Biaryl monobactam compounds and methods of use thereof for the treatment of bacterial infections

A compound of Formula I

• or a pharmaceutically acceptable salt thereof, wherein:
• W is a bond or O;
• RX and RZ are independently hydrogen, —SC1-C3alkyl, C1-C3 alkyl, —(C1-C3alkylene)nOC1-C3alkyl, or —(C1-C3alkylene)nNC1-C3alkyl, wherein the —SC1-C3alkyl, the C1-C3 alkyl, the —(C1-C3alkylene)nOC1-C3alkyl and the —(C1-C3alkylene)nNC1-C3alkyl are optionally substituted with one to seven fluorines;
• or, alternatively, RX and RZ, together with the carbon to which they are attached, form a monocyclic C4-C7 cycloalkyl or a monocyclic C4-C7 heterocycloalkyl with 1, 2, or 3 heteroatom ring atoms independently selected from N, O and S, wherein said C4-C7 cycloalkyl and said C4-C7 heterocycloalkyl are optionally substituted with one to three substituents independently selected from —F, —OH and —OC1-C3alkyl;
• X is N or CR1;
• R1 is hydrogen, C1-C3 alkyl, or halogen;
• wherein said C1-C3 alkyl is optionally substituted with one to three Ra;
• each occurrence of Ra is independently hydrogen, halogen, C1-C3alkyl, —NRcRd or —ORe;
• Z is C1-C3 alkylene, optionally substituted with one to three Rb;
• each occurrence of Rb is independently —C1-C8 alkyl, —C3-C7 cycloalkyl, —C(O)ORe, —C(O)NRcRd, tetrazolyl, oxadiazolonyl, HetA, AryA, —S(O)mRe, —S(O)mNRcRd, or —P(O)(Re)p wherein said —C1-C8 alkyl and said —C3-C7 cycloalkyl are optionally substituted with one to three Ra;
• HetA is a 4- to 6-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R4;
• AryA is a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R4;
• Y is a bond, O, NR2, S, or CH2;
• R2 is hydrogen, —C1-C3 alkyl, —C(O)Re, —C(O)NRcRd, —S(O)mRe, or —S(O)mNRcRd, wherein said —C1-C3 alkyl is optionally substituted with one to three Ra;
• A1 is AryA;
• A2 is:
• wherein * indicates attachment to Q and ** indicates attachment to M;
• each occurrence of R4 is independently:
• —C1-C8 alkyl, —C2-C8 alkenyl, —C2-C8 alkynyl, halogen, —ORe, —S(O)mRe, —S(O)mNRcRd, —C(O)Re, —OC(O)Re, —C(O)ORe, —CN, —C(O)NRcRd, —NRcRd, —(CH2)nNRcRd;
• —NRcC(O)Re, —NRcC(O)ORe, —NRcC(O)NRcRd, —NRcS(O)mRe, ═NH, —CF3, —OCF3, —OCHF2, —C3-C6 cycloalkyl, —O—C3-C6cycloalkyl, —C1-C10alkylene-C3-C6cycloalkyl, —O—C1-C10 alkylene-C3-C6cycloalkyl, HetB, —O-HetB, —C1-C10alkylene-HetB, —O—C1-C10 alkylene-HetB, AryA, —O-AryA, —C1-C10 alkylene-AryA, or —O—C1-C10alkylene-AryA, wherein each R4 is unsubstituted or substituted with one to four substituents selected from halogen, —C1-C6 alkyl and —(CH2)nNRcRd, or wherein R4 and M, together with the atoms to which they are attached, form a 4- to 7-membered cycloheteroalkyl optionally containing one to two additional heteroatoms independently selected from O, S and —NRg;
• HetB is a 3- to 6-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to three Ra;
• Q is a bond, CH2, O, S, —(CH2)nNR3—, or —NR3(CH2)n—, wherein each CH2 is unsubstituted or substituted with one to two substituents selected from halogen, —C1-C6 alkyl, ORe and —(CH2)nNRcRd;
• R3 is hydrogen or —C1-C3 alkyl, wherein said —C1-C3 alkyl is optionally substituted with one to three Ra;
• M is R5, —NHR5, —N(R5)2, —OR5, —(CH2)nR5, —C(O)R5, —CH(NH)R5, or —S(O)mR5;
• R5 is H, C2-C10 alkyl, C3-C7 cycloalkyl, C1-C6 alkyl-C3-C7 cycloalkyl, HetB, AryB, or —NH(C1-C6 alkyl), wherein said C1-C6 alkyl, said C2-C10 alkyl and said C3-C7 cycloalkyl are optionally substituted with one to four R6;
• AryB is a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, O and S, optionally substituted with one to four R4;
• each occurrence of R6 is independently selected from the group consisting of:
• halogen, —ORe, —S(O)mRe, —S(O)mNRcRd, —C(O)Re, —OC(O)Re, —C(O)ORe, —CN, —C(O)NRcRd, —C(NH)NRcRd, —NRcRd, —(CH2)nNRcRd, —N(Rc)(C(O)Re), —N(Rc)(C(O)ORe), —N(Rc)(C(O)NRcRd), —N(Rc)(S(O)mRe), and HetB;
• each occurrence of Rc and Rd is independently:
• hydrogen, —C1-C10 alkyl, —C2-C10 alkenyl, —C3-C6 cycloalkyl, —C1-C10 alkylene-C3-C6 cycloalkyl, HetA, —C1-C10alkylene-HetB, AryB, —C1-C10 alkylene-AryB, and —C1-C10 alkylene-HetB, or, alternatively, Rc and Rd together with the nitrogen atom to which they are attached, form a 4- to 7-membered cycloheteroalkyl optionally containing one to two additional heteroatoms independently selected from O, S and —NRg, and wherein each Rc and Rd is optionally substituted with one to three Rf;
• each occurrence of Re is independently:
• hydrogen, —C1-C10alkyl, —C2-C10 alkenyl, —OH, —OC1-C4 alkyl, —C3-C6 cycloalkyl, —C1-C10 alkylene-C3-C6 cycloalkyl, HetB, —C1-C10 alkylene-HetB, AryB, —C1-C10 alkylene-AryB, or —C1-C10 alkylene-HetB;
• wherein each Re is optionally substituted with one to three Rh;
• each occurrence of Rf is independently:
• halogen, —C1-C10 alkyl, —OH, —OC1-C4 alkyl, —S(O)mC1-C4 alkyl, —CN, —CF3, —OCHF2, —OCF3, or NH2, wherein said —C1-C10 alkyl is optionally substituted with one to three substituents independently selected from:
• —OH, halogen, cyano, and —S(O)2CH3;
• each occurrence of Rg is independently:
• hydrogen, —C(O)Re, and or —C1-C10 alkyl, wherein said —C1-C10alkyl is optionally substituted with one to five fluorines;
• each occurrence of Rh is independently:
• halogen, —C1-C10alkyl, —OH, —OC1-C4 alkyl, —S(O)mC1-C4 alkyl, —CN, —CF3, —OCHF2, or —OCF3;
• wherein said —C1-C10 alkyl is optionally substituted with one to three substituents independently selected from:
• —OH, halogen, cyano, or —S(O)2CH3;
• each n is independently 0, 1, 2, 3 or 4;
• each m is independently 0, 1 or 2, and
• each p is independently 1 or 2.