Combinations of beta 2-adrenergic receptor agonists and metformin for use in treating obesity and reducing body fat

Abstract

There is provided herein a Pz-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, for use in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, wherein the use further comprises administration of metformin.

Description

[0001]COMBINATIONS OF BETA 2-ADRENERGIC RECEPTOR AGONISTS AND METFORMIN FOR USE IN TREATING OBESITY AND REDUCING BODY FAT Field of the Invention The present invention relates to methods for the treatment or prophylaxis of obesity and the reduction of body fat. In particular, the invention relates to methods for the treatment or prophylaxis of obesity and therapeutic and non-therapeutic methods of reducing body fat, involving treatment with a combination of a ǃ2-adrenergic receptor agonist and metformin, and to compositions and kits-of-parts for use in such methods. Background of the Invention 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. The ǃ-adrenergic receptors (ǃ-ARs) are divided into the subtypes, ǃ1, ǃ2, and ǃ3, of which ǃ2-AR is the major isoform in skeletal muscle cells. ARs are G protein coupled receptors (GPCRs) which signal through classical secondary messengers, such as cyclic adenosine monophosphate (cAMP). It has recently been found that treatment with a ǃ2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity (see Kalinovich et al., Diabetologia. 63, 1603-1615 (2020)). It has also been reported that E2-adrenoceptor agonists have the ability to regulate the metabolism and phenotype of adipose and skeletal muscle tissue. In humans, E2- adrenoceptor agonists dose-dependently increase resting metabolic rate by 10–50% and increases muscle mass and reduces fat mass in young healthy individuals (see Hostrup and Onslev, J Physiol, 600, 1209 (2022)). In addition, it has been shown the E2-adrenoceptor agonist clenbuterol improves skeletal muscle glucose uptake implying that E2-adrenoceptor agonists are beneficial for the treatment of type 2 diabetes (see Beak et al., Nat Commun, 14, 179 (2023)). However, clenbuterol is known to give cardiovascular side effects on systemic treatment (ibid), and gives a large increase of muscle mass in rats (see Emery et al., Biosci Rep 483 (1984)). Despite ongoing research and a clear public health need, there are still relatively few effective and well-tolerated treatments for obesity, with those treatments approved thus far typically suffering from limitations derived from their mode of action (such as undesirable side effects). Moreover, although the use of ǃ2-adrenergic receptor agonists in the treatment of conditions characterized by excess body weight, such as obesity, has been investigated, little is known about the suitability of such agents as components in combination treatments. There remains, therefore, a need for new treatments capable of improving metabolic health, such as through the treatment or prophylaxis of obesity and the reduction of body fat. Description of the Invention We have now surprisingly found that a combination of activation of the ǃ2-adrenergic receptor and treatment with metformin represents a promising strategy for the treatment and prophylaxis of conditions characterized by excess body weight, such as obesity and metabolic syndrome, and dyslipidaemia, and for the reduction of body fat, both for therapeutic and non-therapeutic purposes (e.g. cosmetic methods). Uses in medicine In a first aspect of the invention there is provided a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, for use in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, wherein the use further comprises administration of metformin. 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. Preferences and options for a given aspect, embodiment, feature or parameter of the invention should, unless the context indicates otherwise, be regarded as having been disclosed in combination with any and all preferences and options for all other aspects, features and parameters of the invention. Wherever the word “about” is employed herein (for example, in the context of doses of active ingredients) it will be appreciated that such variables are approximate and as such may vary by ± 10%, for example ± 5% and preferably ± 2% (e.g. ± 1%) from the numbers specified herein. Wherever the word “optionally” is employed in relation to features described herein it will take its normal meaning, namely that the relevant feature may or may not be present. In an alternative first aspect of the invention there is provided the use of a ǃ2- adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, wherein the use further comprises administration of metformin. In an alternative first aspect of the invention there is provided the use of a ǃ2- adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, wherein the use further comprises administration of metformin. In an alternative first aspect of the invention there is provided the compound metformin for use in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, wherein the use further comprises administration of a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof. In an alternative first aspect of the invention there is provided the use of the compound metformin in the manufacture of a medicament for: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, wherein the use further comprises administration of a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof. In an alternative first aspect of the invention there is provided the use of the compound metformin in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, wherein the use further comprises administration of a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof. In an alternative first aspect of the invention there is provided a combination of a ǃ2- adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and the compound metformin for use in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia. In an alternative first aspect of the invention there is provided a method for: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, comprising: (a) administration of a therapeutically effective amount of a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof; and (b) administration of a therapeutically effective amount of metformin, to a patient in need thereof. For the avoidance of doubt, uses, methods, compositions and kits-of-parts of other aspects of the invention as described herein (including all embodiments thereof) may have any of the particular features described above for the first aspect of the invention, including all combinations thereof. For the avoidance of doubt, treatments (and associated prophylaxis) as described herein may be referred to herein as the “treatments of the invention”, or the like. The skilled person will understand that references to the “treatment of” a particular condition (and similarly “treating”) 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. In particular, the terms may refer to achieving a reduction in the severity of one or more clinical symptom associated with the condition. As used herein, references to patients will refer to a living subject being treated, including mammalian (e.g. human) patients. In particular embodiments of the relevant aspects of the invention (e.g. the first aspect of the invention), the treatment is in a mammal (e.g. a human). 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). As used herein, the term prophylaxis includes references to the prevention of (and, similarly, preventing) 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). In particular embodiments, references to use in and methods for the treatment or prophylaxis of diseases and disorders as specified herein will refer in particular to uses in and methods for treatment of such diseases and disorders. For the avoidance of doubt, the term “obesity” as used herein will be understood by those skilled in the art to refer to a condition characterised by abnormal or excessive fat accumulation that may impair health, which conditions will be readily identified by those skilled in the art. For example, in particular embodiments obesity may be understood to be a condition characterised by abnormal or excessive fat accumulation that may impair health in which the subject (e.g. an adult subject) has a body mass index (BMI) of 30.0 or higher (e.g. 30.0 to 39.9). For the avoidance of doubt, and without wishing to be bound by theory, the treatments and prophylactic methods and uses as described herein may be characterised by the lowering of body fat composition (i.e. the reduction of body fat; in particular, body fat in the form of adipose tissue) in the patient. In particular, references to the lowering of body fat composition will refer to reducing levels of body fat in the form of adipose tissue. Similarly, references to the treatment or prophylaxis of obesity may refer to the treatment or prophylaxis of obesity by reducing levels of body fat in the form of adipose tissue. In particular, references to the treatment or prophylaxis of obesity may include references to the treatment or prophylaxis of obesity by lowering body fat composition (e.g. by reducing levels of body fat in the form of adipose tissue) and / or reducing body weight. For example, references to the treatment or prophylaxis of obesity may include references to the treatment or prophylaxis of obesity by lowering body fat composition (e.g. by reducing levels of body fat in the form of adipose tissue). The skilled person will understand that references to lowering body fat composition and / or reducing body weight may refer to therapeutic methods and uses (e.g. in patients in need thereof) and non-therapeutic methods and uses (e.g. cosmetic methods and uses). In particular embodiments, references to lowering body fat composition and / or reducing body weight may refer to therapeutic methods and uses in the lowering body fat composition and / or reducing body weight, such as uses and methods performed in an obese patient. For avoidance of doubt, the term “metabolic syndrome” as used herein will be understood by those skilled in the art to refer to a condition characterised by a clustering of at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides and low high-density lipoprotein (HDL) levels, such that the conditions occur together, which conditions will be readily identified by those skilled in the art. In particular embodiments, the treatment or prophylaxis of metabolic syndrome as described herein will include the treatment or prophylaxis (e.g. treatment) of abdominal obesity (e.g. by reducing levels of abdominal body fat in the form of adipose tissue). For the avoidance of doubt, the term “dyslipidaemia” as used herein will be understood by those in skilled in the art to refer to a condition characterised by being defined as an abnormal amount of lipids (e.g. cholesterol and / or fat) in the blood (often due to diet and lifestyle), which condition will be readily identified by those skilled in the art. In particular embodiments, the uses and methods for (i) the treatment or prophylaxis of obesity, (ii) lowering body fat composition and / or reducing body weight, (iii) the treatment or prophylaxis of metabolic syndrome, and (iv) the treatment or prophylaxis of dyslipidaemia, as described herein may each be in a patient who does not have (for example, has not been diagnosed with and / or is not experiencing symptoms associated with) hyperglycaemia or a disorder characterized by hyperglycaemia, such as in a patient who does not have diabetes (e.g. type 2 diabetes), which may be referred to as a non- diabetic (e.g. non-type 2 diabetic) patient. In particular embodiments, references to uses and methods for (i) the treatment or prophylaxis of obesity, (ii) lowering body fat composition and / or reducing body weight, (iii) the treatment or prophylaxis of metabolic syndrome, or (iv) the treatment or prophylaxis of dyslipidaemia, will refer in particular to (i) the treatment or prophylaxis of obesity, (ii) lowering body fat composition and / or reducing body weight. In more particular embodiments, references to uses and methods for (i) the treatment or prophylaxis of obesity, (ii) lowering body fat composition and / or reducing body weight, (iii) the treatment or prophylaxis of metabolic syndrome, or (iv) the treatment or prophylaxis of dyslipidaemia, will refer in particular to (i) the treatment or prophylaxis of obesity. In yet more particular embodiments, references to uses and methods for (i) the treatment or prophylaxis of obesity, (ii) lowering body fat composition and / or reducing body weight, (iii) the treatment or prophylaxis of metabolic syndrome, or (iv) the treatment or prophylaxis of dyslipidaemia, will refer in particular to (i) the treatment or prophylaxis of obesity by lowering body fat composition (e.g. by reducing levels of body fat in the form of adipose tissue). In yet more particular embodiments, references to uses and methods for (i) the treatment or prophylaxis of obesity, (ii) lowering body fat composition and / or reducing body weight, (iii) the treatment or prophylaxis of metabolic syndrome, or (iv) the treatment or prophylaxis of dyslipidaemia, will refer in particular to (i) the treatment or prophylaxis of obesity by lowering body fat composition (e.g. by reducing levels of body fat in the form of adipose tissue) in a patient who does not have (for example, has not been diagnosed with and / or is not experiencing symptoms associated with) hyperglycaemia or a disorder characterized by hyperglycaemia, such as in a patient who does not have diabetes (e.g. type 2 diabetes), which may be referred to as a non-diabetic (e.g. non-type 2 diabetic) patient. The skilled person will understand that treatments of the first to third aspects of the invention may further comprise (i.e. be combined with) further (i.e. additional / other) treatment(s) for the same condition. The skilled person will understand that compounds referred to herein, such as compounds referred to as agonists, may be provided in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include acid addition salts and base addition salts, each of which may be in the form of salts in varying ratios of compound to counter ion (e.g. including hemi 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 comprised in the formulations 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. by rotary evaporation under reduced pressure, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound comprised in the formulations of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. 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, Į-hydroxybutyrate, lactate, tartrate, hemi-tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, 1-naphtoate, 2-naphtoate, 1-hydroxy- 2-naphtoate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts), halide salts (e.g. chloride, bromide or iodide salts), sulphonate salts (e.g. benzenesulphonate, methyl-, bromo- or chloro-benzenesulphonate, xylenesulphonate, methanesulphonate, ethanesulphonate, propanesulphonate, hydroxyethanesulphonate, 1,2-ethanedisulphonate, 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. 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. For the avoidance of doubt, compounds as described herein 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 such compounds exist in crystalline and part crystalline forms, such forms may include solvates, which are included in the scope of the invention. The compounds may also exist in solution. The skilled person will understand that references to an agonist will refer to compounds suitable for acting as such when administrated to a subject to be treated (i.e. a patient, e.g. a human, in need thereof). Suitable compounds may include compounds which provide the required effect and compounds which are converted to compounds providing the required effect after administration (i.e. in vivo), which compounds may be referred to as pro-drugs. Particular compounds that may be mentioned are compounds which elicit the required effect. For the avoidance of doubt, the term “agonist” may be understood to indicate an agent (i.e. a compound) that induces activation of the relevant receptor to produce a biological response (e.g. in a subject, such as a human), such as by binding to the relevant receptor. As such, the term may also refer to partial agonists (which will be understood to refer to compounds that activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist). Agonists (and partial agonists) may display, for example, half maximal effective concentration (EC50) values of less than about 100 ^M, such as less than about 10 ^M, or less than about 1 ^M (e.g. less than about 200, about 150 or about 120 nM). Unless otherwise stated or clear from the context, references herein to agonists will also include pharmaceutically-acceptable (e.g. “protected”) derivatives of compounds which may not possess the relevant activity per se, but may be administered (e.g. parenterally or orally) to a patient and thereafter be metabolised in the body to form compounds possessing the required activity, which compounds may be referred to as prodrugs. Suitable prodrugs of compounds as described herein will be known to those skilled in the art, such as suitable esters (e.g. methyl or ethyl esters, and the like). For the avoidance of doubt, unless otherwise stated or clear from the context, references to compounds that are agonists, and pharmaceutically acceptable salts thereof, will include compounds that are prodrugs of such agonists, and pharmaceutically acceptable salts thereof. Suitable ǃ2-adrenergic receptor agonists (which may also be referred to as ǃ2-agonists) may include those known to those skilled in the art. In certain embodiments, suitable ǃ2-adrenergic receptor agonists will include those that are selective, which term will be known to those skilled in the art (i.e. compounds that are agonists of the relevant receptor(s) but which do not cause significant activation of other ǃ-adrenergic receptors). Suitable ǃ2-adrenergic receptor agonists can be identified using techniques known to those skilled in the art, including those as described in the examples provided herein. Suitable ǃ2-adrenergic receptor agonists that may be employed in the various aspects of the invention include, but are not limited to, those described in: WO 2004 / 071388, EP 0 272 976, FR 2647310, DE 2 157 040, DE 2212600, DE 2015573, ZA 6705591, DE 2128258, WO 91 / 09596, GB 1199630, DE 4209989, BE 611502, NL 7804582, EP 0 043 807, WO 2008 / 022038, DE 2413102, US 2,308,232, BE 823841, BE 660244, WO 2000 / 075114, WO 2005 / 102350, WO 2005 / 110990, JP 56055355, AT 285583, US 4,223,137, US 3,056,836, FR 1324914, DE 638650, DD 45721, US 3,801,631, DE 2259282, DE 2300614, EP 0 290 122, US 2004 / 0266867, US 2010 / 0022658, US 2010 / 0022659, DE 2157040, GB 2133986, WO 2006 / 122788, Woo et al., Molecular Pharmacology, (2009), 75(1) 158-165, Baur et al., J. Med. Chem., (2010), 53(9), 3675-3684, Kaiser et al., J. Med. Chem. (1974), 17(1) 49-57, Baker et al., J. Pharmacology and Experimental Therapeutics, (2006), 319(1), 439-446, Engelhardt et al., Arzneimittel-Forschung, (1972), 22(5), 869-76, WO 2019 / 241744, WO 2019 / 241736, WO 2020 / 198466, WO 2021 / 003161, WO 2021 / 081292, WO 2021 / 127210 and WO 2021 / 247934, the relevant disclosures of each of which (e.g. the examples compounds described therein, and pharmaceutically acceptable salts thereof, and associated methods of preparation) are hereby incorporated by reference in their entirety. For the avoidance of doubt, references to patent publications will typically refer to the initial publication of the full patent specification with the relevant publication number (which may be indicated by the suffix “A1”). Further suitable ǃ2-adrenergic receptor agonists that may be employed in the various aspects of the invention (which compounds may be identified as also being suitable ǃ2- adrenergic receptor agonists) include those described in the following publications, the contents of which are hereby incorporated herein in their entirety (in particular, the biological examples, the generic compound definitions, including all embodiments thereof and associated definitions, and the example compounds provided therein, including pharmaceutically acceptable salts thereof, and associated methods of preparation): WO 2017 / 153737 WO 2019 / 053429 WO 2019 / 053426 WO 2019 / 053425 WO 2020 / 188301 WO 2022 / 063895 WO 2022 / 063889 WO 2023 / 046885 WO 2023 / 046882 WO 2023 / 105035 WO 2023 / 203223 WO 2020 / 198466 A particular ǃ2-adrenergic receptor agonist that may be mentioned is the following compound: and pharmaceutically acceptable salts thereof. Thus, a particular ǃ2-adrenergic receptor agonist that may be mentioned is (R)-2-(tert- butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol, and pharmaceutically acceptable salts thereof. Particular pharmaceutically acceptable salts of the above-mentioned compound (i.e. (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol) that may be mentioned include the hemi-tartrate and dihydrochloride salts (such as the hemi-tartrate salt). In particular embodiments, references to a specific steroisomer of a compound may refer to the specific stereoisomer being present (e.g. in a composition or formulation comprising the same) in the substantial absence of the corresponding opposite stereoisomer. As used herein, references to the substantial absence of the corresponding opposite stereoisomer may refer to the desired stereoisomer being present at a purity of at least 80% (e.g. at least 90%, such as at least 95%) relative to the opposite stereoisomer. Alternatively, in such instances, compounds may be indicated to be present in the substantial absence of the compound in the other configuration, which may indicate that the compound in the relevant configuration is present in an enantiomeric excess (e.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%). In some embodiments, the compound in the relevant configuration is present in an enantiomeric excess (e.e.) of at least 90% (such as at least 95%, at least 98% or, particularly, at least 99%, for example at least 99.9%). In certain embodiments the invention, the ǃ2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, bitolterol, salbutamol, levosalbutamol, terbutaline, metaproterenol, pirbuterol, bambuterol, fenoterol, methoxyfenoterol, isoprenaline, procaterol, ritodrine, indacaterol, olodaterol, colterol, hexaprenaline, carmoterol, isoxsuprine, isoetarine, zinterol, bamethane, (R)- bamethane, clencyclohexerol, tulobuterol, BRL-47672, trantinterol, clenproperol, clenpenterol, brombuterol, ractopamine and abediterol, and pharmaceutically acceptable salts thereof. In further certain embodiments, the ǃ2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, bitolterol, salbutamol, levosalbutamol, terbutaline, metaproterenol, pirbuterol, bambuterol, fenoterol, methoxyfenoterol, isoprenaline, procaterol, ritodrine, indacaterol, olodaterol, colterol, hexaprenaline, carmoterol, isoxsuprine, isoetarine, zinterol, bamethane, (R)-bamethane, clencyclohexerol, tulobuterol, BRL-47672 and trantinterol, and pharmaceutically acceptable salts thereof. In particular embodiments, the ǃ2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, indacaterol, olodaterol, carmoterol, bamethane, (R)-bamethane, clencyclohexerol, tulobuterol, trantinerol and abediterol, and pharmaceutically acceptable salts thereof. In further particular embodiments, the ǃ2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, indacaterol, olodaterol, carmoterol, bamethane, (R)-bamethane, clencyclohexerol, tulobuterol and trantinerol, and pharmaceutically acceptable salts thereof. In more particular embodiments, the ǃ2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, clenbuterol, (R)-clenbuterol, bamethane, (R)-bamethane, tulobuterol and (R)-tulobuterol, and pharmaceutically acceptable salts thereof. In more particular embodiments, the ǃ2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, clenbuterol, (R)-clenbuterol, bamethane, (R)-bamethane and tulobuterol, and pharmaceutically acceptable salts thereof. In yet more particular embodiments, the ǃ2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, clenbuterol, (R)-clenbuterol, bamethane, (R)-bamethane and tulobuterol, and pharmaceutically acceptable salts thereof. For the avoidance of doubt, the structures of bamethane (CAS: 3703-79-5) and (R)- bamethane (CAS: 912804-58-1) are shown below. For the avoidance of doubt, in the case of a discrepancy between the name of the compound and the structure drawn in this specification, the structure should prevail. In further embodiments, the ǃ2-adrenergic receptor agonist is selected from the group consisting of formeterol, arformeterol, salmeterol, clenbuterol, tulobuterol, bambuterol vilanterol, indacaterol, olodaterol, carmoterol and abediterol, and pharmaceutically acceptable salts thereof. In yet further embodiments, the ǃ2-adrenergic receptor agonist is selected from the group consisting of salbutamol, ritodrine, colterol, hexaprenaline, tulobuterol and isoxsuprine, and pharmaceutically acceptable salts thereof. In particular embodiments, the ǃ2-adrenergic receptor agonist is clenbuterol or (R)- clenbuterol, or a pharmaceutically acceptable salt thereof. For the avoidance of doubt, the compound clenbuterol may be understood to have the following structure: In particular embodiments, the ǃ2-adrenergic receptor agonist is tulobuterol or (R)- tulobuterol, or a pharmaceutically acceptable salt thereof. For the avoidance of doubt, the compound tulobuterol may be understood to have the following structure: For the avoidance of doubt, the international nonpropriety name (INN) or developmental drug code (e.g. BRL-47672) for a compound generally indicates the stereochemical configuration of the compound, or a particular mixture of stereoisomers (e.g. a racemate). Within the scope of the present invention, where relevant and unless context indicates otherwise (for example where both the racemate and a single stereoisomer are explicitly named), such names may also be considered to encompass separate stereoisomers that display the relevant biological activity, and which have not presently been assigned an alternative INN or developmental drug code. In particular embodiments, the INN or developmental drug code should be understood to represent the compound to which the relevant name or code has been assigned only. Where no INN or developmental drug code is available for a compound, the compound may be identified by its Chemical Abstracts Service Registry Number (CAS number). As referred to herein, the indication “CAS: XXXXXX-XX-X” (wherein the number of figures in the first group may vary) is used to identify such compounds. Where relevant and unless context indicates otherwise, the CAS number for a compound may also be considered to encompass other stereoisomers, or mixtures thereof, that display the relevant biological activity, and which have not presently been assigned alternative CAS numbers (as described above for INNs and developmental drug codes). In particular embodiments, the CAS number should be understood to represent the compound to which the relevant name or code has been assigned only. In particular embodiments, the ǃ2-adrenergic receptor agonist is selected from the group consisting of (R)-bamethane, bamethane, clencyclohexerol, radopamine, tulobuterol, and (R)-tulobuterol. The present invention also embraces pharmaceutical formulations comprising isotopically-labelled compounds, which are identical to the compounds 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 invention also encompasses pharmaceutical formulations comprising deuterated compounds, i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium. As described herein, it will also be understood that certain compounds acting as ǃ2- adrenergic receptor agonists are able to activate the ǃ2-adrenergic receptor without inducing significant cAMP production. Thus, particular ǃ2-adrenergic receptor agonists that may be mentioned include those able to activate the ǃ2-adrenergic receptor without (or with only a minimal effect in) inducing cAMP production. Further, in particular embodiments, the methods and uses as described herein may be performed without inducing (or without inducing significant levels of) cAMP production. In particular, the ǃ2-adrenergic receptor agonist as described herein may be further described as being a ǃ2-adrenergic receptor agonist that does not induce significant cAMP (i.e. levels and / or production thereof). The skilled person will be able to determine the level of cAMP production provided by compounds, such as those referred to herein, using techniques known to those skilled in the art, such as those described in the examples as provided herein. For example, the level of cAMP production induced by a given compound can be determined by reference to the amount induced by a defined concentration of that compound relative to that induced by the same concentration of a reference compound, such as isoprenaline, using techniques known to those skilled in the art (e.g. following the protocol as described in the biological examples provided in WO 2019 / 053427, i.e. in cells, such as differentiated L6-myotubes, having been stimulated with isoprenaline or the compound with a final concentration of 1x10-5M, for 15 min in stimulation buffer, such as HBSS supplemented with 1 % BSA, 5 mM HEPES and 1 mM IBMX, at pH 7.4). In such embodiments, compounds that do not induce significant cAMP may be defined as being compounds that induce less than 50% (or, in some embodiments, less than 25%) of the cAMP induced by isoprenaline (e.g. in accordance with the protocol described above). Particular compounds acting as ǃ2-adrenergic receptor agonists which are able to activate the ǃ2-adrenergic receptor without (or with only a minimal effect in) inducing cAMP production include those described in the following publications, the contents of which are incorporated herein in their entirety (in particular, the biological examples, the generic compound definitions, including all embodiments thereof and associated definitions, and the example compounds provided therein, including pharmaceutically acceptable salts thereof, and associated methods of preparation): WO 2017 / 153737 WO 2019 / 053429 WO 2019 / 053426 WO 2019 / 053425 WO 2019 / 053427 WO 2020 / 188299 WO 2020 / 188301 WO 2022 / 063895 WO 2022 / 063889 WO 2023 / 046885 WO 2023 / 046882 WO 2023 / 105035 WO 2023 / 203223 Compounds described in publications referenced and incorporated herein were screened in accordance with the procedures outlined in Biological example 1 and Biological example 2 of WO 2019 / 053427. Test results are given in Table 1. If a compound at 10 ^M shows activity of more than 75 % of that of isoproterenol at 10 ^M, 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 -. Compounds are drawn as salt-free molecules in Table 1, but the tested compounds might have been containing additional salt or solvent components that do not contribute to the biological activity. 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). Synthetic procedures and further biological data will be found in the relevant publications. Therefore, particular ǃ2-adrenergic receptor agonists that may be mentioned are provided in Table 1 below. Table 1. Particular compounds of the invention Biological Biological example 1 of example 2 Structure Name WO of WO 2019 / 05342 2019 / 0534 7 (GU) 27 (cAMP) 2-(butylamino)-1-(p- 1 hydroxyphenyl)-1- +++ - ethanol 2-(butylamino)-1-(m- 2 + - chlorophenyl)-1-ethanol p-{2- [(cyclopropylmethyl)ami 3 ++ - no]-1- hydroxyethyl}phenol 2-(tert-butylamino)-1- 4 (p-hydroxyphenyl)-1- +++ + ethanol 2-(sec-butylamino)-1- 5 (p-hydroxyphenyl)-1- ++ - ethanol 2- 6 +++ - [(cyclohexylmethyl)ami no]-1-(p- hydroxyphenyl)-1- ethanol 2- [(cyclohexylmethyl)ami + - no]-1-phenyl-1-ethanol 1-(p-hydroxyphenyl)-2- (1-methylbutylamino)- ++ + 1-ethanol (R)-2-(butylamino)-1- (p-hydroxyphenyl)-1- +++ - ethanol p-[2- (cyclopentylamino)-1- ++ - hydroxyethyl]phenol p-[2-(1- adamantanylamino)-1- + - hydroxyethyl]phenol 2-(butylamino)-1-(p- hydroxyphenyl)-1- ++ - propanol 1-(p-hydroxyphenyl)-2- (1-methylbutylamino)- ++ - 1-propanol -(m-hydroxyphenyl)-2- (1-methylbutylamino)- +++ - 1-ethanol 2-(butylamino)-1-(m- hydroxyphenyl)-1- ++ - ethanol 2-(2- cyclohexylethylamino)- + - 1-(p-hydroxyphenyl)-1- ethanol 2-(hexylamino)-1-(p- hydroxyphenyl)-1- + - ethanol 1-(p-hydroxyphenyl)-2- + - (octylamino)-1-ethanol 1-(3-chloro-4- hydroxyphenyl)-2-(1- + - methylbutylamino)-1- ethanol 2-(butylamino)-1-(3- chloro-4- + - hydroxyphenyl)-1- ethanol 2-(3- cyclohexylpropylamino)- +++ - 1-(p-hydroxyphenyl)-1- ethanol 1-(4-amino-3,5- dichlorophenyl)-2-(1- +++ ++ methylbutylamino)-1- ethanol 2-(butylamino)-1-(3,5- dichloro-4- - - hydroxyphenyl)-1- ethanol p-[2-(2- cyclopropylethylamino)- ++ - 1-hydroxyethyl]phenol 1-(3,5-dichloro-4- hydroxyphenyl)-2-(1- - - methylbutylamino)-1- ethanol 5-[2-(butylamino)-1- ++ - hydroxyethyl]resorcinol (R)-2-[(R)-1- methylbutylamino]-1- +++ + (p-hydroxyphenyl)-1- ethanol (R)-2-[(R)-1- +++ ++ methylbutylamino]-1- (m-hydroxyphenyl)-1- ethanol 1-(4-amino-3,5- dichlorophenyl)-2- +++ + (butylamino)-1-ethanol 2-(3- cyclopropylpropylamino) +++ - -1-(p-hydroxyphenyl)- 1-ethanol 1-(p-hydroxyphenyl)-2- (4,4,4- ++ n / a trifluorobutylamino)-1- ethanol 1-[4-amino-3-chloro-5- (trifluoromethyl)phenyl] +++ + -2-(butylamino)-1- ethanol 1-[4-amino-3-chloro-5- (trifluoromethyl)phenyl] -2-(1- ++ +++ methylbutylamino)-1- ethanol 2-(butylamino)-1-(4- chloro-3- +++ - hydroxyphenyl)-1- ethanol 1-(4-chloro-3- hydroxyphenyl)-2-(1- +++ - methylbutylamino)-1- ethanol 1-(3-amino-4- chlorophenyl)-2- + - (butylamino)-1-ethanol 1-(4-amino-3,5- difluorophenyl)-2- +++ +++ (butylamino)-1-ethanol Racemic mixture of (R)- [(2S,5S)-5-methyl-2- pyrrolidinyl]phenylmeth anol and (S)-[(2R,5R)- + - 5-methyl-2- pyrrolidinyl]phenylmeth anol Racemic mixture of (R)- [(2R,5R)-5-methyl-2- pyrrolidinyl]phenylmeth anol and (S)-[(2S,5S)- ++ - 5-methyl-2- pyrrolidinyl]phenylmeth anol Racemic mixture of m- {(R)-[(2S,5S)-5- methyl-2- pyrrolidinyl]hydroxymet ++ - hyl}phenol and m-{(S)- [(2R,5R)-5-methyl-2- pyrrolidinyl]hydroxymet hyl}phenol Racemic mixture of m- {(R)-[(2R,5R)-5- methyl-2- pyrrolidinyl]hydroxymet +++ - hyl}phenol and m-{(S)- [(2S,5S)-5-methyl-2- pyrrolidinyl]hydroxymet hyl}phenol N-{3-[2-(butylamino)- 1-hydroxyethyl]-2,6- + - difluorophenyl}acetamid e 1-(3-amino-2,4- difluorophenyl)-2- +++ - (butylamino)-1-ethanol 1-(3-amino-4- fluorophenyl)-2- ++ - (butylamino)-1-ethanol (R)-[(2R,6R)-6-propyl- 2-piperidyl](m- +++ - hydroxyphenyl)methano l (R)-2-(butylamino)-1- (p-fluorophenyl)-1- ++ - ethanol (R)-2-(butylamino)-1- (m-fluorophenyl)-1- ++ - ethanol 2-(butylamino)-1-(4- + - pyridyl)-1-ethanol 2-(butylamino)-1-(3- ++ - pyridyl)-1-ethanol (R)-2-[(R)-1- methylbutylamino]-1- +++ - (m-fluorophenyl)-1- ethanol (R)-2-[(S)-1- methylbutylamino]-1- +++ - (m-fluorophenyl)-1- ethanol (R)-2-[(R)-1- methylbutylamino]-1- ++ - (p-fluorophenyl)-1- ethanol (R)-2-[(S)-1- methylbutylamino]-1- ++ - (p-fluorophenyl)-1- ethanol (R)-2-(tert-butylamino)- 1-(m-fluorophenyl)-1- +++ - ethanol 2-(butylamino)-1-(3,5- difluorophenyl)-1- ++ - ethanol 2-(butylamino)-1-(3,4- difluorophenyl)-1- ++ - ethanol m-{(R)-[(2R,5R)-5- propyl-2- +++ ++ pyrrolidinyl]hydroxymet hyl}phenol (R)-[(2R,5R)-5-propyl- 2-pyrrolidinyl](m- +++ + fluorophenyl)methanol (R)-[(2R,6R)-6-propyl- 2-piperidyl](m- + - fluorophenyl)methanol (S)-[(2R,6R)-6-propyl- 2-piperidyl](m- + - fluorophenyl)methanol (R)-2-(1,1- dimethylbutylamino)-1- +++ - (m-fluorophenyl)-1- ethanol 4-[2-(butylamino)-1- hydroxyethyl]-2(1H)- + - pyridinone 5-[2-(butylamino)-1- hydroxyethyl]-2(1H)- + - pyridinone (R)-[(2R,6S)-6-propyl- 2-piperidyl](m- +++ - hydroxyphenyl)methano l (S)-[(2R,6S)-6-propyl- 2-piperidyl](3,4- + - difluorophenyl)methanol (S)-[(2R,6S)-6-propyl- 2-piperidyl](3,5- + - difluorophenyl)methanol (R)-[(2R,6S)-6-propyl- 2-piperidyl](3,4- + - difluorophenyl)methanol (R)-[(2R,6S)-6-propyl- 2-piperidyl](3,5- ++ - difluorophenyl)methanol (R)-[(2R,6S)-6-propyl- 2-piperidyl](m- ++ - fluorophenyl)methanol (S)-[(2R,6S)-6-propyl- 2-piperidyl](m- ++ - fluorophenyl)methanol (S)-1-(2-amino-1,3- thiazol-4-yl)-2- + - (butylamino)-1-ethanol (S)-2-(butylamino)-1- [2-(trifluoromethyl)- + - 1,3-thiazol-4-yl]-1- ethanol (S)-1-(2-amino-4- pyrimidinyl)-2- + - (butylamino)-1-ethanol N-{5-[(S)-2- (butylamino)-1- hydroxyethyl]-1,3- + - thiazol-2-yl}2- methylpropionamide (S)-1-(2-amino-1,3- thiazol-5-yl)-2- + - (butylamino)-1-ethanol (R)-2-(tert-butylamino)- 1-(2,3-difluorophenyl)- +++ + 1-ethanol (R)-2-(butylamino)-1- (2,3-difluorophenyl)-1- +++ - ethanol (R)-2-(tert-butylamino)- 1-(o-fluorophenyl)-1- +++ + ethanol (R)-2-(butylamino)-1- (o-fluorophenyl)-1- +++ - ethanol (R)-2-(tert-butylamino)- 1-(4-fluoro-2- ++ - hydroxyphenyl)-1- ethanol (R)-2-(butylamino)-1- (4-fluoro-2- ++ - hydroxyphenyl)-1- ethanol (R)-1-(m-fluorophenyl)- 2-(1- +++ - methylcyclopropylamino )-1-ethanol (R)-1-(m-fluorophenyl)- 2-(1- +++ + methylcyclobutylamino) -1-ethanol (R)-2-(tert-butylamino)- 1-(4-fluoro-3- +++ ++ hydroxyphenyl)-1- ethanol (R)-2-(butylamino)-1- (4-fluoro-3- +++ - hydroxyphenyl)-1- ethanol (R)-2-(tert-butylamino)- 1-(2-fluoro-3- ++ ++ hydroxyphenyl)-1- ethanol (R)-2-(butylamino)-1- (2-fluoro-3- +++ + hydroxyphenyl)-1- ethanol N-{5-[(R)-2- (butylamino)-1- hydroxyethyl]-2- ++ - pyrimidinyl}2- methylpropionamide (R)-1-(2-amino-5- pyrimidinyl)-2- ++ - (butylamino)-1-ethanol (R)-1-(3-amino-2- fluorophenyl)-2- ++ - (butylamino)-1-ethanol (R)-1-(3-amino-2- fluorophenyl)-2-(tert- +++ + butylamino)-1-ethanol (R)-[(2R,6S)-6-propyl- 2-piperidyl](p- + - fluorophenyl)methanol (R)-[(2R,6S)-6-propyl- 2-piperidyl](o- + - fluorophenyl)methanol (R)-[(2R,6R)-6-propyl- 2-piperidyl](p- ++ - fluorophenyl)methanol 6-[(S)-2-(tert- butylamino)-1- ++ - hydroxyethyl]-3- pyridinol (S)-2-(tert-butylamino)- 1-(5-fluoro-2-pyridyl)- ++ - 1-ethanol (R)-[(2R,6R)-6-propyl- 2-piperidyl](o- ++ - fluorophenyl)methanol 4-[(R)-2-(tert- butylamino)-1- hydroxyethyl]-1- +++ - methyl-2(1H)- pyridinone (R)-2-(tert-butylamino)- 1-(5-fluoro-3-pyridyl)- +++ + 1-ethanol 5-[(R)-2-(tert- butylamino)-1- +++ - hydroxyethyl]-3- pyridinol (S)-[(R)-6,6-dimethyl- 2-piperidyl](m- + - fluorophenyl)methanol (R)-[(R)-6,6-dimethyl- 2-piperidyl](m- ++ - fluorophenyl)methanol (S)-[(R)-6,6-dimethyl- 2-piperidyl](m- + - hydroxyphenyl)methano l (R)-[(R)-6,6-dimethyl- 2-piperidyl](m- + - hydroxyphenyl)methano l (S)-[(2R,6S)-6-propyl- 2-piperidyl](p- + - fluorophenyl)methanol (S)-[(2R,6S)-6-propyl- 2-piperidyl](o- + - fluorophenyl)methanol (S)-[(2R,6R)-6-propyl- 2-piperidyl](o- + - fluorophenyl)methanol (R)-2-(tert-butylamino)- 1-(3-fluoro-4-pyridyl)- + - 1-ethanol (S)-[(R)-5,5-dimethyl- 2-pyrrolidinyl](m- + - fluorophenyl)methanol (R)-[(R)-5,5-dimethyl- 2-pyrrolidinyl](m- +++ - fluorophenyl)methanol m-{(S)-[(R)-5,5- dimethyl-2- ++ - pyrrolidinyl]hydroxymet hyl}phenol m-{(R)-[(R)-5,5- dimethyl-2- +++ - pyrrolidinyl]hydroxymet hyl}phenol (S)-[(2S,6R)-6-propyl- 2-piperidyl](m- ++ - hydroxyphenyl)methano l (S)-[(2S,6R)-6-propyl- 2-piperidyl](m- + - chlorophenyl)methanol (R)-[(2S,6R)-6-propyl- 2-piperidyl](m- +++ - chlorophenyl)methanol (R)-[(2S,6R)-6-propyl- 2-piperidyl](m- + - fluorophenyl)methanol (R)-1-(m-fluorophenyl)- 2-(neopentylamino)-1- + - ethanol (R)-1-(m-fluorophenyl)- 2-[1- ++ - (trifluoromethyl)cyclopr opylamino]-1-ethanol (S)-[(2S,6S)-6-propyl- 2-piperidyl](m- + - fluorophenyl)methanol (R)-[(2S,6S)-6-propyl- 2-piperidyl](m- ++ - fluorophenyl)methanol (S)-[(2S,6S)-6-propyl- 2-piperidyl](m- +++ - hydroxyphenyl)methano l (R)-[(2S,6S)-6-propyl- 2-piperidyl](m- ++ - hydroxyphenyl)methano l (R)-[(2S,6S)-6-propyl- 2-piperidyl](m- + - chlorophenyl)methanol (R)-[(2R,5S)-5-propyl- 2-pyrrolidinyl](m- ++ - fluorophenyl)methanol m-{(R)-[(2R,5S)-5- propyl-2- ++ - pyrrolidinyl]hydroxymet hyl}phenol (S)-[(2R,5R)-5-propyl- 2-pyrrolidinyl](m- + - fluorophenyl)methanol m-{(S)-[(2R,5R)-5- propyl-2- + - pyrrolidinyl]hydroxymet hyl}phenol (R)-[(2R,6S)-6-propyl- 2-piperidyl](m- + - chlorophenyl)methanol (S)-[(2R,6S)-6-propyl- 2-piperidyl](m- + - chlorophenyl)methanol (R)-[(2S,5S)-5-propyl- 2-pyrrolidinyl](m- + - fluorophenyl)methanol (S)-[(2S,5S)-5-propyl- 2-pyrrolidinyl](m- ++ - fluorophenyl)methanol (R)-[(2S,5R)-5-propyl- 2-pyrrolidinyl](m- + - fluorophenyl)methanol (S)-[(2S,5R)-5-propyl- 2-pyrrolidinyl](m- ++ - fluorophenyl)methanol 4-[2-(tert-butylamino)- 1-hydroxyethyl]-3- +++ - pyridinol (R)-[(2R,6S)-6-propyl- 2-piperidyl](o- + - chlorophenyl)methanol (R)-[(2S,6R)-6-propyl- 2-piperidyl](m- +++ - hydroxyphenyl)methano l (S)-[(2R,6R)-6-propyl- 2-piperidyl](m- + - hydroxyphenyl)methano l (R)-2-(tert-butylamino)- 1-(5-chloro-3-pyridyl)- +++ +++ 1-ethanol (S)-[(2R,6S)-6-propyl- 2-piperidyl](5-fluoro-3- - - pyridyl)methanol (R)-[(2R,6S)-6-propyl- 2-piperidyl](5-fluoro-3- - - pyridyl)methanol (R)-[(2R,5R)-5-propyl- 2-pyrrolidinyl](m- ++ - chlorophenyl)methanol m-{(R)-[(S)-5,5- + - dimethyl-2- pyrrolidinyl]hydroxymet hyl}phenol m-{(S)-[(S)-5,5- dimethyl-2- - - pyrrolidinyl]hydroxymet hyl}phenol (R)-[(S)-5,5-dimethyl- 2-pyrrolidinyl](m- - - fluorophenyl)methanol (S)-[(S)-5,5-dimethyl- 2-pyrrolidinyl](m- + - fluorophenyl)methanol (S)-2-(tert-butylamino)- 1-(3-chloro-2-pyridyl)- + - 1-ethanol (S)-2-(tert-butylamino)- 1-(5-chloro-2-pyridyl)- + - 1-ethanol (R)-[(2R,5R)-5-propyl- 2-pyrrolidinyl](o- +++ - chlorophenyl)methanol (R)-1-(3-amino-2,4- difluorophenyl)-2-(tert- +++ + butylamino)-1-ethanol (R)-2-(tert-butylamino)- 1-(3-fluoro-2-tolyl)-1- +++ + ethanol (S)-[(R)-5,5-dimethyl- 2-pyrrolidinyl](o- - - chlorophenyl)methanol (R)-[(R)-5,5-dimethyl- 2-pyrrolidinyl](o- +++ - chlorophenyl)methanol (S)-[(R)-5,5-dimethyl- 2-pyrrolidinyl](m- + - chlorophenyl)methanol (R)-[(R)-5,5-dimethyl- 2-pyrrolidinyl](m- +++ - chlorophenyl)methanol (S)-[(2R,6S)-6-propyl- 2-piperidyl](m- - - hydroxyphenyl)methano l (S)-[(R)-5,5-dimethyl- 2-pyrrolidinyl](5-fluoro- - - 3-pyridyl)methanol (R)-[(R)-5,5-dimethyl- 2-pyrrolidinyl](5-fluoro- +++ - 3-pyridyl)methanol (S)-[(R)-5,5-dipropyl-2- pyrrolidinyl](m- - - fluorophenyl)methanol (R)-[(R)-5,5-dipropyl-2- pyrrolidinyl](m- ++ - fluorophenyl)methanol (R)-[(2R,5R)-5-propyl- 2-pyrrolidinyl](5-fluoro- +++ - 3-pyridyl)methanol (S)-[(2R,5R)-5-propyl- 2-pyrrolidinyl](5-fluoro- + - 3-pyridyl)methanol (R)-[(R)-6,6-dimethyl- 2-piperidyl](o- + - chlorophenyl)methanol (S)-[(R)-6,6-dimethyl- 2-piperidyl](o- +++ - chlorophenyl)methanol (S)-[(R)-6,6-dimethyl- 2-piperidyl](m- ++ - chlorophenyl)methanol (R)-[(R)-6,6-dimethyl- 2-piperidyl](m- + - chlorophenyl)methanol 5-{(S)-[(R)-5,5- dimethyl-2- + - pyrrolidinyl]hydroxymet hyl}-3-pyridinol 5-{(R)-[(R)-5,5- dimethyl-2- ++ - pyrrolidinyl]hydroxymet hyl}-3-pyridinol (R)-{(R)-1-aza-2- spiro[4.4]nonyl}(m- ++ + fluorophenyl)methanol (S)-{(R)-1-aza-2- spiro[4.4]nonyl}(m- - - fluorophenyl)methanol (R)-{(R)-4-aza-5- spiro[2.4]heptyl}(m- ++ - fluorophenyl)methanol (S)-{(R)-4-aza-5- spiro[2.4]heptyl}(m- + - fluorophenyl)methanol (S)-[(R)-5,5-dimethyl- 2-pyrrolidinyl](p- - - fluorophenyl)methanol (R)-[(R)-5,5-dimethyl- 2-pyrrolidinyl](p- ++ - fluorophenyl)methanol (S)-[(R)-5,5-dimethyl- 2-pyrrolidinyl](o- - - fluorophenyl)methanol (R)-[(R)-5,5-dimethyl- 2-pyrrolidinyl](o- +++ + fluorophenyl)methanol (S)-[(R)-6,6-dimethyl- 2-piperidyl](o- +++ + fluorophenyl)methanol (R)-[(R)-6,6-dimethyl- 2-piperidyl](o- ++ - fluorophenyl)methanol (S)-(m-fluorophenyl)(4- methyl-7- + - azabicyclo[2.2.1]hept- 1-yl)methanol (R)-(m-fluorophenyl)(4- methyl-7- ++ - azabicyclo[2.2.1]hept- 1-yl)methanol (S)-(o-fluorophenyl)(4- methyl-7- +++ - azabicyclo[2.2.1]hept- 1-yl)methanol (R)-(o-fluorophenyl)(4- methyl-7- +++ - azabicyclo[2.2.1]hept- 1-yl)methanol (S)-(m-fluorophenyl)(4- propyl-7- - - azabicyclo[2.2.1]hept- 1-yl)methanol (R)-(m-fluorophenyl)(4- propyl-7- ++ + azabicyclo[2.2.1]hept- 1-yl)methanol (S)-(5-fluoro-3- pyridyl)(4-methyl-7- ++ - azabicyclo[2.2.1]hept- 1-yl)methanol (R)-(5-fluoro-3- pyridyl)(4-methyl-7- +++ - azabicyclo[2.2.1]hept- 1-yl)methanol (R)-{(R)-1-methyl-2- azabicyclo[2.1.1]hex-3- +++ ++ yl}(m- fluorophenyl)methanol (S)-{(R)-1-methyl-2- + - azabicyclo[2.1.1]hex-3- yl}(m- fluorophenyl)methanol (R)-{(S)-1-methyl-2- azabicyclo[2.1.1]hex-3- - - yl}(m- fluorophenyl)methanol (S)-{(S)-1-methyl-2- azabicyclo[2.1.1]hex-3- ++ - yl}(m- fluorophenyl)methanol (R)-[(S)-6,6-dimethyl- 2-piperidyl](m- +++ - fluorophenyl)methanol (S)-[(S)-6,6-dimethyl- 2-piperidyl](m- + - fluorophenyl)methanol (S)-[(S)-6,6-dimethyl- 2-piperidyl](o- + - fluorophenyl)methanol (R)-[(S)-6,6-dimethyl- 2-piperidyl](o- +++ + fluorophenyl)methanol (S)-(o-chlorophenyl)(4- methyl-7- +++ - azabicyclo[2.2.1]hept- 1-yl)methanol (R)-(o-chlorophenyl)(4- methyl-7- +++ - azabicyclo[2.2.1]hept- 1-yl)methanol (S)-(m-chlorophenyl)(4- methyl-7- + - azabicyclo[2.2.1]hept- 1-yl)methanol (R)-(m-chlorophenyl)(4- methyl-7- +++ - azabicyclo[2.2.1]hept- 1-yl)methanol (R)-[(R)-4,4-dimethyl- 2-azetidinyl](m- +++ + fluorophenyl)methanol (S)-[(S)-4,4-dimethyl- 2-azetidinyl](m- + - fluorophenyl)methanol (R)-[(S)-4,4-dimethyl- 2-azetidinyl](m- - - fluorophenyl)methanol (S)-[(R)-4,4-dimethyl- 2-azetidinyl](m- - - fluorophenyl)methanol (R)-[(S)-4,4-dimethyl- 2-azetidinyl](o- - - fluorophenyl)methanol (S)-[(R)-4,4-dimethyl- 2-azetidinyl](o- + - fluorophenyl)methanol (R)-[(R)-4,4-dimethyl- 2-azetidinyl](o- +++ + fluorophenyl)methanol (S)-[(S)-4,4-dimethyl- 2-azetidinyl](o- + - fluorophenyl)methanol (R)-{(R)-1-methyl-2- azabicyclo[2.1.1]hex-3- +++ - yl}(m- chlorophenyl)methanol (S)-{(S)-1-methyl-2- azabicyclo[2.1.1]hex-3- + - yl}(m- chlorophenyl)methanol (S)-{(R)-1-methyl-2- azabicyclo[2.1.1]hex-3- ++ - yl}(m- chlorophenyl)methanol (R)-{(S)-1-methyl-2- azabicyclo[2.1.1]hex-3- + - yl}(m- chlorophenyl)methanol (R)-{(R)-1-methyl-2- azabicyclo[2.1.1]hex-3- +++ +++ yl}(o- fluorophenyl)methanol (S)-{(S)-1-methyl-2- azabicyclo[2.1.1]hex-3- +++ - yl}(o- fluorophenyl)methanol (S)-{(R)-1-methyl-2- azabicyclo[2.1.1]hex-3- +++ - yl}(o- fluorophenyl)methanol (R)-{(S)-1-methyl-2- azabicyclo[2.1.1]hex-3- +++ - yl}(o- fluorophenyl)methanol (R)-[(R)-4,4-dimethyl- 2-azetidinyl](5-fluoro-3- +++ - pyridyl)methanol (S)-[(S)-4,4-dimethyl- 2-azetidinyl](5-fluoro-3- + - pyridyl)methanol (R)-[(S)-4,4-dimethyl- 2-azetidinyl](5-fluoro-3- + - pyridyl)methanol (S)-[(R)-4,4-dimethyl- 2-azetidinyl](5-fluoro-3- + - pyridyl)methanol (S)-[(2R,7R)-7-propyl- 2-azepanyl](5-fluoro-3- - - pyridyl)methanol (R)-[(2R,7R)-7-propyl- 2-azepanyl](5-fluoro-3- - - pyridyl)methanol (R)-{(R)-1-methyl-2- azabicyclo[2.1.1]hex-3- +++ - yl}(5-fluoro-3- pyridyl)methanol (S)-{(S)-1-methyl-2- azabicyclo[2.1.1]hex-3- ++ - yl}(5-fluoro-3- pyridyl)methanol (S)-{(R)-1-methyl-2- azabicyclo[2.1.1]hex-3- - - yl}(5-fluoro-3- pyridyl)methanol (R)-{(S)-1-methyl-2- azabicyclo[2.1.1]hex-3- + - yl}(5-fluoro-3- pyridyl)methanol (R)-1-(m-fluorophenyl)- 2-{2-[(1r,4R)-4- + - methoxycyclohexyl]ethy lamino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{2-[(1r,4R)- 4- ++ - methoxycyclohexyl]ethy lamino}-1-ethanol (S)-[(R)-5,5-dimethyl- 2-pyrrolidinyl](3-amino- + - 2- fluorophenyl)methanol (R)-[(R)-5,5-dimethyl- 2-pyrrolidinyl](3-amino- +++ - 2- fluorophenyl)methanol (R)-1-(m-fluorophenyl)- 2-({[(1r,4R)-4- ++ - methoxycyclohexyl]met hyl}amino)-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-({[(1r,4R)-4- ++ - methoxycyclohexyl]met hyl}amino)-1-ethanol (R)-[(R)-4,4-dimethyl- 2-azetidinyl](m- +++ - chlorophenyl)methanol (S)-[(S)-4,4-dimethyl- 2-azetidinyl](m- + - chlorophenyl)methanol (R)-[(S)-4,4-dimethyl- 2-azetidinyl](m- + - chlorophenyl)methanol (S)-[(R)-4,4-dimethyl- 2-azetidinyl](m- - - chlorophenyl)methanol (R)-[(2S,7S)-7-propyl- 2-azepanyl](5-fluoro-3- +++ - pyridyl)methanol (S)-[(2S,7S)-7-propyl- 2-azepanyl](5-fluoro-3- - - pyridyl)methanol (S)-[(R)-5,5-dimethyl- 2-pyrrolidinyl](4-amino- +++ + 3,5- difluorophenyl)methanol (R)-1-(m-fluorophenyl)- 2-{2-[(1s,4S)-4- ++ - methoxycyclohexyl]ethy lamino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{2-[(1s,4S)- 4- +++ - methoxycyclohexyl]ethy lamino}-1-ethanol (R)-1-(m-fluorophenyl)- 2-{1-methyl-1- +++ - [(1r,4R)-4- methoxycyclohexyl]ethy lamino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{1-methyl-1- [(1r,4R)-4- +++ - methoxycyclohexyl]ethy lamino}-1-ethanol (R)-{(R)-1-methyl-2- azabicyclo[2.1.1]hex-3- +++ - yl}(3-amino-2- fluorophenyl)methanol (S)-{(S)-1-methyl-2- azabicyclo[2.1.1]hex-3- ++ - yl}(3-amino-2- fluorophenyl)methanol (S)-{(R)-1-methyl-2- azabicyclo[2.1.1]hex-3- ++ - yl}(3-amino-2- fluorophenyl)methanol (R)-{(S)-1-methyl-2- azabicyclo[2.1.1]hex-3- ++ - yl}(3-amino-2- fluorophenyl)methanol (R)-1-(m-fluorophenyl)- 2-({[(1s,4S)-4- ++ - methoxycyclohexyl]met hyl}amino)-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-({[(1s,4S)-4- ++ - methoxycyclohexyl]met hyl}amino)-1-ethanol (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- methoxycyclohexyl]ethy +++ - lamino}-1-(m- fluorophenyl)-1-ethanol (R)-2-{1,1-dimethyl-2- +++ - [(1s,4S)-4- methoxycyclohexyl]ethy lamino}-1-(5-fluoro-3- pyridyl)-1-ethanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- methoxycyclohexyl]ethy +++ - lamino}-1-(m- fluorophenyl)-1-ethanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- methoxycyclohexyl]ethy ++ - lamino}-1-(5-fluoro-3- pyridyl)-1-ethanol (R)-1-(m-fluorophenyl)- 2-{1-methyl-1- [(1s,4S)-4- - - methoxycyclohexyl]ethy lamino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{1-methyl-1- [(1s,4S)-4- - - methoxycyclohexyl]ethy lamino}-1-ethanol (S)-(3-fluoro-4- pyridyl)(4-methyl-7- - - azabicyclo[2.2.1]hept- 1-yl)methanol (R)-(3-fluoro-4- pyridyl)(4-methyl-7- - - azabicyclo[2.2.1]hept- 1-yl)methanol (R)-2-{1-[(1S,3R)-3- methoxycyclohexyl]-1- methylethylamino}-1- +++ - (m-fluorophenyl)-1- ethanol (R)-2-{1-[(1R,3S)-3- +++ + methoxycyclohexyl]-1- methylethylamino}-1- (m-fluorophenyl)-1- ethanol (R)-2-{1-[(1S,3R)-3- methoxycyclohexyl]-1- methylethylamino}-1- ++ - (5-fluoro-3-pyridyl)-1- ethanol (R)-1-(m-fluorophenyl)- 2-{3-[(1s,4R)-4- +++ ++ methoxycyclohexyl]prop ylamino}-1-ethanol (R)-1-(m-fluorophenyl)- 2-{3-[(1r,4S)-4- + - methoxycyclohexyl]prop ylamino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{3-[(1s,4R)- 4- +++ - methoxycyclohexyl]prop ylamino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{3-[(1r,4S)- 4- - - methoxycyclohexyl]prop ylamino}-1-ethanol (R)-1-(m-fluorophenyl)- 2-({[(1s,4S)-4- (benzyloxy)cyclohexyl] + - methyl}amino)-1- ethanol (R)-1-(5-fluoro-3- pyridyl)-2-({[(1s,4S)-4- (benzyloxy)cyclohexyl] +++ - methyl}amino)-1- ethanol (R)-2-{1,1-dimethyl-3- +++ + [(1s,4R)-4- methoxycyclohexyl]prop ylamino}-1-(m- fluorophenyl)-1-ethanol (R)-2-{1,1-dimethyl-3- [(1r,4S)-4- methoxycyclohexyl]prop ++ - ylamino}-1-(m- fluorophenyl)-1-ethanol (1s,4R)-4- methoxycyclohexyl]prop +++ - ylamino}-1-(5-fluoro-3- pyridyl)-1-ethanol (R)-2-{1,1-dimethyl-3- [(1r,4S)-4- methoxycyclohexyl]prop + - ylamino}-1-(5-fluoro-3- pyridyl)-1-ethanol (R)-1-(m-fluorophenyl)- 2-({[(1s,4S)-4- + - hydroxycyclohexyl]meth yl}amino)-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-({[(1s,4S)-4- + - hydroxycyclohexyl]meth yl}amino)-1-ethanol (R)-2-{1-[(1R,3S)-3- methoxycyclohexyl]-1- methylethylamino}-1- +++ ++ (5-fluoro-3-pyridyl)-1- ethanol (R)-1-(m-fluorophenyl)- 2-({[(1r,4R)-4- (benzyloxy)cyclohexyl] + - methyl}amino)-1- ethanol (R)-1-(m-fluorophenyl)- + - 2-({[(1r,4R)-4- hydroxycyclohexyl]meth yl}amino)-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-({[(1r,4R)-4- (benzyloxy)cyclohexyl] + - methyl}amino)-1- ethanol (R)-1-(5-fluoro-3- pyridyl)-2-({[(1r,4R)-4- - - hydroxycyclohexyl]meth yl}amino)-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{3-[(1s,4R)- 4- ++ - (benzyloxy)cyclohexyl]p ropylamino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{3-[(1r,4S)- 4- + - (benzyloxy)cyclohexyl]p ropylamino}-1-ethanol (R)-1-(m-fluorophenyl)- 2-{3-[(1s,4R)-4- + - (benzyloxy)cyclohexyl]p ropylamino}-1-ethanol (R)-1-(m-fluorophenyl)- 2-{3-[(1r,4S)-4- + - (benzyloxy)cyclohexyl]p ropylamino}-1-ethanol (R)-1-(m-fluorophenyl)- 2-{1-methyl-1- [(1r,4R)-4- ++ - (benzyloxy)cyclohexyl]e thylamino}-1-ethanol (R)-1-(m-fluorophenyl)- 2-{1-methyl-1- +++ - [(1s,4S)-4- (benzyloxy)cyclohexyl]e thylamino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{1-methyl-1- [(1r,4R)-4- ++ - (benzyloxy)cyclohexyl]e thylamino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{1-methyl-1- [(1s,4S)-4- ++ - (benzyloxy)cyclohexyl]e thylamino}-1-ethanol (R)-1-(m-fluorophenyl)- 2-{1-methyl-1- [(1r,4R)-4- ++ - hydroxycyclohexyl]ethyl amino}-1-ethanol (R)-1-(m-fluorophenyl)- 2-{1-methyl-1- [(1s,4S)-4- ++ - hydroxycyclohexyl]ethyl amino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{1-methyl-1- [(1r,4R)-4- ++ - hydroxycyclohexyl]ethyl amino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{1-methyl-1- [(1s,4S)-4- + - hydroxycyclohexyl]ethyl amino}-1-ethanol (R)-1-(m-fluorophenyl)- 2-{2-[(1s,4S)-4- ++ - (benzyloxy)cyclohexyl]e thylamino}-1-ethanol (R)-1-(m-fluorophenyl)- + - 2-{2-[(1r,4R)-4- (benzyloxy)cyclohexyl]e thylamino}-1-ethanol (R)-2-{1,1-dimethyl-3- [(1r,4S)-4- hydroxycyclohexyl]prop + - ylamino}-1-(5-fluoro-3- pyridyl)-1-ethanol (R)-2-{1,1-dimethyl-3- [(1r,4S)-4- hydroxycyclohexyl]prop + - ylamino}-1-(m- fluorophenyl)-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{2-[(1s,4S)- 4- ++ - (benzyloxy)cyclohexyl]e thylamino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{2-[(1r,4R)- 4- - - (benzyloxy)cyclohexyl]e thylamino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{2-[(1s,4S)- 4- + - hydroxycyclohexyl]ethyl amino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{2-[(1r,4R)- 4- + - hydroxycyclohexyl]ethyl amino}-1-ethanol (R)-2-{1,1-dimethyl-3- [(1s,4R)-4- hydroxycyclohexyl]prop +++ - ylamino}-1-(m- fluorophenyl)-1-ethanol (R)-2-{1,1-dimethyl-3- [(1s,4R)-4- hydroxycyclohexyl]prop +++ - ylamino}-1-(5-fluoro-3- pyridyl)-1-ethanol (R)-1-(m-fluorophenyl)- 2-{2-[(1s,4S)-4- ++ - hydroxycyclohexyl]ethyl amino}-1-ethanol (R)-1-(m-fluorophenyl)- 2-{2-[(1r,4R)-4- + - hydroxycyclohexyl]ethyl amino}-1-ethanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- hydroxycyclohexyl]ethyl ++ - amino}-1-(5-fluoro-3- pyridyl)-1-ethanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- hydroxycyclohexyl]ethyl +++ - amino}-1-(m- fluorophenyl)-1-ethanol (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- hydroxycyclohexyl]ethyl +++ - amino}-1-(5-fluoro-3- pyridyl)-1-ethanol (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- hydroxycyclohexyl]ethyl ++ - amino}-1-(m- fluorophenyl)-1-ethanol (R)-1-(m-fluorophenyl)- 2-{3-[(1r,4S)-4- ++ - hydroxycyclohexyl]prop ylamino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{3-[(1s,4R)- 4- ++ - hydroxycyclohexyl]prop ylamino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{3-[(1r,4S)- 4- + - hydroxycyclohexyl]prop ylamino}-1-ethanol (R)-1-(m-fluorophenyl)- 2-{3-[(1s,4R)-4- + - hydroxycyclohexyl]prop ylamino}-1-ethanol N-[(1S,4s)-4-{[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]met ++ - hyl}cyclohexyl]acetamid e N-[(1R,4r)-4-{[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]met ++ - hyl}cyclohexyl]acetamid e N-[(1R,4r)-4-{[(R)-2- (5-fluoro-3-pyridyl)-2- hydroxyethylamino]met ++ - hyl}cyclohexyl]acetamid e N-[(1S,4s)-4-{[(R)-2- (5-fluoro-3-pyridyl)-2- hydroxyethylamino]met + - hyl}cyclohexyl]acetamid e (R)-1-(m-fluorophenyl)- 2-({[(1r,4R)-4- ++ - (mesylamino)cyclohexyl ]methyl}amino)-1- ethanol (R)-1-(m-fluorophenyl)- 2-({[(1s,4S)-4- (mesylamino)cyclohexyl ++ - ]methyl}amino)-1- ethanol (R)-1-(5-fluoro-3- pyridyl)-2-({[(1r,4R)-4- (mesylamino)cyclohexyl + - ]methyl}amino)-1- ethanol (R)-1-(5-fluoro-3- pyridyl)-2-({[(1s,4S)-4- (mesylamino)cyclohexyl ++ - ]methyl}amino)-1- ethanol N-[(1R,4r)-4-{[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]met +++ - hyl}cyclohexyl]benzami de N-[(1S,4s)-4-{[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]met ++ - hyl}cyclohexyl]benzami de N-[(1R,4r)-4-{[(R)-2- (5-fluoro-3-pyridyl)-2- hydroxyethylamino]met ++ - hyl}cyclohexyl]benzami de N-[(1S,4s)-4-{[(R)-2- (5-fluoro-3-pyridyl)-2- hydroxyethylamino]met ++ - hyl}cyclohexyl]benzami de (R)-2-{1,1-dimethyl-3- [(1r,4S)-4- hydroxycyclohexyl]prop +++ - ylamino}-1-(o- fluorophenyl)-1-ethanol (R)-2-{1,1-dimethyl-3- [(1s,4R)-4- hydroxycyclohexyl]prop +++ + ylamino}-1-(o- fluorophenyl)-1-ethanol (1S,4s)-8-[(R)-2-(5- fluoro-3-pyridyl)-2- hydroxyethylamino]-7- ++ - methoxy-p-menthan-7- one methyl (1S,4s)-4-{2- [(R)-2-(5-fluoro-3- pyridyl)-2- +++ - hydroxyethylamino]-2- methylpropyl}cyclohexa necarboxylate (1S,4s)-8-[(R)-2-(5- fluoro-3-pyridyl)-2- hydroxyethylamino]-7- + ++ hydroxy-p-menthan-7- one (1S,4s)-4-{2-[(R)-2-(5- fluoro-3-pyridyl)-2- hydroxyethylamino]-2- + - methylpropyl}cyclohexa necarboxylic acid (S)-[(2R,5S)-5- {[(1r,4S)-4- methoxycyclohexyl]met +++ - hyl}-2-pyrrolidinyl](m- fluorophenyl)methanol (R)-[(2R,5S)-5- +++ - {[(1r,4S)-4- methoxycyclohexyl]met hyl}-2-pyrrolidinyl](m- fluorophenyl)methanol methyl (1S,4s)-4-{2- [(R)-2-(m- fluorophenyl)-2- +++ - hydroxyethylamino]-2- methylpropyl}cyclohexa necarboxylate (1S,4s)-8-[(R)-2-(m- fluorophenyl)-2- hydroxyethylamino]-7- +++ - methoxy-p-menthan-7- one (S)-(m-fluorophenyl){4- (methoxymethyl)-7- + - azabicyclo[2.2.1]hept- 1-yl}methanol (R)-(m-fluorophenyl){4- (methoxymethyl)-7- +++ - azabicyclo[2.2.1]hept- 1-yl}methanol (1S,4s)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- + - methylpropyl}cyclohexa necarboxylic acid (S)-[(2R,5S)-5- {[(1r,4S)-4- methoxycyclohexyl]met + - hyl}-2-pyrrolidinyl](5- fluoro-3- pyridyl)methanol (R)-[(2R,5S)-5- {[(1r,4S)-4- + - methoxycyclohexyl]met hyl}-2-pyrrolidinyl](5- fluoro-3- pyridyl)methanol (S)-[(2R,5R)-5- {[(1r,4R)-4- methoxycyclohexyl]met + - hyl}-2-pyrrolidinyl](m- fluorophenyl)methanol (R)-[(2R,5R)-5- {[(1r,4R)-4- methoxycyclohexyl]met +++ - hyl}-2-pyrrolidinyl](m- fluorophenyl)methanol (S)-[(2R,5S)-5- {[(1r,4S)-4- methoxycyclohexyl]met + - hyl}-2-pyrrolidinyl](o- fluorophenyl)methanol (R)-[(2R,5S)-5- {[(1r,4S)-4- methoxycyclohexyl]met +++ - hyl}-2-pyrrolidinyl](o- fluorophenyl)methanol (S)-[(2R,5R)-5- {[(1r,4R)-4- methoxycyclohexyl]met ++ - hyl}-2-pyrrolidinyl](o- fluorophenyl)methanol (R)-[(2R,5R)-5- {[(1r,4R)-4- methoxycyclohexyl]met +++ + hyl}-2-pyrrolidinyl](o- fluorophenyl)methanol (S)-[(2R,5R)-5- {[(1r,4R)-4- methoxycyclohexyl]met + - hyl}-2-pyrrolidinyl](5- fluoro-3- pyridyl)methanol (R)-[(2R,5R)-5- {[(1r,4R)-4- methoxycyclohexyl]met +++ - hyl}-2-pyrrolidinyl](5- fluoro-3- pyridyl)methanol methyl (1R,4r)-4-{3- [(R)-2-(5-fluoro-3- pyridyl)-2- +++ - hydroxyethylamino]-3- methylbutyl}cyclohexan ecarboxylate (1R,4r)-4-{3-[(R)-2-(5- fluoro-3-pyridyl)-2- hydroxyethylamino]-3- + - methylbutyl}cyclohexan ecarboxylic acid (R)-1-(5-fluoro-3- pyridyl)-2-{1-methyl-1- [(1r,4R)-4- - - aminocyclohexyl]ethyla mino}-1-ethanol (R)-1-(5-fluoro-3- pyridyl)-2-{1-methyl-1- [(1r,4R)-4- + - (mesylamino)cyclohexyl ]ethylamino}-1-ethanol N-[(1R,4r)-4-{1-[(R)-2- (5-fluoro-3-pyridyl)-2- hydroxyethylamino]-1- +++ - methylethyl}cyclohexyl] acetamide (1S,4s)-4-{3-[(R)-2-(5- fluoro-3-pyridyl)-2- hydroxyethylamino]-3- +++ - methylbutyl}cyclohexan ecarboxylic acid (1R,4r)-4-{3-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-3- - - methylbutyl}cyclohexan ecarboxylic acid methyl (1S,4s)-4-{3- [(R)-2-(5-fluoro-3- pyridyl)-2- +++ + hydroxyethylamino]-3- methylbutyl}cyclohexan ecarboxylate methyl (1R,4r)-4-{3- [(R)-2-(m- fluorophenyl)-2- +++ - hydroxyethylamino]-3- methylbutyl}cyclohexan ecarboxylate methyl (1S,4s)-4-{3- [(R)-2-(m- fluorophenyl)-2- +++ + hydroxyethylamino]-3- methylbutyl}cyclohexan ecarboxylate (1S,4s)-4-{3-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-3- + - methylbutyl}cyclohexan ecarboxylic acid methyl (1R,4r)-4-{2- [(R)-2-(m- fluorophenyl)-2- +++ - hydroxyethylamino]-2- methylpropyl}cyclohexa necarboxylate methyl (1R,4r)-4-{2- [(R)-2-(5-fluoro-3- ++ - pyridyl)-2- hydroxyethylamino]-2- methylpropyl}cyclohexa necarboxylate (1R,4r)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- ++ - methylpropyl}cyclohexa necarboxylic acid (1R,4r)-4-{2-[(R)-2-(5- fluoro-3-pyridyl)-2- hydroxyethylamino]-2- - - methylpropyl}cyclohexa necarboxylic acid N-[(1R,4r)-4-{2-[(R)-2- (5-fluoro-3-pyridyl)-2- hydroxyethylamino]-2- +++ - methylpropyl}cyclohexy l]acetamide (R)-2-{1,1-dimethyl-3- [(1r,4R)-4- aminocyclohexyl]propyl + - amino}-1-(5-fluoro-3- pyridyl)-1-ethanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- aminocyclohexyl]ethyla +++ - mino}-1-(5-fluoro-3- pyridyl)-1-ethanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- (mesylamino)cyclohexyl +++ - ]ethylamino}-1-(5- fluoro-3-pyridyl)-1- ethanol N-[(1R,4r)-4-{3-[(R)-2- (5-fluoro-3-pyridyl)-2- hydroxyethylamino]-3- +++ - methylbutyl}cyclohexyl] acetamide (R)-2-{1,1-dimethyl-3- [(1r,4R)-4- (mesylamino)cyclohexyl ++ - ]propylamino}-1-(5- fluoro-3-pyridyl)-1- ethanol (S)-[(2R,5S)-5-methyl- 5-{[(1r,4S)-4- methoxycyclohexyl]met +++ - hyl}-2-pyrrolidinyl](m- fluorophenyl)methanol (R)-[(2R,5S)-5-methyl- 5-{[(1r,4S)-4- methoxycyclohexyl]met +++ ++ hyl}-2-pyrrolidinyl](m- fluorophenyl)methanol (S)-{(2R,5R)-5-[(p- methoxyphenyl)methyl] -5-methyl-2- +++ - pyrrolidinyl}(m- fluorophenyl)methanol (R)-{(2R,5R)-5-[(p- methoxyphenyl)methyl] -5-methyl-2- +++ + pyrrolidinyl}(m- fluorophenyl)methanol (1R,4r)-8-[(R)-2-(m- fluorophenyl)-2- hydroxyethylamino]-7- +++ + methoxy-p-menthan-7- one (1R,4r)-8-[(R)-2-(m- fluorophenyl)-2- hydroxyethylamino]-7- + - hydroxy-p-menthan-7- one (1S,4s)-8-[(R)-2-(m- ++ - fluorophenyl)-2- hydroxyethylamino]-7- hydroxy-p-menthan-7- one (1R,4r)-8-[(R)-2-(5- fluoro-3-pyridyl)-2- hydroxyethylamino]-7- +++ - methoxy-p-menthan-7- one (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- aminocyclohexyl]ethyla +++ - mino}-1-(m- fluorophenyl)-1-ethanol (S)-{(2R,5S)-5-[(p- methoxyphenyl)methyl] +++ - -2-pyrrolidinyl}(m- fluorophenyl)methanol (R)-{(2R,5S)-5-[(p- methoxyphenyl)methyl] +++ + -2-pyrrolidinyl}(m- fluorophenyl)methanol (R)-{(2R,5R)-5-[(p- methoxyphenyl)methyl] +++ - -2-pyrrolidinyl}(m- fluorophenyl)methanol (S)-{(2R,5R)-5-[(p- methoxyphenyl)methyl] +++ - -2-pyrrolidinyl}(m- fluorophenyl)methanol (R)-2-(tert-butylamino)- 1-(2-methyl-3-pyridyl)- 1-ethanol +++ + (S)-{(2R,5S)-5-[(p- methoxyphenyl)methyl] +++ - -2-pyrrolidinyl}(5- fluoro-3- pyridyl)methanol (R)-{(2R,5S)-5-[(p- methoxyphenyl)methyl] -2-pyrrolidinyl}(5- +++ - fluoro-3- pyridyl)methanol (R)-{(2R,5R)-5-[(p- methoxyphenyl)methyl] -2-pyrrolidinyl}(5- +++ - fluoro-3- pyridyl)methanol (S)-{(2R,5R)-5-[(p- methoxyphenyl)methyl] -2-pyrrolidinyl}(5- +++ - fluoro-3- pyridyl)methanol (R)-1-(m-fluorophenyl)- 2-{1-methyl-1- [(1r,4R)-4- ++ - aminocyclohexyl]ethyla mino}-1-ethanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- (mesylamino)cyclohexyl +++ + ]ethylamino}-1-(m- fluorophenyl)-1-ethanol N-[(1R,4r)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- +++ + methylpropyl}cyclohexy l]acetamide N-[(1R,4r)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- +++ +++ methylpropyl}cyclohexy l]benzamide (R)-1-(m-fluorophenyl)- 2-{1-methyl-1- [(1r,4R)-4- ++ - (mesylamino)cyclohexyl ]ethylamino}-1-ethanol N-[(1R,4r)-4-{1-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-1- +++ - methylethyl}cyclohexyl] acetamide 6-[(S)-2-(tert- butylamino)-1- +++ + hydroxyethyl]-2- pyridinecarbonitrile (R)-(4-benzyl-7- azabicyclo[2.2.1]hept- +++ + 1-yl)(m- fluorophenyl)methanol (S)-(4-benzyl-7- azabicyclo[2.2.1]hept- ++ - 1-yl)(m- fluorophenyl)methanol (1R,4r)-8-[(R)-2-(5- fluoro-3-pyridyl)-2- hydroxyethylamino]-7- ++ - hydroxy-p-menthan-7- one (S)-{(2R,5S)-5-[(p- chlorophenyl)methyl]-2- ++ - pyrrolidinyl}(m- fluorophenyl)methanol (R)-{(2R,5S)-5-[(p- chlorophenyl)methyl]-2- +++ - pyrrolidinyl}(m- fluorophenyl)methanol (R)-{(2R,5R)-5-[(p- +++ - chlorophenyl)methyl]-2- pyrrolidinyl}(m- fluorophenyl)methanol (S)-{(2R,5R)-5-[(p- chlorophenyl)methyl]-2- ++ - pyrrolidinyl}(m- fluorophenyl)methanol (S)-(4-{[(p- chlorophenyl)methoxy] methyl}-7- ++ - azabicyclo[2.2.1]hept- 1-yl)(m- fluorophenyl)methanol (R)-(4-{[(p- chlorophenyl)methoxy] methyl}-7- +++ - azabicyclo[2.2.1]hept- 1-yl)(m- fluorophenyl)methanol (S)-2-(tert-butylamino)- 1-[6-(trifluoromethyl)- +++ - 2-pyridyl]-1-ethanol ethyl [(1R,4r)-4-{1- [(R)-2-(m- fluorophenyl)-2- +++ - hydroxyethylamino]-1- methylethyl}cyclohexyl oxy]acetate (1S,4s)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- +++ + methylpropyl}cyclohexa necarbonitrile (S)-(m-fluorophenyl){4- [(p- methoxyphenyl)methyl] ++ - -7- azabicyclo[2.2.1]hept- 1-yl}methanol (R)-(m-fluorophenyl){4- [(p- methoxyphenyl)methyl] +++ - -7- azabicyclo[2.2.1]hept- 1-yl}methanol [(1R,4r)-4-{1-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-1- ++ - methylethyl}cyclohexyl oxy]acetic acid (S)-{(2R,5S)-5-[(p- chlorophenyl)methyl]-2- ++ - pyrrolidinyl}(5-fluoro-3- pyridyl)methanol (R)-{(2R,5S)-5-[(p- chlorophenyl)methyl]-2- +++ - pyrrolidinyl}(5-fluoro-3- pyridyl)methanol (S)-{(2R,5R)-5-[(p- chlorophenyl)methyl]-2- +++ - pyrrolidinyl}(5-fluoro-3- pyridyl)methanol (R)-{(2R,5R)-5-[(p- chlorophenyl)methyl]-2- +++ - pyrrolidinyl}(5-fluoro-3- pyridyl)methanol ethyl [(1S,4s)-4-{1- [(R)-2-(m- fluorophenyl)-2- ++ - hydroxyethylamino]-1- methylethyl}cyclohexyl oxy]acetate [(1S,4s)-4-{1-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-1- ++ - methylethyl}cyclohexyl oxy]acetic acid ethyl [(1R,4r)-4-{1- [(R)-2-(5-fluoro-3- pyridyl)-2- +++ - hydroxyethylamino]-1- methylethyl}cyclohexyl oxy]acetate (S)-(m-fluorophenyl)(4- {2-[(1r,4R)-4- methoxycyclohexyl]ethy ++ - l}-7- azabicyclo[2.2.1]hept- 1-yl)methanol (R)-(m-fluorophenyl)(4- {2-[(1r,4S)-4- methoxycyclohexyl]ethy +++ ++ l}-7- azabicyclo[2.2.1]hept- 1-yl)methanol (S)-(m-fluorophenyl){4- [(p- fluorophenyl)methyl]-7- ++ - azabicyclo[2.2.1]hept- 1-yl}methanol (R)-(m-fluorophenyl){4- [(p- fluorophenyl)methyl]-7- +++ - azabicyclo[2.2.1]hept- 1-yl}methanol (1R,4s)-4-{2-[(S)-2-(6- cyano-2-pyridyl)-2- hydroxyethylamino]-2- ++ - methylpropyl}cyclohexy l 2-methyl-2- propanecarbamate 6-[(R)-2-{1,1-dimethyl- 2-[(1r,4R)-4- ++ - aminocyclohexyl]ethyla mino}-1-hydroxyethyl]- 2-pyridinecarbonitrile 6-[(R)-2-{1,1-dimethyl- 2-[(1s,4S)-4- aminocyclohexyl]ethyla ++ - mino}-1-hydroxyethyl]- 2-pyridinecarbonitrile 6-[(S)-2-{1,1-dimethyl- 2-[(1r,4S)-4- aminocyclohexyl]ethyla +++ + mino}-1-hydroxyethyl]- 2-pyridinecarbonitrile 6-[(S)-2-{1,1-dimethyl- 2-[(1s,4R)-4- aminocyclohexyl]ethyla ++ - mino}-1-hydroxyethyl]- 2-pyridinecarbonitrile [(1R,4r)-4-{1-[(R)-2- (5-fluoro-3-pyridyl)-2- hydroxyethylamino]-1- ++ - methylethyl}cyclohexyl oxy]acetic acid (1R,4r)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- ++ + methylpropyl}cyclohexy l 2-methyl-2- propanecarbamate N-[(1R,4s)-4-{2-[(S)-2- (6-cyano-2-pyridyl)-2- hydroxyethylamino]-2- +++ - methylpropyl}cyclohexy l]acetamide 6-[(S)-2-{1,1-dimethyl- 2-[(1s,4R)-4- ++ - (mesylamino)cyclohexyl ]ethylamino}-1- hydroxyethyl]-2- pyridinecarbonitrile N-[(1S,4s)-4-{2-[(R)-2- (6-cyano-2-pyridyl)-2- hydroxyethylamino]-2- - - methylpropyl}cyclohexy l]acetamide 6-[(R)-2-{1,1-dimethyl- 2-[(1s,4S)-4- (mesylamino)cyclohexyl + - ]ethylamino}-1- hydroxyethyl]-2- pyridinecarbonitrile N-[(1S,4r)-4-{2-[(S)-2- (6-cyano-2-pyridyl)-2- hydroxyethylamino]-2- +++ + methylpropyl}cyclohexy l]acetamide 6-[(S)-2-{1,1-dimethyl- 2-[(1r,4S)-4- (mesylamino)cyclohexyl +++ - ]ethylamino}-1- hydroxyethyl]-2- pyridinecarbonitrile N-[(1R,4r)-4-{2-[(R)-2- (6-cyano-2-pyridyl)-2- hydroxyethylamino]-2- - - methylpropyl}cyclohexy l]acetamide 6-[(R)-2-{1,1-dimethyl- 2-[(1r,4R)-4- (mesylamino)cyclohexyl - - ]ethylamino}-1- hydroxyethyl]-2- pyridinecarbonitrile N-[(1R,4r)-4-{2-[(R)-2- (m-fluorophenyl)-2- +++ + hydroxyethylamino]-2- methylpropyl}cyclohexy l]2,2- dimethylpropionamide (R)-2-{1,1-dimethyl-2- [(1r,4R)-4-(3,3- dimethylureido)cyclohex +++ ++ yl]ethylamino}-1-(m- fluorophenyl)-1-ethanol N-[(1R,4r)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- +++ ++ methylpropyl}cyclohexy l]cyclobutanecarboxami de N-[(1R,4r)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- +++ +++ methylpropyl}cyclohexy l]cyclopropanecarboxam ide N-[(1R,4r)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- +++ + methylpropyl}cyclohexy l]trifluoroacetamide N-[(1R,4r)-4-{2-[(R)-2- hydroxy-2-(2-methyl-3- pyridyl)ethylamino]-2- +++ - methylpropyl}cyclohexy l]acetamide (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- (mesylamino)cyclohexyl + - ]ethylamino}-1-(2- methyl-3-pyridyl)-1- ethanol N-[(1S,4s)-4-{2-[(R)-2- ++ - hydroxy-2-(2-methyl-3- pyridyl)ethylamino]-2- methylpropyl}cyclohexy l]acetamide (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- (mesylamino)cyclohexyl + - ]ethylamino}-1-(2- methyl-3-pyridyl)-1- ethanol (S)-(m-fluorophenyl)(4- {[(p- fluorophenyl)methoxy] - - methyl}-7- azabicyclo[2.2.1]hept- 1-yl)methanol (R)-(m-fluorophenyl)(4- {[(p- fluorophenyl)methoxy] +++ + methyl}-7- azabicyclo[2.2.1]hept- 1-yl)methanol (S)-{4-[(p- chlorophenoxy)methyl]- 7- +++ - azabicyclo[2.2.1]hept- 1-yl}(m- fluorophenyl)methanol (R)-{4-[(p- chlorophenoxy)methyl]- 7- +++ - azabicyclo[2.2.1]hept- 1-yl}(m- fluorophenyl)methanol (S)-(4-{[(p- fluorophenyl)methoxy] + - methyl}-7- azabicyclo[2.2.1]hept- 1-yl)(5-fluoro-3- pyridyl)methanol (R)-(4-{[(p- fluorophenyl)methoxy] methyl}-7- +++ + azabicyclo[2.2.1]hept- 1-yl)(5-fluoro-3- pyridyl)methanol (R)-(o-fluorophenyl){4- [2-(3-pyridyl)ethyl]-7- +++ ++ azabicyclo[2.2.1]hept- 1-yl}methanol (S)-(m-fluorophenyl){4- [2-(3-pyridyl)ethyl]-7- +++ - azabicyclo[2.2.1]hept- 1-yl}methanol (R)-(m-fluorophenyl){4- [2-(3-pyridyl)ethyl]-7- +++ ++ azabicyclo[2.2.1]hept- 1-yl}methanol N-[(1S,4s)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- +++ - methylpropyl}cyclohexy l]cyclopropanecarboxam ide N-[(1S,4s)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- ++ - methylpropyl}cyclohexy l]cyclobutanecarboxami de (1S,4s)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- ++ - methylpropyl}cyclohexy l 2-methyl-2- propanecarbamate (1R,4s)-4-(2-{(S)-2- hydroxy-2-[6- (trifluoromethyl)-2- pyridyl]ethylamino}-2- - - methylpropyl)cyclohexyl 2-methyl-2- propanecarbamate (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- (propylsulfonylamino)cy ++ + clohexyl]ethylamino}-1- (m-fluorophenyl)-1- ethanol N-[(1S,4s)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- +++ - methylpropyl}cyclohexy l]acetamide (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- (mesylamino)cyclohexyl +++ - ]ethylamino}-1-(m- fluorophenyl)-1-ethanol N-[(1S,4s)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- +++ - methylpropyl}cyclohexy l]trifluoroacetamide N-[(1S,4s)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- ++ - methylpropyl}cyclohexy l]2,2- dimethylpropionamide (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- +++ - aminocyclohexyl]ethyla mino}-1-(m- fluorophenyl)-1-ethanol (R)-2-{1,1-dimethyl-2- [(1s,4S)-4-(3,3- dimethylureido)cyclohex +++ + yl]ethylamino}-1-(m- fluorophenyl)-1-ethanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- (trifluoromesylamino)cy +++ - clohexyl]ethylamino}-1- (m-fluorophenyl)-1- ethanol (1S,4r)-4-(2-{(S)-2- hydroxy-2-[6- (trifluoromethyl)-2- pyridyl]ethylamino}-2- +++ - methylpropyl)cyclohexyl 2-methyl-2- propanecarbamate N-[(1S,4r)-4-(2-{(S)-2- hydroxy-2-[6- (trifluoromethyl)-2- ++ - pyridyl]ethylamino}-2- methylpropyl)cyclohexyl ]acetamide (S)-2-{1,1-dimethyl-2- [(1r,4S)-4- (mesylamino)cyclohexyl + - ]ethylamino}-1-[6- (trifluoromethyl)-2- pyridyl]-1-ethanol N-[(1R,4s)-4-(2-{(S)-2- hydroxy-2-[6- (trifluoromethyl)-2- + - pyridyl]ethylamino}-2- methylpropyl)cyclohexyl ]acetamide (S)-2-{1,1-dimethyl-2- [(1s,4R)-4- (mesylamino)cyclohexyl ++ - ]ethylamino}-1-[6- (trifluoromethyl)-2- pyridyl]-1-ethanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- (dimethylaminosulfonyl) + + cyclohexyl]ethylamino}- 1-(m-fluorophenyl)-1- ethanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- (dimethylaminosulfonyl) ++ + cyclohexyl]ethylamino}- 1-(5-fluoro-3-pyridyl)- 1-ethanol (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- aminocyclohexyl]ethyla ++ - mino}-1-(5-fluoro-3- pyridyl)-1-ethanol N-[(1S,4s)-4-{2-[(R)-2- (5-fluoro-3-pyridyl)-2- hydroxyethylamino]-2- +++ - methylpropyl}cyclohexy l]acetamide (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- (mesylamino)cyclohexyl +++ - ]ethylamino}-1-(5- fluoro-3-pyridyl)-1- ethanol (1S,4s)-4-{2-[(R)-2-(5- fluoro-3-pyridyl)-2- +++ - hydroxyethylamino]-2- methylpropyl}cyclohexy l 2-methyl-2- propanecarbamate (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- (dimethylaminosulfonyl) +++ + cyclohexyl]ethylamino}- 1-(m-fluorophenyl)-1- ethanol (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- (dimethylaminosulfonyl) +++ ++ cyclohexyl]ethylamino}- 1-(5-fluoro-3-pyridyl)- 1-ethanol (S)-[4-({p-[(benzyl)-N- mesylamino]phenyl}me thyl)-7- + - azabicyclo[2.2.1]hept- 1-yl](m- fluorophenyl)methanol (R)-[4-({p-[(benzyl)-N- mesylamino]phenyl}me thyl)-7- + - azabicyclo[2.2.1]hept- 1-yl](m- fluorophenyl)methanol (S)-(m-fluorophenyl)(4- {[p- (mesylamino)phenyl]me ++ - thyl}-7- azabicyclo[2.2.1]hept- 1-yl)methanol (R)-(m-fluorophenyl)(4- {[p- (mesylamino)phenyl]me ++ - thyl}-7- azabicyclo[2.2.1]hept- 1-yl)methanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- (methylaminosulfonyl)c +++ + yclohexyl]ethylamino}- 1-(m-fluorophenyl)-1- ethanol (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- (methylaminosulfonyl)c ++ - yclohexyl]ethylamino}- 1-(m-fluorophenyl)-1- ethanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- (methylaminosulfonyl)c + - yclohexyl]ethylamino}- 1-(5-fluoro-3-pyridyl)- 1-ethanol N-[(1R,4s)-4- ({(2S,5R)-5-[(S)-(m- fluorophenyl)hydroxyme thyl]-2- - - pyrrolidinyl}methyl)cycl ohexyl]-N- benzylacetamide N-[(1R,4s)-4- ({(2S,5R)-5-[(R)-(m- fluorophenyl)hydroxyme thyl]-2- - - pyrrolidinyl}methyl)cycl ohexyl]-N- benzylacetamide N-[(1S,4r)-4-({(2S,5R)- 5-[(S)-(m- fluorophenyl)hydroxyme - - thyl]-2- pyrrolidinyl}methyl)cycl ohexyl]-N- benzylacetamide N-[(1S,4r)-4-({(2S,5R)- 5-[(R)-(m- fluorophenyl)hydroxyme thyl]-2- - - pyrrolidinyl}methyl)cycl ohexyl]-N- benzylacetamide N-[(1R,4s)-4- ({(2S,5R)-5-[(S)-(m- fluorophenyl)hydroxyme - - thyl]-2- pyrrolidinyl}methyl)cycl ohexyl]acetamide N-[(1R,4s)-4- ({(2S,5R)-5-[(R)-(m- fluorophenyl)hydroxyme ++ - thyl]-2- pyrrolidinyl}methyl)cycl ohexyl]acetamide N-[(1S,4r)-4-({(2S,5R)- 5-[(R)-(m- fluorophenyl)hydroxyme ++ - thyl]-2- pyrrolidinyl}methyl)cycl ohexyl]acetamide N-[(1S,4r)-4-({(2S,5R)- 5-[(S)-(m- fluorophenyl)hydroxyme ++ - thyl]-2- pyrrolidinyl}methyl)cycl ohexyl]acetamide (S)-(m-fluorophenyl)(4- {[(p- - - trifluoromethoxyphenyl) methoxy]methyl}-7- azabicyclo[2.2.1]hept- 1-yl)methanol (R)-(m-fluorophenyl)(4- {[(p- trifluoromethoxyphenyl) - - methoxy]methyl}-7- azabicyclo[2.2.1]hept- 1-yl)methanol (S)-(5-fluoro-3- pyridyl)(4-{[(p- trifluoromethoxyphenyl) - - methoxy]methyl}-7- azabicyclo[2.2.1]hept- 1-yl)methanol (R)-(5-fluoro-3- pyridyl)(4-{[(p- trifluoromethoxyphenyl) ++ - methoxy]methyl}-7- azabicyclo[2.2.1]hept- 1-yl)methanol N-[(1R,4r)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- +++ - methylpropyl}cyclohexy l]-N-methylacetamide N-[(1S,4s)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- + - methylpropyl}cyclohexy l]-N-methylacetamide (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- (trifluoromesylamino)cy + - clohexyl]ethylamino}-1- (m-fluorophenyl)-1- ethanol (R)-2-{1,1-dimethyl-2- + - [(1s,4S)-4- (cyclopropylsulfonylami no)cyclohexyl]ethylamin o}-1-(m-fluorophenyl)- 1-ethanol (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- (methylaminosulfonyl)c ++ - yclohexyl]ethylamino}- 1-(5-fluoro-3-pyridyl)- 1-ethanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- (cyclopropylsulfonylami ++ - no)cyclohexyl]ethylamin o}-1-(m-fluorophenyl)- 1-ethanol (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- (propylsulfonylamino)cy ++ - clohexyl]ethylamino}-1- (m-fluorophenyl)-1- ethanol (R)-2-{1,1-dimethyl-2- [(1s,4S)-4-(N-mesyl-N- methylamino)cyclohexyl + - ]ethylamino}-1-(m- fluorophenyl)-1-ethanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4-(N-mesyl-N- methylamino)cyclohexyl + - ]ethylamino}-1-(m- fluorophenyl)-1-ethanol (S)-(m-fluorophenyl){4- [(p- trifluoromethoxyphenyl) - - methyl]-7- azabicyclo[2.2.1]hept- 1-yl}methanol (R)-(m-fluorophenyl){4- [(p- trifluoromethoxyphenyl) - - methyl]-7- azabicyclo[2.2.1]hept- 1-yl}methanol (R)-[(2R,5S)-5- ({(1r,4S)-4-[(benzyl)- N- mesylamino]cyclohexyl} - - methyl)-2- pyrrolidinyl](m- fluorophenyl)methanol (S)-[(2R,5S)-5- ({(1r,4S)-4-[(benzyl)- N- mesylamino]cyclohexyl} - - methyl)-2- pyrrolidinyl](m- fluorophenyl)methanol (R)-[(2R,5S)-5- {[(1r,4S)-4- (mesylamino)cyclohexyl ++ - ]methyl}-2- pyrrolidinyl](m- fluorophenyl)methanol (S)-[(2R,5S)-5- {[(1r,4S)-4- (mesylamino)cyclohexyl - - ]methyl}-2- pyrrolidinyl](m- fluorophenyl)methanol N-[(1R,4r)-4-{2-[(R)-2- (5-fluoro-3-pyridyl)-2- hydroxyethylamino]-2- +++ + methylpropyl}cyclohexy l]-N-methylacetamide N-[(1S,4s)-4-{2-[(R)-2- (5-fluoro-3-pyridyl)-2- hydroxyethylamino]-2- ++ - methylpropyl}cyclohexy l]-N-methylacetamide (R)-[(2R,5S)-5- ({(1s,4R)-4-[(benzyl)- N- mesylamino]cyclohexyl} - - methyl)-2- pyrrolidinyl](m- fluorophenyl)methanol (S)-[(2R,5S)-5- ({(1s,4R)-4-[(benzyl)- N- mesylamino]cyclohexyl} - - methyl)-2- pyrrolidinyl](m- fluorophenyl)methanol (R)-[(2R,5S)-5- {[(1s,4R)-4- (mesylamino)cyclohexyl +++ - ]methyl}-2- pyrrolidinyl](m- fluorophenyl)methanol (S)-[(2R,5S)-5- {[(1s,4R)-4- (mesylamino)cyclohexyl + - ]methyl}-2- pyrrolidinyl](m- fluorophenyl)methanol (S)-[4-({m-[(benzyl)-N- mesylamino]phenyl}me thyl)-7- - - azabicyclo[2.2.1]hept- 1-yl](m- fluorophenyl)methanol (R)-[4-({m-[(benzyl)-N- mesylamino]phenyl}me thyl)-7- + - azabicyclo[2.2.1]hept- 1-yl](m- fluorophenyl)methanol (S)-(m-fluorophenyl)(4- {[m- (mesylamino)phenyl]me ++ - thyl}-7- azabicyclo[2.2.1]hept- 1-yl)methanol (R)-(m-fluorophenyl)(4- {[m- (mesylamino)phenyl]me ++ + thyl}-7- azabicyclo[2.2.1]hept- 1-yl)methanol (1R,4r)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- +++ - methylpropyl}cyclohexa nesulfonamide (1S,4s)-4-{2-[(R)-2- (m-fluorophenyl)-2- hydroxyethylamino]-2- + - methylpropyl}cyclohexa nesulfonamide (1R,4r)-4-{2-[(R)-2-(5- fluoro-3-pyridyl)-2- hydroxyethylamino]-2- ++ - methylpropyl}cyclohexa nesulfonamide (1S,4s)-4-{2-[(R)-2-(5- fluoro-3-pyridyl)-2- hydroxyethylamino]-2- +++ - methylpropyl}cyclohexa nesulfonamide (R)-2-{1,1-dimethyl-2- [(1s,4S)-4-(N-mesyl-N- methylamino)cyclohexyl ++ - ]ethylamino}-1-(5- fluoro-3-pyridyl)-1- ethanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4-(N-mesyl-N- methylamino)cyclohexyl ++ - ]ethylamino}-1-(5- fluoro-3-pyridyl)-1- ethanol (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- (trifluoromesylamino)cy +++ - clohexyl]ethylamino}-1- (5-fluoro-3-pyridyl)-1- ethanol (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- (propylsulfonylamino)cy ++ - clohexyl]ethylamino}-1- (5-fluoro-3-pyridyl)-1- ethanol (R)-2-{1,1-dimethyl-2- [(1s,4S)-4- (ethylsulfonylamino)cycl ++ - ohexyl]ethylamino}-1- (m-fluorophenyl)-1- ethanol (R)-2-{1,1-dimethyl-2- [(1r,4R)-4- (ethylsulfonylamino)cycl ++ - ohexyl]ethylamino}-1- (5-fluoro-3-pyridyl)-1- ethanol (R)-2-{1,1-dimethyl-2- ++ - [(1r,4R)-4- (isobutylsulfonylamino)c yclohexyl]ethylamino}- 1-(5-fluoro-3-pyridyl)- 1-ethanol (S)-{4-[2-(p- chlorophenyl)ethyl]-7- azabicyclo[2.2.1]hept- - - 1-yl}(m- fluorophenyl)methanol (R)-{4-[2-(p- chlorophenyl)ethyl]-7- azabicyclo[2.2.1]hept- - - 1-yl}(m- fluorophenyl)methanol (S)-{4-[(E)-3-phenyl-2- propenyl]-7- azabicyclo[2.2.1]hept- + - 1-yl}(5-fluoro-3- pyridyl)methanol (R)-{4-[(E)-3-phenyl-2- propenyl]-7- azabicyclo[2.2.1]hept- +++ + 1-yl}(5-fluoro-3- pyridyl)methanol (S)-(5-fluoro-3- pyridyl){4-(3- phenylpropyl)-7- ++ - azabicyclo[2.2.1]hept- 1-yl}methanol (R)-(5-fluoro-3- pyridyl){4-(3- phenylpropyl)-7- ++ + azabicyclo[2.2.1]hept- 1-yl}methanol (S)-{4-[(E)-3-phenyl-2- propenyl]-7- - - azabicyclo[2.2.1]hept- 1-yl}(m- fluorophenyl)methanol (R)-{4-[(E)-3-phenyl-2- propenyl]-7- azabicyclo[2.2.1]hept- +++ - 1-yl}(m- fluorophenyl)methanol (S)-(m-fluorophenyl){4- (3-phenylpropyl)-7- + - azabicyclo[2.2.1]hept- 1-yl}methanol (R)-(m-fluorophenyl){4- (3-phenylpropyl)-7- +++ + azabicyclo[2.2.1]hept- 1-yl}methanol (R)-(4-{[(benzyl)-N- mesylamino]methyl}-7- azabicyclo[2.2.1]hept- ++ + 1-yl)(m- fluorophenyl)methanol (S)-(4-{[(benzyl)-N- mesylamino]methyl}-7- azabicyclo[2.2.1]hept- ++ - 1-yl)(m- fluorophenyl)methanol (S)-(m-fluorophenyl){4- [2-(p- methoxyphenyl)ethyl]- - - 7- azabicyclo[2.2.1]hept- 1-yl}methanol (R)-(m-fluorophenyl){4- [2-(p- ++ + methoxyphenyl)ethyl]- 7- azabicyclo[2.2.1]hept- 1-yl}methanol (S)-(5-fluoro-3- pyridyl){4-[2-(p- methoxyphenyl)ethyl]- - - 7- azabicyclo[2.2.1]hept- 1-yl}methanol (R)-(5-fluoro-3- pyridyl){4-[2-(p- methoxyphenyl)ethyl]- ++ + 7- azabicyclo[2.2.1]hept- 1-yl}methanol (S)-(5-fluoro-3- pyridyl){4-[2-(p- trifluoromethoxyphenyl) - - ethyl]-7- azabicyclo[2.2.1]hept- 1-yl}methanol (S)-(m-fluorophenyl){4- [2-(p- trifluoromethoxyphenyl) - - ethyl]-7- azabicyclo[2.2.1]hept- 1-yl}methanol (R)-(5-fluoro-3- pyridyl){4-[2-(p- trifluoromethoxyphenyl) - - ethyl]-7- azabicyclo[2.2.1]hept- 1-yl}methanol (R)-(m-fluorophenyl){4- [2-(p- trifluoromethoxyphenyl) - - ethyl]-7- azabicyclo[2.2.1]hept- 1-yl}methanol (S)-(o-fluorophenyl){4- [2-(3-pyridyl)ethyl]-7- 547 +++ - azabicyclo[2.2.1]hept- 1-yl}methanol In particular embodiments, the ǃ2-adrenergic receptor agonist is selected from the group consisting of: 2-(butylamino)-1-(p-hydroxyphenyl)-1-ethanol; 2-(tert-butylamino)-1-(p-hydroxyphenyl)-1-ethanol; 2-[(cyclohexylmethyl)amino]-1-(p-hydroxyphenyl)-1-ethanol; (R)-2-(butylamino)-1-(p-hydroxyphenyl)-1-ethanol; 1-(m-hydroxyphenyl)-2-(1-methylbutylamino)-1-ethanol; 2-(3-cyclohexylpropylamino)-1-(p-hydroxyphenyl)-1-ethanol; (R)-2-[(R)-1-methylbutylamino]-1-(p-hydroxyphenyl)-1-ethanol; 1-(4-amino-3,5-dichlorophenyl)-2-(butylamino)-1-ethanol; 2-(3-cyclopropylpropylamino)-1-(p-hydroxyphenyl)-1-ethanol; 1-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-2-(butylamino)-1-ethanol; 2-(butylamino)-1-(4-chloro-3-hydroxyphenyl)-1-ethanol; 1-(4-chloro-3-hydroxyphenyl)-2-(1-methylbutylamino)-1-ethanol; m-{(R)-[(2R,5R)-5-methyl-2-pyrrolidinyl]hydroxymethyl}phenol and m-{(S)- [(2S,5S)-5-methyl-2-pyrrolidinyl]hydroxymethyl}phenol; 1-(3-amino-2,4-difluorophenyl)-2-(butylamino)-1-ethanol; (R)-[(2R,6R)-6-propyl-2-piperidyl](m-hydroxyphenyl)methanol; (R)-2-[(R)-1-methylbutylamino]-1-(m-fluorophenyl)-1-ethanol; (R)-2-[(S)-1-methylbutylamino]-1-(m-fluorophenyl)-1-ethanol; (R)-2-(tert-butylamino)-1-(m-fluorophenyl)-1-ethanol; (R)-[(2R,5R)-5-propyl-2-pyrrolidinyl](m-fluorophenyl)methanol; (R)-2-(1,1-dimethylbutylamino)-1-(m-fluorophenyl)-1-ethanol; (R)-[(2R,6S)-6-propyl-2-piperidyl](m-hydroxyphenyl)methanol; (R)-2-(tert-butylamino)-1-(2,3-difluorophenyl)-1-ethanol; (R)-2-(butylamino)-1-(2,3-difluorophenyl)-1-ethanol; (R)-2-(tert-butylamino)-1-(o-fluorophenyl)-1-ethanol; (R)-2-(butylamino)-1-(o-fluorophenyl)-1-ethanol; (R)-1-(m-fluorophenyl)-2-(1-methylcyclopropylamino)-1-ethanol; (R)-1-(m-fluorophenyl)-2-(1-methylcyclobutylamino)-1-ethanol; (R)-2-(butylamino)-1-(4-fluoro-3-hydroxyphenyl)-1-ethanol; (R)-2-(butylamino)-1-(2-fluoro-3-hydroxyphenyl)-1-ethanol; (R)-1-(3-amino-2-fluorophenyl)-2-(tert-butylamino)-1-ethanol; 4-[(R)-2-(tert-butylamino)-1-hydroxyethyl]-1-methyl-2(1H)-pyridinone; (R)-2-(tert-butylamino)-1-(5-fluoro-3-pyridyl)-1-ethanol; 5-[(R)-2-(tert-butylamino)-1-hydroxyethyl]-3-pyridinol; (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](m-fluorophenyl)methanol; m-{(R)-[(R)-5,5-dimethyl-2-pyrrolidinyl]hydroxymethyl}phenol; (R)-[(2S,6R)-6-propyl-2-piperidyl](m-chlorophenyl)methanol; (S)-[(2S,6S)-6-propyl-2-piperidyl](m-hydroxyphenyl)methanol; 4-[2-(tert-butylamino)-1-hydroxyethyl]-3-pyridinol; (R)-[(2S,6R)-6-propyl-2-piperidyl](m-hydroxyphenyl)methanol; (R)-[(2R,5R)-5-propyl-2-pyrrolidinyl](o-chlorophenyl)methanol; (R)-1-(3-amino-2,4-difluorophenyl)-2-(tert-butylamino)-1-ethanol; (R)-2-(tert-butylamino)-1-(3-fluoro-2-tolyl)-1-ethanol; (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](o-chlorophenyl)methanol; (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](m-chlorophenyl)methanol; (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](5-fluoro-3-pyridyl)methanol; (R)-[(2R,5R)-5-propyl-2-pyrrolidinyl](5-fluoro-3-pyridyl)methanol; (S)-[(R)-6,6-dimethyl-2-piperidyl](o-chlorophenyl)methanol; (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](o-fluorophenyl)methanol; (S)-[(R)-6,6-dimethyl-2-piperidyl](o-fluorophenyl)methanol; (S)-(o-fluorophenyl)(4-methyl-7-azabicyclo[2.2.1]hept-1-yl)methanol; (R)-(o-fluorophenyl)(4-methyl-7-azabicyclo[2.2.1]hept-1-yl)methanol; (R)-(5-fluoro-3-pyridyl)(4-methyl-7-azabicyclo[2.2.1]hept-1-yl)methanol; (R)-[(S)-6,6-dimethyl-2-piperidyl](m-fluorophenyl)methanol; (R)-[(S)-6,6-dimethyl-2-piperidyl](o-fluorophenyl)methanol; (R)-(o-chlorophenyl)(4-methyl-7-azabicyclo[2.2.1]hept-1-yl)methanol; (R)-(m-chlorophenyl)(4-methyl-7-azabicyclo[2.2.1]hept-1-yl)methanol; (R)-[(R)-4,4-dimethyl-2-azetidinyl](m-fluorophenyl)methanol; (R)-[(R)-4,4-dimethyl-2-azetidinyl](o-fluorophenyl)methanol; (R)-{(R)-1-methyl-2-azabicyclo[2.1.1]hex-3-yl}(m-chlorophenyl)methanol; (S)-{(S)-1-methyl-2-azabicyclo[2.1.1]hex-3-yl}(o-fluorophenyl)methanol; (S)-{(R)-1-methyl-2-azabicyclo[2.1.1]hex-3-yl}(o-fluorophenyl)methanol; (R)-{(S)-1-methyl-2-azabicyclo[2.1.1]hex-3-yl}(o-fluorophenyl)methanol; (R)-[(R)-4,4-dimethyl-2-azetidinyl](5-fluoro-3-pyridyl)methanol; (R)-{(R)-1-methyl-2-azabicyclo[2.1.1]hex-3-yl}(5-fluoro-3-pyridyl)methanol; (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](3-amino-2-fluorophenyl)methanol; (R)-[(R)-4,4-dimethyl-2-azetidinyl](m-chlorophenyl)methanol; (R)-[(2S,7S)-7-propyl-2-azepanyl](5-fluoro-3-pyridyl)methanol; (S)-[(R)-5,5-dimethyl-2-pyrrolidinyl](4-amino-3,5-difluorophenyl)methanol; (R)-1-(5-fluoro-3-pyridyl)-2-{2-[(1s,4S)-4-methoxycyclohexyl]ethylamino}-1- ethanol; (R)-1-(m-fluorophenyl)-2-{1-methyl-1-[(1r,4R)-4-methoxycyclohexyl]ethylamino}- 1-ethanol; (R)-1-(5-fluoro-3-pyridyl)-2-{1-methyl-1-[(1r,4R)-4- methoxycyclohexyl]ethylamino}-1-ethanol; (R)-{(R)-1-methyl-2-azabicyclo[2.1.1]hex-3-yl}(3-amino-2-fluorophenyl)methanol; (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-methoxycyclohexyl]ethylamino}-1-(m- fluorophenyl)-1-ethanol; (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-methoxycyclohexyl]ethylamino}-1-(5-fluoro-3- pyridyl)-1-ethanol; (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-methoxycyclohexyl]ethylamino}-1-(m- fluorophenyl)-1-ethanol; (R)-2-{1-[(1S,3R)-3-methoxycyclohexyl]-1-methylethylamino}-1-(m-fluorophenyl)- 1-ethanol; (R)-2-{1-[(1R,3S)-3-methoxycyclohexyl]-1-methylethylamino}-1-(m-fluorophenyl)- 1-ethanol; (R)-1-(5-fluoro-3-pyridyl)-2-{3-[(1s,4R)-4-methoxycyclohexyl]propylamino}-1- ethanol; (R)-1-(5-fluoro-3-pyridyl)-2-({[(1s,4S)-4-(benzyloxy)cyclohexyl]methyl}amino)-1- ethanol; (R)-2-{1,1-dimethyl-3-[(1s,4R)-4-methoxycyclohexyl]propylamino}-1-(m- fluorophenyl)-1-ethanol; (R)-2-{1,1-dimethyl-3-[(1s,4R)-4-methoxycyclohexyl]propylamino}-1-(5-fluoro-3- pyridyl)-1-ethanol; (R)-1-(m-fluorophenyl)-2-{1-methyl-1-[(1s,4S)-4- (benzyloxy)cyclohexyl]ethylamino}-1-ethanol; (R)-2-{1,1-dimethyl-3-[(1s,4R)-4-hydroxycyclohexyl]propylamino}-1-(m- fluorophenyl)-1-ethanol; (R)-2-{1,1-dimethyl-3-[(1s,4R)-4-hydroxycyclohexyl]propylamino}-1-(5-fluoro-3- pyridyl)-1-ethanol; (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-hydroxycyclohexyl]ethylamino}-1-(m- fluorophenyl)-1-ethanol; (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-hydroxycyclohexyl]ethylamino}-1-(5-fluoro-3- pyridyl)-1-ethanol; N-[(1R,4r)-4-{[(R)-2-(m-fluorophenyl)-2- hydroxyethylamino]methyl}cyclohexyl]benzamide; (R)-2-{1,1-dimethyl-3-[(1r,4S)-4-hydroxycyclohexyl]propylamino}-1-(o- fluorophenyl)-1-ethanol; (R)-2-{1,1-dimethyl-3-[(1s,4R)-4-hydroxycyclohexyl]propylamino}-1-(o- fluorophenyl)-1-ethanol; methyl (1S,4s)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexanecarboxylate; (S)-[(2R,5S)-5-{[(1r,4S)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](m- fluorophenyl)methanol; (R)-[(2R,5S)-5-{[(1r,4S)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](m- fluorophenyl)methanol; methyl (1S,4s)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexanecarboxylate; (1S,4s)-8-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-7-methoxy-p-menthan-7- one; (R)-(m-fluorophenyl){4-(methoxymethyl)-7-azabicyclo[2.2.1]hept-1-yl}methanol; (R)-[(2R,5R)-5-{[(1r,4R)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](m- fluorophenyl)methanol; (R)-[(2R,5S)-5-{[(1r,4S)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](o- fluorophenyl)methanol; (R)-[(2R,5R)-5-{[(1r,4R)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](o- fluorophenyl)methanol; (R)-[(2R,5R)-5-{[(1r,4R)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](5-fluoro-3- pyridyl)methanol; methyl (1R,4r)-4-{3-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-3- methylbutyl}cyclohexanecarboxylate; N-[(1R,4r)-4-{1-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-1- methylethyl}cyclohexyl]acetamide; (1S,4s)-4-{3-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-3- methylbutyl}cyclohexanecarboxylic acid; methyl (1S,4s)-4-{3-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-3- methylbutyl}cyclohexanecarboxylate; methyl (1R,4r)-4-{3-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-3- methylbutyl}cyclohexanecarboxylate; methyl (1S,4s)-4-{3-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-3- methylbutyl}cyclohexanecarboxylate; methyl (1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexanecarboxylate; N-[(1R,4r)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexyl]acetamide; (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-aminocyclohexyl]ethylamino}-1-(5-fluoro-3- pyridyl)-1-ethanol; (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-(mesylamino)cyclohexyl]ethylamino}-1-(5-fluoro- 3-pyridyl)-1-ethanol; N-[(1R,4r)-4-{3-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-3- methylbutyl}cyclohexyl]acetamide; (S)-[(2R,5S)-5-methyl-5-{[(1r,4S)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](m- fluorophenyl)methanol; (S)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-5-methyl-2-pyrrolidinyl}(m- fluorophenyl)methanol; (R)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-5-methyl-2-pyrrolidinyl}(m- fluorophenyl)methanol; (1R,4r)-8-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-7-methoxy-p-menthan-7- one; (1R,4r)-8-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-7-methoxy-p-menthan- 7-one; (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-aminocyclohexyl]ethylamino}-1-(m-fluorophenyl)- 1-ethanol; (S)-{(2R,5S)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(m- fluorophenyl)methanol; (R)-{(2R,5S)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(m- fluorophenyl)methanol; (R)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(m- fluorophenyl)methanol; (S)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(m- fluorophenyl)methanol; (R)-2-(tert-butylamino)-1-(2-methyl-3-pyridyl)-1-ethanol; (S)-{(2R,5S)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3- pyridyl)methanol; (R)-{(2R,5S)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3- pyridyl)methanol; (R)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3- pyridyl)methanol; (S)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3- pyridyl)methanol; (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-(mesylamino)cyclohexyl]ethylamino}-1-(m- fluorophenyl)-1-ethanol; N-[(1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexyl]acetamide; N-[(1R,4r)-4-{1-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-1- methylethyl}cyclohexyl]acetamide; 6-[(S)-2-(tert-butylamino)-1-hydroxyethyl]-2-pyridinecarbonitrile; (R)-(4-benzyl-7-azabicyclo[2.2.1]hept-1-yl)(m-fluorophenyl)methanol; (R)-{(2R,5S)-5-[(p-chlorophenyl)methyl]-2-pyrrolidinyl}(m-fluorophenyl)methanol; (R)-{(2R,5R)-5-[(p-chlorophenyl)methyl]-2-pyrrolidinyl}(m-fluorophenyl)methanol; (R)-(4-{[(p-chlorophenyl)methoxy]methyl}-7-azabicyclo[2.2.1]hept-1-yl)(m- fluorophenyl)methanol; (S)-2-(tert-butylamino)-1-[6-(trifluoromethyl)-2-pyridyl]-1-ethanol; ethyl [(1R,4r)-4-{1-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-1- methylethyl}cyclohexyloxy]acetate; (1S,4s)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexanecarbonitrile; (R)-(m-fluorophenyl){4-[(p-methoxyphenyl)methyl]-7-azabicyclo[2.2.1]hept-1- yl}methanol; (R)-{(2R,5S)-5-[(p-chlorophenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3- pyridyl)methanol; (S)-{(2R,5R)-5-[(p-chlorophenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3- pyridyl)methanol; (R)-{(2R,5R)-5-[(p-chlorophenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3- pyridyl)methanol; ethyl [(1R,4r)-4-{1-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-1- methylethyl}cyclohexyloxy]acetate; (R)-(m-fluorophenyl){4-[(p-fluorophenyl)methyl]-7-azabicyclo[2.2.1]hept-1- yl}methanol; 6-[(S)-2-{1,1-dimethyl-2-[(1r,4S)-4-aminocyclohexyl]ethylamino}-1-hydroxyethyl]- 2-pyridinecarbonitrile; N-[(1R,4s)-4-{2-[(S)-2-(6-cyano-2-pyridyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexyl]acetamide; N-[(1S,4r)-4-{2-[(S)-2-(6-cyano-2-pyridyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexyl]acetamide; 6-[(S)-2-{1,1-dimethyl-2-[(1r,4S)-4-(mesylamino)cyclohexyl]ethylamino}-1- hydroxyethyl]-2-pyridinecarbonitrile; N-[(1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexyl]2,2-dimethylpropionamide; N-[(1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexyl]trifluoroacetamide; N-[(1R,4r)-4-{2-[(R)-2-hydroxy-2-(2-methyl-3-pyridyl)ethylamino]-2- methylpropyl}cyclohexyl]acetamide; (R)-(m-fluorophenyl)(4-{[(p-fluorophenyl)methoxy]methyl}-7-azabicyclo[2.2.1]hept- 1-yl)methanol; (S)-{4-[(p-chlorophenoxy)methyl]-7-azabicyclo[2.2.1]hept-1-yl}(m- fluorophenyl)methanol; (R)-{4-[(p-chlorophenoxy)methyl]-7-azabicyclo[2.2.1]hept-1-yl}(m- fluorophenyl)methanol; (R)-(4-{[(p-fluorophenyl)methoxy]methyl}-7-azabicyclo[2.2.1]hept-1-yl)(5-fluoro-3- pyridyl)methanol; (S)-(m-fluorophenyl){4-[2-(3-pyridyl)ethyl]-7-azabicyclo[2.2.1]hept-1-yl}methanol; N-[(1S,4s)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexyl]cyclopropanecarboxamide; N-[(1S,4s)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexyl]acetamide; (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-(mesylamino)cyclohexyl]ethylamino}-1-(m- fluorophenyl)-1-ethanol; N-[(1S,4s)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexyl]trifluoroacetamide; (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-aminocyclohexyl]ethylamino}-1-(m-fluorophenyl)- 1-ethanol; (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-(3,3-dimethylureido)cyclohexyl]ethylamino}-1-(m- fluorophenyl)-1-ethanol; (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-(trifluoromesylamino)cyclohexyl]ethylamino}-1- (m-fluorophenyl)-1-ethanol; (1S,4r)-4-(2-{(S)-2-hydroxy-2-[6-(trifluoromethyl)-2-pyridyl]ethylamino}-2- methylpropyl)cyclohexyl 2-methyl-2-propanecarbamate; N-[(1S,4s)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexyl]acetamide; (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-(mesylamino)cyclohexyl]ethylamino}-1-(5-fluoro- 3-pyridyl)-1-ethanol; (1S,4s)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexyl 2-methyl-2-propanecarbamate; (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-(dimethylaminosulfonyl)cyclohexyl]ethylamino}-1- (m-fluorophenyl)-1-ethanol; (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-(methylaminosulfonyl)cyclohexyl]ethylamino}-1- (m-fluorophenyl)-1-ethanol; N-[(1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexyl]-N-methylacetamide; N-[(1R,4r)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexyl]-N-methylacetamide; (R)-[(2R,5S)-5-{[(1s,4R)-4-(mesylamino)cyclohexyl]methyl}-2-pyrrolidinyl](m- fluorophenyl)methanol; (1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexanesulfonamide; (1S,4s)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-2- methylpropyl}cyclohexanesulfonamide; (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-(trifluoromesylamino)cyclohexyl]ethylamino}-1- (5-fluoro-3-pyridyl)-1-ethanol; (R)-{4-[(E)-3-phenyl-2-propenyl]-7-azabicyclo[2.2.1]hept-1-yl}(5-fluoro-3- pyridyl)methanol; (R)-{4-[(E)-3-phenyl-2-propenyl]-7-azabicyclo[2.2.1]hept-1-yl}(m- fluorophenyl)methanol; (R)-(m-fluorophenyl){4-(3-phenylpropyl)-7-azabicyclo[2.2.1]hept-1-yl}methanol; and (S)-(o-fluorophenyl){4-[2-(3-pyridyl)ethyl]-7-azabicyclo[2.2.1]hept-1-yl}methanol, and pharmaceutically acceptable salts thereof. The skilled person will understand that the term metformin will refer to the INN of the compound 1,1-dimethylbiguanide monohydrochloride. As such, all references to metformin herein may be replaced with references to 1,1-dimethylbiguanide monohydrochloride. For the avoidance of doubt, unless otherwise stated or apparent to those skilled in the art, other salts of 1,1-dimethylbiguanide may be used without departing from the teaching of the present invention. Thus, references to metformin may be replaced with references to 1,1-dimethylbiguanide and pharmaceutically acceptable salts thereof. Pharmaceutical formulations The skilled person will understand that both the ǃ2-adrenergic receptor agonist, or pharmaceutically acceptable salt thereof, and metformin may be administered in the form of a pharmaceutical formulation, which may further comprise one or more pharmaceutically acceptable excipient. Suitable pharmaceutical formulations may be commercially available or otherwise are described in the literature, such as, Remington, The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995), and Martindale – The Complete Drug Reference (35thEdition), and the documents referred to therein, the relevant disclosures in all of which documents are hereby incorporated by reference in their entirety. Otherwise, the preparation of suitable formulations, and in particular combined preparations including both a ǃ2-adrenergic receptor agonist, or pharmaceutically acceptable salts thereof, and metformin may be achieved by the skilled person using routine techniques. References to pharmaceutically acceptable excipient(s) may be understood to include pharmaceutically acceptable, diluents, carriers and / or adjuvants, as known to those skilled in the art. Various formulations comprising metformin are known to those skilled in the art, including oral solutions and tablets (including film-coated, standard release and extended release formulations). Example formulations comprising metformin include RiometTM(manufactured by RanbaxyTM), FortametTM(Shionogi PharmaTM) and GlumetzaTM(DepomedTM). The skilled person will understand that the invention may also relate to combination products comprising a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and metformin, and uses thereof. Accordingly, in a second aspect of the invention, there is provided a pharmaceutical formulation comprising: (a) a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof; and (b) metformin, and optionally one or more pharmaceutically acceptable excipient, which formulations may be referred to hereinafter as the “formulations of the invention”, or the like. In a third aspect of the invention, there is provided a pharmaceutical formulation comprising: (a) a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof; and (b) metformin, and optionally one or more pharmaceutically acceptable excipient, for use in: (i) the treatment or prophylaxis of obesity; (ii) a therapeutic method of lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, which formulations may be referred to hereinafter as the “formulations of the invention”, or the like, and which treatments (and associated prophylaxis) may be referred to herein after as the “treatments of in the invention”, or the like. In an alternative third aspect of the invention, there is provided a method for: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising: (a) a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof; and (b) metformin, and optionally one or more pharmaceutically acceptable excipient. For the avoidance of doubt, the formulations of the second and third aspects of the invention may have any of the particular features described above for the first aspect of the invention, including all combinations thereof. The skilled person will understand that the combination of a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and metformin may also be provided in the form of a kit-of-parts comprising the same. In a fourth aspect of the invention, there is provided a kit-of-parts comprising components: (A) a pharmaceutical formulation comprising a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, optionally in admixture with one or more pharmaceutically acceptable excipient, and (B) a pharmaceutical formulation comprising metformin, optionally in admixture with one or more pharmaceutically acceptable excipient, wherein components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other. In a particular embodiment, the kit-of-parts is for use in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia. The kits-of-parts of the invention may be referred to herein as the “kits-of-parts of the invention”. In a particular embodiment, the kit-of-parts of the fourth aspect of the invention further comprises instructions to use each component in conjunction with the other in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia. In an alternative fourth aspect of the invention, there is provided a kit-of-parts comprising: (I) one of components (A) or (B) as defined hereinabove, and (II) instructions to use that component in conjunction with the other of the two components in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia. For the avoidance of doubt, kits-of-parts of the fourth aspect of the invention may have any of the particular features described above for the first aspect of the invention, including all combinations thereof. In certain embodiments, the kits-of-parts described herein may comprise more than one formulation including an appropriate quantity / dose of a ǃ2-adrenergic receptor agonist, or pharmaceutically acceptable salt and / or pro drug thereof, and / or more than one formulation including an appropriate quantity / dose of metformin, in order to provide for repeat dosing. If more than one formulation (comprising either active compound) is present, such formulations may be the same, or may be different in terms of the dose of either compound, chemical composition(s) and / or physical form(s). With respect to the treatments, formulations and kits-of-parts of the invention as described herein, references to treatment with or administration of each component will refer to said component being administered in conjunction with the other. Lowering body fat For the avoidance of doubt, references herein to body fat may refer in particular to body fat in the form of adipose tissue. As described herein, the skilled person will understand that pharmaceutical formulations, kits-of-parts, compounds for use, uses and methods of treatment of the invention as defined herein may be useful in lowering body fat composition and / or reducing body weight in a patient (or subject) in need thereof, e.g. a patient who has an above-normal body weight or BMI (e.g. a BMI of 30 or greater), such as in an obese patient, which may be referred to as therapeutically lowering body fat composition and / or reducing body weight. Alternatively, pharmaceutical formulations, kits-of-parts, compounds for use, uses and methods of treatment of the invention may also be useful in lowering body fat composition and / or reducing body weight in a patient (or subject) who has a normal body weight or who is overweight (in each case, with a corresponding BMI). In particular instances, such subjects (e.g. adult subjects) will be non-obese (e.g. having a BMI of less than 30.0), e.g. subjects being overweight (BMI 25.0 to 29.9) or of a healthy weight (BMI 18.5 to 24.9), which may be referred to as non-therapeutically lowering body fat composition and / or reducing body weight. As such, the skilled person will understand that such uses may be performed in patients who are not defined as being obese (e.g. in patients who are defined as being of a healthy weight or overweight but not obese). In particular embodiments, pharmaceutical formulations kits-of-parts, uses and methods of treatment of the invention may be useful in lowering body fat composition and / or reducing body weight in a patient (or subject) who is overweight. For the avoidance of doubt, references to non-therapeutic uses and methods will refer to uses and methods in patients that are not directed to the treatment of a medical condition but which provide the relevant effects for other purposes, such as for cosmetic purposes. As described herein, other uses in medical treatment as described herein may be understood to be further characterised by lowering body fat composition and / or reducing body weight. For example, the treatment or prophylaxis of obesity as described herein may be achieved by lowering body fat composition and / or reducing body weight (e.g. lowering body fat composition). Methods of administration The skilled person will understand that the present invention (i.e. the pharmaceutical formulations, kits-of-parts, compounds for use, uses and methods of treatment as described herein, including all embodiments and preferred features thereof) relates to two components, namely a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and the compound metformin, being administered in conjunction with each other. References to each component being administered in conjunction with the other will include the components being administered, sequentially, separately or simultaneously, as part of a medical intervention directed towards treatment of the relevant condition. In particular, such references may include the components being administered sufficiently close in time to enable a beneficial effect for the patient that is greater, over the course of the treatment of the relevant condition, than if administered in the absence of the other component, over the same course of treatment. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of, treatment of a particular condition will depend upon the condition to be treated or prevented, but may be achieved routinely by the skilled person. The skilled person will understand that references to the components (i.e. the ǃ2- adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and the compound metformin) being administered sequentially (and, therefore, separately) will include that individual doses of each component are administered (i.e. taken by the patient, such as being taken orally) within 48 hours (e.g. within 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes or 10 minutes) of each other. Similarly, references to the components being administered simultaneously (which may be in a combined form or separately) will include the components being administered (i.e. taken by the patient, such as being taken orally) at substantially the same time. In a particular embodiment, the components are administered (i.e. taken by the patient, such as being taken orally) sequentially (and, therefore, as separate doses). For example, in a particular embodiment, the components are administered sequentially at least 2 hours apart (i.e. the interval between the administration of each component to the patient, e.g. orally, is at least 4 hours), such as between 2 hours and 48 hours apart, or between 2 hours and 24 hours apart, or between 2 hours and 12 hours apart. In a more particular embodiment, the components are administered sequentially at least 4 hours apart, such as between 4 hours and 48 hours apart, or between 4 hours and 24 hours apart, or between 4 hours and 12 hours apart. In a yet more particular embodiment, the components are administered sequentially at least 6 hours apart, such as between 6 hours and 48 hours apart, or between 6 hours and 24 hours apart, or between 6 hours and 12 hours apart (e.g. between 6 hours and 10 hours apart). In a yet more particular embodiment, the components are administered sequentially at least 7 hours apart, such as between 7 hours and 48 hours apart, or between 7 hours and 24 hours apart, or between 7 hours and 12 hours apart (e.g. between 7 hours and 9 hours apart). In a yet more particular embodiment, the components are administered sequentially at least 8 hours apart, such as between 8 hours and 48 hours apart, or between 8 hours and 24 hours apart, or between 8 hours and 12 hours apart (e.g. between 8 hours and 9 hours apart). In a yet more particular embodiment, the components are administered sequentially at about 8 hours apart. For the avoidance of doubt, references to the components as the ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and the compound metformin will include references to the respective components (a) and (b) of the third aspect of the invention, and the respective components (A) and (B) of the fourth aspect of the invention. The skilled person will understand that compounds and pharmaceutical formulations as defined herein will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, transdermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form. Pharmaceutical formulations 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. In particular embodiments, compounds and pharmaceutical formulations as described herein are administered orally. As such, in certain embodiments pharmaceutical formulations as described herein may be described as oral pharmaceutical formulations. Thus, in particular embodiments, the pharmaceutical formulation(s) is / are provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, transdermal patches, plasters, inhalants (e.g. to be applied intranasally). 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. In more particular embodiments, the pharmaceutical formulation(s) is / are provided in a pharmaceutically acceptable oral dosage form, including tablets or capsules, which forms may be prepared using techniques known to those skilled in the art. 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. 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. 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 gelatine 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. 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. 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. The skilled person will understand that the compounds described herein, and formulations and kits-of parts comprising the same, 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. 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; however, there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are included within the scope of this invention. As described herein above, the skilled person will understand that the treatments (and methods of prophylaxis) as described here may further comprise (i.e. be combined with) additional (i.e. other) treatment(s) for the same condition. In particular, treatments (and methods of prophylaxis) described herein may be combined with other means for the treatment of excess body weight or a disoder characterized by excess body weight (as defined herein, such as obesity), such as treatment with one or more other therapeutic agent that is useful in the treatment of excess body weight or a disorder characterized by excess body weight (as defined herein, such as obesity). Such 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 formulations and kits-of-parts Pharmaceutical formulations and kits-of-parts as described herein may be prepared in accordance with standard and / or accepted pharmaceutical practice. 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 ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and metformin, with one or more pharmaceutically-acceptable excipients (e.g. an adjuvant, diluent and / or carrier). There is further provided a method of preparing a kit-of-parts as defined hereinbefore, which method comprises bringing component (A) into association with component (B), thus rendering the two components suitable for administration in conjunction with each other. As such, references to bringing into association will mean that the two components are rendered suitable for administration in conjunction with each other. 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, it is contemplated that the two components of the kit of parts may be: (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 (ii) packaged and presented together as separate components of a “combination pack” for use in conjunction with each other in combination therapy. The skilled person will understand that pharmaceutical formulations, kits-of-parts, methods and uses described herein may have the advantage that, in the treatment of the conditions mentioned hereinbefore, they may be more convenient for the physician and / or patient than, be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or may have other useful pharmacological properties over, similar methods (treatments) known in the prior art whether for use in the above-stated indications or otherwise. In particular, such pharmaceutical formulations, kits of parts, methods and uses may have the advantage that they are more efficacious and / or exhibit advantageous properties in vivo. Without wishing to be bound by theory, it is believed that the combination of a ǃ2- adrenergic receptor agonist and metformin provides complementary biological effects which combine to improve energy expenditure / energy intake balance (e.g. by increasing energy expenditure above basal levels for a given patient), which in turn results in a reduction in lipid storage in adipose tissue due to lipolysis. Moreover, certain of the compounds acting as ǃ2-adrenergic receptor agonists, such as those described herein, are able to activate the ǃ2-adrenergic receptor without (or with only a minimal effect in) inducing cAMP production. It is thought that this allows for therapeutic effects as described herein to be obtained with lower levels of side effects than would result from other treatments. The combination of these therapeutic agents is therefore useful in the treatment or prophylaxis of obesity, lowering body fat composition and / or reducing body weight, the treatment or prophylaxis of metabolic syndrome and the treatment or prophylaxis of dyslipidaemia, and may have advantages over compounds used in such methods as described in the prior art, such as the ability to administer one or more of the administered compounds at lower doses, to achieve greater effects and / or to achieve lower levels of adverse events. Brief Description of the Figures Figure 1 shows that the glucose uptake promoted by Compound A is inhibited in a dose-dependent manner by the selective E2-adrenergic receptor antagonist ICI-118551 Figure 2 shows food intake over time in the experiment of Biological Example 2. Figure 3 shows the change in fat mass in the experiment of Biological Example 2. Figure 4 shows the change in body weight in the experiment of Biological Example 2. Figure 5 shows the change in lean mass in the experiment of Biological Example 2. Figure 6 shows the food intake over time in the experiment of Biological Example 3. Figure 7 shows the change in fat mass in the experiment of Biological Example 3. Figure 8 shows the change in body weight in the experiment of Biological Example 3. Figure 9 shows the change in lean mass in the experiment of Biological Example 3. Examples The present invention is illustrated by way of the following examples, which are not intended to be limiting on the overall scope of the invention. For the avoidance of doubt, in the case of a discrepancy between the name of the compound and the structure drawn in this specification, the structure should prevail. The following compound, which be referred to herein as Compound A, was used in the biological examples provided herein in the salt form as specified (and, in the context of which, references to Compound A will refer to that salt form). Compound A: The synthesis of Compound A is described in WO 2019 / 053427 (see Example 17 therein), the contents of which are incorporated herein by reference. Compound Example 1 Compound A: (R)-2-(tert-Butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (a) 2-Chloro-1-(5-fluoropyridin-3-yl)ethan-1-one Isopropylmagnesium chloride (2 M in THF, 10.47 mL, 20.94 mmol) was added to a solution of LiCl (887.69 mg, 20.94 mmol) in THF (8 mL) at rt. After 15 min at rt, 3- bromo-5-fluoropyridine (3.35 g, 19.04 mmol) in THF (30 mL) was added dropwise at 0 °C. The mixture was stirred at rt for 2 h and cooled in an ice-bath. A solution of 2- chloro-N-methoxy-N-methylacetamide (2.62 g, 19.04 mmol) in THF (30 mL) was added dropwise, and the mixture was stirred at rt for 2 h. NH4Cl (aq, 10 %) was added and the mixture was extracted with Et2O. The combined extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography to give the sub-title compound (1.52 g, 20.94 mmol, 46 %). (b) (R)-2-Chloro-1-(5-fluoropyridin-3-yl)ethan-1-one The sub-title compound was prepared from 2-chloro-1-(5-fluoropyridin-3-yl)ethan-1- one in accordance with the procedure in Example 13, Step (d) of WO 2019 / 053427, with the exception that the reaction time was 15 min. ee = 92.5 %. (c) (R)-2-(tert-Butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol tert-Butylamine (11.37 mL, 108.21 mmol) followed by NaOH (476.08 mg, 11.90 mmol) were added to a mixture of 2-chloro-1-(5-fluoropyridin-3-yl)ethan-1-one (1.90 g, 10.82 mmol) and iPrOH (1.66 mL, 21.64 mmol) at rt. The mixture was heated at 75 °C for 4 h, allowed to cool, diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The residue was dissolved in hot EtOAc and allowed to cool. Pentane was added and the mixture kept at -20 °C overnight. The solids were collected and purified by chromatography to give the title compound (1.43 g, 6.74 mmol, 62 %, ee = 98 %).1H NMR (400 MHz, CDCl3): į 8.43 – 8.27 (m, 2H), 7.57 – 7.42 (m, 1H), 4.62 (dd, J = 8.8, 3.7 Hz, 1H), 2.94 (dd, J = 12.1, 3.8 Hz, 1H), 2.53 (dd, J = 12.1, 8.8 Hz, 1H), 1.10 (s, 9H). Compound Example 2 Compound A hemi-tartrate: (R)-2-(tert-Butylamino)-1-(5-fluoropyridin-3-yl)ethan-1- ol hemi-tartrate A solution of L-(+)-tartaric acid (6.21g, 0.5 eq) in EtOH (175 mL) was added to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (17.57 g) in EtOH (525 mL, 30 vol) and H2O (7 mL) at rt. The mixture was refluxed until all precipitate was dissolved, then cooled. The resultant slurry was stirred at rt overnight and then at 0 to 5 °C for 2 h. The solids were collected to give the title salt of (R)-2- (tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (19.9 g, 83%, 100.0% purity by HPLC, 99.8% e.e. by HPLC). Formation of the hemi-tartrate was confirmed by1H-NMR spectrum, which indicated an amine:acid ratio of 2:1. Compound Example 3 Compound A dihydrochloride: (R)-2-(tert-Butylamino)-1-(5-fluoropyridin-3-yl)ethan- 1-ol dihydrochloride HCl (48 mmol, 2 M in Et2O, 24 mL) was added dropwise to a solution of (R)-2-(tert- butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (5.10 g, 24 mmol) in Et2O (90 mL) at rt. After 15 min the precipitate was collected, dried in vacuo and recrystallized from MeCN (250 mL). After having reached rt, the mixture was kept in the refrigerator for 5 h, and the solid was collected and dried in vacuo over P2O5 over 5 d to give the title compound, (6.41 g, 94 %). Elemental analysis found: C, 46.45 %; H, 6.75 %; N, 9.80 %. C11H19Cl2FN2requires: C, 46.32 %; H, 6.71 %; N, 9.82 %. Biological examples WO 2019 / 053427, the contents of which are incorporated herein by reference, describes biological assays showing that Compound A provides significant glucose uptake without inducing significant levels of cAMP (see Biological Examples 1 and 2 therein). In the present examples: in Biological Example 1, Compound A was used in the form of the dihydrochloride (2HCl) salt; in Biological Examples 2 and 3, Compound A was used in the form of the hemi-tartrate salt. Biological example 1: Glucose uptake in the presence of a selective E2-adrenergic receptor inhibitor L6-myoblasts were grown in Dulbecco’s Modified Eagle’s Medium (DMEM) containing 1 g / L glucose supplemented with 10 % fetal bovine serum (FBS), 2 mM L-glutamine, 50 U / mL penicillin, 50 Pg / mL streptomycin and 10 mM HEPES. Cells were plated at 1x 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. The differentiated L6-myotubes were serum-starved overnight in medium containing 0.5 % fatty-acid free BSA and stimulated with Compound A at a final concentration of 1x10-5M in the presence of the selective E2-adrenergic receptor antagonist ICI-118551. After 1 h 40 min the cells were washed with warm, glucose free medium twice and another portion of agonist was added to the glucose free medium. After another 20 min of incubation the cells were exposed to 50 nM3H-2-deoxyglucose for 10 min before washed in ice cold glucose free medium three times and lysed in 400 ^l / 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 E-counter (Tri- Carb 4810TR, Perkin Elmer). Figure 1 shows that the glucose uptake promoted by Compound A is inhibited in a dose-dependent manner by the selective E2-adrenergic receptor antagonist ICI- 118551, which proves that the glucose uptake promoted by Compound A is mediated through the E2-adrenergic receptor. adrenergic receptor inhibitor (Compound A) and metformin Prior to treatment 2.5-month-old male C57Bl / 6 mice were kept on a high-fat high- sucrose diet (45 % fat) at 30 °C for 5 months. The mice had similar body weight and body composition and were divided into four groups (11-12 / group). For the first 11 days of the experiment the mice were treated by oral gavage in the morning with water, 150 mg / kg / day metformin, 1 mg / kg / day Compound A, or 150 mg / kg / day metformin + 1 mg / kg / day Compound A (in one gavage). Five mice from the mixed group became sick and were euthanised during the first 10 days of the experiment, and were excluded from fat mass, weight, and lean mass analysis, but could not be excluded from the food intake analysis. These five mice ate the least, which explains the very low food intake during the first 10 days of the experiment. Starting from 12th day of the experiment until the end of (day 22), the dose of Compound A was reduced to 0.3 mg / kg / day in the group treated with Compound A alone and in the group treated with metformin + Compound A. Food intake, body weight and body composition (by MRI) were measured weekly. As mice were grouped-caged, collective food intake was measured in each cage. Mice in each cage were from the same treatment group. The results are shown in Figures 2-5: Figure 2 shows the food intake over time; Figure 3 shows the change in fat mass; Figure 4 shows the change in body weight; Figure 5 shows the change in lean mass. Biological example 3: Effects on body weight and food intake of a selective E2- adrenergic receptor inhibitor (Compound A) and metformin when Compound A is administered 8 h after metformin Prior to treatment 2.5-month-old male C57Bl / 6 mice were kept on a high-fat high- sucrose diet (45 % fat) at 30 °C for 7 months. The mice had similar body weight and body composition and were divided into four groups (10 / group) and were kept grouped caged (2-3 mice per cage). Three groups were treated by two oral gavages, one in the morning and one in the afternoon, with 8 hours apart. Morning and afternoon gavages were, respectively, either water and water (the control), or 150 mg / kg / day metformin and water, or 150 mg / kg / day metformin and 0.3 mg / kg / day Compound A. Food intake, body weight and body composition (by MRI) were measured weekly. The fourth group was treated with 150 mg / kg / day metformin and 0.3 mg / kg / day Compound A in the same gavage. Some of these mice did not fare well and the whole group was removed from the experiment. As mice were grouped-caged, collective food intake was measured in each cage. Mice in each cage were from the same treatment group. The results are shown in Figures 6-9: Figure 6 shows the food intake over time; Figure 7 shows the change in fat mass; Figure 8 shows the change in body weight; Figure 9 shows the change in lean mass.

Claims

Claims 1. A ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, for use in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, wherein the use further comprises administration of metformin.

2. The compound metformin for use in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, wherein the use further comprises administration of a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof.

3. A combination of a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and the compound metformin for use in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia.

4. A method for: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, comprising:(c) administration of a therapeutically effective amount of a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof; and (d) administration of a therapeutically effective amount of metformin, to a patient in need thereof.

5. A pharmaceutical formulation comprising: (a) a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof; and (b) metformin, and optionally one or more pharmaceutically acceptable excipient.

6. A pharmaceutical formulation comprising: (a) a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof; and (b) metformin, and optionally one or more pharmaceutically acceptable excipient, for use in: (i) the treatment or prophylaxis of obesity; (ii) a therapeutic method of lowering body fat composition and / or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, 7. A kit-of-parts comprising components: (A) a pharmaceutical formulation comprising a ǃ2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, optionally in admixture with one or more pharmaceutically acceptable excipient, and (B) a pharmaceutical formulation comprising metformin, optionally in admixture with one or more pharmaceutically acceptable excipient,wherein components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other.

8. The compound for use, combination for use, formulation, formulation for use or kit-of-parts of any of Claims 1 to 7, wherein the ǃ2-adrenergic receptor agonist is selected from the compounds of Table 1.

9. The compound for use, combination for use, formulation, formulation for use or kit-of-parts of any of Claims 1 to 8, wherein the ǃ2-adrenergic receptor agonist is:or a pharmaceutically acceptable salt thereof.

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