In various embodiments novel allosteric antagonists of the CRFR1 receptor are provided. It discovered that allosteric CRFR1 receptor antagonists are effective to modulate p-Tau levels in Alzheimer's disease (AD) models. In one illustrative embodiment, a compound that is a CRFR1 receptor antagonist is a compound according to the formula ##STR00001## or a pharmaceutically acceptable salt, ester, amide, solvate, or prodrug thereof.

The present invention relates to compounds and pharmaceutically acceptable salts thereof and formulations comprising the compounds or a pharmaceutically acceptable salts thereof that are useful in modulating lyn kinase activity. In particular, the compounds or a pharmaceutically acceptable salts thereof are useful for treating or preventing a disease or disorder including cardiovascular disease, dyslipidemia, dyslipoproteinemia, a disorder of glucose metabolism, metabolic syndrome (i.e., Syndrome X), a peroxisome proliferator activated receptor-associated disorder, septicemia, a thrombotic disorder, type II diabetes, obesity, pancreatitis, hypertension, renal disease, inflammation, or impotence.

The present invention relates to compounds and pharmaceutically acceptable salts thereof and formulations comprising the compounds or a pharmaceutically acceptable salts thereof that are useful in modulating lyn kinase activity. In particular, the compounds or a pharmaceutically acceptable salts thereof are useful for treating or preventing a disease or disorder including cardiovascular disease, dyslipidemia, dyslipoproteinemia, a disorder of glucose metabolism, metabolic syndrome (i.e., Syndrome X), a peroxisome proliferator activated receptor-associated disorder, septicemia, a thrombotic disorder, type II diabetes, obesity, pancreatitis, hypertension, renal disease, inflammation, or impotence.

The compounds of Formula Ib, Formula Ia, and Formula I are described herein along with their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof. The process of preparation of the compounds of Formula Ib, Formula Ia, and Formula I is also described. The compounds described herein, their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof are 2-(benzyloxy)pyrimidine derivatives that are inhibitors of PD-1/PD-L1 activation.

##STR00001##

The compounds of Formula Ib, Formula Ia, and Formula I are described herein along with their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof. The process of preparation of the compounds of Formula Ib, Formula Ia, and Formula I is also described. The compounds described herein, their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof are 2-(benzyloxy)pyrimidine derivatives that are inhibitors of PD-1/PD-L1 activation.

##STR00001##

Cystic fibrosis is developed through mutation of Cystic Fibrosis Transmembrane conductance Regulator (CFTR), which is one type of chloride channel. An object of the present invention is to provide compounds effective in the treatment of cystic fibrosis that open a chloride channel different from CFTR, which is the cause of the disease, and do not depend on CFTR. Compounds of the present invention are compounds or pharmaceutically acceptable salts thereof that open calcium dependent chloride channels (CaCCs) via G-protein coupled receptor 39 (GPR39) agonism to have strong chloride ion-secretory action, and are represented by the following general formula (I): General formula (I): ##STR00001##
wherein, X represents a carboxyl group or a tetrazolyl group; Q represents a C.sub.1-C.sub.3 alkylene group, an oxygen atom, a sulfur atom, etc.; G represents a phenyl group where the phenyl group may have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group, etc.; R.sup.1 represents a C.sub.1-C.sub.6 alkyl group, etc.; R.sup.2 represents a C.sub.1-C.sub.6 alkyl group that may have 1 to 3 substituents independently selected from the following group A, or a group selected from the following group B: Group A: a phenyl group and a pyridyl group, wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D; Group B: —OH, —O-M, —SH, —S-M, —NH.sub.2, —NH-M, and —N-M.sub.2, wherein M is a C.sub.1-C.sub.6 alkyl group that may have 1 or 2 substituents independently selected from the following group C, or a C.sub.3-C.sub.6 cycloalkyl group that may have 1 or 2 substituents independently selected from the following group C; Group C: a halogen atom, a cyano group, a phenyl group, a pyridyl group, etc., wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D; and Group D: a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group, etc.

Cystic fibrosis is developed through mutation of Cystic Fibrosis Transmembrane conductance Regulator (CFTR), which is one type of chloride channel. An object of the present invention is to provide compounds effective in the treatment of cystic fibrosis that open a chloride channel different from CFTR, which is the cause of the disease, and do not depend on CFTR. Compounds of the present invention are compounds or pharmaceutically acceptable salts thereof that open calcium dependent chloride channels (CaCCs) via G-protein coupled receptor 39 (GPR39) agonism to have strong chloride ion-secretory action, and are represented by the following general formula (I): General formula (I): ##STR00001##
wherein, X represents a carboxyl group or a tetrazolyl group; Q represents a C.sub.1-C.sub.3 alkylene group, an oxygen atom, a sulfur atom, etc.; G represents a phenyl group where the phenyl group may have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group, etc.; R.sup.1 represents a C.sub.1-C.sub.6 alkyl group, etc.; R.sup.2 represents a C.sub.1-C.sub.6 alkyl group that may have 1 to 3 substituents independently selected from the following group A, or a group selected from the following group B: Group A: a phenyl group and a pyridyl group, wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D; Group B: —OH, —O-M, —SH, —S-M, —NH.sub.2, —NH-M, and —N-M.sub.2, wherein M is a C.sub.1-C.sub.6 alkyl group that may have 1 or 2 substituents independently selected from the following group C, or a C.sub.3-C.sub.6 cycloalkyl group that may have 1 or 2 substituents independently selected from the following group C; Group C: a halogen atom, a cyano group, a phenyl group, a pyridyl group, etc., wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D; and Group D: a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group, etc.

The invention provides certain nicotine salts, co-crystals, and salt co-crystals and provides novel polymorphic forms of certain nicotine salts. In particular, nicotine salts with orotic acid are described. The invention further provides methods of preparation and characterization of such nicotine salts. In addition, tobacco products, including smoking articles, smokeless tobacco products, and electronic smoking articles comprising nicotine salts, co-crystals, and/or salt co-crystals are also provided.

The invention provides certain nicotine salts, co-crystals, and salt co-crystals and provides novel polymorphic forms of certain nicotine salts. In particular, nicotine salts with orotic acid are described. The invention further provides methods of preparation and characterization of such nicotine salts. In addition, tobacco products, including smoking articles, smokeless tobacco products, and electronic smoking articles comprising nicotine salts, co-crystals, and/or salt co-crystals are also provided.

Methods of treating non-alcoholic steatohepatisis (NASH), non-alcoholic fatty liver disease (NAFLD), fatty acid liver disease (FALD), alcoholic liver disease, and/or liver fibrosis in a mammal by administering a lyn kinase activator are provided herein.