KR100371122B1 - Hydrazine derivatives - Google Patents

Abstract

Hydrazine derivatives of formula (I) or pharmaceutically acceptable salts thereof, inhibit not only the release of tumor necrosis factor (TNF-α) and transforming growth factor (TGF-α) from cells, but also inhibit keratinocyte proliferation :

Formula I

Where

Y means CO or SO ₂ ;

R ¹ means lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl;

R ² means lower alkyl, halo-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl or aryl when Y means SO _2, and lower alkyl, halo-lower when Y means CO Alkyl, lower alkoxy, lower alkoxycarbonyl, acyl, lower cycloalkyl, aryl, aryl-lower alkyl, aryl-lower alkoxy or NR ⁵ R ⁶ ;

R ³ is hydrogen,

Lower alkyl unsubstituted or substituted with cyano, amino, hydroxy, lower alkoxy, lower alkoxycarbonyl, heterocyclyl or heterocyclylcarbonyl,

Lower alkenyl, lower alkynyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl, aryl or heterocyclyl; or

R ² and R ³ together form a residue of a 5-, 6- or 7-membered cyclic amide, cyclic imide, cyclic sulfonamide or cyclic urethane group;

R ⁴ is lower alkyl, hydroxy-lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl or a general formula X-aryl, X-heteroaryl or-(CH ₂ ) _1-2 -CH = CR A group of ⁷ R ⁸ ;

X means a spacer group;

R ⁵ and R ⁶ each independently represent hydrogen, lower alkyl or aryl-lower alkyl;

R ⁷ and R ⁸ together represent a lower alkylene group in which one methylene group is substituted or unsubstituted by a hetero atom.

They are particularly useful as agents for the treatment of inflammation, fever, bleeding, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis or psoriasis.

Description

Hydrazine derivatives {HYDRAZINE DERIVATIVES}

The present invention relates to novel hydrazine derivatives, methods for their preparation and medicaments containing them. The invention also relates to the use of these derivatives as medicaments and for the manufacture of medicaments.

The novel hydrazine derivatives provided by the present invention are compounds of formula (I) or pharmaceutically acceptable salts thereof:

Where

Y means CO or SO ₂ ;

R ¹ means lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl;

R ² means lower alkyl, halo-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl or aryl when Y means SO _2, and lower alkyl, halo-lower when Y means CO Alkyl, lower alkoxy, lower alkoxycarbonyl, acyl, lower cycloalkyl, aryl, aryl-lower alkyl, aryl-lower alkoxy or NR ⁵ R ⁶ ;

R ³ is hydrogen,

Lower alkyl unsubstituted or substituted with cyano, amino, hydroxy, lower alkoxy, lower alkoxycarbonyl, heterocyclyl or heterocyclylcarbonyl,

Lower alkenyl, lower alkynyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl, aryl or heterocyclyl; or

R ² and R ³ together form a residue of a 5-, 6- or 7-membered cyclic amide, cyclic imide, cyclic sulfonamide or cyclic urethane group;

R ⁴ represents lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl or a group of the general formula X-aryl, X-heteroaryl or — (CH ₂ ) _1-2 —CH═CR ⁷ R ⁸ Mean;

X means a spacer group;

R ⁵ and R ⁶ each independently represent hydrogen, lower alkyl or aryl-lower alkyl;

R ⁷ and R ⁸ together represent a lower alkylene group in which one methylene group is substituted or unsubstituted by a hetero atom.

Hydrazine derivatives provided by the present invention are inhibitors of tumor necrosis factor (TNF-α) and transforming growth factor (TGF-α) release from cells. They also inhibit the proliferation of keratinocytes. Therefore, the hydrazine derivatives of the present invention can be used as a medicament especially in the treatment of inflammation, fever, bleeding, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis and psoriasis.

In contrast to structurally related hydroxylamine acid derivatives (see US Pat. No. 5,304,549), the hydrazine derivatives provided by the present invention are a matrix metalloproteinase (MMP) class of enzymes, for example collagenase, straw It shows only mild inhibitory activity against melysine and gelatinase.

The term 'lower alkyl' as used herein, alone or in combination, for example in 'halo-lower alkyl' and 'lower cycloalkyl-lower alkyl', is no more than seven, preferably four Straight or branched chain alkyl groups containing the following carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tert-butyl, n-pentyl and n -Means hexyl. Trifluoromethyl is one example of a halo-lower alkyl group.

The term 'lower alkoxy' alone or in combination as in 'lower alkoxycarbonyl', lower alkyl groups as defined above bound by oxygen atoms, for example methoxy, ethoxy, n-propoxy , Isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Methoxycarbonyl, ethoxycarbonyl and the like are examples of lower alkoxycarbonyl groups.

The term 'lower cycloalkyl', alone or in combination as in 'lower cycloalkyl-lower alkyl', is a cycloalkyl group containing 3 to 7 carbon atoms, ie cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and It means cycloheptyl. Cyclopropylmethyl, 2-cyclobutyl-ethyl and 3-cyclohexyl-propyl are examples of lower cycloalkyl-lower alkyl groups.

The term 'lower alkenyl', alone or in combination as in 'aryl-lower alkenyl', means an alkenyl group containing 2 to 7 carbon atoms, for example allyl, vinyl and butenyl, and the term 'Lower alkynyl' means an alkynyl group containing 2 to 7 carbon atoms, for example propargyl or butynyl.

The term 'lower alkylene' refers to alkylene groups containing 2 to 6 carbon atoms, for example dimethylene, trimethylene, tetramethylene and the like. Thus, R ⁷ and R ⁸ may represent, for example, cyclopentane, cyclohexane or tetrahydropyranyl rings with the carbon atoms to which they are attached.

The term 'acyl' denotes an lower acyl carboxylic acid, ie an acyl group derived from an alkane carboxylic acid containing up to 6 carbon atoms, or from an aromatic carboxylic acid. Examples of the acyl groups include acetyl, propionyl, butyryl, isobuty Reel, pivaloyl, benzoyl, p-chlorobenzoyl and the like.

The term 'aryl' is phenyl or naphthyl unsubstituted or substituted with halogen, ie fluorine, chlorine, bromine or iodine, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, lower alkoxycarbonyl, nitro, phenyl and the like. For example, phenyl, 1-naphthyl, 2-methylphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 4-nitrophenyl and 4-methoxycarbonylphenyl. Benzyl, 4-chlorobenzyl, 4-bromobenzyl, 3-hydroxybenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 2-phenylethyl, 3,4-dimethoxy-phenethyl and the like aryl-lower alkyl Typical examples of groups are benzyloxy, 4-chloro-benzyloxy and 4-nitro-benzyloxy, which are typical examples of aryl-lower alkoxy groups. 2-phenylvinyl and 3-phenylallyl are mentioned as examples of aryl-lower alkenyl groups.

The term 'heterocyclyl' is bonded by a C atom or a secondary N atom (ie -NH-) and contains one or more heteroatoms selected from nitrogen, sulfur and oxygen, for example halogen, lower alkyl, lower 4-, 5- or 6-membered saturated or partially unsaturated, or 5- or 6-membered aromatic heterocyclic group optionally substituted with alkoxy and / or oxo and / or optionally benz-fused . Examples of heterocyclyl groups include pyrrolidinyl, pyrrolinyl, pyrazolinyl, piperidinyl, morpholinyl, thiamorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, furyl, thienyl, thiazolyl , Oxazolyl, isoxazolyl, oxetanyl, imidazolidinyl, dioxolanyl, pyrrolyl, pyridyl, pyrimidinyl, benzofuranyl, benzothienyl, benzthiazolyl, indolyl, isoindoleyl, Quinolyl and isoquinolyl.

The term 'heterocyclylcarbonyl' means a heterocyclyl group as defined above, which is bonded to C (O) by a secondary N atom. Morpholinocarbonyl is a typical example of such heterocyclylcarbonyl groups.

The term 'heteroaryl' refers to an aromatic heterocyclic group in the definition of 'heterocyclyl'.

The cyclic amide, imide, sulfonamide or urethane groups formed by R ² , R ³ and the atoms to which they are attached, ie the C or S atoms of Y and the N atoms, respectively, are, for example, may be a group of (a) to (g), wherein n represents 3, 4 or 5, and R ^a and R ^b together form the remainder of the aromatic or cycloalkane ring:

A preferred spacer group represented by X of the general formula _{- (CH 2) 1-5 -,} -CH 2 -CH = CH-, -CH 2 -C≡C-, -CH 2 NHCO-, - (CH 2) 1 _{or 2} NHCONH-,-(CH ₂ ) _1-5 -S-, in particular -CH ₂ S-, -CH ₂ NHSO _2- , -CH ₂ NHCH ₂ -,-(CH ₂ ) _1-5 -O-,- O- (CH ₂ ) _1-5 -and -S-.

Compounds of formula (I) form pharmaceutically acceptable salts with bases such as alkali metal hydroxides such as sodium and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, barium hydroxide and magnesium hydroxide and the like. Compounds of formula (I) which are basic are inorganic acids such as hydrohalic acid, such as hydrochloric acid and hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid. Pharmaceutically acceptable salts with salicylic acid, citric acid, methanesulfonic acid and p-toluenesulfonic acid.

While the formulas shown herein represent each compound in its absolute stereochemistry, it will be appreciated that the present invention includes not only the stereoisomers shown, but also the corresponding racemate and diastereomeric mixtures. In addition, when the spacer group represented by X contains an olefinic double bond as in —CH ₂ —CH═CH—, the spacer group has a structure (E) or (Z), preferably a structure (E). Can be.

Preferred compounds of the formula (I) are compounds in which Y means CO, R ² means lower alkoxy, in particular methoxy, or Y means SO ₂ and R ² means lower alkyl, in particular methyl. R ¹ preferably means lower alkyl, in particular isobutyl. R ³ preferably means lower alkyl, in particular isobutyl or 2-methylbutyl, lower alkenyl, especially 2-methylallyl, aryl-lower alkyl, in particular unsubstituted benzyl or aryl, in particular unsubstituted phenyl. R ⁴ preferably means a group of the formula X-aryl, especially when X means a spacer group of the formula —CH ₂ —CH═CH— and aryl means unsubstituted phenyl.

Particularly preferred compounds of formula I are as follows:

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methyl Valerohydrazide;

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalle Lohydrazide;

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2 (S) -methylbutyl) valerohydrazide;

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2 -Methylallyl) valerohydrazide; And

Methyl (E) -3- [2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -2-isobutylcarbazate .

According to the process provided by the present invention, the novel hydrazine as defined above is provided by separating the protecting group represented by R ⁹ from the compound of formula II and optionally converting the obtained compound of formula I into a pharmaceutically acceptable salt. Derivatives are prepared:

Where

Y, R ¹ , R ² , R ³ and R ⁴ have the meanings indicated above,

R ⁹ means a protecting group.

The protecting group represented by R ⁹ in the compound of formula II may be any conventional protecting group, but is preferably tetrahydropyranyl, 4-methoxybenzyl, benzyl or tri (lower alkyl) silyl, especially quaternary-butyl Dimethylsilyl.

Separation of the protecting group represented by R ⁹ from the compound of formula II is carried out according to methods known per se. For example, tetrahydropyranyl groups can be separated by treatment with sulfonic acids such as methanesulfonic acid or p-toluenesulfonic acid in lower alkanols such as methanol. Separation of 4-methoxybenzyl groups can be carried out using, for example, trifluoroacetic acid. Hydrogenolysis can be used to separate the benzyl protecting group in the presence of a catalyst such as palladium and in a lower alkanol such as methanol. Tri (lower alkyl) silyl protecting groups can be separated using water or low pH; This separation typically occurs in the preparation of each compound of formula II from the medium from which the compound of formula II is prepared (ie, the separation takes place in situ).

The conversion of the obtained compound of formula (I) into a pharmaceutically acceptable salt is carried out by treatment with an appropriate acid or base in a known manner.

The compounds of formula (II) used as starting materials in the above process are novel and are another object of the present invention. These are exemplified in the following schemes where Y, R ¹ , R ² , R ³ , R ⁴ and R ⁹ have the meanings indicated above, ^t Bu means tert-butyl and Me means methyl It can be prepared by various routes as described.

With respect to Scheme A, in one step, the compound of formula III is condensed with hydrazine or substituted hydrazine of formula IV to yield hydrazide of formula V. The condensation may be carried out under known conditions of the peptide coupling reaction and in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride for a coupling reagent known per se for the coupling, eg For example, it is carried out using 1-hydroxybenzotriazole.

The hydrazide of formula (V) is then reacted with the chloride of formula (VI) or anhydride of formula (VII) to afford the compound of formula (VIII). The reaction is carried out in a known manner, for example in an organic solvent which is inert under reaction conditions and in the presence of an organic base at about 0 ° C. to about room temperature. Suitable solvents are halogenated hydrocarbons such as dichloromethane. Examples of organic bases that can be used are tri (lower alkyl) amines such as triethylamine, pyridine, 4-dimethylaminopyridine and the like. If the base is a liquid under reaction conditions, the base can be used in excess, in which case it can act as the sole solvent.

In the next step, the compound of formula VIII is then deprotected with trifluoroacetic acid (TFA) to give the carboxylic acid of formula IX. The deprotection is carried out in a method known per se, for example at about room temperature, in an organic solvent which is inert under the reaction conditions, for example halogenated hydrocarbons such as dichloromethane.

Finally, the carboxylic acid of formula (IX) is converted to the starting material of formula (II) by condensation with O-protected hydroxylamine of formula (X). The condensation is carried out by methods known per se for peptide coupling reactions and in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, for example conventional coupling reagents such as 1-hydride. It is performed using oxybenzotriazole.

In some cases, compounds produced or prepared by Scheme A may be interconverted or substituted.

Thus, compounds of formula (V) in which R ³ represents hydrogen correspond to the corresponding compounds of formula (V) in which R ³ represents lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl or aryl-lower alkyl according to methods known per se. Can be converted to a compound. For example, a compound of Formula (V) wherein R ³ represents hydrogen may be selected from formula R ³⁰ -CHO in the presence of p-toluenesulfonic acid and molecular sieve, wherein R ³⁰ is lower alkyl, lower alkenyl, lower alkynyl, lower cyclo Condensed with an aldehyde of alkyl, aryl-lower alkyl or aryl, and the resulting substituted imines are preferably alkali metal cyanoborohydride, in particular sodium cyanoborohydride, preferably in situ. Can be reduced within. Alternatively, the compound of formula V wherein R ³ represents hydrogen may be at elevated temperature, suitably at the reflux temperature of the reaction mixture, conveniently in the presence of an organic base, for example tri (lower alkyl) amine, such as triethylamine. And cyclic anhydrides of the formula XI (where n has the meaning indicated above), such as glutaric anhydride, in an organic solvent inert under reaction conditions, for example benzene, toluene, and the like. have:

In this way, a compound of formula VIII is obtained in which R ² , R ³ and the atoms to which they are attached together mean a group of formula (c).

Compounds of formula II wherein R ³ represents hydrogen are conveniently in an organic solvent, for example dimethylformamide, which is inert in the presence of an alkali metal carbonate such as sodium carbonate or potassium carbonate and under reaction conditions. the general formula R ³⁰ -X can be converted to the corresponding compound of formula II by reacting the known compound of formula (wherein, R ³⁰ has the previously indicated meaning, X denotes a halogen) with a R ³⁰ a meaning indicated above.

In addition, compounds of formula (VIII) in which R ⁴ represents phthalimido-lower alkyl are conveniently formulated as hydrazine hydrates in lower alkanols such as methanol or ethanol, conveniently at approximately room temperature, under inert conditions under reaction conditions. The corresponding product of formula VIII, which can be treated and the resultant product, ie, R ⁴ represents amino-lower alkyl, is suitable (in the presence of a coupling reagent in the presence of a base for introducing the desired group R ⁴ (heterogeneous A) aromatic carboxylic acid or sulfonic acid halides, (hetero) aromatic isocyanates or (hetero) aromatic carboxylic acids.

The carboxylic acid of formula IX in Scheme A is novel and is another object of the present invention.

The compounds of formula III used in Scheme A can be prepared as described in or similar to the examples below, provided they are known compounds or analogs of known compounds. In addition, the compounds of formulas IV, VI, VII and X, as well as the aldehydes of formula R ³⁰ -CHO and the cyclic anhydrides of formula XI, which are also used in Scheme A, are known compounds or analogs of known compounds.

With respect to Scheme B, step 1 comprises converting the carboxylic acid of formula III to the corresponding methyl ester of formula XII. The process is known in the art, for example tertiary organic bases such as 4-dimethylaminopyridine and condensing agents, for example diims such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide It is carried out by reacting with methanol in the presence of mead.

The methyl ester of formula (XII) is then deprotected in the tert-butoxycarbonyl group by treatment with trifluoroacetic acid. The deprotection is carried out in a method known per se, for example at about room temperature, in an organic solvent which is inert under the reaction conditions, for example halogenated hydrocarbons such as dichloromethane.

The resulting compound of formula (XIII) is subsequently condensed with O-protected hydroxylamine of formula (X) to give a compound of formula (XIV). The condensation is carried out in a manner known per se for peptide coupling reactions in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, for example conventional coupling reagents such as 1-hydroxy It is carried out using benzotriazole.

In the next step, the compound of formula XIV is reacted with trimethylaluminum and hydrazine or substituted hydrazine of formula IV to give the compound of formula XV. The reaction is conveniently carried out in an organic solvent which is inert under the reaction conditions, for example a halogenated hydrocarbon such as dichloromethane and at a temperature in the approximate range of room temperature to 60 ° C.

Finally, the compound of formula XV is reacted with the chloride of formula VI or anhydride of formula VII to give the starting material of formula II. The reaction is carried out in a known manner, for example in an organic solvent which is inert under reaction conditions at about 0 ° C. to about room temperature and in the presence of an organic base. Suitable solvents are halogenated hydrocarbons, for example dichloromethane. Examples of organic bases that can be used are tri (lower alkyl) amines such as triethylamine, pyridine, 4-dimethylaminopyridine and the like. If the base is a liquid under reaction conditions, the base can be used in excess, in which case it can act simultaneously as a solvent.

In one step of Scheme C, the carboxylic acid of formula XVI is activated by treatment with, for example, oxalyl chloride, followed by reaction with a substituted hydrazine of formula XVII to give a compound of formula XVIII. The reaction is conveniently carried out at about 0 ° C. in an organic solvent which is inert in the presence of a base, especially a tertiary organic amine such as triethylamine and under the reaction conditions, for example a halogenated hydrocarbon such as dichloromethane.

The compound of formula XVIII is then reacted with trimethylaluminum and the O-protected hydroxylamine of formula X to convert it to the starting material of formula II. The reaction is conveniently carried out in an organic solvent which is inert under the reaction conditions, for example a halogenated hydrocarbon such as dichloromethane, and at a temperature of about room temperature to about 60 ° C.

The carboxylic acid of formula (XVI) and substituted hydrazine of formula (XVII) used in Scheme C are known compounds or analogs of known compounds that can be prepared in a manner similar to known compounds.

As mentioned above, the hydrazine derivatives provided by the present invention inhibit the proliferation of keratinocytes as well as the release of TNF and TGF-α. The activities can be demonstrated using the in vitro tests described below.

Test A: Inhibition of TNF-α Release

THP1 cells were cultured in RPMI 1640 medium supplemented with antibiotics and 10% fetal calf serum, harvested by centrifugation and diluted to 5 × 10 ⁵ cells / ml in the medium supplemented with 20 mM HEPES buffer. Aliquots of the cell suspension (200 μl) were plated in 96 well culture plates and incubated at 37 ° C. for 0.5 h before adding test compounds. Test compounds were dissolved in dimethyl sulfoxide (DMSO) at a storage concentration of 1.2 mM diluted with phosphate buffered saline / 10% DMSO solution to provide test compounds at final concentrations of 10 ^-9 to 10 ^-5 M, each of Concentrations were tested in duplicate. After incubating the cells with the test compound for 0.5 hour at 37 ° C., LPS (lipopolysaccharide of bacteria) was added at a concentration of 2 mg / ml and in air containing 5% CO ₂ and at 95% relative humidity. Incubation was continued for 3 hours at ℃. After centrifugation at 260 g for 10 minutes, one aliquot of each supernatant was taken and the amount of TNF-α was assessed by ELISA (R & D Systems Europe Ltd., Irvingdon, UK). . The concentration of test compound (IC ₅₀ ) that resulted in about 50% inhibition of LPS-induced TNF-α release was calculated from the dose-response curve.

Exam B: Inhibition of TGF-α Release

This test is a variation of the method described in RJ Coffrey, R. Derynk, JN Wilcox, TS Bringman, AS Goustin, HL Moses and MR Pittelkow, Nature, 328 , 816-820 (1987). Standard human epidermal keratinocytes (NHEK) (newborn and adult) were supplied by Clonetics Corporation, San Diego, Calif., In a third trend, on a 2 x 10 ³ to 10 ⁴ plate in a 96 well culture plate. The cells were plated / well and grown for 5 days in a humidified incubator with 5% CO ₂ atmosphere at 37 ° C. in serum-free keratocyte growth medium (KGM; Clonetics Corporation). Test compounds were dissolved in DMSO and diluted 10-fold in keratinocyte basal medium (KBM; Clonetics Corporation). Sequential dilutions of test compounds were prepared in 10% DMSO in KBM to provide concentrations 12 times higher than the final assay concentration. Test compound dilutions (or vehicle only as a control) were added to the cells, followed by incubation at 37 ° C. for 0.5 hours. Then 10 ng / ml TPA (phorball 12-myristate 13-acetate) was added to stimulate the release of TGF-α. After further incubation at 37 ° C. for 24 hours, the TGF-α content of the culture medium was determined by TGF-α ELISA (Oncogene Science Inc., Uniondale, NY) or anti- It was measured by a detection system based on electrochemiluminescence (Igen Inc., Gatorsburg, Maryland), formatted with human TGF-α (R & D Systems Europe Limited). The concentration of the test compound (IC ₅₀ , n mol) that inhibited the release of TGF-α by 50% compared to the control group was then calculated.

Exam C: Inhibition of keratinocyte proliferation

This test is described in T. Karashima, H. Hachisuka and Y. Sasai, J. Dermatol. Sci., 12 , 246-254 (1996); and A. Olaniran, BS Baker, JJ Garioch, AV Powles and L. Fry, Arch. Dermatol. Res., 287 , 231-236 (1995). Standard human epidermal keratinocytes (NHEK) (neonatal and adult) were plated at 2 × 10 ³ cells / well on 96 well culture plates. After 24 hours of incubation in a humidified incubator with 5% CO ₂ atmosphere at 37 ° C. in serum-free KGM (see above), the cells were attached to the culture plate, and then the medium was changed to KBM 4 days). Test compounds were dissolved in DMSO and then diluted 10-fold in KBM. Sequential dilutions of the test compound were prepared in 10% DMSO in KBM to give a concentration 11 times higher than the final assay concentration. Cells were then returned to KGM and test compound dilutions (or vehicle only as controls) were added immediately. After 3 days of incubation, for the last 16 hours, 1 μCi / well of ³ H-thymidine with a native activity of 5 Ci / mmol (Amersham International plc, Little Champagne, Buckinghamshire, UK) ) Pulsed. Cells were then separated and harvested using trypsin-EDTA. ³ H-thymidine incorporation was measured by scintillation counting technique as a measure of proliferation. The concentration of the test compound (IC ₅₀ , n mol) that inhibited ³ H-thymidine incorporation by 50% compared to the control group was calculated.

The results obtained in the above tests conducted with representative compounds of formula (I) are summarized in the table below.

compound IC ₅₀ of test A (n mol) IC ₅₀ of test B (n mol) IC ₅₀ of test C (n mol) A 437 210 1300 B 515 255 1100 C 365 N / T N / T D 408 N / T N / T E 531 N / T N / T F 1516 N / T N / T G 428 N / T N / T H 381 N / T N / T I 881 N / T N / T J 933 N / T N / T N / T means not tested.

In the table above,

A is (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'- Phenylvalerohydrazide,

B is (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'- (4-meth Methoxyphenyl) -4-methylvalerohydrazide,

C is (E) -2'-benzyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4- Methylvalerohydrazide,

D is (E) -2 '-(cyclohexylmethyl) -2 ^' (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulphur Phonyl) -4-methylvalerohydrazide,

E is (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4 Methylvalerohydrazide,

F is (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-N- (2,6-dioxopiperidino) Is valericamide,

G is (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'- [2 (S) -methylbutyl] valerohydrazide,

H is (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'- (2-methylallyl) valerohydrazide,

I is methyl (E) -3- [2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -2-isobutylcarba Jade,

J is (E) -2 (R)-[(S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(isobutyl) -2'-(isopentanoyl)- 4-methylvalerohydrazide.

Hydrazine derivatives provided by the present invention can be used, for example, as a medicament in the form of a pharmaceutical preparation. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, they can also be administered rectally, for example in the form of suppositories, or parenterally in the form of injections.

In the preparation of pharmaceutical formulations, hydrazine derivatives may be formulated with a therapeutically inert, inorganic or organic carrier. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like. However, depending on the nature of the active ingredient, generally no carrier is required for soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, saccharides, invert sugar, glucose and the like. Suitable carriers for the preparation of injectable solutions are, for example, water, alcohols, polyols, glycerin, vegetable oils and the like. Natural and hardened oils, waxes, fats, semi-liquid polyols and the like are suitable carriers for the preparation of suppositories.

The pharmaceutical preparations may also contain preservatives, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, fragrances, salts for adjusting osmotic pressure, buffers, coatings or antioxidants.

It is also an object of the present invention as well as a medicament containing the hydrazine derivative and the therapeutically acceptable carrier mentioned above. The method comprises preparing a compound of formula I or a pharmaceutically acceptable salt thereof in a herbal dosage form with a therapeutically inert carrier material and optionally one or more additional therapeutically active substances.

Another object of the invention includes the use of the hydrazine derivatives provided by the invention in the treatment of diseases, in particular in the treatment of inflammation, fever, bleeding, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis and psoriasis. Dosages may vary within wide limits and will, of course, be adjusted to the individual requirements in each particular case. Generally, when administered to an adult, a daily dosage of about 5 to about 30 mg, preferably about 10 to about 15 mg, is appropriate, but the upper limit may be exceeded if found to be advantageous. The daily dose may be administered in a single dose or in divided doses.

The following examples illustrate the invention. The structure of the product and important intermediates was confirmed by NMR spectroscopy.

Example 1

2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenylbutyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide

2 (R)-[1 (S)-(carboxy) -4-phenylbutyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydra in 4 ml anhydrous dimethylformamide The 0.165 g solution of the zide was cooled to 0 ° C. while stirring under nitrogen, and 0.09 g of 1-hydroxybenzotriazole and 0.09 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were continuously Was added. After stirring for 40 minutes at 0 ° C., the solution was treated with 0.18 g of O- (tert-butyldimethylsilyl) hydroxylamine and the mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was washed successively with water, 2M sulfuric acid, water and brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated to give a pale pink rubber which was crystallized from ether to give 0.05 g of 2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenylbutyl] -2'-methanesulfonyl) 4-Methyl-2'-phenylvalerohydrazide was obtained in the form of a gray solid.

MS: 476 (M + H) ⁺ .

nmr (d ₆ DMSO, 353 K): 10.73 (1H, s); 10.30 (1H, broad singlet); 8.46 (1 H, broad singlet); 7.50-7.44 (2H, m); 7.42-7.34 (2H, m); 7.30-7.21 (3H, m); 7.18-7.06 (3H, m); 3.17 (3H, s); 2.64-2.54 (1 H, m); 2.50-2.30 (2H, m); 2.25-2.11 (1 H, m); 1.59-1.23 (6H, m); 1.10-1.02 (1 H, m); 0.84 (1H, doublet, J = 6.5 Hz); 0.76 (1H, doublet, J = 7 Hz).

HPLC: gradient elution with solvent A containing 10% solvent B for 5 minutes and increasing to 90% solvent B from 5 to 15 minutes; Flow rate of 1 ml / min. Retention time: 16.77 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

2 (R)-[1 (S)-(carboxy) -4-phenylbutyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide used as starting material Prepared as follows:

(i) 2 (R)-[1 (S)-(tert-butoxycarbo, prepared in a similar manner as described in Example 2, parts (i) and (ii) in 5 ml dimethylformamide Nil) -4-phenylbutyl] -4-methyl valeric acid 0.35 g solution was cooled to 0 ° C., 0.1 mL N-methylmorpholine, 0.16 g 1-hydroxybenzotriazole, 0.16 g phenylhydrazine And 0.27 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride in succession. The solution was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was washed successively with water, 5% citric acid solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (6: 1) for elution. 0.41 g of yellow oil is obtained, which is crystallized from hexane / ether and then 0.255 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenylbutyl] -4-methyl -2'-phenylvalerohydrazide was obtained in the form of a white solid.

MS: 439 (M + H) ⁺ .

(ii) A solution of 0.19 g of the product of part (i) in 3 mL pyridine was cooled to 0 ° C. and 0.15 g of methanesulfonyl chloride was added. The solution was left at room temperature and the solvent evaporated. The residue was partitioned between ethyl acetate and 2M sulfuric acid and the ethyl acetate layer was washed successively with 2M sulfuric acid, water, 5% aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography using hexane / ethyl acetate (6: 1) for elution. 0.19 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenylbutyl] -2 '-(methanesulfonyl) -4-methyl-2-phenylvalerohydra Zide was obtained in the form of a white solid.

MS: 517 (M + H) ⁺ .

(iii) A solution of 0.19 g of the product of part (ii) was dissolved in a mixture of 8 ml of dichloromethane and 4 ml of trifluoroacetic acid and left at room temperature for 5 hours. The solvent was evaporated and the residue was re-evaporated from toluene. The procedure was repeated two more times to obtain a residue. The residue was triturated with ether and the solid was filtered off. 0.165 g of 2 (R)-[1 (S)-(carboxy) -4-phenylbutyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide as a white solid Obtained in form.

MS: 461 (M + H) ⁺ .

Example 2

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalle Lohydrazide

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- in a mixture of 10 mL methanol and 5 mL dichloromethane. A solution of 0.095 g of butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was treated with 0.043 mg of 4-toluenesulfonic acid. The mixture was stirred at rt for 3 h and then the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was triturated with ether to give 0.051 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl)- 4-Methyl-2'-phenylhydrazide was obtained in the form of a white solid.

MS: 474 (M + H) ⁺ .

nmr (d ₆ DMSO, 353 K): 10.80 (1H, s); 10.30 (1H, broad singlet); 8.48 (1 H, broad singlet); 7.51-7.45 (2H, m); 7.42-7.34 (2H, m); 7.32-7.23 (5H, m); 7.21-7.14 (1H, m); 6.22 (1H, doublet, J = 15.5 Hz); 6.08-5.96 (1 H, m); 3.20 (3H, s); 2.70-2.60 (1 H, m); 2.42-2.12 (3H, m); 1.58-1.48 (1 H, m); 1.46-1.35 (2H, m); 1.14-1.05 (1 H, m); 0.85 (3H, doublet, J = 6.5 Hz); 0.76 (3H, doublet, J = 7.5 Hz).

HPLC: gradient elution with solvent A containing 10% solvent B for 5 minutes and increasing to 90% solvent B from 5 to 15 minutes; Flow rate of 1 ml / min. Retention time: 16.76 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -(Methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was prepared as follows:

(i) A solution of 5.19 g of 4-tert-butyl hydrogen 2 (R) -isobutyl-succinate in 50 ml anhydrous tetrahydrofuran was cooled to -78 ° C while stirring under nitrogen. 25 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran was added dropwise and the mixture was stirred at -78 ° C for 15 minutes. Then a solution of 5.55 g of cinnamil bromide in 25 ml anhydrous tetrahydrofuran was added dropwise and the mixture was allowed to slowly warm to room temperature. After stirring overnight, tetrahydrofuran was evaporated and the residue partitioned between ethyl acetate and 5% citric acid solution. The ethyl acetate layer was washed with two additional portions of 5% citric acid solution, water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to give an orange oil. It was dissolved in 100 ml of hexane, and 2.35 g of cyclohexylamine was added thereto. The mixture was left for 2 hours and the resulting solid was collected by filtration. The solid was suspended in ethyl acetate and shaken with two portions of 2M sulfuric acid to give a clear solution. The ethyl acetate solution was washed twice with water and then with saturated sodium chloride solution and subsequently dried over anhydrous magnesium sulfate. After evaporating the solvent, 6.41 g of (E) -2 (R)-[1 (R)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid was added. Obtained in a light cream solid form.

(ii) The product obtained in part (i) was dissolved in 50 mL anhydrous tetrahydrofuran, cooled to −78 ° C. with stirring, and 20.5 mL of a 2M solution of lithium diisopropylamide in tetrahydrofuran was added dropwise. After stirring 1.75 h at -78 ° C, 8 ml of methanol was added dropwise. The mixture was allowed to warm slowly to room temperature and stirred overnight. Tetrahydrofuran was evaporated and the residue was partitioned between ethyl acetate and 5% citric acid solution. The ethyl acetate layer was washed successively with two additional portions of citric acid solution, two portions of water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After evaporation, 1 (S), 2 (R) and 1 (R) of E-2- [1- (tert-butoxycarbonyl) -4-phenyl-3-butenyl-4-methylvaleric acid, An orange oil containing a mixture of 2 (R) isomers was obtained. The epimerization procedure was repeated three times to obtain a mixture substantially free of 1 (S), 2 (R) isomers. The crude product was dissolved in 100 mL of hexane and the solution was treated with 1.9 g of cyclohexylamine. After standing for 3 hours, the precipitated salts were filtered off and dried. 5.53 g of a light creamy solid were obtained, which were converted to the free acid by a procedure similar to that described in (i). 4.36 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid in the form of a yellow solid It was.

(iii) 0.466 g of (E) -2 (R) -1 (S) starting from 0.7 g of the carboxylic acid prepared in part (ii) of this example, in a similar manner as described in Example 1, part (i) )-(Tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylhydrazide is obtained in the form of a white solid.

MS: 437 (M + H) ⁺ .

(iv) 0.15 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl), in a manner analogous to that described in Example 1, parts (ii) and (iii) 0.14 g of (E) -2 (R)-[1 (S)-(carboxy) -4- starting with -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide Phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid.

(v) the carboxylic acid prepared in the preceding paragraph was dissolved in 3 ml of dimethylformamide, cooled to 0 ° C., 0.064 g of O- (tetrahydro-2H-pyran-2 (RS) -yl) hydroxylamine and Treatment was continued with 0.061 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to warm to rt and stirred overnight. The solvent was evaporated and the residue partitioned between 5% citric acid solution and ethyl acetate. The ethyl acetate layer was washed with water, 5% sodium bicarbonate solution and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and evaporated. The resulting white solid was triturated with ether and filtered to give 0.095 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbonyl] -4- Phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a white powder.

MS: 558 (M + H) ⁺ .

Example 3

Benzyl 3- [2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenylbutyl] -4-methylvaleryl] -2-phenylcarbazate

In a manner similar to that described in the first paragraph of Example 2, 0.05 g of benzyl 3- [2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.032 g of benzyl 3- [2 (R)-[1 (S)-(hydroxycarbamoyl) -4- starting with -4-phenylbutyl] -4-methylvaleryl] -2-phenylcarbazate Phenylbutyl] -4-methylvaleryl] -2-phenylcarbazate was obtained in the form of a light cream solid.

MS: 532 (M + H) ⁺ .

nmr (d ₆ DMSO, 353 K): 10.83 (1H, s); 10.47 (1H, broad singlet); 8.62 (1 H, broad singlet); 7.64 (2H, m); 7.54 (7H, m); 7.41 (3 H, m); 7.33 (1 H, m); 7.24 (2H, m); 5.40 (2H, s); 2.76-2.30 (4H, m); 1.75-1.45 (6H, m); 1.22 (1 H, m); 0.97 (3H, doublet, J = 7 Hz); 0.90 (3H, d, J = 6.5 Hz).

HPLC: gradient elution with 10% solvent B containing 10% solvent B and increasing to 80% solvent B from 10 to 20 minutes; Flow rate of 1 ml / min. Retention time: 19.71 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Benzyl 3- [2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -4-methylvaleryl] used as starting material] 2-Phenylcarbazate was prepared as follows:

(i) 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenylbutyl] -4-methyl-, prepared as described in Example 1, part (i) 0.5 g of 2'-phenylvalerohydrazide was dissolved in 10 ml of diethyl ether and stirred with 10 ml of saturated aqueous sodium hydrogen carbonate solution and 1.0 ml of benzyl chloroformate. After 24 hours, the ether layer was separated, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (9: 1) for elution. 0.767 g of benzyl 3- [2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenylbutyl] -4-methylvaleryl] -2-phenylcarbazate as a white solid Obtained in the form of.

MS: 573 (M + H) ⁺ .

(ii) 0.115 g of benzyl 3- [2 (R), starting with 0.115 g of phenylcarbazate prepared in the preceding paragraph, in a similar manner as described in Example 2, parts (iv) and (v) -[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy)]-4-phenylbutyl] -4-methylvaleryl] -2-phenylcarbazate was obtained in the form of a colorless rubber. .

MS: 616 (M + H) ⁺ .

Example 4

2'-acetyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenylbutyl] -4-methyl-2'-phenylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.09 g of 2'-acetyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.062 g of 2'-acetyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4, starting with -4-phenylbutyl] -4-methyl-2'-phenylvalerohydrazide -Phenylbutyl] -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid.

MS: 440 (M + H) ⁺ .

HPLC: gradient elution with solvent A containing 25% solvent B for 5 minutes and then increasing to 60% solvent B from 5 to 20 minutes; Flow rate of 1 ml / min. Retention time: 14.97 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

2'-acetyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -4-methyl-2 used as starting material '-Phenylvalerohydrazide was prepared as follows:

(i) 2 (R)-[1 (S)-(tert-butylcarbonyl) -4-phenylbutyl], prepared as described in Example 1, part (i) in 2 ml of dichloromethane. A mixture of 0.2 g of 4-methyl-2'-phenylvalerohydrazide, 0.3 ml of acetic anhydride and 0.35 ml of N-methylmorpholine was left at room temperature for 3 days. Dichloromethane was evaporated and the residue was partitioned between ethyl acetate and 5% sodium bicarbonate solution. The ethyl acetate solution was washed with 5% sodium bicarbonate solution, water, 5% citric acid solution, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (1: 1) for elution. White 0.21 g of 2'-acetyl-2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenylbutyl] -4-methyl-2'-phenylvalerohydrazide Obtained in the form of a solid.

MS: 481 (M + H) ⁺ .

(ii) 0.09 g of 2'-acetyl-2 (R)-, starting with 0.21 g of hydrazide prepared in the preceding paragraph, in a manner similar to that described in Example 2, parts (iv) and (v). [1 (S)-[(tetrahydro-2 (RS) -pyranyloxy)] carbamoyl] -4-phenylbutyl] -4-methyl-2'-phenylvalerohydrazide in the form of a white solid Obtained.

MS: 524 (M + H) ⁺ .

Example 5

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2 Pyridyl) valerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.11 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting with -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2-pyridyl) valerohydrazide, the ethyl acetate solution of the product After washing with aqueous sodium hydrogen solution to give a free base, 0.052 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -(Methanesulfonyl) -4-methyl-2 '-(2-pyridyl) valerohydrazide was obtained in the form of a white solid.

MS: 475 (M + H) ⁺ .

nmr (d ₆ DMSO, 353 K): 10.86 (1H, s); 10.27 (1H, broad singlet); 8.45 (1 H, broad singlet); 8.35 (1 H, m); 7.30 (1 H, m); 7.34-7.12 (7H, m); 6.32 (1H, doublet, J = 15.5 Hz); 6.13-6.04 (1 H, m); 3.51 (3H, s); 2.79-2.69 (1 H, m); 2.50-2.30 (3H, m); 1.53-1.50 (2H, m); 1.19-1.10 (1 H, m); 0.91 (3H, doublet, J = 7.0 Hz); 0.83 (3H, doublet, J = 6.5 Hz).

HPLC: gradient elution with solvent A containing 10% solvent B for 5 minutes and increasing to 90% solvent B from 5 to 20 minutes; Flow rate of 1 ml / min. Retention time: 16.20 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -(Methanesulfonyl) -4-methyl-2 '-(2-pyridyl) valerohydrazide was prepared as follows:

In a manner similar to that described in Example 2, parts (iii)-(v), (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3 (E) -2 (R)-[1 (S)-(tetrahydro-2 (RS) -pyranyloxy) carbamoyl starting with -butenyl] -4-methylvaleric acid and 2-hydrazinopyridine ] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2-pyridyl) valerohydrazide in the form of a white solid.

MS: 559 (M + H) ⁺ .

Example 6

(E) -2 '-(2-benzothiazolyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl ) -4-Methylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.086 g of (E) -2 ′-(2-benzothiazolyl) -2 (R)-[1 (S)-[(tetrahydro-2 Starting with (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide, the ethyl acetate solution of the product After washing with aqueous sodium hydrogen carbonate solution, 0.045 g of (E) -2 '-(2-benzothiazolyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3 -Butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 531 (M + H) ⁺ .

HPLC: gradient elution using solvent A containing 5% solvent B for 5 minutes and increasing to 95% solvent B from 5 to 20 minutes; Flow rate of 1 ml / min. Retention time: 18.16 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 '-(2-benzothiazolyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4 used as starting material -Phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:

In a manner similar to that described in Example 2, parts (iii)-(v), (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3 Starting from -butenyl] -4-methylvaleric acid and 2-hydrazinobenzothiazole, (E) -2 '-(2-benzothiazolyl) -2 (R)-[1 (S)-( Tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid It was.

Example 7

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2 -Quinolyl) valerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.05 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting with -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2-quinolyl) valerohydrazide, the ethyl acetate solution of the product After washing with aqueous sodium hydrogen solution, 0.026 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl ) -4-methyl-2 '-(2-quinolyl) valerohydrazide was obtained in the form of a white solid.

MS: 524 (M + H) ⁺ .

HPLC: gradient elution with solvent A containing 10% solvent B for 5 minutes and increasing to 90% solvent B from 5 to 20 minutes; Flow rate of 1 ml / min. Retention time: 17.90 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -(Methanesulfonyl) -4-methyl-2 '-(2-quinolyl) valerohydrazide was prepared as follows:

In a manner similar to that described in Example 2, parts (iii)-(v), (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3 (E) -2 (R)-[1 (S)-(tetrahydro-2 (RS) -pyranyloxy) carbamoyl starting with -butenyl] -4-methylvaleric acid and 2-hydrazinoquinoline ] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2-quinolyl) valerohydrazide in the form of a white solid.

Example 8

1 (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-(4-methoxy Phenyl) -4-methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.338 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.195 g of 1 (E)-, starting with -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-(4-methoxyphenyl) -4-methylvalerohydrazide 2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-(4-methoxyphenyl) -4- Methylvalerohydrazide was obtained in the form of a cream solid.

MS: 504 (M + H) ⁺ .

HPLC: gradient elution using solvent A containing 5% solvent B for 5 minutes and increasing to 95% solvent B from 5 to 20 minutes; Flow rate of 1 ml / min. Retention time: 16.53 minutes. Solvent A: H ₂ O / 0.01% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -(Methanesulfonyl) -2 '-(4-methoxyphenyl) -4-methylvalerohydrazide was prepared as follows:

In a manner similar to that described in Example 2, parts (iii)-(v), (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3 (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy starting with -butenyl] -4-methyl valeric acid and 4-methoxyphenylhydrazide ) Carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-(4-methoxyphenyl) -4-methylvalerohydrazide in the form of a white solid It was.

Example 9

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2 -Methylphenyl) valerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.37 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.192 g of (E) -2 (R) starting with 4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2-methylphenyl) valerohydrazide )-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2-methylphenyl) valerohydra Zide was obtained in the form of a cream solid.

MS: 488 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.37 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -(Methanesulfonyl) -4-methyl-2 '-(2-methylphenyl) valerohydrazide was prepared as follows:

(i) 0.7 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl in a similar manner as described in Example 1, part (i) 0.5 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4, starting with -3-butenyl] -4-methylvaleric acid and o-tolylhydrazine -Phenyl-3-butenyl] -4-methyl-2 '-(2-methylphenyl) valerohydrazide was obtained in the form of a cream solid.

MS: 451 (M + H) ⁺ .

(ii) (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methyl-2'- in 5 ml dichloromethane A solution of 0.15 g of (2-methylphenyl) valerohydrazide was treated with 0.09 g pyridine and 0.1 g methanesulfonic anhydride. After stirring for 1.5 hours, 0.05 g pyridine and 0.06 g methanesulfonic anhydride were further added and the mixture was further stirred for 2 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and 5% citric acid solution. The ethyl acetate solution was washed with water, 5% aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (6: 1) for elution. 0.16 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl -2 '-(2-methylphenyl) valerohydrazide was obtained in the form of a yellow rubber.

(iii) the hydrazide prepared in the previous paragraph was treated in a manner similar to that described in Example 1, part (iii) followed by a method similar to that described in Example 2, part (v) (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl-4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4- Methyl-2 '-(2-methylphenyl) valerohydrazide was obtained in the form of a cream solid.

MS: 572 (M + H) ⁺ .

Example 10

(E) -2 (R)-[1 (S)-(hydroxycarbonyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(1 Naphthyl) valerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.09 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting with -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(1-naphthyl) valerohydrazide, 0.053 g of (E) -2 ( R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(1-naphthyl) valero Hydrazide was obtained in the form of a cream solid.

MS: 524 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.83 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -(Methanesulfonyl) -4-methyl-2 '-(1-naphthyl) valerohydrazide was prepared as follows:

In a method analogous to that described in Example 9, parts (i) to (iii), (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3 (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl starting with -butenyl] -4-methylvaleric acid and 1-naphthylhydrazine ] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(1-naphthyl) valerohydrazide was obtained in the form of a cream solid.

MS: 608 (M + H) ⁺ .

Example 11

(E) -2 '-(3-hydroxybenzyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl ) -4-Methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.375 g of (E) -2 ′-(3-hydroxybenzyl) -2 (R)-[1 (S)-[(tetrahydro-2 0.29 g of (E) -2, starting with (RS) -pyranyloxy) carbonyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide '-(3-hydroxybenzyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl) -4-methyl Valerohydrazide was obtained in the form of a white solid.

MS: 503 (M + H) ⁺ .

nmr (d ₆ DMSO, 353 K): 10.23 (1H, broad singlet); 10.09 (1 H, s); 8.98 (1 H, s); 8.41 (1 H, broad singlet); 7.30 (4H, m); 7.18 (1 H, m); 7.09 (1 H, m); 6.83-6.73 (2H, m); 6.67 (1 H, m); 6.24 (1H, doublet, J = 15.5 Hz); 6.05-5.94 (1 H, m); 4.56-4.48 (2H, m); 3.14 (3H, s); 2.55-2.45 (1 H, m); 2.33-2.18 (2H, m); 2.16-2.02 (1 H, m); 1.50-1.40 (1 H, m); 1.38-1.21 (1 H, m); 1.05-0.95 (1 H, m); 0.75 (3H, doublet, J = 7 Hz); 0.71 (3H, doublet, J = 7 Hz).

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.95 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 '-(3-hydroxybenzyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbonyl] -4 used as starting material -Phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:

In a method analogous to that described in Example 9, parts (i) to (iii), (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3 (E) -2 '-(3-hydroxybenzyl) -2 (R)-[1 (S)-[(tetrahydro) starting with -butenyl] -4-methylvaleric acid and 3-hydroxybenzylhydrazine -2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 588 (M + H) ⁺ .

Example 12

(E) -2 '-(2,4-difluorophenyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-( Methanesulfonyl) -4-methylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.13 g of (E) -2 '-(2,4-difluorophenyl) -2 (R)-[1 (S)-[(tetra Hydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide starting with 0.083 g of (E ) -2 '-(2,4-difluorophenyl) -2 (R)-[1 (S)-(hydroxycarbonyl) -4-phenyl-3-butenyl] -2'-(methanesulphate) Ponyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 510 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.37 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 '-(2,4-difluorophenyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl used as starting material ] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:

In a manner similar to that described in Example 2, parts (iii)-(v), (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3 (E) -2 '-(2,4-difluorophenyl) -2 (R)-[1 (S) starting with -butenyl] -4-methylvaleric acid and 2,4-difluorophenylhydrazine )-[(Tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide as a white solid Obtained in form.

Example 13

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(4 -Nitrophenyl) valerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.1 g of (E) -2 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3 -Butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(4-nitrophenyl) valerohydrazide starting with 0.06 g of (E) -2 (R)-[1 ( S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(4-nitrophenyl) valerohydrazide yellow solid Obtained in form.

MS: 519 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.54 minutes. Solvent A: H ₂ O; Solvent B: CH ₃ CN. Column type: HYPERPEP 300A.

(E) -2 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) used as starting material 4-Methyl-2 '-(4-nitrophenyl) valerohydrazide was prepared as follows:

In a manner similar to that described in Example 2, parts (iii)-(v), (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3 (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl starting with -butenyl] -4-methylvaleric acid and 4-nitrophenylhydrazine ] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(4-nitrophenyl) valerohydrazide was obtained in the form of a yellow solid.

Example 14

(E) -2'-acetyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2 '-(2-pyridyl) Valerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.1 g of (E) -2′-acetyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyl Starting with oxy) carbamoyl] -4-phenyl-3-butenyl] -4-methyl-2 '-(2-pyridyl) valerohydrazide, the ethyl acetate solution of the product was dissolved in 2% aqueous sodium hydrogen carbonate solution. After washing to obtain the free base, 0.035 g of (E) -2'-acetyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4 -Methyl-2 '-(2-pyridyl) valerohydrazide was obtained in the form of a cream solid.

MS: 439 (M + H) ⁺ .

HPLC: gradient elution using solvent A containing 5% solvent B for 5 minutes and increasing to 95% solvent B from 5 to 20 minutes; Flow rate of 1 ml / min. Retention time: 15.67 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2'-acetyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-part used as starting material Tenyl] -4-methyl-2 '-(2-pyridyl) valerohydrazide was prepared as follows:

In a manner similar to that described in Example 4, parts (i) and (ii), (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3 (E) -2'-acetyl-2 (R)-[1 (S)-[(tetrahydro) starting from -butenyl] -4-methyl-2 '-(2-pyridyl) valerohydrazide -2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methyl-2 '-(2-pyridyl) valerohydrazide was obtained in the form of a white solid.

Example 15

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2', 4-dimethylvalerohi Dragged

In a similar manner as described in the first paragraph of Example 2, 0.122 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.033 g of (E) -2 (R)-[1 (S), starting with -4-phenyl-3-butenyl] -2- (methanesulfonyl) -2 ', 4-dimethylvalerohydrazide -(Hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2', 4-dimethylvalerohydrazide was obtained in the form of a gray solid.

MS: 412 (M + H) ⁺ .

nmr (d ₆ DMSO): 10.56 (1H, s); 10.46 (1 H, s); 8.75 (1 H, s); 7.35-7.25 (4H, m); 7.23-7.15 (1H, m); 6.31 (1H, doublet, J = 15.5 Hz); 6.10-6.00 (1 H, m); 3.06 (3H, s); 3.04 (3H, s); 2.55-2.45 (1 H, m); 2.37 (3H, m); 1.54-1.36 (2H, m); 1.02-0.93 (1 H, m); 0.84 (3H, doublet, J = 7 Hz); 0.81 (3H, doublet, J = 7.5 Hz).

HPLC: gradient elution using solvent A containing 10% solvent B for 5 minutes and increasing to 90% solvent B from 5 to 20 minutes; Flow rate of 1 ml / min. Retention time: 14.72 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2- used as starting material (Methanesulfonyl) -2 ', 4-dimethylvalerohydrazide was prepared as follows:

(i) A mixture of 11 g of pentafluorophenol and 4.12 g of 1,3-dicyclohexylcarbodiimide in 50 ml hexane was stirred at room temperature for 5 minutes. The resulting solid was filtered off, washed with hexanes, dried and (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl- in 50 ml dimethoxyethane. To a solution of 5.0 g of 3-butenyl] -4-methylvaleric acid. The mixture was left at 4 ° C. overnight and then filtered to remove dicyclohexylurea. The filtrate was evaporated and the residue was dissolved in 50 ml of dichloromethane and 3 ml of hydrazine hydrate was added to the obtained solution. The mixture was stirred for 6 hours, then washed successively with 5% citric acid solution, saturated sodium bicarbonate solution, water and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with hexane / ethyl acetate (4: 1) and the resulting solid was filtered. 4.68 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide as a gray solid Obtained in form.

MS: 361 (M + H) ⁺ .

(ii) 8.96 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl), in a manner analogous to that described in Example 9, parts (ii) and (iii) 2.83 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS)-, starting with -4-phenyl-3-butenyl] -4-methylvalerohydrazide Pyranyloxy)] carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 482 (M + H) ⁺ .

(iii) A solution of 0.34 g of hydrazide prepared in part (ii) in 7 ml dimethylformamide was treated with 0.126 g of methyl iodide and 0.293 g of anhydrous potassium carbonate. The mixture was stirred at rt for 3 h and the volatiles were removed by evaporation. The residue was partitioned between ethyl acetate and 5% citric acid solution. The ethyl acetate phase was washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (4: 1) followed by hexane / ethyl acetate (2: 1) for elution. 0.122 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl-4-phenyl-3-butenyl] -2 '-(methane Sulfonyl) -2 ', 4-dimethylvalerohydrazide was obtained in the form of a white solid.

Example 16

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.151 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting with -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide, 0.06 g of (E) -2 (R)-[1 (S)-( Hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a gray solid.

MS: 398 (M + H) ⁺ .

nmr (d ₆ DMSO): 10.55 (1H, s); 10.34 (1 H, s); 9.52 (1 H, s); 8.85 (1 H, s); 7.36-7.25 (4H, m); 7.23-7. 16 (1 H, m); 6.30 (1H, doublet, J = 15.5 Hz); 6.08-5.98 (1 H, m); 2.96 (3H, s); 2.56-2.46 (1 H, m); 2.39-2.13 (3H, m); 1.53-1.33 (2H, m); 1.01-0.93 (1 H, m); 0.83 (3H, doublet, J = 6.5 Hz); 0.80 (3H, d, J = 7 Hz).

HPLC: gradient elution with solvent A containing 10% solvent B for 5 minutes, increasing to 90% solvent B from 5 to 20 minutes; Flow rate of 1 ml / min. Retention time: 14.13 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Example 17

(E) -2'-benzyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalle Lohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.183 g of (E) -2′-benzyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyl Oxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide starting with 0.142 g of (E) -2'-benzyl-2 ( R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide in the form of a gray solid .

MS: 488 (M + H) ⁺ .

nmr (d ₆ DMSO, 353 K): 10.22 (1H, broad singlet); 10.1 (1 H, s); 8.40 (1 H, broad singlet); 7.40-7.24 (9H, m); 7.22-7.15 (1 H, m); 6.23 (1H, doublet, J = 15 Hz); 6.05-5.94 (1 H, m); 4.63 (2H, m); 3.15 (3H, s); 2.54-2.44 (1 H, m); 2.31-2.17 (2H, m); 2.14-2.01 (1 H, m); 1.51-1.49 (1H, m); 1.34-1.18 (1 H, m); 1.04-0.95 (1 H, m); 0.74 (3H, d, J = 6.5 Hz); 0.70 (3H, doublet, J = 7.0 Hz).

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.18 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2'-benzyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-part used as starting material Tenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide is prepared in a similar manner as described in Example 15, part (iii), wherein (E) -2 (R)-[1 (S Starting from)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide Prepared by reaction with benzyl bromide.

Example 18

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-(4-methoxybenzyl ) -4-Methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.105 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.061 g of (E) -2 starting with -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-(4-methoxybenzyl) -4-methylvalerohydrazide (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-(4-methoxybenzyl) -4-methyl Valerohydrazide was obtained in the form of a white solid.

MS: 518 (M + H) ⁺ .

HPLC: gradient elution with solvent A containing 35% solvent B for 5 minutes and increasing to 85% solvent B from 5 to 20 minutes; Flow rate of 1 ml / min. Retention time: 7.20 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -(Methanesulfonyl) -2 '-(4-methoxybenzyl) -4-methylvalerohydrazide is prepared in a manner similar to that described in Example 15, part (iii), wherein (E) -2 (R )-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methylsulfonyl) -4-methylvalero Prepared by reaction with 4-methoxybenzyl bromide starting from hydrazide.

Example 19

(E) -2'-allyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalle Lohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.168 g of (E) -2'-allyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyl Oxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide starting with 0.013 g of (E) -2'-allyl-2 ( R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid .

MS: 438 (M + H) ⁺ .

nmr (d ₆ DMSO, 353 K): 10.26 (1H, broad singlet); 10.08 (1 H, s); 8.44 (1 H, broad singlet); 7.35-7.25 (4H, m); 7.22-7.15 (1 H, m); 6.33 (1H, doublet, J = 15.5 Hz); 6.13-6.03 (1 H, m); 5.90-5.78 (1 H, m); 5.28 (1 H, m); 5.18 (1 H, m); 4.05 (1 H, m); 3.06 (3H, s); 2.63-2.53 (1 H, m); 2.44-2.25 (3H, m); 1.59-1.45 (2H, m); 1.14-1.03 (1 H, m); 0.85 (3H, doublet, J = 7 Hz); 0.82 (3H, doublet, J = 6.5 Hz).

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.36 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2'-allyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-part used as starting material Tenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide is prepared in a manner similar to that described in Example 15, part (iii), wherein (E) -2 (R)-[1 (S Starting from)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide Prepared by reaction with allyl bromide.

Example 20

(E) -2 '-(4-bromobenzyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl ) -4-Methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.215 g of (E) -2 '-(4-bromobenzyl) -2 (R)-[1 (S)-[(tetrahydro-2 0.147 g of (E) -2, starting with (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide '-(4-bromobenzyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl) -4-methyl Valerohydrazide was obtained in the form of a white solid.

MS: 566/568 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.90 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 '-(4-bromobenzyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4 used as starting material -Phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide is prepared in a similar manner as described in Example 15, part (iii), wherein (E) -2 (R )-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbonyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalero Prepared by reaction with 4-bromobenzyl bromide starting from hydrazide.

Example 21

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(4 Nitrobenzyl) valerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.159 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.085 g of (E) -2 (starting with -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(4-nitrobenzyl) valerohydrazide R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(4-nitrobenzyl) valero Hydrazide was obtained in the form of a white solid.

MS: 533 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.14 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -(Methanesulfonyl) -4-methyl-2 '-(4-nitrobenzyl) valerohydrazide is prepared in a similar manner as described in Example 15, part (iii), wherein (E) -2 (R) -[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohi Prepared by reaction with 4-nitrobenzyl bromide starting from drazide.

Example 22

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-propargyl Valerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.13 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.04 g of (E) -2 (R)-[starting with -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-propargylvalerohydrazide 1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-propargylvalerohydrazide in the form of a white solid Obtained.

MS: 436 (M + H) ⁺ .

nmr (d ₆ DMSO): 10.57 (1H, s); 10.54 (1 H, s); 8.84 (1 H, broad singlet); 7.35-7.25 (4H, m); 7.22-7. 16 (1 H, m); 6.30 (1H, doublet, J = 15.5 Hz); 6.09-5.99 (1 H, m); 4.32-4.17 (2H, m); 3.44 (1 H, s); 3.11 (3H, s); 2.63-2.54 (1 H, m); 2.41-2.17 (3H, m); 1.56-1.41 (2H, m); 1.03-1.93 (1 H, m); 0.85 (3H, doublet, J = 7.0 Hz); 0.81 (3H, doublet, J = 6.5 Hz).

HPLC: gradient elution from solvent A containing 40% solvent B to 60% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.04 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -(Methanesulfonyl) -4-methyl-2'-propargylvalerohydrazide is prepared in a similar manner as described in Example 15, part (iii), wherein (E) -2 (R)-[1 ( S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide starting from By reaction with propargyl bromide.

Example 23

(E) -2 '-(cyanomethyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl)- 4-methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.18 g of (E) -2 ′-(cyanomethyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) 0.124 g of (E) -2'- starting with) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide (Cyanomethyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydra Zide was obtained in the form of a white solid.

MS: 437 (M + H) ⁺ .

nmr (d ₆ DMSO): 10.94 (1H, s); 10.56 (1 H, s); 8.56 (1 H, broad singlet); 7.37-7.25 (4H, m); 7.23-7.15 (1H, m); 6.33 (1H, doublet, J = 15.5 Hz); 6.10-5.99 (1 H, m); 4.65 (2H, m); 3.17 (3H, s); 2.61-2.52 (1 H, m); 2.40-2.19 (3H, m); 1.55-1.41 (2H, m); 1.06-0.95 (1 H, m); 0.85 (3H, doublet, J = 7 Hz); 0.82 (3H, doublet, J = 6.5 Hz).

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.90 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 '-(cyanomethyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl used as starting material -3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide is prepared in a manner similar to that described in Example 15, part (iii), wherein (E) -2 (R)- [1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydra Prepared by reaction with bromoacetonitrile starting from zide.

Example 24

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2 -Phenylethyl) valerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.158 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting with -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2-phenylethyl) valerohydrazide, 0.093 g of (E) -2 ( R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2-phenylethyl) valero Hydrazide was obtained in the form of a white solid.

MS: 502 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.90 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -(Methanesulfonyl) -4-methyl-2 '-(2-phenylethyl) valerohydrazide is prepared in a similar manner as described in Example 15, part (iii), wherein (E) -2 (R) -[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohi Prepared by reaction with 2-bromoethyl-benzene starting from drazide.

Example 25

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(phthal Imidomethyl) valerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.187 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.127 g of (E) -2 (R) starting with 4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(phthalimidomethyl) valerohydrazide )-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(phthalimidomethyl) valerohydra Zide was obtained in the form of a white solid.

MS: 557 (M + H) ⁺ .

nmr (d ₆ DMSO, 353 K): 10.18 (1H, broad singlet); 10.13 (1 H, s); 8.40 (1 H, broad singlet); 7.92-7.82 (4H, m); 7.32-7.25 (4H, m); 7.22-7.15 (1 H, m); 6.30 (1H, doublet, J = 15.5 Hz); 6.06-5.96 (1 H, m); 5.30 (2H, s); 3.16 (3H, s); 2.56-2.43 (1 H, m); 2.40-2.21 (3H, m); 1.60-1.40 (2H, m); 1.10-0.99 (1 H, m); 0.80 (3H, d, J = 6.5 Hz); 0.77 (3H, doublet, J = 7.0 Hz).

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.03 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -(Methanesulfonyl) -4-methyl-2 '-(phthalimidomethyl) valerohydrazide is prepared in a similar manner as described in Example 15, part (iii), wherein (E) -2 (R)- [1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydra Prepared by reaction with N-bromomethylphthalimide starting from zide.

Example 26

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2 Phthalimidoethyl) valerohydrazide

In a manner analogous to that described in the first paragraph of Example 2, 0.134 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.108 g of (E) -2 (R) starting with 4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(phthalimidoethyl) valerohydrazide )-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(phthalimidoethyl) valerohydra Zide was obtained in the form of a white solid.

MS: 571 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.56 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -(Methanesulfonyl) -4-methyl-2 '-(phthalimidoethyl) valerohydrazide is prepared in a manner similar to that described in Example 15, part (iii), wherein (E) -2 (R)- [1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydra Prepared by reaction with 2-bromoethylphthalimide starting from zide.

Example 27

(E) -3-cyclobutyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-phenyl Propionohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.159 g of (E) -3-cyclobutyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyl Oxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-phenylpropionohydrazide starting with 0.103 g of (E) -3-cyclobutyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-phenylpropionohydrazide in the form of a gray solid Obtained.

MS: 486 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.12 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -3-cyclobutyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-part used as starting material Tenyl] -2 '-(methanesulfonyl) -2'-phenylpropionohydrazide was prepared as follows:

(E) -3-cyclobutyl starting from 4-tert-butyl hydrogen 2 (R)-(cyclobutylmethyl) succinate in a similar manner as described in Example 2, parts (i)-(v) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2 '-Phenylpropionohydrazide was obtained in the form of a white solid.

MS: 570 (M + H) ⁺ .

Example 28

(E) -3-cyclopentyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-phenyl Propionohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.2 g of (E) -3-cyclopentyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyl Oxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-phenylpropionohydrazide starting with 0.132 g of (E) -3 -cyclopentyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-phenylpropionohydrazide in the form of a white solid Obtained.

MS: 500 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.39 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -3-cyclopentyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-part used as starting material Tenyl] -2 '-(methanesulfonyl) -2'-phenylpropionohydrazide was prepared as follows:

In a method analogous to that described in Example 2, parts (i)-(v), starting from 4-tert-butyl hydrogen 2 (R)-(cyclopentylmethyl) succinate (E) -3-cyclopentyl -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2 '-Phenylpropionohydrazide was obtained in the form of a white solid.

MS: 584 (M + H) ⁺ .

Example 29

(E) -2 '-(4-bromophenyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl ) -4-Methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.35 g of (E) -2 ′-(4-bromophenyl) -2 (R)-[1 (S)-[(tetrahydro-2 0.272 g of (E) -2, starting with (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide '-(4-bromophenyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl) -4-methyl Valerohydrazide was obtained in the form of a gray solid.

MS: 552 (M + H) ⁺ .

nmr (d ₆ DMSO): 10.85 (1H, s); 10.31 (1H, broad singlet); 8.48 (1 H, broad singlet); 7.58 (2H, m); 7.32 (2H, m); 7.29 (4H, m); 7.23-7. 16 (1 H, m); 6.23 (1H, doublet, J = 15.5 Hz); 6.07-5.97 (1 H, m); 3.23 (3H, s); 2.60-2.50 (1 H, m); 2.41-2.12 (3H, m); 1.57-1.48 (1 H, m); 1.47-1.35 (1 H, m); 1.16-1.06 (1 H, m); 0.85 (3H, doublet, J = 6.5 Hz); 0.78 (3H, doublet, J = 7.0 Hz).

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.41 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 '-(4-bromophenyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4 used as starting material -Phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:

In a manner similar to that described in Example 2, parts (iii)-(v), (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3 (E) -2 '-(4-bromophenyl) -2 (R)-[1 (S)-[(tetrahydro) starting with -butenyl] -4-methylvaleric acid and 4-bromophenylhydrazine -2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 636/638 (M + H) ⁺ .

Example 30

(E) -2 '-(tert-butyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl) -4-methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.35 g of (E) -2 '-(tert-butyl) -2 (R)-[1 (S)-[(tetrahydro-2 ( RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide starting from 0.272 g of (E) -2' -(Tert-butyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalero Hydrazide was obtained in the form of a gray solid.

MS: 454 (M + H) ⁺ .

HPLC: gradient elution with solvent A containing 10% solvent B for 5 minutes, increasing to 90% solvent B from 5 to 20 minutes; Flow rate of 1 ml / min. Retention time: 16.56 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 '-(tert-butyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- used as starting material Phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:

In a manner similar to that described in Example 2, parts (iii)-(v), (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3 (E) -2 '-(tert-butyl) -2 (R)-[1 (S)-[(tetrahydro-2) starting with -butenyl] -4-methylvaleric acid and tert-butylhydrazine (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 537 (M + H) ⁺ .

Example 31

(E) -2 '-(cyclohexylmethyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl)- 4-methylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.149 g of (E) -2 ′-(cyclohexylmethyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) 0.116 g of (E) -2'- starting with) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide (Cyclohexylmethyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydra Zide was obtained in the form of a white solid.

MS: 494 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B for 15 minutes; Flow rate of 1 ml / min. Retention time: 13.67 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 '-(cyclohexylmethyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl used as starting material -3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide is prepared in a manner similar to that described in Example 15, part (iii), wherein (E) -2 (R)- [1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydra Prepared by reaction with cyclohexylmethyl bromide starting from zide.

Example 32

2 (R)-[1 (R)-(hydroxycarbamoyl) -2-phthalimidoethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.14 g of 2 (R)-[1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2-phthal Starting with imidoethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide, 0.092 g of 2 (R)-[1 (R)-(hydroxycarbamoyl)- 2-phthalimidoethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid.

MS: 517 (M + H) ⁺ .

HPLC: gradient elution using solvent A containing 10% solvent B for 5 minutes and increasing to 90% solvent B from 5 to 20 minutes; Flow rate of 1 ml / min. Retention time: 15.52 minutes. Solvent A: H ₂ O; Solvent B: CH ₃ CN. Column type: HYPERPEP 300A.

2 (R)-[1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2-phthalimidoethyl] -2 '-(methanesulfonyl)-used as starting material 4-Methyl-2'-phenylvalerohydrazide was prepared as follows:

In a manner similar to that described in Example 2, parts (iii) to (v), 2 (R)-[1 (R)-(tert-butoxycarbonyl) -2-phthalimidoethyl] -4- 2 (R)-[1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2-phthalimidoethyl] -2 '-(methane starting with methyl valeric acid and phenylhydrazine Sulfonyl) -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid.

MS: 601 (M + H) ⁺ .

Example 33

2 (R)-[2-benzamido-1 (R)-(hydroxycarbamoyl) ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.084 g of 2 (R)-[2-benzamido-1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carba Moyl] ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide starting with 0.055 g of 2 (R)-[2-benzamido-1 (R)- (Hydroxycarbamoyl) ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid.

MS: 491 (M + H) ⁺ .

HPLC: gradient elution with solvent A containing 5% solvent B for 5 minutes and increasing to 95% solvent B from 5 to 20 minutes; Flow rate of 1 ml / min. Retention time: 15.54 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

2 (R)-[2-benzamido-1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] ethyl] -2 '-(methanesulfonyl) used as starting material 4-Methyl-2'-phenylvalerohydrazide was prepared as follows:

(i) 2 (R)-[1 (R)-(tert-butoxycarbonyl) -2-phthalimidoethyl] -2 '-(methanesulfonyl) -4-methyl-2' in 15 mL methanol A solution of 0.705 g of -phenylvalerohydrazide was treated with 0.51 mL of hydrazine hydrate. The mixture was stirred overnight under nitrogen and then evaporated. The residue was stirred with 25 mL of dichloromethane / methanol / acetic acid / water (120: 15: 3: 2). After 2 hours, the precipitated solids were removed by filtration and the filtrate was evaporated. The residue was purified by chromatography on Kisselgel 60 using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) for elution. Fractions containing the amine product were combined and evaporated, then the residue was dissolved in 30 ml of dichloromethane and washed with three portions of 10 ml of saturated sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate, the solution was evaporated to 0.42 g of 2 (R)-[2-amino-1 (R)-(tert-butoxycarbonyl) ethyl] -2 '-(methanesulfonyl) 4-Methyl-2'-phenylvalerohydrazide was obtained in the form of a pale yellow foam.

MS: 428 (M + H) ⁺ .

(ii) A mixture of 0.42 g of amine prepared in part (i) and 0.138 g of benzoic acid in 7 ml dimethylformamide was cooled to 0 ° C. with stirring, and 0.335 g of 1-ethyl-3- (3-dimethylaminopropyl Carbodiimide was added. The mixture was allowed to warm to rt and stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The ethyl acetate layer was washed successively with saturated sodium bicarbonate solution, 5% citric acid solution, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. Ethyl acetate was evaporated and the residue was triturated with a mixture of ether and hexane to yield 0.331 g of 2 (R)-[2-benzamido-1 (R)-(tert-butoxycarbonyl) ethyl] -2 '. -(Methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a gray solid.

MS: 532 (M + H) ⁺ .

(iii) 2 (R)-[2-benzamido-1 (R)-(tert-butoxycarbonyl) ethyl, in a manner analogous to that described in Example 2, parts (iii)-(v) ] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide starting with 2 (R)-[2-benzamido-1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid.

MS: 575 (M + H) ⁺ .

Example 34

2 (R)-[2-[(5-bromo-2-furyl) carboxamido] -1 (R)-(hydroxycarbamoyl) ethyl] -2 '-(methanesulfonyl) -4- Methyl-2'-phenylvalerohydrazide

In a manner analogous to that described in the first paragraph of Example 2, 0.195 g of 2 (R)-[2-[(5-bromo-2-furyl) carboxamido] -1 (R)-[( 0.127 g of 2 (R) starting with tetrahydro-2 (RS) -pyranyloxy) carbamoyl] ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide -[2-[(5-bromo-2-furyl) carboxamido] -1 (R)-(hydroxycarbamoyl) ethyl] -2 '-(methanesulfonyl) -4-methyl-2' -Phenylvalerohydrazide was obtained in the form of a cream solid.

MS: 560 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.69 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

2 (R)-[2-[(5-bromo-2-furyl) carboxamido] -1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carba used as starting material Moyl] ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was prepared as follows:

In a manner similar to that described in Example 33, parts (ii) and (iii), 2 (R)-[2-amino-1 (R)-(tert-butoxycarbonyl) ethyl] -2'- Starting with (methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide and 5-bromo-2-furoic acid, 2 (R)-[2-[(5-bromo-2- Furyl) carboxamido] -1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenyl Valerohydrazide was obtained in the form of a gray solid.

MS: 644 (M + H) ⁺ .

Example 35

2 (R)-[1 (R)-(hydroxycarbamoyl) -2-[(2-thiazolyl) carboxamido] ethyl] -2 '-(methanesulfonyl) -4-methyl-2' -Phenylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.1 g of 2 (R)-[1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2- [ Starting with (2-thiazolyl) carboxamido] ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide, 0.041 g of 2 (R)-[1 ( R)-(hydroxycarbamoyl) -2-[(2-thiazolyl) carboxamido] ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide Obtained in the form of a gray solid.

MS: 498 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.14 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

2 (R)-[1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2-[(2-thiazolyl) carboxamido] ethyl used as starting material -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was prepared as follows:

In a manner similar to that described in Example 33, parts (ii) and (iii), 2 (R)-[2-amino-1 (R)-(tert-butoxycarbonyl) ethyl] -2'- Starting with (methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide and 2-thiazolecarboxylic acid, 2 (R)-[1 (R)-[(tetrahydro-2 (RS)- Pyranyloxy) carbamoyl] -2-[(2-thiazolyl) carboxamido] ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide as a white solid Obtained in the form of.

MS: 582 (M + H) ⁺ .

Example 36

2 (R)-[1 (R)-(hydroxycarbamoyl) -2-[(2-thienyl) carboxamido] ethyl] -2 '-(methanesulfonyl) -4-methyl-2' -Phenylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.2 g of 2 (R)-[1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2- [ Starting with (2-thienyl) carboxamido] ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide, 0.115 g of 2 (R)-[1 ( R)-(hydroxycarbamoyl) -2-[(2-thienyl) carboxamido] ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide Obtained in the form of a white solid.

MS: 497 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.39 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

2 (R)-[1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2-[(2-thienyl) carboxamido] ethyl used as starting material -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was prepared as follows:

In a manner similar to that described in Example 33, parts (ii) and (iii), 2 (R)-[2-amino-1 (R)-(tert-butoxycarbonyl) ethyl] -2'- Starting with (methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide and thiophene-2-carboxylic acid, 2 (R)-[1 (R)-[(tetrahydro-2 (RS) -Pyranyloxy) carbamoyl] -2-[(2-thienyl) carboxamido] ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide white Obtained in the form of a solid.

MS: 581 (M + H) ⁺ .

Example 37

2 (R)-[1 (R)-(hydroxycarbamoyl) -2- (3-phenylureido) ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohi Dragged

In a similar manner as described in the first paragraph of Example 2, 0.157 g of 2 (R)-[1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2- ( Starting with 3-phenylureido) ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide, 0.072 g of 2 (R)-[1 (R)-(hydr Roxycarbamoyl) -2- (3-phenylureido) ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid.

MS: 507 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.91 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

2 (R)-[1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2- (3-phenylureido) ethyl] -2 '-(used as starting material Methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was prepared as follows:

(i) 2 (R)-[2-amino-1 (R)-(tert-butoxycarbonyl) ethyl, prepared as described in Example 33, part (i) in 10 ml dimethylformamide ] Mixture of 0.8 g of] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide, 0.325 ml of N, N-diisopropylethylamine and 0.21 ml of phenyl isocyanate under nitrogen for 2.5 hours. Stirred at 60 ° C. The solvent was evaporated and the residue was partitioned between ethyl acetate and 1M hydrochloric acid. The ethyl acetate solution was separated and washed with sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with diethyl ether to give 0.705 g of 2 (R)-[1 (R)-(tert-butoxycarbonyl) -2- (3-phenylureido) ethyl] -2 '-(methanesulphur). Ponyl) -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid.

MS: 547 (M + H) ⁺ .

(ii) 2 (R)-[1 (R)-(tetrahydro-, starting from hydrazide prepared in the preceding paragraph, in a manner similar to that described in Example 2, parts (iii)-(v) 2 (RS) -pyranyloxy) carbamoyl] -2- (3-phenylureido) ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide as a white solid Obtained in the form of.

MS: 590 (M + H) ⁺ .

Example 38

2 (R)-[1 (R)-(hydroxycarbamoyl) -2-[(2-thienyl) sulfonamido] ethyl] -2 '-(methanesulfonyl) -4-methyl-2'- Phenylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.28 g of 2 (R)-[1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2- [ Starting with (2-thienyl) sulfonamido] ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide, 0.066 g of 2 (R)-[1 (R )-(Hydroxycarbamoyl) -2-[(2-thienyl) sulfonamido] ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide as a white solid Obtained in form.

MS: 533 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.65 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

2 (R)-[1 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2-[(2-thienyl) sulfonamido] ethyl used as starting material 2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was prepared as follows:

(i) 2 (R)-[2-amino-1 (R)-(tert-butoxycarbonyl) ethyl] -2 '-(methanesulfonyl) -4-methyl-2 in 20 ml dichloromethane A solution of 0.504 g of '-phenylvalerohydrazide was cooled to 0 ° C. with stirring and 0.242 g of 2-thiophenesulfonyl chloride was added. The mixture was allowed to warm to rt and stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and 5% citric acid aqueous solution. The ethyl acetate layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with ether to afford 0.487 g of 2 (R)-[1 (R)-(tert-butoxycarbonyl) -2-[(2-thienyl) sulfonamido] ethyl] -2 '-( Methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid.

MS: 574 (M + H) ⁺ .

(ii) 2 (R)-[1 (R)-(tetrahydro-, starting from hydrazide prepared in the preceding paragraph, in a manner similar to that described in Example 2, parts (iii)-(v) 2 (RS) -pyranyloxy) carbamoyl] -2-[(2-thienyl) sulfonamido] ethyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydra Zide was obtained in the form of a white solid.

MS: 581 (M + H) ⁺ .

Example 39

(E) -2 '-(benzylsulfonyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalle Lohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.1 g of (E) -2 ′-(benzylsulfonyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) 0.051 g of (E) -2 '-(benzylsulfonyl) starting with) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide ) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid. .

MS: 550 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.62 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 '-(benzylsulfonyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl as starting material 3-Butenyl] -4-methyl-2'-phenylvalerohydrazide was prepared as follows:

(i) 0.3 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl in a similar manner as described in Example 1, part (ii) 0.316 g of (E) -2 '-(benzylsulfonyl) -2 (R)-starting from 3-butenyl-4-methyl-2'-phenylhydrazide and 0.543 g of benzylsulfonyl chloride [1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylhydrazide was obtained in the form of a white solid.

MS: 591 (M + H) ⁺ .

(ii) (E) -2- (benzylsulfonyl) -2 from the hydrazide prepared in the preceding paragraph, in a manner similar to that described in Example 1, Part (iii) and Example 2, Part (v) (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbonyl] -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydra Zide was obtained in the form of a white solid.

MS: 634 (M + H) ⁺ .

Example 40

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -3-methyl-2'-phenylbutyl Hydrazide

In a similar manner as described in the first paragraph of Example 2, 0.098 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting with -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -3-methyl-2'-phenylbutylhydrazide, 0.054 g of (E) -2 (R)-[1 ( S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -3-methyl-2'-phenylbutylhydrazide was obtained in the form of a gray solid.

MS: 460 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.72 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -(Methanesulfonyl) -3-methyl-2'-phenylbutylhydrazide was prepared as follows:

In a manner similar to that described in Example 2, parts (i)-(v), starting from 4-tert-butyl hydrogen 2 (R) -isopropylsuccinate, (E) -2 (R)-[ 1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -3-methyl-2'-phenyl Butylhydrazide was obtained in the form of a white solid.

MS: 544 (M + H) ⁺ .

Example 41

(E) -2'-acetyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.23 g of (E) -2'-acetyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyl Starting with oxy) carbamoyl] -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide, 0.09 g of (E) -2'-acetyl-2 (R)-[ 1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid.

MS: 438 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.29 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2'-acetyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-part used as starting material Tenyl] -4-methyl-2'-phenylvalerohydrazide is prepared in a similar manner as described in Example 4, parts (i) and (ii), as described in Example 2, part (i). Prepared from the prepared (E) -2 (R)-[1 (R)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid.

Example 42

(E) -2 '-(ethylcarbamoyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalle Lohydrazide

(E) -2 '-(ethylcarbamoyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carba in a mixture of 2 mL dichloromethane and 0.5 mL methanol Moyl] -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide was treated with 9 ml of methanesulfonic acid. The mixture was stirred at rt for 2 h and the solvent was evaporated. The residue was triturated with 5% sodium hydrogen carbonate solution and dissolved in diethyl ether. The solution was dried over magnesium sulfate and evaporated to give a rubber. Chromatography on silica gel using dichloromethane / methanol (19: 1) for elution gave 0.02 g of (E) -2 '-(ethylcarbamoyl) -2 (R)-[1 (S)-(hydroxycarba). Moyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide as a white solid.

MS: 467 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 40% solvent B to 60% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.80 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 '-(ethylcarbamoyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl used as starting material 3-Butenyl] -4-methyl-2'-phenylvalerohydrazide was prepared as follows:

(i) (E) -2 (R)-[1 (S) -tert-butoxycarbonyl-, prepared as described in Example 2, part (iii) in 8 ml of anhydrous dichloromethane 0.8 g of 4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide was heated with 0.88 mL of ethyl isocyanate at 0 ° C. under nitrogen, and the mixture was stirred at room temperature overnight and then evaporated. To obtain a rubber. Chromatography on silica gel using hexanes / ethyl acetate (2: 1) for elution yielded 0.65 g of (E) -2 ′-(ethylcarbamoyl) -2 (R)-[1 (S)-(tert- Butoxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide was obtained as a white foam.

(ii) 0.64 g of tert-butyl ester prepared according to part (i) was treated with a solution of 50% trifluoroacetic acid in dichloromethane at room temperature for 3 hours and evaporated. Toluene was added twice and evaporated each time. The residue was purified by chromatography on silica gel using dichloromethane / methanol (19: 1) for elution, and 0.36 g of (E) -2 '-(ethylcarbamoyl) -2 (R)-[1 (S)- Carboxy-4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide was obtained as glass.

(iii) 0.35 g of the carboxylic acid prepared according to part (ii) is dissolved in 3 ml of dimethylformamide, cooled to 0 ° C. and 0.26 g of O- (tetrahydro-2H-pyran-2 (RS) -yl ) Hydroxylamine and 0.215 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was stirred at rt overnight then poured into water. The solids were removed by filtration and washed sequentially with 2M hydrochloric acid solution, water, 5% sodium bicarbonate solution and water and dried under vacuum. Chromatography on silica gel using hexanes / ethyl acetate (1: 1) for elution yielded 0.2 g of (E) -2 ′-(ethylcarbamoyl) -2 (R)-[1 (S)-[(tetrahydro -2 (RS) -pyranyloxy) -carbamoyl] -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide was obtained as a white foam.

MS: 551 (M + H) ⁺ .

Example 43

(E) -2 '-(benzylcarbamoyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalle Lohydrazide

0.17 g of (E) -2 '-(benzylcarbamoyl) -2 (R)-[1 (S)-{(O-tert-butyldimethylsilyl) hydroxycarbamoyl} -4-phenyl-3- Butenyl] -4-methyl-2'-phenylvalerohydrazide was stirred in 5 ml of acetic acid / water / tetrahydrofuran (3: 1: 1) at room temperature for 1.5 hours. The solvent was evaporated and the residue was triturated with diethyl ether to give 0.03 g of (E) -2 '-(benzylcarbamoyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl 3-Butenyl] -4-methyl-2'-phenylvalerohydrazide was obtained as a white solid.

TLC: dichloromethane / methanol (3: 1) Rf = 0.43.

MS: 529 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.14 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 '-(benzylcarbamoyl) -2 (R)-[1 (S)-{(O-tert-butyldimethylsilyl) hydroxycarbamoyl} -4-phenyl- used as starting material 3-butenyl] -4-methyl-2'-phenylvalerohydrazide was prepared as follows:

In a manner similar to that described in Examples 42, (i) and (ii), (E) -2 '-(benzylcarbamoyl) -2 (R)-[1 (S) -carboxy-4-phenyl-3 -Butenyl] -4-methyl-2'-phenylvalerohydrazide was prepared.

0.72 g of the carboxylic acid prepared in the previous paragraph was dissolved in 2 ml of dimethylformamide cooled to 0 ° C., 1.0 g of O- (tert-butyldimethylsilyl) hydroxyamine, 0.2 ml of N-ethylmorpholine and 0.3 treated with g 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was stirred at rt overnight and evaporated. The residue was dissolved in dichloromethane and washed sequentially with 5% sodium bicarbonate solution, water, 2M hydrochloric acid, water, 5% sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and then evaporated to a brown semi-solid mass. Obtained. Chromatography on silica gel using dichloromethane / methanol (33: 1) for elution, followed by trituration with ethyl / hexanes to give 0.19 g of (E) -2 '-(benzylcarbamoyl) -2 (R)-[1. (S)-{(O-tert-butyldimethylsilyl) hydroxycarbamoyl} -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide was obtained as a solid.

TLC: dichloromethane / methanol (9:10): Rf = 0.65.

Example 44

(E) -2'-cyclohexyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl Valerohydrazide

0.09 g of (E) -2′-cyclohexyl-2 (R)-[1 (S)-({O-4-methoxybenzyl} hydroxycarbamoyl} -4-phenyl-3-butenyl]- 2 '-(methanesulfonyl) -4-methylvalerohydrazide was dissolved in a mixture of 2.5 ml of dichloromethane, 0.35 ml of trifluoroacetic acid and 0.1 ml of anisole at 0 ° C. The mixture was stirred at room temperature for 6 hours. Stir and hold overnight at 4 ° C. and evaporate 10 ml of toluene was added twice and the mixture was evaporated each time The residue was triturated with diethyl ether to give 0.06 g of (E) -2′-cyclohexyl-. Obtain 2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide as a white solid It was.

MS: 480 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.39 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2'-cyclohexyl-2 (R)-[1 (S)-{{O-4-methoxybenzyl} hydroxycarbamoyl) -4-phenyl-3-butenyl used as starting material ] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:

(i) 10 g of (E) -2 (R)-[(1S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid in 100 ml dichloromethane The solution was treated at 0 ° C. with 0.61 g of 4-dimethylaminopyridine, 6.1 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 2.4 ml of methanol. The mixture was stirred at 0 ° C. for 1 hour, warmed to room temperature, then further stirred for 3 hours and evaporated. The residue in diethyl ether was washed sequentially with 2M hydrochloric acid, water and 5% sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated to give a brown oil. Chromatography on silica gel using hexane / diethyl ether (9: 1) for elution followed by evaporation yielded 6.9 g of diester. It was dissolved in a mixture of 45 mL dichloromethane and 45 mL trifluoroacetic acid, and the solution was stirred for 2 hours and then evaporated. Toluene (2 × 30 mL) was added and evaporated to remove traces of trifluoroacetic acid and the product dried under vacuum to afford succinate monomethyl ester as a light tan solid.

(ii) 2.0 g of the aforementioned succinate monomethyl ester was dissolved in 20 ml of dimethylformamide and the solution was cooled to 0 ° C. 1.06 g hydroxybenzotriazole hydrate, 1.5 g 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1.7 ml N-ethylmorpholine and 1.5 g O- (4-meth Toxybenzyl) hydroxylamine was added. The mixture was stirred at 5 ° C. for 0.5 h and at RT for 2.5 h and then evaporated under high vacuum. The residue in ethyl acetate was washed sequentially with 5% sodium bicarbonate solution, 2M hydrochloric acid, water, 5% sodium bicarbonate and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give a solid. Chromatography on silica gel using ethyl acetate / hexanes (1: 4) for elution yields 1.83 g of methyl (E) -2 (R)-[(1S-({O- (4-methoxybenzyl} hydroxycarba). Moyl) -4-phenyl-3-butenyl] -4-methylvalyrate was obtained as an oil which solidified to leave a white solid.

MS: 440 (M + H) ⁺ .

(iii) 3.45 mL of a solution of trimethylaluminum (2M in hexane) was added dropwise to a suspension of 1.03 g of cyclohexylhydrazine in 5 mL dichloromethane under nitrogen. Active release of gas was observed and the solids dissolved slowly over 1 hour, resulting in solution A.

(iv) 0.44 g of the methyl ester prepared according to (ii) was dissolved in 4 ml of dichloromethane, solution A was added and the mixture was warmed in a water bath for 6 hours (bath temperature 45 ° C.). The solution was cooled, treated very carefully with excess 2M hydrochloric acid (active gas evaporation), and then extracted twice with 20 ml of ethyl acetate each time. The organic phase was washed sequentially with 5% sodium bicarbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give a yellow gum. Chromatography on silica gel using dichloromethane / methanol (24: 1) for elution gave 0.19 g of hydrazide.

MS: 522 (M + H) ⁺ .

(v) 0.11 g of hydrazide prepared according to (iv) was suspended in a mixture of 5 ml dichloromethane and 0.026 ml pyridine under nitrogen. 0.046 g of methanesulfonic anhydride was added and the mixture was stirred at rt for 3 h and then diluted with 15 mL of dichloromethane. The solution was washed sequentially with 2M hydrochloric acid, water and 5% sodium hydrogen carbonate solution, dried over magnesium sulfate and then evaporated to give a white foam. Triturated with diethyl ether to make 0.095 g of (E) -2'-cyclohexyl-2 (R)-[1 (S)-({O-4-methoxybenzyl} hydroxycarbamoyl) -4-phenyl- 3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained as a white solid.

MS: 600 (M + H) ⁺ .

Example 45

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methyl Valerohydrazide

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- in a mixture of 10 mL methanol and 2 mL dichloromethane. A solution of 0.246 g of butenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was treated with 0.006 ml of methanesulfonic acid. The mixture was stirred at rt for 3 h and then the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was triturated with hexane to give 0.119 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2'- (Methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 454 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.17 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -Isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:

(i) (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerolic in 10 ml of dichloromethane A solution of 0.60 g of hydrazide, 0.166 mL of isobutyraldehyde and crystals of 4-toluenesulfonic acid was stirred on a 4 mm molecular sieve for 1 hour. The mixture was filtered, the solvent was evaporated and replaced with 10 mL of methanol. A slight crystal of bromocresol green was added to give a yellow solution. To this, 0.116 g sodium cyanoborohydride was added in a small batch. The yellow color of the solution was maintained by the periodic addition of a 4M solution of hydrogen chloride in dioxane. Methanol was evaporated and the residue was partitioned between dichloromethane and 5% aqueous sodium hydrogen carbonate solution. The aqueous layer was washed twice with dichloromethane, then the combined organic layers were washed twice with 5% aqueous sodium hydrogen carbonate solution. The dichloromethane layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (7: 3) for elution. 0.312 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohi Drazide was obtained in the form of a white solid.

MS: 417 (M + H) ⁺ .

(ii) 0.435 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) in a similar manner as described in Example 2, parts (iv) and (v) 0.249 g of (E) -2 (R)-[1 (S)-[(tetra) starting from -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide Hydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide white Obtained in solid form.

MS: 538 (M + H) ⁺ .

Example 46

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isopropyl-2 '-(methanesulfonyl) -4-methyl Valerohydrazide

In a similar manner as described in Example 45 except for using acetone instead of isobutyraldehyde in step (i), (E) -2 (R)-[1 (S)-(hydroxycarbamoyl)- 4-phenyl-3-butenyl] -2'-isopropyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 440 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.16 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Example 47

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-cyclopentyl-2 '-(methanesulfonyl) -4-methyl Valerohydrazide

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) in a similar manner as described in Example 45 except for using cyclopentanone in place of isobutyraldehyde in step (i) ) -4-phenyl-3-butenyl] -2'-cyclopentyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 466 (M + H) ⁺ .

HPLC: accelerated gradient elution using solvent A with 20% solvent B for 2 minutes and then increasing to 80% solvent B over 18 minutes; Flow rate of 1 ml / min. Retention time: 17.57 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Example 48

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(4-tetrahydropyranyl) -2'-(methanesulphur Ponyyl) -4-methylvalerohydrazide

In a similar manner as described in Example 45 except for using tetrahydro-4H-pyran-4-one in place of isobutyraldehyde in step (i), (E) -2 (R)-[1 (S White)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(4-tetrahydropyranyl) -2'-(methanesulfonyl) -4-methylvalerohydrazide Obtained in solid form.

MS: 482 (M + H) ⁺ .

HPLC: accelerated gradient elution using solvent A with 20% solvent B for 2 minutes and then increasing to 80% solvent B over 18 minutes; Flow rate of 1 ml / min. Retention time: 13.72 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Example 49

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(4-tetrahydrothiopyranyl) -2'-(methane Sulfonyl) -4-methylvalerohydrazide

In a method similar to that described in Example 45, except for using tetrahydrothiopyran-4-one in place of isobutyraldehyde in step (i), (E) -2 (R)-[1 (S)- (Hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(4-tetrahydrothiopyranyl) -2'-(methanesulfonyl) -4-methylvalerohydrazide as a white solid Obtained in form.

MS: 498 (M + H) ⁺ .

HPLC: accelerated gradient elution using solvent A containing 20% solvent B for 2 minutes and then increasing to 80% solvent B over 18 minutes; Flow rate of 1 ml / min. Retention time: 17.35 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Example 50

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(4-piperidinyl) -2'-(methanesulfonyl ) -4-Methylvalerohydrazide

(E) -2 (R) in a similar manner as described in Example 45 except for using 1-3-butoxycarbonyl-4-piperidinone in place of isobutyraldehyde in step (i) -[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(4-piperidinyl) -2'-(methanesulfonyl) -4-methylvalerohi Drazide was obtained in the form of a white solid.

MS: 481 (M + H) ⁺ .

HPLC: accelerated gradient elution using solvent A containing 20% solvent B for 2 minutes and then increasing to 80% solvent B over 18 minutes; Flow rate of 1 ml / min. Retention time: 11.39 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Example 51

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(isobutyl) -2'-(isopentanoyl) -4 Methylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.097 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.047 g of (E) -2 (R) starting with 4-phenyl-3-butenyl] -2 '-(isobutyl) -2'-(isopentanoyl) -4-methylvalerohydrazide -[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(isobutyl) -2'-(isopentanoyl) -4-methylvalerohydrazide Obtained in the form of a white solid.

MS: 460 (M + H) ⁺ , 482 (M + Na) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.79 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -(Isobutyl) -2 '-(isopentanoyl) -4-methylvalerohydrazide was prepared as follows:

(i) (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -2'-isobutyl- in 6 ml dichloromethane A solution of 0.25 g of 4-methylvalerohydrazide, 0.061 mL of pyridine and 4-dimethylaminopyridine was cooled to 0 ° C. under a nitrogen atmosphere. 0.091 mL of isopentanoyl chloride was added and the reaction mixture was allowed to warm to room temperature. After stirring for 2 hours at room temperature, the reaction mixture was diluted with dichloromethane and washed with 2M aqueous hydrochloric acid and then brine. The dichloromethane phase was dried over anhydrous magnesium sulfate and then the solvent was evaporated. The residue was then dissolved in 10 ml of a 20% solution of trifluoroacetic acid in dichloromethane and stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel using 1% methanol in dichloromethane for elution. 0.16 g of (E) -2 (R)-[1 (S)-(carboxy) -4-phenyl-3-butenyl] -2 '-(isobutyl) -2'-(isopentanoyl) -4 Methylvalerohydrazide was obtained in the form of a white foam.

MS: 445 (M + H) ⁺ .

(ii) 0.16 g of (E) -2 (R)-[1 (S)-(carboxy) -4-phenyl-3-butenyl] in a similar manner as described in Example 2, part (v) Starting from -2 '-(isobutyl) -2'-(isopentanoyl) -4-methylvalerohydrazide, 0.097 g of (E) -2 (R)-[1 (S)-[( Tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(isobutyl) -2'-(isopentanoyl) -4-methylvalerohydra Zide was obtained in the form of a white solid.

MS: 544 (M + H) ⁺ .

Example 52

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(isobutyl) -2'-(cyclohexanecarbonyl)- 4-methylvalerohydrazide

In a manner similar to that described in Example 51 except for using cyclohexanecarbonyl chloride in place of isopentanoyl chloride in step (i), (E) -2 (R)-[1 (S)-(hydr Roxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(isobutyl) -2'-(cyclohexanecarbonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 486 (M + H) ⁺ .

HPLC: accelerated gradient elution using solvent A containing 35% solvent B for 5 minutes and increasing to 70% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 15.44 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Example 53

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-N- (2,6-dioxopiperidino) valeramide

In a similar manner as described in the first paragraph of Example 45, 0.095 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting with -4-phenyl-3-butenyl] -4-methyl-N- (2,6-dioxopiperidino) valeramide, 0.027 g of (E) -2 (R)-[1 (S) -(Hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-N- (2,6-dioxopiperidino) valeramide was obtained in the form of a white solid.

MS: 416 (M + H) ⁺ .

HPLC: accelerated gradient elution using solvent A containing 20% solvent B for 5 minutes and increasing to 70% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.79 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4- used as starting material Methyl-N- (2,6-dioxopiperidino) valeramide was prepared as follows:

(i) (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleroheim in 30 ml anhydrous toluene A solution of 1.0 g of drazide, 0.35 g of glutaric anhydride and 0.85 mL of triethylamine was heated to reflux for 7 hours under a nitrogen atmosphere. The mixture was cooled to rt and washed with 2M aqueous hydrochloric acid, 5% aqueous sodium hydrogen carbonate and brine. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was triturated with diethyl ether to give 0.623 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methyl- N- (2,6-dioxopiperidino) valeramide was obtained in the form of a white solid.

MS: 457 (M + H) ⁺ .

(ii) 0.62 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl), in a manner analogous to that described in Example 2, parts (iv) and (v) 0.095 g of (E) -2 (R)-[1 (S) starting from -4-phenyl-3-butenyl] -4-methyl-N- (2,6-dioxopiperidino) valeramide -Tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methyl-N- (2,6-dioxopiperidino) valeramide in the form of a white solid Obtained.

MS: 500 (M + H) ⁺ .

Example 54

(E) -N- (tetrahydro-1,2-thiazin-2-yl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl]- 4-methylvaleramide S, S-dioxide

In a similar manner as described in the first paragraph of Example 45, 0.048 g of (E) -N- (tetrahydro-1,2-thiazin-2-yl) -2 (R)-[1 (S) 0.01 g of (E)-, starting with [[tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvaleramide S, S-dioxide N- (tetrahydro-1,2-thiazin-2-yl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalerir Amide S, S-dioxide was obtained in the form of a white solid.

MS: 438 (M + H) ⁺ .

(E) -N- (tetrahydro-1,2-thiazin-2-yl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyl used as starting material Oxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvaleramide S, S-dioxide was prepared as follows:

(i) A solution of 5.64 g of tert-butyl ester of lactic acid and 3.6 ml of pyridine in 40 ml of dichloromethane was added to a solution of 6.0 ml of trifluoromethanesulfonic anhydride in 60 ml of dichloromethane at 0 ° C. under nitrogen atmosphere. Added dropwise. After 10 minutes the mixture was washed twice with water and then dried over anhydrous magnesium sulfate. The mixture was concentrated to approximately one third of the original volume and then prepared by treating 5.22 g of tert-butylmethyl malonate in 50 ml of dimethylformamide with 1.32 g of a 60% suspension of sodium hydride in mineral oil for 2 hours under a nitrogen atmosphere. To a cooled (0 ° C.) solution of the charged anions. The mixture was allowed to warm to rt overnight then the solvent was evaporated. The residue was dissolved in ethyl acetate and the solution was washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to afford 10.0 g of 1,2-tert-butyl-1,4-dimethyl-1,1,2 (R) -pentane-tricarboxylate in the form of a red oil. .

(ii) 1.53 g of a 60% suspension of sodium hydrate in mineral oil in 1,2 mL-butyl-1,4-dimethyl-1,1,2 (R) -pentanetricarboxyl in 120 mL of dimethylformamide under a nitrogen atmosphere. To a stirred solution of rate 12.55 g was added. The mixture was stirred until gas evolution ceased (about 1 hour), a solution of 7.54 g of cinnamil bromide in 70 ml of dimethylformamide was added dropwise and the mixture was stirred at rt overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed twice with water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel using hexane / ethyl acetate (9: 1) for elution. 15.06 g of (E) -1,2-tert-butyl-1,4-dimethyl-1- (3-phenyl-prop-2-en-1-yl) -1,1,2 (R)- Pentanetricarboxylate was obtained in the form of a pale yellow oil.

(iii) (E) -1,2-tert-butyl-1,4-dimethyl-1- (3-phenylprop-2-ene-1 in 30 ml of a 20% solution of trifluoroacetic acid in dichloromethane A solution of 2.7 g of -yl) -1,1,2 (R) -pentanetricarboxylate was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was dissolved in 20 ml of toluene. 1.6 ml of triethylamine were added and the mixture was stirred at reflux for 2 hours. After cooling the mixture was washed with 2M aqueous hydrochloric acid and water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to give a pale yellow oil. The oil was dissolved in 10 ml of hexane and 0.6 g cyclohexylamine was added. The resulting salt was collected by filtration and then suspended in 20 ml of ether and washed with 1M sulfuric acid. The ether phase was dried over anhydrous magnesium sulfate and evaporated to 1.5 g of (E) -2 (R) -isobutyl-4-methyl-3-[(RS) -3-phenylprop-2-en-1-yl ) -Succinate was obtained in the form of a white solid.

(iv) A solution of 40 g of 4-chloro-1-butanesulfonyl chloride in 400 mL of diethyl ether was added dropwise to a solution of 30.4 g of tert-butyl carbazate and 17 mL of pyridine in 400 mL of diethyl ether at room temperature. . The mixture was stirred at rt for 72 h and then washed with water. The organic phase was separated and dried over anhydrous magnesium sulfate. The oily residue obtained after evaporation of the solvent was purified by flash column chromatography on silica gel using hexane / ethyl acetate (increased to 8: 2, 6: 4) for elution. 10.25 g of tert-butyl 2-[(4-chlorobutyl) sulfonyl] carbazate were obtained in the form of a white solid.

(v) A solution of 10.25 g of tert-butyl-2-[(4-chlorobutyl) sulfonyl] carbazate in 300 ml of anhydrous tetrahydrofuran at room temperature under a nitrogen atmosphere of 1.7 g of a 60% suspension of sodium hydrate in mineral oil. Was added. After stirring for 48 hours at room temperature, the solvent was evaporated and the residue was dissolved in ethyl acetate and washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from ethyl acetate / hexanes to yield 1.86 g of tert-butyl (tetrahydro-1,2-thiazin-2-yl) carbamate S, S-dioxide in the form of a pale yellow solid.

(vi) A solution of 1.86 g of tert-butyl (tetrahydro-1,2-thiazin-2-yl) carbamate S, S-dioxide in 20 ml of 4M hydrogen chloride in ethyl acetate was stirred at room temperature for 1 hour. . The solvent was evaporated and the residue was stirred in ether for 5 minutes and then filtered to yield 1.24 g of tetrahydro-1,2-thiazin-2-amine S, S-dioxide in the form of a white solid.

(vii) 1.39 g of (E) -2 (R) -isobutyl-4-methyl-3 [(RS) -3-phenylprop-2-en-1-yl)]-succinate in 15 ml of dichloromethane The solution of was cooled to -10 ° C under a nitrogen atmosphere. Four drops of dimethylformamide and 0.418 ml of oxalyl chloride were added and the mixture was warmed to 0 ° C. over 1 hour. The solvent was evaporated and replaced with 2 ml of dichloromethane. The resulting solution was then added dropwise to a solution of 1.24 g of tetrahydro-1,2-thiazin-2-amine S, S-dioxide and 1.4 mL of triethylamine in 20 mL of dichloromethane at 0 ° C. under nitrogen atmosphere. The mixture was kept at 0 ° C. overnight and then washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash column chromatography on silica gel using ethyl acetate / hexanes (increased to 2: 8, 10: 0) for elution. 0.44 g of (E) -N- (tetrahydro-1,2-thiazin-2-yl) -2 (R)-[1 (S)-(methoxycarbonyl) -4-phenyl-3-part Tenyl] -4-methylvaleramide S, S-dioxide was obtained in the form of a white solid.

(viii) 0.573 ml of a 2M solution of trimethylaluminum in toluene was added to a solution of 0.134 g of O- (tetrahydro-2H-pyran-2 (RS) -yl) hydroxylamine in 5 ml anhydrous toluene at 0 ° C. under nitrogen atmosphere. It was. After the mixture was stirred at room temperature for 1 hour, 0.10 g of (E) -N- (tetrahydro-1,2-thiazin-2-yl) -2 (R)-[1 (S)-(methoxy Carbonyl) -4-phenyl-3-butenyl] -4-methylvaleramide was added in one portion. The mixture was heated at 55 ° C. for 3 h and then cooled to rt overnight. The mixture was diluted with ethyl acetate and washed successively with 2M aqueous hydrochloric acid and 5% aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was triturated with diethyl ether to remove 0.048 g of (E) -N- (tetrahydro-1,2-thiazin-2-yl) -2 (R)-[1 (S)-[( Tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvaleramide S, S-dioxide was obtained in the form of a white solid.

MS: 522 (M + H) ⁺ .

Example 55

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-phenylhexanohydrazide

In a similar manner as described in the first paragraph of Example 1, 0.37 g of (E) -2 (R)-[1 (S)-[(carboxy) -4-phenyl-3-butenyl] -2 ' 0.10 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3- starting with-(methanesulfonyl) -2'-phenylhexanohydrazide Butenyl] -2 '-(methanesulfonyl) -2'-phenylhexanohydrazide was obtained in the form of a white solid.

MS: 474 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.97 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-(carboxy-4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-phenylhexanohydra used as starting material The prepared was as follows:

(i) In a similar manner as described in Example 54, parts (i) and (ii), except for using benzyl 2-hydroxy-hexanoate and benzyl tert-butyl-malonate, ) -1,2-dibenzyl-1-tert-butyl-1- (3-phenylprop-2-en-1-yl) -1,1,2 (R) -hexanetricarboxylate yellow oil Obtained in the form of.

(ii) A solution of 2.27 g of sodium hydroxide in 20 mL water was added to (E) -1,2-dibenzyl-1-tert-butyl-1- (3-phenylprop-2-ene-1 in 40 mL ethanol. To a solution of 6.47 g of -yl) -1,1,2 (R) -hexanetricarboxylate. The mixture was heated to reflux overnight then cooled and evaporated. The residue was diluted with water and acidified to pH 1 with concentrated hydrochloric acid. The aqueous phase was washed twice with ethyl acetate, then the combined organic phases were washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in 50 ml of toluene. 1.53 ml of triethylamine was added to the mixture and then heated to reflux for 3.5 hours and cooled overnight. The mixture was washed with 2M aqueous hydrochloric acid and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the yellow oil obtained was dissolved in hexane and treated with 1.09 g of cyclohexylamine to give a salt which was collected by filtration. The salt is then partitioned between ethyl acetate and 1N sulfuric acid, the organic phase is washed successively with water, dried over anhydrous magnesium sulfate and evaporated to 1.3 g of (E) -2 (R) -butyl-4-tert-butyl- 3-[(RS)-(3-phenylprop-2-en-1-yl)] succinate was obtained in the form of a light yellow solid.

(iii) (E) -2 (R) -butyl-4-tert-butyl-3-[(RS)-(3) in a manner analogous to that described in Example 1, parts (i)-(iii) -Phenylprop-2-en-1-yl)]-succinate starting from (E) -2 (R)-[1 (S)-(carboxy)]-4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-phenylhexanohydrazide was obtained in the form of a white solid.

MS: 459 (M + H) ⁺ .

Example 56

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2', 3-diphenylpropiono Hydrazide

In a manner similar to that described in the first paragraph of Example 44, 0.162 g of (E) -2 (R)-[1 (S)-({O-4-methoxybenzyl} hydroxycarbamoyl) -4 0.040 g of (E) -2 (R)-[1 (S), starting with -phenyl-3-butenyl] -2 '-(methanesulfonyl) -2', 3-diphenylpropionohydrazide (Hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2', 3-diphenylpropionohydrazide was obtained in the form of a white solid.

MS: 508 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.25 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-({O-4-methoxybenzyl} hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(used as starting material Methanesulfonyl) -2 ', 3-diphenylpropionohydrazide was prepared as follows:

(i) In a similar manner as described in Example 55, parts (i) to (iii), except that starting from benzyl a-hydroxy-benzenepropanoate, (E) -2 (R)-[ 1 (S)-(carboxy) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2', 3-diphenylpropionohydrazide was obtained in the form of a white solid.

(ii) (E) -2 (R)-[1 (S)-(carboxy) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2', 3- in 5 mL DMF 0.29 g of diphenylpropionohydrazide is cooled to 0 ° C. under a nitrogen atmosphere, and 0.18 g of (O-4-methoxybenzyl) hydroxylamine and 0.124 g of 1-ethyl-3- (3-dimethyl Aminopropyl) -carbodiimide hydrochloride was added. The mixture was allowed to warm to rt and stirred overnight. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with diethyl ether to give 0.17 g of (E) -2 (R)-[1 (S)-({O-4- (methoxybenzyl} hydroxycarbamoyl) -4-phenyl-3-part Tenyl] -2 '-(methanesulfonyl) -2', 3-diphenylpropionohydrazide was obtained in the form of a white solid.

Example 57

(E) -2 (RS)-[1 (RS)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2,2'-diphenylacetohai Dragged

In a similar manner as described in the first paragraph of Example 45, 1.05 g of (E) -2 (RS)-[1 (RS)-(tetrahydro-2 (RS) -pyranyloxy} carbamoyl]- Starting with 4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2,2'-diphenylacetohydrazide, 0.598 g of (E) -2 (RS)-[1 (RS) -(Hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2,2'-diphenylacetohydrazide was obtained in the form of a white solid.

MS: 494 (M + H) ⁺ .

HPLC: accelerated gradient elution using solvent A containing 35% solvent B for 5 minutes and increasing to 80% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 8.54 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (RS)-[1 (RS)-(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- used as starting material. (Methanesulfonyl) -2,2'-diphenylacetohydrazide was prepared as follows:

(i) (E) -2 (RS)-[1 (RS)-(carboxy), in a manner analogous to that described in Example 55, parts (i)-(iii), except starting from benzyl mandelate ) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2,2'-diphenylacetohydrazide was obtained in the form of a white solid.

MS: 479 (M + H) ⁺ .

(ii) 1.1 g of (E) -2 (RS)-[1 (RS)-(carboxy) -4-phenyl-3-butenyl] in a similar manner as described in Example 2, part (v) Starting from -2 '-(methanesulfonyl) -2,2'-diphenylacetohydrazide, 1.1 g of (E) -2 (RS)-[1 (RS)-[(tetrahydro-2 ( RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2,2'-diphenylacetohydrazide was obtained in the form of a white solid.

MS: 578 (M + H) ⁺ .

Example 58

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4- (2-thiazolyl) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl- 2'-phenylvalerohydrazide

In a similar manner as described in the first paragraph of Example 45, 0.29 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting with -4- (2-thiazolyl) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide, 0.17 g of (E) -2 ( R)-[1 (S)-(hydroxycarbamoyl) -4- (2-thiazolyl) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalero Hydrazide was obtained in the form of a white solid.

MS: 481 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.97 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (2-thiazolyl) -3-part used as starting material Tenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was prepared as follows:

(i) 4.0 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid in 200 ml dichloromethane The solution of was cooled to -78 ° C and ozone was bubbled through the solution until the solution turned blue. The mixture was allowed to warm to room temperature and 20 ml of dimethyl sulfide were added. The mixture was stirred at rt for 3 h before the solvent was evaporated. The residue was purified by flash column chromatography on silica gel using hexane / ethyl acetate (1: 1) for elution. 1.8 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -propane-3-al] -4-methylvaleric acid were obtained in the form of a light yellow solid.

(ii) 0.25 g of potassium tert-butoxide was added to a solution of 0.79 g of triphenyl (2-thiazolylmethyl) phosphonium chloride in 10 ml anhydrous toluene. After stirring for 3 hours at room temperature, a solution of 0.83 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -propan-3-al] -4-methylvaleric acid in 5 ml toluene Was added and the mixture was further stirred at rt for 48 h. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel using dichloromethane / methanol (95: 5) for elution. 0.43 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4- (2-thiazolyl) -3-butenyl] -methylvaleric acid as a pale yellow oil Obtained as

MS: 354 (M + H) ⁺ .

(iii) in a manner similar to that described in Example 1, parts (i) to (iii), and Example 2, part (v), (E) -2 (R)-[1 (S)-(3 Starting from tert-butoxycarbonyl) -4- (2-thiazolyl) -3-butenyl] -methylvaleric acid, (E) -2 (R)-[1 (S)-[(tetrahydro- 2 (RS) -pyranyloxy) carbamoyl] -4- (2-thiazolyl) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide Was obtained in the form of a white solid.

MS: 565 (M + H) ⁺ .

Example 59

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyryl-2'-isobutyl-4-methylvalero Hydrazide

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- in 10 ml of methanol. A solution of 0.32 g of isobutyryl-2'-isobutyl-4-methylvalerohydrazide was treated with 0.03 g of 4-toluenesulfonic acid. The mixture was stirred at rt for 2 h and then the solvent was evaporated to give glassy. The residue was triturated with diethyl ether to yield 0.15 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyryl -2'-isobutyl-4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 446 (M + H) ⁺ .

HPLC: gradient elution with solvent A containing 20% solvent B for 5 minutes and increasing to 65% solvent B from 5 to 20 minutes; Flow rate of 1 ml / min. Retention time: 17.48 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material Isobutyryl-2'-isobutyl-4-methylvalerohydrazide was prepared as follows:

(i) (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -2'-isobutyl- in 8 ml dichloromethane 0.70 g of 4-methylvalerohydrazide, 0.38 mL of pyridine and a solution of crystals of 4-dimethylaminopyridine were cooled to 0 ° C. under a nitrogen atmosphere. 0.67 mL of isobutyric anhydride was added and the reaction mixture was allowed to warm to room temperature. After stirring for 16 hours at room temperature, the reaction mixture was diluted with dichloromethane and washed with 2M aqueous hydrochloric acid and then brine. The dichloromethane phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. Chromatography on silica gel using ethyl acetate / hexanes (1: 5) for elution followed by evaporation gave 0.56 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl)-. 4-phenyl-3-butenyl] -2'-isobutyryl-2'-isobutyl-4-methylvalerohydrazide was obtained in the form of a white foam.

MS: 487 (M + H) ⁺ .

(ii) 0.56 g tertiary butyl ester was dissolved in 20 ml of a 50% solution of trifluoroacetic acid in dichloromethane and stirred at room temperature for 1.5 hours. The solvent was evaporated, toluene (2 x 10 mL) was added and evaporated to remove traces of trifluoroacetic acid. The residue was triturated with diethyl ether / hexanes (1: 1) to yield 0.39 g of (E) -2 (R)-[1 (S)-(carboxy) -4-phenyl-3-butenyl] -2'-. Isobutyryl-2'-isobutyl-4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 431 (M + H) ⁺ .

(iii) 0.39 g of (E) -2 (R)-[1 (S)-(carboxy) -4-phenyl-3-butenyl] in a similar manner as described in Example 2, part (v) 0.32 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2, starting from -2'-isobutyryl-2'-isobutyl-4-methylvalerohydrazide (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyryl-2'-isobutyl-4-methylvalerohydrazide in the form of a white solid It was.

MS: 530 (M + H) ⁺ .

Example 60

(E) -2'-acetyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydra Jide

In a method similar to that described in Example 59 except for using acetic anhydride instead of isobutyric anhydride in step (i), (E) -2'-acetyl-2 (R)-[1 (S)-( Hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 418 (M + H) ⁺ .

HPLC: elution with solvent A; Flow rate of 1 ml / min. Retention time: 4.86 minutes. Solvent A: H ₂ O / 0.1% TFA. Column type: HYPERPEP 300A.

Example 61

(E) -2'-benzoyl-2'-isobutyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalerohydra Jide

In a similar manner as described in Example 59 except that benzoyl chloride is used in place of isobutyric anhydride in step (i), (E) -2'-benzoyl-2'-isobutyl-2 (R)-[ 1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 480 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B for 15 minutes; Flow rate of 1 ml / min. Retention time: 12.37 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Example 62

Methyl (E)-[2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -1-isobutylhydrazino] glycol Oxylate

Methyl (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4- in 5 mL methanol A solution of 0.34 g of methylvaleryl] -1-isobutylhydrazino] glyoxylate was treated with 0.04 g of 4-toluenesulfonic acid. The mixture was stirred at room temperature for 2.5 hours and then the solvent was evaporated to give a white semi-solid mass. The residue in ethyl acetate was washed with 5% sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated to give a solid. It was triturated with diethyl ether to give 0.19 g of methyl (E)-[2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -1-Isobutylhydrazino] glyoxylate was obtained in the form of a white solid.

MS: 462 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.26 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E)-[2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl-4-phenyl-3-butenyl] -4- used as starting material Methylvaleryl] -1-isobutylhydrazino] glyoxylate was prepared as follows:

(i) (E) -2 (R)-[(1S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -2'-isobutyl-4- in 10 ml dichloromethane A solution of 1.0 g of methylvalerohydrazide, 0.40 mL of pyridine and 4-dimethylaminopyridine was cooled to 0 ° C. under a nitrogen atmosphere. 0.27 mL methyl oxalyl chloride was added and the reaction mixture was allowed to warm to room temperature. After stirring for 16 hours at room temperature, the reaction mixture was evaporated to dryness. The residue in ethyl acetate was washed with 2M aqueous hydrochloric acid, 5% sodium hydrogen carbonate solution and water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was triturated with hexane to give 0.91 g of methyl (E)-[2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalle Reel] -1-isobutylhydrazino] glyoxylate was obtained in the form of a white solid.

MS: 503 (M + H) ⁺ .

(ii) 0.90 g of tertiary butyl ester prepared in paragraph (i) was dissolved in 20 ml of a 50% solution of trifluoroacetic acid in dichloromethane and stirred at room temperature for 3 hours. The solvent was evaporated, toluene (2 x 20 mL) was added and evaporated to remove traces of trifluoroacetic acid. The residue was dried under vacuum to yield 0.95 g of (E)-[2 (R)-[1 (S)-(carboxy) -4-phenyl-3-butenyl] -4-methylvaleryl] -1-isobutyl Hydrazino] glyoxylate was obtained in rubber form.

MS: 446 (M + H) ⁺ .

(iii) the carboxylic acid prepared in paragraph (ii) was dissolved in 5 ml of dimethylformamide, cooled to 0 ° C. and 0.75 g of O- (tetrahydro-2H-pyran-2 (RS) -yl) hydroxyl Treatment was successively with amine and 0.48 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to warm to rt and stirred overnight. The solvent was evaporated and the residue dissolved in ethyl acetate. The ethyl acetate layer was washed with water, 2M hydrochloric acid, 5% sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give a foam. Chromatography on silica gel using ethyl acetate / hexanes (2: 3) for elution followed by evaporation gave 0.350 g of methyl (E)-[2 (R)-[1 (S)-[(tetrahydro-2 (RS) ) -Pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvaleryl] -1-isobutylhydrazino] glyoxylate is obtained in the form of a white solid.

MS: 546 (M + H) ⁺ .

Example 63

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methyl-2 '-(methylglyoxylo Japanese) valerohydrazide

In a similar manner as described in Example 62, (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl} -4-phenyl-3- Starting from butenyl] -2'-isobutyl-4-methyl-2 '-(methylglyoxyloyl) valerohydrazide, (E) -2 (R)-[1 (S)-(hydr Roxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methyl-2 '-(methylglyoxyloyl) valerohydrazide was obtained in the form of a white solid.

MS: 462 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.19 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl) -4-phenyl-3-butenyl] -2 'used as starting material -Isobutyl-4-methyl-2 '-(methylglyoxyloyl) valerohydrazide is described in Examples 62 (i)-(iii) using pyruboyl chloride instead of methyl oxalyl chloride. It was prepared by a similar method as described above.

MS: 530 (M + H) ⁺ .

Example 64

(E) -2 (R)-[1 (RS)-(hydroxycarbamoyl) -4- (3-pyridyl) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl- 2'-phenylvalerohydrazide

(E) -2 (R)-[1 (RS)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (3-pyridyl) -3-butenyl in 5 ml of methanol A solution of 0.21 g of] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was treated with 0.097 g of 4-toluenesulfonic acid. The mixture was stirred at rt for 2.5 h and then diluted with water. The solid was filtered off, washed with water and diethyl ether and dried under vacuum to give 0.138 g of (E) -2 (R)-[1 (RS)-(hydroxycarbamoyl) -4- (3-pyridyl ) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylhydrazide is obtained in the form of a white solid.

MS: 475 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention times: 9.53 and 9.92 minutes (ratio of diastereomers (3: 1)). Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (RS)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (3-pyridyl) -3-part used as starting material Tenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was prepared as follows:

(i) A solution of 6.81 g of 1,2-dibenzyl 1-3-butyl-4-methyl-1 (RS) and 1,2 (R) -pentanetricarboxylate in 50 ml anhydrous tetrahydrofuran was room temperature. Stirred under nitrogen. 0.66 g of 60% sodium hydride was added and the mixture was stirred for 10 minutes. A solution of 2.66 g of 4- (3-pyridyl) allyl acetate and 0.87 g of tetrakis (triphenylphosphine) -palladium (O) in 40 mL anhydrous tetrahydrofuran was added and the mixture was stirred at rt for 4 h. Tetrahydrofuran was evaporated and the residue was partitioned between dichloromethane and saturated sodium chloride solution. The organic solution was dried over anhydrous magnesium sulfate and evaporated to give a light brown oil. Chromatography on silica gel using ethyl acetate / hexanes (2: 3) for elution and evaporation of the solvent yielded 7.50 g of (E) -1,2-dibenzyl 1-3-butyl-4-methyl-1- [ 3- (3-Pyridyl) -prop-2-en-1-yl] -1 (RS), 1,2 (R) -pentanetricarboxylate was obtained.

MS: 572 (M + H) ⁺ .

(ii) A solution of 2.80 g of sodium hydroxide in 40 mL water was added (E) -1,2-dibenzyl 1-3-butyl-4-methyl-1- [3- (3-pyridyl) in 40 mL ethanol. To a solution of 4.00 g of -prop-2-en-1-yl) -1 (RS), 1,2 (R) -pentanetricarboxylate. The mixture was heated to reflux for 20 hours, then cooled and evaporated. The residue was diluted with water and acidified to pH 6.5 with concentrated hydrochloric acid. The aqueous phase was extracted twice with diethyl ether and then the organic phases were combined and extracted with 50 ml of 0.25 M sodium hydroxide solution. The solution was acidified to pH 6.5 with concentrated hydrochloric acid and reextracted with diethyl ether (2 × 50 mL). The combined organic phases are washed with brine, dried over magnesium sulfate and evaporated to 1.73 g of (E) -2 (R) -butyl-4-tert-butyl-3-[(RS)-(3- (3- Pyridyl) prop-2-en-1-yl)] succinate was obtained in the form of a red rubber.

MS: 348 (M + H) ⁺ .

(iii) 0.447 g of (E) -2 (R)-[starting from 0.52 g of the carboxylic acid prepared in part (ii) of this example in a similar manner as described in Example 1, part (i). Obtain 1 (RS)-(tert-butoxycarbonyl) -4- (3-pyridyl) -3-butenyl] -4-methyl-2'-phenylvalerohydrazide in the form of a white solid It was.

MS: 438 (M + H) ⁺ .

(iv) 0.44 g of (E) -2 (R)-[1 (RS)-(tert-butoxycarbonyl) -4- (4) in a manner analogous to that described in Example 1, part (ii) 0.51 g of (E) -2 (R)-[1 (RS)-(tert-part) starting with 3-pyridyl) -3-butenyl] -4-methyl-2'-phenylvalerohydrazide Toxylcarbonyl) -4- (3-pyridyl) -3-butenyl] -4-methyl-2 '-(methanesulfonyl) -2'-phenylvalerohydrazide was obtained in the form of a white solid. .

MS: 516 (M + H) ⁺ .

(v) In a manner similar to that described in Example 1, part (iii), 0.50 g of (E) -2 (R)-[1 (RS)-(tert-butoxycarbonyl) -4- ( 0.36 g of (E) -2 (R)-[1 starting with 3-pyridyl) -3-butenyl] -4-methyl-2 '-(methanesulfonyl) -2'-phenylvalerohydrazide (RS)-(carboxy) -4- (3-pyridyl) -3-butenyl] -4-methyl-2 '-(methanesulfonyl) -2'-phenylvalerohydrazide was obtained.

MS: 460 (M + H) ⁺ .

(iv) the carboxylic acid prepared in paragraph (iii) was dissolved in 2 ml of dimethylformamide, cooled to 0 ° C. and 0.27 g of O- (tetrahydro-2H-pyran-2 (RS) -yl) hydroxyl Treatment was successively with amine and 0.16 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to warm to rt and stirred overnight. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The ethyl acetate layer was washed with water and 5% sodium bicarbonate solution, then dried over anhydrous magnesium sulfate and evaporated. The resulting pale yellow rubber was triturated with diethyl ether to give 0.22 g of (E) -2 (R)-[1 (RS)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (3-Pyridyl) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid.

MS: 559 (M + H) ⁺ .

Example 65

2 (R)-[1 (S)-(hydroxycarbamoyl) -4- (3-pyridyl) butyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohi Dragged

2 (R)-[1 (S)-[(benzyloxy) carbamoyl] -4- (3-pyridyl) butyl] -2'-isobutyl-2 '-(methanesulfonyl)-in 10 ml of methanol A solution of 0.33 g of 4-methylvalerohydrazide was hydrogenated for 1.5 hours in the presence of 80 mg of 10% palladium on carbon. The catalyst was removed by filtration and the solvent was evaporated. The residue was triturated with diethyl ether to give 0.26 g of 2 (R)-[1 (S)-(hydroxycarbamoyl) -4- (3-pyridyl) butyl] -2'-isobutyl-2 '-( Methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 457 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.59 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

2 (R)-[1 (S)-[(benzyloxy) carbamoyl] -4- (3-pyridyl) butyl] -2'-isobutyl-2 '-(methanesulfonyl) used as starting material 4-Methylvalerohydrazide was prepared as follows:

(i) (E) -1,2-dibenzyl 1-3-butyl-4-methyl-1- [3- (3-pyridyl) -prop-2-ene-1- in 35 ml isopropanol A solution of 1.71 g of Ill] -1 (RS), 1,2 (R) -pentanetricarboxylate was hydrogenated over 400 mg of 10% palladium on carbon for 5 hours. The catalyst was removed by filtration and the solvent was evaporated. Toluene (2 × 10 mL) was added and evaporated to remove the final traces of isopropanol. The residue was refluxed for 2 hours in a mixture of 40 ml of toluene and 0.42 ml of triethylamine, and the solvent was removed by evaporation to give a red oil. The oil in 10 ml dichloromethane was cooled to 0 ° C. while stirring under nitrogen, then 0.95 ml of N-ethylmorpholine was added followed by 0.49 g of 1-hydroxybenzotriazole and 0.72 g of 1-ethyl-3- ( 3-dimethylaminopropyl) carbodiimide hydrochloride was added. After stirring at 0 ° C. for 15 minutes, the solution was treated with 0.98 g of isobutylhydrazine tosylate salt and the mixture was allowed to warm to room temperature and then stirred overnight. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, 5% sodium bicarbonate solution and brine, then dried over anhydrous magnesium sulfate and evaporated. Chromatography on silica gel using dichloromethane / methanol (19: 1) for elution gave 0.63 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4- (3-pyridyl ) Butyl] -2'-isobutyl-4-methylvalerohydrazide was obtained as a white solid.

MS: 420 (M + H) ⁺ .

(ii) 0.62 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4- (3-pyridyl) in a similar manner as described in Example 1, part (ii) 0.68 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4- (3- starting with) butyl] -2'-isobutyl-4-methylvalerohydrazide Pyridyl) butyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in solid form.

MS: 498 (M + H) ⁺ .

(iii) 0.68 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4- (3-pyridyl) in a similar manner as described in Example 1, part (iii) 0.55 g of 2 (R)-[1 (S)-(carboxy) -4- () starting with butyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide 3-pyridyl) butyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained.

MS: 442 (M + H) ⁺ .

(iv) the carboxylic acid prepared in paragraph (iii) was dissolved in 3 ml of dimethylformamide, cooled to 0 ° C., 0.45 g of O-benzyl-hydroxylamine and 0.26 g of 1-ethyl-3- (3 Treated sequentially with -dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to warm to rt and stirred overnight. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The ethyl acetate layer was washed with water and 5% sodium bicarbonate solution, then dried over anhydrous magnesium sulfate and evaporated. The resulting rubber was triturated with diethyl ether to yield 0.34 g of 2 (R)-[1 (S)-[(benzyloxy) carbamoyl] -4- (3-pyridyl) butyl] -2'-isobutyl- 2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 547 (M + H) ⁺ .

Example 66

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4- (4-methoxyphenyl) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl -2'-phenylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.079 g of (E) -2 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (4- 0.041 g of (E) -2 (R)-[starting from methoxyphenyl) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide 1 (S)-(hydroxycarbamoyl) -4- (4-methoxyphenyl) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide Was obtained in the form of a white solid.

MS: 504 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.22 minutes. Solvent A: H ₂ O; Solvent B: CH ₃ CN. Column type: HYPERPEP 300A.

(E) -2 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (4-methoxyphenyl) -3-butenyl] -2 'used as starting material -(Methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was prepared as follows:

In a manner analogous to that described in Example 64, parts (i)-(vi), 1,2-dibenzyl 1-3-butyl-4-methyl-1 (RS), 1,2 (R) -pentane Starting with tricarboxylate and 4- (4-methoxyphenyl) -allyl acetate, (E) -2 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- ( 4-methoxyphenyl) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a gray solid.

MS: 588 (M + H) ⁺ .

Example 67

2 (R)-[4-cyclohexyl-1 (S)-(hydroxycarbamoyl) -butyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.17 g of 2 (R)-[4-cyclohexyl-1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl 0.11 g of 2 (R)-[4-cyclohexyl-1 (S) starting from] -butyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide -(Hydroxycarbamoyl) -butyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 462 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.82 minutes. Solvent A: H ₂ O; Solvent B: CH ₃ CN. Column type: HYPERPEP 300A.

2 (R)-[4-cyclohexyl-1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -butyl] -2'-isobutyl-2 'used as starting material -(Methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:

(i) 300 mg of platinum oxide in a solution of 1.0 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-butyl] -4-methylvaleric acid in 30 ml acetic acid Phase was hydrogenated for 1.5 h. The catalyst was removed by filtration and the solvent was evaporated. Toluene (3 × 10 mL) was added and evaporated to remove the final traces of acetic acid. Chromatography on silica gel using diethyl ether / hexane (1: 7) for elution yielded 0.67 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-cyclohexyl-butyl ] -4-methyl valeric acid was obtained as a white solid.

TLC: methanol / dichloromethane (1:19): Rf 0.51.

(ii) 0.66 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-cyclohexyl-butyl] in a similar manner as described in Example 1, part (i) 0.27 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4- (4-cyclohexyl) butyl] -2'-isobutyl starting from 4-methyl valeric acid 4-Methylvalerohydrazide was obtained (from hexane) in the form of a white solid.

MS: 425 (M + H) ⁺ .

(iii) 0.26 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4- (4-cyclohexyl, in a manner similar to that described in Example 1, part (ii) 0.31 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4- (4-cyclo) starting with) butyl] -2'-isobutyl-4-methylvalerohydrazide Hexyl) butyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained.

MS: 503 (M + H) ⁺ .

(iv) 0.30 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4- (4-cyclohexyl, in a manner similar to that described in Example 1, part (iii) 0.24 g of 2 (R)-[1 (S)-(carboxy) -4-, starting with) butyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide (4-cyclohexyl) butyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained.

MS: 447 (M + H) ⁺ .

(v) The carboxylic acid prepared in paragraph (iv) is dissolved in 3 ml of dimethylformamide, cooled to 0 ° C. and 0.19 g of O- (tetrahydro-2H-pyran-2 (RS) -yl) hydroxyl Treatment was successively with amine and 0.113 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to warm to rt and stirred overnight. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The ethyl acetate layer was washed with water, 5% sodium bicarbonate solution and brine, then dried over anhydrous magnesium sulfate and evaporated. The resulting solid was triturated with diethyl ether to give 0.18 g of 2 (R)-[4-cyclohexyl-1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -butyl]- 2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 546 (M + H) ⁺ .

Example 68

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4- (4- (methoxycarbonyl) phenyl) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.110 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.059 g, starting from -4- (4- (methoxycarbonyl) phenyl) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4- (4- (methoxycarbonyl) phenyl) -3-butenyl] -2 '-(methanesulfonyl) 4-Methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid.

MS: 532 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.09 minutes. Solvent A: H ₂ O; Solvent B: CH ₃ CN. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (4- (methoxycarbonyl) phenyl used as starting material ) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide is 4-methoxycarbonyl-cinnamil bromide to cinnamic bromide in step (i). Prepared as a white solid in a similar manner to Examples 2 (i) to (v) except for replacing with.

MS: 616 (M + H) ⁺ .

Example 69

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4- (4-nitrophenyl) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl- 2'-phenylvalerohydrazide

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (4-nitro) in a mixture of 3 ml methanol and 1.5 ml dichloromethane A solution of 0.080 g of phenyl) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was treated with 0.020 g of 4-toluenesulfonic acid. The mixture was stirred at rt for 5 h, then the solution was evaporated. The resulting rubber was triturated with diethyl ether to give 0.063 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4- (4-nitrophenyl) -3-butenyl]- 2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a light brown solid.

MS: 519 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.07 minutes. Solvent A: H ₂ O; Solvent B: CH ₃ CN. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (4-nitrophenyl) -3-part used as starting material Tenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide, in step (i) 4- (3-pyridyl) allyl acetate and tetrakis (triphenylphosphine) Prepared as a white solid in a similar manner to Examples 64 (i)-(vi) except that palladium (O) was replaced with 4-nitro-cinnamil bromide.

MS: 603 (M + H) ⁺ .

Example 70

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[( Morpholinocarbonyl) methyl] valerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.1 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.08 g of (starting from -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[(morpholinocarbonyl) methyl] valerohydrazide, E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[(mor Polynocarbonyl) methyl] valerohydrazide was obtained in the form of a white solid.

MS: 525 (M + H) ⁺ .

nmr (d ₆ DMSO): 10.52 (1H, s); 10.47 (1 H, s); 8.82 (1 H, s); 7.35-7.25 (4H, m); 7.23-7.17 (1 H, m); 6.28 (1H, doublet, J = 15.5 Hz); 6.09-5.98 (1 H, m); 4.40-4.26 (2H, m); 3.64-3.30 (8H, m); 3.15 (3H, s); 2.63-2.54 (1 H, m); 2.37-2.08 (3H, m); 1.50-1.28 (2H, m); 0.98-0.89 (1 H, m); 0.78 (6 H, m).

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.19 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and N-bromoacetylmorpholine.

MS: 609 (M + H) ⁺ .

Example 71

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2 Morpholinoethyl) valerohydrazide

In a similar manner as described in the first paragraph of Example 2, after washing the ethyl acetate solution of the product with sodium hydrogen carbonate solution to obtain the free base, 0.13 g of (E) -2 (R)-[1 ( S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2- 0.1 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(from morpholinoethyl) valerohydrazide Methanesulfonyl) -4-methyl-2 '-(2-morpholinoethyl) valerohydrazide was obtained in the form of a white solid.

MS: 511 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.71 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 4- (2-chloroethyl) morpholine.

MS: 595 (M + H) ⁺ .

Example 72

Methyl (E) -2- [2- [2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -1-[( Methanesulfonyl) hydrazino] acetate

In a manner similar to that described in the first paragraph of Example 2, 0.12 g of methyl (E) -2- [2- [2 (R)-[1 (S)-[(tetrahydro-2 (RS)- 0.09 g of methyl (E) -2 starting from pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvaleryl] -1- (methanesulfonyl) hydrazino] acetate -[2- [2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -1-[(methanesulfonyl) hydra Zino] acetate was obtained in the form of a white solid.

MS: 470 (M + H) ⁺ .

nmr (d ₆ DMSO): 10.77 (1H, s); 10.53 (1 H, m); 8.83 (1 H, m); 7.35-7.25 (4H, m); 7.22-7. 16 (1 H, m); 6.27 (1H, doublet, J = 15.5 Hz); 6.08-5.99 (1 H, m); 4.41-4.17 (2H, m); 3.66 (3H, s); 3.14 (3H, s); 2.62-2.53 (1 H, m); 2.35-2.07 (3H, m); 1.50-1.40 (1 H, m); 1.38-1.25 (1 H, m); 1.00-0.92 (1 H, m); 0.79 (6 H, m).

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.93 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and methylbromoacetate.

MS: 554 (M + H) ⁺ .

Example 73

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(3 -Phenylpropyl) valerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.166 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.091 g of (E) -2 starting from 4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(3-phenylpropyl) valerohydrazide (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(3-phenylpropyl) ballet Lohydrazide was obtained in the form of a gray solid.

MS: 516 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.01 and 13.19 min (double peak). Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 1-bromo-3-phenylpropane.

MS: 600 (M + H) ⁺ .

Example 74

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[( 2-naphthyl) methyl] valerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.156 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.109 g of (E, starting from -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[(2-naphthyl) methyl] valerohydrazide ) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[(2- Naphthyl) methyl] valerohydrazide was obtained in the form of a gray solid.

MS: 538 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.09 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Starting with (methanesulfonyl) -4-methyl-2 '-[(2-naphthyl) methyl] valerohydrazide and 2-bromomethylnaphthalene, as described in Example 15, part (iii) Prepared in a similar manner.

MS: 622 (M + H) ⁺ .

Example 75

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-(methoxyethyl)- 4-methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.133 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.073 g, starting from -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2-methoxyethyl) -4-methylvalerohydrazide (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -2'-(2-methoxyethyl ) -4-methylvalerohydrazide was obtained in the form of a gray solid.

MS: 456 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.67 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 2-bromoethyl methyl ether.

MS: 540 (M + H) ⁺ .

Example 76

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(2-hydroxyethyl) -2'-(methanesulfonyl ) -4-Methylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.148 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.041 g of (E)-, starting from 4-phenyl-3-butenyl] -2 '-(2-hydroxyethyl) -2'-(methanesulfonyl) -4-methylvalerohydrazide 2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(2-hydroxyethyl) -2'-(methanesulfonyl) -4- Methylvalerohydrazide was obtained in the form of a cream solid.

MS: 442 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.16 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 2-bromoethanol.

MS: 526 (M + H) ⁺ .

Example 77

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[( 4-pyridyl) methyl] valerohydrazide p-toluenesulfonate

In a manner similar to that described in the first paragraph of Example 2, 0.097 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.077 g of (E, starting from -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[(4-pyridyl) methyl] valerohydrazide ) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[(4- Pyridyl) methyl] valerohydrazide p-toluenesulfonate was obtained in the form of a gray solid.

MS: 489 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.59 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Starting with (methanesulfonyl) -4-methylvalerohydrazide and 4-bromomethylpyridine hydrobromide, it was prepared in a similar manner as described in Example 15, part (iii).

MS: 573 (M + H) ⁺ .

Example 78

(E) -2 '-(cyclopropylmethyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl)- 4-methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.13 g of (E) -2′-cyclopropylmethyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS)- 0.092 g of (E) -2 '-(starting from pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-(methanesulfonyl) -4-methylvalerohydrazide Cyclopropylmethyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide Was obtained in the form of a white solid.

MS: 452 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.47 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and cyclopropylmethyl bromide.

Example 79

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[2 (S) -methylbutyl] valerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.135 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.101 g of (E, starting from -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[2 (S) -methylbutyl] valerohydrazide ) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[2 (S ) -Methylbutyl] valerohydrazide was obtained in the form of a white solid.

MS: 468 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.70 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Similar to that described in Example 15, Part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and (S)-(+)-1-bromo-2-methylbutane It was prepared by.

Example 80

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-[3-hydroxy-2 (R) -methylpropyl]- 2 '-(methanesulfonyl) -4-methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.13 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from -4-phenyl-3-butenyl] -2 '-[3-hydroxy-2 (R) -methylpropyl] -2'-(methanesulfonyl) -4-methylvalerohydrazide, 0.095 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-[3-hydroxy-2 (R) -methyl Propyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 470 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.20 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Starting with (methanesulfonyl) -4-methylvalerohydrazide and (S)-(+)-3-bromo-2-methyl-1-propanol, described in Example 15, part (iii) Prepared in a similar manner as

Example 81

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-[3-hydroxy-2 (S) -methylpropyl]- 2 '-(methanesulfonyl) -4-methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.13 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from -4-phenyl-3-butenyl] -2 '-[3-hydroxy-2 (S) -methylpropyl] -2'-(methanesulfonyl) -4-methylvalerohydrazide, 0.09 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-[3-hydroxy-2 (S) -methyl Propyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 470 (MH) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.11 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Starting with (methanesulfonyl) -4-methylvalerohydrazide and (R)-(-)-3-bromo-2-methyl-1-propanol, described in Example 15, Part (iii) It was prepared by a similar method as described above.

Example 82

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isopentyl-2 '-(methanesulfonyl) -4-methyl Valerohydrazide

In a method similar to that described in the first paragraph of Example 2, 0.12 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.08 g of (E) -2 (R)-starting from 4-phenyl-3-butenyl] -2'-isopentyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide [1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isopentyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide as a white solid Obtained.

MS: 468 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.63 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 1-bromo-3-methylbutane.

Example 83

(E) -2 '-(cyclobutylmethyl) -2 (R)-[(S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl) -4 Methylvalerohydrazide

In a manner analogous to that described in the first paragraph of Example 2, 0.13 g of (E) -2 '-(cyclobutylmethyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) 0.075 g of (E) -2 'starting from) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-(methanesulfonyl) -4-methylvalerohydrazide -(Cyclobutylmethyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohi Drazide was obtained in the form of a white solid.

MS: 466 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.34 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and cyclobutylmethyl bromide.

Example 84

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(3 -Methyl-2-butenyl) valerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.222 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.137 g of (starting from -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(3-methyl-2-butenyl) valerohydrazide, E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(3- Methyl-2-butenyl) valerohydrazide was obtained in the form of a white solid.

MS: 466 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.95 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 3,3-dimethylallyl bromide.

Example 85

(E) -2'-benzyl-2 '-(butanesulfonyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalle Lohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.17 g of (E) -2'-benzyl-2 '-(butanesulfonyl) -2 (R)-[1 (S)-[(tetra 0.115 g of (E) -2'-benzyl-2 starting from hydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide '-(Butanesulfonyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide in the form of a white solid It was.

MS: 530 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.83 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Starting materials were prepared as follows:

(i) 0.54 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl in a similar manner as described in Example 1, part (ii) 0.425 g of (E) -2 '-(butanesulfonyl) -2 (R)-[1 (starting with 3-butenyl] -4-methylvalerohydrazide and 1-butanesulfonyl chloride S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide was obtained in the form of a white foam.

MS: 481 (M + H) ⁺ .

(ii) 0.416 g of (E) -2 '-(butanesulfonyl) -2 (R)-[1 (S)-(tertiary-) in a similar manner as described in Example 15, part (iii) 0.463 g of (E) -2'-benzyl-2 '-(butanesulfonyl) starting with butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide and benzyl bromide ) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide was obtained in the form of a pale yellow rubber. .

MS: 571 (M + H) ⁺ .

(iii) 0.46 g of (E) -2'-benzyl-2 '-(butanesulfonyl), in a similar manner as described in Example 1, part (iii), followed by Example 2, part (v) 0.174 g of (E) starting from -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide -2'-benzyl-2 '-(butanesulfonyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxycarbonyl] -4-phenyl-3-part Tenyl] -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 614 (M + H) ⁺ .

Example 86

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2 -Methyl allyl) valerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.14 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.063 g of (E) -2, starting from 4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2-methylallyl) valerohydrazide (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2-methylallyl) ballet Lohydrazide was obtained in the form of a gray solid.

MS: 452 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.75 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and methylallyl chloride.

Example 87

(E) -2 '-(2-cyclohexylethyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl ) -4-Methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.183 g of (E) -2 ′-(2-cyclohexylethyl) -2 (R)-[1 (S)-[(tetrahydro-2 0.12 g of (E)-, starting from (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide 2 '-(2-cyclohexylethyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl) -4- Methylvalerohydrazide was obtained in the form of a white solid.

MS: 508 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.93 and 14.02 min (double peak). Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 2-cyclohexylethyl bromide.

Example 88

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-[2- (3-indolyl) ethyl] -2'- (Methanesulfonyl) -4-methylvalerohydrazide

In a manner analogous to that described in the first paragraph of Example 2, 0.128 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.063 g of, starting from -4-phenyl-3-butenyl] -2 '-[2- (3-indolyl) ethyl] -2'-(methanesulfonyl) -4-methylvalerohydrazide (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-[2- (3-indolyl) ethyl] -2'- (Methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a pale orange foam.

MS: 541 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.52 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 3- (2-bromoethyl) indole.

Example 89

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(3 -Phenylallyl) valerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.18 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.123 g of (E) -2 starting from -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(3-phenylallyl) valerohydrazide (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(3-phenylallyl) ballet Lohydrazide was obtained in the form of a pale yellow solid.

MS: 514 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.69 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Starting with (methanesulfonyl) -4-methylvalerohydrazide and cinnamil bromide, it was prepared in a similar manner as described in Example 15, part (iii).

Example 90

(E) -2'-benzyl-2 '-(ethanesulfonyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalle Lohydrazide

In a manner analogous to that described in the first paragraph of Example 2, 0.1 g of (E) -2'-benzyl-2 '-(ethanesulfonyl) -2 (R)-[1 (S)-[(tetra 0.052 g of (E) -2'-benzyl-2 starting from hydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide Obtain '-(ethanesulfonyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide in the form of a gray solid It was.

MS: 502 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.70 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Starting materials include (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide and ethanesulfur Starting with polyvinyl chloride, it was prepared in a similar manner as described in Example 85, Parts (i)-(iii).

Example 91

(E) -2 '-(2,2,2-trifluoroethanesulfonyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl]- 4-methyl-2'-phenylvalerohydrazide

In a method similar to that described in the first paragraph of Example 2, 0.125 g of (E) -2 '-(2,2,2-trifluoroethanesulfonyl) -2 (R)-[1 (S) 0.093 g of ([tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide starting with E) -2 '-(2,2,2-trifluoroethanesulfonyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4 -Methyl-2'-phenylvalerohydrazide was obtained in the form of a gray solid.

MS: 542 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.42 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Starting materials include (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide and 2, Starting with 2,2-trifluoroethanesulfonyl chloride, it was prepared in a similar manner as described in Example 17, parts (i)-(iii).

Example 92

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(3-hydroxypropyl) -2'-(methanesulfonyl ) -4-Methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.191 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.119 g of (E)-, starting from -4-phenyl-3-butenyl] -2 '-(3-hydroxypropyl) -2'-(methanesulfonyl) -4-methylvalerohydrazide 2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(3-hydroxypropyl) -2'-(methanesulfonyl) -4- Methylvalerohydrazide was obtained in the form of a gray solid.

MS: 456 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.61 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 3-bromo-1-propanol.

Example 93

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[2 -(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] valerohydrazide

In a method analogous to that described in the first paragraph of Example 2, 0.196 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[2- (3,4,4-trimethyl-2,5-dioxo-1-imida 0.094 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 starting from zolidinyl) ethyl] valerohydrazide '-(Methanesulfonyl) -4-methyl-2'-[2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] valerohydrazide gray Obtained in the form of a solid.

MS: 566 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.37 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Similar to that described in Example 15, Part (iii), starting with (methanesulfonyl) -4-methylhydrazide and 3- (2-bromoethyl) -1,5,5-trimethylhydantoin It was prepared by the method.

Example 94

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(4 -Pentenyl) valerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.168 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.105 g of (E) -2 starting from -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(4-pentenyl) valerohydrazide (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(4-pentenyl) ballet Lohydrazide was obtained in the form of a white solid.

MS: 466 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.31 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 5-bromo-1-pentene.

Example 95

(E) -2 '-(3-butenyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl) 4-valerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.137 g of (E) -2 '-(3-butenyl) -2 (R)-[1 (S)-[(tetrahydro-2 ( RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-valerohydrazide, starting with 0.081 g of (E) -2' -(3-butenyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-valerohi Drazide was obtained in the form of a white solid.

MS: 452 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.80 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 4-bromo-1-butene.

Example 96

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-propylvalle Lohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.211 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.129 g of (E) -2 (R)-[starting from -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-propylvalerohydrazide 1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-propylvalerohydrazide in the form of a white solid Obtained.

MS: 440 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.77 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 1-bromopropane.

Example 97

(E) -2'-butyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalle Lohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.181 g of (E) -2'-butyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyl 0.129 g of (E) -2'-butyl-2, starting from oxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid Obtained.

MS: 454 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.12 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 1-bromobutane.

Example 98

(E) -2 '-(2-aminoethyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl) 4-Methylvalerohydrazide p-toluenesulfonate

In a manner similar to that described in the first paragraph of Example 2, 0.1 g of (E) -2 ′-(2-aminoethyl) -2 (R)-[1 (S)-[(tetrahydro-2 ( RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide, 0.086 g of (E) -2 '-(2-aminoethyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- (methanesulfonyl) -4-methylvalle Lohydrazide p-toluenesulfonate was obtained in the form of a gray solid.

MS: 441 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.58 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Starting materials were prepared as follows:

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- in 10 mL methanol. A suspension of 0.926 g of (methanesulfonyl) -4-methyl-2 '-(2-phthalimidoethyl) valerohydrazide was treated with 0.25 ml hydrazine hydrate. The mixture was stirred at rt overnight. The suspended white solid was filtered, the filtrate was concentrated and the residue was purified by chromatography on silica gel using 5% methanol in dichloromethane for elution. The product was triturated with ether and then 0.23 g of (E) -2 '-(2-aminoethyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carba Moyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.

MS: 525 (M + H) ⁺ .

Example 99

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[2 -(1-pyrrolyl) ethyl] valerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.163 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.041 g, starting from -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[2- (1-pyrrolyl) ethyl] valerohydrazide (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[2 -(1-pyrrolyl) ethyl] valerohydrazide was obtained in the form of a gray solid.

MS: 491 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.05 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 1- (2-bromomethyl) -pyrrole.

Example 100

(E) -2 '-[2- (1,3-dioxolan-2-yl) ethyl] -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-part Tenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide

In a manner analogous to that described in the first paragraph of Example 2, 0.145 g of (E) -2 '-[2- (1,3-dioxolan-2-yl) ethyl] -2 (R)-[1 From (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide Starting, 0.067 g of (E) -2 '-[2- (1,3-dioxolan-2-yl) ethyl] -2 (R)-[1 (S)-(hydroxycarbamoyl) -4 -Phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a pale orange solid.

MS: 498 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.63 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERSIL ODS.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Starting with (methanesulfonyl) -4-methylvalerohydrazide and 2- (2-bromoethyl) -1,3-dioxolane, in a similar manner as described in Example 15, Part (iii) Prepared.

Example 101

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(4-methoxybenzenesulfonyl) -4-methylvalero Hydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.19 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.115 g of (E) -2 (R)-[1 starting from 4-phenyl-3-butenyl] -2 '-(4-methoxybenzenesulfonyl) -4-methylvalerohydrazide (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(4-methoxybenzenesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 490 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.53 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Starting materials were prepared as follows:

(i) 0.54 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl in a similar manner as described in Example 1, part (ii) 0.492 g of (E) -2 (R)-[1 (S)-(tertiary-, starting with 3-butenyl] -4-methylvalerohydrazide and 4-methoxybenzenesulfonyl chloride Butoxycarbonyl) -4-phenyl-3-butenyl] -2 '-(4-methoxybenzenesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 531 (M + H) ⁺ .

(ii) Example 1, part (iii), followed by 0.482 g of (E) -2 (R)-[1 (S)-(3) in a similar manner as described in Example 2, part (v). 0.194 g of (E)-starting from tert-butoxycarbonyl) -4-phenyl-3-butenyl] -2 '-(4-methoxybenzenesulfonyl) -4-methylvalerohydrazide 2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(4-methoxybenzenesulfonyl ) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 574 (M + H) ⁺ .

Example 102

(E, E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenyl-2 '-[(2- Phenylvinyl) sulfonyl] valerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.245 g of (E, E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carba Moyl] -4-phenyl-3-butenyl] -4-methyl-2'-phenyl-2 '-[(2-phenylvinyl) sulfonyl] valerohydrazide starting from 0.086 g of (E, E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenyl-2 '-[(2-phenylvinyl) Sulfonyl] valerohydrazide was obtained in the form of a white solid.

MS: 562 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.94 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylhydrazide And starting from trans-beta-styrenesulfonyl chloride, followed by Example 1, parts (ii) and (iii), followed by a method similar to that described in Example 2, part (v).

Example 103

(E) -2'-furfural-2 (R)-[1 (S)-(hydroxycarbonyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl Valerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.071 g of (E) -2'-furfural-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyra 0.042 g of (E) -2'-furfural starting from nyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide as a white solid Obtained in form.

MS: 478 (M + H) ⁺ .

HPLC: equivalent elution with 50% CH ₃ CN / water; Flow rate of 1 ml / min. Retention time: 3.82 minutes. Column type: Waters Symmetric 10 cm, C ₁₈ , 0.46 cm inner diameter.

Starting materials were (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide and 2- Starting with puraldehyde, it was prepared in a similar manner as described in Example 45, parts (i) and (ii).

Example 104

(E) -2'-ethyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalle Lohydrazide

In a manner analogous to that described in the first paragraph of Example 2, 0.136 g of (E) -2'-ethyl-2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyl 0.087 g of (E) -2'-ethyl-2 starting from oxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid Obtained.

MS: 426 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 20% solvent B to 80% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 14.12 minutes. Solvent A: 100% 0.05 M triethylammonium phosphate buffer, pH 2.5 (TEAP); Solvent B: 80% CH ₃ CN / (TEAP). Column type: Waters Symmetrical 10 cm, 0.46 cm inner diameter.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Starting with (methanesulfonyl) -4-methylvalerohydrazide and ethyl iodide, it was prepared in a similar manner as described in Example 15, part (iii).

Example 105

(E) -2 '-(2,6-dichlorobenzyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulphur Ponyyl) -4-methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.09 g of (E) -2 '-(2,6-dichlorobenzyl) -2 (R)-[1 (S)-[(tetrahydro- 0.05 g of (E) starting from 2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide -2 '-(2,6-dichlorobenzyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl)- 4-Methylvalerohydrazide was obtained in the form of a white solid.

MS: 556/558 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 30% solvent B to 95% solvent B over 7 minutes; Flow rate of 1 ml / min. Retention time: 7.30 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.1% TFA. Column type: HYPERSIL ODS.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 2,6-dichlorobenzyl bromide.

Example 106

(E) -2 '-(cyclopentylmethyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-(methanesulfonyl)- 4-methylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.04 g of (E) -2 '-(cyclopentylmethyl) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) 0.041 g of (E) -2 'starting from) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-(methanesulfonyl) -4-methylvalerohydrazide -(Cyclopentylmethyl) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohi Drazide was obtained in the form of a white solid.

MS: 480 (M + H) ⁺ .

HPLC: equivalent elution with 60% CH ₃ CN / TEAP; Flow rate of 1 ml / min. Retention time: 3.25 minutes. Column type: Waters Symmetric 10 cm, C ₁₈ , 0.46 cm inner diameter.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and cyclopentylmethyl methanesulfonate.

Example 107

2 (R)-[2- (2-benzofuranyl) -1 (S)-(hydroxycarbamoyl) ethyl-2'-isobutyl-2 '-(methanesulfonyl) -4-methylhydrazide

In a similar manner as described in the first paragraph of Example 2, 0.066 g of 2 (R)-[2- (2-benzofuranyl) -1 (S)-[(tetrahydro-2 (RS) -pyra 0.015 g of 2 (R)-[2- (2-benzo) starting from niloxy) carbamoyl] ethyl-2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide Furanyl) -1 (S)-(hydroxycarbamoyl) ethyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 468 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 98% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.34 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Starting materials were prepared as follows:

(i) 1.14 g of 60% sodium hydride in 1,2-dibenzyl 1-3-butyl-4-methyl-1,1,2 (R)-in 150 ml of dry, ice-cold dimethylformamide under nitrogen atmosphere. 12.35 g of pentanetricarboxylate was added to the stirred solution. The mixture was stirred at freezing temperature for 30 minutes and further at room temperature for 1.5 hours. The mixture was again cooled to freezing temperature and then 5.78 g of 2-bromomethylbenzofuran was added. The mixture was slowly returned to room temperature and stirred overnight. The solution was then evaporated and the residue partitioned between ethyl acetate and 5% citric acid solution. The ethyl acetate solution was washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using hexane / ether (9: 1) for elution. 14.64 g of 1,2-dibenzyl 1-3-butyl-1- (2-benzofuranyl) methyl-4-methyl-1,1,2 (R) -pentanetricarboxylate are obtained in the form of a colorless oil. It was.

(ii) 150 mL of 14.64 g of 1,2-dibenzyl 1-3-butyl-1- (2-benzofuranyl) methyl-4-methyl-1,1,2 (R) -pentanetricarboxylate In ethanol and a solution of 9.8 g of sodium hydroxide in 55 ml of water was added. The mixture was heated to reflux for 24 hours, then cooled and the solvent evaporated. The residue was dissolved in 400 mL of water and the pH was adjusted to 3 by addition of 4 M sulfuric acid solution. The aqueous solution was extracted with 400 ml of ethyl acetate, then the extract was washed successively with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in 150 ml of toluene containing 3.8 ml of triethylamine. The mixture was heated to reflux for 2 hours, cooled and washed successively with 5% citric acid solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was dissolved in 50 ml of hexane and treated with 2.43 g of cyclohexane. After the mixture was kept in the refrigerator for 2 hours, the resulting white solid was filtered and washed with hexane. The solid was suspended in 150 ml of ethyl acetate and shaken with two 50 ml portions of 2M sulfuric acid. The ethyl acetate solution was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. 3.701 g of 4-tert-butyl hydrogen 3 (S)-(2-benzofuranyl) methyl-2 (R) -isobutylsuccinate were obtained in the form of a light yellow rubber.

(iii) 1-bromo-2-methanepropane starting from 4-tert-butyl hydrogen 3 (S)-(2-benzofuranyl) methyl-2 (R) -isobutylsuccinate and in part (iii) In the same manner as described in Example 15, parts (i)-(iii), 2 (R)-[2- (2-benzofuranyl) -1 (S)-[(tetrahydro- 2 (RS) -pyranyloxy) carbamoyl] ethyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 552 (M + H) ⁺ .

Example 108

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[( 3-pyridyl) methyl] valerohydrazide methanesulfonate

In a similar manner as described in the first paragraph of Example 2 except for using methanesulfonic acid instead of p-toluenesulfonic acid, 0.2 g of (E) -2 (R)-[1 (S)-[ (Tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[(3-pyridyl) 0.177 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(starting from methyl] valerohydrazide Methanesulfonyl) -4-methyl-2 '-[(3-pyridyl) methyl] valerohydrazide methanesulfonate was obtained in the form of an orange solid.

MS: 489 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 8.05 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 3-bromomethylpyridine hydrobromide.

Example 109

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[2 -(2-pyridyl) ethyl] valerohydrazide methanesulfonate

In a similar manner as described in the first paragraph of Example 2, except that methanesulfonic acid is used instead of p-toluenesulfonic acid, 0.176 g of (E) -2 (R)-[1 (S)-[ (Tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[(2-pyridyl) 0.13 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(starting from ethyl] valerohydrazide Methanesulfonyl) -4-methyl-2 '-[(2-pyridyl) ethyl] valerohydrazide methanesulfonate was obtained in the form of a pale orange solid.

MS: 503 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.97 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (R) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting with (methanesulfonyl) -4-methylvalerohydrazide and 2- (2-bromoethyl) pyridine hydrobromide.

Example 110

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[2 -(4-pyridyl) ethyl] valerohydrazide methanesulfonate

In a similar manner as described in the first paragraph of Example 2, except that methanesulfonic acid is used instead of p-toluenesulfonic acid, 0.146 g of (E) -2 (R)-[1 (S)-[ (Tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[2- (4-pyri 0.104 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 'starting from dill) ethyl] valerohydrazide -(Methanesulfonyl) -4-methyl-2 '-[2- (4-pyridyl) ethyl] valerohydrazide methanesulfonate was obtained in the form of a pale orange solid.

MS: 503 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.74 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Starting with (methanesulfonyl) -4-methylvalerohydrazide and 4- (2-bromoethyl) pyridine hydrobromide, it was prepared by a method similar to that described in Example 15, part (iii).

Example 111

2 (R)-[3-cyclohexylidene-1 (S)-(hydroxycarbamoyl) -propyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydra Jide

In a manner similar to that described in the first paragraph of Example 2, 0.085 g of 2 (R)-[3-cyclohexylidene-1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) Carbamoyl] propyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide starting from 0.042 g of 2 (R)-[3-cyclohexylidene-1 (S)-(hydroxycarbamoyl) propyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 446 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.20 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Starting materials were prepared as follows:

(i) Example 107, parts (i) and (ii), except that instead of crystallization of the cyclohexylamine salt, the product was purified by flash chromatography on silica gel using hexane / ether (4: 1) for elution. In a similar manner as described, starting with 1,2-dibenzyl 1-3-butyl 4-methyl-1,1,2 (R) -pentanetricarboxylate and (2-bromoethylidene) cyclohexane , 4-tert-butyl hydrogen 3 (S)-[(2-cyclohexylidene) ethyl] -2 (R) -isobutylsuccinate was obtained in the form of a light yellow rubber.

MS: 339 (M + H) ⁺ .

(ii) 4-tert-butyl hydrogen 3 (S)-[(2-cyclohexylidene) ethyl] -2 (R) in a manner analogous to that described in Example 2, parts (iii)-(v) The tertiary butyl ester is deprotected using trimethylsilyl trifluoromethanesulfonate in 1,4-dioxane, starting from the) -isobutylsuccinate and isobutylhydrazine, and 2 (R )-[3-cyclohexylidene-1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] propyl] -2'-isobutyl-2 '-(methanesulfonyl)- 4-Methylvalerohydrazide was obtained in the form of a yellow solid.

MS: 530 (M + H) ⁺ .

Example 112

2 (R)-[3- (tetrahydro-2H-pyran-4-ylidene) -1 (S)-(hydroxycarbamoyl) propyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.09 g of 2 (R)-[3- (tetrahydro-2H-pyran-4-ylidene) -1 (S)-[(tetrahydro- 0.046 g of 2 (R)-, starting from 2 (RS) -pyranyloxy) carbamoyl] propyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide [3- (tetrahydro-2H-pyran-4-ylidene) -1 (S)-(hydroxycarbamoyl) propyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalle Lohydrazide was obtained in the form of a white solid.

MS: 448 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.22 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Starting materials were prepared as follows:

(i) Example 107, parts (i) and (ii), except that instead of crystallization of the cyclohexylamine salt, the product was purified by flash chromatography on silica gel using hexane / ether (4: 1) for elution. In a similar manner as described, 1,2-dibenzyl 1-3-butyl 4-methyl-1,1,2-2 (R) -pentanetricarboxylate and 4- (2-bromoethylidene) tetra Starting with hydro-2H-pyran, 4-tert-butyl hydrogen 3 (S)-[(tetrahydro-2H-pyran-4-ylidene) ethyl] -2 (R) -isobutylsuccinate is light yellow Obtained in the form of a rubber.

MS: 341 (M + H) ⁺ .

(ii) 4-tert-butyl hydrogen 3 (S)-[(tetrahydro-2H-pyran-4-ylidene) ethyl in a similar manner as described in Example 2, parts (iii)-(v) ] 2 (R) -isobutylsuccinate and isobutylhydrazine and deprotected tertiary butyl ester using trimethylsilyl trifluoromethanesulfonate in 1,4-dioxane instead of trifluoroacetic acid , 2 (R)-[3- (tetrahydro-2H-pyran-4-ylidene) -1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] propyl] -2 ' -Isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a gray solid.

MS: 532 (M + H) ⁺ .

Example 113

2 (R)-[3- (tetrahydro-2H-pyran-4-yl) -1 (S)-(hydroxycarbamoyl) -propyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.14 g of 2 (R)-[3- (tetrahydro-2H-pyran-4-yl) -1 (S)-[(tetrahydro-2 0.083 g 2 (R)-[starting from (RS) -pyranyloxy) carbamoyl] propyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide 3- (tetrahydro-2H-pyran-4-yl) -1 (S)-(hydroxycarbamoyl) propyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohi Drazide was obtained in the form of a gray solid.

MS: 450 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.15 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Starting materials were prepared as follows:

(i) a solution of 0.397 g of 4-tert-butyl hydrogen 3 (S)-[(tetrahydro-2H-pyran-4-ylidene) ethyl] -2 (R) -isobutylsuccinate in 10 mL methanol It was shaken under hydrogen atmosphere in the presence of 0.196 g of 10% palladium catalyst on charcoal until no uptake of hydrogen was observed. The catalyst was filtered off and the filtrate was evaporated. 0.331 g of 4-tert-butyl hydrogen 3 (S)-[(tetrahydro-2H-pyran-4yl) ethyl] -2 (R) -isobutylsuccinate was obtained in the form of a colorless rubber.

MS: 343 (M + H) ⁺ .

(ii) 4-tert-butyl hydrogen 3 (R)-(tetrahydro-2H-pyran-4-yl) ethyl-2 in a manner analogous to that described in Example 2, parts (iii)-(v) 2 (R)-[3- (tetrahydro-2H-pyran-4-yl) -1 (S)-[(tetrahydro-2 (RS) starting from (R) -isobutylsuccinate and isobutylhydrazine ) -Pyranyloxy) carbamoyl] propyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 534 (M + H) ⁺ .

Example 114

2 (R)-[3-cyclohexyl-1 (S)-(hydroxycarbamoyl) -propyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.145 g of 2 (R)-[3-cyclohexyl-1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl ] Propyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide starting from 0.093 g of 2 (R)-[3-cyclohexyl-1 (S)- (Hydroxycarbamoyl) propyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 448 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.82 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was prepared in the same manner as described in Example 113, parts (i) and (ii), 4-tert-butyl hydrogen 3 (S)-(2-cyclohexylidene) ethyl-2 (R). Prepared starting from isobutyl succinate.

Example 115

2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butynyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydra Jide

In a similar manner as described in the first paragraph of Example 2, 0.189 g of 2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl 0.098 g of 2 (R)-[1 (S)-(hydr) starting from 3-butynyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide Roxycarbamoyl) -4-phenyl-3-butynyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 452 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.42 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Starting materials were prepared as follows:

(i) 1,2-dibenzyl 1-3-butyl-4-methyl-1,1,2 (R) -pentane in a similar manner as described in Example 107, parts (i) and (ii) 2 (R)-[1 (S) -tert-butoxycarbonyl) -4-phenyl-3-butynyl] starting with tricarboxylate and 1-bromo-3-phenyl-2-propyne 4-Methylvaleric acid was obtained in the form of a pale yellow solid.

(ii) 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3- in a similar manner as described in Example 2, parts (iii)-(v) 2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl- starting with butynyl) -4-methylvaleric acid and isobutylhydrazine 3-butynyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 536 (M + H) ⁺ .

Example 116

2 (R)-[1 (S)-(hydroxycarbamoyl) -3-phenoxypropyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.23 g of 2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -3-phenoxy 0.143 g of 2 (R)-[1 (S)-(hydroxycarbamoyl) starting from cipropyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide ) -3-phenoxypropyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a creamy white solid.

MS: 458 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.89 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Starting materials were prepared as follows:

(i) Example 107, parts (i) and (ii), except that instead of crystallization of the cyclohexylamine salt, the product was purified by flash chromatography on silica gel using hexane / ether (4: 1) for elution. In a similar manner as described, starting with 1,2-dibenzyl 1-3-butyl 4-methyl-1,1,2 (R) -pentanetricarboxylate and (2-iodoethoxy) benzene, Quaternary-butyl hydrogen 3 (S)-(2-phenoxy) ethyl-2 (R) -isobutylsuccinate was obtained in the form of a light yellow oil.

MS: 351 (M + H) ⁺ .

(ii) 4-tert-butyl hydrogen 3 (S)-(2-phenoxy) ethyl-2 (R) -isobutyl in a similar manner as described in Example 2, parts (iii)-(v) 2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -3-phenoxypropyl] -2'-iso starting from succinate and isobutylhydrazine Butyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 542 (M + H) ⁺ .

Example 117

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[( 3-methyl-3-oxetanyl) methyl] valerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.34 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[(3-methyl-3-oxetanyl) methyl] valerohydrazide, 0.22 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2' -[(3-methyl-3-oxetanyl) methyl] valerohydrazide was obtained in the form of a white solid.

MS: 482 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.76 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was prepared in a manner similar to that described in Example 45, parts (i) and (ii), with (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4 -Phenyl-3-butenyl] -4-methylvalerohydrazide and 3-methyl-3-oxetanecarboxaldehyde.

Example 118

2 (R)-[1 (S)-(hydroxycarbamoyl) -3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.58 g of 2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -3-part 0.41 g of 2 (R)-[1 (S)-(hydroxycarbamoyl)-, starting from tenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide 3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid.

MS: 398 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.97 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -3-butenyl] -2 '-(methanesulfonyl) -4 used as starting material -Methyl-2-phenylvalerohydrazide was prepared as follows:

In a manner similar to that described in Example 1, Part (i) and Example 2, Parts (iii) to (v), 2 (R)-[1 (S)-(tert-butoxycarbonyl)- 2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -3-butenyl] -2 starting from 3-butenyl-4-methylvaleric acid '-(Methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid.

MS: 482 (M + H) ⁺ .

Example 119

2 (R)-[1 (S)-(hydroxycarbamoyl) -butyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide

In a manner similar to that described in the first paragraph of Example 65, 0.50 g of 2 (R)-[1 (S)-[(benzyloxy) carbamoyl] butyl] -2 '-(methanesulfonyl) -4 0.36 g of 2 (R)-[1 (S)-(hydroxycarbamoyl) butyl] -2 '-(methanesulfonyl) -4-, starting from -methyl-2'-phenylvalerohydrazide Methyl-2'-phenylvalerohydrazide was obtained in the form of a white solid.

MS: 400 (M + H) ⁺ .

HPLC: gradient elution from 5% solvent A to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.14 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

2 (R)-[1 (S)-[(benzyloxy) carbamoyl] butyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide used as starting material Prepared as follows:

(i) A solution of 3.0 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -3-butenyl] -4-methylvaleric acid in 30 ml ethanol Hydrogenated for 4 hours in the presence of% palladium. The catalyst was removed by filtration and the solvent was evaporated. The residue was dissolved in 30 ml of toluene and the solvent was evaporated again. The procedure was repeated to give 2.83 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) butyl] -4-methylvaleric acid as colorless oil.

(ii) 2 (R)-[1 (S)-(tert-butoxycarbo) in a similar manner as described in Example 1, Part (i) and Example 65, Parts (ii)-(iv) 2 (R)-[1 (S)-[(benzyloxy) carbamoyl] butyl] -2 '-(methanesulfonyl) -4-methyl-2 starting from nil) butyl] -4-methyl valeric acid '-Phenylvalerohydrazide was obtained in the form of a white solid.

MS: 490 (M + H) ⁺ .

Example 120

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-N-phthalimidovaleramide

In a method analogous to that described in the first paragraph of Example 45, 0.126 g of (E) -2 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3 0.034 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3- starting from -butenyl] -4-methyl-N-phthalimidovaleramide Butenyl] -4-methyl-N-phthalimidovaleramide was obtained in the form of a white solid.

MS: 450 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.00 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methyl-N-phthalimido used as starting material Valeramide was prepared as follows:

(i) (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide in 50 ml toluene A solution of 1.0 g and 0.41 g of phthalic anhydride was heated to reflux for 2 hours. The mixture was cooled, the solvent was evaporated and replaced with ethyl acetate. The ethyl acetate solution was washed with 2M aqueous hydrochloric acid, 5% aqueous sodium hydrogen carbonate and then brine. The ethyl acetate phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was triturated with diethyl ether to give 0.60 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methyl- N-phthalimidovaleramide was obtained in the form of a white solid.

MS: 443 (M + H) ⁺ .

(ii) 0.44 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl), in a manner analogous to that described in Example 2, parts (iv) and (v) 0.13 g of (E) -2 (R)-[(tetrahydro-2 (RS) -pyranyloxy starting from 4-phenyl-3-butenyl] -4-methyl-N-phthalimidovaleramide ) Carbamoyl] -4-phenyl-3-butenyl] -4-methyl-N-phthalimidovaleramide in the form of a white solid.

MS: 534 (M + H) ⁺ .

Example 121

Methyl (E) -3- [2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -2-isobutylcarbazate

In a similar manner as described in the first paragraph of Example 2, 0.27 g of methyl (E) -3- [2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy ) Carbamoyl] -4-phenyl-3-butenyl] -4-methylvaleryl] -2-isobutylcarbazate, starting from 0.19 g of methyl (E) -3- [2 (R)-[ 1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -2-isobutylcarbazate was obtained in the form of a white solid.

MS: 434 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.08 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Methyl (E) -3- [2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl used as starting material ] -4-methylvaleryl] -2-isobutylcarbazate was prepared as follows:

(i) 0.50 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methyl Valerohydrazide and 0.12 ml of pyridine were dissolved in 10 ml dichloromethane and cooled to 0 ° C. under nitrogen. A small portion of 0.12 mL of methyl chloroformate and 4-dimethylaminopyridine crystals were added successively, and the mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with dichloromethane and then washed successively with 5% aqueous sodium hydrogen carbonate solution, water, 2M aqueous hydrochloric acid and water and then dried over magnesium sulfate. Evaporate the solvent to give 0.54 g of methyl (E) -3- [2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalle Reel] -2-isobutylcarbazate was obtained in the form of a white foam.

MS: 475 (M + H) ⁺ .

(ii) 0.54 g of (E) -3- [2 (R)-[1 (S)-(tert-butoxy) in a similar manner as described in Example 2, parts (iv) and (v) 0.27 g of methyl (E) -3- [2 (R)-[1 starting from carbonyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -2-isobutylcarbazate (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvaleryl] -2-isobutylcarbazate as a white solid Obtained in form.

MS: 518 (M + H) ⁺ .

Example 122

(E) -2'-cycloheptyl-2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl Valerohydrazide

In a similar manner as described in Example 45 except for using cycloheptanone in place of isobutyraldehyde in step (i), (E) -2'-cycloheptyl-2 (R)-[1 (S) -(Hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 494 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.99 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Example 123

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2-neopentylvalle Lohydrazide

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) in a similar manner as described in Example 45 except that pivalaldehyde is used instead of isobutyraldehyde in step (i) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2-neopentylvalerohydrazide was obtained in the form of a white solid.

MS: 468 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.79 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Example 124

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2 '-(trifluoroacetyl) -4- Methylvalerohydrazide

In a manner similar to that described in Example 59 except for using trifluoroacetic anhydride in place of isobutyric anhydride in step (i), (E) -2 (R)-[1 (S)-(hydroxy Carbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2 '-(trifluoroacetyl) -4-methylvalerohydrazide in the form of a white solid.

MS: 472 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.36 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Example 125

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methyl-2 '-(2-phenylacetyl Valerohydrazide

In a similar manner as described in Example 59 except for using phenylacetyl chloride in place of isobutyric anhydride in step (i), (E) -2 (R)-[1 (S)-(hydroxycarbamoyl ) -4-phenyl-3-butenyl] -2'-isobutyl-4-methyl-2 '-(2-phenylacetyl) valerohydrazide was obtained in the form of a white solid.

MS: 494 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.03 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Example 126

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -N- (2-isothiazolidinyl) -4-methylvaleramide S, S-dioxide

In a method similar to that described in the first paragraph of Example 2, 0.12 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.03 g of (E) -2 (R)-[1 starting from 4-phenyl-3-butenyl] -N- (2-isothiazolidinyl) -4-methylvaleramide S, S-dioxide (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -N- (2-isothiazolidinyl) -4-methylvaleramide S, S-dioxide was obtained in the form of a white solid.

MS: 424 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.90 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -N- used as starting material (2-isothiazolidinyl) -4-methylvaleramide S, S-dioxide was prepared as follows:

(i) 1.85 g of 3-chloropropylsulfonyl chloride and 0.85 g of pyridine were added to (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4 in 40 ml dichloromethane. To a solution of 3.0 g of -phenyl-3-butenyl] -4-methylvalerohydrazide. After stirring for 2 hours at room temperature, the solvent was evaporated and the residue was triturated with diethyl ether. The mixture was filtered and the solvent evaporated to yield 1.92 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -2 '-( 3-Chloropropylsulfonyl) -4-methylvalerohydrazide was obtained in the form of a light yellow oil.

MS: 445 (M + H- ^t Bu) ⁺ .

(ii) 1.59 g of potassium carbonate (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] in 50 ml anhydrous dimethylformamide] To a solution of 1.92 g of -2 '-(3-chloropropylsulfonyl) -4-methylvalerohydrazide was added. After stirring at room temperature overnight, the solvent was evaporated and the residue was dissolved in diethyl ether and washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate / hexanes (1: 2) for elution. 0.93 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -N- (2-isothiazolidinyl) -4 Methylvaleramide S, S-dioxide was obtained in the form of a light yellow oil.

MS: 409 (M + H- ^t Bu) ⁺ .

(iii) 0.90 g of (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl), in a similar manner as described in Example 2, parts (iv) and (v) 0.12 g of (E) -2 (R)-[1 starting from 4-phenyl-3-butenyl] -N- (2-isothiazolidinyl) -4-methylvaleramide S, S-dioxide (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -N- (2-isothiazolidinyl) -4-methylvaleramide S, S-dioxide was obtained in the form of a white solid.

MS: 508 (M + H) ⁺ .

Example 127

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-N- (2-oxo-3-oxazolidinyl) valeric amides

In a similar manner as described in Example 126 except for using 2-bromoethyl chloroformate in place of 3-chloropropylsulfonyl chloride in step (i), (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-N- (2-oxo-3-oxazolidinyl) valeramide was obtained in the form of a white solid.

MS: 390 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.79 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Example 128

2 (S)-[1 (RS)-(hydroxycarbamoyl) (phenylthio) methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 2.98 g of 2 (S)-[1 (RS)-(phenylthio) [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 1.92 g of 2 (S)-[1 (RS)-(hydroxycarbamoyl) starting from methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide (Phenylthio) methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 446 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.36 and 12.64 min. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

2 (S)-[1 (RS)-(phenylthio) [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] methyl] -2'-isobutyl-2 '-(used as starting material Methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:

3.45 g of 2 (S) -isobutyl-3 in a similar manner as described in Example 131, part (v), Example 1, part (iii) and Example 2, parts (iii) and (v) 2.98 g of 2 (S)-[1 starting from (RS) -phenylthiobutane-1,4-dioic acid-4-tert-butyl ester (prepared as described in WO 97/42168) (RS)-(phenylthio) [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydra Zide was obtained in the form of a white solid.

MS: 530 (M + H) ⁺ .

Example 129

2 (R)-[1 (S)-(hydroxycarbamoyl) -4-methylpentyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.77 g of 2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-methyl 0.48 g of 2 (R)-[1 (S)-(hydroxycarbamoyl) starting from pentyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide 4-Methylpentyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 408 (M + H) ⁺ .

HPLC: accelerated gradient elution from solvent A containing 40% solvent B for 5 minutes to 80% solvent B over 10 minutes; Flow rate of 1 ml / min. Retention time: 5.61 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERSIL 120A.

2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-methylpentyl] -2'-isobutyl-2 '-(used as starting material Methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:

(i) 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-methyl-3-pentenyl] -2'-isobutyl-2 '-(methanesulphate in 50 ml methanol A solution of 1.5 g of polyvinyl) -4-methylvalerohydrazide was hydrogenated for 6 hours in the presence of 0.15 g of 10% palladium on carbon. The catalyst was removed by filtration and the solvent was evaporated to yield 1.5 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-methylpentyl] -2'-isobutyl-2- (Methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a colorless oil.

MS: 449 (M + H) ⁺ .

(ii) 1.5 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) in a similar manner as described in Example 1, Part (iii) and Example 2, Part (v) 0.77 g of 2 (R)-[1 (S)-[starting from) -4-methylpentyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide (Tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-methylpentyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide as a white solid Obtained in form.

MS: 492 (M + H) ⁺ .

Example 130

2 (R)-[1 (S)-(hydroxycarbamoyl) -4-methyl-3-pentenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydra Jide

In a manner similar to that described in the first paragraph of Example 2, 0.25 g of 2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-methyl Starting from -3-pentenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide, 0.16 g of 2 (R)-[1 (S)-(hydr Roxycarbamoyl) -4-methyl-3-pentenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 406 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.59 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-methyl-3-pentenyl] -2'-isobutyl- used as starting material 2 '-(methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:

(i) 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-methyl-3-pentenyl] -2'-isobutyl- in 20 ml 1,4-dioxane A solution of 1.5 g of 2 '-(methanesulfonyl) -4-methylvalerohydrazide, 0.51 g of triethylamine and 0.93 g of trimethylsilyl triflate was heated to reflux under a nitrogen atmosphere for 4 hours. The mixture is cooled and the solvent is evaporated. The residue was dissolved in ethyl acetate and washed with 2M aqueous hydrochloric acid, water and brine. The ethyl acetate phase is then dried over anhydrous magnesium sulfate and the solvent is evaporated to yield 1.31 g of 2 (R)-[1 (S)-(carboxy) -4-methyl-3-pentenyl] -2'-isobutyl- 2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a yellow foam.

MS: 391 (M + H) ⁺ .

(ii) 1.31 g of 2 (R)-[1 (S)-(carboxy) -4-methyl-3-pentenyl] -2'- in a similar manner as described in Example 2, part (v) 0.25 g of 2 (R)-[1 (S)-[(tetrahydro- (RS) -pyranyloxy starting from isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide ) Carbamoyl] -4-methyl-3-pentenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide in the form of a pale yellow foam.

MS: 490 (M + H) ⁺ .

Example 131

2 (R)-[(S)-(benzyloxy)-(hydroxycarbamoyl) methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 45, 0.12 g of 2 (R)-[(S)-(benzyloxy)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting with methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide, 0.07 g of 2 (R)-[(S)-(benzyloxy)-(hydr Roxycarbamoyl) methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 444 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 98% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.86 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

2 (R)-[(S)-(benzyloxy)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] methyl] -2'-isobutyl-2 '-(used as starting material Methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:

(i) 4.48 g of 3 (R) -carboxy-2 (S) -hydroxy-5-methylhexanoic acid was stirred in 10 ml trifluoroacetic anhydride under nitrogen for 1.5 hours. The solvent was evaporated and the residue was dissolved in 20 mL of absolute methanol and stirred overnight at room temperature. The solvent was evaporated to give 5.3 g of methyl 3 (R) -carboxy-2 (S) -hydroxy-5-methylhexanoate in the form of an orange oil.

(ii) 2.1 ml of allyl bromide was added to a solution of 4.52 g of methyl 3 (R) -carboxy-2 (S) -hydroxy-5-methylhexanoate and 7.9 g of cesium carbonate in 30 ml dimethylformamide. The mixture was stirred overnight and evaporated. The residue was dissolved in dichloromethane and washed with 2M aqueous hydrochloric acid. The dichloromethane phase was then dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate / hexanes (increased to 1: 9, 2: 8) for elution. 2.88 g of methyl 3 (R)-(allyloxycarbonyl) -2 (S) -hydroxy-5-methylhexanoate were obtained in the form of a light yellow oil.

(iii) 0.51 g of silver oxide (I) and 0.33 ml of benzyl bromide were added to methyl 3 (R)-(allyloxycarbonyl) -2 (S) -hydroxy-5-methylhexanoate in 5 ml dimethylformamide. To 0.27 g of solution. After the mixture was stirred for 24 hours, 0.36 g of cesium carbonate was added and stirring was continued for 3 hours. The mixture was diluted with diethyl ether and filtered. The filtrate was then washed successively with 5% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate, water and brine. The diethyl ether phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel using ethyl acetate / hexanes (1:19) for elution. 0.16 g of methyl 3 (R)-(allyloxycarbonyl) -2 (S) -benzyloxy-5-methylhexanoate were obtained in the form of a clear oil.

(iv) 0.39 ml of morpholine and 0.05 g of tetrakis (triphenylphosphine) -palladium (O) in 5 ml tetrahydrofuran under nitrogen atmosphere in methyl 3 (R)-(allyloxycarbonyl) -2 0.15 g of S) -benzyloxy-5-methylhexanoate was added to the stirred solution. The mixture was stirred for 0.5 h and then the solvent was evaporated. The residue was dissolved in dichloromethane and washed successively with 2M aqueous hydrochloric acid and water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was dissolved in diethyl ether and filtered. The diethyl ether solution was evaporated to yield 0.16 g of methyl-3 (R) -carboxy-2 (S) -benzyloxy-5-methylhexanoate in the form of a yellow oil.

(v) 0.43 g methyl-3 (R) -carboxy-2 in a similar manner as described in Example 1, part (i), and part (ii), except that isobutylhydrazine is used instead of phenylhydrazine. 0.34 g of 2 (R)-[(S)-(benzyloxy)-(methoxycarbonyl) methyl] -2'-isobutyl-, starting with (S) -benzyloxy-5-methylhexanoate 2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a yellow oil.

MS: 443 (M + H) ⁺ .

(vi) 0.530 ml of a 2M solution of trimethylaluminum in toluene was added to a solution of 0.124 g of O- (tetrahydro-2H-pyran-2 (RS) -yl) hydroxylamine in 5 ml anhydrous toluene at 0 ° C. under nitrogen atmosphere. It was. The mixture was stirred at 0 ° C. for 0.5 h and then 0.335 g of 2 (R)-[(S)-(benzyloxy)-(methoxycarbonyl) methyl] -2'-isobutyl-2 '-(methanesulphur) Phonyl) -4-methylvalerohydrazide was added in one portion. This mixture was then warmed to room temperature overnight. The mixture was diluted with ethyl acetate and washed successively with 2M aqueous hydrochloric acid and 5% aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was triturated with hexane / diethyl ether (2: 1). 0.119 g 2 (R)-[(S)-(benzyloxy)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] methyl] -2'-isobutyl-2 '-(methanesulphur Ponyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 528 (M + H) ⁺ .

Example 132

2 (R)-[1 (S)-(hydroxycarbamoyl) -2-phenylethyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 65, 0.063 g of 2 (R)-[1 (S)-(benzyloxycarbamoyl) -2-phenylethyl] -2'-isobutyl-2 ' 0.014 g of 2 (R)-[1 (S)-(hydroxycarbamoyl) -2-phenylethyl] -2'-iso starting from-(methanesulfonyl) -4-methylvalerohydrazide Butyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 428 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 10 minutes; Flow rate of 2 ml / min. Retention time: 7.55 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: H ₂ O / 90% CH ₃ CN / 0.085% TFA. Column type: DYNAMAX 300A.

2 (R)-[1 (S)-[(benzyloxycarbamoyl) -2-phenylethyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalero used as starting material Hydrazide was prepared as follows:

(i) 2 (R)-[1 (S) in a similar manner as described in Example 2, parts (i) and (ii), except that benzyl bromide is used instead of cinnamil bromide in step (i) -(Tert-butoxycarbonyl) -2-phenylethyl] -4-methylvaleric acid was obtained in the form of a clear oil.

MS: 321 (M + H) ⁺ .

(ii) 1.49 g of 2 (R)-[1 (S)-(tert-part) in a similar manner as described in Example 131, part (v) and Example 65 parts (iii) and (iv) From oxycarbonyl) -2-phenylethyl] -4-methyl valeric acid, 0.063 g of 2 (R)-[1 (S)-(benzyloxy-carbamoyl) -2-phenylethyl] -2'-iso Butyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 518 (M + H) ⁺ .

Example 133

2 (R)-[1 (S)-(hydroxycarbamoyl) -2- (phenylthio) ethyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.315 g of 2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2- ( Phenylthio) ethyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide starting from 0.116 g of 2 (R)-[1 (S)-(hydroxy Carbamoyl) -2- (phenylthio) ethyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 460 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.95 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2- (phenylthio) ethyl] -2'-isobutyl-2 used as starting material '-(Methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:

(i) 7.8 mL of piperidine and 20 mL of 40% formaldehyde aqueous solution were dissolved in 1-3 mL-butyl dihydrogen 4-methyl-1 (RS), 1,2 (R) -pentane in 80 mL isopropyl alcohol. To a solution of 6.0 g of tricarboxylate was added and the mixture was stirred overnight under a nitrogen atmosphere. The solvent was evaporated and the residue dissolved in ethyl acetate. The ethyl acetate phase was washed successively with 1M aqueous hydrochloric acid, warm water and brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 3.94 g of 2 (R)-[1- (tert-butoxycarbonyl) vinyl] -4-methylvaleric acid in the form of a clear oil.

(ii) in a manner analogous to that described in Example 131, part (v), starting with 3.4 g of 2 (R)-[1- (tert-butoxycarbonyl) vinyl] -4-methylvaleric acid , 3.57 g of 2 (R)-[1- (tert-butoxycarbonyl) vinyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide as a clear oil Obtained in the form of.

(iii) 0.183 g of thiophenol and 0.356 ml of triethylamine were added to 2 (R)-[1- (tert-butoxycarbonyl) vinyl] -2'-isobutyl-2 '-() in 20 ml toluene. To a solution of 0.500 g of methanesulfonyl) -4-methylvalerohydrazide was added and stirring was continued for 48 hours under a nitrogen atmosphere. 0.183 mL of thiophenol was further added to the mixture and stirring was continued at 60 ° C. for 48 hours. The mixture was then cooled to rt and diluted with ethyl acetate. The mixture was washed successively with 1M aqueous hydrochloric acid, 1M aqueous sodium hydroxide and brine. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. 0.307 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -2- (phenylthio) ethyl] -2'-isobutyl-2 '-(methanesulfonyl) ) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 501 (M + H) ⁺ .

(iv) 0.307 g of 2 (R)-[1 (S)-(tert-butoxycarbonyl) -2- (2) in a manner analogous to that described in Example 2, parts (iv) and (v) Phenylthio) ethyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide starting with 0.315 g of 2 (R)-[1 (S)-[(tetrahydro -2 (RS) -pyranyloxy) carbamoyl] -2- (phenylthio) ethyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide as a white solid Obtained.

MS: 544 (M + H) ⁺ .

Example 134

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4- (1-naphthyl) -3-butenyl] -2'-isobutyl-2 '-(methanesulfonyl ) -4-Methylvalerohydrazide

In a similar manner as described in the first paragraph of Example 2, 0.240 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.155 g of (E)-starting from -4- (1-naphthyl) -3-butenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide 2 (R)-[1 (S)-(hydroxycarbamoyl) -4- (1-naphthyl) -3-butenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4- Methylvalerohydrazide was obtained in the form of a white solid.

MS: 504 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.19 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (1-naphthyl) -3-part used as starting material Tenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:

2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -3-butenyl] -2 '-(methane prepared as described in Example 118) Sulfonyl) -4-methyl-2'-phenylvalerohydrazide 0.500 g, 0.449 g 1-bromo-naphthalene, 0.219 g triethylamine, 0.012 g palladium (II) acetate and 0.033 g tri -o-tolylphosphine was dissolved in 5 ml of dimethylformamide and stirred at 100 ° C for 24 h. The mixture was cooled to rt and partitioned between water and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate and then the organic phases were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using dichloromethane / methanol (9.5 / 0.5) for elution. 0.260 g of (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (1-naphthyl) -3-butenyl) ] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 504 (M + H) ⁺ .

Example 135

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4- (5-pyrimidinyl) -3-butenyl] -2'-isobutyl-2 '-(methanesulphur Ponyyl) -4-methylvalerohydrazide

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) in a similar manner as described in Example 134 except for using 5-bromopyrimidine instead of 1-bromonaphthalene -4- (5-pyrimidinyl) -3-butenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 456 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.89 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Example 136

2 (R)-[(S)-(cyclopentyl) (hydroxycarbamoyl) methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide and 2 (R )-[(S)-(cyclopentyl) (hydroxycarbamoyl) methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methyl-3-pentenohydrazide

In a similar manner as described in the first paragraph of Example 45, 2 (R)-[(S)-(cyclopentyl) [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] methyl] -2 '-Isobutyl-2'-(methanesulfonyl) -4-methylvalerohydrazide and 2 (R)-[(S)-(cyclopentyl) [(tetrahydro-2 (RS) -pyranyloxy ) Carbamoyl] methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methyl-3-pentenohydrazide starting from 0.357 g, 2 (R)-[(S)- (Cyclopentyl) (hydroxycarbamoyl) methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide (Compound A) and 2 (R)-[(S) 0.219 g of a mixture of-(cyclopentyl) (hydroxycarbamoyl) methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methyl-3-pentenohydrazide (Compound B) as a white solid Obtained in the form of. The compounds were then separated by preparative high performance liquid chromatography on a DYNAMAX 5 μm C18 300A column with a diameter of 21.4 × 50 mm using the gradient elution method shown below:

Compound A: MS: 405 (M + H) ⁺ . HPLC: gradient elution with solvent B for 15 minutes; Flow rate of 1 ml / min. Retention time: 11.00 minutes.

Compound B: MS: 403 (M + H) ⁺ . HPLC: gradient elution as described for compound A; Flow rate of 1 ml / min. Retention time: 10.77 minutes.

2 (R)-[(S)-(cyclopentyl) [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] methyl] -2'-isobutyl-2 '-(methane used as starting material Sulfonyl) -4-methylvalerohydrazide and 2 (R)-[(S)-(cyclopentyl) [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] methyl] -2'- A mixture of isobutyl-2 '-(methanesulfonyl) -4-methyl-3-pentenohydrazide was prepared as follows.

(i) 1.1 g of 2 (S) -cyclopentyl-3 (R)-(2-methylallyl) succinic acid 4-benzyl ester (WO 97 / in a similar manner as described in Example 131, part (v) 1.14 g of 2 (R)-[(S)-(benzyloxycarbonyl) (cyclopentyl) methyl] -2'-isobutyl-2 '-(starting as described in 19503) Methanesulfonyl) -4-methyl-4-pentenohydrazide was obtained in the form of a white foam, which can be recrystallized from hexane.

(ii) 2 (R)-[(S)-(benzyloxycarbonyl) (cyclopentyl) methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methyl-4 in 10 ml ethanol A solution of 1.14 g of pentenohydrazide was hydrogenated for 48 hours in the presence of 0.05 g of 10% palladium on carbon. The catalyst was removed by filtration and the solvent was evaporated to afford 2 (R)-[(S)-(carboxy) (cyclopentyl) methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalle Lohydrazide and 2 (R)-[(S)-(carboxy) (cyclopentyl) methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methyl-3-pentenohydrazide 0.91 g of a mixture of was obtained in the form of a white foam.

(iii) 2 (R)-[(S)-(carboxy) (cyclopentyl) methyl] -2'-isobutyl-2 '-(methane, in a manner similar to that described in Example 2, part (v) Sulfonyl) -4-methylvalerohydrazide and 2 (R)-[(S)-(carboxy) (cyclopentyl) methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4- 2 (R)-[(S)-(cyclopentyl) [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] methyl]-starting from 0.91 g of a mixture of methyl-3-pentenohydrazide 2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide and 2 (R)-[(S)-(cyclopentyl) [(tetrahydro-2 (RS) -pyranyl 0.357 g of a mixture of oxy) carbamoyl] methyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methyl-3-pentenohydrazide were obtained in the form of a white solid.

MS: 512 (M + Na) ⁺ and 510 (M + Na) ⁺ .

Example 137

In a manner similar to that described in the first paragraph of Example 45, (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Starting from phenyl-3-butenyl] -2 '-[2- (1-imidazolyl) ethyl] -2'-(methanesulfonyl) -4-methylvalerohydrazide, (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-[2- (1-imidazolyl) ethyl] -2'-(methanesulfonyl ) -4-methylvalerohydrazide methanesulfonic acid was obtained in the form of a white solid.

MS: 492 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.84 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

(E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 'used as starting material -[2- (1-imidazolyl) ethyl] -2 '-(methanesulfonyl) -4-methylvalerohydrazide, in a similar manner as described in Example 15, part (iii) (E) -2 (R)-[(S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4- Prepared by reaction with 1- (2-bromoethyl) imidazole starting from methylvalerohydrazide.

Example 138

(Z) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methyl Valerohydrazide

In a manner similar to that described in the first paragraph of Example 2, 0.075 g of (Z) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.047 g of (Z) -2 (R)-starting from 4-phenyl-3-butenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide [1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide as a white solid Obtained in form.

MS: 454 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.19 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Starting materials were prepared as follows:

(i) 2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butynyl] -2'-isobutyl-4-methylvalerohi in 10 ml pyridine A 0.1 g solution of drazide was shaken in the presence of 5% palladium catalyst on barium sulfate in a hydrogen atmosphere. After 45 minutes, the catalyst was filtered off and the pyridine was evaporated. The residue was evaporated three more times from toluene to give 0.1 g of (Z) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -2'- Isobutyl-4-methylvalerohydrazide was obtained in the form of a straw colored solid.

MS: 417 (M + H) ⁺ .

(ii) (Z) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4- in a similar manner as described in Example 2, parts (iv) and (v) From phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide, 0.075 g of (Z) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) ) -Pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid It was.

MS: 538 (M + H) ⁺ .

Example 139

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[( 2-pyridyl) methyl] valerohydrazide methanesulfonate

In a manner similar to that described in the first paragraph of Example 2, except that methanesulfonic acid is used instead of p-toluenesulfonic acid, 0.266 g of (E) -2 (R)-[1 (S)-[( Tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[(2-pyridyl) methyl ] 0.24 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methane starting from valerohydrazide Sulfonyl) -4-methyl-2 '-[(2-pyridyl) methyl] valerohydrazide methanesulfonate was obtained in the form of a gray solid.

MS: 489 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.95 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

The starting material was (E) -2 (R)-[1 (S)-[(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- Prepared in a similar manner as described in Example 15, part (iii), starting from (methanesulfonyl) -4-methylvalerohydrazide and 2-bromomethylpyridine hydrobromide.

Example 140

(E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2 , 6-dimethyl-4-pyrimidinyl) valerohydrazide methanesulfonate

In a similar manner as described in the first paragraph of Example 2, except that methanesulfonic acid is used instead of p-toluenesulfonic acid, 0.049 g of (E) -2 (R)-[1 (S)-[( Tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2,6-dimethyl-4 0.039 g of (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2, starting from -pyrimidinyl) valerohydrazide '-(Methanesulfonyl) -4-methyl-2'-(2,6-dimethyl-4-pyrimidinyl) valerohydrazide methanesulfonate was obtained in the form of a gray solid.

MS: 504 (M + H) ⁺ .

HPLC: gradient elution from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.00 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: CH ₃ CN / 0.085% TFA. Column type: HYPERPEP 300A.

Starting materials were (E) -2 (R)-[1 (S)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid and 2,4-dimethyl Prepared by a method analogous to that described in Examples 2, parts (iii) to (v), starting from -6-hydrazinopyrimidine. The following examples are typical of the hydrazine derivatives provided by the present invention. A pharmaceutical formulation is illustrated.

Example A

Tablets containing the following ingredients can be prepared by conventional methods:

ingredient Refined sugar amount (mg) Hydrazine derivatives 10.0 Lactose 125.0 Corn starch 75.0 talc 4.0 Magnesium stearate 1.0 Total weight 215.0

Example B

Capsules containing the following ingredients can be prepared by conventional methods:

ingredient Amount per Capsule (mg) Hydrazine derivatives 10.0 Lactose 165.0 Corn starch 20.0 talc 5.0 Capsule Filling Weight 200.0

Claims (25)

A compound of formula (I), a racemate, diastereomeric mixture thereof, or a pharmaceutically acceptable salt thereof: Formula I Where Y means CO or SO ₂ ; R ¹ is (C ₁ -C ₇ ) alkyl, (C ₂ -C ₇ ) alkenyl, (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkyl- (C ₁ -C ₇ ) alkyl , Aryl or aryl- (C ₁ -C ₇ ) alkyl; R ² is (C ₁ -C ₇ ) alkyl, halo- (C ₁ -C ₇ ) alkyl, aryl- (C ₁ -C ₇ ) alkyl, aryl- (C ₂ -C when Y means SO _{2 7} ) alkenyl or aryl; Where Y means CO, (C ₁ -C ₇ ) alkyl, halo- (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkoxycarbonyl, acyl, (C ₃ -C ₇ ) cycloalkyl, aryl, aryl- (C ₁ -C ₇ ) alkyl, aryl- (C ₁ -C ₇ ) alkoxy or NR ⁵ R ⁶ , R ³ is hydrogen; Cyano, amino, hydroxy, (C ₁ -C ₇₎ alkoxy, (C ₁ -C ₇₎ alkoxycarbonyl, substituted by heterocyclyl or heterocyclyl-carbonyl or unsubstituted (C ₁ -C ₇₎ Alkyl; (C ₂ -C ₇ ) alkenyl, (C ₂ -C ₇ ) alkynyl, (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkyl- (C ₁ -C ₇ ) alkyl, aryl - (C ₁ -C ₇₎ alkyl, aryl, - (C ₂ -C ₇₎ alkenyl, aryl or heterocyclyl, or R ² and R ³ together form a residue of a 5-, 6- or 7-membered cyclic amide, cyclic imide, cyclic sulfonamide or cyclic urethane group; R ⁴ is (C ₁ -C ₇ ) alkyl, (C ₂ -C ₇ ) alkenyl, (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkyl- (C ₁ -C ₇ ) alkyl Or a group of the general formula X-aryl, X-heteroaryl or-(CH ₂ ) _1-2 -CH = CR ⁷ R ⁸ ; X means a spacer group; R ⁵ and R ⁶ each independently represent hydrogen, (C ₁ -C ₇ ) alkyl or aryl- (C ₁ -C ₇ ) alkyl; R ⁷ and R ⁸ together represent a (C ₂ -C ₇ ) alkylene group in which one methylene group is substituted or unsubstituted by a hetero atom. The method of claim 1, Y means CO or SO ₂ ; R ¹ is (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkyl- (C ₁ -C ₇ ) alkyl, aryl or aryl- (C ₁ -C ₇ ) alkyl; R ² means (C ₁ -C ₇ ) alkyl, aryl- (C ₁ -C ₇ ) alkyl or aryl when Y means SO ₂ , and when Y means CO, (C _1- C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxy, (C ₃ -C ₇ ) cycloalkyl, aryl- (C ₁ -C ₇ ) alkoxy or NR ⁵ R ⁶ , wherein R ³ is hydrogen; (C ₁ -C ₇ ) alkyl unsubstituted or substituted with cyano, amino or phthalimide; (C ₂ -C ₇ ) alkenyl, (C ₂ -C ₇ ) alkynyl, (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkyl- (C ₁ -C ₇ ) alkyl, aryl -(C ₁ -C ₇ ) alkyl, aryl or heterocyclyl, or R ² and R ³ together represent a residue of a 5-, 6- or 7-membered cyclic amide, cyclic imide or cyclic sulfonamide group Forming; R ⁴ represents phthalimido- (C ₁ -C ₇ ) alkyl or a group of the general formula X-aryl or X-heteroaryl; X means a spacer group; Heteroaryl is C-linked; A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ⁵ and R ⁶ each independently represent hydrogen, (C ₁ -C ₇ ) alkyl or aryl- (C ₁ -C ₇ ) alkyl. The method according to claim 1 or 2, Y means CO and R ² means (C ₁ -C ₇ ) alkoxy or Y means SO ₂ and R ² means (C ₁ -C ₇ ) alkyl. The method of claim 3, wherein Y means CO and R ² means methoxy. The method of claim 3, wherein Y means SO ₂ and R ² means methyl. The method according to claim 1 or 2, R ¹ represents (C ₁ -C ₇ ) alkyl. The method according to claim 1 or 2, R ¹ means isobutyl. The method according to claim 1 or 2, R ³ represents (C ₁ -C ₇ ) alkyl, (C ₂ -C ₇ ) alkenyl, aryl- (C ₁ -C ₇ ) alkyl or aryl. The method of claim 8, R ³ represents isobutyl, 2-methylbutyl, 2-methylallyl, unsubstituted benzyl or unsubstituted phenyl. The method according to claim 1 or 2, X represents the formula _{- (CH 2) 1-5 -,} -CH 2 -CH = CH-, -CH 2 -C≡C-, -CH 2 NHCO-, - (CH 2) 1 _{or 2} NHCONH-, - (CH ₂ ) _1-5 -S-, -CH ₂ NHSO _2- , -CH ₂ NHCH ₂ -,-(CH ₂ ) _1-5 -O-, -O- (CH ₂ ) _1-5 -or- A compound that is a group of S-. The method of claim 10, X represents the formula _{- (CH 2) 1-5 -,} -CH 2 -CH = CH-, -CH 2 -C≡C-, -CH 2 NHCO-, - (CH 2) 1 _{or 2} NHCONH-, - A compound that is a group of CH ₂ S—, —CH ₂ NHSO ₂ — or —CH ₂ NHCH ₂ —. The method according to claim 1 or 2, R ⁴ represents a group of the general formula X-aryl. The method of claim 12, X represents a group of the formula -CH ₂ -CH = CH-, and aryl represents phenyl unsubstituted. The method of claim 1, A compound selected from the group consisting of: (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2 '-(methanesulfonyl) -4-methyl Valerohydrazide, (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-phenylvalle Lohydrazide, (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-[2 (S) -methylbutyl] valerohydrazide, (E) -2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-(methanesulfonyl) -4-methyl-2'-(2 -Methylallyl) valerohydrazide and Methyl (E) -3- [2 (R)-[1 (S)-(hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -2-isobutylcarbazate . A compound of formula II: Formula II Where Y, R ¹ , R ² , R ³ and R ⁴ have the meanings as defined in claim 1, R ⁹ means a protecting group. The method of claim 15, R ⁹ represents tetrahydropyranyl, 4-methoxybenzyl, benzyl or tri (C ₁ -C ₇ alkyl) silyl. Carboxylic Acids of Formula (IX) Where Y, R ¹ , R ² , R ³ and R ⁴ have the meanings as defined in claim 1. delete A process for preparing a compound according to claim 1, comprising deprotecting a compound of formula II and optionally converting the obtained compound of formula I into a pharmaceutically acceptable salt: Formula II Where Y, R ¹ , R ² , R ³ and R ⁴ have the meanings as defined in claim 1, R ⁹ means a protecting group. delete A medicament for the treatment of inflammation, fever, bleeding, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis or psoriasis containing the compound according to claim 1 or 2 and a therapeutically inert carrier material. Inflammation, fever, bleeding, sepsis, comprising preparing the compound according to claim 1 in a therapeutically inert carrier material, and optionally, in a herbal dosage form with one or more additional therapeutically active substances. And a method for the preparation of a medicament for treating rheumatoid arthritis, osteoarthritis, multiple sclerosis or psoriasis. delete delete delete