WO2017005950A1 - Heterocyclic compounds as trpm8 channel antagonists and uses thereof - Google Patents

Abstract

The invention relates to β-lactam derivative compounds, capable of blocking thermoreceptor activation, in particular TRPM8 channels, and to the uses thereof as therapeutic agents for treating diseases of the respiratory system (coughing, asthma, etc.), of the skin (pruritus, atopic dermatitis, allergic contact dermatitis, psoriasis, etc.), of the eye (dry eye syndrome and excessive tearing), diseases derived from cancer chemotherapy (cold allodynia), as well as cancer (melanoma, prostate, kidney, breast, pancreas, osteosarcoma, etc.), inter alia.

Description

 HETEROCYCLIC COMPOUNDS AS CHANNEL ANTAGONISTS

 TRPM8 AND ITS USES

DESCRIPTION

The present invention relates to heterocyclic compounds, which are β-lactam derivatives, capable of blocking the activation of thermoreceptors, in particular TRPM8 channels. STATE OF THE TECHNIQUE

Thermosensory channels, a subfamily within transient potential receptors (TRP), are activated by changes in temperature, voltage, pressure, acids, endogenous ligands and different products of natural origin. These channels, known as thermoTRPs, cover the entire temperature spectrum, from harmful cold (<15 ° C) to harmful heat (> 42 ° C). In addition, alterations in these channels contribute to the thermal hypersensitivity associated with certain painful episodes, in addition to being involved in the pathophysiology of various diseases, such as inflammation, lung disorders, gastrointestinal hypersensitivity, skin sensitivity, neurodegeneration and cancer.

TRPM8 receptors are Ca ²⁺ permeable channels that were initially identified in prostate tumor cells, but are also present along the male urogenital tract, arteries, and pulmonary epithelial cells. These channels are expressed in primary sensory neurons of the skin and mucous membranes, acting as low temperature sensors (10-33 ° C) and chemicals such as menthol and icilin. Under pathological conditions, there is increasing evidence to confirm abnormal over-expression of TRPM8 channels in sensory neurons after injury or inflammation, as well as their participation in allodynia and cold hyperalgesia TRPM8 is also expressed in corneal afferent neurons involved in the regulation of ocular surface moisture.

Among TRPM8 antagonists, different families have been reported to have benzothiophene, benzimidazole and arylglycine residues as the central skeleton (Calvo et al 2012 Bioorganic & Medicinal Chemistry Letters 22: 1903-1907; Matthews et al 2012 Bioorganic & Medicinal Chemistry Letters 22: 2922-2926; Parks et al 201 1 Journal of Medicinal Chemistry 54: 233-247; Zhu et al 2013 Bioorganic & Medicinal Chemistry Letters 23: 2234-2237.). Some of these compounds have shown excellent "in vitro" and "in vivo" activities in animal models of inflammatory and neuropathic pain. The compound JNJ41876666, derived from benzothiophene, has been used, together with another antagonist, AMTB, and RNAi to determine that inhibition of both the expression and function of the TRPM8 channels reduces the rate of prostate tumor cell proliferation (Valero et al., 2012 PLoS ONE 7 (12): e51825). The commercial antagonist N- (3-aminopropyl) -2 - [(3- methylphenyl) methoxy] -N- (2-thienylmethyl) benzamide AMTB has also served to demonstrate that blocking of TRPM8 channels is a new therapeutic opportunity for treatment of overactive and painful bladder syndromes (Lashinger et al. 2008 American Journal of Physiology-Renal Physiology 295: F803-F810).

DESCRIPTION OF THE INVENTION The present invention provides heterocyclic compounds with very significant activity as blockers of thermoreceptors, in particular TRPM8. The blocking activity of the aforementioned channels, which these compounds present allows them to be used as therapeutic agents for the treatment of diseases of the respiratory system (cough, asthma, etc.), of the skin (pruritus, atopic dermatitis, allergen, psoriasis, etc.) , of the eye (dry eye syndrome and excessive tearing) of chemotherapy cancer (cold allodynia), as well as cancer (melanoma, prostate, kidney, breast, pancreas, osteosarcoma, etc.).

Therefore, a first aspect of the present invention relates to a compound of formula (I) or any of its pharmaceutically acceptable salts or stereoisomer thereof (hereinafter compound of the invention):

(I)

where:

R ¹ is selected from (Ci-C ₄ ) alkyl, substituted or unsubstituted, aralkyl (Ci-C ₄ ), substituted or unsubstituted, heteroaralkyl (Ci-C ₄ ), substituted or unsubstituted, aryl, substituted or not substituted, and heteroaryl, substituted or unsubstituted;

R ² is selected from a group -OR ⁶ and -NR ⁷ R ⁸ ;

R ³ is selected from hydrogen and (Ci-C ₄ ) alkyl, substituted or unsubstituted;

R ⁴ is selected from hydrogen, (Ci-C ₄ ) alkyl, substituted or unsubstituted, aralkyl (Ci-C ₄ ), substituted or unsubstituted, heteroaralkyl (Ci-C ₄ ), substituted or unsubstituted, aryl, substituted or unsubstituted, and -COR ⁹ ;

R ⁵ is selected from -NR ¹¹ R ¹⁰ ;

R ⁸ is selected from hydrogen, alkyl (Ci-Ce) and aralkyl (Ci-C ₄ ), heteroaryl, heteroarylalkyl (Ci-C) and -CH (R ¹³ ) COOR ¹² ;

R ⁶ , R ¹¹ , R ¹³ and R ¹⁴ are independently selected from hydrogen, (Ci-Ce) alkyl, substituted or unsubstituted, aralkyl (Ci-C ₄ ), substituted or unsubstituted, heteroaralkyl (Ci-C ₄ ) , substituted or unsubstituted, and aryl, substituted or unsubstituted;

R ⁷ and R ¹² are selected from hydrogen and alkyl (Ο-ι-Οβ), substituted or unsubstituted; R ⁹ is selected from -OR ⁶ and -NR ⁷ R ⁸ ;

R ¹⁰ is selected from hydrogen, (Ο-ι-Οβ), substituted or unsubstituted aralkyl and (C1-C4), substituted or unsubstituted, COOR ^14; Y

n is 1, 2, 3 or 4.

The term "alkyl" refers, in the present invention, to saturated, linear or branched hydrocarbon chains having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, / -propyl, n-butyl , ferc-butyl, sec-butyl, n-pentyl, n-hexyl, etc. Preferably and particularly for some radicals the alkyl group has between 1 and 4 carbon atoms, for example, without being limited, to methyl, ethyl, n-propyl, / -propyl, n-butyl, ferc-butyl, isobutyl or sec -butyl. The alkyl groups may be optionally substituted by one or more substituents such as alkynyl, alkenyl, halogen, hydroxy, alkoxy, carboxyl, cyano, carbonyl, acyl, alkoxycarbonyl, carbamoyl, amino or nitro.

The term "aryl" refers, in the present invention, to aromatic rings, single or multiple, having between 6 and 18 carbon atoms in the ring part, such as but not limited to, phenyl, naphthyl, diphenyl, indenyl, phenanthryl, fluorenyl or anthracil. Preferably the aryl group has 6 to 12 carbon atoms and more preferably the aryl group is a phenyl. The aryl radicals can be optionally substituted in any of their positions by one or more substituents or two substituents forming a condensed aryl cycle and are independently selected from among them such as alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, halogen, hydroxyl , amino, substituted amino, carboxylic acid, carboxylic ester or carboxamide.

The term "heteroaryl" refers to an aryl, which contains between 5 and 12 carbon atoms and at least one non-carbon atom, such as S, N, or O, forming part of the aromatic ring. For example, without being limited to pyridine, pyrazine, pyrimidine or pyridazine. Heteroaryl radicals may be optionally substituted in any of their positions by one or more substituents or two substituents forming a condensed aryl cycle and are independently selected from among them such as alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, halogen, hydroxyl, amino, substituted amino, carboxylic acid, carboxylic ester or carboxamide.

By "aralkyl" is meant in the present invention an aryl group, as defined above, linked to the rest of the molecule by a d-C ₄ alkyl group, as defined above. A non-limiting example of aralkyl is a benzyl or phenethyl group. The aralkyl radicals may be optionally substituted in any of their positions by one or more substituents or two substituents forming an aryl fused cycle and are independently selected from such as alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, halogen, hydroxyl , amino, substituted amino, carboxylic acid, carboxylic ester or carboxamide

The term "heteroaralkyl" refers, in the present invention, to a heteroaryl group, as defined above, linked to the rest of the molecule by a Ci-C ₄ alkyl group, as defined above. The heteroaralkyl radicals can be optionally substituted in any of their positions by one or more substituents or two substituents forming an aryl fused cycle and are independently selected from such as alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, halogen, hydroxyl , amino, substituted amino, carboxylic acid, carboxylic ester or carboxamide. The stereoisomers of the compounds of the present invention, represented by the formula (I) described above, may include racemic mixture, pure enantiomers, diastereoisomeric mixtures, pure diastereoisomers, depending on the presence of one or more stereogenic elements, or isomers, depending on the presence of multiple links (for example, Z, E). Individual isomers, enantiomers or diastereomers and mixtures thereof are included within the scope of the application of the present invention. In a preferred embodiment, R ¹ is (Ci-C ₄ ) alkyl or aralkyl (Ci-C ₄ ), more preferably R ¹ is (Ci-C2) alkyl, benzyl or phenethyl, even more preferably R ¹ is methyl or benzyl.

In another preferred embodiment, when R ² is -OR ⁶ , R ⁶ is hydrogen, (C _1-4 ) alkyl or benzyl, more preferably hydrogen, methyl, ferc-butyl or benzyl.

In another preferred embodiment, when R ² is -NR ⁷ R ⁸ ; R ⁸ is selected from hydrogen, alkyl (Ci-Ce), aralkyl (Ci-C ₄ ), heteroaryl, heteroaralkyl (Ci-C ₄ ) and -CH (R ¹³ ) COOR ¹² and / or R ⁷ is selected from hydrogen and (Ci-C ₄ ) alkyl, more preferably R ⁷ is hydrogen or methyl and / or R ⁸ is selected from benzyl, heteroaryl, heteroaralkyl (Ci) and -CH (R ¹³ ) COOR ¹² ; R ¹³ is preferably hydrogen, methyl or benzyl and / or R ¹² is preferably hydrogen or methyl.

In another preferred embodiment, R ³ is hydrogen or methyl.

In another preferred embodiment, R ⁴ is aralkyl (Ci-C ₄ ) or -COR ⁹ . More preferably, R is benzyl, -COOR ¹ or -CONR ⁷ R ⁸ .

When R ⁴ is -COOR ¹⁴ , preferably R ¹⁴ is hydrogen, (Ci-C ₄ ) alkyl or benzyl, more preferably hydrogen, methyl, ferc-butyl or benzyl.

When R is -CONR ⁷ R ⁸ ; preferably R ⁷ is selected from hydrogen and (Ci-C ₄ ) alkyl, more preferably hydrogen or methyl and even more preferably hydrogen, and / or R ⁸ is selected from hydrogen, (C-C _e ) alkyl and aralkyl (Ci -C), heteroaryl, heteroaralkyl (Ci-C) and -CH (R ¹³ ) COOR ¹² , more preferably benzyl or -CH (R ¹³ ) COOCH ₃ , where R ¹³ is preferably selected from benzyl, methyl, heteroaralkyl (d) or heteroaryl, and even more preferably between benzyl, methyl, pyridinmethyl or pyridine. In a preferred embodiment, R ⁵ is -NR ¹¹ R ¹⁰ and R ¹¹ are selected from hydrogen, methyl and benzyl; and / or R ¹⁰ is selected from hydrogen, methyl, benzyl and COOR ¹⁴ ; where R ¹⁴ is methyl, tere-butyl or benzyl. In another preferred embodiment the compound of the invention is selected from the list consisting of:

 4R, S-Benzyl-4-methoxycarbonyl-1 - [(3'S-ierc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] -2-oxoazetidine

 4R, S-Benzyl-4-methoxycarbonyl-1 - [(3'S-ierc-butoxycarbonylamino-3'-methyloxycarbonyl) prop-1 '-yl] -2-oxoazetidine

 4R, S-Benzyl-4-benzyloxycarbonyl-1 - [(3'S-ierc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] -2-oxoazetidine

 4S-Benzyl-4-benzyloxycarbonyl-1 - [(3'S-ierc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] -2-oxoazetidine

4R-Benzyl-4-benzyloxycarbonyl-1 - [(3'S-ierc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] -2-oxoazetidine

 4R, S-Benzyl-4-benzyloxycarbonyl-1 - [(3'S-ierc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] - (3R, SJ-methyl-2-oxoazetidine

4R, S-Methyl-4-methoxycarbonyl-1 - [(3'S-ierc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1 '-yl] -2-oxoazetidine

 4R, S-Benzyl-4-methoxycarbonyl-1 - [(3'S-benzyloxycarbonylamino-3'-ierc- butoxycarbonyl) prop-1 '-yl] -2-oxoazetidine

 4R, S-Methyl-4-methoxycarbonyl-1 - [(3'S-benzyloxycarbonylamino-3'-ierc- butoxycarbonyl) prop-1 '-yl] -2-oxoazetidine

4R _; S-Benzyl-1 - [4'S - (/ V-Benzyloxycarbonyl- / V-methyl) amino-4'-methoxycarbonyl] but-1-yl] -4-ferc-butoxycarbonyl-2-oxoazetidine

 4R, S-Benzyl-1 - [4'S - [(/ V-methyl) amino-4'-methoxycarbonyl] but-1 '-yl] -4-ierc- butoxycarbonyl-2-oxoazetidine

 4R, S-Benzyl-4-benzyloxycarbonyl-1 - [(4'S-ierc-butoxycarbonylamino-4'-benzyloxycarbonyl) but-1'-yl] -2-oxoazetidine

4R, S-Benzyl-N - [(4'S-benzyloxycarbonylamino-4'-methoxycarbonyl) but-1 '-yl] -4-ierc- butoxycarbonyl-2-oxoazetidine 4'S-N - [(4'-Benzyloxycarbonylamino-4'-methoxycarbonyl) but-1'-yl] -4R _; S-ierc- butyloxycarbonyl-4-methyl-2-oxoazetidine

_4R; S-Benzyl-4-benzyloxycarbonyl-1 - [(2'S-benzyloxycarbonylamino-3'-phenyl) prop-1 '- yl] -2-oxoazetidine

_4R; S-Benzyl-4-benzyloxycarbonyl-1 - [(2'R-benzyloxycarbonylamino-3'-phenyl) prop-1 '- yl] -2-oxoazetidine

 4S-Benzyl-4-benzyloxycarbonyl-3S-methyl-1 - [(2'S-benzyloxycarbonylamino-3'-phenyl) prop-1'-yl] -2-oxoazetidine

 4R-Benzyl-4-benzyloxycarbonyl-3R-methyl-1 - [(2'S-benzyloxycarbonylamino-3'- phenyl] prop-1'-yl] -2-oxoazetidine

 4R-Benzyl-4-benzyloxycarbonyl-3R-methyl-1 - [(2'R-benzyloxycarbonylamino-3'-phenyl) prop-1'-yl] -2-oxoazetidine

 4S-4-Benzyl-4-benzyloxycarbonyl-3S-methyl-1 - [(2'R-benzyloxycarbonylamino-3'-phenyl) prop-1'-yl] -2-oxoazetidine

4S-Benzyloxycarbonyl-3S, 4S-dimethyl-1 - [(2'R-benzyloxycarbonylamino-3'-phenyl) prop- 1'-yl] -2-oxoazetidine

4R _; S-Benzyl-4-benzyloxycarbonyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop-1 '-yl] -2- oxoazetidine

 4S-Benzyl -] - (4-benzyloxycarbonyl-3S-methyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop-1 '- yl] -2-oxoazetidine

 4R-Benzyl-4-benzyloxycarbonyl-3R-methyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop-1'-yl] - 2-oxoazetidine

4R _; S-Benzyl-4-methoxycarbonyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop-1 '-yl] -2- oxoazetidine

4R, S-Benzyl-4-ierc-butoxycarbonyl-1 - [(2'S-dibenzylamino-3-phenyl) prop-1 '-yl] -2- oxoazetidine

 4S-Benzyl-3S-methyl-4-methoxycarbonyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop-1 '-yl] -2- oxoazetidine

 4S-Benzyl-4-ierc-butoxycarbonyl-3S-methyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop-1 '- yl] -2-oxoazetidine

4S-Benzyl-4-ierc-butoxycarbonyl-3S-methyl-1 - [(2'S-benzylamino-3'-phenyl) prop-1 '-yl] - 2-oxoazetidine 4S-Benzyl-4-ierc-butoxycarbonyl-3S-methyl-1 - [(2'S-amino-3'-phenyl) prop-1 -yl] -2- oxoazetidine

 4S-Benzyl-4-ierc-butoxycarbonyl-3S-methyl-1 - [2'S-benzyloxycarbonylamino-3'-phenyl) prop-1'-yl] -2-oxoazetidine

4S-Benzyl-4-ierc-butoxycarbonyl-3S-methyl-1 - [(2'S-ierc-butoxycarbonylamino-3- phenyl) prop-1 '-yl] -4-oxoazetidine

 4R, S-Benzyl-4-carboxy-1 - [3'S-tert-butoxycarbonylamino-3'-carboxy) prop-1 '-yl] -2- oxoazetidine

 4R, S-Benzyl-1 - [4'S-tert-butoxycarbonylamino-4'-carboxy) but-1 '-yl] -4-carboxy-2-oxoazetidine

 4S-Benzyl-4 - [(N-benzyl) carbamoyl] -1 - [(3'S-ierc-butoxycarbonylamino-3 '- [(N-benzyl) carbamoyl] prop-1' -yl] -2-oxoazetidine

4R _; S-Benzyl-1 - [4'S-tert-butoxycarbonylamino-4 '- [(N-benzyl) carbamoyl] but-1' -yl] -4- [(N-benzyl) carbamoyl] -2-oxoazetidine

4S-4-Benzyl-4 - [(N-benzyl) carbamoyl] -3S-methyl-1 - [3'S-ierc-butoxycarbonylamino-3'- [(N-benzyl) carbamoyl] prop-1 '-yl] -2 -oxoazetidine

 4R-4-Benzyl-4 - [(N-benzyl) carbamoyl] -3R-methyl-1 - [3'S-ierc-butoxycarbonylamino-3'- [(N-benzyl) carbamoyl] prop-1 '-yl] -2 -oxoazetidine

 4S-Benzyl-4- [N - [(pindin-4 '' - yl) methyl] carbamoyl-1 - [(3'S-ierc-butoxycarbonylamino-3'- [N - [(pindin-4 "-yl) methyl] carbamoyl] prop-1 '-yl] -2-oxoazetidine

 4R-Benzyl-4- [N - [(pindin-4 '' - il) methyl] carbamoyl] -1 - [3'S-ierc-butoxycarbonylamino-3'-

[N - [(pindin-4 "-yl) methyl] carbamoyl] prop-1 '-yl] -2-oxoazetidine

 4R, S-Benzyl-4 - [(N-pindin-3-yl) carbamoyl] -1 - [(3'S-ierc-butoxycarbonylamino-3 '- [(N- pyridin-3-yl) carbamoyl] prop-1' -il] -2-oxoazetidine

4S-Benzyl-4 - [(N-pindin-4-yl) carbamoyl] -1 - [3'S-tert-butoxycarbonylamino-3 '- [(N-pyridin-4-yl) carbamoyl] prop-1' -yl] -2-oxoazetidine

 4R-Benzyl-4 - [(N- (pindin-4-yl) carbamoyl] -1 - [3'S-tert-butoxycarbonylamino-3 '- [(N- pyridin-4-yl) carbamoyl] prop-1' -yl ] -2-oxoazetidine

4S-Benzyl-1 - [3'S-ferc-butoxycarbonylamino-3 '- [/ V - [(1 "S-methoxycarbonyl) ethyl] carbamoyl] prop-1'-yl] -4 - [/ V - [(1'"S- methoxycarbonyl) ethyl] carbamoyl] -2-oxoazetidine 4R-Benzyl-1 - [3'S-ferc-butoxycarbonylamino-3 '- [/ \ / - [(1 "S-methoxycarbonyl) ethyl] carbamoyl] prop-1'-yl] -4 - [/ V - [(1 '"S- methoxycarbonyl) ethyl] carbamoyl] -2-oxoazetidine

 4R-Benzyl-1 - [3'S-ierc-butoxycarbonylamino-3 '- [/ V - [(1' 'S-methoxycarbonyl-2'-phenyl) ethyl] carbamoyl] prop-1' -yl] -4 - [/ V - [(1 '"S-methoxycarbonyl-2'phenyl) ethyl] carbamoyl] -2- oxoazetidine

 4S-Benzyl-1 - [3'S-ierc-butoxycarbonylamino-3 '- [/ V - [(1' 'S-methoxycarbonyl-2'-phenyl) ethyl] carbamoyl] prop-1' -yl] -4 - [/ V - [(1 '' 'S-methoxycarbonyl-2 enyl) ethyl] carbamoyl] -2- oxoazetidine

4R-Benzyl-1 - [4'S - [(/ V-benzyloxycarbonyl- / V-m

 4- [N - [(1 "S-methoxycarbonyl) ethyl] carbamoyl] -2-oxoazetidine

4R, S-Benzyl-1 - [(4'S-methylamino-4'-methoxycarbonyl) but-1 '-yl] -4- [N - [(1 "S-methoxycarbonyl) ethyl] carbamoyl] -2-oxoazetidine

 4R-Benzyl-1 - [(4'S-benzyloxycarbonylamino-4'-methoxycarbonyl) but-1'-yl] -4- [N - [(1 "S-methoxycarbonyl) ethyl] carbamoyl] -2-oxoazetidine, and

4R _; S-Benzyl-1 - [(4'S-benzyloxycarbonylamino-4'-methoxycarbonyl) but-1'-yl] -4- [N- [(1 "R-methoxycarbonyl) ethyl] carbamoyl] -2-oxoazetidine.

Another aspect of the present invention relates to the process for obtaining the compound of formula (III), that is to say the compound of formula (I) when R ² is -OR ⁶ , which comprises the delation in basic medium of the compound of formula ( II):

 (II) (III)

Another aspect of the present invention relates to the process for obtaining the compound of formula (IV), that is to say the compound of formula (I) when R ² is -NR ⁷ R ⁸ , which comprises the reaction of amines R ⁸ R ⁷ NH with a carboxylic acid derivative of the compound of formula (III), ie the compound of formula (I) when R ² is -OH, in the presence of a coupling agent:

 (IV)

 The coupling agent that can be used is any known to one skilled in the art from among those typically used in the synthesis of peptides such as carbodiimides, phosphonium salts or uronium salts.

The present invention further provides pharmaceutical compositions comprising at least one compound of formula (I), acceptable pharmaceutical salts or stereoisomers thereof, together with an acceptable pharmaceutical carrier, adjuvant or vehicle for administration to a patient. Preferably, said composition also comprises another active ingredient with synergistic or complementary effect.

Therefore, another aspect of the present invention relates to a pharmaceutical composition comprising at least one compound of general formula (I), in addition to at least one pharmaceutically acceptable carrier.

Pharmaceutical forms suitable for oral administration include any solid composition (tablets, pills, capsules, granulated forms, etc.) or liquid (solutions, suspensions, emulsions, syrups, etc.) and may contain conventional excipients known in the art, such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, starch, corn, calcium phosphate, sorbitol or glycine, lubricants for the preparation of tablets, for example magnesium stearate, disintegrants such as starch, polyvinyl pyrrolidone, sodium starch glycolate or microcrystalline cellulose, or pharmaceutically acceptable wetting agents, such as sodium lauryl sulfate.

Solid oral compositions may be prepared by conventional methods of mixing, filling or tabletting. Repeated mixing operations can be used to evenly distribute the active ingredient using large amounts of fillers. These operations are conventional in the art of this invention. The tablets may be prepared, for example, through wet or dry granulation and may optionally be coated by methods well known in normal pharmaceutical practice, particularly with an enteric coating.

The pharmaceutical compositions can also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the appropriate pharmaceutical form. Suitable excipients, such as bulk agents, neutralizers or surfactants may be mentioned.

The compounds or compositions described in the present invention can be administered by any suitable method, such as intravenous infusion, oral preparations and intraperitoneal or intravenous administration. However, the preferred route of administration will depend on the condition of the patient.

The therapeutically effective amount of the compound of formula (I) to be administered in general will depend, among other factors, on the person to be treated, on the severity of the disease, on the chosen form of administration, etc. For this reason, the doses mentioned in this invention should be considered as guidelines for the specialist in the field, and the latter You should adjust the dose according to the variables mentioned above. However, a compound of formula (I) can be administered one or more times a day, for example, 1, 2, 3 or 4 times a day in a typical total daily amount between 1 and 200 mg / kg body weight / day, preferably 1 -10 mg / kg body mass / day.

The compounds described in this invention, their pharmaceutically acceptable salts and / or stereoisomers, as well as the pharmaceutical compositions containing them can be used together with other additional drugs to provide a combination therapy. Such additional drugs may be part of the same pharmaceutical composition or, alternatively, be provided in a form of a separate composition for simultaneous or not administration, with the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable stereoisomer or Get out of it.

Another aspect of the invention relates to the use of the compound of formula (I) for the preparation of a medicament. Another aspect of the present invention relates to the use of the compound of formula (I) for the preparation of a medicament for the treatment and / or prevention of a disease associated with alterations of the thermosensory channels, preferably of the TRPM8 channels, preferably said diseases are selected from inflammation; pulmonary disorders for example problems of the respiratory system selected between cough and asthma; eye diseases such as dry eye syndrome or excessive tearing; gastrointestinal hypersensitivity such as irritable bowel syndrome; skin sensitivity such as pruritus, atopic dermatitis, allergen or psoriasis; neurodegeneration and cancer such as melanoma, leukemia, prostate, kidney, breast, pancreas, ovary, lung, colon, central nervous system, particularly the brain, or osteosarcoma. Throughout the present description, the term "treatment" refers to eliminating, reducing or decreasing the cause or effects of the disease. For the purposes of this invention, treatment includes, but is not limited to, alleviating, reducing or eliminating one or more symptoms of the disease; reduce the degree of disease, stabilize (that is, not worsen) the state of the disease, delay or slow the progression of the disease, alleviate or improve the state of the disease and remit the disease (either totally or partially). Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and figures are provided by way of illustration, and are not intended to be limiting of the present invention.

DESCRIPTION OF THE FIGURES FIG. 1 Response dose curves, representative of the blocking effect of some compounds, of examples 3, 6 and 17 (FIGs. 1A, 1 B and 1 C, respectively). The percentage of activity of the TRPM8 channel is represented in the presence of increasing concentrations of the compounds tested. The activity is normalized against the activity of the channel in the absence of compound. Solid lines show the adjustment to the Hill equation from where IC50 values are obtained. The results represent the mean ± SD for n> 6 measurements.

EXAMPLES

SYNTHESIS OF THE COMPOUNDS OF THE INVENTION The compounds of the present invention, derived from β-lactams, have been prepared following the general scheme of synthesis 1.

5 Scheme 1. General procedure for the preparation of β-lactam derivatives from amino acids.

Nosil amino acid derivatives (2) are coupled with alcohols (3), by Mitsunobu reaction, to give rise to N-nosyl-N-alkyl derivatives0 (4). The elimination of the nosyl group gives rise to the amino derivatives (5), which are reacted with chloroalkanoyl chlorides to give rise to the intermediates (6). The delation in basic medium of the intermediates (6) gives rise to the corresponding β-lactam compounds (EXAMPLES 1-32), which are subsequently transformed into the amide analogs (EXAMPLES 35-51) by coupling the amines R ⁸ NH ₂ to the precursor carboxylates (among others, EXAMPLES 33-34).

SYNTHESIS OF STARTING PRODUCTS AND REACTION INTERMEDIATES 0 Synthesis of Nosil amino acid derivatives (Ns-L-Xaa-OR ⁶ ) (2) To a solution of HL-Xaa-OR ^b HCI (17.15 mmol) in dry CH ₂ CI ₂ (1 15 mL) is added triethylamine (TEA) (17.15 mmol, 2.4 mL) and allowed to stir for 20 min. After this time, at 0 ^o C, TEA (22.25 mmol, 3.1 mL) and 2-nitrobenzenesulfonyl chloride (22.25 mmol, 4.9 g) are added, stirring at room temperature overnight. . The next day the solvent is evaporated to dryness and the reaction crude is extracted with AcOEt and washed with citric acid (10%), NaHC0 ₃ (10%) and saturated NaCl solution, successively. Finally, the organic residue is dried over anhydrous Na ₂ S0 ₄ , filtered and evaporated to dryness. The reaction crude is purified on a silica gel column using the eluent system indicated in each case.

 Ns-L-Phe-OMe (2a) (Albanese, D .; Lardini, D .; Lupi, V .; Pensó, M. Eur. J. Org. Chem. 2000, 1443-1449)

 Ns-L-Phe-O'Bu (2b) (Turner, JJ; Wilschut, N .; Overkleft, HS; Klaffke, W .; Van der Marel, GA; Van Boom, JH Tetrahedron Lett. 1999, 40, 7039- 7042) -L-Phe-OBn (2c)

Simpe Rdto: 89%. Eluent: AcOEt: Hexane (3: 1). HPLC: t _R = 15.33 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (300 MHz, CDCI ₃ ): δ 8.00-6.91 (m, 14H, Ar), 6.07 (d, 1 H, J = 9.0 Hz, NH), 4.92 (d, 1 H, J = 12.1 Hz, OCH ₂ ), 4.87 (d, 1 H, J = 12.1 Hz, OCH ₂ ), 4.52 (m, 1 H, a-Phe), 3.13 (m, 2H, β-Phe). ¹³ C NMR (CDCIs): δ 171.5 (COO), 147.2, 136.6, 136.1, 135.1, 134.4, 132.8, 128.9, 128.6, 128.2, 127.7, 127.6, 127.1, 125.9, 124.2 (Ar), 66.4 (OCH ₂ ), 58.7 (Ca), 35.9 (Οβ). MS (ES) ⁺ : 441.21 [M + H] ⁺ .

Simpe. Rdto: 62%. Eluyente: AcOEtHexano (2:1 ). HPLC: t_R=13.04 min (gradiente de 5% a 100% de A, en 20 min). ¹H RMN (400 MHz, CDCI₃): δ 8.00 (dd, 1 H, J=7.7, 1 .6 Hz, Ar), 7.81 (dd, 1 H, J=7.7, 1 .6 Hz, Ar), 7.34-7.31 (m, 3H, Ar), 7.20-7.17 (m, 2H, Ar), 6.18 (d, 1 H, J=8.6 Hz, NH), 4.96 (d, 1 H, J=12.2 Hz, OCH₂), 4.91 (d, 1 H, J=12.1 Hz, OCH₂), 4.31 (m, 1 H, a-H), 1 .50 (d, 3H, J=7.2 Hz, CH₃). ¹³C RMN (75 MHz, CDCI₃): 171.4 (COO), 147.6, 134.8, 134.1 , 133.7, 132.9, 130.4, 128.7, 128.6, 128.3, 125.7 (C, Ar), 67.4 (OCH₂), 52.6 (Ca), 19.8(CH₃). MS (ES)⁺: 365.09 [M+H]⁺. Ns-L-Ala-OMe (2d) (Biron, E .; Kessler, HJ Org. Chem. 2005, 70, 5183-5189) Ns-L-Ala-OBn (2e)

Simpe Rdto: 62%. Eluent: AcOEtHexano (2: 1). HPLC: t _R = 13.04 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 8.00 (dd, 1 H, J = 7.7, 1 .6 Hz, Ar), 7.81 (dd, 1 H, J = 7.7, 1 .6 Hz, Ar), 7.34-7.31 (m, 3H, Ar), 7.20-7.17 (m, 2H, Ar), 6.18 (d, 1 H, J = 8.6 Hz, NH), 4.96 (d, 1 H, J = 12.2 Hz, OCH ₂ ), 4.91 (d, 1 H, J = 12.1 Hz, OCH ₂ ), 4.31 (m, 1 H, aH), 1.50 (d, 3H, J = 7.2 Hz, CH ₃ ). ¹³ C NMR (75 MHz, CDCI ₃ ): 171.4 (COO), 147.6, 134.8, 134.1, 133.7, 132.9, 130.4, 128.7, 128.6, 128.3, 125.7 (C, Ar), 67.4 (OCH ₂ ), 52.6 (Ca ), 19.8 (CH ₃ ). MS (ES) ⁺ : 365.09 [M + H] ⁺ .

 Ns-L-Ala-O'Bu (2f) (Chapman R. N; Dimartino, G .; Arora, P. S. J. Am. Chem. Soc. 2004, 126, 12252-12253)

Reduction of amino acid derivatives to the corresponding alcohols (3)

To a solution of the corresponding amino acid derivative (12.38 mmol) in dry THF (12 mL) is added successively, at -15 ° C, / V-methylmorpholine (12.38 mmol, 1.36 mL) and the chloroformate of isobutyl (12.38 mmol, 1.60 mL). After 10 min the precipitate of / V-methylmorpholinium hydrochloride formed is removed by filtration, preceding its washing with THF (2x60 mL). The solution thus obtained is cooled to -15 ° C and then a solution of NaBH ₄ (18.57 mmol, 0.7 g) in H ₂ 0 (6 mL) is added.

After the detachment of H ₂ , H ₂ 0 (300 mL) and AcOEt (600 mL) are added, preceding the separation of the two phases. The organic phase is washed successively with citric acid (10%), NaHC0 ₃ (10%) and saturated NaCl, successively dissolved. Finally, the organic residue is dried over anhydrous Na ₂ S0 ₄ , filtered and evaporated to dryness. The reaction crude is purified on a silica gel column using the eluent system indicated in each case.

Boc-L-Hse-OBn (3a) (commercial)

Z-L-Hse-O'Bu (3b) (commercial)

(2S) -2- (N-Methyl benzyloxycarbonyl-N-methyl) amino-5-hydroxypentanoate (3c)

Simpe Rdto: 58%. Eluent: AcOE Hexane (1: 1). Rattan ratio M, m = 2: 1. ¹ H NMR (300 MHz, CDCI _3, majority rotamer): δ 7.40 (s, 5H, Ph), 5.20 (s, 2H, OCH ₂ ), 4.90 (dd, 1 H, J = 10.5, 4.9 Hz, 2- H), 4.41 (m, 2H, 5-H), 3.75 (s, 3H, OMe), 2.92 (s, 3H, NMe), 2.08 (m, 2H, 3-H), 1.85 (m, 1 H, 4-H), 1.62 (m, 1 H, 4-H). MS (ES) ⁺ : 318.14 [M + Na] ⁺ .

 (2S) -2-ferc-Butoxycarbonylamino-5-benzyl hydroxypentanoate (3d)

(Jiang, S .; Li, P .; Lai, C.C .; Kelley, J.A .; Roller, P.P. J. Org. Chem. 2006, 71, 7307-7314.)

(2S) -2- Methyl benzyloxycarbonylamino-5-hydroxypentanoate (3e)

(Feichtinger, K .; Sings, H. L .; Baker, T.J.; Mathews, K .; Goodman, M. J. Org. Chem. 1998, 63, 8432-8439)

Z-S-phenylalaninol (3f) (commercial)

Z-? -Phenylalaninol (3g) (commercial)

(2S) -dibenzylaminophenylalaninol (3h) (commercial)

Synthesis of / V-alkyl-M-nosN amino acid derivatives

To a solution of the corresponding derivative alcohol (7.60 mmol), Ns-L-Xaa-OR ⁶ (7.60 mmol) and triphenylphosphine (7.60 mmol, 2g) in dry THF (66 mL), under Ar atmosphere and at 0 ° C, diisopropyl azodicarboxylate (7.60 mmol, 1.50 mL) is added. The ice bath is removed and left under stirring at room temperature overnight. The next day the solvent is evaporated to dryness and the reaction crude is purified on a silica gel column using the eluent system indicated in each case.

yV - [(3S-íerc-Butoxycarbonylamino-3-benzyloxycarbonyl) prop-1 -yl] -Ns-L-Phe-OMe (4a)

Simpe Rdto: 50% [from Ns-L-Phe-OMe (2a) and Boc-L-Hse-OBn (3a)]. Eluent: AcOEtHexano (1: 2). HPLC: t _R = 16.80 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (300 MHz, CDCI ₃ ): δ 7.76- 7.18 (m, 14H, Ar), 5.20 (d, 1H, J = 12.2 Hz, OCH ₂ ), 5.16 (d, 1H, J = 12.2 Hz, OCH ₂ ), 5.15 (brs, 1H, NH Boc), 4.93 (t, 1H, J = 7.7 Ηζ, α-Phe), 4.26 (m, 1H.3-H), 3.54 (m, 1H, 1-H) , 3.53 (s, 3H, OMe), 3.40 (m, 1H, 1-H), 3.33 (dd, 1H, J = 14.5, 7.1 Hz, β-Phe), 2.92 (dd, 1H, J = 14.5, 8.4 Hz, β-Phe), 2.17 (m, 1H, 2-H), 1.99 (m, 1H, 2-H), 1.45 (s, 9H, CH ₃ ¾u). ¹³ C NMR (75 MHz, CDCI ₃ ): 171.8 (COO), 170.9 (COO), 155.6 (CON), 148.3, 136.0, 135.3, 133.7, 132.9, 131.7, 131.0, 129.1, 128.9, 128.8, 128.7, 128.6, 127.2, 124.2 (C, Ar), 80.3 (C, 'Bu), 67.6 (OCH ₂ ), 61.5 (Ca-Phe), 52.5 (OMe), 52.00 (C3), 43.0 (C1), 36.6 (β-Phe ), 33.3 (C2), 28.5 (CH ₃ ¾u). MS (ES) ⁺ : 656.38 [M + H] ⁺ . / V - [(3S-íerc-Butoxycarbonylamino-3-benzyloxycarbonyl) prop-1 -yl] -Ns-L-Phe-

Simpe Rdto: 38% [from Ns-L-Phe-OMe (2c) and Boc-L-Hse-OBn (3a)]. Eluent: AcOEtHexano (1: 3). HPLC: t _R = 18.23 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.72-7.12 (m, 19H, Ar), 5.17 (s, 2H, OCH ₂ ), 5.12 (d, 1H, J = 7.7 Hz, NH, Boc), 4.98 (d, 1H, J = 13.8 Hz, OCH ₂ ), 4.91 (d, 1H, J = 13.8 Hz, OCH ₂ ), 4.90 (m, 1H, a-Phe), 4.25 (m, 1H, 3-H) , 3.55 (m, 1H, 1-H), 3.37 (m, 2H, β-Phe, 1-H), 2.94 (dd, 1H, J = 14.8, 8.0 Hz, β-Phe), 2.16 (m, 1H , 2-H), 1.96 (m, 1H, 2-H), 1.45 (s, 9H, CH ₃ ¾u). ¹³ C NMR (75 MHz, CDCI ₃ ): 171.7 (COO), 170.1 (COO), 155.5 (CON), 148.1, 135.9, 135.3, 134.9, 133.6, 132.7, 131 .5, 130.8, 129.2, 128.9, 128.85, 128.8, 128.7, 128.6, 128.5, 128.5, 127.1, 124.1 (C, Ar), 80.2 (C, ¾u), 67.52 (OCH ₂ ), 67.5 (OCH ₂ ), 61.5 (Ca-Phe), 52.00 (C3), 43.0 (C1), 36.8 (Οβ-Phe), 33.2 (C2), 28.4 (CH ₃ ¾u). MS (ES) ⁺ : 732.33 [M + H] ⁺ .

/ V - [(3S-ierc-Butoxycarbonylamino-3-benzyloxycarbonyl) prop-1 -yl] -Ns-L-Ala-Me (4c)

Sirupe Rdto: 6% [from Ns-L-Ala-OMe (2d) and Boc-L-Hse-OBn (3a)]. Eluent: AcOEtHexano (1: 2). HPLC: t _R = 17.03 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.96 (d, 1 H, J = 7.8 Hz, Ns), 7.86-7.56 (m, 3H, Ns), 7.36 (s, 5H, Ph), 5.21 (d , 1 H, J = 12.3 Hz, OCH ₂ ), 5.18 (sa, 1 H, NHBoc), 5.16 (d, 1 H, J = 12.3 Hz, OCH ₂ ), 4.76 (m, 1 H, a-Ala) , 4.27 (m, 1 H, 3-H), 3.57 (s, 3H, OMe), 3.51 (m, 1 H, 1-H), 3.22 (m, 1 H, 1-H), 2.23 (m, 1 H, 2-H), 2.09 (m, 1 H, 2-H), 1.47 (d, 3H, J = 7.4 Hz, CH _3, Ala), 1.43 (s, 9H, CH ₃ ¾u ). ¹³ C NMR (100 MHz, CDCI ₃ ): 171.8 (COO), 165.2 (COO), 155.5 (CON), 148.1, 135.3, 133.7, 131 .7, 131 .1, 128.8, 128.7, 128.6, 128.5, 124.2 ( Ar), 80.3 (C 'Bu), 67.6 (OCH ₂ ), 56.2 (Ca-Ala), 52.5 (OMe), 51.9 (C3), 42.7 (C1), 33.7 (C2), 28.4 (CH ₃ ¾u), 16.8 (CH ₃ Ala). MS (ES) ⁺ : 602.41 [M + Na] ⁺ .

W - [(3S-Benzyloxycarbonylamino-3-íerc-butoxycarbonyl) prop-1 -yl] -Ns-L-Phe-

Simpe Rdto: 52% [from Ns-L-Phe-OMe (2a) and ZL-Hse-O'Bu (3b)]. Eluent: AcOEtHexano (1: 2). HPLC: t _R = 16.97 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.77 (d, 1 H, J = 7.8 Hz, Ar), 7.66- 7.49 (m, 3H, Ar), 7.39-7.21 (m, 10H, Ph, Z), 5.43 (d, 1 H, J = 7.7 Hz, NH, Z), 5.17 (d, 1H, J = 12.3 Hz, OCH ₂ ), 5.10 (d, 1H, J = 12.3 Hz, OCH ₂ ), 4.93 (t, 1H, J = 7.7 Hz, a-Phe), 4.18 (m, 1H, 3-H), 3.54 ( s, 3H, OMe), 3.51 (dd, 1H, J = 11.8, 3.8 Hz, 1-H), 3.42 (dd, 1H, J = 11.8, 5.4 Hz, 1-H), 3.36 (m, 1H, β -Phe), 2.95 (dd, 1H, J = 14.4, 8.4, Hz, β-Phe), 2.15 (m, 1H, 2-H), 1.98 (m, 1H, 2-H), 1.47 (s, 9H , CH ₃ ¾u). ¹³ C NMR (75 MHz, CDCI ₃ ): 170.8 (COO), 170.6 (COO), 156.0 (CON), 148.2, 135.9, 133.7, 131.9, 130.9, 129.1, 128.7, 128.6, 128.2, 128.1, 127.1, 124.1 ( C, Ar), 82.8 (C, ¾u), 67.0 (OCH ₂ ), 61.3 (Ca-Phe), 52.8 (C3), 52.5 (OMe), 42.9 (C1), 36.5 (Cp-Phe), 33.4 (C2 ), 28.0 (CH ₃ ¾u). MS (ES) ⁺ : 678.51 [M + Na] ⁺ .

 / V - [(3S-Benzyloxycarbonylamino-3-ierc-butoxycarbonyl) prop-1-yl] -Ns-L-Ala-Me (4e)

Sirupe Rdto: 58% [from Ns-L-Ala-OMe (2d) and ZL-Hse-O'Bu (3b)]. Eluent: AcOEtHexano (1: 2). HPLC: t _R = 15.49 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 8.00 (dd, 1 H, J = 7.9, 1.4 Hz, Ar-Ns), 7.67 (dd, 1H, J = 7.6, 1.4 Hz, Ar-Ns), 7.63 -7.58 (m, 2H, Ar-Ns), 7.37-7.31 (m, 5H, Ph, Z), 5.40 (d, 1H, J = 7.1 Hz, NH, Z), 5.15 (d, 1H, J = 12.0 Hz, OCH ₂ ), 5.09 (d, 1H, J = 12.0 Hz, OCH ₂ ), 4.76 (q, 1H, J = 7.4 Hz, a-Ala), 4.19 (m, 1H, 3-H), 3.58 ( s, 3H, OMe), 3.48 (m, 1H, 1-H), 3.23 (m, 1H, 1-H), 2.14 (m, 2H, 2-H), 1.47 (m, 12H, CH ₃ * Bu , CH ₃ Ala). ¹³ C NMR (75 MHz, CDCI ₃ ): 171.7 (COO), 170.6 (COO), 156.0 (CON), 148.0, 136.4, 133.7, 131.7, 131.0, 128.6, 128.3, 128.1, 124.2 (C, Ar), 82.8 (C, ¾u), 67.0 (OCH ₂ ), 56.1 (Ca-Ala), 52.8 (C3), 52.5 (OMe), 42.7 (C1), 33.8 (C2), 28.0 (CH ₃ ¾u), 16.8 (CH ₃ To). MS (ES) ⁺ : 602.48 [M + Na] ⁺ .

A / - [4S - [(A / -Benzyloxycarbonyl-N-methyl) amino-4-methoxycarbonyl] but-1-yl] -Ns-L- Phe-O'Bu (4f)

Simpe Rdto: 91% [from Ns-L-Phe-O'Bu (2b) and (3c)]. Eluent: AcOEtHexano (1: 1). HPLC: t _R = 17.61 min (gradient from 5% to 100% of A, in 20 min). Rattan ratio M, m = 2: 1. ¹ H NMR (400 MHz, CDCI _{3, major} rotamer): δ 7.87 (dd, 1H, J = 7.8, 1.2 Ar-Ns), 7.60 (m, 1H, Ar-Ns), 7.53 (m, 2H, Ar- Ns), 7.26 (m, 10H, Ph, Z), 5.16 (d, 1H, J = 12.5 Hz, OCH ₂ ), 5.12 (d, 1H, J = 12.5 Hz, OCH ₂ ), 4.79 (t, 1H, J = 7.8 Hz, a-Phe), 4.74 (dd, 1H, J = 10.5, 4.8, 4- H), 3.69 (s, 3H, OMe), 3.55 (m, 1H, 1-H), 3.31 (dd , 1H, J = 14.3, 7.9 Hz, β-Phe), 3.24 (m, 1H, 1-H), 2.97 (dd, 1H, J = 14.3, 7.9 Hz, β-Phe), 2.83 (s, 3H, NMe), 1.92 (m, 1H, 3-H), 1.71 (m, 3H, β-Η, 2-H), 1.21 (s, 9H, CH ₃ 'Bu). ¹³ C NMR (75 MHz, CDCIs): 171.8 (COO), 169.2 (COO), 157.0 (CON), 148.3, 136.7, 133.5, 131.7, 129.2, 128.7, 128.6, 127.9, 126.9, 123.9 (C, Ar), 82.4 (C, 'Bu), 67.6 (OCH ₂ ), 61.8 (Οβ-Phe), 57.9 (C4), 52.3 (OMe), 45.8 (C1), 36.9 (Οβ-Phe), 30.6 (NMe), 27.7 ( CH ₃ 'Bu), 27.1 (C3), 26.1 (C2). MS (ES) ⁺ : 706.68 [M + Na] ⁺ .

/ V - [(4S-íerc-Butoxycarbonylamino-4-benzyloxycarbonyl) but-1 -yl] -Ns-L-Phe-

Sirupe Rdto: 62% [from Ns-L-Phe-OBn (2c) and 3d]. Eluent: AcOEt: Hexane (1: 2). t _R = 18.60 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (300 MHz, CDCI3): δ 7.87-6.84 (m, 19H, Ar), 5.11 (d, 1H, J = 12.0 Hz, OCH ₂ ), 5.06 (d, 1H, J = 12.0 Hz, OCH ₂ ), 4.93 (m, 1H, NH), 4.90 (d, 1H, J = 12.1 Hz, OCH ₂ ), 4.85 (d, 1H, J = 12.2 Hz, OCH ₂ ), 4.81 (m, 1H, a-Phe ), 4.21 (m, 1H, 4-H), 3.40 (ddd, 1H, J = 15.3, 9.9, 5.2 Hz, 1-H), 3.27 (dd, 1H, J = 14.1, 8.0 Hz, β- Phe), 3.17 (m, 1 H, 1-H), 2.92 (dd, 1 H, J = 14.0, 7.1 Hz, β-Phe), 1.60 (m, 4H, 3-H, 2-H), 1 .44 (s, 9H, CH ₃ * Bu). ¹³ C NMR (CDCI ₃ ): δ 172.4, 170.1 (COO), 155.5 (OCON), 148.2, 136.3, 135.4, 134.9, 133.5, 133.0, 131.5, 131 .0, 129.3, 128.8, 128.7, 128.6, 128.5, 128.4 , 127.1, 124.1 (Ar), 80.1 (C, * Bu), 67.5, 67.3 (OCH ₂ ), 61 .5 (Ca-Phe), 53.1 (C4), 46.1 (C1), 36.9 (Οβ-Phe), 30.1 (C3), 28.4 (CH ₃ * Bu), 26.4 (C2). MS (ES) ⁺ : 746.29 [M + H] ⁺ .

A / - [(4S-benzyloxycarbonylamino-4-methyloxycarbonyl) -but-1 -yl] -Ns-L-Phe-O ^t Bu

Simpe Rdto: 68% [from Ns-L-Phe-O'Bu (2b) and (2S) -2- Methyl benzyloxycarbonylamino-5-hydroxypentanoate (3e)]. HPLC-MS: t _R = 8.53 min (gradient from 30% to 95% of A, in 10 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.84 (d, 1 H, J = 7.8 Hz, 3-H Nos), 7.63 (m, 1 H, 6-H Nos), 7.56 (m, 2H, 4 , 5-H Nos), 7.36-7.20 (m, 10H, Ar), 5.33 (d, 1 H, J = 8.2 Hz, 4-NH), 5.1 1 (s, 2H, OCH ₂ ), 4.75 (t, 1 H, J = 7.6 Hz, β-Phe), 4.33 (m, 1 H, 4-H), 3.74 (s, 3H, OMe), 3.55-3.48 (m, 1 H, 1 -H), 3.35- 3.27 (m, 2H, 1-H, β-Phe), 3.99 (dd, 1 H, J = 14.5, 7.1 Hz, β-Phe), 1 .87-1 .80 (m, 1 H, 3-H ), 1 .79-1 .58 (m, 3H, 3-H, 2-H), 1.23 (s, 9H, CH ₃ ¾u). MS (ES) ⁺ : 670.48 [M + H] ⁺ .

A / - [(4S-benzyloxycarbonylamino-4-methyloxycarbonyl) -but-1 -yl] -Ns-L-Ala-O ^t Bu

Simpe Rdto: 63% [from Ns-L-Ala-OMe (2d) and (2S) -2- Methyl benzyloxycarbonylamino-5-hydroxypentanoate (3e)]. HPLC-MS: t _R = 7.62 min (gradient from 30% to 95% of A, in 10 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 8.05 (d, 1 H, J = 6.5 Hz, 3-H Nos), 7.64 (m, 2H, 4.5-H Nos), 7.57 (m, 1 H , 6-H Nos), 7.36-7.30 (m, 5H, Ar), 5.34 (d, 1H, J = 7.9 Hz, 4-NH), 5.11 (s, 2H, OCH ₂ ), 4.62 (q, 1H, J = 7.2 Hz , a-Ala), 4.35 (q, 1H, J = 7.2 Hz, 4-H), 3.74 (s, 3H, OMe), 3.52-3.44 (m, 1H, 1-H), 3.16-3.09 (m, 1H, 1-H), 1.86-1.64 (m, 4H, 3-H, 2-H), 1.45 (d, 3H, J = 7.3 Hz, β-Ala), 1.32 (s, 9H, ClVBu). MS (ES) ⁺ : 594.32 [M + H] ⁺ . / - [(2S-Benzyloxycarbonylamino-3-phenyl) prop-1 -yl] -Ns-L-Phe-OBn (4j)

Simpe Rdto: 51% [from Ns-L-Phe-OBn (2c) and 3f] Eluent: AcOEtHexano (1: 3). HPLC: t _R = 18.52 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.79-7.02 (m, 24H, Ar), 5.42 (d, 1H, J = 7.4 Hz, 2-NH), 5.10 (d, 1H, J = 12.6 Hz, OCH ₂ ), 5.00 (d, 1H, J = 12.6 Hz, OCH ₂ ), 4.84 (s, 2H, OCH ₂ ), 4.82 (dd, 1H, J = 8.4, 6.6 Hz, a-Phe), 4.14 (m , 1H, 2-H), 3.55 (dd, 1H, J = 15.5, 10.1 Hz, 1-H), 3.43 (dd, 1H, J = 15.5, 4.9 Hz, 1-H), 3.24 (dd, 1H, J = 13.9, 8.5 Hz, β-Phe), 3.11 (dd, 1H, J = 13.9, 6.6 Hz, β-Phe), 2.89 (dd, 1H, J = 14.0, 6.0 Hz, 3-H), 2.81 ( dd, 1H, J = 14.0, 7.2 Hz, 3-H). ¹³ C NMR (75 MHz, CDCIs): δ 170.0 (COO), 156.0 (CON), 147.8, 137.3, 136.1, 134.7, 133.6, 133.0, 131.9, 131.1, 129.5, 129.4, 128.6, 128.7, 128.66, 128.65, 128.63 , 128.62, 128.5, 128.1, 127.9, 127.1, 126.8, 124.4 (Ar), 67.5, 66.5 (OCH ₂ ), 62.0 (Ca-Phe), 52.2 (C2), 48.7 (C1), 39.6 (Cp-Phe), 37.3 (C3). MS (ES) ⁺ : 708.43 [M + H] ⁺ .

 - [(2R-Benzyloxycarbonylamino-3-phenyl) prop-1-yl] -Ns-L-Phe-OBn (4k)

Simpe Rdto: 57% [from Ns-L-Phe-OBn (2c) and 3g]. Eluent: AcOEtHexano (1: 3). HPLC: t _R = 18.64 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI3): δ 7.69-6.88 (m, 24H, Ar), 5.22 (d, 1H, J = 7.4 Hz, NH, Z), 5.01 (d, 1H, J = 12.2 Hz, OCH ₂ ), 5.00 (s, 2H, OCH ₂ ), 4.97 (d, 1H, J = 12.2 Hz, OCH ₂ ), 4.83 (t, 1H, J = 7.6 Hz, a-Phe), 4.06 (m, 1H, 2-H), 3.64 (dd, 1 H, J = 15.8, 9.3 Hz, 1-H), 3.45 (dd, 1 H, J = 15.8, 4.5 Hz, 1-H), 3.23 (dd, 1 H, J = 14.5, 7.6 Hz, β- Phe), 2.99 (dd, 1 H, J = 13.9, 6.9 Hz, 3-H), 2.79 (m, 2H, β-Phe, 3-H). ¹³ C NMR (75 MHz, CDCI ₃ ): δ 170.1 (COO), 156.1 (CON), 148.0, 137.8, 135.8, 135.1, 133.7, 132.6, 131 .6, 131.1, 129.4, 129.0, 128.75, 128.7, 128.6, 128.5, 128.05, 127.0, 126.8, 124.2 (Ar), 67.7, 66.5 (OCH ₂ ), 61 .0 (Ca-Phe), 52.4 (C2), 48.4 (C1), 39.2 (C3), 35.6 (Cp-Phe ). MS (ES) ⁺ : 708.42 [M + H] ⁺ .

/ V- 2? -Benzyloxycarbonylamino-3-phenyl) prop-1 -yl] -Ns-L-Ala-OBn (41)

Simpe Rdto: 57% [from Ns-L-Ala-OBn (2e) and 3g]. Eluent: AcOEtHexano (1: 3). HPLC: t _R = 16.91 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.76 (d, 1 H, J = 7.9 Hz, Ar), 7.58-7.14 (m, 13H, Ar), 5.15 (d, 1 H, J = 7.4 Hz NH , Z), 5.00 (m, 4H, OCH ₂ ), 4.69 (q, 1 H, J = 7.3 Hz, a-Ala), 3.99 (m, 2H, 2-H), 3.46 (m, 2H, 1 - H), 2.97 (dd, 1 H, J = 13.8, 6.3 Hz, 3-H), 2.89 (dd, 1 H, J = 13.8, 7.4 Hz, 3-H), 1.36 (d, 1 H, J = 7.3 Hz, CH ₃ ). ¹³ C NMR (75 MHz, CDCIs): δ 171.1 (COO), 156.0 (CON), 148.0, 137.7, 135.2, 133.7, 131 .7, 131.2, 129.4, 129.3, 128.7, 128.6, 128.5, 128.45, 128.4, 128.3 , 128.1, 128.0, 126.7, 124.2 (Ar), 67.5, 66.6 (OCH ₂ ), 56.4 (Ca-Phe), 52.7 (C2), 48.2 (C1), 38.7 (C3), 16.01 (CH ₃ ). MS (ES) ⁺ : 632.33 [M + H] ⁺ .

and - [2S- (3-Phenyl-2-dibenzylamino) prop-1 -yl] -Ns-L-Phe-OBn (4m)

Simpe Rdto: 63% (from 2c and 3h). Eluent: AcOE Hex (1: 5). HPLC: t _R = 18.40 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI3): δ 7.52-6.77 (m, 29H, Ar), 4.66 (s, 2H, OCH ₂ ), 4.54 (dd, 1 H, J = 9.7, 5.5 Hz, a-Phe) , 3.83 (dd, 1 H, J = 14.8, 5.7 Hz, 1-H), 3.68 (d, 2H, J = 13.7 Hz, N-CH ₂ ), 3.53 (d, 2H, J = 13.7 Hz, N-CH ₂ ), 3.32 (dd, 1 H, J = 14.8, 8.5 Hz, 1-H), 3.20 (m, 1 H, 2-H), 2.81 ( dd, 1 H, J = 13.9, 8.5 Hz, 3-H), 2.67 (m, 3H, β-Phe, 3-H). ¹³ C NMR (75 MHz, CDCI ₃ ): δ 169.7 (COO), 148.0, 139.9, 139.8, 136.4, 135.0, 134.0, 133.3, 131 .9, 131.8, 129.7, 129.4, 129.1, 128.6, 128.55, 128.5, 128.4 , 128.3, 128.2, 127.0, 126.9 (Ar), 67.1 (OCH ₂ ), 62.0 (Ca-Phe), 57.8 (C2), 53.2 (N-CH ₂ ), 47.1 (C1), 36.7 (Οβ-Phe), 34.4 (C3). MS (ES) ⁺ : 754.35 [M + H] ⁺ .

 - [(2S-Dibenzylamino-3-phenyl) propyl] -Ns-L-Phe-OMe (4n)

Simpe Rdto: 35% (from 2a and 3h). Eluent: AcOEtHexano (1: 5). HPLC: t _R = 3.60min (gradient of 80% to 95% of A, in 10 min). ¹ H NMR (300 MHz, CDCIs): δ 7.63 (m, 2H, Ar), 7.41 (m, 1 H, Ar), 7.29-7.13 (m, 17H, Ar), 7.02 (m, 2H, Ar), 6.93 (m, 2H, Ar), 4.54 (dd, 1 H, J = 10.0, 5.4 Hz, a-Phe), 3.91 (dd, 1 H, J = 15.0, 5.6 Hz, 1 -H), 3.80 (dd , 2H, J = 13.7 Hz, NCH ₂ ), 3.63 (dd, 2H, J = 13.7 Hz, NCH ₂ ), 3.49 (dd, 2H, J = 15.0, 8.7 Hz, 1 -H), 3.34 (s, 3H , OCH ₃ ), 3.30 (m, 1 H, 2-H), 2.89 (dd, 1 H, J = 14.0, 8.8 Hz, 3-H), 2.80 (dd, 1 H, J = 13.5, 6.3 Hz, 3- H), 2.75 (dd, 1 H, J = 13.2, 10.0 Hz, β-Phe), 2.66 (dd, 1 H, J = 13.3, 5.4 Hz, β-Phe). ¹³ C NMR (75 MHz, CDCI3): δ 170.4 (COO), 140.0-124.5 (C, Ar), 61.8 (a-Phe), 57.8 (C2), 53.3 (NCH ₂ ), 52.2 (OCH ₃ ), 47.1 (C1), 36.6 (β-Phe), 34.7 (C3). MS (ES) ⁺ : 679.51 [M + H] ⁺ .

yV - [(2S-Dibenzylamino-3-phenyl) propyl] -Ns-L-Phe-O ^í Bu (4th)

Simpe. Rdto: 82% (a partir de 2b y 3h). Eluyente: AcOEtHexano (1 :6). HPLC: t_R=5.00 min (gradiente del 80% a 95% de A, en 10 min). ¹H RMN (300 MHz, CDCIs): δ 7.59 (m, 2H, Ar), 7.37 (m, 1 H, Ar), 7.26-7.16 (m, 16H, Ar), 7.08 (m, 3H, Ar), 6.86 (m, 2H, Ar), 4.51 (t, 1 H, J = 7.7 Hz, a-Phe), 4.01 (dd, 1 H, J = 15.0, 5.6 Hz, 1 -H), 3.81 (d, 2H, J = 13.7 Hz, NCH₂), 3.63 (dd, 2H, J = 13.8 Hz, NCH₂), 3.45 (dd, 1 H, J = 15.0, 8.8 Hz, 1 -H), 3.29 (ddd, 1 H, J = 8.6, 5.8, 2.8 Hz, 2-H), 2.83 (m, 2H, 3-H), 2.75 (m, 2H, β-Phe), 1.1 1 (s, 9H, 'Bu). ¹³C RMN (75 MHz, CDCI3): δ 169.0 (COO), 148.2, 140.1 , 139.9, 136.8, 134.6, 133.3, 132.0, 129.7, 129.5, 128.4, 121.3, 128.2, 127.0, 126.9, 126.1 , 124.4 (C, Ar), 82.0 (C, 'Bu), 62.6 (a-Phe), 57.9 (C2), 53.3 (NCH₂), 47.0 (C1 ), 37.1 (β-Phe), 34.7 (C3), 27.7 (CH3, ¾u). MS (ES)⁺: 721.38 [M+H]⁺.

Simpe Rdto: 82% (from 2b and 3h). Eluent: AcOEtHexano (1: 6). HPLC: t _R = 5.00 min (gradient of 80% to 95% of A, in 10 min). ¹ H NMR (300 MHz, CDCIs): δ 7.59 (m, 2H, Ar), 7.37 (m, 1 H, Ar), 7.26-7.16 (m, 16H, Ar), 7.08 (m, 3H, Ar), 6.86 (m, 2H, Ar), 4.51 (t, 1 H, J = 7.7 Hz, a-Phe), 4.01 (dd, 1 H, J = 15.0, 5.6 Hz, 1-H), 3.81 (d, 2H , J = 13.7 Hz, NCH ₂ ), 3.63 (dd, 2H, J = 13.8 Hz, NCH ₂ ), 3.45 (dd, 1 H, J = 15.0, 8.8 Hz, 1 -H), 3.29 (ddd, 1 H , J = 8.6, 5.8, 2.8 Hz, 2-H), 2.83 (m, 2H, 3-H), 2.75 (m, 2H, β-Phe), 1.1 1 (s, 9H, 'Bu). ¹³ C NMR (75 MHz, CDCI3): δ 169.0 (COO), 148.2, 140.1, 139.9, 136.8, 134.6, 133.3, 132.0, 129.7, 129.5, 128.4, 121.3, 128.2, 127.0, 126.9, 126.1, 124.4 (C, Ar), 82.0 (C, 'Bu), 62.6 (a-Phe), 57.9 (C2), 53.3 (NCH ₂ ), 47.0 (C1), 37.1 (β-Phe), 34.7 (C3), 27.7 (CH3, ¾u). MS (ES) ⁺ : 721.38 [M + H] ⁺ .

Elimination of the Nosilo group (Ns)

To a solution of the corresponding denvated / V-Nosyl-alkyl amino acid (4.87 mmol, 3.57 g) in dry CH ₃ CN (82 mL) is successively added K2CO3 (14.49 mmol, 2.02 g) and Thiophenol (9.74 mmol, 0.99 mL) and stir at room temperature overnight. After this time, the solvent is evaporated to dryness and the resulting residue is dissolved in AcOEt: H ₂ 0 (1: 1) and the phases are separated. The organic extract is washed with saturated NaCl solution, dried over anhydrous Na ₂ S0 ₄ and evaporated to dryness. The reaction crude obtained is purified on a silica gel column, using the eluent system indicated in each case.

 yV - [(3S-íerc-Butoxycarbonylamino-3-benzyloxycarbonyl) prop-1 -yl] -L-Phe-OMe

 Simpe Rdto: 85% (from 4th). Eluent: AcOEtHexano (1: 1). HPLC:

t _R = 1 1 .98 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (300 MHz, CDCI3): δ 7.38-7.16 (m, 10H, Ar), 5.81 (d, 1 H, J = 7.6 Hz, NHBoc), 5.22 (d, 1 H, J = 12.5 Hz, OCH ₂ ), 5.14 (d, 1 H, J = 12.5 Hz, OCH ₂ ), 4.41 (m, 1 H, 3-H), 3.66 (s, 3H, OMe), 3.50 (t, 1 H, J = 6.7 Hz, α-Phe), 2.94 (m, 2H, β-Phe), 2.75 (m, 1 H, 1 - H), 2.51 (m, 1 H, 1-H), 1.96 (m, 1 H, 2-H), 1.82 (m, 1 H, 2-H), 1.48 (s, 9H, CH ₃ ¾u). ¹³ C NMR (75 MHz, CDCI ₃ ): 172.9 (COO), 170.7 (COO), 155.9 (OCON), 136.1, 128.7, 128.5, 127.4, 127.1, 126.9 (C, Ar), 79.9 (C ¾u), 65.1 (OCH ₂ ), 55.2 (Ca-Phe), 52.5 (OMe), 52.0 (C3), 41 .5 (C1), 35.1 (Οβ-Phe), 28.6 (C2), 28.3 (ClVBu). MS (ES) ⁺ : 471.02 [M + H] ⁺ .

 W - [(3S-ierc-Butoxycarbonylamino-3-benzyloxycarbonyl-) prop-1 -yl] -L-Phe-OBn

Simpe Rdto: 90% (from 4b). Eluent: AcOEtHexano (1: 1). HPLC: t _R = 15.47 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCIs): δ 7.33-7.07 (m, 15H, Ar), 5.75 (d, 1 H, J = 7.7 Hz, NH, Boc), 5.17 (d, 1 H, J = 12.4 Hz , OCH ₂ ), 5.10 (d, 1 H, J = 12.4 Hz, OCH ₂ ), 5.04 (s, 2H, OCH ₂ ), 4.37 (m, 1 H, 3-H), 3.50 (t, 1 H, J = 6.7 Hz, a-Phe), 2.94 (dd, 1 H, J = 13.5, 6.6 Hz, β-Phe), 2.86 (dd, 1 H, J = 13.5, D7.3 Hz, β-Phe), 2.72 (m, 1 H, 1-H), 2.47 (m, 1 H, 1-H), 1.92 (m, 1 H, 2-H), 1.79 (m, 1 H, 2-H ), 1.44 (s, 9H, CH ₃ ¾u). ¹³ C NMR (75 MHz, CDCI3): 174.2 (COO), 172.6 (COO), 155.6 (CON), 137.0, 135.62, 135.6, 129.3, 128.7, 128.6, 128.55, 128.5, 128.4, 126.8 (C, Ar), 79.8 (C, 'Bu), 67.0, 66.6 (OCH ₂ ), 62.7 (a-Phe), 52.5 (C3), 44.2 (C1), 39.8 (β-Phe), 31.7 (C2), 28.5 (CH ₃ ' Bu). MS (ES) ⁺ : 547.92 [M + H] ⁺ .

 / V - [(3S-íerc-Butoxycarbonylamino-3-benzyloxycarbonyl) prop-1 -yl] -L-Ala-OMe (5c)

Simpe Rdto: 43% (from 4c). Eluent: AcOEtHexano (2: 1). HPLC: t _R = 12.15 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI3): δ 7.34 (s, 5H, Ph), 5.76 (d, 1 H, J = 6.0 Hz, 3-NH), 5.18 (d, 1 H, J = 16.0 Hz, OCH ₂ ), 5.11 (d, 1H, J = 16.0 Hz, OCH ₂ ), 4.39 (m, 1H, 3-H), 3.69 (s, 3H, OMe), 3.28 (q, 1H, J = 7.0 Hz, a-Ala), 2.71 (m, 1H, 1-H), 2.49 (m, 1H, 1-H), 1.87 (m, 2H, 2-H), 1.43 (s, 9H, CH ₃ Bu, ), 1.24 (d, 1H, J = 7.0 Hz, CH _3, Ala). ¹³ C NMR (100 MHz, CDCI3): 175.9 (COO), 172.6 (COO), 155.69 (CON), 135.6, 128.7. 128.4, 128.3, 127.1 (C, Ar), 79.9 (C, ¾u), 67.0 (OCH ₂ ), 56.7 (Ca-Ala), 52.5 (C3), 51.9 (OMe), 43.9 (C1), 31.9 (C2) , 28.4 (CH ₃ ¾u), 19.1 (CH ₃ Ala). MS (ES) ⁺ : 395.35 [M + H] ⁺ .

 W - [(3S-Benzyloxycarbonylamino-3-ierc-butoxycarbonyl) prop-1-yl] -L-Phe-OMe

Simpe Rdto: 78% (from 4d). Eluent: AcOEtHexano (1: 1). HPLC: t _R = 10.73 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI3): δ 7.36-7.14 (m, 10H, Ph, Z), 5.95 (d, 1H, J = 7.5 Hz, NH, Z), 5.10 (s, 2H, OCH ₂ ), 4.27 (m, 1H, 3-H), 3.63 (s, 3H, OMe), 3.51 (t, 1H, J = 6.5 Hz, a-Phe), 2.95 (m, 2H, β-Phe), 2.73 (m , 1H, 1-H), 2.53 (m, 1H, 1-H), 1.97 (m, 1H, 2-H), 1.77 (m, 2H, 2-H), 1.44 (s, 9H, CH ₃ ¾u ). ¹³ C NMR (75 MHz, CDCI3): 174.5 (COO), 171.3 (COO), 156.0 (OCON), 136.9, 136.4, 129.0, 128.3, 127.9, 126.6 (Ar), 81.7 (C 'Bu), 66.6 (OCH ₂ ), 62.6 (Ca-Phe), 53.2 (C3), 51.5 (OMe), 44.1 (C1), 39.5 (Cp-Phe), 31.7 (C2), 27.8 (CH ₃ 'Bu). MS (ES) ⁺ : 471.37 [M + H] ⁺ .

W - [(3S-Benzyloxycarbonylamino-3-íerc-butoxycarbonyl) prop-1-yl] -L-Ala-OMe

Simpe Rdto: 78% (from 4e). Eluent: AcOEtHexano (2: 1). HPLC: t _R = 9.14 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI3): δ 7.33 (m, 5H, Z), 5.97 (d, 1H, J = 7.6 Hz, NH, Z), 5.12 (d, 1H, J = 12.0 Hz, OCH ₂ ), 5.06 (d, 1 H, J = 12.0 Hz, OCH ₂ ), 4.30 (m, 1 H, 3-H), 3.69 (s, 3H, OMe), 3.32 (q, 1 H, J = 7.0 Hz, a-Ala), 2.73 (m, 1 H, 1-H), 2.53 (m, 1 H, 1-H), 1.97 (m, 1 H, 2-H), 1. 79 (m, 1 H, 2-H, NH), 1 .44 (s, 9H, CH ₃ ¾u), 1 .26 (d, 3H, J = 7.0 Hz, CH ₃ Ala). ¹³ C NMR (75 MHz, CDCI3): 175.9 (COO), 171.5 (COO), 156.2 (OCON), 136.6, 128.6, 128.15, 128.1 (Ar), 82.0 (C ¾u), 66.8 (OCH ₂ ), 56.4 ( Ca-Ala), 53.4 (C3), 51.9 (OMe), 44.0 (C1), 32.1 (C2), 28.0 (CH ₃ ¾u), 19.0 (CH ₃ Ala). MS (ES) ⁺ : 395.42 [M + H] ⁺ .

 A / - [4S - [(N-Benzyloxycarbonyl-N-methyl) amino-4-methoxycarbonyl] but-1 -yl] -L- -O'Bu (5f)

Simpe Rdto: 88% (from 4f). Eluent: AcOEtHexano (1: 1). HPLC: t _R = 10.85 min (gradient from 5% to 100% of A, in 20 min). Rattan ratio M, m = 2: 1. ¹ H NMR (400 MHz, CDCI _{3, major} rotamer): δ 7.37- 7.19 (m, 10H, Ph, Z), 5.15 (s, 2H, OCH ₂ ), 4.78 (dd, 1 H, J = 10.8, 5.1 Hz, 3-H), 3.70 (s, 3H, OMe), 3.41 (t, 1 H, J = 7.0 Hz, a-Phe), 2.93 (m, 2H, β-Phe), 2.83 (s, 3H, NMe), 2.63 (m, 2H, 1-H), 1.94 (m, 2H, 3-H), 1.73 (m, 2H, 2-H), 1.33 (s, 9H, CH ₃ 'Bu). ¹³ C NMR (75 MHz, CDCI3): 173.8 (COO), 172.1 (COO), 157.1 (CON), 137.5, 129.5, 128.6, 128.3, 128.1, 127.9, 127.8, 126.6 (C, Ar), 81.3 (C ' Bu), 67.6 (OCH ₂ ), 63.3 (Ca-Phe), 58.4 (C4), 52.2 (OMe), 47.4 (C1), 36.8 (Cp-Phe), 30.4 (NMe), 28.1 (CH ₃ * Bu) , 26.6 (C2), 26.4 (C3). MS (ES) ⁺ : 499.44 [M + H] ⁺ . W - [(4S-íerc-Butoxycarbonylamino-4-benzyloxycarbonyl) but-1 -yl] -HL-Phe-

Sirupe Rdto: 81% (from 4g). Eluent: AcOEtHexano (1: 2). HPLC: t _R = 17.63 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (300 MHz, CDCI3): δ 7.74-6.87 (m, 15H, Ar), 5.62 (d, 1H, J = 8.4 Hz, NH), 5.22 (d, 1H, J = 12.4 Hz, OCH2), 5.16 (d, 1H, J = 12.4 Hz, OCH ₂ ), 5.09 (s, 2H, OCH ₂ ), 4.34 (m, 1H, 4-H), 3.55 (t, 1H, J = 7.5 Hz, a-Phe), 3.00 (m, 2H , β-Phe), 2.64 (m, 1H, 1-H), 2.44 (m, 1H, 1-H), 1.77 (m, 2H, 3-H), 1.46 (m, 9H, ⁽ Bu). ¹³ NMR C (CDCI3): δ 174.5, 172.7 (COO), 155.6 (CON), 137.1, 135.6, 129.4, 128.9, 128.7, 128.6, 128.55, 128.5, 128.4, 128.35, 126.8 (Ar), 79.9 (C ¾u), 67.0, 66.6 (OCH ₂ ), 62.9 (Ca-Phe), 53.5 (C4), 47.5 (C1), 39.8 (Cp-Phe), 30.4 (C2), 28.5 (CH ₃ ¾u), 25.8 (C3). (ES) ⁺ : 561 [M + H] ⁺ .

- [(4S-Benzyloxycarbonylamino-4-methoxycarbonyl) but-1-yl] -L-Phe-O ^t Bu (5h)

Simpe Rdto: 89% (from 4h). HPLC: t _R = 5.29 min (gradient of 15% to 95% of A, in 10 min). HPLC-MS: t _R = 6.77 (gradient of 15% to 95% of A, in 10 min). ¹ H NMR (300 MHz, CDCI3): δ 7.26-7.08 (m, 10H, Ar), 6.03 (d, 1H, J = 7.8 Hz, 4-NH), 5.03 (s, 2H, OCH ₂ ), 4.05 ( m, 1H, 4-H), 3.66 (s, 3H, OMe), 3.25 (dd, 1H, J = 7.7, 6.5 Hz, a-Phe), 2.87 (dd, 1H, J = 13.4, 6.4 Hz, β -Phe), 2.75 (dd, 1H, J = 13.4, 7.7 Hz, β-Phe), 2.56 (m, 1H, 1-H), 2.35 (m, 1H, 1-H), 1.71 (m, 1H, 3-H), 1.48-1.38 (m, 3H, 3 and 2-H), 1.25 (s, 9H, CH ₃ ¾u). MS (ES) ⁺ : 485.32 [M + H] ⁺ .

- [(4S-Benzyloxycarbonylamino-4-methoxycarbonyl) but-1-yl] -L-Ala-O ^t Bu (5i)

Simpe Rdto: 77% (from 4i). HPLC-MS: t _R = 5.20 min (gradient of 15% to 95% of A, in 10 min). ¹ H NMR (300 MHz, CDCI3): δ 7.26 (s, 5H, Ph), 6.15 (d, 1H, J = 7.7 Hz, 4-NH), 5.01 (s, 2H, OCH ₂ ), 4.28 (q, 1H, J = 7.7 Hz, 4-H), 3.65 (s, 3H, OMe), 3.06 (q, 1H, J = 6.9 Hz, a-Ala), 2.58 (m, 1H, 1'-H), 2.33 (dd, 1H, 1'-H), 1.76 (m, 2H, 3'-H), 1.45 (m, 2H, 2'-H), 1.37 (s, 9H, CH ₃ 'Bu), 1.14 (d , 3H, J = 6.9 Hz, β-Ala). MS (ES) ⁺ : 409.33 [M + H] ⁺ . - [(2S-Benzyloxycarbonylamino-3-phenyl) prop-1-yl] -L-Phe-OBn (5j)

Simpe Rdto: 99% (from 4j). Eluent: AcOEtHexano (1: 1). HPLC: t _R = 15.41 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCIs): δ 7.39-7.00 (m, 20H, Ar), 5.09 (s, 4H, OCH ₂ ), 5.08 (m, 1H, NH, Z), 3.87 (m, 1H, 2 -H), 3.49 (dd, 1H, J = 7.9, 6.0 Hz, a-Phe), 2.99 (dd, 1H, J = 13.5, 6.0 Hz, 3-H), 2.86 (dd, 1H, J = 13.5, 7.9 Hz, 3-H), 2.79 (m, 1H, β-Phe), 2.70 (m, 2H, β- Phe, 1-H), 2.40 (dd, 1H, J = 12.3, 5.6 Hz, 1-H ), 1.50 (sa, 1H, NH). ¹³ C NMR (75 MHz, CDCI3): δ 173.7 (COO), 156.2 (CON), 137.7, 137.0, 136.7, 135.5, 129.4, 128.7, 128.6, 128.55, 128.5, 128.1, 127.0, 126.5 (Ar), 66.9, 66.7 (OCH ₂ ), 63.1 (Ca-Phe), 52.2 (C2), 49.8 (C1), 39.2 (C3), 37.5 (Οβ-ΡΙιβ). MS (ES) ⁺ : 523.28 [M + H] ⁺ .

 - [(2? -Benzyloxycarbonylamino-3-phenyl) prop-1-yl] -L-Phe-OBn (5k)

Simpe Rdto: 93% (from 4k). Eluent: AcOEtHexano (1: 3). HPLC: t _R = 15.53 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI3): δ 7.37-7.09 (m, 20H, Ar), 5.06 (s, 2H, OCH ₂ ), 5.04 (s, 2H, OCH ₂ ), 4.99 (sa, 1H, 2- NH), 3.87 (m, 1H, 2-H), 3.45 (t, 1H, J = 6.9 Hz, a-Phe), 2.92 (dd, 1H, J = 13.5, 6.6 Hz, 3-H), 2.85 ( m, 2H, 3-H, β-Phe), 2.64 (m, 2H, 1-H, β-Phe), 2.40 (dd, 1H, J = 12.3, 4.7 Hz, 1-H), 1.59 (sa, 1H, a-NH). ¹³ C NMR (75 MHz, CDCI3): δ 174.5 (COO), 156.0 (CON), 137.8, 137.3, 136.8, 135.6, 129.5, 129.4, 128.7, 128.6, 128.55, 128.5, 128.1, 126.8, 126.5 (Ar), 66.7, 66.65 (OCH ₂ ), 63.4 (Ca-Phe), 52.1 (C2), 49.8 (C1), 40.0 (C3), 39.0 (Οβ-ΡΙηβ). MS (ES) ⁺ : 523.05 [M + H] ⁺ . / V - [(2? -Benzyloxycarbonylamino-3-phenyl) prop-1-yl] -L-Ala-OBn (51)

Simpe Rdto: 90% (from 41). Eluent: AcOEtHexano (1: 3). HPLC: t _R = 10.25 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCIs): δ 7.36-7.16 (m, 15H, Ar), 5.15 (d, 1 H, J = 12.3 Hz, OCH ₂ ), 5.1 1 (m, 3H, NH, Z, OCH ₂ ), 5.10 (d, 1 H, J = 12.3 Hz, OCH ₂ ), 3.92 (m, 1 H, 2-H), 3.30 (q, 1 H, J = 7.0 Hz, a-Ala), 2.89 ( dd, 1 H, J = 13.9, 5.6 Hz, 3-H), 2.70 (dd, 1 H, J = 13.9, 7.8 Hz, 3-H), 2.82 (dd, 1 H, J = 12.0, 6.1 Hz, 1-H), 2.70 (dd, 1 H, J = 12.0, 4.5 Hz, 1-H), 1 .27 (d, 3H, J = 6.9 Hz, CH ₃ Ala). ¹³ C NMR (75 MHz, CDCI3): δ 175.6 (COO), 156.1 (CON), 137.8, 136.7, 135.8, 129.5, 128.9, 128.7, 128.65, 128.6, 128.5, 128.3, 128.2, 126.6 (Ar), 66.7, 66.6 (2C, OCH ₂ ), 57.0 (Ca-Ala), 52.2 (C2), 49.9 (C1), 39.2 (C3), 19.4 (CH ₃ Ala). MS (ES) ⁺ : 447.36 [M + H] ⁺ .

 - [(2S-Dibenzylamino-3-phenyl) prop-1-yl] -H-L-Phe-OBn (5m)

Simpe Rdto: 77% (from 4m). Eluent: AcOE Hex (1: 7). HPLC: t _R = 7.23 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI3): δ 7.28-6.87 (m, 25H, Ar), 4.96 (s, 2H, OCH ₂ ), 3.60 (d, 2H, J = 13.7 Hz, N-CH ₂ ), 3.43 (d, 2H, J = 13.7 Hz, N-CH ₂ ), 3.35 (dd, 1 H, J = 7.8, 5.9 Hz, a-Phe), 2.87 (m, 2H, 3-H, 2-H), 2.85 (dd, 1 H, J = 13.5, 5.8 Hz, β-Phe), 2.73 (dd, 1 H, J = 13.5, 7.8 Hz, β-Phe), 2.50 (m, 2H, 1-H), 2.38 (dd, 1 H, J = 14.9, 10.1 Hz Hz, 3-H). ¹³ C NMR (75 MHz, CDCI3): δ 174.0 (COO), 140.2, 139.9, 137.6, 135.8, 129.5, 129.4, 128.8, 128.6, 128.55, 128.5, 128.4, 127.0, 126.8, 126.0 (Ar), 66.5 (OCH ₂ ), 63.4 (Ca-Phe), 60.0 (C2), 53.9 (NCH ₂ ), 47.7 (C1), 39.5 (Cp-Phe), 34.2 (C3). MS (ES) ⁺ : 569.27 [M + H] ⁺ .

and V - [(2S-Dibenzylamino-3-phenyl) propyl]] - L-Phe-OMe (5n)

Simpe Rdto: 85% (from 4n). Eluent: AcOEtHexano (1: 4). HPLC: t _R = 4.15 min (gradient of 15% to 95% of A, in 5 min). ¹ H NMR (300 MHz, CDCIs): δ 7.36-6.99 (m, 20H, Ar), 3.71 (d, 2H, J = 13.7 Hz, NCH ₂ ), 3.56 (s, 3H, OCH3), 3.50 (d, 2H, J = 13.7 Hz, NCH ₂ ), 3.38 (dd, 1 H, J = 8.2, 5.4 Hz, a-Phe), 3.30 (m, 2H, 2-H, 3-H), 2.93 (dd, 1 H, J = 13.3, 5.4 Hz, 1-H), 2.78 (dd, 1 H, J = 13.4, 8.2 Hz, 1-H), 2.55 (m, 2H, β-Phe), 2.42 (m, 1 H , 3-H). ¹³ C NMR (75 MHz, CDCI3): δ 174.8 (COO), 140.5, 140.2, 138.0, 129.8, 129.6, 129.1, 128.9, 128.7, 127.3, 127.2, 126.3 (C, Ar), 63.8 (a-Phe), 60.5 (C2), 54.2 (NCH ₂ ), 52.0 (OCH ₃ ), 48.0 (C1), 39.8 (β-Phe), 34.2 (C3). MS (ES) ⁺ : 494.10 [M + H] ⁺ .

- [(2S-Dibenzylamino-3-phenyl) propyl] -L-Phe-O ^í Bu (5th)

Simpe Rdto: 88% (from 4th). Eluent: AcOEtHexano (1: 10). HPLC: t _R = 4.50 min (gradient of 15% to 95% of A, in 5 min). ¹ H NMR (300 MHz, CDCI3): δ 7.37-7.17 (m, 18H, Ar), 7.02 (m, 2H, Ar), 3.75 (d, 2H, J = 13.7 Hz, NCH ₂ ), 3.57 (d, 2H, J = 13.7 Hz, NCH ₂ ), 3.30 (dd, 1 H, J = 7.9, 5.8 Hz, a-Phe), 3.00 (m, 2H, 2-H, 3-H), 2.90 (dd, 1 H, J = 13.5, 5.8 Hz, 1-H), 2.80 (dd, 1 H, J = 13.5, 8.0 Hz, 1-H), 2.61 (m, 2H, β-Phe), 2.51 (m, 1 H , 3-H), 1 .33 (s, 9H, ¾u). ¹³ C NMR (75 MHz, CDCI3): δ 173.5 (COO), 140.4, 140.0, 138.0, 129.6, 129.4, 128.9, 128.5, 128.4, 126.9, 126.7, 125.9 (C, Ar), 81.0 (C, 'Bu) , 64.0 (a-Phe), 60.3 (C2), 53.9 (NCH ₂ ), 47.5 (C1), 39.4 (β-Phe), 34.1 (C3), 28.1 (CH ₃ , ¾u). MS (ES) ⁺ : 536.16 [M + H] ⁺ . Synthesis of / v-alkyl- / v-chloroacetyl amino acid derivatives

 To a solution of the corresponding amino acid derivative (1.39 mmol, 0.765 g) in dry THF (5 mL) is added propylene oxide (20.85 mmol, 1.5 mL) and chloroacetyl chloride (1.67 mmol , 0.13 mL). After 1-2 h stirring at room temperature, the organic solvent evaporates to dryness. The resulting residue is purified on a silica gel column, using the eluent system indicated in each case.

 N-Chloroacetyl- / V - [(3S-íerc-butoxycarbonylamino-3-benzyloxycarbonyl) prop-1- -L-Phe-OMe (6a)

Simpe Rdto: 92% (from 5a). Eluent: AcOE Hexane (1: 1). HPLC: t _R = 15.70 min (gradient from 5% to 100% of A, in 20 min). Rattan ratio M, m = 9: 1. ¹ H NMR (400 MHz, CDCI _{3, major} rotamer): δ 7.35-7.09 (m, 10H, Ph), 5.18 (m, 1H, 3-NH), 5.16 (d, 1H, J = 12.0 Hz, OCH ₂ ), 5.07 (d, 1H, J = 12.0 Hz, OCH ₂ ), 4.16 (m, 1H, 3-H), 3.92 (m, 1H, a-Phe), 3.91 (d, 1H, J = 12.5 Hz, CH ₂ CI), 3.86 (d, 1H, J = 12.5 Hz, CH ₂ CI), 3.69 (s, 3H, OMe), 3.30 (m, 2H, β-Phe), 3.13 (m, 1H, 1-H ), 2.70 (m, 1H, 1-H), 1.90 (m, 1H, 2-H), 1.52 (m, 1H, 2-H), 1.41 (s, 9H, CH ₃ ¾u). ¹³ C NMR (75 MHz, CDCI ₃ , majority rotamer): 171.6 (COO), 170.4 (COO), 166.7 (CON), 155.4 (OCON), 137.8, 135.1, 129.4, 128.9, 128.75, 128.7, 127.0 (C, Ar), 80.5 (C ¾u), 67.6 (OCH ₂ ), 63.3 (Ca-Phe), 52.6 (OMe), 51.8 (C3), 47.0 (C1), 41.0 (CH ₂ CI), 34.4 (Cp-Phe) , 31.6 (C2), 28.4 (CH ₃ ¾u). MS (ES) ⁺ : MS (ES) ⁺ : 569.30 [M + Na] ⁺ .

N-Chloroacetyl- / V - [(3S-íerc-butoxycarbonylamino-3-benzyloxycarbonyl) prop-1- yl] -L-Phe-OBn (6b)

Simpe Rdto: 99% (from 5b). Eluent: AcOEtHexano (1: 2). HPLC: t _R = 17.80 min (gradient from 5% to 100% of A, in 20 min). Rattan ratio M, m = 5: 2. ¹ H NMR (400 MHz, CDCI _{3, major} rotamer): δ 7.35-7.08 (m, 15H, Ar), 5.30 (d, 1H, J = 8.0 Hz, 3-NH), 5.15 (m, 2H, OCH ₂ ), 5.13 (d, 1H, J = 12.1 Hz, OCH ₂ ), 5.04 (d, 1H, J = 12.1 Hz, OCH ₂ ), 4.11 (m, 1H, a-Phe), 3.95 (m, 1H, 3 -H), 3.88 (d, 1H, J = 12.4 Hz, CH ₂ CI), 3.83 (d, 1H, J = 12.4 Hz, CH ₂ CI), 3.31 (m, 2H, 1-H), 3.10 (dd , 1H, J = 15.6, 5.3 Hz, β-Phe), 2.73 (m, 1H, β-Phe), 1.86 (m, 2H, 2-H), 1.40 (s, 9H, CH ₃ 'Bu). ¹³ C NMR (75 MHz, CDCI ₃ ): 171.5 (COO), 169.7 (COO), 166.6 (CON), 155.4 (OCON), 137.7, 135.6, 135.0, 129.4, 128.9, 128.7, 128.6, 128.4, 127.0 (C Ar), 80.5 (C 'Bu), 67.6 (OCH ₂ ), 67.4 (OCH ₂ ), 63.5 (Ca-Phe), 51.7 (C3), 47.0 (CH ₂ CI), 41.0 (C1), 34.4 (Οβ - Phe), 31.6 (C2), 28.4 (CH ₃ ¾u). MS (ES) ⁺ : 624.42 [M + H] ⁺ .

 N-Chloroacetyl- / V - [(3S-íerc-butoxycarbonylamino-3-benzyloxycarbonyl) prop-1- yl] -L-Ala-OMe (6c)

Simpe Rdto: 80% (from 5c). Eluent: AcOEtHexano (1: 2). HPLC: t _R = 13.15 min (gradient from 5% to 100% of A, in 20 min). Rattan ratio M, m = 5: 3. ¹ H NMR (400 MHz, CDCI _3, majority rotamer): δ 7.36 (s, 5H, Ph), 5.47 (d, 1H, J = 7.6 Hz, 3-NH), 5.26 (d, 1H, J = 12.0 Hz , OCH ₂ ), 5.14 (d, 1H, J = 12.0 Hz, OCH ₂ ), 4.35 (m, 1H, 3-H), 4.16 (q, 1H, J = 7.0 Hz, a-Ala), 4.09 (s , 2H, CH ₂ CI), 3.68 (s, 3H, OMe), 3.55 (m, 1H, 1-H), 3.39 (t, 1H, J = 8.0 Hz, 1-H), 2.00 (m, 2H, 2-H), 1.44 (d, 3H, J = 7.0 Hz, CH _3, Ala), 1.43 (s, 9H, CH ₃ Bu). ¹³ C NMR (75 MHz, CDCI ₃ ): 171.55, 171.5 (COO), 166.5 (CON), 155.6 (OCON), 135.0, 129.0. 128.9, 128.8 (C Ar), 80.8 (C ¾u), 67.8 (OCH ₂ ), 55.5 (Ca-Ala), 53.0 (C3), 52.5 (OMe), 44.7 (C1), 41.1 (CH ₂ CI), 30.7 (C2), 28.4 (CH ₃ ¾u), 14.5 (CH ₃ Ala). MS (ES) ⁺ : 493.35 [M + Na] ⁺ .

 N-Chloroacetyl- / V - [(3S-benzyloxycarbonylamino-3-ierc-butoxycarbonyl) prop-1- -L-Phe-OMe (6d)

Simpe Rdto: 90% (from 5d). Eluent: AcOEt: Hexane (1: 1). HPLC: t _R = 15.66 min (gradient from 5% to 100% of A, in 20 min). Rattan ratio M, m = 3: 1. ¹ H NMR (400 MHz, CDCI ₃ , majority rotamer): δ 7.37- 7.13 (m, 10H, Ph), 5.46 (d, 1H, J = 7.2 Hz, 3-NH), 5.13 (d, 1H, J = 12.0 Hz, OCH ₂ ), 5.04 (d, 1H, J = 12.0 Hz, OCH ₂ ), 4.09 (m, 1H, 3-H), 3.99 (m, 1H, a-Phe), 3.99 (d, 1H, J = 12.0 Hz, CH ₂ CI), 3.91 (d, 1H, J = 12.0 Hz, CH ₂ CI), 3.73 (s, 3H, OMe), 3.30 (m, 2H, -Phe), 3.20 (m, 1H , 1-H), 2.74 (m, 1H, 1-H), 1.88 (m, 1H, 2- H), 1.59 (m, 1H, 2-H), 1.42 (s, 9H, CH ₃ ¾u). ¹³ C NMR (75 MHz, CDCI ₃ ): 171.3, 170.3 (COO), 167.7 (CON), 156.0 (OCON), 137.6, 129.3, 128.7, 128.6, 128.4, 128.2, 126.9 (Ar), 83.0 (C 'Bu ), 67.2 (OCH ₂ ), 63.2 (Ca-Phe), 52.9 (OMe), 52.6 (C3), 47.0 (CH ₂ CI), 40.9 (C1), 34.3 (Cp-Phe), 31.5 (C2), 28.3 (CH ₃ ¾u). MS (ES) ⁺ : 569.51 [M + Na] ⁺ .

 N-Chloroacetyl- / V - [(3S-benzyloxycarbonylamino-3-íerc-butoxycarbonyl) prop-1- yl -L-Ala-OMe (6e)

Simpe Rdto: 92% (from 5e). Eluent: AcOE Hexane (1: 1). HPLC: t _R = 13.54 min (gradient from 5% to 100% of A, in 20 min). Rattan ratio M, m = 2: 1. ¹ H NMR (400 MHz, CDCI _{3, major} rotamer): δ 7.35 (m, 5H, Ph), 5.58 (d, 1H, J = 7.0 Hz, 3-NH), 5.14 (d, 1H, J = 12.0 Hz , OCH ₂ ), 5.08 (d, 1H, J = 12.0 Hz, OCH ₂ ), 4.24 (m, 2H, 3-H, a-Ala), 4.12 (d, 1H, J = 12.5 Hz, CH ₂ CI), 4.02 (d, 1 H, J = 12.5 Hz, CH ₂ CI), 3.70 (s, 3H, OMe), 3.42 (m, 2H, 1-H), 2.22 (m, 1 H, 2 -H), 1.99 (m, 1 H, 2-H), 1 .48 (s, 9H, CH ₃ ¾u), 1.47 (d, 3H, J = 6.4 Hz, CH ₃ Ala). ¹³ C NMR (75 MHz, CDCI3): 171 .4 (COO), 170.4 (COO), 166.6 (CON), 156.0 (OCON), 136.1, 133.2, 130.0, 128.6, 128.5, 128.3, 128.2, 128.0 (Ar) , 83.1 (C 'Bu), 67.1 (OCH ₂ ), 55.4 (CD-Ala), 52.8 (C3), 52.4 (OMe), 44.6 (CH2CI), 41 .0 (C1), 32.5 (C2), 27.9 ( CH ₃ )u), 14.4 (CH ₃ Ala). MS (ES) ⁺ : 493.42 [M + Na] ⁺ .

 A / - [4S- (N-Benzyloxycarbonyl-N-methyl) amino-4-methoxycarbonyl] but-1 -yl] -N- chloroacetyl-L-Phe-O'Bu (6f)

Simpe Rdto: 94% (from 5f). Eluent: AcOEt: Hexane (1: 1). HPLC: t _R = 16.21 min (gradient from 5% to 100% of A, in 20 min). Rattan ratio M, m = 5: 2. ¹ H NMR (400 MHz, CDCI _3, majority rotamer): δ 7.38-7.12 (m, 10H, Ph), 5.16 (s, 2H, OCH ₂ ), 4.68 (dd, 1 H, J = 10.9, 5.2 Hz, a-Phe), 4.39 (m, 1 H, 4-H), 3.99 (d, 1 H, J = 12.2 Hz, CH ₂ CI), 3.94 (d, 1 H, J = 12.5 Hz, CH2CI), 3.69 (s, 3H, OMe), 3.28 (m, 2H, 1-H), 2.89 (m, 1 H, β-Phe), 2.77 (s, 3H, NCH ₃ ), 2.52 (m, 1 H, β- Phe), 1 .75-1 .60 (m, 4H, 2-H, 3-H), 1 .44 (s, 9H, CH ₃ ¾u). ¹³ C NMR (75 MHz, CDCI3): 171 .5 (COO), 168.9 (COO), 166.2 (CON), 157.1 (OCON), 138.4, 136.5, 129.4, 128.77, 128.7, 128.0, 126.8 (Ar), 82.0 (C ¾u), 67.8 (OCH ₂ ), 64.2 (Ca-Phe), 57.6 (C4), 52.4 (OMe), 50.1 (C1), 41 .1 (CH2CI), 34.4 (Cp-Phe), 30.4 (NCH ₃ ), 28.0 (CH ₃ ¾u), 25.6 (C2), 24.9 (C3). MS (ES) ⁺ : 576.42 [M + H] ⁺ .

 / V - [(4S-íerc-butoxycarbonylamino-4-benzyloxycarbonyl) but-1 -yl] -N- chloroacetyl-L-Phe-OBn (6g)

Simpe. Rdto: 64% (a partir de 5g). Eluyente: AcOE Hexano (1 :3). Proporción de rotámeros M/m=6: 1 . HPLC: t_R=17.68 min (gradiente de 5% a 100% de A, en 20 min). ¹H RMN (300 MHz, CDCI₃, rotámero mayoritario): δ 7.38-7.12 (m, 15H, Ar), 5.18-5.04 (m, 4H, OCH₂), 4.86 (d, 1 H, J=8.4 Hz, 4-NH), 4.18 (m, 1 H, 4-H), 3.94 (d, 1 H, J=12.5 Hz, CH₂CI), 3.87 (d, 1 H, J=12.5 Hz, CH₂CI), 3.82 (dd, 1 H, J = 8.3, 6.9 Hz, a-Phe), 3.36 (m, 2H, β-Phe), 3.12 (dt, 1 H, J=15.4, 7.9 Hz, 1 -H), 2.51 (dt, 1 H, J=15.3, 8.1 Hz, 1 -H), 1 .61 (m, 1 H, 3H), 1 .43 (m, 10H, 'Bu, 3-H), 1 .24 (m, 2H, 2-H). ¹³C (CDCI₃): 172.0, 169.7 (COO), 166.5 (CON), 155.4 (OCON), 137.9, 135.6, 135.5, 129.5, 129.6, 128.9, 128.8, 128.75, 128.7, 128.6, 128.5, 128.4, 127.0 (Ar), 80.3 (C 'Bu), 67.4, 67.3 (OCH₂), 63.5 (Ca-Phe), 52.7 (C4), 50.1 (CH₂CI), 41 .2 (C1 ), 34.4 (Cp-Phe), 29.7 (C3), 28.4 (CH₃ ¾u), 24.3 (C2). MS (ES)⁺: 637.27 [M+H]⁺.

Simpe Rdto: 64% (from 5g). Eluent: AcOE Hexane (1: 3). Rattan ratio M / m = 6: 1. HPLC: t _R = 17.68 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (300 MHz, CDCI ₃ , majority rotamer): δ 7.38-7.12 (m, 15H, Ar), 5.18-5.04 (m, 4H, OCH ₂ ), 4.86 (d, 1 H, J = 8.4 Hz, 4-NH), 4.18 (m, 1 H, 4-H), 3.94 (d, 1 H, J = 12.5 Hz, CH ₂ CI), 3.87 (d, 1 H, J = 12.5 Hz, CH ₂ CI) , 3.82 (dd, 1 H, J = 8.3, 6.9 Hz, a-Phe), 3.36 (m, 2H, β-Phe), 3.12 (dt, 1 H, J = 15.4, 7.9 Hz, 1 -H), 2.51 (dt, 1 H, J = 15.3, 8.1 Hz, 1-H), 1.61 (m, 1 H, 3H), 1.43 (m, 10H, 'Bu, 3-H), 1 .24 (m, 2H, 2-H). ¹³ C (CDCI ₃ ): 172.0, 169.7 (COO), 166.5 (CON), 155.4 (OCON), 137.9, 135.6, 135.5, 129.5, 129.6, 128.9, 128.8, 128.75, 128.7, 128.6, 128.5, 128.4, 127.0 ( Ar), 80.3 (C 'Bu), 67.4, 67.3 (OCH ₂ ), 63.5 (Ca-Phe), 52.7 (C4), 50.1 (CH ₂ CI), 41 .2 (C1), 34.4 (Cp-Phe) , 29.7 (C3), 28.4 (CH ₃ ¾u), 24.3 (C2). MS (ES) ⁺ : 637.27 [M + H] ⁺ .

 N - [(4S-Benzyloxycarbonylamino-4-methoxycarbonyl) but-1'-yl] -N-chloroacetyl-L- -O'Bu (6h)

Sirupe Rdto: 94% (from 5h). HPLC: t _R = 7.68 min (gradient from 30% to 95% of A, in 10 min). Rattan ratio M: m = 2: 1. ¹ H NMR (300 MHz, CDCIs): Major rotamer δ 7.36-7.13 (m, 10H, Ar), 5.27 (d, 1 H, J = 8.3 Hz, 4-NH), 5.10 (s, 2H, OCH ₂ ) , 4.27 (m, 1 H, 4-H), 3.98 (m, 2H, CH ₂ CI), 3.80 (m, 1 H, a-Phe), 3.71 (s, 3H, OMe), 3.30 (m, 2H , β-Phe), 3.17 (m, 2H, 1 ^'-Η), 3.61 (m, 1H, 1' - H), 1.85 (m, 1H, 3'-H), 1 .68 (m, 3H, 3 ', - H 2'-H), 1 .45 (s, 9H, CH ₃ ¾u). MS (ES) ^+: 561.23 [M + H] ^+.

 N - [(4S-Benzyloxycarbonylamino-4-methoxycarbonyl) but-1 -yl] -N-Chloroacetyl-L-Ala-O'Bu (6i)

Simpe. Rdto: 70% (a partir de 5i). HPLC: t_R=6.18 min (gradiente de 30% a 95% de A, en 10 min). Proporción de rotámeros M:m = 2:1 ¹H RMN (300 MHz, CDCIs): rotámero mayoritario δ 7.35 (s, 5H, Ph), 5.44 (sa, 1H, 4-NH), 5.11 (s, 2H, OCH₂), 4.40 (m, 1H, 4-H), 4.12 (s, 2H, CH₂CI), 4.04 (m, 1H, a-Ala), 3.76 (s, 3H, OMe), 3.46 (m, 1H, 1'-H), 3.28 (m, 1H, 1'-H), 1.86 (m, 1H, 3'-H), 1.72 (m, 3H, 3'-H, 2'-H), 1.43 (s, 9H, CH₃ ¾u), 1.28 (d, 3H, J=6.3 Hz, β-Ala). MS (ES)⁺: 485.16 [M+H]⁺.

Simpe Rdto: 70% (from 5i). HPLC: t _R = 6.18 min (gradient from 30% to 95% of A, in 10 min). Rattan ratio M: m = 2: 1 ¹ H NMR (300 MHz, CDCIs): Major rotamer δ 7.35 (s, 5H, Ph), 5.44 (sa, 1H, 4-NH), 5.11 (s, 2H, OCH ₂ ), 4.40 (m, 1H, 4-H), 4.12 (s, 2H, CH ₂ CI), 4.04 (m, 1H, a-Ala), 3.76 (s, 3H, OMe), 3.46 (m, 1H , 1'-H), 3.28 (m, 1H, 1'-H), 1.86 (m, 1H, 3'-H), 1.72 (m, 3H, 3'-H, 2'-H), 1.43 ( s, 9H, CH ₃ ¾u), 1.28 (d, 3H, J = 6.3 Hz, β-Ala). MS (ES) ⁺ : 485.16 [M + H] ⁺ .

 N-Chloroacetyl-W - [(2S-benzyloxycarbonylamino-3-phenyl) prop-1-yl] -L-Phe-OBn

Simpe Rdto: 86% (from 5j). Eluent: AcOE Hexane (1: 2). HPLC: t _R = 22.50 min (gradient from 30% to 95% of A, in 30 min). Rattan ratio M, m = 16: 1. ¹ H NMR (400 MHz, DMSO-d _{6, major} rotamer): δ 7.33-6.97 (m, 20H, Ar), 5.10 (d, 1H, J = 12.6 Hz, OCH ₂ ), 5.08 (sa, 1H, 2 -NH), 5.02 (d, 1H, J = 12.6 Hz, OCH ₂ ), 4.87 (d, 1H, J = 12.6 Hz, OCH ₂ ), 4.78 (d, 1H, J = 12.6 Hz, OCH ₂ ), 4.50 (d, 1H, J = 13.2 Hz, CH ₂ CI), 4.33 (d, 1H, J = 13.2 Hz, CH ₂ CI), 4.30 (dd, 1H, J = 9.4, 5.3 Hz, a-Phe), 3.72 (m, 1H, 2-H), 3.27 (dd, 1H, J = 13.8, 5.2 Hz, β-Phe), 3.19 (dd, 1H, J = 15.5, 6.4 Hz, 1-H), 3.10 (dd, 1H, J = 13.8, 9.4 Hz, β-Phe), 2.84 (dd, 1H, J = 13.5, 4.7 Hz, 3-H), 2.46 (m, 1H, 1-H), 2.40 (dd, 1H, J = 13.4, 6.8 Hz, 3-H). ¹³ C NMR (75 MHz, DMSO-d _{6, major} rotamer): δ 169.4 (COO), 165.5 (CON), 155.7 (OCON), 138.2, 137.6, 136.9, 136.0, 129.3, 128.9, 128.5, 128.4, 128.3, 128.1, 127.8, 127.7, 127.6, 127.45, 126.4, 126.0 (Ar), 66.1, 65.2 (OCH ₂ ), 63.3 (Ca-Phe), 53.5 (C1), 52.8 (C2), 41.3 (CH ₂ CI), 37.4 (C3), 34.0 (Cp-Phe). MS (ES) ⁺ : 599.24 [M + H] ⁺ .

N-Chloroacetyl-W - [(2? -Benzyloxycarbonylamino-3-phenyl) prop-1-yl] -L-Phe-OBn (6k)

Simpe Rdto: 83% (from 5k). Eluent: AcOEtHexano (1: 2). HPLC: t _R = 22.71 min (gradient from 5% to 100% of A, in 20 min). Rattan ratio M, m = 5: 1. ¹ H NMR (400 MHz, DMSO-d _{6, major} rotamer): δ 7.32-7.06 (m, 20H, Ar), 5.11 (sa, 1H, 2-NH), 5.11 (d, 1H, J = 12.6 Hz, OCH ₂ ), 5.07 (d, 1H, J = 12.6 Hz, OCH ₂ ), 4.88 (s, 2H, OCH ₂ ), 4.37 (m, 1H, a-Phe), 4.28 (s, 2H, CH ₂ CI) , 3.85 (m, 1H, 2-H), 3.39 (m, 1H, D-Phe), 3.30 (m, 1H, 1-H), 3.07 (dd, 1H, J = 13.8, 7.7 Hz, β-Phe ), 2.80 (dd, 1H, J = 13.7, 4.5 Hz, 3-H), 2.75 (m, 1H, 1-H), 2.54 (m, 1H, 3-H). ¹³ C NMR (75 MHz, DMSO-d _{6, major} rotamer): δ 169.5 (COO), 166.1 (CON), 155.6 (OCON), 138.4, 138.1, 137.1, 135.9, 129.4, 129.0, 128.3, 128.2, 128.0, 127.8, 127.6, 127.35, 126.3, 126.0 (Ar), 66.1, 64.9 (OCH ₂ ), 62.3 (Ca-Phe), 53.5 (C1), 51.7 (C2), 41.5 (CH ₂ CI), 37.3 (C3), 34.5 (Cp-Phe). MS (ES) ⁺ : 599.15 [M + H] ⁺ .

 N-Chloroacetyl- / V - [(2? -Benzyloxycarbonylamino-3-phenyl) prop-1-yl] -L-Ala-OBn

Simpe Rdto: 86% (from 51). Eluent: AcOEtHexano (1: 3). HPLC: t _R = 15.50 min (gradient from 5% to 100% of A, in 20 min). Rattan ratio M, m = 6: 1. ¹ H NMR (400 MHz, DMSO-d ₆ , major rotamer): δ 7.35-7.12 (m, 15H, Ar), 5.14 (sa, 1H, 2-NH), 5.09 (d, 1H, J = 12.2 Hz, OCH ₂ ), 5.06 (d, 1H, J = 12.2 Hz, OCH ₂ ), 4.92 (d, 1H, J = 12.9 Hz, OCH ₂ ), 4.87 (d, 1H, J = 12.9 Hz, OCH ₂ ), 4.45 (d, 1H, J = 13.4 Hz, CH ₂ CI), 4.28 (d, 1H, J = 13.4 Hz, CH ₂ CI), 4.20 (q, 1H, J = 6.8 Hz, a-Ala), 3.95 (m , 1H, 2-H), 3.48 (dd, 1H, J = 15.1, 9.2 Hz, 1-H), 3.40 (dd, 1H, J = 15.1, 5.0 Hz, 1-H), 2.82 (dd, 1H, J = 13.5, 4.2 Hz, 3-H), 2.58 (dd, 1H, J = 13.5, 10.3 Hz, 3-H), 1.38 (d, 3H, J = 6.8 Hz, CH ₃ ). ¹³ C NMR (75 MHz, DMSO-de, major rotamer): δ 171 .0 (COO), 166.4 (CON), 156.3 (OCON), 138.6, 137.5, 136.3, 129.5, 128.75, 128.7, 128.5, 128.3, 128.0, 127.9, 127.4, 126.6 (Ar), 66.3, 65.3 (OCH ₂ ), 57.0 (Ca-Ala), 53.5 (C1), 51.8 (C2), 42.3 (CH ₂ CI), 38.1 (C3), 14.5 (CH ₃ ). MS (ES) ⁺ : 523.28 [M + H] ⁺ .

 -Chloroacetyl- / V - [(2S-dibenzylamino-3-phenyl-) prop-1 -yl] -L-Phe-OBn (6m)

Simpe Rdto: 92% (from 5m). Eluent: AcOE Hex (1: 9). Rattan ratio, M / m = 5: 1 HPLC: t _R = 7.79 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ , majority rotamer): δ 7.57-6.52 (m, 25H, Ar), 5.10 (d, 1 H, J = 12.2 Hz, OCH ₂ ), 4.95 (d, 1 H, J = 12.2 Hz, OCH ₂ ), 4.17 (d, 1 H, J = 12.2 Hz, CH2CI), 3.86 (d, 1 H, J = 12.2 Hz, CH-CI), 3.56 (m, 4H, NCH ₂ ), 3.41 (dd, 1 H, J = 15.8, 4.8 Hz, 1'-H), 3.1 1 (m, 4-H, a-Phe, β-Phe, 2-H), 2.74 (dd, 1 H, J = 13.2, 6.9Hz, 3'-H), 2.54 (dd, 1 H, J = 13.3, 8.2 Hz, 3'-H), 2.31 (dd, 1 H, J = 15.7, 5.8 Hz, 1'-H ). ¹³ C NMR (75 MHz, CDCI3): δ 169.4 (COO), 167.1 (CON), 138.9, 137.8, 134.4, 133.6, 129.7, 129.3, 128.9, 128.8, 128.6, 128.4, 127.4, 126.6 (Ar), 67.3 ( OCH ₂ ), 64.3 (a-Phe), 61.7 (C2 '), 54.0 (NCH ₂ ), 52.6 (CH ₂ CI), 50.0 (C1'), 41 .6 (C3 '), 34.8 (β-Phe) . MS (ES) ⁺ : 646.23 [M + H] ⁺ .

 -Chloroacetyl-W - [(2S-dibenzylamino-3-phenyl) prop-1-yl] -L-Phe-OMe (6n)

Simpe Rdto: 64% (from 5n). Eluent: AcOE Hexane (1: 6). HPLC: t _R = 8.52 min (gradient from 30% to 95% of A, in 10 min). ¹ H NMR (400 MHz, CDCI3): mixture of 7: 1 δ rotamers 7.29-6.89 (m, 20H, Ar), 4.33 (d, 1 H, J = 1 1 .7 Hz, CH ₂ CI), 3.87 (d, 1 H, J = 12.0 Hz, CH ₂ CI), 3.64 (d, 2H, J = 13.7 Hz, NCH ₂ ), 3.51 (d, 2H, J = 13.7 Hz, NCH ₂ ), 3.47 (m, 1 H, 1-H), 3.45 (s, 3H, OCH ₃ ), 3.14 ( m, 1 H, 2-H), 3.01 (m, 2H, β-Phe), 2.89 (dd, 1 H, J = 13.2, 5.9 Hz, 3-H), 2.76 (dd, 1 H, J = 9.8 , 5.1 Hz, a-Phe), 2.46 (dd, 1 H, J = 13.2, 9.0 Hz, 3-H), 2.25 (dd, 1 H, J = 15.8, 4.9 Hz, 1 -H). ¹³ C NMR (75 MHz, CDCI3): δ 169.8 (COO), 166.8 (CON), 138.8, 138.6, 137.6, 129.7, 129.5, 128.7, 128.5, 128.4, 127.3, 126.6 (C, Ar), 63.6 (a- Phe), 61.7 (C2), 54.0 (NCH ₂ ), 52.7 (C1), 52.0 (OMe), 41.4 (CH ₂ CI), 34.1 (β-Phe), 33.9 (C3). MS (ES) ⁺ : 570.16 [M + H] ⁺ .

-Chloroacetyl-yV - [(2S-dibenzylamino-3-phenyl) prop-1-yl] -L-Phe-O ⁱ Bu (60)

Simpe Rdto: 78% (from 5th). Eluent: AcOEtHexano (1: 6). HPLC: t _R = 8.76 min (gradient from 30% to 95% of A, in 10 min). ¹ H NMR (400 MHz, CDCI3): mixture of 4: 1 δ rotamers 7.36-7.21 (m, 12H, Ar), 7.10-6.95 (m, 8H, Ar), 4.03 (d, 1 H, J = 12.0 Hz, CH ₂ CI), 3.78 (d, 1 H, J = 12.0 Hz, CH ₂ CI), 3.55 (d, 2H, J = 14, 1 Hz, NCH ₂ ), 3.50 (d, 2H, J = 14, 1 Hz, NCH ₂ ), 3.43 (dd, 1 H, J = 15.4, 4.3 Hz, 1-H), 3.34 (m, 1 H, a-Phe), 3.06 (m, 3H, 2-

H, β-Phe), 2.76 (d, 2H, J = 7.5 Hz, 3-H), 2.54 (dd, 1 H, J = 15.5, 7.2 Hz, 1 -H),

I .39 (s, 9H, 'Bu). ¹³ C NMR (75 MHz, CDCI3): δ 168.4 (COO), 167.1 (CON), 139.2, 139.0, 138.3, 129.9, 129.5, 129.3, 128.8, 128.5, 128.2, 127.4, 126.7, 126.6 (C, Ar), 81 .8 (C, 'Bu), 65.0 (Ca-Phe), 60.6 (C2), 53.9 (NCH ₂ ), 52.3 (C1), 41 .4 (CH ₂ CI), 35.2 (C3), 34.7 (Cp -Phe), 28.1 (CH ₃ , ¾u). MS (ES) ⁺ : 612.14 [M + H] ⁺ .

Synthesis of / v-alkyl- / v-chloropropyl amino acid derivatives

To a solution of (R) - or (S) -2-chloropropionic acid (1.74 mmol, 0.15 mL) in dry THF (5 mL) is added trichloroacetonitrile (2.32 mmol, 0.23 mL) . It is then cooled to 0 ° C with an ice bath and triphenylphosphine (1.96 mmol, 0.513 g) is added slowly and allowed to stir at temperature ambient for 1 h. After this time, the reaction is added to a solution of the corresponding N-alkyl derivative of amino acids (0.635 g, 1.16 mmol) and propylene oxide (17.4 mmol, 1.22 ml_) in dry THF (2 ml_) at 0 ° C. It is allowed to react at room temperature for 12h. After this time, the solvent is evaporated and the resulting residue is dissolved in AcOEt and washed successively with citric acid (10%), NaHC0 ₃ (10%) and saturated NaCl solution. Finally, the organic residue is dried over anhydrous Na ₂ S0 ₄ , filtered and evaporated to dryness. The reaction crude is purified on a silica gel column using the eluent system indicated in each case.

/ V - [(3S-íerc-butoxycarbonylamino-3-benzyloxycarbonyl) prop-1 -yl] -N- (2'S-chloropropanoyl) -L-Phe-OBn (7a)

Simpe Rdto: 68% (from 5b). Eluent: AcOE Hexane (1: 3). HPLC: t _R = 10.64 min (gradient from 5% to 100% of A, in 20 min). Rattan ratio M, m = 5: 2. ¹ H NMR (400 MHz, CDCI _{3, major} rotamer): δ 7.35- 7.04 (m, 15H, Ar), 5.14 (d, 1 H, J = 12.4 Hz, OCH ₂ ), 5.13 (s, 2H, OCH ₂ ), 5.03 (d, 1 H, J = 12.1 Hz, OCH ₂ ), 4.93 (d, 1 H, J = 6.5 Hz, 3-NH), 4.31 (q, 2H, J = 6.5 Hz, V-H) , 4.06 (m, 1 H, 3-H), 3.95 (m, 1 H, a-Phe), 3.33 (dd, 1 H, J = 14.1, 5.3, β-Phe), 3.26 (m, 1 H, β-Phe), 3.00 (m, 2H, 1-H), 1.73 (m, 2H, 2-H), 1.59 (d, 3H, J = 6.4 Hz, 2'-H), 1. 41 (s, 9H, CH ₃ ¾u). ¹³ C NMR (75 MHz, CDCI ₃ ): 171.8 (COO), 170.0 (COO), 169.4 (CON), 155.4 (OCON), 138.1, 135.8, 135.4, 129.6, 129.1, 129.0, 128.9, 128.7, 127.4, 127.2 (Ar), 80.8 (C 'Bu), 67.8, 67.7 (2C, OCH ₂ ), 63.8 (Ca-Phe), 51 .7 (C3), 49.7 (CHCI), 46.6 (C1), 34.8 (Cp-Phe ), 31.8 (C2), 28.6 (CH ₃ 'Bu), 21 .6 (C2'). MS (ES) ⁺ : 637.45 [M + H] ⁺ .

/ V - [(2S-Benzyloxycarbonylamino-3-phenyl) prop-1 -yl] -N- (2'S-chloropropanoyl) -L- Phe-OBn (7b)

Simpe Rdto: 51% (from 5j). Eluent: AcOEtHexano (1: 4). HPLC: t _R = 16.54 min (gradient from 5% to 100% of A, in 20 min). Rattan ratio M, m = 10: 1. ¹ H NMR (400 MHz, DMSO-d ₆ , major rotamer): δ 7.33-6.96 (m, 20H, Ar), 5.10 (d, 1H, J = 12.6 Hz, OCH ₂ ), 5.04 (d, 1H, J = 12.6 Hz, OCH ₂ ), 5.01 (q, 1H, J = 6.3 Hz, 1'-H), 4.87 (d, 1H, J = 12.6 Hz, OCH ₂ ), 4.81 (d, 1H, J = 12.6 Hz , OCH ₂ ), 4.39 (dd, 1H, J = 9.0, 5.8 Hz, a-Phe), 3.74 (m, 1H, 2-H), 3.33 (m, 1H, β-Phe), 3.13 (m, 2H , β-Phe, 1-H), 2.90 (dd, 1H, J = 13.5, 4.5 Hz, 3- H), 2.64 (m, 1H, 1-H), 2.50 (m, 1H, 3-H), 1.51 (d, 3H, J = 6.4 Hz, 2'-H). ¹³ C NMR (75 MHz, DMSO-de _, majority rotamer): δ 169.4 (COO, CON), 155.7 (OCON), 138.3, 137.1, 136.8, 135.7, 129.2, 128.9, 128.3, 128.2, 128.1, 128.0, 128.0, 127.9, 127.7, 127.45, 126.4, 126.1 (Ar), 66.2, 65.2 (OCH _2), 63.6 (Ca- Phe), 53.6 (C1), 52.9 (C2), 50.3 (CHCI), 36.8 (C3), 34.2 ( Cp-Phe), 21.7 (C2 '). MS (ES) ⁺ : 613.29 [M + H] ⁺ .

/ V - [(2S-Benzyloxycarbonylamino-3-phenyl) prop-1 -yl] -N- (2 '? - chloropropanoyl) -L- -OBn (7c)

Simpe Rdto: 50% (from 5j). Eluent: AcOEtHexano (1: 4). HPLC: t _R = 17.39 min (gradient from 30% to 95% of A, in 20 min). Rattan ratio M, m = 5: 1. ¹ H NMR (400 MHz, DMSO-d _{6, major} rotamer): δ 7.29-6.94 (m, 20H, Ar), 5.18 (d, 1H, J = 12.5 Hz, OCH ₂ ), 5.07 (q, 1H, J = 6.3 Hz, 1'-H), 4.91 (d, 1H, J = 12.5 Hz, OCH ₂ ), 4.84 (d, 1H, J = 12.6 Hz, OCH ₂ ), 4.74 (d, 1H, J = 12.6 Hz , OCH ₂ ), 4.21 (dd, 1H, J = 10.1, 4.7 Hz, a-Phe), 3.66 (m, 1H, 2-H), 3.23 (m, 2H, β-Phe, 1-H), 3.10 (dd, 1H, J = 13.6, 10.1 Hz, β-Phe), 2.75 (dd, 1H, J = 13.5, 5.1 Hz, 3-H), 2.48 (m, 1H, 3-H), 2.22 (dd, 1H, J = 15.5, 5.9 Hz1-H), 1.42 (d, 3H, J = 6.3 Hz, 2'-H). ¹³ C NMR (75 MHz, DMSO-d _{6, major} rotamer): δ 169.2 (COO), 168.7 (CON), 155.7 (OCON), 138.1, 137.4, 136.9, 136.1, 129.5, 128.9, 128.3, 128.2, 128.1, 127.9, 127.7, 127.4, 126.4, 126.1 (Ar), 65.9, 65.2 (OCH ₂ ), 63.2 (Ca-Phe), 53.2 (C1), 53.0 (C2), 40.0 (C1 '), 37.6 (C3), 33.9 (Οβ- Phe), 20.7 (C2 '). MS (ES) ⁺ : 613.36 [M + H] ⁺ .

 W - [(2? -Benzyloxycarbonylamino-3-phenyl) prop-1-yl] -N- (2'S-chloropropanoyl) -L- -OBn (7d)

Simpe Rdto: 50% (from 5k). Eluent: AcOEtHexano (1: 4). HPLC: t _R = 16.65 min (gradient from 5% to 100% of A, in 20 min). Rattan ratio M, m = 10: 1. ¹ H NMR (400 MHz, DMSO-d _{6, major} rotamer): δ 7.31-7.09 (m, 20H, Ar), 5.07 (s, 2H, OCH ₂ ), 4.97 (q, 1H, J = 6.4 Hz, 1 '-H), 4.90 (d, 1H, J = 12.6 Hz, OCH ₂ ), 4.86 (d, 1H, J = 12.6 Hz, OCH ₂ ), 4.40 (dd, 1H, J = 7.7, 5.9 Hz, a- Phe), 3.93 (m, 1H, 2-H), 3.44 (m, 2H, β-Phe, 1-H), 3.13 (dd, 1H, J = 15.2, 8.4 Hz, 1-H), 3.00 (dd , 1H, J = 14.0, 5.9 Hz, β-Phe), 2.84 (dd, 1H, J = 13.6, 4.2 Hz, 3-H), 2.56 (m, 1H, 3-H), 1.43 (d, 3H, J = 6.3 Hz, 2'-H). ¹³ C NMR (75 MHz, DMSO-de, major rotamer): δ 169.7 (COO), 168.7 (CON), 155.7 (OCON), 138.6, 138.4, 137.1, 135.8, 129.4, 128.9, 128.3, 128.2, 128.1, 127.9 , 127.8, 127.7, 127.35, 127.3, 126.2, 126.1 (Ar), 66.1, 65.0 (OCH ₂ ), 62.2 (Ca-Phe), 53.5 (C1), 51.8 (C2), 49.7 (C1 '), 37.5 (C3 ), 35.0 (Cp-Phe), 21.3 (C2 '). MS (ES) ⁺ : 613.43 [M + H] ⁺ .

 W - [(2? -Benzyloxycarbonylamino-3-phenyl) prop-1-yl] -N- (2 '? - chloropropanoyl) -L- -OBn (7e)

Simpe. Rdto: 50% (a partir de 5k). Eluyente: AcOE Hexano (1:3). HPLC: t_R=17.23 min (gradiente de 30% a 95% de A, en 20 min). Proporción de rotámeros M,m =10:1. ¹H RMN (400 MHz, DMSO-d_6, major rotamer): δ 7.32- 7.01 (m, 20H, Ar), 5.21 (d, 1H, J=12.6 Hz, OCH₂), 4.97 (d, 1H, J=12.6 Hz, OCH₂), 4.88 (s, 2H, OCH₂), 4.54 (q, 1H, J=6.4 Hz, 1'-H), 4.35 (dd, 1H, J=9.5, 5.1 Hz, a-Phe), 3.75 (m, 1H, 2-H), 3.34 (m, 3H, β-Phe, 1-H), 3.14 (m, 1H, β- Phe), 2.66 (m, 1H, 3-H), 2.44 (dd, 1H, J=15.9, 6.4 Hz, 3-H), 1.36 (d, 3H, J=6.3 Hz, 2'-H).¹³C RMN (75 MHz, DMSO-d_6, rotámero mayoritario): δ 169.37 (COO), 168.34 (CON), 155.5 (OCON), 138.3, 137.6, 137.1, 135.9, 129.6, 129.0, 128.3, 128.2, 128.1, 128.0, 127.9, 127.7, 127.4, 126.5, 126.1 (Ar), 66.1, 65.1 (OCH₂), 62.6 (Ca-Phe), 52.9 (C1), 52.2 (C2), 49.5 (C1'), 37.1 (C3), 34.05 (Οβ-Phe), 20.7 (C2'). MS (ES)⁺: 613.29 [M+H]⁺.

Simpe Rdto: 50% (from 5k). Eluent: AcOE Hexane (1: 3). HPLC: t _R = 17.23 min (gradient from 30% to 95% of A, in 20 min). Rattan ratio M, m = 10: 1. ¹ H NMR (400 MHz, DMSO-d _6, major rotamer): δ 7.32-7.01 (m, 20H, Ar), 5.21 (d, 1H, J = 12.6 Hz, OCH ₂ ), 4.97 (d, 1H, J = 12.6 Hz, OCH ₂ ), 4.88 (s, 2H, OCH ₂ ), 4.54 (q, 1H, J = 6.4 Hz, 1'-H), 4.35 (dd, 1H, J = 9.5, 5.1 Hz, a- Phe), 3.75 (m, 1H, 2-H), 3.34 (m, 3H, β-Phe, 1-H), 3.14 (m, 1H, β-Phe), 2.66 (m, 1H, 3-H) , 2.44 (dd, 1H, J = 15.9, 6.4 Hz, 3-H), 1.36 (d, 3H, J = 6.3 Hz, 2'-H). ¹³ C NMR (75 MHz, DMSO-d _{6, major} rotamer): δ 169.37 (COO), 168.34 (CON), 155.5 (OCON), 138.3, 137.6, 137.1, 135.9, 129.6, 129.0, 128.3, 128.2, 128.1, 128.0, 127.9, 127.7, 127.4, 126.5, 126.1 (Ar), 66.1, 65.1 (OCH ₂ ), 62.6 (Ca-Phe), 52.9 (C1), 52.2 (C2), 49.5 (C1 '), 37.1 (C3) , 34.05 (Οβ-Phe), 20.7 (C2 '). MS (ES) ⁺ : 613.29 [M + H] ⁺ .

and V- 2S-dibenzylamino-3-phenyl-) prop-1-yl] -N- (2'S-chloropropanoyl) -L-Phe-OBn

Simpe Rdto: 25% (from 5m). Eluent: AcOE Hex (1: 6). Rattan ratio M / m = 2: 1. HPLC: t _R = 7.93 min (gradient from 5% to 100% of A, in 20 min). MS (ES) ⁺ : 659.19 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCI ₃ , Major Rotamer): δ 7.28-6.79 (m, 25H, Ar), 5.11 (d, 2H, J = 12.9 Hz, OCH ₂ ), 4.32 (q, 1H, J = 6.6 Hz, 1'-H), 3.62 (dd, 1H, J = 9.5, 5.7 Hz, a-Phe), 3.55 (d, 2H, J = 13.9 Hz, NCH ₂ ), 3.47 (d, 2H, J = 13.9 Hz, NCH ₂ ), 3.07 (m, 1H, 2-H), 3.31-3.16 (m, 4H, 3-H, 1-H, β-Phe), 2.90 (dd, 1H, J = 15.4, 8.4 Hz , 1-H), 2.65 (d, 2H, J = 13.2, 7.5 Hz, 3-H), 1.54 (d, 3H, J = 6.5 Hz, 2'-H). ¹³ C NMR (75 MHz, CDCI ₃ ): δ 170.2 (COO), 169.6 (CON), 139.1, 138.9, 138.0, 135.7, 129.8, 129.4, 128.8, 128.75, 128.7, 128.5, 128.3, 127.3, 126.8, 126.5 ( Ar), 67.4 (OCH ₂ ), 64.0 (a-Phe), 59.1 (C2), 53.7 (NCH ₂ ), 52.0 (C1 '), 50.3 (C1), 34.8 (C3) 34.5 (β-Phe), 21.4 (C2 '). MS (ES) ⁺ : 659.35 [M + H] ⁺ . yV - [(2S-Dibenzylamino-3-phenyl-) prop-1-yl] -N- (2 '? -chloropropanoyl) -L-Phe-OBn

Simpe Rdto: 52% (from 5m). Eluent: AcOE Hex (1: 6). Rattan ratio M / m = 7: 1. HPLC: t _R = 7.25 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ , Major Rotamer): δ 7.26-6.76 (m, 25H, Ar), 4.93 (s, 2H, OCH ₂ ), 4.58 (q, 1H, J = 6.5 Hz, 1'- H), 3.53 (dd, 1H, J = 15.9, 4.7 Hz, 1-H), 3.45 (m, 4H, NCH ₂ ), 3.09 (dd, 1H, J = 13.8, 10.1 Hz, β-Phe), 3.03 (dd, 1H, J = 13.8, 4.6 Hz, β-Phe), 3.00 (m, 1H, 2-H), 2.89 (dd, 1H, J = 10.1, 4.7 Hz, a-H), 2.68 (dd, 1H, J = 13.2, 6.6 Hz, 3-H), 2.50 (dd, 1H, J = 13.1, 8.4, 3-H), 2.04 (dd, 1H, J = 15.9, 5.7 Hz, 1-H), 1.34 (d, 3H, J = 6.4 Hz, 2'-H). ¹³ C NMR (75 MHz, CDCIs): δ 169.3 (COO), 169.2 (CON), 138.9, 137.8, 135.9, 129.9, 129.8, 128.75, 128.7, 128.5, 128.3, 127.4, 126.7, 126.6 (Ar), 67.1 ( OCH ₂ ), 64.8 (a- Phe), 62.4 (C2), 53.9 (NCH ₂ ), 52.5 (C1 '), 49.6 (C1), 35.5 (C3), 34.4 (β-Phe), 20.7 (C2') . MS (ES) ⁺ : 659.21 [M + H] ⁺ .

 / V - [(2? -Benzyloxycarbonylamino-3-phenyl) prop-1-yl] - (2'S-chloropropanoyl) -L- -OBn (7h)

Simpe Rdto: 55% (from 51). Eluent: AcOE Hexane (1: 4). HPLC: t _R = 15.50 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI3): δ 7.35-7.10 (m, 15H, Ar), 5.10 (d, 1H, J = 12.8 Hz, OCH ₂ ), 5.03 (d, 1H, J = 12.8 Hz, OCH ₂ ), 5.06 (sa, 1H, 2-NH), 5.01 (q, 1H, J = 6.3 Hz, 1'-H), 4.90 (d, 1H, J = 12.9 Hz, OCH ₂ ), 4.85 (d, 1H , J = 12.9 Hz, OCH ₂ ), 4.20 (q, 1H, J = 6.7 Hz, a-Ala), 3.97 (m, 1H, 2-H), 3.64 (dd, 1H, J = 14.9, 10.5 Hz, 1-H), 3.40 (m, 1H, 1-H), 3.36 (s, 3H, OMe), 2.83 (dd, 1H, J = 13.6, 4.0 Hz, 3-H), 2.58 (dd, 1H, J = 13.6, 10.5 Hz, 3-H), 1.40 (d, 3H, J = 6.9 Hz, 2'-H _), 1.37 (d, 3H, J = 6.3 Hz, CH ₃ ). ¹ C NMR (75 MHz, CDCI ₃ ): δ 170.6 (COO), 168.1 (CON), 155.8 (OCON), 138.3, 137.2, 136.0, 129.1, 128.2, 128.1, 127.8, 127.6, 127.2, 126.1 (Ar), 65.8, 64.8 (OCH ₂ ), 56.8 (Ca-Ala), 53.8 (C1), 51.2 (C2), 49.5 (C1 '), 37.9 (C3), 20.8 (CH ₃ ) 14.5 (C2'). MS (ES) ⁺ : 537.05 [M + H] ⁺ .

 W - [(2S-Dibenzylamino-3-phenyl) prop-1-yl] -yV- (2'S-chloropropanoyl) -L-Phe-OMe

Simpe Rdto: 49% (from 5n). Eluent: AcOEtHexano (1: 8). HPLC: t _R = 7.92 min (gradient from 50% to 95% of A in 10 min). ¹ H NMR (300 MHz, CDCI3): mixture of 5: 1 rotamers, δ major rotamer 7.31-6.84 (m, 20H, Ar), 4.43 (q, 1H, J = 6.6 Hz, 1'-H), 3.64 ( s, 3H, OCH ₃ ), 3.59 (m, 5H, a-Phe, NCH ₂ ), 3.34 (dd, 1H, J = 15.3, 3.9 Hz, 1-H), 3.23 (dd, 1H, J = 14.1, 5.8 Hz, β-Phe), 3.15 (dd, 1H,, J = 14.1, 9.4 Hz, β-Phe), 3.90 (m, 1H, 2-H), 2.99 (dd, 1H,, J = 15.3, 8.1 Hz, 1-H), 2.77 (dd, 1H,, J = 13.4, 8.6 Hz, 3-H), 2.65 (dd, 1H, J = 13.4, 6.4 Hz, 3-H), 1.56 ( d, 3H, J = 6.5 Hz, 2'-H). ¹³ C NMR (75 MHz, CDCI3): □ 170.3 (COO), 170.1 (CON), 139.07, 139.03, 137.9, 129.8, 129.3, 128.7, 128.6, 128.5, 128.4, 127.3, 126.7, 126.6 (C, Ar), 63.6 (a-Phe), 59.0 (C2), 53.6 (NCH ₂ ), 52.4 (OCH ₃ ), 51.8 (C1), 50.4 (C1 '), 34.9 (H3), 34.8 (β-Phe), 21.4 (C2 '). MS (ES) ⁺ : 584.39 (M + H ⁺ ).

W - [(2S-dibenzylamino-3-phenyl) prop-1-yl] -yV- (2'S-chloropropanoyl) -L-Phe-O ^í Bu (7j)

Simpe Rdto: 80% (from 5th). Eluent: AcOEtHexano (1: 8). HPLC: t _R = 5.61 min (gradient from 60% to 95% of A in 10 min). ¹ H NMR (400 MHz, DMSO-d ⁶ ): mixture of 12: 1 rotamers, δ major rotamer 7.30-6.93 (m, 20H, Ar), 4.09 (q, 1 H, J = 6.5 Hz, 1 '-H ), 3.64 (dd, 1 H, J = 9.5, 5.6 Hz, a-Phe), 3.56 (d, 2H, J = 13.8 Hz, NCH ₂ ), 3.45 (d, 2H, J = 13.8 Hz, NCH ₂ ) , 3.25 (dd, 1 H, J = 14.2 Hz, 1-H), 3.19 (dd, 1 H, J = 14.2, 9.6 Hz, 1-H), 3.04 (m, 3H, β-Phe, 2-H ), 2.82 (dd, 1 H, J = 13.6, 4.9, 3-H), 2.65 (dd, 1 H, J = 13.6, 9.3, 3-H), 1.54 (d, 3H, J = 6.5 Hz, 2 '- H), 1 .44 (s, 9H, CH ₃ , ¾u). ¹³ C NMR (75 MHz, CDCI ₃ ): δ 169.9 (COO), 168.8 (CON), 139.3, 139.2, 139.1, 138.6, 129.8, 129.4, 128.8, 128.7, 128.3, 127.3, 126.7, 126.4 (C, Ar) , 82.0 (C, 'Bu), 64.9 (a-Phe), 58.3 (C2), 53.7 (NCH ₂ ), 52.3 (C1), 49.9 (C1'), 35.5 (β-Phe), 34.8 (C3), 28.1 (C2 '), 21 .3 (CH ₃ , ¾u). MS (ES) ⁺ : 626.35 (M + H ⁺ ). PREPARATION OF β-LACTAMIC DERIVATIVES

 Intramolecular cyclization of chlorinated precursors, assisted by base

To a solution of the corresponding derivative / V-alkyl- / V-chloroacetyl or N-chloropropionyl (1.22 mmol, 0.764 g) in dry CH ₃ CN (3 mL), under Ar's atmosphere, BTPP (1, 83 mmol, 0.56 mL) or Cs ₂ CO ₃ (2.44 mmol, 0.793 g) and stir at room temperature. When the reaction is complete the solvent is evaporated to dryness and the resulting residue is dissolved in AcOEt: H ₂ O (1: 1) and the phases are separated. The organic extract is washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ and evaporated to dryness. The reaction crude obtained is purified on a silica gel column, using the eluent system indicated in each case.

EXAMPLE 1 4 ?, S-Benzyl-4-methoxycarbonyl-1 - [(3'S-íerc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] -2-oxoazetidine

Simpe Rdto: 56% (from 6th, B: BTPP). Eluent: AcOEt: Hexane (1: 1). HPLC: t _R = 17.22 min (gradient from 5% to 100% of A, in 20 min). HPLC (Chiral): t _R = 19.02, 22.12 min (Isocratic 9/91 (Acetone / Hexane). Proportion of diastereoisomers M, m = 80: 20. ¹ H NMR (400 MHz, CDCI ₃ , majority diastereoisomer): δ 7.36 -7.08 (m, 10H, Ph), 5.15 (sa, 3H, 3-NH, OCH ₂ ), 4.26 (m, 1 H, 3'-H), 3.71 (s, 3H, OMe), 3.26 (d, 1 H, J = 14.0 Hz, 4-CH ₂ ), 3.20 (m, 2H, 1 '-H), 3.13 (d, 1 H, J = 14.5 Hz. 4-CH ₂ ), 3.12 (d, 1 H , J = 14.7 Hz, 3-H), 2.88 (d, 1 H, J = 14.7 Hz, 3-H), 2.23 (m, 1 H, 2'-H), 1.97 (m, 1 H, 2'-H), 1 .43 (s, 9H, CH ₃ ¾u) ¹³ C NMR (100 MHz, CDCI _3):. 171 9 (COO), 166.4 (CON), 155.5 (OCON), 135.4, 134.5 , 129.7, 128.9, 128.7, 128.6, 127.6 (C Ar), 80.1 (C 'Bu), 67.4 (OCH ₂ ), 63.0 (C4), 52.8 (OMe), 52.0 (C3'), 45.7 (C3), 39.7 (C1 '), 38.7 (4-CH ₂ ), 31.0 (C2'), 28.4 (CH ₃ ¾u) .MS (ES) ⁺ : 51 1 .25 [M + H] ⁺ . Exact mass calculated for C ₂₈ H ₃₄ N ₂ O ₇ : 510.2366; found: 510.2382.

EXAMPLE 2

 4 ?, S-Benzyl-4-methoxycarbonyl-1 - [(3'S-íerc-butoxycarbonylamino-3'-methyloxycarbonyl) prop-1'-yl] -2-oxoazetidine

Simpe. Rdto: 5% (a partir de 6a, B:BTPP). Eluyente: AcOEtHexano (1 :1 ). HPLC: t_R=12.52, 12.65 min (gradiente de 5% a 100% de A, en 20 min). HPLC (Chiral): t_R= 17.17, 18.55 min (Isocratico 9/91 (Acetona/Hexano). Proporción de diastereo-isómeros M,m =86: 14. ¹H RMN (400 MHz, CDCI₃, diastereoisómero mayoritario ): δ 7.33-7.12 (m, 5H, Ph), 5.19 (sa, 1 H, 3-NH), 4.26 (m, 1 H, 3'-H), 3.76 (s, 3H, OMe), 3.74 (s, 3H, OMe), 3.15 (d, 1 H, J=13.9 Hz, 4-CH₂), 3.23 (m, 2H, 1 '-H), 3.18 (d, 1 H, J=14.0 Hz, 4-CH₂), 3.14 (d, 1 H, J=15.0 Hz, 3-H), 2.90 (d, 1 H, J=15.0 Hz, 3-H), 2.24 (m, 1 H, 2'-H), 2.02 (m, 1 H, 2'-H), 1 .45 (s, 9H, CH₃, *Bu). ¹³C RMN (100 MHz, CDCI₃): 172.0 (COO), 166.5 (CON), 155.4 (OCON), 134.6, 129.8, 128.9, 128.8, 127.8 (C Ar), 80.3 (C 'Bu), 63.1 (C4), 52.9 (OMe), 52.7 (OMe), 51 .9 (C3'), 45.8 (C3), 40.0 (4-CH₂), 38.9 (C1 '), 31 .0 (C2'), 28.5 (CH₃ ¾u).MS (ES)⁺: 435.32 [M+H]⁺. Masa exacta calculada para C₂2H₃oN₂O7: 434.20530; encontrada: 434.20662. EJEMPLO 3

Simpe Rdto: 5% (from 6th, B: BTPP). Eluent: AcOEtHexano (1: 1). HPLC: t _R = 12.52, 12.65 min (gradient from 5% to 100% of A, in 20 min). HPLC (Chiral): t _R = 17.17, 18.55 min (Isocratico 9/91 (Acetone / Hexane). Proportion of diastereo-isomers M, m = 86: 14. ¹ H NMR (400 MHz, CDCI ₃ , majority diastereoisomer): δ 7.33-7.12 (m, 5H, Ph), 5.19 (sa, 1 H, 3-NH), 4.26 (m, 1 H, 3'-H), 3.76 (s, 3H, OMe), 3.74 (s, 3H, OMe), 3.15 (d, 1 H, J = 13.9 Hz, 4-CH ₂ ), 3.23 (m, 2H, 1 '-H), 3.18 (d, 1 H, J = 14.0 Hz, 4-CH ₂ ), 3.14 (d, 1 H, J = 15.0 Hz, 3-H), 2.90 (d, 1 H, J = 15.0 Hz, 3-H), 2.24 (m, 1 H, 2'-H), 2.02 (m, 1 H, 2'-H), 1.45 (s, 9H, CH ₃ , * Bu). ¹³ C NMR (100 MHz, CDCI ₃ ): 172.0 (COO), 166.5 (CON), 155.4 (OCON), 134.6, 129.8, 128.9, 128.8, 127.8 (C Ar), 80.3 (C 'Bu), 63.1 (C4), 52.9 (OMe), 52.7 (OMe), 51 .9 (C3'), 45.8 ( C3), 40.0 (4-CH ₂ ), 38.9 (C1 '), 31 .0 (C2'), 28.5 (CH ₃ ¾u) .MS (ES) ⁺ : 435.32 [M + H] ⁺ . Exact mass calculated for C ₂ 2H ₃ oN ₂ O7: 434.20530; found: 434.20662 EXAMPLE 3

 4 ?, S-Benzyl-4-benzyloxycarbonyl-1 - [(3'S-íerc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] -2-oxoazetidine

Simpe Rdto: 4% (from 6th, B: BTPP). Eluent: AcOEtHexano (1: 1). HPLC: t _R = 17.22 min (gradient from 5% to 100% of A, in 20 min). HPLC (Chiralpak): t _R = 20.15, 22.18 min (Isocratic 9/91 (Acetone / Hexane). Proportion of diastereoisomers M, m = 53:47. ¹ H NMR (400 MHz, CDCI ₃ ): ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.35-7.02 (m, 30H, Ar), 5.17 (d, 1 H, J = 12.4 Hz, OCH _2, M), 5.16 (s, 2H, OCH _2, M), 5.14 ( s, 4H, OCH _2, m), 5.1 1 (d, 1 H, J = 12.4 Hz, OCH _2, M), 5.03 (d, 1 H, J = 6.6 Hz, 3-NH, m), 5.01 ( m, 1 H, 3-NH, M), 4.25 (m, 1 H, 3'-H, M), 4.21 (m, 1 H, 3'-H, m), 3.25 (d, 2H, J = 14.2 Hz, 4-CH _2, m, m), 3.24 (m, 2H, 1' - H, m), 3.15 (d, 1H, J = 14.8 Hz, 3-H, m), 3.14 (d, 1 H, J = 14.2 Hz, 4- CH _2, M), 3.13 (m, 3H, 1 '-H, 4-CH _2, m), 2.88 (d, 1 H, J = 14.8 Hz, 3-H, M), 2.86 (d, 1 H , J = 14.8 Hz, 3-H, m), 2.20 (m, 1 H, 2'-H, m), 2.18 (m, 1 H, 2'-H, M), 1.97 (m, 1 H, 2'-H, M), 1.92 (m, 1 H, 2'-H, m), 1.44 (s, 18H, CH ₃ ¾u, M, m). ¹³ C NMR (75 MHz, CDCI ₃ ): 172.0 (COO, M), 171 .9 (COO, m), 171.2 (COO, M, m), 166.5 (COM, M), 166.4 (CON, m), 155.6 (OCON; M), 135.5, 135.4134.9, 134.8134.5, 134.4, 129.8, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 127.7, 127.6 (Ar), 80.3 (C ¾u, M), 80.2 ( C ¾u, m), 67.9 (OCH ₂ , M), 67.8 (OCH ₂ , m), 67.5 (OCH ₂ , M), 67.4 (OCH _2, m), 63.3 (C4, M), 63.1 (C4, m), 52.1 (C3 \ M), 51 .9 (C3 \ m), 46.0 (C3, M), 45.8 (C3, m), 40.1 (C1 \ M), 39.8 (C1 ', m), 39.0 ( 4-CH ₂ , M), 38.9 (4- CH _2, m), 31 .1 (C2 ', M), 30.8 (C2 \ m), 28.5 (CH ₃ ¾u, M), 28.4 (CH ₃ ¾u, m). ¹³ C NMR (100 MHz, CDCI3): 172.0 (COO), 171.9 (COO), 171.2 (COO), 166.5 (CON), 166.4 (CON), 155.9 (OCON), 155.6 (OCON), 135.5, 135.4, 134.9 , 134.8, 134.5, 134.4, 129.8, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 127.7, 127.6 (Ar), 80.3 (C ¾u), 80.2 (C ¾u), 67.9, 67.8, 67.5, 67.4 (OCH ₂ ), 63.3 (C4), 63.1 (C4), 52.1 (C3 '), 51 .9 (C3'), 46.0 (C3), 45.8 (C3), 40.1 (C1 '), 39.8 (C1'), 39.0 ( 4- CH ₂ ), 8.9 (4-CH ₂ ), 31 .1 (C2 '), 30.8 (C2'), 28.5 (CH ₃ ¾u), 28.4 (CH ₃ ¾u). MS (ES) ⁺ : 587.43 [M + H] ⁺ . Exact mass calculated for C _{3 3} 8N 4H ₂ O _7: 586.26790; Found: 586.26869.

EXAMPLE 4

 4S-Benzyl-4-benzyloxycarbonyl-1 - [(3'S-íerc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] -2-oxoazetidine

Simpe Rdto: 29% (from 6b, B: BTPP). Semi-preparative HPLC purification (Chiral C). Eluent: Acetone: Hexane (13:87, t _R = 9.78 min). HPLC: t _R = 17.22 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.35- 7.02 (m, 15H, Ar), 5.17 (d, 1 H, J = 12.4 Hz, OCH ₂ ), 5.16 (s, 2H, OCH ₂ ), 5.1 1 (d, 1 H, J = 12.4 Hz, OCH ₂ ), 5.01 (m, 1 H, 3-NH), 4.25 (m, 1 H, 3'-H), 3.25 (d, 1 H, J = 14.2 Hz, 4 -CH2), 3.24 (m, 2H, 1 '-H), 3.15 (d, 1 H, J = 14.8 Hz, 3-H), 3.14 (d, 1 H, J = 14.2 Hz, 4-CH2), 2.88 (d, 1 H, J = 14.8 Hz, 3-H), 2.18 (m, 1 H, 2'-H), 1.97 (m, 1 H, 2'-H), 1.44 (s , 9H, CH ₃ )u). ¹³ C NMR (75 MHz, CDCI3): 172.0 (COO), 171 .2 (COO), 166.5 (CON), 155.6 (OCON), 135.5, 134.94, 134.5, 129.8, 129.0, 128.9, 128.8, 128.7, 128.5, 127.7 (C Ar), 80.3 (C ¾u), 67.9, 67.5 (OCH ₂ ), 63.3 (C4), 52.1 (C3 '), 46.0 (C3), 40.1 (C1'), 39.0 (4-CH ₂ ), 31 .1 (C2 '), 28.5 (CH ₃ ¾u). MS (ES) ⁺ : 587.46 [M + H] ⁺ . Exact mass calculated for C34H38N2O7: 586.26790; Found: 586.26869.

EXAMPLE 5

 4? -Benzyl-4-benzyloxycarbonyl-1 - [(3'S-íerc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] -2-oxoazetidine

Simpe Rdto: 15% (from 6b, B: BTPP). Semi-preparative HPLC purification (Chiral C). Eluent: Acetone: Hexane (13:87, t _R = 10.75 min). HPLC: t _R = 17.22 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI3): δ 7.35-7.03 (m, 15H, Ar), 5.14 (s, 4H, OCH ₂ ), 5.03 (d, 1 H, J = 6.6 Hz, 3-NH), 4.21 (m, 1 H, 3'-H), 3.25 (d, 1 H, J = 14.0 Hz, 4-CH ₂ ), 3.14 (d, 1 H, J = 14.8 Hz, 3-H), 3.13 (m , 3H, 1'-H, 4-CH ₂ ), 2.86 (d, 1 H, J = 14.8 Hz, 3-H), 2.20 (m, 1 H, 2'-H), 1.92 (m, 1 H, 2'-H), 1.44 (s, 9H, CH ₃ 'Bu). ¹³ C NMR (75 MHz, CDCI3): 171 .9 (COO), 171 .2 (COO), 166.4 (CON), 155.9 (OCON), 135.4, 134.8, 134.4, 129.8, 129.0, 128.9, 128.7, 128.6, 128. 5. 127.6 (Ar), 80.2 (C ¾u), 67.8, 67.4 (OCH ₂ ), 63.1 (C4), 51 .9 (C3 '), 45.8 (C3), 39.8 (C1'), 38.9 (4 -CH ₂ ), 30.8 (C2 '), 28.4 (CH ₃ ¾u). MS (ES) ⁺ : 587.46 [M + H] ⁺ .

EXAMPLE 6 4 ?, S-Benzyl-4-benzyloxycarbonyl-1 - [(3'S-íerc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] - (3?, SJ-methyl-2-oxoazetidine

Simpe Rdto: 61% (from 7th, B: BTPP). Eluent: AcOEtHexano (1: 2). HPLC: t _R = 17.58 min (gradient from 5% to 100% of A, in 20 min). Proportion of diastereoisomers M, m = 58: 42. ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.37-7.04 (m, 15H, Ar), 5.22 (s, 2H, OCH _2, M), 5.12 (s, 2H, OCH _2, m), 5.03 (d , 1 H, J = 6.6 Hz, 3-NH, M), 4.98 (d, 1 H, J = 6.6 Hz, 3-NH, m), 4.14 (m, 1 H, 3'-H), 3.51 ( d, 1 H, J = 15.1 Hz, 4-CH ₂ ), 3.45 (d, 1 H, J = 14.5 Hz, 4-CH ₂ ), 3.03 (m, 4H, 4-CH ₂ , 1'-H, 3- H), 2.24 (m, 1 H, 2'-H), 1.97 (m, 1 H, 2'-H), 1.43 (s, 9H, CH ₃ ¾u), 1 .08 ( d, 3H, J = 7.6 Hz, 3-CH3 _, M), 1.07 (d, 3H, J = 7.6 Hz, 3-CH ₃ , m). ¹³ C NMR (75 MHz, CDCI3): 172.0 (COO), 171.2 (COO), 171.1 (COO), 169.7 (CON), 169.6 (CON), 155.5 (OCON), 135.5, 135.0, 134.9, 134.8, 129.8, 129.15, 129.1, 129.00, 128.95, 128.9, 128.8, 128.6, 128.5, 128.4, 128.3, 127.7, 127.6 (Ar), 79.9 (C 'Bu), 69.0 (C4), 67.7 (C4), 67.2, 67.1 (OCH ₂ ), 54.0 (C3), 53.8 (C3), 52.1 (C3 '), 40.9 (4-CH ₂ ), 40.7 (4-CH ₂ ), 40.1 (C1'), 40.0 (C1 '), 30.8 (C2' ), 30.7 (C2 '), 28.4 (CHs' Bu), 10.4 (3-CH ₃ ), 10.3 (3-CH ₃ ). MS (ES) ⁺ : 601.52 [M + H] ⁺ . Exact masses calculated for C ₃ 5H ₄ or N ₂ O ₇ : 600.28355; Found: 600.28432. EXAMPLE 7

 4 ?, S-Methyl-4-methoxycarbonyl-1 - [(3'S-íerc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] -2-oxoazetidine

Simpe. Rdto: 25% (a partir de 6c, B:BTPP). Eluyente: AcOEtHexano (1 : 1 ). HPLC: t_R=12.64 min (gradiente de 5% a 100% de A, en 20 min). Proporción de diastereoisómeros M,m =91 :9. ¹H RMN (400 MHz, CDCI₃, diastereoisómero mayoritario ): δ 7.35 (s, 5H, Ph), 5.24 (d, 1 H, J=7.8 Hz, 3-NH), 5.17 (s, 2H, OCH₂), 4.30 (m, 1 H, 3'-H), 3.74 (s, 3H, OMe), 3.26 (t, 2H, J=7.9 Hz, 1 '-H), 3.18 (d, 1 H, J=14.8 Hz, 3-H), 2.79 (d, 1 H, J=14.8 Hz, 3-H), 2.20 (m, 1 H, 2'-H), 2.00 (m, 1 H, 2'-H), 1 .43 (s, 12H, 4-CH₃ ¾u). ¹³C RMN (75 MHz, CDCI₃): 172.8 (COO), 172.0 (COO), 166.3 (OCON), 135.4, 128.8. 128.6, 128.5 (Ar), 80.3 (C 'Bu), 67.4 (OCH₂), 59.0 (C4), 58.9 (C3'), 52.8 (OMe), 48.9 (C3), 37.9 (C1 '), 30.9 (C2'), 28.4 (CH₃ ¾u), 20.5 (4-CH₃). MS (ES)⁺: 435.32 [M+H]⁺.

Simpe Rdto: 25% (from 6c, B: BTPP). Eluent: AcOEtHexano (1: 1). HPLC: t _R = 12.64 min (gradient of 5% to 100% A in 20 min). Proportion of diastereoisomers M, m = 91: 9. ¹ H NMR (400 MHz, CDCI ₃ , major diastereoisomer): δ 7.35 (s, 5H, Ph), 5.24 (d, 1 H, J = 7.8 Hz, 3-NH), 5.17 (s, 2H, OCH ₂ ) , 4.30 (m, 1 H, 3'-H), 3.74 (s, 3H, OMe), 3.26 (t, 2H, J = 7.9 Hz, 1'-H), 3.18 (d, 1 H, J = 14.8 Hz, 3-H), 2.79 (d, 1 H, J = 14.8 Hz, 3-H), 2.20 (m, 1 H, 2'-H), 2.00 (m, 1 H, 2'-H), 1.43 (s, 12H, 4-CH ₃ ¾u). ¹³ C NMR (75 MHz, CDCI ₃ ): 172.8 (COO), 172.0 (COO), 166.3 (OCON), 135.4, 128.8. 128.6, 128.5 (Ar), 80.3 (C 'Bu), 67.4 (OCH ₂ ), 59.0 (C4), 58.9 (C3'), 52.8 (OMe), 48.9 (C3), 37.9 (C1 '), 30.9 (C2 '), 28.4 (CH ₃ ¾u), 20.5 (4-CH ₃ ). MS (ES) ⁺ : 435.32 [M + H] ⁺ .

EXAMPLE 8

 4 ?, S-Benzyl-4-methoxycarbonyl-1 - [(3'S-benzyloxycarbonylamino-3'-íerc- butoxycarbonyl) prop-1'-yl] -2-oxoazetidine

Simpe Rdto: 52% (from 6d, B: Cs ₂ CO ₃ ). Eluent: AcOEtHexano (1: 1). HPLC: t _R = 9.06, 9.31 min (gradient from 5% to 100% of A, in 20 min). HPLC (Chiral): t _R = 22.22, 26.12 min (Isochratic 9/91 (Acetone / Hexane). Proportion of diastereoisomers M, m = 90: 10. ¹ H NMR (400 MHz, CDCI ₃ , majority diastereoisomer): δ 7.37 -7.1 1 (m, 10H, Ph), 5.44 (brs, 1 H, 3-NH), 5.13 (d, 1 H, J = 12.0 Hz, OCH ₂ ), 5.09 (d, 1 H, J = 12.0 Hz , OCH ₂ ), 4.20 (m, 1 H, 3'-H), 3.74 (s, 3H, OMe), 3.22 (m, 3H, 1'-H, 4-CH ₂ ), 3.16 (d, 1 H , J = 12.0 Hz, 4-CH ₂ ), 3.14 (d, 1 H, J = 14.8 Hz, 3-H), 2.89 (d, 1 H, J = 14.8 Hz, 3-H), 2.23 (m, 1 H, 2'-H), 2.04 (m, 1 H, 2'-H), 1 .46 (s, 9H, CHs' Bu). ¹ ^ NMR (75 MHz, CDCI ₃ ): 171 .9 ( COO), 170.8 (COO), 166.9 (CON), 156.0 (OCON), 136.4, 129.75, 129.7, 128.9, 128.6, 128.3, 128.2, 127.7 (Ar), 82.6 (C ¾u), 67.0 (OCH ₂ ), 63.1 (C4), 52.9 (OMe, C3 '), 45.8 (C3), 39.9 (4-CH _2), 38.7 (C1'), 31.1 (C2 '), 28.1 (CH ₃ * Bu). MS (ES) ⁺ : 51 1 .55 [M + Na] ⁺ . Exact mass calculated for C28H34N2O7: 510.23660; Found: 510.23824.

EXAMPLE 9

4?, S-Methyl-4-methoxycarbonyl-1 - [(3'S-benzyloxycarbonylamino-3'-íerc- butoxycarbonyl) prop-1'-yl] -2-oxoazetidine

Simpe Rdto: 31% (from 6e, B: Cs ₂ CO ₃ ). Eluent: AcOE Hexane (2: 1). HPLC: t _R = 7.84 min (gradient from 5% to 100% of A, in 20 min). Proportion of diastereoisomers M, m = 69:31. ¹ H NMR (400 MHz, CDCI3, major diastereoisomer): δ 7.35 (s, 5H, Ph), 5.48 (d, 1 H, J = 7.9 Hz, 3-NH), 5.29 (s, 2H, OCH ₂ ), 4.24 (m, 1 H, 3'-H), 3.76 (s, 3H, OMe), 3.50 (m, 1 H, 1'-H), 3.26 (m, 1 H, 1'-H), 3.18 ( d, 1 H, J = 14.9 Hz, 3-H), 2.78 (d, 1 H, J = 14.9 Hz, 3-H), 2.16 (m, 1 H, 2'-H), 1.99 (m , 1H, 2'-H), 1 .46 (s, 12H, CH ₃ ¾u, 4-CH _3). ¹³ C NMR (75 MHz, CDCI3): 172.7 (COO), 170.7 (COO), 166.1 (CON), 156.0 (CON), 136.4, 128, 128.7, 128.25, 128.2 (C, Ar), 82.7 (C, ' Bu), 67.1 (OCH ₂ ), 59.0 (C4), 52.9 (OMe, C3 '), 48.9 (C3), 37.9 (C1'), 31 .3 (C2 '), 28.1 (CH ₃ * Bu), 20.8 (4-CH ₃ ). MS (ES) ⁺ : 457.44 [M + Na] ⁺ . Exact mass calculated for C30H30N2O7: 434.20530; Found: 434.20506.

EXAMPLE 10

4 ?, S-Benzyl-1 - [4'S- (yV-Benzyloxycarbonyl-yV-methyl) amino-4'-methoxycarbonyl] but-1-yl] -4-íerc-butoxycarbonyl-2-oxoazetidine

Simpe Rdto: 77% (from 6f, B: BTPP). Eluent: AcOEtHexano (1: 1). HPLC: t _R = 16.26 min (gradient from 5% to 100% of A, in 20 min). HPLC (Chiral): t _R = 16.82, 17.83 min (Isocratico 10/90 (Acetone / Hexane). Rotamer ratio M, m = 60: 40. ¹ H NMR (400 MHz, CDCI _3, majority rotamer): δ 7.36 -7.13 (m, 10H, Ph, Z), 5.15 (s, 2H, OCH ₂ ), 4.79 (dd, 1 H, J = 10.1, 4.4 Hz, 4'- H), 3.71 (s, 3H, OMe) , 3.29 (d, 1 H, J = 15.1 Hz, 4-CH ₂ ), 3.25-3.10 (m, 4H, 1 '-H, 3-H, 4-CH ₂ ), 3.06 (d, 1 H, J = 14.0 Hz, 3-H), 2.85 (s, 3H, NMe), 1 .94-1 .71 (m, 4H, 2'-H, 3'-H), 1.41 (s, 9H, CH ₃ ¾u) ¹³ C NMR (75 MHz, CDCl3):. 171.8 (COO), 170.3 (COO), 166.9 (CON), 157.1 (OCON), 136.7, 135.1, 129.8, 128.7, 128.6, 128.1, 128.0, 127.9, 127.5 (Ar), 83.0 (C 'Bu), 67.6 (OCH ₂ ), 63.4 (C4), 58.4 (C4'), 52.3 (OMe), 45.8 (C3), 41 .4 (C1 '), 40.0 (4 -CH ₂ ), 30.7 (NMe), 27.9 (CH ₃ ¾u), 26.6 (C3 '), 25.5 (C2'). MS (ES) ⁺ : 539.67 [M + H] ⁺ . Exact mass calculated for C30H38N2O7: 538.26790 ; found: 538.26910.

EXAMPLE 1 1

 4?, S-Benzyl-1 - [4'S - [(W-methyl) amino-4'-methoxycarbonyl] but-1'-yl] -4-íerc- butoxy carbon and I -2-oxoazeti dyne

A solution of the corresponding compound of Example 10 (0.15 mmol, 82 mg) in MeOH (15 mL) is hydrogenated at room temperature and 15 psi pressure for 4 h, using Pd-C (16 mg, 20%) as catalyst. . Once the catalyst has been filtered off, the solvent is evaporated to dryness, the Reaction crude was purified by column chromatography using as eluents MeOH: DCM in proportion (1: 10), obtaining a 48 mg (78%) syrup of the product described below. HPLC: t _R = 8.87 min (gradient from 5% to 100% of A, in 20 min). Proportion of diastereoisomers M, m = 73: 27. ¹ H NMR (400 MHz, CDCI ₃ , major diastereoisomer): δ 7.31 - 7.17 (m, 5H, Ph), 3.74 (s, 3H, OMe), 3.32 (d, 1 H, J = 13.9 Hz, 4-CH ₂ ), 3.21 (m, 3H, 1'-H, 4'-H), 3.16 (d, 1 H, J = 14.8 Hz, 3-H), 3.10 (d, 1 H, J = 13.9 Hz, 4 -CH ₂ ), 2.86 (d, 1 H, J = 14.8 Hz, 3-H), 2.39 (s, 3H, NMe), 1.69 (m, 4H, 3'-H, 2'-H), 1.42 (s, 9H, CH ₃ 'Bu). ¹³ C NMR (75 MHz, CDCI ₃ , majority diastereoisomer): 174.8 (COO), 169.8 (COO), 166.4 (CON), 134.6, 129.3, 128.2, 127.0 (Ar), 82.5 (C 'Bu), 62.9 (C4 ), 62.3 (C4 '), 51.4 (OMe), 45.3 (C3), 41 .2 (C1'), 39.7 (4-CH ₂ ), 34.3 (NMe), 30.3 (C3 '), 27.5 (CH ₃ * Bu), 24.7 (C2 '). MS (ES) ⁺ : 405.49 [M + Na] ⁺ . Exact mass calculated for C22H ₃₂ N ₂ O5: 404.231 12; Found: 404.23245. EXAMPLE 12

 4 ?, S-Benzyl-4-benzyloxycarbonyl-1 - [(4'S-íerc-butoxycarbonylamino-4'-benzyloxycarbonyl) but-1'-yl] -2-oxoazetidine

Sirupe Rdto: 71% (from 6g). Proportion of diastereoisomers, M / m = 5: 1. Eluent: AcOE Hexane (1: 4). HPLC: t _R = 17.18 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ , major diastereoisomer): δ 7.40-6.90 (m, 15H, Ar), 5.17-4.95 (m, 5H, OCH ₂ , 4-NH), 4.22 (m, 1 H, 4 '-H), 3.24 (d, 1 H, J = 14.0 Hz, 4-CH ₂ ), 3.23 (d, 1 H, J = 14.0 Hz, 4-CH ₂ ), 3.1 1 (d, 1 H, J = 14.8 Hz, 3-H), 3.04 (m, 2H, 1'-H), 2.82 (d, 1 H, J = 14.8 Hz, 3-H), 1.60 (m, 2H, 3'-H ), 1 .52 (m, 2H, 2'-H), 1 .36 (s, 9H, ¾u). ¹³ C NMR (CDCI _3): δ 1725, 171 1 (COO), 166.4 (C2), 155.5 (OCON), 135.5, 134.9, 134.6, 129.7, 128.9, 128.8, 128.7, 128.7, 128.5, 128.4, 127.6 ( Ar), 80.0 (C ¾u), 67.7, 67.2 (OCH ₂ ), 63.0 (C4), 53.4 (C4 '), 45.8 (C3), 41 .7 (C3), 40.1 (4-CH ₂ ), 30.3 (C3'), 28.5 (CH ₃ * Bu), 24.6 (C2 '). MS (ES) ⁺ : 623 [M + Na] ⁺ .

EXAMPLE 13

4?, S-Benzyl-N - [(4'S-benzyloxycarbonylamino-4'-methoxycarbonyl) but-1'-yl] -4- ferc-butoxycarbonyl-2-oxoazetidine

Simpe Rdto: 78% (from 6h). HPLC-MS: t _R = 5.51 min (gradient from 50% to 95% of A, in 15 min). HPLC (chiral): t _R = 19.85, 22.39 min (Socratic: 1 1/89: acetone / hexane), proportion of diastereoisomers (4R, 4'S) :( 4S, 4'S), M: m = 5: 1. ¹ H NMR (300 MHz, CDCI ₃ ): Major isomer δ 7.35-7.07 (m, 10H, Ar), 5.46 (d, 1 H, J = 7.8, 4-NH), 5.04 (s, 2H, OCH ₂ ) , 4.30 (m, 1 H, 4'-H), 3.67 (m, 3H, OCH ₃ ), 3.22 (d, 1 H, J = 14.0, 4-CH ₂ ), 3.13-3.01 (m, 3H, 1 '-H, 4-CH ₂ , 3-H), 3.80 (d, 1 H, J = 14.7, 3-H), 1 .80-1 .56 (m, 4H, 2'-H, 3'- H), 1.35 (s, 9H, CH ₃ ¾u). ¹³ C NMR (100 MHz, CDCI3): Major isomer 172.7 (COO), 170.4 (COO), 166.9 (C2), 156.1 (OCON), 136.4, 135.0, 129.8, 128.8, 128.6, 128.3, 128.2, 127.5 (Ar) , 83.1 (C 'Bu), 67.1 (OCH ₂ ), 63.5 (C4), 53.7 (C4'), 52.6 (OMe), 45.9 (C3), 41 .5 (C1 '), 40.0 (4-CH ₂ ) , 29.8 (C3 '), 28.0 (' Bu), 24.6 (C2 '). MS (ES) ⁺ : 525.24 [M + H] ⁺ .

EXAMPLE 14

 4'S-N - [(4'-Benzyloxycarbonylamino-4'-methoxycarbonyl) but-1'-yl] -4?, S-íerc- buti I oxi carbon i I -4-meti I -2-oxoazeti dina

Simpe. Rdto: 58% (a partir de 6i). HPLC-MS: t_R=3,06 min (gradiente de 50% a 95% de A, en 15 min). Proporción de diastereoisómeros (4R,4'S):(4S,4'R), M:m = 2:1.¹H RMN (300 MHz, CDCI₃): isómero mayoritario δ 7.37-7.31 (m, 5H, Ph), 5.54 (d, 1H, J= 7.1 Hz, 4-NH), 5.11 (s, 2H, OCH₂), 4.37 (m, 1H, 4'-H), 3.75 (s, 3H, OMe), 3.20 (m, 2H,1'-H), 3.14 (d, 1H, J=14.5 Hz, 3-H), 2.76 (d, 1H, J=14.5 Hz, 3-H), 1.90 (m, 1H, 3'-H), 1.80-1.63 (m, 3H, 3'-H, 2'-H), 1.59 (s, 3H, 4-CH₃), 1.45 (s, 9H, CH₃ ¾u). MS (ES)⁺: 449.16 [M+H]⁺, 471.46 [M+Na]⁺ .

Simpe Rdto: 58% (from 6i). HPLC-MS: t _R = 3.06 min (gradient from 50% to 95% of A, in 15 min). Proportion of diastereoisomers (4R, 4'S) :( 4S, 4'R), M: m = 2: 1. ¹ H NMR (300 MHz, CDCI ₃ ): Major isomer δ 7.37-7.31 (m, 5H, Ph), 5.54 (d, 1H, J = 7.1 Hz, 4-NH), 5.11 (s, 2H, OCH ₂ ) , 4.37 (m, 1H, 4'-H), 3.75 (s, 3H, OMe), 3.20 (m, 2H, 1'-H), 3.14 (d, 1H, J = 14.5 Hz, 3-H), 2.76 (d, 1H, J = 14.5 Hz, 3-H), 1.90 (m, 1H, 3'-H), 1.80-1.63 (m, 3H, 3'-H, 2'-H), 1.59 (s , 3H, 4-CH ₃ ), 1.45 (s, 9H, CH ₃ ¾u). MS (ES) ^+: 449.16 [M + H] ^+, 471.46 [M + Na] ^+.

EXAMPLE 15

4 ?, S-Benzyl-4-benzyloxycarbonyl-1 - [(2'S-benzyloxycarbonylamino-3'-phenyl) prop-1'-yl] -2-oxoazetidine

Simpe Rdto: 11% (from 6j, B: Cs ₂ CO ₃ ). Eluent: AcOEt: Hexane (1: 3). HPLC: t _R = 20.74 min (30% gradient to 95% A, in 30 min). Proportion of diastereoisomers (4S, 2'S) / (4R, 2'S) M / m = 83: 17. ¹ H NMR (500 MHz, CDCI _{3, major} diastereoisomer): δ 7.34-6.98 (m, 20H, Ar), 5.48 (d, 1H, J = 8.5 Hz, 2-NH), 5.15 (d, 1H, J = 12.0 Hz, OCH ₂ ), 5.09 (d, 1H, J = 12.0 Hz, OCH ₂ ), 5.06 (d, 1H, J = 12.5 Hz, OCH ₂ ), 5.02 (d, 1H, J = 12.5 Hz, OCH ₂ ), 4.15 (m, 1H, 2'-H), 3.37 (dd, 1H, J = 14.5, 8.1 Hz, 1'-H), 3.27 (d, 1H, J = 14.0 Hz, 4-CH ₂ ), 3.22 (d, 1H, J = 14.9 Hz, 3-H), 3.18 (dd, 1H, J = 14.5, 4.3 Hz, 1'-H), 2.98 (d, 1H, J = 14.0 Hz, 4- CH ₂ ), 2.90 (d, 1H, J = 14.9 Hz, 3-H), 2.85 (dd, 1H, J = 14.1, 7.6 Hz, 3'-H), 2.76 (dd, 1H, J = 14.1, 6.8 Hz, 3'-H). ¹³ C NMR (125 MHz, CDCI _{3, major} diastereoisomer): δ 170.8 (COO), 167.4 (C2), 156.1 (OCON), 137.4, 134.9, 134.2, 129.7, 129.4, 128.9, 128.8, 128.7, 128.6, 128.1, 128.0, 127.6, 126.8 (Ar), 67.9, 67.8 (OCH ₂ ), 63.2 (C4), 51.6 (C2 '), 45.4 (C3), 45.2 (C1'), 39.7 (4-CH ₂ ), 39.1 (C3 '). MS (ES) ⁺ : 563.46 [M + H] ⁺ . Exact mass calculated for C ₃₅ H ₃₄ N ₂ O ₅ : 562.24677; Found: 562.24804. EXAMPLE 16

 4 ?, S-Benzyl-4-benzyloxycarbonyl-1 - [(2 '? -Benzyloxycarbonylamino-3'- phenyl) prop-1'-yl] -2-oxoazetidine

Sirupe Rdto: 1 1% (from 6k, B: Cs ₂ CO ₃ ). Eluent: AcOE Hexane (1: 3). HPLC: t _R = 20.70 min (30% gradient to 95% of A, in 30 min). Proportion of diastereoisomers (4S, 2'S) / (4R, 2'S) M / m = 91: 9. ¹ H NMR (400 MHz, CDCI _{3, major} diastereoisomer): δ 7.34-6.99 (m, 20H, Ar), 5.54 (d, 1 H, J = 8.5 Hz, 2-NH), 5.14 (d, 1 H, J = 12.0 Hz, OCH ₂ ), 5.06 (s, 2H, OCH ₂ ), 5.04 (d, 1 H, J = 12.0 Hz, OCH ₂ ), 4.16 (m, 1 H, 2'-H), 3.29 ( d, 1 H, J = 14.0 Hz, 4-CH ₂ ), 3.22 (m, 3H, 3- H, 1 '-H), 3.15 (d, 1 H, J = 14.0 Hz, 4-CH ₂ ), 2.89 (d, 1 H, J = 14.9 Hz, 3-H), 2.78 (dd, 1 H, J = 14.0, 5.5 Hz, 3'-H), 2.72 (dd, 1 H, J = 14.0, 6.8 Hz , 3'-H). ¹³ C NMR (75 MHz, CDCI _3, majority diastereoisomer): δ 170.9 (COO), 167.1 (C2), 156.2 (OCON), 137.2, 134.8, 134.5, 129.6, 129.4, 128.9, 128.8, 128.6, 128.5, 128.1, 127.5, 126.7 (Ar), 67.8, 66.6 (OCH ₂ ), 63.3 (C4), 51 .5 (C2 '), 45.8 (C3), 45.7 (C1'), 40.3 (4-CH ₂ ), 39.1 (C3 '). MS (ES) ⁺ : 563.46 [M + H] ⁺ . Exact mass calculated for C ₃ 5H ₃ 4N ₂ O ₅ : 562.24677; Found: 562.24834. EXAMPLE 17

4S-Benzyl-4-benzyloxycarbonyl-3S-methyl-1 - [(2'S-benzyloxycarbonylamino-3'-phenyl) prop-1'-yl] -2-oxoazetidine

Simpe Rdto: 65% (from 7b, B: BTPP). Eluent: AcOEtHexano (1: 2). HPLC: t _R = 16.20 min (gradient from 30% to 95% of A, in 20 min). Proportion of isomers M (3S, 4S, 2'S): m (3R, 4R, 2'S) = 97: 3. ¹ H NMR (400 MHz, CDCI ₃ , majority isomer): δ 7.35-6.96 (m, 20H, Ar), 5.75 (d, 1 H, J = 7.4 Hz, 2-NH), 5.24 (d, 1 H, J = 12.0 Hz, OCH ₂ ), 5.14 (d, 1 H, J = 12.0 Hz, OCH ₂ ), 5.05 (s, 2H, OCH ₂ ), 4.17 (m, 1 H, 2'-H), 3.43 ( d, 1 H, J = 14.5 Hz, 4-CH ₂ ), 3.23 (dd, 1 H, J = 14.5, 8.0, 1 '-H), 3.1 1 (q, 1 H, J = 7.6 Hz, 3- H), 3.05 (d, 1 H, J = 14.5 Hz, 4-CH ₂ ), 3.00 (dd, 1 H, J = 14.5, 4.0 Hz, 1 '-H), 2.86 (dd, 1 H, J = 14.0, 8.0 Hz, 3'-H), 2.72 (dd, 1 H, J = 14.0, 7.0 Hz, 3'-H), 1.08 (d, 3H, J = 7.5 Hz, 3-CH ₃ ). ¹³ C NMR (75 MHz, CDCIs _, majority isomer): δ 171.01 (COO), 170.57 (C2), 156.03 (OCON), 137.8, 137.0, 134.9, 134.8, 129.7, 129.2, 128.9, 128.85, 128.8, 128.7, 128.5 , 128.45, 127.9, 127.8, 127.5, 126.5 (Ar), 68.68 (C4), 67.67, 66.27 (OCH ₂ ), 53.84 (C3), 51.89 (C2 '), 46.06 (C1'), 40.69 (4-CH ₂ ). 39.10 (C3 '), 10.60 (3-CH ₃ ). MS (ES) ⁺ : 577.3 [M + H] ⁺ .

EXAMPLE 18

 4? -Benzyl-4-benzyloxycarbonyl-3? -Methyl-1 - [(2'S-benzyloxycarbonylamino-3'- phenyl] prop-1'-yl] -2-oxoazetidine

Simpe. Rdto: 10% (a partir de 7c, B: BTPP). Eluyente: AcOEtHexano (1:3). HPLC: t_R=16.36 min (gradiente de 30% a 95% de A, en 20 min). Proporción de isómeros M(3R,4R,2'S):m(3S,4S,2'S)= 85:15. ¹H RMN (400 MHz, CDCI₃, isómero mayoritario): δ 7.37-6.99 (m, 20H, Ar), 5.83 (d, 1H, J=8.1 Hz, 2-NH), 5.27 (d, 1H, J=12.0 Hz, OCH₂), 5.17 (d, 1H, J=12.0 Hz, OCH₂), 5.05 (s, 2H, OCH₂), 4.07 (m, 1H, 2'-H), 3.56 (d, 1H, J=14.5 Hz, 4-CH₂), 3.43 (q, 1H, J=7.6 Hz, 3-H), 3.03 (d, 1H, J=14.5 Hz, 4-CH₂), 2.99 (m, 2H, 1'-H), 2.71 (dd, 1H, J=13.5, 7.4 Hz, 3'-H), 2.64 (dd, 1H, J=13.4, 6.6 Hz, 3'-H), 1.08 (d, 3H, J=7.5 Hz, 3-CH₃). ¹³C RMN (100 MHz, CDCI₃, isómero mayoritario): δ 171.3 (COO), 170.3 (C2), 156.3 (OCON), 137.5, 137.1, 135.1, 134.8, 129.8, 129.5, 129.45, 129.4, 129.2, 129.1, 128.95, 128.9, 128.85, 128.8, 128.6, 128.55, 128.5, 128.0, 127.6, 126.6 (Ar), 69.1 (C4), 67.9, 66.4 (OCH₂), 54.2 (C3), 51.6 (C2'), 47.1 (C1'), 41.3 (4-CH₂).39.4 (C3'), 10.6 (3-CH₃). MS (ES)⁺: 577.3 [M+H]⁺. EJEMPLO 19

Simpe Rdto: 10% (from 7c, B: BTPP). Eluent: AcOEtHexano (1: 3). HPLC: t _R = 16.36 min (gradient from 30% to 95% of A, in 20 min). Proportion of isomers M (3R, 4R, 2'S): m (3S, 4S, 2'S) = 85:15. ¹ H NMR (400 MHz, CDCI ₃ , majority isomer): δ 7.37-6.99 (m, 20H, Ar), 5.83 (d, 1H, J = 8.1 Hz, 2-NH), 5.27 (d, 1H, J = 12.0 Hz, OCH ₂ ), 5.17 (d, 1H, J = 12.0 Hz, OCH ₂ ), 5.05 (s, 2H, OCH ₂ ), 4.07 (m, 1H, 2'-H), 3.56 (d, 1H, J = 14.5 Hz, 4-CH ₂ ), 3.43 (q, 1H, J = 7.6 Hz, 3-H), 3.03 (d, 1H, J = 14.5 Hz, 4-CH ₂ ), 2.99 (m, 2H, 1'-H), 2.71 (dd, 1H, J = 13.5, 7.4 Hz, 3'-H), 2.64 (dd, 1H, J = 13.4, 6.6 Hz, 3'-H), 1.08 (d, 3H, J = 7.5 Hz, 3-CH ₃ ). ¹³ C NMR (100 MHz, CDCI ₃ , majority isomer): δ 171.3 (COO), 170.3 (C2), 156.3 (OCON), 137.5, 137.1, 135.1, 134.8, 129.8, 129.5, 129.45, 129.4, 129.2, 129.1, 128.95, 128.9, 128.85, 128.8, 128.6, 128.55, 128.5, 128.0, 127.6, 126.6 (Ar), 69.1 (C4), 67.9, 66.4 (OCH ₂ ), 54.2 (C3), 51.6 (C2 '), 47.1 (C1 '), 41.3 (4-CH ₂ ) .39.4 (C3'), 10.6 (3-CH ₃ ). MS (ES) ⁺ : 577.3 [M + H] ⁺ . EXAMPLE 19

 4? -Benzyl-4-benzyloxycarbonyl-3? -Methyl-1 - [(2 '? - benzyloxycarbonylamino - ^^ phenyl) prop-1'-yl] -2-oxoazetidine

Simpe Rdto: 44% (from 7e, B: BTPP). Eluent: AcOEtHexano (1: 3). HPLC: t _R = 16.20 min (gradient from 30% to 95% of A, in 20 min). Proportion of isomers M (3R, 4R, 2'R): m (3S, 4S, 2'R) = 77: 23. ¹ H NMR (400 MHz, CDCI _{3, major} diastereoisomer): δ 7.35-6.96 (m, 20H, Ar), 5.75 (d, 1H, J = 7.4 Hz, 2-NH), 5.24 (d, 1H, J = 12.0 Hz, OCH ₂ ), 5.14 (d, 1H, J = 12.0 Hz, OCH ₂ ), 5.05 (s, 2H, OCH ₂ ), 4.17 (m, 1H, 2'-H), 3.43 (d, 1H, J = 14.5 Hz, 4-CH ₂ ), 3.23 (dd, 1H, J = 14.5, 8.0, 1'-H), 3.11 (q, 1H, J = 7.6 Hz, 3-H), 3.05 (d, 1H , J = 14.5 Hz, 4-CH ₂ ), 3.00 (dd, 1H, J = 14.5, 4.0 Hz, 1'-H), 2.86 (dd, 1H, J = 14.0, 8.0 Hz, 3'-H), 2.72 (dd, 1H, J = 14.0, 7.0 Hz, 3'-H), 1.08 (d, 3H, J = 7.5 Hz, 3-CH ₃ ). ¹³ C NMR (75 MHz, CDCI3 _{, major} diastereoisomer): δ 171.01 (COO), 170.57 (C2), 156.03 (OCON), 137.8, 137.0, 134.9, 134.8, 129.7, 129.2, 128.9, 128.85, 128.8, 128.7, 128.5, 128.45, 127.9, 127.8, 127.5, 126.5 (Ar), 68.68 (C4), 67.67, 66.27 (OCH ₂ ), 53.84 (C3), 51 .89 (C2 '), 46.06 (C1'), 40.69 (4-CH ₂ ). 39.10 (C3 '), 10.60 (3-CH ₃ ). MS (ES) ⁺ : 577.18 [M + H] ⁺ . Exact mass calculated for C36H36N2O5: 576.26242; Found: 576.26364.

EXAMPLE 20

 4S-4-Benzyl-4-benzyloxycarbonyl-3S-methyl-1 - [(2 '? -Benzyloxycarbonylamino-' -phenyl) prop-1 '-yl] -2-oxoazetidine

Simpe Rdto: 39% (from 7d, B: BTPP). Eluent: AcOEtHexano (1: 3). HPLC: t _R = 16.36 min (gradient from 30% to 95% of A, in 20 min). ¹ H NMR (400 MHz, CDCI3): δ 7.37-6.99 (m, 20H, Ar), 5.83 (d, 1 H, J = 8.1 Hz, 2-NH), 5.27 (d, 1 H, J = 12.0 Hz , OCH ₂ ), 5.17 (d, 1 H, J = 12.0 Hz, OCH ₂ ), 5.05 (s, 2H, OCH ₂ ), 4.07 (m, 1 H, 2'-H), 3.56 (d, 1 H , J = 14.5 Hz, 4-CH ₂ ), 3.43 (q, 1 H, J = 7.6 Hz, 3-H), 3.03 (d, 1 H, J = 14.5 Hz, 4-CH2), 2.99 (m, 2H, 1'-H), 2.71 (dd, 1 H, J = 13.5, 7.4 Hz, 3'-H), 2.64 (dd, 1 H, J = 13.4, 6.6 Hz, 3'-H), 1. 08 (d, 3H, J = 7.5 Hz, 3-CH ₃ ). ¹³ C NMR (100 MHz, CDCI3): δ 171.3 (COO), 170.3 (C2), 156.3 (OCON), 137.5, 137.1, 135.1, 134.8, 129.8, 129.5, 129.45, 129.4, 129.2, 129.1, 128.95, 128.9, 128.85, 128.8, 128.6, 128.55, 128.5, 128.0, 127.6, 126.6 (Ar), 69.1 (C4), 67.9, 66.4 (OCH ₂ ), 54.2 (C3), 51 .6 (C2 '), 47.1 (C1') , 41 .3 (4-CH ₂ ). 39.4 (C3 '), 10.6 (3-CH ₃ ). MS (ES) ⁺ : 577.25 [M + H] ⁺ . EXAMPLE 21

4S-Benzyloxycarbonyl-3S, 4S-dimethyl-1 - [(2 '? -Benzyloxycarbonylamino-3'- phenyl) prop-1' -yl] -2-oxoazetidine

Simpe Rdto: 30% (from 7h, B: BTPP). Eluent: AcOE Hexane (1: 2). HPLC: t _R = 17.49 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCIs): δ 7.35- 7.15 (m, 15H, Ar), 5.36 (d, 1H, J = 8.4 Hz, 2-NH), 5.18 (d, 1H, J = 12.1 Hz, OCH ₂ ), 5.12 (d, 1H, J = 12.1 Hz, OCH ₂ ), 5.03 (s, 2H, OCH ₂ ), 4.10 (m, 1H, 2'-H), 3.32 (dd, 1H, J = 14.6, 8.1 Hz, 1'-H), 3.22 (dd, 1H, J = 14.6, 5.1 Hz, 1'-H), 2.96 (q, 1H, J = 7.5 Hz, 3-H), 2.87 (dd, 1H, J = 13.8, 6.2 Hz, 3'-H), 2.81 (m, 1H, 3'-H), 1.58 (s, 3H, CH ₃ ), 1.06 (d, 3H, J = 7.5 Hz, CH ₃ ). ¹³ C NMR (75 MHz, CDCI3): δ 171.5 (COO), 170.0 (C2), 156.2 (OCON), 137.3, 136.8, 135.1, 129.5, 128.85, 128.8, 128.7, 128.5, 128.1, 126.7 (Ar), 67.5 , 66.6 (OCH ₂ ), 64.8 (C4), 56.1 (C3), 51.7 (C2 '), 44.6 (C1'), 39.2 (C3 '), 20.8 (4-CH3), 10.4 (CH ₃ ). MS (ES) ⁺ : 501.37 [M + H] ⁺ . Exact mass calculated for C30H32N2O5: 500.23112; Found: 500.23117. EXAMPLE 22

 4 ?, S-Benzyl-4-benzyloxycarbonyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop-1'-in oxoazetidine

Simpe Rdto: 10% (from 6m). Eluent: AcOE Hex (1: 4). Proportion of diastereoisomers, M / m = 5: 1. HPLC: t _R = 7.55 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI3): Major isomer δ 7.40-6.73 (m, 25H, Ar), 5.03 (d, 1H, J = 12.0 Hz, OCH ₂ ), 4.93 (d, 1H, J = 12.0 Hz, OCH ₂ ), 3.69 (d, 2H, J = 13.8 Hz, NCH ₂ ), 3.52 (d, 2H, J = 13.8 Hz, NCH ₂ ), 3.45 (m, 2H, 1'-H), 3.28 (d, 1 H, J = 14.8 Hz, 3-H), 3.21 (m, 1 H, 2'-H), 3.00 (d, 1 H, J = 13.5 Hz, 4- CH ₂ ), 2.92 ( dd, 1 H, J = 14.2, 8.1 Hz, 3'-H), 2.82 (d, 1 H, J = 14.8 Hz 3-H), 2.81 (m, 1 H, 3'-H), 2.38 (d , 1 H, J = 13.4 Hz, 4-CH ₂ ). ¹³ C NMR (75 MHz, CDCI ₃ ): δ 170.0 (COO), 167.1 (C2), 140.2, 139.6, 135.0, 134.7, 129.55, 129.5, 129.1, 128.9, 128.8, 128.3, 127.4, 127.0, 126.1 (Ar) , 67.6 (OCH ₂ ), 63.9 (C4), 58.5 (C2 '), 53.4 (NCH ₂ ), 45.3 (C3), 41 .6 (C1'), 40.6 (4-CH ₂ ), 36.5 (C3 ') . MS (ES) ⁺ : 608.88 [M + H] ⁺ .

EXAMPLE 23

 4S-Benzyl -] - (4-benzyloxycarbonyl-3S-methyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop-1'-yl] -2-oxoazetidine

Simpe Rdto: 25% (from 7f). Eluent: AcOEt: Hex (1: 4). HPLC: t _R = 7.19 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.46-6.89 (m, 25H, Ar), 5.23 (d, 1 H, J = 1 1 .9 Hz, OCH ₂ ), 5.01 (d, 1 H, J = 1 1 .9 Hz, OCH ₂ ), 3.64 (d, 2H, J = 13.9 Hz, NCH ₂ ), 3.49 (m, 1 H, 2'-H), 3.44 (d, 2H, J = 13.9 Hz, NCH ₂ ), 3.41 (dd, 1 H, J = 13.9, 4.0 Hz, 1 '-H), 3.22 (dd, 1 H, J = 13.8, 9.8 Hz, V-H), 3.10 (q, 1 H, J = 7.5 Hz, 3-H), 2.99 (d, 1 H, J = 14.2 Hz, 4-CH ₂ ), 2.93 (d, 1 H, J = 14.2 Hz, 4-CH ₂ ), 2.86 (dd, 1 H, J = 14.4, 5.0 Hz, 3'-H), 2.75 (dd, 1 H, J = 14.4, 9.1 Hz, 3'-H), 1.07 (d, 3H, J = 7.5 Hz, CH ₃ ). ¹³ C NMR (75 MHz, CDCI ₃ ): δ 170.8 (COO), 179.1 (C2), 140.4, 139.7, 135.2, 135.0, 130.0, 129.6, 129.2, 128.9, 128.8, 128.7, 128.6, 128.2, 128.1, 127.3, 126.9, 125.9 (Ar), 68.4 (OCH ₂ ), 67.2 (C4), 57.9 (C2 '), 57.8 (C3), 53.3 (NCH ₂ ), 43.0 (C1'), 40.9 (4-CH ₂ ), 36.2 (C3 '), 10.6 (CH ₃ ). MS (ES) ⁺ : 623.01 [M + H] ⁺ .

EXAMPLE 24

 4 /? - Benzyl-4-benzyloxycarbonyl-3 /? - methyl ^

1 '-yl] -2-oxoazetidine

Simpe Rdto: 57% (from 7g). Eluent: AcOE Hex (1: 4). HPLC: t _R = 7.29 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.37-6.93 (m, 25H, Ar), 5.06 (d, 1 H, J = 12.0 Hz, OCH ₂ ), 4.84 (d, 1 H, J = 12.0 Hz , OCH ₂ ), 3.56 (d, 2H, J = 13.8 Hz, NCH ₂ ), 3.47 (d, 2H, J = 13.9 Hz, NCH ₂ ), 3.46 (m, 1 H, 3-H), 3.37 (m , 1 H, 2'-H), 3.14 (dd, 1 H, J = 14.2, 8.1 Hz, 1'-H), 3.08 (m, 2H, 3'-H, 4-CH ₂ ), 2.81 (m , 3H, 4-CH ₂ , 1'-H, 3'-H), 1 .00 (d, 3H, J = 7.5 Hz, CH ₃ ). ¹³ C NMR (75 MHz, CDCI ₃ ): δ 170.9 (COO), 169.9 (C2), 140.3, 140.0, 135.5, 135.1, 129.9, 129.7, 129.1, 129.0, 128.8, 128.75, 128.7, 128.2, 127.5, 126.9, 126.0 (Ar), 68.6 (C4), 67.3 (OCH ₂ ), 58.7 (C2 '), 54.4 (C3), 53.2 (NCH ₂ ), 42.1 (C1'), 40.6 (4-CH ₂ ), 35.9 (C3 '), 10.5 (CH ₃ ). MS (ES) ⁺ : 622.95 [M + H] ⁺ .

EXAMPLE 25

4 ?, S-Benzyl-4-methoxycarbonyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop-1'-yl] -2- oxoazetidine

Sirupe Rdto: 71% (from 6n). Eluent: AcOE Hexane (1: 6). HPLC: t _R = 6.49, 8.00 min (gradient from 30% to 95% of A in 10 min). Proportion of diastereoisomers, M: m = 1 .8: 1. ¹ H NMR (400 MHz, CDCI ₃ , major diastereoisomer): δ 7.34-6.89 (m, 20H, Ar), 3.72 (m, 4H, NCH ₂ ), 3.62 (m, 1 H, 1'-H), 3.45 (s, 3H, OCH ₃ ), 3.43 (dd, 1 H, J = 14.3, 8.3 Hz, 1'-H), 3.27 (m, 1 H, 2'-H), 3.25 (d, 1 H, J = 14.8 Hz, 3-H), 3.02 (d, 1 H, J = 13.4 Hz, 4-CH ₂ ), 2.82 (d, 1 H, J = 14.9 Hz, 3-H), 3.02 (m, 1 H, 3'-H), 2.80 (m, 1 H, 3'-H), 2.45 (d, 1 H, J = 13.4 Hz, 4-CH ₂ ). ^{1 a} C NMR (75 MHz, CDCI ₃ ): δ 170.6 (COO), 166.9 (CON), 140.2, 140.1, 139.9, 134.6, 129.5, 129.4, 129.2, 128.8, 128.7, 128.5, 128.3, 127.5, 127.0, 127.1 (Ar), 63.7 (C4), 58.8 (NCH ₂ ), 53.4 (C2 '), 52.3 (OCH ₃ ), 45.1 (C3), 41 .4 (CT), 40.6 (4- CH ₂ ), 36.1 (C3 '). MS (ES) ⁺ : 533.27 (M + H ⁺ ).

EXAMPLE 26

 4?, S-Benzyl-4-íerc-butoxycarbonyl-1 - [(2'S-dibenzylamino-3-phenyl) prop-1'-¡n -oxoazetidine

Simpe Rdto: 41% (from 6th). Eluent: AcOEtHexano (1: 6). HPLC: t _R = 7.28, 8.27 min (gradient from 50% to 95% of A in 10 min). Proportion of diastereoisomers, M: m = 1 .8: 1. ¹ H NMR (400 MHz, CDCI ₃ , major diastereoisomer): δ 7.39-6.89 (m, 20H, Ar), 3.81 (d, 2H, J = 13.4, NCH ₂ ), 3.57 (m, 2H, 1'-H ), 3.51 (d, 4H, J = 13.4, NCH ₂ ), 3.30 (m, 1 H, 2'-H), 3.24 (d, 1 H, J = 14.8, 3-H), 3.09 (d, 1 H, J = 13.6, 4-CH _2), 2.94 (m, 2H, 3'-H), 2.82 (d, 1H, J = 14.8, 3-H), 2.40 (d, 1H, J = 13.5 Hz, 4-CH ₂ ), 1.39 (s, 9H, CH ₃ , ¾u). ¹³ C NMR (75 MHz, CDCI ₃ ): δ 169.3 (COO), 167.4 (CON), 140.0, 139.6, 135.2, 129.6, 129.5, 128.8, 128.5, 128.3, 128.2, 127.3, 127.1, 126.1 (Ar), 83.0 (C 'Bu), 64.2 (C4), 58.6 (C2'), 53.5 (NCH ₂ ), 45.6 (C3), 41.8 (CT), 40.9 (4-CH ₂ ), 36.8 (C3 '), 28.1 (CH ₃ , ¾u). MS (ES) ⁺ : 576.40 (M + H ⁺ ).

EXAMPLE 27

4S-Benzyl-3S-methyl-4-methoxycarbonyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop-1'-yl] -2-oxoazetidine

Simpe Rdto: 51% (from 7i). Eluent: AcOEtHexano (1: 8). HPLC: t _R = 8.1 1 min (gradient of 15% to 95% of A in 10 min). ¹ H NMR (400 MHz, CDCIs): δ 7.30-7.02 (m, 20H, Ar), 3.73 (d, 2H, J = 14.2 Hz, NCH ₂ ), 3.69 (d, 2H, J = 14.2 Hz, NCH ₂ ), 3.59 (dd, 1 H, J = 13.7, 5.1 Hz, 1'-H), 3.51 (m, 4H, 2'-H, OCH3), 3.19 (dd, 1 H, J = 13.7, 7.6 Hz, 1 '-H), 3.10 (q, 1 H, J = 7.5 Hz, 3-H), 3.04 (d, 2H, J = 13.6 Hz, 4-CH2), 2.99 (d, 2H, J = 13.6 Hz, 4-CH ₂ ), 2.97 (dd, 1 H, J = 14.1, 7.7 Hz, 3'-H), 2.81 (dd, 1 H, J = 14.1, 6.2 Hz, 3'-H), 1 .14 ( d, 3H, J = 7.5 Hz, 3-CH ₃ ). ¹³ C NMR (75 MHz, CDCI3): δ 171.4 (COO), 169.9 (CON), 140.3, 139.9, 135.1, 130.0, 129.6, 128.8, 128.7, 128.2, 127.4, 126.9, 126.0 (Ar), 68.6 (C4) , 58.7 (C2 '), 53.5 (NCH ₂ ), 53.2 (C3), 51 .9 (OCH ₃ ), 42.7 (C1'), 40.6 (4-CH ₂ ), 36.0 (C3 '), 10.5 (3- CH ₃ ). MS (ES) ⁺ : 548.34 (M + H ⁺ ).

EXAMPLE 28

4S-Benzyl-4-íerc-butoxycarbonyl-3S-methyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop-1'-yl] -2-oxoazetidine

Simpe Rdto: 77% (from 7j). Eluent: AcOEt: Hexane (1: 8). HPLC: t _R = 2.33 min (gradient from 50% to 95% of A in 5 min). ¹ H NMR (400 MHz, CDCI3): δ 7.31 -7.04 (m, 20H, Ar), 3.76 (d, 2H, J = 13.9 Hz, NCH ₂ ), 3.56 (m, 4H, NCH ₂ , 1 '-H , 2'-H), 3.42 (m, 1 H, 1'-H), 3.14 (q, 1 H, J = 7.5 Hz, 3-H), 2.95 (m, 4H, 3'-H, 4- CH ₂ ), 1 .46 (s, 9H, CH ₃ ¾u), 1 .19 (d, 3H, J = 7.5 Hz, 3-CH ₃ ). ¹³ C NMR (75 MHz, CDCI3): δ 170.2 (COO), 169.7 (CON), 140.2, 139.6, 135.6, 129.8, 129.5, 128.6, 128.3, 128.1, 127.9, 127.0, 126.8, 125.7 (Ar), 82.8 (C ¾u), 68.3 (C4), 58.0 (C2 '), 53.3 (NCH ₂ ), 53.1 (C3), 42.7 (C1') , 41 .3 (4-CH ₂ ), 36.4 (C3 '), 28.0 (ClVBu), 10.7 (3-CH ₃ ). MS (ES) ⁺ : 590.20 (M + H ⁺ ). Hydrogenolysis debenzylation of the β-lactam of Example 28.

16 (0.17 mmol, 0.10 g) is dissolved in 20 mL of methanol and the solution is cooled to 0 ° C. A 20% proportion of Pd (OH) ₂ (0.02 g) is added to the mixture, together with HCI (1 eq). The mixture is hydrogenated at 40 psi and at room temperature for 22h to try to completely debencylate. The catalyst is filtered and the solvent is evaporated under reduced pressure. Wash with AcOEt and a 10% solution of NaHC0 ₃ . The organic phase is dried over Na ₂ S0 ₄ and evaporated under reduced pressure. The residue is purified using silica gel column chromatography. EXAMPLE 29

 4S-Benzyl-4-íerc-butoxycarbonyl-3S-methyl-1 - [(2'S-benzylamino-3'-phenyl) prop- '-yl] -2-oxoazetidine

Simpe Rdto: 29% (from the compound of Example 28). Eluent: AcOEt: Hexane (1: 2). HPLC: t _R = 3.62 min (gradient of 15% to 95% of A in 5 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.32-7.12 (m, 15H, Ar), 3.79 (d, 1 H, J = 13.1 Hz, NCH ₂ ), 3.73 (d, 1 H, J = 13.1 Hz , NCH ₂ ), 3.43 (d, 1 H, J = 14.5 Hz, 4-CH ₂ ), 3.29 (m, 1 H, 2'-H), 3.16 (m, 1 H, 1 '-H), 3.09 (m, 3H, 3-H, 1'-H, 4-CH ₂ ), 2.80 (dd, 1 H, J = 13.9, 6.4 Hz, 3'-H), 2.73 (dd, 1 H, J = 13.9 , 6.7 Hz, 3'-H), 1.39 (s, 9H, CH ₃ , ¾u), 1.21 (d, 3H, J = 7.5 Hz, 3-CH ₃ ). ¹³ C NMR (75 MHz, CDCI ₃ ): δ 170.5 (COO), 170.1 (CON), 140.6, 138.9, 135.6, 130.0, 129.5, 128.6, 128.5, 128.4, 128.3, 127.3, 126.9, 126.3 (C, Ar) , 83.2 (C 'Bu), 68.5 (C4), 57.6 (C2'), 53.4 (C3), 51 .4 (NCH ₂ ), 47.5 (C1 '), 41.0 (4-CH ₂ ), 39.5 (C3' ), 28.1 (CH ₃ , ¾u), 10.7 (3-CH ₃ ). MS (ES) ⁺ : 499.07 (M + H ⁺ ). EXAMPLE 30

 4S-Benzyl-4-íerc-butoxycarbonyl-3S-methyl-1 - [(2'S-amino-3'-phenyl) prop-1 -yl] -2- oxoazetidine

Simpe Rdto: 29% (from the compound of Example 28). Eluent: MeOH: AcOEt (1: 3). HPLC: t _R = 3.22 min (gradient of 15% to 95% of A in 5 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.29-7.09 (m, 10H, Ar), 3.47 (d, 1 H, J = 14.6 Hz, 4-CH ₂ ), 3.42 (m, 1 H, 2 ' -H), 3.10 (d, 1 H, J = 14.6 Hz, 4-CH ₂ ), 3.08 (q, 1 H, J = 7.6 Hz, 3-H), 3.02 (m, 2H, 1 '-H) , 2.66 (dd, 1 H, J = 13.5, 5.7 Hz, 3'-H), 2.53 (dd, 1 H, J = 13.5, 8.1 Hz, 3'-H), 1.47 (s, 9H, CH ₃ ¾u), 1 .21 (d, 3H, J = 7.5 Hz, 3-CH ₃ ). ¹³ C NMR (75 MHz, CDCI3): δ 170.5 (COO), 170.4 (CON), 138.7, 135.5, 130.1, 129.4, 128.7, 128.6, 127.5, 126.5 (Ar), 83.4 (C 'Bu), 68.6 (C4 ), 53.6 (C3), 51 .5 (C2 '), 50.1 (C1'), 42.1 (C3 '), 40.7 (4-CH ₂ ), 28.3 (CH ₃ , ¾u), 10.8 (3-CH ₃ ) . MS (ES) ⁺ : 409.09 (M + H ⁺ ).

EXAMPLE 31

 4S-Benzyl-4-íerc-butoxycarbonyl-3S-methyl-1 - [2'S-benzyloxycarbonylamino-3'-phenyl) prop-1'-yl] -2-oxoazetidine

The compound of Example 30 (0.19 mmol, 0.08 g) is dissolved in anhydrous dichloromethane and TEA (0.19 mmol, 0.02 g) is added. The solution is cooled to 0 ° C and propylene oxide (2.90 mmol, 0.17 g) is added, followed by benzyl chloroformate (0.39 mmol, 0.02 g). The reaction advances to room temperature for 1 h 40min. The solvent is evaporated under reduced pressure, the residue is dissolved in AcOEt and washed with water and a saturated NaCl solution. The organic phase is dried over Na ₂ S0 ₄ and evaporated under reduced pressure. The residue is purified using silica gel column chromatography. Simpe Rdto: 69%. Eluent: Hexane (1: 4). HPLC: t _R = 9.05 min (gradient from 30% to 95% of A in 10 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.36- 7.04 (m, 15H, Ar), 6.00 (d, 1 H, J = 8.3 Hz, NH), 4.98 (s, 2H, OCH ₂ ), 4.1 1 (m, 1 H, 2'-H), 3.35 (d, 1 H, J = 14.5 Hz, 4-CH ₂ ), 3.16 (dd, 1 H, J = 14.5, 6.9 Hz, 1 '-H ), 3.07 (m, 2H, 1 '-H, 3-H), 2.99 (d, 1 H, J = 14.5 Hz, 4-CH ₂ ), 2.87 (dd, 1 H, J = 13.9, 7.7 Hz, 3'-H), 2.75 (dd, 1 H, J = 14.1, 6.9 Hz, 3'-H), 1.40 (s, 9H, CH ₃ ¾u), 1.15 (d, 3H, J = 7.5 Hz, 3-CH ₃ ). ¹³ C NMR (75 MHz, CDCI3): δ 170.9 (COO), 170.4 (CON), 156.1 (NCOO), 138.0, 137.0, 135.2, 129.9, 129.4, 128.5, 128.4, 127.9, 127.5, 126.5 (Ar), 83.7 (C 'Bu), 68.6 (C4), 66.3 (OCH ₂ ), 53.5 (C3), 51 .8 (C2'), 46.6 (C1 '), 40.7 (4-CH ₂ ), 38.9 (C3'), 28.2 (CH ₃ ¾u), 10.8 (3-CH ₃ ). MS (ES) ⁺ : 543.16 (M + H ⁺ ).

EXAMPLE 32

 4S-Benzyl-4-íerc-butoxycarbonyl-3S-methyl-1 - [(2'S-íerc-butoxycarbonylamino- -phenyl) prop-1 '-yl] -4-oxoazetidine

Di-ferc-butyl dicarbonate (0.08 mmol, 0.02 g) is added to a solution of the compound of Example 30 (0.05 mmol, 0.02 g) in anhydrous dichloromethane. The reaction mixture is allowed to stir for 24 hours at room temperature, evaporated under reduced pressure and purified by silica gel flash column chromatography. Simpe Rdto: 38%. Eluent: AcOE Hexane (1: 4). HPLC: t _R = 9.31 min (50% to 95% gradient of A in 10 min). ¹ H NMR (300 MHz, CDCI3): δ 7.28-7.10 (m, 10H, Ar), 5.62 (d, 1 H, J = 7.7 Hz, NH), 4.13 (m, 1 H, 2'-H), 3.38 (d, 1 H, J = 14.3 Hz, 4-CH ₂ ), 3.15 (m, 5H, 3-H, 1'-H, 4-CH ₂ ), 2.90 (m, 1 H, 3'-H ), 2.80 (dd, 1 H, J = 13.9, 6.7 Hz, 3'-H), 1.47 (s, 9H, CH ₃ O'Bu), 1.36 (s, 9H, 3-CH ₃ , Boc), 1.21 (d, 3H, J = 7.5 Hz, 3-CH ₃ ). ¹³ C NMR (75 MHz, CDCI ₃ ): δ 170.8 (COO), 170.4 (CON), 155.6 (NCOO), 138.3, 135.3, 130.0, 129.5, 128.7, 128.5, 127.5, 126.4 (Ar), 83.5 (C, O¾u), 79.0 (C, Boc), 68.6 (C4), 53.3 (C3), 51.1 (C2 '), 46.6 (C1'), 40.6 (4-CH ₂ ), 39.0 (C3 '), 28.5 (CH ₃ , O¾u), 28.3 (CH ₃ , Boc), 10.8 (3-CH ₃ ). MS (ES) ⁺ : 509.36 (M + H ⁺ ).

Synthesis of β-lactams dicarboxylate

 A solution of the corresponding substituted 4-benzyloxycarbonyl derivative (0.2 mmol) in MeOH (17 mL) is hydrogenated at room temperature and 15 psi pressure for 7 h, using Pd-C (10%) as catalyst. Once the catalyst has been filtered off, the solvent is evaporated to dryness.

EXAMPLE 33

4 ?, S-Benzyl-4-carboxy-1 - [3'S-tert-butoxycarbonylamino-3'-carboxy) prop-1'- -2-oxoazetidine

Simpe Rdto: 99% (from the compound of Example 3). Proportion of diastereoisomers, M / m = 6: 1. HPLC: t _R = 9.17 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ , major diastereoisomer): δ 9.40 (s, 2H, OH), 7.38-7.06 (m, 5H, Ph), 5.68 (d, 1 H, J = 8.5 Hz, NH), 4.24 (m, 1 H, 3'-H), 3.54-2.73 (m, 6H, 1 '-H, 3-H, 4-CH ₂ ), 2.17 (m, 2H, 2'-H), 1. 43 (s, 9H, ¾u). ¹³ C NMR (CDCI ₃ ): δ 175.7, 174.6 (COO), 168.3 (C2), 156.3 (OCON), 134.1, 130.0, 128.9, 127.7, (Ar), 80.8 (C ¾u), 63.4 (C4), 51 .8 (C3 '), 44.8 (C3), 38.8 (Cr, 4-CH ₂ ), 30.6 (C2'), 28.4 (CH ₃ ¾u). MS (ES) ⁺ : 407.20 [M + H] ⁺ .

EXAMPLE 34 4 ?, S-Benzyl-1 - [4'S-tert-butoxycarbonylamino-4'-carboxy) but-1'-yl] -4-carboxy-oxoazetidine

Simpe Rdto: 74% (from the compound of Example 12). Proportion of diastereoisomers, M / m = 3: 2. HPLC: t _R = 9.46 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (300 MHz, CDCI ₃ , Major Diastereoisomer): δ 10.09 (s, 2H, OH), 7.24-7.07 (m, 5H, Ar), 5.41 (d, 1 H, J = 8.1 Hz, NH), 4.18 (m, 1 H, 4'-H), 3.50-2.62 (m, 6H, 1 '-H, 3-H, 4-CH ₂ ), 1 .88-1 .56 (m, 4H, 3' -H, 2'-H), 1.36 (s, 9H, ¾u). ¹³ C NMR (CDCI ₃ , Major Diastereoisomer): δ 176.2, 174.5 (COO), 168.1 (C2), 156.1 (OCON), 134.6, 129.9, 128.8, 127.5 (Ar), 80.6 (C 'Bu), 63.1 (C4 ), 53.1 (C4 '), 45.1 (C3), 41.9 (C1'), 38.9 (4-CH ₂ ), 29.9 (C3 '), 28.4 (ClVBu), 24.0 (C2'). MS (ES) ⁺ : 421 .26 [M + H] ⁺ .

Synthesis of β-lactam amide

Method A. A solution of the corresponding substituted 4-benzyloxycarbonyl derivative (0.2 mmol) in MeOH (17 ml_) is added 20% by weight of Pd-C and hydrogenated at room temperature and 30 psi for 3h. The corresponding carboxylated derivative (0.143 mmol) is then dissolved in dry CH2CI2 (4 ml_) and the desired amine (0.286 mmol), PyBOP (benzotriazol-1-i! -N-oxy hexafluorophosphate is added consecutively -tris (pirro! idin) phosphonium) (0.286 mmol, 149 mg) and ASD (0.286 mmol, 40 µΙ_). After stirring for 24 hours at room temperature, the solvent is evaporated to dryness. The crude obtained is dissolved in AcOEt and washed successively with 10% citric acid solution, 10% NaHCO ₃ solution, H ₂ O and saturated NaCl solution. The organic phase is dried over Na ₂ SO ₄ and evaporated, the resulting residue being purified by silica gel column chromatography using the eluent system indicated in each case. Method B. To a solution of the corresponding substituted carboxy derivative (0.155 mmol) in dry CH2CI2 (2 ml_) or anhydrous DMF (2 ml_), the desired amine (0.62 mmol), PyBOP (0, is added consecutively , 62 mmol) and TEA (0.62 mmol). After stirring for 24 hours at room temperature, the solvent is evaporated to dryness. The crude obtained is dissolved in AcOEt and washed with 0.1 N HCI solution. The aqueous solution is basified with 1 M NaOH and extracted with AcOEt. The organic phase is washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ and evaporated, the resulting residue being purified by silica gel column chromatography, using the eluent system indicated in each case.

EXAMPLE 35

 4S-Benzyl-4 - [(N-benzyl) carbamoyl] -1 - [(3'S-íerc-butoxycarbonylamino-3 '- [(N-benzyl) carbamoyl] prop-1'-yl] -2-oxoazetidine

Simpe Rdto: 80% (from the compound of Example 33, Method A). Eluent: AcOEt: Hexane (2: 1). HPLC: t _R = 13.79 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI3): δ 7.62 (sa, 1 H, NHCO), 7.31-7.12 (m, 15H, Ar), 6.1 1 (sa, 1 H, NHCO), 5.33 (sa, 1 H, NHCO), 4.44 (m, 2H, NCH ₂ ), 4.40 (dd, 1 H, J = 14.4, 5.7 Hz, NCH ₂ ), 4.30 (dd, 1 H, J = 14.4, 5.7 Hz, NCH ₂ Ph), 4.23 (m, 1 H, 3'-H), 3.47 (m, 1 H, 1'-H), 3.39 (d, 1 H, J = 14.0 Hz, 4-CH ₂ ), 3.32 (m, 2H, 1 '-H, 4-CH ₂ ), 3.04 (d, 1 H, J = 14.6 Hz, 3-H), 2.95 (d, 1 H, J = 14.6 Hz, 3-H), 2.05 (m, 1 H, 2'-H), 1.94 (m, 1 H, 2'-H), 1.42 (s, 9H, CHs' Bu). ¹³ C NMR (75 MHz, CDCI3): 171 .5 (CON), 170.8 (CON), 167.4 (C2), 155.5 (OCON), 138.1, 137.4, 129.8, 128.95, 128.9, 128.8, 128.3, 127.95, 127.9, 127.6 (Ar), 81 .0 (C ¾u), 64.2 (C4), 52.4 (C3 '), 46.4 (C3), 44.0, 43.7 (NHCH ₂ ), 40.6 (C1'), 39.3 (4-CD _D ) , 29.9 (C2 '), 28.5 (CH ₃ ¾u). MS (ES) ⁺ : 585.55 [M + H] ⁺ . Exact mass calculated for C34H40N4O5: 584.29987; Found: 584.30012.

EXAMPLE 36

4?, S-Benzyl-1 - [4'S-tert-butoxycarbonylamino-4 '- [(N-benzyl) carbamoyl] but-1' - -4 - [(N -ben ci I) carbamoi I] -2-oxoazeti dyne

Simpe Rdto: 27% (from the compound of Example 34, Method B). Eluent: AcOE Hex (4: 1). Proportion of diastereoisomers, M / m = 3: 2. HPLC: t _R = 13.80 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI3, Major Diastereoisomer): δ 7.27-6.88 (m, 15H, Ar), 5.95 (m, 1 H, CONH), 5.32 (m, 1 H, CONH), 4.52-4.06 (m , 5H, NCH ₂ , 4'-NH), 3.58 (m, 1 H, 4'-H), 3.51 -2.86 (m, 6H, 1'-H, 3-H, 4-CH ₂ ), 1. 91 -1 .62 (m, 4H, 3'-H, 2'-H), 1 .35 (s, 9H, CH ₃ ¾u). ¹³ C NMR (75 MHz, CDCI ₃ , Major Diastereoisomer): δ 172.3, 171.0 (CONH), 167.2 (C2), 156.1 (OCON), 138.3, 137.3, 135.0, 129.9, 129.8, 128.9, 128.8, 128.7, 128.1, 128.0, 127.7, 127.5, (Ar), 80.0 (C 'Bu), 63.8 (C4), 52.5 (C4'), 46.2 (C3), 43.9, 43.5 (NHCH ₂ ), 41 .1 (C1 '), 39.6 (4-CH ₂ ), 30.9 (C3 '), 28.5 (CH ₃ ¾u), 24.6 (C2'). MS (ES) ⁺ : 599.43 [M + H] ⁺ . EXAMPLE 37

4S-4-Benzyl-4 - [(N-benzyl) carbamoyl] -3S-methyl-1 - [3'S-íerc- butoxycarbonylamino-3 '- [(N-benzyl) carbamoyl] prop-1' -yl] -2 -oxoazetidine

Simpe Rdto: 55% (from the compound of Example 6, Method A). Eluent: Acetone: DCM (1:25). HPLC: t _R = 14.18 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 8.32 (m, 1 H, NHCO), 8.20 (m, 1 H, NHCO), 7.45-7.19 (m, 15H, Ar), 5.99 (d, 1 H, J = 6.6 Hz, 3'-NH), 4.53 (m, 5H, NCH ₂ , 3'-H), 3.69 (d, 1 H, J = 14.9 Hz, 4-CH ₂ ), 3.35 (m, 2H, 1 '-H, 4-CH ₂ ), 3.10 (m, 1 H, 1' -H), 3.04 (q, 1 H, J = 7.5 Hz, 3-H), 2.30 (m, 1 H, 2 ' -H), 1.94 (m, 1 H, 2'-H), 1.39 (s, 9H, CH ₃ 'Bu), 1.01 (d, 3H, J = 7.5 Hz, 3-CH ₃ ). ¹³ C NMR (75 MHz, CDCI ₃ ): 173.2 (CON), 171.0 (CON), 170.0 (CON), 156.5 (OCON), 138.9, 138.2, 135.7, 130.2, 128.9, 128.7, 128.4, 128.2, 127.7, 127.4 , 127.3, 127.1 (Ar), 80.2 (C 'Bu), 69.1 (C4), 53.5 (C3), 51 .9 (C3'), 43.8, 43.6 (NCH ₂ ), 41 .4 (C1 '), 38.6 (4-CH ₂ ), 34.1 (C2 '), 28.4 (CH ₃ ¾u), 9.6 (CH ₃ ). MS (ES) ⁺ : 599.31 [M + H] ⁺ . Exact mass calculated for C ₃ 5H ₄₂ N ₄ O5: 598.31552; Found: 598.31608. EXAMPLE 38

 4? -4-Benzyl-4 - [(N-benzyl) carbamoyl] -3? -Methyl-1 - [3'S-íerc- butoxycarbonylamino-3 '- [(N-benzyl) carbamoyl] prop-1'-yl] -2-oxoazetidine

Simpe Rdto: 37% (from the compound of Example 6, Method A). Eluent: Acetone: DCM (1:15). HPLC: t _R = 14.40 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.96 (sa, 1 H, NHCO), 7.30-7.20 (m, 15H, Ar), 6.81 (sa, 1 H, NHCO), 5.17 (d, 1 H, J = 6.6 Hz, 3'-NH), 4.58 (dd, 1 H, J = 14.9, 6.1 Hz, NCH ₂ ), 4.35 (m, 3H, J = 14.9, 6.1 Hz, NCH ₂ ), 4.14 (m, 1 H, 3'-H), 3.76 (d, 1 H, J = 14.7 Hz, 4-CH ₂ ), 3.1 1 ( m, 4H, 1'-H, 4-CH ₂ , 3-H), 1 .84 (m, 2H, 2'-H), 1.40 (s, 9H, CH ₃ ¾u), 1 .10 (d, 3H, J = 7.5 Hz, CH ₃ ). ³ C NMR (75 MHz, CDCI3): 171 .9 (CON), 170.0 (CON), 155.5 (OCON), 138.0, 136.0, 130.2, 129.9, 128.9, 128.8, 128.7, 128.4, 128.3, 127.8, 127.6, 127.4 (Ar), 78.8 (C ¾u), 69.7 (C4), 54.6 (C3), 52.7 (C3 '), 44.0, 43.6 (NCH ₂ ), 40.7 (4-CH ₂ ), 40.1 (C1'), 32.1 ( C2 '), 28.4 (CH ₃ ¾u), 10.2 (3-CH ₃ ). MS (ES) ⁺ : 599.31 [M + H] ⁺ . Exact mass calculated for C35H4 ₂ N ₄ O ₅ : 598.31552; Found: 598.31608.

EXAMPLE 39

 4S-Benzyl-4- [N - [(pyridin-4 "-yl) methyl] carbamoyl-1 - [(3'S-íerc- butoxycarbonylamino-3 '- [N - [(pyridin-4' '- yl) methyl] carbamoyl] prop-1 '-yl] -2- oxoazetidine

(19a) Simpe. Rdto: 37% (from the compound of Example 33, Method B). Eluent: CH ₂ CI ₂ : MeOH (9: 1). HPL: t _R = 1.67 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.65 (t, 1 H, J = 5.9 Hz, CONH), 8.46 (t, 1 H, J = 5.9 Hz, CONH), 8.43 and 7.31-7.04 ( m, 14H, Ar, 3'-NH), 4.36-4.22 (m, 4H, NCH ₂ ), 3.94 (m, 2H, 3'-H), 3.42 (d, 1 H, J = 13.7 Hz, 4 -CH ₂ ), 3.30-3.18 (m, 2H, 1 '-H), 3.13 (d, 1 H, J = 13.7 Hz, 4-CH ₂ ), 3.12 (d, 1 H, J = 14.7 Hz, 4 -CH ₂ ), 2.89 (d, 1 H, J = 14.7 Hz, 4-CH ₂ ), 2.07 (m, 1 H, 2'-H), 1.88 (m, 1 H, 2'-H) , 1.39 (s, 9H, CHs' Bu). ¹³ C NMR (75 Mz, DMSO-d ₆ ): δ 173.1, 170.1 (CONH), 167.0 (C2), 156.3 (OCON), 149.8, 149.7, 149.4, 148.9, 135.6, 130.5, 129.0, 127.8, 122.9, 122.6 (Ar), 79.5 (C ¾u), 63.9 (C4), 53.6 (C3), 45.1 (C3 '), 42.2, 41 .7 (NCH ₂ ), 39.5 (Cr, 4-CH ₂ ), 30.9 (C2' ), 28.7 (CH ₃ 'Bu). MS (ES) ⁺ : 587.40 [M + H] ⁺ . EXAMPLE 40

 4? -Benzyl-4- [N - [(pyridin-4 "-yl) methyl] carbamoyl] -1 - [3'S-íerc- butoxycarbonylamino-3 '- [N - [(pyridin-4' '- yl) methyl ] carbamoyl] prop-1 '-yl] -2- oxoazetidine

(19b) Simpe. Rdto: 20% (from the compound of Example 33, Method B). Eluent: CH ₂ CI ₂ : 10% MeOH. HPLC: t _R = 1.67 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 8.46 and 7.30-6.97 (m, 13H, Ar), 7.76 (m, 1 H, CONH), 7.10 (m, 1 H, CONH), 5.43 (d, 2H , J = 7.9 Hz, 3'-NH), 4.48-4.21 (m, 4H, NCH ₂ ), 3.57-3.17 (m, 7H, 1'-H, 3'-H, 3-H, 4-CH ₂ ), 1 .50 (m, 2H, 2'-H), 1 .41 (s, 9H, * Bu). ¹³ C NMR (CDCI ₃ ): δ 172.2, 171 .3 (CONH), 167.5 (C2), 155.7 (OCON), 149.9, 149.8, 147.5, 146.9, 135.2, 129.8, 129.0, 127.7, 122.8, 122.4 (Ar) , 80.4 (C ¾u), 64.2 (C4), 52.6 (C3), 45.6 (C3 '), 42.7, 42.4 (NCH ₂ ), 40.2 (4- CH ₂ ), 39.5 (C1'), 32.4 (C3 ') , 28.4 (CH ₃ ¾u). MS (ES) ⁺ : 587.33 [M + H] ⁺ .

EXAMPLE 41

 4?, S-Benzyl-4 - [(N-pyridin-3-yl) carbamoyl] -1 - [(3'S-íerc-butoxycarbonylamino- '- [(N-pyridin-3-yl) carbamoyl] prop-1' -il] -2-oxoazetidine

Simpe Rdto: 26% (from the compound of Example 33, Method B). Eluent: CH ₂ CI ₂ : 10% MeOH. Proportion of diastereoisomers, M / m = 5: 2. HPLC: t _R = 3.27 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI3, Major Diastereoisomer): δ 9.60 (s, 1 H, CONH), 9.13 (s, 1 H, CONH), 8.74 (d, 1 H, J = 2.5 Hz, 2-Py) , 8.62 (d, 1 H, J = 2.7 Hz, 2-Py), 8.36 (dd, 1 H, J = 4.8, 1.5 Hz, Py), 8.32.7.29 (m, 5H, Py), 7.33- 7.14 (m, 5H, Ph), 5.82 (d, 1 H, J = 7.6 Hz, 3'-NH), 4.68 (m, 1 H, 3'-H), 3.58-3.18 (m, 4H, 4- CH ₂ , 1'-H), 3.10 (d, 1 H, J = 15.2 Hz, 3-H), 3.00 (d, 1 H, J = 15.0 Hz, 3-H), 2.39 (m, 1 H, 2'-H), 1 .99 (m, 1 H, 2'-H), 1 .17 (s, 9H, CH ₃ ¾u). ¹³ C NMR (300 MHz, CDCI3): δ 170.3, 169.0 (CONH), 167.6 (C2), 156.5 (OCON), 146.4, 145.9, 144.7, 141 .4, 134.7, 133.9, 130.6, 130.2, 129.9, 129.2, 127.9, 126.9, 123.8, 123.4 (Ar), 80.8 (C 'Bu), 63.9 (C4), 52.6 (C3'), 47.2 (C3), 41.8 (C1 '), 37.3 (4-CH ₂ ), 33.8 ( C2 '), 28.13 (CH ₃ ' Bu). MS (ES) ⁺ : 559.40 [M + H] ⁺ .

EXAMPLE 42

 4S-Benzyl-4 - [(N ^ iridin-4-yl) carbamoyl] - ^

 -pyridin-4-yl) carbamoyl] prop-1 '-yl] -2-oxoazetidine

(23a) Simpe. Rdto: 21% (from the compound of Example 33, Method B). Eluent: CH ₂ CI ₂ : 10% MeOH. HPLC: t _R = 3.26 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.41 (s, 1 H, CONH), 10.20 (s, 1 H, CONH), 8.44 (m, 8H, Py), 7.61-7.20 (m, 6H , Ph, 3'-NH), 4.10 (m, 1 H, 3'-H), 3.42 (d, 1 H, J = 14.0 Hz, 4-CH ₂ ), 3.32 (d, 1 H, J = 14.0 Hz, 4-CH ₂ ), 3.22 (d, 1 H, J = 14.8 Hz, 3-H), 3.01 (m, 2H, 1 '-H), 2.98 (d, 1 H, J = 14.8 Hz, 3 -H), 2.24 (m, 1 H, 2'-H), 2.06 (m, 1 H, 2'-H), 1.39 (s, 9H, CH ₃ ¾u). ¹³ C NMR (75 MHz, CD ₃ OD): δ 173.6, 172.7 (CONH), 169.0 (C2), 157.9 (OCON), 150.8, 150.7, 147.8, 147.5, 135.6, 131.3, 129.7, 128.6, 1 15.7, 1 15.2 (Ar), 80.8 (C ¾u), 66.4 (C4), 55.1 (C3 '), 47.3 (C1'), 45.4 (C3), 40.5 (4-CH ₂ ), 32.1 (C2 '), 28.7 (CH ₃ )u). MS (ES) ⁺ : 559.40 [M + H] ⁺ . EXAMPLE 43

 4 /? - Benzyl-4 - [(N- (pyridin-4-yl) carbam

 -pyridin-4-yl) carbamoyl] prop-1'-yl] -2-oxoazetidine

(23b) Simpe. Rdto: 23% (from the compound of Example 33, Method B). Eluent: CH ₂ CI ₂ : 10% MeOH. HPLC: t _R = 3.26 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.42 (s, 1 H, CONH), 10.26 (s, 1 H, CONH), 8.49 (m, 4H, Py), 7.65 (m, 2H, Py ), 7.62 (m, 2H, Py), 7.36-7.26 (m, 6H, Ph, 3'-NH), 4.18 (m, 1 H, 3'-H), 3.47 (d, 1 H, J = 14.1 Hz, 4-CH ₂ ), 3.37 (d, 1 H, J = 14.1 Hz, 4-CH ₂ ), 3.27 (d, 1 H, J = 14.8 Hz, 3-H), 3.08 (m, 2H, 1 '-H), 2.96 (d, 1 H, J = 14.8 Hz, 3-H), 2.15 (m, 2H, 2'-H), 1.45 (s, 9H, CH ₃ ¾u). ¹³ C NMR (75 MHz, CD3OD): δ 173.7, 172.9 (CONH), 168.7 (C2), 158.0 (OCON), 150.8, 150.7, 147.9, 147.5, 131 .7, 131 .2, 129.7, 128.6, 1 15.9 , 1 15.2 (Ar), 80.9 (C ¾u), 66.2 (C4), 54.9 (C3 '), 45.3 (C3), 40.7 (C3'), 40.5 (4-CH ₂ ), 31 .8 (C2 ') , 28.7 (CH ₃ ¾u). MS (ES) ⁺ : 559.40 [M + H] ⁺ .

Synthesis of dipeptide derivatives

A solution of the corresponding substituted dibenzyloxycarbonyl derivative (0.2 mmol) in MeOH (17 mL) is hydrogenated at room temperature and 15 psi pressure for 7 h, using Pd-C (10%) as catalyst. Once the catalyst has been filtered off, the solvent is evaporated to dryness. Then the corresponding substituted azetidinone dicarboxy (0.33 mmol) is dissolved in dry THF (4 mL) and HL-Ala-OMe HCI or HL-Phe-OMe HCI (0.66 mmol), PyBOP is added consecutively (0.66 mmol, 336 mg) and TEA (1.32 mmol, 0.18 mL). After 24-48 h of stirring at room temperature, it is analyzed by HPLC in order to determine the proportion of formed diastereoisomers. The solvent is then evaporated to dryness. The crude obtained is dissolved in AcOEt and washed with 10% citric acid solution, 10% NaHCO ₃ solution, H ₂ O and saturated NaCl solution. The organic phase is dried over Na ₂ SO ₄ and evaporated, the resulting residue being purified by silica gel column chromatography using the eluent system indicated in each case.

EXAMPLE 44

 4S-Benzyl-1 - [3'S-ferc-butoxycarbonylamino-3 '- [/ V - [(1 "S-methoxycarbonyl) ethyl] carbamoyl] prop-1'-yl] -4 - [/ V - [(1' "S- methoxycarbon I) eti IJcarbamoi I] -2-oxoazetidi na

Simpe Rdto: 28% (from the compound of Example 3). Eluent: MeOH: DCM (1: 30). HPLC: t _R = 4.30 min (gradient of 15% to 95% of A, in 5 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 8.38 (d, 1 H, J = 7.3 Hz, 1 "'-NH), 7.53 (d, 1 H, J = 7.5 Hz, 1" -NH), 7.31 -7.18 (m, 15H, Ar), 5.67 (d, 1 H, J = 7.4 Hz, 3'-NH), 4.70 (q, 1 H, J = 7.5 Hz, 1 "'-H), 4.52 (q , 1 H, J = 7.3 Hz, 1 "-H), 4.34 (m, 1 H, 3'-H), 3.72 (s, 4H, OMe, 1'-H), 3.69 (s, 3H, OMe) , 3.48 (d, 1 H, J = 14.8 Hz, 4-CH ₂ ), 3.38 (d, 1 H, J = 14.8 Hz, 4-CH ₂ ), 3.18 (m, 1 H, 1'-H), 2.98 (d, 1 H, J = 15.1 Hz, 3-H), 2.90 (d, 1 H, J = 15.1 Hz, 3-H), 2.22 (m, 1 H, 2'-H), 2.04 (m , 1 H, 2'-H), 1 .52 (d, 3H, J = 7.2 Hz, 2 "'- H), 1 .38 (d, 3H, J = 7.3 Hz, 2" -H), 1 .37 (s, 9H, CH ₃ 'Bu). ¹³ C NMR (75 MHz, CDCIs): 173.4 (COO), 172.9 (COO), 171.1 (CON '"), 170.8 (CON"), 169.6 (C2), 155.7 (OCON), 135.0, 130.4, 128.9, 127.5 (Ar), 79.9 (C, 'Bu), 63.6 (C4), 52.6 (OMe), 52.55 (OMe), 52.5 (C3'), 48.7 (CT), 48.3 (C1 "), 46.9 (C3), 40.3 (C1 '), 37.2 (4-CH ₂ ), 33.6 (C2'), 28.5 (CH ₃ * Bu), 17.7 (C2 "), 17.1 (C2 '"). MS (ES) ⁺ : 577.47 [M + H] ⁺ Exact mass calculated for C ₂₈ H ₀ NO ₉ : 576.27953; found: 576.27722. EXAMPLE 45

 4? -Benzyl-1 - [3'S-íerc-butoxycarbonylamino-3 '- [yV - [(1

methoxy carbon i I) eti IJcarbamoi I] prop-1 '-i I] -4 - [/ V - [(1 "' S

methoxycarbon i) eti IJcarbamoi I] -2-oxoazetidi na

Simpe Rdto: 12% (from the compound of Example 3). Eluent: MeOH: DCM (1: 30). HPLC: t _R = 4.28 min (gradient of 15% to 95% of A, in 5 min). Proportion of diastereoisomers M, m = 1: 0.7. ¹ H NMR (400 MHz, CDCI _{3, major} diastereoisomer): δ 7.62 (sa, 1 H, NHCO), 7.31 -7.15 (m, 15H, Ar), 7.04 (sa, 1 H, NHCO), 5.43 (d, 1 H, J = 6.6 Hz, 3'-NH), 4.52 (m, 2H, 1 "-H, 1"'-H), 4.34 (m, 1 H, 3'-H), 3.73 (s, 3H , OMe), 3.71 (s, 3H, OMe), 3.52 (m, 1 H, 1'-H), 3.38 (m, 2H, 4-CH ₂ ), 3.25 (m, 1 H, 1'-H) , 3.17 (m, 1 H, 1 '-H), 3.02 (d, 1 H, J = 14.7 Hz, 3-H), 2.97 (d, 1 H, J = 14.7 Hz, 3-H), 2.05 ( m, 1 H, 2'-H), 1 .84 (m, 1 H, 2'-H), 1 .41 (s, 9H, CH ₃ 'Bu), 1 .40 (d, 3H, J = 6.8 Hz, CH ₃ ), 1 .32 (d, 3H, J = 7.2 Hz, CH ₃ ). ¹³ C NMR (75 MHz, CDCI ₃ ): 173.6 (COO), 173.1 (COO), 171.2 (CON), 171 .1 (CON), 167.4 (C2), 155.7 (OCON), 134.9, 130.0, 128.9, 127.5 (Ar), 80.2 (C, )u), 63.6 (C4), 52.8 (OMe), 52.5 (OMe), 52.4 (C3 '), 48.5 (C1'"), 48.3 (C1"), C1 '"), 47.1 (C3), 39.1 (C1 '), 37.1 (4-CH ₂ ), 32.1 (C2'), 28.4 (CH ₃ ¾u), 18.1 (C2 "), 17.6 (C2 '"). MS (ES) ⁺ : 577.47 [M + H] ⁺ .

EXAMPLE 46

4? -Benzyl-1 - [3'S-íerc-butoxycarbonylamino-3 '- [yV - [(1 "S-methoxycarbonyl-2'-phenyl) ethyl] carbamoyl] prop-1' -yl] -4 - [/ V - [(1 '"S-methoxycarbonyl- 2'phenyl) ethyl] carbamoyl] -2-oxoazetidine

Simpe Rdto: 12% (from the compound of Example 3). Semi-preparative HPLC purification (gradient from 50% to 60% of A, in 30 min). HPLC: t _R = 15.13 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.49 (m, 2H, NHCO), 7.28-7.14 (m, 15H, Ar), 5.38 (d, 1 H, J = 6.6 Hz, NHBoc), 4.91 (m , 1 H, 1 "-H), 4.83 (m, 1 H, 1"'-H), 4.33 (m, 1 H, 3'-H), 3.75 (s, 3H, OMe), 3.69 (s, 3H, OMe), 3.34 (m, 2H, 1'-H), 3.31 (m, 2H, 2 "-H), 3.17 (m, 2H, D 2"'- H, 4-CH ₂ ), 3.07 ( m, 2H, 2 "'- H, 4-CH ₂ ), 2.93 (m, 1 H, 1' -H), 2.76 (d, 1 H, J = 14.7 Hz, 3-H), 2.46 (d, 1 H, J = 14.7 Hz, 3-H), 1 .86 (m, 1 H, 2'-H), 1.60 (m, 1 H, 2'-H), 1.43 (s, 9H, CH . ₃ 'Bu) ¹³ C NMR (75 MHz, CDCl3): 172.7 (COO), 171 8 (COO), 171 6 (2C, CON), 167.4 (CON), 155.8 (CON), 136.3, 136.2, 130.1, 129.4, 129.3, 128.85, 128.8, 128.7, 127.4, 127.3, 127.2 (C, Ar), 80.3 (C, 'Bu), 63.3 (C4), 53.6 (2C, C1 "and C1'"), 52.8 ( OMe), 52.4 (OMe), 52.0 (C3 '), 47.5 (C3), 38.7 (4-CH ₂ ), 38.1 (C1'), 37.9, 37.3 (2C, C2 "and C2 '"), 31.3 (C2 '), 28.4 (CH ₃ * Bu). MS (ES) ⁺ : 729.53 [M + H] ⁺ . Exact mass calculated for C40H48N4O9: 728.34213; found: 728.34342.

EXAMPLE 47

4S-Benzyl-1 - [3'S-íerc-butoxycarbonylamino-3 '- [yV - [(1 "S-methoxycarbonyl-2'-phenyl) ethyl] carbamoyl] prop-1' -yl] -4 - [/ V- [(1 '"S-methoxycarbonyl- 2'phenyl) ethyl] carbamoyl] -2-oxoazetidine

Simpe Rdto: 12% (from the compound of Example 3). Semi-preparative HPLC purification (gradient from 50% to 60% of A, in 30 min). HPLC: t _R = 15.47 min (gradient from 5% to 100% of A, in 20 min). ¹ H NMR (400 MHz, CDCI ₃ ): δ 8.44 (d, 1 H, J = 7.6 Hz, NHCO), 7.56 (d, 1 H, J = 7.6 Hz, NHCO), 7.32-7.14 (m, 15H, Ar), 5.66 (d, 1 H, J = 7.1 Hz, NHBoc), 5.04 (m, 1 H, 1 "-H), 4.76 (m, 1 H, 1" - H), 4.29 (m, 1 H , 3'-H), 3.73 (s, 3H, OMe), 3.70 (s, 3H, OMe), 3.63 (m, 2H, 1'-H), 3.38 (m, 2H, 4-CH ₂ ), 3.35 (m, 2H, 2 "-H), 3.16 (dd, 1 H, J = 13.9, 5.8 Hz, 2"'- H), 3.04 (m, 1 H, 1'-H), 2.96 (dd, 1 H, J = 13.5, 8.2 Hz, 2 "'- H), 2.60 (dd, 1 H, J = 14.8 Hz, 3-H), 2.10 (dd, 1 H, J = 14.8 Hz 3-H), 1 .92 (m, 2H, 2'-H), 1 .41 (s, 9H, CH ₃ 'Bu). ¹³ C NMR (75 MHz, CDCI ₃ ): 172.22 (COO), 171.79 (COO), 171.34 ( CON), 171 .09 (CON), 169.69 (CON), 155.65 (CON), 137.59, 136.41, 135.00, 130.33, 129.44, 129.26, 128.85, 128.71, 128.68, 127.42, 127.15, 126.98 (C, Ar), 79.86 (C, * Bu), 63.45 (C4), 54.23, 53.41 (2C, C1 "and C1 '"), 52.46 (OMe), 52.41 (OMe), 51 .87 (C3'), 46.88 (C3), 40.22 (C1 '), 37.87 (4-CH ₂ ), 36.61, 36.40 (2C, C2 "and C2'"), 33.43 (C2 '), 28.49 (CH ₃ * Bu). MS (ES) ⁺ : 729.53 [M + H] ⁺ Exact mass calc ulated for C40H48N4O9: 728.34213; Found: 728.34220.

EXAMPLE 48

4? -Benzyl-1 - [4'S - [(yV-benzyloxycarbonyl-yV-methyl) amino-4'-methoxycarbonyl] but-1'-yl] -4- [N - [(1 "S-methoxycarbonyl) ethyl] carbamoyl] -2- oxoazetidine

To a solution of the substituted 4-ferc-butoxycarbonyl derivative of Example 10 (0.10 mmol, 55 mg) in CH ₂ CI ₂ (1 ml_) is added TFA (0.3 ml_). After 2 h of reaction at room temperature the solvent is evaporated to dryness, coevaporating several times with CH2CI2. Subsequently, the corresponding substituted 4-carboxy azetidinone (0.1 mmol, 52 mg) is dissolved in dry THF (1.2 mL_) and HL-Ala-OMe HCI (0.22 mmol, is added consecutively) 30 mg), PyBOP (0.22 mmol, 1 12 mg) and TEA (0.44 mmol, 61 μΙ_). After 24 h of stirring at room temperature, the proportion of diastereoisomers formed by HPLC is analyzed. The solvent is then evaporated to dryness. The crude obtained is dissolved in AcOEt and washed with 10% citric acid solution, 10% NaHCO ₃ solution, H ₂ O and saturated NaCl solution. The organic phase is dried over Na ₂ SO ₄ and evaporated, the resulting residue being purified by semi-preparative HPLC (gradient from 50% to 60% of A, in 30 min) obtaining 20 mg (33%) of a simpe with the characteristics that They described below. HPLC: t _R = 9.51 min (gradient of 50% to 60% of A, in 15 min). Rattan ratio M, m = 2: 1 ¹ H NMR (400 MHz, CDCI3): δ 7.35-7.15 (m, 10H, Ph, Z), 6.31 (d, 1 H, J = 7.4 Hz, NHCO, M) , 6.20 (d, 1 H, J = 7.4 Hz, NHCO, m), 5.14 (s, 2H, OCH ₂ ), 4.81 (dd, 1 H, J = 9.8, 5.0 Hz, 4'-H), 4.56 ( m, 1 H, 1 "-H), 3.72 (s, 3H, OMe, M), 3.71 (s, 3H, OMe, M), 3.64 (s, 3H, OMe, m), 3.37 (d, 1 H , J = 14.0 Hz, 3-H), 3.25 (m, 2H, 4-CH ₂ ), 3.20 (d, 1 H, J = 14.0 Hz, 3-H), 2.98 (s, 2H, 1 '-H ), 2.86 (s, 3H, NCH ₃ ), 1.94 (m, 1 H, 2Ή), 1.76 (m, 3H, 3'-H, 2'-H), 1.32 (d, 3H, J = 7.1 Hz, CH _3, M), 1.29 (d, 3H, J = 7.1 Hz, CH ₃ , m). ¹³ C NMR (75 MHz, CDCI3): 173.1 (COO), 171.9 (COO, M) , 171 .2 (COO, m), 170.65 (CON, m), 170.6 (CON, m), 166.5 (C2, M), 166.3 (C2, m), 157.0 (OCON, M), 156.9 (OCON, m ), 136.7, 135.2, 135.1, 130.0, 129.9, 129.0, 128.9, 128.7, 128.6, 128.2, 128.1, 127.9, 127.7, 127.6 (Ar), 67.7 (OCH ₂ , M), 67.6 (OCH ₂ , m), 63.7 (C4), 58.7 (C4 \ m), 58.3 (C4 ', M), 52.8 (OMe, m) 52.7 (OMe, M), 52.3 (OMe, M), 52.2 ( OMe, m), 48.4 (C1 ", M), 48.3 (C1", m), 46.9 (C3, m), 46.7 (C3, M), 42.05 (C1 \ m), 42.0 (C1 ', M), 39.9 (4-CH ₂ , m), 39.8 (4- CH ₂ , M), 31 .4 (NMe, m), 30.6 (NMe, M), 26.9 (C3 ', m), 26.5 (C3', M ), 25.4 (C2 \ m), 25.2 (C2 ', M), 18.0 (CH ₃ , Ala). MS (ES) ⁺ : 590.40 [M + Na] ⁺ .

EXAMPLE 49

 4?, S-Benzyl-1 - [(4'S-methylamino-4'-methoxycarbonyl) but-1'-yl] -4- [N - [(1 "S-methoxycarbon i) eti IJcarbamoi I] -2- oxoazetidi na

A solution of the corresponding substituted 4-benzyloxycarbonyl derivative of Example 48 (0.2 mmol) in MeOH (17 mL) is hydrogenated at room temperature and 15 psi pressure for 7 h, using Pd-C (10%) as catalyst. Once the catalyst has been filtered off, the solvent is evaporated to dryness, obtaining a simpe with these characteristics. Rdto: 78%. HPLC: t _R = 7.81, 7.95 min (gradient from 2% to 95% of A, in 15 min). Proportion of diastereoisomers (4S, 4'S, 1 "S) :( 4R, 4'S, 1" S) = 27:73. ¹ H NMR (400 MHz, CDCIs): δ 7.31 -7.17 (m, 5H, Ph), 6.64 (d, 1 H, J = 7.4 Hz, NHCO, M), 6.55 (d, 1 H, J = 7.4 Hz , NHCO, m), 4.56 (m, 2H, 4'-H, 1 "-H,), 3.75 (s, 3H, OMe, M), 3.74 (s, 3H, OMe, m), 3.73 (s, 6H, OMe), 3.40 (d, 1 H, J = 14.2 Hz, 4-CH ₂ M), 3.26 (m, 3H, 1 '-H, 4-CH ₂ ), 3.23 (d, 1 H, J = 14.1 Hz, 4-CH ₂ M), 3.17 (m, 1 H, 1 '-H), 3.08 (d, 1 H, J = 14.7 Hz, 3-H m), 2.96 (s, 2H, 3-HM ), 2.93 (d, 1 H, J = 14.7 Hz, 3-H m), 2.36 (s, 3H, NCH _3, m), 2.35 (s, 3H, NCH ₃ , M), 1 .85-1. 73 (m, 2H, 2'-H), 1 .71 -1.58 (m, 2H, 3'-H), 1.41 (d, 3H, J = 7.2 Hz, 2 "-H, m), 1 .33 (d, 3H, J = 7.2 Hz, 2 "-H, M). ¹³ C NMR (75 MHz, CDCI3): 175.1 (COO, M), 174.9 (COO, m), 173.1 (COO, M) , 171 .0 (COO, m), 171 .0 (CON, m), 170.8 (CON, M), 166.8 (C2, m), 166.6 (C2, M), 135.0, 129.9, 129.8, 128.7, 128.6, 127.4 (Ar), 63.6 (C4, m), 63.5 (C4, M), 62.6 (C4 \ m), 62.4 (C4 \ M), 52.7 (OMe), 52.0 (OMe, m), 51 .9 (OMe , M), 48.6 (C1 ", m), 48.4 (C1", M), 46.9 (C3, M), 46.8 (C3, m), 42.0 (C1 \ m), 41.9 (C1 ', M), 39.3 (4-CH ₂ , m), 39.3 (4-CH ₂ , M), 34.7 (NMe, m), 34.6 (NMe, M), 30.7 (C3 ', M), 30.5 (C3', m), 25.0 (C2 \ m) , 24.9 (C2 ', M), 18.1 (CH ₃ , m), 18.0 (CH ₃ , M). MS (ES) ⁺ : 434.38 [M + H] ⁺ .

EXAMPLE 50

 4 /? - Benzyl-1 - [(4'S-benzyloxycarbonylami

 "S-methoxycarbonyl) ethyl] carbamoyl] -2-oxoazetidine

Simpe Rdto: 27% (from the compound of Example 13). HPLC-MS: t _R = 13.02 min (gradient from 2% to 95% of A, in 15 min). Proportion of isomers (4R, 4'S, 1 "S) :( 4S, 4'S, 1" S) = 16: 1. ¹ H NMR (300 MHz, CDCI ₃ , majority isomer): δ 7.10-7.27 (m, 10H, Ar), 6.30 (d, 1H, J = 7.1 Hz, 4'-NH), 5.56 (d, 1H, J = 8.0 Hz, 1 "-NH), 5.03 (s, 2H, OCH ₂ ), 4.48 (quint, 1H, J = 7.1 Hz, 4'-H), 4.30 (m, 1H, 1" -H), 3.67 (m, 3H, OCH ₃ ), 3.63 (m, 3H, OCH ₃ ), 3.22-3.07 (m, 4H, 4-H, 1'-H), 2.91 (s, 2H, 4-CH ₂ ), 1.79 -1.60 (m, 4H, 2'-H, 3'-H), 1.38 (d, 3H, J = 7.2 Hz, 2 "-H, m), 1.25 (d, 3H, J = 7.2 Hz, 2" -H, M). MS (ES) ⁺ : 554.19 [M + H] ⁺ .

EXAMPLE 51

4?, S-Benzyl-1 - [(4'S-benzyloxycarbonylamino-4'-methoxycarbonyl) but-1'-yl] -4- [N - [(1 "? - methoxycarbonyl) ethyl] carbamoyl] -2-oxoazetidine

Simpe. Rdto: 44% (a partir del compuesto del Ejemplo 13). HPLC-MS: t_R=12.98 min (gradiente de 2% a 95% de A, en 15 min). Proproción de isómeros (4R,4'S, 1 "R):(4S,4'S, 1 "R)=2: 1 . ¹H RMN (300 MHz, CDCI₃): δ 7.27- 7.09 (m, 10H, Ar), 6.44 (d, 1 H, J=6.9 Hz, 4'-NH, M), 6.36 (d, 1 H, J=7.0 Hz, 4'- NH, m), 5.50 (d, 1 H, J=8.1 Hz, 1 "-NH), 5.03 (s, 2H, OCH₂), 4.45 (m, 1 H, 4'-H), 4.29 (m, 1 H, 1 "-H), 3.67 (s, 3H, OCH₃), 3.64 (s, 3H, OCH₃), 3.84-3.34 (m, 6H, 1 '-H, 3-H, 4-CH₂), 1 .90-1 .50 (m, 4H, 2'-H, 3'-H), 1 .32 (d, 3H, J=7.2 Hz , 2"-H, M), 1 .31 (d, 3H, J=7.2 Hz , 2"-H, m). MS (ES)⁺: 554.1 1 [M+H]⁺. Bloqueo de Canales TRPM8

Simpe Rdto: 44% (from the compound of Example 13). HPLC-MS: t _R = 12.98 min (gradient from 2% to 95% of A, in 15 min). Proportion of isomers (4R, 4'S, 1 "R) :( 4S, 4'S, 1" R) = 2: 1. ¹ H NMR (300 MHz, CDCI ₃ ): δ 7.27-7.09 (m, 10H, Ar), 6.44 (d, 1 H, J = 6.9 Hz, 4'-NH, M), 6.36 (d, 1 H, J = 7.0 Hz, 4'- NH, m), 5.50 (d, 1 H, J = 8.1 Hz, 1 "-NH), 5.03 (s, 2H, OCH ₂ ), 4.45 (m, 1 H, 4 ' -H), 4.29 (m, 1 H, 1 "-H), 3.67 (s, 3H, OCH ₃ ), 3.64 (s, 3H, OCH ₃ ), 3.84-3.34 (m, 6H, 1'-H, 3-H, 4-CH ₂ ), 1 .90-1 .50 (m, 4H, 2'-H, 3'-H), 1 .32 (d, 3H, J = 7.2 Hz, 2 "-H , M), 1.31 (d, 3H, J = 7.2 Hz, 2 "-H, m). MS (ES) ⁺ : 554.1 1 [M + H] ⁺ . TRPM8 Channel Lock

The measures of the efficacy of the compounds example 1 -example 51 have been carried out using the Chinese hamster ovary (CHO) cell line that stably expresses the TRPM8 protein. The cells were cultured in monolayer in EMEM medium (Earle's minimum essential medium with Earle's salts, Invitrogen) supplemented with 10% FBS, 2 mM L-glutamine, 1% penicillin-streptomycin solution and 0.4 pg / mL of the antibiotic Geneticin (Sigma) and maintained at 37 ° C in a humidified atmosphere with 5% CO2. To determine the efficacy of the compounds on the TRPM8 channel, Ca ²⁺ fluorimetry tests have been carried out. The cells are seeded in 96-well plates at a density of 25,000 cells / well, after 3 days after planting, the medium is removed and 100 μΙ of the Fluo-4NW fluorescent probe is added at a concentration of 5 μΜ in the presence 0.02% pluronic acid, after 60 minutes of incubation at 37 ° C in a humidified atmosphere with 5% CO2, fluorescence is measured in a microplate reader (POLARstar Omega) with a 485 nm configuration for excitation and 520 nm for emission, for 20 cycles. During the first 3 cycles the baseline fluorescence is measured and then 1 μΙ of the different compounds (examples 1-51) is added to a final concentration of 5 μΜ, after 7 cycles of fluorescence measurement, 10 μΙ is added to all wells of menthol to obtain a final concentration of 100 μΜ. In the wells that are used as negative controls 1 μΙ of AMTB is added (Λ / - (3- Aminopropyl) -2 - [(3-methylphenyl) methoxy] - / V- (2-thienylmethyl) benzamide hydrochloride; Tocris Bioscience) to obtain a final concentration of 10 μΜ, to block the TRPM8 channels. Table 1. Results of the activity of the compounds on TRPM8

Example% Block at 50 μΜ% Block at 5 μΜ

EXAMPLE 1 - 1.01 ± 1.68

EXAMPLE 2 - 0.88 ± 0.21

EXAMPLE 3 90.26 ± 1.58 75.40 ± 9.93

EXAMPLE 4 89.34 ± 2.27 71.44 ± 2.48

EXAMPLE 5 91.02 ± 3.34 73.32 ± 2.13

EXAMPLE 6 122.25 ± 4.64 74.15 ± 17.04

EXAMPLE 8 82.17 ± 29.00 36.86 ± 10.85

EXAMPLE 9 - 8.16 ± 13.90

EXAMPLE 10 88.94 ± 13.13 19.39 ± 16.99

EXAMPLE 11 - 1.99 ± 7.00

EXAMPLE 12 - 50.40 ± 17.82

EXAMPLE 13 - 24.91 ± 17.80

EXAMPLE 14 - 4.37 ± 23.85

EXAMPLE 15 - 95.55 ± 2.48

EXAMPLE 16 - 87.91 ± 6.97

EXAMPLE 17 - 88.66 ± 20.12

EXAMPLE 19 25.69 ± 17.41 8.87 ± 7.12

EXAMPLE 20 - 103.64 ± 3.13

EXAMPLE 21 100.38 ± 3.50 56.89 ± 3.55

EXAMPLE 22 91.78 ± 5.09 86.49 ± 5.17

EXAMPLE 23 76.89 ± 12.62 50.32 ± 8.34

EXAMPLE 24 75.31 ± 13.52 66.23 ± 17.90

EXAMPLE 25 - 97.48 ± 5.83

EXAMPLE 26 - 93.79 ± 7.97

EXAMPLE 27 - 85.81 ± 16.16

EXAMPLE 28 - 77.79 ± 13.44

EXAMPLE 29 - 68.73 ± 12.78

EXAMPLE 30 99.11 ± 4.15 60.08 ± 23.35

EXAMPLE 31 - 85.23 ± 7.01

EXAMPLE 32 84.16 ± 8.74 37.84 ± 12.33 EXAMPLE 33 - 29.88 ± 18.48

EXAMPLE 34 - 7.39 ± 8.37

EXAMPLE 35 69.98 ± 18.60 41, 10 ± 8.87

EXAMPLE 36 70.38 ± 15.23 46.49 ± 10, 18

EXAMPLE 37 103.79 ± 4.93 5.05 ± 3.84

EXAMPLE 38 108.06 ± 2.33 4.74 ± 3.45

EXAMPLE 39 42, 17 ± 1 1, 71 35.31 ± 8.70

EXAMPLE 40 39.28 ± 14.67 15.91 ± 22.29

EXAMPLE 41 64.56 ± 13, 16 43.62 ± 10.44

EXAMPLE 42 52.32 ± 7.59 43.05 ± 14.29

EXAMPLE 43 43.52 ± 9.82 38.54 ± 12.36

EXAMPLE 44 - 3.82 ± 15.23

EXAMPLE 46 99.32 ± 3.36 58.91 ± 6.24

EXAMPLE 47 - 2.28 ± 4.71

EXAMPLE 50 - 1 1, 20 ± 9.30

EXAMPLE 51 - 7.80 ± 14.99

"Patch-Clamp" essays

For the determination of the IC50 of the selected examples, electrophysiological techniques were used using the "patch-clamp" method with the "whole-cell" configuration. The cells were seeded at a density of 250,000 cells / well on round glass covers (18 mm in diameter, thickness 0) in 12-well plates (Costar) and cultured in EMEM. After 24 hours, the covers were mounted in a recording chamber (WPI) and were continuously perfused (1 mL / min) with HBSS (140 mM NaCI, 4 mM KCI, 1 mM MgCI2, 1, 8 mM CaCI2, D-glucose 5 mM, 10 mM Hepes (all from Sigma), pH 7.4) at ~ 22 ° C. The activity of the TRPM8 channels was evoked by applying short pulses of 10 s of 100 μ 100 menthol, using a gravity-activated perfusion system. The compounds dissolved in the HBSS buffer at different concentrations (from 0.1 to 100 μΜ) were applied in the recording chamber near the cells, keeping the same distance between the cells and the perfusion system under all measurement conditions. Pipette tips for the realization of Measurements were prepared from borosilicate capillaries (World Precision Instruments, Sarasota, FL, USA), using a pipette stretcher (P-97, Sutter Instruments, Novato, CA, USA) to obtain a resistance between 2-4 Ω when They are filled with internal solution (144 mM KCI, 2mM MgCI2, 5mM EGTA, and 10 mM HEPES, (all from Sigma), pH 7.2).

The currents and voltages were recorded using the total current configuration with a frequency of 10 kHz (EPC10 amplifier with Pulse software; HEKA Electronics, Lambrecht, Germany) and analyzed using PulseFit 8.54 software (HEKA, Molecular Devices; WinASCD, G Droogmans, Katholieke Universiteit Leuven, Leuven, Belgium) and Origin 7.5 (OriginLab Corp., Southampton MA, USA).

The different currents, caused by the stimulation of the cells with 100 μΜ of menthol in the presence of the different concentrations of the compounds are subtracted from the current caused by the application with 100 μΜ of menthol in the absence of compounds. The results obtained were adjusted to a sigmoid with the software package of the GraphPad Prism software. The results are shown in FIG. one .

Antitumor activity

 The compounds of examples 20 and 28 were tested on 60 human tumor cell lines, which include leukemia, melanoma and lung, colon, brain, ovary, breast, prostate and kidney lines.

Human tumor cell lines of the cancer detection panel are cultured in RPMI 1640 medium containing 5% fetal bovine serum and 2 mM L-glutamine. For a typical screening experiment, the cells are inoculated in 96-well microtiter plates at densities ranging from 5,000 to 40,000 cells / well depending on the doubling time of the cell lines. After cell inoculation, the plates are incubated at 37 ° C, 5% CO2, 95% air and 100% relative humidity, for 24 h before the addition of the experimental drugs. After 24 h, two plates of each cell line are fixed in situ with trichloroacetic acid (TCA), to have a measure of the cell population for each cell line at the time of drug addition (Tz). The compounds to be tested are solubilized in dimethylsulfoxide at 400 times the maximum desired final test concentration and stored frozen before use. At the time of drug addition, an aliquot of the frozen concentrate is thawed and the desired final maximum test concentration is diluted to twice with complete medium containing 50 g / ml_ of gentamicin. Additionally, dilutions are made to provide a total of five concentrations of compound plus control. 100 μotas aliquots of the different compound dilutions are added to the appropriate wells that already contain 100 μΙ of medium, resulting in the required final concentrations.

After the addition of the compounds, the plates are incubated for an additional period of 48 h at 37 ° C, 5% CO2, 95% air, and 100% relative humidity. The test is terminated by the addition of cold TCA. The cells are fixed in situ by the gentle addition of 50 μΙ of 50% (w / v) cold TCA (final concentration, 10% TCA) and incubated for 60 minutes at 4 ° C. The supernatant is discarded, and the plates are washed five times with tap water and air dried. A solution of sulphordamine B (SRB) in 1% acetic acid, (100 μΙ) at 0.4% (w / v) is added to each well, and the plates are incubated for 10 minutes at room temperature. After staining, the unbound dye is washed five times with 1% acetic acid and the plates are air dried. The bound dye is subsequently solubilized with 10 mM Trizma base, and the absorbance is read in an automated plate reader at a wavelength of 515 nm. For the cells in suspension, the methodology is the same except that the assay is terminated by fixing sedimented cells at the bottom of the wells by slowly adding 50 μ de of 80% TCA (final concentration, 16% TCA). Using the seven zero-time absorbance measurements, (Tz), as growth control, (C), and growth in the presence of the five concentrations of the compounds (Ti)], the percentage of final growth for each of the compound concentrations and the percentage of tumor growth inhibition are calculated.

Table 2. Inhibition of tumor cell growth.

 Tumor cell line Inhibition of cell growth (%)

inhibition of the growth of the indicated tumor cells, after addition of the compound at a concentration of 10 μΜ. ^b Only inhibitions greater than 70% are indicated.

Claims

one . Compound of formula (I)

(I)  where: R ¹ is selected from (Ci-C ₄ ) alkyl, substituted or unsubstituted, aralkyl (Ci-C ₄ ), substituted or unsubstituted, heteroaralkyl (Ci-C ₄ ), substituted or unsubstituted, aryl, substituted or not substituted, and heteroaryl, substituted or unsubstituted; R ² is selected from a group -OR ⁶ and -NR ⁷ R ⁸ ; R ³ is selected from hydrogen and (Ci-C ₄ ) alkyl, substituted or unsubstituted; R ⁴ is selected from hydrogen, (Ci-C ₄ ) alkyl, substituted or unsubstituted, aralkyl (Ci-C ₄ ), substituted or unsubstituted, heteroaralkyl (Ci-C ₄ ), substituted or unsubstituted, aryl, substituted or unsubstituted, and -COR ⁹ ; R ⁵ is selected from -NR ¹¹ R ¹⁰ ; R ⁸ is selected from hydrogen, alkyl (Ci-Ce) and aralkyl (Ci-C ₄ ), heteroaryl, heteroarylalkyl (Ci-C) and -CH (R ¹³ ) COOR ¹² ; R ⁶ , R ¹¹ , R ¹³ and R ¹⁴ are independently selected from hydrogen, (Ci-Ce) alkyl, substituted or unsubstituted, aralkyl (Ci-C ₄ ), substituted or unsubstituted, heteroaralkyl (Ci-C ₄ ) , substituted or unsubstituted, and aryl, substituted or unsubstituted; R ⁷ and R ¹² is selected from hydrogen and alkyl (Ci-Ce), substituted or unsubstituted; R ⁹ is selected from -OR ⁶ and -NR ⁷ R ⁸ ; R ¹⁰ is selected from hydrogen, (Ci-Ce) alkyl, substituted or unsubstituted, and aralkyl (Ci-C ₄ ), substituted or unsubstituted, COOR ¹⁴ ; Y n is 1, 2, 3 or 4; or any pharmaceutically acceptable salts or stereoisomers thereof. 2. Compound according to claim 1, wherein R ¹ is (Ci-C ₄ ) alkyl or aralkyl 3. Compound according to claim 2, wherein R ¹ is methyl or benzyl. 4. Compound according to any one of claims 1 to 3, wherein R ² is - OR ⁶ and R ⁶ is hydrogen, (Ci-C ₄ ) alkyl or benzyl, preferably hydrogen, methyl, tere-butyl or benzyl. 5. Compound according to any one of claims 1 to 3, wherein R ² is - NR ⁷ R ⁸ ; R ⁸ is selected from hydrogen, alkyl (Ci-Ce), aralkyl (Ci-C ₄ ), heteroaryl, heteroaralkyl (Ci-C ₄ ) and -CH (R ¹³ ) COOR ¹² and / or R ⁷ is selected from hydrogen and alkyl (Ci-C ₄ ). 6. Compound according to the preceding claim, wherein R ⁷ is hydrogen or methyl. 7. Compound according to any of claims 5 or 6, wherein R ⁸ is selected from benzyl, heteroaryl, heteroaralkyl (d) and - CH (R ¹³ ) COOR ¹² ; R ¹³ is methyl or benzyl and / or R ¹² is methyl. 8. Compound according to any of claims 1 to 7, wherein R ³ is hydrogen or methyl. 9. Compound according to any of claims 1 to 8, wherein R ⁴ is aralkyl (Ci-C) or -COR ⁹ 10. Compound according to claim 9, wherein R is benzyl. 11. Compound according to claim 9, wherein R ⁴ is -COOR ¹⁴ , R ¹⁴ is hydrogen, (Ci-C ₄ ) alkyl or benzyl, preferably hydrogen, methyl, terebutyl or benzyl. 12. Compound according to claim 9, wherein R ⁴ is -CONR ⁷ R ⁸ ; R ⁷ is selected from hydrogen and (Ci-C ₄ ) alkyl, preferably R ⁷ is H, and / or R ⁸ is selected from hydrogen, (Ci-Ce) alkyl, aralkyl (Ci-C ₄ ), heteroaryl, heteroaralkyl (Ci-C) and -CH (R ¹³ ) COOR ¹² and, preferably R ⁸ is benzyl or -CH (R ¹³ ) COOCH ₃ , with R ¹³ selected from benzyl, methyl, heteroaralkyl (d) and heteroaryl. 13. Compound according to any of claims 1 to 12, wherein R ⁵ is -NR ¹¹ R ¹⁰ , wherein R ¹¹ is independently selected from hydrogen, methyl and benzyl; and / or R ¹⁰ is selected from hydrogen, methyl, benzyl and COOR ¹⁴ ; where R ¹⁴ is methyl, tere-butyl or benzyl. 14. Compound according to claim 1, selected from the list consisting of:  4R, S-Benzyl-4-methoxycarbonyl-1 - [(3'S-ierc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] -2-oxoazetidine  4R, S-Benzyl-4-methoxycarbonyl-1 - [(3'S-ierc-butoxycarbonylamino-3'-methyloxycarbonyl) prop-1 '-yl] -2-oxoazetidine  4R, S-Benzyl-4-benzyloxycarbonyl-1 - [(3'S-ierc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] -2-oxoazetidine  4S-Benzyl-4-benzyloxycarbonyl-1 - [(3'S-ierc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] -2-oxoazetidine  4R-Benzyl-4-benzyloxycarbonyl-1 - [(3'S-ierc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] -2-oxoazetidine  4R, S-Benzyl-4-benzyloxycarbonyl-1 - [(3'S-ierc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1'-yl] - (3R, SJ-methyl-2-oxoazetidine 4R, S-Methyl-4-methoxycarbonyl-1 - [(3'S-ierc-butoxycarbonylamino-3'- benzyloxycarbonyl) prop-1 '-yl] -2-oxoazetidine 4R, S-Benzyl-4-methoxycarbonyl-1 - [(3'S-benzyloxycarbonylamino-3'-ierc- butoxycarbonyl) prop-1 '-yl] -2-oxoazetidine _4R; S-Methyl-4-methoxycarbonyl-1 - [(3'S-benzyloxycarbonylamino-3'-ierc- butoxycarbonyl) prop-1 '-yl] -2-oxoazetidine _4R; S-Benzyl-1 - [4'S - (/ V-Benzyloxycarbonyl- / V-methyl) amino-4'- methoxycarbonyl] but-1-yl] -4-ierc-butoxycarbonyl-2-oxoazetidine 4R, S-Benzyl-1 - [4'S - [(/ V-methyl) amino-4'-methoxycarbonyl] but-1 '-yl] -4-ierc- butoxycarbonyl-2-oxoazetidine _4R; S-Benzyl-4-benzyloxycarbonyl-1 - [(4'S-ierc-butoxycarbonylamino-4'- benzyloxycarbonyl) but-1'-yl] -2-oxoazetidine _4R; S-Benzyl-N - [(4'S-benzyloxycarbonylamino-4'-methoxycarbonyl) but-1 '-yl] -4- ferc-butoxycarbonyl-2-oxoazetidine 4'S-N - [(4'-Benzyloxycarbonylamino-4'-methoxycarbonyl) but-1'-yl] -4R _; S-ierc- butyloxycarbonyl-4-methyl-2-oxoazetidine _4R; S-Benzyl-4-benzyloxycarbonyl-1 - [(2'S-benzyloxycarbonylamino-3'-phenyl) prop- 1 '-yl] -2-oxoazetidine _4R; S-Benzyl-4-benzyloxycarbonyl-1 - [(2'R-benzyloxycarbonylamino-3'-phenyl) prop- 1 '-yl] -2-oxoazetidine  4S-Benzyl-4-benzyloxycarbonyl-3S-methyl-1 - [(2'S-benzyloxycarbonylamino-3'-phenyl) prop-1'-yl] -2-oxoazetidine  4R-Benzyl-4-benzyloxycarbonyl-3R-methyl-1 - [(2'S-benzyloxycarbonylamino-3'- phenyl] prop-1'-yl] -2-oxoazetidine  4R-Benzyl-4-benzyloxycarbonyl-3R-methyl-1 - [(2'R-benzyloxycarbonylamino-3'-phenyl) prop-1'-yl] -2-oxoazetidine 4S-4-Benzyl-4-benzyloxycarbonyl-3S-methyl-1 - [(2'R-benzyloxycarbonylamino-3'-phenyl) prop-1'-yl] -2-oxoazetidine  4S-Benzyloxycarbonyl-3S, 4S-dimethyl-1 - [(2'R-benzyloxycarbonylamino-3'- phenyl) prop-1'-yl] -2-oxoazetidine _4R; S-Benzyl-4-benzyloxycarbonyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop-1 '-yl] -2- oxoazetidine 4S-Benzyl -] - (4-benzyloxycarbonyl-3S-methyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop- 1 '-yl] -2-oxoazetidine 4R-Benzyl-4-benzyloxycarbonyl-3R-methyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop- 1'-yl] -2-oxoazetidine _4R; S-Benzyl-4-methoxycarbonyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop-1 '-yl] -2- oxoazetidine _4R; S-Benzyl-4-tert-butoxycarbonyl-1 - [(2'S-dibenzylamino-3-phenyl) prop-1 '-yl] -2- oxoazetidine  4S-Benzyl-3S-methyl-4-methoxycarbonyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop-1 '- yl] -2-oxoazetidine  4S-Benzyl-4-ierc-butoxycarbonyl-3S-methyl-1 - [(2'S-dibenzylamino-3'-phenyl) prop- 1 '-yl] -2-oxoazetidine  4S-Benzyl-4-ierc-butoxycarbonyl-3S-methyl-1 - [(2'S-benzylamino-3'-phenyl) prop- 1'-yl] -2-oxoazetidine  4S-Benzyl-4-ferc-butoxycarbonyl-3S-methyl-1 - [(2'S-amino-3'-phenyl) prop-1-yl] -2- oxoazetidine 4S-Benzyl-4-ierc-butoxycarbonyl-3S-methyl-1 - [2'S-benzyloxycarbonylamino-3'-phenyl) prop-1'-yl] -2-oxoazetidine  4S-Benzyl-4-ierc-butoxycarbonyl-3S-methyl-1 - [(2'S-ierc-butoxycarbonylamino-3- phenyl) prop-1 '-yl] -4-oxoazetidine  4R, S-Benzyl-4-carboxy-1 - [3'S-tert-butoxycarbonylamino-3'-carboxy) prop-1 '-yl] - 2-oxoazetidine  4R, S-Benzyl-1 - [4'S-tert-butoxycarbonylamino-4'-carboxy) but-1 '-yl] -4-carboxy-2-oxoazetidine  4S-Benzyl-4 - [(N-benzyl) carbamoyl] -1 - [(3'S-ierc-butoxycarbonylamino-3 '- [(N-benzyl) carbamoyl] prop-1' -yl] -2-oxoazetidine _4R; S-Benzyl-1 - [4'S-tert-butoxycarbonylamino-4 '- [(N-benzyl) carbamoyl] but-1' - yl] -4 - [(N-benzyl) carbamoyl] -2-oxoazetidine 4S-4-Benzyl-4 - [(N-benzyl) carbamoyl] -3S-methyl-1 - [3 'S-ferc- butoxycarbonylamino-3' - [(N-benzyl) carbamoyl] prop-1 '-yl] -2-oxoazetidine 4R-4-Benzyl-4 - [(N-benzyl) carbamoyl] -3R-methyl-1 - [3'S-ierc- butoxycarbonylamino-3 '- [(N-benzyl) carbamoyl] prop-1' - il] -2-oxoazetidine 4S-Benzyl-4- [N - [(pindin-4 "-yl) methyl] carbamoyl-1 - [(3'S-ierc- butoxycarbonylamino-3 '- [N - [(pindin-4''- il) methyl] carbamoyl] prop-1 '-yl] -2- oxoazetidine  4R-Benzyl-4- [N - [(pindin-4 "-yl) methyl] carbamoyl] -1 - [3'S-ierc- butoxycarbonylamino-3 '- [N - [(pindin-4' '- il) methyl] carbamoyl] prop-1 '-yl] -2- oxoazetidine _4R; S-Benzyl-4 - [(N-pindin-3-yl) carbamoyl] -1 - [(3'S-ierc-butoxycarbonylamino-3'- [(N-pyridin-3-yl) carbamoyl] prop-1 '-yl ] -2-oxoazetidine  4S-Benzyl-4 - [(N-pindin-4-yl) carbamoyl] -1 - [3'S-tert-butoxycarbonylamino-3 '- [(N-pyridin-4-yl) carbamoyl] prop-1' -yl] -2-oxoazetidine  4R-Benzyl-4 - [(N- (pindin-4-yl) carbamoyl] -1 - [3'S-tert-butoxycarbonylamino-3'- [(N-pyridin-4-yl) carbamoyl] prop-1 '-yl] -2-oxoazetidine  4S-Benzyl-1 - [3'S-ierc-butoxycarbonylamino-3 '- [/ V - [(1 "S- methoxycarbonyl) ethyl] carbamoyl] prop-1'-yl] -4 - [/ V - [(1' "S- methoxycarbonyl) ethyl] carbamoyl] -2-oxoazetidine  4R-Benzyl-1 - [3'S-ierc-butoxycarbonylamino-3 '- [/ \ / - [(1 "S- methoxycarbonyl) ethyl] carbamoyl] prop-1'-yl] -4 - [/ V - [(1 '"S- methoxycarbonyl) ethyl] carbamoyl] -2-oxoazetidine  4R-Benzyl-1 - [3'S-ierc-butoxycarbonylamino-3 '- [/ V - [(1 "S-methoxycarbonyl-2'-phenyl) ethyl] carbamoyl] prop-1' -yl] -4 - [/ V - [(1 '"S-methoxycarbonyl- 2'phenyl) ethyl] carbamoyl] -2-oxoazetidine  4S-Benzyl-1 - [3'S-ierc-butoxycarbonylamino-3 '- [/ V - [(1 "S-methoxycarbonyl-2'-phenyl) ethyl] carbamoyl] prop-1'-yl] -4 - [/ V - [(1 '"S-methoxycarbonyl- 2'phenyl) ethyl] carbamoyl] -2-oxoazetidine 4R-Benzyl-1 - [4'S - [(/ V-benzyloxycarbonyl- / V-methyl) amino-4'-methoxycarbonyl] but- 1'-yl] -4- [N - [(1 "S-methoxycarbonyl) ethyl ] carbamoyl] -2-oxoazetidine 4R, S-Benzyl-1 - [(4'S-methylamino-4'-methoxycarbonyl) but-1 '-yl] -4- [N - [(1 "S-methoxycarbonyl) ethyl] carbamoyl] -2-oxoazetidine 4R-Benzyl-1 - [(4'S-benzyloxycarbonylamino-4'-methoxycarbonyl) but-1'-yl] -4- [N- [(1 "S-methoxycarbonyl) ethyl] carbamoyl] -2-oxoazetidine, and _4R; S-Benzyl-1 - [(4'S-benzyloxycarbonylamino-4'-methoxycarbonyl) but-1'-yl] -4- [N- [(1 "R-methoxycarbonyl) ethyl] carbamoyl] -2-oxoazetidine. 15. Process for obtaining the compound of formula (I) when R ² is - OR ⁶ , described according to any one of claims 1 to 4 and 8 to 14, which comprises the delation in basic medium of the compound of formula (II):

 (II) wherein: R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and n have been described in any one of claims 1 to 4 and 8 to 14. 16. Process for obtaining the compound of formula (I), when R ² is - NR ⁷ R ⁸ , described according to any of claims 1 to 3 and 5 to 14, comprising the reaction of amines of formula R ⁸ R ⁷ NH with a carboxylic acid derivative of the compound of formula (I) together with a coupling agetne, wherein the carboxylic acid derivative is a compound of formula (I) when R ² is -OH and R ⁷ and R ⁸ have been described in any of claims 1 to 3 and 5 to 14. 17. Pharmaceutical composition comprising a compound of formula (I) described according to any one of claims 1 to 14 together with a pharmaceutically acceptable carrier. 18. Use of the compound of formula (I) described according to any of claims 1 to 14 for the preparation of a medicament. 19. Use of the compound of formula (I) described according to any of claims 1 to 14, for the preparation of a medicament for the treatment and / or prevention of a disease associated with alterations of the thermosensory channels, preferably of the TRPM8 channels. 20. Use according to claim 19, wherein said diseases are selected from inflammation, lung disorders, eye diseases, gastrointestinal hypersensitivity, skin sensitivity, neurodegeneration and cancer. twenty-one . Use according to claim 20, wherein the lung disorders are problems of the respiratory system selected between cough and asthma. 22. Use according to claim 20, wherein the sensitivity in the skin is selected from pruritus, atopic dermatitis, allergen and psoriasis. 23. Use according to claim 20, wherein the cancer can be selected from melanoma, leukemia, prostate, kidney, breast, pancreas, ovary, lung, colon, central nervous system and osteosarcoma. 24. Use according to claim 20, wherein the eye diseases are selected from dry eye syndrome and excessive tearing.