Fungal efflux pump inhibitors

A pharmaceutical composition comprising

• a pharmaceutically acceptable carrier or excipient;
• and,
• an efflux pump inhibitor having the chemical structure:
• wherein:
• L1 is selected from the group consisting of a single bond and Cx1;
• R1 is selected from the group consisting of:
• (C3-C7)heteroalicyclic containing 1 nitrogen atom and 0 to 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur wherein the heteroalicyclic is substituted with one or more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, —Cx2, ═O, —OCx2, —Cx2OCx3, —Cx2OH, —Cx2(halo), —Cx2OC(═O)Cx3, —Cx2NHC(═O)Cx3, —Cx2NHC(═NH)Cx3, —NHCx2, —NCx2Cx3, —Cx2NH2, —Cx2NHCx3, —Cx2NCx3Cx4 and —C═C—C═C—, wherein the end carbons of the group are covalently bonded to adjacent carbon atoms of the heteroalicyclic ring to form a carbocyclic ring, the adjacent carbon atoms of the heteroalicyclic being double-bonded to one another such that the carbocyclic ring formed is a phenyl group;
• —Cx2NHC(═NH)Cx3;
• —Cx2NCx3C(═NH)Cx3 and,
• —Cx2NHC(═O)Cx3;
• L2 is selected from the group consisting of —C(O)—, —S(O)2—, —C(O)O—, —C(O)NH—, —C(O)NCx5—, —C(S)NH—, —C(S)NCx5—, —C(NH)NH—, —C(NH)NCx5—, —S(O)2NH—;
• and —S(O)2NCx5—;
• R2 is selected from the group consisting of:
• aryl substituted with one or more groups independently selected from the group consisting of hydrogen, halo, —Cx6, —Cx6(halo), —Cx6OH, —Cx6OCx7 and —OCx8;
• and,
• Cx8;
• R3 is selected from the group consisting of aryl substituted with 1 or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, —Cx9, —OCx9, —NH2, —NHCx9, —NCx9Cx10, —CO2H, —CO2Cx9, —C(O)Cx9, —C(O)NH2, C(O)NHCx9 and C(O)NCx9Cx10;
• R4 is selected from the group consisting of Cx11;
• R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, halo, —Cx12, —OCx12 and —O(Cx12)O—;
• Cx1, Cx2, Cx3, Cx4, Cx5, Cx6, Cx7, Cx8, Cx9, Cx10, Cx11, Cx12 and Cx13 are independently (C1-C4)alkyl;
• and,
• the absolute stereochemistry of centers of asymmetry are independently R or S;
• or,
• a pharmaceutically acceptable salt thereof.

A method for inhibiting the growth or proliferation of a fungal cell that employs an efflux pump resistance mechanism, comprising contacting the fungal cell with a anti-fungal agent and a fungal efflux pump inhibitor having the chemical structure:

• wherein:
• L1 is selected from the group consisting of a single bond and Cx1;
• R1 is selected from the group consisting of:
• (C3-C7)heteroalicyclic containing 1 nitrogen atom and 0 to 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur wherein the heteroalicyclic is substituted with one or more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, —Cx2, ═O, —OCx2, —Cx2OCx3, —Cx2OH, —Cx2(halo), —Cx2OC(═O)Cx3, —Cx2NHC(═O)Cx3, —Cx2NHC(═NH)Cx3, —NHCx2;
• —NCx2Cx3, —Cx2NH2, —Cx2NHCx3, —Cx2NCx3Cx4 and —C═C—C═C—, wherein the end carbons of the group are covalently bonded to adjacent carbon atoms of the heteroalicyclic ring to form a carbocyclic ring, the adjacent carbon atoms of the heteroalicyclic being double-bonded to one another such that the carbocyclic ring formed is a phenyl group;
• —Cx2NHC(═NH)Cx3;
• —Cx2NCx3C(═NH)Cx13 and,
• —Cx2NHC(═O)Cx3;
• L2 is selected from the group consisting of —C(O)—, —S(O)2—, —C(O)O—, —C(O)NH—, —C(O)NCx5—, —C(S)NH—, —C(S)NCx5—, —C(NH)NH—, —C(NH)NCx5—, —S(O)2NH—;
• and —S(O)2NCx—;
• R2 is selected from the group consisting of:
• aryl substituted with one or more groups independently selected from the group consisting of hydrogen, halo, —Cx6, —Cx6(halo), —Cx6OH, —Cx6OCx7 and —OCx8;
• and,
• Cx8;
• R3 is selected from the group consisting of aryl substituted with 1 or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, —Cx9, —OCx9, —NH2, —NHCx9, —NCx9Cx10, —CO2H, —CO2Cx9, —C(O)Cx9, —C(O)NH2, C(O)NHCx9 and C(O)NCx9Cx10;
• R4 is selected from the group consisting of Cx11;
• R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, halo, —Cx12, —OCx12 and —O(Cx12)O—;
• Cx1, Cx2, Cx3, Cx4, Cx5, Cx6, Cx7, Cx8, Cx9, Cx10, Cx11, Cx12 Cx13 are independently (C1-C4)alkyl;
• and,
• the absolute stereochemistry of centers of asymmetry are independently R or S;
• or,
• a pharmaceutically acceptable salt thereof.

A method for treating an infection caused by a fungus that employs an efflux pump resistance mechanism, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-fungal agent and an efflux pump inhibitor having the chemical structure:

• wherein:
• L1 is selected from the group consisting of a single bond and Cx1;
• R1 is selected from the group consisting of:
• (C3-C7)heteroalicyclic containing 1 nitrogen atom and 0 to 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur wherein the heteroalicyclic is substituted with one or more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, —Cx2, ═O, —OCx2, —Cx2OCx3, —Cx2OH, —Cx2(halo), —Cx2OC(═O)Cx3, —Cx2NHC(═O)Cx3, —Cx2NHC(═NH)Cx3, —NHCx2, —NCx2Cx3, —Cx2NH2, —Cx2NHCx3, —Cx2NCx3Cx4 and —C═C—C═C—, wherein the end carbons of the group are covalently bonded to adjacent carbon atoms of the heteroalicyclic ring to form a carbocyclic ring, the adjacent carbon atoms of the heteroalicyclic being double-bonded to one another such that the carbocyclic ring formed is a phenyl group;
• —Cx2NHC(═NH)Cx3;
• —Cx2NCx3C(═NH)Cx13 and,
• —Cx2NHC(═O)Cx3;
• L2 is selected from the group consisting of —C(O)—, —S(O)2—, —C(O)O—, —C(O)NH—, —C(O)NCx5—, —C(S)NH—, —C(S)NCx5, —C(NH)NH—, —C(NH)NCx5—, —S(O)2NH—;
• and —S(O)2NCx5—;
• R2 is selected from the group consisting of:
• aryl substituted with one or more groups independently selected from the group consisting of hydrogen, halo, —Cx6, —Cx6(halo), —Cx6OH, —Cx6OCx7 and —OCx8;
• and,
• C8;
• R3 is selected from the group consisting of aryl substituted with 1 or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, —Cx9—OCx9, —NH2, —NHCx9, —NCx9Cx10, —CO2H, —CO2Cx9, —C(O)Cx9, —C(O)NH2, C(O)NHCx9 and C(O)NCx9Cx10;
• R4 is selected from the group consisting of Cx11;
• R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, halo, —Cx12, —OCx12 and —O(Cx12)O—;
• Cx1,Cx2, Cx3, Cx4, Cx5, Cx6, Cx7, Cx8, Cx9, Cx10, Cx11, Cx12 and Cx are independently (C1-C4)alkyl;
• and,
• the absolute stereochemistry of centers of asymmetry are independently R or S;
• or,
• a pharmaceutically acceptable salt thereof.