Modulators of pharmacokinetic properties of therapeutics

A method for increasing blood plasma levels of a drug which is metabolized by cytochrome P450 monooxygenase, comprising administering to a patient treated with the drug a therapeutically effective amount of a compound of formula IID,

• or a pharmaceutically acceptable salt thereof, wherein,
• L1 is selected from the group consisting of —C(R6)2—, —C(O)—, —S(O2)—, —N(R7)—C(O)—, and —O—C(O)—;
• each L3 is independently a covalent bond, alkylene, or substituted alkylene;
• each L4 is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, —O—, —CH2—O—, and —NH—;
• each A is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl,
• with the proviso that when A is H, p is 0;
• Z1 and Z2 are each independently —O— or —N(R7)—;
• Y and X are each independently selected from the group consisting of heterocyclyl and heterocyclylalkyl;
• each Ar is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• R1, R3, and R5 are each independently selected from the group consisting of H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyl;
• R2 is independently selected from the group consisting of H, alkyl, substituted alkyl, alkoxyalkyl, hydroxyalkyl, arylheteroalkyl, substituted arylheteroalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl, substituted aminoalkyl, -alkylene-C(O)—OH, -alkylene-C(O)—Oalkyl, -alkylene-C(O)amino, and -alkylene-C(O)-alkyl;
• R4 and R6 are each independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl;
• each R7 is independently selected from the group consisting of H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl;
• R8 and R9 are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and —CN;
• and
• each p is independently 0 or 1.

A method for inhibiting cytochrome P450 monooxygenase in a patient, comprising administering to a patient in need thereof an amount a compound of formula IID,

• or a pharmaceutically acceptable salt thereof, effective to inhibit cytochrome P450 monooxygenase, wherein,
• L1 is selected from the group consisting of —C(R6)2—, —C(O)—, —S(O2)—, —N(R7)—C(O)—, and —O—C(O)—;
• each L3 is independently a covalent bond, alkylene, or substituted alkylene;
• each L4 is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, —O—, —CH2—O—, and —NH—;
• each A is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl,
• with the proviso that when A is H, p is 0;
• Z1 and Z2 are each independently —O— or —N(R7)—;
• Y and X are each independently selected from the group consisting of heterocyclyl and heterocyclylalkyl;
• each Ar is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• R1, R3, and R5 are each independently selected from the group consisting of H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyl;
• R2 is independently selected from the group consisting of H, alkyl, substituted alkyl, alkoxyalkyl, hydroxyalkyl, arylheteroalkyl, substituted arylheteroalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl, substituted aminoalkyl, -alkylene-C(O)—OH, -alkylene-C(O)—Oalkyl, -alkylene-C(O)amino, and -alkylene-C(O)-alkyl;
• R4 and R6 are each independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl;
• each R7 is independently selected from the group consisting of H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl;
• R8 and R9 are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and —CN;
• and
• each p is independently 0 or 1.

A method for treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula IID,

• or a pharmaceutically acceptable salt thereof, wherein,
• L1 is selected from the group consisting of —C(R6)2—, —C(O)—, —S(O2)—, —N(R7)—C(O)—, and —O—C(O)—;
• each L3 is independently a covalent bond, alkylene, or substituted alkylene;
• each L4 is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, —O—, —CH2—O—, and —NH—;
• each A is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl,
• with the proviso that when A is H, p is 0;
• Z1 and Z2 are each independently —O— or —N(R7)—;
• Y and X are each independently selected from the group consisting of heterocyclyl and heterocyclylalkyl;
• each Ar is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• R1, R3, and R5 are each independently selected from the group consisting of H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyl;
• R2 is independently selected from the group consisting of H, alkyl, substituted alkyl, alkoxyalkyl, hydroxyalkyl, arylheteroalkyl, substituted arylheteroalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl, substituted aminoalkyl, -alkylene-C(O)—OH, -alkylene-C(O)—Oalkyl, -alkylene-C(O)amino, and -alkylene-C(O)-alkyl;
• R4 and R6 are each independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl;
• each R7 is independently selected from the group consisting of H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl;
• R8 and R9 are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and —CN;
• and
• each p is independently 0 or 1,
• in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, CCR5 inhibitors, other drugs for treating HIV, and mixtures thereof.

A method for treating an HCV infection comprising administering to a patient in need thereof a therapeutically effective amount a compound of formula IID,

• or a pharmaceutically acceptable salt thereof, wherein,
• L1 is selected from the group consisting of —C(R6)2—, —C(O)—, —S(O2)—, —N(R7)—C(O)—, and —O—C(O)—;
• each L3 is independently a covalent bond, alkylene, or substituted alkylene;
• each L4 is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, —O—, —CH2—O—, and —NH—;
• each A is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl,
• with the proviso that when A is H, p is 0;
• Z1 and Z2 are each independently —O— or —N(R7)—;
• Y and X are each independently selected from the group consisting of heterocyclyl and heterocyclylalkyl;
• each Ar is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• R1, R3, and R5 are each independently selected from the group consisting of H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyl;
• R2 is independently selected from the group consisting of H, alkyl, substituted alkyl, alkoxyalkyl, hydroxyalkyl, arylheteroalkyl, substituted arylheteroalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl, substituted aminoalkyl, -alkylene-C(O)—OH, -alkylene-C(O)—Oalkyl, -alkylene-C(O)amino, and -alkylene-C(O)-alkyl;
• R4 and R6 are each independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl;
• each R7 is independently selected from the group consisting of H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl;
• R8 and R9 are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and —CN;
• and
• each p is independently 0 or 1,
• in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of interferons, ribavirin, ribavirin analogs, NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, other drugs for treating HCV, and mixtures thereof.