WO2021161222A1

WO2021161222A1 - Compounds useful in inhibiting diacylglycerol o-acyltransferase and methods of making and using the same

Info

Publication number: WO2021161222A1
Application number: PCT/IB2021/051144
Authority: WO
Inventors: Robert Judkins; Lambertus BENTHEM
Original assignee: Inorbit Therapeutics Ab
Priority date: 2020-02-11
Filing date: 2021-02-11
Publication date: 2021-08-19

Abstract

Described herein are compounds that may act as an inhibitor of diacylglycerol O- acyltransferase 2 (DGAT2) and/or that may be useful in the treatment of diseases and/or disorders associated with DGAT2. Compositions including such compounds are also described herein along with methods of preparation and use of such compounds and/or compositions.

Description

COMPOUNDS USEFUL IN INHIBITING DIACYLGLYCEROL O- ACYLTRANSFERASE AND METHODS OF MAKING AND USING THE SAME

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Patent Application Serial No. 62/972,790, filed February 11, 2020, the disclosure of which is incorporated herein by reference in its entirety.

FIELD

The present invention relates to compounds that can act as inhibitors of diacylglycerol O-acyltransferase 2 (DGAT2) and that can be useful in the treatment of diseases and/or disorders associated with DGAT2. In some embodiments, the present invention relates to compounds and compositions that inhibit DGAT2 and methods for their preparation and use.

BACKGROUND

Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steato-Hepatitis (NASH) are liver diseases which resemble alcoholic hepatitis on liver biopsy but can occur in patients who have no known history of alcohol abuse.

NASH is characterized by hyperinsulinemia, insulin resistance, hyperlipidemia, elevated serum transaminases such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and liver cell injury driven by lipid accumulation, hepatic inflammation and lobular infiltration of inflammatory cells such as macrophages, and activation and transformation of hepatic stellate cells into smooth muscle cell phenotype (Luwig, J, et al. Mayo Clin Proc 1980;55:434-438). In humans, NAFLD progresses from the relatively benign stage of hepatic steatosis through an intermediary stage of NASH in which fibrosis appears and begins to accumulate to frank cirrhosis culminating in liver failure.

Due to current high energy intake and sedentary lifestyle characteristics of modern day living, the global prevalence of NAFLD has reached 25% of the adult population and continues to rise. Some 20 % of these NAFLD patients are expected to develop overt NASH with significant chance to develop cirrhosis and ultimately liver failure. Although NAFLD and NASH represent a major burden to the patient and the supporting health system, there is currently no approved pharmacotherapy targeting the disease, emphasizing the current need for novel intervention strategies. Diacylglycerol O-acyltransferases (DGATs) catalyze the esterification of a fatty acid with diacylglycerol to form triglycerides (Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J Lipid Res. 2008 Nov; 49(11):2283-301). DGAT activity contributes to intestinal fat absorption, control of circulating lipid concentrations, flux of lipoproteins between adipose and liver, and muscle energy metabolism (Role of DGAT enzymes in triacylglycerol metabolism, Arch Biochem Biophys, 655 (2018), pp. 1-11). Two structurally unrelated enzymes have been characterised in mammals, DGAT1 which is abundantly expressed in the intestine and plays a central role in fat absorption (DGAT1 is not essential for intestinal triacylglycerol absorption or chylomicron synthesis J Biol Chem, 277 (2002), pp. 25474-25479) and DGAT2 which is highly expressed in liver and adipose tissue

(Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members J Biol Chem, 276 (2001), pp. 38870-38876).

Pharmacological inhibition of DGAT2 in rodents results in the inhibition of hepatic triglyceride synthesis, the adaptive suppression of de-novo lipogenesis and the stimulation of hepatic fatty acid oxidation (Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance J Biol Chem, 282 (2007), pp. 22678-22688). The outcome of which being the reduction of hepatic levels diacylglycerols and triglycerides, which in turn lowers hepatocyte lipids and VLDL-TG secretion (Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice Hepatology, 42 (2005), pp. 362-371).

In addition, small molecule DGAT2 inhibitors have been shown to improve fibrosis in the STAM mouse model (Characterization of the Effects of a Novel DGAT2 Inhibitor of Hepatic Lipid Metabolism. DEUEL Conference, Abstract 21 American Society for Biochemistry and Molecular Biology, Monterey, CA 2015), the choline deficient high fat fed rat model (ACCi/DGAT2i combination therapy for the treatment of NASH. EASL NAFLD Summit European Association for the Study of Liver, Geneva, Switzerland (2018), pp. P01- P09) and the LDLr-/- Leiden NASH rat model (Inhibition of DGAT2 improves hepatic steatosis, inflammation and cardiovascular risk factors in the LDLr-/- Leiden mouse. EASL NAFLD Summit European Association for the Study of Liver, Geneva, Switzerland (2018), pp.

P06-P09).

The small molecule DGAT2 inhibitor PF-06427878 has been orally administered to healthy humans for 2 weeks and magnetic resonance imaging (proton density fat fraction (PDFF)) showed a reduction in hepatic steatosis, highlighting the potential treatment of NASH by DGAT2 inhibitors. (Targeting diacylglycerol acyltransferase 2 for the treatment of nonalcoholic steatohepatitis. Science Translational Medicine, 2019 Nov 27; 11(520)). These observations were also accompanied by improvements in the markers for liver function alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin.

Inhibition of DGAT2 has therefore the potential to be a treatment for a range of diseases including diabetes (T1D and/or T2D), idiopathic T1 D (Type 1 b), latent autoimmune diabetes in adults (LADA), early-onset T2D (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, obesity, eating disorders, excessive sugar craving, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, and low HDL cholesterol), hyperinsulinemia, NAFLD (including related diseases such as steatosis, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma), HFI, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer's Disease, schizophrenia, impaired cognition, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and irritable bowel syndrome.

Although several DGAT2 inhibitors are known and have been disclosed (for recent examples see, Discovery and Pharmacology of a Novel Class of Diacylglycerol Acyltransferase 2 Inhibitors, J Med Chem. 2015 Dec 10;58(23):9345-53; Discovery and Optimization of Imidazopyridine Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2) J Med Chem. 2015 Sep 24;58(18):7173-85), there is still a need for the development of novel and potent compounds for the treatment and prevention of disease. The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

SUMMARY

The present inventors have discovered that replacing a carboxylic acid component with a sulfmic and/or sulfonic group on compounds that are DGAT2 inhibitors can alter the metabolism pathway of the compounds (compared to the metabolism pathway for the compounds with the carboxylic acid component present), which may result in a decrease in harmful metabolites formed, particularly via acyl-glucuronidation, without significant loss of efficacy as DGAT2 inhibitors.

One aspect of the present invention is directed to compounds represented by Formula I, an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof:

wherein:

R₁ is C₁-C₄alkyl or C₃-C₆cycloalkyl optionally substituted with one, two or three substituents each independently selected from fluoro and C₃-C₆cycloalkyl;

X is N or CH;

R₂ is H, C₁-C₄alkyl or C₃-C₆cycloalkyl;

R₃ is hydrogen, halo, C₁-C₄alkyl, C₃-C₆cycloalkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁ -C₄haloalkoxy; and

Y is S(O)OH, CH₂S(O)OH, CH(CH₃)S(O)OH, S(O)₂OH, CH₂S(O)₂OH,

CH(CH₃)S(O)₂OH; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.

In some embodiments, the invention provides a compound selected from the group consisting of sodium 4-((2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)- 3-methylbenzenesulfmate, potassium 4-((2-((R)-3-(2-ethoxyphenoxy)piperidin-1- yl)pyrimidine-5-carboxamido)methyl)benzenesulfmate, potassium 3-((6-((R)-3-(2- ethoxyphenoxy)piperidin-1-yl)nicotinamido)methyl)benzenesulfmate and sodium 3-((2-((R)-

3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4- methoxyb enzene sulfmate .

Another aspect of the present invention is directed to a method of inhibiting DGAT2. The method comprises administering to a subject in need thereof an effective amount of a compound of the present invention (e.g., a compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof).

Another aspect of the present invention is directed to a method of treating and/or preventing a disease and/or disorder in which DGAT2 is indicated. In some embodiments, the disease and/or disorder is hyperlipidemia, Type I diabetes, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset Type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gesta-tional diabetes, coronary heart disease, ischemic stroke, res-tenosis after angioplasty, peripheral vascular disease, inter-mittent claudication, myocardial infarction ( e.g. necrosis and apoptosis ), dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, dia-betic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomemlosclerosis, chronic renal failure, dia-betic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and con-nective tissue disorders, foot ulcerations and ulcerative coli-tis, endothelial dysfunction and impaired vascular compli-ance, hyper apo B lipoproteinemia, Alzheimer's, schizophrenia, impaired cognition, inflammatory bowel dis-ease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, non-alcoholic steatohepatitis (NASH), and/or non-alcoholic fatty liver disease (NAFLD).

The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention (e.g., a compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof)) or a pharmaceutical composition comprising said compound of the present invention. A further aspect of the present invention is directed to a pharmaceutical composition comprising a compound of the present invention (e.g., a compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof) and a pharmaceutically acceptable carrier. The pharmaceutical composition may further include an excipient, diluent, and/or surfactant.

Another aspect of the present invention relates to a compound of the present invention (e.g., a compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof)) for use in the manufacture of a medicament for treating and/or preventing a disease and/or disorder in which diacylglycerol O-acyltransferase (DGAT2) plays a role. In some embodiments, a DGAT2 plays a role in a disease and/or disorder in that the DGAT2 is involved in a pathway, mechanism, or action associated with the disease and/or disorder such as, e.g. hepatic lipogenesis.

DETAILED DESCRIPTION

The present invention is now described more fully hereinafter with reference to the accompanying drawings, in which embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather these embodiments are provided so that this disclosure will be thorough and complete and will fully convey the scope of the invention to those skilled in the art.

The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the invention and the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the present application and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly so defined herein. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. In case of a conflict in terminology, the present specification is controlling.

Also as used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed.

The term “about,” as used herein when referring to a measurable value such as an amount or concentration and the like, is meant to encompass variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of the specified value as well as the specified value. For example, “about X” where X is the measurable value, is meant to include X as well as variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of X. A range provided herein for a measurable value may include any other range and/or individual value therein. “Diacylglycerol O- acyltransferase” or “DGAT2” as used herein is diacylglycerol O-acyltransferase from any source and/or that is present in a subject and/or expressed in any form. In some embodiments, diacylglycerol O-acyltransferase is from and/or is present and/or expressed in an animal such as, e.g., a mammal. In some embodiments, diacylglycerol O-acyltransferase is from and/or is present and/or expressed in a primate, cow, sheep, goat, or horse. In some embodiments, diacylglycerol O-acyltransferase is from and/or is present and/or expressed in a human.

The term “inhibit” refers to the ability of a compound (e.g., a compound of the present invention) to inhibit one or more function(s), action(s), and/or characteristic(s) of DGAT2, either directly or indirectly and may occur in vitro or in vivo.

The term “inhibitor” refers to a compound (e.g., a compound of the present invention) that combines with and/or binds to a specific enzyme (e.g. DGAT2) and decreases a function, action, and/or characteristic associated with the enzyme. In some embodiments, a compound of the present invention is a DGAT2 inhibitor.

“Substantially the same” as used herein in reference to a measurable value and/or response means being within about ± 10% of the compared to value and/or response. The term "C_1-4alkyl" means a saturated or unsaturated alkyl chain having 1 to 4 carbon atoms which may be a straight chain or branched chain. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isopropyl and butyl.

The term “C_1-4alkyloxy” means a straight or branched chain saturated or unsaturated hydrocarbon containing 1-4 carbon atoms containing a terminal oxygen in the chain and the straight or branched chain saturated or unsaturated hydrocarbon is attached to a parent or principal compound through the oxygen. Examples thereof include, but are not limited to, m ethoxy, ethoxy, propoxy and butoxy.

The term "C_1-4haloalkyl" means a straight or branched chain saturated or unsaturated hydrocarbon containing 1-4 carbon atoms and in which one or more hydrogen atoms have been replaced with a halogen atom. Examples thereof include, but are not limited to, dichloromethyl, triflurom ethyl and trifluroethyl.

The term “C_1-4haloalkoxy” means a straight or branched chain saturated or unsaturated hydrocarbon containing 1-4 carbon atoms in which one or more hydrogen atoms have been replaced with a halogen atom, and the chain contains a terminal oxygen through which the chain hydrocarbon is attached to a parent or principal. Example thereof includes, but is not limited to, triflurom ethoxy.

The term “C_3-6 cycloalkyl” means a saturated monocyclic ring system comprising 3 to 6 carbon atoms. Examples thereof include, but are not limited to, cyclopropyl, cyclobutyl, cyclo pentyl and cyclohexyl.

“Halogen” refers to fluorine, chlorine, bromine and iodine. In some embodiments, the halogen is fluorine or chlorine.

The term “sulfmic acid” means the functional group -S(O)OH, consisting of a sulfmyl group and a hydroxyl group.

The term “sulfmate” means the conjugate base of sulfmic acid, where the hydroxyl has been deprotonated to give S(O)O-.

The term “sulfonic acid” means the functional group -S(O)₂OH, consisting of a sulfonyl group and a hydroxyl group.

The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded to other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituent(s) different from hydrogen. For instance, it can, at any point along the chain, be bound to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups.

The term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.

The term "pharmaceutically acceptable salt" refers to a salt of a compound which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and is commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.

For a detailed review of pharmaceutically acceptable salts see J. Pharmaceutical Sciences, 66: 1-19 (1977), by Berge et al. In some embodiments, the salts can be prepared in situ during the final isolation and/or purification for a compound of the invention, or separately by reaction of the free acid function with a suitable inorganic or organic base. Suitable salts include, but are not limited to, metals, such as sodium, potassium and calcium, or amines, such as triethylammonium, ethanolammonium and lysine.

The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

The term "prodrug" refers to a prodrug of a compound which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and/or the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of a compound of the present invention. "Prodrug", as used herein means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to afford a compound of the present invention (e.g., a compound of Formula I). Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, Vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002).

The term "amino acid conjugate" refers to a conjugate of a compound of the present invention (e.g., a compound of Formula I) with an amino acid. Preferably, such amino acid conjugates of the present invention will have the added advantage of enhanced integrity in bile and/or intestinal fluids. Suitable amino acids include, but are not limited to, glycine and taurine. Thus, the present invention encompasses the glycine and taurine conjugates of a compound of Formulas I.

Unless indicated otherwise, nomenclature used to describe chemical groups or moieties as used herein follow the convention where, reading the name from left to right, the point of attachment to the rest of the molecule is at the right-hand side of the name. For example, the group "(C_1-3alkoxy)C_1-3alkyl," is attached to the rest of the molecule at the alkyl end. Further examples include methoxyethyl, where the point of attachment is at the ethyl end, and methylamino, where the point of attachment is at the amine end.

Unless indicated otherwise, where a mono or bivalent group is described by its chemical formula, including one or two terminal bond moieties indicated by it will be understood that the attachment is read from left to right.

Unless otherwise stated, structures depicted herein are meant to include all enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

Provided according to embodiments of the present invention are compounds having a structure represented by Formula I:

wherein:

X is N or CH;

R₂ is H, C₁-C₄alkyl or C₃-C₆cycloalkyl;

R₃ is hydrogen, halo, C₁-C₄alkyl, C₃-C₆cycloalkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, or C₁-C₄haloalkoxy; and

Y is S(O)OH, CH₂S(O)OH, CH(CH₃)S(O)OH, S(O)₂OH, CH₂S(O)₂OH, or CH(CH₃)S(O)₂OH; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.

Compounds of Formula I as defined herein may be useful as DGAT2 inhibitors and/or may have an improved toxicity profile. The improved toxicity profile may be due to a reduced propensity for forming toxic metabolites as compared to a corresponding compound in which the sulfmic acid or sulfonic acid component is replaced with a carboxylic acid component. The compounds or composition of the invention may therefore be used in medicine.

In some embodiments, a compound of the present invention has a different metabolic profile compared to a corresponding carboxylic acid compound (i.e., a compound having a - COOH or -COO- group replacing the mandatory -S(O)OH, -S(O)O-, -S(O)₂OH or -S(O)₂O- group in the compound of Formula I). These corresponding carboxylic acid compounds are typically metabolised to an acyl-glucuronide and such metabolism can give rise to reactive metabolites that cause liver toxicity and drug induced liver injury (Shipkova M, Armstrong VW, Oellerich M, and Wieland E (2003) Acyl glucuronide drug metabolites: Toxicological and analytical implications. Ther Drug Monit 25: 1-16; Regan S, Maggs J, Hammond T, Lambert C, Williams D and Park BK (2010) Acyl glucuronides: the good, the bad and the ugly. Biopharm Drug Dispos 31: 367-395; Shipkova M, Armstrong VW, Oellerich M, and Wieland E (2003) Acyl glucuronide drug metabolites: Toxicological and analytical implications. Ther DrugMonit 25: 1-16).

For example, the compounds of the present invention may only be metabolised by oxidative pathways, such as Cyp oxidation, and/or may minimise the formation of acyl glucuronide-like metabolites compared to a corresponding carboxylic acid compound.

A compound of the present invention may break down in-vivo via a different metabolic pathway than a corresponding carboxylic acid compound and/or the compound of the present invention may have beneficial liver safety effects and/or improved liver safety and/or improved efficacy compared to a corresponding carboxylic acid compound.

In some embodiments, a compound of the present invention may have a different distribution profile when orally dosed in-vivo, such as increased exposure in the liver versus plasma, compared to a corresponding carboxylic acid compound.

In some embodiments, a compound of the present invention may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical or chemical properties than a compound known in the prior art. Such effects may be evaluated clinically, objectively and/or subjectively by a health care professional, a treatment subject or an observer.

In some embodiments, a compound of the present invention is a metabolite (i.e. having undergone metabolism or biotransformation in the subject).

In some embodiments, a compound of the present invention is a sulfmic acid (or its corresponding sulfmate salt) compound or a sulfonic acid (or its corresponding sulfonate salt) compound. In some embodiments, a compound of the present invention may be a sulfmic acid metabolite, which may be a corresponding sulfonic acid of the compound (e.g., a compound having a -S(O)₂OH or -S(O)₂O- group replacing a -S(O)OH or -S(O)O- group in the compound) or a corresponding sulfmate ester of the compound (e.g., a compound having a -S(O)O(C_1-6 alkyl) group replacing a -S(O)OH or -S(O)O- group in the compound).

In some embodiments, a compound of the present invention is a sodium salt. In some embodiments, a compound of the present invention is a sulfmate salt (e.g. a sodium sulfmate salt).

In some embodiments, a compound of the present invention may have beneficial liver safety effects and/or improved liver safety compared to another compound such as, e.g., a corresponding carboxylic acid compound.

A compound of the present invention may have a structure of:

In some embodiments of the invention, a compound of the present invention may reduce liver triglycerides in the liver and/or plasma. In some embodiments, a compound of the present invention may reduce liver triglycerides in the liver and/or plasma by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or more. In some embodiments of the invention, a compound of the present invention may reduce cholesterol in the liver and/or plasma. In some embodiments, a compound of the present invention may reduce cholesterol in the liver and/or plasma by at least about 5%, 10%, 15%, 20%, 25%,

30%, 35%, 40%, 45%, 50%, 55%, 60%, or more.

Provided according to some embodiments of the present invention is a composition (e.g., a pharmaceutical composition) comprising a compound of the present invention (e.g., a compound of Formula I). In some embodiments, a pharmaceutical composition of the present invention comprises a compound of the present invention and a pharmaceutically acceptable carrier.

As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient (e.g., a compound of the present invention), its use in the therapeutic and/or pharmaceutical compositions is contemplated. Compounds of the invention are indicated as pharmaceuticals. According to a further aspect of the invention there is provided a compound of the invention, for use as a pharmaceutical (e.g. for use in medicine).

According to some embodiments, a compound and/or composition of the present invention is administered to a subject. In some embodiments, a method of inhibiting diacylglycerol O-acyltransferase (DGAT2) in a subject is provided, the method comprising administering to the subject a compound of the present invention and/or a composition of the present invention.

In some embodiments, a method of treating and/or preventing a disease or disorder in which diacylglycerol O-acyltransferase (DGAT2) plays a role is provided, the method comprising administering to a subject in need thereof an effective amount (e.g., a therapeutically effective amount, a treatment effective amount, and/or a prevention effective amount) of a compound of the present invention and/or a composition of the present invention. In some embodiments, the disease or disorder is diabetes (T1D and/or T2D), idiopathic T1 D (Type 1 b), latent autoimmune diabetes in adults (LADA), early-onset T2D (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, obesity, eating disorders, excessive sugar craving, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, and low HDL cholesterol), hyperinsulinemia, NAFLD (including related diseases such as steatosis, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma), HFI, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer's Disease, schizophrenia, impaired cognition, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and irritable bowel syndrome.

The term "therapeutically effective amount" refers to an amount of a compound of the present invention (e.g., a compound of Formula I) that is sufficient to achieve or elicit a therapeutically useful response or a stated effect in a subject. Accordingly, a therapeutically effective amount of a compound of Formula I used for the treatment of a condition mediated by DGAT2 can be an amount sufficient for the treatment of the condition mediated by DGAT2.

As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers to, for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

The terms "treat", "treating", "treatment of and grammatical variations thereof in reference to a disease, or condition refer to any type of treatment that imparts a benefit to a subject and may mean that the severity of the subject’s condition is reduced, at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in at least one clinical symptom associated with a disease, disorder, or condition is achieved and/or there is a delay in the progression of the symptom. In some embodiments, the severity of a symptom associated with a disease, disorder, or condition mediated by DGAT2 may be reduced in a subject compared to the severity of the symptom in the absence of a method of the present invention. In some embodiments, "treat", "treating", "treatment of and grammatical variations thereof in reference to a disease or disorder refer to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or disorder or at least one clinical symptom thereof). In some embodiments, "treat", "treating" or "treatment of and grammatical variations thereof in reference to a disease or disorder refer to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the subject. In some embodiments, "treat", "treating" or "treatment of and grammatical variations thereof in reference to a disease or disorder refer to modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both.

In some embodiments, a compound of the present invention may be administered to a subject in a treatment effective amount. A "treatment effective" amount as used herein is an amount that is sufficient to treat (as defined herein) a subject. Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject. In some embodiments, a treatment effective amount may be achieved by administering a composition of the present invention.

The terms "prevent," "preventing" and "prevention" (and grammatical variations thereof) refer to avoidance, reduction and/or delay of the onset of a symptom associated with a disease or disorder (e.g., a disease, disorder, or condition mediated by DGAT2) and/or a reduction in the severity of the onset of symptom associated with a disease or disorder (e.g., a disease, disorder, or condition mediated by DGAT2) relative to what would occur in the absence of a method of the present invention. The prevention can be complete, e.g., the total absence of the symptom. The prevention can also be partial, such that the occurrence of the symptom in the subject and/or the severity of onset is less than what would occur in the absence of a method of the present invention.

In some embodiments, a compound of the present invention may be administered in a prevention effective amount. A "prevention effective" amount as used herein is an amount that is sufficient to prevent (as defined herein) a symptom associated with a disease or disorder (e.g., a disease, disorder, or condition mediated by DGAT2) in a subject. Those skilled in the art will appreciate that the level of prevention need not be complete, as long as some benefit is provided to the subject. In some embodiments, a prevention effective amount may be achieved by administering a composition of the present invention.

The terms "administer", "administering", "administration" and grammatical variations thereof as used herein refer to directly administering to a subject a compound of the present invention (or a pharmaceutically acceptable salt, etc., thereof) and/or a composition of the present invention. In some embodiments, a compound and/or composition of the present invention is administered to the subject in an amount that can form an equivalent amount of the active compound within the subject's body.

A compound of the present invention can be administered in a therapeutically effective amount to treat and/or prevent a disease or disorder and/or to prevent the development thereof in a subject. Administration of a compound of the present invention can be accomplished via any mode of administration for therapeutic agents such as, for example oral, rectal, topical, and/or parenteral administration may be employed. In some embodiments, a compound of the present invention is administered orally.

Depending on the intended mode of administration, a compound of the present invention and/or composition of the present invention can be in a dosage form known to those skilled in the pharmaceutical practices, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, emulsions, syrups, powders, liquids, suspensions, and/or the like. Typical pharmaceutical compositions include, but are not limited to, tablets, pills, powders or gelatin capsules comprising the active ingredient (e.g., a compound of the present invention) and a pharmaceutically acceptable carrier such as for example: a) a diluent, e.g., purified water, com oil, olive oil, sunflower oil, fish oils, such as EPA or DHA or their esters or triglycerides or mixtures thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine: b) a lubricant, e.g., silica, talcum, stearic acid its magnesium or calcium salt and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, natural and synthetic gums such as acacia tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, algic acid or its sodium salt, and/or effervescent mixtures; e) absorbent, colorant, flavorant and/or sweetener; f) an emulsifier or dispersing agent, e.g. Labrasol, HPMC, labrafil, peceol, capmul, vitamin E TGPS and/or other acceptable emulsifier; and/or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, and/or PEG200.

Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, a compound of the present invention is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and/or the like, to thereby form an injectable isotonic solution or suspension. Said composition may be sterilized and/or contain adjuvants, such as preserving, stabilizing wetting or emulsifying agents, solution promoters, salts for regulating osmotic pressure and/or buffers.

A compound of the present invention may also be formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.

A compound of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound is coupled. A compound of the present invention may be coupled with a soluble polymer as a targetable drug carrier. Such polymers can include, but are not limited to, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, a compound of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphiphillic block copolymers of hydrogels. In one embodiment disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.

Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection. In addition, they may also contain other therapeutically valuable substances. Said compositions may be prepared according to conventional mixing, granulating and/or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing a compound of the present invention in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Compositions of the present invention can be prepared according to conventional mixing, granulating and/or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99% of compound by weight or volume.

The present invention further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate by which a compound of the present invention as an active ingredient will decompose. Such agents, which are referred to herein as "stabilizers" include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, and/or salt buffers, etc. The dosage regimen utilizing a compound of the present invention may be selected in accordance with a variety of factors including type, species, age, weight, sex and/or medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; and the particular disclosed compound employed. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.

Effective dosage amounts of a compound of the present invention, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the compound as needed to treat the condition.

In some embodiments, a method of the present invention comprises administering to a subject a compound of the present invention in an amount of about 0.05 to about 5 mg of the compound per kg of the subject, such as, for example, about 0.1 mg/kg to about 5 mg/kg, about 0.1 mg/kg to about 3 mg/kg, about 0.3 mg/kg to about 1 mg/kg, or about 1 mg/kg to about 3 mg/kg. In some embodiments, a compound of the present invention may be administered to a subject in an amount of about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 mg of the compound per kg of the subject. A compound of the present invention may be administered to a subject one or more times per day and/or week (e.g., 1, 2, 3, 4, 5, or more times per day and/or week) for a period of time (e.g., about 1 to about 52 weeks or until a desired therapeutic effect and/or treatment and/or prevention is achieved). In some embodiments, a compound of the present invention is administered to a subject one, two or three times per day. In some embodiments, a compound of the present invention is administered to a subject two or three times a week or every two or three days. In some embodiments, a compound of the present invention is administered to a subject once a day for about 1 to about 52 weeks or until a desired therapeutic effect and/or treatment and/or prevention is achieved.

A compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent(s). A compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other therapeutic agent(s).

In some embodiments, the invention provides a product comprising a compound of Formula I at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In some embodiments, the one or more additional therapeutic agent(s) are an ACE inhibitor, acetyl CoA carboxylase inhibitor, adenosine A3 receptor agonist, adiponectin receptor agonist, AKT protein kinase inhibitor, AMP-activated protein kinases (AMPK), amylin receptor agonist, angiotensin II AT-1 receptor antagonist, autotaxin inhibitors, bioactive lipid, calcitonin agonist, caspase inhibitor, caspase-3 stimulator, cathepsin inhibitor, caveolin 1 inhibitor, CCR2 chemokine antagonist, CCR3 chemokine antagonist, CCR5 chemokine antagonist, chloride channel stimulator, CNR1 inhibitor, cyclin D1 inhibitor, cytochrome P450 7A1 inhibitor, DGAT1/2 inhibitor, dipeptidyl peptidase IV inhibitor, endosialin modulator, eotaxin ligand inhibitor, extracellular matrix protein modulator, famesoid X receptor agonist, fatty acid synthase inhibitors, FGF1 receptor agonist, fibroblast growth factor (FGF-15, FGF-19, FGF-21) ligands, galectin-3 inhibitor, glucagon receptor agonist, glucagon-like peptide 1 agonist, G-protein coupled bile acid receptor 1 agonist, hedgehog (Hh) modulator, hepatitis C virus NS3 protease inhibitor, hepatocyte nuclear factor 4 alpha modulator (HNF4A), hepatocyte growth factor modulator, HMG CoA reductase inhibitor, IL-10 agonist, IL-17 antagonist, ileal sodium bile acid cotransporter inhibitor, insulin sensitizer, integrin modulator, intereukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, Jak2 tyrosine kinase inhibitor, ketohexokinase (KHK), klotho beta stimulator, 5 -lipoxygenase inhibitor, lipoprotein lipase inhibitor, liver X receptor, LPL gene stimulator, lysophosphatidate-1 receptor antagonist, lysyl oxidase homolog 2 inhibitor, matrix metalloproteinases (MMPs) inhibitor, MEKK-5 protein kinase inhibitor, membrane copper amine oxidase (VAP-1) inhibitor, methionine aminopeptidase-2 inhibitor, methyl CpG binding protein 2 modulator, microRNA- 21(miR-21) inhibitor, mitochondrial uncoupler, myelin basic protein stimulator, NACHT LRR PYD domain protein 3 (NLRP3) inhibitor, NAD-dependent deacetylase sirtuin stimulator, NADPH oxidase inhibitor (NOX), nicotinic acid receptor 1 agonist, P2Y13 purinoceptor stimulator, PDE 3 inhibitor, PDE 4 inhibitor, PDE 5 inhibitor, PDGF receptor beta modulator, phospholipase C inhibitor, PPAR alpha agonist, PPAR delta agonist, PPAR gamma agonist, PPAR gamma modulator, protease-activated receptor-2 antagonist, protein kinase modulator, Rho associated protein kinase inhibitor, sodium glucose transporter-2 inhibitor, SREBP transcription factor inhibitor, STAT-1 inhibitor, stearoyl CoAdesaturase-1 inhibitor, suppressor of cytokine signalling-1 stimulator, suppressor of cytokine signalling-3 stimulator, transforming growth factor 3 (TGF-β3), transforming growth factor β activated Kinase 1 (TAKi), thyroid hormone receptor beta agonist, TLR-4 antagonist, transglutaminase inhibitor, tyrosine kinase receptor modulator, GPCR modulator, nuclear hormone receptor modulator, WNT modulators, and/or YAP/TAZ modulator.

In some embodiments, the therapy is the treatment or prevention of a disease or condition mediated by diacylglycerol O-acyltransferase. Products provided as a combined preparation include, but are not limited to, a composition comprising a compound of Formula I and one or more therapeutic agent(s) together in the same pharmaceutical composition, or the compound of Formula I and one or more therapeutic agent(s) in a separate form, e.g. in the form of a kit.

In some embodiments, a compound of the present invention is an isotopically labelled compound. An "isotopically labelled compound" as used herein refers to a compound in which at least one atomic position is enriched in a specific isotope of the designated element to a level which is significantly greater than the natural abundance of that isotope. For example, one or more hydrogen atom positions in a compound can be enriched with deuterium to a level that is significantly greater than the natural abundance of deuterium, for example, enrichment to a level of at least 1%, preferably at least 20% or at least 50%. Such a deuterated compound may, for example, be metabolized more slowly than its non-deuterated analogue, and therefore exhibit a longer half-life when administered to a subject (Annual Reports In Medicinal Chemistry, Vol. 26, 2011, Chapter 24 - Deuterium in Drug Discovery and Development, pages 403-417). Such compounds can be synthesized using methods known in the art, for example, by employing deuterated starting materials. Unless stated to the contrary, isotopically labelled compounds are pharmaceutically acceptable.

The present invention is explained in greater detail in the following non-limiting examples.

EXAMPLES

The reaction schemes described below are intended to provide a general description of the methodology employed in the preparation of the compounds of the present invention. The examples provided herein are offered to illustrate but not limit the compounds of the present invention, as well as the preparation of such compounds and intermediates

All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be routinely prepared by procedures described in the literature, for example, Houben-Weyl “Science of Synthesis” volumes 1-48, Georg Thieme Verlag, and subsequent versions thereof.

A reaction may be carried out in the presence of a suitable solvent or diluent or of mixture thereof in a manner known to those skilled in the art of organic synthesis. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. A reaction may also be carried out, if needed, in the presence of an acid or a base, with cooling or heating, for example in a temperature range from about -30 °C to about 150 °C. In some embodiments, a reaction is carried out in a temperature range from about 0 °C to about 100 °C, and more particularly, in a temperature range from room temperature to about 80 °C, in an open or closed reaction vessel and/or in the atmosphere of an inert gas, for example nitrogen.

Abbreviations aq. Aqueous br broad d doublet

DCM dichloromethane

DIPEA N,N-Diisopropylethylamine

DMSO dimethylsulfoxide

EtOAc ethyl acetate

EtOH ethanol g gramme h hour(s)

H₂ hydrogen

KOH Potassium Hydroxide

LCMS liquid chromatography and mass spectrometry M molar

MeCN acetonitrile

MeOH methanol

MS mass spectrometry

NaHCO₃ sodium hydrogencarbonate

NaOMe sodium methoxide

NH₄CI ammonium chloride mg milligram min(s) minute(s) ml milliliter m mol mmol millimole

MTBE methyl tert-butyl ether

Na₂SO₄ sodium sulfate pet petroleum sat. saturated tert tertiary

Example 1

Preparation of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid

(R)-tert-butyl 3-(2-ethoxyphenoxy)piperidine-1-carboxylate:

Diisopropyl azodi carboxyl ate (115 g, 0.56 mol) was slowly added to a solution of 2- ethoxyphenol (60 g, 0.435 mol), (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (50 g, 0.478 mol) and triphenyl phosphine (150 g, 0.56 mol) in Toluene (600 mL) at room temperature. After completion, the reaction mixture was concentrated under reduced pressure, diethyl ether added, the resulting mixture then filtered and the solid further washed with diethyl ether. The filtrate was concentrated and purified by column chromatography, eluening with 0-20% pet ether and ethyl acetate to give the titled compound 55 g (39 % yield) as a liquid. (R)-3-(2-ethoxyphenoxy)piperidine:

Trifluroacetic acid (100 mL) was slowly added to a solution of (R)-tert-butyl 3-(2- ethoxyphenoxy)piperidine-1-carboxylate (55 g, 0.17 mol) in dichloromethane (550 mL) at room temperature After 16h the reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution added and the mixture extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulphate, filtered and concentrated to give the titled compound 35 g (92 % yield) as solid.

(R)-ethyl 2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylate:

Triethylamine (26 mL, 0.18 mol) and ethyl 2-chloropyrimidine-5-carboxylate (18.5 g, 0.1 mol) were added to a solution of (R)-3-(2-ethoxyphenoxy)piperidine (20 g, 0.09 mol) in DMF (200 mL) and the resulting mixture stirred at 110 °C for 16 h. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate. The combined the organic layers were washed with cold water, brine, dried over anhydrous sodium sulphate, filtered and concentrated.. The crude product was purified by silica gel column chromatography eluting with 0-10 % pet ether and ethyl acetate to give the titled compound 25 g (75% yield) as a liquid.

(R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid:

A solution of lithium hydroxide (8.1 g, 0.335 mol) in water (125 mL) was added to a solution of (R)-ethyl 2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylate (25 g, 0.067 mol) in THF (125 mL). After 48h the reaction mixture was concentrated under reduced pressure, acidified with con. HCl, the precipitate filtered, washed with water and dried under vacuum to give the titled compound 20 g (75% yield) as solid. Example 2

Sodium 4-((2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5- carboxamido)methyl)-3-methylbenzenesulfinate

(R)-N-(4-bromo-2-methylbenzyl)-2-(3-(2-methoxyphenoxy)piperidin-1-yl)pyrimidine-5- carboxamide:

Borane-THF solution (65 ml, 0.065 mol) was added to a solution of 4-bromo-2- methylbenzonitrile (2.5 g, 0.013 mol) in THF (5 mL) in a sealed tube. The resulting mixture was stirred at 70 °C for 16 h, then quenched with methanol and evaporated to dryness to give crude (4-bromo-2-methylphenyl)methanamine (2.2 g), which was used in the next step without further purification.

DIPEA (2 mL, 0.015 mol), followed by EDCI. HCl (0.84 g, 0.0045 ) were added to a solution of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (1 g, 0.003 mol), (4-bromo-2-methylphenyl)methanamine (0.6 g, 0.003 mol) and HOBt (0.6 g, 0.0045 mol ) in DMF (20 mL) at rt. After 16h the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were then washed with cold water, brine solution and purified by silica gel column chromatography, eluting with 0-30 % pet ether in ethyl acetate to give the titled compound (800 mg, 35% yield).

(R)-methyl 3-(4-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido) methyl)- 3 -methylphenyl sulfonyl)propanoate :

Cu(I)I (0.87 g, 0.0046 mol) was added to a solution of (R)-N-(4-bromo-2-methylbenzyl)-2-(3- (2-methoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamide (1.2 g, 0.0022 mol), sodium 3- methoxy-3-oxopropane-1-sulfmate (0.8 g, 0.0046 mol ) and L-proline (1.05 g, 0.0092 mol ) in DMSO (12 mL) at rt. The resulting mixture was then warmed to 130 °C and stirred for a further 16 h. The reaction mixture was portioned with water and ethyl acetate before being filtered through celite. The combined organic layers were washed with cold water, washed with brine and purified by silica gel column chromatography, eluting with 0-70% pet ether and ethyl acetate to give the titled compound (410 mg, 30% yield) as a solid.

Sodium 4-((2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-3- methylbenzenesulfinate:

NaOMe (5 ml, 0.005 mol, 1M in methanolic solution was freshly prepared from 30 % NaOMe methanolic w/v solution) was added to a suspension of (R)-methyl 3-(4-((2-(3-(2- ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-3- methylphenylsulfonyl)propanoate (0.26 g, 0.0004 mol) in methanol (3 mL) at 0 °C. After warming to rt the reaction mixture was stirred for a further 5 h, concentrated under reduced pressure, the residue triturated with diethyl ether and washed with n-pentane to afford the titled compound as a solid (0.21 g, 66 % yield).

Example 3

Potassium 4-((2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5- carboxamidolmethyl)benzenesulfinate

(R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(3-(methylsulfonyl)benzyl)pyrimidine-5- carboxamide:

Triethylamine (4.8 mL, 0.035 mol) and then EDCI.HCl (2.83 g, 0.0165mol) were added to a solution of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (4 g, 0.01 lmol), HOBt (2.2 g, 0.0165 mol) and (3 -(methyl sulfonyl)phenyl)methanamine (1.56 g, 0.0114 mol) in DMF (40 mL) at rt.. After 16h the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with cold water, brine solution, dried over anhydrous sodium sulphate, filtered and concentrated to dryness. The crude compound was purified by silica gel column chromatography eluting with 0-40 % pet ether and ethyl acetate to give the titled compound (3.5 g, 59% yield) as a solid.

Potassium 4-((2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5- carboxamido)methyl)benzenesulfmate:

l-(bromomethyl)-2,4-difluorobenzene (2.82 g, 0.0137 mol) and potassium tert-butoxide (7.0 g, 0.035 mol) was added a stirred solution of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(3- (methylsulfonyl)benzyl)pyrimidine-5-carboxamide (3.5 g, 0.0068 mol) in dry THF (35 mL) at -78 °C. After lh the reaction mixture was quenched with water, washed with ethyl acetate, the aqueous layer lyophilized and the crude compound purified by SFC (Supercritical Fluid Chromatography) to give the titled compound (0.29 g, 8.6%).

Example 4

Potassium 3-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1- yl)nicotinamido)methyl)benzenesulfinate:

(R)-ethyl 2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylate:

Triethylamine (12.6 ml, 0.095 mol) and ethyl 2-chloropyrimidine-5-carboxylate (6.5 g, 0.038 mol) were added to a solution of (R)-3-(2-ethoxyphenoxy)piperidine (7 g, 0.031 mol) in MeCN (200 mL). The resulting mixture was stirred at 90 °C for 16 h. The reaction mixture was quenched with water, extracted with ethyl acetate, the combined organic layers washed with water, brine, dried over anhydrous sodium sulphate, filtered and evaporated to dryness. The crude compound was purified by silica gel column chromatography eluting with 0-10 % pet ether in ethyl acetate to give the titled compound (7 g, 75% yield) as a liquid.

(R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid;

Sodium hydroxide solution (3.1 g, 0.08 mol) in water (35 mL) was added to a solution of (R)- ethyl 2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylate (7 g, 0.019 mol) in THF (35 ml) and the resulting reaction mixture was stirred for 48 hours at 60 °C. The reaction mixture was concentrated, acidified with cone. HCl, the precipitate isolated by filtration, washed with excess of water and dried under vacuum to give the titled compound (5 g, 75%) as a solid.

EDCI.HCl (0.7 g, 0.004 mol) and HOBt (0.6 g, 0.004 mol) were added to a solution of (3- (methylsulfonyl)phenyl)methanamine (1 g, 0.006 mol) and (R)-2-(3-(2- ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (1 g, 0.003 mol), triethylamine (2 mL, 0.008 mol) in DMF (40 ml) at rt. After 16 h the reaction mixture was quenched with water extracted with ethyl acetate, the combined organic layers washed with cold water, brine solution, dried over anhydrous sodium sulphate, filtered and concentrated completely. The crude compound was purified by silica gel column chromatography eluting with 0-60 % pet ether in ethyl acetate to give the titled compound (1.0 g, 57% yield) as a solid.

Potassium 3-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1- yl)nicotinamido)methyl)benzenesulfmate:

l-(bromomethyl)-2,4-difluorobenzene (5.66 g, 0.0275 mol) and potassium tert-butoxide (7.0 g, 0.035 mol) were added to a stirred solution of (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N- (3-(methylsulfonyl)benzyl)nicotinamide (7 g, 0.0137 mol) in dry THF (35 ml) at -78 °C. After lh the reaction mixture was quenched with water, washed with ethyl acetate, the organic layer separated and the aqueous layer was lyophilized before being purified by SFC (Supercritical Fluid Chromatography) to give the titled compound (0.210 g, 3 % yield).

Example 5

Sodium 3-((2-((R)-3-(2-ethoxyDhenoxy)piperidin-1-yl)pyrimidine-5- carboxamido)methyl)-4-methoxybenzenesulfinate

(R)-N-(5-bromo-2-methoxybenzyl)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5- carboxamide:

Borane-THF solution (120 mL, 0.120 moL) was added to a solution of 5-bromo-2- methoxylbenzonitrile (5 g, 0.024 mol) in THF (10 mL) in a sealed tube. The resulting mixture was stirred at 70 °C for 16 h, then quenched with methanol and evaporated under reduced pressure to give the crude titled compound (4.7g) as a solid, which used in next step without further purification.

DIPEA (5 mL, 0.037 mol) and then EDCI.HCl (2.8 g, 0.015 ) were added to a solution of (R)- 2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (3.7 g, 0.0073 mol), (5- bromo-2-methoxylphenyl)methanamine (2.5 g, 0.0073 mol) and HOBt (2.0 g, 0.015 mol) in DMF (37 mL) added at rt. After 16h the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were combined, then washed with cold water, brine solution and purified by silica gel column chromatography eluting with 0-30 % pet ether and ethyl acetate to give the titled compound (1.2 g, 30% yield).

(R)-methyl 3-(4-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido) methyl)-

3 -methoxyphenyl sulfonyl )propanoate :

Cu(I)I (0.6 g, 0.003 mol) was added to a solution of (R)-N-(5-bromo-2-methoxybenzyl)-2-(3- (2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamide (800 mg, 0.0015 mol), sodium 3- methoxy-3-oxopropane-1-sulfmate (0.5 g, 0.003 mol) and L-proline (0.7 g, 0.006 mol) in DMSO (12 mL) in it and the resulting mixture was warmed to 130 °C. After 16 h reaction mixture was portioned with water and ethyl acetate then filtered through celite. The combined organic layers were washed with cold water, brine solution and purified by silica gel column chromatography eluting with 0-70 % pet ether and ethyl acetate to give the titled compound (410 mg, 30% yield).

Sodium 3-((2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4- methoxybenzenesulfmate:

NaOMe (4 mL, 0.004 mol, 1M in methanolic solution, freshly prepared from 30 % NaOMe methanolic w/v solution) was added to the stirred solution of (R)-m ethyl 3-(4-((2-(3-(2- ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-3- methoxyphenylsulfonyl)propanoate (0.21 g, 0.0003 mol) in methanol (3 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for a further 5 h. The reaction mixture was concentrated under reduced pressure, the residue triturated with diethyl ether and then washed with n-pentane (10 mL) to afford the titled compound as a solid (0.12 g, 67 % yield).

Example 6

Assessing Metabolite Formation

The compound is incubated with liver hepatocytes (for example primary human hepatocytes) in an incubator at 37 °C. The reaction is stopped at 15, 30, 60, 90, 120 min by precipitating a sample of incubation mixture with acetonitrile. The precipitated sample is subjected to subsequent analysis by HPLC and mass spectrometry to ascertain which metabolites are formed. The analysis may show that the compound is oxidized to provide hydroxy derivatives, but that there is no presence of acyl-glucuronide like metabolites in which a glucuronide group has been added to the sulfmic acid functionality.

Example 7

In-vitro assessment of lipogenesis in HepG2 cells

Human Adherent HepG2 hepatome cell line from ATCC was put in culture and grown in Eagle’s Minimum Essential Medium, supplemented with foetal bovine serum (10%) and glucose at 4,5 g/1. Cells were cultured on a 75 cm2 culture flask at 37°C in 5% CO2-air and allowed to grow. Once the cells reached 70% to 80% confluence, the cells were rinsed with PBS solution to remove all traces of the serum which contained trypsin inhibitor, and then released with a 0.25% (w/v) Trypsin-0.53 mM EDTA solution. The suspension of released cells were centrifuged and suspended in the appropriate volume of culture medium to reach a concentration of 5 x 10⁵ cells/ml before being inoculated in a 12-well plate. Twenty-four hours later, the medium was changed for a low lipogenic media (low glucose, without FBS) for 18 hours (overnight). Following the starvation step, the cells were inoculated with a high lipogenic medium (high glucose, high acetate and insulin) containing the DGAT1 inhibitor, PF04620110. The hepatocytes were then treated with corresponding compounds (vehicle, positive control or different concentrations of the compounds of Examples 2, 3, 4 and 5. Each condition was repeated in triplicate.

Two hours after the addition of the different compounds, [1-¹⁴C]-acetate was added to the wells for an additional 4 hours. Following this period, the medium from each well was then gently removed and cells were washed twice with PBS. Cells were scraped in 400 μl of PBS. This volume was divided into two tubes; one for protein quantification (100 μl) and one for lipids extraction (300 μl) and put at -20 °C to improve the lysis of cells.

Lipid extraction was performed using the 300 μl obtained from the scrapping step in which 100 μl of the culture medium was added. The extraction was performed with the addition of 1.6 ml of a mix of chloroform/methanol (2:1) and vortex for 10 minutes. The tube was centrifuged, at 15,000 x g for 5 minutes. The organic phase (lower phase) was collected, evaporated under nitrogen and was resolubilized in 50 μl of a mix of chloroform/methanol. One centimeter of thin-layer chromatography solvent was added to the TLC chamber 20 minutes before loading the samples on the plate. An aliquot of 30 μl of the extract was loaded on a thin- layer chromatography plate, along with a triglyceride standard, and allowed for migration to 1 cm of the top (approx. 45 minutes). The TLC plate was dried under the hood and stained in a clean TLC chamber containing iodine stones in the bottom of the chamber. The TLC plate was put in a closed plastic bag and scanned. Each triglyceride spots were scratched and solubilized in 10 mL in a scintillation cocktail (CytoScint, MP Biochemical, USA) to measure the radioactivity in the triglycerides fraction. The results were normalized by protein content and by the amount of radioactivity in each well and final results are expressed as relative values respect to the vehicle condition taken as 100 % of incorporation.

Table 1

Table 1 shows the effect of the compounds of examples 2, 3, 4 and 5 on triglyceride synthesis in HepG2 cells. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

THAT WHICH IS CLAIMED IS:

1. A compound having a structure of Formula I:

X is N or CH; R₂ is H, C₁-C₄alkyl or C₃-C₆cycloalkyl;

or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.

3. The compound of any one of claims 1-2, wherein the compound reduces liver triglycerides in the liver and/or plasma of a subject, optionally wherein the compound reduces liver triglycerides in the liver and/or plasma of the subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% or more.

4. The compound of any one of claims 1-3, wherein the compound reduces cholesterol in the liver and/or plasma of a subject, optionally wherein the compound reduces cholesterol in the liver and/or plasma of the subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%, or more.

5. The compound of any one of claims 1-4, wherein the compound is metabolised via a cyp oxidation pathway upon administration to a subject.

6. The compound of any one of claims 1-5, wherein the compound is not metabolised via acyl-glucuronidation upon administration to a subject.

7. A pharmaceutical composition comprising a compound of any one of claims 1- 6 and a pharmaceutically acceptable carrier.

8. A compound of any one of claims 1-6 or a pharmaceutical composition of claim 7, for use in medicine.

9. A method of inhibiting diacylglycerol O-acyltransferase (DGAT2), the method comprising administering to a subject a compound of any one of claims 1-6 or the pharmaceutical composition of claim 7.

10. A method of treating and/or preventing a disease or disorder in which diacylglycerol O-acyltransferase (DGAT2) plays a role, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-6 or the pharmaceutical composition of claim 7.

11. The method of claim 10, wherein the disease or disorder is T1D, T2D, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, obesity, eating disorders, excessive sugar craving, dyslipidemia, hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, low HDL cholesterol, hyperinsulinemia, NAFLD, steatosis, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, HFI, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer's Disease, schizophrenia, impaired cognition, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and irritable bowel syndrome.