The present disclosure is directed to compounds of formula (I):

##STR00001##

wherein X, Y, Z, R.sup.1, R.sup.2a, R.sup.2b, R.sup.3, and L are as described herein, as stereoisomers, enantiomers, or tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates, or prodrugs thereof, and pharmaceutical compositions comprising the compounds of formula (I), as described herein, which are useful as voltage-gated sodium channel modulators and are therefore are useful in treating seizure disorders such as epilepsy.

Disclosed herein, inter alia, are compounds and methods for inhibiting Caspase 6 and the treatment of diseases, pharmaceutical composition including a compound as described herein and a pharmaceutically acceptable excipient and methods of inhibiting human Caspase 6 protein activity, the method including: contacting the human Caspase 6 protein with a compound as described herein.

Compounds of formula (I) wherein: X is —O—, —S(O).sub.r—, —CH.sub.2—, or —NR—, wherein r is 0, 1, or 2; X.sup.1, X.sup.2, and X.sup.5 are each independently CR.sup.7 or N; one of X.sup.3 or X.sup.4 is C and is attached by a single bond to -L-, and the other is CR.sup.7 or N, provided that no more than three of X.sup.1, X.sup.2, X.sup.3, X or X.sup.5 are N; Ring A is monocyclic C.sub.5-6scycloalkyl or a 5- to 6-membered monocyclic heterocyclyl comprising from 1 to 5 heteroatoms independently selected from N, S, or O; wherein Ring A is further optionally substituted with from 1 to 3 R.sup.4; provided that Ring A is not morpholinyl, thiomorpholinyl or tetrahydro-2H-pyranyl; L is a bond, —O—, —NR—, —S(O).sub.n—, —CH.sub.2—, or —C(O)—, wherein n is 0, 1, or 2; 1 2 L.sup.1 is an C.sub.1-8alkylene, C.sub.3-scycloalkylene, —CH.sub.2-L.sup.2-, or a 3- to 8-membered heterocyclylene comprising 1 to 5; R.sup.1 is C.sub.6-20alkyl or a monocyclic C.sub.3-8cycloalkyl; wherein said C.sub.3-8cycloalkyl is substituted with at least one R.sup.6 and may be optionally substituted with from 1 to 5 additional R.sup.6 substituents, wherein R.sup.6 for each occurrence is independently selected; and R.sup.2 is —C(O)OR.sup.3, —C(O)N(R.sup.3)—S(O).sub.2R.sup.3, —S(O).sub.2OR.sup.3, —C(O)NHC(O)R.sup.3, —Si(O)OH, —B(OH).sub.2, —N(R.sup.3)S(O).sub.2R.sup.3, —S(O).sub.2N(R.sup.3).sub.2, —O—P(O)(OR.sup.3).sub.2, or —P(O)(OR.sup.3).sub.2, —CN, —S(O).sub.2NHC(O)R.sup.3, —C(O)NHS(O).sub.2R3, —C(O)NHOH, —C(O)NHCN, —CH(CF.sub.3)OH, —C(CF.sub.3).sub.2OH, or a selected heteroaryl or heterocyclyl; and pharmaceutically acceptable salts thereof, can modulate the activity of one or more SIP receptors and/or the activity of autotaxin (ATX). ##STR00001##

Compounds of formula (I) wherein: X is —O—, —S(O).sub.r—, —CH.sub.2—, or —NR—, wherein r is 0, 1, or 2; X.sup.1, X.sup.2, and X.sup.5 are each independently CR.sup.7 or N; one of X.sup.3 or X.sup.4 is C and is attached by a single bond to -L-, and the other is CR.sup.7 or N, provided that no more than three of X.sup.1, X.sup.2, X.sup.3, X or X.sup.5 are N; Ring A is monocyclic C.sub.5-6scycloalkyl or a 5- to 6-membered monocyclic heterocyclyl comprising from 1 to 5 heteroatoms independently selected from N, S, or O; wherein Ring A is further optionally substituted with from 1 to 3 R.sup.4; provided that Ring A is not morpholinyl, thiomorpholinyl or tetrahydro-2H-pyranyl; L is a bond, —O—, —NR—, —S(O).sub.n—, —CH.sub.2—, or —C(O)—, wherein n is 0, 1, or 2; 1 2 L.sup.1 is an C.sub.1-8alkylene, C.sub.3-scycloalkylene, —CH.sub.2-L.sup.2-, or a 3- to 8-membered heterocyclylene comprising 1 to 5; R.sup.1 is C.sub.6-20alkyl or a monocyclic C.sub.3-8cycloalkyl; wherein said C.sub.3-8cycloalkyl is substituted with at least one R.sup.6 and may be optionally substituted with from 1 to 5 additional R.sup.6 substituents, wherein R.sup.6 for each occurrence is independently selected; and R.sup.2 is —C(O)OR.sup.3, —C(O)N(R.sup.3)—S(O).sub.2R.sup.3, —S(O).sub.2OR.sup.3, —C(O)NHC(O)R.sup.3, —Si(O)OH, —B(OH).sub.2, —N(R.sup.3)S(O).sub.2R.sup.3, —S(O).sub.2N(R.sup.3).sub.2, —O—P(O)(OR.sup.3).sub.2, or —P(O)(OR.sup.3).sub.2, —CN, —S(O).sub.2NHC(O)R.sup.3, —C(O)NHS(O).sub.2R3, —C(O)NHOH, —C(O)NHCN, —CH(CF.sub.3)OH, —C(CF.sub.3).sub.2OH, or a selected heteroaryl or heterocyclyl; and pharmaceutically acceptable salts thereof, can modulate the activity of one or more SIP receptors and/or the activity of autotaxin (ATX). ##STR00001##

The invention relates to amide-derivatives of 2-hydroxy-2-methyl-4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-butanoic acid for use in a treatment for preventing or suppressing symptoms mediated by enhanced mPGES-1 expression or activity. In particular the invention relates the use of these compounds for treating diseases and conditions in which the inhibition of the enzyme mPGES-1 activity and/or expression would be beneficial such as inflammatory diseases, nociceptive pain, auto-immune diseases, breathing disorders, fever, cancer, inflammation related anorexia, Alzheimer's disease and cardiovascular disease.

The invention is directed to substituted piperidine derivatives. Specifically, the invention is directed to compounds according to Formula IIII:

##STR00001##

wherein A, B, X, Y, L.sup.1, L.sup.2, L.sup.3, R.sup.1, R.sup.2, R.sup.3, R.sup.4 R.sup.5, R.sup.6, R.sup.9, z.sup.2, z.sup.4, z.sup.5, and z.sup.6 are as defined herein, and salts thereof.

The compounds of the invention are inhibitors of the ATF4 pathway and can be useful in the treatment of cancer, pre-cancerous syndromes and diseases associated with activated unfolded protein response pathways, such as Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington’s disease, Creutzfeldt-Jakob Disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting the ATF4 pathway and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

The invention is directed to substituted piperidine derivatives. Specifically, the invention is directed to compounds according to Formula IIII:

##STR00001##

wherein A, B, X, Y, L.sup.1, L.sup.2, L.sup.3, R.sup.1, R.sup.2, R.sup.3, R.sup.4 R.sup.5, R.sup.6, R.sup.9, z.sup.2, z.sup.4, z.sup.5, and z.sup.6 are as defined herein, and salts thereof.

The compounds of the invention are inhibitors of the ATF4 pathway and can be useful in the treatment of cancer, pre-cancerous syndromes and diseases associated with activated unfolded protein response pathways, such as Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington’s disease, Creutzfeldt-Jakob Disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting the ATF4 pathway and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

This invention relates to a method to modulate exogenous gene expression in which an ecdysone receptor complex comprising: a DNA binding domain; a ligand binding domain; a transactivation domain; and a ligand is contacted with a DNA construct comprising: the exogenous gene and a response element; wherein the exogenous gene is under the control of the response element and binding of the DNA binding domain to the response element in the presence of the ligand results in activation or suppression of the gene. The ligands comprise a class of ketones.

This invention relates to a method to modulate exogenous gene expression in which an ecdysone receptor complex comprising: a DNA binding domain; a ligand binding domain; a transactivation domain; and a ligand is contacted with a DNA construct comprising: the exogenous gene and a response element; wherein the exogenous gene is under the control of the response element and binding of the DNA binding domain to the response element in the presence of the ligand results in activation or suppression of the gene. The ligands comprise a class of ketones.

The invention provides compounds and methods, for example, to carry out organocatalytic Michael additions of aldehydes to cyclically constrained nitroethylene compounds catalyzed by a proline derivative to provide cyclically constrained α-substituted-γ-nitro-aldehydes. The reaction can be rendered enantioselective when a chiral pyrrolidine catalyst is used, allowing for Michael adducts in nearly optically pure form (e.g., 96 to >99% e.e.). The Michael adducts can bear a single substituent or dual substituents adjacent to the carbonyl. The Michael adducts can be efficiently converted to cyclically constrained protected γ-amino acid residues, which are essential for systematic conformational studies of γ-peptide foldamers. New methods are also provided to prepare other γ-amino acids and peptides. These new building blocks can be used to prepare foldamers, such as α/γ-peptide foldamers, that adopt specific helical conformations in solution and in the solid state.