There are described RORγ modulators of the formula (I),

##STR00001##

and formula (II)

##STR00002##

or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.

There are described RORγ modulators of the formula (I),

##STR00001##

and formula (II)

##STR00002##

or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.

The present invention provides a compound of formula I:

##STR00001##

a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

The present invention provides a compound of formula I:

##STR00001##

a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

Embodiments of bridged tetrahydroisoquinolines and methods for their use in selectively inhibiting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 are disclosed. The disclosed compounds have a structure according to general formula I or a pharmaceutically acceptable salt thereof:

##STR00001##

wherein “” represents a single or double bond, R.sup.1 is hydrogen, halogen, lower aliphatic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.a is hydrogen, —CH.sub.2R.sup.2, R.sup.3, or —SO.sub.2R.sup.4; R.sup.2 is lower aliphatic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.4 is lower aliphatic, or substituted or unsubstituted aryl; and R.sup.5 is hydrogen, halogen, or lower aliphatic.

Embodiments of bridged tetrahydroisoquinolines and methods for their use in selectively inhibiting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 are disclosed. The disclosed compounds have a structure according to general formula I or a pharmaceutically acceptable salt thereof:

##STR00001##

wherein “” represents a single or double bond, R.sup.1 is hydrogen, halogen, lower aliphatic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.a is hydrogen, —CH.sub.2R.sup.2, R.sup.3, or —SO.sub.2R.sup.4; R.sup.2 is lower aliphatic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.4 is lower aliphatic, or substituted or unsubstituted aryl; and R.sup.5 is hydrogen, halogen, or lower aliphatic.

Metal-chelating compositions having the structure (1a) wherein: R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently selected from the following groups: (i) hydrogen atom, (ii) hydrocarbon groups (R) containing 1-12 carbon atoms; (iii) halogen atoms; (iv) —P(R.sup.5) (═O)OH groups; (v) —C(═O)OH groups; (vi) —S(═O).sub.2OH groups; and (vii) —OH groups, wherein R.sup.5 is selected from hydrocarbon groups (R) and —OH; R.sup.1 and R.sup.2 may optionally interconnect to form Ring A fused to the ring on which R.sup.1 and R.sup.2 are present; R.sup.3 and R.sup.4 may optionally interconnect to form Ring B fused to the ring on which R.sup.3 and R.sup.4 are present; wherein Ring A and Ring B are optionally and independently substituted with one or more of groups (ii)-(vii). Methods of using the above-described compositions for chelating metal ions having an atomic number of at least 56 (e.g., Ba or Ra) are also described. ##STR00001##

3.1.0 and 4.1.0 Azabicycle compounds of Formula (I), pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological disorders (including, but not limited to major depressive disorder, treatment resistant depression, anxious depression, bipolar disorder), cancers and eye conditions. ##STR00001##
wherein X, Y, R.sup.1, R.sup.2a, and R.sup.2b are defined herein.

3.1.0 and 4.1.0 Azabicycle compounds of Formula (I), pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological disorders (including, but not limited to major depressive disorder, treatment resistant depression, anxious depression, bipolar disorder), cancers and eye conditions. ##STR00001##
wherein X, Y, R.sup.1, R.sup.2a, and R.sup.2b are defined herein.

Compounds of formula (I) wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4a, R.sup.4b and R.sup.5 are described herein, or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof, are described herein, as well as other compounds. These compounds are useful in treating inflammation and/or pain. Compositions comprising a compound of the invention are also disclosed, as are methods of using the compounds to treat inflammation and/or pain.