The present disclosure relates to substituted heterocyclic derivative therapeutic compounds, compositions comprising said compounds, and the use of said compounds and compositions for epigenetic regulation by inhibition of bromodomain-mediated recognition of acetyl lysine regions of proteins, such as histones. Said compositions and methods are useful for the treatment of diseases mediated by aberrant cell signalling, such as inflammatory disorders, cancer and neoplastic disease.

The present disclosure relates to substituted heterocyclic derivative therapeutic compounds, compositions comprising said compounds, and the use of said compounds and compositions for epigenetic regulation by inhibition of bromodomain-mediated recognition of acetyl lysine regions of proteins, such as histones. Said compositions and methods are useful for the treatment of diseases mediated by aberrant cell signalling, such as inflammatory disorders, cancer and neoplastic disease.

Certain embodiments are directed to oridonin analogs or derivatives. In certain aspects, the derivatives are used as anticancer or anti-inflammatory agents.

Certain embodiments are directed to oridonin analogs or derivatives. In certain aspects, the derivatives are used as anticancer or anti-inflammatory agents.

This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), having the core structure: pharmaceutical compositions containing at least one such modulator, methods of treatment of mediated diseases, such as cystic fibrosis, using such modulators and pharmaceutical compositions, combination pharmaceutical compositions and therapies comprising such modulators, and processes and intermediates for making such modulators.

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This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), having the core structure: pharmaceutical compositions containing at least one such modulator, methods of treatment of mediated diseases, such as cystic fibrosis, using such modulators and pharmaceutical compositions, combination pharmaceutical compositions and therapies comprising such modulators, and processes and intermediates for making such modulators.

##STR00001##

This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)having the core structure: pharmaceutical compositions containing at least one such modulator, methods of treating CFTR mediated diseases, including cystic fibrosis, using such modulators and pharmaceutical compositions, combination therapies, and processes and intermediates for making such modulators.

##STR00001##

This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)having the core structure: pharmaceutical compositions containing at least one such modulator, methods of treating CFTR mediated diseases, including cystic fibrosis, using such modulators and pharmaceutical compositions, combination therapies, and processes and intermediates for making such modulators.

##STR00001##

This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) having the core structure: pharmaceutical compositions containing at least one such modulator, methods of treatment of CFTR mediated diseases, including cystic fibrosis, using such modulators and pharmaceutical compositions, combination pharmaceutical compositions and combination therapies, and processes and intermediates for making such modulators.

##STR00001##

This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) having the core structure: pharmaceutical compositions containing at least one such modulator, methods of treatment of CFTR mediated diseases, including cystic fibrosis, using such modulators and pharmaceutical compositions, combination pharmaceutical compositions and combination therapies, and processes and intermediates for making such modulators.

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