TW200418858A - Carbapenem derivatives - Google Patents

Abstract

The present invention provides carbapenem compounds of the following formula (I), (wherein, R1 represents a group of formula COOR3, a group of formula CONR4R5, a cyano group, a group of formula CH2OR6 or a group of formula CH2NR7R8, R2 represents a hydrogen atom or C1-C6 alkyl group, n represents 1,2 or 3, X represents a sulfur atom or an oxygen atom), and the pharmaceutically acceptable salts, and the pharmaceutically acceptable esters derivatives thereof.

Description

200418858 发明 Description of the invention [Technical field to which the invention belongs] The present invention relates to a carbon complex compound (I) having excellent antibacterial activity, a pharmacologically acceptable salt or ester derivative thereof, and a medicine containing the compound as an active ingredient. Carbene compound (I) whose pharmacologically acceptable salt or ester derivative is used, or a pharmacologically effective amount of carbene compound (I) 'is pharmacologically acceptable to a warm-blooded animal ) To treat or prevent bacterial infections, especially respiratory infections. [Prior art] There is a great need to develop carbamate derivatives with a strong and balanced antibacterial activity against a wide range of pathogenic bacteria. Japanese Laid-Open Patent Publication No. 2000- 2 1 2 1 8 2 discloses a 1-methyl carbon compound having a structure similar to the present invention, but has a methyl group at the 1-position, which is different from the structure of the compound of the present invention. [Summary of the Invention] As a result of long-term development of carbon compound compounds by the inventors, it has been found that the compound (I) of the present invention has stronger antibacterial power than the previous carbon compound derivatives, and can be effectively used as a treatment or prevention (especially treatment) Bacterial infections, especially medicines (antibacterials) for respiratory infections, have completed the present invention. The present invention relates to a compound such as a carbon compound or a pharmacologically acceptable salt or an ester derivative thereof.

200418858 In the formula, R 1 is a group represented by the formula (1) CO OR3 [wherein, R 3 is hydrogen, an alkyl group, or a C3-C6 cycloalkyl group], (2) a group represented by the formula 001 ^ 114115 [ In the formula, R4 and R5 are the same or different, each is a hydrogen atom, Cl_c6 alkyl (may have 1 to 3 substituents which are the same or different from the following substituent group A), C 3 -C 6 cycloalkane Group, 3 to 7-membered polycyclic group or C 6-C 10 aryl group (may have 1 to 2 aryl groups which are the same or different from the following substituent group B), or with adjacent nitrogen atoms A total of 3 to 7 member nitrogen-containing polycyclic groups are formed (may have 1 or 2 substituents which are the same or different from the following substituent group B)), (3) a cyano group, (4) a formula of CH2OR6 The base shown in the formula [wherein R6 is hydrogen, Ci-C6 base or C3-C6 ring base] or (5) the base represented by formula CH2NR7R8 [where R7 is hydrogen, Ci-C6 base, C3 -C6 ring group, R8 is hydrogen, Ci-C6 ring group 'C3-C6 ring group' Ci-C6 ring group, (C6-C1Garyl) carbonyl group (may have a group selected from the following substituent group B 1 or 2 substituents which are the same or different), (CrC6 alkoxy) carbonyl, 5- or 6-membered aromatic polycyclic carbonyl, C ^ C6 alkylsulfonyl or C6-C1G aromatic Fluorenyl, or R7 and R8 together with adjacent nitrogen atoms to form a succinimide group (which can be fused with a phenyl ring)] 'R2 is a hydrogen atom or a Ci-C6 group; η is 1, 2 or 3, -7- 200418858 X is a sulfur atom or an oxygen atom, the substituent group A is a meridian group, and an amine group (can be substituted with 1 or 2 c ^ c 6 pentyl groups) 'carbamoyl group (the amine group can be substituted with 1 or 2 CC 6 alkyl), carboxyl, cyano, and Ci-C: 6 alkoxy, the substituent group B is a C--C 4 alkyl, amine C!-C 4 alkyl (amino Partially substituted with 1 or 2 C] -C 6 alkyl), carbamoyl (Amino moiety can be substituted with 1 or 2 (: 1-〇6 alkyl), carboxyl, hydroxyl, amine (may Substituted by 1 or 2 (: 1-(: 6 alkyl), (^-(^ alkoxy and C! · C 6 alkyl.) In the above formula, R2, R3, R4, R5, R6, R7 R8, "Cl-C6 alkyl" in the definition of substituent group A and substituent group B is, Cl_c6 straight or branched chain saturated hydrocarbon group, such as methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, second butyl, third butyl, pentyl, isopentyl, 2-methylbutyl 'neopentyl' 1-ethylpropyl, hexyl, iso Hexyl, 4-methylpentyl'3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3, 3-monomethylbutyl, 2,2-dimethylbutyl, 1, dimethylbutyl, 1, dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, methylmethylpropyl and many more. Among the R ^, R3 ', R6', R7 ', and R8' substituent groups A and the substituent group, a C3 alkyl group is preferred, and a methyl group is particularly preferred. In R4, Ci_c3 alkyl is preferred, and methyl or isopropyl is particularly preferred. R5 is preferably a C2-c6 alkyl group, and most preferably is 丄 methyl-2-methylpropyl. In the definition of R3 'R4, R5' R6 'R4R8, "C3_C6 cycloalkyl" is a C3-Ce cyclohydrocarbyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohex-8-200418858, etc., preferably a ring Propyl. In the definitions of R4 and R5, "3 to 7-membered polycyclic group" is a saturated polycyclic group containing 1 or 2 oxygen, nitrogen and sulfur atoms, such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, amido Alkyl, fluorenyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, morpholinyl, piperinyl, thiomorpholinyl, [1 · 4] fluorheptyl, 1-oxosulfanyl Phenolinyl, 1,1-dioxomorpholinyl and the like are preferably 4 to 6 member nitrogen-containing polycyclic groups, more preferably azetidinyl, pyrrolidinyl or piperidinyl. "C6-C1 () aryl" in the definition of R4 and R5 and "(C6-Cio aryl) carbonyl" in the definition of R8 and "C6-C10 aryl" in the "C6-C1 () arylsulfonyl" group For example, phenyl, indenyl, naphthyl, etc., and preferably phenyl. The "nitrogen-containing polycyclic ring" in R4 and R5 that "forms 3 to 7 nitrogen-containing polycyclic groups with adjacent nitrogen atoms" is a saturated polycyclic group containing 1 or 2 nitrogen atoms and may contain oxygen or sulfur atoms. For example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperidinyl, thiomorpholinyl, [1. 4] fluorene heptyl '1 -thiomorpholinyl, 1, 1, -Dioxothiomorpholinyl, etc., preferably 4 to 6 member nitrogen-containing polycyclic rings, more preferably azetidinyl, piperidinyl, morpholinyl or thiomorphyl. "Alkino" in the definition of R8 is C] -C6 straight or branched alkyl alkynyl 'such as formamyl, ethamyl, propionyl, butylamyl, isobutylamyl, pentamyl, isopentamyl, pentamyl, hexamethylene and the like, preferably C PC3 alkyl, most preferably ethyl. The "alkoxy" part of the "(C ^ C6 alkoxy) carbonyl" in the definition of "crc 6 alkoxy" in the definition of R 8 and the substituent group is a C3-C6 straight chain-9-200418858 or a branched alkoxy group A group such as methoxy, ethoxy, propoxy, isopropoxy'butoxy, pentyloxy, hexyloxy, etc. is preferably an alkoxy group, and most preferably a methoxy group. The "5- or 6-membered aromatic polycyclic carbonyl" part of the definition of R8 is an aromatic polycyclic group containing 1 to 3 oxygen, nitrogen and sulfur atoms, such as pyrrolyl, imidazole Group, thiazolyl, oxazolyl, isoxazolyl'furanyl, thienyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl'damoyl, triple well and the like. Preferably it is furyl, thienyl or pyridyl. "Hydroxy C! -C4 alkyl" in the substituent group B is, for example, hydroxymethyl, hydroxyethyl ', hydroxypropyl, hydroxybutyl, etc., preferably hydroxy Ci-Ca alkyl, and also hydroxymethyl. The "amine C ^ C 4 alkyl" in the substituent group B is, for example, amine methyl, amine ethyl 'amine propyl, amine butyl, etc., preferably amine <: 1-0: 2 alkyl, and more preferably The amine methyl group 0 is preferably selected from the group consisting of a hydroxyl group, an amine group (which can be substituted with 1 or 2 C 1-C 3 alkyl groups), and a carbamoyl group, and also an amine group (which can be substituted with 1 or 2). 2 methyl or ethyl). The substituent group B is preferably selected from the group consisting of a hydroxy C 4 alkyl group, an amine C rC 4 alkyl group (the amine moiety may be substituted with 1 or 2 C! -C 3 alkyl groups), and the amine formamidine moiety may be substituted with 1 Or 2 Ci-C3 alkyl), hydroxyl and amine groups (can be replaced by 1 or 2 <: 1-03 alkyl) groups, more preferably methylol, aminemethyl (the amino group can be Substituted with 1 or 2 methyl or ethyl), carbamoyl (the amine moiety can be substituted with 1 or 2 methyl or ethyl), hydroxyl and amine (can be substituted with 1 or 2 methyl or Ethyl), more preferably aminemethyl or amine. -10- 200418858 The "pharmacologically acceptable ester derivative" in compound (i) is a compound (I) carboxyl or hydroxyl group which can be cleaved by chemical or biological methods such as hydrolysis in human or animal body to form compound (I) or its salt Whether or not a protected ester derivative is such a derivative is first administered orally or intravenously to experimental animals such as rats and mice, and the animal body fluids, meta compounds or pharmacologically tolerable salts can be detected for determination. The protecting group for the ester derivative forming a carboxyl group is, for example, cpc 1G alkyl group, C3-C6 cycloalkyl group, C3-C6 cyclofluorenyl group C1-C4 fluorenyl group, C2-C10 fluorenyloxy C1-C4 cyclyl group, (Cl -Cl. Oxy group C1-C4 group, phenyl group (the phenyl group can be substituted with 1 or 2 atoms selected from Ci atom, Ci-C4 group, C1-C4 group oxygen, methylene di Oxy, C1-C6 alkoxy group), Ci-Cio oxo group, phthalo, 5-methyl-2-oxo-1, 3-dioxocene-4 -ylmethyl . The protecting group for the hydroxyl-forming ester derivative is, for example, a C 1Q alkyl group, a (C 6 -Cio aryl) group, a (Ci-Cio group) group, an amine group, and the like. In the above, "Ci-Cio" is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, third butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, hexyl, 2-hexyl, 3-hexyl, isohexyl, heptyl, octyl, nonyl, decyl, etc., preferably Cl_C6 alkyl, more preferably C2-C4 alkyl, Most preferred is ethyl. "C3-C6 cycloalkyl" is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and is preferably cyclopentyl or cyclohexyl. "C3-C6 cycloalkyl Ci-C # alkyl" is, for example, cyclopropylmethyl, cyclo-11-200418858 propylethyl, cyclopropylpropyl, cyclopropylbutyl'cyclobutylmethyl'cyclobutyl Ethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl and the like are preferably cyclopropylmethyl. The "C 2 -C 10 alkylalkoxyoxy C r C 4 alkyl group" is, for example, ethoxymethyl, 1- (ethoxy) ethyl, 1- (ethoxy) propyl, 1- (Ethyloxy) butyl, propionyloxymethyl, 1- (propylpyroxy) ethyl, isopropylpyroxymethyl, 1- (isopropylpyroxy) ethyl, butyryloxymethyl , 1- (butylammonyloxy) ethyl, isobutylammonyloxymethyl, 1- (isobutylammonyloxy) ethyl'-pentamyloxymethyl, 1- (tamopenthyloxy) ethyl, Pentamyloxymethyl, _ 1- (pentamyloxy) ethyl, isoamyloxymethyl, 1- (isopentamyloxy) ethyl, hexamethyleneoxymethyl, 1- (hexamethyleneoxy) ) Ethyl, caprylyloxymethyl '1- (octyloxy) ethyl'decanoateoxymethyl, cyclopentyloxymethyl, 1-methylcyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl Group, 1'-methylcyclohexylcarbonyloxymethyl, etc. 'is preferably (C2-C6 alkylfluorenyloxy) methyl or 1- (C2-C6 alkylfluorenyloxy) ethyl. "(Ci-Cio)" carbonyloxy group "is, for example, methoxychioxymethyl, 1- (methoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1-(ethoxycarbonyl (Oxy) ethyl, ethoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) butyl, propoxycarbonyloxymethyl, propoxycarbonyloxy) ethyl'isopropoxyloxymethyl , Isopropoxycarbonyloxy) ethyl, butoxycarbonyloxymethyl '1- (butoxycarbonyloxy) ethyl, isobutoxycarbonyloxymethyl, isobutoxycarbonyloxy) ethyl, second Butoxycarbonyloxymethyl, (second butoxycarbonyloxy) ethyl, third butoxycarbonyloxymethyl, 1_ (third butoxycarbonyloxy) ethyl, pentoxycarbonyloxymethyl, 2 — (Pentyloxycarbonyloxy) ethyl, (ind_-12-200418858 methylbutoxycarbonyloxy) methyl, 1- (1-methylbutoxycarbonyloxy) ethyl, (2-methylbutyl Oxycarbonyloxy) methyl, 1- (2-methylbutoxycarbonyloxy) ethyl, (3-methylbutoxycarbonyloxy) methyl, 1- (3-methylbutoxycarbonyloxy ) Ethyl, (1-ethylpropoxycarbonyloxy) methyl, 1- (1-ethylpropoxycarbonyloxy) ethyl, hexyloxycarbonyloxymethyl, 1- (hexaneoxycarbonyloxy) Ethyl '(1-methylpentyloxy Oxy) methyl, 1- (1-methylpentyloxycarbonyloxy) ethyl, octyloxycarbonyloxymethyl, octyloxycarbonyloxy) ethyl, decyloxycarbonyloxymethyl, 1- (decyloxy Carbonyloxy) ethyl, cyclopentylcarbonyloxymethyl, 1 cyclopentyloxycarbonyloxy) ethyl, cyclohexylcarbonyloxymethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, etc., preferably (alkane (Oxy) carbonyloxymethyl or 1-{(Cl_C6alkoxy) carbonyloxy} ethyl. "Substitutable phenyl" is, for example, phenyl, 3-fluorophenyl, 4-fluorophenyl '3' 4-difluorophenyl, 3-tolyl, 4-tolyl, 3-methoxyphenyl ' Methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl '3-ethenyloxyphenyl, 4-ethenyloxyphenyl, etc. are preferably unsubstituted phenyl. ^ C 1G alkoxybenzyl "is, for example, 2-ethenyloxybenzyl, 3-ethenyloxybenzyl '4-ethenyloxybenzyl, 3-propenylbenzyl, 4-propenylbenzyl, 4-butanyloxybenzyl, 4-pentanyloxybenzyl, 4-hexamethyleneoxybenzyl, 4-octyloxybenzyl, 4-decyloxybenzyl, etc., preferably 3- or 4- (C2 -C4 alkylfluorenyloxy) benzyl. ^ ei ~ c10 alkyl "is, for example, methyl, ethyl, propyl, propyl, butyl, 1-pentyl, hexyl, octyl, decyl, etc., and is preferably a C2-C 6 alkyl acid base. -13-200418858 "(C 6-C! 0aryl) carbonyl" is, for example, benzylfluorenyl, 1-naphthylfluorenyl '2-naphthylfluorenyl and the like, and is preferably benzamidine. "(Alkoxy) carbonyl" is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decoxycarbonyl, etc., and is preferably (C2-C6 (Alkoxy) carbonyl. "Amine group" is, for example, glycine group, propylamine group, β-propylamine group, leucine, isoleucine, amphetamine group, histamine, aspartate, proline, Glycine and the like are preferably glycine. The compound (I) of the present invention and its pharmacologically acceptable ester can form a "pharmacologically acceptable salt" when necessary. "The pharmacologically acceptable salt" is a salt made of the compound (I) of the present invention, and its salt is preferably an alkali metal salt such as a sodium salt, a potassium salt, a lithium salt, an alkaline earth metal salt such as a calcium salt, a magnesium salt, an aluminum salt, or an iron salt. , Zinc salt, copper salt, nickel salt, cobalt salt and other metal salts; inorganic salts such as ammonium salt, tertiary octylamine salt, benzylamine salt, morpholine salt, glucosamine salt, phenylglycinyl alkyl ester salt, ethylene glycol Amine salt, N-methyl glutamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, proline Caine salt, diethanolamine salt, N-benzyl phenylethylamine salt, piperidine salt, tetramethylammonium salt, amine salt such as organic salt of ginsyl (hydroxymethyl) aminomethane salt; hydrofluoric acid salt, hydrochloric acid Salts, hydrobromides, hydroiodates and other halogen acid salts, nitrates, perchlorates, sulfates, phosphates and other inorganic acid salts; mesylate, triflate, ethanesulfonic acid Low alkane sulfonates such as benzene sulfonates, aromatic sulfonates such as p-toluene sulfonate, acetic acid, malic acid, fumarate, succinate, citrate, tartrate, oxalate ' Along Organic acid salts such as oxalic acid salts; and amino acid salts such as glycine salt, spermine-14-200418858 acid salt, lysine salt, guanine salt, glutamate salt, aspartate salt, etc. . The compound (I) of the present invention, its pharmacologically tolerable salt and its ester derivative also contain its water substance or solvent and substance. Among the compounds of the general formula (I), the following compounds are preferred. (1) In R1, (1-1) R1 is a compound represented by the group represented by the formula CONR4R5, a cyano group or a group represented by the formula c H2NR7R8. (1-2) R1 is a compound represented by the formula: CONR4R5 or a compound represented by the formula: CH2NR7; R8. (1-3) R1 is a compound represented by the formula CONR4R5. (2) A compound in which (2 -1) R 2 in R 2 is hydrogen or a C 3 alkyl group. (2-2) A compound in which R2 is hydrogen. (3) A compound in which (3-l) R3 in R3 is hydrogen or a CrC3 alkyl group. 0 (3-2) Compounds where R3 is hydrogen, methyl or ethyl. (4) A compound in which (4 -1) R4 in R 4 is hydrogen or a C3 alkyl group. (4-2) A compound wherein R4 is hydrogen, methyl or isopropyl. (5) (5-1) in R 5 is hydrogen, C! -C6 alkyl (may have 1 to 3 substituents which are the same or different from substituent group A) or 4 to 6 members containing nitrogen Cyclic compounds. -15-200418858 (5-2) R5 is a compound of hydrogen, alkyl (which may have 1 to 3 substituents which may be the same or different from substituent group A), azetidinyl 'pyrrolidinyl or piperidinyl. (6) (6-1) Among R 4 and R 5, R 4 and R 5 form a 4- to 6-membered nitrogen-containing polycyclic group with adjacent nitrogen atoms (the same or different 1 to 2 may be selected from substituent group B) 2 substituents). (6-2) R 4 and R 5 together with adjacent nitrogen atoms form azetidinyl, piperidinyl, morpholinyl or thiomorpholinyl (these groups may have the same or different 1 to 2 selected from the substituent group B) 2 substituents). (7) A compound in which (6) (6) R6 is hydrogen or alkyl. (7-2) A compound wherein R6 is hydrogen. (8) A compound in which (7-1) R7 in R7 is hydrogen or an alkyl group. (8-2) A compound wherein R7 is hydrogen or methyl. (8-3) A compound wherein R7 is hydrogen. (9) In R8, (9-1) R8 is hydrogen, a C1-C3 group, a C1-C3 group, and a benzyl group (there may be 1 to 2 substitutions which are the same or different from the substituent group B) Group), (Ci-C3 oxo) group, thienyl group, furanyl group or pyridine carbonyl group. (9-2) R8 is hydrogen, benzamidine (there may be 1 or 2 substituents which may be the same or different from the substituent group B), thiophene-2-carbonyl, furan 2--16-200418858 carbonyl or Pyridine-3 -carbonyl compounds. (1 0) A compound in which (10-1) η is 1; (1 1) A compound in which (1 1-1) X is an oxygen atom. Among the above, compounds obtained by any combination of two or more substituents are preferred, such as the following compounds. (1 2) R is a group represented by CONR R5 (in the formula, r4 is hydrogen or 〇- <: 3 alkyl group, R5 is hydrogen, alkyl group (may be the same or different from the substituent group A) 1 to 3 substituents) or 4 to 6-membered nitrogen-containing polycyclic groups), compounds in which R2 is hydrogen, η is 1, X is an oxygen atom or a sulfur atom. (1 3) R1 is a compound represented by the formula CONR4R5 (Wherein R4 is hydrogen, methyl or isopropyl, R5 is hydrogen, alkyl (may have 1 to 3 substituents which may be the same or different from the substituent group A), azetidinyl, pyrrolidinyl Or piperidinyl), compounds in which n is 1, and X is an oxygen atom or a sulfur atom. (1 4) R1 is the group represented by the formula CONR4R5 (where R4 and R5 form a 4 to 6 member nitrogen-containing polycyclic group with adjacent nitrogen atoms (there may be the same or different from the substituent group B) 1 to 2 substituents)), R2 is hydrogen, η is 1, and X is an oxygen or sulfur atom. (1 5) R1 is a group represented by the formula CONR4R5 (wherein R4 and R5 and an adjacent nitrogen atom together form azetidinyl, piperidinyl, morpholinyl, or thiomorpholinyl (these groups may be selected 1 to 200418858 2 substituents which are the same or different from the substituent group B)) A compound in which R2 is hydrogen, n is 1, and x is an oxygen atom or a sulfur atom. (1 6) A compound in which R1 is cyano ', R2 is hydrogen, ^ is 1, and X is an oxygen atom or a sulfur atom. (1 7) R1 is a group represented by the formula CH2NR7R8 (wherein R7 is a hydrogen atom or an alkyl group, R8 is hydrogen, a Ci-c3 alkyl group, and a 3′-yl group) (the group may have a group selected from the substituent group B) The same or different 1 to 2 substituents), (Ci-Cs alkoxy) carbonyl, thiophenecarbonyl, furancarbonyl or pyridinecarbonyl), R2 is hydrogen, η is i, and X is an oxygen atom or a sulfur atom. (1 8) R1 is a group represented by the formula CH2NR7R8 (wherein R7 is a hydrogen atom or a methyl group 'R8 is a hydrogen group and benzylfluorenyl group may have 1 to 2 substitutions which may be the same or different from the substituent group B Compounds), thiophene-2-carbonyl, furan-2-carbonyl or pyridine-3-carbonyl), compounds wherein R2 is hydrogen, n is 1, and X is an oxygen atom or a sulfur atom. The compound (I) of the present invention is specifically exemplified by Tables 1 to 5. However, the compound (I) of the present invention is not limited to the exemplified compounds. In Tables 1 to 5, Me is methyl, Et is ethyl, Pr is propyl, iPr is isopropyl, Bu is butyl, Pen is pentyl, Hex is hexyl, cPr is cyclopropyl, cBu is cyclic Butyl, cPen is cyclopentyl, cHex is cyclohexyl, Azt is azetidinyl, pyr is pyrrolidinyl, Pip is piperidinyl, and Ph is phenyl. The position is the binding position of the sulfur atom. 200418858

(Table 1) OH

Cpd No. X n Position R2 R3 1-1 1-2 ss 1 1 3 3 HHL 1-3 s 1 3 H Et 1-4 s 1 3 H Pr 1-5 s 1 3 H iPr 1-6 s 1 3 H Bu 1-7 s 1 3 H Pen 1-8 s 1 3 H Hex 1-9 s 1 3 H cPr 1-10 s 1 3 H cBu 1-11 s 1 3 H cPen 1-12 s 1 3 H cHex 1-13 s 1 3 Me L 1-14 s 1 3 Me 1-15 s 1 3 Me Et 1-16 s 1 3 Me Pr 1-17 s 1 3 Me iPr 1-18 s 1 3 Me Bu 1-19 s 1 3 Me Pen 1-20 s 1 3 Me Hex 1-21 s 1 3 Me cPr 1-22 s 1 3 Me cBu 1-23 s 1 3 Me cPen 1-24 s 1 3 Me cHex 1-25 s 1 3 Me cHex 1-26 s 2 3 HL 1-27 s 2 3 H 1-28 s 2 3 H Et 1-29 s 2 3 H Pr 1-30 s 2 3 H iPr 1-31 s 2 3 H Bu 1 -32 s 2 3 H Pen 1-33 s 2 3 H Hex 1-34 s 2 3 H cPr 1-35 s 2 3 H cBu 1-36 s 2 3 H cPen 1-37 s 2 3 H cHex 1-38 s 2 3 Me H 1-39 s 2 3 Me Me 1-40 s 2 3 Me Et -19- 200418858 1-41 S 2 3 Me Pr 1-42 S 2 3 Me iPr 1-43 S 2 3 Me Bu 1 -44 S 2 3 Me Pen 1-45 S 2 3 Me Hex 1-46 S 2 3 Me cPr 1-47 S 2 3 Me cBu 1-48 S 2 3 Me cPen 1-49 S 2 3 Me cHex 1-50 S 2 3 Me cHex 1-51 S 3 4 HH 1-52 S 3 4 H Me 1-53 S 3 4 H Et 1-54 S 3 4 H Pr 1-55 S 3 4 H iPr 1-56 S 3 4 H Bu 1-57 S 3 4 H Pen 1-58 S 3 4 H Hex 1-59 S 3 4 H cPr 1-60 S 3 4 H cBu 1- 61 s 3 4 H cPen 1-62 s 3 4 H cHex 1-63 s 3 4 Me L 1-64 s 3 4 Me 1-65 s 3 4 Me Et 1-66 s 3 4 Me Pr 1-67 s 3 4 Me iPr 1-68 s 3 4 Me Bu 1-69 s 3 4 Me Pen 1-70 s 3 4 Me Hex 1-71 s 3 4 Me cPr 1-72 s 3 4 Me cBu 1-73 s 3 4 Me cPen 1-74 s 3 4 Me cHex 1-75 s 3 4 Me cHex 1-76 0 1 3 HH 1-77 0 1 3 H Me 1-78 0 1 3 H Et 1-79 0 1 3 H Pr 1- 80 0 1 3 H iPr 1-81 0 1 3 H Bu 1-82 0 1 3 H Pen 1-83 o 1 3 H Hex 1-84 0 1 3 H cPr 1-85 0 1 3 H cBu 1-86 0 1 3 H cPen 1-87 0 1 3 H cHex 1-88 0 1 3 Me L 1-89 0 1 3 Me 1-90 0 1 3 Me Et

-20- 200418858 1-91 0 1 3 Me Pr 1-92 0 1 3 Me iPr 1-93 〇1 3 Me Bu 1-94 0 1 3 Me Pen 1-95 0 1 3 Me Hex 1-96 〇1 3 Me cPr 1-97 〇1 3 * Me cBu 1-98 0 1 3 Me cPen 1-99 0 1 3 Me cHex 1-100 0 1 3 Me cHex 1-101 0 2 3 HH Bu 102 〇2 3 H Me 1 -103 0 2 3 H Et 1-104 0 2 3 H Pr 1-105 0 2 3 H iPr 1-106 0 2 3 H Bu 1-107 0 2 3 H Pen 1-108 0 2 3 H Hex 1-109 0 2 3 H cPr 1-110 0 2 3 H cBu 1-111 0 2 3 H cPen 1-112 0 2 3 H cHex 1-113 0 2 3 Me H 1-114 0 2 3 Me Me 1-115 0 2 3 Me Et 1-116 0 2 3 Me Pr 1-117 0 2 3 Me iPr 1-118 0 2 3 Me Bu 1-119 0 2 3 Me Pen 1-120 0 2 3 Me Hex 1-121 0 2 3 Me cPr 1-122 0 2 3 Me cBu 1-123 0 2 3 Me cPen 1-124 0 2 3 Me cHex 1-125 0 2 3 Me cHex 1-126 0 3 4 HL 1-127 0 3 4 H 1-128 0 3 4 H Et 1-129 0 3 4 H Pr 1-130 0 3 4 H iPr 1-131 0 3 4 H Bu 1-132 0 3 4 H Pen 1-133 0 3 4 H Hex 1-134 0 3 4 H cPr 1-135 0 3 4 H cBu 1-136 0 3 4 H cPen 1-137 0 3 4 H cHex 1-138 0 3 4 Me H 1-139 0 3 4 Me Me 1-140 0 3 4 Me Et -21- 200418858 1-141 〇 3 4 Me Pr 1-142 〇3 4 Me iPr 1-143 〇3 4 Me Bu M44 〇3 4 Me Pen M45 〇3 4 Me Hex 1-146 〇4 4 Me cPr M47 〇3 4 Me cBu M48 〇3 4 Me cPen 1-149 〇3 4 Me cHex M50 0 3 4 Me cHex (Table 2)

0123456789012345 1 4 00 1 1 11 1 II 11 11 2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2 -2-2-2-2-2- sss lx IX IX IX 1x IX Ίχ IX 1x 1x 11 1x 1x IX 1x ix lx 11 ΊΧ 11 11 1x Ίχ ΊΧ HHHHHHMMMMMEtEtEtEtprprpripipBUHMEtpr

Et Pr iPr Bu Me Et Pr iPr Bu Et Pr iPr Bu Pr iPr Bu iPr Bu Bu CH2CH2〇H CH2CH2〇H CH2CH2OH CH2CH2OH

-22- 200418858 2-26 S 1 3 H iPr ch2ch2oh 2-27 S 1 3 HH CH (CH3) CH2OH 2-28 s 1 3 HH CH (CH2OH) CH2〇H 2-29 s 1 3 HH CH (CH2CH3) CH2OH 2-30 s 1 3 HH CH (CH (CH3) 2) CH2〇H 2-31 s 1 3 HH CH2CH2NH2 2-32 s 1 3 HH CH (CH3) CH2NH2 2-33 s 1 3 HH ch (ch2ch3) ch2nh2 2-34 s 1 3 HH ch (ch (ch3) 2) ch2nh2 2-35 s 1 3 HH CH2COOH 2-36 s 1 3 HH CH (CH3) COOH 2-37 s 1 3 HH CH (CH2〇H) COOH 2-38 s 1 3 HH CH (CH2CH3) COOH 2-39 s 1 3 HH ch (ch (ch3) 2) cooh 2-40 s 1 3 HH CH2CONH2 2-41 s 1 3 HH CH (CH3) CONH2 2 -42 s 1 3 HH CH (CH2OH) CONH2 2-43 s 1 3 HH CH (CH2CH3) CONH2 2-44 s 1 3 HH CH (CH (CH3) 2) CONH2 2-45 s 1 3 HH cPr 2-46 s 1 3 HH cBu 2-47 s 1 3 HH cPen 2-48 s 1 3 HH cHex 2-49 s 1 3 HH 3-Azt 2-50 s 1 3 HH 3-Pyr 2-51 s 1 3 HH 3- Pip 2-52 s 1 3 HH 4-Pip 2-53 s 1 3 HH 2-COOH-Ph 2-54 s 1 3 HH 2-CONHrPh 2-55 s 1 3 HH 3-COOH-Ph 2-56 s 1 3 HH 3-CONH2-Ph 2-57 s 1 3 HH 4-COOH-Ph 2-58 s 1 3 HH 4-CONH2-Ph 2-59 s 1 3 H -CH2CH2CH2- 2-60 s 1 3 H -CH2CH2CH2CH2 -2-61 s 1 3 H -CH2CH2CH 2CH2CH2- 2-62 s 1 3 H-CH2CH2OCH2CHr 2-63 s 1 3 H -CH2CH2SCH2CH2- 2-64 s 1 3 H -CH2CH2NHCH2CH2- 2-65 s 1 3 H -CH2CH (OH) CH2- 2-66 s 1 3 H -CH2CH (OH) CH2CH2- 2-67 s 1 3 H -ch2ch (oh) ch2ch2ch2- 2-68 s 1 3 H -ch2ch2ch (oh) ch2ch2- 2-69 s 1 3 H -CH (C〇0H ) CH2CH2- 2-70 s 1 3 H -CH (CONH2) CH2CH2- 2-71 s 1 3 H -ch (ch2oh) ch2ch2- 2-72 s 1 3 H -ch (ch2nh2) ch2ch2- 2-73 s 1 3 H -CH (COOH) CH2CH2CH2- 2-74 s 1 3 H -ch (conh2) ch2ch2ch2- 2-75 s 1 3 H -ch (ch2oh) ch2ch2ch2- -23- 200418858

2-76 S 1 3 H -CH (CH2NH2) CH2CH2CHr 2-77 S 1 3 H -ch (cooh) ch2ch2ch2ch2- 2-78 s 1 3 H -ch (conh2) ch2ch2ch2ch2- 2-79 s 1 3 H -ch (ch2oh) ch2ch2ch2ch2- 2-80 s 1 3 H -ch (ch2nh2) ch2ch2ch2ch2- 2-81 s 1 3 H -ch2ch (cooh) ch2ch2ch2- 2-82 s 1 3 H -ch2ch (conh2) ch2ch2ch2- 2-83 s 1 3 H -ch2ch (ch2oh) ch2ch2ch2- 2-84 s 1 3 H -ch2ch (ch2nh2) ch2ch2ch2- 2-85 s 1 3 H -ch2ch2ch (cooh) ch2ch2- 2-86 s 1 3 H -CH2CH2CH (CONH2 ) cri2CH2- 2-87 s 1 3 H -CH2CH2CH (CH2OH) CH2CH2- 2-88 s 1 3 H -ch2ch2ch (ch2nh2) ch2ch2- 2-89 s 1 3 Me HH 2-90 s 1 3 Me H Me 2- 91 s 1 3 Me H Et 2-92 s 1 3 Me H Pr 2-93 s 1 3 Me H iPr 2-94 s 1 3 Me H Bu 2-95 s 1 3 Me Me Me 2-96 s 1 3 Me Me Et 2-97 s 1 3 Me Me Pr 2-98 s 1 3 Me Me iPr 2-99 s 1 3 Me Me Bu 2-100 s 1 3 Me Et Et 2-101 s 1 3 Me Et Pr 2-102 s 1 3 Me Et iPr 2-103 s 1 3 Me Et Bu 2-104 s 1 3 Me Pr Pr 2-105 s 1 3 Me Pr iPr 2-106 s 1 3 Me Pr Bu 2-107 s 1 3 Me iPr iPr 2-108 s 1 3 Me iPr Bu 2-109 s 1 3 Me Bu Bu 2-110 s 1 3 Me L CH2CH2OH 2-111 s 1 3 Me CH2CH2OH 2-112 s 1 3 Me Et CH2CH2OH 2-113 s 1 3 Me Pr CH2CH2OH 2-114 s 1 3 Me iPr CH2CH2OH 2-115 s 1 3 Me H CH (CH3) CH2OH 2-116 s 1 3 Me H CH (CH2OH) CH2OH 2-117 s 1 3 Me H CH (CH2CH3) CH2OH 2-118 s 1 3 Me H CH (CH (CH3) 2) CH2〇H 2-119 s 1 3 Me H CH2CH2NH2 2-120 s 1 3 Me H CH (CH3) CH2NH2 2-121 s 1 3 Me H ch (ch2ch3) ch2nh2 2-122 s 1 3 Me H ch (ch (ch3) 2) ch2nh2 2-123 s 1 3 Me H CH2COOH 2-124 s 1 3 Me H CH (CH3) COOH 2-125 s 1 3 Me H CH (CH2OH) COOH 200418858 H CH (CH2CH3) COOH H CH (CH (CH3) 2) COOH H CH2CONH2 H CH (CH3) CONH2 H CH (CH2OH) CONH2 H CH (CH2CH3) CONH2 H ch (ch (ch3) 2) conh2 H cPr H cBu H cPen H cHex H 3-Azt H 3-Pyr H 3-Pip H 4-Pip H 2-COOH-Ph H 2-CONH2 -Ph H 3-COOH-Ph H 3-CONH2-Ph H 4-COOH-Ph H 4-CONH2-Ph 2-126 S 1 3 Me 2-127 S 1 3 Me 2-128 S 1 3 Me 2-129 S 1 3 Me 2-130 s 1 3 Me 2-131 s 1 3 Me 2-132 s 1 3 Me 2-133 s 1 3 Me 2-134 s 1 3 Me 2-135 s 1 3 Me 2-136 s 1 3 Me 2-137 s 1 3 Me 2-138 s 1 3 Me 2-139 s 1 3 Me 2-140 s 1 3 Me 2-141 s 1 3 Me 2-142 s 1 3 Me 2-143 s 1 3 M e 2-144 s 1 3 Me 2-145 s 1 3 Me 2-146 s 1 3 Me 2-147 s 1 3 Me 2-148 s 1 3 Me 2-149 s 1 3 Me 2-150 s 1 3 Me 2-151 s 1 3 Me 2-152 s 1 3 Me 2-153 s 1 3 Me 2-154 s 1 3 Me 2-155 s 1 3 Me 2-156 s 1 3 Me 2-157 s 1 3 Me 2 -158 s 1 3 Me 2-159 s 1 3 Me 2-160 s 1 3 Me 2-161 s 1 3 Me 2-162 s 1 3 Me 2-163 s 1 3 Me 2-164 s 1 3 Me 2- 165 s 1 3 Me 2-166 s 1 3 Me 2-167 s 1 3 Me 2-168 s 1 3 Me 2-169 s 1 3 Me 2-170 s 1 3 Me 2-171 s 1 3 Me 2-172 s 1 3 Me 2-173 s 1 3 Me 2-174 s 1 3 Me 2-175 s 1 3 Me -ch2ch2ch2- -CH2CH2CH2CH2-CH2CH2CH2CH2CH2- -CH2CH20CH2CH2- -CH2CH2SCH2CH2- -CH2CH2NHCH2CH2- -CH2CH (OH) CH2- -CH2CH (OH) CH2CH2- -CH2CH (OH) CH2CH2CHr -CH2CH2CH (OH) CH2CHr -CH (COOH) CH2CH2- -CH (CONH2) CH2CHr -CH (CH2OH) CH2CH2- -ch (ch2nh2) ch2ch2- -CH (COOH ) CH2CH2CH2- -ch (conh2) ch2ch2ch2- -ch (ch2oh) ch2ch2ch2- -ch (ch2nh2) ch2ch2ch2- -ch (cooh) ch2ch2ch2ch2- -ch (conh2) ch2ch2ch2ch2- -CH (CH2OH) CH2CH2CH2CH2-h (ch ch2ch2ch2ch2- -ch2ch (cooh) ch2ch2ch2- -ch2ch (conh2) ch2ch2ch2- -ch2ch (ch2oh) ch2ch2c h2- -CH2CH (CH2NH2) CH2CH2CHr -CH2CH2CH (COOH) CH2CH2- -ch2ch2ch (conh2) ch2ch2- -ch2ch2ch (ch2oh) ch2ch2-

-25- 200418858 2-176 S 1 2-177 S 2 2-178 s 2 2-179 s 2 2-180 s 2 2-181 s 2 2-182 s 2 2-183 s 2 2-184 s 2 2 -185 s 2 2-186 s 2 2-187 s 2 2-188 s 2 2-189 s 2 2-190 s 2 2-191 s 2 2-192 s 2 2-193 s 2 2-194 s 2 2 -195 s 2 2-196 s 2 2-197 s 2 2-198 s 2 2-199 s 2 2-200 s 2 2-201 s 2 2-202 s 2 2-203 s 2 2-204 s 2 2 -205 s 2 2-206 s 2 2-207 s 2 2-208 s 2 2-209 s 2 2-210 s 2 2-211 s 2 2-212 s 2 2-213 s 2 2-214 s 2 2 -215 s 2 2-216 s 2 2-217 s 2 2-218 s 2 2-219 s 2 2-220 s 2 2-221 s 2 2-222 s 2 2-223 s 2 2-224 s 2 2 -225 s 2

3 HH 3 HH 3 H Me 3 H Me 3 H Me 3 H Me 3 H Me 3 H Et 3 H Et 3 H Et 3 H Et 3 H Pr 3 H Pr 3 H Pr 3 H iPr 3 H iPr 3 H Bu 3 3 HHL 3 H Et 3 H Pr 3 H iPr 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 HH 3 HH 3 HH 3 HH

3 Me -CH2CH2CH (CH2NH2) CH2CHr 3 Η H 3 Η H 3 Η H 3 Η H

L

Et

Pr iPr

Bu

Me

Et

Pr iPr

Bu

Et

Pr iPr

Bu

Pr iPr

Bu iPr

Bu

Bu

CH2CH2OH ch2ch2oh

CH2CH2OH

CH2CH2OH

CH2CH2OH

CH (CH3) CH2OH

CH (CH2OH) CH2OH

CH (CH2CH3) CH2OH ch (ch (ch3) 2) ch2oh CH2CH2NH2 CH (CH3) CH2NH2 ch (ch2ch3) ch2nh2 ch (ch (ch3) 2) ch2nh2

CH2COOH

CH (CH3) COOH

CH (CH2OH) COOH

CH (CH2CH3) COOH ch (ch (ch3) 2) cooh CH2CONH2 CH (CH3) CONH2 CH (CH2OH) CONH2 CH (CH2CH3) CONH2 ch (ch (ch3) 2) conh2 cPr cBu cPen cHex 3-Azt

-26- 200418858 2-226 S 2 3 HH 3-Pyr 2-227 S 2 3 HH 3-Pip 2-228 S 2 3 HH 4-Pip 2-229 S 2 3 HH 2-COOH-Ph 2-230 S 2 3 HH 2-CONH2-Ph 2-231 S 2 3 HH 3-COOH-Ph 2-232 S 2 3 HH 3-CONH2-Ph 2-233 S 2 3 HH 4-COOH-Ph 2-234 S 2 3 HH 4-CONH2-Ph 2-235 S 2 3 H -ch2ch2ch2- 2-236 S 2 3 H -CH2CH2CH2CH2- 2-238 S 2 3 H -CH2CH2CH2CH2CH2- 2-238 S 2 3 H -CH2CH2OCH2CH2- 2-239 S 2 3 H -ch2ch2sch2ch2- 2-240 S 2 3 H -CH2CH2NHCH2CH2- 2-241 S 2 3 H -CH2CH (OH) CH2- 2-242 S 2 3 H-ch2ch (oh) ch2ch2- 2-243 S 2 3 H -ch2ch (oh) ch2ch2ch2- 2-244 S 2 3 H -CH2CH2CH (OH) CH2CH2- 2-245 S 2 3 H -CH (COOH) CH2CH2- 2-246 S 2 3 H -ch (conh2) ch2ch2- 2-247 S 2 3 H -ch (ch2oh) ch2ch2- 2-248 S 2 3 H -ch (ch2nh2) ch2ch2- 2-249 S 2 3 H-ch (cooh) ch2ch2ch2- 2-250 S 2 3 H- ch (conh2) ch2ch2ch2- 2-251 s 2 3 H -ch (ch2oh) ch2ch2ch2- 2-252 s 2 3 H -ch (ch2nh2) ch2ch2ch2- 2-253 s 2 3 H -ch (cooh) ch2ch2ch2ch2- 2- 254 s 2 3 H -ch (conh2) ch2ch2ch2ch2- 2-255 s 2 3 H -ch (ch2oh) ch2ch2ch2ch2- 2-256 s 2 3 H -CH (CH2NH2) CH2CH2CH2Clir 2-257 s 2 3 H -CH2CH (COOH) CH2CH2CH2- 2-258 s 2 3 H -ch2ch (conh2) ch2ch2ch2- 2-259 s 2 3 H-CH2CH (CH2OH) CH2CH2CHr 2-260 s 2 3 H -CH2CH (CH2NH2) CH2CH2CHr 2-261 s 2 3 H -CH2CH2CH (COOH) CH2CH2- 2-262 s 2 3 H -CH2CH2CH (CONH2) CH2CHr 2-263 s 2 3 H -CH2CH2CH (CH2OH) CH2CHr 2-264 s 2 3 H -CH2CH2CH (CH2NH2) CH2CHr 2-265 s 2 3 Me HH 2-266 s 2 3 Me H Me 2-267 s 2 3 Me H Et 2-268 s 2 3 Me H Pr 2-269 s 2 3 Me H iPr 2-270 s 2 3 Me H Bu 2-271 s 2 3 Me Me Me 2-272 s 2 3 Me Me Et 2-273 s 2 3 Me Me Pr 2-274 s 2 3 Me Me iPr 2-275 s 2 3 Me Me Bu

-27- 200418858 2-276 S 2 3 Me Et Et 2-277 S 2 3 Me Et Pr 2-278 s 2 3 Me Et iPr 2-279 s 2 3 Me Et Bu 2-280 s 2 3 Me Pr Pr 2 -281 s 2 3 Me Pr iPr 2-282 s 2 3 Me Pr Bu 2-283 s 2 3 Me iPr iPr 2-284 s 2 3 Me iPr Bu 2-285 s 2 3 Me Bu Bu 2-286 s 2 3 Me H CH2CH2OH 2-287 s 2 3 Me Me CH2CH2OH 2-288 s 2 3 Me Et CH2CH2OH 2-289 s 2 3 Me Pr CH2CH2OH 2-290 s 2 3 Me iPr CH2CH2OH 2-291 s 2 3 Me H CH (CH3 ) CH2OH 2-292 s 2 3 Me H CH (CH2〇H) CH2OH 2-293 s 2 3 Me H ch (ch2ch3) ch2oh 2-294 s 2 3 Me H ch (ch (ch3) 2) ch2oh 2-295 s 2 3 Me H CH2CH2NH2 2-296 s 2 3 Me H CH (CH3) CH2NH2 2-297 s 2 3 Me H ch (ch2ch3) ch2nh2 2-298 s 2 3 Me H ch (ch (ch3) 2) ch2nh2 2 -299 s 2 3 Me H CH2COOH 2-300 s 2 3 Me H CH (CH3) COOH 2-301 s 2 3 Me H CH (CH2OH) COOH 2-302 s 2 3 Me H CH (CH2CH3) COOH 2-303 s 2 3 Me H ch (ch (ch3) 2) cooh 2-304 s 2 3 Me H CH2CONH2 2-305 s 2 3 Me H CH (CH3) CONH2 2-306 s 2 3 Me H CH (CH2OH) CONH2 2 -307 s 2 3 Me H CH (CH2CH3) CONH2 2-308 s 2 3 Me H ch (ch (ch3) 2) conh2 2-309 s 2 3 Me H cPr 2-310 s 2 3 M e H cBu 2-311 s 2 3 Me H cPen 2-312 s 2 3 Me H cHex 2-313 s 2 3 Me H 3-Azt 2-314 s 2 3 Me H 3-Pyr 2-315 s 2 3 Me H 3-Pip 2-316 s 2 3 Me H 4-Pip 2-317 s 2 3 Me H 2-COOH-Ph 2-318 s 2 3 Me H 2-CONH2-Ph 2-319 s 2 3 Me H 3 -COOH-Ph 2-320 s 2 3 Me H 3-CONHrPh 2-321 s 2 3 Me H 4-COOH-Ph 2-322 s 2 3 Me H 4-CONH2-Ph 2-323 s 2 3 Me -CH2CH2CH2 -2-324 s 2 3 Me -CH2CH2CH2CH2- 2-325 s 2 3 Me -CH2CH2CH2CH2CH2-

-28- 200418858 2-326 2-327 2-328 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 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 ssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss 22222222222222222222222222233333333333333333333333333 33333333333333333333333333344444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444

Me -CH2CH2OCH2CH2-

Me -CH2CH2SCH2CHr

Me -CH2CH2NHCH2CH2-

Me -CH2CH (OH) CH2-

Me -CH2CH (OH) CH2CHr

Me _CH2CH (OH) CH2CH2CHr

Me -CH2CH2CH (OH) CH2CH2-

Me -CH (COOH) CH2CH2-

Me -CH (CONH2) CH2CH2-

Me -CH (CH2OH) CH2CH2-

Me -CH (CH2NH2) CH2CH2-

Me -CH (COOH) CH2CH2CH2-

Me -CH (CONH2) CH2CH2CH2-

Me -CH (CH2OH) CH2CH2CH2-

Me-CH (CH2NH2) CH2CH2CH2-

Me -CH (COOH) CH2CH2CH2CH2-

Me -CH (CONH2) CH2CH2CH2CH2-

Me -CH (CH2OH) CH2CH2CH2CH2-

Me -CH (CH2NH2) CH2CH2CH2CHr

Me -CH2CH (COOH) CH2CH2CH2-

Me -CH2CH (CONH2) CH2CH2CH2-

Me -CH2CH (CH2OH) CH2CH2CH2-

Me -CH2CH (CH2NH2) CH2CH2CHr

Me -CH2CH2CH (COOH) CH2CH2-

Me -CH2CH2CH (CONH2) CH2CH2-

Me -CH2CH2CH (CH2OH) CH2CH2-

Me -CH2CH2CH (CH2NH2) CH2CH2-

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

Η H CH2CH2OH

H Me CH2CH2OH -29- 200418858 2-376 S 3 4 H Et ch2ch2oh 2-377 S 3 4 H Pr ch2ch2oh 2-378 s 3 4 H iPr ch2ch2oh 2-379 s 3 4 HH CH (CH3) CH2〇H 2- 380 s 3 4 HH CH (CH20H) CH20H 2-381 s 3 4 HH CH (CH2CH3) CH2OH 2-382 s 3 4 HH CH (CH (CH3) 2) CH2〇H 2-383 s 3 4 HH CH2CH2NH2 2- 384 s 3 4 HH CH (CH3) CH2NH2 2-385 s 3 4 HH ch (ch2ch3) ch2nh2 2-386 s 3 4 HH ch (ch (ch3) 2) ch2nh2 2-387 s 3 4 HH CH2COOH 2-388 s 3 4 HH CH (CH3) COOH 2-389 s 3 4 HH CH (CH20H) C00H 2-390 s 3 4 HH CH (CH2CH3) COOH 2-391 s 3 4 HH CH (CH (CH3) 2) COOH 2- 392 s 3 4 HH CH2CONH2 2-393 s 3 4 HH CH (CH3) CONH2 2-394 s 3 4 HH CH (CH2OH) CONH2 2-395 s 3 4 HH CH (CH2CH3) CONH2 2-396 s 3 4 HH CH (CH (CH3) 2) CONH2 2-397 s 3 4 HH cPr 2-398 s 3 4 HH cBu 2-399 s 3 4 HH cPen 2-400 s 3 4 HH cHex 2-401 s 3 4 HH 3-Azt 2-402 s 3 4 HH 3-Pyr 2-403 s 3 4 HH 3-Pip 2-404 s 3 4 HH 4-Pip 2-405 s 3 4 HH 2-COOH-Ph 2-406 s 3 4 HH 2 -CONH2-Ph 2-407 s 3 4 HH 3-COOH-Ph 2-408 s 3 4 HH 3-CONH2-Ph 2-409 s 3 4 HH 4-COOH-Ph 2-410 s 3 4 HH 4-CONH2-Ph 2-411 s 3 4 H -CH2CH2CH2- 2-412 s 3 4 H -CH2CH2CH2CH2- 2-413 s 3 4 H -CH2CH2CH2CH2CH2- 2-414 s 3 4 H -CH2CH2OCH2CH2- 2 -415 s 3 4 H -CH2CH2SCH2CH2- 2-416 s 3 4 H -CH2CH2NHCH2CH2- 2-417 s 3 4 H -CH2CH (OH) CHr 2-418 s 3 4 H -CH2CH (OH) CH2CH2- 2-419 s 3 4 H -ch2ch (oh) ch2ch2ch2- 2-420 s 3 4 H -ch2ch2ch (oh) ch2ch2- 2-421 s 3 4 H -ch (cooh) ch2ch2- 2-422 s 3 4 H -ch (conh2) ch2ch2- 2-423 s 3 4 H -ch (ch2oh) ch2ch2- 2-424 s 3 4 H -ch (ch2nh2) ch2ch2- 2-425 s 3 4 H -CH (COOH) CH2CH2CH2- -30- 200418858 2- 426 S 3 4 H 2-427 S 3 4 H 2-428 s 3 4 H 2-429 s 3 4 H 2-430 s 3 4 H 2-431 s 3 4 H 2-432 s 3 4 H 2-433 s 3 4 H 2-434 s 3 4 H 2-435 s 3 4 H 2-436 s 3 4 H 2-437 s 3 4 H 2-438 s 3 4 H 2-439 s 3 4 H 2-440 s 3 4 H 2-441 s 3 4 Me 2-442 s 3 4 Me 2-443 s 3 4 Me 2-444 s 3 4 Me 2-445 s 3 4 Me 2-446 s 3 4 Me 2-447 s 3 4 Me 2-448 s 3 4 Me 2-449 s 3 4 Me 2-450 s 3 4 Me 2-451 s 3 4 Me 2-452 s 3 4 Me 2-453 s 3 4 Me 2-454 s 3 4 Me 2-455 s 3 4 Me 2-456 s 3 4 Me 2-457 s 3 4 Me 2-458 s 3 4 Me 2-459 s 3 4 Me 2-460 s 3 4 Me 2-461 s 3 4 Me 2-462 s 3 4 Me 2-463 s 3 4 Me 2-464 s 3 4 Me 2-465 s 3 4 Me 2-466 s 3 4 Me 2-467 s 3 4 Me 2-468 s 3 4 Me 2-469 s 3 4 Me 2-470 s 3 4 Me 2 -471 s 3 4 Me 2-472 s 3 4 Me 2-473 s 3 4 Me 2-474 s 3 4 Me 2-475 s 3 4 Me -ch (conh2) ch2ch2ch2- -ch (ch2oh) ch2ch2ch2- -ch (ch2nh2) ch2ch2ch2- -ch (cooh) ch2ch2ch2ch2- -ch (conh2) ch2ch2ch2ch2- -ch (ch2oh) ch2ch2ch2ch2- -CH (CH2NH2) CH2CH2CH2CHr -CH2CH (COOH) CH2CH2CH2- -ch2ch (CH22-CH (CHH2) ) CH2CH2CHr -CH2CH (CH2NH2) CH2CH2CHr -CH2CH2CH (COOH) CH2CH2- -CH2CH2CH (CONH2) CH2CHr -CH2CH2CH (CH2OH) CH2CH2- -CH2CH2CH (CH2NH2) CH2CHr

HHLH Et H Pr H iPr H Bu Me Me Me Et Me Pr Me iPr Me Bu Et Et Et Pr Et iPr Et Bu Pr Pr Pr iPr Pr Bu iPr iPr iPr Bu Bu Bu H CH2CH2OH Me CH2CH2OH Et CH2CH2OH H CH CH2CH2OH iPr CH2CH2OH H CH (CH3) CH2OHH CH (CH2OH) CH2OH H CH (CH2CH3) CH2OH H CH (CH (CH3) 2) CH2OH H CH2CH2NH2 H CH (CH3) CH2NH2 H ch (ch2ch3) ch2nh2 H ch (ch (ch3) 2) ch2nh2 H CH2COOH 200418858 2-476 S 3 4 Me H CH (CH3) COOH 2-477 S 3 4 Me H CH (CH20H) C00H 2-478 s 3 4 Me H CH (CH2CH3) COOH 2-479 s 3 4 Me H ch (ch (ch3) 2) cooh 2-480 s 3 4 Me H CH2CONH2 2-481 s 3 4 Me H CH (CH3) CONH2 2-482 s 3 4 Me H CH (CH2OH) CONH2 2-483 s 3 4 Me H CH (CH2CH3) CONH2 2-484 s 3 4 Me H CH (CH (CH3) 2) CONH2 2-485 s 3 4 Me H cPr 2-486 s 3 4 Me H cBu 2-487 s 3 4 Me H cPen 2-488 s 3 4 Me H cHex 2-489 s 3 4 Me H 3-Azt 2-490 s 3 4 .Me H 3-Pyr 2-491 s 3 4 Me H 3-Pip 2-492 s 3 4 Me H 4-Pip 2-493 s 3 4 Me H 2-COOH-Ph 2-494 s 3 4 Me H 2-CONHrPh 2-495 s 3 4 Me H 3-COOH-Ph 2-496 s 3 4 Me H 3-CONHrPh 2-497 s 3 4 Me H 4-COOH-Ph 2-498 s 3 4 Me H 4-CONHrPh 2-499 s 3 4 Me -CH2CH2CH2- 2-500 s 3 4 Me -CH2CH2CH2CH2- 2-501 s 3 4 Me -CH2CH2CH2CH2CH2- 2-502 s 3 4 Me -CH2CH2OCH2CH2- 2- 503 s 3 4 Me -CH2CH2SCH2CH2- 2-504 s 3 4 Me -CH2CH2NHCH2CH2- 2-505 s 3 4 Me -CH2CH (OH) CH2- 2-506 s 3 4 Me -ch2ch (oh) ch2ch2- 2-507 s 3 4 Me -ch2ch (oh) ch2ch2ch2- 2-508 s 3 4 Me -ch2ch2ch (oh) ch2ch2- 2-509 s 3 4 Me -CH (COOH) CH2CHr 2-510 s 3 4 Me -CH (CONH2) CH2CH2 -2-511 s 3 4 Me -ch (ch2oh) ch2ch2- 2-512 s 3 4 Me -ch (ch2nh2) ch2ch2- 2-513 s 3 4 Me -ch (cooh) ch2ch2ch2- 2-514 s 3 4 Me -ch (conh2) ch2ch2ch2- 2-515 s 3 4 Me -ch (ch2oh) ch2ch2ch2- 2-516 s 3 4 Me -ch (ch2nh2) ch2ch2ch2- 2-517 s 3 4 Me -ch (cooh) ch2ch2ch2ch2- 2 -518 s 3 4 Me -ch (conh2) ch2ch2ch2ch2- 2-519 s 3 4 Me -ch (ch2oh) ch2ch2ch2ch2- 2-520 s 3 4 Me -ch (ch2nh2) ch2ch2ch2ch2_ 2-521 s 3 4 Me -ch2ch ( cooh) ch2ch2ch2- 2-522 s 3 4 Me -ch2ch (conh2) ch2ch2ch2- 2-523 s 3 4 Me -ch2ch (ch2oh) ch2ch2ch2- 2-524 s 3 4 Me -ch2ch (ch2nh2) ch2ch2ch2 · 2-525 s 3 4 Me -CH2CH2CH (COOH) CH2CHr

-32- 200418858

2-526 S 3 4 Me 2-527 S 3 4 Me 2-528 s 3 4 Me 2-529 〇1 3 H 2-530 〇1 3 H 2-531 0 1 3 H 2-532 0 1 3 H 2 -533 〇1 3 H 2-534 0 1 3 H 2-535 0 1 3 H 2-536 0 1 3 H 2-537 0 1 3H 2-538 o 1 3 H 2-539 0 1 3 H 2 -540 0 1 3 H 2-541 0 1 3 H 2-542 0 1 3 H 2-543 0 1 3 H 2-544 0 1 3 H 2-545 0 1 3 H 2-546 0 1 3 H 2- 547 0 1 3 H 2-548 0 1 3 H 2-549 0 1 3 H 2-550 0 1 3 H 2-551 0 1 3 H 2-552 0 1 3 H 2-553 0 1 3 H 2-554 0 1 3 H 2-555 0 1 3 H 2-556 0 1 3 H 2-557 0 1 3 H 2-558 0 1 3 H 2-559 0 1 3 H 2-560 0 1 3 H 2-561 0 1 3 H 2-562 0 1 3 H 2-563 〇1 3 H 2-564 0 1 3 H 2-565 0 1 3 H 2-566 0 1 3 H 2-567 〇 1 3 H 2-568 0 1 3 H 2-569 〇1 3 H 2-570 o 1 3 H 2-571 0 1 3 H 2-572 0 1 3 H 2-573 0 1 3 H 2-574 〇1 3 H 2-575 〇 1 3 H -CH2CH2CH (CONH2) CH2CHr -CH2CH2CH (CH2OH) CH2CH2 Pr Bu iPr iPr iPr Bu Bu Bu H CH2CH2OH Me CH2CH2OH Et CH2CH2OH Pr CH2CH2OH iPr CH2CH2OH H CH (CH3) CH2OH H CH (CH2〇H) CH2OH H CH (CH2CH3) CH2OH H CH (CH (CH3) 2) CH2OH H CH2CH2NH2 H CH (CH3) CH2NH2 H ch (ch2ch3 ) ch2nh2 H ch (ch (ch3) 2) ch2nh2 H CH2COOH H CH (CH3) COOH H CH (CH2OH) COOH H CH (CH2CH3) COOH H CH (CH (CH3) 2) COOH H CH2CONH2 H CH (CH3) CONH2 H CH (CH2OH) CONH2 H CH (CH2CH3) CONH2 H CH (CH (CH3) 2) CONH2 H cPr H cBu H cPen

-33- 200418858 2-576 〇 1 3 Η H cHex 2-577 0 1 3 Η H 3-Azt 2-578 Ο 1 3 Η H 3-Pyr 2-579 0 1 3 Η H 3-Pip 2-580 0 1 3 Η H 4-Pip 2-581 0 1 3 Η H 2-COOH-Ph 2-582 〇1 3 Η H 2-CONHrPh 2-583 ο 1 3 Η H 3-COOH-Ph 2-584 0 1 3 Η H 3-CONHrPh 2-585 ο 1 3 Η H 4-COOH-Ph 2-586 〇1 3 Η H 4-CONH2-Ph 2-587 0 1 3 Η -CH2CH2CH2- 2-588 ο 1 3 Η -CH2CH2CH2CH2 -2-589 〇1 3 Η -CH2CH2CH2CH2CH2- 2-590 ο 1 3 Η -CH2CH2OCH2CH2- 2-591 〇1 3 Η -CH2CH2SCH2CH2- 2-592 ο 1 3 Η -CH2CH2NHCH2CH2- 2-593 ο 1 3 Η -ch2ch (oh) ch2- 2-594 ο 1 3 Η -ch2ch (oh) ch2ch2- 2-595 0 1 3 Η -ch2ch (oh) ch2ch2ch2- 2-596 ο 1 3 Η -CH2CH2CH (OH) CH2CH2- 2-597 0 1 3 Η -CH (COOH) CH2CH2- 2-598 ο 1 3 Η -CH (CONH2) CH2CH2- 2-599 0 1 3 Η -CH (CH2OH) CH2CH2- 2-600 0 1 3 Η -ch (ch2nh2 ) ch2ch2- 2-601 〇1 3 Η -CH (COOH) CH2CH2CH2- 2-602 0 1 3 Η -ch (conh2) ch2ch2ch2- 2-603 ο 1 3 Η -CH (CH2OH) CH2CH2CHr 2-604 0 1 3 Η -ch (ch2nh2) ch2ch2ch2- 2-605 ο 1 3 Η -ch (cooh) ch2ch2ch2ch2- 2-606 0 1 3 Η -CH (CONH 2) CH2CH2CH2Cii2- 2-607 0 1 3 Η -CH (CH2OH) CH2CH2CH2CH2- 2-608 0 1 3 Η • ch (ch2nh2) ch2ch2ch2ch2- 2-609 0 1 3 Η -CH2CH (COOH) CH2CH2CH2- 2-610 0 1 3 Η -ch2ch (conh2) ch2ch2ch2- 2-611 〇1 3 Η -ch2ch (ch2oh) ch2ch2ch2- 2-612 〇1 3 Η -ch2ch (ch2nh2) ch2ch2ch2- 2-613 〇1 3 Η -ch2ch2ch (cooh) ch2ch2- 2-614 〇1 3 Η -CH2CH2CH (CONH2) CH2CHr 2-615 〇1 3 Η -CH2CH2CH (CH2OH) CH2CH2- 2-616 0 1 3 Η -CH2CH2CH (CH2NH2) CH2CHr 2-617 ο 1 3 Me Η H 2-618 〇1 3 Me H Me 2-619 〇1 3 Me H Et 2-620 0 1 3 Me H Pr 2-621 〇1 3 Me H iPr 2-622 〇1 3 Me H Bu 2-623 〇 1 3 Me Me Me 2-624 〇1 3 Me Me Et 2-625 0 1 3 Me Me Pr

-34- 200418858 67890123456789012345678901234567 8 90123456789012 ^ 0 ^ · ^ 62-626262-63-63-63-63-63-63-63-63-63-63-64-64-64-64-64-64-64-64- 64-64-64-65-65-65-65-65-65-65-65-65-65-66-66-66-66-66-66-66-66-66-66-66-66-67-67- 67-67-67-67 2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2 -2-2-2-2-2-2-2-2-2-2-2-2-2-22-2222222222222 0 1 3 Me Me Me iPr 0 1 3 Me Bu 0 1 3 Me Et Et 0 1 3 Me Et Pr 0 1 3 Me Et iPr 0 1 3 Me Et Bu 0 1 3 Me Pr Pr ο 1 3 Me Pr iPr ο 1 3 Me Pr Bu ο 1 3 Me iPr iPr ο 1 3 Me iPr Bu 0 1 3 Me Bu Bu ο 1 3 Me H CH2CH2OH ο 1 3 Me Me CH2CH2OH ο 1 3 Me Et CH2CH2OH ο 1 3 Me Pr CH2CH2OH ο 1 3 Me iPr CH2CH2OH ο 1 3 Me H CH (CH3) CH2OH ο 1 3 Me H CH (CH2 〇H) CH2OH ο 1 3 Me H CH (CH2CH3) CH2OH ο 1 3 Me H CH (CH (CH3) 2) CH2OH ο 1 3 Me H CH2CH2NH2 0 1 3 Me H CH (CH3) CH2NH2 0 1 3 Me H ch (ch2ch3) ch2nh2 0 1 3 Me H ch (ch (ch3) 2) ch2nh2 0 1 3 Me H CH2COOH 0 1 3 Me H CH (CH3) C00H 0 1 3 Me H CH (CH20H) C00H 〇1 3 Me H CH (CH2CH3) COOH 0 1 3 Me H CH (CH (CH3) 2) COOH 0 1 3 Me H CH2CONH2 0 1 3 Me H CH (CH3) CONH2 0 1 3 Me H CH (CH20H) C0NH2 0 1 3 Me H CH (CH2CH3) CONH2 0 1 3 Me H ch (ch (ch3) 2) conh2 0 1 3 Me H cPr 0 1 3 Me H cBu 0 1 3 Me H cPen 0 1 3 Me H cHex 0 1 3 Me H 3-Azt 0 1 3 Me H 3-Pyr 0 1 3 Me H 3-Pip 0 1 3 Me H 4-Pip 0 1 3 Me H 2-C00H-Ph 0 1 3 Me H 2-C0NHrPh 0 1 3 Me H 3-C00NHrPh 0 1 3 Me H 3-C0NHrPh 0 1 3 Me H 4-C00H-Ph 0 1 3 Me H 4 -C0NHrPh 0 1 3 Me -CH2CH2CH2-

-35- 200418858 2-676 0 1 3 Me -CH2CH2CH2CHr 2-677 〇1 3 Me -ch2ch2ch2ch2ch2- 2-678 0 1 3 Me -CH2CH2OCH2CH2- 2-679 0 1 3 Me -CH2CH2SCH2CH2- 2-680 0 1 3 Me -CH2CH2NHCH2CH2- 2-681 0 1 3 Me _CH2CH (OH) CHr 2-682 0 1 3 Me -CH2CH (OH) CH2CH2- 2-683 0 1 3 Me -ch2ch (oh) ch2ch2ch2- 2-684 0 1 3 Me -CH2CH2CH (OH) CH2CHr 2-685 0 1 3 Me -CH (COOH) CH2CH2- 2-686 0 1 3 Me -ch (conh2) ch2ch2- 2-687 0 1 3 Me -ch (ch2oh) ch2ch2- 2- 688 ο 1 3 Me -ch (ch2nh2) ch2ch2- 2-689 ο 1 3 Me -ch (cooh) ch2ch2ch2- 2-690 ο 1 3 Me -ch (conh2) ch2ch2ch2- 2-691 ο 1 3 Me -CH ( CH2OH) CH2CH2CH2- 2-692 ο 1 3 Me -ch (ch2nh2) ch2ch2ch2- 2-693 ο 1 3 Me -ch (cooh) ch2ch2ch2ch2- 2-694 0 1 3 Me -ch (conh2) ch2ch2ch2ch2- 2-695 ο 1 3 Me -ch (ch2oh) ch2ch2ch2ch2- 2-696 0 1 3 Me -CH (CH2NH2) CH2CH2CH2CHr 2-697 ο 1 3 Me -CH2CH (COOH) CH2CH2CH2- 2-698 0 1 3 Me -ch2ch (conh2) ch2ch2ch2 -2-699 ο 1 3 Me -ch2ch (ch2oh) ch2ch2ch2- 2-700 ο 1 3 Me -ch2ch (ch2nh2) ch2ch2ch2- 2-701 ο 1 3 Me -ch2ch2ch (cooh) ch2ch2- 2-702 0 1 3 Me -ch2ch2ch (conh2) c h2ch2- 2-703 0 1 3 Me -ch2ch2ch (ch2oh) ch2ch2- 2-704 ο 1 3 Me -CH2CH2CH (CH2NH2) CH2CHr 2-705 ο 2 3 H Η H 2-706 0 2 3 HH Me 2-707 〇 2 3 HH Et 2-708 ο 2 3 HH Pr 2-709 0 2 3 HH iPr 2-710 ο 2 3 HH Bu 2-711 〇2 3 H Me Me 2-712 〇2 3 H Me Et 2-713 0 2 3 H Me Pr 2-714 〇 2 3 H Me iPr 2-715 〇 2 3 H Me Bu 2-716 ο 2 3 H Et Et 2-717 〇 2 3 H Et Pr 2-718 〇 2 3 H Et iPr 2-719 ο 2 3 H Et Bu 2-720 〇2 3 H Pr Pr 2-721 〇2 3 H Pr iPr 2-722 0 2 3 H Pr Bu 2-723 〇2 3 H iPr iPr 2-724 0 2 3 H iPr Bu 2-725 〇2 3 H Bu Bu -36- 200418858 2-726 0 2 3 Η L ch2ch2oh 2-727 〇2 3 Η ch2ch2oh 2-728 〇2 3 Η Et CH2CH20H 2-729 〇2 3 Η Pr ch2ch2oh 2-730 0 2 3 Η iPr CH2CH20H 2-731 0 2 3 Η Η CH (CH3) CH2OH 2-732 0 2 3 Η Η CH (CH2OH) CH2OH 2-733 0 2 3 Η Η CH (CH2CH3) CH2OH 2-734 0 2 3 Η Η CH (CH (CH3) 2) CH2OH 2-735 0 2 3 Η Η CH2CH2NH2 2-736 0 2 3 Η Η CH (CH3) CH2NH2 2-737 0 2 3 Η ch (ch2ch3 ) ch2nh2 2-738 0 2 3 Η Η ch (ch (ch3) 2) ch2nh2 2-739 0 2 3 Η Η CH2COOH 2-740 0 2 3 Η Η CH (CH3) COOH 2-741 0 2 3 Η Η CH (CH2OH) COOH 2-742 0 2 3 Η ch ch (ch2ch3) co〇h 2-743 0 2 3 Η ch (ch (ch3) 2) cooh 2-744 0 2 3 Η Η CH (CH3) CONH2 2-745 ο 2 3 Η Η CH (CH3) CONH2 2-746 ο 2 3 Η Η CH (CH2OH) CONH2 2-747 ο 2 3 Η Η CH (CH2CH3) CONH2 2-748 ο 2 3 Η Η CH (CH (CH3) 2) CONH2 2-749 0 2 3 Η Η cPr 2-750 0 2 3 Η Η cBu 2-751 0 2 3 Η Η cPen 2-752 0 2 3 Η Η cHex 2-753 0 2 3 Η Η 3-Azt 2-754 0 2 3 Η Η 3-Pyr 2-755 0 2 3 Η Η 3-Pip 2-756 0 2 3 Η Η 4-Pip 2-757 0 2 3 Η Η 2-COOH-Ph 2-758 0 2 3 Η CON 2-CONH2-Ph 2-759 0 2 3 Η Η 3-COOH-Ph 2-760 0 2 3 Η Η 3-CONH2-Ph 2-761 0 2 3 Η Η 4-COOH-Ph 2-762 0 2 3 Η Η 4-CONH2-Ph 2-763 0 2 3 Η -CH2CH2CH2- 2-764 0 2 3 Η -ch2ch2ch2ch2- 2-765 0 2 3 Η -CH2CH2CH2CH2CH2- 2-766 0 2 3 Η -CH2CH2OCH2CH2- 2-767 0 2 3 Η -CH2CH2SCH2CH2- 2-768 0 2 3 Η -CH2CH2NHCH2CH2- 2-769 0 2 3 Η-CH2CH (OH) CH2- 2-770 0 2 3 Η -CH2CH (OH) CH2CH2- 2-771 0 2 3 Η -ch2ch (oh) ch2ch2ch2- 2-772 0 2 3 Η -ch2ch2ch (oh) ch2ch2- 2-773 0 2 3 Η -ch (cooh) ch2ch2- 2-774 0 2 3 Η -ch (conh2) ch2ch2- 2-775 0 2 3 Η > CH (CH2OH) CH2CH2- -37- 200418858 2-776 〇 2 3 Η -ch (ch2nh2) ch2ch2- 2-777 〇 2 3 Η -ch (cooh) ch2ch2ch2- 2-778 〇2 3 Η -ch (conh2) ch2ch2ch2- 2-779 〇 2 3 Η -CH (CH2OH) CH2CH2CHr 2-780 〇2 3 Η -ch (ch2nh2) ch2ch2ch2- 2-781 〇2 3 Η -ch (cooh) ch2ch2ch2ch2- 2-782 〇2 3 Η -CH (CONH2) CH2CH2CH2CHr 2-783 〇2 3 Η -CH (CH2OH) CH2CH2CH2CHr 2-784 0 2 3 Η -CH (CH2NH2) CH2CH2CH2CH2- 2-785 〇2 3 Η -ch2ch (cooh) ch2ch2ch2- 2-786 〇2 3 Η -ch2ch (conh2) ch2ch2ch2- 2-787 〇2 3 Η -CH2CH (CH2OH) CH2CH2CHr 2-788 0 2 3 Η -ch2ch (ch2nh2) ch2ch2ch2- 2-789 ο 2 3 Η -ch2ch2ch (cooh) ch2ch2- 2-790 ο 2 3 Η -ch2ch2ch (conh2) ch2ch2- 2-791 ο 2 3 Η -ch2ch2ch (ch2oh) ch2ch2- 2-792 0 2 3 Η -CH2CH2CH (CH2NH2) CH2CHr 2-793 0 2 3 Me HH 2-794 0 2 3 Me H Me 2-795 ο 2 3 Me H Et 2-796 0 2 3 Me H Pr 2-797 0 2 3 Me H IPr 2-798 0 2 3 Me H Bu 2-799 0 2 3 Me Me Me 2 -800 0 2 3 Me Me Et 2-801 0 2 3 Me Me Pr 2-802 0 2 3 Me Me iPr 2-803 0 2 3 Me Me Bu 2-804 0 2 3 Me Et Et 2-805 0 2 3 Me Et Pr 2-806 0 2 3 Me Et iPr 2-807 0 2 3 Me Et Bu 2-808 0 2 3 Me Pr Pr 2-809 0 2 3 Me Pr iPr 2-810 0 2 3 Me Pr Bu 2-811 0 2 3 Me iPr iPr 2-812 0 2 3 Me iPr Bu 2-813 0 2 3 Me Bu Bu 2-814 0 2 3 Me H CH2CH2OH 2-815 0 2 3 Me Me ch2ch2oh 2-816 0 2 3 Me Et ch2ch2oh 2-817 0 2 3 Me Pr ch2ch2oh 2-818 0 2 3 Me iPr ch2ch2oh 2-819 0 2 3 Me H CH (CH3) CH2OH 2-820 0 2 3 Me H CH (CH2OH) CH2OH 2-821 0 2 3 Me H CH (CH2CH3) CH2OH 2- 822 0 2 3 Me H CH (CH (CH3) 2) CH2OH 2-823 0 2 3 Me H ch2ch2nh2 2-824 0 2 3 Me H CH (CH3) CH2NH2 2-825 0 2 3 Me H ch (ch2ch3) ch2nh2 -38- 200418858 2-826 0 2 3 Me H ch (ch (ch3) 2) ch2nh2 2-827 0 2 3 Me H CH2COOH 2-828 0 2 3 Me H CH (CH3) COOH 2-829 0 2 3 Me H CH (CH2OH) COOH 2-830 〇2 3 Me H ch (ch2ch3) co〇h 2-831 0 2 3 Me H ch (ch (ch3) 2) cooh 2-832 〇2 3 Me H CH2CONH2 2-833 〇2 3 Me H CH (CH3) CONH2 2-834 0 2 3 Me H CH (CH2OH) CONH2 2-835 〇2 3 Me H ch (ch2ch3) conh2 2-8 36 0 2 3 Me H CH (CH (CH3) 2) CONH2 2-837 0 2 3 Me H cPr 2-838 0 2 3 Me H cBu 2-839 0 2 3 Me H cPen 2-840 〇2 3 Me H cHex 2-841 0 2 3 Me H 3-Azt 2-842 0 2 3 Me H 3-Pyr 2-843 〇2 3 Me H 3-Pip 2-844 0 2 3 Me H 4-Pip 2-845 0 2 3 Me H 2-COOH-Ph 2-846 0 2 3 Me H 2-CONH2-Ph 2-847 0 2 3 Me H 3-COOH-Ph 2-848 0 2 3 Me H 3-CONH2-Ph 2-849 0 2 3 Me H 4-COOH ~ Ph 2-850 0 2 3 Me H 4-CONH2-Ph 2-851 0 2 3 Me -CH2CH2CH2- 2-852 0 2 3 Me -CH2CH2CH2CH2- 2-853 0 2 3 Me -CH2CH2CH2CH2CH2- 2-854 0 2 3 Me -CH2CH2OCH2CH2- 2-855 0 2 3 Me -CH2CH2SCH2CH2- 2-856 〇2 3 Me -CH2CH2NHCH2CH2- 2-857 0 2 3 Me -CH2CH (OH) CH2- 2-858 0 2 3 Me -CH2CH (OH) CH2CH2- 2-859 0 2 3 Me -ch2ch (oh) ch2ch2ch2- 2-860 0 2 3 Me -CH2CH2CH (OH; CH2CHr 2-861 0 2 3 Me -CH (COOH) CH2CH2- 2-862 0 2 3 Me -CH (CONH2) CH2CHr 2-863 0 2 3 Me -CH (CH2OH) CH2CHr 2-864 0 2 3 Me -CH (CH2NH2) CH2CHr 2-865 〇2 3 Me -CH (COOH) CH2CH2CH2- 2-866 〇2 3 Me -ch (conh2) ch2ch2ch2- 2-867 〇2 3 Me -CH (CH2OH) CH2CH2CHr 2-868 0 2 3 Me -CH (CH2NH 2) 〇i2CH2CH2- 2-869 〇2 3 Me -CH (COOH) CH2CH2CH2CH2- 2-870 0 2 3 Me -CH (CONH2) CH2CH2CH2CHi2- 2-871 0 2 3 Me -CH (CH2OH) CH2CH2CH2CHr 2-872 〇 2 3 Me -CH (CH2NH2) CH2CH2CH2CH2-2-873 〇 2 3 Me -CH2CH (COOH) CH2CH2CH2- 2-874 0 2 3 Me -CH2CH (CONH2) CH2CH2CHr 2-875 0 2 3 Me -CH2CH (CH2OH) CH2CH2CH2 --39- 200418858 2-876 〇2 2-877 0 2 2-878 0 2 2-879 0 2 2-880 〇2 2-881 〇3 2-882 〇3 2-883 〇3 2-884 〇3 2-885 〇3 2-886 0 3 2-887 0 3 2-888 0 3 2-889 0 3 2-890 0 3 2-891 〇3 2-892 0 3 2-893 0 3 2-894 0 3 2-895 0 3 2-896 0 3 2-897 0 3 2-898 0 3 2-899 0 3 2-900 0 3 2-901 0 3 2-902 0 3 2-903 0 3 2-904 0 3 2-905 0 3 2-906 0 3 2-907 0 3 2-908 0 3 2-909 0 3 2-910 0 3 2-911 0 3 2-912 0 3 2-913 0 3 2-914 0 3 2-915 0 3 2-916 0 3 2-917 0 3 2-918 0 3 2-919 0 3 2-920 0 3 2-921 0 3 2-922 〇3 2-923 0 3 2-924 0 3 2-925 〇 3

4 HH 4 HH 4 HH 4 HH 4 H Me 4 H Me 4 H Me 4 H Me 4 H Me 4 H Et 4 H Et 4 H Et 4 H Et 4 H Pr 4 H Pr 4 H Pr 4 H iPr 4 H iPr 4 H Bu 4 HH 4 H Me 4 H Et 4 H Pr 4 H iPr 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 3 Me -CH2CH (CH2NH2) CH2CH2CHr 3 Me -CH2CH2CH (COOH) CH2CHr 3 Me -CH2CH2CH (CONH2) CH2CH2- 3 Me -CH2CH2CH (CH2OH) CH2CH2- 3 Me -CH2CH2CH (CH2NH2) CH2CHr

4 Η Η H 4 Η H Me

Et

Pr iPr

Bu

Me

Et

Pr iPr

Bu

Et

Pr iPr

Bu

Pr iPr

Bu iPr

Bu

Bu

CH2CH2OH

CH2CH2OH

CH2CH2OH

CH2CH2OH

CH2CH2OH

CH (CH3) CH2OH

CH (CH2OH) CH2OH

CH (CH2CH3) CH2OH

CH (CH (CH3) 2) CH2OH CH2CH2NH2 CH (CH3) CH2NH2 ch (ch2ch3) ch2nh2 ch (ch (ch3) 2) ch2nh2

CH2COOH

CH (CH3) COOH

CH (CH2OH) COOH

CH (CH2CH3) COOH ch (ch (ch3) 2) cooh CH2CONH2 CH (CH3) CONH2 CH (CH2OH) CONH2 CH (CH2CH3) CONH2 CH (CH (CH3) 2) CONH2 cPr

-40- 200418858 2-926 0 3 4 Η H cBu 2-927 0 3 4 Η H cPen 2-928 〇 3 4 Η H cHex 2-929 〇3 4 Η H 3-Azt 2-930 〇3 4 Η H 3-Pyr 2-931 〇3 4 Η H 3-Pip 2-932 〇3 4 ΗH 4-Pip 2-933 〇3 4 ΗH 2-COOH-Ph 2-934 〇3 4 ΗH 2-CONH2- Ph 2-935 0 3 4 Η H 3-COOH-Ph 2-936 ο 3 4 Η H 3-CONHrPh 2-937 ο 3 4 Η H 4-COOH-Ph 2-938 0 3 4 Η H 4-CONH2- Ph 2-939 ο 3 4 Η -ch2ch2ch2- 2-940 〇3 4 Η -CH2CH2CH2CH2- 2-941 ο 3 4 Η -CH2CH2CH2CH2CH2- 2-942 ο 3 4 Η -CH2CH2OCH2CH2- 2-943 0 3 4 Η -CH2CH2SCH2CH2 -2-944 0 3 4 Η -CH2CH2NHCH2CH2- 2-945 0 3 4 Η -CH2CH (OH) CH2- 2-946 〇3 4 Η -CH2CH (OH) CH2CH2- 2-947 0 3 4 Η -CH2CH (OH ) CH2CH2CHr 2-948 0 3 4 Η -CH2CH2CH (OH) CH2CHr 2-949 ο 3 4 Η -ch (cooh) ch2ch2- 2-950 0 3 4 Η -CH (CONH2) CH2CH2- 2-951 0 3 4 Η -ch (ch2oh) ch2ch2- 2-952 0 3 4 Η -ch (ch2nh2) ch2ch2- 2-953 ο 3 4 Η -ch (cooh) ch2ch2ch2- 2-954 ο 3 4 Η -ch (conh2) ch2ch2ch2- 2 -955 0 3 4 Η ch (ch2oh) ch2ch2ch2_ 2-956 〇3 4 Η -ch (ch2nh2) ch2ch2ch2- 2-957 0 3 4 -ch (cooh) ch2ch2ch2ch2- 2-958 〇3 4 Η -ch (conh2) ch2ch2ch2ch2- 2-959 ο 3 4 Η -ch (ch2oh) ch2ch2ch2ch2- 2-960 〇3 4 Η -CH (CH2NH2) CH2CH2CH2CHr 2- 961 〇3 4 Η • CH2CH (COOH) CH2CH2CH2- 2-962 〇3 4 Η -ch2ch (conh2) ch2ch2ch2- 2-963 〇3 4 Η-ch2ch (ch2oh) ch2ch2ch2- 2-964 ο 3 4 Η-CH2CH ( CH2NH2) CH2CH2CHr 2-965 〇3 4 Η -CH2CH2CH (COOH) CH2CH2- 2-966 〇3 4 Η -CH2CH2CH (CONH2) CH2CHr 2-967 〇3 4 Η -CH2CH2CH (CH2OH) CH2CHr 2-968 ο 3 4 Η -CH2CH2CH (CH2NH2) CH2CHr 2-969 〇3 4 Me Η H 2-970 〇3 4 Me H Me 2-971 0 3 4 Me H Et 2-972 〇3 4 Me H Pr 2-973 0 3 4 Me H iPr 2-974 0 3 4 Me H Bu 2-975 〇3 4 Me Me Me -41- 200418858 2-976 〇3 4 Me Me Et 2-977 〇3 4 Me Me Pr 2-978 〇3 4 Me Me iPr 2-979 〇3 4 Me Me Bu 2-980 〇3 4 Me Et Et 2-981 Ο 3 4 Me Et Pr 2-982 Ο 3 4 Me Et iPr 2-983 0 3 4 Me Et Bu 2-984 〇3 4 Me Pr Pr 2-985 Ο 3 4 Me Pr iPr 2-986 0 3 4 Me Pr Bu 2-987 Ο 3 4 Me iPr iPr 2-988 Ο 3 4 Me iPr Bu 2-989 Ο 3 4 Me Bu Bu 2 -990 Ο 3 4 M e L CH2CH2〇H 2-991 〇3 4 Me ch2ch2oh 2-992 Ο 3 4 Me Et ch2ch2oh 2-993 Ο 3 4 Me Pr ch2ch2oh 2-994 Ο 3 4 Me iPr ch2ch2oh 2-995 Ο 3 4 Me H CH ( CH3) CH2OH 2-996 Ο 3 4 Me H CH (CH2OH) CH2OH 2-997 0 3 4 Me H CH (CH2CH3) CH2OH 2-998 0 3 4 Me H CH (CH (CH3) 2) CH2OH 2-999 Ο 3 4 Me H CH2CH2NH2 2-1000 0 3 4 Me H CH (CH3) CH2NH2 2-1001 0 3 4 Me H ch (ch2ch3) ch2nh2 2-1002 0 3 4 Me H CH (CH (CH3) 2) CH2NH2 2- 1003 0 3 4 Me H ch2cooh 2-1004 ο 3 4 Me H CH (CH3) COOH 2-1005 0 3 4 Me H CH (CH2OH) COOH 2-1006 0 3 4 Me H CH (CH2CH3) COOH 2-1007 ο 3 4 Me H ch (ch (ch3) 2) cooh 2-1008 ο 3 4 Me H CH (CH3) CONH2 2 -1010 0 3 4 Me H CH (CH2OH) CONH2 2- 1011 0 3 4 Me H CH (CH2CH3) CONH2 2-1012 0 3 4 Me H ch (ch (ch3) 2) conh2 2-1013 0 3 4 Me H cPr 2-1014 0 3 4 Me H cBu 2-1015 0 3 4 Me H cPen 2-1016 ο 3 4 Me H cHex 2-1017 ο 3 4 Me H 3-Azt 2-1018 0 3 4 Me H 3-Pyr 2-1019 0 3 4 Me H 3-Pip 2-1020 ο 3 4 Me H 4-Pip 2-1021 ο 3 4 Me H 2-COOH-Ph 2-1022 0 3 4 Me H 2-CONHrPh 2-1023 ο 3 4 Me H 3-COOH-Ph 2-1024 0 3 4 Me H 3-CONH2-Ph 2-1025 ο 3 4 Me H 4-COOH-Ph -42- 200418858

2-1026 〇3 4 Me H 4-CONHrPh 2-1027 〇3 4 Me -CH2CH2CH2- 2-1028 〇3 4 Me _ch2ch2ch2ch2- 2-1029 〇3 4 Me -CH2CH2CH2CH2CH2- 2-1030 〇3 4 Me -CH2GH2OCH2CH2- 2-1031 〇3 4 Me -CH2CH2SCH2CH2- 2-1032 〇3 4 Me -CH2CH2NHCH2CH2- 2-1033 〇3 4 Me -CH2CH (OH) CH2- 2-1034 0 3 4 Me -CH2CH (OH) CH2CH2- 2- 1035 〇3 4 Me -ch2ch (oh) ch2ch2ch2- 2-1036 〇3 4 Me -ch2ch2ch (oh) ch2ch2- 2-1037 〇3 4 Me -CH (COOH) CH2CH2- 2-1038 〇3 4 Me -CH ( CONH2) CH2CHr 2-1039 〇3 4 Me -CH (CH2OH) CH2CH2- 2-1040 〇3 4 Me -ch (ch2nh2) ch2ch2- 2-1041 〇3 4 Me -CH (COOH) CH2CH2CH2- 2-1042 〇3 4 Me -ch (conh2) ch2ch2ch2- 2-1043 〇3 4 Me -ch (ch2oh) ch2ch2ch2- 2-1044 0 3 4 Me -CH (CH2NH2) CH2CH2CHr 2-1045 〇3 4 Me -CH (COOH) CH2CH2CH2CH2- 2-1046 〇3 4 Me -ch (conh2) ch2ch2ch2ch2- 2-1047 〇3 4 Me -ch (ch2oh) ch2ch2ch2ch2- 2-1048 〇3 4 Me -ch (ch2nh2) ch2ch2ch2ch2- 2-1049 0 3 4 Me- ch2ch (cooh) ch2ch2ch2- 2-1050 0 3 4 Me -ch2ch (conh2) ch2ch2ch2- 2-1051 〇3 4 Me -CH2CH (CH2OH) CH2CH2CHr 2-1052 〇3 4 Me -ch2ch (ch2nh2) ch2ch2ch2- 2-1053 〇3 4 Me_ch2ch2ch (cooh) ch2ch2- 2 -1054 〇3 4 Me -ch2ch2ch (conh2) ch2ch2- 2-1055 〇3 4 Me -ch2ch2ch (ch2oh) ch2ch2- 2-1056 〇3 4 Me -ch2ch2ch (ch2nh2) ch2ch2- 2-1057 S 1 3 HH CH (CH2 (CH3) 2) CH2OH 2-1058 S 1 3 H h ch (ch2 (ch3) 2) ch2nh2 2-1059 S 1 3 HH CH (CH2 (CH3) 2) COOH 2-1060 S 1 3 HH CH (CH2 (CH3) 2) CONH2 2-1061 S 1 3 HH CH (CH2OH) CH2NH2 2-1062 S 1 3 HH CH ( CH (CH3) CH2CH3) CH2OH 2-1063 S 1 3 H h ch (ch (ch3) ch2ch3) ch2nh2 2-1064 S 1 3 HH CH (CH (CH3) CH2CH3) COOH 2-1065 S 1 3 HH CH (CH (CH3) CH2CH3) CONH2 2 -1066 S 1 3 H Me CH2CH2NH2 2-1067 S 1 3 H Me CH2COOH 2-1068 S 1 3 H Me CH2CONH2 2-1069 S 1 3 H iPr CH2CH2NH2 2-1070 S 1 3 H iPr CH2COOH 2-1071 S 1 3 H iPr CH2CONH2 2-1072 S 1 3 H CH2CH (NH2) CH2 2-1073 S 1 3 H CH2CH (OCH3) CH2 2-1074 S 1 3 H ch2ch (nch3) ch2ch2 2-1075 S 2 3 HH CH (CH2 (CH3) 2) CH2OH -43- 200418858 2-1076 S 2 3 Η Η CH (CH2 (CH3) 2) CH2NH2 2-1077 S 2 3 Η ch (ch2 (ch3) 2) cooh 2-1078 S 2 3 Η Η ch (ch2 (ch3) 2) conh2 2-1079 S 2 3 Η Η CH (CH2OH) CH2NH2 2> 1080 S 2 3 Η ch (ch (ch3) ch2ch3) ch2oh 2-1081 S 2 3 Η ch (ch (ch3) ch2ch3) ch2nh2 2-1082 S 2 3 Η Η CH ( CH (CH3) CH2CH3) COOH 2-1083 S 2 3 Η ch (ch (ch3) ch2ch3) conh2 2-1084 S 2 3 Η Me CH2CH2NH2 2-1085 S 2 3 Η Me CH2COOH 2 -1086 S 2 3 Η Me CH2CONH2 2-1087 S 2 3 Η iPr ch2ch2nh2 2-1088 S 2 3 Η iPr CH2COOH 2-1089 S 2 3 Η iPr CH2CONH2 2-1090 S 2 3 Η CH2CH (NH2) CH2 2-1091 S 2 3 Η CH2CH (OCH3 ) CH2 2-1092 S 2 3 Η ch2ch (nch3) ch2ch2 2-1093 S 3 4 Η H CH (CH2 (CH3) 2) CH2OH 2-1094 S 3 4 Η H ch (ch2 (ch3) 2) ch2nh2 2- 1095 S 3 4 Η H CH (CH2 (CH3) 2) COOH 2-1096 S 3 4 Η H ch (ch2 (ch3) 2) conh2 2-1097 S 3 4 Η H CH (CH2OH) CH2NH2 2-1098 S 3 4 Η H ch (ch (ch3) ch2ch3) ch2oh 2-1099 S 3 4 Η H ch (ch (ch3) ch2ch3) ch2nh2 2-1100 S 3 4 Η H CH (CH (CH3) CH2CH3) COOH 2-1101 S 3 4 Η H ch (ch (ch3) ch2ch3) conh2 2-1102 S 3 4 Η Me CH2CH2NH2 2-1103 S 3 4 Η Me CH2COOH 2-1104 S 3 4 Η Me CH2CONH2 2-1105 S 3 4 Η iPr CH2CH2NH2 2 -1106 S 3 4 Η iPr CH2COOH 2-1107 S 3 4 Η iPr CH2CON H2 2-1108 S 3 4 Η CH2CH (NH2) CH2 2-1109 S 3 4 Η CH2CH (OCH3) CH2 2-1110 S 3 4 Η ch2ch (nch3) ch2ch2 2-1111 0 1 3 Η H CH (CH2 (CH3 ) 2) CH2〇H 2-1112 0 1 3 Η H ch (ch2 (ch3) 2) ch2nh2 2-1113 0 1 3 Η H ch (ch2 (ch3) 2) cooh 2-1114 0 1 3 Η H ch ( ch2 (ch3) 2) conh2 2-1115 0 1 3 Η H CH (CH2OH) CH2NH2 2-1116 0 1 3 Η H ch (ch (ch3) ch2ch3) ch2oh 2-1117 0 1 3 Η H ch (ch (ch3 ) ch2ch3) ch2nh2 2-1118 0 1 3 Η H CH (CH (CH3) CH2CH3) COOH 2-1119 0 1 3 Η H ch (ch (ch3) ch2ch3) conh2 2-1120 0 1 3 Η Me CH2CH2NH2 2-1121 0 1 3 Η Me Me CH2COOH 2-1122 0 1 3 Η CH2CONH2 2-1123 0 1 3 Η iPr CH2CH2NH2 2-1124 0 1 3 Η iPr CH2COOH 2-1125 0 1 3 Η iPr CH2CONH2 200418858 2-1126 2-1127 2 -1128 2-1129 2-1130 2-1131 2-1132 2-1133 2-1134 2-1135 2-1136 2-1137 2-1138 2-1139 2-1140 2-1141 2-1142 2-1143 2-1144 2-1145 2-1146 2-1147 2-1148 2-1149 2-1150 2-1151 2-1152 2-1153 2-1154 2-1155 2-1156 2-1157 2-1158 2-1159 2-1160 2- 1161 2-1162 2-1163 2-1164 111222222222222222222333333333333333333 0000000〇0000000000000000000000000000000 3 Η CH2CH (NH2) CH2 3 Η CH2CH (OCH3) CH2 3 Η ch2ch (nch3) ch2ch2 3 Η Η ch (ch2 (ch3) 2) ch2oh 3 Η Η ch (ch2 (ch3) 2) ch2nh2 3 Η ch ( ch2 (ch3) 2) cooh 3 Η ch (ch2 (ch3) 2) conh2 3 3 Η CH (CH2OH) CH2NH2 3 Η ch (ch (ch3) ch2ch3) ch2oh 3 Η ch (ch (ch3) ch2ch3) ch2nh2 3Η Η CH (CH (CH3) CH2CH3) COOH 3 Η CH2CH (NH2) CH2 3 Η CH2CH (OCH3) CH2 3 Η ch2ch (nch3) ch2ch2 4 Η H CH (CH2 (CH3) 2) CH2OH 4 Η H ch (ch2 (ch3) 2) ch2nh2 4 Η H ch (ch2 (ch3) 2) cooh 4 Η H ch (ch2 (ch3) 2) conh2 4 Η H CH (CH2OH) CH2NH2 4 Η H ch (ch (ch3) ch2ch3) ch2oh 4 Η H ch (ch (ch3) ch2ch3) ch2nh2 4 Η H CH (CH (CH3) CH2CH3) COOH 4 Η H ch (ch (ch3) ch2ch3) conh2 4 ΗMe CH2CH2NH2 4 ΗMe CH2COOH 4 ΗMe CH2CONH2 4 CH2CH (NH2) CH2 4 Η CH2CH (OCH3) CH2 4 Η ch2ch (nch3) ch2ch2 -45- 200418858 (Table 3)

(1-3)

C〇〇H

Cpd No. X n Position R2 3-1 S 1 3 H 3-2 s 1 3 Me 3-3 s 2 3 H 3-4 s 2 3 Me 3-5 s 3 4 H 3-6 s 3 4 Me 3 -7 0 1 3 H 3-8 〇1 3 Me 3-9 〇2 3 H 3-10 0 2 3 Me 3-11 〇3 4 H 3-12 〇3 4 Me

(Table 4) OH Η, ί t1 H .CH2OR6 CHs-H- r (1-4) -N —— ^ \, '' x〆, R2 COOH Cpd No. X n position R2 R6 4-1 S 1 3 H Se 4-2 S 1 3 H 4-3 S 1 3 H Et 4-4 S 1 3 H Pr 4-5 S 1 3 H iPr 4-6 S 1 3 H Bu 4-7 S 1 3 H cPr 4 -8 S 1 3 H cBu 4-9 S 1 3 H cPen 4-10 s 1 3 H cHex 4-11 s 1 3 Me H 4-12 s 1 3 Me Me 4-13 s 1 3 Me Et 4-14 s 1 3 Me Pr 4-15 s 1 3 Me iPr

-46- 200418858 4-16 S 1 3 Me Bu 4-17 S 1 3 Me cPr 4-18 S 1 3 Me cBu 4-19 S 1 3 Me cPen 4-20 S 1 3 Me cHex 4-21 S 2 3 HL 4-22 S 2 3 H 4-23 S 2 3 H Et 4-24 S 2 3 H Pr 4-25 S 2 3 H iPr 4-26 S 2 3 H Bu 4-27 S 2 3 H cPr 4- 28 S 2 3 H cBu 4-29 s 2 3 H cPen 4-30 s 2 3 H cHex 4-31 s 2 3 Me H 4-32 s 2 3 Me Me 4-33 s 2 3 Me Et 4-34 s 2 3 Me Pr 4-35 s 2 3 Me iPr 4-36 s 2 3 Me Bu 4-37 s 2 3 Me cPr 4-38 s 2 3 Me cBu 4-39 s 2 3 Me cPen 4-40 s 2 3 Me cHex 4-41 s 3 4 HH 4-42 s 3 4 H Me 4-43 s 3 4 H Et 4-44 s 3 4 H Pr 4-45 s 3 4 H iPr 4-46 s 3 4 H Bu 4 -47 s 3 4 H cPr 4-48 s 3 4 H cBu 4-49 s 3 4 H cPen 4-50 s 3 4 H cHex 4-51 s 3 4 Me L 4-52 s 3 4 Me 4-53 s 3 4 Me Et 4-54 s 3 4 Me Pr 4-55 s 3 4 Me iPr 4-56 s 3 4 Me Bu 4-57 s 3 4 Me cPr 4-58 s 3 4 Me cBu 4-59 s 3 4 Me cPen 4-60 s 3 4 Me cHex 4-61 0 1 3 H Se 4-62 o 1 3 H 4-63 0 1 3 H Et 4-64 o 1 3 H Pr 4-65 〇1 3 H iPr

-47- 200418858 4-66 0 1 3 Η Bu 4-67 0 1 3 Η cPr 4-68 〇1 3 Η cBu 4-69 0 1 3 Η cPen 4-70 〇1 3 Η cHex 4-71 0 1 3 Me L 4-72 〇1 3 Me 4-73 ο 1 3 Me Et 4-74 ο 1 3 Me Pr 4-75 ο 1 3 Me iPr 4-76 ο 1 3 Me Bu 4-77 ο 1 3 Me cPr 4 -78 ο 1 3 Me cBu 4-79 0 1 3 Me cPen 4-80 〇 1 3 Me cHex 4-81 〇 2 3 HH 4-82 ο 2 3 H Me 4-83 ο 2 3 H Et 4-84 〇 2 3 H Pr 4-85 〇 2 3 H iPr 4-86 ο 2 3 H Bu 4-87 〇 2 3 H cPr 4-88 〇 2 3 H cBu 4-89 〇 2 3 H cPen 4-90 0 2 3 H cHex 4-91 0 2 3 Me L 4-92 0 2 3 Me 4-93 0 2 3 Me Et 4-94 0 2 3 Me Pr 4-95 0 2 3 Me iPr 4-96 0 2 3 Me Bu 4 -97 ο 2 3 Me cPr 4-98 〇 2 3 Me cBu 4-99 〇 2 3 Me cPen 4-100 0 2 3 Me cHex 4-101 0 3 4 HL 4-102 〇3 4 H 4-103 ο 3 4 H Et 4-104 0 3 4 H Pr 4-105 〇3 4 H iPr 4-106 0 3 4 H Bu 4-107 〇3 4 H cPr 4-108 〇3 4 H cBu 4-109 0 3 4 H cPen 4-110 〇3 4 H cHex 4-111 0 3 4 Me H 4-112 0 3 4 Me Me 4-113 〇3 4 Me Et 4-114 0 3 4 Me Pr 4-115 0 3 4 Me iPr

-48- 200418858 4-116 0 3 4 Me Bu 4-117 0 3 4 Me cPr 4-118 0 3 4 Me cBu 4-119 〇 3 4 Me cPen 4-120 〇 3 4 Me cHex (Table 5)

0123456789012345678901 123456789111111111122122222222233 I I I II I-I I I I-I I I I I I-I I I-1 I I-5555555555555555555555555555555555 sssssssssssssssssssssssssssssssssssssssss 1X 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x 1x

HHHHH Me HH Et HH C0CH3 HH COCH2CH3 HH COCH2CH2CH3 HH COPh HH COOMe HH COOEt H Me Me H Et Et H Me COCH3 H Me COPh H Me COOMe H Me COOEt Me HH Me H Me Me H Et Me H COCH3 Me H COCH2CH COCH2CH2CH3 Me H COPh Me H COOMe Me H COOEt Me Me Me Me Et Et Me Me COCH3 Me Me COPh Me Me COOMe Me Me COOEt HHH -49- 200418858 5-32 S 2 3 HH Me 5-33 S 2 3 HH Et 5 -34 S 2 3 HH COCH3 5-35 S 2 3 HH COCH2CH3 5-36 S 2 3 HH COCH2CH2CH3 5-37 S 2 3 HH COPh 5-38 S 2 3 HH COOMe 5-39 S 2 3 HH COOEt 5-40 S 2 3 H Me Me 5-41 S 2 3 H Et Et 5-42 S 2 3 H Me COCH3 5-43 S 2 3 H Me COPh 5-44 S 2 3 H Me COOMe 5-45 S 2 3 H Me COOEt 5-46 S 2 3 Me HL 5-47 S 2 3 Me H 5-48 S 2 3 Me H Et 5-49 s 2 3 Me H COCH3 5-50 s 2 3 Me H COCH2CH3 5-51 s 2 3 Me H COCH2CH2CH3 5-52 s 2 3 Me H COPh 5-53 s 2 3 Me H COOMe 5-54 s 2 3 Me H COOEt 5-55 s 2 3 Me Me Me 5-56 s 2 3 Me Et Et 5- 57 s 2 3 Me Me COCH3 5-58 s 2 3 Me Me COPh 5-59 s 2 3 Me Me COOMe 5-60 s 2 3 Me Me COOEt 5-61 s 3 4 HH Se 5-62 s 3 4 HH 5-63 s 3 4 HH Et 5-64 s 3 4 HH COCH3 5-65 s 3 4 HH COCH2CH3 5-66 s 3 4 HH COCH2CH2CH3 5- 67 s 3 4 HH COPh 5-68 s 3 4 HH COOMe 5-69 s 3 4 HH COOEt 5-70 s 3 4 H Me Me 5-71 s 3 4 H Et Et 5-72 s 3 4 H Me COCH3 5 -73 s 3 4 H Me COPh 5-74 s 3 4 H Me COOMe 5-75 s 3 4 H Me COOEt 5-76 s 3 4 Me HL 5-77 s 3 4 Me H 5-78 s 3 4 Me H Et 5-79 s 3 4 Me H COCH3 5-80 s 3 4 Me H COCH2CH3 5-81 s 3 4 Me H COCH2CH2CH3 200418858 5-82 S 3 4 Me H COPh 5-83 S 3 4 Me H COOMe 5-84 S 3 4 Me H COOEt 5-85 S 3 4 Me Me Me 5-86 S 3 4 Me Et Et 5-87 S 3 4 Me Me COCH3 5-88 S 3 4 Me Me COPh 5-89 S 3 4 Me Me COOMe 5-90 S 3 4 Me Me COOEt 5-91 0 1 3 HHL 5-92 0 1 3 HH 5-93 0 1 3 HH Et 5-94 〇1 3 HH COCH3 5-95 0 1 3 HH COCH2CH3 5- 96 0 1 3 HH COCH2CH2CH3 5-97 0 1 3 HH COPh 5-98 0 1 3 HH COOMe 5-99 0 1 3 HH COOEt 5-100 o 1 3 H Me Me 5-101 0 1 3 H Et Et 5- 102 0 1 3 H Me COCH3 5-103 0 1 3 H Me COPh 5-104 o 1 3 H Me COOMe 5-105 0 1 3 H Me COOEt 5-106 0 1 3 Me HL 5-107 0 1 3 Me H 5-108 0 1 3 Me H Et 5-109 0 1 3 Me H COCH3 5-110 0 1 3 Me H COCH2CH3 5-111 0 1 3 Me H COCH2CH2CH3 5-112 0 1 3 Me H COPh 5-113 0 1 3 Me H COOMe 5-114 0 1 3 Me H COOEt 5-115 0 1 3 Me Me Me 5-116 0 1 3 Me Et Et 5-117 0 1 3 Me Me COCH3 5-118 0 1 3 Me Me COPh 5-119 0 1 3 Me Me COOMe 5-120 0 1 3 Me Me COOEt 5-121 0 2 3 HHH 5-122 0 2 3 HH Me 5-123 0 2 3 HH Et 5-124 0 2 3 HH COCH3 5-125 0 2 3 HH COCH2CH3 5-126 0 2 3 HH COCH2CH2CH3 5-127 0 2 3 HH COPh 5-128 0 2 3 HH COOMe 5-129 0 2 3 HH COOEt 5-130 0 2 3 H Me Me 5-131 0 2 3 H Et Et 200418858 5-132 5-133 5-134 5-135 5-136 5-137 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 5-163 5-164 5-165 5-167 5-168 5-169 5-170 5 > 171 5-172 5-173 5-174 5-175 5-176 5-177 5-178 5-179 5-180 5-181 5-182

Ie [e [e [efttt! Et [e [e [e [eeeeeeeeeee MMMMHHHHHHHHHMEMMMMHHHHHHHHHMEtMMMMHHHHHHHHHMEtMMMMH [leleleleleleleleIeIe [e [e [e [e [eteeeeeeeeeeeeeee hhhhmmmmmmmmmmmmmmmhhhhhhhhhhhhhhhmmmmmmmmmmmmmmmh 33333333333333333334444444444444444444444444444443 22222222222222222223333333333333333333333333333331 〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇 000000000000000000000000000000000000000000 coch3 COPh COOMe COOEt

L

Et COCH3 COCH2CH3 COCH2CH2CH3 COPh COOMe COOEt

Me

Et COCH3 COPh COOMe φ COOEt

L

Et COCH3 COCH2CH3 COCH2CH2CH3 COPh COOMe COOEt

Me

Et COCH3 COPh COOMe COOEt

H

Me

Et COCH3 COCH2CH3 COCH2CH2CH3 COPh COOMe COOEt

Me

Et COCH3 COPh COOMe COOEt CO-cPr -52- 200418858

5-183 S 1 3 HH 5-184 S 1 3 HH 5-185 s 1 3 HH 5-186 s 1 3 HH 5-187 s 1 3 HH 5-188 s 1 3 HH 5-189 s 1 3 HH 5 -190 s 1 3 HH 5-191 s 1 3 HH 5-192 s 1 3 HH 5-193 s 1 3 HH 5-194 s 1 3 HH 5-195 s 1 3 HH 5-196 s 1 3 HH 5- 197 s 1 3 HH 5-198 s 1 3 HH 5-199 s 1 3 HH 5-200 s 1 3 HH 5-201 s 1 3 HH 5-202 s 1 3 HH 5-203 s 1 3 HH 5-204 s 2 3 HH 5-205 s 2 3 HH 5-206 s 2 3 HH 5-207 s 2 3 HH 5-208 s 2 3 HH 5-209 s 2 3 HH 5-210 s 2 3 HH 5-211 s 2 3 HH 5-212 s 2 3 HH 5-213 s 2 3 HH 5-214 s 2 3 HH 5-215 s 2 3 HH 5-216 s 2 3 HH 5-217 s 2 3 HH 5-218 s 2 3 HH 5-219 s 2 3 HH 5-220 s 2 3 HH 5-221 s 2 3 HH 5-222 s 2 3 HH 5-223 s 2 3 HH 5-224 s 2 3 HH 5-225 s 2 3 HH 5-226 s 3 4 HH 5-227 s 3 4 HH 5-228 s 3 4 HH 5-229 s 3 4 HH 5-230 s 3 4 HH 5-231 s 3 4 HH 5-232 s 3 4 HH CO-cBu CO-cPen CO-cHex CO-2-thienyl CO-2-furyl CO-2-pyridyl CO-3-pyridyl CO-4-pyridyl SOrPh

CO-Ph-2-COOH CO-Ph-2-CONH2

CO-Ph-2-CH2OH CO-Ph-2-CH2NH2

COPh-3-COOH CO-Ph-3-CONH2

CO-Ph-3-CH2〇H CO-Ph-3-CH2NH2 CO-Ph-4-COOH · CO-Ph-4-CONH2

CO-Ph-4-CH2〇H CO-Ph-4-CH2NH2 CO-cPr CO-cBu CO-cPen CO-cHex CO-2-thienyl CO-2-furyl CO-2-pyridyl CO-3-pyridyl CO- 4-pyridyl SOrPh

CO-Ph-2-COOH CO-Ph-2-CONH2 CO-Ph-2-CH2OH · CO-Ph-2-CH2NH2

CO-Ph-3-COOH CO-Ph-3-CONH2

CO-Ph each CH2OH CO-Ph-3-CH2NH2

COPh-4-COOH CO-Ph-4-CONH2

CO-Ph-4-CH2OH CO-Ph-4-CH2NH2 CO-cPr CO-cBu CO-cPen CO-cHex CO-2-thienyl CO-2-furyl CO-2-pyridyl -53- 200418858

5-233 S 3 4 HH 5-234 S 3 4 HH 5-235 S 3 4 HH 5-236 S 3 4 HH 5-237 S 3 4 HH 5-238 S 3 4 HH 5-239 S 3 4 HH 5 -240 S 3 4 HH 5-241 S 3 4 HH 5-242 S 3 4 HH 5-243 S 3 4 HH 5-244 S 3 4 HH 5-245 S 3 4 HH 5-246 S 3 4 HH 5- 247 S 3 4 HH 5-248 0 1 3 HH 5-249 0 1 3 HH 5-250 0 1 3 HH 5-251 0 1 3 HH 5-252 0 1 3 HH 5-253 0 1 3 HH 5-254 0 1 3 HH 5-255 0 1 3 HH 5-256 0 1 3 HH 5-257 0 1 3 HH 5-258 0 1 3 HH 5-259 0 1 3 HH 5-260 0 1 3 HH 5-261 0 1 3 HH 5-262 0 1 3 HH 5-263 0 1 3 HH 5-264 〇1 3 HH 5-265 0 1 3 HH 5-266 〇1 3 HH 5-267 〇1 3 HH 5-268 0 1 3 HH 5-269 0 1 3 HH 5-270 〇2 3 HH 5-271 0 2 3 HH 5-272 o 2 3 HH 5-273 o 2 3 HH 5-274 〇2 3 HH 5-275 0 2 3 HH 5-276 〇2 3 HH 5-277 〇2 .3 HH 5-278 0 2 3 HH 5-279 0 2 3 HH 5-280 0 2 3 HH 5-281 0 2 3 HH 5-282 〇2 3 HH CO-3-pyridyl CO-4-pyridyl S02-Ph

CO-Ph-2-COOH CO-Ph-2-CONH2

CO-Ph-2-CH2OH CO-Ph-2-CH2NH2

CO-Pl > 3-COOH CO-Ph-3-CONH2

CaPh-3-CH2OH CO-Ph-3-CH2NH2

CO-Ph-4-COOH CO-Ph-4-CONH2

CO-Ph-4-CH2OH CO-Ph-4-CH2NH2 CO-cPr CO-cBu CO-cHex CO-2-thienyl CO-2-furyl CO-2-pyridyl CO-3-pyridyl CO-4-pyridyl S02- Ph

CO-Ph-2-COOH CO-Ph-2-CONH2

CO-Ph-2-CH2OH COPh-2-CH2NH2

CO-Ph COOH CO-Ph-3-CONH2

CO-Ph each CH2OH CO-Ph-3-CH2NH2

CO-Ph-4-COOH C〇-Ph-4-CONH2

CO-Ph-4-CH2OH CO-Ph-4-CH2NH2 CO-cPr CO-cBu CO-cPen CO-cHex CO-2-thienyl CO-2-furyl CO-2-pyridyl CO-3-pyridyl CO-4- pyridyl SOrPh

CO-Ph-2-COOH CO-Ph-2-CONH2

CO-Ph-2-CH2〇H

-54- 200418858 5-283 5-284 5-285 5-286 5-287 5-288 5-289 5-290 5-291 5-292 5-293 5-294 5-295 5-296 5-297 5 -298 5-299 5-300 5-301 5-302 5-303 5-304 5-305 5-306 5-307 5-308 5-309 5-310 5-311 5-312 5-313 5-314 5-315 5-316 5-317 5-318 5-319 5-320 5-321 5-322 5-323 5-324 5-325

333333333444444444444444444444 4 333344333344 2222222223333333333333333333333112233112233 OOOOOOOOOOOOOOOOOOOOOOOOOOSSSSSSOOOOOO

Η Η CO-Ph-2-CH2NH2 Η Η CO-Ph-3-COOH Η Η CO-Ph-3-CONH2 Η Η CO-Ph-3-CH2OH Η Η CO-Ph-3-CH2NH2 Η Η CO-Ph -4-COOH Η Η CO-Ph-4-CONH2 Η Η CO-Ph-4-CH2OH Η Η CO-Ph-4-CH2NH2 Η Η CO-cPr Η Η CO-cBu Η Η CO-cPen Η Η CO- cHex Η Η CO-2-thienyl Η Η CO-2-furyl Η Η CO-2-pyridyl Η Η CO-3-pyridyl Η Η CO-4-pyridyl Η Η SOrPh Η Η CO-Ph-2-COOH Η Η CO-Ph-2-CONH2 Η Η CO-Ph-2-CH2OH Η Η CO-Ph-2-CH2NH2 Η Η CO-Ph COOH Η Η CO-Ph-3-CONH2 Η Η CO-Ph-3-CH2OH Η Η CO-Ph-3-CH2NH2 Η Η CO-Ph-4-COOH Η Η CO-Ph-4-CONH2 Η Η CO-Ph-4-CH2OH Η Η CO-Ph-4-CH2NH2 Η CO-CH2CH2- CO Η CO-l, 2-Ph-CO Η CO-CH2CH2-CO Η CO-l, 2-Ph-CO Η CO-CH2CH2-CO Η CO-l, 2-Ph-CO Η CO-CH2CH2-CO Η CO-l, 2-Ph-CO Η CO-CH2CH2-CO Η CO-1,2-Ph-CO Η CO-CH2CH2-CO Η CO-l, 2-Ph-CO Among the compounds exemplified in the table above, For compound numbers 1 -1, 1-2, 1-3, 1-13, 1-14, 1-15, Bu 26, Bu 27, 1-28, 1-38, 1-39 -55- 200418858

, 1-40, 1-51, 1-52, 1-53, 1-63, 1-64 »1-65, 1-76, 1-77, 1-78, 1-88, BU 89, BU 90 , Bu 101, 1-102, 1 -103, 1-113, Bu 114, 1-115 »1-126, 1-127, 1-128, 1-138, 1-139 ^ Bu 140, 2-1, 2-2, 2-7, 2-22, 2-26, 2-31, 2-32, 2-34, 2-35, 2-39, 2-40, 2-44, 2-49, 2- 50, 2-51, 2-52, 2-59, 2-62, 2-63, 2-64, 2-65, 2-89, 2-90, 2-95, 2-110, 2-114, 2-119, 2-120, 2-122, 2-123, 2-127, 2-128, 2-132, 2-137, 2-138, 2-139, 2-140, 2-147, 2- 150, 2-151, 2-152, 2-153, 2-152, 2-177, 2-178, 2-183, 2-198, 2-202, 2-207, 2-208, 2-210, 2-211, 2-215, 2-216, 2-220, 2-225, 2-226, 2-227, 2-228, 2-235, 2-238, 2-239, 2-240, 2- 241, 2-265, 2-266, 2-271, 2-286, 2-290, 2-295, 2-296, 2-298, 2-299, 2-303, 2-304, 2-308, 2-313, 2-314, 2-315, 2-316, 2-323, 2-326, 2-327, 2-328, 2-329, 2-353, 2-354, 2-3 59, 2 -37 4, 2-378, 2-3 83, 2-384, 2-386, 2-387, 2-391, 2-392, 2-396, 2-401, 2-402, 2-403, 2-404 , 2-411, 2-414, 2-415, 2-416, 2-417, 2-441, 2-442, 2-447, 2-462, 2-466, 2-471, 2-472, 2 -474, 2-475, 2-479, 2-480, 2-484, 2-489, 2-490, 2-491, 2-492, 2-499, 2-502, 2-503, 2-504 , 2-505, 2-529, 2-530, 2-535, 2-550, 2-554, 2-559, 2-560, 2-562, 2-563, 2-567, 2-568, 2 -572, 2-577, 2-578, 2-579, 2-580, 2-587 ^ 2-590.59 1, 2-592, 2-593, 2-617, 2-618, 2-623, 2- 638, 2-640, 2-647, 2-648, 2-650, 2-651, 2-655, 2-656, 2-660, 2-665 -56- 200418858

, 2-666, 2-675, 2-678, 2-679, 2-680, 2-681, 2-705, 2-706, 2-711, 2-726, 2-730, 2-73 5, 2-753, 2-754, 2-755, 2-756, 2-763, 2-766, 2-767, 2-768, 2-769, 2-793, 2-794, 2-799, 2- 814, 2-818, 2-823, 2-824, 2-826, 2-827, 2-831, 2-832, 2-836, 2-841, 2-851, 2-854, 2-855, 2-856, 2-857, 2-881, 2-882, 2-8 87, 2-902, 2-906, 2-911, 2-912, 2-914, 2-915, 2-919, 2 -920, 2-924, 2-929, 2-930, 2-931, 2-9 3 2, 2-9 3 9, 2-9 4 2, 2-9 4 3, 2-9 4 4, 2 -9 4 5, 2-969, 2-970, 2-975, 2-990, 2-994, 2-999, 2-1000, 2-1002, 2-1003, 2-1007, 2-1008, 2 -1012, 2-1017, 2-1018, 2-1019, 2-1020, 2-1027, 2-1030, 2-1031, 2-1032, 2-1033, 2-1057, 2-1058, 2-1059 , 2-1060, 2-1063, 2-1064, 2-1065, 2-1066, 2-1067, 2-1068, 2-1069, 2-1070, 2-1071, 2-1072, 2-1073, 2 -1074, 2-1075, 2-1076, 2-1077, 2-1078, 2-1081, 2-1082, 2-1083 , 2-1084, 2-1085, 2-1086, 2-1087, 2-1088, 2-1089, 2-1090, 2-1091, 2-1092, 2] 093, 2-1094, 2-1095, 2-1096, 2-1099, 2-1100, 2-1101, 2-1102, 2-1103, 2-1104, 2-1105, 2-1106, 2-1107, 2-1108, 2-1109, 2- 1110, 2-1111, 2-1112, 2-1113, 2-1114, 2-1117, 2-1118, 2-1119, 2-1120, 2-1121, 2-1122, 2-1123, 2-1124, 2-1125, 2-1126, 2-1127, 2-1128, 2-1129, 2-1130, 2-1131, 2-1132, 2-1135, 2-1136, 2-1137, 2-1138, 2- 1139, 2-1140, 2-1141, 2-1142, 2-1143, 2-1144, 2-1145, 2-1146, 2-1147, 2-1148, 2-1149, 2-1150, 2-1153, 2-1154, 2-1155, 2-1156, 2-1157, 2-1158, 2-1159 -57- 200418858

, 2-1160, 2-1161, 2-1162, 2-1163, 2-1164, 3-1, 3-3, 3-5, 3-7, 3-9, 3-11, 4-1, 4 -2, 4-11, 4-12, 4-21, 4-22, 4-31, 4-32, 4-41, 4-42, 4-51, 4-52, 4-61, 4-62 , 4-71, 4-72, 4-81, 4-82, 4-91, 4-92, 4-101, 4-102, 4-111, 4-112, 5-1, 5-2, 5 -4, 5-7, 5-8, 5-10, 5-12, 5-13, 5-14, 5-16, 5-17, 5-19, 5-22, 5-23, 5-25 , 5-27, 5-28, 5-29, 5-31, 5-32, 5-34, 5-37, 5-38, 5-40, 5-42, 5-43, 5-44, 5 -46, 5-47, 5-49, 5-52, 5-53, 5-55, 5-57, 5-58, 5-59, 5-61, 5-62, 5-64, 5-67 , 5-68, 5-70, 5-72, 5-73, 5-74, 5-76, 5-77, 5-79, 5-82, 5-83, 5-85, 5-87, 5 -88, 5-89, 5-91, 5-92, 5-94, 5-97, 5-98, 5-100, 5-102, 5-103, 5-104, 5-106, 5-107 , 5-109, 5-112, 5-113, 5-115, 5-117, 5-118, 5-119, 5-121, 5-122, 5-124, 5-127, 5-128, 5 -130, 5-132, 5-133, 5-134, 5-136, 5-137, 5-139, 5-142, 5-143, 5-145 , 5-147, 5-148, 5-149, 5-151, 5-152, 5-154, 5-157, 5-158, 5-160, 5-162, 5-163, 5-164, 5 -167, 5-168, 5-170, 5-173, 5-174, 5-176, 5-178, 5-179, 5-180, 5-182, 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, 5-202, 5-203, 5-204, 5-205, 5-206, 5-207, 5-208, 5-209, 5-210, 5-211 , 5-212, 5-213, 5-214, 5-215, 5-216, 5-217, 5-218, 5-219, 5-220, 5-221, 5-222, 5-223, 5 -224, 5-225, 5-226, 5-227, 5-228, 5-229, 5-230, 5-231, 5-232, 5-233 -58- 200418858

, 5-234, 5-235, 5-236, 5-237, 5-238, 5-239, 5-240, 5-24 1, 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, 5-268, 5-269, 5-270, 5-271, 5-272, 5-273, 5-274, 5-275, 5-276, 5-277, 5-278, 5-279, 5-280, 5-281, 5-282, 5- 283, 5-284, 5-285, 5-286, 5-287, 5-288, 5-289, 5-290, 5-291, 5-292, 5-293, 5-294, 5-295, 5-296, 5-297, 5-298, 5-299, 5-300, 5-301, 5-302, 5-303, 5-304, 5-305, 5-306, 5-307, 5- 308, 5-309, 5-310, 5-311, 5-312, 5-313, 5-314, 5-315, 5-316, 5-317, 5-318, 5-319, 5-320, 5-321, 5-322, 5-323, 5-324, 5-325 or 5-326. More preferably, the compound number is 3, 1-28, 1-53, 1-78, 1-103, 1- 128, 2-1, 2-2, 2-7, 2-26, 2-31, 2 -32, 2-34, 2-35, 2-39, 2-40, 2-44, 2-49, 2-50, 2-51, 2-52, 2-59 > 2-62

, 2-63, 2-64, 2-65, 2-529, 2-530, 2-535, 2-554, 2-559, 2-560, 2-562, 2-563, 2-567, 2 -568, 2-572, 2-577, 2-578, 2-579, 2-580, 2-587, 2-590, 2-591, 2-592, 2-593, 2-1057, 2-1058 , 2-1059, 2-1060, 2-1063, 2-1068, 2-1069, 2-1070, 2-1071, 2-1072, 2-1073, 2-1074, 2-1111, 2-1112, 2 -1113, 2-1114, 2-1117, 2-1123, 2-1124, 2-1125, 2-1126, 2-1127, 2-1128, 3-1, 3-3, 3-7, 3-11 , 4-1, 4-2, 4-21, 4-22, 4-41, 4-42, 4-61, 4-62, 4-81, 4-82, 4-101, -59- 200418858 4 -102, 5-1, 5-2, 5-4, 5-7, 5-8, 5-91, 5-92, 5-94, 5-97, 5-98, 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, 5-202, 5-203, 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 -2 65, 5-266, 5-267, 5-268, 5-269, 5-314, 5-315, 5-320 or 5-321. Most preferred are the following compounds. (5 S, 6 S)-2-[1-(4-Aminomethylamidino-1, 3 -thiazol-2-yl) Dammatin d aden-3-yl] thio-6- [(R) -1-residual ethyl] -carbobin-2-ene-3 -carboxylic acid (compound No. 2-1), (5S, 6S) -2_ {l- [4-((lS) -1 -Aminemethyl-2 -methyl-propylaminomethyl) -1,3-thiazole-2 -yl} azetidin-3 -yl} thio-6-[(R) -1 -Ethyl] -Carbonate-Article-3 _ Junic acid (Compound Nos. 2-3 and 4), (5 S, 6 S)-2-[1-(4 -morpholinecarbonyl-1, 3 -thiazole-2 -Yl) azetidin-3 -yl] thio-6-[(R)-1 -hydroxyethyl] -carbobin-2-ene-3 -carboxylic acid (compound No. 2-62) , (5 S, 6 S)-2-[1-(4-aminomethylamidino-1, 3-oxazol-2-yl) azetidin-3 -yl] thio-6-[(R) -1 -Hydroxyethyl] -carbobin-2-ene-3 -carboxylic acid (compound No. 2-529), (5 S, 6 S)-2-[1-(4 -morpholine carbonyl -1,3 -oxazole-2 -yl) azetidin-3 -yl] thio-6-[(R)-1 -hydroxyethyl] -carbon-60- 200418858 pyren-2-ene-3 -Carboxylic acid (compound number 2-590 Compound) or (5S, 6S) -2- {l- [4-((N-methyl-N-aminoformamidinemethyl) aminoformamyl) -1,3-thiazole-2-yl} acyl Butidine-3 -yl-thio-6-[(R) -1 -hydroxyethyl] -carbabien-2-ene-3-carboxylic acid (compound No. 2-No. 10 to No. 8). [Embodiment] The carbinol derivative of the general formula (I) of the present invention can be produced by the methods described in the following methods A and B. [Method A] Method A is a method in which a carbon compound of formula (I I) is reacted with a sulfhydryl compound of formula (I I I) and then deprotected to produce compound (I).

-61- 200418858

OH

OH

(IV) (I) In the formula, R1, R2, X and n are as defined above, L1 is a leaving group, P1 is a carboxy protecting group, and Rb is R1 which may have a protecting group. The "carboxy-protecting group" in P1 is, for example, benzyl, 4-methoxybenzyl, 4-nitrobenzyl or 2-nitrobenzyl which may have a substituent (the substituents are nitro, methyl, and chloro) Or methoxy); benzyl; allyl, 2-chloroallyl, 2-methylallyl, etc., which may have a substituent at the 2-position (the substituent is chlorine or methyl) The above-mentioned pharmacologically acceptable ester-forming group is preferably a benzyl group (particularly 4-nitrobenzyl) which may have a substituent. The "leaving group" in L1 is, for example, a group of the formula -OR11 or -S (〇) R12. R11 is mesylsulfonyl, trifluoromethanesulfonyl, ethylsulfonyl, propanesulfone m-62-, isopropyl CrC4 alkylsulfonyl groups such as sulfonyl or butylsulfonyl; benzenesulfonyl 'tosylsulfonyl or naphthylsulfonyl; c 6-C1 () arylsulfonyl; dimethylphosphoranyl, diethylphosphine Diacyl, dipropylphosphonium, diisopropylphosphonium, dibutylphosphonium, dipentylphosphonium or dihexylphosphonium, etc. di c iC: 6 alkylphosphonium or diphenylphosphonium or Di-C6-C10 arylphosphonium groups such as xylylphosphonium group are preferably diphenylphosphonium groups. R 12 is Ci-C4 alkyl such as methyl, ethyl, propyl or isopropyl; fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoropropyl, difluoromethyl, difluoro Halo Ci-Cd alkyl such as ethyl, dichloroethyl, trifluoromethyl or trifluoroethyl; 2-ethylamidoethyl; 2-ethylamidovinyl; phenyl or naphthalene which may have substituents C 6-C1G aryl (such as aryl may have the same or different 1 to 3 substituents. The substituent is a halogen atom such as fluorine, chlorine, bromine; methyl, ethyl, propyl, isopropyl Etc.C PC4 alkyl; CkC * alkoxy such as methoxy, ethoxy, propoxy, isooxy; methoxycarbonyl, ethoxycarbonyl, third butoxycarbonyl (CpC * alkoxy) carbonyl Carbamoyl, mono- or di (alkyl) carbamoyl; nitro; hydroxy or cyano, etc.) or optionally substituted pyridyl or pyrimidinyl, etc., which may have 1 or 2 nitrogen atoms (The heteroaryl group may have the same or different 1 to 3 substituents. The substituents are halogen atoms such as fluorine, chlorine, bromine, etc .; 4 alkyl groups such as methyl'ethyl, propyl, isopropyl, etc .; Cl-C4 alkoxy such as oxy, ethoxy, propoxy, isopropoxy; (C1-C4 alkoxy) carbonyl groups such as oxycarbonyl, ethoxycarbonyl, and third butoxycarbonyl; carbamoyl, mono- or di (Cl-C4 alkyl) carbamoyl; nitro; hydroxyl or cyano.) . In the RP, the "protective group" is, for example, an oxybenzyl group, and the 4-nitrobenzyloxy group-63-200418858 group '4-chlorophosphonium oxoyl group' 4-methoxymethoxy benzyl group can be replaced by an oxybenzyl group. (The substituent is nitro, methyl, chlorine or methoxy); diallyloxy, chloroallyloxycarbonyl, 2-methylallyloxycarbonyl and the like may be substituted at allyloxy Carbonyl (the substituent is, chlorine or methyl); Trimethylsulphonyl radical, diethylsulphonyl radical, didibutyl monomethylxanthridyl radical, and other C1-C4 densyl radicals; the above pharmacology allows esters to form groups , Preferably SC ^ C4 alkylsilyl (especially tertiary butadisilyl). The "amine protecting group" in R i is, for example, an allyloxycarbonyl group which may be substituted at the 2-position, such as allyloxycarbonyl, 2-chloroallyloxycarbonyl, 2-methylallyloxycarbonyl (the substituent is, (Chloro or methyl); benzyloxycarbonyl, 4-methylbenzyloxycarbonyl '4 · methoxybenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl and the like can be substituted (the substitution Is methyl, methoxy, chlorine or nitro), preferably allyloxycarbonyl or 4-nitrobenzyloxycarbonyl, more preferably 4-nitrobenzyloxycarbonyl.

The "carboxy-protecting group" in Ri is a protecting group used in the above-mentioned P1. In this method, a compound of formula (II) is reacted with a compound of formula (III) in the presence of a base to produce a compound of formula (IV) (process A1). The protective group is removed to prepare a compound (I) (section A2 Engineering) method. When L1 is a base represented by formula -OR11, the starting materials and compounds of formula (I I) can be produced by the method described in JP-A No. 5 9-6 8 92 or the standard method. When Li is a base represented by the formula -S (0) R 12, the raw material compound (I I) can be produced according to the method described in Japanese Patent Application Laid-Open No. 6 2-3 0 7 8 1 or a standard method. In the following, each process can be explained-64- 200418858 (A1 project) The A1 project is a process for producing a compound of the general formula (IV). In an inert solvent, in the presence of a base, the compound (II) and the general formula ( III). The solvent used does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain degree, such as dichloromethane, 1,2-dichloroethane, chloroform and other halogenated hydrocarbons; nitriles such as acetonitrile; N, N-dimethylformamide, N, N-dimethylacetamide and other amines; ethyl acetate, methyl acetate and other esters; ether, tetrahydrofuran, dioxane and other ethers, preferably acetonitrile, N, N-dimethylformamide or tetrahydrofuran, particularly preferably acetonitrile. The base used is preferably organic amines such as triethylamine, diisopropylethylamine, pyridine, dimethylamine pyridine, or inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably organic amines (particularly diisopropyl Ethylamine). The reaction temperature is usually -20 ° C to 40 ° C (preferably -10 ° C to 20 ° C). The reaction time is 30 minutes to 108 hours (preferably 1 hour to 18 hours). After the reaction is completed, the target compound (IV) of this project can be recovered from the reaction mixture according to a conventional method. For example, the reaction mixture or the reaction mixture is evaporated to remove the solvent, and water and an organic solvent not mixed with water are added to the obtained residue. 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 chromatography. The desired target compound (IV) can be used in the next project without isolation. (Project A 2) Project A 2 is a project in which the compound (I V) and the compound (I) are converted -65- 200418858, and the protective group of the compound (i v) is removed. The removal of the protecting group may vary depending on the type of the protecting group, and it is generally used in organic synthetic chemistry (for example, TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, Second Edition, John Wiley & Sons, Inc. 1991) ) And reach. (1) When the protecting group is benzyl, benzyl, or benzyloxycarbonyl, which may be substituted, the protection is based on the presence of a reduction catalyst in the presence of a solvent in a solvent to remove it. . The contact reduction catalyst used is, for example, a Pd-C catalyst, a platinum catalyst, a chromium-carbon catalyst, etc., and preferably a Pd-C catalyst. The solvent used does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain degree. It is preferably alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and mixed solvents of organic solvents and water. It is a mixed solvent of tetrahydrofuran and water. The reaction temperature is usually 0 ° c to 5 Ot (preferably 10 ° c to 40 ° C). The reaction time depends on the raw material compound and catalyst type, usually 5 minutes to 12 hours (preferably 30 minutes to 4 hours). After the reaction is completed, the target compound can be recovered from the reaction mixture by a conventional method. For example, 'the reaction mixture is filtered to remove insoluble matters such as catalyst, and then the solvent is distilled off to obtain. The obtained compound can be purified, if necessary, according to a conventional method, such as a recrystallization method, a thin-layer thin-layer analysis, and a column chromatography. (2) When the protecting group is an allyl group which may have a substituent or a propoxycarbonyl group which may have a substituent, the protection is based on a solvent, in the presence of palladium, and tri-Ci-C6 alkyltin hydride And organic carboxylic acid alkali metal salt to remove. Can also be added -66- 200418858 Add organic bases or organic substances that are easy to capture allyl groups. Palladium is preferably bis (triphenylphosphine) palladium chloride or palladium (triphenylphosphine) palladium. The trioxane hydride is preferably tributyltin hydride. The organic carboxylic acid alkali metal salt is preferably potassium 2-ethylhexanoate or sodium 2-ethylhexanoate. The organic base that captures allyl is preferably morpholine, and the organic compound that captures allyl is dimethyl ketone. A preferred combination of deprotecting agents is a combination of bis (triphenylphosphine) palladium chloride and tributyltin hydride or a combination of (triphenylphosphine) palladium and potassium 2-ethylhexanoate. The solvent used does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain degree, 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; nitriles such as acetonitrile; alcohols such as methanol, ethanol or propanol; water or a mixed solvent thereof, preferably dichloromethane, ethyl acetate or Its mixed solvents. The reaction temperature is not specific, and is usually from -20 ° C to 100 ° C. (: (Preferably 0 ° C to 60 ° C), the reaction time is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours). After the reaction is completed, the target compound can The reaction mixture is recovered. For example, 'the reaction mixture is filtered to remove the insoluble matter, and then the solvent is distilled off. The obtained compound can be purified by ordinary methods such as recrystallization, layered thin layer chromatography, column chromatography, etc. if necessary. (3) When the protecting group is a silane-based protecting group, the protection is based on a solvent and treated with tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, potassium fluoride and other compounds that generate fluoride ions. Or remove it with organic acids such as acetic acid, methanesulfonic acid, p-toluenesulfonic acid, 'trifluoroacetic acid', trifluoromethanesulfonic acid, or inorganic acids such as hydrochloric acid. -67- 200418858 For removal of fluoride ions, Organic acids such as formic acid, acetic acid, and propionic acid are added to make the reaction proceed under mild conditions. The solvent used is not limited to the reaction, but it can dissolve the starting materials to a certain degree. It is preferably ether, diisopropyl Ether, tetrahydrofuran, dioxane, dimethoxyethane, Ethers such as ethylene glycol dimethyl ether; nitriles such as acetonitrile, isobutyronitrile; water; organic acids such as acetic acid and their mixed solvents, etc. The reaction temperature is usually 0 ° C to 100 ° C (preferably 10 °) C to 3 ot:), the reaction time is not specific, usually 1 to 24 hours (preferably 1 to 4 hours). After the reaction is completed, the target compound can be recovered from the reaction mixture according to a conventional method. For example, the reaction mixture or reaction The solvent of the mixed solution is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue. After washing with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. (4) When the protecting group is a carboxyl group or a hydroxyl group to form a pharmacologically acceptable ester group, the protecting group can be removed by the action of a hydrolase in water or a mixed solvent of water and an organic solvent. The water and the mixed organic solvent are preferably tetrahydrofuran, Dioxane, methanol, ethanol, propanol and other water and mixed ethers or alcohols. It is suitable to add alkali metal salts such as sodium phosphate, sodium acetate, sodium bicarbonate and phosphate buffer solution to the mixed solvent of water or water and organic cereal cereal. Wait for pΗ buffer to maintain pΗ 6 to 8. The hydrolase is not limited to those that can hydrolyze the ester bond, for example, the liver enzyme of pig liver -68 · 200418858. The reaction temperature is usually 10 minutes to 8 hours (preferably 30 minutes to 2 Hours), the reaction temperature is 10 to 50 ° C (preferably 30 to 40 ° C). After the reaction is completed, the target compound can be isolated and purified by ion exchange chromatography, reverse phase column chromatography, reprecipitation, recrystallization and the like. When the compound (IV) contains more than two kinds of protecting groups, the above-mentioned intermediate deprotection reaction combination can be sequentially performed to obtain the target compound (I). Furthermore, when the pharmacologically acceptable ester derivative of the compound (I) is desired, It is necessary to remove the protective group that forms the pharmacologically acceptable ester group. The compound (I) obtained as described above may be converted to pharmacologically acceptable method or technology in the field of β-hybridamine based antibiotics according to pharmaceutical chemistry, if necessary. Salt or ester derivatives. The pharmacologically acceptable ester derivative of the carboxyl group of the compound (I) can be produced by allowing the compound (I) to react with the corresponding halide of the desired ester residue in the presence of a base. The halide used is chloride, bromide or iodide, etc., preferably iodide. When chloride or bromide is used, a catalyst amount of sodium iodide may be added to the reaction solution to promote the reaction. The bases used are, for example, organic amines such as triethylamine, diisopropylethylamine, 4-dimethylamine pyridine, pyridine; and alkali metal carbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably organic Amines (specifically 4-dimethylaminopyridine). The solvent used does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain degree, such as nitriles such as acetonitrile; amines such as Ν, Ν-dimethylformamide; halogenated hydrocarbons such as dichloromethane And the like, preferably amidoamines (especially di-69-200418858 methylacetamide) or nitriles (especially acetonitrile). The reaction temperature is usually -20 to 50 ° C (preferably -10 to 20 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours). Further, The salt obtained by reacting the compound (I) with a base is isolated, and then reacted with the above-mentioned halogens to produce it. When a condensing agent and a base are present, the corresponding alcohol of the ester residue interacts with the compound (I) to produce a pharmacologically acceptable ester derivative of the carboxyl group of the compound (I). The condensing agent is diethyl azide dicarboxylate, etc. Guangyan reagent; Phosphate-based condensing agents such as diphenylphosphonium azide; carbodiimides such as dicyclohexylcarbodiimide and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide Condensing agent; iodinated 2-chloro-1 -methylpyridine, etc. | Condensing agent. The bases used are organic amines such as triethylamine, tributylamine, diisopropylethylamine, and 4-dimethylpyridine. Other additives are, for example, phosphines such as triphenylphosphine and tributylphosphine, alcohols formed from active esters such as 1-hydroxybenzotriazole, and the like. Examples of the solvent are halogenated hydrocarbons such as dichloromethane and dichloroethane; ammoniums such as N, N-dimethylformamide; nitriles such as acetonitrile; ethers such as tetrahydrofuran. Suitable combinations are, for example, diethyl azide dicarboxylate and triphenylphosphine; iodinated 2-chloro-l-methylpyridine and dibutylamine or diethylamine; 1-ethyl-3 (3- Dimethylaminopropyl) carbodiimide and 4-dimethylaminepyridine or 1-hydroxybenzotriazole. After the reaction is completed, the target compound can be recovered from the reaction mixture by a conventional method. For example, the reaction mixture or the reaction mixture is distilled off, and the obtained residue is obtained by adding water and an organic solvent not mixed with water, and washing the water, and then removing the solvent. If necessary, the obtained target compound can be purified by a conventional method such as recrystallization, reprecipitation or layering. [Method B] The method B is a method for producing the compound (I I I) using the method A as a starting material.

(XII) (HO In the above formula, R] P, R2, X and η are as defined above. P2 is a carboxy protecting group, such as methyl, ethyl, propyl, butyl, etc. C! -C4 alkyl; benzyl May be substituted with benzyl, etc., preferably alkyl (especially ethyl). P 3 is a hydroxy protecting group, such as trimethylsilyl, triethylsilyl, tertiary butadiene Silyl, tertiary stilbene silane, and other silane-based protective groups, etc. 'are diphenyl dibutadiene. L 2 is a leaving group. Example -71- 200418858 Such as chlorine atom, bromine atom, and iodine atom. Isohalogen atoms; methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, tosylsulfonyl, etc. C! -C 4 alkylsulfonyloxy The benzenesulfonyloxy group which may be substituted with an alkyl group or an alkyl group is preferably a C i -C 4 alkanesulfonyloxy group in which a fluorine atom may be substituted. P4 is a sulfhydryl-protecting group such as a methylamino group and an ethylfluorenyl group. , Propionyl, butyl fluorenyl, etc. (: 1-(: 4 alkyl fluorenyl; benzyl fluorenyl, methyl benzyl fluorenyl, anisyl fluorenyl, etc.) can be substituted benzyl fluorenyl, etc., preferably C plant C 4 alkyl (Specially Ethyl) (Project B 1) The B 1 process is a process for producing a compound (ν I) by introducing an amido group of the formula c (= χ) N Η 2 into the nitrogen atom of the compound (v). (1) This process is to make the compound (V) in a solvent It can be achieved by interacting with cyanate or thiocyanate. The solvent used is not to hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain degree, such as ethers such as tetrahydrofuran and ether; , Halogenated hydrocarbons such as dichloroethane; and mixed solvents of solvents and water, etc., preferably mixed solvents of ethers and water (especially mixed solvents of tetrahydrofuran and water). Cyanate or thiocyanate is, for example, Alkali metal salts such as sodium salts, potassium salts, or sodium salts, organic ammonium salts such as triethylammonium salts, etc., are preferably alkali metal salts (particularly potassium salts). Also, cyanate or thiocyanate can be converted by using an acid. Relative acid. These acids are organic acids such as acetic acid, inorganic acids such as hydrochloric acid, etc., preferably acetic acid or hydrochloric acid. The reaction temperature is usually -20 to 150 ° C (preferably 0 to 100 ° C). The reaction time is usually 0.5 to .108 hours (preferably 1 to 2 4 -72- 200418858 hours). After the reaction is over, The compound can be recovered from the reaction mixture according to a conventional method. For example, the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue. After washing with water, the solvent is distilled off to obtain the target compound. If necessary, it can be purified according to ordinary methods, such as recrystallization, reprecipitation or chromatography. (2) This project can also be achieved by other methods. This method is a process for producing the following compound (XIII) from compound (V) and Process for producing compound (v I) by compound (XI ϊ I).

In the formula, X and η are as defined above, and 119 is (: 1-(: 4 alkyl (preferably ethyl)). The process for producing compound (X) II from compound (V) is to make compound (V) in In a solvent, it can be achieved by interacting with a compound of the formula X = C = N-CO〇R9 (wherein X and R9 are as defined above). The solvent used does not hinder the reaction, but can dissolve the starting material to a certain degree There are no restrictions, such as ethers such as tetrahydrofuran, ether, halogenated hydrocarbons such as dichloromethane, dichloroethane, etc., and mixed solvents of this solvent and water, etc., preferably ethers or mixed solvents of ether and water Tetrahydrofuran or a mixed solvent of tetrahydrofuran and water).

The reaction temperature is usually -20 to 150 ° C (preferably -10 to 50 ° C -73- 200418858), 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 recovered from the reaction mixture by a conventional method. For example, the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue. After washing with water, the solvent is distilled off. If necessary, the obtained target compound can be purified by a conventional method such as recrystallization, reprecipitation or layering. The process of producing compound (V I) from compound (X I I I) is achieved by allowing compound (X I I I) to react with a base in a solvent. The solvent used does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain degree. For example, alcohols such as methanol, ethanol, ethers such as tetrahydrofuran, ether, and a mixed solvent of this solvent and water, etc., are preferably Alcohols or mixed solvents of alcohol and water (especially ethanol or mixed solvents of ethanol and water). The bases used are, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate 'and potassium carbonate, and organic bases such as sodium methoxide, sodium ethoxide, etc., preferably sodium hydroxide. The reaction temperature is usually -20 to 15 ° C (preferably -10 to 100 ° c). 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 recovered from the reaction mixture by a conventional method. For example, the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue. After washing with water, the solvent is distilled off. If necessary, the obtained target compound can be purified by a conventional method such as recrystallization, reprecipitation or layering. -74- 200418858 (Project B 2) Project B 2 is a process for producing a compound (V I I) by subjecting the compound (v I) to an amine group for a ring closure reaction. This project is achieved by reacting a compound (V I) in a solvent in the presence of a base with a compound of the formula R2CHL3Cocop2 (wherein R2 and p2 are as defined above, and L3 is a leaving group). The leaving group of L3 is preferably a halogen atom, and particularly preferably a bromine atom. The solvent used does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain degree. For example, alcohols such as methanol, ethanol, ethers such as tetrahydrofuran, ether, and halogenated hydrocarbons such as dichloromethane and dichloroethane. , N, N-dimethylformamide and other amidines, etc., preferably alcohols (especially ethanol). The bases used are, for example, organic bases such as triethylamine, diisopropylamine, inorganic bases such as sodium carbonate, potassium carbonate and sodium bicarbonate, and preferably organic bases (especially triethylamine). The reaction temperature is usually -20 to 1. 5 Ot (preferably -10 to 100 ° C) 'reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours). After the reaction is completed, the target compound can be recovered from the reaction mixture by a conventional method. For example, if the reaction mixture or the solvent of the reaction mixture is distilled off, the obtained residue is drool and an organic solvent not mixed with water. After washing with water, the solvent is distilled off. If necessary, the compound of interest can be purified according to ordinary methods, such as recrystallization, reprecipitation or layer analysis. (Process B3) Process B3 is a process for producing a compound (V I I I) by introducing a protective group P 3 -75- 200418858 into the hydroxyl group of the compound (V I I). This project can be based on customary methods of organic synthetic chemistry technology (for example, T.W.Greene, P.G.M.Wuts, Protective Groups in Organic

Synthesis, Second Edition, John Wiley & Sons, Inc. 1991). The introduction of the silane-based protective group is achieved by reacting the compound (V I I) in a solvent with a silane halide or a silane trifluoride containing a desired substituent in the presence of a base. The silane halides are, for example, trimethylsilyl chloride, triethylsilyl chloride, tertiary butyldimethylsilyl chloride, tertiary butyldiphenylsilyl chloride, etc., and are preferably tributyldiphenylsilyl chloride. Silane trifluoride is, for example, trimethylsilane trifluoride, triethylsilane trifluoride, tertiary butanesilyl trifluoride, tertiary butadiene silane trifluoride, etc., and preferably tertiary butadiene silane trifluoride Fluoride. The solvent used does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain degree. For example, amines such as dimethylformamide, halogenated hydrocarbons such as dichloromethane and dichloroethane, tetrahydrofuran, Ethers, such as ether, are preferably amines (specifically dimethylformamide) or halogenated hydrocarbons (specifically dichloromethane). The base used is, for example, imidazole, triethylamine, dimethylpyridine, pyridine Organic bases such as dimethylamine pyridine and the like are preferably imidazole or 2,6-dimethylpyridine. The reaction temperature is usually -20 to 50 ° C (preferably -10 to 40t), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours -76- 200418858). The target compound can be recovered from the reaction mixture according to a conventional method. For example, 'the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue, and the solvent is obtained after washing with water. If necessary, the compound can be purified by conventional methods, such as recrystallization, reprecipitation, or chromatography. (Project B4) Project B4 is to convert the base of the compound (VIII) formula c〇P2 to the desired R ip. The process of producing compounds (I χ). This project can be achieved using functional group conversion reactions that are customary in the field of organic synthetic chemistry. It will be described in detail from Method C to Method VII below. (Project B 5) Project B 5 is The compound (IX) hydroxyl protecting group P 3 is removed to produce the compound (X). This project can be carried out according to the methods commonly used in the field of organic synthetic chemistry (for example, TW Greene, PGMWuts, Protective Groups in Organic Synthesis, Second Edition) , John Wi ley & Sons, Inc. 1991). When the hydroxy-protecting group P 3 is a silane-based protecting group, its removal can be achieved by the method described in Section A 2 Project (3). (Part B 6 Process) The B6 process is a process for converting the hydroxyl group of the compound (X) with a leaving group L 2 to produce a compound (XI). (1) Where the leaving group L 2 is a variety of sulfonyloxy groups, this process can make the compound (IX ) In a solvent, in the presence of a base, and -77- 200418858 sulfonating agent to achieve. The sulfonating agent used is, for example, methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonate. Chlorine chloride, tosylsulfonium chloride, etc., are preferably methanesulfonyl chloride. The solvent is not restricted to the reaction, but it can dissolve starting materials to a certain degree, such as methylene chloride, dichloroethane, Halogenated hydrocarbons such as chloroform, ethers such as tetrahydrofuran, ether, etc., are preferably halogenated hydrocarbons (particularly dichloromethane). The base used is, for example, triethylamine, diisopropylethylamine, pyridine, dimethylamine pyridine, etc. Organic base, etc., preferably triethylamine. The reaction temperature is usually -20 to 80 ° C (preferably -10 to 4). 0 ° C) '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 recovered from the reaction mixture according to a conventional method. For example,' the reaction mixture or reaction The solvent of the mixed solution is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue. After washing with water, the solvent is distilled off. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. (2) When the leaving group L2 is a halogen atom This project is achieved by allowing the compound (I X) in a solvent to interact with a halogenating agent. The halogenating agents used are, for example, phosphorus pentachloride, sulfenyl chloride, phosphorus oxychloride, iodine 'tetrabromide, carbon tetrachloride, N-chlorobutanediimide, N-bromobutanediimide , Diethylaminesulfon trifluoride, etc., preferably carbon tetrabromide. The solvent used does not hinder the reaction, but it can dissolve the starting material to a specific level of -78-200418858. There is no particular limitation, such as dichloromethane, dichloroethane and other halogenated hydrocarbons, tetrahydrofuran, ether and other ethers. For halogenated hydrocarbons (particularly dichloromethane), the additives used are, for example, triphenylphosphine, tributylphosphine and the like, and preferably triphenylphosphine. The reaction temperature is usually -20 to 100 ° C (preferably -10 to 50 ° C), and the reaction time is usually 10 minutes to 108 hours (preferably 0.5 to 24 hours). After the reaction is completed, the target compound can be recovered from the reaction mixture by a conventional method. For example, the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue. After washing with water, the solvent is distilled off. If necessary, the obtained target compound can be purified by a conventional method such as recrystallization, reprecipitation or layering. (Project B 7) Project B 7 is a process in which the compound (X I) is separated from the group L2 and the protected sulfhydryl group is converted to obtain the compound (X I I). _ This project is to make the compound (X I) in a solvent and react with a hydrogenating agent. The thiohydrogenating agent used is, for example, an alkali metal salt of thiocarbonate such as sodium thioacetate, potassium thioacetate, sodium thiopropionate, sodium thiobenzoate, or an alkali metal salt of 4-methoxybenzylthiohydrogen, etc., preferably potassium thioacetate. The solvent used does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain degree. Dimethylformamide, -79- 200418858 Dimethylamine and other amides, etc., are preferably amines (especially dimethylformamide). The reaction temperature is usually -20 to 150 ° C (preferably 0 to 100 ° C). The reaction time is usually 5 to 108 hours (preferably 1 to 24 hours) ° Reaction After the end, the target compound can be recovered from the reaction mixture by a conventional method. For example, 'the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue. After washing with water, the solvent is distilled off. If necessary, the target compound can be purified by ordinary methods, such as recrystallization, reprecipitation or layering. (Process B 8) Process B 8 is a process in which the protective group P 4 of the sulfhydryl group of the compound (X I I) is removed to produce the compound (I I I). (1) When the protective group P4 is an alkyl group or an arylcarbonyl group This project is achieved by reacting a compound (X I I) in a solvent with a 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 first process. The reaction temperature is not specific, usually -10 ° C to 40 ° C (preferably 10 ° C to 30 ° C). The reaction time depends on the solvent, the reaction temperature and the type of reaction reagents, usually 30 minutes. To 24 hours (preferably 1 hour to 8 hours). After the reaction is completed, the target compound can be recovered from the reaction mixture according to a conventional method. -80- 200418858 For example, the reaction mixture or the solvent of the reaction mixture is distilled off. Water and an organic solvent not mixed with water are added to the obtained residue. After washing with water, the solvent is distilled off. If necessary, the obtained target compound can be purified by a conventional method such as recrystallization, reprecipitation or layering. When the hydrazine compound salt is used as a deprotecting agent, the compound (I I I) can be obtained without using the reaction solution by using the above-mentioned A1 engineering materials. This project is achieved by reacting a compound (X I I I) with a base in a solvent. The base used is, for example, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide and other alkali metal salts, etc., preferably sodium methoxide. The solvent used does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain level, such as alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and ether; and amidines such as dimethylformamide; Halogenated hydrocarbons such as methyl chloride and dichloroethane are preferably alcohols (particularly methanol). The reaction temperature is usually -20 to 100 ° C (preferably -10 to 40 ° C). The reaction time is usually 10 minutes to 108 hours (preferably 0.5 to 24 hours). After the reaction is completed, the target compound can be recovered from the reaction mixture by a conventional method. For example, the reaction mixture or the solvent of the reaction mixture is distilled off, and the obtained residue is obtained by adding water and an organic solvent not mixed with water, neutralizing, washing with water, and distilling off the solvent. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. (2) When P4 is 4-methoxymethoxy This project can make the compound (X 丨 I I) in a solvent and react with an acid to reach -81- 200418858. The acid used is a sulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid, etc., preferably trifluoromethanesulfonic acid. Further, coexistence with anisylmethyl or thioanisole may promote the reaction. The solvent used does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain degree. For example, halogenated hydrocarbons such as dichloromethane, dichloroethane, ethers such as tetrahydrofuran 'ether, acetic acid, trifluoroacetic acid, etc. Acetic acid and the like are preferably acetic acid (especially trifluoroacetic acid). • The reaction temperature is usually -20 to 100 ° C (preferably -10 to 80 ° C). The reaction time is usually 10 minutes to 108 hours (preferably 0.5 to 24 hours). After completion of the reaction ', the target compound can be recovered from the reaction mixture by a conventional method. For example, 'the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue, neutralized, washed with water, and distilled to obtain the solvent. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. [Method C] Method C is a method for producing a compound (I X-1) by converting a protected carboxyl group of a compound (V I I I) into a desired ester residue. -82- 200418858

Section C 3

Project C2

, C〇〇H

Can be

In the above formula, R2, X, η, P2 and P3 are defined as above, and R is protected R3. (C1 Project) The C1 Project is a process for reducing the residual acetic acid group of a compound (V I I I) to a methyl group to produce a compound (X I V). This project can be achieved by using the compound (V I I I) in a solvent and acting as a reducing agent.

The reducing agent used is not limited to those which can reduce carboxylate groups to methylol groups. For example, alkali metal aluminum hydrides such as lithium aluminum hydride, metal borohydrides such as lithium borohydride, sodium borohydride, etc. are preferred. Lithium hydride Ming. The solvent used does not impede the reaction, but is not particularly limited as long as it can dissolve the starting material to a certain level. For example, tetrahydrofuran, ethers such as diethyl ether, etc., is preferably tetrahydrofuran. The reaction temperature is usually -20 to 100 ° C (preferably -10 to 40 t :). The reaction time is usually 10 minutes to 24 hours (preferably 0.5 to 24 hours). After completion of the reaction ', the target compound can be recovered from the reaction mixture by a conventional method. For example, the reaction mixture or the solvent of the reaction mixture is distilled off, and the obtained residue is obtained by adding water and an organic solvent not mixed with water, neutralizing, washing with water, and distilling off the solvent. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. (Project C 2) Project C 2 is a process for oxidizing a methylol group of a compound (X I V) to obtain a compound (X V). This project is achieved by reacting the compound (X I V) in a solvent with an oxidant, oxidizing the methylol group to obtain an aldehyde group, and then oxidizing the aldehyde group to obtain a carboxyl group. ® (1) The oxidant used in the oxidation of methylol groups to obtain aldehyde groups is not limited to those that can oxidize methylol groups to obtain aldehyde groups, such as pyridinium chlorochromate, oxadichloro-dimethylarsine , Anhydrous trifluoroacetic acid-dimethylarsine, active manganese dioxide, Desmartin reagent, etc., should be an active bell dioxide. The solvent used does not impede the reaction, but it is not limited as long as it can dissolve the starting material to a certain degree. For example, dichloromethane, dichloroethane and other halogenated hydrocarbons are preferred. Dichloromethane is preferred. The reaction temperature is usually -100 to 10 CTC (preferably -100 to 50 ° C). The reaction time is usually 30 minutes to 108 hours (preferably 1 to 24 hours). After the reaction is completed, the target compound can be recovered from the reaction mixture by a conventional method. For example, the reaction mixture or the solvent of the reaction mixture is distilled off, and the obtained residue is obtained by adding water and an organic solvent not mixed with water, neutralizing, washing with water, and distilling off the solvent. If necessary, the obtained target compound can be purified by usual methods, such as recrystallization, reprecipitation, or chromatography. (2) The oxidant used in the process of oxidizing aldehyde groups to obtain carboxyl groups is not specific as long as it can oxidize aldehyde groups to carboxyl groups, such as potassium persulfate 'ruthenium tetroxide' sodium chlorite-sodium phosphonate (or potassium) _ a _Methyl-2_ butene, preferably sodium chlorite-sodium dihydrogen phosphate methylbutene. The solvent used does not hinder the reaction, but there is no special limit to those that can dissolve starting materials to a certain level, such as dichloro Halogenated hydrocarbons such as methane, dichloroethane, ethers such as tetrahydrofuran and ether, alcohols such as tertiary butanol and mixed solvents with water, etc., preferably a mixture of tetrahydrofuran-dichloromethane-water-tertiary butanol The reaction temperature of the solvent is usually -20 to 5 CTC (preferably -10 to 4 CTC). The reaction time is usually 10 minutes to 108 hours (preferably 0.5 to 24 hours). After the reaction is completed, the target compound can be recovered from the reaction mixture by a conventional method. For example, 'the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue, neutralized, washed with water, and distilled to obtain the solvent. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. (Project C 3) Project C 3 is achieved by removing the protecting group of the compound (V I I I) by another method of producing a carboxy compound (XV). This project can be made from compound (XIII) according to the method a 2nd project in method A or the B1 project (2) in method B. (V 1) ° -85- 200418858 (C 4 project) C 4 The process is a process for esterifying a carboxyl group of a compound (χν) to produce a compound (XIX-1). (1) This project is achieved by allowing the compound (X V) in a solvent to interact with an alcohol compound of the desired formula R3po in the presence of a condensing agent. The condensing agent used was the one described in the method A 2nd process of the A method to form an ester. This is achieved through the use of oxazole chloride. The solvent used does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain degree. For example, halogenated hydrocarbons such as dichloromethane, dichloroethane, ethers such as tetrahydrofuran, ether, and dimethylformamide. Isoamines, nitriles such as acetonitrile, etc., are preferably halogenated hydrocarbons (particularly dichloromethane). The reaction temperature is usually -50 to 100 ° C (preferably -20 to 50 ° 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 recovered from the reaction mixture by a conventional method. For example, the reaction mixture or the solvent of the reaction mixture is distilled off, and the obtained residue is obtained by adding water and an organic solvent not mixed with water, neutralizing, washing with water, and distilling off the solvent. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. (2) Furthermore, the project can be achieved by reacting the compound (X V) in a solvent with a compound of the desired formula R3pL3 in the presence of a base. L3 is a leaving group, preferably a halogen atom (particularly an iodine or bromine atom). The base used is an inorganic or organic base. The inorganic base is, for example, a carbonate such as sodium carbonate, potassium carbonate, or carbonate; a bicarbonate such as sodium bicarbonate or potassium bicarbonate -86-200418858, etc., is preferably a carbonate. The organic base is, for example, a tertiary amine such as triethylamine, diisopropylethylamine, or the like; and a dicyclic organic base such as D B U, D B N, or the like, preferably diisopropylethylamine. Household solvents use solvents that do not hinder the reaction, but are not limited to those that can dissolve starting materials to a certain level. For example, halogenated hydrocarbons such as dichloromethane, dichloroethane, ethers such as chlorofuran 'ether, and dimethyl ether. Methylamines such as methylformamide and nitriles such as acetonitrile are preferably methylamines (especially dimethylformamide). The reaction temperature is usually -50 to 100 ° C (preferably -20 to 100 φ ° C). The reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours). After completion of the reaction ', the target compound can be recovered from the reaction mixture by a conventional method. For example, 'the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue, neutralized, washed with water, and distilled to obtain the solvent. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. [Method D] _ Method D is a method for producing a compound (I X-2) by converting the carboxyl group of the compound (X V) into a desired amide residue.

In the above formula, R2, X, η and P3 are defined as above, and R4P and r5p are R 4 and R 5 which can be protected. (Project D 1) -87- 200418858 This project can be achieved by reacting the compound (x v) with a desired compound 所 N R 4pr ~ in the presence of a condensing agent. In the above process, the alcohol compound r3p0h is replaced by the amine compound 胺 N R4pR5p in the above C method C 4 project. The condensing agent is a phosphoric acid ester-based condensing agent such as diethylphosphonium cyanide, or a carbonate-based condensing agent such as dimethyl diimide. Should be diethylphosphonium cyanide, carbonyl diimide. [Method E]

The E method is a method for converting a compound (v I I) carboxyethyl group into a compound (I X-2) having a promising residue of amidine.

In the above formula, R2, X, η 'P3, R4p and r5P are as defined above. P 2a is a C 4 group in the carboxy protecting group P 2. (Section E 1)

This project can be achieved by reacting the compound (V I I I) with a amine compound of the desired formula Η N R4PR5P in the presence of a catalyst. The catalyst used is, for example, C 1-C 4 Ming, such as trimethyl aluminum, etc., preferably Trimethyl | Lu. The solvent used does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain degree. For example, aromatic solvents such as benzene, toluene, xylene, halogenated hydrocarbons such as methylene chloride, dichloroethane, etc. Aromatic solvents (especially benzene or toluene) are preferred. The reaction temperature is usually 0 to 150 ° C (preferably -10 to 100-88-200418858 ° c). 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 recovered from the reaction mixture by a conventional method. For example, 'the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue, neutralized, washed with water, and distilled to obtain the solvent. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. [F method] The F method is a method for producing a cyanide (I X-3) by converting a carboxylate group of a compound (V I I I).

In the above formula, R2, X, η, P3 and P2a are as defined above. (Article F 1)

This project is achieved in the above-mentioned E method E1 project, in which the amine compound is replaced by an ammonium salt and the reaction is carried out at a higher reaction temperature. The ammonium salt is preferably ammonium chloride, and the reaction temperature is -20 to 150 ° C (preferably -10 to 1 ο ° C). [Method G] The method G is a method for producing a compound (I X-4) by introducing a desired substituent R into a hydroxyl group of the compound (X I V). -89- 200418858

This project can be achieved by reacting the compound (X I V) with an alkylating agent in the presence of a base, or by reacting a reducing agent with a desired carbonyl compound in the presence of an acid catalyst in a solvent. (1) Alkylation method under basic conditions The solvents used are ammoniums such as N, N-dimethylformamide and ethers such as tetrahydrofuran ether. Phenylamines (especially N, N-dimethylformamide) are used as alkali metal hydrides such as sodium hydride and potassium hydride, inorganic bases such as sodium hydroxide and potassium hydroxide, triethylamine, and diisocyanate. Organic bases such as propylamine are preferably hydrogenated alkali metals (especially, sodium hydride). The alkylating agents used are methyl iodide, ethyl iodide halides, dimethyl sulfuric acid, diethyl sulfuric acid, and other ethane sulfuric acids. .Alkane (especially alkyl iodide) is preferred. The reaction temperature is usually -50 to 100 ° C (preferably -10 to 4 Ot). The reaction time is usually 10 minutes to 108 hours. 0.5 to 24 hours). After the reaction is completed, the target compound can be recovered from the reaction mixture according to a conventional method. For example, 'the reaction mixture or the solvent of the reaction mixture is distilled off, water is added to the residue and organics not mixed with water are added. Solvent, neutralization, washing with water, and evaporation of the solvent. The target compound obtained can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. (2) Alkylation method under acidic conditions -90- 200418858 The solvent used does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain degree. For example, halogenated hydrocarbons such as dichloromethane and dichloroethane, ethers such as tetrahydrofuran 'ether, etc., preferably halogenated hydrocarbons (particularly dichloromethane). The acid catalysts are trimethylsilyl fluoride and triethylsilyl fluoride. Trialkylsilane trifluoride, such as tertiary butanesilyl trifluoride, etc., is preferably trimethylsilyl fluoride. The desired carbonyl compounds are ketones such as acetone, methyl ethyl ketone, cyclohexanone, alkane such as acetonitrile, propionaldehyde, etc. Aldehydes, preferably ketones. Reducing agents are trioxane silanes such as triethylsilane, benzhydryl silane, etc., and are preferably trioxane silanes (especially triethylsilane). The reaction temperature is usually -50 to 100 ° C. (Preferably -10 to 4 CTC) 'The reaction time is usually 10 minutes to 108 hours (preferably 0.5 to 24 hours). After the reaction is completed, the target compound can be recovered from the reaction mixture according to a conventional method. For example, 'the reaction mixture or the solvent of the reaction mixture is distilled off, water and an organic solvent not mixed with water are added to the obtained residue, neutralized, washed with water, and the solvent is distilled off. The obtained target compound can be obtained by a conventional method, if necessary, such as Recrystallization, reprecipitation, or purification by chromatography. Composition (X I V) hydroxyl group by looking formula N R 7pR & yl transform the table, producing the compound (I Χ-5) of the method.

(xiv) (xv)

(IX · 5) 200418858 (Project No. 1) Project No. 1 is the introduction of a leaving group L3 into the compound (X I V), and the process of producing the compound (XV) 'can be accomplished according to the above-mentioned B method B 6 process. (Project XI 2) Project XI 2 is a process for producing an amine compound (I X -5 a) from a compound (X V), and if necessary, introducing a substituent to produce a compound (I X-5 b). (A) Manufacturing process of amine compound (I X-5 a) This process can be achieved by reacting compound (X V) with an aminating agent in a solvent. Alternatively, the compound (X V) is reacted with an azide agent in a solvent to produce an azide compound, and then the compound is reacted with a reducing agent. (1) The solvent used in the method using an aminating agent does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain degree, such as amines such as dimethylformamide, alcohols such as methanol and ethanol 'Ethers such as tetrahydrofuran, ether and the like are preferably amidoamines (especially dimethylformamide). -92- 200418858 The aminating agent used is, for example, methylamine, ethylamine and other first-class substitutable alkylamines; aniline, aminethiazole and other substitutable aromatic amines; methylethylamine 'dimethylamine, etc. Alkylamines and their amine salts (such as hydrochloride) which can be substituted in the second stage. Preferably, the primary or secondary alkylamines and their salts (particularly methylamine hydrochloride or dimethylamine hydrochloride) may be substituted. The reaction temperature is usually 0 to 150 t (preferably 10 to 100 ° C). 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 by a conventional method. Recovered from the reaction mixture. For example, 'the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue, neutralized, washed with water, and distilled to obtain the solvent. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. (2) The method using an azide as a reducing agent does not impede the reaction, but it is not limited to those that can dissolve the starting material to a certain degree. For example, amines such as dimethylformamide and methanol, Alcohols such as ethanol, ethers such as tetrahydrofuran, ether, etc., are preferably amines (especially dimethylformamide). The azide agent is an alkali metal azide such as sodium azide and lithium azide, and is preferably an alkali metal sodium azide (especially sodium azide). The reaction temperature is usually 0 to 15 0 C (and 10 to 10 o ° c), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours). After the end of the reaction, the purpose Compounds can be recovered from the reaction mixture in a conventional manner. -93- 200418858 For example, ‘the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue, neutralized, washed with water, and evaporated to obtain the solvent. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. The obtained azide compound can be reduced to obtain an amine compound (I x-5 a) ° The reducing agents used are alkali metal aluminum hydrides such as lithium aluminum hydride, phosphine 'palladium-carbon such as triphenylphosphine, and platinum catalysts The contact of the catalyst with hydrogen reducing agent. Should be in contact with hydrogen reducing agent (especially where palladium-carbon is the catalyst). The solvent used does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain degree. For example, ethers such as tetrahydrofuran and ether, alcohols such as methanol and ethanol, etc., and ethers (particularly tetrahydrofuran) are preferred. In the case of hydrogen reduction, the solvent used is methanol, alcohols such as ethanol, etc., preferably methanol. The reaction temperature is usually -10 to 150 ° C (preferably 0 to 100 ° c). 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 recovered from the reaction mixture according to a conventional method. For example, 'the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue, neutralized, washed with water, and distilled to obtain the solvent. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. (B) Manufacturing process of compound (I X-5t)) This process can be carried out as needed, and the process of manufacturing amine compound (I X-5 a) by introducing -94- 200418858 substituent to produce compound (I X-5 b). This project can be achieved by reacting an amine compound (I X-5 a) in a solvent in the presence of a base 'with a desired halogenating agent, a sulfonating agent, a phosphating agent, and a chloroformate. The halogenating agent is an acid anhydride such as acetic anhydride, anhydrous benzoic acid, and the like, such as acetic acid chloride, benzyl chloride, and the like, and preferably, chloric acid (especially, acetic acid). The sulfonating agent is sulfonium chloride, such as methanesulfonyl chloride, p-toluenesulfonyl chloride, anhydrous methanesulfonyl, anhydrous p-toluenesulfonyl, and other acid anhydrides. chlorine). Phosphorating agents are diethylphosphonium chloride, dimethylphosphonium chloride, and other dichloride, and diethylphosphonium chloride is preferred. The chloroformate is preferably an ester compound such as methyl chloroformate, ethyl chloroformate, benzyl chloroformate, etc., and is preferably ethyl chloroformate (specifically, methyl chloroformate). The bases used are organic bases such as triethylamine, diisopropylethylamine, pyridine, and inorganic bases such as sodium carbonate 'potassium carbonate, sodium bicarbonate, etc., preferably organic bases (especially, triethylamine). φ The solvent used does not hinder the reaction, but it is not limited if it can dissolve the starting material to a certain level. For example, ethers such as tetrahydrofuran and diethyl ether, halogenated hydrocarbons such as dichloromethane and dichloroethane, etc., preferably ethers. (Specifically tetrahydrofuran). The reaction temperature is usually 0 to 100 t (preferably 10 to 50 ° 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 according to Recovered from the reaction mixture by conventional methods. For example, the reaction mixture or the solvent of the reaction mixture is distilled off, and the obtained residue is -95: 200418858. Water and an organic solvent not mixed with water are added to the residue, and the mixture is neutralized, washed with water, and evaporated to remove the solvent. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. (The third project) The third project is to produce an amine compound (〗 X — 5 a) from a compound (X ν) via an azide compound, and if necessary, introduce a substituent to produce a compound (1 X-5 b). engineering. (A) Manufacturing process of azide compound This project is to make compound (XV) in a solvent and interact with azide agent (specifically diphenylphosphonium azide), diethyl azide dicarboxylate and triphenylphosphine. Come on. The solvent used does not hinder the reaction, but it is not limited to those that can dissolve the starting material to a certain level, such as amines such as dimethylformamide, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and ether, Should be ethers (especially tetrahydrofuran). The reaction temperature is usually 0 to 50 ° C (preferably 10 to 30 t), 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 recovered from the reaction mixture by a conventional method. For example, the reaction mixture or the solvent of the reaction mixture is distilled off, and the obtained residue is obtained by adding water and an organic solvent not mixed with water, neutralizing, washing with water, and distilling off the solvent. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. (B) Manufacturing process of amine compounds This project is to manufacture amine compounds (IX-5 a -96- " UU418858) to reduce azide compounds. (C) Manufacturing process of compound (IX-5b) This process can be carried out as needed, and the process of manufacturing a compound (I X-5 b) by introducing a substituent into an amine compound (I χ _ 5 a), It can be carried out according to the method of the above-mentioned η 2 project (B). The compounds (I χ — i) to (〗 χ _ 5) obtained from the C method to the Η method can be converted according to the projects after the B 5th project of the B method. Compound (III) which is the raw material of the side chain at the 2-position of compound (丨). [Method I] Among the compounds (I χ) which are intermediates synthesized by Method B, χ is an oxygen atom (I X-6) Another manufacturing method.

-97- 200418858

R2 ^ / OH R2> x ^ OH Project I-1 ZHN ^ COOH ZHN ^ R1p (XVIa) (XVI) Project I-2-> R2V ^ 〇P3 ZHN ^ " R1p (XVII) R2 * V. 0P3 R2v.OP3 Project I-3 Project Y Project I_4 Project-^ -i-H2N \ R1p (XVIII) (XIX)

R1p R2

In the above formula, Rb, R2, P3, and n are as defined above, and Z is an amine protecting group, preferably benzyloxycarbonyl. P5 is a hydroxy-protecting group, and is preferably a fluorenyl-based protecting group such as ethenyl, benzyl, and pentamyl, most preferably benzyl. (Project I -1) Project I-1 is a process for producing a compound (X V I) by converting the carboxyl group of the amino acid compound (X V I a) into the desired R 1P. This project can be carried out by the methods C to C above. In addition, the compound in which R 2 is hydrogen in the raw material compound (X V I a) can be produced from serine and the compound wherein R 2 is methyl can be produced from glutamic acid. R 2 is hydrogen, and compounds other than methyl can be produced by a method known to those skilled in the art. (Process I-2) Process I-2 is a process for producing a compound (X V I I) by introducing a protective group into a hydroxyl group of the compound (X V I). This project can be carried out in accordance with the method of project B3, project B3. In addition, the P3 silane-based protecting group is preferably a tertiary butadisilyl group. φ (Project I-3) Project I-3 can remove the amine protecting group of the compound (X V I I) and manufacture the compound (X V I I I). This project can be carried out in accordance with the method of the A project A 2 project (1). The preferred solvent is methanol. (Process I-4) Process I-3 is a process for producing a compound (X I X) by converting the amine group of the compound (X V I I I) with an isothiocyanate group. The Luben project can be achieved by reacting the compound (X V I I I) with carbon disulfide and desulfurizing agent in the presence of a base. The solvent is preferably a halogenated hydrocarbon (particularly dichloromethane). The dehydrogen sulfide agent is preferably a halogenated formate (especially ethyl chloroformate) or a reagent containing level 4 nitrogen (specifically 2-iodo-l-methylpyridine or 2-chloro-l-ethylbenzene). And filed tetrafluoride). The base is preferably triethylamine, diisopropylethylamine, tributylamine and other tertiary amines (especially triethylamine) ° -99-200418858 The reaction temperature is usually -20 to 100 ° C (preferably 0 to 60 ° C), and the reaction time is usually 0.5 to 48 hours (preferably 1 to 12 hours). After the reaction is completed, the target compound can be recovered from the reaction mixture by a conventional method. For example, 'the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue, neutralized, washed with water, and distilled to obtain the solvent. The obtained target compound can be purified by ordinary methods such as recrystallization, reprecipitation or chromatography if necessary. (Younger I-5 Project) · The first I-5 project is a process for producing a compound (X X) by reacting a compound (X I X) with a desired cyclic amine. This project can be carried out in accordance with the method of Project B 1 of Act B. (Project I-6) Project I-6 is a process for producing compound (X X I) by introducing a fluorene-based protective group P 5 into the hydroxyl group of compound (X X), and then removing a silane-based protective group P 3. (1) Introduction project of plutonium base protection group P 5 This project can be carried out according to the method of the second project (B) of the law. (2) Removal project of silane-based protective group P 3 This project can be carried out according to the method of the B method No. B 5 project. (Process I-7) Process I-7 is a process for producing a compound (X X I I) by performing a ring-closure reaction on the compound (X X I). This project can be achieved by reacting the compound (X X I) in a solvent with a cyclization reagent (desulfurization reagent) in the presence of a base. -100- 200418858 The solvents are amines such as dimethylformamide and dimethylacetamide, halogenated hydrocarbons such as dichloromethane, and nitriles such as acetonitrile. Acetonitrile is preferred. Test should be triethylamine, diisopropylethylamine, tributylamine and other tertiary amines (especially triethylamine). Cyclization (desulfurization) test reagents are mercury salts such as mercury oxide, mercury chloride, or the 5th type containing 4 grades of tolerance (specifically iodine: 2-chloro-methyl hydrazone ratio tablets or 2-chloro-1- Ethylbenzophenone tetrafluoride). The reaction temperature is usually -20 to 100. 〇 (preferably 0 to 60 ° C), and the reaction time is usually 0.5 to 48 hours (preferably 1 to 12 hours). After the reaction is completed, the target compound can be recovered from the reaction mixture by a conventional method. For example, 'the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue, neutralized, washed with water, and distilled to obtain the solvent. If necessary, the obtained target compound can be purified according to ordinary methods, such as recrystallization, reprecipitation or chromatography. (Process I-8) Process 1-8 is a process for producing compound (X X I I I) by subjecting compound (XXI I) to a dehydrogenation reaction. This project is to achieve the function of the compound (X X I I) in the solvent and the dehydrogenation reagent. As the solvent, aromatic hydrocarbons such as benzene and toluene, and halogenated hydrocarbons such as dichloromethane and dichloroethane can be used. As the dehydrogenation reagent, an oxidant such as manganese dioxide can be used. The reaction temperature is usually 0 to 100 ° C (preferably 0 to 60 ° C), and the reaction time is usually 0.5 to 48 hours (preferably 1 to 12 hours). -101- 200418858 After the reaction is completed, the target compound can be recovered from the reaction mixture according to a conventional method. For example, 'the reaction mixture or the solvent of the reaction mixture is distilled off, and water and an organic solvent not mixed with water are added to the obtained residue, the insoluble matters are filtered off, and after washing with water, the solvent is distilled off. If necessary, the obtained target compound can be purified according to a conventional method, such as recrystallization, reprecipitation, or chromatography. (Process I-9) Process IX-9 is a process for producing compound (I X -6) by removing ′ of the fluorene-based protective group P 5 of the compound (XXI I I) and then introducing the silane-based protective group P 3. (1) Removal process of the fluorene-based protective group P 5 This process can be carried out by producing a compound (V I) from a compound (X I I I) according to the method of the B1 b1 process (2) of method B. (2) Introduction project of silane-based protective group P 3 This project can be carried out according to the method of project B 3 of method B. [Method J] The compound (1) can be produced by another method of Method A according to the following Method J, and specifically, the compound (1-1) or (1-2) in which R1 is a formula C OOR3 or C 0NR4R5 is produced. -102- 200418858 OP3

OP3

(IV-1)

OP3

(IV-2), R p

xH: 、 R2 (IV-3)

COOP 'J4 Project

OH

K7 I H CH3 persons-n /,

〇 C〇〇H In the above, R1, R1 ?, R2, P1, P3, X, L1 and n are as defined above. P 3 should be the foundation of the second dimethyl methacrylate. -103- 200418858 (J1 Project) The J1 Project is to condense the compound (II -1) and R1!) With a silane-based protective group and the carboxyl compound (III -1) with allyl protection. , And the process of manufacturing compound (IV-1). This project can be carried out according to the method of the A1 project of the above-mentioned A method. The starting material compound (I I-1) is produced by reacting the compound (I I) with a silylating agent, and can be carried out according to the B-th process of the B method. The compound (I I I-1) can be produced according to the B method. (Process J 2) Process J 2 is a process for producing the compound (IV-2) by removing the protective group allyl of the compound (IV-1). This project can be carried out according to the method of the A2 project (2) of the above-mentioned A method. (Process J 3) Process J 3 is a process for producing a compound (IV · 3) by modifying a carboxyl group of the compound (IV-2). When P3 is not hydrogen, this project can be carried out according to the method of the above-mentioned B method B4 project (especially method C and method D). When P3 is hydrogen, it can be carried out according to the method of the above-mentioned D1 process (J4 process). The J4 process can produce the compound (I-3) by removing the protective groups P 3 and P 1 of the compound (I-3). ) Project. (1) Removal of the protective group P 3 This project can be carried out according to the method of the A 2nd project (3) of the above method A. -104- 200418858 (2) Removal of the protecting group P 1 This project can be carried out in accordance with the method of the A 2nd project of Method A above. [Method K] According to the method J, but starting from the starting compound (II-1) and substituting the compound (II) to produce (I), it is particularly suitable for the production of the compound (1-1) where R1 is formula COOR3 or formula CONR4R5. Or (1-2). -105- 200418858

OH

(IV -4) '. N, ΌΟΟΗ

CH

(IV-5) boop1

K4 Project

OH

(l) X, L 1 and n are as defined above. -106- 200418858 (Project κ 1) Project K 1 is a process for producing a compound (I V -4) by condensing a compound (I I) with a carboxyl compound (I I I -1) protected by an allyl group. This project can be carried out in accordance with the method of the first J project of the J method. Furthermore, the compound (I I I-1) can be produced by the method of the B method. (K2 process) The K2 process is a process for producing the compound (IV-5) by removing the protective group allyl of the compound (IV-4). This project can be carried out in accordance with the method of the J project No. J 2 above. (Process K3) Process K3 is a process for producing a compound (IV-6) by modifying the carboxyl group of the compound (IV-5). This project can be carried out in accordance with the method of the above J method J3 project. (K4th process) The K4th process is a process in which the protective group P 1 of the compound (IV-6) is removed and the compound (I) is removed. This project can be carried out according to the method of the A2 project of the above-mentioned A method. [Method L] The compound (XII) is another method of the method B, and is produced according to the following method L, and is particularly suitable for the production of the compound (I-1) or (I - 2 ). -107- 200418858

In the above formula, the definitions of Rb, R2, P2, P4, X, L2 and η are as described above. (L1 project) The L1 project is a process for manufacturing a carboxy compound (XIV), and the protecting group of the compound (VI I) is removed. And reach. This process can be carried out according to the method of the A process A 2 process or the B process B 1 process (2), from the compound (X I I I) to produce the compound (V I). (L2 process) The L2 process is a process for producing a compound (XλA) by protecting the carboxyl group of the compound (X I V) with an allyl group. This project can be carried out in accordance with the method of the above-mentioned C project C4. -108-200418858 (L3 process) The L3 process is a process for producing a compound (X V I) by converting the hydroxyl group of the compound (X V) with a leaving group L 2. This project can be carried out in accordance with the method of the B6th project of Method B above. (L4th Project) The L4th project is a process for producing a compound (X V I I) by converting the compound (X V I) from the group L 2 and converting the protected sulfhydryl group. This project can be carried out in accordance with the method of the B7 project above. φ (L 5th Process) The L 5 process is a process for producing a compound (X V I I I) by removing the protective group allyl of the compound (X V I I). This project can be carried out in accordance with the method of the J project No. J 2 above. (L6th process) The L6th process is a process for preparing a compound (X I I) by modifying the carboxyl group of the compound (XV I I I). This project can be carried out in accordance with the method of the above J method J3 project. _ The carbinol compound or its pharmacologically acceptable salt or its ester derivative of the general formula (I) of the present invention has stronger antibacterial activity than the known 1-β methylcarbinol derivative, and is particularly effective against bacterial infections. Haemophilus influenzae is an excellent pathogen for respiratory infections such as pneumococcus. In particular, it has excellent antibacterial activity against cyanocimin-resistant pneumococcus and β-hybridinase-producing non-Ampicillin-resistant Haemophilus influenzae and β-hybridinase-producing Haemophilus influenzae, which have been clinically problematic . 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 as a bacterial infection caused by various diseases -109-200418858 protozoa, especially for the treatment of respiratory infections or Preventive (preferably curative) antibacterial agents. When the compound (I) or its pharmacologically acceptable salt or its ester derivative is used as medicine, especially as an antibacterial agent, it can be mixed alone or in combination with appropriate pharmacologically acceptable excipients, diluents, etc., and used in the form of tablets, capsules, granules , Powder or syrup orally or parenterally. This formulation can use excipients (eg, sugar derivatives such as lactose, white sugar, glucose, mannose, sorbose, etc .; corn starch, potato starch, alpha starch powder, dextrin, carboxymethyl starch and other starch derivatives; Cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, and internally bridged sodium carboxymethyl cellulose; acacia gum; Polyglucose; Polytriglucose; Light-weight silicic acid, synthetic silicates such as aluminum silicate, aluminum magnesium metasilicate, etc .; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfuric acid such as calcium sulfate Salt derivatives, etc.), binding agents (for example, the above-mentioned excipients; gelatin; polyvinylpyrrolidone; polyethylene glycol, etc.), disintegrating agents (for example, the above-mentioned excipients; methylflavirol sodium, carboxymethyl Sodium modified cellulose, bridged polyvinylpyrrolidone and other chemically modified calcium lakes, cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; calcium stearate, magnesium stearate, etc.) Acid metal salt; colloidal silica; propolis, cetyl wax, etc. Types; Boric acid; Ethylene glycol; Carboxylic acid such as fumaric acid, adipic acid; Sodium carboxylic acid salts such as sodium benzate; Sulfates such as sodium sulfate; Leucine; Sodium undecyl sulfate 'undecyl Dodecyl sulfate such as magnesium sulfate; Anhydrous oxalic acid 'stone evening acid hydrates # oxalic acids; the above-mentioned excipients 丨 powder derivatives, etc.), stabilizers (for example, methyl paraben, p-benzene Propyl formate and other p-hydroxyl-110-200418858 benzoates; chlorobutanol, benzyl alcohol, phenethyl alcohol and other alcohols; benzane ammonium chloride; phenol, cresol and other phenols; thimerosal; acetic anhydride; sorbic acid, etc. ), Flavoring agents (for example, conventional sweeteners, sour flavors, flavors, etc.), suspending agents (for example, polysorbate 80, sodium carboxymethyl cellulose, etc.), diluents, solvents for formulations (for example, water, Additives such as ethanol, glycerin, etc. are manufactured according to conventional methods. 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, 100 mg). Each time, the lower limit is 1 ◦ mg (preferably 100 mg) and the upper limit is 3000 mg (preferably, 200 mg). Adults can administer 1 to 6 times per day according to symptoms. Examples, reference examples, test examples, and formulation examples are described below, but the present invention is not limited thereto. In the examples and reference examples, when NMR was measured with heavy water, sodium trimethylsilylpropionate-d 4 was used as an internal standard, and other solvents were measured using tetramethylsilane as an internal standard. The signal position of protons (HOD) in heavy water is 4.65 ppm when the internal standard substance is not measured by heavy water. (Example 1) (5 S, 6 S)-2 _ [1-(4-aminomethylamino-1,3-thiazol-2-yl) azetidin-3 -yl] thio-6-[ (R)-1 -Hydroxyethyl] -Carboparan-2-ene-3 -carboxylic acid sodium salt (Sodium of Compound No. 2-1 Compound 200418858

HO

N- ^ CONH2 S ')-1 -Hydroxyethyl] -Carbonol-2 -ene-3 -carboxylic acid p-nitrobenzyl ester will be (5 S, 6 S)-6-[(R)-1- Hydroxyethyl] -2 -oxocarbazone-3 -carboxylic acid p-nitrobenzyl ester (Japanese Patent Laid-Open No. 5 9-1 6 8 9 2; 1.75 g, 5.03 mmol) was dissolved in 35 mL of acetonitrile under nitrogen Diisopropylethylamine (0.96 mL, 5.53 mmol) and diphenylphosphonium chloride (1.55 mL, 5.53 mmol) were added at 0 ° C, and the mixture was stirred for 40 minutes. This reaction solution can be used in the next reaction without purification. (lb) (5S, 6S) -2- [1- (4-Allyloxycarbonyl_ 1, 3-thiazole-2 -yl) azetidin-3 -yl] thio-6-[(R)- 1-Hydroxyethyl] -carbobin-2-ene-3 -carboxylic acid p-nitrobenzyl ester 3-ethylsulfanyl-1- (4-allyloxycarbonyl-1,3-thiazole-2- Group) Acridine (W0-02 2 0 4 8 3; 1,000 g, 3.35 mmol) was dissolved in 20 mL of dimethylformamide, and hydrazine acetate (0. 3 7 g, 4 · 0 2 mm ο 1), stir for 30 minutes. After the reaction was completed, (5 S, 6 S)-2-diphenylphosphinooxy-6- [(R) -1- produced in Example 1 (1 a) was added dropwise under ice cooling under nitrogen. Hydroxyethyl] -Carbonol-2-ene-3 -carboxylic acid p-nitrobenzyl ester in acetonitrile solution, followed by diisopropylethylamine (1.89 ml, 10 · 8 6 mm ο 1), in Stir for 2 hours under ice cooling. 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 water'salt-salt water, dried over anhydrous magnesium sulfate, and then filtered 'to concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (cyclohexane: ethyl acetate, 20: 80-0: 100, V / V) to obtain (5 S, 6 S) -2-[1-(4 -ene Propoxycarbonyl-1,3-thiazole-2 -yl) azetidin-3 -yl] thio-6-[(R)-1 -hydroxyethyl] -carbophenan-2 -ene-3 -carboxyl The acid p-nitrobenzyl ester was 1.61 g of a pale yellow solid with a yield of 81.9%. 1H-NMR (400MHz, CDC13): δ 8.21 (2Η, d, J = 8.8Hz), 7.64 (2H, d, J = 8.8Hz), 7.53 (1H, s), 6.06-5.96 (1H, m), 5.49 (1H, d, J = 13.9Hz), 5.41-5.36 (1H, m), 5.29 -5.23 (1H, m), 5.25 (1H, d, J = 1 3.9 Hz), 4 · 8 0-4.7 8 (2H, m), 4.53 (2H, q, J = 8.1Hz), 4.31-4.20 (3H, m), 4.15-4.07 (2H, m), 3.25 -3.22 (1 H, m,)? 3.13-3.00 (2H, m), 2.09 (1H, bs), 1.36 (3H, d, J = 6.6Hz); MS (FAB) m / z: 587 (M + H) +. (1 c) (53, 63) -2- [1- (4-Aminomethylamidino-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -carbon Phenyl-2 -ene-3 -carboxylic acid p-nitrobenzyl ester The (5 S, 6 S)-2-[1-(4-allyloxycarbonyl-1) produced in Example 1 (1 b), 3 -thiazole-2 -yl) azetidin-3 -yl] thio-6-[(R) -1 -hydroxyethyl] -carbanil-2 -ene-3 -carboxylic acid p-nitrobenzyl ester (1.61g, 2.74mmol) dissolved in 35mL of tetrahydrofuran, dimethylketone (0.19g, 1.37mmol), palladium (〇) triphenylphosphine (0.16g, 0.14 mm ο 1), three Phenylphosphine (0.1 6 g, 0.6 1 mm ο 1), under nitrogen and room temperature -113- 20041885 8 down 30 points. After the reaction was completed, diisopropylethylamine (0.57 mL, 3.29 mmol) and ammonia-1,4-dishuyuan solution (16.44 mL, 8.22 mmol) were added under nitrogen and ice cooling. 0.50 mL, 3.29 mmol), and stirred at room temperature for 3 hours. 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 sequentially washed with an aqueous potassium hydrogen sulfate solution, water, and a saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol, 100: 0-90: 10, V / V) to obtain (53,63) -2- [1- (4-aminomethylamido-1) , 3 -Thiazole-2 -yl) azetidin-3 -yl] thio-6-[(R)-1 -.Ethyl] -carbon ligand-2 -ene-3 -carboxylic acid p-nitrate The pale yellow benzyl ester was 0.77 g, and the yield was 51.0%. 1H-NMR (400MHz, DMSO-d6): δ 8.24 (2Η, d, J = 8.4Hz), 7.7 1 (2H, d, J = 8.4Hz), 7.47 (1H, s), 7.44 (1H, bs) , 7.29 (1H, bs), 5.45 (1H, d, J = 13.9Hz), 5.3 1 (1 H, d, J = 1 3 · 9 H z), 5.11 (1H, d, J = 5.1Hz), 4.52-4.40 (3H, m), 4.19-4.14 (1H, m), 4.03-3.92 (3H, m), 3.38-3.12 (3H, m), 1.14 (3H, d, J = 5.9Hz); MS ( FAB) m / z: 546 (M + H) +. (Id) (53,63) -2- [1- (4-aminomethylamido-1, 3 -thiazole-2 -yl) azetidin- 3 -yl] thio-6-[(R)-1 -hydroxyethyl] -carbophenan-2-ene-3 -carboxylic acid sodium salt (5 S, produced in Example 1 (1 c) 6 S)-2-[1-(4-Aminomethyl_yl-1,3-amidino) fluorenyl butanyl-3-yl] thio_ -114- 200418858 6-[(R)-1 -hydroxyl Ethyl] -carbophenan-2-ene-3-carboxylic acid p-nitrobenzyl ester (0.75 g, 1.36 mmol) was dissolved in 25 mL of tetrahydrofuran, 25 mL of 0.1 M sodium phosphate buffer (pH 7.0), and In the presence of 7.5% palladium on carbon (0.75g), reduction with hydrogen was carried out at 30 ° C for 2 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was added to diethyl ether and distilled water to perform a layering operation. The aqueous layer was concentrated under reduced pressure, purified by reverse-phase silica gel column chromatography using Chromatorex-ODS DM 10 20T (manufactured by Fuji Silica) (distilled water: acetonitrile, 1 00: 0-97: 3, V / V), and frozen. The target compound (5 S, 6 S)-2-[1-(4-aminocarbamyl-1,3-thiazole-2 -yl) azetidin-3 -yl] thio-6-[ (R)-1 -Hydroxyethyl] -carbopenem-2-ene-3 -carboxylic acid sodium salt 3 2 2 mg, yield 56.5%. UV (H20) 297,249,210 nm; IR (KBi.) Vmax 1 755, 1 669, 1 596, 1 549, 1 394, 1287 cm · 1 W-NMRMOOMHz, D20, TSP): δ (ρριη) 7.51 (1H, s), 4.56-4.51 (2H, m), 4.34-4.28 (1 H, m), 4.26-4.19 (2H, m), 4.06-4.02 (2H, m), 3.40 (1H, dd, J = 6.6, 2.9 Hz), 3.15-3.03 (2H, m), 1.29 (3H, d, J = 6.6Hz); MS (FAB) m / z: 43 3 (M + H) +. (Example 2) (5 s, 6 s)-2-[1-(4 -morpholinecarbonyl-1,3-thiazole-2 -yl) azetidin-3 -yl] thio-6-[(R)-1- Hydroxyethyl] -Carboparan-2-ene-3 -carboxylic acid sodium salt (Sodium salt of Compound No. 2-62). -1 1 5-200418858

) -1 -Hydroxyethyl] -carboparan-2-ene-3 -carboxylic acid p-nitrobenzyl ester

(5S, 6S) -6-[(R) -l-Ethyl] oxocarbazone-3-carboxylic acid p-nitrobenzyl ester (Japanese Patent Application Laid-Open No. 5 9-1 6 8 9 2; 〇g, 8.34mmol) was dissolved in 30mL of acetonitrile, and under nitrogen, diisopropylethylamine (1.6〇1111 ^, 9.111111111) and diphenylphosphonium chloride (1.91mL 5 9.17mmol) , Stir for 40 minutes. This reaction solution can be used in the next reaction without purification. (2b) (5 S, 6 S)-2-[1-(4-morpholinecarbonyl-1,3-thiazole-2 -yl) azetidin-3 -yl] thio-6-[(R) -1 -Hydroxyethyl] -carbophenan-2 -ene-3 -carboxylic acid p-nitrobenzyl ester

3-Acetylthio-1- (4-morpholinylcarbonyl-1,3-thiazol-2-yl) azetidin (WO-〇2 4 0 4 8 3 described; 1.82 g, 5.56ηιηο1 ) Dissolved in 40 mL of dimethylformamide, added nitrogen acetate (0.61 g, 6.67 mmol) at room temperature under nitrogen, and stirred for 30 minutes. After the reaction was completed, (5 S, 6 S) -2-diphenylphosphinoyloxy-6-[(R) -1-prepared from Example 2 (2a) was added dropwise under ice cooling under nitrogen. Ethyl] -Carbonol-2-ene-3-carboxylic acid p-nitrobenzyl ester acetonitrile solution, followed by diisopropylethylamine (3.87 ml, 2 2 · 2 4 mm ο 1), After stirring under ice cooling for 1 hour, it was placed in a refrigerator overnight. After the reaction is completed, add acetic acid to the reaction system -11 6-200418858

Ethyl acetate and 1% sodium chloride, and the aqueous layer was extracted with ethyl acetate. The organic layer obtained was washed successively with water and saturated brine 'and dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol, 〇〇: 〇-90: 10, ν / ν) 'to obtain (5 S' 6 S) -2-[1-(4 -morpholine Carbonyl-1,3-thiazole-2-yl) azetidin-3-yl] thio- (R) ethyl] -carbon-epoxy-3-carboxylic acid p-nitrobenzyl ester pale yellow amorphous 2.6 lg, yield 76.2%. 1H-NMR (400MHz, DMSO-d6): 6 (ppm) 8.24 (2H, d, J = 8.8Hz), 7.71 (2H, d, J = 8.8Hz), 7.31 (1 H, s), 5 · 4 5 (1 H, d, J = 13.9Hz), 5.3 1 (1 H, d, J = 1 3 · 9 H z), 5 · 1 1 (1H, d, J = 5.1Hz), 4.50- 4.39 (3H, m), 4.19-4.14 (1H, m), 4.06-3.93 (3H, m), 3.82-3.43 (8H, m), 3.39-3.13 (3H, m), 1.14 (3H, d, J = 5.9Hz); MS (FAB) rxi / z: 616 (M + H) +. (2c) (5S '6S)-2- [1- (4-morpholinyl-1, 3 -thiazole-2 -Yl) azetidin-3 -yl] thio-6-[(R) -1 -hydroxyethyl] -carbanil-2 -ene-3 -carboxylic acid sodium salt Example 2 (2b) (5S, 6S) -2- [l- (4-morpholinecarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1- Hydroxyethyl] -carbobin-2-ene-3 -carboxylic acid p-5 succinyl ester (1,000 g, 1.62 mmol) was dissolved in 30 mL of tetrahydrofuran, 0. 1 M sodium phosphate buffer (pH 7.0 ) 30mL, in the presence of 7.5% palladium on carbon (1000g), at 30 ° C contact hydrogen reduction for 1 hour. After the reaction was completed, the reaction mixture was filtered, and ether and distilled water were added to the solution to carry out a liquid separation operation. The -11 7-200418858 aqueous layer was concentrated under reduced pressure and purified by reverse-phase silica gel column chromatography using Chromatorei DS DM1 020T (manufactured by Fuji Silica) (distilled water: acetonitrile, 1 00: 0-93: 7, V / V), freeze-dried to obtain the target compound (5 S, 6 S)-2-[1-(4 -morpholinecarbonyl-1, 3-thiazole-2 -yl) azetidin-3 -yl] thio- 346 mg of 6-[(R) -1-hydroxyethyl] -carbabin-2-en-3-carboxylic acid sodium salt as a white solid with a yield of 42.5%. IR (KBr) vmax 1 758, 1 603, 1 53 8, 1 396, 1 237 cm · 1;

1H-NMR (400MHz, D2〇, TSP): δ 7.14 (1H, s), 4.57-4.52 (2H, m), 4.37-4.31 (1H, m), 4.26-4.19 (2H, m), 4.07 -4.03 (2H, m), 3.95-3.60 (8H, m), 3.41 (1H, dd, J = 5.9, 2.2Hz) 3.17-3.05 (2H, m)? 1.29 (3H, d, J = 5.9Hz) ; MS (FAB) m / z: 479 (M-Na) '(Example 3) (5 S, 6 S) -2-{1-[4-((N-methyl-aminomethyl methyl)) Aminomethyl) -1,3.thiazole-2 -yl} azetidin-3 -yl-6-yl-6-[(R) -1-hydroxyethyl] -carbobin-2-en-3 -Sodium Carboxylate (Sodium salt of Compound No. 2-1068)

N-aminoformamidinemethyl) aminoformamyl) -1,3-thiazole-2-yl] oy TD 3-yl 丨 thio-6-[(R) -1-hydroxyethyl] -carbon ligand Nian-2 -can ^ -118- 200418858 p-nitroester of carboxylic acid The (5 S, 6 S)-2-[1-(4-allyloxycarbonyl-1) produced in Example 1 (1 b), 3 -thiazole-2 -yl) azetidin-3 -yl] thio-6-[(R)-1 -hydroxyethyl] -carbanil-2 -ene-3 -carboxylic acid p-nitrobenzyl ester (1.68g, 2.86mmol) was dissolved in 35mL of tetrahydrofuran, and dimethylketone (0.20g, 1.43mmol), palladium (〇) triphenylphosphine (0.17g, 0.14mmol), triphenylphosphine (0.17g, 0.65 m mol), and stirred at room temperature under nitrogen for 30 minutes. After the reaction was completed, diisopropylethylamine (1.20mL, 6.86mmol), sarcosinamine (0.43mg, 3.43mmol), and diethylphosphoniumphosphonium cyanide (0.52mL) were added under ice cooling under nitrogen. , 3.43 mmol), and stirred at room temperature for 3 hours. 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 brine, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (acetonitrile: methanol, 100 ·· 0-90 ·· 10, V / V) to obtain (5S, 6S) -2- {l- [4-((N -methyl -N-carboxamidinemethyl) carboxamido) -1,3-thiazolyl-2-yl group-azetidine-3-yl} thio-6-[(R) -1-hydroxyethyl]- 1.43 g of pale yellow amorphous of carbamate-2 -ene-3 -carboxylic acid p-nitrobenzyl ester, yield 80.8%. 1H-NMR (400MHz, DMSO-d6): δ 8.24 (2Η, d, J = 8.8Hz) 5 7.71 (2H, d, J = 8.8Hz), 7.43-7.32 (1H, m)? 7.28 (1H? S ), 7.10 ^ 6.91 (1H, m), 5.45 (1H, d, J = 13.9 Hz), 5.31 (1H, d, J =: 13.9Hz), 4.53 ^ 4.38 (3H, m), 4.31-4.14 (2H , m), 4.08- 3.75 (4H, m), 3.50-2.91 (7H, m), 1.14, 1.11 (3H, dx2, -119- 200418858 J = 6.6Hz); MS (FAB) m / z: 617 ( M + H) +. (3b) (5S '6 S)-2-{1 C 4 · ((N -methyl-N -aminoformylmethyl) aminoformyl) -1,3 -thiazole- 2-Alkyl} azetidin-3-yl} · thio-6-[(R) -l-hydroxyethyl] -carban-2-en-3-carboxylic acid sodium salt Example 3 (3a ) (5S, 6S) -2- {l- [4- ((N -methyl-N-amine formamidinemethyl) aminoformamyl) -1,3-mouth acetamidine-2-yl } "Butyl_3-yl} thio-6-[(R) -1-Ethyl] -Carbonidine-2 -ene-3 -carboxylic acid p-nitrobenzyl ester (1.4 (^, 2.27111111〇1) dissolved in 50mL of tetrahydrofuran, 50mL of 0.1M sodium phosphate buffer (pH7.0), in the presence of 7.5% palladium on carbon (1.40g), contact hydrogen reduction at 3 (TC for 2 hours. After the reaction is completed The reaction mixture was filtered and the filtrate was added Ethyl acetate and distilled water were used for liquid separation. The aqueous layer was concentrated under reduced pressure and purified by reverse-phase silica gel column chromatography using Chromatorex-ODS DM1020T (manufactured by Fuji Silica) (distilled water: acetonitrile, 100: 0-98 : 2, V / V), freeze-dried to obtain the target compound (5 S, 6 S)-2-{1-[4-((N -methyl-N -amine formamidinemethyl) aminoformamyl) -1,3 -thiazole-2 -yl} azetidin-3 -yl} thio-6-[(R) -1 -hydroxyethyl] -carbanil-2 -ene-3 -carboxylic acid sodium salt 652 mg of white solid, yield 57.0%. IR (KBr) vmax 1 755, 1 682, 1 60 1, 1 54 1, 1 397, 1 309, cm-1, H-NMR (400MHz, D20, TSP ): δ 7.22, 7.20 (1H, sx2), -120- 200418858 4.5 8-4.50 (2H, m), 4.34-4.31 (2H, m), 4.26-4.20 (3H, m), 4.06-4.01 (2H5 m ), 3.41 (1H, dd? J = 5.9, 2.2Hz), 3.18-3.08 (5H, m), 1.29 (3H, d, J = 6.6Hz); MS (FAB) m / z: 480 (M-Na ) &Example; (Example 4) (5S, 6S) -2- {l- [4-((lS) -l-aminomethyl-2 -methyl-propylaminomethyl) -1,3-thiazole -2 -yl} azetidin-3 -yl} thio-6-[(R)-1 -hydroxyethyl] -carbanil-2 -ene-3 -carboxyl (Compound number 2 - 34 Number of compound)

) -1 -Hydroxyethyl] -carbophenan-2 -ene-3 -carboxylic acid p-nitrobenzyl ester (5 S, 6 S)-6-[(R)-1 -hydroxyethyl] -2 -Oxycarbopeptide-3 -carboxylic acid p-nitrobenzyl ester (Japanese Patent Laid-Open No. 5 9-1 6 8 9 2; 2.47 g, 7.08 mmol) was dissolved in 50 mL of acetonitrile under nitrogen at 0 ° Diisopropylethylamine (1.36 mL, 7.79 mmol) and diphenylphosphonium chloride (1.6 2 mL, 7.79 mmol) were added at C, and stirred for 40 minutes. This reaction solution can be used in the next reaction without purification. (4b) (5S, 6S) -2- [l- (4-{(lS) -2-methyl-121-200418858yl- [1- (p-nitrobenzyloxycarbonylamino) methyl} propylamine formamidine ) -1, 3 -thiazole-2 -yl) azetidin-3 -yl) thio-6-[(R)-1 -hydroxyethyl) -carbanil-2 -mer-3 -residue acid P-Nitrobenzyl 3-ethylammoniumthio-l- (4-{(l S) -2 -methyl- [1- (p ~~ nitrobenzyloxycarbonylamino) methyl} propylaminomethyl) -1,3-thiazole-2 -yl) azetidine (W-002 2 0 4 8 3; 2.46 g, 4.72 mmol) was dissolved in 50 mL of dimethylformamide, under nitrogen, Add hydrazine acetate (0.52 g, 5.66 mmol) at room temperature and stir for 30 minutes. After the reaction was completed, the (5S, 6S) -2-diphenylphosphinoyloxy-6-[(R) -1 -hydroxyethyl group produced in Example 4 (4a) was added dropwise under ice cooling under nitrogen. ] -Carbonidine-2 -ene-3 -carboxylic acid p-nitrobenzyl ester in acetonitrile 'solution was added with diisopropylethylamine (3.29 mL, 18.88 mmol), and stirred under ice-cooling for 2 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 obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate · methanol, 100 ·· 0-95: 5, V / V) to obtain (53,63) -2- [1- (4- {(1 S ) -2 -methyl- [1-((P-nitrobenzyloxycarbonylamino) methyl] -propylaminomethyl) -1,3-thiazole-2-yl) azetidin-3-yl] thio -6-[(R)-1 -Hydroxyethyl] -carbobenzoin-2 -ene-3 -carboxylic acid p-nitrobenzyl ester 3.31 g, yield 86.6%. ] H-NMR (400MHz, DMSO-d6): δ 8.23 (2Η, d, J = 8.8Hz), 8.15 (2H? D, J = 8.8Hz), 7.71 (2H, d, J = 8.8Hz), 7.52 (2H, d, J = 8.8Hz), 7.49-7.46 (3 H, m), 5.45 (1H, d, J = 14.3Hz), -122- 200418858 5.31 (1H, d, J = 14.3 Hz), 5.2, 5.10 (3H, m), 4.50-4.39 (3H, m), 4.19-4.14 (1H, m), 4.06-3.95 (3H, m), 3.88-3.81 (1H, m)? 3.37 ( 1H, dd, J = 5.9, 2.9Hz), 3.26-3.12 (4H, m), 1.87-1.81 (1H, m), 1.14 (3H, d, J = 6.6Hz), 0.89 (3H, d, J- 6.6Hz), 0.85 (3H, d, J = 6.6Hz); MS (FAB) m / z: 810 (M + H) +. (4c) ^ 5S, 6S) -2- {1- (4- ( (is)-1-Aminomethyl-2-methyl-propylamine methylamidino, 3-thiazol-2-yl, galanthidine-3 -yl} thio-6 _ [(R) _1_hydroxy Ethyl} _Carbonol_ 2 _ene_ 3 -carboxylic acid The (5S, 6S) -2- [l_ (4-{(1 S) -2-methyl-) produced in Example 4 (4b) [L_ (p_nitrobenzyloxycarbonylamino) methyl} -propylaminomethyl) -1,3-thiazole-2 -yl) azetidin-3 -yl] thio-6-[(R)- 1-Hydroxyethyl-carbophenan-2-ene-3-carboxylic acid p-nitrobenzyl ester (2.00 g, 2.47 mmol) was dissolved in 60 mL of tetrahydrofuran, 50 mL of distilled water, and 7.5% palladium on carbon. 2.00g) in the presence of hydrogen reduction at 30 ° C for 2 hours. After the reaction, the reaction mixture was filtered, diethyl ether and distilled water were added to the filtrate to perform a liquid separation operation. The aqueous layer was concentrated under reduced pressure, and Chi * was used. omatorex-ODS DM1020T (manufactured by Fuji Silica), purified by reverse-phase silica gel column chromatography (distilled water: acetonitrile, 100: 0-80: 20, V / V), and freeze-dried to obtain the target compound (5 S, 6 S )-2-{1-[4-((1 S) -1-Aminemethyl-2-methyl-propylamine formamyl) _1, 3-thiazole-2 -yl} azetidine-3 -yl} Thio-6-[(R) — 1-hydroxyethyl] -carbophenan-2-en-3-carboxylic acid as a white solid 51..2 mg 'yield 4.2%. -1 2 3-200418858 1H-NMR (400MHz, DMS 〇-d 6 + D 2 〇): δ 7.51 (1H, s), 4.48-4.35 (2H, m), 4.26-4.19 (1H, m), 4.03 -3.71 (5H, m), 3.13-2.84 (5H, m), 1.93-1.85 (lH, m), 1.13 (3H, d? J = 5.9Hz), 0.89 (3H, d? J = 6.6Hz), 0.85 (3H, d, J = 6.6Hz); MS (FAB) m / z: 496 (M + H) +. (Example 5) (5 S, 6 S)-2-[1-(4 -amine Formamidine-1,3-oxazolyl-2-yl) Dybutadidin-3-yl] thio- (R) -1-transethyl] -carbenyl-2 -ene-3 -carboxyl Sodium salt (sodium salt of compound No. 2-529)

) -1 -Hydroxyethyl] -carbophenan-2-ene-3 -carboxylic acid p-nitrobenzyl ester (5 S, 6 S)-6-[(R)-1 -hydroxyethyl]-2 Oxycarbazone-3 -carboxylic acid p-nitrobenzyl ester (Japanese Patent Laid-Open No. 5 9-1 6 8 9 2; 2.66 g, 7.65 nimol) was dissolved in 50 mL of acetonitrile, and diisopropyl was added under nitrogen. Diethylamine (1.47 mL, 8.42 mmol) and diphenylphosphonium chloride (1.7 5 mL, 8.42 mmol) were stirred for 40 minutes. This reaction solution can be used in the next reaction without purification. (5b) (5 S '6 S)-2- [1- (4-Aminomethylamidino 3-sulfayl) fluorene f-butan-3-yl] thio-6-[(R) lion 7 -124- 200418858 group] -Carbonidine-2 -ene-3 -carboxylic acid p-nitrobenzyl ester 3 -Ethylsulfanyl-1-(4-aminocarbamyl-1,3-oxazole-2 -Based) Acridine (W0-0 2 4 0 4 8 3; 1.23 g, 5.10 mmi) dissolved in 100 mL of dimethylformamide, and added hydrazine at room temperature under nitrogen. Acetate (0.56 mg, 6.12 mmol) was stirred for 30 minutes. After the reaction was completed, (5S, 6S) -2-diphenylphosphinoyloxy-6-[(R) -l-hydroxyethyl) produced in Example 5 (5a) was added dropwise under ice cooling under nitrogen. 〕 -Carbonol-2-ene-3 -carboxylic acid p-nitrobenzyl ester in acetonitrile solution, and then add diisopropylethylamine (2.88mL, 16.52mmol), stir for 1 hour under ice cooling, and put in the refrigerator 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 successively with water, sodium bicarbonate water, water, and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol, 100: 0-90: 10, V / V) to obtain (5 S, 6 S)-2-[1-(4-aminocarbamyl -1,3-oxazole-2 -yl) azetidin-3 -yl] thio-6-[(R) -1 -hydroxyethyl] -carbanil-2 -ene-3 -carboxylic acid pair -2.10 g of nitrobenzyl ester as a pale yellow solid, yield 77.8%. 1H-NMR (400MHz, DMSO-d6): δ 8.24 (2H, d, J = 8.8 Hz), 8.06 (1H, s), 7.71 (2H, d, J = 8.8 Hz), 7.35 (1H, bs), 7.28 (1H, bs), 5.45 (1H? D, J = 14.3Hz), 5.31 (1H, d, J = 14.3Hz), 5.10 (1H, d, J = 5.1Hz), 4.2 (2H, q, J = 8.8Hz), 4.42-4.35 (lH, m), 4.19-4.14 (1H, m), 4.05-3.92 (3H, m), 3.36 (1H, dd, J 5.9, 2.9Hz), 3.25-3.11 ( 2H, m), 1.14 (3H, d, -125-200418858 J = 6.6 Η z) i MS (FAB) m / z: 530 (M + H) +. (5c) (5S, 6S) -2- [ l- (4-aminomethylamidino-l, 3-pyrazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -carbon ligand -2 -ene-3 -carboxylic acid sodium salt The (5S, 6S) -2- [l- (4-aminomethylamido-1,3-oxazole-2 -yl) produced in Example 5 (5b) ) Acridine-3 -yl] thio-6-[(R) -1 -hydroxyethyl] -carbobin-2-ene-3 -carboxylic acid p-nitrobenzyl ester (2.00 g, 3-78 mmol) 100 mL of tetrahydrofuran, 100 mL of 0.1 M sodium phosphate buffer solution (ρΗ7.0), and contact hydrogen reduction at 30 ° C for 2 hours in the presence of 7.5% palladium carbon (2.00 g). After the reaction was completed, the reaction mixture was filtered, and diethyl ether and distilled water were added to the filtrate to perform a liquid separation operation. The aqueous layer was concentrated under reduced pressure, and purified by reverse-phase silica gel column chromatography using Chromatorex-ODS DM1020T (manufactured by Fuji Silica) (distilled water: acetonitrile, 100: 0-99: 1, V / V). Target compound (5 S, 6 S)-2-[1-(4-aminomethylamidino-1, 3-oxazole-2 -yl) azetidin-3 -yl] thio-6-[( R)-1 -Hydroxyethyl] -carbopenem-2-ene-3-carboxylic acid sodium salt 497 mg as a white solid, yield 31.6%. υν (Η20) 300, 214 nm; IR (KBr) vmax 1 756, 1 67 1, 1 629, 1 595, 1 387, 1 272, 1250 cm'1; ^ NMRMOOMHz, D2〇): δ 7.93 (1H, s), 4 · 62-4 · 56 (2H, m), 4.33-4.19 (3H, m), 4.15-3.98 (2H, m), 3.40 (1H, dd, J = 5- 9, 2.6Hz), 3.15-3.03 (2H, m) 5 1.29 (3H, d5 J = 6.2Hz); -126- 200418858 MS (FAB) m / z: 417 (M + H) +. (Example 6) (5 S, 6 s)-2-[1-(4 -morpholinecarbonyl-1, 3-oxazole-2 -yl) azetidin-3 -yl] thio-6-[(R)-1 -hydroxyethyl] -Carbonyl-2 -ene-3 -carboxylic acid sodium salt (sodium salt of compound No. 2-590)

HO

(6a) 3-hydroxy-1-(4-allyloxycarbonyl-1,3-oxazolyl-2-yl) azetidine

Document 3-benzylfluorenoxy-1-(4-methoxycarbonyl-1,3-oxazolyl-2-yl) azetidin (WO-〇2 4 0 4 8 3; 2.0 g, 6.62 mmol ) Dissolved in 40 mL of methanol, and added 1N aqueous sodium hydroxide solution (2 6 · 5 ml, 2 6.5 mm ο 1) at room temperature, and stir overnight. After the reaction was completed, a 4 N-hydrochloric acid-1,4-dioxane solution was added under ice cooling to neutralize, and the reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in 37 mL of dimethylformamide, and propylene bromide (1.44 mL, 16.6 mmol) and diisopropylethylamine (2.89 mL, 16.6 mmol) were added at room temperature, followed by stirring in an 80t oil bath for 6 hours. After the reaction was completed, ethyl acetate and 10% saline were added to the system, and the aqueous layer was extracted with ethyl acetate in layers. The obtained organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate, 1: 3, v / v) to obtain 3-hydroxy-1-(4-allyloxycarbonyl--127- 200418858 1 as light brown crystals. , 3-oxazole-2 -yl) azetidine 1. 3 1 g, yield 89%. 1H-NMR (400MHz, CDC13): δ 7.81 (1Η, s), 6.05-5.94 (1H, m), 5.40-5.33 (1 H, m), 5.29-5.24 (1 H, m), 4.82-4.76 ( 1H, m), 4.78 (2H, dt, J = 5 · 9, 1 · 5 H z), 4 · 4 0 (2 H, dd, J = 6.6, 10.3Hz), 4.06 (2H, dd, J = 10.3, 4.4Hz), 2.34 (1H, d, J = 5.9Hz); MS (EI) m / z: 224 (M +). (6b) 1- (4-allyloxycarbonyl-1, 3 -Oxazol-2-yl) -3 -methanesulfonyloxyazetidine The 3-hydroxy-1-(4-allyloxymine-1, 3-fluorene etc. produced in Example 6 (6 a) Amidino-2-yl) azetidine (1.31 g, 5.88 mmol) was dissolved in 40 mL of anhydrous dichloromethane, and methylsulfonyl chloride (683 μί, 8.82 mmol) and triethylamine (1.24 mL, 8.82 mmol) and stirred for 4 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, and then filtered 'to concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate, 1: 2, v / v) to obtain light brown crystals 1-(4 -allyloxycarbonyl-1 '3 oxazole-2 -yl ) -3-mesylate oxazidin 1.68g '95% yield. h-NMRMOOMHz, CDC13): δ 7.84 (1H, s), 6.05-5.94 (1Η, m), 5.41-5.34 (2Η, m), 5.30'5 · 25 (1Η, m), 4.80 ( 2Η, 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) + .-128- 200418858 (6c) 3-ethylsulfanyl-1- (4-allyloxycarbonyl-1, 3-fluorene, etc.-2 -Yl) azetidin The 1- (4-allyloxycarbonyl-1,3-oxazole-2 -yl) -3 -methanesulfonyloxyazetidine (1.69) produced in Example 6 (6b) g, 5.59 mmol) was dissolved in 35 mL of dimethylformamide, potassium thioacetate (3.83 g, 3 3.5 mmol) was added at room temperature, and the mixture was stirred for 10 hours in an 80 t oil bath. 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 dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate, 2: 1, v / v) to obtain 3-ethylamidothio · 1- (4-allyloxycarbonyl-1) as a light brown solid. 3 · oxazole-2 -yl) azetidine 905mg, yield 57.7%. 1H-NMR (400MHz, CDC13): δ 7.82 (1H? S), 6.04-5.94 (1H, m), 5.40-5.3 3 (1 H, m), 5.29-5.24 (1 H, 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, 5.9Ηζ), 2.35 (3H, s); MS (FAB) m / z: 305 (M + Na) +. (6 d) (5 S, 6 S)-2 -diphenylphosphinooxy-6-[(R)- 1-Hydroxyethyl] -carbobin-2-ene-3 -carboxylic acid p-nitrobenzyl ester (5 S, 6 S)-6-[(R)-1 -hydroxyethyl]-2 -oxyl Carboparan-3 -carboxylic acid p-nitrobenzyl ester (Japanese Patent Laid-Open No. 5 9-1 6 8 9 2; 2.96 g, 8.51 mmol) was dissolved in 60 mL of acetonitrile, and under nitrogen, two dichloromethane was added at 0 ° C. Isopropylethylamine (1.63 mL, 9.36m mol) and diphenylphosphine gas (1.9 5 mL, 9.36 mmol) were stirred for 40 minutes. This reaction solution can be used in the next reaction without purification -129- 200418858. (6 e) (5S, 6S) -2- [1- (4-allyloxycarbonyl-1 ′ 3-1% mile-2-yl) pyrimidine dden-3-yl] thio-6- [(R) -l-Hydroxyethyl] -Carboparan-2-ene-3-carboxylic acid p-nitrobenzyl ester The 3-ethylamidinethio-1-(4 produced in Example 6 (6 c)) -Allyloxycarbonyl-1,3-oxazolyl-2-yl) azetidine (1.60g, 5.67mm) dissolved in 35mL of dimethylformamide, and under nitrogen, hydrazine acetate was added at room temperature. (0.63 g, 6.80 mmol) and stirred for 30 minutes. After the reaction was completed, (5 S, 6 S)-2-diphenylphosphinooxy-6- [(R) -1- produced in Example 6 (6 d) was added dropwise under ice cooling under nitrogen. A solution of hydroxyethyl] -carbophenan-2-ene-3 -carboxylic acid p-nitrobenzyl ester in acetonitrile, and diisopropylethylamine (3.20 mL, 18.37 mmol) was added thereto, followed by stirring under ice cooling for 2 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 obtained organic layer was washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (cyclohexane: ethyl acetate, 20: 80-0: 100, V / V) to obtain (5 S, 6 S) -2-[1-(4 -allyloxy Carbonyl-1,3 -oxazole-2 -yl) azetidin-3 -yl] thio-6-[(R)-1 -hydroxyethyl] -carbanil-2 -ene-3 -carboxylic acid The pale yellow amorphous of p-nitrobenzyl ester was 2.57 g, and the yield was 79.3%. 1H-NMR (400MHz, CDC13): δ 8.22 (2Η, d, J = 8.8Hz), 7.83 (1Η, s), 7.64 (2H, d, J = 8.8Hz), 6.03 -5.94 (1 H, m) , 5.49 (1H, d, J = 13.6Hz), 5.3 9-5.34 (1H, m) 5 5.29 ^ 5.26 (1H, m), 5.25 (1H, d, J = 13.6Hz), 4.79 (2H, d, J2 5.9Hz), 4.55 -130- 200418858 (2H, q, J2 7.6Hz), 4.31-4.03 (5H, m), 3.23 (1 H, dd, J2 7. 0, 2.6Hz), 3.12- 2.96 (2H, m), 2.25- 1.50 (lH, m), 1.37 (3H, d, J = 5.9Hz); MS (FAB) m / z: 57 1 (M + H) +. (6 f) (53,63) -2- [1- (4-morpholinecarbonyl-1, 3-oxazole-2 -yl) azetidin-3 -yl] thio-6-[(R)-1 -hydroxyl Ethyl] -carben-2-en-3-carboxylic acid p-nitrobenzyl ester The (5S, 6S) -2- [l- (4-allyloxycarbonyl- 1,3-thiazole-2 -yl) azetidin-3 -yl] thio-6-[(R)-1 -hydroxyethyl] -carbanil · 2-ene-3 -carboxylic acid p-nitrate Benzyl ester (1.27 g, 2.23 mmol) was dissolved in 30 mL of tetrahydrofuran, and dimethyl ketone (0.16 g, 1.12 mmol), palladium (0) triphenylphosphine (0.13 g, 0.11 mmol), and triphenylphosphine (0.13 g) were added. , 0.50 mmol), and stirred at room temperature under nitrogen for 30 minutes. After the reaction was completed, diisopropylethylamine (0.47 mL, 2.68 mmol), morpholine (0.23 mL, 2.68 mmol), diethylphosphonium cyanide (0.41 mL, 2.68 mmol) were added under nitrogen and ice cooling. After stirring at room temperature for 3 hours, it was left at the same temperature 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 sequentially washed with an aqueous potassium hydrogen sulfate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol, 100: 0-9: 10, v / V) to obtain (5S, 6S)-2-[1-(4-? Porphyrincarbonyl-1,3 -Azadin-2-yl) oxetidine_3 -yl] thio-6-[(R)-1-hydroxyethyl] _carbobin-2-ene-3 -Carboxylic acid ·· -nitrobenzyl ester as a pale yellow amorphous 1.0 4 g, yield 7 7.8% -131- 200418858 1 H-NMR (400MHz, CDC13): δ 8.22 (2H, d, J = 8.8Hz) , 7.73 (1H, s), 7.65 (2H, d, J = 8.8Hz), 5.5〇 (1H, d, J = 13.9Hz), 5.25 (1H, d, J = 13.9Hz), 4.51 (2H, q , J = 8.1Hz), 4.31-4.07 (5H, m), 4.31-3.50 (8H, m), 3.22 (1H, dd, J = 7.0, 2.6Hz), 3.12-2.98 (2H, m), 2.25- 1.50 (1 H, m), 1.37 (3H, d, J = 5.9Hz); MS (FAB) m / z: 600 (M + H) +. (6 g) (5 S, 6 S)-2 · [1-(4 -morpholinecarbonyl · i, 3-sulino-2-oxo) pyrimidine-3-yl] thio-[(R) -i-Ethyl] -carbon ligand -2 -ene-3 -carboxylic acid sodium salt The (5S, 6S) _2- [1- (4-morpholinoido-1,3 -sulfonazole-2 -yl) produced in Example 6 (6f) Azetidin-3 -yl] thio-6-[(R) -l-hydroxyethyl] -carbon N--2-en-3-carboxylic acid p-nitrobenzyl ester (1.0 (^, 1.67111111〇1) was dissolved in 30 mL of tetrahydrofuran, 0.1 M sodium phosphate buffer solution (卩 117.0) 301111 ^, sold at 7.5% In the presence of carbon (1,000 g), contact hydrogen reduction at 30 ° C for 2 hours. After the reaction was completed, the reaction mixture was filtered, and ether and distilled water were added to the filtrate to perform a liquid separation operation. The aqueous layer was concentrated under reduced pressure and used Chromatorex-ODS DM1020T (manufactured by Fuji Silica) was purified by reverse-phase silica gel column chromatography (distilled water: acetonitrile, 100: 0-95: 5, V / V) and freeze-dried to obtain the target compound (5 S, 6 S )-2-[1-(4 -morpholinecarbonyl-1,3-oxazole-2 -yl) azetidin-3 -yl] thio-6-[(R)-1 -Ethyl]- Carbophenan-2 -dilute-3 · carboxylic acid sodium salt 3 27 mg, yield 40.3%. -1 3 2-200418858 UV (H20) 300, 222 nm; IR (KBr) vmax 1 75 8, 1619, 1463, 1441, 1 3 8 8, 1247, 1114 cm _1; 1H-NMR (400MHz 5D2〇, TSP ): Δ 7.77 (1H, s), 4.62-4.56 (2H, m), 4.34-4.19 (3H, m), 4.11-4.07 (2H, m), 3.90-3.55 (8H, m), 3.41 (1H, dd, J = 6.6, 2.6Hz), 3.16-3.04 (2H, m), 1.29 (3H, d, J = 6.6Hz); MS (FAB) m / z: 487 (M + H) +. (Example 7) (5 S '6 S)-2-[1-(4-aminocarbamoyl-i, 3-D oxazolyl 2 -yl) azetidin-3 -yl] thio-6-[( R)-1 -Hydroxyethyl] -carbophenan-2 -ene-3 -carboxylic acid 1-(isopropoxycarbonyloxy) ethyl ester (compound number ethyl ester) Code 2-5 29 compound 1- (Isopropoxycarbonyloxy

The (5 S, 6 S)-2-[1-(4-aminomethylamidino-1, 3-oxazole-2 -yl) azetidin-3 -yl] thio group produced in Example 5 was- 6-[(R) -1-Hydroxyethyl] -carbopenan-2-ene-3-carboxylic acid sodium salt (U7mg, 0.425mmol) was dissolved in 9 mL of dimethylacetamide, under nitrogen at Add 1-iodoethyl-isopropyl carbonate (132 mg, 0.5 10 mmol) at ° C and stir for 1 hour. After the reaction was completed, ethyl acetate was added to the reaction system, and the organic layer was sequentially washed with -133- 418858 10% saline 5% aqueous sodium thiosulfate solution, filtered through anhydrous sulfuric acid, and the quenched solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol, 100: 93-7: 7, Wv) to obtain (5 s, 6 S) _ 2: [1 _ (4 _ amine formamyl) _ 丄, 3 _thiazole_ 2 • yl) azetidin-3 _yl] thio_ 6 _ [(R) _ 丄 _hydroxyethyl] _carbon complex _ 2 _ Shaoxi-3-quaternary acid 1 -(Isopropoxycarbonyloxy) ethyl ester 166 mg as a pale yellow amorphous solid, yield 75%. 1H-NMR (400MHz, CDC13): δ 7.80 (1Η, s), 6.89 (0.5H, q, J = 5.9Hz), 6.87 (〇 · 5Η, q, J = 5.9Hz), 6.6 7 (1H , Bs), 5.49 (1H, bs), 4.96-4.86 (1H, m), 4.54-4.47 (2H, m), 4.26-4.15 (3H, m), 4.14-4.07 (2H, m), 3.19 -3.15 (1H, m), 3.09-2.96 (2H, m), 1.96- 1.92 (1H, m), 1.60- 1.58 (3H, m), 1.36-1.28 (9H, m); MS (FAB) m / z: 525 (M + H) +; HRMS (ESI) m / z: calculated 値 C22H28〇9N4SNa (M + Na) +: 547.1474. Found 54: 547.1473. (Example 8) (5 S, 6 S)- 2-[1-(4 -morpholinecarbonyl-1, 3 -epidazol-2 -yl) azetidin-3 -yl] thio-6-[(R)-1 -hydroxyethyl] -carbon ligand Nin-2-ene-3-carboxylic acid 1_ (isopropoxycarbonyloxy) ethyl ester (Compound Nos. 2-5 90-Compound No. 1-(isopropoxycarbonyloxy) ethyl ester) -134- 200418858

HO

(5 s, 6 S)-2-[1-(4-morpholinecarbonyl-1 '3 -oxazole-2 -yl) azetidin-3 -yl] thio group produced in Example 6 -[(R)-1 -Hydroxyethyl] -carbobin-2-ene-3 -carboxylic acid sodium salt (79 mg, 0.162 mmol) was dissolved in 5 mL of dimethylacetamide, and under nitrogen, 1 was added under -Iodoethyl-isopropyl carbonate (55 mg, 0.211 mmol), and stirred for 1 hour. After the reaction was completed, ethyl acetate was added to the reaction system, and the organic layer was washed successively with 10% saline '10% sodium thiosulfate aqueous solution, saturated sodium bicarbonate water, and water' saturated saline, and dried under anhydrous magnesium sulfate. , Filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate, 1: 4; ethyl acetate: methanol, 10: 0: 93: 7, v / v) to obtain (5S, 6S)- 2-[1-(4 -morpholinecarbonyl-1,3-oxazole-2 -yl) azetidin-3 -yl] thio-6-[(R)-1 -hydroxyethyl] -carbon ligand 68.0 mg of 2-yen-3-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester as a pale yellow solid, yield 70%. IR (KBr) vmax 3414, 1781, 1760, 1621, 1 375, 1 268 cm-1 1 H-NMR (500MHz, CDC13): δ 7.74 (1H, s), 6.89 (0.5H, q, J = 4.9Hz )? 6.87 (0.5H, q, J = 4.9Hz), 4.96-4.88 (1 H, m), 4.5 3 -4.48 (2H, m), 4.25 -3.65 (1 3 H, m), 3.18-3.16 ( 1H, m), 200418858 3.09-2.96 (2H, m), 1.75 (1H, d, J = 4.9Hz), 1.61 ^ 1.59 (3H, m), 1.37-1.30 (9H, m) i MS (FAB) m / z: 595 (M + H) +; HRMS (ESI) m / z: C26H34O10N4SNa (M + Na) + calculation 値 6 1 7.1 893 · Measured ·: 6 17.1 902 · (Experiment Example 1) In vitro antibacterial activity and antibacterial activity The activity can be measured by agar plate dilution method, and the minimum development inhibitory concentration (μ g / m 1) against various pathogenic bacteria can be obtained. The results are shown in Table 6. The test bacteria A, B and C in the table are shown below. A: Staphylococcus aureus 209P strain B: Pneumococcus strain 10 6 64 (penicillin-resistant strain) c: Haemophilus influenzae 9 7 8 7 (β-hyperactamase-producing strain) Test compound in the present invention The structural formula is shown below. 200418858

CONHo COO'Na + Example 1 Compound

CON 〇 -s- COO'Na +

CON 〇 COO'Na + Compound llVIe of Example 2 Compound of Example 2

HO CO-N XONH2 COO'Na + compound of Example 3

NH2 f Η H

CON H C〇〇H Example IMe body

CONH, COO'Na + Example 5 Compound '2

HO CH3

CON O COO'Na + IMe bone of the compound of Example 6

-1 3 7-200418858 (Table 6) Minimum development prevention concentration (Pg / m 1) Test compound ABC of test compound Example 1 Compound wound 12 0.10 0.20 (IMe of compound 1 of Example 0.05 0.20 0.10) Example 2 Compound 0.05 0.20 0.39 (Ime body of compound of Example 2 0.10 0.39 0.39) Example 3 compound 0.05 0.20 0.39 (Ime body of compound of Example 3 0.10 0.39 0.39) Example 5 compound 0.025 0.20 0.39 (Ime body of compound of Example 5 0.05 0.20 0.10) Compound of Example 6 0.05 0.20 0.39 (IMe body of compound of Example 6 0.05 0.20 0.39) The above results show that the compound of the present invention has a strong antibacterial activity. (Experiment 2) In vitro antibacterial activity (bactericidal effect) The H. influenzae 1 2760 (BLNAR) bacterial solution was shake-cultured at the end of the logarithmic colony period (about 108 CFU / ml), each compound Add at 1/4, 1 or 4xMIC concentration and shake culture at 37 ° C (use 3 test tubes for each concentration). The number of bacteria was measured 1, 2, and 3 hours after the compound was added. The method of dispersive analysis of repeated measurement data at each concentration was used to test whether the compound of the example and its IMe compound had a bactericidal effect. The test results are shown in Tables 7 and 8. -138- 200418858 (Table 7) 満 _ lion Yanxiantaixiantai (xMIC) ^ mCLo & oCFUM) 〇 Look around 〇 8.4 1 f * 0 8.3 Lion! J1 Hua 174 7.8 1 7.1 4 6.5 Real 5_1 Huabei IMe body 174 8.2 1 7.9 4 7.0 2 Recitation 0 8.8 Zhen_1 Huan do not 1/4 7.4 1 73 4 6.7 plane 丨 J1 Huae »1Me body 1 / 4 8.4 1 7.9 4 7.2 3 and 0 8.9 Window_1 Debe 1/4 7.4 1 7.1 4 6.7 _1 Mixed age body 1/4 8.2 1 7.3 4 7.2 All concentrations of the example compounds and their IMe bodies can be significant Ground (1 / 4xMIC: P < 0.01, lxMIC: P < 0 · 0 1, 4 χ MIC: P < 0.0 5) to reduce the number of bacteria. -139- 200418858 (Table 8) Time after addition (h) Test compound concentration (xMIC) Number of bacteria (Log1GCFU / ix) 0 Control group 0 7.9 1 Control group 0 8.7 Example 5 compound 1/4 8.0 1 7.3 4 7.1 IMe body of the compound of Example 1/4 8.3 1 8.2 4 7.1 2 Control group 0 8.9 Example 5 compound of 1/4 7.8 1 7.2 4 6.6 Ime body of the compound of Example 5 1/4 8.3 1 7.9 4 7.2 3 Control group 0 9.0 Compound of Example 5 1/4 7.4 1 7.4 4 6.9 IMe body of Compound of Example 5 1/4 8.2 1 7.7 4 7.1

All concentrations of the example compounds and their 1 Me body can significantly reduce the number of bacteria (1 / 4XMIC: P < 0.01, lxMIC: P < 0.001, 4xMIC: P < 0.05). The above results show that the compound of the present invention has stronger bactericidal activity than its Me body. -140- 200418858 (Experiment Example 3) In vivo antibacterial activity (Mouse Infection Treatment Experiment) 4 weeks old ddY male mice (SLC Japan), H. influenzae 12760 (BLNAR) A nasal inoculation of 0.1 ml (6 x 10-6 x 10 CFU / mouse) in the nasal cavity caused infection. After 1 and 6 hours of infection, the test compound (20 mg / kg) and cilastatin (CS. 20 mg / kg, only 1H body) were administered subcutaneously to 0.1 ml. Seven mice were used in one group, and the number of bacteria in the lungs was dissected and determined 20 hours after infection, and the difference between the control group and the control group (without treatment) was calculated. The test results are shown in Table 9. (Table 9) Test compound J Log10CFU / lung Example 1 compound + CS 1.9 (Example 1 compound IMe body 0.7) Example 2 compound + CS 1.6 (Example 2 compound IMe body 1.0) Example 3 compound + CS 2.0 (Ime form of compound of Example 3 0.7) Example 4 compound + CS 1.8 (Ime form of compound of Example 4 1.2) Example 5 compound + CS 2.1 (Ime form of compound of Example 5 0.4) Example 6 compound + CS 1.6 (Ime-body 0.8 of the compound of Example 6) (Experiment Example 4) Antibacterial activity in vivo (Mouse Infection Treatment Experiment) Male mice of ddY line (Japanese SLC company) influenzae) 1 2760 (BLNAR) was nasally inoculated from the nasal cavity at 0.1 points (4 X 106 CFU / mouse), causing infection. Infection 1

After 6 hours, a test compound (20 mg / kg) and a mixture of c i 1 a s t a t in (C S -1 4 1-200418858. 20 mg / kg) were administered subcutaneously to 0 ml. One group of mice was dissected to determine the number of bacteria in the lungs after 7 hours of infection with 7 ′ infections, and calculated the difference from the control group (without treatment). The test results are shown in Table 10. (Table 10) Test compound △ Log10CFU / lung Example 1 compound + cs 2.0 (Ime form of compound of Example 1 + CS 0.9) Example 5 compound + CS 1.8 (Ime form of compound of Example 5 + CS 0.9) or more As a result, when cilastatin is used, the compound of the present invention has stronger antibacterial activity than its Me body. (Preparation Example 1) An injection was prepared by dissolving 500 mg of the compound of Example 5 in 5 m 1 of distilled water for injection, followed by filtration through a sterilizing membrane and freeze-drying to obtain a freeze-dried preparation for injection. (Formulation Example 2) Capsule Example 5 compound 50 mg lactose 1 2 8 mg corn starch 70 mg, magnesium stearate 2 mg 250 mg. The above-mentioned prescription powder was mixed, and 250 mg of powder was filled into a No. 3 capsule through a 60-mesh sieve 'to obtain a capsule. (Preparation Example 3) Lozenge -142- 200418858 Example 5 lactose corn starch magnesium stearate After the above prescription was prepared, a tableting machine was used to sugar-coat. Industrial use β-hydantoin of the above-mentioned or its ester derivative of the present invention [schematically speaking, te 〇 compound 500 mg 1 26 mg 2 3 mg 1 mg g 200 mg. The powders were mixed, wet-granulated with corn starch paste, and dried to form 2,000 mg per tablet. If necessary, it may be added. The carbon compound or its pharmacologically acceptable salt of the general formula (I) has excellent antibacterial activity. It produces enzyme stability to various pathogenic bacteria and can be used as medicine, especially as an antibacterial agent. Ming] -143-

Claims (1)

200418858 Scope of patent application 1. A carbon compound or its pharmacologically acceptable salt or its ester derivative of the following formula: [In the formula, R 1 is a group represented by (1) Formula C00R3 [wherein 'R3 is hydrogen, C] -C6 alkyl or c3-C6 cycloalkyl], (2) The group of the table [wherein R4 and R5 are the same or different, each is a hydrogen atom, Cl-C6 alkyl (there may be 1 to 3 substituents which are the same or different from the substituent group A described below), C3 -C6 cycloalkyl, 3 to 7-membered polycyclic group or C6-C1G aryl (may have 1 to 2 substituents which may be the same or different from the substituent group b described below), or may be shared with adjacent nitrogen atoms Forms 3 to 7 member nitrogen-containing polycyclic groups (may have 1 or 2 substituents which are the same or different from the following substituent group B)], (3) cyano, (4) formula CH2OR6 Base [wherein R6 is hydrogen, alkyl or C3-C6 cycloalkyl] or (5) the base represented by formula CH2NR7R8, [wherein 'R is nitrogen' Ci ~ C6 base, C3-C6 ring base The group 'R8 is hydrogen, CC 6 alkyl, c 3-C 6 cycloalkyl, CC 6 alkyl, and (C6-C1 () aryl) carbonyl (may have a phase selected from the following substituent group B- 144- 200418858 Same or different 1 or 2 substituents) '(Cl-c6 alkoxy) carbonyl, 5 or 6-membered aromatic polycyclic mineral groups' alkylsulfonium Or C6 ~ C10 groups, or R7 and R8 together with adjacent nitrogen atoms to form a succinimide group (which can be fused with a phenyl ring)], R 2 is a hydrogen atom or a C i-c 6 alkane Group, η is 1, 2 or 3, X is a sulfur atom or an oxygen atom, the substituent group A is a hydroxyl group, an amine group (which can be substituted with 1 or 2 C, C and 6 alkyl groups), and carbamoyl group (amino group Partially replaceable with 1 or 2 C ^ C6 groups), carboxyl, cyano and ^^^ alkoxy groups, the substituent group B is a hydroxyl C! -C4 alkyl group, and an amine Ci-C4 alkyl group (The amine group can be substituted with 1 or 2 C 1 -C 6 alkyl groups), the aminoformamyl group (the amine group can be substituted with 1 or 2 C!-C 6 alkyl groups), Amine (can be substituted with 1 or 2 C! -C6 alkyl), c! _C6 丨 oxy and C ^ C6 alkyl]. 2. A carbon compound or a pharmacologically acceptable salt or an ester derivative thereof according to item 1 of the scope of the patent application, wherein R1 is a group represented by the formula Connr4R5, and a cyano group is represented by the formula CH2N r7R8. 3. The carbon compound or pharmacologically acceptable salt or ester derivative thereof according to item 1 of the scope of the patent application, wherein R1 is a base represented by the formula CONR4R5 or a base represented by the formula CH2NR7R8. 4. The carbon compound or its pharmacologically acceptable salt or its ester derivative according to item 1 of the scope of patent application, wherein R1 is the base represented by the formula C0Nr4R5 -145- 200418858 5. As the scope of application for patents 1 to 1 The carbon compound or pharmacologically acceptable salt or ester derivative thereof according to any one of 4 items, wherein R 2 is hydrogen or Ci-C 3 radical. 6. The carbon compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of claims 1 to 4 in the scope of the patent application, wherein R 2 is a hydrogen atom. 7. The carbon compound or its pharmacologically acceptable salt or its ester derivative according to any one of the claims 1 to 6, wherein R3 is hydrogen or C! -C3. 8. The carbon compound or a pharmacologically acceptable salt thereof or an ester derivative thereof according to any one of claims 1 to 6, wherein R3 is hydrogen, methyl or ethyl. 9. A carbon compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of items 1 to 8 in the scope of the patent application, wherein R 4 is hydrogen or C! -C 3 alkyl. iO. A carbon compound or a pharmacologically acceptable salt thereof or an ester derivative thereof according to any one of claims 1 to 8 in the scope of the patent application, wherein R 4 is hydrogen, methyl or isopropyl. 11 · The carbon compound or the pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 10 in the scope of the application for a patent, wherein R 5 is hydrogen, and C ^ C 6 alkyl (may be selected from substitutions) 1 to 3 substituents of the same or different group A) or 4 to 6 member nitrogen-containing polycyclic groups. 1 2 · The carbon compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of claims 1 to 10 in the scope of application for a patent, wherein R 5 is hydrogen ′ c! -C6 alkyl (optionally 1 to -146-2 04188583 (3 substituents which are the same or different from the substituent group A), azetidinyl 'pyrrolidinyl or piperidinyl. 1 3. The carbon compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of items 1 to 8 of the scope of the patent application, wherein R 1 2 3 4 and R 5 are co-formed with adjacent nitrogen atoms 4- to 6-membered nitrogen-containing polycyclic group (may have 1 to 2 substituents which may be the same or different from the substituent group B). 14. A carbon compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of claims 1 to 8 in the scope of application for a patent, wherein R 4 and R 5 and an adjacent nitrogen atom together form an azetidinyl group, piperin Group, morpholinyl group or thiomorpholinyl group (these groups may have 1 to 2 substituents which may be the same or different from the substituent group B). 15 · The carbon complex compound or a pharmacologically acceptable salt thereof or an ester derivative thereof according to any one of claims 1 to 14 in the scope of the patent application, wherein R 6 is hydrogen or a c p C 3 alkyl group. 16 · The carbon complex compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of items 1 to 14 in the scope of patent application, wherein R 6 is hydrogen atom -147- 1 7 · The carbon complex compound or a pharmacologically acceptable salt thereof or an ester derivative thereof according to any one of items 1 to 16 in which R 7 is hydrogen or a C 1 -C 3 compound. 3 1 8 · The carbon complex compound or the pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 16 in the scope of the patent application, wherein R 7 is hydrogen or methyl 5. 6 1 9. The carbon 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, in which R 7 is a hydrogen atom 20. A carbon compound or a pharmacologically acceptable salt thereof or an ester derivative thereof according to any one of the items i to i 9 in which R 8 is hydrogen, an alkyl group, an alkyl fluorenyl group, or a benzyl fluorenyl group (may have a substituent selected from 1 or 2 substituents which are the same or different in the group B) '(C1-C3 hoxy) ore, thiophene curtain, sulfanyl, or fluorene π ore. 21 · The carbon compound or the pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 19, wherein R 8 is hydrogen and benzamidine (optionally selected from the group of substituents) 1 to 2 substituents which are the same or different in B), thiophene-2-carbonyl, furan-2-carbonyl or pyridine-3-carbonyl. 22 · As in any one of the scope of patent applications No. 1 to No. 21 Carbamate compounds or pharmacologically acceptable salts or ester derivatives thereof, wherein n is fluorene. 23. The carbon complex compound or a pharmacologically acceptable salt thereof or an ester derivative thereof according to any one of claims 1 to 22 in the scope of patent application, wherein X is an oxygen atom. 24. For example, a carbon compound or a pharmacologically acceptable salt or an ester derivative thereof in the scope of application for a patent, wherein R1 is a group represented by the formula CONR4R5 (where R4 is hydrogen or CrCs alkyl, and R5 is hydrogen, 〇γ (: 6 alkyl (may have the same or different χ to 3 substituents selected from substituent group A) or 4 to 6 member nitrogen-containing polycyclic group), R2 is hydrogen, n is 1, X is An oxygen atom or a sulfur atom. 25. A carbon compound or a pharmacologically acceptable salt or an ester derivative thereof according to item 1 of the scope of the application, wherein R 1 is a group represented by the formula CONR 4 r 5 (wherein, R4 is hydrogen, methyl or isopropyl, R5 is hydrogen, Cl_C6 -148- 200418858 alkyl (may have 1 to 3 substituents which may be the same or different from substituent group A), azetidinyl, pyrrolidinyl Or piperidinyl), η is 1, X is an oxygen atom or a sulfur atom. 26. A carbon compound or a pharmacologically acceptable salt thereof or an ester derivative thereof according to item 1 of the application, wherein R] is the formula C. The bases represented by NR 4 R 5 (wherein R 4 and R 5 form a 4 to 6 member nitrogen-containing polycyclic group with adjacent nitrogen atoms (there may be 1 or 2 of the same or different from the substituent group B) Group)), R2 is hydrogen, η is 1, and X is an oxygen atom or a sulfur atom. 27. For example, a carbon compound or a pharmacologically acceptable salt thereof or an ester derivative thereof according to item 1 of the application, wherein R1 is formula C 〇NR4R5 (in the formula, R 4 and R 5 and adjacent nitrogen atoms together form azetidinyl, piperidinyl, morpholinyl or thiomorpholinyl (this group is the same or different from the substituent group B) , 1 or 2 substitutable groups)), R2 is hydrogen, η is 1, X is an oxygen atom or a sulfur atom. 2 8 · As a carbon compound or a pharmacologically acceptable salt thereof according to the scope of patent application No. 1 or An ester derivative thereof, in which R1 is cyano, R2 is hydrogen, η is 1, X is an oxygen atom or a sulfur atom. 29. For example, a carbon compound or a pharmacologically acceptable salt thereof or an ester derivative thereof R1 is a group represented by the formula C H2N R7R8 (where R7 is a hydrogen atom or a Cl_c3 alkyl group, R8 is hydrogen, Ci_C3 group, C 1-C3 group group, optionally selected 1 to 2 substituents which are the same or different from the substituent group B), (C ^ Cs alkoxy) carbonyl, thiophenecarbonyl, furancarbonyl or pyridinecarbonyl), R 2 is -149- 20041 8858 hydrogen, η is 1, X is an oxygen atom or a sulfur atom. 3 0. As the carbon compound or its pharmacologically acceptable salt or its vinegar derivative of item 1 of the scope of the application for patent, wherein R is represented by the formula C H2M R7r8 (In the formula, R7 is a hydrogen atom or a methyl group, r8 is hydrogen, benzamidine (may have 1 to 2 substituents which may be the same or different from the substituent group B), thiophene-2-carbonyl, furan -2 -carbonyl or pyridine-3 -carbonyl), R 2 is hydrogen, η is 1, and X is an oxygen atom or a sulfur atom. 31. A medicinal composition containing an active ingredient selected from the group consisting of a carbon compound or a pharmacologically acceptable salt thereof or an ester derivative thereof according to any one of claims 1 to 30. 3 2 · An antibacterial agent containing an active ingredient selected from the group consisting of a carbon compound or a pharmacologically acceptable salt thereof or an ester derivative thereof as set forth in any one of claims 1 to 30 of the scope of patent application. 3 3. — A therapeutic or preventive agent for bacterial infections, containing an effective ingredient selected from the group consisting of a carbon compound or a pharmacologically acceptable salt thereof or an ester derived from any one of claims 1 to 30 Thing. Cao 34. A therapeutic agent for bacterial infections, which contains an active ingredient selected from the group consisting of a carbon compound or a pharmacologically acceptable salt thereof or an ester derivative thereof as set forth in any one of claims 1 to 30 of the scope of patent application. 3 5 · —A therapeutic or preventive agent for respiratory system infections' contains an effective ingredient selected from the group consisting of a carbon compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 30 of the scope of patent application Ester derivatives. 3 6. —A therapeutic agent for respiratory infections, containing an active ingredient selected from the group consisting of carbophenanthine-150-200418858 as in any one of claims 1 to 30 of the scope of patent application, or Pharmacologically acceptable salts or their ester derivatives. 37. A method for manufacturing a pharmaceutical composition, using a carbon compound or a pharmacologically acceptable salt or an ester derivative thereof according to any one of claims 1 to 30 of the scope of patent application. 38. 39. A method for treating or preventing a bacterial infection, which comprises administering a pharmacologically effective amount of a carbon compound or a pharmacologically acceptable salt or an ester thereof according to any one of claims 1 to 30 in the scope of patent application. Derivatives to warm-blooded animals. A method for treating or preventing a bacterial infection, which comprises administering a pharmacologically effective amount of a carbophenan compound, or a pharmacologically acceptable salt thereof, or an ester derivative thereof according to any one of claims 1 to 30 in the scope of the patent application. people. 40. The method of treatment or prevention described in item 38 or item 39 of the scope of patent application, wherein the bacterial infection is a respiratory infection. -15 1-200418858 (1) Designated representative map (1) The designated representative map in this case is: None. (II) Brief description of the component representative symbols in this representative picture #J. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention