Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment

A compound represented by formula I:

• 72
• or a pharmaceutically acceptable salt thereof, wherein:
• R1 represents H or methyl;
• CO2M represents a carboxylic acid, a carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group;
• P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group;
• X represents absent, CH2, CHRa, CHRb, C═CHRa, C═CHRb, O, S, SO, SO2, CO, COO, OCO, NRa, NRb, with the proviso that only one Ra and/or one Rb may be present at any one time, the remaining ring positions being substituted with hydrogen;
• Z represents trans-ethenediyl or ethynediyl;
• each R is independently selected from:
• —R*;
• —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;
• 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;
• or Ra and Rb taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRc, with Rc as defined above, or —C(O)—, said ring being unsubstituted or substituted with one to four Ri groups;
• or Rb and Rc taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, NRa, with Ra as defined above, or —C(O)—, said ring being unsubstituted or substituted with one to four Ri 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;
• Re, Rf and Rg represent hydrogen;
• —R*;
• —Cl6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups;
• or Re and Rf taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, —C(O)— or NRg with Rg as defined above, said ring being 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 Rhindependently represents hydrogen, a —C1-6 straight or branched-chain alkyl group, a —C3-C6 cycloalkyl group or phenyl, or when two Rhgroups are present, said Rh groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, —C(O)—, NH and NCH3;
• Q is selected from the group consisting of:
• 73
• wherein:
• a and b are 1, 2 or 3;
• L− is a pharmaceutically acceptable counterion;
• 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:
• 74
• 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;
• or Ru and Rv together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRw or —C(O)—, said ring being unsubstituted or substituted with one to four Ri groups;
• each Rw independently represents hydrogen;
• —C1-6 straight- 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;
• or Rhand Rw taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, NH or NCH3;
• Rx represents hydrogen or a C1-8 straight- or branched-chain alkyl, optionally interrupted 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, or a phenyl or heteroaryl group which is in turn 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;
• 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)—;
• or Rx and Ry together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO2, NRw, N+RhRw or —C(O)—, unsubstituted or substituted with 1-4 Ri groups,
• and when Rx and Ry together represent a 4-6 membered ring as defined above, Rz is as defined above or Rz represents an additional saturated 4-6 membered ring fused to the ring represented by Rx and Ry taken together, optionally interrupted by O, S, NRw or —C(O)—, said rings being unsubstituted or substituted with one to four Ri groups.