FR3111544A1 - New dipeptide compounds, their manufacturing process and a new therapeutic application of dipeptide compounds. - Google Patents

Abstract

New dipeptide compounds, process for their manufacture and a new therapeutic application of dipeptide compounds. The invention relates to a new therapeutic application of dipeptide compounds. The dipeptide compounds are used as inhibitors of β-lactamases, in particular belonging to the carbapenemase class. The invention also relates to novel dipeptide compounds. (No figures)

Description

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

The present invention relates to new dipeptide compounds, their method of manufacture and a new therapeutic application of dipeptide compounds.

Bacterial infections are usually treated with antibiotics capable of inhibiting the growth of the bacteria involved, or even killing it. Among the antibiotics available, those of the β-lactam class are the most widely used in first intention.

However, bacterial resistance to this family of molecules continues to increase. One mechanism of resistance involves the production, by resistant bacteria, of β-lactamase-type enzymes that destroy the molecular structure of β-lactam class antibiotics. Bacterial resistance affects even the newest and most effective antibiotics, namely carbapenems.

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

There are different classification systems for β-lactamase enzymes. The simplest classification is a classification based on the protein sequence of the enzyme. Enzymes are thus divided into 4 classes, A, B, C, and D (Hall BG, Barlow M. Ambler Revised classification of {beta}-lactamases. 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 called “Serine-β-lactamases”, or “ SBLs ”. In these cases, the opening of the lactam ring of an antibiotic molecule takes place 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-β-lactamases”, or “ MBLs ”. A water molecule, or a hydroxide ion can be complexed with said zinc cations. The nucleophilic water molecule, or nucleophilic hydroxide ion can then open the lactam ring of an antibiotic molecule by attacking the carbonyl function of the lactam ring.

Carbapenemase enzymes fall into classes A, B, and D. Figure 1 shows the general structure of carbapenem class antibiotics, as well as the chemical structure of three clinically used carbapenems.

Diagram 1

One way to combat bacterial resistance to β-lactam class antibiotics is to develop β-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 put on the market, such as clavulanic acid, sulbactam, avibactam, or tazobactam. However, these compounds inhibit Serine-β-lactamase (SBL) type enzymes, but are inactive towards B-type metallo-β-lactamase (MBL) enzymes. Only a few compounds with inhibitory activity on all classes A, B, C and D are known to date and no type B β-lactamase inhibitor is used clinically to date.

There is therefore a real need to provide new β-lactamase inhibitors, in order to fight against bacterial resistance, in particular inhibitors having an effect against all classes of β-lactamases.

One of the aims of the invention is the provision of dipeptide compounds for use as β-lactamase inhibitors.

One of the other aims of the invention is the provision of dipeptide compounds having an inhibitory activity on all classes A, B, C and D of β-lactamases.

One of the other objects of the invention is the provision of dipeptide compounds for use as medicine.

One of the other aims of the invention is the provision of new dipeptide compounds.

One of the aims of the invention is the provision of processes for the synthesis of dipeptide compounds.

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

Another object of the invention is the use of these compounds as medicine in combination with an antibiotic treatment, separately or spread over time.

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

in which :

• n represents 0 or 1,
• m represents a value between 0 and 4,
• X represents NH, O, -NHC(O),
• R ₁ represents

• H,
• aryl, especially phenyl,
• heteroaryl, especially imidazoyl,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ heteroalkyl, linear or branched,
• C ₃ -C ₁₀ cycloalkyl, or
• C ₃ -C ₁₀ cycloheteroalkyl,

• R ₂ represents

• H,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ -alkylaryl, in particular benzyl,
• C ₃ -C ₁₀ cycloalkyl, or
• M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R ₃ represents

• aryl, especially phenyl, or
• heteroaryl, especially pyridyl,

• R ₄ represents

• H,
• aryl, especially phenyl,
• heteroaryl, especially imidazoyl,
• C ₁ to C ₁₀ -alkylaryl, in particular benzyl,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ heteroalkyl, linear or branched,
• C ₃ -C ₁₀ cycloalkyl,
• C ₃ -C ₁₀ cycloheteroalkyl,
• trityl, or
• -C(O)R ₆ , R ₆ being an aryl group, in particular phenyl, or a C ₁ to C ₁₀ alkyl group, linear or branched, in particular methyl,

said aryl, alkylaryl or heteroaryl possibly being substituted on the aromatic ring by one or more substituents chosen from:

halogen, especially Cl,

C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,

-OR ₅ , R ₅ being a C ₁ to C ₁₀ alkyl group, linear or branched,

-N(R ₅ ) ₂ , R ₅ being as defined above,

C ₃ -C ₁₀ cycloalkyl,

C ₃ -C ₁₀ 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 disulphide bridge,

said compound of Formula I or its dimer possibly being 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 C ₁ to C ₁₀ alkyl group ” is meant: a C ₁ methyl group, a C ₂ ethyl group _{, a C 3 propyl group, a C 4 butyl} group, a C ₅ pentyl group , a C ₆ hexyl group, a C ₇ heptyl group, a C ₈ octyl group, a C ₉ nonyl group, or a C ₁₀ decyl group.

By “ branched alkyl group ”, it is necessary to understand 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 tert -butyl, sec -butyl and iso-propyl group.

By “linear C ₁ to C ₁₀ heteroalkyl group ” is meant: a linear alkyl chain of 1 to 10 carbon atom(s), in particular 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.

By " branched heteroalkyl group ", it is necessary to understand a heteroalkyl group as defined above comprising substituents chosen from the list of linear alkyl groups or linear heteroalkyl groups defined above, said linear alkyl or linear heteroalkyl groups also being capable to be branched.

By “C ₃ to C ₁₀ cycloalkyl group ” is meant: a C ₃ cyclopropyl group, a C ₄ cyclobutyl group, a C ₅ cyclopentyl group, a C ₆ cyclohexyl group, a C ₇ cycloheptyl group, a C ₈ cyclooctyl group, a C ₉ cyclononyl group, or a C ₁₀ cyclodecyl group.

By “ C ₃ to C ₁₀ cycloheteroalkyl group” is meant: a cycloalkyl group as defined above, further comprising one or more heteroatoms, in particular chosen from O, N, or S, in its ring, 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.

Within the meaning 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.

Within the meaning of the present invention, the term “ 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 hydrochloride, or of trifluoroacetate, or comprising a deprotonated oxygen atom, in the form of the carboxylate.

Within the meaning of the present invention, the expression " said aryl, alkylaryl or heteroaryl which may be substituted on the aromatic ring by one or more substituents " refers, independently of one another, to all the groups R ₁ to R ₄ .

The compounds according to the present invention comprise 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 R ₁ , R ₂ , R ₃ and R ₄ groups can moreover also comprise one or more asymmetric centre(s).

Diagram 2

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 enzymes of the β-lactamase type and can thus be used in antibiotic therapy, in combination with an antibiotic treatment.

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 between 0 and 4,
• X represents NH, O, -NHC(O),
• R ₁ represents

• H,
• aryl, especially 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, especially phenyl, or
• heteroaryl, especially pyridyl,

said aryl or heteroaryl possibly being substituted ortho, meta and/or para by one or more substituents chosen from

halogen, especially Cl,

C ₁ to C ₆ alkyl, in particular methyl,

• R ₄ represents

• H,
• C ₁ to C ₆ alkyl, in particular methyl,
• aryl, especially 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 disulphide bridge,

said compound of Formula I or its dimer possibly being in the form of a pharmaceutically acceptable salt, solvate or 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.

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 0 or 1,
• X represents NH, O, -NHC(O),
• R ₁ represents

• H,
• aryl, especially phenyl, or
• C ₁ to C ₃ alkyl, in particular methyl,

• R ₂ represents

• H,
• C ₁ to C ₃ alkyl, in particular methyl, or
• M ⁺ , M being a metal chosen from Na, K, or Li,

• R ₃ represents

• aryl, in particular a phenyl optionally substituted by one or more C ₁ to C ₃ alkyl substituents, in particular methyl,

• R ₄ represents

• H,
• trityl,
• acetyl, or
• benzoyl,

said compound of Formula I possibly being 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.

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 between 0 and 4,
• X represents NH, O, -NHC(O),
• R ₁ represents

• H,
• aryl, especially phenyl,
• heteroaryl, especially imidazoyl,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ heteroalkyl, linear or branched,
• C ₃ -C ₁₀ cycloalkyl, or
• C ₃ -C ₁₀ cycloheteroalkyl,

• R ₂ represents

• H,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ -C ₁₀ -alkylaryl, in particular benzyl,
• C ₃ -C ₁₀ cycloalkyl, or
• M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R ₃ represents

• aryl,
• heteroaryl, especially pyridyl,

if X = NH, or NH(CO), said aryl is substituted ortho, meta and/or para by one or more substituents chosen from

halogen, especially Cl,

C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,

-OR ₅ , R ₅ being a C ₁ to C ₆ alkyl group, linear or branched,

-N(R ₅ ) ₂ , R ₅ being as defined above,

C ₃ -C ₁₀ cycloalkyl,

C ₃ -C ₁₀ cycloheteroalkyl,

• R ₄ represents

• H,
• aryl, especially phenyl,
• heteroaryl, especially imidazoyl,
• C ₁ -C ₁₀ -alkylaryl, in particular benzyl,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ heteroalkyl, linear or branched,
• C ₃ -C ₁₀ cycloalkyl,
• C ₃ -C ₁₀ cycloheteroalkyl,
• trityl, or
• -C(O)R ₆ , R ₆ being an aryl group, in particular phenyl, or a C ₁ to C ₁₀ alkyl group, linear or branched, in particular methyl,

said aryl, alkylaryl or heteroaryl possibly being substituted on the aromatic ring by one or more substituents chosen from:

halogen, especially Cl,

C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,

-OR ₅ , R ₅ being a C ₁ to C ₁₀ alkyl group, linear or branched,

-N(R ₅ ) ₂ , R ₅ being as defined above,

C ₃ -C ₁₀ cycloalkyl,

C ₃ -C ₁₀ 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 disulphide bridge,

said compound of Formula I or its dimer possibly being in the form of a pharmaceutically acceptable salt, solvate or 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.

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 disulphide bridge,

said compound being a compound of Formula II

in which m, n, X, R ₁ , R ₂ , R ₃ and R ₄ are as defined above,

its pharmaceutically acceptable salt, solvate or hydrate,

wherein 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 I-A

or a dimer of Formula II-A

in which n, R ₁ , R ₂ , R ₃ and R ₄ are as defined above,

said compound of Formula I-A or Formula II-A possibly being in the form of a pharmaceutically acceptable salt, solvate or hydrate,

the asymmetric centers of said compound of Formula I-A or Formula II-A being of 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 I-B

or a dimer of Formula II-B

in which n, R ₁ , R ₂ , R ₃ and R ₄ are as defined above,

said compound of Formula I-B or Formula II-B possibly being in the form of a pharmaceutically acceptable salt, solvate or hydrate,

the asymmetric centers of said compound of Formula I-B or of Formula II-B being of 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 I-C

or a dimer of Formula II-C

in which n, R ₁ , R ₂ , R ₃ and R ₄ are as defined above,

said compound of Formula I-C or Formula II-C possibly being in the form of a pharmaceutically acceptable salt, solvate or hydrate,

the asymmetric centers of said compound of Formula I-C or of Formula II-C being of R or S configuration, or a mixture of these configurations.

In the foregoing and in the following, the term " compound of Formula I " means 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 , Formula II-A, Formula II-B or 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 diastereoisomer, in particular with a diastereomeric excess greater than 95% .

The term “ greater than 95% ” also means 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 β-lactamase belongs to class A, B, C or D.

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

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

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 β-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 which the carbapenemase is of the NDM type, of the OXA type, or of KPC type, in particular of NDM type.

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

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 β-lactamase belongs to class A, B, C or D, in particular to the carbapenemase class, in particular in which the carbapenemase is of the NDM type, of the OXA type, or of the 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 treating infections bacteria.

“ Treatment ” means a means of treating a declared and detectable pathology. A treatment of bacterial infections according to the present invention consists of a treatment by the administration of at least one antibiotic belonging to the class of β-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 β-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 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, separate or spread over time in the 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 spread out use over time ” means that the compound according to the invention and the antibiotic agent are administered independently of one another, 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 between 0 and 4,
• X represents NH, O, -NHC(O),
• R ₁ represents

• H,
• aryl, especially phenyl,
• heteroaryl, especially imidazoyl,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ heteroalkyl, linear or branched,
• C ₃ -C ₁₀ cycloalkyl, or
• C ₃ -C ₁₀ cycloheteroalkyl,

• R ₂ represents

• H,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ -C ₁₀ -alkylaryl, in particular benzyl,
• C ₃ -C ₁₀ cycloalkyl, or
• M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R ₃ represents

• aryl,
• heteroaryl, especially pyridyl,

if X = NH, said aryl is substituted ortho, meta and/or para by one or more substituents chosen from

halogen, especially Cl,

C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,

-OR ₅ , R ₅ being a C ₁ to C ₆ alkyl group, linear or branched,

-N(R ₅ ) ₂ , R ₅ being as defined above,

C ₃ -C ₁₀ cycloalkyl,

C ₃ -C ₁₀ cycloheteroalkyl,

• R ₄ represents

• H,
• aryl, especially phenyl,
• heteroaryl, especially imidazoyl,
• C ₁ -C ₁₀ -alkylaryl, in particular benzyl,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ heteroalkyl, linear or branched,
• C ₃ -C ₁₀ cycloalkyl,
• C ₃ -C ₁₀ cycloheteroalkyl,
• trityl, or
• -C(O)R ₆ , R ₆ being an aryl group, in particular phenyl, or a C ₁ to C ₁₀ alkyl group, linear or branched, in particular methyl,

said aryl, alkylaryl or heteroaryl possibly being substituted on the aromatic ring by one or more substituents chosen from:

halogen, especially Cl,

C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,

-OR ₅ , R ₅ being a C ₁ to C ₁₀ alkyl group, linear or branched,

-N(R ₅ ) ₂ , R ₅ being as defined above,

C ₃ -C ₁₀ cycloalkyl,

C ₃ -C ₁₀ cycloheteroalkyl,

said compound of Formula III possibly being in the form of a dimer in which two molecules of Formula III are linked together by a disulphide bridge,

said compound of Formula III or its dimer possibly being in the form of a pharmaceutically acceptable salt, 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,

for its use as a medicine.

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 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 between 0 and 4,
• X represents NH, O, -NHC(O),
• R ₁ represents

• H,
• aryl, especially 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,
• heteroaryl, especially pyridyl,

said aryl being substituted ortho, meta and/or para by one or more substituents chosen from

halogen, especially Cl,

C ₁ to C ₆ alkyl, in particular methyl,

• R ₄ represents

• H,
• C ₁ to C ₆ alkyl, in particular methyl,
• aryl, especially 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 disulphide bridge,

said compound of Formula III or its dimer possibly being in the form of a pharmaceutically acceptable salt, solvate or hydrate,

the asymmetric centers of said compound of Formula III or 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 compound of Formula III as defined above, for its use as defined above, Formula III in which:

• n represents 0 or 1,
• m represents 0 or 1,
• X represents NH, O, -NHC(O),
• R ₁ represents

• H,
• aryl, especially phenyl, or
• C ₁ to C ₃ alkyl, in particular methyl,

• R ₂ represents

• H,
• C ₁ to C ₃ alkyl, in particular methyl, or
• M ⁺ , M being a metal chosen from Na, K, or Li,

• R ₃ represents

• aryl, substituted by one or more C ₁ to C ₃ alkyl substituents, in particular methyl,

• R ₄ represents

• H,
• trityl,
• acetyl, or
• benzoyl,

said compound of Formula III possibly being in the form of a pharmaceutically acceptable salt, solvate or 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 new compound of Formula IV

in which :

• n represents 0 or 1,
• m represents a value between 0 and 4,
• X represents NH, O, -NHC(O),
• R ₁ represents

• H,
• aryl, especially phenyl,
• heteroaryl, especially imidazoyl,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ heteroalkyl, linear or branched,
• C ₃ -C ₁₀ cycloalkyl, or
• C ₃ -C ₁₀ cycloheteroalkyl,

• R ₂ represents

• H,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ -C ₁₀ -alkylaryl, in particular benzyl,
• C ₃ -C ₁₀ cycloalkyl, or
• M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R ₃ represents

• aryl,
• heteroaryl, especially pyridyl,

if X = NH, or NH(CO), said aryl is substituted ortho, meta and/or para by one or more substituents chosen from

halogen, especially Cl,

C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,

-OR ₅ , R ₅ being a C ₁ to C ₆ alkyl group, linear or branched,

-N(R ₅ ) ₂ , R ₅ being as defined above,

C ₃ -C ₁₀ cycloalkyl,

C ₃ -C ₁₀ cycloheteroalkyl,

• R ₄ represents

• H,
• aryl, especially phenyl,
• heteroaryl, especially imidazoyl,
• C ₁ -C ₁₀ -alkylaryl, in particular benzyl,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ heteroalkyl, linear or branched,
• C ₃ -C ₁₀ cycloalkyl,
• C ₃ -C ₁₀ cycloheteroalkyl,
• trityl, or
• -C(O)R ₆ , R ₆ being an aryl group, in particular phenyl, or a C ₁ to C ₁₀ alkyl group, linear or branched, in particular methyl,

said aryl, alkylaryl or heteroaryl possibly being substituted on the aromatic ring by one or more substituents chosen from:

halogen, especially Cl,

C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,

-OR ₅ , R ₅ being a C ₁ to C ₁₀ alkyl group, linear or branched,

-N(R ₅ ) ₂ , R ₅ being as defined above,

C ₃ -C ₁₀ cycloalkyl,

C ₃ -C ₁₀ 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 disulphide bridge,

said compound of Formula IV or its dimer which may be 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 or S configuration, or a mixture of these configurations.

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

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

• n represents 0 or 1,
• m represents a value between 0 and 4,
• X represents NH, O, -NHC(O),
• R ₁ represents

• H,
• aryl, especially 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 at 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, especially pyridyl,

said heteroaryl possibly being substituted by one or more substituents chosen from

halogen, especially Cl,

C ₁ to C ₆ alkyl, in particular methyl,

• R ₄ represents

• H,
• C ₁ to C ₆ alkyl, in particular methyl,
• aryl, especially 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 disulphide bridge,

said compound of Formula IV or its dimer which may be 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 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 disulphide 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,

wherein 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 new 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

or a dimer of Formula V-A

in which n, R ₁ , R ₂ , R ₃ and R ₄ are as defined above,

said compound of Formula IV-A or Formula V-A possibly being in the form of a pharmaceutically acceptable salt, solvate or hydrate,

the asymmetric centers of said compound of Formula IV-A or Formula V-A being of R or S configuration, or a mixture of these configurations.

According to another particular embodiment, the present invention relates to a new 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

or a dimer of Formula V-B

in which n, R ₁ , R ₂ , R ₃ and R ₄ are as defined above,

said compound of Formula IV-B or Formula V-B possibly being in the form of a pharmaceutically acceptable salt, solvate or hydrate,

the asymmetric centers of said compound of Formula IV-B or Formula V-B 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(CO), and m represents 0,

said compound being a compound of Formula IV-C

or a dimer of Formula V-C

in which n, R ₁ , R ₂ , R ₃ and R ₄ are as defined above,

said compound of Formula IV-C or Formula V-C possibly being in the form of a pharmaceutically acceptable salt, solvate or hydrate,

the asymmetric centers of said compound of Formula IV-C or of Formula V-C being of R or S configuration, or a mixture of these configurations.

In the foregoing and in the following, the term " compound of Formula IV " means 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 diastereoisomer, in particular with a diastereomeric excess greater than 95%.

The term “ greater than 95% ” also means 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 new 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 an addition of cysteine A on an aldehyde B , to lead to a thiazolidine-4-carboxylic product C. The choice of aldehyde B makes it possible to check the identity of the R ₃ group.

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 R ₂ group 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 using a derivative of tryptophan D carrying said R ₁ group. Said tryptophan derivative can be obtained by standard 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.

A reduction in step 3 then makes it possible to open the thiazolidine ring to obtain compound F. Said compound F corresponds to a compound of Formula I in which R ₄ is a hydrogen atom.

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

For example, an R ₄ 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 R ₂ group. Indeed, the raw material D ( Scheme 3 ) is easily available in the form of methyl ester, in which the R ₂ group 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 R ₂ = H, then to implement an esterification reaction during a step 6, in order to obtain the compound I bearing the desired R ₂ 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 a hydrogen atom,

R ₂ represents a C ₁ to C ₁₀ alkyl group, linear or branched, a C ₁ to C ₁₀ -alkylaryl group, or a benzyl group, or a C ₃ to C ₁₀ 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 wherein R ₄ is as previously defined, 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 wherein R ₂ represents H or M ⁺ , M ⁺ being as defined above, and

• optionally a step of esterifying the acid, or 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 ₁ being as defined previously, and

R ₂ represents a linear or branched C ₁ to C ₁₀ alkyl group, an alkylaryl group, or a benzyl group, or a C ₃ to C ₁₀ 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

R ₄ is a hydrogen atom,

R ₂ represents a C ₁ to C ₁₀ alkyl group, linear or branched, a C ₁ to C ₁₀ -alkylaryl group, or a benzyl group, or a C ₃ to C ₁₀ 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 wherein R ₄ is as previously defined, 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 wherein R ₂ represents H or M ⁺ , M ⁺ being as defined above, and

• optionally a step of esterifying the acid, or 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 adding cysteine A to an aldehyde B , to obtain the thiazolidine-4-carboxylic compound C ,

R ₃ being as defined above, and

• a step 2 of peptide coupling between said compound C and a derivative of tryptophan D to obtain the dipeptide E ,

R ₁ being as defined previously, and

R ₂ represents a linear or branched C ₁ to C ₁₀ alkyl group, an alkylaryl group, or a benzyl group, or a C ₃ to C ₁₀ 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

R ₄ is a hydrogen atom,

R ₂ represents a C ₁ to C ₁₀ alkyl group, linear or branched, a C ₁ to C ₁₀ -alkylaryl group, or a benzyl group, or a C ₃ to C ₁₀ 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 wherein R ₄ is as previously defined, 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 wherein R ₂ represents H or M ⁺ , M ⁺ being as defined above, and

• optionally a step of esterifying the acid, or the salt of Formula H , to obtain a compound of Formula I

.

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

Figure 5

The first step, step 1', consists of an acylation reaction of cysteine A allowing the introduction of the R ₃ group. A peptide coupling at the 2′ stage, followed by hydrolysis of the ester and thioester functions makes it possible to isolate the compound N . The R ₂ and R ₄ groups can then be introduced conventionally, 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 :

Figure 6

The first stage, stage 1'', consists of the opening of the epoxide cycle 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 protective group can 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 R ₃ group.

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

A 4'' stage 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 a group O, and m represents 1, comprising:

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

• optionally at least 1 deprotection/refunctionalization 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 3″ step 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 derivative of tryptophan D to obtain the dipeptide E ,

• optionally at least 1 deprotection/refunctionalization 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'' step of alkylation of the alcohol P to obtain an ether of Formula Q

without which R ₃ is as defined in claim 1, and

• a 3″ step of saponification, or hydrolysis of the ester group of the compound of Formula Q, to obtain a carboxylic acid of Formula R,

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

• optionally at least 1 deprotection/refunctionalization 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 1'' step of opening an epoxide of formula O with a nucleophilic thiol protected by a protective group p, to obtain a secondary alcohol of Formula P,

in which p is a protective group, in particular a trityl,

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

without which R ₃ is as defined in claim 1, and

• a 3″ step of saponification, or hydrolysis of the ester group of the compound of Formula Q, to obtain a carboxylic acid of Formula R,

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

• optionally at least 1 deprotection/refunctionalization step to obtain a compound of Formula I

The different raw materials used in the syntheses described above can be used with stereochemistry, R, S or racemic, depending on the stereochemistry that one wishes to obtain in the final product. Furthermore, in the case where R ₄ 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 chromatographic techniques. A thiol compound can also be transformed into 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 1''' oxidation step 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
• a pharmaceutically acceptable excipient.

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

" Pharmaceutically acceptable excipients " means substances that are non-toxic, biologically tolerable and biologically capable of being administered to a subject, such as an inert substance, added to a pharmacological composition or used as a vehicle, carrier or diluent to facilitate administration of an agent and which is compatible with it. 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 spread out use as part 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 β-lactams,

as a combination product for simultaneous, separate or spread out use as part of antibiotic treatment.

According to another particular embodiment, the present invention relates to a pharmaceutical composition for its use, as defined above,

wherein the antibiotic is selected 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 pharmaceutically acceptable salt, solvate or 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 a galenic form, at a rate of 10 to 200 mg/kg of the patient's body weight. .

“10 to 200 mg/kg” means 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 a proportion of 0.2 g to 3 g per unit dose.

“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 the 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 a pharmaceutically acceptable 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 at 10 mg/kg to 200 mg/kg of patient 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 pharmaceutically acceptable salt, solvate or hydrate, in combination with a pharmaceutically acceptable excipient,

said compound of Formula IV or III being in particular being present at a rate 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 a proportion 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 for 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 represents 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 _MgSO4 Magnesium sulfate _{CH2Cl2 _} Dichloromethane MS Mass spectrometry CMI Minimum Inhibitory Concentration NaBH ₃ CN Sodium cyanoborohydride DMF Dimethylformamide NaCl sodium chloride DMSO Dimethyl sulfoxide NaHCO ₃ Sodium bicarbonate EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide NaOH Sodium hydroxide ESI Ionization by electrospray NDM-1 New Delhi metallo-beta-lactamase And ₂ O Diethyl ether OXA-48 Oxacillinase-48 And ₃ N Triethylamine ^13C NMR Carbon nuclear magnetic resonance EtOH Ethanol HRMS High Resolution Mass Spectrometry _H2O Water YOUR Triethylsilane HCI Hydrochloric acid TFA Trifluoroacetic acid HOBt Hydroxybenzotriazole trp Tryptophan CI ₅₀ Median inhibitory concentration TrtSH Triphenylmethane thiol KPC-2 Klebsiella pneumoniae Carbapenemase-2 ¹ H NMR Proton nuclear magnetic resonance

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

Derivatives in which X = NH

Derivatives where X = NHC(O)

Derivatives in which X = 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 EtOH /H ₂ O (80 mL/8 mL). The reaction mixture was stirred under argon and at room temperature for 24 h. The solvent was evaporated off under reduced pressure and the solid thus obtained was washed with Et ₂ O then dried under vacuum to obtain the compound MAF019 .

¹ H NMR (300 MHz, DMSO- d ₆ ) δ = 7.39 (d, J = 8.0 Hz, 1H, C H _Ar ), 7.32 (d, J = 8.0 Hz, 1H, C H _Ar ), 7.16 (m, 2H, C H _Ar ), 5.63 (s, 0.5H, S CH NH), 5.46 (s, 0.5H, S CH NH), 4.24 (dd, J = 7.1 Hz, J = 4.4 Hz, 0.5H, CH COOH ), 3.88 (dd, J = 8.6 Hz, J = 7.3 Hz, 0.5H, CH COOH), 3.40-3.26 (m, 1H, C H ₂ S), 3.17-3.04 (m, 1H, C H ₂ S) , 2.30 (s, 1.5H, CH ₃ ), 2.28 (s, 1.5H, CH ₃ ). ¹³ C NMR (75 MHz, DMSO- d ₆ ) δ = 173.0 ( C OOH), 172.3 ( C OOH), 138.1 ( C _Ar ), 137.6 ( C _Ar ), 136.8 ( C _Ar ), 135.9 ( C _Ar ), 129.0 ( CH _Ar ), 128.8 ( CH _Ar ), 127.2 ( CH _Ar ), 126.9 ( CH _Ar ), 71.7 ( N C HS), 71.1 ( N C HS), 65.4 ( C HN), 64.9 ( C HN), 38.5 ( C H ₂ S), 37.9 ( C H ₂ S), 20.7 ( C H ₃ ), 20.7 ( C H ₃ ). Mass ESI ⁺ : [M+H] ⁺ = 224.1, [M+Na] ⁺ = 246.1. HRMS: (ESI ⁺ -MS, m/z) calculated for C ₁₁ H ₁₃ NNaO 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). Et ₃ N (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 NaHCO ₃ solution (50 mL) was added. The aqueous phase was extracted with AcOEt (3×50 mL), then the combined organic phases were dried over MgSO ₄ , 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). ¹ H NMR (300 MHz, CDCl ₃ ) δ = 8.16 (s, 1 H, CON H ), 7.68 (d, J = 8.0 Hz, 0.8H, C H _Ar ), 7.55 (m, 1H, C H _Ar ) , 7.35 (m, 1H, C H _Ar ), 7.24-7.06 (m, 4H, C H _Ar ), 6.99 (m, 1H, C H _Ar ), 6.95-6.92 (m, 2H, C H _Ar ), 5.49 (s, 0.20H, S CH NH), 4.95 (dd, J = 13.9, 5.9 Hz, 1H, CH COO), 4.70 (s, 0.80H, S CH NH), 4.30 (dd, J = 7.8, 3.7 Hz , 0.8H, NH CH CO), 3.86 (m, 0.2H, NH CH CO), 3.75 (s, 2.4H, COO CH ₃ ), 3.70 (s, 0.6H, COO CH ₃ ), 3.60 (dd, J = 11.0, 3.7 Hz, 0.8H, C H ₂ S), 3.46-3.29 (m, 3.2H, C H ₂ S + C H ₂ ), 2.34 (s, 2.4H, CH ₃ ), 2.34 (s, 0.6 H, CH ₃ ). ¹³ C NMR (75 MHz, CDCl ₃ ) δ = 172.5 (CO), 172.1 (CO), 171.2 (CO), 138.5 ( C _Ar ), 136.2 ( C _Ar ), 136.1 ( C _Ar ), 135.5 ( C _Ar ) , 129.4 ( CH _Ar ), 127.8 ( C _Ar ), 127.4 ( CH Ar ), 127.1 ( CH Ar ), 122.8 ( CH _Ar ) _{, 122.5} ( CH _Ar ), 122.4 ( CH _Ar ), 120.0 ( CH _Ar ) , 118.7 ( CH _Ar ), 118.5 ( CH _Ar ), 111.5 ( CH _Ar ), 110.2 ( C _Ar ), 71.2 (S C H), 71.1 (S C H), 66.7 (N C H), 66.2 (N C H) , 52.8 ( C H ), 52.6 ( C H ₃ ), 38.3 ( C H ₂ S), 37.0 ( C H ₂ S), 27.5 ( C H ₂ ), 21.3 ( C H 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 ₃ O 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 NaBH ₃ CN (79 mg, 1.18 mmol, 1 eq.), was 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 ambient temperature for 3 h, then a saturated aqueous solution of NaHCO ₃ (30 mL) was added. The aqueous phase was extracted with AcOEt (3 x 50 mL). The combined organic phases were washed with a saturated aqueous NaCl solution, dried over MgSO ₄ , 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). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ = 11.07 (s, 2 H, NH), 8.63 (s, 2 H, NH), 7.49 (m, 4 H, NH, CH _Ar ), 7.34 (d , J = 8.0 Hz, 2H, CH _Ar ), 7.21 (m, 2H, CH _Ar ), 7.09 – 6.90 (m, 12H, CH _Ar ), 4.64 (m, 2H, CH COOMe), 3.60 (d, J = 6.9 Hz, 6H, COO CH ₃ ), 3.51-3.24 (m, 8H, SC H H, C H CO, C H ₂ ), 3.16 (d, J = 4.7 Hz, 4H, C H ₂ ), 2.70 (d , J = 5.7 Hz, 2H, SC H H), 2.24 (m, 6H, CH ₃ ). ¹³ C NMR (75 MHz, DMSO- d ₆ ) δ = 172.5 (CO), 136.6 ( C _Ar ), 129.2 ( CH _Ar ), 128.9 ( CH _Ar ), 127.5 ( C _Ar ), 124.3 (CH), 121.4 ( CH _Ar ), 118.9 ( CH _Ar ), 118.5 ( CH _Ar ), 111.9 ( CH _Ar ), 109.5, 62.6 ( C HNH), 53.1 ( C HNH), 52.5 ( C H ₃ ), 50.5 ( C H 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 µL, 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 solution of HCl, 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). ¹ H NMR (300 MHz, MeOD) δ = 7.66 (d, J = 7.8 Hz, 1H, C H _Ar ), 7.20 (m, 2H, C H _Ar ), 7.07-7.02 (m, 4H, C H _Ar ) , 6.90 (d, J = 7.7 Hz, 2H, C H _Ar ), 3.50 – 3.35 (m, 5H), 3.18 (m, 1H, C H H), 2.87 (m, 1H, SC H H), 2.74 ( m, 1H, SC H H), 2.29 (s, 3H, C H ₃ ), 1.97 (s, 3H, S C H ₃ ). ¹³ C NMR (75 MHz, MeOD) δ = 173.5 (CO), 169.1 (CO), 140.1, 138.0 (3 x C _Ar ), 130.7 ( CH _Ar ), 130.5 ( CH _Ar ), 129.0 ( C _Ar ), 124.6 (CH), 122.4 ( CH _Ar ), 119.9 ( CH _Ar ), 119.5 ( CH _Ar ), 112.5 ( CH _Ar ), 111.6 ( C CH), 59.6 ( C HNH), 53.2 ( C HNH), 53.1 ( C H ₂ NH), 35.7 ( C H ₂ S), 29.1 ( C H ₂ ), 21.2 ( C H ₃ ), 15.4 (S C H ₃ ). MS ESI ⁺ : [M+H] ⁺ =426.2, [M+Na] ⁺ =448.2. HRMS: (ESI ⁺ -MS, m/z) calculated for C ₂₃ H ₂₈ N ₃ O 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 H ₂ O. (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 ambient temperature for 30 minutes, then cooled to 0°C. The medium was neutralized by adding a 1M aqueous solution of HCl, which caused the precipitation of the product. The suspension was filtered, then the solid was washed with cold water, then dried under high vacuum. Recrystallization from CHCl ₃ made it possible to isolate the compound MAF027 in the form of a white solid (2.67 g, 98%).

Rf : 0.46 (AcOEt/MeOH 9:1); ¹ H NMR (300 MHz, CDCl ₃ ) δ = 7.95 (d, J = 9.0 Hz, 2 H, 2 x C H _Ar ), 7.80 (d, J = 9.0 Hz, 2 H, 2 x C H _Ar ), 7.61-7.55 (m, 2H, NH, C H _Ar ), 7.45-7.35 (m, 5H, 5 x C H _Ar ), 4.96-4.90 (m, 1 H, CH NH), 3.68 (d, J = 6.0Hz, 2H, CH _2S ). ¹³ C NMR (75 MHz, CDCl ₃ ) δ = 193.8 ( C OS), 173.0 ( C OOH), 168.9 ( C ONH), 136.3 ( C _Ar ), 134.2 ( CH _Ar ), 133.8 ( C _Ar ), 132.8 ( CH _Ar ), 128.9 ( CH _Ar ), 128.8 ( CH _Ar ), 127.7 ( CH _Ar ), 127.5 ( CH _Ar ), 54.7 ( CH NH), 30.1 ( CH ₂ S). MS ESI ⁺ : [M+H] ⁺ =330.1, [M+Na] ⁺ =352.1. HRMS: (ESI ⁺ -MS, m/z) calculated for C ₁₇ H ₁₅ NO ₄ SNa [M+Na] ⁺ : 352.0614, found: 352.0612.

Example 6 Compound MAF028

Compound MAF027 (1 g, 3.04 mmol, 1.0 eq.) was dissolved in an anhydrous DMF mixture (15 mL). Et ₃ N (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 NaHCO ₃ (25 mL) was added. The aqueous phase was extracted with AcOEt (3×50 mL) and the combined organic phases were dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (Cyclohexane/AcOEt, 8:2) to obtain compound MAF028 as a white solid (174 mg, 11%).

Rf : 0.31 (Cyclohexane/AcOEt 6:4); ¹ H NMR (300 MHz, CDCl ₃ ) δ = 7.99 (s, 1 H, NH), 7.94 (dd, J = 3.0 Hz, J = 9.0 Hz, 2H, 2 x C H _Ar ), 7.65-7.35 (m , 9 H, 9 x C H _Ar ), 7.25-7.19 (m, 2 H, C H _Ar, NH), 7.11 (dt, J = 3.0 Hz, J = 9.0 Hz, 1H, C H _Ar ), 7.05- 6.99 (m, 2 H, 2 x C H _Ar ), 4.91-4.84 (m, 2 H, 2 x CH NH), 3.65 (C H ₃ ), 3.61-3.55 (m, 2H, C H ₂ S), 3.32 (t, J = 6.0 Hz, J = 3.0 Hz, 2H, C H ₂ ). ¹³ C NMR (75 MHz, CDCl ₃ ) δ = 193.6 ( C OS), 172.0 (CO), 169.8 (CO), 167.8 (CO), 136.5 ( C _Ar ), 136.1 ( C _Ar ), 134.1 ( CH _Ar ) , 133.1 ( C _Ar ), 132.1 ( CH _Ar ), 128.9 ( CH _Ar ), 128.7 ( CH Ar ), 127.6 ( CH _Ar ), 127.3 ( CH _{Ar )} , 123.3 ( CH _Ar ), 122.3 ( CH _Ar ) , 119.8 ( CH _Ar ), 118.6 ( CH _Ar ), 111.4 ( CH _Ar ), 109.8 ( C _Ar ), 54.6 ( CH NH), 53.3 ( CH NH), 52.6 (CH ₃ ), 30.3 ( CH ₂ S), 27.6 ( C H ₂ ). MS ESI ⁺ : [M+Na] ⁺ =552.2, [2M+Na] ⁺ =1081.3. HRMS: (ESI+-MS, m/z) calculated for C ₂₉ H ₂₇ N ₃ O 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 solution of HCl, then the aqueous phase was extracted with AcOEt. The organic phase was washed with H ₂ O, with a saturated aqueous NaCl solution, then dried over MgSO ₄ , filtered, and concentrated under reduced pressure, to obtain the compound MAF030 in the form of a white solid ( 37 mg, quantitative).

¹ H NMR (300 MHz, MeOD-d ₄ ) δ = 8.0 (s, 1 H, NH), 7.79 (d, J = 6.0 Hz, 2H, 2 x C H _Ar ), 7.57-7.43 (m, 4H, 4 x C H _Ar ), 7.30 (d, J = 9.0 Hz, 1H, C H _Ar ), 7.12 (s, 1 H, C H _Ar ), 7.79 (dt, J = 1.0 Hz, J = 8.0 Hz, 1 H, C H _Ar ), 6.95 (dt, J = 1.0 Hz, J = 8.0 Hz, 1 H, C H _Ar ), 4.78-4.68 (m, 1H + 1H, 2 x CH NH), 3.42-3.20 (m , 2 H, CH ₂ ), 3.01-2.82 (ddd, J = 6.0 Hz, J = 12.0 Hz, J = 24.0 Hz, 2 H, C H ₂ S). ¹³ C NMR (75 MHz, MeOD-d ₄ ) δ = 174.9 (CO), 172.3 (CO), 170.3 (CO), 138.0 ( C _Ar ), 135.1 ( C _Ar ), 133.0 ( CH _Ar ), 129.6 ( CH _Ar ), 128.8 ( C _Ar ), 128.5 ( CH _Ar ), 124.6 ( CH _Ar ), 122.4 ( CH _Ar ), 119.8 ( CH _Ar ), 119.2 ( CH _Ar ), 112.2 ( CH _Ar ), 110.7 ( C CH) , 57.4 ( CHNH ) _, 54.7 ₍ CHNH ), 28.3 ( CH2 ), 26.9 ( CH2S ). MS ESI ⁺ : [M+Na] ⁺ =434.1, [2M+Na] ⁺ =845.2. HRMS: (ESI ⁺ -MS, m/z) calculated for C ₂₁ H ₂₁ N ₃ O 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 Et ₃ N (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); ¹ H NMR (300 MHz, CDCl ₃ ) δ = 7.45-7.42 (m, 6H, 6 x C H _Ar ), 7.32-7.19 (m, 9H, 9 x C H _Ar ), 4.00 (td, J = 6.0 Hz , J = 3.0 Hz, 1H, CH- OH), 3.72 (s, 3 H, CH ₃ ), 2.62 (ddd, J = 24.0 Hz, J = 12.0 Hz, J = 3.0 Hz, 2 H, C H ₂ S ). ¹³ C NMR (75 MHz, CDCl ₃ ) δ = 173.4 (CO), 144.4 ( C _Ar ), 129.5 ( CH _Ar ), 127.9 ( CH _Ar ), 126.7 ( CH _Ar ), 69.3 ( C- OH), 66.6 ( C ), 52.6 ( CH ₃ ), 31.2 ( CH ₂ S). HRMS: (ESI ⁺ -MS, m/z) calculated for C ₂₃ H ₂₂ O 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). H ₂ O (20 mL) was added and the product was extracted with AcOEt (3 x 25 mL). The combined organic phases were washed with a saturated aqueous NaCl solution, dried over MgSO ₄ , 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); ¹ H NMR (300 MHz, CDCl ₃ ) δ = 7.58 (m, 6H, 6 x C H _Ar ), 7.39-7.23 (m, 14H, 14 x C H _Ar ), 4.55 (dd, J = 63.0 Hz, J = 6.0 Hz, 2H, CH ₂ -O), 3.75-3.70 (m, 4 H, CH- O + CH ₃ ), 2.78 (dd, J = 6.0 Hz, J = 3.0 Hz, 2H, C H ₂ S) , 2.44 (s, 3H, CH ₃ ). ¹³ C NMR (75 MHz, CDCl ₃ ) δ = 171.2 (CO), 144.5 ( C _Ar ), 137.4 ( C _Ar ), 134.0 ( C _Ar ), 129.5 ( CH _Ar ), 128.9 ( CH _Ar ), 128.1 ( CH _Ar ), 127.9 ( CH _Ar ), 126.6 ( CH _Ar ), 76.8 ( C- O), 72.5 ( C H ₂ O), 66.8 ( C ), 51.9 ( C H ₃ ), 34.3 ( C H ₂ S), 21.1 ( CH ₃ ). MS ESI ⁺ : [M+Na] ⁺ =505.2, [2M+Na] ⁺ =987.4. HRMS: (ESI ⁺ -MS, m/z) calculated for C ₃₁ H ₃₀ O 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 adding an aqueous solution of 1M HCl. AcOEt was added then the organic phase was washed with H ₂ O and with a saturated aqueous NaCl solution. The organic phase was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain compound MAF051 in the form of a white solid (580 mg, quantitative).

¹ H NMR (300 MHz, CDCl ₃ ) δ = 7.79 (m, 6H, 6 x C H _Ar ), 7.41-7.21 (m, 14H, 14 x C H _Ar ), 4.55 (dd, J = 63.0 Hz, J = 9.0 Hz, 2 H, CH ₂ O), 3.72 (t, J = 6.0 Hz, 1H, CH- O), 2.78 (m, 2 H, CH ₂ S), 2.44 (s, 3 H, C H ₃ ). ¹³ C NMR (75 MHz, CDCl ₃ ) δ = 176.5 (CO), 144.5 ( C _Ar ), 137.6 ( C _Ar ), 133.9 ( C _Ar ), 129.6 ( CH _Ar ), 129.0 ( C _Ar ), 128.3 ( CH _Ar ), 128.0 ( CH _Ar ), 126.7 ( CH _Ar ), 76.5 ( C H-O), 72.5 ( C H ₂ O), 66.9 ( C ), 34.2 ( C H ₂ S), 21.2 ( C H ₃ ). MS ESI ⁺ : [M+Na] ⁺ =491.2, [2M+Na] ⁺ =959.3. HRMS: (ESI ⁺ -MS, m/z) calculated for C ₃₀ H ₂₈ O ₃ 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). Et ₃ N (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 42 h. A saturated aqueous solution of NaHCO ₃ (25 mL) was added, then the aqueous phase was extracted with AcOEt (3×50 mL). The combined organic phases were dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (Cyclohexane/AcOEt 7:3) to obtain compound MAF052 as a white solid (470 mg, 60%).

Rf : 0.69 (Cyclohexane/AcOEt 1:1); ¹ H NMR (300 MHz, CDCl ₃ ) δ = 7.86 (s, 1 H, NH), 7.69 (d, J = 6.0 Hz, 1H, NH), 7.58-7.55 (m, 6H, C H _Ar ), 7.48 -7.35 (m, 17H, C H _Ar ), 7.11 (d, J = 1.0 Hz, 1H, C H _Ar ), 5.07 (dt, J = 9.0 Hz, J = 6.0 Hz, 1H, CH NH), 4.54 ( s, 2H, CH ₂ O), 3.86-3.82 (m, 4H, C H- O + C H ₃ ), 3.46 (d, J = 6.0 Hz, 2H, C H ₂ ), 2.72 (d, J = 6.0 Hz, 2H, C H ₂ S), 2.51 (s, 3H, C H ₃ ). ¹³ C NMR (75 MHz, CDCl ₃ ) δ = 172.2 ( C O), 170.5 (CO), 144.8 ( C _Ar ), 137.9 ( C _Ar ), 136.1 ( C _Ar ), 133.9 ( C _Ar ), 129.8 ( CH ₎ , 129.2 ( CH _Ar ), 128.4 ( CH _Ar ), 128.1 ( CH _Ar ), 127.4 ( C _Ar ), 126.8 ( CH _Ar ), 123.3 ( CH _Ar ), 122.3 ( CH _Ar ), 119.7 ( CH _Ar ) , 118.7 ( CH _Ar ), 111.3 ( CH _Ar ), 109.8 ( C _Ar ), 78.2 ( CH- O), 72.7 ( CH ₂ O), 66.6 ( C ), 52.5 ( CH NH), 52.1 (CH ₃ ), 34.9 ( CH ₂ S), 27.9 ( CH ₂ ), 21.3 (CH ₃ ). HRMS: (ESI ⁺ -MS, m/z) calculated for C ₄₂ H ₄₀ N ₂ O ₄ SNa [M+Na] ⁺ : 691.2601, found: 691.2596.

Example 12 Compound MAF054

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 an aqueous solution of HCl at 1M. AcOEt was added and the organic phase was washed with H ₂ O and with a saturated aqueous NaCl solution. The organic phase was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain compound MAF054 in the form of a white solid (293 mg, quantitative).

¹ H NMR (300 MHz, CDCl ₃ ) δ = 7.63 (s, 1H, NH), 7.45 (d, J = 8.0 Hz, 1H, C H _Ar ), 7.33 – 7.21 (m, 6H, 6xC H _Ar ), 7.19-6.99 (m, 12H, 12xC H _Ar ), 6.91 (d, J = 2.4 Hz, 4H, 4xC H _Ar ), 6.78 (d, J = 2.0 Hz, 1H, C H ), 6.73 (d, J = 8.1 Hz, 1H), 4.77 (d, J = 8.0 Hz, 1H, CH NH), 4.18 (s, 2H, CH ₂ O), 3.54 (t, J = 5.3 Hz, 1H, C H- O), 3.19 (m, 2H, C H ₂ ), 2.42 (d, J = 5.3 Hz, 2H, C H ₂ S), 2.19 (s, 3H, C H ₃ ). ¹³ C NMR (75 MHz, CDCl ₃ ) δ = 175.8 ( C O), 171.4 (CO), 144.7 ( C _Ar ), 137.9 ( C _Ar ), 136.1 ( C _Ar ), 133.7 ( C _Ar ), 129.8 ( CH ₎ , 129.2 ( CH _Ar ), 128.4 ( CH _Ar ), 128.1 ( CH _Ar ), 127.5 ( C _Ar ), 126.9 ( CH _Ar ), 123.5 ( CH _Ar ), 122.3 ( CH _Ar ), 119.8 ( CH _Ar ) , 118.7 ( CH _Ar ), 111.3 ( CH _Ar ), 109.4 ( C _Ar ), 78.1 ( C H-O), 72.7 ( C H ₂ O), 66.7 (C), 52.6 ( CH NH), 34.7 ( C H ₂ S ), 27.5 ( CH ₂ ), 21.3 ( CH ₃ ). HRMS: (ESI ⁺ -MS, m/z) calculated for C ₄₁ H ₃₈ N ₂ O 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 CH ₂ Cl ₂ (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 hrs. The reaction was stopped by adding a saturated aqueous solution of NaHCO ₃ (20 mL) and the product was extracted with CH ₂ Cl ₂ (3×25 mL). The combined organic phases were washed with H ₂ O and with a saturated aqueous NaCl solution, then dried over MgSO ₄ , filtered and concentrated under reduced pressure to obtain the compound MAF055 in the form of a white solid (18 mg, 56%).

¹ H NMR (300 MHz, CDCl ₃ ) δ = 8.08 (s, 1 H, NH), 7.54 (d, J = 6.0 Hz, 1H, C H _Ar ), 7.33 (d, J = 6.0 Hz, 1H, C H _Ar ), 7.27-7.11 (m, 7H, C H _Ar ), 7.04 (d, J = 1.0 Hz, 1H, C H _Ar ), 4.95 (dd, J = 9.0 Hz, J = 6.0 Hz, 1H, CH 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, C H ₃ ) , 3.33 (ddd, J = 12.0 Hz, J = 6.0 Hz, J = 1.0 Hz, 2H, C H ₂ ), 2.83 (m, 2H, C H ₂ S), 2.35 (s, 3H, C H ₃ ), 1.53 (t, J = 9.0 Hz, 1H, SH ). ¹³ C NMR (75 MHz, CDCl ₃ ) δ = 172.2 ( C O), 170.4 (CO), 138.2 ( C _Ar ), 136.2 ( C _Ar ), 133.7 ( C _Ar ), 129.4 ( CH _Ar ), 128.4 ( CH ₎ , 127.5 ( C _Ar ), 123.1 ( CH _Ar ), 122.4 ( CH _Ar ), 119.8 ( CH _Ar ), 118.8 ( CH _Ar ), 111.3 ( CH _Ar ), 109.8 ( C _Ar ), 79.9 ( CH- O ), 72.9 ( CH ₂ O), 52.5 ( CH NH), 52.2 (CH ₃ ), 27.9 ( CH ₂ ), 27.2 ( CH ₂ S), 21.3 (CH ₃ ). HRMS: (ESI ⁺ -MS, m/z) calculated for C ₂₃ H ₂₆ N ₂ O 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 CH ₂ Cl ₂ (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 hrs. The reaction was stopped by adding a saturated aqueous solution of NaHCO ₃ (20 mL) and the product was extracted with CH ₂ Cl ₂ (3×25 mL). The combined organic phases were washed with H ₂ O and with a saturated aqueous NaCl solution, then dried over MgSO ₄ , filtered and concentrated under reduced pressure to obtain the compound MAF056 in the form of a white solid (17 mg, 53%, 80% thiol and 20% dimer mixture by ¹ H NMR).

NMR ¹ H(300 MHz, MeOD-d₄) δ = 7.60 (d,J= 7.8Hz, 1H, CH _Ar), 7.34-6.83 (m, 8H), 4.73 (m, 1H,CHNH), 4.38 (dd,J= 28.7, 11.3Hz, 2H,CH ₂ W), 4.11-4.01 (m, 1H), 3.90 (dd,J= 6.0, 4.2Hz, 1H, OCH), 2.77 – 2.57 (m, 2H, CH ₂ S), 2.29 (2xs, 3H, CH ₃ ), 1.29 (s, 1H, SH).NMR ¹³ VS(75 MHz, CDCl₃) δ = 175.0 (VSO), 171.4 (CO), 138.2 (VS _Ar), 136.2 (VS _Ar), 133.6 (VS _Ar), 129.4 (CH _Ar), 128.4 (CH _Ar), 127.6 (VS _Ar), 123.4 (CH _Ar), 122.4 (CH _Ar), 119.9 (CH _Ar), 118.8 (CH _Ar), 111.4 (CH _Ar), 109.6 (VS _Ar), 79.8 (CH-O), 72.9 (CH ₂ O), 52.8 (CHNH), 27.1 (VSH₂), 27.1 (CH ₂ S), 21.3 (CH₃).HRMS: (ESI⁺-MS, m/z) calculated for C₂₂H₂₄NOT₂O₄SNa [M+Na]⁺: 435.1349, found: 435.1338.

Example 15 Compound MAF063

Compound MAF019 (118 mg, 0.530 mmol, 1.2 eq.) was dissolved in anhydrous DMF (2.5 mL). Et ₃ N (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 (3×50 mL), then the combined organic phases were dried over MgSO 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); ¹ H NMR (300 MHz, CDCl ₃ ) δ = 8.27 (s, 0.4H, CON H ), 8.20 (s, 0.6H, CON H ), 7.97 (d, J = 9.7 Hz, 0.53H, N H ), 7.79 (d, J = 9.5 Hz, 0.41H, N H ), 7.50-6.94 (m, 13H), 6.55 (d, J = 8.1 Hz, 0.41H, C H _Ar ), 5.45-5.27 (m, 1.44H , Ph CH , S CH ), 4.82 (m, 1H, CH COO), 4.35-4.14 (m, 1H, CH CONH), 3.86-3.757 (m, 0.56H), 3.71-3.62 (m, 1H, CH H S), 3.50 – 3.46 (3 xs, 3H, COO CH ₃ ), 3.32-3.20 (m, 1H, CH H S), 2.35 – 2.28 (3 xs, 3H, CH ₃ ). ¹³ C NMR (75 MHz, CDCl ₃ ) δ = 172.10 (CO), 171.41 (CO), 170.98 (CO), 140.39 ( C _Ar ), 139.96 ( C _Ar ), 138.63 ( C _Ar ), 138.57 ( C _Ar ) , 136.41 ( C _Ar ), 135.31 ( C _Ar ) , 135.00 ( C _Ar ), 129.44 ( CH Ar ), 129.33 ( CH _Ar ), 128.64 ( CH _{Ar )} , 128.58 ( CH _Ar ), 128.28 ( CH _Ar ), 127.39 ( CH _Ar ), 127.15 ( CH _Ar ), 127.08 ( CH _Ar ), 122.51 ( CH Ar ), 122.32 ( CH _Ar ), 121.70 ( CH _{Ar )} , 119.82 ( CH _Ar ), 119.38 ( CH Ar ₎ , 119.01 ( CH _Ar ), 114.45 ( C _Ar ), 111.61 ( CH _Ar ), 111.33 ( CH _Ar ), 71.55 (S C H), 71.13 (S C H), 70.63 (S C H), 66.39 (N C H), 66.28 (N C H), 65.92 (N C H), 56.32 ( C H), 56.09 ( C H), 52.36 (COO C H ₃ ), 52.21 (COO C H ₃ ), 45.92 ( C H), 45.64 ( C H), 45.47 ( C H), 38.10 ( C H ₂ S), 36.77 ( C H ₂ S), 36.65 ( C H ₂ S), 21.30 ( C H ₃ ). MS ESI ⁺ : [M+H] ⁺ =500.2, [M+Na] ⁺ =522.2. HRMS: (ESI ⁺ -MS, m/z) calculated for C ₂₉ H ₂₉ N ₃ O ₃ SNa [M+Na] ⁺ : 522.1822, found: 522.1802.

Example 16 Compound MAF064

The compound MAF063 (134 mg, 0.268 mmol, 1.0 eq.) was dissolved in anhydrous MeOH (3 mL) then NaBH ₃ CN (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 ambient temperature for 3 h, then a saturated aqueous solution of NaHCO ₃ (30 mL) was added. The aqueous phase was extracted with AcOEt (3 x 50 mL). The combined organic phases were washed with a saturated aqueous NaCl solution, dried over MgSO ₄ , filtered and concentrated under reduced pressure to obtain the compound MAF064 in the form of a white solid (72 mg, 53%).

Rf : 0.43 (Cyclohexane/AcOEt 4:6); ¹ H NMR (250 MHz, CDCl ₃ ) δ = 8.42 (bs, 1H, CON H ), 8.17-7.88 (m, 1H, N H ), 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, CH COO), 4.92 – 4.88 (m, 0.5H, CH COO), 3.63-3.62 (2 xs, 1.5H, COO CH ₃ ), 3.59-3.54 (m, 1H, CH H NH), 3.50-3.49 (2 xs, 1.5H, COO CH ₃ ), 3.39-3.14 (m, 2H, C H NH, CH H NH,), 2.87-2.63 (m, 2H, CH ₂ S), 2.34-2.30 (m, 3H, CH ₃ ). ¹³ C NMR (75 MHz, CDCl ₃ ) δ = 172.41 (CO), 172.18 (CO), 172.06 (CO), 171.95 (CO), 171.80 (CO), 140.28 ( C _Ar ), 139.35 ( C _Ar ), 139.26 ( C _Ar ), 137.12 ( C _Ar ), 136.43 ( C _Ar ), 135.85 ( C Ar ), 135.74 ( C _Ar ), 135.61 ( C _Ar ), 135.39 ( C _{Ar )} , 129.26 ( CH _Ar ), 128.93 ( CH ₎ , 128.88 ( CH _Ar ), 128.82 ( CH _Ar ), 128.66 ( CH Ar ), 128.57 ( CH _Ar ), 128.28 ( CH _{Ar )} , 128.15 ( CH _Ar ), 128.08 ( CH _Ar ), 127.54 ( CH _Ar ) , 127.20 ( CH _Ar ), 127.14 ( CH _Ar ), 126.80 ( C _Ar ), 122.48 ( CH _Ar ), 122.23 ( CH _Ar ), 119.82 ( CH _Ar ), 119.76 ( CH _Ar ), 119.51 ( CH _Ar ), 119.45 ( CH _Ar ), 119.35 ( CH _Ar ), 119.24 ( CH _Ar ), 115.09 ( C Ar ), 114.09 ( C _Ar ), 114.02 ( C _{Ar )} , 111.44 ( CH _Ar ), 111.28 ( CH Ar ₎ , 62.82 (N C H), 62.62 (N C H), 62.39 (N C H), 56.53 ( C H), 56.02 ( C H), 55.53 ( C H), 55.08 ( C H), 52.50 (COO C H ₃ ), 52.31 (COO C H ₃ ), 51.88 ( C H ₂ NH), 51.75 ( C H ₂ NH), 51.55 ( C H ₂ NH), 51.52 ( C H ₂ NH), 45.37 ( C HCOO), 45.15 ( C HCOO ) _, 44.65 ( CHCOO ), 27.20 ( CH2S ), 27 .06 ( C H ₂ S), 26.92 ( C H ₂ S), 26.83 ( C H ₂ S), 21.22 ( C H ₃ ). MS ESI ⁺ : [M+H] ⁺ =502.2, [M+Na]+=524.2. HRMS: (ESI ⁺ -MS, m/z) calculated for C ₂₉ H ₃₂ N ₃ O ₃ S [M+H] ⁺ = 502.2159, found: 502.2141.

Example 17 Compound MAF065

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 an aqueous solution of HCl at 1M. AcOEt was added and the organic phase was washed with H ₂ O and with a saturated aqueous NaCl solution. The organic phase was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain compound MAF065 in the form of a white solid (45 mg, 93%, complex racemic and thiol/dimer mixture by ¹ H NMR).

¹ H NMR (300 MHz, MeOD-d ₄ ) δ = 7.57 – 6.85 (m, 15H), 5.62-5.20 (m, 1H, Ph CH ), 4.85-4.70 (m, 1H, CH COO), 4.13 – 3.77 (m, 2H, CH ₂ NH), 3.70-3.38 (m, 1H, C H NH), 2.95 – 2.43 (m, 1H, CH H S), 2.33-2.25 (m, 3H, CH ₃ ), 2.04- 1.84 (m, 1H, C H HS), 1.28 (s, 1H, SH). ¹³ C NMR (75 MHz, MeOD-d ₄ ) δ = 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 _Ar ), 142.32 ( C _Ar ), 142.27 ( C _Ar ), 141.95 ( C ₎ , 141.87 ( C _Ar ), 141.10 ( C _Ar ), 140.96 ( C Ar ), 140.83 ( C _Ar ), 140.67 ( C _{Ar )} , 138.12 ( C _Ar ), 137.95 ( C Ar ₎ , 131.37 ( CH _Ar ) , 131.20 ( CH _Ar ), 130.88 ( CH _Ar ), 130.73 ( CH _Ar ), 130.62 ( CH _Ar ), 130.05 ( CH _Ar ), 129.86 ( CH _Ar ), 129.61 ( CH _Ar ), 129.41 ( CH _Ar ), 128.09 ( CH _Ar ), 127.90 ( CH _Ar ), 123.50 ( CH _Ar ), 123.27 ( CH Ar), 122.68 (CH _Ar ), 119.83 ( CH _{Ar )} , 115.42 ( C _Ar ), 114.69 ( C _Ar ) , 112.49 ( CH _Ar ), 112.27 ( C _H ), 61.32 ( C H), 61.15 ( C H), 60.11 ( C H), 59.16 ( C H), 58.40 ( C H), 57.91 ( C H), 51.15 ( C H ₂ NH), 50.81 ( C H ₂ NH), 50.52 ( C H ₂ NH), 46.58 ( C HCOO), 46.33 ( C HCOO), 46.10 ( C HCOO), 30.72 ( C H ₂ SS), 30.43 ( C H ₂ Ss), 30.19 ( C H ₂ S S), 26.83 ( C H ₂ S), 25.43 ( C H ₂ S), 25.13 ( C H ₂ S), 21.26 ( C H ₃ ). MS ESI ⁺ : [M+H] ⁺ =488.2, [M+Na] ⁺ =510.2. HRMS: (ESI+-MS, m/z) calculated for C ₂₈ H ₃₀ N ₃ O ₃ S [M+H] ⁺ : 488.2002, found: 488.1983.

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

IC50 values were determined relative to the purified carbapenemase panel: 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). Compounds were dissolved in 10 mM DMSO stock solutions; 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 μM Zn ²⁺ in the NDM-1 test, and with 50 mM NaHCO ₃ in the OXA-48 test), 100 μM imipenem (Tianam). The reaction was monitored at 297 nm, for 600 seconds at 25°C with 3 minutes incubation (compound/carbapenemase). Each inhibitor compound was dosed at seven different concentrations, in triplicate to calculate an error value with a 95% confidence interval (ρ < 0.05). IC50 values were determined using the equation

CI ₅₀ = ((1/0.5 x v0) - m)/q,

where v0 is the hydrolysis rate of the reporter substrate (v0 being the rate measured in the absence of inhibitor), q the y-axis intercept, and m the slope of the resulting linear regression.

Example 19 General Procedure for Determining Minimum Inhibitory Concentrations

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

Example 20 Results of Inhibition Tests and IC Value Determinations ₅₀

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.

Table 1 Results of inhibition and IC ₅₀ tests

Claims (14)

Compound of Formula I

in which :

• n represents 0 or 1,
• m represents a value between 0 and 4,
• X represents NH, O, -NHC(O),
• R ₁ represents

• H,
• aryl, especially phenyl,
• heteroaryl, especially imidazoyl,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ heteroalkyl, linear or branched,
• C ₃ -C ₁₀ cycloalkyl, or
• C ₃ -C ₁₀ cycloheteroalkyl,

• R ₂ represents

• H,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ -alkylaryl, in particular benzyl,
• C ₃ -C ₁₀ cycloalkyl, or
• M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R ₃ represents

• aryl, especially phenyl, or
• heteroaryl, especially pyridyl,

• R ₄ represents

• H,
• aryl, especially phenyl,
• heteroaryl, especially imidazoyl,
• C ₁ to C ₁₀ -alkylaryl, in particular benzyl,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ heteroalkyl, linear or branched,
• C ₃ -C ₁₀ cycloalkyl,
• C ₃ -C ₁₀ cycloheteroalkyl,
• trityl, or
• -C(O)R ₆ , R ₆ 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 R₁, R₂, R₃and R₄which may be substituted on the aromatic ring by one or more substituents chosen from:
halogen, especially Cl,
C-alkyl₁to C₁₀, linear or branched, in particular methyl,
-GOLD₅, R₅being a C alkyl group₁to C₁₀, linear or ramified,
-N(R₅)₂, R₅being as defined above,
C-cycloalkyl₃to C₁₀,
C-cycloheteroalkyl₃to C₁₀,
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 disulphide bridge,
said compound of Formula I or its dimer possibly being 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. Compound according to Claim 1, for its use according to Claim 1, Formula I in which:

• n represents 0 or 1,
• m represents a value between 0 and 4,
• X represents NH, O, -NHC(O),
• R ₁ represents

• H,
• aryl, especially 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, especially phenyl,
• heteroaryl, especially pyridyl,

said aryl or heteroaryl of R₃which may be substituted ortho, meta and/or para by one or more substituents chosen from
halogen, especially Cl,
C-alkyl₁to C₆, in particular methyl,

• R ₄ represents

• H,
• C ₁ to C ₆ alkyl, in particular methyl,
• aryl, especially 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 disulphide bridge,
said compound of Formula I or its dimer possibly being in the form of a pharmaceutically acceptable salt, solvate or 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. Compound according to one of Claims 1 or 2, for its use according to one of Claims 1 or 2, Formula I in which:
X represents NH, and m represents 1,
said compound being a compound of Formula IA

or a dimer of Formula II-A

wherein n, R ₁ , R ₂ , R ₃ and R ₄ are as defined in claim 1 or 2,
said compound of Formula IA or Formula II-A possibly being in the form of a pharmaceutically acceptable salt, solvate or hydrate,
the asymmetric centers of said compound of Formula IA or of Formula II-A being of 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, R ₁ , R ₂ , R ₃ and R ₄ are as defined in claim 1 or 2,
said compound of Formula IB or Formula II-B possibly being in the form of a pharmaceutically acceptable salt, solvate or hydrate,
the asymmetric centers of said compound of Formula IB or of Formula II-B 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 IC

or a dimer of Formula II-C

wherein n, R ₁ , R ₂ , R ₃ and R ₄ are as defined in claim 1 or 2,
said compound of Formula IC or of Formula II-C possibly being in the form of a pharmaceutically acceptable salt, solvate or hydrate,
the asymmetric centers of said compound of Formula IC or of Formula II-C being of R or S configuration, or a mixture of these configurations. Compound according to one of Claims 1 to 3, for its use according to one of Claims 1 to 3, in which the β-lactamase belongs to class A, B, C or D, in particular to the class of carbapenemases, in particularly wherein the carbapenemase is NDM-like, OXA-like, or KPC-like. Compound according to one of Claims 1 to 4, for its use according to one of Claims 1 to 4, the said compound being chosen from:



or their pharmaceutically acceptable salts, solvates or hydrates. Compound of Formula III

in which :

• n represents 0 or 1,
• m represents a value between 0 and 4,
• X represents NH, O, -NHC(O),
• R ₁ represents

• H,
• aryl, especially phenyl,
• heteroaryl, especially imidazoyl,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ heteroalkyl, linear or branched,
• C ₃ -C ₁₀ cycloalkyl, or
• C ₃ -C ₁₀ cycloheteroalkyl,

• R ₂ represents

• H,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ -C ₁₀ -alkylaryl, in particular benzyl,
• C ₃ -C ₁₀ cycloalkyl, or
• M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R ₃ represents

• heteroaryl, especially pyridyl,
• aryl,

if X = NH, said aryl of R₃is substituted ortho, meta and/or para by one or more substituents chosen from
halogen, especially Cl,
C-alkyl₁to C₁₀, linear or branched, in particular methyl,
-GOLD₅, R₅being a C alkyl group₁to C₆, linear or ramified,
-N(R₅)₂, R₅being as defined above,
C-cycloalkyl₃to C₁₀,
C-cycloheteroalkyl₃to C₁₀,

• R ₄ represents

• H,
• aryl, especially phenyl,
• heteroaryl, especially imidazoyl,
• C ₁ -C ₁₀ -alkylaryl, in particular benzyl,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ heteroalkyl, linear or branched,
• C ₃ -C ₁₀ cycloalkyl,
• C ₃ -C ₁₀ cycloheteroalkyl,
• trityl, or
• -C(O)R ₆ , R ₆ being an aryl group, in particular phenyl, or a C ₁ to C ₁₀ alkyl group, linear or branched, in particular methyl,

said aryl, alkylaryl or heteroaryl of R₁, R₂, R₃and R₄which may be substituted on the aromatic ring by one or more substituents chosen from:
halogen, especially Cl,
C-alkyl₁to C₁₀, linear or branched, in particular methyl,
-GOLD₅, R₅being a C alkyl group₁to C₁₀, linear or ramified,
-N(R₅)₂, R₅being as defined above,
C-cycloalkyl₃to C₁₀,
C-cycloheteroalkyl₃to C₁₀,
said compound of Formula III possibly being in the form of a dimer in which two molecules of Formula III are linked together by a disulphide bridge,
said compound of Formula III or its dimer possibly being in the form of a pharmaceutically acceptable salt, 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,
for its use as a medicine. Compound of Formula III according to Claim 6, for its use according to Claim 6, Formula III in which:
X represents O, or NHC(O). Compound of Formula IV

in which :

• n represents 0 or 1,
• m represents a value between 0 and 4,
• X represents NH, O, -NHC(O),
• R ₁ represents

• H,
• aryl, especially phenyl,
• heteroaryl, especially imidazoyl,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ heteroalkyl, linear or branched,
• C ₃ -C ₁₀ cycloalkyl, or
• C ₃ -C ₁₀ cycloheteroalkyl,

• R ₂ represents

• H,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ -C ₁₀ -alkylaryl, in particular benzyl,
• C ₃ -C ₁₀ cycloalkyl, or
• M ⁺ , M being a metal chosen in particular from Na, K, or Li,

• R ₃ represents

• aryl,
• heteroaryl, especially pyridyl,

if X = NH, or NH(CO), said aryl of R₃is substituted ortho, meta and/or para by one or more substituents chosen from
halogen, especially Cl,
C-alkyl₁to C₁₀, linear or branched, in particular methyl,
-GOLD₅, R₅being a C alkyl group₁to C₆, linear or ramified,
-N(R₅)₂, R₅being as defined above,
C-cycloalkyl₃to C₁₀,
C-cycloheteroalkyl₃to C₁₀,

• R ₄ represents

• H,
• aryl, especially phenyl,
• heteroaryl, especially imidazoyl,
• C ₁ -C ₁₀ -alkylaryl, in particular benzyl,
• C ₁ to C ₁₀ alkyl, linear or branched, in particular methyl,
• C ₁ to C ₁₀ heteroalkyl, linear or branched,
• C ₃ -C ₁₀ cycloalkyl,
• C ₃ -C ₁₀ cycloheteroalkyl,
• trityl,
• -C(O)R ₆ , R ₆ 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 R₁, R₂, R₃and R₄which may be substituted on the aromatic ring by one or more substituents chosen from:
halogen, especially Cl,
C-alkyl₁to C₁₀, linear or branched, in particular methyl,
-GOLD₅, R₅being a C alkyl group₁to C₁₀, linear or ramified,
-N(R₅)₂, R₅being as defined above,
C-cycloalkyl₃to C₁₀,
C-cycloheteroalkyl₃to C₁₀,
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 disulphide bridge,
said compound of Formula IV or its dimer which may be 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 or S configuration, or a mixture of these configurations. A compound of Formula IV according to claim 8, wherein:
X represents NH, and m represents 1,
said compound being a compound of Formula IV-A

or a dimer of Formula VA

wherein n, R ₁ , R ₂ , R ₃ and R ₄ are as defined in claim 8,
said compound of Formula IV-A or Formula VA possibly being in the form of a pharmaceutically acceptable salt, solvate or hydrate,
the asymmetric centers of said compound of Formula IV-A or of Formula VA being of 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

or a dimer of Formula VB

wherein n, R ₁ , R ₂ , R ₃ and R ₄ are as defined in claim 8,
said compound of Formula IV-B or Formula VB possibly being in the form of a pharmaceutically acceptable salt, solvate or 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 wherein X represents NH(CO), and m represents 0,
said compound being a compound of Formula IV-C

or a dimer of Formula VC

wherein n, R ₁ , R ₂ , R ₃ and R ₄ are as defined in claim 8,
said compound of Formula IV-C or Formula VC possibly being in the form of a pharmaceutically acceptable salt, solvate or 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. Compound of Formula IV according to one of Claims 8 or 9, chosen from



or their pharmaceutically acceptable salts, solvates or hydrates. Pharmaceutical composition for its use in association with an antibiotic therapy, comprising,

• a compound of Formula I according to any one of claims 1 to 5, its pharmaceutically acceptable salt, solvate or hydrate,
• an acceptable pharmaceutical excipient,

in which the antibiotic agent in the antibiotic therapy belongs in particular to the class of β-lactams, in particular chosen from penicillin derivatives, cephalosporins, monobactams, and carbapenems, Pharmaceutical composition for its use according to claim 11,
in a form suitable for simultaneous, separate or spread out use in antibiotic therapy. Pharmaceutical composition comprising a compound of Formula IV as defined in one of claims 8 to 10, or a compound of Formula III as defined in one of claims 6 or 7, its pharmaceutically acceptable salt, solvate or hydrate, in combination with an acceptable pharmaceutical excipient,
said compound of Formula IV or III being in particular being present at a rate of 0.2 to 3 g per unit dose. Kit including:

• a first container containing a compound of formula I as defined in one of claims 1 to 5, for its use as defined in one of claims 1 to 5, its pharmaceutically acceptable salt, solvate or hydrate, and
• a second container containing an antibiotic.

in a form suitable for simultaneous, sequential or time-separated use in antibiotic therapy.