The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders. The methods generally comprise administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that is designed to be substantially active in the gastrointestinal (GI) tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein. More particularly, the method comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that inhibits NHE-3, -2 and/or -8 mediated antiport of sodium and/or hydrogen ions in the GI tract and is designed to be substantially impermeable to the layer of epithelial cells, or more specifically the epithelium of the GI tract. As a result of the compound being substantially impermeable, it is not absorbed and is thus essentially systemically non-bioavailable, so as to limit the exposure of other internal organs (e.g., liver, heart, brain, etc.) thereto. The present disclosure is still further directed to a method wherein a mammal is administered such a compound with a fluid-absorbing polymer, such that the combination acts as described above and further provides the ability to sequester fluid and/or salt present in the GI tract.

The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders. The methods generally comprise administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that is designed to be substantially active in the gastrointestinal (GI) tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein. More particularly, the method comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that inhibits NHE-3, -2 and/or -8 mediated antiport of sodium and/or hydrogen ions in the GI tract and is designed to be substantially impermeable to the layer of epithelial cells, or more specifically the epithelium of the GI tract. As a result of the compound being substantially impermeable, it is not absorbed and is thus essentially systemically non-bioavailable, so as to limit the exposure of other internal organs (e.g., liver, heart, brain, etc.) thereto. The present disclosure is still further directed to a method wherein a mammal is administered such a compound with a fluid-absorbing polymer, such that the combination acts as described above and further provides the ability to sequester fluid and/or salt present in the GI tract.

It is related to compounds used as autophagy modulators and a method for preparing and using the same, specifically providing a compound of general formula (I), or pharmaceutically acceptable salts thereof, which is a type of autophagy modulators, particularly mammalian ATG8 homologues modulators. ##STR00001##

Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases, disorders and conditions.

Disclosed are compounds of Formula 1, and pharmaceutically acceptable salts thereof, wherein L, n, R.sup.1, R.sup.2, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, X.sup.3, X.sup.4 and X.sup.5 are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them, and to their use for treating diseases, disorders, and conditions associated with SSTR4.

##STR00001##

Disclosed are compounds of Formula 1, and pharmaceutically acceptable salts thereof, wherein L, n, R.sup.1, R.sup.2, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, X.sup.3, X.sup.4 and X.sup.5 are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them, and to their use for treating diseases, disorders, and conditions associated with SSTR4.

##STR00001##

In an embodiment, the present invention provides a compound of the formula:

##STR00001##

wherein R1 is selected from the group consisting of F and H; R2 is selected from the group consisting of CH.sub.3, CH.sub.3CHCH.sub.3 and —NHCH.sub.2CH(CH.sub.3).sub.2; R3 is selected from the group consisting of H and —CH.sub.2OCH.sub.3; R4 is selected from the group consisting of H and CH.sub.3; R5 is selected from the group consisting of H and CH.sub.3; R6 is selected from the group consisting of H and OH; R7 is selected from the group consisting of

##STR00002##

or a pharmaceutically acceptable salt thereof, and methods of using this compound for positive allosteric modulation of a receptor selected from the group consisting of GLP1, GIP, and glucagon.

In an embodiment, the present invention provides a compound of the formula:

##STR00001##

wherein R1 is selected from the group consisting of F and H; R2 is selected from the group consisting of CH.sub.3, CH.sub.3CHCH.sub.3 and —NHCH.sub.2CH(CH.sub.3).sub.2; R3 is selected from the group consisting of H and —CH.sub.2OCH.sub.3; R4 is selected from the group consisting of H and CH.sub.3; R5 is selected from the group consisting of H and CH.sub.3; R6 is selected from the group consisting of H and OH; R7 is selected from the group consisting of

##STR00002##

or a pharmaceutically acceptable salt thereof, and methods of using this compound for positive allosteric modulation of a receptor selected from the group consisting of GLP1, GIP, and glucagon.

The invention provides certain (phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one related compounds of formula I as D1 positive allosteric modulators (PAMs), and pharmaceutical compositions thereof. The invention further provides methods of using a compound of formula I, to treat certain symptoms of dopaminergic CNS disorders including Parkinson's disease, Schizophrenia, ADHD or Alzheimer's disease.

##STR00001##

The invention provides certain (phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one related compounds of formula I as D1 positive allosteric modulators (PAMs), and pharmaceutical compositions thereof. The invention further provides methods of using a compound of formula I, to treat certain symptoms of dopaminergic CNS disorders including Parkinson's disease, Schizophrenia, ADHD or Alzheimer's disease.

##STR00001##