EP4370519A1

EP4370519A1 - 5,6,7,8-tetrahydro-2,6- and 2,7-naphthyridine derivatives for use in the treatment of diseases responsive to citrate transporter modulation

Info

Publication number: EP4370519A1
Application number: EP22751057.5A
Authority: EP
Inventors: Grit Zahn; Robert Edward ARNOLD; Julia Marie Bainbridge; Giacomo Beretta; Steven Mark Bromidge; Adam James Davenport; Emily Catherine DOCTON; Verity Nicole DOWLING; Stuart Robert FLANAGAN; Laura Jane GLEAVE; Mark Anthony KERRY; Colin Haig MACKINNON; Cristina Lecci; Paula Cristina DE AGUIARPENA; Kevin Michael Thewlis; Patrick Ross WALKER; Christopher John Yarnold
Original assignee: Eternygen Uk Ltd
Current assignee: Eternygen Uk Ltd
Priority date: 2021-07-14
Filing date: 2022-07-14
Publication date: 2024-05-22
Also published as: WO2023285583A1

Abstract

The invention relates to a compound according to general formula (I), which acts as an inhibitor of a citrate transporter, e.g. a sodium-coupled citrate transporter such as INDY (SLC13A5); to a pharmaceutical composition containing one or more of the compound(s) of the invention; to a combination preparation containing at least one compound of the invention and at least one further active pharmaceutical ingredient; and to uses of said compound(s), including the use as a medicament as well as the use in the treatment and/or prevention of a condition associated with the activity of a citrate transporter such as metabolic diseases and age related diseases.

Description

5,6,7,8-TETRAHYDRO-2,6- AND 2,7-NAPHTHYRIDINE DERIVATIVES FOR USE IN THE TREATMENT OF DISEASES RESPONSIVE TO CITRATE TRANSPORTER MODULATION

FIELD OF THE INVENTION

The present invention relates to compounds having utility in the treatment of diseases responsive to citrate transporter modulation. More specifically, the present invention relates to a compound according to general formula (I), which acts as an inhibitor of a citrate transporter, e.g. a sodium- coupled citrate transporter such as SLC13A5 (also referred to as Indy or NaCT); to a pharmaceutical composition containing one or more of the compound(s) of the invention; to a combination preparation containing at least one compound of the invention and at least one further active pharmaceutical ingredient; and to uses of said compound(s), including the above mentioned use as a medicament as well as the use in the treatment and/or prevention of a condition associated with the activity of a citrate transporter such as metabolic diseases and age related diseases.

BRIEF DESCRIPTION OF THE RELATED ART

Energy balance and insulin action are both closely related to life span. Caloric excess leads to obesity and insulin resistance to an increased mortality. Caloric restriction reduces adiposity and increases lipid oxidation, insulin sensitivity, and mitochondrial biogenesis. In addition, caloric restriction reverses obesity, type 2 diabetes, delays aging, and prolongs life in many species, including primates (Hursting et al, 2003, Amur Rev. Med. 54, p. 131-152; Lopez-Lluch et al, 2006, Proc. Natl. Acad. Sci. U. S. A 103, p. 1768-1773; Hunt et al, 2006, Ageing Res. Rev. 5, p. 125-143; Fontana and Klein 2007, JAMA 297, p 986-994; Colman et al, 2009, Science 325, p. 201-204).

Beneficial effects of caloric restriction are mediated by decreased plasma concentrations of anabolic hormones and growth factors, i.e. insulin and insulin like growth factors (Fontana and Klein 2007, JAMA 297, p 986-994; Colman et al, 2009, Science 325, p. 201-204). Reduced expression of the Indy (for / am Not Dead, Tet) gene in D. melanogaster and C. elegans has been shown to promote longevity in a manner akin to caloric restriction, however the cellular mechanism by which reduced expression of Indy leads to increased survival is unknown (Rogina et al, 2000, Science 290, p. 2137-2140; Fei et al, 2004, Biochem. J. 379, p. 191-198; Fei et al, 2003, J. Biol. Chem. 278, p. 6136-6144; Wang et al, 2009, Proc. Natl. Acad. Sci. U. S. A 106, p. 9262-9267).

Indy encodes in D. melanogaster a non-electrogenic dicarboxylate and citrate transporter (Knauf et al, 2006, Biochem. J. 397, p. 25-29; Knauf et al, 2002, Proc. Natl. Acad. Sci. U. S. A 99, p. 14315-14319) and it is mainly expressed in the fat body, mid gut, and oenocyte (Rogina et al, 2000, Science 290, p. 2137-2140), the major organs of intermediary metabolism in flies. In mammals, the gene product of SLC13A5, the sodium-coupled citrate transporter NaCT (mINDY), shares the highest sequence and functional similarity with INDY of D. melanogaster (Inoue et al, 2002, Biochem. J. 367, 313-319, WO 2004/048925) and it is predominantly expressed in liver cells (Inoue et al, 2002, J. Biol. Chem. 277, p. 39469-39476; Knauf et al, 2006, Biochem. J. 397, p. 25-29; Knauf et al, 2002, Proc. Natl. Acad. Sci. U. S. A 99, p. 14315-14319; Gopal et al, 2007, Am. J. Physiol Gastrointest. Liver Physiol 292, G402-G408, WO 2004/048925).

Indy and its mammalian homolog mINDY (Slcl3a5, NaCT) are transporters of tricarboxylic acid (TCA) cycle intermediates. Basically, INDY handles the uptake of citrate via the plasma membrane into the cytosol where citrate is used for the synthesis of fatty acids and cholesterol (Inoue et al, 2002, J. Biol. Chem. 277, p. 39469-39476, Birkenfeld et al, 2011, Cell Metab 14, p. 184-195). In the liver, cytosolic citrate is known as the prime carbon source for the synthesis of fatty acids, triacylglycerols, cholesterols and low-density lipoproteins (Willmes and Birkenfeld 2013 Comput Struct Biotechnol J. 2013 6:7). Moreover citrate leads to the activation of fatty acid synthesis and affects glycolysis and B-oxidation (Spencer and Lowenstein 1962 J Biol Chem 237: 3640-48, Bloch and Vance 1977 Ann Rev Biochem 46:263-298, Ruderman et al. 1999 Am J Physiol 276: El-18). Main organs for fatty acid synthesis are the liver and white adipose tissue and fatty acid synthesis has been shown to directly correlate with cytosolic citrate concentrations, partially depending on the direct import across the plasma membrane by mINDY (Inoue 2002 Biochem Biophys Res Comm 299:465 — 471, Gopal et al, 2007, loc. cit).

Birkenfeld and colleagues described in 2011 that deletion of the mouse homologue of INDY (mlndy) reduces citrate uptake into the liver and sterol and fatty acid synthesis in hepatocytes. Furthermore, it reduces adiposity, prevents lipid accumulation into liver and skeletal muscle and increases insulin sensitivity under high fat diet (HFD) conditions and during aging in mlndy knock-out mice. Loss of mINDY augments energy expenditure associated with increased hepatic fat oxidation and attenuates hepatic lipogenesis (Birkenfeld et al, 2011, Cell Metab 14, p. 184- 195). Furthermore, Pesta and colleagues (Pesta et al. 2015 Aging 7(12), p. 1086-93) showed that a hepatic knockdown of mINDY in rats under HFD improved metabolism by reducing fasting plasma insulin, hepatic glucose production, liver fat accumulation and improving insulin sensitivity. Additionally, Rong et al. showed recently (Rong et al. 2015 Conference abstract Keystone Symposia: Obesity and the Metabolic Syndrome/Liver Metabolism March 2015) that hepatic knockdown of mINDY in mice improved several metabolic parameters such as fed glucose and insulin sensitivity assessed by HOMA-IR, reduced the body weight in animals under high fat diet mainly in liver and adipose tissue weights and reduced liver triglycerides. Expression analysis of INDY in monkey and human liver samples showed that INDY expression is increased in human obesity and fatty liver as well as in monkeys after 2 years high fat diet (Loeffelholz et al. 2013 ADA poster 1868-P)

Reducing INDY expression by knockout and knockdown has been proven beneficial in terms of metabolic regulation and/or life span in all species tested so far. Therefore, mINDY is a drug target for the treatment of metabolic disease, such as obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatis (NASH) and type 2 diabetes, but also hyperlipidemia and hypercholesterolemia (Birkenfeld et al, 2011, Cell Metab 14, p. 184-195, Pesta et al. 2015 Aging 7(12), p. 1086-93, Mancusso et al, 2012, Nature 491, p. 622-626; Frankel and Rogina, 2012, Front Genet 3, p. 13; Schindler, 2012, Ther Adv Endocrinol Metab 3, p. 51-53, WO 2004/048925, Neuschafer-Rube Diabetes. 2014 63(3), p. 1048-57, Willmes 2016 Aging 2, p. 208-9). It can be expected that an inhibitor of mINDY function reducing the uptake of extracellular citrate to the liver will have similar beneficial therapeutic effect as reduction of INDY expression by knockout and knockdown mINDY (WO 2004/048925).

In fact, a very recent work from Huard et al. 2015 (Huard et al. 2015 Sci Rep. 5, p. 17391) has proven this hypothesis with a small molecule citrate analogue and have shown an improvement of metabolism via reduction of hepatic citrate uptake. In this study the inhibition of mINDY recapitulates the main features previously reported for mINDY knockout mice specifically reduction in hepatic lipid production and in plasma glucose levels following oral glucose tolerance test. It has been shown that inhibition of mINDY simultaneously reduce hepatic glucose and lipid production. However, based on the chemical properties and the resulting very high effective doses this molecule can be only considered as a tool compound but not drug like molecule for therapeutic treatment of metabolic diseases

Functionally, loss of mlndy also mimics many aspects of calorically restriction. Moreover, in flies and nematodes, both, reduced expression of Indy, as well as caloric restriction, prolong life span (Rogina et al, 2000, Science 290, p. 2137-2140; Fei et al, 2004, Biochem. J. 379, p. 191-198) and AMPK has been shown to be the mediator of longevity in response to most dietary restriction regimens in C.elegans (Schulz et al, 2007, Cell Metab 6, p. 280-293; Greer et al, 2009, Aging Cell 8, p. 113-127; Mair et al, 2011, Nature 470, p. 404-408). In addition, caloric restriction does not increase life span further in flies with reduced Indy expression (Toivonen et al, 2007, PFoS.

Genet. 3, e95; Wang et al, 2009, Proc. Natl. Acad. Sci. U. S. A 106, p. 9262-9267), pointing to similar underlying mechanisms in both conditions. In fact, a very recent work by Schwarz and colleagues (Schwarz et al. 2015 Aging 7(8), p. 553-67) has been shown that knockdown of Indy in c. elegans extends life span by inducing AMPK, whereas the effect was abolished in worms without functional AMPK. This indicates that the life extending effect of reducing mINDY is at least in part mediated by AMPK. These data suggest that mlndy may be a key mediator of the beneficial effects of dietary energy restriction. Since prolonged caloric restriction is very difficult to achieve in humans, the observations raise the tantalizing possibility that modulating the levels or function of mlndy could lead to some of the health promoting effects of calorie restriction, without requiring severe caloric restriction.

Very recent work by De Costa Goncalves and colleagues showed that loss of mlndy also affects blood pressure (De Costa Goncalves Clin AutonR.es 2014, 24:199-243 abstract 40). Deletion of mINDY reduces blood pressure in animals fed a HFD. These finding raises the possibility that mINDY is part of the signalling pathway linking excessive caloric intake to increased blood pressure. Therefore, it seems plausible to speculate that mINDY might be an interesting target for the treatment of hypertension.

Another recent work by Li and colleagues showing the link between mINDY and drug induced hepatic steatosis (Li et al. 2015 Mol Pharmacol. 87(4):674-82). Knockdown of INDY by antisense oligonucleotides leads to significant decrease of rifampicin induced lipid accumulation in HepG2 via PXR dependent pathway. These data were confirmed by Neuschafer-Rube et al. (Neuschafer- Rube et al. 2015 Toxicology 337, p. 1-9). This work showed the link between mINDY and drug induced hepatic steatosis in vitro by benzo[a]pyrene induced lipid accumulation in primary rat hepatocytes (via arylhyrocarbon receptor). Therefore, mINDY is an interesting target for the treatment of drug induced hepatic steatosis.

Importantly, all known studies to reduce INDY expression in vivo in mice as well as rats showed consistently a reduction of liver fat accumulation in animals under high fat diet (Birkenfeld et al, 2011, Cell Metab 14, p. 184-195, Pesta et al. 2015 Aging 7(12), p. 1086-93, Rong et al. 2015 Conference abstract Keystone Symposia: Obesity and the Metabolic Syndrome/Liver Metabolism March 2015, Huard et al. 2015 Sci Rep. 5, p. 17391, Willmes 2016 Aging 2, p. 208-9) further supporting the hypothesis that mINDY is a drug target for the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

To date, no pharmaceutically effective and specific therapeutic agents with drug-like properties to modulate mINDY function or expression are known, except an antisense oligonucleotide as tool compound. Interestingly, the stimulation of human mINDY activity by Lithium was described in concentrations that are observed during the treatment of bipolar disorders. Aluvila and colleagues disclosed compounds, which inhibit another but not mINDY related citrate transporter, the citrate transport protein (CTP) on the inner mitochondrial membrane (Aluvila et al, 2010, Mol Pharmacol 77, p. 26-34; Irwin and Shoichet, 2005, J Chem Inf Model 45, p. 177-182). Moreover, a compound with selectivity for mINDY over CTP was identified by Sun and co-workers (Sun et al. 2010, Mol Cell Pharmacol 2, p. 101-110). This compound shows inhibitory activity in a millimolar range in a cell free assay. However, in a cellular citrate uptake assay this compound seems to activate Indy.

Pajor and colleagues disclosed an inhibitor of Indy in a high micromolar range (Pajor et al. Mol Pharmacol. 2007 November; 72(5), p. 1330-1336). But it seems that this compound activity is related to cytotoxic side effects. Furthermore, Ganapathy and colleagues disclosed a substrate analogue, hydroxy citrate, as an inhibitor of Indy in a high micromolar range (30-40% inhibition at O.lmM) (WO 2004/048925). However, in a cellular citrate uptake assay it was not possible to reproduce this data. A recent work by Colas and Co-workers (Colas 2015 Biochemistry 54(31), p. 4900-8) used a combined modelling and virtual screening approach to find mINDY inhibitors.

One active compound has been found with an activity in mM range in a vitro assay. Finally,

Huard et al. (Huard et al. 2015 Sci Rep. 5, p. 17391) described a tool compound which was selective for mINDY with submicromolar activities in vitro. However, based on its characteristics and chemical properties very high doses (250 mg/kg bi-daily) are necessary to show a therapeutic effect in vivo. Therefore, this substrate analogue compound class seems to be not a suitable drug like molecule.

It is not known so far, whether such compounds can be used in therapeutic intervention. The high concentration needed to inhibit mINDY with these molecules or potential toxic side effects make it unlikely to become clinically relevant. The discovery of a more potent and specific compound modulating mINDY function could provide a useful tool to delineate the structure and function of mINDY and to become therapeutic drug to treat metabolic diseases. Ultimately, a putative inhibitor of mINDY holds the potential to induce the beneficial effects of caloric restriction, without requiring severe caloric restriction in mammals. (Willmes and Birkenfeld, 2013, Computational and Structural Biotechnology Journal. 6 (7))

Thus, in view of the deficits of the prior art compounds and the severe conditions associated with a pathophysiological uptake of extracellular citrate into the liver, both acute and chronic, there is a need for new inhibitors of citrate transporters such as Indy.

Citrate, in particular free circulating citrate in the blood plasma, also plays a role in bone metabolism as well as in mineral metabolism of other tissues, and it is well known that numerous pathological conditions, including, for example, osteoporosis and kidney stones, are associated with low citrate concentrations in blood plasma (often indicated by low citrate excretion). This was, for instance, clinically proven in studies where it was shown that patients with osteoporosis or kidney stones benefitted from a high citrate diet which enhanced the plasma citrate level and consequently urinary citrate excretion (reviewed by Phillips et al. 2015, Cochrane Database Syst Rev. 6;(10), CD010057; and Granchi et al. 2019, Nutrients ; 11 (11 , p. :2576). Citrate diet can therefore be a therapeutic option for diseases related to low plasma citrate, however, several gastrointestinal side effects, the risk of nocturnal decrease of urinary citrate and a 20% non responder rate (Mattie et al. 2005, Urol Res 33(2), p. 73; Philips et al. 2015, loc. cit. ; Leslie et al. 2022, StatPearls [Internet] Treasure Island (FL): StatPearls Publishing) indicate the need of an alternative method to increase plasma citrate levels and urinary citrate excretion. Examples of a disease or condition that is caused by low plasma citrate concentrations (hypocitricemia) and/or indicated by low urinary citrate excretion (hypocitraturia ) include: surgical stress (Costello et al. 1973 J Surg Res.15(3), p. 182; Costello and Franklin 2016, H SOA J Hum Endocrinol. 1(1), p. 005), osteoporosis (Tashjian and Whedon 1963 J Clin Endocrinol Metab 23, p. 1029), adrenocortical hyperactivity (Tashjian and Whedon 1963, loc. cit.), vitamin D deficiency (Tashjian and Whedon 1963, loc. cit.), ricket (Tashjian and Whedon 1963, loc. cit.), parathyroidectomy (Costello and Franklin 2016, loc. cit.), metaboloc acidosis (Costello and Franklin 2016, loc. cit.), glaucoma (Michalczuk et al. 2017 BMJ Paediatr Open 1(1), p. 23), bariatric surgery (Maalouf et al. 2010 J Urol 183, p. 1026), kidney stones (Granchi et al. 2019, loc. cit.), chronic kidney disease (Granchi et al. 2019, loc. cit.), primary hyperaldesteronism and postmenopause (Granchi et al. 2019, loc. cit.). As the liver is one of the major organs for citrate clearance from the blood (Costello and Franklin 2016, loc. cit.) the reduction of citrate uptake into the liver causes increased citrate concentration in the blood. This has been shown by Birkenfeld et al. in knockout mice (Birkenfeld et al., 2011, Cell Metabolism 14, p. 184) but more importantly also in human using metabolomics analysis of plasma samples from human subjects carrying homozygous loss of function mutation of Indy/slcl3a5 (Bainbridge et al. 2017, Molecular Genetics and Metabolism 121(4), p. 314; Milosavljevic et al. 2022, Metabolites 12(4), p. 351). These analyses proved the involvement of the citrate transporter INDY, and showed an up to three-fold increase of citrate level in plasma. Therefore, diseases related to low plasma citrate concentration can profit from INDY inhibition mediated increase of plasma citrate levels as well.

SUMMARY OF THE INVENTION

The present invention was made in view of the prior art and the needs described above, and, therefore, the object of the present invention is to provide new compounds according to general formula (I), including pharmaceutically acceptable salts, solvates, metabolites and prodrugs thereof, which act as inhibitors for the activity of citrate transporters, such as Indy, and therefore, are useful as agents for the treatment or prevention of diseases or conditions in which citrate transporters play a role, such as diseases or conditions in which citrate transporters participate, are involved in the etiology or pathology of the disease or condition, or contribute to at least one symptom of the disease or condition. Preferably, the compounds of general formula (I), or pharmaceutically acceptable salts, solvates, metabolites and prodrugs thereof, described herein have one or more improved properties, e.g. an improved pharmacokinetic and/or physiochemical property, including bioavailability, solubility, metabolic stability, and a LADME (liberation, absorption, distribution, metabolism, and excretion) property.

In one aspect, provided herein is a compound of the general formula (I):

R^1A is a hydrogen atom or deuterium atom;

R^1B is a hydrogen atom, deuterium atom, (Ci-C3)alkyl, or (C1-C3) haloalkyl group; or R^1A and R^1B are taken together with the carbon atom to which they are attached to form a cyclopropyl group;

R^1C is CN, CH₂CN, CH₂OCH₃, CH₂OCHF₂, CH₂OCF₃ or a cyclopropyl group;

R² is F, Cl, CH₃, OCH₃ or CHF₂;

R³ is CN or CHF₂;

X¹ is (CRⁿR¹²);

R¹¹ is, at each occasion independently, a hydrogen atom, deuterium atom, fluorine atom or

CH₃;

R¹² is, at each occasion independently, a hydrogen atom, deuterium atom, fluorine atom or

CH₃; m is 1 or 2, provided that m is 2 when n is 1 ;

X² is (CR²¹R²²);

R²¹ is, at each occasion independently, a hydrogen atom, deuterium atom, fluorine atom or

CH₃;

R²² is, at each occasion independently, a hydrogen atom, deuterium atom, fluorine atom or

CH₃; n is 1 or 2, provided that n is 2 when m is 1 ;

R^4A is, at each occasion independently, a hydrogen, deuterium, fluorine atom, chlorine atom, CH₃, (CH₂)OH, CN or (Ci) haloalkyl;

R^4B is, at each occasion independently, a hydrogen, deuterium, fluorine or chlorine atom, CH₃, (CH₂)OH, or (Ci) haloalkyl; o is 1, 2 or 3; A is an aryl group; or a mono- or bicyclic, partially unsaturated or aromatic heterocycle having 3 to 10 C atoms and 1 to 4 heteroatom(s) each, independently of one another, selected from N, O or S;

R⁵ is, at each occasion independently, a fluorine or chlorine atom, CH₃, CD₃, OCH₃,

(Ci) haloalkyl, O(Ci) haloalkyl

R^A and R^AA each, independently of one another, represents a hydrogen atom or CH3; p is 0, 1 or 2;

R⁶ represents a hydrogen atom, CN, OH, G, OG, Cyc, OCyc, Hce or OHce;

G represents a (Ci-C₆)alkyl group, in which (i) one C¾ group, or two non-adjacent C¾ groups, may be replaced by O, C(O), OC(O), C(0)0, C(0)NH, NH, NMe and/or by a CH=CH group; and/or in which (ii) 1 to 5 H atoms may, at each occasion independently, be replaced by a halogen atom, OH, CN, R^G1, OR^G1, Cyc, OCyc, Hce, or OHce;

Cyc represents a monocyclic, saturated or partially unsaturated, 3- to 6-membered cycloalkyl group, which is unsubstituted or may be mono-, di-, or tri substituted, at each occasion independently, by a halogen atom, OH, CN, =0, and/or R^G1;

Hce represents a monocyclic, saturated, partially unsaturated or aromatic heterocycle having 3 to 10 C atoms and 1 to 4 heteroatom(s) each, independently of one another, selected from N, O or S, which is unsubstituted or may be mono-, di- or trisubstituted, at each occasion independently, by a halogen atom, OH, CN, =0, and/or R^G1; and

R^G1 represents a (Ci-C3)alkyl, (C1-C3) haloalkyl, (C1-C3) hydroxyalkyl, or (Ci- C4) heteroalkyl group, and methods of uses thereof as described hereinafter and/or defined in the attached claims. Throughout the specification, groups and substituents of the compound of general formula (I) can be chosen by one skilled in the art to provide stable moieties and compounds. In some embodiments, presented herein are compounds selected from active metabolites, tautomers, pharmaceutically acceptable solvates, pharmaceutically acceptable salts or prodrugs of a compound of general formula (I).

In a further aspect, the present invention provides a pharmaceutical composition comprising at least one inhibitor for the activity of a citrate transporter, such as Indy, as described herein. In some embodiments, provided is a pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I). In some embodiments, the pharmaceutical composition also contains at least one pharmaceutically acceptable inactive ingredient, such as a carrier substance, excipient and/or adjuvant. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration, such as formulated as an aerosol, a cream, a gel, a pill, a capsule, a syrup, a solution, a transdermal patch or a pharmaceutical delivery device. In some embodiments, the pharmaceutical composition is a tablet, a pill, a capsule, a liquid, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, or a lotion. Pharmaceutical compositions described herein are administerable to a subject in a variety of ways by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), buccal, topical or transdermal administration routes.

In a further aspect; the present invention provides a combination preparation containing at least one compound of the invention and at least one further active pharmaceutical ingredient. In some embodiments, the at least one further active pharmaceutical ingredient is selected from the group comprising: a. anti-obesity agents selected from the group consisting of orlistat, lorcaserin, Phentermine, Topiramate, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine, 5-HT2c receptor agonists, Bupropion, Naltrexone, methionine aminopeptidase 2 inhibitors, GLP1 agonists; b. anti-diabetes agents comprising insulin, incretin mimetics, SGLT-2 inhibitors, DPPIV inhibitors, PPAR agonist, Glucokinase activator, MTP inhibitors, Glycogen phosphorylase inhibitors, DGAT-1 inhibitor, GLP1 agonists, dual GLPl/glucagon receptor agonists, triagonist for GLPl /glucose-dependent insulinotropic polypeptide/glucagon receptor; c. anti-NASH agents comprising insulin, incretin mimetics, statins, PPAR agonists, AMPK activators, FXR agonists, DGAT-2 inhibitors, DGAT-1 inhibitors, Bile- Acid Conjugates, methionine aminopeptidase 2 inhibitors, PDE4 inhibitors, inhibitors of acetyl-CoA carboxylase, inhibitors of ketohexokinase, inhibitors of ATP citrate lyase, GLP-1 agonist, dual GLPl/glucagon receptor agonists, triagonist for GLPl/glucose-dependent insulinotropic polypeptide/glucagon receptor, inhibitors of ASK-1, CCR2/CCR5 antagonist, inhibitors of SLC10A2, inhibitors of LOXL2, inhibitors of Galectin-3, inhibitors of caspase, FGF21, FGF19, inhibitors of CGRP, AOC3: Amine Oxidase, Copper Containing 3, inhibitors of DPP-4, THR-B agonists, anti-CD3 monoclonal antibody (mAbs), A3AR agonists, inhibitors of SGLT2, inhibitors of SGLT1, inhibitors for TGFB activation, anti-cannabinoid CD1 receptor antibody, antibody agonist of the b- Klotho/FGFRl c receptor complex, inhibitors of the inflammasome, ATP citrate lyase inhibitors, stearoyl-CoA desaturase inhibitors, fatty acid synthesis inhibitors; d. anti-dyslipidaemia agents comprising, statins, ApoB antisense oligonucleotides, PCSK9 inhibitors, Cholesterol-absorption inhibitors, Niacin, Bile-acid-sequestering resins, MTP inhibitors, Fibrates, CETP inhibitors, ATP citrate lyase inhibitors; e. anti-cancer agents comprising chemotherapeutic drugs; and f. anti aging drugs comprising vitamins. In some embodiments, at least one compound of the invention may be combined with at least one: anti-osteoporosis agent; the anti-osteoporosis agent may be selected from the group comprising vitamin D, calcium, calcitonine, bisphosphonates, estrogen, selective estrogen receptor modulators, parathyroid hormone and its analoga, RANKL inhibitors, anti-sclerostin antibody.

In yet a further aspect, the present invention relates to uses of the compound(s) of the invention, including the use as, or for the preparation of, a medicament. In some embodiments, provided herein is a compound, composition or preparation described herein for use in the treatment and/or prevention of a condition associated with the activity of a citrate transporter, including metabolic diseases, such as obesity and diabetes, in particular type 2 diabetes, and age related diseases. The compound of general formula (I) binds to citrate transporters, such as as Indy, and influences their activity. The compound may inhibit the activity of such a citrate transporter directly or allosterically. Allosteric inhibition or regulation means the regulation of the activity of a protein or enzyme by binding to one or more allosteric site(s) of said protein or enzyme, which allosteric site(s) is/are different from the active site(s) of the respective protein or enzyme.

In some embodiments, provided is a method comprising administering a compound of general formula (I), a pharmaceutical composition or combination preparation described herein, to a human with a diseases or condition that is citrate transporter meditated or citrate transporter dependent. The compound may be a compound of general formula (I), a mixture of compounds of general formula (i), or a pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof. In some embodiments, the human is already being administered one or more additional therapeutically active agents other than a compound of general formula (I). In some embodiments, the method further comprises administering one or more additional therapeutically active agents other than a compound of general formula (I).

In some embodiments, the citrate transporter is the gene product of Indy or a homologue thereof. The term “homologues” used in this disclosure refers to genes or proteins having similar or identical biological functions. The similarity or identity of the biological functions can be reflected by sequence similarity or identity (at either the amino acid or nucleotide level) of about 45%, about 70% or about 90%. Sequence similarity or identity (at either the amino acid or nucleotide level) within defined regions of the molecule or across the full-length sequence can be determined through sequence alignments using computer software programs such as BLAST, ALIGN, DNAstar and INHERIT which employ various algorithms to measure homology. A person skilled in the art is familiar with these alignment programs. Sequence regions that are homologous may be called conserved, consensus or canonical sequences and represent the most common choice of base or amino acid at each position. In some embodiments, the citrate transporter meditated or citrate transporter dependent disease or condition, or the condition associated with the activity of a citrate transporter, is: a. a metabolic disease selected from the group comprising insulin resistance, alcoholic and non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), obesity, type 1 diabetes, type 2 diabetes, dyslipidemia, hereditary diseases and metabolic syndrome; b. an eating disorder; c. a chronic liver disease; d. liver cancer and/or cancer related to obesity; e. an age related disease comprising atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension and neurodegenerative diseases like Alzheimer's disease; or f. drug induced hepatic steatosis.

In some embodiments, the citrate transporter meditated or citrate transporter dependent disease or condition, or the condition associated with the activity of a citrate transporter, is a disease or condition that is caused by low plasma citrate concentrations (hypocitricemia) and/or indicated by low urinary citrate excretion (hypocitraturia), and examples include one or more of surgical stress, osteoporosis, adrenocortical hyperactivity, vitamin D deficiency, ricket, parathyroidectomy, metaboloc acidosis, glaucoma, bariatric surgery, kidney stones, chronic kidney disease, primary hyperaldesteronism and postmenopause.

In some embodiments, described herein is a compound of general formula (I), a pharmaceutical composition or combination preparation described herein for use in a method of diagnosis of a citrate transporter meditated or citrate transporter dependent disease or condition, or a condition associated with the activity of a citrate transporter, including the diseases or conditions identified above. In some embodiments, the method of diagnosis is in vivo. In some embodiments, the method of diagnosis is in vitro or ex vivo.

In any of the aspects or embodiments disclosed herein, the mammal is preferably a human. In some embodiments, compounds, compositions or preparations described herein are administered to a human.

In some cases, compounds provided herein are used to diminish, reduce, or eliminate the activity of citrate transporters. In some embodiments, described herein is a method for altering the activity of citrate transporters in vitro or in vivo, said method comprising contacting a citrate transporter with at least one compound described herein, or a salt thereof, under conditions and in an amount sufficient to detectably diminish, reduce, or eliminate the activity of the citrate transporter. In some embodiments, the citrate transporter is contained in a cell, tissue or sample (e.g., a cell sample or tissue sample). In some embodiments, compounds or compositions described herein may be used in detection assays for localizing or detecting a citrate transporter in a cell, tissue or sample, and in some embodiments, such detection assays may use a detectably labelled compound, such as a compound of general formula (I), or a salt thereof, that is linked to a detectable label or functional moiety, such as a radio nucleotide, fluorophore or enzyme.

Articles of manufacture, which include packaging material, a compound of general formula (I) within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for reducing, diminishing or eliminating the effects of citrate transporters, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from a reduction or elimination of citrate transporter activity, are provided.

Still other objects, aspects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following description and examples. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1. Liver triglyceride measurement, ** p<0.01 vs vehicle

Figure 1 shows data for the measurement of triglyceride content in the liver after a 28 days treatment period in high fat diet animals. Animals were treated orally twice a day with compound 199 at three different doses (5, 15 and 50 mg/kg) or with the corresponding vehicle. Data shows the dose dependent reduction of liver fat deposition with a SLC13A5 inhibitor, with a statistically significant reduction for highest dose vs. vehicle. This data indicates amelioration of high fat diet induced steatosis and an improved hepatic lipid metabolism.

Figure 2. Plasma triglyceride measurement, * p<0.05 vs vehicle

Figure 2 shows data for the measurement of triglyceride level in blood plasma after a 28 days treatment period in high fat diet animals. Animals were treated orally twice a day with compound 199 at three different doses (5, 15 and 50 mg/kg) or with the corresponding vehicle. Data shows the dose dependent reduction of plasma triglycerides with a SLC13A5 inhibitor, with a statistically significant reduction for highest dose vs. vehicle. This data indicates amelioration of high fat diet induced hypertriglyceridemia and an improved overall lipid metabolism.

Figure 3. Plasma cholesterol measurement, ** p<0.01 vs low dose

Figure 3 shows data for the measurement of cholesterol level in blood plasma after a 28 days treatment period in high fat diet animals. Animals were treated orally twice a day with compound 199 at three different doses (5, 15 and 50 mg/kg) or with the corresponding vehicle. Data shows the dose dependent reduction of plasma cholesterol with a SLC13A5 inhibitor, with a statistically significant reduction for highest dose vs. low dose and a trend for reduction for highest dose vs. vehicle. This data indicates amelioration of high fat diet induced hypercholesterolaemia and an improved overall lipid metabolism.

Figure 4. Lipogenesis gene expression

Figures 4A and 4B show data for the measurement of mRNA expression levels of key genes involved in hepatic lipogenesis in liver tissue after a 28 days treatment period in high fat diet animals. Animals were treated orally twice a day with compound 199 at three different doses (5, 15 and 50 mg/kg) or with the corresponding vehicle.

4A. SREBF1 * p<0.05 vs low dose. The figure shows the dose dependent down regulation of gene expression of Sterol regulatory element-binding transcription factor 1 (SREBF1) also known as sterol regulatory element-binding protein 1 (SREBP-1), the master regulator for most genes for lipogenesis and typically upregulated with high fat diet feeding, with a statistically significant reduction for highest dose vs. low dose and a trend for reduction for highest dose vs. vehicle. This data indicates an overall reduction of lipogenesis gene expression and fits well with lower liver fat content and an improved overall lipid metabolism

4B. SCD1* p<0.05 vs vehicle. The figure shows the dose dependent down regulation of gene expression of stearoyl-CoA desaturase (SCD1) gene, typically upregulated with high fat diet feeding and always associated with liver fat deposition, with a statistically significant reduction for highest dose vs. vehicle. This data indicates a reduction of expression of a key lipogenesis gene and fits well with lower liver fat content and an improved overall lipid metabolism.

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses novel compounds according to general formula (I), which act as an inhibitor of a citrate transporter, e.g. a sodium-coupled citrate transporter such as INDY (also known as SLC13A5 or NaCT). In experiments performed on two different cellular systems of citrate uptake, HepG2 cells endogenously expressing human INDY (hSLC13A5) and HEK293 cells over-expressing mouse INDY, compounds of the invention showed significant inhibitory activity. This effect is thus attributed to the inhibition of INDY. Also, selectivity of the inhibitory activity within the SLC family of membrane transport proteins could be demonstrated by tests with two different cellular systems of succinate uptake, namely HEK293 cells over-expressing recombinant human SLC 13 A3 and HEK293 cells overexpressing recombinant human SLC13A2, where no inhibitory activity of the compounds of the invention was observed. The relevance of the inhibitory activity for utility in the treatment of diseases and/or conditions associated with or modulated by uptake of extracellular citrate was further demonstrated in a cell assay with HepG2 cells where it could be shown that the compounds of the invention had a considerable inhibitory effect on lipogenesis. Most importantly, the foregoing in vitro cell assay data could be confirmed under physiological conditions in vivo using diet-induced obese (DIO) mice, a well established research model to study high-fat diet-induced diabetes, and fatty liver where a dose dependent reduction of critical metabolites, e.g. liver triglycerides or plasma triglycerides and cholesterol, was observed. The results of these investigations are described in more detail in the section Examples below.

The compounds according to the invention, as defined hereinbefore or hereinafter, including pharmaceutically acceptable salts, prodrugs, and pharmaceutically acceptable solvates thereof, are therefore useful in the treatment or prophylaxis of diseases and/or conditions that are associated with or modulated by uptake of extracellular citrate into the liver, including, but not limited to, the treatment of metabolic and/or age related diseases. The compounds according to the invention, as defined hereinbefore or hereinafter, including pharmaceutically acceptable salts, prodrugs, and pharmaceutically acceptable solvates thereof, are further useful in the treatment or prophylaxis of diseases and/or conditions that are associated with or modulated by low citrate concentrations in the blood plasma (hypocitricemia), and/or indicated by low urinary citrate excretion (hypocitraturia), including, but not limited to, the treatment of osteoporosis and kidney stones.

In one aspect, provided herein is a compound of the general formula (I): or a salt thereof, wherein

R^1A is a hydrogen atom or deuterium atom;

R² is F, Cl, CH₃, OCH₃ or CHF₂;

R³ is CN or CHF₂;

X¹ is (CRⁿR¹²);

CH₃;

CH₃; m is 1 or 2, provided that m is 2 when n is 1 ;

X² is (CR²¹R²²);

CH₃;

CH₃; n is 1 or 2, provided that n is 2 when m is 1 ;

R^4B is, at each occasion independently, a hydrogen, deuterium, fluorine or chlorine atom, CH₃, (CH₂)OH, or (Ci) haloalkyl; o is 1, 2 or 3;

A is an aryl group; or a mono- or bicyclic, partially unsaturated or aromatic heterocycle having 3 to 10 C atoms and 1 to 4 heteroatom(s) each, independently of one another, selected from N, O or S;

R⁵ is, at each occasion independently, a fluorine or chlorine atom, CFF, CD₃, OCH₃,

(Ci) haloalkyl, O(Ci) haloalkyl or N ^ ^;

R^A and R^AA each, independently of one another, represents a hydrogen atom or CFb; p is 0, 1 or 2;

R⁶ represents a hydrogen atom, CN, OH, G, OG, Cyc, OCyc, Hce or OHce; G represents a (Ci-C₆)alkyl group, in which (i) one CH2 group, or two non-adjacent CH2 groups, may be replaced by O, C(O), OC(O), C(0)0, C(0)NH, NH, NMe and/or by a CH=CH group; and/or in which (ii) 1 to 5 H atoms may, at each occasion independently, be replaced by a halogen atom, OH, CN, R^G1, OR^G1, Cyc, OCyc, Hce, or OHce;

R^G1 represents a (Ci-C₃)alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) hydroxyalkyl, or (Ci- C4) heteroalkyl group.

For any and all of the embodiments, substituents are selected from among from a subset of the listed alternatives.

Compounds are usually described herein using standard nomenclature or the definitions presented below. For compounds having asymmetric centers, it should be understood that, unless otherwise specified, all of the optical isomers and mixtures thereof are encompassed. Compounds with two or more asymmetric elements can also be present as mixtures of diastereomers. In addition, compounds with carbon-carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified.

Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. It will be apparent that the compound of the invention may, but need not, be present as a hydrate, solvate or non- covalent complex. In addition, the various crystal forms and polymorphs are within the scope of the present invention, as are prodrugs of the compound of the invention. Recited compounds are further intended to encompass compounds in which one or more atoms are replaced with an isotope, i.e., an atom having the same atomic number but a different mass number. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include ⁿC, ¹³C, and ¹⁴C.

Compounds according to the formulas provided herein, which have one or more stereogenic center(s), have an enantiomeric excess of at least 50%. For example, such compounds may have an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%. Some embodiments of the compounds have an enantiomeric excess of at least 99%. It will be apparent that single enantiomers (optically active forms) can be obtained by asymmetric synthesis, synthesis from optically pure precursors or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.

The compound according to the invention is described herein using a general formula that includes variables such as, e.g. A, G, R^{1A C}, R², R³, R^{4A B}, R⁵, R⁶, Rⁿ-R¹², R²¹-R²², R^A _,R^AA, R^G1, and X'-X². Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R^*, the group may be unsubstituted, or substituted with 1 or 2 group(s) R^*, wherein R^* at each occurrence is selected independently from the corresponding definition of R^*. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds, i.e., compounds that can be isolated, characterized and tested for biological activity.

As used herein a wording defining the limits of a range of length such as, e. g., “from 1 to 5” means any integer from 1 to 5, i. e. 1, 2, 3, 4 and 5. In other words, any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range. For example, the term "C1-C3" refers to 1 to 3, i.e. 1, 2 or 3, carbon atoms; and the term "Ci-Ce" refers to 1 to 6, i.e. 1, 2, 3, 4, 5 or 6, carbon atoms. Further, the prefix "(C_x-y)" as used herein means that the chain, ring or combination of chain and ring structure as a whole, indicated in direct association of the prefix, may consist of a minimum of x and a maximum of y carbon atoms (i.e. x < y), wherein x and y represent integers defining the limits of the length of the chain (number of carbon atoms) and/or the size of the ring (number of carbon ring atoms).

"Pharmaceutically acceptable" as used herein, refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

The term "salt" or "salts" as used herein refers to compounds obtained by reacting a compound of general formula (I) with an acid or a base to form a salt. A "pharmaceutically acceptable salt" of a compound disclosed herein, including all pharmaceutically acceptable solvates (including hydrates), polymorphs, and amorphous phases thereof, refers to a formulation of the compound that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication. Such pharmaceutically acceptable salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.

Examples of suitable pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethane disulfonic, 2- hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC-(CH2)_n-COOH where n is any integer from 0 to 4 ( i.e ., 0, 1, 2, 3, or 4) and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those of ordinary skill in the art will recognize further pharmacologically acceptable salts for the compounds provided herein. In general, a pharmacologically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, is preferred.

A "substituent," as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a substituent on a ring may be a moiety such as a halogen atom, an alkyl, haloalkyl, hydroxy, cyano, or amino group, or any other substituent described herein that is covalently bonded to an atom, preferably a carbon or nitrogen atom, that is a ring member.

The term "substituted," as used herein, means that any one or more hydrogen atom(s) on the designated atom or group (e.g. alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heteroaryl) is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence or the group's number of possible sites for substitution is not exceeded, and that the substitution results in a stable compound, i.e. a compound that can be isolated, characterized and tested for biological activity. When a substituent is oxo, i.e., =0, then 2 hydrogens on the atom are replaced. An oxo group that is a substituent of an aromatic carbon atom results in a conversion of-CH- to -C(=0)- and may lead to a loss of aromaticity. For example, a pyridyl group substituted by oxo is a pyridone. The indication mono-, di-, tri or tetrasubstituted denotes groups having one (mono), two (di), three (tri) or four (tetra) substituents, provided that the substitution does not exceeded the number of possible sites for substitution and results in a stable compound. For example, a monosubstituted imidazolyl group may be an (imidazolidin-2-on)yl group and a disubstituted isoxazolyl group may be a ((3,5- dimethyl)isoxazolyl) group.

As used herein, "comprising", "including", "containing", "characterized by", and grammatical equivalents thereof are inclusive or open-ended terms that do not exclude additional, unrecited elements or method steps. Yet, "Comprising", etc. is also to be interpreted as including the more restrictive terms "consisting essentially of' and "consisting of', respectively.

As used herein, "consisting of' excludes any element, step, or ingredient not specified in the claim.

When trade names are used herein, it is intended to independently include the trade name product formulation, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product.

In general, unless defined otherwise, 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, and are consistent with general textbooks and dictionaries. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. In this application, the use of "or" or "and" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

The expression alkyl or alkyl group denotes a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, more preferably from 1 to 6 carbon atoms, or the number of carbon atoms indicated in the prefix. If an alkyl is substituted, the substitution may take place, independently of one another, by mono-, di-, or tri-substitution of individual carbon atoms of the molecule, e.g. 1, 2, 3, 4, 5, 6, or 7 hydrogen atom(s) may, at each occasion independently, be replaced by a selection from the indicated substituents. The foregoing also applies if the alkyl group forms a part of a group, e.g. haloalkyl, hydroxyalkyl, alkylamino, alkoxy, or alkoxyalkyl. Examples of an alkyl group include methyl, ethyl, propyl, Ao-propyl, n-butyl, Ao-butyl, sec-butyl, /e/V-butyl, «-pentyl, .s -pentyl, «-hexyl, 2,2-dimethylbutyl, or «-octyl, and examples of a substituted alkyl group or a group where the alkyl forms a part of a group, include haloalkyl, e.g. a trifluoromethyl or a difluoromethyl group; hydroxyalkyl, e.g. hydroxymethyl or 2-hydroxyethyl group, and a methoxymethyl group. The term "(Ci-₆) alkyl" includes, for example, EEC-, H₃C-CH₂-, H₃C-CH₂-CH₂-, FEC-CFhUFb)-, H₃C- CH2-CH2-CH2-, H₃C-CH2-CH(CH₃)-, H₃C-CH(CH₃)-CH₂, H₃C-C(CH₃)₂-, H₃C-CH2-CH2-CH₂- CH2-, H₃C-CH2-CH₂-CH(CH₃)-, H₃C-CH₂-CH(CH₃)-CH₂-, H₃C-CH(CH₃)-CH2-CH₂-, H₃C-CH₂- C(CH₃)₂-, H₃C-C(CH₃)₂-CH₂-, H₃C-CH(CH₃)-CH(CH₃)-, H₃C-CH₂-CH(CH₂CH₃)-, - CH₂CH₂CH₂CH₂CH₂CH₃, -CH(CH₃)CH₂CH₂CH₂CH₃, (H₃CH₂C)CH(CH₂CH₂CH₃)-, - C(CH₃)2(CH2CH₂CH₃), -CH(CH₃)CH(CH₃)CH₂CH₃, and -CH(CH₃)CH₂CH(CH₃)₂.

The expressions alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms, especially from 2 to 6 (e.g. 2, 3 or 4) carbon atoms, for example an ethenyl (vinyl), propenyl (allyl), iso-propenyl, butenyl, ethinyl, propinyl, butinyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group. Preferably, alkenyl groups have one or two (especially preferably one) double bond(s), and alkynyl groups have one or two (especially preferably one) triple bond(s).

The expression alkoxy or alkoxy group refers to an alkyl group singular bonded to oxygen, i.e. - O-alkyl, where alkyl is as defined herein. The term "(Oi-Ob) alkoxy" includes, for example, methoxy, ethoxy, n-propoxy, .v -propoxy, n-butoxy, .vec-butoxy, .v -butoxy, /677-butoxy, n- pentyloxy , /677-amyl oxy- or n-hexyloxy, and accordingly (Ci-C₃)alkoxy includes methoxy, ethoxy, n-propoxy, or .vo-propoxy.

The expression alkoxyalkyl or alkoxyalkyl group refers to an alkyl group singular bonded to one or more alkoxy group(s), e.g. -alkyl-O-alkyl or -alkyl-O-alkyl-O-alkyl. The term "(C₂-C₅) alkoxyalkyl" includes, for example, methoxymethyl, methoxyethyl, methoxy -n-propy 1 , methoxy-.vo-propyl, methoxy-n-butyl, methoxy- sec-butyl, methoxy-/.vo-butyl, methoxy-/677-butyl, methoxy ethoxymethyl, methoxy ethoxyethyl, ethoxymethoxy methyl, ethoxymethoxyethyl, and 1- ethoxy ethyl.

The expression haloalkyl or haloalkyl group refers to an alkyl group in which one, two, three or more hydrogen atoms have been replaced independently of each other by a halogen atom. The term "(Ci-C₃) haloalkyl" includes, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, bromomethyl, dibromomethyl, iodomethyl, (1- or 2-)haloethyl (e.g. (1- or 2-)fluoroethyl or (1- or 2-)chloroethyl), (2- or 3-) halopropyl (e.g. (2- or 3-) fluoropropyl or (2- or 3-) chloropropyl).

The expression hydroxyalkyl or hydroxyalkyl group refers to an alkyl group in which one, two, three or more hydrogen atoms have been replaced independently of each other by a hydroxy (OH) group. The term "(C₁-C₄) hydroxyalkyl" includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.

As used herein, the expression heteroalkyl or heteroalkyl group refers to an alkyl group, straight chain or branched as defined above, in which one or more, preferably 1, 2, 3 or 4, carbon atom(s) has/have been replaced, each independently of one another, by an oxygen, nitrogen, selenium, silicon or sulphur atom, preferably by an oxygen, sulphur or nitrogen atom, C(O), OC(O), C(0)0, C(0)NH, NHC(O), NH, SO, or SO2, wherein said heteroalkyl group may contain a CH=CH group and/or may be substituted. Examples of heteroalkyl groups, include, for example, groups of formulae: R^a-0-Y\ R^a-S-Y\ R^a-SO-Y^a-, R^a-S0₂-Y^a-, R^a-N(R^b)-Y^a-, R^a-CO-Y^a-,

R^a-0-C0-Y^a-, R^a-C0-0-Y\ R^a-CO-N(R^b)-Y^a-, R^a-N(R^b)-CO-Y^a-, R^a-0-C0-N(R^b)-Y^a-, R^a-N(R^b)-C0-0-Y^a-, R^a-N(R^b)-CO-N(R^c)-Y^a-, R^a-0-C0-0-Y^a-, R^a-N(R^b)-C(=NR^d)-N(R^c)-Y^a-, R^a-CS-Y^a-, R^a-0-CS-Y^a-, R^a-CS-0-Y^a-, R^a-CS-N(R^b)-Y^a-, R^a-N(R^b)-CS-Y^a-, R^a-0-CS-N(R^b)-Y^a-, R^a-N(R^b)-CS-0-Y^a-, R^a-N(R^b)-CS-N(R^c)-Y^a-, R^a-0-CS-0-Y^a-, R^a-S-CO-Y^a-, R^a-CO-S-Y^a-, R^a-S-CO-N(R^b)-Y^a-, R^a-N(R^b)-CO-S-Y^a-, R^a-S-C0-0-Y^a-, R^a-0-C0-S-Y^a-, R^a-S-CO-S-Y^a-, R^a-S-CS-Y^a-, R^a-CS-S-Y\ R^a-S-CS-N(R^b)-Y^a-, R^a-N(R^b)-CS-S-Y^a-, R^a-S-CS-0-Y^a-, R^a-0-CS-S-Y^a-, wherein R^a being a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; R^b being a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; R^c being a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; R^d being a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group and Y^a being a direct bond, a C1-C6 alkylene, a C2-C6 alkenylene or a C2-C6 alkynylene group, wherein each heteroalkyl group contains at least one carbon atom and at least one heteroatom as defined hereinbefore. The term "(Ci-C4)heteroalkyl group" refers, for example, to a group containing from 1 to 4, e.g. 1, 2, 3 or 4, carbon atoms and 1, 2, 3 or 4, preferably 1, 2 or 3, heteroatoms selected from oxygen, nitrogen and sulphur (especially oxygen and nitrogen). Examples of a heteroalkyl group include alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide, alkoxycarbonyloxy, alkylcarbamoyl, alkylamido, alkylcarbamoylalkyl, alkylamidoalkyl, alkylcarbamoyloxyalkyl, alkylureidoalkyl, alkoxy, alkoxyalkyl, or alkylthio group. The expression alkylthio or alkylthio group refers to an alkyl group, in which one or more non-adjacent CEE group(s) are replaced by sulphur, wherein the alkyl moiety of the alkylthio group may be substituted. Specific examples of a heteroalkyl group include acyl, methoxy, trifluoromethoxy, ethoxy, «-propyloxy, /.sopropyloxy, tert- butyloxy, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino, dimethylamino, diethylamino, /.sopropyl ethyl ami no, methyl aminomethyl, ethylaminomethyl, diisopropylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxy carbonyl, ethoxy carbonyl, isobutyrylamino-methyl, Y-ethyl-Y- methylcarbamoyl, /V-methyl carbamoyl, cyano, nitrile, isonitrile, thiocyanate, isocyanate, isothiocyanate and alkylnitrile.

The expression cycloalkyl or cycloalkyl group refers to a saturated carbocyclic ring group comprising one or more rings (preferably 1 or 2) and containing from 3 to 14 ring carbon atoms, preferably from 3 to 10 (more preferably 3, 4, 5, 6 or 7) ring carbon atoms; the cycloalkyl group may be substituted and can be bonded as a substituent via every suitable position of the ring system. Cycloalkyls may be fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Examples of cycloalkyl include monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. In a bicyclic cycloalkyl group, two rings are joined together so that they have at least two carbon atoms in common. In a spiro-hydrocarbon ring, 2 or 3 rings are linked together by one common carbon atom (spiro-atom). If a cycloalkyl is substituted, the substitution may take place, independently of one another, by mono- or di-substitution of individual ring carbon atoms of the molecule, and the cycloalkyl group as a whole may carry 1, 2, 3, or 4 substituents from the indicated selection of substituents, i.e. 1, 2, 3, or 4 hydrogen atom(s) of the carbon ring atoms may, at each occasion independently, be replaced by a substituent selected from the indicated list of substituents thereby resulting in a mono-, di-, tri-, or tetrasubstituted cycloalkyl group. If a cycloalkyl is partially unsaturated, then the carbocyclic ring contains one or more double-bonded ring-carbon atoms (e.g. one or more groups -CH=CH-), which may be unsubstituted or substituted as mentioned hereinbefore. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthyl), bicyclo[2.2.1]heptyl (norbomyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, and spiro[3.3]heptyl. If a cycloalkyl is partially unsaturated, the group contains one, two or more double bonds, such as, for example, a cycloalkenyl group, including cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, bicyclo[2.2.1 jheptadienyl, and spiro[4,5]decenyl.

The expression heterocycloalkyl or heterocycloalkyl group refers to a cycloalkyl group, saturated or partially unsaturated, as defined above, in which one or more, preferably 1, 2 or 3, ring carbon atom(s) has/have been replaced each independently of one another by an oxygen, nitrogen or sulphur atom, preferably oxygen or nitrogen, or by NO, SO or SO2, with the proviso that any ring does not contain two adjacent O or S atoms, or NO, SO or SO2 moieties; the heterocycloalkyl may be substituted and can be bonded as a substituent via every suitable position of the ring system; at least one carbon atom must be present between two oxygen atoms and between two sulphur atoms or between an oxygen and a sulphur atom; and the ring as a whole must have chemical stability. A heterocycloalkyl group has preferably 1 or 2 ring(s) containing from 3 to 10 (more preferably 3, 4, 5, 6 or 7, and most preferably 5, 6 or 7) ring atoms. Examples of heterocycloalkyl include aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, azolyl, thiazolyl, isothiazolyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperazinyl, morpholinyl, thiomorpholinyl, trioxanyl, azepanyl, oxepanyl, thiepanyl, homopiperazinyl, urotropinyl, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, and examples of substituted heterocycloalkyl include lactam, lactone, and cyclic carbamate, cyclic carbamide as well as cyclic imide ring systems.

The expressions aryl, Ar or aryl group refer to an aromatic group that contains one or more aromatic rings containing from 6 to 14 ring carbon atoms (C6-C14), preferably from 6 to 10 (C₆- C10), more preferably 6 ring carbon atoms; the aryl may be substituted and can be bonded as a substituent via every suitable position of the ring system. Examples of aryl include phenyl, naphthyl, bi-phenyl, indanyl, indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and fluorenyl.

The expression heteroaryl or heteroaryl group refers to an aromatic group that contains one or more aromatic rings containing from 5 to 14 ring atoms, preferably from 5 to 10 (more preferably 5 or 6) ring atoms, and contains one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N), with the proviso that any ring does not contain two adjacent O, P or S atoms; the heteroaryl may be substituted and can be bonded as a substituent via every suitable position of the ring system. Examples of an unsubstituted heteroaryl group include 2-pyridyl, 2-imidazolyl, 3-phenylpyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, pyridazinyl, quinolinyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3'-bifuryl, 3-pyrazolyl and isoquinolinyl.

The expression heterocycle denotes ring systems, which include the above defined heterocycloalkyl and heteroaryl ring systems, e.g. a partially unsaturated heterocycle is synonymous with a partially unsaturated heterocycloalkyl and an aromatic heterocycle, e.g. a 6- membered heteroaromatic group, is synonymous with a heteroaryl. The heterocycle may be substituted and can be bonded as a substituent via every suitable position of the ring system. Examples of a partially unsaturated or aromatic heterocycle include oxetenyl, thietenyl, azetinyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,5-dihydro-lH-pyrrolyl, furanyl, thiophenyl, pyrrolyl, benzo[b]furanyl, benzo[b]thiophenyl, indolyl, benzo[c]pyrrolyl, benzo[a]pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- triazolyl, 1 ,2,4-triazolyl, tetrazolyl, dihydropyridinyl, oxazinyl, pyridinyl, dihydropyranyl, azepinyl, tetrahydropyranyl, dihydrothiopyranyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, and pteridinyl.

The term "aromatic" refers to a planar ring having a delocalized p-electron system containing 4h+2p electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, ten, or more than ten atoms. Aromatics are optionally substituted. The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

The term "carbocyclic" or "carbocycle" refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom which is different from carbon.

The general term ring as used herein, unless defined otherwise, includes the cyclic groups defined herein above, e.g., a cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, and heterocycle.

The expression "alkylene" (or alkanediyl functional group) refers to an unsubstituted, saturated, straight chain hydrocarbon group that contains the indicated number of carbon atoms (in the form of methylene (CH₂) groups) and has the free valencies at the terminal methylene groups, for example a butylene -(0½)4-, n-pentylene -(012)5-, n-hexylene -(CtTf,-, or n-octylene -(CThjs- group.

The expression "alkenylene" refers to an at least partially unsaturated alkanediyl functional group as defined above that contains one or more double bond(s) (i.e. the methylene groups of the alkanediyl functional group are interrupted by -CH=CH- and/or terminated by -CH_2-CH=).

The term "bond" or "single bond" refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.

The term "moiety" refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

The expression halo, halogen or halogen atom as used herein means fluorine, chlorine, bromine, or iodine.

The expression heteroatom as used herein, preferably denotes an oxygen, nitrogen or sulphur atom, more preferably a nitrogen or oxygen atom unless specified otherwise.

In one embodiment, provided herein is a compound of general formula (I), or a salt thereof, wherein

R^1A is a hydrogen atom or deuterium atom;

R^1B is a hydrogen atom, deuterium atom, (Ci-C₃)alkyl, or (C₁-C₃) haloalkyl group; or R^1A and R^1B are taken together with the carbon atom to which they are attached to form a cyclopropyl group; R^1C is CN, CH2CN, CH2OCH3, CH2OCHF2, or CH2OCF3;

R² is F, Cl, CH₃, or CHF₂;

R³ is CN or CHF₂;

X¹ is (CRⁿR¹²);

CH₃;

CH₃; m is 1 or 2, provided that m is 2 when n is 1 ;

X² is (CR²¹R²²);

CH₃;

CH₃; n is 1 or 2, provided that n is 2 when m is 1 ;

R⁵ is, at each occasion independently, a fluorine atom, CFb, OCH3, (Ci) haloalkyl,

O(Ci) haloalkyl or NR^AR^;

R⁶ represents a hydrogen atom, CN, OH, G, OG, Cyc, OCyc, Hce or OHce;

In preferred embodiments, the compound of general formula (I) as defined above, or a salt thereof, can include one or more of the following:

[2] R² is Cl or CH₃;

[3] R² is Cl;

[4] R³ is CN; in one embodiment, R³ is CN, and R² may be defined as in [2] or [3];

[5] R^1A is a hydrogen atom; in one embodiment, R^1A is a hydrogen atom, and the compound or salt may further include any one of [2] to [4];

[6] R^1B is a hydrogen atom; in one embodiment, R^1B is a hydrogen atom, and the compound or salt may further include any one of [2] to [5];

[7] R^1A and R^1B are taken together with the carbon atom to which they are attached to form a cyclopropyl group; in one embodiment, R^1A and R^1B are taken together with the carbon atom to which they are attached to form a cyclopropyl group, and the compound or salt may further include any one of [2] to [4];

[8] R^1C is CN, CH₂OCH₃, CH₂OCHF₂, or CH₂OCF₃; in one embodiment, R^1C is CN, CH₂OCH₃, CH₂OCHF₂, or CH₂OCF₃, and the compound or salt may further include any one of [2] to [7];

[9] R^1C is CN; in one embodiment, R^1C is CN, and the compound or salt may further include any one of [2] to [7];

[10] m is 2 and n is 1; in one embodiment, m is 2 and n is 1, and the compound or salt may further include any one of [2] to [9];

[11] XI is selected from -CH2-, -C(CH3)H-, -C(CH3)2-, -CDH-, -CD2-, -CFH-, -CF2-, - (CH2)2-, -C(CH3)H-CH2-, -CH2-C(CH3)H-, -C(CH3)H-C(CH3)H-, -C(CH3)2-CH2-

, -CH2-C(CH3)2-, -CDH-CH2-, -CD2-CH2-, -CH2-CDH-, -CH2-CD2-, -CFH-CH2-, - CF2-CH2-, -CFH-CFH-, -CH2-CFH-, -CH2-CF2-, -C(CH3)2-CFH-, and -CFH-C(CH3)2- ; in one embodiment, m is 2, n is 1, XI is selected from -(CH2)2-, -C(CH3)H-CH2-, - CH2-C(CH3)H-, -C(CH3)H-C(CH3)H-, -C(CH3)2-CH2-, -CH2-C(CH3)2-, -CDH-CH2-, -CD2-CH2-, -CH2-CDH-, -CH2-CD2-, -CFH-CH2-, -CF2-CH2-, -CFH-CFH-, -CH2- CFH-, -CH2-CF2-, -C(CH3)2-CFH- and -CFH-C(CH3)2-, and the compound or salt may further include any one of [2] to [9]; in one embodiment, m is 2, n is 1, XI is selected from -(CH2)2-, -CDH-CH2-, -CD2-CH2-, -CH2-CDH-, and -CH2-CD2-, and the compound or salt may further include any one of [2] to [9];

[12] X² is selected from -CH₂-, -C(CH )H-, -C(CH₃)₂-, -CDH-, -CD₂-, -CFH-, -CF₂-, -(CH₂)₂-, -C(CH₃)H-CH₂-, -CH₂-C(CH₃)H-, -C(CH₃)H-C(CH₃)H-, -C(CH₃)₂-CH₂-, -CH₂-C(CH₃)₂-,

-CDH-CH₂-, -CD₂-CH₂-, -CH₂-CDH-, -CH₂-CD₂-, -CFH-CH₂-, -CF₂-CH₂-, -CFH-CFH-

, -CH₂-CFH-, -CH₂-CF₂-, -C(CH₃)₂-CFH-, and -CFH-C(CH₃)₂-; m one embodiment, m is 2, n is 1, X² is selected from -CH₂-, -C(CH₃)H-, -C(CH₃)₂-, -CDH-, -CD₂-, -CFH- and - CF₂, and the compound or salt may further include any one of [2] to [9]; in one embodiment, m is 2, n is 1, X² is selected from -CH₂-, -CDH-, and -CD₂-, and the compound or salt may further include any one of [2] to [9];

[13] m is 1 and n is 2; in one embodiment, m is 1 and n is 2, and the compound or salt may further include any one of [2] to [9]; in one embodiment, m is 1, n is 2, X¹ is selected from -CH₂-, -C(CH₃)H-, -C(CH₃)2-, -CDH-, -CD₂-, -CFH- and -CF₂-, and the compound or salt may further include any one of [2] to [9]; in one embodiment, m is 1, n is 2, X¹ is selected from -CH₂-, -CDH-, and -CD2-, and the compound or salt may further include any one of [2] to [9]; in one embodiment, m is 1, n is 2, XI is selected from -CH₂-

, -C(CH₃)H-, -C(CH₃)2-, -CDH-, -CD₂-, -CFH- and -CF₂- (preferably from -CH₂-, - CDH- and -CD₂-), X² is selected from -(CH₂)₂-, -C(CH₃)H-CH₂-, -CH₂-C(CH₃)H-, - C(CH₃)H-C(CH₃)H-, -C(CH₃)₂-CH₂-, -CH₂-C(CH₃)₂-, -CDH-CH₂-, -CD₂-CH₂-, -CH₂- CDH-, -CH₂-CD₂-, -CFH-CH₂-, -CF₂-CH₂-, -CFH-CFH-, -OH-CFH-, -CH₂-CF₂-, - C(CH₃)₂-CFH-, and -CFH-C(CH₃)₂- (preferably from -(CH2)2-, -CDH-CH2-, -CD2-CH2- , -CH2-CDH-, and -CH2-CD2-), and the compound or salt may further include any one of [2] to [9];

[14] o is 1; in one embodiment, o is 1, and the compound or salt may further include any one of [2] to [13];

[15] the group -(CR^4AR^4B)- is selected from -CH₂-, -C(CH₃)H-, -C(CN)H-, -C(CH₃)₂-, -CDH- , -CD₂-, -CFH- and -CF₂- (preferably from -CH₂-, -C(CH₃)H-, -C(CH₃)₂-, -CDH-, and -CD₂-); in one embodiment, the group -(CR^4AR^4B)- is selected from -CH₂-, -C(CH₃)H- , -C(CN)H-, -C(CH₃)₂-, -CDH-, -CD₂-, -CFH- and -CF₂- (preferably from -CH₂- , -C(CH₃)H-, -C(CH₃)₂-, -CDH-, and -CD₂-; more preferably from -CH₂- and -C(CH₃)H- ), and the compound or salt may further include any one of [2] to [14];

[16] ring A represents a phenyl group; or a 5-, 6- or 9-membered heteroaryl group comprising 1 to 4 heteroatom(s) each, independently of one another, selected from N, O or S; and p,

R⁵ and R⁶ are defined as in general formula (I) above; in one embodiment, ring A represents a phenyl group; or a 5-, 6- or 9-membered heteroaryl group comprising 1 to 4 heteroatom(s) each, independently of one another, selected from N, O or S; p, R⁵ and R⁶ are defined as in general formula (I) above, and the compound or salt may further include any one of [2] to [15];

[17] ring A represents a phenyl group; a 5-membered heteroaryl group containing one sulphur ring atom, or one nitrogen and one oxygen or sulphur ring atom; or a 6-membered heteroaryl group containing 1, 2, 3 or 4 nitrogen ring atom(s); and p, R⁵ and R⁶ are defined as in general formula (I) above; in one embodiment, ring A represents a phenyl group; a 5- membered heteroaryl group containing one sulphur ring atom, or one nitrogen and one oxygen or sulphur ring atom; or a 6-membered heteroaryl group containing 1, 2, 3 or 4 nitrogen ring atom(s); p, R⁵ and R⁶ are defined as in general formula (I) above, and the compound or salt may further include any one of [2] to [15];

[18] R⁵ is, at each occasion independently, a hydrogen atom, fluorine atom, CH₃, NH₂ or OCH₃ (preferably a hydrogen atom, fluorine atom or CH₃); in one embodiment, R⁵ is, at each occasion independently, a hydrogen atom, fluorine atom, CH₃, NH₂ or OCH₃ (preferably a hydrogen atom, fluorine atom or CH₃), and the compound or salt may further include any one of [2] to [17];

[19] p is 0; in one embodiment, p is 0, and the compound or salt may further include any one of [2] to [18];

[20] p is 1; in one embodiment, p is 1, and the compound or salt may further include any one of [2] to [18];

[21] p is 2; in one embodiment, p is 2, and the compound or salt may further include any one of [2] to [18];

[22] R⁶ represents CN, G¹, OG¹, Cyc¹, OCyc¹, Hce¹ or OHce¹;

G¹ represents a (Ci-C₆)alkyl group, in which (i) one CH2 group may be replaced by O or NH; and/or in which (ii) 1 to 5 H atoms may, at each occasion independently, be replaced by a fluorine or chlorine (preferably fluorine) atom, OH, CN, R^Gn, OR^Gn, Cyc¹, OCyc¹, Hce¹, or OHce¹;

Cyc¹ represents a monocyclic, saturated 3- to 5-membered cycloalkyl group, which is unsubstituted or may be mono-, di-, or trisubstituted, at each occasion independently, by a fluorine or chlorine (preferably fluorine) atom, CN, =0, and/or R^Gn;

Hce¹ represents a monocyclic, saturated heterocycloalkyl group having 3 to 5 C atoms and 1 or 2 heteroatom(s) each, independently of one another, selected from N or O, which is unsubstituted or may be mono-, di- or trisubstituted, at each occasion independently, by a fluorine or chlorine (preferably fluorine) atom, OH, CN, =0, and/or R^Gn; and R^GU represents a (Ci-C3)alkyl, (C1-C3) haloalkyl, or (C1-C4) heteroalkyl group; in one embodiment, R⁶ represents CN, G¹, OG¹, Cyc¹, OCyc¹, Hce¹ ,OHce' as defined above, and the compound or salt may further include any one of [2] to [21];

[23] the compound has structural formula (II A) or (IIB): and R^1A, R^1b, R^1C, R², R³, R^4A, R^4B, R⁵, R⁶, A, o and p are defined as described herein;

[24] the moiety comprising ring A represents a group: in one embodiment, the moiety comprising ring A represents one of the above groups, and the compound or salt may further include any one of [2] to [23];

[25] the moiety comprising ring A represents a group:

; preferably the moiety comprising ring A represents a group: ; in one embodiment, the moiety comprising ring A represents one of the above grou and the compound or salt may further include any one of [2] to [24]; [26] R⁶ represents a group: in some embodiments, R⁶ represents one of the above groups, and the compound or salt may further include any one of [2] to [25] In general, all suitable combinations of preferred embodiments, i.e. [2] to [26], of the compound according to general formula (I), or a salt thereof, which result in a stable and active compound, are encompassed in the present invention; e.g. a compound or salt thereof including a combination of [3], [4], [5], [6] and [9] or a combination of [3], [4], [7] and [9] These combinations of preferred embodiments of the compound according to general formula (I) may, for example, result in compounds as described in the Examples, or a pharmaceutically acceptable salt thereof; such as, for example: Compounds of general formula (I) described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein. In addition, solvents, temperatures and other reaction conditions presented herein may vary. In some embodiments, the compounds of general formula (I) are prepared from Intermediate 2 described herein as outlined in the following Scheme 1. Scheme 1:

In some embodiments, compounds of general formula (I) have a 7,8-dihydro-5H-2,6- naphthyridine substructure, and therefore share a common intermediate: 6-benzyl-l,3-dichloro- 7,8-dihydro-5H-2,6-naphthyridine-4-carbonitrile (Intermediate 2). This intermediate can be functionalised with an amine using a nucleophilic aromatic substitution reaction, as shown in Scheme 1, step 1. From here, the benzyl group may be switched to an Alloc protecting group (Step 2a), or removed to afford the free amine salt (Step 2b). The Alloc intermediate may then be functionalised with aldehydes or ketones using standard reductive alkylation conditions, with additional in situ deprotection of the Alloc group by palladium tetrakis triphenyphosphine (Step 3a). The free amine salt intermediate may be functionalised using a range of approaches (Step 3b), including but not limited to (i) reductive alkylation using an aldehyde or ketone, (ii) alkylation using an alkyl halide or similar, (iii) amide coupling, with subsequent reduction with borane dimethyl sulfide.

Alternatively, the order of the steps may be reversed, as illustrated in Scheme 2, steps 4-6. Scheme 2:

In general, the starting material used for the synthesis of the compounds of general formula (I) are either synthesized or obtained from commercial sources, such as, but not limited to, Sigma- Aldrich, Fluka, and the like. The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein or otherwise known, including those found in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992 ); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols. A and B (Plenum 2000, 2001 ), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999 ). General methods for the preparation of compounds can be modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formulae as provided herein. For example, compounds of general formula (I) with a 6,8-dihydro-5H-2,7- naphthyridine core may be functionalised in a way similar to those outlined in the above schemes, such as synthesized as outlined in the Examples. Again, groups and substituents thereof are chosen by one skilled in the art to provide stable moieties and compounds.

The compounds provided herein exhibit high inhibitory activity against uptake of extracellular citrate, e. g. an inhibition constant IC50 (half-maximal inhibitory concentration) for inhibition of a citrate transporter, such as INDY, of 20 micromolar (mM) or less, e.g. of from 20 mM to 10 pM; preferably an IC50 of 10 pM or less, e.g. of from 500 nanomolar (nM) to 10 pM; still more preferably an IC50 of 2 pM or less; even more preferably an IC50 of about 500 nM or less, 250 nM or less, or even 100 nM or less in an assay mentioned below. As such the compounds described herein can exhibit a high inhibitory activity on human citrate transporter, such as INDY, but also on homolgues and citrate transporters of species other than human, e.g. rat, mouse, gerbil, guinea pig, rabbit, dog, cat, pig, or cynomolgus monkey.

The activity and more specifically the bioactivity of the compounds according to the present invention can be assessed using appropriate assays known to those skilled in the art, e.g. in vitro or in vivo assays. For instance, the inhibitory effect (expressed as IC50 value) of a compound of the invention on the citrate transporter activity may be determined via a citrate uptake assay described in more detail in the Examples section below.

The therapeutic use of a compound of general formula (I), or of a pharmaceutically acceptable prodrug, hydrate, solvate or salt thereof; and also of a formulation or a pharmaceutical composition containing the same are within the scope of the present invention. The present invention also relates to the use of a compound of general formula (I) as active ingredient in the preparation or manufacture of a medicament.

A pharmaceutical composition provided herein comprises at least one compound of general formula (I), or a pharmaceutically acceptable prodrug, hydrate, solvate or salt thereof, and, optionally, at least one, i.e. one or more, carrier substance, excipient and/or adjuvant. In some embodiments, provided herein are pharmaceutical compositions that include at least one compound of general formula (I), or a pharmaceutically acceptable salt thereof, as described herein (e.g. a compound including one or more of [2] to [24]), and at least one pharmaceutically acceptable inactive ingredient. In some embodiments, the pharmaceutical compositions include other medicinal or pharmaceutical agents, carriers, adjuvants, preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, and/or buffers. In other embodiments, the pharmaceutical compositions include other therapeutically valuable substances., optionally, at least one carrier substance, excipient and/or adjuvant.

The pharmaceutical composition may additionally comprise, for example, one or more of water, buffers (e.g., neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethylsulfoxide, carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives.

In some embodiments, the compounds described herein are provided as pharmaceutical compositions in which a compound of general formula (I) is mixed with at least one other active ingredient (i.e. one or more active ingredient(s)), as in a combination preparation. For instance, one or more compound(s) of the invention may advantageously be contained in a combination preparation that contains at least one further active pharmaceutical ingredient. The further or supplemental active agent or active pharmaceutical ingredient is preferably an active agent or active pharmaceutical ingredient which has utility in the prevention or treatment of one or more condition(s) associated with or modulated by uptake of extracellular citrate, including those mentioned hereinbefore, hereinafter or in the claims. Examples of further active pharmaceutical ingredients, include one or more of the following from (a) to (f): (a) anti-obesity agent(s) selected from the group consisting of orlistat, lorcaserin, Phentermine, Topiramate, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine, 5-HT2c receptor agonists, Bupropion, Naltrexone, methionine aminopeptidase 2 inhibitors, GLP1 agonists; (b) anti-diabetes agent(s) comprising insulin, incretin mimetics, SGLT-2 inhibitors, DPPIV inhibitors, PPAR agonist, Glucokinase activator, MTP inhibitors, Glycogen phosphorylase inhibitors, DGAT-1 inhibitor, GLPl agonists, dual GLPl/glucagon receptor agonists, triagonist for GLPl/glucose-dependent insulinotropic polypeptide/glucagon receptor; (c) anti-NASH agent(s) comprising insulin, incretin mimetics, statins, PPAR agonists, AMPK activators, FXR agonists, DGAT-2 inhibitors, DGAT-1 inhibitors, Bile-Acid Conjugates, methionine aminopeptidase 2 inhibitors, PDE4 inhibitors, inhibitors of acetyl-CoA carboxylase, inhibitors of ketohexokinase, inhibitors of ATP citrate lyase, GLP-1 agonist, dual GLPl/glucagon receptor agonists, triagonist for GLPl/glucose- dependent insulinotropic polypeptide/glucagon receptor, inhibitors of ASK-1, CCR2/CCR5 antagonist, inhibitors of SLC10A2, inhibitors of LOXL2, inhibitors of Galectin-3, inhibitors of caspase, FGF21, FGF19, inhibitors of CGRP, AOC3: Amine Oxidase, Copper Containing 3, inhibitors of DPP-4, THR-B agonists, anti-CD3 monoclonal antibody (mAbs), A3AR agonists, inhibitors of SGLT2, inhibitors of SGLTl, inhibitors for TGFB activation, anti- cannabinoid CD1 receptor antibody, antibody agonist of the b-Klotho/FGFRl c receptor complex, inhibitors of the inflammasome, ATP citrate lyase inhibitors, stearoyl-CoA desaturase inhibitors, fatty acid synthesis inhibitors; (d) anti-dyslipidaemia agent(s) comprising, statins, ApoB antisense oligonucleotides, PCSK9 inhibitors, Cholesterol-absorption inhibitors, Niacin, Bile- acid-sequestering resins, MTP inhibitors, Fibrates, CETP inhibitors ATP citrate lyase inhibitors; (e) anti-cancer agent(s) comprising chemotherapeutic drugs; (f) anti aging drug(s) comprising vitamins; and (g) anti-osteoporosis agent(s) comprising vitamin D, calcium, calcitonine, bisphosphonates, estrogen, selective estrogen receptor modulators, parathyroid hormone and its analoga, RANKL inhibitors, anti-sclerostin antibody.

The pharmaceutical composition, or the combination preparation, provided herein can be used as a medicament, e.g., in the prophylaxis and/or treatment of a disease or condition that is citrate transporter meditated or citrate transporter dependent, or that is associated with the activity of a citrate transporter. For this use, the pharmaceutical composition, or the combination preparation, provided herein may be formulated for any appropriate manner of administration, including, for example, topical (e.g., transdermal or ocular), oral, buccal, nasal, vaginal, rectal or parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, as well as any similar injection or infusion technique. In certain embodiments, compositions in a form suitable for oral use are preferred. Such forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Within yet other embodiments, compositions provided herein may be formulated as a lyophilizate. Formulation for topical administration may be preferred for certain conditions (e.g., in the treatment of skin conditions such as bums or itch). Briefly summarized, the pharmaceutical composition as well as the combination preparation can, for example, be formulated as an aerosol, a cream, a gel, a pill, a capsule, a syrup, a solution, a transdermal patch or a pharmaceutical delivery device.

In one embodiment, the compounds of general formula (I) are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from a reduction of citrate transporter activity. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound of general formula (I) or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject. As used herein, the term "treatment" encompasses both disease-modifying treatment and symptomatic treatment, either of which may be prophylactic (i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms, in order to reduce the severity and/or duration of symptoms). A condition is "associated with or modulated by uptake of extracellular citrate" if modulation of citrate transporter (e.g. INDY) activity results in alleviation of the condition or a symptom thereof. Patients may include but are not limited to mammals, primates (especially humans), domesticated companion animals (such as dogs, cats, horses) and livestock (such as cattle, pigs, sheep), with dosages as described herein.

In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial.

In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound of general formula (I) in order to prevent a return of the symptoms of the disease or condition.

For the prophylaxis and/or treatment of a disease or condition that is citrate transporter meditated or citrate transporter dependent, or that is associated with the activity of a citrate transporter, the dose of drug being administered may vary within wide limits and may be adjusted to individual requirements. Active compounds described herein are generally administered in a therapeutically effective amount. Preferred doses range from about 0.1 mg to about 140 mg per kilogram of body weight per day (about 0.5 mg to about 7 g per patient per day). The daily dose may be administered as a single dose or in a plurality of doses. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination ( i.e . other drugs being used to treat the patient) and the severity of the particular disease undergoing therapy.

The phrase "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In certain embodiments a therapeutically effective amount may achieve one or more of lowering blood glucose level, decreasing insulin resistance and increasing insulin sensitivity, lowering hepatic lipids, lowering hepatic triglycerides, lowering hepatic diacylglycerol, lowering blood cholesterol, lowering blood triglycerides, lowering blood LDL, lowering muscle diacylglycerols.

Examples of a disease or condition that is citrate transporter meditated or citrate transporter dependent, or that is associated with the activity of a citrate transporter, include: (a) metabolic diseases selected from the group comprising insulin resistance, alcoholic and non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), obesity, type 1 diabetes, type 2 diabetes, dyslipidemia, hereditary diseases and metabolic syndrome; (b) eating disorders; (c) chronic liver diseases; (d) liver cancer and cancer related to obesity; (e) age related diseases comprising atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension and neurodegenerative diseases like Alzheimer's disease; (f) drug induced hepatic steatosis; and (g) a disease or condition that is caused by hypocitricemia and/or indicated by hypocitraturia such as osteoporosis and , adrenocortical hyperactive, vitamin D deficiency, ricket, parathyroidectomy, metaboloc acidosis, glaucoma, bariatric surgery, kidney stones, chronic kidney disease, primary hyperaldesteronism and postmenopause.

Diabetes mellitus is a metabolic disease that causes high blood sugar, and it generally refers to fasting plasma glucose values of >126 mg/dL (> 7.0 mmol/1) and insulin resistance is defined here as a fasting blood insulin level greater than 20 mcU/mL. Untreated high blood sugar from diabetes can damage your nerves, eyes, kidneys, and other organs, and types of diabetes include type 1 diabetes, type 2 diabetes, prediabetes and gestational diabetes. Adiposity and obesity both refer to a medical condition in which excess body fat has accumulated to an extent where it may increases the likelihood of various diseases, particularly heart disease, type 2 diabetes, obstructive sleep apnoea, certain types of cancer, and osteoarthritis. Generally adiposity and obesity are related to a Body Mass Index (kg/m²) above 25. NAFLD refers to a wide spectrum of liver clinicopathologic conditions, ranging from pure fatty steatosis (fatty infiltration in >5% of hepatocytes) to non alcoholic steatohepatitis (NASH), which may progress to cirrhosis, liver failure, and hepatocellular carcinoma and is characterized by excessive fat accumulation in the liver parenchyma of patients who have no history of alcohol abuse. NASH refers to a medical condition with presence of specific histological abnormalities on liver biopsy such as a characteristic pattern of steatosis, inflammation and hepatocellular ballooning in the absence of significant alcohol consumption.

Age-related diseases occur with increasing frequency with increasing senescence such as atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension and neurodegenerative diseases like Alzheimer's disease. The incidence of all of these diseases increases rapidly with aging. One aspect of age related diseases concerns pre diabetes, a condition that raises a person's risk for developing type 2 diabetes, heart disease, and stroke. Within the context of the present invention such diseases shall be understood as age related diseases.

Potential cancers to be treated with a compound of general formula (I) comprise liver, pancreas cancer, breast cancer, oesophagus cancer, pancreas cancer, colon cancer, gallbladder cancer, colorectal cancer, endometrium cancer, kidney cancer, gallbladder cancer, thyroid cancer, rectal cancer, melanoma, leukaemia, multiple myeloma, non-Hodgkin lymphoma, prostate cancer, uterine cancer, ovarian cancer, endometrial cancer and cervical cancer.

Within the context of the present invention, a disease or condition that is caused by low plasma citrate concentrations (hypocitricemia) and/or indicated by low urinary citrate excretion (hypocitraturia), includes surgical stress, osteoporosis, adrenocortical hyperactive, vitamin D deficiency, ricket, parathyroidectomy, metaboloc acidosis, glaucoma, bariatric surgery, kidney stones, chronic kidney disease, primary hyperaldesteronism and postmenopause.

In one aspect, the methods and compositions described herein include the use of compounds of general formula (I) in form of pharmaceutically acceptable salts, prodrugs, enantiomers, diastereomers, racemic mixtures, crystalline forms, non-crystalline forms, amorphous forms, unsolvated forms and solvates. In some embodiments, pharmaceutically acceptable salts of the compound of the general formula (I) are prepared with relatively nontoxic (i.e. pharmaceutically acceptable) acids or bases, depending on the particular substituents found on the compounds of the present invention. If, for example, compounds of the present invention contain acidic functionalities, base addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Non-limiting examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. If compounds of the present invention contain basic functionalities, acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Non-limiting examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, phosphoric, partially neutralized phosphoric acids, sulfuric, partially neutralized sulfuric, hydroiodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds of the present invention may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Contacting the salt with a base may regenerate the neutral forms of the compounds of the present invention or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

In some embodiments, compounds described herein are provided as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug under physiological conditions. Additionally, prodrugs can also be converted to the parent drug by chemical or biochemical methods in an ex- vivo environment. For example, prodrugs can be slowly converted to the parent drug when, for example, placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.

The compound of the invention described herein can be administered to the subject at a suitable dose. The compound of the invention is preferably administered to mammals such as domestic and pet animals. Non-limiting examples of domestic and pet animals are pigs, cows, buffalos, sheep, goats, rabbits, horses, donkeys, chickens, ducks, cats, dogs, genuine pigs, or hamsters.

Most preferred it is administered to humans. The preferred way of administration depends on the form of the compound of the invention (having the general formula (I) or (II)). As described herein above, the compound having the general formula (I) or (II) can be in the form of pharmaceutically acceptable salts, prodrugs, enantiomers, diastereomers, racemic mixtures, crystalline forms, non-crystalline forms, amorphous forms, unsolvated forms or solvates. The compound of the invention may be administered orally, parenterally, such as subcutaneously, intravenously, intramuscularly, intraperitoneally, intrathecally, intraocular, transdermally, transmucosally, subdurally, locally or topically via iontopheresis, sublingually, by inhalation spray, aerosol or rectally and the like in dosage unit formulations optionally further comprising conventional pharmaceutically acceptable excipients. The compound of the invention for use in accordance with the present invention can be formulated as a pharmaceutical composition using one or more physiological carriers or excipient, see, for example Ansel et al., "Pharmaceutical Dosage Forms and Drug Delivery Systems", 7th edition, Lippincott Williams & Wilkins Publishers, 1999.

For oral administration, the pharmaceutical composition of the invention can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutical acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, silica), disintegrants (e.g., potato starch, sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulphate). The pharmaceutical composition can be administered with a physiologically acceptable carrier to a patient. In a specific embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium ion, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can be in the form of ointments, solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. A preferred form is an ointment. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. E.W. Martin describes examples of suitable pharmaceutical carriers in “Remington’s Pharmaceutical Sciences”. Such compositions will contain a therapeutically effective amount of the aforementioned compounds, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration. Liquid preparations for oral administration can be in the form of, for example, solutions, syrups, or suspensions, or can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparation can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol, syrup, cellulose derivatives, hydrogenated edible fats), emulsifying agents (e.g., lecithin, acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, fractionated vegetable oils), preservatives (e.g., methyl or propyl-p- hydroxycarbonates, soric acids). The preparations can also contain buffer salts, flavouring, coloring and sweetening agents as deemed appropriate. Preparations for oral administration can be suitably formulated to give controlled release of the pharmaceutical composition of the invention.

For administration by inhalation, the pharmaceutical composition of the invention is conveniently delivered in the form of an aerosol spray presentation from a pressurised pack or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In the case of a pressurised aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatine, for use in an inhaler or insufflator can be formulated containing a powder mix of the pharmaceutical composition of the invention and a suitable powder base such as lactose or starch.

The pharmaceutical composition of the invention can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Site of injections include intra- venous, intra-peritoneal or sub-cutaneous. Formulations for injection can be presented in units dosage form (e.g., in phial, in multi-dose container), and with an added preservative. The pharmaceutical composition of the invention can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, or dispersing agents. Alternatively, the agent can be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition can also include a solubilizing agent and a local anaesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilised powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

It is obvious for a person ordinary skilled in the art that the present invention also encompasses sustained release dosage forms, which are designed to release a drug at a predetermined rate in order to maintain a constant drug concentration for a specific time period of time with minimum side effects. This can be achieved through a variety of formulations or devices, including microspheres, nanoparticles, liposomes, and other polymer matrices such as drug-polymer conjugates like hydrogels or biodegradables like poly(lactic-co-gly colic acid) (PLGA) encapsulating the drug. It is preferred to adapt the release to the specific needs for treating particular diseases, e.g. like sustained release of injections in treating diabetes. Sustained release's definition is more akin to a "controlled release" or “depot medication” rather than "sustained".

The pharmaceutical composition of the invention can also, if desired, be presented in a pack, or dispenser, which can contain one or more unit dosage forms containing the said agent. The pack can for example comprise metal or plastic foil, such as blister pack. The pack or dispenser device can be accompanied with instruction for administration.

The pharmaceutical composition of the invention can be administered as sole active agent or can be administered in combination with other active agents. Such additional active agents should be primarily chosen from active agents being related to the treatment of the same disease. In case that obesity shall be treated an additional active agent should be chosen from the group of anti-obesity drugs. In analogy anti-diabetes and also anti-NAFLD/NASH as well as anti-dyslipidaemia drugs may be used as further active agents. Furthermore, such additional active agent should be chosen from active agents being related to side effects such as body weight gain like anti-psychotic treatments.

For obesity combinations may comprise combination therapies that are administered in conjunction with exercise, combination therapies that are administered in conjunction with sensible diet, combination therapies with anti-obesity agents are selected from the group consisting of orlistat, lorcaserin, Phentermine, Topiramate, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine. Further examples of combinations with a compound of general formula (I) or (II) are lipase inhibitors (e.g. Orlistat Xenical®, Roche, Alii®, GSK, Cetilistat), 5- HT2c receptor agonists (e.g. Lorcaserin, Belviq® Arena Inc., Eisai), phentermine and topiramate (e.g. Qsymia®, Vivus Inc), noradrenergic anorectic agents (e.g. phentermine, mazindol) , appetite suppressants (for example, bupropion), bupropion and Naltrexone (e.g. Contrave®, Orexigen Inc.), drugs affecting endogenous signaling of appetite-regulating hormones, neuropeptides, neurotransmitters (e.g. targeting neuro peptide Y receptor, MOR, AgRP, MCHR 1, H3 R), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or reverse agonists, neuropeptide-Y antagonists, MCR-4 agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors (e.g. JNJ16269110, J&J), GR-II antagonist (e.g.CORT108297, Corcept Therapeutics Inc), GLPl agonists (e.g. Exenatide (Byetta®, Ely Lilly), Liraglutide (Victoza®), Novo Nordisk), Glucokinase activator (e.g. AZD1656, AstraZeneca), SGLT-2 inhibitor (e.g. gliflozines such as Invokana™ (canagliflozin), J&J; remogliflozin, Kissei, GSK, Dapagliflozin (Forxiga®, BMS, AstraZeneca)), PPAR alpha and -gamma agonist (e.g. glitazars such as LBM642 (cevoglitazar), Novartis, Aleglitazar, Roche), MetAP inhibitor (e.g.CKD732 (beloranib), Zafgen), cholescystokinin-A (CCK-A) agonists, serotonin and norepinephrine reuptake inhibitors (e.g. sibutramine), sympathomimetic agents, b3 adrenergic receptor agonists, dopamine agonists (e.g. bromocriptine), cannabinoid 1 receptor antagonists e.g. SR141716: N-(piperidin-l-yl)-5-(4- chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxamide], leptons (the OB protein), leptin analogues, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e., Orlistat), anorectic agents (such as a bombesin agonist), thyromimetic agents, dehydroepiandrosterone or an analogue thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide- 1 receptor agonists, ciliary neutrotrophic factors (such as Axokine™ Regeneron Pharmaceuticals) and neuromedin U receptor agonists.

For T2DM combinations may be selected from Incretin mimetics, GLP1 agonists (e.g. Exenatide (Byetta®, Ely Lilly), Liraglutide (Victoza®), Novo Nordisk), dual GLPl/glucagon receptor agonists, triagonist for GLPl/glucose-dependent insulinotropic polypeptide/glucagon receptor, GPR119 agonist (e.g. PSN-821, AstraZeneca), GPR40 agonist (e.g. Fasiglifam, Takeda, ASP5034, Astellas), SGLT-2 inhibitor (e.g. gliflozines such as Dapagliflozin (Forxiga®, BMS, Astra Zeneca), Canagliflozin (Ivokana® J&J)), DPPIV inhibitors (e.g. gliptine such as Sitagliptin (Januvia®, Merck)), PPAR agonist (e.g. glitazones such as Rosiglitazone (Avandia®), GSK),

Dual PPAR alpha and -gamma agonists (e.g. glitazars such as Cevoglitazar, Novartis, Aleglitazar, Roche)), Glucokinase activator (e.g. AZD1656, AstraZeneca), MTP inhibitors (e.g. JNJ16269110, J&J), Glycogen phosphorylase inhibitor, ll-beta-HSD-l(e.g. INCB13739 Incyte, AZD4017 AZ), DGAT-1 inhibitor, aldose reductase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase IB inhibitor, an insulin mimetic, metformin, acarbose, a sulfonylurea, glipazide, glyburide, or chlorpropamide, glucosidase inhibitor, meglitimide and an aP2 inhibitor.

For NAFLD/NASH combinations may comprise incretin mimetics, GLPl agonists (e.g. Exenatide (Byetta®, Ely Lilly), Liraglutide (Victoza®), semaglutide, Novo Nordisk), dual GLPl/glucagon receptor agonists, triagonist for GLPl/glucose-dependent insulinotropic polypeptide/glucagon receptor, GPR119 agonist (e.g. PSN-821, AstraZeneca), GPR40 agonist (e.g. Fasiglifam, Takeda, ASP5034, Astellas), statins (HMG-CoA Reductase, e.g. atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor) and simvastatin (Zocor)), PPARgamma agonists (e.g. Pioglitazone), PPAR agonist (e.g. glitazones such as Rosiglitazone (Avandia®), GSK), dual PPAR alpha and -gamma agonists (e.g. glitazars such as Cevoglitazar, panPPAR alpha/gamma/delta agonists (e.g. lanifibranor), AMPK (e.g. Metformin, PXL770), Drugs which increase cholesterol secretion into bile by synthetic Fatty-Acid / Bile-Acid Conjugates (e.g. Aramchol (Galmed)), FXR agonist (e.g. INT747, obetecholic acid (Intercept Pharm.), MET409), Px-102/104 (Phenex)), Cysteamine bitartrate (adiponectin multimerization) (e.g. RP103 (Raptor Pharm)), DGAT-1 inhibitor (e.g. LCQ908 (Novartis)), SAMe (methionine metabolism), oral (anti-CD3 antibody) (e.g. OKT3 (NasVax)), LOXL2 Mab (e.g. Simtuzumab (Gilead)), Omega-3 fatty acid (e.g. EPA-E (Moichida Pharm)), Dual PPARa/d agonist GFT505 (GENFIT), PDE4 inhibitor (e.g. Roflumilast (Takeda)), immunomodulation by glucospingolipid (e.g. EGS21 (Enzo)), inhibitors of acetyl-CoA carboxylase, inhibitors of ketohexokinase (e.g. PF-06835919), inhibitors of ATP citrate lyase, GLP-1 agonist, inhibitors of ASK-1 (e.g. GS4977), CCR2/CCR5 antagonist (e.g. cenicriviroc), inhibitors of SLC10A2, inhibitors of LOXL2, inhibitors of Galectin-3, inhibitors of caspase, FGF21 (e.g. BI089-100, BMS-986036), FGF19 (e.g. NGM282), inhibitors of CGRP, AOC3: Amine Oxidase, Copper Containing 3, inhibitors of DPP-4 (e.g. linagliptin, sitagliptin), THR-B agonists (e.g. MGL3196, VK2809), anti-CD3 monoclonal antibody (mAbs), A3AR agonists, inhibitors of SGLT2 (e.g. canagliflozin, dapagliflozin), inhibitors of SGLT1, inhibitors for TGFB activation, anti-cannabinoid CD1 receptor antibody, antibody agonist of the b-Klotho/FGFRl c receptor complex, inhibitors of the inflammasome, DGAT-2 antagonist, ATP citrate lyase inhibitors (e.g. bempedoic acid), stearoyl-CoA desaturase inhibitors (e.g. Aramchol™, CVT- 12805), fatty acid synthesis inhibitors (e.g. TVB-2640).

For hyper/dyslipidemia combinations may comprise statins (e.g. HMG-CoA reductase inhibitor such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor) and simvastatin (Zocor), ApoB antisense oligonucleotides (e.g. mipomersen, Kynamro), PCSK9 inhibitors (e.g. antibodies such as AMG145 (Amgen), lD05-IgG2 (Merck & Co.), and SAR236553/REGN727 (Aventis/Regeneron) or antisense RNA such as ALN-PCS, Amgen), cholesterol-absorption inhibitors (e.g. NPC1L1 inhibitors such as ezetimibe), niacin, bile-acid-sequestering resins (e.g. Cholestyramine (Questran), Colesevelam (Cholestagel, Welchol), Colestipol (Colestid) Colestipid, MTP inhibitors (e.g. lomitapide), fibrates (e.g. Bezafibrate (e.g. Bezalip), Ciprofibrate (e.g. Modalim), Clofibrate, Gemfibrozil (e.g. Lopid), Fenofibrate (e.g. TriCor)), CETP inhibitors (e.g. dalcetrapib, torcetrapib anacetrapib and evacetrapib), ATP citrate lyase inhibitors (e.g. bempedoic acid).

For anti-psychotic treatment combinations may comprise Butyrophenones (e.g. Haloperidol), Diphenylbutylpiperidine (e.g. Fluspirilene, Penfluridol, Pimozide), Phenothiazines (e.g. Fluphenazine Perazine Perphenazine Promethazine Trifluoperazine), Thioxanthenes (e.g. Clopenthixol Tiotixene) or Clozapine, Olanzapine, quetiapine, zotepine). For use in the therapeutic applications described herein, kits and articles of manufacture are also described herein. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from any acceptable material including, e.g., glass or plastic. For example, the container(s) can comprise one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.

A kit will typically comprise one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Nonlimiting examples of such materials include, but not limited to, buffers, diluents, fdters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.

A label can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. A label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein.

Compounds of general formula (I) provided herein can also be used as an inhibitor of a citrate transporter, such as INDY, in a variety of applications, both in vitro and in vivo. Inhibitors of citrate transporters according to the present invention may be used to inhibit the uptake of extracellular citrate by binding to the transporter (e.g., INDY) in vitro or in vivo. This use includes, for example, a method of inhibiting binding of extracellular citrate to INDY in vitro or in vivo, wherein said method comprises contacting INDY with at least one compound or salt described herein under conditions and in an amount sufficient to detectably inhibit binding or transport of extracellular citrate or any other substance to INDY. In some embodiments, the citrate transporter is contained in a cell, tissue or sample (e.g., a cell sample or tissue sample). In some embodiments, compounds or compositions described herein may be used in detection assays for localizing or detecting a citrate transporter in a cell, tissue or sample, and in some embodiments, such detection assays may use a detectably labelled compound, such as a compound of general formula (I), or a salt thereof, that is linked to a detectable label or functional moiety, such as a radio nucleotide, fluorophore or enzyme.

The present invention is now further illustrated by the following examples from which further features, embodiments and advantages of the present invention may be taken. However, the invention should not be construed to be limited to the examples, but encompasses the subject- matter defined in the claims.

EXAMPLES Materials and methods

Chemical names are generally IUPAC names, and abbreviations have their meanings customary per se to the skilled person. In some cases generally accepted names of commercially available reagents are used in place of IUPAC names. Abbreviations used herein as far as they are not explained within the text body include: aq. Aqueous

Alloc-Cl allyl chloroformate

BMS borane dimethylsulfide

DAST N,N-Diethylaminosuflur trifluoride

DCE 1,2-dichloroethane

DBU l,8-Diazabicyclo[5.4.0]undec-7-ene

DCM Dichloromethane

DIPEA N,N-diisopropyl-N-ethylamine

DMF N,N-dimethylformamide

DMSO Dimethylsulfoxide

DPEphos (Oxydi-2, 1 -phenylene)bis(diphenylphosphine)

ESI electron-spray ionization

Et20 diethyl ether

EtOAc ethyl acetate

FCC flash column chromatography

HATU 1 -[bis(diniethylaniino)methylene]- 1 H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

HC1 hydrochloric acid

HPLC high-performance liquid chromatography

KHMDS Potassium hexadimethyldisilazide

KOtBu potassium tert-butoxide IPA Isopropanol

LC liquid chromatography

LCMS liquid chromatography - mass spectrometry

LiAlH4 Lithium aluminium hydride

M Molar

MeCN Acetonitrile

Mel Iodomethane

MeMgBr methylmagnesium bromide

MeOH Methanol

MgS0₄ magnesium sulfate

MHz mega Hertz

Mn02 Manganese dioxide pL microlitre(s) min minute(s) mg milligram(s) mL milliliter(s) mmol millimole(s)

NaH sodium hydride

NaHC0₃ sodium bicarbonate

NaOH sodium hydroxide

Na₂S0₄ sodium sulfate n-BuLi n-butyllithium

NH₄C1 ammonium chloride

NMP N -methy lpy rroli dinone

NMR nuclear magnetic resonance

Pd(PPh₃) Tetrakis(triphenylphosphane)palladium(0)

R.P.B reverse phase biotage

Rt retention time

RT Room Temperature sat. Saturated

SFC supercritical fluid chromatography

STAB sodium triacetoxyborohydride

TBME tert-butyl methyl ether

THF Tetrahydrofuran Specific examples for the preparation of compounds of general formula (I) are provided below. Unless otherwise specified all starting materials and reagents are of standard commercial grade, and are used without further purification, or are readily prepared from such materials by routine methods. Those skilled in the art of organic synthesis will recognize that starting materials and reaction conditions may be varied including additional steps employed to produce compounds encompassed by the present invention. Analytical methods and conditions used for the chemical characterization of compounds are summarized below.

NMR Spectroscopy

Unless otherwise stated, ¾ NMR spectra were recorded at 500 MHz, 400 MHz or 250 MHz on either a Bruker Avance III HD 500 MHz, Bruker Avance III HD 400 MHz spectrometer or Bruker Avance PI HD 250 MHz spectrometer respectively. Chemical shifts, d, are quoted in parts per million (ppm) and are referenced to the residual solvent peak. The following abbreviations are used to denote the multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad).

Analytical HPLC conditions

Method 1

Analytical (Method 1) HPLC-MS were performed on a Shimadzu LCMS systems using a Kinetex Core shell C18 column (2.1 mm x 50 mm, 5 pm; temperature: 40 °C) and a gradient of 5-100% B (A= 0.1% formic acid in H2O; B= 0.1% formic acid in MeCN) over 1.2 min then 100% B for 0.1 min. A second gradient of 100-5% B was then applied over 0.01 min with an injection volume of 3 pL at a flow rate of 1.2 mL/min. UV spectra were recorded at 215 nm using a SPD-M20A photo diode array detector spectrum range: 200-400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

Method 2

Analytical (Method 2) uHPLC-MS were performed on a Waters Acquity uPLC system using a Waters UPLC® BEH™ Cl 8 column (2.1 mm x 50 mm, 1.7 pm; temperature 40 °C) and a gradient of 5-100% B (A= 0.1% formic acid in H2O: B= 0.1 % formic acid in MeCN) over 1.1 min then 100% B for 0.25 min. A second gradient of 100-5% B was then applied over 0.05 min and held for 0.1 min with an injection volume of 1 pL at a flow rate of 0.9 mL/min. UV spectra were recorded at 215 nm on a Waters Acquity PDA with a spectrum range of 200-400 nm. Mass spectra were obtained using a Waters QDa. Data were integrated and reported using Waters MassLynx and OpenLynx software.

Method 3

Analytical (Method 3) HPLC-MS were performed on a Agilent G1312A system with Waters PDA and ELS detectors using a Phenomenex Gemini-NX Cl 8 column (2.0 mm x 50 mm, 3 mM; temperature: 40 °C) and a gradient of 1-100% (A= 2 mM ammonium bicarbonate, buffered to pH 10 with ammonium hydroxide solution; B = MeCN) over 1.8 min then 100% B for 0.3 min, with an injection volume of 3 pL and a flow rate of 1.0 mL/min. UV spectra were recorded at 215 nm using a Waters 2996 photo diode array detector. Mass spectra were obtained over the range m/z 150 to 850 at a sampling rate of 5 scans per sec using a Waters ZQ. Data were integrated and reported using Waters MassLynx and OpenLynx software.

Method 4

Analytical (Method 4) uHPLC-MS were performed on a Waters ACQUITY uPLC system using a Waters uPLC® BEHTM Cl 8 column (2.1 mm x 30 mm, 1.7 pm; temperature 55 °C) and a gradient of 1-100% B (A= 2 mM ammonium bicarbonate, buffered to pH 10; B = ACN) over 1.1 min, then 100% B for 0.25 min. A second gradient of 100-1% B was then applied over 0.05 min and held for 0.4 min with an injection volume of 1 pL at a flow rate of 1.0 mL/min. UV spectra were recorded at 215 nm on a Waters ACQUITY PDA with a spectrum range of 200-400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector or a Waters SQD2. Data were integrated and reported using Waters MassLynx and OpenLynx software.

Method 5

Analytical (Method 5) uHPLC-MS were performed on a Waters Acquity uPLC system using a Phenomenex Kinetex-XB Cl 8 column (2.1 mm x 100 mm, 1.7 pM; temperature: 40 °C) and a gradient of 5-100% B (A = 0.1% formic acid in ¾0; B = 0.1% formic acid in MeCN) over 5.3 min then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min with an injection volume of 1 pL at flow rate of 0.6 mL/min. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector spectrum range: 200-400 nm, ELS data was collected using a Water Acquity ELS detector (where fitted) were reported. Mass spectra were obtained using a Waters SQD or Waters Acquity QDA. Data were integrated and reported using Waters MassLynx and OpenLynx software.

Method 6

Analytical (Method 6) HPLC-MS were performed on Shimadzu LCMS systems using a Waters Atlantis dC18 column (2.1 mm x 100 mm, 3 pm; temperature: 40 °C) and a gradient of 5-100% B (A= 0.1% formic acid in ¾0; B= 0.1% formic acid in MeCN) over 5 min then 100% B for 0.4 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.58 min with an injection volume of 3 pL at flow rate of 0.6 mL/min. UV spectra were recorded at 215 nm using a SPD-M20A photo diode array detector spectrum range: 200-400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS- Solutions and PsiPort software.

Method 7

Analytical (Method 7) HPLC-MS were performed on an Agilent G1312A system using a Phenomenex Gemini NX Cl 8 column (2.0 mm x 100 mm, 3 pm; temperature: 40 °C) and a gradient of 5-100% B (A= 2 mM ammonium bicarbonate, buffered to pH 10; B = MeCN) over 5.5 min then 100% B for 0.4 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.08 min with an injection volume of 3 pL and at flow rate of 0.6 mL/min. UV spectra were recorded at 215 nm using a Waters 2996 photo diode array detector spectrum range: 200-400 nm. ELS data was collected using a Water 2420 detector when reported. Mass spectra were obtained using a Waters ZQ mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software.

Method 8

Analytical (Method 8) uPLC-MS were performed on a Waters Acquity uPLC system using a Waters UPLC® BEH™ C18 column (2.1 mm x 100mm, 1.7pm column; temperature: 40°C) and a gradient of 5-100% (A= 2 mM ammonium bicarbonate, buffered to pH 10; B = MeCN) over 5.3 min then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min with an injection volume of 1 pL and at flow rate of 0.6 mL/min. UV spectra were recorded at 215 nm using a Waters Acquity photo diode array detector Spectrum range: 200- 400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software.

Method 9

Analytical (Method 9) uPLC-MS were performed on a Waters Acquity uPLC system using a Waters Acquity uPLC CSH Cl 8 column (50 mm x 2.1 mm i.d. 1.7 pm; temperature: 40 °C) and a gradient of 3-100% (A = 0.1% v/v solution of formic acid in ¾0; B 0.1% v/v solution of formic acid in MeCN) over 1.5 min, then 100% B for 0.4 min. A second gradient of 100-3% B was then applied over 0.1 min with an injection volume of 1 pL and at flow rate of 1 mL/min. UV spectra were recorded using a Waters Acquity uPLC Tunable UV Detector Spectrum range 210-350 nm. Mass spectra were obtained using a Waters ZQ mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software.

Method 10

Analytical (Method 10) uPLC-MS were performed on a Waters Acquity uPLC system using a Waters UPLC® BEHTM C18 column (2.1 mm x 100mm, 1.7pm column; temperature: 55°C) and a gradient of 5-100% (A= 2 mM ammonium bicarbonate, buffered to pH 10; B = MeCN) over 5.3 min then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min with an injection volume of 1 pL and at flow rate of 0.6 mL/min. UV spectra were recorded at 215 nm using a Waters Acquity photo diode array detector Spectrum range: 200- 400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software.

Chiral Analytical HPLC conditions

Method Cl

Analytical chiral LC (Method Cl) were performed on Waters LC system using a Cellulose-4 column (4.6mm x 250mm, 5pm) at RT and an isocratic eluent of 8.5/1.5 heptane/ethanol over 25mins, with an injection volume of 20pL and a flow rate of 0.5mL/min. UV spectra were recorded at 254nm using a Waters 2996 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.

Method C2

Analytical chiral LC (Method C2) were performed on Waters LC system using a Chiralcel OD-H column (4.6mm x 250mm, 5pm) at RT and an isocratic eluent of 8.5/1.5 heptane/ethanol over 25mins, with an injection volume of 20pL and a flow rate of lmL/min. UV spectra were recorded at 254nm using a Waters 2996 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.

Method C3

Analytical chiral LC (Method C3) were performed as for Method C2, except that a Chiralpak AD-H column was used.

Method C4

Analytical chiral LC (Method C4) were performed as for Method C2, except that a Chiralcel OJ- H column was used.

Method C5

Analytical chiral LC (Method C5) were performed on Waters LC system using a Chiralcel OD-H column (4.6mm x 250mm, 5pm) at RT and an isocratic eluent of 8/2 heptane/isopropanol over 25mins, with an injection volume of 20pL and a flow rate of lmL/min. UV spectra were recorded at 254nm using a Waters 2996 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software. Method C6

Analytical chiral SFC (Method C6) were performed on Waters Thar SFC using a Cellulose-4 column (4.6mm x 250mm, 5pm) at 40°C and an isocratic eluent of 8/2 CC /methanol over 5mins, with an injection volume of lOpL and a flow rate of 4mL/min, backpressure of 120bar. UV spectra were recorded at 215nm using a Waters 2998 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.

Method C7

Analytical chiral SFC (Method C7) were performed on Waters Thar SFC using a Chiralcel OJ-H column (4.6mm x 250mm, 5pm) at 40°C and an isocratic eluent of 7/3 CC /isopropanol over 5mins, with an injection volume of lOpL and a flow rate of 4mL/min, backpressure of 120bar.

UV spectra were recorded at 215nm using a Waters 2998 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.

Method C8

Analytical chiral SFC (Method C8) were performed on Waters Thar SFC using a Chiralcel OJ-H column (4.6mm x 250mm, 5pm) at 40°C and an isocratic eluent of 6.5/3.5 C0₂/methanol over 5mins, with an injection volume of lOpL and a flow rate of 4mL/min, backpressure of 120bar.

Method C9

Analytical chiral SFC (Method C9) were performed on Waters Thar SFC using a Chiralpak AD- H column (4.6mm x 250mm, 5pm) at 40°C and an isocratic eluent of 8.5/1.5 C0₂/methanol over 5mins, with an injection volume of lOpL and a flow rate of 4mL/min, backpressure of 120bar.

Method CIO

Analytical chiral SFC (Method CIO) were performed as for Method C9, except that an isocratic eluent of 8/2 C0₂/ethanol was used.

Method Cll

Analytical chiral SFC (Method Cll) were performed as for Method C9, except that an isocratic eluent of 7.5/2.5 C0₂/ethanol was used.

Method C12

Analytical chiral SFC (Method C12) were performed as for Method C9, except that a Chiralpak AS-H column was used. Method C13

Analytical chiral SFC (Method C13) were performed on Waters Thar SFC using a Chiralpak IC column (4.6mm x 250mm, 5pm) at 40°C and an isocratic eluent of 8/2 CC /isopropanol over 5mins, with an injection volume of 10pL and a flow rate of 4mL/min, backpressure of 120bar. UV spectra were recorded at 215nm using a Waters 2998 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.

Method C14

Analytical chiral SFC (Method C14) were performed as for Method C2, except that an isocratic eluent of 8.5/1.5 heptane/isopropanol was used.

Method C15

Analytical chiral SFC (Method C15) were performed as for Method C6, except that an isocratic eluent of 8.5/1.5 C02/acetonitrile was used.

Preparative HPLC conditions

Method A: BASIC STANDARD METHOD

Purifications were performed on a Gilson LC system using a Waters X-Bridge Cl 8 column (30 mm x 10 mm, 10 mM; temperature: r.t.) and a gradient of 30-95% B (A= 0.2% ammonium hydroxide in water; B= 0.2% ammonium hydroxide in ACN) over 11.00 min then 95% B for 2.10 min. A second gradient of 95-30% B was then applied over 0.21 min with an injection volume of 1500 pL at flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.

Method B: BASIC EARLY METHOD

Purifications were performed on a Gilson LC system using a Waters X-Bridge Cl 8 column (30 mm x 100 mm, 10 pM; temperature: r.t.) and a gradient of 10-95% B (A= 0.2% ammonium hydroxide in H20; B= 0.2% ammonium hydroxide in ACN) over 14.44 min then 95% B for 2.11 min. A second gradient of 95-10% B was then applied over 0.2 min with an injection volume of 1500 pL at flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.

Method C: ACIDIC EARLY METHOD

Purifications were performed on a Gilson LC system using a Waters Sunfire Cl 8 column (30 mm x 100 mm, 10 pM; temperature: r.t.) and a gradient of 10-95% B (A= 0.1% formic acid in H20; B= 0.1% formic acid in ACN) over 14.44 min then 95% B for 2.11 min. A second gradient of 95- 10% B was then applied over 0.2 min with an injection volume of 1500 pL at flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector. Synthesis of compounds Intermediate 1

Potassium 6-benzyl-4-cyano-l-oxo-l,2,5,6,7,8-hexahydro-2,6-naphthyridin-3-olate

Ethyl 1 -benzyl-3 -oxopiperidine-4-carboxylate hydrochloride (240 g, 806 mmol) was partitioned between DCM and sat. aq. NaHCCE solution. The organic layer was separated, dried over anhydrous INfeSCE and concentrated in vacuo to give the free base which was dissolved in MeOH

(1.76 L) with stirring under nitrogen. 2-cyanoacetamide (67.8 g, 806 mmol) and potassium hydroxide (1 M in MeOH, 1.04 L) was added. The reaction was stirred at 74 °C for 3 h, during which time a pale precipitate formed. The reaction mixture was cooled to RT then filtered. The resulting solid was washed with TBME and dried to give 246 g (96% yield, 100% purity) of the title compound as an off-white solid. m/z: 282 [M+H]+, (ESI+), Rt = 0.35 mm, Method 9

1HNMR (400 MHz, DMSO-d6) d [ppm]: 9.37 (s, 1H), 7.40 - 7.30 (m, 4H), 7.30 - 7.20 (m, 1H), 3.58 (s, 2H), 3.20 - 3.10 (m, 2H), 2.19 (t, 2H). 2 protons not observed.

Intermediate 2

6-benzyl-l,3-dichloro-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile

Intermediate 1 (100 g, 313 mmol) was mixed with DIPEA hydrochloride (67.2 g, 407 mmol). To the solid mixture, cooled with an ice bath, phosphorus oxychloride (134.4 g, 877 mmol) was cautiously added. After the addition the mixture was stirred at RT for 30 min. The mixture was cooled to 0 °C and DIPEA (44.5 g, 344 mmol) was added dropwise, the mixture was warmed to RT and stirred for 30 min. The solid mixture was stirred at 120 °C (external temp) for 6 h under nitrogen. The mixture was allowed to cool and the slurry poured cautiously into a mixture of sat. aq. NaHCCE solution and ice, and stirred for 20 min (pH > 6). EtOAc was added and the mixture stirred for 30 min. The aqueous phase was extracted again with EtOAc and the combined organic layers were concentrated in vacuo. Purification through a silica gel pad (eluting with 80% EtOAc in cyclohexane) followed by trituration in cyclohexane gave 41 g (41% yield, 99% purity) of the title compound as a brown solid. m/z: 318/320/322 [M+H]+, (ESI+), Rt = 0.99 min, Method 9

1HNMR (400 MHz, Chloroform-d) d [ppm]: 7.41 - 7.31 (m, 5H), 3.83 (s, 2H), 3.77 (s, 2H), 2.89 - 2.83 (m, 2H), 2.83 - 2.78 (m, 2H).

Intermediate 3

6-benzyl-3-chloro-l-[(cyanomethyl)amino]-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile

To a stirred solution of Intermediate 2 (1.97 g, 5.94 mmol) in NMP (33 mL) was added DIPEA (1.90 mL, 10.8 mmol), followed by 2-aminoacetonitrile (510 mg, 8.91 mmol). The reaction was stirred at 110 °C for 5 h before cooling to RT and stirring for 16 h. On completion, the reaction mixture was diluted with TBME and water and the organic layers separated. The aqueous phase was extracted with TBME and the combined organic extracts washed with water. The organic phase was separated, partially concentrated in vacuo and then filtered. The filter cake was washed with TBME and the filtrate partially concentrated in vacuo. The resulting precipitate was collected via filtration and the filter cake washed with TBME. The two crops of solid were combined, dissolved in EtOAc and concentrated in vacuo to give a solid. The aqueous phase was further extracted with EtOAc and the organic layer combined with the filtrate and concentrated in vacuo. Purification of material by FCC (silica gel, eluting with EtOAc in heptane, 0 - 100% gradient) gave a solid. The two crops of solid were dissolved in EtOAc, combined with mixing, and concentrated in vacuo. Subsequent trituration with Et₂0 gave 1.46 g (71% yield, 98% purity) of the title compound as a pale brown solid m/z: 338/340 [M+H]+, (ESI+), Rt = 0.96 mm, Method 1

1HNMR (500 MHz, Chloroform-d) d [ppm]: 7.38 - 7.27 (m, 5H), 4.97 (t, 1H), 4.46 (d, 2H), 3.75 - 3.69 (m, 4H), 2.78 (t, 2H), 2.46 - 2.38 (m, 2H). Example 1: Synthesis of Compound 1

6-benzyl-3-chloro-l-[(2-methoxyethyl)amino]-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Compound 1 was prepared from Intermediate 2, using a similar method to that used in the synthesis of Intermediate 3. m/z: 357 / 359 [M+H]+, (ESI+), Rt = 4.74 mm, Method 7

1HNMR (500 MHz, Chloroform-d) d [ppm]: 7.36 - 7.32 (m, 4H), 7.31 - 7.27 (m, 1H), 5.15 (t, 1H), 3.73 - 3.68 (m, 4H), 3.68 - 3.65 (m, 2H), 3.57 - 3.53 (m, 2H), 3.37 (s, 3H), 2.75 (t, 2H), 2.40 - 2.36 (m, 2H).

Intermediate 4

3-chloro-l-[(cyanomethyl)amino]-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride To a solution of Intermediate 3 (590 mg, 1.71 mmol) in anhydrous MeCN (12 mL) was added 1- chloroethyl chloroformate (0.38 mL, 3.49 mmol) and the reaction stirred at 40 °C under nitrogen for 1.5 h. The reaction mixture was concentrated in vacuo and the residue dissolved in methanol (12 mL) and stirred at RT for 3 days. The mixture was concentrated in vacuo and the residue triturated in 20% EtOAc in heptane. The solvent was decanted and the product dried in vacuo to give 621 mg (83% yield, 65% purity) of the title compound as a brick-red coloured solid. m/z: 248/250 [M+H]+, (ESI+), Rt = 0.73 mm, Method 1 Intermediate 5

3-bromo-6-isopropoxy-2-methyl -pyridine

To a solution of propan-2-ol (282 uL, 3.69 mmol) and 3-bromo-6-fluoro-2-methylpyridine (98%, 828 uL, 2.84 mmol) in NMP (4.4 mL) was added potassium tert-butoxide (4.3 mL, 4.25 mmol). The reaction mixture was stirred at RT for 2.5 h. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were washed with water and brine (15 mL), dried over Na2S04, filtered and concentrated. The material was purified by FCC (25g silica column, 0-10% EtOAc in heptane) and the product containing fractions concentrated to give the title compound (502 mg, 2.14 mmol, 75% Yield) as a pale yellow oil. lH NMR (500 MHz, DMSO-d6) d [ppm]: 7.79 (d, J = 8.6 Hz, 1H), 6.58 - 6.47 (m, 1H), 5.19 (hept, J = 6.2 Hz, 1H), 2.46 (s, 3H), 1.27 (d, J = 6.2 Hz, 6H).

Intermediate 6

6-isopropoxy-2-methyl-pyridine-3-carbaldehyde

A solution of Intermediate 5 (250 mg, 1.09 mmol) in anhydrous THF (5 mL) was cooled to -78 °C under nitrogen and treated dropwise with a solution of 2.5 M n-BuLi in hexanes (0.87 mL, 2.17 mmol). The reaction mixture was stirred for lh at -78 °C. To the mixture was added DMF (0.092 mL, 1.20 mmol) at -78 °C and the mixture allowed to warm to RT overnight. The mixture was quenched with sat. aq. NH4C1 solution (2 mL), then diluted with water and extracted with EtOAc (x2). The combined organic extracts were dried (MgS04), filtered and concentrated. The material was purified by FCC (25g silica column, 0-50% EtOAc in heptane) and the product containing fractions concentrated to give the title compound (75% purity) (EV-IRU001-624-001) (96 mg, 0.402 mmol, 37% Yield) as a pale yellow oil. lH NMR (400 MHz, DMSO-d6) d [ppm]: 10.15 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 5.37 (h, J = 6.2 Hz, 1H), 2.71 (s, 3H), 1.31 (d, J = 6.2 Hz, 6H). Example 2: Synthesis of Compound 2

To a stirred suspension of Intermediate 4 (60% purity, 150 mg, 0.317 mmol) and Intermediate 6 (75%, 91 mg, 0.380 mmol) in DCE (4.3 mL) was added triethylamine (132 uL, 0.950 mmol) and the mixture stirred at RT for 15min. Sodium triacetoxyborohydride (168 mg, 0.792 mmol) was added and the mixture stirred at RT for 5.5 h. The mixture was diluted with DCM and sat. aq. NaHC03 and stirred for 15 min. The layers were separated and the aqueous extracted with DCM (x2). The combined organic was passed through a phase separator and then concentrated. The crude material was purified by prep HPLC (Method A). The product containing fractions were combined then concentrated and dried in the vacuum oven overnight to give 3-chloro-l- (cyanomethylamino)-6-[(6-isopropoxy-2-methyl-3-pyridyl)methyl]-7,8-dihydro-5H-2,6- naphthyridine-4-carbonitrile (99.0%) (36 mg, 0.0867 mmol, 27% Yield) as a tan solid m/z: 411.3 [M+H]+, (ESI+), Rt = 2.62 mm, Method 5 lHNMR (400 MHz, DMSO-d6) d [ppm]: 7.91 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 5.23 (hept, J = 6.2 Hz, 1H), 4.37 (s, 2H), 3.61 (s, 2H), 3.58 (s, 2H), 2.72 (t, J = 5.7 Hz, 2H), 2.45 - 2.36 (m, 5H), 1.27 (d, J = 6.2 Hz, 6H).

Example 3: Compounds 3 to 60 and 255

The compounds 3 to 60 and 255 shown in the following Table 1 are further representative examples of compounds according to general formula (I) of the present invention. These compounds have been synthesized using methods similar to that described in relation to the preparation of Compound 2 above, together with synthetic methods disclosed herein or known in the art of synthetic organic chemistry, and variations thereon as appreciated by those skilled in the art. Aldehydes were prepared using similar methods to Intermediate 6 or were purchased from commercial suppliers. In any event, those skilled in the art of organic synthesis will recognize the starting materials and reaction conditions including variations to produce the compounds. Table 1: Compounds 3 to 60 and 255

Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No.

Intermediate 7

3-bromo-6-(difluoromethoxy)-2-methylpyridine

5-bromo-6-methylpyridin-2-ol (1.80 g, 9.57 mmol), l,3-bis[2,6-di(propan-2-yl)phenyl]-4,5- dihydro-lH-imidazol-3-ium chloride (235 mg, 0.685 mmol), and sodium carbonate (203 mg, 1.92 mmol) were suspended in toluene (60 mL), then trimethyl silyl difluoro(fluorosulfonyl)acetate (3.8 mL, 19.1 mmol) was added at RT. The reaction was stirred at 80 °C for 1.5 h under nitrogen, then cooled to RT and quenched with 1M NaOH. The organic phase was separated, dried over MgSCH, fdtered and concentrated in vacuo. The aqueous layer was extracted with DCM (x3). The DCM extracts were combined, dried over MgSCH, filtered, added to the previously concentrated organics and then the combined organics were concentrated in vacuo. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0-100% gradient) followed by further purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 40% gradient) gave 1.15 g (50% yield, 99% purity) of the title compound as a pale yellow oil. m/z: 238/240 [M+H]+, (ESI+), Rt = 1.01 mm, Method 2

1HNMR (400 MHz, Chloroform-d) d [ppm]: 7.78 (d, 1H), 7.44 (t, 1H), 6.65 - 6.61 (m, 1H), 2.56

(s, 3H).

Intermediate 8

6-(difluoromethoxy)-2-methylpyridine-3-carbaldehyde

To a solution of Intermediate 7 (99%, 400 mg, 1.66 mmol) in dry diethyl ether (11 mL) at -78 °C was added 2.5 M n-BuLi in hexanes (0.88 mL, 2.20 mmol) over 5 min. The reaction mixture was stirred for 45 min at -78 °C under nitrogen and then dry DMF (0.58 mL, 7.49 mmol) was added over 10 seconds. The reaction mixture was allowed to warm to RT and then to the reaction mixture was added sat. aq. NH₄CI solution and water and the reaction mixture was stirred at RT for 5 min. The organics were extracted with Et₂0 and washed with water and then brine. The organics were dried over MgSCL, fdtered and then concentrated in vacuo. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 65% gradient) gave 170 mg (51% yield, 93% purity) of the title compound as a pale yellow oil. m/z: 188 [M+H]+, (ESI+), Rt = 0.81 mm, Method 2

1HNMR (400 MHz, Chloroform-d) d [ppm]: 10.26 (s, 1H), 8.15 (d, 1H), 7.59 (t, 1H), 7.01 - 6.58 (m, 1H), 2.80 (s, 3H). Example 4: Synthesis of Compound 61

3-chloro-l-(cyanomethylamino)-6-[[6-(difluoromethoxy)-2-methyl-3-pyridyl]methyl]-7,8- dihydro-5H-2,6-naphthyridine-4-carbonitrile

Compound 61 was prepared from Intermediate 8 and Intermediate 4, using a similar method to that used to prepare Compound 2. m/z: 418.2 / 421.2 [M+H]+, (ESI+), Rt = 3.08 min, Method 5 lH NMR (500 MHz, DMSO-d6) d [ppm]: 7.93 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.68 (t, J = 73.2 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 4.37 (s, 2H), 3.69 (s, 2H), 3.61 (s, 2H), 2.73 (t, J = 5.8 Hz, 2H), 2.46 (s, 3H), 2.41 (t, J = 5.6 Hz, 2H).

Intermediate 9

2-amino-6-(2,2-difluoroethoxy)pyridine-3 -carboxylic acid

To a mixture of sodium hydride (60%, 0.5 g) in anhydrous NMP (10 mL) at 0 °C was added 2,2- difluoroethanol (1.7 mL, 26.8 mmol) and methyl 2-amino-6-chloropyridine-3-carboxylate (1.00 g, 5.36 mmol). The mixture was stirred at 120 °C for 2h. Mixture cooled, acidified to pH3 by 1 M (aq.) HC1 (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried with magnesium sulfate and concentrated in vacuo to give a brown oil. Purification by LCC (silica gel, eluting with ethyl acetate in heptane, 0 - 100% gradient and with methanol in ethyl acetate, 0-20% gradient) gave the title compound (794 mg, 35% purity, 24% yield) as a dark red gum. m/z: 219.1 [M+H]+, (ESI+), Rt = 0.68 min, Method 2

Intermediate 10

[2-amino-6-(2,2-difluoroethoxy)-3-pyridyl]methanol

To a solution of Intermediate 9 (35%, 794 mg, 1.27 mmol) in anhydrous THF (5 mL) at 0°C was added 2.4 MLiAlH4 in THF (1.1 mL, 2.55 mmol) dropwise. Mixture slowly allowed to warm to RT and stirred for 3h. Three further portions of 2.4 M LiAlH4 in THF were added over 9 hours. The mixture was quenched with 1M NaOH and the resulting suspension was filtered and the precipitate washed with ethyl acetate. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (MgS04) and concentrated in vacuo to give a yellow oil (258 mg). Purification by FCC (silica gel, eluting with ethyl acetate in heptane, 0 - 100% gradient) gave 118 mg (29% yield, 64% purity) of the title compound as a yellow oil. lH NMR (500 MHz, DMSO-d6) d [ppm]: 7.32 (d, J = 7.9 Hz, 1H), 6.36 (tt, J = 55.2, 3.8 Hz, 1H), 5.97 (d, J = 7.8 Hz, 1H), 5.76 (s, 2H), 4.98 (t, J = 5.4 Hz, 1H), 4.42 (td, J = 14.9, 3.8 Hz, 2H), 4.29 (d, J = 5.4 Hz, 2H).

Intermediate 11

2-amino-6-(2,2-difluoroethoxy)pyridine-3-carbaldehyde

To a solution of Intermediate 10 (64%, 118 mg, 0.370 mmol) in DCM (5 mL) was added dioxomanganese (96 mg, 1.11 mmol) at RT and the mixture was stirred at RT. Further dioxomanganese (96 mg, 1.11 mmol) was added after 5h, and then again after a further 2h. The mixture was stirred at RT overnight. The mixture was fdtered through celite, and the filtrate was concentrated in vacuo to give the title compound (116 mg, 64% yield) as a yellow gum. m/z: 203.1 [M+H]+, (ESI+), Rt = 0.72 mm, Method 2 Example 5: Synthesis of Compound 62

6-[[2-amino-6-(2,2-difluoroethoxy)-3-pyridyl]methyl]-3-chloro-l-(cyanomethylamino)-7,8- dihydro-5H-2,6-naphthyridine-4-carbonitrile

Compound 62 was prepared from Intermediate 11 and Intermediate 4, using a similar method to that used to prepare Compound 2. m/z: 434.3 / 436.3 [M+H]+, (ESI+), Rt = 2.53 mm, Method 5

1HNMR (500 MHz, DMSO-d6) d [ppm]: 7.93 (s, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.37 (tt, J = 55.2, 3.8 Hz, 1H), 6.02 - 5.98 (m, 3H), 4.44 (td, J = 14.9, 3.8 Hz, 2H), 4.37 (s, 2H), 3.58 (s, 2H), 3.51 (s, 2H), 2.69 (t, J = 5.8 Hz, 2H), 2.41 (t, J = 5.5 Hz, 2H).

Intermediate 12

6-bromo-3-(dimethoxymethyl)-2-methylpyridine

To a solution of 6-bromo-2-methyl-pyridine-3-carbaldehyde (1.48 g, 7.40 mmol) in anhydrous methanol (45 mL) was added p-toluenesulfonic acid monohydrate (141 mg, 0.741 mmol) and trimethyl orthoformate (0.90 mL, 8.23 mmol). The reaction mixture was stirred at RT under nitrogen for 18 h and then concentrated in vacuo. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 15% gradient) gave 1.39 g (73% yield, 95% purity) of the title compound as a colourless oil. m/z: 246/248 [M+H]+, (ESI+), Rt = 0.68 mm, Method 10

1HNMR (400 MHz, Chloroform-d) d [ppm]: 7.69 (d, 1H), 7.33 (d, 1H), 5.42 (s, 1H), 3.30 (s, 6H), 2.56 (s, 3H). Intermediate 13

3-[5-(dimethoxymethyl)-6-methylpyridin-2-yl]oxetan-3-ol

To a solution of Intermediate 12 (95%, 1.15 g, 4.44 mmol) in dry diethyl ether (30 mL) at -78 °C under nitrogen was added 2.3 M butyllithium (2.3 mL, 5.29 mmol) over 15 seconds. The reaction mixture was stirred at -78 °C for 30 min and then oxetan-3-one (0.57 mL, 8.89 mmol) was added and the reaction mixture allowed to warm to RT and stirred for a further 2 h. To the reaction mixture was added sat. aq. NH4C1 solution, water and diethyl ether. The organics were washed with water, then brine, dried over MgS04, filtered and concentrated in vacuo. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 40% gradient) gave 543 mg (49% yield, 95% purity) of the title compound as a colourless oil. m/z: 240 [M+H]+, (ESI+), Rt = 0.46 mm, Method 2

1HNMR (400 MHz, Chloroform-d) d [ppm]: 8.03 (d, 1H), 7.82 (d, 1H), 6.19 (s, 1H), 5.49 (s,

1H), 5.10 - 5.06 (m, 2H), 4.74 - 4.66 (m, 2H), 3.34 (s, 6H), 2.59 (s, 3H).

Intermediate 14

3-[5-(dimethoxymethyl)-6-methylpyridin-2-yl]oxetan-3-yl lH-imidazole-l-carbothioate

To a solution of Intermediate 13 (83%, 500 mg, 1.73 mmol) in anhydrous THF (17 mL) at 0 °C was added NaH (60%, 209 mg, 5.23 mmol). The reaction mixture was allowed to warm to RT and stirred for 2 h under nitrogen. 1 , 1 '-Thiocarbonyldiimidazole (400 mg, 2.24 mmol) was then added. The reaction mixture was stirred rapidly for 1 h and then sat. aq. NH4C1 solution was added. The organics were diluted with EtOAc and washed with water and brine. The organics were passed through a phase separator and concentrated in vacuo. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 100% gradient) gave 145 mg (22% yield, 90% purity) of the title compound as a yellow oil. m/z: 282 [M-imidazole]+, (ESI+), Rt = 0.81 min, Method 2

1HNMR (400 MHz, Chloroform-d) d [ppm]: 8.45 - 8.38 (m, 1H), 7.85 (d, 1H), 7.73 - 7.68 (m, 1H), 7.25 (d, 1H), 7.12 - 7.07 (m, 1H), 5.46 (s, 1H), 5.24 - 5.17 (m, 4H), 3.32 (s, 6H), 2.59 (s, 3H).

Intermediate 15

2-methyl-6-(oxetan-3 -yl)pyridine-3 -carbaldehyde To a stirring solution of Intermediate 14 (87%, 540 mg, 1.34 mmol) in anhydrous toluene (60.0 mL) was added diphenylsilane (2.0 mL, 10.8 mmol) and the reaction mixture was heated to reflux under nitrogen. A solution of lauroyl peroxide (810 mg, 2.03 mmol) in anhydrous toluene (20.0 mL) was prepared which was added to the refluxing mixture in 3 aliquots (4 mL each) at intervals of 15 min. After a total of 45 min at reflux the reaction mixture was cooled to RT and concentrated in vacuo. Purification by LCC (silica gel Cl 8, eluting with acetonitrile (0.1% formic acid) in water (0.1% formic acid), 10 - 100% gradient) followed by purification by preparative HPLC (Method B) gave 80 mg (19% yield, 57% purity) of the title compound as an off-white powder. m/z: 178 [M+H]+, (ESI+), Rt = 0.39 mm, Method 2 1HNMR (500 MHz, Chloroform-d) d [ppm]: 10.33 (s, 1H), 8.13 (d, 1H), 7.37 (d, 1H), 5.13 - 5.05 (m, 2H), 4.97 - 4.89 (m, 2H), 4.53 - 4.43 (m, 1H), 2.93 (s, 3H).

Example 6: Synthesis of Compound 63

3-Chloro-l-(cyanomethylamino)-6-[[2-methyl-6-(oxetan-3-yl)-3-pyridyl]methyl]-7,8-dihydro-5H-

2,6-naphthyridine-4-carbonitrile Compound 63 was prepared from Intermediate 14 and Intermediate 4, using a similar method to that used to prepare Compound 2. m/z: 409.3 / 411.2 [M+H]+, (ESI+), Rt = 2.85 mm, Method 8

1HNMR (500 MHz, DMSO-d6) d [ppm]: 7.92 (s, 1H), 7.63 (d, 1H), 7.16 (d, 1H), 4.87 (dd, 2H), 4.78 (dd, 2H), 4.38 (s, 2H), 4.37 - 4.30 (m, 1H), 3.70 (s, 2H), 3.62 (s, 2H), 2.79 - 2.72 (m, 2H), 2.53 (s, 3H), 2.45 - 2.38 (m, 2H).

Intermediate 16

Prop-2-en-l-yl 7-chloro-8-cyano-5-[(cyanomethyl)amino]-l,2,3,4-tetrahydro-2,6-naphthyridine- 2-carboxylate

Intermediate 3 (8.90 g, 26.3 mmol) was dissolved in anhydrous MeCN (150 mL), treated with DIPEA (9.0 mL, 51.5 mmol) and cooled to 0 °C. Alloc-Cl (3.6 mL, 33.7 mmol) was dissolved in anhydrous MeCN (50 mL) and added to the previously made solution. The reaction mixture was stirred at 40 °C for 90 min. Additional Alloc-Cl (1.0 mL, 9.37 mmol) was added and the reaction was stirred at 40 °C for 30 min. The mixture was concentrated and suspended in sat. aq. NaHC03 solution and extracted into EtOAc. The combined organic extracts were dried over Na2S04, filtered and concentrated in vacuo. Purification by LCC (silica gel, eluting with EtOAc in heptane, 0 - 100% gradient) gave 7.73 g (88% yield, 99% purity) of the title compound as an off-white solid. m/z: 332/334 [M+H]+, (ESI+), Rt = 0.83 mm, Method 2 lHNMR (500 MHz, DMSO-d6) d [ppm]: 8.06 (s, 1H), 5.95 (ddt, 1H), 5.30 (d, 1H), 5.25 - 5.16 (m, 1H), 4.68 - 4.57 (m, 4H), 4.38 (s, 2H), 3.67 (br. s, 2H), 2.46 (t, 2H). Example 7: Synthesis of Compound 64

3 -Chloro- 1 - [(cy anomethyl)amino] -6- { [2-methyl-6-(oxan-4-yloxy)pyri din-3 -yl]methyl } -7,8- dihydro-5H-2,6-naphthyridine-4-carbonitrile

To a solution of Intermediate 16 (139 mg, 0.415 mmol) and 2-methyl-6-tetrahydropyran-4- yloxy-pyridine-3-carbaldehyde (synthesised by a similar method to that used in Intermediate 6, 84% purity, 92 mg, 0.349 mmol) in anhydrous THF (3 mL) was added sodium triacetoxyborohydride (296 mg, 1.40 mmol) followed by palladium tetrakis(triphenylphosphine) (17 mg, 0.0147 mmol) and the reaction stirred at 40 °C for 1 hour in a sealed tube. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. Purification by FCC (eluting with ethyl acetate in heptane, 0 - 100% gradient) followed by preparitive HPLC (Method A) gave 46 mg (29% yield, 100% purity) of the title compound as a white solid m/z: 453.4 / 455.4 [M+H]+, (ESI+), Rt = 3.48 mm, Method 8

1HNMR (400 MHz, DMSO-d6) d [ppm]: 7.91 (s, 1H), 7.55 (d, J = 8.3 Hz, 1H), 6.59 (d, J = 8.3 Hz, 1H), 5.20 - 5.12 (m, 1H), 4.37 (s, 2H), 3.85 (dt, J = 11.5, 4.2 Hz, 2H), 3.61 (s, 2H), 3.58 (s, 2H), 3.54 - 3.45 (m, 2H), 2.72 (t, J = 5.7 Hz, 2H), 2.43 - 2.37 (m, 5H), 2.03 - 1.94 (m, 2H), 1.66 - 1.54 (m, 2H).

Example 8: Compounds 65 to 76 and 256 to 268

The compounds 65 to 76 and 256 to 268 shown in the following Table 2 are further representative examples of compounds according to general formula (I) of the present invention. These compounds have been synthesized using methods similar to that described in relation to the preparation of Compound 64 above, together with synthetic methods disclosed herein or known in the art of synthetic organic chemistry, and variations thereon as appreciated by those skilled in the art. In any event, those skilled in the art of organic synthesis will recognize the starting materials and reaction conditions including variations to produce the compounds.

Table 2: Compounds 65 to 76 and 256 to 268 Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No.

N

Intermediate 17

3 -bromo-6-(3 ,3 -difluorocy clobutoxy)-2-methylpyridine

To a solution of 5-bromo-6-methylpyridin-2-ol (200 mg, 1.06 mmol) in anhydrous THF (7 mL) was added triphenylphosphine (420 mg, 1.60 mmol), diisopropyl azodicarboxylate (275 uL, 1.40 mmol) and 3,3-difluorocyclobutan-l-ol (100 uL, 1.20 mmol). The reaction mixture was stirred at 35 °C for 42 h, cooled to RT and copper(I) chloride (100 mg) added. The reaction mixture was stirred for 30 min at RT and then passed through a short pad of celite and washed through with EtOAc. The organics were concentrated in vacuo. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 30% gradient) gave 183 mg (61% yield, 98% purity) of the title compound as a pale yellow oil. m/z: 278/280 [M+H]+, (ESI+), Rt = 1.13 mm, Method 2 1HNMR (400 MHz, Chloroform-d) d [ppm]: 7.64 (d, 1H), 6.50 - 6.43 (m, 1H), 5.14 - 5.03 (m, 1H), 3.16 - 3.02 (m, 2H), 2.79 - 2.61 (m, 2H), 2.52 (s, 3H).

Intermediate 18

6-(3 ,3 -difluorocyclobutoxy)-2-methylpyridine-3 -carbaldehyde Intermediate 18 was prepared from Intermediate 17, using a similar method to that used for

Intermediate 6. m/z: 228 [M+H]+, (ESI+), Rt = 0.92 mm, Method 2

1HNMR (400 MHz, Chloroform-d) d [ppm]: 10.22 (s, 1H), 8.02 (d, 1H), 6.69 (d, 1H), 5.27 - 5.17 (m, 1H), 3.19 - 3.08 (m, 2H), 2.75 (s, 3H), 2.81 - 2.67 (m, 2H).

Example 9: Synthesis of Compound 77

3 -Chloro- 1 - [(cy anomethyl)amino] -6- { [6-(3 ,3 -difluorocyclobutoxy)-2-methylpyri din-3 - yl]methyl}-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile

Compound 77 was prepared from Intermediate 18 and Intermediate 16, using a similar method to that used to prepare Compound 64. m/z: 459.3 / 461.3 [M+H]+, (ESI+), Rt = 4.08 mm, Method 8

1HNMR (500 MHz, DMSO-d6) d [ppm]: 7.92 (s, 1H), 7.60 (d, 1H), 6.66 (d, 1H), 5.13 - 5.04 (m, 1H), 4.37 (s, 2H), 3.63 (s, 2H), 3.58 (s, 2H), 3.19 - 3.07 (m, 2H), 2.76 - 2.65 (m, 4H), 2.42 (s,

3H), 2.42 - 2.38 (m, 2H).

Example 10: Compounds 78 to 86 and 269 to 272

The compounds 78 to 86 and 269 to 272 shown in the following Table 3 are further representative examples of compounds according to general formula (I) of the present invention. These compounds have been synthesized using methods similar to that described in relation to the preparation of Compound 77 above, together with synthetic methods disclosed herein or known in the art of synthetic organic chemistry, and variations thereon as appreciated by those skilled in the art. In any event, those skilled in the art of organic synthesis will recognize the starting materials and reaction conditions including variations to produce the compounds. Table 3: Compounds 78 to 86 and 269 to 272

Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No. Example 11: Compounds 87 to 89

The compounds 87 to 89 shown in the following Table 4 are further representative examples of compounds according to general formula (I) of the present invention. These compounds have been synthesized using methods similar to those described above in relation to the preparation of Intermediate 8 and Compound 41, respectively, together with synthetic methods disclosed herein or known in the art of synthetic organic chemistry, and variations thereon as appreciated by those skilled in the art. In any event, those skilled in the art of organic synthesis will recognize the starting materials and reaction conditions including variations to produce the compounds. Intermediate 19

6-(2,2-Difluoroethyl)-3-(dimethoxymethyl)-2-methylpyridine

To 1,2-dimethoxy ethane - dichloronickel (1:1) (2.6 mg, 5.85 mhioΐ) and 4,4'-di-tert-butyl-2,2'- bipyridine (3.2 mg, 5.85 mhioΐ) was added DME (2 mL) and the mixture stirred for 10 min at RT. This mixture was then added to a mixture of Intermediate 12 (96%, 300 mg, 1.17 mmol), 1,1- difluoro-2-iodoethane (320 uL, 3.63 mmol), (4,4'-Di-t-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5- trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (13 mg, 0.0116 mmol), tris(trimethylsilyl)silane (370 uL, 1.20 mmol), 2,6-dimethylpyridine (300 uL, 2.58 mmol) and DME (11 mL). The reaction mixture was purged with nitrogen and then exposed to blue

LEDs for 12 h using the Penn Photoreactor (Wavelength: 450 nm, UV intensity: 100%, Stir: 1000 rpm, Pan: 5000 rpm). The organics were diluted with EtOAc and washed with water, then brine, then dried over MgS04, filtered and concentrated in vacuo. Purification by PCC (silica gel, eluting with EtOAc in heptane, 0 - 100% gradient) gave 66 mg (22% yield, 90% purity) of the title compound as a colourless oil. m/z: 232 [M+H]+, (ESI+), Rt = 0.64 mm, Method 4

1HNMR (500 MHz, Chloroform-d) d [ppm]: 7.82 (d, 1H), 7.11 (d, 1H), 6.20 (tt, 1H), 5.45 (s, 1H), 3.39 - 3.27 (m, 2H), 3.32 (s, 6H), 2.58 (s, 3H).

Example 12: Synthesis of Compound 90 3 -Chloro- 1 - [(cy anomethyl)amino] -6- { [6-(2,2-difluoroethyl)-2-methylpyri din-3 -yl]methyl } -

5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile

To Intermediate 19 (22 mg, 0.0951 mmol) in THF (0.4 mL) was added 3 M aq. HC1 (0.40 mL, 1.20 mmol) and the reaction mixture stirred at RT for 4 h. To the reaction mixture was added EtOAc and the organics were washed with sat. aq. NaHCCb solution (x2), then brine, dried over MgS04, fdtered and concentrated in vacuo. The residue was dissolved in THF (1 mL) and 3 M aq. HC1 (1.0 mL, 3.00 mmol) added. The reaction mixture was stirred at RT for 1 h. To the reaction mixture was added EtOAc and the organics were washed with sat. aq. NaHC0₃ solution (x2), then brine, dried over MgS04, fdtered and concentrated in vacuo.

To a solution of the residue and Intermediate 16 (99%, 35 mg, 0.104 mmol) in anhydrous THE (1 mL) was added STAB (74 mg, 0.349 mmol) and then Pd(PPli3)4 (4.0 mg, 3.46 pmol) and the reaction mixture stirred for 1 h at 40 °C under nitrogen. The reaction was quenched with water and sat. aq. NaHC0₃ solution and was extracted with EtOAc. The organics were dried over MgS0₄, fdtered and concentrated in vacuo. Purification by preparative HPLC (Method C) followed by purification by preparative HPLC (Method B) gave 17 mg (43% yield, 100% purity) of the title compound as a white solid m/z: 417.2 / 419.2 [M+H]+, (ESI+), Rt = 2.2 mm, Method 5

1HNMR (400 MHz, DMSO-d6) d [ppm]: 7.93 (s, 1H), 7.64 (d, 1H), 7.19 (d, 1H), 6.40 (tt, 1H), 4.37 (s, 2H), 3.69 (s, 2H), 3.61 (s, 2H), 3.36 - 3.24 (m, 2H), 2.78 - 2.71 (m, 2H), 2.51 (s, 3H), 2.45 - 2.39 (m, 2H).

Intermediate 20

3-bromo-6-(difluoromethyl)-2-methylpyridine

A solution of 5-bromo-6-methyl-pyridine-2-carbaldehyde (300 mg, 1.50 mmol) in chloroform (15 mL) was cooled to 0 °C and then DAST (0.84 mL, 6.38 mmol) was added, and stirred for 4 h under nitrogen. The mixture was poured onto sat. aq. NaHCCb solution and stirred for 30 min.

The phases were separated, and the aqueous layer was extracted with DCM (x2). The combined organics were dried over INfeSCb, fdtered, and concentrated in vacuo to afford 340 mg (97% yield, 95% purity) of the title compound as a pale yellow oil.

1HNMR (500 MHz, Chloroform-d) d [ppm]: 7.67 (d, 1H), 7.43 (d, 1H), 6.75 (t, 1H), 2.62 (s, 3H).

Example 13: Synthesis of Compound 91

3-chloro-l-[(cyanomethyl)amino]-6-{[6-(difluoromethyl)-2-methylpyridin-3-yl]methyl}-7,8- dihydro-5H-2,6-naphthyridine-4-carbonitrile Compound 91 was synthesised from Intermediate 20 and Intermediate 16, using methods described to prepare Intermediate 8 and Compound 64, respectively m/z: 403.4 / 405.4 [M+H]+, (ESI+), Rt = 3.13 mm, Method 10 lH NMR (500 MHz, DMSO-d6) d [ppm]: 7.94 (s, 1H), 7.91 (d, 1H), 7.45 (d, 1H), 7.23 (t, 1H), 4.38 (s, 2H), 3.86 (s, 2H), 3.69 (s, 2H), 2.81 (t, 2H), 2.56 (s, 3H), 2.45 (t, 2H).

Intermediate 21

[6-(2,2-difluoroethoxy)-2-methylpyridin-3-yl](²H)formaldehyde

To a solution of 3-bromo-6-(2,2-difluoroethoxy)-2-methylpyridine (prepared using a similar method to that used for Intermediate 17, 300 mg, 1.19 mmol) in dry diethyl ether (5 mL) at -78 °C was added 2.5 M n-BuLi in hexanes (619 uL, 1.55 mmol) over 30 seconds under nitrogen. The reaction mixture was stirred for 20 min at -78 °C and then DMF-d7 (227 uL, 2.98 mmol) was added. The reaction mixture was allowed to warm to RT and stirred for a further 45 min. To the reaction mixture was added sat. aq. NH4C1 solution and the reaction mixture was stirred at RT for 5 min. The organics were diluted with Et20 and washed with water then brine. The organics were dried over Na2S04, filtered and concentrated. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 100% gradient) gave 203 mg (81% yield, 96% purity) of the title compound as a white solid. m/z: 203 [M+H]+, (ESI+), Rt = 0.80 min, Method 2

1HNMR (400 MHz, DMSO-d6) d [ppm]: 8.13 (d, 1H), 6.93 (d, 1H), 6.42 (tt, 1H), 4.67 (td, 2H), 2.74 (s, 3H). Example 14: Synthesis of Compound 92

3-chloro-l-[(cyanomethyl)amino]-6-{[6-(2,2-difluoroethoxy)-2-methylpyridin-3-yl](²H₂)methyl}-

5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile

To a stirring mixture of sodium borodeuteride (100 mg, 2.39 mmol) and toluene (20 mL) at 10 °C was added acetic acid-d (424 uL, 7.29 mmol) dropwise. After addition was complete the mixture was allowed to warm to RT and stirred for 6 h under nitrogen. The slurry was fdtered and the resultant white powder washed with three portions of dry diethyl ether. The powder was dried under vacuum overnight to give 448 mg of sodium triacetoxy(deuterio)boranuide as a white solid. To a mixture of Intermediate 4 (94%, 50 mg, 0.190 mmol), Intermediate 21 (96%, 44 mg, 0.209 mmol) and DCE (2 mL) was added sodium triacetoxy(deuterio)boranuide (81 mg, 0.380 mmol). The reaction mixture was stirred at 40 °C for 1.5 h under nitrogen. The mixture was diluted with DCM and sat. aq. NaHC03 solution and the layers separated. The aqueous was extracted with further DCM (x2), the combined organics were passed through a phase separator and then concentrated. Purification by preparative HPLC (Method B) gave 40 mg (48% yield, 98% purity) of the title compound as a white solid m/z: 435/437 [M+H]+, (ESI+), Rt = 2.74 mm, Method 5

1HNMR (500 MHz, DMSO-d6) d [ppm]: 7.93 (s, 1H), 7.63 (d, 1H), 6.75 - 6.69 (m, 1H), 6.39 (tt, 1H), 4.54 (td, 2H), 4.37 (s, 2H), 3.59 (s, 2H), 2.72 (t, 2H), 2.44 (s, 3H), 2.42 - 2.36 (m, 2H).

Example 15: Compounds 93 to 95 and 273 to 276

The compounds 93 to 95 and 273 to 276 shown in the following Table 5 are further representative examples of compounds according to general formula (I) of the present invention. These compounds have been synthesized using a similar method to that described above in relation to the preparation of Compound 92, together with synthetic methods disclosed herein or known in the art of synthetic organic chemistry, and variations thereon as appreciated by those skilled in the art. In any event, those skilled in the art of organic synthesis will recognize the starting materials and reaction conditions including variations to produce the compounds.

Table 5: Compounds 93 to 95 and 273 to 276

Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No.

N

Intermediate 22

1 - [6-(2,2-difluoroethoxy)pyri din-3 -yl] ethan- 1 -ol To a stirring solution of l-[6-(2,2-difluoroethoxy)pyridin-3-yl]ethan-l-one (prepared from l-(6- chloropyri din-3 -yl)ethanone using a similar method to that used for Intermediate 5, 2.17 g, 10.4 mmol) in MeOH (40 mL) was added sodium borohydride (434 mg, 11.5 mmol). The reaction mixture was stirred at RT under nitrogen for 30 min. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM and HC1 (0.2 M). The organic layer was separated, dried over anhydrous Na2S04 and the solvent was removed in vacuo to give 2.07 g (98% yield, 100% purity) of the title compound as a colourless oil. m/z: 204 [M+H]+, (ESI+), Rt = 0.95 mm, Method 1

1HNMR (400 MHz, Chloroform-d) d [ppm]: 8.11 - 8.07 (m, 1H), 7.67 (dd, 1H), 6.81 (d, 1H), 6.12 (tt, 1H), 4.90 (qd, 1H), 4.53 (td, 2H), 1.86 (d, 1H), 1.50 (d, 3H).

Intermediate 23

5-(l-bromoethyl)-2-(2,2-difluoroethoxy)pyridine To an ice-cooled stirring solution of Intermediate 22 (800 mg, 3.86 mmol) in DCM (20 mL) under nitrogen was added phosphorous tribromide (0.73 mL, 7.77 mmol) dropwise. The resulting mixture was stirred at RT under nitrogen for 3 h, diluted with DCM, cooled in an ice-bath and quenched with a sat. aq. NaHC03 solution (until at neutral pH). The aqueous layer was separated, extracted with further DCM and the combined organic layers were dried over Na2S04 and concentrated in vacuo to give 913 mg (84% yield, 95% purity) of the title compound as a yellow oil.

1HNMR (400 MHz, Chloroform-d) d [ppm]: 8.15 (d, 1H), 7.75 (dd, 1H), 6.83 (d, 1H), 6.12 (tt, 1H), 5.20 (q, 1H), 4.54 (td, 2H), 2.04 (d, 3H).

Example 16: Synthesis of Compound 96 3-chloro-l-[(cyanomethyl)amino]-6-{l-[6-(2,2-difluoroethoxy)pyridin-3-yl]ethyl} -7, 8-dihydro-

5H-2,6-naphthyridine-4-carbonitrile

A mixture of Intermediate 4 (69%, 106 mg, 0.257 mmol), Intermediate 23 (92%, 74 mg, 0.256 mmol) and triethylamine (100 uL, 0.717 mmol) in acetonitrile (2 mL) was stirred at reflux in a sealed tube for 4 hours. The reaction mixture was allowed to cool to room temperature overnight, diluted with ethyl acetate (10 mL) and washed with water (2 x 10 mL). The combined aqueous layers were washed with further ethyl acetate (10 mL). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica chromatography (10 g column, 0-100% ethyl acetate in heptane followed by 0-10% methanol in ethyl acetate) followed by trituration in 1:3 ethyl acetate/heptane (2 mL) to afford the title compound (17 mg, 0.0373 mmol, 15% Yield) as a cream coloured solid.

Example 17: Compounds 97 to 103 and 277 to 279

The compounds 97 to 103 and 277 to 279 shown in the following Table 6 are further representative examples of compounds according to general formula (I) of the present invention. These compounds have been synthesized using a similar method to that described above in relation to the preparation of Compound 96, together with synthetic methods disclosed herein or known in the art of synthetic organic chemistry, and variations thereon as appreciated by those skilled in the art. Alkyl bromides were prepared using a similar method to that described above in relation to the preparation of Intermediate 23 or were purchased from commercial suppliers. In any event, those skilled in the art of organic synthesis will recognize the starting materials and reaction conditions including variations to produce the compounds. Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No.

Intermediate 24 l-[6-(difluoromethoxy)-2-methylpyri din-3 -yl]ethan-l-ol To a stirring solution of Intermediate 7 (95%, 600 mg, 2.39 mmol) in anhydrous THF (14 mL) at -78 °C was added 2.5 M n-BuLi in hexanes (1.3 mL, 3.33 mmol). The reaction mixture was stirred at -78 °C for 40 min and then acetaldehyde (0.67 mL, 11.9 mmol) was added. The reaction mixture was allowed to warm to RT and then stirred for 90 min. To the reaction mixture was added sat. aq. NH4C1 solution and the organics were extracted with EtOAc. The organics were washed with water, then brine, dried (hydrophobic frit) and concentrated. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 100% gradient) gave 242 mg (45% yield, 90% purity) of the title compound as a yellow oil. m/z: 204 [M+H]+, (ESI+), Rt = 0.74 mm, Method 2

1HNMR (500 MHz, DMSO-d6) d [ppm]: 7.89 (d, 1H), 7.65 (t, 1H), 6.91 - 6.84 (m, 1H), 5.25 (d, 1H), 4.95 - 4.84 (m, 1H), 2.41 (s, 3H), 1.29 (d, 3H).

Example 18: Synthesis of Compound 104

3-chloro-l-[(cyanomethyl)amino]-6-{l-[6-(difluoromethoxy)-2-methylpyridin-3-yl]ethyl}-7,8- dihydro-5H-2,6-naphthyridine-4-carbonitrile

Compound 104 was synthesised from Intermediate 24 and Intermediate 4 using methods described to prepare Intermediate 23 and Compound 96, respectively m/z: 433.4 / 435.4 [M+H]+, (ESI+), Rt = 3.79 mm, Method 8 lH NMR (400 MHz, DMSO-d6) d [ppm]: 7.90 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.68 (t, J = 73.2 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.37 (s, 2H), 3.95 (q, J = 6.7 Hz, 1H), 3.72 (d, J = 16.9 Hz, 1H), 3.56 (d, J = 16.9 Hz, 1H), 2.83 - 2.71 (m, 1H), 2.70 - 2.60 (m, 1H), 2.47 (s, 3H), 2.40 - 2.29 (m, 2H), 1.34 (d, J = 6.6 Hz, 3H).

Example 19: Compounds 105 to 107

The compounds 105 to 107 shown in the following Table 7 are further representative examples of compounds according to general formula (I) of the present invention. These compounds have been synthesized using a similar method to that described above in relation to the preparation of Compound 104, together with synthetic methods disclosed herein or known in the art of synthetic organic chemistry, and variations thereon as appreciated by those skilled in the art. Alkyl bromides were prepared using a similar method to that described above in relation to the preparation of Intermediate 24 or were purchased from commercial suppliers. In any event, those skilled in the art of organic synthesis will recognize the starting materials and reaction conditions including variations to produce the compounds. Table 7: Compounds 105 to 107

Intermediate 25 l-(2,6-difluoropyridin-3-yl)ethan-l-ol

To a solution of 2,6-difluoropyridine-3-carbaldehyde (400 mg, 2.80 mmol) in anhydrous THF (5 mL) at -78 °C was added 3 M MeMgBr in Et20 (0.93 mL, 2.80 mmol) under nitrogen. The reaction mixture was allowed to warm to RT and stirred at RT for 3 h. The mixture was cooled to 0 °C and 3 M MeMgBr in Et20 (0.47 mL, 1.40 mmol) added. The mixture was stirred at RT for 2 h. The reaction mixture was quenched with sat. aq. NH4C1 solution and then EtOAc added. IPA : CHC13 (1:3 ratio) was added and the resulting layers separated. The aqueous was extracted with further IPA : CHC13 (1:3 ratio). The combined organic phases were passed through a phase separator and then concentrated. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 100% gradient) gave 297 mg (63% yield, 94% purity) of the title compound as a colourless oil. m/z: 160 [M+H]+, (ESI+), Rt = 0.56 mm, Method 2 lH NMR (400 MHz, DMSO-d6) d [ppm]: 8.25 - 8.08 (m, 1H), 7.16 (dd, 1H), 5.51 (d, 1H), 5.02 - 4.74 (m, 1H), 1.34 (d, 3H). Intermediate 26

3-Chloro-l-[(cyanomethyl)amino]-6-[l-(2,6-difluoropyridin-3-yl)ethyl]-5,6,7,8-tetrahydro-2,6- naphthyridine-4-carbonitrile Intermediate 26 was synthesised from Intermediate 25 and Intermediate 4 using methods described to prepare Intermediate 23 and Compound 96, respectively, m/z: 289/391 [M+H]+, (ESI+), Rt = 0.83 mm, Method 2

1HNMR (400 MHz, DMSO-d6) d [ppm]: 8.28 - 8.15 (m, 1H), 7.91 (s, 1H), 7.20 (dd, 1H), 4.37 (s, 2H), 4.08 (q, 1H), 3.71 (d, 1H), 3.55 (d, 1H), 2.87 - 2.78 (m, 1H), 2.64 - 2.55 (m, 1H), 2.42 - 2.35 (m, 2H), 1.42 (d, 3H).

Example 20: Synthesis of Compound 108

3-chloro-l-[(cyanomethyl)amino]-6-{l-[2-fluoro-6-(oxetan-3-yloxy)pyridin-3-yl]ethyl}-5,6,7,8- tetrahydro-2,6-naphthyridine-4-carbonitrile To a solution of oxetan-3-ol (95%, 13 mg, 0.171 mmol) in NMP (1.5 mL) at 0°C was added KOtBu (38 mg, 0.342 mmol) and the reaction was stirred for 5 min. To the reaction was added Intermediate 26 (95%, 70 mg, 0.171 mmol) and the mixture stirred at 50°C for 1 h under nitrogen. The mixture was allowed to cool to RT, further KOtBu (19 mg, 0.171 mmol) was added and the mixture stirred at 50 °C for 1 h. The mixture was diluted with water : brine (1:1) and EtOAc and the layers separated. The aqueous was extracted with further EtOAc. The combined organics were washed with water and brine, then dried (Na2S04) filtered and concentrated. Purification by preparative HPLC (Method B) followed by purification by preparative HPLC (Method C). Product containing fractions were neutralised with sat. aq. NaHC03 solution and then concentrated in vacuo. The aqueous was then extracted with DCM (x3) and the combined organics passed through a phase separator and then concentrated to give 24 mg (31% yield, 98% purity) of the title compound as a white solid m/z: 443/445 [M+H]+, (ESI+), Rt = 2.42 mm, Method 5

1HNMR (400 MHz, DMSO-d6) d [ppm]: 7.97 (dd, 1H), 7.91 (s, 1H), 6.86 (d, 1H), 5.55 - 5.47 (m, 1H), 4.92 - 4.87 (m, 2H), 4.58 - 4.48 (m, 2H), 4.36 (s, 2H), 3.99 (q, 1H), 3.67 (d, 1H), 3.51 (d, 1H), 2.83 (dt, 1H), 2.60 - 2.53 (m, 1H), 2.40 - 2.36 (m, 2H), 1.39 (d, 3H).

Example 21: Synthesis of Compound 109

3-Chloro-l-[(cyanomethyl)amino]-6-{l-[6-fluoro-2-(oxetan-3-yloxy)pyridin-3-yl]ethyl}-5,6,7,8- tetrahydro-2,6-naphthyridine-4-carbonitrile

Compound 109 was also isolated from the reaction used to prepare Compound 108 (13 mg, (17% yield, 99% purity) of the title compound as a white solid) m/z: 443/445 [M+H]+, (ESI+), Rt = 2.15 mm, Method 5

1HNMR (400 MHz, DMSO-d6) d [ppm]: 7.98 (t, 1H), 7.91 (s, 1H), 6.79 (dd, 1H), 5.56 - 5.46 (m, 1H), 4.90 - 4.82 (m, 2H), 4.61 - 4.52 (m, 2H), 4.37 (s, 2H), 4.14 (q, 1H), 3.72 (d, 1H), 3.5^ (d, 1H), 2.90 (dt, 1H), 2.62 - 2.55 (m, 1H), 2.43 - 2.37 (m, 2H), 1.40 (d, 3H). Intermediate 27

[2-(2,2-difluoroethoxy)-6-methylpyridin-4-yl]methanol

Methyl 2-(2,2-difluoroethoxy)-6-methylpyridine-4-carboxylate (prepared according to the method described for Intermediate 5, 75% purity, 507 mg, 1.65 mmol) was dissolved in THF (15 mL), placed under nitrogen and cooled to 0 °C. Then, 4 M LiAlH4 (in Et20) (0.82 mL, 3.29 mmol) was added and the mixture stirred for 1 h. The reaction was quenched with water (0.1 mL), 1 M NaOH (0.1 mL) and water (0.1 mL). The resulting suspension was filtered through Celite, washed with EtOAc, and concentrated in vacuo to afford 415 mg (99% yield, 80% purity) of the title compound as a pale yellow oil. m/z: 204 [M+H]+, (ESI+), Rt = 0.80 mm, Method 2

1HNMR (400 MHz, DMSO-d6) d [ppm]: 6.83 (s, 1H), 6.60 (s, 1H), 6.36 (tt, 1H), 5.35 (t, 1H), 4.53 (td, 2H), 4.46 (d, 2H), 2.37 (s, 3H).

Intermediate 28

2-(2,2-Difluoroethoxy)-6-methylpyridine-4-carbaldehyde

To a solution of Intermediate 27 (80%, 415 mg, 1.63 mmol) in DCM (15 mL) was added Mn02 (426 mg, 4.90 mmol) at RT and the mixture stirred at RT for 2 h. Further Mn02 (426 mg, 4.90 mmol) was added at RT and stirring continued for 16 h. More Mn02 (426 mg, 4.90 mmol) was added and stirring continued for 2 h. More Mn02 (426 mg, 4.90 mmol) was added and stirring continued for 2 h. The mixture was fdtered through celite and concentrated in vacuo. The residue was dissolved in DCM (15 mL) and stirred for 2 h. Mn02 (1000 mg, 11.5 mmol) was added and the mixture stirred for 16 h at RT. Additional Mn02 (1000 mg, 11.5 mmol) was added and the mixture stirred for 3 h. The reaction mixture was filtered through celite, and the filtrate concentrated in vacuo to give 257 mg (50% yield, 64% purity) of the title compound as a pale yellow oil. m/z: 202 [M+H]+, (ESI+), Rt = 0.85 min, Method 2

1HNMR (400 MHz, DMSO-d6) d [ppm]: 10.00 (s, 1H), 7.33 - 7.29 (m, 1H), 7.18 - 7.15 (m, 1H), 6.41 (tt, 2H), 4.61 (td, 2H). CH3 not observed.

Example 22: Synthesis of Compound 110

Compound 110 was synthesised from Intermediate 28 and Intermediate 4, using a similar method to that described to prepare Compound 2. m/z: 433.2 / 435.2 [M+H]+, (ESI+), Rt = 3.16 mm, Method 5 lHNMR (400 MHz, Chloroform-d) d [ppm] 6.78 (s, 1H), 6.61 (s, 1H), 6.13 (tt, J = 55.8, 4.3 Hz, 1H), 4.95 (t, J = 5.9 Hz, 1H), 4.53 (td, J = 13.6, 4.2 Hz, 2H), 4.48 (d, J = 6.0 Hz, 2H), 3.71 (s, 2H),

3.64 (s, 2H), 2.78 (t, J = 5.8 Hz, 2H), 2.46 (t, J = 5.8 Hz, 2H), 2.43 (s, 3H).

Intermediate 29 l,3-dichloro-6-[2-(2,2-difluoroethoxy)pyridine-4-carbonyl]-5,6,7,8-tetrahydro-2,6-naphthyridine- 4-carbonitrile l,3-dichloro-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride (prepared using a similar method to that used in Intermediate 4, 255 mg, 0.752 mmol), 2-(2,2- difluoroethoxy)pyridine-4-carboxylic acid (166 mg, 0.817 mmol), HATU (315 mg, 0.828 mmol) and DIPEA (400 pL, 2.29 mmol) were dissolved in DCM (8 mL) and stirred at RT for 2 h. The reaction mixture was quenched with sat. aq. NH4C1 solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2S04 and the solvent was removed in vacuo. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 100% gradient) gave 259 mg (82% yield, 98% purity) of the title compound as a yellow solid m/z: 413/415/417 [M+H]+, (ESI+), Rt = 1.21 mm, Method 1 Intermediate 30

3-chloro-l-[(cyanomethyl)amino]-6-[2-(2,2-difluoroethoxy)pyridine-4-carbonyl]-5,6,7,8- tetrahydro-2,6-naphthyridine-4-carbonitrile Intermediate 29 (255 mg, 0.605 mmol), 2-aminoacetonitrile (52 mg, 0.927 mmol), and DIPEA (210 pL, 1.20 mmol) were dissolved in NMP (4 mL) and the reaction stirred at 110 °C for 5 h. The reaction mixture was allowed to cool to RT, diluted with EtOAc and washed with water. The combined aqueous layers were extracted with EtOAc and the combined organic layers were concentrated in vacuo. Purification by reverse phase FCC (Cl 8 silica gel, eluting with MeCN (+0.1% formic acid) in water (+0.1% formic acid), 5 - 100% gradient) gave 82 mg (31% yield,

100% purity) of the title compound as an orange gum. m/z: 433/435 [M+H]+, (ESI+), Rt = 1.13 mm, Method 1

Example 23: Synthesis of Compound 111

3-chloro-l-[(cyanomethyl)amino]-6-{[2-(2,2-difluoroethoxy)pyridin-4-yl]methyl}-5,6,7,8- tetrahydro-2,6-naphthyridine-4-carbonitrile To a stirred solution of Intermediate 29 (82 mg, 0.189 mmol) in anhydrous THF (2 mL) at 0 °C was added BMS (2M in THF, 190 mT, 0.380 mmol). The reaction was stirred at RT for 3 h, BMS (2M in THF, 190 mT, 0.380 mmol) was added and the reaction stirred at 30 °C for 2 h. The reaction was cooled to 0 °C, MeOH (1 mL) added and stirred RT for 16 h. HC1 (2 M, 190 pL, 0.380 mmol) was added the reaction refluxed for 1 h before cooling to RT. The solution was neutralised using sat. aq. NaHC03 solution, and extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na2S04 and the solvent removed in vacuo. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 100% gradient) gave 32 mg (38% yield, 96% purity) of the title compound as a white solid m/z: 419/421 [M+H]+, (ESI+), Rt = 2.95 mm, Method 5

1HNMR (500 MHz, Chloroform-d) d [ppm]: 8.10 (d, 1H), 6.96 - 6.91 (m, 1H), 6.82 (s, 1H), 6.13 (tt, 1H), 5.00 (t, 1H), 4.54 (td, 2H), 4.48 (d, 2H), 3.72 (s, 2H), 3.70 (s, 2H), 2.79 (t, 2H), 2.49 - 2.42 (m, 2H).

Example 24: Compounds 112 to 114

The compounds 112 to 114 shown in the following Table 8 are further representative examples of compounds according to general formula (I) of the present invention. These compounds have been synthesized using a similar method to that described above in relation to the preparation of Compound 111, together with synthetic methods disclosed herein or known in the art of synthetic organic chemistry, and variations thereon as appreciated by those skilled in the art. In any event, those skilled in the art of organic synthesis will recognize the starting materials and reaction conditions including variations to produce the compounds.

Table 8: Compounds 112 to 114

Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No.

Intermediate 31

7-benzyl-l,3-dichloro-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile

The title compound was prepared as described in Bioorg. Med. Chem. Lett. 20 (2010) 2785-2789. m/z: 318/320/322 [M+H]+, (ESI+), Rt = 1.90 mm, Method 3

¾ NMR (500 MHz, Chloroform-d) d [ppm]: 7.60 - 7.30 (m, 5H), 4.07 - 3.79 (m, 2H), 3.78 - 3.49 (m, 2H), 3.30 - 3.00 (m, 2H), 2.98 - 2.53 (m, 2H).

Example 25: Synthesis of Compound 115

7-benzyl-3-chloro-l-[(cyanomethyl)amino]-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile Intermediate 31 (100 mg, 0.295 mmol), 2-aminoacetonitrile hydrochloride (17 mg, 0.295 mmol) and DBU (88 pL, 0.59 mmol) were combined in DMF (1.5 mL) and stirred at 100 °C for 1.5 h using microwave irradiation. The reaction mixture was cooled to RT and further DBU (44 pL, 0.295 mmol) added. The reaction was stirred at 100 °C for 30 min using microwave irradiation. The reaction mixture was cooled to RT, quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSCri and concentrated in vacuo. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 100% gradient) gave 4 mg (3% yield, 87% purity) of the title compound as a brown solid m/z: 338/340 [M+H]+, (ESI+), Rt = 1.79 mm, Method 5 1HNMR (500 MHz, Chloroform-d) d [ppm]: 7.39 - 7.34 (m, 4H), 7.34 - 7.31 (m, 1H), 4.71 - 4.64 (m, 1H), 4.41 (d, 2H), 3.76 (s, 2H), 3.26 - 3.20 (m, 2H), 3.01 - 2.95 (m, 2H), 2.81 (t, 2H).

Example 26: Compounds 116 and 117

The compounds 116 and 117 shown in the following Table 9 have been synthesized using a similar method to that described above in relation to the preparation of Compound 115, together with synthetic methods disclosed herein or known in the art of synthetic organic chemistry, and variations thereon as appreciated by those skilled in the art. In any event, those skilled in the art of organic synthesis will recognize the starting materials and reaction conditions including variations to produce the compounds. Cpd.

Structure Analytical data

No.

Intermediate 32

3-chloro-l-[(cyanomethyl)amino]-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile hydrochloride

To a stirred suspension of Compound 115 (9.50 g, 28.1 mmol) in MeCN (268 mL) was added 1- chloroethyl chloroformate (6.1 mL, 56.4 mmol) dropwise. The reaction was stirred at RT under nitrogen for 18 h. The reaction mixture was concentrated in vacuo and the residue dissolved in methanol (268 mL). The mixture was stirred at RT for 18 h and then concentrated in vacuo to give 8.90 g (87% yield, 78% purity) of the title compound as a pale brown solid m/z: 248/250 [M+H]+, (ESI+), Rt = 0.68 mm, Method 1

Example 27: Compounds 118 to 197 and 280 to 287

The compounds 118 to 197 and 280 to 287 shown in Table 10 below were synthesised from Intermediate 32 (or from intermediates prepared in a similar way) using a similar method to that described above in relation to the preparation of Compound 2, together with synthetic methods disclosed herein or known in the art of synthetic organic chemistry, and variations thereon as appreciated by those skilled in the art. Aldehydes and ketones were sourced from commercial suppliers or were prepared as described herein. In any event, those skilled in the art of organic synthesis will recognize the starting materials and reaction conditions including variations to produce the compounds. Table 10: Compounds 118 to 197 and 280 to 287 Cpd.

Structure Analytical Data

No. Cpd.

Structure Analytical Data

No. Cpd.

Structure Analytical Data

No. Cpd.

Structure Analytical Data

No. Cpd.

Structure Analytical Data

No. Cpd.

Structure Analytical Data

No. Cpd.

Structure Analytical Data

No. Cpd.

Structure Analytical Data

No. Cpd.

Structure Analytical Data

No. Cpd.

Structure Analytical Data

No. Cpd.

Structure Analytical Data

No. Example 28: Compounds 198 to 206

The compounds 198 to 206 shown in Table 11 below were synthesised from Intermediate 32 (or from intermediates prepared in a similar way) using a similar method to that described above in relation to the preparation of Compound 96, together with synthetic methods disclosed herein or known in the art of synthetic organic chemistry, and variations thereon as appreciated by those skilled in the art. Alkyl bromides were prepared using a similar method to that to prepare Intermediate 23 or were purchased from commercial suppliers. In any event, those skilled in the art of organic synthesis will recognize the starting materials and reaction conditions including variations to produce the compounds. Table 11: Compounds 198 to 206 Cpd.

Structure Analytical data

No.

Example 29: Synthesis of Compound 207

3-chloro-7-[cyano(phenyl)methyl]-l-[(2-methoxyethyl)amino]-5,6,7,8-tetrahydro-2,7- naphthyridine-4-carbonitrile

A solution of benzaldehyde (60 pL, 0.59 mmol) in MeOH (3 mL) was added dropwise to a solution of 3-chloro-l-[(2-methoxyethyl)amino]-5,6,7,8-tetrahydro-2,7-naphthyridine-4- carbonitrile hydrochloride (prepared using a similar method to that used for Intermediate 32,

79% purity, 200 mg, 0.52 mmol) and potassium cyanide (40 mg, 0.61 mmol) in water (3 mL). The mixture was stirred at RT under nitrogen for 48 h. The reaction was concentrated under a stream of air. The residue was diluted with sat. aq. NaHCCL solution and extracted into DCM.

Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 100% gradient) followed by trituration in EtOAc / heptane (1 :4) gave 124 mg (62% yield, 100% purity) of the title compound as a white powder. m/z: 382/384 [M+H]+, (ESI+), Rt = 4.85 mm, Method 7

1HNMR (500 MHz, DMSO-d6) d [ppm]: 7.59 - 7.55 (m, 2H), 7.48 - 7.41 (m, 3H), 5.13 (s, 1H), 4.87 (t, 1H), 3.76 - 3.63 (m, 2H), 3.58 - 3.50 (m, 2H), 3.45 - 3.34 (m, 5H), 2.99 - 2.85 (m, 3H), 2.84 - 2.78 (m, 1H). Intermediate 33

6-(3 -hydroxy oxetan-3 -yl)-2-methylpyridine-3 -carbaldehy de

To Intermediate 13 (95%, 470 mg, 1.87 mmol) in THF (9.4 mL) was added 1 M aq. HC1 (7.5 mL, 7.50 mmol) and the reaction mixture stirred at RT for 30 h. To the reaction mixture was added EtOAc and the organics were washed with sat. aq. NaHC03 solution and brine (lOmL), dried over MgS04, fdtered and concentrated in vacuo. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 30% gradient) gave 260 mg (69% yield, 95% purity) of the title compound as a colourless solid m/z: 194 [M+H]+, (ESI+), Rt = 0.46 mm, Method 2

1H NMR (400 MHz, Chloroform-d) d [ppm]: 0.37 (s, 1H), 8.30 (d, 1H), 8.02 (d, 1H), 5.94 (s, 1H), 5.24 - 5.02 (m, 2H), 4.82 - 4.64 (m, 2H), 2.90 (s, 3H).

Intermediate 34

3 -chloro- 1 - [(cyanomethyl)amino] -6- { [6-(3 -hydroxy oxetan-3 -yl)-2-methylpyri din-3 -yl]methyl } - 5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile

To a solution of Intermediate 33 (95%, 120 mg, 0.590 mmol) in DCE (9 mL) was added, sequentially, Intermediate 4 (65%, 284 mg, 0.650 mmol), triethylamine (0.10 mL, 0.717 mmol) and STAB (176 mg, 0.830 mmol) and the reaction mixture stirred at RT for 5.5 h under nitrogen. The organics were diluted with DCM (20 mL) and washed with sat. aq. NaHC03 solution. The aqueous was extracted with DCM, then the organics were combined, passed through a phase separator and concentrated in vacuo. Purification by preparative HPLC (method B) followed by trituration in isopropanol gave 82 mg (33% yield, 100% purity) of the title compound as an off- white solid. m/z: 425/427 [M+H]+, (ESI+), Rt = 2.81 mm, Method 10 1H NMR (400 MHz, DMSO-d6) d [ppm]: 7.92 (s, 1H), 7.69 (d, 1H), 7.42 (d, 1H), 6.43 (s, 1H), 4.92 (d, 2H), 4.63 (d, 2H), 4.38 (s, 2H), 3.72 (s, 2H), 3.63 (s, 2H), 2.81 - 2.73 (m, 2H), 2.56 (s, 3H), 2.47 - 2.38 (m, 2H).

Example 30: Synthesis of Compound 208

3 -chloro- 1 - [(cyanomethyl)amino] -6- { [6-(3 -fluorooxetan-3 -yl)-2-methylpyri din-3 -yl] methyl } -7,8- dihydro-5H-2,6-naphthyridine-4-carbonitrile

To a solution of Intermediate 34 (98%, 53 mg, 0.0577 mmol) in DCM (4 mL) at -10 °C was added rapidly dropwise DAST (38 uL, 0.291 mmol) and the reaction mixture was stirred at -10 °C for 1 h. To the reaction mixture was added sat. aq. NaHC03 solution and the organics were extracted with DCM, passed through a phase separator and concentrated in vacuo. Purification by preparative HPLC (method A) gave 19 mg (36% yield, 100% purity) of the title compound as a white solid. m/z: 427/429 [M+H]+, (ESI+), Rt = 3.25 mm, Method 10

1H NMR (400 MHz, DMSO-d6) d [ppm]: 7.93 (s, 1H), 7.78 (d, 1H), 7.37 (d, 1H), 5.05 (ddd, 2H), 4.88 (ddd, 2H), 4.38 (s, 2H), 3.75 (s, 2H), 3.65 (s, 2H), 2.80 - 2.73 (m, 2H), 2.58 (s, 3H), 2.46 - 2.39 (m, 2H).

Example 31: Compounds 209 to 211

The compounds 209 to 211 shown in Table 12 below were synthesised using a similar method to that described above in relation to the preparation of Compound 208, together with synthetic methods disclosed herein or known in the art of synthetic organic chemistry, and variations thereon as appreciated by those skilled in the art. In any event, those skilled in the art of organic synthesis will recognize the starting materials and reaction conditions including variations to produce the compounds. Table 12: Compounds 209 to 211

Example 32: Synthesis of Compound 212

3 -chloro- 1 - [(cyanomethyl)amino] -7- [(6- { [ 1 ,3-dihydroxy-2-(trifluoromethyl)propan-2- yl]oxy}pyridin-3-yl)methyl]-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile Compound 133 (10 mg, 0.0209 mmol) in acetonitrile (2.5 mL) and water (2.5 mL) was stirred at RT for 24 h followed by stirring at 70 °C for 24 h. The reaction mixture was then concentrated in vacuo to give 9 mg (85% yield, 98% purity) of the title compound as a pale brown solid. m/z: 497/499 [M+H]+, (ESI+), Rt = 2.68 mm, Method 10

1HNMR (500 MHz, DMSO-d6) d [ppm]: 7.78 (t, 1H), 7.62 (d, 1H), 7.55 (dd, 1H), 6.70 (s, 1H), 6.54 (d, 1H), 5.34 (dd, 1H), 4.49 (d, 1H), 4.37 (d, 2H), 4.15 (d, 1H), 3.56 - 3.42 (m, 3H), 3.36 - 3.25 (m, 3H), 2.86 - 2.77 (m, 2H), 2.75 - 2.66 (m, 2H).

Example 33: Synthesis of Compound 213 1 -[(cyanomethyl)amino]-6- { [6-(2,2-difluoroethoxy)-2-methylpyridin-3-yl]methyl} -3-methyl-7,8- dihydro-5H-2,6-naphthyridine-4-carbonitrile

A mixture of Compound 28 (95%, 150 mg, 0.329 mmol), trimethylboroxine (3.5 M in THF) (100 uL, 0.350 mmol), potassium carbonate (67 mg, 0.485 mmol) and palladium tetrakis(triphenylphosphine) (39 mg, 0.0337 mmol) in anhydrous 1,4-dioxane (3 mL) was degassed with nitrogen for 2 minutes. The mixture was then stirred at 140°C for 30 minutes via microwave irradiation. The reaction mixture was diluted with water (5 mL) and extracted ethyl acetate (3 x 5 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give a brown oil (291 mg). Purification by LCC (10 g silica gel column, eluting with ethyl acetate in heptane, 0 - 80% gradient) followed by preparitive HPLC (Method A) gave 66 mg (49% yield, 100% purity) of the title compound as an off- white solid m/z: 413.5 [M+H]+, (ESI+), Rt = 3.61 mm, Method 8 lH NMR (500 MHz, DMSO-d6) d [ppm]: 7.63 (d, J = 8.3 Hz, 1H), 7.46 - 7.41 (m, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.39 (tt, J = 54.9, 3.6 Hz, 1H), 4.54 (td, J = 15.1, 3.6 Hz, 2H), 4.36 (d, J = 4.4 Hz,

2H), 3.64 (s, 2H), 3.54 (s, 2H), 2.71 (t, J = 5.8 Hz, 2H), 2.48 (s, 3H), 2.44 (s, 3H), 2.41 - 2.37 (m, 2H).

Example 34: Compounds 214 to 216 and 288

The compounds 214 to 216 and 288 shown in Table 13 below were synthesised using a similar method to that described above in relation to the preparation of Compound 213, together with synthetic methods disclosed herein or known in the art of synthetic organic chemistry, and variations thereon as appreciated by those skilled in the art. In any event, those skilled in the art of organic synthesis will recognize the starting materials and reaction conditions including variations to produce the compounds.

Table 13: Compounds 214 to 216 and 288

Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No.

Example 35: Synthesis of Compound 217

7-benzyl-3-fluoro-l-[(2-methoxyethyl)amino]-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile A mixture of Compound 116 (169 mg, 0.474 mmol) and cesium fluoride (150 mg, 0.987 mmol) in DMSO (2 mL) was stirred at 150 °C for 1.5 h using microwave irradiation. On completion, the reaction was allowed to cool to RT, diluted with EtOAc and washed with water. The aqueous layers were extracted with EtOAc, the combined organic layers dried over anhydrous Na₂S0₄ and the solvent removed in vacuo. Recrystallisation from EtOAc in heptane gave 117 mg (70% yield, 96% purity) of the title compound as a brown powder m/z: 341 [M+H]+, (ESI+), Rt = 4.59 mm, Method 7 1HNMR (500 MHz, Chloroform-d) d [ppm]: 7.37 - 7.33 (m, 4H), 7.33 - 7.28 (m, 1H), 4.96 - 4.88 (m, 1H), 3.75 (s, 2H), 3.65 (q, 2H), 3.55 - 3.50 (m, 2H), 3.35 (s, 3H), 3.26 - 3.23 (m, 2H), 2.93 - 2.87 (m, 2H), 2.75 (t, 2H).

Example 36: Compound 218 Compound 218 shown below was synthesised using a similar method to that described above in relation to the preparation of Compound 217, together with synthetic methods disclosed herein or known in the art of synthetic organic chemistry, and variations thereon as appreciated by those skilled in the art. 218 m/z: 366 [M+H]+, (ESI+), Rt = 3.5 min, Method 8

Example 37: Synthesis of Compound 219

7-{[4-(difluoromethoxy)phenyl]methyl}-3-(difluoromethyl)-l-[(2-methoxyethyl)amino]-5,6,7,8- tetrahydro-2,7-naphthyridine-4-carbonitrile

A suspension of Compound 193 (125 mg, 0.296 mmol), [l,3-bis[2,6-bis(propan-2- yl)phenyl]imidazolidin-2-ylidene](difluoromethyl)silver (211 mg, 0.384 mmol), DPEphos (8 mg, 0.015 mmol) and tris(dibenzylideneacetone)dipalladium(0) (17.0 mg, 0.03 mmol) in degassed anhydrous toluene (1.2 mL) was degassed for 5 min and stirred at 80°C for 18 h. The reaction was re-treated with [l,3-bis[2,6-bis(propan-2-yl)phenyl]imidazolidin-2-ylidene] (difluoromethyl) silver (211 mg, 0.384 mmol) and stirred at 80 °C for 18 h. The mixture was re-treated with [1,3- bis[2,6-bis(propan-2-yl)phenyl]imidazolidin-2-ylidene](difluoromethyl)silver (317 mg, 0.576 mmol) and DPEphos (8 mg, 0.0148 mmol) and stirred at 85 °C for 42 h. The reaction solvent was removed in vacuo. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 42% gradient) and subsequent purification by basic reverse phase FCC (Cl 8 silica gel, eluting with 0.1% ammonium hydroxide in MeCN-0.1% ammonium hydroxide in water, 10 - 100%) gave 18 mg (14% yield, 100% purity) of the title compound as a yellow solid m/z: 439 [M+H]+, (ESI+), Rt = 4.74 mm, Method 7

1HNMR (500 MHz, Chloroform-d) d [ppm]: 7.42 - 7.32 (m, 2H), 7.18 - 7.07 (m, 2H), 6.58 (t, 1H), 6.52 (t, 1H), 4.87 (t, 1H), 3.78 - 3.70 (m, 4H), 3.55 (t, 2H), 3.36 (s, 3H), 3.28 (s, 2H), 2.95 (t, 2H), 2.76 (t, 2H).

Intermediate 35

6-benzyl-l,3-dichloro-5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile

To a stirring suspension of KOtBu (800 mg, 7.13 mmol) in anhydrous THF (20 mL) at -78 °C was added 2.5 Mn-BuLi in hexanes (2.9 mL, 7.15 mmol) dropwise over 10 min under nitrogen. The mixture was stirred for 20 min at -78 °C and then a suspension of Intermediate 2 (97%, 2.00 g, 6.10 mmol) in anhydrous THF (70 mL) was added over 15 min. The reaction mixture was stirred for 10 min at -78 °C and then Mel (610 uL, 9.80 mmol) was added dropwise and the reaction mixture was allowed to warm to RT and stirred for a further 30 min. The reaction mixture was quenched with a sat. aq. NH4C1 solution and extracted with ethyl acetate. The combined organic extracts were dried over Na2S04 and concentrated in vacuo to give a dark gum. Purification twice by FCC (silica gel, eluting with EtOAc in heptane, 0 - 40% gradient) gave 650 mg (29% yield, 90% purity) of the title compound as a yellow oil. m/z: 332/334/336 [M+H]+, (ESI+), Rt = 0.99 mm, Method 2

1HNMR (500 MHz, Chloroform-d) d [ppm]: 7.42 - 7.27 (m, 5H), 4.33 - 4.17 (m, 1H), 3.87 - 3.75 (m, 1H), 3.72 - 3.58 (m, 1H), 3.13 - 2.90 (m, 2H), 2.88 - 2.63 (m, 2H), 1.53 - 1.43 (m, 3H). Example 38: Compound 220

6-benzyl-3-chloro-l-[(cyanomethyl)amino]-5-methyl-7,8-dihydro-5H-2,6-naphthyridine-4- carbonitrile Compound 220 was synthesised from Intermediate 35 using a similar method to that described in relation to the preparation of Intermediate 3. m/z: 352.3/354.3 [M+H]+, (ESI+), Rt = 3.52 mm, Method 7

Example 39: Compound 221

3-chloro-l-[(cyanomethyl)amino]-6-{[6-(2,2-difluoroethoxy)-2-methylpyridin-3-yl]methyl}-5- methyl-7, 8-dihydro-5H-2,6-naphthyridine-4-carbonitrile

Compound 221 was synthesised from Compound 220 using similar methods to those described to prepare Intermediate 16 and Compound 64. m/z: 447.4 / 449.4 [M+H]+, (ESI+), Rt = 3.80 mm, Method 8 lH NMR (500 MHz, CD3CN) d [ppm]: 7.56 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 6.34 - 6.08 (m, 2H), 4.54 (td, J = 14.6, 3.9 Hz, 2H), 4.34 (d, J = 5.9 Hz, 2H), 3.88 (q, J = 6.8 Hz, 1H), 3.69 (d, J = 13.7 Hz, 1H), 3.56 (d, J = 13.7 Hz, 1H), 3.15 (ddd, J = 13.6, 11.2, 5.4 Hz, 1H), 2.92 - 2.86 (m, 1H), 2.51 - 2.38 (m, 4H), 2.17 - 2.10 (m, 1H), 1.38 (d, J = 6.9 Hz, 3H). Intermediate 36

7-benzyl-l,3-dichloro-5-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile

Example 40: Compound 222 3-chloro-l-[(cyanomethyl)amino]-7-{[6-(2,2-difluoroethoxy)-2-methylpyridin-3-yl]methyl}-5- methyl-6, 8-dihydro-5H-2,7-naphthyridine-4-carbonitrile

Compound 222 was synthesised from Intermediate 36, using a similar method to that described to prepare Intermediate 3, Intermediate 16 and Compound 64. m/z: 447.3 / 449.3 [M+H]+, (ESI+), Rt = 4.00 mm, Method 8 lH NMR (400 MHz, DMSO-d6) d [ppm]: 7.77 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 8.2

Hz, 1H), 6.38 (tt, J = 54.9, 3.6 Hz, 1H), 4.54 (td, J = 15.1, 3.5 Hz, 2H), 4.34 (s, 2H), 3.69 - 3.61

(m, 2H), 3.54 (d, J = 16.0 Hz, 1H), 2.95 (d, J = 15.9 Hz, 1H), 2.99 - 2.89 (m, 1H), 2.70 (d, J =

11.5 Hz, 1H), 2.52 - 2.51 (m, 1H), 2.46 (s, 3H), 1.28 (d, J = 6.9 Hz, 3H).

Intermediate 37

7-benzyl-l,3-dichloro-5,5-dimethyl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile To a solution of Intermediate 31 (3.50 g, 11.0 mmol) in anhydrous THF (100 mL) at -78 °C under nitrogen was added 1 M KHMDS (in THF) (16 mL, 16.1 mmol) and the reaction mixture was stirred for 30 min at -78 °C. To the reaction mixture was added Mel (1.1 mL, 18.0 mmol) and the reaction mixture was allowed to warm to RT and stirred for 30 min. The reaction mixture was then cooled to - 78 °C and to the reaction mixture was added 1 M KHMDS (in THF) (22 mL, 21.7 mmol) and the reaction mixture was stirred for 30 min at -78 °C. To the reaction mixture was added Mel (1.1 mL, 18.0 mmol) and the reaction mixture was allowed to warm to RT and stirred for a further 30 min. To the reaction mixture was added sat. aq. NH4C1 solution and the reaction mixture was stirred for 10 min at RT. The organics were diluted with EtOAc and washed with water, then brine. The organics were dried over MgS04, fdtered and concentrated in vacuo. Purification by FCC (silica gel, eluting with Et20 in heptane, 0 - 20% gradient) followed by trituration in diethyl ether gave 608 mg (15% yield, 95% purity) of the title compound as an off- white solid. m/z: 346/348/350 [M+H]+, (ESI+), Rt = 1.23 mm, Method 2

1HNMR (500 MHz, Chloroform-d) d [ppm]: 7.43 - 7.29 (m, 5H), 3.77 (s, 2H), 3.66 (s, 2H), 2.46 (s, 2H), 1.55 (s, 6H).

Example 41: Compound 223

3-chloro-l-[(cyanomethyl)amino]-7-{[6-(2,2-difluoroethoxy)-2-methylpyridin-3-yl]methyl}-5,5- dimethyl-6, 8-dihydro-2,7-naphthyridine-4-carbonitrile

Compound 223 was synthesised from Intermediate 37 using similar methods to those described to prepare Intermediate 3, Intermediate 4 and Compound 2. m/z: 461.4 / 463.3 [M+H]+, (ESI+), Rt = 4.11 mm, Method 10 lH NMR (500 MHz, DMSO-d6) d [ppm]: 7.80 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.38 (tt, J = 54.9, 3.6 Hz, 1H), 4.54 (td, J = 15.1, 3.6 Hz, 2H), 4.33 (s, 2H), 3.61 (s, 2H), 3.22 (s, 2H), 2.45 (s, 3H), 2.41 (s, 2H), 1.37 (s, 6H). Example 42: Compound 224

3-chloro-l-[(cyanomethyl)amino]-7-{[6-(difluoromethoxy)-2-methylpyridin-3-yl]methyl}-5,5- dimethyl-6, 8-dihydro-2,7-naphthyridine-4-carbonitrile Compound 224 was synthesised from Intermediate 37 using similar methods to those described to prepare Intermediate 3, Intermediate 4 and Compound 2. m/z: 447.3 / 449.3 [M+H]+, (ESI+), Rt = 4.09 mm, Method 10

1HNMR (500 MHz, DMSO-d6) d [ppm]: 7.81 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.68 (t, J = 73.2 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 4.33 (s, 2H), 3.65 (s, 2H), 3.23 (s, 2H), 2.48 (s, 3H), 2.43 (s, 2H), 1.38 (s, 6H).

Intermediate 38 prop-2-en-l-yl 6-chloro-5-cyano-8-[(cyanomethyl)[(prop-2-en-l-yloxy)carbonyl]amino]-l,2,3,4- tetrahydro-2,7-naphthyridine-2-carboxylate

To a solution of Compound 115 (95%, 200 mg, 0.562 mmol) in anhydrous THF (5 mL) was added Alloc-Cl (1.5 mL, 14.1 mmol) and the reaction was cooled to 0 °C with stirring under nitrogen. NaH (60% in mineral oil, 80 mg, 2.00 mmol) was added and the reaction was stirred at 40 °C for 32 h. The reaction was diluted with DCM and quenched with water. The layers were separated and the aqueous layer was extracted with DCM (x2). The combined organics were passed through a phase separator and concentrated. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 100% gradient) gave 220 mg (78% yield, 83% purity) of the title compound as a yellow oil. m/z: 416/418 [M+H]+, (ESI+), Rt = 0.96 min, Method 2

1HNMR (500 MHz, DMSO-d6) d [ppm]: 6.01 - 5.87 (m, 2H), 5.38 - 5.12 (m, 4H), 4.77 (s, 2H), 4.74 - 4.69 (m, 2H), 4.60 - 4.53 (m, 2H), 4.45 (s, 2H), 3.69 (s, 2H), 3.11 (t, 2H). Intermediate 39

Prop-2-en-l-yl 6-chloro-5-cyano-8-{[cyano(²H2)methyl]amino}-l,2,3,4-tetrahydro(4,4-²H)-2,7- naphthyridine-2-carboxylate To Intermediate 38 (83%, 190 mg, 0.379 mmol) in a mixture of deuterium oxide (0.40 mL, 22.2 mmol) and anhydrous THF (1.3 mL) at 0 °C was added NaH (60% in mineral oil, 16 mg, 0.400 mmol) slowly. The reaction was stirred at RT for 24 h. To the reaction was added sat. aq. NH4C1 solution and water. The aqueous layer was extracted with EtOAc (x3) and the combined organic layers were concentrated. Purification by FCC (silica gel, eluting with EtOAc in heptane, 0 - 50% gradient) gave 60 mg (28% yield, 60% purity) of the title compound as a colourless oil. m/z: 336/338 [M+H]+, (ESI+), Rt = 0.86 mm, Method 2

1HNMR (400 MHz, DMSO-d6) d [ppm]: 8.05 (s, 1H), 5.95 (ddt, 1H), 5.32 (dq, 1H), 5.21 (dq, 1H), 4.60 (dt, 2H), 4.30 (s, 2H), 3.65 (s, 2H).

Example 43: Compounds 225, 293 and 294 Compound 225: 3-chloro-l-{[cyano(²H2)methyl]amino}-7-{[6-(difluoromethoxy)pyridin-3- yl]methyl}-5,6,7,8-tetrahydro(5,5-²H2)-2,7-naphthyridine-4-carbonitrile Compound 225 was synthesised from Intermediate 39, using a similar method to that described to prepare Compound 64. m/z: 409.2 / 411.2 [M+H]+, (ESI+), Rt = 2.5 mm, Method 5

1HNMR (500 MHz, DMSO-d6) d [ppm]: 8.22 (d, 1H), 7.90 (dd, 1H), 7.79 (s, 1H), 7.71 (t, 1H), 7.08 (d, 1H), 3.74 (s, 2H), 3.26 (s, 2H), 2.72 (s, 2H).

The compounds 293 and 294 shown in Table A below were synthesised using a similar method to that described above in relation to the preparation of Compound 225, together with synthetic methods disclosed herein or known in the art of synthetic organic chemistry, and variations thereon as appreciated by those skilled in the art. In any event, those skilled in the art of organic synthesis will recognize the starting materials and reaction conditions including variations to produce the compounds.

Table A: Compounds 293 and 294 Example 44: Preparation of enantiomers of example compounds

The compounds 226 to 254 and 289 to 292 shown in the following Table 14 were obtained from racemic mixtures using chiral chromatography to afford single enantiomers. Table 14: Compounds 226 to 254 and 289 to 292 Cpd.

Structure Analytical data

No. Cpd.

Structure Analytical data

No. m/z: 371 / 373 [M+H]+,

250 (ESI+), Rt = 5.02 min, Method 7, Enantiomer 1 Details of the separation methods and chiral analytical data of the compounds 226 to 254 and 289 to 292 are summarized in the following Table 15.

Table 15: Chiral chromatography of Compounds 226 to 254 and 289 to 292

Cpd.

Chiral analytical data Chiral purification method No.

SFC,

226 Chiralpak AS-H (10 x 250mm, 5pm),

Rt = 30.87 min, Method Cl

15% Methanol / 85% C02 15 mL / min

SFC,

227 Chiralpak AS-H (10 x 250mm, 5pm),

Rt = 32.81 min, Method Cl

15% Methanol / 85% C02,

15 mL / min

SFC,

228 Chiralpak AD-H (10 x 250mm, 5pm), 10% Ethanol /

Rt = 8.27 min, Method C2 90% C02,

15 mL / min

SFC,

229 Chiralpak AD-H (10 x 250mm, 5pm), 10% Ethanol /

Rt = 11.56 min, Method C2 90% C02,

15 mL / min

SFC,

230

Rt = 10.23 min, Method C3 Chiralcel OJ-H (10 x 250mm, 5pm),

15% isopropanol / 85% C02, Cpd.

Chiral analytical data Chiral purification method

No.

15 mL / min SFC,

231 Chiralcel OJ-H (10 x 250mm, 5pm),

Rt = 6.33 min, Method C6 15% isopropanol / 85% C02,

15 mL / min

LC,

232 Chiralcel OD-H (20 x 250mm, 5pm),

Rt = 7.17 min, Method C6 85% Heptane / 15% Ethanol,

18 mL / min

LC,

233 Chiralcel OD-H (20 x 250mm, 5pm),

Rt = 9.01 min, Method C2 85% Heptane / 15% Ethanol,

18 mL / min

SFC,

234 Chiralpak IC (10 x 250mm, 5pm),

Rt = 5.35 min, Method C13 20% isopropanol / 80% C02,

15 mL / min

SFC,

235 Chiralpak IC (10 x 250mm, 5pm),

Rt = 6.6 min, Method Cl 3 20% isopropanol / 80% C02,

15 mL / min

SFC,

236 Cellulose-4 (10 x 250mm, 5pm),

Rt = 2.21 min, Method C12 15% Methanol / 85% C02,

15 mL/min

SFC,

237 Cellulose-4 (10 x 250mm, 5pm),

Rt = 2.63 min, Method C12 15% Methanol / 85% C02,

15 mL/min

LC,

238 Rt = 3.55 min, Method C7 Cellulose-4 (21.2 x 250mm, 5pm), 85% Heptane / 15% Ethanol, Cpd.

Chiral analytical data Chiral purification method

No.

9 mL/min

LC,

239 Cellulose-4 (21.2 x 250mm, 5pm),

Rt = 4.08 min, Method C7 85% Heptane / 15% Ethanol,

9 mL/min

SFC,

240 Chiralpak AD-H (10 x 250mm, 5pm),

Rt = 13.41 min, Method C2 15% Ethanol / 85% C02,

15 mL/min

SFC,

241 Chiralpak AD-H (10 x 250mm, 5pm),

Rt = 15.99 min, Method C2 15% Ethanol / 85% C02,

15 mL/min

SFC,

242 Chiralcel OJ-H (10 x 250mm, 5pm),

Rt = 11.34 min, Method C5 20% Methanol / 80% C02,

15 mL/min

SFC,

243 Chiralcel OJ-H (10 x 250mm, 5pm),

Rt = 15.57 min, Method C5 20% Methanol / 80% C02,

15 mL/min

SFC,

244 Chiralpak AD-H (10 x 250mm, 5pm),

Rt = 2.43 min, Method CIO 10% Ethanol / 90% C02,

15 mL/min

SFC,

245 Chiralpak AD-H (10 x 250mm, 5pm),

Rt = 2.92 min, Method CIO 10% Ethanol / 90% C02,

15 mL/min

LC,

246

Rt = 4.00 min, Method C9 Chiralcel OD-H (20 x 250 mm, 5 um), 85% Heptane / 15% Ethanol, Cpd.

Chiral analytical data Chiral purification method

No.

18 mL/min LC,

247 Chiralcel OD-H (20 x 250 mm, 5 um),

Rt = 5.79 min, Method C9 85% Heptane / 15% Ethanol,

18 mL/min

LC,

248 Chiralpak AD-H (20 x 250mm, 5pm),

Rt = 1.76 min, Method Cll 85% Heptane / 15% Ethanol,

18 mL/min

LC,

249 Chiralpak AD-H (20 x 250mm, 5pm),

Rt = 2.63 min, Method Cll 85% Heptane / 15% Ethanol,

18 mL/min

LC,

250 Chiralcel OJ-H (20 x 250 mm, 5 um),

Rt = 12.43 min, Method C4 85% Heptane / 15% Ethanol,

18 mL/min

LC,

251 Chiralcel OD-H (20 x 250mm, 5pm),

Rt = 2.48 min, Method C8 80% Heptane / 20% isopropanol,

18 mL/min

LC,

252 Chiralcel OD-H (20 x 250mm, 5pm),

Rt = 2.9 min, Method C8 80% Heptane / 20% isopropanol,

18 mL/min

LC,

253 Chiralcel OD-H (20 x 250 mm, 5 um),

Rt = 11.9 min, Method C2 85% Heptane / 15% Ethanol,

18 mL/min

LC,

254 Rt = 7.83 min, Method C3 Chiralcel OD-H (20 x 250 mm, 5 um), 85% Heptane / 15% Ethanol, Cpd.

Chiral analytical data Chiral purification method No.

18 mL/min SFC,

289 Cellulose-4 (10 x 250mm, 5pm),

Rt = 19.59 min, Method Cl 5

15% Acetonitrile + 0.2% diethylamine / 85% C02, 15 mL / min

SFC,

290 Cellulose-4 (10 x 250mm, 5pm),

Rt = 22.57 min, Method Cl 5

15% Acetonitrile + 0.2% diethylamine / 85% C02, 15 mL / min

LC,

291 Chiralcel OD-H (20 x 250mm, 5pm),

Rt = 20.00 min, Method C14

85% Heptane / 15% isopropanol,

18 mL / min

LC,

292 Chiralcel OD-H (20 x 250mm, 5pm),

Rt = 22.79 mm, Method C14

85% Heptane / 15% isopropanol,

18 mL / min

Example 45: Compound 295

3-chloro-l-(cyanomethylamino)-7-[l-[6-(oxetan-3-yloxy)-3-pyridyl]ethyl]-6,8-dihydro-5H-2,7- naphthyridine-4-carbonitrile To a solution of 3 -hydroxy oxetane (95% purity, 30 mg, 0.385 mmol) in NMP (1.5 mL) at 0 °C was added potassium tert-butoxide (110 mg, 0.980 mmol) and the reaction was stirred for 5 min To the reaction was added 3-chloro-l-(cyanomethylamino)-7-[l-(6-fluoro-3-pyridyl)ethyl]-6,8- dihydro-5H-2,7-naphthyridine-4-carbonitrile (prepared using a similar method as described in Example 16 (Synthesis of Compound 96), 95% purity, 132 mg, 0.338 mmol) and a second aliquot of NMP (1.5 mL). The reaction mixture was heated at 50 °C for 22 h. The reaction mixture was diluted with waterbrine (1 : 1, 20 mL) and EtOAc (20 mL) and the layers separated. The aqueous phase was extracted with additional EtOAc (20 mL). The combined organic phases were washed with water and brine, then dried over Na2S04, filtered and concentrated. The residue was purified by preparative HPLC (Method A), then further purified by preparative HPLC (Method C). The product-containing fractions were combined and neutralised with sat aq. NaHC03 and then concentrated to remove the MeCN. The aqueous phase was then extracted with DCM (x3), the combined organics were dried over Na2S04 and then concentrated and lyophilised to afford the title compound (17 mg, 11% Yield) as a tan solid m/z: 425.2/427.2 [M+H]+, (ESI+), Rt = 1.93 mm, Method 5 lH NMR (500 MHz, DMSO) d 8.08 (d, J = 2.3 Hz, 1H), 7.84 (s, 1H), 7.75 (dd, J = 8.5, 2.4 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 5.61 - 5.47 (m, 1H), 4.88 (t, J = 7.0 Hz, 2H), 4.61 - 4.51 (m, 2H), 4.38 (s, 2H), 3.77 (q, J = 6.8 Hz, 1H), 3.36 (d, J = 15.8 Hz, 1H), 3.22 (d, J = 15.8 Hz, 1H), 2.74 (t, J = 5.3 Hz, 2H), 2.70 - 2.62 (m, 1H), 2.55 - 2.50 (m, 1H), 1.40 (d, J = 6.8 Hz, 3H).

Example 46: Compound 296 l-(cyanomethylamino)-6-[[6-(2,2-difluoroethoxy)-2-methyl-3-pyridyl]methyl]-3-methoxy-7,8- dihydro-5H-2,6-naphthyridine-4-carbonitrile

A mixture of Compound 28 (95% purity, 98 mg, 0.215 mmol) and sodium methoxide powder (60 mg, 1.11 mmol) in anhydrous methanol (3 mL) was degassed with nitrogen and then stirred at 70 °C for 24 hours in a sealed tube. Further sodium methoxide powder (40 mg, 0.741 mmol) was added and stirring at 70 °C continued for a further 6 hours. The reaction mixture was allowed to cool, diluted with ethyl acetate (20 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo and the residue was purified by preparative HPLC (Method C). The resulting solid was loaded onto a 1 g PE -AX column in MeCN (1 mL) and eluted with 20% MeOH in MeCN (15 mL). The filtrate was concentrated in vacuo and vacuum oven dried at 40 °C to give 12 mg (13% yield, 100% purity) of the title compound as a pale yellow solid m/z: 429.3 [M+H]+, (ESI+), Rt = 2.25 mm, Method 5 1HNMR (400 MHz, DMSO-d6) d 7.67 - 7.57 (m, 2H), 6.72 (d, J = 8.3 Hz, 1H), 6.38 (tt, J = 54.8, 3.6 Hz, 1H), 4.54 (td, J = 15.1, 3.7 Hz, 2H), 4.37 (d, J = 4.8 Hz, 2H), 3.96 (s, 3H), 3.62 (s, 2H), 3.52 (s, 2H), 2.72 - 2.67 (m, 2H), 2.44 (s, 3H), 2.38 - 2.33 (m, 2H).

Example 47: Compound 297

3-chloro-l-(cyanomethylamino)-6-[[6-(2,2-difluoroethoxy)-2-(trideuteriomethyl)-3- pyridyl]methyl]-7,8-dihydro-5H-2,6-naphthyridine-4-carbonitrile

Step 1

Sodium hydride (60% in mineral oil, 338 mg, 8.44 mmol) was added to a solution of 2,6- dibromopyridine (2.00 g, 8.44 mmol) in anhydrous DMF (8 mL) and the mixture was allowed to stir for 10 minutes. 2,2-Difluoroethanol (0.64 mL, 10.1 mmol) was then added slowly and the mixture was heated at 60 °C for 1.5 h. The reaction mixture was then partitioned between water and diethyl ether and the layers were separated. The organic layer was washed with further water then brine, dried over magnesium sulfate and concentrated to give 2-bromo-6-(2,2- difluoroethoxy)pyridine (2.01 g, 93% purity 93% yield) as a pale brown oil. lH NMR (500 MHz, DMSO) d 7.76 - 7.69 (m, 1H), 7.31 (d, J = 7.5 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.38 (tt, J = 54.4, 3.4 Hz, 1H), 4.55 (td, J = 15.2, 3.4 Hz, 2H).

Step 2

To a solution of 2-bromo-6-(2,2-difluoroethoxy)pyridine (93% purity, 1.0 g, 3.91 mmol) in dry diethyl ether (12 mL) at -78 °C was added 2.5 M n-butyllithium in hexanes (2.0 mL, 5.08 mmol) dropwise. The reaction mixture was stirred for 30 min at -78 °C and then iodo d3 -methane (0.31 mL, 5.08 mmol) was added. The reaction mixture was allowed to warm to RT and was stirred for a further 45 min. To the reaction mixture was added sat. aq. NH4C1 (20 mL) and the reaction mixture was stirred at RT for 5 minutes. The organics were diluted with diethyl ether (60 mL) and water (20 mL) and the layers separated. The organic layer was washed with water then brine. The organics were dried (Na2S04), fdtered and concentrated. The residue was purified by FCC (50 g silica column, 0-100% EtOAc in heptane) followed by reverse phase FCC (30g Cl 8 column, 10- 100% MeCN (0.1% formic acid) in Water (0.1% formic acid)). The product fractions were extracted with DCM (x3) and the organic layers were concentrated under vacuum to afford 2-(2,2- difluoroethoxy)-6-(trideuteriomethyl)pyridine (305 mg, 71% purity, 31% Yield) as a yellow oil. m/z: 177.0 [M+H]+, (ESI+), Rt = 0.88 mm, Method 2 lH NMR (500 MHz, DMSO) d 7.64 (dd, J = 8.2, 7.3 Hz, 1H), 6.92 - 6.87 (m, 1H), 6.72 - 6.66 (m, 1H), 6.38 (tt, J = 54.9, 3.6 Hz, 1H), 4.53 (td, J = 15.1, 3.6 Hz, 2H).

Step 3

To a solution of 2-(2,2-difluoroethoxy)-6-(trideuteriomethyl)pyridine (71% purity, 305 mg, 1.23 mmol) in anhydrous THF (2.4 mL) was added l,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (176 mg, 0.615 mmol) and the mixture was stirred at RT for 2.5 h. Further l,3-dibromo-5,5- dimethylimidazolidine-2,4-dione (176 mg, 0.615 mmol) was added and the mixture was stirred at RT for approximately 18 hours. Further l,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (176 mg, 0.615 mmol) was added and the mixture was stirred at RT for 1 h. The mixture was quenched with the addition of sat. aq. Na2S203, then diluted with DCM and water and the layers separated. The aqueous was extracted with further DCM (x2), the combined organics passed through a phase separator and then concentrated. The residue was purified by FCC (25 g silica column, 0-100% EtOAc in heptane) to afford 3-bromo-6-(2,2-difluoroethoxy)-2-(trideuteriomethyl)pyridine (153 mg, 77% purity, 38% Yield) as a pale yellow oil. m/z: 254.8/256.8 [M+H]+, (ESI+), Rt = 1.05 mm, Method 2 lH NMR (500 MHz, DMSO) d 7.91 (d, J = 8.6 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H), 6.38 (tt, J =

54.7, 3.5 Hz, 1H), 4.54 (td, J = 15.1, 3.5 Hz, 2H).

Step 4

To a solution of 5-bromo-2-(2,2-difluoro-l, 1 -dimethyl-ethoxy )pyridine (77% purity, 150 mg, 0.434 mmol) in dry diethyl ether (4 mL) at -78 °C was added 2.5 M n-butyllithium in hexanes (226 uL, 0.564 mmol) over 30 seconds. The reaction mixture was stirred for 30 min at -78 °C and then DMF (0.064 mL, 0.868 mmol) was added. The reaction mixture was allowed to warm to RT and was stirred for a further 45 min. To the reaction mixture was added sat. aq. ammonium chloride (10 mL) and the reaction mixture was stirred at RT for 5 minutes. The organics were diluted with diethyl ether (40 mL) and water (10 mL) and the layers separated. The organic layer was washed with water then brine and dried (Na2S04), filtered and concentrated. The residue was purified by FCC (10 g silica column, 0-100% EtOAc in heptane) to afford 6-(2,2-difluoroethoxy)- 2-(tri deuteri omethyl)pyridine-3-carbaldehyde (45 mg, 89% purity, 45% Yield) as a colourless oil. lH NMR (500 MHz, DMSO) d 10.18 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.42 (tt, J = 54.6, 3.4 Hz, 1H), 4.67 (td, J = 15.1, 3.5 Hz, 2H).

Step 5

Intermediate 16 (94% purity, 94 mg, 0.27 mmol), 6-(2,2-difluoroethoxy)-2- (trideuteriomethyl)pyridine-3-carbaldehyde (89% purity, 45 mg, 0.2 mmol), palladium triphenylphosphane (12 mg, 0.01 mmol) and sodium triacetoxyborohydride (174 mg, 0.82 mmol) were combined in a pressure vial and placed under nitrogen. Anhydrous THF (3 mL) was added and the reaction was heated at 40 °C for 1.5 h. The mixture was diluted with DCM and sat. aq. NaHC03, the layers were separated and the aqueous extracted with further DCM (x2). The combined organic was passed through a phase separator and then concentrated. The residue was purified by preparative HPLC (Method B) to afford the title compound (25 mg, 28% yield) as an off- white solid. m/z: 436.0 [M+H]+, (ESI+), Rt = 2.82 mm Method 5 lH NMR (500 MHz, DMSO) d 7.94 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.39 (tt, J = 54.9, 3.6 Hz, 1H), 4.54 (td, J = 15.1, 3.6 Hz, 2H), 4.37 (s, 2H), 3.64 (s, 2H), 3.58 (s, 2H), 2.72 (t, J = 5.8 Hz, 2H), 2.40 (t, J = 5.8 Hz, 2H).

Example 48: Compounds 298, 299 and 300

Synthesis of Compound 298

3 -chloro- 1 -(cyanomethylamino)-6- [ [6-(3 -hydroxy-3 -methyl-cy cl obutoxy)-2-methyl-3 - pyridyl]methyl]-7,8-dihydro-5H-2,6-naphthyridine-4-carbonitrile

Step 1

To a stirring solution of Intermediate 16 (350 mg, 1.044 mmol) and 6-[3-[tert- butyl(dimethyl)silyl]oxy-3-methyl-cyclobutoxy]-2-methyl-pyridine-3-carbaldehyde (synthesised using similar methods to Intermediate 6, 85% purity, 402 mg, 1.02 mmol) in anhydrous THF (10 mL) at room temperature was added sodium triacetoxyborohydride (863 mg, 4.00 mmol) in portions over 5 minutes followed by palladium tetrakis(triphenylphosphine) (50 mg, 0.0433 mmol) and the reaction stirred at 40 °C for 1 hour under nitrogen. The reaction was cooled then quenched with a saturated aqueous solution of sodium bicarbonate (40 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by FCC (25 g silica column, 0 - 50% gradient of EtOAc in heptane) gave 361 mg (62% yield, 100% purity) of 6-[[6-[3-[tert- butyl(dimethyl)silyl]oxy-3-methyl-cyclobutoxy]-2-methyl-3-pyridyl]methyl]-3-chloro-l- (cyanomethylamino)-7,8-dihydro-5H-2,6-naphthyridine-4-carbonitrile as an off-white solid. 1HNMR (400 MHz, DMSO) d 7.91 (s, 1H), 7.55 (d, J = 8.3 Hz, 1H), 6.61 - 6.54 (m, 1H), 5.23 - 4.73 (m, 1H), 4.37 (s, 2H), 3.61 (s, 2H), 3.57 (s, 2H), 2.72 (t, J = 5.7 Hz, 2H), 2.63 - 2.53 (m, 2H), 2.42 - 2.36 (m, 5H), 2.16 - 2.05 (m, 2H), 1.44 - 1.33 (m, 3H), 0.90 - 0.82 (m, 9H), 0.11 - 0.05 (m, 6H).

Step 2

To a stirring solution of 6-[[6-[3-[tert-butyl(dimethyl)silyl]oxy-3-methyl-cyclobutoxy]-2-methyl- 3-pyridyl]methyl]-3-chloro-l-(cyanomethylamino)-7,8-dihydro-5H-2,6-naphthyridine-4- carbonitrile (355 mg, 0.626 mmol) in anhydrous THF (5 mL) at 0 °C was added tetrabutylammonium fluoride (TBAF) (1M in THF) (650 uL, 0.650 mmol) dropwise. The resulting mixture was stirred at 0 °C for 60 minutes under nitrogen and then allowed to warm up to room temperature and stirred for 2 hours. Further TBAF (1M in THF) (650 uL, 0.650 mmol) was added and stirring at RT continued for a further 2 hours. The reaction mixture was then stirred at 35 °C for 2 hours. The reaction mixture was cooled, retreated with TBAF (1M in THF) (650 uL, 0.650 mmol) and stirred at RT for 1 hour, then allowed to stand for 64h. The reaction mixture was quenched with brine (20 mL) and extracted into ethyl acetate (3 x 20 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by FCC (silica column, 0 - 100% gradient of EtOAc in heptane) followed by trituration with 15% ethyl acetate in heptane to afford 178 mg (61% yield, 97% purity) of Compound 298 as a pale beige solid. m/z: 453.3/455.3 [M+H]+, (ESI+), Rt = 3.15/3.12 mm Method 8 lHNMR (400 MHz, DMSO-d6) d 7.91 (s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 6.59 - 6.52 (m, 1H), 5.09 - 4.89 (m, 1H), 5.25 - 4.69 (m, 1H), 4.37 (s, 2H), 3.61 (s, 2H), 3.57 (s, 2H), 2.72 (t, J = 5.6 Hz, 2H), 2.48 - 2.43 (m, 2H), 2.42 - 2.37 (m, 5H), 2.12 - 1.97 (m, 2H), 1.32 - 1.24 (m, 3H).

Separation of regioisomers

Compound 298 (3 -chloro- 1 -(cy anomethylamino)-6- [ [6-(3 -hydroxy-3 -methyl-cy clobutoxy)-2- methyl-3-pyridyl]methyl]-7,8-dihydro-5H-2,6-naphthyridine-4-carbonitrile) was purified by preparitive HPLC to afford separation of the regioisomers - Compound 299 and Compound 300.

The purifications was performed using a Waters X-B ridge Cl 8 column (30 mm x 10 mm, 5 mM) and a gradient of 5-95% B (A= 0.2% ammonium hydroxide in water; B= 0.2% ammonium hydroxide in ACN) over 16 min then 95% B for 2 min. A second gradient of 95-5% B was then applied over 2 min with a flow rate of 40 mL/min. The first-eluting component was isolated to afford 16 mg of the regioisomeric Compound 299 (10% yield, 100% purity): as a white solid. m/z: 453.3/455.3 [M+H]+, (ESI+), Rt = 3.12 min Method 8

1HNMR (500 MHz, DMSO-d6) d 7.91 (s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 8.2 Hz, 1H), 5.26 - 5.17 (m, 1H), 4.91 (s, 1H), 4.37 (s, 2H), 3.61 (s, 2H), 3.57 (s, 2H), 2.72 (t, J = 5.7 Hz, 2H), 2.47 - 2.37 (m, 7H), 2.04 - 1.97 (m, 2H), 1.31 (s, 3H).

The second-eluting component was isolated to afford 69 mg of the regioisomeric Compound 300 (43% yield, 100% purity): as a white solid. m/z: 453.3/455.3 [M+H]+, (ESI+), Rt = 3.14 mm Method 8 lH NMR (500 MHz, DMSO-d6) d [ppm]: 7.92 (s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 8.2 Hz, 1H), 5.07 (s, 1H), 4.74 (p, J = 7.2 Hz, 1H), 4.37 (s, 2H), 3.60 (s, 2H), 3.57 (s, 2H), 2.72 (t, J = 5.8 Hz, 2H), 2.49 - 2.46 (m, 2H), 2.39 (s, 5H), 2.12 - 2.05 (m, 2H), 1.26 (s, 3H).

Example 49: Compound 301

3 -chloro- 1 - [(cyanomethyl)amino] -6-( {2-methyl-6-trans-3 -fluoro-3 -methylcy clobutoxy ]pyri din-3 - yl}methyl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile To Compound 300 from Example 48 (50 mg, 0.110 mmol) in DCM (2 mL) at -10 °C was added (diethylamino)sulfur trifluoride (35 uL, 0.265 mmol) in one portion. The reaction mixture was stirred at -10 °C for 5 minutes and was then allowed to warm to room temperature and was stirred for further 10 minutes. To the reaction mixture was added NaHC03 (4 mL of a saturated aqueous solution) and the organics were extracted with DCM (2 x 4 mL), passed through a phase separator, and then concentrated in vacuo. The residue was purified by preparative HPLC (Method A) to afford the title compound (29 mg, 92% purity, 52% yield) as a white solid. m/z: 455.3 / 457.3 [M+H]+, (ESI+), Rt = 3.02 mm Method 5 lH NMR (400 MHz, DMSO) d 7.92 (s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 5.33 - 5.19 (m, 1H), 4.37 (s, 2H), 3.61 (s, 2H), 3.57 (s, 2H), 2.83 - 2.68 (m, 4H), 2.40 (s, 3H), 2.43 - 2.36 (m, 2H), 2.30 - 2.17 (m, 2H), 1.51 (d, J = 22.3 Hz, 3H).

Example 50: Determination of activity and selectivity of selected compounds

The following cell-based assays A to D were used to determine the activity of example compounds towards citrate transporters.

A. Citrate uptake assay

Activity on human INDY was determined by measuring citrate uptake into HepG2 cells, which endogenously expressed INDY (Gopal et al. 2007 Am J Physiol Gastrointest Liver Physiol 292). To determine activity on mouse INDY, HEK293 cells overexpressing mouse INDY were used. Cloning of mouse INDY was done in analogy as described in Birkenfeld et al. (Birkenfeld et al., 2011, Cell Metabolism 14, 184-195, 2011).

Cells were maintained in cell medium using cell culture grade flasks (T175 Greiner). The following media were used: HEK overexpressing INDY: MEM (no glutamine) + 10% FCS, 1 x P/S, 2 mM Glutamax, and cells were cultured in the presence of G418 (800pg/ml); HepG2: MEM (NEAA, no glutamine) + 10% FCS, 1 x P/S, 2 mM Glutamax, 1 mM sodium pyruvate; HEK293 cells expressing SLC13A3 and SLC13A2: DMEM + 10% FBS, 100 U/mL penicillin and 0.1 mg/mL streptomycin and cells were cultured in the presence of 150 pg/pL hygromycine The selection antibiotic G418 (800pg/ml) was added during cultivation but not for seeding into assay plates. For splitting, cells were washed with PBS (w/o Ca2+, Mg2+, phenol red) and detached with Trypsin/EDTA. Throughout cultivation cells were kept sub-confluent.

For the radiometric ¹⁴C-citrate uptake assay the scintillation proximity assay (SPA) principle has been employed. A special plate type (Cytostar-T, Perkin Elmer#RPNQ0166) is used, where the scintillation substance is present in the clear bottom of the plate. Only radioactivity which is present inside the cell and which is therefore in close proximity to the plate bottom can generate a signal. For the assay 20,000 HepG2 cells per well were seeded on collagen coated 384-well Cytostar-T plates or 5000 HEK293 cells per well were seeded on ploy-D-lysine coated 384-well Cytostar-T plates. On the following day culture medium was changed to assay buffer (20 mΐ): Citrate uptake buffer: 120mMNaCl, 5.4mM KCl, 0.8mM MgSO4, 5mM glucose, 1.8mM CaC12, 25mMHepes, 25mM MES, pH 6.5 (human) and pH 7.5 (mouse). Afterwards 100 nl of compound dilutions in 100% DMSO was added and cells were incubated at 37°C for 20 min. The substrate ¹⁴C-citrate (3 mM for HEK cells and 10 mM for HepG2 cells) was added and the cells were incubated for 50 min at 37°C. To stop the uptake the plates were cooled down for 15 min at 4°C. Afterwards the counts were measured using a Microbeta2 reader system (Perkin Elmer).

B. Succinate uptake assay

As a selectivity assay, ¹⁴C-succinate uptake by the SLC13A3 transporter was used. The principle of the assay is to measure the uptake of ¹⁴C-succinate into HepG2 cells.

HepG2 cells were maintained in cell medium using cell culture grade flasks (T175 sarstedt). The following media were used: MEM (NEAA, no glutamine) + 10% FCS, 1 x P/S, 2 mM Glutamax,

1 mM sodium pyruvate. For splitting, cells were washed with PBS (w/o Ca2+, Mg2+, phenol red) and detached with Trypsin/EDTA. Throughout cultivation cells were kept sub-confluent.

For the radiometric ¹⁴C-succinate uptake assay the scintillation proximity assay (SPA) principle has been employed. A special plate type (Cytostar-T, Perkin Elmer#RPNQ0166) is used, where the scintillation substance is present in the clear bottom of the plate. Only radioactivity which is present inside the cell and which is therefore in close proximity to the plate bottom can generate a signal.

For the assay 20,000 HepG2 cells per well were seeded on collagen coated 384-well Cytostar-T plates. On the following day culture medium was changed to assay buffer (20 mΐ): Succinate uptake buffer: 120mM NaCl, 5.4mM KCl, 0.8mMMgSO4, 5mM glucose, 1.8mM CaC12, 25mM Hepes, 25mM MES, pH 7.5. Afterwards 100 nl of compound dilutions in 100% DMSO was added and cells were incubated at 37°C for 20 min. 15 mM substrate ¹⁴C-succinate was added and the cells were incubated for 180 min at 37°C. To stop the uptake the plates were cooled down for 15 min at 4°C. Afterwards the counts were measured using a Microbeta² reader system (Perkin Elmer).

C. Alternative succinate uptake assay

Succinate uptake buffer was HBSS buffer, supplemented with 20 mM HEPES, pH 7.4.

As a counter assay, succinate uptake by the SLC13A3 and SLC13A2 transporter was used. The principle of the assay is to measure the uptake of ¹⁴C labelled succinate into HEK cells, which overexpress human SLC13A3 or SLC13A2. For uptake assays, 24-well plates are pre-treated with poly-D-lysine hydrobromide solution (0.1 mg/mL). Each well is coated with 0.5 mL poly-D-lysine solution and incubated for at least 15 minutes. After complete removal of the solution the plates are dried for 30 minutes. Cells (vector-transfected and transporter-transfected) treated with trypsin/EDTA are immediately seeded into 24-well plates (2 x 105 cells in 0.5 mL medium per well) and cultured for 3 days before used for transport experiments. For the uptake assay, growth medium is aspirated and each well is rinsed three times with 0.5 mL incubation buffer (HBSS buffer, supplemented with 20 mM HEPES, pH 7.4) and incubated for 20 min at 37°C. The incubation buffer is removed and 270 pL incubation buffer containing the non-labeled test item or reference inhibitor, respectively, is added to each well and incubated at 37°C. After 30 min pre-incubation the ¹⁴C-labeled succinic acid (30 pL) is added with final concentration of 1 pM. After 5 min incubation, uptake is terminated by aspirating the reaction mixture and washing the cells three times with 0.4 mL ice-cold PBS buffer. Cells are solubilized with 0.6 mL of IN NaOH overnight and transferred into scintillation vials. Radio-labelled content will be measured after addition of 2.5 mL scintillator in a liquid scintillation counter.

D. Fatty acid synthesis (FAS) assay in HepG2 - test for inhibition of in vitro lipogenesis

To test the functional activity of selected compounds and to bridge between the in vitro assay for citrate uptake to the physiological relevant lipid accumulation in liver cells a further functional cell assay was performed. This assay measured the effect of selected compounds on the citrate mediated fatty acid synthesis in a hepatocellular cell line. More specifically, fatty acids that are generated within HepG2 cells from an applied labelled substrate, in this case ¹⁴C-citrate, are determined, and the data are indicative for the inhibition of lipogenesis.

Fatty acid synthesis (FAS) assay in HepG2: The principle of the assay is to measure the generation of ¹⁴C-labelled fatty acids after uptake of ¹⁴C labelled citrate into HepG2 cells. HepG2 cells were seeded into black clear-bottom 96-well plates (Coming 3340 cell plate) 75,000/well and incubated at 37°C for 16-24 hours. After that plates were washed once with lOOpl PBS (+CaCb +MgCb) and 50pl assay medium (RPMI 1860 containing llmM glucose, lOmM HEPES and InM Insulin) per well was added. Test substances in assay medium were added (lOpl, 5% DMSO) and incubated for 20 min at 37°C. After that lOpl assay medium containing ¹⁴C-citrate (final concentration 50pM) and PrestoBlue reagent (lx final concentration; ThermoFisher) were added and incubated for 180 min (37°C, 5% CCh). Cell viability was measured (ViewLux instrument,). Medium was removed by vacuum aspirating and cells were washed once with 100 pi PBS(+CaCb +MgCb). Cells were lysed with 50 pi lysis buffer (0. IN NaOH, 0.1% Triton X-100) and plate was sealed with Tape Pads and vortexed. For the saponification reaction plates were incubated for 16 - 24 hours at 70°C in humidified environment. Seals were removed and 200 pi 0. IN HC1 was added for neutralisation of the pH. 150pl from each well was transferred into the corresponding wells of a 96-well Flash plate (Perkin Elmer) and sealed with TopSeal A (Perkin Elmer). Plates were incubated for 4h at 70°C and for at least 3h at room temperature in the dark. Signal of ¹⁴C radioactivity was measured (microbeta², perkin elmer). As a positive control 50mM unlabelled citrate or C75 (Sigma, C5490) was applied.

Measurement results of selected example compounds in the above-described assays for determining activity and selectivity are summarized in Table 16. The IC50 values were ranked as follows:

A: <50nM, B: 50-500nM, C: 500hM-1mM, and D: >1mM. Compounds were considered to be selective with an at least 5-fold, preferably 10-fold, higher activity for INDY than for the other two transporters. None of the tested compounds showed any toxic effects in the cell-based test systems.

Table 16: Illustrative activity and selectivity data for representative compounds disclosed herein

Example 46: In vivo testing using diet-induced obese (DIO) mice - an established model to study high fat diet induced fatty liver and other metabolic complications

To test the functional activity of a selected compound in vivo and to bridge between the in vitro assay for citrate uptake and fatty acid synthesis to the physiological relevant readouts in a disease model, a diet induced obesity model was performed with readouts for liver fat, blood lipids and genes for lipogenesis.

The diet-induced obese (DIO) mouse is a common research model to study obesity-induced diabetes. In this experiment C57BL/6N male mice are used which are fed a high-fat diet (HFD, 60 kcal% fat, D12492; Research Diets, Inc.; New Brunswick, USA) from age of 4 weeks on for 11 weeks. After initial feeding mice were treated for 4 weeks.

Mice were housed at a temperature of 22-24 °C, a day/night cycle of 12/12 hours (07:00-19:00- 07:00) and had access to the appropriate diet and tap water ad libitum. Food was only withdrawn for overnight fasting on study day 27 overnight before section on day 28. Groups were randomized cage wise according to random fed blood glucose levels and body weight before treatment start.

Compound example 199 was applied at three different doses 2 times per day (5, 15 and 50 mg/kg) and corresponding vehicle, application route was per os (p.o.) by gavage. During the study body weight was measured and plasma sampled for blood glucose analysis. At the end of the study blood and liver samples were taken for analysis.

Blood glucose levels were determined by analysing tail tip blood samples with the “Accu-Chek® Performa” glucometer (Roche Deutschland Holding GmbH, range <33.3 mmol/1). Random fed blood glucose was determined during the study. Fasting blood glucose was determined after overnight fasting.

Mice were sectioned on study day 28. Retro-orbital bleeding was performed on anesthetized animals and blood collected in non-coated tubes (Sarstedt). Animals were sacrificed by cervical dislocation. Livers were weighed and pieces were immediately frozen in liquid nitrogen for further analysis.

For serum sample generation the collected blood was centrifuged at 4000 g for 10 min, the serum samples were dispensed into a 110 mΐ plus an additional aliquot. The samples were stored at - 80°C. For Piccolo® system (Abaxis) analysis (lipid panel including triglycerides and cholesterol) a 110 mΐ-aliquot of serum was used.

The frozen tissue samples from liver were used to determine the triglycerides content via triglyceride assay according to the manufacturer’s protocol (Sigma, Cat.No.TROlOO) using glycerol as a standard (Sigma, Glycerol G7793).

For expression analysis: RNA was isolated from individual samples of liver tissue from all animals in the study in 1,5 ml Trizol reagent (Life Technologies, Germany) at 4°C according to the manufacturer’s instructions. Then, total RNA was purified utilizing the RNeasy Mini Kit (Qiagen, Germany) with DNase-treatment to completely remove the genomic DNA according to the instructions of the manufacturers. Subsequently, RNA was reverse transcribed using Superscript II RnaseH Reverse Transcriptase (Life Technologies, Germany) and subjected to Taqman analysis using the Taqman Fast Advanced Master Mix (Applied Biosystems, Weiterstadt, Germany). The Mix contains AmpliTaq® Fast DNA Polymerase, AmpErase UNG, dNTPs with dUTP, passive reference Rox and optimized buffer components. Quantitative PCR was performed in the Quantstudio 7 Flex System (Applied Biosystems, Weiterstadt, Germany). The relative expression of genes was analysed by the AACt value method using 18s ribosomal RNA as endogenous control.

The following primer probe pairs were used:

The results of the in vivo experiments are shown in Figs. 1 to 4. In brief, liver fat deposition was reduced in a dose-dependent manner (cf. Fig. 1) indicating amelioration of high fat diet induced steatosis and an improved hepatic lipid metabolism. Plasma triglycerides were reduced in a dose- dependent manner (cf. Fig. 2) indicating amelioration of high fat diet induced hypertriglyceridemia and an improved overall lipid metabolism. Cholesterol level in blood plasma was reduced in a dose-dependent manner (cf. Fig. 3) indicating amelioration of high fat diet induced hypercholesterolaemia and an improved overall lipid metabolism, and dose-dependent down regulation of key genes involved in hepatic lipogenesis was observed in liver tissue after a 28 days treatment period in high fat diet animals (cf. Figs. 4A and 4B).

Claims

1. A compound of the general formula (I):

R^1A is a hydrogen atom or deuterium atom;

R^1B is a hydrogen atom, deuterium atom, (Ci-C₃)alkyl, or (Ci-C₃) haloalkyl group; or R^1A and R^1B are taken together with the carbon atom to which they are attached to form a cyclopropyl group;

R^1C is CN, CH₂CN, CH₂OCH₃, CH₂OCHF₂, a cyclopropyl group or CH₂OCF₃;

R² is F, Cl, CH , OCH3 or CHF₂;

R³ is CN or CHF₂;

X¹ is (CRⁿR¹²);

CH₃;

CH₃; m is 1 or 2, provided that m is 2 when n is 1 ;

X² is (CR²¹R²²);

CH₃;

CH₃; n is 1 or 2, provided that n is 2 when m is 1 ; R^4A is, at each occasion independently, a hydrogen, deuterium, fluorine atom, chlorine atom, CH , (CH₂)OH, CN or (Ci) haloalkyl;

(Ci) haloalkyl, O(Ci) haloalkyl or N ^ ^;

R^A and R^AA each, independently of one another, represents a hydrogen atom or CH₃; p is 0, 1 or 2;

R⁶ represents a hydrogen atom, CN, OH, G, OG, Cyc, OCyc, Hce or OHce;

G represents a (Ci-C₆)alkyl group, in which (i) one CH₂ group, or two non-adjacent CH₂ groups, may be replaced by O, C(O), OC(O), C(0)0, C(0)NH, NH, NMe and/or by a CH=CH group; and/or in which (ii) 1 to 5 H atoms may, at each occasion independently, be replaced by a halogen atom, OH, CN, R^G1, OR^G1, Cyc, OCyc, Hce, or OHce;

R^G1 represents a (Ci-C₃)alkyl, (Ci-C₃) haloalkyl, (Ci-C₃) hydroxyalkyl, or (Ci- C4) heteroalkyl group.

2. The compound or salt according to claim 1, wherein R² is Cl or CH_3.

3. The compound or salt according to claim 1 or 2, wherein R³ is CN.

4. The compound or salt according to any one of claims 1 to 3, wherein R^1A and R^1B represent a hydrogen atom.

5. The compound or salt according to any one of claims 1 to 3, wherein R^1A and R^1B are taken together with the carbon atom to which they are attached to form a cyclopropyl group_.

6. The compound or salt according to any one of claims 1 to 5, wherein R^1C is CN.

7. The compound or salt according to any one of claims 1 to 6, wherein the compound has structural formula (IIA) or (IIB):

8 The compound or salt according to any one of claims 1 to 7, wherein o is 1 and the group -(CR^4AR^4B)- is selected from -CH2-, -C(CH3)H-, -CDH-, and -CD2-.

9. The compound or salt according to any one of claims 1 to 8, wherein R⁵ is, at each occasion independently, a hydrogen atom, fluorine atom, CH₃, NTh or OCH₃.

10. The compound or salt according to any one of claims 1 to 9, wherein the moiety comprising ring A represents a group:

11. The compound or salt according to any one of claims 1 to 10, wherein the moiety comprising ring A represents a group:

12. The compound or salt according to any one of claims 1 to 11, wherein R⁶ represents a group:

13. A pharmaceutical composition that comprises one or more compound(s) according to any one of claims 1 to 12 or a pharmaceutically acceptable prodrug, hydrate, solvate or salt thereof, and, optionally, at least one carrier substance, excipient and/or adjuvant.

14 The pharmaceutical composition of claim 13, further containing at least one further active pharmaceutical ingredient selected from the group comprising: (a) anti-obesity agent(s) selected from the group consisting of orlistat, lorcaserin, Phentermine, Topiramate, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine, 5-HT2c receptor agonists, Bupropion, Naltrexone, methionine aminopeptidase 2 inhibitors, GLP1 agonists;

(b) anti-diabetes agent(s) comprising insulin, incretin mimetics, SGLT-2 inhibitors, DPPIV inhibitors, PPAR agonist, Glucokinase activator, MTP inhibitors, Glycogen phosphorylase inhibitors, DGAT-1 inhibitor, GLPl agonists, dual GLPl/glucagon receptor agonists, triagonist for GLPl/glucose-dependent insulinotropic polypeptide/glucagon receptor;

(c) anti-NASH agent(s) comprising insulin, incretin mimetics, statins, PPAR agonists, AMPK activators, FXR agonists, DGAT-2 inhibitors, DGAT-1 inhibitors, Bile- Acid Conjugates, methionine aminopeptidase 2 inhibitors, PDE4 inhibitors, inhibitors of acetyl-CoA carboxylase, inhibitors of ketohexokinase, inhibitors of ATP citrate lyase, GLP-1 agonist, dual GLPl/glucagon receptor agonists, triagonist for GLPl/glucose-dependent insulinotropic polypeptide/glucagon receptor, inhibitors of ASK-1, CCR2/CCR5 antagonist, inhibitors of SLC10A2, inhibitors of LOXL2, inhibitors of Galectin-3, inhibitors of caspase, FGF21, FGF19, inhibitors of CGRP, AOC3: Amine Oxidase, Copper Containing 3, inhibitors of DPP-4, THR-B agonists, anti-CD3 monoclonal antibody (mAbs), A3AR agonists, inhibitors of SGLT2, inhibitors of SGLTl, inhibitors for TGFB activation, anti- cannabinoid CD1 receptor antibody, antibody agonist of the b-Klotho/FGFRl c receptor complex, inhibitors of the inflammasome ATP citrate lyase inhibitors, stearoyl-CoA desaturase inhibitor, fatty acid synthesis inhibitors;

(d) anti-dyslipidaemia agent(s) comprising, statins, ApoB antisense oligonucleotides, PCSK9 inhibitors, Cholesterol-absorption inhibitors, Niacin, Bile-acid-sequestering resins, MTP inhibitors, Fibrates, CETP inhibitors, ATP citrate lyase inhibitors;

(e) anti-cancer agent(s) comprising chemotherapeutic drugs;

(f) anti aging drug(s) comprising vitamins; and

(g) anti-osteoporosis agent(s) comprising vitamin D, calcium, calcitonine, bisphosphonates, estrogen, selective estrogen receptor modulators, parathyroid hormone and its analoga, RANKL inhibitors, anti-sclerostin antibody.

15. The compound or salt according to any one of claims 1 to 12 for use as a medicament.

16. The pharmaceutical composition according to claim 13 or 14 for use as a medicament.

17. The compound or salt according to any one of claims 1 to 12 for use in the treatment and/or prevention of a disease or condition selected from one or more of (a) to (g):

(a) metabolic diseases selected from the group comprising insulin resistance, alcoholic and non alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), obesity, type 1 diabetes, type 2 diabetes, dyslipidemia, hereditary diseases and metabolic syndrome;

(b) eating disorders;

(c) chronic liver diseases;

(d) liver cancer and cancer related to obesity; (e) age related diseases comprising atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension and neurodegenerative diseases like Alzheimer's disease;

(f) drug induced hepatic steatosis;

(g) a disease or condition that is caused by hypocitricemia and/or indicated by hypocitraturia such as osteoporosis, adrenocortical hyperactivity, vitamin D deficiency, ricket, parathyroidectomy, metaboloc acidosis, glaucoma, bariatric surgery, kidney stones, chronic kidney disease, primary hyperaldesteronism and postmenopause.

18. The pharmaceutical composition according to claim 13 or 14 for use in the treatment and/or prevention of a disease or condition that is citrate transporter meditated or citrate transporter dependent, or that is associated with the activity of a citrate transporter, wherein the disease or condition is selected from one or more of (a) to (g) as defined in claim 17.

19. A method of treating or preventing a disease or condition that is citrate transporter meditated or citrate transporter dependent, or that is associated with the activity of a citrate transporter, in a patient comprising administering to the patient an effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 12.

20. A method of treating or preventing a disease or condition that is citrate transporter meditated or citrate transporter dependent, or that is associated with the activity of a citrate transporter, in a patient comprising administering to the patient an effective amount of a pharmaceutical composition according to claim 13 or 14.

21. Use of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 12 in the manufacture of a medicament for treating or preventing a disease or condition that is citrate transporter meditated or citrate transporter dependent, or that is associated with the activity of a citrate transporter.

22. Use of a pharmaceutical composition according to claim 13 or 14 in the manufacture of a medicament for treating or preventing a disease or condition that is citrate transporter meditated or citrate transporter dependent, or that is associated with the activity of a citrate transporter.

23. The method of claim 19 or 20, or the use of claim 21 or 22, wherein the disease or condition that is citrate transporter meditated or citrate transporter dependent, or that is associated with the activity of a citrate transporter, is one or more selected from (a) to (g) as defined in claim 17.