Aspects of the present invention are directed to structurally modified opioids (SMOs) that result in improved modulating activity at the NMDAR and improved PK and PD parameters over existing drugs with NMDAR modulating activity. The structural modifications of an opioid or opioid enantiomer that result in the SMOs can be obtained by starting the synthetic process de novo; by modifying the synthetic process for the opioid at any intermediate step during the synthesis of the racemate or of one enantiomer; or by modifying the structure of the opioid or opioid enantiomer after the synthesis. The nitric acid ester substitutions are of particular relevance, especially when associated to deuterated substitutions and/or halogen substitutions.

Disclosed herein are substituted phenyl compounds of formula I as defined herein that may be utilized as inhibitors of the interaction between the subunits of hyperpolarization-activated cyclic-nucleotide gated (HCN) channels, such as HCN1, and an auxiliary subunit of HCN channels which is the tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). The disclosed compounds may be used in pharmaceutical compositions and methods for treating neurological diseases and disorders such as depression, and in particular Major Depressive Disorder (MDD).

Disclosed herein are substituted phenyl compounds of formula I as defined herein that may be utilized as inhibitors of the interaction between the subunits of hyperpolarization-activated cyclic-nucleotide gated (HCN) channels, such as HCN1, and an auxiliary subunit of HCN channels which is the tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). The disclosed compounds may be used in pharmaceutical compositions and methods for treating neurological diseases and disorders such as depression, and in particular Major Depressive Disorder (MDD).

The present invention discloses novel compounds which are useful as potassium channel openers, in particular as openers of the Kv7.4 potassium channel. The novel compounds are compounds according to formula I,

##STR00001##

wherein n=0 or 1, RL is a substituent selected from the group consisting of unsubstituted or substituted cycloalkyl groups, in particular bicycloalkyl groups, unsubstituted or substituted phenyl groups, unsubstituted or substituted thienyl groups or cyclopentathienyl groups, and unsubstituted or substituted indanyl groups, which optionally contain heteroatoms, and RR is a substituent selected from the group consisting of unsubstituted or substituted phenyl groups or unsubstituted or substituted benzyl groups, which optionally contain heteroatoms, or a stereoisomer, a tautomer, a prodrug or a salt, preferably pharmaceutically acceptable salt thereof.

The present invention discloses novel compounds which are useful as potassium channel openers, in particular as openers of the Kv7.4 potassium channel. The novel compounds are compounds according to formula I,

##STR00001##

wherein n=0 or 1, RL is a substituent selected from the group consisting of unsubstituted or substituted cycloalkyl groups, in particular bicycloalkyl groups, unsubstituted or substituted phenyl groups, unsubstituted or substituted thienyl groups or cyclopentathienyl groups, and unsubstituted or substituted indanyl groups, which optionally contain heteroatoms, and RR is a substituent selected from the group consisting of unsubstituted or substituted phenyl groups or unsubstituted or substituted benzyl groups, which optionally contain heteroatoms, or a stereoisomer, a tautomer, a prodrug or a salt, preferably pharmaceutically acceptable salt thereof.

The present invention discloses novel compounds which are useful as potassium channel openers, in particular as openers of the Kv7.4 potassium channel. The novel compounds are compounds according to formula I, ##STR00001##
wherein n=0 or 1, RL is a substituent selected from the group consisting of unsubstituted or substituted cycloalkyl groups, in particular bicycloalkyl groups, unsubstituted or substituted phenyl groups, unsubstituted or substituted thienyl groups or cyclopentathienyl groups, and unsubstituted or substituted indanyl groups, which optionally contain heteroatoms, and RR is a substituent selected from the group consisting of unsubstituted or substituted phenyl groups or unsubstituted or substituted benzyl groups, which optionally contain heteroatoms, or a stereoisomer, a tautomer, a prodrug or a salt, preferably pharmaceutically acceptable salt thereof.

The present invention discloses novel compounds which are useful as potassium channel openers, in particular as openers of the Kv7.4 potassium channel. The novel compounds are compounds according to formula I, ##STR00001##
wherein n=0 or 1, RL is a substituent selected from the group consisting of unsubstituted or substituted cycloalkyl groups, in particular bicycloalkyl groups, unsubstituted or substituted phenyl groups, unsubstituted or substituted thienyl groups or cyclopentathienyl groups, and unsubstituted or substituted indanyl groups, which optionally contain heteroatoms, and RR is a substituent selected from the group consisting of unsubstituted or substituted phenyl groups or unsubstituted or substituted benzyl groups, which optionally contain heteroatoms, or a stereoisomer, a tautomer, a prodrug or a salt, preferably pharmaceutically acceptable salt thereof.

An oxidative homocoupling method of synthesizing certain 2,2-bithiophenes from thiophenes using oxygen as the terminal oxidant is disclosed. In non-limiting examples, the method uses oxygen along with a catalytic system that includes palladium, an assistive ligand, and a non-palladium metal additive to catalyze one of the following reactions:

##STR00001##

Associated catalytic systems and compositions are also disclosed.

Compounds are provided having the structure of Formula (I):

##STR00001##

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein A, X.sup.1, X.sup.2, Q, R.sup.1, R.sup.2 and n are as defined herein. Such compounds function as thyromimetics and have utility for treating diseases such as neurodegenerative disorders and fibrotic diseases. Pharmaceutical compositions containing such compounds are also provided, as are methods of their use and preparation.

Compounds are provided having the structure of Formula (I):

##STR00001##

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein A, X.sup.1, X.sup.2, Q, R.sup.1, R.sup.2 and n are as defined herein. Such compounds function as thyromimetics and have utility for treating diseases such as neurodegenerative disorders and fibrotic diseases. Pharmaceutical compositions containing such compounds are also provided, as are methods of their use and preparation.