Penem antibacterial compounds, compositions and methods of treatment

A compound represented by formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• the molecule contains no more than two positive charges balanced by two negatively charged counterions consisting of L− and/or CO2M, wherein CO2M is a carboxylate anion, to provide overall charge neutrality thereto;
• CO2M represents a carboxylic acid, a carboxylate anion, balanced by a positively charged R group, or a cation, or a pharmaceutically acceptable ester group;
• P represents hydrogen, hydroxyl or halo;
• each R is independently selected from:
• —R*;
• A—(CH2)n—Q;
• —Q;
• hydrogen;
• halo;
• —CN;
• —NO2;
• —NRaRb;
• —ORc;
• —SRc;
• —C(O)NRaRb;
• —C(O)ORh;
• —S(O)Rc;
• —SO2Rc;
• —SO2NRaRb;
• —NRaSO2Rb;
• —C(O)Ra;
• —OC(O)Ra;
• —OC(O)NRaRb;
• —NRaC(O)NRbRc;
• —NRaCO2Rh;
• —OCO2Rh;
• —NRaC(O)Rb;
• —C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups;
• and —C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups;
• A represents O, S or CH2;
• n=0-3;
• each Ra, Rb and Rc independently represents hydrogen, —R*, —C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups, or —C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups;
• each Rd independently represents halo;
• —CN;
• —NO2;
• —NReRf;
• —ORg;
• —SRg;
• —CONReRf;
• —COORg;
• —SORg;
• —SO2Rg;
• —SO2NReRf;
• —NReSO2Rf;
• —CORe;
• —NReCORf;
• —OCORe;
• —OCONReRf;
• —NReCONRfRg;
• —NReCO2Rh;
• —OCO2Rh;
• —C(NRe)NRfRg;
• —NReC(NH)NRfRg;
• —NReC(NRf)Rg;
• —R* or —Q;
• wherein when —ORg is OH, the OH group can be optionally protected by a hydroxyl protecting group;
• Re, Rf and Rg represent hydrogen;
• —R*;
• —C1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups;
• each Ri independently represents halo;
• —CN;
• —NO2;
• phenyl;
• —NHSO2Rh;
• —ORh, —SRh;
• —N(Rh)2;
• —N+(Rh)3;
• —C(O)N(Rh)2;
• —SO2N(Rh)2;
• heteroaryl;
• heteroarylium;
• —CO2Rh;
• —C(O)Rh;
• —OCORh;
• —NHCORh;
• guanidinyl;
• carbamimidoyl or ureido;
• each Rh independently represents hydrogen, a —C1-6 straight or branched-chain alkyl group, a —C3-C6 cycloalkyl group or phenyl, or when two Rh groups are present,
• Q is selected from the group consisting of:
• wherein:
• a and b are 1, 2 or 3;
• L− is a pharmaceutically acceptable counterion and can be present or absent as necessary to maintain the appropriate charge balance and represents a negative charge;
• α represents O, S or NRs;
• β, δ, λ, μ and σ represent CRt, N or N+Rs, provided that no more than one of β, δ, λ, μ and σ is N+Rs;
• R* is selected from the group consisting of:
• wherein:
• d represents O, S or NRk;
• e, g, x, y and z represent CRm, N or N+Rk, provided that no more than one of e, g, x, y and z in any given structure represents N+Rk;
• Rk represents hydrogen;
• —C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
• or —(CH2)nQ where n=1, 2 or 3 and Q is as previously defined;
• each Rm independently represents a member selected from the group consisting of:
• hydrogen;
• halo;
• —CN;
• —NO2;
• —NRnRo;
• —ORn;
• —SRn;
• —CONRnRo;
• —COORh;
• —SORn;
• —SO2Rn;
• —SO2NRnRo;
• —NRnSO2Ro;
• —CORn;
• —NRnCORo;
• —OCORn;
• —OCONRnRo;
• —NRnCO2Rh;
• —NRnCONRoRh;
• —OCO2Rh;
• —CNRnNRoRh;
• —NRnCNHNRoRh;
• —NRnC(NRo)Rh;
• —C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
• —C3-7 cycloalkyl, unsubstituted or substituted with one to four Ri groups;
• and —(CH2)nQ where n and Q are as defined above;
• Rn and Ro represent hydrogen, phenyl;
• —C1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups;
• each Rs independently represents hydrogen;
• phenyl or —C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
• each Rt independently represents hydrogen;
• halo;
• phenyl;
• —CN;
• —NO2;
• —NRuRv;
• —ORu;
• —SRu;
• —CONRuRv;
• —COORh;
• —SORu;
• —SO2Ru;
• —SO2NRuRv;
• —NRuSO2Rv;
• —CORu;
• —NRuCORv;
• —OCORu;
• —OCONRuRv;
• —NRuCO2Rv;
• —NRuCONRvRw;
• —OCO2Rv;
• —C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
• Ru and Rv represent hydrogen or —C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
• each Rw independently represents hydrogen;
• —C1-6straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
• C3-6 cycloalkyl optionally substituted with one to four Ri groups;
• phenyl optionally substituted with one to four Ri groups, or heteroaryl optionally substituted with 1-4 Ri groups;
• Rx represents hydrogen or a C1-8 straight- or branched-chain alkyl, optionally interrupted or terminated by one or two of O, S, SO, SO2, NRw, N+RhRw, or —C(O)—, said chain being unsubstituted or substituted with one to four of halo, CN, NO2, ORw, SRw, SORw, SO2Rw, NRhRw, N+(Rh)2Rw, —C(O)—Rw, C(O)NRhRw, SO2NRhRw, CO2Rw, OC(O)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRw, phenyl or heteraryl, said phenyl and heteroaryl being optionally substituted with from one to four Ri groups or with one to two C1-3 straight- or branched-chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four Ri groups;
• and
• Ry and Rz represent hydrogen;
• phenyl;
• —C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Ri groups, and optionally interrupted by O, S, NRw, N+RhRw or —C(O)—.