NOVEL HETEROCYCLIC COMPOUNDS AND THEIR USE IN PREVENTING OR TREATING BACTERIAL INFECTIONS

The present invention relates to heterocyclic compounds especially as prodrug compounds, their process of preparation, the pharmaceutical compositions comprising these compounds and use thereof, optionally in combination with other antibacterial agents and/or beta-lactams, for the prevention or treatment of bacterial infections. The present invention also relates to the use of these compounds as beta-lactamase inhibitors and/or antibacterial agent.

It has been described that there is a continuous evolution of antibacterial resistance which could lead to bacterial strains against which known antibacterial compounds are inefficient. There is thus a need to provide novel compounds and composition that can overcome bacterial antibiotic resistance.

There is also a need to provide antibacterial agents and/or beta-lactamase inhibitors with oral bioavailability. The medical community urgently needs effective oral drugs for the treatment of uncomplicated UTIs.

The objective of the present invention is to provide new heterocyclic compounds, and especially new prodrugs, that can be used as antibacterial agent and/or beta-lactamase inhibitor.

An objective of the present invention is also to provide new heterocyclic compounds, and especially new prodrugs, that can be used for the prevention or treatment of bacterial infections.

Another objective of the present invention is to provide such new compounds which can overcome bacterial antibiotic resistance.

An objective of the invention is also to provide composition comprising these new heterocyclic compounds, optionally in combination with one or more other antibacterial agent, for the prevention or treatment of bacterial infections and which can overcome bacterial antibiotic resistance.

Other objectives will appear throughout the following description of the invention.

The present invention relates to compounds of formula (I)

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wherein

Y¹represents CHF or CF₂;

Y²represents linear or branched (C3-C16)-alkyl, (C3-C11)-cycloalkyl, (C5-C11)-cycloalkenyl, (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, (C5-C10)-heteroaryl comprising from 1 to 4 heteroatom chosen among N, O or S, (C6-C10)-aryl, (C7-C16)-aralkyl, (C7-C16)-heteroaralkyl comprising from 1 to 4 heteroatom chosen among N, O or S, a (C1-C6)alkyl-heterocycle wherein the heterocycle comprises from 4 to 5 carbon atoms and 1 to 2 heteroatoms chosen among N, O or S, preferably N and O, a polyethylene glycol group (PEG), a cetal group or an acetal group, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, aryl, aralkyl, heterocycle and heteroaralkyl is optionally substituted;

R¹represents H, CN, CH₂OQ¹, C(═O)OQ¹, C(═O)NQ¹Q², C(═O)NQ¹OQ², C(═O)NQ¹NQ¹Q²or C(═O)ONQ¹Q²;

Q¹and Q², identical or different, represents H, linear or branched (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (4-, 5-, 6-membered)-heterocycle aromatic, saturated or partially unsaturated with at least 1 N and optionally 1 or 2 other heteroatom chosen among N, O or S, linear or branched C(═O)(C1-C6)-alkyl, C(═O)(C1-C6)-cycloalkyl, C(═O)(4-, 5-, 6-membered)-heterocycle aromatic, saturated or partially unsaturated with at least 1 N and optionally 1 or 2 other heteroatom chosen among N, O or S or Q¹and Q²form together a saturated or partially unsaturated (4-, 5-, 6-membered)-heterocycle comprising 1 to 4 heteroatoms chosen among N, O or S; the alkyl, cycloalkyl and heterocycle is optionally substituted; A-B represents CH₂—C(═NOR²), C(R³)═C(R⁴);

R²represents H, linear or branched (C1-C6)-alkyl, (C1-C6)alkyl-C(═O)NH₂, (C3-C6)-cycloalkyl, (4-, 5-, 6-membered)-heterocycle aromatic, saturated or partially unsaturated with at least 1 N, the alkyl, cycloalkyl and heterocycle is optionally substituted; R³and R⁴, different, represents H, (4 to 10-membered)-heterocycle, aromatic, saturated or partially or totally unsaturated, optionally substituted, or R³and R⁴form together with the carbon atoms to which they are linked a non-aromatic cycle of formula (II)

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n represents 0 or 1 and Z represents S, N(R⁶) or C(R⁶) with the condition that if Z is S then n=0;

R⁵represents a linear or branched (C1-C6)-alkyl, a linear or branched (C1-C6)-alkyl-OH, a linear or branched (C1-C6)-alkyl-NH₂, optionally substituted or a (C3-C6)-cycloalkyl optionally substituted;

R⁶represents H, a linear or branched (C1-C6)-alkyl optionally substituted or a (C3-C6)-cycloalkyl optionally substituted;

- any carbon atom present within a group selected from alkyl, cycloalkyl, cycloalkenyl, heterocycle can be oxidized to form a C(O) group;
- any sulphur atom present within an heterocycle can be oxidized to form a S(O) group or a S(O)₂group;
- any nitrogen atom present within a group wherein it is trisubstituted (thus forming a tertiary amine) or within an heterocycle can be further quaternized by a methyl group;
  
  with the exception that one of R³and R⁴is H and at most one of R³and R⁴is H;
  
  and a pharmaceutically acceptable salt, a zwitterion, an optical isomer, a racemate, a diastereoisomer, an enantiomer, a geometric isomer or a tautomer thereof.

The presence of at least one fluorine atom on the molecule, and specifically at the position 2 of the ester function, renders this molecule highly hydrolysable and it is thus very difficult to provide a prodrug sufficiently stable for the targeted effect.

Preferably, in the compounds according to the invention:

- the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, aryl, aralkyl, heterocycle and heteroaralkyl representing Y²is optionally substituted by one or more group chosen among: halogen, ═O, Y³, OY³, OC(═O)Y³, SY³, NY³Y⁴, NY³C(═O)Y⁴, NY³S(═O)₂Y⁴, C(═O)Y³, C(═O)OY³, C(═O)NY³Y⁴, S(═O)Y³, S(═O)₂Y³or S(═O)₂NY³Y⁴, and
- Y³and Y⁴, identical or different, represent H, linear or branched (C1-C6)-alkyl, (C3-C11)-cycloalkyl, (C6-C10)-aryl, (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, (C5-C10)-heteroaryl comprising from 1 to 4 heteroatom chosen among N, O or S, or form together with the nitrogen atom to which they are linked a (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, the alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is optionally substituted by one or more linear or branched (C1-C10)-alkyl, OH, O(C1-C6)-alkyl, NH₂, NH(C1-C6)-alkyl, N[(C1-C6)-alkyl]₂, C(═O)NH₂, C(═O)NH(C1-C6)-alkyl or C(═O)N[(C1-C6)-alkyl]₂;
- the alkyl, cycloalkyl and heterocycle representing Q¹, Q²and R²is optionally substituted by one or more T¹chosen among F, ═O, CN, OT³, OC(═O)NT³T⁴, NT³C(═O)T⁴, NT³S(═O)₂T⁴, NT³S(═O)₂NT³T⁴, NT³C(═O)OT⁴, NT³C(═O) NT³T⁴, NT³T⁴, NT³C(═NT³)NT³T⁴, NT³CH(═NT⁴), C(═O)NT³T⁴, C(═O)NT³OT⁴, C(═O)NT³NT³T⁴, C(═NT³)NT³T⁴, linear or branched (C1-C6)-alkyl, (C3-C6)-cycloalkyl, S(═O)NT³T⁴, S(═O)₂NT³T⁴, (4-, 5-, 6-membered)-heterocycle aromatic, saturated or partially unsaturated with at least 1 N; the alkyl, cycloalkyl, and Heterocycle is optionally substituted by one or more T²; and
- the heterocycle representing R³and/or R⁴is optionally substituted by one or more T¹;
- the alkyl, cycloalkyl and heterocycle representing T¹is optionally substituted by one or more T²;
- T², identical or different, is chosen among F, CN, NT³T⁴, NT³C(═NT³)NT³T⁴, NT³CH(═NT⁴), OT³, NT³C(═O)T⁴and C(═O)NT³T⁴,
- T³and T⁴, identical or different, represent H, linear or branched (C1-C6)-alkyl, (C3-C10)-cycloalkyl, the alkyl and cycloalkyl is optionally substituted by one or more OH, NH₂or CONH₂, and
- the alkyl or cycloalkyl representing R⁵and R⁶is optionally substituted by one or more T².

Preferably, in the compounds of formula (I):

Y¹represents CHF or CF₂;

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wherein R⁷represents a linear or branched (C1-C6)-alkyl or C(═O)(C1-C6)-alkyl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aralkyl, heterocycle and heteroaralkyl is optionally substituted by one or more group chosen among: halogen, ═O, Y³, OY³, OC(═O)Y³, SY³, NY³Y⁴, NY³C(═O)Y⁴, NY³S(═O)₂Y⁴, C(═O)Y³, C(═O)OY³, C(═O)NY³Y⁴, S(═O)Y³, S(═O)₂Y³or S(═O)₂NY³Y⁴;

R¹represents H, CN, CH₂OQ¹, C(═O)OQ¹, C(═O)NQ¹Q², C(═O)NQ¹OQ²or C(═O)NQ¹NQ¹Q²;

Q¹and Q², identical or different represents H, linear or branched (C1-C6)-alkyl, (5-, 6-membered)-heterocycle aromatic, saturated or partially unsaturated with at least 1 N and optionally 1 or 2 other heteroatom chosen among N, O or S, C(═O)(4-, 5-, 6-membered)-heterocycle aromatic, saturated or partially unsaturated with at least 1 N and optionally 1 or 2 other heteroatom chosen among N, O or S; the alkyl and heterocycle is optionally substituted by one or more T¹;

A-B represents CH₂—C(═NOR²), C(R³)═C(R⁴);

R²represents H, linear or branched (C1-C6)-alkyl, (C1-C6)alkyl-C(═O)NH₂, the alkyl is optionally substituted by one or more T¹;

R³and R⁴, different, represents H, (5-, 6-membered)-heterocycle aromatic optionally substituted by one or more T¹, or R³and R⁴form together with the carbon atoms to which the following cycle:

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R⁵different represents a linear or branched (C1-C6)-alkyl optionally substituted by one or more T², a linear or branched (C1-C6)-alkyl-OH, a linear or branched (C1-C6)-alkyl-NH₂, or a (C3-C6)-cycloalkyl optionally substituted by one or more T²;

R⁶represents H, a linear or branched (C1-C6)-alkyl optionally substituted by one or more T²or a (C3-C6)-cycloalkyl optionally substituted by one or more T²; Y³and Y⁴, identical or different, represent H, linear or branched (C1-C6)-alkyl, (C3-C11)-cycloalkyl, (C6-C10)-aryl, (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, (C5-C10)-heteroaryl comprising from 1 to 4 heteroatom chosen among N, O or S, or form together with the nitrogen atom to which they are linked a (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S; the alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is optionally substituted by one or more linear or branched (C1-C10)-alkyl, OH, O(C1-C6)-alkyl, NH₂, NH(C1-C6)-alkyl, N[(C1-C6)-alkyl]₂, C(═O)NH₂, C(═O)NH(C1-C6)-alkyl or C(═O)N[(C1-C6)-alkyl]₂;

T¹, identical or different, represents F, ═O, CN, OT³, OC(═O)NT³T⁴, NT³C(═O)T⁴, NT³S(═O)₂T⁴, NT³S(═O)₂NT³T⁴, NT³C(═O)OT⁴, NT³C(═O) NT³T⁴, NT³T⁴, NT³C(═NT³)NT³T⁴, NT³CH(═NT⁴), C(═O)NT³T⁴, C(═O)NT³OT⁴, C(═O)NT³NT³T⁴, C(═NT³)NT³T⁴, linear or branched (C1-C6)-alkyl, (C3-C6)-cycloalkyl, S(═O)NT³T⁴, S(═O)₂NT³T⁴, (4-, 5-, 6-membered)-heterocycle aromatic, saturated or partially unsaturated with at least 1 N; the alkyl, cycloalkyl, and Heterocycle is optionally substituted by one or more T²; and

T², identical or different, is chosen among CN, NT³T⁴, OT³and C(═O)NT³T⁴, T³and T⁴, identical or different, represent H, linear or branched (C1-C6)-alkyl, (C3-C10)-cycloalkyl, the alkyl and cycloalkyl is optionally substituted by one or more OH, NH₂or CONH₂;

- any carbon atom present within a group selected from alkyl, cycloalkyl, cycloalkenyl, heterocycle can be oxidized to form a C(O) group;
- any sulphur atom present within an heterocycle can be oxidized to form a S(O) group or a S(O)₂group;
- any nitrogen atom present within a group wherein it is trisubstituted (thus forming a tertiary amine) or within an heterocycle can be further quaternized by a methyl group;
  
  with the exception that one of R³and R⁴is H and at most one of R³and R⁴is H; and a pharmaceutically acceptable salt, a zwitterion, an optical isomer, a racemate, a diastereoisomer, an enantiomer, a geometric isomer or a tautomer thereof.

Preferably, in the compounds of formula (I) Y²represents linear or branched (C3-C16)-alkyl, (C3-C11)-cycloalkyl, (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, (C7-C16)-aralkyl, (C7-C16)-heteroaralkyl comprising from 1 to 4 heteroatom chosen among N, O or S, a polyethylene glycol group (PEG), (C1-C6)alkyl-heterocycle wherein the heterocycle comprises from 4 to 5 carbon atoms and 1 to 2 heteroatoms chosen among N, O or S, preferably N and O, (C5-C11)-cycloalkenyl, or a group of formula

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wherein R⁷represents a linear or branched (C1-C6)-alkyl or C(═O)(C1-C6)-alkyl, the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aralkyl, heterocycle, and heteroaralkyl is optionally substituted by one or more group chosen among ═O, linear or branched (C1-C6)-alkyl.

Preferably, in the compounds of formula (I) R¹is H or C(═O)NH₂.

Preferably, in the compounds of formula (I):

Y²represents linear or branched (C3-C16)-alkyl, (C3-C11)-cycloalkyl, (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, (C7-C16)-aralkyl, (C7-C16)-heteroaralkyl comprising from 1 to 4 heteroatom chosen among N, O or S, a polyethylene glycol group (PEG), (C1-C6)alkyl-heterocycle wherein the heterocycle comprises from 4 to 5 carbon atoms and 1 to 2 heteroatoms chosen among N, O or S, preferably N and O, (C5-C11)-cycloalkenyl, or a group of formula

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wherein R⁷represents a linear or branched (C1-C6)-alkyl or C(═O)(C1-C6)-alkyl, the alkyl, cycloalkenyl, cycloalkyl, heterocycloalkyl, heterocycle, aralkyl and heteroaralkyl is optionally substituted by one or more group chosen among ═O, linear or branched (C1-C6)alkyl; and

R¹is H or C(═O)NH₂.

In a particular embodiment, the present invention relates to compound of formula (I)

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wherein

R¹, A, B and Y¹are as defined above and

Y²represents CY⁵Y⁶Y⁷;

Y⁵, Y⁶and Y⁷, identical or different, represent (C1-C3)-alkyl, (C3-C6)-cycloalkyl, (C4-C8)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N—Y⁸, O or S, a group CH₂—O—(C1-C3)-alkyl, or a group CH₂—O—(CH₂)₂—O—(C1-C3)-alkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more Y⁹; or

Y⁵and Y⁶could form together with the carbon atom to which they are linked a (C3-C6)-cycloalkyl or a (C4-C8)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N—Y⁸, O or S, wherein the cycloalkyl and heterocycloalkyl is optionally substituted by one or more Y⁹;

Y⁸represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, C(═O)(C1-C6)-alkyl or C(═O)(C3-C6)-cycloalkyl;

Y⁹represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, O(C1-C6)-alkyl or O(C3-C6)-cycloalkyl,

- any carbon atom present within a group selected from alkyl, cycloalkyl, cycloalkenyl, heterocycle can be oxidized to form a C(O) group;
- any sulphur atom present within an heterocycle can be oxidized to form a S(O) group or a S(O)₂group;
- any nitrogen atom present within a group wherein it is trisubstituted (thus forming a tertiary amine) or within an heterocycle can be further quaternized by a methyl group;
  
  with the exception that one of R³and R⁴is H and at most one of R³and R⁴is H;
  
  and a pharmaceutically acceptable salt, a zwitterion, an optical isomer, a racemate, a diastereoisomer, an enantiomer, a geometric isomer or a tautomer thereof.

In a particular embodiment, the invention relates to compound of formula (I) wherein R¹represents H, CN, CH₂OQ¹, C(═O)OQ¹, C(═O)NQ¹Q², C(═O)NQ¹OQ²or C(═O)NQ¹NQ¹Q²; preferably R¹is H or C(═O)NH₂.

A-B represents CH₂—C(═NOR²), C(R³)═C(R⁴);

R²represents H, linear or branched (C1-C6)-alkyl, (C1-C6)alkyl-C(═O)NH₂, the alkyl is optionally substituted by one or more T¹;

R³and R⁴, different, represents H, (5-, 6-membered)-heterocycle aromatic optionally substituted by one or more T¹, or R³and R⁴form together with the carbon atoms to which the following cycle:

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R⁶represents H, a linear or branched (C1-C6)-alkyl optionally substituted by one or more T²or a (C3-C6)-cycloalkyl optionally substituted by one or more T²;

- any carbon atom present within a group selected from alkyl, cycloalkyl, cycloalkenyl, heterocycle can be oxidized to form a C(O) group;
- any sulphur atom present within an heterocycle can be oxidized to form a S(O) group or a S(O)₂group;
- any nitrogen atom present within a group wherein it is trisubstituted (thus forming a tertiary amine) or within an heterocycle can be further quaternized by a methyl group;
  
  with the exception that one of R³and R⁴is H and at most one of R³and R⁴is H;
  
  and a pharmaceutically acceptable salt, a zwitterion, an optical isomer, a racemate, a diastereoisomer, an enantiomer, a geometric isomer or a tautomer thereof, Y²is chosen from:

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Preferably, the compounds of formula (I) are compounds of formula (IA):

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wherein

Y¹represents CHF or CF₂;

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R¹represents H, CN, CH₂OQ¹, C(═O)OQ¹, C(═O)NQ¹Q², C(═O)NQ¹OQ²or C(═O)NQ¹NQ¹Q²;

R²represents H, linear or branched (C1-C6)-alkyl, (C1-C6)alkyl-C(═O)NH₂, the alkyl is optionally substituted by one or more T¹;

Y³and Y⁴, identical or different, represent H, linear or branched (C1-C6)-alkyl, (C3-C11)-cycloalkyl, (C6-C10)-aryl, (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, (C5-C10)-heteroaryl comprising from 1 to 4 heteroatom chosen among N, O or S, or form together with the nitrogen atom to which they are linked a (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, the alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is optionally substituted by one or more linear or branched (C1-C10)-alkyl, OH, O(C1-C6)-alkyl, NH₂, NH(C1-C6)-alkyl, N[(C1-C6)-alkyl]₂, C(═O)NH₂, C(═O)NH(C1-C6)-alkyl or C(═O)N[(C1-C6)-alkyl]₂;

T¹, identical or different, represents OT³, NT³T⁴, C(═O)NT³T⁴, linear or branched (C1-C6)-alkyl, (5-, 6-membered)-heterocycle aromatic, saturated or partially unsaturated with at least 1 N; the alkyl and Heterocycle is optionally substituted by one or more T²; and

Preferably, in the compounds of formula (IA):

Y¹represents CF₂;

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wherein R¹represents a linear or branched (C1-C6)-alkyl or C(═O)(C1-C6)-alkyl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aralkyl, heterocycle and heteroaralkyl is optionally substituted by one or more group chosen among: halogen, ═O, Y³, OY³, OC(═O)Y³, SY³, NY³Y⁴, NY³C(═O)Y⁴, NY³S(═O)₂Y⁴, C(═O)Y³, C(═O)OY³, C(═O)NY³Y⁴, S(═O)Y³, S(═O)₂Y³or S(═O)₂NY³Y⁴;

R¹represents H, CN, C(═O)NH₂, CH₂OH, CH₂OMe, or group of formula

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R²represents H, linear or branched (C1-C6)-alkyl, (C1-C6)alkyl-C(═O)NH₂, the alkyl is optionally substituted by one or more T¹;

Y³and Y⁴, identical or different, represent H, linear or branched (C1-C6)-alkyl, (C3-C11)-cycloalkyl, (C6-C10)-aryl, (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, (C5-C10)-heteroaryl comprising from 1 to 4 heteroatom chosen among N, O or S, or form together with the nitrogen atom to which they are linked a (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S; the alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is optionally substituted by one or more linear or branched (C1-C10)-alkyl, OH, O(C1-C6)-alkyl, NH₂, NH(C1-C6)-alkyl, N[(C1-C6)-alkyl]₂, C(═O)NH₂, C(═O)NH(C1-C6)-alkyl or C(═O)N[(C1-C6)-alkyl]₂;

T¹, identical or different, represents OH, OMe, NH₂, CN, C(═O)NH₂, linear or branched (C1-C6)-alkyl; the alkyl is optionally substituted by one or more T²; and

T², identical or different, is chosen among OH, OMe, NH₂, CN, C(═O)NH₂.

Preferably, in compounds of formula (IA) R¹is C(═O)NH₂.

Preferably, in compounds of formula (IA) R²is (C1-C6)alkyl-C(═O)NH₂.

Preferably, in compounds of formula (IA) R¹is C(═O)NH₂and R²is (C1-C6)alkyl-C(═O)NH₂

In a particular embodiment, the present invention relates to compound of formula (IA)

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wherein R¹, R²and Y¹are as defined above and

Y²represents CY⁵Y⁶Y⁷;

Y⁸represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, C(═O)(C1-C6)-alkyl or C(═O)(C3-C6)-cycloalkyl;

Y⁹represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, O(C1-C6)-alkyl or O(C3-C6)-cycloalkyl,

- any carbon atom present within a group selected from alkyl, cycloalkyl, cycloalkenyl, heterocycle can be oxidized to form a C(O) group;
- any sulphur atom present within an heterocycle can be oxidized to form a S(O) group or a S(O)₂group;
- any nitrogen atom present within a group wherein it is trisubstituted (thus forming a tertiary amine) or within an heterocycle can be further quaternized by a methyl group;
  
  with the exception that one of R³and R⁴is H and at most one of R³and R⁴is H;
  
  and a pharmaceutically acceptable salt, a zwitterion, an optical isomer, a racemate, a diastereoisomer, an enantiomer, a geometric isomer or a tautomer thereof, preferably Y²is chosen from:

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Preferably, the compounds of formula (I) are compounds of formula (IB):

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wherein

Y¹represents CHF or CF₂;

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wherein R⁷represents a linear or branched (C1-C6)alkyl or C(═O)(C1-C6)alkyl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aralkyl, heterocycle and heteroaralkyl is optionally substituted by one or more group chosen among: halogen, ═O, Y³, OY³, OC(═O)Y³, SY³, NY³Y⁴, NY³C(═O)Y⁴, NY³S(═O)₂Y⁴, C(═O)Y³, C(═O)OY³, C(═O)NY³Y⁴, S(═O)Y³, S(═O)₂Y³or S(═O)₂NY³Y⁴;

R¹represents H, CN, CH₂OQ¹, C(═O)OQ¹, C(═O)NQ¹Q², C(═O)NQ¹OQ²or C(═O)NQ¹NQ¹Q²;

R³and R⁴, different, represents H, (5-, 6-membered)-heterocycle aromatic optionally substituted by one or more T¹, or R³and R⁴form together with the carbon atoms to which the following cycle:

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R⁶represents H, a linear or branched (C1-C6)-alkyl optionally substituted by one or more T²or a (C3-C6)-cycloalkyl optionally substituted by one or more T²;

Y³and Y⁴, identical or different, represent H, linear or branched (C1-C6)-alkyl, (C3-C11)-cycloalkyl, (C6-C10)-aryl, (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, (C5-C10)-heteroaryl comprising from 1 to 4 heteroatom chosen among N, O or S, or form together with the nitrogen atom to which they are linked a (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S; the alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is optionally substituted by one or more linear or branched (C1-C10)-alkyl, OH, O(C1-C6)-alkyl, NH₂, NH(C1-C6)-alkyl, N[(C1-C6)-alkyl]₂, C(═O)NH₂, C(═O)NH(C1-C6)-alkyl or C(═O)N[(C1-C6)-alkyl]₂;

T¹, identical or different, represents F, OT³, NT³C(═O)T⁴, NT³T⁴, CN, C(═O)NT³T⁴, C(═O)NT³OT⁴, C(═O)NT³NT³T⁴, linear or branched (C1-C6)-alkyl, (5-, 6-membered)-heterocycle aromatic, saturated or partially unsaturated with at least 1 N; the alkyl, and Heterocycle is optionally substituted by one or more T²; and

Preferably, in the compounds of formula (IB):

Y¹represents CF₂;

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R¹represents H, CN, CONH₂, CH₂OH, CH₂OMe, or group of formula

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R³and R⁴, different, represents H, (5-, 6-membered)-heterocycle aromatic optionally substituted by one or more T¹, or R³and R⁴form together with the carbon atoms to which the following cycle:

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R⁶represents H, a linear or branched (C1-C6)-alkyl optionally substituted by one or more T²or a (C3-C6)-cycloalkyl optionally substituted by one or more T²;

Y³and Y⁴, identical or different, represent H, linear or branched (C1-C6)-alkyl, (C3-C11)-cycloalkyl, (C6-C10)-aryl, (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, (C5-C10)-heteroaryl comprising from 1 to 4 heteroatom chosen among N, O or S, or form together with the nitrogen atom to which they are linked a (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S; the alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is optionally substituted by one or more linear or branched (C1-C10)-alkyl, OH, O(C1-C6)-alkyl, NH₂, NH(C1-C6)-alkyl, N[(C1-C6)-alkyl]₂, C(═O)NH₂, C(═O)NH(C1-C6)-alkyl or C(═O)N[(C1-C6)-alkyl]₂;

T², identical or different, is chosen among CN, NH₂, OH, OMe, and C(═O)NH₂, T³and T⁴, identical or different, represent H, linear or branched (C1-C6)-alkyl, (C3-C10)-cycloalkyl, the alkyl and cycloalkyl is optionally substituted by one or more OH, NH₂or CONH₂.

In a particular embodiment, the present invention relates to compound of formula (IB)

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Wherein R¹, R³, R⁴and Y¹are as defined above and

Y²represents CY⁵Y⁶Y⁷;

Y⁸represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, C(═O)(C1-C6)-alkyl or C(═O)(C3-C6)-cycloalkyl;

Y⁹represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, O(C1-C6)-alkyl or O(C3-C6)-cycloalkyl,

- any carbon atom present within a group selected from alkyl, cycloalkyl, cycloalkenyl, heterocycle can be oxidized to form a C(O) group;
- any sulphur atom present within an heterocycle can be oxidized to form a S(O) group or a S(O)₂group;
- any nitrogen atom present within a group wherein it is trisubstituted (thus forming a tertiary amine) or within an heterocycle can be further quaternized by a methyl group;
  
  with the exception that one of R³and R⁴is H and at most one of R³and R⁴is H;
  
  and a pharmaceutically acceptable salt, a zwitterion, an optical isomer, a racemate, a diastereoisomer, an enantiomer, a geometric isomer or a tautomer thereof,
  
  preferably Y²is chosen from:

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Preferably, the compounds of formula (IB) are compounds of formula (IB1):

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wherein

Y¹represents CHF or CF₂;

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wherein R⁷represents a linear or branched (C1-C6)alkyl or C(═O)(C1-C6)alkyl, a polyethylene glycol group (PEG), wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aralkyl, heterocycle and heteroaralkyl is optionally substituted by one or more group chosen among: halogen, ═O, Y³, OY³, OC(═O)Y³, SY³, NY³Y⁴, NY³C(═O)Y⁴, NY³S(═O)₂Y⁴, C(═O)Y³, C(═O)OY³, C(═O)NY³Y⁴, S(═O)Y³, S(═O)₂Y³or S(═O)₂NY³Y⁴;

R¹represents H, CN, CH₂OQ¹, C(═O)OQ¹, C(═O)NQ¹Q², C(═O)NQ¹OQ²or C(═O)NQ¹NQ¹Q²;

n is 0 or 1;

Z is S, NR⁶or CR⁶

R⁶represents H, a linear or branched (C1-C6)-alkyl optionally substituted by one or more T²or a (C3-C6)-cycloalkyl optionally substituted by one or more T²;

Y³and Y⁴, identical or different, represent H, linear or branched (C1-C6)-alkyl, (C3-C11)-cycloalkyl, (C6-C10)-aryl, (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, (C5-C10)-heteroaryl comprising from 1 to 4 heteroatom chosen among N, O or S, or form together with the nitrogen atom to which they are linked a (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S; the alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is optionally substituted by one or more linear or branched (C1-C10)-alkyl, OH, O(C1-C6)-alkyl, NH₂, NH(C1-C6)-alkyl, N[(C1-C6)-alkyl]₂, C(═O)NH₂, C(═O)NH(C1-C6)-alkyl or C(═O)N[(C1-C6)-alkyl]₂;

T², identical or different, is chosen among CN, NT³T⁴, OT³and C(═O)NT³T⁴,

T³and T⁴, identical or different, represent H, linear or branched (C1-C6)-alkyl, (C3-C10)-cycloalkyl, the alkyl and cycloalkyl is optionally substituted by one or more OH, NH₂or CONH₂.

Preferably, in the compounds of formula (IB1):

Y¹represents CF₂;

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wherein R⁷represents a linear or branched (C1-C6)-alkyl or C(═O)(C1-C6)-alkyl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycle, heterocycloalkyl, aralkyl and heteroaralkyl is optionally substituted by one or more group chosen among: halogen, ═O, Y³, OY³, OC(═O)Y³, SY³, NY³Y⁴, NY³C(═O)Y⁴, NY³S(═O)₂Y⁴, C(═O)Y³, C(═O)OY³, C(═O)NY³Y⁴, S(═O)Y³, S(═O)₂Y³or S(═O)₂NY³Y⁴;

R¹represents H, CH₂OH, CH₂OMe, or group of formula

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represents

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R⁶represents H, a linear or branched (C1-C6)-alkyl optionally substituted by one or more T²or a (C3-C6)-cycloalkyl optionally substituted by one or more T²;

Y³and Y⁴, identical or different, represent H, linear or branched (C1-C6)-alkyl, (C3-C11)-cycloalkyl, (C6-C10)-aryl, (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, (C5-C10)-heteroaryl comprising from 1 to 4 heteroatom chosen among N, O or S, or form together with the nitrogen atom to which they are linked a (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S; the alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is optionally substituted by one or more linear or branched (C1-C10)-alkyl, OH, O(C1-C6)-alkyl, NH₂, NH(C1-C6)-alkyl, N[(C1-C6)-alkyl]₂, C(═O)NH₂, C(═O)NH(C1-C6)-alkyl or C(═O)N[(C1-C6)-alkyl]₂;

In a particular embodiment, the present invention relates to compound of formula (IB1)

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Wherein R¹, R⁵, Z, n and Y¹are as defined above and

Y²represents CY⁵Y⁶Y⁷;

Y⁸represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, C(═O)(C1-C6)-alkyl or C(═O)(C3-C6)-cycloalkyl;

Y⁹represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, O(C1-C6)-alkyl or O(C3-C6)-cycloalkyl,

- any carbon atom present within a group selected from alkyl, cycloalkyl, cycloalkenyl, heterocycle can be oxidized to form a C(O) group;
- any sulphur atom present within an heterocycle can be oxidized to form a S(O) group or a S(O)₂group;
- any nitrogen atom present within a group wherein it is trisubstituted (thus forming a tertiary amine) or within an heterocycle can be further quaternized by a methyl group;
  
  and a pharmaceutically acceptable salt, a zwitterion, an optical isomer, a racemate, a diastereoisomer, an enantiomer, a geometric isomer or a tautomer thereof,
  
  preferably Y²is chosen from:

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Preferably, in the compounds of formula (IB) and (IB1):

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represents

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wherein R⁵and R⁶are as mentioned above, preferably R⁵is linear or branched (C1-C6)-alkyl, linear or branched (C1-C6)-alkyl-OH, linear or branched (C1-C6)-alkyl-NH²and R⁶is H or linear or branched (C1-C6)alkyl.

Preferably, in the compounds of formula (IB) and (IB1) R¹is H.

Preferably, in the compounds of formula (IB) and (IB1):

R¹is H, and

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represents

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Preferably, the compounds of formula (IB) are compounds of formula (IB2):

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wherein

Y¹represents CHF or CF₂;

Y²represents linear or branched (C3-C16)-alkyl, (C3-C11)-cycloalkyl, (C1-C6)alkyl-heterocycle wherein the heterocycle comprises from 4 to 5 carbon atoms and 1 to 2 heteroatoms chosen among N, O or S, preferably N and O, (C5-C11)-cycloalkenyl, (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, (C7-C16)-aralkyl, (C7-C16)-heteroaralkyl comprising from 1 to 4 heteroatom chosen among N, O or S, a polyethylene glycol group (PEG), or a group of formula

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wherein R⁷represents a linear or branched (C1-C6)alkyl or C(═O)(C1-C6)alkyl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycle, heterocycloalkyl, aralkyl and heteroaralkyl is optionally substituted by one or more group chosen among: halogen, ═O, Y³, OY³, OC(═O)Y³, SY³, NY³Y⁴, NY³C(═O)Y⁴, NY³S(═O)₂Y⁴, C(═O)Y³, C(═O)OY³, C(═O)NY³Y⁴, S(═O)Y³, S(═O)₂Y³or S(═O)₂NY³Y⁴;

R¹represents H, CN, CH₂OQ¹, C(═O)OQ¹, C(═O)NQ¹Q², C(═O)NQ¹OQ²or C(═O)NQ¹NQ¹Q²;

R³and R⁴, different, represents H, (5-, 6-membered)-heterocycle aromatic optionally substituted by one or more T¹,

Y³and Y⁴, identical or different, represent H, linear or branched (C1-C6)-alkyl, (C3-C11)-cycloalkyl, (C6-C10)-aryl, (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, (C5-C10)-heteroaryl comprising from 1 to 4 heteroatom chosen among N, O or S, or form together with the nitrogen atom to which they are linked a (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S; the alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is optionally substituted by one or more linear or branched (C1-C10)-alkyl, OH, O(C1-C6)-alkyl, NH₂, NH(C1-C6)-alkyl, N[(C1-C6)-alkyl]₂, C(═O)NH₂, C(═O)NH(C1-C6)-alkyl or C(═O)N[(C1-C6)-alkyl]₂;

T², identical or different, is chosen among CN, NT³T⁴, OT³and C(═O)NT³T⁴,

T³and T⁴, identical or different, represent H, linear or branched (C1-C6)-alkyl, (C3-C10)-cycloalkyl, the alkyl and cycloalkyl is optionally substituted by one or more OH, NH₂or CONH₂.

Preferably, in the compounds of formula (IB2) one of R³and R⁴is H and the other is a 5-membered heteroaryl comprising at least one nitrogen atom and another heteroatom chosen among N or O.

Preferably, in the compounds of formula (IB2) Y¹is CF₂.

Preferably, in the compounds of formula (IB2) Y²represents linear or branched (C3-C16)-alkyl, (C3-C11)-cycloalkyl, (C4-C10)-heterocycloalkyl comprising from 1 to 2 heteroatoms chosen among N, O or S, (C7-C16)-aralkyl, (C7-C16)-heteroaralkyl comprising from 1 to 4 heteroatom chosen among N, O or S, or a group of formula

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wherein R⁷represents a linear or branched (C1-C6)alkyl or C(═O)(C1-C6)alkyl, the alkyl, cycloalkyl, heterocycloalkyl, aralkyl and heteroaralkyl is optionally substituted by one or more group chosen among ═O, linear or branched (C1-C6)alkyl.

Preferably, in the compounds of formula (IB2), one of R³and R⁴is H and the other is chosen from oxazole, Pyrazole or triazole.

Preferably, in the compounds of formula (IB2) R¹is H.

Preferably, in the compounds of formula (IB2):

one of R³and R⁴is H and the other is a 5-membered heteroaryl comprising at least one nitrogen atom and another heteroatom chosen among N or O, preferably one of R³and R⁴is H and the other is chosen from oxazole, Pyrazole or triazole;

Y¹is CF₂;

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R¹is H.

In a particular embodiment, the present invention relates to compound of formula (IB2)

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Wherein R¹, R³, R⁴and Y¹are as defined above and

Y²represents CY⁵Y⁶Y⁷;

Y⁸represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, C(═O)(C1-C6)-alkyl or C(═O)(C3-C6)-cycloalkyl;

Y⁹represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, O(C1-C6)-alkyl or O(C3-C6)-cycloalkyl,

- any carbon atom present within a group selected from alkyl, cycloalkyl, cycloalkenyl, heterocycle can be oxidized to form a C(O) group;
- any sulphur atom present within an heterocycle can be oxidized to form a S(O) group or a S(O)₂group;
- any nitrogen atom present within a group wherein it is trisubstituted (thus forming a tertiary amine) or within an heterocycle can be further quaternized by a methyl group;
  
  with the exception that one of R³and R⁴is H and at most one of R³and R⁴is H;
  
  and a pharmaceutically acceptable salt, a zwitterion, an optical isomer, a racemate, a diastereoisomer, an enantiomer, a geometric isomer or a tautomer thereof,
  
  preferably Y²is chosen from:

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Preferably, the compounds of formula (I) according to the invention are compounds of formula (I*)

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wherein R¹, A, B, Y¹and Y²are as defined above.

Preferably, the compounds of formula (IA) according to the invention are compounds of formula (IA*)

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wherein R¹, R², Y¹and Y²are as defined above.

Preferably, the compounds of formula (IB) according to the invention are compounds of formula (IB*)

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wherein R¹, R³, R⁴, Y¹and Y²are as defined above.

Preferably, the compounds of formula (IB1) according to the invention are compounds of formula (IB1*)

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wherein R¹, R⁵, Z, n, Y¹and Y²are as defined above.

Preferably, the compounds of formula (IB2) according to the invention are compounds of formula (IB2*)

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wherein R¹, R³, R⁴, Y¹and Y²are as defined above.

The compounds of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1*), (IB2*) according to the invention with Y²different from H, can be used as a pro-drug of a compound of formula (I′), (1′*), (IA′), (IA′*), (IB′), (IB′*)

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wherein R¹, R², R³, R⁴, A-B, n, R⁵, Z and Y¹are as defined above and Y⁵represents H or a base addition salts for example chosen among ammonium salts such as tromethamine, meglumine, epolamine; metal salts such as sodium, lithium, potassium, calcium, zinc, aluminium or magnesium; salts with organic bases such as methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris(hydroymethyl)aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, N-methyl-D-glucamine; salts with amino acids such as arginine, lysine, ornithine and so forth; phosphonium salts such as alkylphosphonium, arylphosphonium, alkylarylphosphonium and alkenylarylphosphonium; and salts with quaternary ammonium such as tetra-n-butylammonium. List of suitable salts may be found in Remington's Pharmaceutical Sciences, 17^thed. Mack Publishing Company, Easton, Pa., 1985, p 1418, P. H. Stahl, C. G. Wermuth, Handbook of Pharmaceutical salts—Properties, Selection and Use, Wiley-VCH, 2002 and S. M. Berge et al. “Pharmaceutical Salts” J. Pharm. Sci, 66: p. 1-19 (1977).

The term “alkyl”, as used herein, refers to an aliphatic-hydrocarbon group which may be linear or branched, having 1 to 16 carbon atoms in the chain unless specified otherwise. Specific examples of alkyl groups, linear or branched, include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl. Preferably, the alkyl group, straight or branched, is or, propyl, pentyl, heptyl, hexadecyl.

The term “cycloalkyl” refers to a saturated monocyclic, polycyclic or spirocyclic non-aromatic hydrocarbon ring of 3 to 11 carbon atoms. Specific examples of monocyclic, polycyclic or spirocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, decalyl, norbornyl, isopinocamphyl, norpinanyl, adamantyl, spirohexane, spiroheptane, spirooctane, spirononane, spirodecane, spiroundecane. Preferably, the cycloalkyl group is cyclohexyl, adamantyl.

The term “cycloalkenyl” refers to a saturated monocyclic or bicyclic non-aromatic hydrocarbon ring of 5 to 11 carbon atoms and comprising at least one unsaturation. Specific examples of cycloalkenyl groups include, but are not limited to cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl. Preferably, the cycloalkenyl group is cyclohexenyl.

The term “heterocycle” or “heterocycloalkyl”, as used herein and without contrary definition specifically mentioned, either alone or in combination with another radical, refers to a monocyclic, bicyclic or spirocyclic saturated or partially unsaturated hydrocarbon radical, preferably 4 to 10-membered, comprising one or two heteroatom, such as N, O, S, and linked to the structure of the compounds by a carbon atom of the heterocycloalkyl. Suitable heterocycloalkyl are also disclosed in the Handbook of Chemistry and Physics, 76^thEdition, CRC Press, Inc., 1995-1996, pages 2 25 to 2-26. Specific examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, oxazolidinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxanyl, pyrrolidinyl, imidazolidinyl, pyranyl, tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, oxepanyl, azaspirooctanyl, azaspirodecanyl, oxaspirooctanyl, oxaspirodecanyl, thiaspirooctanyl, thiaspirodecanyl. Preferably, the heterocycloalkyl group is piperidinyl, pyranyl, oxepanyl, morpholinyl, thiomorpholinyl.

The term “heteroaryl”, as used herein and without contrary definition specifically mentioned, either alone or in combination with another radical, refers to a monocyclic or bicyclic aromatic hydrocarbon radical, preferably 5 to 10-membered, comprising one, two, three or four heteroatom, such as N, O, S. Suitable heteroaryl are also disclosed in the Handbook of Chemistry and Physics, 76^thEdition, CRC Press, Inc., 1995-1996, pages 2-25 to 2-26. Specific examples of heteroaryl groups include, but are not limited to, oxazolyl, oxadiazolyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazolyl, thienyl, thiazolyl, furanyl, thiadiazolyl, isothiazolyl, isoxazolyl. Preferably, the heteroaryl group is pyridinyl, furanyl, thiazolyl, thienyl, imidazolyl.

The term “aryl”, as used herein and without contrary definition specifically mentioned, either alone or in combination with another radical, refers to a monocyclic or bicyclic aromatic hydrocarbon radical. Specific examples of aryl groups include phenyl, naphtyl.

The term “aralkyl”, as used herein and without contrary definition specifically mentioned, refers to an alkyl substituted by an aryl, the alkyl and aryl being as defined above. By (C7-C16)-aralkyl it should be understand that the aralkyl group comprises in total from 7 to 16 carbon atoms. Specific examples of aralkyl groups include, but are not limited to benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, phenylheptyl, phenyloctyl, phenylnonyln phenyldecyl, naphtylethyl, naphtylpropyl, naphtylbutyl, naphtylpentyl, naphtylhexyl.

The term “heteroaralkyl”, as used herein and without contrary definition specifically mentioned, refers to an alkyl substituted by an heteroaryl, the alkyl and heteroaryl being as defined above. By (C7-C16)-heteroaralkyl it should be understand that the heteroaralkyl group comprises in total from 7 to 16 carbon atoms.

The term “cetal”, as used herein and without contrary definition specifically mentioned, refers to a group consisting of Y²of formula

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and the oxygen atom to which Y²is linked, wherein R⁷represents a linear or branched (C1-C6)alkyl or C(═O)(C1-C6)alkyl. The term “acetal”, as used herein and without contrary definition specifically mentioned, refers to a group consisting of Y²of formula

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and the oxygen atom to which Y²is linked, wherein R⁷represents a linear or branched (C1-C6)-alkyl or C(═O)(C1-C6)-alkyl.

The term “PEG” or “polyethylene glycol”, as used herein and without contrary definition specifically mentioned, refers to a group Y²of formula

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wherein m is an integer from 1 to 10.

Moreover some compounds according to this invention may contain a basic amino group and thus may form an inner zwitterionic salt (or zwitterion) with the acidic group—OCHFCO₂H or —OCF₂CO₂H where Y²is H and such inner zwitterionic salts are also included in this invention.

The term “optionally substituted” means “non-substituted or substituted”.

The term “racemate” is employed herein to refer to an equal amount of two specific enantiomers.

The term “enantiomer” is employed herein to refer to one of the two specific stereoisomers which is a non-superimposable mirror image with one other but is related to one other by reflection.

The compounds of the invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The compounds of the invention can be used in the present invention as a single isomer or as a mixture of stereochemical isomeric forms. Diastereoisomers, i.e., nonsuperimposable stereochemical isomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation. The optical isomers (enantiomers) can be obtained by using optically active starting materials, by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base or by using chiral chromatography column.

The expression “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, the expression “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which comprises a basic or an acidic moiety, by conventional chemical methods.

Furthermore, the expression “pharmaceutically acceptable salt” refers to relatively non-toxic, inorganic and organic acid or base addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. In particular, the acid addition salts can be prepared by separately reacting the purified compound in its purified form with an organic or inorganic acid and by isolating the salt thus formed. Among the examples of acid addition salts are the hydrobromide, hydrochloride, hydroiodide, sulfamate, sulfate, bisulfate, phosphate, nitrate, acetate, propionate, succinate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, tosylate, citrate, maleate, fumarate, tartrate, naphthylate, mesylate, glucoheptanate, glucoronate, glutamate, lactobionate, malonate, salicylate, methylenebis-b-hydroxynaphthoate, gentisic acid, isethionate, di-p-toluoyltartrate, ethanesulfonate, benzenesulfonate, cyclohexyl sulfamate, quinateslaurylsulfonate salts, and the like. Examples of base addition salts include ammonium salts such as tromethamine, meglumine, epolamine, etc, metal salts such as sodium, lithium, potassium, calcium, zinc or magnesium salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine. Lists of suitable salts may be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, P. H. Stahl, C. G. Wermuth, Handbook of Pharmaceutical salts—Properties, Selection and Use, Wiley-VCH, 2002 and S. M. Berge et al. “Pharmaceutical Salts” J. Pharm. Sci, 66: p. 1-19 (1977).

Compounds according to the invention also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described above and are not limited to ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁹F, ¹⁸F, ¹⁵N, ¹³N, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁷O or ¹⁸O. In one embodiment, isotopically-labeled compounds are useful in drug and/or substrate tissue distribution studies. In another embodiment, substitution with heavier isotopes such as deuterium (²H) affords greater metabolic stability (for example increased in vivo half-life or reduced dosage requirements). Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

The present invention also relates to a pharmaceutical composition comprising at least a compound of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* according to the invention.

This pharmaceutical composition can further comprise at least one pharmaceutically acceptable excipient.

The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” is employed for any excipient, solvent, dispersion medium, absorption retardant, diluent or adjuvant etc., such as preserving or antioxidant agents, fillers, binders, disintegrating agents, wetting agents, emulsifying agents, suspending agents, solvents, dispersion media, coatings, antibacterial agents, isotonic and absorption delaying agents and the like, that does not produce a secondary reaction, for example an allergic reaction, in humans or animals. Typical, non-limiting examples of excipients include mannitol, lactose, magnesium stearate, sodium saccharide, talcum, cellulose, sodium croscarmellose, glucose, gelatin, starch, lactose, dicalcium phosphate, sucrose, kaolin, magnesium carbonate, wetting agents, emulsifying agents, solubilizing agents, sterile water, saline, pH buffers, non-ionic surfactants, lubricants, stabilizing agents, binding agents and edible oils such as peanut oil, sesame oils and the like. In addition, various excipients commonly used in the art may be included. Pharmaceutically acceptable carriers or excipients are well known to a person skilled in the art, and include those described in Remington's Pharmaceutical Sciences (Mack Publishing Company, Easton, USA, 1985), Merck Index (Merck & Company, Rahway, N.J.), Gilman et al (Eds. The pharmacological basis of therapeutics, 8th Ed., pergamon press., 1990). Except insofar as any conventional media or adjuvant is incompatible with the active ingredient according to the invention, its use in the therapeutic compositions is contemplated.

The pharmaceutical composition according to the invention can further comprise at least one compound selected from an antibacterial compound, preferably a β-lactam compound. Thus, the pharmaceutical composition according to the invention can comprise:

- a single compound of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* according to the invention; or
- at least one compound of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* according to the invention and one or more antibacterial compound; or
- at least one compound of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* according to the invention and one or more β-lactam compound; or
- at least one compound of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* according to the invention, one or more antibacterial compound and one or more β-lactam compound.

The term “beta-lactam” or “β-lactam” refers to antibacterial compounds comprising a β-lactam unit, i.e. a group.

The expression “antibacterial agent” as used herein, refers to any substance, compound or their combination capable of inhibiting, reducing or preventing growth of bacteria, inhibiting or reducing ability of bacteria to produce infection in a subject, or inhibiting or reducing ability of bacteria to multiply or remain infective in the environment, or decreasing infectivity or virulence of bacteria.

The antibacterial agent is selected among the following families: aminoglycosides, beta-lactams, glycylcyclines, tetracyclines, quinolones, fluoroquinolones, glycopeptides, lipopeptides, macrolides, ketolides, lincosamides, streptogramins, oxazolidinones and polymyxins alone or in mixture.

Preferably, the further antibacterial agent is selected among the beta-lactam families, and more preferably among penicillin, cephalosporins, penems, carbapenems and monobactam, alone or in mixture.

Among the penicillin the antibacterial agent is preferably selected in the group consisting of amoxicillin, ampicillin, azlocillin, mezocillin, apalcillin, hetacillin, bacampicillin, carbenicillin, sulbenicillin, temocillin, ticarcillin, piperacillin, mecillinam, pivmecillinam, methicillin, ciclacillin, talampacillin, aspoxicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, nafcillin, and pivampicillin, alone or in mixture.

Among the cephalosporin, the antibacterial agent is preferably selected in the group consisting of cefatriazine, cefazolin, cefoxitin, cephalexin, cephradine, ceftizoxime, cephacetrile, cefbuperazone, cefprozil, ceftobiprole, ceftobiprole medocaril, ceftaroline, ceftaroline fosaminyl, cefalonium, cefminox, ceforanide, cefotetan, ceftibuten, cefcapene pivoxil, cefditoren pivoxil, cefdaloxime cefroxadine, ceftolozane and S-649266, cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidine, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil, cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbef, and latamoxef, alone or in mixture.

Among the carbapenem, the antibacterial agent is preferably selected in the group consisting of imipenem, doripenem, meropenem, biapenem, ertapenem, tebipenem, sulopenem, SPR994 and panipenem, alone or in mixture.

Among the monobactam the antibacterial agent is preferably selected in the group consisting of aztreonam, tigemonam, carumonam, BAL30072 and nocardicin A, alone or in mixture.

Preferably, in the pharmaceutical composition according to the invention:

- the antibacterial compound is selected from aminoglycosides, β-lactams, glycylcyclines, tetracyclines, quinolones, fluoroquinolones, glycopeptides, lipopeptides, macrolides, ketolides, lincosamides, streptogramins, oxazolidinones, polymyxins and mixtures thereof; or
- the β-lactam compound is selected from β-lactams and mixtures thereof, preferably penicillin, cephalosporins, penems, carbapenems and monobactam.

Preferably, in the pharmaceutical composition according to the invention:

- the antibacterial compound is selected from orally bioavailable aminoglycosides, β-lactams, glycylcyclines, tetracyclines, quinolones, fluoroquinolones, glycopeptides, lipopeptides, macrolides, ketolides, lincosamides, streptogramins, oxazolidinones, polymyxins and mixtures thereof; or
- the β-lactam compound is selected from orally available β-lactams or prodrugs of β-lactams, and mixtures thereof, preferably penicillin, cephalosporins, penems, carbapenems and monobactam.

Preferably, in the pharmaceutical composition according to the invention the β-lactam is chosen among amoxicillin, amoxicillin-clavulanate, sultamicillin cefuroxime, cefazolin, cefaclor, cefdinir, cefpodoxime, cefprozil, cephalexin, loracarbef, cefetamet, ceftibuten, tebipenem pivoxil, sulopenem, SPR994, cefixime, preferably cefixime.

The present invention also relates to a kit comprising:

- a pharmaceutical composition according to the invention, and
- at least one other composition comprising one or more antibacterial agent(s), preferably at least one of these antibacterial agent(s) is a beta-lactam, the antibacterial agent being as defined above.

The two composition can be prepared separately each with one specific pharmaceutically acceptable carrier, and can be mix especially extemporaneity.

The present invention also refer to a compound of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* according to the invention for use as a medicine.

The present invention also refer to the use of a compound of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* according to the invention or of a composition according to the invention for the preparation of a medicine.

The present invention also provides the use of the compounds of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* on the control of bacteria. The compound according to the invention is usually used in combination with pharmaceutically acceptable excipient.

The present invention also refer to a compound of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* according to the invention for use as antibacterial agent.

The present invention also refer to a compound of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* according to the invention for use as inhibitor of beta-lactamase.

The present invention also refer to a compound of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* or a composition according to the invention or a kit according to the invention for use for the treatment or prevention of bacterial infections.

The terms “prevention”, “prevent” and “preventing” as used herein are intended to mean the administration of a compound or composition according to the invention in order to prevent infection by bacteria or to prevent occurrence of related infection and/or diseases. The terms “prevention”, “prevent” and “preventing” also encompass the administration of a compound or composition according to the present invention in order preventing at least one bacterial infection, by administration to a patient susceptible to be infected, or otherwise at a risk of infection by this bacteria.

The terms “treatment”, “treat” and “treating” as used herein are intended to mean in particular the administration of a treatment comprising a compound or composition according to the present invention to a patient already suffering from an infection. The terms “treatment”, “treat” and “treating” as used herein, also refer to administering a compound or composition according to the present invention, optionally with one or more antibacterial agent, in order to:

- reduce or eliminate either a bacterial infection or one or more symptoms associated with bacterial infection, or
- retard the progression of a bacterial infection or of one or more symptoms associated with bacterial infection, or
- reduce the severity of a bacterial infection or of one or more symptoms associated with the bacterial infection, or
- suppress the clinical manifestation of a bacterial infection, or
- suppress the manifestation of adverse symptoms of the bacterial infection.

The expression “infection” or “bacterial infection” as used herein, includes the presence of bacteria, in or on a subject, which, if its growth were inhibited, would result in a benefit to the subject. As such, the term “infection” or “bacterial infection” in addition to referring to the presence of bacteria also refers to normal flora, which is not desirable. The term “infection” includes infection caused by bacteria. Exemplary of such bacterial infection are urinary tract infection (UTI), kidney infections (pyelonephritis), gynecological and obstetrical infections, respiratory tract indection (RTI), acute exacerbation of chronic bronchitis (AECB), Community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), ventilator associated pneumonia (VAP), intra-abdominal pneumonia (IAI), acute otitis media, acute sinusitis, sepsis, catheter-related sepsis, chancroid, chlamydia, skin infections, bacteremia.

The term “growth” as used herein, refers to the growth of one or more microorganisms and includes reproduction or population expansion of the microorganism, such as bacteria. The term also includes maintenance of on-going metabolic processes of a microorganism, including processes that keep the microorganism alive.

The bacteria are chosen amongst gram-positive bacteria or gram-negative bacteria, preferably the gram-negative bacteria.

The bacteria can be also chosen among bacteria producing “beta-lactamase” or “1-lactamase”. These bacteria are well known by the skilled person. The term “beta-lactamase” or “β-lactamase” as used herein, refers to any enzyme or protein or any other substance that is able to break down a beta-lactam ring. The term “beta-lactamase” or “β-lactamase” includes enzymes that are produced by bacteria and that have the ability to hydrolyze, either partially or completely, the beta-lactam ring present in a compound such as an antibacterial agent.

Among the gram-positive bacteria, the bacteria according to the invention is preferably chosen among Staphylococcus, Streptococcus, Staphylococcus species (including Staphylococcus aureus, Staphylococcus epidermidis), Streptococcus species (including Streptococcus pneumonia, Streptococcus agalactiae), Enterococcus species (including Enterococcus faecalis and Enterococcus faecium).

Among the gram-negative bacteria, the bacteria according to the invention is preferably chosen among Acinetobacter species (including Acinetobacter baumannii), Citrobacter species, Escherichia species (including Escherichia coli), Haemophilus influenza, Morganella morganii, Klebsiella species (including Klebsiella pneumonia), Enterobacter species (including Enterobacter cloacae), Neisseria gonorrhoeae, Burkholderia species (including Burkholderia cepacia), Proteus species (including Proteus mirabilis), Serratia species (including Serratia marcescens), Providencia species, Pseudomonas aeruginosa.

The invention thus preferably refers to a compound of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* or a composition according to the invention or a kit according to the invention for use for the treatment or prevention of bacterial infection, preferably caused by bacteria producing one or more beta-lactamase(s). Preferably, the bacteria are chosen amongst gram-positive bacteria or gram-negative bacteria, preferably gram-negative bacteria.

The present invention also refer to the use of a compound of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* or a composition according to the invention for the preparation of a medicine for the treatment or prevention of bacterial infection, preferably caused by bacteria producing one or more beta-lactamase(s). Preferably, the bacteria are chosen amongst gram-positive bacteria or gram-negative bacteria, preferably gram-negative bacteria.

The present invention also refers to the kit as defined above, for a simultaneous, separated or sequential administration to a patient in need thereof for use for the treatment or prevention of bacterial infections, preferably caused by bacteria producing one or more beta-lactamase(s). Preferably, the bacteria are chosen amongst gram-positive bacteria or gram-negative bacteria, preferably gram-negative bacteria.

The present invention also refers to compound of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* for use in combination with one or more further antibacterial agent, preferably at least one of the further antibacterial agent is a beta lactam, for the treatment or prevention of bacterial infections, preferably caused by bacteria producing one or more beta-lactamase(s). Preferably, the bacteria are chosen amongst gram-positive bacteria or gram-negative bacteria, preferably gram-negative bacteria. Wherein the compounds of formula (I) or (I*) and the further antibacterial agent are administered simultaneously, separately or sequentially.

The present invention also refers to the use of a compound of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* or a composition according to the invention or a kit according to the invention for the prevention or treatment of bacterial infections, preferably of bacterial infection, preferably caused by bacteria producing one or more beta-lactamase(s). Preferably, the bacteria are chosen amongst gram-positive bacteria or gram-negative bacteria, preferably gram-negative bacteria.

The present invention also relates to a method for the treatment or prevention of bacterial infections, preferably caused by bacteria producing one or more beta-lactamase(s) comprising the administration of a therapeutically effective amount of compound of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)*, a composition according to the invention or a kit according to the invention to a patient in need thereof. Preferably, the bacteria are chosen amongst gram-positive bacteria or gram-negative bacteria, preferably gram-negative bacteria.

The term “patient” means a person or an animal at risk of being infected by bacteria or, a person or an animal being infected by bacteria, preferably by gram-positive and/or by gram-negative bacteria. As used herein, the term “patient” refers to a warm-blooded animal such as a mammal, preferably a human or a human child, who is afflicted with, or has the potential to be afflicted with one or more infections and conditions described herein. The identification of those subjects who are in need of treatment of herein-described diseases and conditions is well within the ability and knowledge of one skilled in the art. A veterinarian or a physician skilled in the art can readily identify, by the use of clinical tests, physical examination, medical/family history or biological and diagnostic tests, those subjects who are in need of such treatment.

The expression “therapeutically effective amount” or “pharmaceutically effective amount” as used herein, refer to an amount of a compound according to the invention, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compound has utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or a clinician. The amount of a compound according to the invention which constitutes a “therapeutically effective amount” will vary, notably depending on the compound itself and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient. Such a “therapeutically effective amount” can be determined by one of ordinary skilled in the art having regard to its own knowledge, and this disclosure. Preferably, the compounds according to the invention are administered in an amount comprised between 0.1 to 30 g per day.

The compounds according to the invention may be provided in an aqueous physiological buffer solution for parenteral administration.

The compounds of the present invention are also capable of being administered in unit dose forms, wherein the expression “unit dose” means a single dose which is capable of being administered to a patient, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising either the active compound itself, or as a pharmaceutically acceptable composition, as described hereinafter. Compounds provided herein can be formulated into pharmaceutical compositions by admixture with one or more pharmaceutically acceptable excipients. Such unit dose compositions may be prepared for use by oral administration, particularly in the form of tablets, simple capsules or soft gel capsules; or intranasally, particularly in the form of powders, nasal drops, or aerosols; or dermally, for example, topically in ointments, creams, lotions, gels or sprays, or via transdermal patches.

The compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example, as described in Remington: The Science and Practice of Pharmacy, 20^thed.; Gennaro, A. R., Ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2000.

Preferred formulations include pharmaceutical compositions in which a compound of the present invention is formulated for oral or parenteral administration.

For oral administration, tablets, pills, powders, capsules, troches and the like can contain one or more of any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, or gum tragacanth; a diluent such as starch or lactose; a disintegrant such as starch and cellulose derivatives; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, or methyl salicylate. Capsules can be in the form of a hard capsule or soft capsule, which are generally made from gelatin blends optionally blended with plasticizers, as well as a starch capsule. In addition, dosage unit forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents. Other oral dosage forms syrup or elixir may contain sweetening agents, preservatives, dyes, colorings, and flavorings. In addition, the active compounds may be incorporated into fast dissolved, modified-release or sustained-release preparations and formulations, and wherein such sustained-release formulations are preferably bi-modal. Preferred tablets contain lactose, cornstarch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, or talc in any combination. For oral administration, tablets, pills, powders, capsules, troches and the like can be coated or can comprise a compound or composition enables to neutralize the gastric acid o in order for the compounds according to the invention to pass through the stomach without any degradation.

Liquid preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. The liquid compositions may also include binders, buffers, preservatives, chelating agents, sweetening, flavoring and coloring agents, and the like. Non-aqueous solvents include alcohols, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and organic esters such as ethyl oleate. Aqueous carriers include mixtures of alcohols and water, buffered media, and saline. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds. Intravenous vehicles can include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Other potentially useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.

Alternative modes of administration include formulations for inhalation, which include such means as dry powder, aerosol, or drops. They may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Formulations for buccal administration include, for example, lozenges or pastilles and may also include a flavored base, such as sucrose or acacia, and other excipients such as glycocholate. Formulations suitable for rectal administration are preferably presented as unit-dose suppositories, with a solid based carrier, and may include a salicylate. Formulations for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which can be used include petroleum jelly, lanolin, polyethylene glycols, alcohols, or their combinations. Formulations suitable for transdermal administration can be presented as discrete patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive.

The pharmaceutical composition according to the invention can also comprise any compound or excipient for sustain release of the active compounds.

The present invention also relates to process for the preparation of compounds of formula ((I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* as defined above.

Preparation of the Compounds and Biological Activity:

Abbreviations or symbols used herein include:

ACHN: 1,1′-azobis(cyclohexanecarbonitrile)
ACN: acetonitrile
AcOH: acetic acid
Bn: benzyl
Boc: tert-butoxycarbonyl
Boc₂O: tert-butoxycarbonyl anhydride
BocON: [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile]
bs: broad singlet
Burgess reagent: methyl N-(triethylammoniosulfonyl)carbamate
Cbz: carboxybenzyl
CbzCl: benzyl chloroformate
CFU: colony-forming units
CLSI: clinical laboratory standards institute
d: doublet
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene
DCM: dichloromethane
DCE: 1,2-dichloroethane
dd: doublet of doublet
ddd: doublet of doublet of doublet
ddt: doublet of doublet of triplet
dq: doublet of quartet
dt: doublet of triplet
DTA: di-tert-butylazodicarboxylate
DEAD: diethyl azodicarboxylate
Dess-Martin periodinane: 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one
DIAD: diisopropyl azodicarboxylate
DIPEA: N,N-diisopropylethylamine
DMAP: 4-dimethylaminopyridine
DMF: N,N-dimethylformamide
DMSO: dimethylsulfoxide
EtOAc: ethyl acetate
Et₂O: diethyl ether
h: hours
HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate
iPrOH: isopropanol
m: multiplet
min: minutes
MeOH: methanol
MeONa: sodium methoxide
MIC: minimum inhibitory concentration
MS: mass spectrometry
MsCI: methanesulfonyl chloride
NBS: N-bromosuccinimide
NMR: nuclear magnetic resonance spectroscopy
Ns: nosyl, nitrobenzenesulfonyl
OMs: methanesulfonate
OTs: toluenesulfonate
OTf: trifluoromethanesulfonate
Pd(Ph₃)₄: tetrakis(triphenylphosphine)palladium(0)
PG: protective group
PhSH: thiophenol
PMe₃: trimethylphosphine
PPh₃: triphenylphosphine
Ppm: parts per million
q: quartet
rt: room temperature
s: singlet
SEM: [2-(trimethylsilyl)ethoxy]methyl
t: triplet
td: triplet of doublet
TBAF: tetra-n-butylammonium fluoride
TBDMSOTf: trifluoromethanesulfonic acid tert-butyldimethylsilyl ester
TBSOTf: trimethylsilyl trifluoromethanesulfonate
tBuOK: potassium tert-butoxide
TEA: triethylamine
Tf: trifluoromethanesulfonate
TFA: trifluoroacetic acid
THF: tetrahydrofuran
THP: tetrahydropyranyl
TLC: thin layer chromatography
TMSI: lodotrimethylsilane
Tr: trityl (triphenylmethyl)

The compounds of the present invention of formula (I), (I*), (IA), (IA*), (IB), (IB*), (IB1), (IB1*), (IB2) or (IB2)* can be prepared respectively by the following reaction schemes 1 to 4.

It should be understood that the processes of schemes 1 to 4 can be adapted for preparing further compounds according to the invention. Further processes for the preparation of compounds according to the invention can be derived from the processes of schemes 1 to 4.

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Nucleophilic Substitution could be performed by reaction of the appropriate ester (II) with compounds of formula (III) in a solvent such as DMSO, DMF, THF or ACN, preferably DMSO, in a presence of a base such as DBU, TEA, K₂CO₃or Cs₂CO₃, preferably DBU and K₂CO₃. Y¹, Y², R¹and A-B are described as above.

The preparation of compounds of formula (III) can be derived by the skilled person from WO2016156346 when A-B is CH₂—C(═NOR²) and from WO2016156597 and WO2016177862 when A-B is C(R³)═C(R⁴).

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Compounds of formula (V) can be obtained from compounds of formula (III) by Nucleophilic Substitution with the appropriate ester (IV), wherein PG¹is a protecting group such as ethyl, allyl or benzyl, in a solvent such as DMSO, DMF, THF or ACN, preferably DMSO and DMF, and in a presence of a base such as DBU, TEA, K₂CO₃or Cs₂CO₃, preferably DBU and K₂CO₃.

Compounds of formula (VI) can be obtained from compounds of formula (V) by hydrogenolysis in a solvent such as THF, MeOH, EtOH, DCM, DMF, preferably THF, in a presence of a catalytic amount of Pd/C and in a presence or not of a base such as DIPEA or TEA, or by saponification in a solvent such as THF, H₂O, MeOH, dioxane, preferably THF and H₂O, in a presence of a base such as NaOH, LiOH or KOH, preferably LiOH. Compounds of formula (I) and (I*) can be obtained from compounds of formula (VI) by Nucleophilic substitution with the appropriate compounds of formula (VII), wherein X is a leaving group such as Cl, Br, I, OTf, OMs or OTs, in a solvent such as DMSO, DMF, THF or ACN, preferably DMSO and DMF, and in a presence of a base such as DBU, TEA, K₂CO₃or Cs₂CO₃, preferably DBU and K₂CO₃.

The preparation of compounds of formula (VI) can be derived by the skilled person from WO2016156346 when A-B is CH₂—C(═NOR²) and from WO2016156597 and WO2016177862 when A-B is C(R³)═C(R⁴).

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Compounds of formula (IX) can be obtained from compounds of formula (III) by Nucleophilic Substitution with the appropriate ester (VIII), wherein M is H, Li, Na or K, in a solvent such as DMSO, DMF, THF or ACN, preferably DMSO and DMF, and in a presence of a base such as DBU, TEA, K₂CO₃or Cs₂CO₃, preferably DBU and K₂CO₃. Compounds of formula (I) and (I*) can be obtained from compounds of formula (IX) by Nucleophilic substitution with compounds of formula (VII), wherein X is a leaving group such as Cl, Br, I, OTf, OMs or OTs, in a solvent such as DMSO, DMF, THF or ACN, preferably DMSO and DMF, and in a presence or not of a base such as DBU, TEA, K₂CO₃or Cs₂CO₃, preferably DBU and K₂CO₃.

The preparation of compounds of formula (IX) can be derived by the skilled person from WO2016156346 when A-B is CH₂—C(═NOR²) and from WO2016156597 and WO2016177862 when A-B is C(R³)═C(R⁴).

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Transesterification could be performed by reaction of the appropriate ester (X) with appropriate alcohol (XI) neat or in a solvent such as Toluene or Dioxane, in a presence or not of a catalytic amount of acid such as MeSO₃H.

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Acylation could be performed by reaction of the appropriate acyl chloride (XII) with appropriate alcohol (XI) in a solvent such as ACN or Et₂O, in a presence of a base such as pyridine or TEA.

EXAMPLES

The following examples are provided for the purpose of illustrating the present invention and by no means should be interpreted to limit the scope of the present invention.

The first part represents the preparation of the compounds (intermediates and final compounds) whereas the second part describes the evaluation of antibacterial activity and bioavailability of compounds according to the invention.

Example 1: Synthesis of [2,2-difluoro-2-[(4-isoxazol-4-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetyl]oxymethyl 2,2-dimethylpropanoate

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Lithium difluoro-(4-isoxazol-4-yl-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-3-en-6-yloxy)-acetate (prepared according to the procedure described in WO2016177862 Example 6) (20 mg, 0.06 mmol) was solubilised in DMF (1 mL) with iodomethyl 2,2-dimethylpropanoate (16 mg, 0.06 mmol) and stirred for 1 h at rt. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel (Cyclohexane to remove diiode then DCM/Et₂O 9/1) to provide [2,2-difluoro-2-[(4-isoxazol-4-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetyl]oxymethyl 2,2-dimethylpropanoate (Example 1) (18 mg, 0.04 mmol, 67%) as a colourless oil.

MS m/z ([M+H]⁺) 416

¹H NMR (300 MHz, CDCl₃): δ (ppm) 1.21 (s, 9H), 3.27 (dd, J=11.4, 0.7 Hz, 1H), 3.68 (dd, J=18.7, 2.0, 1H), 3.92 (dd, J=18.8, 2.0 Hz, 1H), 4.04 (dd, J=18.8, 3.4 Hz, 1H), 4.27-4.29 (m, 1H), 5.86 (d, J=5.4 Hz, 1H), 5.92-5.95 (m, 2H), 8.35 (s, 1H), 8.50 (s, 1H).

Example 2: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2,2-difluoro-2-[(4-isoxazol-4-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetate

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Lithium difluoro-(4-isoxazol-4-yl-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-3-en-6-yloxy)-acetate (prepared according to the procedure described in WO2016177862 Example 6) (20 mg, 0.06 mmol) was dissolved in DMF (0.7 mL) with 4-Iodomethyl-5-methyl-[1,3]dioxol-2-one (17 mg, 0.07 mmol) and stirred at rt for 1 h. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel (DCM to DCM/Et₂O: 9/1) to provide (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2,2-difluoro-2-[(4-isoxazol-4-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetate (Example 2) (8.4 mg, 0.02 mmol, 32%) as a beige solid.

MS m/z ([M+H]⁺) 414

¹H NMR (400 MHz, CDCl₃): δ (ppm) 2.19 (s, 3H), 3.30 (dd, J=11.4, 0.7 Hz, 1H), 3.69 (dd, J=11.4, 2.8 Hz, 1H), 3.94 (dd, J=18.8, 2.1 Hz, 1H), 4.03 (dd, J=18.8, 3.5 Hz, 1H), 4.27 (d, J=2.8 Hz, 1H), 5.00 (d, J=13.8 Hz, 1H), 5.05 (d, J=13.8 Hz, 1H) 5.93-5.96 (m, 1H), 8.35 (s, 1H), 8.47 (s, 1H).

Example 3: Synthesis of 1-[2,2-difluoro-2-[(4-isoxazol-4-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetyl]oxyethyl 2,2-dimethylpropanoate

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Lithium difluoro-(4-isoxazol-4-yl-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-3-en-6-yloxy)-acetate (prepared according to the procedure described in WO2016177862 Example 6) (30 mg, 0.10 mmol) was solubilised in DMF (1 mL) with 1-iodoethyl 2,2-dimethylpropanoate (27 mg, 0.11 mmol) and stirred at rt for 1 h. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel (DCM to DCM/Et₂O: 9/1) to provide 1-[2,2-difluoro-2-[(4-isoxazol-4-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetyl]oxyethyl 2,2-dimethylpropanoate (Example 3) as mixture of both diastereoisomers (8.1 mg, 0.02 mmol, 25%).

MS m/z ([M+H]⁺) 430

¹H NMR (400 MHz, CDCl₃): δ (ppm) 1.19 (s, 9H), 1.52 and 1.58 (d, J=5.5 Hz, 3H), 3.25 and 3.28 (d, J=11.2 Hz, 1H), 3.66-3.73 (m, 1H), 3.88-4.07 (m, 2H), 4.27 and 4.29 (d, J=2.8 Hz, 1H), 5.89-5.97 (m, 1H), 6.90 and 6.94 (q, J=5.5 Hz, 1H), 8.36 and 8.37 (s, 1H), 8.49 and 8.56 (s, 1H).

Example 4: Synthesis of cyclohexyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetate

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Step 1: Preparation of Intermediate cyclohexyl 2-bromo-2,2-difluoro-acetate (4a)

In a sealed vial, a solution of ethyl 2-bromo-2,2-difluoro-acetate (2 mL, 15.6 mmol) and cyclohexanol (1.56 g, 15.6 mmol) was heated at 120° C. for 65 h. The reaction mixture was slightly concentrated. The crude was purified by chromatography on silica gel (Heptane/DCM 100/0 to 50/50) to afford cyclohexyl 2-bromo-2,2-difluoro-acetate (4a) (1.03 g, 5.06 mmol, 32%).

¹H NMR (300 MHz, CDCl₃): δ(ppm) 1.30-1.46 (m, 3H), 1.51-1.65 (m, 3H), 1.74-1.82 (m, 2H), 1.88-1.93 (m, 2H), 4.97 (tt, J=3.8, 8.5 Hz, 1H).

Step 2: Preparation of cyclohexyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetate, Example 4

To a solution of 6-hydroxy-3-oxazol-2-yl-1,6-diaza-bicyclo[3.2.1]oct-3-en-7-one (prepared according to the procedure described in WO2016177862 compound 37f) (0.08 g, 0.386 mmol) in DMF (4 mL) were added DBU (0.063 mL, 0.430 mmol) and cyclohexyl bromo-difluoroacetate (4a) (0.258 g, 1.00 mmol). The mixture was stirred at −20° C. for 30 min. The reaction mixture was diluted with diisopropyl Ether and the insolubles were removed by filtration. The filtrate was washed with water, dried over Na₂SO₄and concentrated in vacuo. The residue was purified by chromatography on silica gel (DCM/acetone: 100/0 to 90/10) to provide cyclohexyl difluoro-(3-oxazol-2-yl-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-3-en-6-yloxy)-acetate (Example 4) (0.97 g, 0.253 mmol, 65%).

MS m/z ([M+H]⁺) 384

¹H NMR (400 MHz, CDCl₃) δ (ppm): 1.24-1.43 (m, 3H), 1.51-1.61 (m, 3H), 1.72-1.81 (m, 2H), 1.87-1.95 (m, 2H), 3.22 (d, J=11.2 Hz, 1H), 3.66 (d, J=11.2 Hz, 1H), 4.17 (dd, J=2.1, 18.0 Hz, 1H), 4.27 (dd, J=2.5, 5.2 Hz, 1H), 4.44 (dd, J=1.3, 18.0 Hz, 1H), 4.90-4.97 (m, 1H), 7.08-7.11 (m, 1H), 7.15 (s, 1H), 7.62 (s, 1H).

Example 5: Synthesis of cyclohexyl 2,2-difluoro-2-[(7-oxo-3-pyrazol-1-yl-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetate

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Step 1: Preparation of Intermediate 6-hydroxy-3-pyrazol-1-yl-1,6-diaza-bicyclo[3.2.1]oct-3-en-7-one (5a)

A solution of 6-allyloxy-3-pyrazol-1-yl-1,6-diaza-bicyclo[3.2.1]oct-3-en-7-one (prepared according to the procedure described in WO2016177862 compound 47a) (0.100 g, 0.41 mmol) in anhydrous DCM (4 mL) was degassed for 10 min under argon atmosphere. AcOH (0.047 mL, 0.81 mmol) and Pd(PPh₃)₄(0.237 g, 0.205 mmol) were successively added. After stirring for 30 min at rt, the precipitate was filtered off and washed with DCM to afford 0.05 mg of white solid. The filtrate was concentrated in vacuo and purified by preparative TLC on silica gel (DCM/acetone 6/4) to give additional 0.013 g. Both solids were mixed to give 6-hydroxy-3-pyrazol-1-yl-1,6-diaza-bicyclo[3.2.1]oct-3-en-7-one (5a) (0.063 g, 0.31 mmol, 75%).

MS m/z ([M+H]⁺) 207

¹H NMR (400 MHz, DMSO-d₆): δ(ppm) 3.22 (d, J=10.7 Hz, 1H), 3.36 (dd, J=2.5, 10.8 Hz, 1H), 4.02 (dd, J=2.5, 5.6 Hz, 1H), 4.18 (s, 2H), 6.45 (dd, J=2.0, 2.4 Hz, 1H), 6.65 (d, J=5.2 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 8.18 (d, J=2.4 Hz, 1H), 9.65 (s, 1H).

Step 2: Preparation of cyclohexyl 2,2-difluoro-2-[(7-oxo-3-pyrazol-1-yl-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetate, Example 5

To a solution of 6-hydroxy-3-pyrazol-1-yl-1,6-diaza-bicyclo[3.2.1]oct-3-en-7-one (5a) (0.40 g, 0.194 mmol) in DMSO (1.9 mL) were added DBU (0.032 mL, 0.213 mmol) and cyclohexyl bromodifluoroacetate (0.130 mL, 0.504 mmol). The mixture was stirred for 30 min at rt then poured in a 2M NaH₂PO₄solution. The product was extracted with ethyl acetate. The organic layer was filtered on a pad of silica and concentrated in vacuo. The residue was purified on silica gel (DCM/acetone: 10/0 to 9/1) to provide cyclohexyl difluoro-(7-oxo-3-pyrazol-1-yl-1,6-diaza-bicyclo[3.2.1]oct-3-en-6-yloxy)-acetate (Example 5) (0.064 g, 0.167 mmol, 86%).

MS m/z ([M+H]⁺) 383

¹H NMR (400 MHz, CDCl₃): δ (ppm) 1.25-1.43 (m, 3H), 1.52-1.62 (m, 3H), 1.75-1.82 (m, 2H), 1.87-1.95 (m, 2H), 3.23 (d, J=11.1 Hz, 1H), 3.64 (dd, J=1.7, 11.2 Hz, 1H), 4.25-4.33 (m, 2H), 4.58 (d, J=17.7 Hz, 1H), 4.88-4.99 (m, 1H), 6.38 (dd, J=2.6, 1.8 Hz, 1H), 6.39-6.43 (m, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.64 (d, J=2.6 Hz, 1H).

Example 6: Synthesis of n-Cetyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]-acetate

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Step 1: Preparation of Intermediate n-cetyl 2-bromo-2,2-difluoro-acetate (6a)

In a sealed vial, a solution of ethyl 2-bromo-2,2-difluoro-acetate (300 μL, 2.34 mmol) and n-Cetyl alcohol (200 mg, 0.82 mmol) was heated at 115° C. for 2.5 hours. The middle was slightly concentrated. The crude was purified by chromatography on silica gel (Heptane/DCM 100/0 to 70/30) to afford n-cetyl 2-bromo-2,2-difluoro-acetate (6a) (155 mg, 0.388 mmol, 47%).

¹H NMR (300 MHz, CDCl₃): δ (ppm) 0.86-0.90 (m, 3H), 1.20-1.41 (m, 26H), 1.70-1.79 (m, 2H), 4.35 (t, J=6.6 Hz, 2H).

Step 2: Preparation of n-Cetyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]-acetate, Example 6

At room temperature, a solution of DBU (61 μL, 0.41 mmol) in DMSO (500 μL) was slowly added to a solution of 6-Hydroxy-3-oxazol-2-yl-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (prepared according to the procedure described in WO2016177862 compound 37f) (85 mg, 0.41 mmol) and n-Cetyl 2-bromo-2,2-difluoro-acetate (6a) (245 mg, 0.61 mmol) in a mixture of DMSO (2 mL) and THF (2 mL). The middle was stirred at rt for 2.5 hours and then diluted with AcOEt. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (DCM/Acétone 95/5) to provide n-cetyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]-acetate (Example 6) (71 mg, 0.135 mmol, 33%). MS m/z ([M+H]⁺) 526.

¹H NMR (300 MHz, CDCl₃): δ (ppm) 0.86-0.90 (m, 3H), 1.20-1.41 (m, 26H), 1.67-1.78 (m, 2H), 3.23 (d, J=11.1 Hz, 1H), 3.62-3.70 (m, 1H), 4.17 (dd, J=2.2, 18.1 Hz, 1H), 4.26-4.33 (m, 3H), 4.45 (dd, J=1.4, 18.1 Hz, 1H), 7.08-7.11 (m, 1H), 7.15 (d, J=0.8 Hz, 1H), 7.61 (d, J=0.8 Hz, 1H).

Example 7: Synthesis of n-Hexyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]-acetate

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Step 1: Preparation of Intermediate n-Hexyl 2-bromo-2,2-difluoro-acetate (7a)

In a sealed vial, a solution of ethyl 2-bromo-2,2-difluoro-acetate (1 mL, 7.8 mmol) and 1-hexanol (980 mg, 7.8 mmol) was heated at 115° C. for 2.5 hours. The middle was slightly concentrated. The crude was purified by chromatography on silica gel (Heptane/DCM 100/0 to 70/30) to afford n-Hexyl 2-bromo-2,2-difluoro-acetate (6a) (215 mg, 0.83 mmol, 11%).

¹H NMR (300 MHz, CDCl₃): δ (ppm) 0.88-0.92 (m, 3H), 1.29-1.45 (m, 6H), 1.70-1.79 (m, 2H), 4.35 (t, J=6.6 Hz, 2H).

Step 2: Preparation of n-Hexyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]-acetate, Example 7

At room temperature, a solution of DBU (72 μL, 0.41 mmol) in DMSO (250 μL) was slowly added to a solution of 6-Hydroxy-3-oxazol-2-yl-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (prepared according to the procedure described in WO2016177862 compound 37f) (100 mg, 0.48 mmol) and n-Hexyl 2-bromo-2,2-difluoro-acetate (7a) (215 mg, 0.83 mmol) in DMSO (2 mL). The middle was stirred at room temperature for 10 minutes and then diluted with AcOEt. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (DCM/Acetone 95/5) to provide n-Hexyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]-acetate (Example 7) (100 mg, 0.259 mmol, 54%).

MS m/z ([M+H]⁺) 386.

¹H NMR (300 MHz, CDCl₃): δ (ppm) 0.86-0.90 (m, 3H), 1.25-1.42 (m, 6H), 1.73 (pent, J=6.9 Hz, 2H), 3.23 (d, J=11.2 Hz, 1H), 3.66-3.71 (m, 1H), 4.17 (dd, J=2.1, 18.1 Hz, 1H), 4.24-4.35 (m, 3H), 4.45 (dd, J=1.4, 18.1 Hz, 1H), 7.08-7.10 (m, 1H), 7.15 (d, J=0.8 Hz, 1H), 7.62 (d, J=0.8 Hz, 1H).

Example 8: Synthesis of 2-Adamantyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]-acetate

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Step 1: Preparation of Intermediate 2-Adamantyl 2-bromo-2,2-difluoro-acetate (8a)

In a sealed vial, a solution of ethyl 2-bromo-2,2-difluoro-acetate (1 mL, 7.8 mmol) and 2-Adamantanol (1 g, 6.57 mmol) in Dioxane (12 mL) was heated at 115° C. for 16 hours. The middle was slightly concentrated and triturated with Cyclohexane to remove excess of 2-Adamantanol. The crude was purified by chromatography on silica gel (Heptane/DCM 100/0 to 50/50) to afford 2-Adamantyl 2-bromo-2,2-difluoro-acetate (8a) (210 mg, 0.68 mmol, 10%).

¹H NMR (300 MHz, CDCl₃): δ (ppm) 1.58-1.67 (m, 2H), 1.73-1.84 (m, 4H), 1.85-1.96 (m, 4H), 2.01-2.17 (m, 4H), 5.10-5.13 (m, 1H).

Step 2: Preparation of 2-Adamantyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]-acetate, Example 8

At room temperature, a solution of DBU (72 μL, 0.48 mmol) in DMSO (250 μL) was slowly added to a solution of 6-Hydroxy-3-oxazol-2-yl-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (prepared according to the procedure described in WO2016177862 compound 37f) (100 mg, 0.48 mmol) and 2-Adamantyl 2-bromo-2,2-difluoro-acetate (8a) (210 mg, 0.68 mmol) in DMSO (2 mL). The middle was stirred at room temperature for 35 minutes and then diluted with AcOEt. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (DCM/Acetone 95/5) to provide 2-Adamantyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]-acetate (Example 8) (116 mg, 0.266 mmol, 55%).

MS m/z ([M+H]⁺) 436.

¹H NMR (300 MHz, CDCl₃): δ(ppm) 1.51-1.64 (m, 4H), 1.69-1.94 (m, 6H), 2.00-2.14 (m, 4H), 3.22 (d, J=11.2 Hz, 1H), 3.64-3.69 (m, 1H), 4.17 (dd, J=2.2, 18.1 Hz, 1H), 4.28 (dd, J=2.5, 5.3 Hz, 1H), 4.45 (dd, J=1.4, 18.1 Hz, 1H), 5.08-5.13 (m, 1H), 7.09-7.11 (m, 1H), 7.15 (d, J=0.8 Hz, 1H), 7.62 (d, J=0.8 Hz, 1H).

Example 9: Synthesis of Benzyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]-acetate

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Step 1: Preparation of Intermediate Benzyl 2-bromo-2,2-difluoro-acetate (9a)

In a sealed vial, a solution of ethyl 2-bromo-2,2-difluoro-acetate (1 mL, 7.8 mmol) and Benzyl alcohol (800 μL, 7.8 mmol) was heated at 120° C. for 20 hours. The middle was slightly concentrated. The crude was purified by chromatography on silica gel (Heptane/DCM 100/0 to 50/50) to afford Benzyl 2-bromo-2,2-difluoro-acetate (9a) (590 mg, 2.22 mmol, 28%).

¹H NMR (300 MHz, CDCl₃): δ (ppm) 5.36 (s, 2H), 7.41 (s, 5H).

Step 2: Preparation of Benzyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]-acetate, Example 9

At room temperature, a solution of DBU (72 μL, 0.48 mmol) in DMSO (250 μL) was slowly added to a solution of 6-Hydroxy-3-oxazol-2-yl-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (prepared according to the procedure described in WO2016177862 compound 37f) (100 mg, 0.48 mmol) and Benzyl 2-bromo-2,2-difluoro-acetate (9a) (250 mg, 0.94 mmol) in DMSO (2 mL). The middle was stirred at room temperature for 35 minutes and then diluted with AcOEt. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (DCM/Acetone 95/5) to provide Benzyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]-acetate (Example 9) (142 mg, 0.363 mmol, 76%).

MS m/z ([M+H]⁺) 392.

¹H NMR (300 MHz, CDCl₃): δ (ppm) 3.15 (d, J=11.1 Hz, 1H), 3.48-3.53 (m, 1H), 4.14 (dd, J=2.4, 12.9 Hz, 1H), 4.17 (d, J=2.2 Hz, 1H), 4.43 (dd, J=1.3, 18.0 Hz, 1H), 5.33 (s, 2H), 7.04-7.07 (m, 1H), 7.15 (d, J=0.8 Hz, 1H), 7.37-7.42 (m, 5H), 7.61 (d, J=0.8 Hz, 1H).

Example 10: Synthesis of 4-Heptanyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]-acetate

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Step 1: Preparation of Intermediate 4-Heptanyl 2-bromo-2,2-difluoro-acetate (10a)

In a sealed vial, a solution of ethyl 2-bromo-2,2-difluoro-acetate (1 mL, 7.8 mmol) and 4-Heptanol (906 mg, 7.8 mmol) was heated at 120° C. for 60 hours. The middle was slightly concentrated. The crude was purified by chromatography on silica gel (Heptane/DCM 100/0 to 50/50) to afford 4-Heptanyl 2-bromo-2,2-difluoro-acetate (10a) (510 mg, 1.86 mmol, 24%).

¹H NMR (300 MHz, CDCl₃): δ (ppm) 0.93 (t, J=7.3 Hz, 6H), 1.28-1.47 (m, 4H), 1.54-1.75 (m, 4H), 5.07 (tt, J=4.9, 7.7 Hz, 1H).

Step 2: Preparation of 4-Heptanyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]-acetate, Example 10

At room temperature, a solution of DBU (72 μL, 0.48 mmol) in DMSO (250 μL) was slowly added to a solution of 6-Hydroxy-3-oxazol-2-yl-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (prepared according to the procedure described in WO2016177862 compound 37f) (100 mg, 0.48 mmol) and 4-Heptanyl 2-bromo-2,2-difluoro-acetate (10a) (262 mg, 0.96 mmol) in DMSO (2 mL). The middle was stirred at room temperature for 35 minutes and then diluted with AcOEt. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (DCM/Acetone 95/5) to provide 4-Heptanyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]-acetate (Example 10) (120 mg, 0.30 mmol, 62%).

MS m/z ([M+H]⁺) 400.

¹H NMR (300 MHz, CDCl₃): δ (ppm) 0.91 (td, J=0.9, 7.3 Hz, 6H), 1.24-1.43 (m, 4H), 1.43-1.72 (m, 4H), 3.22 (d, J=11.3 Hz, 1H), 3.63-3.68 (m, 1H), 4.17 (dd, J=2.1, 18.1 Hz, 1H), 4.28 (dd, J=2.5, 5.3 Hz, 1H), 4.45 (dd, J=1.3, 18.0 Hz, 1H), 5.02-5.10 (m, 1H), 7.08-7.10 (m, 1H), 7.15 (d, J=0.8 Hz, 1H), 7.62 (d, J=0.8 Hz, 1H).

Example 11: Synthesis of cycloheptyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetate

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Step 1: Preparation of Intermediate cycloheptyl 2-bromo-2,2-difluoro-acetate (11a)

To a solution of ethyl 2-bromo-2,2-difluoro-acetate (1 g, 4.93 mmol) and cycloheptanol (2.8 g, 24.6 mmol) in THF (5 mL) under inert atmosphere at 0° C., was added t-BuOK (1M in THF, 2.46 mL). After stirring at room temperature for 16 hours, the mixture was quenched with a 1N HCl solution, extracted with AcOEt, dried over Na₂SO₄and filtered. The solvent was removed in vacuo. The crude was purified by chromatography on silica gel (Heptane/DCM 10/0 to 7/3) to afford cycloheptyl 2-bromo-2,2-difluoro-acetate (11a) (339 mg, 1.25 mmol, 26%).

¹H NMR (400 MHz, CDCl₃): δ (ppm) 1.44-1.53 (m, 2H), 1.58-1.61 (m, 4H), 1.67-1.76 (m, 2H), 1.77-1.85 (m, 2H), 1.94-2.02 (m, 2H), 5.09-5.16 (m, 1H).

Step 2: Preparation of cycloheptyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetate, Example 11

At room temperature, a solution of DBU (61.4 μL, 0.41 mmol) in DMSO (207 μL) was slowly added to a solution of 6-Hydroxy-3-oxazol-2-yl-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (prepared according to the procedure described in WO2016177862 compound 37f) (85 mg, 0.41 mmol) and cycloheptyl 2-bromo-2,2-difluoro-acetate (11a) (133 mg, 0.49 mmol) in DMSO (5 mL). The mixture was stirred at room temperature for 30 minutes then diluted with AcOEt. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (DCM/Acetone 9/1) to provide cycloheptyl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetate (Example 11) as a white solid (78 mg, 0.20 mmol, 48%).

MS m/z ([M+H]⁺) 398.

¹H NMR (400 MHz, acetone-d₆): δ(ppm) 1.47-1.61 (m, 6H), 1.66-1.84 (m, 4H), 1.95-2.02 (m, 2H), 3.49 (dd, J=11.4, 0.8 Hz, 1H), 3.60-3.64 (m, 1H), 4.25 (d, J=1.8 Hz, 2H), 4.42 (dd, J=5.2, 2.5 Hz, 1H), 5.09-5.16 (m, 1H), 7.10-7.12 (m, 1H), 7.24 (d, J=0.8 Hz, 1H), 7.97 (d, J=0.8 Hz, 1H).

Example 12: Synthesis of indan-2-yl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetate

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Step 1: Preparation of Intermediate indan-2-yl 2-bromo-2,2-difluoro-acetate (12a)

In a sealed vial, a solution of ethyl 2-bromo-2,2-difluoro-acetate (1.5 g, 7.39 mmol) and 2-Indanol (992 mg, 7.39 mmol) was heated at 110° C. for 16 hours. The mixture was concentrated in vacuo. The crude was purified by chromatography on silica gel (Heptane/DCM 100/0 to 50/50) to afford indan-2-yl 2-bromo-2,2-difluoro-acetate (12a) (318 mg, 1.09 mmol, 15%).

¹H NMR (400 MHz, acetone-d₆): (ppm) 3.14 (dd, J=17.5, 2.2 Hz, 2H), 3.47 (dd, J=17.5, 6.1 Hz, 2H), 5.78-5.83 (m, 1H), 7.19-7.23 (m, 2H), 7.27-7.32 (m, 2H).

Step 2: Preparation of indan-2-yl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetate, Example 12

At room temperature, a solution of DBU (79.4 μL, 0.53 mmol) in DMSO (268 μL) was slowly added to a solution of 6-Hydroxy-3-oxazol-2-yl-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (prepared according to the procedure described in WO2016177862 compound 37f) (110 mg, 0.53 mmol) and indan-2-yl 2-bromo-2,2-difluoro-acetate (12a) (186 mg, 0.64 mmol) in DMSO (5.8 mL). The mixture was stirred at room temperature for 30 minutes and then diluted with AcOEt. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (DCM/AcOEt 8/2) to provide indan-2-yl 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetate (Example 12) (108 mg, 0.26 mmol, 13%).

MS m/z ([M+H]⁺418).

¹H NMR (300 MHz, acetone-d₆): (ppm) 3.13 (dd, J=17.4, 2.3 Hz, 2H), 3.39-3.49 (m, 3H), 3.55 (ddd, J=11.5, 2.6, 1.3 Hz, 1H), 4.22-4.25 (m, 3H), 5.72-5.79 (m, 1H), 6.99-7.03 (m, 1H), 7.18-7.22 (m, 2H), 7.23 (d, J=0.8 Hz, 1H), 7.28-7.31 (m, 2H), 7.96 (d, J=0.8 Hz, 1H).

Example 13: Synthesis of (2,2,6,6-tetramethyltetrahydropyran-4-yl) 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetate

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Step 1: Preparation of Intermediate (2,2,6,6-tetramethyltetrahydropyran-4-yl) 2-bromo-2,2-difluoro-acetate (13a)

In a sealed vial, a solution of ethyl 2-bromo-2,2-difluoro-acetate (1.5 g, 7.39 mmol), methane sulfonic acid (10 μL) and 2,2,6,6-tetramethyltetrahydropyran-4-ol (1 g, 9.43 mmol) was heated at 100° C. for 16 hours. The mixture was concentrated in vacuo. The crude was purified by chromatography on silica gel (Heptane/DCM 100/0 to 50/50) to afford (2,2,6,6-tetramethyltetrahydropyran-4-yl) 2-bromo-2,2-difluoro-acetate (13a) (900 mg, 2.85 mmol, 30%).

¹H NMR (300 MHz, CDCl₃): δ (ppm) 1.28 (s, 6H), 1.32 (s, 6H), 1.50-1.58 (m, 2H), 1.99-2.04 (m, 2H), 5.33-5.43 (m, 1H).

Step 2: Preparation of (2,2,6,6-tetramethvltetrahvdropyvran-4-yl) 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetate, Example 13

At room temperature, DBU (76 μL, 0.5 mmol) was slowly added to a solution of 6-Hydroxy-3-oxazol-2-yl-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (prepared according to the procedure described in WO2016177862 compound 37f) (100 mg, 0.48 mmol) and (2,2,6,6-tetramethyltetrahydropyran-4-yl) 2-bromo-2,2-difluoro-acetate (13a) (228 mg, 0.72 mmol) in DMSO (1 mL). The mixture was stirred at room temperature for 10 minutes and then diluted with AcOEt. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (DCM/Acetone 10/0 to 4/6) to provide (2,2,6,6-tetramethyltetrahydropyran-4-yl) 2,2-difluoro-2-[(3-oxazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy]acetate (Example 13) (95 mg, 0.21 mmol, 45%).

MS m/z ([M+H]⁺442).

¹H NMR (300 MHz, CDCl₃): δ (ppm) 1.26 (s, 6H), 1.30 (s, 6H), 1.47-1.60 (m, 2H), 1.97-2.02 (m, 2H), 3.23 (d, J=11.2 Hz, 1H), 3.66-3.71 (m, 1H), 4.17 (dd, J=2.1/18.1 Hz, 1H), 4.28 (dd, J=2.5/5.3 Hz, 1H), 4.45 (dd, J=1.4/18.1 Hz, 1H), 5.30-5.41 (m, 1H), 7.08-7.11 (m, 1H), 7.16 (d, J=0.8 Hz, 1H), 7.63 (d, J=0.8 Hz, 1H).

¹⁹F NMR (300 MHz, CDCl₃): δ (ppm) −83.70 (d, J=139.8 Hz, 1F), −83.04 (d, J=139.8 Hz, 1F).

Biological Activity

Compound AF1, described as example 6 in WO2016177862, is the active form of prodrug compounds of formula (I) as Examples 1 to 3.

Compound AF2, described as example 37 in WO2016177862, is the active form of prodrug compounds of formula (I) as Example 4 and 6 to 13.

Compound AF3, which can be prepared by following the general procedure described in WO2016177862, is the active form of prodrug of formula (I) compound as Example 5.

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Method 1: β-Lactamase Inhibitory Activity, Determination of IC₅₀(Table 1)

Enzyme activity was monitored by spectrophotometric measurement of nitrocefin (NCF—TOKU-E, N005) hydrolysis at 485 nm, at room temperature and in assay buffer A: 100 mM Phosphate pH7, 2% glycerol and 0.1 mg/mL Bovine serum albumin (Sigma, B4287). Buffer A was supplemented with 100 mM NaHCO₃for several OXA-type enzymes (OXA-1, OXA-11, OXA-15 and OXA-163). Enzymes were cloned in E. coli expression vector, expressed and purified in house using classical procedures. To a transparent polystyrene plate (Corning, 3628) were added in each well 5 μL DMSO or inhibitor dilutions in DMSO and 80 μL enzyme in buffer A. Plates were immediately read at 485 nm in a microplate spectrophotometer (BioTek, Powerwave HT) to enable background subtraction. After 30 min of pre-incubation at room temperature, 15 μL of NCF (100 μM final) were finally added in each well. Final enzyme concentrations were 0.1 nM (TEM-1), 0.075 nM (SHV-1), 1.5 nM (SHV-12), 0.4 nM (CTX-M-15), inM (KPC-2), 5 nM (PC1 S. aureus), 0.2 nM (P99 AmpC), 0.2 nM (CMY-37), 0.8 nM (DHA-1), 0.4 nM (AmpC P. aeruginosa), 0.2 nM (OXA-1), 1.2 nM (OXA-11), 0.4 nM (OXA-15), 0.2 nM (OXA-23), 0.4 nM (OXA-40), 0.3 nM (OXA-48), 75 nM (OXA-51), 0.5 nM (OXA-58) and 0.15 nM (OXA-163). After 20 min incubation at room temperature, plates were once again read at 485 nm. Enzyme activity was obtained by subtracting the background from the final signal, and was converted to enzyme inhibition using non inhibited wells. IC₅₀curves were fitted to a classical Langmuir equilibrium model with Hill slope using XLFIT (IDBS).

TABLE 1

IC50 of compounds AF1, AF2, AF3 against bacterial beta-lactamases

beta-
IC50 (μM)

lactamase
AF1
AF2
AF3

TEM-1
0.010
0.0026
0.00081

SHV-1
0.020
0.012
0.0060

SHV-12
0.0038
0.0041
0.0043

CTX-M-15
0.0024
0.0015
0.00066

KPC-2
0.51
0.069
0.077

SAU PC1
0.56
0.22
0.12

P99 ampC
2.2
0.73
0.27

CMY-37
2.0
0.45
0.15

DHA-1
11
0.37
0.21

PAE ampC
4.5
0.28
0.098

OXA-1
1.6
2.1
1.1

OXA-11
0.25
0.084
0.040

OXA-15
0.024
0.14
0.12

OXA-23
0.11
7.4
9.6

OXA-40
0.12
8.3
8.9

OXA-48
0.0030
0.0024
0.0051

OXA-51
0.086
0.45
0.52

OXA-58
0.015
0.58
1.0

OXA-163
0.0072
0.011
0.0059

Method 2: MIC of Compounds Alone and Combined with Antibacterials Against Bacterial Isolates

Compounds of the present invention were assessed against genotyped bacterial strains (Table 3, 4) alone or in combination with an antibacterial (Table 2). In the assays, MICs of said compounds or combination of antibiotics with fixed concentrations of said compounds (4 or 8 μg/mL) were determined by the broth microdilution method according to the Clinical Laboratory Standards Institute (CLSI—M7-A7). Briefly, compounds alone according to the invention were prepared in DMSO and spotted (2 μL each) on sterile polystyrene plates (Corning, 3788). Combinations of compounds and antibiotics dilutions were prepared in DMSO and spotted (1 μL each) on sterile polystyrene plates (Corning, 3788). Log phase bacterial suspensions were adjusted to a final density of 5.10⁵CFU/mL in cation-adjusted Mueller-Hinton broth (ca-MHB; Becton-Dickinson and Company) and added to each well (98 μL). Microplates were incubated for 16-20 h at 35° C. in ambient air. The MIC of the compounds was defined as the lowest concentration of said compounds that prevented bacterial growth as read by visual inspection. The MIC of ATB at each compound concentration was defined as the lowest concentration of ATB that prevented bacterial growth as read by visual inspection.

Results are presented in Tables 4, 5 and 6. They show the advantage of combining antibiotics including Cefixime with the active forms AF1, AF2 or AF3 of the prodrugs herein described to combat resistant isolates.

TABLE 2

Antibacterials or beta-lactamase inhibitors used in

MIC and combination studies

Abbreviations - Antibacterials

ATB
Antibiotic

AMX
Amoxicillin

CAZ
Ceftazidime

CDR
Cefdinir

FIX
Cefixime

FUR
Cefuroxime

POD
Cefpodoxime

CLA
Clavulanic acid

TABLE 3

Bacterial species used in MIC determination

Abbreviations - Strains

ECO

Escherichia coli

KPN

Klebsiella pneumoniae

ECL

Enterobacter cloacae

EAE

Enterobacter aerogenes

CFR

Citrobacter freundii

CKR

Citrobacter koseri

CMU

Citrobacter murliniae

MMO

Morganella morganii

PMI

Proteus mirabilis

PRE

Providencia rettgeri

PST

Providencia stuartii

KOX

Klebsiella oxytoca

SMA

Serratia marcescens

STY

Salmonella typhimurium

TABLE 4

List of the bacterial isolates, their resistance genotype, and the MIC of reference antibiotics.

MIC (μg/mL)

Resistance
ATB

Strains ID
genotype
CAZ
FIX
AMX
FUR
POD
CDR

ECO
ompC-, ompF-
2
2
16
64
4
2

UFR86

ECO
CTX-M-15
16
32
>256
>256
>256
256

260304

ECO
CTX-M-132
128
>128
>256
>256
>256
>256

260096

KPN
TEM-1, SHV-1,
128
>128
>256
>256
>256
>256

270077
CTX-M-15

ECL
TEM-1, CTX-M-15
64
>128
>256
>256
>256
>256

260508

ECO
CTX-M-1
4
16
>256
>256
>256
256

190549

ECO
CTX-M-1
8
16
>256
>256
>256
>256

190314

ECO
TEM-1, CTX-M-15
64
128
>256
>256
>256
>256

180070

ECO
TEM-1, CTX-M-14
2
8
>256
>256
>256
256

200159

ECO
CTX-M-14
2
8
>256
>256
>256
256

200259

ECO
CTX-M-1
8
32
>256
>256
>256
>256

200344

KPN
SHV-18, OXA-2
64
16
>256
32
16
4

700603

ECL UFR60
TEM-1, CTX-M-15,
>128
>128
>256
>256
>256
>256

KPC-2

ECO
TEM-1, KPC-2
>128
32
>256
>256
>256
>256

UFR61O

ECO
TEM-1, CTX-M-9,
8
128
>256
>256
>256
>256

UFR62
KPC-2

KPN UFR65
TEM-1, SHV-11,
128
>128
>256
>256
>256
>256

KPC-2

KPN UFR66
TEM-1, SHV-11,
>128
512
>256
>256
>256
>256

CTX-M-15, KPC-2

KPN
TEM-1, SHV-11,
>128
>128
>256
>256
>256
>256

260251
SHV-12, CTX-M-15,

KPC-2

KPN
TEM-1, SHV-11,
256
>128
>1024
>512
>512
>256

BAA-1898
SHV-12, KPC-2

KPN
TEM-1, SHV-1,
64
>128
>256
>256
>256
>256

160143
CTX-M-15, KPC-2,

OXA-1

KPN UFR67
TEM-1, SHV-11,
>128
>128
>256
>256
>256
>256

KPC-3

KPN UFR68
TEM-1, SHV-11,
512
>128
>1024
>256
>256
>256

CTX-M-15, KPC-3

KPN
TEM-1, SHV-11,
>256
>128
>256
>256
>256
>256

140513
CTX-M-15, KPC-3

KPN
TEM-1, SHV-11,
>128
>128
>256
>256
>256
>256

260252
KPC-3

ECL
TEM-1, KPC-3
>128
>128
>256
>256
>256
>256

260253

ECL P99
AmpC
128
>128
>1024
>512
>512
>256

ECL
AmpC
256
>128
>256
>256
>256
>256

190310

ECL
AmpC
>256
>128
>256
>256
>256
>256

200138

ECL
AmpC
>256
>128
>256
>256
>256
256

260323

ECL
AmpC
512
>128
>256
>256
>256
>256

260033

ECL
AmpC
128
>128
>256
>256
>256
>256

NEM146383

EAE
TEM-x, AmpC
128
>128
>256
>256
>256
>256

200261

EAE 49469
AmpC
128
>128
>1024
>128
>128
>128

CFR UFR83
TEM-3, AmpC
>128
>128
>256
>256
>256
>256

ECL UFR84
TEM-1, AmpC,
>128
>128
>256
>256
>256
>256

OXA-1

ECL UFR85
TEM-1, CTX-M-15,
128
>128
>256
>256
>256
>256

AmpC

KPN UFR76
TEM-155, SHV-11,
>128
>128
>256
>256
>256
>256

ACT-1, OXA-2

ECL UFR70
TEM-1, CTX-M-15,
>128
>128
>256
>256
>256
>256

CMY-2, OXA-1,

Porin loss

KPN UFR77
CMY-2
32
128
>256
64
64
64

PMI UFR82
CMY-2
4
8
256
16
64
16

ECO
SHV-1, DHA-1
64
>128
>256
>256
>256
>256

UFR74

KPN UFR79
DHA-1, OXA-1
16
>128
>256
>256
32
256

KPN UFR80
SHV-11, DHA-1,
0.5
<=0.25
>256
32
2
1

OXA-1

KPN UFR78
TEM-1, SHV-1,
>256
>128
>256
>256
>256
>256

CTX-M-15, CMY-2,

OXA-1, OXA-48

KPN UFR81
TEM-1, SHV-1,
128
>128
>256
>256
>256
>256

DHA-1, OXA-48

ECL UFR14
TEM-1, SHV-12,
>256
>128
>256
>256
>256
>256

CTX-M-15, DHA-1,

OXA-1, OXA-48

ECO
TEM-1, CTX-M-15,
>128
>128
>256
>256
>256
>256

UFR17
CMY-2, OXA-1,

OXA-181

ECO
CTX-M-15, CMY-2,
128
>128
>256
>256
>256
>256

UFR19
OXA-1, OXA-204

KPN
TEM-1, SHV-1,
128
>128
>256
>256
>256
>256

110376
CTX-M-15, OXA-1,

OXA-48

CFR UFR10
OXA-48
128
>128
>256
>256
>256
>256

CFR UFR11
TEM-1, OXA-1,
8
32
>256
>256
>256
>256

OXA-48

ECL UFR12
CTX-M-9, OXA-48
2
16
>256
>256
128
>256

ECL UFR13
TEM-1, SHV-12,
>256
>128
>256
>256
>256
>256

CTX-M-9, OXA-48

ECO
TEM-1, OXA-48
0.5
1
>256
16
2
>256

UFR15

ECO
TEM-1, CTX-M-15,
64
>128
>256
>256
>256
>256

UFR16
OXA-1, OXA-48

ECO
CTX-M-15, OXA-
128
>128
>256
>256
>256
>256

UFR18
204

ECO
TEM-1, OXA-48
0.5
<=0.25
>1024
8
1
256

131119

ECO
SHV-1, CTX-M-15,
128
512
>256
>256
>256
>256

UFR20
OXA-1, OXA-232

KOX UFR21
TEM-1, CTX-M-15,
128
>128
>256
>256
>256
>256

OXA-48

KPN
TEM-1, SHV-1,
2
<=0.25
>256
32
1
>256

UFR22_O
OXA-48

KPN UFR23
TEM-1, SHV-1,
0.5
<=0.25
>256
8
0.5
>256

OXA-48

KPN UFR24
TEM-1, SHV-2,
>128
>128
>256
128
256
>256

SHV-11, OXA-1,

OXA-48, OXA-47

KPN UFR25
TEM-1, SHV-11,
128
>128
>256
>256
>256
>256

CTX-M-15, OXA-

162

KPN UFR27
TEM-1, SHV-28,
>128
>128
>256
>256
>256
>256

CTX-M-15, OXA-

204

KPN UFR28
TEM-1, SHV-1,
64
256
>256
>256
>256
>256

CTX-M-15, OXA-1,

OXA-232

SMA
OXA-405
8
1
>256
>256
32
>256

UFR30

CKO ROU
TEM-1, SHV-12,
1
1
>256
64
4
>256

CTX-M-15, OXA-1,

OXA-48

KPN LIB
SHV-11, OXA-48
0.25
<=0.25
>256
16
1
>256

ECL 2185D
OXA-163
>128
>128
>256
>256
>256
>256

KPN ARA
TEM-1, SHV-11,
128
>128
>256
>256
>256
>256

CTX-M-15, OXA-1,

OXA-48

KPN 6299
TEM-1, SHV-11,
256
8
>1024
>512
64
256

OXA-163

KPN
TEM-1, SHV-11,
>128
>128
>256
>256
>256
>256

131119
CTX-M-15, OXA-1,

OXA-48

ECO
OXA-1
0.5
<=0.25
>1024
16
2
0.5

RGN238

STY S3371
OXA-1
0.5
<=0.25
>256
32
4
0.5

ECO 5302
TEM-1, OXA-1
0.5
0.5
>256
32
4
1

ECO 4133
TEM-30, OXA-1
0.5
0.5
>256
16
2
0.5

ECO
CTX-M-15, OXA-1
16
128
>256
>256
>256
>256

190457

ECO
TEM-1, CTX-M-15,
128
>128
>256
>256
>256
>256

260508
OXA-1

KPN
TEM-1, SHV-32,
>128
>128
>256
>256
>256
>256

190128
CTX-M-15, OXA-1

KPN
TEM-1, SHV-76,
128
>128
>256
>256
>256
>256

190270
CTX-M-15, OXA-1

KPN
TEM-1, SHV-32,
128
>128
>256
>256
>256
>256

200047
CTX-M-15, OXA-1

KPN
TEM-1, SHV-1,
64
>128
>256
>256
>256
>256

190551
CTX-M-15, OXA-1

KPN
TEM-1, SHV-1,

190425
CTX-M-15, OXA-1
128
>128
>256
>256
>256
>256

KPN
TEM-1, SHV-1,

200327
CTX-M-15, OXA-1
32
64
>256
>256
>256
>256

ECO
TEM-1, SHV-12,
128
>128
>1024
>512
>512
>256

190317
CTX-M-15, OXA-1

ECL
TEM-1, CTX-M-15,
128
512
>256
>256
>256
>256

190408
OXA-1

ECL
TEM-1, CTX-M-15,
>128
>128
>256
>256
>256
>256

200322
OXA-1

MMO
TEM-1, CTX-M-15,
16
>128
>256
>256
>256
256

200321
OXA-1

KPN
SHV-1, SHV-49,
128
>128
>256
>256
>256
>256

260376
OXA-1

ECO
TEM-1, VEB-1,
>128
128
>256

UFR32
OXA-10

KPN UFR33
TEM-2, SHV-12,
>128
>128
>256

CTX-M-15, OXA-1,

OXA-10

ECL HAN
OXA-35
256
>128
>256

CFR UFR37
TEM-1, CTX-M-15,
>128
>128
>256

NDM-1

ECL UFR38
CTX-M-15, NDM-1
>256
>128
>256

ECO
CTX-M-15, NDM-1
>256
>128
>1024
>256
>256

UFR39

ECO
TEM-1, CTX-M-15,
>128
>128
>256

UFR41
CMY-2, OXA-1,

NDM-4

KPN UFR42
SHV-2, CTX-M-15
>128
>128
>256
>256
>256

OXA-1, OXA-181,

NDM-1

KPN UFR43
SHV-11, CTX-M-15,
>128
>128
>256

CMY-2, OXA-1,

NDM-1

KPN
SHV-1, NDM-1
>256
>128
>256
>256
>256

121206

CMU
VIM-4
>128
>128
>256

210102

ECO
TEM-1, CMY-4,
2
>128
>256

UFR45
OXA-1, OXA-48,

VIM-1

KPN UFR46
TEM-1, SHV-12,
>128
>128
>256

CTX-M-15, OXA-9,

VIM-1

ECL UFR51
SHV-12, IMP-8
>256
>128
>256

ECO
TEM-1, SHV-12,
>128
>128
>256

UFR52
IMP-8

KPN UFR53
TEM-1, IMP-1
>128
>128
>256

PST UFR94
CTX-M-14
1
0.5
>128
>256
32
64

PST UFR95
TEM-24
64
4
>128
128
16
32

PMI
TEM-1, SHV-11,
<=0.25
0.5
>128
>256
>256
64

UFR120
CTX-M-14

PMI
TEM-1, TEM-52
16
128
>128
>256
>256
>256

UFR121

PMI
TEM-1, CTX-M-15
1
1
>128
>256
64
16

UFR122

PMI
CTX-M-1
2
128
>128
>256
>256
>256

UFR123

PMI
CTX-M-2
2
>128
>128
>256
>256
>256

UFR124

PMI
CTX-M-71
2
0.5
>128
>256
>256
256

UFR125

PMI
TEM-2, PER-1
>128
1024
>128
>256
>256
>256

UFR126

PMI
VEB-1
>128
>128
>128
>256
128
>256

UFR127

PMI
TEM-1, VEB-6
>128
>128
>128
>256
>256
>256

UFR129

SMA
TEM-1, BES-1
8
>128
>128
>256
>256
256

UFR134

EAE
TEM-1, SHV-12,
128
>128
>128
>256
>256
>256

UFR201
CTX-M-15

EAE
TEM-24
>256
>128
>128
>256
>256
256

UFR202

ECO
CTX-M-15
64
>128
>128
>256
>256
>256

UFR207

ECO
SHV-12
128
>128
>128
>256
>256
>256

UFR208

ECO
TEM-1, CTX-M-15
128
1024
>128
>256
>256
>256

UFR209

ECO
SHV-12
32
32
>128
>256
>256
>256

UFR210

ECO
TEM-24
>128
>128
>128
64
32
32

UFR211

EAE
TEM-24
>256
>128
>128
>256
256
256

UFR213

KPN
SHV-27, CTX-M-15
>128
>128
>128
>256
>256
>256

UFR215

KPN
SHV-28, CTX-M-15
128
>128
>128
>256
>256
>256

UFR216

KPN
TEM-1, SHV-1,
128
>128
>128
>256
>256
>256

UFR217
CTX-M-15

ECO
TEM-1, SHV-1,
64
>128
>128
>256
>256
>256

UFR218
CTX-M-15

KPN
SHV-12, CTX-M-15
256
>128
>128
>256
>256
>256

UFR219

KPN
TEM-x, SHV-x,
>128
>128
>128
>256
>256
>256

UFR227O
CTX-M-x

MMO
TEM-1, CTX-M-15
8
>128
>128
>256
>256
128

UFR144

KOX
OXY2-2
8
16
>128
>256
>256
>256

UFR173

PST
VEB-1
>128
512
>128
256
128
256

UFR235

PMI
VEB-6
>128
>128
>128
>256
>256
>256

UFR237

MMO
CTX-M-9
0.5
1
>128
>256
256
64

UFR240

MMO
TEM-1, CTX-M-15
8
>128
>128
>256
>256
128

UFR241

MMO
TEM-52
32
1024
>128
>256
>256
>256

UFR242

CFR
CTX-M-15
128
>128
>128
>256
>256
>256

UFR248

CFR
TEM-1, CTX-M-15
64
>128
>128
>256
>256
>256

UFR249

CFR
TEM-1, SHV-28,
128
>128
>128
>256
>256
>256

UFR250
CTX-M-15

ECO
TEM-1, KPC-2,
8
8
>128
>256
>256
>256

UFR174
OXA-1

ECO
TEM-1, KPC-2,
32
64
>128
>256
>256
>256

UFR175
OXA-9

ECO
KPC-3, OXA-9*
256
64
>128
>256
>256
>256

UFR176

SMA
TEM-1, KPC-2
32
64
>128
>256
>256
>256

UFR135

SMA
TEM-1, SHV-12,
>256
>128
>128
>256
>256
>256

UFR136
KPC-2

CFR
TEM-1, KPC-2
32
64
>128
>256
>256
256

UFR146

EAE
TEM-1b, SHV-12,
>256
>1024
>128
>256
>256
>256

UFR199
KPC-2, OXA-9

ECL
TEM-1, SHV-12,
>256
>128
>128
>256
>256
>256

UFR200
KPC-2

SMA
SME-1
0.5
0.5
>128
256
1
4

UFR137

SMA
SME-1
<=0.25
0.5
>128
256
2
8

UFR138

SMA
SME-2
<=0.25
1
>128
>256
8
64

UFR139

PMI
CMY-2
4
8
>128
8
128
16

UFR130

ECO
CMY-2
128
>128
>128
>256
>256
>256

UFR212

KPN
TEM-1, SHV-12,
>128
>128
>128
>256
>256
>256

UFR220
DHA-1

KPN
TEM-1, SHV-11,
16
64
>128
>256
256
128

UFR221
CTX-M-14, DHA-1

KPN
DHA-2
>256
>128
>128
>256
>256
>256

UFR222

SMA
ESAC
32
2
>128
256
16
128

UFR239

MMO
DHA-1
1
8
>128
128
64
64

UFR243

MMO
DHA-1
0.5
4
>128
64
16
32

UFR244

MMO
DHA-1
8
32
>128
128
64
64

UFR245

MMO
DHA-1
4
32
>128
128
64
64

UFR246

MMO
DHA-1
0.5
16
>128
>256
64
128

UFR247

PMI
VEB-1, OXA-10
>128
>128
>128

UFR128

PMI
OXA-23
<=0.25
<=0.25
>128

UFR133

PRE UFR99
OXA-1, OXA-181
>256
>128
>128
>256
>256
>256

KOX
SHV-11, OXA-48
0.5
<=0.125
>128
8
0.5
>256

UFR223

KOX
CTX-M-15, OXA-48
64
>128
>128
>256
>256
>256

UFR224

SMA
OXA-48
1
2
>128
>256
8
>256

UFR141

SMA
OXA-48
0.5
2
>128
>256
8
>256

UFR142

SMA
CTX-M-15, OXA-1,
64
512
>128
>256
>256
>256

UFR143
OXA-48

CKO
OXA-48
>128
0.5
>128
>256
>256
>256

UFR149

CKO
TEM-1, OXA-48
4
2
>128
64
16
>256

UFR150

ECO
CTX-M-15, CMY-4,
128
>128
>128
>256
>256
>256

UFR184
OXA-1, OXA-204

ECO
OXA-48
>256
>128
>128
>256
>256
>256

UFR185

ECO
TEM-1, CTX-M-14,
8
32
>128
>256
>256
>256

UFR186
OXA-48

ECO
CTX-M-15, OXA-48
8
32
>128
>256
>256
>256

UFR187

ECO
TEM-1, CTX-M-15,
128
>128
>128
>256
>256
>256

UFR189
OXA-48

ECO
CTX-M-24, OXA-48
2
64
>128
>256
>256
>256

UFR190

ECO
TEM-1, CTX-M-24,
4
>128
>128
>256
>256
>256

UFR191
OXA-48

ECL
OXA-48
1
4
>128
32
16
>256

UFR194

ECL
TEM-1, CTX-M-15,
128
>128
>128
>256
>256
>256

UFR195
OXA-1, OXA-48

ECL
TEM-1, CTX-M-15,
>256
>128
>128
>256
>256
>256

UFR196
OXA-1, OXA-48

ECL
TEM-1, CTX-M-15,
128
>128
>128
>256
>256
>256

UFR197
OXA-1, OXA-48

ECL
TEM-1, SHV-12,
>256
>128
>128
>256
>256
>256

UFR198
CTX-M-15, DHA-1,

OXA-1, OXA-48

PRE
TEM-1, OXA-48
32
32
>128
64
64
>256

UFR236

CFR
TEM-1, SHV-12,
>128
>128
>128
32
32
>256

UFR253
OXA-48

CFR
VEB-1b, OXA-48,
128
32
>128
32
32
256

UFR254
qnrA

SMA
OXA-48
0.5
1
>128
>256
8
>256

UFR238

PRE UFR96
CTX-M-15, NDM-1
>128
>128
>128

PRE UFR97
TEM-1, NDM-1
>128
>128
>128

PST UFR98
TEM-1, CMY-6,
>256
>128
>128

OXA-1, NDM-1,

RmtC

PMI
CMY-16, OXA-1,
>128
>128
>128

UFR131
OXA-10, NDM-1,

ArmA

PMI
VEB-6, DHA-1,
>128
>128
>128

UFR132
NDM-1, AphA6,

AacA4

SMA
IMP-1
>128
>128
>128

UFR140

MMO
CTX-M-15, NDM-1
>128
>128
>128

UFR145

CFR
TEM-1, CTX-M-15,
>128
>128
>128

UFR147
OXA-1, OXA-181,

OXA-10, OXA-9,

NDM-1, ArmA,

dfrA12, aadA2

CFR
TEM-1, TEM-2,
>128
>128
>128

UFR148
CTX-M-15, NDM-1

KPN
SHV-28, TEM-1,
>256
>128
>128

UFR162
CTX-M-15, OXA-

181, OXA-181,

NDM-1

KPN
TEM-1, SHV-1,
>256
>128
>128

UFR163
CTX-M-15, OXA-

232, OXA-9, NDM-

1, qnrB1, qepA,

RmtB

KPN
SHV-11, CTX-M-15,
>256
>128
>128

UFR164
OXA-1, OXA-181,

NDM-1

KPN
TEM-1, SHV-11,
>256
>128
>128

UFR165
CTX-M-15, OXA-1,

OXA-181, NDM-1

KPN
TEM-1, TEM-1,
>256
>128
>128

UFR166
CTX-M-15, OXA-

181, OXA-9, NDM-1

KPN
TEM-1, SHV-12,
>256
>128
>128

UFR167
CTX-M-15, OXA-9,

NDM-1

KPN
SHV-2, CTX-M-15,
>256
>128
>128

UFR168
OXA-1, OXA-181,

NDM-1, ArmA

KPN
TEM-1, SHV-28,
>256
>128
>128

UFR169
CTX-M-15, CMY-4,

OXA-1, NDM-1

KPN
TEM-1, SHV-28,
>256
>128
>128

UFR170
CTX-M-15, CMY-6,

OXA-1, OXA-9,

NDM-1

KPN
TEM-1, SHV-28,
>256
>128
>128

UFR171
CTX-M-15, OXA-1,

OXA-10, NDM-1,

RmtA

KPN
SHV-38, CMY-16,
>128
>128
>128

UFR172
OXA-10, NDM-1

ECO
TEM-1, CTX-M-15,
>256
>128
>128

UFR177
OXA-1, OXA-2,

NDM-1, RmtC

ECO
TEM-1, CTX-M-15,
>256
>128
>128

UFR178
OXA-9, NDM-1

ECO
TEM-1, SHV-12,
>256
>128
>128

UFR179
CTX-M-15, NDM-1

ECO
TEM-1, CMY-30,
>256
>128
>128

UFR180
OXA-1, NDM-1

ECO
TEM-1, CTX-M-15,
>256
>128
>128

UFR181
NDM-5

ECO
CTX-M-15, OXA-1,
>256
>128
>128

UFR182
NDM-6

ECO
CTX-M-15, OXA-1,
>256
>128
>128

UFR183
NDM-7

ECL
TEM-1, NDM-1
>128
>128
>128

UFR192

ECL
TEM-1, CTX-M-15,
>128
>128
>128

UFR193
OXA-1, NDM-1,

RmtC

ECO
NDM-1
>128
>128
>128

UFR255

KPN
CTX-M-15, NDM-1
>128
>128
>128

140347

ECL
TEM-1, SHV-12,
>256
>128
>128

UFR203
VIM-1

ECO
TEM-1, CMY-4,
>128
>128
>128

UFR204
OXA-48, VIM-1

ECO
CTX-M-15, VIM-4
>128
>128
>128

UFR205

ECO
TEM-1, CTX-M-15,
>128
>128
>128

UFR206
OXA-1, VIM-4

ECL
TEM-1, SHV-31,
>128
>128
>128

UFR214
CTX-M-15, VIM-4

KPN
SHV-12, VIM-1
>128
>128
>128

UFR229O

CFR
SHV-11, VIM-1
>256
>128
>128

UFR251

CFR
VIM-2
64
>128
>128

UFR252

ECO
VIM-2
>256
>128
>128

UFR252GO

ECL
VIM-2
>256
>128
>128

UFR252PT

TABLE 5

MIC of AF2, AF3 alone or combined with antibacterials.

MIC ATB (μg/mL) in combination

MIC
AF2 @
AF2 @
AF2 @
AF3 @
AF3 @

(μg/mL)
8 μg/mL
8 μg/mL
8 μg/mL
8 μg/mL
8 μg/mL
CLA @ 4 μg/mL

Strains ID
AF2
AF3
CAZ
FIX
AMX
CAZ
FIX
FIX
AMX

ECO
16
16
<0.25
0.5
2
0.5
0.5
2
8

UFR86

ECO
4
8
<0.25
<0.25
<0.25
<0.25
<0.25
0.5
4

260304

ECO
16
16
<0.25
<=0.25
0.5
<=0.25
<=0.25
1
4

260096

KPN
>32
>32
1
0.5
32
1
<=0.25
0.5
32

270077

ECL
8
8
<0.25
<0.25
<0.25
<=0.25
<=0.25
32
>128

260508

ECO
4
4
<0.25
<0.25
<0.25
<0.25
<0.25
0.5
8

190549

ECO
8
8
<0.25
<0.25
<0.25
<0.25
<0.25
2
8

190314

ECO
8
4
<0.25
<0.25
<0.25
<0.25
<0.25
2
16

180070

ECO
4
4
<0.25
<0.25
<0.25
<0.25
<0.25
<=0.25
8

200159

ECO
4
4
<0.25
<0.25
<0.25
<0.25
<0.25
<=0.25
8

200259

ECO
8
4
<0.25
<0.25
<0.25
<0.25
<=0.25
0.5
16

200344

KPN
32
32
0.5
<=0.25
4
0.5
0.5
0.5
8

700603

ECL
16
16
4
128
>128
8
8
128
>128

UFR60

ECO
8
16
<0.25
<=0.25
4
<0.25
<0.25
32
>128

UFR61O

ECO
8
8
<0.25
<0.25
<0.25
<0.25
<0.25
32
>128

UFR62

KPN
16
32
4
0.5
>128
2
<=0.25
128
>128

UFR65

KPN
32
32
4
4
>128
16
4
64
>128

UFR66

KPN
16
16
<=0.25
<=0.25
4
<0.25
<=0.25
32
>128

260251

KPN
8
16
<0.25
<=0.25
>128
0.5
<=0.25
64
>512

BAA-

1898

KPN
8
4
<0.25
<0.25
<0.25
<0.25
<0.25
2
>128

160143

KPN
32
32
8
4
>128
32
4
128
>128

UFR67

KPN
16
16
<0.25
0.5
128
4
0.5
64
>128

UFR68

KPN
32
32
>128
8
<128
128
32
>128
>128

140513

KPN
16
>32
64
16
>128
128
16
128
>128

260252

ECL
8
32
<0.25
<0.25
<0.25
2
<=0.25
64
>128

260253

ECL P99
8
16
1
4
>128
<=0.25
8
>128
>512

ECL
32
32
4
>128
>128
8
64
>128
>128

190310

ECL
16
16
8
>128
>128
16
>128
>128
>128

200138

ECL
8
16
0.5
<0.25
<0.25
128
<0.25
>128
>128

260323

ECL
16
16
16
>128
>128
32
>128
>128
>128

260033

ECL
32
16
4
>128
>128
<0.25
16
>128
>128

NEM146383

EAE
16
8
<=0.25
8
16
<0.25
<0.25
>128
>128

200261

EAE
8
8
<0.25
<0.25
<=0.25
<0.25
<0.25
>128
>128

49469

CFR
>32
>32
>128
>128
>128
>128
>128
>128
>128

UFR83

ECL
32
32
8
>128
>128
8
64
>128
>128

UFR84

ECL
8
16
<0.25
<0.25
<0.25
1
1
>128
>128

UFR85

KPN
>32
>32
64
>128
>128
64
>128
>128
>128

UFR76

ECL
8
8
<0.25
<=0.25
0.5
<0.25
<0.25
>128
>128

UFR70

KPN
8
8
<0.25
0.5
<0.25
<0.25
<=0.25
128
>128

UFR77

PMI
4
4
<0.25
<0.25
<0.25
<0.25
<0.25
4
>128

UFR82

ECO
8
8
<0.25
<0.25
<0.25
<0.25
<0.25
>128
>128

UFR74

KPN
16
32
<=0.25
2
>128
<=0.25
2
>128
>128

UFR79

KPN
16
32
<0.25
<=0.25
64
<=0.25
<=0.25
0.5
128

UFR80

KPN
32
>32
>128
>128
>128
>128
>128
>128
>128

UFR78

KPN
16
16
128
64
>128
4
32
>128
>128

UFR81

ECL
16
32
2
32
>128
4
32
>128
>128

UFR14

ECO
16
>32
4
>128
>128
8
>128
>128
>128

UFR17

ECO
8
8
<0.25
<0.25
<0.25
<0.25
<0.25
>128
>128

UFR19

KPN
8
16
<=0.25
<0.25
0.5
<=0.25
<=0.25
128
>128

110376

CFR
4
16
<=0.25
<0.25
1
<0.25
<=0.25
32
>128

UFR10

CFR
>32
>32
8
16
>128
4
32
32
>128

UFR11

ECL
16
8
<0.25
<=0.25
<0.25
<=0.25
<=0.25
8
>128

UFR12

ECL
16
32
1
4
>128
1
2
128
>128

UFR13

ECO
8
8
<0.25
<0.25
<0.25
<0.25
<0.25
1
>128

UFR15

ECO
8
8
<0.25
<0.25
<0.25
<0.25
<0.25
4
>128

UFR16

ECO
8
8
<0.25
<0.25
<0.25
<0.25
<0.25
>128
>128

UFR18

ECO
4
4
<0.25
<0.25
<0.25
<0.25
<0.25
<=0.25
>512

131119

ECO
4
8
1
<=0.25
<=0.25
<0.25
2
>128
>128

URF20

KOX
16
>32
0.5
2
>128
4
4
>128
>128

UFR21

KPN
8
16
<0.25
<=0.25
0.5
<0.25
<=0.25
<=0.25
>128

UFR22_O

KPN
16
8
<0.25
<=0.25
4
<0.25
<0.25
<=0.25
>128

UFR23

KPN
16
32
<=0.25
0.5
32
0.5
0.5
64
>128

UFR24

KPN
8
8
<0.25
<0.25
<0.25
<0.25
<0.25
64
>128

UFR25

KPN
16
16
0.5
8
128
0.5
8
>128
>128

UFR27

KPN
16
16
1
<0.25
<=0.25
<0.25
2
64
>128

UFR28

SMA
16
8
0.5
0.5
64
<=0.25
<=0.25
1
>128

UFR30

CKO
16
32
1
0.5
8
1
1
2
>128

ROU

KPN LIB
8
8
<0.25
<0.25
<=0.25
<0.25
<0.25
<=0.25
>512

ECL
32
32
64
>128
>128
16
>128
>128
>128

2185D

KPN
8
8
<0.25
<=0.25
<=0.25
<0.25
<0.25
128
>128

ARA

KPN
16
16
<=0.25
<=0.25
2
<=0.25
<=0.25
8
>512

6299

KPN
8
8
0.5
<=0.25
>128
1
<=0.25
>128
>512

131119

ECO
4
8
<0.25
<0.25
<0.25
<0.25
<0.25
<=0.25
128

RGN238

STY
8
8
<0.25
<0.25
<0.25
<0.25
<0.25
<=0.25
128

S3371

ECO
4
4
<0.25
<0.25
<0.25
<0.25
<0.25
0.5
>128

5302

ECO
8
4
<0.25
<0.25
<0.25
<0.25
<0.25
0.5
>128

4133

ECO
4
4
<0.25
<0.25
<0.25
<0.25
<0.25
0.5
>128

190457

ECO
8
8
<0.25
<0.25
<0.25
<0.25
<0.25
0.5
64

260508

KPN
16
32
2
1
>128
1
1
0.5
128

190128

KPN
16
32
1
0.5
>128
1
0.5
1
128

190270

KPN
4
4
<0.25
<0.25
<0.25
<0.25
<0.25
<=0.25
32

200047

KPN
4
4
<0.25
<0.25
<0.25
<0.25
<0.25
<=0.25
128

190551

KPN
16
16
<=0.25
0.5
>128
<=0.25
<=0.25
<=0.25
128

190425

KPN
4
4
<0.25
<0.25
<0.25
<0.25
<0.25
<=0.25
32

200327

ECO
4
4
<0.25
<0.25
<0.25
<0.25
<0.25
0.5
64

190317

ECL
4
4
<0.25
<0.25
<=0.25
<0.25
<0.25
128
>128

190408

ECL
8
8
<0.25
<=0.25
<0.25
<0.25
<0.25
64
>128

200322

MMO
32
32
<=0.25
1
>128
<=0.25
1
32
>128

200321

KPN
4
4
<0.25
<0.25
<0.25
<0.25
<0.25
<=0.25
>128

260376

ECO
8
8
<0.25
<0.25
<0.25
<0.25
<0.25
1
128

UFR32

KPN
8
>32
32
<=0.25
8
128
>128
>128
>128

UFR33

ECL
32
32
64
>128
>128
32
>128
>128
>128

HAN

CFR
4
8
8
<=0.25
<0.25
<0.25
<=0.25
>128
>128

UFR37

ECL
8
8
<0.25
<0.25
<=0.25
>128
>128
>128
>128

UFR38

ECO
8
8
<0.25
<0.25
<0.25
<0.25
<0.25
>128
>128

UFR39

ECO
8
8
<0.25
<0.25
<0.25
<0.25
<0.25
>128
>128

UFR41

KPN
16
16
>128
128
>128
16
>128
>128
>128

UFR42

KPN
8
8
<0.25
<0.25
<0.25
<0.25
<0.25
>128
>128

UFR43

KPN
16
16
>128
>128
>128
>128
>128
>128
>128

121206

CMU
16
16
64
>128
>128
128
>128
>128
>128

210102

ECO
4
4
<0.25
<0.25
<0.25
<0.25
<0.25
32
>128

UFR45

KPN
32
32
>128
>128
>128
>128
>128
>128
>128

UFR46

ECL
8
8
<0.25
<0.25
<0.25
<0.25
<0.25
>128
>128

UFR51

ECO
32
8
128
>128
>128
<=0.25
>128
>128
>128

UFR52

KPN
16
8
<0.25
<0.25
<0.25
<0.25
<=0.25
128
>128

UFR53

PST
16
16
<=0.25
<=0.25

<=0.25
<=0.25
2
128

UFR94

PST
32
>32
<=0.25
<=0.25

<=0.25
<=0.25
8
128

UFR95

PST
8
8
<0.25
<0.25

<0.25
<0.25
<=0.25
8

UFR120

PST
4
8
<0.25
<0.25

<0.25
<0.25
<=0.25
4

UFR121

PST
4
4
<0.25
<0.25

<0.25
<0.25
<=0.25
8

UFR122

PST
8
4
<=0.25
<0.25

<0.25
<0.25
<=0.25
16

UFR123

PST
8
8
<=0.25
<0.25

<0.25
<0.25
<=0.25
128

UFR124

PST
8
4
<=0.25
<0.25

<0.25
<0.25
<=0.25
4

UFR125

PMI
8
4
<0.25
<0.25

<0.25
<0.25
<=0.25
16

UFR126

PMI
8
8
<0.25
<0.25

<0.25
<0.25
<=0.25
32

UFR127

PMI
4
4
<0.25
<0.25

<0.25
<0.25
<=0.25
2

UFR129

SMA
16
32
<=0.25
0.5

0.5
<=0.25
32
>128

UFR134

EAE
4
8
<0.25
<0.25

<0.25
<0.25
<=0.25
16

UFR201

EAE
32
32
4
16

1
4
>128
>128

UFR202

EAE
4
8
<0.25
<0.25

<0.25
<0.25
1
32

UFR207

ECO
16
16
2
>128

8
>128
>128
>128

UFR208

ECO
8
8
<0.25
<0.25

<0.25
<0.25
1
32

UFR209

ECO
4
4
<0.25
<0.25

<0.25
<0.25
0.5
8

UFR210

ECO
4
8
<0.25
<0.25

<0.25
<0.25
2
8

UFR211

EAE
16
16
1
16

0.5
<=0.25
>128
>128

UFR213

KPN
32
32
0.5
<=0.25

0.5
<=0.25
1
128

UFR215

KPN
8
4
<0.25
<0.25

<0.25
<0.25
<=0.25
128

UFR216

KPN
8
8
<0.25
<0.25

<0.25
<0.25
<=0.25
128

UFR217

KPN
4
4
<0.25
<0.25

<0.25
<0.25
1
32

UFR218

KPN
32
16
<=0.25
0.5

0.5
<=0.25
0.5
>128

UFR219

KPN
>32
>32
4
8

16
16
>128
>128

UFR227O

MMO
>32
32
<=0.25
1

<=0.25
0.5
32
>128

UFR144

KOX
16
16
<=0.25
<=0.25

<=0.25
<=0.25
4
>128

UFR173

PST
16
16
<=0.25
<=0.25

<=0.25
<=0.25
8
128

UFR235

PMI
8
8
<0.25
<0.25

<0.25
<0.25
<=0.25
4

UFR237

MMO
>32
>32
<=0.25
<=0.25

<=0.25
<=0.25
8
>128

UFR240

MMO
>32
32
<=0.25
2

<=0.25
0.5
32
>128

UFR241

MMO
>32
32
<=0.25
<=0.25

<=0.25
1
64
>128

UFR242

CFR
8
8
<0.25
<0.25

<0.25
<=0.25
4
>128

UFR248

CFR
16
8
<=0.25
<=0.25

<0.25
<=0.25
2
>128

UFR249

CFR
16
16
<=0.25
<0.25

<0.25
<0.25
2
128

UFR250

ECO
2
4
<0.25
<0.25

<0.25
<0.25
2
>128

UFR174

ECO
8
16
<0.25
<0.25

<0.25
<=0.25
16
>128

UFR175

ECO
8
8
<0.25
<0.25

<0.25
<0.25
32
>128

UFR176

SMA
>32
>32
2
2

4
2
32
>128

UFR135

SMA
>32
>32
2
4

1
4
>128
>128

UFR136

CFR
32
32
2
2

1
1
64
>128

UFR146

EAE
16
16
0.5
0.5

0.5
<=0.25
16
>128

UFR199

ECL
32
16
0.5
1

<=0.25
0.5
16
>128

UFR200

SMA
16
32
<=0.25
<=0.25

0.5
<=0.25
1
128

UFR137

SMA
16
16
0.5
<=0.25

<=0.25
<=0.25
0.5
>128

UFR138

SMA
>32
32
1
1

<=0.25
<=0.25
2
>128

UFR139

PMI
4
4
<0.25
<0.25

<0.25
<0.25
8
>128

UFR130

ECO
4
8
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR212

KPN
8
4
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR220

KPN
8
4
<0.25
<0.25

<0.25
<0.25
128
>128

UFR221

KPN
8
8
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR222

SMA
32
16
4
0.25

0.5
<=0.25
2
64

UFR239

MMO
>32
>32
<=0.25
0.5

<=0.25
<=0.25
32
>128

UFR243

MMO
>32
>32
<=0.25
<=0.25

<=0.25
<=0.25
8
>128

UFR244

MMO
>32
32
<=0.25
1

<=0.25
<=0.25
64
>128

UFR245

MMO
>32
32
<=0.25
1

<=0.25
0.5
64
>128

UFR246

MMO
32
16
<=0.25
<=0.25

<=0.25
<=0.25
32
>128

UFR247

PMI
8
4
<0.25
<0.25

<0.25
<0.25
0.5
2

UFR128

PMI
4
4
<0.25
<0.25

<0.25
<0.25
<=0.25
>128

UFR133

PRE
16
16
>128
>128

>128
>128
>128
>128

UFR99

KOX
8
8
<0.25
<0.25

<0.25
<0.25
<=0.25
>128

UFR223

KOX
8
8
<0.25
<0.25

<0.25
<0.25
8
>128

UFR224

SMA
>32
32
<=0.25
<=0.25

0.5
0.5
0.5
>128

UFR141

SMA
32
>32
0.5
0.5

0.5
1
2
>128

UFR142

SMA
32
32
<=0.25
<=0.25

<=0.25
<=0.25
64
>128

UFR143

CKO
16
16
<0.25
<0.25

<0.25
<0.25
1
>128

UFR149

CKO
>32
>32
4
2

4
2
2
>128

UFR150

ECO
4
8
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR184

ECO
8
8
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR185

ECO
8
8
<0.25
<0.25

<0.25
<0.25
8
>128

UFR186

ECO
16
32
0.5
<=0.25

0.5
0.5
2
>128

UFR187

ECO
4
8
<0.25
<0.25

<0.25
<0.25
4
>128

UFR189

ECO
8
8
<0.25
<0.25

<0.25
<0.25
8
>128

UFR190

ECO
8
8
<0.25
<0.25

<0.25
<0.25
4
>128

UFR191

ECL
8
16
<=0.25
<=0.25

<=0.25
<=0.25
8
>128

UFR194

ECL
16
16
2
8

0.5
0.5
>128
>128

UFR195

ECL
16
16
0.5
8

1
2
>128
>128

UFR196

ECL
8
16
2
32

0.5
4
128
>128

UFR197

ECL
32
32
4
128

2
32
>128
>128

UFR198

PRE
32
32
0.5
<=0.25

<=0.25
<=0.25
32
>128

UFR236

CFR
16
32
8
1

4
8
>128
>128

UFR253

CFR
4
32
<0.25
<=0.25

0.5
0.5
16
>128

UFR254

SMA
16
32
0.5
0.5

<=0.25
0.5
2
>128

UFR238

PRE
8
4
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR96

PRE
>32
32
>128
>128

>128
>128
>128
>128

UFR97

PST
32
16
>128
64

<0.25
32
>128
>128

UFR98

PMI
8
4
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR131

PMI
4
8
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR132

SMA
>32
>32
>128
>128

>128
>128
>128
>128

UFR140

MMO
>32
>32
>128
>128

>128
>128
>128
>128

UFR145

CFR
8
4
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR147

CFR
8
16
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR148

KPN
16
16
>128
>128

<0.25
<0.25
>128
>128

UFR162

KPN
16
16
>128
>128

<0.25
<0.25
>128
>128

UFR163

KPN
16
16
>128
>128

>128
>128
>128
>128

UFR164

KPN
16
16
>128
64

>128
>128
>128
>128

UFR165

KPN
32
>32
>128
>128

>128
>128
>128
>128

UFR166

KPN
>32
>32
>128
>128

>128
>128
>128
>128

UFR167

KPN
16
16
>128
>128

>128
>128
>128
>128

UFR168

KPN
>32
>32
>128
>128

>128
>128
>128
>128

UFR169

KPN
16
16
>128
<0.25

>128
>128
>128
>128

UFR170

KPN
8
8
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR171

KPN
8
8
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR172

ECO
4
8
<0.25
<=0.25

<0.25
<0.25
>128
>128

UFR177

ECO
8
16
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR178

ECO
4
16
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR179

ECO
4
8
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR180

ECO
16
16
<0.25
<=0.25

>128
>128
>128
>128

UFR181

ECO
8
16
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR182

ECO
32
32
>128
>128

>128
>128
>128
>128

UFR183

ECL
16
32
>128
>128

>128
>128
>128
>128

UFR192

ECL
16
16
>128
>128

64
<=0.25
>128
>128

UFR193

ECO
4
4
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR255

KPN
32
32
>128
>128

>128
>128
>128
>128

140347

ECL
32
32
128
>128

128
>128
>128
>128

UFR203

ECO
8
8
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR204

ECO
8
8
<0.25
<=0.25

<0.25
<=0.25
>128
>128

UFR205

ECO
16
16
16
>128

32
>128
>128
>128

UFR206

ECL
32
>32
>128
>128

>128
>128
>128
>128

UFR214

KPN
16
32
>128
>128

>128
>128
>128
>128

UFR229O

CFR
16
8
0.5
<0.25

<0.25
<0.25
>128
>128

UFR251

CFR
16
32
8
>128

16
>128
>128
>128

UFR252

ECO
8
8
<0.25
<0.25

<0.25
<0.25
>128
>128

UFR252GO

ECL
>32
>32
>128
>128

>128
>128
>128
>128

UFR252PT

TABLE 6

MIC of AF1 alone or combined with Cefixime.

MIC (μg/mL)

FIX

+ AF1

FIX
AF1
@8 μg/mL

ECO 190317
>128
2
<0.25

ECO 190457
128
4
<0.25

ECO UFR16
>128
8
<0.25

ECO UFR20
512
16
1

ECO UFR61O
32
8
<=0.25

ECO UFR209
1024
8
<=0.25

EAE UFR199
>1024
32
0.5

PMI UFR126
1024
8
<=0.25

PMI UFR127
>128
4
<=0.25

SMA UFR143
512
32
<=0.25

PST UFR235
512
>32
<=0.25

CFR UFR250
>128
>32
<=0.25

KPN 110376
>128
>32
<=0.25

KPN 131119
>128
>32
<=0.25

KPN 190270
>128
>32
1

KPN UFR25
>128
>32
<=0.25

KPN UFR66
512
>32
2

KPN UFR68
>128
>32
<=0.25

Method 3: Rat Intraduodenal Bioavailability Determination (Table 7)

Intravenous (jugular) or intraduodenal catheterized Male Sprague-Dawley (SD) rats (250-270 g) were obtained from Janvier Labs (Le Genest-Saint-Isle, France). All rats were housed in a −temperature (20±2° C.) and −humidity (55%±10%) controlled room with 12h light/dark cycle, and were acclimatized for at least 4 days before experimentation. Water and food were available ad libitum throughout the study. All rats were handled in accordance with the institutional and national guidelines for the care and use of laboratory animals.

Rats were allocated to two groups based on the administration route: intravenous or intraduodenal administration (n=3/group).

In the intravenous administration study, drugs (10 mg/kg in phosphate buffer 10 mM, pH7.4) were administered under isoflurane anesthesia via the catheter placed in the jugular vein.

In the intraduodenal administration study, drugs (20 mg/kg in phosphate buffer 10 mM, pH5.0, 30-35% hydroxyl-propyl-beta-cyclodextrin, DMSO 0-10%) were administered under isoflurane anesthesia via the catheter placed in the duodenum. For all groups, blood samples (100 μL) were withdrawn from the tail vein at 5, 10, 20, 30, 45, 60, 120 and 240 min after drug administration using Heparin-Lithium Microvette (Sarstedt, France) and immediately placed on ice. The collected blood was centrifuged at 2000×g and 4° C. for 5 min to obtain plasma. Plasma samples were stored at −80° C. until bioanalysis.

Method 4: Plasma Samples Bioanalysis and Data Analysis

The plasma samples (20 μl) were thawed at 0° C. The samples were protein precipitated using 3-25 fold volume of acetonitrile, shaken and centrifuged for 20 min at 15 000×g, diluted with a varying volume of deionized water, and pipetted to 96-well plates to wait for the LC-MS/MS analysis. Standard samples were prepared by spiking the blank plasma into concentrations 10-5 000 ng/ml and otherwise treated as the samples. Chromatographic separation was achieved with columns (T3 or C18 Cortex of Waters) and mobile phases according to the polarity of the drugs. Mass spectrometric detection involved electrospray ionization in the negative mode followed by multiple reaction monitoring of the drugs and internal standard transitions. Actual drug concentrations were deduced from interpolation of the standard curve. The pharmacokinetic parameters were calculated using XLfit (IDBS) and Excel (Microsoft) software, using standard non-compartmental methods. The intraduodenal bioavailability was calculated by dividing the AUC obtained from the intraduodenal administration by the AUC obtained from the intravenous administration.

TABLE 7

Rat intraduodenal bioavailability of Examples 4, 6, 8, 10, 11, 13

Animal
Rat

Compound

Example
Example
Example
Example
Example
Example

administered
AF2
4
6
8
10
11
13

Route of
Intravenous
Intraduodenal

administration

Dose (mg/kg)
10
20

Compound titrated in
AF2
AF2

plasma

AUC 0-∞ (h*ng/mL)
11022
10789
4620
435
10641
12431
6056
13152

Bioavailability (%)
—
21
2
49
57
28
60

As shown in Table 7, the intraduodenal administration to rats of the prodrug Examples 4, 6, 8, 10, 11, 13 leads to the effective detection in plasma of their hydrolyzed form AF2, with intraduodenal bioavailabilities generally higher than 20% and culminating at 60% with Example 13. The best prodrug examples are therefore effectively absorbed in the gastro-intestinal tract of the rats, and then effectively hydrolyzed into the active form AF2.

NOVEL HETEROCYCLIC COMPOUNDS AND THEIR USE IN PREVENTING OR TREATING BACTERIAL INFECTIONS

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