Cycloalkyl or heterocycloalkyl beta-hydroxy alkyl amines and their use in the treatment of hyperglycaemia or disorders characterised by hyperglycaemia

Abstract

There are herein provided compounds of formula (I), (I) wherein Q1 to Q5, R1, ring A, Z, W and n have meanings as provided in the description. Medical uses thereof are also provided herein.

Description

[0001] CYCLOALKYL OR HETEROCYCLOALKYL BETA-HYDROXY ALKYL AMINES AND THEIR USE IN THE TREATMENT OF HYPERGLYCAEMIA OR DISORDERS CHARACTERISED BY HYPERGLYCAEMIA

[0002] Field of the Invention

[0003] The present invention relates to novel compounds and compositions, and their use in medicine, such as in the treatment of hyperglycaemia and disorders characterised by hyperglycaemia, such as type 2 diabetes. In particular, the invention relates to novel compounds, compositions and methods for the treatment of conditions such as type 2 diabetes through activation of the 02-adrenergic receptor. Importantly, such compounds are thought to have a beneficial side-effect profile as they do not exert their effect through significant cAMP release. Such compounds are also of use in treating other diseases or disorders, the treatment of which is mediated by activation of the 2 adrenergic receptor.

[0004] Background of the Invention

[0005] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0006] Hyperglycaemia, or high blood sugar is a condition in which an excessive amount of glucose circulates in the blood plasma. If not treated, hyperglycaemia can be a serious problem, potentially developing into life-threatening conditions such as ketoacidosis. For example, chronic hyperglycemia may cause injury to the heart, and is strongly associated with heart attacks and death in subjects with no coronary heart disease or history of heart failure. There are various causes of hyperglycaemia, including diabetes and severe insulin resistance.

[0007] Severe insulin resistance (SIR) is a condition wherein the patent experiences very low levels of (or, in extreme cases, no significant) response to insulin. There are several syndromes characterized by SIR, including Rabson-Mendenhall syndrome, Donohue's syndrome (leprechaunism), Type A and Type B syndromes of insulin resistance, the HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, and lipodystrophy. The majority of these conditions have genetic causes, such as mutations in the insulin receptor gene. The prevalence for Donohue's syndrome, Rabson-Mendenhall syndrome and Type A syndrome of insulin resistance, has been reported to vary from about 50 reported cases to 1 in 100,000. However, since some diseases are severe and extremely rare, it is likely that many patients do not get diagnosed before they die, particularly in less developed areas of the world. Thus, the exact number of patients with these syndromes is difficult to assess.

[0008] The current standard for hyperglycaemia treatment in patients having SIR is a controlled diet, supplemented with drugs affecting insulin receptor sensitivity, such as metformin, or insulin supplement. However, particularly for disorders caused by mutations in the insulin receptor gene, this treatment is not sufficiently effective and ultimately proves unsuccessful.

[0009] Diabetes comprises two distinct diseases, type 1 (or insulin-dependent diabetes) and type 2 (insulin-independent diabetes), both of which involve the malfunction of glucose homeostasis. Type 2 diabetes affects more than 400 million people in the world and the number is rising rapidly. Complications of type 2 diabetes include severe cardiovascular problems, kidney failure, peripheral neuropathy, blindness and, in the later stages of the disease, even loss of limbs and, ultimately death. Type 2 diabetes is characterized by insulin resistance in skeletal muscle and adipose tissue, and there is presently no definitive cure. Most treatments used today are focused on remedying dysfunctional insulin signalling or inhibiting glucose output from the liver but many of those treatments have several drawbacks and side effects. There is thus a great interest in identifying novel insulin-independent ways to treat type 2 diabetes.

[0010] In type 2 diabetes, the insulin-signalling pathway is blunted in peripheral tissues such as adipose tissue and skeletal muscle. Methods for treating type 2 diabetes typically include lifestyle changes, as well as insulin injections or oral medications to regulate glucose homeostasis. People with type 2 diabetes in the later stages of the disease develop 'beta-cell failure' i.e. the inability of the pancreas to release insulin in response to high blood glucose levels. In the later stages of the disease patients often require insulin injections in combination with oral medications to manage their diabetes. Further, most common drugs have side effects including downregulation or desensitization of the insulin pathway and / or the promotion of lipid incorporation in adipose tissue, liver and skeletal muscle. There is thus a great interest in identifying novel ways to treat metabolic diseases including type 2 diabetes that do not include these side effects.

[0011] Following a meal, increased blood glucose levels stimulate insulin release from the pancreas. Insulin mediates normalization of the blood glucose levels. Important effects of insulin on glucose metabolism include facilitation of glucose uptake into skeletal muscle and adipocytes, and an increase of glycogen storage in the liver. Skeletal muscle and adipocytes are responsible for insulin-mediated glucose uptake and utilization in the fed state, making them very important sites for glucose metabolism.

[0012] The signalling pathway downstream from the insulin receptor has been difficult to understand in detail. In brief, control of glucose uptake by insulin involves activation of the insulin receptor (IR), the insulin receptor substrate (IRS), the phosphoinositide 3-kinase (PI3K) and thus stimulation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), the mammalian target of rapamycin (also called the mechanistic target of rapamycin, mTOR), Akt / PKB (Akt) and TBC1D4 (AS160), leading to translocation of the glucose transporter 4 (GLUT4) to the plasma membrane. Akt activation is considered necessary for GLUT4 translocation.

[0013] It should be noted that skeletal muscles constitute a major part of the body weight of mammals and have a vital role in the regulation of systemic glucose metabolism, being responsible for up to 85% of whole-body glucose disposal. Glucose uptake in skeletal muscles is regulated by several intra- and extracellular signals. Insulin is the most well studied mediator but others also exist. For example, AMP activated kinase (AMPK) functions as an energy sensor in the cell, which can increase glucose uptake and fatty acid oxidation. Due to the great influence skeletal muscles have on glucose homeostasis it is plausible that additional mechanisms exist. In the light of the increased prevalence of type 2 diabetes, it is of great interest to find and characterize novel insulin-independent mechanisms to increase glucose uptake in muscle cells.

[0014] Blood glucose levels may be regulated by both insulin and catecholamines, but they are released in the body in response to different stimuli. Whereas insulin is released in response to the rise in blood sugar levels (e.g. after a meal), epinephrine and norepinephrine are released in response to various internal and external stimuli, such as exercise, emotions and stress, and also for maintaining tissue homeostasis. Insulin is an anabolic hormone that stimulates many processes involved in growth including glucose uptake, glycogen and triglyceride formation, whereas catecholamines are mainly catabolic.

[0015] Although insulin and catecholamines normally have opposing effects, it has been shown that they have similar actions on glucose uptake in skeletal muscle (Nevzorova et al., Br. J. Pharmacol, 137, 9, (2002)). In particular, it has been reported that catecholamines stimulate glucose uptake via adrenergic receptors (Nevzorova et al., Br. J. Pharmacol, 147, 446, (2006); Hutchinson, Bengtsson, Endocrinology 146, 901, (2005)) to supply muscle cells with an energy-rich substrate. Thus it is likely that in mammals, including humans, the adrenergic and the insulin systems can work independently to regulate the energy needs of skeletal muscle in different situations. Since insulin also stimulates many anabolic processes, including some that promote undesired effects such as stimulation of lipid incorporation into tissues, leading to e.g. obesity, it would be beneficial to be able to stimulate glucose uptake by other means; for example, by stimulation of the adrenergic receptors (ARs).

[0016] All ARs are G protein-coupled receptors (GPCRs) located in the cell membrane and characterized by an extracellular N-terminus, followed by seven transmembrane a-helices (TM-1 to TM-7) connected by three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3), and finally an intracellular C-terminus. There are three different classes of ARs, with distinct expression patterns and pharmacological profiles: ai-, 02- and -ARs. The ai-ARs comprise the O IA, O IB and OID subtypes while 02-ARS are divided into O2A, O2B and 02c. The -ARs are also divided into the subtypes Pi, 2, and 3, of which 2-AR is the major isoform in skeletal muscle cells. ARs are G protein coupled receptors (GPCRs) that signal through classical secondary messengers such as cyclic adenosine monophosphate (cAMP) and phospholipase C (PLC).

[0017] Many effects occurring downstream of ARs in skeletal muscles have been attributed to classical secondary messenger signalling, such as increase in cAMP levels, PLC activity and calcium levels. Stimulation involving the classical secondary messengers has many effects in different tissues. For example, it increases heart rate, blood flow, airflow in lungs and release of glucose from the liver, which all can be detrimental or be considered unwanted side effects if stimulation of ARs should be considered as a type 2 diabetes treatment. Adverse effects of classical AR agonists are, for example, tachycardia, palpitation, tremor, sweats, agitation and increased glucose levels in the blood (glucose output from the liver). It would thus be beneficial to be able to activate ARs without activating these classical secondary messengers, such as cAMP, to increase glucose uptake in peripheral tissues without stimulating the unwanted side effects.

[0018] Glucose uptake is mainly stimulated via facilitative glucose transporters (GLUT) that mediate glucose uptake into most cells. GLUTs are transporter proteins that mediate transport of glucose and / or fructose over the plasma membrane down the concentration gradient. There are fourteen known members of the GLUT family, named GLUT1-14, divided into three classes (Class I, Class II and Class III) dependent on their substrate specificity and tissue expression. GLUT1 and GLUT4 are the most intensively studied isoforms and, together with GLUT2 and GLUT3, belong to Class I which mainly transports glucose (in contrast to Class II that also transports fructose). GLUT1 is ubiquitously expressed and is responsible for basal glucose transport. GLUT4 is only expressed in peripheral tissues such as skeletal muscle, cardiac muscle and adipose tissues. GLUT4 has also been reported to be expressed in, for example, the brain, kidney, and liver. GLUT4 is the major isoform involved in insulin stimulated glucose uptake. The mechanism whereby insulin signalling increases glucose uptake is mainly via GLUT4 translocation from intracellular storage to the plasma membrane. It is known that GLUT4 translocation is induced by stimulation of the 2-adrenergic receptor.

[0019] Thus, a possible treatment of a condition involving dysregulation of glucose homeostasis or glucose uptake in a mammal, such as type 2 diabetes, would involve the activation of the 2-adrenergic receptor leading to GLUT4 translocation to the plasma membrane and promotion of glucose uptake into skeletal muscle leading to normalization of whole body glucose homeostasis. In addition, it would be advantageous if the treatment does not involve signalling through cAMP as this would lead to a favourable side-effect profile.

[0020] Description of the Invention

[0021] We have now surprisingly found that certain cycloalkyl or heterocycloalkyl betahydroxy alkyl amines acting as agonists at the 2-adrenergic receptor increase glucose uptake in skeletal muscle.

[0022] In addition, we have found that this effect is not mediated through significant cAMP release, such that many of the commonly described side effects seen with traditional 2-adrenergic agonists (e.g. tachycardia, palpitation, tremor, sweats, agitation, and the like) can be reduced.

[0023] The use of such compounds in medicine represents a promising strategy for the treatment of conditions as described herein, such as those characterized by high blood sugar levels (i.e. hyperglycaemia), such as type 2 diabetes.

[0024] Compounds of the invention

[0025] In a first aspect of the invention, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof, wherein :

[0026] R1represents H or Ci-6 alkyl; each of Q1to Q5independently represent carbon, a heteroatom or a direct bond such that the ring comprising Q1to Q5represents: a phenyl optionally substituted with one or more Y1, or a 5- or 6- membered heteroaryl optionally substituted with one or more Y2; each Y1independently represents halo, Ral, -CN, -N3, -N(Rbl)Rclor -ORdl; each Y2independently represents halo, Ra2, -CN, -N3, -N(Rb2)Rc2or -ORd2; ring A represents 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl comprising one or two heteroatoms selected from N or O; when present on a carbon atom, W represents C1-6 alkyl substituted with one or more groups selected from -CN, -ORd4, or =0, wherein the C1-6 alkyl may be further optionally substituted with one or more groups independently selected from halo and G1, when present on a nitrogen atom, W represents

[0027] -C(0)0Ci-6alkyl, -C(0)C4-ealkyl, -S(O)Ci-ealkyl, or C2-6-alkyl substituted with at least one -N(Rb4)Rc4and at least one =0, wherein the C2-6 alkyl may be further optionally substituted with one or more groups independently selected from halo and G1; n represents 0 to 5; when present on a carbon atom, each Z independently represents halo, Ra3, -CN, -N3, -N(Rb3)Rc3, -0Rd3, -S(O)PRe3, -S(O)qN(Rf3)R93, -N(Rh3)S(O)tRi3, or =0; when present on a nitrogen atom, each Z independently represents Ra3, -S(O)PRe3or -S(O)qN(Rf3)Rg3; each Raland Ra2independently represents Ci-6 alkyl optionally substituted by one or more halo; each Raland Ra2independently represents Ci-6 alkyl optionally substituted by one or more halo; each Ra3, Re3, and R'3independently represents Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl each optionally substituted by one or more groups independently selected from halo and G1; each Rbl, Rb2, Rb3, Rcl, Rc2, Rc3, Rdl, Rd2, Rd3, Rf3, Rg3and Rh3independently represents H, or

[0028] C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl each optionally substituted by one or more groups independently selected from halo and G2; or alternatively any of Rb3and Rc3, and / or Rf3and Rg3may be linked together to form, together with the nitrogen atom to which they are attached, a 4- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C1-3 alkyl optionally substituted by one or more halo, and =0; each G1and G2independently represents Ra4, -CN, -N3, -N(Rb4)Rc4, -0Rd4, -S(O)PRe4, -S(O)qN(Rf4)Rg4, -N(Rh4)S(O)rR'4or =0; each Ra4independently represents phenyl or 5- or 6-membered heteroaryl, each optionally substituted by one or more group selected halo, Ra5, -CN, -N3, -N(Rb5)Rc5, - 0Rd5, -S(O)PRe5, -S(O)qN(Rf5)Rg5, or -N(Rh5)S(O)tRi5; each Rb4, Rc4, Rd4, Rf4, Rh4and Rg4independently represents H, or C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl optionally substituted by one or more halo, -CN or =0; each Re4and R'4independently represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl each optionally substituted by one or more halo or -CN; or alternatively any of Rb4and Rc4and / or Rf4and Rg4may be linked together to form, together with the nitrogen atom to which they are attached, a 4- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C1-3 alkyl optionally substituted by one or more halo, and =0; each Ra5, Re5, and R'5independently represents C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl each optionally substituted by one or more groups independently selected from from halo, C1-3 alkyl optionally substituted by one or more halo, and =0; each Rb5, Rc5, Rd5, Rf5, Rg5and Rh5independently represents

[0029] H, or

[0030] C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl each optionally substituted by one or more groups independently selected from halo, C1-3 alkyl optionally substituted by one or more halo, and =0; or alternatively any of Rb5and Rc5, and / or Rf5and Rg5may be linked together to form, together with the nitrogen atom to which they are attached, a 4- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C1-3 alkyl optionally substituted by one or more halo, and =0; each p independently represents 0, 1 or 2; each q independently represents 1 or 2; each r independently represents 1 or 2; and each t independently represents 1 or 2, which compounds (including pharmaceutically acceptable salts) may be referred to herein as "compounds of the invention".

[0031] For the avoidance of doubt, the skilled person will understand that references herein to compounds of particular aspects of the invention (such as the first aspect of the invention, e.g. compounds of formula I) will include references to all embodiments and particular features thereof, which embodiments and particular features may be taken in combination to form further embodiments. Unless indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0032] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

[0033] Particular acid addition salts that may be mentioned include carboxylate salts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, a-hydroxybutyrate, lactate, tartrate, hemi-tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxy-benzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts), halide salts (e.g. hydrochloride, hydrobromide or hydroiodide salts), sulphonate salts (e.g. benzenesulphonate, methyl-, bromo- or chloro-benzenesulphonate, xylenesulphonate, methanesulphonate, ethanesulphonate, propanesulphonate, hydroxyethanesulphonate, 1- or 2- naphthalene-sulphonate or 1,5-naphthalenedisulphonate salts) or sulphate, pyrosulphate, bisulphate, sulphite, bisulphite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, and the like.

[0034] The skilled person will understand that the term "hemi" used herein in relation to a hemi-tartrate salt of a compound of formula I means that the stoichiometry between the compound of formula I and tartrate in the salt is 1:0.5 (i.e. equivalent to 2: 1).

[0035] Particular base addition salts that may be mentioned include salts formed with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine and lysine) and inorganic bases (such as ammonia and aluminium hydroxide). More particularly, base addition salts that may be mentioned include Mg, Ca and, most particularly, K and Na salts.

[0036] Particular pharmaceutically acceptable salts that may be mentioned include hydrochloride (e.g. mono-hydrochloride or di-hydrochloride) or acetate salts, such as acetate salts.

[0037] More particular pharmaceutically acceptable salts that may be mentioned include hydrochloride salts.

[0038] For the avoidance of doubt, compounds of the first aspect of the invention may exist as solids, and thus the scope of the invention includes all amorphous, crystalline and part crystalline forms thereof, and may also exist as oils. Where compounds of the first aspect of the invention exist in crystalline and part crystalline forms, such forms may include solvates, which are included in the scope of the invention. Compounds of the first aspect of the invention may also exist in solution.

[0039] Compounds of the first aspect of the invention may contain double bonds and may thus exist as E (entgegen and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.

[0040] Compounds of the first aspect of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.

[0041] Compounds of the first aspect of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and / or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers (i.e. enantiomers) may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be obtained from appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution); for example, with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.

[0042] As used herein, references to halo and / or halogen groups will each independently refer to fluoro, chloro, bromo and iodo (for example, fluoro (F) and chloro (Cl), such as F).

[0043] Unless otherwise specified, Ci-Zalkyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain and / or cyclic (so forming a C3- z-cycloalkyl group). When there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Part cyclic alkyl groups that may be mentioned include cyclopropylmethyl and cyclohexylethyl. When there is a sufficient number of carbon atoms, such groups may also be multicyclic (e.g. bicyclic or tricyclic) or spirocyclic.

[0044] For the avoidance of doubt, alkyl groups may be linear (otherwise referred to as straight-chained), branched (otherwise referred to as branched-chain) and / or cyclic. More particularly, alkyl groups may be linear (otherwise referred to as straight- chained) or branched (otherwise referred to as branched-chain).

[0045] Unless otherwise specified, C2-Z alkenyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain.

[0046] Unless otherwise specified, C2-Z alkynyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, be branched-chain.

[0047] For the avoidance of doubt, the skilled person will understand that the term alkyl will refer to saturated hydrocarbon moieties, whereas the term alkenyl will refer to unsaturated hydrocarbon moieties containing at least one carbon-carbon double bond and the term alkynyl will refer to unsaturated hydrocarbon moieties containing at least one carbon-carbon triple bond.

[0048] As used herein, the term heterocyclyl may refer to non-aromatic monocyclic and bicyclic heterocyclyl groups (which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between three and twelve (e.g. between five and ten and, most preferably, between three and eight, e.g. a 5- or 6-membered heterocyclyl group). Further, such heterocyclyl groups may be saturated, forming a heterocycloalkyl, or unsaturated containing one or more carbon-carbon or, where possible, carbon-heteroatom or heteroatom-heteroatom double and / or triple bonds, forming for example a C2-Z (e.g. C4-z) heterocycloalkenyl (where z is the upper limit of the range) or a C?-z heterocycloalkynyl group. C2-Z heterocyclyl groups that may be mentioned include 7-azabicyclo-[2.2.1]heptanyl, 6- aza bicyclo [3.1.1] hepta nyl, 6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, 2,3-dihydroisothiazolyl, dihydropyranyl, dihydropyridinyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, isothiazolidinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetra hydrofury I, tetrahydropyridinyl (such as 1,2,3,4-tetrahydropyridinyl and 1, 2,3,6- tetrahydropyridinyl), thietanyl, thiiranyl, thiolanyl, tetrahydrothiopyranyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like. Substituents on heterocyclyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocyclyl group, forming a so-called "spiro"-compound. The point of attachment of heterocyclyl groups may be via any atom in the ring system including (where appropriate) a further heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocyclyl groups may also be in the N- or S- oxidised form.

[0049] As described herein, ring A represents a 4- to 7-membered cycloalkyl or 4- to 7- membered heterocycloalkyl comprising one or two heteroatoms (such as only one heteroatom) selected from N (nitrogen) or O (oxygen).

[0050] In some embodiments, when ring A represents a 4- to 7-membrered heterocycloalkyl, ring A comprises no other heteroatoms in its ring structure, i.e. the only heteroatoms of ring A are selected from N and O.

[0051] In particular embodiments, ring A represents a 4- to 7-membered heterocycloalkyl, such as 5- to 6- membered heterocycloalkyl. Various heterocycloalkyl groups will be well-known to those skilled in the art, such as dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3 dioxanyl and 1,4 dioxanyl), imidazolidinyl, morpholinyl, piperazinyl, piperidinyl (including 2-, 3-, or 4- piperidinyl), pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl (including 2- or 3- pyrrolidinyl), tetra hydropyranyl, tetra hydrofuryl.

[0052] In particular embodiments, ring A may comprise one heteroatom selected from O (oxygen) and N (nitrogen). For example, ring A may comprise one O (oxygen) or ring A may comprise one N (nitrogen).

[0053] In alternative embodiments, ring A may comprise two heteroatoms selected from O (oxygen) and N (nitrogen). For example, ring A may comprise two O (oxygen) or two N (nitrogen). Alternatively, ring A may comprise one O (oxygen) and one N (nitrogen).

[0054] In particular embodiments, ring A may be a 4-membered heterocycloalkyl, optionally substituted with one or more (e.g. one) Z. In more particular embodiments ring A may be azetidinyl, such as 3-azetidinyl (referring to standard numbering wherein the N atom represents the 1-position).

[0055] In particular embodiments, ring A may be a 5- or 6-membered heterocycloalkyl, optionally substituted with one or more (e.g. one) Z.

[0056] In more particular embodiments, ring A may be a 6-membered heterocycloalkyl, optionally substituted with one or more (e.g. one) Z.

[0057] More particular heterocycloalkyl groups representing ring A that may be mentioned include piperidinyl, such as piperidin-3-yl or piperidin-4-yl (referring to standard numbering wherein the N atom represents the 1-position).

[0058] In particular embodiments, ring A represents a 4- to 7-membered cycloalkyl, such as a 5- to 6-membered cycloalkyl. In more particular embodiments, ring A represents a 6-membered cycloalkyl (i.e. cyclohexyl).

[0059] In particular embodiments, ring A represents cyclobutyl. In particular such embodiments, the skilled person will understand that W is present on a carbon atom of ring A. For the avoidance of doubt, ring A may be substituted by a number of Z groups, as defined herein, as appropriate in the circumstances. The skilled person will understand that the (maximum) number and position of such substituents will be dictated by the nature of the ring, such as by the size of the ring and the level of saturation thereof. Moreover, the skilled person will understand that such substituents may be present on suitable moieties comprised within ring A, e.g. suitable C (carbon) or N (nitrogen) moieties.

[0060] In particular embodiments, the compounds of formula I may be compounds of formula

[0061] IX or IY wherein the ring comprising Q1to Q5, R1, W, Z, and n are as defined for compounds of formula I (including all embodiments thereof), and wherein X represents C (carbon) or N (nitrogen), ml and m2 independently represent 0 to 2, m3 represents 0 to 3 and m4 represents 0 to 2. For the avoidance of doubt, W may be present on any carbon or nitrogen atom of ring A, including on the X atom of formula IX and IY.

[0062] In a particular embodiment, ml and m2 each represent 0. In an alternative embodiment, ml and m2 each represent 1. In an alternative embodiment, ml represents 2 and m2 represents 0.

[0063] In a particular embodiment, the sum of ml and m2 is at least 1 (e.g. the sum is one or two).

[0064] In a particular embodiment, m3 and m4 each represent 0. In an alternative embodiment, m3 represents 1 and m4 represents 0 to 2 (such as 1 or 2).

[0065] In a particular embodiment, the sum of m3 and m4 is at least 1 (e.g. the sum is one or two). As described herein, the ring comprising Q1to Q5(which may be referred to as ring Q) represents a phenyl or a 5- or 6- membered heteroaryl optionally substituted with one or more Y (i.e. one or more of Y1or Y2).

[0066] As such, the skilled person will understand that Q1to Q5will either: each represent carbon atoms, so as to form a phenyl group; or together represent carbon atoms, one or more heteroatom and, where the ring containing Q1to Q5is 5-membered, a direct bond, so as to form suitable heteroaryl groups as known to those skilled in the art.

[0067] Thus, the skilled person will understand that the ring representing Q1to Q5may comprise, in addition to carbon atoms, one or more heteroatom, so as to form suitable heteroaryl groups as known to those skilled in the art. Moreover, the skilled person will understand that where the ring containing Q1to Q5is 5-membered, one of Q1to Q5(e.g. Q5) will represent a direct bond (i.e. that group will not be present).

[0068] For the avoidance of doubt, the depiction of the ring containing the Q1to Q5groups with a circle therein (for example, such as in formula I) will be understood to indicate that the ring is aromatic.

[0069] For the avoidance of doubt, as used herein, references to heteroatoms will take their normal meaning as understood by one skilled in the art. Particular heteroatoms that may be mentioned include phosphorus, selenium, tellurium, silicon, boron, oxygen, nitrogen and sulphur (e.g. oxygen, nitrogen and sulphur).

[0070] For the avoidance of doubt, references to polycyclic (e.g. bicyclic or tricyclic) groups (e.g. when employed in the context of cycloalkyl groups) will refer to ring systems wherein at least two scissions would be required to convert such rings into a straight chain, with the minimum number of such scissions corresponding to the number of rings defined (e.g. the term bicyclic may indicate that a minimum of two scissions would be required to convert the rings into a straight chain). For the avoidance of doubt, the term bicyclic (e.g. when employed in the context of alkyl groups) may refer to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring, and may also referto groups in which two non-adjacent atoms are linked by an alkylene group, which later groups may be referred to as bridged. The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Hence, the compounds of the invention also include deuterated compounds, i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.

[0071] For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which two or more Y groups are present, those Y groups may be the same or different. Similarly, where two or more Y groups are present and each represent halo, the halo groups in question may be the same or different. Likewise, when more than one Rais present and each independently represents Ci-6 alkyl substituted by one or more G group, the identities of each G are in no way interdependent.

[0072] The skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation, e.g. from a reaction mixture, to a useful degree of purity.

[0073] All embodiments of the invention and particular features mentioned herein may be taken in isolation or in combination with any other embodiments and / or particular features mentioned herein (hence describing more particular embodiments and particular features as disclosed herein) without departing from the disclosure of the invention.

[0074] In a particular embodiment, there is the proviso that the compound of formula I is not any of the following :

[0075] (A) (B)

[0076] For the avoidance of doubt, the ring comprising Q1to Q5(also referred to herein as ring Q) represents a phenyl optionally substituted with one or more Y1, or a 5- or 6- membered heteroaryl optionally substituted with one or more Y2.

[0077] Various heteroaryl groups will be well-known to those skilled in the art, such as pyridinyl, pyridonyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl and the like. The oxides of heteroaryl / heteroaromatic groups are also embraced within the scope of the invention (e.g. the / V-oxide).

[0078] In particular embodiments, when representing a heteroaryl, the ring comprising Q1to Q5as defined herein may comprise one or more (e.g. one or two, such as one) heteroatoms, which may be selected from O, S and N (e.g. from O and N, such as N). For example, ring Q as defined herein may comprise one heteroatom, which may be selected from O, S and N (e.g. O and N, such as N).

[0079] In particular embodiments, where representing heteroaryl, the ring comprising Q1to Q5as defined herein may be a 6-membered heteroaryl. As such, the ring comprising Q1to Q5may represent phenyl optionally substituted with one or more (e.g. one) Y1, or a 5- or 6- membered heteroaryl optionally substituted with one or more (e.g. one) Y2. More particular heteroaryl groups representing the ring comprising Q1to Q5that may be include pyridinyl, such as pyridin-3-yl (referring to standard numbering wherein the N atom represents the 1-position).

[0080] In particular embodiments, the ring comprising Q1to Q5may represent: phenyl optionally substituted with one or more (e.g. one) Y1, or pyridyl optionally substituted with one or more (e.g. one) Y2.

[0081] In more particular embodiments, the ring comprising Q1to Q5may represent: phenyl optionally substituted with one or more (e.g. one) Y1, or pyridin-3-yl optionally substituted with one or more (e.g. one) Y2.

[0082] Thus, in particular embodiments, the compound of formula IX may be represented as a compound of formula IA or IB wherein R1, W, Z, Y1, Y2, ml, m2, and n are as defined for compounds of formula IX (including all embodiments thereof), v represents 0 to 5 and w represents 0 to 4.

[0083] For the avoidance of doubt, the structure of the ring comprising Q1to Q5as provided in formulas IA and IB (and in further embodiments thereof) may also be applied to formula I (including all embodiments thereof).

[0084] For the avoidance of doubt, the ring comprising Q1to Q5may be substituted by a number of Y1or Y2groups, as defined herein, as appropriate in the circumstances. The skilled person will understand that the (maximum) number and position of such substituents will be dictated by the nature of the ring, such as by the size of the ring and the level of saturation thereof. Moreover, the skilled person will understand that such substituents may be present on suitable moieties comprised within ring Q, e.g. suitable C (carbon) moieties.

[0085] In particular embodiments, the ring comprising Q1to Q5is substituted with up to two (i.e. 0 to 2) Y1or Y2groups, as appropriate. In more particular embodiments, the ring comprising Q1to Q5is substituted with up to one (i.e. 0 or 1) Y1or Y2groups, as appropriate.

[0086] In more particular embodiments, the ring comprising Q1to Q5is (i.e. is required to be) substituted with one Y1or Y2group, as appropriate (i.e. in compounds of formula IA, v is 1, and in compounds of formula IB, w is 1).

[0087] In particular embodiments, taking the point of attachment to the essential -CH(OH)- moiety as the 1-position, at least one (or, when only one such group is present, the) Y1or Y2group, as appropriate, may be located in the 2- or 3-position (which may also be referred to as the ortho and meta positions, respectively).

[0088] In particular embodiments, the ring comprising Q1to Q5may represent: phenyl substituted with one or more (e.g. one) Y1, or

[0089] 6- membered heteroaryl substituted with one or more (e.g. one) Y2.

[0090] In more particular embodiments, the ring comprising Q1to Q5may represent: phenyl substituted with one or more (e.g. one) Y1, or pyridyl (also referred to as pyridinyl) substituted with one or more (e.g. one) Y2.

[0091] For example, the ring comprising Q1to Q5may represent: phenyl substituted with one Y1(e.g. in the 2- or 3-position using standard numbering) or pyridin-3-yl substituted with one Y2(e.g. in the 5-position using standard numbering, which may also be referred as the 3-position when the point of attachment to the essential

[0092] -CH(OH)- moiety is taken as the 1-position).

[0093] Thus, in particular embodiments, the compounds of formula IA and IB may be represented as compounds of formula IA' and IB', respectively wherein R1, Z, Y2, n, ml, and m2 are as defined for compounds of formula IX (such as compounds of formula IA and IB; including all embodiments thereof), and wherein one of Ylaand Ylb(particularly, Ylb) represents Y1and the other represents H.

[0094] In further embodiments, there are provided compounds of formula IC' wherein R1, Z, n, ml, and m2 are as defined for compounds of formula I (including all embodiments thereof), and wherein Ylc, Yldand Yleeach represent Y1(e.g. Ylcrepresents F, Yldrepresents -NH2 and Ylerepresents F).

[0095] In particular embodiments, each Y1independently represents Ral, halo (e.g. F or Cl), -CN, -N(Rbl)Rclor -ORdl.

[0096] In particular embodiments, Ralrepresents C1-3 alkyl (such as linear or branched C1-3 alkyl, e.g. linear C1-3 alkyl) optionally substituted by one or more halo.

[0097] In more particular embodiments, Ralrepresents Ci alkyl (i.e. methyl) optionally substituted by one or more halo. For example, Ralmay represent -CH3 or -CF3.

[0098] In more particular embodiments, each Y1independently represents halo (e.g. F or Cl) or -CN.

[0099] In more particular embodiments, each Y1independently represents Cl or F.

[0100] In more particular embodiments, each Y1independently represents F.

[0101] In more particular embodiments, each Y1independently represents -CN.

[0102] In particular embodiments, one or more (e.g. each) Y1represents -ORdl. In more particular embodiments, Rdlrepresents H.

[0103] In particular embodiments, one or more (e.g. each) Y1represents -NRblRcl. In more particular embodiments, Rblrepresents H. In more particular embodiments, RC1represents H or C1-4 alkyl, such as H. In particular embodiments, each Y2independently represents Ra2, halo (e.g. F or Cl), -CN, -N(Rb2)Rc2or -ORd2.

[0104] In particular embodiments, Ra2represents C1-3 alkyl (such as linear or branched C1-3 alkyl, e.g. linear C1-3 alkyl) optionally substituted by one or more halo.

[0105] In more particular embodiments, Ra2represents Ci alkyl (i.e. methyl) optionally substituted by one or more halo. For example, Ralmay represent -CH3 or -CF3.

[0106] In more particular embodiments, each Y2independently represents Cl or F.

[0107] In more particular embodiments, each Y2independently represents F.

[0108] In particular embodiments, Rd2represents H.

[0109] In particular embodiments, Rb2represents H and / or (e.g. and) Rc2represents H or C1-4 alkyl, e.g. H.

[0110] For the avoidance of doubt, as indicated herein, embodiments of the invention will include combinations of embodiments as described herein.

[0111] In particular embodiments, each Y1and Y2independently represents Ral, halo (e.g. F or Cl) or -CN.

[0112] For example, in certain embodiments that may be mentioned : each Y1independently represents Ral, halo (e.g. F or Cl) or -CN;

[0113] Ralrepresents C1-3 alkyl (such as linear or branched C1-3 alkyl, e.g. linear C1-3 alkyl) optionally substituted by one or more halo; each Y2independently represents Ra2, halo (e.g. F or Cl) or -CN; and

[0114] Ra2represents C1-3 alkyl (such as linear or branched C1-3 alkyl, e.g. linear C1-3 alkyl) optionally substituted by one or more halo.

[0115] In certain embodiments, each Y1and Y2represents Cl or F (particularly, F). In particular embodiments, n represents at least 1 (i.e. there is a requirement that at least one Z group is present). In further embodiments n represents up to 5, such as up to 4, up to 3 or up to 2.

[0116] In particular embodiments: where ring A represents a cycloalkyl, n represents 1 to 5 (e.g. 1 to 3, such as 1 or 2, e.g. 1); and where ring A represents a heterocycloalkyl, n represents 0 to 5 (e.g. 0 to 3, such as 0, 1 or 2, e.g. 1).

[0117] In further embodiments: where ring A represents a cycloalkyl, n represents 1 to 3 (such as 1 or 2, e.g. 1); and where ring A represents a heterocycloalkyl, n represents 1 to 3 (such as 1 or 2, e.g. 1).

[0118] For example, in particular embodiments, n represents 1 to 4, such as 1 to 3.

[0119] In more particular embodiments, n represents 1 or 2.

[0120] In more particular embodiments, n represents 1.

[0121] In particular embodiments, R1represents H or Ci-4 alkyl (such as C1-2 alkyl, such as methyl).

[0122] In particular embodiments, R1represents H. In alternative embodiments, R1represents methyl.

[0123] In particular embodiments, the sum of ml and m2 is 1 or 2.

[0124] In more particular embodiments, the sum of ml and m2 is 2.

[0125] In particular embodiments, ml and m2 both represent 1.

[0126] In particular embodiments, X represents C (carbon). In more particular embodiments, X represents C (carbon) and ml and m2 represent 1. Accordingly, in such embodiments, ring A (e.g. the ring comprising X) represents cyclohexyl.

[0127] Thus, in some embodiments, compounds of formula I may be present as a compound of formula IC wherein R1, the ring comprising Q1to Q5, W, Z, and n are as described herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof). For the avoidance of doubt, W may be present on any carbon or nitrogen atom of ring A (in the case of formula IC, the skilled person will understand that ring A is cyclohexyl).

[0128] In particular embodiments, X represents N (nitrogen).

[0129] In more particular embodiments, X represents N (nitrogen) and ml and m2 represent 1. Accordingly, in such embodiments, ring A (e.g. the ring comprising X) represents piperidin-4-yl.

[0130] Thus, in some embodiments, compounds of formula I may be present as a compound of formula ID ID, wherein R1, the ring comprising Q1to Q5, Z, and n are as described herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof). For the avoidance of doubt, one Z group may be present on the N of the piperidine ring. For the avoidance of doubt, W may be present on any carbon or nitrogen atom of ring A (i.e. the piperidinyl in the case of formula ID), including on the NH of formula ID (in which case, the skilled person will understand that the H of NH of the piperidine will be replaced with W to form a -NW- group). In particular embodiments (e.g. formula IX, where n represents 1; and ml and m2 represents 1), the Z group is present in the 3- or 4- position of the ring comprising the X group (relative to the point of attachment to the essential core of the compound).

[0131] Thus, in certain embodiments ring A can be depicted as follows: wherein the wavy line indicates the point of attachment to the essential core of the compound, W is as defined herein and Z1represents Z as defined herein or H.

[0132] For example, in certain embodiments that may be mentioned, Z1represents H. As such, in certain embodiments, the compounds of formula I may be compounds of formula IE wherein R1, the ring comprising Q1to Q5, W, and X are as described herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof).

[0133] When present on a carbon atom of ring A, W represents Ci-6 alkyl (such as C2-6 alkyl, e.g. C2-alkyl) substituted with one or more groups selected from -CN, -ORd4, or =0, wherein the C1-6 alkyl may be further optionally substituted with one or more groups independently selected from halo and G1.

[0134] In particular embodiments, when present on a carbon atom of ring A, W represents - CH2CN, -CH2C(O)OMe, or -CH2C(O)OH.

[0135] In more particular embodiments, when present on a carbon atom of ring A, W represents -CH2C(0)0Me, or -CH2C(0)0H.

[0136] When present on a nitrogen atom of ring A, W represents -C(0)0Ci-6alkyl, -C(0)C4-ealkyl, -S(O)Ci-ealkyl or C2-6-alkyl (such as C2-4 alkyl, e.g. C2 alkyl) substituted with at least one -N(Rb4)Rc4and at least one =0, wherein the C2-6 alkyl may be further optionally substituted with one or more groups independently selected from halo and G1.

[0137] In particular embodiments, when present on a nitrogen atom of ring A, W represents -CH2C(O)NMe2, -CH2C(O)NH2, -CH2C(O)NHMe, or -CH2C(CH3)2NHC(O)Me.

[0138] In particular embodiments, when present on a nitrogen atom of ring A, W represents -C(0)0Ci-6alkyl, such as -C(0)0Ci-4alkyl, e.g. -C(O)O-tert-butyl (i.e. Boc).

[0139] In particular embodiments, when present on a nitrogen atom of ring A, W represents -C(0)C4-ealkyl, such as -C(0)C4-alkyl, e.g. -C(O)-n-butyl.

[0140] In particular embodiments, when present on a nitrogen atom of ring A, W represents -S(0)C4-alkyl, e.g. -S(O)-tert-butyl.

[0141] In particular embodiments, n represents 0 (i.e. no Z group is present).

[0142] In particular embodiments, when present on a carbon atom, Z independently represents Ra3, -CN, -N3, -N(Rb3)Rc3, -0Rd3, -S(O)PRe3, -S(O)qN(Rf3)Rg3, -N(Rh3)S(O)tRi3, or =0.

[0143] In more particular embodiments, when present on a carbon atom, each Z independently represents Ra3, -CN, -N(Rb3)Rc3, -0Rd3, -S(O)qN(Rf3)Rg3, -N(Rh3)S(O)tR'3, or =0.

[0144] In more particular embodiments, when present on a carbon atom, each Z independently represents Ra3, -N(Rb3)Rc3, -0Rd3, -N(Rh3)S(O)tR'3, or =0.

[0145] In more particular embodiments, when present on a carbon atom, each Z independently represents Ra3, -N(Rb3)Rc3, -0Rd3, or -N(Rh3)S(O)tR'3, such as Ra3.

[0146] In particular embodiments, each t represents 2.

[0147] In particular embodiments, where representing a Z group present on a carbon atom, Ra3represents C1-6 alkyl (e.g. C1-4 alkyl, such as C2 or C4 alkyl) optionally substituted by one or more (e.g. one or two, e.g. one) G1groups. For example, in certain such embodiments, Z2represents Ra3, optionally substituted by one or more (e.g. one or two, such as one) G1groups, and Z1represents H.

[0148] In certain such embodiments, G1represents -N(Rb4)Rc4or -N(Rh4)S(O)rR'4.

[0149] In particular such embodiments, Rb4represents H and / or (e.g. and) Rc4represents Ci- 2 alkyl optionally substituted by one or more halo or =0, such as C2 alkyl optionally substituted by =0

[0150] In particular such embodiments, Rh4represents H and / or (e.g. and) R'4represents Ci- 2 alkyl, optionally substituted by one or more halo, such as Ci alkyl.

[0151] In particular embodiments, r represents 2.

[0152] For example, in certain such embodiments, e.g. where a substituent on a Z group present on a carbon atom, G1represents -NH(O)Me or -NHS(0)2Me.

[0153] In particular embodiments, Rb3and / or (e.g. or) Rc3represents H.

[0154] In particular embodiments, Rb3and / or (e.g. or) Rc3represents C1-6 alkyl optionally substituted by one or more groups selected from halo and G2. In particular such embodiments, G2may represent Ra4or =0.

[0155] In particular embodiments, Rd3represents C1-6 alkyl (such as C1-2 alkyl, e.g. methyl or ethyl), optionally substituted by one or more groups independently selected from halo and G2. In particular such embodiments, G2may represent Ra4, -OH or =0.

[0156] In particular embodiments, Rh3represents H.

[0157] In particular embodiments, R'3represents C1-6 alkyl (such as C1-2 alkyl, e.g. methyl or ethyl) optionally substituted by one or more groups independently selected from halo and G2.

[0158] As described herein, when present on a nitrogen atom, Z independently represents Ra3, -S(O)PRe3, or -S(O)qN(Rf3)R93. In particular embodiments, when present on a nitrogen atom, Z independently represents Ra3or -S(O)PRe3.

[0159] In particular embodiments, where representing a Z group present on a nitrogen atom, Ra3represents Ci-6 alkyl (e.g. Ci-4 alkyl, such as Ci or C2 alkyl) optionally substituted by one or more (e.g. one or two) G1groups. For example, G1may independently represent -ORd4(such as -OMe or -OH), -N(Rb4)Rc4(such as -NMe2) or =0.

[0160] For example, in certain such embodiments, Z2represents Ra3, optionally substituted by one or more (e.g. one or two) G1groups, and Z1represents H.

[0161] In certain such embodiments, G1represents =0.

[0162] In particular embodiments, where representing a Z group present on a nitrogen atom, -S(O)PRe3represents S(O)PRe3wherein Re3represents C1-4 alkyl, such as methyl.

[0163] In particular embodiments, p represents 2.

[0164] For example, when present on a nitrogen atom, Z may independently represent -CH2C(O)OMe, -CH2C(O)OH, -C(O)Me, -S(O)2CH2C(O)OMe, -S(O)2CH2C(O)OH, - S(O)2nBu or -S(O)2Me, such as -C(O)Me or -S(O)2Me.

[0165] For the avoidance of doubt, "when present on a carbon (or nitrogen as may be the case) atom" refers to when Z is present on a carbon (or nitrogen, as may be the case) of ring A (including all embodiments thereof).

[0166] The skilled person will understand that particular R1groups, X, ml, m2, ring Q, and substituents thereon, and Z groups (including any substituents thereon) that may be mentioned include those present in the examples provided herein.

[0167] Particular compounds of the first aspect of the invention that may be mentioned include the compounds of the examples provided herein, and pharmaceutically acceptable salts thereof.

[0168] As described herein, compounds of the first aspect of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and / or diastereoisomerism. Moreover, it has been found that certain such optical and / or diastereoisomers may show increased utility in the treatment of conditions as described herein, e.g. hyperglycaemia or disorders characterized by hyperglycaemia (such as type 2 diabetes).

[0169] Thus, the compound of formula I may be present as a compound of formula IF and IG wherein R1, the ring comprising Q1to Q5, W, Z, X, n, ml, and m2 are as described herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof). For the avoidance of doubt, W may be present on any carbon or nitrogen atom of ring A, including on the X atom of formula IF and IG.

[0170] In particular embodiments, the compound of formula I is a compound of formula IF.

[0171] For the avoidance of doubt, the stereochemistry as depicted in compounds of formula IF and IG may apply to all embodiments of compounds of formula I.

[0172] The skilled person will understand that, in addition to the carbon bearing the essential hydroxy group, compounds of the invention may comprise further sterocentres. For the aviodance of doubt, unless specified, the stereochemistry at all stereocentres (including stereochemistry present in positions other than the carbon bearing the essential hydroxy group) may be in either configuration (i.e. in the R or S configuration), or may be present in compounds as a mixture thereof (e.g. a racemic mixture).

[0173] Thus, in a particular embodiment, the compound of formula IF may be a compound of formula IH or IJ wherein R1, ring Q, W, Z, X, n, ml, and m2 are as described herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof). For the avoidance of doubt, W may be present on any carbon or nitrogen atom of ring A, including on the X atom of formula IH and IJ.

[0174] In more particular embodiments, where X represents C (carbon), the compound of formula IH is a compound of formula IK or a compound of formula IL, and the compound of formula IJ is a compound of formula IM or a compound of formula IN wherein R1, ring Q, W, ml and m2 are as described herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof).

[0175] In more particular embodiments, the compound of formula IF is a compound of formula

[0176] IO or a compound of formula IP wherein R1, Yla, Ylb, Y2, Z, X, n, ml and m2 are as described herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof). For the avoidance of doubt, W may be present on any carbon or nitrogen atom of ring A, including the X atom of formula IO and IP.

[0177] The skilled person will understand that references to specific stereoisomer(s) of a compound of formula I (e.g. in the case of compounds of formula I, where the carbon substituted by the essential -OH group is in the R configuration will refer to the specific stereoisomer present in the substantial absence of the other (corresponding) stereoisomer(s) (e.g. in the case of compounds of formula I, where the carbon substituted by the essential -OH group is in the opposite configuration, i.e. the S configuration).

[0178] As used herein, references to the substantial absence of the corresponding opposite stereoisomer will refer to the desired stereoisomer (e.g. in the case of compounds of formula I, where the carbon substituted by the essential -OH group is in the (R) configuration) being present at a purity of at least 80% (e.g. at least 90%, such as at least 95%) relative to the other (e.g. the opposite) stereoisomer (e.g. in the case of compounds of formula I, where the carbon substituted by the essential -OH group is in the S configuration). Alternatively, in such instances, compounds may be indicated to be present in the substantial absence of the compound in the other configuration (s) (i.e. (S) configuration), which may indicate that the compound in the relevant configuration is present in an enantiomeric excess (e.e.), or when two or more stereogenic centres are defined, in a diastereomeric excess (d.e.), of at least 80%% (such as at least 90%, at least 95%, at least 98% or, particularly, at least 99%, for example at least 99.9%).

[0179] In some embodiments, the compound in the relevant configuration is present in an enantiomeric excess (e.e.), or when two or more stereogenic centres are defined, in a diastereomeric excess (d.e.), of at least 90% (such as at least 95%, at least 98% or, particularly, at least 99%, for example at least 99.9%).

[0180] For the avoidance of doubt, where the stereochemistry of more than one position is specified, the compound will be present in the substantial absence of all other diastereoisomers.

[0181] For the avoidance of doubt, where the sterochemistry of a particular position is not specified, compounds of the invention will include compounds wherein that position has either available sterochemical configuration, and mixtures (e.g. racemic mixtures) thereof. Thus, compounds referred to as having a specific stereochemistry at a defined position (e.g. in the case of compounds of formula I, the carbon substituted by the essential -OH group being in the R configuration) may also have stereochemistry at one or more other positions, and so may exist as mixtures of enantiomers or diastereoisomers in relation to the stereochemistry at those positions.

[0182] Particular compounds of the invention that may be mentioned include: tert-butyl (R)-4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpi peridi ne-1- carboxylate;

[0183] (R)-l-(4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidin-l-yl)pentan-

[0184] 1-one;

[0185] (R)-2-(4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidin-l-yl)- / V, / V- di methylacetamide;

[0186] (R)-2-(4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidin-l-yl)- / V- methylacetamide acetate;

[0187] (R)-2-(4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidin-l-yl)- acetamide acetate;

[0188] (R)-N-(l-(4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidin-l-yl)-2- methylpropan-2-yl)acetamide;

[0189] 2-((trans)-3-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclobutyl)acetonitrile; methyl 2-((trans)-3-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclobutyl)- acetate;

[0190] 2-((trans)-3-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclobutyl)acetic acid; methyl trans)-3-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclobutane-l- carboxylate; methyl c / s)-3-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclobutane-l- carboxylate;

[0191] (lR)-2-((l-(tert-butylsulfinyl)-4-methylpiperidin-4-yl)amino)-l-(3-fluorophenyl)- ethan-l-ol, and pharmaceutically acceptable salts thereof.

[0192] Further particular compounds of the invention that may be mentioned include: tert-butyl (R)-3-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-3-methylazetidine-l- carboxylate; tert-butyl (R)-3-((2-(3-amino-2,4’difluorophenyl)-2-hydroxyethyl)amino)-3-methyl- azetidine-1 -carboxylate;

[0193] (R)-l-(4-((2-(3-amino-2,4’difluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidin- l-yl)pentan-l-one; tert-butyl (R)-4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)piperidine-l-carboxylate;

[0194] (R)-l-(4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)piperidin-l-yl)pentan- 1-one; tert-butyl (R)-4-((2-(4-chlororophenyl)-2-hydroxyethyl)amino)-4-methylpi peridine- 1- carboxylate; (R)-l-(4-((2-(4-chlorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidin-l-yl)pentan- 1-one; methyl (lS,4s)-4-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclohexane-l- carboxylate, and pharmaceutically acceptable salts thereof.

[0195] Medical uses

[0196] As indicated herein, the compounds of the invention, and therefore compositions and kits comprising the same, are useful as pharmaceuticals.

[0197] Thus, according to a second aspect of the invention there is provided a compound of the first aspect of the invention, as hereinbefore defined (i.e. a compound as defined in the first aspect of the invention, including all embodiments and particular features thereof), for use in medicine (i.e. for use as a pharmaceutical, which may be described as use as a medicament).

[0198] In an embodiment of the second aspect, the compound is as defined in the first aspect, but without proviso (B).

[0199] Compounds described herein are 2 adrenergic receptor agonists and therefore suitable in treating diseases such as those described herein. Such activity may be observed in compounds of the invention by identifying compounds which stimulate the uptake of glucose in skeletal muscle cells, which activity may be confirmed to be mediated by activation of the 02 receptor by observation that such activity is prevented or diminished in the presence of a (e.g. selective) 02 adrenergic receptor antagonist (such in the biological example provided herein).

[0200] Thus, in a third aspect of the invention, there is provided a compound of the first aspect of the invention, as hereinbefore defined, for use in treating a disease or disorder the treatment of which is mediated by activation of the 02 adrenergic receptor.

[0201] In an alternative third aspect of the invention, there is provided the use of a compound of the first aspect of the invention in the manufacture of a medicament for use in treating a disease or disorder the treatment of which is mediated by activation of the 02 adrenergic receptor. In a further alternative third aspect of the invention, there is provided a method of treating a disease or disorder the treatment of which is mediated by activation of the 2 adrenergic receptor comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the first aspect of the invention .

[0202] For the avoidance of doubt, references to compounds as defined in the first aspect of the invention will include references to compounds of formula I (including all embodiments thereof) and pharmaceutically acceptable salts thereof.

[0203] In an embodiment of the third aspect, the compound is as defined in the first aspect, but without provisos (B) to (M).

[0204] As indicated herein, the compounds of the invention act by inducing uptake of glucose in skeletal muscle cells, thus allowing for the reduction of blood glucose levels in vivo. Thus, compounds of the invention may be of particular use in treating hyperglycaemia or a disorder characterized by hyperglycaemia.

[0205] In a particular embodiment of the third aspect of the invention, there is provided a compound of the first aspect of the invention, as hereinbefore defined, for use in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia.

[0206] In an alternative embodiment of the third aspect of the invention, there is provided the use of a compound of the first aspect of the invention in the manufacture of a medicament for use in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia.

[0207] In a further alternative embodiment of the third aspect of the invention, there is provided a method of treating hyperglycaemia or a disorder characterized by hyperglycaemia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the first aspect of the invention.

[0208] For the avoidance of doubt, the term "hyperglycaemia" as used herein will be understood by those skilled in the art to refer to a condition wherein an excessive amount of glucose circulates in blood plasma of the subject experiencing the same. In particular, it may refer to a subject (e.g a human subject) having blood glucose levels higher than about 10.0 mmol / L (such as higher than about 11.1 mmol / L, e.g. higher than about 15 mmol / L), although it may also refer to a subject (e.g. a human subject) having blood glucose levels higher than about 7 mmol / L for an extended period of time (e.g. for greater than 24 hours, such as for greater than 48 hours).

[0209] The skilled person will understand that references to the treatment of a particular condition (or, similarly, to treating that condition) take their normal meanings in the field of medicine. In particular, the terms may refer to achieving a reduction in the severity of one or more clinical symptom associated with the condition. For example, in the case of type 2 diabetes, the term may refer to achieving a reduction of blood glucose levels. In particular embodiments, in the case of treating hyperglycaemia or conditions characterised by hyperglycaemia, the term may refer to achieving a reduction of blood glucose levels (for example, to or below about 10.0 mmol / mL (e.g. to levels in the range of from about 4.0 mmol / L to about 10.0 mmol / L), such as to or below about 7.5 mmol / mL (e.g. to levels in the range of from about 4.0 mmol / L to about 7.5 mmol / L) or to or below about 6 mmol / mL (e.g. to levels in the range of from about 4.0 mmol / L to about 6.0 mmol / L)).

[0210] As used herein, references to patients will refer to a living subject being treated, including mammalian (e.g. human) patients. Thus, in particular embodiments of the first aspect of the invention, the treatment is in a mammal (e.g. a human).

[0211] As used herein, the term therapeutically effective amount will refer to an amount of a compound that confers a therapeutic effect on the treated patient. The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and / or feels an effect).

[0212] Although compounds of the first aspect of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention. Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the active compounds to which they are metabolised) may therefore be described as "prodrugs" of compounds of the invention.

[0213] As used herein, references to prodrugs will include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time, following enteral or parenteral administration (e.g. oral or parenteral administration). All prodrugs of the compounds of the first aspect of the invention are included within the scope of the invention.

[0214] For the avoidance of doubt, the compounds of the first aspect of the invention are useful because they possess pharmacological activity, and / or are metabolised in the body following oral or parenteral administration to form compounds that possess pharmacological activity. In particular, as described herein, compounds of the first aspect of the invention are useful in the treatment of hyperglycaemia or disorders characterized by hyperglycaemia (such as type 2 diabetes), which terms will be readily understood by one of skill in the art (as described herein).

[0215] In a particular embodiment, the treatment is of a disorder (which may also be referred to as a condition or disease) characterised by hyperglycaemia.

[0216] In particular embodiments of the first aspect of the invention, the disorder is type 2 diabetes, such as type 2 diabetes of a sub-type selected from the list consisting of maturity-onset diabetes in the young (MODY), ketosis-prone diabetes in adults, latent autoimmune diabetes of adults (LADA), and gestational diabetes.

[0217] In further embodiments, the disorder is type 1 diabetes, particularly wherein the treatment further comprises treatment with insulin (or a derivative and / or functional mimetic thereof).

[0218] In particular embodiments, compounds of the invention (i.e. compounds of formula I, including all embodiments thereof) are for use in the treatment of type 2 diabetes (or useful in the manufacture of a medicament for such treatment, or useful in a method for such treatment, as described herein).

[0219] In further particular embodiments, the treatment of type 2 diabetes is in a non-obese patient.

[0220] For the avoidance of doubt, the skilled person will understand that patients with a Body Mass Index (BMI) of greater than 30 are considered to be obese.

[0221] In particular embodiments, the treatment may be of hyperglycaemia in a patent who is at risk of developing type 2 diabetes, which condition may be defined as prediabetes. Thus, compounds of the invention may be useful in the prevention of type 2 diabetes (e.g. in a patient having pre-diabetes). As used herein, the term prevention (and, similarly, preventing) includes references to the prophylaxis of the disease or disorder (and vice-versa). As such, references to prevention may also be references to prophylaxis, and vice versa. In particular, the term may refer to achieving a reduction in the likelihood of the patient (or healthy subject) developing the condition (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction).

[0222] In more particular embodiments, the type 2 diabetes is characterised by the patient displaying severe insulin resistance (SIR).

[0223] In further embodiments, the treatment may be of hyperglycaemia in a patient having type 1 diabetes. Thus, compounds of the invention may be useful in the treatment of hyperglycaemia in type 1 diabetes.

[0224] The skilled person will understand that compounds of the invention may be useful in treating hyperglycaemia in patients having impaired insulin production, such as in patients having cystic fibrosis. Thus, in further embodiments, the disorder characterized by hyperglycaemia is cystic fibrosis-related diabetes.

[0225] In particular embodiments that may be mentioned, the disorder characterised by hyperglycaemia is (or is characterized by) severe insulin resistance (SIR), which may be understood by those in the art to refer to disorders wherein typically the subject has normal, or in some cases increased, insulin production but significantly reduced insulin sensitivity. In particular instances, such patients may be non-obese (e.g. being of a healthy weight). Thus, in particular embodiments, such treatments are performed in patients who are not defined as being obese (e.g. in patients who are defined as being of a healthy weight).

[0226] For example, SIR may be identified in a patient based in said patient having fasting insulin > 150 pmol / L and / or a peak insulin on glucose tolerance testing of > 1,500 pmol / L, particularly in individuals with a BMI < 30 kg / m2(which patient may otherwise have normal glucose tolerance).

[0227] More particularly, SIR may be characterised by the patient having no significant response to the presence of insulin, which may result from a defect (e.g. a genetic defect) in the function of the insulin receptor. Particular disorders that may be characterised by SIR include: Rabson-Mendenhall syndrome, Donohue's syndrome (leprechaunism), Type A and Type B syndromes of insulin resistance, the HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndromes, pseudoacromegaly, and lipodystrophy.

[0228] More particular disorders that may be characterised by SIR include Donohue's syndrome and Type A syndrome of insulin resistance and, yet more particularly, Rabson-Mendenhall syndrome.

[0229] The skilled person will understand that treatment with compounds of the first aspect of the invention may further comprise (i.e. be combined with) further (i.e. additional / other) treatment(s) for the same condition. In particular, treatment with compounds of the invention may be combined with other means for the treatment of type 2 diabetes, such as treatment with one or more other therapeutic agent that is useful in the treatment of type 2 diabetes as known to those skilled in the art, such as therapies comprising requiring the patient to undergo a change of diet and / or undertake exercise regiments, and / or surgical procedures designed to promote weight loss (such as gastric band surgery).

[0230] In particular, treatment with compounds of the invention may be performed in combination with (e.g. in a patient who is also being treated with) one or more (e.g. one) additional compounds (i.e. therapeutic agents) that:

[0231] (i) are capable of reducing blood sugar levels; and / or

[0232] (ii) are insulin sensitizers; and / or

[0233] (iii) enhance insulin release, all of which are described herein below.

[0234] In alternative embodiments, compounds of the first aspect of the invention (i.e. compounds of the invention) may be useful in the treatment of a non-alcoholic fatty liver disease (NAFLD).

[0235] Non-alcoholic fatty liver disease (NAFLD) is defined by excessive fat accumulation in the form of triglycerides (steatosis) in the liver (designated as an accumulation of greater than 5% of hepatocytes histologically). It is the most common liver disorder in developed countries (for example, affecting around 30% of US adults) and most patients are asymptomatic. If left untreated, the condition may progressively worsen and may ultimately lead to cirrhosis of the liver. NAFLD is particularly prevalent in obese patents, with around 80% thought to have the disease.

[0236] A sub-group of NAFLD patients (for example, between 2 and 5% of US adults) exhibit liver cell injury and inflammation in addition to excessive fat accumulation. This condition, designated as non-alcoholic steatohepatitis (NASH), is virtually indistinguishable histologically from alcoholic steatohepatitis. While the simple steatosis seen in NAFLD does not directly correlate with increased short-term morbidity or mortality, progression of this condition to NASH dramatically increases the risks of cirrhosis, liver failure and hepatocellular carcinoma. Indeed, NASH is now considered to be one of the main causes of cirrhosis (includeing cryptogenic cirrhosis) in the developed world.

[0237] The exact cause of NASH has yet to be elucidated, and it is almost certainly not the same in every patient. It is most closely related to insulin resistance, obesity, and the metabolic syndrome (which includes diseases related to diabetes mellitus type 2, insulin resistance, central (truncal) obesity, hyperlipidaemia, low high-density lipoprotein (HDL) cholesterol, hypertriglyceridemia, and hypertension). However, not all patients with these conditions have NASH, and not all patients with NASH suffer from one of these conditions. Nevertheless, given that NASH is a potentially fatal condition, leading to cirrhosis, liver failure and hepatocellular carcinoma, there exists a clear need for an effective treatment.

[0238] In particular embodiments, compounds of the invention (i.e. compounds of formula I, including all embodiments thereof) are for use in the treatment of a non-alcoholic fatty liver disease (or useful in the manufacture of a medicament for such treatment, or useful in a method for such treatment, as described herein).

[0239] The process by which the triglyceride fat accumulates in liver cells is called steatosis (i.e. hepatic steatosis). The skilled person will understand that the term "steatosis" encompasses the abnormal retention of fat (i.e. lipids) within a cell. Thus, in particular embodiments of the first aspect of the invention, the treatment or prevention is of a fatty liver disease which is characterized by steatosis.

[0240] During steatosis, excess lipids accumulate in vesicles that displace the cytoplasm of the cell. Over time, the vesicles can grow large enough to distort the nucleus, and the condition is known as macrovesicular steatosis. Otherwise, the condition may be referred to as microvesicular steatosis. Steatosis is largely harmless in mild cases; however, large accumulations of fat in the liver can cause significant health issues. Risk factors associated with steatosis include diabetes mellitus, protein malnutrition, hypertension, obesity, anoxia, sleep apnea and the presence of toxins within the cell.

[0241] As described herein, fatty liver disease is most commonly associated with alcohol or a metabolic syndrome (for example, diabetes, hypertension, obesity or dyslipidemia). Therefore, depending on the underlying cause, fatty liver disease may be diagnosed as alcohol-related fatty liver disease or non-alcoholic fatty liver disease (NAFLD).

[0242] Particular diseases or conditions that are associated with fatty liver disease that are not related to alcohol include metabolic conditions such as diabetes, hypertension, obesity, dyslipidemia, abetalipoproteinemia, glycogen storage diseases, Weber- Christian disease, acute fatty liver of pregnancy, and lipodystrophy. Other non-alcohol related factors related to fatty liver diseases include malnutrition, total parenteral nutrition, severe weight loss, refeeding syndrome, jejunoileal bypass, gastric bypass, polycystic ovary syndrome and diverticulosis.

[0243] The compounds of the invention have been found to be particularly useful in the treatment or prevention of NAFLD, which may be referred to as a fatty liver disease which is not alcohol related. A fatty liver disease which is "not alcohol related" may be diagnosed wherein alcohol consumption of the patient is not considered to be a main causative factor. A typical threshold for diagnosing a fatty liver disease as "not alcohol related" is a daily consumption of less than 20 g for female subjects and less than 30 g for male subjects.

[0244] If left untreated, subjects suffering from fatty liver disease may begin to experience inflammation of the the liver (hepatitis). It has been postulated that one of the possible causes of this inflammation may be lipid peroxidative damage to the membranes of the liver cells. Inflammation of a fatty liver can lead to a number of serious conditions and it is therefore desirable to treat or prevent fatty liver disease before inflammation occurs. Thus, in particular embodiments of the first aspect of the invention, the treatment or prevention is of a NAFLD which is associated with inflammation.

[0245] Non-alcoholic steatohepatitis (NASH) is the most aggressive form of NAFLD, and is a condition in which excessive fat accumulation (steatosis) is accompanied by inflammation of the liver. If advanced, NASH can lead to the development of scar tissue in the liver (fibrosis) and, eventiually, cirrhosis. As described above, the compounds of the invention have been found to be useful in the treatment or prevention of NAFLD, particularly when accompanied by inflamation of the liver. It follows that the compounds of the invention are also useful in the treatment or prevention of NASH. Therefore, in a further embodiment of the first aspect of the invention, the treatment or prevention is of non-alcoholic steatohepatitis (NASH).

[0246] The skilled person will understand that treatment with compounds of the first aspect of the invention may further comprise (i.e. be combined with) further (i.e. additional / other) treatment(s) for the same condition. In particular, treatment with compounds of the invention may be combined with other means for the treatment of a fatty liver disease, as described herein, such as treatment with one or more other therapeutic agent that is useful in the treatment of a fatty liver disease as known to those skilled in the art; for example, therapies comprising requiring the patient to undergo a change of diet and / or undertake exercise regiments, and / or surgical procedures designed to promote weight loss (such as gastric band surgery).

[0247] In particular, treatment with compounds of the invention may be performed in combination with (e.g. in a patient who is also being treated with) one or more (e.g. one) additional compounds (i.e. therapeutic agents) that are capable of reducing the level of fat (e.g. triglycerides) in the liver.

[0248] References to treatment of a fatty liver disease may refer to achieving a therapeutically significant reduction of fat (e.g. triglycerides levels) in liver cells (such as a reduction of at least 5% by weight, e.g. a reduction of at least 10%, or at least 20% or even 25%).

[0249] As described herein, compounds of the invention may be of use in treating a disease or disorder the treatment of which is mediated by activation of the 02 adrenergic receptor.

[0250] In particular embodiments, the compounds of the first aspect of the invention may be understood to positively modulate the 02 adrenergic receptor, which compounds may be referred to as a 02-adrenergic receptor agonist.

[0251] The skilled person will appreciate what is meant by "02 adrenergic receptor" (or "02- AR"). Such receptors are known in the art and have been reviewed in, e.g., Johnson. M., J. Allergy Clin. Immunol., 117, 18-24 (2006). For the avoidance of doubt, adrenergic receptors are a class of G protein-coupled receptors which bind and are activated by their endogenous ligands, the catecholamines, adrenaline and noradrenaline. The adrenergic receptor falls into five types: oi, 02, Pi, 2 and 3. These subtypes are expressed in distinct patterns and involved in different physiological processes, such that ligands that can selectively target one subtype have therapeutic potential for multiple diseases. The present invention is concerned with the 2 adrenergic receptor, although compounds may interact with one or more other adrenergic receptor (e.g. one or more other adrenergic receptor).

[0252] The term "positively modulates P2-adrenergic receptor activity" will be understood to mean that the compound is capable of altering the signalling of the receptor.

[0253] As used herein, the term "P2 agonist" is used to mean P2 adrenergic receptor agonist. In certain embodiments, the term P2 agonist is understood to include compounds that are primarily P2 agonists, but may also exhibit some agonism for other adrenergic receptors. In this application, the terms "P2 adrenergic receptor agonist", "P2 AR agonist", "P2A agonist" and "P2 agonist" may be used interchangeably.

[0254] Thus, in certain embodiments, references to P2 agonists may include both selective and non-selective agonists.

[0255] In certain embodiments, references to P2 agonists may include any ligand that change receptor signalling including but not limited to full and partial agonists. Further, P2 agonists that may be used in accordance with various aspects and embodiments of the present disclosure may be short-acting, long acting or ultra long-acting.

[0256] As used herein, the term "mediated by activation of the P2 adrenergic receptor" is used to indicate that activation of the receptor regulates or causes a physiological response which will in turn provide a biological effect corresponding to (or leading to) treatment of the disease or disorder.

[0257] As used in herein, references to diseases and disorders the treatment of which is "mediated by activation of the P2 adrenergic receptor" may also refer to diseases and disorders (and in particular the treatment thereof) being, inter alia, "associated with", "mediated by", "affected by", "regulated by", "modulated by" and "linked to" the P2 adrenergic receptor.

[0258] As described herein, diseases and disorders the treatment of which is mediated by activation of the 2 adrenergic receptor will be known to those skilled in the art. Thus, the skilled person will understand that in respect of certain of the diseases and disorders described herein the suitability of compounds of the invention for the treatment of such diseases and disorders may be known to those skilled in the art; for example, based on the disclosures referred to herein below (the contents of which are incorporated herein by reference).

[0259] In addition to those as may be described herein above, particular diseases and disorders the treatment of which is mediated by activation of the 2 adrenergic receptor that may be mentioned include: neurodegenerative diseases, such as MCI (mild cognitive impairment), aMCI (amnestic MCI), vascular dementia, mixed dementia, FTD (front-temporal dementia), HD (Huntington disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, EKS (Wernicke- Korsakoff syndrome), normal pressure hydrocephalus, hypersomnia (narcolepsy), ASD (autistic spectrum disorders), FXS (fragile X syndrome), YSC (tubular sclerosis complex), prion-related disorders, CJD (Creutzfeldt-Jakob disease), depressive disorders, DLC (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early AD and DS (Down syndrome); muscle dystrophy or a disorder characterised by muscular dystrophy, such as muscle damage, muscle wasting, muscle atrophy, muscle degeneration or sclerosis; kidney disease, such as CKD (chronic kidney disease), ESRD (end-stage renal disease) and diabetic nephropathy; inflammation or a disorder characterised by inflammation, such as sepsis, psoriasis, dermatitis, psoriasis-like skin dermatitis, lacerations or HDF (human dermal fibroblasts), and including localised acute inflammation, such as that related to endotoxemia and Acute Lung Injury (ALI), and respiratory conditions associated with inflammation, such as asthma and other pulmonary disorders, such as chronic obstructive pulmonary disease (COPD); and an autoimmune disease, such as SLE (systemic lupus erythematosus, RA (rheumatoid arthritis), MG (myasthenia gravis) MS and GD (Grave's disease).

[0260] The suitability of 02 adrenergic receptor agonists for treating such conditions may be demonstrated by the data provided herein and by reference to the literature known to those skilled on the art, such as that described herein (the whole contents of which, in particular the experimental results presented, will be understood to be incorporated herein by reference). In particular, the suitability of 2 adrenergic receptor agonists for treating certain of the diseases and disorders referred to herein may be identified in and, in some instances, confirmed by the disclosures of WO 2020 / 198466 Al and WO 2021 / 003161 Al (which, for the avoidance of doubt, are incorporated herein by reference, in particular the examples as provided therein).

[0261] In a particular embodiment, there is provided a compound of the first aspect of the invention, as hereinbefore defined, for use in treating neurodegenerative diseases.

[0262] In particular embodiments, the neurodegenerative disease is selected from MCI (mild cognitive impairment), aMCI (amnestic MCI), vascular dementia, mixed dementia, FTD (front-temporal dementia), HD (Huntington disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, EKS (Wernicke-Korsakoff syndrome), normal pressure hydrocephalus, hypersomnia (narcolepsy), ASD (autistic spectrum disorders), FXS (fragile X syndrome), YSC (tubular sclerosis complex), prion-related disorders, CJD (Creutzfeldt-Jakob disease), depressive disorders, DLC (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early AD and DS (Down syndrome).

[0263] Mittal. S., et al., Science., 357(6354), 891-898 (2017) describes that 02-adrenergic receptor agonists promote dopamine neuron health by reducing SNCA expression through H2K27 deacetylation and mitochondrial free radicals. This may benefit nigral dopamine neurons, which are prone to mitochondrial bioenergetics dysfunction at early stages of Lewy body neuropathy. 02-adrenergic receptor agonists are expressed in the substantia nigra and cortex, regions that are progressively affected by Parkinson's disease (PD). Therefore, 02-adrenergic receptor agonists can be used to reduce the risk and affect of PD.

[0264] Hishida. R., The Lancet, 870 (1992) describes that 02-adrenergic receptor agonists can beneficially affect wearing-off in patients with Parkinson's disease on long-term levodopa. Uc, E. Y., et al., Clin. Neuropharmacol., 26(4), 207-212 (2003) describes that 02- adrenergic receptor agonist, albuterol, benefited patients with PD through two mechanisms, an increased response to levodopa and an increase in muscle mass.

[0265] O'Neill, et al., Br. J. Pharmacol., 177, 282-297 (2019) describes that 02-adrenergic receptor agonists restrict microglial activation and protect against the onset and progression of dopamine neuronal cell loss and related motor deficits provoke by central or systemic inflammation. Therefore, targeting 02-adrenergic receptors with a 02-adrenergic receptor agonist imbues an intervening prophylactic mechanism to protect against the progression of neurodegeneration and exacerbated decline in motor function associated with systemic and central inflammation. As a result, 02-adrenergic receptor agonists may be beneficial in the treatment of PD-related neuropathy and motor impairments induced by inflammation.

[0266] In alternative embodiments, there is provided a compound of the first aspect of the invention, as hereinbefore defined, for use in treating muscle dystrophy or a disorder characterised by muscular dystrophy.

[0267] In particular such embodiments, the muscle dystrophy is muscle damage, muscle wasting, muscle atrophy, muscle degeneration or sclerosis.

[0268] Jiang, G., et al., ISRN Pharma., 2011, 1-7 (2011) describes that 02-AR agonists ameliorate animal wasting in denervation, amyotrophic lateral sclerosis, muscular dystrophy, disuse, aging and myocardial unloading models. Further, in patients with immobilization conditions or muscular dystrophy, 02-AR agonists increase lean body mass and enhance skeletal muscle functions. Also, 02-AR agonists were found to promote myocardial recovery in patients with myocardial unloading atrophy resulting from application of left ventricular assist devise.

[0269] Bartus, R. T., et al., Neurobiol. Dis., 85, 11-24, 2016 indicates that 02-adrenergic receptor agonists may enhance muscle bulk and muscle strength in amyotrophic lateral sclerosis (ALS) patients by increasing neurotrophic factors.

[0270] In alternative embodiments, there is provided a compound of the first aspect of the invention, as hereinbefore defined, for use in treating kidney disease.

[0271] In particular such embodiments, the kidney disease is selected from CKD (chronic kidney disease), ESRD (end-stage renal disease) and diabetic nephropathy. Cleveland, K., et al., FASEB Journal, 33(1), 514 (2019) describes that 02-adrenergic receptor agonists have been shown to induce mitochondrial biogenesis (MB) and promote recovery from acute kidney injury, and may find use as a potential therapy for diabetic nephropathy (DN).

[0272] Jesinkey, S. R., et al., J. Am. Soc. Nephrol., 25, 1157-1162 (2014) describes the necessity for mitochondrial biogenesis as an adaptive response for meeting the increased metabolic and energy demands during organ recovery after an acute injury. In particular, renal mitochondrial dysfunction has been linked to pathogenesis of acute kidney injury (AKI), a disorder characterised by a rapid decrease in kidney excretory function and subsequent retention of harmful waste products.

[0273] In alternative embodiments, there is provided a compound of the first aspect of the invention, as hereinbefore defined, for use in treating inflammation or a disorder characterised by inflammation.

[0274] In particular embodiments, the inflammation is (or is characterised by) sepsis, psoriasis, dermatitis, psoriasis-like skin dermatitis, lacerations or HDF (human dermal fibroblasts).

[0275] As the skilled person will know, inflammation is a tightly controlled process that ensures proper localization of immune cells, release of pro- and anti-inflammatory mediators, clearance of dead cells, and containment of the pathogen.

[0276] The skilled person will know that inflammation may also be a cause of respiratory conditions, such as asthma and other pulmonary disorders, such as chronic obstructive pulmonary disease (COPD).

[0277] Grailer, J. J. et al, J Innate Immun, 6, 607-618 (2014) shows that blockade of the 02 adrenergic receptor reduced survival and enhanced injury in mouse models of endotoxemia and LPS-induced acute lung injury, respectively. These results demonstrate the suitability of 02AR activation in the treatment of localised acute inflammation, such as that related to endotoxemia and Acute Lung Injury.

[0278] Agac, D., et al., Brain, Behaviour and Immunity, 74, 176-185 (2018) describes that there is a unique synergistic pathway that converts acute inflammatory signals into an anti-inflammatory response and likely explains a variety of phenomena known to be involved in 02-adrenergic receptor agonists mediated immune suppression. In particular, 02-adrenergic receptor agonists signalling directly controls antiinflammatory cytokine, IL-10, expression. These results suggest the use of P2AR agonists in the treatment of inflammatory disorders, such as sepsis.

[0279] Liu, F., et al., Cells, 511(9), 1-17 (2020) describes that 02-adrenergic receptor agonists demonstrated significant anti-psoriasis effects, which may involve regulating the Thl7 / Tregs axis balances and glycerophospholipid metabolism in response to imiquimod (IMQ) induced psoriasis.

[0280] Provost, G. S., et al., J. Investig. Dermatol., 135, 279-288 (2015) describes that 02- adrenergic receptor agonists reduces human dermal fibroblast (HDF) differentiation, therefore reducing scarring to a patient following a laceration or open wound.

[0281] In alternative embodiments, there is provided a compound of the first aspect of the invention, as hereinbefore defined, for use in treating an autoimmune disease.

[0282] In particular such embodiments, the autoimmune disease is selected from SLE (systemic lupus erythematosus, RA (rheumatoid arthritis), MG (myasthenia gravis) MS and GD (Grave's disease).

[0283] Wu, et al., Front. Pharmacol., 1313(9), 1-9 (2018) describes that 02-adrenergic receptor agonists may be a target treatment for autoimmune diseases (AD), such as SLE (systemic lupus erythematosus, RA (rheumatoid arthritis), MG (mysasthenia gravis) MS and GD (Grave's disease).

[0284] Pharmaceutical compositions

[0285] As described herein, compounds of the first and, therefore, the second and third aspects of the invention are useful as pharmaceuticals. Such compounds may be administered alone or may be administered by way of known pharmaceutical compositions / formulations.

[0286] In a fourth aspect of the invention, there is provided a pharmaceutical composition comprising a compound as defined in the second or third aspect of the invention, and optionally one or more pharmaceutically acceptable adjuvant, diluent and / or carrier. The skilled person will understand that references herein to compounds of the first aspect of the invention being for particular uses (and, similarly, to uses and methods of use relating to compounds of the invention) may also apply to pharmaceutical compositions comprising compounds of the invention as described herein.

[0287] In a fifth aspect of the invention, there is provided a pharmaceutical composition for use in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia (as defined herein, such as type 2 diabetes) comprising a compound as defined in the first aspect of the invention, and optionally one or more pharmaceutically acceptable adjuvant, diluent and / or carrier.

[0288] In an alternative fifth aspect of the invention, there is provided a pharmaceutical composition for use in the treatment or prevention of a non-alcoholic fatty liver disease, as defined herein.

[0289] In an alternative fifth aspect of the invention, there is provided a pharmaceutical composition for use in the treatment or prevention of a non-alcoholic fatty liver disease, as defined herein.

[0290] The skilled person will understand that compounds of the first (and, therefore, second and third) aspect of the invention may act systemically and / or locally (i.e. at a particular site).

[0291] The skilled person will understand that compounds and compositions as described in the first to fifth aspects of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form. Pharmaceutical compositions as described herein will include compositions in the form of tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. Alternatively, particularly where such compounds of the invention act locally, pharmaceutical compositions may be formulated for topical administration.

[0292] Thus, in particular embodiments of the fourth and fifth aspects of the invention, the pharmaceutical formulation is provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, inhalants (e.g. to be applied intranasally), or forms suitable for topical administration. For the avoidance of doubt, in such embodiments, compounds of the invention may be present as a solid (e.g. a solid dispersion), liquid (e.g. in solution) or in other forms, such as in the form of micelles.

[0293] For example, in the preparation of pharmaceutical formulations for oral administration, the compound may be mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules or compressed into tablets.

[0294] Soft gelatin capsules may be prepared with capsules containing one or more active compounds (e.g. compounds of the first and, therefore, second and third aspects of the invention, and optionally additional therapeutic agents), together with, for example, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Similarly, hard gelatine capsules may contain such compound(s) in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.

[0295] Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the compound(s) mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.

[0296] Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the compound(s) and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.

[0297] Solutions for parenteral administration may be prepared as a solution of the compound(s) in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and / or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.

[0298] The skilled person will understand that compounds of the invention, and pharmaceutically-acceptable salts thereof, may be administered (for example, as formulations as described hereinabove) at varying doses, with suitable doses being readily determined by one of skill in the art. Oral, pulmonary and topical dosages (and subcutaneous dosages, although these dosages may be relatively lower) may range from between about 0.01 pg / kg of body weight per day (pg / kg / day) to about 200 pg / kg / day, preferably about 0.01 to about 10 pg / kg / day, and more preferably about 0.1 to about 5.0 pg / kg / day. For example, when administered orally, treatment with such compounds may comprise administration of a formulations typically containing between about 0.01 pg to about 2000 mg, for example between about 0.1 pg to about 500 mg, or between 1 pg to about 100 mg (e.g. about 20 pg to about 80 mg), of the active ingredient(s). When administered intravenously, the most preferred doses will range from about 0.001 to about 10 pg / kg / hour during constant rate infusion. Advantageously, treatment may comprise administration of such compounds and compositions in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily (e.g. twice daily with reference to the doses described herein, such as a dose of 10 mg, 20 mg, 30 mg or 40 mg twice daily, or 10 pg, 20 pg, 30 pg or 40 pg twice daily).

[0299] In any event, the skilled person (e.g. the physician) will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

[0300] As described herein above, the skilled person will understand that treatment with compounds of the first aspect of the invention may further comprise (i.e. be combined with) further (i.e. additional / other) treatment(s) for the same condition. In particular, treatment with compounds of the invention may be combined with other means for the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia(as defined herein, such as type 2 diabetes), such as treatment with one or more other therapeutic agent that is useful in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia(as defined herein, such as type 2 diabetes).

[0301] In particular embodiments of the fourth and fifth aspects of the invention, the pharmaceutical composition may further comprise one or more additional (i.e. other) therapeutic agent.

[0302] In more particular embodiments, the one or more additional therapeutic agent is an agent for the treatment of type 2 diabetes as known to those skilled in the art, such as metformin, sulfonylureas (e.g. carbutamide, acetohexamide, chlorpropamide, tolbutamide, glipizide (glucotrol), gliclazide, glibenclamide, glyburide (Micronase), glibornuride, gliquidone, glisoxepide, glyclopyramide, glimepiride (Amaryl), glimiprime, JB253 or JB558), thiazolidinediones (e.g. pioglitazone, rosiglitazone (Avandia), lobeglitazone (Duvie) and troglitazone (Rezulin)), dipeptidyl peptidase-4 inhibitors (e.g. sitagliptin, vildagliptin, saxagliptin, linagliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, gemigliptin, dutogliptin and omarigliptin), SGLT2 inhibitors (e.g. dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, and ertugliflozin), and glucagon-like peptide-1 (GLP-1) analogues.

[0303] The skilled person will understand that combinations of therapeutic agents may also described as a combination product and / or provided as a kit-of-parts.

[0304] In a sixth aspect of the invention, there is provided a combination product comprising:

[0305] (A) a compound as defined in the first aspect of the invention; and

[0306] (B) one or more additional therapeutic agent, wherein each of components (A) and (B) is formulated in admixture, optionally with one or more a pharmaceutically-acceptable adjuvant, diluent or carrier.

[0307] In a seventh aspect of the invention, there is provided a kit-of-parts comprising:

[0308] (a) a compound as defined in the first (or second and / or third) aspect of the invention, (or a pharmaceutical composition comprising the same) or a pharmaceutical composition as defined in the fourth or fifth aspect of the invention; and

[0309] (b) one or more other therapeutic agent, optionally in admixture with one or more pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other. In particular embodiments (e.g. of the sixth and seventh aspects of the invention), the additional therapeutic agent is a therapeutic agent that is useful for the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia (e.g. type 2 diabetes), as known to those skilled in the art (such as those described herein).

[0310] For example, in particular embodiments of the fourth to fifth aspects of the invention, the additional therapeutic agent is an agent that:

[0311] (i) is capable of reducing blood sugar levels; and / or

[0312] (ii) is an insulin sensitizer; and / or

[0313] (iii) is able to enhance insulin release, which agents will be readily identified by those skilled in the art and include, in particular, such therapeutic agents that are commercially available (e.g. agents that the subject of a marketing authorization in one or more territory, such as a European or US marketing authorization).

[0314] The skilled person will understand that references to therapeutic agents capable of reducing blood glucose levels may refer to compounds capable of reducing levels of blood by at least 10% (such as at least 20%, at least 30% or at least 40%, for example at least 50%, at least 60%, at least 70% or at least 80%, e.g. at least 90%) when compared to the blood glucose levels prior to treatment with the relevant compound.

[0315] In alternative embodiments of the sixth and seventh aspects of the invention, the additional therapeutic agent is an agent for the treatment or prevention of a nonalcoholic fatty liver disease (such as NASH), which agents will be readily identified by those skilled in the art and include, in particular, such therapeutic agents that are commercially available (e.g. agents that the subject of a marketing authorization in one or more territory, such as a European or US marketing authorization).

[0316] In alternative embodiments of the sixth and seventh aspects of the invention, the additional therapeutic agent is an agent for treating a disease or disorder the treatment of which is mediated by activation of the 02 adrenergic receptor, which diseases and disorders will include those described herein, and which agents will be readily identified by those skilled in the art and include, in particular, such therapeutic agents that are commercially available (e.g. agents that the subject of a marketing authorization in one or more territory, such as a European or US marketing authorization). Preparation of compounds / compositions

[0317] Pharmaceutical compositions / formulations, combination products and kits as described herein may be prepared in accordance with standard and / or accepted pharmaceutical practice.

[0318] Thus, in a further aspect of the invention there is provided a process for the preparation of a pharmaceutical composition / formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, with one or more pharmaceutically-acceptable adjuvant, diluent or carrier.

[0319] In further aspects of the invention, there is provided a process for the preparation of a combination product or kit-of-parts as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable salt thereof with the other therapeutic agent that is useful in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia (e.g. type 2 diabetes), and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.

[0320] As used herein, references to bringing into association will mean that the two components are rendered suitable for administration in conjunction with each other.

[0321] Thus, in relation to the process for the preparation of a kit of parts as hereinbefore defined, by bringing the two components "into association with" each other, we include that the two components of the kit of parts may be:

[0322] (i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or

[0323] (ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.

[0324] Compounds as defined in the first aspect of the invention (i.e. compounds of the invention) may be prepared in accordance with techniques that are well known to those skilled in the art, such as those described in the examples provided hereinafter.

[0325] For example, there is provided a process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R1represents H and the remaining substituents are as defined in the first aspect of the invention, which process comprises:

[0326] (i) reaction of a compound of formula II wherein ring A, R1, W, Z and n are as defined herein, and wherein M1represents a suitable metal or metal halide, with a compound of formula III wherein Q1to Q5(and, therefore ring Q) are as defined herein, under conditions known to those skilled in the art;

[0327] (ii) reaction of a compound of formula IV

[0328] Q2Q M2

[0329] QT Q!4Q5 wherein Q1to Q5are as defined herein, and wherein M2represents a suitable metal or metal halide, with a compound of formula V wherein ring A, R1, W, Z and n are as defined herein, under conditions known to those skilled in the art.

[0330] Compounds of formulae II, III, IV, V are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials (e.g. appropriately substituted benzaldehydes, styrenes or phenacyl bromides (or phenacylchloride, and the like) using appropriate reagents and reaction conditions. In this respect, the skilled person may refer to inter alia "Comprehensive Organic Synthesis" by B. M. Trost and I. Fleming, Pergamon Press, 1991. Further references that may be employed include "Science of Synthesis", Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

[0331] The substituents Y and Z, as hereinbefore defined, may be modified one or more times, after or during the processes described above for preparation of compounds of formula I by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, dehydrogenations, alkylations, dealkylations, acylations, hydrolyses, esterifications, etherifications, halogenations and nitrations. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence. The skilled person may also refer to "Comprehensive Organic Functional Group Transformations" by A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press, 1995 and / or "Comprehensive Organic Transformations" by R. C. Larock, Wiley-VCH, 1999.

[0332] Such compounds may be isolated from their reaction mixtures and, if necessary, purified using conventional techniques as known to those skilled in the art. Thus, processes for preparation of compounds of the invention as described herein may include, as a final step, isolation and optionally purification of the compound of the invention (e.g. isolation and optionally purification of the compound of formula I).

[0333] The skilled person will understand that compounds of formula I having specific stereochemistry may be provided by reacting suitable starting materials having the required stereochemistry in processes as described herein. Further, the skilled person will understand that suitable starting materials having the required stereochemistry may be prepared by analogy with the processes described herein.

[0334] It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups. The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.

[0335] Protecting groups may be applied and removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds / intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques. The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis. The use of protecting groups is fully described in "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1999).

[0336] Compounds as described herein (in particular, compounds as defined in the first and, therefore, second and third aspects of the invention) may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and / or have a better pharmacokinetic profile (e.g. higher oral bioavailability and / or lower clearance) than, and / or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise. In particular, such compounds may have the advantage that they are more efficacious and / or exhibit advantageous properties in vivo.

[0337] Without wishing to be bound by theory, compounds as described herein are thought to be potent agonists of the 02-adrenergic receptor, which allows for increased glucose uptake in skeletal muscle cells.

[0338] In addition, compounds as described herein are thought to be agonists of the 02- adrenergic receptor without (or with only a minimal effect in) inducing cAMP production. It is thought that this allows for effects such as the increased glucose uptake in skeletal muscle cells with lower levels of side effects than would result from other treatments. Further, combining compounds as described herein with other therapeutic agents, such as those that are able to decrease blood glucose levels, is thought to provide an effective combination therapy.

[0339] Examples

[0340] The present invention is illustrated by way of the following examples.

[0341] Chemicals and reagents were obtained from commercial suppliers and were used as received unless otherwise stated. All reactions involving moisture sensitive reagents were performed in oven or flame dried glassware under a positive pressure of nitrogen or argon.

[0342] Example compounds In the event that there is a discrepancy between nomenclature and the structure of compounds as depicted graphically, it is the latter that presides (unless contradicted by any experimental details that may be given and / or unless it is clear from the context).

[0343] Example l:tert-Butyl (R)-4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methyl- piperidine-l-carboxylate

[0344] A mixture of tert-butyl 4-amino-4-methylpiperidine-l-carboxylate (327 mg, 1.45 mmol), (R)-2-(3-fluorophenyl)oxirane (200 mg, 1.45 mmol,) and / PrOH (6 mL) was stirred at 80 °C for 18 h. The mixture was concentrated and the residue was purified by chromatography to give the title compound (267 mg, 52 %).

[0345] XH NMR (400 MHz, CDCI3) 6 7.29 (td, J = 8.0, 5.8 Hz, 1H), 7.13 - 7.06 (m, 2H), 6.95 (tdd, J = 8.6, 2.6, 1.0 Hz, 1H), 5.29 (s, 1H), 4.64 (dd, J = 8.6, 3.6 Hz, 1H), 3.48 - 3.33 (m, 4H), 2.89 (dd, J = 11.8, 3.6 Hz, 1H), 2.57 (dd, J = 11.8, 8.6 Hz, 1H), 1.55 - 1.46 (m, 4H), 1.45 (s, 9H), 1.11 (s, 3H).

[0346] [O] D20- 20.0 (c 1.10, MeOH).

[0347] Example 2:(R)-l-(4-((2-(3-Fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidin- 1 -yl)pentan-l-one

[0348] Pentanoyl chloride (15 pL, 0.12 mmol) was slowly added to a stirred mixture of (R)-l- (3-fluorophenyl)-2-((4-methylpiperidin-4-yl)amino)ethan-l-ol (30 mg, 0.12 mmol), EtsN (20 pL, 0.14 mmol) and CH2CI2 (3 mL) at 0 °C. The mixture was stirred at rt for 2 h. NaHCOs (aq, sat) and CH2CI2 were added. The mixture was stirred vigorously for 5 min and the layers were separated. The aq layer was extracted with CH2CI2 and the combined organics phases were washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by chromatography to give the title compound (31 mg, 78 %).

[0349] XH NMR (300 MHz, CD3OD) 5 7.35 (td, J = 7.9, 5.8 Hz, 1H), 7.23 - 7.11 (m, 2H), 6.99 (tdd, J = 8.3, 2.7, 1.1 Hz, 1H), 4.73 (dd, J = 7 A, 5.1 Hz, 1H), 3.74 - 3.52 (m, 2H), 3.51 - 3.36 (m, 2H), 2.85 - 2.69 (m, 2H), 2.44 - 2.30 (m, 2H), 1.70 - 1.46 (m, 6H), 1.44 - 1.30 (m, 2H), 1.19 (s, 3H), 0.94 (t, J = 7.3 Hz, 3H).

[0350] [O] D20-14.3 (c 0.96, MeOH).

[0351] Example 3:(R)-2-(4-((2-(3-Fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidin-

[0352] 1 -yl)-N,N-dimethylacetamide

[0353] (R)-l-(3-Fluorophenyl)-2-((4-methylpiperidin-4-yl)amino)ethan-l-ol and 2-bromo- / V, / V-dimethylacetamide were allowed to react according to the procedure in Example 2. After the chromatographic purification on silica gel, the crude product was dissolved in Et2O and HCI (4 M in dioxane) was added and the mixture was sonicated and the solids collected by centrifugation. The obtained material was dried and purified by preparative HPLC (Atlantis T3, 30x100 mm, 5 pm, 0.01 % AcOH H2O:MeCN = 95:5 to 5:95, 25 min gradient). The product was still not pure and was partitioned between NH3 (aq, 25 %) and EtOAc. The aq phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give the title compound.

[0354] XH NMR (400 MHz, CDCI3) 6 7.34 - 7.27 (m, 1H), 7.14 - 7.07 (m, 2H), 6.96 (tdd, J = 8.4, 2.6, 1.0 Hz, 1H), 4.60 (dd, J = 8.6, 3.7 Hz, 1H), 3.18 (s, 2H), 3.07 (s, 3H), 2.94 (s, 3H), 2.90 (dd, J = 11.9, 3.7 Hz, 1H), 2.57 - 2.46 (m, 5H), 1.59 (d, J = 5.5 Hz, 4H), 1.08 (s, 3H).

[0355] [O] D20-19.5 (c 0.77, MeOH) (for the HCI salt).

[0356] Example 4:(R)-2-(4-((2-(3-Fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidin- l-yl)-N-methylacetamide acetate

[0357] (R)-l-(3-Fluorophenyl)-2-((4-methylpiperidin-4-yl)amino)ethan-l-ol and 2-bromo- / V- methylacetamide were allowed to react according to the procedure in Example 2. Purification was achieved by chromatography on silica gel, elution with CH2Cl2 / / PrOH / NH4OH = 90: 10: 1 to 80:20: 1, followed by preparative HPLC (Atlantis T3, 10x100 mm, 5 pm, 0.1 % AcOH in H2O: MeCN = 99 : 1 to 10:90, 25 min gradient). The relevant fractions were pooled and concentrated to give the title compound.

[0358] XH NMR (400 MHz, CD3OD) 5 7.40 (td, J = 8.0, 5.8 Hz, 1H), 7.27 - 7.18 (m, 2H), 7.08

[0359] - 7.01 (m, 1H), 4.89 (d, J = 3.2 Hz, 1H, overlapping with H2O), 3.09 (dd, J = 12.1, 3.3 Hz, 1H), 3.05 (s, 2H), 2.95 (dd, J = 12.1, 10.0 Hz, 1H), 2.77 (s, 3H), 2.76 - 2.69 (m, 2H), 2.41 (td, J = 11.7, 3.2 Hz, 2H), 1.93 (s, 3H), 1.93 - 1.85 (m, 2H), 1.81 - 1.70 (m, 2H), 1.32 (s, 3H).

[0360] [O] D20-17.6 (c 0.63, MeOH).

[0361] Example 5:(R)-2-(4-((2-(3-Fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidin- 1 -yl)acetamide acetate .AcOH

[0362] (R)-l-(3-Fluorophenyl)-2-((4-methylpiperidin-4-yl)amino)ethan-l-ol and 2-bromo- acetamide were allowed to react according to the procedure in Example 2. Purification was achieved by preparative HPLC (Atlantis T3, 10x100 mm, 5 pm, 0.1 % AcOH in H2O: MeCN = 100 :0 to 60 :40, 20 min gradient)). The relevant fractions were pooled and concentrated to give the title compound.

[0363] XH NMR (400 MHz, CD3OD) 6 7.41 (td, J = 8.0, 5.8 Hz, 1H), 7.30 - 7.20 (m, 2H), 7.10

[0364] - 7.03 (m, 1H), 4.91 (dd, J = 10.1, 3.2 Hz, 1H), 3.16 (dd, J = 12.3, 3.2 Hz, 1H), 3.08 (s, 2H), 3.01 (dd, J = 12.3, 10.1 Hz, 1H), 2.88 - 2.79 (m, 2H), 2.43 (td, J = 11.8, 2.9 Hz, 2H), 2.00 - 1.90 (m, 2H), 1.96 (s, 3H), 1.86 - 1.75 (m, 2H), 1.37 (s, 3H).

[0365] [O] D20- 27.6 (c 0.39, MeOH).

[0366] Example 6:(R)-N-(l-(4-((2-(3-Fluorophenyl)-2-hydroxyethyl)amino)-4-methyl- piperidin-l-yl)-2-methylpropan-2-yl)acetamide

[0367] (a) / V-(2-Methyl-l-oxopropan-2-yl)acetamide

[0368] AC2O (0.4 mL, 4.28 mmol) was added dropwise to an ice-cooled solution of 2-amino- 2-methylpropan-l-ol (0.4 mL, 4.19 mmol) in CH2CI2 (10 mL). The mixture was stirred at rt overnight and concentrated. The residue was purified by chromatography to give / V-(l-hydroxy-2-methylpropan-2-yl)acetamide that was dissolved in CH2CI2 (10 mL) and cooled in an ice-bath. Dess-Martin periodinane (2.67 g, 6.29 mmol) was added in one portion followed by NaHCOs (704 mg, 8.38 mmol) and the stirred mixture was slowly allowed to reach rt over 20 h. NaHCOs (aq, sat, 3 mL) and Na2S20s (aq, sat, 3 mL) were added and the mixture was stirred vigorously for 30 min and extracted with CH2CI2. The combined extracts were dried over Na2SC>4 and concentrated. The residue was recrystallized twice from hexane / EtOAc to give the sub-title compound (178 mg, 33 %).

[0369] (b) tert-Butyl (l-(2-acetamido-2-methylpropyl)-4-methylpiperidin-4-yl)carbamate tert-Butyl (4-methylpiperidin-4-yl)carbamate (443 mg, 2.07 mmol) followed by diisopropylethylamine (0.48 mL, 2.76 mmol) were added to a stirred mixture of / V-(2- methyl-l-oxopropan-2-yl)acetamide (178 mg, 1.38 mmol) and 1,2-dichloroethane (14 mL) at rt. The mixture was stirred at rt for 4 h and NaBH(OAc)3 (876 mg, 4.13 mmol) was added in one portion and the mixture was stirred at rt for 72 h and concentrated. NaHCOs (aq, sat) was added to the residue and the mixture was extracted with CH2CI2. The combined extracts were washed with brine, dried over Na2SC>4 and concentrated and the residue was purified by chromatography to give the sub-title compound (177 mg, 39 %).

[0370] (c) / V-(l-(4-Amino-4-methylpiperidin-l-yl)-2-methylpropan-2-yl)acetamide dihydrochloride .2HCI

[0371] HCI (5 M in / PrOH, 1.83 mL, 9.16 mmol) was added to a stirred solution of tert-butyl (l-(2-acetamido-2-methylpropyl)-4-methylpiperidin-4-yl)carbamate (150 mg, 0.46 mmol) in MeOH (5 mL) at rt. The mixture was stirred overnight and another portion of HCI (5 M in / PrOH, 1.83 mL, 9.16 mmol) was added. After 72 h the mixture was concentrated to give the sub-title compound (136 mg, 99 %) which was used in the following step without further purification.

[0372] (d) (R)-2-Bromo-l-(3-fluorophenyl)ethan-l-ol

[0373] Borane dimethyl sulfide complex (1.75 mL, 18.4 mmol) was added dropwise to a mixture of (R)-2-methyl-CBS-oxazaborolidine (1 M in toluene, 4.60 mL, 4.60 mmol) and tetra hydrofuran (THF; 20 mL) at rt. The mixture was stirred 15 min at rt and a solution of 3-fluorophenacyl bromide (5.00 g, 23.04 mmol) in THF (50 mL) was added dropwise over 30 min and the mixture was stirred at rt for 40 min. MeOH (80 mL) was slowly added and the mixture was stirred for 30 min and concentrated. Purification by chromatography gave the sub-title compound (4.60 g, 91 %, 98 % ee).

[0374] (e) (R)- / V-(l-(4-((2-(3-Fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidin-l- yl)-2-methylpropan-2-yl)acetamide KOH (flakes, 47 mg, 0.85 mmol) was added to a stirred mixture of (7 )-2-bromo-l-(3- fluorophenyl)ethan-l-ol (60 mg, 0.27 mmol), / V-(l-(4-amino-4-methylpiperidin-l-yl)- 2-methylpropan-2-yl)acetamide dihydrochloride (132 mg, 0.44 mmol) and / PrOH (0.63 mL, 8.22 mmol) at rt. The mixture was stirred at 80 °C for 10 h and allowed to reach rt. H2O (2 mL) and CH2CI2 (5 mL) were added and the mixture was vigorously stirred for 5 min. The layers separated and aq phase was extracted with CH2CI2. The combined organic phases were washed with brine and dried over Na2SO4 and concentrated. The residue was purified by chromatography on silica gel followed by preparative HPLC (Chiralpak IE, 20 % / PrOH, 80 % heptane, 0.1 % EtsN), giving the title compound (17 mg, 17%).

[0375] XH NMR (400 MHz, CDCI3) 6 7.30 (td, J = 8.0, 5.8 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.95 (tdd, J = 8.4, 2.6, 1.1 Hz, 1H), 5.91 (s, 1H), 4.60 (dd, J = 8.4, 3.6 Hz, 1H), 2.87 (dd, J = 11.8, 3.6 Hz, 1H), 2.62 - 2.45 (m, 5H), 2.43 (s, 2H), 1.91 (s, 3H), 1.59 - 1.46 (m, 4H), 1.30 (s, 6H), 1.07 (s, 3H).

[0376] [Q] D20-38.2 (c 1.50, CDCI3).

[0377] Example 7: 2-( ( trans)-3-( ((R)-2-(3-Fluorophenyl)-2-hydroxyethyl)amino)- cyclobutyl)acetonitrile

[0378] (a) tert-Butyl (trans)-3-(hydroxymethyl)cyclobutyl)carbamate

[0379] Borane dimethyl sulfide complex (2.19 mL, 23.04 mmol) was added dropwise to an ice-cooled solution of trans-3-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid (1.60 g, 7.43 mmol) in THF (160 mL). The cooling bath was removed, and the mixture was stirred at rt for 3 h. MeOH (5 mL) was added, and the mixture was concentrated. MeOH (10 mL) was added to the residue and the mixture was concentrated. This procedure was repeated two more times. NaHCOs (aq, sat, 10 mL) and NH3 (aq, sat, 0.5 mL) were added and the mixture was vigorously stirred for 5 min. EtOAc was added and the vigorous stirring was continued for 15 min. The layers were separated and the aq phase was extracted with EtOAc. The combined organic phases were washed with H2O and brine, dried over Na?SO4 and concentrated. The residue was purified by chromatography to give the sub-title compound (1.43 g, 95 %).

[0380] (b) trans-3-((tert-Butoxycarbonyl)amino)cyclobutyl)methyl methanesulfonate

[0381] Methanesulfonyl chloride (0.62 mL, 8.00 mmol) was added dropwise to a stirred ice- cooled mixture of tert-butyl (trans)-3-(hydroxymethyl)cyclobutyl)carbamate (1.40 g, 6.96 mmol), EtsN (1.26 mL, 9.04 mmol) and CH2CI2 (53 mL). The mixture was stirred at 0 °C for 2 h and H2O was added. The layers were separated and the aq phase was extracted with CH2CI2. The combined organic phases were washed with H2O, brine, dried over Na2SC>4 and concentrated. The residue was purified by chromatography to give the sub-title compound (1.71 g, 88 %).

[0382] (c) tert-Butyl ((trans)-3-(cyanomethyl)cyclobutyl)carbamate

[0383] NaCN (895 mg, 18.26 mmol) was added to a solution of trans-3- tert- butoxycarbonyl)amino)cyclobutyl)methyl methanesulfonate (1.70 g, 6.09 mmol) in DMSO (17 mL). The mixture was stirred at 90 °C for 4 h and cooled to rt. The mixture was partitioned between EtOAc and brine and the layers were separated and aq layer extracted with EtOAc. The combined extracts were washed with brine, dried over Na?SO4 and concentrated. The residue was purified by chromatography to give the sub-title compound (1.12 g, 87 %).

[0384] (d) 2-((trans)-3-Aminocyclobutyl)acetonitrile hydrochloride .HCI HCI (2 M in Et?O, 29.7 mL, 59.44 mmol) was added to a solution of tert-butyl ((trans)- 3-(cyanomethyl)cyclobutyl)carbamate (250 mg, 1.19 mmol) in Et?O (5 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min and at rt for 16 h and concentrated to give the sub-title compound (173 mg, 99 %).

[0385] (e) (R)-2-Bromo-l-(3-fluorophenyl)ethan-l-ol atg 12012

[0386] Borane dimethyl sulfide complex (1.75 mL, 18.4 mmol) was added dropwise to a mixture of (R)-2-methyl-CBS-oxazaborolidine (1 M in toluene, 4.60 mL, 4.60 mmol) and tetra hydrofuran (THF; 20 mL) at rt. The mixture was stirred 15 min at rt and a solution of 3-fluorophenacyl bromide (5.00 g, 23.04 mmol) in THF (50 mL) was added dropwise over 30 min and the mixture was stirred at rt for 40 min. MeOH (80 mL) was slowly added and the mixture was stirred for 30 min and concentrated. Purification by chromatography gave the sub-title compound (4.60 g, 91 %, 98 % ee).

[0387] (f) 2-((trans)-3-(((R)-2-(3-Fluorophenyl)-2-hydroxyethyl)amino)cyclobutyl)- acetonitrile

[0388] KOH (134 mg, 2.06 mmol) was added to a stirred mixture of (R)-2-bromo-l-(3- fluorophenyl)ethan-l-ol (215 mg, 0.98 mmol), 2-((trans)-3-aminocyclobutyl)aceto- nitrile hydrochloride (173 mg, 1.18 mmol) and / PrOH (2.3 mL, 8.22 mmol) at rt. The mixture was stirred at 80 °C for 18 h and concentrated. The residue was purified by chromatography on silica gel followed by preparative HPLC (Chiralpak IE, 0.1 % ethanolamine in 5 % / PrOH, 30 % CH2CI2 and 65 % heptane). The relevant fractions were pooled and concentrated. The residue was dissolved in CH2CI2, washed with H2O, dried over Na2SO4 and concentrated to give the title compound (71 mg, 29 %).

[0389] XH NMR (400 MHz, CDCI3) 6 7.34 - 7.27 (m, 1H), 7.15 - 7.05 (m, 2H), 7.02 - 6.89 (m, 1H), 4.67 (dd, J = 8.7, 3.7 Hz, 1H), 3.52 - 3.44 (m, 1H), 2.83 (dd, J = 12.3, 3.7 Hz, 1H), 2.69 - 2.57 (m, 2H), 2.48 (d, J = 7.2 Hz, 2H), 2.27 - 1.87 (m, 5H).

[0390] [Q] D20- 39.1 (c 0.59, CHCI3). Example 8: Methyl 2-( ( trans)-3-( ((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)- cyclobutyl)acetate

[0391] AcCI (223 pL, 3.14 mmol) was added dropwise to MeOH (0.52 mL) at 0 °C. The solution was stirred at 0 °C for 5 min. 2-((trans)-3-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)- amino)cyclobutyl)acetonitrile (26 mg, 0.11 mmol) was added and the mixture was warmed to rt and stirred for 18 h and concentrated. The residue was purified by chromatography to give the title compound (23 mg, 78 %).

[0392] XH NMR (400 MHz, CDCI3) 6 7.33 - 7.27 (m, 1H), 7.14 - 7.07 (m, 2H), 6.99 - 6.90 (m, 1H), 4.67 (dd, J = 8.8, 3.7 Hz, 1H), 3.66 (s, 3H), 3.46 - 3.36 (m, 1H), 2.83 (dd, J = 12.2, 3.6 Hz, 1H), 2.70 - 2.55 (m, 2H), 2.48 (d, J = 8.0 Hz, 2H), 2.14 (d, J = 36.8 Hz, 2H), 2.03 - 1.94 (m, 4H).

[0393] [Q] D20-31.1 (c 0.32, CHCI3);

[0394] Example 9: 2-( ( trans)-3-( ((R)-2-(3-Fluorophenyl)-2-hydroxyethyl)amino)- cyclobutyl)acetic acid

[0395] LiOH monohydrate (9 mg, 0.373 mmol) was added to a solution of methyl 2- trans)- 3-(((7<)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclobutyl)acetate (21 mg, 0.075 mmol) in THF / H2O (1 : 1, 5 mL) at rt. The solution was stirred at rt for 18 h and AcOH (1 mL) was added. The mixture was stirred for 15 min at rt, filtered through a syringe filter (PTFE, 0.2 pm) and concentrated. The residue was purified by reversed phase chromatography (Biotage®SNAP KP-C18-HS, 60 g, ZEOprep 60 / 40-63 pm, gradient from 0.1 % AcOH in H2O to 100% MeCN. The relevant fractions were pooled and concentrated to give the title product (12 mg, 60 %).

[0396] XH NMR (400 MHz, CD3OD) 6 7.45 - 7.36 (m, 1H), 7.26 - 7.18 (m, 2H), 7.08 - 7.01 (m, 1H), 4.93 (dd, J = 10.0, 3.3 Hz, 1H), 3.88 - 3.76 (m, 1H), 3.08 (dd, J = 12.7, 3.3 Hz, 1H), 3.00 - 2.89 (m, 1H), 2.79 - 2.67 (m, 1H), 2.46 - 2.28 (m, 4H), 2.22 - 2.11 (m, 2H).

[0397] [Q] D20-29.4 (c 0.32, MeOH). Example 10: Methyl (trans)-3-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)- cyclobu tane-l-carb oxy la te

[0398] The title compound was prepared from (R)-2-bromo-l-(3-fluorophenyl)ethan-l-ol (see

[0399] Example 7, Step (e)) and methyl (trans)-3-aminocyclobutane-l-carboxylate hydrochloride in accordance with the procedure in Example 7, Step (f).

[0400] XH NMR (400 MHz, CDCI3) 5 7.33 - 7.27 (m, 1H), 7.13 - 7.07 (m, 2H), 6.99 - 6.92 (m, 1H), 4.71 (dd, J = 8.8, 3.6 Hz, 1H), 3.70 (s, 3H), 3.64 - 3.51 (m, 1H), 3.12 -

[0401] 3.02 (m, 1H), 2.85 (dd, J = 12.3, 3.6 Hz, 1H), 2.66 - 2.59 (m, 1H), 2.55 - 2.46 (m,

[0402] 4H), 2.14 - 2.00 (m, 2H).

[0403] [O] D20-31.9 (c 0.43, CHCI3).

[0404] Example 11: Methyl (cis)-3-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)- cyclobu tane-l-carb oxy la te

[0405] The title compound was prepared from (R)-2-bromo-l-(3-fluorophenyl)ethan-l-ol (see Example 7, Step (e)) and methyl (cis)-3-aminocyclobutane-l-carboxylate hydrochloride in accordance with the procedure in Example 7, Step (f).

[0406] XH NMR (400 MHz, CDCI3) 6 7.33-7.26 (m, 1H), 7.14 - 7.06 (m, 1H), 6.99-6.92 (m, 1H), 4.65 (dd, J = 8.8, 3.6 Hz, 1H), 3.67 (s, 3H), 3.29-3.18 (m, 1H), 2.86 (dd, J = 12.2, 3.6 Hz, 1H), 2.77 (tt, J = 9.5, 8.0 Hz, 1H), 2.61 (dd, J = 12.3, 8.7 Hz, 1H), 2.56 - 2.44 (m, 2H), 2.05 - 1.89 (m, 2H).

[0407] [O] D20-40.8 (c 1.00, CHCI3).

[0408] Example 12: (lR)-2-( (l-( tert-Butylsulfinyl)-4-methylpiperidin-4-yl)amino)-l- (3-fluorophenyl)ethan-l-ol

[0409] (a) tert- Butyl (R)-4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methyl- piperidine-l-carboxylate

[0410] The sub-title compound was prepared from (R)-2-(3-fluorophenyl)oxirane and tertbutyl 4-amino-4-methylpiperidine-l-carboxylate in accordance with the procedures in Example 1, Step (a).

[0411] (b) (R)-l-(3-Fluorophenyl)-2-((4-methylpiperidin-4-yl)amino)ethan-l-ol

[0412] HCI (aq, 4 M, 3.1 mL) was added to a solution of tert-butyl tert-butyl (R)-4-((2-(3- fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidine-l-carboxylate (136 mg, 0.39 mmol) in MeOH at rt. The mixture was stirred at rt overnight and another portion of HCI (aq, 4 M, 3.1 mL) was added. The mixture was stirred at rt for 14 and concentrated. The residue was partitioned between H2O and CH2CI2 and the pH was adjusted to 12 by addition of NaOH (s). The layers were separated and the aq phase was extracted with CH2CI2 and the combined extracts were washed with brine, dried over Na2SC>4 and concentrated to give the sub-title compound (95 mg, 98 %) that was used in the following step without any further purification.

[0413] (c) (lR)-2-((l-(tert-Butylsulfinyl)-4-methylpiperidin-4-yl)amino)-l-(3-fluoro- phenyl)ethan-l-ol tert-Butylsulfinyl chloride (25.8 pL, 0.208 mmol) was added slowly to a solution of (R)- l-(3-fluorophenyl)-2-((4-methylpiperidin-4-yl)amino)ethan-l-ol (50 mg, 0.198 mmol) and EtsN (33.1 pL, 0.238 mmol) in CH2CI2 (2 mL) at -5 °C. The mixture was stirred at rt for 2 h and NaHCOs (aq, sat) was added. The mixture was extracted with CH2CI2 and the combined extracts were washed with brine and dried over Na2SC>4. The residue was purified by preparative HPLC (Atlantis T3, 30x100 mm, 5 pm, 0.1 % AcOH in FhCH MeCN = 100:0 to 60 :40, 20 min gradient). The relevant fractions were lyophilized to give the title compound (6 mg, 8 %).

[0414] XH NMR (300 MHz, CD3OD) 6 7.43 - 7.32 (m, 1H), 7.28 - 7.15 (m, 2H), 7.07 - 6.97 (m, 1H), 4.85 - 4.82 (m, 1H), 3.45 - 3.32 (m, 2H), 3.17 - 2.94 (m, 3H), 2.94 - 2.81 (m, 1H), 1.84 - 1.65 (m, 4H), 1.30 (s, 3H), 1.18 (s, 9H).

[0415] Example 13: tert-Butyl (R)-3-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-3-methyl- azetidine-1 -carboxylate

[0416] A mixture of (R)-2-(3-fluorophenyl)oxirane (189 mg, 1.37 mmol, 95% ee), tert-butyl 3-amino-3-methylazetidine-l-carboxylate (331 mg, 1.78 mmol) and / PrOH (0.4 mL) was stirred at 80 °C for 16 h in a sealed vial. The mixture was concentrated and the residue purified by chromatography to give the title compound (200 mg, 45 %).

[0417] XH NMR (400 MHz, CDCI3) 6 7.39 - 7.26 (m, 1H), 7.18 - 7.03 (m, 2H), 7.02 - 6.87 (m, 1H), 4.68 (dd, J = 8.5, 3.5 Hz, 1H), 4.0-3.1 (br s, 1H), 3.74 (dd, J = 8.7, 4.2 Hz, 2H), 3.68 - 3.59 (m, 2H), 2.96 - 2.81 (m, 1H), 2.70 - 2.57 (m, 1H), 2.0-1.5 (br s, 1H), 1.43 (s, 9H), 1.39 (s, 3H).

[0418] [a]D20= -40.0 (c 1.00, CHCI3).

[0419] Example 14: tert-Butyl (R)-3-((2-(3-amino-2,4-difluorophenyl)-2-hydroxyethyl)- amino)-3-methylazetidine-l -carboxylate

[0420] (a) / V-(2,6-Difluorophenyl)acetamide

[0421] Acetic anhydride (8.0 mL, 85.2 mmol) was added to an ice-cooled solution of 2,6-difluoroaniline (10.0 g, 77.46 mmol) in toluene (56 mL). The mixture was stirred at rt for 16 h and at 0 °C for 1 h. The white precipitate was collected, washed with cold toluene, and dried to give the sub-title compound (12.9 g, 97 %).

[0422] (b) / V-(3-Bromo-2,6-difluorophenyl)acetamide

[0423] / V-Bromosuccinimide (13.1 g, 73.6 mmol) was added in portions over 50 min to an ice- cooled solution of / V-(2,6-difluorophenyl)acetamide (12.6 g, 73.6 mmol) in H2SO4 (cone, 145 mL). The mixture was stirred at 0 °C for 3 h and at rt for 16 h. Crushed ice and H2O were added, and the mixture was cooled in an ice-bath and stirred for 10 min. The precipitate was collected, washed with H2O, and dried to give the sub-title compound (17.48 g, 95 %).

[0424] (c) / V-(3-(l -Butoxyvinyl) -2,6-difluorophenyl)acetam ide A mixture of dioxane (82 mL) and H2O (42 mL) was degassed (5 vacuum-ultrasound- argon cycles). A pressure tube was charged with / V-(3-bromo-2,6- difluorophenyl)acetamide (6.0 g, 24.0 mmol), Pd(OAc)2 (323 mg, 1.43 mmol) and l,l'-bis(diphenylphosphino)ferrocene (2.39 g, 4.31 mmol) and purged with Ar for 10 min. The degassed dioxane / water mixture (120 mL) was added followed by butyl vinyl ether (12.4 mL, 96.0 mmol) and diisopropylethylamine (8.3 mL, 48.0 mmol). The pressure tube was sealed, and the mixture was stirred at 100 °C for 18 h. The mixture was cooled to rt and diluted with Et2<D and H2O. The layers were separated, and the aq phase was extracted with Et20. The combined extracts were dried over Na2SC>4 and concentrated. The residue was dissolved in CH2CI2 and filtered through a pad of silica gel, which was washed with hexanes followed by hexanes / Et2O 1: 1. The fractions containing the desired product were concentrated to give the sub-title compound (5.8 g, 90 %).

[0425] (d) / V-(3-(2-Chloroacetyl)-2,6-difluorophenyl)acetamide

[0426] / V-Chlorosuccinimide (5.24 g, 39.2 mmol) was added to / V-(3-(l-butoxyvinyl)-2,6- difluorophenyl)acetamide (8.80 g, 32.7 mmol) in THF (132 mL) and water (28 mL) at rt. The mixture was stirred for 2 h. Et2<D was added, and the organic phase was washed with H2O, dried over Na2SC>4, and concentrated. The residue was dissolved in CH2CI2, washed with H2O, dried over Na2SC>4 and concentrated to give the sub-title compound (8.0 g, 99 %), that was used in next step without further purification.

[0427] (e) (R)- / V-(3-(2-Chloro-l-hydroxyethyl)-2,6-difluorophenyl)acetamide

[0428] RuCI(p-cymene)[(S,S)-Ts-DPEN] (144 mg, 0.23 mmol) followed by HCOOH / EtsN (2.15 / 1,24 mL) were added to a solution of / V-(3-(2-chloroacetyl)-2,6- difluorophenyl)acetamide (8.0 g, 32.3 mmol) in DMF (75 mL) at rt. The mixture was stirred at rt for 1 h, diluted with CH2CI2 , washed with H2O and Na2COs (aq, sat), dried over Na?SO4 and concentrated. The residue was dissolved in Et?O and filtered through silica gel, which was eluted with Et?O. The fractions containing the desired product were concentrated. CH2CI2 was added to the residue and the mixture was sonicated for 2 min. The solids were collected, washed with CH2CI2 and dried to give the sub-title compound (6.5 g, 81 %).

[0429] XH NMR (400 MHz, CD3OD) 6 7.49 (td, J = 8.3, 5.9 Hz, 1H), 7.06 (td, J = 9.0, 1.7 Hz, 1H), 5.11 (dd, J = 7.2, 4.3 Hz, 1H), 3.75 (dd, J = 11.3, 4.4 Hz, 1H), 3.66 (dd, J = 11.3, 7.2 Hz, 1H), 2.17 (s, 3H) ppm.

[0430] Chiral HPLC analysis: Chiralpack IH (4.6mmx250mm, 5pm) column, eluent 5% IPA, 15% DCM, 80% Heptane; flow rate 1.0 mL / min. Wavelenght 254 nm, tR=27.403 min ((R)-isomer, 99.4%), tR=29.925 min ((S)-isomer, 0.6%). ee 98%.

[0431] [O] D20= -37.5 (c 0.8, MeOH).

[0432] (f) ((R)- / V-(2,6-Difluoro-3-(oxiran-2-yl)phenyl)acetamide

[0433] NaOH (aq, 4 M. 0.396 mL, 1.54 mmol) was added to a suspension of (R)- / V-(3-(2- chloro-l-hydroxyethyl)-2,6-difluorophenyl)acetamide (350 mg, 1.40 mmol) in / PrOH (1.5 mL) and the mixture was stirred at rt for 1 h. EtOAc and H2O were added and the layers were separated. The aq phase was extracted with EtOAc and the combined extracts were washed with H2O and brine, dried over Na2SO4 and concentrated to give the sub-title compound (273 mg, 91 %) that was used in next step without further purification.

[0434] (g) tert- Butyl (R)-3-((2-(3-acetamido-2,4-difluorophenyl)-2-hydroxyethyl)amino)-3- methylazetidine-l-ca rboxylate

[0435] A mixture of ((R)- / V-(2,6-difluoro-3-(oxiran-2-yl)phenyl)acetamide (273 mg, 1.28 mmol), tert-butyl 3-amino-3-methylazetidine-l-carboxylate (310 mg, 1.66 mmol) and / PrOH (0.8 mL) was heated in a sealed vial at 80 °C for 18 h. The mixture was cooled to rt and concentrated. The residue was purified by chromatography to give the subtitle compound (300 mg, 59 %).

[0436] (h) tert-Butyl (R)-3-((2-(3-amino-2,4-difluorophenyl)-2-hydroxyethyl)amino)-3- methylazetidine-l-ca rboxylate

[0437] NaOH (aq, 4 M, 131 pL, 0.53 mmol) was added to a solution of tert-butyl (R)-3-((2- (3-acetamido-2,4-difluorophenyl)-2-hydroxyethyl)amino)-3-methylazetidine-l- carboxylate (30 mg, 0.075 mmol) in EtOH (0.5 mL) in a pressure vial. The vial was sealed, and the mixture was stirred at 70 °C for 16 h, cooled to rt and concentrated. The residue was partitioned between CH2CI2 and H2O. The aq phase was extracted with CH2CI2 and the combined organic phases were dried over Na2SC>4 and concentrated. The residue was purified by chromatography to give the title compound (12 mg, 45 %).

[0438] 1H NMR (400 MHz, CDCI3) 6 6.90 - 6.74 (m, 2H), 4.95 (dd, J = 8.4, 3.4 Hz, 1H), 3.82 - 3.62 (m, 4H), 3.02 - 2.82 (m, 1H), 2.67 (dd, J = 12.0, 8.4 Hz, 1H), 2.2 - 1.7 (br s, 4H), 1.43 (s, 9H), 1.41 (s, 3H).

[0439] [a]D20= -41.3 (c 1.00, CHCI3).

[0440] Example 15: (R)-l-(4-((2-(3-Amino-2,4-difluorophenyl)-2-hydroxyethyl)amino)-4- methylpiperidin-1 -yl)pentan-l -one dihydrochloride

[0441] (a) tert-Butyl (R)-4-((2-(3-acetamido-2,4-difluorophenyl)-2-hydroxyethyl)amino)- 4-methylpiperidine-l-ca rboxylate

[0442] (R)- / V-(3-(2-Chloro-l-hydroxyethyl)-2,6-difluorophenyl)acetamide (Example 14, step (e), 397 mg, 1.59 mmol) followed by NaOH (60.6 mg, 1.52 mmol) were added to a solution of 4-amino-4-methyl-piperidine-l-carboxylic acid tert-butyl ester (325 mg, 1.52 mmol) in / PrOH (0.46 mL, 6.07 mmol) in a vial. The vial was sealed, and the mixture was stirred at 80 °C for 18 h and cooled to rt. CH2CI2 and H2O were added and the aq phase was extracted with EtOAc. The combined organic phases were washed with H2O and brine, dried over Na2SC>4 and concentrated. The residue was purified by chromatography to give the sub-title compound (324 mg, 50 %).

[0443] (b) (R)- / V-(2,6-Difluoro-3-(l-hydroxy-2-((4-methylpiperidin-4- yl)amino)ethyl)phenyl)acetamide dihydrochloride

[0444] HCI (4 M in dioxane, 5.68 mL, 22.7 mmol) was added to tert-butyl (R)-4-((2-(3- acetamido-2,4-difluorophenyl)-2-hydroxyethyl)amino)-4-methyl piperidine- 1- carboxylate (324 mg, 0.757 mmol) in dioxane (0.8 mL) at 0 °C. The mixture was stirred at rt for 18 h and concentrated to give the sub-title compound (302 mg, 99 %) that was used in next step without further purification.

[0445] (c) (R)- / V-(2,6-Difluoro-3-(l-hydroxy-2-((4-methyl-l-pentanoylpiperidin-4- yl)amino)ethyl)phenyl)acetamide

[0446] THF (3.1 mL), EtsN (0.86 mL, 0.619 mmol) and valeryl chloride (25.2 mg, 0.209 mmol) were added to a solution of (R)- / V-(2,6-difluoro-3-(l-hydroxy-2-((4-methylpiperidin- 4-yl)amino)ethyl)phenyl) acetamide dihydrochloride (80 mg, 0.199 mmol) in CH2CI2 (5.8 mL) at -5 °C. The mixture was stirred at 0 °C for 1 h, and at rt for 1 h, and then concentrated. The residue was purified by chromatography to give the sub-title compound (56 mg, 68 %).

[0447] (d) (R)-l-(4-((2-(3-Amino-2,4-difluorophenyl)-2-hydroxyethyl)amino)-4-methyl- piperidin-l-yl)pentan-l-one dihydrochloride

[0448] A mixture of (R)-l-(4-((2-(3-amino-2,4-difluorophenyl)-2-hydroxyethyl)amino)-4- methylpiperidin-l-yl)pentan-l-one dihydrochloride (50 mg, 1.121 mmol), EtOH (1.0 mL) and NaOH (aq, 4 M, 0.151 mL, 0.607 mmol) was stirred at 75 °C for 48 h in a sealed vial. The mixture was concentrated and HCI (4 N, 0.1 mL) was added to pH~4. The mixture was purified by reverse phase chromatography (Biotage® Sfar C18 D - Duo 100 A 30 pm 12 g, HCI (aq 0.1 %) / MeCN (gradient 0-50% MeCN) to give the title compound (23 mg, 43 %).

[0449] XH NMR (400 MHz, CD3OD) 6 7.67 (q, J = 8.4 Hz, 1H), 7.28 (t, J = 10.0 Hz, 1H), 5.32 (d, J = 8.8 Hz, 1H), 4.53 (d, J = 13.4 Hz, 1H), 4.03 (d, J = 13.1 Hz, 1H), 3.34 (s, 1H), 3.17 (t, J = 11.3 Hz, 1H), 2.87 (t, J = 12.5 Hz, 1H), 2.45 (t, J = 7.6 Hz, 2H), 1.89 (d, J = 70.2 Hz, 4H), 1.56 (d, J = 18.7 Hz, 5H), 1.46 - 1.31 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H).

[0450] [Q] D25= 2.6 (c 0.390, MeOH).

[0451] Example 16: tert-Butyl (R)-4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)piperidine- 1 -carboxylate tert-Butyl 4-aminopiperidine-l-carboxylate (219 mg, 1.10 mmol) and NaOH (22 mg, 0.55 mmol) were added to (R)-2-bromo-l-(3-fluorophenyl)ethan-l-ol (120 mg, 0.55 mmol) and / PrOH (1.3 mL) and the mixture was stirred at 80 °C for 18 h in a sealed vial. The mixture was a cooled to rt and concentrated. The material was combined with another batch similarly prepared from (R)-2-bromo-l-(3-fluorophenyl)ethan-l-ol (160 mg, 0.73 mmol) and purified by chromatography to give the title compound (132 mg, 31 %).

[0452] XH NMR (400 MHz, CD3OD) 6 7.38 - 7.31 (m, 1H), 7.20 - 7.10 (m, 2H), 7.04 - 6.93 (m, 1H), 4.76 (dd, J = 9.2, 3.7 Hz, 1H), 4.11 - 3.97 (m, 2H), 2.96 - 2.62 (m, 5H), 1.95 - 1.81 (m, 2H), 1.45 (s, 9H), 1.30 - 1.18 (m, 2H).

[0453] Example 17: (R)-l-(4-((2-(3-Fluorophenyl)-2-hydroxyethyl)amino)piperidin-l- yl)pentan-l-one

[0454] (a) (R)-l-(3-Fluorophenyl)-2-(piperidin-4-ylamino)ethan-l-ol dihydrochloride

[0455] HCI (4 M in dioxane, 1.5 mL, 6.1 mmol) was added at rt to a solution of tert-butyl (R)- 4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino) pi peridi ne-1 -carboxylate (Example 16) (103 mg, 0.30 mmol) in 2 mL dioxane. The mixture was stirred for 30 min at rt, sonicated for 1 h and concentrated. Et?O (4 mL) was added to the residue and the mixture was stirred until a suspension was formed. The solvent was decanted off and the Et?O washing was repeated two more times. The solid was dried to give the subtitle compound (90 mg, 95 %).

[0456] (b) (R)-l-(4-((2-(3-Fluorophenyl)-2-hydroxyethyl)amino)piperidin-l-yl)pentan-lone EtsN (72 pL, 0.51 mmol) was added dropwise at 0 °C, followed by a solution of valeryl chloride (16 pL, 0.14 mmol) in CH2CI2 (1 mL) to a stirred mixture of (R)-l-(3- fluorophenyl)-2-(piperidin-4-ylamino)ethan-l-ol dihydrochloride (40 mg, 0.13 mg) in CH2CI2 (1 mL). The mixture was stirred at rt for 40 min and diluted CH2CI2. The mixture was washed with H2O and brine, dried over Na2SC>4 and concentrated. The residue was and purified by chromatography to give the title compound (17 mg, 41 %).

[0457] XH NMR (400 MHz, CDCI3) 6 7.27-7.20 (m, 1H), 7.09 - 6.99 (m, 2H), 6.93-6.85 (m, 1H), 4.62-4.55 (m, 1H), 4.47-4.38 (m, 1H), 3.82 - 3.68 (m, 1H), 3.05 - 2.86 (m, 2H), 2.71 - 2.53 (m, 3H), 2.25 (dd, J = 8.7, 6.7 Hz, 2H), 1.93 - 1.74 (m, 2H), 1.59 - 1.47 (m, 2H), 1.36 - 1.23 (m, 2H), 1.24 - 1.10 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H).

[0458] [O] D20=-35.0 (c=0.7, MeOH).

[0459] Example 18: tert-Butyl (R)-4-((2-(4-chlororophenyl)-2-hydroxyethyl)amino)-4- methylpiperidin e-1- carboxy la te

[0460] A mixture of tert-butyl 4-amino-4-methylpiperidine-l-carboxylate (292 mg, 1.3 mmol), (R)-4-chlorostyrene oxide (200 mg, 1.3 mmol, ee=92 %) and / PrOH (1.5 mL, 19.5 mmol) was stirred for 18 h at 80 °C and concentrated. The residue was purified by chromatography to give the title compound (360 mg, 75 %).

[0461] XH NMR (400 MHz, CDCI3) 6 7.37 - 7.30 (m, 4H), 4.61 (dd, J = 8.6, 3.7 Hz, 1H), 3.52

[0462] - 3.36 (m, 4H), 2.89 (dd, J = 11.8, 3.7 Hz, 1H), 2.56 (dd, J = 11.8, 8.6 Hz, 1H), 1.57

[0463] - 1.49 (m, 4H), 1.48 (s, 9H, overlapping), 1.13 (s, 3H).

[0464] [a]D25= -48.3 (c=0.5, CHCI3).

[0465] Example 19: (R)-l-(4-((2-(4-Chlorophenyl)-2-hydroxyethyl)amino)-4-methyl- piperidin- 1-yl) pentan- 1-one (a) (R)-l-(4-Chlorophenyl)-2-((4-methylpiperidin-4-yl)amino)ethan-l-ol

[0466] HCI (4 M in dioxane, 4 mL, 16.3 mmol) was added to a solution of tert-butyl (R)-4-((2- (4-ch loropheny I) -2-hydroxyethyl)amino)-4-methylpiperidine-l -carboxy late (Example 18, 290 mg, 0.79 mmol) in dioxane (2 mL) at rt. The mixture was sonicated for 1 h and concentrated. The residue was washed with Et2<D and dried in vacuo at 50 °C. The material was dissolved in H2O (2 mL) and treated dropwise with NaOH (aq, 4 M) until no more precipitate was formed. The mixture was extracted with CH2CI2, and the combined extracts were washed with brine, dried over Na2SC>4 and concentrated to give the sub-title compound (195 mg, 86 %). The material was unstable and was stored under Ar at 5 °C.

[0467] (b) (R)-l-(4-((2-(4-Chlorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidin-l- yl)pentan-l-one

[0468] EtsN (31 pL, 0.22 mmol) was added to a solution of (R)-l-(4-chlorophenyl)-2-((4- methylpiperidin-4-yl)amino)ethan-l-ol (42 mg, 0.16 mmol) in CH2CI2 (2 mL). The mixture was cooled to -5 °C and valeryl chloride (23 pL, 0.19 mmol) was added. The mixture was stirred for 30 min while allowing the temperature to rise to 0 °C. NaHCOs (aq, sat) was added, and the mixture was extracted with CH2CI2. The combined extracts were dried over Na2SC>4 and concentrated, and the residue was purified by chromatography to give the free base of the title compound. The material was dissolved in THF (1 mL), and HCI (4 M in dioxane, 20 pL) was added. The mixture was concentrated, and the residue was triturated with Et2<D and dried in vacuo at 50 °C to give the title compound (32 mg, 59 %).

[0469] XH NMR (400 MHz, CDCI3) 6 7.35 - 7.28 (m, 4H), 4.61 (dd, J = 8.5, 3.6 Hz, 1H), 3.80 - 3.68 (m, 1H), 3.56 - 3.33 (m, 3H), 2.87 (ddd, J = 11.8, 6.5, 3.7 Hz, 1H), 2.56 (ddd, J = 16.1, 11.9, 8.6 Hz, 1H), 2.35 - 2.26 (m, 2H), 1.67 - 1.26 (m, 8H), 1.13 (s, 3H), 0.93 (t, J = 7.3 Hz, 3H). [a]D20=-45.1 (c=0.83, CHCI3).

[0470] Example 20 Methyl (cis)-4-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)- cyclohexane-l-carboxylate

[0471] KOH (146 mg, 2.25 mmol) was added to a stirred mixture of (R)-2-bromo-l-(3- fluorophenyl)ethan-l-ol (164 mg, 0.75 mmol), methyl (c / s)-4-aminocyclohexane-l- carboxylate hydrochloride (290 mg, 1.50 mmol) and MeOH (0.92 mL) at rt and the mixture was heated in a sealed vial at 80 °C for 18 h. The mixture was allowed to cool to rt and concentrated, and the residue was purified by chromatography to give the title compound (76 mg, 34 %).

[0472] XH NMR (400 MHz, CDCI3) 6 7.33 - 7.26 (m, 1H), 7.13 - 7.07 (m, 2H), 6.98 - 6.90 (m, 1H), 4.65 (dd, J = 8.9, 3.6 Hz, 1H), 3.67 (s, 3H), 2.96 (dd, J = 12.2, 3.6 Hz, 1H), 2.81 (s, 1H), 2.69 - 2.58 (m, 2H), 2.51 - 2.45 (m, 1H), 2.02 - 1.92 (m, 2H), 1.73 - 1.66 (m, 2H), 1.64 - 1.56 (m, 2H), 1.53 - 1.44 (m, 2H).

[0473] [a]D20= -44 (c, 1.00 CHCI3).

[0474] Biological examples

[0475] L6-myoblasts were grown in Dulbecco's Modified Eagle's Medium (DMEM) containing 1 g / L glucose supplemented with 10 % fetal bovine serum, 2 mM L-Glutamine, 50 U / mL penicillin, 50 pg / mL streptomycin and 10 mM HEPES. Cells were plated at lx 105cells per mL in 24- well plates. After reaching 90 % confluence the cells were grown in medium containing 2 % FBS for 7 days where upon cells differentiated into myotubes.

[0476] Biological example 1 : Glucose uptake at 10 pM.

[0477] Differentiated L6-myotubes were serum-starved overnight in medium containing 0.5 % fatty-acid free BSA and stimulated with an agonist, with a final concentration of 10 pM. After 1 h 40 min the cells were washed with warm glucose free medium or PBS twice and another portion of agonist was added to the glucose free medium. After 20 min the cells were exposed to 50 nM3H-2-deoxyglucose for another 10 min before washed in ice cold glucose free medium or PBS three times and lysed in 400 pL / well 0.2 M NaOH for 1 h at 60 °C. The cell lysate was mixed with 4 mL scintillation buffer (Emulsifier Safe, Perkin Elmer) and the radioactivity was detected in a p-counter (TriCarb 4810TR, Perkin Elmer). The activity for each compound is compared to that of isoproterenol. If a compound at 10 pM shows activity of more than 75 % of that of isoproterenol at 10 pM, the activity is denoted with + + + ; if it is between 75 and 50 % it is denoted with + + ; if it is between 50 and 25 % it is denoted with +; if it less than 25 % it is denoted with -.

[0478] Biological example 2: Glucose uptake at 1 pM.

[0479] Differentiated L6-myotubes were serum-starved overnight in medium containing 0.5 % fatty-acid free BSA and stimulated with an agonist, with a final concentration of 1 pM. After 1 h 40 min the cells were washed with warm glucose free medium or PBS twice and another portion of agonist was added to the glucose free medium. After 20 min the cells were exposed to 50 nM3H-2-deoxyglucose for another 10 min before washed in ice cold glucose free medium or PBS three times and lysed in 400 pL / well 0.2 M NaOH for 1 h at 60 °C. The cell lysate was mixed with 4 mL scintillation buffer (Emulsifier Safe, Perkin Elmer) and the radioactivity was detected in a p-counter (TriCarb 4810TR, Perkin Elmer). The activity for each compound is compared to that of isoproterenol. If a compound at 1 pM shows activity of more than 75 % of that of isoproterenol at 10 pM, the activity is denoted with + + + ; if it is between 75 and 50 % it is denoted with + + ; if it is between 50 and 25 % it is denoted with +; if it less than 25 % it is denoted with -.

[0480] Biological example 3: Measurement of intracellular cAMP levels.

[0481] Differentiated cells were serum-starved overnight and stimulated with an agonist, final concentration lxlO-5M, for 15 min in stimulation buffer (HBSS supplemented with 1 % BSA, 5 mM HEPES and 1 mM IBMX, pH 7.4). The medium was aspirated and 100 mL of 95 % EtOH was added to each well of the 24-well plate and cells were kept at - 20 °C overnight. The EtOH was allowed to evaporate and 500 mL of lysis buffer (1 % BSA, 5 mM HEPES and 0.3 % Tween- 20, pH 7.4) was added to each well. The plate was kept at -80 °C for 30 min and then at -20 °C until the day of detection when the samples were thawed. Intracellular cAMP levels were detected using an alpha screen cAMP kit (6760635D from Perkin Elmer). The activity for each compound is compared to that of isoproterenol. If a compound at 10 pM shows activity of more than 75 % of that of isoproterenol at 10 pM, the activity is denoted with + + + ; if it is between 75 and 50 % it is denoted with + + ; if it is between 50 and 25 % it is denoted with +; if it less than 25 % it is denoted with

[0482] Using the assays described in Biological Examples 1, 2 and 3 the following results were obtained. nt = not tested

Claims

Claims1. A compound of formula Ior a pharmaceutically acceptable salt thereof, wherein :R1represents H or Ci-6 alkyl; each of Q1to Q5independently represent carbon, a heteroatom or a direct bond such that the ring comprising Q1to Q5represents: a phenyl optionally substituted with one or more Y1, or a 5- or 6- membered heteroaryl optionally substituted with one or more Y2; each Y1independently represents halo, Ral, -CN, -N3, -N(Rbl)Rclor -ORdl; each Y2independently represents halo, Ra2, -CN, -N3, -N(Rb2)Rc2or -ORd2; ring A represents 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl comprising one or two heteroatoms selected from N or O; when present on a carbon atom, W represents C1-6 alkyl substituted with one or more groups selected from -CN, -ORd4, or =0, wherein the C1-6 alkyl may be further optionally substituted with one or more groups independently selected from halo and G1, when present on a nitrogen atom, W represents-C(0)0Ci-6alkyl, -C(0)C4-ealkyl, -S(O)Ci-ealkyl, or C2-6-alkyl substituted with at least one -N(Rb4)Rc4and at least one =0, wherein the C2-6 alkyl may be further optionally substituted with one or more groups independently selected from halo and G1; n represents 0 to 5;when present on a carbon atom, each Z independently represents halo, Ra3, -CN, -N3, -N(Rb3)Rc3, -ORd3, -S(O)PRe3, -S(O)qN(Rf3)Rg3, -N(Rh3)S(O)tRi3, or =0; when present on a nitrogen atom, each Z independently represents Ra3, -S(O)PRe3, or -S(O)qN(Rf3)Rg3; each Raland Ra2independently represents C1-6 alkyl optionally substituted by one or more halo; each Raland Ra2independently represents C1-6 alkyl optionally substituted by one or more halo; each Ra3, Re3, and R'3independently represents C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl each optionally substituted by one or more groups independently selected from halo and G1; each Rbl, Rb2, Rb3, Rcl, Rc2, Rc3, Rdl, Rd2, Rd3, Rf3, Rg3and Rh3independently represents H, orC1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl each optionally substituted by one or more groups independently selected from halo and G2; or alternatively any of Rb3and Rc3, and / or Rf3and Rg3may be linked together to form, together with the nitrogen atom to which they are attached, a 4- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C1-3 alkyl optionally substituted by one or more halo, and =0; each G1and G2independently represents Ra4, -CN, -N3, -N(Rb4)Rc4, -0Rd4, -S(O)PRe4, -S(O)qN(Rf4)Rg4, -N(Rh4)S(O)rR'4or =0; each Ra4independently represents phenyl or 5- or 6-membered heteroaryl, each optionally substituted by one or more group selected from halo, Ra5, -CN, -N3, - N(Rb5)Rc5, -0Rd5, -S(O)PRe5, -S(O)qN(Rf5)Rg5, or -N(Rh5)S(O)tRi5; each Rb4, Rc4, Rd4, Rf4, Rh4and Rg4independently represents H, or C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl optionally substituted by one or more halo, -CN or =0; each Re4and R'4independently represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl each optionally substituted by one or more halo or -CN;or alternatively any of Rb4and Rc4and / or Rf4and Rg4may be linked together to form, together with the nitrogen atom to which they are attached, a 4- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C1-3 alkyl optionally substituted by one or more halo, and =0; each Ra5, Re5, and R'5independently represents C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl each optionally substituted by one or more groups independently selected from from halo, C1-3 alkyl optionally substituted by one or more halo, and =0; each Rb5, Rc5, Rd5, Rf5, Rg5and Rh5independently representsH, orC1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl each optionally substituted by one or more groups independently selected from halo, C1-3 alkyl optionally substituted by one or more halo, and =0; or alternatively any of Rb5and Rc5, and / or Rf5and Rg5may be linked together to form, together with the nitrogen atom to which they are attached, a 4- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C1-3 alkyl optionally substituted by one or more halo, and =0; each p independently represents 0, 1 or 2; each q independently represents 1 or 2; each r independently represents 1 or 2; and each t independently represents 1 or 2, with the provisos (A) to (C) that the compound of formula I is not any of the following :(A)2. The compound according to Claim 1, wherein ring A represents a 6-membered heterocycloalkyl comprising one or two heteroatoms selected from N or O.

3. The compound according to Claim 1, wherein ring A represents a 4-membered cycloalkyl (i.e. cyclobutyl).

4. The compound according to any one of the preceding claims, wherein the ring comprising Q1to Q5represents: phenyl optionally substituted with one or more Y1; or pyridyl optionally substituted with one or more Y2, such as phenyl optionally substituted with one or more Y1.

5. The compound according to any one of the preceding claims, wherein each Y1independently represents Ral, halo or -CN.

6. The compound according to any one of the preceding claims, wherein each Y1and Y2represents F.

7. The compound according to any one of the preceding claims, wherein R1represents methyl.

8. The compound according to any one of the preceding claims, wherein when present on a carbon atom, W represents Ci-6 alkyl (e.g. C2-6 alkyl such as C2 alkyl) substituted with at least two (e.g. only two) groups selected from -CN, -ORd4, and =0.

9. The compound according to any one of the preceding claims, wherein when present on a carbon atom, W represents -CH2C(O)OMe or -CH2C(O)OH.

10. The compound according to any one of Claims 1 to 7, wherein when present on a carbon atom, W represents -CH2CN.

11. The compound according to any one of the preceding claims, wherein when present on a nitrogen atom, W represents -CH2C(O)NMe2, -CH2C(O)NHMe, - CH2C(O)NH2, or -CH2C(CH3)2NHC(O)Me.

12. The compound according to any one of Claims 1 to 10, wherein when present on a nitrogen atom, W represents -C(O)OCi-ealkyl, -C(O)C4-ealkyl, or -S(O)Ci-ealkyl.

13. The compound according to any one of the preceding claims, wherein n represents 0 or 1, such as 0.

14. The compound of any one of the preceding claims, wherein the compound of formula I is a compound of formula IXwhereinQ1to Q5, R1, W, n and Z are as defined in any preceding claim;X represents C or N; ml and m2 independently represent 0 to 2.

15. The compound according to claim 14, wherein the compound of formula IX is a compound of formula IEwherein the ring comprising Q1to Q5, R1and W are as defined in any preceding claim, and X is as defined in Claim 14.

16. A compound as defined in any one of Claims 1 to 15, for use in medicine.

17. A pharmaceutical composition comprising a compound as defined in any one of Claims 1 to 15, and optionally one or more pharmaceutically acceptable adjuvant, diluent and / or carrier.

18. A compound as defined in any one of Claims 1 to 15, for use in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia.

19. The use of a compound as defined in any one of Claims 1 to 15, for the manufacture of a medicament for the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia.

20. A method of treating hyperglycaemia or a disorder characterized by hyperglycaemia comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of Claims 1 to 15.

21. The compound for use, method or use according to any one of Claims 18 to 20, wherein the hyperglycaemia or disorder characterised by hyperglycaemia is, or is characterised by, the patient displaying severe insulin resistance.

22. The compound for use, method or use according to any one of Claims 18 to 21, wherein the disorder characterised by hyperglycaemia is selected from the group consisting of Type 2 diabetes, Rabson-Mendenhall syndrome, Donohue's syndrome (leprechaunism), Type A and Type B syndromes of insulin resistance, the HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndromes, pseudoacromegaly, and lipodystrophy.

23. A compound as defined in anyone of Claims 1 to 15, for use in the treatment of a non-alcoholic fatty liver disease.

24. The use of a compound as defined in any one of Claims 1 to 15, in the manufacture of a medicament for the treatment or prevention of a non-alcoholic fatty liver disease.

25. A method of treating or preventing a non-alcoholic fatty liver disease as defined in comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of Claims 1 to 15.

26. A compound as defined in anyone of Claims 1 to 15, for use in treating a disease or disorder the treatment of which is mediated by activation of the 02 adrenergic receptor.

27. The use of a compound as defined in any one of Claims 1 to 15, in the manufacture of a medicament for use in treating a disease or disorder the treatment of which is mediated by activation of the 02 adrenergic receptor.

28. A method of treating a disease or disorder the treatment of which is mediated by activation of the 02 adrenergic receptor comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of Claims 1 to 15.

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