Pyrimido-pyrrolo-oxazine-dione compound inhibitors of the cystic fibrosis transmembrane conductance regulator protein and uses therefor

摘要

Provided herein are benzopyrimido-pyrrolo-oxazine-dione (BPO) compounds and pyrimido-pyrrolo-quinoxalinedione (PPQ) compounds, and compositions comprising these compounds, that inhibit cystic fibrosis transmembrane conductance regulator (CFTR) mediated ion transport and that are useful for treating diseases and disorders associated with aberrantly increased CFTR chloride channel activity, such as polycystic kidney disease and secretory diarrheas. The compounds and compositions comprising the compounds described herein may be used for inhibiting expansion or preventing formation of cysts in persons who have polycystic kidney disease.

主权项

1. A compound having the following structure (I): as an isolated enantiomer or a racemic mixture of enantiomers, or as a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide, thereof, wherein: m is 1, 2, 3, or 4; n is 1, 2, 3, 4 or 5; p is an integer from 0 to 4; q is an integer from 1 to 4; R1 at each occurrence is the same or different and independently H, halo, haloalkyl, C1-C6 alkyl, —(CH2)p—C(O)—R4a, —S(O)2R4a, —NO2, or tetrazolyl; R1a at each occurrence is the same or different and independently H, halo, haloalkyl, C1-C6 alkyl, —(CH2)p—C(O)—R4a, —S(O)2R4a, —NO2, or tetrazolyl; R2a and R2b are each the same or different and independently H, or C1-C6 alkyl; R4a is —OR7, —NR7R8, —O(CH2)q—OC(O)R7, or an amino acid residue; R7 and R8 are each the same or different and independently H, C1-C20 alkyl, a saccharide, or an amino acid residue; and Z is aryl or heteroaryl, wherein the amino acid residue is selected from residues of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutylic acid, cirtulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, tert-butylglycine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, glycosylated threonine, glyclosylated serine, and glycosylated asparagine.