SEQUENCE LISTING

The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is “1274_SequenceListing.” The text file created on Dec. 17, 2018, is about 1 kilobyte and submitted electronically via EFS-Web.

FIELD

The present disclosure relates to compounds that bind to and act as agonists or modulators of the Farnesoid X Receptor (FXR) and act as agonists or modulators of FXR. The disclosure further relates to the use of the compounds for the treatment and/or prophylaxis of diseases and/or conditions by said compounds.

BACKGROUND

The Farnesoid X Receptor (FXR), also often referred to as NR1H4 (nuclear receptor subfamily 1, group H, member 4) when referring to the human receptor, is a nuclear hormone receptor. FXR has been associated with multiple biological functions. FXR is primarily expressed in the liver and throughout the entire gastrointestinal tract, but is also found in the kidney, adrenal glands, and ovary. FXR is associated with controlling intracellular gene expression, and may be involved in paracrine and endocrine signaling. In the intestine and liver, FXR functions as a regulator of bile acid homeostasis and hepatic lipogenesis. FXR has also been associated with Kupffer cells and liver sinusoidal endothelial cells of the liver, wherein it is believed to have functions related to inflammation, fibrosis, and portal hypertension.

A number of FXR agonsists are known and are being investigated in connection with a number of physiological conditions, including liver diseases. FXR agonists can have benefits in steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis.

FXR agonism can lead to different effects in different regions in the body. In the distal small intestine and systemically in organs such as the liver, activation of FXR directly causes the expression and secretion of the hormone FGF19. FGF19 modulates bile acid by down regulating bile acid synthesis, which can be beneficial for example in conditions such as liver disease. FXR agonists have also been associated with detrimental effects, such as pruritis. Such detrimental effects, and the degree to which they are experienced, could depend upon the site of FXR agonism. Pruritis, for instance, has been suggested to be associated with non-intestinal FXR agonism.

A need remains for FXR agonists with desirable potency, selectivity, and reduced detrimental effects.

SUMMARY

The present disclosure provides compounds that bind to the NR1H4 receptor (FXR) and act as agonists or modulators of FXR. The disclosure further relates to the use of the compounds for the treatment and/or prophylaxis of diseases and/or conditions through binding of said nuclear receptor by said compounds.

The present disclosure provides a compound of Formula (I):


or a pharmaceutically acceptable salt thereof.

Some embodiments provide for pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable excipient.

Some embodiments provide solid forms of a compound of Formula (I) or a pharmaceutically acceptable salt thereof

Also provided herein are methods of treating a patient having an FXR mediated condition comprising administering a compound of Formula (I) to a patient in need thereof.

