Gram-positive carbapenem antibacterials and processes for their preparation

A carbapenem compound of the formula [(I),] (II), (III) or

• (IV):
• or a pharmaceutically acceptable salt or prodrug thereof, wherein:
• R1 is either H or alkyl;
• CO2M is independently a carboxylic acid, a carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group;
• P is independently hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group;
• X is independently O, S, S(O)x, wherein x is 0, 1 or 2, phosphate, carbonyl, thiocarbonyl, iminyl, P(O)2, P(O)3, C(O), C(O)O, OC(O), C(O)NH, C(O)NR, NHC(O), NRC(O), amine, NH, or NR;
• each R is independently H or alkyl;
• each
• is independently a 5- or 6-membered monocyclic aromatic or heteroaromatic ring;
• Z is selected from the group consisting of a bond, C═CR2, C═CY1, O, S, carbonyl,
• thiocarbonyl, iminyl, C(O), C(O)O, OC(O), C(O)NH, C(O)NR, NHC(O), NRC(O), N(A-(CH2)n-Q)C(O), CON(A-(CH2)n-Q), C(═NH), C(═NR), C(═N-A-(CH2)n-Q), amine, NH, NR, or N(A-(CH2)n-Q);
• each Y1 and Y2 is independently selected from the group consisting of 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, —C2-6 straight- or branched-chain alkenyl, or —C2-6 straight- or branched-chain alkynyl, unsubstituted or substituted with 1 to 4 Rd groups;
• -A-(CH2)n-Q;
• —(CH2)nA-Q;
• —[(CH2)nA]m(CH2)p-Q;
• —CH2N-Q;
• and —C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups;
• A is O, S, NH, NCH3, NR, or —CH2—;
• each m, n, and p is independently 0, 1, 2 or 3;
• each Ra, Rb and Rc is independently selected from hydrogen, —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 form a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRc, or —C(O)—, said ring being unsubstituted or substituted with one to four Ri groups;
• or Rb and Re taken together with any intervening atoms form a 4-6 membered saturated ring optionally interrupted by one to three of O, S, NRa, or —C(O)—, said ring being unsubstituted or substituted with one to four Ri groups;
• each Rd is independently selected from the group consisting of 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 or —NReC(NRf)Rg;
• each Re, Rf and Rg is independently selected from hydrogen;
• —R;
• —C1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups;
• or Re and Rf taken together with any intervening atoms form a 4-6 membered saturated ring
• optionally interrupted by one to three of O, S, —C(O)— or NRg, said ring being unsubstituted or substituted with one to four Ri groups;
• each Ri is independently selected from 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 is independently selected from hydrogen, a —C1-6 straight or branched-chain alkyl
• group, a —C3-C6 cycloalkyl group or phenyl, or when two Rh groups are present, said Rh groups can form a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, —C(O)—, NH and NCH3;
• each Q is selected from the group consisting of:
• wherein:
• a and b are 1, 2 or 3;
• L− is a pharmaceutically acceptable counterion;
• α is O, S or NRs;
• β, δ, λ, μ and σ are independently selected from CRt, N or N+Rs, provided that no more than one of β, δ, λ, μ, and σ is N+Rs;
• each Rs is independently selected from hydrogen;
• phenyl or C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
• each Rt is independently selected from 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;
• each Ru and Rv is independently 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 form 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 is independently 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 Rh and 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 is independently 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 are independently 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 form 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 form a 4-6 membered ring, 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;
• wherein if the compound is of formula (III), X is O and R is CH3, then the substituent