UA58561C2 - Hydrazine derivatives - Google Patents

Abstract

Hydrazine derivatives of formula (I) wherein Y signifies CO or SO2; R1 signifies lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl; R2 signifies lower alkyl, halo-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl or aryl when Y signifies SO2 and signifies lower alkyl, halo-lower alkyl, lower alkoxy, lower alkoxycarbonyl, acyl, lower cycloalkyl, aryl, aryl-lower alkyl, aryl-lower alkoxy or NR5R6 when Y signifies CO; and R3 signifies hydrogen, lower alkyl optionally substituted by cyano, amino, hydroxy, lower alkoxy, lower alkoxycarbonly, heterocyclyl or heterocyclylcarbonyl, lower alkenyl, lower alkynyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl, aryl or heterocyclyl; or R2 and R3 together form the residue of a 5-, 6- or 7- membered cyclic amide, cyclic imide, cyclic sulphonamide or cyclic urethane group; R4 signifies lower alkyl, hydroxy-lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl or a grouping of the formula X-aryl, X-heteroaryl or -(CH2)1-2-CH-CR7R8; X signifies a spacer group; R5 and R6 each individually signify hydrogen, lower alkyl or aryl-lower alkyl; and R7 and R8 together represent a lower alkylene group in which one methylene group is optionally replaced by a hetero atom; and their phanmaceutically acceptable salts inhibit not only the release of tumour necrosis factor (TNF-i) and transforming growth factor (TGF-)) from cells, but also keratinocyte proliferation. They are useful as medicaments, especially for the treatment of inflammation, fever, haemorrhage, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis or psoriasis.

Description

Description of the invention

This invention is related to new hydrazine derivatives, the method of their preparation, and medicinal products containing them. This invention is also related to the use of these derivatives as medicinal products and for the preparation of medicinal products.

The new hydrazine derivatives provided by this invention are compounds of the general formula:

NN 2 in? c) 3 7 where

M stands for CO or 505;

B represents a lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl group;

B2 means lower alkyl, halogen-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl or aryl, in the case where M is 505, and lower alkyl, halogen-lower alkyl, lower alkyl, lower alkoxycarbonyl, acyl, lower cycloalkyl , an aryl, aryl-lower alkyl, aryl-lower alkyl group or MERE, in the case where U means CO; and

BZ means hydrogen, lower alkyl, optionally substituted cyano, amino, hydroxyl, lower alkyl, lower alkoxycarbonyl, heterocyclyl or heterocyclylcarbonyl, lower i9)alkenyl, lower alkynyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, aryl- a lower alkenyl, aryl or heterocyclyl group; or 22 and VZ together form the remainder of a 5-, 6- or 7-membered cyclic amide, cyclic imide, cyclic sulfonamide or cyclic urethane group; co

B" means a lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl group or a group of the formula X-aryl, X-heteroaryl or -"СН2»»и5-СН-СВ in; o

X stands for space group; so 2? and VC, each individually, means hydrogen, lower alkyl, or aryl-lower alkyl; and

B and C together represent a lower alkylene group in which one methylene group is optionally substituted with a heteroatom; and their pharmaceutically acceptable salts.

Said hydrazine derivatives provided by this invention are inhibitors of the release of tumor necrosis factor alpha (TME-o) and transforming growth factor (TOF-o) from cells. They also inhibit the proliferation of keratinocytes. Accordingly, the mentioned hydrazine derivatives can be used as medicinal products, in particular, in the treatment of inflammation, fever, hemorrhage, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis and psoriasis.

In contrast to structurally related hydroxamic acid derivatives (see US Pat. No. 5,304,549), said hydrazine derivatives provided by this invention exhibit only weak inhibitory activity against enzymes of the matrix metalloproteinase (MMP) family, such as collagenases, stromelysins, and gelatinases. (ee) The term "lower alkyl" as used herein, alone or in combination, e.g. in the expression "halo-lower alkyl" or "lower cycloalkyl-lower alkyl", means an alkyl group with an unbranched or a branched chain, the composition of which includes up to 7 carbon atoms, according to (e)) 50, the preferred option is up to 4 carbon atoms, for example, methyl, ethyl, p-propyl, isopropyl, p-butyl, isobutyl, tert-butyl, tert- butyl, p-pentyl and p-hexyl. An example of a halogen-lower alkyl group is trifluoromethyl.

The term "lower alkyl group", as used herein, alone or in combination, for example, in the expression "lower alkoxycarbonyl group", means a lower alkyl group, as defined above, which is attached through an oxygen atom, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Examples of lower alkoxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, etc.

GF) The mentioned term "lower cycloalkyl group", which is used in this description, alone or in combination with, for example, in the expression "lower cycloalkyl-lower alkyl group", means a cycloalkyl group, which includes from 3 atoms to 7 carbon atoms , for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of lower cycloalkyl-lower alkyl groups are cyclopropyl methyl, 2-cyclobutyl-ethyl and 3-cyclohexyl-propyl.

The term "lower alkenyl" as used herein, alone or in combination, for example in the expression "aryl-lower alkenyl", refers to an alkenyl group having from 2 carbon atoms to 7 carbon atoms, e.g. allyl, vinyl and butenyl, and the term "lower alkynyl" refers to an alkynyl group having from 2 carbon atoms to 7 carbon atoms, for example 65 propargyl or butynyl.

The mentioned term "lower alkylene group" means an alkylene group, the composition of which includes from 2 carbon atoms to b carbon atoms, for example, dimethylene, trimethylene, tetramethylene, etc. Thus, B and 8, together with the carbon atom to which they are attached, can represent, for example, a cyclopentane, cyclohexane or tetrahydropyranyl ring.

The mentioned term "acyl group" means an acyl group that has been obtained from a lower alkanecarboxylic acid, for example, an alkanecarboxylic acid containing up to 6 carbon atoms, or from an aromatic carboxylic acid. Examples of such acyl groups are acetyl, propionyl, butyryl, isobutyryl, pivaloyl, benzoyl, p-chlorobenzoyl, etc. 70 The term "aryl" referred to means phenyl or naphthyl optionally substituted with a halogen such as fluorine, chlorine, bromine or iodine, a lower alkyl group, a lower alkyl group, a trifluoromethyl group, a hydroxyl group, a lower alkoxycarbonyl group, a nitro group, a phenyl group, etc. etc., 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, 75 4-nitrobenzyl, 2-phenylethyl, 3,4-dimethoxy-phenethyl etc. are typical examples of aryl-lower alkyl groups, and benzyloxy, 4-chlorobenzyloxy and 4-nitro-benzyloxy are typical examples of aryl-lower 2-phenylvinyl and 3-phenylallyl may be mentioned as examples of aryl-lower alkenyl groups.

The term "heterocyclic group" referred to means a 4-, 5- or b-lane saturated or partially unsaturated or 5- or b-lane aromatic heterocyclic group bonded through a C atom or a secondary M atom (eg -MH-) , which includes one or more heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, and which are optionally substituted by, for example, halogen, lower alkyl, lower alkyl, and/or oxo, and/or optionally benzofused. Examples of heterocyclic groups are pyrrolidinyl, pyrrolinyl, pyrazolinyl, piperidinyl, morpholinyl, thiamorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, oxetanyl, Ha imidazolidinyl, dioxolanyl, pyrrolyl, pyridyl, pyrimidinyl, benzofuranyl, benzodazolthienyl, inyl , isoindolyl, quinolyl and isoquinolyl. at

The mentioned term "heterocyclylcarbonyl group" means a heterocyclyl group, as defined before, connected to C(O) through a secondary M atom. Morpholinocarbonyl is a typical example of such a heterocyclylcarbonyl group. "h-

The mentioned term "heteroaryl group" means an aromatic heterocyclic group within the meaning of "heterocyclic group". at

Said cyclic amide, imide, sulfonamide or urethane group formed in, BZ and atoms to which IS o) they are attached, for example, a C atom or a 5 U atom, and, accordingly, an M atom, can be, for example, a group of the following then formulas (a)-(9), where n means 3, 4 or 5, and KZ together with E? form the remainder of an aromatic or cycloalkane ring:

Da - Snu --yp (Snada -K o i- - KA z i" (c) (c) i i (s) (8) 1 o Go! oh ry X (ee) ve yo p: / o iy what 7 she t (g) o

And (is) F (in)

Preferable spatial groups marked X are groups of the formulas -(СН»)4.в5-, -"СНО-СНе:СН-, -СН-С-С-, о -бСнНь.Мнео-, -СНоа) or "МНСОМН -, -(СН»).85-5-, in particular, -СНв5-, -СН»ОМНБЗО»-, -СНОМНОН»-, -«(СН»)4.в-О-, ko -0-(СН »).4 5 and -5-.

Said compounds of formula I form pharmaceutically acceptable salts with bases, for example, hydroxides of alkali metals, for example, sodium hydroxide and potassium hydroxide, hydroxides of alkaline earth metals, for example, calcium hydroxide, barium hydroxide and magnesium hydroxide, etc. Compounds of formula I, which belong to the basic group, can form pharmaceutically acceptable salts with inorganic acids, for example with hydrohalic acids, for example, hydrochloric acid and hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and with organic acids, 65 for example , with acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulfonic acid and p-toluenesulfonic acid.

It will be understood that, although the formulas given herein show the corresponding compounds in their absolute stereochemical form, this invention encompasses not only the stereoisomers shown, but also the corresponding racemates and mixtures of diastereoisomers. In addition, when the space group labeled X includes an olefinic double bond, as for example in -СНо-СНАСН-, it may have the (E) or (7) configuration, with (E) being preferred configuration.

To the preferred compounds of the formula | belong to compounds where У stands for CO, В? represents a lower alkyl group, in particular methoxy, or Y represents 50", and K2 represents a lower alkyl group, in particular methyl. BK", in a preferred variant, means a lower alkyl group, in particular, isobutyl. KZ, in a preferred variant, means a lower alkyl group, in particular, isobutyl or 2-methylbutyl, a lower alkenyl group, in particular, 2-methyl-allyl, aryl- a lower alkyl group, in particular, unsubstituted benzyl or aryl, in particular, unsubstituted phenyl. B", in a preferred variant, means a group of the formula X-aryl, in particular, when X means a space group of the formula -"CH0-SNACH- and aryl means unsubstituted phenyl.

Particularly preferred compounds of the formula | are: ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2"-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide; ()-2(KO- I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide; (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4 -phenyl-3-butenyl|-2i(methanesulfonyl)-4-methyl-2'-(2(5)-methylbutyl)vale rohydrazide; ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl -3-butenyl|-2'(methanesulfonyl)-4-methyl-2'-(2-methylallyl)valerohydrazide; and methyl (E)-3-I2(K)-I1(5)-(hydroxycarbamoyl)-4 -phenyl-3-butenyl|-4-methylvaleryl) - 2-isobutyl carbazate.

According to the method provided by the present invention, the mentioned new hydrazine derivatives, the definition of which was given before, are obtained by removing the protective group designated by K 9 from a compound having the general formula C 29: n no an a «- n E I neo v i-o ! where U, B", B, EZ and E7 have the meaning given before, and B? means a protecting group, and, if necessary, by converting the resulting compound of formula | into a pharmaceutically acceptable salt.

Said protecting group, denoted as B in the compound of formula II, can be any conventional protecting group, but is preferably tetrahydropyranyl, 4-methoxybenzyl, benzyl or tri(lower alkyl)silyl, in particular tert-butyldimethylsilyl. "

Cleavage of the mentioned protective group, which is denoted by MK 9, from the compound of formula II is carried out by methods known in the art. For example, the mentioned tetrahydropyranyl group can be cleaved by treatment with a sulfonic acid, for example, methanesulfonic acid or p-toluenesulfonic acid, in a lower alkanol, for example, methanol. Cleavage of said 4-methoxybenzyl group can be carried out, for example, with trifluoroacetic acid. Hydrogenolysis in the presence of a catalyst, such as palladium, in a lower alkanol, such as methanol, can be used to cleave said benzyl protecting group. Tri(lower alkyl)silyl the protecting group can be cleaved with water or low pH; said 1 cleavage usually occurs during isolation of the corresponding compound of formula II from the medium in which it was obtained (for example, the cleavage occurs ipsi.

The conversion of the obtained compounds of formula I into pharmaceutically acceptable salts is carried out by treating 1 with a suitable acid or base in a known manner. b 50 The mentioned compounds of formula II, which were used as starting materials in the previous method, are new and represent an additional purpose of the present invention, they can be obtained in different ways, as shown in "6 below Reaction Schemes, where M, B", 2 , KZ, BK" and KU have the meaning given before, "Vy means tert-butyl and Me means methyl.

F) name) 60 b5

Reaction scheme A I shoos. HM in soon (SHO . and

V-NM-mn" (TU) in in!

N

1 Grew up Mche from MN (U) and I no o vi

K-U si (MOog sch (8"-rO (USH) o

AND! - nn "vchoos t sho

Ky a (LYU) with "Ya yu v yaz so

IC c)

TEA « shi s 1 m in "» n nos Kk z;

ZK yes ah)

And to the

She in VZ (ee) 1 20 9

F vom, (X) - (1)

IF) og - or; име) ТРА - trifluoroacetic acid

Regarding Reaction Scheme A, at the first stage, the compound of the formula IS is condensed with hydrazine or 60-substituted hydrazine of the formula IM to obtain the hydrazide of the formula M. The said condensation is carried out under known conditions of peptide coupling reactions and with the help of coupling reagents, which are known for such couplings, for example, of 1-hydroxybenzotriazole, in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

After that, the hydrazide of the formula M reacts with the chloride of the formula MI or with the anhydride of the formula MI! to obtain 65 compounds of the formula MIII. This reaction is carried out in a known manner, for example, in an organic solvent, which remains inert under the conditions of the mentioned reaction, and in the presence of an organic base at a temperature from about 07C to about room temperature. Suitable solvents are halogenated hydrocarbons, for example, dichloromethane. Examples of organic bases that can be used are tri(lower alkyl)amines, for example triethylamine, pyridine, 4-dimethylaminopyridine, etc. In the case when the mentioned basis is liquid for

Under the mentioned reaction conditions, it can be used in excess, in which case it can be used as the only solvent.

Then, at the next stage, the compound of the formula MI! gets rid of the protective group with the help of trifluoroacetic acid (TEA) to obtain the carboxylic acid of formula IX. Said cleavage of the protective group is carried out by a method known in the art, for example, in an organic solvent that is inert under the conditions of the said reaction, 7/0, for example, a halogenated hydrocarbon, for example, dichloromethane, at about room temperature.

And, finally, the carboxylic acid of formula IX is converted into the starting material of formula I! by condensation with an O-protected hydroxylamine of the formula X. Said condensation is carried out in a way known to reg ze for peptide coupling reactions and with the help of traditional coupling reagents, for example, 1-hydroxybenzotriazole, in the presence of 1-ethyl-3-(3-dimethylaminopropyl) hydrochloride carbodiimide.

If necessary, the compounds that occur in Reaction Scheme A or that are obtained by the route shown in Reaction Scheme A can be interconverted or substituted.

Thus, the compound of the formula M, where BZ represents hydrogen, can be transformed into the corresponding compound of the formula

M, where BZ represents a lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl or aryl-lower alkyl group in a manner known in the art. For example, a compound of the formula M, where BZ represents hydrogen, can condense with an aldehyde of the general formula K2O-CHO, where KO is a lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl-lower alkyl or aryl group, for example, in the presence of p- of toluenesulfonic acid and molecular sieves, and the resulting substituted imine can be reduced, in a preferred option, by means of an alkali metal cyanoborohydride, in particular, sodium cyanoborohydride. Alternatively, the compound of the formula M, where BO represents hydrogen, can react with a cyclic anhydride of the general formula He) c)

D - zo bu (Dreams (XI) o

She, oh,; so where n has the value given before, e.g., glutaric anhydride, conventionally in the presence of an organic base, e.g., a tri(lower alkyl)amine, e.g., triethylamine, and in an organic solvent that remains inert under said reaction conditions, e.g. , an aromatic hydrocarbon, for example, benzene, toluene, etc., at an elevated temperature, in an acceptable variant, at the temperature of the distillation of the mentioned reaction mixture. Thus, a compound of formula MI is obtained, where B2, EZ and the atoms with which they are connected together form the group of formula (c), which was given - c before. h» Thus, a compound of the formula II, where BZ represents hydrogen, can be converted into the corresponding compound of the formula "I, where BO has the value given before, by reacting with a known compound of the general formula 230.X, where BZ has the value, which has been given before, and X represents a halogen, conventionally in the presence of a base, for example an alkali metal carbonate, for example sodium carbonate or potassium carbonate, and

Mn in an organic solvent that remains inert under the conditions of the mentioned reaction, for example, dimethylformamide. (ee) Additionally, a compound of formula IIi wherein B" represents a phthalimide-lower alkyl group may be treated with hydrazine hydrate, conventionally in an organic solvent which remains inert under said reaction conditions, for example, a lower alkanol such as methanol or ethanol, at at about room temperature, and (2) the resulting product, a compound of formula MIII, in which B 7 is an amine-lower alkyl group, may further be reacted with the appropriate (heteroaromatic carboxylic acid or sulfonic acid halide, (hetero)aromatic isocyanate or (a heteroaromatic carboxylic acid in the presence of a coupling reagent in the presence of a base in order to introduce the necessary group B".

The mentioned carboxylic acids of formula IX in Reaction Scheme A are new and form an additional object of the present invention.

F) The mentioned compounds of formula I, which are used in Reaction Scheme A, since they are unknown compounds or analogs of known compounds, can be obtained as described in the following Examples or by analogy to them. Moreover, the mentioned compounds of the formulas IM, MI, MI! and X, also used in Reaction Scheme A, as well as the mentioned aldehydes of the formula 230-CHO and the mentioned cyclic anhydrides of the formula Xi, are known compounds or analogues of known compounds. b5

Reaction Scheme B in! itshoos AH.

In soon (PI) in! men 1 i "vchoos "Ж - sooMme (ХП) those

TEA with in! at

In sooMe (HP) t - "co

EOMN" (X) yu i; with o in! in po ro -

M. sooMe (HU « in what s . Ame; » from " VZMN-MN. (U) t 1

Ge v (ee) A n o i-y zn s MNN (ХУ) n 2 I (22) no o yaZ -

KU SI (Mog 2 in (8Y-UYUO (MI)

F) t (1)

Regarding Reaction Scheme B, the first step involves the conversion of the carboxylic acid of formula I to the corresponding methyl ether of formula XI. This is done in a known manner, for example by reacting with methanol in the presence of a tertiary organic base, for example 4-dimethylaminopyridine, and a condensing agent, for example a diimide, for example 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

After that, the mentioned methyl ether of the formula XII! deprotect the tert-butoxycarbonyl group by treatment with trifluoroacetic acid. Said cleavage of the protective group is carried out by a method known to the public, for example, in an organic solvent, which is inert under the conditions of the said reaction,

for example, a halogenated hydrocarbon, such as dichloromethane, at about room temperature.

The resulting compound of formula XII is further condensed with O-protected hydroxylamine of formula X to obtain the compound of formula XIM. Said condensation is carried out in a way known to reg ze for peptide coupling reactions and with the help of traditional coupling reagents, for example, 1-hydroxybenzotriazole, in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

At the next stage, the compound of formula XIM reacts with trimethylaluminum and hydrazine or substituted hydrazine of formula IM to obtain the compound of formula XM. Said reaction is traditionally carried out in an organic solvent that is inert under said reaction conditions, for example, a halogenated hydrocarbon, such as dichloromethane, at a temperature in the approximate range from room temperature to a temperature of 60".

And, finally, the necessary starting material of the formula II is obtained by reacting the compound of the formula XM with the chloride of the formula MI or the anhydride of the formula MII. This reaction is carried out in a known manner, for example, in an organic solvent, which remains inert under the conditions of the mentioned reaction, and in the presence of an organic /5 base at a temperature from about 0"C to about room temperature. Suitable solvents are halogenated hydrocarbons, for example, dichloromethane. Examples of organic bases that can be used are tri(lower alkyl)amines, for example, triethylamine, pyridine, 4-dimethylaminopyridine, etc. In the case where said base is liquid under said reaction conditions, it can be used in excess, and in this case, it can simultaneously be used as the mentioned solvent.

Reaction Scheme C vd! meoOos "Zh . Ge: dream (HU) oh wow! "- 30 . And 1) Astsuayopy o i) NoM-MVO-U-v (HUP) to her s oyu in! « n - meroOos M

AK s: m in: 0 (SMP)

I" no 1 p o VZ 45 . 1 so AIMez 9 sl voMno 0) b 50 u -

Asiamyop - activation

At the first stage of Reaction Scheme C, the carboxylic acid of the formula HMI is activated, for example, by

HF) treatment with oxalyl chloride, followed by reaction with substituted hydrazine of the formula HMI! to obtain 7 compounds of formula XM. This reaction is traditionally carried out in the presence of a base, in particular, a tertiary organic amine, for example, triethylamine, and in an organic solvent that is inert under the conditions mentioned in the reaction, for example, a halogenated hydrocarbon, for example, dichloromethane, at a temperature of about 0"C.

Next, the compound of the XM formula! converted to the required starting material of formula II by reaction with trimethylaluminum and an O-protected hydroxylamine of formula X. This reaction is traditionally carried out in an organic solvent that remains inert under the conditions of the mentioned reaction, for example, a halogenated hydrocarbon, for example, dichloromethane, and at a temperature of from about room to about 60"C. in The mentioned carboxylic acids of the formula HMI and substituted hydrazines of the formula HMIII used in the Reaction Scheme

C, are known compounds or analogs of known compounds that can be obtained by a method similar to the method of obtaining the mentioned known compounds.

As previously mentioned, the hydrazine derivatives provided by the present invention inhibit the release of TME and

TOE-9, as well as the proliferation of keratinocytes. Said activity can be demonstrated by means of ip mig tests, which are described below.

Test A: Inhibition of TME-o release,

TNRI1 cells were cultured in KRMI 1640 medium supplemented with antibiotics and 1095 fetal bovine serum, collected by centrifugation and diluted to 5x10 C cells/ml in the aforementioned medium supplemented with 20 mM HEPES buffer. Aliquots (20 μl) of 70 of the obtained cell suspension were seeded on 96-well culture plates and incubated for 0.5 hours at a temperature of 37"C before adding the mentioned experimental compounds. The latter were dissolved in dimethyl sulfoxide (0OM5BO) to obtain 1.2 mM of a concentrated solution, which was diluted with a mixture of phosphate-buffered physiological solution and 1095 solution of dimethyl sulfoxide to obtain experimental compounds with a final concentration from 109M to 109M, and each concentration was subjected to a double 72 test. The mentioned cells were incubated with experimental compounds for 0.5 hours at a temperature of 37"С, after which bacterial lipopolysaccharide was added (I P) to a concentration of 2 mg/mg and subsequent incubation was carried out for 3 hours at a temperature of 37"C in an atmosphere that included 595 CO »5 and at 9590 relative humidity. After centrifugation at 260 x for 10 minutes, an aliquot of each supernatant was removed and the amount of TME was determined using solid-phase and immunoenzyme analysis (EGIZA) (company 250 bZuvietv Eigore Tsa., Aripdaop, England). The concentration of the experimental compound, which caused approximately 5095 inhibition of lipopolysaccharide-induced release of TME-o, (ISvo), was calculated using a dose-dependent curve.

Test B: Inhibition of release of TOR-o,

This test is an adaptation of a method described by R.J. Coffrey (K.). Sopgeu), R. Derynkom with (B. Oegupkyu), J.N. Wilcox (9U.M. UMiisoh), T.S. Bringman (T.5. Vgipdtap), A.S. Gastin (A.5. Soyviyp), (U

GL. Moses (N.M. Mozev) and M.R. Pittelkov (M.K. RitseiKkom/), Maishge, (1987), 328, 816-820. Normal human epidermal keratinocytes (NECs) (neonatal and adult) were supplied by Siopeiis5

Sogrogayop, San Diego, CA, SILA, which during the third passage were plated in 96b-well culture 20 plates at a density of 2 x 109 cells to 107 cells per well and grown in a humid chamber at 595 atmospheres -

CO" at a temperature of 37"C for 5 days on a serum-free nutrient medium for growing (Se) keratocytes (KOM; Siopeiisv Sogrogayop company). The experimental compounds were dissolved in dimethyl sulfoxide, after which they were diluted in a tenfold volume of the basal nutrient medium for growing keratinocytes ( KVM; Siopeiisv Sogrogayop company). Serial dilutions of the mentioned experimental compounds (ee) were carried out in 10956 dimethylsulfoxide in KVM to obtain concentrations that were 12 times higher than the final experimental concentration. The mentioned dilutions of the experimental compounds (or only the carrier as a control) were added to the cells. followed by incubation at a temperature of 377"C for 0.5 hours. After this allocation

TOog-9 was stimulated by adding 1 ng/ml of TPA (phorbol 12-myristate 13-acetate). After additional incubation at a temperature of 377°C for 24 hours, the content of TOB in the culture medium was determined using TOE-o,

EPIZA (Opsodepe Zsiepse Ips., Opiopdaie, New York, USA) or electrochemiluminescence-based detection systems (Idepe Ips., Saipegerigd, Maryland, USA) formatted with anti-human TOE-o (K 50 Bouvietvs Epgore I(4.) After that, the concentration of the experimental compound was calculated, which provided 5095 inhibition of the release of TOE- in relation to the mentioned control (ISvo nmol).

Test C: Inhibition of Wasp Keratinocyte Proliferation This test is an adaptation of the methods described by T. Karashima (T. Kagazpita), H. Hachisaka (N. Naspizyka) and Y. Sasai (U. Zavzai), in Oeptaiyi. Zsi, (1996), 12, 246-254, and A. Olaniran (A. so OIapigap), V.S. Baker (8.5. WaKeg), J.J. Gariochem (9.9. (Zagposi), A.V. Poulsom (A.M. Romiev) and L. Fryem os (S. gu), Agsp. YuOegptaiyo!. Kevz., (1995), 287, 231-236. Normal Human Epidermal Keratinocytes (HEC) b 50 (newborn and adult) were seeded into 9b-well culture plates at a density of 2 x 109 cells per well. After cell attachment to the plate by incubation for 24 hours in a humid chamber with 590 -. and CO atmosphere" at a temperature of 37"C on a serum-free nutrient medium for growing keratocytes (KOM, see before), the mentioned nutrient medium was replaced with KVM (see before) for 4 days in order to stop the growth of the mentioned cells. The experimental compounds were dissolved in dimethyl sulfoxide, after which they were diluted in ten times the volume of the basal nutrient medium for the growth of keratinocytes (KVM). Serial dilutions of the mentioned experimental compounds were carried out in 1090 dimethyl sulfoxide in KVM with obtaining concentrations that were 11 times higher than the final experimental concentration ntration After that, the mentioned cells were returned to the KOM with the immediate addition of the mentioned dilutions of the experimental compounds (or only the vehicle as a control). After incubation for 3 days, the mentioned cells were subjected to pulse labeling with ZN-thymidine (1 μCurie/well, the company Ategeyat Ipiegpayopa! ris, I and She

Spaiopi, Wyskipopatzgpige, Great Britain) for at least 16 hours. After that, the cells were separated using a trypsin-ethylenediaminetetraacetic acid solution and collected. The inclusion of ZN-thymidine, as a criterion of proliferation, was determined by the method of counting scintillation flashes.

After that, the concentration of the experimental compound was calculated, which provided 5095 inhibition of 62 of the inclusion of ZH-thymidine relative to the mentioned control (ISvo nmol).

Generalized results obtained with representative compounds of formula I! during the tests, the description of which was given before, is presented in the following Table. and in 51116001 at MO: MON WED WED MON WED THROUGH FRI

M/T-Not tested;

A-(E)-2(KO)-I(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide;

BA(E)-2(KO-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-2-(4-methoxyphenyl)-4-methyl valerohydrazide;

CA(E)-2'-benzyl-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerohydrase d.

OrA(E)-2i(cyclohexylmethyl)-2(K)-I(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylbs ov allerohydrazide.

E-(E)-2(KO-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydra o zide).

E(E)-2(KO-I(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-M-(2,6-dioxopiperidine)valeramide. -(E)-2 (KO)-(1(5)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2-12(5)-methylbutyl-isolerohydrazide.

НА(Е)-2(КО-И1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-(methanesulfonyl)-4-methyl-2'-(2-methylallyl)valerohyde, dist.

I-methyl (E)-3-I2(KO)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methylvaleryl)-2-isobutyl carbazate.

IC(E)-2(KO-((5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl)|-2-(isobutyl)-2-(isopentanoyl)-4-methylvalerohydrazide; so

Said hydrazine derivatives provided by this invention can be used as medicinal products, for example, in the form of pharmaceutical preparations. Said pharmaceutical preparations can be administered orally, for example, in the form of tablets, enteric-coated tablets that disintegrate in the intestines, 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, for example, in the form of solutions for injection. "

In the manufacture of pharmaceutical preparations, the mentioned hydrazine derivatives can be included in their composition together with therapeutically inert, inorganic or organic carriers. Lactose, corn starch or their derivatives, talc, stearic acid or its salts can be used, for example, as such carriers for "" tablets, enteric-coated tablets that disintegrate in the intestines, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes,

Fats, semi-solid and liquid polyols, etc. Depending on the nature of the active ingredient, however, carriers, such as soft gelatin capsules, are generally not required. Suitable carriers for making solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc. Suitable carriers for the manufacture of injection solutions are, for example, water, alcohols, polyols, glycerin, vegetable oils, etc. «sl Natural and solidified oils, waxes, fats, semi-liquid polyols, etc. are suitable carriers for the manufacture of 5p suppositories.

Fo The composition of the mentioned pharmaceutical preparations may also include preservatives, stabilizers, - M moisturizing substances, emulsifiers, sweeteners, dyes, corrigents, salts for regulating osmotic pressure, buffers, enteric coating substances or antioxidants.

Medicinal products, the composition of which includes the above-mentioned hydrazine derivative and a therapeutically acceptable carrier, as well as the method of obtaining such medicinal products, are also objects of the present invention. This method includes the introduction of a compound of formula I or a pharmaceutically acceptable salt thereof into a galenic dosage form for administration along with

F) a therapeutically inert carrier and, if necessary, one or more additional therapeutically active substances.

An additional object of the present invention is the use of the mentioned hydrazine derivatives provided by this invention for the treatment of diseases, in particular, for the treatment of inflammation, fever, hemorrhage, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis and psoriasis. The dosage can vary widely and will, of course, be regulated by individual requirements in each specific case. In general, when administered to adults, a daily dose of from about 5mg to about 30mg, preferably from about 10mg to about 15mg, would be appropriate, although, if necessary, the mentioned upper limit bb may be exceeded. The mentioned daily dose can be administered as a single dose or in divided doses.

The following Examples illustrate this invention. The structure of the mentioned products and the main intermediates was confirmed by means of NMR spectroscopy.

Example 1 2(K)-(1(5)-(hydroxycarbamoyl)-4-phenylbutyl|-2'(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide

A solution of 0.165 g of 2(K)-I1(5)-(carboxy)-4-phenylbutyl|-2'-(methanesulfonyl)-4-methyl-2'--phenylvalerohydrazide in 4 ml of dry dimethylformamide was cooled to a temperature of 0"C with simultaneous with stirring in a nitrogen atmosphere, after which 0.09g of 1-hydroxybenzotriazole and 0.09g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added. After stirring for 40 minutes at a temperature of 07C, the resulting solution was treated with 0.18g of O-(tert -butyldimethylsilyl)hydroxylamine; the resulting mixture was kept with /o heating to room temperature with further stirring overnight. The mentioned solvent was evaporated and the resulting residue was partitioned between ethyl acetate and 595 aqueous sodium hydrogen carbonate solution. The obtained ethyl acetate layer was washed successively with water, 2M sulfuric acid, water and brine, after which it was dried over anhydrous magnesium sulfate. mol)-4-phenylbutyl/|-2'-methanesulfonyl)-4-methyl-2-phenylvalerohydrazide as an off-white solid.

Mass spectrometry: 476 (MAN) 7.

Nuclear magnetic resonance (d5 dimethylsulfoxide at 353K): 10.73 (1Н, singlet); 10.30 (IN, wide singlet); 8.46 (IN, wide singlet); 7.50-7.44 (2H, multiplet); 7.42-7.34 (2H, multiplet); 7.30-7.21 (ZN, 2o Mmultiplet); 7.18-7.06 (ZN, multiplet); Z,17 (ZN, singlet); 2.64-2.54 (1H, multiplet); 2.50-2.30 (2H, multiplet); 2.25-2.11 (1H, multiplet); 1.59-1.23 (6H, multiplet); 1.10-1.02 (1H, multiplet); 0.84 (1H, doublet, 4): Hz); 0.76 (1H, doublet, .)- Hz).

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 1096 of solvent B for 5 minutes, followed by increasing the content of solvent B to 9095 from 5 minutes to Ha for 15 minutes; flow rate Tml/minute. Holding time: 16.77 minutes. Solvent A: H 20/0.195. TEA (tetrafluoroacetic acid); solvent B: SNUZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER i)

ZOO 2(K)-(1(5)-(carboxy)-4-phenylbutyl|-2(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide, which was used as a starting material, was obtained in the following way: "- ( ) A solution of 0.35 g of 2(K)-I1(5)-(tert-butoxycarbonyl)-4-phenylbutyl|-4-methylvaleric acid, which was obtained by a method similar to the method described in Example 2, part (iii ) and (iii), cooled to a temperature of 0"C in a bml of dimethylformamide and successively treated with 0.1ml of M-methylmorpholine, 0.1bg of 1-hydroxybenzotriazole, 0.16g of phenylhydrazine and 0.27g of 1-ethyl-3-hydrochloride (3-dimethylaminopropyl)carbodiimide. The resulting solution was kept with heating to room temperature with further stirring overnight. The mentioned solvent was evaporated and the resulting residue was partitioned between ethyl acetate and 595 aqueous sodium hydrogen carbonate solution. The resulting ethyl acetate layer was successively washed with water, 596 citric acid solution , water and saturated sodium chloride solution, dried over anhydrous sulfate ma rot and evaporated. The resulting residue was purified by means of gel chromatography under vacuum eluting with a mixture of hexane/ethyl acetate (6:1). 70 0.41 g of a yellow oil was obtained, which, after crystallization from a mixture of hexane/ether, provided - c obtaining 0.255 g of 2(K)-(1(5)-(tert-butoxycarbonyl)-4-phenylbutyl)|-4- methyl-2-phenylvalerohydrazide as a white solid. "» Mass spectrometry: 439 (MAN) 7. (iii) A solution of 0.19 g of the product from part (i) in 3 ml of pyridine was cooled to a temperature of 0"C and 0.15 g of methanesulfonyl chloride was added. The resulting solution was kept at room temperature and the mentioned solvent 1 was evaporated. The resulting residue was partitioned between ethyl acetate and 2M sulfuric acid; the obtained ethyl acetate layer was successively washed with 2M sulfuric acid, water, 595% aqueous sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mentioned 1 solvent was evaporated, the resulting residue was purified by distillation under vacuum, eluting with a mixture of b50 hexane/ethyl acetate (6:1). 0.19 g of 2(K)-(1(5)-(tert-butoxycarbonyl)-4-phenylbutyl/|-2'-(methanesulfonyl)-4-methyl-2-phenylvalerohydrazide was obtained as a white solid .

Mass spectrometry: 517 (MAN) 7. (its) A solution of 0.19 g of the product from part (ii) was dissolved in a mixture of 1 ml of dichloromethane and 4 ml of trifluoroacetic acid and stood at room temperature for 5 hours. The mentioned solvent was evaporated and the obtained residue was re-evaporated from toluene. The mentioned procedure was additionally repeated twice to obtain the remainder. The mentioned residue was dissolved in ether and the solid was filtered off. 0.165 g of 2(K)-(11(5)-(carboxy)-4-phenylbutyl/|-2'-(methanesulfonyl)-4-methyl-2--phenylvalerohydrazide was obtained as a white solid. 6o Mass spectrometry: 461 (MAN) 7.

Example 2 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide

A solution of 0.095 g of (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2"- phenboilvalerohydrazide in a mixture of 10 ml of methanol and ml of dichloromethane was treated with 0.04 mg of 4-toluenesulfonic acid. The resulting mixture was stirred for 3 hours at room temperature, after which the mentioned solvent was evaporated. The resulting residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous sulfate magnesium and the mentioned solvent were evaporated. The obtained residue was dissolved in ether to obtain 0.051 g of (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methyl- 2-phenylhydrazide as a white solid.

Mass spectrometry: 474 (MAN) 7.

Nuclear magnetic resonance (d5 dimethylsulfoxide at 353K): 10.80 (1H, singlet); 10.30 (IN, wide 70 singlet); 8.48 (IN, wide singlet); 7.51-7.45 (2H, multiplet); 7.42-7.34 (2H, multiplet); 7.32-7.23 (5H, multiplet); 7.21-7.14 (IN, multiplet); 6.22 (1H, doublet, U-15.5Hz); 6.08-5.96 (1H, multiplet); 3.20 (ZN, singlet); 2.70-2.60 (1H, multiplet); 2.42-2.12 (ZN, multiplet); 1.58-1.48 (IN, multiplet); 1.46-1.35 (2H, multiplet); 1.14-1.05 (1H, multiplet); 0.85 (ZN, doublet, U-6.5Hz); 0.76 (ZN, doublet, U-7.5 Hz).

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 75 1095 of solvent B, for 5 minutes, followed by increasing the content of solvent B to 9095 from 5 minutes to minutes; flow rate Tml/minute. Holding time: 16.76 minutes. Solvent A: H 20/0.1956 TEA (tetrafluoroacetic acid); solvent B: SNUZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER

ZOO (E)-2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2" - phenylvalerohydrazide, which was used as a starting material, was obtained in the following manner: (І) A solution of 5.19 g of 4-tert-butyl hydrogen 2(K)-isobutyl succinate in 5 Oml of dry tetrahydrofuran was cooled to a temperature of -78"C with simultaneous stirring in the atmosphere nitrogen 25 ml of a 2M solution of lithium isopropylamide in tetrahydrofuran was added dropwise and the resulting mixture was stirred at a temperature of -78"C for 15 minutes. After that, a solution of 5.55 g of cinnamyl bromide in 25 ml of dry tetrahydrofuran was added dropwise and the resulting mixture was kept with gradual heating to room temperature. After stirring overnight tetrahydrofuran was evaporated, the resulting residue was partitioned between ethyl acetate and 596 citric acid solution. The resulting ethyl acetate layer was washed with two additional portions of 595 citric acid solution, water, and saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated to give an orange oil color. The resulting oil was dissolved in 100 ml of hexane, to which 2.35 g of cyclohexylamine was added. The resulting mixture was allowed to stand for 2 hours and the resulting solid was filtered off. The said solid was suspended in ethyl acetate and mixed with two portions of 2M sulfuric acid with holding a clear solution. The obtained ethyl acetate solution was washed twice with water, then with saturated sodium chloride solution, followed by drying over anhydrous magnesium sulfate. After evaporation of the mentioned solvent, 41 g of Е)-2(K)-I1(K)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvaleric acid was obtained as a pale-cream solid color (i) The product obtained in part (i) was dissolved in 5 ml of dry tetrahydrofuran, cooled to a temperature of -78°C with simultaneous stirring, and 20.5 ml of a 2M solution of lithium isopropylamide in tetrahydrofuran was added dropwise. After stirring for 1.75 hours ml of methanol was added at a temperature of -78"C. The resulting mixture was kept with gradual heating to room temperature, after which it was stirred overnight. The tetrahydrofuran was evaporated, the resulting residue was partitioned between ethyl acetate and 595% citric acid solution. The obtained ethyl acetate layer was successively washed with two additional portions of citric acid solution, two portions of water and saturated sodium chloride solution, and then dried over magnesium sulfate. After evaporation, an orange oil was obtained,

WHICH included a mixture of 1(5),2(Kk) and 1015O),2(K) isomers of (E)-2-(1-(tert-butoxycarbonyl)-4-phenyl-3-butenyl-4-methylvaleric acid). The above-mentioned epimerization procedure was repeated three times to obtain a mixture significantly enriched in the 1(5),2(K) isomer. The resulting crude product was dissolved in 100 ml of hexane and the resulting solution was treated with 1.9 g of cyclohexylamine. After standing for 3 hours, the salt was filtered and dried , which precipitated. 5.53 g of a pale cream-colored solid were obtained, which was converted to the free acid using a procedure similar to the procedure described in (I). 4.36 g of M ()-2(KO -(1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvaleric acid in the form of a yellow solid. (iii) In a method similar to the method described in Example 1, part (i), starting with

0.1 g of carboxylic acid, which was obtained in part (its) of this example, 0.466 g ()-2(KO-(1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4- methyl-2'-phenylhydrazide as a solid

F, white. ime) Mass spectrometry: 437 (MAN) 7. (m) In a method similar to the method described in Example 1, parts (ii) and (ii), with 6bo initiation of Kk! 0 15g of (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methyl-2'-phenylvalerohydrazide, 0.14g of ()-2(KO- 1(5)carboxy)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-phenylvalerohydrazide as a white solid. (y) The carboxylic acid which was obtained in the previous paragraph, dissolved in 3 ml of dimethylformamide, 65 cooled to room temperature and successively treated with 0.4 g

O-(tetrahydro-2H-pyran-2(K5)-yl)hydroxylamine and 0.061 g of hydrochloride

1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mentioned solvent was evaporated and the resulting residue was partitioned between 595 citric acid solution and ethyl acetate. The obtained ethyl acetate layer was washed

Water, 570 sodium bicarbonate solution and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and evaporated. The resulting white solid was mixed with ether and filtered to obtain 0.095 g of (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbonyl|-4-phenyl-3-butenyl|-2' -(methanesulfonyl)-4-methyl-2'-phenyl valerohydrazide in the form of a white powder. 70 Mass spectrometry: 558 (MAN) 7.

Example C

Benzyl 3-I2(K)-I1(5)-(hydroxycarbamoyl)-4-phenylbutyl)|-4-methylvaleryl|/|-2-phenylcarbamate

In a manner similar to the method described in the first paragraph of Example 2, starting with

О,О5g of benzyl 75... Z-I2(KO-I1(5)-Ktetrahydro-2(К5)-pyranyloxy)carbamoyl|-4-phenylbutyl)|-4-methylvaleryl|-2-phenylcarbazate, 0.032g of benzyl was obtained 3-I2(K)-I1(5)-(Hydroxycarbamoyl)-4-phenylbutyl)-4-methylvaleryl|-2-phenylcarbazate In the form of a pale cream-colored solid.

Mass spectrometry: 532 (MAN) 7.

Nuclear magnetic resonance (d6 dimethylsulfoxide at 353K): 10.83 (1H, singlet); 10.47 (IN, wide singlet); 8.62 (IN, wide singlet); 7.64 (2H, multiplet); 7.54 (7/H, multiplet); 7.41 (ZN, multiplet); 7.33 (1H, multiplet); 7.24 (2H, multiplet); 5.40 (2H, singlet); 2.76-2.30 (4H, multiplet); 1.75-1.45 (BN, multiplet); 1.22 (1H, multiplet); 0.97 (ZN, doublet, 1-7Hz); 0.90 (ZN, doublet, U-6.5Hz).

High-performance liquid chromatography: Gradient elution with solvent A, which includes 1095 of solvent B, for 5 minutes, followed by increasing the content of solvent B to 8095 from 10 minutes to cm 20 minutes; flow rate Iml/minute. Holding time: 19.71 minutes. Solvent A: H 20/0.195 TEA (5) (tetrafluoroacetic acid); solvent B: SNUZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER

ZOO

Benzyl 3-I2(KO)-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenylbutyl|-4-methylvaleryl/|-2-phenylcarbamate, which -- was used as a starting material, was obtained in the following manner: () 0 b5g of 2(K)-(1(5)-(tert-butoxycarbonyl) of 4-phenylbutyl|-4-methyl-2'--phenylvalerohydrazide, which was obtained according to the description, which is given in Example 1, part (i), was dissolved in 1Oml of diethyl ether and IC o) was mixed with 1Oml of a saturated aqueous solution of sodium hydrogencarbonate and 1.0ml of benzyl chloroformate. After 24 hours, the resulting ether layer was separated, washed with a saturated solution of sodium chloride and dried with over anhydrous magnesium sulfate After removal of the mentioned solvent, the obtained residue was purified by IC) gel chromatography under vacuum eluting with a mixture of hexane/ethyl acetate (9:11). 0.767 g of benzyl 3-I2(K)-I1(5)-(tert-butoxycarbonyl)-4-phenylbutyl| -4-methylvaleryl|-2-phenylcarbazate as a white solid. "

Mass spectrometry: 573 (MAN) 7. (i) In a method similar to the method described in Example 2, parts (im) and (m), starting with 0.115 g of phenylcarbazate, which was obtained in the previous paragraph , obtained 0.115 g of benzyl 3-I2(K)-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)|-4-phenylbutyl|-4-methylvaleryl/|-2-phenylcarbazate in the form of a colorless resin.

Mass spectrometry: 616 (MAN) 7.

Example 4 about 2-acetyl-2(K)-I(1(5)-(hydroxycarbamoyl)-4-phenylbutyl|-4-methyl-2'-phenylvalerohydrazide

Go! In a manner similar to the method described in the first paragraph of Example 2, starting with 0,bog o 2"-acetyl-2(K)-(1(5)-Ctetrahydro-2(K5)-tranyloxy)carbamoyl)| -4-phenylbutyl/|-4-methyl-2'"-phenylvalerohydrazide,

Fu 70 obtained 0.062 g of 2"-acetyl-2(K)-(1(5)-Ktetrahydro-2-(K5)-pyranyloxy)carbamoyl|-4-phenylbutyl|-4-methyl-2'-phenylvalerohydrazide -6 in in the form of a white solid substance.

Mass spectrometry: 440 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A containing 25 2595 of solvent B for 5 minutes, followed by increasing the content of solvent B to 6095 from 5 minutes to

GF) 20 minutes; flow rate Tml/minute. Holding time: 14.97 minutes. Solvent A: H 20/0.1956 TEA (tetrafluoroacetic acid); solvent B: SNUZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER

ZOO 2"-Acetyl-2(K)-(1(5)-Ctetrahydro-2(KZ)-pyranyloxy)carbamoyl-1|-4-phenylbutyl/|-4-methyl-2"--phenylvalerohydrase, which was used as starting material was obtained in the following way: () A mixture of 0.2 g of 2(K)-(1(5)-(tert-butoxycarbonyl)-4-phenylbutyl|-4-methyl-2'--phenylvalerohydrazide, which was obtained according to the description given in Example 1, part (It), 0.3ml of acetic anhydride and 0.33Bml

M-methylmorpholine in 2 ml of dichloromethane was maintained at room temperature for 3 days. The dichloromethane was evaporated and the resulting residue was partitioned between ethyl acetate and 595 g of sodium bicarbonate solution. bo The obtained ethyl acetate solution was washed with 595% sodium bicarbonate solution, water, 595% citric acid solution, water and saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The mentioned solvent was evaporated, the resulting residue was purified by gel chromatography under vacuum eluting with a mixture of hexane/ethyl acetate (1:17). 0.21 g of 2"-acetyl-2(K)-(1(5)-(tert-butoxycarbonyl)-4-phenylbutyl|-4-methyl-2'--phenylvalerohydrazide was obtained as a white solid.

Mass spectrometry: 481 (MAN) 7. (i) In a method similar to the method described in Example 2, parts (im) and (m), starting with 0.21 g of hydrazide, which was obtained in the previous paragraph, obtained 0.09 g of 70. 2-acetyl-2(K)-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenylbutyl)|-4-methyl-2'-phenylvalerohydrazide in the form of a solid white substances.

Mass spectrometry: 524 (MAN) 7.

Example 5 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-methanesulfonyl)-4-methyl-2 75 -(2-pyridyl)valerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with O11g (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoylI|-4-phenyl-3- butenyl|-2'(methanesulfonyl)-4-methyl-2'-(2-pyridyl)valerohydrazide, was obtained after washing the solution of the mentioned product in ethyl acetate with 295% aqueous solution of sodium bicarbonate in order to obtain the free base, 0.052g ()- 2(KO-I1(5)-(hydrocarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2'-(2-pyridyl)valerohydrazide as a white solid.

Mass spectrometry: 475 (MAN) 7.

Nuclear magnetic resonance (de6 dimethylsulfoxide at 353K): 10.86 (1H, singlet); 10.27 (AN, wide SM singlet); 8.45 (1H, wide singlet); 8.35 (1H, multiplet); 7.30 (IN, multiplet); 7.34-7.12 (7Н, о multiplet); 6.32 (1H, doublet, 9U-15.5Hz); 6.13-6.04 (1H, multiplet); 3.51 (ZN, singlet); 2.79-2.69 (1H, multiplet); 2.50-2.30 (ZN, multiplet); 1.53-1.50 (2H, multiplet); 1.19-1.10 (1H, multiplet); 0.91 (ZN, doublet, U-7.0Hz); 0.83 (ZN, doublet, 1-6.5 Hz).

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes -- 1095 solvent B, for 5 minutes, followed by increasing the content of solvent B to 9095 from 5 minutes to 20 minutes; flow rate Tml/minute. Holding time: 16.20 minutes. Solvent A: H 20/0.1956 TEA (tetrafluoroacetic acid); solvent B: SNUSN/O,08595 tetrafluoroacetic acid. Column type: NUREVBRER

ZOO co (E)-2(KO-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2" -(2-pyridyl)valerohydrazide, which was used as a starting material, was obtained in the following way:

In a method similar to the method described in Example 2, part ((iii)-(y), starting with ()-2(KO-(1(5)-(tert-butoxycarbonyl)-4-phenyl-3 -butenyl|-4-methylvaleric acid and 2-hydrazinopyridine, obtained "(E)-2(KO-I1(5)-(tetrahydro-2(KZ)-pyranyloxy)carbamoyl1|-4-phenyl-3-butenyl|- 2'(methanesulfonyl)-4-methyl-2'-(2-p iridyl)valerohydrazide in the form of a white solid substance. mass spectrometry: 559 (MAN) 7. "» Example 6 " (E)-2' -(2-benzothiazolyl)-2(K)-1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl valerohydrazide

In a manner similar to the method described in the first paragraph of Example 2, starting with ini 0,ovbg

Go! (E)-2'-(2-benzothiazolyl)-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-2-(methanesulfonyl )-4-methylvalerohydrazide was obtained after washing the solution of the mentioned product in ethyl acetate with 290 g of sodium bicarbonate aqueous solution, 0.045 g of 20. (E)-2'-(2-benzothiazolyl)-2(K)-(1 5)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide as a white solid.

With Mass spectrometry: 531 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, over 5 minutes, followed by increasing the content of solvent B to 95905 from 5 minutes to 20 29 minutes; flow rate Iml/minute. Holding time: 18.16 minutes. Solvent A: H 250/0.195 TEA

HF) (tetrafluoroacetic acid); solvent B: SNUZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER

ZOO o (E)-2'-(2-benzothiazolyl)-2(K)-(1(5)-(tetrahydro-2(K5)-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-2-( methanesulfonyl)-4-methylvalerohydrazide, which was used as a starting material, was obtained in the following manner:

In a method similar to the method described in Example 2, part ((iii)-(y), starting with (E)-2(CO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3 -butenyl|-4-methylvaleric acid and 2-hydrazinobenzothiazole, obtained (E)-2'-(2-benzothiazolyl)-2(К)-(1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl1|- 4-phenyl-3-butenyl|-2-(methanesulfonyl)-4-methylvalerohydrazide as a white solid.

Example 7 ()-2(KO-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-(2-quinolyl)valerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.05 g of (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl- 3-butenyl|-2'(methanesulfonyl)-4-methyl-2'-(2-quinolyl)valerohydrazide was obtained after washing the solution of the mentioned product in ethyl acetate with 290 g of aqueous sodium bicarbonate solution, 0.026 g 70. "E)- 2(KO-11(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl)-2'(methanesulfonyl)-4-methyl-2'-(2-quinolyl)valerohydrazide in the form of a white solid.

Mass spectrometry: 524 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 1096 of solvent B for 5 minutes, followed by increasing the content of solvent B to 9095 from 5 minutes to 75 for 20 minutes; flow rate Tml/minute. Holding time: 17.90 minutes. Solvent A: H 20/0.195. TEA (tetrafluoroacetic acid); solvent B: SNUZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER

ZOOA (E)-2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2" -(2-quinolyl)valerohydrazide, which was used as a starting material, was obtained in the following manner:

In a method similar to the method described in Example 2, part ((iii)-(y), starting with ()-2(KO-(1(5)-(tert-butoxycarbonyl)-4-phenyl-3 -butenyl|-4-methylvaleric acid and 2-hydrazinoquinoline, obtained (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoylI|-4-phenyl-3-butenyl|-2' -(methanesulfonyl)-4-methyl-2'-(2-quinolyl)valerohydrazide as a white solid.

Example 8 1(E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-2-(4-methoxyphenyl)-4-methylvale i9)rohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.338 g of "-"E)-2(K)-1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4- phenyl-3-butenyl|-2'-(methanesulfonyl)-2'-(4-methoxyphenyl)-4-methylvalerohydrazide, 0.195 g of 1(E)-2(KO-(1(5)-(hydroxycarbamoyl) -4-phenyl-3-butenyl|-2'-(methanesulfonyl)-2'-(4-methoxyphenyl)-4-methylvalerogy drazide as a cream-colored solid.

Mass spectrometry: 504 (MAN) 7. so

High-performance liquid chromatography: Gradient elution using solvent A, which includes 590 ml of solvent B, for 5 minutes, followed by increasing the content of solvent B to 95905 from 5 minutes to 20 minutes; flow rate tTml/minute. Holding time: 16.53 minutes. Solvent A: H 250/0.01956 TEA (tetrafluoroacetic acid); solvent B: SNUZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER «

ZOO (E)-2(KO)-1(5)-Ctetrahydro-2(KZ)-pyranyloxy)carbamoyl-1H-4-phenyl-3-butenyl|-2'(methanesulfonyl)-2'-(4-methyl-csiphenyl) )-4-methylvalerohydrazide, which was used as a starting material, was obtained by the following method: )-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvaleric acid and 4-methoxyphenylhydrazide, 1 (E)-2(KO-I1(5)- Tetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-2-(4-methoxyphenyl)-4-methylvalerohydrazide as a white solid.

Example 9 1 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2-(methanesulfonyl)-4-methyl-2'-(2-methylphenyl)valerog hydrazide ( 22).

In a method similar to the method described in the first paragraph of Example 2, starting with - 0.37 g of (E)-2(КО-(1(5)-Ktetrahydro-2-(К5)-pyranyloxy)carbamoyl1|-4 -phenyl-3-butenyl|-2(methanesulfonyl)-4-methyl-2'-(2-methylphenyl)valerohydrazide, obtained 0.192 g of (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl -3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-(2-methylphenyl)valerohydra oside as a cream-colored solid.

Mass spectrometry: 488 (MAN) 7. de High-performance liquid chromatography: Gradient elution with solvent A, which includes 596 of solvent B, followed by increasing the content of solvent B to 9095 over 15 minutes; flow rate 60 Lml/minute. Holding time: 12.37 minutes. Solvent A: H»O/0.195 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2" - (2-Methylphenyl)valerohydrazide, which was used as a starting material, was obtained in the following manner: () In a manner similar to the method described in Example 1, part (i), starting with b5 and (E)-2 (KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvaleric acid and o-tolylhydrazine, 0.5g were obtained

(E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methyl-2-(2-methylphenyl)valerohydrazide as a cream-colored solid.

Mass spectrometry: 451 (MAN) 7. (ii) Solution 0 15g (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methyl-2- (2-methylphenyl)valerohydrazide in ml of dichloromethane was treated with 0.09g of pyridine and 0.1g of methanesulfonhydride. After stirring for 1.5 hours, 0.05g of pyridine and 0.0bg of methanesulfonhydride were additionally added, and the resulting mixture was further stirred for 2 hours. The mentioned solvent was evaporated and the resulting residue was partitioned between 70% ethyl acetate and 595% citric acid solution. The resulting ethyl acetate solution was washed with water, 590% sodium bicarbonate solution, and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by gel chromatography under vacuum with elution with a mixture of hexane/ethyl acetate (6:11). 0.16 g of (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)- 4-methyl-2'-(2-methylphenyl)valerogi 75 drazide in the form of a yellow resin.(iii) Hydr. The azide obtained in the previous paragraph was treated in a manner similar to that described in Example 1, part (iii), followed by further treatment in a manner similar to that described in Example 2, part (M), Ck! by obtaining (E)-2(K)-1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methyl-2'-(2 -m ethylphenyl)valerohydrazide in the form of a cream-colored solid.

Mass spectrometry: 572 (MAN) 7.

Example 10 ()-2(KO-(1(5)-(hydroxycarbonyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-(1-naphthyl)valerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.09 g of (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoylI|-4- phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2-(1-naphthyl)valerohydrazide, 0.053 g of (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl- 3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-(1-naphthyl)valerohydrazide as a cream-colored solid.

Mass spectrometry: 524 (MAN) 7. "co

High-performance liquid chromatography: Gradient elution with solvent A, which includes 596 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate MO 1ml/minute. Holding time: 12.83 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent so

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2" Is ) -(1-naphthyl)valerohydrazide, which was used as a starting material, was obtained in the following way:

In a method similar to the method described in Example 9, part (1)-(iii), starting with (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3- of butenyl|-4-methylvaleric acid and 1-naphthylhydrazine, (E)-2(К)-(1(5)-Ktetrahydro-2(К5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|- 2i(methanesulfonyl)-4-methyl-2'-(1-tc naphthyl)valerohydrazide in the form of a cream-colored solid. "» Mass spectrometry: 608 (MAN) 7. " Example 11 (E)-2-(3 -hydroxybenzyl)-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl valerohydrazide o In a method similar to the method described in the first paragraph of Example 2, starting with about 0.375 g of (E)-2-(3-hydroxybenzyl)-2(K)-I(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbonyl|-4-phenyl- 3-butenyl|-2(methanesulfonyl)-4-methylvalerohydrazide, 0.29 g were obtained

Ge" 20. (E)-2'-(3-hydroxybenzyl)-2(B3-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog hydrazide as a white solid.

With Mass spectrometry: 503 (MAN) 7.

Nuclear magnetic resonance (d5 dimethylsulfoxide at 353K): 10.23 (IN, broad singlet); 10.09 (1H, singlet); 8.98 (1H, singlet); 8.41 (IN, wide singlet); 7.30 (4H, multiplet); 7.18 (IN, multiplet); 7.09 29 (IN, multiplet); 6.83-6.73 (2H, multiplet); 6.67 (1H, multiplet); 6.24 (1H, doublet, 9U-15.5Hz); 6.05-5.94

HF) (1H, multiplet); 4.56-4.48 (2H, multiplet); 3.14 (ZN, singlet); 2.55-2.45 (1H, multiplet); 2.33-2.18 (2H, multiplet); 2.16-2.02 (1H, multiplet); 1.50-1.40 (1H, multiplet); 1.38-1.21 (IN, multiplet); 1.05-0.95 o (1H, multiplet); 0.75 (ZN, doublet, U-7Hz); 0.71 (ZN, doublet, 9U-7Hz).

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 60 Bor of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 10.95 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2-(3-hydroxybenzyl)-2(K)-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbonyl|-4-phenyl-3-butenyl|-2-(methanesulfonyl) -4-methylvalerohydrazide, which was used as a starting material, was obtained in the following 62 way:

In a method similar to the method described in Example 9, part (1)-(iii), starting with (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3- butenyl|-4-methylvaleric acid and

(E)-2-(3-hydroxybenzyl)-2(K)-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2' -(methanesulfonyl)-4-methylvalerohydrazide as a white solid.

Mass spectrometry: 588 (MAN) 7.

Example 12 (E)-2-(2,4-difluorophenyl)-2(K)-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvale 70 rohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0 13g (E)-2'-(2,4-difluorophenyl)-2(K)-I(1(5)-Ktetrahydro-2 (K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2-(methanesulfonyl)-4-methylvalerohydrazide, 0.083g were obtained 15. (E)-2'(2,4-difluorophenyl)-2 (K)-(1(5)-(hydroxycarbonyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydride as a white solid.

Mass spectrometry: 510 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate ml/minute. Holding time: 12.37 minutes. Solvent A: HNO/0.195 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2'-(2,4-difluorophenyl)-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl| -2-(methanesulfonyl)-4-methylvalerohydrazide, which was used as a starting material, was obtained in the following way: c

In a method similar to the method described in Example 2, part ((iii)-(y), starting with o (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl- 3-butenyl|-4-methylvaleric acid and 2,4-difluorophenylhydrazine, (E)-2'-(2,4-difluorophenyl)-2(K)-I1(5)(tetrahydro-2(K5)-pyranyloxy )carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide as a white solid. --

Example 13 "co ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-(4-nitrophenyl)valerog hydrazide Io )

In a manner similar to the method described in the first paragraph of Example 2, starting with (E)-2(K)-tetrahydro-2(K5)-pyranyloxy)carbamoyl-1-4-phenyl-3-butenyl- 2'(methanesulfonyl)-4-methyl-2'-(4-nitrophyl)enyl)valerohydrazide, 0.0 g (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3- butenyl|-2i(methanesulfonyl)-4-methyl-2-(4-nitrophenyl)-valerohydrazide as a yellow solid.

Mass spectrometry: 519 (MAN) 7.

High-performance liquid chromatography: Gradient elution using solvent A, which includes C with 590 solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate » 1ml/minute. Holding time: 12.54 minutes. Solvent A: H2O; solvent B: SNZSM. Column type: NUREKRER

ZOO (E)-2(CO-Ctetrahydro-4(K5)-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-(4-nitrophenyl)valerohydrazide , which was used as a starting material, was obtained in the following way: o In a way similar to the method described in Example 2, parts ((iii)-(u), starting with

Go! (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvaleric acid and 4-nitrophenylhydrazine was obtained by (E)-2(KO-I1(5 )-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2"-(4-

He» 20 nitrophenyl)valerohydrazide in the form of a yellow solid.

Example 14 -6 (E)-2'-acetyl-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-2'-(2-pyridyl)valerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with b1g 99 (E)-2'-acetyl-2(K)-I1(8)-Ctetrahydro-2(B5)-pyranyloxy)carbamoyl1- 4-phenyl-3-butenyl|-4-methyl-2'-(2-pyridyl)va

F! lerohydrazide was obtained after washing the solution of the mentioned product in ethyl acetate with 2" aqueous solution of sodium bicarbonate in order to obtain the free base, 0.035 g of (E)-2'-acetyl-2(K)-(1(5)-( hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-2'-(2-pyridyl)valerohydrazide Cream-colored solid 60 Mass spectrometry: 439 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B for 5 minutes, followed by increasing the content of solvent B to 95905 from 5 minutes to 20 minutes; flow rate Iml/minute. Holding time: 15.67 minutes. Solvent A: H 250/0.195 TEA (tetrafluoroacetic acid); solvent B: SNUZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER bo ZOOD.

(E)-2'-acetyl-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-4-methyl-2-(2- pyrides l) valerohydrazide, which was used as a starting material, was obtained in the following way:

In a method similar to the method described in Example 4, parts (Hii) and (ii), starting with (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3- butenyl|-4-methyl-2'-(2-pyridyl)valerohydrazide, obtained (E)-2'-acetyl-2(К)-(1(5)-Ktetrahydro-2(К5)-pyranyloxy)carbamoyl|- 4-phenyl-3-butenyl|-4-methyl-2-(2-pyridyl)va lerohydrazide in the form of a white solid.

Example 15 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenide|-2(methanesulfonyl)-2',4-dimethylvalerohydrazide 70 In a method similar to the method described in the first paragraph of Example 2, starting with 0.122 g of (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoylI|-4-phenyl-3-butenyl|-2-(methanesulfonyl)-24 -dimethylvalerohydrazide, obtained 0.033 g of (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-2'4-dimethylvalerohydrazide.- In 7/5 Form solid substance of almost white color.

Mass spectrometry: 412 (MAN) 7.

Nuclear magnetic resonance (d5 dimethylsulfoxide): 10.56 (1Н, singlet); 10.46 (1H, singlet); 8.75 (1H, singlet); 7.35-7.25 (4H, multiplet); 7.23-7.15 (1H, multiplet); 6.31 (1H, doublet, U-15.5Hz); 6.10-6.00 (1H, multiplet); 3.06 (ZN, singlet); 3.04 (ZN, singlet); 2.55-2.45 (1H, multiplet); 2.37 (ZN, multiplet); 20. 1.54-1.36 (2H, multiplet); 1.02-0.93 (1H, multiplet); 0.84 (ZN, doublet, U-7Hz); 0.81 (ZN, doublet, 9U-7.5Hz).

High-performance liquid chromatography: Gradient elution with solvent A, which includes 1096 of solvent B, for 5 minutes, followed by increasing the content of solvent B to 9095 from 5 minutes to minutes; flow rate Tml/minute. Holding time: 14.72 minutes. Solvent A: H 20/0.1956 TEA (tetrafluoroacetic acid); solvent B: SNUSIM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER su

ZOO (E)-2(KO-I1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl1|-4-phenyl-3-butenyl|-2-(methanesulfonyl)-2',4-dimethyl i9)valerohydrazide, which was used as the starting material, was obtained in the following manner: () A mixture of 11 g of pentafluorophenol and 4.12 g of 1,3-dicyclohexylcarbodiimide in bHOml of hexane was stirred at room temperature for 5 minutes. The obtained solid was filtered off, washed with hexane, dried, and then added to a solution of 5.Og ()-2(KO-(1(5)-(tert-butoxycarbonyl-4-phenyl-3-butenyl|-4-methylvalerian acid in 5 bBOml of dimethoxyethane

The resulting mixture was allowed to stand at a temperature of 47"C overnight, after which it was filtered to remove dicyclohexylurea. The resulting filtrate was evaporated, the residue was dissolved in 5 Oml of dichloromethane, and 3 ml of hydrazine hydrate was added to the resulting solution. The resulting mixture was stirred for 6 hours, after which it was washed successively 595 citric acid solution, a saturated solution of sodium hydrogen carbonate, water (CH3) and a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was mixed with a mixture of hexane/ethyl acetate (4:11) and the resulting solid was filtered.

4.68 g of (E)-2(K)-(1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvalerohydrazide was obtained as an almost white solid.

Mass spectrometry: 361 (MAN) 7. - c (i) In a method similar to the method described in Example 9, parts (ii) and (ii), starting with 8.96 bg (E)-2( K)-(1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvalerohydrazide, 2.83 g of (E)-2(KO-(1(5)-Ktetrahydro- 2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog hydrazide in the form of a white solid. 1 Mass spectrometry: 482 (MAN) "7. o (ii) A solution of 0.34 g of hydrazide, which was obtained in part (ii), in 7 ml of dimethylformamide was treated with 0.126 g of methyl iodide and 0.293 g of anhydrous potassium carbonate. The resulting mixture was stirred at room temperature for 1 hour and the volatiles were removed by evaporation. The resulting balance was distributed among

FO 20 ethyl acetate and 595 citric acid solution. The obtained ethyl acetate phase was washed with water and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate. After evaporating the mentioned solvent, the resulting residue was purified by gel chromatography under vacuum, eluting first with a mixture of hexane/ethyl acetate (4:11), then with a mixture of hexane/ethyl acetate (2:11). 0.122 g of ()-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-2,4-dimethylvalerohydrazide were obtained in in the form of a white solid substance.

Gee! Example 16 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide de In a method similar to the method described in the first paragraph Example 2, starting from 0151 g 60 0 (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)- 4-methylvalerohydrazide, 0,obg ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methylvalerohydrazide was obtained as an almost white solid.

Mass spectrometry: 398 (MAN) 7. bo Nuclear magnetic resonance (d5 dimethylsulfoxide): 10.55 (1Н, singlet); 10.34 (1H, singlet); 9.52 (1H,

singlet); 8.85 (1H, singlet); 7.36-7.25 (4H, multiplet); 7.23-7.16 (1H, multiplet); 6.30 (1H, doublet, 9-15.5Hz); 6.08-598 (1H, multiplet); 2.96 (ZN, singlet); 2.56-2.46 (1H, multiplet); 2.39-2.13 (ZN, multiplet); 1.53-1.33 (2H, multiplet); 1.01-0.93 (IN, multiplet); 0.83 (ZN, doublet, U-6.5Hz); 0.80 (ZN, doublet, 9-7 Hz).

High-performance liquid chromatography: Gradient elution with solvent A, which includes 1096 of solvent B, for 5 minutes, followed by increasing the content of solvent B to 9095 from 5 minutes to minutes; flow rate Tml/minute. Holding time: 14.13 minutes. Solvent A: H 20/0.1956 TEA (tetrafluoroacetic acid); solvent B: SNUZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER 70 ZOOA.

Example 17 (E)-2'-benzyl-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.183 g of 75. (E)-2-benzyl-2(K)-11(5)-(tetrahydro-2(K5)-pyranyloxy) carbamoyl)-4-phenyl-3-butenyl|-2-(methanesulfonyl)-4-methylvalerohydrazide, 0.142 g of (E)-2'-benzyl-2(K)-(1(5)-(hydroxycarbamoyl)- 4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerohydrazide In the form of a solid substance of almost white color.

Mass spectrometry: 488 (MAN) 7. 20 Nuclear magnetic resonance (d5 dimethylsulfoxide at 353K): 10.22 (1H, broad singlet); 10.1 (1H, singlet); 8.40 (1H, wide singlet); 7.40-7.24 (9H, multiplet); 7.22-7.15 (IN, multiplet); 6.23 (1H, doublet, 9U-15Hz); 6.05-5.р94 (1H, multiplet); 4.63 (2H, multiplet); 3.15 (ZN, singlet); 2.54-2.44 (1H, multiplet); 2.31-2.17 (2H, multiplet); 2.14-2.01 (1H, multiplet); 1.51-1.49 (1H, multiplet); 1.34-1.18 (1H, multiplet); 1.04-0.95 (1H, multiplet); 0.74 (ZN, doublet, U-6.5Hz); 0.70 (ZN, doublet, 9U-7.0Hz). Ha

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate i9) 1 ml/minute. Holding time: 12.18 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2'-benzyl-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)- h-4-methylvalerohydrazide, which was used as a starting material, was prepared in a manner similar to the method described in Example 15, part (ii), starting with o (E)-2(KO-(1(5)- Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerogen hydrazide by reaction with benzyl bromide.

Example 18 co ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-2'-methoxybenzyl)-4-methylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 01o5g "(E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoylI|-4-phenyl-3 -butenyl|-2'-(methanesulfonyl)-2-(4-methoxybenzyl)-4-methylvalerohydrazide was obtained Obig Sh- c (E)-2(K)-(1(5)-(hydroxycarbamoyl)-4- phenyl-3-butenyl|-2'(methanesulfonyl)-2'-(4-methoxybenzyl)-4-methylvaleroxy drazide in the form of a white solid. "» Mass spectrometry: 518 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes C595 solvent B, for 5 minutes, followed by increasing the content of solvent B to 8595 from 5 minutes to 1 20 minutes; flow rate 1Tml/minute. Holding time: 7.20 minutes. Solvent A: H 20/0.195 TEA with Soprafluoroacetic acid); solvent B: CH3CM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER 1 (E)-2(KO)-I1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenylI|-2'i(methanesulfonyl)-2-( 4-metho b 50 xybenzyl)-4-methylvalerohydrazide, which was used as a starting material, was prepared in a manner similar to the method described in Example 15, part (iii), starting with -. and (E)-2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide, by reaction with 4-methoxybenzyl bromide.

Example 19 (E)-2'-allyl-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'("methanesulfonyl)-4-methylvalerohydrazide o Method B, similar to the method , the description of which is given in the first paragraph of Example 2, starting with 0.168 g of im) (E)-2'-allyl-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl)|- 4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide, 0.013 g of 60 0 (E)-2'-allyl-2(K)-I1(5)-(hydroxycarbamoyl)-4 -phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerohydrazide In the form of a white solid.

Mass spectrometry: 438 (MAN) 7.

Nuclear magnetic resonance (d5 dimethylsulfoxide at 353K): 10.26 (IN, broad singlet); 10.08 (1H, singlet); 8.44 (1H, wide singlet); 7.35-7.25 (4H, multiplet); 7.22-7.15 (IN, multiplet); 6.33 (1H, 65 doublet, 49-15.5Hz); 6.13-6.03 (IN, multiplet); 5.90-5.78 (1H, multiplet); 5.28 (1H, multiplet); 5.18 (1H, multiplet); 4.05 (1H, multiplet); 3.06 (ZN, singlet); 2.63-2.53 (1H, multiplet); 2,44-225 (ZN,

multiplet); 1.59-1.45 (2H, multiplet); 1.14-1.03 (IN, multiplet); 0.85 (ZN, doublet, .-7Hz); 0.82 (ZN, doublet, U-6.5 Hz).

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 11.36 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2'-allyl-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4 - methylvalerohydrazide, which was used as a starting material, was obtained by a method similar to the method described in Example 15, part (ii), starting with (E)-2(KO-I1(5)-Ktetrahydro- 2(K5)-tranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerogy drazide, by reaction with allyl bromide.

Example 20 (E)-2-(4-bromobenzyl)-2(K)-I(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvaleroic hydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.215 g of (E)-2-(4-bromobenzyl)-2(K)-(1(5)-Ktetrahydro-2(KZ)- pyranyloxy)carbamoyl-1I-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerohydrazide, 0.147 g of (E)-2'-(4-bromobenzyl)-2(K)-I 1 (5) were obtained -(hydroxycarbamoyl)-4-phenyl-3-butenyl| -2'methanesulfonyl)-4-methylvalerohydrazide as a white solid.

Mass spectrometry: 566/568 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 5905 solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate su

ml/minute. Holding time: 12.90 minutes. Solvent A: H»O/0.195 TPA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. and9) (E)-2-(4-bromobenzyl)-2(K)-(1(5)-Ctetrahydro-2(KZ)-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-2'-( methanesulfonyl)-4-methylvalerohydrazide, which was used as a starting material, was prepared in a manner similar to that described in Example 15, part (iii), starting with "h-"E)-2(KO-I1 5)-Ktetrahydro-2(KZ)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'("methanesulfonyl)-4-methylvalerog hydrazide, by reaction with 4-bromobenzyl bromide. at

Example 21 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-(4-nitrobenzyl)valero hydrazide co

In a method similar to the method described in the first paragraph of Example 2, starting with 0.159 g of (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl- 3-butenyl|-2'(methanesulfonyl)-4-methyl-2"-(4-nitrobenzyl)valerohydrazide, 0.085 g of ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl- 3-butenyl|-2i(methanesulfonyl)-4-methyl-2'-(4-nitrobenzyl)valerohydride 70 azide as a white solid.- c Mass spectrometry: 533 (MAN) 7. a High-performance liquid chromatography: Gradient eluting with Solvent A, which includes 590 Solvent B, followed by increasing the content of Solvent B to 9595 over 15 minutes; flow rate 1 ml/min. Retention time: 12.14 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid), solvent

In: SNizCM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER ZOO. - (4-nitrobenzyl)valerohydrazide, which was used as a starting material, was prepared in a manner similar to that described in Example 15, part (ii), starting from 1(E)-2(KO-I1(5)- Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerog b 50 hydrazide, by reaction with 4-nitrobenzyl bromide.

Example 22 -. and ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2'-propargylvalerohydrazide

In a manner similar to the method described in the first paragraph of Example 2, starting with

Sh 013gH o (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2- about pargylvalerohydrazide, obtained 0.04 g of ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methyl-2'-propargylvalerohydrazide in the form of a solid white substance 60 Mass spectrometry: 436 (MAN) 7.

Nuclear magnetic resonance (d5 dimethylsulfoxide): 10.57 (1Н, singlet); 10.54 (1H, singlet); 8.84 (1H, wide singlet); 7.35-7.25 (4H, multiplet); 7.22-7.16 (IN, multiplet); 6.30 (1H, doublet, .)-15.5Hz); 6.09-5.99 (IN, multiplet); 4.32-4.17 (2H, multiplet); 3.44 (1H, singlet); 3.11 (ZN, singlet); 2.63-2.54 (1H, multiplet); 2.41-2.17 (ZN, multiplet); 1.56-1.41 (2H, multiplet); 1.03-0.93 (IN, multiplet); 0.85 65 (ZN, doublet, 4-7.0Hz); 0.81 (ZN, doublet, 9U-6.5Hz).

High-performance liquid chromatography: Gradient elution using solvent A, which includes

4095 of solvent B, with subsequent increase in the content of solvent B to 090 for 15 minutes; flow rate Tml/minute. Holding time: 11.04 minutes. Solvent A: H»O/0.195 TEA (tetrafluoroacetic acid); solvent B: СНЗзСМ/О,08590 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2" - propargylvalerohydrazide, which was used as starting material, was prepared in a manner similar to that described in Example 15, part (iii), starting from (E)-2(KO-(1(5)-Ktetrahydro-2(K5 )-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog hydrazide by reaction with 4-propargyl bromide. 70 Example 23 (E)-2-(cyanomethyl)-2( K)-I(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide

In a manner similar to the method described in the first paragraph of Example 2, starting with

O, 18g 75. "E)-2-(cyanomethyl)-2(K)-11(5)-(tetrahydro-2(K5)-pyranyloxy)carbamoyl)-4-phenyl-3-butenyl|-2(methanesulfonyl )-4-methylvalerohydrazide, 0.124 g of (E)-2(cyanomethyl)-2(K)-(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerohydrazide were obtained in in the form of a white solid.

Mass spectrometry: 437 (MAN) 7.

Nuclear magnetic resonance (d5 dimethylsulfoxide): 10.94 (1Н, singlet); 10.56 (1H, singlet); 8.56 (1H, wide singlet); 7.37-7.25 (4H, multiplet); 7.23-7.15 (IN, multiplet); 6.33 (1H, doublet, .)-15.5Hz); 6.10-5.99 (1H, multiplet); 4.65 (2H, multiplet); 3.17 (ZN, singlet); 2.61-2.52 (1H, multiplet); 2.40-2.19 (ZN, multiplet); 1.55-1.41 (2H, multiplet); 1.06-0.95 (1H, multiplet)"; 0.85 (ZN, doublet, U9-7Hz); 0.82 (ZN, doublet, U-6.5 Hz). with

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate i9) 1 ml/minute. Holding time: 10.90 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2'(cyanomethyl)-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfon onyl)-4-methylvalerohydrazide, which was used as a starting material, was prepared in a manner similar to that described in Example 15, part (ii), starting with o (E)-2(KO-(1(5) -Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerogen hydrazide by reaction with bromoacetonitrile.

Example 24 co (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-(2-phenylethyl)valerogen drazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.158 g of (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl- 3-butenyl|-2'(methanesulfonyl)-4-methyl-2'-(2-phenylethyl)valerohydrazide, 0.093 g of (E)-2(K)-(1(5)-(hydroxycarbamoyl)-4- phenyl-3-butenyl|-2'-methanesulfonyl)-4-methyl-2-(2-phenylethyl)valerohydrase c as a white solid. "» Mass spectrometry: 502 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 59% of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 1ml/minute. Holding time: 12.90 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent co B: SNUuSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2" 1 -(2-phenylethyl)valerohydrazide, which was used as starting material, was prepared in a manner similar to that described in Example 15, part (ii), starting from (E)-2(KO-(1 5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog-hydrazide, by reacting with 2-bromomethyl-benzene.

Example 25 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-(phthalimidomethyl)valer hydrazide o o i similar the method, the description of which is given in the first paragraph of Example 2, starting with .187 g of im) |-2'(methanesulfonyl)-4-methyl-2'-(ftalimidomethyl)valerohydrazide, obtained 0.127g 60 0 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl |-2'(methanesulfonyl)-4-methyl-2-(phthalimidomethyl)valerohydride as a white solid.

Mass spectrometry: 557 (MAN) 7.

Nuclear magnetic resonance (d5 dimethylsulfoxide at 353K): 10.18 (IN, broad singlet); 10.13 (1H, singlet); 8.40 (IN, wide singlet); 7.92-7.82 (4H, multiplet); 7.32-7.25 (4H, multiplet); 7.22-7.15 (1H, 65 multiplet); 6.30 (1H, doublet, 49-15.5Hz); 6.06-5.96 (IN, multiplet); 5.30 (2H, singlet); 3.16 (ZN, singlet); 2.56-2.43 (1H, multiplet); 2.40-2.21 (ZN, multiplet); 1.60-140 (2H, multiplet); 1.10-0.99 (1H,

multiplet); 0.80 (ZN, doublet, U-6.5Hz); 0.77 (ZN, doublet, 9-7.0Hz).

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 12.03 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2(KO-I1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-(phthalimidomethyl) valerohydrazide, which was used as starting material, was prepared in a manner similar to that described in Example 15, part (iii), starting from 70 (E)-2(KO-(1(5)-Ktetrahydro-2( C5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvaleroic hydrazide, by reaction with M-2-bromomethylphthalimide.

Example 26 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-(2-phthalimidoethyl)vale rohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.134 g of (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3 -butenylI|-2'-(methanesulfonyl)-4-methyl-2'-(2-phthalimidoethyl)valerohydrazide, 0.1o8g of (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl- 3-butenyl|-2i(methanesulfonyl)-4-methyl-2-(2-phthalimidoethyl)valerogi 2o drazide as a white solid.

Mass spectrometry: 571 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate

Tml/minute. Holding time: 12.56 minutes. Solvent A: H»O/0.195 TPA (tetrafluoroacetic acid); solvent su

In: СНзУСН/О,08590 of tetrafluoroacetic acid. Column type: NUREKRER ZOO. (E)-2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2" i9 )-(2-phthalimidoethyl)valerohydrazide, which was used as starting material, was prepared in a manner similar to that described in Example 15, part (ii), starting from (E)-2(KO-(1(5 )-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerogen from hydrazide by reaction with 2-bromomethylphthalimide.

Example 27 o (E)-3-cyclobutyl-2(K)-I(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-2"-phenylpropionhydrous azide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.159 g of (E)-3-cyclobutyl-2(K)-1(5)-tetrahydro-2(K5)-pyranyloxy)carbamoyl |-4-phenyl-3-butenyl|-2'(methanesulfonyl)-2 "-phenylpropionhydrazide, obtained 0.103 g of (E)-3-cyclobutyl-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl -3-butenyl|-2i(methanesulfonyl)-2"-phenylpropionhydrazide" in the form of an almost white solid.

Mass spectrometry: 486 (MAN) 7. - c High-performance liquid chromatography: Gradient elution using solvent A, which includes 590 g of solvent B, with subsequent increase in the content of solvent B to 9595 g over 15 minutes; flow rate 1 ml/minute. Holding time: 12.12 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-3-cyclobutyl-2(K)-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'(methanesulfone 1 l)-2'- phenylpropionhydrazide, which was used as a starting material, was obtained by the following method: in a method similar to the method described in Example 2, parts (i)-(u), starting from 4-tert-butyl hydrogen 2(K) -(cyclobutylmethyl)succinate obtained 1 (E)-3-cyclobutyl-2(K)-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'- (methanesulfonyl)-2 b 50 "-phenylpropionhydrazide as a white solid.

Mass spectrometry: 570 (MAN) 7. -. Example 28 (E)-3-cyclopentyl-2(K)-I(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2-(methanesulfonyl)-2"-phenyl propionhydrazide 22 In the method, similar to the method described in the first paragraph of Example 2, starting with

HF) 0.2 g (E)-3-cyclopentyl-2(K)-I(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'(methanesulfonyl )- to 2"-phenylpropionhydrazide, 0.132 g of (E)-3-cyclopentyl-2(K)-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)- 2 " 60 -phenylpropionhydrazide in the form of a white solid.

Mass spectrometry: 500 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 12.39 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent bo B: SNUSM/0.08596 of tetrafluoroacetic acid. Column type: NUREBERER ZOO.

(E)-3-cyclopentyl-2(K)-1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-2'(methanesulfonyl)-2'-phenylpropionhydrazide , which was used as the starting material, was obtained in the following way:

In a method similar to the method described in Example 2, parts (i)-(u), starting from a-tert-butyl hydrogen 2(K)-(cyclopentylmethyl)succinate, (E)-3-cyclopentyl-2 (K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'(methanesulfonyl)-2"-phenylpropionhydrazide as a white solid.

Mass spectrometry: 584 (MAN) 7.

Example 29 70 (E)-2-(4-bromophenyl)-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.35 g of (E)-2'-(4-bromophenyl)-2(K)-(1(5)-Ktetrahydro-2(K5 )-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-2'-(methanesulfonyl 75 l)-4-methylvalerohydrazide, 0.272 g of (E)-2'-(4-bromophenyl)-2(K)- (1(5)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrase occurs as an almost white solid.

Mass spectrometry: 552 (MAN) 7.

Nuclear magnetic resonance (d5 dimethylsulfoxide): 10.85 (1Н, singlet); 10.31 (IN, wide singlet); 8.48 (IN, wide singlet); 7.58 (2H, multiplet); 7.32 (2H, multiplet); 7.29 (4H, multiplet); 7.23-7.16 (IN, multiplet); 6.23 (1H, doublet, U-15.5Hz); 6.07-5.97 (1H, multiplet); 3.23 (ZN, singlet); 2.60-2.50 (1H, multiplet); 2.41-2.12 (ZN, multiplet); 1.57-1.48 (1H, multiplet); 1.47-1.35 (IN, multiplet); 1.16-1.06 (1H, multiplet); 0.85 (ZN, doublet, U-6.5Hz); 0.78 (ZN, doublet, U-7.0Hz).

High-performance liquid chromatography: Gradient elution with solvent A, which includes 59 c of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate by 1 ml/minute. Holding time: 13.41 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUSM/0.08595 tetrafluoroacetic acid. (E)-2-(4-bromophenyl)-2(K)-(1(5)-Ctetrahydro-2(K5)-tranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl )-4-methylvalerohydrazide, which was used as a starting material, was obtained in the following way: h

In a method similar to the method described in Example 2, part ((iii)-(y), starting with (E)-2(CO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3 (E)-2-(4-bromophenyl)-2(K)-(1(5)-Ktetrahydro-2(KZ)- pyranyloxy)carbamoyl1|-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerohydrazide in the form of a white solid.

Mass spectrometry: 636/638 (MH) 7. IF)

Example 30 (E)-2'-(tert-butyl)-2(K)-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide "

In a method similar to the method described in the first paragraph of Example 2, starting with 40. 0.35Bg o) s (E)-2(tert-butyl)-2(K)-I1(5)-Ktetrahydro-2 (K5)-pyranyloxy)carbamoyl1|-4-phenyl-3-butenyl|-2i(methanesulfonyl h)-4-methylvalerohydrazide, 0.272 g of (E)-2-(tert-butyl)-2(K)-I1 were obtained (5)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrase as an almost white solid.

Mass spectrometry: 454 (MAN)7. o High-performance liquid chromatography: Gradient elution using solvent A, which includes

Go) 1096 of solvent B, for 5 minutes, with a subsequent increase in the content of solvent B to 9095 from 5 minutes to 20 minutes; flow rate Tml/minute. Holding time: 16.56 minutes. Solvent A: H 20/0.1956 TEA o (tetrafluoroacetic acid); solvent B: SNUZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER b 20 ZOOA. (E)-2(tert-butyl)-2(K)-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'(methanesulfonyl) -4-methylvalerohydrazide, which was used as a starting material, was obtained in the following way:

In a method similar to the method described in Example 2, part ((iii)-(y), starting with (E)-2(CO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3 -butenyl|-4-methylvaleric acid and tert-butylhydrazine 259 were obtained

HF) (E)-2-(tert-butyl)-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl|-2'methanesulfonyl )-4-methylvalerohydrazide as a white solid. o Mass spectrometry: 537 (MAN) 7.

Example 31 60 (E)-2'(cyclohexylmethyl)-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.149 g of (E)-2'(cyclohexylmethyl)-2(K)-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl |-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide, 0.116 g were obtained

(E)-2(cyclohexylmethyl)-2(K)-I(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'i(methanesulfonyl)-4-methylvalerog hydrazide as a white solid color

Mass spectrometry: 494 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 13.67 minutes. Solvent A: H»O/0.1965. TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2'(cyclohexylmethyl)-2(K)-I(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(meta 70 nsulfonyl )-4-methylvalerohydrazide, which was used as starting material, was prepared in a manner similar to that described in Example 15, part (iii) starting with (E)-2(KO-(1(5)-Ktetrahydro- 2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog hydrazide, by reaction with cyclohexylmethyl bromide.

Example 32 2(k-((K)-(hydroxycarbamoyl)-2-phthalimidoethyl/|-2(methanesulfonyl)-4-methyl)-4-methyl-2'-phenylvalerohydrase d

In a method similar to the method described in the first paragraph of Example 2, starting with 0.14 g of 2(kO-P(K)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-2-phthalimidoethyl/|-2( methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide, 0.092 g of 2(kO-P(K)-(hydroxycarbamoyl)-2-phthalimidoethyl -2'-(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide were obtained in the form white solid.

Mass spectrometry: 517 (MAN) 7.

High-performance liquid chromatography: Gradient elution with solvent A, which includes 1096 of solvent B, for 5 minutes, followed by increasing the content of solvent B to 9095 from 5 minutes to cm 20 minutes; flow rate Tml/minute. Holding time: 15.52 minutes. Solvent A: H 20; solvent B: o

SNZSM Column type: NUREKRER ZOO. 2(kO)-P1(k)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-2-phthalimidoethyl|-2(methanesulfonyl)-4-methyl-2'"-phenyl valerohydrazide, which was used as a starting material, obtained in the following way:

In a method similar to the method described in Example 2, part ((iii)-(y), starting with -- 2(K3-I1(K)-(tert-butoxycarbonyl)-2-phthalimidoethyl|-4- of methylvaleric acid and phenylhydrazine, 2(kO)-P1(k)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-2-phthalimidoethyl|-2(methanesulfonyl)-4-methyl-2'-phenylvaleyl-o hydrazide was obtained in in the form of a white solid substance. IF)

Mass spectrometry: 601 (MAN) 7. so

Example 33 2(K)-(2-benzamide-1(K)-(hydroxycarbamoyl)ethyl/|-2-(methanesulfonyl)-4-methyl-2'--phenylvalerohydrazide)

In a method similar to the method described in the first paragraph of Example 2, starting with 0.084 g of 2(K)-(2-benzamido-1(K)-(tetrahydro-2(K5)-pyranyloxy)carbamoyl|-2 -(methanesulfonyl)-4-methyl-2'-phenylvalerohyde, 0.055 g of 40 were obtained. 2(K)-(2-benzamido-1(K)-(hydroxycarbamoyl)ethyl|-2'-(methanesulfonyl)- of 4-methyl-2'--phenylvalerohydrazide as a white solid. "» Mass Spectrometry: 491 (MAN) 7. " High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 solvent B, over 5 minutes, followed by increasing the content of solvent B to 95905 from 5 minutes to 20 minutes; flow rate Iml/minute. Retention time: 15.54 minutes. Solvent A: H 20/0.190. TEA o (tetrafluoroacetic acid); solvent B: SNUSUSM /0.08595 of tetrafluoroacetic acid. Column type: NUREKRER o ZOOA. 2(K)-(2-benzamido-1(K)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|ethyl)|-2-(methanesulfonyl)- 4-methyl-2'"-phenyl o valerohydrazide, which was used but as a starting material, it was obtained in the following way: bu 70 () Solution 0.705 g of 2(K)-(1(K)-(tert-butoxycarbonyl)-2-phthalimidoethyl|-2(methanesulfonyl)-4-methyl-2 0.51 ml of hydrazine hydrate was treated with phenylvalerohydrazide in 15 ml -6 ml of methanol. The resulting mixture was stirred under a nitrogen atmosphere overnight, after which it was evaporated. The obtained residue was mixed with 25 ml of a mixture of dichloromethane/methanol/acetic acid/water (120:15:3:2). After 2 hours, the solid substance that precipitated was filtered off and the obtained filtrate was evaporated. The resulting residue was purified by chromatography on a Kieselgel 60 column

HF) (Kiesede! 60) eluting with a mixture of dichloromethane/methanol/acetic acid/water (240:24:3:2). The fractions, which included the amine product, were combined and evaporated, the obtained residue was dissolved in 30 ml of dichloromethane and washed with three 10 ml portions of saturated sodium bicarbonate solution. After drying over anhydrous magnesium sulfate, the resulting solution was evaporated to obtain 0.42 g of 60 2(8)3-(2-amino-1(K)-(tert-butoxycarbonyl)ethyl-2'-(methanesulfonyl)-4-methyl-2 -phenylvalerohydrazide in the form of pale yellow foam.

Mass spectrometry: 428 (MAN) 7. (its mixture of 0.42 g of the amine that was obtained in part (i) and 0.138 g of benzoic acid in 7 ml of dimethylformamide was cooled to a temperature of 0 °C with stirring and 0.335 g of bo 1- of ethyl 3-(3-dimethylaminopropyl)carbodiimide. The resulting mixture was warmed to room temperature and stirred overnight. The mentioned solvent was evaporated and the resulting residue was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The resulting ethyl acetate layer was washed successively with saturated sodium hydrogen carbonate solution, 590 citric acid solution, water and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate. Ethyl acetate was evaporated and the resulting residue was mixed with a mixture of ether and hexane to obtain 0.331 g of 2(K)-(2-benzamide-1 (K) - ( tert-butoxycarbonyl)ethyl|-2(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide as an almost white solid.

Mass spectrometry: 532 (MAN) 7.70 (her) In a method similar to the method described in Example 2, part (III)-(m), starting with Kk! 2(K)-(2-benzamide-1(K)-(tert-butoxycarbonyl)ethyl/|-2(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide, 2(K)-(2-benzamido-2 (K)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|ethyl|-2(methanesulfonyl)-4-methyl-2'-phenylvale 75 rohydrazide in the form of a white solid.

Mass spectrometry: 575 (MAN) 7.

Example 34 2(K)-(2-K5-bromo-2-furyl)carboxamido!|-1(K)-(hydroxycarbamoyl)ethyl|-2'-(methanesulfonyl)-4-methyl-2"-phenylalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.195 g of 2(K)-12-K5-bromo-2-furyl)carboxamido!|-1(K)-Ktetrahydro-2(K5) -pyranyloxy)carbamoyl|ethyl/|-2(methanesulfonyl)-4-methyl-2'--phenylvalerohydrazide, obtained 0.127 g of 2(Kk)-I2-K5-bromo-2-furyl)carboxamido)-1(K)- (hydroxycarbamoyl)ethyl|-2-(methanesulfonyl)-4-methyl-2'--phenylvalerohydrazide as a solid

Cream color. at

Mass spectrometry: 560 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 10.69 minutes. Solvent A: H»O/0.195 TPA (tetrafluoroacetic acid); the same solvent in: SNUSnH/O, 08595 of tetrafluoroacetic acid. Column type: NUREKRER ZOO. "so 2(K)-(2-K5-bromo-2-furyl)carboxamido!|-1(K)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|ethyl/|-2'-(methanesulfonyl)- 4-methyl-2"-phenylvalerohydrazide, which was used as a starting material, was obtained in the following manner:

In a manner similar to the method described in Example 33, parts (ii) and (ii), beginning with Kk! iv) 2(K)-(2-amino-1(K)-(tert-butoxycarbonyl)ethyl/|-2'-(methanesulfonyl)-4-methyl-2'--phenylvalerohydrazide and 2-bromo-2-furancarbon acid, obtained 2(K)-(2-K5-bromo-2-furyl)carboxamido!-1(K)-(Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|ethyl|-2'-(methanesulfonyl) « - 4-methyl-2"--phenylvalerohydrazide in the form of a solid substance of almost white color.

Mass spectrometry: 644 (MAN)7. From c Example 35 "» 2(k-((K)-(hydroxycarbamoyl)-2-((2-thiazolyl)ucarboxamido|ethyl-2'-(methanesulfonyl)-4-methyl-2'-phenylvalero" hydrazide

In a manner similar to the method described in the first paragraph of Example 2, starting with bilg o 2(kO)-1(k)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl1|-2-(2-thiazolyl)carboxamido |ethyl|-2'-(methanesulfonyl)-4-m

Go! of ethyl-2-phenylvalerohydrazide, 0.041 g of 2(kO-((K)-(hydroxycarbamoyl)-2-((2-thiazolyl)/ucarboxamido|ethyl)-2-(methanesulfonyl)-4-methyl-2'-phenylvalerohyde) was obtained o raside in the form of a solid substance of almost white color.

Ge») 20 Mass spectrometry: 498 (MAN) 7. ah High-performance liquid chromatography: Gradient elution with solvent A, which includes 7" 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/ minute. Retention time: 10.14 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); Solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. 2(k)-P1(k)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl1|-2-((2-thiazolyl)carboxamido|ethyl|-2'-(methanesulfonyl)

HF) -4-methyl-2'--phenylvalerohydrazide, which was used as a starting material, was obtained in the following manner: o In a manner similar to the method described in Example 33, parts (ii) and (ii), with the initiation of Kk! 60 2(K)-(2-amino-1(K)-(tert-butoxycarbonyl)ethyl/|-2'-(methanesulfonyl)-4-methyl-2'--phenylvalerohydrazide and 2-thiazolecarboxylic acid, obtained 2( kO)-1(k)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl1|-2-(2-thiazolyl)carboxamido|ethyl|-2'-(methanesulfonyl)-4-m ethyl-2'-phenylvalerohydrazide in the form white solid.

Mass spectrometry: 582 (MAN) 7. bo Example 36

2(k)-P(K)-(hydroxycarbamoyl)-2-((2-thienyl)carboxamido|ethyl|-2'-(methanesulfonyl)-4-methyl-2'-phenylvaleroic hydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with bi2g 2(K)-P(K)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl)-2-

K2-thienyl)ucarboxamido|ethyl|-2'-(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide, 0.115 g of 2(KO)-P(K)-(hydroxycarbamoyl)-2-((2-thienyl) /carboxamido|ethyl|-2'-(methanesulfonyl)-4-methyl-2"-phenylvalerohydrazide as a white solid.

Mass Spectrometry: 497 (MAN) 7. 70 High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 10.39 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. 2(kO-P1(kK)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-2- 75. ((2-thienyl)carboxamido|ethyl|-2(methanesulfonyl)-4-methyl-2'--phenylvalerohydrazide , which was used as the starting material, was obtained in the following way:

In a manner similar to the method described in Example 33, parts (ii) and (ii), beginning with Kk! 2(K)-(2-amino-1(K)-(tert-butoxycarbonyl)ethyl/|-2'-(methanesulfonyl)-4-methyl-2'--phenylvalerohydrazide and thiophene-2-carboxylic acid, obtained 2 (k)-P(K)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-2-((2-thienyl)ucarboxamido|ethyl|-2'-(methanesulfonyl)-4-methyl-2"-phenylvalerohydrazide in the form of a white solid.

Mass spectrometry: 581 (MAN) 7.

Example 37 Hey! 2(kO)-((K)-(hydroxycarbamoyl)-2-(3-phenylureido)ethyl/|-2-(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide o

In a method similar to the method described in the first paragraph of Example 2, starting with 0.157 g of 2(kO-P1(k)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-2-(3-phenylureido)ethylI| -2-(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide, obtained 0.072 g of 2(K)-I(K)-(hydroxycarbamoyl)-2-(3-phenylureido)ethyl|-2-(methanesulfonyl) )-4-methyl-2'-phenylvalerohydrazide. In the form of a white solid. and

Mass spectrometry: 507 (MAN) 7. IF)

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 590 parts of solvent B, followed by increasing the content of solvent B to 9595 parts over 15 minutes; flow rate ml/minute. Holding time: 10.91 minutes. Solvent A: HNO/0.195 TPA (tetrafluoroacetic acid); solvent M)

In: СНХСМ/0.08596 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. 2(kO-P1(k)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-2-(3-phenylureido)ethyl/|-2-(methanesulfonyl)-4-methyl-?! -phenylvalerohydrazide, which was used as a starting material, was obtained in the following way: "(i) Mixture O.8g 40. 2(K)-(2-amino-1(K)-(tert-butoxycarbonyl)ethyl|-2 of '-(methanesulfonyl)-4-methyl-2"-phenylvalerohydrazide, which was prepared according to the description given in Example 33, part (i), 0.325 ml of M,M-diisopropylethylamine and 0.21 ml of h phenyl isocyanate in ml dimethylformamide was stirred at a temperature of 607C under a nitrogen atmosphere for 2.5 hours. The mentioned solvent was evaporated and the resulting residue was partitioned between ethyl acetate and 1 M hydrochloric acid. The obtained ethyl acetate solution was separated and washed with sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and 1 was evaporated. The resulting residue was mixed with diethyl ether and /0.705 g of 2(K)-(1(K)-(tert-butoxycarbonyl)-2-(3-phenylureido)ethyl/|-2'-(methanesulfonyl) was obtained -4-methyl-2'-phenylvalerohydrazide in the form of a white solid. o Mass spectrometry: 547 (MAN) 7.

Ge» 20 (i) In a method similar to the method described in Example 2, parts (ii)-(m), starting from the hydrazide that was obtained in the previous paragraph, -6i 2(kO-P1(k) was obtained )-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-2-(3-phenylureido)ethyl|-2-(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide as a white solid.

Mass spectrometry: 590 (MAN) 7. 29 Example 38

HF) 2(k-((K)-(hydroxycarbamoyl)-2-((2-thienyl)usulfonamide|ethyl|-2'-(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide) a method similar to the method described in the first paragraph of Example 2, starting with 0.28 g of 60 2(kO-1(k)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl1|-2-K(2-thienyl) usulfonamide|ethyl I-2'-(methanesulfonyl)-4-methyl-2--phenylvalerohydrazide, 0.06bg 2(k-((K)-(hydroxycarbamoyl)-2-((2-thienyl)usulfonamide|ethyl)) was obtained -2'(methanesulfonyl)-4-methyl-2'-phenylvalerohydrase occurs as a white solid.

Mass spectrometry: 533 (MAN) 7. bo High-performance liquid chromatography: Gradient elution using solvent A, which includes

590 to solvent B, with a subsequent increase in the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 10.65 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: СНуСМ/0.08595 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. 2(K)-P(K)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl-2-(2-thienyl)usulfonamide|ethyl-2'-(methanesulfonyl)-4-methyl-2"-phenylvalerohydrazide, which was used as starting material, obtained in the following manner: (i) Solution of 0.504 g of 2(K)-(2-amino-1(K)-(tert-butoxycarbonyl)ethyl/|-2'(methanesulfonyl)-4-methyl of -2-phenylvalerohydrazide in 2 Oml of dichloromethane was cooled to a temperature of 0"C with stirring and /0.242 g of 7/0 2-thiophenesulfonyl chloride was added. The resulting mixture was kept with heating to room temperature and stirred overnight. The mentioned solvent was evaporated and the obtained residue was partitioned between ethyl acetate and 595 aqueous solution of citric acid. The obtained ethyl acetate layer was washed with a saturated solution of sodium bicarbonate, then with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was mixed with ether and 0.487 g of 75. 2(К)-1(К) was obtained. -(tert-butoxycarbonyl)-2-((2-thienyl)sulfonamide|ethyl)-2-(methanesulfonyl)-4-methyl-2-f enylvalerohyde raside in the form of a white solid.

Mass spectrometry: 574 (MAN) 7. (i) In a method similar to the method described in Example 2, parts (ii)-(m), starting from the shydrazide obtained in the previous paragraph, 20 was obtained. 2(K)-M(K)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl-2-(2-thienyl)usulfonamide|ethyl|-2'-(methanesulfonyl)-4-methyl-2'--phenylvalerohydrazide in the form of a white solid.

Mass spectrometry: 581 (MAN) 7.

Example 39 (E)-2'(benzylsulfonyl)-2(K)-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-2'-phenylvalerohydrazide c

In a method similar to the method described in the first paragraph of Example 2, starting with o b1g (E)-2'(benzylsulfonyl)-2(K)-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl |-4-phenyl-3-butenyl|-4-methyl-2"-phenylvalerohydrazide, 0.051 g of (E)-2'(benzylsulfonyl)-2(K)-I1(5)-(hydroxycarbamoyl)-4- phenyl-3-butenyl|-4-methyl-2'-phenylvalerohydrazide In the form of a white solid.

Mass spectrometry: 550 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes Ic) 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate is 1 ml/minute. Holding time: 13.62 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER ZOO. iv) (E)-2'(benzylsulfonyl)-2(K)-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-4-methyl-2"- phenylvalerohydrazide, which was used as a starting material, was obtained in the following manner: () In a manner similar to the method described in Example 1, part (iii), beginning with "

O,Zg (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methyl-2'"-phenylhydrazide and 0.543g of benzylsulfonyl chloride, 0.316g of ts were obtained (E)-2'(benzylsulfonyl)-2(K)-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methyl-2'-phenylhydrazide. In the form of a solid white color." Mass spectrometry: 591 (MAN) 7. () In a method similar to the method described in Example 1, part (iii), and Example 2, part (mM), from the hydrazide that was obtained in in the previous paragraph, obtained o methyl-2'-pheny

Go! Lvalerohydrazide is a white solid.

Mass spectrometry: 634 (MAN) 7. ini Example 40

Ge») 20 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-3-methyl-2"--phenylbutylhydrazide ah In a similar way of the method, the description of which is given in the first paragraph of Example 2, starting with 7" 0.098 g of (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl |-2'(methanesulfonyl)-3-methyl-2"-phenylbutylhydrazide, 0.054 g ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'( methanesulfonyl)-3-methyl-2'-phenylbutylhydrazide U

HF) in the form of an almost white solid substance. 7 Mass spectrometry: 460 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; the flow rate is 1 ml/minute. Holding time: 11.72 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-3-methyl-2" - phenylbutylhydrazide, which was used as a starting material, was obtained in the following way:

In a method similar to the method described in Example 2, parts (i)-(y), starting with bo 4-tert-butyl hydrogen 2(K)-isopropyl succinate, was obtained

(E)-2(KO-I1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-3-methyl-2'-phenylbutylhydrazide in the form of a white solid.

Mass spectrometry: 544 (MAN) 7.

Example 41 (E)-2'-acetyl-2(K)-I(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-2'-phenylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.23 g of (E)-2'-acetyl-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy) carbamoyl1|-4-phenyl-3-butenyl|-4-methyl-2'"-phenylvaleroge 70 drazide, 0.09 g of (E)-2'-acetyl-2(K)-(1(5)-(hydroxycarbamoyl) was obtained )-4-phenyl-3-butenyl|-4-methyl-2-phenylvalerohydrazide as a white solid.

Mass spectrometry: 438 (MAN) 7.

High-performance liquid chromatography: Gradient elution using solvent A, which includes 75.59% of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 11.29 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2'-acetyl-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-4-methyl-2"--phenylvale rohydrazide, which was used as a starting material, was obtained in a manner analogous to the method described in Example 4, part (i)-ii), starting from (E)-2(KO-I1(K)-(tert- butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvaleric acid, which was prepared as described in Example 2, part (i).

Example 42 (E)-2'-ethylcarbamoyl)-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-2'-phenylvalerohydrazide c

A solution of 0.190 g of (E)-2''(ethylcarbamoyl)-2(K)-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-4-methyl -2'-phenyl valerohydrazide in a mixture of 2 ml of dichloromethane and 0.5 ml of methanol was treated with 1 ml of methanesulfonic acid.

The resulting mixture was stirred for 2 hours at room temperature, the solvent was evaporated. The resulting residue was mixed with 595% sodium bicarbonate solution and dissolved in diethyl ether. The resulting solution was dried over magnesium sulfate and evaporated to obtain a resin. By gel chromatography eluting with a mixture of dichloromethane/methanol (19:1), 0.02 g of (E)-2'-ethylcarbamoyl)-2(K)-I(1(5)-(hydroxycarbamoyl)-4-phenyl- 3-butenyl|-4-methyl-2'-phenylvalerohydrazide.- In the form of a solid white substance. co

Mass spectrometry: 467 (MAN) 7.

High-performance liquid chromatography: Gradient elution using solvent A, which includes Is) 4095 solvent B, followed by increasing the content of solvent B to 090 for 15 minutes; flow rate Tml/minute. Holding time: 11.80 minutes. Solvent A: H»O/0.195 TEA (tetrafluoroacetic acid); solvent B: СНЗзСМ/О,08590 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2'(ethylcarbamoyl)-2(K)-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-4-methyl-2-phenylvalerohydrazide, which was used as a starting material, was obtained in the following way: - c () 08ho (E)-2(KO-I1(5)-tert-butoxycarbonyl-4-phenyl-3-butenyl|-4-methyl-2' -- of phenylvalerohydrazide, which was obtained according to the description given in Example 2, part (iii), in one ml of dry dichloromethane was heated at a temperature of 07C in a nitrogen atmosphere with 0.8 ml of ethyl isocyanate and the resulting mixture was stirred overnight at room temperature, after 0.65 g of 1 (E)-2'(ethylcarbamoyl)-2(K)-I(1(5)-(tert-butoxycarbamoyl) was obtained by gel chromatography eluting with a mixture of hexane/ethyl acetate (27) )-4-phenyl-3-butenyl|-4-methyl-2'-phenylvalerohydrazide as a white foam. (i) 0.64 g of tert-butyl ether, which was obtained according to part (i), was treated with a solution of 5090 of trifluoroacetic acid in dichloromethane for 3 hours at room temperature temperature and evaporated. Toluene was added twice at 50 with evaporation each time. The resulting residue was purified by gel chromatography eluting with a mixture of dichloromethane/methanol (19:1) to obtain O,Zbg "6 (E)-2'(ethylcarbamoyl)-2(K)-(1(5)-carboxy-4- phenyl-3-butenyl|-4-methyl-2'-phenylvalerohydrazide in the form of a glass. (its) 0.35 g of carboxylic acid, which was obtained according to part (its), was dissolved in 3 ml of dimethylformamide, cooled to temperature es and treated with 0 26 g of 22 O-(tetrahydro-2H-pyran-2(K5)-yl)hydroxylamine and 0.215 g of hydrochloride

Gee! 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The resulting mixture was stirred overnight at room temperature, after which it was poured into water. The resulting solid was filtered and washed successively with 2M hydrochloric acid solution, water, 595% sodium hydrogen carbonate solution and water, and then dried with oil. 6002g of (E)-2'(ethylcarbamoyl)-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl-1|-4-phenyl was obtained by gel chromatography eluting with a mixture of hexane/"ethyl acetate -3-butenyl|-4-methyl-2'-phenyl valerohydrazide in the form of white foam.

Mass spectrometry: 551 (MAN) 7.

Example 43 bo (E)-2'(benzylcarbamoyl)-2(K)-I(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-2"-phenylvalerohydrazide

0.17g (E)-2'(benzylcarbamoyl)-2(K)-(1(5)-(O-tert-butyldimethylsilyl)-hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl- 2- phenylvalerohydrazide was mixed in 5 ml of a mixture of acetic acid/water/tetrahydrofuran (3:1:1) for 1.5

Hours at room temperature. The mentioned solvent was evaporated, the resulting residue was mixed with diethyl ether to obtain O,oZg (E)-2'(benzylcarbamoyl)-2(K)-I(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|- 4-methyl-2'--phenylvalerohydrazide In the form of a white solid.

Thin-layer chromatography: dichloromethane/methanol (3:1). Retention ratio K,; - 0.43. 70 Mass spectrometry: 529 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 13.14 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: СНЗуСнН/О,085965 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2'(benzylcarbamoyl)-2(K)-(1(5)-(O-tert-butyldimethylsilyl)-hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-2'-phenylvalerohydrazide , which was used as a starting material, was obtained in the following manner: (E)-2'(benzylcarbamoyl)-2(K)-(1(5)-carboxy-4-phenyl-3-butenyl|-4-methyl- 2'-phenylvalerohydrazide was obtained in a manner similar to the method described in Example 42 (1)-(iii). 0.72 g of the carboxylic acid obtained in the previous paragraph was dissolved in 2 ml of dimethylformamide, which was cooled to a temperature of 0 "C, and processed 1.0 g

O-(tert-butyldimethylsilyl)hydroxylamine, O2 ml of M-ethylmorpholine and O,3g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride. The resulting mixture was stirred at room temperature overnight and evaporated. The resulting residue was dissolved in dichloromethane, washed successively with 595% sodium hydrogen carbonate solution, water, 2M hydrochloric acid, water, 595% sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to obtain a brown semi-solid mass. 0.19 g of (E)-2'(benzylcarbamoyl)-2(K)-(1(5)- (O-tert-butyldimethylsilyl)hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-2 "-phenylvalerohydrazide in the form of a solid substance.

Thin layer chromatography: dichloromethane/methanol (9:10): Retention ratio K, - 0.65.

Example 44 and (E)-2-(cyclohexyl)-2(K)-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvaleroyl drazid 0.09g (E)-2'-cyclohexyl-2(K)-I(1(5)-(0-4-methoxybenzyl))-hydroxycarbamoyl)-4-phenyl-3-butenyl|-2- co (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 room temperature. The resulting mixture was stirred for 6 hours at room temperature, kept at a temperature of 4"C overnight, after which it was evaporated. Twice 100 ml of toluene was added, and the resulting mixture was evaporated each time. As a result of mixing the obtained residue with diethyl ether, 0.00 mg of E) was obtained. -2'-cyclohexyl-2(K)-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide is a white solid. a Mass Spectrometry: 480 (MAN) 7. "» High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate

mml/minute. Holding time: 12.39 minutes. Solvent A: H2O/0.195. TPA (tetrafluoroacetic acid); solvent 1 V: SNUuSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. bo (E)-2'-cyclohexyl-2(K)-1(5)-(O-4-methoxybenzyl))hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide , which was used as a starting material, was obtained in the following manner: b 50 () Solution 10 g (E)-2(K)-(1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl| -4-methylvaleric acid. In 100 ml of dichloromethane, 0.61 g of 4-dimethylaminopyridine, b.1 g -. and 1-ethyl-3-(3-dimethylaminopropyl)ucarbodiimide and 24 ml of methanol were treated at a temperature of 0"C. The resulting mixture was stirred at a temperature of 0 "C for 1 hour, kept with heating to room temperature, further stirred for 3 hours, after which it was evaporated. The obtained residue in diethyl ether was washed successively with 2M hydrochloric acid, water and 595% sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give an oil 6.9 g of di ether ime) The mentioned diester was dissolved in a mixture of 45 ml of dichloromethane and 45 ml of trifluoroacetic acid and the resulting solution was stirred for 2 hours followed by evaporation. Traces of trifluoroacetic acid were removed by adding and evaporating toluene (2 x 30 ml) and the resulting product was dried over mass to obtain succinate monomethyl ether as a yellowish-brown solid. (its 2.0 g of succinate monomethyl ether, which was obtained before, was dissolved in 20 ml of dimethylformamide and the resulting solution was cooled to a temperature of 0"C. 1.06 g of hydroxybenzotriazole hydrate, 1.5 g of 1-ethyl-3-(3-dimethylaminopropyl) hydrochloride were added) -carbodi|imide, 1.7 ml of 65 M-ethylmorpholine and 1.5 g of O-(4-methoxybenzyl)hydroxylamine. The resulting mixture was stirred for 0.5 hour at a temperature of 5"C and for 2.5 hours at room temperature, after which evaporated under high vacuum. The resulting residue in ethyl acetate was washed successively with 595 sodium hydrogencarbonate solution, 2M hydrochloric acid, water, 595 sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give a solid. By gel chromatography eluting with a mixture of ethyl acetate/hexane (1:4) yielded 1.83 g of methyl ()-2(KO-(1(5)-(O-(4-methoxybenzyl))hydroxycarbamoyl)-4-phenyl-3-butenyl|-Z-- methyl valerate in the form of oil, which was confirmed by standing to obtain a white solid.

Mass spectrometry: 440 (MAN) 7. (its) 345 ml of a solution of trimethylaluminum (2M in hexane) was added to a suspension of 1.03 g of 70 cyclohexylhydrazine in bml of dichloromethane in a nitrogen atmosphere. Extremely energetic gas formation was observed and the mentioned solid gradually dissolved over 1 hour to obtain solution A. (m) 0.44 g of methyl ether, which was obtained according to (iii), was dissolved in 4 ml of dichloromethane, solution A was added, and the resulting mixture was heated in a water bath for 6 hours (bath temperature 457C).

The resulting solution was cooled, very carefully treated with an excess of 2M hydrochloric acid 75 (extremely active gas formation), after which it was extracted twice with 20 ml of ethyl acetate each time. The obtained organic phase was successively washed with 595% sodium bicarbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to obtain a yellow resin. By gel chromatography eluting with a mixture of dichloromethane/methanol (24:11), 0.19 g of hydrazide was obtained.

Mass spectrometry: 522 (MAN) "7. (m) 0.11 g of the mentioned hydrazide, which was obtained according to (im), was suspended in a mixture of bml of dichloromethane and 0.02 bml of pyridine in a nitrogen atmosphere. 0.046 g of methanesulfonhydride was added and the resulting mixture stirred for 3 hours at room temperature with further dilution with 15 ml of dichloromethane.

The obtained solution was successively washed with 2M hydrochloric acid, water and 595% sodium bicarbonate solution, dried over magnesium sulfate and evaporated to obtain a white foam. with

As a result of mixing Kk! with diethyl ether, 0.095 g of (E)-2'-cyclohexyl-2(K)-I(1(5)-(O-(4-methoxybenzyl)) hydroxycarbamoyl)-4-phenyl-3-butenyl|-2' was obtained -(methanesulfonyl)-4-methylvalerohydrazide as a white solid.

Mass spectrometry: 600 (MAN) 7.

Example 45 - ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-isobutyl-2'(methanesulfonyl-4-methylvalerohydrazide "so

A solution of 0.246 g of (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-isobutyl-2'-(methanesulfonyl)-4 - Iz) of methylvalerohydrazide in a mixture of 10 ml of methanol and 2 ml of dichloromethane was treated with 0.00 bml of methanesulfonic acid. The resulting mixture was stirred for 3 hours at room temperature, after which the mentioned solvent was evaporated. The resulting residue was partitioned between ethyl acetate and water. The resulting ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting residue was mixed with Kk! hexane Kk! obtaining 0.119 g of ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2"-isobutyl-2(methanesulfonyl)-4-methylvalerohydrazide" in the form of a white solid.

Mass spectrometry: 454 (MAN)7. High-performance liquid chromatography: Gradient elution with solvent A, which includes "from 590 to solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate " 1 ml/minute. Holding time: 12.17 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-isobutyl-2'(methanesulfonyl o )-4-methylvalerohydrazide, which was used as a starting material, was obtained in the following way:

Go! () A solution of 0.bOg (E)-2(K)-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvalerohydrazide, 0.16 bml of isobutyraldehyde and crystalline 4-toluenesulfonic acid in 10 ml of dichloromethane was mixed for 1 hour with 4 molecular sieves. The resulting mixture was filtered, the mentioned solvent was evaporated and replaced

Ge") 20 10 ml of methanol. A few crystals of bromocresol green were added to obtain a yellow solution.

0.116 g of sodium cyanoborohydride was added to the resulting solution in small portions. The yellow color of the mentioned solution was maintained by periodically adding a 4M solution of hydrogen chloride in dioxane. The methanol was evaporated and the resulting residue was partitioned between dichloromethane and 5956 aqueous sodium bicarbonate solution. The resulting aqueous layer was washed twice with dichloromethane, after which the mixed organic layers were washed twice with 595% aqueous sodium bicarbonate solution. The obtained dichloromethane layer was dried over

F! anhydrous magnesium sulfate and the solvent was evaporated. The resulting residue was purified by gel chromatography under vacuum eluting with a mixture of hexane/ethyl acetate (7:3). 0.312 g of (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-2'-isobutyl-4-methylvalerohydrazide was obtained as a white solid. 60 Mass spectrometry: 417 (MAN) 7. (i) In a method similar to the method described in Example 2, parts (im) and (m), starting with Kk! 0.435g (E)-2(KO-I1(5 )-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-2'-isobutyl-4-methylvalerohydrazide, 0.249 g of bo (E)-2(KO-I1(5)-Ktetrahydro-2(K5) was obtained -pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-isobutyl-2'-(methanesulfonyl)-4-

methyl valerohydrazide as a white solid.

Mass spectrometry: 538 (MAN) 7.

Example 46 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2"-isopropyl-2'(methanesulfonyl)-4-methylvalerohydrazide

(E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3- butenyl|-2-isopropyl-2'(methanesulfonyl)-4-methylvalerohydrazide as a white solid.70 Mass spectrometry: 440 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 11.16 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 590 solvent B, followed by increasing the content of solvent B to 9595, over 15 minutes;

Example 47 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-cyclopentyl-2-(methanesulfonyl)-4-methylvalerohydrazide

(E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3- butenyl|-2'-cyclopentyl-2"-(methanesulfonyl)-4-methylvalerohydrazide as a white solid.

Mass spectrometry: 466 (MAN) 7. p

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes about 2095 solvent B, over 2 minutes, followed by increasing the content of solvent B to 80956 over 18 minutes; flow rate Iml/minute. Holding time: 17.57 minutes. Solvent A: H 250/0.195 TEA (tetrafluoroacetic acid); solvent B: СНиЗзСМ/0.08595 tetrafluoroacetic acid. Column type: NUREKRER

ZO0A -

Example 48 "co ()-2(KO-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(4-tetrahydropyranyl)-2'-(methanesulfonyl)-4-methyl valerohydrazide iv)

In a method similar to the method described in Example 45, but using co-tetrahydro-4H-pyran-4-one instead of isobutyraldehyde in step (Y), (E)-2(K)-(1(5)) was obtained -(Hydroxycarbamoyl)-4-phenyl-3-butenyl|-2-(4-tetrahydropyranyl)-2'(methanesulfonyl)-4-methylvale)rohydrazide as a white solid.

Mass spectrometry: 482 (MAN) "7.

High Performance Liquid Chromatography: Accelerated gradient elution with solvent A, which includes 2095 of solvent B over 2 minutes, followed by increasing the content of solvent B to 8090 over 18 minutes; flow rate 1 ml/minute. Holding time: 13.72 minutes. Solvent A: NYOU, 1956 TEA c) c (tetrafluoroacetic acid); solvent B: SNUZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER » ZOO.

Example 49 ()-2(KO-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2-(4-tetrahydrothiopyranyl)-2'(methanesulfonyl)-4-methylvalerohydrazide o In the method, similar to the method described in Example 45, but using

Go! of tetrahydrothiopyran-4-one instead of isobutyraldehyde in step (Y), ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2-(4-tetrahydrothiopyranyl)-2' was obtained (methanesulfonyl)-4-methylb o allerohydrazide as a white solid.

He») 20 Mass Spectrometry: 498 (MAN) 7. ah High Performance Liquid Chromatography: Accelerated gradient elution with solvent A, 7" which includes 2095 solvent B, over 2 minutes, followed by increasing the content of solvent B to 8090 over 18 minutes ; flow rate Tml/minute. Retention time: 17.35 minutes. Solvent A: H»O/0.196. TPA (tetrafluoroacetic acid); Solvent B: SNUSUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER 59 ZOOA.

HF) Example 50 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-(methanesulfonyl)-4-methylvalerohydrazide o In a method similar to the method described in Example 45, but using 1-tert- butoxycarbonyl-4-piperidone instead of isobutyraldehyde in step (Y), 60 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2-(4-piperidinyl)-2 was obtained (methanesulfonyl)-4-methylvalerohydr azide as a white solid.

Mass spectrometry: 481 (MAN) 7.

High Performance Liquid Chromatography: Accelerated gradient elution with solvent A, which includes 2095 of solvent B, over 2 minutes, followed by increasing the content of solvent B to 8090 bo over 18 minutes; flow rate Tml/minute. Holding time: 11.39 minutes. Solvent A: H»O/0.196. TRA

(tetrafluoroacetic acid); solvent B: SNUZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER

ZOO

Example 51 (E)-2(K)-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl/|-2-(isobutyl)-2-(isopentanoyl)-4-methylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.097 g of (E)-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl -3-butenyl|-2-(isobutyl)-2-(isopentanoyl)-4-methylvalerohydrazide, 0.047 g of (E)-2(K)-(/1(5)-(hydroxycarbamoyl)-4-phenyl- 3-butenyl|-2-(isobutyl)-2'-(isopentanoyl)-4-methylvalerohydrazide in the form of a white solid. 70 Mass spectrometry: 460 (M.--H)7, 482 (MaMa)".

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 12.79 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOOA (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-2'-(isobutyl)-2-(isopentanoyl )-4-methylvalerohydrazide, which was used as a starting material, was obtained in the following manner: (i) Solution of 0.25 g of (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3 -butenyl|-2'-isobutyl-4-methylvalerohydrazide, 0.0 biml of pyridine and crystalline 4-dimethylaminopyridine in bml of dichloromethane were cooled to a temperature of 0"С in an atmosphere of 20 nitrogen. 0.091 ml of isopentanoyl chloride was added and the resulting reaction mixture was heated to room temperature.

After stirring for 2 hours at room temperature, the resulting reaction mixture was diluted with dichloromethane and washed first with a 2M aqueous solution of hydrochloric acid, then with brine.

The obtained dichloromethane phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. After that, the resulting residue was dissolved in T7Oml of 2095 trifluoroacetic acid solution in dichloromethane and stirred at room temperature for 2 hours. The mentioned solvents were evaporated and the resulting residue was purified by gel chromatography under vacuum eluting with a 195 solution of methanol in i) dichloromethane. 0.16 g of (E)-2(KO-I1(5)-(carboxy)-4-phenyl-3-butenyl|-2-(isobutyl)-2-(isopentanoyl)-4-methylvalerohydrazide was obtained in the form of a white foam --

Mass spectrometry: 445 (MAN) 7. (i) In a method similar to the method described in Example 2, part (y), starting with i-o 0.16g (E)-2(KO-I1( 5)-(carboxy)-4-phenyl-3-butenyl|-2-(isobutyl)-2-(isopentanoyl)-4-methylvalerohydrazide, IC o) 0.097g of (E)-2(KO-I1(5 )-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(isobutyl)-2-(isopentanoyl)-4-methyl valerohydrazide as a white solid. i am

Mass spectrometry: 544 (MAN) 7.

Example 52 (B)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(isobutyl)-2-(cyclohexanecarbonyl)-4-methylvalero" hydrazide

In a method similar to the method described in Example 51, but with the use of cyclohexanecarbonyl chloride instead of isopentanoyl chloride in step (Y), it was obtained h ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl- 3-butenyl|-2'-(isobutyl)-2'-(cyclohexanecarbonyl)-4-methylvalerohydr » azide in the form of a white solid.

Mass spectrometry: 486 (MAN) 7.

High Performance Liquid Chromatography: Accelerated gradient elution with solvent A containing 3595 of solvent B for 5 minutes, followed by increasing the content of solvent B to 7090

Go! within 15 minutes; flow rate Tml/minute. Holding time: 15.44 minutes. Solvent A: H»O/0.196. TPA (tetrafluoroacetic acid); solvent B: SNUZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER and ZOOA. bu 70 Example 53 ()-2(KO-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-M-(2.6-dioxopiperidino)valeramide -6) In a method similar to the method, the description of which is given in the first paragraph of Example 45, starting with 0.095 g of -M-(2,6-dioxopiperidino)va 22 Lleramide, 0.027g were obtained

HF) ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-M-(2,6-dioxopiperidino)valeramide in the form of a white solid. o Mass - spectrometry: 416 (MAN) 7.

High Performance Liquid Chromatography: Accelerated gradient elution with solvent A, 60 which includes 2095 solvent B, for 5 minutes, followed by increasing the content of solvent B to 70905, for 15 minutes; flow rate Timl/minute. Solvent A: HNO/0.196 TEA (tetrafluoroacetic acid); solvent B: CH3CH/O, 08590 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2(KO-I1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-4-methyl-M-(2,6-dioxopiperidine o)valeramide, which was used as a starting material, was obtained in the following manner: () Solution of 1.0 g of (E)-2(K)-(1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|- 4-methylvalerohydrazide, -0.35 g of glutaric anhydride and 0.85 ml of triethylamine in 30 ml of dry toluene were heated in a reflux flask at the distillation temperature under nitrogen atmosphere for 7 hours. The resulting mixture was cooled to room temperature and washed with 2M aqueous hydrochloric acid solution, 595 sodium bicarbonate solution and brine. The resulting organic phase was dried over anhydrous magnesium sulfate, after which the mentioned solvent was evaporated. The resulting residue was mixed with diethyl ether to obtain 0.623 g of (E)-2(KO-I1(5)-(tert-butoxycarbonyl)- 4-phenyl-3-butenyl)|-4-methyl-M-(2,6-dioxopiperidino)valeramide as a white solid.

Mass spectrometry: 457 (MAN) 7. 70 (i) In a method similar to the method described in Example 2, parts (im) and (m), starting with Kk! 0.62g of (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methyl-M-(2,6-dioxopiperidino)valeramide, 0.095g were obtained ( E)-2(KO-I1(5)-tetrahydro-2(K5)-pyranyloxy)carbamoyl1|-4-phenyl-3-butenyl|-4-methyl-M-(2,6-dioxopiperidino)vale 75 ramid in in the form of a white solid substance.

Mass spectrometry: 500 (MAN) 7.

Example 54 (E)-M-(tetrahydro-1,2-thiazin-2-yl)-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methylvaleramide 5, C-dioxide

In a method similar to the method described in the first paragraph of Example 45, with 0.048 g of (E)-M-(tetrahydro-1,2-thiazin-2-yl)-2(K)-I1(5)-Ctetrahydro- 2(K5)-pyranyloxy)carbamoyl| -4-phenyl-3-butenyl-4-methylvaleramide from,3-dioxide, b.01 g of (E)-M-(tetrahydro-1,2-thiazin-2-yl)-2(K)-I1(5 )-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4--methylvaleramide 8,8-dioxide as a white solid. with

Mass spectrometry: 438 (MAN) 7. o (E)-M-(tetrahydro-1,2-thiazin-2-yl)-2(K)-I1(5)-Ktetrahydro-2(K5)-pyranyloxy) carbamoyl|-4-phenyl-33-butenyl-4-methylvaleramide 5,5-dioxide, which was used as a starting material, was obtained in the following way: (I) A solution of 5.64 g of leuco-acid tert-butyl ether and 33.bml of pyridine in 40 ml of dichloromethane was added dropwise to a solution of b.Oml of trifluoromethanesulfonhydride in bbml of dichloromethane in a nitrogen atmosphere at a temperature of 0"C. "co

After 10 minutes, the resulting mixture was washed twice with water, after which it was dried over anhydrous magnesium sulfate.

The resulting mixture was concentrated to approximately one-third of the original volume, after which it was added to M of a cooled (temperature 0"C) solution of the anion, which was obtained by treating 5.22 g of tert-butylmethylmalonate with 1.32 g of 6095 sodium hydride suspension in Hmol of dimethylformamide in mineral oil under a nitrogen atmosphere for 2 hours. The resulting mixture was kept with heating to room temperature (I) overnight, after which the mentioned solvent was evaporated. The resulting residue was dissolved in ethyl acetate and the resulting solution was washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated with by obtaining 10.0 g of 1,2-tert-butyl-1,4-dimethyl-1,1,4(K)-pentane-tricarboxylate in the form of red oil. (i) 1.53 g of 6095 sodium hydride suspension in mineral oil was added to the stirred solution of 12.55 g of 1,2-tert-butyl-1,4-dimethyl-1,1,4(K)-pentanetricarboxylate in 120 ml of dimethylformamide in a nitrogen atmosphere. The resulting mixture was stirred until gas formation stopped (pr approximately 1 hour), a solution of 7.54 g of cinnamyl bromide in 7 Oml of dimethylformamide was added dropwise, and the resulting mixture was stirred at room temperature overnight. The mentioned solvent was evaporated and the obtained residue was dissolved in ethyl acetate and washed twice with water. The obtained organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. o The resulting residue was purified by gel chromatography on columns under vacuum eluting with a mixture of o hexane/ethyl acetate (9.1). 15.06 g of (E)-1,2-tert-butyl-1,4-dimethyl-1-(3-phenyl-prop-2-en-1-yl)-1,1,2(K)-pentanetricarboxylate was obtained in the form butter 1 pale yellow. b 20 (iii) Solution 2,1g (E)-1,2-tert-butyl-1,4-dimethyl-1-(3-phenyl-prop-2-en-1-yl)-1,1,2 (K)-pentanetricarboxylate in 30 ml of 2095 ml of a solution of "6 trifluoroacetic acid in dichloromethane was stirred at room temperature for 1 hour. The mentioned solvents were evaporated and the obtained residue was dissolved in 20 ml of toluene. 1.bml of triethylamine was added, after which the resulting mixture was stirred at the temperature of distillation for 2 hours. After cooling, the mentioned 22 mixture was washed with a 2M aqueous solution of hydrochloric acid and water. The resulting organic phase was dried over anhydrous magnesium sulfate and evaporated to give a pale yellow oil. The resulting oil was dissolved in 1 Oml of hexane and 0.bg of cyclohexylamine was added. The resulting salt filtered, after which it was suspended in 20 ml of ether and washed with 1 M sulfuric acid. The resulting ether phase was dried over anhydrous magnesium sulfate and evaporated to obtain 1.5 g of 60 (E)-2(K)-isobutyl-4-methyl-3-(К5 )-3-phenylprop-2-en-1-yl)|-succinate in the form of a solid white metal. (m) A solution of 40 g of 4-chloro-1-butanesulfonyl chloride in 400 ml of diethyl ether was added to a solution of 30.4 g of tert-butyl carbazate and 17 ml of pyridine in 4000 ml of diethyl ether at room temperature. The resulting mixture was stirred at room temperature for 72 hours, after which it was washed with water. The separated organic phase was dried over anhydrous magnesium sulfate. The oily residue, which was obtained after b5 evaporation of the solvent, was purified by gel chromatography on columns under vacuum, eluting with a mixture of hexane/ethyl acetate (8:2, increasing to 6:4). 10.25 g of tert-butyl(4-chlorobutyl)sulfonyl|carbazate was obtained as a white solid. (m) 1.77 6095 of a suspension of sodium hydride in mineral oil was added to a solution of 10.25 g of tert-butyl(4-chlorobutyl)sulfonylcarbazate in 30 Oml of dry tetrahydrofuran at room temperature in a nitrogen atmosphere. After stirring at room temperature for 48 hours, the mentioned solvent was evaporated and the resulting residue was dissolved in ethyl acetate and washed with water. The obtained organic phase was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was recrystallized from a mixture of ethyl acetate/hexane to obtain 1.86 g of tert-butyl(tetrahydro-1,2-thiazin-2-yl)carbamate 5,5-dioxide as a pale yellow solid. 70 (ml) A solution of 1.86 g of tert-butyl(tetrahydro-1,2-thiazin-2-yl)carbamate 5,5-dioxide in 20 ml of 4M hydrogen chloride in ethyl acetate was stirred at room temperature for 1 hour. The mentioned solvent was evaporated and the resulting residue was stirred in ether for 5 minutes, after which it was filtered to obtain 1.24 g of tetrahydro-1,2-thiazine-2-amine 5,5-dioxide as a white solid. (ml) A solution of 1.39 g of (E)-2(K)-isobutyl-4-methyl-3-(K5)-3-phenylprop-2-en-1-yl)|-succinate in 15 ml of 7/5 dichloromethane was cooled to a temperature of -10"C in a nitrogen atmosphere. 4 drops of dimethylformamide and 0.418 ml of oxalyl chloride were added, and the resulting mixture was kept until heating to a temperature of 0"C for 1 hour.

The mentioned solvent was evaporated and replaced with 2 ml of dichloromethane. After that, the obtained solution was added dropwise to a solution of 1.24 g of tetrahydro-1,2-thiazine-2-amine 5,5-dioxide and 14 ml of triethylamine in 20 ml of dichloromethane in a nitrogen atmosphere at a temperature of 0°C. The resulting mixture was kept at a temperature of 0°C for at night, after which it was washed with water for 2 hours. The obtained organic phase was dried over anhydrous magnesium sulfate and evaporated.

The obtained residue was purified by gel chromatography on columns under vacuum with elution with a mixture of ethyl acetate/hexane (2:68, Kk! increasing to 10:90). 0.44 g of z,Z-dioxide (E)-M-(tetrahydro-1,2-thiazin-2-yl)-2(K)-I1(5)-(methoxycarbonyl)-4-phenyl-3-butenyl was obtained |-4-methylvaleramide. in the form of a white solid. 0.573 ml of a 2M solution of trimethylaluminum in toluene was added to a solution of 0.134 g

O-(tetrahydro-2H-pyran-2(K5)-yl)-hydroxylamine in ml of dry toluene at a temperature of 0"C in a nitrogen atmosphere. i)

The resulting mixture was stirred at room temperature for 1 hour, after which 010 g of (E)-M-tetrahydro-1,2-thiazin-2-yl)-2(K)-(1(5)-(methoxycarbonyl)- 4-phenyl-3-butenyl|-4--methylvaleramide. The resulting mixture was heated at 5573 for 3 hours, after which it was allowed to cool to room temperature overnight. The mentioned mixture was diluted with ethyl acetate and washed successively with 2M aqueous solution hydrochloric acid and 5956 aqueous solution of sodium hydrogen carbonate, after which it was dried over anhydrous magnesium sulfate. The mentioned solvent was evaporated and the obtained residue was mixed with diethyl ether to obtain 0.048 g of 5"E)-M-(tetrahydro-1,2-thiazine-2 -yl)-2(K)-11(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl)-4-methylvaleramide and 5,5-dioxide as a white solid.

Mass spectrometry: 522 (MAN) "7.

Example 55 "(E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-2-phenylhexanehydrazide

In a method similar to the method described in the first paragraph of Example 1, starting with 0.37 g of (E)-2(KO-I1(5)-(carboxy)-4-phenyl-3-butenyl|-2 -(methanesulfonyl)-2"-phenylhexanehydrazide, obtained c0.1og ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2(methanesulfonyl)-2"-phenylhexanehydrazide in the form of a white solid.

Mass spectrometry: 474 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 1590 of solvent B, followed by increasing the content of solvent B to 9595, over 15 minutes; flow rate is 1 ml/minute. Holding time: 11.97 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOOA 1 (E)-2(KO-I1(5)-(carboxy)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-2'"-phenylhexanehydrazide, which would be used as starting material was obtained in the following way: () In a way similar to the method described in Example 54, parts (i) and (ii), but with the use of benzyl 2-hydroxyhexanoate and benzyl tert-butyl alonate, (E)-1,2-dibenzyl-1-tert-butyl-1-(3-phenyl-prop-2-en-1-yl)-1,1,2(K)-hexanetricarboxylate was obtained in the form of a yellow oil color. (i) A solution of 2.27 g of sodium hydroxide in 20 ml of water was added to a solution of 6.47 g of 1 yl)-1,1,2(K)-hexanetricarboxylate in 40 ml of ethanol. The resulting mixture was heated in a reflux flask at the distillation temperature overnight, then cooled and evaporated. ime) The resulting residue was diluted with water and acidified to pH 1 by with concentrated hydrochloric acid.The resulting aqueous phase was extracted twice with ethyl acetate , after which the mixed organic phases were washed with water and dried over anhydrous magnesium sulfate. The mentioned solvents were evaporated and the obtained residue was dissolved in 50 ml of toluene. 1.53 ml of triethylamine was added to the mentioned mixture, after which it was heated in a reflux flask at the distillation temperature for 3.5 hours and allowed to cool overnight. The obtained mixture was washed with a 2M aqueous solution of hydrochloric acid, after which it was dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting yellow oil 65 was dissolved in hexane and treated with 1.09 g of cyclohexylamine to give a salt which was filtered off. After that, the mentioned salt was partitioned between ethyl acetate and 1M sulfuric acid, the resulting organic phase was further washed with water, dried over anhydrous magnesium sulfate and evaporated to give 1,3g (E)-2(K)-butyl-4-tert-butyl-3 -(K5)-(3-phenylprop-2-en-1-yl)|-succinate as a pale yellow solid. (her) In a method similar to the method described in Example 1, part (1)-(iii), starting with (E)-2(K)-butyl-4-tert-butyl-3-(K5) -(3-phenylprop-2-en-1-yl)|-succinate, obtained (E)-2(KO-I1(5)-(carboxy)-4-phenyl-3-butenylI|-2'i(methanesulfonyl )-2'i--phenylhexanehydrazide as a white solid.

Mass spectrometry: 459 (MAN) 7. 70 Example 56 (E)-2-(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-2", 3Z-diphenylpropionhydrazide

In a method similar to the method described in the first paragraph of Example 44, starting with 0.162 g of (E)-2(KO-I1(5)-4O-4-methoxy-benzyl)hydroxycarbamoyl)-4-phenyl-3- butenyl|-2'-(methanesulfonyl)-2",3-diphenylprop 75 ionhydrazide, 0.040 g of ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'- (methanesulfonyl)-2,3-diphenylpropionhydrazide as a white solid.

Mass spectrometry: 508 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 590 solvent B, followed by increasing the content of solvent B to 9595, over 15 minutes; flow rate

Lml/minute. Holding time: 12.25 minutes. Solvent A: HNO/0.195 TEA (tetrafluoroacetic acid); solvent

In: СНуСМ/0.08595 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2(KO-I1(5)-4O-4-methoxy-benzyl)hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-2",3-diphenyl propionhydrazide, which was used as a starting material, was obtained in the following manner: () In a manner similar to the method described in Example 55, part (1)-(iii), but with the initiation of benzyl α-hydroxy-benzenepropanoate, it was obtained o ()-2(KO-I1(5)-(carboxy)-4-phenyl-3-butenyl|-2-(methanesulfonyl)-2",3-diphenylpropionhydrazide in the form of a white solid. (ii) Solution 0 29g of ()-2(KO-(1(5)-(carboxy)-4-phenyl-3-butenyl|-2-(methanesulfonyl)-2",3-diphenylpropionhydrazide in bml w: dimethylformamide was cooled to a temperature of 0" Sat in a nitrogen atmosphere and added 0.18 g of (O-4-methoxybenzyl)hydroxylamine and 0.124 g of 1-ethyl-3-(3-dimethyl-aminopropyl)-carbodiimide hydrochloride.

The resulting mixture was allowed to warm to room temperature and stirred overnight. The mentioned M) solvent was evaporated and the resulting residue was dissolved in dichloromethane and washed with water. The obtained organic phase was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was mixed with sodium chloride diethyl ether Kk! obtaining 0.17 g of IC o) ()-2(KO-(1(5)-40-4-(methoxybenzyl)hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-2",3 -diphenylprop ionhydrazide as a white solid.

Example 57 "()-2(K5)-P1(K5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-2,2'-diphenylacetohydrazide

In a method similar to the method described in the first paragraph of Example 45, starting with 1.05 g of (E)-2-(к5)-1(кК5)-(tetrahydro-2(К5)-pyranyl-oxy )carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-2,2'--diphenylacetohydrazide, 0.598g of (E)-2(K5)-P1(K5)-(hydroxycarbamoyl )-4-phenyl-3-butenyl|-2(methanesulfonyl)-2,2'i-diphenylacetohydrazide In the form of a white solid. 1 Mass Spectrometry: 494 (MAN) 7. o High Performance Liquid Chromatography: Accelerated gradient elution with solvent A, which includes 3595 of solvent B, for 5 minutes, with a further increase to 8095, for 15 minutes; o flow rate Tml/minute. Holding time: 8.54 minutes. Solvent A: H20/0.1965. TRA (tetrafluoroacetate

FO 20 acid); solvent B: СНУзСМ/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2-(k5)-1(kK5)-(tetrahydro-2(K5)-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-2(methanesulfonyl)-2,2'-diph -. enylacetohydrazide, which was used as a starting material, was obtained in the following manner: () In a manner similar to the method described in Example 55, part (1)-(iii), but with the initiation of Kk! benzyl mandelate, (E)-2(K5)-P(K5)-(carboxy)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-2,2'-diphenylacetohydrazide was obtained in the form

Gee! white solid.

Mass spectrometry: 479 (MAN) 7. o (i) In a method similar to the method described in Example 2, part (m), with LH (E)-2(K5)-P1(K5)-(carboxy )-4-phenyl-3-butenyl|-2'(methanesulfonyl)-2,2'i-diphenylacetohydrazide, 1.1 g of 60 (E)-2(85)-(1(85)-((tetrahydro-2 (K5)-pyranyloxy)carbamoyl-1-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-2,2'-diphenyl acetohydrazide as a white solid.

Mass spectrometry: 578 (MAN) 7.

Example 58 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-(2-thiazolyl)-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-phenylvalerohyde borazide

In a method similar to the method described in the first paragraph of Example 45, with 0.29 g of (E)-2(КО-(1(5)-Ktetrahydro-2(К5)-pyranyl-oxy)carbamoyl|-4-( 2-thiazolyl)-3-butenyl|-2(methanesulfonyl)-4-methyl-2-phenylvalerohydrazide, 0.17 g of ()-2(KU-I1(K5)-(hydroxycarbamoyl)-4-(2- thiazolyl)-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-phenylvalerohydrase is a white solid.

Mass spectrometry: 481 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 590 solvent B, followed by increasing the content of solvent B to 9595, over 15 minutes; flow rate 70 ml/minute. Holding time: 9.97 minutes. Solvent A: H2O/0.195 TPA (tetrafluoroacetic acid); solvent

In: СНуСМ/0.08595 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|)|-4-(2-thiazolyl)-3-butenyl|-2'(methanesulfonyl)-4-m ethyl-2'-phenylvalerohydrazide, which was used as a starting material, was obtained in the following manner: () Solution of 4.0 g of (E)-2(K)-I1(5)-(tert-butoxycarbonyl)-4-phenyl- of 3-butenyl|-4-methylvaleric acid in 75 200 ml of dichloromethane was cooled to a temperature of -78"С and bubbled with ozone until the mentioned solution turned blue. The resulting mixture was kept with heating to room temperature and 20 ml of dimethyl sulfide was added. The resulting mixture was stirred at room temperature for 3 hours, after which the solvent was evaporated. The resulting residue was purified by gel chromatography on columns under vacuum eluting with a mixture of hexane/ethyl acetate (1:17). 1.8 g of 20. 2(K)-(I1(5)-(tert) was obtained -butoxycarbonyl)-propan-3-al|-4-methylvaleric acid in the form of a pale 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 I go to 1 Oml of dry toluene. After stirring at room temperature for 3 hours, a solution of 0.83 g of 2(K)-11(5)-(tert-butoxycarbonyl)-propan-3-al|-4-methylvaleric acid in ml of toluene was added, and the resulting mixture was further stirred for 48 hours at room temperature. The mentioned solvent was evaporated, the obtained residue was purified by gel chromatography on columns under vacuum with elution with a mixture of i) dichloromethane/methanol (95:5). 0.43 g of (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-(2-thiazolyl)-3-butenyl|-methylvaleric acid was obtained in the form of a pale yellow oil.

Mass spectrometry: 354 (MAN) 7. (its) In a method similar to the method described in Example 1, parts (1)-(iii), and in Example 2, part (M), starting with IS o ) (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-(2-thiazolyl)-3-butenyl|-"methylvaleric acid, (E)-2(KO-I1(5) was obtained )-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-(2-thiazolyl)-3-butenyl|-2'-(methanesulfonyl)-4-methyl co-2-phenylvalerohydrazide as a white solid.

Mass spectrometry: 565 (MAN) 7.

Example 59 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2-isobutyryl-2-isobutyl-4-methylvalerohydrazide "

Solution 0.32" 40. (E)-2(KO-I1(5)-Ktetrahydro-2(К5)-pyranyl-oxy)carbamoyl-1|-4-phenyl-3-butenyl|-2-isobutyryl-2'- 0.03 g of 4-toluenesulfonic acid was treated with isobutyl-4-methyl ts of valerohydrazide in 10 ml of methanol. The resulting mixture was stirred for 2 hours at room temperature, after which the mentioned solvent was evaporated to give a glass. This residue was mixed with diethyl ether to give /-0.15g ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2"-isobutyryl-2'-isobutyl-4-methylvalerohydrazide.- in the form of a white solid o Mass spectrometry: 446 (MAN) 7.

Go! High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 2096 of solvent B, over 5 minutes, followed by increasing the content of solvent B to 6595, over 5 1 minutes to 20 minutes; flow rate Tml/minute. Holding time: 17.48 minutes. Solvent A: HNO/0.195 TEA

F 20 (tetrafluoroacetic acid); solvent B: СНЗзСМ/0.08595 tetrafluoroacetic acid. Column type: NUREVRER

ZOO -6(E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-2'-isobutyryl-2'-isobutyl-4-methylvalerohydrazide , which was used as a starting material, was obtained in the following manner: (i) Solution of 0.70 g of 99 (E)-2(E3-I1(8)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|- 2'-isobutyl-4-methylvalerohydrazide, 0.38 ml of pyridine

HF) and crystalline 4-dimethylaminopyridine in 1 ml of dichloromethane was cooled to a temperature of 0"C in a nitrogen atmosphere. 0.67 ml of isobutyric anhydride was added and the resulting reaction mixture was heated to room temperature. where After stirring for 16 hours at room temperature, the resulting reaction mixture was diluted with dichloromethane and washed first with a 2M aqueous solution of hydrochloric acid, then with brine. 60 The obtained dichloromethane phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. By gel chromatography with elution with a mixture of ethyl acetate/hexane (1:5) and subsequent evaporation, 0.56 g ()-2 was obtained (KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3Z-butenyl|-2'-isobutyryl-2"-isobutyl-4-methylvalerohydrazide In the form of a white foam. bo Mass spectrometry: 487 (MAN ) 7.

(ii) 0.56 g of tert-butyl ether was dissolved in 20 ml of a 5095 solution of trifluoroacetic acid in dichloromethane and stirred at room temperature for 1.5 hours. The mentioned solvents were evaporated and traces of trifluoroacetic acid were removed by adding and evaporating toluene (2 x 10ml). The resulting residue was mixed with Kk! with a mixture of diethyl ether/hexane (17) Kk! obtaining 0.39 g of (E)-2(KO-I1(5)-(carboxy)-4-phenyl-3-butenyl|-2'-isobutyryl-2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.

Mass spectrometry: 431 (MAN) 7. (ii) In a method similar to the method described in Example 2, part (y), starting with 70. 0.39g 0 (E)-2(KO-I1( 5)-(carboxy)-4-phenyl-3-butenyl)|-2'-isobutyryl-2'-isobutyl-4-methylvalerohydrazide, 0.32 g of (E)-2(KO-I1(5)-CteIrahydro- 2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-isobutyryl-2'-isobutyl-4-methylvalerohydrazide as a white solid.

Mass spectrometry: 530 (MAN) 7.

Example 60 (E)-2'-acetyl-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-isobutyl-4-methylvalerohydrazide

(E)-2'-acetyl-2(K)-(1(5)-( hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-isobutyl-4-methylvalerohydrazide as a white solid.

Mass spectrometry: 418 (MAN) 7.

High-performance liquid chromatography: Elution using solvent A; flow rate 1 ml/minute. Holding time: 4.86 minutes. Solvent A: H 20/0.190 TEA (tetrafluoroacetic acid). Column type: NUREVERER ZOOA. with

Example 61 o (E)-2-benzoyl-2'-isobutyl-2(K)-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methylvalerohydrazide

In a method similar to the method described in Example 59, but using benzoyl chloride instead of isobutyric anhydride in step (Y), (E)-2-benzoyl-2-isobutyl-2(K)-(1(5)) was obtained -(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methylvalerohydrazide in the form of a white solid.

Mass spectrometry: 480 (MAN) 7.

High-performance liquid chromatography: Gradient elution using solvent A, which includes about 590 of solvent B, with a further increase in the content of solvent B to 9595, during 15 minutes; flow rate by 1 ml/minute. Holding time: 12.37 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNZSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER ZOO. at

Example 62

Methyl (E)-I2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methylvaleryl/|-1-isobutylhydrazine|glyoxylate

Solution O,za4g methyl "f (E)-(2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-4-methylvaleryl/-1- isobutyl hydrase 50 niglyoxylate in 5 ml of methanol was treated with 0.04 g of 4-toluenesulfonic acid. The resulting mixture was stirred with s for 2.5 hours at room temperature, after which the mentioned solvent was evaporated to obtain a white semi-solid mass. This residue in ethyl acetate was washed with 5905 solution of sodium bicarbonate, dried over magnesium sulfate and evaporated to obtain a solid. -3-butenyl|-4-methylvaleryl/-1-isobutylhydrazine|glyoxylate.- in the form of a white solid substance. (ee) Mass spectrometry: 462 (MAN) 7.

High-performance liquid chromatography: Gradient elution using solvent A, which includes about 590 of solvent B, with a further increase in the content of solvent B to 9595, during 15 minutes; flow rate (o) 50 1ml/minute. Holding time: 12.26 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent that B: СНуСМ/0.08595 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

Methyl (E)-12(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl-4-phenyl-3-butenyl|-4-methylvaleryl/-1-isobutylhydrazine glyoxylate, which was used as starting material , obtained in the following way: 59 (u) Solution 1.0 g

HF) (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-2'-isobutyl-4-methylvalerohydrazide, 0.4 Oml of pyridine t and crystalline 4-dimethylaminopyridine y 10 ml of dichloromethane was cooled to a temperature of 0"C in a nitrogen atmosphere. 0.27 ml of methyloxalyl chloride was added and the resulting reaction mixture was heated to room temperature.

After stirring for 16 hours at room temperature, the resulting reaction mixture was evaporated to dryness. The obtained residue in ethyl acetate was washed with 2M aqueous hydrochloric acid, 595% sodium bicarbonate solution and water. The obtained organic phase was dried over anhydrous magnesium sulfate and the mentioned solvent was evaporated. As a result of mixing the obtained residue with hexane, 0.91 g of methyl (E)-I2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvaleryl/-1-isobutylhydrazineglyoxylate was obtained. in the form of a white solid substance b5 Mass spectrometry: 503 (MAN) 7.

(of which 0.90 g of tert-butyl ether, which was obtained in paragraph (i), was dissolved in 20 ml of a 5095 solution of trifluoroacetic acid in dichloromethane and stirred at room temperature for 3 hours. The mentioned solvents were evaporated and traces of trifluoroacetic acid were removed by adding and evaporating toluene (2x20ml). The resulting residue was dried in a vacuum to obtain 0.95 g of methyl (E)-12(KO-I1(5)-(carboxy)-4-phenyl-3-butenyl|-4-methylvaleryl/|-1-isobutylhydrazine |glyoxylate in the form of resin.

Mass spectrometry: 446 (MAN) 7. (its) Carboxylic acid, which was obtained in paragraph (ii), was dissolved in bBml of dimethylformamide, cooled to room temperature and successively treated with 0.75 g 70. O-(tetrahydro-2H-pyran -2(K5)-yl)hydroxylamine and 0.48 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mentioned solvent was evaporated and the resulting residue was dissolved in ethyl acetate. The obtained ethyl acetate layer was washed with water, 2M hydrochloric acid, 595% sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and 75% evaporated to give a foam. 0.350 g of methyl (E)-T2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl was obtained by gel chromatography eluting with a mixture of ethyl acetate/hexane (2:3) followed by evaporation -3-butenyl|-4-methylvaleryl/-1-isobutylhydrase niglyoxylate as a white solid.

Mass spectrometry: 546 (MAN) 7.

Example 63 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-isobutyl-4-methyl-2-(methylglyoxyloyl)valerohydrazide

In a method similar to the method described in Example 62, starting with (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoylI|-4-phenyl-3-butenyl|- 2'-isobutyl-4-methyl-2-(methylglyoxyloyl)-valerohydrazide, obtained with (E)-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'- isobutyl-4-methyl-2-(methylglyoxyloyl)-valerohydrazide as a white solid.

Mass spectrometry: 462 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 590 solvent B, followed by increasing the content of solvent B to 9595, over 15 minutes; flow rate --

M1ml/minute. Holding time: 12.19 minutes. Solvent A: H»O/0.195 TEA (tetrafluoroacetic acid); solvent Ge)

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2(KO-I1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-isobutyl-4-methyl-2-(methylhydrolyoxy) -valerohydrazide, which was used as a starting material, was obtained by a method similar to the method described in Example 62 (1)-(iii), using pyruvoyl chloride instead of 30 Mmethyloxalyl chloride. at

Mass spectrometry: 530 (MAN) 7.

Example 64 ()-2(KO-I1(K5)-(hydroxycarbamoyl)-4-(3-pyridyl)-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-phenylvalerohyde "razide 50 Solution 0.21 g of C (E)-12(KO-I1(Kk5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoylI|-4-(3Z-pyridyl)-3-butenyl|-2'-(methanesulfonyl)- 0.097 g of 4-toluenesulfonic acid was treated with l-2'-phenylvalerohydrazide in 1 ml of methanol. The resulting mixture was stirred for 2.5 hours at room temperature, after which it was diluted with water. The resulting solid was filtered, washed with water and diethyl ether and dried under vacuum to obtain 0.138 g of ()-2(KO-I1(K5)-(hydroxycarbamoyl)-4-(3-pyridyl)-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2' -phenylvalerohydrase

Mn is a white solid. (ee) Mass spectrometry: 475 (MAN) 7. sl High-performance liquid chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595, during 15 minutes; flow rate c. I ; and (o) 1 ml/minute. Retention time: 9.53 and 9.92 minutes (diastereoisomer ratio 3:1). Solvent A: (H2O)/0.196 TPA (tetrafluoroacetic acid); solvent B: СНЗзСМ/0.08590 tetrafluoroacetic acid. Column type:

NUREKRER ZO0A ()-2(KO-I1(k)-Ktetrahydro-2(K5)-pyranyloxy)carbamoylI-4-(3-pyridyl)-3-butenyl|-2'("methanesulfonyl)-4-m ethyl- 2'-phenylvalerohydrazide, which was used as a starting material, was obtained in the following way: 59 () Solution 6.81 g of 1,2-dibenzyl 1-tert-butyl-4-methyl-1(K5), 1,2(K )-pentane tricarboxylate in 5 Oml dry

HF) of tetrahydrofuran was stirred in a nitrogen atmosphere at room temperature. 0.6 bbg of 6095 hydride was added

HF sodium and the resulting mixture were stirred for 10 minutes. A solution of 2.66 g of 4-(3-pyridyl)allyl acetate and 0.87 g of tetrakis(triphenylphosphine)-palladium(0) in 4 Oml of dry tetrahydrofuran was added and the resulting mixture was stirred at room temperature for 4 hours. Tetrahydrofuran was evaporated and the resulting residue was partitioned between dichloromethane and saturated sodium chloride solution. The obtained organic solution was dried over anhydrous magnesium sulfate and evaporated to obtain a light brown oil. 7.50 g of (E)-1,2-dibenzyl 1-tert-butyl-4-methyl-1-3-(3-pyridyl) )-prop-2-en-1-yl|-1(K5), in 1,2(K)-pentanetricarboxylate.

Mass spectrometry: 572 (MAN) 7.

(a solution of 2.80 g of sodium hydroxide in 40 ml of water was added to a solution of 4.00 g of (E)-1,2-dibenzyl 1-tert-butyl-4-methyl-1-I3-(3-pyridyl)-prop-2- en-1-yl|-1(K5),1,2(K)-pentane tricarboxylate in 40 Oml of ethanol.

The resulting mixture was heated in a reflux flask at the distillation temperature for 20 hours, cooled and evaporated. The resulting residue was diluted with water and acidified to pH 6.5 with concentrated hydrochloric acid. The obtained aqueous phase was extracted twice with diethyl ether and the mixed organic phases were extracted with 5 ml of 0.25 M sodium hydroxide solution. The resulting solution was acidified to pH 6.5 with concentrated hydrochloric acid and re-extracted with diethyl ether (2x5Oml).

The mixed organic phases were washed with brine, dried over magnesium sulfate and evaporated to obtain 1.7 g of 70. prop-2-en-1-yl)|-succinate in the form of a red resin.

Mass spectrometry: 348 (MAN) 7. (ii) In a method similar to the method described in Example 1, part (i), starting with 0.52 g of carboxylic acid, which was obtained in part (i) of this Example , obtained 0.447 g of ()-2(KO-I1(K5)-(tert-butoxy-carbonyl)-4-(3-pyridyl)-3-butenyl|-4-methyl-2-phenylvalerohydrazide in the form of 75 white solid color

Mass spectrometry: 438 (MAN) 7. (m) In a method similar to the method described in Example 1, part (iii), starting with 0.44 g of (E)-2(KO-P(K5)- (tert-butoxycarbonyl)-4-(33-pyridyl)-3-butenyl|-4-methyl-2'-phenylvalerohydrazide obtained 0.51 g of 20 (E)-2(K)-P(K5)-(tert-butoxycarbonyl )-4-(3-pyridyl)-3-butenyl|-4-methyl-2-(methanesulfonyl)-2'-phenylvalerohydrazide as a white solid.

Mass spectrometry: 516 (MAN) 7. (m) In a method similar to the method described in Example 1, part (ii), starting with 0.5 Ω s 25 (E)-2(2)-P1( 0.36 g of ()-2(KO -I1(К5)-(carboxy)-4-(3-pyridyl)-3-butenyl|-4-methyl-2'-(methanesulfonyl)-2'-phenylvalerohydrazide.

Mass spectrometry: 460 (MAN) 7. (mi) Carboxylic acid, which was obtained in paragraph (m), was dissolved in 2 ml of dimethylformamide, cooled to room temperature for 30 minutes and treated successively with 0.27 g of Ge)

O-(tetrahydro-2H-pyran-2(K5)-yl)hydroxylamine and 0.16 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mentioned solvent was evaporated and the obtained residue (3) was distributed between water and ethyl acetate. The obtained ethyl acetate layer was washed with water and 595 g of sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated. The resulting pale yellow resin was mixed with diethyl ether to obtain 0.22 g ()-2(KO-I1(k)-Ctetrahydro-2(KZ)-pyranyloxy)carbamoyl1I-4-(3-pyridyl)-3-butenyl|-2'(methanesulfonyl)-4-methyl -2'-phenylvalerohydrazide in the form of a white solid substance.

Mass spectrometry: 559 (MAN) 7.

Example 65 not with 2(K)-(1(5)-(hydroxycarbamoyl)-4-(3-pyridyl)butyl-2'-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide with Solution 0.33 g of 2(KO )-I1(5)-Cbenzyloxy)carbamoyl|-4-(3-pyridyl)butyl/|-2-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide in TOml of methanol was hydrogenated in the presence of VOmg 10956 palladium-on-carbon for 1.5 hours. Catalyst 395 was removed by filtration, and the solvent was evaporated. The obtained residue was mixed with diethyl ether to obtain 0.26 g of 2(KO-I1(5)-(hydroxycarbamoyl)-4-(3-pyridyl) (o)butyl/)-2'-isobutyl-2'-(methanesulfonyl) -4-methylvalerohydrazide as a white solid. sl Mass spectrometry: 457 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes (o) 590 solvent B, followed by increasing the content of solvent B to 9595, over 15 minutes; the flow rate is another 1ml/minute. Holding time: 9.59 minutes. Solvent A: H»O/0.195 TPA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. 2(K)-I1(5)-Cbenzyloxy)carbamoyl1|-4-(3-pyridyl)butyl)-2-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide, which was used as a starting material, was obtained in the following manner: (i) Solution of 1.71 g of (E)-1,2-dibenzyl 1-tert-butyl-4-methyl-1-3-(3-pyridyl)-prop-2-en-1-yl |-1(K5), (F) 1,2(K)-pentane tricarboxylate in 35 ml of isopropanol was hydrogenated over 400 mg of 1095 palladium-on-carbon during

Gee 5 hours. The catalyst was removed by filtration, the solvent was evaporated. Residual traces of isopropanol were removed by adding and evaporating toluene (2 x 10 mL). The resulting residue was heated in a reflux flask with a refrigerator at the distillation temperature for 2 hours in a mixture of 400 ml of toluene and 0.42 ml of triethylamine, and the solvent was removed by evaporation to obtain a red oil. The mentioned oil in 10 ml of dichloromethane was cooled to a temperature of 0"C with stirring in a nitrogen atmosphere, after which 09 bml of M-ethylmorpholine, then 0.49 g of 1-hydroxybenzotriazole and 0.72 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added first. . After stirring for 15 minutes at a temperature of 07C 65, the resulting solution was treated with 0.98 g of isobutyl hydrazine intosylate salt and the resulting mixture was kept with heating to room temperature with further stirring overnight. The solvent was evaporated and the resulting residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, 595 sodium bicarbonate solution and brine, after which it was dried over anhydrous magnesium sulfate and evaporated.

By gel chromatography eluting with a mixture of dichloromethane/methanol (19:11) and subsequent evaporation of the mentioned solution, 0.6 g of 2(KO)-I1(5)-(tert-butoxycarbonyl)-4-(3-pyridyl)butyl|- 2'-isobutyl-4-methylvalerohydrazide as a white solid.

Mass spectrometry: 420 (MAN) 7. (i) In a method similar to the method described in Example 1, part (ii), starting with 70 0.62g 2(K)-(1(5)-( tert-butoxycarbonyl)-4-(3-pyridyl)butyl|-2'-isobutyl-4-methylvalerohydrazide was obtained

O,bvg 2(KO-I1(5)-(tert-butoxycarbonyl)-4-(3-pyridyl)butyl|-2"-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide as a solid.

Mass spectrometry: 498 (MAN) 7. (ii) In a method similar to the method described in Example 1, part (ii), starting with

O,bvg 2(K)-(1(5)-(tert-butoxycarbonyl)-4-(3-pyridyl)butyl|-2-isobutyl-2'(methanesulfonyl)-4-methylvalerohydrazide, 0.55 g of 2( K)-(1(5)-(carboxy)-4-(3-pyridyl)butyl/|-2-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide.

Mass spectrometry: 442 (MAN) 7. (m) Carboxylic acid, which was obtained in paragraph (iii), was dissolved in 3 ml of dimethylformamide, cooled to a temperature of 0"C and successively treated with 0.45 g of O-benzyl-hydroxylamine and 0. 26 g of 1-ethyl-3--(3-dimethylaminopropyl)ucarbodiimide hydrochloride. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mentioned solvent was evaporated and the residue obtained. CM was partitioned between water and ethyl acetate. The obtained ethyl acetate layer was washed with water and 595 solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate and evaporated. 2-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide in the form of a white solid. --

Mass spectrometry: 547 (MAN) 7. "co

Example 66 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-(4-methoxyphenyl)-3-butenyl|-2'i("methanesulfonyl)-4-methyl-2'-phenylvaler ohydrazide so

In a method similar to the method described in the first paragraph of Example 2, starting with 0.079 g of (E)-2(KO-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl1I-4-(4-methoxyphenyl)-3- butenyl|-2'(methanesulfonyl)-4-methyl-2 "-phenylvalerohydrazide, 0.041 g of ()-2(KO-(1(5)-(hydroxycarbamoyl)-4-(4-methoxyphenyl)-3-butenyl) was obtained -2'(methanesulfonyl)-4-methyl-2"-phenylvalerohyde" raside as a white solid. 70 Mass spectrometry: 504 (MAN) 7.8 s High-performance liquid chromatography: Gradient elution with solvent A, which includes "with 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/min. Retention time: 11.22 minutes. Solvent A: H2O; solvent B: SNHSM. Column type: NURECRER

ZOO ()-2(CO-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl-1N-4-(4-methoxyphenyl)-3-butenyl|-2'(methanesulfonyl)-4-methyl-yl-2'-phenylvalerohydrazide, which was used as starting material, was obtained in the following manner: (ee) In a manner similar to the method described in Example 64, parts (1)-(mi), starting with 1,2-dibenzyl and 1-tert -butyl-4-methyl-1(K5),1,2(K)-pentanetricarboxylate and 4-(4-methoxyphenyl)-allyl acetate, and the

Ge») 20 (E)-2(KO-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl-1I-4-(4-methoxyphenyl)-3-butenyl|-2'(methanesulfonyl)-4-methyl-2 ah "- phenylvalerohydrazide as an off-white solid 7 Mass spectrometry: 588 (MAN) 7.

Example 67 2(K)-(4-cyclohexyl-1(5)-(hydroxycarbamoyl)-butyl|-2-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide 55 In a method similar to the method described in the first paragraph of Example 2, starting with

HF) 0.17g 2(K)-(4-cyclohexyl-1(5)-Ktetrahydro-2(K5) 7-pyranyloxy)carbamoyl|-butyl/|-2'-isobutyl-2'(methanesulfonyl)-4- of methyl valerohydrazide, 0.11 g of 2(K)-(4-cyclohexyl-1(5)-(hydroxycarbamoyl)-butyl|-2'-isobutyl-2'(methanesulfonyl)-4-methylvalerohydrazide was obtained in the form of a white solid.

Mass spectrometry: 462 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 13.82 minutes. Solvent A: H2O; solvent B: SNZSM. Column type: NUREKRER be ZOOA. 2(К)-(4-cyclohexyl-1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl|-butyl/|-2'-isobutyl-2'-(methanesulfonyl)-

4-methylvalerohydrazide, which was used as a starting material, was obtained in the following manner: () A solution of 1.0 g of 2(K)-I1(5)-(tert-butoxycarbonyl)-4-phenyl-butyl|-4-methylvaleric acid in 30 ml of acetic acid hydrogenated over 30 mg of platinum oxide for 1.5 hours. The aforementioned catalyst was removed by filtration, and the solvent was evaporated. Residual traces of acetic acid were removed by adding and evaporating toluene (3 x 100 ml). By means of gel chromatography eluting with a mixture of diethyl ether/hexane (1:7) and subsequent evaporation, 0.7 g of 2(K)-(1(5)-(tert-butoxycarbonyl)-4-cyclohexyl-butyl|-4-methylvalerian was obtained acid as a white solid. 70 Thin-layer chromatography: methanol/dichloromethane (1:19): Retention ratio K,; - 0.51. (i) In a method similar to the method described in Example 1, part (i) ), starting with 0.bbg /2(K)-I1(5)-(tert-butoxycarbonyl)-4-cyclohexyl-butyl|-4-methylvaleric acid, obtained 0.27 g of 2(K)-(1(5 )-(tert-butoxycarbonyl)-4-(4-cyclohexyl)butyl|-2'-isobutyl-4-methylvalerohydrazide as a white solid (from hexane).

Mass spectrometry: 425 (MAN) 7. (ii) In a method similar to the method described in Example 1, part (ii), starting with 0.26 bg 2(K)-I1(5)-(tert- butoxycarbonyl)-4-(4-cyclohexyl)butyl/|-2'-isobutyl-4-methylvalerohydrazide, 0.3 g of 2(K)-(1(5)-(tert-butoxycarbonyl)-4-(4-cyclohexyl) was obtained )butyl|-2-isobutyl-2(methanesulfonyl)-4-methylvalerohydrase du.

Mass spectrometry: 503 (MAN) 7. (m) In a method similar to the method described in Example 1, part (iii), starting with

O,zOg 2(KO-(1(5)-(tert-butoxycarbonyl)-4-(4-cyclohexyl) butyl)-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide was obtained 024 se 2 (K)-I(1(5)-(carboxy)-4-(4-cyclohexyl)butyl|-2-isobutyl-2'(methanesulfonyl)-4-methylvalerohydrazide.

Mass spectrometry: 447 (MAN) "7. (m) The carboxylic acid, which was obtained in paragraph (ii), was dissolved in 3 ml of dimethylformamide, cooled to room temperature and successively treated with 0.19g

O-(tetrahydro-2H-pyran-2(K5)-yl)hydroxylamine and 0.113 g of 1-ethyl-3-(3-dimethylaminopropyl)ucarbodiimide hydrochloride. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mentioned solvent was evaporated and the resulting residue was partitioned between water and ethyl acetate. The obtained ethyl acetate layer was washed with water, 595% sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated. The resulting solid substance was mixed with diethyl ether to obtain 0.18 g

Zo 2(B)-(D-cyclohexyl-1(5)-(tetrahydro-2(5)-pyranyloxy)carbamoyl|-butyl1-2-isobutyl-2'-(methanesulfonyl)-4-me Scheo, tyvalerohydrazide in the form white solid.

Mass spectrometry: 546 (MAN) 7.

Example 68 "(E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-(4-methoxycarbonyl)phenyl)-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-f 50 enylvalerohydrazide C c In a method similar to the method described in the first paragraph of Example 2, starting with "» 0.1t1og (E)-2(K)-(1(5)-(tetrahydro-2(K5)- pyranyloxy)carbamoyl -4-(4-(methoxycarbonyl)phenyl)-3-butenyl " -2'-(methanesulfonyl)-4-methyl-2'--phenylvalerohydrazide, 0.0059g of (E)-2(KO-I1 (5)-(hydroxycarbamoyl)-4-(4-(methoxycarbonyl)phenyl)-3-butenyl|-2'(methanesulfonyl)-4-methyl-2'-phenyl valerohydrazide in the form of a white solid. -spectrometry: 532 (MAN) 7. (ee) High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes, flow rate i-th 1 ml/min. Retention time: 12.09 minutes Solvent A: H2O Solvent B: SNZSM Column type: NUREKRER

F" 70 zlotys. ... 4-Methyl-2'-phenylvalerohydrazide, which was used as the starting material, was obtained as a white solid in a manner similar to that described in Example 2 (I)-(m), substituting, however, of cinnamyl bromide in step (i) to 4-methoxycarbonyl-cinnamyl bromide. | AND

Mass spectrometry: 616 (MAN).

GF) Example 69

He ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-(4-nitrophenyl)-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-phenylvaleroic hydrazide in Solution 0.080g (E)-2(KO-I1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl-1|-4-(4-(nitrophenyl)-3-butenyl|-2'(methanesulfonyl)-4-methyl- 2'--phenylvalerohydrazide in a mixture of 3 ml of methanol and 1.5 ml of dichloromethane was treated with 0.020 g of 4-toluenesulfonic acid. The resulting mixture was stirred for 5 hours at room temperature and the resulting solution was evaporated. The resulting resin was mixed with diethyl ether to obtain 0.063 g of ()- 2(KO-I1(5)-(hydroxycarbamoyl)-4-(4-nitrophenyl)-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide in the form of a light brown solid .

Mass spectrometry: 519 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate

ml/minute. Holding time: 12.07 minutes. Solvent A: H2O; solvent B: SNUSM. Column type: NUREKRER

ZOO (E)-2(KO-I1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl|)|-4-(4-nitrophenyl)-3-butenyl|-2'(methanesulfonyl)-4-methyl- 2'"--phenylvalerohydrazide, which was used as a starting material, was obtained as a white solid in a manner similar to that described in Example 64 (1)-(mi), with the substitution, 70, however, 4- (Z-pyridyl)allyl acetate and tetrakis(triphenylphosphine)-palladium(0) in step (i) to 4-nitro-cinnamyl bromide.

Mass spectrometry: 603 (MAN) 7.

Example 70 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-Cmorpholinocarbonyl)m ethyl|valerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with b 1g (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3 -butenylI|-2'i(methanesulfonyl)-4-methyl-2-KmM orfolinocarbonyl)methyl|valerohydrazide, 0.Ovg (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3 -butenyl I|-2i(methanesulfonyl)-4-methyl-2-(morpholinocarbonyl)methyl |valerohydrazide as a white solid.

Mass spectrometry: 525 (MAN) 7.

Nuclear magnetic resonance (d5 dimethylsulfoxide): 10.52 (1H, singlet); 10.47 (1H, singlet); 8.82 (1H, singlet); 7.35-7.25 (4H, multiplet); 7.23-7.17 (1H, multiplet); 6.28 (1H, doublet, U-15.5Hz); 6.09-5.98 (1H, multiplet); 4.40-4.26 (2H, multiplet); 3.64-3.30 (8H, multiplet); 3.15 (ZN, singlet); 2.653-2.54 (1H, c multiplet); 2.37-2.08 (ZN, multiplet); 1.50-1.28 (2H, multiplet); 0.98-0.89 (1H, multiplet); 0.78 (6H, o multiplet).

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 10.19 minutes. Solvent A: H»O/0.195 TPA (tetrafluoroacetic acid); the same solvent in: SNUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER ZOO. "co

The starting material was prepared in a manner analogous to the method described in Example 15, part (iii), starting with (E)-2(KO-I1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl |-4-Phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerogen with hydrazide and M-bromoacetylmorpholine.

Mass spectrometry: 609 (MAN) 7. Fr

Example 71 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-(2-morpholinoethyl)vale rohydrazide "

In a method similar to the method described in the first paragraph of Example 2, after washing the solution of the mentioned product in ethyl acetate with the help of a solution of sodium hydrogen carbonate in order to obtain the free base C, C 0.13 g "" (E)-2(KO-I1 (5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-methanesulfonyl)-4-methyl-2'-(2-m " orpholinoethyl)valerohydrazide would be obtained 1g ( E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methyl-2-(2-morpholinoethyl) valerogen drazide in the form of a white solid. i-th Mass spectrometry: 511 (MAN) "7. (ee) High-performance liquid chromatography: Gradient elution using solvent A, which includes 590 ml of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml /minute Retention time: 10.71 minutes Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

Ge") 20 in: SNUSM/O,08595 of tetrafluoroacetic acid. Column type: NUREKRER ZOO. ah The starting material was prepared in a manner similar to that described in Example 15, part 7"(iii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(К5)-pyranyloxy )carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide and 4-(2-chloroethyl)-morpholine.

Mass spectrometry: 595 (MAN) 7.

HF) Example 72 7 Methyl (E)-2-(2-I2(KI1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methylvaleryl/-1-

Cmethanesulfonyl)hydrazino)acetate

In a method similar to the method described in the first paragraph of Example 2, starting with 60 0.12 g of methyl (E)-2-(2-I2(KU-I1(5)-Ctetrahydro-2(K5)-pyranyloxy) carbamoyl) -4-phenyl-3-butenyl|-4-methylvaleryl/|-1-(methanesulfonyl)hydrazino|acetate, obtained 0,bog methyl (E)-2-(2-I2(KYU-I1(5)- (hydroxycarbamoyl)-4-phenyl-3-butenyl|-4--methylvaleryl..- -1-Cmethanesulfonyl)hydrazino)acetate as a white solid. 65 Mass spectrometry: 470 (MAN) 7.

Nuclear magnetic resonance (d5s dimethylsulfoxide): 10.77 (1Н, singlet); 10.53 (1H, multiplet); 8.83

(IN, multiplet); 7.35-7.25 (4H, multiplet); 7.22-7.16 (IN, multiplet); 6.27 (1H, doublet, 9-15.5Hz); 6.08-5.99 (1H, multiplet); 4.41-4.17 (2H, multiplet); 3.66 (ZN, singlet); 3.14 (ZN, singlet); 2.62-2.53 (IN, multiplet); 2.35-2.07 (ZN, multiplet); 1.50-1.40 (1H, multiplet); 1.38-1.25 (1H, multiplet); 1.00-0.92 (1H, multiplet); 0.79 (6H, multiplet).

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 10.93 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. 70 The starting material was prepared in a manner analogous to that described in Example 15, part (ii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl |-4-Phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog hydrazide and methyl bromoacetate.

Mass spectrometry: 554 (MAN) 7.

Example 73 (E)-2(KO-I1(5)-hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-(3-phenylpropyl)valeroghydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.166 g of 20. -phenyl-3-butenyl|-2'-methanesulfonyl)-4-methyl-2'-(3-phenylpropyl)valerohydrazide, 0.091 g of (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4 -phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2-(3-phenylpropyl)valerohydrazide as an off-white solid.

Mass spectrometry: 516 (MAN) 7. p

High-performance liquid chromatography: Gradient elution using solvent A, which includes about 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate

Tml/minute. Retention time: 13.01 and 13.19 minutes (double peak). Solvent A: H 20/0.195 ТРА (tetrafluoroacetic acid); solvent B: SNUZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER

ZOO "-

The starting material was prepared in a manner similar to the method described in Example 15, part (ii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(К5)-pyranyloxy )carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog IS o) hydrazide and 1-bromo-3-phenylpropane. co

Mass spectrometry: 600 (MAN) 7.

Example 74 Io) ()-2(KO-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-|(2-naphthyl)methyl |vale rohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.156 g of 40. phenyl-3-butenyl|-2'-methanesulfonyl)-4-methyl-2'-|(2-nthyl)methyl|valerohydrazide, 0.109 g of (E)-2(KO-I1(5) were obtained -(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methyl-2-|((2-naphthyl)methyl|valerogy" drazide in the form of an almost white solid.

Mass spectrometry: 538 (MAN) 7.

High-performance liquid chromatography: Gradient elution using solvent A, which includes about 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate

Go) 1 ml/minute. Holding time: 13.09 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. 1 The starting material was obtained by a method similar to the method described in Example 15, part 20 (iii), starting with (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy) carbamoyl)|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-|(2-6'-naphthyl)methyl|valerohydrazide and 2-bromomethylnaphthalene.

Mass spectrometry: 622 (MAN) 7.

Example 75 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-2-(methoxyethyl)-4-methylvalerogy

Ф) drazid kyu In a method similar to the method described in the first paragraph of Example 2, starting with 0.133 g of (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)|- 4-phenyl-3-butenyl|-2'-methanesulfonyl)-4-methyl-2'-(2-methyl-ethoxyethyl)-4-methylvalerohydrazide, 0.073 g ()-2(KO-I1(5)-( hydroxycarbamoyl)-4-phenyl-3-butenyl|-2(methanesulfonyl)-2'-2-methoxyethyl)-4-methylvalerohydrazide as an off-white solid.

Mass spectrometry: 456 (MAN) 7.

High-performance liquid chromatography: Gradient elution with solvent A, which includes 65,590 of solvent B, followed by increasing the content of solvent B to 9,595 over 15 minutes; flow rate

1 ml/minute. Holding time: 10.67 minutes. Solvent A: H»O/0.1965. TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was prepared in a manner similar to that described in Example 15, part (ii), starting with (E)-2-(CO-I1(5)-Ctetrahydro-2(K5)-tranyloxy)carbamoyl|- 4-Phenyl-3-butenyl I|-2'(methanesulfonyl)-4-methylvalerogy drazide and 2-bromomethyl methyl ether.

Mass spectrometry: 540 (MAN) 7.

Example 76 70 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(2-hydroxyethyl)-2-(methanesulfonyl)-4-methylvaler hydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.148 g of (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3 -butenyl|-2-(2-hydroxyethyl)-2(methanesulfonyl)-4-methylvalerohydrazide, obtained b.041 g of (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3- butenyl|-2-(2-hydroxyethyl)-2-(methanesulfonyl)-4-methylvalerohydride as a cream-colored solid.

Mass spectrometry: 442 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 59% of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 10.06 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was prepared in a manner similar to that described in Example 15, part (ii), starting with (E)-2(K)-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl1 |-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methylvalerog o hydrazide and 2-bromomethanol.

Mass spectrometry: 526 (MAN) 7.

Example 77 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-((4-pyridyl)methyl)val - - erohydrazide p-toluenesulfonate "so

In a method similar to the method described in the first paragraph of Example 2, starting with 0.097 g of (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl -3-butenyl|-2'(methanesulfonyl)-4-methyl-2-((4 co -pyridyl)methyl|valerohydrazide, 0.077 g of (E)-2(K)-(1(5)-(hydroxycarbamoyl) was obtained p-toluenesulfonate -4-phenyl-3-butenyl-2'(methanesulfonyl)-4-methyl-2-((4-pyridyl)methyl)hydrazide as an almost white solid.

Mass spectrometry: 489 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 590% solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate ml/minute. Holding time: 9.59 minutes. Solvent A: H»O/0.195 TPA (tetrafluoroacetic acid); solvent C with B: SNUuSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZO0OA "» The starting material was obtained in a method similar to the method described in Example 15, part "(ii), starting with (E)-2(KO-I1(5)-Ktetrahydro-2( C5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvaleroic hydrazide and 4-bromomethylpyridine hydrobromide. i-th Mass spectrometry: 573 (MAN) 7. (ee) Example 78 (E)-2'(cyclopropylmethyl)-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl| -2'-(methanesulfonyl)-4-methylvalin erohydrazide

Ge") 20 In a method similar to the method described in the first paragraph of Example 2, starting with 0 13g

C (E)-2'(cyclopropylmethyl)-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl) -4-methylvalerohydrazide, obtained 0.092 g of (E)-2'(cyclopropylmethyl)-2(K)-I(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)- 4-Methylvalerog hydrazide is a white solid.

HF) Mass Spectrometry: 452 (MAN) "7.7 High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/min. Time retention: 11.47 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent B: SNUuSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was prepared in a manner analogous to the method described in Example 15, part (ii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl| -4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerogen hydrazide and cyclopropyl methyl bromide. Example 79

(E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-I2(5)-methylbutyl) valerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with b135g (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3- butenyl|-2'(methanesulfonyl)-4-methyl-2-I2(5)-methylbutyl|valerohydrazide, 0.101 g of (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3- butenyl|-2i(methanesulfonyl)-4-methyl-2-12(5)-methylbutyl|valerogi drazide in the form of a white solid. 70 Mass spectrometry: 468 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 12.70 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was prepared in a manner analogous to the method described in Example 15, part (ii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl| -4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog hydrazide and (5)-(-)-1-bromo-2-methylbutane.

Example 80 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(3-hydroxy-2(K)-methylpropyl|-2'-(methanesulfonyl) - 4-methylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0 13g (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl- 3-butenyl/|-2-(3-hydroxy-2(K)-methylpropyl|-2 Ha 285 "-(methanesulfonyl)-4-methylvalerohydrazide, 0.095 g of (E)-2(KO-I1(5)- (hydroxycarbamoyl)-4-phenyl-3-butenyl-2-3-hydroxy-2(K)-methylpropyl|-2'-(methanesulfonyl)-4-m and) ethyl valerohydrazide as a white solid.

Mass spectrometry: 470 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes -- 595 solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 10.20 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent and

In: СнзСМ/0.08596 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. IC o)

The starting material was prepared in a manner similar to that described in Example 15, part (iii), starting with (E)-2-(CO-I1(5)-tetrahydro-2(K5)-pyranyloxy)carbamoyl| -4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvaleroic hydrazide and (5)-(-)-3-bromo-2-methyl-1-propanol.

Example 81 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-3-hydroxy-2(5)-methylpropyl|-2(methanesulfonyl) « -4- methyl valerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with - with 0.13 g of (E)-2(K)-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl "from -4-phenyl-3-butenyl|-2'-I(3-hydroxy-2(5)-methylpropyl|-2("methanesulfonyl)-4-methylvalerohydrazide, 0,bog (E)-2(KO- 1(5)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-3-hydroxy-2(5)-methylpropyl|-2(methanesulfonyl)-4-methylvalerohydrazide in the form of a white solid. 1 Mass Spectrometry: 470 (M-H)". o High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 1 ml/min. Time retention: 10.11 minutes Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

FO 20 V: SNUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER ZOO.

The starting material was prepared in a manner similar to that described in Example 15, part "6(iii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(К5)-pyranyloxy) carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog hydrazide and (K)-(-)-3-bromo-2-methyl-1-propanol.

Example 82

Gee! ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-isopentyl-2'-(methanesulfonyl)-4-methylvalerohydrazide In a method similar to the method described in the first paragraph of Example 2, starting with 0.12 g of (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl|-2'- isopentyl-2'-(methanesulfonyl)-4 60 -methylvalerohydrazide, obtained 0.08 g ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2"-isopentyl-2- (methanesulfonyl)-4-methylvalerohydrazide as a white solid.

Mass spectrometry: 468 (MAN) 7.

High-performance liquid chromatography: Gradient elution using solvent A, which includes 595% of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate

1 ml/minute. Holding time: 12.63 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was prepared in a manner analogous to the method described in Example 15, part (ii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl| -4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerogen hydrazide and 1-bromo-3-methylbutane.

Example 83 (E)-2'(cyclobutylmethyl)-2(K)-((5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvaler 70 ohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0 13g (E)-2'"cyclobutylmethyl)-2(K)-(1(5)-Ctetrahydro-2(KZ)-pyranyloxy) carbamoyl1|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide, 0.075 g of 75. "E)-2-(cyclobutylmethyl)-2(K)-(1(5)- (hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerogy drazide as a white solid.

Mass spectrometry: 466 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate

ml/minute. Holding time: 12.34 minutes. Solvent A: H»O/0.195 TPA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was prepared in a manner analogous to the method described in Example 15, part (ii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl| -4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerogen of Ha hydrazide and cyclobutyl methyl bromide.

Example 84 o ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-(3-methyl-2-butenyl) )va lerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with "h- 0.222g (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoylI|-4- phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2"-(3-omethyl-2-butenyl)valerohydrazide, 0137 g of (E)-2(KO-I1(5)-(hydroxycarbamoyl )-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methyl-2'-(3-methyl-2-butenyl)valero hydrazide in the form of a white solid.

Mass spectrometry: 466 (MAN) 7. Yuyu

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 11.95 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent "

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was obtained in a method similar to the method described in Example 15, part - c (iii), starting with a (E)-2(KO-I1(5)-Ktetrahydro-2(К5)-pyranyloxy) carbamoyl I|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog,» hydrazide and 3,3-dimethylallyl bromide.

Example 85 (E)-2'-benzyl-2-(butanesulfonyl)-2(K)-11(5)-hydroxycarbamoyl-4-phenyl-3-butenyl -4-methylvalerohydrazide 1 In a method similar to the method described in the first paragraph of Example 2, starting with 0.17 g of (E)-2'-benzyl-2-(butanesulfonyl)-2(K)-I1(5 )-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl 1-4-methylvalerohydrazide, 0.115 g of 50 (E)-2'-benzyl-2'(butanesulfonyl)-2( K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methylvalerohydrazide In the form of a white solid. "6 Mass spectrometry: 530 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 22 Mml/minute. Holding time: 13.83 minutes. Solvent A: HNO/0.195. TPA (tetrafluoroacetic acid); solvent o B: SNUuSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. () In a method similar to the method described in Example 1, part (ii), starting with where 0.54g ()-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3 -butenyl|-4-methylvalerohydrazide and 1-butanesulfonyl chloride, obtained 0.425 g of 60 (E)-2'(butanesulfonyl)-2(K)-(1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl |-4-methylvalerohydrazide in the form of white foam.

Mass spectrometry: 481 (MAN) 7. (i) In a method similar to the method described in Example 15, part (ii), starting with 0.416 g of (E)-2-(butanesulfonyl)-2(K) -I(1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvalerohydrazide and bo benzyl bromide, 0.463 g of -BO0- were obtained

(E)-2'-benzyl-2-(butanesulfonyl)-2(K)-(1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl-4-methylvalerohydrazide in the form of a pale yellow resin color

Mass spectrometry: 571 (MAN) 7. (its) In a method similar to the method described in Example 1, part (iii), and with further application of the method described in Example 2, part (m), with starting with 0.46 g of (E)-2'-benzyl-2-(butanesulfonyl)-2(K)-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvalerohydrazide was obtained 0.174g (E)-2'-benzyl-2-(butanesulfonyl)-2(K)-(1(5)-Ktetrahydro-2(K5)-pyranyloxycarbonyl)-4-phenyl-3-butenyl|-4-meth 70 ml of valerohydrazide in the form of a white solid.

Mass spectrometry: 614 (MAN) "7.

Example 86 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2'-(2-methylallyl)valerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.14 g of (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl- 3-butenyl|-2'(methanesulfonyl)-4-methyl-2'-(2-methylallyl)valerohydrazide, 0.063 g of (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3 -butenyl|-2i(methanesulfonyl)-4-methyl-2'-(2-methylallyl)valerohydrase as an almost white solid.

Mass spectrometry: 452 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1Tml/minute. Holding time: 11.75 minutes. Solvent A: HNO/0.195 TPA (tetrafluoroacetic acid); solvent.i SM

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. at

The starting material was prepared in a manner analogous to the method described in Example 15, part (ii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl| -4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerogen of hydrazide and methylallyl chloride.

Example 87 "co (E)-2'-(-2-cyclohexylethyl)-2(K)-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methylva lerohydrazide Io)

In a method similar to the method described in the first paragraph of Example 2, starting with 0.183 g of (E)-2'-(2-cyclohexylethyl)-2(K)-(1(5)-Ktetrahydro-2(K5 )-pyranyloxy)carbamoyl1|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide, 0.12 g of (E)-2'-(2-cyclohexylethyl)-2(K )-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalero hydrazide as a white solid.

Mass spectrometry: 508 (MAN) 7.

High-performance liquid chromatography: Gradient elution using solvent A, which includes C with 590 solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate "» 1Tml/minute. Retention time: 13.93 minutes and 14.02 minutes (double peak). Solvent A: H 20/0.1956 ТРА " (tetrafluoroacetic acid); solvent B: SNUZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREKRER

ZOO

The starting material was prepared in a manner similar to that described in Example 15, part o(iii), starting with

Go! (E)-2(KO-(1(5)-Ktetrahydro-2(К5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide and 2-cyclohexylethyl bromide 1 Example 88

He» 20 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(2-(3-indolyl)ethylI|-2i(methanesulfonyl)-4-methylva lerohydrazide -6' In a method similar to the method described in the first paragraph of Example 2, starting with 0.128 g of (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoylI|-4- phenyl-3-butenyl/|-2'-(2-(3-indolyl)ethyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide, obtained 0.ob6Zg

HF) ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(2-(3-indolyl)ethyl|-2i(methanesulfonyl)-4-methylvalero hydrazide in the form of pale orange foam o Mass spectrometry: 541 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 60 Bor of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 12.52 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was prepared in a manner similar to that described in Example 15, part (ii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl |-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog hydrazide and 3-(2-bromomethyl)-indole.

Example 89 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methyl-2'-(33-phenylallyl) valerogen

In a manner similar to the method described in the first paragraph of Example 2, starting with

O.18g (E)-2(KO-I1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2"- (3-phenylallyl)valerohydrazide, 0.123 g were obtained 70. "E)-2(KO-11(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2(methanesulfonyl)-4-methyl-2-( Z-phenylallyl)valerohydrase occurs as a pale yellow solid.

Mass spectrometry: 514 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 75 ml/minute. Holding time: 12.69 minutes. Solvent A: H»O/0.195 TPA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was obtained in a manner similar to that described in Example 15, part (it, starting with /(E)-2(K)-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl| /-4-phenyl-3-butenyl-2'-(methanesulfonyl)-4-methylvalerohydrazide and cinnamyl bromide.

Example 90 (E)-2'-benzyl-2'-(ethanesulfonyl)-2(K)-I(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with b1g (E)-2'-benzyl-2'(ethanesulfonyl)-2(K)-(1(5)-Ctetrahydro-2(K5 )-pyranyloxy)carbamoyl1|-4-phenyl-3-butenyl|-4-meth Haylvalerohydrazide, 0.054 g of (E)-2'-benzyl-2'(ethanesulfonyl)-2(K)-I(1( 5)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methylvalerohydrazide In i9) in the form of an almost white solid.

Mass spectrometry: 502 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes -- 595 solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 12.70 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent and

In: СнзСМ/0.08596 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. IC o)

The starting material was obtained in a manner similar to the method described in Example 85, part ()-(iii), starting with (E)-2(KO)-I1(5)-(tert-butoxycarbonyl)-4 -phenyl-3-butenyl|-4-methylvalerohydrazide and ethanesulfonyl chloride. i am

Example 91 (E)-2-(2,2,2-trifluoroethanesulfonyl)-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-2'-phenylvalerohydrazide "

In a method similar to the method described in the first paragraph of Example 2, starting with 400. 0.093 g of (E)-2-(2,2,2-trifluoroethanesulfonyl) -2(К)-/1 "» (5)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-2'i-phenylvalerohydrazide in the form of an almost white solid.

Mass spectrometry: 542 (MAN) 7. 1 High-performance liquid chromatography: Gradient elution with solvent A, which includes oo 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 13.42 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent 1 V: SNUuSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. b 20 The starting material was obtained in a method similar to the method described in Example 17, part ()-(ii), starting with "6 (E)-2(KO-I1(5)-(tert-butoxycarbonyl) -4-phenyl-3-butenyl|-4-methylvalerohydrazide and 2,2,2-trifluoroethanesulfonyl chloride.

Example 92 22 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2-(3-hydroxypropyl)-2'-(methanesulfonyl)-4-methylval

Gee! erohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0191g (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoylI|-4-phenyl-3 -butenyl-2'-(3-hydroxypropyl)-2-(methanesulfonyl)-4-methylvalerohydrazide, obtained 0.119 g ()-2(KO-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl -3-butenyl/|-2'-(3-hydroxypropyl)-2i(methanesulfonyl)-4-methylvalerohydrazide as an off-white solid.

Mass spectrometry: 456 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 595% of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate

1 ml/minute. Holding time: 9.61 minutes. Solvent A: H»O/0.195 TPA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was obtained in a manner similar to that described in Example 15, part (it, starting with /(E)-2(K)-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl| /-4-phenyl-3-butenyl-2'-(methanesulfonyl)-4-methylvalerohydrazide and 3-bromo-1-propanol.

Example 93 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methyl-2'-(2-(3,4,4-trimethyl -2, 5-dioxo-1-imidazolidinyl)ethyl|valero-hydrazide 70 In a method similar to the method described in the first paragraph of Example 2, starting with 0.196 g of (E)-2(K)-I1(5) -Ctetrahydro-2(K5)-pyranyloxy)carbamoyl-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2'-(2-(3,4,4-trimethyl-2,5- dioxo-1-imidazolidinyl)ethyl|valerog hydrazide, obtained 0.094 g of (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methyl-2 -(2-(3,4,4-trimethyl-2,5-di 7/5 oxo-1-imidazolidinyl)ethyl|valerohydrazide as an almost white solid).

Mass spectrometry: 566 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 11.37 minutes. Solvent A: H»O/0.1965. TEA (tetrafluoroacetic acid); solvent

In: CH3CM/0.08590 tetrafluoroacetic acid. Column type: NUREKRER ZOO.

The starting material was prepared in a manner similar to that described in Example 15, part (iii), starting with (E)-2-(CO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoylI|- 4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylhydrase and 3-(2-bromomethyl)-1,5,5-trimethylhydantoin. Ha

Example 94 (B)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2'-(4-pentenyl)valerohyde and 9) azide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.168 g of "-"E)-2(KO-I1(5)-Ctetrahydro-2(KZ)-pyranyloxy)carbamoyl-1-4-phenyl- 3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-(4-pentenyl)valerohydrazide, 01o5g of (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl- 3-butenyl|-2(methanesulfonyl)-4-methyl-2'-(4-pentenyl)valerohydrase is available as a white solid.

Mass spectrometry: 466 (MAN) 7. so

High-performance liquid chromatography: Gradient elution using solvent A, which includes 590 ml of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 12.31 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. "

The starting material was obtained in a method similar to the method described in Example 15, part (ii), Kk) starting with - c (E)-2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy )carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide and 5-bromo-1-pentene. ,» Example 95 (E)-2-(3-butenyl)- 2(K)-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-valerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 1 0.137 g of (E)-2-(3-butenyl)-2(K)-(1(5)-Ktetrahydro-2(K5 )-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-valerohydrazide, 0.081 g of 1 (E)-2-(3-butenyl)-2(K)-( 1(5)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i("methanesulfonyl)-4-valerohydrazide" in the form of a white solid.

Mass Spectrometry: 452 (MAN) 7. "6 High Performance Liquid Chromatography: Gradient elution with solvent A containing 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1ml/min. Retention time: 11.80 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); Solvent 25 B: CH3SM/0.08590 tetrafluoroacetic acid. Column type: NUREKRER ZOOA.

Gee! The starting material was prepared in a manner similar to that described in Example 15, part (iii), starting with where -4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog hydrazide and 4-bromo-1-butene. bo Example 96 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2-propylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.211 g of (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoylI|-4-phenyl-3 -butenyl|-2'-(methanesulfonyl)-4-methyl-2-pro b5 pilvalerohydrazide, 0.129 g ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i were obtained (methanesulfonyl)-4-methyl-2'--propylvalerohydrazide.- In the form of a white solid.

Mass spectrometry: 440 (MAN) 7.

High-performance liquid chromatography: Gradient elution using solvent A, which includes

From solvent B, followed by increasing the content of solvent B to 9595 for 15 minutes; flow rate 1 ml/minute. Holding time: 9.77 minutes. Solvent A: H»O/0.195. TPA (tetrafluoroacetic acid); solvent

In: SNUSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO.

The starting material was prepared in a manner similar to that described in Example 15, part (iii), starting from 70. carbamoyl|-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvaleroge hydrazide and 1-bromopropane.

Example 97 (E)-2'-butyl-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.181 g of (E)-2'-butyl-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl |-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerohydrazide, 0.129 g of (E)-2'-butyl-2(K)-(1(5)-(hydroxycarbamoyl)-4 -phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerohydrazide.- In the form of a white solid substance.

Mass spectrometry: 454 (MAN) "7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 12.12 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. with

The starting material was prepared in a manner similar to that described in Example 15, part o(iii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl |-4-Phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvaleroge hydrazide and 1-bromobutane.

Example 98 h (E)-2-(2-aminoethyl)-2(K)-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerogydrazid p -toluenesulfonate and

In a method similar to the method described in the first paragraph of Example 2, starting with IS o) b 1g (E)-2-(2-aminoethyl)-2(K)-(1(5)-Ktetrahydro-2( (KZ)-pyranyloxy)carbamoyl 1|-4-phenyl-3-butenyl|-2'(methanesulfonyl salt)-4-methylvalerohydrazide, obtained O8bg (E)-2-(2-aminoethyl)-2(K)-(1 (5)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide p-toluenesulfonate as an off-white solid.

Mass spectrometry: 441 (MAN) "7. "

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 59% of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate t s 1 ml/minute. Holding time: 9.58 minutes. Solvent A: H2O0/0.195. TPA (tetrafluoroacetic acid); solvent h B: SNUuSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. -» The starting material was obtained in the following way:

Suspension 0.926 g of (E)-2(K)-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2' -(2-1 phthalimidoethyl)valerohydrazide in 1 ml of methanol was treated with 0.25 ml of hydrazine hydrate. The resulting mixture was stirred at room temperature overnight. The suspended white solid was filtered off, the resulting filtrate was concentrated, the resulting residue was purified by means of 1 gel chromatography, eluting with a mixture of 595 methanol in dichloromethane. 0.23 g of b 50 (E)-2-(2-aminoethyl)-2(K)-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl| -2'-methanesulfonyl)-4-methylvalerohydrazide as a white solid after mixing the mentioned product with -6 ether. Mass spectrometry: 525 (MAN).

Example 99 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methyl-2'-(2-(1-pyrrolyl)ethyl) 22 Chlorohydrazide

HF) In a method similar to the method described in the first paragraph of Example 2, starting with 0.163 g of (E)-2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-4 -phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2"-(2-(1-pyrrolyl)ethyl|valerohydrazide, 0.041g of 60 (E)-2(2)-(1( 5)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-(2-(1-pyrrolyl)lethyl|valero hydrazide) as an off-white solid.

Mass spectrometry: 491 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; the flow rate is 1 ml/minute. Holding time: 12.05 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent -B4-

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was prepared in a manner analogous to the method described in Example 15, part (ii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl| -4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog hydrazide and 1-(2-bromomethyl)-pyrrole.

Example 100 (E)-2'-I2-(1,3-dioxolan-2-yl)ethylI|-2(K)-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2 '-(methanesulfonyl)-4-methylvalerohydrazide 70 In a method similar to the method described in the first paragraph of Example 2, starting with 0.145 g of (E)-2'-(2-(1,3-dioxolan-2-yl) )ethylI|-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl)-2-(methanesulfonyl)-4-methylvalerohydrazide, 0.06b7g were obtained (E)-2'-(2-(1,3-dioxolan-2-yl)ethyl I|-2(K)-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2' -(methanesulfonyl)-4-me/5 tyvalerohydrazide as a pale orange solid.

Mass spectrometry: 498 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 10.63 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: CH3CM/0.08590 tetrafluoroacetic acid. Column type: NUREKRER ZOO.

The starting material was prepared in a manner analogous to the method described in Example 15, part (ii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl| -4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvaleroghydrazide and 2-(2-bromomethyl)-1,3-dioxolane.

Example 101 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(4-methoxybenzenesulfonyl)-4-methylvalerohydrazide i9)

In a method similar to the method described in the first paragraph of Example 2, starting with 0 19g (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl- 3-butenyl|-2'-(4-methoxybenzenesulfonyl)-4-methylvalerohydrazide, 0.115 g of (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl| -2'-(4-methoxybenzenesulfonyl)-4-methylvalerohydrazide.- In the form of a white solid substance.

Mass spectrometry: 490 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 59% solvent B, followed by increasing the content of solvent B to 95956 over 15 minutes; flow rate M) 1ml/minute. Holding time: 11.53 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was obtained in the following way: « () In a way similar to the method described in Example 1, part (ii), from 0.54 g of 40. (E)-2(K)-(1(5) -(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvalerohydrazide and - with 4-methoxybenzenesulfonyl chloride yielded 0.492 g of (E)-2(K)-a (1(5)-(tert-butoxycarbonyl)- 4-phenyl-3-butenyl|-2'-(4-methoxybenzenesulfonyl)-4-methylvalerohydrazide in the form of a white solid.

Mass spectrometry: 531 (MAN) 7. (i) In a method similar to the method described in Example 1, part (iii), and further using the method described in Example 2, part (m), from 0.482g of (E)-2(KO-(1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-2'-(4-methoxybenzenesulfonyl)-4-methylvalerohydrazide), 0.194g were obtained 1 (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)-4-phenyl-3-butenyl|-2'(4-methoxybenzenesulfonyl)-4-m b 50 ethylvalerohydrazide in the form white solid.

Mass spectrometry: 574 (MAN) "7. -Z Example 102 (E,E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-2"- phenyl-2-((2-phenylvinyl)usulfonyl|valer hydrazide 59 In a method similar to the method described in the first paragraph of Example 2, starting with

HF) 0.245 g (E,E)-2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl-1I-4-phenyl-3-butenyl|-4-methyl-2"-phenyl-2 -((2-phenylvinyl)usulfonyl|valerohydrazide, 0.086 g of (E,E)-2(KO-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl- 2"-phenyl-2-((2-phenylvinyl)usulfonyl|valerohyde 60) is a white solid.

Mass spectrometry: 562 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 13.94 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent bo V. SNUSM/O,08595 of tetrafluoroacetic acid. Column type: NUREKRER ZOO.

The starting material was obtained in a manner similar to the method described in Example 1, parts (i) and (its), and with further application of the method described in Example 2, part (x), with ()-2( KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methyl-2'-phenylhydrazide and trans-beta-styrenesulfonyl chloride.

Example 103 (E)-2'-furfural-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerohydrase d

In a manner similar to the method described in the first paragraph of Example 2, starting with 7/0. 0071 (E)-2'-furfural-2(K)-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4- methyl valerohydrazide, 0.042 g of (E)-2'-furfural-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerohydrazide was obtained in the form of a solid white substances.

Mass spectrometry: 478 (MAN) 7.

High-performance liquid chromatography: Isocratic elution using a 5095 mixture of CH with CM/water; flow rate TIml/minute. Holding time: 3.82 minutes. Type of column: U/a company (eg zuteiygu, 1Osm, St, inner diameter 0.46bsm.

The starting material was prepared in a manner similar to that described in Example 45, parts 2o (i) and (ii), starting with ()-2(CO-I1(5)-(tert-butoxycarbonyl)-4- of phenyl-3-butenyl|-4-methylvalerohydrazide and 4-furaldehyde.

Example 104 (E)-2'-ethyl-2(K)-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.136 g of (E)-2'-ethyl-2(K)-I/1(5)-tetrahydro-2(K5)-pyranyloxy )carbamoyl-1I-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylv i9) allerohydrazide, 0.087 g of (E)-2'-ethyl-2(K)-I1(5)-(hydroxycarbamoyl) was obtained -4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerohydrazide as a white solid. "h-

Mass spectrometry: 426 (MAN) 7.

High-performance liquid chromatography: Gradient elution using solvent A, which includes 2095 of solvent B, followed by increasing the content of solvent B to 8095, over 15 minutes; IC speed c) flow TIml/minute. Holding time: 14.12 minutes. Solvent A: 10095 0.05M triethylammonium phosphate buffer, pH 2.5 (triethylammonium phosphate); solvent B: 80956 СН3СМ/triethylammonium phosphate (TEAR); Column type: company co

MMaiegz zutteigu, 10cm, inner diameter 0.46bsm. i am

The starting material was prepared in a manner analogous to the method described in Example 15, part (ii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl| -4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog « hydrazide and ethyl iodide.

Example 105 - with (E)-2'-(2,6-dichlorobenzyl)-2(K)-((5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4- methylvale a rohydrazide "» In a method similar to the method described in the first paragraph of Example 2, starting with 0,bog (E)-2'-(2,6-dichlorobenzyl)-2(K)-I1(5) -Ctetrahydro-2(K5)-pyranyloxycarbamoyl-1|-4-phenyl-3-butenyl|-2'-(methanesul-1-phenyl)-4-methylvalerohydrazide, 0.05g of (E)-2-(2,6-dichlorobenzyl) was obtained )-2(К)-(5)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerogy drazide in the form of a white solid. o Mass spectrometry: 556/558 (MAN) 7. b 20 High-performance liquid chromatography: Gradient elution using solvent A, which includes

C090 solvent B, with a subsequent increase in the content of solvent B to 9595, for 7 minutes; flow rate - With 1 ml/minute. Holding time: 7.30 minutes. Solvent A: H 20/0.195 trifluoroacetic acid; solvent B:

SNUSM/O,195 trifluoroacetic acid; Column type: NUREXY 005.

The starting material was prepared in a manner similar to that described in Example 15, part 29(iii), starting with

Gee! (E)-2(KO-(1(5)-Ktetrahydro-2(К5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog hydrazide and 2,6 Example 106 (E)-2''cyclopentylmethyl)-2(K)-(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvale 60 rohydrazide

In a manner similar to the method described in the first paragraph of Example 2, starting with

O,O4g (E)-2'(cyclopentylmethyl)-2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxycarbamoyl|-4-phenyl-3-butenyl|-2-(methanesulfonyl)- 4-methylvalerohydrazide, 0.041 g of 65 (E)-2''Ecyclopentylmethyl)-2(K)-(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerohydrazide were obtained in the form of a white solid. -58c-

Mass spectrometry: 480 (MAN) 7.

High-performance liquid chromatography: Isocratic elution using a 60905 mixture of SNZZSM/TEAR; flow rate TIml/minute. Holding time: 3.25 minutes. Type of column: U/a company (ex.

The inner diameter is 0.46 bcm.

The starting material was prepared in a manner similar to that described in Example 15, part (ii), starting with (E)-2(KO-I1(5)-Ctetrahydro-2(KB)-pyranyloxy)carbamoyl1|- 4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide and cyclopentylmethylmethanesulfonate. 70 Example 107 2(K)-(2-(2-benzofuranyl)-1(5)-(hydroxycarbamoyl)ethyl-2'-isobutyl-2-(methanesulfonyl)-4-methylhydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.06 bg of 2(K)-(2-(2-benzofuranyl)-1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl |ethyl|)-2'-isobutyl-2'-(methanesulfonyl)-4 75 -methylvalerohydrazide, obtained 0.015 g of 2(K)-(2-(2-benzofuranyl)-1(5)-(hydroxycarbamoyl)ethyl/| -2-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide as a white solid.

Mass spectrometry: 468 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 59% of solvent B, followed by increasing the content of solvent B to 9895 over 15 minutes; flow rate 1 ml/minute. Holding time: 12.34 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was obtained in the following manner: () 1.14 g of 6095 sodium hydride was added to a stirred solution of 12.35 g of 1,2-dibenzyl 1-tert-butyl CM 4-methyl-1,1,4(K)-pentanetricarboxylate in 150 ml of dry dimethyl formate, which had the melting temperature of ice, in a nitrogen atmosphere. The resulting mixture was stirred at the melting temperature of ice for 30 minutes and additionally at room temperature for 1.5 hours. The mentioned mixture was again cooled to the melting temperature of ice before adding 5.78 g of 2-bromomethylbenzofuran. The resulting mixture was kept with slow heating to room temperature and stirring overnight. After that, the mentioned solution was evaporated and the obtained residue was partitioned between ethyl acetate and 595 citric acid solution.

The ethyl acetate solution was washed with water, saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The mentioned solvent was evaporated and the resulting residue was purified by gel chromatography IV) under vacuum eluting with a mixture of hexane/ether (9:11). 14.64 g of 1,2-dibenzyl 1-tert-butyl-1-(2-benzofuranyl)methyl-4-methyl-1,1,4(K)-pentanetricarboxylate was obtained in the form of a colorless oil. so (ii) 14, 64 g of 1,2-dibenzyl-1-tert-butyl-1-(2-benzofuranyl)methyl-4-methyl-1,1,2(K)-pentanetricarboxylate MU was distilled into 15 ml of ethanol and a solution was added 9.8 g of sodium hydroxide in 55 ml of water. The resulting mixture was heated in a reflux flask at the distillation temperature for 24 hours, cooled and the mentioned solvents were evaporated. The obtained residue was dissolved in 400 ml of water and the pH was adjusted to level C by adding a 4M sulfuric acid solution. The obtained aqueous solution was extracted with 400 ml of ethyl acetate, the obtained extract was successively washed with water and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was dissolved in 150 ml of toluene, which included 3.8 ml of triethylamine. The resulting mixture was heated in a reflux flask at the temperature of distillation for 2 hours, cooled and successively washed with 595% citric acid solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mentioned solvent was evaporated and the resulting residue was dissolved in 50 ml of hexane and treated with 2.43 g of cyclohexane. The resulting mixture 1 was stored in the refrigerator for 2 hours; the white solid that formed was filtered off with sodium chloride and washed with hexane. The mentioned solid was suspended in 150 ml of ethyl acetate and shaken with two

BOml portions of 2M sulfuric acid. The obtained ethyl acetate solution was successively washed with water and 1 saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. 50 C.701 g of 4-tert-butyl hydrogen 3(5)-(2-benzofuranyl)methyl-2(K)-isobutyl succinate would be obtained in the form of a pale yellow resin. -. and (its) In a method similar to the method described in Example 15, part (1)-(ii), with 3(5)-(2-benzofuranyl)methyl-2(K) starting from 4-tert-butyl hydrogen )-isobutylsuccinate, and with the use of 1-bromo-2-methanepropane in part (iii), obtained 0 2(К)-(2-(2-benzofuranyl)-1(5)-Ctetrahydro-2(К5)-pyranyloxy) carbamoyl ethyl/|-2-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide as a white solid. about M to her; as-spectrometry: 552 (MAN). ko Example 108 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methyl-2-((3-tridyl)methyl)|vale 60 rohydrazide methanesulfonate

In a method similar to the method described in the first paragraph of Example 2, using, however, methanesulfonic acid instead of p-toluenesulfonic acid, starting with 0.2 g of (E)-2(KO-(1(5)-Ktetrahydro- 2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-|((Z -pyridyl)methyl|valerohydrazide, 0.177 g 65 (E) were obtained -2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-|((3-tridyl)methylivalerogy drazide methanesulfonate solid orange color

Mass spectrometry: 489 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate

ml/minute. Holding time: 8.05 minutes. Solvent A: H2O/0.195. TPA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was prepared in a manner analogous to the method described in Example 15, part (ii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl| -4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerog 70 of hydrazide and 3-bromomethylpyridine hydrobromide.

Example 109 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2-I(2-tridyl)ethyl|valero hydrazide methanesulfonate

In a method similar to the method described in the first paragraph of Example 2, using, however, methanesulfonic acid instead of p-toluenesulfonic acid, starting with 0.176 g of (E)-2(KO-I1(5)-Ktetrahydro-2 (K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-(2-pyridyl)ethyl|valerohydrazide, 0.13 g of (E)-2 was obtained (KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2-(2-tridyl)ethyl|valerohydrazide methanesulfonate as a pale orange solid color

Mass spectrometry: 503 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 9.97 minutes. Solvent A: H»O/0.195. TPA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. with

The starting material was prepared in a manner similar to that described in Example 15, part o(iii), starting with (E)-2(KO-(1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl |-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerogen of hydrazide and 2-(2-bromomethyl)pyridine hydrobromide.

Example 110 h ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-(2-(4-pyridyl)ethyl |va lerohydrazide methanesulfonate i-o

In a method similar to the method described in the first paragraph of Example 2, with the use of IC o) but methanesulfonic acid instead of p-toluenesulfonic acid, starting with 0.146 g of (E)-2(KO-(1(5)- Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2"-(2- co (4-pyridyl)ethyl|valerohydrazide, 0104g were obtained (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-(2-(4-pyridyl)ethyl| valero hydrazide methanesulfonate as a pale orange solid.

Mass spectrometry: 503 (MAN) 7. «

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 59% of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate t s 1 ml/minute. Holding time: 9.74 minutes. Solvent A: H»2O/0.195. TPA (tetrafluoroacetic acid); solvent h B: SNUuSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. -» The starting material was obtained in a manner similar to that described in Example 15, part (ii), starting with (E)-2(K)-I1(5)-Ctetrahydro-2(K5)-pyranyloxy) carbamoyl|-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerog 1 hydrazide and 4-(2-bromomethyl)pyridine hydrobromide. o Example 111 2(K)-(3-cyclohexylidene-1(5)-(hydroxycarbamoyl)propyl|-2"-isobutyl-2-(methanesulfonyl)-4-methylvalerohydra 1 zide b 20 In a method similar to the method described given in the first paragraph of Example 2, with 0.085 g of 2(K)-(3-cyclohexylidene-1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|propyl|-2'-isobutyl-2'-(methanesulfonyl) - "6 4-methylvalerohydrazide obtained 0.042 g of 2(K)-IZ-cyclohexylidene-1(5)-(hydroxycarbamoyl)propyl/|-2'-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide in the form of a white solid .

Mass Spectrometry: 446 (MAN) 7. 59 High Performance Liquid Chromatography: Gradient Elution with Solvent A, which includes

HF) 590 to solvent B, with a subsequent increase in the content of solvent B to 9595 within 15 minutes; flow rate 1 ml/minute. Holding time: 12.20 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent o B: SNUuSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was obtained in the following manner: 6o () In a manner similar to that described in Example 107, parts (i) and (ii), except that the product mentioned was purified by gel chromatography under vacuum with elution with a mixture of hexane/ether (4:1) instead of crystallization of the cyclohexylamine salt, starting from 1,2-dibenzyl 1-tert-butyl-4-methyl-1,1,4(K)-pentanetricarboxylate and (2-bromomethylidene)ucyclohexane was obtained 4-tert-butyl hydrogen 3(5)-((2-cyclohexylidene)ethyl I|-2(K)-isobutyl succinate in the form of a pale yellow resin. for Mass spectrometry: 339 (MAN) 7.

(i) In a method similar to the method described in Example 2, part (ii)-(m), starting with 4-tert-butyl hydrogen /3(5)-(2-cyclohexylidene)ethyl|-2 (K)-isobutylsuccinate and isobutylhydrazine, and using trimethylsilyl trifluoromethanesulfonate in 1,4-dioxane instead of trifluoroacetic acid to remove the protective group from the tertiary butyl ether, 2(K)-IZ-cyclohexylidene-1(5)-(tetrahydro-2( K5)-pyranyloxy)carbamoyl|propyl)-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide as a yellow solid.

Mass spectrometry: 530 (MAN) 7.

Example 112 70 2(K)-(3-(tetrahydro-2H-pyran-4-ylidene)-1(5)-(hydroxycarbamoyl)propyl|-2'-isobutyl-2'-(methanesulfonyl)-4-m ethylvalerohydrazide

In a manner similar to the method described in the first paragraph of Example 2, starting with 0,bog 2(K)-IZ-(tetrahydro-2H-pyran-4-ylidene)-1(5)-Ktetrahydro-2(K5 )-pyranyloxy)carbamoyl|propyl|-2-isobutyl-2-(m 75 ethanesulfonyl)-4-methylvalerohydrazide, obtained 0.046 bg of 2(K)-I(3-(tetrahydro-2H-pyran-4-ylidene)-1 (5)-(Hydroxycarbamoyl)propyl)|-2'-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide as a white solid.

Mass spectrometry: 448 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 59% of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 10.22 minutes. Solvent A: HNO/0.1 95 TPA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was prepared as follows: () In a manner similar to that described in Example 107, parts (i) and (ii), except that said product was purified by gel chromatography under vacuum eluting with with a mixture of hexane/ether (4:1) instead of crystallization of the cyclohexylamine salt, starting with 1,2-dibenzyl 1-tert-butyl 4-methyl-1,1,2-24(K)-pentanetricarboxylate and 4-(2- bromomethylidene)tetrahydro-2H-pyran obtained 4-tert-butyl hydrogen C3(5)-Ktetrahydro-2H-pyran-4-ylidene)ethyl I|-2(K)-isobutylsuccinate in the form of a pale yellow resin. "-

Mass spectrometry: 341 (MAN) 7. "so (i) In a method similar to the method described in Example 2, parts (ii)-(m), starting with 4-tert-butyl hydrogen 3(5) -(tetrahydro-2H-pyran-4-ylidene)ethyl I|-2(K)-isobutyl succinate and I) isobutylhydrazine, and using trimethylsilyltrifluoromethanesulfonate in 1,4-dioxane instead of trifluoroacetic acid to remove the protective group from tertiary butyl ether, obtained 2(K)-3-(tetrahydro-2H-pyran-4-ylidene)-1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|propyl|-2'-isobutyl-2'-me Is)tansulfonyl )-4-methylvalerohydrazide as an almost white solid.

Mass spectrometry: 532 (MAN) 7.

Example 113 "2(K)-(3-(tetrahydro-2H-pyran-4-yl)-1(5)-(hydroxycarbamoyl)propyl|-2'-isobutyl-2'-methanesulfonyl)-4-methylvalerohydrazide o) c In a method similar to the method described in the first paragraph of Example 2, starting with "» 0.14 g " 2(K)-I3-(tetrahydro-2H-pyran-4-yl)-1(5) -Ktetrahydro-2(K5)-(pyranyloxy)carbamoyl|propyl|-2-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide, 0.083 g of 2(B)-I(3-(tetrahydro-2H-pyran) were obtained -4-yl)-1(5)-(hydroxycarbamoyl)propyl/-2-isobutyl-2'-methanesulfonyl)-4-methylvaler ohydrazide as an off-white solid. (ee) Mass spectrometry: 450 (MAN) 7.

High-performance liquid chromatography: Gradient elution using solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate

Ge") 250 1ml/minute. Holding time: 10.15 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent x B: SNUuSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. The starting material was obtained in the following way: () Solution of 0.397 g of 4-tert-butyl hydrogen 3(5)-((tetrahydro-2H-pyran-4-ylidene)ethyl|-2(K)-isobutylsuccinate. in 1Oml of methanol was shaken under an atmosphere of hydrogen in the presence of 0.196 g of catalyst, 1095 palladium on charcoal 29, until no additional absorption of hydrogen was observed.

HF) the resulting filtrate was evaporated. 0.331 g of 4-tert-butyl hydrogen ky 3(5)-Ktetrahydro-2H-pyran-4-yl)ethyl)|-2(K)-isobutyl succinate was obtained in the form of a colorless resin.

Mass spectrometry: 343 (MAN) 7. (i) In a method similar to the method described in Example 2, parts (ii)-(m), starting with 4-tert-butyl hydrogen C3(K)- (tetrahydro-2H-pyran-4-yl)ethyl|-2(K)-isobutylsuccinate and isobutylhydrazine, 2(K)-(3-(tetrahydro-2H-pyran-4-yl)-1(5)-Ktetrahydro -2(K5)-pyranyloxy)carbamoyl|propyl/|-2-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide as a white solid. 65 Mass spectrometry: 534 (MAN) 7.

Example 114

2(K)-3-cyclohexyl-1(5)-(hydroxycarbamoyl)propyl|-2'-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide

In a manner similar to the method described in the first paragraph of Example 2, starting with 0.145g. 2(K)-(3-cyclohexyl-1(5)-((tetrahydro-2(K) 5"pyranyloxy)carbamoyl|propyl)-2-isobutyl-2(methanesulfonyl)-4-methylvalerohydrazide, 0.093g of 2( K)-3-cyclohexyl-1(5)-(hydroxycarbamoyl)propyl)|-2-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide.- In the form of a white solid.

Mass spectrometry: 448 (MAN) 7.

High-performance liquid chromatography: Gradient elution using solvent A, which includes 70.59% of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 12.82 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was prepared in a manner similar to that described in Example 113, parts (i) and (ii), starting from 4-tert-butyl hydrogen 3(5)-(2-cyclohexylidene)ethyl-2(K )-isobutyl succinate.

Example 115 2(KO-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butynyl/|-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.189 g of 2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl1|-4-phenyl-3-butynyl|- 2-isobutyl-2-(methanesulfonyl)-4-methyl 2-valerohydrazide, obtained 0.098 g of 2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butynyl|-2'-isobutyl-2-(methanesulfonyl )-4-methylvalerohydrazide In the form of a white solid.

Mass spectrometry: 452 (MAN) 7.

High-performance liquid chromatography: Gradient elution with solvent A, which includes 59 c of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate by 1 ml/minute. Holding time: 12.42 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was obtained in the following manner: () In a manner similar to the method described in Example 107, parts (ii) and (ii), with --

2(K)-(1( 5)-tert-butoxycarbonyl)-4-phenyl-3-butynyl-4-methylvaleric acid as a pale yellow solid. IS o) (i) In a method similar to the method described in Example 2, parts (ii)-(m), with starting from 2(K)-I1(5)-(tert-butoxycarbonyl)-4-phenyl -3-butynyl)-4-methylvaleric acid and isobutylhydrazine, 2(К)-(1(5)-Ktetrahydro-2(К5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butynyl)|- 2'-isobutyl-2'(methanesulfonyl)-4-methyl valerohydrazide is a white solid.

Mass spectrometry: 536 (MAN) 7.

Example 116 2(K)-(1(5)-(Hydroxycarbamoyl)-3-phenoxypropyl)-2"-isobutyl-2'(methanesulfonyl)-4-methylvalerohydrazide t c In a method similar to the method described in the first paragraph Example 2, starting with h 023g » 2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-33-phenoxypropyl|-2-isobutyl-2-(methanesulfonyl)-4-methyl of allerohydrazide, 0.143 g of 2(K)-I1(5)-(hydroxycarbamoyl)-3-phenoxypropyl|)|-2'-isobutyl-2'(methanesulfonyl)-4-methylvalerohydrazide was obtained in the form of a cream-white solid.

Go! Mass spectrometry: 458 (MAN) 7.

High-performance liquid chromatography: Gradient elution using solvent A, which includes about 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate

F 20 1ml/minute. Holding time: 11.89 minutes. Solvent A: H»2O/0.195 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. -C The starting material was obtained in the following manner: () In a manner similar to that described in Example 107, parts (i) and (iii), except that the product mentioned was purified by gel chromatography under vacuum with elution of 22 with a mixture of hexane/ether (4:1) instead of crystallization of the cyclohexylamine salt, starting with 1,2-dibenzyl

HF) 1-tert-butyl 4-methyl-1,1,4(K)-pentanetricarboxylate and (2-iodethoxy)benzene gave 4-tert-butyl hydrogen 3(5)-(2-phenoxy)ethyl-2(K )-isobutyl succinate in the form of pale yellow oil. o Mass spectrometry: 351 (MAN) 7. (i) In a method similar to the method described in Example 2, parts (ii)-(m), starting with 4-tert-butyl hydrogen 3(5) -(2-phenoxy)ethyl-2(K)-isobutylsuccinate and isobutylhydrazine, 2(K)-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-3Z-phenoxypropyl|-2-isobutyl- 2-(methanesulfonyl)-4-methylvalerohydrazide is a white solid.

Mass spectrometry: 542 (MAN) "7. for Example 117

()-2(KO-K5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-|(3-methyl-3-oxetanyl) methyl|valerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with bug butenyl|-2-(methanesulfonyl)-4-methyl-2'-((3-methyl-3-oxetanyl)methylvalerohydrazide, 0.22 g of (E)-2(KO-5)-(hydroxycarbamoyl)-4-phenyl was obtained -3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-(3-methyl-3-oxetanyl)methyl valerohydrazide as a white solid. 70 Mass spectrometry: 482 (MAN) "7 .

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 10.76 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was prepared in a manner similar to that described in Example 45, parts (i) and (iii), starting with (E)-2-(CO-I1(5)-tert-butoxycarbonyl)-4-phenyl -3-butenyl|-4-methylvalerohydrazide and

C-methyl-3-oxetanecarboxaldehyde.

Example 118 2(KO-(1(5)-(hydroxycarbamoyl)-3-butenyl|-2'(methanesulfonyl)-4-methyl-2"--phenylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.58 g of 2(K)-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-3-butenyl|-2i (methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide, obtained 041 s 2(K)-I1(5)-(hydroxycarbamoyl)-3-butenyl|-2'(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide in the form of a white solid substance.

Mass spectrometry: 398 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; the flow rate is the same

mml/minute. Holding time: 9.97 minutes. Solvent A: H»O/0.195. TPA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. i-o 2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-3-butenyl|-2i(methanesulfonyl)-4-methyl-2-phenylvalerog IS o) hydrazide, which was used as a starting material, was obtained in the following way:

In a method similar to the method described in Example 1, part (i), and Example 2, part 09 (ii)-(m), starting with 2(K)-I1(5)-(tert-butoxycarbonyl) -3-butenyl-4-methylvaleric acid, 2(K)-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-3-butenyl|-2i(methanesulfonyl)-4-methyl-2 '-phenylvalerohydrazide as a white solid. "

Mass spectrometry: 482 (MAN) 7.

Example 119 - c 2(K)-(1(5)-(hydroxycarbamoyl)-butyl|-2'(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide h In a method similar to the method described in the first paragraph of the Example 65, starting with » 0,BOg 2(K)-(I1(5)-Cbenzyloxy)carbamoyl|-butyl|-2(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide, obtained

O,Zbg 0 2(K)-(1(5)-(hydroxycarbamoyl)-butyl|-2'(methanesulfonyl)-4-methyl-2-phenylvalerohydrazide in the form of a white solid substance. o Mass spectrometry: 400 (MAN ) 7.

Go! High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate by 1 ml/minute. Holding time: 10.14 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

Ф 250 V: SNZUSM/0.08595 tetrafluoroacetic acid. Column type: NUREERER ZOOA. 2(K)-(1(5)-Cbenzyloxy)carbamoyl-butyl|-2-(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide, which was used as starting material, was obtained in the following manner: () A solution of 3.0 g of 2(K)-(1(5)-tert-butoxycarbonyl)-3-butenyl|-4-methylvaleric acid in 30 mL of ethanol was hydrogenated in the presence of 0.3 g of 596 palladium-on-carbon for 4 hours. The catalyst was removed by 2595 filtration, the solvent was evaporated. The obtained residue was dissolved in 30 ml of toluene and the solvent again

HF) was evaporated. By repeating the mentioned procedure, 2.83 g of 2(K)-(1(5)-tert-butoxycarbonyl)-butyl|-4-methyl-valeric acid was obtained in the form of a colorless oil. where (i) In a method similar to the method described in Example 1, part (ii), and Example 65, part ()-(im), starting with /2(K)-(1(5)-(third) -butoxycarbonyl)-butyl|-4-methyl-valeric acid, 60 obtained 2(K)-(1(5)-Kbenzyloxy)carbamoyl|-butyl|-2-(methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide in in the form of a white solid substance.

Mass spectrometry: 490 (MAN) 7.

Example 120 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-M-phthalimidovaleramide b In a method similar to the method described in the first paragraph of Example 45 , starting with

0.126g of (E)-2(K)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-4-methyl-M-phthalimidovaleramide, 0.034g of (E)-2(K )-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-M-phthalimidovaleramide as a white solid.

Mass spectrometry: 450 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 12.00 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. 70 (E)-2(CO-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl1|-4-phenyl-3-butenyl|-4-methyl-M-phthalimidovaleramide, which was used as starting material, was obtained in the following method: () Solution of 1.0 g of (E)-2(K)-(1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvalerohydrazide and 0.41 g of phthalic anhydride in 5 Oml of toluene heated in a reflux flask at the distillation temperature for 2 hours. The resulting mixture was cooled, the solvent was evaporated and replaced with ethyl acetate. 75 The resulting ethyl acetate solution was washed with 2M aqueous hydrochloric acid, 596 aqueous sodium bicarbonate, then brine. The resulting ethyl acetate phase was dried over anhydrous magnesium sulfate and the solvent was evaporated.The resulting residue was mixed with diethyl ether to give

O,bOg 0 (E)-2(K)-(1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methyl-M-phthalimidovaleramide as a white solid.

Mass spectrometry: 443 (MAN) 7. (i) In a method similar to the method described in Example 2, parts (im) and (m), starting with Kk! 0.44g of (E)-2(KO-I1(5)-(tertbutoxycarbonyl)-4-phenyl-3-butenyl|-4-methyl-M-phthalimidovaleramide, 0.13g of (E)-2(KO-Ktetrahydro -2(K5)-pyranyloxy)carbamoyl-1I-4-phenyl-3-butenyl|-4-methyl-M-phthalimidovaleramide in the form of a white solid substance.

Mass spectrometry: 534 (MAN) 7.

Example 121 (E)-3-I2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methylvaleryl)-2-isobutyl carbazate

In a method similar to the method described in the first paragraph of Example 2, starting with -- 0.27 g of methyl "co (E)-3-I2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy) carbamoyl|-4-phenyl-3-butenyl|-4-methylvaleryl/d-2-isobutylcarbamate, 0.19 g of methyl IF) (E)-3-I2(KO-I1(5)-(hydroxycarbamoyl)-4 -phenyl-3-butenyl|-4-methylvaleryl/)-2-isobutylcarbazate as a white solid.

From Mass spectrometry: 434 (MAN)7. at

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 12.08 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent "

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

Methyl C c (E)-3-I2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl1|-4-phenyl-3-butenyl|-4-methylvaleryl/-2-isobutylcarba"» substance, which was used as a starting material, was obtained in the following manner: '-isobutyl-4-methylvalerohydrazide - and

0.12 ml of pyridine was dissolved in 10 ml of dichloromethane and cooled to a temperature of 0"C in a nitrogen atmosphere.

0.12 ml of methyl chloroformate and several crystals of 4-dimethylaminopyridine were successively added, and the resulting mixture was heated to room temperature, after which it was stirred for 1 hour.

Go! The resulting mixture was diluted with dichloromethane, after which it was successively washed with 595% aqueous solution of sodium hydrogen carbonate, water, 2M aqueous solution of hydrochloric acid and water, after which it was dried over magnesium sulfate. The mentioned solvent was evaporated to obtain 0.54 g of methyl b 20 (E)-3-I2(P)-I1(8)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvaleryl-2-isobutylcarbamate in in the form of white foam.

C Mass spectrometry: 475 (MAN) 7. (i) In a method similar to the method described in Example 2, parts (im) and (m), starting with Kk! 0.54 g of methyl (E)-3-I2(KO-I1(5)-tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4-methylvaleryl|-2-isobutyl carbazate was obtained

HF) 0.27 g methyl (E)-3-I2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl) ky -4-phenyl-3-butenyl|-4-methylvaleryl/|-2 - isobutylcarbazate in the form of a white solid.

Mass spectrometry: 518 (MAN) 7.

Example 122 60 (E)-2'-cycloheptyl-2(K)-I(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide

(E)-2'-cycloheptyl-2(K)-I(1(5)-(hydroxycarbamoyl )-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methylvalerohydrazide as a white solid.

Mass spectrometry: 494 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate

ml/minute. Holding time: 12.99 minutes. Solvent A: H»O/0.190 TPA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

Example 123 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methyl-2-neopentylvalerohydrase d 70 In a method similar to the method described in Example 45, but using semialaldehyde instead of isobutyraldehyde in step (Y), ()-2(KO-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)- 4-methyl-2-neopentylvalerohydrazide. - in the form of a white solid.

Mass spectrometry: 468 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 12.79 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

Example 124 ()-2(KO-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2"-isobutyl-2-(trifluoroacetyl)-4-methylvalerohydrazide

()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3 -butenyl|-2"-isobutyl-2-(trifluoroacetyl)-4-methylvalerohydrazide.- In the form of a white solid.

Mass spectrometry: 472 (MAN) "7. o

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 13.36 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. --

Example 125 "co ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2"-isobutyl-4-methyl-2-(2-phenylacetyl)valerohydrazide

In a method similar to the method described in Example 59, but using phenylacetyl chloride instead of isobutyric anhydride in step (Y), (y)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl- 3-butenyl|-2-isobutyl-4-methyl-2'-(2-phenylacetyl)valerohydrazide.- in the form of a white solid substance. IF)

Mass spectrometry: 494 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate « 1ml/minute. Holding time: 13.03 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent 49. In: SNUSM/0.08595 tetrafluoroacetic acid. Column type: NUREBRER ZOO. From c Example 126 "()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-M-(2-isothiazolidinyl)-4-methylvaleramide 5,5-dioxide" Method , similar to the method described in the first paragraph of Example 2, starting with 0.12 g of (E)-2(B)-(1(5)-K(tetrahydro-2(B5)-pyranyloxy)carbamoyl|-4- phenyl-3-butenyl|-M-(2-isothiazolidinyl)-4-methylvaler o amide z,Z-dioxide, 0.oZg was obtained

Go! ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-M-(2-isothiazolidinyl)-4-methylvaleramide З, З-dioxide in the form of a white solid substance. i- and Mass spectrometry: 424 (MAN) 7.

He») 20 High Performance Liquid Chromatography: Gradient elution using solvent A, which includes x 590 solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 7" 1ml/minute. Retention time: 9.90 minutes. Solvent A: H»O/0.195. TPA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2(KO-I1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl1|-4-phenyl-3-butenyl|-M-(2-isothiazolidinyl)-4-methylb 29 of alleramide 5.5 -dioxide, which was used as a starting material, was obtained in the following way:

HF) (i) 1.857 g of 3-chloropropylsulfonyl chloride and 0.85 g of pyridine were added to a solution of 3.0 g of (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-4- -methylvalerohydrazide in 4 Oml of dichloromethane. After stirring at room temperature for 2 hours, the mentioned solvent was evaporated, the resulting residue was mixed with diethyl ether. The resulting mixture was filtered, the solvent was evaporated to obtain 1.92 g of (E)-2(KO-I1(5) -(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-2'-(3-chloropropylsulfonyl)-4-methylvalerohydrazide Pale yellow oil.

Mass spectrometry: 445 (MAN-!Vshsh". (ii) 1.59 g of potassium carbonate was added to a solution of 1.92 g of bo (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl- 3-butenyl|-2'-(3-chloropropylsulfonyl)-4-methylvalerohydrazide.

5 ml of dry dimethylformamide. After stirring at room temperature overnight, the solvent was evaporated, the resulting residue was dissolved in diethyl ether and washed with water. The obtained organic phase was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by gel chromatography under vacuum eluting with a mixture of ethyl acetate/hexane (1:2). 0.93 g of (E)-2(KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-M-(2-isothiazolidinyl)-4-methylvaleramide 5,5-dioxide was obtained pale yellow oil.

Mass spectrometry: 409 (MAN-!Vshsh". (her) In a method similar to the method described in Example 2, parts (im) and (mM), with 70 starting with 0.90g of (E)-2( KO-I1(5)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl|-M-(2-isothiazolidinyl)-4-methylvaleramide z,3-dioxide obtained 0.12 g of (E)-2(KO -I1(5)-Ktetrahydro-2(K5)-tranyloxy)carbamoyl|-4-phenyl-3-butenyl|-IM-(2-isothiazolidinyl)-4-methylvalera copper 5,5-dioxide in the form of a white solid .

Mass spectrometry: 508 (MAN) 7.

Example 127 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methyl-M-(2-oxo-3-oxazolidinium)valeramide

In a method similar to the method described in Example 126, but using 2-bromomethylchloroformate instead of 3-chloropropylsulfonyl chloride in step (), 20 was obtained. (E)-2(K)-I1(5)-(hydroxycarbamoyl)- 4-phenyl-3-butenyl|-4-methyl-N-(2-oxo-3-oxazolidinyl)uvaleramide as a white solid.

Mass spectrometry: 390 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 595 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; CM flow rate

mml/minute. Holding time: 9.79 minutes. Solvent A: HNO/0.195. TEA (tetrafluoroacetic acid); solvent o

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

Example 128 2(5)-P(K5)-(hydroxycarbamoyl)u(phenylthio)methyl|-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with -- zo 2.98 g of 2(5)-P(K5)-(phenylthio) (tetrahydro-2(K5)-pyranyloxy)carbamoyl| methyl)-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide was obtained in 1927. (methanesulfonyl)-4-methylvalerohydrazide. - in the form of a white solid substance.

From Mass spectrometry: 446 (MAN)7. at

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Retention time: 11.36 and 12.64 minutes. Solvent A: HNO/0.196. TEA (tetrafluoroacetic acid); Solvent B: СНЗзСМ/О.08590 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. 2(5)-P(K5)-(phenylthio) (tetrahydro-2(K5)-pyranyloxy)carbamoyl|methyl)-2'-isobutyl-2'-(methanesulfonyl)-4-methyl-valerohydrazide, which was used as a starting material, was obtained in the following manner: "» In a manner similar to the method described in Example 131, part (xi), Example 1, part (its) " and Example 2, part (y) , starting with 3.45 g of 2(5)-isobutyl-3(K5)-phenylthiobutane-1,4-dioic acid 4-tert-butyl ether (which was obtained according to the description given in MO 97/42168), obtained 2.98 g of 2(8)-P1(k5)-(phenylthio)(tetrahydro-2(K5)-tranyloxy)carbamoyl|-methyl-2'-isobutyl-2-(methanesulfonyl)-4-methylva

Go! lerohydrazide in the form of a white solid.

Mass spectrometry: 530 (MAN) 7. ini Example 129

He») 20 2(K)-I1(5)-(hydroxycarbamoyl)-4-methylpentyl/d|-2"-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide ah In a method similar to the method described in the first paragraph of Example 2, starting with 7" 0.77 g of 2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-methylpentyl|)-2'-isobutyl-2' -(methanesulfonyl)-4-methylvalerohydrazide, 0.48 g of 25 2(KO-I1(5)-(hydroxycarbamoyl)-4-methylpentyl)-2'-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide were obtained.

HF) in the form of a white solid substance. 7 Mass spectrometry: 408 (MAN) 7.

High Performance Liquid Chromatography: Accelerated gradient elution using solvent A, which includes 4095 bo of solvent B, over 5 minutes, followed by increasing the content of solvent B to 8090 bo over 10 minutes; flow rate Tml/minute. Holding time: 5.61 minutes. Solvent A: HNO/0.195. TEA (tetrafluoroacetic acid); solvent B: CH3CM/0.08590 tetrafluoroacetic acid. Column type: NUREXIA. 120A. 2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-methylpentyl|)-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide, which was used as a starting material, was obtained in the following way: (i) Solution 1.5 g

2(K)-(1(5)-(tert-butoxycarbonyl)-4-methyl-3-pentenyl|-2'-isobutyl-2'(methanesulfonyl)-4-methylvalerohydrazide in 5 ml of methanol was hydrogenated in the presence of 0.15 g of 1095 palladium-on-carbon for b hours. The catalyst was removed by filtration, the solvent was evaporated to give 1.5 g of 2(KO-(1(5)-(tert-butoxycarbonyl)-4-methylpentyl/d-2-isobutyl-2-(methanesulfonyl )-4-methylvalerohydrazide In the form of a colorless oil.

Mass spectrometry: 449 (MAN) "7. (i) In a method similar to the method described in Example 1, part (ii) and Example 2, part (M), starting with 1.5g 70. 2( K)-(1(5)-(tert-butoxycarbonyl)-4-methylpentyl/|-2-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide, 0.77 g of 2(K)-I1(5)-Ktetrahydro was obtained -2(K5)-pyranyloxy)carbamoyl)-4-methylpentyl-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide as a white solid.

Mass spectrometry: 492 (MAN) 7.

Example 130 2(K)-(1(5)-(hydroxycarbamoyl)-4-methyl-33-pentenyl|-2"-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.25 g of 2(K)-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-methyl-Z -pentenyl/|-2'-isobutyl-2'(methanesulfonyl)-4-methylvalerohydrazide, 0.16 g of 20. 2(K3-I1(5)-(hydroxycarbamoyl)-4-methyl-3-pentenyl|-2 '-isobutyl-2'(methanesulfonyl)-4-methylvalerohydrazide as a white solid.

Mass spectrometry: 406 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 595 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; CM flow rate

mml/minute. Holding time: 11.59 minutes. Solvent A: HNO/0.195 TEA (tetrafluoroacetic acid); solvent o

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. 2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-4-methyl-3-pentenyl/|-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide, which was used as starting material, was obtained in the following manner: (i) Solution of 15g of 00-x 2(K)-(1(5)-(tert-butoxycarbonyl)-4-methyl-3-pentenyl/|-2' -isobutyl-2'(methanesulfonyl)-4-methylvalerohydrazide, with 0.51 g of triethylamine and 0.93 g of trimethylsilyl triflate in 2 Oml of 1,4-dioxane was heated in a reflux flask at the distillation temperature under a nitrogen atmosphere for 4 hours. The resulting mixture was cooled , MO solvent was evaporated. The resulting residue was dissolved in ethyl acetate and washed with a 2M aqueous solution of hydrochloric acid, water and brine. After that, the obtained ethyl acetate phase was dried over anhydrous magnesium sulfate and the mentioned solvent was evaporated to obtain 1.91 g of Is) 2(K)-( 1(5)-(carboxy)-4-methyl-3-pentenyl|-2"-isobutyl-2(methanesulfonyl)-4-methylvalerohydrazide in the form of a yellow foam.

Mass spectrometry: 391 (MAN) 7. « (i) In a method similar to the method described in Example 2, part (y), starting with 1.31g ne) c 2(KO-I1(5)- (carboxy)-4-methyl-33-pentenyl/|-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide" was obtained

From" 0.25g 2(K)-I1(5)-

Ctetrahydro-(C5)-pyranyloxy)carbamoyl|-4-methyl-3-pentenyl/|-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide in the form of a pale yellow foam. 15 Mass spectrometry: 490 (MAN) 7. 1

Example 131 (ee) 2(K)-K5)-(benzyloxy)-(hydroxycarbamoyl)methyl)i-2-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide sl In a method similar to the method described in the first paragraph of Example 45, starting with 0.12 g (o) 50 2(Kk)-K5)-(benzyloxy)-((tetrahydro-2(K5)-pyranyloxy)carbamoyl|methyl)|-2-isobutyl-2'- (methanesulfonyl)-4-methyl valerohydrazide, obtained 0.07 g of 2(Kk)-(5)-(benzyloxy)-hydroxycarbamoyl)methyl/)-2-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide In the form of a solid white substances.

Mass spectrometry: 444 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes (F) 590 solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate

GI 1ml/minute. Holding time: 11.86 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. in 2(Kk)-(5)-(benzyloxy)-(tetrahydro-2(K5)-pyranyloxy)carbamoyl|methyl/)-2'-isobutyl-2'-(methanesulfonyl)-4-m ethylvalerohydrazide, which was used as a starting material, was obtained in the following way: () 4.48 g of C(K)-carboxy-2(5)-hydroxy-5-methylhexanoic acid was stirred in a nitrogen atmosphere in 1 Oml of trifluoroacetic anhydride for 1.5 hours. The mentioned solvent was evaporated, the resulting residue was dissolved in 20 ml of dry methanol and stirred overnight at room temperature. The solvent was evaporated to give 5.3 g of methyl C(K)-carboxy-2(5)-hydroxy-5-methylhexanoate as an orange oil.

(i) 2.ml of allyl bromide was added to a solution of 4.52g of methyl C(K)-carboxy-2(5)-hydroxy-5-methylhexanoate and 7.9g of cesium carbonate in 30ml of dimethylformamide. The resulting mixture was stirred overnight and then evaporated. The resulting residue was dissolved in dichloromethane and washed with a 2M aqueous solution

Hydrochloric acid. After that, the obtained dichloromethane phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by gel chromatography under vacuum eluting with a mixture of ethyl acetate/hexane (1:19, increasing to 2:8). 2.88 g of methyl were obtained

C(K)-(allyloxycarbonyl)-2(5)-hydroxy-5-methylhexanoate in the form of a pale yellow oil. (its) 0.51g of silver oxide (I) and 0.33ml of benzyl bromide were added to a solution of 0.27g of methyl 70Z(K)-(allyloxycarbonyl)-2(5)-hydroxy-5-methylhexanoate in Bbml of dimethylformamide. After stirring the resulting mixture for 24 hours, 0.36 bg of cesium carbonate was added and stirring was continued for

From hours The resulting mixture was diluted with diethyl ether and filtered. After that, the obtained filtrate was successively washed with 595 aqueous solution of citric acid, water, 595 aqueous solution of sodium bicarbonate, water and brine. The obtained diethyl ether phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting residue was purified by gel chromatography under vacuum eluting with a mixture of ethyl acetate/hexane (1:19). 0.16 mg of methyl C(K)-(allyloxycarbonyl)-2(5)-benzyloxy-5-methylhexanoate was obtained in the form of a clear oil. (m) 0.3U9ml of morpholine and 0.05g of tetrakis(triphenylphosphine)palladium(0) were added to a stirred solution of 0.15g of methyl C(K)-(allyloxycarbonyl)-2(5)-benzyloxy-5-methylhexanoate in bBml of tetrahydrofuran in 2o nitrogen atmosphere. After stirring the resulting mixture for 0.5 hours, the solvent was evaporated. The resulting residue was dissolved in dichloromethane and successively washed with 2M aqueous solution of hydrochloric acid and water.

The obtained organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting residue was dissolved in diethyl ether and filtered. The resulting diethyl ether solution was evaporated to obtain 0.16 g of methyl C(K)-carboxy-2(5)-benzyloxy-5-methylhexanoate as a yellow oil. сч (m) In a method similar to the method described in Example 1, part (i), but using isobutylhydrazine instead of phenylhydrazine, and part (ii) starting with 043g methyl i)

3(K)-carboxy-2(5)-benzyloxy-5-methylhexanoate, 0.34 g of 2(Kk)-(5)-(benzyloxy)-(methoxycarbonyl)methylide|-2"-isobutyl-2-(methanesulfonyl) was obtained )-4-methylvalerohydrazide In the form of a yellow oil.

Mass spectrometry: 443 (MAN) 7. (m) bO5ZOml. A 2M solution of trimethylaluminum in toluene was added to a solution of /0.124 g of

O-(tetrahydro-2H-pyran-2(K5)-yl)-hydroxylamine in 5 ml of dry toluene at a temperature of 0"C in a nitrogen atmosphere.

The resulting mixture was stirred at a temperature of 0°C for 0.5 hours, after which 0.335 g of 2(K)-(5)-(benzyloxy)-(methoxycarbonyl)methyl/|-2"-isobutyl-2(methanesulfonyl) was added in one portion )-4-methylvalerohydrazide. The resulting mixture was allowed to warm to room temperature overnight. The mentioned mixture was diluted with ethyl acetate and successively washed with a 2M aqueous solution of hydrochloric acid and a 596% aqueous solution of sodium bicarbonate, after which it was dried over anhydrous magnesium sulfate. The mentioned solvent was evaporated and the resulting residue was mixed with a mixture of hexane/diethyl ether (2:11) to obtain 0.119 g of 2(k)-(5)-(benzyloxy)-(tetrahydro-2(K5)-pyranyloxy)-carbamoyl|methylide |-2-isobutyl-2-(methanesulfonyl)-4-methyl 70 pvalerohydrazide as a white solid. - c Mass spectrometry: 528 (MAN) 7. a Example 132 "» 2(KO-(1(5)-(hydroxycarbamoyl)-2-phenylethyl/|-2"-isobutyl-2'(methanesulfonyl)-4- methyl valerohydrazide

In a method similar to the method described in the first paragraph of Example 65, starting with 0.06 g of 2(K)-1(5)-(benzyloxycarbamoyl)-2-phenylethyl/|-2'-isobutyl-2'-( methanesulfonyl)-4-methylvalerohydrazide, 1 obtained 0.014 g of 2(K)-(1(5)-hydroxycarbamoyl)-2-phenylethyl|-2'-isobutyl-2'(methanesulfonyl)-4-methylvalerohydrazide as a white solid color o Mass spectrometry: 428 (MAN) 7. b 20 High-performance liquid chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 10 minutes; flow rate - With 2 ml/minute. Holding time: 7.55 minutes. Solvent A: H»O/0.195. TPA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. 2(K)-(1(5)-(benzyloxycarbamoyl)-2-phenylethyl)|-2"-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide, which was used as the starting material, was obtained in the following manner :

Gee! () In a method similar to the method described in Example 2, parts (ii) and (ii), but using benzyl bromide instead of cinnamyl bromide in step (Y), de 2(K)-(1(5)- (tert-butoxycarbonyl)-2-phenylethyl|-4-methylvaleric acid as a clear oil.

Mass spectrometry: 321 (MAN) 7.6o (i) In a method similar to the method described in Example 131, part (m) and Example 65, parts (ii) and (im), with 1.49g of 2( K)-(1(5)-(tert-butoxycarbonyl)-2-phenylethyl|-4-methylvaleric acid obtained 0.063 g of 2(K)-(1(5)-(benzyloxy-carbamoyl)-2-phenylethyl|)- 2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide In the form of a white solid, mass spectrometry: 518 (MAN) 7.

Example 133 2(KO-(1(5)-(hydroxycarbamoyl)-2-(phenylthio)dethyl|-2-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with b, 315g of 2(K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl/|-2-(phenylthio) ethyl/|-2'-isobutyl-2'-(methanesulfonyl)-4-methyl valerohydrazide, 0.116 g of 2(K)-(1(5)-(hydroxycarbamoyl)-2-(phenylthio)ethyl|-2-isobutyl -2--(methanesulfonyl)-4-methylvalerohydrazide White solid 70 Mass spectrometry: 460 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 11.95 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. 2(K)-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoylI|-2-(phenylthio)ethyl|/|-2'-isobutyl-2'-(methanesulfonyl)-4-m ethylvalerohydrazide, which was used as the starting material, it was obtained in the following way: (Y) 7.8 ml of piperidine and 200 ml of 4095 aqueous solution of formaldehyde were added to a solution of 6b.0g of 1-tert-butyl dihydro-4-methyl-1(K5),1, 2(K)-pentane tricarboxylate in 8 Oml of isopropyl alcohol and the resulting mixture was stirred overnight in a nitrogen atmosphere. The solvent was evaporated, the resulting residue was dissolved in ethyl acetate. The obtained ethyl acetate phase was successively washed with 1 M aqueous solution of hydrochloric acid, warm water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 3.94 g of 2K-(1-(tert-butoxycarbonyl)vinyl|-4-methylvaleric acid in the form of a clear oil. (i) In a method similar to the method described in Example 131, part (y), with the initiator of

ZAG of 2K-|1(tert-butoxycarbonyl)vinyl|-4-methylvaleric acid, obtained 35/g with 2(K)-(1-(tert-butoxycarbonyl)-vinyl|-2'-isobutyl-2-(methanesulfonyl) -4-methylvalerohydrazide in the form of a clear oil. i) (ii) 0.183 g of thiophenol and 0.35 bml of triethylamine were added to a solution of 0.500 g of 2(K)-(1(tert-butoxycarbonyl)vinyl|-2'-isobutyl-2'- (methanesulfonyl)-4-methylvalerohydrazide in 20 ml of toluene and stirred in a nitrogen atmosphere for 48 hours. 0.183 ml of thiophenol -"ee was additionally added to the mentioned mixture and stirring was continued at a temperature of 60"C for 48 hours. After that, the resulting mixture was cooled to room temperature and diluted with ethyl acetate. The mentioned mixture was successively washed with 1M aqueous hydrochloric acid solution, TM aqueous sodium hydroxide solution and brine. The obtained organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. By mixing with hexane, 0.307g of so 2(K)-I1( 5)-(tert-butoxycarbonyl)-2-(phenylthio)ethyl)|-2-isobutyl-2-(methane lfonyl)-4-methylvalerohydrazide in the form of a white solid.

Mass spectrometry: 501 (MAN) 7. (m) In a method similar to the method described in Example 2, parts (im) and (m), with the beginning of Kk! 0.307 g of 40. 2(K)-I1(5)-(tert-butoxycarbonyl)-2-(phenylthio)ethyl I|-2-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide, 0.315 g and 2( K)-(1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl|-2-(phenylthio)ethyl|-2'-isobutyl-2'-(methanesulfonyl)-4-methyl"valerohydrazide in the form of a solid white substances.

Mass spectrometry: 544 (MAN) 7.

Example 134 1 ()-2(KO-(1(5)-(hydroxycarbamoyl)-4-(1-naphthyl)-3-butenyl-2"-isobutyl-2-(methanesulfonyl)-4-methyl-valerogy o drazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.240 g of 50 (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-4- (1-naphthyl)-3-butenyl|-2"-isobutyl-2(methanesulfonyl)-4-methylvalerohydrazide, 0.155 g of "6 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-( 1-naphthyl)-3-butenyl-2"-isobutyl-2(methanesulfonyl)-4-methylvalerohydrase as a white solid.

Mass Spectrometry: 504 (MAN) 7. 59 High Performance Liquid Chromatography: Gradient Elution with Solvent A, which includes

HF) 590 to solvent B, with a subsequent increase in the content of solvent B to 9595 within 15 minutes; flow rate 1 ml/minute. Holding time: 13.19 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent o B: SNUuSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2(KO-I1(5)-Ctetrahydro-2(K5)-pyranyloxy)carbamoyl-1|-4-(1-naphthyl)-3-butenyl|-2"-isobutyl-2(methanesul 60 fonyl)- 4-Methylvalerohydrazide, which was used as a starting material, was obtained in the following manner: 0.500 g of 2(K)-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl|-3-butenyl|-2i( methanesulfonyl)-4-methyl-2'-phenylvalerohydrazide, which was obtained according to the description given in Example 118, 0.449g of 1-bromonaphthalene, 0.219g of triethylamine, 0.012g of palladium acetate (II) and 0.033g of tri -o-tolylphosphine was dissolved in 5 ml of dimethylformamide and stirred at a temperature of 1007" for 24 hours. After that, the resulting mixture was cooled to room temperature and partitioned between water and ethyl acetate. The obtained aqueous phase was extracted twice with ethyl acetate, after which the mixed organic phases were dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by gel chromatography under vacuum eluting with a mixture of dichloromethane/methanol (9.5:0.5). 0.260 g of (E)-2(KO-I1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl-1|-4-(1-naphthyl)-3-butenyl|-2-isobutyl-2'(methanesulfonyl) were obtained -4-methylvalerohydrazide as a white solid.

Mass spectrometry: 504 (M-TNR'AN) 7.70 Example 135 ()-2(KO-I1(5)-(hydroxycarbamoyl)-4-(5-pyrimidinyl)-3-butenyl|-2-isobutyl- 2--(methanesulfonyl)-4-methyl valerohydrazide

In a method similar to the method described in Example 134, but using 5-bromopyrimidine instead of 1-bromonaphthalene), 75 was obtained. (E)-2(K)-I1(5)-(hydroxycarbamoyl)-4-( 5-pyrimidinyl)-3-butenyl|-2-isobutyl-2'(methanesulfonyl)-4-methylvalerog hydrazide as a white solid.

Mass spectrometry: 456 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate

Lml/minute. Holding time: 9.89 minutes. Solvent A: HNO/0.195. TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

Example 136 2(k)-(5)-(cyclopentyl)(hydroxycarbamoyl)methyl|-2-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide and 2(k)-(5)-(cyclopentyl)(hydroxycarbamoyl)methyl |-2-isobutyl-2-(methanesulfonyl)-4-methyl-3-pentenehydrazide c

In a method similar to the method described in the first paragraph of Example 45, starting with 0.357 g of a mixture of 2(k)-(5)-(cyclopentyl)|(tetrahydro-2(K5)-pyranyloxy)carbamoyl|methyl/) -2-isobutyl-2'-(methanesulfonyl)-4-methyl valerohydrazide and 2(Kk)-(5)-(cyclopentyl)(tetrahydro-2(K5)-pyranyloxy)carbamoyl|methyl/-2-isobutyl-2' -(methanesulfonyl)-4-methyl -- -3-pentanehydrazide, obtained 0.219 g of a mixture of 2(k)-(5)-(cyclopentyl)(hydroxycarbamoyl)methyl|-2'-isobutyl-2'-(methanesulfonyl)-4 -methyl-valerohydrazide (compound A) and 2(k)-(5)-(cyclopentyl)(hydroxycarbamoyl)methyl|-2'-isobutyl-2'-(methanesulfonyl)-4-methyl-3-pentenehydrazide (compound B) as a white solid. After that, the obtained compounds were separated using preparative high-performance liquid chromatography on an OMMAMAX 5μm C18 column

ZO0A with dimensions of 21.4 x 5 ΩMM using the gradient elution method, the description of which was given earlier.

Compound A: Mass Spectrometry: 405(M-H)". High Performance Liquid Chromatography: Gradient elution " with solvent B for 15 minutes; flow rate 1 mL/minute. Retention time: 11.00 minutes.

Compound B: Mass Spectrometry: 403(M--H)". High Performance Liquid Chromatography: Gradient elution With c as described for compound A. Retention time: 10.77 minutes. "» The mentioned mixture " 2(k )-(5)-(cyclopentyl)|(tetrahydro-2-(K5)-pyranyloxy)carbamoyl)methyl/d-2"-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide and 2(B)-I( 5)-(cyclopentyl)|(tetrahydro-2-(B5)-pyranyloxy)carbamoyl)methyl-2'-isobutyl-2'-(methanesulfonyl)-4-methyl o l-3-pentenehydrazide, which was used as a starting material , was obtained in the following way:

Go! (Y) In a manner similar to the method described in Example 131, part (y), starting with 1.1 g. 2(5)-cyclopentyl-3(K)-(2-methylallyl)/succinic acid 4-benzyl ether (which was obtained 1 according to the description given in I) 97/19053), 1.14 g were obtained

He» 20 2(g)-((5)-(benzyloxycarbonyl)(ucyclopentyl)methyl-2-isobutyl-2'-(methanesulfonyl)-4-methyl-4-pentenehydrazide.- In the form of a white foam that could be Recrystallize from hexane. in TOml of ethanol was hydrogenated in the presence of 0.05 g of 1095 palladium-on-carbon and the solvent was evaporated to obtain 0.91 g of the mixture

HF) 2(k)-(5)-(carboxyl)cyclopentyl)methyl/)-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide and 2(k)-(5)-(carboxyl)(cyclopentyl) )methyl/|-2-isobutyl-2'-(methanesulfonyl)-4-methyl-3-pentenehydrazide in the form of a white foam. (iii) In a method similar to the method described in Example 2, part (y), starting with 60 g of the mixture 2(823-(8)-(carboxyl) (cyclopentyl)-methyl/)|-2-isobutyl -2'(methanesulfonyl)-4-methylvalerohydrazide and 2(k)-(5)-(carboxyl)(cyclopentyl)methyl/|-2-isobutyl-2'-(methanesulfonyl)-4-methyl-3-pentenehydrazide obtained 0.357 g of a mixture of 2(Kk)-(5)-(cyclopentyl)|(tetrahydro-2-(K5)-pyranyloxy)carbamoyl|methyl|)-2'-isobutyl-2'-(methanesulfonyl)-4-methyl valerohydrazide and

Solid white color

Mass spectrometry: 512 (Ma-Ma)" and 510 (Ma-Ma)".

Example 137

In a method similar to the method described in the first paragraph of Example 45, starting with (E)-2(KO-(1(5)-Ktetrahydro-2(K5)-pyranyloxy)carbamoyl)-4-phenyl-3- butenyl|-2'-(2-(1-imidazolyl)ethyl|-2'(methanesulfonyl)-4-methylvalerohydrazide, methanesulfonic acid salt 70 was obtained. (E)-2(K)-I1(5)-(hydroxycarbamoyl) -4-phenyl-3-butenyl|-2'-(2-(1-imidazolyl)ethyl|-2'(methanesulfonyl)-4-methyl valerohydrazide as a white solid.

Mass spectrometry: 492 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; the flow rate is 75 ml/minute. Holding time: 9.84 minutes. Solvent A: HNO/0.195. TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. (E)-2(KO-I1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl|-4-phenyl-3-butenyl|-2'-(2-(1-imidazolyl)ethyl/|-2 -(methanesulfonyl)-4-methylvalerohydrazide, which was used as starting material, was prepared in a manner similar to that described in Example 15, part (ii) starting with 20. (E)-2(KO)-K5 )-Ctetrahydro-2-(K5)-pyranyloxy)carbamoyl1|-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methylvaleroghydrazide, by reaction with 1-(2-bromomethyl)imidazole.

Example 138 (7)-2(KO)-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide

In a method similar to the method described in the first paragraph of Example 2, starting with 0.075 g of (7)-2(KO)-(1(5)-Ctetrahydro-2(К5)-pyranyloxy)carbamoyl1|-4 -phenyl-3-butenyl|-2-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide, 0.047g of (7)-2(KO-(1(5)-(hydroxycarbamoyl)-4-phenyl-

3-butenyl|-2'-isobutyl-2-(methanesulfonyl)-4-methylvalerohydrazide as a white solid.

Mass spectrometry: 454 (MAN) "7. --

High Performance Liquid Chromatography: Gradient elution using solvent A, which includes 590% solvent B, followed by increasing the content of solvent B to 9595% over 15 minutes; flow rate 1 ml/minute. Holding time: 12.19 minutes. Solvent A: H»O/0.195 TEA (tetrafluoroacetic acid); Solvent KO

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A. co

The starting material was obtained in the following manner: () Solution of 2(2K)-(1(5)-tert-butoxycarbonyl)-4-phenyl-3-butynyl|-2'-isobutyl-4-methylvalerohydrazide in 10 ml of pyridine shaken in a hydrogen atmosphere in the presence of a catalyst, 596 palladium-on-barium sulfate. After 45 minutes, the mentioned catalyst was filtered off, and the pyridine was evaporated. The resulting residue was additionally evaporated three times from toluene and 1 g of (22-2(K)-I1(5)-tert-butoxycarbonyl)-4-phenyl-3-butenyl|-2'-isobutyl-4-methylvalerohydrazide was obtained as a solid straw-colored substances. t c Mass spectrometry: 417 (MEN) 7. "" (i) In a method similar to the method described in Example 2, parts (im) and (m), with " (2)-2(KO)- 0.075 g of (1(5)-tert-butoxycarbonyl)-4-phenyl-3-butenyl|-2'-isobutyl-4-methylvalerohydrazide was obtained (7)-2(KO)-(1(5)-Ktetrahydro-2( K5)-pyranyloxy)carbamoyl-1|-4-phenyl-3-butenyl|-2-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide as a white solid. i-th Mass spectrometry: 538 (MAN) 7. (ee) Example 139 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4 -methyl-2'-(2-pyridyl)methyl|vale i-th rohydrazide methanesulfonate

Ge") 20 In a method similar to the method described in the first paragraph of Example 2, but using ah methanesulfonic acid instead of p-toluenesulfonic acid, starting with 0.266 bg 7" (E)-2(KO-I1(5) -Ctetrahydro-2(K5)-pyranyloxy)carbamoyl)|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-|(2-pyridyl)methyl|valerohydrazide, 0.24 g were obtained (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2-(2-pyridyl)methyl|valerogy drazide methanesulfonate in the form solid substance of almost white color.

HF) Mass Spectrometry: 489 (MAN) 7. 7 High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 9.95 minutes. Solvent A: H»O/0.195 TPA (tetrafluoroacetic acid); solvent bo B: SNUuSM/0.085905 tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was prepared in a manner similar to that described in Example 15, part (iii), starting with (E)-2(KO-I1(5)-(tetrahydro-2(K5)-pyranyloxy)carbamoyl1| -4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methylvalerogen drazide and 2-bromomethylpyridine hydrobromide. Example 140

(B)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2'-(2,6-dimethyl-4-pyrimidinyl) )valerohydrazide methanesulfonate

In a method similar to the method described in the first paragraph of Example 2, but using methanesulfonic acid instead of p-toluenesulfonic acid, starting with 0.049 g of (E)-2(KO-I1(5)-Ktetrahydro-2(K5) -pyranyloxy)carbamoyl1|-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2'-(2,b-dimethyl-4-pyrimidinyl)valerohydrazide, 0.039g of (E)-2 was obtained (KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2i(methanesulfonyl)-4-methyl-2-(2,6-dimethyl-4-pyrimidine l)valerohydrazide methanesulfonate as a solid almost white in color.70 Mass spectrometry: 504 (MAN) 7.

High Performance Liquid Chromatography: Gradient elution with solvent A, which includes 590 of solvent B, followed by increasing the content of solvent B to 9595 over 15 minutes; flow rate 1 ml/minute. Holding time: 12.00 minutes. Solvent A: H»O/0.1965 TEA (tetrafluoroacetic acid); solvent

In: SNUuSM/0.085905 of tetrafluoroacetic acid. Column type: NUREKRER ZOO0A.

The starting material was prepared in a manner similar to that described in Example 2, parts (ii)-(m), starting with (E)-2(K)-I1(5)-(tert-butoxycarbonyl)-4 -phenyl-3-butenyl|-4-methylvaleric acid and 2,4-dimethyl-6-hydrazinepyrimidine.

The following Examples illustrate typical pharmaceutical preparations comprising said hydrazine derivatives provided by the present invention:

Example A

Tablets containing the following ingredients can be made in the traditional way: Example B

Capsules, which include the following ingredients, can be made in the traditional way:

Claims (24)

The formula of the invention p 1. Derivatives of hydrazine of the general formula 1 со НО M - : vav: v? 1 n E- c) pi o VZ - where M means CO or 505; B" means (C.-C7) alkyl, (Co-C7) alkenyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkyl-(C.-C7) alkyl, aryl or aryl-(C.4-C7) alkyl; B2 means (C.4-C7) alkyl, halo-(C.i-C7) alkyl, aryl-(C--C7) alkyl, aryl-(Co-C7) alkenyl or aryl, in the case, (F , when M means 50", and (C4-C7) alkyl, halo-(C4-C7) alkyl, (Ci-C7) alkoxy group, (C4i-C7) alkoxycarbonyl, co acyl, (C3z-C7) cycloalkyl, aryl, aryl-(Ci-C7) alkyl, aryl-(C--C7) alkoxy group or ME?B", in the case where U is CO; and 60 BZ is hydrogen, (C.4-C7) alkyl optionally substituted with cyano , amino group, hydroxyl, (C4-C7) alkoxy group, (Ci-C7) alkoxycarbonyl, heterocyclyl or heterocyclylcarbonyl, (Co-C7) alkenyl, (C5-C7) alkynyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkyl -(C--C7) alkyl, aryl-(C4-C7) alkyl, aryl-(Co-C7) alkenyl, aryl or heterocyclyl; or B? and KZ together form a 5-, 6- or 7-membered cyclic amide residue , cyclic imide, cyclic sulfonamide or cyclic urethane group; B means (C4-C7) alkyl, (Co-C7) alkenyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkyl-(Ci-C7) alkyl or a group of the formula X-aryl, X-heteroaryl or -(СНо »)і5-SNASV B; X stands for township group; BE and VU, each independently of the other, means hydrogen, (C4-C7) alkyl or aryl-(C4-C7) alkyl; and B and KZ together represent a (C 2-C7) alkylene group in which one methylene group is optionally replaced by a heteroatom; racemates of these compounds and mixtures of diastereoisomers of these compounds; and pharmaceutically acceptable salts of these compounds. 2. Compounds of formula (I), given in claim 1, where: M means CO or 505; B means (C4-C7) alkyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkyl-(Ci-C7) alkyl, aryl or aryl-(C.4-C7) alkyl; 2 means (C4-C7) alkyl, aryl-(C4-C7) alkyl or aryl, in the case when U means 30", and (C4-C7) alkyl, (C4-C7) /5 alkoxy group, (Ca-C7 ) cycloalkyl, aryl-(C1-C7) alkoxy group or MAP, in the case where U means CO; and BZ means hydrogen, (Ci-C7) alkyl optionally substituted with cyano, amino group or phthalimido group, (C.-C7) alkenyl, (Co-C7) alkynyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkyl-(C4-C7) alkyl, aryl-(C1-C7) alkyl, aryl or heterocyclyl; or B? and VZ together form the residue of a 5-, 6- or 7-membered cyclic amide, cyclic imide, cyclic sulfonamide group; B" means phthalimido-(C1-C7) alkyl or a group of the formula X-aryl or X-heteroaryl; X means a bridging group; heteroaryl is bonded to C; and BE and BU, each independently of the other, means hydrogen, ( C4-C7) alkyl or aryl-(C4-C7) alkyl; c and pharmaceutically acceptable salts of these compounds. d) 3. Compounds according to claim 1 or claim 2, where M means CO and B? means (C1-C7) alkoxy group or U means 50" and VC? means (C.4-C7) alkyl. 4. Compounds according to claim 3, where U means CO and K2 means a methoxy group. 5. Compounds according to claim 3, where U means ZO" and B2 means methyl. - 6. Compounds according to any of claims 1-5, where B! means (C4-Cu) alkyl. ise) 7. Compounds according to any of claims 1-6, where B is isobutyl. yu 8. Compounds according to any of claims 1-7, where BZ means (C4-C7) alkyl, (C0-C7) alkenyl, aryl-(C4-C7) alkyl or aryl. co 9, Compounds according to claim 8, where BZ means isobutyl, 2-methylbutyl, 2-methylallyl, unsubstituted benzyl or unsubstituted phenyl. iv) 10. Compounds according to any of claims 1-9, where X is a group of the formula -(СН 2)4-5-, -СНо-СН:СН-, -СНо-С--С-, -ССНОМНеОО-, - ЯСНо) or 2МнСОМН-, -(СН»)4.в-5-, -СНХМнЗо»-, -СнН.Мнен»-, -(СН»)4.в-О-, -0-(СН»)4 5 or -5-. 11. Compounds according to claim 10, where X is a group of the formula -(CH»o)1/5-, -СНО-СНАСН-, -СНХ-С-б-, -СНОМНОО.-, "-"СН2")x or ""MNSOMN-, -CHN5-, -"SNOMNO"- or -"SNOMNON5-. From 70 12. Compounds according to any of claims 1-11, where E7 means a group of formula X-aryl. with 13. Compounds according to claim 12, where X means a group of the formula -"СНо-СН-СН- and aryl means unsubstituted phenyl. :with" 14. The compound according to claim 1, selected from the group which includes: )-4-methylvalerohydrazide, (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'i(methanesulfonyl)-4-methyl-2'--phenylvalerohydrazide, sl 15 (E)-2(KO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'(methanesulfonyl)-4-methyl-2-I2(5)-methylbutyl|vale rohydrazide, ( ee) (E)-2(CO-I1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-2'-(methanesulfonyl)-4-methyl-2-(2-methylallyl)valerosyl drazide and methyl (E)-3-(2(K)-(1(5)-(hydroxycarbamoyl)-4-phenyl-3-butenyl|-4-methylvaleryl-2-isobutylcarbazate. (o) 20 15. Compounds of the general formula -x Ge! in! that 8, N 2. zi uch Nn t. I, o n c) p Ge where U, B", 2, VZ and E7 have the values given in point 1, and VE? means a protective group. 16. Compounds according to claim 15, where KZ means tetrahydropyranyl, 4-methoxybenzyl, benzyl or tri(C.--C7 alkyl)silyl. in 17. Carboxylic acids of the general formula b5 c! ; (х) nos К и 2 2 Й А В о ВЗ where У, В", В, ВЗ and 27 have the values given in clause 1. 70 18. Compounds according to any one of claims 1-14 for use as therapeutically active substances, in particular for use as therapeutically active substances in the treatment of inflammation, fever, hemorrhage, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis or psoriasis. 19. The method of obtaining compounds according to any of claims 1-14, which includes the removal of the protective group from the compound of the general formula o in! ; (1). and K "means a protecting group, and, if necessary, conversion of the resulting compound of formula I into a pharmaceutically acceptable salt. 20. Medicinal product containing a compound according to any one of claims 1-14 and a therapeutically inert carrier. 21. Medicinal product for the treatment of inflammation, fever, hemorrhage, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis or psoriasis, comprising a compound according to any one of claims 1-14 and a therapeutically inert carrier. and) 22. A method of manufacturing a medicinal product, in particular for the treatment of inflammation, fever, hemorrhage, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis or psoriasis, which includes the manufacture of a galenic preparation containing a compound according to any of claims 1-14 and a therapeutically inert carrier , as well as, where necessary, one or more additional therapeutically active substances. 23. An active ingredient for the manufacture of a medicinal product for the treatment of diseases, in particular for the treatment of inflammation, fever, hemorrhage, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis or psoriasis, which is a compound according to any of claims 1-14. 24. Compounds according to any of claims 1-14, produced using the method according to claim 19. | | that Is) Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2003, M 8, 15.08.2003. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. " - . and? 1 (ee) 1 (o) - ime) 60 b5