Thiazoles and oxazoles useful as modulators of ATP-binding cassette transporters

A method of treating cystic fibrosis, hereditary emphysema, or COPD, comprising administering to a patient a compound of formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein X is O or S;
• R1 is hydrogen, or is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R1 is optionally substituted at one or more carbon or nitrogen atoms with x independent occurrences of -QRx;
• wherein x is 0-5;
• wherein Q is a bond or is a C1-C6 alkylidene chain wherein up to two methylene units of Q are independently optionally replaced by —CO—, —CO2—, —COCO—, —CONR—, —OCONR—, —NRNR—, —NRNRCO—, —NRCO—, —NRCO2—, —NRCONR—, —SO—, —SO2—, —NRSO2—, —SO2NR—, —NRSO2NR—, —O—, —S—;
• or —NR—;
• and each occurrence of Rx is independently selected from R′, halogen, NO2, or CN, or -QRx is ═O, ═S, or ═NR′;
• Z is a bond or is an optionally substituted C1-C4alkylidene chain;
• each occurrence of R is independently hydrogen or an optionally substituted C1-C6 aliphatic group;
• and each occurrence of R′ is independently hydrogen or an optionally substituted C1-C6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• R2 is halogen, —CN, —NO2, or -TqR;
• R3 is UmR′ and R4 is VpCy1,
• wherein m, and q are each independently 0 or 1, p is 1, and U and V are each independently an optionally substituted C1-4 alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —CO—, —CO2—, —COCO—, —CONR—, —OCONR—, —NRNR—, —NRNRCO—, —NRCO—, —NRCO2—, —NRCONR—, —SO—, —SO2—, —NRSO2—, —SO2NR—, —NRSO2NR—, —O—, —S—;
• or —NR—;
• T is an optionally substituted C1-4 alkylidene chain;
• Cy1 is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy1 is optionally substituted at one or more carbon or nitrogen atoms with y independent occurrences of —WRW;
• wherein y is 0-5;
• wherein W is a bond or is a C1-C6 alkylidene chain wherein up to two methylene units of W are independently optionally replaced by —CO—, —CO2—, —COCO—, —CONR—, —OCONR—, —NRNR—, —NRNRCO—, —NRCO—, —NRCO2—, —NRCONR—, —SO—, —SO2—, —NRSO2—, —SO2NR—, —NRSO2NR—, —O—, —S—;
• or —NR—;
• and each occurrence of RW is independently selected from R′, halogen, NO2, or CN, or —WRW is ═O, ═S, or ═NR′;
• or
• R3 and R4, taken together with the nitrogen atom to which they are bound form an optionally substituted 5-, 6- or 7-membered saturated, partially unsaturated or fully unsaturated ring having the structure:
• wherein r is 0, 1, or 2;
• one of X3, X4, or X5 is CH—Vp-Cy1 or N—Vp-Cy1, and the others of X3, X4, or X5 is CHR′ or NR′;
• and each occurrence of X1, when present, and X2 are each independently C(R′)2, —CO—, or —CS—.