 3-51 3- 52 3-53 3-54 3-55 3-56 3-57 3-58 3-59 3-60 3-61 3-62 3-63 4 Η 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me

3 H

3 H

3 H

3 H

3 H

3 H

3 H 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me

3 H

3 H

3 H

3 H

3 H

3 H

3 H 2 2 Ph 2 2 Me 2 2 Et 2 2 Pr 2 2 iPr 2 2 cPr 2 2 Bu 2 2 Ph 2 2 Me 2 2 Et 2 2 Pr 2 2 iPr 2 2 cPr 2 2 Bu 2 2 Ph 2 2 Me 2 2 Et 2 2 Pr 2 2 iPr 2 2 cPr 2 2 Bu 2 2 Ph 2 2 Me 2 2 Et 2 2 Pr 2 2 iPr 2 2 cPr 2 2 Bu 2 2 Ph

• 81 200403244 3-64 3-65 3-66 3-67 3-68 3-69 3-70 3-71 3-72 3-73 3-74 3-75 3-76 3-77 3-78 3- 79 3-80 3-81 3-82 3-83 3-84 3-85 3-86 3-87 0

3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 4 H 4 H 4 H 4 H 4 H 4 H 4 H 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 3 H 3 H 4 H 2 2 Me 2 2 Et 2 2 Pr 2 2 iPr 2 2 cPr 2 2 Bu 2 2 Ph 2 2 Me 2 2 Et 2 2 Pr 2 2 iPr 2 2 cPr 2 2 Bu 2 2 Ph 2 2 Me 2 2 Et 2 2 Pr 2 2 iPr 2 2 cPr 2 2 Bu 2 2 Ph 2 2 cHex 2 2 cHex 2 2 cHex

(Table 6) -82- 200403244

(l-3a) Compound number X η position R1. rs R2 R9 3a- 1 3a- 2 3a- 3 3a- 4 3a- 5 3a- 6 3a- 7 3a- 8 3a- 9 3a-10 3a-l1 3a- 12 3a ~ l 3 3a-14 3a-15 3a-16 3a-17 3a -18 3a- · 19 3a-20 3a-21 3a ~ 22 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4

H H H H H H H H H H H

H H

2 2 Me H 2 2 Et H 2 2 Pr H 2 2 iPr H 2 2 cPr H 2 2 Bu H 2 2 Ph H 2 2 cHex H 2 2 Me H 2 2 Et H 2 2 Pr H 2 2 iPr H 2 2 cPr H 2 2 Bu H 2 2 Ph H 2 2 cHex H 2 2 Me H 2 2 Et H 2 2 Pr H 2 1 iPr H 2 2 cPr H 2 2 Bu H

-83- .6 200403244 2 2 Ph H 2 2 cHex H 2 2 Me Et 2 2 Me Pr 2 2 Me iPr 2 2 Me Bu 2 2 Ph Et 2 2 Ph Pr 2 2 Ph iPr 2 2 Ph Bu 2 2 cHex Et 2 2 cHex Pr 2 2 cHex iPr 2 2 cHex Bu 3a-23 S3 4 Η 3a-24 S3 4 Η

3a-25 SI 3 H

3a-26 SI 3 H

3a-27 SI 3 H

3a-28 SI 3 H

3a-29 SI 3 H

3a-30 SI 3 H

3a-31 S 1 3 H

3a-32 SI 3 H

3a ~ 33 SI 3 H

3a-34 SI 3 H

3a-35 S 1 3 H

3a-36 SI 3 H (Table 7)

Compound number X n Position R1 R1 R2 R3 R4 R2 Η Η Η H Me Η Η Η H Et Η Η Η H Pr Η Η i H iPr Η Η Η H cPr -84- 1

1 SI 3 H 2

4- 2 S 1 3 H 3

4- 3 SI 3 H 4

4- 4 SI 3 H

4- 5 SI 3 H 200403244 4- 6 4-7 4 one 8 4- 9 4- 10 4-11 4- 12 4- 13 4- 14 4- 15 4-16 4- 17 4-18 4- 19 4 -20 4-21 4- 22 4-23 4-24 4-25 4-26 4-27 4- 28 4- 29 4-30 4-31 4-32 4-33 4- 34

Η Η Η Η Η Η Η Η Η Me Η Η Η Me Η Η Η Me Η Η Η Me Η Η Η Me Η Η Η Me Η Η Η Me Η Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η

HH Me HHH Me HHH Me HHH Me HHH Me HHH Me HHH Me HH Me Me HH Me Me HH Me Me HH Me Me HH Me Me HH Me Me HH Me Me HH Et HH Η Et Η Η Η Et Η Η Η Et Η Η Η Η Et Η Η Η Et Η Η

Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu

-85- 200403244 4- 35 4- 36 4- 37 4- 38 4- 39 4-40 4- 41 4- 42 4- 43 4- 44 4- 45 4-46 4- 47 4- 48 4- 49 4 -50 4- 51 4- 52 4- 53 4- 54 4- 55 4- 56 4- 57 4- 58 4- 59 4- 60 4-61 4- .62 4- 63 Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η

Et Η Η Η Η Η Η Η Pr Pr Pr Pr Pr Pr Pr Pr H H H H H H H

Et Et Et Et Et Et Et

H H H H H H Pr Pr Pr Pr Pr Pr Pr Pr

H H H H H

Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph

iPr HH Me iPr HH Et iPr HH Pr iPr HH iPr iPr HH cPr iPr HH Bu iPr HH Ph -86- 200403244 4-64 4- 65 4-66 4- 67 4-68 4-69 4-70 4-71 4 -72 4- 73 4-74 4- 75 4- 76 4- 77 4- 78 4- 79 4- 80 4- 81 4- 82 4-83 4-84 4-85 4- 86 4-87 4-88 4- 89 4-90 4- 91 4- 92 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η P Η Η Η Η Η Η Η iPr Η Me Η Η iPr Η Et Η Η iPr Η Pr Η Η iPr Η iPr Η Η iPr Η cPr Η Η iPr Η Bu Η Η P iPr Η Ph Η Bu Η Η Η Me Η Et Η Bu Η Η Pr Η Bu Η Η iPr Η Bu Η Η cPr Η Bu Η Η Bu Η Bu Η Η Ph Η Η Bu Η Me Η Η Bu Η Et Η Η Bu Η Pr Η Η Bu Η iPr Η Η Bu Η Η cPr Η Η Bu Η Bu Η Η Bu Η Ph

Me Η Η Η Me Me Η Η Η t Et Me Η Η Η Pr Me Η Η Η iPr Me Η Η Η cPr Me Η Η Η Bu Me Η Η Η Ph Me Me Η Η Me -87- 200403244 4- 93 4- 94 4- 95 4- 96 4-97 4- 98 4_ 99 4- 100 4- 101 4- 102 4- 103 4- 104 4- 105 4- 106 4- 107 4- 108 4- 109 4- no 4-in 4-112 4- 113 4-114 4- 115 4- 116 4-117 4- Π8 4- 119 4-120 4- 121 Η Me Me HH Et Η Me Me HH Pr Η Me Me HH iPr Η Me Me HH cPr Η Me Me HH Bu Η Me Me HH Ph Η Η Η Η Η Η Η Η

Me Me Me Me Me Me Me

Me Me Me Me Me Me

Et H Me Et HH Me Et HH Me Et HH Me Et HH Me Et HH Me Et HH Me H Et H Me H Et H Me H Et H Me H Et H Me H Et H Me H Et H Me H Et H Me Pr HH Me Pr HHH

H H H H H H H H H H H H H

Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et

-88200403244 4- 122 4- 123 4-124 4-125 4-126 4- 127 4- 128 4- 129 4-130 4- 131 4- 132 4- 133 4- 134 4-135 4- 136 4 -137 4- 138 4-139 4-140 4- 141 4- 142 4- 143 4- 144 4- 145 4- 146 1 Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η

Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me

Pr Pr Pr Pr Pr iPr iPr Pr Pr Pr Pr iPr

H H H Pr Pr Pr Pr Pr Pr Pr Pr H

H H H H H

H

H H H H H H H H

Pr H Pr H Pr H Pr H Pr H Pr H Pr H

Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr. IPr cPr Bu

4-147 S 1 3 H Me H iPr H Ph 4-148 S 1 3 H Me Bu HH Me 4-149 S 1 3 H Me Bu HH Et 4-150 S 1 3 H Me Bu HH Pr -89- 200403244 4 -151 4-152 4- 153 4- 154 4- 155 4- 156 4- 157 4-158 4- 159 4- 160 4- 161 4- 162 4-163 4-164 4- 165 4- 166 4- 167 4-168 4-169 4-170 4- 171 4-172 4- 173 4- 174 4-175 4- 176 4- 177 4- 178 4-179 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η

Me Bu Η Η iPr Me Bu Η Η cPr Me Bu Η H Bu Me Bu Η H Ph Me H Bu H Me Me H Bu H Et

Me H Bu Me H Bu Me H Bu Me H Bu Me H Bu Η Η H Η Η Η H Η Η H Η Η H Η Η H Η Η H Η Η HH Me HH Me HH Me HH Me HH Me HH Me HH Me HH Pr H iPr H cPr H Bu H Ph Me Me Me Et Me Pr Me iPr Me cPr Me Bu Me Ph Me Me Et Me Pr Me iPr Me cPr Me Bu Me Ph

Η H Me Me Me Η H Me Me Et Η H Me Me Pr Η H Me Me iPr -90- 200403244 4- 180 4- 181 4- 182 4-183 4- 184 4- 185 4- 186 4- 187 4- 188 4-189 4-190 4- 191 4- 192 4- 193 4-194 4- 195 4-196 4- 197 4- 198 4- 199 4- 200 4- 201 4- 202 4- 203 4- 204 4 -205 4-206 4- 207 4- 208 3 Η Me H Me Me cPr 3 Η Η H Me Me Bu 3 HHH Me Me Ph 3 HH Et H Me Me 3 HH Et H Me Et 3 HH Et H Me Pr 3 HH Et H Me iPr 3 HH Et H Me cPr 3 HH Et H Me Bu 3 HH Et H Me Ph 3 HHH Et Me Me 3 HHH Et Me 'Et 3 HHH Et Me Pr 3 HHH Et Me iPr 3 HHH Et Me cPr 3 HHH Et Me Bu 3 HHH Et Me Ph 3 HH Pr H Me Me 3 Η H Pr H Me Et 3 Η H Pr H Me Pr 3 Η H Pr H Me iPr 3 Η H Pr H Me cPr 3 Η H Pr H Me Bu 3 Η H Pr H Me Ph 3 Η Η H Pr Me Me 3 Η Η H Pr Me Et 3 Η Η H Pr Me Pr 3 Η Η H Pr Me iPr 3 Η Pr H Pr Me cPr

-91- 200403244 4- 209 4- 210 4- 211 4- 212 4-213 4-214 4- 215 4- 216 4- 217 4-218 4- 219 4-220 4- 221 4- 222 4-223 4 -224 4- 225 4- 226 4- 227 4- 228 4- 229 4- 230 4- 231 4- 232 4- 233 4-234 4- 235 4- 236 4- 237

Pr Me Bu Pr Me Ph ， S 1 3 3 3 3 3 3 3 3 3 3 3 3 HH iPr H Me Me HH iPr H Me Et HH iPr H Me Pr HH iPr H Me iPr HH iPr H Me cPr HH iPr H Me Bu HH iPr H Me Ph HHH iPr Me Me HHH iPr Me Et HHH iPr Me Pr HHH iPr Me iPr HHH iPr Me cPr HHH iPr Me Bu HHH iPr Me Ph HH Bu H Me Me H Bu H Me Et

Η Η Η Η Η Η Η Η Η Η Η Η Η Η

Bu Η Me Pr Bu H Me iPr Bu H Me cPr Bu H Me Bu Bu H Me Ph H Bu Me Me H Bu Me Et H Bu Me Pr H Bu Me iPr H Bu Me cPr H Bu Me Bu • 92- 200403244 4- 238 4- 239 4- 240 4-241 4-242 4- 243 4- 244 4- 245 4- 246 4- 247 4- 248 4- 249 4- 250 4-251 4-252 4-253 4-254 4 -255 4- 256 4- 257 4-258 4- 259 4- 260 4- 261 4-262 4- 263 4-264 4- 265 4- 266 3 Η Η H Bu Me Ph 3 H Me Η H Me Me 3 H Me Η H Me Et 3 H Me Η H Me Pr 3 H Me Η H Me iPr 3 H Me Η H Me cPr 3 H Me Η H Me Bu 3 H Me Η H Me Ph 3 H Me Me H Me Me 3 H Me Me H Me Et 3 H Me Me H Me Pr 3 H Me Me H Me iPr 3 H Me Me H Me cPr 3 H Me Me H Me Bu 3 H Me Me H Me Ph 3 H Me H Me Me 3 H Me H Me Me Et 3 H Me H Me Me Pr 3 H Me H Me Me iPr 3 H Me H Me Me cPr 3 H Me H Me Me Bu 3 H Me H Me Me Ph 3 H Me Et H Me Me 3 H Me Et H Me Et 3 H Me Et H Me Pr 3 H Me Et H Me iPr 3 H Me Et H Me cPr 3 H Me Et H Me Bu 3 H Me Et H Me Ph

-93- 200403244 4- 267 4- 268 4- 269 4- 270 4-271 4-272 4- 273 4- 274 4- 275 4- 276 4- 277 4- 278 4- 279 4- 280 4-281 4 -282 4- 283 4-284 4- 285 4-286 4- 287 4-288 4- 289 4- 290 4- 291 4- 292 4- 293 4-294 4- 295 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 3 3 3 Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η

Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me

Pr Pr Pr Pr Pr Pr Pr Pr

Et Et Et Et Et Et Et H H H H

H H

Pr Pr Pr Pr Pr Pr Pr Pr

Pr Pr Pr Pr Pr Pr Pr H

H iPr

Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me

Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me

-94- 200403244 4- 296 4- 297 4-298 4- 299 4- 300 4- 301 4- 302 4- 303 4- 304 4-305 4- 306 4- 307 4-308 4- 309 4-310 4 -311 4- 312 4-313 4-314 4- 315 4- 316 4-317 4- 318 4- 319 4- 320 4-321 4-322 4- 323 200403244 4-325 4- 326 4- 327 4- 328 4- 329 4- 330 4- 331 4-332 4- 333 4- 334 4- 335 4- 336 4- 337 4- 338 4- 339 4-340 4-341 4, 342 4- 343 4-344 4 -345 4- 346 4-347 4- 348 4 one 349 200403244 4-354 4-355 4- 356 4- 357 4-358 4-359 4-360 4- 361 4-362 4-363 4-364 4- 365 4- 366 4_ 367 4- 368 4- 369 4- 370 4- 371 4- 372 4- 373 4- 374 4- 375 4- 376 4- 377 4-378 4- 379 4- 380 4- 381 4- 382 S 1

Bn Bn. Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn

Pr Pr Pr Pr

H H H

H Pr HH Pr HH Pr HH Pr HH Pr HH Pr HH Pr H iPr Η H Pr Η H Pr Η H Pr Η H Pr Η H Pr Η H iPr Η H Pr H Pr H Pr H iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr

Bn H iPr H iPr Bn H iPr H cPr Bn H iPr H Bu Bn H iPr H Ph Bn Bu HH Me Bn Bu HH Et Bn Bu HH Pr Bn Bu HH iPr • 97- 200403244 4- 383 4- 384 4- 385 4 -386 4- 387 4- 388 4-389 4-390 4- 391 4- 392 4- 393 4- 394 4- 395 4- 396 4-397 4- 398 4-399 4- 400 4- 401 4- 402 4-403 4-404 4- 405 4- 406 4- 407 4- 408 4- 409 4-410 4 a 411 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η

Bn Bu Η Η cPr Bn Bu Η Η Bu Bn Bu Η Η Ph Βη Η Bu Η Me Βη Η Bu Η Et Βη Η Bu Η Pr Βη Η Bu Η iPr Βη Η Bu Η cPr Βη Η Bu Η Bu Βη Η Bu Η Ph Η Η Β Βη Me Η Η Η Βη Et Η Η Η Βη Pr Η Η Η Βη iPr Η Η Β Βη cPr Η Η Β Βη Bu Η Η Η Βη Ph Η Me Η ΒηMe Η Me Η Βη Et

Η Η Η Η Η Η Η Η Η Η Me Η Βη Pr Η Me Η Βη iPr Η Me Η Βη cPr Η Me Β Βη Bu Η Me Η Βη Ph Η Η Me Βη Me Η Η Me Βη Et Η Η Me Βη Pr Η Η Me Βη iPr Η Η Me Βη cPr -98- 200403244 4-412 SI 3 Η Η H Me Bn Bu 4- 413 SI 3 Η Η H Me Bn Ph 4- 414 SI 3 Η H Et H Bn Me 4- 415 SI 3 Η H Et H Bn Et 4- 416 S 1 3 Η H Et H Bn Pr 4-417 SI 3 Η H Et H Bn i Pr 4- 418 SI 3 Η H Et H Bn cPr 4-419 SI 3 Η H Et H Bn Bu

4- 420 S 1 3 Η H Et H Bn Ph 4- 421 SI 3 Η Η H Et Bn Me 4- 422 SI 3 Η Η H Et Bn Et 4- 423 SI 3 Η Η H Et Bn Pr 4- 424 SI 3 Η Η H Et Bn iPr 4- 425 SI 3 Η Η H Et Bn cPr 4- 426 SI 3 Η Η H Et Bn Bu 4- 427 SI 3 Η Η H Et Bn Ph 4- 428 S 1 3 Η H Pr H Bn Me 4- 429 SI 3 Η H Pr H Bn Et Φ 4- 430 S 1 3 H. H Pr H Bn Pr 4- 431 S 1 3 Η H Pr H Bn iPr 4- 432 S 1 3 Η H Pr H Bn cPr 4- 433 SI 3 Η H Pr H Bn Bu 4- 434 SI 3 Η H Pr H Bn Ph 4- 435 SI 3 Η Η H Pr Bn Me 4- 436 SI 3 Η Η H Pr Bn Et 4- 437 S: 1 3 Η Η H Pr Bn Pr 4- 438 SI 3 Η Η H Pr Bn iPr 4- 439 SI 3 Η Η H Pr Bn cPr 4- 440 SI 3 Η Η H Pr Bn Bu -99- 200403244 4- 441 4- 442 4- 443 4- 444 4- 445 4- 446 4- 447 4- 448 4- 449 4- 450 4- 451 4-452 4- 453 4- 454 4- 455 4- 456 4- 457 4- 458 4- 459 4- 460 4- 461 4- 462 4-463 4- 464 4- 465 4- 466 4-467 200403244 4- 470 SI 3 Η Η Ph H Ph Me 4- 471 SI 3 Η Η Η Η Ph Et 4- 472 SI 3 Η Η Η Η Ph Pr 4- 473 SI 3 Η Η Η i Ph iPr 4- 474 S 1 3 Η Η Η Η Ph cPr 4- 475 SI 3 Η Η Η Ph Bu 4- 476 SI 3 Η Η Me Η Ph Ph 4- 477 SI 3 Η H Me H Ph Me 4- 478 S 1 3 Η H Me H Ph Et

4 ~ 479 SI 3 Η H Me H Ph Pr 4 " 480 SI 3 Η H Me H Ph iPr 4- 481 S 1 3 Η H Me H Ph cPr 4- 482 S 1 3 Η H Me H Ph Bu 4- 483 SI 3 Η H Me H Ph Ph 4- 484 SI 3 Η Η H Me Ph Me 4- 485 SI 3 Η Η H Me Ph Et 4- 486 SI 3 Η Η H Me Ph Pr 4- 487 S 1 3 Η Me H Me Ph iPr

4- 488 S 1 3 Η Η H Me Ph cPr 4- 489 SI 3 Η Η H Me Ph Bu 4- 490 S 1 3 Η Η H Me Ph Ph 4- 491 SI 3 Η H Et H Ph Me 4- 492 S 1 3 Η H Et H Ph Et 4- 493 SI 3 Η H Et H Ph Pr 4- 494 S 1 3 Η H Et H Ph iPr 4- 495 SI 3 Η H Et H Ph cPr 4- 496 SI 3 Η H Et H Ph Bu 4- 497 SI 3 Η H Et H Ph Ph 4- 498 S 1 3 Η Η H Et Ph Me -101- 200403244 4-499 4- 500 4- 501 4-502 4- 503 4- 504 4- 505 4- 506 4-507 4- 508 4- 509 4-510 4-511 4- 512 4- 513 4-514 4- 515 4-516 4- 517 4-518 4-519 4- 520 4- 521 4 -522 4- 523 4-524 4-525 4- 526 4-527 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 3 3 Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η ΗΗ

Et Et Et Et Et Et Η Η Η Η Η Η

Pr Pr Pr Pr Pr Pr Pr H H iPr H H iPr H H iPr H H iPr H H iPr H H iPr H H iPr H H H H H iPr iPr

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph

Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et

-102- 200403244 4- 528 4- 529 4- 530 4-531 4- 532 4-533 4- 534 4-535 4- 536 4-537 4- 538 4-539 4- 540 4- 541 4- 542 4 -543 4- 544 4-545 4-546 4-547 4-548 4- 549 4- 550 4- 551 4- 552 4- 553 4-554 4- 555 4- 556 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 3 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me

H H H H H H H H H H H H

H H H H H H H

Bu Bu Bu Bu Bu Bu Bu H H H H H H H

iPr iPr iPr iPr iPr H H H H H H Bu Bu Bu Bu Bu Bu Bu H H H H H H

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph H H H H H H

Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu

HHHH Ph H Me HH Me H Me HH Et H Me HH Pr -103- 200403244 4- 557 4- 558 4- 559 4-560 4- 561 4-562 4- 563 4- 564 4- 565 4- 566 4- 567 4-568 4-569 4- 570 4-571 4- 572 4- 573 4- 574 4- 575 4- 576 4-577 4- 578 4-579 4- 580 4- 581 4-582 4- 583 4 -584 4-585 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me

H Me Η HH Me Η HH Me Η HH Me Η H Η H Me H Η H Me H Η H Me H Η H Me H Η H Me H Η H Me H Η H Me HH Me Me HH Me Me HH Me Me HH Me Me HH Me Me HH Me Me HH Me Me HH Et Η HH Et Η HH Et Η HH Et Η HH Et Η HH Et Η HH Et Η H Η H Et H Η H Et H Η H Et H iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr iPr cPr Bu Ph Me Et Pr

Et H iPr -104- 200403244 4- 586 4- 587 4- 588 4- 589 4- 590 4- 591 4-592 4- 593 4-594 4- 595 4-596 4-597 4- 598 4-599 4 -600 4- 601 4- 602 4-603 4- 604 4- 605 4-606 4- 607 4- 608 4- 609 4-610 4- 611 4- 612 4-613 4- 614 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me

Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me

HHHHHHHHHHHHHHHHHHHHHHH HHHHHHHHHHHHHPH Et H Bu H 'Et H Ph Pr Η H Me Pr Η H Et Pr Η H Pr Pr Η H iPr Pr Η H cPr Pr Η H Bu Pr Η H Ph H Pr H Me H Pr H Et H Pr H Pr H Pr H iPr H Pr H cPr H Pr H Bu H Pr H Ph

iPr H H Me iPr H H Et iPr H H Pr iPr H H iPr iPr H H cPr iPr H H Bu iPr H H Ph H iPr H Me H iPr H Et H iPr H Pr H iPr H iPr H iPr H cPr

-105- 200403244 4- 615 4-616 4- 617 4- 618 4- 619 4-620 4- 621 4- 622 4-623 4-624 4-625 4- 626 4- 627 4-628 4-629 4 -630 4- 631 4- 632 4- 633 4- 634 4- 635 4- 636 4- 637 4- -638 4-639 4- 640 4- 641 4- 642 4- 643 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me HHHHHHHHHHHHHHHHH Me Me H iPr H Bu H iPr H Ph Bu HH Me Bu HH Et Bu HH Pr Bu HH iPr Bu HH cPr Bu HH Bu Bu HH Ph H Bu H Me

H Bu H Et H Bu H Pr H Bu H iPr H Bu H cPr H Bu H Bu H Bu H Ph Η Η H Me Me Η H Me

Me H Me H Me Me Et HH Me Me H Et H Me Me Pr HH Me Me H Pr H Me Me iPr HH Me Me H iPr H Me Me Bu HH Me Me Bu H Me HHH Me Me H Me H Me Me- 106- 200403244 4- 644 4- 645 4- 646 4- 647 4- 648 4- 649 4-650 4- 651 4-652 4- 653 4- 654 4- 655 4- 656 4- 657 4-658 4- 659 4- 660 4- 661 4-662 4- 663 4- 664 4-665 4- 666 4- 667 4- 668 4- 669 4- 670 4- 671 4- 672 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me Me H Me Me Me H. Et H Me Me Η H Et Me Me H Pr H Me Me Η H Pr Me Me H iPr H Me Me Η H iPr Me Me H Bu H Me Me Η H Bu Me Me Me Η H Me Me Me Me H Me Me H Me Me Me Et H Me Me Me H Et Me Me Me Pr H Me Me Me H Pr Me Me

3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me

Me iPr H Me Me Me H iPr Me Me Bu H Me Me H Bu Me Me

Bn Bn Bn Bn Bn Bn Bn Bn Bn HHH Me Me HH Me H Me H Me Et HH Me H Et H Me Pr HH Me H Pr H Me iPr HH Me H iPr H Me -107- 200403244 4- 673 S 1 3 Me Bn Bu Η H Me 4- 674 S 1 3 Me Bn H Bu H Me 4- 675 SI 3 Me Η Η H Bn Me 4- 676 SI 3 Me H Me H Bn Me 4- 677 SI 3 Me Η H Me Bn Me 4- 678 S 1 3 Me H Et H Bn Me 4- 679 S 1 3 Me Η H Et Bn Me 4- 680 S 1 3 Me H Pr H Bn Me 4-681 SI 3 Me Η H Pr Bn Me

4- 682 S 1 3 Me H iPr H Bn Me 4- 683 SI 3 Me Η H iPr Bn Me 4- 684 S 1 3 Me H Bu H Bn Me 4- 685 S 1 3 Me Η H Bu Bn Me 4- 686 SI 3 Me Η Ph H Ph Me 4- 687 SI 3 Me H Me H Ph Me 4- 688 SI 3 Me Η H Me Ph Me 4- 689 SI 3 Me H Et H Ph Me 4- 690 S 1 3 Me Η H Et Ph Me

4- 691 S 1 3 Me H Pr H Ph Me 4- 692 SI 3 Me Η H Pr Ph Me 4- 693 S 1 3 Me H iPr H Ph Me 4- 694 SI 3 Me Η H iPr Ph Me 4- 695 SI 3 Me H Bu H Ph Me 4- 696 SI 3 Me Η H Bu Ph Me 4- 697 S 2 3 Η Η Η Η H Me 4- 698 S 2 3 Η H Me Η H Me 4- 699 S 2 3 Η Η H Me H Me 4- 700 S 2 3 Η H Me Me H Me 4- 701 S 2 3 Η H Et Η H Me 200403244 4- 702 4- 703 4- 704 4- 705 4- 706 4- 707 4-708 4- 709 4- 710 4- 711 4-712 4-713 4- 714 4- 715 4-716 4-717 4- 718 4-719 4- 720 4- 721 4- 722 4- 723 4- 724 4- 725 4- 726 4- 727 4- 728 4- 729 4 one 730 200403244 4- 731 4- 732 4- 733 4- 734 4- 735 4- 736 4- 737 4- 738 4- 739 4- 740 4- 741 4-742 4- 743 4- 744 4-745 4- 746 4-747 4- 748 4- 749 4- 750 4- 751 4- 752 4- 753 4- 754 4- 755 4- 756 4- 757 4- 758 4- 759 200403244 4-760 4- 761 4-762 4- 763 4- 764 4- 765 4- 766 4- 767 4- 768 4- 769 4- 770 4- 771 4- 772 4- 773 4- 774 4- 775 4-776 4- 777 4-778 4- 779 4-780 4-781 4-782 4- 783 4- 784 4- 785 4- 786 4- 787 4- 788 200403244 4-789 4-790 4 -791 4- 792 4- 793 4- 794 4- 7 95 4- 796 4- 797 4- 798 4- 799 4- 800 4- 801 4- 802 4- 803 4- 804 4-805 4- 806 4-807 4- 808 4- 809 4- 810 4-811 4 -812 4- 813 4- 814 4- 815 4- 816 4- 817 S 2 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me 3 Me

Me H Me H Me Et Η H Me H Et H Me Pr Η H Me H Pr H Me iPr Η H Me H iPr H Me Bu Η H Me H Bu H Η Η H Me H Me H Me Η H Me Me H Et H Me Η H Et Me H Pr H Me Η H Pr Me H iPr H Me Η H iPr Me H Bu H Me Η H Bu Me Me Η H Me Me Me H Me Me H Me Me Et H Me Me H Et Me Me Pr H Me Me H Pr Me Me iPr H Me Me H iPr Me

Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me

-112- 200403244 4- 818 4-819 4-820 4- 821 4- 822 4- 823 4-824 4- 825 4- 826 4- 827 4- 828 4-829 4-830 4- 831 4- 832 4 -833 4- 834 4- 835 4-836 4- 837 4- 838 4- 839 4-840 4- 841 4- 842 4- 843 4- 844 200403244 4-847 4- 848 4- 849 4- 850 4- 851 4-852 4- 853 4- 854 4- 855 4- 856 4-857 4- 858 4- 859 4-860 4-861 4- 862 4- 863 4-864 4- 865 4-866 4- 867 4 -868 4- 869 4- 870 4-871 4- 872 4- 873 4- 874 4- 875 200403244 4- 876 4-877 4- 878 4- 879 4- 880 4- 881 4-882 4-883 4- 884 4-885 4- 886 4- 887 4-888 4- 889 4-890 4- 891 4-892 4- 893 4- 894 4- 895 4- 896 4- 897 4- 898 4- 899 4- 900 4 -901 4-902 4- 903 4-904 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 HHHHHHHHHHHHHHHHHHHHHHHH HH Me H Me H Me H Me H Me H Me H Me Η H Me Me Η Me Η Me Me Et H Me H Et Me Pr H Me H Pr Me iPr H Me H iPr Me Bu H Me H Bu Me Η H Me Me H Me H Me Me Et H Me H Et Me Pr H Me H Pr Me

Me iPr H Me H iPr H Me Bu H H Me H Bu H Bn H H H Bn Me H H Bn H Me H Bn Et H H Bn H Et H Bn Pr H H Bn H Pr

Me Me Me Me H H H H H H

Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me -115- 200403244 4-905 4- 906 4- 907 4- 908 4-909 4- 910 4- 911 4-912 4- 913 4-914 4-915 4-916 4- 917 4-918 4- 919 4-920 4-921 4-922 4- 923 4- 924 4-925 4-926 4 -927 4- 928 4-929 4-930 4- 931 4-932 4- 933 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 H Bn iPr HH Me H Bn H iPr H Me H Bn Bu HH Me H Bn H Bu H Me HHHH Bn Me HH Me H Bn Me HHH Me Bn Me HH Et H Bn Me Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Me Me Me Η Η Η Η Η Η Η Η Η Η Η Η Η Ρ γ

Et Ρ Ργ Η iPr Η Bu Η Η Me Η Et Βη Βη Βη Βη Βη Βη Βη Ph Ph Ph Ph Ph Ph

Me Me Me Me Me Me Me Me Me Me HH Pr Ph Me H iPr H Ph Me HH iPr Ph Me H Bu H Ph Me HH Bu Ph Me HHHH Me H Me HH Me HH Me H Me -116- 200403244 4 -934 4-935 4- 936 4-937 4- 938 4-939 4-940 4-941 4- 942 4-943 4- 944 4- 945 4-946 4- 947 4- 948 4- 949 4- 950 4- 951 4-952 4-953 4- 954 4- 955 4- 956 4- 957 4-958 4- 959 4- 960 4- 961 4- 962 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me H Me Me H Me H Et HH Me HH Et H Me H Pr HH Me HH Pr H Me H iPr HH Me Η H iPr H Me H Bu Η H Me Η H Bu H Me Me Η Η H Me Me Η H Me Me H Me H Me Me Et Η H Me Me H Et H Me Me Pr Η H Me

Me Me Me Me Me HHHHHHHHHHH Pr H Me iPr Η H Me H iPr H Me Bu Η H Me H Bu H Me Η H Me Me Me H Me Me H Me Me Et H Me Me H Et Me Me Pr H Me Me H Pr Me Me iPr H Me Me H iPr Me Me

-117- 200403244 4- 963 4-964 4-965 4- 966 4- 967 4- 968 4- 969 4- 970 4- 971 4- 972 4- 973 4-974 4-975 4- 976 4- 977 4 -978 4- 979 4- 980 4-981 4- 982 4- 983 4- 984 4-985 4-986 4-987 4- 988 4- 989 4- 990 4- 991 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me

Η Η Me Me Me Me Me Me Me Me Me Me Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn H H H H H

Bu H Me Me H Bu Me Me Η H Me Me Me H Me Me H Me Me Me Et H Me Me H Et Me Me Pr H Me Me H Pr Me Me iPr H Me Me H iPr Me Me Bu H Me Me H Bu Me Me HHH Me Me HH Me H Me H Me

Et Η H Me H Et H Me Pr Η H Me H Pr H Me iPr H H Me H iPr H Me Bu H H Me H Bu H Me H H Bn Me Me H Bn Me H Me Bn Me Et H Bn Me H Et Bn Me

-118- 200403244 4- 992 S3 4 Me H Pr H Bn Me 4- 993 S3 4 Me Η H Pr Bn Me 4- 994 S 3 4 Me H iPr H Bn Me 4- 995 S3 4 Me Η H iPr Bn Me 4 -996 S3 4 Me H Bu H Bn Me 4- 997 S3 4 Me Η H Bu Bn Me 4- 998 S3 4 Me Η Η H Ph Me 4- 999 S3 4 Me H Me H Ph Me

4-1000 S3 4 Me Η H Me Ph Me 4-1001 S3 4 Me H Et H Ph Me 4-1002 S3 4 Me Η H Et Ph Me 4-1003 S3 4 Me H Pr H Ph Me 4-1004 S3 4 Me Η H Pr Ph Me 4-1005 S3 4 Me H iPr H Ph Me 4-1006 S3 4 Me Η H iPr Ph Me 4-1007 S 3 4 Me H Bu H Ph Me 4-1008 S 3 4 Me HH Bu Ph Me 4-1009 0 1 3 HHHHH Me 4-1010 0 1 3 HHHHH Et 4-1011 0 1 3 HHHHH Pr 4-1012 0 1 3 HHHHH iPr 4-1013 0 1 3 HHHHH cPr 4-1014 0 1 3 HHHHH Bu

4 -1015 0 1 3 Η Η Η Ph H Ph 4-1016 0 1 3 Η H Me Η H Me 4 -1017 0 1 3 Η H Me Η H Et 4-1018 0 1 3 Η H Me Η H Pr 4- 1019 0 1 3 Η H Me Η H iPr 4-1020 0 1 3 Η H Me Η H cPr -119- 200403244 4-1021 01 3 Η 4-1022 01 3 Η 4-1023 01 3 Η 4-1024 01 3 Η 4-1025 01 3 Η 4-1026 01 3 Η 4-1027 01 3 Η 4-1028 01 3 Η 4-1029 01 3 Η 4-1030 01 3 Η 4-1031 01 3 Η 4-1032 01 3 Η 4- 1033 0 1 3 Η 4-1034 01 3 Η 4-1035 01 3 Η 4-1036 01 3 Η 4-1037 01 3 Η 4-1038 01 3 Η 4-1039 01 3 Η 4-1040 01 3 Η 4-1041 01 3 Η 4-1042 0 1 3 Η 4-1043 01 3 Η 4-1044 0 1 3 Η 4-1045 01 3 Η 4-1046 01 3 Η 4-1047 01 3 Η 4-1048 01 3 Η 4-1049 01 3 Η Η Me Η Η Bu Η Me Η Η Ph Η Η Me Η Me Η Η Me Η Et Η Η Me Η Pr Η Η Me Η iPr Η Η Me Η cPr Η Η Me Η Bu Η Η Me Η Ph Η Me Me Η Me Η Me Me Η Et Η Me Me H Pr H Me Me H iPr H Me Me H cPr H Me Me H Bu H Me H Ph H Et Η H Me H Et Η H Et H Et Η H Pr H Et Η H iPr H Et Η H cPr H Et Η H Bu H Et Η H Ph Η H Et H Me Η H Et H Et Η H Et HP r Η H Et H iPr Η H Et H cPr Η H Et H Bu

> 120- 200403244 4-1050 4-1051 4-1052 4-1053 4-1054 4-1055 4-1056 4-1057 4-1058 4-1059 4-1060 4-1061 4-1062 4-1063 4-1064 4-1065 4-1066 4-1067 4-1068 4-1069 4-1070 4-1071 4-1072 4-1073 4-1074 4-1075 4-1076 4-1077 4 to 1078 3 Η Η H Et H Ph 3 Pr H Pr Η H Me 3 Η Η Pr Η Η Et 3 Η Η Pr Η Η Pr 3 Η Η Pr Η Η iPr 3 Η Η Pr Η Η cPr 3 Η Η Pr Η Η Bu 3 Η Η Pr Η Η Ph 3 Η Η Η Pr Η Me 3 Η Η Η Pr Η Et 3. Η η Η Pr Η Pr 3 Η Η Η Pr Η iPr 3 Η Η Η Pr Η cPr 3 Η Η Η Pr Η Bu 3 Η Η Η Pr Η Ph 3 Η Η iPr Η Η Me 3 Η Η iPr Η Η Et 3 Η Η iPr Η Η Pr 3 Η Η iPr Η Η iPr 3 Η Η iPr Η Η cPr 3 Η Η iPr Η Η Bu 3 Η Η iPr Η Η Ph 3 Η Η iPr Η Me 3 Η Η Η iPr Η Et 3 Η Η Η iPr Η Pr 3 Η Η Η iPr Η iPr 3 Η Η Η iPr Η cPr 3 Η Η iPr Η Βυ 3 Η Η Η iPr Η Ph

• 121- 200403244 4-1079 4-1080 4-1081 4-1082 4-1083 4-1084 4-1085 4-1086 4-1087 4-1088 4-1089 4-1090 4-1091 4-1092 4-1093 4 -1094 4-1095 4-1096 4-1097 4-1098 4-1099 4-1100 4-1101 4-1102 4-1103 4-1104 4-Π05 4 one 1106 4 one 1107 200403244 4-1108 4-1109 4- 1110 4-1111 4-1112 4-Π13 4-1114 4-1115 4-1116 4-1117 4-1118 4-1119 4-1120 4-Π21 4-1122 4-1123 4-Π24 4-Π25 4-1126 4 -1127 4-1128 4-1129 4-1130 4-1131 4-1132 4-1133 4-1134 4 a 1135 4-Π36 200403244 4-1137 4 -1138 4-1139 4-mo 4-Π41 4-1142 4- 1143 4-1144 4-1145 4-1146 4-1147 4-1148 4-1149 4-1150 4-1151 4-1152 4-1153 4-1154 4-1155 4-1156 4-1157 4-1158 4-1159 4 -1160 4-1161 4-1162 4H163 4-1164 4-1165

3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η 3 Η

Me Η Pr Η Pr Me Η Pr Η iPr Me Η Pr Η cPr Me H Pr H Bu Me H Pr H Ph Me iPr Η H Me Me iPr Η H Et Me iPr Η H Pr Me iPr Η H iPr Me iPr Η H cPr Me iPr Η H Bu Me iPr Η H Ph Me H iPr H Me Me H iPr H Et Me H iPr H Pr Me H iPr H iPr Me H iPr H cPr Me H iPr H Bu Me H iPr H Ph

Me Bu HH Me Me Bu HH Et Me Bu HH Pr Me Bu HH iPr Me Bu HH cPr Me Bu HH Bu Me Bu HH Ph Me H Bu H Me H Bu H Et Me H Bu H Pr -124 · 200403244 4-Π66 0 1 3 Η 4-1167 01 3 Η 4-Π68 0 1 3 Η 4-Π 69 0 1 3 Η 4-1170 01 3 Η 4-1171 01 3 Η 4-1172 01 3 Η 4-1173 01 3 Η 4 -1174 0 1 3 Η 4-1175 01 3 Η 4-1176 01 3 Η 4-1177 01 3 Η 4-1178 01 3 Η 4-1179 0 1 3 Η 4-1180 01 3 Η 4-1181 0 1 3 Η 4-1182 01 3 Η 4-1183 01 3 Η 4-1184 01 3 Η 4-1185 01 3 Η 4-1186 01 3 Η 4-1187 01 3 Η 4-1188 01 3 Η 4-1189 01 3 Η 4- 1190 01 3 Η 4-1191 01 3 Η 4-1192 01 3 Η 4-1193 01 3 Η 4-1194 01 3 Η

Me H Bu H iPr Me H Bu H cPr Me H Bu H Bu Me H Bu H Ph HHH Me Me HHH Me Et HHH Me Pr HHH Me iPr HHH Me cPr HHH Me Bu HHH Me Ph Η Me Η Me Me Η Me Η Me Et Η Me Η Me Pr H Me H Me iPr H Me H Me cPr H Me H Me Bu H Me H Me Ph Η H Me Me Η H Me Me Et Η H Me * Me Pr Η H Me Me iPr Η H Me Me cPr Η H Me Me Bu Η H Me Me Ph H Et H Me Me H Et H Me Et H Et H Me Pr H Et H Me iPr

-125- 200403244 4-1195 4-1196 4-1197 4-1198 4-1199 4-1200 4-1201 4-1202 4-1203 4-1204 4-1205 4-1206 4-1207 4-1208 4-1209 4 -1210 4-1211 4-1212 4-1213 4-1214 4-1215 4-1216 4-1217 4-1218 4-1219 4-1220 4-1221 4-1222 4-1223 3 Η Η Et H Me cPr 3 Η Η Et H Me Bu 3 Η t Et H Me Ph 3 Η Η Η Et Me Me 3 Η Η Η Et Me Et 3 Η Η t Et Me Pr 3 Η Η Η Et Me iPr 3 Η Η Η Et Me cPr 3 Η Η Η Η Et Me Bu 3 Η Η t Et Me Ph 3 Η Η Pr H Me Me 3 Η Η Pr H Me Et 3 Η Η Pr H Me Pr 3 Η Η Pr H Me iPr 3 Η Η Pr H Me cPr 3 Η Η Pr H Me Bu 3 Η Η Pr H Me Ph 3 Η Η H Pr Me Me 3 Η Η H Pr Me Et 3 Η Η H Pr Me Pr 3 Η Η H Pr Me iPr 3 Η Η H Pr Me cPr 3 Η Η H Pr Me Bu 3 Η Η H Pr Me Ph 3 Η Η iPr H Me Me 3 Η Η iPr H Me Et 3 Η Η iPr H Me Pr 3 Η Η iPr H Me iPr 3 Η Η iPr H Me cPr

-126- 200403244 4-1224 0 1 3 Η Η iPr Η Me Bu 4-1225 0 1 3 Η H iPr Η Me Ph 4-1 226 0 1 3 Η Η Η iPr Me Me 4-1 227 0 1 3 Η Η Η Η iPr Me Et 4-1 228 0 1 3 Η Η Η iPr Me Pr 4-1 229 0 1 3 Η Η Η iPr Me iPr 4-1 230 0 1 3 Η Η Η iPr Me cPr 4-1231 0 1 3 Η Η Η iPr Me Bu

4-1232 0 1 3 Η Η Η iPr Me Ph 4 -1 233 0 1 3 Η H Bu H Me Me 4-1234 0 1, 3 Η H Bu H Me Et 4-1235 0 1 3 Η H Bu H Me Pr 4-1236 0 1 3 Η H Bu H Me iPr 4-1237 0 1 3 Η H Bu H Me cPr 4-1238 0 1 3 Η H Bu H Me Bu 4-1239 0 1 3 Η H Bu H Me Ph 4- 1240 0 1 3 Η Η H Bu Me Me 4-1241 0 13 Η Η H Bu Me Et

4-1 242 0 1 3 Η Η H Bu Me Pr 4-1243 0 1 3 Η Η H Bu Me iPr 4-1244 0 1 3 Η Η H Bu He cPr 4-1245 0 1 3 Η Η H Bu Me Bu 4 -1246 0 1 3 Η Η H Bu Me Ph 4-1247 0 1 3 H Me Η H Me Me 4-1248 0 1 3 H Me Η H Me Et 4-1249 0 1 3 H Me Η H Me Pr 4-1250 0 1 3 H Me Η H Me iPr 4-1251 0 1 3 H Me Η H Me cPr 4-1 252 0 1 3 H Me Η H Me Bu -127- 200403244 4-1253 0 1 3 Η Me HH Me Ph 4 -1254 0 1 3 Η Me Me H Me Me 4-1255 0 1 3 Η Me Me H Me Et 4-1256 0 1 3 Η Me Me H Me Pr 4-1257 0 1 3 Η Me Me H Me iPr 4-1258 0 1 3 Η Me Me H Me cPr 4-1259 0 1 3 Η Me Me H Me Bu 4-1260 0 1 3 Η Me Me H Me Ph 4 1261 0 1 3 Η Me H Me Me Me

4-1262 01 3 H Me H Me. Me Et 4-1 263 0 1 3 H Me H Me Me Pr 4-1264 0 1 3 H Me H Me Me iPr 4-1 265 0 1 3 H Me H Me Me cPr 4-1 266 0 1 3 H Me H Me Me Bu 4 1 1 267 0 1 3 H Me H Me Me Ph 4-1268 0 1 3 H Me Et H Me Me 4 -1 269 0 1 3 H Me Et H Me Et 4-1270 0 1 3 H Me Et H Me Pr

4 -1271 0 1 3 H Me Et H Me iPr 4 -1272 0 1 3 H Me Et H Me cPr 4-1 273 0 1 3 H Me Et H Me Bu 4-1274 0 1 3 H Me Et H 'Me Ph 4-1275 0 1 3 H Me H Et Me Me 4-1276 0 1 3 H Me H Et Me Et 4-1277 0 1 3 H Me H Et Me Pr 4-1278 0 1 3 H Me H Et Me iPr 4- 1 279 0 1 3 H Me H Et Me cPr 4-1280 0 1 3 H Me H Et Me Bu 4-1281 0 1 3 H Me H Et Me Ph -128- 200403244 4 -1 282 0 1 3 H Me Pr H Me Me 4-1 283 0 1 3 H Me Pr H Me Et 4-1 284 0 1 3 H Me Pr H Me Pr 4-1 285 0 1 3 H Me Pr H Me iPr 4-1 286 0 1 3 H Me Pr H Me cPr 4-1 287 0 1 3 H Me Pr H Me Bu 4-1 288 0 1 3 H Me Pr H Me Ph 4-1 289 0 1 3 H Me H Pr Me Me

4-1 290 0 1 3 H Me H Pr Me Et 4 -1291 0 1 3 H Me H Pr Me Pr 4-1292 0 1 3 H Me H Pr Me iPr 4-1293 0 1 3 H Me H Pr Me cPr 4 -1294 0 1 3 H Me H Pr Me Bu 4 1295 0 1 3 H Me H Pr Me Ph 4-1296 0 1 3 H Me iPr H Me Me 4-1297 0 1 3 H Me iPr H Me Et 4-1298 0 1 3 H Me iPr H Me Pr 4-1299 01 3 H Me iPr H Me iPr

4-1 300 0 1 3 H Me iPr H Me cPr 4-1301 0 1 3 H Me iPr H Me Bu 4-1302 0 1 3 H Me iPr H Me Ph 4-1 303 0 1 3 H Me H iPr Me Me 4-1304 0 1 3 H Me H iPr Me Et 4-1 305 0 1 3 H Me H iPr Me Pr 4-1306 01.3 H Me H iPr Me iPr 4-1307 01 3 H Me H iPr Me cPr 4-1 308 0 1 3 H Me H iPr Me Bu 4 1 1 309 0 1 3 H Me H iPr Me Ph 4-1310 0 1 3 H Me Bu H Me Me -129- 200403244 4-1311 0] 3 H Me Bu H Me Et 4-1312 0 1 3 H Me Bu H Me Pr 4 -1313 0 1 3 H Me Bu H Me iPr 4 -1314 0 1 3 H Me Bu H Me cPr 4 -1315 0 1 3 H Me Bu H Me Bu 4- 1316 0 1 3 H Me Bu H Me Ph 4 -1317 0 1 3 H Me H Bu Me Me 4-1318 0 1 3 H Me H Bu Me Et

4-1319 0 1 3 H Me H Bu Me Pr 4-1 320 0 1 3 H Me H Bu Me iPr 4 -1321 0 1 3 H Me H Bu Me cPr 4-1 322 0 1 3 H Me H Bu Me Bu 4-1 323 0 1 3 H Me H Bu Me Ph 4-1 324 0 1 3 Η Bn Η Η H Me 4-1 325 0 1 3 Η Bn Η Η H Et 4-1 326 0 1 3 Η Bn Η Η H Pr 4-1327 0 1 3 Η Bn Η Η H iPr 4-1328 0 1 3 Η Bn Η Η H cPr

4-1329 0 1 3 Η Bn Η Η H Bu 4-1 330 0 1 3 Η Bn Η Η H Ph 4-1331 0 1 3 H Bn Me Η H Me 4-1 332 0 1 3 H Bn Me Η H Et 4-1 333 0 1 3 H Bn Me Η H Pr 4-1 334 0 1 3 H Bn Me Η H iPr 4-1335 0 1 3 H Bn Me Η H cPr 4-1 336 0 1 3 H Bn Me Η H Bu 4-1 337 0 1 3 H Bn Me Η H Ph 4-1 338 0 1 3 Η Bn H Me H Me 4-1 339 0 1 3 Η Bn H Me H Et -130- 200403244 4-1340 01 3 Η 4-1341 01 3 Η 4-1342 01 3 Η 4-1343 01 3 Η 4-1344 01 3 Η 4-1345 01 3 Η 4-1346 01 3 Η 4-1347 01 3 Η 4-1348 01 3 Η 4- 1349 01 3 Η 4-1350 01 3 Η 4-1351 01 3 Η 4-1352 01 3 Η 4-1353 01 3 Η 4-1354 01 3 Η 4-1355 01 3 Η 4-1356 01 3 Η 4-1357 01 3 Η 4-1358 01 3 Η 4-1359 01 3 Η 4-1360 01 3 Η 4-1361 01 3 Η 4-1362 0 1 3 Η 4-1363 01 3 Η 4-1364 0 1 3 Η 4-1365 01 3Η 4-1366 01 3Η 4-1367 01 3Η 4-1368 01 3 Βη Et Η Η Et Βη Et Η Η Pr Βη Et Η Η iPr Βη Et Η Η cPr Βη Et Η Η Bu Βη Et Η Ph Βη Η Et Η Me Βη Η Et Η Et Βη Η Et Η Pr Βη Η Et Η iPr Βη Η Et Η cPr Βη Η Et Η Bu Βη Η Et Η Ph Βη Pr Η Η Me Βη Pr Η Η Prt β Βη Pr Η Η iPr Βη Pr Η Η cPr Βη Pr Η Η Bu Βη Pr Η Η Ph Βη Η Pr Η Me Βη Η Pr Η Et Βη Η Pr Η Pr

-131- 200403244 4-1369 4-1370 4-1371 4-1372 4-1373 4-1374 4-1375 4-1376 4-1377 4-1378 4 -1379 4-1380 4-1381 4-1382 4-1383 4 -1384 4-1385 4-1386 4-1387 4-1388 4-1389 4-1390 4-1391 4-1392 4-1393 4-1394 4 -1395 4-1396 4 a 1397 200403244 4-1398 0 1 3 Η Bn Η Bu Η cPr 4-1399 0 1 3 Η Bn H Bu H Bu 4-1400 0 1 3 Η Bn H Bu H Ph 4-1401 0 1 3 Η Η Η H Bn Me 4-1402 0 1 3 Η Η Η Η Bn Et 4-1403 0 1 3 Η Η Η ΗBn Pr 4-1404 0 1 3

4-1407 0 1 3 Η Η Η Η Bn Ph 4-1408 0 1 3 Η Η Me Η Bn Me 4-1409 0 1 3 Η Η Me Η Bn Et 4-1410 0 1 3 Η Η Me Η Bn Pr 4- 1411 0 1 3 Η Η Me Η Bn iPr 4 -1412 0 1 3 Η Η Me Η Bn cPr 4 -1413 0 1 3 Η Η Me Η Bn Bu 4-1414 0 1 3, Η Η Me Η Bn Ph 4-1415 0 1 3 Η Η Η Me Bn Me

4-1416 0 1 3 Η Η B Me Bn Et 4 -1417 0 1 3 Η Η Η Me Bn Pr 4-1418 0 1 3 Η Η Η Me Bn iPr 4-1419 0 1 3 Η Η Η Me Bn cPr 4- 1420 0 1 3 Η Η Η Me Bn Bu 4-1421 0 1 3 Η Η Η Me Bn Ph 4-1422 0 1 3 Η Η Et Η Bn Me 4-1423 0 1 3 Η Η Et Η Bn Et 4-1424 0 1 3 Η Η Et Η Bn Pr 4-1425 0 1 3 Η Η Et Η Bn iPr 4-1426 0 1 3 Η Η Et Η Bn cPr -133- 200403244 4-1427 0 1 3 Η H Et Η Bn Bu 4- 1428 0 1 3 Η Η Et Η Bn Ph 4-1429 0 1 3 Η Η Η Et Bn Me 4-1430 0 1 3 Η Η Η Et Bn Et 4 -1431 0 1 3 Η Η Η Et Bn Pr 4-1432 01 3 Η Η Η Et Bn iPr 4 -1433 0 1 3 Η Η Η Et Bn cPr 4-1434 0 1 3 Η Η Η Et Bn Bu 4-1435 0 1 3 Η Η Η Et Bn Ph

4-1436 0 1 3 Η Η Pr Η Bn Me 4-1437 0 1 3 Η Η Pr Η Bn Et 4-1438 0 1 3 Η Η Pr Η Bn Pr 4-1439 0 1 3 Η Η Pr Η Bn iPr 4- 1440 0 1 3 Η Η Pr Η Bn cPr 4-1441 0 1 3 Η Η Pr Η Bn Ph 4 -1443 0 1 3 Η Η Pr Η Bn Ph 4 -1443 0 1 3 Η Η Η Pr Bn Me 4-1444 0 1 3 Η Η Η Pr Bn Et

4-1445 0 1 3 Η Η B Pr Bn Pr 4-1446 0 1 3 Η Η Η Pr Bn * iPr 4-1447 0 1 3 Η Η Η Pr Bn cPr 4-1448 0 1 3 Η Η Η Pr Bn Bu 4 -1449 0 1 3 Η Η B Pr Bn Ph 4-1450 0 1 3 Η Η-iPr Ή Bn Me 4 11451 0 1 3 Η Η iPr Η Bn Et 4-1452 0 1 3 Η. Η iPr Η Bn Pr 4 -1453 0 1 3 Η Η iPr Η Bn iPr 4-1454 0 1 3 Η Η iPr Η Bn cPr 4-1455 0 1 3 Η Η iPr Η Bn Bu '134- 200403244 4 -1456 0 1 3 Η H iPr Η Bn Ph 4-1457 0 1 3 Η Η iPr Bn Me 4-1458 0 1 3 Η Η Η iPr Bn Et 4-1459 0 1 3 Η Η Η iPr Bn Pr 4-1460 0 1 3 Η Η Η iPr Bn iPr 4 -1461 0 1 3 Η Η Η iPr Bn cPr 4-1462 0 1 3 Η Η Η iPr Bn Bu 4-1463 0 1 3 Η Η Η iPr Bn Ph

4-1464 0 1 3 Η Η Bu Η Bn Me 4-1465 0 1 3 Η Η Bu Η Bn Et 4-1466 0 1 3 Η Η Bu Η Bn Pr 4-1467 0 1 3 Η Η Bu Η Bn iPr 4- 1468 0 1 3 Η Η Bu Η Bn cPr 4-1469 0 1 3 Η Η Bu Η Bn Bu 4 -1470 0 1 3 Η Η Bu Η Bn Ph 4-1471 0 1 3 Η Η Η Bu Bn Me 4-1472 0 1 3 Η Η Η Bu Bn Et 4-1473 0 1 3 Η Η Η Bu Bn Pr

4-1474 0 1 3 Η Η Η Bu Bn iPr 4-1475 0 1 3 Η Η Η Bu Bn cPr 4-1476 0 1 3 Η Η Η Bu Bn Bu 4-1477 0 1 3 Η Η Η Bu Bn Ph 4- 1478 0 1 3 Η Η Η Η Ph Me 4-1479 0 1 3 Η Η Η Η Ph Et 4-1480 0 1 3 Η Η Η Η Ph Pr 4-1481 0 1 3 Η Η Η Η Ph iPr 4-1482 0 1 3 Η Η Η Η Ph cPr 4 -1483 0 1 3 Η Η Η Bu Ph Bu 4 -1484 0 1 3 Η Η Me Η Ph Ph -135- 200403244 4-1485 0 1 3 Η Η Me Η Ph Me 4- 1 486 0 1 3 Η Η. Me Η Ph Et 4-1487 0 1 3 Η H Me H Ph Pr 4-1488 0 1 3 Η H Me Η Ph iPr 4-1489 0 1 3 Η Η Me Η Ph cPr 4-1490 0 1 3 Η Η Me Η Ph Bu 4 -1491 0 1 3 Η H Me H Ph Ph 4-1492 0 1 3 Η Η H Me Ph Me 4-1493 0 1 3 Η Η Ph Me Ph Et

4-1494 0 1 3 Η Η Ph Me Ph Pr 4-1495 0 1 3 Η Η Η Me Ph iPr 4-1496 0 1 3 Η Η H Me Ph cPr 4-1497 0 1 3 Η Η H Me Ph Bu 4- 1498 0 1 3 Η Η Ph Me Ph Ph 4-1499 0 1 3 Η Η Et Η Ph Me 4-1500 0 1 3 Η Η Et Η Ph Et 4 -1501 0 1 3 Η H Et Η Ph Pr 4-1502 0 1 3 Η H Et H Ph iPr

4-1503 0 1 3 Η Η Et Η Ph cPr 4-1504 0 1 3 Η Η Et Η Ph Bu 4-1505 0 1 3 Η Η Et Η Ph Ph 4-1506 0 1 3 Η Η Η Et Ph Me 4- 1507 0 1 3 Η Η Η Et Ph Et 4-1508 0 1 3 Η Η H Et Ph Pr 4-1509 0 1 3 Η Η Η Et Ph iPr 4-1510 0 1 3 Η Η Η Et Ph cPr 4 -1511 0 1 3 Η Η H Et Ph Bu 4-1512 0 1 3 Η Η H Et Ph Ph 4-1513 0 1 3 Η H Pr H Ph Me • 136- 200403244 4-1514 01 3 Η Η 4-1515 · 〇1 3 Η Η 4-1516 01 3 Η Η 4-1517 01 3 Η Η 4-1518 01 3 Η Η 4-1519 01 3 Η Η 4-1520 01 3 Η Η 4-1521 01 3 Η Η 4-1522 01 3 Η Η 4-1523 01 3 Η Η 4-1524 01 3 Η Η 4-1525 013 Η Η 4-1526 01 3 Η Η 4-1527 01 3 Η Η 4-1528 01 3 Η Η 4-1529 01 3 Η Η 4 -1530 01 3 Η Η 4-1531 01 3 Η Η 4-1532 01 3 Η Η 4-1533 01 3 Η Η 4-1534 01 3 Η Η 4-1535 01 3 Η Η 4-1536 01 3 Η Η 4- 1537 0 1 3 Η Η 4Η 538 0 1 3 Η Η 4-1539 01 3 Η Η 4-1540 01 3 Η Η 4-1541 01 3 Η Η 4-1542 01 3 Η Η

Pr Η Ph Et Pr Η Ph Pr Pr H Ph iPr Pr H Ph cPr Pr H Ph Bu Pr H Ph Ph H Pr Ph Me H Pr Ph Et H Pr Ph Pr H Pr Ph iPr H Pr Ph cPr H Pr Ph Bu H Pr Ph Ph iPr H Ph Me iPr H Ph Et iPr H Ph Pr iPr H Ph iPr iPr H Ph cPr iPr H Ph Bu iPr H Ph Ph H iPr Ph Me H iPr Ph Et H iPr Ph Pr H iPr Ph iPr H iPr Ph cPr H iPr Ph Bu H iPr Ph Ph Bu H Ph Me Bu H Ph Et

-137- 200403244 4 -1543 0 1 3 Η H Bu H Ph Pr 4 -1 544 0 1 3 Η Η Bu Η Ph iPr 4-1 545 0 1 3 Η Η Bu Η Ph cPr 4-1 546 0 1 3 Η Η Bu Η Ph Bu 4-1547 0 1 3 Η Η Bu Η Ph Ph 4-1548 0 1 3 Η Η Η Bu Ph Me 4-1 549 0 1 3 Η Η Η. Bu Ph Et 4-1 550 0 1 3 Η Η Η Bu Ph Pr 4 -1551 0 1 3 Η Η Η Bu Ph iPr

4-1 552 0 1 3 Η Η Ph Bu Ph cPr 4-1 553 0 1 3 Η Η H Bu Ph Bu 4-1 554 0 1 3 Η Η Η Bu Ph Ph 4-1 555 0 1 3 Me Η Η Η H Me 4-1 556 0 1 3 Me Η Η Η Η Et 4-1 557 0 1 3 Me Η Η Η Η Pr 4-1 558 0 1 3 Me Η Η Η Η iPr 4-1 559 0 1 3 Me Η Η Η Η cPr 4-1 560 0 1 3 Me Η Η Η Η Bu

4-1561 0 1 3 Me Η Η Η Η Ph 4-1 562 0 1 3 Me Η Me Η Η Me 4 -1563 0 1 3 Me H Me Η H Et 4-1 564 0 1 3 Me H Me Η H Pr 4-1565 0 1 3 Me H Me Η H iPr 4-1 566 0 1 3 Me H Me Η H cPr 4-1567 0 1 3 Me H Me Η H Bu 4-1 568 0 1 3 Me H Me Η H Ph 4-1 569 0 1 3 Me Η Η Me Η Me 4-1 570 0 1 3 Me Η Η Me Η Et 4-1571 0 1 3 Me Η Η Me Η Pr -138- 200403244 4-1572 4-1573 4- 1574 4-1575 4-1576 4-1577 4-1578 4-1579 4-1580 4-1581 4-1582 4-1583 4 -1584 4-1585 4-1586 4-1587 4-1588 4-1589 4-1590 4 -1591 4-1592 4-1593 4-1594 4 -1595 4-1596 4-1597 4-1598 4-1599 4 -1600 200403244 4 -1601 0 1 3 Me H Pr Η Η cPr 4-1602 0 1 3 Me H Pr Η H Bu 4-1 603 0 1 3 Me Η Pr Η H Ph 4-1604 0 1 3 Me Η H Pr H Me 4-1605 0 1 3 Me Η Η Pr Η Et 4-1606 0 1 3 Me Η Η Pr Η Pr 4-1607 0 1 3 Me Η Η Pr Η iPr 4-1 608 0 1 3 Me Η H Pr H cPr

4-1609 0 1 3 Me Η H Pr H Bu 4-1610 0 1 3 Me Η H Pr H Ph

4-1611 0 1 3 Me H iPr HH Me 4-1612 0 1 3 Me H iPr HH Et 4-1613 0 1 3 Me H iPr HH Pr 4-1614 0 1 3 Me H iPr HH iPr 4-1615 0 1 3 Me H iPr HH cPr 4-1616 0 1 3 Me H iPr HH Bu 4-1617 0 1 3 Me H iPr HH Ph 4-1618 0 1 3 Me HH iPr H Me 4-1619 0 1 3 Me HH iPr H Et 4 -1620 0 1 3 Me H, H iPr H Pr 4-1621 0 1 3 Me HH iPr H iPr 4-1622 0 1 3 Me HH iPr H cPr 4-1623 0 1 3 Me HH iPr H Bu 4-1624 0 1 3 Me HH iPr H Ph 4-1625 0 1 3 Me H Bu HH Me 4-1626 0 1 3 Me H Bu HH Et 4-1627 0 1 3 Me H Bu HH Pr 4-1628 0 1 3 Me H Bu HH iPr 4-1629 0 1 3 Me H Bu HH cPr -140- 200403244 4-1630 0 1 3 Me H Bu Η Η Bu 4-1631 0 1 3 Me Η Bu Η Η Ph 4-1632 0 1 3 Me Η H Bu H Me 4-1633 0 1 3 Me Η H Bu Η Et 4-1634 0 1 3 Me Η H Bu H Pr 4-Ί635 0 1 3 Me Η H Bu H iPr 4-1636 0 1 3 Me Η H Bu H cPr 4 -1637 0 1 3 Me Η Η Bu Η Bu 4-1638 0 1 3 Me Η H Bu H Ph

4-1639 0 1 3 Me Me Η Η H Me 4-1640 0 1 3 Me Me Me Η H Me 4-1641 0 1 3 Me Me H Me H Me 4-1642 0 1 3 Me Me Et Η H Me 4- 1643 0 1 3 Me Me H Et H Me 4-1644 0 1 3 Me Me Pr Η H Me 4-1645 0 1 3 Me Me H Pr H Me 4-1646 0 1 3 Me Me iPr Η H Me 4-1647 0 1 3 Me Me H iPr H Me

4-1648 0 1 3 Me Me Bu Η H Me 4-1649 0 1 3 Me Me H Bu H Me 4-1650 0 1 3 Me Η Η H Me Me 4 -1651 0 1 3 Me H Me H Me Me 4- 1652 0 1 3 Me Η H Me Me Me 4-1653 0 1 3 Me H Et H Me Me 4 -1654 0 1 3 Me Η H Et Me Me 4-1655 0 1 3 Me H Pr H Me Me 4-1 656 0 1 3 Me Η H Pr Me Me 4 -1657 0 1 3 Me H iPr H Me Me 4-1658 0 1 3 Me Η H iPr Me Me -141- 200403244 4-1 659 0 1 3 Me H Bu H Me Me 4-1660 0 1 3 Me Η H Bu Me Me 4-1661 0 1 3 Me Me Η H Me Me 4-1662 0 1 3 Me Me Me H Me Me 4-1663 0 1 3 Me Me H Me Me Me 4- 1664 0 1 3 Me Me Et H Me Me 4-1665 0 1 3 Me Me H Et Me Me 4-1666 0 1 3 Me Me Pr H Me Me 4-1667 0 1 3 Me Me H Pr Me Me

4-1668 0 1 3 Me Me iPr H Me Me 4-1669 01 3 Me Me H iPr Me Me 4-1670 0 1 3 Me Me Bu H Me Me 4-1671 0 1 3 Me Me H Bu Me Me 4-1672 0 1 3 Me Bn Η Η H Me 4-1673 0 1 3 Me Bn Me Η H Me 4-1674 0 1 3 Me Bn H Me H Me 4-1675 0 1 3 Me Bn Et Η H Me 4-1676 0 1 3 Me Bn H Et H Me

4-1677 01 3 Me Bn Pr Η H * Me 4-1678 0 1 3 Me Bn H Pr H Me 4-1679 0 1 3 Me Bn iPr Η H Me 4-1680 0 1 3 Me Bn H iPr H Me 4- 1681 0 1 3 Me Bn Bu Η H Me 4-1682 0 1 3 Me Bn H Bu H Me 4-1683 0 1 3 Me Η Η H Bn Me 4 -1684 0 1 3 Me H Me H Bn Me 4-1685 0 1 3 Me Η H Me Bn Me 4-1686 0 1 3 Me H Et H Bn Me 4-1687 0 1 3 Me Η H Et Bn Me -142- 200403244 4-1688 0 1 3 Me H Pr Η Bn Me 4- 1689 0 1 3 Me Η H Pr Bn Me 4-1690 0 1 3 Me H iPr H Bn Me 4-1691 0 1 3 Me Η H iPr Bn Me 4-1692 0 1 3 Me H Bu H Bn Me 4-1693 0 1 3 Me Η H Bu Bn Me 4-1694 0 1 3 Me Η Η H Ph Me 4-1695 0 1 3 Me H Me H Ph Me 4-1 696 0 1 3 Me Η H Me Ph Me

4-1697 0 1 3 Me H Et H Ph Me 4-1698 0 1 3 Me Η H Et Ph Me 4-1699 0 1 3 Me H Pr H Ph Me 4-1700 0 1 3 Me Η H Pr Ph Me 4- 1701 0 1 3 Me H iPr H Ph Me 4-1702 0 1 3 Me Η H iPr Ph Me 4-1703 0 1 3 Me H Bu H Ph Me 4-1704 0 1 3 Me Η H Bu Ph Me 4-1705 0 2 3 Η Η Η Η H Me

4-1706 0 2 3 Η H Me Η H Me 4-1707 0 2 3 Η Η H Me H Me 4-1708 0 2 3 Η H Me Me H Me 4-1709 0 2 3 Η H Et Η H Me 4- 1710 0 2 3 Η Η H Et H Me 4-171 1 0 2 3 Η H Pr Η H Me 4-171 2 0 2 3 Η Η H Pr H Me 4-171 3 0 2 3 Η H iPr Η H Me 4 -1714 0 2 3 Η Η H iPr H Me 4-171 5 0 2 3 Η H Bu Η H Me 4-171 6 0 2 3 Η Η H Bu H Me 143- 200403244 4-1717 02 3 Η 4-1718 02 3 Η 4-1719 02 3 Η 4-1720 02 3 Η 4-1721 02 3 Η 4-1722 02 3 Η 4-1723 02 3 Η 4-1724 02 3 Η 4-1725 02 3 Η 4-1726 02 3 Η 4-1727 02 3 Η 4-1728 0 23 Η 4-1729 02 3 Η 4-1730 02 3 Η 4-1731 02 3 Η 4-1732 02 3 Η 4-1733 02 3 Η 4-1734 02 3 Η 4- 1735 02 3 Η 4-1736 02 3 Η 4-1737 02 3 Η 4-1738 02 3 Η 4-1739 02 3 Η 4-1740 0 2 3 Η 4-1741 02 3 Η 4-1742 02 3 Η 4-1743 02 3 Η 4-1744 0 2 3 Η 4-1745 02 3 Η

Me Η Η Η Me Me Me Η Η Me Me Η Me Η Me Me Et Η H Me Me H Et H Me Me Pr Η H Me Me H Pr H Me Me iPr Η H Me Me H iPr H Me Me Bu Η H Me Me H Bu H Me Η Η H Me Me H Me. H Me Me Η H Me Me Me H Et H Me Me

HH Et Me Me H Pr H, Me Me HH Pr Me Me H iPr H Me Me HH iPr Me Me H Bu H Me Me HH Bu Me Me HH Me Me Me H Me Me H Me Me Me Et H Me Me Me H Et Me Me Me Pr H Me Me Me H Pr Me Me

-144- 200403244 4-1746 0 2 3 H Me iPr H Me Me 4-1747 0 2 3 H Me H iPr Me Me 4-1748 0 2 3 H Me Bu H Me Me 4-1749 0 2 3 H Me H Bu Me Me 4-1750 0 2 3 Η Bn Η Η H Me 4-1751 0 2 3 H Bn Me Η H Me 4-1752 0 2 3 Η Bn H Me H Me 4-1753 0 2 3 H Bn Et Η H Me 4-1754 0 2 3 Η Bn H Et H Me

4-1755 0 2 3 H Bn Pr Η H Me 4-1756 0 2 3 Η Bn H Pr H Me 4-1757 0 2 3 H Bn iPr Η H Me 4-1758 0 2 3 Η Bn H iPr H Me 4- 1759 0 2 3 H Bn Bu Η H Me 4-1760 0 2 3 Η Bn H Bu H Me 4-1761 0 2 3 Η Η Η H Bn Me 4-1762 0 2 3 Η H Me H Bn Me 4-1763 0 2 3 Η Η H Me Bn Me

4-1764 0 2 3 Η H Et H Bn Me 4-1765 0 2 3 Η Η H Et Bn Me 4-1766 0 2 3 Η H Pr H Bn Me 4-1767 0 2 3 Η Η H Pr Bn Me 4- 1768 0 2 3 Η H iPr H Bn Me 4-1769 0 2 3 Η Η H iPr Bn Me 4-1770 0 2 3 Η H Bu H Bn Me 4-1771 0 2 3 Η Η H Bu Bn Me 4-1772 0 2 3 Η Η Η H Ph Me 4-1773 0 2 3 Η H Me H Ph Me 4-1774 0 2 3 Η Η H Me Ph Me -145- 200403244 4-1775 0 2 3 Η Η Et Η Ph Me 4- 1776 0 2 3 Η Η Η Et Ph Me 4-1777 0 2 3 Η Η Pr Η Ph Me 4-1778 0 2 3 Η Η Η Pr Ph Me 4-1779 0 2 3 Η Η iPr Η Ph Me 4-1780 0 2 3 Η Η Η iPr Ph Me 4-1781 0 2 3 Η H Bu H Ph Me 4-1782 0 2 3 Η Η Η Bu Ph Me 4-1783 0 2 3 Me Η Η Η Η Me

4-1784 0 2 3 Me Η Me Η Η Me 4-1785 0 2 3 Me Η Η Me Η Me 4-1786 0 2 3 Me Η Me Me Η Me 4-1787 0 2 3 Me H Et Η H Me 4- 1788 0 2 3 Me Η Η Et Η Me 4-1789 0 2 3 Me H Pr Η H Me 4-1790 0 2 3 Me Η H Pr H Me 4-1791 0 2 3 Me H iPr Η Η Me 4-1792 0 2 3 Me Η H iPr Η Me

4-1793 0 2 3 Me H Bu Η H Me 4-1794 0 2 3 Me Η H Bu Η Me 4-1795 0 2 3 Me Me Η Η H Me 4-1796 0 2 3 Me Me Me Η H Me 4- 1797 0 2 3 Me Me H Me H Me 4-1798 0 2 3 Me Me Et Η H Me 4-1799 0 2 3 Me Me H Et H Me 4-1800 0 2 3 Me Me Pr Η H Me 4-1801 0 2 3 Me Me H Pr H Me 4-1802 0 2 3 Me Me iPr Η H Me 4-1803 0 2 3 Me Me H iPr H Me -146- 200403244 4-1804 0 2 3 Me Me Bu Η H Me 4 I 1805 0 1 3 Me Me H Bu H Me 4-1806 0 2 3 Me Η Η H Me Me 4-1807 0 2 3 Me H Me Me 4-1808 0 2 3 Me Η H Me Me Me 4 1809 0 2 3 Me H Et H Me Me 4-1810 0 2 3 Me Η H Et Me Me 4-181 1 0 2 3 Me H Pr H Me Me 4-1812 0 2 3 Me Η H Pr Me Me

4-1813 0 2 3 Me H iPr H Me Me 4-1814 0 2 3 Me Η H iPr Me Me 4-1815 0 2 3 Me H Bu H Me Me 4-1816 0 2 3 Me Η H Bu Me Me 4- 1817 0 2 3 Me Me Η H Me Me 4-1818 0 2 3 Me Me Me H Me Me 4-1819 0 2 3 Me Me Me Me 4-1820 0 2 3 Me Me Et H Me Me 4-1821 0 2 3 Me Me H Et Me Me

4-1822 0 2 3 Me Me Pr H Me Me 4-1823 0 2 3 Me Me H Pr Me Me 4-1824 0 2 3 Me Me iPr H Me Me 4-1825 0 2 3 Me Me H iPr Me Me 4- 1826 0 2 3 Me Me Bu H Me Me 4 1827 0 2 3 Me Me H Bu Me Me 4-1828 0 2 3 Me Bn Η Η H Me 4-1829 0 2 3 Me Bn Me Η H Me 4-1830 0 2 3 Me Bn H Me H Me 4-1831 0 2 3 Me Bn Et Η H Me 4 -1832 0 2 3 Me Bn H Et H Me -147- 200403244 4-1833 4-1834 4-1835 4-1836 4- 1837 4-1838 4-1839 4-1840 4-1841 4-1842 4-1843 4-1844 4-1845 4-1846 4-1847 4-1848 4-1849 4-1850 4-1851 4-1852 4-1853 4 -1854 4-1855 4-1856 4-1857 4-1858 4-1859 4-1860 4a 1861 200403244 4-1862 4-1863 4-1864 4-1865 4-1866 4-1867 4-1868 4-1869 4- 1870 4-1871 4-1872 4-1873 4-1874 4-1875 4-1876 4-1877 4-1878 4-1879 4-1880 4-1881 4-1882 4-1883 4-1884 4-1885 4-1886 4 -1887 4-1888 4-1889 4H890

0 3 0 3

4

4 Η 4 Η 4 Η 4 Η Η Me Η Η Me Η Η Me Η Me Η Me Me Η Me Η Et Η Η Me Η Η Et Η Me Η Pr Η Η Me Η Η Pr Η Me Η iPr Η Η Me Η Η Η iPr Η Me Η Bu Η Η Me Η Η Bu Η Me Me Η Η Η Me Me Me Η Η Me Me Η Me Η Me Me Et Η H Me Me H Et H Me Me Pr Η H Me Me H Pr H Me Me iPr Η H Me Me H iPr H Me Me Bu Η H Me Me H Bu H Me Η Me H Me Me H Me H Me Me Η H Me Me Me H Et H Me Me Η H Et Me Me H Pr H Me Me Η H Pr Me Me

-149- 200403244 4 -1891 0 3 4 Η H iPr Η Me Me 4-1892 0 3 4 Η Η Η iPr Me Me 4-1893 0 3 4 Η Η Bu Η Me Me 4-1894 0 3 4 Η Bu H Bu Me Me 4-1895 0 3 4 H Me Η Η Me Me 4-1896 0 3 4 H Me Me H Me Me 4-1897 0 3 4 H Me H Me Me Me 4-1898 0 3 4 H Me Et H Me Me

4-1899 0 3 4 H Me H Et Me Me 4-1900 0 3 4 H Me Pr H Me Me 4-1901 0 3 4 H Me H Pr Me Me 4-1902 0 3 4 H Me iPr H Me Me 4- 1903 0 3 4 H Me H iPr Me Me 4-1904 0 3 4 H Me Bu H Me Me 4 1905 0 3 4 H Me-H Bu Me Me 4-1906 0 3 4 Η Bn Η Η H Me 4-1907 0 3 4 H Bn Me Η H Me 4-1908 0 3 4 Η Bn H Me H Me

4-1909 0 3 4 H Bn Et Η H Me 4-1910 0 3 4 Η Bn H Et H Me 4-191 1 0 3 4 H Bn Pr Η H Me 4-1912 0 3 4 Η Bn H Pr H Me 4 -1913 0 3 4 H Bn iPr Η H Me 4-1914 03 4 Η Bn H. IPr H Me 4-1915 0 3 4 H Bn Bu Η H Me 4 -1 916 0 3 4 Η Bn H Bu H Me 4- 1917 0 3 4 HHHH Bn Me 4-1918 0 3 4 HH Me H Bn Me 4-1919 0 3 4 HHH Me Bn Me -150- 200403244 4-1 920 0 3 4 Η H Et H Bn Me 4-1 921 0 3 4 Η Η Η Et Bn Me 4-1 922 0 3 4 Η Η Pr Η Bn Me 4-1 923 0 3 4 Η Η H Pr Bn Me 4-1 924 0 3 4 Η Η iPr Η Bn Me 4-1 925 0 3 4 Η Η Η iPr Bn Me 4-1 926 0 3 4 Η Η Bu Η Bn Me 4-1 927 0 3 4 Η Η Η Bu Bn Me

4-1 928 0 3 4 Η Η Η Η Ph Me 4-1 929 0 3 4 Η Η Me Η Ph Me 4-1 930 0 3 4 Η Η Η Me Ph Me 4-1 931 0 3 4 Η E r Et Η Ph Me 4-1 932 0 3 4 Η Η H Et Ph Me 4-1 933 0 3 4 Η H Pr H Ph Me 4-1934 0 3 4 Η Η H Pr Ph Me 4-1 935 0 3 4 Η H iPr Η Ph Me 4-1 936 0 3 4 Η Η Η iPr Ph Me 4-1 937 0 3 4 Η Η Bu Η Ph Me

4-1 938 0 3 4 Η Η Η Bu Ph Me 4-1 939 0 3 4 Me Η Η Η H Me 4-1 940 0 3 4 Me Η Me Η Η Me 4-1 941 0 3 4 Me Η Η Me Η Me 4-1 942 0 3 4 Me Η Me Me Η Me 4-1 943 0 3 4 Me H Et Η H Me 4-1 944 0 3 4 Me Η H Et H Me 4-1 945 0 3 4 Me Η Pr Η Η Me 4-1 946 0 3 4 Me Η H Pr H Me 4 -1 947 0 3 4 Me H iPr Η Η Me 4 -1 948 0 3 4 Me Η H iPr Η Me -151- 200403244 4-1949 4-1950 4-1951 4 -1952 4 -1953 4-1954 4 -1955 4-1956 4-1957 4-1958 4-1959 4-1960 4-1961 4-1962 4 -1963 4-1964 4 -1965 4- 1966 4-1967 4 -1968 4-1969 4-1970 4-1971 4-1972 4 -1973 4 -1974 4-1975 4-1976 4-1977 200403244 4-1978 4-1979 4-1980 4-1981 4-1982 4-1983 4-1984 4-1985 4-1986 4-1987 4-1988 4-1989 4-1990 4-1991 4-1992 4-1993 4-1994 4-1995 4-1996 4-1997 4-1998 4- 1999 4-2000 4-2001 4-2002 4-2003 4-2004 4-2005 4-1 2006 200403244 4-2007 4-2008 4-2009 4-2010 4-2011 4-2012 4-2013 4-2014 4-2015 4-2016 4-2017 4-2018 4-2019 0 3

4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 4 Me 3 H 3 H 4 H

H H H H H H H H H H H H

Me H Ph H Me Ph Et H Ph H Et Ph Pr H Ph H Pr Ph iPr H Ph H iPr Ph Bu H Ph H Bu Ph iPr Η H iPr Η H iPr Η H

Me Me Me Me Me Me Me Me cHex cHex cHex

(Table 8)

Compound number X n Position R1 R4 R5 R6 R7 R2 R9 4a- 1 s 1 3 HH iPr HH Me H 4a- 2 s 1 3 HH iPr HH Et H 4a- 3 s 1 3 HH iPr HH Pr H 4a- 4 s 1 3 HH iPr HH iPr H 4a- 5 s 1 3 HH iPr HH cPr H 4a- 6 s 1 3 HH iPr HH Bu H 154-200403244 4a- 7 4a- 8 4a- 9 4a -10 4a-11 4a-12 4a -13 4a-14 4a-15 4a- · 16 4a-17 4a-18 4a-19 4a-20 4a-21 4a-22 4a-23 4a-24 4a-25 4a-26 4a-27 4a-28 4a- 29 4a-30 4a-31 4a-32 4a-33 4a-34 4a-35 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 3 3 3 3 3 3 3 3 3 3 3

H H H H H H H H H H H H H H H H H H H H H H H H H H

H iPr Η HH iPr Η HH iPr Η HH iPr Η HH iPr Η HH iPr Η HH iPr Η HH iPr Η HH iPr Η HH iPr Η HH iPr Η HH iPr Η HH iPr Η HH iPr Η Η HH iPr Η HH iPr Η HH iPr Η HH iPr Η HH iPr Η HH iPr HH iPr Η HH iPr Η HH iPr Η HH iPr Η HH iPr Η HH iPr Η H

Ph H cHex H Me H Et H Pr H iPr H cPr H Bu H Ph H cHex H Me H Et H Pr H iPr H cPr H Bu H Ph H cHex H Me Et Me Pr Me iPr Me Bu Ph Et Ph Pr Ph iPr Ph Bu cHex Et cHex Pr cHex i Pr

155 200403244 4a-36 SI 3 Η H iPr Η H cHex Bu Among the compounds exemplified in Tables 1 to 8 above, suitable compounds are compound numbers 1-1, 1 _ 2, 1-3, 1-4 'Ί-5, 1 -6, 1-7, 1-8 '1-9, 1-10' 1-11, 1-12, 1-13 '1-14' 1-15, Bu 16, Bu 17, Bu 18, 11 19, 1-20, 1-21, 1-379, Bu 380, 1-381, 1-382, 1-383, 1-384, 1-385, 1-386, 1-387, 1-388, 1 -389, 1-390, 1-391, 1-392, 1- 393, 1-394, 1-395 '1-396, 1-397, 1-398, 1-399, Bu 757, 1-758, 1-759, 1-

766, 1-767, 1-768, 2-1, 2-2, 2-3 '2-4' 2-5 '2-6, 2-7' 2_8, 2-9'2-10, 2_ 11 , 2-12 '2-13, 2-14, 2-15, 2-16, 2-17, 2H8, 2-19, 2-20, 2-21, 2-379, 2-380, 2-381 , 2-382, 2-383, 2-384, 2-385, 2-386, 2-387, 2_388, 2-389, 2- 390, 2-391, 2-392, 2-393 '2-394 , 2-395, 2-396, 2-397, 2-398, 2-399, 2- 757, 2-758 '2-759' 2-766, 2-767, 2-768 '3-1, 3 -2 '3-3, 3-4' 3-5, 3-6, 3-7, 3-43, 3-44 '3-45, 3-46, 3_47, 3-48, 3-49, 3 -85 '4-1, 4-2, 4-3, 4-4, 4- 5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11' 4-12 , 4-13 '4_14, 4-15' 4-16, 4-17, 4- 18, 4-19, 4-20, 4-21, 4-22 '4-23' 4-24, 4-25 , 4-26 '4-27, 4-28, 4-29, 4- 30, 4-31' 4-32, 4-33, 4-34 '4-35, 4-36, 4-37, 4 -38, 4-39 '4-40, 4-41, 4- 42, 4-43, 4-44, 4-45, 4-46, 4-47, 4-48, 4-49, 4-50 , 4-51, 4-52, 4-53 '4-

54, 4-55, 4-56 '4-57' 4-58, 4-59 '4-60' 4-61, 4-62 '4-63, 4-64, 4-65, 4-66, 4-67 '4-68, 4-69, 4-70' 4-71 '4-72, 4-73, 4-74' 4-75, 4-76 '4-77, 4- 78, 4- 79, 4-80, 4-81, 4-82, 4-83, 4-84, 4-1009, 4--1010, 4-1011 '4-1012, 4-1013, 4-1014, 4-1015' 4-1016, 4-1017, 4-1018, 4-1019, 4-1020, 4H021, 4-1022, 4-1023, 4-1024, 4-1025, 4-1026, 4-1027, 4-1028, 4-1029, 4-1030, 4-1031, 4-1032, 4-1033, 4-1034, 4-1035, 4-1036, 4-1037, 4-1038, 4-1039, 4-1040, 4- 1041, 4H042, 4-1043, 4-1044, 4-1045, 4-1046, 4-1047, 4-1048, 4-1049, 4-1050, 4-1051, 4-1052, 4-1053, 4- 1054, 4-1055, 4-1056, 4-1057, 4-1058, 4-1059, 4-1060, 4-1061, 4-1062, 4-1063, 4-1064, 4-1065, 4-1066, 4-1067, 4H 068, 4-1069, 4-1070, 4-1071, 4H 072, 4H073, 4-1074, 4-1 075, 4H076, 4-1077, 4-1078, 4-1079, 4-1080 , 4-1081, 4-1082, 4-1083, 4-1084, -156- 200403244 4-1085, 4-1086, 4-1087, 4-1088, 4-1089 '4-1090, 4-1091, 4-1092 or 4-2017. More preferably compound numbers 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, Bu 8, 1-9,;-

10, 1-11, Bu 12, Bu 13, 1-14 'Bu 15' 1-21, 1-379, 1-380, 1-381 'Bu 382, Bu 383, 1-384, Bu 385, 1- 386, 1-387, 1-388, 1-389, Bu 390, Bu 391, 1-392, 1-393, Bu 399, 1-757, Bu 758, Bu 759, 1-766, 1-767, 1 -768, 2-1, 2-2, 2-3, 2-4, 2-5, 2-6, 2-7 '2-8, 2-14, 2H5, 2-21, 2-379, 2 -380, 2-381, 2-382, 2-383, 2-384, 2-385, 2-386, 2-389, 2-392, 2-757, 2-758, 2-759'2-766 , 2-767, 2-768, 3H, 3-2, 3-3, 3-4, 3-5 '3-6' 3-7, 3-85, 4-29, 4-30'4-31 , 4-32, 4-33, 4-34, 4-35, 4-43, 4-44, 4-45, 4-46 '4-47, 4-48, 4-49, 4-57, 4 -58, 4-59, 4-60, 4-61, 4-62, 4-63, 4-64, 4-67, 4-70, 4-71, 4-72, 4-73, 4-74 , 4-75, 4-76, 4-77, 4--1037, 4-1038, 4-1039, 4-1040, 4-1041, 4-1042, 4-1043, 4-1051, 4-1052, 4 -1053, 4-1054, 4-1055, 4-1056, 4-1057, 4-1065, 4-1066, 4-1067, 4-1068, 4-1069, 4-1070, 4-1071, 4-1079 , 4-1080, 4-1081, 4-108 Compounds of 2, 4-1083, 4-1084, 4-1085, or 4-2017 ° and more preferably compound numbers 1-1, 2, 2, 1-3, 1-4, 1-5, 1-6, 1 -7, 1-8, Bu 14, Bu 15, Bu 21, 1-757, 1-758, W59, 2-1, 2-2, 2-3, 2-4 '2-5, 2-6, 2-7,

3-1, 3-2, 3-3, 3-4 '3-5' 3-6, 3-7, 4-29, 4-30, 4-31, 4-32, 4-33 '4- 34 '4-35, 4-43' 4-44, 4-45, 4-46, 4-47, 4-48, 4-49, 4-57, 4-58, 4-59, 4-60, 4- 61, 4-62, 4-63, 4-71, 4-72, 4-73 '4-74, 4-75, 4-76, 4-77, 4- 1037, 4- 1038, 4- 1039, 4-1040, 4-1041, 4-1042, 4-1043, 4-1051, 4-1052, 4-1053, 4-1054, 4-1055, 4-1056, 4-1057, 4-1065, 4H066, 4-1067, 4-1068, 4_1069, 4_ 1070, 4-1071, 4-1079, 4-1080 '4-1081, 4-one 1082, 4-1083, 4-1084, 4-1085, or 4-2 0 1 7 compounds. Optimally Compound No. 1-1, Bu 7, Bu 8, 1-1 4, 1-1 5, 1-2 1, 1-757, Bu 758, Bu 759, 4-57, 4-63, or 4- Compounds of 2017 ° The pharmacologically acceptable salt of the compound (I) of the present invention or its ester derivative is shown in Table 9 with specific examples -157-200403244. However, the salt or ester derivative of the present invention is not limited to the illustrated compounds. In Table 9, the hydroxyl group is the hydroxyl group of the 6-hydroxyethyl group of the carbon, and the carboxyl group is the carboxyl group of the 3-position of the carbon. In the protecting group of the hydroxyl group or the carboxyl group of Table 9, Η is the group of the compound (I), the group is not protected, Na A sodium salt is formed for the compound (I). (Table 9) Compound No. Compound (I) Hydroxyl Protecting Group Carboxyl Protecting Group 5-1 Compound No. 1-8 MeCO Η 5-2 Compound No. 1-8 EtCO Η 5-3 Compound No. 1-8 PrCO Η 5-4 Compound No. 1-8 iPrCO Η 5-5 Compound No. 1-8 BuCO Η 5-6 Compound No.]-8 tBuCO Η 5-7 Compound No. 1-8 PhCO Η 5-8 Compound No. 1-8 MeCO Na 5-9 Compound No. 1-8 EtCO Na 5-10 Compound No. 1-8 PrCO Na 5-11 Compound No. 1-8 iPrCO Na 5- 12 Compound No. 1-8 BuCO Na 5-13 Compound No. 1-8 tBuCO Na 5> 14 Compound No. 1-8 PhCO Na 5-15 Compound No. 1-8 H Na 5-16 Compound Compound No. 1-8 H Me 5-17 Compound No. 1-8 H Et -158- 200403244 5- 18 Compound No. 1-8 Η Pr 5- 19 Compound No. 1-8 Η cPr 5- 20 Compounds of compound numbers 1-8 Η iPr 5-21 Compound number conversion Compound Η Bu 5- 22 Compound No. 1-8 Η cBu 5- 23 Compound No. 1-8 Η Pent 5-24 Compound No. 1-8 Η cPent 5- 25 Compound No. 1-8 Η Hex 5- 26 Compound No. 1-8Η cHex 5- 27 Compound No. 1-8Η Ph 5- 28 Compound No. 1-8Η Bn 5- 29 Compound No. 1-8Η CH2cPent 5 -30 Compound No. 1-8-8 CH2cHex 5-31 Compound No. 1-8Η CH20C0Me 5-32 Compound No. 1-8Η CH20C0Et 5- 33 Compound No. 1-8Η CH20C0Pr 5-34 Compound of Compound No. 8Η CH20C0iPr 5-35 Compound of Compound No. 1-8-8 CH20C0cPr 5-36 Compound of Compound No. 1-8, Η CH20C0Bu 5- 37 Compound of Compound No. 1-8 Η CH20C0tBu 5- 38 Compound No. Compounds 1-8 Η CH20C0Pent 5- 39 Compounds 1-8 Η CH20C0cPent 5- 40 Compounds 1-8 Η CH2OCOCH2cHex 5- 41 Compounds 1-8 Η CH20C0Ph 5- 42 Item No.]-8 Compound Η CH20C02Me 5- 43 Compound No. 1-8 Η CH20C02Et 5- 44 Compound No. 1-8 Η CH20C02Pr 5- 45 Compound No. Η CH20C02iPr 5-46 Compound No. 1-8 Compound of CH20C02cPr -159- 200403244 5- 47 Compound of compound number 1-8 Η CH20C02Bu 5- 48 Compound of compound number 1-8 Η CH20C02tBu 5- 49 Compound of compound number 1-8 Η CH20C02Pent 5- 50 Compound number 1 Compound of -8 CH20C02cPent 5-51 Compound of compound number 1-8 Η CH20C02CH2cHex 5- 52 Compound of compound number 1-8 Η CH20C02Ph 5- 53 Compound of compound number 1-8 Η CH (Me) 0C0Me 5- 54 compound Compound No. 1-8Η CH (Me) OCOEt 5-55 Compound No. 1-8Η CH (Me) 0C0Pr 5- 56. Compound No. 1-8Η CH (Me) 0C0iPr 5- 57 Compound No. Compound 1-8-8 CH (Me) 0C0Bu 5-58 Compound No. 1-8Η CH (Me) 0C0tBu 5- 59 Compound No. 1-8Η CH (Me) 0C0Ph 5- 60 Compound No. 1- Compound of 8 Η CH (Me) 0C02M e 5- 61 Compound of compound number 1-8-8 CH (Me) 0C02Et 5-62 Compound of compound number 1-8Η CH (Me) 0C02Pr 5- 63 Compound of compound number 1-8Η CH (Me) 0C02iPr 5 -64 Compound of compound number 1-8Η CH (Me) 0C02Bu 5- 65 Compound of compound number 1-8Η CH (Me) 0C02tBu 5-66 Compound of compound number 1-8Η CH (Me) 0C02Ph 5-67 Compound No. 1-8 Compound CHrQ 5-68 Compound No. 4-57 MeCO H 5-69 Compound No. 4-57 Compound EtCO H 5- 70 Compound No. 4-57 Compound PrCO H 5- 71 Compound No. Compound 4-57 iPrCO H 5-72 Compound 4-57 BuCO H 5-73 Compound 4-57 tBuCO H 5-74 Compound 4-57 PhCO H 5- 75 Compound 4- Compound of 57 MeCO .Na -160- 200403244 5- 76 5- 77 5- 78 5- 79 5- 80 5-81 5-82 5-83 5- 84 5-85 5- 86 5- 87 5- 88 5 -89 5-90 5-91 5-92 5- 93 5-94 5-95 5- 96 5-97 5- 98 5- 99 5-100 5-101 5-102 5-103 5-104

Compound EtCO of compound number 4-57 Compound of compound No. 4-57 PrCO Compound of compound number 4-57 iPrCO Compound of number 4-57 BuCO Compound of number 4-57 tBuCO Compound of number 4-57 PhCO Compound number Compound H of 4-57 Compound H of Compound No. 4-57 Compound H of Compound No. 4-57 Compound H of Compound No. 4-57 Compound H of Compound No. 4-57 Compound H of Compound No. 4-57 Compound H of Compound No. 4- Compound H of 57 Compound H of Compound No. 4-57 Compound H of Compound No. 4-57 Compound H of Compound No. 4-57 Compound H of Compound No. 4-57 Compound H of Compound No. 4-57 Compound H of Compound No. 4-57 Compound H Compound No. 4-57 Compound H Compound No. 4-57 Compound H Compound No. 4-57 Compound H Compound No. 4-57 Compound H Compound No. 4-57 Compound H Compound No. 4-57 Compound H Compound No. 57 Compound H Compound No. 4-57 Compound H Compound No. 4-57 Compound H Compound H of Compound No. 4-57

Na Na Na Na Na Na Na Me

Pr cPr iPr Bu cBu Pent cPen t Hex cHex

CH2cPent CH2cHex CH20C0Me CH20C0Et CH20C0Pr CH20C0iPr CH20C0cPr CH20C0Bu CH20C0tBu -161- 200403244 5-105 5-106 5-107 5-109 5-110 5-111 5-112 5-113 5-114 5-115 5-116 5 -117 5 -118 5-119 5-120 5-.121 5-122 5-123 5-124 5-125 5-126 5-127 5-128 5-129 5-130 5-131 5-132 5- 133 Compound with compound number 4-57 Η CH20C0Pent Compound with compound number 4-57 Η CH20C0cPent Compound with compound number 4-57 Η CH2OCOCH2cHex Compound with compound number 4-57 Η CH20C0Ph Compound with compound number 4-57 Η CH20C02Me Compound number 4- Compound of 57 Η CH20C02Et Compound of 4-57 Η CH20C02Pr Compound of 4-57 Η CH20C02iPr Compound of 4-57 Η CH20C02cPr Compound of 4-57 Η CH20C02Bu Compound of 4-57 Η CH20C02tBu Compound No. 4-57 Η CH20C02Pent Compound No. 4-57 Η CH20C02cPent Compound No. 4-57 Η CH20C02CH2cHex Compound No. 4-57 Η CH20C02Ph. Compound 4-57 Η CH (Me) 0C0Me Compound No. 4-57 57 CH (Me) OCOEt Compound No. 4-57 Η CH (Me) OCOPr Compound No. 4-57 Η CH (Me) OCOiPr Compound No. 4-5757 CH (Me) OCOBu Compound No. 4-57Η CH (Me) 0C0tBu Compound No. 4-57Η CH (Me) 0C0Ph Compound No. 4-57Η CH (Me ) 0C02Me Compound No. 4-57 Η CH (Me) 0C02Et Compound No. '57 Η CH (Me) 0C02Pr Compound No. 4-57 Η CH (Me) 0C02iPr Compound No. 4-57 Η CH ( Me) 0C02Bu Compound No. 4-57 Η CH (Me) 0C02tBu Compound No. 4-57 Η CH (Me) 0C02Ph -162- 200403244 5-134 5-135 5-136 5-137 5-138 5-138 5- 139 5-140 5-141 5-142 5-143 5-144 5-145 5-146 5-147 5-148 5-149 5-150 5-151 5-152 5-153 5-154 5-155 5 -156 5-157 5-158 5-159 5-160 5-161 5-162

Compound No. 4-57 Η Compound No. 1-758 MeCO Compound No. 758 Compound EtCO Compound No. 1-758 PrCO Compound No. 758 Compound iPrCO Compound No. 1-758 BuCO Compound No. 758 Compound tBuCO Compound No. 1-758 PhCO Compound No. 1-758 MeCO Compound No. 1-758 Compound EtCO Compound No. 758 Compound PrCO Compound No. 7% Compound iPrCO Compound No. 1-758 BuCO Compound tBuCO of compound number 1-758 compound of compound 1-758 PhCO compound of compound number 758 compound H of compound number 1-758 compound of compound number 1-758 of compound H compound of compound number 1-758 of compound H compound number 1 Compound H of -758 Compound H of Compound No. 1-758 Compound H of Compound No. 1-758 Compound H of Compound No. 1-758 Compound H of Compound No. ^ 58 Compound H of Compound No. 8 Compound H of Compound No. 1-758 Compound H Compound H Compound of Compound No. 1-758 U58 of Compound H Compound No. 1-758 of H CHrQ Η Η Η Η Η Η

Na Na Na Na Na Na Me Et

cPr iPr Bu cBu Pent cPen t Hex cHex Ph Bn -163- 200403244 5-163 Compound No. 1-758758 CH2cPent 5-164 Compound No. 1-758Η CH2cHex 5-165 Compound No. 758Η CH20C0Me 5-166 Compound of compound number 1-758 Η CH20C0Et 5-167 Compound of compound number 1-758 Η CH20C0Pr 5-168 Compound of compound number 1-758 Η CH20C0iPr 5-169 Compound of compound number 1-758 Η CH20C0cPr 5- 170 Compound of compound number 1-758 Η CH20C0Bu 5-171 Compound of compound number 1-758 Η CH20C0tBu 5-172 'Compound of compound number 1-758 Η CH20C0Pent 5-173 Compound of compound number 1-758 Η CH20C0cPent 5-174 Compound No. 1-758Η CH20C0CH2cHex 5-175 Compound No. 1-758Η CH20C0Ph 5-176 Compound No. 1-758Η CH20C02Me 5-177 Compound No. 1-758Η CH20C02Et 5-178 Compound No. Compound 1-758758 CH20C02Pr 5-179 Compound No. 1-758Η CH20C02iPr 5-180 Compound No. 1-758 Η CH20C02cPr 5-181 Compound No. 1-758Η CH20C02Bu 5-182 Compound No. 1-758Η CH20C02tBu 5-183 Compound No. 1-758 化合物 CH20C02Pent 5-184 Compound No. 1-758Η CH20C02cPen t 5 -185 Compound of compound number 1-758758 CH20C02CH2cHex 5 ~ 186 Compound of compound number 1-75820 CH20C02Ph 5 ~ 187 Compound of compound number 1-758Me CH (Me) OCOMe 5-188 Compound of compound number 1-758Η CH (Me) OCOEt 5-189 Compound No. 1-758758 CH (Me) OCOPr 5-190 Compound No. 1-758Η CH (Me) 0C0iPr 5-191 Compound No. 1-758Η CH ( Me) 0C0Bu

-164- 200403244 5-192 Compound No. -758 Compound Η CH (Me) 0C0tBu 5-193 Compound No. 1-758 Η CH (Me) OCOPh 5-194 Compound No. 1-758 Η CH (Me ) 0C02Me 5-195 Compound No. 1-758 Η CH (Me) 0C02Et 5-196 Compound No. 1-758 Η CH (Me) 0C02Pr 5-197 Compound No. 1-758 Η CH (Me) 0C02iPr 5-198 Compound No. 1-758758 CH (Me) 0C02Bu 5-199 Compound No. 1-758758 CH (Me) 0C02tBu 5-200 Compound No. 1-758Η CH (Me) 0C02Ph 5- 201 Compound of compound number 1-758758 CHrQ 5-202 Compound of compound number 4-2017 MeCO H 5-203 Compound of compound number 4-2017 EtCO H 5-204 Compound of compound number 4-2017 PrCO H 5-205 compound Compound No. 4-2017 iPrCO H 5-206 Compound No. 4-2017 BuCO H 5-207 Compound No. 4-2017 Compound tBuCO H 5-208 Compound No. 4-2017 Compound PhCO H 5-209 Compound No. 4 -2017 Compound MeCO Na 5-210 Compound No. '2017 EtCO Na 5-211 Compound No. 4-2017 Compound PrCO Na 5-212 Compound No. 4-2017 Compound iPrCO Na 5-213 Compound No. 4-2017 Compound BuCO Na 5-214 Compound No. 4_2017 Compound tBuCO Na 5- 215 Compound No. 4-2017 Compound PhCO Na 5-216 Compound No. 4-2017 Compound H Na 5-217 Compound No. 4-2017 Compound H Me 5-218 Compound No. 4-2017 Compound H Et 5-219 Compound Compound No. 4-2017 H Pr 5-220 Compound No. 4-2017 Compound H cPr -165- 200403244 5-221 Compound No. 4-2017 Compound H iPr 5-222 Compound No. 4-2017 Compound Η Bu 5- 223 Compound of compound number 4-20172017 cBu 5-224 Compound of compound number 4-2017Η Pent 5-225 Compound of compound number 4-2017Η cPent 5-226 Compound of compound number 4-2017Η Hex 5-227 compound Compound No. 4-2017Η cHex 5-228 Compound No. 4-2017Η Ph 5-229 Compound No. 4-2017Η Bn 5-230 Compound No. 4-2017Η CH2cPent 5-231 Compound Compound No. 4-2017 Η CH2cHex 5-232 Compound No. 4-2017 Η CH20C0Me 5-233 Compound No. '2017' Compound Η CH20C0Et 5-234 Compound No. '2017' Η CH20C0Pr 5-235 Compound No. 4-20 Compound of Π CHz0C0iPr 5-236 Compound of compound number 4-20172017 CH20C0cPr 5-237 Compound of compound number 4-20174- CH20C0Bu 5-238 Compound of compound number 4-2017Η CH20C0tBu 5-239 Compound of number 4-2017 Compound Η CH20C0Pent 5-240 Compound No. 4-2017 Η CH20C0cPent 5-241 Compound No. 4-2017 Η CH20C0CH2cHex 5-242 Compound No. 4-2017 Η CH20C0Ph 5-243 Compound No. 4-2017 Compound H CH20C02Me 5-244 Compound No. 4-2017 Compound Η CH20C02Et 5-245 Compound No. 4-2017 Compound H CH20C02Pr 5-246 Compound No. 4-2017 Compound Η CH20C02iPr 5-247 Compound No. 4-2017 Compound Η CH20C02cPr 5 -248 Compound of compound number 4-20Π Η CH2OC〇2Bu 5-249 Compound of compound number 4-2017 Property㈠ CH20C02tBu

-166-

5-250 Compound of Compound No. 4-2017Η CH20C02Pen t 5-251 Compound of Compound No. 4-2017Η CH20C02cPent 5-252 Compound of Compound No. 4-2017Η CH20C02CH2cHex 5-253 Compound of Compound No. 4-2017Η CH20C02Ph 5 -254 Compound of compound number 4-20172017 CH (Me) 0C0Me 5-255 Compound of compound number 4-2017Η CH (Me) 0C0Et 5-256 Compound of compound number 4-20174- CH (Me) 0C0Pr 5-257 Compound of compound number 4-2017Η CH (Me) 0C0iPr 5-258 Compound of compound number '20172017 CH (Me) 0C0Bu 5-259 Compound of compound number 4-2017Η CH (Me) 0C0tBu 5-260 compound number 4 Compound of -2017Η CH (Me) 0C0Ph 5-261 Compound of Compound No. 4-2017Η CH (Me) 0C02Me 5-262 Compound of Compound No. 4-2017Η CH (Me) 0C0zEt 5-263 Compound No. 4-2017 Compound of compound Η CH (Me) 0C02Pr 5-264 Compound of compound No. 4-2017 Η CH (Me) 0C02iPr 5-265 Compound of compound No. 4-2017 Η CH (Me) 0C02Bu 5-266 Compound of compound No. 4-2017 Η CH (Me) 0C0ztBu 5-267 Compound No. 4-2017 Compound Η CH (Me) 0C02Ph 5-268 Compound No. 4-2017Η CHrQ 200403244 Among the compounds exemplified in Table 9 above, suitable compounds are Compound Nos. 5 -1 7, 5-31, 5-32, 5-33, 5-34, 5-35, 5-36, 5-37 '5-38, 5-39, 5-40, 5-41, 5-42, 5' 43, 5-44, 5-45, 5- 46, 5-47, 5-48, 5-49, 5-50, 5-51, 5-52, 5-53, 5-54, 5-55, 5-56, 5-57, 5-58, 5-59, 5-60, 5-61, 5-62, 5-63, 5-64 '5-65, 5-66, 5- 67, 5-84, 5-98' 5-99, 5- 100, 5-101, 5-102 '5H03, 5-104, 5-105' 5-106, 5- 107, 5-108, 5-109, 5-110, 5-111, 5-112, 5- 113, 5-114, 5-115, 5-116, 5- 117, 5-118, 5-119, 5-120, 5-121, 5-122, 5-123, 5-124 '5-125, 5-126, 5- 127 '5-128, 5-129, 5-130' 5-131, 5-132, 5H33, 5-134, 5-151, 5-165, 5- -167- 200403244 166, 5-167, 5-168, 5H69 '5-170' 5-171, 5-172 '5H73, 5-174, 5-175' 5-176, 5-177, 5-178, 5-179, 5- 180, 5-181, 5-182, 5-183, 5-184, 5-185, 5-186, 5_187, 5-188, 5-189 5-190, 5-191, 5-192, 5-193, 5-194, 5-195, 5- 196, 5-197, 5-198, 5-199, 5-200, 5-201, 5- 218 '5-232, 5-233, 5-234, 5- 235, 5_236, 5-237, 5-238, 5-239, 5-240' 5-241, 5-242, 5-243, 5- 244 '5- 245, 5-246, 5-247, 5-248, 5-249, 5_250, 5-251, 5-252, 5-253, 5-254, 5-255, 5-256, 5_257, 5-258, 5-259 '5-260, 5-261, 5-262, 5-263, 5-264, 5-265, 5-266, 5-267, or 5-268. More preferably, compound numbers 5-17, 5-42, 5-43, 5-44, 5-45, 5-46, 5-47, 5-48, 5-49, 5-50, 5-51, 5 -52, 5-53, 5-54 '5-55, 5-56, 5-57, 5-58, 5-59, 5- 60, 5-61, 5-62, 5-63, 5-64 , 5-65, 5-66, 5-67, 5-84, 5-109, 5-110, 5-111, 5-112, 5-113, 5-114, 5-115, 5-116, 5 -117, 5-118, 5-119, 5-120, 5-112, 5-122, 5-123, 5-124, 5-125, 5-126, 5-127, 5-128, 5-129 , 5-130, 5-131, 5- 132, 5-133, 5-134, 5-151, 5-176, 5-177, 5-178, 5-179, 5-180, 5-181, 5 -182, 5-183, 5-184, 5-185, 5-186, 5-187, 5-188, 5-189, 5-190, 5-191, 5- 192, 5-193, 5-194 , 5-195, 5-196, 5-197, 5-198, 5-199, 5-200, 5-201, 5- 218, 5-243, 5-244, 5-245, 5-246, 5 -247 '5-248, 5-249, 5-250, 5-251, 5- 252, 5-253, 5-254, 5 "255, 5-256, 5-257, 5-258, 5-259 , 5-260, 5-261, 5- 262, 5-263, 5-264, 5-265, 5-266, 5-267, or 5-268. Optimum compound number 5- 17, 5-53, 5-60, 5-61, 5-62, 5-63, 5-64, 5-65, 5-66, 5-67, 5-84, 5-120, 5-127, 5-128, 5-129, 5-130, 5-131, 5-132, 5-133, 5-134, 5-151, 5-187, 5-194, 5-195, 5H96, 5H97, 5-198 , 5-199, 5- 200, 5-201, 5-218, 5-254 '5-261, 5-262' 5-263 '5-264, 5-265' 5-266, 5-267, or 5 -A compound of 2 6 8. The 1 yS-methylcarbanilide derivative of the general formula (I) of the present invention can be produced by the method described in the following method A or B. -168- 200403244 [Method A] Method A is to react a carbon complex compound of formula (II a) with a sulfur hydrogen compound of formula (III), and if necessary, perform a deprotection reaction to produce compounds (I), (la) And (lb) ^ 〇〇R9 〇hsv < \ n_

OH CH3H y i-H h3c · -N- 、 COPO 丨 (Ma) (Ml) A 1 Project

R2 A 2 Engineering (IV)

(I)

(la) ❿

(lb) is a carboxy protecting group, and P2 is a "protecting group formed by a carboxy ester derivative -169- 200403244" is a "protecting group formed by a hydroxy ester derivative". The "residue protecting group" of P1 is a benzyl group which may have a substituent such as carbyl, 4.methoxypine, 4-nitrobenzyl or 2-nitrobenzyl (the substituent is such as nitro, methyl , Chlorine or methoxy); benzyl; allyl, 2-chloroallyl, or 2-methylallyl, and the like may have a substituent at the 2-position (the substituent such as chlorine or methyl The above-mentioned pharmacologically acceptable ester-forming group is preferably a benzyl group (particularly a 4-nitro group) which may have a substituent. And, "when p 1 is a" protecting group formed by a carboxyl ester derivative ", the compound (IV) includes an ester derivative of the compound VII of the present invention. The "free radical" of L1 is the radical of formula -0111 () or _3 (0) 1111. RlG is methylsulfonyl, trifluoromethanesulfonyl, ethylsulfonyl, sulfonyl, propionyl or butylsulfonyl and other C1-C4 alkylsulfonyl; benzenesulfonyl, methylbenzyl C6-C1Q arylsulfonyl groups such as fluorenyl or naphthylbenzenesulfonyl; dimethylphosphoranyl, diethylphosphoranyl, dipropylphosphoranyl, diisopropylphosphoranyl, dibutylphosphoranyl pentyl fef C! -C6 alkylphosphonium groups such as fluorenyl or monohexyl phosphate, or C6-C1G arylphosphonium groups such as diphenylphosphonium toluophosphonium, preferably diphenylphosphonium. R is such as methyl, ethyl Cl-c4 radicals such as propyl, propyl or isopropyl. Radicals, chloromethyl, fluoroethyl, chloroethyl, fluoropropyl, difluoromethyl, mono-ethyl, dichloroethyl, trifluoromethyl Halogen or C1-C4 alkyl group such as trifluoroethyl group, ethylamino group; 2-ethenylamine vinyl group; benzene which may have substituents

Fluoromethyl

® or naphthalene has the same or different substituents ~ and the other substituents are halogen, chlorine, bromine and other halogen atoms; methyl, 7 its > ethyl, 1 ¾ ¾, '' C, etc. C1-C4 alkyl; methoxy, ethyl Isopropyloxy, C4 alkoxy, etc .; methoxycarbonyl, ethoxycarbonyl, second, etc. —Joxycarbonyl (oxy); carbonyl; carbamoyl, mono or mono (C (C ^ C4 alkyl) amine and other aryl groups (the aryl group may have 1-170- 200403244 formamidine group; nitro group; via a cyano group or a cyano group) or a pyridyl or pyrimidinyl group having a substituent Heterocyclic groups that may have 1 or 2 halogen atoms (the heteroaryl group may have 1 to 3 substituents which may be the same or different. The substituent I θ 1 is halogen such as fluorine, chlorine, bromine, etc. Atoms: C, C4, such as methyl, ethyl, pendant, isopropyl; methoxy, ethoxy, propoxy, isopropoxy, and other groups; methoxyfluorene, ethoxycarbonyl, and tert-butyl Oxycarbonyl and other (Ck4Hymene, tamidine-m-like 1 ^ 4 / wuxingji) carbonyl; carbamoyl, mono- or di (Cl-C4 alkyl) carbamoyl; nitro; Or cyano).

In this method, a compound of formula (Ila) is reacted with a compound of formula (111) to produce a compound of formula (IV) (Al Engineering) in the presence of a compound. If necessary, a protective group removal reaction can be performed to produce compound (I). (A2 project), and protective groups can be introduced to obtain compounds (la) and (Ib) (A3 project and A4 project). When L1 is a formula -OR group, the starting material and the compound of formula (Πa) can be prepared according to the method described in 0 · η · sh i η et al., Heterocycles 21, 29 (19 9 4) or a known method. When L 1 or formula -S (Ο) R 1 1 is used, the starting compound (A) a) can be prepared according to the method described in JP 6-2-3 0 7 8 1 or a known method. Each project is explained below.

(Process A1) Process A1 is a process for manufacturing a compound of general formula (IV). In the presence of an inert solvent, compound (11a) is reacted with a thiohydrogen derivative of general formula (IΠ). The inert solvent used is not specific as long as it does not affect the reaction, such as dichloromethane, 1,2-dichloroethane, chloroform and other halogenated hydrocarbons; acetonitrile and other nitriles; N, N-dimethylformamide Ammonium amines such as amidine, N, N-dimethylacetamide; esters such as ethyl acetate, methyl acetate; ether, tetrahydrofuran, dioxin-171-200403244 and other ugly 'preferably acetonitrile' N, N-dimethylformamide or tetrahydrofuran, particularly acetonitrile. The test used is organic amines such as triethylamine, diisopropylethylamine, pyridine, and dimethylamine, or inorganic bases such as potassium carbonate, sodium carbonate, and sodium bicarbonate. Organic amines (specifically Should be diisopropylethylamine). The reaction temperature is usually -2 0 ° c to 4 0 r (preferably -1 0 to 20 ° C). The reaction time is 30 minutes to 108 hours (preferably w ", hours to 8 hours). After the reaction is completed, the object compound (IV) of this project can be prepared from the reaction mixture according to a conventional method. The reaction mixture or the solvent of the reaction mixture is distilled off, and the residue is added with water and an unmixed organic solvent. After washing with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography if necessary. The target compound (IV) can be used in the next project without isolation. (A2 process) A2 process is a process in which compound (IV) is converted into compound (1), and the protecting group of compound (IV) is removed to achieve it. The removal of the protecting group may be different depending on the kind of the protecting group, and it is generally used in organic synthetic chemistry, for example, T.W.Greeree, P.G.M.wut S, Protective Groups in Organic Synthesis, Second Edition, The method described in J ohn Wi i 1 ey & S ns, I nc. 1 9.1. (1) When the protecting group is a benzyl group, a benzyl group which may have a substituent, or a benzyloxycarbonyl group which may have a substituent, the protection is removed by reaction with hydrogen in the presence of a 'contact reduction catalyst in a solvent. The contact reduction catalyst used is, for example, a Pd-C catalyst, a platinum catalyst, a chromium-carbon catalyst, etc., and is preferably a Pd-C catalyst. -172- 200403244 The inert solvent used is not specific as long as it does not affect the reaction, such as alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and mixed solvents of organic solvents and water, preferably tetrahydrofuran Mixed solvent with water. The reaction temperature is usually 0 ° C ~ 50 ° C (preferably 1 (TC ~ 40 ° C)), and the reaction time depends on the raw material compound and catalyst type, usually 5 minutes to 12 hours (preferably 30 minutes) ~ 4 hours). After the reaction is completed, the target compound can be prepared from the reaction mixture according to the usual method. The insoluble matter such as the catalyst of the reaction mixture is filtered off and the solvent is distilled off. The obtained target compound can be obtained according to the usual method if necessary, such as Purification by recrystallization, layered thin layer chromatography, or column chromatography, etc. (2) When the protecting group is an allyl group which may have a substituent or when the protecting group is an allyloxycarbonyl group which may have a substituent, the This protection is based on the reaction with tri-Ci-G alkyltin hydride and the alkali metal salt of organic carboxylic acid in the presence of palladium in the solvent to remove it. An organic base or organic substance that can easily capture allyl groups can also be added. The palladium is preferably Bis (triphenylphosphine) palladium chloride or tris (triphenylphosphine) palladium. The trioxane hydride is preferably tributyltin hydride. The alkali metal salt of the organic carboxylic acid is preferably potassium 2-ethylhexanoate or 2-ethyl Sodium hexanoate. The organic base that captures allyl is preferably morpholine, and the organic that captures allyl is dimethyl ketone. Deprotection The preferred combination is a combination of bis (triphenylphosphine) palladium chloride and tributyltin hydride or a combination of (triphenylphosphine) palladium and potassium 2-ethylhexanoate. As long as the inert solvent used does not affect the reaction, There are no specific materials that can be dissolved, such as halogenated hydrocarbons such as dichloromethane, chloroform, or 1,2-dichloroethane; esters such as ethyl acetate; ethers such as tetrahydrofuran, dioxane, or 1,2-dimethoxyethane Class-173- 200403244 'Yisheng Temple Shou Song' A, ethanol or propanol; alcohol, water or its mixed solvent 'is preferably a methyl chloride, ethyl acetate or its mixed solvent. The reaction temperature is not limited, usually -2 0 ° c to 100 ° C (preferably 0 ° c to 60 t :) 'The reaction time is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours). After the reaction is completed, the target compound It can be prepared from the reaction mixture according to the usual method. The insoluble matter of the reaction mixture is filtered off and the solvent is distilled off. The obtained target compound can be obtained according to the usual method, such as recrystallization, layered thin layer chromatography, or column chromatography, if necessary. (3) When the protecting group is a silane-based protecting group, the protection is based on a solvent and treated with tetrafluoride. Ammonium, hydrofluoric acid, hydrofluoric acid-pyridine, potassium fluoride and other compounds that generate fluoride anions, or organic acids such as acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid or hydrochloric acid For removal of inorganic acids, organic acids such as formic acid, acetic acid, and propionic acid can be added to remove the fluorine anion to make the reaction proceed under mild conditions. The inert solvent used is not specific as long as it does not affect the reaction, and the raw materials for the solvent can be used. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; water; organic acids such as acetic acid and mixtures thereof Solvent: The reaction temperature is usually 0 ° C ~ 100 ° C (preferably 10 ° C ~ 30 ° C), and the reaction time is not limited, usually 1 hour ~ 24 hours (preferably 1 hour ~ 4 hours) ). After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. The required target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography. (4) When the protective group is a carboxyl group or a pharmacologically acceptable ester group formed on a hydroxyl group, these protective groups can be removed by the action of a hydrolase in water or a mixed solvent of water and an organic solvent. The solvent mixed with water is preferably water and mixed ethers or alcohols such as tetrahydrofuran, dioxane, methanol, ethanol, and propanol. Alkali metal salts such as sodium phosphate, sodium acetate, and sodium bicarbonate, and pH buffers such as phosphate buffers can be added to water or a mixed solvent of water and organic solvents to maintain p 6 between 6 and 80. The hydrolytic enzyme used is compatible with Ester-binding can be carried out without any limitation, such as esterase from pig liver. The reaction time is usually 10 minutes to 8 hours (preferably 30 minutes to 2 hours), and the reaction temperature is usually 0 ° C to 5 (TC (preferably 30 ° C to 40 ° C). After the reaction is completed, the target compound It can be isolated and purified by ion exchange chromatography, reverse phase column chromatography, reprecipitation, recrystallization, etc. According to the compound (I) obtained above, if necessary, according to pharmaceutical chemistry, it is particularly preferred to be / 3-acetamidine-based antibody. The conventional method or technology in the biological field is converted into a pharmacologically acceptable salt or ester derivative. (A 3 Project) The A 3 Project is a process for converting Compound (I) to Compound (I a) to protect the carboxyl group of Compound ⑴. The carboxyl protecting group may vary depending on the kind of protecting group, and it is generally used in organic synthesis chemistry, for example, 'T. W. Gree η, P · G. M. Wuts, by P r tectective Groups in Organic Synthesis, Second Edition, John Wiley 200403244 & S ns, I nc. 1 9 1 1. For example, the salt (preferably sodium salt) produced by the reaction of the compound (I) with a base is pre-isolated, and In the presence of a solvent and a base, the ester residue is reacted with the corresponding halide. Should be produced. The halide used, such as chloride, bromide or iodide, is preferably iodide. When chloride or bromide is used, a catalyst amount of sodium iodide can be added to promote the reaction. The base used is, for example, Organic amines such as triethylamine, diisopropylethylamine, 4-methylamine pyridine, pyridine; and alkali metal carbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably organic amines (especially 4 -Methylamine pyridine). The inert solvent used is not specific as long as it does not affect the reaction, such as nitriles such as acetonitrile; ammoniums such as N, N-dimethylformamide; halogenated hydrocarbons such as dichloromethane The reaction temperature is preferably amines (especially dimethylacetamide) or nitriles (especially acetonitrile). The reaction temperature is usually -20 ° C ~ 50 ° C (-10 ° C ~ 20 ° C), the reaction time is usually 0.5 hours to 108 hours (preferably 1 hour to 24 hours). In the presence of a condensing agent and a base, the ester residue is allowed to interact with the corresponding alcohol to perform The condensing agent is a light-delayed test agent such as diethyl azide carboxylic acid ester; a phosphate ester type condensing agent such as diphenylphosphonium azide; dicyclohexyl carbonization Carbodiimide-based condensing agents such as imine and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide; iron-based condensing agents such as iodo-2-chloro-1-formamidine ingot The base used is organic amines such as triethylamine, tributylamine, diisopropylethylamine, 4-dimethylamine pyridine, etc. -176- 200403244 Other additives are phosphines such as triphenylphosphine, tributylphosphine, etc. Alcohol formed from active esters such as 1,1-hydroxybenzotriazole. The solvents are, for example, halogenated hydrocarbons such as methylene chloride and dichloroethane; ammoniums such as N, N-dimethylformamide; nitriles such as acetonitrile; and ethers such as tetrahydrofuran. Suitable combinations are, for example, diethyl azide carboxylate and triphenylphosphine; 2-chloro-1-methylpyridine iodide and tributylamine or triethylamine; 1-ethyl-3- (3-dimethyl Aminopropyl) carbodiimide and 4-dimethylaminopyridine or 1-hydroxybenzotriazole. After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography if necessary. (A4 project) The A4 project is a process for converting compound (la) into compound (lb), which is achieved by introducing a protective group into the hydroxyl group of compound (la). The protection of the hydroxyl group varies depending on the type of the protecting group, and is generally used in organic synthetic chemistry. For example, TW Green, PGM Wuts, Protective Groups in Organic Synthesis, Second Edition, John Wiley & Sons, Inc. 1991 Come on. For example, compound (la) is reacted with a carboxylic acid in a solvent, in the presence of a condensing agent and a base, to produce compound (lb). The condensing agent is a light-delayed test agent such as diethyl azide carboxylate; a phosphate condensing agent such as diphenylphosphonium azide; dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethyl Aminopropyl) carbodiimide-based condensing agents such as carbodiimide; fluorene-based condensing agents such as iodinated 2-chloro-l-methylpyridine. -177- 200403244 The base used is, for example, organic amines such as triethylamine, tributylamine, diisopropylethylamine, and 4-dimethylaminepyridine. Other additives are alcohols formed from phosphines such as triphenylphosphine and tributylphosphine, and active esters such as 1-hydroxybenzotriazole. Suitable combinations are, for example, diethyl azide carboxylate and triphenylphosphine; iodinated 2-chloro-b methylpyridine and tributylamine or triethylamine; ethyl-3- (3-dimethylaminepropyl ) Carbodiimide and 4-dimethylaminopyridine or __hydroxybenzotriazole. The solvent is a halogenated hydrocarbon such as dichloromethane and dichloroethane; ethers such as tetrahydrofuran are preferably halogenated hydrocarbons (particularly dichloromethane). The reaction temperature is usually -2 0 ° C ~ 80 0 t (preferably -1 (TC ~ 4 0 ° C), and the reaction time is usually 0.5 hour ~ 108 hours (preferably 1 hour ~ 24 hours) After the reaction is complete, 'the target compound can be prepared from the reaction mixture according to the usual method. Add water and unmixed organic solvents to the reaction mixture or remove the residue of the solvent from the reaction mixture, and after washing with water, remove the solvent. The obtained target compound is necessary. It can be purified according to conventional methods, such as recrystallization, reprecipitation or column chromatography. This project is to make compound (1b) in a solvent in the presence of a salt and react with halogen halide or anhydride to produce compound (1b). The base is, for example, organic amines such as trimethylamine, diisopropylethylamine, pyridine, 4-dimethylaminepyridine (preferably triethylamine). The solvent is a halogenated hydrocarbon such as dichloromethane, dichloroethane, etc .; Ethers such as tetrahydrofuran; preferably halogenated hydrocarbons (especially dichloromethane). The reaction temperature is usually -20 ° C ~ 80 ° C (preferably -10 ° C ~ 40 ° C), and the reaction time is usually It is 0.5 to 108 hours (preferably 1 to 24 hours). After the reaction is completed, the target compound is It can be prepared from the reaction mixture according to the usual method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. Ordinary method 'such as recrystallization, reprecipitation or column chromatography for purification. [Method B] Method B reacts a carbon compound of formula (lib) with a sulfhydryl compound of formula (III), and performs a deprotection reaction if necessary. In order to produce compounds (lb) and (Ic).

B 1 project

Project B 2 (IVa)

V

(Ic)

B 3 Engineering V

(lb) where R, R2, r3, ^, χ, a, pi, p2, p3, and L! are as defined above. In this method, 'the compound of formula (IIb) is reacted with a chelating compound of formula (III) in the presence of a base to produce a compound of formula (IV a) (B 1 process), and the carboxy protecting group may be removed to produce the compound if necessary (I c) (B 2 project), and -179- 200403244 protecting group may be introduced to manufacture compound (1 b) if necessary (B 3 project). The raw material compound (Π b) is the hydroxyl group of compound (Ila) in method A. It is generally used in organic synthetic chemistry, for example, T.W. Green, P.G.M. Wuts, Protective Groups in

Organic Synthesis, Second Edition, manufactured by John Wiley & Sons, Inc. 1991. The following can explain each project. (Project B1) Project B1 is a process for producing a compound of general formula (IVa), and is produced by reacting compound (lib) with a sulfhydryl derivative of general formula (III) in the presence of an inert solvent and a base. This project can be implemented according to the method of A 1 project in Method A. (B2 process) The B2 process is a process for converting a compound (IVa) into a compound (Ic), and the carboxylic acid protecting group of the compound (IVa) is removed and executed. This project can be implemented according to the method of A2 project in Method A. (B3 process) The B3 process is a process for converting a compound (Ic) into a compound (Ib) by introducing a protective group into the carboxyl group of the compound (Ic). This project can be implemented according to the method of A3 project in Method A. [C method] The c method is a method for producing the compound (X) by using the compound (II) in the raw materials starting from the methods A and B. -180- 200403244

In the formula, 'R1, η, and X are as defined above, and P is hydrogen or a silicon-containing group (for example, trimethylsilyl). P4 is a carboxy protecting group, such as C ^ C4 alkyl such as methyl, ethyl, propyl, butyl and the like; benzyl, 4-methoxybenzyl and the like may be substituted with benzyl, preferably alkyl (especially as Ethyl). P5 is a hydroxy-protecting group, for example, a silyl-based protecting group such as trimethylsilyl, triethylsilyl, tertiary butadiylsilyl, tertiary butadiphenylsilyl, etc., and is preferably a tertiary butadiphenylsilyl group. (C 1 Project) The C 1 Project is a process in which a nitrogen atom of the compound (V) is introduced into the amine group of the formula c (= X) NH2 to produce the compound (VI). (1) This project is to make compound (V) in a solvent 'with cyanate, thiocyanate or silicon-containing isocyanate (preferably silicon-containing isocyanate, and also Sanyuan Shixi Alkane isocyanate, more preferably trimethylsilane isocyanate). The solvent used is not specific as long as it can dissolve the raw materials without affecting the reaction ', for example, ethers such as tetrahydrofuran and diethyl ether; halogenated hydrocarbons such as methylene chloride and dichloroethane; and a mixed solvent of solvent and water' is preferably methylene chloride. , Ammonium salt or

The salt of cyanic acid or thiocyanic acid is a metal salt such as sodium salt, potassium salt, etc. -181- 200403244 Organic ammonium salt such as diethylammonium salt, etc., preferably an alkali metal salt (especially a potassium salt). Also, 'cyanate or thiocyanate can be converted to the corresponding acid using an acid. These acids are, for example, organic acids such as acetic acid, and inorganic acids such as hydrochloric acid, preferably acetic acid or hydrochloric acid. The reaction temperature is usually -20 ° C ~ 150 ° C (preferably-lot: ~ i〇 (Tc), and the reaction time is usually 0.5 hours to 108 hours (preferably 1 hour to 24 hours). Reaction After the end, the target compound can be prepared from the reaction mixture according to the usual method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. Purify by conventional methods, such as recrystallization, reprecipitation, or column chromatography. When the compound (VI) produced in this project contains a silyl group, the compound can be used in the next project. (2) This project consists of the following The method is completed. This method is a process for producing the following compound (XXXII) from compound (V), and a process for producing compound (VI) from compound (XXXII).

(XXX! I) wherein X and η are as defined above, and 卩 1 () is an alkyl group (preferably an ethyl group). The process of producing compound (XXXII) from compound (V) is carried out by reacting compound (ν) in a solvent with a compound of formula X = C = N-COOP1G (wherein X and PIG are as defined above). The solvent used is not specific as long as it does not affect the reaction, and can dissolve the raw materials, such as ethers such as tetrahydrofuran and ether; halogenated hydrocarbons such as dichloromethane and dichloroethane; and mixed solvents of solvents and water, preferably ethers or ether A mixed solvent with water (especially tetrahydrofuran or a mixed solvent of tetrahydrofuran and water). -182- 200403244 The reaction temperature is usually -20 ° C ~ 150 ° C (preferably -10t ~ 50t), and the reaction time is usually 0.5 ~ 108 hours (preferably 1 hour ~ 24 hours). After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography if necessary. The process for producing compound (VI) from compound (XXXII) is performed by reacting compound (XXXII) with a base in a solvent. The solvent used is not specific as long as it does not affect the reaction, and it can dissolve the raw materials. For example, alcohols such as methanol and ethanol, tetrahydrofuran, ethers and other ethers, and solvents and water mixed solvents, preferably alcohols or alcohols and water. Solvent (especially ethanol or a mixed solvent of ethanol and water). Examples of the base to be used include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, and potassium carbonate, and organic bases such as sodium methoxide and sodium ethoxide, and sodium oxyhydroxide is preferred. The reaction temperature is usually -20 ° C ~ 15 ° c (preferably -10 ° C ~ 100 ° c), and the reaction time is usually 0.5 hours to 108 hours (preferably 1 hour to 24 hours). After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography if necessary. (C 2 process) The C 2 process is a process in which the amine group of the compound (VI) undergoes a ring-closing reaction to produce the compound (VII). -183- 200403244 In this project, the compound (ιν) is reacted with a compound of the formula R] CHL5COCOOP4 (where R1 and P4 are as defined above, and L5 is an ionic group) in the presence of a base to perform. The radical of L 5 should preferably be halogen, particularly preferably desert. The solvent used does not affect the reaction as long as it can dissolve the raw materials. For example, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and ether, halogenated hydrocarbons such as dichloroethane and dichloroethane, N, N- Dimethylformamide and other amidines are preferably alcohols (especially ethanol). The bases used are, for example, organic bases such as diethylamine, monoisopropylethylamine, and inorganic bases such as potassium carbonate, sodium carbonate, and sodium carbonate, and are preferably organic tests (especially zr ethylamine). The reaction temperature is usually -2CTC ~ 15 (TC (preferably -lot ~ loot), and the reaction time is usually 0.5 hours to 108 hours (preferably 1 hour to 24 hours). After the reaction is completed, the target compound can be reacted by ordinary methods. The mixture is prepared. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture. After washing with water, the solvent is distilled off. The obtained target compound can be re-crystallized, re-precipitated or Purification by column chromatography. (C3 project) The C3 project is a process in which a protective group P5 is introduced into the hydroxyl group of the compound (VII) to produce the compound (V 111). This project is generally used in organic synthetic chemistry, for example, T.W . Green, PGM Wuts by 'Pi.otective Groups in Organic

Synthesis, Second Edition, John Wiley & Sons, Inc. 1991 describes the introduction of a silane-based protective group in which the compound (VI1) is in a solvent, and the base is -184- 200403244. Halogen or silane trifluoride reaction to perform. Silane halides are, for example, trimethylsilyl chloride, triethylsilyl chloride, tertiary butyldimethylsilyl chloride, tertiary butyldiphenylsilyl chloride, and preferably tributyldiphenylsilyl chloride. Silane trifluoride species are, for example, trimethylsilane trifluoride, triethylsilane trifluoride, third butyldimethylsilane trifluoride, third butyldiphenylsilane trifluoride, and preferably third butyldibenzene Silane trifluoride. The solvent used is not specific as long as it does not affect the reaction and can dissolve the raw materials. For example, amines such as dimethylformamide and ethers such as halogenated hydrocarbons such as dichloromethane and dichloroethane, such as tetrahydrofuran and ether, are preferred. Amines (especially dimethylformamide) or halogenated hydrocarbons (especially dichloromethane). The base used is, for example, an organic base such as imidazole, triethylamine, dimethylpyridine, pyridine, dimethylaminopyridine, etc., preferably imidazole or 2,6-dimethylpyridine. The reaction temperature is usually -2 0 ° C to 50 ° C (preferably -1 0 ° C to 4 0 t), and the reaction time is usually 0.5 hours to 108 hours (preferably 1 hour to 24 hours). ). After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography if necessary. (C 4 process) The C 4 process is a process for reducing a carboxylate group of a compound (VIII) to a methylol group to produce a compound (IX). This process is performed by reacting compound (VIII) in a solvent with a reducing agent. The reducing agent used is not limited to -185- 200403244 for those that can reduce the carboxylate group to methylol, for example, alkali metal aluminum hydrides such as lithium aluminum hydride, lithium borohydride, sodium borohydride and other alkali metal boron The hydride is preferably lithium aluminum hydride. The solvent used is not specific as long as it does not affect the reaction and can dissolve the raw materials. For example, ethers such as tetrahydrofuran and diethyl ether are preferably tetrahydrofuran. The reaction temperature is usually -20 ° c ~ 100 ° C (preferably -10 ° c ~ 40r), and the reaction time is usually 10 minutes to 24 hours (preferably 0.5 hour to 24 hours). After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. If necessary, the obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography. (C5 process) The C5 process is a process for oxidizing the methylol group of the compound (IX) to obtain the compound (χ). In this project, the compound (IX) is made in a solvent and reacted with an oxidizing agent, and the methyl group is oxidized to obtain an acid group, and the @ 1 group is oxidized to obtain a residue. (1) Oxidation of methylol groups to obtain aldehyde groups® The oxidant used is not limited to those that can oxidize methylol groups to obtain aldehyde groups, such as pyridinium chlorochromate, chloracetin-dimethylaniline, Anhydrous trifluoroacetic acid-dimethylarsine, active manganese dioxide, Desmartin reagent, preferably active dioxide. The solvent used is not specific as long as it does not affect the reaction, and it can dissolve the raw materials. For example, halogenated hydrocarbons such as dichloromethane and dichloroethane are preferred as dichloromethanes. The reaction temperature is usually -100C to 100C (preferably -100 ° C to 50 ° C), and the reaction time is usually 30 minutes to 108 hours (preferably 1 hour to 2 hours). -186- 200403244 After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography if necessary. (2) The oxidant used in the oxidization of aldehyde groups to obtain carboxyl groups is not specific as long as it can oxidize aldehyde groups to carboxyl groups, such as potassium permanganate, ruthenium tetroxide, sodium chlorite-sodium dihydrogen phosphate (or potassium sulfide) Methyl-2-butene is preferably sodium chlorite-sodium dihydrogen phosphate-2 -methyl · 2-butane. The solvent used is not specific as long as it does not affect the reaction and can dissolve the raw materials, such as methylene chloride Halogenated hydrocarbons such as dichloroethane, acids such as tetrahydrofuran and diethyl ether, alcohols such as tertiary butanol, and water mixed solvents thereof are preferably mixed solvents of tetrahydrofuran-dichloromethane-water-tertiary butanol. The reaction temperature is usually It is -20 ° C to 50 ° C (preferably -10 ° C to 40 °. (:), and the reaction time is usually 10 minutes to 103 hours (preferably 0.5 hours to 24 hours). After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. Water and an unmixed organic solvent are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. It can be purified by usual methods, such as recrystallization, reprecipitation or column chromatography. (C6 Project) The C6 project is another way to manufacture the carboxyl compound (X), and the protective group of the compound (VIII) is removed. This process can be carried out according to the method of the second A project in the A method. [D method] The D method is used Method A and method B starting from raw materials to produce compounds (Ilia) -187- 200403244

(XII) 0 R9 ‘EtS’, 〇 ’'Cly NH Cl R2

HN0N ° (X.V) ° '

(XV) (XVI) l2 ^ n ^ An0n X, \ R1 〇 X (XVII) D 6

pascH

or ‘(XVI I la) D7 Engineering HS,

〇 N

nt ^ nCZ ^, 〇 × 人 FT

Έ1

R " (Ilia) -188 200403244 where R1, R2, R3, η, X and P5 are as defined above, P6 is a carboxy protecting group, such as a third butyl group; benzyl, 4-methoxybenzyl, etc. may have The benzyl group of the substituent is preferably a benzyl group (particularly 4-nitrobenzyl) which may have a substituent. L2 is a radical, such as halogens such as chlorine, bromine, and iodine; methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, tosylsulfonyloxy and the like may be substituted Ci-C * alkanesulfonyloxy or benzenesulfonyloxy which may be substituted by alkyl is preferably alksulfonyloxy which may be substituted by fluorine. The following formula

Is the following formula in A

(In the formula, P, q, 1, · s, and Aik are as defined above. If the nitrogen atom to which R3a is bonded is bonded to the group -C02CH (R9) 0C0R2, it has the same meaning as R3 except for the hydrogen atom. When the nitrogen atom of the -C02CH (R9) 0C0R2 group is bonded, it has the same meaning as R3. If the nitrogen atom of R4a and R5a is bonded to the -C〇2CH (R) 〇COR ** group, the R4a ammonia-removing atom In addition, it has the same meaning as R4. The definition of R5a is as described above. When R5, the nitrogen atom bound to R4a is not combined with the formula • C02CH (R9) 〇COR2 group, the definition of R4a is as described above. Same meaning). Pa is a (CrG alkyl) ore group (such as ethenyl). An arylcarbonyl group which may have a substituent (such as benzamidine) or an aralkyl group which may have a substituent (such as benzyl or methoxybenzyl), preferably For ethenyl. (D1 process) The D1 process is a process for manufacturing a compound of general formula (XIII). In an inert solvent 200403244 and the presence of a base, the compound (XI) is reacted with ethyl chloroformate (XII) to be carried out. The solvent used is not specific as long as it does not affect the reaction and can dissolve the raw materials, such as halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; ethers such as diethyl ether, tetrahydrofuran, and dioxane, which are preferably halogenated hydrocarbons (Especially dichloromethane). The base used is, for example, an organic amine such as triethylamine, diisopropylethylamine, pyridine, dimethylamine, or pyridine, and is preferably triethylamine or dimethylaminepyridine. The reaction temperature is usually -20C to 80C (preferably -10C to 40 ° C), and the reaction time is usually 30 minutes to 108 hours (preferably 1 hour to 24 hours). Φ After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography if necessary. The target compound can also be used directly in the next project without isolation. The starting compound of formula (XII) can be produced according to the method described in Synthesis 1 99 0, 1 159 or a standard method. (D2 process) φ D2 process is a process for converting compound (XIII) into compound (XIV) by removing the C02P6 group in compound (XIII). (1) When P 6 is a benzyl group which may have a substituent, C 0 2 P 6 is removed in a solvent based on reaction with hydrogen in the presence of a contact reduction catalyst. The contact reduction catalyst used is, for example, a Pd-C catalyst, a platinum catalyst, a chromium-carbon catalyst, etc., and is preferably a P d -C catalyst. The solvent used is not specific as long as it does not affect the reaction and can dissolve the raw materials. -190- 200403244 For example, alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and mixed solvents of organic solvents and water, preferably alcohols. (Especially methanol or ethanol). The reaction temperature is usually 0 ° C ~ 50 ° C (preferably 10 t ~ 4 0 ° c). The reaction and time depend on the type of raw material compound and catalyst, usually 5 minutes ~ i 2 hours (preferably 3 minutes) 0 minutes to 4 hours). After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. It is obtained by filtering off insoluble matters such as the catalyst of the reaction mixture, and distilling off the solvent. The obtained target product can be purified according to a conventional method such as recrystallization, layered thin-layer chromatography, or column chromatography if necessary. (2) When P is di-dibutyl ', co2P6 is removed by reaction with an acid in a solvent. The solvent used is not specific as long as it does not affect the reaction, and can dissolve the raw materials, such as halogenated hydrocarbons such as dichloromethane, 152-dichloroethane, and chloroform; ethers such as tetrahydrofuran and dioxane. The acid used is, for example, an organic acid such as trifluoroacetic acid; the inorganic acid such as hydrochloric acid or sulfuric acid is preferably trifluoroacetic acid or hydrochloric acid. The reaction temperature is usually -20 ° C ~ 80 ° C (preferably -10 ° C ~ 4CTC). The reaction time depends on the types of raw materials and catalysts, usually 30 minutes ~; 〇8 hours (and 1 Hours ~ 2 4 hours). After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. It is obtained by filtering off insoluble matters such as the catalyst of the reaction mixture, and distilling off the solvent. The obtained target compound may be purified by a conventional method such as recrystallization, layered thin layer chromatography, or column chromatography, if necessary. -191- 200403244 (D3 Project) The D3 Project is a process for manufacturing compounds of general formula (XV). The compounds (XIV) are reacted with the compound (χ) in an inert solvent in the presence of a base. The solvent used is not specific as long as it does not affect the reaction, and can dissolve the raw materials, such as halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; nitriles such as acetonitrile; Ν, Ν-dimethylmethdonamine , Ν, Ν-dimethylacetamide and other amines; ethyl acetate, methyl acetate and other esters; ethers, tetraaminofuran, Ershuyuan and other ethers' preferably dichloromethane, acetonitrile, Ν, N-dimethylformamide or tetrahydrofuran 'is particularly N, N-dimethylformamide. The base used is, for example, organic amines such as triethylamine, diisopropylethylamine, pyridine, dimethylamine pyridine, or inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably organic amines (especially three Ethylamine). As the condensing agent, a phosphoric acid ester-based condensing agent such as diphenylphosphonium azide, or a carbonyl diimidazole carbonate-based condensing agent can be used. Preferably, diphenylphosphine azide and carbonyl diimide are used. The reaction temperature is usually -20 ° c ~ 40 ° c (preferably -lot ~ 20 ° c), and the reaction time is usually 30 minutes to 1.08. Hours (preferably 1 hour to 18 hours). At the end of the reaction, the compound (X V) of this project can be prepared from the reaction mixture according to a conventional method. Add water and unmixed organic solvents to the reaction mixture or evaporate the solvent residue from the reaction mixture. After washing with water, evaporate the solvent. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography if necessary. The target compound (XV) can be directly used in the next project without isolation. (D 4 process) The D 4 process is a process for converting a compound (X V) into a compound (X V I), which is achieved by removing a protective group of a chemical 200403244 compound (x v). This project can be implemented according to the method of a 2 project in Method A. (D5 process) The D5 process is a process in which the hydroxyl group of the compound (XVI) is converted to the compound (XVII) by using the radical L2. (1) When the ionic group L2 is various expanded oxygen groups This project is achieved by reacting the compound (XVI) in a solvent with a sulfonating agent in the presence of a base. The sulfonating agent used is, for example, methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, etc., and preferably is methanesulfonyl chloride. The solvent used is not specific as long as it does not affect the reaction, and can dissolve the raw materials. For example, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, ethers such as tetrahydrofuran, ether, etc., are preferably halogenated hydrocarbons (especially dichloromethane). ). The base used is, for example, an organic base such as triethylamine, diisopropylethylamine, pyridine, dimethylamine, or pyridine, and preferably triethylamine. The reaction temperature is usually -2 (TC ~ 80 ° C (preferably -10 ° C ~ 40 ° C)), and the reaction time is usually 0.5 hours to 108 hours (preferably 1 hour to 24 hours). After the end, the object compound (IV) of this project can be prepared from the reaction mixture according to the usual method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent distilled from the reaction mixture, and after washing with water, the solvent is distilled off. If necessary, the target compound can be purified according to ordinary methods, such as recrystallization, reprecipitation or column chromatography. (2) When the ionic group L2 is a halogen atom, the project is achieved by reacting the compound (XVI) in a solvent with a halogenating agent. 200403244 The halogenating agents used are, for example, phosphorus pentachloride, sulfenyl chloride, phosphorus oxychloride, iodine, carbon tetrabromide, carbon tetrachloride, N-chlorobutanediimide, bromobutanediamine Amine, diethylamine sulfonate trifluoride is preferably carbon tetrabromide. The solvent used is not specific as long as it does not affect the reaction and can dissolve the raw materials, such as halogenated hydrocarbons such as dichloromethane and dichloroethane, tetrahydrofuran, ether, etc. Ethers, preferably halogenated hydrocarbons (especially dichloromethane). The additives used are Phosphines such as triphenylphosphine and tributylphosphine are preferably triphenylphosphine. The reaction temperature is usually -20 ° C ~ 100Ϊ: (preferably -10 t ~ 50 ° C), and the reaction time is usually 10 minutes to 1 0 8 hours (preferably 0.5 hours to 24 hours). After the reaction is completed, the target compound (IV) of this project can be prepared from the reaction mixture according to a conventional method. Water is added to the reaction mixture or the solvent residue is distilled off from the reaction mixture to add water And unmixed organic solvent, after washing with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography if necessary. (D6 Project) D6 Project is to separate the compound (χνιΐ) Acetylation of radical l2 and conversion to sulfhydryl group to obtain compound (XVIIIa). This project is achieved by reacting compound (XV 11) in a solvent with a hydrogenating agent. The sulfur gasifying agent used is, for example, sulfur Sodium acetate, thionium thioacetate, sodium thiopropionate, etc. c 2-C 7 aliphatic sulfur residual acid test metal salts, sodium thiobenzoate, etc. can be substituted metal test salts or 4 -methoxy; sulfur hydrogen Alkali metal salts which can be substituted, such as alkali metal salts, are preferably potassium thioacetate. -1 94- 200403244 The gluten used is not specific as long as it does not affect the reaction, and can dissolve the raw materials. For example, ethers such as tetrahydrofuran and ~ pentane, esters such as ethyl acetate and methyl acetate, and nitriles such as acetonitrile. Acid amines such as formamidine and dimethyl ethylamine are also amines (especially dimethylformamide). The reaction temperature is usually-20t: ~ 15 (rc (preferably 0t: ~ 10 (rc), the reaction time is 0.5 hours to 108 hours (preferably 丨 hours to 24 hours). After the end of the reaction, 'the object compound (IV) of this project can be prepared from the reaction mixture according to a conventional method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography if necessary. (D7 process) The D7 process is a process for obtaining the compound (Ilia) by removing the sulfanyl group of the compound (xVIIIa). This project is to make the compound (XV II la) in a solvent and react with the hydrazine compound salt. The hydrazine compound salt is, for example, hydrazine · acetic acid, N, N-dimethylhydrazine · acetic acid, and preferably hydrazine · acetic acid. The solvent used is the same as that used in the aforementioned A 1 process. The reaction temperature is not specific, usually -10 ° C ~ 40 ° C (preferably 1 (TC ~ 30 ° C), the reaction time depends on the solvent, the reaction temperature and the type of reaction reagent, usually 30 minutes to 24 hours (It is preferably 1 hour to 8 hours.) After the reaction is completed, the target compound can be prepared from the reaction mixture according to the usual method. Water is added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture and the mixture is not mixed -195- 200403244 After the organic solvent is washed with water, the solvent is distilled off. The obtained target compound can be purified by conventional methods such as recrystallization, reprecipitation or column chromatography if necessary. When a hydrazine compound salt is used as a deprotecting agent, the compound (Π 丨 a) It can be obtained by using the raw materials of the A 1 process or the B 1 process without isolation from the reaction solution. This process is achieved by reacting the compound (XVIII a) in a solvent with a base. The base used is, for example, sodium hydroxide, hydrogen Salts of alkali metals such as potassium oxide, potassium carbonate, sodium carbonate, sodium methoxide, and sodium ethoxide are preferably sodium methoxide. The solvent used is not specific as long as it does not affect the reaction and can dissolve the raw materials, such as alcohols such as methanol and ethanol Class, tetrahydrofuran, Ethers such as ethers, ammoniums such as dimethylformamide, halogenated hydrocarbons such as dichloromethane, dichloroethane, etc., are preferably alcohols (especially methanol). The reaction temperature is usually -20 ° C ~, 1 0 0 ° C (preferably -10 0 to 4 0 ° C), the reaction time is usually 10 minutes to 108 hours, preferably (0.5 hours to 24 hours). After the reaction is completed, the target compound It can be prepared from the reaction mixture according to the usual method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture. After washing with water, the solvent is distilled off. Purification by recrystallization, reprecipitation, or column chromatography. [Method E] Method E is a method for producing the compound (XVIIIb) by starting from the starting compound (III) using methods A and B. 200403244

OH HN A ”(XIX) P50.

μ XOOH ⑴

〇 p5〇cK

N A

L3

R6 I NH (XX)

(XXV) ❿

(XXVI)

(XVI lib) -197- 200403244 where R, R, R, n, X, p5 and pa are as defined above, r6 $ is defined as R3, R4, or R5, preferably hydrogen, and P7 is a carboxy protecting group, such as Tributyl; phenyl, 4-methoxy; benzyl, which may have a substituent, such as tributyl, preferably tert-butyl. L3 and L4 are each an ionic group, for example, halogens such as chlorine, bromine, and iodine; The C! -C4 alkanesulfonyloxy group substituted by fluorine or the benzenesulfonyloxy group which may be substituted by alkyl group is preferably a Cl_C4 alkanesulfonyloxy group which may be substituted by fluorine. The following formula

OH is where A is

HO

R5 or, Alk, R4

OH (where R4, R5, p, q and Aik are as defined above). (E 1 process) The E 1 process is a manufacturing process of a compound of general formula (XX), which is achieved by reacting compound (XIX) with compound (X) in an inert solvent in the presence of a base. This project can be implemented according to the method of D 3 project in D method. (E2 process) The E2 process is a process of introducing the radical L3 into the compound (XX) to produce the compound (XXI). This project can be implemented according to the method of D 5 project in D method. (E3 process) The E3 process is a compound in which R5 is hydrogen from compound (XXI) to produce an amine compound (XXHa) [compound -198-200403244 (XXII). ], If necessary, a substituent can be introduced to obtain the compound (XXIIb) [Compound (χχΙΙ) R6 is a compound other than hydrogen] engineering. (A) Manufacturing process of amine compound (XXIIa) This project is to make compound (XXI) in a solvent and react with an aminating agent. Alternatively, the compound (X X I) is reacted with an azide agent in a solvent to produce an azide compound 'and then reacted with a reducing agent. (1) The solvent used in the method using an aminating agent is not specific as long as it does not affect the reaction, and can dissolve the raw materials, such as methylamines such as methylformamide, alcohols such as methanol and ethanol, tetrahydrofuran, and ether Other ethers are preferably amidoamines (especially dimethylformamide). Examples of the aminating agent used are primary-substituted alkylamines such as methylamine and ethylamine; aniline'amine thiazole and other aromatic amines; secondary-substituted alkylenes such as methylethylamine and dimethylamine Amines and their amine salts (e.g. hydrochloride). Preferably, they are primary or primary substituted alkylamines and their salts (especially methylamine hydrochloride or dimethylamine hydrochloride). The reaction temperature is usually 〇 t ~;! 〇 t (preferably i Ot ~ 1 〇 t), the reaction time is usually 0.5 hours ~; [〇 8 hours (preferably 1 hour ~ 24 hours). After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography if necessary. (2) The solvent used in the method using azide and reducing agent is not specific as long as it does not affect the reaction and can dissolve the raw materials. For example, amines such as dimethylformamide, alcohols such as methanol and ethanol, and tetrahydrogen Furan-199-200403244 ethers such as sulfan and diethyl ether are preferably amidoamines (especially dimethylformamide). The azide is an alkali metal azide such as sodium azide, lithium azide, etc., and is preferably an alkali metal sodium azide (especially sodium azide). The reaction temperature is usually 0 ° C to 150 ° C (preferably 10 ° c to 100 ° c), and the reaction time is usually 0.5 hour to 108 hours (preferably 1 hour to 24 hours). After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography if necessary. The obtained azide compound can be subjected to a reduction reaction to obtain an amine compound (XXII a). The reducing agent used is, for example, an alkali metal aluminum hydride such as lithium aluminum hydride, a phosphine such as triphenylphosphine, and a metal hydride reducing agent such as Pd-C or a platinum catalyst. It should be in contact with a hydrogenation reducing agent (especially Pd-C). The solvent used is not specific as long as it does not affect the reaction, and can dissolve the raw materials. For example, ethers such as tetrahydrofuran and diethyl ether, alcohols such as methanol and ethanol, and ethers (particularly tetrahydrofuran) are preferred. Cereals used in contact with vaporizers are alcohols such as methanol and ethanol. Methanol is preferred. The reaction temperature is usually -10 ° c to 150 ° c (preferably 0 ° C to 100 ° c), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours). After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography if necessary. -200- 200403244 (B) Manufacturing process of compound (XXIIb) This project is a process of introducing a substituent into an amine compound (XX Π a) to produce a compound (XXIIb), if necessary. This project is achieved by reacting an amine compound (XXIIa) with a halogenating agent, a sulfonating agent, a phosphating agent, and a chloroformate in the presence of a base. The halogenating agents are acid anhydrides such as acetic anhydride and benzyl anhydride, acetic acid chloride, and acid chlorides, such as acetic acid, and preferably acetic acid (especially acetic acid). The sulfonating agents are sulfonium chloride such as methanesulfonyl chloride, p-toluenesulfonyl chloride, and other anhydrides such as methanesulfonyl anhydride and p-toluenesulfonyl anhydride, preferably sulfonium chloride (especially methanesulfonyl chloride). Lu Phosphorating agents are tritium gases such as diethylphosphonium chloride, dimethylphosphonium chloride, etc., preferably diethylphosphonium chloride. The chloroformates are ester compounds such as methyl chloroformate, ethyl chloroformate, and chloroformic acid; the esters are preferably ethyl chloroformate (especially methyl chloroformate). The base used is, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine, etc., and inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, etc., preferably organic bases (particularly triethylamine). The solvent used is not specific as long as it does not affect the reaction, and can dissolve the raw materials. * For example, ethers such as tetrahydrofuran and diethyl ether; halogenated hydrocarbons such as dichloromethane and dichloroethane are preferably ethers (particularly tetrahydrofuran). The reaction temperature is usually 0 ° C ~ 100 ° C (preferably 10 ° C ~ 50 ° C), and the reaction time is usually 0.5 hours ~ 丨 8 hours (preferably 1 hour ~ 24 hours) . After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. After the reaction, the combined solution or the residue of the solvent distilled from the reaction mixture is added with water and the unmixed organic solvent is washed with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography when necessary. (E4 project) The E4 project is a process for producing an amine compound (XXI la) from compound (XX) through an azide compound, and if necessary, introducing a substituent to produce (XX lib). (A) Manufacturing process of azide compound This project is to make compound (XX) in a solvent, together with an azide agent (preferably diphenylphosphonium azide), diethyl azide dicarboxylate, and triphenylphosphine The response was reached. The solvent used is not specific as long as it does not affect the reaction, and can dissolve the raw materials. For example, amines such as dimethylformamide, ethers such as methanol and ethanol, and ethers such as tetrahydrofuran and ether, preferably ethers (especially as Tetrahydrofuran). The reaction temperature is usually Ot ~ 50 ° C (preferably 10 ° C ~ 30 ° C), and the reaction time is usually 0.5 hour to 108 hours (preferably 1 hour to 24 hours). After the reaction is completed, the target compound can be prepared from the reaction mixture according to a conventional method. Water and unmixed organic solvents are added to the reaction mixture or the residue of the solvent is distilled off from the reaction mixture, and after washing with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or column chromatography if necessary. (B) Manufacturing process of amine compound This project is a process of reducing azide compound to obtain amine compound (XXII a), which can be carried out according to the above-mentioned reduction process of E3 project (A) (1). (C) Manufacturing process of compound (XXIIb) This process is a process for manufacturing (XXIIb) by introducing a substituent into an amine compound (XXIIa) as needed, and can be carried out according to the method of the above-mentioned E3 project (B). (E5 project) E5 project is a process for manufacturing compounds of general formula (XXIII), and can be generally used in the method of -202- 200403244 organic synthesis chemistry ', for example, T. W. Gree η, P. G. M. W uts, Protective Groups in Organic Synthesis, Second Edition, John Wiley & Sons, Inc. 1991 达成 The method has been achieved. (E6 project) The E6 project is a process for converting a compound (X X 111) into a compound (χ χ I V), and the protective group of the compound (XXIII) is removed and reached. This project can be carried out according to the method of A 2 project in the above A method. (E7 process) The E7 process is a process for converting the hydroxyl group of the compound (XXIV) into an ionic L4 to produce a compound (XXV). This project can be carried out according to the method of D 5 project in the above D method. (E8 process) The E8 process is a process of converting the acetylated group L4 of the compound (XXV) to sulfhydryl to obtain the compound (XXVI). This project can be carried out according to the method of D 6 project in the above D method. (E9 process) The E9 process is a process for converting a compound (XX VI) into a compound (χχν n). The reaction is performed in an inert solvent with an acid to remove the CO2P7 group in the compound (XXVI). The solvent used is not specific as long as it does not affect the reaction and can dissolve the raw materials, such as ethers such as tetrahydrofuran and diethyl ether, methylene chloride, dichloroethane, and the like. The acids used are organic acids such as trifluoroacetic acid; inorganic acids such as hydrochloric acid. -203- 200403244 After the reaction, the target compound is obtained by e.g. evaporating the solvent and drying it, and filtering the crystals precipitated in the solvent. (E10 process) The E10 process is a process for producing a compound of general formula (xvnib). The compound (XXVII) is reacted with a chloroformate of general formula (χπ) in an inert solvent and in the presence of a base. This project can be carried out according to the method of D1 project in the above D method. [F method] The F method is a method for producing a compound (X X111 a) by starting from a raw material compound (II) using a method A and a method β.

(XIX)

HN

OH

OH F2 Engineering P, X 0

p9 where R1 '

r71n

(XXVIII)

(XXIX)

As defined above, P8 is a carboxyl protecting group, such as Ci_C4 alkyl such as methyl, ethyl, propyl, τ and the like; benzyl-204-200403244, which may be substituted, such as benzyl, Imethoxybenzyl, etc., is preferably Benzyl which can be substituted (preferably benzyl). R7 is defined as R3, R4 or R5, and is preferably hydrogen. p9 is a carboxy protecting group, such as a third butyl group; benzyl, 4-methoxypentyl and the like may be substituted with a benzyl group, and is preferably a third butyl group. (F1 process) The F1 process is a process for manufacturing a compound of general formula (χχνιΙΙ). The compound (χιχ) is reacted with a chloroformate represented by the formula C1C02P8 in an inert solvent and in the presence of a base. This project can be carried out according to the method of D 1 project in the above D method. (F2 project) The F2 project is a process for manufacturing a compound of general formula (χχιχ), and can be carried out according to the method of E2 project and E3 project, or E4 project in the above method. (F3 project) The F3 project is a process for manufacturing a compound of the general formula (XX). The compound (XXIX) is reacted with a chloroformate represented by the formula C1C02p9 in an inert solvent and in the presence of a base. This project can be carried out according to the method of D 1 project in the above D method. (F4 process) The F4 process is a process for converting a compound (X X X) into a compound (X X X 1). The reaction is performed in an inert solvent with an acid to remove the formula C02P8 group contained in the compound (XXX). This project can be carried out according to the method of E 9 project in the above E method. (F5 process) The F5 process is a process for manufacturing a compound of general formula (XX III a). The compound (XXXI) is reacted with the compound (X) in an inert solvent and in the presence of a base to reach -205- 200403244. This project can be carried out according to the method of d 3 in the above D method. The compound of the general formula (I) of the present invention or a pharmacologically acceptable salt or an ester derivative thereof is shown to contain gram-positive bacteria such as staphylococcus and subtilis, coliform, pneumococcus, red bacterium, proteus, serratia A wide range of pathogenic bacteria such as Gram-negative bacteria such as Enterobacter and anaerobes such as Bacteroides fragile have strong and balanced antibacterial activity, especially suitable for pathogens such as pneumococcus (including penicillin-resistant bacteria) and influenza against respiratory infections. Haemophilus (containing bacteria that can produce ^ · lactamase) has strong antibacterial activity. The compound (1) of the present invention has high stability to various / 3-lactamase enzymes other than metal- / 3-lactamase enzyme. When the compound (I) of the present invention can be administered orally or non-orally (preferably orally) to a subject, due to high blood concentration, long half-life in blood, and excellent dynamics in the body, the agent can reduce the number of administrations And low dosage to achieve the effect of treating infections. The compound (I) of the present invention has low toxicity to the kidney. Therefore, the compound of the general formula (I) or its pharmacologically acceptable salt or its ester derivative of the present invention can be used as medicine, especially for the treatment or prevention (especially suitable) of pathogenic bacteria by bacterial infections of various pathogenic bacteria, especially respiratory infections. Antibacterial agents for diseases. When compound (I) or its pharmacologically acceptable salt or its ester derivative is used as medicine, especially as an antibacterial agent, it can be used alone or in combination with appropriate pharmacologically acceptable excipients, diluents, etc., such as tablets or capsules. Preparations, granules, powders or syrups orally or parenterally. This formulation can use excipients (for example, sugar derivatives such as lactose, white sugar, glucose, #mannose, sorbose; corn starch, potato starch, alpha powder, dextrin and other source powder derivatives, crystalline cellulose Cellulose derivatives such as low-substituted propyl, cellulose-206-200403244, propyl methyl cellulose, xiao methyl cellulose, xiao methyl cellulose, internal bridged carboxymethyl cellulose sodium; acacia gum ; Polydextrose; Polytribuose; Light sand anhydride, sodium oxalate, magnesium meta sandate, and other salt derivatives of salt I; gastric acid derivatives, such as carbonate derivatives: carbonate derivatives, etc. ; Sulfate derivatives such as calcium sulfate, etc.), binding agents (for example, the above-mentioned excipients; gelatin; polyvinylpyrrolidone; polyethylene glycol, etc.), disintegrating tablets! I (for example, the above-mentioned excipients; nail fiber Chemically modified starches such as sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, and bridged polyvinylpyrrolidone, cellulose derivatives, etc.), slippery (such as talc; stearic acid; calcium stearate, magnesium stearate, etc.) Metal stearates; colloidal silica; propolis, cetyl wax, etc .; boric acid Ethylene glycol; carboxylic acids such as fumaric acid, adipic acid; sodium salts of carboxylic acids such as sodium benzate; sulfuric acid salts such as sodium sulfate; leucine; sodium dodecyl sulfate, magnesium dodecyl sulfate Dibasic sulfates; Silicates such as anhydrous silicic acid and silicic acid hydrate; starch derivatives in the above excipients; stabilizers (such as parabens such as methyl paraben and propyl paraben) Esters; alcohols such as chlorobutanol, benzyl alcohol, phenethyl alcohol; benzane ammonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid, etc .; flavoring agents (such as conventional sweeteners, Sour ingredients, flavors, etc.), suspending agents (such as' polysorbate 80, sodium carboxymethyl cellulose, etc.), diluents, formulation solvents (such as water, ethanol, glycerol, etc.), and other additives, according to customary methods Manufacturing. The dosage varies according to symptoms, age, etc. For example, when taken orally, the lower limit is 10 mg (preferably 50 mg) and the upper limit is 2000 mg (preferably 1000 mg) for adults. For adults, the daily lower limit is 10 mg (preferably 100 mg) and the upper limit is 3000 mg (preferably 2.00 mg). It can be administered 1 to 6 times per day according to symptoms -207-200403244. The compound (I) of the present invention has a pharmacologically acceptable salt or an ester derivative thereof which, when administered orally, shows that the active substance has excellent in vivo dynamics (can maintain high blood concentration, etc.). [Embodiment] Examples, reference examples, test examples, and preparation examples will be described below, but the present invention is not limited thereto. In the examples and reference examples, when the NMR was measured with heavy water, if not specified, dimethyl sulfonyl sodium propionate-d4 was used as the internal standard, and other solvents were measured using tetramethylsilane as the internal standard. When using an internal standard substance for heavy water measurement, the signal position of protons (HOD) in heavy water is 4.6 5 ppm. (Example 1) (1R, 5S56S) -2- (l- {4-[(3S) -1- (l-acetamidoethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino] -1, 3-thiazol-2-yl} azetidin-3-yl) sulfide-6-[(R) -1-hydroxyethyl] -1-methyl-carban-2-en-3-carboxylic acid sodium salt

(1 a) 0- (1-ethylethoxy) -S-ethylthiocarboxylic acid ester 0- (1-chloroethyl) -S-ethylthiocarboxylic acid ester (WO-02 092 5 5 5 Numbered person: 1 0.0 g, 59 mol) dissolved in toluene (500 ml), successively add sodium iodide (23.1 g, 154 mol), 18-crown-6 (4.70 g, 17.8 Millimoles), and stirred at 100 ° C. for 6 · 5 hours under nitrogen. The reaction solution was cooled to room temperature, washed with water and a 5% sodium thiosulfate aqueous solution in this order, dried 'over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product of 0- (diiodoethyls-208-200403244 ethyl thiocarboxylic acid ester. Acetic acid (3.4 ml, 59.3 mmol), tetra-n-butylammonium hydrogen sulfate Salt (20.i g, 59.3 mmol) was dissolved in water (170 ml) and dichloromethane (100 ml), followed by sodium bicarbonate (10.0 g, 1 19 mmol) After stirring at room temperature for 2 hours, the above-obtained crude 0- (1-iodoethyl) _S_ethylthiocarboxylic acid ester was added and stirred at room temperature overnight. After the reaction was completed, the reaction solution was separated into layers. The aqueous layer was extracted with dichloromethane in layers. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Zhengjiyuan · Ethyl Acetate '9 5: 5- (90:10, V / V) purification, a colorless oil was obtained. ◦-(1-ethylacetoxy) -S-ethylthiocarboxylic acid ester (5.20 g, yield 46%). Ή NMR (CDCI3, 400 MHz): δ 6.95 (1Η, q, J = 7.8 Hz), 2.82-2.94 (2H, m), 2.09 (3H, s), 1.51 (3H, d, J = 5.8 Hz), 1.32 (3H, t, J = 7.8 Hz). (Lb) 1-Ethyloxyethyl chloroformate Example 1 (la) 0- (1-Ethyloxy) -S-ethylthiocarboxylic acid ester (800 mg, 4.16 mmol) was obtained, and stirred under nitrogen, and sulfonyl chloride (351 (Microliter, 4.37 mmol), stirred at 0 ° C for 20 minutes, and concentrated under reduced pressure at room temperature to obtain a crude product of 1-ethoxyethyl chloroformate. (Lc) (3S) -3- ( Third butoxycarbonylamino) -1- (1-acetamidoethoxycarbonyl) pyrrolidine (3S) -3- (third butoxycarbonylamino) pyrrolidine (1.45 g, 7.80 mmol) Dissolve in dichloromethane (75 ml), and add 1-ethoxyethyl chloroformate (1.30 g, 7.80 mmol), triethylamine (ΐ · 09 ml) obtained in Example i (lb) under ice cooling. '7.80 millimolar), and stirred at room temperature for 1 hour. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. After washing with brine, it was dried under -209-200403244 anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate, 2: 1-1: 1, (V / V) purification, the light yellow amorphous (3 S) -3- ( Tributoxycarbonylamino) -1- (1-acetamidoethoxycarbonyl) pyrrolidine (1.70 g, yield 69%). ^ NMR (CDCI3, 400MHz): δ 6.84-6.78 (1H, m ), 4.66- 4.52 (1H, m), 4.26-4.15 (1H, m), 3.70-3.60 (1H, m), 3.53-3.41 (2H, m), 3.32 -3.16 (1H, m), 2.18-2.09 (1H, m), 2.08-2.04 (3H, m), 1.90 -1.76 (1H, m), 1.49 (1.5H, d, J = 5.1 Hz), 1.47 (1.5H, d, J = 5.1 Hz), 1.45 (9H, s); MS (FAB) m / z: 317 (M + H) +. _ (Ld) 3-Third-butadiphenylsilyloxy- l- {4-[(3S) -l- (l-Acetyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino] -1,3-thiazol-2-yl} azetidine The (3 S)-3 obtained in Example 1 (1 c) -(Third butoxycarbonylamino) -1-(丨 -ethoxycarbonylethoxycarbonyl) pyrrolidine (1.70 g, 5.40 mmol) was dissolved in dichloromethane (50 ml) and added under ice cooling Trifluoroacetic acid (17 ml) was stirred for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was dried under reduced pressure to obtain a crude (3S) -3-amino-1- (1-acetamidoethoxycarbonyl) pyrrolidine trifluoroacetate. The obtained (3 S)-3 -amino-1-(1 -acetamidooxyethoxycarbonyl) pyrrolidine trifluoro · acetate and 3-tert-butyldiphenylsilyloxy- -carboxy-1,3 -Thiazol-2-yl) Butanidine (described in Dream Case Example 1; 2.37 mg, 5.40 mmol) dissolved in dimethylformamide (70 ml), and added under nitrogen and ice cooling Diethylphosphonium cyanide (833 µl, 5.40 mmol), triethylamine (3.03 ml, 21.6 mmol) were stirred at room temperature overnight. After the reaction was completed, ethyl acetate and 5% saline were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated sodium bicarbonate water and saturated brine in that order, dried over anhydrous -210-200403244 sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate, 1: 1 ~ 2: 3, V / V) to obtain 3-aqueous butadiphenylsilyloxy-[(3 S ) -1- (1-Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylammonyl; μ!, 3-thiazol-2-yl} azetidine (2.5 7 g, yield 75%) . ] H NMR (CDCI3, 400ΜΗζ): δ 7.64-7.60 (4Η, m), 7.49- 7.38 (6Η, m), 7.36 (1H, s), 7.22-7.13 (1H, m), 6.87-6.80 (1H, m), 4.89-4.72 (1H, m), 4.65-4.56 (1H, m), 4. 16 ~ 4.08 (2H, m), 4.06 -3.99 (2H, m), 3.80-3.73 (1H, m), 3. 64-3.46 (2H, m), 3.40-3.29 (1H, m), 2. 30-2.20 (1H, m), 2.08-2.04 (3H, m), 2.04-1.88 (1H, m), 1.52 -1.45 (3H, m), 1.07 (9H, s); MS (FAB) m / z: 637 (M + H) +. (Le) 3 -hydroxyl- l- {4-[(3S) -l- (l -Ethyloxyethoxycarbonyl) pyrrolidinylaminomethyl} -1,3-thiazole-2 -yl} ργ Butane D The 3-tertiary stilbenesilane obtained in Example 1 (1d) Oxy-1-{4-[(3 S) -1- (1-acetamidooxyethoxy-based) hydrazinoxidine-3-ylaminomethylamido] -1,3-_fluorene- 2-yl} azetidine (2.57 g, 4.05 mmol) was dissolved in anhydrous tetrahydrofuran (77 ml), and acetic acid (27 8 µl, 4.86 mmol) was added in succession under ice cooling, followed by 1.0 M tetrabutyl fluoride. Saddle-tetrahydrofuran solution (4.86 ml, 4.86 mmol). Stir overnight. After the reaction was completed, ethyl acetate and water were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated sodium bicarbonate water and saturated brine, and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 95 to 5, V / V) to obtain 3-hydroxy (3S) -1- (1-acetamidine) as a white amorphous substance. Oxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino]-!, 3-thio200403244 azole-2 -yl} azetidin (1.57 g, 97% yield). NMR (CDCI3, 400MHz): δ 7.39 (TΗ, s), 7.24-7.18 (1Η, m), 6.83 (0 · 5Η, q, `` = 5.1 Hz), 6.82 (0.5H, q, J = 5.1 Hz), 4.89-4.80 (1H, m), 4.65-4.56 (1H, m), 4.38-4.30 (2H, m), 4.80-4.75 (2H, m), 3.80 -3.73 (1H, m), 3.62-3.46 (2H, m), 3.40 ~ 3.30 (1H, m), 2.52-2.43 (1H, m), 2.30-2.20 (1H, m), 2.08-2.04 (3H, m), 2.04-1.90 (1H , m), 1.52-1.45 (3H, m); MS (FAB) m / z: 399 (M + H) +. (1 £) 3-methanesulfonyloxy-1- {4-[(33) -1- (1-Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazole-2-yl} azetidine The 3-hydroxy group obtained in Example 1 (le) was used. -l- {4-[(3S) -l- (buthyloxyethoxycarbonyl) pyrrolidine-3 -ylaminomethylmethyl] -1,3-thiazole-2 -yl} azetidine (1. 5 7 mg, 3.94 mmoles) were dissolved in dichloromethane (47 ml), and methyl methane chloride (913 µl, 11.8 mmoles) and triethylamine (1.65 ml, 1 1 · 8) were added under ice cooling. Millimoles) and stirred for 2.5 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 1 00: 0 to 95: 5, V / V) to obtain 3-methylsulfonyloxy-l- {4- [ (3S) -l- (Buethoxyoxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin (1.82 g, yield 97%). ] H NMR (CDCI3, 400ΜΗζ): δ 7.46 (1Η, s), 7.20-7.12 (1Η, m), 6.83 (0.5H, q, J = 5.1 Hz), 6.82 (0.5H, q, J = 5.1 Hz ), 5.46-5.40 (1H, m), 4.66-4.57 (1H, m), 4.51-4.43 (2H, m), 4.31-4.24 (2H, m), 3.80 -3.73 (1H, m), 3.64-3.46 (2H, m), 3.42-3.30 (1H, m), 3.11 (3H, s), 2.30-2.20 (1H, m), 2.09-2. 04 (3H, m), 2.04-1.90 (1H, m) , 1.52-1.46 (3H, m). 200403244 (lg) 3-Acetylthio- l- {4-[(3S) _l- (i-Acetyloxyethoxycarbonyl) pyrrolidine-3 -ylaminomethyl Amidinobu 1,3-thiazole-2 -yl} azetidine will carry 3-methylsulfonyloxy-1- {4-[(33) -1- (buyi 醯Oxyethoxycarbonyl) pyrrolidin-3-ylaminomethyl] -i, 3 -thi-π-2-yl} azetidine Ding (1.82 mg, 3.82 mmol) dissolved in dimethylformamide (91 ml), potassium thioacetate (2.6 2 g, 2 2 · 9 mmol) was added at room temperature, and stirred in an oil bath at 80 ° C for 1 hour. After the reaction was completed, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane · ethyl acetate = 1: 3 -1: 4, V / V) to obtain a light brown amorphous 3-ethylamidinethio-1-{4-[ (3 S)-1-(1 · Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino] -1,3-thiazol-2-yl} azetidine (1.49 g, yield 8 5 %) 〇] H NMR (CDCI3, 400ΜΗζ): δ 7.42 (1Η, m), 6.83 (0.5Η, q, J = 5.1 Hz), 6.82 (0.5H, q, J = 5.1 Hz), 4.65-4.58 ( 1H, m), 4.54 (2H, t, J = 8.8 Hz), 4.48 ~ 4.40 (1H, m), 4.00 (2H, ddd, J = 2.2, 5.1, 8.1 Hz), 3.81-3.73 (1H, m) , 3.62-3.48 (2H, m), 3.40-3.29 (1H, m), 2.37 (3H, s), 2.30-2.20 (1H, m), 2.09-2.06 (3H, m), 2.04-1.90 (1H, m), 1.52-1.05 (3H, m) · (lh) (lR, 5S, 6S) -2- (l- {4-[(3S) -l- (l-acetamidooxyethoxycarbonyl) Pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfan-6-[(R) -1-hydroxyethyl] -1-methyl -Carbonidine-2-ene-3-carboxylic acid p-nitrobenzyl ester The 3-ethenylthio-l- {4-[(3S) -l- (l-acetamidine) obtained in Example 1 (lg) Oxyethoxycarbonyl) pyrrolidine-3 -ylaminomethylmethyl] -1 5 3 -thiazole-2 -yl} Acridine-213-200403244 (K49 g, 3.26 mmol) dissolved in dimethylformamide (75 ml) 'Add nitrogen acetate (360 mg, 3.92 mmol) at room temperature under nitrogen and stir 1 hour. After the reaction was completed, (1 R, 5 S, 6 s)-2-(diphenylphosphinoyloxy) -6-[(R) -l-hydroxyethyl] -1 · was added dropwise under nitrogen and ice cooling. A solution of methyl-carbopene-2-en-3-carboxylic acid p-nitrobenzyl ester (1.94 g, 3.26 mmol) in acetonitrile (97 ml), followed by diisopropylethylamine (2.2 7 ml ' 1 3.1 mmol) slowly warmed to room temperature and stirred overnight. After the reaction was completed, ethyl acetate and 5% brine were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed successively with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 to 95: 5, V / V) to obtain (lR, 5S, 6S) -2- (l- {4 -[(3S)-: l- (Buethoxybenzyloxyethoxycarbonyl) pyrrolidin-3-ylamine formamidineb 1,3.thiazol-2-yl} azetidin-3-yl) sulfur-6 -[(R) -l-Hydroxyethyl] -p-methyl-carbobin-2-ene-3-carboxylic acid p-nitrobenzyl ester (2.09 g, yield 84%). ] H NMR (CDCI3, 400ΜΗζ): δ 8.23 (2Η, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8

Hz), 7.44 (1H, s), 7.20-7.10 (1H, m), 6.86-6.79 (1H, m), 5.51 (1H, d, J = 13.9 Hz), 5.25 (1H, d, J = 13.9 Hz ), 4. 66-4.58 (1H, m), 4.56-4.46 (2H, m), 4.33-4.24 (3H, m), 4.11-4.02 (2H, m), 3.80 -3.72 (1H, m), 3.62 -3. 49 (2H, m), 3.42-3.33 (1H, m), 3.30 (1H, dd, J = 7.3, 2.2 Hz), 3.22 (1H, dq, J = 8.8, 7.3 Hz), 2.30-2.20 (1H, m), 2.08-2.05 (3H, m), 2.04-1.90 (1H, m), 1.52-1.46 (3H, m), 1.38 (3H, d, J = 5.9 Hz), 1.28 (3H, d , J = 7.3 Hz). (Li) (lR, 5S56S) -2- (l- {4-[(3S) -l- (l-acetamidooxyethoxycarbonyl) pyrrolidin-3-ylamine formamidine Yl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -l-r λ -214- 200403244 via ethyl] -1 -methyl-carbon ligand Nian-2 -dilute-3 -sodium salt The (lR, 5S, 6S) -2- (l- {4-[(3S) -l- (l-acetamidine) obtained in Example l (lh) Oxycarbonyl) pyrrolidine · 3-ylamine formamidine 13-thiazole_2_yl 丨 azetidin-3-yl) sulfur-6-[(R Nian-2 · ene-carboxylic acid p-nitrobenzyl ester (2.08 g, 2.74 mmol) was dissolved in tetrahydrofuran (60 ml) and evaporated Saturated with water (60 ml), in the presence of 10% Pd-C (2.08 g), reduced by contact with hydrogenation at room temperature for 2.5 hours. After the reaction, the reaction mixture was filtered. To the filtrate was added sodium bicarbonate (230 mg, 2.74 mmol). (Mol), ethyl acetate, and distilled water, and the layers were separated. The aqueous layer was concentrated under reduced pressure, and reversed phase chromatography using CO sm SiO 1 (distilled water: acetonitrile, 100: 0 to 8 5 ·· 1 5 , V / V) purified, freeze-dried to obtain the target compound as a white amorphous (lR, 5S, 6S) -2- (l- {4-[(3S) -1- (1-acetamidoethoxycarbonyl) Pyrrolidin-3-ylaminomethylamidino] -1,3-thiazol-2-yl} 1 ^ butanidine-3-yl) sulfur-6-[(R) -l-Ethyl] -1- Methyl-carbophenan-2-propane-3-carboxylic acid sodium salt (1.01 g, 57.7% yield). NMR (D20, 400MHz): (5 7.51 (1H, s), 6.76-6.70 (1H, m), 4.59-4.50 (3H, m), 4.39-4.30 (1H, m), 4.25 (1H, dq, J = 6.6,5.9 Hz), 4.21-4.15 (1H, m), 4.08-4.00 (2H, m), 3.78-3.66 (1H, m), 3.61-3.37 (4H, m), 3.28-3.18 (1H, m ), 2.33-2.22 (1H, m), 2.13 -2.01 (4H, m), 1.53 (1.5H, d, J = 5.1), 1.51 (1.5H, d, J = 5.1), 1.31 (3H, d, J = 6.6 Hz), 1.19 (3H, d, J = 7.3 Hz); IR (KBr): 1743, 1663, 1604, 1 544, 1490, 1470, 1450, 1422, 1390, 1 314, 1244 cm'1 ; MS (FAB) m / z: 668 (M + Na) +; HRMS (ESI) m / z: calcd. For C26H3209N5S2Na2 (M + Na) +: 668.1437. Found 668 · 1473. -215- 200403244 (Example 2) (1R, 5s, 6s) -2_ (Bu 丨 4-[(3S) -i- (Buethoxypyrrolidinylaminomethylmethyl) -1,3-thiazol-2-yl} azetidine Pyridin-3-yl [(R) _ 1-hydroxyethyl] -1-methyl-carbanil-2-en-3-carboxylic acid trimethyl methyl ester < yl)) sulfur-6-ethyl Krypton

The (1r, 5S, 6S) -2-(({r [4-[(3S) -1- (l-ethoxy-based) pyrrolidin-3-ylaminomethylamidino) -1 obtained in Example 1] -1 , 3 -thiazol-2-yl} azetyl) thio-6-[(R) -l-hydroxyethyl] • p-methyl-carbin-2-en-3-carboxylic acid (250 mg, 0.387 mmol Mol) was dissolved in dimethylacetamide (12.53 under nitrogen and 0 ° C, and methyl valerate iodide (113 mg, 0.465) was added, and the mixture was stirred for 1 hour. After the reaction was completed, ethyl acetate was added. The organic solution was washed with 10% saline, 5% aqueous sodium thiosulfate solution, 0.05 M saturated sodium bicarbonate solution, saturated brine ', and filtered under anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel. Purification by column chromatography (B: methanol = 1 0 0: 0 to 9 8: 2, v / V), the target compound yellow amorphous (lR, 5S, 6S) -2- (l- {4-[( 3S) -l- (l · Ethyloxyzyl) pyrrolidine-3 -ylaminomethylmethyl] -1,3 -thio- 2 -yl} azetidine-3 -6-[(R)- 1-Ethyl] -methyl-carbapene-2-ene-3-carboxylic acid trimethoxymethyl ester (279 mg, yield 98%), i-ethoxyethylpyridin-3-yl internal salt (1 liter), Mol) layer in turn hydrochloric acid, dried, (ethyl acetate Material light: oxycarbonyl-thio) thioacetamidine-216- 200403244 NMR (CDCI3, 400MHz): δ 7.43 (1H, s), 7.20-7.10 (1H, m), 6.86 -6.78 (1H, m), 5.98 (1H, d, J = 5.1 Hz), 5.84 (1H, d, J = 5.1Hz), 4.66-4.57 (1H, m), 4.54-4.46 (2H, m) 4.32 ~ 4.22 (2H, m ), 4.24 (1H, dd, J = 9.5, 2.6 Hz), 4.10-4.02 (2H, m), 3.80-3.73 (1H, m), 3.62 -3.46 (2H, m), 3.42-3.30 (1H, m ), 3.26 (1H, dd, J = 7.0, 2.6 Hz), 3.20 (1H, dq, J = 9. 5, 7.3 Hz), 2.30-2.20 (1H, m) 7 2.09-2. 04 (3H, m ), 2.04 -1.90 (1H, m), 1.82-1.76 (1H, rn), 1.52-1.46 (3H, m), 1.35 (3H, d, J = 6.6 Hz), 1.27 (3H, d, J = 7.3 Hz), 1.22 (9H, s); IR (KBr): 1777, 1756, 171 9, 1665, 1 543, 1481, 1472, 1451, 1422, 1 390, 1374 cm'1. MS (FAB) m / z : 738 (M + H) +; HRMS (ESI) m / z: calcd. For C32H440nN5S2 (M + H) +: 738.2479. Found 738.2473. (Example 3) (lR, 5S, 6S) -2- (l -{4-[(3S) -l- (l · Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin-3-yl ) Sulfur-6-[(R) -l-hydroxyethyl] -1-methyl-carbon complex 2-ene-3-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester

The (1 R, 5 S, 6 S)-2-(1-{4-[(3 S)-1-(1-acetamidoethoxycarbonyl) pyrrolidine-3 -ylaminomethyl) obtained in Example 1 Fluorenyl] -1,3-thiazole-2 -yl} azetidin-3 -yl) sulfan-6-[(R) -l-hydroxyethyl] methyl-carbanil-2_ene-3 — Carboxylic acid sodium salt (250 mg, 0.387 mmol) was dissolved in dimethylacetamide (12.5 ml), and 1-iodoethyl-isopropyl carboxylic acid (120 mg, 0.465) was added under nitrogen at 0 ° C. -217- 200403244 millimoles) and stir for 1 hour. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 0.05 M hydrochloric acid, 5% sodium thiosulfate aqueous solution, saturated sodium bicarbonate solution, and saturated saline in anhydrous sulfuric acid. It was dried over sodium, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 95 ~ 5, V / V) to obtain the target compound as a pale yellow amorphous (1R, 5S, 6S) -2- (1- {4- [(3 S) -1- (1-Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino; 1-1,3-thiazol-2-yl} azetidine Pyridin-3 -yl) thio-6-[(R) -l-hydroxyethyl] -1 · methyl-carbobenzon-2-ene-3-carboxylate (isopropoxycarbonyloxy) ethyl ester (258 mg, 88% yield). ] H NMR (CDCI3, 500MHz): δ 7.43 (1Η, d, J = 2.0 Hz), 7.20-7.10 (1H, m), ^ 6.91-6.86 (1H, m), 6.86-6.80 (1H , m), 4.64 -4.57 (1H, m), 4.54 -4.45 (2H, m), 4.32-4.20 (3H, m), 4.10 ~ 4.03 (2H, m), 3.80 -3.74 (1H, m), 3.62 -3.46 (2H, m), 3.41-3.30 (1H, m), 3.24 (1H, dd, J = 6.8, 2.9 Hz), 3.19 (1H, dq, J = 8.8, 6.8 Hz), 2.30-2.20 (1H , m), 2.09-2.04 (3H, m), 2.04-1.90 (1H, m), 1.76-1.74 (1H, m), 1.61 (1.5H, d, J = 5.9 Hz), 1.59 (1.5H, d , J = 5.9 Hz), 1.52-1.24 (1 2H, m); IR (KBr): 1759, 1718, 1665, 1543, 1491, 1471, 1450, 1423, 1 389, 1375, 1 322, 1271 cm'1 ; MS (FAB) m / z: 776 (M + Na) +; HRMS (ESI) m / z: calcd. For C32H43012N5S2Na (M + Na) +: 776.2248. Found 776.2239. (Example 4) (lR, 5S , 6S) -2- (l- {4-[(3S) -l- (Buethionyloxyethoxycarbyl) pyrrolidin-3 -ylaminomethylmethyl] -1,3-thiazole-2 -yl } Azetidin-3 -yl) sulfan-6-[(R) -l-hydroxyethyl] -1-methyl-carbinenecarboxylic acid (% methyloxy-1,3-difluorenyl- 4-yl) methyl ester 200403244

(111,5 3,63) -2- (1- {4-[(33) -1- (1-Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminemethylamidino] obtained in Example 1] -1,3-thiazol-2-yl} azetidinyl) sulfur-6-[(R) -l-hydroxyethyl] -bumethyl-carbophenan-2-ene-3-carboxylic acid sodium salt (150 mg, 0.232 millimolar) braided in dimethylacetamide (7.5 ml) under nitrogen and Ot: (5-methyl-2-oxo-1,3-difluoren-4-yl) methyl chloride (69 mg, 0.348 mmol), and sodium iodide (157 mg, 1.05 mmol), and stirred at room temperature for 6 hours. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 10% aqueous sodium thiosulfate solution, 0.05M hydrochloric acid, saturated sodium bicarbonate solution, saturated saline, and anhydrous sodium sulfate. It was dried under reduced pressure, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 9 8: 2-9 5: 5, V / V) to obtain the target compound as a pale yellow amorphous (1 R, 5 S, 6 S). -2-(1-{4 · [(3 S)-1 gas 1 _ acetamoxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazol-2-yl} 〇γ Butidin-3-yl) sulfur-6-[(R) -l-hydroxyethyl] -bromomethylcarben-2-ene-3-carboxylic acid (5-methyl-2-oxo-1,3 -Dipyrocen-4-yl) methyl ester (127 mg, 75% yield). -219- 200403244] H NMR (CDCI3, 500MHz): δ 7.44 (1H, s), 7.20 -7.11 (1H, m), 6.85 -6.80 (1H, rn), 5.05 (1H, d, J = 13.7 Hz) , 4.97 (1H, d, J = 13.7 Hz), 4.65 -4.58 (1H, m), 4.56-4.47 (2H, m), 4.32-4.28 (2H, m), 4.25 (1H, dd, J = 8.8, 2.2, Hz), 4.12-4.04 (2H, m), 3.80-3.73 (1H, m), 3.61-3.49 (2H, m), 3.42-3.30 (1H, rn), 3.25 (1H, dd, J = 6.8 , 2.2

Hz), 3.21 (1H, dq, J = 8.8, 7.8 Hz), 2.28-2.20 (1H, m), 2.21 (3H, s), 2.09 -2.05 (3H, m), 2.00-1.90 (1H, m) , 1.74-1.69 (1H, m), 1.52-1.46 (3H, m), 1.36 (3H, d, J = 5.9 Hz), 1.27 (3H, d, J = 7.8 Hz); IR (KBr): 1820, 1774, 1735, 1716, 1663, 1543, 1491, 1472, 1449, 1425, 1 389, 1 325 cm'1; MS (FAB) m / z: 758 (M + Na) +; HRMS (ESI) m / z : calcd. for C31H37012N5S2Na (M + Na) +: 758.7778. Found # 758.1771. (Example 5) (lR, 5S, 6S) -2- (l- {4-[(3R) -l- (l-ethyl (Methoxyethoxycarbonyl) pyrrolidin-3 -ylaminomethylmethyl] -1,3-thiazole-2 -yl} azetidin-3 -yl) thio-6-[(R) -l-hydroxyethyl ] -1-Methyl-Carbonen-2-en-3-carboxylic acid sodium salt

(5a) (3R) -3- (Third-butoxycarbonylamino) -1- (1-acetamidoethoxycarbonyl) pyrrole (3R) -3- (third-butoxycarbonylamino) pyrrole Pyridine (291 mg, 1.56 mmol) was dissolved in dichloromethane (15 ml), and 1-ethoxyethyl chloroformate (260 mg, 1.56 mmol) obtained in Example 1 (1 b) was cooled under ice-cooling. Ear), triethylamine (219 μl, 1.56 mmol), and stirred at room temperature for 4 hours. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added, and the aqueous layer was extracted with ethyl acetate in layers. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate -220-200403244, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 2: 1-1: 2, V / V) to obtain (3R) -3- (second butoxymine amine group) as a pale yellow amorphous substance. ) -1- (1-Ethyloxyethoxylate-based) acetone ratio D (36 mg, yield 68%).屮 NMR (CDCI3, 400MHz): (5 6-84-6.78 (1H, m), 4.69- 4.55 (1H, m), 4.25-4.15 (1H, m), 3.70-3. 60 (1H , m), 3.54-3.40 (2H, tn), 3.32-3:16 (1H, m), 2.19-2.09 (1H, m), 2.08-2.04 (3H, m), 1.90-1.76 (1H, m ), 1.50-1.46 (3H, m), 1.45 (9H, s). (5b) 3-Third-butadiphenylsilyloxy-1 · {4-[(3ΙΙ) -1 · (1-acetamidine Ethoxycarbonyl) pyrrolidine-3 -ylaminomethyl] -1,3-thiazole-2 -yl} azetidine The (3 R) -3- (third butoxy) obtained in Example 5 (5 a) Carboxamido) -1- (1-acetamidoethoxycarbonyl) pyrrolidine (2.12 g, 6.70 mmol) was dissolved in dichloromethane (64 ml), and trifluoroacetic acid (21 ml) was added under ice-cooling. ), And stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was dried under reduced pressure to obtain (3R) -3-amino-1- (1-acetamidoethoxycarbonyl) pyrrolidine trifluoro Crude acetate. The obtained (3 R) -3-amino-1- (1-acetamidoethoxycarbonyl) pyrrolidine trifluoroacetate and 3-tert-butyldiphenylsilyloxy-1- ( 4-carboxy-1,3-thiazol-2-yl) azetidin (described in Reference Example 1; 2.94 mg , 6.70 mmoles) were dissolved in dimethylformamide (88 ml), and diethylphosphonium cyanide (1.03 ml, 6.70 mmoles) and triethylamine (1.03 ml) were added under nitrogen and ice cooling. 2.82 ml, 6.70 mmol), and stirred at room temperature overnight. After the reaction was completed, ethyl acetate and 5% brine were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was saturated. The sodium bicarbonate solution and the saturated saline solution were sequentially washed, then dried under anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to -221- 200403244 silica gel column chromatography (n-hexane: ethyl acetate, i: 1β1). : 2, v / v) purification, can be obtained as a pale yellow amorphous 3-third stilbenesilyloxy_bu {4-[(3 R) -1- (1 · ethenoxyethoxy mine based)卩 卩 卩 卩 卩 基 基 3-yl amine methyl amidinyl] 1, 3-thiocarba-2-yl} azetidin (2.63 g, yield 62%). ^ NMR (CDCI3, 400MHz): 5 7.62 (4H , d, J = 7.8 Hz), 7.49-7.38 (6H, m), 7.47 (1H, s), 7.26-7.17 (1H, m), 6.86-6.80 (1H, m), 4.80-4.72 (2H, m ), 4.64-4.56 (1H, m), 4.16-4.09 (2H, in), 4.05-4.00 ( 2H, m), 3.80-3.73 (1H, m), 3.63-3.45 (2H, m), 3.40-3,30 (1H, m), 2.29-2.20 (1H, m), 2.09-2.04 (3H, m ), 2.04-1.92 (1H, m), 1.52 -1.45 (3H, m), 1.07 (9H, s); MS (FAB) m / z: 637 (M + H) +. '(5c) 3 -hydroxyl -l- {4-[(3R) -l- (l-acetamidoethoxycarbonyl) pyrrolidin-3 • ylaminomethylamido: thiazol-2-yl} azetidine will be described in Example 5 (5 b ) The obtained 3-third stilbenesilyloxy group [4 _ [(3 R) -1- (1-acetamidooxyethoxycarbonyl) pyrrolidin-3-ylaminemethylamidino] -i, 3 -Thiazole- 2-yl} azetidine (2.63 g, 4.13 mmol) was dissolved in anhydrous tetrahydrofuran (130 ml). Acetic acid (2 8 4 µl, 4.96 mmol) was added sequentially under ice cooling. 1.0 M tetrabutylammonium fluoride-tetrahydrofuran solution (4.96 ml, 4.96 mmol), and stir for 1 hour. After the reaction was completed, ethyl acetate and water were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 ~ 95: 5'V / V) to obtain 3-hydroxy-l- {4-[(3R) -l- (l-Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1 5 3-_azole-2 -yl} azetidine (1.69 g, yield 100%) . -222- 200403244 ^ NMR (CDCI3, 400MHz): (5 7 · 38 (1H, s), 7.25 ~ 7.19 (1H, m), 6.83 (0.5H, q, J = 5.9 Hz), 6.81 (0.5H , q, J = 5.9 Hz), 4.88-4.80 (1H, m), 4.64-4.56 (1H, m), 4.37-4.30 (2H, m), 4.00-3.94 (2H, m) , 3.80-3.73 (1H, m), 3.64-3.44 (2H, m), 3.40-3.30 (a, m), 2 73 (0 · 5Η, d, J = 6.6 Hz), 2.67 (0.5H, d, J = 6.6 Hz), 2. 30-2.20 (1H, m), 2.09-2.04 (3H, m), 2.09-1.90 (1H, m), 1.52-1.44 ( 3H, m) · (5d) 3-Methanesulfonyloxy · 1- {4-[(3ΙΙ) -1- (1-ethyloxoxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl]- 1,3-thiazol-2-yl} πγ butidine. The 3-hydroxy · acetamoxyethoxycarbonyl) pyrrolidin-3-ylaminemethylamidinyl group obtained in Example 5 (5c)]-1,3-exazole -2-yl} azetidine (1.68 mg, 4.13 mmol) was dissolved in dichloromethane (84 ml), and methylsulfonyl chloride (959 μl, 12.4 mmol) and triethyl chloride were added under ice cooling. Amine (1.74 ml, 1 2.4 mmol), stir for 1 hour. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 to 95: 5, V / V) to obtain 3-methylsulfonyloxy-l- {4-[(3R ) -l "l-Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamyl: l·l, 3-thiazol-2-yl} PY butidine (1.96 g, yield 100%) .] H NMR (CDCI3, 400ΜΗζ): δ 7.46 (1Η, s), 7.21-7.10 (1Η, m), 6.83 (0.5H, q, J = 5.9 Hz), 6.82 (0.5H, q, J = 5. 9 Hz), 5.46-5.40 (1H, m), 4.66-4.57 (1H, m), 4.51-4.43 (2H, m), 4.31-4.24 (2H, m), 3.80 -3.73 (1H, m) , 3.64-3.44 (2H, m), 3.42-3.31 (1H, m), 3.11 (3H, s), 2.30-2.20 (1H, m), 2.09-2.05 (3H, m), 2.10-1.90 (1H, m), 1.53-1.45 (3H, m); MS (FAB) m / z: 477 (M + H) +. -223- 200403244 (5e) 3-ethylsulfanyl- l- {4-[(3R ) -l- (l-Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -i, 3-thienyl-2-yl} azetidine will be carried out in Example 5 (5 d ) The obtained 3 -methanesulfonyloxy-1-{4-[(3 R)-1-(1-ethylethoxyethoxyl) pyrrolidine-3-ylaminomethyl-yl]- i, 3-thiazetidine 2 -yl} ργ butidine (1.96 G '4.13 mmol) dissolved in dimethylformamide (100 ml), and bromothioacetate (2.83 g, 24.8 mmol) was added at room temperature at 80. < 3 Stir in an oil bath for 10 hours. After the reaction is completed, add ethyl acetate and 10 ° / 0 brine to the reaction system, and extract the aqueous layer with ethyl acetate. The organic layer obtained is saturated with sodium bicarbonate. The solution and saturated brine were washed, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (n-hexane ·· ethyl acetate = 1: 4 -1: 5, V / V) purification, can be obtained as a light brown amorphous 3-acetamidinethio-l- {4-[(3R) -1- (l-acetamoxyethoxycarbonyl) pyrrolidin-3-ylamine formamidine Group] -1,3 -thiazol-2-yl} azetidine (1.54 g, yield 82%) ° -NMRiCDC ^, 400MHz): < 5 7.42 (1H, s), 7.24-7.16 (1H, m), 6.83 (0.5H, q, J = 5.9 Hz), 6.81 (0.5H, q, J = 5.9 Hz), 4.64-4.57 (1H, m), 4.54 (2H, dt, J = 1.9, 8.8 Hz), 4.47-47.41 (1H, m), 4.00 (2H, ddd, J = 3.5, 5.5, 8.8 Hz), 3.80-3.73 (1H, m), 3.63-3.43 (2H, m), 3.40 -3.30 (1H, m), 2.37 (3H, s), 2.30-2.20 (1H, m), 2. 09-2.04 (3H, m), 2.09-1.90 (1H, m), 1.52-1.45 (3H, m); MS ( FAB) m / z: 457 (M + H) +. (5〇 (111,53,63) -2- (Bu [4-[(311) -1- (1-acetamidoethoxycarbonyl) pyrrole Pyridin-3-ylaminomethylammonyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfan-6-[(R) -1-hydroxyethyl] -methyl-carbon 2-Benzen-3-carboxylic acid p-nitrobenzyl ester The 3-ethylsulfanylthiol-l- {4-[(3R) -1- (ethylacetoxyl 403002 ethoxycarbonyl) obtained in Example 5 (5e) Pyrrolidin-3-ylamine formamidine μm, 3_ 嗟 _-1,3 -thiazole-2-yl} azetidine

A solution of p-nitrobenzyl carboxylic acid (2.01 g, 3.38 mmol) in acetonitrile (100 mL) 'Add isopropylethylamine (2.35 mL, 13.5 mmol) and slowly warm to room temperature' Stir overnight. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed successively with 5% saline, saturated sodium bicarbonate solution, and saturated saline water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 to 9 5: 5, V / V) to obtain (lR, 5S, 6S) -2- (l- { 4-[(3R) -l- (l-Ethyloxyethoxycarbonyl) pyrrolidine · 3-ylaminomethylamidino] _1,3-thiazol-2-yl} azetidin-3-yl) sulfur- 6-[(R) -Hydroxyethyl] -1-methyl-carbanil-2-ene-3-carboxylic acid p-nitrobenzyl ester (2.33 g '91% yield). ] H NMR (CDCI3, 500MHz): δ 8.23 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 7.44 (1H, s), 7.22-7.11 (1H, m), 6.85-6.79 (1H, m), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H, d, J = 13.7 Hz), 4.66-4.58 〇H, m), 4.56-4.45 (2H, m) , 4.33-4.24 (3H, m), 4.10-4.02 (2H, m), 3.79 -3.73 (1H, m), 3.62-3.46 (2H, m), 3.40 ~ 3.11 (1H, m), 3.30 (1H, dd, J = 6.8, 2.9 Hz), 3.22 (1H, dq, J = 9.1, 7.8 Hz), 2.29-2.19 (1H, m), 2.09-2.03 (3H, m), 2.00-1.90 (1H, m) , 1.52-1.45 (3H, m), 1.38 (3H, d, J = 6.8 Hz), 1.28 (3H, d, J = 7.8 Hz). (5g) (lR, 5S, 6S) -2- (l- {4-[(3R) -l- (l-ethoxyethoxycarbonyl) pyrrole-225- 200403244 pyridin-3 -ylaminomethylmethyl] -1,3-thiazole-2 -yl} azetidine— 3-()-sulfur-6 · [(R) -1 -hydroxyethyl] -1-methyl-carbobenzoin-2-enecarboxylic acid sodium salt obtained from Example 5 (5 f) (1 R, 5 S, 6 S)-2-(1-{4-[(3 R) -1-(1 -Ethyloxyethoxylate) pyrrole Didine · 3 · Aminopyrazine 1,3 -thiazide Π sitting -2 -yl} azetidin -3 -yl) thio-6-[(R)-1 -hydroxyethyl] -1 -formyl -Carbonyl-2-ene-3 -carboxylic acid p-nitrobenzyl ester (2.63 g, 3.47 mmol) was dissolved in tetrahydrofuran (100 ml) and distilled water (100 ml) in the presence of 10% pd _C (2.6 3 g) at room temperature for 2 · 5 hours with contact hydrogenation. After the reaction was completed, the reaction mixture was filtered. Add sodium bicarbonate (292 mg, 3.47 mmol), ethyl acetate, and distilled water 'for layer separation. The aqueous layer was concentrated under reduced pressure, and purified by reversed phase chromatography (distilled water: acetonitrile, 100: 0 to 8 5: 15, V / V) and freeze-dried to obtain the target compound as a white non-white Crystal form (lR55S, 6S) -2- (l- {4-[(3R) -l- (l-acetamidoethoxycarbonyl) pyrrolidine-3 · ylaminomethylamidino] -1,3-thiazole- 2-yl} azetidin-3-yl) sulfan-6-[(R) -l-hydroxyethyl] -1 · methyl-carban-2-en-3-carboxylic acid sodium salt (1. 21 g, 54% yield). ] H NMR (D20, 400ΜΗζ): δ 7.52-7.49 (1Η, m), 6.76 -6.66 (1Η, m), 4.57 -4.47 (3Η, m), 4.36-4. 29 (1H, m), 4.25 ( 1H, dq, J = 6.4, 6.2 Hz), 4.19-4.13 (1H, m), 4.06 ~ 3.95 (2H, m), 3.76-3.63 (1H, m), 3.60 -3.38 (4H, m), 3.24- 3.12 (1H, m), 2.32-2.21 (1H, m), 2.12-2.00 (4H, m), 1.54-1.49 (3H, m), 1.31 (3H, d, J = 6.4 Hz). 1.18 (3H, dd, J = 6.8, 4.2 Hz); IR (KBr): 1743, 1663, 1603, 1545, 1490, 1470, 1450, 1423, 1 390, 1314, 1 244 cm "1; MS (FAB) m / z: 646 (M + H) +; HRMS (ESI) m / z: calcd. For C26H3309N5S2Na (M + H) +: 646.1 61 8. Found 646.1620. Anal · calcd. For C26H32N509S2Na.7 / 3H20: C, 45 · 41 %; H, 5.37%; N, 10. 18%; S, 9.32% · Found C, 45.36%; Η, 5.59%; N, 10.30%; S, 9.27% · 200403244 (Example 6) (111 , 53,63) -2- (1- {4-[(311) -Bu (bu-ethyloxoethoxycarbonyl) pyrrolidine-3 -ylamine formamidinebu 1,3-thiazole-2 -yl} Azetidin-3 -yl) thio-6-[(R) -l-hydroxyethyl] -1-methyl-carbanil-2-en-3-carboxylic acid trimethylacetoxymethyl

(1 foot, 53,63) -2- (b) {4-[(311) -1- (1-acetamidoethoxycarbonyl) pyrrolidin-3-ylaminomethylamidinyl]- l, 3-thiazole_2-yl} azetidin-3-yl) thio-6-[(R) -l-hydroxyethylb 1-methyl-carban-2-en-3-carboxylic acid Sodium salt (370 mg, 0.573 mmol) was dissolved in dimethylacetamide (19 ml), and methyl pivalate (167 mg, 0.688 mmol) was added under nitrogen at 0 ° C, and stirred 40 marks. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 5% saline, 0.5 M hydrochloric acid, saturated sodium bicarbonate solution, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate · 'methanol = 100: 0 ~ 95: 5, V / V) to obtain (111,53,63) -2- (a pale yellow amorphous form of the target compound) BU {4- [(3 R) -1- (1-Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino] -1,3-thiazol-2-yl} azetidin-3- ) Sulfur-6-[(R) -l-hydroxyethyl] -1-methyl-carbanil-2-en-3-carboxylic acid trimethylacetoxymethyl ester (42 5 mg, yield 100%). > 227- 200403244 'H NMR (CDCI3, 400MHz): δ 7.44 (1H, s), 7.22-7.12 (1H, m), 6.83 (0.5H, q, J = 5.8 Hz), 6.82 (0.5H, q , J = 5.8 Hz), 5.98 (1H, d, J = 5.1 Hz), 5.84 (1H, d, J = 5.1 Hz), 4.60-4.58 (1H, m), 4.56-4.46 (2H, m), 4.33 -4.22 (3H, m), 4.10-4.02 (2H, m), 3.80 -3.73 (1H, m), 3. 62-3.49 (2H, m), 3.42-3.30 (1H, m), 3.25 (1H, dd, J = 6.6, 2.2 Hz), 3.20 (1H, dq, J = 9.5, 7.3 Hz), 2.30-2.20 (1H, m), 2.09-2.04 (3H, m), 2.05-1.90 (1H, m) , 1.52-1.46 (3H, m), 1.35 (3H, d, J = 5.9 Hz), 1.27 (3H, d, J = 7.3 Hz), 1.22 (9H, s); 1R (KBr): 1776, 1755, 1719, 1666, 1543, 1481, 1471, 1451, 1423, 1 390, 1374, 1344, 1325 cmH; MS (FAB) m / z: 738 (M + H) +; HRMS (ESI) m / z: calcd. for C32H440nN5S2 (M + H) +: 738.2479. Found 738.2500. (Example 7) (lR, 5S, 6S) -2- (l- {4-[(3R) -l- (l-acetamidine) Ethoxycarbonyl) pyrrolidin-3 -ylaminomethyl] -1,3-thiazole-2 -yl} azetidin-3 -yl) sulfur-6-[(R) -1-transethyl]- 1-methyl-carbophenan-2-acid-3-residual acid 1- (isopropoxide ) Ethyl

(1 foot, 53,63) -2- (1- {4-[(311) -1- (1-acetamidoethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] obtained in Example 5] -1,3 -thiazole-2 -yl} azetidin-3 -yl) thio-6-[(R)-1 -hydroxyethyl] -i -methyl-carbophenan-2 -ene-3- Carboxylic acid sodium salt (3 70 mg, 0.5 7 3 mmol) was dissolved in dimethylacetamide (19 ml), and 1-iodoethyl isopropylcarboxylate (177 mg, 0.688 mmol-228-200403244 ears), stir for 30 minutes. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 5% saline, 0.5 M hydrochloric acid, saturated sodium bicarbonate solution, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed. concentrate. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 to 95: 5, V / V) to obtain the target compound as a pale yellow amorphous (ir, 5S, 6S) -2- (l -{4-[(3R) -l- (l-acetamidoethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin-3-yl ) Sulfur-6-[(R) -l · hydroxyethyl] -p-methyl-carbobenzon-2-ene-3-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester (403 mg, yield Rate 9 3%). 1H NMR (CDCI3, 500ΜΗζ): δ 7.43 (1Η, d, J = 2.0 Hz), 7.21-7.12 (1H, m) K 6.89 (0.5H, d, J = 4.9 Hz), 6.88 (0.5H, d, J = 4.9 Hz), 6.85-6.80 (1H, m), 4.94-4.86 (1H, m), 4.65-4.57 (1H, m), 4.55 -4.45 (2H, m), 4.32-4.20 (3H, m), 4.10-4.02 (2H, m), 3.80-3.74 (1H, m), 3.60 -3.48 (2H, m), 3.41-3.30 (1H, m), 3.25 (1H, dd, J = 7.3, 2.4 Hz), 3.19 (1H, dq, J = 8.8, 7.8 Hz), 2.30-2.20 (1H, m), 2.09-2.05 (3H, m), 2.00 ~ 1.92 (1H, m), 1.76-1.74 (1H, m), 1.62 (1.5H, d, J = 4.9

Hz), 1.59 (1.5H, d, J = 4.9 Hz), 1.52-1.46 (3H, m), 1.38-1.24 (12H, m); IR (KBr): 1758, 1718, 1665 1 543 , 1491, 1470, 1450, 1423, 1 389, 1 375, 1323,1271 cmH; MS (FAB) m / z: 754 (M + H) +; HRMS (ESI) m / z: calcd. For C32H44012N5S2 (M + H) +: 754.2428. Found 754.2441. (Example 8) (lR, 5S, 6S) -2- (l- {4- [l- (l- (acetamidine.oxyethoxycarbonyl) azetidine-3 -Amineaminomethyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfur-6-[(R) -butoxyethyl] -l-methyl-carbon 2-ene-3-carboxylic acid sodium salt-229- 200403244

(8a) 3-Hydroxy-1- (1-acetamidoethoxycarbonyl) azetidine Dissolve dibenzyl-3-hydroxyazetidine (7.5 g, 31.3 mmol) in methanol (225 ml ), In the presence of 10% P d-C (7.5 grams), in a water bath at 50 ° C for 1.5 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was washed with methanol. The obtained filtrate was added under cooling with 4-dimethylaminepyridine (3.82 g, 31.3 mmol), and 1-ethoxyethyl chloroformate (3.82 g, 31.3 mmol) obtained in Example 1 (1 b). ), And stirred at room temperature for 1.5 hours. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was dried over anhydrous sodium sulfate, filtered ', and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1-2: 3, V / V) to obtain 3-hydroxy-1- (buthyloxyethoxycarbonyl) as a colorless oil. Acridine (5.56 g, 87.7% yield). lH NMR (CDCI3, 400ΜΗζ): δ 6.77 (1Η, q, J = 5.1 Hz), 4.69-4.60 (1H, m), 4.27-4.20 (2H, m), 3.89 (2H, dd, J = 9.5 , 4.4 Hz), 2.20 (1H, d, J = 5.9 Hz), 2.07 (3H, s), 1-47 (3H, d, J = 5.1 Hz) MS (FAB) m / z: 204 (M + H) +. (8b) 3 -methanesulfonyloxy- (buthyloxyethoxycarbonyl) azetidine The 3-hydroxy-1- (1-acetamidoxyethoxy) obtained in Example 8 (8a) Carbonyl) azetidine (5.56 g, 27.3 mmol) dissolved in dichloromethane (170 ml) under ice-cold 200403244, but then added methanesulfonyl chloride (2.33 ml, 30.1 mmol), triethylamine (4.22 ml , 3 0.1 millimoles), and stirred for 1 hour. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1 ·· Bu2: 3, V / V) to obtain 3-methanesulfonyloxy-1- (buethylhydrazone) as a colorless oil. Ethoxycarbonyl) azetidine (7.20 g, 94% yield). ^ NMR (CDCI3, 400MHz): (5 6.76 (1H, q, J = 5.9 Hz), 5.27-5.21 (1H, m), 4.40-4.33 (2H, m), 4.21 -4.14 (2H, m), 3.08 (3H, s), 2.07 (-3H, s), 1.47 (3H, d, J = 5.9 Hz); MS (FAB) m / z: 282 (M + H) +. (80-azido -1- (1-Ethyloxyethoxycarbonyl) -PY butidine The 3-methylsulfonyloxy-1- (1-ethoxyethoxycarbonyl) acididine (7.20) obtained in Example 8 (8b) was used. G, 25.6 mmoles) was dissolved in dimethylformamide (220 ml), sodium azide (4.99 g '76. 8 mmoles) was added and stirred in an oil bath at 100 ° C Overnight. After the reaction was completed, ethyl acetate and 5% saline were added to the reaction system, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1-3: 1, V / V) to obtain 3-azide-1- (1-acetamidoethyl) as a colorless oil. Oxycarbonyl) azetidin (1.80 g, yield 3 1 ° / 〇).] H NMR (CDCI3, 400MHz): (5 6.76 (1H, q, J = 5.9 Hz), 4.31-4.24 (3H, m) , 4.00-3.94 (2H, m ), 2.07 (3H, s), 1.47 (3H, d, J = 5.9 Hz); MS (FAB) m / z: 229 (M + H) +. 200403244 (8d) -Acetyloxyethoxycarbonyl) azetidin-3-ylamine formamidine, ^ thiazol-2-yl} azetidin Example 8 (8c)% azido_1- (1 -Acetyloxyethoxycarbonyl) _azetidine (1.80 g '7.89 mmol) dissolved in methanol (54 ml) in the presence of 10% Pd-C (1.80 g), and subjected to contact hydrogenation reduction at room temperature! Hours. After the reaction was completed, the catalyst was filtered, the filtrate was washed with methanol, and the filtrate was concentrated under reduced pressure. This crude product and 3-tert-butadiene oxide-oxyl-residue-, 3-thiazole- 2-based) ΠΥ butadidin (documented in Reference Example 1; 3.46 mg, 7.89 mmol) i Valley monomethyl methylamine (104 ml), diethyl ether was added under nitrogen and ice cooling Phosphonium cyanide (1.22 ml, 7.89 mol), triethylamine (111 ml, 789 pens; mol), and stirred at room temperature for 1.5 hours. After the reaction was completed, ethyl acetate and 5 ° / 0 brine were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1 _ i .1, V / V). -{4- [1- (1-Ethyloxyethoxycuryl) ργ butanidine-3-ylaminomethylmethyl] _; [, 2 -thiazole-2 -yl} azetidine (3 · 3 4 g, 68% yield).屮 NMR (CDCI3, 400MHz): (5 6.64-7.60 (4H, m), 7.52 · 7.38 (6H, m) 7.36 (1H, m), 6.79 (1H, q, J = 5.9 Hz), 4.88 _ 4.80 (1H, m), 4.80 · 4-73 (1H, m), 4.38 (2H, t, J = 7.3Hz), 4.! 3 (2H, t; J = '. 3 Hz) 4.04 (2H, dd, J = 8.8, 5.1 Hz), 3.95 (2H, tt, J = 5.9, 2.9 Hz) 2 08 (3H, s), 1.47 (3H, d, J = 5.9 Hz ), 1.08 (9H, s); MS (FAB) m / z: 623 (M + H) +. (8e) 3-Hydroxyacetamidooxyethoxycarbonyl) ργ butanidine amine methylamidino] -1, 3-thiazole-2.yl} azetidin-232- 200403244 The 3-tert-butadiphenylsilyloxy-1- {4- [1 · (1-acetamidoethoxy) obtained in Example 8 (8d) Carbonyl) azetidin-3-ylamine formamidine; M, 3-thiazol-2-yl} azetidin (3.34 g, 5.36 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml), successively under ice cooling Add acetic acid (369 μl, 6.44 mmol), 1.0 M tetrabutylammonium fluoride-tetrahydrofuran solution (6.44 ml, 6.44 mmol), and stir overnight. After the reaction was completed, ethyl acetate and saturated brine were added to the reaction solution, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 1 0 0: 0 to 9 8 ·· 2, V / V) to obtain colorless amorphous 3-hydroxy-1-{4-[1- (1-Acetyloxyethoxycarbonyl) azetidine · 3-methylaminomethylamidino] -1,3-thiazol-2-yl} azetidine (2.04 g, yield 99%). Ή NMR (CDCI3, 400ΜΗζ): δ 7.53 (1Η, bd, J = 8.8 Hz), 7.39 (1H, s), 6.78 (1H, q, J = 5.1 Hz), 4.89-4.80 (2H, m), 4.41 -4.32 (4H, m), 4.00 -3.93 (4H, m), 2.45 (1H, bd, J = 5.9 Hz), 2.07 (3H, s), 1.47 (3H, d, J = 5.1 Hz); MS ( FAB) m / z: 385 (M + H) +. (8〇3-methanesulfonyloxy-1- {4- [1- (1-acetamidoethoxycarbonyl) azetidin-3-ylamine Formamyl: l · 1,3-thiazol-2-yl} Acetidine The 3-hydroxy-1-{4-[1-(1 -acetamoxyethoxycarbonyl) obtained in Example 8 (8 e) Acridine-3-ylamine formamidine] -1,3-thiazol-2-yl} azetidine (2.04 g, 5.31 mmol) was dissolved in dichloromethane (62 ml j, added under ice cooling) Methanesulfonyl chloride (1.23 ml, 15.9 mmol), triethylamine (2.23 ml, 15.9 mmol), and stirred for 2 hours. After the reaction, add ethyl acetate and saturated sodium bicarbonate water to the reaction solution, The aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate). , -233- 200403244 can be obtained as a pale yellow amorphous 3-methanesulfonyloxy group 丨 丨 {4 _ [丨 _ (; [-ethylacetoxyethoxymethyl) azetidine-3-ylamine methyl Fluorenyl] _1,3_thiazole-2_yl} azetidin (2.33 g 'yield 95%).] H NMR (CDCI3, 400MΗζ): δ 7.49 (1Η, bd, J = 6.6 Hz), 7.46 ( 1H, s), 6.78 (1H, q, J = 5.1 Hz), 5.47-5.40 (1H, m), 4.90-4.80 (1H, m), 4.48 (2H, dd, J = 10.3, 6.6 Hz), 4.39 (2H, t, J = 9.5 Hz), 4.29 (2H, dd, J = 10.3, 4.4 Hz), 3.98-3.93 (2H, m), 3.12 (3H, s), 2.07 (3H, s), 1.47 ( 3H, d, J = 5.1 Hz); MS (FAB) m / z: 463 (M + H) +. (8g) 3.Ethylsulfanyl-l- {4- [l- (l-ethyl Ethoxyethoxycarbonyl) azetidin-3-ylaminemethylamidinyl] -1,3-thiazole-2-yl} HY butanyl 3-methanesulfonyloxy-butanone obtained in Example 8 (8f) Acetyloxyethoxycarbonyl) azetidin-3-ylaminomethylamidinyl]-; ι, 3_thiazole_2-yl} azetidin (2.33 g, 5.04 mmol) dissolved in dimethylformamidine Amine (115 ml), potassium thioacetate (3.45 g, 3 0.2 mmol) was added at room temperature, and stirred in an oil bath at 80 ° C overnight. After the reaction was completed, ethyl acetate and 5% saline were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was dried over anhydrous sodium sulfate, filtered ', and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: 2, V / V) to obtain a light brown amorphous 3-acetylsulfanyl-1- {4 — [1-(1-ethyl (Methoxyethoxycarbonyl) azetidin-3-ylaminomethylmethyl] -1,3-pyrazol-2-yl> azetidin (1.69 g, yield 76%).屮 NMR (CDCI3, 400MHz): δ 7.50 (bd, J = 8.1 Hz), 7.43 (1H, S), 6.79 (1H, q, J = 5.9 Hz), 4.89-4.82 (1H, m), 4.56 (2H, t, J = 8.1 Hz), 4.50-4.44 (1H, m), 4.39 (2H, t, J = 8.1 Hz), 4.02 (2H, dd, J = 8.1, 5.9 Hz), 3.96 (2H, tt, J = 5.9, 2.9 Hz), 2.38 (3H, s), 2.08 (3H, s), 1.48 (3H, d, J = 5.9 Hz); MS (FAB) m / z: 443 (M + H) +., -234- 200403244 (8h) (lR, 5S, 6S) -2- (l- {4- [l- (l- (ethylacetoxyethoxycarbonyl) azetidine) Pyridin-3-ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfan-6-[(11) -1-hydroxyethyl] -1 -methyl- Carbophenan-2-en-3-carboxylic acid p-nitrobenzyl ester The 3-acetamidinethio group d — H —acetamidineoxyethoxycarbonyl) azetidin-3-ylamine methyl obtained in Example 8 (8g) Fluorenyl] ― 丨, 3-thiazol-2-yl} azetidine (1.69 g '3.82 mmol) was dissolved in dimethylformamide (115 ml), and hydrazine acetate ( 4 2 2 mg, 4.5 8 mmol), and stirred for 1 hour. After the reaction was completed, (1 R, 5 S, 6 S) · 2- (diphenylphosphinoyloxy) -6-[(R) -l-Ethyl] -1- was added dropwise under nitrogen and ice cooling. A solution of methyl-carbophenan-2-carbon-3-carboxylic acid p-nitrate; an ester (2.27 g, 3.8 2 'mmol) in acetonitrile (115 ml), and then diisopropylethylamine (2.65 ml, 15.2 mmol), slowly warm to room temperature, and stir overnight. After the reaction was completed, ethyl acetate and 5% saline were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 ~ 98: 2, V / V) to obtain (lR, 5S, 6S) -2- (l- {4 -[l- (l · Ethylacetoxycarbonyl) azetidin-3-ylaminomethylamidino] -1,3-thiazol-2-yl} azetidin-3 · yl) sulfur-6-[( R) -l-Hydroxyethyl] -1-methyl-carban-2-en-3-carboxylic acid p-nitrobenzyl ester (2.58 g, 91% yield). 1H NMR (CDCI3, 500MHz): (5 8.23 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8

Hz), 7.48 (1H, bd, J = 7.8 Hz), 7.44 (1H, s), 6.78 (1H, q, J = 5.9

Hz), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H, d, J = 13.7 Hz), 4.89-4.81 (1H, m), 4.52 (2H, q, J = 7.8 Hz), 4.39 ( 2H, t, J = 7.8 Hz), 4.33 -4.25 (3H, m), 4.08 (2H, dt, J = 8.8, 4.9 Hz), 3.95 (2H, dt, J = 8.8, 4.9

Hz), 3.30 (1H, dd, J = 6.8, 2.0 Hz), 3.22 (1H, dq, J = 8.8, 6.8 Hz), 2.07 (3H, s), 1.87 (1H, bd, J = 3.9 Hz), 1.47 (3H, d, J = 5.9 Hz), 1.38 (3H, d, J = 5.9 Hz), 1.29 (3H, d, J = 6.8 Hz); MS (FAB) m / z: 745 (M + H) +. -235- 200403244 (8i) (1R, 5S, 6S) -2- (1- {4- [1- (1-acetamidoethoxycarbonyl) azetidin-3-ylaminemethylamidino ] · 1,3 -thiazole-2 -yl} PY butidin-3 -yl) sulfur-6-[(R)-1 -hydroxyethyl] -1-methyl-carbanil-2-thione-3 -Residual sodium salt: (1 foot, 5 3,63) -2- (1- {4- [1- (1-ethylacetoxyethoxybutyridin-3-yl) obtained in Example 8 (811) Amine methyl group] -1,3-_mile-2-yl} azetidine D-deoxy-3-yl) sulfur-6-[(R) -l-hydroxyethyl] -1-methyl-carbon ligand P-2-nitro-3-carboxylic acid p-nitrobenzyl ester (3.92 g, 5.26 mmol) was dissolved in tetrahydrofuran (110 ml) and distilled water (110 ml) in the presence of 10% Pd-C (3.92 g). Contact hydrogenation reduction was performed at room temperature for 3 hours. After the reaction was completed, the reaction was filtered. To the filtrate were added sodium bicarbonate (442 mg, 5.26 mmol), ethyl acetate, and distilled water, and the layers were separated. The aqueous layer was separated by Wash the aforementioned mixed solvent , Concentrated under reduced pressure, purified by Cosmosil reversed phase chromatography (distilled water ·· acetonitrile = 1〇〇 ·· 〇 ～ 85: 15, V / V), and freeze-dried to obtain the target white amorphous (1R, 5S, 6S) ) Acetyl ethoxycarbonyl) azetidin-3-ylamine formamidine] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -l-hydroxyl Ethyl] -1-methyl-carban-2-en-3-carboxylic acid sodium salt (1.90 g, 57% yield). ] H NMR (D20, 400ΜΗζ): δ 7.52 (1Η, s), 6.71 (1Η, q, J = 5.5 Hz), 4.57 (2H, t, J = 8.1 Hz), 4.48-4.32 (4H, m), 4.24 (1H, dq, J = 6.4, 6.2 Hz), 4. 18 (1H, dd, J = 9, 2, 2.4 Hz), 4.24-4.02 (4H, m), 3.43 (1H, dd, J = 6.2 , 2.4 Hz), 3.24 (1H, dq, J = 9.2, 7.3 Hz), 2.12 (3H, s), 1.50 (3H, d, J = 5.5 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.19 (3H, d, J = 7.3 Hz); 1 (^ 0 ^): 1749,1663,1603,1 545,1 390,1245,1 1 30,1072 (^: MS (FAB) m / z: 632 (M + H) +; HRMS (FAB) m / z: calcd. For C25H3009N5S2Na (M + H) +: 632.1461. Found 632.1440. Anal, calcd. For C26H3 () N5009S2Na.2 / 3H20: C, 46.65 %; H, 4.9U; N, 1Q. 88%; S, 9.96%. Found C, 46.42%; H, 5.44%; N, 11.12%; S, 9.47%. -236- 200403244 (Example 9) (Example 9) ( 111,53,63) -2- (1- {4- [1- (1-Ethylacetoxycarbonyl) azetidin-3-ylaminomethylmethyl] -u-thiazole_2-yl} azetidine Pyridin-3-yl) sulfur-6-[(R) -l-hydroxyethyl] -1 -methyl-carbophenan-2-ene-3 -carboxylic acid trimethylacetoxymethyl

The (11 ^, 53,63) -2- (1- {4- [1- (1-acetamidineethoxycarbonyl) azetidin-3 -ylaminomethylmethyl] obtained in Example 8 was obtained from Example 8. 3 -Thiazole-2 -yl} azetidin-3 -yl) thio-6-[(R) -l-hydroxyethyl M -methyl-carban-2-en-3-carboxylic acid sodium salt (3 00 mg '0.475 mmol) dissolved in dimethylacetamide (15 ml) under nitrogen and 0%:

Next, methyl pivalate (138 mg, 0.570 mmol) was added and stirred for 2 hours. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% brine, 5% aqueous sodium thiosulfate solution, 0.1 μ hydrochloric acid, and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate ·· methanol = 1 0 0: 0 to 9 8: 2, V / V) to obtain the target compound (1 R, 5 S, 6 S) as a white amorphous substance. -2-(1 · {4 -Π- (1-Acetylethoxycarbonyl) azetidine · 3-ylaminomethylamidino] -1,3 -thiazol-2-yl} azetidin-3-yl ) Sulfur-6-[(R)-;!-Hydroxyethylmethyl-carbophenan-2-en-3-carboxylic acid trimethylacetoxymethyl ester (335 mg, yield 98%). -237- 200403244… NMR (CDCl3, 500MHz): δ 7 · 50 (1H, bd, J = 7.8 Hz), 7.44 (1H, s), 6.78 (1H, q, J = 4.9 Hz), 5.98 ( 1H, d, J = 5.9 Hz), 5.84 (1H, d, J = 5.9 Hz), 4.89-4.81 (1H, m), 4.52 (2H, q, J = 7.8 Hz), 4.39 (2H, t, J = 8.8 Hz), 4.33-4.24 (2H, m), 4.24 (1H, dd, J = 9.8, 2.9 Hz), 4.10-4.04 (2H, m), 3.95 (2H, dt, J = 9.8, 4.9 Hz) , 3.26 (1H, dd, J = 6.8, 2.9

Hz), 2.07 (3H, s), 1.82 (1H, d, J = 4.9 Hz), 1.47 (3H, d, J = 4.9 Hz), 1.36 (3H, d, J = 5.9 Hz), 1.27 ( 3H, d, J = 7.8 Hz), 1.22 (9H, s); IR (KBr): 1754, 1726, 1 665, 1 542, 1491, 1 472, 1454cm-1; MS (FAB) m / z: 724 (M + H) +; HRMS (ESI) m / z: calcd. For C31H41011N5S2 (M + H) +: 724.2323. Found 724.231 3. (Example 1〇) (1 &, 53,63) -2- ( 1- {4- [1- (1-Acetylethoxycarbonyl) azetidin-3-ylaminemethylamidino] -1,3-thiazol-2-yl} azetidin-3-yl) sulfur- 6-[(R) -1-hydroxyethyl] -1-methyl-carbanil-2-ene-3-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester

(1 foot, 53,63) -2- (1- {4- [1- (1-ethylammonium ethoxycarbonyl) azetidin-3-ylaminomethylmethyl] -1,3 obtained in Example 8 · Thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -l-hydroxyethyl] -1-methyl-carbanil-2-ene-3-carboxylic acid sodium salt (300 mg, 0.475 mmol) was dissolved in dimethylacetamide (15 ml), and nitrogen iodide isopropylcarboxylate (147 mg, 0.570 mmol) was added under nitrogen and stirred for 1 · 5 hours. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 5% sodium thiosulfate aqueous solution, 0.1 M hydrochloric acid, saturated weight-238-200403244 sodium carbonate solution, saturated The brine was dried under anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 ~ 98: 2, V / V) to obtain the target compound. (111,53,63) -2- (1- {4- [1- (1-Ethylacetoxycarbonyl) azetidin-3-ylaminomethylmethyl] -1,3- Thiazole-2 -yl} azetidin-3 -yl) sulfan-6-[(R)-;! -Hydroxyethylb 1 -methyl-carbanil_2_ene-3-carboxylic acid 1-( Isopropoxycarbonyloxy) ethyl ester (335 Mg, yield 96%).

] H NMR (CDCI3, 500MHz): δ 7.53-7.48 (1Η, m), 7.44 (0.5Η, s), 7.43 (0.5H, s), 6.89 (0.5H, q, J = 4.9 Hz ), 6.88 (0.5H, q, J = 4.9 Hz), 6.78 (1H, q, J = 5.9 Hz), 4.96-4.82 (2H, m), 4.54-4.48 (2H, m), 4.39 (2H, t, J = 8.8 Hz), 4.33-4.20 (3H, m), 4.10-4.05 (2H, m), 3.99-3.93 (2H, m), 3.25 (1H, dd, J = 6.8, 2.9 Hz), 3.19 (1H, dq, J = 9.8, 7.8 Hz), 2.07 (3H, s), 1.85-1.81 (1H, m), 1.63-1.58 (3H, m), 1.47 (3H, d, J = 5.9 Hz), 1.38-1.25 (12H, m); IR (KBr): 1758, 1728, 1667, 1543, 1493, 1272, 1073cmH; MS (FAB) m / z: 740 (M + H) +; HRMS (ESI) m / z: calcd. for C31H41012N5S2 (M + H) +: 740.2271. Found 740.2292.

(Example 1 1) (1 R, 5 S, 6 S)-2-(1-{4-[1-(Buethenylethoxycarbonyl) azetidine-3 -ylaminomethylmethyl] -1 , 3 -Thiazole-2 -yl} azetidin-3 -yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carban-2-en-3-carboxylic acid (5-methyl-2-oxo-1,3-

239- 200403244 (1 R, 5 S, 6 S) obtained in Example 8-2-(1-{4-[1-(1 -Ethylacetoxycarbonyl) , 3-thiazol-2-yl} azetidin-3-yl) sulfide-6-transethyl μ-methyl-carbobenzoin-2-ene-3_carboxylic acid sodium salt (300 mg ' (0.575 mmol) dissolved in dimethylacetamide (15 ml), and A (5-methyl-2-oxo-1,3-difluorenyl-4-yl) was added under nitrogen at 0 ° C. ) Methyl chloride (143 mg, 0.712 mmol), sodium iodide (321 mg, 2.14 mmol), and stirred for 6.5 hours. After the reaction is complete, add ethyl acetate and wash the organic layer in order. 0% saline, 5% sodium thiosulfate aqueous solution, 0.05M hydrochloric acid, saturated silver bicarbonate I solution, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 〇〇〇: 〇〜95 = 5 'V / V) to obtain the target compound (1R, 5S, 6S) -2- (yellow amorphous) l- {4- [l- (l-Ethylacetoxycarbonyl) azetidin-3-ylaminomethylmethyl; l·l, 3-thiazol-2-yl} lγbutidine · 3-yl) sulfur -6-[(R) -l-hydroxyethyl] -l-methyl-carbophenan-2-ene-3-carboxylic acid (5-methyl-2-oxo-l, 3-diphosphone- 4-yl) methyl ester (237 mg, 69% yield). ] H NMR (CDCI3, 500MHz): δ 7.50 (1Η, bd, J = 7.8 Hz), 7.44 (1H, s), 6.78 (1H, q, J = 5.1 Hz), 5.05 (1H, d, J = 13.7 Hz), 4.98 (1H, d, J = 13.7 Hz), 4.89-4.81 (1H, m), 4.52 (2H, q, J = 7.8 Hz), 4.39 (2H, t, J = 8.8 Hz), 4.33- 4.26 (2H, m), 4.25 (1H, dd, J = 8.8, 2.0 Hz), 4.12 -4.05 (2H, m) 3.95 (2H, dt, J = 9.8, 4.9 Hz), 3.26 (1H, dd, J = 6.8, 2.0 Hz), 3.22 (1H, dq, J = 8.8, 6.8 Hz), 2.21 (3H, s), 2.07 (3H, s), 1.78 (1H, bd, J = 4.9 Hz), 1.47 (3H , d, J = 5.1 Hz), 1.37 (3H, d, J = 6.8 Hz), 1.27 (3H, d, J = 6.8 Hz); IR (KBr): 1 820, 1771, 1732,1665, 1 543, 1 340, 1 31 1, 1 235, H31cniH; MS (FAB) m / z: 722 (M + H) +; HRMS (ESI) m / z: calcd. For C30H35012N5S2 (M + H) +: 722.1802. Found 722.1818. -240- 200403244 (Example 12) (11155356 3) -2- (1- {4-[(18) -1- (Buethoxyoxyethoxycarbonylamino) methyl-2 -methyl- Propylamine formyl 1,3-thiazole-2 -yl} azetidin-3 -yl) sulfan-6-[(R) -l-hydroxyethyl] -1-methyl-carbophenan-2- Ene-3-carboxylic acid sodium salt

(1 2a) 3-Third-butadiphenylsilyloxy-1- {4-[(IS) -1-hydroxymethyl-2-methyl-propylaminomethyl] -1,3-thiazole-2- } Acridine, L-Valamine alcohol (364 mg, 2.74 mmol), 3-tert-butyldiphenylsilyloxy-1-(4-carboxy-1,3-thiazol-2-yl ) Acridine (described in Reference Example 1; 1.00 g, 2.28 mmol) was dissolved in dimethylformamide (30 ml), and diethylphosphonium cyanide (4 22 was added under nitrogen and ice cooling). Μl, 2.74 mmoles), triethylamine (76 8 μl, 2.74 mmoles), and stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate and 5% saline were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed successively with a saturated sodium bicarbonate solution and a saturated saline solution, and then dried over anhydrous sodium sulfate'filtration ', and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1 to 1: 2, V / V) to obtain a pale yellow amorphous 3-tert-butadiphenylsilyloxy-hydroxymethyl group. 2-methyl-propylamine formamidine; 1-1,3-thiazol-2-yl} azetidin (1.04 g, yield 87%). ] H NMR (CDCI3, 400ΜΗζ): δ 7.64-7.60 (4Η, m), 7.50- 7.38 (6Η, m), 7.36 (1H, s), 7.36-7.32 (1H, bd, J = 8.1 Hz), 4.80 -4.72 (1H, m), 4.11 (2H, t, J = 7.3 Hz), 4.01 (2H, dd, J = 5.1; 8.8 Hz), 3.84 -3.70 (3H, m), 2.82 (1H, t, J = 5.9 Hz), 2.06-1.97 (1H, m), 1.07 (9H, s), 1.02 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz); MS (FAB) m / z: 524 (M + H) +. 200403244 (1213) 3-Third-butadiphenylsilyloxy-1_ {4 _ [(13) _ ^ Azidemethyl-2-methyl-propylaminemethyl] -1,3-thiazole-2-yl} azetidin The 3-tert-butadiphenylsilyloxy-1_ {4-[(1S) -1-hydroxymethyl-2- Methyl-propylamine formamidine 1,3-thiazol-2-yl} azetidine (1.04 g, 1.98 mmol) was dissolved in tetrahydrofuran (30 ml), and the mixture was added under nitrogen and ice cooling. Phenylphosphonium azide (642 μl, 2.98 mmol), triphenylphosphine (782 mg, 2.98 mmol), diethyl azide dicarboxylate-40% toluene solution (1.1 0 g, 2.98 mmol), and stirred overnight. After the reaction was completed, ethyl acetate and saturated brine were added to the reaction solution, and the layers were extracted. The organic layer was dried over anhydrous sodium sulfate, filtered, and the mash was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane ·· ethyl acetate = 5: 1 ~ 3: 1, V / V) to obtain 3-third-butadiphenylsilyloxyazidemethyl as a pale yellow oil. -2-methyl-propylaminomethylmethyl] -1,3-thiazol-2-yl} azetidine (949 mg, yield 87%) ^ NMR (CDCI3, 400MHz): δ 7.64-7.60 (4Η , m), 7.50- 7.38 (6H, m), 7.36 (1H, s), 7.22-7.18 (1H, bd, J = 9. 5 Hz), 4.80-4.72 (1H, m), 4.16-4.09 (2H , m), 4.06-3.94 (3H, m), 3.53 (2H, t, J = 4.4 Hz), 2.00-1.90 (1H, m), 1.07 (9H, s), 1.00 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 6.6 Hz); MS (FAB) m / z: 549 (M + H) +. (12〇3-tert-butyldiphenylsilyloxy tert-butoxycarbonylamine Methyl-2-methyl-propylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin The 3-tert-butyldiphenylsilyloxy-1_ {4- obtained in Example 12 (12b) [(1S) -1-Azidemethyl-2-methyl-propylaminemethyl] -l, 3-thiaπ-2-yl} azetidine (940 mg, 1.71 mmol) dissolved in methanol (47 ml), in the presence of 10% Pd-C (940 200403244 mg), and subjected to hydrogenation reduction at room temperature for 1 hour. After the reaction, Ditributyl oxycarbonate (5 61 mg, 2.57 mmol) was added at room temperature, and stirred at room temperature for 2.5 hours. After the reaction was completed, the filtrate was concentrated under reduced pressure. The resulting residue was subjected to a silica gel column. Purification by chromatography (n-hexane: ethyl acetate = 3: 1, V / V), a white amorphous 3-tert-butadiphenylsilyloxy-b {4-[(lS) -tert-butane Oxycarbonylaminomethyl-2-methyl-propylaminomethylmethyl] -1,3-thiazol-2-yl} azetidine (930 mg, yield 87%).] H NMR (CDCI3, 400M 400ζ): δ 7.64-7.60 (4Η, m), 7.49- 7.38 (6Η, m), 7.35 (1H, s), 7.21-7.15 (1H, bd, J = 9.5 Hz), 4.92-4.85 (1H, m), 73- 4 72 (1H, m), 4.16-4.09 (2H, m), 4.02 (2H, dt, J = 5.1, 8.1 Hz), 3.99-3.90 (1H, m), 3.37 (1H, dt, J = 12.5, 4.8 Hz), 3.30-3.18 (1H, m), 1.92-1.82 (1H, m), 1.37 (9H, s), 1.07 (9H, s), 0.99 (3H, d, J = 6.6 Hz), 0.98 ( 3H, d, J = 6.6 Hz); MS (FAB) m / z: 623 (M + H) +. (12d) 3-hydroxy-1- {4 _ [(1S) -1-third butoxycarbonyl amine Methyl-2-methylpropylamine formamidine] -1,3-thiazol-2-yl} azetidin The 3-tert-butyldiphenylsilyl obtained in Example 12 (12c) Oxy-1- {4 _ [(1S) -1-Third-butoxycarbonylaminomethyl-2-methyl-propylaminemethylmethyl] -1,3-thiazol-2-yl} azetidin (1.38 g (2.22 mmol) was dissolved in anhydrous tetrahydrofuran (41 ml), and a 1.0 M tetrabutylammonium fluoride-tetrahydrofuran solution (2.66 ml, 2.66 mmol) was sequentially added under ice cooling, and stirred for 1 hour. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with a saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 2 ~ -243- 200403244 1: 3, V / V) to obtain 3 _hydroxy___ 4-[( 1 s) -1 -Third-butoxycarbonylaminomethyl-2-methylpropylamine formamidine-thiazole-2 -yl-butanidine (829 mg, yield 97%). ^ NMR (CDCI3, 400MHz): δ 7.36 (1H, s), 7.25 ~ 7.19 (1H, bd, J = 8.8 Hz) \ 4.98-4.90 (1H, m), 4.88-4.79 (1H, m), 4.33 ( 2H, t, J = 7.7 Hz), 3.98 (2H, dt, J = 8.8, 4.2 Hz), 3.98-3.88 (1H, m), 3.37 (1H, dt, J = 14.6, 4.8 Hz), 3.30-3.18 (1H, m), 2.78-2.72 (1H, m), 1.92-1.82 (1H, m), 1.68-1.62 (1H, br), 1.37 (9H, s), 0.99 (3H, d, J = 6.6 Hz ), 0.97 (3H, d, J = 6.6 Hz); MS (FAB) m / z: 3 8 5 (M + H) +. (12e) 3-Methanesulfonyloxy-1- {4 _ [(1S) -1-Third-butoxycarbonylaminomethyl-2-methyl-propylaminemethylmethyl] -1,3-thiazole-2- Methyl} azetidine The 3-hydroxy-1- {4-[(1S) -1-tertiary butoxymine amine methyl-2-methylpropylamine formamyl group] obtained in Example 12 (12 2d) -1 3, thiazol-2-yl} azetidine (820 mg, 2.13 mmol) was dissolved in dichloromethane (41 ml), and methanesulfonyl chloride (495 µl, 6.40 mmol) was added under ice cooling. 3. Triethylamine (897 μl, 6.40 mmol), stir for 30 minutes. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 2, V / V) to obtain pale yellow amorphous 3.methanesulfonyloxy-tert-butoxycarbonylamine methyl-2. -Methyl-propylamine formamyl] -1,3-thiazol-2-yl} azetidine (829, yield 99%). 200403244 ^ -NMR ^ DC ^, 400MHz): δ 7.44 (1H, s), 7.22-7.16 (1H, bd, J = 8.8 Hz), 5.45-5.40 (1H, m), 4.94-4.84 (1H, m) , 4.47 (2H, t, J = 7.7 Hz), 4.28 (2H, dt, J = 10-3, 4.6 Hz), 4.00 — 3.90 (1H, m), 3.33 (1H, dt, J = 13.9, 4.4 Hz), 3. 32-3.22 (1H, m), 3. Π (3H, s), K 93-1.83 (1H, m), 1.37 (9H, s), 1.00 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 6.6 Hz); MS (FAB) m / z: 463 (M + H) +. (12〇3-ethylsulfanyl-1- {4-[( 13) -1-Third-butoxycarbonylaminomethyl-2-methyl-propylaminomethyl] -1,3-thiazol-2-yl} azetidine Methanesulfonyloxy-l- {4-[(IS) -1-Third-butoxycarbonylamidomethyl-2-methyl-propylamine formamidine; | -1,3-thiazol-2-yl} to Ding Diao (970 mg, 2.10 mmol) was dissolved in dimethylformamide (50 ml), potassium thioacetate (1.44 g, 12.6 mmol) was added at room temperature, and stirred in an oil bath at 80 ° C 5 hours. After the reaction was completed, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was saturated with a sodium bicarbonate solution. After washing with saturated brine, it was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 2 ~ 1: 1, V / V). , Can be obtained as a light brown amorphous 3-ethylsulfanyl third butoxycarbonylaminomethyl-2-methyl-propylamine methylsulfanyl: thiazol-2-yl} azetidine (6 3 2 mg, yield 68%). 1H ~ NMR (CDCI3, 400MHz): δ 7.40 (1H, s), 7.21-7.16 (1H, bd, J = 10.2 Hz), 4.92-4.86 (1H, m), 4.54 (2H, dt, J = 1.5, 8.2 Hz), 4.48 to 4.41 (1H, m), 4.00 (2H, dt, J = 8.8, 5.7 Hz), 3.98-3.90 (1H, m), 3.37 (1H, dt, J = 13.9, 4.8 Hz), 3.30-3.21 (1H, m), 1.92-1.82 (1H, rn), 1.37 (9H, s), 0.99 (3H, d, J = 7.3 Hz), 0.97 (3H, d, J = 6.6 Hz); MS (FAB) m / z: 443 (M + H) +. (12g) 3 · Ethylthio-l- {4-[(lS) -l- (Buethyloxyethoxycarbonyl) Aminomethyl-245-200403244-2-methyl-propylaminomethylmethyl] -i, 3-thiazol-2-yl} azetidine The 3-ethylpyridylthio group obtained in Example 12 (12f) _b { 4-[(ls) -1-Third-butoxycarbonylamidomethyl-2-methyl-propylamine formamidine 1,3-thienyl-2-yl} 0 mg 'i.42 mmol) was dissolved in U4_dioxane (63 ml), and a 4N-HC1 / 1,4-dioxane solution (6.3 ml) was added under ice cooling, at room temperature Stir for 1 hour. After the reaction was completed, ether was added and the crystals were filtered. The crystals were washed with diethyl ether to obtain pale brown amorphous 3-ethylamidinethio_ b {4-[(1 S) -1-aminomethyl-2-methyl-propylaminomethyl] -1], A crude product of 3-thieneta-2-yl} ργ butnidine hydrochloride. The obtained 3-ethylamidinethio-1 · {4-[(1 S)-1 -aminomethyl-2 -methyl-propylaminomethylmethyl; 1-1,3-thiazol-2-yl} azetidine The crude product of pyridine hydrochloride (5 50 mg, 1.42 mmol) was dissolved in dichloromethane (28 ml), and the ethyl acetate oxyethyl chloroformate (23 7) was added under ice-cooling. (Mg, 1.42 mmol), 4-dimethylaminopyridine (434 mg, 3.55 mole), and stirred at room temperature for 1 hour. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: '2, V / V) to obtain 3-ethylfluorenylthio-1] 4-[(1S) -1 as a pale yellow amorphous substance. -(1-Ethyloxyethoxycarbonyl) aminemethyl-2-methyl-propylaminemethylmethyl] -1,3-thiazol-2-yl} azetidine (5 8 4 mg, yield 87%) . ] H NMR (CDCI3, 400ΜΗζ): δ 7.41 (1Η, s), 7.22-7.16 (1Η, m), 6.79 (0.5H, q, J = 5.9 Hz), 6.74 (0.5H, q, J = 5.9 Hz ), 5.44-5.25 (1H, m), 4.55 (2H, dt, J = 1.5, 8.4 Hz), 4.49-4.40 (1H, m), 4.01 (2H, dt, J = 8.1, 4.6 Hz), 3.76- 3.70 (1H, m), 3.52-3.41 (1H, m), 3.36 -3.20 (1H, m), 2.37 (3H, s), 2.05 (3H, d, J = 2.9 Hz), 1.94-1.82 (1H, ui), 1.43 (1.5H, d, J = 5.9 Hz), 1.38 (1.5H, d, J = 5.9 Hz), 1.00 (3H, d, J = 6.6 Hz), 0.98 (3H, d , J = 6.6 Hz); MS (FAB) m / z: 473 (M + H) +. 200403244 (12h) (lR, 5S, 6S) -2- (l- {4-[(lS) -l- (l -Ethyloxyethoxycarbonylamino) methyl-2-methyl-propylaminomethyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfur-6-[( 11) -1-Hydroxyethyl] -1-methyl-carbobin-2-ene-3-carboxylic acid p-nitrobenzyl ester The 3-ethenylthioethenyloxyethoxylate obtained in Example 12 (12 g) Carboxamido) methyl-2-methyl-propylamine formamidine] -1,3-thiazol-2-yl} azetidine (580 mg, 1.23 mmol) dissolved in dimethylformamide (29 Ml), add hydrazine acetate (135 mg, 1.47 mmol) under nitrogen and room temperature, stir 1 hour. After the reaction was completed, (lR, 5S, 6S) -2- (diphenylphosphoniumoxy) -6-[(R) -1-hydroxyethyl] -1-methyl- was added dropwise under nitrogen and ice cooling. A solution of carbenil-2-en-3-carboxylic acid p-nitrobenzyl ester (731 mg, 1.23 mmol) in acetonitrile (37 ml), followed by diisopropylethylamine (855 μl, 4.91 mmol) ), Slowly warm to room temperature, and stir overnight. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was extracted in layers with ethyl acetate. The obtained organic layer was washed successively with 5% saline and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1..5 ~ ethyl acetate..methanol = 98: 2, V / V) to obtain a pale yellow amorphous (1R, 5S, 6S). Bu 2. (1- {4 _ [(1S) -1- (1-Ethyloxyethoxycarbonylamino) methyl-2-methyl-propylaminomethylmethyl] -1,3-thizone-2 -Yl} azetidin-3-yl) sulfan-6-[(R) -l-hydroxyethylbenzene ^ methyl-carbophenan-2-ol-3_residual acid paranitrate vinegar (795 mg, Yield 83%). -247- 200403244] H NMR (CDCI3, 500MHz): 6 8.23 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 7.42 (1H, d, J = 1.9 Hz), 7.19 (1H, t, J = 10.7 Hz), 6.80 (0.5H, q, J = 4.9 Hz), 6.72 (0.5H, q, J = 4.9 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.36 -5.31 (0.5H, m), 5.30-5.25 (0.5H, m), 5.26 (1H, d, J = 13.7 Hz), 4.57 -4.46 (2H, m), 4.34- 4.23 (3H, m), 4.08 (2H, t, J = 6.8 Hz), 4.00: 3.91 (1H, m), 3.52-3.42 (1H, m), 3.40-3.33 (1H, m), 3.30 (1H, dd, J = 6.8, 2.9 Hz), 3.29-3.20 (1H, m), 2.05 (3H, s), 1.92-1.80 (2H, m), 1.44 (1.5H, d, J = 5.9 Hz), 1.38 (3H d, J = 6.8 Hz), 1.35 (1.5H, d, J = 5.9 Hz), 1.28 (3H, d, J = 6.8 Hz), 1.〇〇 (3H, d, J = 7.3 Hz), 0.98 (3H, d, J = 7.3 Hz); MS (FAB) m / z: 775 (M + H) +. (12i) (lR, 5S, 6S) -2- (l- {4-[(lS) -l- (l-acetamidoethoxycarbonylamino) methyl-2-methyl- Propylamine formyl] -1,3 -thiow-2-yl} ργ butn-n-d-3-yl) sulfur-6-[(R) -l-hydroxyethyl] -1-methyl-carbon ligand -2-ene-3-carboxylic acid sodium salt

(LR, 5S, 6S) -2- (l- {4-[(lS) -1- (lZ ethoxyethoxycarbonylamino) methyl-2-methyl-propylamine obtained in Example 12 (12h) Methylfluorenyl] -1,3-thiazol-2-yl} azetidin-3 -yl) sulfan-6-[(R)-1 -hydroxyethyl] -1 -methyl-carbon ligand-2- Ene · 3-residue acid p-nitrate; esters (7.90 g; 1.0 mmol) were dissolved in tetrahydrofuran (40 ml) and distilled water (40 ml) in the presence of 10% C (790 mg), subjected to contact hydrogenation reduction at room temperature for 2 hours. After the reaction was completed, the reaction mixture was filtered. To the filtrate were added sodium bicarbonate (86 mg, 1.0 mmol), ethyl acetate, and distilled water 'for layered extraction. The aqueous layer was washed with the above-mentioned mixed solvent, and then concentrated under reduced pressure, and purified by reverse phase chromatography (distilled water: acetonitrile, 100: 0 to 80: 20, V / V), and freeze-dried. A white amorphous (lR, 5S, 6S) -2- (l- {4-[(lS) -l- (l-ethoxyethoxycarbamino) methyl-2-methyl) -Diamine formamyl] -1,3-thiazol-2-yl} azetidine-248- 200403244 pyridin-3-yl) sulfur-6-[(R)-; l-hydroxyethyl] -1-formyl -Carbonen-2-en-3-carboxylic acid sodium salt (282 mg, 42% yield). ] H NMR (D20, 400MHz): δ 7.48 (T, d, J = 1.5 Hz), 6.69 (0.5H, q, J = 5.5 ^

Hz), 6.63 (0.5H, q, J = 5.5 Hz), 4.57 (2H, t, J = 8.1 Hz), 4.40-4.32 (1H, m), 4.25 (1H, dq, J = 6-4, 6.1 Hz), 4.20 (1H, dd, J = 9.1, 2.5

Hz), 4.11-4.04 (1H, m), 3.48-3.43 (1H, m), 3.43 (1H, dd, J = 6.1, 2.5 Hz), 3.32-3.21 (2H, m), 2.08 (1.5H, s ), 1.96 (1.5H, s), 1.92- 1.81 (1H, m), 1.44 (1.5H, d, J = 5.5 Hz), 1.38 (1.5H, d, J = 5.5 Hz), 1.30 (3H, d , J = 6.4 Hz), 1-20 (3H, d, J = 7.3 Hz), 0.98 (3H, d, J = 6.9 Hz), 0.94 (1.5H, d, J = 6.9 Hz), 0.93 (1.5H , d, J = 6.9 Hz); IR (KBr): 1745, 1654, 1598, 1 546, 1493, 1470, 1 392, 1 376, 1 314, 1 290, 1262, 1241 cmH; MS (FAB) m / z: 662 (M + H) +; HRMS (ESI) m / z: calcd. for C27H36N4S209Na (M + H) +: 662.1930. Found 662.1926. (Example 13) (lR, 5S, 6S) -2 -(l- {4-[(lS) -l- (l-acetamidoethoxycarbonylamino) methyl-2-methyl-propylaminemethyl] -1,3-thiazol-2-yl} Acridine-3-yl) sulfur 6-[(R)-:!-Hydroxyethyl] -p-methyl-carbanil-2-ene-3-carboxylic acid trimethylacetoxymethyl

The (1R, 5S, 6 S) -2- (1- {4-[(IS) -1- (1-acetamidoethoxycarbonylamino) methyl-2-methyl-propylamine obtained in Example 12 Formamylthiazol-2-yl} azetidin-3-yl) sulfan-6-[(R) -l-hydroxyethyl] -1-methyl-carban-2-en-3-carboxyl 200403244 Sodium salt (250 mg '0.3 7 8 mmol) was dissolved in dimethylacetamide (12 ml)' under nitrogen and 0 ° C was added iodized methyl pivalate (1 丨 〇 (Mg, 0.45 4 mmol), and stirred for 1 hour. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 10% sodium thiosulfate aqueous solution, 0.01M hydrochloric acid, saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Zhengjiyuan: ethyl acetate = 1: 3 ~ 1: 4, V / V), and the target compound was obtained as (111,58,63) -2- (light yellow amorphous) 1- {4-[(13) -1- (1-Ethyloxyethoxycarbonylamino) methyl-2-methyl-propylaminemethyl] -1,3-thiazol-2-yl} azetidine Pyridin-3-yl) sulfur-6-[(R) -l-Ethyl] -1-methyl-carbanil-2_yan-3 -residue trimethylacetoxymethyl ester (264 mg , Yield 93%). ^ NMR (CDCI3, 500MHz): δ 7.42 (0.5Η, s), 7.42 (0.5H, s), 7.28-7.22 (1H, m), 6.80 (0.5H, q, J = 5.9 Hz), 6.72 ( 0.5H, q, J = 5.9 Hz), 5.98 (1H, d, J = 5.1 Hz), 5.84 (1H, d, J = 5.1 Hz), 5.38 (0.5H, t, J = 5.9

Hz), 5.33 (0.5H, t, J = 5.9 Hz), 4. 58-4.46 (2H, m), 4. 35-4.20 (3H, in), 4.12-4.04 (2H, m), 4.00-3.91 (1H, m), 3.52-3.17 (4H, m), 2.05 (1.5H, s), 2.05 (1.5H, s), 1.98-1.85 (2H, m), 1.44 (1.5H, d, J = 5.9 Hz), 1.36 (1.5H, d, J = 5.9 Hz), 1.35 (1H, d, J = 6.6 Hz), 1.27 (3H, d, J = 7.3 Hz), 1.22 (9H, s), 1.00 (3H , d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz); IR (KBr): 1753, 1 658, 1 543, 1492, 1471cm-1; MS (FAB) m / z: 754 ( M + H) +; HRMS (ESI) m / z: calcd. For 〇33Η47〇ηΝ552 (M + H) +: 754.2792 Found 754.2771. (Example 14) (1R, 5S, 6S) -2 · (b. { 4-[(lS) -l- (l-acetamidoethoxycarbonylamino) methyl-2-methyl-propylaminomethylamido-thiazol-2-yl} 〇Y butanidine-3. ) Sulfur-6-[(R)-1 -Hydroxyethyl] -p-methyl-carbanil-2 -ene-3 -carboxylic acid 1-(iso-250- 200403244 propoxycarbonyloxy) ethyl ester

(1 R, 5 S, 6 S)-2-(1-{4-[(1 S)-1-(1-Ethyloxyethoxycarbonylamino) methyl-2- Methyl-propylamine formamidine 1,3-thiazol-2-yl} azetidine n-di-3-yl) sulfur-6-[(R) -1-transethyl] -1-methyl-carbon ligand Nian-2-Article-3-residual sodium salt (2 70 mg, 0.40 8 mmol) was dissolved in dimethylacetamide (14 ml), and isopropylcarboxylic acid was added under nitrogen at 0 ° C. 1 -Ethyl iodoethyl ester (126 mg, 0.49 mmol), stirred for 1 hour. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 5% sodium thiosulfate aqueous solution, 0.05M hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution under anhydrous sodium sulfate. Dry, filter, and concentrate the filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 98 to 2, V / V) to obtain (11 ^, 53, 63) -2 of the target compound as a pale yellow amorphous substance. -(1- {4-[(13) -1- (1-Ethyloxyethoxycarbonylamino) methyl-2-methyl-propylaminomethyl]] 1,3-thiazol-2-yl} acyl Butidin-3-yl) sulfur-6-[(R) -l-hydroxyethyl] -1-methyl-carbobenzoin-2-ene-3-carboxylic acid 1- (isopropoxycarbonyloxy) Ethyl ester (281 mg, 90% yield). -251- 200403244] H NMR (CDCI3, 500MHz): δ 7.42 (1H, t, J = 1.9 Hz), 7.23-7.17 (1H, m), 6.89 (1H, dt, J = 9.8, 4.9 Hz), 6.80 (0.5H, q, J = 5.9 Hz), 6.73 (0.5 H, q, J = 4.9 Hz), 5.38-5.34 (0.5H, br), 5.33-5.28 (0.5H, br), 4.95- 4.86 (1H, m), 4. 56-4.45 (2H, m), 4.34-4.21 (3H, m), 4.10- 4.04 (2H, m), 3.99-3. 92 (1H, m), 3.51-3.30 (2H, m), 3.25 (1H, dd, J = 6.8, 2.0 Hz), 3.20 (1H, dq, J = 6.8, 6.6 Hz), 2.05 (1.5H, s), 1.97 (1.5H, s), 1.95-1.86 (1H, m), 1.79 (0.5H, d, J = 4.9 Hz). 1.76 (0.5H, d, J = 4.9Hz), 1.62 (1.5H, d, J = 4.9 Hz), 1_59 (1.5 ·, d, J = 4.9 Hz), 1.45-1.24 (1 2H, m), 1.00 (3H, d, J = 6.8 Hz), 0.99 (3H, d, J = 6.8 Hz) ; 'IR (KBr): 1756, 1659, 1544, 1493, 1470, 1374, 1320, 1 271, 1229, 1 181, 1 143,1 102, 1075 cm-1; MS (FAB) m / z: 770 ( M + H) +; HRMS (ESI) m / z: calcd. For C33H48012N5S2 (M + H) +: 770.2741. Found 770.2743. (Example 15) (lR, 5S, 6S) -2- (l- {4 -[(lS) -l- (l-Ethyloxyethoxycarbonylamino) methyl-2-methyl-propylaminomethyl]- 1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carban-2-en-3-carboxyl (5-methyl-2-oxo-1,3-difluoren-4-yl) methyl ester

(111,53,63) -2- (1- {4-[(18) -1- (1-Ethoxyoxyethoxycarbonylamino) methyl-2-methyl-propylamine methyl obtained in Example 12 Fluorenyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfan-6-[(R) -l-hydroxyethyl] -1-methyl-carbanil-2-ene -3-carboxylic acid sodium salt (250 mg, 0.378 mmol) was dissolved in dimethylacetamide (13 mmol 200,403,244 liters), and (5-methyl-2-oxo-1) was added under nitrogen at 0 ° C. , 3-Difluoren-4-yl) methyl chloride (114 mg, 0.567 mmol), sodium iodide (255 mg '1.70 mmol) was added and stirred for 8.5 hours. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 10% sodium thiosulfate aqueous solution, 0.01M hydrochloric acid, saturated sodium bicarbonate solution, saturated saline, and anhydrous sodium sulfate. It was dried under reduced pressure, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 00 to 98: 2 'V / V) to obtain (lR, 5S, 6S) -2-of a pale yellow amorphous compound of interest. (l- {4-[(lS) -l- (l-acetamidoethoxycarbonylamino) methyl-2-methyl-propylaminomethylamido] -1,3-thiazol-2-yl} acyl Butidin-3-yl) sulfur-6-[(R) · 1-hydroxyethyl] -1-methyl-carbophenan-2-ene-3-carboxylic acid (5-methyl-2-oxo- 1,3-Difluorenyl-4-yl) methyl ester (228 mg, 80% yield). ] H NMR (CDCI3, 500ΜΗζ): δ 7.43 (0.5Η, s), 7.42 (0.5Η, s), 7.21 (1H, bt, J = 9.5 Hz), 6.80 (0.5H, q, J = 5.9 Hz ), 6.72 (0.5H, q, J = 5.9 Hz), 5.35 (0.5H, bt, J = 4.9 Hz), 5.29 (0.5H, bt, J = 4.9 Hz) 7 5.05 (1H, d, J = 13.9 Hz), 4.97 (1H, d, J = 13.9 Hz), 4.57 -4.46 (2H, m), 4.35-4.22 (3H, m), 4.12-4.06 (2H, m), 4.00-3.92 (1H, in) , 3.51- 3.19 (4H, m), 2.21 (3H, s), 2.05 (3H, s), 1.93-1.82 (2H, m), 1.44 (1.5H, d, J = 5.9 Hz), 1.37 (3H, d, J = 5.9 Hz), 1.36 (1.5H, d, J = 5.9 Hz), 1.27 (3H, d, J = 7.3 Hz), 1.00 (3H, d, J = 6.6 Hz), 0.99 (3H , d, J = 6.6 Hz); IR (KBr): 1820, 1738, 1658, 1543, 1492, 1471 cm'1; MS (FAB) m / z: 752 (M + H) +; HRMS (ESI) m / z: calcd. for C33H41012N5S2 (M + H) +: 752.2272 · Found 752.2278. (Example 16) (lR, 5S, 6S) -2- (l- {4- [3- (l-acetamidine Oxycarbonylamino) azetidin-1-carbonyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfur-6-[(R via ethyl; 1-1-methyl -Carbonyl-2-ene-3-carboxylic acid sodium salt-253- 200403244

(16 &) 3-Third-butadiphenylsilyloxy-1- {4- [3-hydroxyazetidine-1-carbonyl] -1,3-thiazol-2-yl} azetidine Benzyl-3- is dissolved in methanol (180 ml) by BY butidine (6.00 g, 25.1 mmol) in the presence of i0% pd-C (6.0 g) at 50 Contact hydrogenation reduction in a water bath at ° C for 2 hours. After the reaction was completed, the mixture was filtered, the filtrate was washed with methanol, and the filtrate was concentrated under reduced pressure. The obtained crude product, 3-butadiphenylsilyloxy-1- (4-carboxy-1,3-thiazol-2-yl) azetidin (described in Reference Example 1; 6.0 g, 25.1 mmol) Dissolve in dimethylformamide (220 ml), add diphenylphosphonium cyanide (3.87 ml, 25.1 mol), triethylamine (3.24 ml, 25.1 mmol) under nitrogen and ice cooling, and stir overnight . After the reaction was completed, 'ethyl acetate and 5% saline were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed successively with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and n-hexane were added to the obtained residue and filtered to obtain 3-tert-butadiphenylsilyloxy-l- {4- [3-hydroxyazetidine-1-carbonyl group as a pale yellow solid; 1-1 , 3-thiazol-2-yl} azetidin (5.94 g, 48% yield). NMR (CDCI3, 400MΗζ): δ 7.64-7.60 (4Η, m), 7.48-7.38 (6Hr m), 7-39 (1H, s), 4.84-4.71 (2H, m), 4.69-4.62 (1H, m ), 4.42-4.35 (2H ^ m), 4.08 (2H, t, J = 7.8 Hz), 4.02-3.75 (3H, m), 2.22 (1H, d, J = 6.6 Hz), 1.07 (9H, s) ; MS (FAB) m / z: 385 (M + H) +. (10b) 3-tert-butyldiphenylsilyloxy 4- (443-methanesulfonyloxyazetidine-1- -254- 200403244 carbonyl ] -1,3-thiazol-2-yl} azetidin Example 3- (6-thibutadiphenylsilyloxy) -l- {4- [3-hydroxybutane-oxocarbonyl] obtained in Example 6 (16a) ] _1,3-thiazol-2-yl} azetidine (6.78 g, 13.7 mmol) was dissolved in dichloromethane (203 ml), and methanesulfonyl chloride (1.59 ml '20.6 mmol) was added under nitrogen and ice cooling. Mol), triethylamine (2.89 ml, 20.6 mmol), and stirred for 3.5 hours. After the reaction, ethyl acetate and saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was separated with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (n-hexane). : Ethyl acetate = 1: 3 ~ 1: 4, V / V) Purification, 3-tert-butadiphenylsilyloxy-methanesulfonyloxazidin-1-carbonyl group was obtained as a pale yellow solid] -1 , 3-thiazol-2-yl} azetidin (7.41 g, yield 95%).] H NMR (CDCI3, 400MHz): δ 7.64-7.60 (4Η, m), 7.49-7.37 (6H, m ), 7.40 (1H, s), 5. 32-5.28 (1H, m), 4.99-4.90 (1H, m), 4.78-4.62 (2H, m), 4.53-4.41 (1H, m), 4.28-4.20 (1H, m), 4.09 (2H, t, J = 7.8 Hz), 3.99 (2H, dd, J = 8.8, 5.1 Hz), 3.09 (3H, s), 1.07 (9H, s) (16c) 3 -Third-butadiphenylsilyloxy-l- {4- [3-azidoazetidin-1-carbonyl] -1,3-thiazole-2-yl} azetidin Example 16 (16b) The obtained 3-tert-butyldiphenylsilyloxy-1- {4- [3-methanesulfonyloxyazetidine-oxocarbonyl] -1,3-thiazol-2-yl} azetidine (7.41 g, 13.0 MM) was dissolved in dimethylformamide (220 ml). Sodium azide (2.53 g, 38. 9 mmol) was added at room temperature in an oil bath at 90 ° C. Stir overnight. After the reaction was completed, ethyl acetate and 5% brine were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was under anhydrous sodium sulfate

-255- 200403244 Dried, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Zhengjiyuan: ethyl acetate = 2: 1 ~ 1: 1 'V / V)' to obtain the light yellow amorphous 3-tertiary succinic acid sand oxy-1 -{4-[3 -Azide to butidine-oxocarbonyl]-1,3-thiazole-2-yl} azetidine (6.27 g, yield 93%).屮 NMR (CDCI3, 400MHz): δ 7.64-7.60 (4H, m), 7.49-7.38 (6H, ITI), 7.39 (1H, s), 4.89-4.82 (1H, m), 4.80-4.73 (1H, m), 4.52- 4.45 (1H, m), 4.45-4.37 (1H, m), 4.34-4.28 (1H, m), 4.12-4.05 (3H, m), 3.99 (2H, dd, J = 8.8, 5.1 Hz), 1.07 (9H, s); MS (FAB) m / z: 519 (M + H) +. (16 (1) 3-Third-butadiphenylsilyloxy-1- {4- [3- (Third-butoxycarbonylamino) azetidine-1 · carbonyl] -1,3-thiazol-2-yl} azetidine The 3-tertiary-butadiene obtained in Example 16 (1 6 c) Diphenylsilyloxy-1-{4-[3 -azidoazetidine-1-carbonyl: thiazol-2-yl} azetidine (6.27 g, 12.1 mmol) was dissolved in methanol (190 ml ), In the presence of 10% Pd-C (6.27 g), subjected to contact hydrogenation reduction at room temperature for 1.5 hours. After the reaction, ditrityl oxycarbonate (3.96 g, 18.1 mmol) was added to the reaction system. Ear), and stirred overnight. After the reaction was completed, the filtrate was washed with methanol, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1, V / V). Available as a pale yellow solid Butadienesilyloxy-1- {4- [3- (third butoxycarbonylamino) azetidin-1-carbonyl] -1,3 -thiazol-2-yl} ργ Butidine (6.2 9 g , Yield 8 8%).。 NMR (CDCI3, 400MHz): δ 7.64-7.60 (4H, m), 7.49-7.38 (6H, m), 7.37 (1H, s), 5.00-4.92 (1H, m), 4.92-4.82 (1H, m), 4.78-4.71 (1H, m), 4.55-4.40 (2H, m), 4.34-4.27 (1H, m), 4.08 (2H, t, J = 8.1 Hz) , 3.99 (2H, dd, J = 8.8, 5.1 Hz), 3.92-3.85 (1H, m), 1.46 (9H, s), 1.07 (9H, s); MS (FAB) m / z: 593 (M + H) +. -256- 200403244 U6e) 3-hydroxy-1 · {4- [3- (third butoxycarbonylamino) azetidine-1-carbonyl] -1, 3 -thiazole-2-yl} Acridine. The 3-tertiary butadiphenylsilyloxy-1-{4-[3-(third butoxycarbonylamino) aziridine-1-carbonyl group] obtained in Example 16 (1 6 d) was used. _1,3-thiazol-2-yl} azetidine (6.29 g, 10.6 mmol) was dissolved in anhydrous tetrahydrofuran (90 ml), and 1.0M tetrabutylammonium fluoride-tetrahydrofuran solution (12.7 Ml, 1 2 · 7 mmol) and stir for 30 minutes. After the reaction was completed, ethyl acetate and saturated brine were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. After adding ethyl acetate and filtering, 3-hydroxy-1- {4- [3- (third butoxycarbonylamino) azetidine-1-carbonyl] -1,3-thiazole-2- can be obtained as white crystals. Yl} azetidine (3.66 g, yield 97 / °). ] H NMR (DMS0-d6, 500MHz): δ 7.56 (1H, bd, J = 7.8 Hz), 7.41 (1H, s), 5.82 (1H, d, J = 6.8 Hz), 4.69-4.58 (2H, m ), 4.36-4.25 (1H, m), 4.25-4.12 (4H, m), 3.82-3.73 (3H, m), 1.39 (9H, s); MS (FAB) m / z: 355 (M + H) +. (16〇3-methanesulfonyloxy-1- {4- [3- (third butoxycarbonylamino) azetidin-1-carbonyl] -1,3-thiazol-2-yl} acyl Butidine was used in Example 16 (3-hydroxy-l- {4- [3- (third butoxycarbonylamino) azetidin-1-carbonylbu 1,3-thiazol-2-yl} azetidine obtained in Example 16 Pyridine (3.66 g, 10.3 mmol) was dissolved in a mixed solvent of dichloromethane (37 ml) and pyridine (37 ml). Methanesulfonyl chloride (2.40 ml, 31.0 mmol) and triethyl ether were added under ice-cooling. Amine (4.3 4 ml, 3 1.0 mmol) was stirred overnight. After the reaction was completed, ethyl acetate and water were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained -257- 200403244 was obtained The organic layer was washed with a potassium hydrogen sulfate aqueous solution 'saturated sodium bicarbonate solution and saturated brine in that order, dried over anhydrous sodium sulfate, and filtered' and the filtrate was concentrated under reduced pressure. Ethyl acetate was added. And Zhengjiyuan after filtering 'can be obtained as a pale yellow solid of 3-methanesulfonyloxy third butoxycarbonylamino group) ° Y butan-1-yl group] fluoren-2-yl} azetidine (4 · 77 g 'yield 100%).' H NMR (CDCI3, 400MHz): < 5 7.47 (1H, s), 5.45-5.39 (1H, m), 5.00 -4.92 (1H, m), 4.92-4.83 ( 1H, m), 4.58-4.42 (2H, m), 4.43 (2H, dd, J = 9.5, 6.6 Hz), 4.37-4.28 (1H, m), 4.24 (2H, dd, J = 9.5, 4.4 Hz) , 3.98-3.86 (1H, m), 3.11 (3H, s), 1.46 (9H, s); MS (FAB) m / z: 432 (M + H) +. (16g) 3 -ethylsulfanyl- l- {4- [3- (Third-butoxycarbonylamino) butan-1-carbonyl] -1,3-thiazole-2-yl} azetidine The obtained from Example 16 (16 f) 3-Methanesulfonyloxy-1-{4-[3-(third butoxycarbonylamino) azetidine-1-carbonyl] -1,3-thiazol-2-yl} azetidine (4.45 g :: 10.3 millimoles) dissolved in dimethylformamide (220 ml), potassium thioacetate (7.06 g, 6 1.8 millimoles) was added at room temperature, and the oil at 80 ° C Stir in the bath for 8 hours. After the reaction was completed, ethyl acetate and 5% saline were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane ·· ethyl acetate = 1 ·· 3, V / V) to obtain 3-ethylsulfanyl-1- {4- [3- ( Tributoxycarbonylamino) azetidin-1-carbonyl] -1,3-thiazol-2-yl} azetidin (3.18 g, yield 75%). ] H NMR (CDCI3, 400MHz): (5 7.43 (1H, s), 5.02-4.94 (1H, m), 4.92 -4.83 (1H, m), 4.50 (2H, t, J = 8.1 Hz), 4.48- 4.40 (2H, m), 4.35 -4.29 (1Ή, m), 3.96 (2H, dd, J = 8.8, 5.1 Hz), 2.36 (3H, s), 1.45 (9H, s); MS (FAB) m / z: 433 (M + H) +. -258- 200403244 (16h) 3-Ethylsulfanyl- l- {4- [3- (ethoxyethoxycarbonylamino) azetidinyl-1-carbonyl]- 1,3-thiazol-2-yl} azetidin The 3-acetamidinethio-1- {4- [3- (third butoxycarbonylamino) azetidin-bu obtained in Example 16 (16g) was used. Carbonyl] -1,3-thiazole-2-yl} azetidine (3.18 g, 7.71 mmol) was dissolved in 1,4-dioxane (32 ml), and 4N- HC1 / 1,2-dioxane solution (32 ml), stirred at room temperature for 1 hour. After the reaction was completed, diethyl ether was added to the reaction system and filtered, and the filtrate was washed with ether to obtain a white solid. 3-Acetylthio-amine-azetidinyl-1-carbonyl) -1,3-thiazole-2-yl] azetidin hydrochloride (3.23 g, yield 100%). This 3-acetamidinethio · 1- [4- (3-aminoazetidinyl-1-carbonyl) -1,3-thiazol-2-yl] azetidin hydrochloride (3.23 g, 7.71 mmol) ) Dissolved in dichloromethane (120 ml), and 4-dimethylaminopyridine (1.13 g, 9.25 mmol) was added under nitrogen, and the 1-ethyl chloroformate obtained in Example 1 (1 b) Phenoxyethyl (1.54 g, 9.25 mmol), stirred for 1.5 hours. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: 30 ~ 0: 100, V / V) to obtain 3-ethylfluorenylthio-1- {4- [3- ( Acetyloxyethoxycarbonylamino) azetidinyl] -1,3-thiazole-2-yl} azetidin (639 mg, yield 19%). ] H NMR (CDCI3, 400MHz): 5 7.43 (1H, s), 6.81 (1H, q, J = 5.1 Hz), 5.3] -5.24 (1H, m), 4.92-4.82 (1H, m), 4.60- 4.40 (5H, m), 4.40-4 32 (1H, m), 4.00 ~ 3. 90 (3H, m), 2. 37 (3H, s), 2.07 (3H, s), 1 48 (3H, d7 J = 5.1 Hz); MS (FAB) m / z: 443 (M + H) +..

-259- 200403244 (16i) (lR55S, 6S) -2- (l- {4- [3- (l-acetamidoethoxycarbonylamino) azetidine-1-ylcarbonyl] -1,3-thiazole -2 -yl} azetidin-3 -yl) sulfan-6-[(R)-1 -hydroxyethyl] -1-methyl-carbophenan-2-ene-3 -residue acid p-nitrobenzyl ester Example 16 (16 h) 3 -Ethylthiol-1-{4-[3-(Ethyloxyethoxycarbonylamino) DY butyridinyl-1-fluorenyl] -i, 3- Thiazepine-2-yl} ^ Butidine D (1.92 g, 4.34 mmol) was dissolved in dimethylformamide (57 ml), and hydrazine acetate (480 mg, 5.2 1 mmol) and stir for 1 hour. After the reaction was completed, (1 R, 5 S, 6 S)-2-(diphenylphosphinooxy) -6-[(R) -l-hydroxyethyl] _1_form was added dropwise under nitrogen and ice cooling. A solution of p-nitrobenzyl-2-carben-3-carboxylic acid p-nitrobenzyl ester (2.58 g, 4.34 mmol) in acetonitrile (80 ml), and diisopropylethylamine (3.01 ml, 1 7 · 3 mmol), slowly warm to room temperature, and stir for 5 hours. After the reaction was completed, ethyl acetate and 10% saline water were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 1 0 0: 0 to 95: 5, V / V) to obtain (1R, 5S, 6s) -2 · (l- {4- [3- (l-Acetylethoxycarbonylamino) pγbutidin-resylcarbonyl] -1,3-thiazol-2-yl} azetidine-3 · yl) sulfur-6-[( R) -l-Hydroxyethyl] -l-methyl-carbanil-2-en-3-carboxylic acid p-nitrobenzyl ester (2.40 g, 74% yield). ] H NMR (CDCI3, 500MHz): (5 8. 22 (2H, d, J = 7.8 Hz), 7.66 (2H, d, J = 7.8 Hz), 7.45 (1H, s), 6.81 (1H, q, J = 5.2 Hz), 5.51 (1H, d, J = 13.7 Hz), 5.40 (1H, bd, J = 6.8 Hz), 5.25 (1H, d, J = 13.7 Hz), 4.91-4.84 (1H, m) , 4.57-4.50 (1H, m), 4. 50-4.42 (3H, m), 4.40-4.32 (1H, m), 4.30-4.23 (3H, m), 4.05-3.99 (2H, m), 3.99- 3.92 (1H, m), 3.29 (1H, ddy J = 6.8, 2.0 Hz), 3.20 (1H, dq, J = 7.8, 7.8

Hz), 2.07 (3H, s), 2.03-1.99 (1H, m), 1.48 (3H, d, J = 5.2 Hz), 1.38 (3H, d, J = 6.8 Hz), 1.27 (3H, d, J = 7.8 Hz); MS (FAB) m / z: 745 (M + H) +. -260- 200403244 (16〗) (111, 58, 63) -2- (1- {4- [3- (1 -Acetylethoxycarbonylamino) azetidin-1-ylcarbonyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfur-6-[(R) -l-hydroxyethyl Group] _ 1-methyl-carbapene-2-ene-3-carboxylic acid sodium salt The (111,53,63) -2- (1- {4- [3- ( 1-acetamidineethoxycarbonylamino) azetidin-1-ylcarbonyl] -1,3 · thiazol-2-yl} azetidin-3-yl) sulfur-6-[(R) ~; l- Hydroxyethyl] -1-methyl-carbinol-2-en-3-carboxylic acid p-nitrobenzyl ester (3.26 g, 4.39 mmol) was dissolved in tetrahydrofuran (100 ml), and distilled water (100 ml) ), In the presence of 10% P d-C (3.62 g), subjected to contact hydrogenation reduction at room temperature for 2.5 hours. After the reaction was completed, it was filtered. Sodium bicarbonate (369 mg, 4.39 mmol), ethyl acetate, and distilled water were added for layered extraction. The aqueous layer was washed with the aforementioned mixed solvent, and then concentrated under reduced pressure, and purified by Cosmosil reverse phase chromatography (distilled water: acetonitrile = 100: 0 to 85: 15 'V / V), and freeze-dried to obtain a white non-white (1R, 5 S, 6S) _ 2- (1- {4- [3- (1-Ethylethoxycarbonylamino) azetidin-1-ylcarbonyl] -1,3 -thiazole-2 -Yl} azetidin-3-yl) sulfur-6-[(R) -l-hydroxyethyl] -p-methyl-carbanil-2-ene-3 -carboxylic acid sodium salt (1.57 g Yield 57.7%). 1H NMR (D20, 400ΜΗζ): δ 7.39 (1Η, s), 6.74 (1Η, q, J = 5.5 Hz), 4.58-4.32 (6H, m), 4.25 (1H, dq, J = 6.4, 6.2 Hz) , 4.19 (1H, dd, J = 9.2, 2.4

Hz), 4.08-4.02 (4H, m), 3.43 (1H, dd, J = 6.2, 2.4 Hz), 3.24 (1H, dq, J = 9.2, 7.1 HZ), 2. Π (3H, s), 1.49 (3H, d, J = 5.5 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.19 (3H, d, J = 7.1Hz); IR (KBr): 1747, 1608, 1 538, 1447, * 1390, 1376, 1307, 1 290, 1264, 1 242 crrf1; MS (FAB) m / z: 632 (M + H) +; HRMS (FAB) m / z: calcd. For C25H3009N5S2Na (M + H) +: 632.1461. Found 632.1465; Anal, calcd. For C26H30N509S2Na-2H20: C, 44.97%; Η, 'δ.13%; Ν, IO.49%; S, 9.60%. Found C, 44.94%; Η, 5.94 %; M, 10.70%; S, 9.30% · 200403244 (Example 17) (lR, 5S, 6S) -2- (l- {4- [3- (l-acetamidoethoxycarbonylamino) azetidine Pyridin-1-ylcarbonyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -l-hydroxyethyl] -1-methyl-carbon ligand -2-ene-3-carboxylic acid trimethylacetoxymethyl

The (111,53,63) -2- (1- {4- [3- (buthylacetoxycarbonylamino) azetidin-1-ylcarbonyl] -1,3-thiazole- 2-yl} azetidin-3-yl) sulfan-6-[(R) -l-hydroxyethyl] -1-methyl-carbanil-2-en-3-carboxylic acid sodium salt (3 0 (0 mg, 0.475 mmol) was dissolved in dimethylacetamide (125 ml), and methyl pivalate (138 mg, 0.570 mmol) was added under nitrogen at 0 ° C, and stirred for 1 hour . After the reaction was completed, ethyl acetate was added to the organic layer, and the organic layer was washed successively with 10 ° / 0 brine, 5% sodium thiosulfate aqueous solution, 0.5 M hydrochloric acid, and saturated sodium bicarbonate solution, and then dried over anhydrous sodium sulfate It was dried under reduced pressure, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 to 9 5: 5, V / V) to obtain the target compound as a white amorphous (1r, 5S, 6S) _ 2- (1- {4- [3- (Buethenylethoxycarbonylamino) azetidine-butoxycarbonyl] -u-thiazol-2-yl} azetidin-3-yl) sulfur-6-[( R) -l-Hydroxyethyl] -1-methyl-carbanil-2-en-3-carboxylic acid trimethylacetoxymethyl ester (325 mg, yield 95%). -262- 200403244] H NMR (CDCI3, 400MHz): δ 7.45 (1H, s), 6.81 (1H, q, J = 5.9 Hz), 5.97 (1H, d, J = 5.9 Hz), 5.84 (1H, d , J = 5.9 Hz), 5.49-5.42 (1H, m), 4.92-4.83 (1H, m), 4.58-4.50 (1H, m), 4.50-4.40 (3H, m), 4.40 -4.32 (1H, m ), 4.30-4.20 (3H, m), 4.05-3.92 (3H, m), 3.25 (1H, dd, J = 6.6, 2.9 Hz), 3.18 (1H, qd, J = 8.8, 7.3 Hz), 2.07 ( 3H, s), 2.03-1.99 (1H, m), 1.48 (3H, d, J = 5.9 Hz), 1.35 (3H, d, J = 6.6 Hz), 1.25 (3H, d, J = 7.3 Hz), 1.22 (9H, s,); IR (KBr): 1754, 1 618, 1 536, 1448, 1 346, 1 307, 1 279cm'1; MS (FAB) m / z: 724 (M + H) +; HRMS (ESI) m / z: calcd. For C31H41011N5S2 (M + H) +: 724.2322 Found 724.2312. (Example 18) (lR, 5S, 6S) -2- (l- {4- [3- (l- Acetylethoxycarbonylamino) azetidin-1-ylcarbonyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl ] -1-Methyl-carbapene-2-ene-3-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl

(111,58,63) -2- (1- {4_ [3- (1-Ethylacetoxycarbonylamino) azetidin-1-ylcarbonyl] -1,3-thiazole- 2 -yl} azetidin-3 -yl) sulfan-6-[(R) -1-hydroxyethyl] -1-methyl-carban-2-en-3-carboxylic acid sodium salt (3 0 0 mg, 0.475 mmoles) dissolved in dimethylacetamide (15 ml), and 1-iodoethyl isopropylcarboxylate (147 mg, 0.570 mmoles) was added under nitrogen at 0 ° C, and stirred for 2.5 hour. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 5% sodium thiosulfate aqueous solution, 0.1 M hydrochloric acid, saturated sodium bicarbonate solution, saturated saline, and anhydrous sodium sulfate. It was dried under reduced pressure, filtered through -263- 200403244, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 1 00: 0 to 95: 5, V / V) to obtain the target compound as a pale yellow amorphous (1, 53, 63) -2- (1- {4- [3- (1-Acetylethoxycarbonylamino) azetidin-1-ylcarbonyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfur- 6-[(R) -l-Hydroxyethyl: 1-l-methyl-carbobenzoin-2-ene-3-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester (3 1 0 mg, Yield 88%). ] H NMR (CDCI3, 500ΜΗζ): δ 7.45 (1Η, s), 6.88 (0.5Η, q, J = 5.9 Hz), 6.88 (0.5H, q, J = 5.9 Hz), 6.81 (1H, q, J = 5.9 Hz), 5.61-5.45 (1H, m) 7 4.95-4.83 (2H, m) 4. 58-4. 50 (1H, m), 4.50-4.41 (3H, m), 4.40 -4.32 (1H, m), 4.30-4.20 (3H, m), 4. 05-3.93 (3H, m), 3.24 (1H, dd, J = 6.8, 2.9 Hz), 3.17 (1H, dq, J = 7.8, 6.8 Hz) , 2.09-2.06 (3H, m), 1.62 (3H, d, J = 5.9 Hz), 1.48 (3H, d, J-5.9 Hz), 1.38 1.23 (12H, m); IR (KBr): 1757, 1619 , 1536, 1446, 1374, 1270, 1 105, 1074cmH; MS (FAB) m / z: 740 (M + H) +; HRMS (ESI) m / z: calcd. For C31H41012N5S2 (M + H) +: 740.2272 Found 740.2281. (Example 19) (111,58,63) -2- (1- {4- [3- (1-Acetylethoxycarbonylamino) azetidin-1-ylcarbonyl] -1 , 3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -l-hydroxyethyl] -1-methyl-carban-2-en-3-carboxylic acid (5-methyl-2-oxo-1,3-difluoren-4-yl) methyl ester

The (111,58 ^ 8) -2- (1- {4- [3- (1-acetamidoethoxycarbonylethynyl) fluorobutyridine-1-ylfluorenyl] -1 obtained in Example 16-1, 3-thiazol-2-yl} 1 ^ butanidine-3-yl) sulfur-6 · -264- 200403244 [(R) -l-hydroxyethylb-methyl-carbanil-2-ene-3- Carboxylic acid sodium salt (300 mg, 0.475 mmol) was dissolved in dimethylacetamide (15 ml), and (5-methyl-2-oxo-1,3-) was added under nitrogen at 0 ° C. Difluoren-4-yl) methyl chloride (143 mg, 0.712 mmol), sodium iodide (321 mg, 2.14 mmol), and stirred overnight. After the reaction was completed, the organic layer was washed with 10% sodium chloride solution, 5% sodium thiosulfate aqueous solution, 0.5M hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride 'in the order of "adding ethyl acetate" and dried over anhydrous sodium sulfate. 'Filter and concentrate the filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 to 9 5: 5, V / V) to obtain (lR, 5S, 6S) -2 as a pale yellow amorphous compound of interest. -(l- {4_ [3- (l-Ethylacetoxycarbonylamino) azetidin-1-ylcarbonyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfur- 6-[(R) -l-Hydroxyethyl] -1 · methyl-carboxanil-2-supron-3-residue (5-methyl-2-oxo-1,3 -isopentan-4 -Yl) methyl acetate (273 mg, 80% yield). ] H NMR (CDCI3, 500MHz): (5 7.46 (1H, s), 6.81 (1H, q, J = 4.9 Hz), 5.44 -5.36 (1H, m), 5.05 (1H, d, J = 13.7 Hz) , 4.97 (1H, d, J = 13.7 Hz), 4.92-4.85 (1H, m), 4.57-4.50 (1H, m), 4.50-4.42 (3H, m), 4.41- 4.34 (1H, m) 4.10- 4.22 (3H, m) 4.07-4.01 (2H, m), 4.00-3.93 (1H, m), 3.26 (1H, dd, J = 6.8, 2.0 Hz), 3.19 (1H, dq, J = 7.8, 6.8 Hz ), 2.21 (3H, s), 2.07 (3H, s), 1.97-1.92 (1H, s), 1.48 (3H, d, J = 4.9 Hz), 1.37 (3H, d, J = 6.8 Hz), 1.27 (3H, d, J = 6.8 Hz); IR (KBr): 1820, 1738, 1618, 1 536, 1445, 1307, 1 232, 1 202cm'1; MS (FAB) m / z: 722 (M + H ) +; HRMS (ESI) m / z: calcd. For C3〇H35012N5S2 (M + Na) +: 744.1621. Found 744.1609. (Example 20) (111,53,63) -2- (1- {4- [(311)-(Ethyloxyethoxycarbonyl) pyrrolidin-3 -ylamine formamidine 1,3-oxazole-2 -yl} azetidine-3 -yl) sulfan-6-[( R) -Hydroxyethyl] -1-methyl-carbanil-2-ene-3-carboxylic acid sodium salt 200403244

(20a) 3-Hydroxy-1- (4-allyloxycarbonyl-1,3-oxazol-2-yl) azetidine 3-; methoxy-1- (4-methoxycarbonyl-1, 3-oxazol-2-yl) azetidin (described in Reference Example 2; 2.0 g, 6.62 mmol) was dissolved in methanol (40 ml), and a 1N aqueous sodium hydroxide solution (26.5 ml, 26.5) was added at room temperature. Millimoles) and stir overnight. After the reaction was completed, 4N HC 1 / 1,4-dioxane was added under cooling to neutralize, and the reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in dimethylformamide (37 ml), and allyl bromide (1.44 ml, 16.6 mmol) and diisopropylethylamine (2.89 ml, 16.6 mmol) were added at room temperature. Stir in an oil bath at 80 ° C for 6 hours. After the reaction was completed, ethyl acetate and 10% brine were added, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was dried under anhydrous sodium sulfate ', and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane · ethyl acetate = 1 ·· 3, V / V) to obtain 3-hydroxy-1-(4-allyloxycarbonyl-1, 3 as light brown crystals. 3 -Oxazole-2-yl) BY butidine (1.31 g, yield 89%). 1H-NMR (400MHz, CDCI3): 6 7.81 (1H, s), 6.05-5.94 (1H, m), 5.40-5.33 (1H, m), 5.29-5.24 (1H, m), 4.82-4.76 〇H, m), 4.78 (2H, dt, J = 5.9, 1.5Hz), 4.40 (2H, dd, J = 6.6, 10.3Hz), 4.06 (2H, dd, J = 10.3, 4.4Hz), 2.34 〇H, d , J = 5.9Hz); MS (El) m / z: 224 (M +). (2 0 b) 3 -methanesulfonyloxy-1-(4-allyloxycarbonyl-1,3 -oxazole- 2-Methyl) azetidine The 3-hydroxy-1- (4-allyloxycarbonyl-1,3-oxazole-266- 200403244 -2 -yl) Petidine (1.31 g) obtained in Example 20 (20a) , 5.88 millimoles) dissolved in anhydrous dichloromethane (40 ml) 'under ice cooling, add methanesulfonyl chloride (6 8 3 microliters, 8 82 millimoles), triethylamine (1.24 ml, 8.82 Millimoles) and stirred for 4 hours. After completion of the reaction ', ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried 'over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 2, V / V) to obtain 3-methanesulfonyloxy- 丨 _ (4-allyloxycarbonyl-1) as light brown crystals. , 3-oxazole-2-yl) azetidine (1.68 g, yield 95%). 'H-NMR (400MHz, CDCI3): δ 7.84 (1Η, s), 6.05-5.94 (1H, m), 5.41-5.34 (2H, m), 5.30-5.25 (1H, m), 4.80 (2H, dt , J = 5.9, 1.5Hz), 4.53 (2H, ddd, J = 8.8, 5.9, 1.5Hz), 4.35 (2H, ddd, J = 11.0, 4.4, 1.5Hz), 3.09 (3H, s); MS ( FAB) m / z: 303 (M + H) +. (20c) 3-Ethylthio-1- (4-allyloxycarbonyl-i, 3-oxazol-2-yl) PY Butidine will be implemented The 3-methylsulfonyloxy-1- (4-allyloxycarbonyl-1,3-oxazol-2-yl) azetidine (1.69 g, 5.59 mmol) obtained in Example 20 (20b) was dissolved. In dimethylformamide (3.5 ml), potassium thioacetate (3.83 g, 33.5 mmol) was added at room temperature, and stirred in an oil bath at 80 ° C for 10 hours. After the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2 ·· 1, V / V) to obtain 3-acetamylthio-1- (4-allyloxycarbonyl-1) as a light brown solid. , 3-oxazol-2-yl) azetidine (905 mg, 57.7% yield). λ -267- 200403244 ^ -NMR (400MHz, CDCI3): δ 7.82 (1H, s), 6.04-5.94 (1H, m), 5.40-5.33 (1H, m), 5.29-5.24 (1H, m), 4.79 (2H, dt, J = 5.9, 1.5Hz), 4.60 (2H, t, J = 8.8Hz), 4.44-4.35 (1H, m), 4.07 (2H, dd, J = 8.8, 5.9Hz), 2.35 ( 3H, s); MS (FAB) m / z: 305 (M + Na) +. (20d) 3-Ethylthio-l- {4-[(3R) -l- (Buethyloxyethoxy Carbonyl) pyrrolidin-3.ylaminomethylmethyl] -1,3-oxazol-2-yl} azetidine The 3-ethylsulfanyl-1- (4-allyl) obtained in Example 20 (20c) Oxycarbonyl-1,3-oxazol-2-yl) azetidine (800 mg, 2.83 mmol) was dissolved in dichloromethane (40 ml), and triphenylphosphine (111 (Mg, 0.425 mmol), dimethyl ketone (199 mg, 1.42 mmol), palladium (0) triphenylphosphine (327 mg, 0.2 8 3 mmol), and stirred for 1 hour. After the reaction was completed, the (3 R) -3-amino-1- (1-acetamidoethoxycarbonyl) pyrrolidine trifluoroacetate crude product obtained in Example 5 (5 b) was added under nitrogen and ice cooling ( 2.05 grams, 4.25 millimoles), triethylamine (1.39 mL, 9.91 millimoles), diethylphosphonium cyanide (656 microliters, 4.525 millimoles), and stirred overnight. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 2 ~ 1: 4, V / V) to obtain 3-ethylfluorenylthio-l- {4-[( 3R) -l- (l-Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-oxazol-2-yl} azetidine (1.43 g, yield 100%) . 'H-NMR (400MHz, CDCI3): δ 7.75 (1H, s), 6.86-6.78 (2Η, m), 4.64 -4.55 (1H, m), 4.57 (2H, t, J = 8.8 Hz), 4.45- 4.36 (1H, m), 4.04 (2H, dd, J = 8.8, 5.9 Hz), 3.79-3.72 (1H, m), 3.62-3.49 (2H, m), 3.40-3.29 (1H, m), 2.36 ( 3H, s), 2.30-2.18 (1H, m), 2 09-2 07 (3H, m), 2.04-1.90 (1H, m), 1.52-1.46 (3H, m); MS (FAB) m / z : 441 (M + H) +. -268- 200403244 (20e) (lR, 5S, 6S) -2- (Bu {4-[(3R) -l- (Buethylacetoxyethoxycarbonyl) pyrrolidine- 3-ylaminomethylmethyl] -1,3-oxazol-2-yl} azetidin-3-yl) sulfur-6-[(R) -hydroxyethyl] -1-methyl-carbon ligand -2-ene-3-carboxylic acid p-nitrobenzyl ester The 3-acetamidothio-1- {4 _ [(3R) -1- (1-acetamidoethoxycarbonyl) pyrrole obtained in Example 20 (20d) Pyridin-3-ylamine formamidine] -1,3-oxazol-2-yl} azetidine (1.25 g, 2.83 mmol) was dissolved in dimethylformamide (38 ml) under nitrogen and Add hydrazine acetate (3 13 mg, 3.40 mmol) at room temperature and stir for 1 hour. After the reaction was completed, (1R, 5 S, 6S) -2- (diphenylphosphinoyloxy) -6-[(R) -l-hydroxyethyl] -1-methyl was added dropwise under nitrogen and ice cooling. -Carbobenz-2-en-3-carboxylic acid p-nitrobenzyl ester (1.68 g, 2.83 mmol) in acetonitrile (50 ml), followed by diisopropylethylamine (1.97 ml, 1 1.3 mmol), slowly warm to room temperature, and stir overnight. After the reaction was completed, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was saturated with a sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered ', and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 ~ 95: 5, V / V) to obtain (111,53,63) -2- (l- {4 -[(3R) -l- (l-Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino] -1,3 -oxazole-2 -yl} azetidine-3 -yl) sulfur 6-[(R) -1 -Hydroxyethyl] -1 -methyl-carbopentan-2-en-3-carboxylic acid p-nitrobenzyl ester (1.70 g, yield 81%). NMR (CDCI3, 400MHz): δ 8.25-8.21 (2Η, m), 7.76 (1Η, s), 7.68 -7.64 (2H, m), 6.86-6.78 (1H, s), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H, d, J = 13.7 Hz), 4.65-4.58 (1H, m), 4.53 (2H, q, J = 8. 1 Hz), 4.30-4.20 (3H, m), 4.14- 4.07 (2H, m), 3.78-3.72 (1H, m), 3.60 -3.48 (2H, m), 3.40-3.32 (1H, m), 3.29 (1H, dd, J = 6.6, 2.9 Hz), 3.20 ( 1H, dq, J = 8.8, 7.3 Hz), 2.30-2.18 (1H., M), 2.09-2.05 (3H, m) 2.00-1.90 (1H, m), 1.88-1.80 (1H, m) 1.52-1.46 (3H, m), 1.38 (3H, d, J = 5.9 Hz), 1.27 (3H, d, J = 7.3 Hz); MS (FAB) m / z: 743 _) + · -269- 200403244 (20f) (lR, 5S, 6S) -2- (l- {4-[(3R) -l- (l-acetamidooxyethoxycarbonyl) pyrrolidin-3-ylaminemethylamidino] -1,3 · Oxazol-2-yl} azetidin-3-yl) sulfan-6-[(κ) -1-hydroxyethyl] -1-methyl-carbinen-3-carboxylic acid sodium salt 20 (20e) The obtained compound (lR, 5S, 6S) -2- (l- {4-U3R). 1-(1-ethylacetoxyethoxycarbonyl) pyrrolidine-3 -ylaminomethylmethyl] -1 , 3 · hydrazone _ 2 _ group} azetidin-3-yl) sulfur-6-[(R) -l-hydroxyethyl] -1-methyl-carbon Nian-2_burn-3-carboxylic acid p-nitrobenzyl ester (3.03 g, 4.09 mmol) was dissolved in tetrahydrofuran (75 ml) and distilled water (75 ml) in the presence of 10% Pd-C (3.03 g) Then, contact hydrogenation reduction was performed at room temperature for 3 hours. After the end of the reaction, it was filtered. Sodium bicarbonate (344 mg, 4.09 mmol), ethyl acetate, and distilled water were added to the filtrate, and the layers were extracted. The aqueous layer was concentrated under reduced pressure and purified by reversed phase chromatography (distilled water: acetonitrile = 100: 0 to 85: 15, V / V) and freeze-dried to obtain a white amorphous form of the target compound. (1 R, 5 S, 6 S)-2-(1-{4-[(3R) -1- (1-Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminemethylamidino] -1 , 3-oxazol-2-yl} azetidin-3-yl) thio-6-[(R) -l-hydroxyethyl] -1-methyl-carban-2-en-3-carboxyl Sodium salt (1.70 g, 66% yield). ] H NMR (D20, 400ΜΗζ): δ 7.92 (1Η, s), 6.74 (0.5Η, q, J = 5.5 Hz), 6.73 (0.5H, q, J = 5.5 Hz), 4.59 (2H, t , J = 8. 2 Hz), 4.56-4.50 (1H, m), 4.36-4.27 (1H, m), 4.25 (1H, dq, J = 6.4, 6.2 Hz), 4.20 (1H, dd, J = 9.2 , 2.4 Hz), 4.12-4.05 (2H, m), 3.76-3.39 (4H, m), 3.43 (1H, dd, J = 6.2, 2.4 Hz), 3.24 (1H, dq, J = 9.2, 7.3 Hz) , 2.34-2.22 (1H, m) 2.12-2.08 (3H, m) 2.10-2.20 (1H, m), 1.53 (1.5H, d, J = 5. 5

Hz), 1.52 (1.5H, d, J = 5.5 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.19 (3H, d, J = 7.3 Hz); IR (KBr): 1744, 1624, 1518 , 1450, 1423, 1390, 1245cmH; -270- 200403244 MS (FAB) m / z: 630 (M + H) +; HRMS (ESI) m / z: calcd. For C26H32010N5SNa (M + H) +: 630.1846. Found 630.1846; Anal, calcd. For C26H32N5O10SNa · 2H20: 0,46.91%; H, 5.45%; NJ0.52%; S, 4.82t Found C, 46.80%; H, 5.44%; N, 10.40%; S, 4.8 U. (Example 21) (lR, 5S, 6S) -2- (l- {4-[(3R) -1- (1-Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino ] -1,3-oxazol-2-yl} azetidin-3 · yl) sulfur-6-[(R) -1-hydroxyethyl] -1-methyl-carban-2-en- 3-carboxylic acid trimethylacetoxymethyl

(111,53,68) -2- (1- {4-[(311) -1- (1-Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminemethylamidino]- 1,3-oxazol-2-yl} azetidin-3-yl) sulfan-6-[(R) -l-hydroxyethyl] -1-methyl-carban-2-en-3- Carboxylic acid sodium salt (250 mg, 0.397 mmol) was dissolved in dimethylacetamide (12 ml), and methyl pivalate iodide (115 mg, 0.476 mmol) was added under nitrogen at 0 ° C. Ear), stir for 1.5 hours. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 5% sodium thiosulfate aqueous solution, 0.5M hydrochloric acid, saturated sodium bicarbonate solution, saturated saline, and dried over anhydrous sodium sulfate. , Filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 to 95: 5, V / V), and the target compound was obtained as a pale yellow amorphous (1 foot, 53, 68) -2- (1 -{4-[(311) -1- (1-acetamidoethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino; | -1,3-oxazol-2-yl} azetidine-3 -

-27 K 200403244 group) Sulfur-6-[(R) -l-Ethyl] -1-methyl-carbobenzine-2-flame-3-carboxytrimethylacetoxymethyl (256 mg , Yield 90%). 'H NMR (CDCI3, 400ΜΗζ): δ 7.76 (1Η, s), 6.86-6.78 (2H, m), 5.97 (1H, d, J = 5.9 Hz), 5.84 (1H, d, J = 5.9 Hz), 4.64-4.58 (1H, m), 4.53 (2H, q, J = 8.8 Hz), 4. 28-4.20 (3H, m), 4.14-4.06 (2H, m), 3.78-3.72 (1H, m), 3.62-3.48 (2H, m), 3.40-3.29 (1H, m), 3.25 (1H, dd, J = 6.6, 2.9 Hz), 3.18 (1H, dq, J = 9.5, 7.3 Hz), 2.30-2.18 ( 1H, m), 2.09-2.05 (3H., M), 2.04-1.90 (1H, m), 1.82-1.78 (1H, bs), 1.52-1.46 (3H, m), 1.35 (3H, d, J = 5. 9 Hz), 1.25 (3H, d, J = 7.3 Hz); IR (KBr): 1777, 1757, 1719, 1665, 1625, Π 1 9, 1084ογπη; MS (FAB) m / z: 722 (M + H) +; HRMS (ESI) m / z: calcd. For C32H43012N5S (M + H) +: 722.2707. Found 722.2699. (Example 22) (lR, 5S, 6S) -2- (l- {4- [(3R) -l- (l-Acetyloxyethoxycarbonyl) pyrrolidin-3 -ylaminomethylamidino] -1, 3 -oxazole-2 -yl} azetidine-3 -yl) sulfur- 6-[(R) -l-Hydroxyethyl] -1-methyl-carbanil-2-ene-3-carboxylic acid 1- (isopropoxyloxy) ethyl ester

(1 R, 5 S, 6 S)-2-(1-{4-[(3 R)-1-(1 -Ethyloxyethoxy iron-based)) ratio of Example 2 -3-basal limb methylamido] · 1,3 · 卩 琴 卩 座 _ 2 _ 基} jjy 丁 JJ 定 • 3 -yl) sulfur-6-[(R)-1 -hydroxyethyl] _ 丨 · Methyl_Carbonate_ 2 _ene_ 3 _ Carboxylic acid sodium salt (250 mg '0.3 97 7 mmol) dissolved in dimethylacetamide (12 ml), ^ 272 ^ 200403244 under nitrogen and To the solution was added ethyl iodoacetate (123 mg, 0.476 mmol) under Ot, and the mixture was stirred for 1.5 hours. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 5% sodium thiosulfate aqueous solution, 0.5 M hydrochloric acid, and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 1 00: 0 to 95: 5, V / V) to obtain the target compound (lR, 5S, 6S) -2- (l as pale yellow amorphous). -{4-[(3R) -l- (Buethenyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino] -1,3-oxazol-2-yl} azetidin-3-yl ) Sulfur-6-[(11) -1-hydroxyethyl] -1-methyl-carbanil-2-ene-3-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester (2 3 7 Mg, yield 81%). ] H NMR (CDCI3, 400ΜΗζ): δ 7.76 (0.5Η, s), 7.76 (0.5Η, s), 6.91-6.79 (2H, m), 4.96-4.85 (1H, m), 4.65-4.58 (1H, m), 4.56-4.48 (2H, m), 4.28-4.18 (3H, m), 4.12-4.06 (2H, m), 3.79-3.72 (1H, m), 3.60-3.48 (2H, m) 3.40-3.30 (1H, m), 3.24 (1H, dd, J = 6.6, 2.9 Hz), 3.17 (1H, dq, J = 8.8, 7.3 Hz), 2.30-2.18 (1H, m), 2.09-2.05 (3H, m ), 2.04-1.90 (1H, m), 1.80-1.75 (lH, bs), 1.61 (1.5H, d, J = 5.1 Hz), 1.59 (1.5H, d, J = 5.1 Hz), 1.52-1.46 ( 3H, m), 1.37-1.22 (1 2H, m); IR (KBr): 1760, 1718, 1 666, 1625, 1 376, 1272, 1075 cmH; MS (FAB) m / z: 738 (M + H ) +; 'HRMS (ESI) m / z: calcd. For C32H43013N5S (M + H) +: 738.2657. Found 738.2664. (Example 23) (lR, 5S, 6S) -2- (l- {4- [ (3R) -1- (1-Ethyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-oxazol-2-yl} azetidin-3-yl) sulfur-6 -[(R) -l-hydroxyethyl] -1-methyl-carbanil-2-ene-3-carboxylic acid (5-methyl-2-oxo-1,3-diphosphone-4- Methyl) -273- 200403244

The (1R, 5S, 6s) -2- (l- {4-[(3R) -1- (buthyloxyethoxycarbonyl) pyrrolidin-3 -ylaminomethylmethyl] -1 obtained in Example 20) , 3-oxazole-2 -yl} azetidin-3-yl) thio-6-[(R) -l-hydroxyethylmethyl-carbenenen-3-carboxylic acid sodium salt (300 mg ' 0.476 mmol) dissolved in dimethylacetamide (15 ml), (5-methyl-2-oxo-1,3-difluorenyl-4-yl) methyl was added under nitrogen at 0 ° C Chlorine (144 mg, 0.715 mmol) and sodium iodide (321 mg, 2.14 mmol) were stirred overnight. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% brine, 5% sodium thiosulfate aqueous solution, 0.5 M hydrochloric acid, saturated sodium bicarbonate water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 ~ 95: 5, V / V) to obtain the target compound (111, 53, 63) -2- (l- {4-[(3R) -l- (Buethenyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino] -1,3-oxazol-2-yl} azetidin-3-yl) Sulfur-6-[(11) -butoxyethyl] -1-methyl-carbophenan-2-ene-3-carboxylic acid (5-methyl-2-oxo-1,3-diphosphone- 4-yl) methyl ester (265 mg, 77% yield). ^ NMR (CDCI3, 400ΜΗζ): δ 1.11 (1Η, s), 6.86-6.79 (2H, m), 5.04 (1H, d, 13.9 Hz), 4.97 (1H, d, J = 13.9 Hz), 4.64-4.58 (1H, m), 4.54 (2H, q, J = 8.1 Hz), 4.29-4.20 (3H, m), 4. 14-4.07 (2H, m) 3, 78-3.72 (1H, m), 3.60-3.48 (2H, m), 3.40-3.29 (1H, m), 3.25 (1H, dd, J = 6.6, 2.9 Hz), 3.19 (1H, dq, J = 8.8, 7.3 Hz), 2.28-2.22 ( 1H, m), 2.09-2.05 (3H, m), 2.04-1.90 (1H, m), 1.77 (1H, bd, J = 5.1 Hz), 1.52-1.46 (3H, m), 1.36 (3H, d, J = 5. 9 Hz) 7 1.26 (3H, d, J = 7.3 Hz); -274- 200403244 IR (KBr): 1821, 1773, 1737, 1715, 1665, 1625, 1233, 1202, 1130 cr1; MS ( FAB) m / z: 720 (M + H) +; HRMS (ESI) m / z: calcd. For C31H37013N5S (M + H) +: 720.2187. Found 720.21 76. (Example 24) (1 R, 5S, 6S) -2- (l- {4- [1- (1-Ethyloxyethoxycarbonyl) piperidin-4-ylaminomethanyl] -1,3 -pentan-2-yl} [ ΓΥ Butyl D 疋 -3-yl) sulfur-6-[(R) _1-hydroxyethyl] -1-methyl-carban-2-en-3-carboxylic acid sodium salt

(24a) 4-hydroxy-1- (1-acetamidoethoxycarbonyl) piperidine

4-Hydroxypiperidine (1.22 g, 12.0 mmol) was dissolved in dichloromethane (60 ml), and 1 · ethoxyethyl chloroformate (2.00 g) obtained in Example 1 (1 b) was added under ice-cooling. , 12.0 mmoles), 4-dimethylaminopyridine (1.47 g, 12.0 mmoles), and stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane · ethyl acetate = 1: 2 ~ 1: 4, V / V) to obtain 4-hydroxy-1- (1-acetamidooxyethyl) as a pale yellow oil. Oxycarbonyl) piperidine (2.19 g, 79% yield). ] H NMR (CDCI3, 500MHz): δ 6.82 (1Η, q, J = 4.9 Hz), 3.94-3.80 (3H, m), 3.21-3.12 (2H, m), 2.07 (3H, s), 1.93-1.84 (2H, m), 1.56-1.48 (2H, m) 1.50 (3H, d, J = 4.9 Hz); MS (FAB) m / z: 232 (M + H) +. (24b) 4-A Sulfonyloxy-1- (1-acetamidoethoxycarbonyl) piperidine-275- 200403244 The 4-hydroxy-1- (1-acetamidoethoxycarbonyl) piperidine obtained in Example 24 (24a) ( 2 · 19g, 9 · 50mmol) was dissolved in dichloromethane (70ml), and methylsulfonyl chloride (1.10mg, 14.3mmol) was added under ice cooling, and triethylamine (2.00ml) , 1 4.3 millimoles), and stirred for 3.5 hours. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1 ~ 1: 2, V / V) to obtain 4-methanesulfonyloxy-1- (1-ethyl Phenoxyethoxycarbonyl) piperidine (2.85 g, yield 97 ° /.) ◦ 'H NMR (CDCI3, 400MHz): (5 6.81 (1H, q, J = 5.9 Hz), 4.95- 4.89 (1H, m ), 3.76-3.66 (2H, m), 3.47-3.38 (2H, m), 3.05 (3H, s), 2.07 (3H, s), 2.05-1.94 (2H, m), 1.92-1.82 (2H, m ), 1.49 (3H, d, J = 5.9 Hz); MS (FAB) m / z: 310 (M + H) +. (24c) 4 -azido-1- (1-acetamidooxyethyl Oxycarbonyl) piperidine The 4-methanesulfonyloxy-1- (buethoxoethoxy) piperidine (2.85 g, 9.22 mmol) was dissolved in dimethylformamide obtained in Example 24 (24b). Methylformamide (90 ml), add sodium azide (65 9 mg, 10.1 mmol) at room temperature and stir in an oil bath at 100 ° C for 2 hours. After the reaction is completed, add acetic acid to the reaction system Ethyl acetate and 5% brine, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: Ethyl acetate = 3: 1, V / V) Purification 'can give 4-azide-1-(1-acetamidoethoxycarbonyl) piperidine (1.95 g, yield Rate 8 3%). -276- 200403244] H NMR (CDCI3, 400MHz): δ 6.81 (1H, q, J = 5.9 Hz), 3.88-3.74 (2H, m), 3.66-3.60 (1H, m), 3.26-3.17 (2H, m), 2.07 (3H, s), 1.93-l.83 (2H, m), 1.66-1.57 (1H, m), 1.49 (3H, d, J = 5.9 Hz); MS (FAB) m / z: 257 (M + H) +. (24d) 3-Ethylsulfanyl-l- {4- [l- (Buethyloxyethoxycarbonyl) piperidin-4-ylamine Methylfluorenyl] -1,3-oxazol-2-yl} azetidin The 4-azide-1- (1-ethyl alcohol-ethenyl) piperidine obtained in Example 24 (24c) (1 .95 g, 7.61 mmol) were dissolved in methanol (60 ml) 'in the presence of 10% Pd-C (1.95 g), and subjected to contact hydrogenation reduction at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was filtered. The filtrate was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain a crude 4-amino-1- (1-acetamidoethoxycarbonyl) piperidine. The 3-ethenylthio-1- (4-allyloxycarbonyl-1,3-oxazol-2-yl) BY butidine (1.64 g, 5.83 mmol) obtained in Example 20 (20c) was dissolved. In dichloromethane (80 mL), add triphenylphosphine (230 mg '0.875 mmol), dimethyl ketone (409 mg, 2.92 mmol), and palladium (〇) triphenylphosphine under nitrogen at room temperature. (674 mg, 0.5 8 3 mmol) and stir for 1 hour. After the reaction was completed, the obtained crude 4-amino-1-(1-acetamidooxyethoxycarbonyl) piperidine (1.75 g, 7.00 mmol) and triethylamine (981 µl) were added under nitrogen and ice cooling. '7.00 millimoles), diethylphosphonium cyanide (1.0 ml, 7.0 millimoles), and stirred for 2 hours. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: 1 ~ 1: 3, V / V) to obtain a pale brown amorphous 3-ethylfluorenylthio-acetoxyethoxy 200403244 mineral group) Ηη 定 -4 -ylaminomethylmethyl] -1,3-Π 萼 η 坐 -2 -yl} BY butyl Ding (1.56 g, yield 59%) 〇-NMRUOOMHz, CDCI3): δ8 · 25 _ 8.21 (2H, m) 7.75 (chuan, s), 7.68-7.64 (2Η, m), 6.81 (1Η, q, "= 5.9 Hz, 6.72- 6.64 (1Η, m), 5.51 (2H, d, J = 13.7 Hz), 5.25 (2H, d, J = 13.7 Hz), 4.52 (2H, q, J = 8.1 Hz), 4.28-4.20 (3H , m), 4.18-4.00 (5H, m), 3.20 _ 3.16 (1H, m), 3.15-3.08 (1H, m), 3. 06-2.92 (2H, m), 2.07 ( 3H, s), 2.02-1.95 (2H, m), 1.80-1.70 (1H, m), 1.49 (3H, d, J = 5 9 Hz), 1.48-1.40 (2H, m), 1.38 (3H, d, J = 6.6 Hz), 1.27 (3H, d, J = 7.3 Hz); MS (FAB) m / z: 757 (M + H) +. (24e) (lR, 5S, 6S)- 2- (l- {4- [l- (l- (ethoxyethoxycarbonyl) piperidin-4-ylaminomethylamidino] -1,3-oxazol-2-yl} azetidin-3-yl ) Sulfur-6-[(R) -l-hydroxyethyl] -1-methyl-carbophenan-2-ene- 3-p-nitronic acid; the ester will be obtained in Example 2 4 (2 4 d) 3 -ethyl_thio_ 1 _ {4-[1-(1 -ethoxyethoxyethoxy)) -Methylamine methyl group] 噚 η²_2-yl} azetidine (1.56 g, 3.43 mmol) was dissolved in dimethylformamide (47 ml), and hydrazine acetate was added under nitrogen at room temperature. Salt (37.9 mg, 4.12 mmol), stir for 1 hour. After the reaction was completed, the obtained (1 R, 5 S 5 6 S) · 2- (diphenylphosphinoyloxy) -6-[(R) -1-hydroxyethyl] _ 丨 was added dropwise under nitrogen and ice cooling. _Methyl-carbobenzon-2-en-3-carboxylic acid p-nitrobenzyl ester (2.04 g, 3.43 mmol) in acetonitrile (61 ml), followed by addition of diisopropyl Ethylamine (2.39 mL, 13.7 mmol) was slowly warmed to room temperature and stirred overnight. After the reaction was completed, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate 200403244 ester: methanol = 1 00: 0 to 95: 5, V / V) to obtain (lR, 5S, 6S) -2- (l- {4- [l- (l-Ethyloxyethoxycarbonyl) piperidin-4-ylaminomethylamidino] -1,3-oxazol-2-yl} azetidin-3-yl) sulfur-6 -[(R) _1-hydroxyethyl l · 1-methyl-carbophenan-2-ene-3-carboxylic acid p-nitrobenzyl ester (1.70 g, yield 81%). ] H NMR (CDCI3, 400ΜΗζ): δ 8.25-8.21 (2Η, m), 7.75 (1Η, s), 7.68 -7.64 (2H, m), 6.81 (1H, q, J = 5.9 Hz), 6.72-6.64 (1H, m), 5.51 (2H, d, J = 13.7 Hz), 5.25 (2H, d, J = 13.7 Hz), 4.52 (2H, q, J = 8.1

Hz), 4.28-4.20 (3H, m), 4.18-4.00 (5H, m), 3.20-3.16 (1H, m), 3.15-3.08 (1H, m), 3.06-2.92 (2H, m), 2.07 ( 3H, s), 2.02 -1.95 (2H, m), 1.80-1.70 (1H, m), 1.49 (3H, d, J = 5.9 Hz), 1.48-1.40 (2H, m), 1.38 (3H, d, J = 6.6 Hz), 1.27 (3H, d, J = 7.3 Hz); MS (FAB) m / z: 757 (M + H) +. (24f) (lR, 5S, 6S) -2- (l- {4- [l- (l-Ethyloxyethoxycarbonyl) piperidin-4-ylaminomethylmethyl] -1,3-oxazole-2 -yl} azetidin-3 -yl) sulfan-6 -[(R)-1 -Hydroxyethyl] -1-methyl-carbanil-2-ene-3-carboxylic acid sodium salt The compound (lR, 5S, 6S) -2 obtained in Example 24 (24e) -(l- {4- [l- (l-Ethyloxyethoxycarbonyl) piperidin-4-ylaminomethylamidino] -1,3 · oxazol-2-yl} azetidin-3-yl ) Sulfur-6-[(R) -1-hydroxyethyl] -1-methyl-carbobin-2-en-3-carboxylic acid p-nitrobenzyl ester (1.83 g, 2.41 mmol) was dissolved in Tetrahydrofuran (55 ml) and distilled water (55 ml) were subjected to contact hydrogenation reduction at room temperature for 3.5 hours in the presence of 10% Pd-C (1.83 g). After the reaction was completed, the mixture was filtered, and sodium bicarbonate (202 mg, 2.41 mmol), ethyl acetate, and distilled water were added to the filtrate to perform layered extraction. The aqueous layer was concentrated under reduced pressure, and purified by reversed phase chromatography (distilled water: acetonitrile, 100: 0 to 82: 18, V / V) and freeze-dried -279- 200403244 to obtain the target compound in white Amorphous (1R, 5S, 6S) -2- (1- {4- [1- (1-Ethyloxyethoxycarbonyl) piperidin-4-ylaminemethylamidino] -1,3-oxazole -2-yl} azetidin-3.yl) sulfan-6-[(R) -l-hydroxyethyl] -1-methyl-carbanil-2-ene-3-carboxylic acid sodium salt (1 70 g, 66% yield). NMR (D20, 400MHz): 6 7.90 (1H, s), 6.74 (1H, q, J = 5.5 Hz), 4.59 (2H, t, J = 8.2 Hz), 4.35-4.27 (1H, m), 4.25 ( 1H, dq, J = 6.4, 6.2

Hz) 4.20 (1H, dd, J = 9.0, 2.4 Hz), 4. 16-3.98 (5H, m), 3.43 (1H, dd, J = 6.2, 2.4 Hz), 3.24 (1H, dq, J = 9.0 , 7.1 Hz), 3.15-2.98 (2H, m), 2.12 (3H, s), 2.02-1.92 (2H, m), 1.61-1.53 (2H, m), 1.52

(3H, d, J = 5.5 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.19 (3H, d, J = 7.1 Hz); IR (KBr): 1749, 1717, 1623, 1 378, 1224 , 1080 cnf1; MS (FAB) m / z: 644 (M + H) +; HRMS (ESI) m / z: calcd. For C27H34010N5SNa (M + H) +: 644.2002. Found 644.2006; Anal, calcd. For C27H34N5010SNa 8 / 3Hz0: C, 46.88%; H, 5.73%; N, 10.13%; S, 4.64X. Found C, 46.79%; H, 5.4U; N, 10.17%; S, 4.37%. (Example 25 ) (lR, 5S, 6S) -2- (l- {4- [l- (l- (Ethyloxyethoxycarbonyl) piperidine-4-ylaminomethylamidino] -1,3-oxazole-2 -Yl} azetidin-3 -yl) thio-6 · [(R)-

1-Hydroxyethylmethyl-carben-2-en-3-carboxylic acid trimethylacetoxymethyl

The (10,53,63) -2- (1- {4- [1- (1-acetamidooxyethoxycarbonyl) piperidin-4-ylaminemethylamidino group obtained in Example 24; μ〗, Oxazole-2 _yl 丨 azetidin-3-yl) sulfan-6-[(R)-; l-hydroxyethyl] -bumethyl-carbobenzoin-2_ene-3 —carboxylic acid sodium salt (2 50 mmol-280-200403244 g '0.388 halo ear) was dissolved in dimethylacetamide (12 ml), and methyl pivalate iodide (113 mg, 0.466 mmol) was added under nitrogen at 0 ° C. Ear), stir for 2 hours. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 5% sodium thiosulfate aqueous solution, 0.5M hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine, and dried over anhydrous sodium sulfate. , Filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 to 98: 2'V / V) to obtain the target compound (lR, 5S, 6S) -2- (l- {4- [l · (l-Ethyloxyethoxycarbonyl) piperidine-4 · ylaminomethylamidino l·l, 3-oxazol-2-yl} [Jγbutidin-3-yl) thio · 6. [(R) -l-Hydroxyethyl; | -p-methyl-carbobenzon-2-ene-3-carboxylic acid trimethylacetoxymethyl ester (256 mg, yield 90%). 'H NMR (CDCI3, 400ΜΗζ): δ 7.75 (1H, s), 6.81 (1H, q, J = 5.1 Hz), 6.69 ^ (1H, bd, J = 8.8 Hz), 5.97 (1H, d, J = 5.9 Hz), 5.84 (1H, d, J = 5.9 Hz), 4.52 (2H, q, J = 8.8 Hz), 4. 28-4.20 (3H, m), 4.20-4.00 (5H, m), 3.25 ( 1H, dd, J = 6.8, 2.9 Hz), 3.18. (1H, dq, J = 8.8, 7.8 Hz), 3.06-2.92 (2H, m), 2.07 (3H, s), 2.03-1.95 (2H, m ), 1.83 (1H, bd, J = 4.4 Hz), 1.49 (3H, d, J = 5.1 Hz), 1.48-1.40 (2H, m), 1.37 (3H, d, J = 7.3 Hz), 1.25 (3H, d, J = 7.3 Hz), 1.22 (9H, s); IR (KBr): 1778, 1756, 1715, 1625, 1223, 1 141, Π 16, 10820 ^: MS (FAB) m / z: 736 (M + H) +; HRMS (ESI) m / z: calcd. For C33H45012N5S (M + H) +: 736.2864. Found 736.2872. (Example 26) (lR, 5S, 6S) -2- (l- {4- [l- (l-Ethyloxyethoxycarbonyl) piperidin-4-ylaminomethylmethyl] · 1,3-oxazol-2-yl} azetidin-3-yl) sulfur-6 · [(ΙΙ) -1-Hydroxyethyl] -1-methyl-carbanil-2-ene-3-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester-281- 200403244

(1 R, 5 s, 6 s) obtained from Example 2 4 _ 2 _ (丨 · {4 4 丨 丨 _ acetamidooxyethoxycarbonyl) piperidine-4 -ylamine formamidine, 3 _ Oxazole-2 _yl 丨 azetidin-3 _yl) thio-6-[(R) -l-hydroxyethyl] -1-methyl-carbanil-2-ene-3_carboxylic acid sodium salt (25.0 mg '0.388 mmol) was dissolved in dimethylacetamide (13 ml), and 1-iodoethyl isopropylcarboxylate (120 mg, 0.466 mmol) was added under nitrogen at 0 ° C. ), Disturb for 1 hour. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 5% sodium thiosulfate aqueous solution, 0.5M hydrochloric acid, and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 1 00 ·· 〇 ~ 9 5: 5, 乂 / ¥) to obtain the target compound (111,53,63) -2 as a pale yellow amorphous substance. -(1- {4- [1- (1-Ethyloxyethoxycarbonyl) piperidin-4-ylaminomethylmethyl] -1,3-oxazol-2-yl} azetidin-3-yl ) Sulfur-6-[(R)-;!-Hydroxyethyl] -1-methyl-carbanil-2-ene-3-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester (250 mg , Yield 86%). ^ NMR (CDCI3, 400MHz): δ 7.75 (0.5H, s), 7.75 (0.5H, s), 6.88 (0.5H, q, J = 5.1 Hz), 6.88 (0.5H, q, J = 5. 1 Hz), 6.81 (1H, q, J = 5.1 Hz), 6.72 -6.66 (1H, m), 4.98-4.84 (1H, m), 4.56-4.47 (2H, m), 4.28 -4.18 (3H, m ), 4.18-4.00 (5H, m), 3.24 (1H, dd, J = 6.6, 2.9 Hz), 3.16 (1H, dq, J = 9, 5, 7.3 Hz), 3.06-2.90 (2H, m), 2.08-2.05 (3H, m), 2.02-1.95 (2H, m), 1.80-1.75 (1H, m), 1.61 (1.5H, d, J = 5.1 Hz), 1.59 (1.5H, d, J = 5. 1 Hz), 1.49 (3H, d, J = 5.1 Hz), 1.48-1.40 (2H, m), 1.38-1.22 (1 2H, m); -282- 200403244 丨 R (KBr): 1760, 1714, 1625, 1 376, 1 273, 1 223, 1078 crrf1; MS (FAB) m / z: 752 (M + H) +; HRMS (ESI) m / z: calcd. For C33H45013N5S (M + H ) +: 752.281 3. Found 752.2814. (Example 27) (lR, 5S, 6S) -2- (l- {4-[(3S) -l- (buisobutoxyethoxycarbonyl) pyrrolidine-3 -Methylaminomethyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfur • 6-[(R) -l-hydroxyethyl] -1-methyl-carbon ligand -2-ene-3 · carboxylic acid sodium salt

(27 &) 0- (1-isobutoxyethyl) -3-ethylthiocarboxylic acid ester 0- (1-chloroethyl) -S-ethylthiocarboxylic acid ester (WO-020 92 5 5 Recorder No. 5; 10.0 g, 59 mM) dissolved in toluene (2 80 ml), sodium iodide (23.1 g, 154 mM), 18-crown-6 (4.70 g, 17.8 mM) ), And stirred under nitrogen at 100 ° C for 6 hours. Cool to room temperature, rinse with water '5% sodium thiosulfate aqueous solution, saturated brine, then dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 0-(1-iodoethyl)- S-ethylthiocarboxylic acid crude. Isobutyric acid (5.5 ml, 59.3 mmol), tetra-n-butylammonium hydrogen sulfate (20.1 g, 59.3 mmol) were dissolved in water (150 ml) and dichloromethane ( 50 ml), sodium bicarbonate (10.0 g, 119 mmol) was added, and the mixture was stirred at room temperature for 4 hours, and the above-obtained 0- (1-iodoethyls_ethylthio) was added. The crude carboxylic acid ester was stirred overnight at room temperature. After the reaction was completed, the reaction solution was separated into layers, and the aqueous layer was extracted with dichloromethane. The obtained organic layer was dried under anhydrous magnesium sulfate-283-200403244, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1 00: 0 ~ 2 0: 1, V / V) to obtain 0- (buisodine as a colorless oil. Oxyethyl) -S-ethylthiocarboxylic acid ester (7.23 g 'yield 5 5%). Ή NMR (CDCI, 500 MHz): δ 6.93 (1Η, q, J = 5.5 Hz), 2.93-2.81 ( 2H, m), 3 2.59-2.52 (1H, m), 1.50 (3H, d, J = 5.4 Hz), 1.32 (3H, t, J = 7.5 Hz), 1.18 (3H, d, J = 7.0 Hz) , 1.17 (3H, d, J = 6.9 Hz); MS (ESI) m / z: 243 (M + Na) +; HRMS (ESI) m / z: calcd. For C9H1604SNa (M + Na) +: 243.0667. Found 243.0658. (27b) 1-isobutoxyethyl chloroformate The 0- (1-isobutoxyethyl) -S-ethylthiocarboxylic acid obtained in Example 27 (27a) Ester (2.0 g, 9.08 mmol), stirred under nitrogen at -78 ° C, added sulfonyl chloride (7 66 μl, 9.53 mmol), and stirred at 0 ° C for 20 minutes. At room temperature Concentrated under reduced pressure to obtain a crude product of 1 · isobutoxyethyl chloroformate. (27c) (3S) -3- (third butoxycarbonylamino) -1- (1-isobutoxyethoxycarbonyl) pyrrole (3S) -3- (Third-butoxycarbonylamino) pyrrolidine (1.69 g, 9.08 mmol) was dissolved in dichloromethane (80 ml), and 4-dimethylaminopyridine was added under ice cooling. (1.16 g, 9.53 mmol), 1-isobutoxyethyl chloroformate obtained in Example 27 (27b) was stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added, and The aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 5: 1 ~ 2.5: 1, V / V) Yellow (3S) _3- (third butoxycarbonylamino)-]-(1-isobutoxyethoxycarbonyl) pyrrolidine (2.61 g, yield 83%). -284- 200403244 1H NMR (CDCI3, 400MHz): δ 7.00-6.78 (1H, m), 4.72- 4.5〇 (ih, m), 4.27-4.06 (1H, m), 3.69-3.58 (1H, m), 3.56-3.35 (2H, m), 3.33 -3.16 (1H, m), 2.60-2. 46 (1H, m), 2.20-2.08 (1H, m), 1.92 -1.75 (1H, m), 1.49 »1.47 (3H, m), 1.45 (9H, s),]. 25 (3H, d, J = 7.3 Hz), 1.16 (3H, d, J = 7.4 Hz); MS (FAB) m / z: 345 (M + H) +; HRMS (ESI) m / z: calcd. For C16H2806N2Na (M + Na) +: 367.1845. Found 367.1860. (27d) 3-ethylsulfanyl- l- {4-[(3S) -l -(l-isobutoxyethoxycarbonyl) pyrrolodin-3-ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidine. (3 S) _3 obtained in Example 27 (27c) -(Third butoxycarbonylamino group_isobutoxyethoxy group) 卩 略 略 略 略 略 略 略 (1.6 g, 4.65 mmol) dissolved in dichloromethane (40 ml), add trifluoro under ice cooling Acetic acid (13 ml) was stirred for 2 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure and dried under reduced pressure to obtain a crude product of (33) -3_amino-1-(1-isobutoxyethoxy-based) pyridine trifluoroacetate. 3-Acetylthio-1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) azetidine (described in Reference Example 3; 1.0 g, 3.75 mmol) was dissolved in dichloride Methane (40 ml) with triphenylphosphine (148 mg, 0.56 mmol), palladium (0) triphenylphosphine (433 mg, 0.38 mmol), and dimethylketone (263 mg, 1.88 mmol) Stir under nitrogen and room temperature for 1.5 hours. After the reaction was completed, triethylamine (1.95 ml, 13.9 mmol) was added under nitrogen and ice cooling, and the (3 S) -3-amino-1- (1-isobutoxyethoxycarbonyl) pyrrole obtained above was added. The crude pyridinium trifluoroacetate and diethylphosphonium cyanide (0.78 ml, 5.0 mmol) were stirred at room temperature for 6.5 hours. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with a saturated sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (n-hexane : Ethyl acetate = 3: 1 ~ 1: 2, V / V), can be obtained as a white amorphous 3-acetamidinethio-1-{4-[(3 S)-1-(1 -isobutyl Oxyethoxycarbonyl) pyrrolidine-3.-285-200403244 ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin (1-49 g, yield 82%). ^ NMR (CDCI3, 400MHz): δ 7.42 (1H, s), 7.21-7.08 (1H, m), 6.83 -6.79 (1H, m), 4.63-4.58 (1H, m), 4.54 (2H, t, J = 8.0 Hz), 4.47 -4.41 (1H, m), 4.02 -3.98 C 2H, m), 3.80-3.74 (1H, m), 3.61-3.49 (2H, m), 3. 36-3. 27 (iH , m), 2.56-2. 49 (1H, m), 2.37 (3H, s), 2.32-2. 20 (1H, m), 2.04-1.92 (1H, m), 1.51-1.46 (3H, m) , 1.18 -1.15 (6H, m); MS (FAB) m / z: 485 (M + H) +; HRMS (ESI) m / z: calcd. For C20H2906N4S2 (M + H) +: 485.1 529. Found 485.1 538. (27e) (lR, isobutoxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] thiazol-2-yl 丨 azetidin-3-yl) sulfur-6 _ [(R) _ Ethyl] -1 -Methyl-Carbonol-2 -Bake-3 -Residual acid p-nitrate; the ester was obtained from the ethyl 3-ethylsulfanyl-l- {4-[(3S) obtained in Example 27 (27d) -l- (l-isobutoxyethoxyl) pyrrolidine-3 -ylaminomethylmethyl] -1,3-oxazole-2.-yl} azetidin (1.49 g '3.07 mmol) Dissolve in dimethylformamide (40 ml), add hydrazine acetate (340 mg, 3.69 mmol) at room temperature under nitrogen and stir for 1 hour. After the reaction was completed, (1R, 5S, 6S) _2- (diphenylphosphinoyloxy) -6-[(R) -l-hydroxyethyl] -l-methyl-carbon was added dropwise under nitrogen and ice cooling. A solution of 2-n-2-en-3-carboxylic acid p-nitrobenzyl ester (1.82 g, 3.07 mmol) in acetonitrile (50 ml) was added, followed by diisopropylethylamine (2.1 ml, 12.3 mmol) ) And stirred at room temperature for 5 hours. After the reaction was completed, ethyl acetate and 10% sodium chloride were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed successively with 10% sodium chloride solution, sodium bicarbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 1˜1 00: 〇, ethyl acetate: methanol = 1 00: 0˜30: 1, V / V), and a pale yellow color was obtained. Amorphous (111558,68) -2- (l- {4-[(3S: M- (l-isobutoxyethoxycarbonyl) pyrrolidin-3-ylaminemethylamidino] -286- 200403244 -1 , 3-thiazol-2-yl} azetidin-3-yl) thio-6-[(11) -1-hydroxyethyl] -1-methyl-carbanil-2 -ene-3 -carboxylic acid P-Nitrobenzyl ester (2.16 g, yield 89%). ^ NMR (CDCI3, 500MHz): δ 8.23 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz) , 7.43 (1H, s), 7.22-7.11 (1H, m), 6.82-6.80 (1H, m), 5.51 (1H, d, J = 13.6 Hz), 5.25 (1H, d, J = 13.6 Hz), 4.65-4.58 〇H, m), 4.57-4.45 (2H, m), 4.31-4.25 (3H, m), 4.10-4.02 (2H, m), 3.80 -3.70 (1H, m), 3.60-3.42 (2H , m), 3.42-3.30 (1H, m), 3.29 (1H, dd, J = 6.8, 1.9 Hz), 3.24-3.20 (1H, m), 2.57-2.51 (1H, m), 2.25-2.21 (1H , m), 2.01-1.91 (1H, m), 1.75-1.73 (1H, m), 1.51 -1.46 (3H, m), 1.37 (3H, d, J = 5.9 Hz), 1.28 (3H, d, J = 7.8 Hz), 1.17 -1. 14 (6H , m); IR (KBr): 3385, 2973, 1773, 1714, 1 544, 1344, 1 325 cmH; MS (FAB) m / z: 787 (M + H) +; HRMS (ESI) m / z: calcd. for C35H430nNsS2 (M + H) +: 787.2432 · Found 787.2429 · (2 7 『） （11155 3,63) -2- (卜 {4-[(3 3) -1- (1-isobutoxyethyl Oxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1 -Sodium salt of methyl-carbophenan-2-ene-3-carboxylic acid The compound (1 R, 5 S, 6 S) obtained in Example 2 7 (2 7 e)-2-(1-{4-[ (3S:)-1- (1-isobutoxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazole-2-yl} azetidin-3-yl) sulfur- 6-[(R) -l-Hydroxyethyl] -1-methyl-carbanil-2-en-3-carboxylic acid p-nitrobenzyl ester (1.5 g, 1.91 mmol) was dissolved in tetrahydrofuran (50 ml ) And distilled water (50 ml), in the presence of 10 ° / 0 Pd-C (1.5 g), contact hydrogenation reduction at room temperature for 2 hours. After the end of the reaction, it was filtered. To the filtrate were added sodium bicarbonate (160 mg, 1.91 mmol), ethyl acetate, and distilled water for layered extraction. The aqueous layer was concentrated under reduced pressure, purified by Cosmo sil reverse phase chromatography (distilled water: acetonitrile = 100: 0 to 79: 21, V / V), and freeze-dried to obtain -287- 200403244 the target compound as a white amorphous (1R, 5S, 6S) -2- (l- {4-[(3S) -l- (l-isobutoxyethoxyl) pyridine D-D-3--3-aminocarbamate] -1,3-blind 1 ^ x-2-yl} Py, butanidine-3-yl) sulfur-6-[(R) -l-Ethyl] -1-methyl-carboxanil Sodium salt (0.84 g, yield 61%). ^ NMR (D20, 400MHz): (5 7.52-7.50 (1H, m), 6.76-6.67 (1H, m), 4.56-4.50 (2H, m) 7 4.48-4.32 (1H, m), 4.25 (1H, dq, J = 6.6, 6.2 Hz) ,. 4.20-4. 14 (1H, m), 4.07-3.97 (2H, m), 3.72-3.65 (1H, m), 3.61 -3.52 (3H, m), 3 . 52-3.39 (1H, m), 3.27-3.16 (1H, m), 2.66-2.51 (2H, m), 2.31 -2.22 (1H, m), 2.11 -2.04 (1H, m), 1.55 -1.51 ( 3H, m), 1.30 (3H, d, J = 6.4 Hz), 1.27 -1.10 (6H, m), 1.06 (1.5H, d, J = 6.9 Hz), 1.05 (1.5H, d, J = 7.1 Hz ); IR (KBr): 3393, 2971, 1745, 1 666, 1605, 1 545, 1 390 cnT 丨; MS (FAB) m / z: 674 (M + H) +. HRMS (ESI) m / z: calcd. for C28H3709N5S2 Na (M + H) +: 674.1 931. Found 674.1926. (Example 28) (lR, 5S, 6S) -2- (l- {4-[(3S) -l- (l-iso Butoxyethoxycarbonyl) pyrrolidin-3-ylaminomethane] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl ] -1-Methyl-carbapene-2-ene-3-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester

(111,53,63) -2- (Bu [{[[[38] -1- (Buisobutoxyethoxycarbonyl) pyrrolidin-3-ylaminomethane]]-1,3 obtained in Example 27 -Thiazol-2-yl} azetidin-3-3-288-200403244) sulfur-6-[(R) -1-hydroxyethylbenzene 丨 methyl-carbanil-2 Sodium salt (300 mg, 0.445 mmol) was dissolved in dimethylacetamide (15 ml), and iodoethyl isopropylcarboxylate (150 mg, 0.57 mmol) was added under nitrogen at 0 ° C. (Ear)) Stir for 1 hour. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% brine, 5% sodium thiosulfate aqueous solution, saturated sodium bicarbonate solution, and saturated brine, and then dried over anhydrous magnesium sulfate, filtered, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 4: 1 ~ 100: 0, ethyl acetate: methanol = 100: 15 ~ 1, V / V), and the target compound was obtained in white. Amorphous (1 R, 5 S, 6 S)-2-(1-{4-[(3 S) -1-(1 -isobutoxyethoxycarbonyl) pyrrolidine-3 _ylaminomethylmethyl) ] -1,3 -Thiazole-2 -yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carban-2-en-3 -1- (isopropoxycarbonyloxy) carboxylic acid ethyl ester (3 65 mg, 100% yield). NMR (CDCI3, 500MHz): (5 7.43 (0.5H, s), 7.43 (0.5H, s), 7.23-7.15 (1H, m), 6.91-6.86 (1H, m), 6.83-6.80 (1H, m ), 4.95 -4.86 (1H, m), 4.65-4.55 (1H, m), 4.55-4.45 (2H, m), 4.31-4.21 (3H, m), 4.11-4.05 (2H, m), 3.80-3.70 (1H, m), 3.62-3. 45 (2H, m), 3.24 (1H, dd, J = 6.9, 3, 0 Hz), 3.19 (1H, dq, J = 8.8, 6.9 Hz), 2.58-2.50 (1H, m), 2.29-2.21 (1H, m), 2.04-1.91 (1H, m), 1.71 (1H, d, J = 4.8 Hz), 1.61 〇.5H, d, J = 5.8 Hz), 1.58 (1.5H, d, J = 4.8 Hz), 1.51-1.46 (3H, m), 1.38-1.24 (12H, m), 1.18-1.14 (6H, m) ,; IR (KBr): 3394, 2978, 1752 , 1718, 1 544, 1324, 1272 cmH; MS (FAB) m / z: 782 (M + H) +; HRMS (ESI) m / z: calcd. For C34H48012N5S2 (M + H) +: 782.2741. Found 782.2714 (Example 29) (1 R, 5S, 6S) -2- (l- {4-[(3S) -1- (1-isobutoxymethoxycarbonyl) zine Fluorenyl] -1,3 -thiow-2-yl} ^ but !! din-3-yl) sulfur-6-[(R)-1-hydroxyethylbubyl-carbenyl-2 -ene- 3-carboxylate sodium salt

(29a) 0- (isobutoxymethyl) -s-ethylthiocarboxylic acid ester. 0- (chloromethyl ethylthiocarboxylic acid ester (Synthesis, 〖1. 10.0 grams, 64.6 millimoles) were dissolved in acetone (100 milliliters), and sodium sulfide (19.4 grams, 130 millimoles), sodium bicarbonate (0.54 grams, 6.5 halo) were added successively. Stir for 3 hours under nitrogen and 40 ° C. Cool to room temperature and filter. The filtrate was concentrated under reduced pressure, n-hexane was added, and the organic layer was washed with 5% sodium bicarbonate solution, 5% sodium thiosulfate aqueous solution, and water in this order. After cleaning, it was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 0- (iodomethyl ethylthiocarboxylic acid crude product. Isobutyric acid (6.0 ml, 64 6 mmol), four N-Butyl ammonium bisulfate (21.9 g '64.6 mmol) was dissolved in water (150 ml) and dichloromethane (50 ml)'. Sodium bicarbonate (10.9 g, 129 mmol) was added at room temperature. Add the crude __ (iodomethyl) _s-ethylthiocarboxylic acid ester obtained above and stir for 2 hours, and sample overnight at room temperature. After the reaction is completed, separate the reaction solution and separate the aqueous layer Chloroform Collected by the hospital. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 100 ·· 〇 ~ 20: i 'v / v) Purification to obtain 0- (isobutoxymethyl) -S-ethylthiocarboxylic acid ester as a colorless oil (9.88 g, yield 73%).] H NMR (CDCIa, 400 MHz ): δ 5.81 (2Η, s), 2.89 (2Η, q, J = 7.3 Hz), 2.65-2 · 57 (1H, m), 1.33 (3H, t, ″ = 7.3 Hz), 119 (6H ， D ， ”= 7.3 Hz); MS (ESI) m / z: 229 (M + Na) +; HRMS (ESI) m / z: calcd. For C8H14〇4SNa (M + Na) +: 229.051 1 Found 229.0498. -290- 200403244 (29b) Isobutoxymethyl chloroformate The 0- (isobutoxymethyl) -S-ethylthiocarboxylic acid ester (2.0 g, 9.70 mmol) obtained in Example 29 (29a) Mol), add sulfonium chloride (818 μl, 10.2 mmol) under nitrogen and stirring at -78 ° C, and stir at 0 ° C for 20 minutes. Concentrate under reduced pressure at room temperature to obtain isochloroformate Crude butoxymethyl. (29c) (3S) -3- (third butoxycarbonylamino) -1- (1-isobutoxymethoxycarbonyl) pyrrolidine Tributoxycarbonylamino) pyrrolidine (1.81 , 9.70 mmol) dissolved in dichloromethane (80 ml), 4-dimethylaminopyridine (1.24 g, 10.2 mmol) was added under ice cooling, and isobutyl chloroformate obtained in Example 20 (20b) was added. The oxymethyl ester was stirred at room temperature for 3.5 hours. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1 ~ 2: 1, V / V) to obtain (3S) -3- (third butoxycarbonylamino)-as a white solid. 1- (1-isobutoxymethoxycarbonyl) pyrrolidine (1.72 g, 54% yield). 'H NMR (CDCI3, 400MHz): (5 5.77 (1H, s), 5.77 (1H, s), 4.65-4.45 (1H, m), 4.30-4.10 (1H, m), 3.69-3.64 〇H, m ), 3.55-3.45 (2H, m), 3.30-3.20 (1H, m), 2.63-2.57 (1H, m), 2.20-2.10 (1H, m), 1.90-1.75 (1H, m), 1.45 (9H , s), 1.19 (6H, d, J = 6.8 Hz); IR (KBr): 3314, 2980, 1759, 1713, 1694, 1529, 1462, 1402, 1282, 1 245 cmH; MS (FAB) m / z : 331 (M + H) +; HRMS (ESI) m / z: calcd. For C15H2606N2Na (M + Na) +: 353.1 689. Found 353.1697. (29d) 3-ethylsulfanyl- l- {4- [ (3S) -l- (isobutoxymethoxycarbonyl) pyrrolidin-3-ylaminomethane] -1,3-thiazol-2-yl} azetidine. Example 2 9 (2 9c) was obtained as ( 3 S) -3- (Third-butoxycarbonylamino) -1- (isobutyl 200403244 oxymethoxycarbonyl) P-ridine (1.54 g'4.65 mmol) was dissolved in dichloromethane (4〇 Ml), trifluoroacetic acid (13 ml) was added under ice cooling, and the mixture was stirred for 2 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, dried under reduced pressure, and dried to obtain (3 S) · 3-amino-1-(isobutoxymethoxycarbonyl) pyrrolidine trifluoroacetate crude product. 3-Acetylthio-1- (4-propionyloxyferroyl-l, 3-b-pyridine-2-yl) oxobutidine (described in Reference Example 3; 1.0 g, 3.75 mmol) Dissolve in dichloromethane (40 ml), add triphenylphosphine (148 mg, 0.56 mmol), palladium (0) triphenylphosphine (433 mg, 0.38 mmol), dimethyl ketone (263 mg, 1.88 millimolar) 'Stir for 1 hour under nitrogen at room temperature. After the reaction was completed, triethylamine (3.06 ml, 21.8 mmol) was added under nitrogen and ice cooling to obtain (38) -3-amino-1-(isobutoxymethoxycarbonyl) pyrrolidine trifluoroacetic acid. The crude salt, diethylphosphonium cyanide (0.78 ml, 5.00 mmol) was stirred at room temperature. After the reaction was completed, ethyl acetate was added to the reaction system, and the organic layer was sequentially washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Zhengjiyuan: ethyl acetate = 3: 1 ~ 1: 2, V / V) to obtain 3-ethylfluorenylthio-l- {4-[(3S ) -l- (isobutoxymethoxyfluorenyl) pyridine-3-ylaminoformamidine; M, 3-thiazol-2-yl} azetidine (1.26 g, 71% yield). ] H NMR (CDCI3, 400ΜΗζ): δ 7.42 (1Η, s), 7.15 (TΗ, d, J = 7.8 Hz), 5.79- 5.75 (2H, m), 4.65-4.58 (1H, m), 4.54 (2H , t, J = 8.8 Hz), 4.47-4.41 (1H, m), 4.01-3.95 (2H, m), 3.82-3.74 (1H, m), 3.64-3.47 (2H, m), 3.41-3.31 (1H , m), 2.64-2.53 (1H, m), 2.37 (3H, s), 2. 28-2. 22 (1H, m), 2.05-1.93 (1H, m), 1.20-1.17 (6H, m); ^ MS (FAB) m / z: 471 (M + H) +; HRMS (ESI) m / z: calcd. for C19H2706N4S2 (M + H) +: 471.1 372. Found 471.1 362. (29e) ( lR, 5S, 6S) -2- (l- {4-[(3S) -l- (isobutoxymethoxycarbonyl) pyrrolidin-3-ylaminomethane]]-1,3-thiazole-2- } Acridine-3-yl) sulfan-6-[(&)-hydroxy200403244 ethyl] -1 -methyl-carbanil-2 -anthyl-3 -residual acid p-nitropine ester 29 (29d) 3-Ethylsulfanyl-l- {4-[(3S) -1- (isobutoxymethoxycarbonyl) pyrrolidin-3-ylaminemethylamidino] -1,3-thiazole- 2-yl} azetidine (1.45 g, 3.08 mmol) dissolved in dimethylformamide (40 ml). Add phosphonium acetate (341 mg, 3.70 mmol) at room temperature under nitrogen. 'Stir for 1 hour. After the reaction was completed, (lR, 5S, 6S) -2- (diphenylphosphinoyloxy) -6-[(R) -1-hydroxyethyl] -1-methyl- was added dropwise under nitrogen and ice cooling. A solution of carbamate-2-en-3-carboxylic acid p-nitrobenzyl ester (1.83 g, 3.0 8 mmol) in acetonitrile (50 ml), followed by diisopropylethylamine (2.2 ml, 12.3 mmol) and stirred at room temperature overnight. After the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed successively with 10% sodium chloride solution, sodium bicarbonate solution, water, and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 1 ~ 100: 00, ethyl acetate: methanol = 100: 0 ~ 15: 1, V / V), and a pale yellow amorphous form was obtained. Of (1R, 5S, 6S)-2- (l- {4-[(3S) -l- (isobutoxyethoxycarbonyl) pyrrolidin-3-ylaminemethylamidino] -1,3-thiazole- 2-yl} azetidin-3-yl) thio-6-[(R) -l-hydroxyethyl] -1-methylcarbanil-2-en-3-carboxylic acid p-nitrobenzyl ester (1.44 G, yield 60%). 'H NMR (CDCI3, 400MHz): (5 8.23 (2H, d, J = 8.7 Hz), 7.66 (2H, d, J = 8.7 Hz), 7.44 (1H, s), 7.22-7.04 (1H, m) , 5.80-5.75 (2H, m), 5.50 (1H, d, J = 13.7 Hz), 5.25 (1H, d, J = 14.6 Hz), 4.66-4.57 (1H, m), 4.54-4.46 (2H, m ), 4.33-4.24 (3H, m), 4.10-4.00 (2H, m), 3.82 -3.72 (1H, m), 3.64-3.46 (2H? M), 3.43-3.32 (1H, m), 3.30 (1H , dd, J = 6.8, 2.9 Hz), 3.22 (1H, dq, J = 8.8, 6.8 Hz), 2.62-2.56 (1H, m), 2.30-2.21 (1H, m), 2.04-1.90 (1H, m ), 1.71 (1H, d, J = 2.9 Hz), 1.38 (3H, d, J = 6.9 Hz), 1.28 (3H, d, J = 7.8 Hz), 1.20 -1.17 (6H, m);- 293- 200403244 IR (KBr): 3385, 2973, 1769, 1757, 1719, 1544, 1525, 1344 cmH; MS (FAB) m / z: 773 (M + H) +; HRMS (ESI) m / z: calcd for C34H40OnN6S2Na (M + Na) +: 795.2194. Found 795.2101. (2 9f) (lR55S56S) -2- (l- {4-[(3S) -l- (isobutoxymethoxycarbonyl) pyrrolidine-3 -Ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfan-6-[(11) -1-hydroxyethyl; Nin-2-ene-3-carboxylic acid sodium salt obtained from Example 2 9 (2 9 e) Compound (1 R, 5 S, 6 S)-2-(1-{4-[(3 S) -1- (isobutoxymethoxycarbonyl) pyrrolidin-3-ylaminomethane]] 1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -l-hydroxyethyl] -1-methyl-carban-2-en-3-carboxyl P-nitrobenzyl acid (1.46 g, 1.89 mmol) was dissolved in tetrahydrofuran (50 ml) and distilled water (50 ml), and subjected to contact hydrogenation reduction at room temperature in the presence of 10% Pd-C (1.5 g). 4.5 hours. After the reaction was completed, the reaction mixture was filtered. To the filtrate were added sodium bicarbonate (159 mg, 1.89 mmol), ethyl acetate, and distilled water to perform layered extraction. The aqueous layer was concentrated under reduced pressure, and purified by Cosmosil reversed phase chromatography (distilled water ·· acetonitrile = 1 00: 0 to 85: 15 'V / V), and freeze-dried to obtain the target compound (11 ^, 53) , 63) -2-([{[[[33]-1- (Isobutoxymethoxycarbonyl) pyrrolidin-3-ylaminomethyl]]-1,3-thiazol-2-yl} Acridine-3-yl) thio-6-[(R) -l-hydroxyethyl] -bumethyl-carbobin-2-ene-3-carboxylic acid sodium salt (0.6 0 g, yield 48% ). ] H NMR (D20, 400ΜΗζ): δ 7.52-7.50 (1Η, in), 5.77-5.70 (2Η, m), 4.57 -4.50 (3Η, m), 4.38-4.31 (1H, m), 4.25 (1H, dq, J = 6.4, 6.2 Hz), 4.20-4.16 (1H, m), 4.18 (1H, dd, J = 9.1, 2.6 Hz), 4.06-3.99 (2H, m), 3.73-3.66 (1 H, m ), 3.61-3.45 (3H, m), 3.43 (1H, dd, J = 6.2, 2.6 Hz), 3.22 (1Ή, dq, J = 7.4, 6.9 Hz), 2.70-2.58 (1H, m), 2.31- 2.23 (1H, m), 2.10 -2.05 (1H, rn), 1.30 (3H, d, J = 6.4 Hz), 1.19 (3H, d, J = 7.3 Hz), 1.16-1.04 (6H, m); 200403244 IR (KBr): 3387, 2971, 1751, 1727, 1 661, 1 602, 1 546, 1470, 1 392 cm'1; MS (FAB) m / z: 660 (M + H) +; HRMS (ESI) m / z: calcd. for C27H3509N5S2Na (M + H) +: 660.1774. Found 660.1777. (Example 30) (lR55S, 6S) -2- (l- {4-[(3S) -l- (isobutoxy Methoxycarbonyl) pyrrolidin-3-ylamine formamyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfur-6-[(R) -1 ·· Ethyl] 1-Methyl-Carboparan-2--2--3-carboxylic acid 1- (isopropoxyloxy) ethyl ester

(LR, 5S, 6S) -2- (l- {4-[(3S) -1- (isobutoxymethoxycarbonyl) pyrrolidin-3 -ylaminomethyl)]-1 obtained in Example 29, 3-thiazole-2 -yl} azetidin-3 -yl) thio-6-[(R) -l-hydroxyethyl] -1-methyl-carban-2-en-3-carboxylic acid sodium The salt (300 mg, 0.455 mmol) was dissolved in dimethylacetamide (15 ml), and 1-iodoethyl isopropylcarboxylate (153 mg, 0.591 mmol) was added under nitrogen at 0 ° C. Stir for 1 hour. After the reaction was completed, ethyl acetate was added, and the organic layer was washed with 10% brine, 5% sodium thiosulfate aqueous solution, saturated sodium bicarbonate solution, water, and saturated brine in that order, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:;! ~; [〇〇: 〇, ethyl acetate: methanol = 1〇: 〇〜4〇: 丨, v / v), The target compound can be obtained as white amorphous (1 R, 5 S, 6 S)-2-(1-{4-[(3S) -1- (isobutoxymethoxycarbonyl) pyrrolidin-3-ylamine methylamine Fluorenyl] -1,3-thiazole-295- 200403244 -2-yl} p-butanidine-3-yl) sulfur-6-[(R) -l-ethylidene] -1-methyl-carbohydrate Nian-2ene-3 -carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester (2 3 2 mg, yield 98%). ] H NMR (CDCI3, 500MHz): (5 7.43 (0.5H, s), 7.43 (0.5H, s), 7.18-7.10 (1H, m), 6.91-6.85 (1H, m), 5.81-5.75 (2H, m), 4.95 -4.86 (1H, m), 4.66-4.56 (1H, m), 4.53-4.45 (2H, m), 4.32-4.20 (3H, m), 4.10-4.02 (2H, m) , 3.82-3.74 (1H, m), 3.65-3.45 (2H, m), 3.44 -3.32 (1H, m), 3.24 (1H, dd, J = 6.8, 2.9 Hz), 3.18 (1H, dq, J = 7.8, 6.9 Hz), 2.63-2.56 (1H, m), 2.31-2.20 (1H, m), 2.04-1.91 (1H, m), 1.69 (1H, d, J = 3.9 Hz), 1.61 (1.5H, d, J = 5.8 Hz), 1.59 (1.5H, d, J = 5.8 Hz), 1.38-1.25 (9H, m), 1.29 (3H, d, J = 5.9 Hz), 1.20-1.17 (6H, m) ; IR (KBr): 3386, 2978, 1757, 1722, 1665, 1544, 1272 cmH; MS (FAB) m / z: 768 (M + H) +; HRMS (ESI) m / z: calcd. For C33H46012N5S2 ( M + H) +: 768.2585. Found 768.2574. (Example 31) (lR, 5S, 6S) -2- (l- {4-[(3S) -l- (l-cyclohexylcarbonyloxyethoxycarbonyl) Pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfan-6-[(R) -l-hydroxyethyl] -1-methyl -Carbonyl-2-ene-3-carboxylic acid sodium salt

(31a) (lR, 5S, 6S) -2- [l- (4-allyloxycarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] sulfur-6-[(R) -l · Hydroxyethyl] -1-methyl-carbobenzoin-2-ene-3-carboxylic acid p-nitrobenzyl ester 3-ethyl ethylthio-1- (4-propanyloxypropyl-1, 3-Thiowan-2-yl) butyltinidine (described in Reference Example 3; 9.00 g, 30.2 mmol) was dissolved in dimethylformamidine-296- 200403244 amine (200 ml) under nitrogen and Add hydrazine acetate (3.33 g, 3 6.2 mmol) at room temperature and stir for 40 minutes. After the reaction was completed, (lR, 5S, 6S) -2- (diphenylphosphinoyloxy) -6-[(R) -l-hydroxyethylbenzene 1-methyl was added dropwise under nitrogen at -20 ° C. A solution of p-nitrobenzyl-2-carbene-3 -carboxylic acid p-nitrobenzyl ester (2. 5.2 g, 3 6.2 mmol) in diethyl benzyl alcohol, and then diisopropylethylamine (15.10 ml, 86.9) Millimoles) 'Stir for 2 hours at -20 ° C and place in the freezer for three nights. After completion of the reaction, 'ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (cyclohexane: ethyl acetate = 20: 8 0 ~ 0: 100, V / V) to obtain a pale yellow amorphous (1 R, 5 S, 6 S)- 2-[1-(4-Allyloxycarbonyl • 1,3-thiazole-2 -yl) azetidin-3 -yl] thio-6-[(R)-1 -hydroxyethyl] -1 -formyl P-nitrobenzyl-2-carben-3-carboxylic acid p-nitrobenzyl ester (7.0 g, yield 94.6%). 'H NMR (CDCi3, 400MHz): 6 8.22 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 7.53 (1H, s), 6.06-5.96 (1H, m), 5.50 (1H, d, J = 13.9 Hz), 5.41-5.36 (1H, m), 5.30-5.24 (1H, m), 5.25 (1H, d, J = 13.9 Hz), 4.81-4.79 (2H, m) , 4.57 -4.52 (2H, m), 4.31 -4.24 (3H, m), 4. 15 -4.07 (2H, m), 3.29 (1H, dd, J = 7.0, 2.5 Hz), 3.24-3.16 ( 1H, m), 2.09-2.03 (1H, m), 1.37 (3H, d, J = 6.6 Hz), 1.26 (3H, d, J = 6.6 Hz); MS (FAB) m / z: 601 (M + H) +. (3 1 b) O-(1 -cyclohexylcarbonyloxyethyl) _ s-ethylthiocarboxylic acid ester cyclohexanecarboxylic acid (3.04 g, 23.7 mmol), Tetrabutylammonium hydrogen sulfate (8.05 g '23.7 mmol) was dissolved in water (60 ml) and dichloromethane (20 ml).' Sodium bicarbonate (3.9 9 g, 47. 4 mmol) was added to Stir at room temperature for 2 -297- 200403244 hours, and add the 0- (1-iodoethyl) -S-ethylthiocarboxylic acid ester (6 · 16 g, 2 3 · 7) obtained in Example 2 7 (2 7a). Millimoles) and stirred at room temperature overnight. After the reaction was completed, the reaction solution was separated into layers, and the resulting organic layer was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (cyclohexane ·· ethyl acetate = 99 ·· 1 ~ 98: 2, V / V) to obtain 0- (1-cyclohexylcarbonyloxyethyl) as a colorless oil. -S-ethylthiocarboxylic acid ester (2.99 g, yield 48.5%) 〇Ή NMR (CDCIa, 400 MHz): δ 6. 94 (1Η, q, J = 5.5 Hz), 2.94-2.81 (2H, m ), 2.35.-2.27 (〗 H, m), 1.92-1.91 (2H, m), 1.77-1.72 (2H, m), 1.65-1.20 (6H, m), 1.50 (3H, d, J = 5.9 Hz), 1.31 (3H, t, J = 7.4 Hz); MS (FAB) m / z: 261 (M + H) +. (31c) Chloroformic acid 1-cyclohexylcarbonyloxyethyl Example 3 1 (3 1 b) Obtained 0-(1 -cyclohexylcarbonyloxyethyl) -S -ethylthiocarboxylic acid ester (2.70 g, 10.4 mmol), and add sulfonyl chloride under nitrogen and -78 ° C under stirring (0.88 ml, 1 0.9 mmol), and stirred at 0 ° C for 30 minutes. The crude product was obtained by concentrating under reduced pressure at room temperature. (31d) (3S) -3- (third butoxycarbonylamino) -1- (1-cyclohexylcarbonyloxyethoxycarbonyl) pyridine ) Pyrrolidine (1.94 g, 10.4 mmol) was dissolved in dichloromethane (50 ml), and 4-dimethylaminopyridine (1.27 g, 0.4 mmol) was added under ice-cooling. (Ear), 1-cyclohexylcarbonyloxyethyl chloroformate obtained in Example 3 1 (3 1 c), and stirred under cooling for 2 hours. After the reaction was completed, ethyl acetate was added, and the organic layer was washed with saturated sodium bicarbonate solution and saturated brine, -298-200403244, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (cyclohexane: ethyl acetate = 8 0: 2 0˜7 0: 30, V / V) to obtain (3 S) -3- (third white amorphous). Butoxycarbonyl) amino-1- (1-cyclohexylcarbonyloxyethoxycarbonyl) pyrrolidine (3.451 g, yield 86.2%). NMR (CDCI3, 400MHz): (5 6.81-6.75 (1H, m), 4.74-4.66 (1H, m), 4.20 (1H, bs), 3.66-3.60 (1H, m), 3.55-3.41 (2H, m ), 3.26 -3.12 (1H, m), 2.34-2.27 (1H, m), 2.18-2.06 (1H, m), 1.92-1.74 (5H, m), 1.64 -1.16 (9H, m), 1.45 (9H, s); MS (FAB) m / z: 385 (M + H) +. (31e) (lR, 5S, 6S) -2- (l- {4-[(3S)- l- (bucyclohexylcarbonyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfur-6-[(R) 1-Hydroxyethyl] -1-methyl-carbanil-2-en-3-carboxylic acid p-nitrobenzyl ester The (3S) -3- (third butoxy) obtained in Example 31 (31 d) Carboxamido) -1- (1-cyclohexylcarbonyloxyethoxycarbonyl) pyrrolidine (0.96 g, 2.50 mmol) was dissolved in dichloromethane (30 ml), and trifluoroacetic acid (1 (0 ml), and stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and dried under reduced pressure to obtain (3 S) -3-amino-1- (1-cyclohexyloxyethoxycarbonyl) pyrrolidine. Crude trifluoroacetate. (LR, 5S, 6S) -2- [l- (4-allyloxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Example 31 (31a)- 3-yl] sulfur-6- [(R) -l-Hydroxyethyl] -1-methyl-carban-2-en-3-carboxylic acid p-nitrobenzyl ester (1.50 g, 2.50 mmol) was dissolved in tetrahydrofuran (30 ml), Add triphenylphosphine (140 mg, 0.53 mol), palladium (0) triphenylphosphine (140 mg, 0.13 mol), dimethyl ketone (180 mg, 1.5 2 mol), Stir under nitrogen and room temperature for 0.5 hours. After the reaction is complete, add diisopropylethylamine (1.57 ml, 9.00 mmol) under nitrogen and ice cooling. (3S)- 3-amino-1- (bucyclohexylcarbonyloxyethoxycarbonyl)

-299- 200403244 crude pyrrolidine trifluoroacetate, diethylphosphonium cyanide (0.7 6 ml, 5.0 mmol), stirred at room temperature for 2 hours, and placed in a freezer overnight. After the reaction was completed, ethyl acetate and water were added, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with a sodium bicarbonate solution, water, and saturated brine in that order, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 95 to 5, V / V) to obtain (1R, 5S, 6S) -2- (1- {4-[(3S) -1- (i_cyclohexylcarbonyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino] -1,3-thiazol-2-yl} azetidinidine-3- Sulphur-6-[(R) -l-Ethyl] -1-methyl-carbaphenate-2-carbo-3-residue p-nitrobenzyl ester (1.96 g, yield 94.8%) . ] H NMR (CDCI3, 400MHz): 8.22 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 7.44 (1H, s), 7.18-7.15 (1H, m) 7 6 . 80-6.79 (1H, m), 5.51 (1H, d, J = 13.6 Hz), 5.25 (1H, d, J = 13.6 Hz), 4.61- 4.50 (3H, m), 4.30-4.25 (3H, m ), 4.15-4.06 (2H, m), 3.78-3.73 (1H, m), 3.58-3.48 (2H, m), 3.37-3.21 (2H, m), 3.30 (1H, dd, J = 6.6, 2.9 Hz), 2.32-2.24 (2H, m), 2.05-1.63 (8H, m), 1.50-1.24 (10H, m), 1.38 (3H, d, J = 6.9 Hz) j MS (FAB) m / z : 827 (M + H) +. (31f) (lR, 5S, 6S) -2- (l- {4-[(3S) -l- (l-cyclohexylcarbonyloxyethoxycarbonyl) pyrrolidine-3 -Methylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfan-6-[(R) -butoxyethyl] -1-methyl-carbamoyl- 2-ene-3-carboxylic acid sodium salt The compound (1 R, 5S, 6S) obtained from Example 3 1 (3 1 e) -2- (l-{4-[(3 S) -1- (1- Cyclohexylcarbonyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfur-6-[(R) -l-hydroxyl Ethyl 1-methyl-carbobenzon-2-ene-3-carboxylic acid p-nitrobenzyl ester (1.90 g, 2.30 mmol) was dissolved in tetrahydrofuran-300- 200403244 (100 Ml) and 0.1 M-sodium phosphate buffer (100 ml) in the presence of 7.5% Pd-C (1.90 g), subjected to hydrogenation reduction at room temperature for 2 hours. After the reaction was completed, the reaction mixture was filtered. Diethyl ether and distilled water were added and the layers were extracted. The aqueous layer was concentrated under reduced pressure, and purified by Cosmo sil reverse phase silica gel column chromatography (distilled water: acetonitrile = 1 00: 0 to 8 0: 20, V / V), and freeze-dried to obtain the target compound as a pale yellow amorphous ( lR, 5S56S) -2- (l- {4-[(3S) -l- (l-cyclohexylcarbonyloxyethoxycarbonyl) pyrrolidin-3-ylaminemethylamidino] -1,3-thiazole-2 -Yl} azetidin-3-yl) sulfan-6-[(R) -l-hydroxyethyl] -1 -methyl-carban-2-en-3-carboxylic acid sodium salt (1 · 〇 0 g, yield 60.8%). ] H NMR (D20, 400MHz): δ 7.50-7.49 (1Η, m), 6.73-6.63 (1H, m), 4.52 -4.48 (3H, m), 4.34-4.13 (3H, m), 4.02-3. 96 (2H, m), 3.69-3.36 (5H, m), 3.22-3. Π (1H, m), 2.35-2.24 (2H, m), 2.08-2.05 (1H, m), 1.85-1.48 (8H , m), 1.40-1.05 (5H, m), 1.30 (3H, d, J = 5.9 Hz) 1.17 (3H, d, J = 7.3 Hz); IR (KBr): 3393, 2933, 2858, 1741, 1666 , 1605, 1 545, 1390, 131 3 cm'1; MS (FAB) m / z: 714 (M + H) +;

Anal, calcd. For C31H40N509S2Na · 2HZ0: C, 49.66%; H, 5.9U; N, 9.34%; S, 8.55%; Na, 3.07L Found C, 49.9U; H, 5.84%; Ν, 9.34% S, 8.64%; Na, 3.533. (Example 32) (1 R, 5S, 6S) -2- (l- {4-[(3S) -1- (1-cyclohexylcarbonyloxyethoxycarbonyl) ) Pyrrolidin-3-ylaminocarbamyl] -1,3-thiazol-2-yl} azetidinyl) Sulfur-6-[(R) -l-hydroxyethylb-methyl Trimethylacetoxymethyl 2-ene-3-carboxylic acid

-301- 200403244 The (1 R, 5 S, 6 S) obtained in Example 3 1-2-(1-{4-[(3 S)-1-(1-cyclohexyloxyethoxycarbonyl) pyrrolidine -3 -Amineaminomethyl]] ,, 3_thiazole_ 2_yl} azetidin-3-yl) sulfur-6-[(11) -1-Ethyl] -1_methyl-carbon Bennin-2_ene-3-carboxylic acid sodium salt (310 mg '0.43 mmol) was dissolved in dimethylacetamide (15 ml), and methyl iodide was added under nitrogen at 0 ° C. Valerate (40 mg, 0.56 mmol) was stirred for 30 minutes. After the reaction was completed, ethyl acetate was added, and the organic layer was washed successively at 10 ° /. Brine, 5% sodium thiosulfate aqueous solution, saturated sodium bicarbonate solution, water, and saturated brine were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 1 00: 0 to 95: 5, V / V) to obtain the target compound (1R, 5S, 6S) -2- (b {4-[(3S) -l- (i_cyclohexylcarbonyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino] -1,3-thiazol-2-yl} azetidin-3-yl ) Sulfur-6-[(11) -1-Ethyl] methyl-carbobenzon-2-yi-3-residue trimethylethylglycosyloxymethyl (338 mg, yield 97.5%). NMR (CDCI3, 400MΗζ): δ 7.44 (1Η, s), 7.20-7.14 (1Η, m), 6.81-'6.78 (1H, m), 5.97 (1H, d, J = 5.5 Hz), 5.84 (1H, d, J = 5.5 Hz), 4.67 -4.57 (1H, m), 4.54-4.48 (2H, m), 4.33-4.21 (3H, m), 4.15-4.05 (2H, m), 3.79-3.72 ( 1H, m), 3.58-3.48 (2H, m), 3.40-3.17 (2H, m), 3.25 (1H, dd, J = 7.0, 2.6 Hz), 2.33-2.21 (2H, m), 2.10 -1.89 ( 3H, in), 1.73-1.61 (4H, m), 1.50-1.06 (8H, m), 1.35 (3H, d, J = 5.9 Hz), 1.27 (3H, d, J = 6.6 Hz), 1.22 (9H , s); IR (KBr): 3394, 2971, 2935, 2860, 1779, 1735, 1667, 1 543, 1 31 5 cm "1; MS (FAB) m / z: 806 (M + H) +. ( Example 33) (lR, 5S, 6S) -2- (l- {4-[(3S) -1- (l-cyclohexylcarbonyloxyethoxycarbonyl) pyrrolidine-3 -ylaminomethylmethyl]- 1,3-thiazole-2 -yl} azetidin-3-yl) -302- 200403244 sulfur-6-[(R) -bhydroxyethyl] -1-methyloxycarbonyloxy) ethyl ester-carbon Phenyl-2 -ene-3 -carboxylic acid 1-(isopropyl

(Ir55s, 6s), 2- (i_ {4 _ [(3s bu (bucyclohexylcarbonyloxyethoxycarbonyl) pyrrolidin-3 -ylaminomethane)] obtained in Example 31_1,3_ Thiazole_ 2 _yl 丨 azetidin-3-yl) sulfan-6-[(R)-:!-Hydroxyethyl; methyl-carbapene-2-enecarboxylic acid sodium salt (320 mg, 0.405 mmol (Ear) was dissolved in dimethylacetamide (15 ml). Under nitrogen and 0C, isopropylcarboxylic acid and ethyl iodoethyl ester (15 mg, 058 mmol) were added and stirred for 2 hours. The reaction was completed. Then, ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 5% sodium thiosulfate aqueous solution, saturated sodium bicarbonate solution, water, and saturated saline, dried over anhydrous magnesium sulfate, filtered, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methyl alcohol = 100 · 0 to 95: 5, V / V) to obtain the target compound (1R, 5S, 6S) as a white amorphous substance. ) -2- (Bu {4-[(3S) -l- (l-cyclohexylcarbonyloxyethoxycarbonyl) pyrrolidin-3-ylaminemethylamidino] -1,3-thiazol-2-yl} acyl Butidin-3-yl) sulfur-6-[(R) _ 1-Ethyl] -1-methyl-carbobenzoin-2-dilute-3-residual acid 1- (isopropoxycarbonyloxy) Ethyl ester (342 G, yield 92.5%). -303-200403244] H NMR (CDCI3, 400MHz): δ 7.43 (1H, s), 7.21-7.14 (1H, m), 6.91-6.86 (1H, m), 6.81-6.78 (1H, m), 4.95-4.86 (1H, m), 4.64-4.61 (1H, m), 4.53-4.47 (2H, m), 4.32-4.22 (3H, m), 4.15-4.06 (2H, m) , 3.79-3.72 (1H, m), 3.58-3.40 (2H, m), 3.39-3.15 (2H, m), 3.25 (1H, dd, J = 7.0, 2.6 Hz), 2.33-2.22 (2H, m) , 2.05 -1.89 (4H, m), 1.73-1.58 (7H, m), 1.50-1.17 (19H, m); IR (KBr): 3393, 2980, 2936, 2859, .1750, 1720, 1667, 1 543 , 1 320, 1 273 cm · 1; MS (FAB) m / z: 822 (M + H) +. (Example 34) (lR, 5S, 6S) -2- (l- {4-[(3S ) -l- (l-octyloxyethoxycarbonyl) pyrrolidine-3 -ylaminomethylmethyl] -1,3-thiazole-2 -yl} azetidin-3 -yl) thio-6-[( R) -l-Hydroxyethyl] -1-methyl-carbobenzoin-2.ene-3_carboxylic acid sodium salt

(34a) (3S) -3- (Third butoxycarbonylaminochloroethoxycarbonyl) pyrrolidine (3S) -3 .- (Third butoxycarbonylamino) pyrrolidine (3.0 g, 16.1 Millimoles) In the dichloromethane compound (40 ml), add Pididine (1.30 ml, 16.1 mmol), chloroformic acid, and chloroethyl ester (-20 ml) at -20 ° C. 1.74 ml, 16.1 mmol.) 'Stir at room temperature for 1.5 hours. After the reaction was completed, dichloromethane was added to the reaction system, and the obtained organic layer was washed with a saturated aqueous ammonium chloride solution, 0.05 M hydrochloric acid, a saturated sodium bicarbonate solution, water, and saturated brine, and then dried over anhydrous magnesium sulfate. , Filtered, and the filtrate was concentrated under reduced pressure to obtain (3 S) -3- (third butoxycarbonylamino) -1- (buchloroethoxycarbonyl) pyrrolidine crude product (3.26 g, yield 69%) . -304- 200403244] H NMR (CDCI3, 500MHz): δ 6.60-6.56 (1H, m), 4.67- 4.48 (1H, m), 4.25-4.15 (1H, m), 3.73-3.60 (1H, m ), 3.59-3.40 (2H, m), 3.33-3.20 (1H, m), 2.21-2.06 (1H, m), 1.92-i.7〇 (4H, m), 1.45 (9H, s). (34b) (3S) -3- (Third-butoxycarbonylamino) -1- (1-octyloxyethoxycarbonyl) pyridin. Caprylic acid (985 mg, 6.83 mmol) was dissolved in dimethyl Formamidine (12 ml) and tetrahydrofuran (10 ml), add carbon shavings (1.10 g, 3.39 mmol), 18-crown-6 (1.81 g, 6.83 mmol), and stir under nitrogen at room temperature 2 0 marks. At room temperature, (3 S)-3-(third butoxycarbonylamino) -1- (1-chloroethoxycarbonyl) pyrrolidine (800 mg, 2.73 mmol) obtained in Example 3 4 (3 4 a) was added at room temperature. Mol), and stirred at room temperature for 4 hours. After the reaction was completed, ethyl acetate and saturated brine were added to the reaction solution, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1 ~ 1: 3, V / V) to obtain (3 S) -3- (third butoxycarbonylamino) as a white amorphous substance. ) -1- (1-octyloxyethoxycarbonyl) pyrrolidine (668 mg, yield 85%). ] H NMR (CDCI3, 400MHz): < 5 6.84-6.78 (1H, m), 4.64-4. 56 (1H, m), 4.22-4.09 (1H, m), 3.63-3.58 (1H, m), 3.57-3.41 (2H, m), 3.25 -3. 12 (1H, m), 2. 33-2. 26 (2H, m), 2.18-2.07 (1H, m), 1.90-1.74 (1H, m) , 1.64-1.52 (3H, m), 1.45 (9H, s), 1.49-1.40 (2H, m), 1.38-1.20 (8H, m), 0.90-0.86 (1H, m); IR (Liquid film): 3343, 2932, 1 71 6, 1 526, 1451, 1424, 1 391, 1 367 cm'1; MS (FAB) m / z: 401 (M + H) +; HRMS (ESI) m / z: calcd. for C20H3606N2Na (M + Na) +: 423.2471. Found 423.2489. -305- 200403244 (34c) (1R, 5S, 6S) -2- (1- {4-[(3S) -1- (Businoxyloxyethyl Oxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1 -hydroxyethyl] -1 -Methyl-Carbonyl-2-ene-3 -p-nitrobenzyl carboxylic acid The (3S) -3- (third butoxycarbonylamino) -1- (1) obtained in Example 3 4 (34b) -Caprylyloxyethoxycarbonyl) pyrrolidine (0.98 g, 2.45 mmol) was dissolved in dichloromethane (30 ml), and trifluoroacetic acid (9 ml) was added under ice cooling, and the mixture was stirred for 1.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was dried under reduced pressure to obtain (3S) _3-amino-1- (1-octyloxyethoxycarbonyl) pyrrolidine trifluoroacetate as a crude product. (LR, 5S, 6S) -2- [l- (4-allyloxycarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] sulfur-6 obtained in Example 31 (31a) -[(R) -l-Hydroxyethyl] -1-methyl-carbanil · 2-ene-3 -carboxylic acid p-nitrobenzyl ester (1.19 g, 1.97 mmol) In dichloromethane (30 ml), triphenylphosphine (78 mg, 0.30 mmol), palladium (0) triphenylphosphine (228 mg, 0.20 mmol), and dimethyl ketone (138 mg, 0 ··) were added. 9 9mmol), and stirred at room temperature under nitrogen for 1.5 hours. After the reaction was completed, diisopropylethylamine (1.5 ml, 8.3 mmol) was added under nitrogen and ice cooling. (3S) -3-amino-1- (1-octyloxyethyl) obtained above Oxycarbonyl) crude pyrrolidine trifluoroacetate, diethylphosphonium cyanide (0.40 ml, 2.36 mmol), and stirred at room temperature for 6 hours. After the reaction was completed, ethyl acetate was added to the reaction system, and the organic layer was sequentially washed with a saturated sodium bicarbonate solution, saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3: 1 ~ 1 0 0: 〇, ethyl acetate: methanol = 1 0: 0 ~ 1 5: 1, V / V) to obtain (LR, 5S, 6S) -2- (l- {4-[(3S) -l- (l-octyloxyethoxycarbonyl) pyrrolidin-3-ylaminemethane]] 1,3-thiazol-2-yl} azetidin-3-yl) sulfur-6-306-200403244 [(R) -l-hydroxyethyl] -1-methyl-carbanil-2-ene P-Nitrobenzyl-3-carboxylic acid (1.55 g, yield 93%). ] H NMR (CDCI3, 500MHz): δ 8.23 (2Η, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 7.44 (1H, s), 7.22 (1H, bs), 6.83- 6.79 〇H, m), 5.50 (1H, d, J = 13.7 Hz), 5.25 (1H, d, J = 13.7 Hz), 4.67 ~ 4.55 (1H, m), 4.55 -4.47 (2H, m), 4 . 33-4. 22 (3H, m), 4. 18-4.03 (2H, m), 3.81-3.71 (1H, m), 3.62-3.41 (2H, m), 3.41-3.32 (1H, m), 3.30 (1H, dd, J = 6.9, 3.0 Hz), 3.24-3.17 (1H, m), 2.37-2.21 (3H, m), 2.02 -1.92 (1H? M), 1.80-1.70 (1H, m), 1.65-1.42 (5H, m), 1.48 (3H, d, J = 5.8 Hz), 1.47-1.21 (11H, m), 0.88-0.83 (3H, m); IR (KBr): 3391, 2930, 1772, 1715, 1 666, 1544, 1 525 cnf1; MS (FAB) m / z: 843 (M + H) +; HRMS (ESI) m / z: calcd. For C39H 50 011N6S2Na (M + Na) +: 865.2877. Found 865.2877. (34d) (lR, 5S, 6S) -2- (l- {4-[(3S) -l- (l-octyloxyethoxycarbonyl) pyrrolidine-3 -ylaminomethylmethyl]] -1,3 -Thiazole-2 -yl} azetidin-3 -yl) sulfur-6-[(R) -Ethyl] -1-methyl-carbobenzoin-2 -flame-3-residue acid Sodium salt obtained from Example 3 4 (3 4 c) (1 R, 5 S, 6 S) -2-(1-{4-[(3 S)-1-(1-octyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3 -thiazol-2-yl} acyl Butidin-3-yl) sulfur-6-[(R) -l-hydroxyethyl] -1-methyl-carbobenzon-2-ene-3 · carboxylic acid p-nitrobenzyl ester (1.55 g ' 1.84 mmol) was dissolved in tetrahydrofuran (75 ml) and distilled water (60 ml) in the presence of 10% Pd-C (1.55 g), and subjected to contact hydrogenation reduction at room temperature for 1.5 hours. After the reaction was completed, the reaction mixture was filtered. Sodium bicarbonate (154 mg, 1.84 mmol), ethyl acetate, and distilled water were added to the filtrate to perform layered extraction. The aqueous layer was concentrated under reduced pressure and purified by reversed phase chromatography (distilled water: acetonitrile = 00: 0 to 6 4: 36, V / V), and frozen-307-200403244 dried to obtain The target compound is white amorphous (111,53,63) -2- (1- {4-[(3 S) -1- (1-octyloxyethoxycarbonyl) pyrrolidin-3-ylaminemethanemethyl ] -1,3-thiazol-2-yl} azetidin-3-yl) sulfur-6-[(R) -l-hydroxyethyl] -1-methyl-carbanil-2 -ene-3 -Sodium carboxylate (0.4 8 g, 36% yield). ] H NMR (D20, 400ΜΗζ): δ 7.50-7.46 (1Η, m), 6.78-6.65 〇H, m), 4.57 -4.43 (3H, m), 4.37-4.12 (3H, m), 4.08-3.91 ( 2H, m), 3.74-3.32 (5H, m), 3.23-3.10 (1H, m), 2.40-2.15 (3H, m), 2.14-1.98 (1H, m), 1.62-1.39 (5H, m), 1.39-1.10 (14H, m), 0.88-0.73 (3H, m); IR (KBr): 3394, 2929, 1746, 1665, 1 605, 1545, 1390, 1 314 cm "1; MS (FAB) m / z: 730 (M + H) +; HRMS (ESI) m / z: calcd. for C32H4509N5S2Na (M + H) +: 730.2526. Found 730.2540; Anal, calcd. for C32H44N5〇9S2Na 4 / 3H20: C, 50.98 ^ :; H, 6.24%; N, 9.29%; S, 8.5U; Na, 3.05¾. Found C, 50.73%; Η, 6.31ϋί; Ν, 9.40%; S, 8.41%; Na, 2.96% (Example 35) (lR, 5S, 6S) -2- (l- {4-[(3S) -1- (l-octyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino] -1,3-thiazol-2-yl} azetidin-3-yl) sulfur-6-[(R) -l-hydroxyethyl] -1-methyl-carban-2-en-3- Trimethylacetoxymethyl carboxylate

The (1R, 5 S, 6S) -2- (1- {4-[(3 S) -1- (1-octyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethane group obtained in Example 34) ] -1,3-thiazol-2-yl} azetidin-3 -yl) sulfan-6-[(R) -butoxyethyl] -1-methyl-carban-2-en-3- Sodium carboxylate-308-200403244 salt (160 mg, 0.22 mmol) was dissolved in dimethylacetamide (8 ml), and methyl pivalate iodide (64 mg, 0.26 mmol) and stir for 1.5 hours. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% brine, 5% sodium thiosulfate aqueous solution, saturated sodium bicarbonate solution, water, saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 to 40: 1, V / V) to obtain the target compound (lR, 5S, 6S) -2- (l- { 4-[(3S) -l- (l-octyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl: 1-1,3-thiazol-2-yl} azetidin-3-yl) Sulfur-6-[(R) -1-hydroxyethyl] -1-methyl-carbobenzoin-2-ene-3-carboxylic acid trimethylacetoxymethyl ester (176 mg, yield 97%) . ^ NMR (CDCI3, 500MHz): δ 7.43 (1H, s), 7.27-7.18 (1H, m), 6.84 -6.79 (1H, m), 5.98 (1H, d, J = 5.8 Hz), 5.84 (1H, d, J = 5.8Hz), 4.64-4.57 (1H, m), 4.57-4.50 (2H, m), 4.34-4.21 (2H, m), 3.81-3.72 (1H, m), 3.70-3.42 (2H, m), 3.42 -3.26 (1H, m), 3.25 (1H, dd, J = 6.8, 2.9 Hz), 3.22-3.18 (ΊΗ, m), 2.37-2.22 (3H, m), 2.06-1.92 (1H, m), 1.80 -1.43 (6H, m), 1.36 (3H, d, J = 6.9 Hz), 1.32-1.20 (11H, m), 1.22 (9H, s), 0.88-0.80 (3H, m); IR (KBr): 3393, 2962, 2931, 1777, 1753, 1719, 1 544, 1 325 cm "1; MS (FAB) m / z: 822 (M + H) +; HRMS (ESI) m / z: calcd for C38H5S0nNsS2 (M + H) +: 822.3418. Found 822 · 3419. (Example 36) (lR55S56S) -2- (l- {4-[(3S) -l- (Businoxyloxyethoxy carbon group) ) Pyrrolidine-3 -ylaminomethylmethyl] -1,3-thiazolyl-2-yl} ΠΥ butyl Didine-3 -yl) thio-6-[(11) -1-hydroxyethyl] -1- Methyl-carbapene-2-ene-3-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester-309- 200403244

(1 R, 5 S, 6 S)-2-(1-{4-[(3 S)-1-(1-octyloxyethoxycarbonyl) pyrrolidin-3-ylamine obtained in Example 3 4 Formamyl] -1,3-thiazol-2-yl} azetidin-3 -yl) sulfan-6-[(R) -1-hydroxyethyl] -1-methyl-carbanil-2- Ene-3-carboxylic acid sodium salt (160 mg, 0.22 mmol) was dissolved in dimethylacetamide (8 ml), and 1-iodoethyl isopropylcarboxylate (74 mg) was added under nitrogen at 0 ° C. , 0.28 mmol), stirring for 1.5 hours. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% brine, 5% sodium thiosulfate aqueous solution, saturated sodium bicarbonate solution, water, and saturated brine, and then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 to 15: 1, V / V) to obtain the target compound (1R, 5S, 6S) -2- (l- { 4-[(3S) -l- (l-octyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin-3-yl) Sulfur-6-[(11)-; 1-hydroxyethylmethyl-carbobenzoin-2-ene-3-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester (141 mg, 77% yield ). ] H NMR (CDCI3, 500MHz): ά 7.43 (1Η, s), 7.30-7.22 (1Η, m), 6.92 -6 · 80 (2H, m), 4.97-4.86 (1H, m), 4.66- 4.57 (1H, ιτι), 4.57-4.49 (2Η, m), 4.33-4.21 (3Η, m), 4.12-4.05 (2H, m), 3.81-3.72 (1Η, m), 3.64 -3.44 (2Η, m), 3.44-3.28 (1H, m), 3.24 (1H, dd, J = 6.9, 2.0 Hz), 3.23-3.15 (1H, m), 2. 37-2.22 (3H, m) , 2.08-1.92 (1H, m), 1.78-1.43 (9H, m), 1.38-1.21 (20H, m), 0.88-0.82 (3H, m); IR (KBr): 3392, 2932, 1756, 1718, 1665, 1544, 1 323, 1272 cm'1; MS (FAB) m / z: 838 (M + H) +; HRMS (ESI) m / z: calcd. For C38H56012N5S2 (M + H) +: 838.3367 Found 838.3364. -310- 200403244 (Implementation Example 37) (lR, 5S, 6S) -2- (Bu {4-[(3S) -l- (l · hexadecyloxyethoxy carbon-based) la slightly Pyridin-3-ylaminomethylmethyl] -13-thiazol-2-yl} azetidin-3-yl) sulfur-6-[(R)-1 -hydroxyethyl] _ 丨 _methyl-carbon ligand Nin-2 _ene-3 _ carboxylic acid sodium salt

(37a) 0- (l-hexadecyloxyethyl) -S-ethylthiocarboxylic acid ester hexadecanoic acid (6.08 g, 23.7 mmol), tetrabutylammonium hydrogen sulfate (8.05 G '23.7 mmol) dissolved in water (60 ml) and dichloromethane (20 ml), sodium bicarbonate (3.99 g, 4 7.4 mmol) was added, and stirred at room temperature for 2 hours Then, add 0- (1 · iodoethyl) -S-ethylthiocarboxylic acid ester (6.16 g, 2 3 · 7 mmol) obtained according to Example 27 (27a), and stir at room temperature overnight . After the reaction was completed, the reaction solution was separated into layers, and the obtained organic layer was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (cyclohexane: ethyl acetate = 99: 1 ~ 98: 2, V / V) to obtain 0- (1-hexadecyloxyethyl)-as a colorless oil. S-ethylthiocarboxylic acid ester (4.90 g, yield 53. 2%). ^ NMR (CDCI3, 400 MHz): δ 6.95 (1H, q, J = 5.5 Hz), 2.94-2.81 (2H, m), 2.38 -2.26 (2H, m), 1.65-1.49 (5H, m), 1.33 -1.25 (27H, m), 1.25 (3H, t, J = 6.6 Hz); MS (FAB) m / z: 411 (M + Na) +. (3 7 b) chloroformic acid 1 -hexadecyloxyethyl Ester-311- 200403244 The 0- (1-hexadecyloxyethyl) _S-ethylthio residual ester (4.10 g, 10.6 mmol) obtained in Example 3 7 (3 7 a) was dissolved in dichloromethane (4 ml) 'Add sulfonium chloride (0.89 ml, Π.1 mmol) under nitrogen and -78 t stirring.' After stirring at 0 ° C for 10 hours, place in a freezer overnight. Concentrated under reduced pressure at room temperature to obtain a crude product of 1-hexadecyl ethyl chloroformate. (37c) (3S) -3- (Third-butoxycarbonylamino) -1- (1-hexadecyloxyethoxycarbonyl) pyrrolidine Pyrrolidine (1.97 g, 10.6 mmol) was dissolved in dichloromethane (40 ml), and 4-dimethylaminopyridine (1.29 g, 10.6 mmol) was added under ice cooling, Example 37 ( 37b) The obtained 1-hexadecyl ethyl chloroformate was stirred under cooling for 7 hours, and then placed in a freezer overnight. After the reaction was completed, ethyl acetate was added to the reaction system, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (cyclohexane: ethyl acetate = 99: 1 ~ 75: 25, V / V) to obtain (3S) -3- (third butoxycarbonylamino) as an oil. 1- (1-hexadecyloxyethoxycarbonyl) pyrrolidine (2.13 g, 39.2% yield). ] H NMR (CDCI3, 400MHz): (5 6. 83-6. 78 (1H, m), 4.66-4.61 (1H, m), 4.21 (1H, bs), 3.67-3.61 (1H, m), 3.54 -3.43 (2H, m), 3.28 -3.17 (1H, m), 2.35-2.26 (2H, m), 2.16-2.08 (1H, m), 1.88-1.78 (1H, m), 1.64-1.58 (2H, m), 1.49-1.42 (3H, m), 1.45 (9H, s) 1 · 28-1 · 25 (24H, m), 0.88 (3H, t, J = 7.0 Hz); MS (FAB) m / z: 513 (M + H) +. (37d) (lR, 5S, 6S) -2- (l- {4-[(3S) -l- (l-hexadecyloxyethoxycarbonyl) pyrrolidine -3-ylaminomethylamidinyl] -1,3-thiazol-2-yl} PY butidinyl) sulfur-6 _ [(11) 1-1-hydroxyethyl] -1-methyl-carbinol-2-ene -3-carboxylic acid p-nitrobenzyl ester ··· -312- 200403244 The (3S) -3- (third butoxycarbonylamino) -1- (bu hexadecane) obtained in Example 3 7 (3 7c) Oxyethoxycarbonyl) pyrrolidine (1.28 g, 2.50 mmol) was dissolved in dichloromethane (30 ml), and trifluoroacetic acid (10 ml) was added under ice cooling, and the mixture was stirred for 30 minutes. After the reaction was completed, The reaction solution was concentrated under reduced pressure, and the residue was dried under reduced pressure to obtain (3S) -3-amino-1- (1-hexadecyloxyethoxycarbonyl) pyrrolidine trifluoroacetate crude product. The (lR, 5S, 6S) -2- [l- (4-allyloxy-yl-1,3-thiazol-2-yl) azetidin-3-yl] sulfur obtained in Example 31 (31a) -6-[(11) -1-hydroxyethyl] -1-methyl-carbanil-2-en-3-carboxylic acid p-nitrobenzyl ester (1.50 g, 2.50 mmol) per tetrahydrofuran (30 Ml), added triphenylphosphine (140 mg, 0.53 mmol), palladium (0) triphenylphosphine (140 mg, 0.13 mmol), dimethyl ketone (180 mg, 1.2 5 mmol) Ear), stirred under nitrogen and room temperature for 4 hours. After the reaction was completed, diisopropylethylamine (1.57 ml, 9.00 mm) was added under nitrogen and ice cooling, and the (3S) -3-amine obtained above -1- (1-hexadecyloxyethoxycarbonyl) crude pyrrolidine trifluoroacetate, diethylphosphonium cyanocyanide (0.7 6 ml, 5 · 0 0 _ ear), stirred at room temperature 2 hours and left in the freezer overnight. After the end of the reaction, ethyl acetate and water were added to the reaction system under ice-cooling, and the aqueous layer was extracted with ethyl acetate in layers. The organic layer was sequentially washed with a sodium bicarbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol 0 ~ 95: 5, V / V) to obtain (lR, 5S, 6S) -2- (l- {4- [ (3S) -1- (1-hexadecyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-thienyl-2-yl} 〇 butyl butan-3-yl) Sulfur-6-[(R) -l-hydroxyethyl] -1-methyl-carbanil-2-en-3-carboxylic acid p-nitrobenzyl ester (1.90 g, yield 79.6%). 200403244 'H NMR (CDCI3, 400MHz): 8.23 (2Η, d, J = 8.8 Hz), 7.66 (2H, d, J = 7.8 Hz), 7.43 (1H, s), 7.19-7.12 (1H, m), 6.85-6.80 (1H, m), 5.51 (1H, d, J = 13.7 Hz), 5.25 (1H, d, J = 13.7 Hz), 4.64- 4.59 (1H, m), 4.54-4.57 (2H, m) , 4.33-4.24 (3H, m), 4.15-4.06 (2H, m), 3.79-3.73 (1H, m), 3.62-3.47 (2H, m), 3.4Γ- 3.18 (2H, m), 3.30 (ih , dd, J = 7.〇, 2.6 Hz), 2.35-2.20 (3H, m), 2.09-1.58 (3H, m), 1.51 -1.46 (3H, m), 1.38 (3H, d, J = 6.2 Hz ), 1.35-1.25 (28H, m), 0.88 (3H, t, J = 6.9 Hz); MS (FAB) m / z: 955 (M + H) +. (37e) (lR, 5S, 6S)- 2- (l- {4-[(3S) -l- (l-hexadecyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino] -i, 3-thiazol-2-yl} azetidine Pyridin-3-yl) sulfur-6-[(R)-1-hydroxyethylmethyl-carbanil-2-ene-3-carboxylic acid sodium salt The compound obtained in Example 3 7 (3 7 d) ( lR, 5S, 6S) -2- (l パ 4-[(3Sbl- (l-hexadecyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl) _ 2 -yl} azetidine D-3 -yl) sulfur-6-[(R) -1 -Ethyl] -1 -methyl-carbon complex · 2 _ P-Nitrobenzyl-3-carboxylic acid (1.00 g, 1.05 mmol) was dissolved in tetrahydrofuran (75 ml) and distilled water (50 ml), butane was present in 7.5% Pd-C (1.00 g), and contacted at room temperature Hydrogenated for 3 hours. After the reaction was completed, it was filtered. Added distilled water, potassium hydrogen sulfate solution, and ethyl acetate were added for layered extraction. The organic layer was sequentially washed with water and saturated brine, and then dried over anhydrous sulfuric acid Dry under sodium 'filter, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 0.1 M-sodium phosphate buffer (100 ml), distilled water (100 ml). = 1〇〇: 〇 ~ 5 5: 4 5, V / V) purified, freeze-dried to obtain the target compound of thin yellow amorphous (1 R, 5 S, 6 S;)-2-(; 1-- 314- 200403244 {4-[(3 S) -1- (1-hexadecyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino] -1,3-thiazol-2-yl} azetidine -3-yl) sulfur-6-[(11) -1-hydroxyethyl] -1-methyl-carbophenan-2-ene-3 -carboxylic acid sodium salt (0.65 g, yield 7 3.9%). ^ NMR (DIMETHYLSULFOXIDE-d6, 400MHz): (5 8.12 (1H, t, J = 5.9 Hz), 7.42 (1H, s), 6.69-6.64 (1H, m), 4.99 (1H, d, J = 5. 1 Hz), 4.48-4.37 (3H, m), 4.27-4.15 (1H, m), 3.95 (1H, dd, J = 9.5, 2.2 Hz), 3.92-3.86 (3H, m), 3.62-3.50 (1H , m), 3.45-3.42 (1H, m), 3.37-3.19 (2H, m), 3.03 (1H, dd, J = 7.3, 2.2 Hz), 2.99-2.91 (1H, m), 2.30 -2.25 (2H , m), 2.11-1.94 (2H, m), 1.51-1.48 (2H, m), 1.42-1.39 (3H, m), 1.29-1.23 (24H, m), 1.15 (3H, d, J = 5.9 Hz ), 1.02 (3H, d, J = 7.3 Hz), 0.85 (3H, t, J = 7.3 Hz); 'IR (KBr): 3391, 2925, 2854, 1747, 1665 1604, 1 545, 1 390, 1 314 cm'1; MS (FAB) m / z: 842 (M + H) +;

Anal, calcd. For C40H60N509S2Na · Hz0: C, 55. 86%; H, 7.27%; N, 8.14%; S, 7.46%, Na, 2.67% · Found C, 55.70%; H, 7.44%; Ν, 8 11%; S, 7.40%, Na, 2.74% (Example 38) (lR, 5S, 6S) -2- (l- {4-[(3S) -l- (l-hexadecyloxyethyl) (Oxycarbonyl) pyrrolidine-3 -ylaminomethylmethyl] -1,3-thiazole-2 -yl} azetidin-3 -yl) sulfan-6-[(R) -l-hydroxyethyl] -1 -Methyl-carbobenzoin-2-ene-3-carboxylic acid trimethylacetoxymethyl

(1R, 5S, 6S) -2- (l- {4-[(3S) -1- (l- + A_oxyethoxycarbonyl) pyrrolidin-3 -ylaminomethylmethyl]- 1, 3 -thiazole-2 -yl} azetidin- 315- 200403244 -3-yl) sulfur-6-[(R bu hydroxyethyl] methyl-carbophenan-2_ene-3_carboxylic acid Sodium salt (310 mg '0.37 mmol) was dissolved in dimethylacetamide (15 ml), and methyl pivalate iodide (120 mg, 0.48 mmol) was added under nitrogen and 0C, and stirred 30 minutes. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 5% sodium thiosulfate aqueous solution, saturated sodium bicarbonate solution, water, saturated saline, and anhydrous magnesium sulfate. Dry, filter, and concentrate the filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 0: 0 ~ 95: 5, V / V) to obtain the target compound (1R, 5S) as a white amorphous substance. , 6S) -2- (1- {4-[(3SM- (i · hexadecyloxyethoxycarbonyl) pyrrolidin-3 -ylaminomethylamidino] -1,3-thiazole-2 -yl} acyl Butidine-3 -yl) thio-6-[(R)-1 -hydroxyethyl] -1-methyl-carbobenzoin-2-ene-3-carboxylic acid trimethylacetoxymethyl ester (324 Mg, yield 9 3 · 6%).] H NMR (CDCI3, 400MΗζ): δ 7.44 (1Η, s), 7.20-7.14 (1Η, m), 6.84 -6.80 (1H, m), 5.98 (1H, d, J = 5.9. Hz), 5.84 (1H, d, J = 5.9 Hz), 4.64-4.59 (1H, m), 4.53-4.48 (2H, m), 4.32-4.22 (3H, m), 4.09-4.03 (2H, m ), 3.80 ~ 3.74 (1H, m), 3.58-3.49 (2H, m), 3.41-3.17 (2H, m), 3.26 (1H, dd, J = 7.0, 2.6 Hz), 2.33 ~ 2.22 (3H, m ), 2.06 -1.94 (2H, m), 1.68-1.58 (3H, m), 1.51-1.46 (2H, m), 1.38 -1.10 (27H, in), 1.35 (3H, d, J = 6.6 Hz), 1.22 (9H, .s), 0.88 (3H, t, J = 7.0

Hz); IR (KBr): 3385, 2958, 2926, 2854, 1778, 1 753, 171 9, 1664, 1 544, 1 326 cmH; MS (FAB) m / z: 934 (M + H) +. ( Example 39) (lR, 5S, 6S) -2- (l- {4-[(3S) -1- (l-hexadecyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino]- 1,3-thiazol-2-yl} azetidin-3-yl) sulfur-6-[(R) -l-hydroxyethyl] -1-methyl-carban-2-en-3-carboxyl 1- (isopropoxycarbonyloxy) ethyl acetate-316- 200403244

(1K, 5δ, 6 ^ 2_ (ι_ {心 [(3s) small (Bus 16th oxygen ethoxycarbonyl) pyrrolidin-3-ylamine formamidine BU, 3thiazole_2 _Yl} azetidin-3-yl) sulfur-6-[(R) small via ethyl methyl ^ methyl-carbon complex · 2_ sodium pyrolite

Salt (310 grams, 0.37 pen ears) was dissolved in dimethylacetamide (05 ml), and isoisocyanic acid κ iodoethyl ester (120 mg, 048 mmol) was added under nitrogen at 0 t. , Stir in 2 small day inches. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 5% sodium thiosulfate aqueous solution, saturated sodium bicarbonate solution, water, and saturated saline, and then dried over anhydrous magnesium sulfate and filtered. 'The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 1 00 · 0 ~ 95 · 5, V / V) to obtain the target compound (1R, 5S, 6S) -2- (l- {4-[(3S) -l- (1-hexadecyloxyethoxycarbonyl) pyrrolidine-3 -ylaminomethylmethyl] -1,3 -thiazole-2 -yl} azetidine-3 -yl ) Sulfur-6-[(R)-

1-Hydroxyethyl 1-methyl-carben-2-en-3-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester (305 mg, yield 86.6%). ] H NMR (CDCI3, 400ΜΗζ): δ 7.43 (1Η, s), 7.21-7.13 (1Η, m), 6.91 -6.80 (2H, m), 4.95-4.86 (1H, m), 4.64-4.58 (1H, m), 4.52-4.47 (2H, m), 4.32 ~ 4.21 (3H, ni), 4.08-4.06 (2H, m), 3.81-3.74 (1H, m), 3.58-3.49 (2H, m), 3.41- 3.15 (2H, m), 3.25 (1H, dd, J = 7.0, 2.6 Hz), 2.33-2.21 (3H, m), 2.10-1.90 (2H, m), 1.66-1.58 (6H, m), 1.51- 1.46 (3H, m), 1.37-1.10 (35H, m), 0.88 (3H, t, J = 7.0 Hz); IR (KBr): 3381, 2926, 2854, 1 756, 171 8, 1663 1 544 , 1 323, 1 272 cmH; MS (FAB) m / z: 950 (M + H) +. -317- 200403244 (Example 40) (1 R, 5 S, 6S) _2benzyloxyethoxycarbonyl group) Pyrrolidin-3-ylamine formamidine 13-thiazole_2_yl} azetidin-3_yl) sulfan-6-[(R)-1 -hydroxyethylbenzene 丨 _methyl-carbon complex -2 -ene-3 -carboxylic acid sodium salt

(4〇 &) 0- (1-benzylacetoxyethyl) -8-ethylthiocarboxylic acid ester benzyl acid (2.90 g '23.7 mmol), tetrabutylammonium hydrogen sulfate (8 0.05 G '23.7 mmol) dissolved in water (60 ml) and dichloromethane (20 ml), sodium bicarbonate (3.99 g, 47.4 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The 0- (1-iodoethyl) -S-ethylthiocarboxylic acid ester (6.16 g '23.7 mmol) obtained in Example 27 (27a) was stirred at room temperature overnight. After completion of the reaction, the reaction solution was separated into layers, and the aqueous layer was extracted with dichloromethane in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: dichloromethane: ethyl acetate = 2: 1: 〇 ~ 20: 10: 1, V / V / V) to obtain 0- (1 as a colorless oil. -Benzyloxoethyl) -S-ethylthiocarboxylic acid ester (3.15 g, 52% yield). NMR (CDCI3, 400 MHz): δ 8.06 (2Η, d, J = 7.8 Hz), 7.59 (1H, t, J = 7.8 Hz), 7.45 (2H, d, J = 7.8 Hz), 7.21 (1H, q , J = 5.9 Hz), 2.95-2.04 (2H, m), 1.65 (3H, d, J = 5.9 Hz), 1.32 (3H, t, J = 6.9 Hz); IR (Thin film): 1737, 1452, 1 394, 1317, 1273 cm'1; MS (FAB) m / z: 255 (M + H) +; HRMS (ESI) m / z: calcd. For C12H1404SNa (M + Na) +: 277.05Π. Found 277.0503 (40b) 1-Benzylpyroxyethyl chloroformate> 318- 200403244 The 0- (1-ping_oxoethyl) -S-ethylthio sulfonic acid ester obtained in Example 4 0 (4 0 a) ( 3.05 g, 1 2.0 millimoles), and under nitrogen and -7 8 t stirring was added dichloromethane (1.0 ml, 1 2.6 millimoles), and stirred at 0 t: 1 hour. It was concentrated under reduced pressure at room temperature to obtain a crude product of 1-benzyloxyethyl chloroformate. (40c) (3S) -3- (third butoxycarbonylamino) -1- (1-benzyloxyethoxycarbonyl) pyrrole (3S) -3- (third butoxycarbonyl Amine) pyrrolidine (2.24 g, 12.0 mmol) was dissolved in dichloromethane (60 mmol; liter), and 4-dimethylamine n-didine (1.54 g, 12.6 mmol) was added under ice cooling. Mol), benzyloxyethyl chloroformate obtained in Example 40 (4 Ob), and stirred under cooling for 4 hours. After the reaction was completed, ethyl acetate was added, and the organic layer was washed with a sodium bicarbonate solution and a saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5 ·· 1-2: 3, V / V) to obtain (3 S) -3- (third butoxycarbonylamine) as a white amorphous substance. Yl) -1- (1-benzylacetoxyethoxycarbonyl) pyrrolidine (4.15 g, yield 91 1%). ^ NMR (CDCI3, 500MHz): δ 8.08-8.02 (2Η, m), 7.60-7.51 (1H, m), 7.50-7.39 (2H, m), 7.10-7.01 (1H, m), 4.70- 4.52 (1H , m), 4.25 -4.08 (1H, m), 3.73-3.58 (1H, m), 3.58-3.40 (2H, m), 3.34-3.10 (1H, in), 2.20-2.05 (1H, m), 1.93 -1.70 (1H, m), 1.64-1.61 (3H, m), 1.45 (9H, s); IR (Thin film): 3340, 2979, 1714, 1 525, 1452, 1426, 1 391 cm "1; MS (FAB) m / z: 379 (M + H) +; HRMS (ESI) m / z: calcd. For C19H2606N2Na (M + Na) +: 401.1689. Found 401.1704. (40d) (lR, 5S, 6S)- 2- (l- {4-[(3S) -l- (l-benzyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazole-2 -yl} azetidine- 3 -yl) sulfur-6-[(R) -1-hydroxyethyl] -1-methyl-carbobin-2-ene-3-carboxylic acid p-nitrobenzyl ester-319-200403244 Example 4 (40) (33) -3- (Third-butoxycarbonylamino) -1- (obbenzyloxyethoxycarbonyl) pyrrolidine (1.56 g, 4.13 mmol) was dissolved in dichloromethane (40. Ml), trifluoroacetic acid (12 ml) was added under ice cooling, and stirred for 1.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was dried under reduced pressure to obtain (3S) -3-amino-1- (bubenzyloxyethoxycarbonyl) pyridine trifluoroacetate. The crude product (lR, 5S) obtained in Example 31 (31a) was obtained. , 6S) -2- [l- (4-allyloxycarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] sulfan-6-[(R) -1-hydroxyethyl] 1-Methyl-carbophenan-2-en-3-carboxylic acid p-nitropyrene (2.0 g, 3.33 mmol) was dissolved in dichloromethane (40 ml), and triphenylphosphine (131 mg, 0 50 mmol), palladium (0) triphenylphosphine (385 mg, 0.33 mmol), dimethyl ketone (233 mg, 1.66 mmol), and stirred at room temperature under nitrogen for 30 minutes. The reaction is complete Then, diisopropylethylamine (2.33 ml, 13.4 mmol) was added under nitrogen and ice cooling to obtain (3 S) · 3-amino-1- (1-benzyloxyethoxycarbonyl) pyrrole. The crude pyridinium trifluoroacetate and diethylphosphonium cyanide (0.78 ml, 4.00 mmol) were stirred at room temperature for 3 hours. After the reaction was completed, ethyl acetate and water were added under ice-cooling, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was successively decanted with a sodium bicarbonate solution, water, and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 4: 1 ~ 100: 0, ethyl acetate: methanol = 100: 0 ~ 20: 1, V / V), and a pale yellow amorphous substance was obtained. (111,53,63) -2- (l- {4-[(3S) -1- (l-benzylacetoxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazole -2-yl} azetidin-3-yl) sulfan-6-[(11) -1-hydroxyethyl] -1-methyl-carbanil-2-en-3-carboxylic acid p-nitrobenzyl ester (2.47 g, 90% yield). -320- 200403244 'H NMR (CDCI3, 500MHz): 8.23 (2H, d, J = 8.8 Hz), 8.08-8.02 (2H, m), 7.66 (2H, d, J = 7.8 Hz), 7.60-7.53 ( 1H, m), 7.48-7.40 (3H, m), 7.19-7.06 (2H, m), 5.51 (1H, d, J = 13.6 Hz), 5.25 (1H, d, J = 13.6 Hz), 4.65- 4.57 (1H, m), 4. 57-4.42 (1H, m), 4. 34-4.22 (3H, m), 4. 17-4.00 (2H, m), 3.80-3.72 (1H, m), 3.65- 3.44 (2H, m), 3.44 -3.12 (3H, m), 2.31-2.19 (1H, m), 2.04-1.90 (1H, m), 1.75-1.72 (1H, m), 1. 63-1.60 (3H , m), 1.38 (3H, d, J = 6.9 Hz), 1.27 (3H, d, J = 7.8 Hz); IR (KBr): 3388, 2970, 1773, 1727, 1665, 1 543, 1 525, 1 344 cm'1; MS (FAB) m / z: 821 (M + H) +; HRMS (ESI) m / z: calcd. For C38H4O0nN6S2Na (M + Na) +: 843.2095. Found 843.2092. # (40e) ( lR, 5S, 6S) -2- (l- {4-[(3S) -l- (l-benzyloxyethoxycarbonyl) pyrrolidin-3-ylaminemethylamidino] -1,3-thiazole- 2-yl} azetidin-3-yl) thio-6-[(R) -1 -hydroxyethyl] -1 · methyl-carbophenan-2-ene-3-carboxylic acid sodium salt Examples 40 (40d) (lR, 5S, 6S) -2- (l- {4-[(3S) -l- (l- ^ ethoxyethoxycarbonyl Pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfan-6-[(R) -l-hydroxyethyl] -1-methyl -Carbenil-2-en-3-carboxylic acid p-nitrobenzyl ester (1.96 g, 2.41 mmol) was dissolved in tetrahydrofuran (100 ml) and distilled water (80 ml) at 10% P d-C (1.98 g) was subjected to contact hydrogenation reduction at room temperature for 2 hours. After the end of the reaction, it was filtered. To the filtrate were added sodium bicarbonate (203 mg, 2.41 mmol), ethyl acetate and distilled water, and the layers were extracted. The aqueous layer was concentrated under reduced pressure, and purified by Cosmosil reverse phase chromatography (distilled water: acetonitrile = 100: 00 to 66: 33, V / V), and freeze-dried to obtain the target compound as a thin yellow amorphous (111 , 53,63) -2- (Bu [4-[(33) -1- (1-benzylacetoxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazole-2 -Yl} azetidin-3-yl) thio-6-[(R) -l-hydroxyethyl] -1-methyl-carban-2-en-3-carboxylic acid sodium salt (1.1 1 g, 65.5% yield). -321- 200403244] H NMR (D20, 400MHz): δ 8.01-7.80 (2H, m), 7.68-7.32 (4H, m), 7.02 -6.89 (1H, m), 4.44-4.13 (6H, m) 7 3.95-3.83 (2H, m), 3.68-3.38 (5H, m), 3.12-3.09 (1H, m), 2.24-2.00 (2H, m), 1.67-1.62 (3H, m), 1.32-1.29 (3H, m), 1.17 -1.11 (3H, m); IR (KBr): 3392, 2966, 1730, 1664, 1 602, 1 545, 1 390, 1 274 cm'1; MS (FAB) m / z : 708 (M + H) +; HRMS (ESI) m / z: calcd. For C31H3409N5S2Na2 (M + Na) +: 730.1 593. Found 730.1601;

Anal, calcd. For C31H34N509S2Na · Π / 5Η20: C, 49.82%; H, 5.18? C; N, 9.37%; S, 8.58 ^ Na, 3.08%. Found C, 49.68%; H, 5.18%; N, 9.67 %; S, 8.725 $, Na, 2.97%. (Example 41) (lR, 5S, 6S) -2- (l- {4-[(3S) -l- (l -benzyloxyethoxycarbonyl)) Pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazol-2-yl} azetidin-3-yl) sulfan-6-[(R)-; l-hydroxyethyl] -1-methyl -Carbonyl-2-en-3-carboxylic acid trimethylacetoxymethyl

The (111,53,63) -2- (1- {4-[(33) -1- (1-benzylacetoxyethoxycarbonyl) pyrrolidin-3-ylaminomethylamidino group obtained in Example 40: | -1,3-thiazol-2-yl} azetidin-3-yl) sulfur-6-[(R) -l-hydroxyethyl] -1-methyl-carban-2-en-3- Carboxylic acid sodium salt (250 mg, 0.35 mmol) was dissolved in dimethylacetamide (12 ml), and methyl pivalate iodide mg, 0.42 mmol was added under nitrogen and 0 ° C, Stir for 1 hour. After the reaction was completed, 'ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 5% sodium thiosulfate aqueous solution, saturated sodium bicarbonate solution, water, and saturated brine' and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate ·· Zhengjiyuan-322- 200403244 = 4: 1 ~ 1 0 0: 〇, ethyl acetate: methanol = 1 〇〇 ·· 〇〜1 5 ·· 1 V / V) purification, the target compound was obtained in the form of white amorphous (1 R, 5 S, 6 S)-2-(1-丨 4-[(3 S)-1- (1-benzyloxyethoxycarbonyl)) Pyrrolidin-3-ylaminomethylmethyl] -1,3-thiazole-2-yl} azetidin-3-yl) sulfan-6-[(R) -l-hydroxyethyl] -1-methyl -Carbonen-2-en-3-carboxylic acid trimethylacetoxymethyl ester (259 mg, yield 92%). 'H NMR (CDCI3, 400ΜΗζ): δ 8.08-8.02 (2H, m), 7.60-7.52 (1H, m), 7.47-7.40 (3H, m), 7.15 (1H, q, J = 7.3 Hz), 7.18 -7.08 (1H, m), 5.98 (1H, d, J = 5.8 Hz), 5.84 (1H, d, J = 5.8Hz), 4.68-4.57 (1H, m), 4.57-4.41 (2H, m), 4.35-4.18 (3H, m), 4.15-4.01 (2H, m), 3.82 -3.73 (1H, m), 3.65-3.42 (2H, m), 3.41 -3.30 (. 1H, m), 3.30-3.12 ( 2H, m), 2.32- 2.20 (1H, m), 2.05-1.89 (1H, m), 1.75 -1.72 (1H, m), 1.66-1.60 (3H, m), 1.36 (3H, d, J = 5.8 Hz), 1.29-1.24 (3H, m), 1.22 (9H, s); IR (KBr): 3393, 2973, 1778, 1729, 1666, 1 544, 1278 cm'1; MS (FAB) m / z : 800 (M + H) +; HRMS (ESI) m / z: calcd. For C37H460nN5S2 (M + H) +: 800.2636. Found 800.2650. (Example 42) (lR55S, 6S) -2- (Bu {4 -[(3S) -l- (l-benzyloxyethoxycarbonyl) pyrrolidine-3 -ylaminomethylmethyl] -1,3-thiazole · 2-yl} azetidine-3 -yl) thio- 6-[(R) -l-Hydroxyethylbenzene 丨 -methyl-carbobenzon-2-ene-3-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester

(丨 R, 5 S, 6 S)-2-(1-{4 · [(3 S)-1-(1 -benzyloxyethoxycarbonyl) pyrrolidine · 3-ylamine obtained in Example 40 Formamyl] -1, 3 -thiazole-2 · yl} azetidin-3-yl) sulfan-6-[(R) -l-hydroxyethylb-methyl-carben-2-en-3-carboxyl Sodium ο η η 200403244 salt (300 mg, 0.42 mmol) was dissolved in dimethylacetamide (12 ml), and 1-iodoethyl isopropylcarboxylate (143 was added under nitrogen at 0 ° C) Mg, 0.55 mmol) 'stir for 2 hours. After the reaction was completed, ethyl acetate was added, and the organic layer was sequentially washed with 10% saline, 5% sodium thiosulfate aqueous solution, saturated sodium bicarbonate solution, water, saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 4: 1 ~ 100: 〇, ethyl acetate: methanol = 100: 〇 ~ 15: 1, V / V), and the target compound was obtained as a white amorphous form. Of (1 R, 5 S, 6 S)-2-(1-{4-[(3S) -1- (1-benzyloxyethoxycarbonyl) pyrrolidin-3-ylaminomethylmethyl]]; [, 3-thiazol-2-yl} PY butidin-3-yl) sulfur-6-[(R) -1 · hydroxyethyl] -1-methyl-carban-2-en-3-carboxyl 1- (isopropoxycarbonyloxy) ethyl acid (293 mg, 85% yield). NMR (CDCI3, 500MΗζ): δ 8.09-8.01 (2Η, m), 7.60-7.53 (1Η, m), 7.48-7.41 (3Η, m), 7.21-7.05 (2H, m), 6.90-6.83 ( 1H, m), 4.96 -4.84 (1H, m), 4.66 -4.56 (1H, m), 4.54-4.42 (2H, m), 4.32 -4. 15 (3H, m), 4.08-4.02 (2H, m ), 3. 82-3.74 (1H, m), 3.64-3.46 (2H, m), 3.42-3.30 (1H, m), 3.26-3.12 (2H, m), 2.28-2.20 (1H, m), 2.05 -1.95 (1H, m), 1.72-1.69 (1H, m), 1.66-1.55 (6H, m), 1.38-1.23 (12H, m); IR (KBr): 3393, 2980, 1762, 1728, 1667, 1543, 1 317, 1 273 cr1; MS (FAB) m / z: 816 (M + H) +; HRMS (ESI) m / z: calcd. For C37H45012N5S2Na (M + Na) +: 838.2403. Found '838.2408. (Reference Example 1) 3-Third-butadiphenylsilyloxy-1- (4-carboxy-1,3-thiazole-2-yl) azetidine (la) (3-hydroxyazetidine-buthithio Carboxamido) urethane Dissolved 20 g (83.6 mmol) of N-benzyl-3-hydroxyazetidine in 60 ml of methanol in the presence of 10% Pd-C (20 g) In a water-324-200403244 bath at 1 atmosphere and 50 ° C, contact hydrogenation reduction was performed for 2 hours. After completion of the reaction ', the reaction mixture was filtered, and after the catalyst was filtered off, the obtained filtrate was concentrated under reduced pressure. Ethyl acetate and distilled water were added to the residue, the layers were extracted, and the organic layer was extracted with distilled water. The obtained aqueous layer was concentrated under reduced pressure to obtain a red oily product. After drying the compound under reduced pressure, dissolve in 180 ml of tetrahydrofuran and 60 ml of distilled water, and add 19.7 ml (167 mmol) of ethoxycarbonyl isothiocyanate under ice cooling. After 10 minutes, return to room temperature. , And stirred overnight. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine in layers. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1: 1 to ethyl acetate) to obtain (3-hydroxyazetidine-thiothiocarbamyl) amine as a yellow oil. Ethyl formate (7.4 g, 43% yield). MR (400MHz, CDCI3): (5 (ppm) 7.63 (1H, br s), 4.80-4.50 (3H, m), 4.40-4.00 (4H, m including 2H, q, at 4.18, J = 7.3Hz), 2.28 (1H, br s), 1.29 (3H, t, 7.3Hz). (Lb) l- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine 14.4 g (70.5 mmol) of (3-hydroxyazetidine-1-thiocarboxyfluorenyl) carbamate obtained in 1 (1 a) was dissolved in 72 ml of ethanol and 72 ml of distilled water, and sodium hydroxide was added to the solution. 14.1 g (35.3 mmol) was heated under reflux for 16 hours. After the reaction was completed, it was cooled to room temperature, and 88 ml of a 4N-HC1 / dioxane solution was added under ice cooling. Then 2-bromo was added. 17.7 ml (141 mmol) of ethyl pyruvate and 19.8 ml (141 mmol) of triethylamine were heated under reflux for 1 hour. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added. Ethyl acetate was extracted in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure -325-200403244. The obtained residue was subjected to silica gel column chromatography (eluent: toluene : Ethylamine = 3 ·· 1 ~ 1: 1) Purified to obtain light brown 1- (4-ethoxycarbonyl-1,3-thiab-2-yl) -3 -hydroxyazetidine (8.5 g, yield 53%). ^ -NMR (400MHz, CDCI3): (3 (ppm) 7.46 〇H, s), 4.88-4.78 〇H, m), 4.42-4.32 (4H, m), 4.02 (2H, ddd, J = 10.3, 5.6, 1.5Hz), 2.05 〇H, br s), 1.37 (3H, t, 7.3Hz). (lc) 3-Third-butadiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiocarbyl) Acridine will be referred to Example 1 (lb) 8.5 g (37.2 mmol) of 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine dissolved in 255 ml of dimethylformamide 'With ice cooling, add 19.4 g (74.5 mmol) of tertiary stilbenesilyl chloride and 5.07 g (74.5 mmol) of imidazole, return to room temperature after 10 minutes, and stir for 2.5 hours. After the reaction was completed, 2.59 ml of ethanol was added under ice-cooling and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 6 · 1 to 2: 1) to obtain 3-tert-butadiphenylsilyloxy-1-(4 as a light brown solid. -Ethoxycarbonyl-1,3-thiazole-2 -yl) azetidine (14.85 g, yield 86%). MR (400MHz, CDCI3): 5 (ppm) 7.64-7.58 (4H, m), 7.50-7.36 (6H, m), 7.43 (1H, s), 4.79-4.50 (1H, m), 4.35 (2H, q , J = 7.3Hz), 4.13 (2H, dd, J = 9.0, 6.6Hz), 4.06 (2H. Dd, J = 9.0, 5.1Hz), 1.36 (3H, t, J = 7.1Hz), 1.06 (9H , s). -326- 200403244 (ld) 3 -Third-butadiphenylsilyloxy-1- (4-hydroxymethyl-1,3-thienyl-2-yl) [^ butidine will be referred to the example 5.0 g (10.7 mmol) of 3-tert-butyldiphenylsilyloxyethoxyl-1,3-thiazol-2-yl) azetidine obtained in l (lc) was dissolved in anhydrous tetrahydrofuran 1 0 0 ml 'was added dropwise 2.5 ml of anhydrous tetrahydrofuran containing 1.22 g (32 1 mmol) of lithium hydride under ice-cooling, and stirred under the same conditions for 1.5 hours. After the reaction was completed, magnesium sulfate 10 hydrate was slowly added under the same conditions to cause foaming in the reaction system, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and saturated brine were slowly added in this order. The aqueous layer was extracted with ethyl acetate in layers. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 3: 1 ~ 1: 2) to obtain 3-tert-butadiphenylsilyloxy-1- (4-hydroxyl Methyl-1,3-thiazol-2-yl) azetidine (3.88 g, 86% yield). MR (400MHz, CDCI3): (5 (ppm) 7.66-7.58 (4H, m), 7.50-7.38 (6H, m), 6.40 (1H, s), 4.78-4.70 (1H, m), 4.53 (2H, s), 4.10 (2H, dd, J = 9.2, 6.6Hz), 4.01 (2H, ddd, J = 9.2, 5.1, 1.3Hz), 2.24 (1H, br s), 1.06 (9H, s). (le ) 3-Third-butadiphenylsilyloxymethyl-thiazole-2-yl) 〇Y Butidine The 3-tert-butadiphenylsilyloxymethyl-1 obtained in Reference Example 1 (1d), 3.88 g (3-thiazol-2-yl) azetidine was dissolved in 1.94 ml of anhydrous dichloromethane, 19.4 g of active manganese dioxide was added to the solution, and the mixture was stirred at room temperature for 7 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 3: 1 to 1: 1) to obtain 3-tert-butyldiphenylsilyloxy-1- (4- -327- 200403244 formamidine-1,3-thithio-2-yl) azetidin (354 g, yield 92%). 'HN MR (400MHz, CDCI3): δ (ppm) 9.69 (1H, s), 7. 64-7. 59- (4H,, m), 7.50- 7 · 36 (7H, m), 4.80- 4.72 (in, m), 4 · 16 (2H, dd, .J = 9.5, 6.6Hz), 4.08 (2H, ddd, J = 9.5, 5.1 · 1.5Hz), I ·% (9H, s) (If) 3 -Second-butanesylalkoxycarboxy-itthiazol-2-yl) azetidine will refer to Reference Example Ule) to obtain 3 _three-butadiphenylsilyloxy-formyl-1, 3- Exposure-2-yl) RY Butyl 3.5 g (8.28 mmol) was dissolved in 21 ml of anhydrous dichloromethane, added 105 ml of third butanol, 2 M 2 -methyl-2 -Butene tetrahydrofuran solution 4 1 · 4 ml. Then, under ice cooling, 1.88 g (16.6 mmol) of sodium hypochlorite and 2 1 l of an aqueous solution of 99 g (16.6 mmol) of sodium dihydrogen phosphate were added dropwise, and stirred for 1 hour. After the reaction was completed, ethyl acetate and 1 M · hydrochloric acid (ρΗ: 2 ~ 3) were added. The aqueous layer was extracted with ethyl acetate in layers, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered 'and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent ·· ethyl acetate ~ 5% methanol-ethyl acetate) to obtain a brown syrup 3_third stilbene benzoate oxo-1--1- (4- Residue-1,3 -thiazole-2-yl) DY Butidine (2.43 g, yield 6 7%) 〇-N MR (400MHz, CDCI3): (5 (ppm) 7.62-7.56 (4H, m), 7.50 (1H, s), 7.49-7.36 (6H, m), 4.81-4.72 (1H, m), 4.16-4.08 (2H, m), 4.04 (2H, dd, J = 9.5, 5.1 Hz ), 2.00 (1H, br s), 1.07 (9H, s) (Reference Example 2) 3-benzyloxy-1- (4-methoxycarbonyl-1,3-oxazol-2-yl) υγ butan (2 a) Tertiary stilbenesilyloxy-N-carboxybenzyloxy-L-serine formazan, N-carboxybenzyloxy-L-serine 4.0 g (16.7 mmol) ) Dissolved in 200 ml of benzene and 50 ml of methanol, and added 2 M-trimethyl sand under ice-cooling. Finished Eryu Yufang-328- 200403244 ketone ketone solution 1 0.9 ml (2 1 · 7 fashion Mol), stir at room temperature for 3 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent: n-hexane ·· ethyl acetate = 1 ·· 1 ~ 1: 3) Purification to obtain N-carboxybenzyloxy- L-serine methyl ester (4.40 g, yield 50%). N-carboxybenzyloxy-L-serine methyl ester 4.40 g (167 mmol) was dissolved in dimethylformamide In 210 ml, 5.20 ml (20.0 mmol) of tertiary stilbene chloride and 1.36 g (20.0 mmol) of imidazole were added under ice cooling, and the mixture was stirred at room temperature for 3 days. After the reaction was completed, ethyl acetate was added. The ester and 10% sodium chloride were subjected to layered extraction. The aqueous layer was extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent ·· n-hexane: ethyl acetate = 8 ·· 1 ~ 6: 1) to obtain tert-butyldiphenylsilyloxycarboxybenzyloxy silk. Methyl Urethane (8.18 g, yield 99%). 'HN MR (400MHz, CDCI 3): δ (ppm) 7. 61-7. 56 (4H, m), 7. 45-7. 31 (11H , m), 5.69-5.62 (1H, br d, J = 8.8Hz), 5.12 (2H, s), 4.45 (1H, dt, J = 8.1, 2.9Hz), 4.09 (1H, dd, J = 10.3, 2.9Hz), 3.90 (1H, dd, J = 10.3, 2.9Hz), 3.74 (3H, s). (2b) (2S) -3- (Third-butadienesilane (Oxy) -2-isothiocyanate-methyl propionate 32.0 g of the third stilbenesilyloxy-N-carboxybenzyloxy-L-serine methyl ester obtained in Reference Example 2 (2a) ( 65.1 mmol) was dissolved in 960 ml of methanol and subjected to contact hydrogenation reduction at room temperature for 2 hours in the presence of 2.0 g of 10% Pd-C3. After the reaction was completed, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane ·· methanol = 95: 5) to obtain colorless -329- 200403244 oily third stilbene Silyloxy-L-serine methyl ester (19.7 g, yield 85%). Dissolve 19.7 g (55.0 millimoles) of the obtained tertiary succinic acid syloxy-L-serine in 590 mL of dichloromethane, and add 6.62 mL (110 millimoles) of dithiocarbon at room temperature. 19.3 ml (138 mmol) of triethylamine and stir overnight. Then, 13.2 ml (138 mmol) of ethyl chloroformate and 19 · 3 ml (138 mmol) of triethylamine were added and stirred for 1 hour. After the reaction was completed, methanol was added and stirred for 30 minutes. Ethyl acetate and saturated brine were added to the reaction solution, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: toluene) to obtain (2S) -3- (third-butadiphenylsilyloxy) -2-isothiocyanate · methyl propionate (yellow crystal) 14.8 g, yield 6 7%) Η] -N MR (400MHz, C DC I 3): δ (ppm) 7.70-7.62 (4H, m), 7.48-7.38 (6H, m), 4.28 (1H, dd, J = 3.7, 5.1Hz), 4.05 (1H, dd, J = 5.1, 10.3Hz), 3.95 (1H, dd, J = 3.7, 10.3Hz), 3.80 (3H, s), 1.06 (9H, s ) (2〇 (23) -3- (Third-butadiphenylsilyloxy) -2-[(3-hydroxyazetidinyl-1-thiocarboxamido) -amino] -methyl propionate 13.2 g (3 S) of 3- (tertiary-butadiphenylsilyloxy) -2-isothiocyanate-propionate (23.5) obtained in Example 2 (2 b) was dissolved in 24 5 ml of tetrahydrofuran, At room temperature, 50 ml of an aqueous solution of 4.90 g (67 · 1 mmol) of 3-butadiazine obtained in Reference Example 4 was added and stirred overnight. After the reaction was completed, ethyl acetate was added to the reaction solution and saturated. The aqueous layer was extracted with ethyl acetate in layers. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography ( Chaotropic: toluene ~ toluene

-330- 200403244 • Ethylene = 3: 1) (2S) -3_ (Third-Butadiphenylsilyloxy) -2-[(3 -Acridinyl, (Methenyl) -amino] -methyl propionate (9.60 g, 61% yield). ] HN MR (400MHz, C DC I 3): δ (ppm) 7.61 — 7.55 (4H, m), 7.47 — 7.36 (6H, m), 5.94 (1H, br d, J = 8.1Hz), 5.19 〇H, dt, J = 2.9, 8.1Hz), 4.71 -4.64 (1H, m), 4.40-4.33 (1H, m), 4.31-4.23 〇H, m), 4.18 (1H, dd, J = 2.2, 10.3Hz), 4.04 〇H, dd, J = 2.9, 10.3Hz), 4.02-3.96 〇H, m), 3.94 -3.88 (1H, m), 3.76 (3H, s), 2.24 (1H, br d, J = 5.9Hz), 1.04 (9H, s) (2 (1) (2 3) -2-{[3- (benzylacetoxy) _azetidinyl-thiothiocarbamyl] -amino group}- 3-(Third-butadiphenylsilyloxy) _methyl propionate will be obtained from Reference Example 2 (2 c) (2 S)-3-(Third-butadiphenylsilyloxy) -2-[(3- Hydroxyl hydrazone butyridinyl-1 -thiocarboxamido) -aminomethyl propionate 2 1.1 g (4 4.6 mmol) was dissolved in 630 ml of pyridine, and 30.0 g of benzyl anhydride was added under ice cooling ( 133 mmol), 545 mg (4.46 mmol) of 4-dimethylaminopyridine, and stirred at room temperature for 2 hours. After the reaction, add ethyl acetate and saturated sodium bicarbonate solution to the reaction system. 5 Ν The layered extraction was performed, and the aqueous layer was extracted with ethyl acetate. -Hydrochloric acid water, saturated sodium bicarbonate solution, and saturated saline solution were sequentially washed, dried under anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: n-hexane: ethyl acetate = 4: 1) Purification to obtain (2S) -2-{[3- (benzylfluorenyloxy) -azetidinyl-1-thiocarboxyfluorenyl] -amino} -3- (third Butadienesilyloxy) -methyl propionate (2 3 · 3 g, yield 9 1%). 屮 -NMR (400MHz, CDC 1 3) ·· (5 (ppm) 8 · 10-8. 05 (2H m), 7. 65-7. 54 (4H, m), 7.52-7.45 (3H, m), 7.44-7.35 (6H, m), 5.96 (1H, br d, J = 8.1Hz), 5.47 -5.40 〇H, m), 5.20 (1H, dt, J = 8.1, 2.9Hz), 4.57-4.51 〇H, m), 4.49-4.40 (1H, m), 4.27-4.20 (1H, m), 4.20 〇H, dd, J = 2.2, 10.3Hz), 4.06 (1H, dd, J = 2.9, 10.3Hz), 3.77 (3H, s), 1.04 (9H, s) 200403244 (2 ^ (23)- 2-{[3- (Benzylfluorenyloxy) -azetidinyl-1-thiocarboxyfluorenyl] -amino group} -3-hydroxy-propionic acid methyl ester (2 S) obtained from Reference Example 2 (2 d) -2-{[3- (benzylfluorenyloxy) · azetidinyl-1-thiocarboxyfluorenyl; l · amino} -3- (third butyldiphenylsilyloxy )-Methyl propionate 2 3.3 g (40.0 mmol) were dissolved in 700 ml of tetrahydrofuran, and 1.0M tetrabutylammonium fluoride-tetrahydrofuran solution 48.4 ml (48.4 mmol) was added under ice cooling, and stirred overnight . After the reaction was completed, ethyl acetate and saturated brine were added to the reaction solution to separate the layers, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: toluene: acetonitrile = 3: 1) to obtain (2S) -2-{[3- (benzyloxy) -azetidinyl-1-thioxo as a white solid. Carboxyfluorenyl] -aminobie 3-hydroxy-propionic acid methyl ester (12. 6 g, yield 92 2%). ] Η- NMR (400MHz, CDCI 3): δ (ppm) 8. 08-8. 04 (2H, m), 7.64- 7. 59 (1H, m), 7.51-7.45 (2H, m), 6.00 ( 1H, d, J = 7.3Hz), 5.49-5.43 〇H, m), 5.25 (1H, dt, J = 7.3, 3.7Hz), 4.63-4.56 (2H, m), 4.32-4.24 (2H, rn) , 4.12-4.02 (2H, m), 3.82 (3H, s) (20-benzyloxo-1-[(48) -4-methoxycarbonyl-1,3-oxazoline-2-yl ] Acridine A reference solution of 15.1 g (55.9 mmol) of acetonitrile 3 800 ml of 2-chloro-3-ethylbenzoxazole tetrafluoroborane was added dropwise to Reference Example 2 under ice-cooling and nitrogen e) 12.6 g (37.2 mmol) of (23) -2-{[3- (benzylacetoxy) _azetidin-1-thiocarboxamidobmidinobu 3-hydroxy-propionate methyl ester ) 500ml solution of acetonitrile and stir for 1 hour. Add 0.4 ml (7 4.4 millimoles) of triethylamine and stir for 1.5 hours. After the reaction is completed, add ethyl acetate and saturated weight to the reaction solution. The sodium carbonate solution was subjected to layered extraction, and the aqueous layer was extracted with ethyl acetate. The organic layer obtained was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was concentrated in silicon. Purification by column chromatography (eluent: 00200200403244 liquid: ethyl acetate ~ ethyl acetate: methanol = 9 5: 5), 3-benzyloxy-l-[(4S) -4- Methoxycarbonyl hydrazone 11 oxolin-2-yl] azetidine (9.12 g, yield 81%). 'H-NMR (400MHz, CDCI 3): (5 (ppm) 8. 08-8 04 (2H, m), 7.63-7. 58 (1H, m), 7.49-7.44 (2H, m), 5.50-5.44 (1H, m), 4. 69 (1H, dd, J = 6.6, 9.5 Hz), 4.55 (1H, dd, J = 6.6, 8.1Hz), 4.51-4.44 (3H, m), 4.20-4.14 (2H, m), 3.78 (3H, s) (2 g) 3-benzylhydrazone 1-1- (4-methoxycarbonyl-1,3-oxazol-2-yl) ΠΥ Butidine The 3-; fluorenyl-bK43) -4-methoxy group obtained from Reference Example 2 (2f) -1, oxazoline-2-yl] azetidine 9.12 g (3.0 mmol) was dissolved in 450 ml of toluene and 180 ml of dichloromethane, 63.8 g of manganese dioxide was added, and the mixture was heated under reflux for 5 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: toluene: acetamidine = 1: 1) to obtain 3-benzylacetoxy-1-(4-methoxycarbonyl-1,3-oxazole) as pale yellow crystals. -2 -yl) azetidine (5.24 g 'yield 58%). ^ -NMR (400MHz, CDC I 3): (5 (ppm) 8.08-8.04 (2Η, m), 7.84 〇h, s), 7.63-7.58 〇H, m), 7.50-7.44 (2H, m), 5.60-5.53 〇H, m), 4.61 (1H, dd, J = 5.9, 9.5Hz), 4.31 (1H, dd, J = 3.4, 9.5Hz), 3.89 (3H, s) (Reference example 3) 3-Ethylthio-1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) azetidine (3a) l- (4-allyloxycarbonyl-1,3-thiazole-2 -Yl) -3-Tertiary succinic acid oxyazetidine The 3-tertiary succinic acid _4 -carboxyl- 丨, 3 _ _-2-yl) obtained in Reference Example 1 PY butanidine 6.73 g (15.3 mmol) was dissolved in 330 ml of dimethylformamide, and 159 ml (18. 4 mmol) of allyl bromide and 1 isopropyl group were added at room temperature. 3 ml of acetabulum (1.8 ml) was stirred in an oil bath at 80 ° C for -333-200403244 for 10 hours. After the reaction was completed, ethyl acetate and 10% brine were added, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 5: 1) to obtain 1-(4-allyloxycarbonyl-1,3-thiazole-2 -yl) as a brown oil. Azidine-3-tertiary stilbenesilyloxyazetidine (5.31 g, 73% yield). ^ -NMR (400MHz, CDC I 3) δ (ppm) 7.63-7.59 (4Η, m), 7.46 〇H, s), 7.47-7.36 (6H, m), 6.04-5.95 〇H, m), 5.40- 5.35 (1H, m), 5.28-5.24 OH, m), 4.80-4.78 (2H, m), 4.77-4.71 〇H, m), 4.16 (2H, dd, J = 8.8, 6.6Hz), 4.06 (2H, dd, J = 8.8, 4.4Hz), 1.06 (9H, s) (3b) 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine 5.31 g (11.1 mmol) of 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3-third-butadiphenylsilyloxyazetidine obtained in Reference Example 3 (3a) Dissolved in 266 ml of anhydrous tetrahydrofuran, and add 1 M tetrabutylammonium fluoride-tetrahydrofuran solution 13.3 ml (13. 3 mmol) under ice cooling. Stir overnight at room temperature. After the reaction was completed, the solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl φ ethyl acetate) to obtain 1- (4-allyloxycarbonyl-1,3-thiazole-2) as light brown crystals. -Yl) -3 -hydroxyazetidine (2.91 g, 100% yield). ^ -NMR (400MHz, CDC I 3): (5 (ppm) 7.49 (1H, s), 6.06-5.96 〇H, m), 5.42-5.35 (1H, m), 5.29-5.24 (1H, m), 4.87-4.80 (1H, m), 4.79 (2H, d, J = 5.9Hz), 4.38 (2H, t, J = 8.8Hz), 4.02 (2H, dd, J = 9.8, 3.9Hz), 2.52-2.37 (1H, br s) (3c) l- (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine. Reference Example 3 (3b) obtained 1- ( 4-allyloxycarbonyl-1,3-thiazol-2-yl) -3_ hydroxyazetidine 2.91 g (11. 1 mmol) dissolved in anhydrous dichloromethane 1 4 6 mmol-334- 200403244 liters Under ice cooling, add 2.5 8 ml (33.3 mmol) of methanesulfonyl chloride and 4.67 ml (33.3 mmol) of triethylamine. After 10 minutes, warm to room temperature and stir for 2 hours. After the reaction was completed, ethyl acetate and a saturated sodium bicarbonate solution were added, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered ', and the filtrate was concentrated under reduced pressure. Ethyl acetate and isopropyl ether were added to the obtained residue, followed by filtration, and the filtrate was washed with isopropyl ether to obtain 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) as light brown crystals- 3-Methanesulfonyloxyazetidine (2.71 g, 77% yield). -NMR (400MHz, CDC l3): (5 (ppm) 7.55 (1H, s), 6.07-5.96 (1H, m), 5.45-5.35 (2H, m), 5.30-5.25 (1H, m ), 4.81 (2H, dt, J = 5.9, 1.5Hz), 4.51 (2H, dd, J = 11.0, 6.6, 1.5Hz), 4.31 (2H, ddd, J = 11.0, 4.4, 1.5Hz), 3.10, (3H, s) (3d) 3-Acetylthio-1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) azetidine. Reference Example 3 (3c) gives 1- (4 -Allyloxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine 2.70 g (8.51 mmol) dissolved in dimethylformamide 1 3 5 ml at room temperature Add 5.3 g of potassium thioacetate (5 1 · 1 mmol) and stir in an oil bath at 80 ° C for 10 hours. After the reaction is completed, add ethyl acetate and 10% saline, and add water. The layer was extracted with ethyl acetate in layers. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: Zhengjiyuan: acetic acid). Ethyl ester == 2: 1) Purified to obtain 3 _acetamidinethio_ ^ (4 _ allyloxycarbonyl-1,3-thiazol-2-yl) azetidine (ι · 61 g Yield, 63%). 1H-NMR (400MHz, CDCI 3): (5 (ppm) 7.51 (1H, s), 6.06-5.96 〇H, m), 5.41-5.35 〇H, m), 5.29-5.26 (1H, m), 4.58 (2H, t, J = 8.1Hz), 4.47 -4.40 (1H, m), 4.04 (2H, dd, J = 9.5, 5.9Hz), 2.36 (3H, s) 200403244 (Reference Example 4) 10.0 g of benzyl-3-hydroxyazetidine (41.8 millimoles) were dissolved in 300 ml of methanol and subjected to contact hydrogenation reduction at room temperature for 3 hours in the presence of 10% Pd-C 10.0 g. After the reaction was completed, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate and distilled water were added to perform layered extraction, and the organic layer was extracted with distilled water. The aqueous layer was concentrated under reduced pressure to obtain a red oil. This product was not formed but was used for the next reaction. (Experimental example 1) Antibacterial activity in vitro After the culture medium of the pre-culture medium at 37 ° C overnight was adjusted to about 106 CFU / ml with Mueller * Hinton broth, the culture plate was drawn on a petri dish with 1 inoculation loop (inner diameter 1mm) After smearing and incubating at 37 t for 18 to 20 hours, the minimum concentration of the test substance that inhibits the growth of bacteria (the most growth-inhibiting concentration (micrograms / ml)) is determined. In addition, the lowest growth inhibitory concentration was obtained by using the test bacteria added with horse blood maggot infiltration at 37 t for 1 hour in the same way as above. The results are shown in Table 10. In the table, the test bacteria A, B, C, and D are shown below. A: Staphylococcus aureus 209P strain B: Pneumococcus 1 0664 strain (penicillin-resistant strain) C: Haemophilus influenzae 9 7 8 7 strain (spot-lactamase-producing strain) D: E. coli NIHJ strain (Table 10) Living Minimum inhibitory growth concentration of test compound for external antibacterial activity (μg / ml) Test compound ABCD Example 1 Compound 0.10 0.20 3.13 12.5

-336- 200403244 Compound of Example 1 + Hematoxylin 0.025 0.39 0.78 1.56 Compound of Example 2 0.39 0.20 3. 13 > 100 Compound of Example 2 + Hexam 0.05 0.39 0.78 3.13 Compound of Example 3 1.56 0.20 3. 13 > 100 Compound of Example 3 + Hematoxylin 0.025 0.39 0.78 1.56 Compound of Example 4 0.10 0.20 3.13 12.5 Compound of Example 4 + Hematoxylin 0.025 0.39 0.78 1.56 Compound of Example 5 0.05 0.20 3.13 12.5 Example 5 Compound + blood serum 0.05 0.39 0.78 1.56 Compound of Example 6 0.20 0.20 3.13 100 Compound of Example 6 + blood serum 0.025 0.20 1.56 1.56 Compound of Example 7 1.56 0.10 1.56 100 Compound of Example 7 blood serum 0.05 0.20 0.78 3. 13 Compound of Example 8 0.10 0.20 1.56 6.25 Compound of Example 8 + Hexam 0.025 0.20 0.78 3. 13 Compound of Example 9 0.20 0.20 3. 13 100 Compound of Example 9 + Hexam 0.05 0.39 0.78 3.13 Compound of Example 10 3.13 0.20 6.25 > 100 Compound of Example 10 + Hexam 0.05 0.39 0.78 3.13 Compound of Example 11 0.1 10 0.20 3. 13 12.5 Example 1 Compound of 1 + blood sacral 0.05 0.39 0.78 3. 13 Compound of Example 12 0. 10 0.20 3. 13 12.5 Compound of Example 12 + blood sacral 0.1 10 0.20 1.56 3. 13 Compound of Example 13 0.39 0.39 12.5 > 100 Compound of Example 13 + Hematoxylin 0.110 0.20 1.56 3. 13 Example of Compound III + Hematoxylin 3.13 0.39 50 > 100 Compound of Example 14 + Hematoxylin 0.1 10 0.20 1.56 3. 13 Example 15 Compound 0. 10 0.20 6.25 25 Compound of Example 15 + Hematoxylin 0.1 10 0.20 1.56 3. 13 -337- 200403244 Compound of Example 16 0.10 0.20 0.78 6.25 Compound of Example 16 + Hexam 0.025 0.20 0.39 0.78 Implementation Compound of Example Π 0.78 0.20 1.56 > 100 Compound of Example 17 + Hexam 0.05 0.20 0.78 3. 13 Compound of Example 18 3.13 0.20 1.56 > 100 Compound of Example 18 + Hexam 0.05 0.20 0.78 3. 13 Implementation Compound of Example 19 0.10 0.20 1.56 12.5 Compound of Example 19 + Hexam 0.05 0.20 0.78 3. 13 Compound of Example 27 0.10 0.20 6.25 12.5 Compound of Example 27 + Hexam 0.05 0.20 0.78 1.56 Compound of Example 28 1.56 0.20 25 100 real Compound of Example 28 + Hematoxylin 0.05 0.20 0.78 1.56 Compound of Example 29 0.05 0.20 3. 13 6.25 Compound of Example 29 + Hexam 0.05 0.20 0.78 1. 56 Compound of Example 30 1.56 0.20 3. 13 100 Example Compound of 30 + blood serum 0.05 0.20 0.78 1. 56 Compound of Example 31 0.05 0.20 12.5 12.5 Compound of Example 31 + blood serum 0.025 0.39 0.78 1.56 Compound of Example 32 0.20 0.39 > 100 100 Compound of Example 32 + Serum 0.025 0.39 0.78 1.56 Compound of Example 33 3.13 0.20 > 100 > 100 Compound of Example 33 + Serum 0.05 0.05, 20 0.78 1.56 Compound of Example 34 0.05 0.78 6.25 12.5 Compound of Example 34 + Serum 0.025 0.39 0.39 0.78 Compound of Example 35 0.78 0.78 > 100 25 Compound of Example 35 + blood serum 0.025 0.39 0.78 1.56 Compound of Example 36 3. 13 0.78 > 100 50 Compound of Example 36 + blood serum 0.025 0.39 0.78 1. 56 Compound of Example 37 6.25 12. 5 25 12.5

-338- 200403244 Compound of Example 37 + Hematoxylin 0.05 0.78 0.78 1.56 Compound of Example 38 6.25 > 100 > 100 > 100 Compound of Example 38 + Hexam 0.20 3.13 6.25 3.13 Compound of Example 39 6.25 100 > 100 100 Compound of Example 39 + Haematopores 0.20 1.56 3.13 3.13 Compound of Example 40 0.05 0.20 12.5 12.5 Compound of Example 40 + Haemosphere 0.10 0.78 1.56 1.56 Compound S of Example 41 0.20 0.78 > 100 > 100 Compound of Example 41 + Hematoxylin 0.1 10 0.39 1.56 1.56 Compound of Example 42 1.56 0.78 > 100 > 100 Compound of Example 42 + Hematoxylin 0.10 0.78 1.56 1.56 The above result 'The compound of the present invention sealed various fine Alas, shows strong antibacterial activity. Even those with weaker antibacterial activity showed strong antibacterial activity after treatment with blood pupa. (Experimental Example 2) Antibacterial activity in vivo (Mouse Infection Treatment Experiment) 4 weeks old ddY male mice (SLC Japan) were inoculated with 0.2 ml of pneumococcus (S. pneum〇iiiae) 9605 (PRSP) from the abdominal cavity (Containing 5% mucin, 2.6 x 104cfu / mouse), 0.2 ml of a 50% PEG400 solution of the test compound was orally administered 4 hours after infection. Seven mice were used per group, and the test compound was diluted by two times in stages. After 7 acetabies, the ED 5G was calculated by the probit method. The test results are shown in Table 11. -339- 200403244 (Table 1 η Test compound ed5G (mg / kg / dose) Compound of Example 32 10.4 Compound of Example 33 < 25 Compound of Example 40 < 25 Compound of Example 42 < 25 Implementation Example 32, 33, 40, or 42. Active body of compound> 25 In Table 11, the active body of the compound of Example 3 2, 3, 3, 40, or 42 is as follows,

(Experimental Example 3) Antibacterial activity in vivo (Mouse Infection Treatment Experiment) In accordance with the pneumococcal infection method (Antimicr 〇b. A gents C hem ther, 1998 42: 23-27), Haemophilus influenzae (H. influenzae Intranasal inoculation test), the compound of the present invention showed good results. (Preparation Example 1) Capsule Compound of Example 1 50 mg lactose 128 mg corn starch 70 mg g magnesium stearate 2 mg 250 mg The above-mentioned prescription powder was mixed and passed through a 60-mesh sieve, and the powder Capsules can be obtained by filling 250 mg with No. 3 capsules. -340- 200403244 (Formulation Example 2) Lozenge Compound of Example 1 50 mg lactose 126 mg corn starch 23 mg magnesium stearate 1 mg 200 mg The above prescription powder was mixed, and corn starch paste was used for wet granulation and dried. With a tablet mill, 200 mg tablets are prepared. Sugar coating if necessary. [Industrial Applicability] The 10-methyl carbon complex of the general formula (I) or its pharmacologically acceptable salt and ester derivative of the present invention has excellent antibacterial activity and is stable to dehydropeptidase and yS-lactamase 4, medicine with low renal toxicity, especially suitable for antibacterial use. -341-

Claims (1)

Pick up and apply for patents: 1. A compound of the following formula or its pharmacologically acceptable salt or its ester derivative ... 112 is Ci-Cis alkyl, c3-c7 cycloalkyl, or c6-c1G aryl, η is 1, 2 or 3, X is a sulfur atom or an oxygen atom, and A is a group of the formula N— (a-1) 「NN— Vs or (a-2) — νΓΑΠ <, ν— R4 R5 (a-3) {wherein R3, R4, and R5 are each hydrogen, Cl-c6 alkyl, hydroxyl CrCs alkyl, 〇3-06 cycloalkyl, 〇7 < 2 aralkyl or c6-Cio aryl, Aik is a C2-Ci () alkylene which can be substituted (the substituent is hydroxy, c3 -C6 cyclic alkyl group, carbamoyl group which can be substituted (the substituent is C! -C6 alkyl group and 2 nitrogen atoms which can be combined with these substituents are shown as possible substitutions 3 ~ 7 Member nitrogen-containing heterocyclic group) or c6-Cl () aryl}, h, 9, 1 ,: and 3 are each 1, 2, or 3}]. 2 · If the compound of the scope of application for a patent or its pharmacological allowance A salt to a derivative, in which A is the formula Ap Rr / Alk \ -N— \ N — ——N, N— —N, N— Mq, Ws, or & (a-1) (a- 2) (a-3) > 342- 200403244 {wherein R3, R4 and R5 are each hydrogen, Ci-Cs alkyl, C5-C6 cycloalkyl, benzyl or phenyl, and A 1 k is optionally substituted C 2-C 6 alkylene (when the substituent is C 5-C 6 cycloalkyl or phenyl), 戸, 9, 1 *, and 5 are each 1 or 2}. Combination of 1 item Or a pharmacologically acceptable salt or ester derivative thereof, wherein A is a group of the formula (Wherein R3 is hydrogen, and P and q are each 1 or 2). 4. The compound or pharmacologically acceptable salt or ester derivative thereof according to item 1 of the scope of patent application, wherein A is a group of the formula (In the formula, R3 is hydrogen, p is 1, and q is 2). 5. A compound or a pharmacologically acceptable salt or an ester derivative thereof according to item 1 of the scope of the patent application, wherein A is a group of the following formula: r —N N— (a-2) Vs (where both r and s are 2). 6. The compound or pharmacologically acceptable salt or ester derivative thereof according to item 1 of the scope of patent application, wherein A is the following formula R4 R5 -343- 200403244 (where R4 and R5 are both hydrogen and Aik is C2-C6) alkyl). 7. The compound or pharmacologically acceptable salt or ester derivative thereof according to item 1 of the scope of patent application, wherein A is a group of the formula (Wherein R is C2-C4 alkyl). 8. The compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of claims 1 to 7 of the scope of the patent application, wherein R1 is hydrogen or an alkyl group. 9. A compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of claims 1 to 7 of the scope of patent application, wherein R 1 is hydrogen. 10. The compound or a pharmacologically acceptable salt thereof or an ester derivative thereof according to any one of claims 1 to 9 of the scope of application for a patent, wherein R2 is an alkyl group, a C5-C6 cycloalkyl group or a phenyl group. 1 1. The compound or a pharmacologically acceptable salt thereof or an ester derivative thereof according to any one of claims 1 to 9 of the scope of patent application, wherein R2 is methyl, cyclohexyl or phenyl. 12. The compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of claims 1 to 11 in the scope of application for a patent, wherein η is 1. 13. The compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of claims 1 to 11 in the scope of the patent application, wherein η is 1, and the substitution position of the sulfur atom is the 3-position of the azetidine ring. 14. The compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of claims 1 to 13 in the scope of application for a patent, wherein X is a sulfur atom. 15. The compound according to any one of claims 1 to 14 or a pharmacologically acceptable salt or an ester derivative thereof, wherein R9 is hydrogen or an alkyl group. -344- 2 | D0403244 1 6. The compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of claims 1 to 14 in the scope of patent application, wherein R9 is methyl. 17. The compound or pharmacologically acceptable salt or ester derivative thereof according to any one of the items 1 to 16 of the scope of patent application, wherein R1 and R9 are each hydrogen or an alkyl group, and 112 is an alkyl group and a C5-C6 ring Alkyl or phenyl, η is 1, X is a sulfur atom, and A is a formula (a -1) (Wherein R3 is hydrogen, and p and q are each 1 or 2). 18. The compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of claims 1 to 16 of the scope of application for a patent, wherein R1 and R9 are each hydrogen or alkyl, 112 is C! -C3 alkyl, C5-C6 cycloalkyl or phenyl, η is 1, X is a sulfur atom, and A is a radical of the following formula: r —NN— (a-2) Vs (where both r and s are 2). _ 1. If the compound or pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 16 of the scope of patent application, wherein R1 and R9 are each hydrogen or Ci-Cs alkyl, and 2 is Cl- C3 alkyl, C5-C6 cycloalkyl or phenyl, η is 1, X is a sulfur atom, A is a radical of the formula (a-3) " fir (where R4 and R5 are both hydrogen and Aik is C2- C6 alkylene). 2 0. The compound or the pharmacological 200403244 permissible salt or ester derivative thereof according to any one of the items 1 to 16 of the scope of the applied patent, wherein R1 is hydrogen, R9 is methyl, and R2 is methyl, cyclohexyl or benzene Group, η is 1, the substitution position of the sulfur atom is the 3-position of the azetidine ring, and A is a group of the formula (Wherein R3 is hydrogen, p is i, and q is 2). 2 1 · The compound or pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 16 in the scope of patent application, wherein R1 is hydrogen, R9 is methyl, and R2 is methyl, cyclohexyl or phenyl , Η is 1, the substitution position of the sulfur atom is the 3 position of the azetidine ring, X is a sulfur atom, and A is a formula (Where both r and s are 2). 2 2. The compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of claims 1 to 16 in the scope of patent application, wherein R1 is hydrogen, R9 is methyl, and R2 is methyl, cyclohexyl or phenyl , Η is 1, the substitution position of the sulfur atom is the 3 position of the azetidine D ring, X is a sulfur atom, and A is a group of the formula (Wherein R is C2-C4 alkyl). 2 3. A pharmaceutical composition containing an active ingredient selected from the group consisting of a compound or a pharmacologically acceptable salt thereof or an ester derivative thereof according to any one of items 1 to 22 of the scope of patent application. 2 4. An antibacterial agent containing an effective ingredient selected from the group consisting of a compound or a pharmacologically acceptable salt thereof or an ester derivative thereof according to any one of the scope of application for patents Nos. 1 200403244 to 22. 25. An antibacterial agent for preventing or treating bacterial infections, containing an effective ingredient selected from the group consisting of a compound or any of its pharmacologically acceptable salts or ester derivatives thereof as set forth in any one of claims 22 to 22 of the patent application scope. 26. An antibacterial agent for treating or preventing respiratory infections, containing an effective ingredient selected from the group consisting of a compound according to any one of claims 1 to 22 or a pharmacologically acceptable salt or an ester derivative thereof. 27. An antibacterial agent for the treatment of respiratory infections, containing an active ingredient selected from the group consisting of a compound or any of its pharmacologically acceptable salts or ester derivatives thereof as set forth in any of claims 1 to 22 of the scope of patent application. 2 ··· Uses for producing a pharmaceutical composition using the compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of claims 1 to 22 of the scope of patent application. 29. A method for treating or preventing a disease, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 to 22 or a pharmacologically acceptable salt or an ester derivative thereof. 30. A method for preventing or treating a bacterial infection, comprising administering a therapeutically effective amount of a compound or a pharmacologically acceptable salt thereof or an ester derivative thereof according to any one of claims 1 to 22 of the scope of patent application to a mammal. ΊΛΠ 200403244 柒 Designated representative map: (1) The designated representative map in this case is: (). (2) Brief description of the element representative symbols in this representative map: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: