KR20010083071A - Hydrazine derivatives - Google Patents

Abstract

The present invention provides a hydrazine derivative of formula (I) wherein R < 1 > and R < 2 >, R < 2 >, and pharmaceutically acceptable salts thereof, which inhibit the release of tumor necrosis factor alpha

Formula I

In this formula,

R <^1> is lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl;

R ² is an acyl group derived from an alpha, beta, gamma or [delta] - (amino, hydroxy or thiol) carboxylic acid wherein the amino, hydroxy or thiol group is optionally lower alkylated or the amino group is optionally acylated, Sulfonylated or amidated, and all functional groups present in the side chain are optionally protected) or a group of formula Het (CH ₂ ) _m CO;

R ³ is selected from the group consisting of hydrogen, lower alkyl, halo-lower alkyl, cyano-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl- Lower alkenyl, lower alkynyl, lower cycloalkyl, aryl-lower alkenyl, aryl, or heterocyclyl; R &lt; 2 &gt;

R ⁴ is lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, or a group of formula X-aryl, X-heteroaryl or - (CH ₂ ) _n -CH = CR ⁵ R ⁶ ;

R ⁵ and R ⁶ together are a CH ₂ group is a lower alkylene optionally substituted with a hetero atom;

Het is heterocyclyl;

X is a spacer group;

m is 0, 1, 2, 3 or 4;

n is 1 or 2;

They can be used as medicines in the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory diseases, tumors, cachexia, cardiovascular diseases, fever, hemorrhage and sepsis.

Description

[0001] HYDRAZINE DERIVATIVES [0002]

The present invention relates to a novel hydrazine derivative, a method for producing the same, and a pharmaceutical agent containing the same. The invention also relates to the use of these derivatives as medicaments and their use for the manufacture of medicaments.

The hydrazine derivatives provided by the present invention are compounds of the general formula (I) and pharmaceutically acceptable salts thereof.

In this formula,

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

R ² is an acyl group derived from an alpha, beta, gamma or [delta] - (amino, hydroxy or thiol) carboxylic acid wherein the amino, hydroxy or thiol group is optionally lower alkylated or the amino group is optionally acylated, Sulphonylated or amidated, and all functional groups present in the side chain are optionally protected) or a group of formula Het (CH ₂ ) _m CO;

R ³ is selected from the group consisting of hydrogen, lower alkyl, halo-lower alkyl, cyano-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl- , Aryl-lower alkyl, heterocyclyl-lower alkyl, heterocyclylcarbonyl-lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl-lower alkenyl, aryl or heterocyclyl;

R ⁴ represents lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, or a group of formula X-aryl, X-heteroaryl or - (CH ₂ ) _n -CH = CR ⁵ R ⁶ ;

R ⁵ and R ⁶ together represent lower alkylene in which one CH ₂ group is optionally substituted by a heteroatom;

Het represents heterocyclyl;

X represents a spacer group;

m represents 0, 1, 2, 3 or 4;

n represents 1 or 2;

The hydrazine derivatives provided by the present invention are inhibitors of the release of tumor necrosis factor alpha (TNF-a) from cells. These include, but are not limited to, inflammatory and autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and psoriasis, osteoarthritis, respiratory diseases such as asthma and chronic obstructive pulmonary disease, tumors, cachexia, , Fever, bleeding and sepsis.

Unlike structurally related hydroxamic acid derivatives, the hydrazine derivatives provided by the present invention exhibit mild inhibition against enzymes of the matrix metalloproteinase (MMP) family, such as collagenase, stromelysin and gelatinase Activity.

The term "lower alkyl" as used herein, alone or in combination, such as, for example, in "halo-lower alkyl" or "lower cycloalkyl-lower alkyl" means up to 8, preferably up to 4 carbon atoms Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl and n-hexyl.

The term "halo-lower alkyl" means a lower alkyl group as defined above having one or more halogen atoms. Examples of halo-lower alkyl groups are chloromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.

The term " lower alkoxy ", alone or in combination as in " lower alkoxy-carbonyl ", refers to lower alkyl groups as defined above bonded through an oxygen atom such as methoxy, ethoxy, n-propoxy, iso Propoxy, n-butoxy, isobutoxy and t-butoxy. Methoxycarbonyl, ethoxycarbonyl and the like are examples of a lower alkoxy-carbonyl group.

The term " lower cycloalkyl ", alone or in combination as in " lower cycloalkyl-lower alkyl ", refers to a cycloalkyl group containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, Cycloheptyl. Cyclopropylmethyl, 2-cyclobutyl-ethyl and 3-cyclohexyl-propyl are examples of lower cycloalkyl-lower alkyl groups.

The term " lower alkenyl ", alone or in combination as in " aryl-lower alkenyl ", means alkenyl groups containing 2 to 7 carbon atoms such as allyl, vinyl and butenyl.

The term " lower alkylene " means an alkylene group containing 2 to 6 carbon atoms, such as dimethylene, trimethylene, tetramethylene, and the like. Thus, R ⁵ and R ⁶ together with the carbon atoms to which they are attached may represent, for example, cyclopentane or cyclohexane ring. One CH ₂ group may be optionally substituted with a heteroatom. Such a heteroatom may be selected from NH, S or O, wherein the hydrogen in the NH group may be optionally substituted with a lower alkyl group. Such as R &lt; ⁵ &gt; and R &lt; ⁶ &gt; together with the carbon atom to which they are attached form a tetrahydropyran ring.

The term " lower alkynyl " means an alkynyl group containing 2 to 7 carbon atoms, such as propanyl or butynyl.

The term " aryl ", alone or in combination as in " aryl-lower alkyl ", refers to a halogen, such as fluorine, chlorine, bromine or iodine, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, lower alkoxycarbonyl, Nitro, phenyl or the like or naphthyl such as phenyl, 1-naphthyl, 2-methylphenyl, 4-methoxyphenyl, 2,4- difluorophenyl, 4-nitrophenyl and 4- Carbonylphenyl. &Lt; / RTI &gt; Benzyl, 4-chlorobenzyl, 4-bromobenzyl, 3-hydroxybenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 2-phenylethyl, And benzyloxy, 4-chlorobenzyloxy and 4-nitrobenzyloxy are representative examples of aryl-lower alkoxy groups. Examples of the aryl-lower alkenyl group include 2-phenylvinyl and 3-phenylallyl.

The term " heterocyclyl &quot;, alone or in combination as in " heterocyclyl-lower alkyl &quot;, refers to a monovalent group selected from the group consisting of nitrogen, sulfur and oxygen bonded through a C atom or a secondary N atom Preferably 1 to 4 heteroatoms and / or SO or SO ₂ groups and is optionally substituted by halogen, lower alkyl, lower alkoxy, imino, thioxo and / or oxo, and / Refers to a benz-condensed 4, 5, 6 or 7 membered saturated or partially unsaturated or 5 or 6 membered aromatic heterocyclic ring. Examples of such heterocyclyl groups are pyrrolidinyl, pyrrolinyl, pyrazolinyl, piperidinyl, N-methylpiperidinyl, morpholinyl, thiamorpholinyl, thiamorpholinyl S, S-dioxide, Wherein R is selected from the group consisting of tetrahydropyranyl, tetrahydrothiopyranyl, hexahydroazepinyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, oxetanyl, imidazolidinyl, dioxolanyl, pyrrolyl, , Pyrimidinyl, benzofuranyl, benzothienyl, benzthiazolyl, 1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinyl, 2-thioxo-4-oxo- 5-thiazolidinyl, 1-methyl-3-pyrrolyl, indolyl, isoindolyl such as phthalimido, quinolyl and isoquinolyl.

The term " heterocyclylcarbonyl " means a heterocyclyl group as defined above linked to C (O) via a secondary N atom. Morpholinocarbonyl is a representative example of such a heterocyclylcarbonyl group.

The term " heteroaryl " means an aromatic heterocyclic group within the definition of " heterocyclyl ".

The term " halo " means fluoro, chloro, bromo or iodo unless stated otherwise.

The acyl group R &lt; ² &gt; can be derived from this acid if the L-, D- or racemic-, hydroxy- or thiolcarboxylic acid contains a chiral center. Thus, R ² is an acyl group derived from an alpha -aminocarboxylic acid such as glycine, L- or D-alanine, L- or D-valine, L- or D- leucine, L- or D- - serine, L- or D-phenylalanine, 2-amino-n-butanoic acid or 2-amino-n-pentanoic acid. Examples of? -Aminocarboxylic acids from which the acyl group R ² can be derived are? -Alanine, 3-aminobutanoic acid and 3-amino-2-methylpropanoic acid. The amino moiety of the acyl group R &lt; ² &gt; may optionally be mono-or di-lower alkylated as in the case of N-methylglycyl, N, N-dimethylglycyl, N, N- Alkylated or acylated as in the case of N-acetylglycyl or N-acetyl-alanyl, or amidated as in the case of N-aminocarbonylglycyl and N-aminocarbonylalanyl, for example. When R ² represents an acyl group derived from? -,? -,? - or? -Hydroxycarboxylic acids, the acid may be, for example, an?,? -,? - or? -Hydroxyalkanecarboxylic acid such as hydroxyacetic acid, 2 -Hydroxypropionic acid, and the like. The hydroxy group of the acyl group derived from? -,? -,? -, or? -hydroxycarboxylic acid may be lower alkylated, such as in the case of methoxyacetyl. In addition, when R ² represents an acyl group derived from α-, β-, γ- or δ-thiolcarboxylic acid, the acid may be an α-, β-, γ- or δ-thiolalkanecarboxylic acid such as mercaptoacetic acid have. Also, the thiol group can be lower alkylated as in the case of methylthio-acetic acid, for example. The acyl group R ² can also be a group of the formula R ^a -COOH wherein R ^a is a carbon substituted at the 1, 2, 3 or 4 position with amino, hydroxy or thiol, preferably amino at the 1-position Lt; / RTI &gt; represents a cycloalkyl of 3 to 7 atoms). Examples of such carboxylic acids are 1-amino-1-cyclopropanecarboxylic acid, 1-amino-1-cyclopentanecarboxylic acid, 1-amino-1-cyclohexanecarboxylic acid and 4-aminocyclohexanecarboxylic acid.

Preferably, R ² is an acyl group derived from? - or? - (amino, hydroxy or thiol) carboxylic acid wherein the amino, hydroxy or thiol group is optionally lower alkylated or the amino group is optionally acylated, amidated Or sulphonylated, preferably acylated or amidated, and all functional groups present in the side chain are optionally protected, or a group of formula Het (CH ₂ ) _m CO wherein m represents 0, 1 or 2 .

In particular, R ² is an acyl group R ⁸ CO where R ⁸ is the side chain of an α-, β-, γ- or δ- (amino, hydroxy or thiol) substituted lower alkyl, a lower cycloalkyl or a natural amino acid, wherein the amino , The hydroxy or thiol group is optionally lower alkylated or the amino group is optionally acylated, sulfonylated or amidated and all functional groups present in the side chain are optionally protected, or a group of formula Het (CH ₂ ) _m and m represents 0, 1, 2, 3 or 4). In one preferred example, R ⁸ represents a side chain of an a- or b- (amino, hydroxy or thiol) substituted lower alkyl, a lower cycloalkyl or a naturally occurring amino acid, wherein the amino, hydroxy or thiol groups are optionally lower alkylated Or the amino group is optionally acylated, amidated or sulfonated, preferably acylated or amidated, and all of the functional groups present in the side chain are optionally protected and m is 0 in the group of formula Het (CH ₂ ) _m , &Lt; / RTI &gt; In another preferred example, R ⁸ is a cycloalkyl of 3 to 7 carbon atoms substituted at the 1, 2, 3 or 4 position with amino, hydroxy or thiol, preferably amino at the 1-position Alkyl. In another preferred embodiment, R ⁸ is selected from the group consisting of? -Amino-substituted lower alkyl,? -Amino-substituted side chains of natural amino acids,? -Amino-substituted lower cycloalkyl,? -Hydroxy- Lt; / RTI &gt; substituted side chain.

All functional (ie, reactive) groups of the side chain of the acyl group represented by R ² can be protected, the protecting group is known per se in peptide chemistry. For example, the amino group may be substituted with one or more substituents selected from the group consisting of t-butoxycarbonyl, formyl, trityl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, 2- Or an isobornyloxycarbonyl group, or in the form of a phthalimido group. Carboxy groups can be protected in the form of esters, such as methyl, ethyl, t-butyl or benzyl esters. The protection of the hydroxy group may be in the form of an ether, such as methyl, t-butyl, benzyl or tetrahydroxypyranyl ether, or in the form of an ester, such as acetate. The mercapto group may be protected, for example, by a t-butyl or benzyl group.

The spacer group represented by X is, for example, a group of the formula - (CH ₂ ) _p --Y - (CH ₂ ) _q -, wherein p and q are each independently 0, 1, 2, 3, 4 or 5, preferably 0 , 1, 2 or 3 and Y is absent or is -CH = CH-, -C? C-, -S-, -O-, -NH-, -NHCO-, -CONH-, -SO ₂ - , -NHSO ₂ -, -SO ₂ NH-, -NHCONH- or -NHSO ₂ NH-). Representative examples of the spacer group is _{- (CH 2) p -,} -CH 2 -CH = CH-, -CH 2 -C≡C-, -CH 2 NHCO-, - (CH 2) n NHCONH-, - ( _{CH 2) p -S-, -S-,} -CH 2 NHSO 2 -, -CH 2 NHCH 2 -, - (CH 2) p -O- and -O- (CH _{2) q} - group (where n And p and q represent an integer of 1 to 5).

The compounds of formula I which are acidic form a pharmaceutically acceptable salt with bases such as alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides, such as calcium hydroxide, barium hydroxide and magnesium hydroxide. The compounds of formula I which are basic can be prepared by reacting a compound of formula I with an inorganic acid such as hydrochloric acid and hydrohalic acid such as hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, lt; RTI ID = 0.0 &gt; pharmaceutically &lt; / RTI &gt; acceptable salt with p-toluenesulfonic acid.

While the formulas provided herein represent representative compounds in absolute stereochemistry, it will be appreciated that the present invention encompasses the stereoisomers as well as the corresponding racemates and diastereomeric mixtures. If the 1 (S) compound is the desired product, it said unlike this as being independent of the terms R or S, means that R ⁴ in the compound of formula (I) when in the "down". Further, when the spacer group represented by X contains an olefinic double bond such as -CH ₂ -CH═CH-, the present compound may have (E) or (Z) configuration, preferably have.

Preferred compounds of formula I are those in which R &lt; ¹ &gt; represents lower alkyl, especially isobutyl, or lower cycloalkyl-lower alkyl, especially cyclopropylmethyl or cyclopentylmethyl. R ² preferably represents an acyl group derived from an? -Aminocarboxylic acid or? -Hydroxycarboxylic acid or a group of the formula Het (CH ₂ ) _m CO in which _m represents 0 or 1. R ³ preferably represents lower alkyl, especially isobutyl, halo-lower alkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, aryl or heterocyclyl. R ⁴ preferably represents a group of the formula X-aryl, in particular of the formula -CH ₂ -CH = CH-Ph, wherein Ph represents unsubstituted phenyl.

Particularly preferred compounds of formula (I) are:

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl- Methyl valero hydrazide,

(R) -hydroxypropionyl) -2 ' - (2-hydroxyethyl) -2 '-( 2- Isobutyl-4-methylvalerohydrazide,

-2 ' - [2- (1-imidazolyl) acetyl] -2 '-( methanesulfonyl) - isobutyl-4-methylvalerohydrazide,

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Ridinil) carbamoyl] valero hydrazide

And pharmaceutically acceptable salts thereof.

Another preferred compound of formula I is 2'-benzyl-2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] -1,2,3-triazol-1-yl) acetyl] valerohydrazide or a pharmaceutically acceptable salt thereof.

According to the process provided by the present invention, there are novel hydrazine derivatives defined above protecting groups represented by R ⁷ from a compound of formula II, and cutting all the protecting groups present in R ²⁰ and / or R ³⁰ according to the requirements , If desired, into the pharmaceutically acceptable salts.

Wherein R ¹ and R ⁴ have the meanings given above, R ⁷ represents a protecting group and R ²⁰ has the same meaning as R ² , provided that in the case of an acyl group, an amino, hydroxy or thiol group (R ² is not lower alkylated, acylated, sulfonylated or amidated) is selectively protected, and all functional groups present in the side chain are selectively protected, and R ³⁰ has the same meaning as R ³ above, Provided that all amino or hydroxy groups present therein are optionally protected.

The protecting group represented by R ⁷ in the compound of formula (II) may be any conventional protecting group, preferably tetrahydropyranyl, benzyl, 4-methoxybenzyl or tri (lower alkyl) silyl, especially t-butyldimethylsilyl . Likewise, all protecting groups present at R &lt; ²⁰ &gt; may be conventional protecting groups. An example of such a protecting group has been previously disclosed in relation to the protection of the functional group of R &lt; ^{2 &} gt ;.

The cleavage of the protecting group represented by R &lt; ⁷ &gt; from the compound of the formula (II) is carried out according to a per se known method. For example, the tetrahydropyranyl group may be removed by treatment with an acid in dioxane such as, for example, hydrogen chloride, or a lower alkanol, such as a sulfonic acid in methanol, such as a lower alkanesulfonic acid such as methanesulfonic acid or an aromatic sulfonic acid such as p- ). &Lt; / RTI &gt; Cleavage of the benzyl group can be done by hydrogenolysis in the presence of a catalyst, such as palladium, in a lower alkanol, such as methanol. The tri (lower alkyl) silyl protecting group can be cleaved by treating each protected compound with water or by treating with a lower pH.

All protecting groups present at R &lt; ²⁰ &gt; and / or R &lt; ³⁰ &gt; may be cleaved according to methods known per se for cleavage of each protecting group. Thus, for example, the t-butoxycarbonyl group can be cleaved by treatment with an acid and the 9-fluorenylmethoxycarbonyl group can be cleaved by treatment with piperidine. Cleavage of phthaloyl can be done by treatment with hydrazine hydrate.

R ²⁰ in the amino, hydroxy or is a thiol group is protected and / or R ³⁰ of the amino or hydroxy in the case where the hydroxy group is protected, the protecting group (s) protecting the cutting of the protective group (s) according to a selection represented by R ⁷ of the Before, during or after the cutting operation. Further, the acyl group if the side chain is to prepare the compound of formula (I) containing a protected functional group, the protecting groups are protecting groups in the side chain is represented by R ⁷ as retention and R ²⁰ and / or any protecting groups present in R ³⁰ is of the The protector and cutting conditions are selected to be cut.

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

The compounds of formula (II) used as starting materials in the above process are novel and form a further object of the present invention. These may be prepared by various routes as illustrated in the following Schemes A, B, C and D, wherein R ¹ , R ⁴ , R ⁷ , R ²⁰ and R ³⁰ have the meanings given above, ^t Bu is t- Butyl, Me represents methyl, and M represents an alkali metal, particularly sodium.

Referring to Scheme A, in a first step, the compound of formula III is condensed with a hydrazine of formula IV or a substituted hydrazine to give the hydrazide of formula V. [ This condensation is carried out in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and N-methylmorpholine in the presence of coupling reagents known per se for peptide coupling such as 1-hydroxybenzotriazole &Lt; / RTI &gt; using a sol as described above.

In the second step, the hydrazide of formula V is reacted with trifluoro acetic anhydride to give the compound of formula VI. This reaction is carried out in a known manner, for example in the presence of an organic base in an organic solvent which is inert under the reaction conditions at from about 0 째 C to about room temperature. Halogenated hydrocarbons such as dichloromethane are suitable solvents, and tri (lower alkyl) amines such as triethylamine, pyridine, 4-dimethylaminopyridine and the like are suitable solvents. The base can be used in excess if it is liquid under the reaction conditions, in which case the base can serve as both a base and a solvent.

In the next step, the compound of formula VI is deprotected using trifluoroacetic acid (TFA) to give the carboxylic acid of formula VII. This deprotection is carried out in a manner known per se, for example in an organic solvent which is inert under the reaction conditions, for example at about room temperature, for example in halogenated hydrocarbons (e.g. dichloromethane).

In a subsequent step, the carboxylic acid of formula VII is condensed with an O-protected hydroxylamine of formula VIII to give the compound of formula IX. This condensation is carried out in a manner known per se for the peptide coupling reaction, for example in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, in an organic solvent which is inert under the reaction conditions, Dimethylformamide. &Lt; / RTI &gt;

In the next step the trifluoroacetyl protecting group is cleaved from the compound of formula IX by treatment with an alkali metal carbonate, such as sodium carbonate or potassium carbonate. This treatment is conveniently carried out by dissolving the compound of formula IX in a lower alkanol, such as methanol, ethanol, etc., adding an aqueous alkali metal carbonate solution, and keeping the mixture at about room temperature until cleavage is complete.

The compound of formula X is then acylated. Acylation can be carried out in a manner known per se. Such as a coupling reagent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride in an organic solvent that is inert under the reaction conditions, such as dimethylformamide, at a temperature from about 0 & Can be reacted with an acid of formula R ²⁰ OH (XI), wherein R ²⁰ has the meaning given above. The acid of formula (XI) can be converted to the corresponding acid fluoride or acid chloride, in which case the reaction is carried out at about room temperature in an organic solvent which is inert under the reaction conditions, for example a base in a halogenated hydrocarbon such as dichloromethane, Is conveniently carried out in the presence of an amine (e.g., triethylamine, pyridine, 4-dimethylaminopyridine, etc.). The compound of formula X may also be prepared in a conventional manner, for example at a low temperature, for example from about 0 to 10 ° C, in an organic solvent which is inert under the reaction conditions, such as a base in a halogenated hydrocarbon such as dichloromethane, (such as triethylamine) expression in the presence of XI acylated by a reactive derivative of an acid (wherein R ²⁰ is formula Het (CH ₂₎ represents a group of _m CO, this time Het and m are previously have the meaning given) .

Finally, when the acylated product contains a protected acyl group R ²⁰ , the protecting group (s) can be cleaved in a manner similar to that described above. In addition, when R ³⁰ in the acylation product contains a protected amino or protected hydroxy group, each protecting group may be cleaved as previously described.

The compound of formula (III) used in Scheme A may be prepared as described in the following examples or analogously, as long as it is not a known compound or an analogue of a known compound. Similarly, compounds of formula IV, VIII and XI used in Scheme A are known compounds or analogs of known compounds.

Compounds of formula III can be prepared by methods described in published patent applications EP-497 192-A, EP-574 758-A, EP-684 240-A and in the literature by Beckett et al, Synlett 1993, , Synlett 1998, 531). Compounds of formula IV are obtained from commercial suppliers or prepared by the method of Zwierzak, Synthesis 1987, 485. Compounds of formula VIII were obtained from commercial suppliers or prepared by the method of Teodozyl et al, Rocz, Chem 1976, 50 (2), 367 (CAN 85: 62908). Compounds of formula (XI) are obtained from commercial suppliers or are prepared according to the methods described in WO 98/43968-A1; EP 314 060-A2, DE 1,9503,827-A1; Pesticide. Chem., Pro. Int. Congr. Pestic. Chem., 2nd (1972), 5, 209]; U.S. Patent 4,684,483-A; And J. Med. Med. Chem., 1971, 14, 990; Chem. Lett., 1974, 8, 859; Bioorg. Med., Chem., 1994, 2, 305 and Bioorg. Med. Chem. Lett., 1992, 2, 1717).

Referring to Scheme B, the following steps are carried out, each step, namely acylation of a compound of formula V with a compound of formula XII, deprotection by the latter TFA and reaction of the obtained compound of formula XIII with an O-protected hydroxylamine of formula VIII Can be carried out in a manner analogous to that described in Scheme A, corresponding to the acylation of the compound of formula X, the deprotection of the compound of formula VI and the condensation of the compound of formula VII with the O-protected hydroxylamine of formula VIII This is done in a similar way. When the product obtained from the condensation of the compound of the formula XIII with the O-protected hydroxylamine of the formula VIII contains a protected acyl group R ²⁰ and / or contains a protecting group in R ³⁰ , the protecting group (s) Can be cut in a similar manner.

If desired, certain compounds shown in Scheme B can be interconverted. As a result, for example, R ⁴ -CH ₂ CH = The compound of formula V represents a CH ₂ Pd (OAc) ₂ and a tri (lower alkyl) amine, such as tri aryl or heteroaryl in the presence of an amine and an aryl iodide by reacting R To give the corresponding compounds of formula (V) which represent ⁴ - (CH ₂ ) ₃ - (aryl or heteroaryl). Also, for example, compounds of formula (XII) wherein R &lt; ⁴ &gt; represents phthalimido-lower alkyl are conveniently treated at about room temperature with hydrazine hydrate in an organic solvent which is inert under the reaction conditions, such as methanol or lower alkanols such as ethanol To give a product of formula XII, corresponding to formula XII, wherein R &lt; ⁴ &gt; represents amino-lower alkyl. Subsequently, the amino group is displaced in a conventional manner, for example by reaction with a suitable (hetero) aromatic carboxylic acid or a reactive derivative thereof, e.g. a corresponding carboxylic acid halide, to produce the desired R ⁴ group.

Referring to Scheme C, the first step involves the conversion of a carboxylic acid of formula III to the corresponding methyl ester of formula XIV. This is done in a known manner, for example by reaction with methanol in the presence of a condensing agent such as a tertiary organic base such as 4-dimethylaminopyridine and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide .

Deprotection of the compound of formula XIV by the next two steps of Scheme C, namely TFA, and condensation of the obtained compound of formula XV with the O-protected hydroxylamine of formula VIII afforded the deprotection of the compound of formula VI and the resulting compound of formula VII Is carried out in a manner analogous to that described in Scheme A with respect to the condensation of an acid of formula VIII with an O-protected hydroxylamine of formula VIII.

In the next step, the obtained compound of formula (XVI) is converted to a compound of formula (X) by reaction with trimethylaluminium and hydrazine or substituted hydrazine of formula (IV). The reaction is suitably carried out in an organic solvent which is inert under the reaction conditions such as halogenated hydrocarbons (e.g. dichloromethane) at a temperature from about room temperature to about 60 캜.

Subsequently, the acylation product of the compound of formula (V) is selectively cleaved when the acylated product contains the protected acyl group R ²⁰ and / or contains a protecting group in R ³⁰ . This acylation and selective deprotection is carried out in a manner analogous to that described above with respect to Scheme A. [

In the first step of Scheme D, the carboxylic acid of formula XVII is conveniently activated using oxalyl chloride and then reacted with a substituted hydrazine of formula XVIII to give a compound of formula XIX. The reaction is conveniently carried out in the presence of a base, for example a tertiary organic amine such as triethylamine, in an organic solvent which is inert under the reaction conditions, for example in halogenated hydrocarbons such as dichloromethane, at about 0 ° C.

Followed by reaction of the compound of formula (XIX) with trimethylaluminum and the O-protected hydroxylamine of formula (VIII) followed by selective deprotection of all protected acyl groups present in the reaction product to give the desired starting material of formula (II). Conveniently, the reaction may be carried out in an organic solvent which is inert under the reaction conditions, such as halogenated hydrocarbons such as dichloromethane, at a temperature from about room temperature to about 60 DEG C, while deprotection may be carried out in a manner analogous to that described above.

The carboxylic acid of formula (XVII) used in Scheme D and the substituted hydrazine of formula (XVIII) are known compounds or analogs of known compounds which may be prepared by analogous methods to known compounds.

As noted above, the hydrazine derivatives provided by the present invention inhibit the release of TNF-a from mammalian cells. This can be demonstrated using in vitro test methods described below.

The THP1 cells were diluted such that the antibiotic and 10% bovine cultured in RPMI 1640 medium supplemented with fetal calf serum and collected by centrifugation, ⁵ × 10 5 cells / ㎖ in the above medium supplemented with 20mM HEPES buffer. A aliquot (200 ml) of this cell suspension was plated on a 96 well culture plate and incubated at 37 [deg.] C for 0.5 hour before the test compound was added. The test compound was dissolved in dimethylsulfoxide (DMSO) to a concentration of 1.2 mM, and this was diluted with phosphate buffered saline / 10% DMSO solution to a final concentration of test compound of 10 ^-9 to 10 ^-5 M, The concentration was tested twice. The cells are incubated at 37 ℃ with the test compounds for 0.5 hour, then LPS (bacterial lipopolysaccharide), a concentration of 2mg / ㎖ was added such that, for incubation at a relative humidity of 95% in an atmosphere containing 5% CO ₂ 37 Lt; 0 &gt; C for 3 hours. After centrifugation at 260 g for 10 minutes, aliquots of each supernatant were removed and the amount of TNF- [alpha] was assessed by ELISA (R & D Systems Europe Ltd., Aberdeen, UK). The concentration of the test compound (IC ₅₀ ), which inhibits approximately 50% of the TNF-a release induced by LPS, is calculated by the computer from the dose-response curve.

The results obtained in the above tests using representative compounds of formula I are listed in Table 1 below.

compound IC ₅₀ (nM) A 303 B 589 C 201 D 345

compound:

A = (E) -2 '-( D-alanyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) 4-methylvalerohydrazide,

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

2 '- [2- (1-imidazolyl) acetyl] - (4-phenyl-3-butenyl] 2'-isobutyl-4-methylvalerohydrazide,

D = (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- - &lt; / RTI &gt; piperidinyl) carbamoyl] valerohydrazide

The hydrazine derivatives provided by the present invention (i. E. The compounds of formula I and their pharmaceutically acceptable salts) can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the pharmaceutical preparations may also be administered rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

For the preparation of pharmaceutical preparations the present hydrazine derivatives may be formulated with a therapeutically inert inorganic or organic carrier. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts may be used as carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. However, depending on the nature of the active ingredient, no carrier is generally required in the case of soft gelatine capsules. Suitable carriers for the preparation of solutions and syrups are water, polyols, sucrose, phosgene, glucose and the like. Suitable carriers for the preparation of injection solutions are, for example, water, alcohols, polyols, glycerin, vegetable oils and the like. Natural oils, hardened oils, waxes, fats, semi-liquid polyols and the like are suitable carriers for the production of suppositories.

The pharmaceutical preparations may also contain preservatives, stabilizers, wetting agents, emulsifiers, flavoring agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, blocking agents or antioxidants. The pharmaceutical preparations may also contain other therapeutically active substances .

It is also an object of the present invention to prepare medicaments containing hydrazine derivatives and therapeutically acceptable carriers as described above, as well as to prepare such medicaments. Said method comprising making a compound of formula I, or a pharmaceutically acceptable salt thereof, in a galenical administration form together with a therapeutically inert carrier material and, if desired, one or more additional therapeutically active substances.

It is a further object of the present invention to provide a method of treating diseases, particularly inflammatory and autoimmune diseases (such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and psoriasis), osteoarthritis, respiratory diseases (such as asthma and chronic obstructive pulmonary disease) The use of the hydrazine derivatives provided by the present invention in the treatment of cardiovascular diseases (e. G., Congestive heart failure), fever, hemorrhage and sepsis. The dosage can vary within wide limits and is, of course, adjusted to the individual requirements in each particular case. Generally, when administered to an adult, a daily dosage of about 1 to 20 mg / kg, preferably about 3 to 5 mg / kg is suitable, but may exceed the upper limit if it is found convenient to exceed the upper limit. This daily dose can be administered as a single dose or as divided doses.

The following examples illustrate the invention.

Example 1

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

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-2 '-( Nt-butoxycarbonyl-D-prolyl) -4-methylvalerohydrazide in 5 ml dioxane was treated with 4 ml 4 M hydrogen chloride in dioxane. The mixture was stirred at room temperature for 2 hours and diluted with diethyl ether. The solid was filtered off and washed with diethyl ether and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] 0.367 g of 2 '-( D-prolyl) -4-methylvalerohydrazide hydrochloride were obtained in the form of a white solid.

MS: 473 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A with Solvent B and Solvent B content 20% for 5 minutes and increasing to 60% from 5 minutes to 20 minutes; Flow rate 1 ml / min. Retention time: 15.585 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-2 '-( Nt-butoxycarbonyl-D-prolyl) -4-methylvalerohydrazide was prepared as follows.

(i) A solution of 253.3 g of 4-t-butyl hydrogen 2 (R) -isobutylsuccinate in 2 l anhydrous tetrahydrofuran was cooled to -70 C with stirring under nitrogen. 1.2 L of a 2M solution of lithium diisopropylamide in tetrahydrofuran was added dropwise and the mixture was stirred at -70 캜 for 30 minutes. A solution of 282 g of cinnamylbromide in 2 l anhydrous tetrahydrofuran was added dropwise and the mixture was allowed to gradually warm to room temperature. After stirring overnight, the tetrahydrofuran was evaporated and the residue partitioned between ethyl acetate and 2M hydrochloric acid solution. The ethyl acetate layer was washed with an additional 2M hydrochloric acid solution, water and saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and a gummy solid was obtained and suspended in 2 L of hexane. The product was filtered off (Product 1: 77.3 g). The hexane solution was treated with 109 g of cyclohexylamine and the mixture was allowed to stand at room temperature for 1 hour and at 4 [deg.] C for 16 hours. The solid formed was collected by filtration and dissolved in methyl t-butyl ether 2.5 and 1.5 L of 2 M hydrochloric acid to give a clear solution. The separated organic phase was washed twice with water and saturated sodium chloride solution and subsequently dried over anhydrous magnesium sulfate. After evaporation of the solvent, 189.8 g of solid (Product 2) was obtained. The two products were combined and dried to give 267.1 g of (E) -2 (R) - [1 (R) - (t- butoxycarbonyl) -4-phenyl- Obtained as a cream colored solid.

(ii) Synthesis of (E) -2 (R) - [1 (R) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 2-isobutyl-2 '- (Nt-butoxycarbonyl-D-prolyl) -4-methylvaleric acid was dissolved in 2.5 L of anhydrous tetrahydrofuran, And 860 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran was added dropwise over 2 hours. After stirring for 0.5 h at -78 &lt; 0 &gt; C, 330 ml of methanol was added dropwise. The mixture was allowed to gradually warm to room temperature and stirred overnight. The tetrahydrofuran was evaporated and the residue partitioned between ethyl acetate and 2M hydrochloric acid solution. The ethyl acetate phase was washed successively with two portions of hydrochloric acid solution, two portions of water and saturated sodium chloride solution, and then dried over magnesium sulfate. After evaporation, 1 (S), 2 (R) and 1 (R) of E-2- [1- (t-butoxycarbonyl) 2 (R) &lt; / RTI &gt; isomers. The epimerization procedure was repeated three times to obtain a substantially enriched mixture of 1 (S), 2 (R) isomers. The crude product was dissolved in 2500 ml of hexane and the solution was treated with 89 ml of t-butylamine. After standing at 4 [deg.] C, the precipitated salt was filtered out and dried. 210.3 g of a pale cream colored solid was obtained which was converted to the free acid by the procedure described above and (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) Butenyl] -4-methylvaleric acid as a yellow solid.

(iii) To a solution of (E) -2 (R) - [1 (S) - (t- butoxycarbonyl) carbamoyl] -4-phenyl-3-butenyl] -4-methylvaleric acid 4.05 kg of the solution was cooled to 4 DEG C and treated with 1.97 kg of hydroxybenzotriazole hydrate and 2.466 kg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and stirred at 4 DEG C for 2 hours . After 3.895 kg of isobutyl hydrazine ditosylate salt was added, 2.36 L of N-methylmorpholine was added. The mixture was stirred for 2 h at 4 &lt; 0 &gt; C and stirred at room temperature for 50 h, diluted with 12 l of 2M hydrochloric acid and 12 l of methyl t-butyl ether and the organic layer was separated. The organic phase was washed with water, saturated sodium bicarbonate solution and water and evaporated to give a thick creamy solid. Recrystallization from hexane afforded (E) -2 (R) - [1 (S) - (t- butoxycarbonyl) -4-phenyl-3-butenyl] -2'-isobutyl- Hydrazide 2.47 kg in the form of a cream colored solid.

MS: 417 (M + H) &lt; ⁺ & gt ^; .

(iv) To a solution of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -2'- A solution of 40.0 g of methyl valerohydrazide and 11.2 ml of pyridine was stirred under a nitrogen atmosphere. 16.3 ml of trifluoroacetic anhydride was added and the mixture was stirred for 10 minutes at room temperature and then evaporated. The residue in ethyl acetate was washed with 5% sodium bicarbonate solution, water, 2M aqueous hydrochloric acid and water. The ethyl acetate phase was dried over anhydrous magnesium sulfate and the solvent was evaporated to give (E) -2 (R) - [1 (S) - (t- butoxycarbonyl) -Isobutyl-2 '-( trifluoroacetyl) -4-methylvalerohydrazide in the form of a thick orange gum.

MS: 513 (M + H) &lt; ⁺ & gt ^; .

(v) The crude t-butyl ester obtained in part (iv) was dissolved in 250 ml of a 40% solution of trifluoroacetic acid in dichloromethane and the solution was stirred at room temperature for 2.5 hours. The solvent was evaporated and a trail of trifluoroacetic acid was removed by addition of toluene (2 x 30 mL) and evaporation. The residue was triturated with hexane to give (E) -2 (R) - [1 (S) - (carboxy) -4-phenyl-3-butenyl] -2 ' -isobutyl-2 '-( trifluoroacetyl ) -4-methylvalerohydrazide in the form of an off-white solid.

(vi) The carboxylic acid prepared in part (v) was dissolved in 90 ml of dimethylformamide and the solution was cooled to 0 C and successively O- (tetrahydro-2H-pyran-2 (RS) g and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to reach room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The ethyl acetate phase was washed with water until neutral, dried over anhydrous magnesium sulphate and evaporated. The resulting solid was triturated with hexane and eluted to give (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) 2-isobutyl-2 '-( trifluoroacetyl) -4-methylvalerohydrazide in the form of a white solid.

(vii) To a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 2-isobutyl-2 '- (trifluoroacetyl) -4-methylvalerohydrazide was dissolved in 200 ml of methanol and treated with a solution of 18.7 g of potassium carbonate in 50 ml of water for 16 hours at room temperature Respectively. Removal of the methanol by evaporation yielded a solid that was washed with water and vacuum dried over sodium hydroxide to give (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy ) Carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 460 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.46 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(viii) To a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2'-isobutyl-4-methylvalerohydrazide in 20 ml of dichloromethane was added at room temperature under nitrogen to a solution of 0.25 ml of pyridine in 4 ml of dichloromethane and 0.427 g of Nt-butoxycarbonyl-D-prolinic acid fluoride Lt; / RTI &gt; The mixture was stirred at room temperature for 16 hours and evaporated. The residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate solution. The ethyl acetate layer was washed successively with water, 5% citric acid solution and water and then dried over anhydrous magnesium sulfate. The solvent was evaporated to give (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 0.696 g of isobutyl-2 '-( Nt-butoxycarbonyl-D-prolyl) -4-methylvalerohydrazide was obtained in the form of a white foam.

MS: 657 (M + H) &lt; ⁺ & gt ^; .

Example 2

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2 '-( L- Methylvalerohydrazide hydrochloride

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Butyl-2 '- (Nt-butoxycarbonyl-L-prolyl) -4-methylvalerohydrazide in 4 ml of dioxane was treated with 4 ml of 4 M hydrogen chloride in dioxane. The mixture was stirred at room temperature for 2 hours and diluted with diethyl ether. The solid was filtered off and washed with diethyl ether and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] 2 '- (L-prolyl) -4-methylvalerohydrazide hydrochloride 0.337 g in the form of a white solid.

MS: 473 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A with Solvent B and Solvent B content 20% for 5 minutes and increasing to 60% from 5 minutes to 20 minutes; Flow rate 1 ml / min. Retention time: 15.44 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-2 '- (Nt-butoxycarbonyl-L-prolyl) -4-methylvalerohydrazide was prepared as follows.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (E) -2 (R) - [1 &lt; / RTI &gt; &lt; RTI ID = 0.0 & (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 &apos; -isobutyl-2 &apos;-( Nt-butoxycarbonyl- -Propyl) -4-methylvalerohydrazide in the form of a white solid.

Example 3

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- Methylvalerohydrazide hydrochloride

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- butenyl] -2'-isobutyl--2 '- (N, N - ?? di -t- butoxycarbonylamino -D- Lai chamber) -4-methyl ballet starting from hydrazide (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Zid &lt; / RTI &gt; hydrochloride as a white solid.

MS: 504 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 9.955 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- '- (N ^?, N ^? - di-t-butoxycarbonyl-D-lysyl) -4-methylvalerohydrazide was used as starting material as follows.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide and N?, N ^{? -Di} -t-butoxycarbonyl-D-lysine acid fluoride as starting materials (R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- Methylvalerohydrazide hydrochloride in the form of a white solid.

Example 4

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

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- butenyl] -2'-isobutyl--2 '- (N, N - ?? di -t- butoxycarbonylamino -L- Lai chamber) -4-methyl ballet starting from hydrazide (E) -2 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2 &apos;-( L-lysyl) -4- methylvalerohydra Zid &lt; / RTI &gt; hydrochloride as a white solid.

MS: 504 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 9.955 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- '- (N ^?, N ^? - di-t-butoxycarbonyl-L-lysyl) -4-methylvalerohydrazide was used as starting material as follows.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide and N?, N ^{? -Di} -t-butoxycarbonyl-L-lysine acid fluoride as starting materials (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- '- (N ^?, N ^? - di-t-butoxycarbonyl-L-lysyl) -4-methylvalerohydrazide in the form of a white solid.

MS: 788 (M + H) &lt; ⁺ & gt ^; .

Example 5

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

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- A solution of 0.38 g of isobutyl-2 '- (Ot-butyl-D-seryl) -4-methylvalerohydrazide was treated with 0.144 g of p-toluenesulfonic acid. The mixture was stirred at room temperature for 3.5 hours and evaporated to give a solid. This was triturated with diethyl ether and then dried and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- '- (Ot-butyl-D-seryl) -4-methylvalerohydrazide p-Toluenesulfonate 0.38 g in the form of a white solid.

MS: 519 (M + H) &lt; ⁺ & gt ^; .

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

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-2 '-( Ot-butyl-D-seryl) -4-methylvalerohydrazide was prepared as follows.

(i) To a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Methyl-2-isobutyl-4-methylvalerohydrazide in 5 ml of dichloromethane was added dropwise to a solution of N- (9-fluorenylmethyloxycarbonyl) -Ot-butyl-D-serine 0.578 g of a solution of the acid fluoride and 0.119 g of pyridine. The mixture was stirred at room temperature for 16 hours and diluted with ethyl acetate. The solution was washed with 5% aqueous sodium bicarbonate solution, water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to give (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) 0.88 g of isobutyl-2 '- [N- (9-fluorenylmethyloxycarbonyl) -Ot-butyl-D-seryl] -4-methylvalerohydrazide was obtained in the form of a white foam.

MS: 825 (M + H) &lt; ⁺ & gt ^; .

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4 -Phenyl-3-butenyl] -2'-isobutyl-2'- [N- (9-fluorenylmethyloxycarbonyl) -Ot- butyl- D -seryl] -4- methylvalerohydrazide 0.86 g of the solution was stirred at room temperature for 3 hours. The solution was evaporated and the residue was treated with diethyl ether. The ethereal solution was filtered and evaporated. (E) -2 (R) - [1 (S) - [(Tetrahydro-2 (RS) -pyranyloxy) -lH- Carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyl-2'- [N- (9- fluorenylmethyloxycarbonyl) -Ot-butyl- 0.39 g of valero hydrazide was obtained in the form of a gum.

MS: 603 (M + H) &lt; ⁺ & gt ^; .

Example 6

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

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy ) Carbamoyl] -4-phenyl-3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide in 50 ml of tetrahydrofuran was treated with 0.14 g of p-toluenesulfonic acid. The mixture was stirred at room temperature for 1.7 hours and evaporated to give a foam. This foam was triturated with diethyl ether and dried and dried to give (E) -2 ' - [(1-amino- 1 -cyclopentyl) carbonyl] -2 (R) - [1 (S) - Yl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide 0.32 g of p-toluenesulfonate was obtained in the form of a white solid.

MS: 487 (M + H) &lt; ⁺ & gt ^; .

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

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyl Oxy) carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide was prepared as follows.

(i) To a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2'-isobutyl-4-methylvalerohydrazide in 10 ml of dimethylformamide was treated at room temperature under nitrogen with 0.119 g of pyridine and 0.42 g of N- (9-fluorenylmethyloxycarbonyl) Lt; / RTI &gt; acid chloride. The mixture was stirred at room temperature for 16 hours and diluted with ethyl acetate. The solution was washed with 5% aqueous sodium bicarbonate solution, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a foam which was crystallized from diethyl ether / hexane to give (E) -2 ' - [(1-amino- 1- (9- fluorenylmethyloxycarbonyl) 4-phenyl-3-butenyl] -2 &apos; -isobutyl-4 (S) - [(tetrahydro- -Methylvalerohydrazide in the form of a white solid.

MS: 793 (M + H) &lt; ⁺ & gt ^; .

(ii) A solution of (E) -2 '- [(1-amino-1- (9-fluorenylmethyloxycarbonyl) -1-cyclopentyl) carbonyl ] -2 (R) - [1 (S) - [(tetrahydro-2 (RS) A solution of 0.69 g of valerohydrazide was stirred at room temperature for 1 hour. The solution was evaporated and the residue was treated with diethyl ether. The ethereal solution was filtered and evaporated. Chromatography on silica gel using methanol / dichloromethane (1:33) for elution followed by evaporation gave (E) -2 ' - [(1-amino- 1- cyclopentyl) carbonyl] -2 Carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide (0.36 g, &Lt; / RTI &gt; in the form of a white foam.

MS: 571 (M + H) &lt; ⁺ & gt ^; .

Example 7

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

The title compound was prepared following the procedure described in Example 6 (6), but using 1- [N- (9-fluorenylmethyloxycarbonyl) amino] -cyclopropanecarboxylic acid instead of N- (9-fluorenylmethyloxycarbonyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-propyl] -3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide p-toluenesulfonate as a white solid.

MS: 459 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.41 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 8

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl- Methylvalerohydrazide hydrochloride

(E) -2 '-( Nt-Butoxycarbonyl- beta -alaninyl) -2 (R) - [1 (S) - [(tetrahydro- Phenyl) -3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide in 10 ml of tetrahydrofuran was stirred at room temperature for 2 hours and washed with diethyl ether. The solid was filtered off and diluted with diethyl ether to give (E) -2 '-( p-alanyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) ] -2'-isobutyl-4-methylvalerohydrazide hydrochloride in the form of a white solid.

MS: 447 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.54 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(S) - [(tetrahydro-2 (RS) -pyranyloxy) -2 '-( Nt-butoxycarbonyl- beta -alaninyl) -2 ) Carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide was prepared as follows.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '- isobutyl-4-methylvalerohydrazide in 5 ml of dichloromethane was cooled to 0 ° C and 0.378 g of Nt-butoxy-carbonyl-β-alanine and 1-ethyl-3- (3- ) Carbodiimide hydrochloride (0.383 g). The mixture was stirred at room temperature for 16 hours and diluted with ethyl acetate. The solution was washed successively with water, 5% citric acid solution and water, dried over anhydrous magnesium sulfate and evaporated. (E) -2 '-( Nt-Butoxycarbonyl- beta -alaninyl) -2 (R) - [1 ( Phenyl-3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide as a white foam (0.48 g) Lt; / RTI &gt;

MS: 631 (M + H) &lt; ⁺ & gt ^; .

Example 9

(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- ) -Piperidinyl) carbonyl] valerohydrazide hydrochloride &lt; RTI ID = 0.0 &gt;

(E) - (R) - [Lambda] / - [Lambda] / - piperidinecarboxylic acid was prepared in a manner similar to the method described in Example 8, but substituting Nt-butoxycarbonyl-R-piperolinic acid for Nt-butoxycarbonyl- (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- The crude derazide hydrochloride was obtained in the form of a white solid.

MS: 487 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.02 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 10

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- ) -Piperidinyl) carbonyl] valerohydrazide hydrochloride &lt; RTI ID = 0.0 &gt;

(E) - (R) - [l- (4-methoxyphenyl) -N- (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- The crude derazide hydrochloride was obtained in the form of a white solid.

MS: 487 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Time of stay: 10.825 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 11

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl- 4-methylvalerohydrazide

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4 -Phenyl-3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide in 10 ml of DMF was treated with 0.044 g of p-toluenesulfonic acid. The mixture was stirred at room temperature for 1.5 hours and evaporated. The residue was triturated with diethyl ether, dried and dried to give (E) -2 '-( 2-acetamidoacetyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4- Phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 475 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.63 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - 4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide was prepared as follows.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-Isobutyl-4-methylvalerohydrazide in 5 ml of dichloromethane was cooled to 0 ° C and 0.351 g of N-acetyl-glycine and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 690 Mg. The mixture was stirred at room temperature for 16 hours and evaporated. The residue in ethyl acetate was washed with 5% sodium bicarbonate solution and water, dried over anhydrous magnesium sulphate and evaporated. The resulting solid was triturated with diethyl ether and filtered to give (E) -2 '- 4-phenyl-3-butenyl] -2 ' -isobutyl-4- &lt; / RTI & 0.436 g of methyl valerohydrazide were obtained in the form of a white solid.

MS: 559 (M + H) &lt; ⁺ & gt ^; .

Example 12

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

(E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyllithium in 5 ml of 4M hydrogen chloride in dioxane ] -2'-isobutyl-4-methyl-2 '- (2-ureidoacetyl) valerohydrazide in 50 ml of dichloromethane was stirred at room temperature for 2 hours and diluted with diethyl ether. The solid was filtered off, washed with diethyl ether and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- -4-methyl-2 '-( 2-ureido-acetyl) valerohydrazide in the form of a white solid.

MS: 476 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.30 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Isobutyl-4-methyl-2 '- (2-ureidoacetyl) valerohydrazide was prepared in analogy to example 11 using hydantoic acid instead of N-acetyl-glycine.

Example 13

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl- - methylvalerohydrazide

(E) -2 '-( 2-hydroxyacetyl) -2 (R) - [1 (S) - ( Hydroxy-carbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 434 (M + H) &lt; ⁺ & gt ^; .

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

Example 14

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Dile) carbonyl] valerohydrazide p-toluenesulfonate

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-isoxazole-4-carbaldehyde in analogy to the method described in example 11 using 4-pyridinecarboxylic acid instead of N- 3-butenyl] -2'-isobutyl-4-methyl-2 '- [(4-pyridyl) carbonyl] valerohydrazide p-toluenesulfonate as an off-white solid.

MS: 481 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Time of stay: 10.915 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 15

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Dile) carbonyl] valerohydrazide p-toluenesulfonate

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-isoxazole-4-carboxylic acid ethyl ester was obtained by a method similar to the method described in Example 11, using 3-pyridinecarboxylic acid instead of N- 3-butenyl] -2'-isobutyl-4-methyl-2 '- [(3-pyridyl) carbonyl] valerohydrazide p-toluenesulfonate as a white solid.

MS: 481 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Time of stay: 11.00 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 16

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl- Carbonyl] valerohydrazide p-toluenesulfonate &lt; RTI ID = 0.0 &gt;

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- A solution of 0.225 g of isobutyl-4-methyl-2 '- [(2-pyrrolyl) carbonyl] valerohydrazide was treated with 0.095 g of p-toluenesulfonic acid. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was triturated with hexane and then dried and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- -Methyl-2 ' - [(2-pyrrolyl) carbonyl] valerohydrazide p-toluenesulfonate in the form of a white solid.

MS: 469 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.93 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-iso Butyl-4-methyl-2 '- [(2-pyrrolyl) carbonyl] valerohydrazide was prepared as follows.

To a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-4-methylvalerohydrazide in 10 ml of dichloromethane was treated with a solution of the acid chloride prepared from 0.28 ml of triethylamine and 0.166 g of 2-pyrrolecarboxylic acid in 3 ml of dichloromethane at 0 &lt; 0 &gt; C under nitrogen. The mixture was stirred at 0 &lt; 0 &gt; C for 2 hours and evaporated. The residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous sodium bicarbonate solution, water, 5% citric acid solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give a solid. Chromatography of this solid on silica gel using dichloromethane methanol (50: 1) for elution followed by evaporation and trituration with diethyl ether gave (E) -2 (R) - [1 (S) - [ Methyl-2 '- [(2-pyrrolyl) carbonyl] valero &lt; / RTI &gt; 0.225 g of hydrazide were obtained in the form of a white solid.

MS: 553 (M + H) &lt; ⁺ & gt ^; .

Example 17

(RS) -hydroxypropionyl) -2 '-( 2-hydroxyethyl) -2 '-( 2- Isobutyl-4-methylvalerohydrazide

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] -4-phenyl-3-butenyl] -2 ' - (2 (RS) -hydroxypropionyl) -2 ' -isobutyl-4-methyl-valerohydrazide in 20 ml of dichloromethane was treated with 0.071 g of p-toluenesulfonic acid. The mixture was stirred at room temperature for 1 hour and evaporated to give a foam. This foam was triturated with diethyl ether, dried and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl- (RS) -hydroxypropionyl) -2 ' -isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 448 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution in which solvent B is 20% for 5 minutes and increases to 50% for 5 minutes to 35 minutes; Flow rate 1 ml / min. Retention time: 18.34 min and 18.64 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

HPLC: using 22.5% CH ₃ CN in water elution; Flow rate 1 ml / min. Retention time: 27.2 minutes and 29.5 minutes. Column type: Symmetry C ₁₈ 5μ

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (2 (RS) -hydroxypropionyl) -2'-isobutyl-4-methylvalerohydrazide was prepared as follows.

(i) A mixture of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] ] -2'-isobutyl-4-methylvalerohydrazide in 10 ml of dichloromethane was treated under nitrogen at 0 ° C with 0.557 ml of triethylamine and 0.396 g of acetyl-RS-lactic acid in 5 ml of dichloromethane Lt; / RTI &gt; The mixture was stirred at room temperature for 2 hours and diluted with dichloromethane. The solution was washed with 5% aqueous sodium bicarbonate solution, water, 5% citric acid solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give a foam. The foam was triturated with hexane to give (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 2 '- (2 (RS) -acetoxypropionyl) -2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 574 (M + H) &lt; ⁺ & gt ^; .

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-butyric acid methyl ester in a mixture of methanol (8 ml) A solution of 1.11 g of 3-butenyl] -2 '- (2 (RS) -acetoxypropionyl) -2' isobutyl-4-methylvalerohydrazide was treated with 0.524 g of potassium carbonate. The mixture was stirred at room temperature for 2 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over anhydrous magnesium sulfate and evaporated to give a foam. This foam was triturated with diethyl ether to give (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] ] -2 '- (2 (RS) -hydroxypropionyl) -2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 532 (M + H) &lt; ⁺ & gt ^; .

Example 18

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

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- A solution of 0.175 g of isobutyl-4-methyl-2 '- (D-seryl) valerohydrazide was treated with 0.073 g of p-toluenesulfonic acid. The mixture was stirred at room temperature for 3 hours and evaporated. The residue was triturated with diethyl ether and dried and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- Butyl-4-methyl-2 '-( D-seryl) valerohydrazide p-toluenesulfonate 0.160 g in the form of a white solid.

MS: 463 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.75 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-4-methyl-2 '-( D-seryl) valerohydrazide was prepared as follows.

(i) To a solution of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -2'- A solution of 0.624 g of methyl valero hydrazide is added at room temperature under nitrogen to a solution of 0.78 g of N- (9-fluorenylmethyloxycarbonyl) -Ot-butyl-D-serine acid fluoride in 5 ml of dichloromethane and a solution of pyridine 0.158 g. The mixture was stirred at room temperature for 16 hours and diluted with ethyl acetate. The solution was washed with 2M hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to give (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -2'-isobutyl- - (9-fluoromethyloxycarbonyl) -Ot-butyl-D-seryl] -4-methylvalerohydrazide in the form of a white foam.

MS: 782 (M + H) &lt; ⁺ & gt ^; .

(ii) To a solution of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -2'- Methyl-2 '-( D-seryl) valerohydrazide in 10 ml of tetrahydrofuran was treated with 5 ml of trifluoroacetic acid under nitrogen at room temperature. The mixture was stirred at room temperature for 2.5 hours and evaporated. A final trail of trifluoroacetic acid was added three times in 10 ml portions of toluene and evaporated. The residue in diethyl ether was treated with hexane to give (E) -2 (R) - [1 (S) - (carboxy) -4-phenyl-3-butenyl] -2'- 0.78 g of [N- (9-fluorenylmethyloxycarbonyl) -D-seryl] -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 670 (M + H) &lt; ⁺ & gt ^; .

(iii) 0.68 g of O- (tetrahydro-2H-pyran-2 (RS) -yl) hydroxyamine was dissolved successively by dissolving the carboxylic acid prepared in part (ii) in 3 ml of dimethylformamide and cooling to 0 & Ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride. The mixture was allowed to warm to room temperature, stirred overnight and diluted with ethyl acetate. The solution was successively washed with 5% aqueous sodium bicarbonate solution, water, 5% citric acid solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give a foam. The residue in chloromethane was treated with hexanes to give (E) -2 (R) - [1 (S) - (tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] 2-isobutyl-2 '- [N- (9-fluorenylmethyloxycarbonyl) -D-seryl] -4-methylvalerohydrazide in the form of a white solid.

MS: 769 (M + H) &lt; ⁺ & gt ^; .

(iv) A mixture of (E) -2 (R) - [1 (S) - (tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] -4 -Phenyl-3-butenyl] -2 'isobutyl-2' - [N- (9-fluorenylmethyloxycarbonyl) -D-seryl] -4- methylvalerohydrazide in Stir at room temperature for 1.75 h. The solution was evaporated to give a solid. Chromatography on silica gel using methanol / dichloromethane (1:12) for elution followed by evaporation to give (E) -2 (R) - [1 (S) - (Tetrahydro-2 (RS) -pyranyloxy ) -Carbamoyl] -4-phenyl-3-butenyl] -2'isobutyl-4-methyl-2 '- (D-seryl) -methyl valerohydrazide in the form of a white solid.

MS: 547 (M + H) &lt; ⁺ & gt ^; .

Example 19

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

Instead of N- (9-fluorenylmethyloxycarbonyl) -Ot-butyl-D-serine acid fluoride, N- (9-fluorenylmethyloxycarbonyl) -Ot-butyl- (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-Isobutyl-4-methyl-2' - (L-seryl) valerohydrazide p-toluenesulfonate as a white solid.

MS: 463 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.27 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 20

(R) -hydroxypropionyl) -2 ' - (2-hydroxyethyl) -2 '-( 2- Isobutyl-4-methylvalerohydrazide

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 & (2 (R) -hydroxypropionyl) -2 ' -isobutyl-4-methylvalerohydrazide in 10 ml of methanol was treated with 0.212 g of p-toluenesulfonic acid. The mixture was stirred at room temperature for 0.5 hour and evaporated to give a foam. This foam in ethyl acetate was washed with 5% aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate and evaporated to low volume. The separated solid was washed with cold ethyl acetate and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' R) -hydroxypropionyl) -2 ' -isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 448 (M + H) &lt; ⁺ & gt ^; .

HPLC: using 22.5% CH ₃ CN in water elution; Flow rate 1 ml / min. Retention time: 27.1 minutes. Column type: Simmetry C ₁₈ 5μ

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (2 (R) -hydroxypropionyl) -2'-isobutyl-4-methylvalerohydrazide was prepared as follows.

(i) A solution of (E) -2 (R) - [1 (S) - (tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] 2-isobutyl-4-methylvalerohydrazide in 100 ml of tetrahydrofuran was added dropwise at 0 ° C under nitrogen to a solution of 1.47 g of acetyl-R-lactic acid and 1.47 g of 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide Lt; / RTI &gt; The mixture was stirred at room temperature for 3 hours and evaporated. The residue in ethyl acetate was washed with 5% aqueous sodium bicarbonate solution, water, 5% citric acid solution, 5% aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give a foam. This foam in diethyl ether was treated with hexane to give (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) -2 '-( 2 (R) -acetoxapropionyl) -2 ' -isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 574 (M + H) &lt; ⁺ & gt ^; .

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-butyric acid methyl ester in a mixture of 20 ml of methanol and 10 ml of water. 2.71 g of 3-butenyl] -2 '- (2 (R) -acetoxypropionyl) -2'-isobutyl-4-methylvalerohydrazide was treated with 1.35 g of potassium carbonate. The mixture was stirred at room temperature for 2 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate phase was washed with water, dried over anhydrous magnesium sulphate and evaporated to give a foam. This foam was triturated with diethyl ether to give (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] ] -2 '- (2 (R) -hydroxypropionyl) -2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 532 (M + H) &lt; ⁺ & gt ^; .

Example 21

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Carbonyl) valerohydrazide hydrochloride &lt; RTI ID = 0.0 &gt;

(E) -2 (R) -methanone in a manner similar to that described in Example 8, but using Nt-butoxycarbonyl-azetidine-3-carboxylic acid in place of Nt-butoxycarbonyl- - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Hydrazide hydrochloride was obtained in the form of a white solid.

MS: 459 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.043 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 22

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl- Methylvalerohydrazide hydrochloride

(E) -2 ' - (L-alanyl) -L-alanine was prepared by a method similar to the method described in Example 8, but using Nt-butoxycarbonyl-L-alanine instead of Nt-butoxycarbonyl- ) - 2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide hydrochloride as a white solid .

MS: 447 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.35 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 23

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl- Methylvalerohydrazide p-toluenesulfonate

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl -3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide in 10 ml of DMF was treated with 0.300 g of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 3 hours and evaporated. The residue was triturated with diethyl ether and dried to give (E) -2 '-( D-alanyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) Butenyl] -2'-isobutyl-4-methylvalerohydrazide 0.858 g of p-toluenesulfonate was obtained in the form of a white solid.

MS: 447 (M + H) &lt; ⁺ & gt ^; .

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

(R) - [(S) - (tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl -3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide was prepared as follows.

(iv) and (v) except that (i) N- (9-fluorenylmethoxycarbonyl) -D-alanine acid chloride was used in place of trifluoroacetic anhydride. Phenyl) -3-butenyl] -2'-isobutyl-2 '- [N- (9-fluorenylmethoxy) Carbonyl) -D-alanyl] -4-methylvalerohydrazide in the form of a white foam.

(ii) To a solution of (E) -2 (R) - [1 (S) - (carboxy) -4-phenyl-3-butenyl] -2'-isobutyl- (Tetrahydro-2H-pyran-2 (RS) -yl) hydroxylamine 0.60 g of the title compound was obtained as a colorless oil g and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was stirred at room temperature overnight, then diluted with ethyl acetate and washed with 5% aqueous citric acid, 5% sodium bicarbonate and brine. The ethyl acetate layer was then dried over magnesium sulphate and evaporated. The residue was triturated with hexane / diethyl ether (2: 1) to give (E) -2 (R) - [1 (S) - (Tetrahydro-2- (RS) -pyranyloxy) Phenyl-3-butenyl] -2'-isobutyl-2 '- [N- (9-fluorenylmethoxycarbonyl) -D-alanyl] -4- methylvalerohydrazide as white Obtained as a solid.

MS: 753 (M + H) &lt; ⁺ & gt ^; .

(R) - [1 (S) - (tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -2'-isobutyl-2'- [N- (9-fluorenylmethoxycarbonyl) -D-alanyl] -4- methylvalerohydrazide And the mixture was stirred at room temperature for 2 hours. The solution was evaporated and the residue was triturated with hexane / diethyl ether (2: 1). The residue was purified by flash column chromatography on silica gel using methanol / dichloromethane (5:95) for elution to give (E) -2 '-( D-alanyl) -2 (R) (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide as a white In the form of a foam.

MS: 531 (M + H) &lt; ⁺ & gt ^; .

Example 24

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4- Methylvalerohydrazide p-toluenesulfonate

(RS) -pyranyloxy) carbamoyl] -4-phenyl-isoquinoline-2-carboxylic acid ethyl ester in 10 ml of methanol was added to a solution of (E) -2 '-( 2- 3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide in 10 ml of tetrahydrofuran was treated with 0.144 g of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 3 hours and evaporated. The residue was triturated with diethyl ether and dried and dried to give (E) -2 '-( 2-aminoacetyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) 3-butenyl] -2'-isobutyl-4-methylvalerohydrazide 0.350 g of p-toluenesulfonate was obtained in the form of a white solid.

MS: 433 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.38 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - (tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] -4- Phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide was prepared as follows.

(i) The title compound was prepared in analogy to Example 23, parts (i) and (ii) except that (N-phthaloyl) -glycine acid chloride was used in place of N- (9-fluorenylmethoxycarbonyl) (R) - [1 (S) - (tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] -4-phenyl-3- 2'-isobutyl-2 '- [(N-phthaloyl) -2-aminoacetyl] -4-methylvalerohydrazide in the form of a white solid.

(R) - [1 (S) - (tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] -2 ' -Isobutyl-2 ' - [(N-phthaloyl) -2-aminoacetyl] -4-methylvalerohydrazide in 5 ml of tetrahydrofuran was treated with 5.5 ml of hydrazine hydrate. The mixture was stirred at room temperature for 2 hours and then evaporated. The residue was taken up in ethyl acetate and washed with water and brine. The ethyl acetate phase was then dried over magnesium sulphate and evaporated. The residue was triturated with hexane to give (E) -2 '-( 2-aminoacetyl) -2 (R) - [1 (S) - (tetrahydro- 2 (RS) -pyranyloxy) Phenyl-3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide in the form of a white solid.

Example 25

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

(E) -2 (R) - [1 (S) - (tetrahydro-2 (RS) - (Nt-butoxycarbonyl-L-leucyl) -4-methylvalerohydrazide were treated with 3 ml of 4M hydrogen chloride in dioxane. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was triturated with diethyl ether, filtered off and dried to obtain (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl- Isobutyl-2 '-( L-leucyl) -4-methylvalerohydrazide hydrochloride in the form of a white solid.

MS: 489 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.50 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-2 '- (Nt-butoxycarbonyl-L-leucyl) -4-methylvalerohydrazide was prepared as follows.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- (R) - [1 &lt; RTI ID = 0.0 &gt; (R) -2-methylbutanoic &lt; / RTI &gt; acid ethyl ester was prepared in analogy to the method described in example 1 part (viii) starting from 2- (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 &apos; -isobutyl-2 &apos;-( Nt-butoxycarbonyl- Lt; / RTI &gt; leucyl) -4-methylvalerohydrazide in the form of a white solid.

MS: 673 (M + H) &lt; ⁺ & gt ^; .

Example 26

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Valerohydrazide hydrochloride

(E) -2 ((2-ethoxy-4-fluoro-phenyl) -ethanone was obtained by a method similar to the method described in Example 25, except that Nt-butoxycarbonyl-D-leucic acid fluoride was used instead of Nt-butoxycarbonyl- R ') - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Lt; / RTI &gt; chloride in the form of a white solid.

MS: 489 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 20% to 99% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.47 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 27

(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- L-alanyl) valerohydrazide hydrochloride

(R) - [1 (S) - (tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] -4-phenyl-3-butenyl] -2 ' A solution of 0.600 g of isobutyl-4-methyl-2 '- (N-methyl-Nt-butoxy-carbonyl-L-alanyl) valerohydrazide in 1 ml of dioxane was treated with 1 ml of 4M hydrogen chloride in dioxane. The mixture was stirred at room temperature for 2.5 hours and then diluted with 50 mL of diethyl ether. Filtered to obtain (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Methyl-L-alanyl) valerohydrazide hydrochloride in the form of a white solid.

MS: 461 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.78 min. Solvent A: H2O / 0.1% TFA; Solvent B: CH3CN / 0.085% TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-4-methyl-2 '- (N-methyl-Nt-butoxycarbamoyl-L-alanyl) valerohydrazide hydrochloride was prepared as follows.

A solution of 0.233 g of N-methyl-Nt-butoxycarbamoyl-L-alanine in 10 ml of tetrahydrofuran was cooled to -10 DEG C and treated with 0.140 ml of N-ethylmorpholine and 0.143 ml of isobutyl chloroformate. The mixture was stirred for an additional 10 min at -10 <0> C and then (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) Phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide. The mixture was heated to &lt; RTI ID = 0.0 &gt; 0 C &lt; / RTI &gt; The mixture was then diluted with ethyl acetate and washed successively with 5% aqueous citric acid, 5% aqueous sodium bicarbonate and brine. Dried over magnesium sulphate and evaporated to give (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- phenyl- 0.608 g of 2'-isobutyl-4-methyl-2 '- (N-methyl-Nt-butoxycarbamoyl-L-alanyl) valerohydrazide was obtained in the form of a white solid.

MS: 645 (M + H) &lt; ⁺ & gt ^; .

Example 28

(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- D-alanyl) valerohydrazide hydrochloride

Butoxycarbonyl-D-alanine was used in place of N-methyl-Nt-butoxycarbonyl-L-alanine, (E) - 2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- ) &Lt; / RTI &gt; valerohydrazide hydrochloride as a white solid.

MS: 461 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.15 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 29

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-iso Butyl-4-methylvalerohydrazide

(R) - [(S) - (tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - 4-phenyl-3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide in 5 ml of DMF was treated with 0.06 g of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was triturated with diethyl ether and dried to give (E) -2 '- (N-acetyl-L-alanyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4- Phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 489 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.82 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2 '-( N-acetyl-L- ] -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide was prepared as follows.

A solution of 0.144 g of N-acetyl-L-alanine in 10 ml of tetrahydrofuran was cooled to -10 DEG C and treated with 0.140 ml of N-ethylmorpholine and 0.143 ml of isobutyl chloroformate. The mixture was stirred at 10 [deg.] C for a further 10 min and then (E) -2 (R) - [1 (S) - [(tetrahydro- -3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide. The mixture was allowed to warm to 0 &lt; 0 &gt; C and stirred continuously for 1.5 hours. The mixture was then diluted with ethyl acetate and washed successively with 5% aqueous citric acid, 5% aqueous sodium bicarbonate and brine. Dried over magnesium sulfate and evaporated to give (E) -2 '- (N-acetyl-L-alanyl) -2 (R) - [1 (S) - [(tetrahydro- Carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 573 (M + H) &lt; ⁺ & gt ^; .

Example 30

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-iso Butyl-4-methylvalerohydrazide

(E) -2 '- (N-acetyl-L-alanyl) -L-alanine was obtained in a manner similar to the method described in Example 29, except that N-acetyl- -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide as a white solid .

MS: 489 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.84 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 31

Methyl-2 '-( 2 (RS) - &lt; / RTI &gt; -Ureido &lt; / RTI &gt; propionyl) valerohydrazide

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- A solution of 0.232 g of isobutyl-4-methyl-2 '- (2 (RS) -ureidopropionyl) valerohydrazide was treated with 0.03 g of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was triturated with diethyl ether and dried and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- Butyl-4-methyl-2 '- (2 (RS) -ureidopropionyl) valerohydrazide in the form of a white solid.

MS: 490 (M + H) &lt; ⁺ & gt ^; .

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

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-4-methyl-2 '- (2 (RS) -ureidopropionyl) valerohydrazide was prepared as follows.

A solution of 0.145 g of N-carbamyl-DL-alanine in 5 ml of dimethylformamide was treated with 0.140 ml of N-ethylmorpholine and (E) -2 (R) - [1 (S) - [(tetrahydro- ) -Pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide. The mixture was treated with 0.15 g of 1-hydroxy-benzotriazole and 0.211 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. Stirring was continued at room temperature and then the mixture was diluted with ethyl acetate and successively washed with 5% aqueous citric acid, 5% aqueous sodium bicarbonate and brine. Drying over magnesium sulfate and evaporation gave 0.570 g of a white foam which was purified by flash column chromatography on silica gel using ethyl acetate for elution to give a white foam which was used in the next step to give (E) -2 (R) - [1 Methyl-2 '-( 2 (RS) -2-methyl-2 '-( isobutyl) -Ureidopropionyl) valerohydrazide in the form of a white solid.

MS: 574 (M + H) &lt; ⁺ & gt ^; .

Example 32

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Amino) acetyl] valerohydrazide p-toluenesulfonate

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- A solution of 0.590 g of isobutyl-4-methyl-2 '- [2- (dimethylamino) acetyl] valerohydrazide was treated with 0.210 g of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was triturated with diethyl ether and dried and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- Butyl-4-methyl-2 '- [2- (dimethylamino) acetyl] valerohydrazide p-toluenesulfonate in the form of a white solid.

MS: 461 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 10% to 99% over 15 minutes; Flow rate 1 ml / min. Retention time: 13.76 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-4-methyl-2 '- [2- (dimethylamino) acetyl] valerohydrazide was prepared as follows.

A solution of 0.155 g of N, N-dimethylglycine in 10 ml of dimethylformamide was successively added to a solution of 0.167 ml of N-ethylmorpholine, 0.216 g of 1-hydroxybenzotriazole and 1 g of 1-ethyl-3- (3- Lt; / RTI &gt; carbodiimide hydrochloride. After stirring at room temperature for 1 hour, a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) &Lt; / RTI &gt; 2-isobutyl-4-methylvalerohydrazide were added. After continued stirring overnight, the mixture was diluted with ethyl acetate and washed successively with 5% aqueous sodium bicarbonate and brine. Dried over magnesium sulphate and evaporated to give (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- phenyl- 2'-isobutyl-4-methyl-2 '- [2- (dimethylamino) acetyl] valerohydrazide in the form of a white solid.

MS: 545 (M + H) &lt; ⁺ & gt ^; .

Example 33

(RS) - (hydroxycarbamoyl) -4-phenylbutyl] -2 ' -isobutyl-4-methylvalerohydrazide

(RS) - [(benzyloxy) carbamoyl] -4-phenylbutyl] -2 '-( 2-methoxy- Isobutyl-4-methylvalerohydrazide in 50 ml of tetrahydrofuran was hydrogenated in the presence of 0.240 g of 5% Pd / C over 1.5 hours. The catalyst was filtered off and the solvent was evaporated. The residue was triturated with diethyl ether to give 2'- (D-alanyl) -2 (R) - [1 (RS) - (hydroxycarbamoyl) -4-phenylbutyl] -2'- 4-methylvalerohydrazide 0.480 g Obtained as a colorless glass.

MS: 449 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.62 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(RS) - [(benzyloxy) carbamoyl] -4-phenylbutyl] -2 '-( benzyloxycarbonyl-D-alanyl) -Isobutyl-4-methylvalerohydrazide is prepared as follows:

(i) Starting from 2 (R) - [1 (RS) - (t-butoxycarbonyl) -4-phenylbutyl] -4-methylvaleric acid and isobutylhydrazine ditosylate salt as starting materials, (RS) - [(t-butoxycarbonyl) -4-phenylbutyl] -2 ' -isobutyl-4-methylvaletate in the same manner as in the method described in Part Lohydrazide was obtained in the form of a clear oil.

(ii) To a solution of 2 (R) - [1 (RS) - [(t-butoxycarbonyl) -4-phenylbutyl] -2 ' -isobutyl-4- methylvalerohydrazide 1.5 in 25 ml dichloromethane g was treated with 0.454 g of 4-ethylmorpholine and 0.880 g of N-benzyloxycarbonyl-D-alaninate fluoride and the mixture was then stirred overnight at room temperature. The mixture was successively washed with water, 2M aqueous hydrochloric acid, water and brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a residue which was purified by flash column chromatography on silica gel using ethyl acetate / hexane (1: 3) for elution to give 2'- (N-benzyloxycarbonyl-D-alanyl ) -2 (R) - [1 (RS) - (t-butoxycarbonyl) -4-phenylbutyl] -2'-isobutyl-4-methylvalerohydrazide in the form of a clear oil Respectively.

MS: 624 (M + H) &lt; ⁺ & gt ^; .

(iii) To a solution of 2 '- (N-benzyloxycarbonyl-D-alanyl) -2 (R) - [1 (RS) - (t-butoxycarbonyl) -4-phenylbutyl] -2'-isobutyl-4-methylvalerohydrazide in 5 ml of trifluoroacetic acid was treated with 5 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to give 2'- (N-benzyloxycarbonyl-D-alanyl) -2 (R) - [1 (RS) - (carboxy) -4-phenylbutyl] -2'- -Methylvalerohydrazide in the form of a pale yellow foam.

(iv) To a solution of 2 '- (N-benzyloxycarbonyl-D-alanyl) -2 (R) - [1 (RS) - (carboxy) -4-phenylbutyl] Isobutyl-4-methylvalerohydrazide in 10 ml of tetrahydrofuran was cooled to 0 &lt; 0 &gt; C under a nitrogen atmosphere. The mixture was then treated with 1.25 g of O-benzylhydroxylamine and 0.467 g of 1-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide hydrochloride and warmed to room temperature overnight. The mixture was diluted with water and extracted twice with ethyl acetate. The ethyl acetate layer was then washed with aqueous 2M hydrogen chloride, water and brine. Dried over anhydrous magnesium sulfate and the solvent was evaporated to give 2 '- (N-benzyloxycarbonyl-D-alanyl) -2 (R) - [1 (RS) - [(benzyloxy) carbamoyl] Butyl] -2 &apos; -isobutyl-4-methylvalerohydrazide in the form of a white foam.

Example 34

(RS) - (hydroxycarbamoyl) butyl] -2 ' -isobutyl-4-methylvalerohydrazide hydrochloride

(RS) - [(benzyloxy) carbamoyl] -3-butenyl] -2 '-( 2-methoxy- A solution of 0.560 g of isobutyl-4-methylvalerohydrazide was hydrogenated in the presence of 0.150 g of 5% Pd / C for 2 hours. The catalyst was filtered off and the solvent was evaporated. The residue was triturated with diethyl ether to give 2'- (D-alanyl) -2 (R) - [1 (RS) - (hydroxycarbamoyl) butyl] -2'-isobutyl- 0.480 g of rohiodrazide were obtained in the form of a white solid. The solids were then dissolved in 2 ml of dioxane and the solution was treated with 0.5 ml of 4M hydrogen chloride in dioxane. The mixture was stirred at room temperature over 15 minutes and then diluted with diethyl ether. Filtered and dried to give 0.188 g of 2 '-( D-alanyl) -2 (R) - [1 (RS) - (hydroxycarbamoyl) butyl] -2'-isobutyl-4-methylvalerohydrazide Lt; / RTI &gt; as a white solid.

MS: 373 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.54 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(RS) - [(benzyloxy) carbamoyl] -3-butenyl] -2 '-( 2-methyl- -Isobutyl-4-methylvalerohydrazide was prepared as follows.

(RS) - (t-butoxycarbonyl) -4-methylvaleric acid instead of 2 (R) - [1 (RS) - (t- (N-benzyloxycarbonyl-phenyl) -acetamide was prepared in the same manner as described in part (i) to (iv) of example 33, but using 3- 2-isobutyl-4-methylvalerohydrazide in the form of a colorless glass in the form of a colorless glass in the form of a colorless glass (R) - [(RS) - [(benzyloxy) carbamoyl] .

MS: 595 (M + H) &lt; ⁺ & gt ^; .

Example 35

(RS) - (hydroxycarbamoyl) butyl] -2 ' -isobutyl-4-methylvalerohydrazide

(R) - [4- (4-tert-butoxycarbonyl) -4-phenylbutyl] -2'-isobutyl-4-methylvalerohydrazide instead of 2 (R) Cyclohexyl-1 (RS) - [t-butoxycarbonyl) butyl] -2'-isobutyl-4-methylvalerohydrazide was used in a manner similar to the method described in Example 33 - (D-alanyl) -2 (R) - [4-cyclohexyl-1 (RS) - (hydroxycarbamoyl) butyl] -2'- Obtained as a solid.

MS: 455 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.87 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(RS) - (t-butoxycarbonyl) butyl] -2'-isobutyl-4-methylvalerohydrazide used as a starting material was prepared as follows .

(RS) - (t-butoxycarbonyl) -4-phenylbutyl] -2 ' -isobutyl ester prepared in Example 33, part (i) Butyl-4-methylvalerohydrazide in 20 ml of tetrahydrofuran was hydrogenated in the presence of 0.300 g of palladium (IV) oxide for 2 hours. The catalyst was filtered off and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel using ethyl acetate / hexane (1: 5) for elution to give 2 (R) - [4-cyclohexyl-1 (RS) - (t- Carbonyl) butyl] -2 ' -isobutyl-4-methylvalerohydrazide in the form of a colorless oil.

MS: 425 (M + H) &lt; ⁺ & gt ^; .

Example 36

(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Nyl) valerohydrazide p-toluenesulfonate

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] A solution of 0.288 g of isobutyl-4-methyl-2 '- (D-phenylalanyl) valerohydrazide was treated with 0.099 g of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 3 hours and evaporated. The residue was triturated with diethyl ether and then triturated with hexane and then dried and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) ] -2'-isobutyl-4-methyl-2 '- (D-phenylalanyl) valerohydrazide 0.232 g of p-toluenesulfonate in the form of a pale yellow solid.

MS: 523 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and Solvent B content of 10% for 5 minutes and increasing to 99% from 5 minutes to 15 minutes; Flow rate 1 ml / min. Retention time: 12.01 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-4-methyl-2 '- (D-phenylalanyl) valerohydrazide was prepared as follows.

(i) To a solution of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -2'- A solution of 1.01 g of methyl-valerohydrazide was treated with 0.22 ml of pyridine and 1.04 g of N- (9-fluorenylmethyloxycarbonyl) -D-phenylalanylic acid fluoride. The mixture was stirred at room temperature overnight and then evaporated and the residue taken up in ethyl acetate. The ethyl acetate phase was washed with 2M aqueous hydrogen chloride, 5% aqueous sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate. The solvent was evaporated to give (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -2'-isobutyl- - (9-fluorenylmethoxycarbonyl) - (D-phenylalanyl) -4-methylvalerohydrazide as a pale yellow oil.

MS: 786 (M + H) &lt; ⁺ & gt ^; .

(ii) Synthesis of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -2'-isobutyl- (V) - (vi) by proceeding in analogy to the procedure described in example 1, part (v) - (vi), starting from 7- (4-fluorenylmethyloxycarbonyl) (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- - [N- (9-fluorenylmethyloxycarbonyl) - (D-phenylalanyl)] - 4-methylvalerohydrazide as a white solid.

MS: 745 (M-THP + H) &lt; ⁺ & gt ^; .

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-iso (Iii), starting from butyl-2 '- [N- (9-fluorenylmethyloxycarbonyl) - (D- phenylalanyl)] - 4- methylvalerohydrazide, -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-4-methyl-2 '-( D-phenylalanyl)] - valerohydrazide as a cloudy pink solid.

MS: 607 (M + H) &lt; ⁺ & gt ^; .

Example 37

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- - &lt; / RTI &gt; pyrrolidinyl) acetyl] valerohydrazide p-toluenesulfonate

To a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] A solution of 0.363 g of butyl-4-methyl-2 '- [2- (1-pyrrolidinyl) acetyl] valerohydrazide was treated with 0.133 g of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 4 hours and evaporated. The residue was triturated with diethyl ether, dried and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'isobutyl -4-methyl-2 '- [2- (1-pyrrolidinyl) acetyl] valerohydrazide 0.317 g of p-toluenesulfonate in the form of a white solid.

MS: 487 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 10% to 99% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.24 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Isobutyl-4-methyl-2 '- [2- (1-pyrrolidinyl) acetyl] valerohydrazide was prepared as follows.

A solution of 0.309 g of 2- (1-pyrrolidinyl) acetic acid hydrogen bromide in 20 ml of dimethylformamide was successively added to a solution of 0.324 ml of N-ethyl-morpholine, 0.212 g of 1-hydroxybenzotriazole, &Lt; / RTI &gt; 3-dimethylaminopropyl) -carbodiimide hydrochloride. After stirring at room temperature for 1 hour, a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) &Lt; / RTI &gt; 2-isobutyl-4-methylvalerohydrazide were added. After stirring at room temperature overnight, the solvent was evaporated and replaced by ethyl acetate. The ethyl acetate phase was washed with 5% aqueous sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate. Evaporation and trituration of the residue with diethyl ether gave (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Butenyl] -2 'isobutyl-4-methyl-2' - [2- (1-pyrrolidinyl) acetyl] valerohydrazide in the form of a white solid.

MS: 571 (M + H) &lt; ⁺ & gt ^; .

Example 38

(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Nocetyl] valerohydrazide p-toluenesulfonate

(E) -2 (R) - [1 - (1-Pyrrolidinyl) methanone (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methyl- The sulfonate was obtained in the form of a white solid.

MS: 503 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 10% to 99% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.10 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 39

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

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 ' -Isobutyl-2 '-( 2-methoxyacetyl) -4-methylvalerohydrazide in 5 ml dioxane was treated with 1 ml 4 M hydrogen chloride in dioxane. The mixture was stirred at room temperature for 1.5 hours and then diluted with 80 ml of diethyl ether. Filtered to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl-2 '-( 2- methoxyacetyl) -4-methylvalerohydrazide in the form of a white solid.

MS: 448 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.13 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-2 '-( 2-methoxyacetyl) -4-methylvalerohydrazide was prepared as follows.

A solution of 0.180 g of methoxyacetic acid in 10 ml of dimethylformamide was successively added to a solution of 0.254 ml of N-ethylmorpholine, 0.270 g of 1-hydroxy-benzotriazole and 1 g of 1-ethyl-3- (3-dimethylaminopropyl) Lt; RTI ID = 0.0 &gt; 0.384g &lt; / RTI &gt; After stirring at room temperature for 1 hour, a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] ] -2'-isobutyl-4-methylvalerohydrazide were added. After stirring overnight at room temperature the solvent was evaporated and replaced with ethyl acetate. The ethyl acetate layer was washed with 5% aqueous citric acid, 5% aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. Evaporated and triturated with diethyl ether to give (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2'-isobutyl-2 '- (2-methoxyacetyl) -4-methylvalerohydrazide in the form of a white solid.

MS: 532 (M + H) &lt; ⁺ & gt ^; .

Example 40

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Amino) acetyl] valerohydrazide

(E) -2 (R) - [1 (S) - (hydroxymethyl) -lH-indole in a manner similar to the method described in Example 39, but using Nt-butoxycarbonyl-N-methylglycine instead of methoxyacetic acid. 4-methyl-2 '- [2- (methylamino) acetyl] valerohydrazide hydrochloride as a white solid. Respectively.

MS: 447 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.54 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 41

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt; dl) carbonyl] valerohydrazide hydrochloride

-2 (R) - [1 (S) - (hydroxy- (R) -2-methyl-1 H-pyrrolo [2,3-d] pyrimidin- 4-methyl-2 '- [(2-pyridyl) - carbonyl] valerohydrazide hydrazide in the form of a white solid .

MS: 481 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.38 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 42

2 '- [(3 (RS) -2- (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] ) -Piperidinyl) carbonyl] valerohydrazide hydrochloride &lt; RTI ID = 0.0 &gt;

(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -3-phenyl-N-butoxycarbonyl-β-alanine was used in place of racemic Nt-butoxycarbonyl nipecotic acid. (3 (RS) -piperidinyl) carbonyl] valerohydrazide hydrochloride was obtained as a white solid in the form of a white solid &lt; RTI ID = 0.0 &gt; .

MS: 487 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.89 min and 11.01 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 43

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 2-methoxy- -Isobutyl-4-methylvalerohydrazide &lt; / RTI &gt;

(E) -2 '-( tetrahydro-2 (RS) -carboxylic acid was prepared by a method similar to the method described in Example 8 but using tetrahydro-2 (RS) -furan carboxylic acid instead of Nt-butoxycarbonyl- (RS) -furoyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide Lt; / RTI &gt; as a white solid.

MS: 474 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.39 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 44

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Carbonyl] valerohydrazide hydrochloride &lt; RTI ID = 0.0 &gt;

(E) -2 (R) - [1 - ((R) -2-methyl-isoxazolyl) propionic acid in analogy to the method described in example 8, but using Nt-butoxycarbonyl isonipecotic acid instead of Nt-butoxycarbonyl- Methyl-2 '- [(4-piperidinyl) carbonyl] valerohydrazide hydro Lt; / RTI &gt; chloride in the form of a white solid.

MS: 487 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.55 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 45

(L-valyl) -2'-isobutyl-4-methyl-2'- (L-valyl) Valerohydrazide hydrochloride

(R) - [1 (S (R) - [1 (S) -2-ethoxy- ) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl-4-methyl-2 '-( L- valyl) valerohydrazide hydrochloride as a white solid Respectively.

MS: 475 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.09 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 46

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl Methyl valerohydrazide hydrochloride &lt; RTI ID = 0.0 &gt;

(E) -2 '-( D- [alpha] -D- [alpha] -aminobutyric acid was prepared by a method similar to the method described in Example 8, but using Nt-butoxycarbonyl D-alpha aminobutyric acid instead of Nt-butoxycarbonyl- -Aminobutyryl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4- methylvalerohydrazide hydrochloride Lt; / RTI &gt; as a white solid.

MS: 461 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.89 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 47

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- -2 (S) -pyrrolidinyl) carbonyl] valerohydrazide

-2 (R) - [1 (S) - (hydroxy- (R) - [ Carbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl-4-methyl-2 '-( 5-oxo-2- (S) -pyrrolidinyl) carbonyl] valerohydrazide Lt; / RTI &gt; as a white solid.

MS: 487 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.56 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 48

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- -2 (R) -pyrrolidinyl) carbonyl] valerohydrazide

(E) -2 (R) - [1 (S) - (hydroxy- &lt; RTI ID = 0.0 &gt; Methyl-2 '- [(5-oxo-2 (R) -pyrrolidinyl) carbonyl] valerohydrazide Lt; / RTI &gt; as a white solid.

MS: 487 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.54 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 49

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl Methyl valerohydrazide hydrochloride &lt; RTI ID = 0.0 &gt;

(E) -2 '-( DL- [beta] -D-glucopyranosyl- [beta] -aminobutyric acid was prepared by a method similar to the method described in Example 8, but using Nt-butoxycarbonyl [ -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide hydrochloride Obtained as a white solid.

MS: 461 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.54 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 50

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Dinoacetyl) valerohydrazide p-toluenesulfonate

(E) -2 (R) - [1 &lt; / RTI &gt; (1-pyrrolidinyl) acetamide was obtained by a method similar to the method described in Example 37 but using 2-piperidinoc acetic acid hydrogen bromide instead of 2- (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methyl- The sulfonate was obtained in the form of a white solid.

MS: 501 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 10% to 99% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.62 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 51

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

(E) - (R) - [l- (4-methoxyphenyl) -N- Phenyl-3-butenyl] -2 ' -isobutyl-4-methyl-2 '-( D-norvalyl) valerohydrazide hydrochloride) Obtained as a white solid.

MS: 475 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution to vary the content of solvent B from 5% to 95% over 15 minutes; Retention time: 11.30 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 52

Phenyl-3-butenyl] -2 ' -isobutyl-4-methyl-2 '-( D-valyl) Valerohydrazide p-toluenesulfonate

(9-fluorenylmethyloxycarbonyl) -O-tert-butyl-D-serine acid fluoride instead of N- (9-fluorenylmethyloxycarbonyl) -D-valine acid fluoride (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' - Isobutyl-4-methyl-2 '-( D-valyl) valerohydrazide p-toluenesulfonate as a white solid.

MS: 475 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.11 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 53

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

(E) -methanone was obtained in a manner similar to the method described in Example 8, except that Nt-butoxycarbonyl-3-amino-2 (RS) -methylpropionic acid was used instead of Nt-butoxycarbonyl- -2 '- (3-amino-2 (RS) -methylpropionyl) -2 (R) Isobutyl-4-methylvalerohydrazide hydrochloride in the form of a white solid.

MS: 461 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.75 min and 10.87 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.85%} TFA. Column type: HYPERPEP 300A.

Example 54

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

2- (1-pyrrolidinyl) acetic acid The title compound was prepared in analogy to the procedure described in Example 37 but using 2- (diethylamino) acetic acid hydrogene bromide in place of hydrogene bromide. (E) -2'- (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvaleric acid Hydrazide p-toluenesulfonate was obtained in the form of a white solid.

MS: 489 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution increasing the content of solvent B from 10% to 99% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.65 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 55

(R) - [1 (S) -hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- ) &Lt; / RTI &gt; acetyl] valerohydrazide hydrochloride

(E) -2 (R) - [1 (S) -hydro-quinolinecarboxylic acid was prepared by a method similar to the method described in Example 8, but using (methylthio) acetic acid instead of Nt-butoxycarbonyl- 4-methyl-2 ' - [2- (methylthio) acetyl] valerohydrazide hydrochloride as a white solid Respectively.

MS: 464 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.09 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 56

-2 ' - [2- (1-imidazolyl) acetyl] -2 '-( methanesulfonyl) -Isobutyl-4-methylvalerohydrazide p-Toluenesulfonate

(E) -2 (R) - [1 (S) - ((R) - Hydroxy-carbamoyl) -4-phenyl-3-butenyl] -2 '-( 2- (1- imidazolyl) acetyl] -2 '-( isobutyl-4-methylvalerohydrazide p- The title compound was obtained as a white solid.

MS: 464 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.99 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 57

Methyl-2 ' - [2- (l- (l- &lt; / RTI &gt; Piperazinyl) acetyl] valerohydrazide hydrochloride &lt; RTI ID = 0.0 &gt;

(E) -2 (R) - [1 - ((1-piperazinyl) acetic acid was prepared by a method similar to the method described in Example 8, but using 2- (1-piperazinyl) acetic acid instead of Nt-butoxycarbonyl- Methyl-2 ' - [2- (1-piperazinyl) acetyl] valerohydrazide Hydrochloride Lt; / RTI &gt; chloride in the form of a white solid.

MS: 502 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.48 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 58

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( tetrahydro- -2'-isobutyl-4-methylvalerohydrazide p-Toluenesulfonate

(E) -2 ' - ((2-ethoxy-4-thiazin-4-yl) acetic acid) was prepared in analogy to the procedure described in example 11, (S) -hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4- Methylvalerohydrazide p-toluenesulfonate as a white solid.

MS: 551 (M + H) &lt; ⁺ & gt ^; .

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

Example 59

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( Cyclopropylmethyl) -2- (R) -4-methylvalerohydrazide p-toluenesulfonate

(RS) -pyranyloxy) carbamoyl) -2 '-( D-alanyl) -2 '-( cyclopropylmethyl) -2 (R) - [1 (S) - [(tetrahydro- -2 '- (D-alanyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide in a manner analogous to that described in the first paragraph of Example 5 using 0.083 g of Phenyl) -3-butenyl] -4-methylvalerohydrazide p-toluenesulfonyl chloride was used in place of 4- (2-chloro- 0.064 g of toluene sulfonate were obtained in the form of a pale pink solid.

MS: 445 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.392 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyran-2-ylmethyl) -2 '-( D- Phenyl) -3-butenyl] -4-methylvalerohydrazide was prepared as follows.

(i) A mixture of 11 g of pentafluorophenol and 4.12 g of 1,3-dicyclohexylcarbodiimide in 50 ml of hexane was stirred at room temperature for 5 minutes. The resulting solid was filtered, washed with hexane, and then dried and diluted with (E) -2 (R) - [1 (S) - (t- butoxycarbonyl) &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt; decenyl] -4-methylvaleric acid. The mixture was left overnight at 4 &lt; 0 &gt; C and filtered to remove dicyclohexylurea. The filtrate was evaporated, the residue was dissolved in 50 ml of dichloromethane and 3 ml of hydrazine hydrate was added to the resulting solution. The mixture was stirred for 6 hours and then washed successively with 5% citric acid solution, saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with hexane / ethyl acetate (4: 1) and the resulting solid was filtered. 4.68 g of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide was obtained in the form of off-white solid Respectively.

MS: 361 (M + H) &lt; ⁺ & gt ^; .

(ii) To a solution of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4- methylvalerohydrazide in 5 ml dichloromethane , 0.097 g of cyclopropanecarboxaldehyde and a solution of 4-toluenesulfonic acid crystals was stirred for 0.2 hour on a 4 A molecular sieve. The mixture was filtered and the solvent was evaporated with 5 mL of methanol. Several bromocresol green crystals were added to make a yellow solution. 0.092 g of sodium cyanoborohydride was added thereto several times. A 4M solution of hydrogen chloride in dioxane was added periodically to keep the solution yellow. The methanol was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The ethyl acetate phase was washed twice with 5% sodium bicarbonate and then with saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified on silica gel using hexane / ethyl acetate (4: 1) for elution. (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydra 0.258 g of zid were obtained in the form of a white solid.

MS: 415 (M + H) &lt; ⁺ & gt ^; .

(iii) (E) -2 '-( cyclopropylmethyl) -2 (R) - [1 (S) - (t- butoxycarbonyl) (I) to (iv) using the same procedure as described in example 18, part (i) to (iv), using the starting material as a starting material and N- (9-fluorenylmethyloxycarbonyl) (S) - [(tetrahydro) -2 (RS) -pyranyloxy) carbonyl] -2 '-( D- alanyl) -2 '-( cyclopropylmethyl) -2 Yl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide in the form of a gum.

MS: 529 (M + H) &lt; ⁺ & gt ^; .

Example 60

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl Valerohydrazide p-toluenesulfonate

(RS) -pyranyloxy) carbamoyl-4 (S) - [(tetrahydro) -2 '-( D-alanyl) -2 (3-butenyl] -4-methylvalerohydrazide in a manner analogous to that described in the first paragraph of Example 5, -Benzyl-2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide 0.096 g of p-toluenesulfonate as a pale pink Obtained as a solid.

MS: 481 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.190 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2 '-( D-alanyl) Yl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide was prepared as follows.

(i) 3.46 g of (E) -2 (R) - [1 (S) - (t- , 4.0 g of N-methylmorpholine, 2.95 g of benzylhydrazine dihydrochloride and 1.7 g of 1-hydroxybenzotriazole hydrate was cooled to 0 占 폚 with stirring under nitrogen and 1-ethyl-3- (3-dimethylamino Propyl) carbodiimide were added. The mixture was allowed to slowly warm to room temperature and stirred overnight. The dimethylformamide was evaporated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The ethyl acetate phase was washed sequentially with water, 5% citric acid solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, ethyl acetate was evaporated to give a yellow gum. Hexane to give (E) -2 ' -benzyl-2 (R) - [l (S) - (t- butoxycarbonyl) -4-phenyl-3-butenyl] -4- methylvalerohydra 1.87 g of zid was obtained in the form of a white solid.

MS: 451 (M + H) &lt; ⁺ & gt ^; .

(ii) Synthesis of (E) -2 ' -benzyl-2 (R) - [1 (S) - (t- butoxycarbonyl) -4-phenyl-3-butenyl] -4- methylvalerohydrazide (E) - (l-) -methanone was obtained by a method similar to the method described in Example 18, Part (i) to (iv) using N- (9-fluorenylmethyloxycarbonyl) 2 - (D-alanyl) -2'-benzyl-2 (R) - [1 (S) - [(tetrahydro) -2 (RS) -pyranyloxy) carbamoyl- Butenyl] -4-methylvalerohydrazide in the form of a white foam.

MS: 565 (M + H) &lt; ⁺ & gt ^; .

Example 61

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2 '-( 3-methyl-2-butenyl) valerohydrazide p-Toluenesulfonate

(RS) -pyranyloxy) carbamoyl] -4-phenyl-3- (4-fluorophenyl) (E) -2 (3-methyl-2-butenyl) valerohydrazide was obtained in a manner similar to that described in the first paragraph of Example 5 using 0.072 mg of 2- - (D-alanyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -Butenyl) valerohydrazide p-toluenesulfonate (0.052 g) as an off-white solid.

MS: 459 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.052 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -4-methyl-2 '- (3-methyl-2-butenyl) valerohydrazide was prepared as follows.

(E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide and 3-methyl crotonaldehyde -2 '- (D-alanyl) -2 (R) - [1 (S) - [( (3-methyl-2-butenyl) valerohydrazide was prepared from sword Lt; / RTI &gt;

MS: 543 (M + H) &lt; ⁺ & gt ^; .

Example 62

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-octyl Valerohydrazide p-toluenesulfonate

(RS) -pyranyloxy) carbamoyl] -4-phenyl-3- (4-fluorophenyl) -2 '- (D-alanyl) - butenyl] -4-methyl-2'-octylvalerohydrazide in a manner analogous to that described in the first paragraph of Example 5, 0.131 g of 2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'- octylvalerohydrazide p- Obtained as a solid.

MS: 503 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Time of stay: 13.283 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -4-methyl-2'-octylvalerohydrazide was prepared as follows.

(R) - [(S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide and octylaldehyde as starting materials to give (R) - [1 (S) - [(tetrahydro-2 (R) - (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methyl-2'-octylvalerohydrazide in the form of a gum.

MS: 587 (M + H) &lt; ⁺ & gt ^; .

Example 63

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-p-tolylcarbamoyl] -2 '-( D- &Lt; / RTI &gt; decenyl] -4-methylvalerohydrazide p-Toluenesulfonate

(R) - [(S) - [(tetrahydro) -2 (RS) -pyranyloxy) -2 '-( D-alanyl) -2 '-( cyclohexyl) -2 '-( 2-fluorophenyl) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide in a manner analogous to that described in the first paragraph of Example 5, Phenyl) -3-butenyl] -4-methylvaleric acid as a colorless oil. 0.196 g of hydrazide p-toluenesulfonate were obtained in the form of a pale yellow solid.

MS: 487 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.987 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(RS) - [(S) - [(tetrahydro-2 (RS) -2-methyl- -Pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide was prepared as follows.

(R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide and cyclohexanecarboxaldehyde -2 '-( D-alanyl) -2 ' - [(cyclohexyl) methyl] -2 &lt; RTI ID = 0.0 &gt; Phenyl) -3-butenyl] -4-methylvalerohydrazide was obtained in the form of a gum. Respectively.

MS: 571 (M + H) &lt; ⁺ & gt ^; .

Example 64

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-neo Pentyl valerohydrazide p-toluenesulfonate

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- -2 '- (D-alanyl) - 1 -methyl-2'-neopentylvalerohydrazide in a manner analogous to that described in the first paragraph of Example 5, 0.065 g of 2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'- neopentylvalerohydrazide p- Obtained as a light yellow solid.

MS: 461 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.45 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -4-methyl-2'-neopentylvalerohydrazide was prepared as follows.

(S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide and trimethylacetaldehyde as starting materials -2 '- (D-alanyl) -2 (R) - [1 (S) - [(tetrahydro-thiophene-2-carboxylic acid ethyl ester)] was prepared by a method similar to the method described in example 59, part (ii) -2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methyl-2'-neopentylvalerohydrazide in the form of a gum.

MS: 545 (M + H) &lt; ⁺ & gt ^; .

Example 65

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2 '-( 3,3-dimethylbutyl) valerohydrazide p-Toluenesulfonate

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- (E) -2 '-( 3-methylpiperazin-1-yl) -1H-imidazol- Phenyl-3-butenyl] -4-methyl-2 '-( 3,3-dimethylbutyl) valerate &lt; / RTI &gt; 0.163 g of rohiodrazide p-toluenesulfonate in the form of a pale pink solid.

MS: 475 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.652 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -4-methyl-2 '- (3,3-dimethylbutyl) valerohydrazide was prepared as follows.

(E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4- methylvalerohydrazide and 3,3- -2 '- (D-alanyl) -2 (R) - [1 (S) -piperazin- Phenyl] -3-butenyl] -4-methyl-2 '- (3,3-dimethylbutyl) valerohydrazide was reacted with In the form of a gum.

MS: 559 (M + H) &lt; ⁺ & gt ^; .

Example 66

(E) -2 '-( D-alanyl) -2 '-( 2-ethylbutyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) ] -4-methylvalerohydrazide p-Toluenesulfonate

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2 '-( D-alanyl) -2 '-( D- (4-methylphenyl) -3-butenyl] -4-methylvalerohydrazide in a manner analogous to that described in the first paragraph of Example 5, Phenyl) -3-butenyl] -4-methylvalerohydrazide (2-ethoxyethyl) -2 '-( 2-ethylbutyl) -2 0.188 g of p-toluenesulfonate was obtained in the form of a pale pink solid.

MS: 475 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.735 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(S) - [(tetrahydro-2 (RS) - (2-ethylbutyl) Phenyl) -3-butenyl] -4-methylvalerohydrazide was prepared as follows.

(R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide and 2-ethylbutyraldehyde -2 '-( D-alanyl) -2 '-( 2-ethylbutyl) -2 ( Phenyl) -3-butenyl] -4-methylvalerohydrazide was obtained in the form of a gum. Respectively.

MS: 559 (M + H) &lt; ⁺ & gt ^; .

Example 67

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3- (2- Butenyl] -4-methylvalerohydrazide p-Toluenesulfonate

(R) - [(S) - [(tetrahydro) -2 (RS) -pyranyl] -2 '-( 2,2-dichloroethyl) 2-yl) oxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide was used in the manner analogous to the method described in the first paragraph of Example 5, (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl 0.057 g of valerohydrazide p-toluenesulfonate was obtained in the form of a pale pink solid.

MS: 487 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.127 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -2 '-( D-alanyl) -2 '-( 2,2- dichloroethyl) ) -Pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide was prepared as follows.

(S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide and dichloroacetaldehyde as starting materials -2 '-( D-alanyl) -2 '-( 2,2-dichloroethyl) -2 (R ) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide in gum form .

MS: 571 (M + H) &lt; ⁺ & gt ^; .

Example 68

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

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- 2 '- (D-alanyl) -2'-isopropyl-4-methylvalerohydrazide was prepared in analogy to the method described in the first paragraph of Example 5 using 0.082 g as starting material. (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isopropyl-4-methylvalerohydrazide p-toluenesulfonate 0.072 g in the form of a pale pink solid.

MS: 433 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.337 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -2 ' -isopropyl-4-methylvalerohydrazide was prepared as follows.

(R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide and acetone as starting materials to give (R) - [1 (S) - [(tetrahydro-2 (R) - (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-isopropyl-4-methylvalerohydrazide in the form of a gum.

MS: 517 (M + H) &lt; ⁺ & gt ^; .

Example 69

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2 '-( 2 (S) -methylbutyl) valerohydrazide p-Toluenesulfonate

(RS) -pyranyloxy) carbamoyl] -4-phenyl-3- (4-fluorophenyl) (E) - (4-methyl-2 '- (2 (S) -methylbutyl) valerohydride as starting materials in a manner analogous to that described in the first paragraph of Example 5, Phenyl) -3-butenyl] -4-methyl-2 '- (2 (S) -Methylbutyl) valerohydrazide p-toluenesulfonate (0.121 g) in the form of an off-white solid.

MS: 461 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.237 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -4-methyl-2 '- (2 (S) -methylbutyl) valerohydride was prepared as follows.

(i) To a solution of (E) -2 (R) - [1 (S) - (t- butoxycarbonyl) -4-phenyl-3-butenyl] -4- methylvalerohydrazide And 0.288 g of p-toluenesulfonyl chloride was stirred at room temperature for 2 hours. The pyridine was evaporated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed successively with water, 1 M hydrochloric acid, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was crystallized from ether / hexane to give (E) -2 (R) - [1 (S) - (t- butoxycarbonyl) -4-phenyl- (p-toluenesulfonyl) valerohydride in the form of a white solid.

MS: 515 (M + H) &lt; ⁺ & gt ^; .

(ii) To a solution of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl- 0.323 g of (p- toluenesulfonyl) valerohydrazide, 0.111 g of (S) (+) - l-bromo-2-methylbutane and 0.053 g of anhydrous potassium carbonate was stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (5: 1) for elution. (S) -methylbutyl] -4-methyl-2 '- (2 (S) -methylbutyl) -2 &apos;-( p-toluenesulfonyl) valerohydrazide in the form of a gum. MS: 585 (M + H) &lt; ⁺ & gt ^; . The column was subsequently eluted to yield 0.21 g of the hydrazide used in the reaction.

(iii) (E) -2 (R) - [1 (S) - (t-Butoxycarbonyl) -4-phenyl- Methylbutyl) -2 '- (p-toluenesulfonyl) valerohydrazide and 0.135 g of magnesium powder was placed in an ultrasonic bath for 1.5 hours. The methanol was evaporated and the residue was partitioned between diethyl ether and potassium hydrogen sulphate solution. The ether layer was washed sequentially with potassium hydrogen sulfate solution, 5% sodium bicarbonate solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (5: 1) for elution. (S) -methylbutyl] -4-methyl-2 '- (2 (S) -methylbutyl) 0.146 g of valero hydrazide was obtained in the form of a white solid.

MS: 431 (M + H) &lt; ⁺ & gt ^; .

(iv) (E) -2 (R) - [1 (S) - (t-Butoxycarbonyl) -4-phenyl- (I) to (iv) using N- (methylbutyl) valerohydrazide and N- (9-fluorenylmethyloxycarbonyl) -D-alanine fluoride as starting materials, -2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-lH-pyrrolo [2,3-d] -3-butenyl] -4-methyl-2 '- (2 (S) -methylbutyl) valerohydrazide in gum form.

MS: 544 (M + H) &lt; ⁺ & gt ^; .

Example 70

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenyl Valerohydrazide p-toluenesulfonate

(RS) -pyranyloxy) carbamoyl] -4-phenyl-3- (4-fluorophenyl) -2 '- (D-alanyl) -4'-methyl-2'-phenylvalerohydrazide was prepared in a manner similar to that described in the first paragraph of Example 5 using 0.189 g of Phenyl) -3-butenyl] -4-methyl-2 ' -phenylvalerohydrazide as a pale pink solid &lt; RTI ID = 0.0 &gt;Lt; / RTI &gt;

MS: 467 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.328 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -4-methyl-2 ' -phenylvalerohydrazide was prepared as follows.

(i) 1.75 g of (E) -2 (R) - [1 (S) - (t- butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid in 15 ml of dimethylformamide Was cooled to 0 C and a solution of 0.5 ml of N-methylmorpholine, 0.8 g of 1-hydroxybenzotriazole, 0.6 g of phenylhydrazine and 1 g of 1-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide Lt; / RTI &gt; chloride. The solution was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous sodium hydrogen carbonate solution. The ethyl acetate phase was washed sequentially with water, 5% citric acid solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (6: 1) for elution. A yellow oil was obtained which was crystallized from hexane to give (E) -2 (R) - [1 (S) - (t- butoxycarbonyl) -4-phenyl- Apos; -phenylhydrazide &lt; / RTI &gt; in the form of a white solid.

MS: 437 (M + H) &lt; ⁺ & gt ^; .

(ii) To a solution of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methyl- A solution of 0.35 g of hydrazide was cooled to 0 &lt; 0 &gt; C and 0.9 g of pyridine was added. A solution of 0.24 g of N-phthaloyl-D-alanine in 4 ml of dichloromethane was added dropwise, and the mixture was stirred at 0 ° C for 2.5 hours. The dichloromethane was evaporated and the residue was dissolved in ethyl acetate and washed sequentially with 5% citric acid solution, water, 2 min of 5% sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (3: 1) for elution and partially racemized to give 0.316 g of product containing 13% 2- (S) -phthalimidopropyl isomer . The product was recrystallized from a mixture of 4 ml of dichloromethane and 20 ml of hexane to obtain (E) -2 (R) - [1 (S) - (tert- -4-methyl-2'-phenyl-2 '- (2 (R) -phthalimidopropyl) valerohydrazide was obtained.

MS: 638 (M + H) &lt; ⁺ & gt ^; .

(iii) (E) -2 (R) - [1 (S) - (t-Butoxycarbonyl) -4-phenyl-3-butenyl] -4-methyl- 2 (R) - [1 ((R) -phthalimidopropyl) valerohydrazide was prepared by a method similar to the method described in Example 18, Part (ii) and (iii) Methyl-2'-phenyl-2 '- (2 (R) -phthalate Imidopropyl) valerohydrazide in the form of a colorless glass.

MS: 681 (M + H) &lt; ⁺ & gt ^; .

(iv) To a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] -4- phenyl- -4-methyl-2'-phenyl-2 '- (2 (R) -phthalimidopropyl) valerohydrazide in 10 ml of tetrahydrofuran was treated with 0.04 g of hydrazine hydrate. The mixture was stirred for 5.5 hours and then the solvent was evaporated. The residue was suspended in 2 mL of dichloromethane and stirred at 4 &lt; 0 &gt; C overnight. The suspended solids were filtered off and the filtrate was evaporated and the residue was purified by flash chromatography on silica gel using dichloromethane / methanol (20: 1) for elution. (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- Phenyl] -4-methyl-2 &apos; -phenylvalerohydrazide in the form of a colorless foam.

MS: 551 (M + H) &lt; ⁺ & gt ^; .

Example 71

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenyl Valerohydrazide p-toluenesulfonate

(RS) -pyranyloxy) carbamoyl] -4-phenyl-3-p-tolylcarbamoyl) -2 '-( l- 2 '- (L-alanyl) -2-methyl-2'-phenylvalerohydrazide as starting materials in a manner analogous to that described in the first paragraph of Example 5, ) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2 ' -phenylvalerohydrazide p- Toluene sulfonate 0.068 g Lt; / RTI &gt; as a pink solid.

MS: 467 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.337 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -4-methyl-2 ' -phenylvalerohydrazide was prepared as follows.

(E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylhydrazide and N- -2 '-( L-alanyl) -2 (R) -2 '-( R) -alanine chloride was used in analogy to the method described in example 70, part (ii) Phenyl] -3-butenyl] -4-methyl-2 &apos; -phenylvalerohydrazide was obtained as colorless &lt; RTI ID = 0.0 & &Lt; / RTI &gt; in the form of a foam.

MS: 551 (M + H) &lt; ⁺ & gt ^; .

Example 72

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2 '-( D) - (1-naphthyl) valerohydrazide p-Toluenesulfonate

(RS) -pyranyloxy) carbamoyl] -4-phenyl-3 (R) -2 '-( D) (E) -2 &lt; / RTI &gt; (tert-butoxycarbonylamino) -propionamide was obtained by a method similar to that described in the first paragraph of Example 5 using 0.131 g of the title compound as a starting material. Phenyl-3-butenyl] -4-methyl-2 '- (1-naphthyl) Yl) valerohydrazide p-toluenesulfonate (0.165 g) in the form of a pale pink solid.

MS: 517 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.122 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(RS) -pyranyloxy) carbamoyl] -2 '-( D, L-alanyl) -2 (R) - [1 (S) - [(tetrahydro- -4-phenyl-3-butenyl] -4-methyl-2 '- (1-naphthyl) valerohydrazide was prepared as follows.

(i) from (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid and 1-naphthylhydrazine (R) - [1 (S) - (t-Butoxycarbonyl) -4-phenyl-3-butenyl] -4- Methyl-2 '-( 1-naphthyl) valerohydrazide in the form of a white solid.

MS: 487 (M + H) &lt; ⁺ & gt ^; .

(ii) (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) (Ii) from 4-phenyl-3-butenyl] -4-methyl-2 '-( 1-naphthyl) -valerohydrazide and N-phthaloyl-D- (R) - [1 (S) - [(tetrahydro- (2 (RS) - Phenyl-3-butenyl] -4-methyl-2 '-( 1-naphthyl) valerohydrazide in the form of a pale cream colored foam. Beautification occurs during (ii).

Example 73

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-isoquinolin- (3-butenyl] -4-methylvalerohydrazide p-toluenesulfonate and (E) -2 '- (D-alanyl) -2 '-( tetrahydro-4-thiopyranyl) -2- S) - [1 (R) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide p-toluenesulfonate

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyran-2 '-( tetrahydro-4-thiopyranyl) -2 '- (D-alanyl) -2' - (tetrahydro-4-thiophen-2- Phenyl) -3-butenyl] -4-methylvalerohydra (4-methylpyrrolyl) -2 (S) - [1 (R) - [(tetrahydro- (E) -2 '-( D-alanyl) -2 '-( tetrahydro-4 &lt; RTI ID = 0.0 &gt; -4-methylvalerohydrazide p-toluenesulfonate and (E) - (thiopyranyl) -2 (R) ) -2 '-( D-alanyl) -2 &apos;-( tetrahydro-4-thiopyranyl) -2 (S) - [1 (R) - (hydroxycarbamoyl) Butenyl] -4-methylvalerohydrazide in 0.09 g of a 1: 1 mixture in the form of a pink solid.

MS: 491 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution increasing the content of solvent B from 25% to 55% over 15 minutes; Flow rate 1 ml / min. Retention time: 8.535 min (Isomer 1) and 9.252 min (Isomer 2). Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (R) -2 '-( D-alanyl) -2 '-( tetrahydro-4-thiopyranyl) (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide and (E) -2 '-( D-alanyl) (S) - [1 (R) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] A mixture of methyl valero hydrazide was prepared as follows.

(i) By a method similar to that described in Example 1, parts (i) and (ii) using 4-t-butylhydrogen 2 (RS) -isobutylsuccinate and cinnamylbromide as starting materials, -2 (S) - (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4- methylvalerohydrazide and A 1: 1 mixture of [1 (R) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide was obtained in the form of a white solid.

MS: 361 (M + H) &lt; ⁺ & gt ^; .

(ii) (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4- methylvalerohydrazide and Using a 1: 1 mixture of 2 (S) - [1 (R) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide as starting material -2 '-( D-alanyl) -2 '-( tetrahydro-4-thiopyranyl) -2- (R) -methanone in analogy to the method described in example 59, part (ii) -4-methylvalerohydrazide and (E) -2 ' - [(S) - [(tetrahydro- - (D-alanyl) -2 '-( tetrahydro-4-thiopyranyl) -2 (S) - [1 (R) - [(tetrahydro- -4-phenyl-3-butenyl] -4-methylvalerohydrazide in the form of a white powder.

MS: 575 (M + H) &lt; ⁺ & gt ^; .

Example 74

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( dibenzylamino) Isobutyl propiono hydrazide p-toluenesulfonate

(RS) -pyranyloxy) carbamoyl] -4-tert-butoxycarbonylamino-2 '-( D-alanyl) -2 '- (D-phenyl-3-butenyl] -2'-isobutylpropiono hydrazide was prepared in analogy to the method described in the first paragraph of Example 5 using 0.076 g as starting material. Phenyl) -3-butenyl] -2'-isobutylpropionohydrazide A solution of p-toluene (1 ml) 0.0 &gt; sulfonate &lt; / RTI &gt; in the form of a pale pink solid.

MS: 459 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Time of stay: 10.987 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2 '-( D-alanyl) Yl] -4-phenyl-3-butenyl] -2 ' -isobutyl propionohydrazide was prepared as follows.

(i) 4-t-Butylhydrogen 2 (R) - (cyclobutylmethyl) succinate and cinnamyl bromide as starting materials in analogy to the method described in example 1, parts (i) to (iii) Phenyl) -3-butenyl] -3-cyclobutyl-2 ' -isobutylpropionohydrazide &lt; / RTI &gt;Lt; / RTI &gt; as a white solid.

MS: 428 (M + H) &lt; ⁺ & gt ^; .

(ii) Synthesis of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -3-cyclobutyl- (I) to (iv) using the same method as that described in Example 18, parts (i) to (iv), using N- (9-fluorenylmethyloxycarbonyl) ) -2 - (D-alanyl) -3-cyclobutyl-2 (R) - [1 (S) - [(tetrahydro- 3-butenyl] -2'-isobutylpropionohydrazide as a colorless gum.

MS: 543 (M + H) &lt; ⁺ & gt ^; .

Example 75

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( D) Isobutyl propiono hydrazide p-toluenesulfonate

(RS) -pyranyloxy) carbamoyl] -4 &lt; RTI ID = 0.0 &gt; (E) -2 '-( D-alanyl) -3- cyclopentyl- (E) -2 '-( D (3-Phenyl-3-butenyl] -2 &apos; -isobutylpropionohydrazide as starting materials in a similar manner to that described in the first paragraph of Example 5 using 0.205 g Phenyl) -3-cyclopentyl-2 (R) - [1 (S) - 0.222 g of toluene sulfonate were obtained in the form of a pale pink solid.

MS: 473 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.417 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2 '-( D-alanyl) -3- cyclopentyl- Yl] -4-phenyl-3-butenyl] -2 ' -isobutyl propionohydrazide was prepared as follows.

(i) 4-t-Butylhydrogen 2 (R) - (cyclopentylmethyl) succinate and cinnamyl bromide as starting materials in analogy to the method described in example 1, parts (i) to (iii) -3-cyclopentyl-2 ' -isobutylpropionohydrazide &lt; / RTI &gt; (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) Lt; / RTI &gt; as a white solid.

MS: 443 (M + H) &lt; ⁺ & gt ^; .

(ii) Synthesis of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -3-cyclopentyl- (I) to (iv) using the same method as that described in Example 18, parts (i) to (iv), using N- (9-fluorenylmethyloxycarbonyl) ) -2-tert-butoxycarbonylamino-4-phenyl-isoquinolin-2- 3-butenyl] -2'-isobutylpropionohydrazide as a colorless gum.

MS: 557 (M + H) &lt; ⁺ & gt ^; .

Example 76

(R) - [(S) - (hydroxycarbamoyl) -4- (3-pyridyl) -3-butenyl] -2'- Isobutyl-4-methylvalerohydrazide p-toluenesulfonate

(R) - [(S) - (tetrahydro) -2 (RS) -pyranyloxy) carbamoyl] -4- ( 3-pyridyl) -3-butenyl] -2'-isobutyl-4-methylvalerohydrazide in 10 ml of DMF was treated with 0.014 g of p-toluenesulfonic acid monohydrate. The mixture was stirred for 2 hours at room temperature and evaporated. The residue was triturated with diethyl ether, filtered and dried to give (E) -2 '-( D-alanyl) -2 (R) - [l (S) - (hydroxycarbamoyl) -4- Pyridyl) -3-butenyl] -2'-isobutyl-4-methylvalerohydrazide p-Toluenesulfonate 0.030 g in the form of a white solid.

MS: 448 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 8.46 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - (tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- ( 3-pyridyl) -3-butenyl] -2'-isobutyl-4-methylvalerohydrazide was prepared as follows.

(i) (R) - [(R) - [(S) - (t-Butoxycarbonyl) The title compound was prepared in a manner similar to that described in Example 1, part (i) except that 1 (RS) - (t-butoxycarbonyl) -3-butenyl] ) - [1 (RS) - (t-butoxycarbonyl) -3-butenyl] -2'-isobutyl-4-methylvalerohydrazide as a yellow oil.

MS: 341 (M + H) &lt; ⁺ & gt ^; .

(ii) A solution of 2 (R) - [1 (RS) - (t-butoxycarbonyl) -3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide 0.500 in 10 ml dimethylformamide g was treated with 0.465 g of 3-bromopyridine, 0.297 g of triethylamine, 0.017 g of palladium (II) acetate and 0.045 g of tri- (o-tolyl) phosphine. The mixture was treated at 100 &lt; 0 &gt; C for 24 hours. After cooling to room temperature, the mixture was diluted with water and extracted three times with ethyl acetate. The ethyl acetate extracts were combined, washed with water and brine, then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue on silica gel using ethyl acetate / hexane was purified by flash column chromatography (E) -2 (R) - [1 (S) - (t- butoxycarbonyl) -4- -Pyridyl) -3-butenyl] -2 &apos; -isobutyl-4-methylvalerohydrazide in the form of a yellow oil.

MS: 418 (M + H) &lt; ⁺ & gt ^; .

(iii) (E) -2 (R) - [1 (S) - (t-Butoxycarbonyl) -4- (3- pyridyl) -3-butenyl] -2'- (Ii) and (iii) using methyl valero hydrazide and N- (9-fluorenylmethoxycarbonyl) -D-alanylic acid fluoride as starting materials in a manner similar to that described in Example 33, -2-isobutyl-2 ' - [N- (9- (3-pyridyl) Fluorenylmethoxycarbonyl) -D-alanyl] -4-methylvalerohydrazide trifluoroacetate in the form of a white solid.

MS: 655 (M + H) &lt; ⁺ & gt ^; .

(iv) Synthesis of (E) -2 (R) - [1 (S) - (carboxy) -4- (3-pyridyl) -3-butenyl] -2'-isobutyl- (Ii) and (iii), using as starting materials, the title compound was obtained as a white amorphous solid in the same manner as in Example 23, (R) - [(S) - (tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (3- Pyridyl) -3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 532 (M + H) &lt; ⁺ & gt ^; .

Example 77

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- -Tetrazol-5-yl) acetyl] valerohydrazide hydrochloride

(E) -2 (R) - (4-methylpiperazin-1-yl) -ethanone was obtained by a method similar to the method described in Example 8, but using 2- (1H-tetrazol-5-yl) acetic acid instead of Nt-butyloxycarbonyl- [1 (S) - (hydroxycarbamoyl) -4-phenyl-1-butenyl] -2'-isobutyl- ] Valerohydrazide hydrochloride as a white solid.

MS: 486 (M + H) &lt; ⁺ & gt ^; .

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

Example 78

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Methyl-1-piperazinyl) acetyl] valerohydrazide p-Toluenesulfonate

(E) -2 (R) - [1 (S) -tetrahydropyran-2-yl) -ethanone in a similar manner to that described in Example 11, but using 2- - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methyl- Drazide p-toluenesulfonate was obtained in the form of a white solid.

MS: 516 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.47 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 79

(R) - [4-cyclohexyl-1 (S) - (hydroxycarbamoyl) butyl] -4-methyl- 1-yl) acetyl] valerohydrazide p-toluenesulfonate

(RS) -pyranyloxy) carbamoylbutyl] -4-methyl-2 ' - [2 &lt; RTI ID = 0.0 &gt; - (1,2,4-triazol-1-yl) acetyl] valerohydrazide as starting materials, 2'-benzyl-2 (S) - (hydroxycarbamoyl) butyl] -methyl-2'- [2- (1,2,4-triazol-1-yl) acetyl] valero 0.61 g of hydrazide p-toluenesulfonate was obtained in the form of a white solid.

MS: 527 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution increasing the content of solvent B from 10% to 90% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.82 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: 90% CH 3 CN /} 10% H 2 O / 0.085% TFA. Column type: WMC, C18, 50 x 4.6 mm

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] butyl] -4-methyl-pyrrolidine- 2 '- [2- (1,2,4-triazol-1-yl) acetyl] valerohydrazide was prepared as follows.

(i) Using (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methyl valeric acid 2 (R) - [1 (S) - (t-butoxycarbonyl) -4-cyclohexylbutyl] -4-methylvaleric acid in the form of a yellow gum.

(ii) Using 2 (R) - [1 (S) - (t-butoxycarbonyl) -4-cyclohexylbutyl] -4-methylvaleric acid and benzylhydrazine and using Nt-butoxy (Iii) to (vii) and Example 8 using 2, &lt; RTI ID = 0.0 &gt; 4-triazol-1-acetic & (S) - [(tetrahydro-2- (RS) -pyranyloxy) carbamoyl] butyl] -4-methyl-2 &apos; - [2- , 4-triazol-1-yl) acetyl] valerohydrazide in the form of a white solid.

MS: 611 (M + H) &lt; ⁺ & gt ^; .

Example 80

(S) - (hydroxycarbamoyl) butyl] -2'- [2- (1-imidazolyl) -acetyl] -4-methyl Valerohydrazide p-toluenesulfonate

(RS) -pyranyloxy) carbamoyl] butyl] -2 ' - [2- (l- Benzyl-2 (R) - [4- (4-fluorophenyl) imidazolyl) acetyl] -4-methylvalerohydrazide as starting materials in a manner analogous to that described in the first paragraph of Example 5, (S) - (hydroxycarbamoyl) butyl] -2'- [2- (1-imidazolyl) acetyl] -4-methylvalerohydrazide 0.554 g of p-toluenesulfonate as white Obtained as a solid.

MS: 526 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution increasing the content of solvent B from 10% to 90% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.17 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: 90% CH 3 CN /} 10% H 2 O / 0.085% TFA. Column type: WMC, C18, 50 x 4.6 mm

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] butyl] -2 '-( 1-imidazolyl) acetyl] -4-methyl-valerohydrazide was prepared as follows.

4-cyclohexylbutyl] -4-methylvaleric acid and benzylhydrazine were used as the starting materials and N- (t (2-hydroxyphenyl) (Iii) to (vii) and Example 8, except that imidazole-1-acetic acid was used instead of 2-benzyl-2- (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] butyl] -2 ' - [2- (1-imidazolyl) -4-methylvalerohydrazide in the form of a white solid.

MS: 610 (M + H) &lt; ⁺ & gt ^; .

Example 81

(R) - [4-cyclohexyl-1 (S) - (hydroxycarbamoyl) butyl] -4-methyl- 1-yl) acetyl] valerohydrazide p-toluenesulfonate

(RS) -pyranyloxy) carbamoyl] butyl] -2 ' - [2- (1, 2-yl) acetyl] valerohydrazide as starting materials in a manner analogous to that described in the first paragraph of Example 5 using 2'-benzyl-2 (R) - (S) - (hydroxycarbamoyl) butyl] -4-methyl-2'- [2- (1,2,3-triazol- 1- yl) acetyl] valerohydra 0.545 g of zid p-toluenesulfonate were obtained in the form of a white solid.

MS: 527 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution increasing the content of solvent B from 10% to 90% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.12 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: 90% CH 3 CN /} 10% H 2 O / 0.085% TFA. Column type: WMC, C18, 50 x 4.6 mm

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] butyl] -2 ' - [ 2- (1,2,3-triazol-1-yl) acetyl] valerohydrazide was prepared as follows.

Butoxycarbonyl-4-methylvaleric acid and benzylhydrazine in the same manner as in Example 8 using 2 (R) - [1 (S) - (t-butoxycarbonyl) benzyl-2 ((4-methoxypyridin-2-yl) -methanone was obtained by a method similar to the method described in Example 1, Part (iii) to (vii) and Example 8 using 1,2,3- Carbonyl] butyl] -2 ' - [2- (l, 2,3-triazol- Yl) acetyl] valerohydrazide in the form of a white solid.

MS: 611 (M + H) &lt; ⁺ & gt ^; .

Example 82

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 2- hydroxy Ethyl) -4-methylvalerohydrazide p-Toluenesulfonate

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- (4-methylpiperazin-1-yl) phenyl] -2'- [2- (tetrahydro-2 (RS) -pyranyloxy) ethyl] -4- methylvalerohydrazide was used as the starting material. -2 '- (D-alanyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl- (2-hydroxyethyl) -4-methylvalerohydrazide 0.009 g of p-toluenesulfonate was obtained in the form of off-white solid.

MS: 435 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution increasing the content of solvent B from 10% to 90% over 15 minutes; Flow rate 1 ml / min. Retention time: 8.80 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: 90% CH 3 CN /} 10% H 2 O / 0.085% TFA. Column type: WMC, 18C, 50 x 4.6 mm.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -2 '- [2- (tetrahydro-2 (RS) -pyranyloxy) ethyl] -4-methylvalerohydrazide was prepared as follows.

(i) Synthesis of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid and 2-hydroxyethylhydrazine (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -2 '-( 2-hydroxyethyl) -4-methylvalerohydrazide in the form of a yellow gum.

MS: 405 (M + H) &lt; ⁺ & gt ^; .

(ii) To a solution of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl- Hydroxyethyl) -4-methylhydrazide, 1.08 ml of t-butylchlorodiphenylsilane and 0.596 g of imidazole was stirred at room temperature for 3.5 hours under nitrogen. The solvent was evaporated and the residue was partitioned between ethyl acetate and 0.5 M aqueous hydrochloric acid. The ethyl acetate layer was washed sequentially with 0.5 M aqueous hydrochloric acid, water and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Ethyl acetate was evaporated to give (E) -2 '-( 2-t-butyldiphenylsilyloxyethyl) -2 (R) - [l (S) - (t-butoxycarbonyl) 3-butenyl] -4-methylvalerohydrazide in the form of a pale yellow gum.

MS: 643 (M + H) &lt; ⁺ & gt ^; .

(iii) Synthesis of (E) -2 '-( 2-t-butyldiphenylsilyloxy) -2 (R) - [1 (S) - (tert- butoxycarbonyl) ] - 4-methylvalerohydrazide and N- (9-fluorenylmethoxycarbonyl) -D-alaninate fluoride as starting materials, (R) - [1 (S) - [(tetrahydro-furan-2-ylmethoxy) -phenyl] -methanone following purification by flash chromatography on silica gel using ethyl acetate / hexane (1: 2 '- [(9-fluorenylmethoxycarbonyl) -D-alanyl] -2 '-( 2-hydroxyethyl) -4-methylvalerohydrazide in the form of a white foam.

(iv) To a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] 2'- (2-hydroxyethyl) -4-methylvalerohydrazide, 0.131 g of 2, 2 '- [N- (9-fluorenylmethoxycarbonyl) Pyridine and 0.05 g of 3-dihydro-4H-pyran and p-toluenesulfonic acid crystal was stirred at room temperature for 2 days under a nitrogen atmosphere. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed sequentially with 2 portions of 5% aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, ethyl acetate was evaporated and the residue was purified by flash chromatography on silica gel using ethyl acetate / hexanes (2: 1) for elution. (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] (RS) -pyranyloxy) ethyl] -4-methylvalerohydrazide were added to a solution of 5-bromo-4-methylvalerohydrazide Lt; / RTI &gt;

MS: 847 (M + Na) &lt; ⁺ & gt ^;

(v) (R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) ethyl] -4-methylvalerohydrazide 0.1 &lt; RTI ID = 0.0 &gt; (R) - [1 (S) - [(tetrahydro-2 (R) - (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 ' - [2- (tetrahydro- 0.034 g of dragise was obtained in the form of a gum.

MS: 603 (M + H) &lt; ⁺ & gt ^; .

Example 83

2'- (D-alanyl) -2 (R) - [1 (RS) - (hydroxycarbamoyl) -4-phenylbutyl] -2'- isobutyl- 3-methylbutyrohydrazide p- Toluene sulfonate

(RS) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -2 ' -isobutyl (R) - [1 &lt; / RTI &gt; (RS) -3-methylbutyrola hydrazide as a starting material in a manner similar to the method described in the first paragraph of Example 5 using 0.689 g of ) - (hydroxycarbamoyl) -4-phenyl-3-butyl] -2'-isobutyl-3-methylbutyrohydrazide 0.768 mg of p-toluenesulfonate in the form of a white solid.

MS: 435 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.495 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(RS) - [(tetrahydro-2 (RS) -pyranyloxycarbamoyl] -4-phenylbutyl] -2 '-( D- -Isobutyl-3-methylbutyrohydroazide was prepared as follows.

(i) A solution of (E) -2 (R) - [1 (RS) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -3-methylbutyric acid in ethanol And shaken in hydrogen atmosphere in the presence of 10% palladium catalyst in charcoal until stopped. The catalyst was filtered off and the solvent was evaporated to give 2 (R) - [1 (RS) - (t-butoxycarbonyl) -4-phenylbutyl] -3-methylbutyric acid in the form of a pale yellow oil.

MS: 335 (M + H) &lt; ⁺ & gt ^; .

(ii) Synthesis of 2 (R) - [1 (RS) - (t-butoxycarbonyl) -4-phenylbutyl] -3-methylbutyric acid and N- (9-fluorenylmethoxycarbonyl) (R) - [1 &lt; / RTI &gt; (RS) - [ (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -2 &apos; -isobutyl-3-methylbutyro hydrazide in the form of a gum.

MS: 519 (M + H) &lt; ⁺ & gt ^; .

Example 84

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-3- Methylbutyroid hydrazide p-toluenesulfonate

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- 2 '- (D-alanyl) thienyl] -2'-isobutyl-3-methylbutyl hydrazide was prepared in a manner similar to that described in the first paragraph of Example 5 using 0.088g as starting material. (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-3-methylbutyrohydrazide p- Toluenesulfonate 0.090 g was obtained in the form of a white solid.

MS: 433 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.467 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [tetrahydro-2 (RS) -pyranyloxycarbamoyl] -4-phenyl- 3-butenyl] -2'-isobutyl-3-methylbutylohydroazide was prepared as follows.

(i) By a method similar to that described in Example 1, parts (i) to (iii) using 4-t-butylhydrogen 2 (R) -isopropyl succinate and cinnamyl bromide as starting materials, ) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -2'-isobutyl-3-methyl butyryl hydrazide as a cream white solid Lt; / RTI &gt;

MS: 403 (M + H) &lt; ⁺ & gt ^; .

(ii) Synthesis of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -2'-isobutyl- (E) - (3,4-dimethoxy-phenyl) -methanone was prepared by a method similar to that described in Example 18, Part (i) 2 - (D-alanyl) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] '- isobutyl-3-methylbutyro hydrazide in the form of a gum.

MS: 517 (M + H) &lt; ⁺ & gt ^; .

Example 85

(R) - [1 (S) - (hydroxycarbamoyl) -4-tert-butoxycarbonylamino-2- (tetrahydro- Phenyl-3-butenyl] -4-methylvalerohydrazide p-Toluenesulfonate

(RS) - [(S) - [(tetrahydro) -2 (RS) -2 '-( D-alanyl) -2 '-( tetrahydro- ) -Pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide was used as the starting material in a manner analogous to that described in the first paragraph of Example 5 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl- lH-pyran- -3-butenyl] -4-methyl-valerohydrazide in the form of an off-white solid.

MS: 475 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution increasing the content of solvent B from 5% to 70% over 15 minutes; Flow rate 1 ml / min. Retention time: 13.907 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-thiophen-2-yl) -2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide was prepared as follows.

-4-methylvalerohydrazide and tetrahydro-4H-pyran-2-one (E) -2 (R) - [1 (S) - (t- -2 '- (D-alanyl) -2' - (tetrahydro-2H) -quinolinone -4-methyl-butenyl] -4-methyl-pyran-4-yl) -2 (R) - [1 (S) - [(tetrahydro- Valero hydrazide in the form of a pale yellow gum.

MS: 559 (M + H) &lt; ⁺ & gt ^; .

Example 86

(R) - [1 (S) - (hydroxycarbamoyl) -4- (2-fluoroethyl) Phenyl-3-butenyl] -4-methylvalerohydrazide p-Toluenesulfonate

(R) - [1 (S) - [(tetrahydro) -2 (RS) -2 '-( D-alanyl) -2 '-( 2,2,2- trifluoroethyl) ) -Pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide was used as starting material in a manner analogous to that described in the first paragraph of Example 5 (R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4- Methylvalerohydrazide p-toluenesulfonate (0.115 mg) in the form of a pale yellow solid.

MS: 473 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Time of stay: 10.785 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydrofuran-2-ylmethyl) -2 ' -2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide was prepared as follows.

(i) (E) -2 (R) - [1 (S) - [(t-butoxycarbonyl) -4-phenyl-3-butenyl] -4- methyl valeric acid and 2,2,2- (R) - [1 (S) - (t-butoxycarbonyl) - (tert- butoxycarbonyl) - Phenyl-3-butenyl] -2 '-( 2,2,2-trifluoroethyl) -4-methylvalerohydrazide in the form of a pale yellow solid.

MS: 443 (M + H) &lt; ⁺ & gt ^; .

(ii) Synthesis of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -2 '-( 2,2,2-trifluoro (I) to (iv) were prepared using N- (4-fluorophenyl) ethyl) -4-methylvalerohydrazide and N- (9-fluorenylmethoxycarbonyl) 2 '- (2,2,2-trifluoroethyl) -2 (R) - [1 (S) - [(tetra (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide in the form of a gum.

MS: 557 (M + H) &lt; ⁺ & gt ^; .

Example 87

(E) -2 '-( D-alanyl) -2 '-( 2-cyanoethyl) -2 (R) - [ &Lt; / RTI &gt; decenyl] -4-methylvalerohydrazide p-Toluenesulfonate

(S) - [(tetrahydro) -2 (RS) -pyranyloxy) -2 '-( D-alanyl) -2 '-( 2-cyanoethyl) -2 ) Carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide was used as the starting material, the title compound was obtained from (E) -2- - (D-alanyl) -2 '- (2-cyanoethyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) 0.034 g of methylvalerohydrazide p-toluenesulfonate are obtained in the form of an off-white solid.

MS: 444 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 9.957 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(RS) - [(S) - [(tetrahydro-2 (RS) -Pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide was prepared as follows.

(i) Synthesis of (E) -2 (R) -2 (R) - [1 (S) - (tert- Butoxycarbonyl) (R) - [1 (S) - (t-butoxycarbonyl) -4 (S) - -Phenyl-3-butenyl] -2 '-( 2-cyanoethyl) -4-methylvalerohydrazide in the form of a white solid.

MS: 414 (M + H) &lt; ⁺ & gt ^; .

(ii) Synthesis of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) (I) to (iv) using methyl valero hydrazide and N- (9-fluorenylmethoxycarbonyl) -D-alanic acid fluoride as starting materials in a manner similar to that described in Example 18, parts (S) - [(tetrahydro-2 (RS) -pyranyloxy) -2 '-( 2-cyanoethyl) ) Carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide in the form of a gum.

MS: 528 (M + H) &lt; ⁺ & gt ^; .

Example 88

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4- Methylvalerohydrazide p-toluenesulfonate

(RS) -pyranyloxy) &lt; / RTI &gt; carbamoyl] - (R) -2 '-( D) (E) -2 '-( D-4-Phenyl-3-butenyl] -4-methylvalerohydrazide was prepared in a manner similar to that described in the first paragraph of Example 5 using 0.17 g as starting material. 2-cyclohexyl-2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4- methylvalerohydrazide p- Lt; / RTI &gt; acid as an off-white solid.

MS: 473 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.257 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(S) - [(tetrahydro-2 (RS) -pyranyloxy) -2 '-( D-alanyl) -2 ' -cyclohexyl- Carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide was prepared as follows.

(i) A mixture of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid and cyclohexylhydrazine as starting materials (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -2'-cyclohexyl-4-methylvalerohydrazide in the form of an off-white solid.

(ii) (E) -2 (R) - [1 (S) -t-Butoxycarbonyl-4-phenyl-3-butenyl] -2'- cyclohexyl-4-methylvalerohydrazide and (E) -2 ', by a method analogous to that described in Example 18, parts (i) to (iv) using N- (9-fluorenylmethoxycarbonyl) - (D-alanyl) -2'-cyclohexyl-2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] &Lt; / RTI &gt; enyl] -4-methylvalerohydrazide in the form of a gum.

MS: 557 (M + H) &lt; ⁺ & gt ^; .

Example 89

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2 '-( 2-phenylethyl) valerohydrazide p-Toluenesulfonate

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- 2'- (2-phenylethyl) valerohydrazide as starting materials in a manner analogous to that described in the first paragraph of Example 5, (D-alanyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl- 0.148 g of hydrazide p-toluenesulfonate were obtained in the form of a cream colored solid.

MS: 495 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.355 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -4-methyl-2 '- (2-phenylethyl) valerohydrazide was prepared as follows.

(i) (E) -2 (R) - [1 (S) - (t-butoxycarboxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid and phenelzine sulphate as starting materials (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl ] -4-methyl-2 '- (2-phenylethyl) valerohydrazide in the form of a cream colored solid.

MS: 465 (M + H) &lt; ⁺ & gt ^; .

(ii) Synthesis of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) (I) to (iv) by using valerohydrazide and N- (9-fluorenylmethoxycarbonyl) -D-alaninate fluoride as starting materials in a manner similar to that described in Example 18, parts (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- &Lt; / RTI &gt; decenyl] -4-methyl-2 '-( 2-phenylethyl) valerohydrazide in the form of a gum.

MS: 579 (M + H) &lt; ⁺ & gt ^; .

Example 90

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4- Methylvalerohydrazide p-toluenesulfonate and (E) -2 '- (D-alanyl) -2'-cyclopentyl-2 (S) - [1 (R) - (hydroxycarbamoyl) - Phenyl-3-butenyl] -4-methylvalerohydrazide A mixture of p-toluenesulfonate

(R) - [(S) - [tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl) -3-butenyl] -4-methylvalerohydrazide and (E) -2 '-( D-alanyl) -2 ' -cyclopentyl- (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide was used as the starting material, (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-isoquinolin-2- (R) -2 '-( D-alanyl) -2 ' -cyclopentyl-2 (S) - (hydroxycarbonyl) -4-phenyl-3-butenyl] -methyl valerohydrazide p-toluenesulfonate in the form of a pale pink solid.

MS: 459 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution increasing the content of solvent B from 20% to 40% over 15 minutes; Flow rate 1 ml / min. Retention time: 6.607 min (Isomer 1) and 7.390 min (Isomer 2). Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(S) - [(tetrahydro-2 (RS) -pyranyloxy) -2 '-( D-alanyl) -2 ' -cyclopentyl- -2-cyclopentyl-2 (S) - [1 &lt; / RTI &gt; (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide was prepared as follows.

(E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4- methylvalerohydrazide and ) - [1 (R) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide and cyclopentanone as starting materials. , (R) - [1 (S) - [(tetrahydro-2 ((R) Phenyl) -3-butenyl] -4-methylvalerohydrazide and (E) -2 '-( D-alanyl) -2 ' -cyclopentyl- A mixture of 2 (S) - [1 (R) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4- methylvalerohydrazide As a colorless gum.

MS: 543 (M + H) &lt; ⁺ & gt ^; .

Example 91

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl- Valerohydrazide p-toluenesulfonate

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- 2'-propylvalerohydrazide In a similar manner to that described in the first paragraph of Example 5 using 0.148 g of p-toluenesulfonate as starting material, (E) -2 ' - (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-propylvalerohydrazide p- 0.146 g of toluene sulfonate were obtained in the form of a white solid.

MS: 433 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.218 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -4-methyl-2 ' -propylvalerohydrazide was prepared as follows.

(E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide and propionaldehyde as starting materials -2 '- (D-alanyl) -2 (R) - [1 (S) - [(tetrahydro- 2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methyl-2'-propylvalerohydrazide in gum form.

MS: 517 (M + H) &lt; ⁺ & gt ^; .

Example 92

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 5-hydroxy- Pentyl) -4-methylvalerohydrazide p-Toluenesulfonate

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- -2 '- (5-hydroxypentyl) -4-methylvalerohydrazide as starting materials, by a similar method to that described in the first paragraph of Example 5, using 0.042 g of -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 5-hydroxypentyl) 0.05 g of valerohydrazide p-toluenesulfonate in the form of an orange foam.

MS: 477 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 9.317 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] -4 -Phenyl-3-butenyl] -2 '-( 5-hydroxypentyl) -4-methylvalerohydrazide was prepared as follows.

(i) Synthesis of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4- methylvalerohydrazide and 5-hydroxy (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenylpyridinium iodide as a starting material in a similar manner to that described in Example 59, Part -3-butenyl] -2 '-( 5-hydroxypentyl) -4-methylvalerohydrazide in the form of a gum.

MS: 447 (M + H) &lt; ⁺ & gt ^; .

(ii) To a solution of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl- Hydroxypentyl) -4-methylvalerohydrazide in 50 ml of tetrahydrofuran was treated with 0.31 ml of t-butylchlorodiphenylsilane and 0.169 g of imidazole. The mixture was treated at room temperature for 3 h and the solvent was evaporated. The residue was partitioned between ethyl acetate and 1M hydrochloric acid and the ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give (E) -2 '-( t-butyldiphenylsilyloxypentyl) 0.629 g of (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide was obtained in the form of a gum.

MS: 685 (M + H) &lt; ⁺ & gt ^; .

(i) Synthesis of (E) -2 '-( t-butyldiphenylsilylpentyl) -2 (R) - [1 (S) - (t- butoxycarbonyl) (I) to (iv) using 4-methylvalerohydrazide and N- (9-fluorenylmethoxycarbonyl) -D-alaninate fluoride as starting materials, In a similar manner, (E) -2 '-( D-alanyl) -2 (R) - [1 (S) - [(tetrahydro- 3-butenyl] -2 '-( 5-hydroxy-pentyl) -4-methylvalerohydrazide in the form of a gum.

MS: 561 (M + H) &lt; ⁺ & gt ^; .

Example 93

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 3-hydroxy- -2,2-dimethylpropyl) -4-methylvalerohydrazide p-Toluenesulfonate

(RS) -pyranyloxy) carbamoyl] -4-phenyl-3- (4-fluorophenyl) 2'- (3-hydroxy-2,2-dimethylpropyl) -4-methyl-valerohydrazide as starting materials in analogy to the procedure described in the first paragraph of Example 5 -2 (R) - [(1S) -hydroxycarbamoyl) -4-phenyl-4-butenyl] -2 '-( 3- Hydroxy-2,2-dimethylpropyl) -4-methylvalerohydrazide in the form of a pale orange solid.

MS: 477 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 8.21 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: 95% CH 3 CN /} 5% H 2 O / 0.085% TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -2 '- (3-hydroxy-2,2-dimethylpropyl) -4-methylvalerohydrazide was prepared as follows.

(S) - (t-butoxycarbonyl) -4-phenyl] -4-methylvalerohydrazide and 2,2-dimethyl-3-hydroxypropionaldehyde - (D-alanyl) -2 (R) - [1 (S) - (2-isopropylphenyl) -2 - [(3-hydroxy-2,2-dimethylpropyl) -4-methylvalero Hydrazine was obtained in the form of a sword.

MS: 561 (M + H) &lt; ⁺ & gt ^; .

Example 94

(S) - (hydroxycarbamoyl) butyl] -4-methyl-2'- [2- (3-pyridyl) acetyl] valero Hydrazide p-toluenesulfonate

(RS) -pyranyloxy) carbamoylbutyl] -4-methyl-2 ' - [2 &lt; RTI ID = 0.0 &gt; - (3-pyridyl) acetyl] valero hydrazide was prepared in analogy to the procedure described in the first paragraph of Example 5 using 0.311 g of 2'-benzyl-2 (R) - [ (S) - (hydroxycarbamoyl) butyl] -4-methyl-2 '- [2- (3-pyridyl) acetyl] valerohydrazide 0.33 g of p- toluenesulfonate as an off- white solid .

MS: 537 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.885 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] butyl] -4-methyl-pyrrolidine- 2 '- [2- (3-pyridyl) acetyl] valerohydrazide was prepared as follows.

4-cyclohexylbutyl] -4-methylvaleric acid and benzylhydrazine as starting materials and using Nt-butoxycarbonyl-β (R) - [1 (S) - (t-butoxycarbonyl) -Benzyl-2 (R) - [4-cyclohexyl-1 (S) -pyridazo [l, l-acetic acid in analogy to the method described in example 1, part (iii) ) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] butyl] -4-methyl-2 '-( 2- (3- pyridyl) acetyl] valerohydrazide as a white foam .

MS: 621 (M + H) &lt; ⁺ & gt ^; .

Example 95

2 '- (2-phenylethyl) -2' - [2- (1H-1,2,3,4-tetrahydroisoquinolin- 2,4-triazol-1-yl) acetyl] valerohydrazide p-Toluenesulfonate

Methyl-2 '-( 2-phenylethyl) - &lt; RTI ID = 0.0 &gt; (R) - [4-cyclohexyl- (S) - [(tetrahydro-2 (RS) -pyranyloxy) 2 ' - [2- (lH-l, 2,4-triazol-l-yl) acetyl] valerohydrazide as a starting material in analogy to the method described in the first paragraph of Example 5 -2 - [(2-phenylethyl) -2 '- [2- (1H-1-benzyloxycarbonyl) , 2,4-triazol-1-yl) acetyl] valerohydrazide in the form of an off-white solid.

MS: 541 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.972 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] butyl] -4-methyl-2 '-( 2 -Phenylethyl) -2 '- [2- (1H-1,2,4-triazol-1-yl) acetyl] valerohydrazide was prepared as follows.

4-cyclohexylbutyl] -4-methylvaleric acid and 2-phenylethyl hydrazine were used in the same manner as in Example 8, except that Nt-butoxycarbo (2R) - [ (R) - [4-Cyclohexylamino-2-pyrrolidin-1-yl) -ethanone was obtained by a method similar to the method described in Example 1, Part (iii) to (vii) using 1,2,4- -2 ' - [2- (lH-1 (S) - [(tetrahydro- , 2,4-triazol-1-yl) acetyl] valerohydrazide in the form of a white solid.

MS: 625 (M + H) &lt; ⁺ & gt ^; .

Example 96

2 - (2-phenylethyl) -2 '- [2- (3-pyridyl) ) &Lt; / RTI &gt; acetyl] valerohydrazide p-toluenesulfonate

Methyl-2 '-( 2-phenylethyl) -2 '-( 2-phenylethyl) (R) - [4- (3-pyridyl) acetyl] valerohydrazide was prepared by a method similar to that described in the first paragraph of Example 5 using 0.09 g of the starting material, (2-phenylethyl) -2 '- [2- (3-pyridyl) acetyl] valerohydrazide 0.103 g of p-toluenesulfonate were obtained in the form of a white solid.

MS: 551 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.537 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] butyl] -4-methyl-2 '-( 2 -Phenylethyl) -2 ' - [2- (3-pyridyl) acetyl] valerohydrazide was prepared as follows.

Butoxycarbonyl) -4-cyclohexylbutyl] -4-methylvaleric acid and 2-phenylethyl hydrazine were used in the same manner as in Example 8, except that Nt-butoxy (R) - [4-cyclohexyl-1 (S) -pyridin-2-yl) -ethanone in a similar manner to that described in Example 1, parts (iii) to (vii) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl) butyl] -4-methyl- &Lt; / RTI &gt; dyl) acetyl] valero hydrazide in the form of a white solid.

MS: 635 (M + H) &lt; ⁺ & gt ^; .

Example 97

2 '- [2- (lH-imidazol-l-yl) acetyl] -4-methyl-2 '-( methanesulphonyl) - (2-phenylethyl) valerohydrazide p-toluenesulfonate

(S) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] butyl] piperidine was prepared by a method similar to the method described in the first paragraph of Example 5, Starting from 0.28 g of 2 (R) - [4 (R) - [2- (1H-imidazol- (S) - (hydroxycarbamoyl) butyl] -2 '- [2- (lH-imidazol- l-yl) acetyl] 0.282 g of valerohydrazide p-toluenesulphate was obtained in the form of a white solid.

MS: 540 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.970 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl) butyl] -2 ' - [2- Imidazol-1-yl) acetyl] -4-methyl-2 '- (2-phenylethyl) valerohydrazide was prepared as follows.

(R) - [1 (S) -t-butoxycarbonyl) -4-cyclohexylbutyl] -4, 4-dihydroxybenzoate was prepared by a method similar to that described in Example 1, Part (iii) (R) - [4-cyclohexyl-l, 2-benzodiazepin-1-yl) -methanone was prepared using l- (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] butyl] -2'- (2-phenylethyl) valerohydrazide in the form of a white solid.

MS: 624 (M + H) &lt; ⁺ & gt ^; .

Example 98

2 '- (2-phenylethyl) -2' - [2- (1H-1,2,3,4-tetrahydroisoquinolin- 2,3-triazol-1-yl) acetyl] valerohydrazide p-Toluenesulfonate

(S) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] butyl] piperidine was prepared by a method similar to the method described in the first paragraph of Example 5, Starting from 0.3 g of 4-methyl-2 '- (2-phenylethyl) -2' - [2- (lH) -1,2,3-triazol- 2 - (2-phenylethyl) -2 '- [2- (lH) -1 (S) - , 2,3-triazol-1-yl) acetyl] valerohydrazide in the form of a white solid.

MS: 541 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 13.27 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl) butyl] -4-methyl-2 '-( 2 - phenylethyl) -2 '- [2- (1H-1,2,3-triazol-1-yl) acetyl] valerohydrazide was prepared as follows.

(R) - [1 (S) -t-butoxycarbonyl) -4-cyclohexylbutyl] -4, 4-dihydroxybenzoate was prepared by a method similar to that described in Example 1, Part (iii) -Methyl valeric acid and 2-phenylethyl hydrazine was used instead of Nt-butoxycarbonyl -? - alanine of Example 8 to give 2 (R) - [4- -2 - (2-phenylethyl) -2 ' - [2- (1H) -quinolinone &lt; RTI ID = 0.0 & -1,2,3-triazol-1-yl) acetyl] valerohydrazide in the form of a white solid.

MS: 625 (M + H) &lt; ⁺ & gt ^; .

Example 99

Methyl-2 '- [2- (lH-1,2,3-triazole (2-benzyl- -1-yl) acetyl] valerohydrazide p-toluenesulfonate

Benzyl-2 (R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] -4-piperidinecarbaldehyde was prepared by a method similar to that described in the first paragraph of Example 5, Benzyl-2 (R) -phenylbutyl] -4-methyl-2 '- [2- (lH-1,2,3- triazol- 1- yl) acetyl] valerohydrazide. ) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methyl- 0.234 g of valerohydrazide p-toluene-sulphonate were obtained in the form of a white solid.

MS: 521 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.278 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPBDS, C18.

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -4-methyl-2 '- [2- (1H-1,2,3-triazol-1-yl) -acetyl] valerohydrazide was prepared as follows.

(S) -t-butoxycarbonyl) -4-phenylbutyl] -4-tert-butoxycarbonylamino-2-pyrrolidinone in a manner analogous to that described in Example 1, Part (iii) Benzyl-2 (R) - [1 &lt; / RTI &gt; (R) - (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -4- methyl- Yl) acetyl] valerohydrazide in the form of a white foam.

MS: 605 (M + H) &lt; ⁺ & gt ^; .

Example 100

Methyl-2 '- [2- (lH-l, 2,4-triazole &lt; / RTI &gt; -1-yl) acetyl] valerohydrazide p-toluenesulfonate

Benzyl-2 (R) -1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl Benzyl-2 (R) -piperidine-1-carboxylic acid ethyl ester was prepared starting from 0.285 g of &lt; RTI ID = - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methyl-2 ' 0.31 g of rohiodrazide p-toluene-sulphonate are obtained in the form of an off-white solid.

MS: 521 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.963 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPBDS, C18.

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -4-methyl-2 '- [2- (1H-1,2,4-triazol-1-yl) -acetyl] valerohydrazide was prepared as follows.

(S) - (t-butoxycarbonyl) -4-phenylbutyl] -4 (S) - - benzyl-2 (R) - [l- (4-methylpiperidin-l-yl) -methyl] -piperidine-l- 4-Methyl-2 '- [2- (1H-1,2,4-triazole) -1-yl) acetyl] valerohydrazide in the form of a white foam.

MS: 605 (M + H) &lt; ⁺ & gt ^; .

Example 101

Methyl-2 '- [2- (3-pyridyl) acetyl] valero hi-2'-benzyl-2 (R) - [1 (S) - (hydroxycarbamoyl) Drazide p-toluenesulfonate

Benzyl-2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Benzyl-2 (R) - [1 (S) - (hydroxymethyl) -2-methyl-2 '- [2- (3-pyridyl) acetyl] valerohydrazide (3-pyridyl) acetyl] valerohydrazide p-toluenesulfonate in the form of a cream-colored solid.

MS: 531 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPBDS, C18.

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -4-methyl-2 '- [2- (3-pyridyl) acetyl] valerohydrazide was prepared as follows.

(S) - (t-butoxycarbonyl) -4-phenylbutyl] -4 (S) - -Benzyl-2 (R) - [1 (S) - [((R) -methoxy-benzyl] -thiazol- (3-pyridyl) acetyl] valerohydrazide is obtained in the form of a white foam .

MS: 615 (M + H) &lt; ⁺ & gt ^; .

Example 102

(S) - (hydroxycarbamoyl) butyl] -4-methylvalerohydrazide p (4-aminobutyryl) -2'- - toluene sulfonate

(R) - [4-cyclohexyl-1 (S) - (tetrahydro-isoquinolin- (R) - [(RS) -pyranyloxy) carbamoyl] butyl] -4-methylvalerohydrazide, starting from 0.303 g of 2 '- Cyclohexyl-1 (S) - (hydroxycarbamoyl) butyl] -4-methylvalerohydrazide 0.191 g of p-toluenesulfonate was obtained in the form of a white solid.

MS: 503 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.36 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPBDS, C18.

(S) - [(tetrahydro-2 (RS) -pyranyloxy) -2 '-( 4-cyclohexyl- ) &Lt; / RTI &gt; carbamoylbutyl] -4-methylvalerohydrazide was prepared as follows.

(R) - [1 (S) - (t-butoxycarbonyl) -4-cyclohexyl (meth) acrylate was prepared in a manner similar to that described in Example 1, Part (iii) Butyl-4-methylvaleric acid and benzylhydrazine was used instead of Nt-butoxycarbonyl- beta -alanine of Example 8 to give 2'-benzyl-2 '- (4- (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] butyl] -4-methylvaleric acid as a colorless amorphous solid. Hydrazide was obtained in the form of a white solid.

MS: 721 (M + H) &lt; ⁺ & gt ^; .

(ii) A mixture of 2'-benzyl-2'- (4-benzyloxycarbonylaminobutyryl) -2 (R) - [4-cyclohexyl- 1 (S) - [(tetrahydro- - pyranyloxy) carbamoyl] butyl] -4-methylvalerohydrazide in 10 mL of a solution of 10% palladium-on-charcoal catalyst under a hydrogen atmosphere for 3 hours. The catalyst was filtered and the methanol was evaporated to give 2'- (4-aminobutyryl) -2'-benzyl-2 (R) - [4-cyclohexyl- 1 (S) - [(tetrahydro- - pyranyloxy) carbamoyl] butyl] -4-methylvalerohydrazide in the form of a white solid.

MS: 587 (M + H) &lt; ⁺ & gt ^; .

Example 103

2 '- (2 (S) -methylbutyl) -4-methylbutyl] -4 ' ) Valero Hydrazide

(E) -2 (R) - [1 (S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 4- benzyloxycarbonylaminobutyryl) A solution of 0.216 g of 4-methyl-2 '- (2 (S) -methylbutyl) valerohydrazide was hydrogenated for 1 hour in the presence of 0.1 g of 10% palladium catalyst on carbon. The catalyst was filtered off and the methanol was evaporated. The residue was re-evaporated with diethyl ether and triturated with a mixture of diethyl ether and hexane to give 2 '- (4-aminobutyryl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methyl-2 '- (2 (S) -methylbutyl) valerohydrazide in the form of a white solid.

MS: 477 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.198 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPBDS, C18.

(E) -2 (R) - [1 (S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 4- benzyloxycarbonylaminobutyryl ) -4-methyl-2 '- (2 (S) -methylbutyl) valerohydrazide was prepared as follows.

(E) -2 (R) - [1 (S) -tetrahydroisoquinoline-2-carboxylic acid using O-benzylhydroxyalanine in part (vi) by a method similar to that described in example 1, part (iv) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2 '- (2 (S) -methylbutyl) valerohydrazide in the form of a pale yellow solid.

MS: 480 (M + H) &lt; ⁺ & gt ^; .

(ii) In a similar manner to that described in Example 8, (E) -2 (R) - [1 (S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] (R) - [2 (S) -methylbutyl) valerohydrazide using 4-benzyloxycarbonylaminobutyric acid instead of Nt-butoxycarbonyl- (S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 4- benzyloxycarbonylaminobutyryl) -4-methyl- Methylbutyl) valerohydrazide in the form of a white solid.

MS: 699 (M + H) &lt; ⁺ & gt ^; .

Example 104

2 (S) -methylbutyl) -2 ' - [2- (lH-pyrrolo [ 1,2,4-triazol-1-yl) acetyl] valerohydrazide

(E) -2 (R) - [1 (S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2 '-( Starting from 0.212 g of 2 (S) -methylbutyl) -2 '- [2- (1H-1,2,4- triazol- 1 -yl) acetyl] valerohydrazide 2 (R) (S) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methyl-2 ' Lt; / RTI &gt; yl) acetyl] valerohydrazide in the form of a white solid.

MS: 501 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.39 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2 '-( 2 (S) - Methylbutyl) -2 '- [2- (1H-1,2,4-triazol-1-yl) acetyl] valerohydrazide was prepared as follows.

(E) -2 (R) - [1 (S) - (Benzyloxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2 '-( 2 (R) - (S) -methylbutyl) valerohydrazide using 1,2,4-triazole-1-acetic acid instead of Nt-butoxycarbonyl- -2 ' - [2- (lH-1 (S) - (benzyloxycarbamoyl) -4-phenyl- , 2,4-triazol-1-yl) acetyl] valerohydrazide in the form of a gum.

Example 105

2 ' - [2- (lH-imidazol-l-yl) acetyl] -4-methyl-2 '-( 2- (2 (S) -methylbutyl) valerohydrazide

(E) -2 (R) - [1 (S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 ' - [2- (S) - (hydroxymethyl) -2-methyl-2 '- (2 (S) -methylbutyl) valerohydrazide (2 (S) -methylbutyl) -2 ' - [2- (lH-imidazol- l-yl) acetyl] -4- methyl- 0.065 g of zid was obtained in the form of a white solid.

MS: 500 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.273 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(E) -2 (R) - [1 (S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 ' - [2- Yl) acetyl] -4-methyl-2 '- (2 (S) -methylbutyl) valerohydrazide was prepared as follows.

(E) -2 (R) - [1 (S) - (Benzyloxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2 '-( 2 (R) - [1 (S) -methylbutyl) valerohydrazide in place of Nt-butoxycarbonyl- beta -alanine of Example 8, (S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 ' - [2- (lH-imidazol- S) -methylbutyl) valerohydrazide in the form of a gum.

MS: 588 (M + H) &lt; ⁺ & gt ^; .

Example 106

-2 ' - [2- (lH-imidazol-l-yl) acetyl] -4- Methylvalerohydrazide p-toluenesulfonate

(RS) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] -4 &lt; RTI ID = 0.0 &gt; Benzyl-2 (R) - [1 (S) - (4-methylpiperazin-1- (Hydroxycarbamoyl) -4-phenylbutyl] -2 '- [2- (1H-imidazol-1-yl) acetyl] -4-methylvalerohydrazide 0.246 g of p-toluenesulfonate as a cream colored solid Lt; / RTI &gt;

MS: 520 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.107 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -2 ' - [ - (1-imidazolyl) acetyl] -4-methylvalerohydrazide was prepared as follows.

(S) - (t-butoxycarbonyl) -4-phenylbutyl] -4 (S) - -Benzyl-2 (R) - [1 (S) - [1, &lt; / RTI &gt; (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -2 &apos; - [2- (1-imidazolyl) acetyl] -4-methylvalerohydrazide .

Example 107

(S) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methylvalerohydrazide p- Toluene sulfonate

(RS) - [(S) - [(tetrahydro-2 (RS) - (4-aminobutyryl) -2 ' -benzyl-2 (R) - [1 &lt; / RTI &gt; (S) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methylvalerohydrazide p-toluenesulfonate as an off-white solid.

MS: 497 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Time of stay: 10.623 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4 -Phenylbutyl] -4-methylvalerohydrazide was prepared as follows.

(R) - [1 (S) - (t-butoxycarbonyl) -4-phenylbutyl) -2-methylpropanoate in a similar manner to that described in Example 1, Part (iii) ] -4-methylvaleric acid and benzylhydrazine was used 4-benzyloxycarbonylaminobutyric acid instead of Nt-butoxycarbonyl- beta -alanine of Example 8 to obtain 2'-benzyl-2 '- (4-benzyl (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -4-methylvalerohydra (4-methylpiperazin-1- The zide was obtained in the form of a white solid.

MS: 715 (M + H) &lt; ⁺ & gt ^; .

(R) - [1 (S) - [(tetrahydro-thiophene-2-carboxylic acid ethyl ester)] was prepared by a method similar to the method described in Example 102, part (ii) 2 '- benzyl-2 (R) - [1 (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -4-methylvalerohydrazide. (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -4-methylvalerohydrazide in gum form.

MS: 581 (M + H) &lt; ⁺ & gt ^; .

Example 108

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl- L-prolyl) valerohydrazide p-toluenesulfonate

-2 (R) - [1 (S) - (hydroxycarbamoyl) propyl] -amino] Methyl-L-propyl) valerohydrazide p-toluenesulfonate as a white solid in the form of a white solid .

MS: 487 (M + H) &lt; ⁺ & gt ^; .

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

Example 109

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

(E) -2 (R) - [1 (S) - (hydroxymethyl) -1H-pyrazole in a manner analogous to that described in Example 11, but using 2- (2-thienyl) acetic acid instead of N- Phenyl-3-butenyl] -2 ' -isobutyl-4-methyl-2 ' - [2- (2-thienyl) acetyl] valerohydrazide as a white solid Respectively.

MS: 500 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Time of stay: 13.00 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 110

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- - thienyl) acetyl] valerohydrazide

(E) -2 (R) - [1 (S) - (hydroxymethyl) -1H-pyrazole in a manner analogous to that described in Example 11, but using 2- (3-thienyl) acetic acid instead of N- 4-methyl-2 '- [2- (3-thienyl) acetyl] valerohydrazide was obtained in the form of a white solid Respectively.

MS: 500 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.91 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 111

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl- Methylvalerohydrazide

-2 '-( 2-furoyl) -2 (R) - [1, (R) -2 ' S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide as an off-white solid.

MS: 470 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.11 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 112

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

(E) -2 '-( 3-furoyl) -2 (R) - [1 &lt; / RTI &gt; S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 470 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.10 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 113 Synthesis of

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

(R) - [1 (S) - (hydroxycarbamoyl) - (R) -2-methyl- Phenyl-3-butenyl] -2'-isobutyl-2 '- [2- (methanesulfonyl) acetyl] -4-methylvalerohydrazide in the form of a white solid.

MS: 496 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.84 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 114

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- - pyrrolyl) acetyl] valerohydrazide

(E) -2 (R) - [1 (S) - (hydroxy- 1-pyrrolidin-1-yl) -ethanone was obtained in a manner similar to the method described in Example 11, but using 2- 4-methyl-2 '- [2- (1-pyrrolyl) acetyl] valerohydrazide in the form of a white solid .

MS: 483 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.80 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 115

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl- D-pyrrolyl) valerohydrazide p-toluenesulfonate

(R) - [1 (S) - (hydroxycarbamoyloxy) -2-methyl-D-proline was obtained in a manner similar to the method described in Example 11, Phenyl) -3-butenyl] -2 ' -isobutyl-4-methyl-2 '-( l-methyl- D-pyrrolyl) valerohydrazide in the form of a white solid.

MS: 487 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.56 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 116

(E) -2 ' - [2- (1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinyl) Hydroxy-carbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide

(E) -2 ' - [2- (l, 2,3, 4-tetraazacyclododecanyl)] was prepared in analogy to the method described in example 8, substituting 4-uracacetate for Nt-butyloxycarbonyl- (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 -Isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 528 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.61 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 117

(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- -Thioxo-4-oxo-5 (RS) -thiazolidinyl) acetyl] valerohydrazide

(E) -2 (R) - [1 (S) - ((R) -2- (2-hydroxyethyl) -1H-pyrrolo [2,3-d] pyrimidine was prepared by a method similar to the method described in Example 8, but using 3-rhodamineacetic acid instead of Nt-butyloxycarbonyl- Methyl-2 '- [2- (2-thioxo-4-oxo-5 (RS) -thiazolidinyl ) &Lt; / RTI &gt; acetyl] valerohydrazide as a white solid.

MS: 549 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.92 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 118

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

(R) - [1 (S) - (hydroxymethyl) -2-methyl-pyrrole-2-carboxylic acid was obtained in a manner similar to the method described in Example 11, 4-methyl-2 '- [(1-methyl-2-pyrrolyl) carbonyl] valerohydrazide as a white solid Lt; / RTI &gt;

MS: 483 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.58 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 119

-2 '- [2- (3-indolyl) acetyl] -2 '-( 2-fluorophenyl) Isobutyl-4-methylvalerohydrazide

(E) -2 (R) - [1 (S) - (hydroxymethyl) -1H-pyrazole in a similar manner to the procedure described in Example 8, but using 3-indoleacetic acid instead of Nt-butyloxycarbonyl- 2-isobutyl-4-methylvalerohydrazide was obtained in the form of a white solid. Respectively.

MS: 533 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.86 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 120

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

(R) - [1 &lt; RTI ID = 0.0 &gt; (R) -l-leucinic acid &lt; / RTI &gt; fluoride in a manner similar to the method described in Example 25 but using dinamoylstadane acid fluoride instead of Nt-butoxycarbonyl- (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 &apos;-( 3- (4- imidazolyl) propionyl] -2 &apos; -isobutyl- Lt; / RTI &gt; hydrochloride was obtained in the form of a white solid.

MS: 498 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.72 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 121

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- -Pyrazolyl) acetyl] valerohydrazide p-Toluenesulfonate

(E) -2 (R) -methanone in analogy to the procedure described in Example 37, but using 2- (1-pyrazolyl) acetic acid hydrogen bromide in place of 2- (1-pyrrolidinyl) acetic acid hydrogen bromide. - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Hydrazide p-toluene-sulfonate was obtained in the form of a white solid.

MS: 484 (M + H) &lt; ⁺ & gt ^; .

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

Example 122

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- -1,2,3-triazol-1-yl) acetyl] valerohydrazide p-Toluenesulfonate

Similar to the method described in Example 37 but substituting 2- (1H-1,2,3-triazol-1-yl) acetic acid hydrogen bromide for 2- (1-pyrrolidinyl) acetic acid hydrogen bromide Phenyl) -3-butenyl] -2 ' -isobutyl-4-methyl-2 ' - [2- (1H-1,2,3-triazol-1-yl) acetyl] valerohydrazide p-toluenesulfonate as an off-white solid.

MS: 485 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.42 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 123

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- -1,2,4-triazol-1-yl) acetyl] valerohydrazide p-Toluenesulfonate

Similar to the method described in Example 37 but using 2- (1H-1,2,4-triazol-1-yl) acetic acid hydrogen bromide instead of 2- (1-pyrrolidinyl) acetic acid hydrogen bromide Phenyl) -3-butenyl] -2 ' -isobutyl-4-methyl-2 ' - [2- (1H-1,2,4-triazol-1-yl) acetyl] valerohydrazide p-toluenesulfonate as an off-white solid.

MS: 485 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.07 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 124

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-pvridin-2- &Lt; / RTI &gt; 2-isobutyl-4-methylvalerohydrazide

(E) -2 ' - [2- (l- (4-methoxypyridin-2-yl) Yl) acetyl] -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- Methylvalerohydrazide in the form of a white solid.

MS: 502 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.62 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 125

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- Isobutyl-4-methylvalerohydrazide p-toluenesulfonate

(E) -2 ' - [4- (diethylamino) butyric acid) was prepared in analogy to the procedure described in example 11, but using 4- (diethyl- Phenyl] -3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide p-Toluenesulfonate (R) Lt; / RTI &gt; as a white solid.

MS: 517 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and Solvent B being 10% for 5 minutes and increasing to 90% over 10 minutes; Flow rate 1 ml / min. Retention time: 11.18 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: LUNA 3U C18 (2) GRAD.

Example 126

-2 ' - [2- (4-imidazolyl) acetyl] -2 '-( methanesulphonyl) -Isobutyl-4-methylvalerohydrazide hydrochloride &lt; RTI ID = 0.0 &gt;

(E) -2 &lt; RTI ID = 0.0 &gt; (E) -2- &lt; / RTI &gt; 2 '- [2- (4-imidazolyl) acetyl] -2'-isobutyl-4- Methylvalerohydrazide hydrochloride in the form of a white solid.

MS: 484 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 90% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.73 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 127

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- -Methyl-4-piperidinyl) acetyl] valerohydrazide p-Toluenesulfonate

(E) -methanone was obtained by a method similar to the one described in Example 37, except that 2- (1-methyl-4-piperidine) acetic acid hydrogen bromide was used instead of 2- (1-pyrrolidinyl) acetic acid hydrogen bromide. Methyl-2 ' - [2- (1-methyl-piperazin-1- 4-piperidinyl) acetyl] valerohydrazide p-toluene-sulfonate as a white solid.

MS: 515 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.53 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 128

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- &Lt; RTI ID = 0.0 &gt; midopropionyl) valerohydrazide

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] -4-phenyl-3-butenyl] -2 ' -Isobutyl-4-methyl-2 '-( 3-phthalimidopropionyl) valerohydrazide in 5 ml of DMF was treated with 0.005 g of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 1 hour and evaporated. The residue was triturated with diethyl ether, filtered and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- -4-methyl-2 '-( 3-phthalimidopropionyl) valerohydrazide in the form of an off-white solid.

MS: 577 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 13.16 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-4-methyl-2 '- (3-phthalimidopropionyl) valerohydrazide was reacted with 2-isoindolinopropionic acid fluoride instead of (N-phthaloyl) Was prepared in a manner analogous to that described in Example 24, Part (i).

Example 129

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- -Phthalimidopropionyl) valerohydrazide &lt; / RTI &gt;

(E) -2 (R) - [1 (S (2 S) -Pyrrolidinecarbonitrile was obtained by a method similar to the method described in Example 128 but using 2 (S) -phthalimidopropionic acid fluoride instead of 2-isoindolinopropionic acid chloride. Methyl-2 '- (2 (S) -phthalimidopropionyl) valerohydrazide was prepared from Obtained as a white solid.

MS: 577 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.60 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 130

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 2-methyl- Isobutyl-4-methylvalerohydrazide p-toluenesulfonate

The procedure of Example 6 was repeated except that 2- (9-fluorenylmethyloxycarbonyl) amino-isobutyric acid was used instead of N- (9-fluorenyl-methyloxycarbonyl) (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] - 2'-isobutyl-4-methylvalerohydrazide p-toluenesulfonate as a white solid.

MS: 461 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.49 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 131

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalerate Yl] -1-isobutylhydrazino] carbonyl] propionic acid trifluoroacetate

To a solution of (E) -2 (S) -amino-3 - [[2- [2 (R) - [1 (S) - (hydroxy-carbamoyl) ] -4-methylvaleryl] -1-isobutyl hydrazino] carbonyl] -t-butoxypropionate hydrogen chloride in 50 ml of tetrahydrofuran was treated with 0.400 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 4 hours and evaporated. The residue was triturated with diethyl ether, filtered and dried to give (E) -2 (S) -amino-3 - [[2- [2 (R) - [1 (S) - (hydroxycarbamoyl) Phenyl-3-butenyl] -4-methylvaleryl] -1-isobutylhydrazino] carbonyl] propionic acid trifluoroacetate as a white solid.

MS: 491 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.23 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -thiazol-2- -4-methylvaleryl] -1-isobutylhydrazino] carbonyl] -t-butoxypropionate Hydrogen fluoride was converted to Nt-butoxycarbonyl- [beta] -alanine instead of Nt-butoxycarbonyl- L-aspartic acid &lt; RTI ID = 0.0 &gt; a-t-butyl &lt; / RTI &gt; ester.

MS: 547 (M + H) &lt; ⁺ & gt ^; .

Example 132

(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- -Pyridyl) acetyl] valerohydrazide hydrochloride &lt; RTI ID = 0.0 &gt;

(E) -2 (R) - [1 ((R) -2- (2-Pyridyl) acetic acid was prepared by a method similar to the method described in Example 8, but using 2- (2-pyridyl) acetic acid instead of Nt-butyloxycarbonyl- Methyl-2 '- [2- (2-pyridyl) acetyl] valerohydrazide hydro- Chloride as a pale yellow solid.

MS: 495 (M + H) &lt; ⁺ & gt ^; .

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

Example 133

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- - pyridyl) acetyl] valerohydrazide p-Toluenesulfonate

(E) -2 (R) - [1 (S) - (hydroxymethyl) -2-methylpropionic acid was prepared by a method similar to the method described in Example 11, but using 2- (3-pyridyl) acetic acid instead of N- Methyl-2 ' - [2- (3-pyridyl) acetyl] valerohydrazide p-toluenesulfonate Obtained as a white solid.

MS: 495 (M + H) &lt; ⁺ & gt ^; .

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

Example 134

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- - pyridyl) acetyl] valerohydrazide p-Toluenesulfonate

(E) -2 (R) - [1 (S) - (hydroxymethyl) -1H-pyrazole in a manner analogous to that described in Example 11, but using 2- (4-pyridyl) acetic acid instead of N- 4-methyl-2 '- [2- (4-pyridyl) acetyl] valerohydrazide p-toluenesulfonate was reacted with Obtained as a white solid.

MS: 495 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.62 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 135

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- -Tetrazol-5-yl) acetyl] valerohydrazide

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] -4-phenyl-3-butenyl] -2 ' -Isobutyl-4-methyl-2 '- [2- (lH-tetrazol-5-yl) acetyl] valerohydrazide in 10 ml of DMF was treated with 0.020 g of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was triturated with diethyl ether, filtered and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- -4-methyl-2 '- [2- (lH-tetrazol-5-yl) acetyl] valerohydrazide in the form of a white solid.

MS: 486 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.09 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-4-methyl-2 '- [2- (1H-tetrazol-5-yl) acetyl] valerohydrazide was prepared as follows.

(i) To a solution of (E) -2 (R) - [1 (S) - (t- butoxycarbonyl) -4-phenyl-3-butenyl] -2'-isobutyl- -Methylvalerohydrazide and 0.282 g of 2- (lH-tetrazol-5-yl) acetic acid were added to a solution of l-ethyl-3- (3- dimethylaminopropyl) -carbodiimide Lt; / RTI &gt; chloride. The mixture was stirred at room temperature for 0.5 h and evaporated. The residue was dissolved in ethyl acetate and washed with 5% aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give (E) -2 (R) - [ Methyl-2 '- [2- (lH-tetrazol-5-yl) acetyl] valerohydrazide 0.630 g &lt; / RTI &gt; as an off-white foam.

MS: 527 (M + H) &lt; ⁺ & gt ^; .

(R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-isoxazole- 3-butenyl] -2'-isobutyl-2 '- [N- (9-fluorenylmethyloxy- carbonyl) -O- tert -butyl-D-seryl] -4- methylvalerohydrazide Instead of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -2'-isobutyl- (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy ) Carbamoyl] -4-phenyl-3-butenyl] -2 ' -isobutyl-4-methyl-2 ' - [2- (lH-tetrazol- 5- yl) acetyl] valerohydrazide Obtained as a solid.

MS: 570 (M + H) &lt; ⁺ & gt ^; .

Example 136

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- - &lt; / RTI &gt; piperidinyl) acetyl] valerohydrazide hydrochloride

(E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] -4-phenyl-3-butenyl ] -2'-isobutyl-4-methyl-2 '- [2- (4-piperidinyl) acetyl] valerohydrazide in 10 ml of dichloromethane was stirred at room temperature for 2.5 hours and diluted with diethyl ether . The solids were filtered, washed with diethyl ether and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- Butyl-4-methyl-2 '- [2- (4-piperidinyl) acetyl] valerohydrazide hydrochloride as an off-white solid.

MS: 501 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.56 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-4-methyl-2 '- [2- (4-piperidinyl) acetyl] valerohydrazide was prepared as follows.

(i) To a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] 2-isobutyl-4-methylvalerohydrazide in 10 ml of dichloromethane was added dropwise to a solution of 2- [N- (9-fluorenylmethyloxycarbonyl) -4-piperidine] acetic acid And 0.132 g of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride. The mixture was stirred at room temperature overnight and evaporated. The residue was dissolved in ethyl acetate and washed with 5% aqueous citric acid solution, 5% aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give (E) -2 (R) ) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyl- Ylmethyloxycarbonyl) -4-piperidyl) acetyl] -4-methylvalerohydrazide in the form of a clear oil.

MS: 807 (M + H) &lt; ⁺ & gt ^; .

(ii) To a mixture of 1.6 ml of dichloromethane and 0.4 ml of piperidine was added (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) 4-Phenyl) -3-butenyl] -2'-isobutyl-2 '- [2- (N- (9- fluorenylmethyl- A solution of 0.500 g of valerohydrazide was stirred at room temperature for 3 hours. The solution was evaporated and the residue was triturated with hexane. The resulting solid was filtered and dried to give (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] ] -2'-isobutyl-4-methyl-2 '- [2- (4-piperidinyl) acetyl] valerohydrazide in the form of a white solid.

MS: 585 (M + H) &lt; ⁺ & gt ^; .

Example 137

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4 - methylvalerohydrazide

(E) -2 ' was prepared by a method similar to that described in Example 8, except that N- (t-butyloxycarbonyl) -4-aminobutyric acid was used instead of Nt-butyloxycarbonyl- - (4-aminobutyryl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydra The zide was obtained in the form of a white solid.

MS: 461 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.36 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 138

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl- 4-methylvalerohydrazide trifluoroacetate &lt; RTI ID = 0.0 &gt;

To a solution of (E) -2 '-( (Nt-butyloxycarbonyl) -D- alpha - (t- butyloxy) -glutamyl) -2 (R) (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide in 5 ml of dichloromethane was treated with trifluoroacetic acid 6 Ml &lt; / RTI &gt; The mixture was stirred at room temperature under nitrogen for 2.5 hours and evaporated. The residue was triturated with diethyl ether, filtered and further purified by flash column chromatography on silica gel using dichloromethane / methanol (80:20) for elution. The solvent was evaporated to give (E) -2 &apos;-( D- alpha -glutamyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -Isobutyl-4-methylvalerohydrazide trifluoroacetate in the form of a light brown solid.

MS: 505 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.77 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tert-butyloxycarbonyl) -D- (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide was prepared as follows.

To a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] (1, 1-dimethyl-ethoxy) carbonyl] -5- (l, l-dimethylethyl) ester &lt; / RTI &gt; -D-glutamic acid and 0.383 g of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride. The mixture was stirred at 0 &lt; 0 &gt; C for an additional 1 hour and then at room temperature overnight. The solvent was evaporated to give a residue which was dissolved in ethyl acetate and washed with 5% aqueous citric acid solution, 5% aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel using hexane / ethyl acetate (2: 1) for elution and evaporated to give (E) -2 '- ((Nt-butyloxycarbonyl) - (D- (RS) -pyranyloxy) carbamoyl)] - 4-phenyl-3-p-tolyl- / RTI &gt; 2'-isobutyl-4-methylvalerohydrazide was obtained.

MS: 745 (M + H) &lt; ⁺ & gt ^; .

Example 139

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

(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -2-methyl-2-thiophenecarboxylic acid was prepared in a manner similar to the method described in Example 11, ) -4-phenyl-3-butenyl] -2'-isobutyl-4-methyl-2 '- (2-thienoyl) valerohydrazide as a white solid.

MS: 486 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.58 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 140

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

(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -carbamic acid tert-butyl ester in a manner analogous to that described in Example 11, but using 3-thio-picarboxylic acid instead of N- ) -4-phenyl-3-butenyl] -2'-isobutyl-4-methyl-2 '- (3-thienoyl) valerohydrazide as a white solid.

MS: 486 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.28 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 141

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- , 3-thiadiazol-4-yl) carbonyl] valerohydrazide

(E) -2 (R) - [1 (S (2R, 3S) -triazol-4-yl) -ethanone was obtained in a manner similar to the method described in Example 11, ) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methyl-2 '- [(1,2,3-thiadiazol- ] Valero hydrazide in the form of an off-white solid.

MS: 488 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.96 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 142 [

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

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- A solution of 0.332 g of isobutyl-2 '- [(N- (methanesulfonyl) -D-alanyl] -4-methylvalerohydrazide was treated with 0.040 g of p- toluene-sulfonic acid monohydrate. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was triturated with diethyl ether, filtered and dried to give 0.010 g as an off-white solid.

MS: 525 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.40 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-2 ' - [N- (methanesulfonyl) -D-alanyl] -4-methylvalerohydrazide was prepared as follows.

(R) - [(S) - (tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl -3-butenyl] -2'-isobutyl-4-methylvalerohydrazide (prepared as described in Example 23, parts (i) - (iii) above) And methanesulfonic anhydride (0.210 g) and stirred overnight at room temperature. Evaporation gave a residue which was dissolved in ethyl acetate and washed with 5% aqueous citric acid solution, 5% aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give (E) - 2 - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyl- -Methanesulfonyl) -D-alanyl] -4-methylvalerohydrazide in the form of a clear oil.

MS: 609 (M + H) &lt; ⁺ & gt ^; .

Example 143

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 '-( tetrahydro- -Isobutyl-4-methylvalerohydrazide &lt; / RTI &gt;

(E) -2 '-( tetrahydro-3 (RS) - (R) -methyl-2-methyl-pyrrolidine was prepared in analogy to the method described in example 11, but using tetrahydro-3 Phenyl) -3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide as a white solid in the form of &lt; RTI ID = 0.0 & .

MS: 474 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.46 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 144

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 2RS) -Isobutyl-4-methylvalerohydrazide hydrochloride &lt; RTI ID = 0.0 &gt;

(E) -2 &lt; RTI ID = 0.0 &gt; (RS) -azetidinecarboxylic acid, Nt-butyloxycarbonyl- - (2 (RS) -azetidinyl) carbonyl] -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- -4-methylvalerohydrazide hydrochloride in the form of a white solid.

MS: 459 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.89 min and 11.04 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 145

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- - methylvalerohydrazide hydrochloride &lt; RTI ID = 0.0 &gt;

(E) -2 '-( L- (4-methylpiperazin-1-yl) -ethanone was obtained by a method similar to the method described in Example 8, except that (L) -Nt- butyloxycarbonyl- -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide hydrochloride Obtained as a white solid.

MS: 490 (M + H) &lt; ⁺ & gt ^; .

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

Example 146

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl Methyl valerohydrazide trifluoroacetate &lt; RTI ID = 0.0 &gt;

Butyl ester was replaced by Nt-butyloxycarbonyl-L-aspartic acid? -Tric butyl ester instead of Nt-butoxycarbonyl-L-aspartic acid? -T-butyl ester and the method described in Example 131 -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( D- alpha -aspartyl) -Isobutyl-4-methylvalerohydrazide trifluoroacetate as a white solid.

MS: 491 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.58 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 147

(RS) -hydroxyvaleryl) -2 '-( 2-hydroxyethyl) -2 '-( 4- Isobutyl-4-methylvalerohydrazide

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- (4 (RS) -hydroxyvaleryl) -2 ' -isobutyl-4-methylvalerohydrazide in 10 ml of DMF was treated with 0.015 g of p-toluene-sulfonic acid monohydrate. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was triturated with diethyl ether, filtered and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl- 4 (RS) -hydroxyvaleryl) -2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 476 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.61 min and 11.03 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (4 (RS) -hydroxyvaleryl) -2'-isobutyl-4-methylvalerohydrazide was prepared as follows.

(i) To a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] 2-isobutyl-4-methylvalerohydrazide was treated with 0.232 g of levulinic acid and 0.384 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Respectively. The mixture was stirred at room temperature overnight and evaporated. The residue in ethyl acetate was washed with 5% aqueous citric acid solution, 5% aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give (E) -2 (R) (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( 4-oxobalenyl) -2 ' -isobutyl- 0.50 g of Drazide in the form of a white foam.

MS: 558 (M + H) &lt; ⁺ & gt ^; .

(ii) A mixture of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] -4- phenyl- -2 '-( 4-oxobalenyl) -2 ' -isobutyl-4-methylvalerohydrazide in 10 ml of tetrahydrofuran was treated with 0.012 g of sodium borohydride. The mixture was stirred for 48 hours, diluted with ethyl acetate, and washed with water and saturated sodium chloride solution. Dried over anhydrous magnesium sulphate and evaporated to give (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] ] -2 '- (4 (RS) -hydroxyvaleryl) -2'-isobutyl-4-methylvalerohydrazide in the form of a white foam.

MS: 560 (M + H) &lt; ⁺ & gt ^; .

Example 148

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3 &lt; RTI ID = 0.0 & -Butenyl] -2 &apos; -isobutyl-4-methylvalerohydrazide

(E) -2 ' - [(tetrahydro-quinolin-2-yl) -methanone was obtained in analogy to the method described in example 11, but using tetrahydro-2H-pyran-2 (RS) (RS) -yl) carbonyl] -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- -Methylvalerohydrazide in the form of a white solid.

MS: 488 (M + H) &lt; ⁺ & gt ^; .

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

Example 149

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl &lt; / RTI &gt; ] -2'-isobutyl-4-methylvalerohydrazide

(E) -2 ' - [(tetrahydro-quinolin-2-yl) -methanone in a similar manner to that described in Example 11, but using tetrahydro-2H- (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methyl Valero hydrazide in the form of a white solid.

MS: 488 (M + H) &lt; ⁺ & gt ^; .

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

Example 150

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' - [2- (2-imino-1-imidazolidinyl ) Acetyl] -2 ' -isobutyl-4-methylvalerohydrazide hydrochloride

(2-imino-1-imidazoline) acetic acid fluoride instead of Nt-butoxycarbonyl-L-leucinic acid fluoride was used in a manner analogous to that described in Example 25 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' - [2- (2-imino-1-imidazolidinyl ) Acetyl] -2 ' -isobutyl-4-methylvalerohydrazide hydrochloride as a white solid.

MS: 501 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 90% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.02 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 151

(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Carbonyl] valerohydrazide hydrochloride &lt; RTI ID = 0.0 &gt;

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- -Methyl-2 '- [(2-t-butyloxycarbonyl-1-pyrazolidinyl) carbonyl] valerohydrazide in 4 ml of dioxane was treated with 2 ml of 4M hydrogen chloride in dioxane, Lt; / RTI &gt; The mixture was diluted with diethyl ether and the resulting solid was filtered and washed with diethyl ether and dried to give (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4- Phenyl-3-butenyl] -2'-isobutyl-4-methyl-2 '- [(1-pyrazolinyl) carbonyl] valerohydrazide hydrochloride in the form of light yellow solid.

MS: 474 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.56 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-4-methyl-2 '- [(2-t-butyloxycarbonyl-1-pyrazolidinyl) carbonyl] valerohydrazide was prepared as follows.

A solution of 0.241 g of 2-t-butyloxycarbonyl-pyrazolidine in 5 ml of toluene was slowly added to a solution of 0.725 ml of phosgene in 5 ml of toluene at 0 &lt; 0 &gt; C under nitrogen. The mixture was allowed to warm to room temperature over 2 hours and a solution of (E) -2 (R) - [1 (S) - [(tetrahydro- Phenyl) -3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide in 50 ml of tetrahydrofuran was added dropwise. The mixture was stirred at room temperature for 48 hours and evaporated. The residue was dissolved in ethyl acetate, washed with 2N aqueous hydrochloric acid and water, dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with ether to give (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- phenyl- 2'-isobutyl-4-methyl-2 '- [(2-t-butyloxycarbonyl-1-pyrazolidinyl) carbonyl] valerohydrazide in the form of light yellow solid.

MS: 658 (M + H) &lt; ⁺ & gt ^; .

Example 152

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 (R) '- isobutyl-4-methylvalerohydrazide

(E) -2 ' - [2 (R) - (Benzyloxy) -propionic acid was prepared by a method similar to the method described in Example 11, but using 2 (R) - (benzyloxy) ) Propyl] -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl- 4- methylvalerohydrazide as a pale yellow foam Lt; / RTI &gt;

MS: 538 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 13.23 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 153

(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- 4-methylvalerohydrazide &lt; / RTI &gt;

(E) -2 (R) - [1 (S) - ((R) - (2R) -methoxypropionyl) -4-methylvalerohydrazide was obtained as a white solid in the form of a white solid .

MS: 462 (M + H) &lt; ⁺ & gt ^; .

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

Example 154

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- - pyridyl) propionyl] valerohydrazide p-Toluenesulfonate

(E) -2 (R) - [1 (S) - (Hydroxy-phenyl) -propionic acid was prepared by a method similar to the method described in Example 11, but using 3- (3-pyridine) Methyl-2 '- [3- (3-pyridyl) propionyl] valerohydrazide p-toluenesulfonate was prepared from Obtained as a white solid.

MS: 509 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.66 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 155

(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4 - methylvalerohydrazide hydrochloride &lt; RTI ID = 0.0 &gt;

(E) -2 '-( 5 (tert-butoxycarbonyl-5-aminovaleric acid) was prepared by a method similar to the method described in Example 8, except that Nt-butyloxycarbonyl- -Aminovaleryl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide hydrochloride Lt; / RTI &gt; as a white solid.

MS: 475 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.34 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 156

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Amino) butyryl] valero hydrazide p-Toluenesulfonate

-2 (R) - [1 (S) - (hydroxycarbamoyl) butyric acid was prepared by a method similar to the method described in Example 11, but using 4- (dimethylamino) Methyl-2 ' - [4- (dimethylamino) butyryl] valerohydrazide p-toluenesulfonate as an off-white solid .

MS: 489 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.64 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 157

(E) -2 ' - [(4-aminocyclohexyl) carbonyl] -2 (R) - [1 (S) - (hydroxycarbamoyl) '- isobutyl-4-methylvalerohydrazide hydrochloride

(E / Z) -2 ', by a similar method to that described in Example 8, but using Nt-butyloxycarbonyl-4-aminocyclohexanecarboxylic acid in place of Nt-butyloxycarbonyl- - [(4-aminocyclohexyl) carbonyl] -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- Valero hydrazide hydrochloride as an off-white solid.

MS: 501 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.54 min and 10.96 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 158

(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalerate Yl] -1-isobutylhydrazino] carbonyl] t-butoxypropionate Hydrogen chloride

(E) -2 (S) -amino &lt; / RTI &gt; acid was obtained in a manner similar to the method described in Example 8 but using Nt-butoxycarbonyl-L-aspartic acid instead of Nt-butyloxycarbonyl- -3 - [[2- [2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -1-isobutyl hydrazino ] Carbonyl] t-butoxypropionate hydrogen chloride in the form of a white solid.

MS: 547 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.27 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 159

(R) - (hydroxycarbamoyl) ethyl] -2'-isobutyl-4-methylvaleryl hydrazide

(R) - (benzyloxycarbamoyl) ethyl] -2 '-( 2-benzyloxycarbonyl-D-alanyl) -Isobutyl-4-methylvaleryl hydrazide in 50 ml of tetrahydrofuran was hydrogenated in the presence of 0.037 g of 5% palladium on carbon catalyst for 12 hours. The catalyst was filtered off and the solvent was evaporated. The residue was triturated with diethyl ether to give 2'- (D-alanyl) -2 (R) - [2-benzamido 1 (R) - (hydroxycarbamoyl) ethyl] -2'- 0.068 g of 4-methylvaleryl hydrazide was obtained in the form of a white solid.

MS: 464 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.05 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - (benzyloxycarbamoyl) ethyl] -2 '-( 2-benzyloxycarbonyl-D-alanyl) -2 -Isobutyl-4-methylvaleryl hydrazide was prepared as follows.

(i) A solution of 3.16 g of 2 (R) - [2-benzamido-1 (R) - (tert- butoxycarbonyl) ethyl] -4-methylvaleric acid in 50 ml of dichloromethane was cooled , And 2.22 ml of N-ethylmorpholine, 1.84 g of 1-hydroxybenzotriazole, 2.08 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1.76 g of benzyloxycarbonylhydrazine Lt; / RTI &gt; The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed with a 5% aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. Dried over anhydrous magnesium sulfate and evaporated to give a residue which was purified by flash chromatography on silica gel using methanol / dichloromethane (2:98) for elution. 1.55 g of 2 (R) - [2-benzamido-1 (R) - (t-butoxycarbonyl) ethyl] -2'- benzyloxycarbonyl-4-methylvaleryl hydrazide was obtained in the form of a white foam .

MS: 512 (M + H) &lt; ⁺ & gt ^; .

(ii) To a solution of 2 (R) - [2-benzamido-1 (R) - (t- butoxycarbonyl) ethyl] -2'- benzyloxycarbonyl-4-methylvaleryl A solution of 0.500 g of hydrazide was treated with 0.405 g of potassium carbonate and 0.135 g of bromo-2-methyl-prop-2-ene at room temperature under nitrogen. The mixture was stirred at room temperature overnight and evaporated. The residue was dissolved in ethyl acetate and washed with water until neutral, dried over anhydrous magnesium sulfate, filtered and evaporated to give 2 (R) - [2-benzamido-1 (R) - Ethoxycarbonyl) ethyl] -2'-isobut-2-en-4-methylvaleryl hydrazide in the form of a white foam.

(iii) To a solution of 2 (R) - [2-benzamido-1 (R) - (t-butoxycarbonyl) ethyl] -2'-isobut- A solution of 0.300 g of hydrazide was hydrogenated in the presence of a 5% palladium catalyst on carbon for 3 hours. The catalyst was distilled off and the solvent was evaporated to give 2 (R) - [2-benzamido-1 (R) - (t- butoxycarbonyl) ethyl] -2'-isobutyl- 0.21 g of dryz in the form of a white foam.

(iv) 2 (R) - [2-Benzamido-1 (R) - (t-butoxycarbonyl) ethyl] - (N-benzyloxycarbonyl-D-alanyl) -2 (R) - [2-benzamido-1 (R) - (benzyloxycarbamoyl) ethyl] -2 ' -isobutyl-4-methylvaleryl hydrazide.

MS: 688 (M + H) &lt; ⁺ & gt ^; .

Example 160

2 '- [2- (1-imidazoyl) acetyl] -2'-isobutyl-4-methylvalera Rehydrazide p-toluenesulfonate

To a solution of 2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -2'- Yl) acetyl] -2 ' -isobutyl-4-methylvalerohydrazide in 10 ml of DMF was treated with 0.143 g of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 1 hour and evaporated. The residue was triturated with diethyl ether, filtered and dried to give a clear solution of 2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] -2'- Yl) acetyl] -2'-isobutyl-4-methylvalerohydrazide 0.320 g of p-toluenesulfonate were obtained in the form of a pink solid.

MS: 486 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.79 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -2 ' - [2- Diazo) acetyl] -2'-isobutyl-4-methylvalerohydrazide was prepared as follows.

(i) A solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) -carbamoyl] -4- phenyl- -2'-isobutyl-4-methylvalerohydrazide in 30 ml of tetrahydrofuran was hydrogenated in the presence of 0.100 g of 5% palladium on carbon catalyst for 0.5 hour. The catalyst was filtered off and the solvent was evaporated to give 2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -2'- 0.0 &gt; 4-methylvalerohydrazide &lt; / RTI &gt; in the form of a white solid.

MS: 462 (M + H) &lt; ⁺ & gt ^; .

(ii) 0.415 g of 2- (1-imidazoyl) acetic acid hydrogen bromide in 5 ml of dimethylformamide and 0.415 g of 2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) Ylmethyl] -4-phenylbutyl] -2 ' -isobutyl-4-methylvalerohydrazide in 5 ml of dichloromethane was treated with 0.230 g of N- Carbodiimide hydrochloride and the mixture was stirred overnight at room temperature. Evaporation gave a residue which was dissolved in ethyl acetate and washed with water and a saturated aqueous sodium chloride solution. Dried over anhydrous magnesium sulfate, evaporated, triturated with diethyl ether and filtered to give 2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) Phenylbutyl] -2 '- [2- (1-imidazoyl) acetyl] -2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 567 (M + H) &lt; ⁺ & gt ^; .

Example 161

Methyl-2 ' - [2- (1-imidazoyl) acetyl] -2 '-( isobutyl) Valerohydrazide p-toluenesulfonate

(RS) -pyranyloxy) carbamoyl] butyl] -2 ' -isobutyl-4-methyl- A solution of 0.205 g of 2 '- [2- (1-imidazoyl) acetyl] valerohydrazide was treated with 0.075 g of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 6 hours and evaporated. The residue was purified by flash column chromatography on silica gel using methanol / dichloromethane (5:95) as eluent to give 2 (R) - [4-cyclohexyl-1 (S) - (hydroxycarbamoyl ) Butyl] -2'-isobutyl-4-methyl-2 '- [2- (1-imidazoyl) acetyl] valerohydrazide p-Toluenesulfonate in the form of a white solid.

MS: 492 (M + H) &lt; ⁺ & gt ^; .

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

(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] butyl] -2'-isobutyl-4-methyl -2 '- [2- (1-imidazoyl) acetyl] valerohydrazide was prepared as follows.

(i) A solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] A solution of 1.0 g of 2'-isobutyl-4-methylvalerohydrazide was hydrogenated in the presence of 0.300 g of palladium (II) oxide for 2 hours. The catalyst was filtered off and the solvent was evaporated and triturated with hexane to give 2 (R) - [4-cyclohexyl-1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) -2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 468 (M + H) &lt; ⁺ & gt ^; .

(ii) 0.429 g of 2- (1-imidazoyl) acetic acid hydrogen bromide in 5 ml of dimethylformamide and 0.429 g of 2 (R) - [4-cyclohexyl-1 (S) - [(tetrahydro- -Pyrnyloxy) carbamoyl] butyl] -2 ' -isobutyl-4-methylvalerohydrazide in 50 ml of tetrahydrofuran was treated with 0.230 g of N- ethylmorpholine and 1 g of 1-ethyl- 3- ) Carbodiimide hydrochloride, and the mixture was stirred overnight at room temperature. Evaporation gave a residue which was dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. Purification by flash column chromatography on silica gel using methanol / dichloromethane (5:95) as eluent gave 2 (R) - [4-cyclohexyl-1 (S) - [(tetrahydro- Carbamoyl] butyl] -2'-isobutyl-4-methyl-2 '- [2- (1-imidazoyl) acetyl] valerohydrazide in the form of a white foam.

MS: 576 (M + H) &lt; ⁺ & gt ^; .

Example 162

2-isobutyl-4-methyl-2 '- [2- (3-pyridyl) acetyl] valerate Rohiodrazide p-toluenesulfonate

2 (R) - [4-cyclohexyl-1 (S) -pyridin-3-ylamine in a similar manner to that described in Example 161, but using pyridine- ) - (hydroxycarbamoyl) butyl] -2'-isobutyl-4-methyl-2 '- [2- (3-pyridyl) acetyl] valerohydrazide p-toluenesulfonate as a white solid .

MS: 503 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.90 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 163

2'- (4-aminobutyryl) - [2 (R) - [4-cyclohexyl-1 (RS) - (hydroxycarbamoyl) butyl] -2'-isobutyl- Zid hydrochloride

2 '- (N-benzyloxycarbonyl-4-aminobutyryl) - [2 (R) - [4-cyclohexyl- 1 (RS) - (hydroxycarbamoyl) butyl] -2' -Isobutyl-4-methylvalerohydrazide in 50 ml of tetrahydrofuran was hydrogenated in the presence of 0.040 g of 5% palladium on carbon catalyst for 1 hour. Filtration and evaporation gave a residue which was triturated with 1M hydrogen chloride solution in diethyl ether. Filtered to give 2 '- (4-aminobutyryl) - [2 (R) - [4-cyclohexyl-1 (RS) - (hydroxycarbamoyl) butyl] -2'- 0.142 g of hydrazide hydrochloride was obtained in the form of a pale pink solid.

MS: 469 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.94 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(R) - [4-Cyclohexyl-1 (RS) - (hydroxycarbamoyl) butyl] -2 '-( N-benzyloxycarbonyl- '- isobutyl-4-methylvalerohydrazide was prepared as follows.

(i) Similar to the method described in example 161, part (ii) but using (N-benzyloxycarbonyl) -4-aminobutyric acid in place of 2- (1-imidazoyl) acetic acid hydrogen bromide (R) - [4-cyclohexyl-1 (S) - [(tetrahydro-2 (RS) -pyranyl Oxy) carbamoyl] butyl] -2 ' -isobutyl-4-methylvalerohydrazide in the form of a clear glass.

MS: 687 (M + H) &lt; ⁺ & gt ^; .

(ii) A solution of 2 '- [(N-benzyloxycarbonyl) -4-aminobutyryl] -2 (R) - [4-cyclohexyl- 1 (S) - [(tetrahydro- RS) -pyranyloxy) carbamoyl] butyl] -2 ' -isobutyl-4-methylvalerohydrazide in 5 ml of DMF was treated with 0.123 g of p-toluene-sulfonic acid monohydrate for 1.5 h. 2 '- (N-Benzyloxycarbonyl-4-aminobutyryl) - [2 (R) - [4-cyclohexyl- 1 (RS) - (hydroxycarbamoyl) butyl] Isobutyl-4-methylvalerohydrazide in the form of a white foam.

Example 164

2 ' - [2- (1-methyl-4-piperidyl) -2 '-( isobutyl) Nyl) acetyl] valerohydrazide p-toluenesulfonate

2- (l-Imidazoyl) 2 (R) -ethanone in a manner analogous to that described in Example 161, but using 2- (l-methyl-4-piperidinyl) acetic acid instead of hydrogen bromide acetate. - [2- (1-methyl-4-piperidinyl) acetyl] -2-methyl- The valerohydrazide p-toluenesulfonate was obtained in the form of a white solid.

MS: 523 (M + H) &lt; ⁺ & gt ^; .

Example 165

(RS) - (hydroxycarbamoyl) pentyl] -2 ' -isobutyl-4-methylvalerohydrazide p '-( D-alanyl) -2- (R) - toluene sulfonate

(RS) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] pentyl] - (D-alanyl) A solution of 0.210 g of 2'-isobutyl-4-methylvalerohydrazide was treated with 0.080 g of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 6 hours and evaporated. The residue was triturated with diethyl ether to give 2'- (D-alanyl) -2 (R) - [5-cyclohexyl-1 (RS) - (hydroxycarbamoyl) pentyl] 0.0 &gt; 4-methylvalerohydrazide p-toluenesulfonate &lt; / RTI &gt; in the form of a white solid.

MS: 469 (M + H) &lt; ⁺ & gt ^; .

(RS) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] pentyl] -2 '-( 5-cyclohexyl- -2'-isobutyl-4-methylvalerohydrazide was prepared as follows.

(i) 7.54 g of (E) -4-cyclohexyl-2-butenol in 200 ml of diethyl ether was treated with 9.99 g of acetic anhydride and 7.42 g of triethylamine and stirred overnight at room temperature. The mixture was then treated with 0.005 g of 4-dimethylaminopyridine and stirred for a further 0.5 h. The mixture was washed with 5% aqueous sodium bicarbonate, water and brine, then dried over anhydrous magnesium sulfate and evaporated. The residue was dried under vacuum to obtain 9.50 g of (E) -4-cyclohexyl-2-butenol acetate as a pale yellow oil.

(ii) A solution of 22.2 g of 1,2-dibenzyl 1-t-butyl-4-methyl-1 (RS), 1,2 (R) -pentanetricarboxylate in 200 ml of anhydrous tetrahydrofuran was added dropwise under a nitrogen atmosphere Treated with 2.35 g of 60% sodium hydride at room temperature. The mixture was stirred until the hydrogen evolution ceased and then 9.50 g of (E) -4-cyclohexyl-2-butenol acetate in 50 mL anhydrous tetrahydrofuran and tetrakis (triphenylphosphine) -palladium g. The mixture was stirred at room temperature overnight and evaporated. The residue was partitioned between ethyl acetate and water and the ethyl acetate layer was further washed with water and a saturated aqueous sodium chloride solution. Dried over anhydrous magnesium sulfate and evaporated to give a residue which was purified by column chromatography on silica gel using ethyl acetate / hexane (1: 9) for elution to give (E) -1,2-dibenzyl 1-t (RS), 1,2 (R) -pentanetricarboxylate (14.27 g) in the form of a clear oil.

MS: 535 (MH +) ⁺ .

(iii) To a solution of (E) -1,2-dibenzyl 1-t-butyl-1- (4-cyclohexyl- 2 (R) -pentanetricarboxylate in 20 ml of tetrahydrofuran was hydrogenated for 1.5 hours in the presence of 1.4 g of 10% palladium on carbon. The catalyst was filtered off and the solvent was evaporated. The residue was dissolved in 200 ml of toluene and heated to reflux for 3 hours in the presence of 2.44 g of triethylamine. The mixture was cooled to room temperature overnight and then washed with 2M aqueous hydrochloric acid, water and saturated aqueous sodium chloride. Dried over anhydrous magnesium sulfate and evaporated to give 8.18 g of 2 (R) -isobutyl-4-t-butyl-3 - [(RS) - (4-cyclohexylbutyl)] succinate as a clear oil.

(iv) A solution of 3.0 g of (2R) -isobutyl-4-t-butyl-3 - [(RS) - (4-cyclohexylbutyl)] succinate in 50 ml of dichloromethane was cooled to 0 & A solution of 3.85 g of ethyl morpholine, 1.49 g of 1-hydroxybenzotriazole, 4.89 g of isobutylhydrazine ditosylate and 1.88 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added successively Respectively. The solution was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was washed successively with water, 5% citric acid solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by flash column chromatography on silica gel using hexane / ethyl acetate (5: 1) for elution. (RS) - (t-butoxycarbonyl) pentyl] -2 &apos; -isobutyl-4-methylvalerohydrazide in the form of a clear oil .

MS: 439 (M + H) &lt; ⁺ & gt ^; .

(v) 2 (R) - [1 (RS) - (t-Butoxycarbonyl) -4-phenylbutyl] -2 '-( isobutyl-4-methylvalerohydrazide) Example 33, part (ii), except that [5-cyclohexyl-1 (RS) - (t-butoxycarbonyl) pentyl] -2 ' -isobutyl- (R) - [5-cyclohexyl-1 (RS) - (carbonyl) pentyl (2-fluorophenyl) ] -2'-isobutyl-4-methylvalerohydrazide in the form of a clear glass.

MS: 676 (M + H) &lt; ⁺ & gt ^; .

(vi) Synthesis of 2 '- (N-benzyloxycarbonyl-D-alanyl) -2 (R) - [5-cyclohexyl- 1 (RS) - (carbonyl) pentyl] (R) - [(R) - [2- (4-fluorophenyl) (RS) -pyranyloxy) carbamoyl] pentyl] -2 ' -isobutyl-4-methylvalerohydrazide was obtained in the form of a white solid Respectively.

MS: 553 (M + H) &lt; ⁺ & gt ^; .

Example 166

(RS) - (hydroxycarbamoyl) -5-phenylpentyl] -2'-isobutyl-4-methylbutyro hydrazide p- Toluene sulfonate

Was obtained in a similar manner to the procedure described in example 165, but using (E) -4-phenyl-2-buteno in place of (E) -4-cyclohexyl- Phenylbutyl] -2 ' -isobutyl-4-methylbutyrohydrazide p-toluenesulfonate as a white solid &lt; RTI ID = 0.0 &gt;Lt; / RTI &gt;

MS: 463 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.09 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 167

2 ' - [2- (imidazolyl) acetyl] -4-methylvalero [l, 2- Hydrazide

To a solution of 2 (R) - [1 (S) - (N-benzyloxycarbamoyl) -4-cyclopentylbutyl] -2'-isobutyl-2'- [2- (imidazolyl) -4-methylvalerohydrazide in 50 ml of tetrahydrofuran was hydrogenated in the presence of 0.040 g of 5% palladium on carbon for 4 hours. Filtered and evaporated to give a residue which was triturated with diethyl ether. (S) - (hydroxycarbamoyl) butyl] -2'-isobutyl-2'- [2- (imidazolyl) acetyl] -4- 0.083 g of methylvalerohydrazide were obtained in the form of a white solid.

MS: 478 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.64 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(S) - (N-benzyloxycarbamoyl) -4-cyclopentylbutyl] -2'-isobutyl-2 '- [2- (imidazolyl) acetyl ] -4-methylvalerohydrazide was prepared as follows.

(i) A solution of 30 g of (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid in 400 ml of ethyl acetate Was treated with 9.63 g of triethylamine and 16.31 g of benzyl bromide and then heated to reflux for 4 hours. The mixture was cooled to room temperature, filtered and the filtrate was evaporated to give a residue which was purified by column chromatography on silica gel using ethyl acetate / hexane (1: 9) for elution to give (E) -benzyl-2 ) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerate in the form of a clear oil.

MS: 381 (M-tBu + H) &lt; ⁺ & gt ^; .

(ii) To a solution of (E) -benzyl-2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerate 15.8 g was cooled to -78 &lt; 0 &gt; C and the mixture was bubbled with ozone until blue color persisted. The mixture was treated with 20 mL dimethylsulfide and stirred overnight at room temperature. Evaporation gave a residue which was purified by column chromatography on silica gel using ethyl acetate / hexane (1: 9 to 1: 4) for elution to give (E) -benzyl-2 (R) S) - (t-butoxycarbonyl) -propan-3-ol] -4-methylvalerate as a yellow oil.

MS: 307 (M-tBu + H) &lt; ⁺ & gt ^; .

(iii) 5.65 g of cyclopentylmethyltriphenylphosphonium iodide in 200 ml of toluene was treated with 1.34 g of potassium t-butoxide and the mixture was stirred at room temperature for 4 hours. A solution of 2.9 g of (E) -benzyl-2 (R) - [1 (S) - (t-butoxycarbonyl) Min. &Lt; / RTI &gt; The mixture was further stirred at room temperature for 48 hours and evaporated. The residue was stirred in 100 mL of hexane for 20 minutes, then filtered and evaporated. The residue was purified by column chromatography on silica gel using hexane / ethyl acetate (6: 1) to elute (E) to give (Z) -benzyl-2 (R) - [4-cyclopentyl- (S) - (t-butoxycarbonyl) -3-butenyl] -4-methylvalerate in the form of a colorless oil.

MS: 429 (M + H) &lt; ⁺ & gt ^; .

(iv) To a solution of (E), (Z) -benzyl-2 (R) - [4-cyclopentyl-1- (S) - (t-butoxycarbonyl) -4-methylvalerate were hydrogenated in the presence of 0.100 g of 10% palladium on carbon. The mixture was filtered and evaporated to give 2 (R) - [4-cyclopentyl-1- (S) - (t-butoxycarbonyl) -butyl] -4-methylvaleric acid in the form of a clear oil.

(v) 2 (R) - [4-Cyclohexyl-1 (S) -isobutyl-4-t-butyl-3 - [(RS) - (4-cyclohexylbutyl)] succinate ), was prepared in a manner similar to the one described in example 165, part (iv), but using 2- (R) - [4-cyclohexylmethoxy) Pentyl-1 (S) - (t-butoxycarbonyl) -butyl] -2'-isobutyl-4-methylvalohydrazide as a pale yellow oil.

(vi) To a solution of 2 (R) - [4-cyclopentyl-1 (S) - (t- butoxycarbonyl) -butyl] -2 ' -isobutyl-4-methylvalohydrazide in 10 ml dimethylformamide Was treated with 0.308 g of 2- (1-imidazolyl) acetic acid hydrogen bromide, 1.712 g of N-ethylmorpholine and 0.286 g of 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride And then stirred overnight at room temperature. The mixture was diluted with diethyl ether and washed with water and a saturated aqueous sodium chloride solution. Dried over anhydrous magnesium sulfate and evaporated to give a residue that was purified by column chromatography on silica gel using ethyl acetate / hexane (1: 3) followed by dichloromethane / methanol (3: 1) (S) - (t-butoxycarbonyl) -butyl] -2'-isobutyl-2'- 0.255 g of methyl valohydrazide are obtained in the form of a yellow oil.

(vii) 2 '- (N-benzyloxycarbonyl-D-alanyl) -2 (R) - [1 (RS) - (t- (S) - (t-butoxycarbonyl) -butyl] -2 ' -isobutyl-2 '-( tert-butoxycarbonyl) 2 (R) -methanone was prepared by a method similar to that described in Example 33, Part (iii) to (iv) but using 2- (1-imidazolyl) acetyl] - [1 (S) - (N-benzyloxycarbamoyl) -4-cyclopentylbutyl] -2'-isobutyl-2 '- [2- (imidazolyl) The zide was obtained in the form of a clear glass.

MS: 568 (M + H) &lt; ⁺ & gt ^;

Example 168

2-isobutyl-2 ' - [2- (imidazolyl) acetyl] -4-methylvaleric acid Hydrazide

2 (R) - [1 (S) - (4-methylpiperidin-l-yl) cyclopentylmethyltriphenylphosphonium iodide was obtained in a manner similar to the method described in Example 167, but using isobutylmethyltriphenylphosphonium iodide in place of cyclopentylmethyltriphenylphosphonium iodide. (Hydroxycarbamoyl) -5-methyl-hexyl] -2'-isobutyl-2 '- [2- (imidazolyl) acetyl] -4-methylvalerohydrazide in the form of a white solid.

MS: 452 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.41 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 169

(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- - hexamethyleneimino) acetyl] valerohydrazide p-Toluenesulfonate

(E) -2 ((1-Pyrrolidinyl) methanesulfonamide was obtained by a method similar to the one described in Example 37, except that 2- (1-hexamethyleneimino) acetic acid hydrogen bromide was used instead of 2- R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Acetyl] valerohydrazide p-toluenesulfonate as a white solid.

MS: 515 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.47 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

Example 170

(RS) - (hydroxycarbamoyl) -4- (2-thienyl) -3-butenyl] -2 '-( 2- Isobutyl-4-methylvalerohydrazide

(RS) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4 - ((E) -2 '-( D-alanyl) 2-thienyl) -3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide in 10 ml of tetrahydrofuran was treated with 0.077 g of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was purified by column chromatography on silica gel using dichloromethane / methanol (95: 5) for elution to give (E) -2 '-( D-alanyl) -2 (R) ) - (hydroxycarbamoyl) -4- (2-thienyl) -3-butenyl] -2'-isobutyl-4-methylvalerohydrazide as an off-white solid.

MS: 453 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.32 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(RS) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-tert-butoxycarbonylamino- (2-thienyl) -3-butenyl] -2'-isobutyl-4-methylvalerohydrazide was prepared as follows.

(i) Example 165, part (i), except that (E) -3- (2-thienyl) -2-propenol was used in place of (E) -4-cyclohexyl- (E) -1,2-dibenzyl 1-t-butyl-1- (3- (2-thienyl) -2-propenyl) -4- methyl- (RS), 1,2 (R) -pentanetricarboxylate in the form of a pale yellow oil.

MS: 521 (M-tBu + H) &lt; ⁺ & gt ^; .

(ii) A mixture of (E) -1,2-dibenzyl 1-t-butyl-1- (3- (2-thienyl) -2- A solution of 7.22 g of 1,2 (R) -pentanetricarboxylate was treated with 32 ml of 4 M aqueous sodium hydroxide and heated to reflux overnight. Cool to room temperature and evaporate the ethanol and dilute the residue with water and acidify with 4M aqueous sodium chloride. This was washed with ether and then the combined organic phases were washed with water and saturated aqueous sodium chloride. Dried over anhydrous magnesium sulfate and evaporated to give a residue which was dissolved in 50 ml of toluene and treated with 1.26 g of triethylamine. The mixture was heated to reflux for 3 hours, then cooled to room temperature and washed with 2M aqueous sodium chloride, water and saturated aqueous sodium chloride. Dried over anhydrous magnesium sulfate and evaporated to give a residue which was purified by column chromatography on silica gel using ethyl acetate / hexane (1: 5) for elution to give 2 (R) -isobutyl- Butyl-3 - [(RS) - (3- (2-thienyl) -2-propenyl)] succinate as a yellow oil.

(iii) 2 (R) -isobutyl-4-t-butyl-4-t-butyl-3 - [(RS) - (4-cyclohexylbutyl)] succinate instead of 2 (R) (E) -methanone in a manner analogous to that described in Example 165, Part (iv) but using 3- [(RS) - (3- (2- thienyl) -2- propenyl)] succinate. -2 (R) - [1 (RS) - [(t-butyloxy) carbonyl] -4- (2-thienyl) -3-butenyl] -2'-isobutyl- Lt; / RTI &gt; as a pale yellow oil.

MS: 423 (M + H) &lt; ⁺ & gt ^; .

(iv) N- (9-fluorenylmethyloxycarbonyl) -D-alanine acid fluoride instead of N- (9-fluorenylmethyloxycarbonyl) -Ot-butyl- (R) - [1 (RS) - [(t-butyloxy) carbonyl] -4- ( 2-thienyl) -3-butenyl] -2'-isobutyl-2'- [N- (9- fluorenylmethyloxycarbonyl) -D-alanyl] -4- methylvalerohydrazide &Lt; / RTI &gt; in the form of a white foam.

MS: 716 (M + H) &lt; ⁺ & gt ^; .

(v) To a solution of (E) -2 (R) - [1 (RS) - [(t- butyloxy) carbonyl] -4- (2-thienyl) -3-butenyl] A solution of 1.04 g of isobutyl-2 '- [N- (9-fluorenylmethyloxycarbonyl) -D-alanyl] -4- methylvalerohydrazide in 33% solution of hydrogen bromide in acetic acid At -15 &lt; 0 &gt; C. The mixture was stirred at this temperature for 1.5 hours, then washed with water and dried over anhydrous magnesium sulfate. After evaporation, hexane was added and the resulting precipitate was filtered. The precipitate was dried to give (E) -2 (R) - [1 (RS) - [(carboxy)] - 4- (2-thienyl) -3-butenyl] -2'- N- (9-fluorenylmethyloxycarbonyl) -D-alanyl] -4-methylvalerohydrazide in the form of a pale brown solid.

MS: 660 (M + H) &lt; ⁺ & gt ^; .

(vi) Synthesis of (E) -2 (R) - [1 (RS) - [(carboxy)] -4-phenyl-3-butenyl] -2'- (RS) - [(carboxy)] - 4- (2-thienylmethyloxycarbonyl) -D-seryl] -4-methylvalerohydrazide instead of (E) Yl) -3-butenyl] -2'-isobutyl-2 '- [N- (9-fluorenylmethyloxycarbonyl) -D-alanyl] -4- methylvalerohydrazide -2 '- (D-alanyl) -2 (R) - [1 (RS) - [( (2-thienyl) -3-butenyl] -2 ' -isobutyl-4-methylvalerohydrazide as a yellow oil in the form of a yellow oil .

MS: 537 (M + H) &lt; ⁺ & gt ^; .

Example 171

2 '- [2- (1H-1,2,3,4-tetrahydroisoquinolin-2-ylmethyl) , 3-triazol-1-yl) acetyl] valerohydrazide

2 '- (2-ethylbutyl) -4-methyl-2' - [(1S) - (benzyloxycarbonyl) 2- (1H-1,2,3-triazol-1-yl) acetyl] valerohydrazide was prepared in analogy to the procedure described in Example 103, starting from 2 '- R) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methyl- 0.198 g of valero hydrazide was obtained in the form of a white solid.

MS: 515 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 12.358 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(E) -2 (R) - [1 (S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 2- ethylbutyl) -4-methyl -2 '- [2- (1H-1,2,3-triazol-1-yl) acetyl] valerohydrazide was prepared as follows.

(i) (E) -2 (R) - [1 (S) - (t-Butoxycarbonyl) -4-phenyl- (E) -2 (R) - (4-methyl-pyridin-2-yl) -ethanone in a similar manner to that described in Example 1, parts (iv) to (vii), starting from valerohydrazide and using O- benzylhydroxylamine in part Phenyl] -3-butenyl] -2 '-( 2-ethylbutyl) -4-methylvalerohydrazide in the form of a white solid.

MS: 494 (M + H) &lt; ⁺ & gt ^; .

(ii) (E) -2 (R) - [1 (S) - (Benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 2- ethylbutyl) (E) -2 (R) - [1 (S (2R) -2-hydroxy-2- ) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 2- ethylbutyl) -4-methyl- -1-yl) acetyl] valerohydrazide in the form of a gum.

Example 172

2 '- [2- (1H-1,2,3,4-tetrahydroisoquinolin-2-ylmethyl) , 4-triazol-1-yl) acetyl] valerohydrazide

2 '- (2-ethylbutyl) -4-methyl-2' - [(1S) - (benzyloxycarbonyl) 2 - (2-ethylbutyl) -2 ((2-ethylbutyl) -2-methylpropyl) -ethanone was obtained by a method similar to the one described in Example 103, R) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methyl- 0.10 g of valerohydrazide were obtained in the form of a white solid.

MS: 515 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.918 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(E) -2 (R) - [1 (S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 2- ethylbutyl) -4-methyl -2 '- [2- (1H-1,2,4-triazol-1-yl) acetyl] valerohydrazide was prepared as follows.

(E) -2 (R) - [1 (S) - (Benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 2- ethylbutyl) -4- methylvalerohydrazide (E) -2 (R) - [1 (R) -2- (4-fluorophenyl) -1,2,4-triazol-1-yl] -acetic acid in place of Nt-butoxycarbonyl- S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 2- ethylbutyl) -4-methyl- Yl) acetyl] valerohydrazide in the form of a gum.

Example 173

-2 ' - [2- (lH-imidazol-l-yl) -2 '-( 2-ethylbutyl) -2- (R) Acetyl] -4-methylvalerohydrazide

-2 '-( 2- (1H) -quinolin-2 '-( 2-ethylbutyl) (2-ethylbutyl) -2 (R) - [1 (R) - [2- S) - (hydroxycarbamoyl) -4-phenylbutyl] -2 '- [2- (1H-imidazol-1-yl) acetyl] -4-methylvalerohydrazide as a white solid .

MS: 514 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 11.838 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(E) -2 (R) - [1 (S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 2- ethylbutyl) [2- (1H-imidazol-1-yl) acetyl] -4-methylvalerohydrazide was prepared as follows.

(E) -2 (R) - [1 (S) - (Benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 2- ethylbutyl) -4- methylvalerohydrazide -2 (R) - [1 (S) - (benzyloxy) -7-methoxy-benzaldehyde was prepared by a method similar to the method described in Example 8, using imidazole-1-acetic acid instead of Nt-butoxycarbonyl- -2-f2- (lH-imidazol-l-yl) acetyl] -4-valerohydrazide In the form of a sword.

Example 174

2 '- (4-aminobutyryl) -2' - (2-ethylbutyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] Hydrazide

(E) -2 (R) - [1 (S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 4- benzyloxycarbonylaminobutyryl) (4-aminobutyryl) -2 '-( 2-ethylbutyl) -2 (2-ethylbutyl) -4-methylvalerohydrazide was prepared in analogy to the method described in Example 103, starting from 2- (R) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methylvalerohydrazide in the form of a white solid.

MS: 491 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Time of stay: 11.002 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.

(E) -2 (R) - [1 (S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 4- benzyloxycarbonylaminobutyryl ) -2 '-( 2-ethylbutyl) -4-methylvalerohydrazide was prepared as follows.

(E) -2 (R) - [1 (S) - (Benzyloxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 2- ethylbutyl) -4- methylvalerohydrazide (E) -2 (R) - [1 (S) - ((R) -2- (2-hydroxyethyl) -1H-pyrazole-3-carbaldehyde in analogy to the method described in example 8, using 4-benzyloxycarbonylaminobutyric acid instead of Nt-butoxycarbonyl- -2 '-( 2-ethylbutyl) -4-methylvalerohydrazide was reacted with 2- (4-benzyloxycarbonylaminobutyryl) In the form of a gum.

Example 175

2 (S) -methylbutyl) -2 ' - [2- (lH-pyrrolo [ 1,2,3-triazol-1-yl) acetyl] valerohydrazide

Methyl-2 '- (2 (S) -methylbutyl) -2 (R) - [1 (S) - (benzyloxycarbamoyl) 2 (R) - [1 (S) -acetyl] valero hydrazide in a manner similar to the method described in Example 103, starting from 2- ) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methyl-2 '-( 2- (S) Yl) acetyl] valerohydrazide in the form of a white solid.

MS: 501 (M + H) &lt; ⁺ & gt ^; .

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

(S) - (benzyloxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2 '-( 2 (S) - Methylbutyl) -2 '- [2- (1H-1,2,3-triazol-1-yl) acetyl] valerohydrazide was prepared as follows.

Methyl-2 '- (2 (S) -methylbutyl) valero (E) -2 (R) - [1 (S) - (benzyloxycarbamoyl) (E) - (R) - (2-methyl-pyridin-2-yl) -methanone was prepared from hydrazide by a method similar to that described in Example 8, using 1,2,3-triazole-1-acetic acid instead of Nt-butoxycarbonyl- -2 ' - [2- (lH-1 (S) - (benzyloxycarbamoyl) -4-phenyl- , 2,3-triazol-1-yl) acetyl] valerohydrazide in the form of a gum.

MS: 589 (M + H) &lt; ⁺ & gt ^; .

Example 176

2 '- [2- (1H-imidazol-1-yl) acetyl] -2'-isobutyl -4-methylvalerohydrazide

To a solution of 2 (R) - [3-benzamido-1 (S) - (benzyloxycarbamoyl) propyl] -2 '-( 2- (1H- imidazol- 1 -yl) '- isobutyl-4-methylvalerohydrazide in 50 ml of tetrahydrofuran was hydrogenated for 12 hours in the presence of 0.126 g of 5% palladium on carbon. The catalyst was filtered off and the solvent was evaporated. The residue was triturated with diethyl ether to give 2 (R) - [3-benzamido-1 (S) - (hydroxycarbamoyl) propyl] -2 '- [2- ) Acetyl] -2 ' -isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 515 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.12 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPBDSC18.

(S) - (benzyloxycarbamoyl) propyl] -2 ' - [2- (lH-imidazol- l-yl) acetyl] - 2'-isobutyl-4-methylvalerohydrazide was prepared as follows.

(i) A solution of 1.0 g (E) -2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid in 10 ml of dimethylformamide Was treated successively with 2.0 g of potassium carbonate and 0.45 ml of benzyl bromide. The mixture was stirred at room temperature for 1 hour, then the solvent was evaporated and the residue was dissolved in ethyl acetate and washed with water until the washings were neutral (pH = 7). Dried over anhydrous magnesium sulfate and evaporated to give (E) -benzyl-2 (R) - [1 (S) - (t- butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerate 1.28 g &lt; / RTI &gt; as an orange oil.

MS: 381 (M-tBu + H) &lt; ⁺ & gt ^; .

(ii) To a solution of (E) -benzyl-2 (R) - [1 (S) - (t-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerate 32.12 g &lt; / RTI &gt; was cooled to-78 C and then ozone was bubbled through the mixture for 2.5 hours. 35 ml of dimethylsulfide was then added to the mixture and stirring was continued at room temperature overnight. The solvent was evaporated to give an orange oil. This was dissolved in 300 mL of methanol, cooled to 0 &lt; 0 &gt; C under nitrogen and then treated with 5.6 g of sodium borohydride in portions. The mixture was then quenched with glacial acetic acid and evaporated. The residue was dissolved in ethyl acetate and washed successively with 2M aqueous hydrogen chloride, water, 5% aqueous sodium bicarbonate and brine then dried over anhydrous magnesium sulfate. Filtration and evaporation gave a residue which was purified by flash column chromatography on silica gel using ethyl acetate / hexane (increasing from 2: 8 to 4.6) eluting with benzyl-2 (R) - [1 S) - (t-butoxycarbonyl) -3-hydroxypropyl] -4-methylvalerate as a pale yellow oil.

(iii) A solution of 1.5 g of benzyl-2 (R) - [1 (S) - (t-butoxycarbonyl) -3-hydroxypropyl] -4-methylvalerate in 30 ml of dichloromethane was stirred at 0 Lt; 0 &gt; C and then treated with 3.3 ml of pyridine and 3.5 g of methanesulfonic anhydride. The mixture was stirred for 1 hour and then the solvent was evaporated. The residue was dissolved in ethyl acetate and washed successively with 2M aqueous hydrogen chloride, 5% aqueous sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate. Filtration and evaporation gave a yellow oil which was purified by flash column chromatography on silica gel using ethyl acetate / hexane (2: 8) for elution to give benzyl-2 (R) - [1 (S) - -Butoxycarbonyl) -3-methanesulfonyloxypropyl] -4-methylvalerate as a colorless oil.

MS: 465 (M + Na) &lt; ⁺ & gt ^; .

(iv) A solution of 1.0 g of benzyl-2 (R) - [1 (S) - (t-butoxycarbonyl) -3-methanesulfonyloxypropyl] -4-methylvalerate in 10 ml of anhydrous dimethylformamide Was treated with 0.735 g of sodium azide and 0.034 g of sodium iodide and was treated at 50 &lt; 0 &gt; C for 12 hours under nitrogen. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed with water (twice). , Dried over anhydrous magnesium sulfate, filtered and evaporated to give 0.88 g of benzyl-2 (R) - [3-azido-1 (S) - (t- butoxycarbonyl) propyl] -4-methylvalerate as a white solid .

(v) A solution of 0.880 g of benzyl-2 (R) - [3-azido-1 (S) - (t-butoxycarbonyl) propyl] -4-methylvalerate in 10 ml of ethanol was added to 5% In the presence of 0.090 g of palladium for 12 hours. The catalyst was filtered off and the solvent was evaporated to give 0.600 g of 2 (R) - [3-amino-1 (S) - (t- butoxycarbonyl) propyl] -4-methylvaleric acid as a white solid

(vi) A solution of 1.0 g of 2 (R) - [3-amino-1 (S) - (t-butoxycarbonyl) propyl] -4-methylvaleric acid in 20 ml of dichloromethane was cooled And treated with a solution of 1.3 ml of triethylamine and 0.54 g of benzoyl chloride in 10 ml of dichloromethane. The mixture was stirred at room temperature overnight and then the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with 2M aqueous hydrogen chloride and water. Dried over anhydrous magnesium sulfate, filtered and evaporated to give a pale yellow oil which was purified by flash column chromatography on silica gel using ethyl acetate / hexane (3: 1) for elution to give 2 (R) - [ Amide-1 (S) - (t-butoxycarbonyl) propyl] -4-methylvaleric acid in the form of a colorless oil.

(vii) A solution of 0.78 g of 2 (R) - [3-benzamido-1 (S) - (t-butoxycarbonyl) propyl] -4-methylvaleric acid in 10 ml of dichloromethane was stirred at 5 [ , And treated sequentially with 0.80 ml of N-ethylmorpholine, 0.437 g of hydroxybenzotriazole hydrate and 0.50 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was stirred for 5 minutes at 0 DEG C and then 1.1 g of isobutylhydrazine was added. The residue was dissolved in ethyl acetate and washed with 5% aqueous sodium bicarbonate, water, 2M aqueous hydrogen chloride and saturated aqueous sodium chloride. Dried over anhydrous magnesium sulfate, filtered and evaporated to give 2 (R) - [3-benzamido-1 (S) - (t- butoxycarbonyl) propyl] -2 ' -isobutyl- 0.763 g of dryz as an off-white foam.

MS: 448 (M + H) &lt; ⁺ & gt ^;

(viii) To a solution of 2 (R) - [3-benzamido-1 (S) - (t- butoxycarbonyl) propyl] -2'-isobutyl-4-methylvalerohydra A solution of 0.763 g of zid and 0.780 g of 2- (1H-imidazol-1-yl) acetic acid hydrogen bromide was cooled to 0 ° C under nitrogen and 0.45 ml of N-ethylmorpholine and 1-ethyl-3- Propyl) carbodide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated to give a residue which was dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride. Dried over anhydrous magnesium sulfate, filtered and evaporated to give 2 (R) - [3-benzamido-1 (S) - (t- butoxycarbonyl) propyl] -2 ' -isobutyl- 0.914 g of dragid was obtained in the form of off-white foam.

MS: 556 (M + H) &lt; ⁺ & gt ^; .

(ix) To a solution of 2 (R) - [3-benzamido-1 (S) - (t- butoxycarbonyl) propyl] -2 ' - [2- (lH-imidazol- Yl) acetyl] -2 ' -isobutyl-4-methylvalerohydrazide in 5 ml of tetrahydrofuran was treated with 6 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours and then the solvent was evaporated. The residue was dried in vacuo to give 2 (R) - [3-benzamido-1 (S) - (carboxy) propyl] -2 ' - [2- (lH-imidazol- -Isobutyl-4-methylvalerohydrazide in the form of a pale orange oil.

MS: 500 (M + H) &lt; ⁺ & gt ^; .

(x) A solution of 2 (R) - [3-benzamido-1 (S) - (carboxy) propyl] -2 '- [2- (lH-imidazol- -2'-isobutyl-4-methylvalerohydrazide in 10 ml of dichloromethane was cooled to 0 ° C under nitrogen and treated with 0.23 ml of N-ethylmorpholine and 1 ml of 1-ethyl-3- (3- dimethylaminopropyl) Lt; / RTI &gt; hydrochloride. The mixture was allowed to warm to room temperature and then stirred overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. Filtered and evaporated to give a yellow oil which was purified by flash column chromatography on silica gel using methanol / dichloromethane (2:98 increasing to 10:90) for elution. The purified material was triturated with diethyl ether to give 2 (R) - [3-benzamido-1 (S) - (benzyloxycarbamoyl) propyl] -2 '- [2- Yl) acetyl] -2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.

MS: 605 (M + H) &lt; ⁺ & gt ^; .

Example 177

-2 ' - [2- (lH-imidazol-l-yl) acetyl] -2 '-( 2-pyrrolidin- -Isobutyl-4-methylvalerohydrazide &lt; / RTI &gt;

(R) - [3- (Benzenesulfonamido) -1 (S) - (R) - (3- methoxy-benzenesulfonylamino) -ethanone in a similar manner to that described in Example 176, but using benzenesulfonyl chloride instead of benzoyl chloride in step (Hydroxycarbamoyl) propyl] -2 '- [2- (1H-imidazol-1-yl) acetyl] -2'-isobutyl-4-methylvalerohydrazide as a white solid Respectively.

MS: 551 (M + H) &lt; ⁺ & gt ^; .

HPLC: gradient elution using Solvent A containing Solvent B and increasing the content of Solvent B from 5% to 95% over 15 minutes; Flow rate 1 ml / min. Retention time: 10.40 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPBDSC18.

Claims (26)

Claims 1. Compounds of the general formula &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt; Formula I In this formula, R ¹ represents lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl; R ² is an acyl group derived from an alpha, beta, gamma or [delta] - (amino, hydroxy or thiol) carboxylic acid wherein the amino, hydroxy or thiol group is optionally lower alkylated or the amino group is optionally acylated, Sulphonylated or amidated, and all functional groups present in the side chain are optionally protected) or a group of formula Het (CH ₂ ) _m CO; R ³ is selected from the group consisting of hydrogen, lower alkyl, halo-lower alkyl, cyano-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl- , Aryl-lower alkyl, heterocyclyl-lower alkyl, heterocyclylcarbonyl-lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl-lower alkenyl, aryl or heterocyclyl; R ⁴ represents lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, or a group of formula X-aryl, X-heteroaryl or - (CH ₂ ) _n -CH = CR ⁵ R ⁶ ; R ⁵ and R ⁶ together represent lower alkylene in which one CH ₂ group is optionally substituted by a heteroatom; Het represents heterocyclyl; X represents a spacer group; m represents 0, 1, 2, 3 or 4; n represents 1 or 2; The method according to claim 1, R ² is an acyl group derived from? - or? - (amino, hydroxy or thiol) carboxylic acid wherein the amino, hydroxy or thiol group is optionally lower alkylated or the amino group is optionally acylated, amidated or sulfonylated , All functional groups present in the side chain are optionally protected) or a group of the formula Het (CH ₂ ) _m CO wherein m represents 0, 1 or 2. 3. The method according to claim 1 or 2, Wherein R &lt; ¹ &gt; represents lower alkyl, lower cycloalkyl-lower alkyl. The method of claim 3, Lt; ¹ &gt; represents isobutyl, cyclobutylmethyl or cyclopentylmethyl. 5. The method according to any one of claims 1 to 4, R ² represents an acyl group derived from an? -Aminocarboxylic acid or? -Hydroxycarboxylic acid. 5. The method according to any one of claims 1 to 4, R ² represents a group of the formula Het (CH ₂ ) _m CO (wherein m has the meaning given in the paragraph 1 or 2). 7. The method according to any one of claims 1 to 6, R ³ represents lower alkyl, halo-lower alkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, aryl or heterocyclyl. 8. The method of claim 7, Wherein R &lt; ³ &gt; represents lower alkyl. 9. The method of claim 8, And R ³ represents isobutyl. 10. The method according to any one of claims 1 to 9, X is a group of formula - (CH ₂ ) _p -Y- (CH ₂ ) _q -, wherein p and q each independently represent 0, 1, 2, 3, 4 or 5 and Y is absent or -CH = CH-, -C≡C-, -S-, -O- , -NH-, -NHCO-, -CONH-, -SO 2 -, -NHSO 2 -, -SO 2 NH-, -NHCONH- or It represents a compound showing a -NHSO ₂ NH-). 11. The method of claim 10, X is formula _{- (CH 2) p -,} -CH 2 -CH = CH-, -CH 2 -C≡C-, -CH 2 NHCO-, - (CH 2) n NHCONH-, - (CH 2) p A group of -S-, -S-, -CH ₂ NHSO ₂ -, -CH ₂ NHCH ₂ -, - (CH ₂ ) _p -O- or -O- (CH ₂ ) _q - And p and q each represent an integer of 1 to 5). 12. The method according to any one of claims 1 to 11, R &lt; ⁴ &gt; represents a group of the formula X-aryl (wherein X has the meaning given in claim 10). 13. The method of claim 12, R ⁴ represents a group of the formula -CH ₂ -CH = CH-Ph (wherein Ph represents unsubstituted phenyl). (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl- Methyl valero hydrazide, (R) -hydroxypropionyl) -2 ' - (2-hydroxyethyl) -2 '-( 2- Isobutyl-4-methylvalerohydrazide, -2 ' - [2- (1-imidazolyl) acetyl] -2 '-( methanesulfonyl) - isobutyl-4-methylvalerohydrazide, (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Ridinil) carbamoyl] valero hydrazide And pharmaceutically acceptable salts thereof. &Lt; / RTI &gt; Methyl-2 '- [2- (lH-1,2,3-triazole (2-benzyl- -1-yl) acetyl] valerohydrazide or a pharmaceutically acceptable salt thereof. &Lt; / RTI &gt; (II) Wherein R ¹ and R ⁴ have the meanings given in claim 1 and R ⁷ represents a protecting group and R ²⁰ has the same meaning as R ² in claim ¹ with the proviso that in the case of an acyl group amino, Or a thiol group (if not lower alkylated, acylated, sulfonylated or amidated as specified in R ² ) is selectively protected and all functional groups present in the side chain are optionally protected; and R ³⁰ is R ³ , with the proviso that all amino or hydroxy groups present therein are optionally protected. 17. The method of claim 16, R ⁷ represents tetrahydropyranyl, benzyl, 4-methoxybenzyl or tri (lower alkyl) silyl. 15. Use of a therapeutically active substance as claimed in any one of claims 1 to 15 for use as a therapeutically active substance in the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory diseases, tumors, cachexia, cardiovascular diseases, fever, hemorrhage and sepsis &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof. Any one of claims 1 to 15 wherein in a compound and a method of pharmaceutically usable acceptable salt thereof as claimed in any one of the preceding, to protecting groups represented by R ⁷ from a compound of formula II, and in response to a request R ²⁰ and / or R ³⁰ and, if desired, converting the resulting compound of formula I into a pharmaceutically acceptable salt. (II) Wherein R ¹ and R ⁴ have the meanings given in claim 1 and R ⁷ represents a protecting group and R ²⁰ has the same meaning as R ² in claim ¹ with the proviso that in the case of an acyl group amino, Or a thiol group (if not lower alkylated, acylated, sulfonylated or amidated as specified in R ² ) is selectively protected and all functional groups present in the side chain are optionally protected; and R ³⁰ is R ³ , with the proviso that all amino or hydroxy groups present therein are optionally protected. 15. A medicament containing a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier substance. 15. A pharmaceutical composition for the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory diseases, tumors, cachexia, cardiovascular diseases, and the like, which comprises a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier substance. , Fever, bleeding and sepsis. A method for the manufacture of a medicament for the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory diseases, tumors, cachexia, cardiovascular diseases, fever, hemorrhage and sepsis, which comprises administering to a patient in need thereof a compound according to any one of claims 1 to 15 Comprising the step of bringing into association a pharmaceutically acceptable salt thereof with a therapeutically inert carrier material and, if desired, one or more additional therapeutically active substances, into a galenical administration form. The use of a compound according to any one of claims 1 to 15 for the treatment of disease, in particular in the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory diseases, tumors, cachexia, cardiovascular diseases, fever, hemorrhage and sepsis, Uses of acceptable salts. A compound according to any one of claims 1 to 15 for the manufacture of a medicament for the treatment of disease, in particular for the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory diseases, tumors, cachexia, cardiovascular diseases, fever, The use of a pharmaceutically acceptable salt thereof. 19. A compound according to any one of claims 1 to 15 and a pharmaceutically acceptable salt thereof, which is prepared according to the process as claimed in claim 19 or a corresponding process. The invention as hereinbefore described.