JPH10505582A - Difluorostatone antiviral agent - Google Patents

Abstract

(57) Abstract: The present invention provides a compound of the general formula (I) useful as an antiviral agent: The present invention provides a novel difluorostatone derivative of More specifically, these novel compounds are useful as inhibitors of retroviral proteases required for replication, particularly HIV-1 and HIV-2 viral proteases, to prevent or prevent infection by human immunodeficiency virus (HIV). It is useful in therapy and in the treatment of consequent pathological diseases such as acquired immune deficiency syndrome (AIDS) in mammals infected by the HIV virus.

Description

DETAILED DESCRIPTION OF THE INVENTION                   Difluorostatone antiviral agentBackground of the Invention   Retroviruses use their genetic material as the ribonucleic acid rather than as deoxyribonucleic acid. It is a virus that transports as an acid. Retroviruses are widespread in humans Associated with various diseases. One of these diseases is AIDS. Useful for treating AIDS Other antiviral agents have been disclosed (e.g., in patent applications EP 0 218 688, EP 0 218 352 000 and PCT / US 91/099741), however, the compounds of the invention Not disclosed. PCT / US91 / 09741 is hereby incorporated by reference.SUMMARY OF THE INVENTION   The present invention provides a compound represented by the general formula (I): And stereoisomers, hydrates, isosteres and pharmaceutically acceptable salts thereof It is about.   In the above equation,   P₁Is   [Where T is [(O)_b-W-R] and T 'is [(O)_b'-W'-R'] or water And W and W ′ are each independently C_{1 ~ 6}Alkylene Or does not exist and   When W is directly bonded to a nitrogen atom in R, W is C_{Two ~ 6}Alkylene ,   When W 'is directly bonded to the nitrogen atom in R', W 'is C_{Two ~ 6}Alkylene And   When R or R 'are each independently aryl, W or W' is Independently C_{1 ~ 6}Alkylene];   P_TwoIs C_{1 ~ 6}Alkyl, cyclopentyl, hydroxy C_{1 ~ 6}Alkyl, phenyl , Benzyl or 3-tetrahydrofuryl;   R and R ′ are each independently —CH_TwoCHO, hydroxy C_{1 ~ 6}Alkyl, C_{1 ~ 6} Alkoxy C_{1 ~ 6}Alkyl, C_{1 ~ 6}Alkyl, C_{1 ~ 6}Alkenylene, piperazinyl, substituted piperazinyl, piperidyl, molybdenum Rufolinyl, pyridyl, pyrazinyl, pyrimidinyl or phenyl; and Substituted piperazinyl may have CHO, C (O) NHR ′ on its one nitrogen atom._Four, C_{1 ~Four} Alkyl or CO_TwoR_FourPiperazinyl substituted by   R₁Is Is;   R_ThreeIs C_{1 ~ 6}Allenyl C_{1 ~ 6}Alkoxy, C_{1 ~ 6}Alkylene, hydroxy C_{1 ~ 6}A Lucil, C_{1 ~ 6}Alkyl or OH;   R_FourIs C_{1 ~ 6}Alkyl, phenyl or benzyl;   R ′_FourIs hydrogen or C_{1 ~ 6}Alkyl;   R_FiveIs hydrogen, C_{1 ~ 15}Alkyl, OH, hydroxy C_{1 ~ 15}Alkyl, -CH ([(CH_Two)_d -O-CH_Two]_x-R ′₈)_Two, -CH_TwoSi (CH_Three)_Two(R_Three), PDL,-(C_{1 ~ 6}Alkylene) -OR_Four, -CH (Y) ( Z), (Where PDL is-(CH_Two)_a-2-, 3- or 4-pyrudyl or p Substituted benzyloxy (substituted nitro, OH, amino, C_{1 ~ 6}Alkoki Si, hydroxy C_{1 ~ 6}Is alkylene or halogen); Y is C_{1 ~ 15} Alkyl, hydroxy C_{1 ~ 15}Alkyl, C_{1 ~ 6}Alkyl or-(CH_Two)_e-C₆H_Four-(V)_e '; Z is-(CH_Two)_d-O-CHO, C_{1 ~ 6}Alkylene-O- (CH_Two)_d-(O-CH_Two-CH_Two)_e-O-C_{1 ~ 6} Alkyl, CHO, CO_TwoR_Four, CO_TwoNHR_Four,-(CH_Two)_d-O- (CH_Two)_d'-R'₇,-(CH_Two)_e-OR_Four Or (Where V is OR_FourOr hydroxy C_{1 ~ 6}Alkylene and R '₇ Is piperazinyl, substituted piperazinyl, piperidyl or morpholinyl D '= 2).   R₆Is R_FiveIf is hydrogen₆Is a condition other than hydrogen R_FiveAs defined for or R_FiveAnd R₆Are these combined Together with the nitrogen atom Selected from the group consisting of:   R₇Is CH_TwoOR_Four, C (O) NHR_FourOr CHO;   R ′₇Is piperazinyl, substituted piperazinyl, piperidyl, morpholinyl , Pyridyl, pyrazinyl, pyrimidinyl or phenyl (in these groups, The substituted piperazinyl can be CHO, C (O) NHR on one of its nitrogen atoms_Four, C_{1 ~Four} Alkyl or CO_TwoR_FourIs piperazinyl substituted by   R₈Is (H, OH) or = O;   R ′₈Is pyrimidyl, pyridyl, pyrazinyl or phenyl;   a is 0, 1, 2, or 3;   b and b 'are each independently 0 or 1;   d and d 'are each independently 1 or 2;   e and e 'are each independently 0, 1 or 2; and   x is 0 or 1.DETAILED DESCRIPTION OF THE INVENTION   The terms “halo”, “halogen” or “halide” are chlorine, bromine or iodine. Means elementary atom.   Isotopes of the compounds of formula I include (a) P₁And P_TwoSubstituted α-amino acid residue is unnatural Compound in configuration (if there is a natural configuration) or (b) example (Keto), -CH (OH) CH_Two-(Hydroxy), -CH (NH_Two) CH_Two-(Amino), -CH_TwoCH_Two-(Carbide Compounds where the normal peptide amide bond, such as You. Preferably, the compounds of the present invention should not be in the form of isotopes. Especially Unless otherwise stated, the α-amino acids are preferably in the L-configuration.   The compounds of the invention may be in free form, eg, amphoteric or salt form, eg, acid addition salts Or it can be in the form of an anionic salt. Compounds in free form are available in the art. Can be converted to the salt form by methods known in and vice versa It is possible.   Pharmaceutically acceptable salts of the peptides of formula I (water- or oil-soluble or dispersible Salts in the form of a compound) are usually formed from, for example, inorganic or organic acids or bases. Non-toxic salts or quaternary ammonium salts. Examples of such acid addition salts are , Acetate, adipate, alginate, aspartate, benzoate, ben Zensulfonate, acid sulfate, butyrate, citrate, camphorate, camphor sulfone Acid salt, cyclopentane propionate, digluconate, dodecyl sulfate, eta Sulfonate, fumarate, glucoheptanate, glycerophosphate, hemisulfate Acid salt, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 -Hydroxyethanesulfonate, lactate, maleate, methanesulfonate , 2-naphthalenesulfonate, nicotinate, oxalate, paemoate, pectin Ninate, persulfate, 3-phenylpropionate, picrate, pivalate , Propionate, succinate, tartrate, thiocyanate Acid salts, tosylate and undecanoate. The base salt is an ammonium salt Alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, E.g. calcium and magnesium salts, salts with organic bases, e.g. dicyclohexyl Silamine salts, N-methyl-D-glucamine salts, and amino acids such as And salts with nin and lysine. Further, the basic-nitrogen-containing group is a halogenated group. Chloride, bromide of lower alkyls such as methyl, ethyl, propyl and butyl And iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dib sulfate Tyl and diamyl sulfates; long-chain halides such as decyl, lauryl, myris Chloro and stearyl chlorides, bromides and iodides; aralkyl halides It can be quaternized with agents such as benzyl bromide and phenethyl bromide. Wear.   Hydrates of the compounds of formula I have the partial structure And generally in active form in end use applications You.   In general, the term "alkyl" as used herein, in particular, Unless otherwise specified, straight-chain, branched-chain and cyclic groups, especially methyl, ethyl, isoprene Ropyl, n-butyl, t-butyl, -CH_Two-t-butyl, cyclopropyl, n-propyl Ropyl, pentyl, cyclopentyl, n-hexyl, cyclohexyl and cyclo Include groups such as rohexylmethyl. As used herein of The term "aralkyl" refers to an alkylene bridge moiety, preferably methyl or ethyl. And an aryl moiety attached to the aryl group.   "Aryl" includes both carbocyclic and heterocyclic moieties, of which , Phenyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, indazoly Of particular interest are furyl, furyl and thienyl. These parts are Sex, such as 2-, 3- or 4-pyridyl, 2- or 3-furyl and thie Nil, 1-, 2- or 3-indolyl or 1- and 3-indazolyl, Including dihydro and tetrahydro analogs of furyl and thienyl moieties You. Also within the scope of the term "aryl" are fused carbocyclic moieties, e.g. Pentalenyl, indenyl, naphthalenyl, azulenyl, heptalenyl, acena Phthenyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl , Acephenanthrenyl, aceanthrenyl, triphenylenyl, pyrenyl , Chrysenyl and naphthacenyl. Also, the term "aryl" Within the scope are other heterocyclic groups such as 2- or 3-benzo [b] thienyl, 2 -Or 3-naphtho [2,3-b] thienyl, 2- or 3-thianthrenyl, 2H -Pyran-3- (or 4- or 5-) yl, 1-isobenzo-furanyl, 2H -Chromen-3-yl, 2- or 3-phenoxathiinyl, 2- or 3- Pyrrolyl, 4- or 3-pyrazolyl, 2-pyrazinyl, 2-pyrimidinyl, 3 -Pyridazinyl, 2-indolizinyl, 1-isoindolyl, 4H-quinolidine- 2-yl, 3-isoquinolyl, 2-quinolyl, 1-phthalazinyl, 1,8-naphthy Lysinyl, 2-quinoxalinyl, 2-quinazolinyl, 3-cinnolinyl, 2-p Teridinyl, 4aH-f Lubazol-2-yl, 2-carbazolyl, β-carbolin-3-yl, 3-f Enanthridinyl, 2-acridinyl, 2-perimidinyl, 1-phenazinyl, 3-isothiazolyl, 2-phenothiazinyl, 3-isoxazolyl, 2-pheno Xazinyl, 3-isochromanyl, 7-chromanyl, 2-pyrolin-3-yl, 2-imidazolidinyl, 2-imidazolin-4-yl, 2-pyrazolidinyl, 3 -Pyrazolin-3-yl, 2-piperidyl, 2-piperazinyl, 1-indolini 1-isoindolinyl, 3-morpholinyl, benzo [b] isoquinolinyl, And benzo [b] furanyl (including these positional isomers).   Similarly, the term “alkylene” includes straight or branched moieties. . Some examples of branched alkylene moieties include ethylethylene, 2-methyl Limethylene, 2,2-dimethyltrimethyle   C_{1 ~ 6}Alkyl, C_{1 ~ 6}Allenyl, C_{1 ~ 6}Alkoxy and hydroxy C_{1 ~ 6}Al All like kill (C_{1 ~ 6}) Moiety is more preferably C_{1 ~ 3}Portion (1-6 charcoal Containing 1 to 3 carbon atoms in place of the elementary atoms).   The fluorenylmethyloxy moiety is the moiety commonly referred to by its abbreviation FMOC. And attached to the 9-position of the fluorenyl moiety -CH_TwoIt is a fluorenyl moiety having O. As defined herein Exists only on one nitrogen atom which is not bonded to You. The substitution is CHO, C (O) NHR_Four, C_{1 ~Four}Alkyl or CO_TwoR_FourIt is.   The term “Bn” refers to the formula Means the benzyl functional group of   Pyrimidinyl, pyridyl and pyrazinyl Is attached to the rest of the molecule at any position other than the respective nitrogen atom But piperidinyl and morpholinyl Is attached to the rest of the molecule via each nitrogen atom.   See P_TwoIs C_{1 ~ 6}Alkyl or hydroxy C_{1 ~ 6}Places that are alkyl In the case, -C (CH_Three)_Three, -CH (CH_Three)_Two, -CH (CH_Three) (C_TwoH_Five), -C (OH) (CH_Three)_TwoAnd -CH (OH) CH_ThreeIs preferred. “Hydroxy C_{1 ~ 6}An “alkyl” moiety is an example -CH_TwoDescribed by -OH, "C_{1 ~ 6}Alkoxy C_{1 ~ 6}The “alkyl” part is , In one example -CH_Two-OCH_Three(In each case, C_{1 ~ 6} The alkylene can be straight or branched and the hydroxy Si groups are not limited to the terminal carbon atom of the alkyl moiety).   It is often quite advantageous to have what is called an amino protecting group (Pg) Wherein the range of compounds of Formula I is acetyl (Ac), with adjacent carbonyl moieties, Succinyl (Suc), benzoyl (Bz), t-butyloxycarbonyl (Boc), Benzyloxycarbonyl (CBZ), Tosyl (Ts), Dansyl (DNS), Isovale Ril (Iva), methoxysuccinyl (MeOSuc), 1-adamantansulfonyl (Ad SO_Two), 1-adamantaneacetyl (AdAc), phenylacetyl, t-butylacetate Tyl (Tba), bis [(1-naphthyl) methyl] acetyl (BNMA) and Rz [Rz Independently, fluorine, chlorine, bromine, iodine, trifluoromethyl, hydroxy, 1 to Alkyl containing 6 carbons, alkoxy containing 1-6 carbons, carbo Xy, alkylcarbonylamino wherein the alkyl group contains 1 to 6 carbons, 5- Tetrazolo and acylsulfonamides containing 1 to 15 carbons (ie, Acylaminosulfonyl and sulfonylaminocarbonyl) An aryl group as defined above, suitably substituted by one to three selected groups. R to form a group such as₁Part. However, acyl sulfonamide If it contains reels, the aryl may also be fluorine, chlorine, bromine, iodine and diphenyl. It may be substituted by a group selected from Toro.   Examples of classes of amino protecting groups contemplated include (1) acyl-type protecting groups such as formyl, Trifluoroacetyl, phthalyl, p-toluenesulfonyl (tosyl), benze Sulphonyl, nitrophenylsulphenyl, tritylsulphenyl, o-nitro Lofenoxyacetyl and α-chlorobutyryl; (2) aromatic urethane-type protecting group , For example Ben Zyloxycarbonyl and substituted benzyloxycarbonyl, for example p- Chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p -Nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 1 -(P-biphenylyl) -1-methylethoxycarbonyl, α, α-dimethyl-3 5,5-dimethoxybenzyloxycarbonyl and benzhydryloxycarbonyl (3) aliphatic urethane protecting groups such as tert-butyloxycarbonyl (Boc), Isopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxyca Rubonyl and allyloxycarbonyl; (4) cycloalkylurethane-type protection Groups such as cyclopentyloxycarbonyl, adamantyloxycarbonyl and And cyclohexyloxycarbonyl; (5) thiourethane-type protecting groups such as Nylthiocarbonyl; (6) alkyl-type protecting groups such as triphenylmethyl (tri (7) trialkylsilane protecting groups such as, for example, In some cases, it is trimethylsilane. Preferred α-amino protecting groups are tert-butyl Oxycarbonyl (Boc) or benzyloxycarbonyl (CBZ). amino acid The use of Boc as an α-amino protecting group for is described by Bodansky et al. In “The P practicice of Peptide Synthesis ”, Springer-Verlag, Berlin (1984), p. 20 It is listed.   The term “stereoisomers” differ only in the orientation of the atoms in space. General term for all isomers of a particular molecule. It is an enantiomer (Enantiomers), geometric (cis / trans) isomerism and not mirror images of each other Includes isomers (diastereoisomers) of compounds with more than one chiral center Include. Ami For acid acids, the IUPAC-IUB Joint Commission on Biochemical Nomenclature, Eur. J, Biochem. 138: 9-37 (1984), L / D or R The / S notation can be used.   In general, the compounds of the invention are prepared using standards similar to those known in the art. It can be manufactured using chemical reactions. More specifically, compounds of structure (3) Are known in the art and are generally described in Schirlin, D .; And V an Dorsselaer, V. By WO 92/12123 by international publication number July 1992 It is described in PCT / US 91/099741, published on the 23rd.   Compounds of formula (I) are described in Reaction Schemes A, A ', A ", B, C and D. It can be manufactured in this way. Unless otherwise specified, all substitutions are As described above. Reagents and starting materials are readily obtained by one skilled in the art.   In step (a) of Scheme A, under Refor-matski conditions Wherein the aldehyde of formula (3) is converted under an inert atmosphere of nitrogen or argon. In the presence of zinc and anhydrous aprotic solvents such as tetrahydrofuran, In ter, dimethoxyethane, etc., esters of bromodifluoroacetic acid are preferred. Is subjected to a condensation reaction with ethyl ester. Bring the reaction mixture to about 60 ° C. for about 1-12 hours Heat gently or sonicate to form compound (4).   Alternatively, in step (a) of Reaction Scheme A, compound (4) Condensation to produce higher yields and lower It can be achieved at the reaction temperature. Under an inert atmosphere such as nitrogen, The aldehyde (3) is dissolved in a suitable anhydrous organic solvent. Examples of suitable anhydrous organic solvents are Tetrahydrofuran, diethyl ether, t-butyl methyl ether, etc. . Cool the solution to about 0 ° C. To this solution was added about 0.30 equivalents of silver acetate and about 2.1 equivalents of zinc powder. And about 2 equivalents of ethyl bromodifluoroacetate. Reaction temperature below 12 ° C While holding, about 0.34 equivalents of diethylaluminum chloride (solution in toluene ) Is slowly added to the reaction mixture. The reaction mixture is kept at about 0 ° C. for 1-3 hours. And stir at room temperature for 4-12 hours. Then, cool the reaction mixture to about 10 ° C And quench with saturated aqueous aluminum chloride. Then, compound (4) was simply added. Release and purify by techniques known in the art. For example, tartaric acid A solution of sodium hydrogen is added and the reaction mixture is warmed from 10 ° C. to room temperature. mixture The product is filtered, the solid is washed with a suitable organic solvent, for example ethyl acetate, and the filtrate layer is washed. Is separated. aqueous Extract the layers with ethyl acetate, combine the organic layers and extracts, and dry over anhydrous magnesium. Dry, filter and concentrate. Residue as cyclohexane / ethyl acetate Chromatography on silica gel using suitable eluents Obtain 4).   In step (b) of Scheme A, the formation of compound (5) or (14) is directly Or it can be done indirectly. In one method, water and parts are added at about room temperature. Partially water-miscible solvents (eg, tetrahydrofuran, dimethoxyethane, dioxane) Sun) in the presence of a suitable base such as LiOH, KOH, NaOH, etc. The ester of formula (4) or (13) is deesterified. The resulting acid is then The appropriate R using quasi-peptide uniform coupling conditions_FiveR₆-With a substituted amine Can be mined. Selection of an appropriate coupling reaction operation is well known in the art. It is in the range of kneading. Coupling reactions are performed using standard coupling procedures, such as azide Method, mixed carbonate anhydride (isobutyl chloroformate) method, carbodiimide [dicyclohexane Xylcarbodiimide, diisopropylcarbodiimide or water-soluble carbodiimide Mido, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC)] method, active ester (p-nitrophenyl ester, N-hydroxy Imide ester) method, Woodward reagent K method, carbonyldiimidazole method The reaction can be carried out using a phosphorus reagent such as BOP-Cl or an oxidation-reduction method. This Some of these methods (especially the carbodiimide method) use hydroxybenzotriazole (HOBT) can be enhanced, e.g., CH_TwoCl_Two, Tetrahide DCC and hydrochloride at room temperature in a solvent such as lofuran or dimethylformamide. Mix using xybenzotriazole An anhydride method can be used.   Alternatively, the ester (4) or (13) can be dissolved in a solvent at a temperature between 0 and 18 ° C. Without or directly using a solvent (tetrahydrofuran), the appropriate R_FiveR₆− Reaction with the displaced amine.   Alternatively, if appropriate, a suitable protected R_Five, R₆-The substituted amine Dissolved in a suitable organic solvent, such as dichloromethane, under an inert atmosphere such as nitrogen I do. A corresponding amount of a 2M solution of trimethylaluminum in toluene was added to this solution. Add dropwise to the liquid. After about 15 minutes, the solution is washed with a suitable organic solvent, such as To about 0.3 equivalents of the ester (4) or (13) dissolved in the solution. The reaction mixture is Stir at room temperature to 40 ° C for about 15 to 24 hours. The product is then known in the art. Isolate using known techniques. For example, cold dilute aqueous hydrochloric acid and ethyl acetate Add. The organic layer was separated, washed with water, brine, and dried over anhydrous magnesium sulfate. , Filtered and concentrated in vacuo to give compound (5) or (14).   In step (c), the compound (6), (8) or (11) Standard operations known in the art [T.H. Green, “Protective Groups in Org anic Synthesis ”, John Wiley and Sons, 1981]₁Protective group Manufactured by removal. Then use potassium iodide at room or reflux temperature. Use in the presence of a base (potassium carbonate or cesium) Active solvent (preferably anhydrous dioxane, anhydrous acetone or anhydrous dimethyl In the formamide), the free phenol function is converted to a suitable alkyl halide And react with.   Process (c₁In (), compound (13) is known in the art such as hydrogenation. Standard operation [T.H. Green, “Protective Groups in Organic Synthesis” , John Wiley and Sons, 1981].₁Manufactured by removing protecting groups Is done. P_OHIs the compound obtained. POH is free phenol.   Process (c_Two)), The compound (6), (8) or (11) is inactive in the presence of a base. Reaction with an appropriate alkyl halide in the agent_OHDerivatives (14), (16 ) Or (17). For example, P_OHThe derivative is combined with a suitable organic solvent, such as Dissolve in seton. About 1.2 equivalents of a suitable base such as potassium carbonate is added and then Add about 1.15 equivalents of alkyl logenide. Then add a catalytic amount of potassium iodide Then the reaction mixture is stirred for 1-3 days. The product is isolated and It is purified by techniques known in the art, for example by extraction and recrystallization. For example, anti The reaction mixture is poured into a suitable solvent mixture, for example ethyl acetate / dilute aqueous sodium chloride. And separate the organic layer. The organic layer is then diluted with dilute aqueous potassium hydroxide, bra Washed with anhydrous, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo I do. The residue is separated from a suitable solvent mixture such as cyclohexane / ethyl acetate. Purification by recrystallization gives compound (6), (8) or (11).   In the step (d) for producing the compounds (7), (9) and (15), the protecting group Pg Is a standard operation known in the art [T.H. Green, “Protective Group s in Organic Synthesis ", John Wiley and Sons, 1981]. Include acid / base hydrolysis (eg, with formic acid at room temperature followed by sodium carbonate) Free salt after treatment Extraction of the group).   In the step (e), the compound (7), (9) or (15) is used as described in the present specification. Using a coupling (or any other coupling known in the art) (By operation or as described in European Patent Application 93 401 785.6) , The formula R ′₁CONHCH (P_Two) CO_TwoH or R '₁CO_TwoPeptide peptide with an appropriately protected acid of H Compound (8) and (11) [from compound (7)]; Compound (10) And (12) [from compound (9)]; and compounds (16) and (17) [from compound (15) ] Is generated. R ′₁Is recognized by those of ordinary skill in the art. R as₁R except when protection of the group is necessary₁Is defined as For example , R₁The hydroxyl function on the alkyl portion of the group is retained prior to oxidation in step (f). Must be protected.   In step (f), the oxidation of compounds (8) and (11) is known in the art. By a known method, for example by a Swern oxidation operation or 1,1,1 -Triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -O Can be used to give compounds of formulas IA and IB.   Generally, Swern oxidation (see Synthesis (1981), 165) is about -70 ° C to -30 ° C. Inert atmosphere (eg nitrogen or equivalent) under anhydrous conditions at a temperature of Gas) under dimethylsulfoxide (DMSO) about 2-20 equivalents trifluoroacetic anhydride Object ((CF_ThreeCO)_TwoO] or oxalyl chloride ((COCl)_Two1 to 10 equivalents (reactant is inert Solvents such as methylene chloride (CH_TwoCl_TwoDissolve in)) and react in the reaction system To form a sulfonium adduct, to which a suitable alcohol, That is, the reaction is carried out by adding about 1 equivalent of the compounds (8) and (11). Like Alternatively, the alcohol is an inert solvent such as CH_TwoCl_Two, Tetrahydrofuran or Dissolve in a minimal amount of DMSO and warm the reaction mixture to about -50 ° C or -20 ° C (about 20-60 minutes) and then a tertiary amine such as triethylamine, diisopro Reaction by addition of about 3 to 30 equivalents of pyrethylamine, N-methylmorpholine, etc. Complete.   Instead, oxidation is carried out by Dess-Martin Periodinane (ie, 1,1,1-triacetoxy-1,1-dihydro-1,2 -Benziodoxol-3 (1H) -one) [Dess Martin, J. et al. Org. Chem.48,Four 155 (1983)]. This oxidation is carried out at 0 ° C to 50 ° C (good Under an inert atmosphere (preferably nitrogen) under anhydrous conditions at room temperature, About 1 equivalent of alcohol is contacted with 1 to 10 equivalents of periodinane (preferably 5 equivalents or more). (Reagents are suspended in an inert solvent such as methylene chloride) and the reactants are It is carried out by allowing them to react for about 1 to 48 hours. Optional removal of amine protecting groups Protection can be performed as needed after isolating the ketone.   Generally, the reaction is carried out at about 0 ° C. to 50 ° C., preferably at room temperature, in the presence of Contacting together in a trapped molecular sieve powder, for example a milled 3 Å molecular sieve By reacting the alcohol with pyridinium dichromate. The modified Jones oxidation operation is advantageously carried out and then isolated and then In some cases, the amine protecting group can be removed.   Alternatively, an inert solvent (0 ° C. to 50 ° C.) under anhydrous conditions and under an inert atmosphere ( For example CH_TwoCl_Two), The chromic anhydride-pyridine complex (ie, the reaction system Sarett reagent manufactured in Japan) [Fieser and Fieser “Reagents for Or ganic Synthesis "Vol. 1, pp. 145 and Sarett et al., J.A.C.S.twenty five, 422 (1953) 1) to 5 equivalents are treated with 1 equivalent of alcohol. The reaction mixture is allowed to Stir. The product is isolated and purified by techniques known in the art The amine protecting group is then optionally removed.   In the step (g), the compound represented by the formula IA or IB (wherein R ′₁Protected as needed ) Can be prepared under conditions known in the art [T.H. Green, “Protective Groups in Organic Synthesis”, John Wiley and Sons, 1981 In the formula IA 'and formula IB' (wherein R "₁Is protected as required Which is a substitution requiring). For example, protected compounds can be Dissolved in a suitable organic solvent, for example methylene chloride and TFA / H_TwoProcess with O. Reaction mixture The mixture is stirred at room temperature for about 4-10 hours and then it is concentrated under vacuum. Remaining The distillate can be obtained by techniques known in the art, for example by extraction methods and then by filtration. Purify by lash chromatography (silica gel, hexane / ethyl acetate). To give the deprotected compound.   Coupling with the required aldehyde of formula (3) and compound (7), (9) or (15) For the production of₁And / or P_TwoPart is a residue of a natural amino acid Or another non-natural amino acid residue, another alkylation operation is used. Used. P₁Or P_TwoThe moiety is a residue of a natural amino acid (or a small variant thereof, For example, P₁Also Is P_TwoIs the benzyl or methyl ether of tyrosine) These compounds are either known or known in the art in the preparation of It is manufactured by methods and techniques known in the art.   formula Wherein Pg is an amino protecting group;_ThreeIs P ′₁Or P '_TwoPart (P ′₁And P ′_TwoIs Except that they are not residues of naturally occurring amino acids , Each P₁And P_TwoAnd R₉Is al A kill group, preferably P_ThreeIs P '₁Is methyl and P_ThreeIs P '_TwoIf d An alternative method can be used to make the intermediate of   formula The following reaction scheme can be utilized to produce the intermediate of   In the above formula, P_ThreeIs as described above and X is a leaving group, preferably Preferably halogen or triflate and R₉Is P_ThreeIs P '₁If Methyl and P_ThreeIs P '_TwoIs ethyl.   In essence, the preparation of compound (19) is based on the Krapcho method for alkylation [Tetrahedron Letters,26, 2205 (1976)]. In this method According to standard Clapco conditions, compound (18) can be converted to a base such as LDA (lithium diiso Propylamide) and then treated with HMPA (ie, hepamethylphosphonamide). ) In a solvent (tetrahydrofuran) with or without TM The desired P in the presence of EDA (i.e., tetramethylethylenediamine)_ThreeX and anti Respond. After alkylation, the compound is treated with a solvent such as an ether at about -78 ° C for about 1 hour. Aluminum hydride in a mixture of water, toluene, hexane and tetrahydrofuran. Subject to reduction using isobutyl (Dibal). After production of the aldehyde of formula (10B), The compound is subjected to the methods of Reaction Schemes A, A 'and / or A ".   Instead, the compound of (19) is illustrated by the following reaction scheme As in the Malonate / Curtius type reaction sequence Can be manufactured.   Although other selectively removable acid protecting groups can be utilized , T-Bu is t-butyl and P_ThreeX is as described above. This reaction is Alkylation of the acid ester (20) followed by selective removal of the t-butyl protecting group Compound (22). These compounds then form the intermediate The conversion to the protected amine via the resulting acyl azide and isocyanate Conversion to compound (19) using the accompanying Curtius rearrangement. Then you get The amine is protected with a standard amino protecting group. Amine is protected in the reaction system .   P_ThreeIs P '₁In particular, when indicating a part, this state (P₁Is the residue of natural amino acids Group), the ester is converted to the desired compound of formula (3) using standard Dival reduction techniques. Convert to aldehyde. Instead of doing this, (as preferred, P₁Is heaven (If it is a residue of an amino acid) None, its equivalent And convert the hydroxamate to aluminum hydride It is converted to its aldehyde by treatment with murium. P_ThreeIs P '_TwoPart Where indicated, the ethyl ester of compound (19) was removed and the resulting compound Used for coupling as shown in Scheme A '.   Scheme D shows an alternative method of preparing the compound of formula IA.   In step (a) of scheme D, the compound of formula (7) is converted to a compound of step (e) of scheme A ′ ) In a manner similar to that described above in formula PgNHCH (P_Two) CO_TwoH moderately protection The compound is subjected to a coupling reaction with the acid to give a compound of the formula (23).   In step (b) of scheme D, the method described in step (d) of scheme A In a similar manner to the method, the compound of formula (23) is deprotected to give a compound of formula (24).   In steps (c) and (d) of Scheme D, the compound of formula (24) is first In a manner similar to that described in step (e) of Scheme A ', the formula R'₁CO_TwoH Reaction with the acid of Scheme 1 and then the coupling product is reacted with Scheme A 'To oxidize the compound of formula IA in a manner similar to that described in step (f). Get things.   As will be appreciated by those having ordinary skill in the art, Equation (9) and In addition to the operations described in Schemes A ′ and A ″, Operating in an analogous manner to formula (7) in D, formulas IA, IA ', IB and IB 'can be obtained.   Having generally described the methods for making the compounds of the present invention, the following specific examples Describes the chemistry and techniques by which the synthesis can be performed.   The following examples illustrate typical syntheses described in Schemes A, A ', A "and D. You. These examples are described for illustrative purposes only and It is understood that the present invention is not intended to limit the scope of the present invention in any respect. Should be. The following terms as used herein have the following meanings: . "G" is "Mmol" means millimoles; "ml" means milliliters; " “bp” means boiling point; “mp” means melting point; “° C.” means degrees Celsius; “Hg” means millimeters of mercury; “μl” means microliter; "g" means microgram; "μM" means micromol; "Cbz" is carbohydrate. "DMF" means dimethylformamide; "THF" "TBF" means tetrabutylammonium fluoride "NMM" means N-methylmorpholine; "DMSO" means dimethylsulfone "HOBT" means hydroxybenzotriazole and " EDC "is 1- (3-dimethylaminopyrropur) -3-ethylcarbodiimide hydrochloride Means salt. Example 1 α, α-difluoro-γ-[((2- (R)-[[(hydroxy) phenylacetyl] Amino] -3-methyl-1-oxobutyl] amino] -β-oxo-4- (f Production of (Nylmethoxy) -N- (phenylmethyl) -benzenepentanamide Step A O-benzyl-N- (tert-butoxycarbonyl) -L-tyrosinal (reaction scheme) Of the starting material) [PCT published on July 23, 1992 with the international publication number of WO 92/12123 By operation of Schirlin, D and Van Dorsselaer, V in US 91/099741]   N-tert-butoxycarbonyl-LO-be in anhydrous dichloromethane (350 ml) Undiltyrosine (37.1 g, 100 mmol), dicyclohexylcarbodiimide (20.6 g, 100 mmol) and N-hydroxybenzotriazole hydrate (15.3 g, 10 (0 mmol) is stirred at 0 ° C. for 10 minutes. To this, at 0 ° C, N, O-dimethyl Hydroxylamine hydrochloride (9.75 g, 100 mmol) and N-methylmorpholine ( 10.1 g, 100 mmol). Warm the temperature to room temperature and continue stirring for 15 hours You. Then the white precipitate is filtered off and rinsed with dichloromethane. Vacuum the filtrate Under reduced pressure and the residue is purified by flash chromatography (silica gel, 2: 8 ethyl acetate / cyclohexane) to give N-tert. Toxicarbonyl-LO-benzyltyrosine-N, O-dimethyl-hydroxame (1: 1 ethyl acetate / R in cyclohexane_F= 0.36) (34.3 g).   N-tert-butoxycarbonyl-LO-benzyltyrosine-N, O-dimethyl- Hydroxamate (18.2 g, 44 mmol) was added to anhydrous diethyl ether / dimethoate. Dissolve in a mixture (300 ml) of xyethane (4: 1) and cool to 0 ° C. to this And lithium aluminum hydride (1.82 g, 48 mmol) are added in small portions. reaction The mixture is stirred at 0 ° C. for 1.5 hours. A 1 M solution of potassium hydrogen sulfate (55 ml) was stirred. While stirring, add dropwise to the reaction mixture. After the addition is complete, the aqueous phase is decanted off and Extract with ethyl acetate (2 × 200 ml). The combined organic layers were combined with 3N hydrochloric acid (250 ml), water ( 200ml), saturated sodium bicarbonate (150ml) And washed with brine (200 ml). The organic layer is then dried over anhydrous magnesium sulfate. , Filtered and concentrated in vacuo. The residue is treated with ethyl acetate / pentane Recrystallized from N-tert-butoxycarbonyl-LO-benzyltyrosinal (13 g) was obtained. Step B 4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy-5- Production of (4-benzyloxy) phenylpentanoic acid ethyl ester   Reaction Scheme A, Step (a): N in anhydrous tetrahydrofuran (120 ml) at 0 ° C -Tert-butoxycarbonyl-LO-benzyltyrosinal (13.0 g, 36.6 mm Mol), silver acetate (1.82 g, 10.9 mmol), activated zinc powder (5.02 g, 75.8 mg atom Washed with 3N hydrochloric acid, water, acetone and ether) and bromodifluoroacetic acid To a stirred mixture of ethyl (14.8 g, 72.9 mmol) was added diethylamine over 20 minutes. Monium chloride (22.4 ml of a 1.8 M solution in toluene) is added. During addition, temperature Is kept below 12 ° C. The reaction mixture is then left at 0 ° C. for 90 minutes and then Stir at warm for 4 hours. Then the reaction mixture was cooled to 10 ° C and saturated aqueous chloride Quench with ammonium (200 ml). 1M solution of sodium bitartrate (200ml) And warm the reaction mixture to room temperature. The reaction mixture is filtered and the solid is Rinse with ethyl acid. The filtrate layer is separated and the aqueous layer is extracted with ethyl acetate. Combination Layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. You. The residue was purified by flash chromatography (4: 1 cyclohexane / acetic acid Ethyl) to give the title compound (8.34 g). Diastereomeric ratio Is about 1: It is one. Process C 4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy-5- Of (4-benzyloxy) phenyl-N- (phenylmethyl) -pentanamide Manufacture   Reaction Scheme A, step (b): 4-tert. In anhydrous tetrahydrofuran (50 ml) Butoxycarbonylamino-2,2-difluoro-3-hydroxy-5- (4-beta Dissolution of ethyl (benzyloxy) phenylpentanoate (5.5 g, 11.5 mmol) To the solution at 0 ° C. is added benzylamine (6.15 g, 57.5 mmol). The reaction mixture Stir at 0 ° C. for 3 hours then at room temperature for 15 hours. The reaction mixture is then Dilute with ethyl (100 ml), 0.1N aqueous hydrochloric acid (2 × 50 ml), water (50 ml), brine ( 50 ml) and dried over anhydrous magnesium sulfate. And then Filter and concentrate under vacuum. The residue was recrystallized from ethyl acetate / pentane The title compound (5.17 g) was obtained as a white solid. Process D 4-amino-2,2-difluoro-3-hydroxy-5- (4-benzyloxy) phenyl Preparation of phenyl-N- (phenylmethyl) pentanamide   Reaction Scheme A, step (d): 4-tert-butoxy in trifluoroacetic acid (100 ml) Carbonylamino-2,2-difluoro-3-hydroxy-5- (4-benzylo Xy) phenyl-N- (phenylmethyl) pentanamide (5.1 g, 9.4 mmol) Is stirred at 0 ° C. for 1 hour. Then the solvent is removed under vacuum and the residual Thing with ethyl acetate Dissolve in 100ml (100ml). The organic layer solution was washed with saturated sodium bicarbonate (3 × 50 ml), Wash with line, dry over anhydrous magnesium sulfate, filter and concentrate under vacuum Reduction afforded the title compound as a white solid. R_f= 0.62 (silica gel, 6: 2: 2 butanol / acetic acid / water). Step E N- (R)-[[[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyla Production of [cetyl] -L-valine   (R)-(-) in DMF (100 ml) while maintaining the reaction mixture at around 25 ° C in a cold water bath. -Mandelic acid (5.6 g, 37 mmol) and tert-butylchlorodimethylsilane (15. Imidazole (16.7 g, 245 mmol) for 15 minutes. Add in small portions over. After 17 hours, the mixture was diluted with water and ether Extract twice with. The combined extracts were cooled to -10 ° C and rapidly cooled (-10 ° C). Wash twice with cold HCI, cold water, dry over anhydrous sodium sulfate, filter and filter. Concentrate under air to give 15.0 g of a yellow oil, which is then_ThreeOH (250ml) and TH Dissolve in F (80 ml). Dissolution of potassium carbonate (14 g, 100 mmol) in water (140 ml) The solution is added with vigorous stirring. After 1 hour, the mixture was partially concentrated under vacuum. Shrink and dilute the remaining clear, light yellow solution with brine (300 ml). The cloudy mixture was cooled to -10 ° C and 1M KHSO_FourAcidify to pH 5 with. Extract with cold (-10 ° C) ether and wash the extract twice with brine and dry with anhydrous After drying over sodium sulfate, filtration and concentration in vacuo, (R)- 6.6 g (67%) of O-tert-butyldimethyl-silylmandelic acid were obtained. This crude The silylating acid (25 mmol) is converted to CH_ThreeDissolved in CN (80 ml) and the resulting solution Cool to -10 ° C. To this stirred solution, add NMM (2.52 g, 24.9 mmol) and then Isobutyl lologate (3.72 g, 27.2 mmol) was added. 10 minutes later, H_TwoO (20ml L-valine methyl ester hydrochloride (7.32 g, 42.7 mmol) and NMM (4.08 g, 40.3 mmol) is added and stirring is continued at -10 DEG C. for 20 minutes. Reaction mixing The product is poured into ice-cold dilute HCl containing some NaCl and extracted twice with ethyl acetate . Wash the combined extracts with water, aqueous saturated sodium bicarbonate, brine and dry Dry over magnesium sulfate, filter and concentrate under vacuum. Flash twice Chromatographic treatment (12% ethyl acetate in cyclohexane) Coupling purified with butyloxycarbonyl-L-valine methyl ester The silylated ester (R_f0.4, 4/1 cyclohexane / ethyl acetate) 4.4 g Obtained. The silylated ester (4.4 g, 12 mmol) was added with stirring to THF (15 ml). And 1M tetrabutylammonium fluoride in THF (11.6 ml) Add the solution of (TBAF). After 1.25 hours, the solution was concentrated under vacuum and the residue was concentrated. By flash chromatography (cyclohexane / ethyl acetate 4/1) N-[(R) -manderoyl] -L-valine methyl ester as an oil 2.4 g (37% overall yield from O-tert-butyldimethylsilylmandelic acid) were obtained. Up After operation in a manner similar to that described, the material is purified by flash chromatography. -Treatment (12% ethyl acetate in cyclohexane) with a yield of 82% Reconverted to tyldimethylsilyl ether. CH_ThreeIn OH (125 ml) and water (5 ml) To a stirred solution of this ester (13.5 mmol) was added LiOH_TwoO (0.59 g, 14 mmol) Add. 17 hours later, LiOH ・ H_TwoAdd an additional amount of O (0.06 g) and stir Continue for 2 hours. The solution was concentrated under vacuum and the residue was diluted with water (100 ml). And wash with ether. The aqueous layer was acidified with ice-cold 6N HCl and extracted with ether Extract twice. Wash the combined extracts with water, dry over anhydrous magnesium sulfate, Filter and concentrate under vacuum to give the title compound as a white solid in 48% yield. Was. 146-148 ° C. IR (CHCl_Three) Ν_max 2957,2932,1718,1678,1516,1096 , 863,840cm^-1;¹H NMR (CHCl_Three) Δ 9.17 (bs, 1H), 7.51 (d, 1H, J = 9.0 Hz), 7 .43-7.40 (m, 2H), 7.32-7.25 (m, 3H), 5.15 (s, 1H), 4.51 (dd, 1H, J = 9.0, 4.3H z), 2.34-2.28 (m, 1H), 1.00 (d, 3H, J = 6.9 Hz), 0.97 (d, 3H, J = 7.0 Hz), 0.94 ( s, 9H), 0.11 (s, 3H), -0.08 (s, 3H);¹³C NMR (CHCl_Three) Δ 175.49,172.65,13 9.36, 128.32, 128.21, 126.68, 75.66, 56.60, 31.04, 25.66, 19.01, 18.02, 17.44, -4.83, -5.31; Mass spectrum, m / z 394 (M⁺+29), 366 (M⁺+1 and 100), 350, 308; exact mass C₁₉H₃₂NO_FourSi CH_ThreeOH).   C₁₉H₃₁NO_FourAnalytical value for Si:     Calculated value: C 62.43 H 8.55 N 3.83     Found: C 62.22 H 8.61 N 3.65 Step F [3ξ, 4 (S, R)]-2,4,5-trideoxy-4-[[2-[[[((1,1-dimethyl Ethyl) dimethylsilyl] oxy] phenylacetyl] amino] -3-methyl- 1-oxobutyl] amino] -2,2-difluoro-5- [4- (phenylmethoxy C) Preparation of phenyl] -N- (phenylmethyl) -L-glycero-pentanamide Construction   Reaction scheme A ', step (e): N- (R)-[[[(1, 1-dimethylethyl) dimethylsilyl] oxy] phenylacetyl] -L-valine (25 mmol) in CH_ThreeDissolve in CN (80 ml) and cool the resulting solution to -10 ° C You. To this stirred solution was added N-methylmorpholine (2.52 g, 24.9 mmol, NMM) Then, isobutyl chloroformate (3.72 g, 27.2 mmol) is added. 10 minutes later, H_TwoO ( 4-amino-2,2-difluoro-3-hydroxy-5- (4-benzyl Oxy) phenyl-N- (phenylmethyl) pentanamide (in step (d) above) And a solution of 43.7 mmol) and NMM (4.08 g, 40.3 mmol) was added. And continue stirring at -10 ° C for 20 minutes. Ice-cold dilute HC containing some NaCl and extract twice with ethyl acetate. Extract the combined extract with water, aqueous saturated Wash with sodium carbonate, brine, dry over anhydrous magnesium sulfate and filter And concentrate under vacuum. The title compound as a clear colorless oil in 76% yield Obtained. This oil was flash chromatographed (CH_TwoCl_Two6% acetone in medium) Later, it is crystallized by standing. 117-120 ° C. 1R (KBr) ν_max3418, 1704, 16 77, 1653, 1540, 1513, 1246, 1095, 839cm^-1;¹H NMR (CDCl_Three) Δ7.44-7.18 (m , 16H), 6.96 (d, 3H, J = 8.7Hz), 6.84 (d, 2H, J = 8.7Hz), 6.10 (d, 1H, J = 8.1Hz) , 5.10 (s, 1H), 5.01 (s, 2H), 4.69 (d, 1H, J = 6.9 Hz), 4.43 (dd, 1H, J = 14.7, 6 .0Hz), 4.34 (dd, 1H, J = 14.7, 6.0Hz), 3.96 (dd, 1H, J = 8.5, 6.9Hz), 3.91-3.8 2 (m, 2H), 2.76 (dd, 1H, J = 13.8, 7.8Hz), 2.66 (dd, 1H, J = 13.8, 7.8Hz), 2.2 2-2.11 (m, 1H), 0.94 (s, 9H), 0.88 (d, 3H, J = 6.6Hz), 0.86 (d, 3H, J = 6.9Hz), 0.09 (s, 3H), -0.06 (s, 3H);¹³ C NMR (CDCl_Three) Δ 173.37, 171.91, 163.92 (t, J = 35Hz), 159.01, 139.62, 13 7.40,137.31,130.47,129.60,129.16,128.94,128.80,128.70,128.37,12 8.31, 128.22, 127.83, 126.63, 115.50 (t, J = 257 Hz), 115.36, 76.21, 70.67 (t , J = 25Hz), 70.37, 58.79, 51.93, 43.76, 36.52, 29.97, 26.08, 19.80, 18.47 , 17.96, -4.41, -4.89;¹⁹F NMR (CDCl_Three) Δ -118.40 (s), -118.45 (s); Vector, m / z 816 (M⁺+29), 788 (M⁺+1), 573, 469, 441, 423 (100); exact Mass C₄₄H₅₆F_TwoN_ThreeO₆Against Si CH_ThreeOH).   C₄₄H₅₅F_TwoN_ThreeO₆Analytical value for Si:     Calculated value: C 67.06 H 7.04 N 5.33     Obtained value: C 67.07 H 7.14 N 5.18 Process G Preparation of final title compound   Reaction Scheme A ', Steps (b) and (g): alcohol prepared as described above Is oxidized under Swelln conditions as described below. 2 at -60 ° C under nitrogen M oxalyl chloride / CH_TwoCl_Two(2.0 ml) to a stirred solution of anhydrous DMSO (0.42 ml, 5.9 mm Mol) is added dropwise. 10 minutes later, CH_TwoCl_Two(3 ml) and anhydrous DMSO (1.5 ml) 3ξ, 4 (S, R)]-2,4,5-trideoxy-4-[[2-[[[((1,1-dimethyle Tyl) dimethylsilyl] oxy] phenylacetyl] amino] -3-methyl-1 -Oxobutyl] amino] -2,2-difluoro-5- [4- (phenylmethoxy ) Phenyl] -N- (phenylmethyl) -L-glyceropentanamide (0.50 Solution). this The solution is stirred at -65 ° C to -55 ° C for 5 hours. Then heat it to -20 ° C and then With triethylamine (1.39 ml, 10.0 mmol) is added over 5 minutes. Or that The reaction mixture is then warmed to room temperature overnight. Then, add it to ethyl acetate (60 ml ), Filter and wash the solid with ethyl acetate. The filtrate was washed with 0.1 M HCl (3 × 15 ml), brine, dried over anhydrous magnesium sulfate, filtered and filtered. Concentration under air gave 375 mg of crude ketone. This is 4/1 acetic acid / H_TwoO (50ml) Dissolve. The stirring solution is heated at 80 ° C. for 19 hours, cooled to room temperature, and then diluted with water. And CH_TwoCl_TwoExtract twice with. Wash the combined extracts with water, brine and dry Dry over magnesium sulfate, filter and concentrate under vacuum. Residue residue Chromatography (CH_TwoCl_TwoResidual 10% acetone) This gave 180 mg of the title compound which had been impure by purification. From ethyl acetate / pentane Two recrystallizations gave 30 mg (8.8%) of the final title compound as a pale yellow solid. Obtained. 144-150 ° C. IR (KBr) ν_max3398, 3300, 1683, 1656, 1540, 1513, 1454, 1244, 698cm^-1;¹H NMR (DMSO-d₆) Δ 9.77-9.72 (m, 1H), 8.69 (d, 1H, J = 7.6Hz), 7.80 and 7.73 (2d, 1H total, J = 9.3Hz), 7.45-7.21 (m, 15H), 7 .12 and 7.10 (2d, 2H total, J = 8.7Hz), 6.89 and 6.87 (2d, 2H total , J = 8.8, 8.4Hz), 6.21 and 6.20 (2d, 1H total, J = 5.1Hz), 5.05 (s, 2H ), 5.02 and 5.00 (2s, 1H total), 5.03-4.90 (m, 1H), 4.38 (d, 2H, J = 5.7 Hz), 4.23-4.17 (m, 1H), 3.14-3.07 and 2.65-2.57 (m, 2H total), 1.97-1 .88 and 1.78-1.73 (m, 1H total), 0.73 and 0,71 (2d, 3H total, J = 6.7Hz), 0.57 and 0.49 (2d, 3H total, J = 6.9, 6.7Hz);¹⁹F NMR (DMSO-d₆) Δ-110.31 (d, J = 268Hz), -110.54 (d, J = 268 Hz), -122.21 (d, J = 268 Hz), -112.25 (d, J = 269 Hz); mass spectrum, m / z 700 ( M⁺+29), 672 (M⁺+1,100), 652,439,421,402; Exact mass: C₃₈H₄₀F_TwoN_ThreeO₆To Calculated 672.2885, found 672.2842. Example 2 [6S- (6R^*, 9R^*, 13S^*)]-4,4-difluoro-9- (1-methylethyl) -3,5, 8,11-tetraoxo-1,13-diphenyl-6-[[4- (phenylmethoxy) phenyl [Enyl] methyl] -12-oxa-2,7,10-triazatetradecane-14-oic Of acid methyl ester Step A [3ξ, 4 (S)]-2,4,5-trideoxy-4-[[2-[[(1,1-dimethylethoxy B) carbonyl] amino] -3-methyl-1-oxobutyl] amino-5- [4 -(Phenylmethoxy) phenyl] -N- (phenylmethyl) -L-glycerope Manufacture of tantanamide   Reaction Scheme D, Step (a): 2: 1 dry CH_TwoCl_Two4-A in DMF (13.5 ml) Mino-2,2-difluoro-3-hydroxy-5- (4-benzyloxy) phenyl Ru-N- (phenylmethyl) pentanamide (prepared in Example 1, Step D, 5 HOBT (0.19 g, 1.2 mmol), DCC (0. 26 g, 1.3 mmol) and Nt-Boc-L-valine (0.27 g, 1.2 mmol). Add. The reaction mixture was warmed to 25 ° C. overnight, then ethyl acetate / cyclohexa Wash with diluted sodium bicarbonate, water, brine, and dry with anhydrous magnesium sulfate. Dry over nesium, filter and concentrate under vacuum to give a gummy solid. this , CH_TwoCl_TwoAnd filtered to remove some dicyclohexylurea. Leave. The filtrate is concentrated under vacuum and the residue is purified by flash chromatography. (3: 2 cyclohexane / ethyl acetate) to give an ivory solid 694 mg (88%) of the title compound were obtained. The main diastereomer is ether / CH_TwoCl_Two Was isolated in 69% yield. Step B formula Production of chloroformate   Nitrogenated CH_TwoCl_Two(25 ml) to a stirred solution of triphosgene (6.65 g, 22.4 mmol) , (R)-(-)-methyl mandelate (5.36 g, 32.3 mmol) was added and then CH_TwoC l_TwoPyridine (2.66 ml, 32.9 ml) in (2.5 ml) Solution) is added rapidly. The reaction mixture is warmed to reflux and pyridinyl chloride Um. After 17 hours at room temperature, the reaction mixture was partially concentrated under vacuum, Dilute with ethyl acetate and filter. The filtrate is concentrated under vacuum and the residue And ethyl acetate and filtered. Concentrate under vacuum to give chloroformate: A pale yellow oil consisting of an approximately 20: 1: 1 mixture of carbonate: methyl mandelate 7. 25 g were obtained. IR (neat) ν for chloroformate_max(177.2, 1750cm^-1;  ¹H NMR (CDCl_Three) Δ 7.5-7.37 (m, 5H), 5.98 (s, 1H), 3.78 (s, 3H). Process C (5ξ, 6S- (6R^*, 9R^*, 13S^*)]-4,4-Difluoro-5-hydroxy-9- (1- Methylethyl) -3,8,11-trioxo-1,13-diphenyl-6-[[4- (fe Nilmethoxy) phenyl] methyl] -12-oxa-2,7,10-triazatetradeca Production of N-14-Oic Acid Methyl Ester   Reaction Scheme D, Steps (b) and (c): [3ξ, 4 (S)]-2,4,5-trideoxy -4-[[2-[[(1,1-dimethylethoxy) carbonyl] amino] -3-methyl Ru-1-oxobutyl] amino-5- [4- (phenylmethoxy) phenyl]- The main diastereomer of N- (phenylmethyl) -L-glycero-pentanamide Flask (403 mg, 0.630 mmol) was immersed in an ice bath and ice-cooled. Trifluoroacetic acid (TFA) (5 ml) is added with stirring. After 30 minutes, the solution is Concentrate under vacuum at 0 ° C. and carefully concentrate the residue with ethyl acetate and aqueous saturated bicarbonate. Partition between thorium. Separate the organic layer, wash with brine and dry with anhydrous sulfuric acid. Dried on gnesium, Filter and concentrate under vacuum to give 334 mg (98%) of the deprotected amine. this Immediately at 0 ℃ CH_TwoCl_Two(5 ml) and CH_TwoCl_TwoNMM (7 ml) dissolved in 7 μl, 0.70 mmol) and the chloroformate prepared above (160 mM g, 0.7 mmol). After stirring for 1.5 hours, the reaction mixture was / Pour into dilute aqueous ammonium chloride. Separate the organic layer and dilute aqueous sodium bicarbonate Washed with brine, dried over anhydrous magnesium sulfate, filtered and vacuum Concentrate below. Flash chromatography of the residue (4: 1 CH_TwoCl_Two/ Ethyl acetate) to give a single diastereomer of the title compound as a white foam. 332 mg (72%) of the teleomer were obtained.¹H NMR (CDCl_Three) Δ 7.44-7.26 (m, 15H) 、 7.12 (d , 2H, J = 8.4Hz), 6.89 (d, 2H, J = 8.4Hz), 6.53 (d, 1H, J = 8.4Hz), 5.89 (s, 1H) , 5.40 (d, 1H, J = 7.9 Hz), 5.02 (s, 2H), 4.70 (d, 1H, J = 7.0 Hz), 4.49 (apparent d, 2 H, J = 5.8Hz), 4.3-4.1 (m, 2H), 3.85 (dd, 1H, J = 7.8, 5.5Hz), 3.63 (s, 3H), 3. 05-2.87 (m, 2H), 2.2-2.04 (m, 1H), 1.90 (s, 1H), 0.83 (d, 3H, J = 6.7Hz), 0.71 (d, 3H, J = 6.8Hz);¹⁹F NMR (CDCl_Three) Δ-116.60 (dd, 1F, J = 259, 9Hz), -118.73 (dd, 1F, J = 259, 15Hz). Process D Production of final title compound   Reaction scheme A ', step (b): The alcohol produced as described above is In the same manner as the method described above in Step G of Example 1, under Swern oxidation conditions Multiply. The residue was purified by flash chromatography (4: 1 CH_TwoCl_Two/ Ethyl acetate To give 52% of the final title compound. From the ethyl acetate solution Precipitated with tin This gave 29% of the final title compound as a white powder. IR (KBr) ν_max 3399 , 3316, 1745, 1699, 1668, 1534, 1513, 1241cm^-1;¹H NMR (CDCl_Three) Δ 5.89, 5.87 and 5.82 (3s, ratio of 6.0: 1.8: 1.0, 1H); 5,05 and 5.03 (2s, 1: 1. 3.69, 3.67 and 3.65 (3s, ratio of 2.5: 1.0: 1.9, 3H);¹⁹F NMR (CDCl_Three) Δ -122.53 (s), -122.60 (s), -116.25 (d, J = 256Hz), -177.00 (d, J = 25 6Hz), -120.21 (d, J = 256Hz), -120.78 (d, J = 256Hz), (s: d ratio 4: 1); mass spec Torr, m / z 770 (M⁺+41), 758 (M⁺+29), 731,730 (M⁺+1,100); Exact mass: C₄₀ H₄₂F_TwoN_ThreeO₈Against CH_ThreeOH).   C₄₀H₄₁F_TwoN_ThreeO₈Analytical value for:     Calculated value: C 65.83 H 5.66 N 5.76     Found: C 65.16 H 5.69 N 5.79 Example 3 α, α-difluoro-γ-[[3-methyl-1-oxo-2-[[(1-oxo Trans-3-phenyl-2-propenyl) amino] butyl] amino] -β-o Oxo-4- (phenylmethoxy) -N- (phenylmethyl) -benzene-pentana Manufacture of mid Step A Production of N- (trans-cinnamoyl) -L-valine   CH_TwoCl_Two(15 ml) and L-valine methyl ester hydrochloride (1.97 g) in DMF (20 ml) , 11.8 mmol) and NMM (1.10 g, 10.8 mmol) in a stirred solution._TwoCl_Two(28ml Of 1-trans-cinnamoyl imidazole (2.15 g, 10.8 mmol) in Add the liquid. After 18 hours, additional L-valine methyl ester hydrochloride (0.36 g, 2.1 Mmol) and the reaction mixture is stirred for 5 hours, then diluted with water (100 ml) And CHCl_ThreeExtract with The organic extract is washed three times with water and dried (MgSO_Four) Shisoshi And concentrate in vacuo. Short silica gel column (1/1 ethyl acetate / cyclohexa) ) And filtered through N- (trans-cinnamoyl) -L-valine methyl ester. 2.0 g (71%) of stell were obtained. CH_ThreeThis ester in OH (125 ml) and water (5 ml) (13.5 mmol) in LiOH.H_TwoO (0.59 g, 14 mmol) is added. 17 After an hour, LiOH_TwoAn additional amount of O (0.06 g) is added and stirring is continued for 2 hours. The solution is concentrated in vacuo and the residue is diluted with water (100 ml) and washed with ether I do. The aqueous layer is acidified with ice-cold 6N HCl and extracted twice with ether. Combination The extracted extract was washed with water and dried (MgSO_Four). Concentrate in vacuo to a white solid 67% of the title compound were obtained as the product. 63-68 ° C. IR (CHCl_Three) Ν_max 3008,297 0, 1718, 1670, 1629, 1512, 1196, 667cm^-1;¹H NMR (CDCl_Three) Δ 9.94 (bs, 1H) , 7.65 (d, 1H, J = 15.6 Hz), 7.50-7.46 (m, 2H), 7.35-7.31 (m, 3H), 6.56 (d, 1H , J = 8.7Hz), 6.52 (d, 1H, J = 15.6Hz), 4.75 (dd, 1H, J = 8.7, 4.8Hz), 2.34-2.28 (m, 1H), 1.02 (d, 3H, J = 6.9Hz), 0.99 (d, 3H, J = 6.6Hz);¹³C NMR (CDCl_Three) Δ 175.31,166.66,142.42,134.50,129.93,128.79,127.94,119.75,57.47,3 1.19, 19.00, 17.78; mass spectrum, m / z 276 (M⁺+29), 248 (M⁺+1), 203, 131 (100); exact mass C₁₄H₁₈NO_ThreeTo CH_ThreeOH).   C₁₄H₁₇NO_Three・ 0.1H_TwoAnalytical value for O:     Calculated value: C 67.51 H 6.96 N 5.62     Obtained value: C 67.30 H 7.10 N 5.57 Step B [3ξ, 4 (S)]-2,4,5-trideoxy-2,2-difluoro-4-[[3-methyl- 1-oxo-2-[(1-oxo-trans-3-phenyl-2-propenyl) a [Mino] butyl] amino] -5- [4- (phenylmethoxy) phenyl] -N- ( Preparation of (phenylmethyl) -L-glycero-pentanamide   Reaction scheme A ', step (e): N- (trans- Cinnamoyl) -L-valine (25 mmol) is converted to CH_ThreeDissolved in CN (80mml) and The resulting solution is cooled to -10C. Add N-methylmorpholine (NMM, 2. 52 g, 24.9 mmol) and then isobutyl chloroformate (3.72 g, 27.2 mmol) Add. 10 minutes later, H_Two4-Amine prepared in Example 1, Step D, in O (20 ml) No-2,2-difluoro-3-hydroxy-5- (4-benzyloxy) phenyl -N- (phenylmethyl) pentanamide (43.7 mmol, Example 1, Step D Solution) and NMM (4.08 g, 40.3 mmol) were added and stirred at -10 ° C. For 20 minutes. Pour the reaction mixture into ice-cold dilute HCl containing some NaCl. And extract twice with ethyl acetate. Extract the combined extracts with water, aqueous saturated sodium bicarbonate , Washed with brine, dried over anhydrous magnesium sulfate, filtered and Concentrate under vacuum. The residue was recrystallized from ethyl acetate / pentane to give a light yellow 61% of a 2: 1 mixture of diastereomers of the title compound were obtained as a brown solid. 222-2257 ° C. IR (KBr) ν_max3410, 3287, 1682, 1652, 1620, 1540, 1512 , 1243,1217,697cm^-1; 1H NMR (DMSO-d₆) Δ9.17-9.11 (m, 1H), 8.05 and  8.01 (2d, 1H total, J = 9.1, 9.1Hz), 7.85 and 7.71 (2d, 1H total, J = 9.1, 9.0Hz), 7.59-7.22 (m, 16H), 7.12 (d, 2H, J = 8.5Hz), 6.94-6.85 (m, 3H), 6 .26 (d, 1H, J = 7.6Hz), 5.04 and 4.96 (2s, 2H total), 4.42-3.99 (m, 5H) , 2.79-2.63 (m, 2H), 2.09-1.98 and 1.92-1.85 (2m, 1H total), 0.86 And 0.74 (2d, 3H total, J = 6.9Hz), 0.83 and 0.64 (2d, 3H total, J = 6.9Hz) Hz);¹⁹F NMR (DMSO-d₆) Δ-111.11 (dd, J = 255,6Hz),-112.12 (dd, J = 254,8Hz ), -120.35 (dd, J = 254, 19Hz), -122.04 (dd, J = 225, 20Hz); mass spectrum, m / Z 698 (M⁺+29), 670 (M⁺+1, 100), 650, 441, 423.   C₃₉H₄₁F_TwoN_ThreeO_FiveAnalytical value for:     Calculated value: C 69.94 H 6.17 N 6.27     Obtained value: C 68.59 H 6.32 N 5.90 Process C Preparation of final title compound   Reaction scheme A ′, step (f): The alcohol produced as described above is Oxidizes under swelling conditions as shown below. 2M chloride at -60 ℃ under nitrogen Salil / CH_TwoCl_Two(2.0 ml) to a stirred solution of anhydrous DMSO (0.42 ml, 5.9 mmol) was added dropwise. I do. 10 minutes later, CH_TwoCl_Two(3 ml) and anhydrous DMSO (1.5 mml) as described above A A solution of rucol (0.5 mmol) is added. Stir the solution at -65 ° C to -55 ° C for 5 hours You. Then it was warmed to -20 ° C and triethylamine (1.39 ml, 10.0 ml Is added over 5 minutes. Then warm the reaction mixture to room temperature overnight . Then dilute it with ethyl acetate (60 ml), filter and solid with ethyl acetate Wash. The filtrate was washed with 0.1 M HCl (3 × 15 ml), brine and dried over anhydrous magnesium sulfate. Dry over sodium, filter and concentrate under vacuum. Flash chromatograph (CH_TwoCl_Two(6% acetone in) and then recrystallized from ethyl acetate / pentane. This gave 34% of the final title compound as a white solid. 187-194 ° C. IR (KBr ) Ν_max3403, 3285, 1691, 1654, 1623, 1540, 1513, 1454, 1243, 1219, 1178 , 697cm^-1;¹H NMR (DMSO-d₆) Δ9.77-9.68 (m, 1H) 、 8.67-8.62 (m, 1H) 、 8.05-8 .00 (m, 1H), 7.56 (d, 2H, J = 7.0Hz), 7.50-7.21 (m, 14H), 7.14 (d, 2H, J = 8.5Hz ), 6.91-6.83 (m, 3H), 5.04-4.95 (m, 3H), 4.42-4.33 (m, 3H), 3.14-3.05 (m, 1H ), 2.74-2.61 (m, 1H), 2.02-1.76 (m, 1H), 0.84 and 0.81 (2d, 3H total, J = 7.0, 6.9Hz), 0.64 and 0.59 (2d, 3H total, J = 7.1, 6.9Hz);¹⁹F NMR (DM SO-d₆) Δ -110.26 (d, J = 269Hz), -110.53 (d, J = 268Hz), -112.03 (d, J = 269Hz) , -112.04 (d, J = 268 Hz)-main diastereomer pair; -105.07 (d, J = 265 Hz), -10 5.08 (d, J = 266 Hz), -110.59 (d, J = 265 Hz), -110.61 (d, J = 266 Hz)-small amount of dia Tereomer pair; mass spectrum, m / z 696 ((M⁺+29), 668 (M⁺+1), 439,230,2 02, 131, 124, 91 (100); exact mass C₃₉H₄₀F_TwoN_ThreeO_FiveTo DMSO-d₆).   C₃₉H₃₉F_TwoN_ThreeO_FiveAnalytical value for:     Calculated value: C 70.15 H 5.89 N 6.29     Obtained value: C 69.63 H 5.85 N 6.01 Example 4 α, α-difluoro-γ-[[2- [2-hydroxy-1-oxo-4- (Fe Nilbutyl) amino] -3-methyl-1-oxobutyl] amino] -β-oxo -4- (phenylmethoxy) -N- (phenylmethyl) -benzene-pentana Manufacture of mid Step A (R)-[[2-[(1,1-dimethylethyl) dimethylsilyl] oxy] -4-f Enylbutyryl] -L-valine   Standard coupling conditions in a manner similar to that described above, such as Step A of Example 2. In the following, (R)-(-)-2-hydroxy-4-phenylbutyric acid is converted to L-valine methyl ester. (R)-(2-) as a yellow solid in 89% yield by coupling with terhydrochloride. (Hydroxy-4-phenylbutyryl) -L-valine methyl ester is obtained. N- ( R)-[[[(1,1-dimethylethyl) dimethylsilyl] oxy] phenylacetyl The production of -L-valine was carried out in the same manner as described above in Example 1. Flash chromatography after treatment with tributyldimethylsilyl chloride After treatment (9/1 cyclohexane / ethyl acetate) as a colorless oil in 83% yield This gives an ester of the title compound. This ester was converted to N- (R)-[[[(1,1-dimethylethyl) dimethylsilyl] Xy] phenylacetyl] -L-valine as described above in Example 1. LiOH ・ H in the same way as_TwoHydrolysis with O as a white solid in 58% yield The title compound was obtained. 110-113 ° C. IR (KBr) ν_max3387, 2958, 2932, 2897, 2860, 1719, 1626, 1531, 1251, 1097, 839cm^-1;¹H NMR (CDCl_Three) Δ 7.24-7.12 (m, 7H), 4.54 (dd, 1H, J = 8.7, 4.5Hz), 4.32 (t, 1-H, J = 4.8Hz), 2.76-2.55 (m , 2H), 2.36-2.25 (m, 1H), 2.19-2.07 (m, 1H), 2.02-1.90 (m, 1H), 1.00 (d, 3H , J = 7.2Hz), 0.97 (d, 3H, J = 6.9Hz), 0.97 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H);  ¹³C NMR (CDCl_Three) δ175.64,174.08,141.69,128.42,128.30,125.77,72.73 , 59.64, 36.98, 30.75, 30.02, 25.67, 19.05, 17.93, 17.54, -4.79, -5.15; Mass spectrum, m / z 394 (M⁺+1), 393 CH_ThreeOH).   C_{twenty one}H₃₅NO_FourAnalytical value for Si:     Calculated value: C 64.08 H 8.96 N 3.56     Found: C 63.87 H 9.07 N 3.45 Step B [3ξ, 4 (S, R)]-2,4,5-trideoxy-4-[[2-[[2-[[(1,1-dimethyl Tylethyl) dimethylsilyl] oxy] -1-oxo-4-phenylbutyl] a Mino] -3-methyl-1-oxobutyl] amino] -5- [4- (phenylmeth Xy) phenyl] -N- (phenylmethyl) -L-chrysero-pentanamide Manufacture   Reaction Scheme A ', Step (e): For example, in Step A of Example 2, In the same manner as described above, (R)-[[2- [(1,1-dimethylethyl) dimethylsilyl] oxy] -4-phenylbutyryl] -L-valine was replaced with 4-amino-2,2-difluene prepared in Step D of Example 1. Oro-3-hydroxy-5- (4-benzyloxy) phenyl-N- (phenyl Methyl) pentanamide coupled with flash chromatography Processing (CH_TwoCl_Two(6% acetone in) after 61% yield as a tan foam The title compound was obtained. 62-67 ° C.¹H NMR (CDCl_Three) Δ 7.44-7.11 (m, 17H), 7.0 4 (d, 2H, J = 8.7Hz), 6.86 (d, 2H, J = 8.7Hz), 6.11 (d, 1H, J = 8.1Hz), 5.01 (s, 2H ), 4.71 (d, 1H, J = 6.9 Hz), 4.52 (dd, 1H, J = 14.6, 6.5 Hz), 4.35 (dd, 1H, J = 14. 4,5.4Hz), 4.28 (t, 1H, J = 4.8Hz), 4.15-3.93 (m, 3H), 2.91 (d, 2H, J = 7.8Hz) , 2.72 (ddd, 1H, J = 13.2, 12.0, 4.8Hz), 2.57 (ddd, 1H, J = 13.5, 12.3, 5.4Hz) , 2.15-1.90 (m, 3H), 0.98 (s, 9H), 0.87 (d, 3H, J = 2.4 Hz), 0.85 (d, 3H, J = 2.1 Hz), 0.14 (s, 3H), 0.10 (s, 3H);¹⁹F NMR (CDCl_Three) Δ-117.17 (dd, J = 259,15Hz ), -18.62 (dd, J = 259, 10 Hz); mass spectrum, m / z 844 (M⁺+29), (c 0.547, CH_ThreeOH).   C₄₆H₅₉F_TwoN_ThreeO₆Analytical value for Si:     Calculated value: C 67.70 H 7.29 N 5.15     Example: C 67.32 H 7.22 N 5.15 Process C Preparation of final title compound   Reaction Scheme A ', Steps (f) and (g): Step G of Example 1 Manufactured under the swelling conditions in the same manner as described above. Oxidized alcohol and flash chromatography (CH_TwoCl_Two6% of The protected ketone was obtained as a light brown oil in 72% yield after (acetone). Implementation In a manner similar to that described above in Step G of Example 1, the ketone (217 mg) was deprotected. And flash chromatography (CH_TwoCl_Two6%, 10% and finally 15% of After acetone), 104 mg (58%) of the title compound was obtained as a bright yellow glassy substance. Was. CH_TwoCl_TwoCrystallization from ethyl acetate / ether and three recrystallizations from ethyl acetate / pentane The crystals gave 34 mg (19%) of the title compound as a white solid. IR (KBr) ν_max 3394, 3300, 1686, 1651, 1534, 1513, 1498, 1243, 698cm^-1;¹H NMR (DMSO-d₆ ) Δ 9.76-9.69 (m, 1H), 8.70-8.66 (m, 1H), 7.52-7.11 (m, 19H), 6.88 and 6.87 (2d, 2H total, J = 8.7Hz), 5.73 (t, 1H, J = 5.8Hz), 5.03 and 5.00 (2s, Duplicate m, 3H total, J = 8.3Hz), 4.35 (apparent d, 2H, J = 6.1Hz), 4.26-4.20 (m, 1H) , 3.94-3.87 (m, 1H), 3.15-3.06 (m, 1H), 2.73-2.58 (m, 2H), 1.96-1.66 (m, 3H) , 0.77 and 0.76 (2d, 3H total, J = 6.7Hz), 0.63 and 0.53 (2d, 3H total , J = 6.8, 6.6Hz);¹⁹F NMR (DMSO-d₆) Δ -110.35 (d, J = 268Hz), -110.47 (d, J = 268Hz), -112.14 (d, J = 268Hz), -112.20 (d, J = 268Hz); mass spectrum, m / z  700 (M⁺+1), 680, 622, 439 (100), 421, 254, 91. Example 5 N- [1-[[[3,3-difluoro-4-[[2-methyl-1-[(phenylmeth (Xy) methyl] -propyl] amino] -2,4-dioxo-1-[[4- (phenyl Methoxy) phenyl] -methyl] butyl] a Mino] carbonyl] -2-methylpropyl] -β-oxo-4-morpholinepro Manufacture of panamide Step A (1 (R), 3ξ, 4 (S))-2,4,5-trideoxy-4-[((1,1-dimethylethoxy) -Carbonyl] amino] -2,2-difluoro-N- [2-methyl-1-[( Nilmethoxy) methyl] propyl] -5- [4- (phenylmethoxy) phenyl Production of -L-glycero-pentanamide   Reaction Scheme A, Step (b): CH_TwoCl_TwoO-benzyl-D-valino in (15 ml) (5.42 g, 28.0 mmol) in a stirred solution of (CH_Three)_ThreeAl / toluene 2M solution ( (14.0 ml, 28.0 mmol) are added over 20 minutes. During addition, additional CH_TwoCl_Two(10ml ) To convert the resulting paste into a thin slurry. As the addition proceeds When heated and refluxed, forms a solution again with vigorous gas evolution . After the addition is complete, stir at reflux for 15 minutes when gas evolution has ceased. Chamber with solution Cool to warm and CH_TwoCl_Two4-tert-butoxycarbonylamino-2,2 in (20 ml) -Difluoro-3-hydroxy-5- (4-benzyloxy) phenylpentane A solution of the acid ethyl ester (prepared in Example 1, 5.38 g, 11.2 mmol) was Add under mild gas evolution over 15 minutes. Heat the resulting solution to reflux overnight. You. The reaction mixture was cooled to 0 ° C and carefully quenched with excess methanol. Touch. Wash the resulting solution with 1N HCl. Extract the aqueous layer with ether. Combination The organic extract was washed with water, dried over anhydrous magnesium sulfate, filtered and filtered. And concentrated under vacuum and flash chromatography (4: 1 cyclohexane). (Xan / ethyl acetate) to give 5.5 g (78%) of the title compound as a beige powder. Was. Step B [1 (R), 3ξ, 4 (S)]-4-amino-2,4,5-trideoxy-2,2-difluoro-N -[2-methyl-1-[(phenylmethoxy) methyl] propyl] -5- [4- Production of (phenylmethoxy) phenyl] -L-glycero-pentanamide   Reaction Scheme A, Step (d): HCO_TwoManufactured as described above in H (50 ml) A solution of the alcohol (3.6 g, 5.7 mmol) is stirred at room temperature for 3 hours. then The solution is concentrated under vacuum at 35 ° C. The residue is dissolved in ethyl acetate and aqueous Add sodium bicarbonate with vigorous stirring. Separate the layers and wash the organic layer with water Wash with. The combined aqueous layers are extracted again with ethyl acetate. No combined organic extracts Dried over magnesium sulfate in water, filtered and concentrated in vacuo to give an orange This gave 3.0 g (99%) of the title compound as an oil. Process C [1 (R), 3ξ, 4 (S)]-2,4,5-trideoxy-4-[[2-[[(1,1-dimethyle Toxy) carbonyl] amino] -3-methyl-1-oxobutyl] amino] -2,2 -Difluoro-N- [2-methyl-1-[(phenylmethoxy) methyl] propyl -5- [4- (phenylmethoxy) phenyl] -L-glycero-pentana Manufacture of mid   Reaction Scheme D, Step (a): As in Step A of Example 2. In the same manner as described above, under standard conditions, the The min was converted to N- (tert-butoxycarbonyl) -L-valine (1.21 g, 5.61 mmol). ) And flash chromatography (9: 1 CH_TwoCl_Two / Ethyl acetate) to give 2.3 g (60%) of the title compound as a yellow powder. Process D [1 (R), 3ξ, 4 (S)]-4-[[2-amino-3-methyl-1-oxobutyl] a Mino] -2,4,5-trideoxy-2,2-difluoro-N- [2-methyl-1-[( Phenylmethoxy) methyl] -propyl] -5- [4- (phenylmethoxy) phenyl Enyl) -L-glycero-pentanamide   Reaction Scheme D, Step (b): HCO_TwoManufactured as described above in H (25 ml) A solution of the amide (2.0 g, 2.8 mmol) is stirred at room temperature for 6 hours. Add 30 Concentrate in vacuo at C and dissolve the residue in ethyl acetate. Aqueous bicarbonate sodium Is added with vigorous stirring. The precipitated white solid is filtered and (S) -It was found to be the formate salt of an amino alcohol. Separate the organic layer of the filtrate Release, wash with water, dry over anhydrous magnesium sulfate, filter and remove under vacuum Concentrate to give an amber oil containing some white solids. (R)-and (S) -Amino alcohol and lactam by-products are present. The residue was washed with CHCl_ThreeInside Slurry for 1 hour and reprecipitated solid, form of (S) -amino alcohol Collect the salt. The filtrate is concentrated under vacuum and the residue is_TwoCl_TwoDissolved in Further, the formate salt of (S) -amino alcohol is collected. Flash chromatography of residual oil Mattographic processing (5: 1 to remove lactams) CH_TwoCl_Two/ Ethyl acetate, then 9: 1 CH_TwoCl_Two: CH_ThreeOH), (S) -amido (R) -aminoalcohol which is impure with 5% of the alcoholic formate A yellow semi-solid was obtained. Yield: 800 mg of formate salt of (S) -amino alcohol (43% ) And 640 mg (37%) of (R) -amino alcohol. (S) -aminoal in ethyl acetate To a stirred suspension of cole's formate salt (800 mg, 1.19 mmol) was added 10% aqueous bicarbonate. Add sodium. After 2 hours at room temperature, the solid dissolves. Separate the organic layer and water , Dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo This gave 712 mg (95%) of the title compound as a white powder. 160-164 ° C. IR (KBr) umax 3383, 3327, 1676, 1632, 1530, 1514, 1244, 1109cm^-1;¹H NMR (CDCl_Three) δ 7.73 (d, 1H, J = 6.9Hz), 7.43-7.29 (m, 10H), 7.10 (d, 2H, J = 8.4Hz), 6.90 (d , 2H, J = 8.7Hz), 6.78 (d, 1H, J = 9.0Hz), 5.56 (bs, 1H), 5.04 (s, 2H), 4.55 (d , 1H, J = 12.0Hz), 4.47 (d, 1H, J = 12.0Hz), 4.33-4.18 (m, 2H), 3.92-3.83 (m, 1 H), 3.60 (dd, 1H, J = 9.6, 3.6Hz), 3.45 (dd, 1H, J = 9.6, 3.6Hz), 3.16 (d, 1H, J = 3.9Hz), 3.03-3.00 (m, 2H), 2.18-1.93 (m, 2H), 1.44 (bs, 2H), 0.94 (d, 6H, J = 6.9Hz), 0.85 (d, 3H, J = 6.9Hz), 0.53 (d, 3H, J = 6.9Hz);¹⁹F NMR (CDCl_Three) Δ  -110.67 (dd, J = 259, 5Hz), -121.74 (dd, J = 258, 18Hz); mass spectrum, m / z  654 (M⁺+29), 626 (M⁺+1), 325, 92, 91 (100), 72.   C₃₅H₄₅F_TwoN_ThreeO_FiveAnalytical value for:     Calculated value: C 67.18 H 7.25 N 6.72     Obtained value: C 67.34 H 7.21 N 6.66 Step E [1 (R), 3ξ, 4 (S)]-2,4,5-trideoxy-2,2-difluoro-4-[[3-me Tyl-2-[[3- (4-morpholinyl) -1,3-dioxopropyl] amino]- 1-oxobutyl] amino] -N- [2-methyl-1-[(phenylmethoxy) meth [Tyl] propyl] -5- [4- (phenylmethoxy) phenyl] -L-glycero -Production of pentanamide   Reaction Scheme D, Step (c): The standard kit described above as in Step A of Example 2. (R) -Amino alcohol prepared as described above under coupling conditions (169 mg, 0.270 mmol) was converted to 2- (4-morpholinylcarbonyl) ethanic acid (real (Compound B prepared in Example 5a, 49 mg, 0.28 mmol) And flash chromatography (3% CH_ThreeOH / CHCl_Three) With tan powder after This gave 185 mg (88%) of the title compound. 87-94 ° C. IR (KBr) ν_max 3428, 33 25, 1651, 1535, 1512, 1454, 1238, 1115cm^-1;¹⁹F NMR (CDCl_Three) Δ -116.11 (d , J = 259 Hz), -119.49 (dd, J = 259, 15 Hz); mass spectrum, m / z 809 (M⁺+29), 781 (M⁺+1), 509, 255, 243, 227, 88 (100). Step F Preparation of final title compound   Reaction Scheme D, Step (d): similar to the method described in Step G of Example 1. In a process, the alcohol prepared as described above under swern conditions (177 mg, 0.283 mmol) was oxidized and subjected to flash chromatography (3 % CH_ThreeOH / CHCl_ThreeAfter this, 170 mg (100%) of the final title compound are obtained. CH_TwoCl_Two/ether To give 49 mg (28%) of the final title compound as a light tan powder. Obtained. 119-128 ° C. IR (KBr) ν_max 3306,1661,1638,1539,1514,1454 , 1238, 1117cm^-1;¹H NMR (CDCl_Three) Δ7.77 and 7.75 and 7.61 and 7 .47 (4d, 1H total, J = 7.1, 7.1, 8.7, 8.9Hz, respectively), 7.43-7.29 (m, 10H), 7 .16-7.03 (m, 3H), 6.91-6.72 and 6.38-6.35 (2m, 3H total), 5.74 and 5 .53-5.46 and 5.24-5.17 (bs and 2m, 1H total), 5.02 (s, 2H), 4.56 And 4.48 (2d, 1H total, J = 12.1Hz), 4.55 and 4.47 (2d, 1H total, J J = 12.0Hz), 4.27 and 4.23 and 4.12 (3dd, 1H total, J = 8.8, respectively) 5.3 and 8.7, 5.7 and 7.3, 5.1 Hz), 3.89-3.80 (m, 1H), 3.69-3.59 (m, 7H) , 3.52-3.40 (m, 3H), 3.32-3.21 (m, 3H), 2.94-2.75 (m, 1H), 2.29-1.87 (m, 2H) , 0.94 and 0.93 and 0.92 and 0.91 and 0.89 and 0.88 and And 0.84 and 0.81 and 0.80 and 0.76 and 0.59 and 0.55 (12d , 12H total, J = 6.8 and 7.0 and 7.0 and 6.9 and 6.9, respectively  And 7.0 and 7.0 and 7.0 and 6.8 and 6.8 and 6.9 and And 6.8Hz);¹⁹F NMR (CDCl_Three) Δ -114.46 (d, J = 274Hz), -112.74 (s), -113.47 (d , J = 274Hz), hydrate: -114.43 (d, J = 253Hz), -116.47 (d, J = 254Hz), -120.63 (d , J = 253 Hz), -122.73 (d, J = 253 Hz); mass spectrum, m / z 807 (M⁺+29), 779 (M⁺ +1), 401, 361, 243 (100), 227; exact mass C₄₂H₅₃F_TwoN_FourO₈779. 3831, found 779.3878. Example 5a 4-morpholineacetic acid trifluoroacetate (A) and 2- (4-morpholinyl carb Production of (bonyl) ethanic acid (B) Production of 4-morpholineacetic acid 1,1-dimethylethyl ester   T-butyl bromoacetate (1.61 ml, 10.0 mmol) in tetrahydrofuran (25 ml) Morpholine (1.74 ml, 20.0 mmol). Suspension, 1. Stir for 5 hours and then concentrate under vacuum. The residue is washed with saturated sodium carbonate (50 ml) and dissolved in methylene chloride (50 ml). Separate layers and aqueous The phases are extracted with methylene chloride (2 × 25 ml). Combine the organic extracts and add saturated sodium carbonate (20 ml), brine (30 ml) and dried over anhydrous magnesium sulfate. , Filter and concentrate under vacuum. The residue was triturated with ethyl acetate (15 ml). Crushed, filtered and the filtrate was concentrated in vacuo to give the title compound (2.01 g) as a colorless oil. ) Got. TLC R_f= 0.45 (silica gel, ethyl acetate). Preparation of final title compound (A)   Trifluoroacetic acid (15 ml) was added to the ester (1.00) prepared as described above. g, 4.97 mmol). The solution is stirred for 5 hours and then vacuum Concentrate under to obtain a yellow oil. This is rubbed with diethyl ether (25 ml). Crushing gave the final title compound (A) (1.06 g, 82%) as an off-white solid. Fusion Point 118-121 ° C. Production of 2- (4-morpholinylcarbonyl) ethane acid methyl ester   Methylmalonyl chloride (10.0 g, 73.2 mmol) in methylene chloride (200 ml) at 0 ° C To a solution of morpholine (16.0 g, 0.183 mmol, 50 ml) in methylene chloride (50 ml). 16.0 ml) of the solution are rapidly added dropwise. The reaction mixture is stirred at room temperature for 4 hours. So Then the reaction mixture is filtered and the filtrate is diluted with additional methylene chloride (200 ml). Confuse. This was then washed with 1N HCl, saturated sodium bicarbonate and brine. Cleanse. The organic phase is then concentrated under vacuum to give a yellow oil, which is flushed Purify by chromatography (silica gel, ethyl acetate) to give a pale yellow oil This gave the title compound (9.7 g, 71%). R_f= 0.28 (ethyl acetate). Preparation of final title compound (B)   Amide prepared as described above (1.70 g, 9.08 in methanol (45 ml)) Mmol), 1N lithium hydroxide (10 ml, 9.99 mmol) is added. Anti The reaction mixture is stirred at room temperature for 2.5 hours. Adjust the pH to 3 with 1N HCl and react The mixture is concentrated under vacuum. The residue was recrystallized from acetonitrile to give a white solid. To give the title compound (B) (0.216 g, 14%). Example 6 [1R- (1R^*, 2S^*))-Α, α-difluoro-γ-[[2- (R)-[((hydroxy) Phenylacetyl] -amino] -3-methyl-1-oxobutyl] amino] -N -[2-methyl-1-[(phenylmethoxy) methyl] propyl] -β-oxo Production of 4- (phenylmethoxy) -benzenepentanamide Step A [1 (R), 3ξ, 4 (S)]-2,4,5-trideoxy-4-[[2-[[4-[[2-[[ [[(1,1-dimethyl-ethyl) dimethylsilyl] oxy] phenylacetyl] a Mino] -3-methyl-1-oxobutyl] amino] -2,2-difluoro-N- [ 2-methyl-1-[(phenylmethoxy) -methyl] propyl] -5- [4- (f Preparation of phenylmethoxy) -phenyl] -L-glycero-pentanamide   Reaction Scheme A ', Step (e): Same as the method described above as Step A in Example 2. Prepared in step B of Example 5 under standard coupling conditions [ 1 (R), 3ξ, 4 (S))-4-amino-2,4,5-trideoxy-2,2-difluoro-N- [2-methyl-1-[(phenylmethoxy) methyl] propyl] -5- [4- ( Phenylmethoxy) phenyl] -L-glycero-pentanamide (0.87 g, 1.6 mm ol is the (R) -O-tert-butyldimethyl-silylmane prepared in Example 1. Coupling with delic acid (0.44 g, 1.2 mmol) and flash chromatography Feet treatment (3: 2, then 1: 1 hexane / ethyl acetate) to yellow oil This gave 0.36 g (35%) of the title compound. IR (film) ν_max 3405, 3325, 2959, 2932 , 2895, 2876, 2861, 1684, 1657, 1512, 1470, 1454, 1244, 1221, 1179, 1098 , 864cm^-1;¹⁹F NMR (CDCl_Three) Δ -117.20 (d, J = 258 Hz), -118.99 (s), -120.55 ( d, J = 262Hz); mass spectrum (CI, 70 eV), m / z 874 (M⁺ +1), 509, 221 (100); exact mass C₄₉H₆₆F_TwoN_ThreeO₇874.4638 calculated for Si, actual 874.4651. Step B Preparation of final title compound   Reaction scheme A ', steps (f) and (g): same as described above in Example 1. In a similar method, under swelling conditions, the alcohol produced as described above (345 mg, 0.39 mmol) was oxidized and flash chromatographed ( After hexane / ethyl acetate (3: 2) 154 mg (45 mg) of ketone as a yellow glass. %). IR (film) ν_max 3408, 3298, 2961, 2932, 2861, 1655, 1613, 1514, 1470, 14 54, 1246, 1179, 1098, 1072, 839 cm^-1;¹⁹F NMR (CDCl_Three) δ -112.68 (S), -117. 29 (d, J = 253 Hz), -120.03 (d, J = 253 Hz); mass spectrum (CI, 70 eV), m / z 87 2 (M⁺+1), 221 (100), 197; exact mass C₄₉H₆₄F_TwoN_ThreeO₇872.4482 calculated for Si , Found 872.4500.   CH_TwoCl_Two(4 ml) to a stirred solution of ketone in TFA / H_TwoAdd O (9: 1, 1 ml) . The reaction mixture is stirred at room temperature for 7 hours and then concentrated under vacuum. Residue , CH_TwoCl_TwoAnd wash the solution with saturated aqueous sodium bicarbonate, brine , Dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Residue Was purified by flash chromatography (1: 1 hexane / ethyl acetate). To give 85 mg (64%) of the final title compound as a white powder. IR (film) ν_max 3397, 3314, 2965, 2934, 2874, 1750, 1688, 1663, 1532, 15 14, 1468, 1454, 1242, 1179, 1113, 826 cm^-1;¹⁹F NMR (CDCl_Three) Δ -112.30 (d , J = 271 Hz), -113.50 (d, J = 271 Hz), -117.54 (d, J = 254 Hz), -119.32 (d, J = 254 Hz); mass spectrum (CI, 70 e V), m / z 758 (M⁺+1), 107 (100), 91.   C₄₃H₄₉F_TwoN_ThreeO₇・ 0.6H_TwoAnalytical value for O:     Calculated value: C 67.19 H 6.58 N 5.47     Found: C 67.11 H 6.55 N 5.39 Example 7 N- [1-[[[3,3-difluoro-4-[[2-methyl-1-[(phenylmeth Toxy) -methyl] -propyl] amino] -2,4-dioxy-1-[[4- (f Enylmethoxy) phenyl] -methyl] -butyl] amino] carbonyl] -2- Methylpropyl] -6- (4-morpholinyl-carbonyl) -3-pyridinecar Production of boxamide Step A Production of 6- (4-morpholinylcarbonyl) -3-pyridinecarboxylic acid   CH at 5 ℃ under nitrogen_TwoCl_TwoO-tert-butyl-N, N'-dicyclohexyl in (20 ml) Isourea [Mathias, L,Synthesis, 570, 1979]. In the solution, 2-methylisocin comeronate [produced by Isagawa, K.Nippon Kagak u Zasshi ,88, 553, 1967] 1.49 g (8.24 mmol) in small portions over 2 minutes Add After 15 minutes, remove the cold water bath. Precipitation of dicyclohexylurea At that time, the reaction mixture is again placed in a cold water bath at 15-20 ° C. The mixture CH_TwoCl_Two(5 ml) and stir at room temperature overnight. Then the mixture CH_TwoCl_Two( 30 ml), filter and filter the turquoise solid in CH_TwoCl_TwoWash with. Filtrate and washing The solution is diluted with ether and washed with dilute aqueous sodium bicarbonate, water, brine, Dry over anhydrous magnesium sulfate, filter and concentrate under vacuum to give a light blue 1.36 g of a colored solid are obtained. Flash chromatography (55:45 cyclohexane With dioxane / ethyl acetate), the following diester (1.01 g, 52%) was obtained as white crystals. %). Recrystallization from ether / pentane gave rise to entangled white needles The diester was obtained. 111-112 ° C. IR (KBr) ν_max 3420, 2984, 1711, 137 9,1310,1290,1246,1134,1126,746cm^-1;¹H NMR (CDCl_Three) Δ 9.26 (d, 1H , J = 2.1 Hz), 8.39 (dd, 1H, J = 8.1, 2.1 Hz), 8.19 (dd, 1H, J = 8.1, 0.7 Hz), 4 .04 (s, 3H), 1.63 (s, 9H); mass spectrum (EI), m / z 238 (M⁺+1), 237 (M⁺), 18 2, 179, 164, 57 (100); CI m / z 238 (M⁺+1), 210, 182 (100).   C₁₂H_FifteenNO_FourAnalytical value for:     Calculated value: C 60.75 H 6.37 N 5.90     Obtained value: C 60.80 H 6.31 N 5.75   The diester (935 mg, 3.94 mmol) and morpholine (2 .0 ml, 23 mmol) is stirred at reflux under nitrogen for 24 h. Further morpholine ( 2.0 ml, 23 mmol) and heat Continue. After more than 3 days, the solution is concentrated under vacuum and the residue is taken up in ethyl acetate. Dissolve and wash the solution twice with water. The organic layer is concentrated under vacuum to a light yellow 1.01 g of a solid was obtained. Recrystallize twice from ether / pentane and filter through a filter aid. The following amide ester (542 mg, 47%) was obtained as fine cream crystals. Was. 91-93 ° C.   IR (KBr) ν_max 2984, 2965, 1707, 1634, 1370, 1317, 1287, 1169, 1132, 1 117 cm^-1;¹H NMR (CDCl_Three) Δ 9.13 (dd, 1H, J = 2.1, 1.0 Hz), 8.36 (dd, 1H, J = 8.1, 2.1 Hz), 7.75 (dd, 1H, J = 8.1, 0.9 Hz), 3.83 (s, 4H), 3.73-3.55 (m, 4H) , 1.62 (s, 9H); mass spectrum, m / z 293 (M⁺+1), 292, 123, 86 (100).   C_FifteenH₂₀N_TwoO_FourAnalytical value for:     Calculated value: C 61.63 H 6.90 N 9.58     Found: C 61.62 H 6.91 N 9.64   HCl gas, CH_ThreeNO_Two(43.5 ml) (103.5 mg, 0.354 mm) in amide ester Mol) through the solution for 20-25 minutes. After standing for another 20 minutes, the solution Is concentrated under vacuum and the residue is triturated with acetone to give a pale yellow solid. To give the title compound (acid). This substance was obtained from a similar experiment (from 502 mg 14) And recrystallized from acetone to give the target as short thick white needles. 335 mg (69%) of the title compound were obtained. Melting point 181-183 <0> C. IR (KBr) ν_max 2928, 2872, 1717, 1601, 1285, 1262, 1111 cm^-1;¹H NMR (CD_ThreeOD) δ 9.26 (d , 1H, J = 1.1 Hz), 8.78 (dd, 1H, J = 8.1, 2.0 Hz), 8.0 (d, 1H, J = 8.1 Hz), 3.80 (s, 4H), 3.67 (nm, 2H), 3.51 (nm, 2H); mass spectrum, m / z 277 (M⁺+41), 26 5 (M⁺+29), 238, 237 (M⁺+1,100).   C₁₁H₁₂N_TwoO_FourAnalytical value for:     Calculated value: C 55.93 H 5.13 N 11.86     Found: C 56.15 H 5.32 N 11.46 Step B [1 (R), 3ξ, 4 (S)]-2,4,5-trideoxy-2,2-difluoro-4-[[3-me Tyl-2-[[[[6- (4-morpholinylcarbonyl) -3-pyridinyl] cal [Bonyl] amino] -1-oxobutyl] -amino] -N- [2-methyl-1- [ (Phenylmethoxy) methyl] -propyl] -5- [4- (phenylmethoxy) Preparation of [phenyl] -L-glycero-pentanamide   Reaction Scheme D, Step (c): similar to the method described above, such as Step A of Example 2. In a method prepared under step D of Example 5 under standard coupling conditions (S) -amino alcohol (185 mg, 0.296 mmol) was prepared as described above. Coupled to the acid (77 mg, 0.33 mmol) Roughy treatment (5% CH_ThreeOH / CHCl_Three) After the title compound as a white powder 227mg (91%) I got 218-220 ° C. IR (KBr) ν_max 3287, 1674, 1663, 1636, 1557, 153 9,1514,1244,1115 cm^-1;¹H NMR (CDCl_Three+ DMSO-d₆) Δ 9.05 (d, 1H, J = 1.8 H z), 8.29 (dd, 1H, J = 8.1, 2.1 Hz), 8.03 (d, 1H, J = 9.3 Hz), 7.70 (d, 1H, J = 8. 4 Hz), 7.46 (d, 1H, J = 8.4 Hz), 7.37-7.22 (m, 11H), 7.09 (d, 2H, J = 8.1 Hz), 6.67 (d, 2H, J = 8.4 Hz) , 5.89-5.85 (m, 1H), 4.88 (d, 1H, J = 11.7 Hz), 4.83 (d, 1H, J = 11.7 Hz), 4.54 ( d, 1H, J = 12.0 Hz), 4.47 (d, 1H, J = 12.0 Hz), 4.45-4.35 (m, 1H), 4.31 (t, 1H , J = 9.0Hz), 4.24-4.13 (m, 1H), 3.92-3.82 (m, 1H), 3.77 (s, 4H), 3.64-3.48 (m , 6H), 3.08-3.02 (m, 1H), 2.76 (dd, 1H, J = 14.4, 10.5 Hz), 2.15-1.92 (m, 2H) , 0.94 (d, 6H, J = 6.9 Hz), 0.88 (d, 6H, J = 6.6 Hz);¹⁹F NMR (CDCl_Three+ DMSO-d₆ ) Δ -109.78 (d, J = 256 Hz), -122.05 (dd, J = 256, 19 Hz); mass spectrum, m / z 872 (M⁺+29), 844 (M⁺+1), 509 (100), 418, 318, 290, 219.   C₄₆H₅₅F_TwoN_FiveO₈Analytical value for:     Calculated value: C 65.47 H 6.57 N 8.30     Found: C 65.07 H 6.65 N 9.12 Process C Preparation of final title compound   Reaction Scheme D, Step (d): A method similar to that described above in Example 1 And under the swelling conditions, the alcohol produced as described above ( 196 mg (0.232 mmol) were oxidized and flash chromatographed (3%  CH_ThreeOH / CHCl_Three196 mg (100%) of the crude final title compound as an orange oil ) Got. CH_TwoCl_Two/ Pentane, then CH_TwoCl_Two/ By recrystallization from ether This gave 100 mg (51%) of the final title compound pure as a cream-coloured granulate. Fusion Point 108-135 ° C. IR (KBr) ν_max 3422, 3306, 1638, 1535, 1514, 1454, 1115 cm^-1 ;¹H NMR (CDCl_Three) Δ 8.95-8.87 (m, 1H), 8.16 and 8.13 and 8.12-8.08 (2d d and m, 1H, total, J = 2.2, 1.1 Hz), 7.74 and 7.71 and 7.68-7.67 (2dd and m, 1H total, J = 5.8, 0.7 Hz), 7.43-7.27 (m, 10H), 7.14-7.04 and 7.13 and 7.09 and 7.06 (m and 3d, 2H total, J = 8.5, 8.8, 8.8 Hz, respectively), 6.95-6.77 and 6.8 8 and 6.85 (m and 2d, 4H total, J = 8.7 Hz), 6.49 and 6.39 and 6.23 ( 3d, 1H total, J = 7.2, 6.7, 9.0 Hz, respectively), 5.60-5.56, 5.46, and 5 .33-5.21 (m and bs and m, 1H total), 5.02 and 4.98 and 4.93 (3s, 2H  (Total), 4.57-4.40 (m, 3H), 3.81 (bs, 5H), 3.67-3.59 (m, 5H), 3.50-3.43 ( m, 1H), 3.36-3.27 (m, 1H), 2.95-2.76 (m, 1H), 2.17-1.91 (m, 2H), 0.96-0.88 And 0.83 and 0.82 and 0.71 and 0.59 (m and 4d, 12H total, J = 6.8 Hz);¹⁹F NMR (CDCl_Three) Δ -111.54 (d, J = 270 Hz), -112.47 (d, J = 269 Hz), -113 .76 (d, J = 270 Hz), -114.62 (d, J = 270 Hz), hydrate: -114.80 (d, J = 253 Hz), -1 18.53 (s), -118.68 (s), -122.82 (d, J = 254 Hz); mass spectrum, m / z 870 (M⁺+ 29), 842 (M⁺+1), 197, 194, 91 (100); exact mass C₄₆H₅₄F_TwoN_FiveO₈Calculated value for 842.3940, found 842.3994.   C₄₆H₅₃F_TwoN_FiveO₈Analytical value for:     Calculated value: C 65.62 H 6.35 N 8.32     Found: C 64.80 H 6.46 N 8.27 Example 8 7,7-difluoro-4,12-bis (1-methylethyl) -6,8,11-trioxo-1- Phenyl-9-[[4- (phenylmethoxy) phenyl] methyl] -2-oxa -5,10,13-Triazatetradecane-14-oic acid, 3-pyridinylmethyle Manufacturing of steles Step A Production of N-[(3-pyridinylmethoxy) carbonyl] -L-valine   L-valine methyl ester hydrochloride (2.0 g, 12 mmol) in toluene (15 ml) ) Was added to triphosgene (1.78 g, 6 mmol) and DMF (0.15 ml, 2 ml). Lmol). Stir the heterogeneous mixture at room temperature for 30 minutes. To this mixture Butylamine (0.1 ml, 0.4 mmol) is added dropwise over 2 minutes. Reaction mixture Is heated to reflux for 1 hour. Analysis by IR spectroscopy is 2250cm^-1Smell A strong signal indicating the presence of the isocyanate. Bring the homogeneous solution to 0 ° C Cool and add 3-pyridyl carbinol (0.9 ml, 9 mmol) over 10 minutes. And drop it. A white precipitate forms during the addition. Allow the reaction mixture to warm to room temperature. And stir for 16 hours. Additional 3-pyridylcarbinol (1.8 ml, 18 mmol) was added. The cloudy mixture is heated to reflux for 3 hours. The solution is concentrated under vacuum and acetic acid Wash with ethyl and wash three times with water. This solution is mixed with anhydrous magnesium sulfate Dry over, filter and concentrate under vacuum to obtain an oil. This oil flash Matography processing (8: 1 CH_TwoCl_Two/ C_TwoH_FiveOH) to give N- as a yellow oil. [(3-pyridinylmethoxy) carbonyl] -L-valine methyl ester 1.46 g (60%).¹H NMR (CDCl_Three) Δ 8.61 (s, 1H), 8.56 (d, 1H, J = 6.5 Hz), 7.71 (d, 1H, J = 10.2 Hz), 7.29 (dd, 1H, J = 8.1, 6.6 Hz), 5.38 (bs, 1H), 5.13 ( s, 2H), 4.29 (dd, 1H, J = 8.2, 5.9 Hz), 2.12 (m, 1H), (c 0.85, CHCl_Three).   C₁₃H₁₈N_TwoO_FourAnalytical value for:     Calculated value: C 58.65 H 6.77 N 10.53     Found: C 57.62 H 7.03 N 10.47   Alternatively, N-[(3-pyridinylmethoxy) carbonyl]- L-valine methyl ester can be produced as follows. L- Valine methyl ester (newly produced from hydrochloride by neutralization with 50% aqueous NaOH) 4.25 g, 34 mmol) in CH_TwoCl_Two1,1'-Carbonidiimidazo in (30 ml) (4.86 g, 30 mmol) to the stirred mixture over 15 minutes. After more than 15 minutes To the solution, 3-pyridylcarbinol (5.0 ml, 51 mmol) is added dropwise to the homogeneous solution . The resulting solution is heated at 45 ° C. for 3 hours and then stirred at room temperature overnight. CH_Two Cl_TwoIs removed under vacuum and the residue is dissolved in toluene (70 ml). This solution Is heated at 70 ° C. for 6 hours and then concentrated under vacuum. Residue, CH_TwoCl_Two And the resulting solution is washed three times with water and dried over anhydrous magnesium sulfate. Dry, filter and concentrate to give an oil, which is subjected to flash chromatography. Further purification, N-[(3-pyridinylmethoxy) carbonyl] as a yellow oil -L-valine methyl ester was obtained.   CH_ThreeN-[(3-pyridinylmethoxy) carbonyl] -L-ba in OH (6 ml) To a stirred solution of phosphorus methyl ester (1.4 g, 5.3 mmol) was added LiOH.H_TwoO (0.24 g, 5 .8 mmol). Heterogeneous mixture in the chamber Stir at warm for 16 hours. The reaction mixture is diluted with water until completely homogeneous, Acidify with HCl (11.6 ml, 5.8 mmol) and concentrate under vacuum to give a white solid , This is 8: 1 CH_TwoCl_Two/ C_TwoH_FiveCrystallized from OH to form a white crystalline solid 0.53 g (40%) of the title compound was obtained. Mp 242-244 ° C.¹H NMR (DMSO-d₆) 8.9 ( m, 2H), 8.5 (d, 1H, J = 8 Hz), 8.05 (m, 1H), 7.7 (d, 1H, J = 9 Hz), 5.22 (s, 2H) , 3.9 (m, 1H), 2.05 (m, 1H), 0.85 (m, 6H). Step B [1 (R), 3ξ, 4 (S)]-2,4,5-trideoxy-2,2-difluoro-4-[[3-me Tyl-1-oxo-2-[[(3-pyridinylmethoxy) carbonyl] amino] bu [Tyl] amino] -N- [2-methyl-1-[(phenylmethoxy) methyl] pro Pill] -5- [4- (phenylmethoxy) phenyl] -L-glycero-pentane Production of amide   Under the standard coupling conditions described above as in step A of example 2, The amino alcohol prepared in Step D of Step 5 (0.28 g, 0.53 mmol) was added to the above Coupling with the acid prepared as described (0.19 g, 0.74 mmol) To give 0.20 g (50%) of the title compound as a white powder after crystallization from ethyl acetate. . 187-191 ° C. IR (KBr) ν_max 3426, 3300, 2960, 1698, 1674, 1657, 154 1,1512,1246,1177,1151,1105,1028,698 cm^-1;¹H NMR (DMSO-d₆) 8.5 8 (d, 1H, J = 1.6 Hz), 8.49 (dd, 1H, J = 4.7, 1.4 Hz), 7.76 (d, 1H, J = 7.9 Hz), 7 .46-7.24 (m, 13H), 7.13-7.07 (2d, 2H total, J = 8.8 Hz), 6.88 and 6.81 (2 d, 2H total, J = 8.8, 8.3 Hz), 8.34, 7.97, and 6.18 (3d, 1H total), 5 .08 and 5.03 (d and s, 2H total, J = 5.7 Hz), 4.99 (d, 2H, J = 2.2 Hz), 4.46 (d, 2H, J = 3.8 Hz), 4.21 (m, 1H), 4.06-3.92 (m, 1H), 3.87-3.73 (m, 2H), 3.52 (d, 2H, J = 6.9 Hz), 2.93 (d, 1H, J = 12.2 Hz), 2.6 (m, 1H), 1.93-1.75 (m, 2H), 0.87 (apparent t, 8H, J = 6.6 Hz), 0.68 (dd, 4H, J = 6.8, 6.6 Hz);¹⁹F NMR (D MSO-d₆) Δ Main diastereomer: -108.9 (dd, J = 251, 7 Hz), -119.8 (dd, J = 245, 19 Hz), small amount of diastereomer: -111.6 (dd, J = 252, 8 Hz), -117.1 (dd , J = 250, 18 Hz); mass spectrum, m / z 761 (M⁺+1), 555,138,121,110,92 .   C₄₂H₅₀F_TwoN_FourO₇Analytical value for:     Calculated value: C 66.32 H 6.58 N 7.37     Found: C 62.43 H 6.36 N 6.79 Process C Preparation of final title compound   Reaction Scheme D, Step (d): A method similar to that described above in Example 1 And oxidize the alcohol produced as described above under Swellen conditions. , Flash chromatography (8: 1 CH_TwoCl_Two/ C_TwoH_FiveOH) white powder after To give 100 mg (50%) of the final title compound. 108-111 ° C. IR (KBr) ν_{ma x}  3416, 3308, 2963, 1696, 1660, 1537, 1514, 1246, 1115, 1028 cm^-1;¹H NM R (DMSO-d₆) Δ 8.91 (d, 1H, J = 8.8 Hz), 8.58-8.51 (m, 2H), 7.75 (d, 1H, J = 7. 7 Hz), 7.45 to 7.23 (m, 12H), 7.16 (d, 1H, J = 8.6 Hz), 6.90 (d, 2H, J = 8.6 Hz), 5.06-4.99 (m, 5H), 4.45 (d, 2H, J = 3.1 Hz), 3.92-3.8 (m, 2H), 3.52 (m, 2H), 3 .10 (dd, 1H, J = 14.9, 3.1 Hz), 2.69 (dd, 1H, J = 14.1, 9.9 Hz), 1.87 (m, 2H), 0.84 and 0.78 (2dd, 10H total, J = 10.8, 7.1 Hz and J = 6.4, respectively) 4.8 Hz), 0.60 (dd, 2H, J = 8.7, 6.9 Hz);¹³C NMR (DMSO-d₆) Δ 171.2,157.15 , 155.8, 149.0, 148.95, 148.9, 138.3, 137.1, 135.5, 132.6, 130.2, 130.07 , 128.8,128.7,128.37,128.16,127.75,127.67,127.6,127.5,127.44,12 7.36, 123.43, 114.5, 71.9, 69.5, 69.45, 69.1, 69.0, 63.16, 59.6, 55.25, 54.76, 54.67, 33.8, 33.75, 30.35, 28.8, 28.77, 19.4, 19.33, 18.98, 18.59 , 17.86;¹⁹F NMR (DMSO-d₆) Δ -111.36 (d, J = 272 Hz), -114.36 (d, J = 270 Hz) , -112.96 (s), -117.06 (d, J = 255 Hz); -120.00 (d, J = 250 Hz); mass spectrum , M / z 759 (M⁺+1), 460, 110, 91.   C₄₂H₄₈F_TwoN_FourO₇・ H_TwoAnalytical value for O:     Calculated value: C 64.94 H 6.44 N 7.22     Found: C 64.70 H 6.36 N 7.24 Example 9 (1R- (1R^*, 2S^*)]-Α, α-difluoro-γ-[[3-methyl-2-[[4- ( 4-morpholinylsulfonyl) benzoyl] amino] -1-oxobutyl] amido No] -N- [2-methyl-1-[(phenylmethoxy) methyl] propyl] -β Production of -oxo-4- (phenylmethoxy) -benzenepentanamide Step A [1 (R), 3ξ, 4 (S)]-2,4,5-trideoxy-2,2-difluoro-4-[[3-me Tyl-2-[[4- (4-morpholinylsulfonyl) benzoyl] amino] -1 -Oxobutyl] -amino] -N- [2-methyl-1-[(phenylmethoxy) Methyl] propyl] -5- [4- (phenylmethoxy) phenyl] -L-glyce Production of ro-pentanamide   Reaction Scheme D, Step (c): similar to the method described above, such as Step A of Example 2. In a method prepared under step D of Example 5 under standard coupling conditions (S) -amino alcohol (161 mg, 0.26 mmol) [Sycheva, T.P., etc.Sbornik Statei Obshchei Khim , Akad. Nauk SSSR,1 , 568-571 (1953)] (77 mg, 0 mg). .28 mmol) and flash chromatography (1 : 1 ethyl acetate / CH_TwoCl_Two) To give 140 mg (62%) of the title compound as a white solid . Recrystallized from ethyl acetate / cyclohexane to give the title compound as a white powder Was. 172.5-190.5 ° C (172.5-174, then 189.5-190.5 ° C). IR (KBr) ν_{m ax}  3420, 3322, 2965, 1643, 1534, 1514, 1171, 1113 cm^-1;¹H NMR (CDCl_Three) δ 7.90 (d, 2H, J = 8.4 Hz), 7.79 (d, 2H, J = 8.3 Hz), 7.4-7.25 (m, 10H), 7.08 ( d, 2H, J = 8.6 Hz), 6.78 (d overlap m, 4H, J = 8.5 Hz), 6.65 (d, 1H, J = 8.6 Hz), 4. 93 (s, 2H), 4.53 (d, 1H, J = 12.0 Hz), 4.47 (d, 1H, J = 12.0 Hz), 4.45-4.24 (m, 4H), 3.82 (m , 1H), 3.73-3.65 (nm, 4H), 3.62 (dd, 1H, J = 9.7, 4.1 Hz), 3.46 (dd, 1H, J = 10 .0, 3.9 Hz), 3.1-2.85 (m, 6H), 2.12 (m, 1H), 1.98 (m, 1H), 0.97-0.89 (m, 12H );¹⁹F NMR (CDCl_Three) Δ -110.18 (dd, J = 261, 4 Hz), -12.09 (dd, J = 261, 18 Hz) ); Mass spectrum, m / z 879 (M⁺+1, 100), 527, 325, 254.   C₄₆H₅₆F_TwoN_FourO₉Analytical value for S:     Calculated value: C 62.85 H 6.42 N 6.37     Found: C 62.65 H 6.43 N 6.26 Step B Preparation of final title compound   Reaction Scheme D, Step (d): In a manner similar to that described in Example 1, Swelln the alcohol (133 mg, 0.151 mmol) prepared as described above. Oxidation under conditions and flash chromatography (3: 2 ethyl acetate / After cyclohexane) 82 mg of the final diastereomeric mixture of the title compound were obtained. The mixture is partially crystallized from cyclohexane / ethyl acetate by evaporation of the solvent. To Grind the sticky pale yellow solid with ether to form a white 59 mg (44%) of the single diastereomer of the final title compound was obtained as a powder. Fusion Point 114-116 ° C. IR (KBr) ν_max 3426, 2971, 1686, 1663, 1512, 1171, 1115 cm^-1 ;¹H NMR (CDCl_Three) Δ 7.92 (d, 2H, J = 8.3 Hz), 7.81 (d, 2H, J = 8.3 Hz), 7.41 -7.29 (m, 10H), 7.06 (d, 2H, J = 8.6 Hz), 6.85 (d, 2H, J = 8.6 Hz), 6.78 (d, 2H , J = 8.6 Hz), 6.29 (d, 1H, J = 6.7 Hz), 5.26 (m, 1H), 4.99 (s, 2H, main peak ), 4.55 (d, 1H, J = 12.0 Hz), 4.48 (d, 1H, J = 12.0 Hz), 4.43 (dd, 1H, J = 8.4, 6.4 Hz), 3.84 (m, 1H), 3.72 (small m, 4H), 3.63 (dd, 1H, J = 9.8, 3.8 Hz), 3.47 (dd, 1H, J = 9.7, 3.8 Hz), 3.31 (dd, 1H, J = 14.4, 5.0 Hz), 3.00-2.87 (m, 5H), 2.14 (m, 1H), 2.00 (m, 1H), 0.96 (d, 3H, J = 6.7 Hz), 0.95 (d, 3H, J = 6.7 Hz), 0.94 (d, 3H, J = 6.7 Hz), 0.92 (d, 3H, J = 6 .7 Hz);¹⁹F NMR (CDCl_Three) Δ -112.45 (d, J = 270 Hz), -113.69 (d, J = 270 Hz),- 117.94 (d, J = 255 Hz), -119.29 (d, J = 255 Hz); mass spectrum (CI), m / z 905 (M⁺ +29), 877 (M⁺+1), 525, 507, 401, 353 (100), 197, 107.   C₄₆H₅₄F_TwoN_FourO₉S0.5H_TwoAnalytical value for O:     Calculated value: C 62.36 H 6.26 N 6.32     Found: C 62.24 H 6.30 N 6.27 Example 10 (1R- (1R^*, 2S^*)]-Α, α-difluoro-γ-[[3-methyl-2-[[4- ( 4-morpholinylcarbonyl) benzoyl] amino] -1-oxobutyl] amido No] -N- [2-methyl-1-[(phenylmethoxy) methyl] propyl] -β Production of -oxo-4- (phenylmethoxy) -benzenepentanamide Step A [1 (R), 3ξ, 4 (S)]-2,4,5-trideoxy-2,2-difluoro-4-[[3-me Tyl-2-[[4- (4-morpholinylcarbonyl) be Zonyl] amino] -1-oxobutyl] -amino] -N- [2-methyl-1- [(Phenylmethoxy) methyl] propyl] -5- [4- (phenylmethoxy) Preparation of [phenyl] -L-glycero-pentanamide   Reaction Scheme D, Step (c): In a manner similar to that described above, Prepared in Step D of Example 5 under standard coupling conditions as in Step A (R) amino alcohol (171 mg, 0.274 mmol) was added to 4 (4-morpholinyl carb Bonyl) benzoic acid (prepared in Example 10a, 68 mg, 0.29 mmol) And then flash chromatography (3% CH_ThreeOH / CHCl_Three) Yellow 217 mg (94%) of the title compound were obtained as a colored powder. IR (KBr) ν_max 3428, 3322, 1636, 1534, 1512, 1456, 1279, 1258, 1244, 1115 cm^-1;¹⁹F NMR (CDCl_Three) Δ -110.19 (d, J = 259 Hz), -117.26 (d, J = 259 Hz), -120.14 (d, J = 259 Hz), -121.4 0 (dd, J = 259, 20 Hz) + impurity; mass spectrum, m / z 871 (M⁺+29), 843 (M⁺+1) , 527, 509, 329, 317 (100), 289, 250, 218. Step B Preparation of final title compound   Reaction Scheme D, (d): The alcohol produced as described above is reacted with Thus, it is oxidized under Swelln conditions. -45 ° C anhydrous CH_TwoCl_Two(3 ml) and anhydrous Alcohol prepared as described above in DMSO (0.36 ml, 5.1 mmol) (215 mg, 0.255 mmol) in 2M oxalyl chloride / CH_TwoCl_Two(1.0ml) Is added over 5 minutes. The solution is stirred at -40 ° C to -30 ° C for 2.5 hours. So The solution was then cooled to -70 ° C and diisopropylethylamine (0.67 ml, 3.8 mmol) is added over 5 minutes. The solution was warmed to room temperature and CH_Two Cl_TwoDiluted with water, washed twice with water, dried over anhydrous magnesium sulfate, filtered and filtered. And concentrate under vacuum. The residue was purified by flash chromatography (3% CH_ThreeOH / CH_ThreeCl_Three) To give 210 mg (98%) of the final title compound as an amber oil. ) Got. CH_TwoCl_Two/ Recrystallized from pentane to give an amber powder 80 mg (37%) of the title compound were obtained. 87-92 ° C. IR (KBr) ν_max 3306, 1636 , 1534, 1514, 1454, 1279, 1258, 1244, 1115cm^-1;¹H NMR (CDCl_Three) Δ 7.82-7 .75 (m, 2H), 7.48-7.30 (m, 12H), 7.11-7.04 (m, 2H), 6.91-6.82 (m, 2H), 6.78 ( d, 1H, J = 8.7 Hz), 6.68 (d, 1H, J = 8.7 Hz), 6.44 and 6.33 (2d, 1H, J = 6.9 Hz) ), 5.31-5.22 (m, 1H), 5.05-4.94 (m, 2H), 4.57-4.38 (m, 3H), 3.88-3.28 (m, 12 H), 2.94-2.81 (m, 1H), 2.16-1.93 (m, 2H), 0.96-0.58 (m, 12H);¹⁹F NMR (CDCl_Three ) Δ -111.56 (d, J = 270 Hz), -112.56 (d, J = 270 Hz), -113.63 (d, J = 270 Hz), -114.54 (d, J = 270 Hz), hydrate: -113.53 (d, J = 292 Hz), -114.85 (d, J = 252 Hz) , -118.71 (d, J = 292 Hz), -122.88 (d, J = 252 Hz); mass spectrum, m / z 869 (M⁺ +29), 841 (M⁺+1), 525, 317, 279, 218, 197, 157 (100). Exact mass C₄₇H₅₅F_Two N_FourO₈841.3988, found 841.4043.   C₄₇H₅₄F_TwoN_FourO₈Analytical value for:     Calculated value: C 67.13 H 6.47 N 6.66     Found: C 65.80 H 6.60 N 6.69 Example 10a Production of 4- (4-morpholinylcarbonyl) benzoic acid Production of 4- (4-morpholinylcarbonyl) benzoic acid methyl ester   Terephthal in methylene chloride (500 ml) and dimethylformamide (4 ml) To a stirred suspension of monomethyl acid salt (25.0 g, 0.14 mmol) under vigorous gas evolution Oxalyl chloride (12.1 ml, 0.14 mol) is added dropwise. After gas generation stops The reaction mixture is stirred for 45 minutes and then cooled in an ice-water bath. Then, Ruphorin (48.4 ml, 0.56 mol) is added. A fever occurs. After the addition is complete, mix The mixture is warmed to room temperature and stirred for 1 hour. The reaction mixture was then added to 0.5N HCl (2 × 500 ml), half-saturated sodium bicarbonate (2 × 500 ml), water (2 × 500 ml) and Wash with brine (300 ml). Dry the reaction mixture over anhydrous magnesium sulfate And filtered and concentrated in vacuo to afford the title compound as a white solid (33.8 g, 98 %). 74-76 ° C. Preparation of final title compound   Stirring solution of the above ester (50.1 g, 0.20 mmol) in methanol (800 ml) To this is added 1N lithium hydroxide (241 ml, 0.24 mol) and then water (160 ml). room temperature After stirring for 7 hours, additional water (100 ml) is added. Then, add the reaction mixture. And stirred for 24 hours and then concentrated to remove methanol. Aqueous layer, salt Extract with methylene chloride (2 × 100 ml) and diethyl ether (200 ml). Or that The aqueous layer was cooled in an ice-water bath and acidified with 12N HCl (about 20 ml). Adjust to pH 1. Filtration gives a crude white solid. Chloride this solid substance Suspend in styrene (21) and heat to reflux. Then cool it to room temperature, Treat with anhydrous magnesium sulfate and filter. The filtrate is concentrated under vacuum, The final title compound (42.2 g, 89%) was obtained as a white solid. Mp 194-196 ° C. Example 11 N- [1-[[[3,3-difluoro-4-[[2-methyl-1-[(phenylmeth Toxy) methyl] -propyl] amino] -2,4-dioxo-1-[[4- (Fe Nilmethoxy) phenyl] -methyl] butyl] amino] carbonyl] -2-methyl [Propyl] -4-morpholineacetamide Step A [1 (R), 3ξ, 4 (S)]-2,4,5-trideoxy-2,2-difluoro-4-[[3-me Tyl-2-[[(4-morpholinyl) acetyl] amido] -1-oxobutyl] a Mino] -N- [2-methyl-1-[(phenylmethoxy) methyl] propyl]- 5- [4- (phenylmethoxy) phenyl] -L-glycero-pentanamide Manufacture   Reaction Scheme D, Step (c): A method similar to that described above (1.1 equivalents of NMM added) (R, S) prepared in Step D of Example 5 under standard coupling conditions -Amino alcohol (201 mg, 0.321 mmol) Lorate (Example 5a (92 mg, 0.35 mmol) of compound (A) prepared in Chromatographic treatment (4% CH_ThreeOH / CDCl_Three) After beige powder 224 mg (92%) of the compound were obtained. 110-117 ° C. IR (KBr) ν_max 3298, 2963, 16 74, 1649, 1545, 1512, 1238, 1115, 698 cm^-1;¹⁹F NMR (CDCl_Three) Δ Astereomer -110.56 (dd, J = 260, 5 Hz), -120.79 (dd, J = 260, 18 Hz); mass Spectrum, m / z 781 (M⁺+29), 753 (M⁺+1、100) 、 752 (M⁺), 291, 100, 91. Step B Preparation of final title compound   Reaction Scheme D, Step (d): In a manner similar to that described in Example 1. The alcohol (206 mg, 0.274 mmol) produced as described above was , Oxidize under Swelln conditions and flash chromatography (3% CH_ThreeO H / CHCl_ThreeAfter this, 170 mg (83%) of an orange glass were obtained. CH_TwoCl_Two/ Ether Recrystallization gave 70 mg (34%) of the final title compound as sticky amber crystals. ) Got. 48-53 ° C. IR (CHCl_Three) Ν_max 2969, 1686, 1512, 1242, 1117, 7 60,750,731cm^-1;¹H NMR (CDCl_Three) Δ 7.55-7.50 (m, 1H), 7.43-7.29 (m, 10H), 7.14-7.07 (m, 2H), 6.92-6.78 (m, 3H), 6.52-6.49 and 6.40-6.37 (2m, 1H ), 5.33-5.19 (m, 1H), 5.03 (apparent d, J = 3.6 Hz), 4.55 (d, 1H, J = 11.9 Hz) , 4.48 and 4.47 (2d, 1H total, J = 11.9 Hz), 3.88-3.80 (m, 1H), 3.74-3.6 1 (m, 5H), 3.50-3.44 (m, 1H), 3.32-3.25 (m, 1H), 2.99-2.81 (m, 3H), 2.49-2.4 6 (m, 4H), 2.14-1.95 (m, 2H), 1.28-1.24 and 0.95-0.70 and 0.50 (2m and d , 12H total, J = 6.7 Hz);¹⁹ F NMR (CDCl_Three) Δ -111.32 (d, J = 273 Hz), -112.96 (S), -114.64 (d, J = 272 Hz) Mass spectrum, m / z 779 (M⁺+29), 751 (M⁺+1), 226, 100 (100), 86; accurate Mass C₄₁H₅₃F_TwoN_FourO₇Calculated 751.3882, found 751.3892.   C₄₁H₅₂F_TwoN_FourO₇・ 1.3H_TwoAnalytical value for O:     Calculated value: C 63.60 H 6.77 N 7.24     Found: C 63.64 H 6.80 N 6.84 Example 12 N- [1-[[[3,3-difluoro-4-[[2-methyl-1-[(phenylmethan Xy) methyl] -propyl] amino] -2,4-dioxo-1-[[4- (phenyl Methoxy) phenyl] methyl] -butyl] amino] carbonyl] -2-methyl Preparation of [propyl] -1H-imidazole-1-acetamide Step A Production of 1H-imidazole-1-acetic acid / HCl   CH at 0 ° C under nitrogen_TwoCl_TwoOf imidazole (1.50 g, 22.0 mmol) in (25 ml) To the stirred solution is added dropwise tert-butyl bromoacetate (1.62 ml, 10.0 mmol). Ice bath Remove and stir the solution at room temperature for 22 hours. The solution is concentrated under vacuum and the residue Is partitioned between ethyl acetate and water. The organic layer is washed with water and concentrated under vacuum And 1.22 g of 1H-imidazole-1-tert-butyl acetate as a white crystalline solid. (67%). Melting point 110-113 ° C;¹H NMR (CDCl_Three) Δ 7.49 (s, 1H), 6.95 (s, 1H) , 4.59 (s, 2H), 1.47 (s, 9H). HCl gas, CH_ThreeNO_Two1H-imi in (4-5 ml) Bubble through a solution of dazole-1-tert-butyl acetate for 20-25 minutes. 20 minutes or less After standing on top, the solution was concentrated under vacuum and CH_ThreeCN / CH_ThreeRecrystallized from OH, 70% To give the title compound. 206-209 ° C.¹H NMR (DMSO-d₆) Δ 9.12 (d, 1H , J = 1.4 Hz), 7.73 (small m, 1H), 7.68 (d, 1H, J = 1.4 Hz), 5.15 (s, 2H).   C_FiveH₆N_TwoO_Two-Analytical value for HCl:     Calculated value: C 36.94 H 4.34 N 17.23     Found: C 37.21 H 4.36 N 17.39 Step B [1 (R), 3ξ, 4 (S)]-2,4,5-trideoxy-2,2-difluoro-4-[[2- [ (1H-Imidazol-1-ylacetyl) amino] -3-methyl-1-oxo [Butyl] amino] -N- [2-methyl-1-[(phenylmethoxy) methyl] p Ropyl] -5- [4- (phenylmethoxy) phenyl] -L-glycero-penta Of amide   Reaction Scheme D, Step (c): anhydrous CH_TwoCl_Two(4 ml) and anhydrous DMF (7 ml) (R) -amino alcohol prepared in Step D of Example 5 (205 mg, 0.32 8 mmol) in a solution of 1H-imidazole-1 prepared as described above. Add acetic acid / HCl (56 mg, 0.34 mmol) and NMM (35 μl, 0.32 mmol) You. All of the 1H-imidazole-1-acetic acid does not dissolve. Then, HOBT (53mg , 0.34 mmol) and EDC (66 mg, 0.34 mmol) and The resulting mixture is stirred overnight at room temperature. The mixture is concentrated under vacuum and the residue is Dissolve in ethyl acid. Wash organic layer with water, 10% aqueous sodium bicarbonate, brine And dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a yellow Get a solid. This solid is TLC (10% CH_ThreeOH / CHCl_Three) By two big sports Contain Chromatographic treatment (Introduction 4% CH_ThreeOH / CHCl_ThreeEluted with , Secondly 1: 1 CH_ThreeOH / CHCl_Three) To separate the two compounds. small The more polar material is the starting formamide, while the more polar material is The title compound (110 mg 45%) and is isolated as a white powder. Melting point 190 ~ 193 ° C. IR (KBr) ν_max 3430, 3297, 1678, 1647, 1549, 1512, 1240, 1082 c m^-1;¹⁹F NMR (CDCl_Three+ DMSO-d₆) δ main diastereomer -115.66 (dd, J = 259 , 7 Hz), -120.48 (dd, J = 259, 18 Hz); mass spectrum, m / z 762 (M⁺+29), 734 (M⁺+1), 91 (100). Process C Preparation of final title compound   Reaction Scheme D, step (d): In a manner similar to that described in Example 1. And the alcohol (101 mg, 0.138 mmol) produced as described above was swallowed. Oxidation under Ehrn conditions and flash chromatography (2: 1 CHCl_Three / CH_ThreeAfter OH), 101 mg (100%) of an orange oil were obtained. CH_TwoCl_Two/ From pentane The crystals yielded 50 mg (50%) of the final title compound as a beige solid. 112-116 ° C. IR (KBr) ν_max 3428, 3295, 2963, 1647, 1551, 1512, 1240 , 1113, 698 cm^-1;¹H NMR (DMSO-d₆) δ 9.00 and 8.93 and 8.66 and 8.64 ( 4d, 1H total, J = 9.0, 9.0, respectively 7.2, 7.2 Hz), 8.16 (apparent triplet, 1H, J = 8.4 Hz), 7.59 (bs, 1H), 7.46-7.26 ( m, 11H), 7.15 and 7.14 (2d, 1H total, J = 8.6 Hz), 7.06 (bs, 1H), 6.90, And 6.89 (apparent 2d, 3H, J = 8.7 Hz), 5.05 (s, 2H), 5.01 (dd, 1H, J = 7.5, 3.4 Hz ), 4.79-4.61 (m, 2H), 4.50-4.39 (m, 2H), 4.30-4.20 (m, 1H), 3.85-3.76 (m, 1H ), 3.54-3.50 (m, 2H), 3.20-3.08 (m, 1H), 2.72-2.57 (m, 1H), 2.00-1.72 (m, 2H ), 1.27-1.21 and 0.87-0.69 and 0.61-0.52 (m, 12H total);¹⁹F NMM (DMS O-d₆) Δ -108.87 (d, J = 267 Hz), -109.82 (d, J = 268 Hz), -111.37 (d, J = 268 Hz) ), -112.32 (d, J = 254 Hz), 112.58 (d, J = 268 Hz), -117.61 (d, J = 254 Hz); Mass Spectrum, m / z 760 (M⁺+29), 732 (M⁺+1), 712, 180, 91 (100), 69; exact quality Quantity C₄₀H₄₈F_TwoN_FiveO₆732.3573, found 732.3541.   C₄₀H₄₇F_TwoN_FiveO₆・ 2H_TwoAnalytical value for O:     Calculated value: C 62.57 H 6.69 N 9.12     Found: C 62.07 H 6.49 N 9.05 Example 13 [1-[[[3,3-difluoro-2,4-dioxo-1-[[4- (phenylmethoxy C) phenyl] -methyl] -4-[(2-pyridinylmethyl) amino] butyl] Amino] carbonyl] -2-methylpropyl] -carbamic acid, 3-pyridinyl Production of methyl ester Step A [1 (R), 3ξ] -2,4,5-trideoxy-4-[[(1,1-dimethylethoxy) carbo Nil] -amino] -2,2-difluoro-5- [4- (phenylmethoxy) -fe Nyl] -N- (2-pyridinylmethyl) -L-glycero-pentanamide   Reaction Scheme A, Step (b): prepared in Step B of Example 1 in dry THF (16 ml). 4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy Ci-5- (4-benzyloxy) phenylpentanoic acid ethyl ester (1.5 g, 3 0.1 mmol) to a stirred solution of 2- (aminomethyl) pyridine (0.38 ml, 3.8 mmol). Mol). The homogeneous solution is heated at reflux for 4 hours and cooled to room temperature. cooling The dense white precipitate formed by filtration and washing with ether gives a white powder As a result, 0.80 g (48%) of the title compound was obtained. 166-170 ° C.¹H NMR (DMSO-d₆) δ 9.23 (bs, 1H), 8.51 (m, 1H), 7.78 (t, 1H, J = 7.5 Hz), 7.5-7.25 (m, 8H), 7. 12 (d, 2H, J = 8.4 Hz), 6.91 (d, 2H, J = 8.4 Hz), 6.69 (d, 1H, J = 10.4 Hz), 6.19 (d, 1H, J = 8.9 Hz), 5.08 (s, 2H), 4.58-4.32 (m, 2H), 4.15-3.91 (m, 1H), 3.82 (m, 1H), 2.95 (d, 1H, J = 10.9 Hz), 1.15 (s, 9H);¹⁹F NMR (DMSO-d₆) Δ main Diastereomer: -103.30 (dd, J = 253, 9 Hz), -117.67 (dd, J = 252, 17 Hz) , Small amount of diastereomer: -111.37 (dd, J = 254, 8 Hz), -121.27 (dd, J = 256, 18 Hz). Step B [3ξ, 4 (S)]-2,4,5-trideoxy-2,2-difluoro-4-[[3-methyl- 1-oxo-2-[[(3-pyridinylmethoxy) carbonyl] amino] butyl] Amino] -5- [4- (phenylmethoxy) Phenyl] -N- (2-pyridinylmethyl) -L-glycero-pentanamide Manufacture   Reaction Schemes A and A ', steps (d) and (e): prepared as described above. The amide (0.2 g, 0.4 mmol) was prepared as described above in Step B of Example 5. In a similar manner to HCO_TwoDeprotect by treating with H. Then play The released amine is reacted under standard coupling conditions in a manner similar to that described above. N-[(3-pyridinylmethoxy) carbonyl] -L prepared in Example 8 -Coupling with valine (0.38 g, 1.5 mmol) and reconstitution from ethyl acetate After crystallization, 0.09 g (40%) of the title compound was obtained as a white powder. 201-210 ° C.¹H N MR (DMSO-d₆) Δ 9.48 (bs, 1H), 8.79 (m, 1H), 8.65 (m, 2H), 8.02-7.85 (m, 3H) , 7.39-7.65 (m, 9H), 7.24 (d, 2H, J = 8.5 Hz), 6.96 (d, 2H, J = 8.5 Hz), 6.48 (d , 1H, J = 10.4 Hz), 5.25 (d, 2H, J = 3.8 Hz), 5.14 (s, 2H), 4.63-4.55 (m, 2H), 4.36 (m, 1H), 4.17 (m, 1H), 3.91 (dd, 1H, J = 7.8, 6.0 Hz), 3.14-3.03 (m, 1H) , 2.81-2.55 (m, 1H), 1.95 (m, 1H), 0.81 (dd, 6H, J = 9.1, 7.0 Hz);¹⁹F NMR (D MSO-d₆) Δ -110.17 (dd, J = 254, 11 Hz), -119.79 (dd, J = 247, 16 Hz). Process C Preparation of final title compound   Reaction scheme A ', step (f): 2M oxalyl chloride / CH_TwoCl_Two(0.6ml, 1mmimo ), DMSO (0.19 ml, 2.6 mmol) and diisopropylethylamine (0.41 ml , 2.4 mmol) using a method similar to that described above, as in step G of Example 1. In the above, the alcohol produced as described above (0.08 g, 0.1 mmol) Swern conditions To give 0.04 g (50%) of the final title compound as a tan powder. Melting point 95 ° C. IR (KBr) ν_max 3401, 3306, 1699, 1599, 1437, 1298, 1242, 1178, 111 3,1026 cm^-1;¹H NMR (CDCl_Three) Δ 8.63-8.52 (m, 2H), 8.42 and 8.19 and 8. 05 (3m, 2H total), 7.77-7.62 (m, 2H), 7.46-7.22 (m, 9H), 7.18 (t, 1H, J = 5. 5 Hz), 7.05 (d, 2H, J = 8.2 Hz), 6.89 (d, 2H, J = 8.2 Hz), 5.35 and 5.22 (2d, 1H total, J = 8.5 Hz), 5.10 (s, 2H), 5.05 (s, 2H), 4.87-4.66 (m, 1H), 4.60 -4.48 (m, 1H), 3.81 (dd, 1H, J = 9.2, 6.7 Hz), 3.32 and 3.27 (2d, 1H total , J = 5.2 and 4.8 Hz), 3.18 and 3.13 (2d, 1H total, J = 9.2 and 8.4 H z), 1.91 (m, 1H), 1.31 (d, 1H, J = 6.8 Hz), 0.73 and 0.78 and 0.82 (3d, 5H Total, J = 6.8 Hz);¹⁹F NMR (CDCl_Three) Δ -110.48 (d, J = 276 Hz), -113.38 (s ), -113.51 (d, J = 276 Hz), hydrate: -118.75 (d, J = 254 Hz), -120.75 (d, J = 255) Hz); mass spectrum, m / z 674 (M⁺+1), 460, 348, 280, 272, 252, 207, 138, 110 (100), 92. Example 14 [1-[[[3,3-difluoro-2,4-dioxo-1-[[4- (phenylmethoxy C) phenyl] -methyl] -4-[(3-pyridinylmethyl) amino] butyl] Amino] carbonyl] -2-methylpropyl] -carbamic acid, 3-pyridinyl Production of methyl ester Step A [1 (R), 3ξ] -2,4,5-trideoxy-4-[[(1,1-dimethylethoxy) carbo Nil] -amino] -2,2-difluoro-5- [4- (phenylmethoxy) -fe Nyl] -N- (3-pyridinylmethyl) -L-glycero-pentanamide   Reaction Scheme A, Step (b): The title compound was prepared as described in Step A of Example 13. In a similar manner to 4-tert-butoxy prepared in step B of Example 1, Carbonylamino-2,2-difluoro-3-hydroxy-5- (4-benzylo Xy) phenylpentanoic acid ethyl ester (1.5 g, 3.1 mmol) and 3- ( Prepared from (aminomethyl) pyridine (0.38 ml, 3.8 mmol). Precipitated solid Was washed with ether and recrystallized from ethyl acetate to give the title compound as a white powder. 0.80 g (45%) of the product were obtained. 158-160 ° C.¹H NMR (CDCl_Three) Δ 8.55 (bs, 2H), 7. 7 (d, 1H, J = 7.2 Hz), 7.5-7.2 (m, 8H), 7.1 (d, 2H, J = 8.4 Hz), 6.9 (d, 2H, J = 8 .3 Hz), 5.0 (s, 2H), 4.9 (d, 1H, J = 9.8 Hz), 4.5 (d, 2H, J = 2.6 Hz), 4.1-3.9 ( m, 2H), 3.0-2.8 (m, 2H), 1.4 (s, 9H);¹⁹F NMR (DMSO-d₆) Δ -110.84 (d, J = 27 2 Hz), -122.56 (dd, J = 273, 21 Hz); mass spectrum, m / e 542 (M⁺+1), 486,4 42, 424, 344, 244, 224, 197, 109, 91. Step B [3ξ, 4 (S)]-2,4,5-trideoxy-2,2-difluoro-4-[[3-methyl- 1-oxo-2-[[(3-pyridinylmethoxy) carbonyl] amino] butyl] Amino] -5- [4- (phenylmethoxy) phenyl] -N- (3-pyridinyl Preparation of methyl) -L-glycero-pentanamide   Reaction Schemes A and A ', steps (d) and (e): as described above The amide (0.27 g, 0.49 mmol) prepared in_TwoProcess with H. Reaction mixture The mixture becomes homogeneous within 5 minutes. The solution is stirred at room temperature for 3 hours. Then it Is concentrated under vacuum. Then, dissolve the yellow oil in ethyl acetate and add aqueous 1N heavy carbon Washed twice with sodium acid, dried over anhydrous magnesium sulfate, filtered and Concentrate in vacuo to afford the corresponding free amine as a yellow solid (0.18 g, 0.41 mM Get). This is CH_TwoCl_Two/ DMF in a 1: 1 mixture (6 ml). Room temperature saw HOBT (0.07 g, 0.5 mmol), NMM (0.05 ml, 0.5 mmol), real N-[(3-pyridinylmethoxy) carbonyl] -L prepared in Example 8 Add valine (0.13 g, 0.52 mmol) and EDC (0.1 g, 0.5 mmol). After 16 hours, the mixture was CH_TwoCl_TwoAnd wash with water. White precipitate separates You. This was filtered, washed several times with ether and recrystallized from ethyl acetate to give white This gave 0.12 g (45%) of the title compound as a colored powder. 195-196 ° C.¹H NMR (DM SO-d₆) Δ 8.7-8.4 (m, 4H), 7.75 (d, 1H, J = 10.4 Hz), 7.65 (d, 1H, J = 11.2 Hz) , 7.5-7.3 (m, 7H), 7.15 (d, 2H, J = 8.4 Hz), 6.9 (d, 2H, J = 8.4 Hz), 5.12 (s, 2 H), 5.08 (s, 2H), 4.5-4.2 (m, 3H), 4.1-3.9 (m, 2H), 2.8-2.6 (m, 2H), 2.0 (m, 1H), 0.8 (m, 6H);¹⁹F NMR (DMSO-d₆) Δ -111.2 (d, J = 257 Hz), -122.05 (dd, J = 250, 20 Hz); mass spectrum, m / z 676 (M⁺+1), 567, 424, 150, 138, 110 (10 0), 92.   C₃₆H₃₉F_TwoN_FiveO₆Analytical value for:     Calculated value: C 63.31 H 5.87 N 10.25     Found: C 63.07 H 5.90 N 10.23 Process C Preparation of final title compound   Reaction scheme A ′, step (f): The alcohol produced as described above is In a similar manner to that in Example 1, oxidation was performed under Swelln conditions as follows. I do. -45 ° C CH_TwoCl_Two(2 ml) and DMSO (0.21 ml) as described above. To a slightly cloudy solution of the prepared alcohol (0.08 g, 0.12 mmol) was added 2M salt Oxalyl chloride / CH_TwoCl_Two(0.6 ml, 1 mmol) are added over 5 minutes. -3 solution Stir at 5 ° C to -45 ° C for 2.5 hours and then cool to -78 ° C. Diisopropyl Ethylamine (0.42 ml, 2.4 mmol) is added over 5 minutes. Solution in 1.5 hours Warm up to room temperature, CH_TwoCl_TwoWash with light. The yellow precipitate that formed Filter and wash three times with ether to give the final title compound as a tan powder. 04 g (50%) were obtained. 103-105 ° C. IR (KBr) ν_max 3422, 3295, 2965, 169 7, 1649, 1537, 1512, 1244 cm^-1;¹H NMR (DMSO-d₆) Δ 9.19 (bs, 1H), 8.61- 8.43 (m, 4H), 7.75 to 7.59 (m, 2H), 7.45 to 7.28 (m, 7H), 7.09 (d, 2H, J = 8.5 Hz), 6.81 (d, 2H, J = 8.5 Hz), 5.09-4.98 (m, 4H), 4.50-4.26 (m, 3H), 3.90-3.61 (m, 2H), 3.12 (m, 2H), 2.55 (m, 1H), 1.79 (m, 1H), 1.27 (t, 5H, J = 8.6 Hz), 0.77 ( t, 1H, J = 6.2 Hz);¹⁹F NMR (DMSO-d₆) Δ small amount of diastereomer: -111.34 ( Apparent double line, J = 184 Hz), main diastereomer: -113.24 (d, J = 254 Hz),- 117.56 (d, J = 254 Hz); mass spectrum, m / z 674 (M⁺+1), 565,460,252,207 , 143, 139, 110 (100), 92.   C₃₆H₃₇F_TwoN_FiveO₆・ 2H_TwoAnalytical value for O:     Calculated value: C 60.93 H 5.78 N 9.87     Found: C 60.00 H 6.15 N 9.56 Example 15 [1-[[[3,3-difluoro-2,4-dioxo-1-[[4- (phenylmethoxy B) -Phenyl] -methyl] -4-[(2-pyridinylmethyl) amino] butyl ] -Amino] carbonyl] -2-methylpropyl] -carbamic acid, 2-pyridi Production of Nyl Methyl Ester Step A N-[(2-pyridinylmethoxy) carbonyl] -L-valine methyl ester Manufacture   N-[(3-Pyridinylmethoxy) carbonyl] -L-valine in Example 8 In the same manner as in the production of the above, the title compound was converted to L-valine methyl ester hydrochloride (5.0 g, 30 mmol), triphosgene (4.66 g, 15.7 mmol) and (n-Bu)_ThreeN (0.05 ml, 0.4 mmol). However, 2-pyridylcarbino (10.0 ml, 100 mmol, 3.3 eq) is added dropwise to the intermediate isocyanate. By flash chromatography as in Example 8, a yellow oil was obtained. As a result, 2.63 g (33%) of the title compound was obtained. IR (neat) ν_max 3345, 2965, 1726, 1533, 1439, 1314, 1271, 1236, 1213, 1105cm^-1:¹H NMR (CDCl_Three) Δ 8.61 (d, 1H, J = 4.6 Hz), 7.7 (td, 1H, J = 7.6, 1.8 Hz), 7.38 (d, 1H, J = 7.7 Hz), 7.27 (d d, 1H, J = 7.3, 4.6 Hz), 5.45 (d, 1H, J = 8.9 Hz), 5.25 (s, 2H), 4.35 (dd, 1H, J = 9.2, 4.7 Hz), 3.75 (s, 3H), 2.24 (m, 1H), 1.0 (d, 3H, J = 6.8 Hz), 0.9 (d, 3H, J = 6.8 Hz);¹³C NMR (CDCl_Three) Δ 172.4, 156.2, 155.9, 149.4, 136 .7, 122.7, 121.6, 67.4, 59.1, 52.1, 31.2, 18.9, 17.5; mass spectrum, m / z 267 (M⁺+1 and 100), 136 and 110.   C₁₃H₁₈N_TwoO_FourAnalytical value for:     Calculated value: C 58.65 H 6.77 N 10.53     Found: C 58.25 H 6.86 N 10.46 Step B Production of N-[(2-pyridinylmethoxy) carbonyl] -L-valine   In a manner similar to that described above in Example 8, the above ester (2.5 g, 9.4 mmol) CH_ThreeLiOH ・ H in OH_TwoHydrolysis with O (0.79 g, 18.8 mmol) gives a white 2.0 g (85%) of the title compound were obtained as a colored solid. IR (KBr) ν_max 3366, 3065, 29 63, 2936, 1722, 1616, 1602, 1577, 1526, 1433, 1279, 1250, 1219, 1109, 76 4,627 cm^-1;¹H NMR (DMSO-d₆) Δ 8.58 (d, 1H, J = 4.7 Hz), 7.96 (t, 1H, J = 8. 0 Hz), 7.6 (d, 1H, J = 8.0 Hz), 7.43 (d, 1H, J = 7.5 Hz), 7.4 (dd, 1H, J = 7.5, 5 .2 Hz), 5.15 (s, 2H), 3.9 (dd, 1H, J = 8.5, 5.9 Hz), 2.1 (m, 1H), 0.92 (dd, 6H , J = 6.6, 3.7 Hz);¹³C NMR (DMSO-d₆) Δ 173.1, 156.3, 156.2, 148.6, 137.4 , 123.0, 121.4, 65.9, 59.6, 29.5, 19.1, 18.0; mass spectrum, m / z 253 (M⁺ +1), 237, 209, 136 (100), 109, 92, 65. Process C [3ξ, 4 (S)]-2,4,5-trideoxy-2,2-difluoro-4-[[3-methyl- 1-oxo-2-[[(2-pyridinylmethoxy) carbonyl] amino] butyl] Amino] -5- [4- (phenylmethoxy) Phenyl] -N- (2-pyridinylmethyl) -L-glycero-pentanamide Manufacture   Reaction Schemes A and A ', Steps (d) and (e): In Step A of Example 13 The prepared [1 (R), 3ξ] -2,4,5-trideoxy-4-[[((1,1-dimethylethy (Xy) carbonyl] -amino] -2,2-difluoro-5- [4- (phenylmethoxy) B) -phenyl] -N- (2-pyridinylmethyl) -L-glycero-pentana The amide (0.34 g, 0.63 mmol) was deprotected as in step (d) of Example 13. And under standard coupling conditions in a manner similar to that described above. Coupled with the prepared acid (0.21 g, 0.82 mmol) to give a white powder This gave 0.14 g (30%) of the title compound. 224-225.5 ° C. IR (KBr) ν_max 329 1, 1697, 1680, 1657, 1618, 1599, 1572, 1537, 1512, 1454, 1439, 1398, 134 1,1300,1244,700 cm^-1;¹H NMR (DMSO-d₆) Δ 9.31 (bs, 1H), 7.82-7.71 (m, 3H), 7.48-7.23 (m, 10H), 7.10 (d, 2H, J = 8.6 Hz), 6.82 (d, 2H, J = 8.6 Hz), 5. 05-4.95 (m, 4H), 4.47 (d, 2H, J = 5.8 Hz), 4.23 (m, 1H), 4.04 (m, 1H), 3.79 (t , 1H, J = 6.0 Hz), 4.40 and 3.69 and 3.14 (3m, 1H total), 2.94 (d, 1H, J = 13.0 Hz), 2.63 (dd, 1H, J = 14.6, 10.8 Hz), 1.83 (m, 1H), 0.70 (dd, 5H, J = 9 .2, 7.1 Hz), 0.57 and 0.47 (2d, 1H total, J = 6.9 Hz);¹³CNMR (DMSO-d₆ ) Δ 170.1, 157.4, 156.7, 156.6, 155.7, 148.97, 148.8, 137.2, 136.8, 130 .76, 130.21, 128.4, 127.7, 127.5, 122.75, 121.25, 121.0, 120.8, 114.2, 6 9.0, 66.2, 60.38, 49.9, 44.1, 44.0, 34.0, 30.3, 19.2, 17.95;¹⁹F NMR (DM SO-d₆) Δ Main diastereomer: -110.07 (d, J = 248 Hz), -119.9 (d, J = 252 Hz), small volume Diastereomer: -110.03 (dm, J = 250 Hz), -118.34 (dm, J = 250 Hz), -111.72 ( dm, J = 250 Hz), -123.5 (dm, J = 250 Hz); mass spectrum, m / z 676 (M⁺+1), 595 , 567, 110, 92 (100). Process D Preparation of final title compound   Reaction scheme A ', step (f): In a manner similar to that described above in Example 1. Oxidize the above alcohol (0.13 g, 0.19 mmol) under Swern conditions. And flash chromatography (8: 1 CH_TwoCl_Two/ C_TwoH_FiveOH), then tan This gave 0.04 g (30%) of the final 1: 1 mixture of the title compound as a powder. Melting point 140 ~ 142 ° C. IR (KBr) ν_max 3304, 1695, 1668, 1537, 1514, 1439, 1296, 1244, 1109, 1042 cm^-1;¹H NMR (DMSO-d₆) Δ 9.09 and 8.85 and 8.09 (d, m, d, 1 H total), 8.56 (m, 1H), 8.17 (m, 1H), 7.78-7.65 (m, 2H), 7.45-7.15 (m, 10 H), 7.05 (d, 2H, J = 8.6 Hz), 6.89 (d, 2H, J = 8.6 Hz), 5.56 and 5.43 (2d, 1H Total, J = 9.2, 9.2 Hz), 5.30-4.95 (m, 5H), 4.84-4.45 (m, 2H), 3.85-3.7 (m , 1H), 3.32-3.27 (2d, 1H, J = 4.9, 4.0 Hz), 3.16-2.80 (2m, 1H), 1.90-1.70 (m , 1H), 0.83-0.75 (m, 5H), 0.56 (d, 1H, J = 6.8 Hz);¹⁹F NMR (DMSO-d₆) Δ -11 0.07 (d, J = 275 Hz), -113.25 (apparent d, J = 9 Hz), -113.45 (d, J = 276 Hz), hydration Object: -118.5 (d, J = 257 Hz), -121.00 (d, J = 253 Hz); mass spectrum, m / z 674 (M⁺ +1), 460, 143, 110, 92. Example 16 [1-[[[3,3-difluoro-2,4-dioxo-1-[[4- (phenylmethoxy C) -phenyl] -methyl] -4-[(3-pyridinylmeth Tyl) amino] butyl] -amino] carbonyl] -2-methylpropyl] -cal Production of bamic acid, 3-pyridinyl methyl ester Step A [3ξ, 4 (S)]-2,4,5-trideoxy-2,2-difluoro-4-[[3-methyl- 1-oxo-2-[[(2-pyridinylmethoxy) carbonyl] amino] butyl] Amino] -5- [4- (phenylmethoxy) phenyl] -N- (3-pyridinyl Preparation of methyl) -L-glycero-pentanamide   Reaction Schemes A and A ', Steps (d) and (e): Prepared in Step A of Example 14. (1 (R), 3ξ) -2,4,5-trideoxy-4-[((1,1-dimethylethoxy) ca Rubonyl] amino] -2,2-difluoro-5- [4- (phenylmethoxy) Nil] -N- (3-pyridinylmethyl) -L-glycero-pentanamide (0.35 7g, 0.709 mmol) was deprotected as in step (d) of Example 14 and Under the standard coupling conditions described above, the N-[(2- Pyridinylmethoxy) carbonyl] -L-valine (0.157 g, 0.620 mmol) Pull the hot CH of the crude material_ThreeAfter treatment with OH, filtration and concentration in vacuo, 180 mg (54%) of the title compound were obtained as a white powder. IR (KBr) ν_max 3298, 1697, 1680, 1659, 1537, 1512, 1298, 1244, 1103 cm^-1;¹H NMR (DMSO-d₆) Δ 9.36- 9.32 (m, 1H), 8.52-8.46 (m, 3H), 7.82-7.68 (m, 3H), 7.41-7.26 (m, 7H), 7.19 ( d, 1H, J = 9.6 Hz), 7.07 (d, 2H, J = 8.4 Hz), 6.81 (d, 2H, J = 8.4 Hz), 6.27 (d, 1H , J = 7.2 Hz), 5.12 (d, 1H, J = 13.5 Hz), 5.06 (d, 1H, J = 13.5 Hz), 5.02 (d, 1H , J = 12.0 Hz), 4.97 (d, 1H, J = 12.0 Hz), 4.44 (dd, 1H, J = 15.3, 6.0 Hz), 4.35 (dd, 1H, J = 15.3, 5.7 Hz), 4.24-4.15 (m, 1H), 4.11 (dd, 1H, J = 10.5, 5.1 Hz) , 4.06-3.95 (m, 1H), 3.79 (dd, 1H, J = 9.3, 6.9 Hz), 2.93-2.88 (m, 1H), 2.60 ( dd, 1H, J = 13.8, 11.1 Hz), 1.82-1.77 (m, 1H), 0.71 (d, 3H, J = 6.9 Hz), 0.68 ( d, 3H, J = 6.9 Hz);¹⁹F NMR (DMSO-d₆) Δ -109.87 (dd, J = 252, 8 Hz), -120.07 (dd, J = 253, 17 Hz); mass spectrum, m / z 704 (M⁺+29), 676 (M⁺+1), 424,241 , 138, 110, 92 (100).   C₃₆H₃₉F_TwoN_FiveO₆Analytical value for:     Calculated value: C 63.99 H 5.82 N 10.36     Found: C 60.62 H 5.97 N 9.83 Step B Preparation of final title compound   Reaction scheme A ', step (f): In a manner similar to that described above in Example 1. The alcohol (152 mg, 0.225 mmol) produced as described above was Oxidation under Werne conditions and flash chromatography (19: 1 CHCl_Three / CH_ThreeAfter OH), 104 mg (68%) of the final title compound were obtained. CH this_TwoCl_Two/pen Recrystallize twice from tan to give 34 mg (22%) of the final title compound as a cream powder I got 97-102 ° C. IR (KBr) ν_max 3405, 3324, 1699, 1534, 1512, 1437 , 1242, 1178, 1113 cm^-1;¹H NMR (CDCl_Three) Δ 8.56-8.51 (m, 3H) 、 7.71-7.62 (m , 2H), 7.43-7.19 (m, 10H), 7.10-7.05 (m, 2H), 6.91-6.83 (m, 2H), 6.48-6.37 ( m, 1H), 5.48-5.10 (m, 3H), 5.02 and 5.00 (2s, 2H total), 4.61-4.46 (m, 2H), 3.90 and 3.87-3 .81 (dd and m, 1H total, J = 8.7, 6.1 Hz), 3.36-3.23 (m, 1H), 2.91-2.73 ( m, 1H total), 2.07-1.88 (m, 1H), 0.86 and 0.79, 0.76 and 0.75 And 0.61 and 0.59 (6d, 6H total, J = 6.6 Hz);¹⁹F NMR (CDCl_Three) Δ -111.6 5 (d, J = 277 Hz), -111.73 (d, J = 276 Hz), -113.15 (d, J = 276 Hz), -113.20 (d, J = 277 Hz), hydrate: -115.64 (d, J = 257 Hz), -116.55 (d, J = 256 Hz), -120.42 (d , J = 256 Hz), -121.55 (d, J = 256 Hz); mass spectrum, m / z 702 (M⁺+29), 674 ( M⁺+1), 138, 110, 92 (100).   C₃₆H₃₇F_TwoN_FiveO₆Analytical value for:     Calculated value: C 64.18 H 5.54 N 11.87     Found: C 61.96 H 5.80 N 10.38 Example 17 N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L-valyl) ami No-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy) phenyl- Production of [pentyl] -O- (3-pyridylmethyl) -D-valinol Step A Production of N-trityl-D-valinol   D-valinol (4.95 g, 48.06 mmol) in dry dichloromethane (75 ml), Triethylamine (7.4 ml, 52.87 mmol) and trityl chloride (14.74 g, 52. (87 mmol) is stirred at room temperature for 17 hours. Wash the organic solution with water (2x75ml) Clean, dry over anhydrous sodium sulfate, filter and concentrate under vacuum. Get Flash chromatography (silica gel, ethyl acetate / petroleum ether) (15.85) to give the title compound (13.5 g, 81%). R_f= 0.45 (vinegar Ethyl acid / petroleum ether, 15/85). Step B Production of N-trityl-O-3-pyridylmethyl-D-valinol   Under a nitrogen atmosphere, sodium hydride (1.3 g, 30 ml) in dry DMF (3 ml) was used. Into a suspension of (1 mol%), a 55% dispersion in oil previously washed twice with pentane. N-trityl-D-valinol (3.45 g, 10 mmol) in DMF (23 ml) Add the solution. The reaction mixture was stirred at room temperature for 30 minutes and then cooled to 0 ° C. Then, tetrabutylammonium iodide (0.37 g, 1 mmol) is added. Or that 3-picolyl chloride HCl (1.81 g, 11 mmol) was added to the reaction mixture over 5 minutes. Add small amounts to each. After the addition is complete, remove the cooling bath and allow the mixture to stand at room temperature for 17 hours. Stir. Then the reaction mixture is cooled in a water bath and hydrolyzed with water (100 ml) You. Then the mixture is extracted with ethyl acetate (2 × 100 ml). This organic extract Was washed with water (2 × 50 ml), dried over anhydrous sodium sulfate, filtered and vacuum Concentrate. The resulting yellow oil was purified by flash chromatography (silica gel). Kagel, 9/1 dichloromethane / ethyl acetate, R_f= 0.42) The title compound (3.4 g, 78%) was obtained as an oil. Process C Production of O-3-pyridylmethyl-D-valinol   N-trityl-O-3-pyridylmethyl-D-valinol in formic acid (30 ml) (3.63 g, 8.3 mmol) is kept at room temperature for 5.5 hours. Formic acid removed under vacuum And dissolve the residue in water (100 ml). Extract the mixture with ethyl acetate (100 ml, 50 ml). Remove to remove trityl alcohol. The aqueous phase was washed with saturated sodium carbonate (50 ml) And made basic with 4N sodium hydroxide (3 ml). Then the aqueous mixture Extract with ethyl acetate (4 × 50 ml). Soak the organic extract with brine (2 x 50ml) And combined, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound A compound (1.32 g, 82%) was obtained. R_f= 0.12 (silica gel, 8/2 dichloromethane /methanol). Process D N- [4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy -1-oxo-5- (4-benzyloxy) phenyl-pentyl] -O- (3- Preparation of (pyridylmethyl) -D-valinol   Reaction Scheme A, Step (b): Ester in dry tetrahydrofuran (1.5 ml) 1.14 g, 2.38 mmol) and O-3-pi prepared as in Step B of Example 1. Lysylmethyl-D-valinol (1.32 g, 6.8 mm, prepared in Step C above) Is heated to reflux for 2 days. After cooling, the reaction mixture was washed with ethyl acetate (5m l), dilute with pentane (10 ml) and collect the precipitate by filtration. Pen it Rinsed with tan and re-dissolved in dichloromethane / methanol / pentane Crystallization gave the title compound (0.8 g, 54%) as a white solid. R_f= 0.5 (serial Kagel, ethyl acetate). Mass spectrum m / z 628 (MH⁺). Step E N- [4-amino-2,2-difluoro-3-hydroxy-1-oxo-5- [N -(Benzyloxy) phenyl-pentyl] -O- (3-pyridylmethyl) -D -Manufacture of Valinol   Reaction Scheme A, Step (d): The title compound was prepared as described in Step C of Example 17. Can be obtained in a yield of 91% by a deprotection operation in the same manner as in the above. Step F N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L-valyl) amino -2,2-difluoro-3-hydroxy-1-oxo-5- (4-benzyloxy ) Preparation of phenyl-pentyl] -O- (3-pyridylmethyl) -D-valinol   Reaction Scheme A ', Step (e): N- (2-pyridylmethyi) in anhydrous DMF (2 ml) Ruoxycarbonyl) -L-valine (0.101 prepared in step B of Example 15) g, 0.4 mmol) in a nitrogen atmosphere under N-hydroxybenz. Triazole hydrate (0.115 g, 0.4 mmol), 1-ethyl-3- (3-dimethyl Laminopropyl) carbodiimide (0.085 g, 0.44 mmol) and DMF (1 ml) Add. The reaction mixture was stirred at room temperature for 30 minutes and N- [4-A in DMF (1 ml). Mino-2,2-difluoro-3-hydroxy-1-oxo-5- (N- (benzyl Oxy) phenyl-pentyl] -O- (3-pyridylmethyl) -D-valinol (Manufactured as described above 0.211 g, 0.4 mmol). The reaction mixture was stirred for 15 hours and then Dilute with ethyl acetate (80 ml) and wash with water (2 × 80 ml). Ethyl acetate aqueous phase Extract with The combined organic extracts are dried over anhydrous sodium sulfate, filtered and filtered. And concentrate under vacuum. The residue was purified by flash chromatography (2 ×, silica Kagel, 95/5 dichloromethane / ethanol, R_f= 0.15) The title compound (0.170 g, 56%) was obtained. Mass spectrum m / z 762 (MH⁺). Process G Preparation of final title compound   Reaction Scheme A ′, Step (f): Salification in anhydrous dichloromethane (0.5 ml) at −60 ° C. Dioxane was added to a solution of oxalyl (0.195 ml, 2.23 mmol) under an atmosphere of nitrogen. Freshly distilled dimethyl sulfoxide (0.316 ml, 4.46 ml) in dichloromethane (1.5 ml) ) Is slowly added. After stirring at -60 ° C for 10 minutes, raise the temperature to -15 ° C . The alcohol prepared as described above (0.170 in dichloromethane (7 ml)) g, 0.223 mmol) and dimethyl sulfoxide (0.5 ml). Add dropwise to the reaction mixture. The reaction mixture was then stirred at -15 ° C for 1.75 hours and Then cool to -78 ° C. Diisopropylethylamine (0.93 ml, 6.69 mmol ) And the reaction mixture is stirred for a further 10 minutes. Then place the reaction mixture in the chamber Warm to warm and dilute with dichloromethane (25 ml). The reaction mixture was washed with water (2 × 25 ml). The aqueous phase is extracted with dichloromethane (25ml). Combined organic extraction The liquid is dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Residual The product is subjected to flash chromatography. (Silica gel, ethyl acetate, R_f= 0.17) Then from dichloromethane / pentane Purification by recrystallization from afforded the title compound (0.120 g, 71%). Mass spec Torr, m / z 760 (MM⁺);¹H NMR (DMSO-d₆) Δ 9.12-8.96 (m, 1H) 、 8.66-8.55 (m, 2 H), 7.96 to 7.85 (m, 1H), 7.85 to 7.75 (m, 1H), 7.60 to 7.35 (m, 7H), 7.30 to 7.19 (m, 2 H), 7.08-6.83 (m, 2H), 5.20 (s, 2H), 5.17-5.05 (m, 3H), 4.65-4.53 (m, 2H), 4 .07-3.87 (2m, 2H), 3.72-3.60 (m, 2H), 3.28-3.14 and 2.86-2.78 (m, 2H), 2.0 9-1.83 (m, 2H), 1.27-0.67 (m, 12H);¹⁹F NMR (DMSO-d₆, T = 60 ℃) δ (C₆F₆) 52 .94 (d, J = 269 Hz), 52.30 (d, J = 270 Hz), 51.25 (d, J = 270 Hz), 50.35 (d, J = 269 Hz)  Hz).   C₄₁H₄₇N_FiveO₇F_Two・ 0.25H_TwoAnalytical value for O:     Calculated value: C 64.43 H 6.26 N 9.16     Obtained value: C 64.24 H 6.25 N 9.01 Example 18 N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L-valyl) ami No-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy) phenyl- Production of [pentyl] -O- (3-pyridylmethyl) -D-valinol Step A N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L-valyl) amino -2,2-difluoro-3-hydroxy-1-oxo- 5- (4-benzyloxy) phenyl-pentyl] -O- (3-pyridylmethyl) -Production of D-valinol   Reaction Scheme A ', Step (e): The title compound was prepared as described in Step F of Example 17. In a manner similar to the pulling operation, the amino acid produced in step E of Example 17 And the acid produced in Step A of Example 8. Title compound Was obtained in 84% yield. R_f= 0.43 (silica gel, 95/5 dichloromethane /ethanol). Mass spectrum m / z 762 (MH⁺).   C₄₁H₄₉N_FiveO₇F_Two・ 0.5H_TwoAnalytical value for O:     Calculated value: C 63.88 H 6.54 N 9.08     Found: C 63.87 H 6.47 N 9.06 Step B Preparation of final title compound   Reaction Scheme A ′, Step (f): The title compound was prepared by reacting the reaction scheme A ′ in Example 17. In a similar manner to swernic acid described in step (f), the alcohol is Manufactured using. The title compound was obtained in 50% yield. R_f= 0.1 (silica gel , Ethyl acetate).¹H NMR (DMSO-d₆) Δ 9.04-8.90 (m, 1H) 、 8.71-8.50 (m, 3H) , 7.90-7.70 (m, 2H), 7.60-6.85 (m, 12H), 5.27-5.02 (m, 5H), 4.50-4.66 (m, 2H ), 3.85-4.07 (m, 2H), 3.72-3.57 (m, 2H), 3.30-3.12 and 2.85.2.65 (m, 2H), 2.05-1.8 (m, 2H), 1.20-0.59 (m, 12H);¹⁹F NMR (DMSO-d₆) Δ (C₆F₆) 52.93 (d , J = 268 Hz), 52.15 (d, J = 269 Hz), 50.92 (d, J = 269 Hz), 49.68 (d, J = 268 Hz);  Hydrate, 49.31 (d, J = 254 Hz), 48.31 (d, J = 254 Hz), 46.22 (d, J = 254 Hz), 44. 68 (d, J = 254 Hz).   C₄₁H₄₇N_FiveO₇F_Two・ H_TwoAnalytical value for O:     Calculated value: C 63.31 H 6.35 N 9.00     Found: C 62.56 H 6.26 N 8.66 Example 19 N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L-valyl) ami No-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy) phenyl- Pentyl] -O-methyl-D-valinol Step A Production of N-tert-butoxycarbonyl-D-valinol   D-Valinol (5.1 g, 49.4 mmol) and methanol in methanol (60 ml) A solution of tributyl dicarbonate (10.9 g, 50 mmol) was stirred at room temperature for 17 hours. You. The reaction mixture is concentrated under vacuum and the residue is purified by flash chromatography. -(Silica gel, 3/7 ethyl acetate / petroleum ether, R_f= 0.37) This gave the title compound (10.07 g) as a colorless oil in quantitative yield. Mass spec M / z 204 (MH⁺). Step B Production of N-tert-butoxycarbonyl-O-methyl-D-valinol   N-tert. In dry tetrahydrofuran (45 ml) at 0 ° C. under nitrogen atmosphere Tributoxycarbonyl-D-valinol (5.075 g, 25 mmol) and methyl iodide (27.5 ml of a 1 M solution in tetrahydrofuran, 27.5 mmol) with stirring. While adding potassium tert-butoxide (3.086 g, 27.5 mmol) in three portions You. The reaction mixture is kept at room temperature for 5.5 hours and then with a saturated solution of sodium chloride. Hydrolyze and extract with ethyl acetate (2 × 300 ml). The organic extract was washed with brine (2 × 300 ml), combined, dried over anhydrous sodium sulfate, filtered and vacuum Concentrate below. The residue was purified by flash chromatography (silica gel, 1/9 Of ethyl acetate / petroleum ether, R_f= 0.25) to give the title compound as an oil (2.93 g, 54%). Process C Production of O-methyl-D-valinol   N-tert-butoxycarbonyl- in dry ether (11 ml) saturated with hydrogen chloride A solution of O-methyl-D-valinol (2.93 g, 13.5 mmol) was added at room temperature for 3.5 hours. Stir. Then the reaction mixture is concentrated under vacuum. Leave pentane (50ml) To the distillate was added diethylamine (7 ml). Then mix the mixture for 10 minutes Stir and remove the solids by filtration. The filtrate is kept under vacuum (150 bar) at room temperature To give the title compound (1.30 g, 82%) as a colorless oil. Process D N- [4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy -1-oxo-5- (4-benzyloxy) phenyl-pentyl] -O-methyl -Production of D-valinol   Reaction Scheme A, Step (b): The title compound was prepared in the same manner as in Step D of Example 17. In the method, the ester of Step B of Example 1 and The O-methyl-D-valinol prepared as described above was coupled and Prepared by flash chromatography (78% yield) . R_f= 0.19 (small amount) and R_f= 0.09 (main) (silica gel, 35/65 ethyl acetate / Petroleum ether). Mass spectrum m / z 551 (MH⁺), 568 (MNH_Four ⁺). Step E N- [4-amino-2,2-difluoro-3-hydroxy-1-oxo-5- (4 Preparation of -benzyloxy) phenyl-pentyl] -O-methyl-D-valinol   Reaction Scheme A, Step (d): The title compound was obtained by the deprotection operation of Step C in Example 17. In a similar manner, N- [4-tert-butoxyca prepared as described above Rubonylamino-2,2-difluoro-3-hydroxy-1-oxo-5- (4- Benzyloxy) phenyl-pentyl] -O-methyl-D-valinol (Quantitative yield). Mass spectrum m / z 451 (MH⁺). Step F N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L-valyl) amino -2,2-difluoro-3-hydroxy-1-oxo-5- (4-benzyloxy ) Preparation of phenyl-pentyl] -O-methyl-D-valinol   Reaction Scheme A ', Step (e): The title compound was prepared as described in Step F of Example 17. In a method similar to the pulling method, N- [4 -Amino-2,2-difluoro-3-hydroxy-1-oxo-5- (4-benzyl Oxy) phenyl-pentyl] -O-methyl-D-valinol and Example 8 Made in process A Made from the acid produced. For crystallization (ethyl acetate + 10% ethanol / pentane) Further purification provided the title compound in 58% yield. Mass spectrum m / z 685 (MH⁺) . Process G Preparation of final title compound   Reaction Scheme A ', Step (f): The final title compound is described in Step G of Example 17. In the same manner as the Swelln oxidation described above, the N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L-valyl) amino-2, 2-difluoro-3-hydroxy-1-oxo-5- (4-benzyloxy) phenyl Enyl-pentyl] -O-methyl-D-valinol (15% yield). R_f = 0.1 (silica gel, 4/6 dichloromethane / ethyl acetate).¹H NMR (DMSO-d₆ ) Δ 9.07-8.93 (m, 1H), 8.87-8.50 (m, 2H), 8.40-8.31 (m, 1H), 7.94-7.81 (m, 1H) 1H), 7.60-6.59 (some m, 11H), 5.29-5.01 (m, 5H), 4.10-3.78 (m, 2H), 3 .58-3.43 (m, 2H), 3.35-3.25 (some s, 3H), 3.30-3.08 and 2.85-2.6 3 (m, 2H), 2.11-1.72 (m, 2H), 1.04-0.48 (m, 12H);¹⁹F NMR (DMSO-d₆) Δ (C₆F₆ ) 53.27 (d, J = 267 Hz), 52.60 (d, J = 269 Hz), 51.32 (d, J = 269 Hz), 49.76 (d, J = 267 Hz), 49.89 (d, J = 254 Hz), 48.61 (d, J = 254 Hz), 46.49 (d, J = 254 Hz), 44 .73 (J = 254 Hz); mass spectrum, m / z 683 (MH⁺).   C₃₆H₄₄N_FourO₇F_Two・ H_TwoAnalytical value for O:     Calculated value: C 61.70 H 6.62 N 7.99     Found: C 62.07 H 6.46 N 7.84 Example 20 N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L-valyl) amino -2,2-difluoro-1,3-dioxo-5- (4-benzyloxy) phenyl-pe Production of N-methyl-O- (2-pyridylmethyl) -D-valinol Step A Production of N-trityl-O-2-pyridylmethyl-D-valinol   The title compound was prepared in a manner analogous to the procedure described in Step B of Example 17. Prepared from the alcohol of Step A of Example 17 and 2-picolyl chloride HCl in 81% yield. Was. R_f= 0.52 (silica gel, 9/1 dichloromethane / ethyl acetate). Step B Production of O-2-pyridylmethyl-D-valinol   The title compound was prepared in a similar manner to the procedure described in Step C of Example 17 N-trityl-O-2-pyridylmethyl-D-valino prepared as described above In 80% yield. Process C N- [4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy -1-oxo-5- (4-benzyloxy) phenyl-pentyl] -O- (2- Preparation of (pyridylmethyl) -D-valinol   Reaction Scheme A, Step (b): The title compound was prepared as described in Step D of Example 17. In the same manner as in Example 1, the ester of Step B of Example 1 And O-2-pyridylmethyl-D-valinol prepared as described above In 63% yield. R_f= 0.65 (silica gel, ethyl acetate). Process D N- [4-amino-2,2-difluoro-3-hydroxy-1-oxo-5- (4 -Benzyloxy) phenyl-pentyl] -O- (2-pyridylmethyl) -D- Manufacture of Valinol   Reaction Scheme A, Step (d): The title compound was deprotected as described in Step C of Example 17. In the same manner as the protection operation, the N- [4-third block prepared as described above is used. Toxylcarbonylamino-2,2-difluoro-3-hydroxy-1-oxo-5 -(4-benzyloxy) phenyl-pentyl] -O- (2-pyridylmethyl) Prepared from -D-valinol in 91% yield. This compound is directly used in the next step. Used. Mass spectrum m / z 628 (MH⁺). Step E N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L-valyl) amino -2,2-difluoro-3-hydroxy-1-oxo-5- (4-benzyloxy ) Preparation of phenyl-pentyl] -O- (2-pyridylmethyl) -D-valinol   Reaction Scheme A ', Step (e): The title compound is described in Step F of Example 17. In a manner similar to the procedure described above, the amine and fruit prepared as described above Prepared from the acid prepared in Step A of Example 8 in 53% yield. R_f= 0.14 (main Required) and R_f= 0.08 (small amount) (silica gel, 95/5 dichloromethane / ethanol) Le). Mass spectrum m / z 762 (MH⁺). Step F Preparation of final title compound   Reaction Scheme A ', Step (f): The final title compound is described in Step G of Example 17. Produced in a manner similar to the Swelln oxidation procedure described above. Prepared from alcohol in 72% yield. R_f= 0.09 (silica gel, ethyl acetate).¹ H NMR (CDCl_Three) Δ 8.65-8.53 (m, 1H), 7.79-7.64 (m, 2H), 7.53-6.80 (some M, 14H), 6.60-6.10 (some m, 2H), 5.57-5.33 (m, 1H), 5.30-5.10 (m, 3H), 4.99 (s, 2H), 4.68-4.56 (m, 2H), 4.03-3.85 (m, 2H), 3.85-3.34 (m, 2H), 3.42-3.24 and 2.97-2.75 (m, 2H), 2.13-1.88 (m, 2H), 1.05-0.57 (m, 12H);¹⁹ F NMR (CDCl_Three) Δ (C₆F₆) 50.26 (d, J = 271 Hz), 49.97 (d, J = 263 Hz), 49.18 (d , J = 261 Hz), 48.60 (d, J = 271 Hz), 45.17 (d, J = 252 Hz), 45.10 (d, J = 251 Hz) , 41.77 (d, J = 252 Hz), 40.91 (d, J = 251 Hz); mass spectrum, m / z 760 (MH⁺).   C₄₁H₄₇N_FiveO₇F_TwoAnalytical value for:     Calculated value: C 64.81 H 6.23 N 9.22     Found: C 62.91 H 6.16 N 8.66 Example 21 N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L-valyl) ami No-2,2-difluoro-1,3-dioxo-5- (4- {3-pyridylmethyl} oxo C) Preparation of phenyl-pentyl] -O- (3-pyridylmethyl) -D-valinol Step A 4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy-5- Production of (4-hydroxy) phenylpentanoic acid ethyl ester   Reaction scheme A, step (C₁): 4-tert-butoxycarbo in ethanol (50 ml) Nylamino-2,2-difluoro-3-hydroxy-5-[(4-benzyloxy ) Phenyl] pentanoic acid ethyl ester (0.719 g, 1.5 mmol) Hold for 7.5 hours under hydrogen atmosphere in the presence of carbon with palladium (0.074g) . The hydrogen atmosphere is then exchanged for a nitrogen atmosphere. The suspension is filtered and the filtrate is Concentrate under vacuum to give the title compound (0.500 g, 83%). R_f= 0.51 (silica gel , 1/1 petroleum ether / ethyl acetate). Step B N- [4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy -1-oxo-5- (4-hydroxy) phenyl-pentyl] -O- (3-pyri Preparation of (zylmethyl) -D-valinol   Reaction Scheme A, Step (b): The title compound was prepared as described in Step D of Example 19. In a similar manner, the ester prepared as described above and Example 17 Prepared in 82% yield from the amine prepared in step C of the above procedure. R_f= 0.46 (serial Kagel, ethyl acetate). Process C N- [4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy -1-oxo-5- (4-hydroxy) phenyl-pentyl] -O- (3-pyri Preparation of (zylmethyl) -D-valinol   Reaction scheme A, step (C_Two): N- [4-tert-butoxy in anhydrous DMF (7 ml) Carbonylamino-2,2-difluoro-3-hydroxy-1-oxo-5- (4 -Hydroxy) phenyl-pentyl] -O- (3-pyridylmethyl) -D-vari Knol (0.376 g, 0.7 mmol, prepared as described above), 3-pico chloride Lil HCl (0.161 g, 0.98 mmol), cesium carbonate (0.775 g, 2.38 mmol) and And potassium iodide (0.016 g, 0.098 mmol) in a nitrogen atmosphere Stir for hours. The reaction mixture was diluted with ethyl acetate (50 ml) and water (2 × 50 ml). ). The aqueous rinse is extracted with ethyl acetate (50ml). Combined organic The extract is dried over anhydrous sodium sulphate, filtered and concentrated under vacuum. The residue was flash chromatographed (silica gel, 95/5 ethyl acetate). / Methanol, R_f= 0.25) to give the title compound (0.245 g, 56%). mass Spectrum m / z 629 (MH⁺). Process D N- [4-amino-2,2-difluoro-3-hydroxy-1-oxo-5- (4- {{3-pyridylmethyl} oxy) phenyl-pentyl] -O- (3-pyridylmethyl Production of chill) -D-valinol   Reaction Scheme A, Step (d): The title compound was deprotected as described in Step C of Example 17. In the same manner as the protection operation, the N- [4-third block prepared as described above is used. Toxylcarbonylamino-2,2-difluoro-3-hydroxy-1-oxo-5 -(4-Hydroxy) phenyl-pentyl] -O- (3-pyridylmethyl) -D -Made from barinol in 84% yield. Mass spectrum m / z 529 (MH⁺). Step E N- [4- {2-pyridylmethyl} oxycarbonyl-L-valyl) amino-2, 2-difluoro-3-hydroxy-1-oxo-5- (4- {3-pyridylmethyi) [Ruoxy) phenyl-pentyl] -O- (3-pyridylmethyl) -D-valino Manufacturing   Reaction Scheme A ', Step (e): The title compound was prepared as described in Step F of Example 17. In the same manner as the coupling operation, the amine and the And from the acid prepared in Step B of Example 15 in 56% yield. R_f= 0. 20 (silica gel, 95/5 dichloromethane / ethanol). Mass spectrum m / z  763 (MH⁺). Step F Preparation of final title compound   Reaction Scheme A ', Step (f): The final title compound is described in Step G of Example 17. Produced in a manner similar to the Swelln oxidation procedure described above. Prepared from alcohol in 70% yield. R_f= 0.19 (silica gel, 1/1 acetic acid Chill / acetone). Mass spectrum m / z 761 (MH⁺).¹H NMR (DMSO-d₆) Δ 9.11- 8.97 (m, 1H), 8.80-8.50 (m, 5H), 8.50-8.30 (m, 1H), 8.13-7.70 (m, 4H), 7.69- 6.60 (m, 8H), 5.40-5.00 (m, 5H), 4.71-4.49 (m, 2H), 4.10-3.80 (m, 2H), 3.80-3.51 (m, 2H), 3.51-3.30 and 2.86-2.60 (m, 2H), 2.12-1.72 (m , 2H), 1.17-0.47 (m, 12H);¹⁹F NMR (DMSO-d₆) Δ (C₆F₆) 52.91 (d, J = 268 Hz), 52.11 (d, J = 269 Hz), 50.86 (d, J = 269 Hz), 50.42 (d, J = 268 Hz), 49.34 (d, J = 2 54.39 (d, J = 254 Hz), 46.17 (d, J = 254 Hz), 44.63 (d, J = 254 Hz).   C₄₀H₄₆N₆O₇F_TwoAnalytical value for:     Calculated value: C 63.15 H 6.09 N 11.05     Found: C 62.26 H 6.24 N 10.76 Example 22 N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L-valyl) ami No-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy) phenyl- Production of [Pentyl] -O- (2-pyridylmethyl) -D-valinol Step A N- [4- {2-pyridylmethyl} oxycarbonyl-L-valyl) amino-2, 2-difluoro-3-hydroxy-1-oxo-5- (4-benzyloxy) phenyl Preparation of [enyl-pentyl] -O- (2-pyridylmethyl) -D-valinol   Reaction Scheme A ', Step (e): The title compound is described in Step F of Example 17. Reaction Scheme A of Example 20, Steps Amine prepared in (d) and practice Prepared from the acid prepared in Step B of Example 15 in 57% yield. R_f= 0.17 (main ) And R_f= 0.12 (small) (silica gel, 95/5 dichloromethane / ethanol) ). Mass spectrum m / z 762 (MH⁺). Step B Preparation of final title compound   Reaction Scheme A ', Step (f): The final title compound is described in Step G of Example 17. Produced in a manner similar to the Swelln oxidation procedure described above. Made from alcohol in 80% yield. R_f= 0.22 (silica gel, ethyl acetate). Mass spectrum m / z 760 (MH⁺).¹H NMR (CDCl_Three) Δ 8.63-8.48 (m, 2H), 7.77-7.6 0 (m, 2H), 7.55-6.80 (some m, 13H), 6.49-6.02 (some m, 2H), 5.5 5-5.30 (m, 1H), 5.30-4.95 (some m, 5H), 4.72-4.52 (m, 2H), 4.05-3.82 ( m, 2H), 3.82-3.35 (m, 2H), 3.42-3.23 and 2.97-2.77 (m, 2H), 2.13-1.83 (m, 2H, 1.05-0.54 (m, 12H);¹⁹F NMR (CDCl_Three) Δ (C₆F₆) 50.18 (d, J = 271 Hz), 49. 87 (d, J = 277 Hz), 49.02 (d, J = 271 Hz), 48.41 (d, J = 271 Hz), 44.97 (d, J = 252 Hz), 44.78 (d, J = 252 Hz), 41.85 (d, J = 252 Hz), 41.12 (d, J = 252 Hz).   C₄₁H₄₇N_FiveO₇F_Two・ H_TwoAnalytical value for O:     Calculated value: C 63.31 H 6.35 N 9.00     Found: C 63.37 H 6.19 N 8.85 Example 23 N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L-valyl) ami No-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy) phenyl- Pentyl] -O-methyl-D-varino Manufacturing Step A N- [4- {2-pyridylmethyl} oxycarbonyl-L-valyl) amino-2, 2-difluoro-3-hydroxy-1-oxo-5- (4-benzyloxy) phenyl Preparation of [enyl-phenyl-pentyl] -O-methyl-D-valinol   Reaction Scheme A ', Step (e): The title compound is described in Step F of Example 17. Steps of Reaction Scheme A of Example 19 in a manner similar to the coupling operation described 55% yield from the amine prepared in (d) and the acid prepared in Step B of Example 15 Manufactured by. R_f= 0.23 (silica gel, ethyl acetate). Mass spectrum m / z 685 (M H⁺).   C₃₆H₄₆N_FourO₇F_Two・ 0.5H_TwoAnalytical value for O:     Calculated value: C 62.32 H 6.83 N 8.08     Found: C 62.36 H 6.64 N 7.91 Step B Preparation of final title compound   Reaction Scheme A ', Step (f): The final title compound is described in Step G of Example 17. Produced in a manner similar to the Swelln oxidation procedure described above. Prepared from alcohol in 44% yield. R_f= 0.3 (silica gel, 3/7 dichloride Dichloromethane / ethyl acetate). Mass spectrum m / z 683 (MH⁺).¹H NMR (DMSO-d₆) Δ  9.10-8.92 (m, 1H), 8.67-8.51 (m, 2H), 7.95-7.87 (m, 1H), 7.64-6.82 (some m, 11H), 5 .30-5.03 (m, 5H), 4.10-3.93 (m, 1H), 3.93-3.78 (m, 1H), 3.60-3.37 (m, 2H), 3 .35-3.25 (some s, 3H), 3.32-3.10 and 2.87-2.68 (m, 2H), 2.14-1.80 ( m, 2H), 1.10-0.60 (m, 12H);¹⁹F NMR (DMSO-d₆) Δ (C₆F₆) 52.80 (d, J = 267 Hz ), 52.21 (d, J = 269 Hz), 50.93 (d, J = 269 Hz), 52.21 (d, J = 269 Hz), 50.93 (d, J = 269 Hz) J = 269 Hz), 49.36 (d, J = 267 Hz).   C₃₆H₄₄N_FourO₇F_Two・ 0.5H_TwoAnalytical value for O:     Calculated value: C 62.51 H 6.56 N 8.10     Found: C 62.65 H 6.50 N 7.93 Example 24 N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L-valyl) ami No-2,2-fluoro-1,3-dioxo-5- (4-benzyloxy) phenyl-pe Preparation of N-methyl-O-benzyl-D-valinol Step A N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L-valyl) amino -2,2-difluoro-3-hydroxy-1-oxo-5- (4-benzyloxy ) Preparation of phenyl-pentyl] -O-benzyl-D-valinol   Reaction Scheme A ', Step (e): The title compound was prepared as Step F in Example 17. In the same manner as the coupling operation described in 52% from the amine prepared in Example 15 and the acid prepared in Step B of Example 15. Manufactured in yield. R_f= 0.28 (silica gel, 3/7 petroleum ether / ethyl acetate) . Step B Preparation of final title compound   Reaction Scheme A ', Step (f): The final title compound is described in Step G of Example 17. Produced in a manner similar to the Swelln oxidation procedure described above. Prepared from alcohol in 62% yield. R_f= 0.07 (Alumina neutral Act III, 20/10 /0.2 tetrahydrofuran / dichloromethane / water), R_f= 0.27 (silica gel, 7/3 ethyl acetate / petroleum ether). Mass spectrum m / z 759 (MH⁺).¹H NMR ( CDCl_Three) δ 8.73-8.51 (m, 1H), 7.79-7.65 (m, 1H), 7.42-6.45 (some m, 18H ), 5.70-5.10 (m, 4H), 5.06-4.93 (m, 211), 4.58-4.40 (m, 2H), 4.05-3.80 (m, 2 H), 3.74-3.58 and 3.55-3.40 (m, 2H), 3.35-3.20 and 3.00-2.80 (m, 2H), 2. 13-1.90 (m, 2H), 1.10-0.50 (m, 12H);¹⁹F NMR (CDCl_Three) Δ (C₆F₆) 50.67 (d, J = 273 Hz), 49.50 (broad s), 48.35 (d, J = 273 Hz), 47.24 (d, J = 255 Hz), 45.7 0 (d, J = 255 Hz), 42.01 (d, J = 255 Hz), 40.00 (d, J = 255 Hz).   C₄₂H₄₈N_FourO₇F_Two・ 0.5H_TwoAnalytical value for O:     Calculated value: C 65.70 H 6.43 N 7.30     Found: C 65.69 H 6.25 N 7.19 Example 25 N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L- Valyl) amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy ) Phenyl-pentyl] -O- [2- (2-methoxyethoxy) -1-ethyl] -Production of D-valinol Step A N-trityl-O- [2- (2-methoxyethoxy) -1-ethyl] -D-bali Production of Knoll   The title compound was prepared in a similar manner to the alkylation procedure described in Step B of Example 17. The compound prepared in Step A of Example 17 and 2- (2-methoxyethyl Prepared in 86% yield from (toxic) ethyl-1-bromide. R_f= 0.74 (silica Gel, 2/8 acetone / petroleum ether). Step B Production of O- [2- (2-methoxyethoxy) -1-ethyl] -D-valinol   N-trityl-O- [2- (2 (2) in dry ether (20 ml) saturated with hydrogen chloride -Methoxyethoxy) -1-ethyl] -D-valinol (1.0 g, 2.28 mmol, The solution (prepared as described above) is kept at room temperature for 2.5 hours. Reaction mixture Is concentrated in vacuo and the residue is purified by flash chromatography (silica gel). First, dichloromethane and then it to elute trityl alcohol 95/5 dichloromethane / diethylamine, R_f= 0.20) Purification provided the title compound (0.46 g, 100%) as a colorless oil. Process C N- [4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy -1-oxo-5- (4-benzyloxy) phenyl-pentyl] -O- [2- Production of (2-methoxyethoxy) -1-ethyl] -D-valinol   Reaction Scheme A, Step (b): The title compound was prepared as described in Step D of Example 19. In a similar manner to the ester of step B of Example 1 and as described above O- [2- (2-methoxyethoxy) -1-ethyl] -D-valino produced To a 51% yield. R_f= 0.37 (silica gel, 3/7 petroleum ether / Ethyl acetate). Process D N- [4-amino-2,2-difluoro-3-hydroxy-1-oxo-5- (4 -Benzyloxy) phenyl-pentyl] -O- [2- (2-methoxyethoxy) Production of -1-ethyl) -D-valinol   Reaction Scheme A, Step (d): The title compound was described in Step C of Example 17. In the same manner as in the deprotection operation described above, the N- [4- Tertiary butoxycarbonylamino-2,2-difluoro-3-hydroxy-1-oxo So-5- (4-benzyloxy) phenyl-pentyl] -O- [2- (2-meth (Xyethoxy) -1-ethyl] -D-valinol in 97% yield. The lever was used directly in the next step. Mass spectrum m / z 539 (MH⁺). Step E N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L- (Valyl) amino-2,2-difluoro-3-hydroxy-1-oxo-5- (4-beta Benzyloxy) phenyl-pentyl] -O- [2- (2-methoxyethoxy)- Production of 1-ethyl] -D-valinol   Reaction Scheme A ', Step (e): The title compound was prepared as described in Step F of Example 17. In the same manner as the coupling operation, the amine and the And from the acid prepared in Step A of Example 8 in 52% yield. R_f= 0. 18 (silica gel, ethyl acetate). Mass spectrum m / z 773 (MH⁺). Step F Preparation of final title compound   Reaction Scheme A ', Step (f): The final title compound is described in Step G of Example 17. Produced in a manner similar to the Swelln oxidation procedure described above. Prepared from alcohol in 76% yield. R_f= 0.09 (silica gel, ethyl acetate). quality Mass spectrum m / z 771 (MH⁺).¹H NMR (DMSO-d₆) Δ 9.05-8.88 (m, 1H), 8.77-8. 55 (m, 2H), 8.40-8.27 (m, 1H), 7.94-7.81 (m, 1H), 7.76-6.55 (some m, 1 1H), 5.31-4.97 (m, 5H), 4.10-3.79 (m, 2H), 3.76-3.37 (m, 10H), 3.32 (s, 3H) , 3.29-3.11 and 2.89-2.60 (m, 2H), 2.09-1.79 (m, 2H), 1.11-0.44 (m, 12H);¹⁹ F NMR (DMSO-d₆) Δ (C₆F₆) 52.97 (d, J = 267 Hz), 52.12 (d, J = 269 Hz), 50.8 8 (d, J = 269 Hz), 49.45 (d, J = 254 Hz), 45.35 (d, J = 267 Hz), 48.17 (d, J = 254 H z), 46.17 (d, J = 254 Hz), 44.31 (d, J = 254 Hz).   C₄₀H₅₂N_FourO₉F_TwoAnalytical value for:     Calculated value: C 62.32 H 6.80 N 7.27     Obtained value: C 61.78 H 6.77 N 7.12 Example 26 N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L-valyl) amino -2,2-difluoro-1,3-dioxo-5- (4- {2-N-morpholyl} ethyl Preparation of [oxy) phenyl-pentyl] -O-methyl-D-valinol Step A N- [4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy -1-oxo-5- (4-hydroxy) phenyl-pentyl] -O-methyl-D -Manufacture of Valinol   Reaction Scheme A, Step (b): The title compound was prepared as described in Step D of Example 17. In the same manner as in Example 21, the ester of Step A of Example 21 and Step C of Example 19 were used. From the amine prepared above in 83% yield. R_f= 0.15 (silica gel, 6 / 4 petroleum ether / ethyl acetate). Mass spectrum m / z 461 (MH⁺). Step B N- [4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy -1-oxo-5- (4- {2-N-morpholyl} ethyloxy) phenyl-pe Preparation of [N-tyl] -O-methyl-D-valinol   Reaction scheme A, step (C_Two): N- [4-tert-butoxyca in dry DMF (20 ml) Rubonylamino-2,2-difluoro-3-hydroxy- 1-oxo-5- (4-hydroxy) phenyl-pentyl] -O-methyl-D- Valinol (1.117 g, 2.43 mmol, prepared as described above), N- (2 -Chloroethyl) morpholine HCl (0.633 g, 3.40 mmol), cesium carbonate (2. Mixture of 69 g, 8.26 mmol) and potassium iodide (0.056 g, 0.34 mmol) Was stirred at room temperature for 140 hours, then the reaction mixture was washed with ethyl acetate (100 ml). Wash and wash with brine (2 × 100 ml). Extract the aqueous phase with ethyl acetate (100ml) I do. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and vacuum Concentrate below. The residue was purified by flash chromatography (silica gel, Chill, R_f= 0.18) to give the title compound (0.993 g, 71%). Process C N- [4-amino-2,2-difluoro-3-hydroxy-1-oxo-5- (4 -{2-N-morpholyl} ethyloxy) phenyl-pentyl] -O-methyl- Production of D-valinol   Reaction Scheme A, Step (d): The title compound was deprotected as described in Step C of Example 17. In the same manner as the protection operation, the N- [4-third block prepared as described above is used. Toxylcarbonylamino-2,2-difluoro-3-hydroxy-1-oxo-5 -(4- {2-N-morpholyl} ethyloxy) phenyl-pentyl] -O-me 85% yield from chill-D-valinol and used directly in the next step . Process D N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L-valyl) amino -2,2-difluoro-3-hydroxy-1-oxo-5- (4- {2-N-mol (Holyldiethyloxy) phenyl-pen Production of [Tyl] -O-methyl-D-valinol   Reaction Scheme A ', Step (e): The title compound was prepared as described in Step F of Example 17. The amine prepared as described above and Example 8 Prepared in 80% yield from the acid prepared in step A of the above procedure. R_f= 0.19 (silica gel , Ethyl acetate / methanol 9/1). Mass spectrum m / z 708 (MH⁺). Step E Preparation of final title compound   Reaction scheme A ', step (f): freshly distilled dichloromethane (10 ml, P_TwoO_FiveUp Alcohol (0.280 g, 0.396 mmol) ), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one (0.672 g, 1.583 mmol, Dess-Martin periodinane and A mixture of tributanol (0.075 ml, 0.792 mmol) is stirred at room temperature for 15 minutes. It From the reaction mixture is hydrolyzed with isopropanol (1.2 ml) and concentrated in vacuo. Shrink. The residue is suspended in dichloromethane (3 ml) and passed through a Fluropore filter. And rinse the filter with dichloromethane (2 × 1 ml). The filtrate Concentrate under vacuum and concentrate the residue by flash chromatography (2 ×, silica Gel, 99/1 dichloromethane / to remove by-products of Dess-Martin reagent Methanol then 98/2 and 96/4 dichloromethane to elute the title compound (Methane / methanol) to give 0.112 g (28%) of the title compound. R_f = 0.11 (95/5 dichloromethane / methanol). Mass spectrum m / z 706 (MH⁺ ).¹H NMR (DMSO-d₆) Δ 8.99-8.70 (m, 1H) 、 8.64-8.43 (m, 3H) 、 7.82-7.73 (m , 1H), 7.47-6.70 (some m, 6H), 5.16-4.92 (m, 3H), 4.08-3.95 (broad s, 2H) , 3.95 to 3.71 (m, 1H), 3.71 to 3.65 (m, 1H), 3.60 to 3.48 (broad s, 4H), 3.43-3. 34 (m, 2H), 3.22-3.18 (2s, 3H), 3.24-3.03 and 2.77-2.56 (m, 2H), 2.54-2.34 (m, 4H), 2.02-1.70 (m, 2H), 1.10-0.50 (m, 12H);¹⁹F NMR (DMSO-d₆) Δ (C₆F₆ ) 52.87 (d, J = 267 Hz), 52.22 (d, J = 269 Hz), 50.91 (d, J = 269 Hz), 49.38 (d, J = 267 Hz).   C₃₅H₄₉N_FiveO₈F_Two・ 0.5H_TwoAnalytical value for O:     Calculated value: C 58.81 H 7.05 N 9.80     Found: C 58.61 H 6.88 N 9.93   In yet another embodiment, the present invention is directed to the use of a compound of formula (I) as an effective antiviral Providing a method for treating patients suffering from viral infections comprising administering an amount to the patient I do.   The term “viral infection” as used herein refers to the viral transfer of a cell. Aberrant conditions or diseases characterized by viral replication and multiplication. To taste. Viral infections for which treatment with compounds of formula (I) is particularly useful include, for example, Although not specified, HTLV-I, HTLV-II, HTLV-III (HIV virus), Us leukemia virus, feline leukemia virus, cytomegalovirus, avian sarcoma Includes retroviruses such as irs and the like. Further, according to the compound of formula (I) Treatment is widespread in HIV infection: symptomatic and asymptomatic ΛIDS, ARC (AIDS Related complex) and useful for handling actual or possible exposure to HIV It is. For example, the compounds of the invention may be used, for example, for transfusion, accidental needle puncture or surgery. Suspected past post-exposure to HIV due to blood exposure of pregnant patients It is useful to prevent infection.   The term “effective antiviral amount” of a compound of formula (I) is intended to be used once or once for a patient. Is more than expected in the absence of treatment with multiple dose administrations. Means an amount that is effective to inhibit ills growth or prolong patient survival . The term “suppress viral infection” as used herein, refers to the Slows, interrupts, or pauses virus conversion or virus replication and growth Means to stop or stop and necessarily indicates total removal of the virus It is not something.   Further, the present invention provides for administering to a patient an effective inhibitory amount of a compound of formula (I). A method of inhibiting HIV protease in a patient.   Patients infected with a retrovirus, such as HTLV-III, may have a compound of formula (I) It is to be understood that the need for various HIV protease inhibitors.   As used herein, the term "patient" refers to whether a particular viral infection is affected. Means a warm-blooded animal, such as a mammal. Humans, mice and rats are "patients" It should be understood that they are encompassed within the term "".   Administration of a compound of formula (I) to a patient will result in inhibition of HIV protease in the patient. Invite. That is, treatment of a patient with a compound of formula (I) results in increased HTLV-III. Such retroviruses are inhibited or prevented.   Patients may have HIV protease as a contributing factor in disease progression In the event of a viral infection, the patient will receive the compound of formula (I) Requires treatment with an agent that inhibits HIV protease, such as a substance.   Skilled technicians based on standard clinical and laboratory tests and procedures As an examining physician, agents that inhibit HIV protease, such as compounds of formula (I), It is possible to easily identify the patient who needs the treatment.   The term “effective inhibitory amount” of a compound of formula (I) refers to a single or multiple dose to a patient. A dose effective to confer HIV protease inhibition in a single dose. You.   As used herein, an "effective amount" refers to the effective amount of the compound of formula (I). Effective antiviral load or inhibitor. Effective amounts can be determined using known techniques. Or become familiar with the technology by observing the results obtained under similar circumstances. Can be easily determined by the examining physician. Effective amount or throw In determining the dosage, the type of mammal is not limited to; Animal size, age and general health: Specific viral infections involved: Virus Degree of infection: individual patient response; specific compound administered; method of administration; Bioavailability characteristics of the formulation; selected dosage form; A number of factors are considered by the attending physician, including other relevant situations.   An effective amount of a compound of formula (I) is about 0.1 mg / kg body weight per day (mg / kg / day). ) To about 100 mg / kg / day. The preferred amount is about 0.5-10 mg / kg / Day.   In the effective treatment of patients suffering from viral infections, the compound of formula (I) What makes it possible to use biologically in effective amounts It can be administered in any form or method, for example, orally and parenterally . For example, the compounds of formula (I) can be administered orally, subcutaneously, intramuscularly, intravenously, or It can be administered transdermally, intranasally, rectally and by other means of administration. Oral administration is generally preferred. Experts in the technology of manufacturing prescriptions are selected The specific properties of the compound, the viral infection to be treated, the stage of infection and other relevant Depending on the situation, appropriate dosage forms and administration methods can be readily selected.   The compound of formula (I) alone or together with a pharmaceutically acceptable carrier or excipient may be used. The composition can be administered in the form of a pharmaceutical composition. Proportion and properties of the composition Are the solubility and chemical properties of the selected compound, Determined by associate pharmaceutical practice. The compounds of the present invention are themselves effective. However, for purposes such as stability, convenience of crystallization, and increased solubility, It can be formulated and administered in the form of a pharmaceutically acceptable salt.   In another embodiment, the present invention provides a combination of one or more inert carriers. There is provided a composition comprising a compound of formula (I) in admixture. These compositions, for example, As a standard for assaying potency, as an advantageous means of performing bulk transport or with pharmaceutical compositions Useful. Assayable amounts of the compound of formula (I) are known and will be apparent to those skilled in the art. Can be easily measured by more recognized standard calibration procedures and techniques Amount. Assayable amounts of a compound of formula (I) will generally range from about 0.001 to 75 times the composition weight. % Can be varied. An inert carrier does not degrade the compound of formula (I) or May be any substance that does not covalently react with the compound of formula (I). Proper inactivity An example of an aqueous carrier is water; Aqueous buffers such as those useful for high performance liquid chromatography (HPLC) analysis Liquids; organic solvents such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceuticals It is a chemically acceptable carrier or excipient.   More particularly, the present invention relates to one or more pharmaceutically acceptable carriers. Or a medicament containing a therapeutically effective amount of a compound of formula (I) mixed with excipients A composition is provided.   Pharmaceutical compositions are manufactured in a manner known in the pharmaceutical art. Carrier or An excipient is a solid that can serve as a vehicle or medium for the active ingredient. , Semi-solid or liquid substances. Suitable carriers or excipients are known in the art. It is known. The pharmaceutical composition is adapted for oral or parenteral use and Can be administered to patients in the form of tablets, capsules, suppositories, solutions, suspensions, etc. .   The compounds of the invention may be administered orally, for example, with an inert diluent or an edible carrier. can do. These can be enclosed in gelatin capsules or compressed into tablets can do. For the purpose of oral therapeutic administration, the compound can be mixed with excipients. Tablets, troches, capsules, elixirs, suspensions, syrups, wafers, It can be used in the form of chewing gum or the like. These preparations have a specific form Although it may vary depending on the condition, the compound of the present invention as an active ingredient is at least 4% And advantageously between 4% and about 70% of the weight of the unit. Can be. The amount of compound present in the composition is such that a suitable dosage will be obtained. Quantity. Preferred compositions and preparations according to the present invention are those wherein the oral dosage unit form is It is prepared to contain 5.0-300 mg of a compound of the invention.   Tablets, pills, capsules, troches etc. may also contain one or more of the following supplements: Agents can be included: binders, such as microcrystalline cellulose, tragacanth Gum or gelatin; excipients, such as starch or lactose; disintegrants, such as a Luginic acid, primogel, corn starch, etc .; lubricants such as stearic acid Gnesium or stellotex; glidants such as colloidal silicon dioxide; and Sweeteners such as sucrose or saccharin or flavoring agents such as peppermint , Methyl salicylate or orange flavor. When the dosage unit form is a capsule It may be a liquid carrier, for example, polyethylene glycol, in addition to the above type of substance. Or it may contain a fatty oil. Other dosage unit forms are based on the physical Various other substances that modify the form can be included, for example, coatings. That is, tablets or pills are coated with sugar, shellac or other enteric coatings. Can be coated. Syrup can be used as a sweetener in addition to the compounds of the present invention. May contain sucrose and certain preservatives, dyes and colorants and flavors it can. The materials used in the manufacture of these various compositions are pharmaceutically pure It must be non-toxic in the amounts used.   For the purpose of parenteral therapeutic administration, the compounds of the invention may be in solution or suspension. Can be mixed. These preparations contain at least 0.1% of the compound of the invention. Must have, but can vary between 0.1 and about 50% of the weight of the formulation You. The amount of the compound of the present invention present in such compositions will result in suitable dosages. Is such an amount. Preferred compositions and preparations according to the present invention are intended for parenteral administration. It is prepared so that a unit contains 5.0-100 mg of the compound of the invention.   These solutions or suspensions may also contain one or more of the following adjuvants: Can be: sterile diluents, such as water for injection, saline solution, fixed oil , Polyethylene glycol, glycerin, propylene glycol or other synthetic Solvents; antimicrobial agents such as benzyl alcohol or methyl paraben; antioxidants, eg Eg ascorbic acid or sodium acid sulfite; chelating agents such as ethylene Diaminetetraacetic acid; buffers such as acetate, citrate or phosphate and tonics Agents to control the degree, such as sodium chloride or dextrose. Parenteral preparations Ampules, disposable syringes or multiple ampules made of glass or plastic It can be enclosed in several dose vials.   The present invention also relates to the use of PNPase inhibitors with or without HIV protease inhibitor compounds in combination therapy with I and PNPase inhibitors And one or more agents useful in the treatment of AIDS, such as HIV1 and HIV2 In combination with known antiviral agents suitable for the treatment of Is what you do.   The compounds of the present invention can be used to inhibit HIV-protease using the following published techniques. Can be inspected for harm.   Testing for retroviral enzyme production and protease inhibition. (A) Production of retroviral enzymes   To produce a recombinant protease, the European Journal of Pharmacology, Molecular Pharmacology Section, 172 (1989) 443- E. Expressed via E. coli. (B) Test for inhibition of recombinant viral protease   Protease and peptide substrate (Ser-Gln-Asn-Tyr-Pro-Ile-Va1-NH_Two, Km = 1 mM) Inhibition of the reaction with 50 mM sodium acetate, pH 5.5, 10% glycerol for 1 hour at 37 ° C. Performed in 5% ethylene glycol. Different concentrations of inhibitor in 10 μl of DMSO To 80 μl of test solution and add 10 μl (1.6 μg) of recombinant protease to the reaction To start with. The reaction is stopped with 16 μl of 4M perchloric acid. The product of the reaction is H PLC (VYDAC wide pore (wide pore) 5cm C-18 reverse phase, acetonitrile gradient, 0.1 % Trifluoroacetic acid). The degree of inhibition of the reaction depends on the product peak. Measure from the height of HPLC of separately synthesized products provides a quantitative standard for product composition and And give confirmation.   By the techniques described above and by the use of other known techniques and Comparison with known compounds known to be useful for the treatment of advanced disease states Will ensure that those skilled in the art have access to sufficient I believe it can be done.   It has been discovered that most classes of compounds have been found to be useful in the pharmaceutical industry. True, certain compounds, such as those shown in the chart below, are more preferable.   The following list illustrates compounds according to the invention.   1. α, α-difluoro-γ-[[(2- (R)-[[(hydroxy) phenylacetate Tyl] amino] -3-methyl-1-oxobutyl] amino] -β-oxo-4- (Phenylmethoxy) -N- (phenylmethyl) -benzene-pentanamide;   2. (6S- (6R^*, 9R^*, 13S^*)]-4,4-Difluoro-9- (1-methylethyl) -3 , 5,8,11-Tetraoxo-1,13-diphenyl-6-[[4- (phenylmethoxy ) Phenyl] methyl] -12-oxa-2,7,10-triazatetradecane-14-oi Acid, methyl ester;   3. α, α-difluoro-γ-[[3-methyl-1-oxo-2-[[(1-O Oxo-trans-3-phenyl-2-propenyl) amino] butyl] amino]- β-oxo-4- (phenylmethoxy) -N- (phenylmethyl) -benzene- Pentanamide;   4. α, α-difluoro-γ-[[2- [2-hydroxy-1-oxo-4- (Phenylbutyl) amino] -3-methyl-1-oxobutyl] amino] -β- Oxo-4- (phenylmethoxy) -N- (phenylmethyl) -benzene-pen Tanamide;   5. N- [1-[[[3,3-difluoro-4-[[2-methyl-1-[(phenyl Rumethoxy) methyl] -propyl] amino] -2,4-dioxo-1-[[4- ( Phenylmethoxy) phenyl] -methyl] butyl] amino] carbonyl] -2- Methylpropyl] -β-oxo-4-morpholinepropanamide;   6. (1R- (1R^*, 2S^*)]-Α, α-difluoro-γ-[[2- (R)-[[(hydro [Xy) phenylacetyl] amino] -3-methyl-1-oxobutyl] amino] -N- [2-methyl-1-[(phenylmethoxy) methyl] propyl] -3-o Xo-4- (phenylmethoxy) -benzenepentanamide;   7. N- [1-[[[3,3-difluoro-4-[[2-methyl-1-[(Fe Nilmethoxy) -methyl] -propyl] amino] -2,4-di Oxo-1-[[4- (phenylmethoxy) phenyl] -methyl] -butyl] a Mino] carbonyl] -2-methylpropyl] -6- (4-morpholinyl-carbo Nyl) -3-pyridinecarboxamide;   8.7,7-difluoro-4,12-bis (1-methylethyl) -6,8,11-trioxo -1-phenyl-9-[[4- (phenylmethoxy) phenyl] methyl] -2- Oxa-5,10,13-triazatetradecane-14-oic acid, 3-pyridinylme Tilester;   9. [1R- (1R^*, 2S^*)]-Α, α-difluoro-γ-[[3-methyl-2-[[ 4- (4-morpholinylsulfonyl) benzoyl] amino] -1-oxobutyl ] Amino] -N- [2-methyl-1-[(phenylmethoxy) methyl] propyl] -Β-oxo-4- (phenylmethoxy) -benzenepentanamide;   Ten. [1R- (1R^*, 2S^*)]-Α, α-difluoro-γ-[[3-methyl-2-[[ 4- (4-morpholinylcarbonyl) benzoyl] amino] -1-oxobutyl ] Amino] -N- [2-methyl-1-[(phenylmethoxy) methyl] propyl ] -Β-oxo-4- (phenylmethoxy) -benzenepentanamide:   11． N- [1-[[[3,3-difluoro-4-[[2-methyl-1-[(Fe Nilmethoxy) methyl] -propyl] amino] -2,4-dioxo-1-[[4- (Phenylmethoxy) phenyl] -methyl] butyl] amino] carbonyl] -2 -Methylpropyl] -4-morpholineacetamide;   12． N- [1-[[[3,3-difluoro-4-[[2-methyl-1-[(Fe Nilmethoxy) methyl] -propyl] amino] -2,4-dioxo-1-[[4- (Phenylmethoxy) phenyl] methyl] -bu [Tyl] amino] carbonyl] -2-methylpropyl] -1H-imidazole-1 -Acetamide;   13. [1-[[[3,3-difluoro-2,4-dioxo-1-[[4- (phenyl Methoxy) phenyl] -methyl] -4-[(2-pyridinylmethyl) amino] bu Tyl] amino] carbonyl] -2-methylpropyl] -carbamic acid, 3-pyri Dinyl methyl ester;   14. [1-[[[3,3-difluoro-2,4-dioxo-1-[[4- (phenyl Methoxy) phenyl] -methyl] -4-[(3-pyridinylmethyl) amino] bu Tyl] amino] carbonyl] -2-methylpropyl] -carbamic acid, 3-pyri Dinyl methyl ester;   15． [1-[[[3,3-difluoro-2,4-dioxo-1-[[4- (phenyl Methoxy) -phenyl] -methyl] -4-[(2-pyridinylmethyl) amino] [Butyl] -amino] carbonyl] -2-methylpropyl] -carbamic acid, 2- Pyridinyl methyl ester;   16． [1-[[[3,3-difluoro-2,4-dioxo-1-[[4- (phenyl Methoxy) -phenyl] -methyl] -4-[(3-pyridinylmethyl) amino] [Butyl] -amino] carbonyl] -2-methylpropyl] -carbamic acid, 2- Pyridinyl methyl ester;   17． N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L-valyl) Amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy) phenyl Ru-pentyl] -O- (3-pyridylmethyl) -D-valinol;   18． N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L-valyl) Amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy) phenyl Ru-pentyl] -O- (3-pyridylme Chill) -D-valinol;   19. N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L-valyl) Amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy) phenyl Ru-pentyl] -O-methyl-D-valinol;   20. N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L-valyl) Amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy) phenyl -Pentyl] -O- (2-pyridylmethyl) -D-valinol;   twenty one. N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L-valyl) Amino-2,2-difluoro-1,3-dioxo-5- (4- {3-pyridylmethyl} Oxy) phenyl-pentyl] -O- (3-pyridylmethyl) -D-valinol;   twenty two. N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L-valyl) Amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy) phenyl -Pentyl] -O- (2-pyridylmethyl) -D-valinol;   twenty three. N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L-valyl) Amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy) phenyl -Pentyl] -O-methyl-D-valinol;   twenty four. N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L-valyl) Amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy) phenyl -Pentyl] -O-benzyl-D-valinol;   twenty five. N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L-valyl) Amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy) phenyl -Pentyl] -O- [2- (2-methoxyethoxy) -1-ethyl] -D-bali Knoll; and   26. N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L-valyl) Amino-2,2-difluoro-1,3-dioxo-5- (4- {2-N-morpholyl} [Ethyloxy) phenyl-pentyl] -O-methyl-D-valinol.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/535 AED A61K 31/535 AED C07C 231/12 C07C 231/12 269/06 269/06 271/22 271/22 C07D 213 / 30 C07D 213/30 C07F 7/10 C07F 7/10 Q C07K 5/023 C07K 5/023 5/062 5/062 5/065 5/065 5/078 5/078 5/083 5/083 (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, MW, SD, SZ, UG), AM, AT, AU, BB, BG, BR, BY, CA, CH , CN, CZ, DE, DK, EE , ES, FI, GB, GE, HU, IS, JP, KE, KG, KP, KR, KZ, LK, LR, LT, LU, LV, MD, MG, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, TT, UA, UZ, VN (72) Inventor Jianwick, David A. Illinois, USA 60087. Beach Park. Gunstar Road 37070 (72) Inventor Coleman, Daniel Tay, Kentucky, USA 41042. Florence. Mikkelsen Drive 161 (72) Inventors Vuan Dorselaer, Vive Vian, F-67100, France Strasbourg. Riudoura Groso 8 (72) Inventors Shirlin, Daniel Gier F-67450, France Lampertheim. Ryudo Limousin 18 (72) Inventor Tarnus, Serine F-67000, France Strasbourg. Grand-Rille 63

Claims (1)

[Claims] 1. formula   And stereoisomers, hydrates, isosteres and pharmaceutically acceptable salt.     In the above equation,     P₁Is   [Where T is [(O)_b-W-R] and T 'is [(O)_b'-W'-R'] or water And W and W ′ are each independently C_{1 ~ 6}Alkylene Or does not exist and     When W is directly bonded to a nitrogen atom in R, W is C_{Two ~ 6}Alkylene And     When W 'is directly bonded to the nitrogen atom in R', W 'is C_{Two ~ 6}With alkylene Yes,     When R or R 'are each independently aryl, W or W' is Independently C_{1 ~ 6}Alkylene];     P_TwoIs C_{1 ~ 6}Alkyl, cyclopentyl, hydroxy C_{1 ~ 6}Alkyl, phenyl Benzyl, or 3-tetrahydrofuryl;     R and R ′ are each independently —CH_TwoCHO, hydroxy C_{1 ~ 6}Alkyl, C_{1 ~ 6} Alkoxy C_{1 ~ 6}Alkyl, C_{1 ~ 6}Alkyl, C_{1 ~ 6}Alkenylene, piperazinyl, substituted piperazinyl, piperidyl, molybdenum Rufolinyl, pyridyl, pyrazinyl, pyrimidinyl or phenyl; and Substituted piperazinyl may have CHO, C (O) NHR ′ on its one nitrogen atom._Four, C_{1 ~Four} Alkyl or CO_TwoR_FourPiperazinyl substituted by     R₁Is Is;     R_ThreeIs C_{1 ~ 6}Allenyl C_{1 ~ 6}Alkoxy, C_{1 ~ 6}Alkylene, hydroxy C_{1 ~ 6} Alkyl, C_{1 ~ 6}Alkyl or OH;     R_FourIs C_{1 ~ 6}Alkyl, phenyl or benzyl;     R ′_FourIs hydrogen or C_{1 ~ 6}Alkyl;     R_FiveIs hydrogen, C_{1 ~ 15}Alkyl, OH, hydroxy C_{1 ~ 15}Alkyl, C_{1 ~ 6}Al Coxy, -CH ([(CH_Two)_d-O-CH_Two]_x-R ′₈)_Two, -CH_TwoSi (CH_Three)_Two(R_Three), PDL,-(C_{1 ~ 6}Al (Kiren) -OR_Four, -CH (Y) (Z),   (Where PDL is-(CH_Two)_a-2-, 3- or 4-pyridyl or p-substituted Benzyloxy (substituted nitro, OH, amino, C_{1 ~ 6}Alkoxy, hydro Kiss C_{1 ~ 6}Is alkylene or halogen); Y is C_{1 ~ 15}Alkyl, Hydroxy C_{1 ~ 15}Alkyl, C_{1 ~ 6}Alkyl or-(CH_Two)_e-C₆H_Four-(V)_e'; Z is-(CH_Two)_d-O-CHO, C_{1 ~ 6}Alkylene-O- (CH_Two)_d-(O-CH_Two-CH_Two)_e-O-C_{1 ~ 6}Archi , CHO, CO_TwoR_Four, CO_TwoNHR_Four,-(CH_Two)_d-O- (CH_Two)_d'-R'₇,-(CH_Two)_e-OR_FourOr   (Where V is OR_FourOr hydroxy C_{1 ~ 6}Alkylene, and However, R '₇Is piperazinyl, substituted piperazinyl, piperidyl or mole Holinyl, d '= 2)];     R₆Is R_FiveIf is hydrogen₆Is a condition other than hydrogen Then R_FiveAs defined for or R_FiveAnd R₆Are these Together with the nitrogen atom Selected from the group consisting of:     R₇Is CH_TwoOR_Four, C (O) NHR_FourOr CHO;     R ′₇Is piperazinyl, substituted piperazinyl, piperidyl, morpholini , Pyridyl, pyrazinyl, pyrimidinyl or phenyl (in these groups , The substituted piperazinyl is CHO, C (O) NHR on its one nitrogen atom_Four, C_{1 ~Four} Alkyl or CO_TwoR_FourIs piperazinyl substituted by     R₈Is (H, OH) or = O;     R ′₈Is pyrimidyl, pyridyl, pyrazinyl or phenyl;     a is 0, 1, 2, or 3;     b and b 'are each independently 0 or 1;     d and d 'are each independently 1 or 2;     e and e 'are each independently 0, 1 or 2; and     x is 0 or 1. 2. P₁But The compound according to claim 1, which is 3. x is 1 and P_Two3. The compound according to claim 2, wherein is isopropyl. 4. R₁But The compound according to claim 3, which is 5. R₁But The compound according to claim 3, which is 6. R_FiveIs hydrogen and R₆But The compound according to claim 3, which is 7. R_FiveIs hydrogen and R₆But The compound according to claim 3, which is 8. R_FiveIs hydrogen and R₆But The compound according to claim 3, which is 9. R_FiveIs hydrogen and R₆But The compound according to claim 3, which is Ten. When the compound is α, α-difluoro-γ-[[(2- (R)-[[(hydroxy) Nylacetyl] amino] -3-methyl-1-oxobutyl] amino-β-oxo -4- (phenylmethoxy) -N- (phenylmethyl) -benzene-pentana The compound according to claim 1, which is a mido. 11． When the compound is [6S- (6R^*, 9R^*, 13S^*)]-4,4-Difluoro-9- (1- Methylethyl) -3,5,8,11-tetraoxo-1,13-diphenyl-6-[[4- ( Phenylmethoxy) phenyl] methyl] -12-oxa-2,7,10-triazatetra The compound according to claim 1, which is decane-14-oic acid, methyl ester. 12． The compound is α, α-difluoro-γ-[[3-methyl-1-oxo-2-[[( 1-oxo-trans-3-phenyl-2-propenyl) amino] butyl] ami No] -β-oxo-4- (phenylmethoxy) -N- (phenylmethyl) -ben The compound according to claim 1, which is zen-pentanamide. 13. When the compound is α, α-difluoro-γ-[[2- [2-hydroxy-1-oxo -4- (phenylbutyl) amino] -3-methyl-1-oxobutyl] amino] -Β-oxo-4- (phenylmethoxy) -N- (phenylmethyl) -benzene The compound according to claim 1, which is -pentanamide. 14. When the compound is N- [1-[[[3,3-difluoro-4-[[2-methyl-1-[( Phenylmethoxy) methyl] -propyl] amino] -2,4-dioxo-1-[[4 -(Phenylmethoxy) phenyl] -methyl] butyl] amino] carbonyl] -2 -Methylpropyl] -β-oxo-4-morpholinepropanamide. 2. The compound according to 1. 15． When the compound is [1R- (1R^*, 2S^*)]-Α, α-difluoro-γ-[[2- (R)-[[ (Hydroxy) phenylacetyl] -amino] -3-methyl-1-oxobutyl] Amino] -N- [2-methyl-1-[(phenylmethoxy) methyl] propyl] -Β-oxo-4- (phenylmethoxy) -benzenepentanamide Item 1 A compound as described. 16． When the compound is N- [1-[[[3,3-difluoro-4-[[2-methyl-1-[( Phenylmethoxy) -methyl] -propyl] amino] -2,4-dioxo-1-[[ 4- (phenylmethoxy) phenyl] -methyl] -butyl] amino] carbonyl] -2-methylpropyl] -6- (4-morpholinyl-carbonyl) -3-pyridi 2. The compound according to claim 1, which is uncarboxamide. 17． If the compound is 7,7-difluoro-4,12-bis (1-methylethyl) -6,8,11-tri Oxo-1-phenyl-9-[[4- (phenylmethoxy) phenyl] methyl]- 2-oxa-5,10,13-triazatetradecane-14-oic acid, 3-pyridini The compound according to claim 1, which is a methyl ester. 18． When the compound is [1R- (1R^*, 2S^*)]-Α, α-difluoro-γ-[[3-methyl-2 -[[4- (4-morpholinylsulfonyl) benzoyl] amino] -1-oxo [Butyl] amino] -N- [2-methyl-1-[(phenylmethoxy) methyl] pro Pill] -β-oxo-4- (phenylmethoxy) -benzenepentanamide A compound according to claim 1, wherein 19. When the compound is [1R- (1R^*, IS^*) -Α, α-difluoro-γ-[[3-methyl-2- [[4- (4-morpholinylcarbonyl) benzoyl] amino] -1-oxob [Tyl] amino] -N- [2-methyl-1-[(phenylmethoxy) methyl] prop L] -β-oxo-4- (phenylmethoxy) -benzenepentanamide. A compound according to claim 1. 20. When the compound is N-[[[3,3-difluoro-4-[[2-methyl-1 [(Phenylmethoxy) methyl] -propyl] amino] -2,4-dioxo-1- [ [4- (phenylmethoxy) phenyl] -methyl] butyl] amino] carbonyl] -2-Methylpropyl] -4-morpholineacetamide. Compound. twenty one. When the compound is N- [1-[[[3,3-difluoro-4-[[2-methyl-1- [ (Phenylmethoxy) methyl] -propyl] amino] -2,4-dioxo-1- [ [4- (phenylmethoxy) phenyl] methyl] -butyl] amino] carbonyl] -2-Methylpropyl] -1H-imidazole-1-acetamide. A compound as described. twenty two. When the compound is [1-[[[3,3-difluoro-2,4-dioxo-1-[[4- (f Enylmethoxy) phenyl] -methyl] -4-[(2-pyridinylmethyl) amido [Butyl] amino] carbonyl] -2-methylpropyl] -carbamic acid, 3 The compound according to claim 1, which is -pyridinyl methyl ester. twenty three. When the compound is [1-[[[3,3-difluoro-2,4-dioxo-1-[[4- (f Enylmethoxy) phenyl] -methyl] -4-[(3-pyridinylmethyl) amido [Butyl] amino] carbonyl] -2-methylpropyl] -carbamic acid, 3 The compound according to claim 1, which is -pyridinyl methyl ester. twenty four. When the compound is [1-[[[3,3-difluoro-2,4-dioxo-1-[[4- (f Enylmethoxy) -phenyl] -methyl] -4-[(2-pyridinylmethyl) a Mino] butyl] -amino] carbonyl] -2-methylpropyl] -carbamic acid The compound according to claim 1, which is 2,2-pyridinylmethyl ester. twenty five. When the compound is [1-[[[3,3-difluoro-2,4-dioxo-1-[[4- (f Enylmethoxy) -phenyl] -methyl] -4-[(3-pyridinylmethyl) amido [No] butyl] -amino] carbonyl] -2-methylpropyl] -carbamic acid, The compound according to claim 1, which is 2-pyridinyl methyl ester. 26. When the compound is N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L- Valyl) amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy ) -Phenyl-pentyl] -O- (3-pyridylmethyl) -D-valinol A compound according to claim 1. 27. When the compound is N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L- Valyl) amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy ) -Phenyl-pentyl] -O- (3-pyridylmethyl) -D-valinol A compound according to claim 1. 28. When the compound is N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L- Valyl) amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy ) -Phenyl-pentyl] -O-methyl-D-valinol. Compound. 29. When the compound is N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L- Valyl) amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy ) -Phenyl-pentyl] -O- (2-pyridylmethyl) -D-valinol A compound according to claim 1. 30. When the compound is N- [4- (N- {2-pyridylmethyl} oxycal Bonyl-L-valyl) amino-2,2-difluoro-1,3-dioxo-5- (4- { 3-pyridylmethyldioxy) phenyl-pentyl] -O- (3-pyridylmethyl (2) The compound according to the above (1), which is -D-valinol. 31. When the compound is N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L- Valyl) amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy ) -Phenyl-pentyl] -O- (2-pyridylmethyl) -D-valinol A compound according to claim 1. 32. When the compound is N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L- Valyl) amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy ) -Phenyl-pentyl] -O-methyl-D-valinol. Compound. 33. When the compound is N- [4- (N- {2-pyridylmethyl} oxycarbonyl-L- Valyl) amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy ) -Phenyl-pentyl] -O-benzyl-D-valinol. Compound. 34. When the compound is N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L- Valyl) amino-2,2-difluoro-1,3-dioxo-5- (4-benzyloxy ) Phenyl-pentyl] -O- [2- (2-methoxyethoxy) -1-ethyl] The compound according to claim 1, which is -D-valinol. 35. When the compound is N- [4- (N- {3-pyridylmethyl} oxycarbonyl-L- Valyl) amino-2,2-difluoro-1,3-dioxo-5- (4- [2-N-mol (Holyl) ethyloxy) phenyl- Pentyl] -O-methyl-D-valinol. 36. Administering an effective antiviral amount of the compound of claim 1 to a patient. How to treat a patient with a viral infection. 37. A virus comprising administering an effective antiviral amount of the compound of claim 1. How to control viral infections in patients suffering from infection. 38. Claims 1. A method comprising administering to a patient an effective inhibitory amount of the compound of claim 1. To inhibit HIV protease in mice. 39. An amount capable of assaying the potency of the compound according to claim 1 mixed with an inert carrier. A pharmaceutical composition having 40. 40. The pharmaceutical composition according to claim 39 for treating a viral infection. 41. The compound of claim 1 for use in treating a viral infection. 42. The compound of claim 1 for use in inhibiting HIV protease. 43. Pharmaceutical composition for the manufacture of a pharmaceutical composition for the treatment of viral infection Use of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier. 44. Possibly pharmaceutically acceptable for producing HIV protease inhibitors Use of a compound according to claim 1 in combination with a carrier. 45. formula   (Wherein all of the substituents are as described below). Expression   中     P₁Is   [Where T is [(O)_b-W-R] and T 'is [(O)_b'-W'-R'] or water And W and W ′ are each independently C_{1 ~ 6}Alkylene Or does not exist and     When W is directly bonded to a nitrogen atom in R, W is C_{Two ~ 6}Alkylene And     When W 'is directly bonded to the nitrogen atom in R', W 'is C_{Two ~ 6}With alkylene Yes,     When R or R 'are each independently aryl, W or W' is Independently C_{1 ~ 6}Alkylene];     P_TwoIs C_{1 ~ 6}Alkyl, cyclopentyl, hydroxy C_{1 ~ 6}Alkyl, phenyl Benzyl, or 3-tetrahydrofuryl;     R and R ′ are each independently —CH_TwoCHO, hydroxy C_{1 ~ 6}Alkyl, C_{1 ~ 6} Alkoxy C_{1 ~ 6}Alkyl, C_{1 ~ 6}Alkyl, C_{1 ~ 6}Alkenylene, piperazinyl, substituted piperazinyl, Peridyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl or phenyl And substituted piperazinyl is CHO, C on its one nitrogen atom (O) NHR '_Four, C_{1 ~Four}Alkyl or CO_TwoR_FourPiperazinyl substituted by ;     R₁Is Is;     R_ThreeIs C_{1 ~ 6}Allenyl C_{1 ~ 6}Alkoxy, C_{1 ~ 6}Alkylene, hydroxy C_{1 ~ 6} Alkyl, C_{1 ~ 6}Alkyl or OH;     R ′_FourIs hydrogen or C_{1 ~ 6}Alkyl;     R_FiveIs hydrogen, C_{1 ~ 15}Alkyl, OH, hydroxy C_{1 ~ 15}Alkyl, C_{1 ~ 6}Al Coxy, -CH ([(CH_Two)_d-O-CH_Two]_x-R ′₈)_Two, -CH_TwoSi (CH_Three)_Two(R_Three), PDL,-(C_{1 ~ 6}Al (Kiren) -OR_Four, -CH (Y) (Z),   (Where PDL is-(CH_Two)_a-2-, 3- or 4-pyridyl or p-substituted Benzyloxy (substituted nitro, OH, amino, C_{1 ~ 6}Alkoxy, hydro Kiss C_{1 ~ 6}Is alkylene or halogen); Y is C_{1 ~ 15}Alkyl, Hydroxy C_{1 ~ 15}Alkyl, C_{1 ~ 6}Alkyl or-(CH_Two)_e-C₆H_Four-(V)_e'; Z is-(CH_Two)_d-O-CHO, C_{1 ~ 6}Alkylene-O- (CH_Two)_d-(O-CH_Two-CH_Two)_e-O-C_{1 ~ 6}Archi , CHO, CO_TwoR_Four, CO_TwoNHR_Four,-(CH_Two)_d-O- (CH_Two)_d'-R'₇,-(CH_Two)_e-OR_FourOr   (Where V is OR_FourOr hydroxy C_{1 ~ 6}Alkylene and R '₇ Is piperazinyl, substituted piperazinyl, piperidyl or morpholinyl In some cases, d '= 2)).     R₆Is R_FiveIf is hydrogen₆Is something other than hydrogen R_FiveAs defined for or R_FiveAnd R₆These Together with the attached nitrogen atom Selected from the group consisting of:     R₇Is CH_TwoOR_Four, C (O) NHR_FourOr CHO;     R ′₇Is piperazinyl, substituted piperazinyl, piperidyl, morpholini , Pyridyl, pyrazinyl, pyrimidinyl or phenyl (in these groups , The substituted piperazinyl is CHO, C (O) NHR on its one nitrogen atom_Four, C_{1 ~Four} Alkyl or CO_TwoR_FourIs piperazinyl substituted by     R₈Is (H, OH) or = O;     R ′₈Is pyrimidyl, pyridyl, pyrazinyl or phenyl;     a is 0, 1, 2, or 3;     b and b 'are each independently 0 or 1;     d and d 'are each independently 1 or 2;     e and e 'are each independently 0, 1 or 2; and     x is 0 or 1, the compound of｝, and its stereoisomers, hydrates and isosteres Preparation of body and pharmaceutically acceptable salts. 46. Equation (a)   (Where R ′₁Is protected R₁And the remaining substituents are as described below. Oxidizing the compound of   (b) then deprotecting the oxidized product of step (a)   中     P₁Is   [Where T is [(O)_b-W-R] and T 'is [(O)_b'-W'-R'] or water And W and W ′ are each independently C_{1 ~ 6}Alkylene Or does not exist and     When W is directly bonded to a nitrogen atom in R, W is C_{Two ~ 6}Al Kiren,     When W 'is directly bonded to the nitrogen atom in R', W 'is C_{Two ~ 6}With alkylene Yes,     When R or R 'are each independently aryl, W or W' is Independently C_{1 ~ 6}Alkylene];     P_TwoIs C_{1 ~ 6}Alkyl, cyclopentyl, hydroxy C_{1 ~ 6}Alkyl, phenyl Benzyl, or 3-tetrahydrofuryl;     R and R ′ are each independently —CH_TwoCHO, hydroxy C_{1 ~ 6}Alkyl, C_{1 ~ 6} Alkoxy C_{1 ~ 6}Alkyl, C_{1 ~ 6}Alkyl, C_{1 ~ 6}Alkenylene, piperazinyl, substituted piperazinyl, piperidyl, molybdenum Rufolinyl, pyridyl, pyrazinyl, pyrimidinyl or phenyl; and Substituted piperazinyl may have CHO, C (O) NHR ′ on its one nitrogen atom._Four, C_{1 ~Four} Alkyl or CO_TwoR_FourPiperazinyl substituted by     R₁Is Is;     R_ThreeIs C_{1 ~ 6}Allenyl C_{1 ~ 6}Alkoxy, C_{1 ~ 6}Alkylene, hydroxy C_{1 ~ 6} Alkyl, C_{1 ~ 6}Alkyl or OH;     R_FourIs C_{1 ~ 6}Alkyl, phenyl or benzyl;     R ′_FourIs hydrogen or C_{1 ~ 6}Alkyl;     R_FiveIs hydrogen, C_{1 ~ 15}Alkyl, OH, hydroxy C_{1 ~ 15}Alkyl, C_{1 ~ 6}Al Coxy, -CH ([(CH_Two)_d-O-CH_Two]_x-R ′₈)_Two, -CH_TwoSi (CH_Three)_Two(R_Three), PDL,-(C_{1 ~ 6}Al (Kiren) -OR_Four, -CH (Y) (Z),   (Where PDL is-(CH_Two)_a-2-, 3- or 4-pyrudyl or p-substituted benzyloxy (substituents are nitro, OH, amino, C_{1 ~ 6}Arco Xy, hydroxy C_{1 ~ 6}Is alkylene or halogen); Y is C_{1 ~ 1 Five} Alkyl, hydroxy C_{1 ~ 15}Alkyl, C_{1 ~ 6}Alkyl or-(CH_Two)_e-C₆H_Four-(V)_e '; Z is-(CH_Two)_d-O-CHO, C_{1 ~ 6}Alkylene-O- (CH_Two)_d-(O-CH_Two-CH_Two)_e-O- C_{1 ~ 6}Alkyl, CHO, CO_TwoR_Four, CO_TwoNHR_Four,-(CH_Two)_d-O- (CH_Two)_d'-R'₇,-(CH_Two)_e-OR_Four Or   (Where V is OR_FourOr hydroxy C_{1 ~ 6}Alkylene and R '₇ Is piperazinyl, substituted piperazinyl, piperidyl or morpholinyl In some cases, d '= 2)).     R₆Is R_FiveIf is hydrogen₆Is a condition other than hydrogen Then R_FiveAs defined for or R_FiveAnd R₆Are these Together with the nitrogen atom Selected from the group consisting of:     R₇Is CH_TwoOR_Four, C (O) NHR_FourOr CHO;     R ′₇Is piperazinyl, substituted piperazinyl, piperidyl, morpholini , Pyridyl, pyrazinyl, pyrimidinyl or phenyl (in these groups , The substituted piperazinyl is CHO, C (O) NHR on its one nitrogen atom_Four, C_{1 ~Four} Alkyl or CO_TwoR_FourIs piperazinyl substituted by     R₈Is (H, OH) or = O;     R ′₈Is pyrimidyl, pyridyl, pyrazinyl or phenyl;     a is 0, 1, 2, or 3;     b and b 'are each independently 0 or 1;     d and d 'are each independently 1 or 2;     e and e 'are each independently 0, 1 or 2; and   x is 0 or 1, the compound of｝, and its stereoisomers, hydrates and isotopes And the preparation of pharmaceutically acceptable salts.