Orally administered combinations of beta-lactam antibiotics and avibactam derivatives for treating bacterial infections

A method of treating a bacterial infection in a patient in need of such treatment comprising orally administering to the patent a therapeutically effective amount of:

• a β-lactam antibiotic or a pharmaceutically acceptable salt thereof;
• and
• an avibactam derivative of Formula (1):
• or a pharmaceutically acceptable salt thereof, wherein,
• each R1 is independently selected from C1-6 alkyl, or each R1 and the geminal carbon atom to which they are bonded forms a C3-6 cycloalkyl ring, a C3-6 heterocycloalkyl ring, a substituted C3-6 cycloalkyl ring, or a substituted C3-6 heterocycloalkyl ring;
• R2 is selected from a single bond, C1-6 alkanediyl, C1-6 heteroalkanediyl, C5-6 cycloalkanediyl, C5-6 heterocycloalkanediyl, C6 arenediyl, C5-6 heteroarenediyl, substituted C1-6 alkanediyl, substituted C1-6 heteroalkanediyl, substituted C5-6 cycloalkanediyl, substituted C5-6 heterocycloalkanediyl, substituted C6 arenediyl, and substituted C5-6 heteroarenediyl;
• R3 is selected from C1-6 alkyl, —O—C(O)—R4, —S—C(O)—R4, —NH—C(O)—R4, —O—C(O)—O—R4, —S—C(O)—O—R4, —NH—C(O)—O—R4, —C(O)—O—R4, —C(O)—S—R4, —C(O)—NH—R4, —O—C(O)—O—R4, —O—C(O)—S—R4, —O—C(O)—NH—R4, —S—S—R4, —S—R4, —NH—R4, —CH(—NH2)(—R4), C5-6 heterocycloalkyl, C5-6 heteroaryl, substituted C5-6 cycloalkyl, substituted C5-6 heterocycloalkyl, substituted C5-6 aryl, substituted C5-6 heteroaryl, and —CH═C(R4)2, wherein,
• R4 is selected from hydrogen, C1-8 alkyl, C1-8 heteroalkyl, C5-8 cycloalkyl, C5-8 heterocycloalkyl, C5-10 cycloalkylalkyl, C5-10 heterocycloalkylalkyl, C6-8 aryl, C5-8 heteroaryl, C7-10 arylalkyl, C5-10 heteroarylalkyl, substituted C1-8 alkyl, substituted C1-8 heteroalkyl, substituted C5-8 cycloalkyl, substituted C5-8 heterocycloalkyl, substituted C5-10 cycloalkylalkyl, substituted C5-10 heterocycloalkylalkyl, substituted C6-8 aryl, substituted C5-8 heteroaryl, substituted C7-10 arylalkyl, and substituted C5-10 heteroarylalkyl;
• R5 is selected from hydrogen, C1-6 alkyl, C5-8 cycloalkyl, C6-12 cycloalkylalkyl, C2-6 heteroalkyl, C5-8 heterocycloalkyl, C6-12 heterocycloalkylalkyl, substituted C1-6 alkyl, substituted C5-8 cycloalkyl, substituted C6-12 cycloalkylalkyl, substituted C2-6 heteroalkyl, substituted C5-8 heterocycloalkyl, and substituted C6-12 heterocycloalkylalkyl;
• and
• R6 is selected from hydrogen, C1-6 alkyl, C5-8 cycloalkyl, C6-12 cycloalkylalkyl, C2-6 heteroalkyl, C5-8 heterocycloalkyl, C6-12 heterocycloalkylalkyl, substituted C1-6 alkyl, substituted C5-8 cycloalkyl, substituted C6-12 cycloalkylalkyl, substituted C2-6 heteroalkyl, substituted C5-8 heterocycloalkyl, and substituted C6-12 heterocycloalkylalkyl.