WO2021255156A1

WO2021255156A1 - Novel dipeptide compounds, method for the production thereof and a novel therapeutic use of dipeptide compounds

Info

Publication number: WO2021255156A1
Application number: PCT/EP2021/066367
Authority: WO
Inventors: Laurent SALMON; Stéphanie SALZBURG; Raphaël LABRUERE; Marta ABELLAN-FLOS; Alba DIEZ MARTINEZ; Maud GAYRAL; Bogdan IORGA; Thierry NAAS; Saoussen OUESLATI
Original assignee: Universite Paris-Saclay; Centre National De La Recherche Scientifique; Assistance Publique-Hopitaux De Paris (Ap-Hp)
Priority date: 2020-06-18
Filing date: 2021-06-17
Publication date: 2021-12-23
Also published as: FR3111544A1

Abstract

The invention relates to a novel therapeutic use of dipeptide compounds having formula (I). The dipeptide compounds are useful as inhibitors of P-lactamases, in particular belonging to the class of carbapenemases. The invention also relates to novel dipeptide compounds.

Description

New dipeptide compounds, their manufacturing process and a new therapeutic application of dipeptide compounds.

The present invention relates to novel dipeptide compounds, their manufacturing process and a novel therapeutic application of dipeptide compounds.

Bacterial infections are usually treated with antibiotics that can inhibit the growth of the bacteria involved or even kill it. Among the antibiotics available, those of the b-lactam class are the most used in first intention. However, bacterial resistance to this family of molecules continues to increase. A mechanism of resistance involves the production by resistant bacteria of β-lactamase enzymes which destroy the molecular structure of the antibiotics of the β-lactam class. Bacterial resistance affects even the newest and most effective antibiotics, namely carbapenems.

Carbapenemases are a class of enzymes among the β-lactamases. Enzymes of the carbapenemase class are so called because they are able to hydrolyze the lactam cycle of antibiotics belonging to the Carbapenem class.

There are different classification systems for b-lactamase enzymes. The simplest classification is a classification based on the protein sequence of the enzyme. The enzymes are thus divided into 4 classes, A, B, C, and D (Hall BG, Barlow M. Revised Ambler classification of (beta} 4actamases. J Antimicrob. Chemother. 2005 June, 55 (6), 1050-1) .

Classes A, C, and D are enzymes having a serine residue in the active site and are therefore also referred to as "Serine ^ -lactamases", or "SBLs". In these cases, the opening of the lactam ring of an antibiotic molecule occurs by nucleophilic attack of the hydroxyl group of the aforementioned serine, on the carbonyl function of the lactam ring.

Class B are enzymes having one or two zinc cations in their active site. We then speak of “metallo ^ -lactamases”, or “MBLs”. A water molecule, or a hydroxide ion can be complexed with zinc cations. The nucleophilic water molecule, or ion of nucleophilic hydroxide can then open the lactam ring of an antibiotic molecule by attacking the carbonyl function of the lactam ring.

The carbapenemase enzymes are found among classes A, B, and D. Figure 1 shows the general structure of antibiotics of the Carbapenem class, as well as the chemical structure of three clinically used Carbapenems.

general structure of carbapenems

Imipenem Meropenem Doripenem

Diagram 1

One way to fight against bacterial resistance to antibiotics of the b-lactam class is to develop b-lactamase inhibitors. Interesting results have been obtained in combination therapy, in which the administration of an antibiotic can be accompanied by the administration of a β-lactamase inhibitor. Thus, several inhibitors have been placed on the market, such as, for example, clavulanic acid, sulbactam, avibactam, or tazobactam. However, these compounds inhibit serine-β-lactamase (SBL) -type enzymes, but are inactive towards metallo-β-lactamase type B (MBL) enzymes. Only a few compounds having inhibitory activity on all classes A, B, C and D are known to date and no type B β-lactamase inhibitor has been used clinically to date. There is therefore a real need to make available new inhibitors of β-lactamase, in order to fight against bacterial resistance, in particular inhibitors having an effect against all the classes of β-lactamases. One of the aims of the invention is to provide dipeptide compounds for use as β-lactamase inhibitors.

One of the other objects of the invention is to provide dipeptide compounds having inhibitory activity on all classes A, B, C and D of b-lactamases. One of the other objects of the invention is to provide dipeptide compounds for use as a medicament.

One of the other objects of the invention is to provide new dipeptide compounds.

One of the aims of the invention is to provide methods for the synthesis of dipeptide compounds.

One of the other objects of the invention is to provide pharmaceutical compositions comprising these dipeptide compounds.

Another aim of the invention is the use of these compounds as a medicament in combination with antibiotic treatment, separately or over time.

A first object of the present invention is a compound of Formula I

Formula I

in which :

• n represents 0 or 1,

• m represents a value from 0 to 4,

• X represents NH, O, -NHC (O),

• Ri represents

^■ H,

^■ aryl, in particular phenyl,

^■ heteroaryl, in particular imidazoyl,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ linear or branched C 1 to C 10 heteroalkyl,

^■ C3 to Cio cycloalkyl, or

^■ C ₃ to Cio cycloheteroalkyl, • R-2 represents

■ H,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ Ci to Cio-alkylaryl, in particular benzyl,

^■ C3 to Cio cycloalkyl, or

^■ M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R ₃ represents

^■ aryl, in particular phenyl, or

^■ heteroaryl, in particular pyridyl,

• R ₄ represents

^■ H,

^■ aryl, in particular phenyl,

^■ heteroaryl, in particular imidazoyl,

^■ Ci to Cio-alkylaryl, in particular benzyl,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ linear or branched C 1 to C 10 heteroalkyl,

^■ C ₃ to Cio cycloalkyl,

^■ C ₃ to Cio cycloheteroalkyl,

^■ trityl, or

^■ -C (0) R ₆ , Ri, being an aryl group, in particular phenyl, or a linear or branched C 1 to C 10 alkyl group, in particular methyl, said aryl, alkylaryl or heteroaryl possibly being substituted on the aromatic ring by a or several substituents chosen from: halogen, in particular Cl, linear or branched C1 to Cio alkyl, in particular methyl,

-OR ₅ , R ₅ being a linear or branched C1 to Cio alkyl group,

-N (¾) 2, RS being as defined above, cycloalkyl C ₃ -C, cycloheteroalkyl, C ₃ -C, said compound of Formula I may be in the form of a dimer in which two molecules of Formula I are linked together by a disulfide bridge, said compound of Formula I or its dimer may be in the form of a pharmaceutically acceptable salt, solvate or hydrate, the asymmetric centers of said compound of Formula I or of its dimer being of R or S configuration, or a mixture of these configurations, for its use as a β-lactamase inhibitor.

The term “aryl” denotes an aromatic group comprising 5 to 16 carbon atoms within the aromatic ring, in particular from 6 to 12 carbon atoms, in particular comprising 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 carbon atoms. Phenyl or naphthyl are examples of aryl groups according to the present invention.

The term “heteroaryl” denotes an aryl group as defined above, comprising atoms other than carbon atoms, in particular N, O or S within the aromatic ring. Pyridyl, imidazoyl, or furanyl are examples of heteroaryl groups according to the present invention.

By "linear alkyl Ci-Cio" means: methyl Cl, ethyl C2, propyl C3, butyl C4, pentyl C5, a hexyl group _{Cr> ,} a C7 heptyl group, a Cx octyl group, a C9 nonyl group, or a C10 decyl group.

The term "branched alkyl group" should be understood to mean a linear alkyl group as defined above comprising substituents chosen from the list of linear alkyl groups defined above, said linear alkyl groups also being capable of being branched. Among the branched alkyl groups, mention may in particular be made of a / f / V-butyl, .svc-butyl and iso-propyl group.

The term “linear C 1 to C 10 heteroalkyl group” should be understood to mean: a linear alkyl chain of 1 to 10 carbon atom (s), in particular of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atom (s), in particular from 2 to 10, or from 5 to 10 carbon atoms, comprising one or more heteroatoms, in particular chosen from O, or N, in particular 1, 2, 3, 4 or 5 heteroatoms. Mention may in particular be made of a chain based on ethylene glycol or ethylene amine.

The term “branched heteroalkyl group” should be understood to mean a heteroalkyl group as defined above comprising substituents chosen from the list of linear alkyl or linear heteroalkyl groups defined above, said linear alkyl or linear heteroalkyl groups also being susceptible to be branched.

By “C 1 to C 10 cycloalkyl group” is meant: a C ₃ cyclopropyl group, a C ₄ cyclobutyl group, a C ₅ cyclopentyl group, a Cr _> cyclohexyl group, a C ₇ cycloheptyl group, a group Cx cyclooctyl, a C ₉ cyclononyl group, or a C 10 cyclodecyl group.

The term “C ₃ to Cio cycloheteroalkyl group” should be understood to mean: a cycloalkyl group as defined above, further comprising one or more heteroatoms, in particular chosen from O, N, or S, in its ring, in in particular 1 or 2 heteroatoms. Among the cycloheteroalkyl groups, mention may be made of morpholine or tetrahydropyranyl.

By “C 1 to C 10 -alkylaryl group” is meant an aryl group as defined above, bonded to the oxygen atom, in the case of R ₂ , or to the sulfur atom in the case of R ₄ , with a C 1 to C 10 alkyl group as defined above.

For the purposes of the present invention, the term "pharmaceutically acceptable" is understood to mean that which is useful in the preparation of a pharmaceutical composition and which is of sufficient purity and quality for veterinary or human use.

For the purposes of the present invention, “in the form of a salt” is understood to mean a salified compound, preferably an ammonium salt comprising a protonated nitrogen atom, in particular in the form of the hydrochloride or of the trifluoroacetate, or comprising a deprotonated oxygen atom, in the form of a carboxylate.

For the purposes of the present invention, the expression “said aryl, alkylaryl or heteroaryl possibly being substituted on the aromatic ring by one or more substituents” refers, independently of one another, to all of the groups R 1 to R ₄ . The compounds according to the present invention contain at least two asymmetric centers, in particular 2 or 4 asymmetric centers. Indeed, said compounds are dipeptides consisting of a cysteine derivative and a tryptophan derivative (Scheme 2). Each of these two derivatives comprises an asymmetric center * whose configuration can be R, or S, or a mixture of these configurations. The groups R 1, R 2, R 3 and R 4 can moreover also comprise one or more asymmetric center (s).

The inventors have found that the compounds according to the present invention can be used in the fight against bacterial resistance to antibiotics belonging to the class of β-lactams. It has been found that the molecules according to the present invention inhibit the enzymes of the b-lactamase type and can thus be used in antibiotic therapy, in combination with an antibiotic treatment.

In other words, the compounds of Formula I can be used in the context of the prevention or treatment of a bacterial infection, in which the bacterial infection is treated with at least one antibiotic belonging to the class of b4actams. .

These are in particular infections involving a Gram negative bacterium of clinical interest in human or veterinary medicine. Among the germs targeted, mention may in particular be made, by way of example: of Enterobacteriaceae, Pseudomonas spp and Acinetobacter spp. By way of example, and without limitation, among the bacterial infections we can cite: pneumopathies, bacteremia, urinary tract infections (cystitis and pyelonephritis), soft tissue infections, skin infections or site infections operative. According to a particular embodiment, the present invention relates to a compound of Formula I as defined above, for its use as defined above, Formula I in which: X represents NH.

According to another particular embodiment, the present invention relates to a compound of Formula I as defined above, for its use as defined above, Formula I in which:

• n represents 0 or 1,

• m represents a value from 0 to 4,

• X represents NH, O, -NHC (O),

• Ri represents

^■ H,

^■ aryl, in particular phenyl, or

^■ C 1 to C 6 alkyl, in particular methyl,

• R2 represents

^■ H,

^■ C 1 to 6 alkyl, in particular methyl, or

^■ M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R3 represents

^■ aryl, in particular phenyl, or

^■ heteroaryl, including pyridyl, said aryl or heteroaryl can be substituted in ortho, meta and / or para positions by one or more substituents selected from halogen, in particular Cl, alkyl -C _O, in particular methyl,

• R4 represents

^■ H,

^■ alkyl -C _O, in particular methyl,

^■ aryl, in particular phenyl,

^■ trityl,

^■ acetyl, or

^■ benzoyl, said compound of Formula I may be in the form of a dimer in which two molecules of Formula I are linked together by a disulfide bridge, said compound of Formula I or its dimer may be in the form of a salt, a solvate or a pharmaceutically acceptable hydrate, the asymmetric centers of said compound of Formula I or of its dimer being of R or S configuration, or a mixture of these configurations.

• n represents 0 or 1,

• m represents 0 or 1,

• X represents NH, O, -NHC (O),

• Ri represents

^■ H,

^■ aryl, in particular phenyl, or

^■ C1 to C3 alkyl, in particular methyl,

• R2 represents

^■ H,

^■ C1 to C3 alkyl, in particular methyl, or

^■ M ⁺ , M being a metal chosen from Na, K, or Li,

• R3 represents

^■ aryl, in particular a phenyl optionally substituted with one or more C1 to C3 alkyl substituents, in particular methyl,

• R4 represents

^■ H,

^■ trityl,

^■ acetyl, or

^■ benzoyl, said compound of Formula I may be in the form of a pharmaceutically acceptable salt, solvate or hydrate, the asymmetric centers of said compound of Formula I being of R or S configuration, or a mixture of these configurations.

• n represents 0 or 1,

• m represents a value from 0 to 4,

• X represents NH, O, -NHC (O),

• Ri represents

^■ H,

^■ aryl, in particular phenyl,

^■ heteroaryl, in particular imidazoyl,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ linear or branched C 1 to C 10 heteroalkyl,

^■ C3 to Cio cycloalkyl, or

^■ C3 to Cio cycloheteroalkyl,

• R2 represents

^■ H,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ Ci-Cio-alkylaryl, in particular benzyl,

^■ C3 to Cio cycloalkyl, or

^■ M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R ₃ represents

^■ aryl,

^■ heteroaryl, in particular pyridyl, if X = NH, or NH (CO), said aryl is substituted in ortho, meta and / or para by one or more substituents chosen from halogen, in particular Cl, C1 to Cio alkyl, linear or branched , especially methyl, -OR _5, R ₅ being an alkyl group _Ci-Cr> linear or _branched,

-N (¾) 2, R _Ô being as defined above, C3 to Cio cycloalkyl, C3 to Cio cycloheteroalkyl,

• R ₄ represents

^■ H,

^■ aryl, in particular phenyl,

^■ heteroaryl, in particular imidazoyl,

^■ Ci-Cio-alkylaryl, in particular benzyl,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ linear or branched C 1 to C 10 heteroalkyl,

^■ C ₃ to Cio cycloalkyl,

^■ C ₃ to Cio cycloheteroalkyl,

^■ trityl, or

^■ -C (0) R ₆ , FC, being an aryl group, in particular phenyl, or a linear or branched C1 to Cio alkyl group, in particular methyl, said aryl, alkylaryl or heteroaryl possibly being substituted on the aromatic ring by a or several substituents chosen from: halogen, in particular Cl, linear or branched C1 to Cio alkyl, in particular methyl,

-OR ₅ , R ₅ being a linear or branched C1 to Cio alkyl group,

-N (¾) _2, R¾ being as defined above, cycloalkyl C ₃ -C, cycloheteroalkyl, C ₃ -C, said compound of Formula I may be in the form of a dimer in which two molecules of Formula I are linked together by a disulfide bridge, said compound of Formula I or its dimer possibly being in the form of a salt, a solvate or a pharmaceutically acceptable hydrate, the asymmetric centers of said compound of Formula I or of its dimer being of R or S configuration, or a mixture of these configurations. According to a particular embodiment, the present invention relates to a compound of Formula I as defined above, for its use as defined above, Formula I in which: said compound of Formula I is in the form of a dimer of two molecules of Formula I linked together by a disulfide bridge, said compound being a compound of Formula II

in which m, n, X, Ri, R ₂ , R ₃ and R ₄ are as defined above, its pharmaceutically acceptable salt, solvate or hydrate, in which the asymmetric centers being of R or S configuration, or a mixture of these configurations.

In this embodiment, the molecules of Formula I, comprising a thiol - SH group, ie in the case where R ₄ is H, are in the form of a dimer of Formula II, in which the thiol groups are oxidized into groups dithiol -SS-.

According to another particular embodiment, the present invention relates to a compound of Formula I as defined above, for its use as defined above, Formula I in which: X represents NH, and m represents 1, said compound being a compound of Formula IA

wherein n, R1, R2, R3 and R4 are as defined above, said compound of Formula IA or of Formula II-A possibly being in the form of a salt, a solvate or a pharmaceutically hydrate acceptable, the asymmetric centers of said compound of Formula IA or Formula II-A being of the R or S configuration, or a mixture of these configurations.

According to another particular embodiment, the present invention relates to a compound of Formula I as defined above, for its use as defined above, formula I in which: X represents O, and m represents 1, said compound being a compound of Formula IB

Formula IB

or a dimer of Formula II-B

wherein n, Ri, R ₂ , R ₃ and R ₄ are as defined above, said compound of Formula IB or Formula II-B possibly being in the form of a salt, a solvate or a pharmaceutically acceptable hydrate, the asymmetric centers of said compound of Formula IB or Formula II-B being of the R or S configuration, or a mixture of these configurations. According to another particular embodiment, the present invention relates to a compound of Formula I as defined above, for its use as defined above, Formula I in which: X represents NH (CO), and m represents 0 , said compound being a compound of Formula IC

Formula IC

or a dimer of Formula II-C

in which n, Ri, R ₂ , R ₃ and R ₄ are as defined above, said compound of Formula IC or Formula II-C may be in the form of a pharmaceutically acceptable salt, solvate or hydrate, the asymmetric centers of said compound of Formula IC or Formula II-C being of the configuration R or S, or a mixture of these configurations.

In the foregoing and in what follows, the expression “compound of Formula I” is understood to mean a compound of Formula I which may also be in the form of a compound of Formula II, of Formula IA, of Formula IB, of Formula IC , of Formula II-A, of Formula II-B or of Formula II-C.

According to another particular embodiment, the present invention relates to a compound of Formula I, for its use as defined above, said compound being present in the form of a single diastereomer, in particular with a diastereomeric excess greater than 95%. .

The term “greater than 95%” is also understood to mean greater than 96%, greater than 97%, greater than 98% and in particular greater than 99%.

According to another particular embodiment, the present invention relates to a compound of Formula I, for its use as defined above, in which the b-lactamase belongs to class A, B, C or D.

The inventors have surprisingly found that the molecules of the present invention act both on the enzymes of the serine-P-lactamase type, as well as on the enzymes of the etal 1 obl actamase type, which however do not operate by the same mechanism.

The molecules of the present invention are in particular inhibitors of the b-lactamase enzymes of class A, B and D.

According to another particular embodiment, the present invention relates to a compound of Formula I, as defined above, for its use as defined above, in which the b-lactamase belongs to the class of carbapenemases.

According to another particular embodiment, the present invention relates to a compound of Formula I, as defined above, for its use as defined above, in in which the carbapenemase is of NDM type, of OXA type, or of KPC type, in particular of NDM type.

The inventors have found that the compounds of the present invention can show a selectivity in the inhibition of the various β-lactamase enzymes. By way of example, the compound of structure below, does not inhibit the enzymes of the type OXA-48 (class B) and KPC-2 (class A), but considerably inhibits the enzyme NDM-1 ( class B), namely 92% inhibition at 5 mM.

According to another particular embodiment, the present invention relates to a compound of Formula I, as defined above, for its use as defined above, in which the b-lactamase belongs to class A, B, C or D, in particular to the class of carbapenemases, in particular in which the carbapenemase is of NDM type, of OXA type, or of KPC type.

According to another particular embodiment, the present invention relates to a compound of Formula I, as defined above, for its use as defined above, said use being a use in the context of a treatment of infections. bacterial.

By “treatment” is meant a means of treating a declared and detectable pathology. Treatment of bacterial infections according to the present invention consists of treatment by administering at least one antibiotic belonging to the class of b-lactams, in particular belonging to the class of carbapenems.

According to another particular embodiment, the present invention relates to a compound of Formula I, for its use as defined above, said compound being used in combination with an antibiotic belonging to the class of b-lactams.

According to another particular embodiment, the present invention relates to a compound of Formula I, as defined above, for its use as defined above, in in which the antibiotic is chosen from penicillin derivatives, cephalosporins, monobactams and carbapenems, in particular chosen from carbapenems. According to another particular embodiment, the present invention relates to a compound of Formula I, as defined above, for its use as defined above, said use being simultaneous use, separate or spread over time in the field. during antibiotic treatment. The expression “simultaneous use” means that the compound according to the invention and the antibiotic agent are administered at the same time.

The expression "separate or staggered use" means that the compound according to the invention and the antibiotic agent are administered independently of each other, for example with or without a time lag.

According to another particular embodiment, the present invention relates to a compound of Formula I, as defined above, for its use as defined above, said compound being chosen from:

or their pharmaceutically acceptable salts, solvates or hydrates.

A second object of the present invention is a compound of Formula III

in which :

• n represents 0 or 1,

• m represents a value from 0 to 4,

• X represents NH, O, -NHC (O),

• Ri represents

^■ H,

^■ aryl, in particular phenyl,

^■ heteroaryl, in particular imidazoyl,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ linear or branched C 1 to C 10 heteroalkyl,

^■ C3 to Cio cycloalkyl, or

^■ C3 to Cio cycloheteroalkyl,

• R2 represents

^■ H,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ Ci-Cio-alkylaryl, in particular benzyl,

^■ C ₃ to Cio cycloalkyl, or

^■ M ⁺ , M being a metal chosen in particular from Na, K, or Li, • R-3 represents

^■ aryl,

^■ heteroaryl, in particular pyridyl, if X = NH, said aryl is substituted in ortho, meta and / or para by one or more substituents chosen from halogen, in particular Cl, linear or branched C1 to C10 alkyl, in particular methyl,

-OR _5, R ₅ being an alkyl group _Ci-Cr> linear or _branched,

-N (¾) 2, FC being as defined above, C3 to Cio cycloalkyl, C ₃ to Cio cycloheteroalkyl,

• R ₄ represents

^■ H,

^■ aryl, in particular phenyl,

^■ heteroaryl, in particular imidazoyl,

^■ Ci-Cio-alkylaryl, in particular benzyl,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ linear or branched C 1 to C 10 heteroalkyl,

^■ C ₃ to Cio cycloalkyl,

^■ C ₃ to Cio cycloheteroalkyl,

^■ trityl, or

^■ -C (0) R ₆ , FC, being an aryl group, in particular phenyl, or a linear or branched C1 to Cio alkyl group, in particular methyl, said aryl, alkylaryl or heteroaryl possibly being substituted on the aromatic ring by a or more substituents chosen from: halogen, in particular Cl, linear or branched C1 to Cio alkyl, in particular methyl,

-OR ₅ , R ₅ being a linear or branched C1 to Cio alkyl group,

-N (¾) _2, R¾ being as defined above, cycloalkyl C ₃ -C, cycloheteroalkyl, C ₃ -C, said compound of Formula III may be in the form of a dimer in which two molecules of Formula III are linked together by a disulfide bridge, said compound of Formula III or its dimer may be in the form of a salt, a solvate or a pharmaceutically acceptable hydrate, the asymmetric centers of said compound of Formula III or of its dimer being of the R or S configuration, or a mixture of these configurations, for its use as a medicament.

According to a particular embodiment, the present invention relates to a compound of Formula III as defined above, for its use as defined above, Formula III in which: X represents O, or NHC (O).

According to a particular embodiment, the present invention relates to a compound of Formula III as defined above, for its use as defined above, Formula III in which: X represents O, or NH.

According to another particular embodiment, the present invention relates to a compound of Formula III as defined above, for its use as defined above, Formula III in which:

• n represents 0 or 1,

• m represents a value from 0 to 4,

• X represents NH, O, -NHC (O),

• Ri represents

^■ H,

^■ aryl, in particular phenyl, or

^■ C 1 to C 6 alkyl, in particular methyl,

• R2 represents

^■ H,

^■ C 1 to 6 alkyl, in particular methyl, or

^■ aryl,

^■ heteroaryl, in particular pyridyl, said aryl being substituted in ortho, meta and / or para by one or more substituents chosen from halogen, in particular Cl, C 1 to C 6 alkyl, in particular methyl,

• R.4 represents

^■ H,

^■ C 1 to 6 alkyl, in particular methyl,

^■ aryl, in particular phenyl,

^■ trityl,

^■ acetyl, or

^■ benzoyl, said compound of Formula III possibly being in the form of a dimer in which two molecules of Formula I are linked together by a disulfide bridge, said compound of Formula III or its dimer possibly being in the form of a salt. , of a pharmaceutically acceptable solvate or hydrate, the asymmetric centers of said compound of Formula III or of its dimer being of R or S configuration, or a mixture of these configurations.

• n represents 0 or 1,

• m represents 0 or 1,

• X represents NH, O, -NHC (O),

• Ri represents

^■ H,

^■ aryl, in particular phenyl, or ^■ C 1 to C ₃ alkyl, in particular methyl,

• R2 represents

^■ H,

^■ C 1 to C ₃ alkyl, in particular methyl, or

^■ M ⁺ , M being a metal chosen from Na, K, or Li,

• R3 represents

^■ aryl, substituted by one or more C1 to C ₃ alkyl substituents, in particular methyl,

• R4 represents

^■ H,

^■ trityl,

^■ acetyl, or

^■ benzoyl, said compound of Formula III possibly being in the form of a salt, a solvate or a pharmaceutically acceptable hydrate, the asymmetric centers of said compound of Formula III being of R or S configuration, or a mixture of these configurations.

A third object of the present invention is a novel compound of Formula IV

Formula IV

in which :

• n represents 0 or 1,

• m represents a value from 0 to 4,

• X represents NH, O, -NHC (O),

• Ri represents

^■ H,

^■ aryl, in particular phenyl, ^■ heteroaryl, in particular imidazoyl,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ linear or branched C 1 to C 10 heteroalkyl,

^■ C3 to Cio cycloalkyl, or

^■ C ₃ to Cio cycloheteroalkyl,

• R ₂ represents

^■ H,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ Ci-Cio-alkylaryl, in particular benzyl,

^■ C ₃ to Cio cycloalkyl, or

^■ M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R ₃ represents

^■ aryl,

^■ heteroaryl, in particular pyridyl, if X = NH, or NH (CO), said aryl is substituted in ortho, meta and / or para by one or more substituents chosen from halogen, in particular Cl, C1 to Cio alkyl, linear or branched , especially methyl,

-OR _5, R ₅ being an alkyl group _Ci-Cr> linear or _branched,

-N (¾) 2, R _O is as defined above, cycloalkyl C ₃ -C, cycloheteroalkyl, C ₃ -C,

• R ₄ represents

^■ H,

^■ aryl, in particular phenyl,

^■ heteroaryl, in particular imidazoyl,

^■ Ci-Cio-alkylaryl, in particular benzyl,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ linear or branched C 1 to C 10 heteroalkyl,

^■ C ₃ to Cio cycloalkyl,

^■ C ₃ to Cio cycloheteroalkyl,

^■ trityl, or

^■ -C (0) R ₆ , Ri, being an aryl group, in particular phenyl, or a linear or branched C1 to Cio alkyl group, in particular methyl, said aryl, alkylaryl or heteroaryl possibly being substituted on the aromatic ring by one or more substituents chosen from: halogen, in particular Cl, linear or branched C1 to C10 alkyl, in particular methyl,

-OR ₅ , R ₅ being a linear or branched C1 to Cio alkyl group,

-N (¾) 2, R _Ô being as defined above, C3 to Cio cycloalkyl, C3 to Cio cycloheteroalkyl, said compound of Formula IV possibly being in the form of a dimer in which two molecules of Formula III are linked together by a disulfide bridge, said compound of Formula IV or its dimer possibly in the form of a salt, a solvate or a pharmaceutically acceptable hydrate, the asymmetric centers of said compound of Formula IV or its dimer being of R or S configuration, or a mixture of these configurations.

According to a preferred embodiment, the present invention relates to a novel compound of Formula IV as defined above, in which X represents NH.

According to a particular embodiment, the present invention relates to a novel compound of Formula IV as defined above, in which:

• n represents 0 or 1,

• m represents a value from 0 to 4,

• X represents NH, O, -NHC (O),

• Ri represents

^■ H,

^■ aryl, in particular phenyl, or

^■ C 1 to C 6 alkyl, in particular methyl

R ₂ represents ■ H, ^■ C 1 to C 6 alkyl, in particular methyl, or

^■ M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R.3 represents

^■ aryl, substituted in ortho, meta and / or para by one or more substituents chosen from halogen, in particular Cl, C 1 to C 6 alkyl, in particular methyl,

^■ heteroaryl, in particular pyridyl, said heteroaryl possibly being substituted by one or more substituents chosen from halogen, in particular Cl, C 1 to 6 alkyl, in particular methyl,

• R.4 represents

^■ H,

^■ alkyl -C _O, in particular methyl,

^■ aryl, in particular phenyl,

^■ trityl,

^■ acetyl, or

^■ benzoyl, said compound of Formula IV possibly being in the form of a dimer in which two molecules of Formula IV are linked together by a disulfide bridge, said compound of Formula IV or its dimer possibly being in the form of a salt. , of a pharmaceutically acceptable solvate or hydrate, the asymmetric centers of said compound of Formula IV or of its dimer being of R or S configuration, or a mixture of these configurations.

According to another particular embodiment, the present invention relates to a novel compound of Formula IV as defined above, in which said compound of Formula IV is in the form of a dimer of two molecules of Formula IV linked together by a disulfide bridge, said compound being a compound of Formula V

in which n, R 1, R ₂ , R ₃ and R ₄ are as defined above, its pharmaceutically acceptable salt, solvate or hydrate, in which the asymmetric centers being of R or S configuration, or a mixture of these configurations.

According to another particular embodiment, the present invention relates to a novel compound of Formula IV as defined above, in which X represents NH, and m represents 1, said compound being a compound of Formula IV-A

Formula IV-A

or a dimer of Formula VA

in which n, Ri, R ₂ , R ₃ and R ₄ are as defined above, said compound of Formula IV-A or Formula VA may be in the form of a pharmaceutically acceptable salt, solvate or hydrate, the asymmetric centers of said compound of Formula IV-A or Formula VA being of the configuration R or S, or a mixture of these configurations.

According to another particular embodiment, the present invention relates to a novel compound of Formula IV as defined above, in which: X represents O, and m represents 1, said compound being a compound of Formula IV-B

Formula IV-B

or a dimer of Formula VB

wherein n, R1, R2, R3 and R4 are as defined above, said compound of Formula IV-B or of Formula VB may be in the form of a salt, a solvate or a pharmaceutically hydrate acceptable, the asymmetric centers of said compound of Formula IV-B or Formula VB being of the R or S configuration, or a mixture of these configurations.

According to another particular embodiment, the present invention relates to a novel compound of Formula IV as defined above, in which X represents NH (CO), and m represents 0, said compound being a compound of Formula IV-C

Formula IV-C

or a dimer of Formula VC

wherein n, R1, R2, R3 and R4 are as defined above, said compound of Formula IV-C or of Formula VC may be in the form of a salt, a solvate or a pharmaceutically hydrate acceptable, the asymmetric centers of said compound of Formula IV-C or Formula VC being of the R or S configuration, or a mixture of these configurations.

In the foregoing and in what follows, by “compound of Formula IV” is meant a compound of Formula IV which may also be in the form of a compound of Formula V, of Formula IV-A, of Formula IV-B , Formula IV-C, Formula VA, Formula VB or Formula VC.

According to another particular embodiment, the present invention relates to a new compound of Formula IV as defined above, said compound being present in the form of a single diastereomer, in particular with a diastereomeric excess of greater than 95%.

The term “greater than 95%”, greater than 96%, greater than 97%, greater than 98% and in particular greater than 99% is also understood. According to another particular embodiment, the present invention relates to a novel compound of Formula IV as defined above, chosen from:

or their pharmaceutically acceptable salts, solvates or hydrates.

Procedures for obtaining the compounds according to the invention

The compounds according to the present invention can be obtained by methods known to those skilled in the art. The inventors have also developed an innovative synthetic route, illustrated by Scheme 3, for the case where X = NH, and m represents 1

Diagram 3

The first step consists of adding cysteine A to an aldehyde B, to produce a thiazolidine-4-carboxylic product C. The choice of aldehyde B makes it possible to control the identity of the group R _3.

A step 2 of peptide coupling between the carboxylic acid C and the derivative of Tryptophan D makes it possible to isolate the dipeptide E. The group R ₂ is a group forming an ester with the carboxylic acid of tryptophan, preferably a methyl group. At this stage the R 1 group can be chosen by reuse of a tryptophan derivative D carrying said R 1 group. Said tryptophan derivative can be obtained by conventional methods, such as for example those described in the publication Tetrahedron, 2000, 56, p.5479-5492, or in the publication Eur. J. Org. Chem., 2000, p.3051-3057.

Reduction in step 3 then opens the thiazolidine ring to obtain compound F. Said compound F corresponds to a compound of Formula I in which R4 is a hydrogen atom.

Compound F can then be refunctionalized according to Scheme 4, in order to access other compounds of Formula F

For example, an R4 group other than a hydrogen atom can optionally be introduced during a step 4 of alkylation of the thiol group to yield compound G.

2 additional steps 5 and 6 can then optionally be implemented to modify the group R2. Indeed, the raw material D (Scheme 3) is easily available in the form of methyl ester, in which the group R2 is a methyl. It is then possible to hydrolyze, or saponify, said ester G during a step 5, to obtain the carboxylic acid of formula H, in which R2 = H, then to carry out an esterification reaction during a step 6, in order to obtain the compound I carrying the desired R2 group.

Diagram 4

A fourth object of the present invention is therefore a process for the synthesis of a compound of Formula I, in which X represents an NH group, and m represents 1, comprising:

• a step 3 of reduction of a dipeptide E to obtain a compound F,

said compound of formula F having the structure of Formula I wherein R ₄ is hydrogen,

R ₂ represents a linear or branched C1 to Cio alkyl group, C1 to Cio-alkylaryl group, or a benzyl group, or a C ₃ to Cio cycloalkyl group, and

• optionally a step 4 of alkylation of the thiol function of compound F, to obtain the compound of Formula G,

said compound of Formula C having the structure of Formula I in which R ₄ is as defined above, and optionally a step of hydrolysis or saponification of the ester of Formula G, to obtain an acid, or a salt of Formula H

said compound of Formula H having the structure of Formula I in which R ₂ represents H or M ⁺ , M ⁺ being as defined above, and • optionally an esterification step of the acid, or of the salt of Formula H, to obtain a compound of Formula I

According to a particular embodiment, the present invention relates to a process for the synthesis as defined above, of a compound of Formula I as defined above, said process comprising: a step 2 of peptide coupling between said compound C and a derivative of tryptophan

D to obtain the dipeptide E,

R _I being as defined above, and

R2 represents a linear or branched C1 to Cio alkyl group, alkylaryl group, or a benzyl group, or a C3 to Cio cycloalkyl group, and a step 3 of reduction of a dipeptide E to obtain a compound F,

said compound of formula F having the structure of Formula I wherein R4 is hydrogen,

R2 represents a linear or branched C1 to Cio alkyl group, C1 to Cio-alkylaryl group, or a benzyl group, or a C ₃ to Cio cycloalkyl group, and

said compound of Formula C having the structure of Formula I wherein R4 is as defined above, and

• optionally a step of hydrolysis or saponification of the ester of Formula G, to obtain an acid, or a salt of Formula H

said compound of Formula H having the structure of Formula I in which R2 represents H or M ⁺ , M ⁺ being as defined above, and • optionally a step of esterification of the acid, or of the salt of Formula H , to obtain a compound of Formula I

According to another particular embodiment, the present invention relates to a process for the synthesis as defined above, of a compound of Formula I as defined above, said process comprising: a step 1 of addition of cysteine A on an aldehyde B, to obtain the thiazolidine-4-carboxylic compound C, step 1

-

R. ₃ being as defined above, and a step 2 of peptide coupling between said compound C and a tryptophan derivative D to obtain dipeptide E,

R _I being as defined above, and

R. ₂ represents a linear or branched C1 to Cio alkyl group, alkylaryl group, or a benzyl group, or a C ₃ to Cio cycloalkyl group, and • a step 3 of reduction of a dipeptide E to obtain a compound F,

R ₂ represents a linear or branched C1 to Cio alkyl group, C1 to Cio-alkylaryl group, or a benzyl group, or a C ₃ to Cio cycloalkyl group, and optionally a step 4 of alkylation of the thiol function of the compound F, to obtain the compound of Formula G,

said compound of Formula C having the structure of Formula I wherein R ₄ is as defined above, and

The inventors have also developed the synthesis of Scheme 5 for the case where X = NH (CO) and m represents 0:

The first step, step 1 ′, consists of an acylation reaction of cysteine A making it possible to introduce the R ₃ group. Peptide coupling in stage 2 ′, followed by hydrolysis of the ester and thioesters functions makes it possible to isolate the compound N. The R ₂ and R _{4 groups} can then be introduced in a conventional manner, respectively by an esterification reaction, and by an alkylation reaction of the thiol function.

The inventors have also developed the synthesis of Scheme 6 for the case where X = O:

Diagram 6

The first step, step 1 ”, consists in opening the epoxy ring of the raw material O, by a protected thiolate, making it possible to obtain the compound P, in which the thiol function is protected by a protective group. Said protecting group may be a trityl group, or another group conventionally used to protect a thiol function. The P group can also be an R ₄ group as defined above. A conventional alkylation reaction during step 2 ”then makes it possible to form the ether bond, and to introduce the R3 group.

The ester group can be saponified or hydrolyzed in step 3 "to yield compound R in the form of carboxylic acid, or carboxylate.

A step 4 "of peptide coupling between the carboxylic acid R and the derivative of Tryptophan D makes it possible to isolate the dipeptide S. Conventional reactions of deprotection, saponification, alkylation and esterification give access to the other compounds of Formula I.

A fifth object of the present invention is therefore a process for the synthesis of a compound of Formula I as defined above, in which X represents an O group, and m represents 1, comprising:

• a step 4 ”of peptide coupling between said compound C and a tryptophan derivative D to obtain dipeptide E,

D optionally at least 1 deprotection / re-functionalization step to obtain a compound of Formula I

According to a particular embodiment, the present invention relates to a process for the synthesis as defined above, of a compound of Formula I as defined above, said process comprising: a step 3 ”of saponification, or d hydrolysis of the ester group of the compound

Formula Q, to obtain a carboxylic acid of Formula R,

a step 4 of peptide coupling between said compound C and a tryptophan derivative D to obtain dipeptide E,

• optionally at least 1 deprotection / re-functionalization step to obtain a compound of Formula I

According to another particular embodiment, the present invention relates to a process for the synthesis as defined above, of a compound of Formula I as defined above, said process comprising:

• a 2 '' stage of alkylation of the alcohol P to obtain an ether of Formula Q

without which R3 is as defined in claim 1, and • a step 3 ”of saponification, or hydrolysis of the ester group of the compound of Formula Q, to obtain a carboxylic acid of Formula R,

a step 4 ”of peptide coupling between said compound C and a tryptophan derivative D to obtain dipeptide E,

• a step 1 ”of opening of an epoxide of formula O with a nucleophilic thiol protected by a protective group p, to obtain a secondary alcohol of formula P,

O in which p is a protecting group, in particular a trityl, a step 2 ”of alkylation of the alcohol P to obtain an ether of Formula Q

The different raw materials used in the syntheses described above can be used with stereochemistry, R, S or racemic, depending on the stereochemistry that it is desired to obtain in the final product. Moreover, in the case where R4 is a hydrogen atom, the compound can be obtained in the form of a thiol, or else in the form of a dimer as defined above. Mixtures can be obtained, and the two compounds can then be separated, for example by chromatography techniques. A thiol compound can also be converted to a dimer under oxidizing conditions, for example in the presence of oxygen. A sixth object of the present invention relates to a process for the synthesis of a dimer of Formula I as defined above, comprising:

• a step G ”of oxidation of a compound of Formula I:

A seventh object of the present invention is a pharmaceutical composition for its use as an inhibitor of β-lactamases, in combination with an antibiotic agent, comprising,

• a compound of Formula I as defined above, its pharmaceutically acceptable salt, solvate or hydrate, and

• an acceptable pharmaceutical excipient.

The term “excipient” is understood to mean any non-active substance associated with the active principle of a medicament and the function of which is to facilitate the administration, storage and / or transport of the active principle to its site of absorption.

"Pharmaceutically acceptable excipients" are understood to mean substances which are non-toxic, biologically tolerable and biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or used as a vehicle, carrier or diluent to facilitate the administration. administration of an agent and which is compatible therewith. According to the invention, a pharmaceutically acceptable excipient can be, for example, and without limitation: saline, physiological, isotonic, buffered solutions, gelling agents, dispersants, solubilizers, stabilizers, preservatives, sweeteners, etc. According to a particular embodiment, the present invention relates to a pharmaceutical composition for its use, as defined above, as a combination product for simultaneous, separate or staggered use in the context of antibiotic treatment.

According to a particular embodiment, the present invention relates to a pharmaceutical composition for its use, as defined above, comprising a compound of Formula I as defined above, its pharmaceutically acceptable salt, solvate or hydrate, and an antibiotic agent, in particular an antibiotic agent belonging to the class of b-lactams, as a combination product for simultaneous, separate use or spread over time as part of an antibiotic treatment.

According to another particular embodiment, the present invention relates to a pharmaceutical composition for its use, as defined above, in which the antibiotic is chosen from penicillin derivatives, cephalosporins, monobactams, and carbapenems.

According to a particular embodiment, the present invention relates to a pharmaceutical composition in combination with an antibiotic agent, comprising,

• a compound of Formula I as defined above, its salt, solvate or pharmaceutically acceptable hydrate,

• an acceptable pharmaceutical excipient, in which said antibiotic agent belongs in particular to the class of β-lactams, in particular chosen from penicillin derivatives, cephalosporins, monobactams and carbapenems.

According to another particular embodiment, the present invention relates to a pharmaceutical composition for its use, as defined above, said composition being formulated for an intravenous mode of administration, or for an oral mode of administration.

According to a particular embodiment, the present invention relates to a pharmaceutical composition for its use, as defined above, said compound of Formula I being in galenic form, at a rate of 10 to 200 mg / kg of the patient's body weight. .

"10-200 mg / kg" refers to all doses from 10 mg / kg to 200 mg / kg, for example 10, 50, 100, 150 or 200 mg / kg.

According to a particular embodiment, the present invention relates to a pharmaceutical composition for its use, as defined above, said compound of Formula I being present in an amount of 0.2 g to 3 g per unit dose. From "0.2 to 3 g per unit dose" means all doses from 0.2 g to 3 g, for example 0.2, 0.5, 1, 2 or 3 g.

The compositions of the present invention are in particular administered at a rate of 2 to 4 doses per day.

An eighth object of the present invention is a pharmaceutical composition comprising a novel compound of Formula IV as defined above, or a compound of Formula III as defined above, its pharmaceutically acceptable salt, solvate or hydrate, in combination with an acceptable pharmaceutical excipient.

According to a particular embodiment, the present invention relates to a pharmaceutical composition comprising a novel compound of Formula IV as defined above, or a compound of Formula III as defined above, its pharmaceutically acceptable salt, solvate or hydrate, said compound being present in an amount of 10 mg / kg to 200 mg / kg of the patient's body weight.

According to a particular embodiment, the present invention relates to a pharmaceutical composition comprising a compound of Formula IV as defined above, or a compound of Formula III as defined above, its salt, solvate or pharmaceutically acceptable hydrate, in combination with an acceptable pharmaceutical excipient, said compound of Formula IV or III being in particular being present in an amount of 0.2 to 3 g per unit dose.

According to a particular embodiment, the present invention relates to a pharmaceutical composition comprising a novel compound of Formula IV as defined above, or a compound of Formula III as defined above, its pharmaceutically acceptable salt, solvate or hydrate, said compound being present in an amount of 0.2 to 3 g per unit dose.

According to a particular embodiment, the present invention relates to a pharmaceutical composition as defined above, comprising a compound chosen from:

A ninth object of the present invention is a method of treating bacterial infections in humans or animals, comprising the administration, in combination with an antibiotic belonging to the class of β-lactams, of a therapeutically effective amount. of a compound of formula I as defined above, its pharmaceutically acceptable salt, solvate or hydrate.

A tenth object of the present invention is a kit comprising:

- a first container containing a compound of Formula I as defined above, for its use as defined above, its pharmaceutically acceptable salt, solvate or hydrate, and

- a second container containing an antibiotic, as a combination product for simultaneous, sequential or separate use in antibiotic therapy.

The following examples and figures illustrate the invention without limiting its scope.

Figure 1 shows the proton NMR spectrum of the MAF056 molecule. A is a signal characteristic of the thiol monomer. B is a signal characteristic of the dithiol dimer. Examples

ABBREVIATIONS

AcOEt Ethyl acetate MeOH Methanol

BzCl Benzoyl chloride MgS0 ₄ Magnesium sulfate

CH2CI2 Dichl oromethane MS Mass Spectrometry

Minimum Cyanoborohydride Concentration

Sodium inhibition MIC NaBEFCN

DMF Dimethylformamide NaCl Sodium chloride

DMSO Dimethyl sulfoxide NaHC0 ₃ Sodium bicarbonate l-Ethyl-3- (3-

EDCI dimethylaminopropyl) NaOH Sodium hydroxide carbodiimide

New Delhi metallo-beta

ESI NDM-1 lactamase electrospray ionization

EÎ2Ü Diethyl ether OXA-48 Oxacillinase-48

Magnetic resonance

Et ₃ N Triethylamine ¹³ C nuclear NMR of carbon Mass Spectrometry

EtOH Ethanol HRMS High Resolution

H ₂ 0 Water TES Triethylsilane

HCl Hydrochloric acid TFA Trifluoroacetic acid

HOBt Hydroxybenzotriazole Trp Tryptophan

Inhibitory concentration

CI50 TrtSH Triphenylmethane thiol median Klebsiella pneumoniae

KPC-2

Carbapenemase-2 Magnetic resonance

Proton nuclear Ή NMR

The compounds described in the examples below were prepared according to the following schemes:

Derivatives in which X = NH

Derivatives in which X = NHC (O)

Example 1 Compound MAF019

4-Methylbenzaldehyde (1.07 mL, 9.07 mmol, 1.1 eq.) Was added to a solution of L- cysteine (1 g, 8.25 mmol, 1 eq.) in a mixture of EtOH / H ₂ 0 (80 mL / 8 mL). The reaction mixture was stirred under argon and at room temperature for 24 h. The solvent was evaporated under reduced pressure and the solid thus obtained was washed with 1Έΐ2q and then dried in vacuo to obtain the compound MAF019. NMR Ή (300 MHz, DMSO-Î¾) d = 7.39 (d, J = 8.0 Hz, 1H, CH _I ), 7.32 (d, J = 8.0 Hz, 1H, CH _A Î), 7.16 (m, 2H, CH _M ), 5.63 (s, 0.5H, SO / NH), 5.46 (s, 0.5H, SO / NH), 4.24 (dd, J = 7.1 Hz, J = 4.4 Hz, 0.5H, Œ / COOH), 3.88 (dd, J = 8.6 Hz, J = 7.3 Hz, 0.5H, Œ / COOH), 3.40- 3.26 (m, 1H, G¾S), 3.17-3.04 (m, 1H, CH ₂ S), 2.30 (s, 1.5 H, / ₃ ), 2.28 (s, 1.5H, / ₃ ). ¹³ C NMR (75 MHz, DMSO- ^) d = 173.0 (COOH), 172.3 (COOH), 138.1 (C _M ), 137.6 (C _M ), 136.8 (CM), 135.9 (CM), 129.0 (CH r) , 128.8 (CH A r), 127.2 (CH A r), 126.9 (CH A r), 71.7

(NCHS), 71.1 (NCHS), 65.4 (CHN), 64.9 (CHN), 38.5 (CH ₂ S), 37.9 (CH ₂ S), 20.7 (CH), 20.7 (CH). ESI ⁺ mass: [M + H] ⁺ = 224.1, [M + Na] ⁺ = 246.1. HRMS: (ESL-MS, m / z) calculated for NCHI NNa0 ₂ S [M + Na] ^+: 246.0559, found: 246.0565. Example 2 Compound MAF021

Compound MAF019 (489 mg, 2.19 mmol, 1.0 eq) was dissolved in anhydrous DMF (10 mL). ₃ N Et (0.92 mL, 6.57 mmol, 3 eq.), HOBt (355 mg, 2.63 mmol, 1.2 eq.), EDCI (0.46 mL , 2.63 mmol, 1.2 eq.) And L-Trp-COOMe were added at room temperature. The mixture was stirred under argon and at room temperature for 5 days, then a saturated aqueous solution of NaHCO ₃ (50 mL) was added. The aqueous phase was extracted with AcOEt (3 x 50 mL), then the combined organic phases were dried over MgSCO, filtered and concentrated under reduced pressure. The reaction crude was purified by chromatography on silica gel (cyclohexane / AcOEt 8/2) to obtain compound MAF021 in the form of a white solid (583 mg, 65%).

Rf: 0.71 (Cyclohexane / AcOEt 3: 7). NMR Ή (300 MHz, CDC1 ₃ ) d = 8.16 (s, 1H, CONtf), 7.68 (d, J = 8.0 Hz, 0.8H, CH _M ), 7.55 (m, 1H, CH _M ), 7.35 (m , 1H, CH _M ), 7.24-7.06 (m, 4H, CH _M ), 6.99 (m, 1H, CH _M ), 6.95-6.92 (m, 2H, CH _M ), 5.49 (s, 0.20H, SO / NH), 4.95 (dd, J = 13.9, 5.9 Hz, 1H, CHCOO), 4.70 (s, 0.80H, SO / NH), 4.30 (dd, J = 7.8, 3.7 Hz, 0.8H, NHŒ / CO), 3.86 (m, 0.2H, NHŒ / CO), 3.75 (s, 2.4H, COOŒC), 3.70 (s, 0.6H, COOCH3), 3.60 (dd, J = 11.0, 3.7 Hz, 0.8H , G¾S), 3.46-3.29 (m, 3.2H, G¾S + CH 2), 2.34 (s, 2.4H, CH3), 2.34 (s, 0.6H, CH3). ¹³ C NMR (75 MHz, CDCI3) d = 172.5 (CO), 172.1 (CO), 171.2 (CO), 138.5 (CM), 136.2 (CM), 136.1 (CM), 135.5 (CM), 129.4 (CHM) , 127.8 (CM), 127.4 (CHM), 127.1 (CHM), 122.8 (CHM), 122.5 (CHM), 122.4 (CHM), 120.0 (CHM), 118.7 (CHM), 118.5 (CHM), 111.5 (CHM) , 110.2 (CM), 71.2 (SCH), 71.1 (SCH), 66.7 (NCH), 66.2 (NCH), 52.8 (CH), 52.6 (CH ₃ ), 38.3 (CH ₂ S), 37.0 (CH ₂ S) , 27.5 (CH ₂ ), 21.3 (CH ₃ ). MS ESI ⁺ : [M + H] ⁺ = 424.2, [M + Na] ⁺ = 446.2, [2M + Na] ⁺ = 869.3. HRMS: (ESI + -MS, m / z) Calculated for C ₂₃ H ₂₅ N ₃₀ ₃ SNa [M + Na] ⁺ : 446.1509, found: 446.1501.

Example 3 Compound MAF024 - Dimer

Compound MAF021 (500 mg, 1.18 mmol, 1.0 eq.) Was dissolved in anhydrous MeOH (12 mL), then ₃ CN NaBH (79 mg, 1.18 mmol, 1 eq.), A was added at room temperature. The mixture was stirred under argon for 15 minutes, then TFA (0.18 mL, 2.36 mmol, 2.0 eq.) Was added dropwise. The reaction medium was stirred under argon and at room temperature for 3 h, then a saturated aqueous solution of NaHCO ₃ (30 mL) was added. The aqueous phase was extracted with TAcOEt (3 x 50 mL). The combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSCL, filtered and concentrated under reduced pressure to obtain the compound MAF024 - dimer in the form of a white solid (452 mg, 90%).

Rf: 0.49 (Cyclohexane / AcOEt 3: 7). Ή NMR (300 MHz, DMSO-ÎC) d = 11.07 (s, 2 H, NH), 8.63 (s, 2 H, NH), 7.49 (m, 4 H, NH, CH _M ), 7.34 (d, J = 8.0 Hz, 2H, CH _M ), 7.21 (m, 2H, CH _M ), 7.09 - 6.90 (m, 12H, CH _M ), 4.64 (m, 2H, tfCOOMe), 3.60 (d, J = 6.9 Hz, 6H, COO CH), 3.51-3.24 (m, 8H, SOH, CtfCO, CH 2), 3.16 (d, J = 4.7 Hz, 4H, CH 2), 2.70 (d, J = 5.7 Hz, 2H, SC77H) , 2.24 (m, 6H, CH3). ¹³ C NMR (75 MHz, DMSO-ÎC) d = 172.5 (CO), 136.6 (CM), 129.2 (CHM), 128.9 (CHM), 127.5 (CM), 124.3 (CH), 121.4 (CHM), 118.9 ( CHM), 118.5 (CHM), 111.9 (CHM), 109.5, 62.6 (CHNH), 53.1 (CHNH), 52.5 (CH ₃ ), 50.5 (CH ₂ NH), 27.4 (CH ₂ ), 26.7 (CH ₂ S), 21.2 (CH ₃ ). HRMS: (ESI ⁺ -MS, m / z) Calculated for C ₄₆ H ₅₃ N ₆ O ₆ S ₂ [M + H] ⁺ : 849.3468, found: 849.3456.

Example 4 Compound MAF025

Compound MAF024 (100 mg, 0.235 mmol, 1.0 eq.) Was dissolved at room temperature in anhydrous MeOH (5 mL). NaOH (19 mg, 0.470 mmol, 2 eq.), Trimethyl phosphate (55 pL, 0.470 mmol, 2 eq.), And 1,4-dithioerythritol (145 mg, 0.940 mmol, 4 eq.) Were added and the mixture was stirred under argon and at room temperature for 16 h. The reaction medium was acidified to pH 1 by adding a 1M aqueous HCl solution, then concentrated under reduced pressure. The product was purified by flash column chromatography (CH ₂ Cl ₂ / MeOH, 95: 5) to obtain compound MAF025 in the form of a white solid (35 mg, 35%).

Rf: 0.40 (CH ₂ Cl ₂ / MeOH, 9: 1). Ή NMR (300 MHz, MeOD) d = 7.66 (d, J = 7.8 Hz, 1H, CH _AX ), 7.20 (m, 2H, C // _Al ), 7.07-7.02 (m, 4H, C // _Al ) , 6.90 (d, J = 7.7 Hz, 2H, C // _Al ), 3.50 - 3.35 (m, 5H), 3.18 (m, 1H, CHK), 2.87 (m, 1H, SOH), 2.74 (m, 1H , SOH), 2.29 (s, 3H,

CH ₃ ), 1.97 (s, 3H, SCH ₃ ). ¹³ C NMR (75 MHz, MeOD) d = 173.5 (CO), 169.1 (CO), 140.1, 138.0 (3 x CM), 130.7 (CH A r), 130.5 (CH A r), 129.0 (CM), 124.6 (CH), 122.4 (CH A r), 119.9 (CH Ac), 119.5 (CHM), 112.5 (CH A r), 111.6 (CCH), 59.6 (CHNH), 53.2 (CHNH), 53.1 (CH ₂ NH) , 35.7 (CH ₂ S), 29.1 (CH ₂ ), 21.2 (CH ₃ ), 15.4 (SCH ₃ ). MS ESI ⁺ : [M + H] ⁺ = 426.2, [M + Na] ⁺ = 448.2. HRMS: (ESI ⁺ -MS, m / z) Calculated for C ₂₃ H ₂₈ N ₃₀ ₃ S [M + H] ⁺ : 426.1846, found: 426.1837.

Example 5 Compound MAF027

L-Cysteine (1 g, 8.25 mmol, 1.0 eq.) Was dissolved in distilled GH2O. (25 mL) and NaOH (1 g, 24.80 mmol, 3 eq.) Was added. The solution thus obtained was cooled to 0 ° C and BzCl (2 mL, 17.23 mmol, 2.1 eq.) Was added with vigorous stirring, while keeping the temperature of the medium below 5 ° C. The reaction medium was stirred at room temperature for 30 minutes, then cooled to 0 ° C. The medium was neutralized by adding 1M aqueous HCl solution, resulting in precipitation of the product. The suspension was filtered, then the solid was washed with cold water, then dried under high vacuum. Recrystallization from CHCL allowed compound MAF027 to be isolated in the form of a white solid (2.67 g, 98%).

Rf: 0.46 (AcOEt / MeOH 9: 1); NMR * H (300 MHz, CDCL) d = 7.95 (d, J = 9.0 Hz, 2 H, 2 x C # Ar), 7.80 (d, J = 9.0 Hz, 2 H, 2 x CH _I ), 7.61- 7.55 (m, 2H, NH, CH _I ), 7.45-7.35 (m, 5H, 5 x CH _AI ), 4.96-4.90 (m, 1H, Œ / NH), 3.68 (d, J = 6.0 Hz, 2H, CH ₂ S). ¹³ C NMR (75 MHz, CDCL) d = 193.8 (COS), 173.0 (COOH), 168.9 (CONH), 136.3 (C _M ), 134.2 (CH _A r), 133.8 (CM), 132.8 (CHM), 128.9 (CH r), 128.8 (CH A r), 127.7 (CH A r), 127.5 (CH A r), 54.7 (Œ / NH), 30.1 (CH ₂ S). MS ESI ⁺ : [M + H] ⁺ = 330.1, [M + Na] ⁺ = 352.1. HRMS: (ESU-MS, m / z) Calculated for Ci ₇ Hi ₅ N0 ₄ SNa [M + Na] ⁺ : 352.0614, found: 352.0612.

Example 6 Compound MAE028

Compound MAF027 (1 g, 3.04 mmol, 1.0 eq.) Was dissolved in a mixture of anhydrous DMF (15 mL). Et3N (1.27 mL, 9.11 mmol, 3 eq.), HOBt (492 mg, 3.64 mmol, 1.2 eq.), EDCI (0.64 mL, 3 , 64 mmol, 1.2 eq.), And L-Trp-COOMe (773 mg, 3.04 mmol, 1 eq.) Were added sequentially at room temperature. The mixture thus obtained was stirred under argon for 36 h at 40 ° C, then a saturated aqueous solution of NaHCC (25 mL) was added. The aqueous phase was extracted with AcOEt (3 x 50 mL) and the combined organic phases were dried over anhydrous MgSCL, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography. (Cyclohexane / AcOEt, 8: 2) to obtain compound MAF028 in the form of a white solid (174 mg,

Rf: 0.31

7.99 (s, 1H, NH), 7.94 (dd, J = 3.0 Hz, J = 9.0 Hz, 2H, 2 x C // _Ar ), 7.65-7.35 (m, 9 H, 9 x C // _Ar ) , 7.25-7.19 (m, 2 H, CH _Ai, NH), 7.11 (dt, J = 3.0 Hz, J = 9.0 Hz, 1H, / _Ar ), 7.05-6.99 (m, 2 H, 2 x / _Ar ) , 4.91- 4.84 (m, 2H, 2 x Œ / NH), 3.65 (C Hj), 3.61-3.55 (m, 2H, G¾S), 3.32 (t, J = 6.0 Hz, J = 3.0 Hz, 2H, C Hi). ¹³ C NMR (75 MHz, CDCh) d = 193.6 (COS), 172.0 (CO), 169.8 (CO), 167.8 (CO), 136.5 (CA _T ), 136.1 (C _Ar ), 134.1 (Œ / _Ar ), 133.1 (C _Ar ), 132.1 (Œ / _Ar ), 128.9 (Œ / _Ar ), 128.7 (Œ / _Ar ), 127.6 ((// _.Ai ), 127.3 (C // _Al ), 123.3 (CH _Ar ), 122.3 (C // _Al ), 119.8 (C // _Al ), 118.6 (C // _Al ), 111.4 (Œ / _Ar ), 109.8 (CA _T ), 54.6 (Œ / NH), 53.3 (Œ / NH) , 52.6 (CH), 30.3 (ŒfcS), 27.6 (CH ₂ ).

MS ESI ⁺ : [M + Na] ⁺ = 552.2, [2M + Na] ⁺ = 1081.3. HRMS: (ESI + -MS, m / z) Calculated for C ₂₉ H ₂₇ N ₃₀ ₅ SNa [M + Na] ⁺ : 552.1564, found: 552.1553.

Example 7 Compound MAF030

Compound MAF028 (50 mg, 0.094 mmol, 1.0 eq.) Was dissolved at room temperature in anhydrous EtOH (5 mL). NaOH (23 mg, 0.566 mmol, 6 eq.) Was added and the mixture was stirred under argon and at room temperature for 2 h. The reaction medium was acidified to pH 1 by adding a 1M aqueous HCl solution, then the aqueous phase was extracted with AcOEt. The organic phase was washed with H ₂ 0, with an aqueous solution saturated with NaCl, then dried over MgS0 ₄ , filtered, and concentrated under reduced pressure, to obtain the compound MAF030 in the form of a white solid ( 37 mg, quantitative).

NMR Ή (300 MHz, MeOD-d ₄ ) d = 8.0 (s, 1H, NH), 7.79 (d, J = 6.0 Hz, 2H, 2 x CH _Ï ), 7.57-7.43 (m, 4H, 4 x CH _Aï ), 7.30 (d, J = 9.0 Hz, 1H, CH _Ai ), 7.12 (s, 1 H, CH _Ai ), 7.79 (dt, J =

1.0 Hz, J = 8.0 Hz, 1 H, C tf _Ar ), 6.95 (dt, J = 1.0 Hz, J = 8.0 Hz, 1 H, C tf _Ar ), 4.78-4.68 (m, 1H + 1H, 2 x Œ / NH), 3.42-3.20 (m, 2H, CH ₂ ), 3.01-2.82 (ddd, J = 6.0 Hz, J = 12.0 Hz, J = 24.0 Hz, 2H, G¾S). ¹³ C NMR (75 MHz, MeOD-d ₄ ) d = 174.9 (CO), 172.3 (CO), 170.3 (CO), 138.0 (CA r), 135.1 (CAT), 133.0 (CH r), 129.6 (CHA r), 128.8 (CAT), 128.5 (CH _Aî ), 124.6 (CH r), 122.4 (CH r), 119.8 (CH _Ar ), 119.2 (CH _Ar ), 112.2 (CH _Ar ), 110.7 (CCH), 57.4 (CHNH), 54.7 (CHNH), 28.3 (CH ₂ ), 26.9 (CH ₂ S). MS ESI ⁺ : [M + Na] ⁺ = 434.1, [2M + Na] ⁺ = 845.2. HRMS: (ESI ⁺ -MS, m / z) Calculated for C _2i H _2i N ₃ 0 ₄ SNa [M + Na] ⁺ : 434.1145, found: 434.1133.

Example 8 Compound MAF047

Methyl (2S) -glycidate (0.20 mL, 2.29 mmol, 1.0 eq) was dissolved at room temperature in anhydrous MeOH (22 mL). TrtSH (948 mg, 3.435 mmol, 1.5 eq.) And ₃ N Et (0.32 mL, 2.29 mmol, 1.0 eq.) Were added and the mixture was stirred at 65 ° C under argon for 48 h, then the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (Cyclohexane / AcOEt 8: 2) to obtain compound MAF047 as a colorless oil (705 mg, 81%).

Rf: 0.43 (Cyclohexane / AcOEt 7: 3); Ή NMR (300 MHz, CDCh) d = 7.45-7.42 (m, 6H, 6 x C # _Ar ), 7.32-7.19 (m, 9H, 9 x CH _Ar ), 4.00 (td, J = 6.0 Hz, J = 3.0 Hz, 1H, CH- OH), 3.72 (s, 3H, C¾), 2.62 (ddd, J = 24.0 Hz, J = 12.0 Hz, J = 3.0 Hz, 2H, G¾S). ¹³ C NMR (75 MHz, CDCL) d = 173.4 (CO), 144.4 (CA _T ), 129.5 (CHA r), 127.9 (CHA r), 126.7 (CHA r), 69.3 (C-OH), 66.6 (C ), 52.6 (C¾), 31.2 (CH ₂ S). HRMS: (ESC-MS, m / z) calculated for C ₂₃ H ₂₂ 0 ₃ SNa

[M + Na] ⁺ : 401.1182, found: 401.1195.

Example 9 Compound MAF048

Compound MAF047 (680 mg, 1.80 mmol, 1.0 eq.) And 4-methylbenzyl bromide (366 mg, 1.98 mmol, 1.1 eq.) Were dissolved in anhydrous DMF (6 mL). ). The solution was cooled to 0 ° C, then 60% NaH (79 mg, 1.98 mmol, 1.1 eq.) Was added. The mixture was stirred under argon and at room temperature for 16 h then the reaction was stopped by adding absolute EtOH (5 mL). GH2O (20 mL) was added and the product was extracted with AcOEt (3 x 25 mL). The combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSCE, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (Cyclohexane / AcOEt 9: 1) to obtain compound MAF048 as a colorless oil (630 mg, 73%).

Rf: 0.77 (Cyclohexane / AcOEt 7: 3); Ή NMR (300 MHz, CDCl3) d = 7.58 (m, 6H, 6 x CH _I ), 7.39-7.23 (m, 14H, 14 x CH _I ), 4.55 (dd, J = 63.0 Hz, J = 6.0 Hz, 2H, CH ₂ - O), 3.75-3.70 (m, 4 H, CH- O + C¾), 2.78 (dd, J = 6.0 Hz, J = 3.0 Hz, 2H, G¾S), 2.44 (s, 3 H, C¾). ¹³ C NMR (75 MHz, CDCI3) d = 171.2 (CO), 144.5 (CM), 137.4 (CM), 134.0 (CM), 129.5 (CH A r), 128.9 (CH _I ), 128.1 (CHM), 127.9 (CHM), 126.6 (CHM), 76.8 (CO), 72.5 (CH ₂ 0), 66.8 (Q, 51.9 (CH3), 34.3 (CH ₂ S), 21.1 (CH). MS ESI ⁺ : [M + Na ] ⁺ = 505.2, [2M + Na] ⁺ = 987.4 HRMS:. (ESL-MS, m / z) calculated for C ₃ H _3i o0 ₃ SNa [m + Na] ^+: 505.1808, found: 505.1799.

Example 10 Compound MAF051

Compound MAF048 (600 mg, 1.243 mmol, 1.0 eq) was dissolved at room temperature in anhydrous EtOH (10 mL). NaOH (149 mg, 3.729 mmol, 3 eq.) Was added and the mixture was stirred under argon and at room temperature for 2.5 h. The reaction mixture was acidified to pH 1 by addition of 1M aqueous HCl solution. AcOEt was added then the organic phase was washed with H ₂ O and with a saturated aqueous solution of NaCl. The organic phase was dried over MgSCL, filtered, and concentrated under reduced pressure to obtain compound MAF051 as a white solid (580 mg, quantitative).

NMR Ή (300 MHz, CDCl3) d = 7.79 (m, 6H, 6 x CH _M ), 7.41-7.21 (m, 14H, 14 x CH _M ), 4.55 (dd, J = 63.0 Hz, J = 9.0 Hz, 2H, CH 2 O), 3.72 (t, J = 6.0Hz, 1H, CH- O), 2.78 (m, 2H, CH ₂ S), 2.44 (s, 3H, CH 3). ¹³ C NMR (75 MHz, CDCI3) d = 176.5 (CO), 144.5 (CM), 137.6 (CM), 133.9 (CM), 129.6 (CHM), 129.0 (CM), 128.3 (CHM), 128.0 (CHM) , 126.7 (CHM), 76.5 (CH-O), 72.5 (CH ₂ 0), 66.9 (C), 34.2 (CH ₂ S), 21.2 (CH). MS ESI ⁺ : [M + Na] ⁺ = 491.2, [2M + Na] ⁺ = 959.3. HRMS: (ESL-MS, m / z) calcd _{for C 3} _{oH 28} ₀₃ SNa [M + Na] ⁺ : 491.1651, found: 491.1649. Example 11 Compound MAF052

Compound MAF048 (550 mg, 1.174 mmol, 1.0 eq.) Was dissolved in anhydrous DMF (6 mL). Et3N (0.49 mL, 3.521 mmol, 3 eq.), HOBt (190 mg, 1.408 mmol, 1.2 eq.), EDCI (0.25 mL, 1.408 mmol, 1, 2 eq.), And L-Trp-COOMe (299 mg, 1.174 mmol, 1 eq.), Were added sequentially at room temperature. The mixture was stirred under argon and at room temperature for 42h. A saturated aqueous solution of NaEICC (25 mL) was added, then the aqueous phase was extracted with AcOEt (3 x 50 mL). The combined organic phases were dried over _{anhydrous MgS0 4} , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (Cyclohexane / AcOEt 7: 3) to obtain compound MAF052 in the form of a white solid (470 mg,

Rf: 0.69

7.86 (s, 1H, NH), 7.69 (d, J = 6.0 Hz, 1H, NH), 7.58-7.55 (m, 6H, CH), 7.48-7.35 (m, 17H, CH), 7.11 (d, J = 1.0

Hz, 1H, CH _Ai ), 5.07 (dt, J = 9.0 Hz, J = 6.0 Hz, 1H, Œ / NH), 4.54 (s, 2H, CH ₂ O), 3.86-3.82 (m, 4H, CH- 0 + G%), 3.46 (d, J = 6.0 Hz, 2H, G ¾), 2.72 (d, J = 6.0 Hz, 2H, G¾S), 2.51 (s, 3H, CH ₃ ). ¹³ C NMR (75 MHz, CDCla) d = 172.2 (CO), 170.5 (CO), 144.8 (CA _T ), 137.9 (CA _T ), 136.1 (CAT), 133.9 (CAT), 129.8 (CHA r), 129.2 (CH r), 128.4 (CH r), 128.1 (CH A r), 127.4 (CAT), 126.8 (CHA r), 123.3 (CHA r), 122.3 (CHA r), 119.7 (CHA r), 118.7 (CHA r), 111.3 (CHA r), 109.8 (CA _T ), 78.2 (CH- O), 72.7 (CH ₂ O), 66.6 (C), 52.5 (CHN H), 52.1 (CHa), 34.9 (CH ₂ S ), 27.9 (CH ₂ ), 21.3 (CHa). HRMS: (ESL-MS, m / z) calculated for C ₄₂ H ₄ oN ₂ 0 ₄ SNa [M + Na] ^+: 691.2601, found: 691.2596. Example 12 Compound MAE054

Compound MAF052 (300 mg, 0.449 mmol, 1.0 eq.) Was dissolved at room temperature in anhydrous EtOH (2.5 mL). NaOH (54 mg, 1.346 mmol, 3 eq.) Was added and the mixture was stirred under argon and at room temperature for 3 h. The reaction mixture was acidified to pH 5 by addition of 1M aqueous HCl solution. AcOEt was added and the organic phase was washed with ELO and with saturated aqueous NaCl solution. The organic phase was dried over MgSCL, filtered, and concentrated under reduced pressure to obtain compound MAF054 as a white solid (293 mg, quantitative). Ή NMR (300 MHz, CDCh) d = 7.63 (s, 1H, NH), 7.45 (d, J = 8.0 Hz, 1H, C // _Ar ), 7.33 - 7.21 (m, 6H, 6x / _Ar ), 7.19 -6.99 (m, 12H, 12x / _Ar ), 6.91 (d, J = 2.4 Hz, 4H, 4xC f / _Ar ), 6.78 (d, J = 2.0 Hz, 1H, CH), 6.73 (d, J = 8.1 Hz, 1H), 4.77 (d, J = 8.0 Hz, 1H, Œ / NH), 4.18 (s, 2H, CH ₂ O), 3.54 (t, J = 5.3 Hz, 1H, CH-O), 3.19 ( m, 2H, G), 2.42 (d, J = 5.3Hz, 2H, G¾S), 2.19 (s, 3H, CH ₃ ). ¹³ C NMR (75 MHz, CDCh) d = 175.8 (CO), 171.4 (CO), 144.7 (C _Ar ), 137.9 (CA _T ), 136.1 (C _Ar ), 133.7 (C _Ar ), 129.8 (/ _Ar ), 129.2 (Œ / _Ar ), 128.4 (Œ / _Ar ), 128.1

(Œ / _Ar ), 127.5 (CA _T ), 126.9 (Œ / _Ar ), 123.5 (Œ / _Ar ), 122.3 (Œ / _Ar ), 119.8 (Œ / _Ar ), 118.7 (Œ / _Ar ), 111.3 (Œ / _Ar ), 109.4 (C _Ar ), 78.1 (CH-O), 72.7 (CH ₂ 0), 66.7 (C), 52.6 (Œ / NH), 34.7 (CH ₂ S), 27.5 (CH ₂ ), 21.3 (CH). HRMS: (ESL-MS, m / z) calculated for C _4i H ₈ N ₂ 0 ₄ SNa [M + Na] ^+: 677.2444, found: 677.2430.

Example 13 Compound MAF055

Compound MAF052 (50 mg, 0.075 mmol, 1.0 eq.) Was dissolved at room temperature in anhydrous CH2Cl2 (4 mL). TFA (13 µL, 0.164 mmol, 2.2 eq.) And TES (1.2 µL, 0.0075 mmol, 0.1 eq.) Were added and the mixture was stirred under argon and at room temperature. for 2 h. The reaction was stopped by adding a saturated aqueous solution of NaHCO ₃ (20 mL) and the product was extracted with CH2Cl2 (3 x 25 mL).

The combined organic phases were washed with GH2O and with a saturated aqueous NaCl solution, then dried over MgSCL, filtered and concentrated under reduced pressure to obtain the compound MAF055 in the form of a white solid (18 mg, 56%). .

Ή NMR (300 MHz, CDCL) d = 8.08 (s, 1 H, NH), 7.54 (d, J = 6.0 Hz, 1H, Ctf _Ar ), 7.33 (d, J = 6.0 Hz, 1H, C # _Ar ), 7.27-7.11 (m, 7H, CH _Aï ), 7.04 (d, J = 1.0 Hz, 1H, CH _Aï ), 4.95 (dd, J =

9.0 Hz, J = 6.0 Hz, 1H, Œ / NH), 4.48 (q, J = 9.0 Hz, 2H, CH ₂ O), 4.00 (dd, J = 6.0 Hz, J = 3.0 Hz, 1H, CH. O ), 3.67 (s, 3H, CH ₃ ), 3.33 (ddd, J = 12.0 Hz, J = 6.0 Hz, J = 1.0 Hz, 2H, CH 2), 2.83 (m, 2H, G¾S), 2.35 (s, 3H, CH ₃ ), 1.53 (t, J = 9.0Hz, 1H, SH). ¹³ C NMR (75 MHz, CDCL) d = 172.2 (CO), 170.4 (CO), 138.2 (C _Ar ), 136.2 (C _Ar ), 133.7 (C _Ar ), 129.4 (CH _Aî ), 128.4 (CH _AÏ ) , 127.5 (C _Ar ), 123.1 (CH _Aî ), 122.4 (CH _Aî ), 119.8 (CH _Aî ), 118.8 (CH _Aî ), 111.3

(CH _Al ), 109.8 (C _AT ), 79.9 (CH- O), 72.9 (CH ₂ O), 52.5 CHN H), 52.2 (CH ₃ ), 27.9 (CH ₂ ), 27.2

(CH 2 S), 21.3 (C¾). HRMS: (ESL-MS, m / z) calculated for C ₂₃ H ₂₆ N ₂ 0 ₄ SNa [M + Na] ^+: 449.1505, found: 449.1497. Example 14 Compound MAF056

Compound MAF054 (50 mg, 0.076 mmol, 1.0 eq.) Was dissolved at room temperature in anhydrous CH2Cl2 (4 mL). TFA (13 µL, 0.168 mmol, 2.2 eq.) And TES (1.3 µL, 0.0077 mmol, 0.1 eq.) Were added and the mixture was stirred under argon and at room temperature. for 2 h. The reaction was stopped by adding a saturated aqueous solution of NaHCO ₃ (20 mL) and the product was extracted with CH2Cl2 (3 x 25 mL). The combined organic phases were washed with IΉ2O and with a saturated aqueous NaCl solution, then dried over MgSCL, filtered and concentrated under reduced pressure to obtain obtain the compound MAF056 in the form of a white solid (17 mg, 53%, mixture 80% thiol and 20% dimer by ¾ NMR).

Ή NMR (300 MHz, MeOD-d ₄ ) d = 7.60 (d, J = 7.8 Hz, 1H, CH _I ), 7.34-6.83 (m, 8H), 4.73 (m, 1H, Œ / NH), 4.38 ( dd, J = 28.7, 11.3 Hz, 2H, CH ₂ O), 4.11-4.01 (m, 1H), 3.90 (dd, J = 6.0, 4.2 Hz, 1H, O CH), 2.77 - 2.57 (m, 2H, CH ₂ S), 2.29 (2xs, 3H, C Hj), 1.29 (s, 1H, SH).

¹³ C NMR (75 MHz, CDCh) d = 175.0 (CO), 171.4 (CO), 138.2 (C _M ), 136.2 (C _M ), 133.6 (CM), 129.4 (CHM), 128.4 (CHM), 127.6 ( CM), 123.4 (CHM), 122.4 (CHM), 119.9 (CHM), 118.8 (CHM), 111.4 (CHM), 109.6 (CM), 79.8 (CH- O), 72.9 (CH ₂ O), 52.8 (Œ / NH), 27.1 (CH ₂ ), 27.1 (CH ₂ S), 21.3 (CH). HRMS: (ESC-MS, m / z) calculated for C ₂₂ H ₂₄ N ₂ 0 ₄ SNa [M + Na] ⁺ : 435.1349, found: 435.1338.

Example 15 Compound MAE063

Compound MAF019 (118 mg, 0.530 mmol, 1.2 eq.) Was dissolved in anhydrous DMF (2.5 mL). ₃ N Et (0.18 mL, 1.326 mmol, 3 eq.), HOBt (72 mg, 0.530 mmol, 1.2 eq.), EDCI (0.09 mL, 0.530 mmol, 1.2 eq.), And the compound AD128, prepared according to the method described in the publication Tetrahedron, 2000, 56, p.5479-5492, (130 mg, 0.442 mmol, 1.0 eq.) Were added at temperature ambient. The mixture was stirred under argon for 40 h at room temperature then a saturated aqueous solution of NaHCO ₃ (25 mL) was added. The aqueous phase was extracted with AcOEt (3 x 50 mL), then the combined organic phases were dried over MgS0 ₄ , filtered and concentrated at reduced pressure. The reaction crude was purified by chromatography on silica gel (cyclohexane / AcOEt 8/2) to obtain compound MAF063 in the form of a white solid (144 mg, 65%).

Rf: 0.51 (Cyclohexane / AcOEt 1: 1); NMR Ή (300 MHz, CDC1 ₃ ) d = 8.27 (s, 0.4H, CONtf), 8.20 (s, 0.6H, CONtf), 7.97 (d, J = 9.7 Hz, 0.53H, N //), 7.79 ( d, J = 9.5 Hz, 0.41H, N //),

7.50-6.94 (m, 13H), 6.55 (d, J = 8.1 Hz, 0.41H, CH _M ), 5.45-5.27 (m, 1.44H, Ph CH, S CH), 4.82 (m, 1H, Œ / COO ), 4.35-4.14 (m, 1H, Œ / CONH), 3.86-3.757 (m, 0.56H), 3.71-3.62 (m, 1H, CH // S), 3.50 - 3.46 (3 xs, 3H, COO CH ₃ ), 3.32-3.20 (m, 1H, CH // S), 2.35 - 2.28 (3 xs, 3H, CH ₃ ). ¹³ C NMR (75 MHz, CDCh) d = 172.10 (CO), 171.41 (CO), 170.98 (CO), 140.39 (CM), 139.96 (CM), 138.63 (CM), 138.57 (CM), 136.41 (CM) , 135.31 (CM), 135.00 (CM), 129.44 (CH AI), 129.33 (CH r), 128.64 (CH r), 128.58 (CH r), 128.28 (CH r), 127.39 (CH r), 127.15 (CH AI), 127.08 (CH r), 122.51 (CH r), 122.32 (CH A r), 121.70 (CH A r), 119.82 (CH A r), 119.38 (CH _I ), 119.01 (CH A r), 114.45 (CM), 111.61 (CH A r), 111.33 (CH A r), 71.55 (SCH),

71.13 (SCH), 70.63 (SCH), 66.39 (NCH), 66.28 (NCH), 65.92 (NCH), 56.32 (CH), 56.09 (CH), 52.36 (COOCH), 52.21 (COOCH3), 45.92 (CH), 45.64 (CH), 45.47 (CH), 38.10 (CH ₂ S), 36.77 (CH ₂ S), 36.65 (CH ₂ S), 21.30 (CH). MS ESI ⁺ : [M + H] ⁺ = 500.2, [M + Na] ⁺ = 522.2. HRMS: (ESL-MS, m / z) Calculated for C ₂₉ H ₂₉ N ₃₀ ₃ SNa [M + Na] ⁺ : 522.1822, found: 522.1802.

Example 16 Compound MAE064

Compound MAF063 (134 mg, 0.268 mmol, 1.0 eq.) Was dissolved in anhydrous MeOH (3 mL) then NaBILCN (18 mg, 0.268 mmol, 1 eq.) Was added at room temperature. The mixture was stirred under argon for 15 minutes then TFA (0.04 mL, 0.536 mmol, 2.0 eq.) Was added dropwise. The reaction medium was stirred under argon and at room temperature for 3 h, then a saturated aqueous solution of NaHCC (30 mL) was added. The aqueous phase was extracted with TAcOEt (3 x 50 mL). The combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSCL, filtered and concentrated under reduced pressure to obtain compound MAF064 in the form of a white solid (72 mg, 53%).

Rf: 0.43 (Cy cl ohexane / AcOEt 4: 6); Ή NMR (250 MHz, CDCh) d = 8.42 (bs, 1H, CONtf), 8.17-7.88 (m, 1H, Ntf), 7.43 - 6.94 (m, 13H), 6.81 (d, J = 8.0 Hz, 0.5H ), 5.56 - 5.24 (m, 1H, Ph CH), 4.99 (d, J = 5.5 Hz, 0.5H, CHCOO), 4.92 - 4.88 (m, 0.5H, CHCOO), 3.63-3.62 (2 xs, 1.5H , COOCH ₃ ), 3.59-3.54 (m, 1H, CH / NH), 3.50-3.49 (2 xs, 1.5H, COO CH ₃ ), 3.39-3.14 (m, 2H, ŒNH, CH / NH,), 2.87 -2.63 (m, 2H, CH ₂ S), 2.34-2.30 (m, 3H, CH ₃ ). ¹³ C NMR (75 MHz, CDCh) d = 172.41 (CO), 172.18 (CO), 172.06 (CO), 171.95 (CO), 171.80 (CO), 140.28 (CM), 139.35 (CM), 139.26 (CM), 137.12 (CM) , 136.43 (CM), 135.85 (CM), 135.74 (CM), 135.61 (CM), 135.39 (CM), 129.26 (CHM), 128.93 (CHM), 128.88 (CHM), 128.82 (CHM), 128.66 (Œ / _Ar ), 128.57 (CHM), 128.28 (CHM), 128.15 (CHM), 128.08 (CHM), 127.54 (CHM), 127.20 (CHM), 127.14 (CHM), 126.80 (CM), 122.48 (CHM), 122.23 ( CHM), 119.82 (CHM), 119.76 (CHM), 119.51 (CHM), 119.45 (CHM), 119.35 (CHM), 119.24 (CHM), 115.09 (CM), 114.09 (CM), 114.02 (CM), 111.44 ( CHM), 111.28 (CHM), 62.82 (NCH), 62.62 (NCH), 62.39 (NCH), 56.53 (CH), 56.02 (CH), 55.53 (CH), 55.08 (CH), 52.50 (COOCH), 52.31 ( COOCH3), 51.88 (CH2NH), 51.75 (CH ₂ NH), 51.55 (CH ₂ NH), 51.52 (CH ₂ NH), 45.37 (CHCOO), 45.15 (CHCOO), 44.65 (CHCOO), 27.20 (CH ₂ S) , 27.06 (CH ₂ S), 26.92 (CH ₂ S), 26.83 (CH ₂ S), 21.22 (C¾). MS ESI ⁺ : [M + H] ⁺ = 502.2, [M + Na] + = 524.2. HRMS: (ESI ⁺ - MS, m / z) calculated for C ₂₉ H ₃₂ N ₃ 0 ₃ S [M + H] ⁺ = 502.2159, found: 502.2141.

Example 17 Compound MAE065

Compound MAF064 (50 mg, 0.100 mmol, 1.0 eq.) Was dissolved at room temperature in anhydrous EtOH (1.5 mL). NaOH (12 mg, 0.299 mmol, 3 eq.) Was added and the mixture was stirred under argon and at room temperature for 3 h. The reaction mixture was acidified to pH 3 by addition of 1M aqueous HCl solution. AcOEt was added and the organic phase was washed with ELO and with saturated aqueous NaCl solution. The organic phase was dried over MgS0 ₄ , filtered, and concentrated under reduced pressure to obtain the compound MAF065 in the form of a white solid (45 mg, 93%, complex racemic mixture and thiol / dimer by ¹ H NMR).

Ή NMR (300 MHz, MeOD-d ₄ ) d = 7.57 - 6.85 (m, 15H), 5.62-5.20 (m, 1H, Ph CH), 4.85- 4.70 (m, 1H, CHCOO), 4.13 - 3.77 (m , 2H, ŒCNH), 3.70-3.38 (m, 1H, ŒNH), 2.95 - 2.43

(m, 1H, CH // S), 2.33-2.25 (m, 3H, CH ₃ ), 2.04-1.84 (m, 1H, OHS), 1.28 (s, 1H, SH). ¹³ C NMR (75 MHz, MeOD-d ₄ ) d = 173.89 (COOH), 173.73 (COOH), 172.63 (COOH), 172.52 (COOH), 172.28 (COOH), 172.19 (COOH), 172.03 (COOH), 167.76 (CONH), 167.59 (CONH), 167.27 (CONH), 167.20 (CONH), 166.93 (CONH), 166.81 (CONH), 142.49 (C _M ), 142.32 (CM), 142.27 (CM), 141.95 (CM), 141.87 (CM), 141.10 (CM), 140.96 (CM), 140.83 (CM), 140.67 (CM), 138.12 (CM), 137.95 (CM), 131.37 (CHM), 131.20 (CHM), 130.88 (CHM), 130.73 (CHM), 130.62 (CHM), 130.05 (CHM), 129.86 (CHM), 129.61 (CHM), 129.41 (CHM), 128.09 (CHM), 127.90 (CHM), 123.50 (CHM), 123.27 (CHM), 122.68 (CHM), 119.83 (CHM), 115.42 (CM), 114.69 (CM), 112.49 (CHM), 112.27 (CHM), 61.32 (CH), 61.15 (CH), 60.11 (CH), 59.16 (CH), 58.40 (CH), 57.91 (CH), 51.15 (CH ₂ NH), 50.81 (CH ₂ NH), 50.52 (CH ₂ NH) , 46.58 (CHCOO), 46.33 (CHCOO), 46.10 (CHCOO), 30.72 (CH ₂ SS), 30.43 (CH ₂ SS), 30.19 (CH ₂ SS), 26.83 (CH ₂ S), 25.43 (CH ₂ S) , 25.13 (CH ₂ S), 21.26 (C¾). MS ESI ⁺ : [M + H] ⁺ = 488.2, [M + Na] ⁺ = 510.2. HRMS: (ESI + -MS, m / z) Calculated for C ₂₈ H ₃ oN ₃ 0 ₃ S [M + H] ⁺ : 488.2002, found: 488.1983.

Example 18 General procedure for in vitro b-lactamase inhibition tests

The IC50 values were determined relative to the panel of purified carbapenemase: OXA-48, KPC-2 and NDM-1 by spectrophotometric assay, using the ULTROSPEC 2000 UV spectrophotometer and SWIFT II software (GE Healthcare, Velizy-Villacoublay , France). The compounds were dissolved in stock solutions of 10 mM DMSO; more dilute stock solutions were then prepared if necessary by also dissolving them in DMSO. The test conditions were as follows: 100 mM phosphate buffer, pH 7 (added with 50 mM Zn ²⁺ in the NDM-1 test, and with 50 mM NaHCO ₃ in the OXA-48 test), 100 pM of imipenem (Tianam). The reaction was followed at 297 nm, for 600 seconds at 25 ° C with 3 minutes incubation (compound / carbapenemase). Each inhibitor compound was assayed at seven different concentrations, in triplicate to calculate an error value with a 95% confidence interval (p <0.05). The IC50 values were determined using the equation IC50 = ((1 / 0.5 x vO) - m) / q, where vO is the rate of hydrolysis of the reporter substrate (vO being the rate measured in the absence of inhibitor), q the intercept of the y-axis and m the slope of the resulting linear regression.

Example 19 General procedure for determining minimum inhibition concentrations

MIC values were determined by microdilution of the broth, in triplicate, in cation-adjusted Mueller Hinton broth according to Clinical guidelines. Laboratory Standards Institute (CLSI). Clinical enterobacterial E. coli NDM-1 GUE strains expressing NDM-1 carbapenemase were used. The experiments were performed in microtiter plates containing the medium with imipenem and inhibitors (dissolved in DMSO). Three concentrations of inhibitors were tested: 50, 100 and 200 mM. The plates were incubated overnight at 37 ° C for 18-24 hrs.

Example 20 Results of the inhibition tests and of the determinations of the IC 50 values Table 1 summarizes the results obtained during the inhibition tests according to Example 18, and the determinations of the IC ₅₀ values according to Example 19. The compounds obtained according to Examples 1 to 18 were tested, as well as other compounds which were obtained in the same way by the implementation of said examples.

Claims

1. Compound of Formula I

Formula I

in which :

• n represents 0 or 1,

• m represents a value from 0 to 4,

• X represents NH, O, -NHC (O),

• Ri represents

^■ H,

^■ aryl, in particular phenyl,

^■ heteroaryl, in particular imidazoyl,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ linear or branched C 1 to C 10 heteroalkyl,

^■ C3 to Cio cycloalkyl, or

^■ C3 to Cio cycloheteroalkyl,

• R2 represents

^■ H,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ Ci to Cio-alkylaryl, in particular benzyl,

^■ C3 to Cio cycloalkyl, or

^■ M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R ₃ represents

^■ aryl, in particular phenyl, or

^■ heteroaryl, in particular pyridyl,

• R4 represents

^■ H,

^■ aryl, in particular phenyl,

^■ heteroaryl, in particular imidazoyl,

^■ Ci to Cio-alkylaryl, in particular benzyl, ^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ linear or branched C 1 to C 10 heteroalkyl,

^■ C3 to Cio cycloalkyl,

^■ C3 to Cio cycloheteroalkyl,

^■ trityl, or

^■ -C (0) R ₆ , FC, being an aryl group, in particular phenyl, or a linear or branched C 1 to C 10 alkyl group, in particular methyl, said aryl, alkylaryl or heteroaryl of R 1, R ₂ , R ₃ and R ₄ possibly being substituted on the aromatic ring by one or more substituents chosen from: halogen, in particular Cl, linear or branched C1 to Cio alkyl, in particular methyl,

-OR ₅ , R ₅ being a linear or branched C1 to Cio alkyl group,

-N (¾) 2, RS being as defined above, C3 to Cio cycloalkyl, C3 to Cio cycloheteroalkyl, said compound of Formula I possibly being in the form of a dimer in which two molecules of Formula I are linked together by a disulfide bridge, said compound of Formula I or its dimer possibly being in the form of a salt, solvate or pharmaceutically acceptable hydrate, the asymmetric centers of said compound of Formula I or its dimer being of R or S configuration, or a mixture of these configurations, for its use as a β-lactamase inhibitor.

2. A compound of Formula I according to claim 1, for use thereof according to claim 1, Formula I wherein:

• n represents 0 or 1,

• m represents a value from 0 to 4,

• X represents NH, O, -NHC (O), • Ri represents

^■ H,

^■ aryl, in particular phenyl, or

^■ C 1 to C 6 alkyl, in particular methyl,

• R ₂ represents

^■ H,

^■ C 1 to 6 alkyl, in particular methyl, or

^■ M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R ₃ represents

^■ aryl, in particular phenyl,

^■ heteroaryl, including pyridyl, said aryl or heteroaryl of R ₃ can be substituted in ortho, meta and / or para positions by one or more substituents selected from halogen, in particular Cl, alkyl -C _O, in particular methyl,

• R ₄ represents

^■ H,

^■ alkyl -C _O, in particular methyl,

^■ aryl, in particular phenyl,

^■ trityl,

^■ acetyl, or

^■ benzoyl, said compound of Formula I possibly being in the form of a dimer in which two molecules of Formula I are linked together by a disulfide bridge, said compound of Formula I or its dimer possibly being in the form of a salt. , of a pharmaceutically acceptable solvate or hydrate, the asymmetric centers of said compound of Formula I or of its dimer being of R or S configuration, or a mixture of these configurations.

3. A compound of Formula I according to one of claims 1 or 2, for use thereof according to one of claims 1 or 2, Formula I wherein:

• n represents 0 or 1,

• m represents 0 or 1,

• X represents NH, O, -NHC (O),

• Ri represents

^■ H,

^■ aryl, in particular phenyl, or

^■ C1 to C3 alkyl, in particular methyl,

• R2 represents

^■ H,

^■ C1 to C3 alkyl, in particular methyl, or

^■ M ⁺ , M being a metal chosen from Na, K, or Li,

• R3 represents

• R4 represents

^■ H,

^■ trityl,

^■ acetyl, or

^■ benzoyl, said compound of Formula I possibly being in the form of a salt, a solvate or a pharmaceutically acceptable hydrate, the asymmetric centers of said compound of Formula I being of R or S configuration, or a mixture of these configurations.

4. A compound according to one of claims 1 to 3, for its use according to one of claims 1 to 3, Formula I wherein:

X represents NH, and m represents 1, said compound being a compound of Formula IA

wherein n, R1, R2, R3 and R4 are as defined in claim 1 to 3, said compound of Formula IA or Formula II-A may be in the form of a salt, solvate or a pharmaceutically acceptable hydrate, the asymmetric centers of said compound of Formula IA or of Formula II-A being of the R or S configuration, or a mixture of these configurations, or in which:

X represents O, and m represents 1, said compound being a compound of Formula IB

or a dimer of Formula II-B

wherein n, R1, R2, R3 and R4 are as defined in claim 1 to 3, said compound of Formula IB or Formula II-B may be in the form of a salt, solvate or a pharmaceutically acceptable hydrate, the asymmetric centers of said compound of Formula IB or of Formula II-B being of the R or S configuration, or a mixture of these configurations, or in which:

X represents NH (CO), and m represents 0, said compound being a compound of Formula I-C

Formula IC

or a dimer of Formula II-C

wherein n, Ri, R2, R3 and R4 are as defined in claim 1 to 3, said compound of Formula IC or Formula II-C may be in the form of a pharmaceutically acceptable salt, solvate or hydrate, the asymmetric centers of said compound of Formula IC or Formula II-C being of the configuration R or S, or a mixture of these configurations.

5. Compound according to one of claims 1 to 4, for its use according to one of claims 1 to 4, in which the pdactamase belongs to class A, B, C or D.

6. Compound according to claim 5, in which the pdactamase belongs to the class of carbapenemases, in particular in which the carbapenemase is of the NDM type, of the OXA type, or of the KPC type.

7. Compound according to one of claims 1 to 6, for its use according to one of claims 1 to 6, said compound being chosen from:

or their pharmaceutically acceptable salts, solvates or hydrates.

8. Compound of Formula III

in which :

• n represents 0 or 1,

• m represents a value from 0 to 4,

• X represents NH, O,

• Ri represents

^■ H,

^■ aryl, in particular phenyl,

^■ heteroaryl, in particular imidazoyl,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ linear or branched C 1 to C 10 heteroalkyl,

^■ C3 to Cio cycloalkyl, or

^■ C3 to Cio cycloheteroalkyl,

• R2 represents

^■ H,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ Ci-Cio-alkylaryl, in particular benzyl,

^■ C ₃ to Cio cycloalkyl, or ^■ M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R.3 represents

^■ heteroaryl, in particular pyridyl,

^■ aryl, if X = NH, said aryl of R ₃ is substituted in ortho, meta and / or para by one or more substituents chosen from halogen, in particular Cl, linear or branched C1 to Cio alkyl, in particular methyl,

-OR _5, R ₅ being an alkyl group _Ci-Cr> linear or _branched,

• R ₄ represents

^■ H,

^■ aryl, in particular phenyl,

^■ heteroaryl, in particular imidazoyl,

^■ Ci-Cio-alkylaryl, in particular benzyl,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ linear or branched C 1 to C 10 heteroalkyl,

^■ C ₃ to Cio cycloalkyl,

^■ C ₃ to Cio cycloheteroalkyl,

^■ trityl, or

^■ -C (0) R ₆ , Ri, being an aryl group, in particular phenyl, or a linear or branched C 1 to C 10 alkyl group, in particular methyl, said aryl, alkylaryl or heteroaryl of R 1, R ₂ , R ₃ and R ₄ possibly being substituted on the aromatic ring by one or more substituents chosen from: halogen, in particular Cl, linear or branched C1 to Cio alkyl, in particular methyl,

-OR ₅ , R ₅ being a linear or branched C1 to Cio alkyl group,

9. A compound of Formula III according to claim 8 for use thereof according to claim 6, Formula III wherein:

X represents O or NH.

10. Compound of Formula IV

Formula IV

in which :

• n represents 0 or 1,

• m represents a value from 0 to 4,

• X represents NH, O, -NHC (O),

• Ri represents

^■ H,

^■ aryl, in particular phenyl,

^■ heteroaryl, in particular imidazoyl,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ linear or branched C 1 to C 10 heteroalkyl,

^■ C3 to Cio cycloalkyl, or

^■ C ₃ to Cio cycloheteroalkyl, • R-2 represents

■ H,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ Ci-Cio-alkylaryl, in particular benzyl,

^■ C3 to Cio cycloalkyl, or

^■ M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R ₃ represents

^■ aryl,

^■ heteroaryl, in particular pyridyl, if X = NH, or NH (CO), said aryl of R ₃ is substituted in ortho, meta and / or para by one or more substituents chosen from halogen, in particular Cl, C1 to Cio alkyl, linear or branched, in particular methyl,

-OR _5, R ₅ being an alkyl group _Ci-Cr> linear or _branched,

• R ₄ represents

^■ H,

^■ aryl, in particular phenyl,

^■ heteroaryl, in particular imidazoyl,

^■ Ci-Cio-alkylaryl, in particular benzyl,

^■ linear or branched C1 to Cio alkyl, in particular methyl,

^■ linear or branched C 1 to C 10 heteroalkyl,

^■ C ₃ to Cio cycloalkyl,

^■ C ₃ to Cio cycloheteroalkyl,

^■ trityl,

^■ -C (0) R ₆ , Ri, being an aryl group, in particular phenyl, or a linear or branched C 1 to C 10 alkyl group, in particular methyl, said aryl, alkylaryl or heteroaryl of R 1, R ₂ , R ₃ and R ₄ possibly being substituted on the aromatic ring by one or more substituents chosen from: halogen, in particular Cl, linear or branched C1 to Cio alkyl, in particular methyl, -OR ₅ , R ₅ being a linear or branched C1 to Cio alkyl group,

-N (R5) 2, R5 being as defined above, C3 to Cio cycloalkyl, C3 to Cio cycloheteroalkyl, said compound of Formula IV possibly being in the form of a dimer in which two molecules of Formula III are linked together by a disulfide bond, said compound of Formula IV or its dimer possibly being in the form of a salt, solvate or pharmaceutically acceptable hydrate, the asymmetric centers of said compound of Formula IV or its dimer being of R or S configuration, or a mixture of these configurations.

11. A compound of Formula IV as defined in claim 10, wherein:

• n represents 0 or 1,

• m represents a value from 0 to 4,

• X represents NH, O, -NHC (O),

• Ri represents

^■ H,

^■ aryl, in particular phenyl, or

^■ C 1 to C 6 alkyl, in particular methyl

• R2 represents

^■ H,

^■ C 1 to 6 alkyl, in particular methyl, or

^■ M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R ₃ represents

^■ aryl, substituted at the ortho, meta and / or para positions by one or more substituents selected from halogen, in particular Cl, alkyl -C _O, in particular methyl,

^■ heteroaryl, including pyridyl, wherein said heteroaryl may be substituted by one or more substituents selected from halogen, in particular Cl, alkyl -C _O, in particular methyl, R4 represents

H, C1 to C6 alkyl, in particular methyl, aryl, in particular phenyl, trityl, acetyl, or benzoyl, said compound of Formula IV possibly being in the form of a dimer in which two molecules of Formula IV are linked together by a disulfide bridge, said compound of Formula IV or its dimer possibly being in the form of a pharmaceutically acceptable salt, solvate or hydrate, the asymmetric centers of said compound of Formula IV or its dimer being of R configuration or S, or a mixture of these configurations.

12. A compound of Formula IV any of claims 10 or 11 "wherein:

X represents NH, and m represents 1, said compound being a compound of Formula IV-A

Formula IV-A

or a dimer of Formula VA

wherein n, R1, R2, R3 and R4 are as defined in claim 10 or 11, said compound of Formula IV-A or Formula VA may be in the form of a salt, solvate or a pharmaceutically acceptable hydrate, the asymmetric centers of said compound of Formula IV-A or of Formula VA being of the R or S configuration, or a mixture of these configurations, or in which: X represents O, and m represents 1, said compound being a compound of Formula IV-B

Formula IV-B

or a dimer of Formula VB

wherein n, R1, R2, R3 and R4 are as defined in claim 10 or 11, said compound of Formula IV-B or Formula VB may be in the form of a salt, solvate or a pharmaceutically acceptable hydrate, the asymmetric centers of said compound of Formula IV-B or of Formula VB being of R or S configuration, or a mixture of these configurations, or in which X represents NH (CO), and m represents 0, said compound being a compound of Formula IV-C

wherein n, R1, R2, R3 and R4 are as defined in claim 10 or 11, said compound of Formula IV-C or Formula VC may be in the form of a salt, solvate or a pharmaceutically acceptable hydrate, the asymmetric centers of said compound of Formula IV-C or of Formula VC being of R or S configuration, or a mixture of these configurations.

13. A compound of Formula IV according to one of claims 10 to 12, selected from

or their pharmaceutically acceptable salts, solvates or hydrates.

14. Pharmaceutical composition for its use in combination with antibiotic therapy, comprising, · a compound of Formula I according to any one of claims 1 to 7, its pharmaceutically acceptable salt, solvate or hydrate,

• an acceptable pharmaceutical excipient, in which the antibiotic agent in G antibiotic therapy belongs to the class of b-lactams, in particular chosen from penicillin derivatives, cephalosporins, monobactams and carbapenems.

15. Pharmaceutical composition for its use according to claim 14, in a form suitable for simultaneous, separate or staggered use in antibiotic therapy.

16. Pharmaceutical composition comprising a compound of Formula IV as defined in one of claims 10 to 13, or a compound of Formula III as defined in one of claims 8 or 9, its salt, solvate or pharmaceutically acceptable hydrate. , in combination with an acceptable pharmaceutical excipient.

17. The pharmaceutical composition of claim 16, wherein said compound of Formula IV or III is present in an amount of 0.2 to 3 g per unit dose.

18. Kit including: - a first container containing a compound of formula I as defined in one of claims 1 to 7, for its use as defined in one of claims 1 to 7, its pharmaceutically acceptable salt, solvate or hydrate, and

- a second container containing an antibiotic, in a form suitable for simultaneous, sequential or separate use over time in antibiotic therapy.