Amido heteroaromatic compounds useful in the treatment of liver diseases

Abstract

The specification relates to compounds of Formula (I): and to pharmaceutically acceptable salts thereof, to processes and intermediates used for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of diseases such as liver disease.

Description

AMIDO HETEROAROMATIC COMPOUNDSCROSS‑REFERENCE TO RELATED PATENT APPLICATIONSThis specification claims the benefit of priority to U.S. Provisional Patent Applications No. 63 / 364,976 (filed 19 May 2022), 63 / 367,843 (filed 7 July 2022) and 63 / 383,982 (filed 16 November 2022).  The entire text of the above-referenced patent applications is incorporated by reference into this specification.This specification relates to certain amido heteroaromatic compounds and pharmaceutically acceptable salts thereof that inhibit 17β hydroxy steroid dehydrogenase 13 (17βHSD13 or HSD17B13), and their use in treating diseases such as liver disease. This specification also relates to processes and intermediate compounds involved in the preparation of the amido heteroaromatic compounds and to pharmaceutical compositions containing them.IntroductionNon-alcoholic fatty liver disease (NAFLD) represents a spectrum of liver disease ranging from simple steatosis (non-alcoholic fatty liver), to non-alcoholic steatohepatitis (NASH) with or without fibrosis, to cirrhosis. Hepatic steatosis is defined as excess fat accumulation in the liver with greater than 5% induced by causes other than alcohol intake. NASH is defined by hepatic steatosis with inflammation and hepatocyte injury, with or without fibrosis. It is estimated that approximately 25% of the global population has NAFLD, and mortality due to NAFLD-related disease is expected to increase significantly through 2030.To date, there are no approved treatments for NAFLD (such as NASH) and therapeutic interventions focus on addressing co-morbidities that contribute to the pathogenesis of NAFLD, including treating insulin resistance, obesity, type II diabetes mellitus, and dyslipidemia.Recently, a variant in the 17βHSD13 gene, was associated in an allele dose-dependent manner with decreased serum aminotransferases levels, as well as a lower risk of liver disease, including alcoholic and non-alcoholic liver disease, cirrhosis and hepatocellular carcinoma (HCC) (Abul-Husn et al, N Engl J Med. 2018, 378(12), 1096-106, Wang et al, Eur Rev Med Pharmacol Sci, 2020, 24(17), 8997-9007). The 17βHSD13 splice variant (rs72613567:TA) results in a truncated, unstable and enzymatically inactive protein and has thus been characterized as an 17βHSD13 Loss of Function (LoF) variant (Ma et al, Hepatology 2019, 69(4), 1504-19). The association between the LoF 17βHSD13 (rs72613567:TA) and decreased disease severity has been replicated in additional cohorts with histologically proven NAFLD and was also associated with lower plasma transaminases, reduced risk of cirrhosis, HCC and liver related mortality in a study of 111612 individuals from the Danish general population (Gellert-Kristensen et al, Hepatology, 2020, 71(1), 56-66). Interestingly, the protective effect of the LoF 17βHSD13 (rs72613567:TA) variant on plasma transaminases levels appears to be amplified by several key risk factors of liver disease such as obesity, alcohol consumption, as well as established genetic risk factors such as, but not limited to, the (rs738409 C>G) variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3). Further, two additional 17βHSD13LoF variants (rs62305723) and (rs143404524) were also reported to confer protection from chronic liver disease progression (Kozlitina et al, N Engl J Med, 2018, 379(19), 1876-7). In general, the LoF 17βHSD13 protective variants has a stronger association with fibrosis and progression to advance liver disease but is not associated with steatosis.Based on the genetic validation of 17βHSD13LoF variants conferring protection against liver disease risk and progression, inhibition of 17βHSD13 activity with small molecules inhibitors could be an effective therapeutic approach for treating liver diseases such as NAFLD (for example NASH, liver fibrosis, cirrhosis and isolated steatosis), liver inflammation, alcoholic steatohepatitis (ASH), hepatitis C virus (HCV) and hepatocellular carcinoma (HCC), such as in individuals harbouring several key risk factors of liver disease such as obesity, alcohol consumption, as well as established genetic risk factors such as the (rs738409 C>G) variant in PNPLA3.The compounds of the disclosure provide an anti-liver disease effect by, as a minimum, acting as 17βHSD13 inhibitors. Further, compounds of the disclosure may selectively inhibit 17βHSD13 over 17βHSD4 and / or 17βHSD9.Fifteen 17βHSD (HSD17B) members have been identified in human. The sequence homology among the different members is rather low, but the overall structure seems conserved. 17β-Hydroxysteroid dehydrogenases are mainly involved in sex hormone metabolism. Some 17βHSD enzymes also play key roles in cholesterol and fatty acid metabolism (Labrie et al. Journal of Molecular Endocrinology, 2000, 25, 1–16, Wen Su et al. Molecular and Cellular Endocrinology, 2019, 489, 119–125). A clean off-target profile is an advantage for a 17βHSD13 inhibitor to avoid potential toxicity caused by off-target activity. This includes selectivity to other 17βHSD members. 17βHSD4 / D-bifunctional protein (DBP) is involved in fatty acid β-oxidation and steroid metabolism. 17βHSD4 is ubiquitously expressed and play an important role in the inactivation of estrogens in a large series of peripheral tissues. Mutations in17βHSD4 are known to cause DBP deficiency, an autosomal-recessive disorder of peroxisomal fatty acid β-oxidation that is generally fatal within the first two years of life. A homozygous missense variant in 17βHSD4 has been identified in Perrault syndrome, a recessive disorder characterized by ovarian dysgenesis in females, sensorineural deafness in both males and females, and in some patients, neurological manifestations (Pierce et al. Am. J. Hum. Genet., 2010, 87, 282-8; and Chen et al. BMC Med Genet., 2017, 18, 91).17βHSD9 / RDH5 (retinol dehydrogenase 5) is involved in retinoid metabolism. The enzyme is mainly expressed in the retinal pigment epithelium. The RDH5 gene encodes the enzyme that is a part of the visual cycle, the 11-cis retinol dehydrogenase, catalysing the reduction of 11-cis-retinol to 11-cis-retinal. RDH5 gene mutations cause a progressive cone dystrophy or macular dystrophy as well as night blindness. Fundus albipunctatus is a rare, congenital form of night blindness with rod system impairment, characterised by the presence of numerous small, white-yellow retinal lesions. This disorder is caused mostly by mutations in the RDH5 gene (Hotta et al. Am. J. Ophthalmol., 2003, 135, 917-9; and Skorczyk-Werner et al. J. Appl. Genet., 2015, 56, 317-27).The compounds of the specification may also exhibit advantageous physical properties (for example, lower lipophilicity, higher aqueous solubility, higher permeability, lower plasma protein binding, and / or greater chemical stability), and / or favourable toxicity profiles (for example a decreased activity at hERG), and / or favourable metabolic or pharmacokinetic profiles, in comparison with other known 17βHSD13 inhibitors. Such compounds may therefore be especially suitable as therapeutic agents, such as for the treatment of liver disease.General DescriptionAccording to one aspect of the specification there is provided a compound of Formula (I);wherein,A is selected from each RA is independently selected from H, halo, RX, -ORx, and -CN, wherein each RX is independently C1-3 alkyl optionally substituted with one to three F;RB is halo, -CHF2, -CF3,-OCHF2 or -OCF3;one of X1,X2 and X3 is selected from NH, O and S and the other two of X1, X2 and X3 are independently selected from N and CRY, wherein each RY is independently H, -CN, -C(=O)N(R7)2 or RXA, whereinRXA is independently C1-3 alkyl optionally substituted with one to three F;R1 and R2 are such that;(i) R1 and R2, taken together with the N atom to which they are attached, form a ring system, wherein the ring system is optionally substituted with one or more RC,wherein each RC is independently selected from F, R3 , R4, -O(R4), -O(R5), R5, R6, -OH, -CN, oxo and -C(=O)N(R7A)2;(ii) R1 is selected from R8 and R4A, and R2 is selected from R8A and H; or(iii) R1 is R5A and R2 is R8B; each R3 is independently C1-4 alkyl or C3-6 cycloalkyl, each of which are optionally substituted with one or more groups independently selected from R4X, R5x, -O(R4X), -O(R5X) and F;each R3X is independently C1-4 alkyl or C3-6 cycloalkyl, each of which are optionally substituted with one or more F;each R4 and R4B are independently monocyclic or bicyclic 5 to 9 membered heteroaryl, each of which are optionally substituted with one or more groups independently selected from R4X, -O(R4X), R5X, -O(R5X), -OH, -CN, C1-4 alkoxy, -C(=O)OH, -C(=O)O(C1-4 alkyl), -C(=O)N(R7B)2,R3 and halo;R4A is a 5 membered monocyclic heteroaryl, optionally substituted with one or more groups independently selected from R4X, -O(R4X), R5X, -O(R5X), -OH, -CN, C1-4 alkoxy, -C(=O)OH, -C(=O)O(C1-4 alkyl), -C(=O)N(R7B)2,R3 and halo;each R5, R5A and R5B are independently phenyl, each of which are optionally substituted with one or more groups independently selected from R4X, -O(R4X), R5X, -O(R5X), -OH, -CN, C1-4 alkoxy, -C(=O)OH, -C(=O)O(C1-4 alkyl), -C(=O)N(R7B)2,R3 and halo;each R4X is independently monocyclic or bicyclic 5 to 9 membered heteroaryl, each of which are optionally substituted with one or more groups independently selected from -OH, -CN, C1-4 alkoxy, -C(=O)OH, -C(=O)N(R7B)2,R3X and halo;each R5X is independently phenyl, each of which are optionally substituted with one or more groups independently selected from -OH, -CN, C1-4 alkoxy, -C(=O)OH, -C(=O)N(R7B)2,R3x and halo;R6 is C1-4 alkoxy optionally substituted with one or more groups independently selected from R4X, R5x and F; each R7, R7A, R7B and R7C are independently H, C1-4 alkyl or C3-6 cycloalkyl; R8, R8A,R8B are independently C1-4 alkyl or C3-6 cycloalkyl, each of which are optionally substituted with one or more groups independently selected from R4B, R5B, F, -OH, -CN, C1-4 alkoxy, -C(=O)O(C1-4 alkyl) and -C(=O)N(R7C)2;wherein the ring system is a saturated or partly saturated, monocyclic, bicyclic or tricyclic, 4-13 membered ring comprising one N atom, and optionally one or two further heteroatoms independently selected from N, O and S; and wherein each heteroaryl is independently an aromatic ring containing one or more heteroatoms independently selected from N, O and S,or a pharmaceutically acceptable salt thereof.In a further aspect there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.In a further aspect there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in therapy.In a further aspect there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of liver disease. In a further aspect there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament. In a further aspect there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of liver disease. In a further aspect there is provided a method of treating liver disease in a patient comprising administering to the patient an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.In a further aspect there is provided intermediates useful for the synthesis of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. DefinitionsSo that the present specification may be more readily understood, certain terms are explicitly defined below. In addition, definitions are set forth as appropriate throughout the detailed description.As used herein the term “alkyl” refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. In this specification the prefix Cx-y, as used in terms such as “Cx-y alkyl” and the like where x and y are integers, indicates the numerical range of carbon atoms that are present in the group. Examples of suitable C1-3 alkyl groups include methyl, ethyl, n-propyl, and i-propyl. Examples of suitable C1-4 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. In this specification the prefix X-Y membered, as used in terms such as “X-Y membered ring” and the like where X and Y are integers, indicates the numerical range of atoms (i.e. carbon atoms and heteroatoms) that are present in the group. As used herein the term “alkoxy” refers to a saturated group comprising the specified number of carbon atoms and one oxygen atom. For the avoidance of doubt, the alkoxy group may be a straight chain or a branched chain. Examples of suitable C1-3 alkoxy groups include methoxy (OMe), ethoxy (OEt), n-propoxy (OnPr) and i-propoxy (OiPr). Examples of suitable C1-4 alkoxy groups include methoxy (OMe), ethoxy (OEt), n-propoxy (OnPr), i-propoxy (OiPr), n-butoxy (OnBu), i-butoxy (OiBu), s-butoxy (OsBu) and t-butoxy (OtBu).As used herein the term “cycloalkane” refers to a saturated carbocyclic ring. Examples of C3-6 cycloalkane groups are cyclopropane, cyclobutane, cyclopentane and cyclohexane. As used herein the term “cycloalkylidyne” refers to a 1,1-diradical of a cycloalkane. Examples of C3-6 cycloalkylidyne are cyclopropylidene (i.e. ), cyclobutylidene (i.e. ), cyclopentylidene (i.e. ) and cyclohexylidene (i.e. ).Unless otherwise stated, “halo” is selected from Cl, F, Br and I. In embodiments, halo is selected from Cl and F. The term “heteroatom” refers to N, O or S. Unless otherwise stated, the term “heteroaryl” is an aromatic, monocyclic or bicyclic, 5 to 9 membered ring containing one or more heteroatoms independently selected from N, O and S. Where a compound of the disclosure comprises more than one heteroaryl groups, the heteroaryl groups may be the same or different. A heteroaryl may be a 5 or 6 membered monocyclic heteroaryl. Examples of suitable 5 membered heteroaryl groups include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, furazanyl, 1,3,4-thiadiazolyl and tetrazolyl. Examples of suitable 6 membered heteroaryl groups include pyridyl (such as 2-pyridyl, 3-pyridyl or 4-pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,4-triazinyl. A heteroaryl may be a 9-membered bicyclic heteroaryl. Where a heteroaryl is bicyclic, one or both rings may be aromatic. Examples of a suitable 9 membered heteroaryl groups include indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, indolinyl, isoindolinyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, [1,2,4]triazolo[4,3-b]pyridazinyl (such as 6-[1,2,4]triazolo[4,3-b]pyridazinyl) and benzo[d]oxazolyl (such as 2-benzo[d]oxazolyl). Unless otherwise stated, the term “heterocycloalkyl” refers to a saturated monocyclic, bicyclic or tricyclic ring comprising one N atom, and one further heteroatom selected from N, O and S. For the avoidance of doubt, the other atoms of the ring are carbon. Examples of suitable heterocycloalkyl groups include 4-8 membered monocyclic heterocycloalkyl, 8-11 membered spirocyclic bicyclic heterocycloalkyl, 7-10 membered fused bicyclic heterocycloalkyl and 8-10 membered bridged bicyclic heterocycloalkyl.The term “4-8 memberedmonocyclic heterocycloalkyl” refers to a saturated, 4-8 membered monocyclic ring comprising one nitrogen atom and optionally one further heteroatom selected from nitrogen, oxygen and sulfur, For the avoidance of doubt, the other atoms of the ring are carbon. A suitable 4 membered heterocycloalkyl group is azetidin-1-yl. A suitable 5 membered heterocycloalkyl group is pyrrolidin-1-yl. Examples of suitable 6 membered heterocycloalkyl groups include piperidin-1-yl, piperazin-1-yl, morpholin-4-yl and thiomorpholin-4-yl. Examples of suitable 7 membered heterocycloalkyl groups include azepan-1-yl, 1,4-diazepan-1-yl, 1,4-oxazepan-4-yl and 1,4-thiazepan-4-yl. Examples of suitable 8 membered heterocycloalkyl groups include azocan-1-yl, 1,4-diazocan-1-yl, 1,5-diazocan-1-yl ,1,4-oxazocan-4-yl, 1,5-oxazocan-5-yl, 1,4-thiazocanyl and 1,5-thiazocanyl.The term “8-11 membered spirocyclicbicyclicheterocycloalkyl” refers to a saturated, 8-11 memberedbicyclic, spirocyclic ring comprising one nitrogen atom and optionally one further heteroatom selected from N, O and S. For the avoidance of doubt, the other atoms of the ring are carbon. Examples of suitable 8 membered spirocyclic heterocycloalkyl groups include 5-azaspiro[2.5]octan-5-yl, 4,7-diazaspiro[2.5]octan-7-yl, 4-oxa-7-azaspiro[2.5]octan-7-yl and 4-thia-7-azaspiro[2.5]octan-7-yl. Examples of suitable 9 membered spirocyclic heterocycloalkyl groups include 6-azaspiro[3.5]nonan-6-yl, 5,8-diazaspiro[3.5]nonan-8-yl, 5-oxa-8-azaspiro[3.5]nonan-8-yl and 5-thia-8-azaspiro[3.5]nonan-8-yl. Examples of suitable 10 membered spirocyclic heterocycloalkyl groups include 7-azaspiro[4.5]decan-7-yl, 6,9-diazaspiro[4.5]decan-9-yl, 6-oxa-9-azaspiro[4.5]decan-9-yl and 6-thia-9-azaspiro[4.5]decan-9-yl. Examples of suitable 11 membered spirocyclic heterocycloalkyl groups include 2-azaspiro[5.5]undecane-2-yl, 1,4-diazaspiro[5.5]undecan-4-yl, 1-oxa-4-azaspiro[5.5]undecan-4-yl and 1-thia-4-azaspiro[5.5]undecan4-yl.The term “7-10 membered fused bicyclicheterocycloalkyl” refers to a saturated, 7-10 membered bicyclic, fused ring comprising one nitrogen atom and optionally one further heteroatom selected from N, O and S. For the avoidance of doubt, the other atoms of the ring are carbon. Examples of suitable 7 membered fused bicyclic heterocycloalkyl groups include 2-azabicyclo[4.1.0]heptan-2-yl, 2,5-diazabicyclo[4.1.0]heptan-2-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl and 2-thia-5-azabicyclo[4.1.0]heptan-5-yl. Examples of suitable 8 membered fused bicyclic heterocycloalkyl groups include 2-azabicyclo[4.2.0]octan-2-yl, 2,5-diazabicyclo[4.2.0]octan-2-yl, 2-oxa-5-azabicyclo[4.2.0]octan-5-yl and 2-thia-5-azabicyclo[4.2.0]octan-5-yl. Examples of suitable 9 membered fused bicyclic heterocycloalkyl groups include octahydro-1H-cyclopenta[b]pyridin-1-yl, octahydro-1H-cyclopenta[b]pyrazin-1-yl, octahydrocyclopenta[b][1,4]oxazin-4-yl and octahydrocyclopenta[b][1,4]thiazin-4-yl. Examples of suitable 10 membered fused bicyclic heterocycloalkyl groups include decahydroquinolin-1-yl, decahydroquinoxalin-1-yl, octahydro-2H-benzo[b][1,4]oxazin-4-yl and octahydro-2H-benzo[b][1,4]thiazin-4-yl.The term “8-10 membered bridged bicyclicheterocycloalkyl” refers to a saturated, 8-10 membered bicyclic, bridged ring comprising one nitrogen atom and optionally one further heteroatom selected from nitrogen, oxygen and sulfur, wherein the remaining atoms of the 8-10 membered fused bicyclic heterocycloalkyl group are carbon. Examples of a suitable 8-10 membered bridged bicyclic heterocycloalkyl groups include 3-azabicyclo[3.2.1]octan-3-yl, 3-azabicyclo[3.2.2]nonane and 3-azabicyclo[3.3.2]decane-3-yl. The term “oxo” refers to a oxygen atom forming a double bond (i.e. =O) to a suitable atom, such as carbon.Unless otherwise stated, the term “ring system” refers to a saturated or partly saturated, monocyclic, bicyclic or tricyclic, 4-13 membered ring comprising one N atom, and optionally one or two further heteroatoms independently selected from N, O and S. For the avoidance of doubt, the other atoms of the ring are carbon. Where the ring system is bicyclic, it may be spirocyclic, fused or bridged. Examples of suitable monocyclic ring systems include 4-6 membered heterocycloalkyl. Examples of suitable bicyclic ring systems include 8-11 membered spirocyclic bicyclic heterocycloalkyl, 7-10 membered fused bicyclic heterocycloalkyl and 8-10 membered bridged bicyclic heterocycloalkyl.The term “saturated or partially saturated” ring system refers to a ring system that is aliphatic, or which contains at least one aliphatic ring and one or two aromatic rings. Unless specifically stated, the bonding of an atom or group may be any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl.For the avoidance of doubt, where multiple substituents are independently selected from a given group, the selected substituents may comprise the same substituents or different substituents from within the given group.For the avoidance of doubt, the use of a circle within a 5 membered ring indicates that the 5 membered ring is an aromatic ring. By way of illustration only, indicates an aromatic ring selected from For the avoidance of doubt, the use of “ ” in formulas of this specification denotes the point of attachment between different groups. By way of illustration only, denotes a 3-hydroxyphenyl radical which is attached to a different group through the carbon atom meta- to the OH substituent.For the avoidance of doubt, the use of a bond between a substituent and the centre of a ring denotes that the substituent may replace any hydrogen atom directly attached to the ring, whether that hydrogen atom be attached to a C or N atom. By way of illustration only,  indicates a group selected from Where any embodiment within this specification includes a group which is said to be “optionally substituted”, then a further embodiment will include that embodiment wherein the said group is unsubstituted.For the avoidance of doubt, where multiple substituents are independently selected from a given group, the selected substituents may comprise the same substituents or different substituents from within the given group.Units, prefixes, and symbols are denoted in their International System of Units (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range.Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.Description of FigureEmbodiments and experiments illustrating the principles of the disclosure will now be discussed with reference to the accompanying figure in which:Figure 1 illustrates the synthesis of Intermediate 1 in flow. Detailed DescriptionIn one aspect there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined above.In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is an aliphatic, monocyclic, bicyclic or tricyclic, 4-13 membered ring comprising one N atom, and optionally one or two further heteroatoms independently selected from N, O and S.In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is an aliphatic, monocyclic or bicyclic, 4-11 membered ring comprising one N atom, and optionally one or two further heteroatoms independently selected from N, O and S (wherein the ring system is optionally substituted with one or more RC).In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is an aliphatic, monocyclic or bicyclic, 5-11 membered ring comprising one N atom, and optionally one further heteroatom selected from N, O and S (wherein the ring system is optionally substituted with one or more RC). In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is an aliphatic, monocyclic or bicyclic, 5-8 membered ring comprising one N atom, and optionally one further heteroatom selected from N, O and S (wherein the ring system is optionally substituted with one or more RC).In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is an aliphatic, monocyclic or bicyclic, 5-11 membered ring comprising one N atom, and one further heteroatom selected from N, O and S (wherein the ring system is optionally substituted with one or more RC).In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is an aliphatic, monocyclic or bicyclic, 5-8 membered ring comprising one N atom, and one further heteroatom selected from N, O and S (wherein the ring system is optionally substituted with one or more RC).In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is an aliphatic, monocyclic or bicyclic, 5-8 membered ring comprising one N atom and one O atom (wherein the ring system is optionally substituted with one or more RC).In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is an aliphatic monocyclic 5-8 membered ring comprising one N atom and one O atom (wherein the ring system is optionally substituted with one or more RC).In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is a 4-8 membered monocyclic heterocycloalkyl, optionally substituted with one or more RC. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is a 5-7 membered monocyclic heterocycloalkyl, optionally substituted with one or more RC. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is an 8-11 membered spirocyclic bicyclic heterocycloalkyl, optionally substituted with one or more RC. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is an 7-10 membered fused bicyclic heterocycloalkyl, optionally substituted with one or more RC.

Claims

1. A compound Formula (III): wherein one of X 1 , X 2 and X 3 is selected from NH, O and S and the other two of X 1 , X 2 and X 3 are independently selected from N and CR Y , wherein each R Y is independently H, -CN, -C(=O)N(R 7 ) 2 or R XA , wherein R XA is independently C 1-3 alkyl unsubstitueted or substituted with one to three F; J is selected from O, S, CH 2, NH and a covalent bond, x is selected from 0 to 3; each R 9 is independently selected from R 3 , R 4 and R 5 ; R E is H or halo, each R 3 is independently C 1-4 alkyl or C 3-6 cycloalkyl, each of which are unsubstitueted or substituted with one or more groups independently selected from R 4X , R 5x , -O(R 4X ), -O(R 5X ) and F; each R 3X is independently C 1-4 alkyl or C 3-6 cycloalkyl, each of which are unsubstitueted or substituted with one or more F; each R 4 is independently monocyclic or bicyclic 5 to 9 membered heteroaryl, each of which are unsubstitueted or substituted with one or more groups independently selected from R 4X , -O(R 4X ), R 5X , -O(R 5X ), -OH, -CN, C 1-4 alkoxy, -C(=O)OH, -C(=O)O(C 1-4 alkyl), -C(=O)N(R 7B ) 2 , R 3 and halo; each R 5 is independently phenyl, each of which are unsubstitueted or substituted with one or more groups independently selected from R 4X , -O(R 4X ), R 5X , -O(R 5X ), -OH, -CN, C 1-4 alkoxy, -C(=O)OH, -C(=O)O(C 1-4 alkyl), -C(=O)N(R 7B ) 2 , R 3 and halo; each R 4X is independently monocyclic or bicyclic 5 to 9 membered heteroaryl, each of which are unsubstitueted or substituted with one or more groups independently selected from -OH, -CN, C 1-4 alkoxy, -C(=O)OH, -C(=O)N(R 7B ) 2 , R 3X and halo; each R 5X is independently phenyl, each of which are unsubstitueted or substituted with one or more groups independently selected from -OH, -CN, C 1-4 alkoxy, -C(=O)OH, -C(=O)N(R 7B ) 2 , R 3x and halo; each R 7 and R 7B are independently H, C 1-4 alkyl or C 3-6 cycloalkyl; and wherein each heteroaryl is independently an aromatic ring containing one or more heteroatoms independently selected from N, O and S, or a pharmaceutically acceptable salt thereof. 2.            The compound of Formula (III), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein (i) X 1 is N, X 2 is O and X 3 is N; (ii) X 1 is N, X 2 is N and X 3 is O; (iii) X 1 is CR Y , X 2 is CR Y and X 3 is S; (iv) X 1 is O, X 2 is N and X 3 is CR Y ; (v) X 1 is N, X 2 is O and X 3 is CR Y ; (vi) X 1 is CR Y , X 2 is N and X 3 is O; (vii) X 1 is O, X 2 is N and X 3 is N; (viii) X 1 is N, X 2 is N and X 3 is S; (ix) X 1 is CR Y , X 2 is S and X 3 is CR Y ; or (x) X 1 is CR Y , X 2 is N and X 3 is S. 3.            The compound of Formula (III), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein X 1 is N, X 2 is O and X 3 is N . 4.            The compound of Formula (III), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein J is O. 5.            The compound of Formula (III), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein each R 3 is independently C 1-4 alkyl unsubstitueted or substituted with one to three F. 6.            The compound of Formula (III), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein each R 4 is independently monocyclic or bicyclic 5 to 9 membered heteroaryl, each of which are unsubstitueted or substituted with one or more groups independently selected from OH, -CN, C 1-4 alkoxy, -C(=O)OH, -C(=O)O(C 1-4 alkyl) -C(=O)N(R 7B ) 2 , R 3X and halo. 7.            The compound of Formula (III), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein each R 5 is independently phenyl, each of which are unsubstitueted or substituted with one or more groups independently selected from OH, -CN, C 1-4 alkoxy, -C(=O)OH, -C(=O)O(C 1-4 alkyl), -C(=O)N(R 7B ) 2 , R 3X and halo. 8.            The compound of Formula (III), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein R E is H. 9.            The compound of Formula (III), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, that is selected from ((2 R ,6 S )-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone, (3-(2-Methoxyphenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ( R )-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone, 3-(4-(3-(4-Fluorophenoxy)propyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile, 3-(4-(Pyridin-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile, 3-(4-(3-Methoxyphenyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile, 5-(2,4,5-Trifluoro-3-hydroxyphenyl)-3-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazine-1-carbonyl)isoxazole-4-carbonitrile, (S)-3-(3-(4-Chlorophenyl)pyrrolidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile, 3-((2 R ,6 S )-2,6-Dimethylmorpholine-4-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile, 3-(4-(Benzo[ d ]oxazol-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile, 3-(4-(4-(4-Fluorophenyl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile, ( R )-(3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone, (3-Isopropylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((3 R ,5 S )-3,5-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((3 R ,5 S )-3,5-Dimethylpiperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2 R ,5 S )-2,5-Dimethylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, Morpholino(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, Thiomorpholino(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, 3-(4-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-2-yl)benzonitrile, Piperidin-1-yl(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ( S )-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(2-(trifluoromethyl)morpholino)methanone, (2-Isobutylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (3,3-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ( R )-(2-(Fluoromethyl)morpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2 R ,5 R )-2,5-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2 S ,6 S )-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (4-(4-Methoxyphenyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, 4-(1-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperidin-4-yl)benzonitrile, (4-(3-(4-Fluorophenoxy)propyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (4-(Pyridin-2-yl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (4-(3-Methoxyphenyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (4-(3-Chloro-5-(2-methyl-2 H -tetrazol-5-yl)pyridin-2-yl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (4-(2-((5-Bromopyridin-2-yl)oxy)ethyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (4-(Benzo[ d ]oxazol-2-yl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (3-Propylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (4-Phenylpiperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, 2-(4-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-1-yl)benzonitrile, 4-(4-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-1-yl)benzonitrile, (4-(2-Methoxyphenyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2 R ,6 S )-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2 R ,6 R )-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2 R ,6 S )-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone, ( R )-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ( S )-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ( R )-(3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone, ((2 S ,6 R )-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxy-6-iodophenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2 R ,6 S )-2,6-Dimethylmorpholino)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone, ((3 R ,5 S )-3,5-Dimethylpiperidin-1-yl)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone, (5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(2,2,6-trimethylmorpholino)methanone, ((3 R ,5 S )-3,5-Dimethylpiperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2 R ,6 S )-2,6-Dimethylmorpholino)(2-(2,4,5-trifluoro-3-hydroxyphenyl)thiazol-5-yl)methanone, rac -((2 R ,6 S )-2-Ethyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, rac -((2 R ,6 S )-2-isopropyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, and (5-(2-Bromo-3,4,6-trifluoro-5-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)((2R,6S)-2,6-dimethylmorpholino)methanone , or a pharmaceutically acceptable salt thereof. 10.          The compound of Formula (III), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, that is ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone or a pharmaceutically acceptable salt thereof. 11.          The compound of Formula (III), as claimed in claim 10, that is ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone . 12.          The pharmaceutical composition comprising a compound of Formula (III), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, and a pharmaceutically acceptable excipient. 13.          The compound of Formula (III), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, for use in therapy. 14.          The compound of Formula (III), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, for use in the treatment of liver disease. 15.          The compound of Formula (III), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, for use in the treatment of a liver disease selected from alcoholic liver disease, non-alcoholic liver disease, NAFLD, NASH, liver fibrosis, cirrhosis, isolated steatosis, liver inflammation, alcoholic steatohepatitis (ASH), hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). 16.          The compound for use as claimed in claim 15, wherein the liver disease is liver fibrosis. 17.          The compound for use as claimed in claim 15, wherein the liver disease is cirrhosis. 18.          A combination for use in the treatment of liver disease comprising a compound of Formula (III) or a pharmaceutically acceptable salt thereof, as claimed any one of claims 1 to 3, and (i)            a glucagon-like peptide-1 receptor (GLP1) agonist, (ii) a sodium-glucose transport protein 2 (SGLT2) inhibitor, or (iii) a ThrB agonist.

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